Elsevier Inc.

1600 John F. Kennedy Blvd., Suite 1800

Philadelphia, Pennsylvania 19103-2899

TEXTBOOK OF MEDICAL PHYSIOLOGY

ISBN 0-7216-0240-1

International Edition ISBN 0-8089-2317-X

any means, electronic or mechanical, including photocopying, recording, or any information storage

and retrieval system, without permission in writing from the publisher. Permissions may be sought

directly from Elsevier’s Health Sciences Rights Department in Philadelphia, PA, USA: phone: (+1)

215 239 3804, fax: (+1) 215 239 3805, e-mail: healthpermissions@elsevier.com. You may also complete

your request on-line via the Elsevier homepage (http://www.elsevier.com), by selecting “Customer

Support” and then “Obtaining Permissions”.

NOTICE

Knowledge and best practice in this field are constantly changing. As new research and experience

broaden our knowledge, changes in practice, treatment and drug therapy may become necessary

or appropriate. Readers are advised to check the most current information provided (i) on

procedures featured or (ii) by the manufacturer of each product to be administered, to verify the

recommended dose or formula, the method and duration of administration, and contraindications.

It is the responsibility of the practitioner, relying on their own experience and knowledge of the

patient, to make diagnoses, to determine dosages and the best treatment for each individual

patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the

Publisher nor the Author assumes any liability for any injury and/or damage to persons or

property arising out or related to any use of the material contained in this book.

Library of Congress Cataloging-in-Publication Data

Guyton, Arthur C.

Textbook of medical physiology / Arthur C. Guyton, John E. Hall.—11th ed.

p. ; cm.

Includes bibliographical references and index.

ISBN 0-7216-0240-1

1. Human physiology.

2. Physiology, Pathological. I. Title: Medical physiology. II. Hall,

John E. (John Edward) III. Title.

[DNLM:

1. Physiological Processes. QT 104 G992t 2006]

QP34.5.G9

2006

612—dc22

2004051421

Publishing Director: Linda Belfus

Acquisitions Editor: William Schmitt

Managing Editor: Rebecca Gruliow

Publishing Services Manager: Tina Rebane

Project Manager: Mary Anne Folcher

Design Manager: Steven Stave

Marketing Manager: John Gore

Cover illustration is a detail from Opus 1972 by Virgil Cantini, Ph.D., with permission of the artist and

Mansfield State College, Mansfield, Pennsylvania.

Chapter opener credits: Chapter 43, modified from © Getty Images 21000058038; Chapter 44, modified

from © Getty Images 21000044598; Chapter 84, modified from © Corbis.

Working together to grow

libraries in developing countries

Printed in China

www.elsevier.com

| www.bookaid.org

| www.sabre.org

Last digit is the print number:

I N M E M O R I A M

The sudden loss of Dr. Arthur C. Guyton in an automobile accident on April 3,

2003, stunned and saddened all who were privileged to know him. Arthur

Guyton was a giant in the fields of physiology and medicine, a leader among

leaders, a master teacher, and an inspiring role model throughout the world.

Arthur Clifton Guyton was born in Oxford, Mississippi, to Dr. Billy S.

Guyton, a highly respected eye, ear, nose, and throat specialist, who later

became Dean of the University of Mississippi Medical School, and Kate Small-

wood Guyton, a mathematics and physics teacher who had been a missionary

in China before marriage. During his formative years, Arthur enjoyed watching

his father work at the Guyton Clinic, playing chess and swapping stories with

William Faulkner, and building sailboats

(one of which he later sold to

Faulkner). He also built countless mechanical and electrical devices, which he

continued to do throughout his life. His brilliance shone early as he graduated

top in his class at the University of Mississippi. He later distinguished himself

at Harvard Medical School and began his postgraduate surgical training at

Massachusetts General Hospital.

His medical training was interrupted twice—once to serve in the Navy during

World War II and again in 1946 when he was stricken with poliomyelitis during

his final year of residency training. Suffering paralysis in his right leg, left arm,

and both shoulders, he spent nine months in Warm Springs, Georgia, recuper-

ating and applying his inventive mind to building the first motorized wheelchair

controlled by a “joy stick,” a motorized hoist for lifting patients, special leg

braces, and other devices to aid the handicapped. For those inventions he

received a Presidential Citation.

He returned to Oxford where he devoted himself to teaching and research

at the University of Mississippi School of Medicine and was named Chair of the

Department of Physiology in 1948. In 1951 he was named one of the ten out-

standing men in the nation. When the University of Mississippi moved its

Medical School to Jackson in 1955, he rapidly developed one of the world’s

premier cardiovascular research programs. His remarkable life as a scientist,

author, and devoted father is detailed in a biography published on the occasion

of his “retirement” in 1989.¹

A Great Physiologist. Arthur Guyton’s research contributions, which include

more than 600 papers and 40 books, are legendary and place him among the

greatest physiologists in history. His research covered virtually all areas of car-

diovascular regulation and led to many seminal concepts that are now an inte-

gral part of our understanding of cardiovascular disorders, such as hypertension,

heart failure, and edema. It is difficult to discuss cardiovascular physiology

without including his concepts of cardiac output and venous return, negative

interstitial fluid pressure and regulation of tissue fluid volume and edema,

regulation of tissue blood flow and whole body blood flow autoregulation,

renal-pressure natriuresis, and long-term blood pressure regulation. Indeed, his

concepts of cardiovascular regulation are found in virtually every major text-

book of physiology. They have become so familiar that their origin is sometimes

forgotten.

One of Dr. Guyton’s most important scientific legacies was his application of

principles of engineering and systems analysis to cardiovascular regulation. He

used mathematical and graphical methods to quantify various aspects of circu-

latory function before computers were widely available. He built analog com-

puters and pioneered the application of large-scale systems analysis to modeling

the cardiovascular system before the advent of digital computers. As digital

computers became available, his cardiovascular models expanded dramatically

to include the kidneys and body fluids, hormones, and the autonomic nervous

system, as well as cardiac and circulatory functions.² He also provided the first

comprehensive systems analysis of blood pressure regulation. This unique

approach to physiological research preceded the emergence of biomedical

vii

viii

In Memoriam

engineering—a field that he helped to establish and to

and 20/20 described the remarkable home environ-

promote in physiology, leading the discipline into a

ment that Arthur and Ruth Guyton created to raise

quantitative rather than a descriptive science.

their family. His devotion to family is beautifully

It is a tribute to Arthur Guyton’s genius that his

expressed in the dedication of his Textbook of Medical

concepts of cardiovascular regulation often seemed

Physiology⁵:

heretical when they were first presented, yet stimu-

lated investigators throughout the world to test them

My father for his uncompromising principles that

experimentally. They are now widely accepted. In fact,

guided my life

many of his concepts of cardiovascular regulation

My mother for leading her children into intellectual

are integral components of what is now taught in

pursuits

most medical physiology courses. They continue to

My wife for her magnificent devotion to her family

be the foundation for generations of cardiovascular

My children for making everything worthwhile

physiologists.

Dr. Guyton received more than 80 major honors

Dr. Guyton was a master teacher at the University

from diverse scientific and civic organizations and uni-

of Mississippi for over 50 years. Even though he was

versities throughout the world. A few of these that are

always busy with service responsibilities, research,

especially relevant to cardiovascular research include

writing, and teaching, he was never too busy to talk

the Wiggers Award of the American Physiological

with a student who was having difficulty. He would

Society, the Ciba Award from the Council for High

never accept an invitation to give a prestigious lecture

Blood Pressure Research, The William Harvey Award

if it conflicted with his teaching schedule.

from the American Society of Hypertension, the

His contributions to education are also far reach-

Research Achievement Award of the American Heart

ing through generations of physiology graduate

Association, and the Merck Sharp & Dohme Award

students and postdoctoral fellows. He trained over

of the International Society of Hypertension. It was

150 scientists, at least 29 of whom became chairs of

appropriate that in 1978 he was invited by the Royal

their own departments and six of whom became pres-

College of Physicians in London to deliver a special

idents of the American Physiological Society. He gave

lecture honoring the 400th anniversary of the birth of

students confidence in their abilities and emphasized

William Harvey, who discovered the circulation of the

his belief that “People who are really successful in the

blood.

research world are self-taught.” He insisted that his

Dr. Guyton’s love of physiology was beautifully

trainees integrate their experimental findings into a

articulated in his president’s address to the American

broad conceptual framework that included other

Physiological Society in 1975,³ appropriately entitled

interacting systems. This approach usually led them

Physiology, a Beauty and a Philosophy. Let me quote

to develop a quantitative analysis and a better

just one sentence from his address: What other person,

understanding of the particular physiological systems

whether he be a theologian, a jurist, a doctor of medi-

that they were studying. No one has been more pro-

cine, a physicist, or whatever, knows more than you, a

lific in training leaders of physiology than Arthur

physiologist, about life? For physiology is indeed an

Guyton.

explanation of life. What other subject matter is more

Dr. Guyton’s Textbook of Medical Physiology, first

fascinating, more exciting, more beautiful than the

published in 1956, quickly became the best-selling

subject of life?

medical physiology textbook in the world. He had a

gift for communicating complex ideas in a clear and

A Master Teacher. Although Dr. Guyton’s research

interesting manner that made studying physiology fun.

accomplishments are legendary, his contributions as an

He wrote the book to teach his students, not to impress

educator have probably had an even greater impact.

his professional colleagues. Its popularity with stu-

He and his wonderful wife Ruth raised ten children,

dents has made it the most widely used physiology

all of whom became outstanding physicians—a

textbook in history. This accomplishment alone was

remarkable educational achievement. Eight of the

enough to ensure his legacy.

Guyton children graduated from Harvard Medical

The Textbook of Medical Physiology began as

School, one from Duke Medical School, and one from

lecture notes in the early 1950s when Dr. Guyton was

The University of Miami Medical School after receiv-

teaching the entire physiology course for medical stu-

ing a Ph.D. from Harvard. An article published in

dents at the University of Mississippi. He discovered

Reader’s Digest in 1982 highlighted their extraordinary

that the students were having difficulty with the text-

family life.⁴

books that were available and began distributing

The success of the Guyton children did not occur by

copies of his lecture notes. In describing his experi-

chance. Dr. Guyton’s philosophy of education was to

ence, Dr. Guyton stated that “Many textbooks of

“learn by doing.” The children participated in count-

medical physiology had become discursive, written pri-

less family projects that included the design and

marily by teachers of physiology for other teachers of

construction of their home and its heating system,

physiology, and written in language understood by

the swimming pool, tennis court, sailboats, go-carts

other teachers but not easily understood by the basic

and electrical cars, household gadgets, and electronic

student of medical physiology.”⁶

instruments for their Oxford Instruments Company.

Through his Textbook of Medical Physiology, which

Television programs such as Good Morning America

is translated into 13 languages, he has probably done

In Memoriam

more to teach physiology to the world than any other

We celebrate the magnificent life of Arthur Guyton,

individual in history. Unlike most major textbooks,

recognizing that we owe him an enormous debt. He

which often have 20 or more authors, the first eight

gave us an imaginative and innovative approach to

editions were written entirely by Dr. Guyton—a feat

research and many new scientific concepts. He gave

that is unprecedented for any major medical textbook.

countless students throughout the world a means of

For his many contributions to medical education, Dr.

understanding physiology and he gave many of us

Guyton received the 1996 Abraham Flexner Award

exciting research careers. Most of all, he inspired us—

from the Association of American Medical Colleges

with his devotion to education, his unique ability to

(AAMC). According to the AAMC, Arthur Guyton

bring out the best in those around him, his warm and

“. . . for the past 50 years has made an unparalleled

generous spirit, and his courage. We will miss him

impact on medical education.” He is also honored each

tremendously, but he will remain in our memories as

year by The American Physiological Society through

a shining example of the very best in humanity. Arthur

the Arthur C. Guyton Teaching Award.

Guyton was a real hero to the world, and his legacy is

everlasting.

An Inspiring Role Model. Dr. Guyton’s accomplish-

ments extended far beyond science, medicine, and edu-

References

cation. He was an inspiring role model for life as well

as for science. No one was more inspirational or influ-

1. Brinson C, Quinn J: Arthur C. Guyton—His Life, His

ential on my scientific career than Dr. Guyton. He

Family, His Achievements. Jackson, MS, Hederman

taught his students much more than physiology—

Brothers Press, 1989.

he taught us life, not so much by what he said but by

2. Guyton AC, Coleman TG, Granger HJ: Circulation:

his unspoken courage and dedication to the highest

overall regulation. Ann Rev Physiol 34:13-46, 1972.

3. Guyton AC: Past-President’s Address. Physiology, a

standards.

Beauty and a Philosophy. The Physiologist 8:495-501,

He had a special ability to motivate people through

1975.

his indomitable spirit. Although he was severely chal-

4. Bode R: A Doctor Who’s Dad to Seven Doctors—So Far!

lenged by polio, those of us who worked with him

Readers’ Digest, December, 1982, pp. 141-145.

never thought of him as being handicapped. We were

5. Guyton AC: Textbook of Medical Physiology. Philadel-

too busy trying to keep up with him! His brilliant

phia, Saunders, 1956.

mind, his indefatigable devotion to science, education,

6. Guyton AC: An author’s philosophy of physiology text-

and family, and his spirit captivated students and

book writing. Adv Physiol Ed 19: s1-s5, 1998.

trainees, professional colleagues, politicians, business

leaders, and virtually everyone who knew him. He

John E. Hall

would not succumb to the effects of polio. His courage

Jackson, Mississippi

challenged and inspired us. He expected the best and

somehow brought out the very best in people.

P R E F A C E

The first edition of the Textbook of Medical Phys-

iology was written by Arthur C. Guyton almost 50

years ago. Unlike many major medical textbooks,

which often have 20 or more authors, the first

eight editions of the Textbook of Medical Physi-

ology were written entirely by Dr. Guyton with

each new edition arriving on schedule for nearly

40 years. Over the years, Dr. Guyton’s textbook

became widely used throughout the world and was translated into 13 languages.

A major reason for the book’s unprecedented success was his uncanny ability

to explain complex physiologic principles in language easily understood by stu-

dents. His main goal with each edition was to instruct students in physiology,

not to impress his professional colleagues. His writing style always maintained

the tone of a teacher talking to his students.

I had the privilege of working closely with Dr. Guyton for almost 30 years

and the honor of helping him with the 9th and 10th editions. For the 11th

edition, I have the same goal as in previous editions—to explain, in language

easily understood by students, how the different cells, tissues, and organs of the

human body work together to maintain life. This task has been challenging and

exciting because our rapidly increasing knowledge of physiology continues to

unravel new mysteries of body functions. Many new techniques for learning

about molecular and cellular physiology have been developed. We can present

more and more the physiology principles in the terminology of molecular and

physical sciences rather than in merely a series of separate and unexplained bio-

logical phenomena. This change is welcomed, but it also makes revision of each

chapter a necessity.

In this edition, I have attempted to maintain the same unified organization

of the text that has been useful to students in the past and to ensure that

the book is comprehensive enough that students will wish to use it in later life

as a basis for their professional careers. I hope that this textbook conveys

the majesty of the human body and its many functions and that it stimulates

students to study physiology throughout their careers. Physiology is the link

between the basic sciences and medicine. The great beauty of physiology is

that it integrates the individual functions of all the body’s different cells, tissues,

and organs into a functional whole, the human body. Indeed, the human

body is much more than the sum of its parts, and life relies upon this total func-

tion, not just on the function of individual body parts in isolation from the

others.

This brings us to an important question: How are the separate organs and

systems coordinated to maintain proper function of the entire body? Fortu-

nately, our bodies are endowed with a vast network of feedback controls that

achieve the necessary balances without which we would not be able to live.

Physiologists call this high level of internal bodily control homeostasis. In

disease states, functional balances are often seriously disturbed and homeosta-

sis is impaired. And, when even a single disturbance reaches a limit, the whole

body can no longer live. One of the goals of this text, therefore, is to emphasize

the effectiveness and beauty of the body’s homeostasis mechanisms as well as

to present their abnormal function in disease.

Another objective is to be as accurate as possible. Suggestions and critiques

from many physiologists, students, and clinicians throughout the world have

been sought and then used to check factual accuracy as well as balance in the

text. Even so, because of the likelihood of error in sorting through many thou-

sands of bits of information, I wish to issue still a further request to all readers

to send along notations of error or inaccuracy. Physiologists understand the

importance of feedback for proper function of the human body; so, too, is feed-

back important for progressive improvement of a textbook of physiology. To

the many persons who have already helped, I send sincere thanks.

xii

Preface

A brief explanation is needed about several features

wish to study particular physiologic mechanisms more

of the 11th edition. Although many of the chapters

deeply.

have been revised to include new principles of physi-

The material in large print constitutes the funda-

ology, the text length has been closely monitored

mental physiologic information that students will

to limit the book size so that it can be used effec-

require in virtually all their medical activities and

tively in physiology courses for medical students and

studies.

health care professionals. Many of the figures have

I wish to express my thanks to many other persons

also been redrawn and are now in full color. New

who have helped in preparing this book, including

references have been chosen primarily for their pres-

my colleagues in the Department of Physiology &

entation of physiologic principles, for the quality of

Biophysics at the University of Mississippi Medical

their own references, and for their easy accessibility.

Center who provided valuable suggestions. I am also

Most of the selected references are from recently

grateful to Ivadelle Osberg Heidke, Gerry McAlpin,

published scientific journals that can be freely

and Stephanie Lucas for their excellent secretarial

accessed from the PubMed internet site at http://

services, and to William Schmitt, Rebecca Gruliow,

www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed.

Mary Anne Folcher, and the rest of the staff of

Use of these references, as well as cross-references

Elsevier Saunders for continued editorial and produc-

from them, can give the student almost complete cov-

tion excellence.

erage of the entire field of physiology.

Finally, I owe an enormous debt to Arthur Guyton

Another feature is that the print is set in two sizes.

for an exciting career in physiology, for his friendship,

The material in small print is of several different kinds:

for the great privilege of contributing to the Textbook

first, anatomical, chemical, and other information that

of Medical Physiology, and for the inspiration that he

is needed for immediate discussion but that most stu-

provided to all who knew him.

dents will learn in more detail in other courses; second,

physiologic information of special importance to

certain fields of clinical medicine; and, third, informa-

John E. Hall

tion that will be of value to those students who may

Jackson, Mississippi

TABLE OF CONTENTS

The DNA Code in the Cell Nucleus Is

U N I T I

Transferred to an RNA Code in the

Introduction to Physiology: The

Cell Cytoplasm—The Process

of Transcription

Cell and General Physiology

Synthesis of RNA

Assembly of the RNA Chain from Activated

Nucleotides Using the DNA Strand

C H A P T E R

as a Template—The Process of

Functional Organization of the

“Transcription”

Messenger RNA—The Codons

Human Body and Control of the

Transfer RNA—The Anticodons

“Internal Environment”

Ribosomal RNA

Cells as the Living Units of the Body

Formation of Proteins on the Ribosomes—

Extracellular Fluid—The “Internal

The Process of “Translation”

Environment”

Synthesis of Other Substances in the

“Homeostatic” Mechanisms of the Major

Cell

Functional Systems

Control of Gene Function and

Homeostasis

Biochemical Activity in Cells

Extracellular Fluid Transport and Mixing

Genetic Regulation

System—The Blood Circulatory System

Control of Intracellular Function by

Origin of Nutrients in the Extracellular Fluid

Enzyme Regulation

Removal of Metabolic End Products

The DNA-Genetic System Also Controls

Regulation of Body Functions

Cell Reproduction

Reproduction

Cell Reproduction Begins with Replication

Control Systems of the Body

of DNA

Examples of Control Mechanisms

Chromosomes and Their Replication

Characteristics of Control Systems

Cell Mitosis

Summary—Automaticity of the Body

Control of Cell Growth and Cell

Reproduction

Cell Differentiation

C H A P T E R

Apoptosis—Programmed Cell Death

Cancer

The Cell and Its Functions

Organization of the Cell

Physical Structure of the Cell

Membranous Structures of the Cell

U N I T I I

Cytoplasm and Its Organelles

Nucleus

Membrane Physiology, Nerve,

Nuclear Membrane

Nucleoli and Formation of Ribosomes

and Muscle

Comparison of the Animal Cell with

Precellular Forms of Life

Functional Systems of the Cell

C H A P T E R

Ingestion by the Cell—Endocytosis

Transport of Substances Through

Digestion of Pinocytotic and Phagocytic

Foreign Substances Inside the Cell—

the Cell Membrane

Function of the Lysosomes

The Lipid Barrier of the Cell Membrane,

Synthesis and Formation of Cellular

and Cell Membrane Transport

Structures by Endoplasmic Reticulum

Proteins

and Golgi Apparatus

Diffusion

Extraction of Energy from Nutrients—

Diffusion Through the Cell Membrane

Function of the Mitochondria

Diffusion Through Protein Channels, and

Locomotion of Cells

“Gating” of These Channels

Ameboid Movement

Facilitated Diffusion

Cilia and Ciliary Movement

Factors That Affect Net Rate of Diffusion

Osmosis Across Selectively Permeable

Membranes—“Net Diffusion” of Water

“Active Transport” of Substances

C H A P T E R

Through Membranes

Genetic Control of Protein Synthesis,

Primary Active Transport

Cell Function, and Cell Reproduction

Secondary Active Transport—Co-Transport

Genes in the Cell Nucleus

and Counter-Transport

Genetic Code

Active Transport Through Cellular Sheets

xiii

xiv

Table of Contents

C H A P T E R

Membrane Potentials and Action

Excitation of Skeletal Muscle:

Potentials

Neuromuscular Transmission and

Basic Physics of Membrane

Excitation-Contraction Coupling

Potentials

Transmission of Impulses from Nerve

Membrane Potentials Caused by

Endings to Skeletal Muscle Fibers:

Diffusion

The Neuromuscular Junction

Measuring the Membrane Potential

Secretion of Acetylcholine by the Nerve

Resting Membrane Potential of Nerves

Terminals

Origin of the Normal Resting Membrane

Molecular Biology of Acetyline

Potential

Formation and Release

Nerve Action Potential

Drugs That Enhance or Block

Voltage-Gated Sodium and Potassium

Transmission at the Neuromuscular

Channels

Junction

Summary of the Events That Cause the

Myasthenia Gravis

Action Potential

Muscle Action Potential

Roles of Other Ions During the Action

Spread of the Action Potential to the

Potential

Interior of the Muscle Fiber by Way of

Initiation of the Action Potential

“Transverse Tubules”

Propagation of the Action Potential

Excitation-Contraction Coupling

Re-establishing Sodium and Potassium

Transverse Tubule-Sarcoplasmic Reticulum

Ionic Gradients After Action Potentials

System

Are Completed—Importance of Energy

Release of Calcium Ions by the

Metabolism

Sarcoplasmic Reticulum

Plateau in Some Action Potentials

Rhythmicity of Some Excitable Tissues—

Repetitive Discharge

C H A P T E R

Special Characteristics of Signal

Contraction and Excitation of

Transmission in Nerve Trunks

Smooth Muscle

Excitation—The Process of Eliciting

Contraction of Smooth Muscle

the Action Potential

Types of Smooth Muscle

“Refractory Period” After an Action

Contractile Mechanism in Smooth Muscle

Potential

Regulation of Contraction by Calcium Ions

Recording Membrane Potentials and

Nervous and Hormonal Control of

Action Potentials

Smooth Muscle Contraction

Inhibition of Excitability—“Stabilizers”

Neuromuscular Junctions of Smooth

and Local Anesthetics

Muscle

Membrane Potentials and Action Potentials

in Smooth Muscle

Effect of Local Tissue Factors and

Hormones to Cause Smooth Muscle

C H A P T E R

Contraction Without Action Potentials

Contraction of Skeletal Muscle

Source of Calcium Ions That Cause

Contraction (1) Through the Cell

Physiologic Anatomy of Skeletal

Membrane and (2) from the Sarcoplasmic

Muscle

Reticulum

Skeletal Muscle Fiber

General Mechanism of Muscle

Contraction

Molecular Mechanism of Muscle

U N I T I I I

Contraction

Molecular Characteristics of the

The Heart

Contractile Filaments

Effect of Amount of Actin and Myosin

C H A P T E R

Filament Overlap on Tension Developed

Heart Muscle; The Heart as a Pump

by the Contracting Muscle

Relation of Velocity of Contraction to

and Function of the Heart Valves

103

Load

Physiology of Cardiac Muscle

103

Energetics of Muscle Contraction

Physiologic Anatomy of Cardiac Muscle

103

Work Output During Muscle Contraction

Action Potentials in Cardiac Muscle

104

Sources of Energy for Muscle Contraction

The Cardiac Cycle

106

Characteristics of Whole Muscle

Diastole and Systole

106

Contraction

Relationship of the Electrocardiogram to

Mechanics of Skeletal Muscle Contraction

the Cardiac Cycle

107

Remodeling of Muscle to Match Function

Function of the Atria as Primer Pumps

107

Rigor Mortis

Function of the Ventricles as Pumps

108

Table of Contents

Function of the Valves

109

Flow of Electrical Currents in the Chest

Aortic Pressure Curve

109

Around the Heart

126

Relationship of the Heart Sounds to

Electrocardiographic Leads

127

Heart Pumping

109

Three Bipolar Limb Leads

127

Work Output of the Heart

110

Chest Leads (Precordial Leads)

129

Graphical Analysis of Ventricular Pumping

110

Augmented Unipolar Limb Leads

129

Chemical Energy Required for Cardiac

Contraction: Oxygen Utilization by

the Heart

111

C H A P T E R

Regulation of Heart Pumping

111

Intrinsic Regulation of Heart Pumping—

Electrocardiographic Interpretation

The Frank-Starling Mechanism

111

of Cardiac Muscle and Coronary

Effect of Potassium and Calcium Ions on

Blood Flow Abnormalities: Vectorial

Heart Function

113

Effect of Temperature on Heart Function

114

Analysis

131

Increasing the Arterial Pressure Load

Principles of Vectorial Analysis of

(up to a Limit) Does Not Decrease the

Electrocardiograms

131

Cardiac Output

114

Use of Vectors to Represent Electrical

Potentials

131

Direction of a Vector Is Denoted in Terms

C H A P T E R

of Degrees

131

Axis for Each Standard Bipolar Lead and

Rhythmical Excitation of the Heart

116

Each Unipolar Limb Lead

132

Specialized Excitatory and Conductive

Vectorial Analysis of Potentials Recorded

System of the Heart

116

in Different Leads

133

Sinus (Sinoatrial) Node

116

Vectorial Analysis of the Normal

Internodal Pathways and Transmission of

Electrocardiogram

134

the Cardiac Impulse Through the Atria

118

Vectors That Occur at Successive Intervals

Atrioventricular Node, and Delay of Impulse

During Depolarization of the Ventricles—

Conduction from the Atria to the Ventricles

118

The QRS Complex

134

Rapid Transmission in the Ventricular

Electrocardiogram During Repolarization—

Purkinje System

119

The T Wave

134

Transmission of the Cardiac Impulse in the

Depolarization of the Atria—The P Wave

136

Ventricular Muscle

119

Vectorcardiogram

136

Summary of the Spread of the Cardiac

Mean Electrical Axis of the Ventricular

Impulse Through the Heart

120

QRS—And Its Significance

137

Control of Excitation and Conduction

Determining the Electrical Axis from

in the Heart

120

Standard Lead Electrocardiograms

137

The Sinus Node as the Pacemaker of the

Abnormal Ventricular Conditions That Cause

Heart

120

Axis Deviation

138

Role of the Purkinje System in Causing

Conditions That Cause Abnormal

Synchronous Contraction of the

Voltages of the QRS Complex

140

Ventricular Muscle

121

Increased Voltage in the Standard Bipolar

Control of Heart Rhythmicity and Impulse

Limb Leads

140

Conduction by the Cardiac Nerves: The

Decreased Voltage of the Electrocardiogram

140

Sympathetic and Parasympathetic Nerves

121

Prolonged and Bizarre Patterns of the

QRS Complex

141

Prolonged QRS Complex as a Result of

C H A P T E R

Cardiac Hypertrophy or Dilatation

141

The Normal Electrocardiogram

123

Prolonged QRS Complex Resulting from

Characteristics of the Normal

Purkinje System Blocks

141

Electrocardiogram

123

Conditions That Cause Bizarre QRS

Depolarization Waves Versus

Complexes

141

Repolarization Waves

123

Current of Injury

141

Relationship of Atrial and Ventricular

Effect of Current of Injury on the QRS

Contraction to the Waves of the

Complex

141

Electrocardiogram

125

The J Point—The Zero Reference Potential

Voltage and Time Calibration of the

for Analyzing Current of Injury

142

Electrocardiogram

125

Coronary Ischemia as a Cause of Injury

Methods for Recording

Potential

143

Electrocardiograms

126

Abnormalities in the T Wave

145

Pen Recorder

126

Effect of Slow Conduction of the

Flow of Current Around the Heart

Depolarization Wave on the

During the Cardiac Cycle

126

Characteristics of the T Wave

145

Recording Electrical Potentials from a

Shortened Depolarization in Portions of

Partially Depolarized Mass of Syncytial

the Ventricular Muscle as a Cause of

Cardiac Muscle

126

T Wave Abnormalities

145

xvi

Table of Contents

C H A P T E R

Volume-Pressure Curves of the Arterial

and Venous Circulations

172

Cardiac Arrhythmias and Their

Arterial Pressure Pulsations

173

Electrocardiographic Interpretation

147

Transmission of Pressure Pulses to the

Abnormal Sinus Rhythms

147

Peripheral Arteries

174

Tachycardia

147

Clinical Methods for Measuring Systolic

Bradycardia

147

and Diastolic Pressures

175

Sinus Arrhythmia

148

Veins and Their Functions

176

Abnormal Rhythms That Result from

Venous Pressures—Right Atrial Pressure

Block of Heart Signals Within the

(Central Venous Pressure) and

Intracardiac Conduction Pathways

148

Peripheral Venous Pressures

176

Sinoatrial Block

148

Blood Reservoir Function of the Veins

179

Atrioventricular Block

148

Incomplete Atrioventricular Heart Block

149

Incomplete Intraventricular Block—

C H A P T E R

Electrical Alternans

150

The Microcirculation and the

Premature Contractions

150

Lymphatic System: Capillary Fluid

Premature Atrial Contractions

150

A-V Nodal or A-V Bundle Premature

Exchange, Interstitial Fluid, and

Contractions

150

Lymph Flow

181

Premature Ventricular Contractions

151

Structure of the Microcirculation and

Paroxysmal Tachycardia

151

Capillary System

181

Atrial Paroxysmal Tachycardia

152

Flow of Blood in the Capillaries—

Ventricular Paroxysmal Tachycardia

152

Vasomotion

182

Ventricular Fibrillation

152

Average Function of the Capillary System

183

Phenomenon of Re-entry—“Circus

Exchange of Water, Nutrients, and

Movements” as the Basis for Ventricular

Other Substances Between the Blood

Fibrillation

153

and Interstitial Fluid

183

Chain Reaction Mechanism of Fibrillation

153

Diffusion Through the Capillary Membrane

183

Electrocardiogram in Ventricular Fibrillation

154

The Interstitium and Interstitial Fluid

184

Electroshock Defibrillation of the Ventricle

154

Fluid Filtration Across Capillaries Is

Hand Pumping of the Heart

Determined by Hydrostatic and

(Cardiopulmonary Resuscitation) as

Colloid Osmotic Pressures, and

an Aid to Defibrillation

155

Capillary Filtration Coefficient

185

Atrial Fibrillation

155

Capillary Hydrostatic Pressure

186

Atrial Flutter

156

Interstitial Fluid Hydrostatic Pressure

187

Cardiac Arrest

156

Plasma Colloid Osmotic Pressure

188

Interstitial Fluid Colloid Osmotic Pressure

188

Exchange of Fluid Volume Through the

Capillary Membrane

189

U N I T I V

Starling Equilibrium for Capillary Exchange

189

The Circulation

Lymphatic System

190

Lymph Channels of the Body

190

Formation of Lymph

191

C H A P T E R

Rate of Lymph Flow

192

Role of the Lymphatic System in Controlling

Overview of the Circulation; Medical

Interstitial Fluid Protein Concentration,

Physics of Pressure, Flow, and

Interstitial Fluid Volume, and Interstitial

Resistance

161

Fluid Pressure

193

Physical Characteristics of the

Circulation

161

Basic Theory of Circulatory Function

163

C H A P T E R

Interrelationships Among Pressure,

Local and Humoral Control of Blood

Flow, and Resistance

164

Flow by the Tissues

195

Blood Flow

164

Local Control of Blood Flow in Response

Blood Pressure

166

to Tissue Needs

195

Resistance to Blood Flow

167

Mechanisms of Blood Flow Control

196

Effects of Pressure on Vascular Resistance

Acute Control of Local Blood Flow

196

and Tissue Blood Flow

170

Long-Term Blood Flow Regulation

200

Development of Collateral Circulation—A

Phenomenon of Long-Term Local Blood

C H A P T E R

Flow Regulation

201

Vascular Distensibility and Functions

Humoral Control of the Circulation

201

of the Arterial and Venous Systems

171

Vasoconstrictor Agents

201

Vascular Distensibility

171

Vasodilator Agents

202

Vascular Compliance (or Vascular

Vascular Control by Ions and Other

Capacitance)

171

Chemical Factors

202

Table of Contents

xvii

C H A P T E R

Cardiac Output Regulation Is the Sum of

Blood Flow Regulation in All the Local

Nervous Regulation of the Circulation,

Tissues of the Body—Tissue Metabolism

and Rapid Control of Arterial Pressure

204

Regulates Most Local Blood Flow

233

Nervous Regulation of the Circulation

204

The Heart Has Limits for the Cardiac Output

Autonomic Nervous System

204

That It Can Achieve

234

Role of the Nervous System in Rapid

What Is the Role of the Nervous System in

Control of Arterial Pressure

208

Controlling Cardiac Output?

235

Increase in Arterial Pressure During Muscle

Pathologically High and Pathologically

Exercise and Other Types of Stress

208

Low Cardiac Outputs

236

Reflex Mechanisms for Maintaining Normal

High Cardiac Output Caused by Reduced

Arterial Pressure

209

Total Peripheral Resistance

236

Central Nervous System Ischemic

Low Cardiac Output

237

Response—Control of Arterial Pressure

A More Quantitative Analysis of Cardiac

by the Brain’s Vasomotor Center in

Output Regulation

237

Response to Diminished Brain Blood

Cardiac Output Curves Used in the

Flow

212

Quantitative Analysis

237

Special Features of Nervous Control

Venous Return Curves

238

of Arterial Pressure

213

Analysis of Cardiac Output and Right Atrial

Role of the Skeletal Nerves and Skeletal

Pressure, Using Simultaneous Cardiac

Muscles in Increasing Cardiac Output

Output and Venous Return Curves

241

and Arterial Pressure

213

Methods for Measuring Cardiac

Respiratory Waves in the Arterial Pressure

214

Output

243

Arterial Pressure “Vasomotor” Waves—

Pulsatile Output of the Heart as Measured

Oscillation of Pressure Reflex Control

by an Electromagnetic or Ultrasonic

Systems

214

Flowmeter

243

Measurement of Cardiac Output Using the

Oxygen Fick Principle

244

C H A P T E R

Indicator Dilution Method for Measuring

Cardiac Output

244

Dominant Role of the Kidney in Long-

Term Regulation of Arterial Pressure

C H A P T E R

and in Hypertension: The Integrated

Muscle Blood Flow and Cardiac

System for Pressure Control

216

Renal-Body Fluid System for Arterial

Output During Exercise; the

Pressure Control

216

Coronary Circulation and Ischemic

Quantitation of Pressure Diuresis as a Basis

Heart Disease

246

for Arterial Pressure Control

217

Blood Flow in Skeletal Muscle

Chronic Hypertension (High Blood Pressure)

and Blood Flow Regulation

Is Caused by Impaired Renal Fluid

During Exercise

246

Excretion

220

Rate of Blood Flow Through the Muscles

246

The Renin-Angiotensin System:

Control of Blood Flow Through the Skeletal

Its Role in Pressure Control and in

Muscles

247

Hypertension

223

Total Body Circulatory Readjustments

Components of the Renin-Angiotensin

During Exercise

247

System

223

Coronary Circulation

249

Types of Hypertension in Which Angiotensin

Physiologic Anatomy of the Coronary Blood

Is Involved: Hypertension Caused by a

Supply

249

Renin-Secreting Tumor or by Infusion

Normal Coronary Blood Flow

249

of Angiotensin II

226

Control of Coronary Blood Flow

250

Other Types of Hypertension Caused by

Special Features of Cardiac Muscle

Combinations of Volume Loading and

Metabolism

251

Vasoconstriction

227

Ischemic Heart Disease

252

“Primary (Essential) Hypertension”

228

Causes of Death After Acute Coronary

Summary of the Integrated,

Occlusion

253

Multifaceted System for Arterial

Stages of Recovery from Acute

Pressure Regulation

230

Myocardial Infarction

254

Function of the Heart After Recovery

from Myocardial Infarction

255

C H A P T E R

Pain in Coronary Heart Disease

255

Cardiac Output, Venous Return,

Surgical Treatment of Coronary Disease

256

and Their Regulation

232

Normal Values for Cardiac Output at

C H A P T E R

Rest and During Activity

232

Cardiac Failure

258

Control of Cardiac Output by Venous

Return—Role of the Frank-Starling

Dynamics of the Circulation in

Mechanism of the Heart

232

Cardiac Failure

258

xviii

Table of Contents

Acute Effects of Moderate Cardiac Failure

258

Neurogenic Shock—Increased Vascular

Chronic Stage of Failure—Fluid Retention

Capacity

285

Helps to Compensate Cardiac Output

259

Anaphylactic Shock and Histamine

Summary of the Changes That Occur After

Shock

285

Acute Cardiac Failure—“Compensated

Septic Shock

286

Heart Failure”

260

Physiology of Treatment in Shock

286

Dynamics of Severe Cardiac Failure—

Replacement Therapy

286

Decompensated Heart Failure

260

Treatment of Shock with Sympathomimetic

Unilateral Left Heart Failure

262

Drugs—Sometimes Useful, Sometimes

Low-Output Cardiac Failure—

Not

287

Cardiogenic Shock

262

Other Therapy

287

Edema in Patients with Cardiac Failure

263

Circulatory Arrest

287

Cardiac Reserve

264

Effect of Circulatory Arrest on the Brain

287

Quantitative Graphical Method for Analysis

of Cardiac Failure

265

U N I T V

C H A P T E R

The Body Fluids and Kidneys

Heart Valves and Heart Sounds;

Dynamics of Valvular and Congenital

C H A P T E R

Heart Defects

269

The Body Fluid Compartments:

Heart Sounds

269

Extracellular and Intracellular Fluids;

Normal Heart Sounds

269

Interstitial Fluid and Edema

291

Valvular Lesions

271

Fluid Intake and Output Are Balanced

Abnormal Circulatory Dynamics in

During Steady-State Conditions

291

Valvular Heart Disease

272

Daily Intake of Water

291

Dynamics of the Circulation in Aortic

Daily Loss of Body Water

291

Stenosis and Aortic Regurgitation

272

Body Fluid Compartments

292

Dynamics of Mitral Stenosis and Mitral

Intracellular Fluid Compartment

293

Regurgitation

273

Extracellular Fluid Compartment

293

Circulatory Dynamics During Exercise in

Blood Volume

293

Patients with Valvular Lesions

273

Constituents of Extracellular and

Abnormal Circulatory Dynamics in

Intracellular Fluids

293

Congenital Heart Defects

274

Ionic Composition of Plasma and

Patent Ductus Arteriosus—A Left-to-Right

Interstitial Fluid Is Similar

293

Shunt

274

Important Constituents of the Intracellular

Tetralogy of Fallot—A Right-to-Left Shunt

274

Fluid

295

Causes of Congenital Anomalies

276

Measurement of Fluid Volumes in the

Use of Extracorporeal Circulation

Different Body Fluid Compartments—

During Cardiac Surgery

276

The Indicator-Dilution Principle

295

Hypertrophy of the Heart in Valvular

Determination of Volumes of Specific

and Congenital Heart Disease

276

Body Fluid Compartments

295

Regulation of Fluid Exchange and

C H A P T E R

Osmotic Equilibrium Between

Intracellular and Extracellular Fluid

296

Circulatory Shock and Physiology of

Basic Principles of Osmosis and

Its Treatment

278

Osmotic Pressure

296

Physiologic Causes of Shock

278

Osmotic Equilibrium Is Maintained

Circulatory Shock Caused by Decreased

Between Intracellular and

Cardiac Output

278

Extracellular Fluids

298

Circulatory Shock That Occurs Without

Volume and Osmolality of Extracellular

Diminished Cardiac Output

278

and Intracellular Fluids in Abnormal

What Happens to the Arterial Pressure in

States

299

Circulatory Shock?

279

Effect of Adding Saline Solution to the

Tissue Deterioration Is the End Result of

Extracellular Fluid

299

Circulatory Shock, Whatever the Cause

279

Glucose and Other Solutions

Stages of Shock

279

Administered for Nutritive Purposes

301

Shock Caused by Hypovolemia—

Clinical Abnormalities of Fluid Volume

Hemorrhagic Shock

279

Regulation: Hyponatremia and

Relationship of Bleeding Volume to

Hypernatremia

301

Cardiac Output and Arterial Pressure

279

Causes of Hyponatremia: Excess Water or

Progressive and Nonprogressive

Loss of Sodium

301

Hemorrhagic Shock

280

Causes of Hypernatremia: Water Loss or

Irreversible Shock

284

Excess Sodium

302

Hypovolemic Shock Caused by Plasma

Edema: Excess Fluid in the Tissues

302

Loss

284

Intracellular Edema

302

Hypovolemic Shock Caused by Trauma

285

Extracellular Edema

302

Table of Contents

xix

Summary of Causes of Extracellular Edema

303

Importance of GFR Autoregulation in

Safety Factors That Normally Prevent

Preventing Extreme Changes in Renal

Edema

304

Excretion

323

Fluids in the “Potential Spaces” of

Role of Tubuloglomerular Feedback in

the Body

305

Autoregulation of GFR

323

Myogenic Autoregulation of Renal Blood

Flow and GFR

325

C H A P T E R

Other Factors That Increase Renal Blood

Flow and GFR: High Protein Intake and

Urine Formation by the Kidneys:

Increased Blood Glucose

325

I. Glomerular Filtration, Renal Blood

Flow, and Their Control

307

Multiple Functions of the Kidneys in

Homeostasis

307

C H A P T E R

Physiologic Anatomy of the Kidneys

308

Urine Formation by the Kidneys:

General Organization of the Kidneys and

II. Tubular Processing of the

Urinary Tract

308

Renal Blood Supply

309

Glomerular Filtrate

327

The Nephron Is the Functional Unit of the

Reabsorption and Secretion by the

Kidney

310

Renal Tubules

327

Micturition

311

Tubular Reabsorption Is Selective and

Physiologic Anatomy and Nervous

Quantitatively Large

327

Connections of the Bladder

311

Tubular Reabsorption Includes

Transport of Urine from the Kidney

Passive and Active Mechanisms

328

Through the Ureters and into

Active Transport

328

the Bladder

312

Passive Water Reabsorption by Osmosis

Innervation of the Bladder

312

Is Coupled Mainly to Sodium

Filling of the Bladder and Bladder Wall

Reabsorption

332

Tone; the Cystometrogram

312

Reabsorption of Chloride, Urea, and Other

Micturition Reflex

313

Solutes by Passive Diffusion

332

Facilitation or Inhibition of Micturition

Reabsorption and Secretion Along

by the Brain

313

Different Parts of the Nephron

333

Abnormalities of Micturition

313

Proximal Tubular Reabsorption

333

Urine Formation Results from

Solute and Water Transport in the Loop

Glomerular Filtration, Tubular

of Henle

334

Reabsorption, and Tubular Secretion

314

Distal Tubule

336

Filtration, Reabsorption, and Secretion of

Late Distal Tubule and Cortical Collecting

Different Substances

315

Tubule

336

Glomerular Filtration—The First Step in

Medullary Collecting Duct

337

Urine Formation

316

Summary of Concentrations of Different

Composition of the Glomerular Filtrate

316

Solutes in the Different Tubular

GFR Is About 20 Per Cent of the Renal

Segments

338

Plasma Flow

316

Regulation of Tubular Reabsorption

339

Glomerular Capillary Membrane

316

Glomerulotubular Balance—The Ability

Determinants of the GFR

317

of the Tubules to Increase Reabsorption

Increased Glomerular Capillary Filtration

Rate in Response to Increased Tubular

Coefficient Increases GFR

318

Load

339

Increased Bowman’s Capsule Hydrostatic

Peritubular Capillary and Renal Interstitial

Pressure Decreases GFR

318

Fluid Physical Forces

339

Increased Glomerular Capillary Colloid

Effect of Arterial Pressure on Urine

Osmotic Pressure Decreases GFR

318

Output—The Pressure-Natriuresis and

Increased Glomerular Capillary Hydrostatic

Pressure-Diuresis Mechanisms

341

Pressure Increases GFR

319

Hormonal Control of Tubular Reabsorption

342

Renal Blood Flow

320

Sympathetic Nervous System Activation

Renal Blood Flow and Oxygen

Increases Sodium Reabsorption

343

Consumption

320

Use of Clearance Methods to Quantify

Determinants of Renal Blood Flow

320

Kidney Function

343

Blood Flow in the Vasa Recta of the Renal

Inulin Clearance Can Be Used to Estimate

Medulla Is Very Low Compared with Flow

GFR

344

in the Renal Cortex

321

Creatine Clearance and Plasma Creatinine

Physiologic Control of Glomerular

Clearance Can Be Used to Estimate

Filtration and Renal Blood Flow

321

GFR

344

Sympathetic Nervous System Activation

PAH Clearance Can Be Used to Estimate

Decreases GFR

321

Renal Plasma Flow

345

Hormonal and Autacoid Control of Renal

Filtration Fraction Is Calculated from GFR

Circulation

322

Divided by Renal Plasma Flow

346

Autoregulation of GFR and Renal

Calculation of Tubular Reabsorption or

Blood Flow

323

Secretion from Renal Clearance

346

Table of Contents

C H A P T E R

Regulation of Extracellular Fluid

Renal Regulation of Potassium,

Osmolarity and Sodium

Calcium, Phosphate, and Magnesium;

Concentration

348

Integration of Renal Mechanisms for

The Kidneys Excrete Excess Water

Control of Blood Volume and

by Forming a Dilute Urine

348

Extracellular Fluid Volume

365

Antidiuretic Hormone Controls Urine

Regulation of Potassium Excretion

Concentration

348

and Potassium Concentration in

Renal Mechanisms for Excreting a

Extracellular Fluid

365

Dilute Urine

349

Regulation of Internal Potassium

The Kidneys Conserve Water by

Distribution

366

Excreting a Concentrated Urine

350

Overview of Renal Potassium Excretion

367

Obligatory Urine Volume

350

Potassium Secretion by Principal Cells of

Requirements for Excreting a Concentrated

Late Distal and Cortical Collecting

Urine—High ADH Levels and Hyperosmotic

Tubules

367

Renal Medulla

350

Summary of Factors That Regulate

Countercurrent Mechanism Produces a

Potassium Secretion: Plasma Potassium

Hyperosmotic Renal Medullary Interstitium

351

Concentration, Aldosterone, Tubular Flow

Role of Distal Tubule and Collecting Ducts in

Rate, and Hydrogen Ion Concentration

368

Excreting a Concentrated Urine

352

Control of Renal Calcium Excretion

Urea Contributes to Hyperosmotic Renal

and Extracellular Calcium Ion

Medullary Interstitium and to a

Concentration

371

Concentrated Urine

353

Control of Calcium Excretion by the

Countercurrent Exchange in the Vasa Recta

Kidneys

372

Preserves Hyperosmolarity of the

Regulation of Renal Phosphate Excretion

372

Renal Medulla

354

Control of Renal Magnesium Excretion

Summary of Urine Concentrating Mechanism

and Extracellular Magnesium Ion

and Changes in Osmolarity in Different

Concentration

373

Segments of the Tubules

355

Integration of Renal Mechanisms for

Quantifying Renal Urine Concentration

Control of Extracellular Fluid

373

and Dilution: “Free Water” and Osmolar

Sodium Excretion Is Precisely Matched to

Clearances

357

Intake Under Steady-State Conditions

373

Disorders of Urinary Concentrating

Sodium Excretion Is Controlled by Altering

Ability

357

Glomerular Filtration or Tubular Sodium

Control of Extracellular Fluid Osmolarity

Reabsorption Rates

374

and Sodium Concentration

358

Importance of Pressure Natriuresis and

Estimating Plasma Osmolarity from Plasma

Pressure Diuresis in Maintaining Body

Sodium Concentration

358

Sodium and Fluid Balance

374

Osmoreceptor-ADH Feedback System

358

Pressure Natriuresis and Diuresis Are Key

ADH Synthesis in Supraoptic and

Components of a Renal-Body Fluid

Paraventricular Nuclei of the

Feedback for Regulating Body Fluid

Hypothalamus and ADH Release from

Volumes and Arterial Pressure

375

the Posterior Pituitary

359

Precision of Blood Volume and Extracellular

Cardiovascular Reflex Stimulation of ADH

Fluid Volume Regulation

376

Release by Decreased Arterial Pressure

Distribution of Extracellular Fluid

and/or Decreased Blood Volume

360

Between the Interstitial Spaces and

Quantitative Importance of Cardiovascular

Vascular System

376

Reflexes and Osmolarity in Stimulating

Nervous and Hormonal Factors Increase

ADH Secretion

360

the Effectiveness of Renal-Body Fluid

Other Stimuli for ADH Secretion

360

Feedback Control

377

Role of Thirst in Controlling Extracellular

Sympathetic Nervous System Control of

Fluid Osmolarity and Sodium

Renal Excretion: Arterial Baroreceptor and

Concentration

361

Low-Pressure Stretch Receptor Reflexes

377

Central Nervous System Centers for Thirst

361

Role of Angiotensin II In Controlling Renal

Stimuli for Thirst

361

Excretion

377

Threshold for Osmolar Stimulus of Drinking

362

Role of Aldosterone in Controlling Renal

Integrated Responses of Osmoreceptor-ADH

Excretion

378

and Thirst Mechanisms in Controlling

Role of ADH in Controlling Renal Water

Extracellular Fluid Osmolarity and Sodium

Excretion

379

Concentration

362

Role of Atrial Natriuretic Peptide in

Role of Angiotensin II and Aldosterone

Controlling Renal Excretion

378

in Controlling Extracellular Fluid

Integrated Responses to Changes in

Osmolarity and Sodium Concentration

362

Sodium Intake

380

Salt-Appetite Mechanism for

Conditions That Cause Large Increases

Controlling Extracellular Fluid

in Blood Volume and Extracellular

Sodium Concentration and Volume

363

Fluid Volume

380

Table of Contents

xxi

Increased Blood Volume and Extracellular

Renal Correction of Acidosis—Increased

Fluid Volume Caused by Heart Diseases

380

Excretion of Hydrogen Ions and

Increased Blood Volume Caused by

Addition of Bicarbonate Ions to the

Increased Capacity of Circulation

380

Extracellular Fluid

396

Conditions That Cause Large Increases

Acidosis Decreases the Ratio of HCO3-/H⁺ in

in Extracellular Fluid Volume but with

Renal Tubular Fluid

396

Normal Blood Volume

381

Renal Correction of Alkalosis—Decreased

Nephrotic Syndrome—Loss of Plasma

Tubular Secretion of Hydrogen Ions

Proteins in Urine and Sodium Retention

and Increased Excretion of

by the Kidneys

381

Bicarbonate Ions

396

Liver Cirrhosis—Decreased Synthesis of

Alkalosis Increases the Ratio of HCO3-/H⁺

Plasma Proteins by the Liver and

in Renal Tubular Fluid

396

Sodium Retention by the Kidneys

381

Clinical Causes of Acid-Base Disorders

397

Respiratory Acidosis Is Caused by

Decreased Ventilation and Increased PCO₂

397

Respiratory Alkalosis Results from Increased

C H A P T E R

Ventilation and Decreased PCO₂

397

Regulation of Acid-Base Balance

383

Metabolic Acidosis Results from Decreased

Hydrogen Ion Concentration Is

Extracellular Fluid Bicarbonate

Precisely Regulated

383

Concentration

397

Acids and Bases—Their Definitions

Treatment of Acidosis or Alkalosis

398

and Meanings

383

Clinical Measurements and Analysis of

Defenses Against Changes in Hydrogen

Acid-Base Disorders

398

Ion Concentration: Buffers, Lungs,

Complex Acid-Base Disorders and Use of

and Kidneys

384

the Acid-Base Nomogram for Diagnosis

399

Buffering of Hydrogen Ions in the Body

Use of Anion Gap to Diagnose Acid-Base

Fluids

385

Disorders

400

Bicarbonate Buffer System

385

Quantitative Dynamics of the Bicarbonate

C H A P T E R

Buffer System

385

Phosphate Buffer System

387

Kidney Diseases and Diuretics

402

Proteins: Important Intracellular

Diuretics and Their Mechanisms of

Buffers

387

Action

402

Respiratory Regulation of Acid-Base

Osmotic Diuretics Decrease Water

Balance

388

Reabsorption by Increasing Osmotic

Pulmonary Expiration of CO₂ Balances

Pressure of Tubular Fluid

402

Metabolic Formation of CO₂

388

“Loop” Diuretics Decrease Active

Increasing Alveolar Ventilation Decreases

Sodium-Chloride-Potassium Reabsorption

Extracellular Fluid Hydrogen Ion

in the Thick Ascending Loop of Henle

403

Concentration and Raises pH

388

Thiazide Diuretics Inhibit Sodium-Chloride

Increased Hydrogen Ion Concentration

Reabsorption in the Early Distal Tubule

404

Stimulates Alveolar Ventilation

389

Carbonic Anhydrase Inhibitors Block

Renal Control of Acid-Base Balance

390

Sodium-Bicarbonate Reabsorption in the

Secretion of Hydrogen Ions and

Proximal Tubules

404

Reabsorption of Bicarbonate Ions

Competitive Inhibitors of Aldosterone

by the Renal Tubules

390

Decrease Sodium Reabsorption from and

Hydrogen Ions Are Secreted by Secondary

Potassium Secretion into the Cortical

Active Transport in the Early Tubular

Collecting Tubule

404

Segments

391

Diuretics That Block Sodium Channels

Filtered Bicarbonate Ions Are Reabsorbed

in the Collecting Tubules Decrease

by Interaction with Hydrogen Ions in the

Sodium Reabsorption

404

Tubules

391

Kidney Diseases

404

Primary Active Secretion of Hydrogen Ions in

Acute Renal Failure

404

the Intercalated Cells of Late Distal and

Prerenal Acute Renal Failure Caused by

Collecting Tubules

392

Decreased Blood Flow to the Kidney

405

Combination of Excess Hydrogen Ions

Intrarenal Acute Renal Failure Caused by

with Phosphate and Ammonia Buffers

Abnormalities within the Kidney

405

in the Tubule—A Mechanism for

Postrenal Acute Renal Failure Caused by

Generating “New” Bicarbonate Ions

392

Abnormalities of the Lower Urinary

Phosphate Buffer System Carries Excess

Tract

406

Hydrogen Ions into the Urine and

Physiologic Effects of Acute Renal Failure

406

Generates New Bicarbonate

393

Chronic Renal Failure: An Irreversible

Excretion of Excess Hydrogen Ions and

Decrease in the Number of Functional

Generation of New Bicarbonate by the

Nephrons

406

Ammonia Buffer System

393

Vicious Circle of Chronic Renal Failure

Quantifying Renal Acid-Base Excretion

394

Leading to End-Stage Renal Disease

407

Regulation of Renal Tubular Hydrogen Ion

Injury to the Renal Vasculature as a Cause

Secretion

395

of Chronic Renal Failure

408

xxii

Table of Contents

Injury to the Glomeruli as a Cause of

C H A P T E R

Chronic Renal Failure—

Resistance of the Body to Infection: II.

Glomerulonephritis

408

Injury to the Renal Interstitium as a

Immunity and Allergy

439

Cause of Chronic Renal Failure—

Innate Immunity

439

Pyelonephritis

409

Acquired (Adaptive) Immunity

439

Nephrotic Syndrome—Excretion of Protein

Basic Types of Acquired Immunity

440

in the Urine Because of Increased

Both Types of Acquired Immunity Are

Glomerular Permeability

409

Initiated by Antigens

440

Nephron Function in Chronic Renal Failure

409

Lymphocytes Are Responsible for

Effects of Renal Failure on the Body

Acquired Immunity

440

Fluids—Uremia

411

Preprocessing of the T and B Lymphocytes

440

Hypertension and Kidney Disease

412

T Lymphocytes and B-Lymphocyte

Specific Tubular Disorders

413

Antibodies React Highly Specifically

Treatment of Renal Failure by Dialysis

Against Specific Antigens—Role of

with an Artificial Kidney

414

Lymphocyte Clones

442

Origin of the Many Clones of Lymphocytes

442

Specific Attributes of the B-Lymphocyte

System—Humoral Immunity and the

U N I T V I

Antibodies

443

Special Attributes of the T-Lymphocyte

Blood Cells, Immunity, and Blood

System-Activated T Cells and Cell-

Clotting

Mediated Immunity

446

Several Types of T Cells and Their Different

Functions

446

C H A P T E R

Tolerance of the Acquired Immunity

Red Blood Cells, Anemia, and

System to One’s Own Tissues—Role

Polycythemia

419

of Preprocessing in the Thymus and

Red Blood Cells (Erythrocytes)

419

Bone Marrow

448

Production of Red Blood Cells

420

Immunization by Injection of Antigens

448

Formation of Hemoglobin

424

Passive Immunity

449

Iron Metabolism

425

Allergy and Hypersensitivity

449

Life Span and Destruction of Red Blood

Allergy Caused by Activated T Cells:

Cells

426

Delayed-Reaction Allergy

449

Anemias

426

Allergies in the “Allergic” Person, Who Has

Effects of Anemia on Function of the

Excess IgE Antibodies

449

Circulatory System

427

Polycythemia

427

C H A P T E R

Effect of Polycythemia on Function of the

Blood Types; Transfusion; Tissue and

Circulatory System

428

Organ Transplantation

451

Antigenicity Causes Immune Reactions

C H A P T E R

of Blood

451

Resistance of the Body to Infection: I.

O-A-B Blood Types

451

Leukocytes, Granulocytes, the

A and B Antigens—Agglutinogens

451

Agglutinins

452

Monocyte-Macrophage System, and

Agglutination Process In Transfusion

Inflammation

429

Reactions

452

Leukocytes (White Blood Cells)

429

Blood Typing

453

General Characteristics of Leukocytes

429

Rh Blood Types

453

Genesis of the White Blood Cells

430

Rh Immune Response

453

Life Span of the White Blood Cells

431

Transfusion Reactions Resulting from

Neutrophils and Macrophages Defend

Mismatched Blood Types

454

Against Infections

431

Transplantation of Tissues and Organs

455

Phagocytosis

431

Attempts to Overcome Immune Reactions

Monocyte-Macrophage Cell System

in Transplanted Tissue

455

(Reticuloendothelial System)

432

Inflammation: Role of Neutrophils and

C H A P T E R

Macrophages

434

Inflammation

434

Hemostasis and Blood Coagulation

457

Macrophage and Neutrophil Responses

Events in Hemostasis

457

During Inflammation

434

Vascular Constriction

457

Eosinophils

436

Formation of the Platelet Plug

457

Basophils

436

Blood Coagulation in the Ruptured

Leukopenia

436

Vessel

458

The Leukemias

437

Fibrous Organization or Dissolution of the

Effects of Leukemia on the Body

437

Blood Clot

458

Table of Contents

xxiii

Mechanism of Blood Coagulation

459

C H A P T E R

Conversion of Prothrombin to Thrombin

459

Pulmonary Circulation, Pulmonary

Conversion of Fibrinogen to Fibrin—

Formation of the Clot

460

Edema, Pleural Fluid

483

Vicious Circle of Clot Formation

460

Physiologic Anatomy of the Pulmonary

Initiation of Coagulation: Formation of

Circulatory System

483

Prothrombin Activator

461

Pressures in the Pulmonary System

483

Prevention of Blood Clotting in the

Blood Volume of the Lungs

484

Normal Vascular System—Intravascular

Blood Flow Through the Lungs and

Anticoagulants

463

Its Distribution

485

Lysis of Blood Clots—Plasmin

464

Effect of Hydrostatic Pressure

Conditions That Cause Excessive

Gradients in the Lungs on Regional

Bleeding in Human Beings

464

Pulmonary Blood Flow

485

Decreased Prothrombin, Factor VII,

Zones 1, 2, and 3 of Pulmonary Blood Flow

485

Factor IX,and Factor X Caused by

Effect of Increased Cardiac Output on

Vitamin K Deficiency

464

Pulmonary Blood Flow and Pulmonary

Hemophilia

465

Arterial Pressure During Heavy Exercise

486

Thrombocytopenia

465

Function of the Pulmonary Circulation

Thromboembolic Conditions in the

When the Left Atrial Pressure Rises as a

Human Being

465

Result of Left-Sided Heart Failure

487

Femoral Venous Thrombosis and Massive

Pulmonary Capillary Dynamics

487

Pulmonary Embolism

466

Capillary Exchange of Fluid in the Lungs,

Disseminated Intravascular Coagulation

466

and Pulmonary Interstitial Fluid Dynamics

487

Anticoagulants for Clinical Use

466

Pulmonary Edema

488

Heparin as an Intravenous Anticoagulant

466

Fluid in the Pleural Cavity

489

Coumarins as Anticoagulants

466

Prevention of Blood Coagulation Outside

C H A P T E R

the Body

466

Blood Coagulation Tests

467

Physical Principles of Gas Exchange;

Bleeding Time

467

Diffusion of Oxygen and Carbon

Clotting Time

467

Dioxide Through the Respiratory

Prothrombin Time

467

Membrane

491

Physics of Gas Diffusion and Gas

U N I T V I I

Partial Pressures

491

Molecular Basis of Gas Diffusion

491

Respiration

Gas Pressures in a Mixture of Gases—

“Partial Pressures” of Individual Gases

491

C H A P T E R

Pressures of Gases Dissolved in Water

Pulmonary Ventilation

471

and Tissues

492

Mechanics of Pulmonary Ventilation

471

Vapor Pressure of Water

492

Muscles That Cause Lung Expansion and

Diffusion of Gases Through Fluids—

Contraction

471

Pressure Difference Causes Net

Movement of Air In and Out of the Lungs

Diffusion

493

and the Pressures That Cause the

Diffusion of Gases Through Tissues

493

Movement

472

Composition of Alveolar Air—Its Relation

Effect of the Thoracic Cage on Lung

to Atmospheric Air

493

Expansibility

474

Rate at Which Alveolar Air Is Renewed by

Pulmonary Volumes and Capacities

475

Atmospheric Air

494

Recording Changes in Pulmonary Volume—

Oxygen Concentration and Partial Pressure

Spirometry

475

in the Alveoli

494

Abbreviations and Symbols Used in

CO₂ Concentration and Partial Pressure in

Pulmonary Function Tests

476

the Alveoli

495

Determination of Functional Residual

Expired Air

495

Capacity, Residual Volume, and Total

Diffusion of Gases Through the

Lung Capacity—Helium Dilution Method

476

Respiratory Membrane

496

Minute Respiratory Volume Equals

Factors That Affect the Rate of Gas

Respiratory Rate Times Tidal Volume

477

Diffusion Through the Respiratory

Alveolar Ventilation

477

Membrane

498

“Dead Space” and Its Effect on Alveolar

Diffusing Capacity of the Respiratory

Ventilation

477

Membrane

498

Rate of Alveolar Ventilation

478

Effect of the Ventilation-Perfusion

Functions of the Respiratory

Ratio on .Al.eolar Gas Concentration

499

Passageways

478

PO₂-PCO₂, VA/Q

Diagram

500

Trachea, Bronchi, and Bronchioles

478

Concept

Normal Respiratory Functions of the

(When VA/Q

Is Greater Than Normal)

500

Nose

480

Abnormalities of Ventilation-Perfusion Ratio

501

xxiv

Table of Contents

C H A P T E R

Chronic Breathing of Low Oxygen Stimulates

Respiration Even More—The Phenomenon

Transport of Oxygen and Carbon

of “Acclimatization”

519

Dioxide in Blood and Tissue Fluids

502

Composite Effects of PCO₂, pH, and PO₂ on

Transport of Oxygen from the Lungs to

Alveolar Ventilation

519

the Body Tissues

502

Regulation of Respiration During

Diffusion of Oxygen from the Alveoli to the

Exercise

520

Pulmonary Capillary Blood

502

Other Factors That Affect Respiration

521

Transport of Oxygen in the Arterial Blood

503

Sleep Apnea

522

Diffusion of Oxygen from the Peripheral

Capillaries into the Tissue Fluid

503

Diffusion of Oxygen from the Peripheral

C H A P T E R

Capillaries to the Tissue Cells

504

Respiratory Insufficiency—

Diffusion of Carbon Dioxide from the

Pathophysiology, Diagnosis, Oxygen

Peripheral Tissue Cells into the

Capillaries and from the Pulmonary

Therapy

524

Capillaries into the Alveoli

504

Useful Methods for Studying Respiratory

Role of Hemoglobin in Oxygen Transport

505

Abnormalities

524

Reversible Combination of Oxygen with

Study of Blood Gases and Blood pH

524

Hemoglobin

505

Measurement of Maximum Expiratory Flow

525

Effect of Hemoglobin to “Buffer” the

Forced Expiratory Vital Capacity and Forced

Tissue PO₂

507

Expiratory Volume

526

Factors That Shift the Oxygen-Hemoglobin

Physiologic Peculiarities of Specific

Dissociation Curve—Their Importance for

Pulmonary Abnormalities

526

Oxygen Transport

507

Chronic Pulmonary Emphysema

526

Metabolic Use of Oxygen by the Cells

508

Pneumonia

527

Transport of Oxygen in the Dissolved State

509

Atelectasis

528

Combination of Hemoglobin with Carbon

Asthma

529

Monoxide—Displacement of Oxygen

509

Tuberculosis

530

Transport of Carbon Dioxide in the Blood

510

Hypoxia and Oxygen Therapy

530

Chemical Forms in Which Carbon Dioxide

Oxygen Therapy in Different Types of

Is Transported

510

Hypoxia

530

Carbon Dioxide Dissociation Curve

511

Cyanosis

531

When Oxygen Binds with Hemoglobin,

Hypercapnia

531

Carbon Dioxide Is Released (the Haldane

Dyspnea

532

Effect) to Increase CO₂ Transport

511

Artificial Respiration

532

Change in Blood Acidity During Carbon

Dioxide Transport

512

Respiratory Exchange Ratio

512

U N I T V I I I

C H A P T E R

Aviation, Space, and Deep-Sea

Regulation of Respiration

514

Diving Physiology

Respiratory Center

514

Dorsal Respiratory Group of Neurons—Its

Control of Inspiration and of Respiratory

C H A P T E R

Rhythm

514

Aviation, High-Altitude, and Space

A Pneumotaxic Center Limits the Duration

Physiology

537

of Inspiration and Increases the

Respiratory Rate

514

Effects of Low Oxygen Pressure on the

Ventral Respiratory Group of Neurons—

Body

537

Functions in Both Inspiration and

Alveolar PO₂ at Different Elevations

537

Expiration

515

Effect of Breathing Pure Oxygen on Alveolar

Lung Inflation Signals Limit Inspiration—

PO₂ at Different Altitudes

538

The Hering-Breuer Inflation Reflex

515

Acute Effects of Hypoxia

538

Control of Overall Respiratory Center

Acclimatization to Low PO₂

539

Activity

516

Natural Acclimatization of Native Human

Chemical Control of Respiration

516

Beings Living at High Altitudes

540

Direct Chemical Control of Respiratory

Reduced Work Capacity at High Altitudes

Center Activity by Carbon Dioxide and

and Positive Effect of Acclimatization

540

Hydrogen Ions

516

Acute Mountain Sickness and High-Altitude

Peripheral Chemoreceptor System for

Pulmonary Edema

540

Control of Respiratory Activity—Role

Chronic Mountain Sickness

541

of Oxygen in Respiratory Control

518

Effects of Acceleratory Forces on the

Effect of Low Arterial PO₂ to Stimulate

Body in Aviation and Space Physiology

541

Alveolar Ventilation When Arterial Carbon

Centrifugal Acceleratory Forces

541

Dioxide and Hydrogen Ion Concentrations

Effects of Linear Acceleratory Forces on the

Remain Normal

519

Body

542

Table of Contents

xxv

“Artificial Climate” in the Sealed

C H A P T E R

Spacecraft

543

Sensory Receptors, Neuronal Circuits

Weightlessness in Space

543

for Processing Information

572

Types of Sensory Receptors and the

C H A P T E R

Sensory Stimuli They Detect

572

Physiology of Deep-Sea Diving and

Differential Sensitivity of Receptors

572

Transduction of Sensory Stimuli into

Other Hyperbaric Conditions

545

Nerve Impulses

573

Effect of High Partial Pressures of

Local Electrical Currents at Nerve Endings—

Individual Gases on the Body

545

Receptor Potentials

573

Nitrogen Narcosis at High Nitrogen

Adaptation of Receptors

575

Pressures

545

Nerve Fibers That Transmit Different

Oxygen Toxicity at High Pressures

546

Types of Signals, and Their

Carbon Dioxide Toxicity at Great Depths

Physiologic Classification

576

in the Sea

547

Transmission of Signals of Different

Decompression of the Diver After Excess

Intensity in Nerve Tracts—Spatial and

Exposure to High Pressure

547

Temporal Summation

577

Scuba (Self-Contained Underwater

Transmission and Processing of Signals

Breathing Apparatus) Diving

549

in Neuronal Pools

578

Special Physiologic Problems in

Relaying of Signals Through Neuronal

Submarines

550

Pools

579

Hyperbaric Oxygen Therapy

550

Prolongation of a Signal by a Neuronal

Pool—“Afterdischarge”

581

Instability and Stability of Neuronal

U N I T I X

Circuits

583

Inhibitory Circuits as a Mechanism for

The Nervous System: A. General

Stabilizing Nervous System Function

583

Synaptic Fatigue as a Means for Stabilizing

Principles and Sensory Physiology

the Nervous System

583

C H A P T E R

Organization of the Nervous System,

C H A P T E R

Basic Functions of Synapses,

Somatic Sensations: I. General

“Transmitter Substances”

555

Organization, the Tactile and

General Design of the Nervous System

555

Central Nervous System Neuron: The Basic

Position Senses

585

Functional Unit

555

CLASSIFICATION OF SOMATIC SENSES

585

Sensory Part of the Nervous System—

Detection and Transmission of Tactile

Sensory Receptors

555

Sensations

585

Motor Part of the Nervous System—

Detection of Vibration

587

Effectors

556

TICKLE AND ITCH

587

Processing of Information—“Integrative”

Sensory Pathways for Transmitting

Function of the Nervous System

556

Somatic Signals into the Central

Storage of Information—Memory

557

Nervous System

587

Major Levels of Central Nervous System

Dorsal Column-Medial Lemniscal System

588

Function

557

Anterolateral System

588

Spinal Cord Level

557

Transmission in the Dorsal Column—

Lower Brain or Subcortical Level

558

Medial Lemniscal System

588

Higher Brain or Cortical Level

558

Anatomy of the Dorsal Column—Medial

Comparison of the Nervous System

Lemniscal System

588

with a Computer

558

Somatosensory Cortex

589

Central Nervous System Synapses

559

Somatosensory Association Areas

592

Types of Synapses—Chemical and

Overall Characteristics of Signal

Electrical

559

Transmission and Analysis in the Dorsal

Physiologic Anatomy of the Synapse

559

Column-Medial Lemniscal System

592

Chemical Substances That Function as

Position Senses

594

Synaptic Transmitters

562

Interpretation of Sensory Stimulus Intensity

593

Electrical Events During Neuronal Excitation

564

Judgment of Stimulus Intensity

594

Electrical Events During Neuronal

Position Senses

594

Inhibition

566

Transmission of Less Critical Sensory

Special Functions of Dendrites for Exciting

Signals in the Anterolateral Pathway

595

Neurons

568

Anatomy of the Anterolateral Pathway

595

Relation of State of Excitation of the Neuron

Some Special Aspects of

to Rate of Firing

569

Somatosensory Function

596

Some Special Characteristics of

Function of the Thalamus in Somatic

Synaptic Transmission

570

Sensation

596

xxvi

Table of Contents

Cortical Control of Sensory Sensitivity—

Pupillary Diameter

618

“Corticofugal” Signals

597

Errors of Refraction

619

Segmental Fields of Sensation—The

Visual Acuity

621

Dermatomes

597

Determination of Distance of an Object

from the Eye—“Depth Perception”

621

Ophthalmoscope

622

C H A P T E R

Fluid System of the Eye—Intraocular

Somatic Sensations: II. Pain,

Fluid

623

Headache, and Thermal Sensations

598

Formation of Aqueous Humor by the Ciliary

Body

623

Types of Pain and Their Qualities—

Outflow of Aqueous Humor from the Eye

623

Fast Pain and Slow Pain

598

Intraocular Pressure

624

Pain Receptors and Their Stimulation

598

Rate of Tissue Damage as a Stimulus

for Pain

599

C H A P T E R

Dual Pathways for Transmission of Pain

The Eye: II. Receptor and Neural

Signals into the Central Nervous

Function of the Retina

626

System

600

Anatomy and Function of the

Dual Pain Pathways in the Cord and Brain

Structural Elements of the Retina

626

Stem—The Neospinothalamic Tract and

Photochemistry of Vision

628

the Paleospinothalamic Tract

600

Rhodopsin-Retinal Visual Cycle, and

Pain Suppression (“Analgesia”) System

Excitation of the Rods

629

in the Brain and Spinal Cord

602

Automatic Regulation of Retinal Sensitivity—

Brain’s Opiate System—Endorphins and

Light and Dark Adaptation

631

Enkephalins

602

Color Vision

632

Inhibition of Pain Transmission by

Tricolor Mechanism of Color Detection

632

Simultaneous Tactile Sensory Signals

603

Color Blindness

633

Treatment of Pain by Electrical Stimulation

603

Neural Function of the Retina

633

Referred Pain

603

Neural Circuitry of the Retina

633

Visceral Pain

603

Ganglion Cells and Optic Nerve Fibers

636

Causes of True Visceral Pain

604

Excitation of the Ganglion Cells

637

“Parietal Pain” Caused by Visceral Disease

604

Localization of Visceral Pain—“Visceral”

and the “Parietal” Pain Transmission

C H A P T E R

Pathways

604

The Eye: III. Central

Some Clinical Abnormalities of Pain

Neurophysiology of Vision

640

and Other Somatic Sensations

605

Hyperalgesia

605

Visual Pathways

640

Herpes Zoster (Shingles)

605

Function of the Dorsal Lateral Geniculate

Tic Douloureux

605

Nucleus of the Thalamus

640

Brown-Séquard Syndrome

606

Organization and Function of the Visual

Headache

606

Cortex

641

Headache of Intracranial Origin

606

Layered Structure of the Primary Visual

Thermal Sensations

607

Cortex

642

Thermal Receptors and Their Excitation

607

Two Major Pathways for Analysis of Visual

Transmission of Thermal Signals in the

Information—(1) The Fast “Position” and

Nervous System

609

“Motion” Pathway; (2) The Accurate Color

Pathway

643

Neuronal Patterns of Stimulation During

Analysis of the Visual Image

643

U N I T X

Detection of Color

644

Effect of Removing the Primary Visual

The Nervous System: B.

Cortex

644

The Special Senses

Fields of Vision; Perimetry

644

Eye Movements and Their Control

645

Fixation Movements of the Eyes

645

C H A P T E R

“Fusion” of the Visual Images from the

The Eye: I. Optics of Vision

613

Two Eyes

647

Physical Principles of Optics

613

Autonomic Control of Accommodation

Refraction of Light

613

and Pupillary Aperture

648

Application of Refractive Principles to

Control of Accommodation (Focusing the

Lenses

613

Eyes)

649

Focal Length of a Lens

615

Control of Pupillary Diameter

649

Formation of an Image by a Convex Lens

616

Measurement of the Refractive Power of a

C H A P T E R

Lens—“Diopter”

616

The Sense of Hearing

651

Optics of the Eye

617

The Eye as a Camera

617

Tympanic Membrane and the Ossicular

Mechanism of “Accommodation”

617

System

651

Table of Contents

xxvii

Conduction of Sound from the Tympanic

Reciprocal Inhibition and Reciprocal

Membrane to the Cochlea

651

Innervation

681

Transmission of Sound Through Bone

652

Reflexes of Posture and Locomotion

682

Cochlea

652

Postural and Locomotive Reflexes of

Functional Anatomy of the Cochlea

652

the Cord

682

Transmission of Sound Waves in the

Scratch Reflex

683

Cochlea—“Traveling Wave”

654

Spinal Cord Reflexes That Cause

Function of the Organ of Corti

655

Muscle Spasm

683

Determination of Sound Frequency—The

Autonomic Reflexes in the Spinal

“Place” Principle

656

Cord

683

Determination of Loudness

656

Spinal Cord Transection and Spinal

Central Auditory Mechanisms

657

Shock

684

Auditory Nervous Pathways

657

Function of the Cerebral Cortex in Hearing

658

Determination of the Direction from Which

C H A P T E R

Sound Comes

660

Cortical and Brain Stem Control of

Centrifugal Signals from the Central

Motor Function

685

Nervous System to Lower Auditory

Centers

660

MOTOR CORTEX AND CORTICOSPINAL

Hearing Abnormalities

660

TRACT

685

Types of Deafness

660

Primary Motor Cortex

685

Premotor Area

686

Supplementary Motor Area

686

C H A P T E R

Some Specialized Areas of Motor Control

The Chemical Senses—Taste and

Found in the Human Motor Cortex

686

Transmission of Signals from the Motor

Smell

663

Cortex to the Muscles

687

Sense of Taste

663

Incoming Fiber Pathways to the Motor

Primary Sensations of Taste

663

Cortex

688

Taste Bud and Its Function

664

Red Nucleus Serves as an Alternative

Transmission of Taste Signals into the

Pathway for Transmitting Cortical Signals

Central Nervous System

665

to the Spinal Cord

688

Taste Preference and Control of the Diet

666

“Extrapyramidal” System

689

Sense of Smell

667

Excitation of the Spinal Cord Motor Control

Olfactory Membrane

667

Areas by the Primary Motor Cortex and

Stimulation of the Olfactory Cells

667

Red Nucleus

689

Transmission of Smell Signals into the

Role of the Brain Stem in Controlling

Central Nervous System

668

Motor Function

691

Support of the Body Against Gravity—

Roles of the Reticular and Vestibular

Nuclei

691

U N I T X I

Vestibular Sensations and Maintenance

The Nervous System: C. Motor and

of Equilibrium

692

Vestibular Apparatus

692

Integrative Neurophysiology

Function of the Utricle and Saccule in the

Maintenance of Static Equilibrium

694

Detection of Head Rotation by the

C H A P T E R

Semicircular Ducts

695

Motor Functions of the Spinal Cord;

Vestibular Mechanisms for Stabilizing the

the Cord Reflexes

673

Eyes

696

Organization of the Spinal Cord for Motor

Other Factors Concerned with Equilibrium

696

Functions

673

Functions of Brain Stem Nuclei in

Muscle Sensory Receptors—Muscle

Controlling Subconscious, Stereotyped

Spindles and Golgi Tendon Organs—

Movements

697

And Their Roles in Muscle Control

675

Receptor Function of the Muscle Spindle

675

Muscle Stretch Reflex

676

C H A P T E R

Role of the Muscle Spindle in Voluntary

Contributions of the Cerebellum and

Motor Activity

678

Basal Ganglia to Overall Motor

Clinical Applications of the Stretch

Reflex

678

Control

698

Golgi Tendon Reflex

679

Cerebellum and Its Motor Functions

698

Function of the Muscle Spindles and Golgi

Anatomical Functional Areas of the

Tendon Organs in Conjunction with Motor

Cerebellum

699

Control from Higher Levels of the Brain

680

Neuronal Circuit of the Cerebellum

700

Flexor Reflex and the Withdrawal

Function of the Cerebellum in Overall

Reflexes

680

Motor Control

703

Crossed Extensor Reflex

681

Clinical Abnormalities of the Cerebellum

706

xxviii

Table of Contents

Basal Ganglia—Their Motor Functions

707

Hypothalamus, a Major Control

Function of the Basal Ganglia in Executing

Headquarters for the Limbic System

732

Patterns of Motor Activity—The Putamen

Vegetative and Endocrine Control

Circuit

708

Functions of the Hypothalamus

733

Role of the Basal Ganglia for Cognitive

Behavioral Functions of the Hypothalamus

Control of Sequences of Motor Patterns—

and Associated Limbic Structures

734

The Caudate Circuit

709

“Reward” and “Punishment” Function of

Function of the Basal Ganglia to Change

the Limbic System

735

the Timing and to Scale the Intensity of

Importance of Reward or Punishment in

Movements

709

Behavior

736

Functions of Specific Neurotransmitter

Specific Functions of Other Parts of

Substances in the Basal Ganglial

the Limbic System

736

System

710

Functions of the Hippocampus

736

Integration of the Many Parts of the

Functions of the Amygdala

737

Total Motor Control System

712

Function of the Limbic Cortex

738

Spinal Level

712

Hindbrain Level

712

C H A P T E R

Motor Cortex Level

712

What Drives Us to Action?

713

States of Brain Activity—Sleep, Brain

Waves, Epilepsy, Psychoses

739

Sleep

739

C H A P T E R

Slow-Wave Sleep

739

Cerebral Cortex, Intellectual Functions

REM Sleep (Paradoxical Sleep,

of the Brain, Learning and Memory

714

Desynchronized Sleep)

740

Basic Theories of Sleep

740

Physiologic Anatomy of the Cerebral

Physiologic Effects of Sleep

741

Cortex

714

Brain Waves

741

Functions of Specific Cortical Areas

715

Origin of Brain Waves

742

Association Areas

716

Effect of Varying Levels of Cerebral

Comprehensive Interpretative Function of

Activity on the Frequency of the EEG

743

the Posterior Superior Temporal Lobe—

Changes in the EEG at Different Stages of

“Wernicke’s Area” (a General

Wakefulness and Sleep

743

Interpretative Area)

718

Epilepsy

743

Functions of the Parieto-occipitotemporal

Grand Mal Epilepsy

743

Cortex in the Nondominant Hemisphere

719

Petit Mal Epilepsy

744

Higher Intellectual Functions of the

Focal Epilepsy

744

Prefrontal Association Areas

719

Psychotic Behavior and Dementia—

Function of the Brain in

Roles of Specific Neurotransmitter

Communication—Language Input

Systems

745

and Language Output

720

Depression and Manic-Depressive

Function of the Corpus Callosum and

Psychoses—Decreased Activity of the

Anterior Commissure to Transfer

Norepinephrine and Serotonin

Thoughts, Memories, Training, and

Neurotransmitter Systems

745

Other Information Between the Two

Schizophrenia—Possible Exaggerated

Cerebral Hemispheres

722

Function of Part of the Dopamine

Thoughts, Consciousness, and Memory

723

System

745

Memory—Roles of Synaptic Facilitation and

Alzheimer’s Disease—Amyloid Plaques

Synaptic Inhibition

723

and Depressed Memory

746

Short-Term Memory

724

Intermediate Long-Term Memory

724

Long-Term Memory

725

C H A P T E R

Consolidation of Memory

725

The Autonomic Nervous System and

the Adrenal Medulla

748

C H A P T E R

General Organization of the Autonomic

Behavioral and Motivational

Nervous System

748

Mechanisms of the Brain—The

Physiologic Anatomy of the Sympathetic

Nervous System

748

Limbic System and the

Preganglionic and Postganglionic

Hypothalamus

728

Sympathetic Neurons

748

Activating-Driving Systems of the Brain

728

Physiologic Anatomy of the

Control of Cerebral Activity by Continuous

Parasympathetic Nervous System

750

Excitatory Signals from the Brain Stem

728

Basic Characteristics of Sympathetic

Neurohormonal Control of Brain Activity

730

and Parasympathetic Function

750

Limbic System

731

Cholinergic and Adrenergic Fibers—

Functional Anatomy of the Limbic

Secretion of Acetylcholine or

System; Key Position of the

Norepinephrine

750

Hypothalamus

731

Receptors on the Effector Organs

752

Table of Contents

xxix

Excitatory and Inhibitory Actions of

Physiological Anatomy of the

Sympathetic and Parasympathetic

Gastrointestinal Wall

771

Stimulation

753

Neural Control of Gastrointestinal

Effects of Sympathetic and Parasympathetic

Function—Enteric Nervous System

773

Stimulation on Specific Organs

753

Differences Between the Myenteric and

Function of the Adrenal Medullae

755

Submucosal Plexuses

774

Relation of Stimulus Rate to Degree of

Types of Neurotransmitters Secreted by

Sympathetic and Parasympathetic Effect

756

Enteric Neurons

775

Sympathetic and Parasympathetic “Tone”

756

Hormonal Control of Gastrointestinal

Denervation Supersensitivity of Sympathetic

Motility

776

and Parasympathetic Organs after

Functional Types of Movements in the

Denervation

756

Gastrointestinal Tract

776

Autonomic Reflexes

757

Propulsive Movements—Peristalsis

776

Stimulation of Discrete Organs in Some

Mixing Movements

777

Instances and Mass Stimulation in

Gastrointestinal Blood Flow—

Other Instances by the Sympathetic

“Splanchnic Circulation”

777

and Parasympathetic Systems

757

Anatomy of the Gastrointestinal Blood

“Alarm” or “Stress” Response of the

Supply

778

Sympathetic Nervous System

758

Effect of Gut Activity and Metabolic

Medullary, Pontine, and Mesencephalic

Factors on Gastrointestinal Blood

Control of the Autonomic Nervous

Flow

778

System

758

Nervous Control of Gastrointestinal Blood

Pharmacology of the Autonomic

Flow

779

Nervous System

759

Drugs That Act on Adrenergic Effector

Organs—Sympathomimetic Drugs

759

C H A P T E R

Drugs That Act on Cholinergic Effector

Organs

759

Propulsion and Mixing of Food in the

Drugs That Stimulate or Block Sympathetic

Alimentary Tract

781

and Parasympathetic Postganglionic

Ingestion of Food

781

Neurons

759

Mastication (Chewing)

781

Swallowing (Deglutition)

782

C H A P T E R

Motor Functions of the Stomach

784

Storage Function of the Stomach

784

Cerebral Blood Flow, Cerebrospinal

Mixing and Propulsion Of Food in the

Fluid, and Brain Metabolism

761

Stomach—The Basic Electrical Rhythm

Cerebral Blood Flow

761

of the Stomach Wall

784

Normal Rate of Cerebral Blood Flow

761

Stomach Emptying

785

Regulation of Cerebral Blood Flow

761

Regulation of Stomach Emptying

785

Cerebral Microcirculation

763

Movements of the Small Intestine

786

Cerebral Stroke Occurs When Cerebral

Mixing Contractions (Segmentation

Blood Vessels are Blocked

763

Contractions)

786

Cerebrospinal Fluid System

763

Propulsive Movements

787

Cushioning Function of the Cerebrospinal

Function of the Ileocecal Valve

788

Fluid

763

Movements of the Colon

788

Formation, Flow, and Absorption of

Defecation

789

Cerebrospinal Fluid

764

Other Autonomic Reflexes That Affect

Cerebrospinal Fluid Pressure

765

Bowel Activity

790

Obstruction to Flow of Cerebrospinal Fluid

Can Cause Hydrocephalus

766

Blood-Cerebrospinal Fluid and Blood-Brain

Barriers

766

C H A P T E R

Brain Edema

766

Secretory Functions of the Alimentary

Brain Metabolism

767

Tract

791

General Principles of Alimentary Tract

Secretion

791

U N I T X I I

Anatomical Types of Glands

791

Basic Mechanisms of Stimulation of the

Gastrointestinal Physiology

Alimentary Tract Glands

791

Basic Mechanism of Secretion by Glandular

C H A P T E R

Cells

791

Lubricating and Protective Properties of

General Principles of Gastrointestinal

Mucus, and Importance of Mucus in the

Function—Motility, Nervous Control,

Gastrointestinal Tract

793

and Blood Circulation

771

Secretion of Saliva

793

General Principles of Gastrointestinal

Nervous Regulation of Salivary Secretion

794

Motility

771

Esophageal Secretion

795

xxx

Table of Contents

Gastric Secretion

794

Diarrhea

822

Characteristics of the Gastric Secretions

794

Paralysis of Defecation in Spinal Cord

Pyloric Glands—Secretion of Mucus and

Injuries

823

Gastrin

797

General Disorders of the

Surface Mucous Cells

797

Gastrointestinal Tract

823

Stimulation of Gastric Acid Secretion

797

Vomiting

823

Regulation of Pepsinogen Secretion

798

Nausea

824

Inhibition of Gastric Secretion by Other

Gastrointestinal Obstruction

824

Post-Stomach Intestinal Factors

798

Chemical Composition of Gastrin And Other

Gastrointestinal Hormones

799

Pancreatic Secretion

799

U N I T X I I I

Pancreatic Digestive Enzymes

799

Secretion of Bicarbonate Ions

800

Metabolism and Temperature

Regulation of Pancreatic Secretion

800

Regulation

Secretion of Bile by the Liver; Functions

of the Biliary Tree

802

Physiologic Anatomy of Biliary Secretion

802

Function of Bile Salts in Fat Digestion and

C H A P T E R

Absorption

804

Metabolism of Carbohydrates,

Liver Secretion of Cholesterol and

and Formation of Adenosine

Gallstone Formation

804

Secretions of the Small Intestine

805

Triphosphate

829

Secretion of Mucus by Brunner’s Glands in

Release of Energy from Foods, and the

the Duodenum

805

Concept of “Free Energy”

829

Secretion of Intestinal Digestive Juices by

Role of Adenosine Triphosphate in

the Crypts of Lieberkühn

805

Metabolism

829

Regulation of Small Intestine Secretion—

Central Role of Glucose in

Local Stimuli

806

Carbohydrate Metabolism

830

Secretions of the Large Intestine

806

Transport of Glucose Through the

Cell Membrane

831

Insulin Increases Facilitated Diffusion of

C H A P T E R

Glucose

831

Digestion and Absorption in the

Phosphorylation of Glucose

831

Gastrointestinal Tract

808

Glycogen Is Stored in Liver and

Muscle

831

Digestion of the Various Foods by

Glycogenesis—The Process of Glycogen

Hydrolysis

808

Formation

832

Digestion of Carbohydrates

809

Removal of Stored Glycogen—

Digestion of Proteins

810

Glycogenolysis

832

Digestion of Fats

811

Release of Energy from the Glucose

Basic Principles of Gastrointestinal

Molecule by the Glycolytic Pathway

832

Absorption

812

Summary of ATP Formation During the

Anatomical Basis of Absorption

812

Breakdown of Glucose

836

Absorption in the Small Intestine

813

Control of Energy Release from Stored

Absorption of Water

814

Glycogen When the Body Needs Additional

Absorption of Ions

814

Energy

836

Absorption of Nutrients

815

Anaerobic Release of Energy—“Anaerobic

Absorption in the Large Intestine:

Glycolysis”

836

Formation of Feces

817

Release of Energy from Glucose by the

Pentose Phosphate Pathway

837

C H A P T E R

Glucose Conversion to Glycogen or Fat

838

Formation of Carbohydrates from

Physiology of Gastrointestinal

Proteins and Fats—“Gluconeogenesis”

838

Disorders

819

Blood Glucose

839

Disorders of Swallowing and of the

Esophagus

819

Disorders of the Stomach

819

C H A P T E R

Peptic Ulcer

820

Specific Causes of Peptic Ulcer in the

Lipid Metabolism

840

Human Being

821

Transport of Lipids in the Body Fluids

840

Disorders of the Small Intestine

821

Transport of Triglycerides and Other Lipids

Abnormal Digestion of Food in the Small

from the Gastrointestinal Tract by

Intestine—Pancreatic Failure

821

Lymph—The Chylomicrons

840

Malabsorption by the Small Intestine

Removal of the Chylomicrons from the

Mucosa—Sprue

822

Blood

841

Disorders of the Large Intestine

822

“Free Fatty Acids” Are Transported in the

Constipation

822

Blood in Combination with Albumin

841

Table of Contents

xxxi

Lipoproteins—Their Special Function in

C H A P T E R

Transporting Cholesterol and

Dietary Balances; Regulation of

Phospholipids

841

Fat Deposits

842

Feeding; Obesity and Starvation;

Adipose Tissue

842

Vitamins and Minerals

865

Liver Lipids

842

Energy Intake and Output Are Balanced

Use of Triglycerides for Energy:

Under Steady-State Conditions

865

Formation of Adenosine Triphosphate

842

Dietary Balances

865

Formation of Acetoacetic Acid in the

Energy Available in Foods

865

Liver and Its Transport in the Blood

844

Methods for Determining Metabolic

Synthesis of Triglycerides from

Utilization of Proteins, Carbohydrates,

Carbohydrates

844

and Fats

866

Synthesis of Triglycerides from Proteins

845

Regulation of Food Intake and Energy

Regulation of Energy Release from

Storage

865

Triglycerides

846

Neural Centers Regulate Food Intake

867

Obesity

846

Factors That Regulate Quantity of Food

Phospholipids and Cholesterol

846

Intake

870

Phospholipids

846

Obesity

872

Cholesterol

847

Decreased Physical Activity and

Cellular Structural Functions of

Abnormal Feeding Regulation as

Phospholipids and Cholesterol—

Causes of Obesity

872

Especially for Membranes

848

Treatment of Obesity

873

Atherosclerosis

848

Inanition, Anorexia, and Cachexia

874

Basic Causes of Atherosclerosis—The

Starvation

874

Roles of Cholesterol and Lipoproteins

850

Vitamins

875

Other Major Risk Factors for

Vitamin A

875

Atherosclerosis

850

Thiamine (Vitamin B₁)

875

Prevention of Atherosclerosis

850

Niacin

876

Riboflavin (Vitamin B₂)

876

Vitamin B₁₂

876

C H A P T E R

Folic Acid (Pteroylglutamic Acid)

877

Protein Metabolism

852

Pyridoxine (Vitamin B₆)

877

Basic Properties

852

Pantothenic Acid

877

Amino Acids

852

Ascorbic Acid (Vitamin C)

877

Transport and Storage of Amino Acids

854

Vitamin D

878

Blood Amino Acids

854

Vitamin E

878

Storage of Amino Acids as Proteins in the

Vitamin K

878

Cells

854

Mineral Metabolism

878

Functional Roles of the Plasma

Proteins

855

C H A P T E R

Essential and Nonessential Amino Acids

855

Energetics and Metabolic Rate

881

Obligatory Degradation of Proteins

857

Adenosine Triphosphate (ATP)

Hormonal Regulation of Protein

Functions as an “Energy Currency”

Metabolism

857

in Metabolism

881

Phosphocreatine Functions as an

Accessory Storage Depot for Energy

C H A P T E R

and as an “ATP Buffer”

882

The Liver as an Organ

859

Anaerobic Versus Aerobic Energy

882

Physiologic Anatomy of the Liver

859

Summary of Energy Utilization by the

Hepatic Vascular and Lymph

Cells

883

Systems

859

Control of Energy Release in the Cell

884

Blood Flows Through the Liver from the

Metabolic Rate

884

Portal Vein and Hepatic Artery

860

Measurement of the Whole-Body Metabolic

The Liver Functions as a Blood Reservoir

860

Rate

885

The Liver Has Very High Lymph Flow

860

Energy Metabolism—Factors That

Regulation of Liver Mass—Regeneration

860

Influence Energy Output

885

Hepatic Macrophage System Serves a

Overall Energy Requirements for Daily

Blood-Cleansing Function

861

Activities

885

Metabolic Functions of the Liver

861

Basal Metabolic Rate (BMR)—The

Carbohydrate Metabolism

861

Minimum Energy Expenditure for the

Fat Metabolism

861

Body to Exist

886

Protein Metabolism

862

Energy Used for Physical Activities

887

Other Metabolic Functions of the Liver

862

Energy Used for Processing Food—

Measurement of Bilirubin in the Bile

Thermogenic Effect of Food

887

as a Clinical Diagnostic Tool

862

Energy Used for Nonshivering

Jaundice—Excess Bilirubin in the

Thermogenesis—Role of Sympathetic

Extracellular Fluid

863

Stimulation

887

xxxii

Table of Contents

C H A P T E R

Growth Hormone Promotes Growth of

Many Body Tissues

922

Body Temperature, Temperature

Growth Hormone Has Several Metabolic

Regulation, and Fever

889

Effects

922

Normal Body Temperatures

889

Growth Hormone Stimulates Cartilage and

Body Temperature Is Controlled by

Bone Growth

923

Balancing Heat Production Against

Growth Hormone Exerts Much of Its Effect

Heat Loss

889

Through Intermediate Substances Called

Heat Production

889

“Somatomedins” (Also Called “Insulin-Like

Heat Loss

890

Growth Factors”)

923

Regulation of Body Temperature—Role

Regulation of Growth Hormone Secretion

924

of the Hypothalamus

894

Abnormalities of Growth Hormone Secretion

926

Neuronal Effector Mechanisms That

Posterior Pituitary Gland and Its

Decrease or Increase Body Temperature

895

Relation to the Hypothalamus

927

Concept of a “Set-Point” for Temperature

Chemical Structures of ADH and Oxytocin

928

Control

896

Physiological Functions of ADH

928

Behavioral Control of Body Temperature

897

Oxytocic Hormone

929

Abnormalities of Body Temperature

Regulation

898

C H A P T E R

Fever

898

Exposure of the Body to Extreme Cold

900

Thyroid Metabolic Hormones

931

Synthesis and Secretion of the Thyroid

Metabolic Hormones

931

Iodine Is Required for Formation of

U N I T X I V

Thyroxine

931

Iodide Pump (Iodide Trapping)

932

Endocrinology and Reproduction

Thyroglobulin, and Chemistry of Thyroxine

and Triiodothyronine Formation

932

Release of Thyroxine and Triiodothyronine

C H A P T E R

from the Thyroid Gland

933

Introduction to Endocrinology

905

Transport of Thyroxine and Triiodothyronine

to Tissues

934

Coordination of Body Functions by

Physiologic Functions of the Thyroid

Chemical Messengers

905

Hormones

934

Chemical Structure and Synthesis of

Thyroid Hormones Increase the

Hormones

906

Transcription of Large Numbers of Genes

934

Hormone Secretion, Transport, and

Thyroid Hormones Increase Cellular

Clearance from the Blood

908

Metabolic Activity

934

Feedback Control of Hormone Secretion

909

Effect of Thyroid Hormone on Growth

936

Transport of Hormones in the Blood

909

Effects of Thyroid Hormone on Specific

“Clearance” of Hormones from the Blood

909

Bodily Mechanisms

936

Mechanisms of Action of Hormones

910

Regulation of Thyroid Hormone

Hormone Receptors and Their Activation

910

Secretion

938

Intracellular Signaling After Hormone

Anterior Pituitary Secretion of TSH Is

Receptor Activation

910

Regulated by Thyrotropin-Releasing

Second Messenger Mechanisms for

Hormone from the Hypothalamus

938

Mediating Intracellular Hormonal

Feedback Effect of Thyroid Hormone to

Functions

912

Decrease Anterior Pituitary Secretion

Hormones That Act Mainly on the Genetic

of TSH

939

Machinery of the Cell

915

Diseases of the Thyroid

940

Measurement of Hormone

Hyperthyroidism

940

Concentrations in the Blood

915

Symptoms of Hyperthyroidism

940

Radioimmunoassay

915

Hypothyroidism

941

Enzyme-Linked Immunosorbent Assay

Cretinism

942

(ELISA)

916

C H A P T E R

Adrenocortical Hormones

944

Pituitary Hormones and Their Control

Synthesis and Secretion of

by the Hypothalamus

918

Adrenocortical Hormones

944

Pituitary Gland and Its Relation to the

Functions of the Mineralocorticoids-

Hypothalamus

918

Aldosterone

947

Hypothalamus Controls Pituitary

Renal and Circulatory Effects of

Secretion

919

Aldosterone

948

Hypothalamic-Hypophysial Portal Blood

Aldosterone Stimulates Sodium and

Vessels of the Anterior Pituitary Gland

920

Potassium Transport in Sweat Glands,

Physiological Functions of Growth

Salivary Glands, and Intestinal Epithelial

Hormone

921

Cells

949

Table of Contents

xxxiii

Cellular Mechanism of Aldosterone Action

950

Calcium in the Plasma and Interstitial

Possible Nongenomic Actions of

Fluid

978

Aldosterone and Other Steroid Hormones

950

Inorganic Phosphate in the Extracellular

Regulation of Aldosterone Secretion

950

Fluids

979

Functions of the Glucocorticoids

950

Non-Bone Physiologic Effects of Altered

Effects of Cortisol on Carbohydrate

Calcium and Phosphate Concentrations

Metabolism

951

in the Body Fluids

979

Effects of Cortisol on Protein Metabolism

952

Absorption and Excretion of Calcium and

Effects of Cortisol on Fat Metabolism

952

Phosphate

980

Cortisol Is Important in Resisting Stress

Bone and Its Relation to Extracellular

and Inflammation

952

Calcium and Phosphate

980

Other Effects of Cortisol

954

Precipitation and Absorption of Calcium

Cellular Mechanism of Cortisol Action

954

and Phosphate in Bone—Equilibrium

Regulation of Cortisol Secretion by

with the Extracellular Fluids

981

Adrenocorticotropic Hormone from the

Calcium Exchange Between Bone and

Pituitary Gland

955

Extracellular Fluid

982

Adrenal Androgens

957

Deposition and Absorption of Bone—

Abnormalities of Adrenocortical

Remodeling of Bone

982

Secretion

957

Vitamin D

983

Hypoadrenalism-Addison’s Disease

957

Actions of Vitamin D

985

Hyperadrenalism-Cushing’s Syndrome

958

Parathyroid Hormone

985

Primary Aldosteronism (Conn’s Syndrome)

959

Effect of Parathyroid Hormone on Calcium

Adrenogenital Syndrome

959

and Phosphate Concentrations in the

Extracellular Fluid

986

Control of Parathyroid Secretion by

C H A P T E R

Calcium Ion Concentration

988

Insulin, Glucagon, and Diabetes

Calcitonin

988

Mellitus

961

Summary of Control of Calcium Ion

Concentration

989

Insulin and Its Metabolic Effects

961

Pathophysiology of Parathyroid

Effect of Insulin on Carbohydrate

Hormone, Vitamin D, and Bone

Metabolism

963

Disease

990

Effect of Insulin on Fat Metabolism

965

Primary Hyperparathyroidism

990

Effect of Insulin on Protein Metabolism

Secondary Parathyroidism

991

and on Growth

966

Rickets—Vitamin D Deficiency

991

Mechanisms of Insulin Secretion

967

Osteoporosis—Decreased Bone Matrix

991

Control of Insulin Secretion

968

Physiology of the Teeth

992

Other Factors That Stimulate Insulin

Function of the Different Parts of the

Secretion

969

Teeth

992

Role of Insulin (and Other Hormones) in

Dentition

993

“Switching” Between Carbohydrate and

Mineral Exchange in Teeth

993

Lipid Metabolism

969

Dental Abnormalities

994

Glucagon and Its Functions

970

Effects on Glucose Metabolism

970

Regulation of Glucagon Secretion

971

C H A P T E R

Somatostatin Inhibits Glucagon and

Reproductive and Hormonal

Insulin Secretion

971

Functions of the Male (and Function

Summary of Blood Glucose

of the Pineal Gland)

996

Regulation

971

Diabetes Mellitus

972

Physiologic Anatomy of the Male

Type I Diabetes—Lack of Insulin Production

Sexual Organs

996

by Beta Cells of the Pancreas

972

Spermatogenesis

996

Type II Diabetes—Resistance to the

Steps of Spermatogenesis

996

Metabolic Effects of Insulin

974

Function of the Seminal Vesicles

999

Physiology of Diagnosis of Diabetes

Function of the Prostate Gland

999

Mellitus

975

Semen

999

Treatment of Diabetes

976

Male Sexual Act

1001

Insulinoma—Hyperinsulinism

976

Abnormal Spermatogenesis and Male

Fertility

1001

Neuronal Stimulus for Performance of the

C H A P T E R

Male Sexual Act

1001

Parathyroid Hormone, Calcitonin,

Stages of the Male Sexual Act

1002

Calcium and Phosphate

Testosterone and Other Male Sex

Hormones

1003

Metabolism, Vitamin D, Bone,

Secretion, Metabolism, and Chemistry of

and Teeth

978

the Male Sex Hormone

1003

Overview of Calcium and Phosphate

Functions of Testosterone

1004

Regulation in the Extracellular Fluid

Basic Intracellular Mechanism of Action of

and Plasma

978

Testosterone

1006

xxxiv

Table of Contents

Control of Male Sexual Functions by

Response of the Mother’s Body to

Hormones from the Hypothalamus and

Pregnancy

1034

Anterior Pituitary Gland

1006

Changes in the Maternal Circulatory System

Abnormalities of Male Sexual Function

1008

During Pregnancy

1035

Prostate Gland and Its Abnormalities

1008

Parturition

1036

Hypogonadism in the Male

1008

Increased Uterine Excitability Near Term

1036

Testicular Tumors and Hypergonadism in

Onset of Labor—A Positive Feedback

the Male

1009

Mechanism for Its Initiation

1037

Pineal Gland—Its Function in Controlling

Abdominal Muscle Contractions During

Seasonal Fertility in Some Animals

1009

Labor

1037

Mechanics of Parturition

1037

Separation and Delivery of the Placenta

1038

C H A P T E R

Labor Pains

1038

Female Physiology Before Pregnancy

Involution of the Uterus After Parturition

1038

and Female Hormones

1011

Lactation

1038

Physiologic Anatomy of the Female

Development of the Breasts

1038

Sexual Organs

1011

Initiation of Lactation—Function of

Female Hormonal System

1011

Prolactin

1039

Monthly Ovarian Cycle; Function of the

Ejection (or “Let-Down”) Process in Milk

Gonadotropic Hormones

1012

Secretion—Function of Oxytocin

1040

Gonadotropic Hormones and Their Effects

Milk Composition and the Metabolic Drain

on the Ovaries

1012

on the Mother Caused by Lactation

1041

Ovarian Follicle Growth—The “Follicular”

Phase of the Ovarian Cycle

1013

C H A P T E R

Corpus Luteum—“Luteal” Phase of the

Fetal and Neonatal Physiology

1042

Ovarian Cycle

1014

Growth and Functional Development

Summary

1015

of the Fetus

1042

Functions of the Ovarian Hormones—

Development of the Organ Systems

1042

Estradiol and Progesterone

1016

Adjustments of the Infant to

Chemistry of the Sex Hormones

1016

Extrauterine Life

1044

Functions of the Estrogens—Their Effects

Onset of Breathing

1044

on the Primary and Secondary Female Sex

Circulatory Readjustments at Birth

1045

Characteristics

1017

Nutrition of the Neonate

1047

Functions of Progesterone

1018

Special Functional Problems in the

Monthly Endometrial Cycle and Menstruation

1018

Neonate

1047

Regulation of the Female Monthly

Respiratory System

1047

Rhythm—Interplay Between the

Circulation

1047

Ovarian and Hypothalamic-Pituitary

Fluid Balance, Acid-Base Balance, and

Hormones

1019

Renal Function

1048

Feedback Oscillation of the Hypothalamic-

Liver Function

1048

Pituitary-Ovarian System

1021

Digestion, Absorption, and Metabolism

Puberty and Menarche

1021

of Energy Foods; and Nutrition

1048

Menopause

1022

Immunity

1049

Abnormalities of Secretion by the

Endocrine Problems

1049

Ovaries

1023

Special Problems of Prematurity

1050

Female Sexual Act

1023

Immature Development of the Premature

Female Fertility

1024

Infant

1050

Instability of the Homeostatic Control

C H A P T E R

Systems in the Premature Infant

1050

Pregnancy and Lactation

1027

Danger of Blindness Caused by Excess

Oxygen Therapy in the Premature Infant

1051

Maturation and Fertilization of the Ovum

1027

Growth and Development of the Child

1051

Transport of the Fertilized Ovum in the

Behavioral Growth

1052

Fallopian Tube

1028

Implantation of the Blastocyst in the Uterus

1029

Early Nutrition of the Embryo

1029

Function of the Placenta

1029

U N I T X V

Developmental and Physiologic Anatomy

Sports Physiology

of the Placenta

1029

Hormonal Factors in Pregnancy

1031

Human Chorionic Gonadotropin and Its

Effect to Cause Persistence of the

C H A P T E R

Corpus Luteum and to Prevent

Sports Physiology

1055

Menstruation

1032

Secretion of Estrogens by the Placenta

1032

Muscles in Exercise

1055

Secretion of Progesterone by the Placenta

1033

Strength, Power, and Endurance of Muscles

1055

Human Chorionic Somatomammotropin

1033

Muscle Metabolic Systems in Exercise

1056

Other Hormonal Factors in Pregnancy

1034

Phosphocreatine-Creatine System

1057

C H A P T E R

Functional Organization of the

Human Body and Control of the

“Internal Environment”

The goal of physiology is to explain the physical and

chemical factors that are responsible for the origin,

development, and progression of life. Each type of

life, from the simple virus to the largest tree or the

complicated human being, has its own functional

characteristics. Therefore, the vast field of physiol-

ogy can be divided into viral physiology, bacterial

physiology, cellular physiology, plant physiology,

human physiology, and many more subdivisions.

Human Physiology. In human physiology, we attempt to explain the specific char-

acteristics and mechanisms of the human body that make it a living being. The

very fact that we remain alive is almost beyond our control, for hunger makes

us seek food and fear makes us seek refuge. Sensations of cold make us look

for warmth. Other forces cause us to seek fellowship and to reproduce. Thus,

the human being is actually an automaton, and the fact that we are sensing,

feeling, and knowledgeable beings is part of this automatic sequence of life;

these special attributes allow us to exist under widely varying conditions.

Cells as the Living Units of the Body

The basic living unit of the body is the cell. Each organ is an aggregate of many

different cells held together by intercellular supporting structures.

Each type of cell is specially adapted to perform one or a few particular

functions. For instance, the red blood cells, numbering 25 trillion in each

human being, transport oxygen from the lungs to the tissues. Although the red

cells are the most abundant of any single type of cell in the body, there are

about 75 trillion additional cells of other types that perform functions different

from those of the red cell. The entire body, then, contains about 100 trillion

cells.

Although the many cells of the body often differ markedly from one another,

all of them have certain basic characteristics that are alike. For instance, in all

cells, oxygen reacts with carbohydrate, fat, and protein to release the energy

required for cell function. Further, the general chemical mechanisms for chang-

ing nutrients into energy are basically the same in all cells, and all cells deliver

end products of their chemical reactions into the surrounding fluids.

Almost all cells also have the ability to reproduce additional cells of their

own kind. Fortunately, when cells of a particular type are destroyed from one

cause or another, the remaining cells of this type usually generate new cells until

the supply is replenished.

Extracellular Fluid—The “Internal Environment”

About 60 per cent of the adult human body is fluid, mainly a water solution of

ions and other substances. Although most of this fluid is inside the cells and is

called intracellular fluid, about one third is in the spaces outside the cells and

Unit I Introduction to Physiology: The Cell and General Physiology

is called extracellular fluid. This extracellular fluid is in

Extracellular Fluid Transport and

constant motion throughout the body. It is transported

Mixing System—The Blood

rapidly in the circulating blood and then mixed

Circulatory System

between the blood and the tissue fluids by diffusion

through the capillary walls.

Extracellular fluid is transported through all parts of

In the extracellular fluid are the ions and nutrients

the body in two stages. The first stage is movement of

needed by the cells to maintain cell life. Thus, all cells

blood through the body in the blood vessels, and the

live in essentially the same environment—the extra-

second is movement of fluid between the blood capil-

cellular fluid. For this reason, the extracellular fluid is

laries and the intercellular spaces between the tissue

also called the internal environment of the body, or the

cells.

milieu intérieur, a term introduced more than 100 years

Figure 1-1 shows the overall circulation of blood.

ago by the great 19th-century French physiologist

All the blood in the circulation traverses the entire cir-

Claude Bernard.

culatory circuit an average of once each minute when

Cells are capable of living, growing, and performing

the body is at rest and as many as six times each minute

their special functions as long as the proper concen-

when a person is extremely active.

trations of oxygen, glucose, different ions, amino acids,

As blood passes through the blood capillaries,

fatty substances, and other constituents are available

continual exchange of extracellular fluid also occurs

in this internal environment.

between the plasma portion of the blood and the

Differences Between Extracellular and Intracellular Fluids.

The extracellular fluid contains large amounts of

Lungs

sodium, chloride, and bicarbonate ions plus nutrients

for the cells, such as oxygen, glucose, fatty acids, and

amino acids. It also contains carbon dioxide that is

being transported from the cells to the lungs to be

excreted, plus other cellular waste products that are

being transported to the kidneys for excretion.

The intracellular fluid differs significantly from

O₂

CO₂

the extracellular fluid; specifically, it contains large

amounts of potassium, magnesium, and phosphate ions

Right

Left

instead of the sodium and chloride ions found in the

heart

pump

extracellular fluid. Special mechanisms for transport-

ing ions through the cell membranes maintain the ion

concentration differences between the extracellular

Gut

and intracellular fluids. These transport processes are

discussed in Chapter 4.

“Homeostatic” Mechanisms of

Nutrition and excretion

the Major Functional Systems

Kidneys

Homeostasis

The term homeostasis is used by physiologists to mean

maintenance of nearly constant conditions in the inter-

nal environment. Essentially all organs and tissues of

Regulation

Excretion

the body perform functions that help maintain these

constant conditions. For instance, the lungs provide

electrolytes

oxygen to the extracellular fluid to replenish the

oxygen used by the cells, the kidneys maintain con-

Venous

Arterial

stant ion concentrations, and the gastrointestinal

end

system provides nutrients.

A large segment of this text is concerned with the

manner in which each organ or tissue contributes to

homeostasis. To begin this discussion, the different

functional systems of the body and their contributions

Capillaries

to homeostasis are outlined in this chapter; then we

briefly outline the basic theory of the body’s control

Figure 1-1

systems that allow the functional systems to operate in

support of one another.

General organization of the circulatory system.

Chapter 1

Functional Organization of the Human Body and Control of the “Internal Environment”

Arteriole

the gastrointestinal tract. Here different dissolved

nutrients, including carbohydrates, fatty acids, and

amino acids, are absorbed from the ingested food into

the extracellular fluid of the blood.

Liver and Other Organs That Perform Primarily Metabolic Func-

tions. Not all substances absorbed from the gastroin-

testinal tract can be used in their absorbed form by the

cells. The liver changes the chemical compositions of

many of these substances to more usable forms, and

other tissues of the body—fat cells, gastrointestinal

Venule

mucosa, kidneys, and endocrine glands—help modify

the absorbed substances or store them until they are

needed.

Musculoskeletal System. Sometimes the question is

asked, How does the musculoskeletal system fit into

Figure 1-2

the homeostatic functions of the body? The answer is

Diffusion of fluid and dissolved constituents through the capillary

obvious and simple: Were it not for the muscles, the

walls and through the interstitial spaces.

body could not move to the appropriate place at the

appropriate time to obtain the foods required for

nutrition. The musculoskeletal system also provides

motility for protection against adverse surroundings,

interstitial fluid that fills the intercellular spaces. This

without which the entire body, along with its homeo-

process is shown in Figure 1-2. The walls of the capil-

static mechanisms, could be destroyed instantaneously.

laries are permeable to most molecules in the plasma

of the blood, with the exception of the large plasma

protein molecules. Therefore, large amounts of fluid

Removal of Metabolic End Products

and its dissolved constituents diffuse back and forth

between the blood and the tissue spaces, as shown by

Removal of Carbon Dioxide by the Lungs. At the same time

the arrows. This process of diffusion is caused by

that blood picks up oxygen in the lungs, carbon dioxide

kinetic motion of the molecules in both the plasma and

is released from the blood into the lung alveoli; the res-

the interstitial fluid. That is, the fluid and dissolved

piratory movement of air into and out of the lungs

molecules are continually moving and bouncing in all

carries the carbon dioxide to the atmosphere. Carbon

directions within the plasma and the fluid in the inter-

dioxide is the most abundant of all the end products

cellular spaces, and also through the capillary pores.

of metabolism.

Few cells are located more than 50 micrometers from

a capillary, which ensures diffusion of almost any sub-

Kidneys. Passage of the blood through the kidneys

stance from the capillary to the cell within a few

removes from the plasma most of the other substances

seconds. Thus, the extracellular fluid everywhere in the

besides carbon dioxide that are not needed by the

body—both that of the plasma and that of the inter-

cells. These substances include different end products

stitial fluid—is continually being mixed, thereby

of cellular metabolism, such as urea and uric acid; they

maintaining almost complete homogeneity of the

also include excesses of ions and water from the food

extracellular fluid throughout the body.

that might have accumulated in the extracellular fluid.

The kidneys perform their function by first filtering

large quantities of plasma through the glomeruli into

Origin of Nutrients in the

the tubules and then reabsorbing into the blood those

Extracellular Fluid

substances needed by the body, such as glucose, amino

acids, appropriate amounts of water, and many of the

Respiratory System. Figure 1-1 shows that each time the

ions. Most of the other substances that are not needed

blood passes through the body, it also flows through

by the body, especially the metabolic end products

the lungs. The blood picks up oxygen in the alveoli,

such as urea, are reabsorbed poorly and pass through

thus acquiring the oxygen needed by the cells. The

the renal tubules into the urine.

membrane between the alveoli and the lumen of the

pulmonary capillaries, the alveolar membrane, is only

0.4 to 2.0 micrometers thick, and oxygen diffuses by

Regulation of Body Functions

molecular motion through the pores of this membrane

into the blood in the same manner that water and ions

Nervous System. The nervous system is composed of

diffuse through walls of the tissue capillaries.

three major parts: the sensory input portion, the central

nervous system (or integrative portion), and the motor

Gastrointestinal Tract. A large portion of the blood

output portion. Sensory receptors detect the state of

pumped by the heart also passes through the walls of

the body or the state of the surroundings. For instance,

Unit I Introduction to Physiology: The Cell and General Physiology

receptors in the skin apprise one whenever an object

concentration of carbon dioxide in the extracellular

touches the skin at any point. The eyes are sensory

fluid. The liver and pancreas regulate the concentra-

organs that give one a visual image of the surrounding

tion of glucose in the extracellular fluid, and the

area. The ears also are sensory organs. The central

kidneys regulate concentrations of hydrogen, sodium,

nervous system is composed of the brain and spinal

potassium, phosphate, and other ions in the extracel-

cord. The brain can store information, generate

lular fluid.

thoughts, create ambition, and determine reactions

that the body performs in response to the sensations.

Appropriate signals are then transmitted through the

Examples of Control Mechanisms

motor output portion of the nervous system to carry

out one’s desires.

Regulation of Oxygen and Carbon Dioxide Concentrations in the

A large segment of the nervous system is called the

Extracellular Fluid. Because oxygen is one of the major

autonomic system. It operates at a subconscious level

substances required for chemical reactions in the cells,

and controls many functions of the internal organs,

it is fortunate that the body has a special control

including the level of pumping activity by the heart,

mechanism to maintain an almost exact and constant

movements of the gastrointestinal tract, and secretion

oxygen concentration in the extracellular fluid. This

by many of the body’s glands.

mechanism depends principally on the chemical char-

acteristics of hemoglobin, which is present in all red

Hormonal System of Regulation. Located in the body are

blood cells. Hemoglobin combines with oxygen as the

eight major endocrine glands that secrete chemical

blood passes through the lungs. Then, as the blood

substances called hormones. Hormones are trans-

passes through the tissue capillaries, hemoglobin,

ported in the extracellular fluid to all parts of the body

because of its own strong chemical affinity for oxygen,

to help regulate cellular function. For instance, thyroid

does not release oxygen into the tissue fluid if too

hormone increases the rates of most chemical reac-

much oxygen is already there. But if the oxygen con-

tions in all cells, thus helping to set the tempo of bodily

centration in the tissue fluid is too low, sufficient

activity. Insulin controls glucose metabolism; adreno-

oxygen is released to re-establish an adequate con-

cortical hormones control sodium ion, potassium ion,

centration. Thus, regulation of oxygen concentration

and protein metabolism; and parathyroid hormone

in the tissues is vested principally in the chemical

controls bone calcium and phosphate. Thus, the hor-

characteristics of hemoglobin itself. This regulation is

mones are a system of regulation that complements

called the oxygen-buffering function of hemoglobin.

the nervous system. The nervous system regulates

Carbon dioxide concentration in the extracellular

mainly muscular and secretory activities of the body,

fluid is regulated in a much different way. Carbon

whereas the hormonal system regulates many meta-

dioxide is a major end product of the oxidative reac-

bolic functions.

tions in cells. If all the carbon dioxide formed in the

cells continued to accumulate in the tissue fluids, the

mass action of the carbon dioxide itself would soon

Reproduction

halt all energy-giving reactions of the cells. Fortu-

nately, a higher than normal carbon dioxide concen-

Sometimes reproduction is not considered a homeo-

tration in the blood excites the respiratory center,

static function. It does, however, help maintain home-

causing a person to breathe rapidly and deeply. This

ostasis by generating new beings to take the place of

increases expiration of carbon dioxide and, therefore,

those that are dying. This may sound like a permissive

removes excess carbon dioxide from the blood and

usage of the term homeostasis, but it illustrates that, in

tissue fluids. This process continues until the concen-

the final analysis, essentially all body structures are

tration returns to normal.

organized such that they help maintain the automatic-

ity and continuity of life.

Regulation of Arterial Blood Pressure. Several systems con-

tribute to the regulation of arterial blood pressure.

One of these, the baroreceptor system, is a simple and

Control Systems of the Body

excellent example of a rapidly acting control mecha-

nism. In the walls of the bifurcation region of the

The human body has thousands of control systems in

carotid arteries in the neck, and also in the arch of the

it. The most intricate of these are the genetic control

aorta in the thorax, are many nerve receptors called

systems that operate in all cells to help control intra-

baroreceptors, which are stimulated by stretch of the

cellular function as well as extracellular function. This

arterial wall. When the arterial pressure rises too high,

subject is discussed in Chapter 3.

the baroreceptors send barrages of nerve impulses to

Many other control systems operate within the

the medulla of the brain. Here these impulses inhibit

organs to control functions of the individual parts

the vasomotor center, which in turn decreases the

of the organs; others operate throughout the entire

number of impulses transmitted from the vasomotor

body to control the interrelations between the organs.

center through the sympathetic nervous system to the

For instance, the respiratory system, operating in

heart and blood vessels. Lack of these impulses causes

association with the nervous system, regulates the

diminished pumping activity by the heart and also

Chapter 1

Functional Organization of the Human Body and Control of the “Internal Environment”

dilation of the peripheral blood vessels, allowing

vast numbers of control systems that keep the body

increased blood flow through the vessels. Both of these

operating in health; in the absence of any one of these

effects decrease the arterial pressure back toward

controls, serious body malfunction or death can result.

normal.

Conversely, a decrease in arterial pressure below

Characteristics of Control Systems

normal relaxes the stretch receptors, allowing the

vasomotor center to become more active than usual,

The aforementioned examples of homeostatic control

thereby causing vasoconstriction and increased heart

mechanisms are only a few of the many thousands in

pumping, and raising arterial pressure back toward

the body, all of which have certain characteristics in

normal.

common. These characteristics are explained in this

section.

Normal Ranges and Physical Characteristics

of Important Extracellular Fluid Constituents

Negative Feedback Nature of Most

Table 1-1 lists the more important constituents and

Control Systems

physical characteristics of extracellular fluid, along

Most control systems of the body act by negative feed-

with their normal values, normal ranges, and maximum

back, which can best be explained by reviewing some

limits without causing death. Note the narrowness of

of the homeostatic control systems mentioned pre-

the normal range for each one. Values outside these

viously. In the regulation of carbon dioxide concen-

ranges are usually caused by illness.

tration, a high concentration of carbon dioxide in the

Most important are the limits beyond which abnor-

extracellular fluid increases pulmonary ventilation.

malities can cause death. For example, an increase

This, in turn, decreases the extracellular fluid carbon

in the body temperature of only 11°F (7°C) above

dioxide concentration because the lungs expire greater

normal can lead to a vicious cycle of increasing cellu-

amounts of carbon dioxide from the body. In other

lar metabolism that destroys the cells. Note also the

words, the high concentration of carbon dioxide initi-

narrow range for acid-base balance in the body, with

ates events that decrease the concentration toward

a normal pH value of 7.4 and lethal values only

normal, which is negative to the initiating stimulus.

about 0.5 on either side of normal. Another important

Conversely, if the carbon dioxide concentration falls

factor is the potassium ion concentration, because

too low, this causes feedback to increase the concen-

whenever it decreases to less than one third normal,

tration. This response also is negative to the initiating

a person is likely to be paralyzed as a result of the

stimulus.

nerves’ inability to carry signals. Alternatively, if

In the arterial pressure-regulating mechanisms, a

the potassium ion concentration increases to two or

high pressure causes a series of reactions that promote

more times normal, the heart muscle is likely to be

a lowered pressure, or a low pressure causes a series

severely depressed. Also, when the calcium ion con-

of reactions that promote an elevated pressure. In both

centration falls below about one half of normal, a

instances, these effects are negative with respect to the

person is likely to experience tetanic contraction of

initiating stimulus.

muscles throughout the body because of the sponta-

Therefore, in general, if some factor becomes exces-

neous generation of excess nerve impulses in the

sive or deficient, a control system initiates negative

peripheral nerves. When the glucose concentration

feedback, which consists of a series of changes that

falls below one half of normal, a person frequently

return the factor toward a certain mean value, thus

develops extreme mental irritability and sometimes

maintaining homeostasis.

even convulsions.

These examples should give one an appreciation for

“Gain” of a Control System. The degree of effectiveness

the extreme value and even the necessity of the

with which a control system maintains constant

Table 1-1

Important Constituents and Physical Characteristics of Extracellular Fluid

Normal Value

Normal Range

Approximate Short-Term

Unit

Nonlethal Limit

Oxygen

35-45

10-1000

mm Hg

Carbon dioxide

35-45

5-80

mm Hg

Sodium ion

142

138-146

115-175

mmol/L

Potassium ion

4.2

3.8-5.0

1.5-9.0

mmol/L

Calcium ion

1.2

1.0-1.4

0.5-2.0

mmol/L

Chloride ion

108

103-112

70-130

mmol/L

Bicarbonate ion

24-32

8-45

mmol/L

Glucose

75-95

20-1500

mg/dl

Body temperature

98.4

(37.0)

98-98.8 (37.0)

65-110 (18.3-43.3)

∞F (∞C)

Acid-base

7.4

7.3-7.5

6.9-8.0

Unit I Introduction to Physiology: The Cell and General Physiology

conditions is determined by the gain of the negative

feedback. For instance, let us assume that a large

volume of blood is transfused into a person whose

baroreceptor pressure control system is not function-

Return to

ing, and the arterial pressure rises from the normal

normal

level of 100 mm Hg up to 175 mm Hg. Then, let us

Bled 1 liter

assume that the same volume of blood is injected into

the same person when the baroreceptor system is func-

tioning, and this time the pressure increases only

25 mm Hg. Thus, the feedback control system has

Bled 2 liters

caused a “correction” of -50 mm Hg—that is, from

175 mm Hg to 125 mm Hg. There remains an increase

in pressure of +25 mm Hg, called the “error,” which

means that the control system is not 100 per cent effec-

tive in preventing change. The gain of the system is

Death

then calculated by the following formula:

Hours

Correction

Gain

Error

Figure 1-3

Thus, in the baroreceptor system example, the correc-

tion is -50 mm Hg and the error persisting is +25 mm

Recovery of heart pumping caused by negative feedback after 1

Hg. Therefore, the gain of the person’s baroreceptor

liter of blood is removed from the circulation. Death is caused by

positive feedback when 2 liters of blood are removed.

system for control of arterial pressure is -50 divided

by +25, or -2. That is, a disturbance that increases or

decreases the arterial pressure does so only one third

as much as would occur if this control system were not

present.

Positive feedback is better known as a “vicious

The gains of some other physiologic control systems

cycle,” but a mild degree of positive feedback can be

are much greater than that of the baroreceptor

overcome by the negative feedback control mecha-

system. For instance, the gain of the system controlling

nisms of the body, and the vicious cycle fails to

internal body temperature when a person is exposed

develop. For instance, if the person in the aforemen-

to moderately cold weather is about -33. Therefore,

tioned example were bled only 1 liter instead of 2

one can see that the temperature control system is

liters, the normal negative feedback mechanisms for

much more effective than the baroreceptor pressure

controlling cardiac output and arterial pressure would

control system.

overbalance the positive feedback and the person

would recover, as shown by the dashed curve of

Positive Feedback Can Sometimes Cause

Figure 1-3.

Vicious Cycles and Death

One might ask the question, Why do essentially all

control systems of the body operate by negative feed-

Positive Feedback Can Sometimes Be Useful. In some

back rather than positive feedback? If one considers

instances, the body uses positive feedback to its advan-

the nature of positive feedback, one immediately sees

tage. Blood clotting is an example of a valuable use of

that positive feedback does not lead to stability but to

positive feedback. When a blood vessel is ruptured

instability and often death.

and a clot begins to form, multiple enzymes called clot-

Figure 1-3 shows an example in which death can

ting factors are activated within the clot itself. Some

ensue from positive feedback. This figure depicts the

of these enzymes act on other unactivated enzymes

pumping effectiveness of the heart, showing that the

of the immediately adjacent blood, thus causing

heart of a healthy human being pumps about 5 liters

more blood clotting. This process continues until the

of blood per minute. If the person is suddenly bled 2

hole in the vessel is plugged and bleeding no longer

liters, the amount of blood in the body is decreased to

occurs. On occasion, this mechanism can get out of

such a low level that not enough blood is available for

hand and cause the formation of unwanted clots.

the heart to pump effectively. As a result, the arterial

In fact, this is what initiates most acute heart

pressure falls, and the flow of blood to the heart muscle

attacks, which are caused by a clot beginning on the

through the coronary vessels diminishes. This results in

inside surface of an atherosclerotic plaque in a coro-

weakening of the heart, further diminished pumping,

nary artery and then growing until the artery is

a further decrease in coronary blood flow, and still

blocked.

more weakness of the heart; the cycle repeats itself

Childbirth is another instance in which positive

again and again until death occurs. Note that each

feedback plays a valuable role. When uterine contrac-

cycle in the feedback results in further weakening of

tions become strong enough for the baby’s head to

the heart. In other words, the initiating stimulus causes

begin pushing through the cervix, stretch of the cervix

more of the same, which is positive feedback.

sends signals through the uterine muscle back to the

Chapter 1

Functional Organization of the Human Body and Control of the “Internal Environment”

body of the uterus, causing even more powerful

Summary—Automaticity

contractions. Thus, the uterine contractions stretch

of the Body

the cervix, and the cervical stretch causes stronger

contractions. When this process becomes powerful

The purpose of this chapter has been to point out, first,

enough, the baby is born. If it is not powerful enough,

the overall organization of the body and, second, the

the contractions usually die out, and a few days pass

means by which the different parts of the body operate

before they begin again.

in harmony. To summarize, the body is actually a social

Another important use of positive feedback is

order of about 100 trillion cells organized into differ-

for the generation of nerve signals. That is, when

ent functional structures, some of which are called

the membrane of a nerve fiber is stimulated, this

organs. Each functional structure contributes its share

causes slight leakage of sodium ions through sodium

to the maintenance of homeostatic conditions in the

channels in the nerve membrane to the fiber’s interior.

extracellular fluid, which is called the internal envi-

The sodium ions entering the fiber then change

ronment. As long as normal conditions are maintained

the membrane potential, which in turn causes more

in this internal environment, the cells of the body con-

opening of channels, more change of potential,

tinue to live and function properly. Each cell benefits

still more opening of channels, and so forth. Thus, a

from homeostasis, and in turn, each cell contributes its

slight leak becomes an explosion of sodium entering

share toward the maintenance of homeostasis. This

the interior of the nerve fiber, which creates the

reciprocal interplay provides continuous automaticity

nerve action potential. This action potential in turn

of the body until one or more functional systems lose

causes electrical current to flow along both the outside

their ability to contribute their share of function. When

and the inside of the fiber and initiates additional

this happens, all the cells of the body suffer. Extreme

action potentials. This process continues again and

dysfunction leads to death; moderate dysfunction

again until the nerve signal goes all the way to the end

leads to sickness.

of the fiber.

In each case in which positive feedback is useful, the

positive feedback itself is part of an overall negative

feedback process. For example, in the case of blood

References

clotting, the positive feedback clotting process is a

negative feedback process for maintenance of normal

Adolph EF: Physiological adaptations: hypertrophies and

blood volume. Also, the positive feedback that causes

superfunctions. Am Sci 60:608, 1972.

nerve signals allows the nerves to participate in

Bernard C: Lectures on the Phenomena of Life Common to

thousands of negative feedback nervous control

Animals and Plants. Springfield, IL: Charles C Thomas,

systems.

1974.

Cabanac M: Regulation and the ponderostat. Int J Obes

Relat Metab Disord 25(Suppl 5):S7, 2001.

Cannon WB: The Wisdom of the Body. New York: WW

More Complex Types of Control Systems—

Norton, 1932.

Adaptive Control

Conn PM, Goodman HM: Handbook of Physiology: Cellu-

Later in this text, when we study the nervous system,

lar Endocrinology. Bethesda: American Physiological

we shall see that this system contains great numbers

Society, 1997.

of interconnected control mechanisms. Some are

Csete ME, Doyle JC: Reverse engineering of biological com-

simple feedback systems similar to those already

plexity. Science 295:1664, 2002.

discussed. Many are not. For instance, some move-

Danzler WH (ed): Handbook of Physiology, Sec 13: Com-

ments of the body occur so rapidly that there is not

parative Physiology. Bethesda: American Physiological

enough time for nerve signals to travel from the

Society, 1997.

peripheral parts of the body all the way to the brain

Dickinson MH, Farley CT, Full RJ, et al: How animals move:

an integrative view. Science 288:100, 2000.

and then back to the periphery again to control the

Garland T Jr, Carter PA: Evolutionary physiology. Annu Rev

movement. Therefore, the brain uses a principle called

Physiol 56:579, 1994.

feed-forward control to cause required muscle con-

Gelehrter TD, Collins FS: Principles of Medical Genetics.

tractions. That is, sensory nerve signals from the

Baltimore: Williams & Wilkins, 1995.

moving parts apprise the brain whether the movement

Guyton AC: Arterial Pressure and Hypertension. Philadel-

is performed correctly. If not, the brain corrects the

phia: WB Saunders, 1980.

feed-forward signals that it sends to the muscles the

Guyton AC, Jones CE, Coleman TG: Cardiac Output and Its

next time the movement is required. Then, if still

Regulation. Philadelphia: WB Saunders, 1973.

further correction is needed, this will be done again for

Guyton AC, Taylor AE, Granger HJ: Dynamics and

subsequent movements. This is called adaptive control.

Control of the Body Fluids. Philadelphia: WB Saunders,

1975.

Adaptive control, in a sense, is delayed negative

Hoffman JF, Jamieson JD: Handbook of Physiology: Cell

feedback.

Physiology. Bethesda: American Physiological Society,

Thus, one can see how complex the feedback

1997.

control systems of the body can be. A person’s life

Krahe R, Gabbiani F: Burst firing in sensory systems. Nat

depends on all of them. Therefore, a major share of

Rev Neurosci 5:13, 2004.

this text is devoted to discussing these life-giving

Lewin B: Genes VII. New York: Oxford University Press,

mechanisms.

2000.

C H A P T E R

The Cell and Its Functions

Each of the 100 trillion cells in a human being is a

living structure that can survive for months or many

years, provided its surrounding fluids contain appro-

priate nutrients. To understand the function of

organs and other structures of the body, it is essen-

tial that we first understand the basic organization

of the cell and the functions of its component

parts.

Organization of the Cell

A typical cell, as seen by the light microscope, is shown in Figure 2-1. Its two

major parts are the nucleus and the cytoplasm. The nucleus is separated from

the cytoplasm by a nuclear membrane, and the cytoplasm is separated from the

surrounding fluids by a cell membrane, also called the plasma membrane.

The different substances that make up the cell are collectively called proto-

plasm. Protoplasm is composed mainly of five basic substances: water, elec-

trolytes, proteins, lipids, and carbohydrates.

Water. The principal fluid medium of the cell is water, which is present in most

cells, except for fat cells, in a concentration of 70 to 85 per cent. Many cellular

chemicals are dissolved in the water. Others are suspended in the water as solid

particulates. Chemical reactions take place among the dissolved chemicals or at

the surfaces of the suspended particles or membranes.

Ions. The most important ions in the cell are potassium, magnesium, phosphate,

sulfate, bicarbonate, and smaller quantities of sodium, chloride, and calcium.

These are all discussed in more detail in Chapter 4, which considers the inter-

relations between the intracellular and extracellular fluids.

The ions provide inorganic chemicals for cellular reactions. Also, they are

necessary for operation of some of the cellular control mechanisms. For

instance, ions acting at the cell membrane are required for transmission of elec-

trochemical impulses in nerve and muscle fibers.

Proteins. After water, the most abundant substances in most cells are proteins,

which normally constitute 10 to 20 per cent of the cell mass. These can be

divided into two types: structural proteins and functional proteins.

Structural proteins are present in the cell mainly in the form of long filaments

that themselves are polymers of many individual protein molecules. A promi-

nent use of such intracellular filaments is to form microtubules that provide the

“cytoskeletons” of such cellular organelles as cilia, nerve axons, the mitotic

spindles of mitosing cells, and a tangled mass of thin filamentous tubules that

hold the parts of the cytoplasm and nucleoplasm together in their respective

compartments. Extracellularly, fibrillar proteins are found especially in the col-

lagen and elastin fibers of connective tissue and in blood vessel walls, tendons,

ligaments, and so forth.

The functional proteins are an entirely different type of protein, usually com-

posed of combinations of a few molecules in tubular-globular form. These

Unit I Introduction to Physiology: The Cell and General Physiology

surrounding extracellular fluid so that it is readily

available to the cell. Also, a small amount of carbohy-

Cell

drate is virtually always stored in the cells in the form

membrane

of glycogen, which is an insoluble polymer of glucose

Cytoplasm

that can be depolymerized and used rapidly to supply

Nucleolus

the cells’ energy needs.

Nucleoplasm

Nucleus

Nuclear

membrane

Physical Structure of the Cell

The cell is not merely a bag of fluid, enzymes, and

chemicals; it also contains highly organized physical

Figure 2-1

structures, called intracellular organelles. The physical

nature of each organelle is as important as the cell’s

Structure of the cell as seen with the light microscope.

chemical constituents for cell function. For instance,

without one of the organelles, the mitochondria, more

than 95 per cent of the cell’s energy release from nutri-

ents would cease immediately. The most important

organelles and other structures of the cell are shown

proteins are mainly the enzymes of the cell and, in con-

in Figure 2-2.

trast to the fibrillar proteins, are often mobile in the

cell fluid. Also, many of them are adherent to mem-

branous structures inside the cell. The enzymes come

Membranous Structures of the Cell

into direct contact with other substances in the cell

fluid and thereby catalyze specific intracellular chem-

Most organelles of the cell are covered by membranes

ical reactions. For instance, the chemical reactions

composed primarily of lipids and proteins. These mem-

that split glucose into its component parts and then

branes include the cell membrane, nuclear membrane,

combine these with oxygen to form carbon dioxide

membrane of the endoplasmic reticulum, and mem-

and water while simultaneously providing energy for

branes of the mitochondria, lysosomes, and Golgi

cellular function are all catalyzed by a series of protein

apparatus.

enzymes.

The lipids of the membranes provide a barrier that

impedes the movement of water and water-soluble

substances from one cell compartment to another

Lipids. Lipids are several types of substances that are

because water is not soluble in lipids. However, protein

grouped together because of their common property

molecules in the membrane often do penetrate all the

of being soluble in fat solvents. Especially important

way through the membrane, thus providing specialized

lipids are phospholipids and cholesterol, which

pathways, often organized into actual pores, for

together constitute only about 2 per cent of the total

passage of specific substances through the membrane.

cell mass. The significance of phospholipids and cho-

Also, many other membrane proteins are enzymes that

lesterol is that they are mainly insoluble in water and,

catalyze a multitude of different chemical reactions,

therefore, are used to form the cell membrane and

discussed here and in subsequent chapters.

intracellular membrane barriers that separate the dif-

ferent cell compartments.

Cell Membrane

In addition to phospholipids and cholesterol, some

The cell membrane (also called the plasma mem-

cells contain large quantities of triglycerides, also

brane), which envelops the cell, is a thin, pliable,

called neutral fat. In the fat cells, triglycerides often

elastic structure only 7.5 to 10 nanometers thick. It

account for as much as 95 per cent of the cell mass. The

is composed almost entirely of proteins and lipids.

fat stored in these cells represents the body’s main

The approximate composition is proteins, 55 per cent;

storehouse of energy-giving nutrients that can later be

phospholipids, 25 per cent; cholesterol, 13 per cent;

dissoluted and used to provide energy wherever in the

other lipids, 4 per cent; and carbohydrates, 3 per cent.

body it is needed.

Lipid Barrier of the Cell Membrane Impedes Water Penetration.

Figure 2-3 shows the structure of the cell membrane.

Carbohydrates. Carbohydrates have little structural

Its basic structure is a lipid bilayer, which is a thin,

function in the cell except as parts of glycoprotein mol-

double-layered film of lipids—each layer only one

ecules, but they play a major role in nutrition of the

molecule thick—that is continuous over the entire cell

cell. Most human cells do not maintain large stores of

surface. Interspersed in this lipid film are large globu-

carbohydrates; the amount usually averages about 1

lar protein molecules.

per cent of their total mass but increases to as much

The basic lipid bilayer is composed of phospholipid

as 3 per cent in muscle cells and, occasionally, 6 per

molecules. One end of each phospholipid molecule is

cent in liver cells. However, carbohydrate in the

soluble in water; that is, it is hydrophilic. The other end

form of dissolved glucose is always present in the

is soluble only in fats; that is, it is hydrophobic. The

Chapter 2

The Cell and Its Functions

Chromosomes and DNA

Centrioles

Secretory

granule

Golgi

apparatus

Microtubules

Nuclear

Cell

membrane

Nucleolus

Glycogen

Ribosomes

Lysosome

Figure 2-2

Reconstruction of a typical

Mitochondrion

Granular

Smooth

Microfilaments

cell, showing the internal

endoplasmic

(agranular)

organelles in the cytoplasm

reticulum

endoplasmic

and in the nucleus.

reticulum

phosphate end of the phospholipid is hydrophilic, and

body fluids. Cholesterol controls much of the fluidity

the fatty acid portion is hydrophobic.

of the membrane as well.

Because the hydrophobic portions of the phospho-

lipid molecules are repelled by water but are mutually

Cell Membrane Proteins. Figure 2-3 also shows globular

attracted to one another, they have a natural tendency

masses floating in the lipid bilayer. These are mem-

to attach to one another in the middle of the mem-

brane proteins, most of which are glycoproteins. Two

brane, as shown in Figure 2-3. The hydrophilic phos-

types of proteins occur: integral proteins that protrude

phate portions then constitute the two surfaces of the

all the way through the membrane, and peripheral pro-

complete cell membrane, in contact with intracellular

teins that are attached only to one surface of the mem-

water on the inside of the membrane and extracellular

brane and do not penetrate all the way through.

water on the outside surface.

Many of the integral proteins provide structural

The lipid layer in the middle of the membrane is

channels (or pores) through which water molecules

impermeable to the usual water-soluble substances,

and water-soluble substances, especially ions, can

such as ions, glucose, and urea. Conversely, fat-soluble

diffuse between the extracellular and intracellular

substances, such as oxygen, carbon dioxide, and

fluids. These protein channels also have selective prop-

alcohol, can penetrate this portion of the membrane

erties that allow preferential diffusion of some sub-

with ease.

stances over others.

The cholesterol molecules in the membrane are also

Other integral proteins act as carrier proteins for

lipid in nature because their steroid nucleus is highly

transporting substances that otherwise could not pen-

fat soluble. These molecules, in a sense, are dissolved

etrate the lipid bilayer. Sometimes these even trans-

in the bilayer of the membrane. They mainly help

port substances in the direction opposite to their

determine the degree of permeability (or imperme-

natural direction of diffusion, which is called “active

ability) of the bilayer to water-soluble constituents of

transport.” Still others act as enzymes.

Unit I Introduction to Physiology: The Cell and General Physiology

Carbohydrate

Extracellular

fluid

Integral protein

Lipid

bilayer

Figure 2-3

Peripheral

protein

Structure of the cell membrane,

showing that it is composed

Intracellular

mainly of a lipid bilayer of phos-

fluid

pholipid molecules, but with large

numbers of protein molecules

Cytoplasm

protruding through the layer.

Also, carbohydrate moieties are

attached to the protein molecules

on the outside of the membrane

and to additional protein mole-

cules on the inside.

(Redrawn

Integral protein

from Lodish HF, Rothman JE: The

assembly of cell membranes. Sci

240:48,

1979. Copyright

George V. Kevin.)

Integral membrane proteins can also serve as recep-

cell surface. Many other carbohydrate compounds,

tors for water-soluble chemicals, such as peptide hor-

called proteoglycans—which are mainly carbohydrate

mones, that do not easily penetrate the cell membrane.

substances bound to small protein cores—are loosely

Interaction of cell membrane receptors with specific

attached to the outer surface of the cell as well.

ligands that bind to the receptor causes conforma-

Thus, the entire outside surface of the cell often has a

tional changes in the receptor protein. This, in turn,

loose carbohydrate coat called the glycocalyx.

enzymatically activates the intracellular part of the

The carbohydrate moieties attached to the outer

protein or induces interactions between the receptor

surface of the cell have several important functions:

and proteins in the cytoplasm that act as second mes-

(1) Many of them have a negative electrical charge,

sengers, thereby relaying the signal from the extracel-

which gives most cells an overall negative surface

lular part of the receptor to the interior of the cell. In

charge that repels other negative objects. (2) The gly-

this way, integral proteins spanning the cell membrane

cocalyx of some cells attaches to the glycocalyx of

provide a means of conveying information about the

other cells, thus attaching cells to one another. (3)

environment to the cell interior.

Many of the carbohydrates act as receptor substances

Peripheral protein molecules are often attached to

for binding hormones, such as insulin; when bound,

the integral proteins. These peripheral proteins func-

this combination activates attached internal proteins

tion almost entirely as enzymes or as controllers of

that, in turn, activate a cascade of intracellular

transport of substances through the cell membrane

enzymes. (4) Some carbohydrate moieties enter into

“pores.”

immune reactions, as discussed in Chapter 34.

Membrane Carbohydrates—The Cell

“Glycocalyx.” Mem-

brane carbohydrates occur almost invariably in

Cytoplasm and Its Organelles

combination with proteins or lipids in the form of gly-

coproteins or glycolipids. In fact, most of the integral

The cytoplasm is filled with both minute and large dis-

proteins are glycoproteins, and about one tenth of the

persed particles and organelles. The clear fluid portion

membrane lipid molecules are glycolipids. The “glyco”

of the cytoplasm in which the particles are dispersed

portions of these molecules almost invariably protrude

is called cytosol; this contains mainly dissolved pro-

to the outside of the cell, dangling outward from the

teins, electrolytes, and glucose.

Chapter 2

The Cell and Its Functions

Dispersed in the cytoplasm are neutral fat globules,

endoplasmic reticulum are large numbers of minute

glycogen granules, ribosomes, secretory vesicles, and

granular particles called ribosomes. Where these are

five especially important organelles: the endoplasmic

present, the reticulum is called the granular endoplas-

reticulum, the Golgi apparatus, mitochondria, lyso-

mic reticulum. The ribosomes are composed of a

somes, and peroxisomes.

mixture of RNA and proteins, and they function to

synthesize new protein molecules in the cell, as dis-

Endoplasmic Reticulum

cussed later in this chapter and in Chapter 3.

Figure 2-2 shows a network of tubular and flat vesic-

ular structures in the cytoplasm; this is the endoplas-

Agranular Endoplasmic Reticulum. Part of the endoplasmic

mic reticulum. The tubules and vesicles interconnect

reticulum has no attached ribosomes. This part is

with one another. Also, their walls are constructed

called the agranular, or smooth, endoplasmic reticu-

of lipid bilayer membranes that contain large amounts

lum. The agranular reticulum functions for the syn-

of proteins, similar to the cell membrane. The total

thesis of lipid substances and for other processes of the

surface area of this structure in some cells—the liver

cells promoted by intrareticular enzymes.

cells, for instance—can be as much as 30 to 40 times

the cell membrane area.

Golgi Apparatus

The detailed structure of a small portion of endo-

The Golgi apparatus, shown in Figure 2-5, is closely

plasmic reticulum is shown in Figure 2-4. The space

related to the endoplasmic reticulum. It has mem-

inside the tubules and vesicles is filled with endoplas-

branes similar to those of the agranular endoplasmic

mic matrix, a watery medium that is different from the

reticulum. It usually is composed of four or more

fluid in the cytosol outside the endoplasmic reticulum.

stacked layers of thin, flat, enclosed vesicles lying near

Electron micrographs show that the space inside the

one side of the nucleus. This apparatus is prominent

endoplasmic reticulum is connected with the space

in secretory cells, where it is located on the side of

between the two membrane surfaces of the nuclear

the cell from which the secretory substances are

membrane.

extruded.

Substances formed in some parts of the cell enter

The Golgi apparatus functions in association with

the space of the endoplasmic reticulum and are then

the endoplasmic reticulum. As shown in Figure 2-5,

conducted to other parts of the cell. Also, the vast

small “transport vesicles” (also called endoplasmic

surface area of this reticulum and the multiple enzyme

reticulum vesicles, or ER vesicles) continually pinch off

systems attached to its membranes provide machinery

from the endoplasmic reticulum and shortly thereafter

for a major share of the metabolic functions of the cell.

fuse with the Golgi apparatus. In this way, substances

entrapped in the ER vesicles are transported from the

Ribosomes and the Granular Endoplasmic Reticulum.

endoplasmic reticulum to the Golgi apparatus. The

Attached to the outer surfaces of many parts of the

transported substances are then processed in the Golgi

apparatus to form lysosomes, secretory vesicles, and

other cytoplasmic components that are discussed later

in the chapter.

Golgi vesicles

Matrix

Golgi

apparatus

ER vesicles

Endoplasmic

Granular

reticulum

endoplasmic

Agranular

reticulum

endoplasmic

reticulum

Figure 2-4

Figure 2-5

Structure of the endoplasmic reticulum. (Modified from DeRober-

tis EDP, Saez FA, DeRobertis EMF: Cell Biology, 6th ed. Philadel-

A typical Golgi apparatus and its relationship to the endoplasmic

phia: WB Saunders, 1975.)

reticulum (ER) and the nucleus.

Unit I Introduction to Physiology: The Cell and General Physiology

Lysosomes

Secretory

Lysosomes, shown in Figure

2-2, are vesicular

granules

organelles that form by breaking off from the Golgi

apparatus and then dispersing throughout the cyto-

plasm. The lysosomes provide an intracellular digestive

system that allows the cell to digest (1) damaged cel-

lular structures,

(2) food particles that have been

ingested by the cell, and (3) unwanted matter such as

bacteria. The lysosome is quite different in different

types of cells, but it is usually 250 to 750 nanometers

in diameter. It is surrounded by a typical lipid bilayer

membrane and is filled with large numbers of small

granules 5 to 8 nanometers in diameter, which are

protein aggregates of as many as 40 different hydro-

Figure 2-6

lase

(digestive) enzymes. A hydrolytic enzyme is

Secretory granules

(secretory vesicles) in acinar cells of

the

capable of splitting an organic compound into two or

pancreas.

more parts by combining hydrogen from a water mol-

ecule with one part of the compound and combining

the hydroxyl portion of the water molecule with the

other part of the compound. For instance, protein

Outer membrane

is hydrolyzed to form amino acids, glycogen is

hydrolyzed to form glucose, and lipids are hydrolyzed

Inner membrane

to form fatty acids and glycerol.

Crests

Matrix

Ordinarily, the membrane surrounding the lysosome

prevents the enclosed hydrolytic enzymes from

coming in contact with other substances in the cell and,

therefore, prevents their digestive actions. However,

some conditions of the cell break the membranes of

some of the lysosomes, allowing release of the diges-

tive enzymes. These enzymes then split the organic

substances with which they come in contact into small,

Oxidative

highly diffusible substances such as amino acids and

phosphorylation

glucose. Some of the more specific functions of lyso-

Outer chamber

enzymes

somes are discussed later in the chapter.

Figure 2-7

Peroxisomes

Structure of a mitochondrion. (Modified from DeRobertis EDP,

Peroxisomes are similar physically to lysosomes, but

Saez FA, DeRobertis EMF: Cell Biology, 6th ed. Philadelphia: WB

they are different in two important ways. First, they are

Saunders, 1975.)

believed to be formed by self-replication (or perhaps

by budding off from the smooth endoplasmic reticu-

lum) rather than from the Golgi apparatus. Second,

they contain oxidases rather than hydrolases. Several

vesicles store protein proenzymes (enzymes that are

of the oxidases are capable of combining oxygen with

not yet activated). The proenzymes are secreted later

hydrogen ions derived from different intracellular

through the outer cell membrane into the pancreatic

chemicals to form hydrogen peroxide (H₂O₂). Hydro-

duct and thence into the duodenum, where they

gen peroxide is a highly oxidizing substance and is

become activated and perform digestive functions on

used in association with catalase, another oxidase

the food in the intestinal tract.

enzyme present in large quantities in peroxisomes, to

oxidize many substances that might otherwise be poi-

Mitochondria

sonous to the cell. For instance, about half the alcohol

The mitochondria, shown in Figures 2-2 and 2-7, are

a person drinks is detoxified by the peroxisomes of the

called the “powerhouses” of the cell. Without them,

liver cells in this manner.

cells would be unable to extract enough energy from

the nutrients, and essentially all cellular functions

Secretory Vesicles

would cease.

One of the important functions of many cells is secre-

Mitochondria are present in all areas of each cell’s

tion of special chemical substances. Almost all such

cytoplasm, but the total number per cell varies from

secretory substances are formed by the endoplasmic

less than a hundred up to several thousand, depending

reticulum-Golgi apparatus system and are then

on the amount of energy required by the cell. Further,

released from the Golgi apparatus into the cytoplasm

the mitochondria are concentrated in those portions

in the form of storage vesicles called secretory vesicles

of the cell that are responsible for the major share of

or secretory granules. Figure 2-6 shows typical secre-

its energy metabolism. They are also variable in size

tory vesicles inside pancreatic acinar cells; these

and shape. Some are only a few hundred nanometers

Chapter 2

The Cell and Its Functions

in diameter and globular in shape, whereas others are

elongated—as large as 1 micrometer in diameter and

7 micrometers long; still others are branching and

filamentous.

The basic structure of the mitochondrion, shown

in Figure

2-7, is composed mainly of two lipid

bilayer-protein membranes: an outer membrane and

an inner membrane. Many infoldings of the inner

membrane form shelves onto which oxidative enzymes

are attached. In addition, the inner cavity of the mito-

chondrion is filled with a matrix that contains large

quantities of dissolved enzymes that are necessary for

extracting energy from nutrients. These enzymes

operate in association with the oxidative enzymes on

the shelves to cause oxidation of the nutrients, thereby

forming carbon dioxide and water and at the same

time releasing energy. The liberated energy is used to

synthesize a “high-energy” substance called adenosine

Figure 2-8

triphosphate (ATP). ATP is then transported out of the

mitochondrion, and it diffuses throughout the cell to

Microtubules teased from the flagellum of a sperm.

(From

Wolstenholme GEW, O’Connor M, and The publisher, JA Churchill,

release its own energy wherever it is needed for per-

1967. Figure 4, page 314. Copyright the Novartis Foundation

forming cellular functions. The chemical details of ATP

formerly the Ciba Foundation.)

formation by the mitochondrion are given in Chapter

67, but some of the basic functions of ATP in the cell

are introduced later in this chapter.

Mitochondria are self-replicative, which means that

Nucleus

one mitochondrion can form a second one, a third one,

and so on, whenever there is a need in the cell for

The nucleus is the control center of the cell. Briefly, the

increased amounts of ATP. Indeed, the mitochondria

nucleus contains large quantities of DNA, which are

contain DNA similar to that found in the cell nucleus.

the genes. The genes determine the characteristics of

In Chapter 3 we will see that DNA is the basic chem-

the cell’s proteins, including the structural proteins, as

ical of the nucleus that controls replication of the cell.

well as the intracellular enzymes that control cyto-

The DNA of the mitochondrion plays a similar role,

plasmic and nuclear activities.

controlling replication of the mitochondrion itself.

The genes also control and promote reproduction of

the cell itself. The genes first reproduce to give two

Filament and Tubular Structures of the Cell

identical sets of genes; then the cell splits by a special

The fibrillar proteins of the cell are usually organized

process called mitosis to form two daughter cells, each

into filaments or tubules. These originate as precursor

of which receives one of the two sets of DNA genes.

protein molecules synthesized by ribosomes in the

All these activities of the nucleus are considered in

cytoplasm. The precursor molecules then polymerize

detail in the next chapter.

to form filaments. As an example, large numbers of

Unfortunately, the appearance of the nucleus under

actin filaments frequently occur in the outer zone of

the microscope does not provide many clues to the

the cytoplasm, called the ectoplasm, to form an elastic

mechanisms by which the nucleus performs its control

support for the cell membrane. Also, in muscle cells,

activities. Figure

2-9 shows the light microscopic

actin and myosin filaments are organized into a special

appearance of the interphase nucleus

(during the

contractile machine that is the basis for muscle con-

period between mitoses), revealing darkly staining

traction, as discussed in detail in Chapter 6.

chromatin material throughout the nucleoplasm.

A special type of stiff filament composed of poly-

During mitosis, the chromatin material organizes in

merized tubulin molecules is used in all cells to con-

the form of highly structured chromosomes, which can

struct very strong tubular structures, the microtubules.

then be easily identified using the light microscope, as

Figure

2-8 shows typical microtubules that were

illustrated in the next chapter.

teased from the flagellum of a sperm.

Another example of microtubules is the tubular

skeletal structure in the center of each cilium that radi-

Nuclear Membrane

ates upward from the cell cytoplasm to the tip of the

cilium. This structure is discussed later in the chapter

The nuclear membrane, also called the nuclear enve-

and is illustrated in Figure 2-17. Also, both the centri-

lope, is actually two separate bilayer membranes, one

oles and the mitotic spindle of the mitosing cell are

inside the other. The outer membrane is continuous

composed of stiff microtubules.

with the endoplasmic reticulum of the cell cytoplasm,

Thus, a primary function of microtubules is to act as

and the space between the two nuclear membranes is

a cytoskeleton, providing rigid physical structures for

also continuous with the space inside the endoplasmic

certain parts of cells.

reticulum, as shown in Figure 2-9.

Unit I Introduction to Physiology: The Cell and General Physiology

Pores

Nucleoplasm

15 nm — Small virus

150 nm — Large virus

Endoplasmic

reticulum

350 nm — Rickettsia

Nucleolus

1 mm Bacterium

Nuclear envelope -

outer and inner

membranes

Cell

Chromatin material (DNA)

Cytoplasm

5 - 10 mm +

Figure 2-9

Figure 2-10

Structure of the nucleus.

Comparison of sizes of precellular organisms with that of the

average cell in the human body.

The nuclear membrane is penetrated by several

thousand nuclear pores. Large complexes of protein

molecules are attached at the edges of the pores so

(4) a bacterium, and (5) a nucleated cell, demonstrat-

that the central area of each pore is only about 9

ing that the cell has a diameter about 1000 times that

nanometers in diameter. Even this size is large enough

of the smallest virus and, therefore, a volume about 1

to allow molecules up to 44,000 molecular weight to

billion times that of the smallest virus. Correspond-

pass through with reasonable ease.

ingly, the functions and anatomical organization of the

cell are also far more complex than those of the virus.

The essential life-giving constituent of the small

Nucleoli and Formation of Ribosomes

virus is a nucleic acid embedded in a coat of protein.

This nucleic acid is composed of the same basic nucleic

The nuclei of most cells contain one or more highly

acid constituents (DNA or RNA) found in mammalian

staining structures called nucleoli. The nucleolus,

cells, and it is capable of reproducing itself under

unlike most other organelles discussed here, does not

appropriate conditions. Thus, the virus propagates its

have a limiting membrane. Instead, it is simply an accu-

lineage from generation to generation and is therefore

mulation of large amounts of RNA and proteins of the

a living structure in the same way that the cell and the

types found in ribosomes. The nucleolus becomes con-

human being are living structures.

siderably enlarged when the cell is actively synthesiz-

As life evolved, other chemicals besides nucleic acid

ing proteins.

and simple proteins became integral parts of the

Formation of the nucleoli (and of the ribosomes in

organism, and specialized functions began to develop

the cytoplasm outside the nucleus) begins in the

in different parts of the virus. A membrane formed

nucleus. First, specific DNA genes in the chromosomes

around the virus, and inside the membrane, a fluid

cause RNA to be synthesized. Some of this is stored

matrix appeared. Specialized chemicals then devel-

in the nucleoli, but most of it is transported outward

oped inside the fluid to perform special functions;

through the nuclear pores into cytoplasm. Here, it is

many protein enzymes appeared that were capable of

used in conjunction with specific proteins to assemble

catalyzing chemical reactions and, therefore, deter-

“mature” ribosomes that play an essential role in

mining the organism’s activities.

forming cytoplasmic proteins, as discussed more fully

In still later stages of life, particularly in the rick-

in Chapter 3.

ettsial and bacterial stages, organelles developed inside

the organism, representing physical structures of

chemical aggregates that perform functions in a more

Comparison of the Animal Cell

efficient manner than can be achieved by dispersed

with Precellular Forms of Life

chemicals throughout the fluid matrix.

Finally, in the nucleated cell, still more complex

Many of us think of the cell as the lowest level of life.

organelles developed, the most important of which is

However, the cell is a very complicated organism that

the nucleus itself. The nucleus distinguishes this type

required many hundreds of millions of years to

of cell from all lower forms of life; the nucleus pro-

develop after the earliest form of life, an organism

vides a control center for all cellular activities, and it

similar to the present-day virus, first appeared on

provides for exact reproduction of new cells genera-

earth. Figure 2-10 shows the relative sizes of (1) the

tion after generation, each new cell having almost

smallest known virus, (2) a large virus, (3) a rickettsia,

exactly the same structure as its progenitor.

Chapter 2

The Cell and Its Functions

Functional Systems of the Cell

Proteins

Receptors

Coated pit

In the remainder of this chapter, we discuss several

Clathrin

representative functional systems of the cell that make

it a living organism.

Ingestion by the Cell—Endocytosis

If a cell is to live and grow and reproduce, it must

Actin and myosin

Dissolving clathrin

obtain nutrients and other substances from the sur-

rounding fluids. Most substances pass through the cell

membrane by diffusion and active transport.

Diffusion involves simple movement through the

membrane caused by the random motion of the mol-

ecules of the substance; substances move either

through cell membrane pores or, in the case of lipid-

soluble substances, through the lipid matrix of the

Figure 2-11

membrane.

Active transport involves the actual carrying of a

Mechanism of pinocytosis.

substance through the membrane by a physical pro-

tein structure that penetrates all the way through the

membrane. These active transport mechanisms are so

membrane change in such a way that the entire pit

important to cell function that they are presented in

invaginates inward, and the fibrillar proteins sur-

detail in Chapter 4.

rounding the invaginating pit cause its borders to close

Very large particles enter the cell by a specialized

over the attached proteins as well as over a small

function of the cell membrane called endocytosis. The

amount of extracellular fluid. Immediately thereafter,

principal forms of endocytosis are pinocytosis and

the invaginated portion of the membrane breaks away

phagocytosis. Pinocytosis means ingestion of minute

from the surface of the cell, forming a pinocytotic

particles that form vesicles of extracellular fluid and

vesicle inside the cytoplasm of the cell.

particulate constituents inside the cell cytoplasm.

What causes the cell membrane to go through the

Phagocytosis means ingestion of large particles, such

necessary contortions to form pinocytotic vesicles

as bacteria, whole cells, or portions of degenerating

remains mainly a mystery. This process requires energy

tissue.

from within the cell; this is supplied by ATP, a high-

energy substance discussed later in the chapter. Also,

Pinocytosis. Pinocytosis occurs continually in the cell

it requires the presence of calcium ions in the extra-

membranes of most cells, but it is especially rapid

cellular fluid, which probably react with contractile

in some cells. For instance, it occurs so rapidly in

protein filaments beneath the coated pits to provide

macrophages that about 3 per cent of the total macro-

the force for pinching the vesicles away from the cell

phage membrane is engulfed in the form of vesicles

membrane.

each minute. Even so, the pinocytotic vesicles are so

small—usually only 100 to 200 nanometers in diame-

Phagocytosis. Phagocytosis occurs in much the same

ter—that most of them can be seen only with the elec-

way as pinocytosis, except that it involves large

tron microscope.

particles rather than molecules. Only certain cells

Pinocytosis is the only means by which most large

have the capability of phagocytosis, most notably the

macromolecules, such as most protein molecules, can

tissue macrophages and some of the white blood cells.

enter cells. In fact, the rate at which pinocytotic vesi-

Phagocytosis is initiated when a particle such as a

cles form is usually enhanced when such macro-

bacterium, a dead cell, or tissue debris binds with

molecules attach to the cell membrane.

receptors on the surface of the phagocyte. In the case

Figure 2-11 demonstrates the successive steps of

of bacteria, each bacterium usually is already attached

pinocytosis, showing three molecules of protein

to a specific antibody, and it is the antibody that

attaching to the membrane. These molecules usually

attaches to the phagocyte receptors, dragging the bac-

attach to specialized protein receptors on the surface

terium along with it. This intermediation of antibodies

of the membrane that are specific for the type of

is called opsonization, which is discussed in Chapters

protein that is to be absorbed. The receptors generally

33 and 34.

are concentrated in small pits on the outer surface of

Phagocytosis occurs in the following steps:

the cell membrane, called coated pits. On the inside of

1. The cell membrane receptors attach to the surface

the cell membrane beneath these pits is a latticework

ligands of the particle.

of fibrillar protein called clathrin, as well as other pro-

2. The edges of the membrane around the points of

teins, perhaps including contractile filaments of actin

attachment evaginate outward within a fraction of

and myosin. Once the protein molecules have bound

a second to surround the entire particle; then,

with the receptors, the surface properties of the local

progressively more and more membrane receptors

Unit I Introduction to Physiology: The Cell and General Physiology

attach to the particle ligands. All this occurs

occurs in the uterus after pregnancy, in muscles during

suddenly in a zipper-like manner to form a closed

long periods of inactivity, and in mammary glands at

phagocytic vesicle.

the end of lactation. Lysosomes are responsible for

3. Actin and other contractile fibrils in the cytoplasm

much of this regression. The mechanism by which lack

surround the phagocytic vesicle and contract

of activity in a tissue causes the lysosomes to increase

around its outer edge, pushing the vesicle to the

their activity is unknown.

interior.

Another special role of the lysosomes is removal of

4. The contractile proteins then pinch the stem of

damaged cells or damaged portions of cells from

the vesicle so completely that the vesicle

tissues. Damage to the cell—caused by heat, cold,

separates from the cell membrane, leaving the

trauma, chemicals, or any other factor—induces lyso-

vesicle in the cell interior in the same way that

somes to rupture. The released hydrolases immedi-

pinocytotic vesicles are formed.

ately begin to digest the surrounding organic

substances. If the damage is slight, only a portion of

the cell is removed, followed by repair of the cell. If

Digestion of Pinocytotic and

the damage is severe, the entire cell is digested, a

Phagocytic Foreign Substances Inside

process called autolysis. In this way, the cell is com-

the Cell—Function of the Lysosomes

pletely removed, and a new cell of the same type ordi-

narily is formed by mitotic reproduction of an adjacent

Almost immediately after a pinocytotic or phagocytic

cell to take the place of the old one.

vesicle appears inside a cell, one or more lysosomes

The lysosomes also contain bactericidal agents that

become attached to the vesicle and empty their acid

can kill phagocytized bacteria before they can cause

hydrolases to the inside of the vesicle, as shown in

cellular damage. These agents include (1) lysozyme,

Figure 2-12. Thus, a digestive vesicle is formed inside

which dissolves the bacterial cell membrane; (2) lyso-

the cell cytoplasm in which the vesicular hydrolases

ferrin, which binds iron and other substances before

begin hydrolyzing the proteins, carbohydrates, lipids,

they can promote bacterial growth; and (3) acid at a

and other substances in the vesicle. The products of

pH of about 5.0, which activates the hydrolases and

digestion are small molecules of amino acids, glucose,

inactivates bacterial metabolic systems.

phosphates, and so forth that can diffuse through the

membrane of the vesicle into the cytoplasm. What is

left of the digestive vesicle, called the residual body,

Synthesis and Formation of Cellular

represents indigestible substances. In most instances,

Structures by Endoplasmic Reticulum

this is finally excreted through the cell membrane by

and Golgi Apparatus

a process called exocytosis, which is essentially the

opposite of endocytosis.

Specific Functions of the

Thus, the pinocytotic and phagocytic vesicles con-

Endoplasmic Reticulum

taining lysosomes can be called the digestive organs of

The extensiveness of the endoplasmic reticulum and

the cells.

the Golgi apparatus in secretory cells has already been

emphasized. These structures are formed primarily of

Regression of Tissues and Autolysis of Cells. Tissues of the

lipid bilayer membranes similar to the cell membrane,

body often regress to a smaller size. For instance, this

and their walls are loaded with protein enzymes that

catalyze the synthesis of many substances required by

Lysosomes

the cell.

Most synthesis begins in the endoplasmic reticulum.

The products formed there are then passed on to the

Golgi apparatus, where they are further processed

before being released into the cytoplasm. But first, let

us note the specific products that are synthesized in

Pinocytotic or

specific portions of the endoplasmic reticulum and the

phagocytic

Golgi apparatus.

vesicle

Digestive vesicle

Proteins Are Formed by the Granular Endoplasmic Reticulum.

The granular portion of the endoplasmic reticulum is

characterized by large numbers of ribosomes attached

to the outer surfaces of the endoplasmic reticulum

Residual body

membrane. As we discuss in Chapter 3, protein mole-

cules are synthesized within the structures of the ribo-

somes. The ribosomes extrude some of the synthesized

Excretion

protein molecules directly into the cytosol, but they

also extrude many more through the wall of the endo-

Figure 2-12

plasmic reticulum to the interior of the endoplasmic

Digestion of substances in pinocytotic or phagocytic vesicles by

vesicles and tubules, that is, into the endoplasmic

enzymes derived from lysosomes.

matrix.

Chapter 2

The Cell and Its Functions

Synthesis of Lipids by the Smooth Endoplasmic Reticulum.

Protein

Lipid

Secretory

The endoplasmic reticulum also synthesizes lipids,

Ribosomes

formation

Lysosomes

vesicles

especially phospholipids and cholesterol. These are

rapidly incorporated into the lipid bilayer of the endo-

plasmic reticulum itself, thus causing the endoplasmic

reticulum to grow more extensive. This occurs mainly

in the smooth portion of the endoplasmic reticulum.

To keep the endoplasmic reticulum from growing

beyond the needs of the cell, small vesicles called ER

vesicles or transport vesicles continually break away

from the smooth reticulum; most of these vesicles then

migrate rapidly to the Golgi apparatus.

Other Functions of the Endoplasmic Reticulum. Other sig-

nificant functions of the endoplasmic reticulum, espe-

cially the smooth reticulum, include the following:

Transport

1. It provides the enzymes that control glycogen

Glycosylation

vesicles

breakdown when glycogen is to be used for

Granular

Smooth

Golgi

energy.

endoplasmic

apparatus

2. It provides a vast number of enzymes that are

reticulum

capable of detoxifying substances, such as drugs,

that might damage the cell. It achieves

Figure 2-13

detoxification by coagulation, oxidation,

Formation of proteins, lipids, and cellular vesicles by the endo-

hydrolysis, conjugation with glycuronic acid, and

plasmic reticulum and Golgi apparatus.

in other ways.

Specific Functions of the Golgi Apparatus

additional carbohydrate moieties are added to the

Synthetic Functions of the Golgi Apparatus. Although the

secretions. Also, an important function of the Golgi

major function of the Golgi apparatus is to provide

apparatus is to compact the endoplasmic reticular

additional processing of substances already formed

secretions into highly concentrated packets. As the

in the endoplasmic reticulum, it also has the capability

secretions pass toward the outermost layers of the

of synthesizing certain carbohydrates that cannot be

Golgi apparatus, the compaction and processing

formed in the endoplasmic reticulum. This is especially

proceed. Finally, both small and large vesicles contin-

true for the formation of large saccharide polymers

ually break away from the Golgi apparatus, carrying

bound with small amounts of protein; the most impor-

with them the compacted secretory substances, and in

tant of these are hyaluronic acid and chondroitin sulfate.

turn, the vesicles diffuse throughout the cell.

A few of the many functions of hyaluronic acid and

To give an idea of the timing of these processes:

chondroitin sulfate in the body are as follows: (1) they

When a glandular cell is bathed in radioactive amino

are the major components of proteoglycans secreted

acids, newly formed radioactive protein molecules can

in mucus and other glandular secretions; (2) they are

be detected in the granular endoplasmic reticulum

the major components of the ground substance outside

within 3 to 5 minutes. Within 20 minutes, newly formed

the cells in the interstitial spaces, acting as filler

proteins are already present in the Golgi apparatus,

between collagen fibers and cells; and (3) they are

and within 1 to 2 hours, radioactive proteins are

principal components of the organic matrix in both

secreted from the surface of the cell.

cartilage and bone.

Types of Vesicles Formed by the Golgi Apparatus—Secretory

Processing of Endoplasmic Secretions by the Golgi Apparatus—

Vesicles and Lysosomes. In a highly secretory cell, the

Formation of Vesicles. Figure

2-13 summarizes the

vesicles formed by the Golgi apparatus are mainly

major functions of the endoplasmic reticulum and

secretory vesicles containing protein substances that

Golgi apparatus. As substances are formed in the

are to be secreted through the surface of the cell mem-

endoplasmic reticulum, especially the proteins, they

brane. These secretory vesicles first diffuse to the cell

are transported through the tubules toward portions

membrane, then fuse with it and empty their sub-

of the smooth endoplasmic reticulum that lie nearest

stances to the exterior by the mechanism called exo-

the Golgi apparatus. At this point, small transport vesi-

cytosis. Exocytosis, in most cases, is stimulated by the

cles composed of small envelopes of smooth endo-

entry of calcium ions into the cell; calcium ions inter-

plasmic reticulum continually break away and diffuse

act with the vesicular membrane in some way that is

to the deepest layer of the Golgi apparatus. Inside these

not understood and cause its fusion with the cell mem-

vesicles are the synthesized proteins and other prod-

brane, followed by exocytosis—that is, opening of the

ucts from the endoplasmic reticulum.

membrane’s outer surface and extrusion of its contents

The transport vesicles instantly fuse with the Golgi

outside the cell.

apparatus and empty their contained substances into

Some vesicles, however, are destined for intracellu-

the vesicular spaces of the Golgi apparatus. Here,

lar use.

Unit I Introduction to Physiology: The Cell and General Physiology

Use of Intracellular Vesicles to Replenish Cellular Membranes.

all these digestive and metabolic functions are given

Some of the intracellular vesicles formed by the Golgi

in Chapters 62 through 72.

apparatus fuse with the cell membrane or with the

Briefly, almost all these oxidative reactions occur

membranes of intracellular structures such as the

inside the mitochondria, and the energy that is

mitochondria and even the endoplasmic reticulum.

released is used to form the high-energy compound

This increases the expanse of these membranes and

ATP. Then, ATP, not the original foodstuffs, is used

thereby replenishes the membranes as they are used

throughout the cell to energize almost all the subse-

up. For instance, the cell membrane loses much of its

quent intracellular metabolic reactions.

substance every time it forms a phagocytic or pinocy-

totic vesicle, and the vesicular membranes of the Golgi

Functional Characteristics of ATP

apparatus continually replenish the cell membrane.

In summary, the membranous system of the endo-

plasmic reticulum and Golgi apparatus represents a

NH₂

highly metabolic organ capable of forming new intra-

N C

cellular structures as well as secretory substances to be

extruded from the cell.

Adenine

Extraction of Energy from Nutrients—

CH O P

O-

Function of the Mitochondria

O-

Phosphate

The principal substances from which cells extract

C C H

energy are foodstuffs that react chemically with

oxygen—carbohydrates, fats, and proteins. In the

OH OH

human body, essentially all carbohydrates are con-

Ribose

verted into glucose by the digestive tract and liver

Adenosine triphosphate

before they reach the other cells of the body. Similarly,

proteins are converted into amino acids and fats into

ATP is a nucleotide composed of (1) the nitrogenous

fatty acids. Figure 2-14 shows oxygen and the food-

base adenine, (2) the pentose sugar ribose, and (3)

stuffs—glucose, fatty acids, and amino acids—all enter-

three phosphate radicals. The last two phosphate rad-

ing the cell. Inside the cell, the foodstuffs react

icals are connected with the remainder of the molecule

chemically with oxygen, under the influence of

by so-called high-energy phosphate bonds, which are

enzymes that control the reactions and channel the

represented in the formula above by the symbol ~.

energy released in the proper direction. The details of

Under the physical and chemical conditions of the

body, each of these high-energy bonds contains about

12,000 calories of energy per mole of ATP, which is

many times greater than the energy stored in the

average chemical bond, thus giving rise to the term

2ADP

2ATP

high-energy bond. Further, the high-energy phosphate

bond is very labile, so that it can be split instantly on

Glucose

Pyruvic acid

demand whenever energy is required to promote

Fatty acids

FA Acetoacetic

36 ADP

other intracellular reactions.

acid

When ATP releases its energy, a phosphoric acid

Amino acids

Acetyl-CoA

radical is split away, and adenosine diphosphate (ADP)

is formed. This released energy is used to energize vir-

tually all of the cell’s other functions, such as synthe-

Acetyl-CoA

sis of substances and muscular contraction.

O₂

ADP

To reconstitute the cellular ATP as it is used up,

CO₂

CO₂+H₂O

ATP

energy derived from the cellular nutrients causes ADP

and phosphoric acid to recombine to form new ATP,

and the entire process repeats over and over again. For

H₂O

36 ATP

these reasons, ATP has been called the energy currency

of the cell because it can be spent and remade contin-

Mitochondrion

ually, having a turnover time of only a few minutes.

Nucleus

Cell

membrane

Chemical Processes in the Formation of ATP—Role of the

Mitochondria. On entry into the cells, glucose is sub-

Figure 2-14

jected to enzymes in the cytoplasm that convert it

into pyruvic acid (a process called glycolysis). A small

Formation of adenosine triphosphate (ATP) in the cell, showing

amount of ADP is changed into ATP by the energy

that most of the ATP is formed in the mitochondria. ADP, adeno-

sine diphosphate.

released during this conversion, but this amount

Chapter 2

The Cell and Its Functions

accounts for less than 5 per cent of the overall energy

Ribosomes

metabolism of the cell.

Membrane

By far, the major portion of the ATP formed in the

Endoplasmic

transport

cell, about 95 per cent, is formed in the mitochondria.

reticulum

The pyruvic acid derived from carbohydrates, fatty

acids from lipids, and amino acids from proteins are

eventually converted into the compound acetyl-CoA

Protein synthesis

in the matrix of the mitochondrion. This substance, in

Na⁺

ATP

ADP

turn, is further dissoluted (for the purpose of extract-

ing its energy) by another series of enzymes in the

ADP

mitochondrion matrix, undergoing dissolution in a

Mitochondrion

sequence of chemical reactions called the citric acid

cycle, or Krebs cycle. These chemical reactions are

ATP

ADP

so important that they are explained in detail in

Chapter 67.

In this citric acid cycle, acetyl-CoA is split into its

ATP

ADP

component parts, hydrogen atoms and carbon dioxide.

The carbon dioxide diffuses out of the mitochondria

and eventually out of the cell; finally, it is excreted

from the body through the lungs.

Muscle contraction

The hydrogen atoms, conversely, are highly reactive,

and they combine instantly with oxygen that has also

Figure 2-15

diffused into the mitochondria. This releases a tremen-

dous amount of energy, which is used by the mito-

Use of adenosine triphosphate (ATP) (formed in the mitochon-

drion) to provide energy for three major cellular functions: mem-

chondria to convert very large amounts of ADP to

brane transport, protein synthesis, and muscle contraction. ADP,

ATP. The processes of these reactions are complex,

adenosine diphosphate.

requiring the participation of large numbers of protein

enzymes that are integral parts of mitochondrial mem-

branous shelves that protrude into the mitochondrial

matrix. The initial event is removal of an electron from

the hydrogen atom, thus converting it to a hydrogen

phate ions, chloride ions, urate ions, hydrogen ions,

ion. The terminal event is combination of hydrogen

and many other ions and various organic substances.

ions with oxygen to form water plus the release of

Membrane transport is so important to cell function

tremendous amounts of energy to large globular pro-

that some cells—the renal tubular cells, for instance—

teins, called ATP synthetase, that protrude like knobs

use as much as 80 per cent of the ATP that they form

from the membranes of the mitochondrial shelves.

for this purpose alone.

Finally, the enzyme ATP synthetase uses the energy

In addition to synthesizing proteins, cells synthesize

from the hydrogen ions to cause the conversion of

phospholipids, cholesterol, purines, pyrimidines, and a

ADP to ATP. The newly formed ATP is transported

host of other substances. Synthesis of almost any

out of the mitochondria into all parts of the cell cyto-

chemical compound requires energy. For instance, a

plasm and nucleoplasm, where its energy is used to

single protein molecule might be composed of as many

energize multiple cell functions.

as several thousand amino acids attached to one

This overall process for formation of ATP is called

another by peptide linkages; the formation of each of

the chemiosmotic mechanism of ATP formation. The

these linkages requires energy derived from the break-

chemical and physical details of this mechanism are

down of four high-energy bonds; thus, many thousand

presented in Chapter 67, and many of the detailed

ATP molecules must release their energy as each

metabolic functions of ATP in the body are presented

protein molecule is formed. Indeed, some cells use as

in Chapters 67 through 71.

much as 75 per cent of all the ATP formed in the cell

simply to synthesize new chemical compounds, espe-

Uses of ATP for Cellular Function. Energy from ATP is

cially protein molecules; this is particularly true during

used to promote three major categories of cellular

the growth phase of cells.

functions: (1) transport of substances through multiple

The final major use of ATP is to supply energy for

membranes in the cell,

(2) synthesis of chemical

special cells to perform mechanical work. We see in

compounds throughout the cell, and (3) mechanical

Chapter 6 that each contraction of a muscle fiber

work. These uses of ATP are illustrated by examples

requires expenditure of tremendous quantities of ATP

in Figure 2-15: (1) to supply energy for the transport

energy. Other cells perform mechanical work in other

of sodium through the cell membrane, (2) to promote

ways, especially by ciliary and ameboid motion, which

protein synthesis by the ribosomes, and (3) to supply

are described later in this chapter. The source of

the energy needed during muscle contraction.

energy for all these types of mechanical work is ATP.

In addition to membrane transport of sodium,

In summary, ATP is always available to release its

energy from ATP is required for membrane transport

energy rapidly and almost explosively wherever in the

of potassium ions, calcium ions, magnesium ions, phos-

cell it is needed. To replace the ATP used by the cell,

Unit I Introduction to Physiology: The Cell and General Physiology

much slower chemical reactions break down carbohy-

remainder of the cell body is pulled forward toward the

drates, fats, and proteins and use the energy derived

point of attachment. This attachment is effected by

from these to form new ATP. More than 95 per cent

receptor proteins that line the insides of exocytotic vesi-

cles. When the vesicles become part of the pseudopodial

of this ATP is formed in the mitochondria, which

membrane, they open so that their insides evert to the

accounts for the mitochondria being called the “pow-

outside, and the receptors now protrude to the outside

erhouses” of the cell.

and attach to ligands in the surrounding tissues.

At the opposite end of the cell, the receptors pull

away from their ligands and form new endocytotic vesi-

Locomotion of Cells

cles. Then, inside the cell, these vesicles stream toward

By far the most important type of movement that occurs

the pseudopodial end of the cell, where they are used

in the body is that of the muscle cells in skeletal, cardiac,

to form still new membrane for the pseudopodium.

and smooth muscle, which constitute almost 50 per cent

The second essential effect for locomotion is to

of the entire body mass. The specialized functions of

provide the energy required to pull the cell body in the

these cells are discussed in Chapters 6 through 9. Two

direction of the pseudopodium. Experiments suggest

other types of movement—ameboid locomotion and

the following as an explanation: In the cytoplasm of all

ciliary movement—occur in other cells.

cells is a moderate to large amount of the protein actin.

Much of the actin is in the form of single molecules that

do not provide any motive power; however, these poly-

Ameboid Movement

merize to form a filamentous network, and the network

contracts when it binds with an actin-binding protein

Ameboid movement is movement of an entire cell in

such as myosin. The whole process is energized by the

relation to its surroundings, such as movement of white

high-energy compound ATP. This is what happens in

blood cells through tissues. It receives its name from the

the pseudopodium of a moving cell, where such

fact that amebae move in this manner and have pro-

a network of actin filaments forms anew inside the

vided an excellent tool for studying the phenomenon.

enlarging pseudopodium. Contraction also occurs in

Typically, ameboid locomotion begins with protrusion

the ectoplasm of the cell body, where a preexisting

of a pseudopodium from one end of the cell. The

actin network is already present beneath the cell

pseudopodium projects far out, away from the cell

membrane.

body, and partially secures itself in a new tissue area.

Then the remainder of the cell is pulled toward the

Types of Cells That Exhibit Ameboid Locomotion. The most

pseudopodium. Figure 2-16 demonstrates this process,

common cells to exhibit ameboid locomotion in the

showing an elongated cell, the right-hand end of which

human body are the white blood cells when they move

is a protruding pseudopodium. The membrane of this

out of the blood into the tissues in the form of tissue

end of the cell is continually moving forward, and the

macrophages. Other types of cells can also move by

membrane at the left-hand end of the cell is continually

ameboid locomotion under certain circumstances. For

following along as the cell moves.

instance, fibroblasts move into a damaged area to help

repair the damage, and even the germinal cells of the

Mechanism of Ameboid Locomotion. Figure 2-16 shows the

skin, though ordinarily completely sessile cells, move

general principle of ameboid motion. Basically, it results

toward a cut area to repair the rent. Finally, cell loco-

from continual formation of new cell membrane at the

motion is especially important in development of the

leading edge of the pseudopodium and continual

embryo and fetus after fertilization of an ovum. For

absorption of the membrane in mid and rear portions

instance, embryonic cells often must migrate long dis-

of the cell. Also, two other effects are essential for

tances from their sites of origin to new areas during

forward movement of the cell. The first effect is attach-

development of special structures.

ment of the pseudopodium to surrounding tissues so

Control of Ameboid Locomotion—Chemotaxis. The most

that it becomes fixed in its leading position, while the

important initiator of ameboid locomotion is the

process called chemotaxis. This results from the appear-

ance of certain chemical substances in the tissues.

Movement of cell

Any chemical substance that causes chemotaxis to

occur is called a chemotactic substance. Most cells

Endocytosis

that exhibit ameboid locomotion move toward the

source of a chemotactic substance—that is, from an area

of lower concentration toward an area of higher con-

Pseudopodium

centration—which is called positive chemotaxis. Some

cells move away from the source, which is called nega-

tive chemotaxis.

But how does chemotaxis control the direction of

Exocytosis

ameboid locomotion? Although the answer is not

certain, it is known that the side of the cell most exposed

to the chemotactic substance develops membrane

changes that cause pseudopodial protrusion.

Surrounding tissue

Receptor binding

Cilia and Ciliary Movements

Figure 2-16

A second type of cellular motion, ciliary movement, is a

Ameboid motion by a cell.

whiplike movement of cilia on the surfaces of cells. This

Chapter 2

The Cell and Its Functions

The flagellum of a sperm is similar to a cilium; in fact,

Tip

it has much the same type of structure and same type

of contractile mechanism. The flagellum, however, is

much longer and moves in quasi-sinusoidal waves

instead of whiplike movements.

In the inset of Figure 2-17, movement of the cilium is

shown. The cilium moves forward with a sudden, rapid

whiplike stroke 10 to 20 times per second, bending

Membrane

sharply where it projects from the surface of the cell.

Then it moves backward slowly to its initial position.

Cross section

The rapid forward-thrusting, whiplike movement

pushes the fluid lying adjacent to the cell in the direc-

tion that the cilium moves; the slow, dragging movement

Filament

in the backward direction has almost no effect on fluid

movement. As a result, the fluid is continually propelled

in the direction of the fast-forward stroke. Because most

ciliated cells have large numbers of cilia on their sur-

faces and because all the cilia are oriented in the same

direction, this is an effective means for moving fluids

Forward stroke

from one part of the surface to another.

Mechanism of Ciliary Movement. Although not all aspects of

ciliary movement are clear, we do know the following:

Basal plate

First, the nine double tubules and the two single tubules

are all linked to one another by a complex of protein

Cell

cross-linkages; this total complex of tubules and cross-

membrane

linkages is called the axoneme. Second, even after

Backward stroke

removal of the membrane and destruction of other ele-

Basal body

ments of the cilium besides the axoneme, the cilium can

still beat under appropriate conditions. Third, there are

two necessary conditions for continued beating of the

Rootlet

axoneme after removal of the other structures of the

cilium: (1) the availability of ATP and (2) appropriate

ionic conditions, especially appropriate concentrations

of magnesium and calcium. Fourth, during forward

motion of the cilium, the double tubules on the front

edge of the cilium slide outward toward the tip of the

Figure 2-17

cilium, while those on the back edge remain in place.

Fifth, multiple protein arms composed of the protein

Structure and function of the cilium. (Modified from Satir P: Cilia.

dynein, which has ATPase enzymatic activity, project

Sci Am 204:108, 1961. Copyright Donald Garber: Executor of the

from each double tubule toward an adjacent double

estate of Bunji Tagawa.)

tubule.

occurs in only two places in the human body: on the

Given this basic information, it has been determined

sufaces of the respiratory airways and on the inside

that the release of energy from ATP in contact with the

surfaces of the uterine tubes (fallopian tubes) of the

ATPase dynein arms causes the heads of these arms to

reproductive tract. In the nasal cavity and lower respi-

“crawl” rapidly along the surface of the adjacent double

ratory airways, the whiplike motion of cilia causes a

tubule. If the front tubules crawl outward while the back

layer of mucus to move at a rate of about 1 cm/min

tubules remain stationary, this will cause bending.

toward the pharynx, in this way continually clearing

The way in which cilia contraction is controlled is not

these passageways of mucus and particles that have

understood. The cilia of some genetically abnormal cells

become trapped in the mucus. In the uterine tubes, the

do not have the two central single tubules, and these

cilia cause slow movement of fluid from the ostium of

cilia fail to beat. Therefore, it is presumed that some

the uterine tube toward the uterus cavity; this move-

signal, perhaps an electrochemical signal, is transmitted

ment of fluid transports the ovum from the ovary to the

along these two central tubules to activate the dynein

uterus.

arms.

As shown in Figure 2-17, a cilium has the appearance

of a sharp-pointed straight or curved hair that projects

2 to 4 micrometers from the surface of the cell. Many

References

cilia often project from a single cell—for instance, as

many as 200 cilia on the surface of each epithelial cell

Alberts B, Johnson A, Lewis J, et al: Molecular Biology of

inside the respiratory passageways. The cilium is

the Cell. New York: Garland Science, 2002.

covered by an outcropping of the cell membrane, and it

Bonifacino JS, Glick BS: The mechanisms of vesicle budding

is supported by

11 microtubules—9 double tubules

and fusion. Cell 116:153, 2004.

located around the periphery of the cilium, and 2 single

Calakos N, Scheller RH: Synaptic vesicle biogenesis,

tubules down the center, as demonstrated in the cross

docking, and fusion: a molecular description. Physiol Rev

section shown in Figure 2-17. Each cilium is an out-

76:1, 1996.

growth of a structure that lies immediately beneath the

Danial NN, Korsmeyer SJ: Cell death: critical control points.

cell membrane, called the basal body of the cilium.

Cell 116:205, 2004.

Unit I Introduction to Physiology: The Cell and General Physiology

Deutsch C: The birth of a channel. Neuron 40:265, 2003.

Maxfield FR, McGraw TE: Endocytic recycling. Nat Rev

Dröge W: Free radicals in the physiological control of cell

Mol Cell Biol 5:121, 2004.

function. Physiol Rev 82:47, 2002.

Mazzanti M, Bustamante JO, Oberleithner H: Electrical

Duchen MR: Roles of mitochondria in health and disease.

dimension of the nuclear envelope. Physiol Rev 81:1, 2001.

Diabetes 53(Suppl 1):S96, 2004.

Perrios M: Nuclear Structure and Function. San Diego: Aca-

Edidin M: Lipids on the frontier: a century of cell-membrane

demic Press, 1998.

bilayers. Nat Rev Mol Cell Biol 4:414, 2003.

Ridley AJ, Schwartz MA, Burridge K, et al: Cell migration:

Gerbi SA, Borovjagin AV, Lange TS: The nucleolus: a site of

integrating signals from front to back. Science 302:1704,

ribonucleoprotein maturation. Curr Opin Cell Biol 15:318,

2003.

Scholey JM: Intraflagellar transport. Annu Rev Cell Dev

Hamill OP, Martinac B: Molecular basis of mechanotrans-

Biol 19:423, 2003.

duction in living cells. Physiol Rev 81:685, 2001.

Schwab A: Function and spatial distribution of ion channels

Lange K: Role of microvillar cell surfaces in the regulation

and transporters in cell migration. Am J Physiol Renal

of glucose uptake and organization of energy metabolism.

Physiol 280:F739, 2001.

Am J Physiol Cell Physiol 282:C1, 2002.

Vereb G, Szollosi J, Matko J, et al: Dynamic, yet structured:

Mattaj IW: Sorting out the nuclear envelope from the

the cell membrane three decades after the Singer-

endoplasmic reticulum. Nat Rev Mol Cell Biol

5:65,

Nicolson model. Proc Natl Acad Sci U S A 100:8053,

2004.

2003.

C H A P T E R

Genetic Control of Protein

Synthesis, Cell Function,

and Cell Reproduction

Virtually everyone knows that the genes, located in

the nuclei of all cells of the body, control heredity

from parents to children, but most people do not

realize that these same genes also control day-to-

day function of all the body’s cells. The genes

control cell function by determining which sub-

stances are synthesized within the cell—which struc-

tures, which enzymes, which chemicals.

Figure 3-1 shows the general schema of genetic control. Each gene, which is

a nucleic acid called deoxyribonucleic acid (DNA), automatically controls the

formation of another nucleic acid, ribonucleic acid (RNA); this RNA then

spreads throughout the cell to control the formation of a specific protein.

Because there are more than 30,000 different genes in each cell, it is theoreti-

cally possible to form a very large number of different cellular proteins.

Some of the cellular proteins are structural proteins, which, in association with

various lipids and carbohydrates, form the structures of the various intracellu-

lar organelles discussed in Chapter 2. However, by far the majority of the pro-

teins are enzymes that catalyze the different chemical reactions in the cells. For

instance, enzymes promote all the oxidative reactions that supply energy to the

cell, and they promote synthesis of all the cell chemicals, such as lipids, glyco-

gen, and adenosine triphosphate (ATP).

Genes in the Cell Nucleus

In the cell nucleus, large numbers of genes are attached end on end in extremely

long double-stranded helical molecules of DNA having molecular weights

measured in the billions. A very short segment of such a molecule is shown in

Figure 3-2. This molecule is composed of several simple chemical compounds

bound together in a regular pattern, details of which are explained in the next

few paragraphs.

Basic Building Blocks of DNA. Figure 3-3 shows the basic chemical compounds

involved in the formation of DNA. These include (1) phosphoric acid, (2) a

sugar called deoxyribose, and (3) four nitrogenous bases (two purines, adenine

and guanine, and two pyrimidines, thymine and cytosine). The phosphoric acid

and deoxyribose form the two helical strands that are the backbone of the DNA

molecule, and the nitrogenous bases lie between the two strands and connect

them, as illustrated in Figure 3-6.

Nucleotides. The first stage in the formation of DNA is to combine one mole-

cule of phosphoric acid, one molecule of deoxyribose, and one of the four bases

to form an acidic nucleotide. Four separate nucleotides are thus formed, one for

each of the four bases: deoxyadenylic, deoxythymidylic, deoxyguanylic, and

deoxycytidylic acids. Figure 3-4 shows the chemical structure of deoxyadenylic

acid, and Figure 3-5 shows simple symbols for the four nucleotides that form

DNA.

Organization of the Nucleotides to Form Two Strands of DNA Loosely Bound to Each Other.

Figure 3-6 shows the manner in which multiple numbers of nucleotides are

Chapter 3

Genetic Control of Protein Synthesis, Cell Function, and Cell Reproduction

Adenine

Phosphate

Deoxyadenylic acid

Deoxythymidylic acid

Deoxyribose

Deoxyguanylic acid

Deoxycytidylic acid

Figure 3-4

Deoxyadenylic acid, one of the nucleotides that make up DNA.

Figure 3-5

Symbols for the four nucleotides that combine to form DNA.

Each nucleotide contains phosphoric acid (P), deoxyribose (D),

and one of the four nucleotide bases: A, adenine; T, thymine;

G, guanine; or C, cytosine.

D P

Figure 3-6

Arrangement of deoxyribose nucleotides

in a double strand of DNA.

bound together to form two strands of DNA. The two

so many times during the course of their function in

strands are, in turn, loosely bonded with each other by

the cell.

weak cross-linkages, illustrated in Figure 3-6 by the

To put the DNA of Figure 3-6 into its proper phys-

central dashed lines. Note that the backbone of each

ical perspective, one could merely pick up the two ends

DNA strand is comprised of alternating phosphoric

and twist them into a helix. Ten pairs of nucleotides

acid and deoxyribose molecules. In turn, purine and

are present in each full turn of the helix in the DNA

pyrimidine bases are attached to the sides of the

molecule, as shown in Figure 3-2.

deoxyribose molecules. Then, by means of loose

hydrogen bonds (dashed lines) between the purine

and pyrimidine bases, the two respective DNA strands

are held together. But note the following:

Genetic Code

1. Each purine base adenine of one strand always

bonds with a pyrimidine base thymine of the other

The importance of DNA lies in its ability to control

strand, and

the formation of proteins in the cell. It does this by

2. Each purine base guanine always bonds with a

means of the so-called genetic code. That is, when the

pyrimidine base cytosine.

two strands of a DNA molecule are split apart, this

Thus, in Figure 3-6, the sequence of complementary

exposes the purine and pyrimidine bases projecting to

pairs of bases is CG, CG, GC, TA, CG, TA, GC, AT, and

the side of each DNA strand, as shown by the top

AT. Because of the looseness of the hydrogen bonds,

strand in Figure 3-7. It is these projecting bases that

the two strands can pull apart with ease, and they do

form the genetic code.

Unit I Introduction to Physiology: The Cell and General Physiology

DNA strand

Figure 3-7

P R

Triphosphate

RNA molecule

Combination of ribose nucleotides

with a strand of DNA to form a

molecule of RNA that carries the

genetic code from the gene to the

RNA polymerase

cytoplasm. The RNA polymerase

enzyme moves along the DNA

strand and builds the RNA molecule.

Figure 3-8

P R

Portion of an RNA molecule, showing three RNA

“codons”—CCG, UCU, and GAA—which control

Proline

Serine

Glutamic acid

attachment of the three amino acids proline,

serine, and glutamic acid, respectively, to the

growing RNA chain.

The genetic code consists of successive “triplets” of

The RNA, in turn, diffuses from the nucleus through

bases—that is, each three successive bases is a code

nuclear pores into the cytoplasmic compartment,

word. The successive triplets eventually control the

where it controls protein synthesis.

sequence of amino acids in a protein molecule that is

to be synthesized in the cell. Note in Figure 3-6 that

the top strand of DNA, reading from left to right, has

Synthesis of RNA

the genetic code GGC, AGA, CTT, the triplets being

separated from one another by the arrows. As we

During synthesis of RNA, the two strands of the DNA

follow this genetic code through Figures 3-7 and 3-8,

molecule separate temporarily; one of these strands is

we see that these three respective triplets are respon-

used as a template for synthesis of an RNA molecule.

sible for successive placement of the three amino

The code triplets in the DNA cause formation of com-

acids, proline, serine, and glutamic acid, in a newly

plementary code triplets (called codons) in the RNA;

formed molecule of protein.

these codons, in turn, will control the sequence of

amino acids in a protein to be synthesized in the cell

cytoplasm.

The DNA Code in the Cell

Basic Building Blocks of RNA. The basic building blocks of

Nucleus Is Transferred to

RNA are almost the same as those of DNA, except for

an RNA Code in the Cell

two differences. First, the sugar deoxyribose is not used

Cytoplasm—The Process

in the formation of RNA. In its place is another sugar

of Transcription

of slightly different composition, ribose, containing an

extra hydroxyl ion appended to the ribose ring struc-

Because the DNA is located in the nucleus of the cell,

ture. Second, thymine is replaced by another pyrimi-

yet most of the functions of the cell are carried out in

dine, uracil.

the cytoplasm, there must be some means for the DNA

genes of the nucleus to control the chemical reactions

Formation of RNA Nucleotides. The basic building blocks

of the cytoplasm. This is achieved through the inter-

of RNA form RNA nucleotides, exactly as previously

mediary of another type of nucleic acid, RNA, the for-

described for DNA synthesis. Here again, four sepa-

mation of which is controlled by the DNA of the

rate nucleotides are used in the formation of RNA.

nucleus. Thus, as shown in Figure 3-7, the code is trans-

These nucleotides contain the bases adenine, guanine,

ferred to the RNA; this process is called transcription.

cytosine, and uracil. Note that these are the same bases

Chapter 3

Genetic Control of Protein Synthesis, Cell Function, and Cell Reproduction

as in DNA, except that uracil in RNA replaces

c. When the RNA polymerase reaches the

thymine in DNA.

end of the DNA gene, it encounters a new

sequence of DNA nucleotides called the

chain-terminating sequence; this causes the

“Activation” of the RNA Nucleotides. The next step in

polymerase and the newly formed RNA chain

the synthesis of RNA is “activation” of the RNA

to break away from the DNA strand. Then the

nucleotides by an enzyme, RNA polymerase. This

polymerase can be used again and again to

occurs by adding to each nucleotide two extra phos-

form still more new RNA chains.

phate radicals to form triphosphates (shown in Figure

d. As the new RNA strand is formed, its weak

3-7 by the two RNA nucleotides to the far right during

hydrogen bonds with the DNA template break

RNA chain formation). These last two phosphates are

away, because the DNA has a high affinity for

combined with the nucleotide by high-energy phos-

rebonding with its own complementary DNA

phate bonds derived from ATP in the cell.

strand. Thus, the RNA chain is forced away

The result of this activation process is that

from the DNA and is released into the

large quantities of ATP energy are made available to

nucleoplasm.

each of the nucleotides, and this energy is used to

Thus, the code that is present in the DNA strand is

promote the chemical reactions that add each new

eventually transmitted in complementary form to the

RNA nucleotide at the end of the developing RNA

RNA chain. The ribose nucleotide bases always

chain.

combine with the deoxyribose bases in the following

combinations:

Assembly of the RNA Chain from

Activated Nucleotides Using the DNA

DNA Base

RNA Base

Strand as a Template—The Process

of “Transcription”

guanine

cytosine

guanine

adenine

uracil

Assembly of the RNA molecule is accomplished in

thymine

adenine

the manner shown in Figure 3-7 under the influence

of an enzyme, RNA polymerase. This is a large protein

enzyme that has many functional properties necessary

Three Different Types of RNA. There are three different

for formation of the RNA molecule. They are as

types of RNA, each of which plays an independent and

follows:

entirely different role in protein formation:

In the DNA strand immediately ahead of the

1. Messenger RNA, which carries the genetic code to

initial gene is a sequence of nucleotides called

the cytoplasm for controlling the type of protein

the promoter. The RNA polymerase has an

formed.

appropriate complementary structure that

2. Transfer RNA, which transports activated amino

recognizes this promoter and becomes attached to

acids to the ribosomes to be used in assembling

it. This is the essential step for initiating formation

the protein molecule.

of the RNA molecule.

3. Ribosomal RNA, which, along with about 75

After the RNA polymerase attaches to the

different proteins, forms ribosomes, the physical

promoter, the polymerase causes unwinding of

and chemical structures on which protein

about two turns of the DNA helix and separation

molecules are actually assembled.

of the unwound portions of the two strands.

Then the polymerase moves along the DNA

strand, temporarily unwinding and separating the

two DNA strands at each stage of its movement.

Messenger RNA—The Codons

As it moves along, it adds at each stage a new

activated RNA nucleotide to the end of the newly

Messenger RNA molecules are long, single RNA

forming RNA chain by the following steps:

strands that are suspended in the cytoplasm. These

a. First, it causes a hydrogen bond to form

molecules are composed of several hundred to several

between the end base of the DNA strand and

thousand RNA nucleotides in unpaired strands, and

the base of an RNA nucleotide in the

they contain codons that are exactly complementary

nucleoplasm.

to the code triplets of the DNA genes. Figure 3-8

b. Then, one at a time, the RNA polymerase

shows a small segment of a molecule of messenger

breaks two of the three phosphate radicals

RNA. Its codons are CCG, UCU, and GAA. These are

away from each of these RNA nucleotides,

the codons for the amino acids proline, serine, and glu-

liberating large amounts of energy from the

tamic acid. The transcription of these codons from the

broken high-energy phosphate bonds; this

DNA molecule to the RNA molecule is shown in

energy is used to cause covalent linkage of the

Figure 3-7.

remaining phosphate on the nucleotide with

the ribose on the end of the growing RNA

RNA Codons for the Different Amino Acids. Table 3-1 gives

chain.

the RNA codons for the 20 common amino acids

Unit I Introduction to Physiology: The Cell and General Physiology

found in protein molecules. Note that most of the

Table 3-1

amino acids are represented by more than one codon;

RNA Codons for Amino Acids and for Start and Stop

also, one codon represents the signal “start manufac-

turing the protein molecule,” and three codons repre-

sent “stop manufacturing the protein molecule.” In

Amino Acid

RNA

Codons

Table 3-1, these two types of codons are designated CI

Alanine

GCU GCC GCA GCG

for “chain-initiating” and CT for “chain-terminating.”

Arginine

CGU CGC CGA CGG AGA

AGG

Asparagine

AAU AAC

Aspartic acid

GAU GAC

Cysteine

UGU UGC

Transfer RNA—The Anticodons

Glutamic acid GAA GAG

Glutamine

CAA CAG

Another type of RNA that plays an essential role in

Glycine

GGU GGC GGA GGG

protein synthesis is called transfer RNA, because it

Histidine

CAU CAC

Isoleucine

AUU AUC AUA

transfers amino acid molecules to protein molecules as

Leucine

CUU CUC CUA CUG UUA

UUG

the protein is being synthesized. Each type of transfer

Lysine

AAA AAG

RNA combines specifically with 1 of the 20 amino

Methionine

AUG

acids that are to be incorporated into proteins. The

Phenylalanine

UUU UUC

transfer RNA then acts as a carrier to transport its

Proline

CCU CCC CCA CCG

Serine

UCU UCC UCA UCG AGC

AGU

specific type of amino acid to the ribosomes, where

Threonine

ACU ACC ACA ACG

protein molecules are forming. In the ribosomes, each

Tryptophan

UGG

specific type of transfer RNA recognizes a particular

Tyrosine

UAU UAC

codon on the messenger RNA (described later) and

Valine

GUU GUC GUA GUG

Start (CI)

AUG

thereby delivers the appropriate amino acid to the

Stop (CT)

UAA UAG UGA

appropriate place in the chain of the newly forming

protein molecule.

CI, chain-initiating; CT, chain-terminating.

Transfer RNA, which contains only about

nucleotides, is a relatively small molecule in com-

parison with messenger RNA. It is a folded chain of

nucleotides with a cloverleaf appearance similar to

that shown in Figure 3-9. At one end of the molecule

messenger RNA. The specific code in the transfer

is always an adenylic acid; it is to this that the trans-

RNA that allows it to recognize a specific codon is

ported amino acid attaches at a hydroxyl group of the

again a triplet of nucleotide bases and is called an anti-

ribose in the adenylic acid.

codon. This is located approximately in the middle

Because the function of transfer RNA is to cause

of the transfer RNA molecule (at the bottom of the

attachment of a specific amino acid to a forming

cloverleaf configuration shown in Figure 3-9). During

protein chain, it is essential that each type of transfer

formation of the protein molecule, the anticodon bases

RNA also have specificity for a particular codon in the

combine loosely by hydrogen bonding with the codon

Alanine

Cysteine

Forming protein

Histidine

Alanine

Phenylalanine

Serine

Transfer RNA

Proline

Start codon

GGG

Figure 3-9

AUG

GCC

UGU

CAU

GCC

UUU

UCC

CCC

AAA

CAG

GAC

UAU

A messenger RNA strand is moving through two

ribosomes. As each “codon” passes through,

Messenger

Ribosome

an amino acid is added to the growing protein

RNA movement

chain, which is shown in the right-hand ribo-

some. The transfer RNA molecule transports

each specific amino acid to the newly forming

protein.

Chapter 3

Genetic Control of Protein Synthesis, Cell Function, and Cell Reproduction

bases of the messenger RNA. In this way, the respec-

bases called the “chain-initiating” codon. Then, as

tive amino acids are lined up one after another along

shown in Figure 3-9, while the messenger RNA travels

the messenger RNA chain, thus establishing the

through the ribosome, a protein molecule is formed—

appropriate sequence of amino acids in the newly

a process called translation. Thus, the ribosome reads

forming protein molecule.

the codons of the messenger RNA in much the same

way that a tape is “read” as it passes through the play-

back head of a tape recorder. Then, when a “stop” (or

Ribosomal RNA

“chain-terminating”) codon slips past the ribosome,

the end of a protein molecule is signaled and the

The third type of RNA in the cell is ribosomal RNA;

protein molecule is freed into the cytoplasm.

it constitutes about 60 per cent of the ribosome. The

remainder of the ribosome is protein, containing about

Polyribosomes. A single messenger RNA molecule can

75 types of proteins that are both structural proteins

form protein molecules in several ribosomes at the

and enzymes needed in the manufacture of protein

same time because the initial end of the RNA strand

molecules.

can pass to a successive ribosome as it leaves the first,

The ribosome is the physical structure in the cyto-

as shown at the bottom left in Figure 3-9 and in Figure

plasm on which protein molecules are actually syn-

3-10. The protein molecules are in different stages of

thesized. However, it always functions in association

development in each ribosome. As a result, clusters of

with the other two types of RNA as well: transfer RNA

ribosomes frequently occur, 3 to 10 ribosomes being

transports amino acids to the ribosome for incorpora-

attached to a single messenger RNA at the same time.

tion into the developing protein molecule, whereas

These clusters are called polyribosomes.

messenger RNA provides the information necessary

It is especially important to note that a messenger

for sequencing the amino acids in proper order for

RNA can cause the formation of a protein molecule

each specific type of protein to be manufactured.

in any ribosome; that is, there is no specificity of ribo-

Thus, the ribosome acts as a manufacturing plant in

somes for given types of protein. The ribosome is

which the protein molecules are formed.

simply the physical manufacturing plant in which the

chemical reactions take place.

Formation of Ribosomes in the Nucleolus. The DNA genes

Many Ribosomes Attach to the Endoplasmic Reticulum. In

for formation of ribosomal RNA are located in five

Chapter 2, it was noted that many ribosomes become

pairs of chromosomes in the nucleus, and each of these

attached to the endoplasmic reticulum. This occurs

chromosomes contains many duplicates of these par-

because the initial ends of many forming protein mol-

ticular genes because of the large amounts of riboso-

ecules have amino acid sequences that immediately

mal RNA required for cellular function.

attach to specific receptor sites on the endoplasmic

As the ribosomal RNA forms, it collects in the

reticulum; this causes these molecules to penetrate the

nucleolus, a specialized structure lying adjacent to the

reticulum wall and enter the endoplasmic reticulum

chromosomes. When large amounts of ribosomal RNA

matrix. This gives a granular appearance to those por-

are being synthesized, as occurs in cells that manufac-

tions of the reticulum where proteins are being formed

ture large amounts of protein, the nucleolus is a large

and entering the matrix of the reticulum.

structure, whereas in cells that synthesize little protein,

Figure 3-10 shows the functional relation of mes-

the nucleolus may not even be seen. Ribosomal RNA

senger RNA to the ribosomes and the manner in

is specially processed in the nucleolus, where it binds

which the ribosomes attach to the membrane of the

with “ribosomal proteins” to form granular condensa-

endoplasmic reticulum. Note the process of translation

tion products that are primordial subunits of ribo-

occurring in several ribosomes at the same time in

somes. These subunits are then released from the

response to the same strand of messenger RNA. Note

nucleolus and transported through the large pores of

also the newly forming polypeptide (protein) chains

the nuclear envelope to almost all parts of the cyto-

passing through the endoplasmic reticulum membrane

plasm. After the subunits enter the cytoplasm, they

into the endoplasmic matrix.

are assembled to form mature, functional ribosomes.

Yet it should be noted that except in glandular cells

Therefore, proteins are formed in the cytoplasm of the

in which large amounts of protein-containing secre-

cell, but not in the cell nucleus, because the nucleus

tory vesicles are formed, most proteins synthesized by

does not contain mature ribosomes.

the ribosomes are released directly into the cytosol

instead of into the endoplasmic reticulum. These pro-

teins are enzymes and internal structural proteins of

Formation of Proteins on

the cell.

the Ribosomes—The Process

of “Translation”

Chemical Steps in Protein Synthesis. Some of the chemical

events that occur in synthesis of a protein molecule are

When a molecule of messenger RNA comes in contact

shown in Figure 3-11. This figure shows representative

with a ribosome, it travels through the ribosome,

reactions for three separate amino acids, AA₁, AA₂,

beginning at a predetermined end of the RNA mole-

and AA₂₀. The stages of the reactions are the follow-

cule specified by an appropriate sequence of RNA

ing: (1) Each amino acid is activated by a chemical

Unit I Introduction to Physiology: The Cell and General Physiology

Messenger

Small

Ribosome

Transfer RNA

RNA

subunit

Figure 3-10

Physical structure of the ribosomes,

as well as their functional relation to

messenger RNA, transfer RNA, and

the endoplasmic reticulum during

Large

the formation of protein molecules.

Amino acid

Polypeptide

subunit

(Courtesy of Dr. Don W. Fawcett,

chain

Montana.)

Amino acid

AA₁

AA₂

AA₂₀

ATP

Activated amino acid

AMP

AA₁

AMP

AA₂

AMP

AA₂₀

tRNA₁

tRNA₂

tRNA₂₀

RNA-amino acyl complex

tRNA₁

AA₁

tRNA₂

AA₂

tRNA₂₀

AA₂₀

Messenger RNA

GCC

UGU

AAU

CAU

CGU

AUG

GUU

GCC

UGU

AAU

CAU

CGU

AUG

GUU

Complex between tRNA,

messenger RNA, and

amino acid

GTP

Protein chain

AA₁

AA₅

AA₃

AA₉

AA₂

AA₁₃

AA₂₀

Figure 3-11

Chemical events in the formation of

a protein molecule.

process in which ATP combines with the amino acid

energy from two additional high-energy phosphate

to form an adenosine monophosphate complex with the

bonds, making a total of four high-energy bonds used

amino acid, giving up two high-energy phosphate

for each amino acid added to the protein chain. Thus,

bonds in the process. (2) The activated amino acid,

the synthesis of proteins is one of the most energy-con-

having an excess of energy, then combines with its

suming processes of the cell.

specific transfer RNA to form an amino acid-tRNA

complex and, at the same time, releases the adenosine

Peptide Linkage. The successive amino acids in the

monophosphate. (3) The transfer RNA carrying the

protein chain combine with one another according to

amino acid complex then comes in contact with the

the typical reaction:

messenger RNA molecule in the ribosome, where

the anticodon of the transfer RNA attaches tem-

porarily to its specific codon of the messenger RNA,

NH₂

thus lining up the amino acid in appropriate sequence

to form a protein molecule. Then, under the influence

R C C OH + H N C COOH

of the enzyme peptidyl transferase (one of the proteins

in the ribosome), peptide bonds are formed between

NH₂

the successive amino acids, thus adding progressively

N C COOH +

H₂O

to the protein chain. These chemical events require

Chapter 3

Genetic Control of Protein Synthesis, Cell Function, and Cell Reproduction

In this chemical reaction, a hydroxyl radical (OH^-)

There are basically two methods by which the bio-

is removed from the COOH portion of the first amino

chemical activities in the cell are controlled. One of

acid, and a hydrogen (H⁺) of the NH₂ portion of the

these is genetic regulation, in which the degree of acti-

other amino acid is removed. These combine to form

vation of the genes themselves is controlled, and the

water, and the two reactive sites left on the two suc-

other is enzyme regulation, in which the activity levels

cessive amino acids bond with each other, resulting

of already formed enzymes in the cell are controlled.

in a single molecule. This process is called peptide

linkage. As each additional amino acid is added, an

additional peptide linkage is formed.

Genetic Regulation

The “Operon” of the Cell and Its Control of Biochemical Syn-

Synthesis of Other

thesis—Function of the Promoter. Synthesis of a cellular

Substances in the Cell

biochemical product usually requires a series of reac-

tions, and each of these reactions is catalyzed by a

Many thousand protein enzymes formed in the

special protein enzyme. Formation of all the enzymes

manner just described control essentially all the other

needed for the synthetic process often is controlled by

chemical reactions that take place in cells. These

a sequence of genes located one after the other on

enzymes promote synthesis of lipids, glycogen, purines,

the same chromosomal DNA strand. This area of the

pyrimidines, and hundreds of other substances. We

DNA strand is called an operon, and the genes respon-

discuss many of these synthetic processes in relation

sible for forming the respective enzymes are called

to carbohydrate, lipid, and protein metabolism in

structural genes. In Figure

3-12, three respective

Chapters 67 through 69. It is by means of all these

structural genes are shown in an operon, and it is

substances that the many functions of the cells are

demonstrated that they control the formation of three

performed.

respective enzymes that in turn cause synthesis of a

specific intracellular product.

Note in the figure the segment on the DNA strand

Control of Gene Function and

called the promoter. This is a group of nucleotides that

Biochemical Activity in Cells

has specific affinity for RNA polymerase, as already

discussed. The polymerase must bind with this pro-

From our discussion thus far, it is clear that the genes

moter before it can begin traveling along the DNA

control both the physical and the chemical functions

strand to synthesize RNA. Therefore, the promoter is

of the cells. However, the degree of activation of

an essential element for activating the operon.

respective genes must be controlled as well; otherwise,

some parts of the cell might overgrow or some chem-

Control of the Operon by a

“Repressor Protein”—The

ical reactions might overact until they kill the cell.

“Repressor Operator.” Also note in Figure 3-12 an addi-

Each cell has powerful internal feedback control

tional band of nucleotides lying in the middle of the

mechanisms that keep the various functional opera-

promoter. This area is called a repressor operator

tions of the cell in step with one another. For each gene

because a “regulatory” protein can bind here and

(more than 30,000 genes in all), there is at least one

prevent attachment of RNA polymerase to the pro-

such feedback mechanism.

moter, thereby blocking transcription of the genes of

Activator

Repressor

operator

Operon

Structural

Promoter

Gene A

Gene B

Gene C

Enzyme A Enzyme B Enzyme C

Inhibition of

the operator

Figure 3-12

Substrates

Synthesized

Function of an operon to control synthesis of a non

product

protein intracellular product, such as an intra-

(Negative feedback)

cellular metabolic chemical. Note that the synthe-

sized product exerts negative feedback to inhibit

the function of the operon, in this way automatically

controlling the concentration of the product itself.

Unit I Introduction to Physiology: The Cell and General Physiology

this operon. Such a negative regulatory protein is

by still other proteins. As long as the DNA is in

called a repressor protein.

this compacted state, it cannot function to form

RNA. However, multiple control mechanisms are

Control of the Operon by an “Activator Protein”—The “Activa-

beginning to be discovered that can cause selected

tor Operator.” Note in Figure 3-12 another operator,

areas of chromosomes to become decompacted

called the activator operator, that lies adjacent to but

one part at a time so that partial RNA

ahead of the promoter. When a regulatory protein

transcription can occur. Even then, some specific

binds to this operator, it helps attract the RNA po-

“transcriptor factor” controls the actual rate of

lymerase to the promoter, in this way activating the

transcription by the separate operon in the

operon. Therefore, a regulatory protein of this type is

chromosome. Thus, still higher orders of control

called an activator protein.

are used for establishing proper cell function. In

addition, signals from outside the cell, such as

Negative Feedback Control of the Operon. Finally, note in

some of the body’s hormones, can activate specific

Figure 3-12 that the presence of a critical amount

chromosomal areas and specific transcription

of a synthesized product in the cell can cause negative

factors, thus controlling the chemical machinery

feedback inhibition of the operon that is responsible

for function of the cell.

for its synthesis. It can do this either by causing a

Because there are more than 30,000 different genes

regulatory repressor protein to bind at the repressor

in each human cell, the large number of ways in which

operator or by causing a regulatory activator protein

genetic activity can be controlled is not surprising. The

to break its bond with the activator operator. In either

gene control systems are especially important for con-

case, the operon becomes inhibited. Therefore, once

trolling intracellular concentrations of amino acids,

the required synthesized product has become abun-

amino acid derivatives, and intermediate substrates

dant enough for proper cell function, the operon

and products of carbohydrate, lipid, and protein

becomes dormant. Conversely, when the synthesized

metabolism.

product becomes degraded in the cell and its concen-

tration decreases, the operon once again becomes

Control of Intracellular Function

active. In this way, the desired concentration of the

by Enzyme Regulation

product is controlled automatically.

In addition to control of cell function by genetic

Other Mechanisms for Control of Transcription by the Operon.

regulation, some cell activities are controlled by intra-

Variations in the basic mechanism for control of the

cellular inhibitors or activators that act directly on spe-

operon have been discovered with rapidity in the past

cific intracellular enzymes. Thus, enzyme regulation

2 decades. Without giving details, let us list some of

represents a second category of mechanisms by which

them:

cellular biochemical functions can be controlled.

1. An operon frequently is controlled by a

regulatory gene located elsewhere in the genetic

Enzyme Inhibition. Some chemical substances formed in

complex of the nucleus. That is, the regulatory

the cell have direct feedback effects in inhibiting the

gene causes the formation of a regulatory protein

specific enzyme systems that synthesize them. Almost

that in turn acts either as an activator or as a

always the synthesized product acts on the first

repressor substance to control the operon.

enzyme in a sequence, rather than on the subsequent

2. Occasionally, many different operons are

enzymes, usually binding directly with the enzyme and

controlled at the same time by the same

causing an allosteric conformational change that inac-

regulatory protein. In some instances, the same

tivates it. One can readily recognize the importance of

regulatory protein functions as an activator

inactivating the first enzyme: this prevents buildup of

for one operon and as a repressor for another

intermediary products that are not used.

operon. When multiple operons are controlled

Enzyme inhibition is another example of negative

simultaneously in this manner, all the operons

feedback control; it is responsible for controlling

that function together are called a regulon.

intracellular concentrations of multiple amino acids,

3. Some operons are controlled not at the starting

purines, pyrimidines, vitamins, and other substances.

point of transcription on the DNA strand but

farther along the strand. Sometimes the control is

not even at the DNA strand itself but during the

Enzyme Activation. Enzymes that are normally inactive

processing of the RNA molecules in the nucleus

often can be activated when needed. An example of

before they are released into the cytoplasm;

this occurs when most of the ATP has been depleted

rarely, control might occur at the level of protein

in a cell. In this case, a considerable amount of cyclic

formation in the cytoplasm during RNA

adenosine monophosphate

(cAMP) begins to be

translation by the ribosomes.

formed as a breakdown product of the ATP; the pres-

4. In nucleated cells, the nuclear DNA is packaged

ence of this cAMP, in turn, immediately activates the

in specific structural units, the chromosomes.

glycogen-splitting enzyme phosphorylase, liberating

Within each chromosome, the DNA is wound

glucose molecules that are rapidly metabolized and

around small proteins called histones, which in

their energy used for replenishment of the ATP stores.

turn are held tightly together in a compacted state

Thus, cAMP acts as an enzyme activator for the

Chapter 3

Genetic Control of Protein Synthesis, Cell Function, and Cell Reproduction

enzyme phosphorylase and thereby helps control

Centromere

Chromosome

intracellular ATP concentration.

Nuclear

Another interesting instance of both enzyme inhi-

membrane

bition and enzyme activation occurs in the formation

of the purines and pyrimidines. These substances are

Nucleolus

needed by the cell in approximately equal quantities

for formation of DNA and RNA. When purines are

Centriole

formed, they inhibit the enzymes that are required for

Aster

formation of additional purines. However, they acti-

vate the enzymes for formation of pyrimidines. Con-

versely, the pyrimidines inhibit their own enzymes but

activate the purine enzymes. In this way, there is con-

tinual cross-feed between the synthesizing systems

for these two substances, resulting in almost exactly

equal amounts of the two substances in the cells at all

times.

Summary. In summary, there are two principal methods

by which cells control proper proportions and proper

quantities of different cellular constituents: (1) the

mechanism of genetic regulation and (2) the mecha-

nism of enzyme regulation. The genes can be either

activated or inhibited, and likewise, the enzyme

systems can be either activated or inhibited. These reg-

ulatory mechanisms most often function as feedback

control systems that continually monitor the cell’s

biochemical composition and make corrections as

needed. But on occasion, substances from without the

cell

(especially some of the hormones discussed

throughout this text) also control the intracellular

biochemical reactions by activating or inhibiting one

or more of the intracellular control systems.

Figure 3-13

The DNA-Genetic System Also

Stages of cell reproduction.

and

C, Prophase.

Prometaphase. E, Metaphase. F, Anaphase. G and H, Telophase.

Controls Cell Reproduction

(From Margaret C. Gladbach, Estate of Mary E. and Dan Todd,

Kansas.)

Cell reproduction is another example of the ubiqui-

tous role that the DNA-genetic system plays in all life

processes. The genes and their regulatory mechanisms

determine the growth characteristics of the cells and

Except in special conditions of rapid cellular repro-

also when or whether these cells will divide to form

duction, inhibitory factors almost always slow or stop

new cells. In this way, the all-important genetic system

the uninhibited life cycle of the cell. Therefore, differ-

controls each stage in the development of the human

ent cells of the body actually have life cycle periods

being, from the single-cell fertilized ovum to the whole

that vary from as little as 10 hours for highly stimu-

functioning body. Thus, if there is any central theme to

lated bone marrow cells to an entire lifetime of the

life, it is the DNA-genetic system.

human body for most nerve cells.

Life Cycle of the Cell. The life cycle of a cell is the period

from cell reproduction to the next cell reproduction.

Cell Reproduction Begins

When mammalian cells are not inhibited and are repro-

with Replication of DNA

ducing as rapidly as they can, this life cycle may be as

little as 10 to 30 hours. It is terminated by a series of

As is true of almost all other important events in the

distinct physical events called mitosis that cause divi-

cell, reproduction begins in the nucleus itself. The first

sion of the cell into two new daughter cells. The events

step is replication (duplication) of all DNA in the chro-

of mitosis are shown in Figure 3-13 and are described

mosomes. Only after this has occurred can mitosis take

later. The actual stage of mitosis, however, lasts for

place.

only about 30 minutes, so that more than 95 per cent

The DNA begins to be duplicated some 5 to 10

of the life cycle of even rapidly reproducing cells is

hours before mitosis, and this is completed in 4 to 8

represented by the interval between mitosis, called

hours. The net result is two exact replicas of all DNA.

interphase.

These replicas become the DNA in the two new

Unit I Introduction to Physiology: The Cell and General Physiology

daughter cells that will be formed at mitosis. After

abnormal cellular function and sometimes even cell

replication of the DNA, there is another period of 1 to

death. Yet, given that there are 30,000 or more genes

2 hours before mitosis begins abruptly. Even during

in the human genome and that the period from one

this period, preliminary changes are beginning to take

human generation to another is about 30 years, one

place that will lead to the mitotic process.

would expect as many as 10 or many more mutations

in the passage of the genome from parent to child. As

Chemical and Physical Events of DNA Replication. DNA is

a further protection, however, each human genome is

replicated in much the same way that RNA is tran-

represented by two separate sets of chromosomes with

scribed in response to DNA, except for a few impor-

almost identical genes. Therefore, one functional gene

tant differences:

of each pair is almost always available to the child

Both strands of the DNA in each chromosome

despite mutations.

are replicated, not simply one of them.

Both entire strands of the DNA helix are

replicated from end to end, rather than small

Chromosomes and Their Replication

portions of them, as occurs in the transcription of

RNA.

The DNA helixes of the nucleus are packaged in chro-

The principal enzymes for replicating DNA

mosomes. The human cell contains 46 chromosomes

are a complex of multiple enzymes called DNA

arranged in 23 pairs. Most of the genes in the two chro-

polymerase, which is comparable to RNA

mosomes of each pair are identical or almost identical

polymerase. It attaches to and moves along the

to each other, so it is usually stated that the different

DNA template strand while another enzyme,

genes also exist in pairs, although occasionally this is

DNA ligase, causes bonding of successive DNA

not the case.

nucleotides to one another, using high-energy

In addition to DNA in the chromosome, there is a

phosphate bonds to energize these attachments.

large amount of protein in the chromosome, composed

Formation of each new DNA strand occurs

mainly of many small molecules of electropositively

simultaneously in hundreds of segments along

charged histones. The histones are organized into vast

each of the two strands of the helix until the

numbers of small, bobbin-like cores. Small segments of

entire strand is replicated. Then the ends of the

each DNA helix are coiled sequentially around one

subunits are joined together by the DNA ligase

core after another.

enzyme.

The histone cores play an important role in the reg-

Each newly formed strand of DNA remains

ulation of DNA activity because as long as the DNA

attached by loose hydrogen bonding to the

is packaged tightly, it cannot function as a template for

original DNA strand that was used as its template.

either the formation of RNA or the replication of new

Therefore, two DNA helixes are coiled together.

DNA. Further, some of the regulatory proteins have

Because the DNA helixes in each chromosome

been shown to decondense the histone packaging of

are approximately 6 centimeters in length and

the DNA and to allow small segments at a time to form

have millions of helix turns, it would be

RNA.

impossible for the two newly formed DNA helixes

Several nonhistone proteins are also major compo-

to uncoil from each other were it not for some

nents of chromosomes, functioning both as chromoso-

special mechanism. This is achieved by enzymes

mal structural proteins and, in connection with the

that periodically cut each helix along its entire

genetic regulatory machinery, as activators, inhibitors,

length, rotate each segment enough to cause

and enzymes.

separation, and then resplice the helix. Thus, the

Replication of the chromosomes in their entirety

two new helixes become uncoiled.

occurs during the next few minutes after replication of

the DNA helixes has been completed; the new DNA

DNA Repair, DNA “Proofreading,” and “Mutation.” During

helixes collect new protein molecules as needed. The

the hour or so between DNA replication and the

two newly formed chromosomes remain attached to

beginning of mitosis, there is a period of very active

each other (until time for mitosis) at a point called the

repair and “proofreading” of the DNA strands. That is,

centromere located near their center. These duplicated

wherever inappropriate DNA nucleotides have been

but still attached chromosomes are called chromatids.

matched up with the nucleotides of the original tem-

plate strand, special enzymes cut out the defective

areas and replace these with appropriate complemen-

Cell Mitosis

tary nucleotides. This is achieved by the same DNA

polymerases and DNA ligases that are used in repli-

The actual process by which the cell splits into two new

cation. This repair process is referred to as DNA

cells is called mitosis. Once each chromosome has

proofreading.

been replicated to form the two chromatids, in many

Because of repair and proofreading, the transcrip-

cells, mitosis follows automatically within 1 or 2 hours.

tion process rarely makes a mistake. But when a

mistake is made, this is called a mutation. The muta-

Mitotic Apparatus: Function of the Centrioles. One of the

tion causes formation of some abnormal protein in the

first events of mitosis takes place in the cytoplasm,

cell rather than a needed protein, often leading to

occurring during the latter part of interphase in or

Chapter 3

Genetic Control of Protein Synthesis, Cell Function, and Cell Reproduction

around the small structures called centrioles. As shown

chromosomes. One of these sets is pulled toward one

in Figure 3-13, two pairs of centrioles lie close to each

mitotic aster and the other toward the other aster as

other near one pole of the nucleus. (These centrioles,

the two respective poles of the dividing cell are pushed

like the DNA and chromosomes, were also replicated

still farther apart.

during interphase, usually shortly before replication of

the DNA.) Each centriole is a small cylindrical body

Telophase. In telophase (see Figure 3-13G and H), the

about 0.4 micrometer long and about 0.15 micrometer

two sets of daughter chromosomes are pushed com-

in diameter, consisting mainly of nine parallel tubular

pletely apart. Then the mitotic apparatus dissolutes,

structures arranged in the form of a cylinder. The two

and a new nuclear membrane develops around each

centrioles of each pair lie at right angles to each other.

set of chromosomes. This membrane is formed from

Each pair of centrioles, along with attached pericen-

portions of the endoplasmic reticulum that are already

triolar material, is called a centrosome.

present in the cytoplasm. Shortly thereafter, the cell

Shortly before mitosis is to take place, the two pairs

pinches in two, midway between the two nuclei. This is

of centrioles begin to move apart from each other. This

caused by formation of a contractile ring of micro-

is caused by polymerization of protein microtubules

filaments composed of actin and probably myosin (the

growing between the respective centriole pairs and

two contractile proteins of muscle) at the juncture of

actually pushing them apart. At the same time, other

the newly developing cells that pinches them off from

microtubules grow radially away from each of the cen-

each other.

triole pairs, forming a spiny star, called the aster, in

each end of the cell. Some of the spines of the aster

penetrate the nuclear membrane and help separate

Control of Cell Growth and

the two sets of chromatids during mitosis. The complex

Cell Reproduction

of microtubules extending between the two new cen-

triole pairs is called the spindle, and the entire set of

We know that certain cells grow and reproduce all the

microtubules plus the two pairs of centrioles is called

time, such as the blood-forming cells of the bone

the mitotic apparatus.

marrow, the germinal layers of the skin, and the epithe-

lium of the gut. Many other cells, however, such as

Prophase. The first stage of mitosis, called prophase, is

smooth muscle cells, may not reproduce for many

shown in Figure 3-13A, B, and C. While the spindle is

years. A few cells, such as the neurons and most stri-

forming, the chromosomes of the nucleus (which in

ated muscle cells, do not reproduce during the entire

interphase consist of loosely coiled strands) become

life of a person, except during the original period of

condensed into well-defined chromosomes.

fetal life.

In certain tissues, an insufficiency of some types of

Prometaphase. During this stage (see Figure 3-13D),

cells causes these to grow and reproduce rapidly until

the growing microtubular spines of the aster fragment

appropriate numbers of them are again available. For

the nuclear envelope. At the same time, multiple

instance, in some young animals, seven eighths of

microtubules from the aster attach to the chromatids

the liver can be removed surgically, and the cells of

at the centromeres, where the paired chromatids are

the remaining one eighth will grow and divide until the

still bound to each other; the tubules then pull one

liver mass returns almost to normal. The same occurs

chromatid of each pair toward one cellular pole and

for many glandular cells and most cells of the bone

its partner toward the opposite pole.

marrow, subcutaneous tissue, intestinal epithelium,

and almost any other tissue except highly differenti-

Metaphase. During metaphase (see Figure 3-13E), the

ated cells such as nerve and muscle cells.

two asters of the mitotic apparatus are pushed farther

We know little about the mechanisms that maintain

apart. This is believed to occur because the micro-

proper numbers of the different types of cells in

tubular spines from the two asters, where they inter-

the body. However, experiments have shown at least

digitate with each other to form the mitotic spindle,

three ways in which growth can be controlled. First,

actually push each other away. There is reason to

growth often is controlled by growth factors that come

believe that minute contractile protein molecules

from other parts of the body. Some of these circulate

called “motor molecules,” perhaps composed of the

in the blood, but others originate in adjacent tissues.

muscle protein actin, extend between the respective

For instance, the epithelial cells of some glands, such

spines and, using a stepping action as in muscle,

as the pancreas, fail to grow without a growth factor

actively slide the spines in a reverse direction along

from the sublying connective tissue of the gland.

each other. Simultaneously, the chromatids are pulled

Second, most normal cells stop growing when they

tightly by their attached microtubules to the very

have run out of space for growth. This occurs when

center of the cell, lining up to form the equatorial plate

cells are grown in tissue culture; the cells grow until

of the mitotic spindle.

they contact a solid object, and then growth stops.

Third, cells grown in tissue culture often stop growing

Anaphase. During this phase (see Figure 3-13F), the

when minute amounts of their own secretions are

two chromatids of each chromosome are pulled apart

allowed to collect in the culture medium. This, too,

at the centromere. All 46 pairs of chromatids are

could provide a means for negative feedback control

separated, forming two separate sets of 46 daughter

of growth.

Unit I Introduction to Physiology: The Cell and General Physiology

Regulation of Cell Size. Cell size is determined almost

affecting another part, and this part affecting still other

entirely by the amount of functioning DNA in the

parts.

nucleus. If replication of the DNA does not occur, the

Thus, although our understanding of cell differenti-

cell grows to a certain size and thereafter remains at

ation is still hazy, we know many control mechanisms

that size. Conversely, it is possible, by use of the chem-

by which differentiation could occur.

ical colchicine, to prevent formation of the mitotic

spindle and therefore to prevent mitosis, even though

replication of the DNA continues. In this event, the

Apoptosis—Programmed

nucleus contains far greater quantities of DNA than

it normally does, and the cell grows proportionately

Cell Death

larger. It is assumed that this results simply from

increased production of RNA and cell proteins, which

The 100 trillion cells of the body are members of a

in turn cause the cell to grow larger.

highly organized community in which the total number

of cells is regulated not only by controlling the rate of

cell division but also by controlling the rate of cell

Cell Differentiation

death. When cells are no longer needed or become a

threat to the organism, they undergo a suicidal pro-

A special characteristic of cell growth and cell division

grammed cell death, or apoptosis. This process involves

is cell differentiation, which refers to changes in

a specific proteolytic cascade that causes the cell to

physical and functional properties of cells as they pro-

shrink and condense, to disassemble its cytoskeleton,

liferate in the embryo to form the different bodily

and to alter its cell surface so that a neighboring

structures and organs. The description of an especially

phagocytic cell, such as a macrophage, can attach to

interesting experiment that helps explain these pro-

the cell membrane and digest the cell.

cesses follows.

In contrast to programmed death, cells that die as a

When the nucleus from an intestinal mucosal cell of

result of an acute injury usually swell and burst due to

a frog is surgically implanted into a frog ovum from

loss of cell membrane integrity, a process called cell

which the original ovum nucleus was removed, the

necrosis. Necrotic cells may spill their contents, causing

result is often the formation of a normal frog. This

inflammation and injury to neighboring cells. Apopto-

demonstrates that even the intestinal mucosal cell,

sis, however, is an orderly cell death that results in

which is a well-differentiated cell, carries all the

disassembly and phagocytosis of the cell before any

necessary genetic information for development of all

leakage of its contents occurs, and neighboring cells

structures required in the frog’s body.

usually remain healthy.

Therefore, it has become clear that differentiation

Apoptosis is initiated by activation of a family of

results not from loss of genes but from selective

proteases called caspases. These are enzymes that are

repression of different genetic operons. In fact, elec-

synthesized and stored in the cell as inactive procas-

tron micrographs suggest that some segments of DNA

pases. The mechanisms of activation of caspases are

helixes wound around histone cores become so con-

complex, but once activated, the enzymes cleave and

densed that they no longer uncoil to form RNA mol-

activate other procaspases, triggering a cascade that

ecules. One explanation for this is as follows: It has

rapidly breaks down proteins within the cell. The cell

been supposed that the cellular genome begins at a

thus dismantles itself, and its remains are rapidly

certain stage of cell differentiation to produce a regu-

digested by neighboring phagocytic cells.

latory protein that forever after represses a select

A tremendous amount of apoptosis occurs in tissues

group of genes. Therefore, the repressed genes never

that are being remodeled during development. Even

function again. Regardless of the mechanism, mature

in adult humans, billions of cells die each hour in

human cells produce a maximum of about 8000 to

tissues such as the intestine and bone marrow and

10,000 proteins rather than the potential 30,000 or

are replaced by new cells. Programmed cell death,

more if all genes were active.

however, is precisely balanced with the formation

Embryological experiments show that certain cells

of new cells in healthy adults. Otherwise, the body’s

in an embryo control differentiation of adjacent cells.

tissues would shrink or grow excessively. Recent

For instance, the primordial chorda-mesoderm is called

studies suggest that abnormalities of apoptosis may

the primary organizer of the embryo because it forms

play a key role in neurodegenerative diseases such as

a focus around which the rest of the embryo develops.

Alzheimer’s disease, as well as in cancer and auto-

It differentiates into a mesodermal axis that contains

immune disorders. Some drugs that have been used

segmentally arranged somites and, as a result of induc-

successfully for chemotherapy appear to induce apop-

tions in the surrounding tissues, causes formation of

tosis in cancer cells.

essentially all the organs of the body.

Another instance of induction occurs when the

developing eye vesicles come in contact with the ecto-

Cancer

derm of the head and cause the ectoderm to thicken

into a lens plate that folds inward to form the lens of

Cancer is caused in all or almost all instances by muta-

the eye. Therefore, a large share of the embryo devel-

tion or by some other abnormal activation of cellular

ops as a result of such inductions, one part of the body

genes that control cell growth and cell mitosis. The

Chapter 3

Genetic Control of Protein Synthesis, Cell Function, and Cell Reproduction

abnormal genes are called oncogenes. As many as 100

Chemical substances of certain types also have a

different oncogenes have been discovered.

high propensity for causing mutations. It was

Also present in all cells are antioncogenes, which

discovered long ago that various aniline dye

suppress the activation of specific oncogenes. There-

derivatives are likely to cause cancer, so that

fore, loss of or inactivation of antioncogenes can allow

workers in chemical plants producing such

activation of oncogenes that lead to cancer.

substances, if unprotected, have a special

Only a minute fraction of the cells that mutate in the

predisposition to cancer. Chemical substances that

body ever lead to cancer. There are several reasons for

can cause mutation are called carcinogens. The

this. First, most mutated cells have less survival capa-

carcinogens that currently cause the greatest

bility than normal cells and simply die. Second, only

number of deaths are those in cigarette smoke.

a few of the mutated cells that do survive become

They cause about one quarter of all cancer

cancerous, because even most mutated cells still

deaths.

have normal feedback controls that prevent excessive

Physical irritants also can lead to cancer, such as

growth.

continued abrasion of the linings of the intestinal

Third, those cells that are potentially cancerous are

tract by some types of food. The damage to

often, if not usually, destroyed by the body’s immune

the tissues leads to rapid mitotic replacement of

system before they grow into a cancer. This occurs in

the cells. The more rapid the mitosis, the greater

the following way: Most mutated cells form abnormal

the chance for mutation.

proteins within their cell bodies because of their

In many families, there is a strong hereditary

altered genes, and these proteins activate the body’s

tendency to cancer. This results from the fact that

immune system, causing it to form antibodies or sen-

most cancers require not one mutation but two or

sitized lymphocytes that react against the cancerous

more mutations before cancer occurs. In those

cells, destroying them. In support of this is the fact

families that are particularly predisposed to

that in people whose immune systems have been sup-

cancer, it is presumed that one or more cancerous

pressed, such as in those taking immunosuppressant

genes are already mutated in the inherited

drugs after kidney or heart transplantation, the prob-

genome. Therefore, far fewer additional mutations

ability of a cancer’s developing is multiplied as much

must take place in such family members before a

as fivefold.

cancer begins to grow.

Fourth, usually several different activated onco-

In laboratory animals, certain types of viruses can

genes are required simultaneously to cause a cancer.

cause some kinds of cancer, including leukemia.

For instance, one such gene might promote rapid

This usually results in one of two ways. In the case

reproduction of a cell line, but no cancer occurs

of DNA viruses, the DNA strand of the virus can

because there is not a simultaneous mutant gene to

insert itself directly into one of the chromosomes

form the needed blood vessels.

and thereby cause a mutation that leads to

But what is it that causes the altered genes? Con-

cancer. In the case of RNA viruses, some of these

sidering that many trillions of new cells are formed

carry with them an enzyme called reverse

each year in humans, a better question might be, Why

transcriptase that causes DNA to be transcribed

is it that all of us do not develop millions or billions of

from the RNA. The transcribed DNA then inserts

mutant cancerous cells? The answer is the incredible

itself into the animal cell genome, leading to

precision with which DNA chromosomal strands are

cancer.

replicated in each cell before mitosis can take place,

and also the proofreading process that cuts and repairs

Invasive Characteristic of the Cancer Cell. The major dif-

any abnormal DNA strand before the mitotic process

ferences between the cancer cell and the normal cell

is allowed to proceed. Yet, despite all these inherited

are the following: (1) The cancer cell does not respect

cellular precautions, probably one newly formed cell

usual cellular growth limits; the reason for this is that

in every few million still has significant mutant

these cells presumably do not require all the same

characteristics.

growth factors that are necessary to cause growth of

Thus, chance alone is all that is required for muta-

normal cells. (2) Cancer cells often are far less adhe-

tions to take place, so we can suppose that a large

sive to one another than are normal cells. Therefore,

number of cancers are merely the result of an unlucky

they have a tendency to wander through the tissues, to

occurrence.

enter the blood stream, and to be transported all

However, the probability of mutations can be

through the body, where they form nidi for numerous

increased manyfold when a person is exposed to

new cancerous growths. (3) Some cancers also produce

certain chemical, physical, or biological factors, includ-

angiogenic factors that cause many new blood vessels

ing the following:

to grow into the cancer, thus supplying the nutrients

1. It is well known that ionizing radiation, such as

required for cancer growth.

x-rays, gamma rays, and particle radiation from

radioactive substances, and even ultraviolet light

Why Do Cancer Cells Kill? The answer to this question

can predispose individuals to cancer. Ions formed

usually is simple. Cancer tissue competes with normal

in tissue cells under the influence of such

tissues for nutrients. Because cancer cells continue to

radiation are highly reactive and can rupture

proliferate indefinitely, their number multiplying day

DNA strands, thus causing many mutations.

by day, cancer cells soon demand essentially all the

Unit I Introduction to Physiology: The Cell and General Physiology

nutrition available to the body or to an essential part

Cooke MS, Evans MD, Dizdaroglu M, Lunec J: Oxidative

of the body. As a result, normal tissues gradually suffer

DNA damage: mechanisms, mutation, and disease.

nutritive death.

FASEB J 17:1195, 2003.

Cullen BR: Nuclear RNA export. J Cell Sci 116:587, 2003.

Fedier A, Fink D: Mutations in DNA mismatch repair genes:

implications for DNA damage signaling and drug sensi-

References

tivity. Int J Oncol 24:1039, 2004.

Hahn S: Structure and mechanism of the RNA polymerase

Alberts B, Johnson A, Lewis J, et al: Molecular Biology of

II transcription machinery. Nat Struct Mol Biol 11:394,

the Cell. New York: Garland Science, 2002.

2004.

Aranda A, Pascal A: Nuclear hormone receptors and gene

Hall JG: Genomic imprinting: nature and clinical relevance.

expression. Physiol Rev 81:1269, 2001.

Annu Rev Med 48:35, 1997.

Balmain A, Gray J, Ponder B: The genetics and genomics of

Jockusch BM, Hüttelmaier S, Illenberger S: From the nucleus

cancer. Nat Genet 33(Suppl):238, 2003.

toward the cell periphery: a guided tour for mRNAs. News

Bowen ID, Bowen SM, Jones AH: Mitosis and Apoptosis:

Physiol Sci 18:7, 2003.

Matters of Life and Death. London: Chapman & Hall,

Kazazian HH Jr: Mobile elements: drivers of genome

1998.

evolution. Science 303:1626, 2004.

Burke W: Genomics as a probe for disease biology. N Engl

Lewin B: Genes IV. Oxford: Oxford University Press, 2000.

J Med 349:969, 2003.

Nabel GJ: Genetic, cellular and immune approaches to

Caplen NJ, Mousses S: Short interfering RNA (siRNA)-

disease therapy: past and future. Nat Med 10:135, 2004.

mediated RNA interference (RNAi) in human cells. Ann

Pollard TD, Earnshaw WC: Cell Biology. Philadelphia:

N Y Acad Sci 1002:56, 2003.

Elsevier Science, 2002.

C H A P T E R

Transport of Substances Through

the Cell Membrane

Figure 4-1 gives the approximate concentrations of

important electrolytes and other substances in the

extracellular fluid and intracellular fluid. Note that

the extracellular fluid contains a large amount of

sodium but only a small amount of potassium.

Exactly the opposite is true of the intracellular fluid.

Also, the extracellular fluid contains a large amount

of chloride ions, whereas the intracellular fluid con-

tains very little. But the concentrations of phosphates and proteins in the intra-

cellular fluid are considerably greater than those in the extracellular fluid. These

differences are extremely important to the life of the cell. The purpose of this

chapter is to explain how the differences are brought about by the transport

mechanisms of the cell membranes.

The Lipid Barrier of the Cell Membrane,

and Cell Membrane Transport Proteins

The structure of the membrane covering the outside of every cell of the body

is discussed in Chapter 2 and illustrated in Figures 2-3 and 4-2. This membrane

consists almost entirely of a lipid bilayer, but it also contains large numbers of

protein molecules in the lipid, many of which penetrate all the way through the

membrane, as shown in Figure 4-2.

The lipid bilayer is not miscible with either the extracellular fluid or the intra-

cellular fluid. Therefore, it constitutes a barrier against movement of water

molecules and water-soluble substances between the extracellular and intracel-

lular fluid compartments. However, as demonstrated in Figure 4-2 by the left-

most arrow, a few substances can penetrate this lipid bilayer, diffusing directly

through the lipid substance itself; this is true mainly of lipid-soluble substances,

as described later.

The protein molecules in the membrane have entirely different properties for

transporting substances. Their molecular structures interrupt the continuity of

the lipid bilayer, constituting an alternative pathway through the cell mem-

brane. Most of these penetrating proteins, therefore, can function as transport

proteins. Different proteins function differently. Some have watery spaces all

the way through the molecule and allow free movement of water as well as

selected ions or molecules; these are called channel proteins. Others, called

carrier proteins, bind with molecules or ions that are to be transported; confor-

mational changes in the protein molecules then move the substances through

the interstices of the protein to the other side of the membrane. Both the

channel proteins and the carrier proteins are usually highly selective in the types

of molecules or ions that are allowed to cross the membrane.

“Diffusion” Versus “Active Transport.” Transport through the cell membrane, either

directly through the lipid bilayer or through the proteins, occurs by one of two

basic processes: diffusion or active transport.

Although there are many variations of these basic mechanisms, diffusion

means random molecular movement of substances molecule by molecule, either

through intermolecular spaces in the membrane or in combination with a carrier

Unit II

Membrane Physiology, Nerve, and Muscle

EXTRACELLULAR

INTRACELLULAR

FLUID

Na⁺---------------

142 mEq/ L ---------10 mEq/ L

K⁺-----------------

4 mEq/ L ------------

140 mEq/ L

Ca⁺⁺--------------

2.4 mEq/ L ----------0.0001 mEq/ L

Mg⁺⁺--------------1.2 mEq/ L ----------58 mEq/ L

Cl^-----------------

103 mEq/ L ---------4 mEq/ L

HCO_3------------

28 mEq/ L -----------10 mEq/ L

Phosphates-----

4 mEq/ L -------------75 mEq/ L

SO4- -------------

1 mEq/L -------------2 mEq/L

Glucose ---------

90 mg/dl ------------

0 to 20 mg/dl

Amino acids ---- 30 mg/dl ------------ 200 mg/dl ?

Figure 4-3

Cholesterol

Diffusion of a fluid molecule during a thousandth of a second.

Phospholipids

0.5 g/dl-------------- 2 to 95 g/dl

Neutral fat

PO₂---------------

35 mm Hg ---------

20 mm Hg ?

the basic physics and physical chemistry of these two

PCO₂-------------

46 mm Hg ---------

50 mm Hg ?

processes.

pH -----------------7.4 -------------------

7.0

Proteins ----------2 g/dl ----------------

16 g/dl

Diffusion

(5 mEq/ L)

(40 mEq/ L)

All molecules and ions in the body fluids, including

water molecules and dissolved substances, are in con-

stant motion, each particle moving its own separate

Figure 4-1

way. Motion of these particles is what physicists call

“heat”—the greater the motion, the higher the tem-

Chemical compositions of extracellular and intracellular fluids.

perature—and the motion never ceases under any

condition except at absolute zero temperature. When

a moving molecule, A, approaches a stationary mole-

Channel

Carrier proteins

cule, B, the electrostatic and other nuclear forces of

protein

molecule A repel molecule B, transferring some of the

energy of motion of molecule A to molecule B. Con-

sequently, molecule B gains kinetic energy of motion,

while molecule A slows down, losing some of its

kinetic energy. Thus, as shown in Figure 4-3, a single

molecule in a solution bounces among the other

molecules first in one direction, then another, then

Energy

another, and so forth, randomly bouncing thousands of

Simple

Facilitated

diffusion

times each second. This continual movement of mole-

cules among one another in liquids or in gases is called

Diffusion

Active transport

diffusion.

Ions diffuse in the same manner as whole molecules,

Figure 4-2

and even suspended colloid particles diffuse in a

Transport pathways through the cell membrane, and the basic

similar manner, except that the colloids diffuse far

mechanisms of transport.

less rapidly than molecular substances because of their

large size.

protein. The energy that causes diffusion is the energy

of the normal kinetic motion of matter.

Diffusion Through the Cell Membrane

By contrast, active transport means movement of

ions or other substances across the membrane in com-

Diffusion through the cell membrane is divided into

bination with a carrier protein in such a way that the

two subtypes called simple diffusion and facilitated

carrier protein causes the substance to move against

diffusion. Simple diffusion means that kinetic move-

an energy gradient, such as from a low-concentration

ment of molecules or ions occurs through a membrane

state to a high-concentration state. This movement

opening or through intermolecular spaces without any

requires an additional source of energy besides kinetic

interaction with carrier proteins in the membrane.

energy. Following is a more detailed explanation of

The rate of diffusion is determined by the amount of

Chapter 4

Transport of Substances Through the Cell Membrane

substance available, the velocity of kinetic motion, and

diffusion directly along these channels from one side

the number and sizes of openings in the membrane

of the membrane to the other. The protein channels

through which the molecules or ions can move.

are distinguished by two important characteristics: (1)

Facilitated diffusion requires interaction of a carrier

they are often selectively permeable to certain sub-

protein. The carrier protein aids passage of the mole-

stances, and (2) many of the channels can be opened

cules or ions through the membrane by binding

or closed by gates.

chemically with them and shuttling them through the

membrane in this form.

Selective Permeability of Protein Channels. Many of the

Simple diffusion can occur through the cell mem-

protein channels are highly selective for transport of

brane by two pathways: (1) through the interstices of

one or more specific ions or molecules. This results

the lipid bilayer if the diffusing substance is lipid

from the characteristics of the channel itself, such as

soluble, and (2) through watery channels that pene-

its diameter, its shape, and the nature of the electrical

trate all the way through some of the large transport

charges and chemical bonds along its inside surfaces.

proteins, as shown to the left in Figure 4-2.

To give an example, one of the most important of the

protein channels, the so-called sodium channel, is only

Diffusion of Lipid-Soluble Substances Through the Lipid Bilayer.

0.3 by 0.5 nanometer in diameter, but more important,

One of the most important factors that determines

the inner surfaces of this channel are strongly nega-

how rapidly a substance diffuses through the lipid

tively charged, as shown by the negative signs inside

bilayer is the lipid solubility of the substance. For

the channel proteins in the top panel of Figure 4-4.

instance, the lipid solubilities of oxygen, nitrogen,

These strong negative charges can pull small dehy-

carbon dioxide, and alcohols are high, so that all these

drated sodium ions into these channels, actually pulling

can dissolve directly in the lipid bilayer and diffuse

the sodium ions away from their hydrating water

through the cell membrane in the same manner that

molecules. Once in the channel, the sodium ions

diffusion of water solutes occurs in a watery solution.

diffuse in either direction according to the usual laws

For obvious reasons, the rate of diffusion of each of

of diffusion. Thus, the sodium channel is specifically

these substances through the membrane is directly

selective for passage of sodium ions.

proportional to its lipid solubility. Especially large

Conversely, another set of protein channels is selec-

amounts of oxygen can be transported in this way;

tive for potassium transport, shown in the lower panel

therefore, oxygen can be delivered to the interior of

of Figure 4-4. These channels are slightly smaller than

the cell almost as though the cell membrane did not

the sodium channels, only 0.3 by 0.3 nanometer, but

exist.

they are not negatively charged, and their chemical

bonds are different. Therefore, no strong attrac-

Diffusion of Water and Other Lipid-Insoluble Molecules Through

tive force is pulling ions into the channels, and the

Protein Channels. Even though water is highly insoluble

potassium ions are not pulled away from the water

in the membrane lipids, it readily passes through chan-

nels in protein molecules that penetrate all the way

through the membrane. The rapidity with which water

molecules can move through most cell membranes is

astounding. As an example, the total amount of water

Outside

Gate

Na⁺

closed

that diffuses in each direction through the red cell

Gate open

membrane during each second is about 100 times as

great as the volume of the red cell itself.

Other lipid-insoluble molecules can pass through

the protein pore channels in the same way as water

–

molecules if they are water soluble and small enough.

Inside

However, as they become larger, their penetration falls

off rapidly. For instance, the diameter of the urea

molecule is only 20 per cent greater than that of water,

yet its penetration through the cell membrane pores is

about 1000 times less than that of water. Even so, given

Outside

the astonishing rate of water penetration, this amount

of urea penetration still allows rapid transport of urea

through the membrane within minutes.

Gate open

Diffusion Through Protein Channels,

Gate

and “Gating” of These Channels

Inside

closed

K⁺

Computerized three-dimensional reconstructions of

Figure 4-4

protein channels have demonstrated tubular pathways

Transport of sodium and potassium ions through protein channels.

all the way from the extracellular to the intracellu-

Also shown are conformational changes in the protein molecules

lar fluid. Therefore, substances can move by simple

to open or close “gates” guarding the channels.

Unit II

Membrane Physiology, Nerve, and Muscle

molecules that hydrate them. The hydrated form of

the potassium ion is considerably smaller than the

hydrated form of sodium because the sodium ion

Open sodium channel

attracts far more water molecules than does potas-

sium. Therefore, the smaller hydrated potassium ions

can pass easily through this small channel, whereas the

larger hydrated sodium ions are rejected, thus provid-

ing selective permeability for a specific ion.

Gating of Protein Channels. Gating of protein channels

provides a means of controlling ion permeability of the

channels. This is shown in both panels of Figure 4-4

for selective gating of sodium and potassium ions. It is

believed that some of the gates are actual gatelike

extensions of the transport protein molecule, which

can close the opening of the channel or can be lifted

Milliseconds

away from the opening by a conformational change in

the shape of the protein molecule itself.

The opening and closing of gates are controlled in

Recorder

two principal ways:

Voltage gating. In this instance, the molecular

conformation of the gate or of its chemical bonds

responds to the electrical potential across the cell

membrane. For instance, in the top panel of Figure

4-4, when there is a strong negative charge

on the inside of the cell membrane, this presumably

could cause the outside sodium gates to remain

tightly closed; conversely, when the inside of the

membrane loses its negative charge, these gates

To recorder

would open suddenly and allow tremendous

quantities of sodium to pass inward through the

sodium pores. This is the basic mechanism for

eliciting action potentials in nerves that are

responsible for nerve signals. In the bottom panel

of Figure 4-4, the potassium gates are on the

intracellular ends of the potassium channels, and

they open when the inside of the cell membrane

becomes positively charged. The opening of these

gates is partly responsible for terminating the

action potential, as is discussed more fully in

Chapter 5.

Chemical (ligand) gating. Some protein channel

gates are opened by the binding of a chemical

substance (a ligand) with the protein; this causes a

conformational or chemical bonding change in the

protein molecule that opens or closes the gate. This

Membrane

is called chemical gating or ligand gating. One of

“patch”

the most important instances of chemical gating

is the effect of acetylcholine on the so-called

acetylcholine channel. Acetylcholine opens the gate

of this channel, providing a negatively charged pore

about 0.65 nanometer in diameter that allows

Figure 4-5

uncharged molecules or positive ions smaller

than this diameter to pass through. This gate is

A, Record of current flow through a single voltage-gated sodium

exceedingly important for the transmission of nerve

channel, demonstrating the “all or none” principle for opening and

signals from one nerve cell to another (see Chapter

closing of the channel. B, The “patch-clamp” method for record-

ing current flow through a single protein channel. To the left,

45) and from nerve cells to muscle cells to cause

recording is performed from a “patch” of a living cell membrane.

muscle contraction (see Chapter 7).

To the right, recording is from a membrane patch that has been

torn away from the cell.

Open-State Versus Closed-State of Gated Channels.

Figure 4-5A shows an especially interesting charac-

membrane. Note that the channel conducts current

teristic of most voltage-gated channels. This figure

either “all or none.” That is, the gate of the channel

shows two recordings of electrical current flowing

snaps open and then snaps closed, each open state

through a single sodium channel when there was an

lasting for only a fraction of a millisecond up to several

approximate 25-millivolt potential gradient across the

milliseconds. This demonstrates the rapidity with

Chapter 4

Transport of Substances Through the Cell Membrane

which changes can occur during the opening and

closing of the protein molecular gates. At one voltage

potential, the channel may remain closed all the time

Simple diffusion

or almost all the time, whereas at another voltage

Facilitated diffusion

level, it may remain open either all or most of the time.

At in-between voltages, as shown in the figure, the

gates tend to snap open and closed intermittently,

V_max

giving an average current flow somewhere between

the minimum and the maximum.

Patch-Clamp Method for Recording Ion Current Flow Through

Single Channels. One might wonder how it is technically

possible to record ion current flow through single

protein channels as shown in Figure 4-5A. This has been

achieved by using the “patch-clamp” method illustrated

in Figure 4-5B. Very simply, a micropipette, having a tip

diameter of only 1 or 2 micrometers, is abutted against

Concentration of substance

the outside of a cell membrane. Then suction is applied

inside the pipette to pull the membrane against the tip

of the pipette. This creates a seal where the edges of the

pipette touch the cell membrane. The result is a minute

Figure 4-6

membrane “patch” at the tip of the pipette through

which electrical current flow can be recorded.

Effect of concentration of a substance on rate of diffusion through

Alternatively, as shown to the right in Figure 4-5B,

a membrane by simple diffusion and facilitated diffusion. This

the small cell membrane patch at the end of the pipette

shows that facilitated diffusion approaches a maximum rate called

can be torn away from the cell. The pipette with

the V_max.

its sealed patch is then inserted into a free solution.

This allows the concentrations of ions both inside the

micropipette and in the outside solution to be altered

Transported

as desired. Also, the voltage between the two sides of

molecule

the membrane can be set at will—that is, “clamped” to

Binding point

a given voltage.

It has been possible to make such patches small

enough so that only a single channel protein is found

in the membrane patch being studied. By varying the

concentrations of different ions, as well as the voltage

across the membrane, one can determine the transport

characteristics of the single channel and also its gating

properties.

Carrier protein

and

conformational

change

Facilitated Diffusion

Facilitated diffusion is also called carrier-mediated dif-

fusion because a substance transported in this manner

diffuses through the membrane using a specific carrier

protein to help. That is, the carrier facilitates diffusion

of the substance to the other side.

Release

Facilitated diffusion differs from simple diffusion in

of binding

the following important way: Although the rate of

simple diffusion through an open channel increases

Figure 4-7

proportionately with the concentration of the diffus-

ing substance, in facilitated diffusion the rate of

Postulated mechanism for facilitated diffusion.

diffusion approaches a maximum, called V_max, as the

concentration of the diffusing substance increases. This

difference between simple diffusion and facilitated dif-

pore large enough to transport a specific molecule

fusion is demonstrated in Figure 4-6. The figure shows

partway through. It also shows a binding “receptor” on

that as the concentration of the diffusing substance

the inside of the protein carrier. The molecule to be

increases, the rate of simple diffusion continues to

transported enters the pore and becomes bound. Then,

increase proportionately, but in the case of facilitated

in a fraction of a second, a conformational or chemi-

diffusion, the rate of diffusion cannot rise greater than

cal change occurs in the carrier protein, so that the

the V_max level.

pore now opens to the opposite side of the membrane.

What is it that limits the rate of facilitated diffusion?

Because the binding force of the receptor is weak, the

A probable answer is the mechanism illustrated in

thermal motion of the attached molecule causes it to

Figure 4-7. This figure shows a carrier protein with a

break away and to be released on the opposite side of

Unit II

Membrane Physiology, Nerve, and Muscle

the membrane. The rate at which molecules can be

Outside

Inside

transported by this mechanism can never be greater

than the rate at which the carrier protein molecule

can undergo change back and forth between its two

states. Note specifically, though, that this mechanism

C_o

C_i

allows the transported molecule to move—that is, to

“diffuse”—in either direction through the membrane.

Among the most important substances that cross

cell membranes by facilitated diffusion are glucose and

Membrane

most of the amino acids. In the case of glucose, the

carrier molecule has been discovered, and it has a

molecular weight of about 45,000; it can also transport

- -

several other monosaccharides that have structures

similar to that of glucose, including galactose. Also,

insulin can increase the rate of facilitated diffusion of

glucose as much as 10-fold to 20-fold. This is the prin-

- -

cipal mechanism by which insulin controls glucose use

in the body, as discussed in Chapter 78.

Factors That Affect Net Rate

of Diffusion

By now it is evident that many substances can diffuse

through the cell membrane. What is usually important

Piston

P₁

P₂

is the net rate of diffusion of a substance in the desired

direction. This net rate is determined by several

factors.

Effect of Concentration Difference on Net Diffusion Through a

Figure 4-8

Membrane. Figure 4-8A shows a cell membrane with a

substance in high concentration on the outside and low

Effect of concentration difference (A), electrical potential differ-

concentration on the inside. The rate at which the sub-

ence affecting negative ions (B), and pressure difference (C) to

cause diffusion of molecules and ions through a cell membrane.

stance diffuses inward is proportional to the con-

centration of molecules on the outside, because this

concentration determines how many molecules strike

the outside of the membrane each second. Conversely,

right, creating the condition shown in the right panel

the rate at which molecules diffuse outward is propor-

of Figure 4-8B, in which a concentration difference of

tional to their concentration inside the membrane.

the ions has developed in the direction opposite to the

Therefore, the rate of net diffusion into the cell is pro-

electrical potential difference. The concentration dif-

portional to the concentration on the outside minus

ference now tends to move the ions to the left, while

the concentration on the inside, or:

the electrical difference tends to move them to the

right. When the concentration difference rises high

Net diffusion µ (C_o - C_i)

enough, the two effects balance each other. At normal

in which C_o is concentration outside and C_i is concen-

body temperature (37°C), the electrical difference

tration inside.

that will balance a given concentration difference of

univalent ions—such as sodium (Na⁺) ions—can be

Effect of Membrane Electrical Potential on Diffusion of Ions—

determined from the following formula, called the

The

“Nernst Potential.” If an electrical potential is

Nernst equation:

applied across the membrane, as shown in Figure

4-8B, the electrical charges of the ions cause them to

EMF(in millivolts)=±

61 log^C1

move through the membrane even though no concen-

C₂

tration difference exists to cause movement. Thus, in

in which EMF is the electromotive force (voltage)

the left panel of Figure 4-8B, the concentration of

between side 1 and side 2 of the membrane, C₁ is the

negative ions is the same on both sides of the mem-

concentration on side 1, and C₂ is the concentration on

brane, but a positive charge has been applied to the

side 2. This equation is extremely important in under-

right side of the membrane and a negative charge to

standing the transmission of nerve impulses and is dis-

the left, creating an electrical gradient across the mem-

cussed in much greater detail in Chapter 5.

brane. The positive charge attracts the negative ions,

whereas the negative charge repels them. Therefore,

net diffusion occurs from left to right. After much time,

Effect of a Pressure Difference Across the Membrane. At

large quantities of negative ions have moved to the

times, considerable pressure difference develops

Chapter 4

Transport of Substances Through the Cell Membrane

between the two sides of a diffusible membrane.

Water

NaCl solution

This occurs, for instance, at the blood capillary mem-

brane in all tissues of the body. The pressure is about

20 mm Hg greater inside the capillary than outside.

Pressure actually means the sum of all the forces of

the different molecules striking a unit surface area at

a given instant. Therefore, when the pressure is higher

on one side of a membrane than on the other, this

means that the sum of all the forces of the molecules

striking the channels on that side of the membrane is

greater than on the other side. In most instances, this

is caused by greater numbers of molecules striking the

membrane per second on one side than on the other

side. The result is that increased amounts of energy are

available to cause net movement of molecules from

the high-pressure side toward the low-pressure side.

Osmosis

This effect is demonstrated in Figure 4-8C, which

shows a piston developing high pressure on one side

Figure 4-9

of a “pore,” thereby causing more molecules to strike

Osmosis at a cell membrane when a sodium chloride solution is

the pore on this side and, therefore, more molecules to

placed on one side of the membrane and water is placed on the

“diffuse” to the other side.

other side.

Osmosis Across Selectively

where there is pure water, than on the right side, where

Permeable Membranes—

the water concentration has been reduced. Thus, net

“Net Diffusion” of Water

movement of water occurs from left to right—that is,

osmosis occurs from the pure water into the sodium

By far the most abundant substance that diffuses

chloride solution.

through the cell membrane is water. Enough water

ordinarily diffuses in each direction through the red

Osmotic Pressure

cell membrane per second to equal about 100 times the

If in Figure 4-9 pressure were applied to the sodium

volume of the cell itself. Yet, normally, the amount that

chloride solution, osmosis of water into this solution

diffuses in the two directions is balanced so precisely

would be slowed, stopped, or even reversed. The exact

that zero net movement of water occurs. Therefore, the

amount of pressure required to stop osmosis is called

volume of the cell remains constant. However, under

the osmotic pressure of the sodium chloride solution.

certain conditions, a concentration difference for water

The principle of a pressure difference opposing

can develop across a membrane, just as concentration

osmosis is demonstrated in Figure 4-10, which shows

differences for other substances can occur. When this

a selectively permeable membrane separating two

happens, net movement of water does occur across the

columns of fluid, one containing pure water and the

cell membrane, causing the cell either to swell or to

other containing a solution of water and any solute

shrink, depending on the direction of the water move-

that will not penetrate the membrane. Osmosis of

ment. This process of net movement of water caused

water from chamber B into chamber A causes the

by a concentration difference of water is called

levels of the fluid columns to become farther and

osmosis.

farther apart, until eventually a pressure difference

To give an example of osmosis, let us assume the

develops between the two sides of the membrane great

conditions shown in Figure 4-9, with pure water on

enough to oppose the osmotic effect. The pressure dif-

one side of the cell membrane and a solution of

ference across the membrane at this point is equal to

sodium chloride on the other side. Water molecules

the osmotic pressure of the solution that contains the

pass through the cell membrane with ease, whereas

nondiffusible solute.

sodium and chloride ions pass through only with diffi-

culty. Therefore, sodium chloride solution is actually a

Importance of Number of Osmotic Particles (Molar Concentra-

mixture of permeant water molecules and nonperme-

tion) in Determining Osmotic Pressure. The osmotic pres-

ant sodium and chloride ions, and the membrane is

sure exerted by particles in a solution, whether they

said to be selectively permeable to water but much less

are molecules or ions, is determined by the number of

so to sodium and chloride ions. Yet the presence of the

particles per unit volume of fluid, not by the mass of

sodium and chloride has displaced some of the water

the particles. The reason for this is that each particle

molecules on the side of the membrane where these

in a solution, regardless of its mass, exerts, on average,

ions are present and, therefore, has reduced the con-

the same amount of pressure against the membrane.

centration of water molecules to less than that of pure

That is, large particles, which have greater mass (m)

water. As a result, in the example of Figure 4-9, more

than small particles, move at slower velocities (v). The

water molecules strike the channels on the left side,

small particles move at higher velocities in such a way

Unit II

Membrane Physiology, Nerve, and Muscle

osmolality of the extracellular and intracellular fluids

is about 300 milliosmoles per kilogram of water.

Relation of Osmolality to Osmotic Pressure. At normal body

temperature, 37°C, a concentration of 1 osmole per

liter will cause 19,300 mm Hg osmotic pressure in the

solution. Likewise, 1 milliosmole per liter concentra-

tion is equivalent to 19.3 mm Hg osmotic pressure.

Multiplying this value by the 300 milliosmolar con-

centration of the body fluids gives a total calculated

osmotic pressure of the body fluids of 5790 mm Hg.

The measured value for this, however, averages only

Non-

diffusible

about 5500 mm Hg. The reason for this difference is

solute

that many of the ions in the body fluids, such as sodium

Semipermeable

membrane

and chloride ions, are highly attracted to one another;

consequently, they cannot move entirely unrestrained

in the fluids and create their full osmotic pressure

Water

potential. Therefore, on average, the actual osmotic

pressure of the body fluids is about 0.93 times the cal-

culated value.

The Term “Osmolarity.” Because of the difficulty of meas-

uring kilograms of water in a solution, which is required

to determine osmolality, osmolarity, which is the

Figure 4-10

osmolar concentration expressed as osmoles per liter of

solution rather than osmoles per kilogram of water, is

Demonstration of osmotic pressure caused by osmosis at a semi-

used instead. Although, strictly speaking, it is osmoles

permeable membrane.

per kilogram of water (osmolality) that determines

osmotic pressure, for dilute solutions such as those in

the body, the quantitative differences between osmo-

that their average kinetic energies (k), determined by

larity and osmolality are less than 1 per cent. Because it

the equation

is far more practical to measure osmolarity than osmo-

lality, this is the usual practice in almost all physiologic

studies.

“Active Transport” of

are the same for each small particle as for each large

Substances Through

particle. Consequently, the factor that determines the

osmotic pressure of a solution is the concentration of

Membranes

the solution in terms of number of particles (which is

the same as its molar concentration if it is a nondisso-

At times, a large concentration of a substance is

ciated molecule), not in terms of mass of the solute.

required in the intracellular fluid even though the

extracellular fluid contains only a small concentration.

“Osmolality”—The Osmole. To express the concentration

This is true, for instance, for potassium ions. Con-

of a solution in terms of numbers of particles, the unit

versely, it is important to keep the concentrations of

called the osmole is used in place of grams.

other ions very low inside the cell even though their

One osmole is 1 gram molecular weight of osmoti-

concentrations in the extracellular fluid are great. This

cally active solute. Thus, 180 grams of glucose, which

is especially true for sodium ions. Neither of these two

is 1 gram molecular weight of glucose, is equal to 1

effects could occur by simple diffusion, because simple

osmole of glucose because glucose does not dissociate

diffusion eventually equilibrates concentrations on the

into ions. Conversely, if a solute dissociates into two

two sides of the membrane. Instead, some energy

ions,

1 gram molecular weight of the solute will

source must cause excess movement of potassium ions

become 2 osmoles because the number of osmotically

to the inside of cells and excess movement of sodium

active particles is now twice as great as is the case for

ions to the outside of cells. When a cell membrane

the nondissociated solute. Therefore, when fully disso-

moves molecules or ions “uphill” against a concentra-

ciated, 1 gram molecular weight of sodium chloride,

tion gradient (or “uphill” against an electrical or pres-

58.5 grams, is equal to 2 osmoles.

sure gradient), the process is called active transport.

Thus, a solution that has 1 osmole of solute dissolved

Different substances that are actively transported

in each kilogram of water is said to have an osmolality

through at least some cell membranes include sodium

of 1 osmole per kilogram, and a solution that has

ions, potassium ions, calcium ions, iron ions, hydrogen

1/1000 osmole dissolved per kilogram has an osmo-

ions, chloride ions, iodide ions, urate ions, several dif-

lality of

1 milliosmole per kilogram. The normal

ferent sugars, and most of the amino acids.

Chapter 4

Transport of Substances Through the Cell Membrane

Primary Active Transport and Secondary Active Transport.

3Na⁺

Active transport is divided into two types according to

Outside

the source of the energy used to cause the transport:

2K⁺

primary active transport and secondary active trans-

port. In primary active transport, the energy is derived

directly from breakdown of adenosine triphosphate

(ATP) or of some other high-energy phosphate com-

pound. In secondary active transport, the energy is

derived secondarily from energy that has been stored

in the form of ionic concentration differences of

secondary molecular or ionic substances between the

ATPase

two sides of a cell membrane, created originally by

primary active transport. In both instances, transport

3Na⁺

depends on carrier proteins that penetrate through the

ATP

ADP

cell membrane, as is true for facilitated diffusion.

Inside

2K⁺

However, in active transport, the carrier protein func-

tions differently from the carrier in facilitated diffu-

Figure 4-11

sion because it is capable of imparting energy to the

transported substance to move it against the electro-

Postulated mechanism of the sodium-potassium pump. ADP,

adenosine diphosphate; ATP, adenosine triphosphate; Pi,

chemical gradient. Following are some examples

phosphate ion.

of primary active transport and secondary active

transport, with more detailed explanations of their

and three sodium ions bind on the inside, the ATPase

principles of function.

function of the protein becomes activated. This then

cleaves one molecule of ATP, splitting it to adenosine

diphosphate

(ADP) and liberating a high-energy

Primary Active Transport

phosphate bond of energy. This liberated energy is

then believed to cause a chemical and conformational

Sodium-Potassium Pump

change in the protein carrier molecule, extruding the

Among the substances that are transported by primary

three sodium ions to the outside and the two potas-

active transport are sodium, potassium, calcium,

sium ions to the inside.

hydrogen, chloride, and a few other ions.

As with other enzymes, the Na⁺-K⁺ ATPase pump

The active transport mechanism that has been

can run in reverse. If the electrochemical gradients for

studied in greatest detail is the sodium-potassium

Na⁺ and K⁺ are experimentally increased enough so

(Na⁺-K⁺) pump, a transport process that pumps

that the energy stored in their gradients is greater than

sodium ions outward through the cell membrane of all

the chemical energy of ATP hydrolysis, these ions will

cells and at the same time pumps potassium ions from

move down their concentration gradients and the Na⁺-

the outside to the inside. This pump is responsible for

K⁺ pump will synthesize ATP from ADP and phos-

maintaining the sodium and potassium concentration

phate. The phosphorylated form of the Na⁺-K⁺ pump,

differences across the cell membrane, as well as for

therefore, can either donate its phosphate to ADP to

establishing a negative electrical voltage inside the

produce ATP or use the energy to change its confor-

cells. Indeed, Chapter 5 shows that this pump is also

mation and pump Na⁺ out of the cell and K⁺ into the

the basis of nerve function, transmitting nerve signals

cell. The relative concentrations of ATP, ADP, and

throughout the nervous system.

phosphate, as well as the electrochemical gradients for

Figure 4-11 shows the basic physical components of

Na⁺ and K⁺, determine the direction of the enzyme

the Na⁺-K⁺ pump. The carrier protein is a complex of

reaction. For some cells, such as electrically active

two separate globular proteins: a larger one called the

nerve cells, 60 to 70 per cent of the cells’ energy

a subunit, with a molecular weight of about 100,000,

requirement may be devoted to pumping Na⁺ out of

and a smaller one called the b subunit, with a molec-

the cell and K⁺ into the cell.

ular weight of about 55,000. Although the function of

the smaller protein is not known (except that it might

Importance of the Na⁺-K⁺ Pump for Controlling Cell Volume.

anchor the protein complex in the lipid membrane),

One of the most important functions of the Na⁺-K⁺

the larger protein has three specific features that are

pump is to control the volume of each cell. Without

important for the functioning of the pump:

function of this pump, most cells of the body would

1. It has three receptor sites for binding sodium ions

swell until they burst. The mechanism for controlling

on the portion of the protein that protrudes to the

the volume is as follows: Inside the cell are large

inside of the cell.

numbers of proteins and other organic molecules that

2. It has two receptor sites for potassium ions on the

outside.

cannot escape from the cell. Most of these are nega-

3. The inside portion of this protein near the sodium

tively charged and therefore attract large numbers of

binding sites has ATPase activity.

potassium, sodium, and other positive ions as well. All

To put the pump into perspective: When two potas-

these molecules and ions then cause osmosis of water

sium ions bind on the outside of the carrier protein

to the interior of the cell. Unless this is checked, the

Unit II

Membrane Physiology, Nerve, and Muscle

cell will swell indefinitely until it bursts. The normal

In the renal tubules are special intercalated cells in

mechanism for preventing this is the Na⁺-K⁺ pump.

the late distal tubules and cortical collecting ducts that

Note again that this device pumps three Na⁺ ions to

also transport hydrogen ions by primary active trans-

the outside of the cell for every two K⁺ ions pumped

port. In this case, large amounts of hydrogen ions are

to the interior. Also, the membrane is far less perme-

secreted from the blood into the urine for the purpose

able to sodium ions than to potassium ions, so that

of eliminating excess hydrogen ions from the body

once the sodium ions are on the outside, they have a

fluids. The hydrogen ions can be secreted into the

strong tendency to stay there. Thus, this represents a

urine against a concentration gradient of about

net loss of ions out of the cell, which initiates osmosis

900-fold.

of water out of the cell as well.

If a cell begins to swell for any reason, this auto-

Energetics of Primary Active Transport

matically activates the Na⁺-K⁺ pump, moving still more

The amount of energy required to transport a sub-

ions to the exterior and carrying water with them.

stance actively through a membrane is determined by

Therefore, the Na⁺-K⁺ pump performs a continual sur-

how much the substance is concentrated during trans-

veillance role in maintaining normal cell volume.

port. Compared with the energy required to concen-

trate a substance 10-fold, to concentrate it 100-fold

Electrogenic Nature of the Na⁺-K⁺ Pump. The fact that the

requires twice as much energy, and to concentrate

Na⁺-K⁺ pump moves three Na⁺ ions to the exterior for

1000-fold requires three times as much energy.

every two K⁺ ions to the interior means that a net of one

In other words, the energy required is proportional

positive charge is moved from the interior of the cell to

to the logarithm of the degree that the substance

the exterior for each cycle of the pump. This creates pos-

is concentrated, as expressed by the following

itivity outside the cell but leaves a deficit of positive ions

formula:

inside the cell; that is, it causes negativity on the inside.

Therefore, the Na⁺-K⁺ pump is said to be electrogenic

because it creates an electrical potential across the cell

Energy(in calories per osmole)=

1400 log^C1

membrane. As discussed in Chapter 5, this electrical

C₂

potential is a basic requirement in nerve and muscle

fibers for transmitting nerve and muscle signals.

Thus, in terms of calories, the amount of energy

required to concentrate 1 osmole of substance 10-fold

Primary Active Transport of Calcium Ions

is about 1400 calories; or to concentrate it 100-fold,

Another important primary active transport mecha-

2800 calories. One can see that the energy expenditure

nism is the calcium pump. Calcium ions are normally

for concentrating substances in cells or for removing

maintained at extremely low concentration in the

substances from cells against a concentration gradient

intracellular cytosol of virtually all cells in the body, at

can be tremendous. Some cells, such as those lining the

a concentration about 10,000 times less than that in the

renal tubules and many glandular cells, expend as

extracellular fluid. This is achieved mainly by two

much as 90 per cent of their energy for this purpose

primary active transport calcium pumps. One is in the

alone.

cell membrane and pumps calcium to the outside of

the cell. The other pumps calcium ions into one or

more of the intracellular vesicular organelles of the

Secondary Active Transport—

cell, such as the sarcoplasmic reticulum of muscle cells

Co-Transport and Counter-Transport

and the mitochondria in all cells. In each of these

instances, the carrier protein penetrates the membrane

When sodium ions are transported out of cells by

and functions as an enzyme ATPase, having the same

primary active transport, a large concentration gradi-

capability to cleave ATP as the ATPase of the sodium

ent of sodium ions across the cell membrane usually

carrier protein. The difference is that this protein has

develops—high concentration outside the cell and

a highly specific binding site for calcium instead of for

very low concentration inside. This gradient represents

sodium.

a storehouse of energy because the excess sodium

outside the cell membrane is always attempting to

Primary Active Transport of Hydrogen Ions

diffuse to the interior. Under appropriate conditions,

At two places in the body, primary active transport of

this diffusion energy of sodium can pull other sub-

hydrogen ions is very important: (1) in the gastric

stances along with the sodium through the cell mem-

glands of the stomach, and (2) in the late distal tubules

brane. This phenomenon is called co-transport; it is one

and cortical collecting ducts of the kidneys.

form of secondary active transport.

In the gastric glands, the deep-lying parietal cells

For sodium to pull another substance along with it,

have the most potent primary active mechanism for

a coupling mechanism is required. This is achieved by

transporting hydrogen ions of any part of the body.

means of still another carrier protein in the cell mem-

This is the basis for secreting hydrochloric acid in the

brane. The carrier in this instance serves as an attach-

stomach digestive secretions. At the secretory ends of

ment point for both the sodium ion and the substance

the gastric gland parietal cells, the hydrogen ion con-

to be co-transported. Once they both are attached, the

centration is increased as much as a millionfold and

energy gradient of the sodium ion causes both the

then released into the stomach along with chloride

sodium ion and the other substance to be transported

ions to form hydrochloric acid.

together to the interior of the cell.

Chapter 4

Transport of Substances Through the Cell Membrane

In counter-transport, sodium ions again attempt to

Other important co-transport mechanisms in at

diffuse to the interior of the cell because of their large

least some cells include co-transport of chloride ions,

concentration gradient. However, this time, the sub-

iodine ions, iron ions, and urate ions.

stance to be transported is on the inside of the cell and

must be transported to the outside. Therefore, the

Sodium Counter-Transport of Calcium and

sodium ion binds to the carrier protein where it pro-

Hydrogen Ions

jects to the exterior surface of the membrane, while

Two especially important counter-transport mecha-

the substance to be counter-transported binds to the

nisms (transport in a direction opposite to the primary

interior projection of the carrier protein. Once both

ion) are sodium-calcium counter-transport and

have bound, a conformational change occurs, and

sodium-hydrogen counter-transport.

energy released by the sodium ion moving to the

Sodium-calcium counter-transport occurs through

interior causes the other substance to move to the

all or almost all cell membranes, with sodium ions

exterior.

moving to the interior and calcium ions to the exterior,

both bound to the same transport protein in a counter-

Co-Transport of Glucose and Amino Acids

transport mode. This is in addition to primary active

Along with Sodium Ions

transport of calcium that occurs in some cells.

Glucose and many amino acids are transported into

Sodium-hydrogen counter-transport occurs in

most cells against large concentration gradients; the

several tissues. An especially important example is in

mechanism of this is entirely by co-transport, as shown

the proximal tubules of the kidneys, where sodium ions

in Figure 4-12. Note that the transport carrier protein

move from the lumen of the tubule to the interior

has two binding sites on its exterior side, one for

of the tubular cell, while hydrogen ions are counter-

sodium and one for glucose. Also, the concentration of

transported into the tubule lumen. As a mechanism for

sodium ions is very high on the outside and very low

concentrating hydrogen ions, counter-transport is not

inside, which provides energy for the transport. A

nearly as powerful as the primary active transport of

special property of the transport protein is that a con-

hydrogen ions that occurs in the more distal renal

formational change to allow sodium movement to the

tubules, but it can transport extremely large numbers

interior will not occur until a glucose molecule also

of hydrogen ions, thus making it a key to hydrogen

attaches. When they both become attached, the con-

ion control in the body fluids, as discussed in detail in

formational change takes place automatically, and the

Chapter 30.

sodium and glucose are transported to the inside of the

cell at the same time. Hence, this is a sodium-glucose

co-transport mechanism.

Active Transport Through

Sodium co-transport of the amino acids occurs in the

Cellular Sheets

same manner as for glucose, except that it uses a dif-

ferent set of transport proteins. Five amino acid trans-

At many places in the body, substances must be trans-

port proteins have been identified, each of which is

ported all the way through a cellular sheet instead of

responsible for transporting one subset of amino acids

simply through the cell membrane. Transport of this

with specific molecular characteristics.

type occurs through the (1) intestinal epithelium, (2)

Sodium co-transport of glucose and amino acids

epithelium of the renal tubules, (3) epithelium of all

occurs especially through the epithelial cells of the

exocrine glands, (4) epithelium of the gallbladder, and

intestinal tract and the renal tubules of the kidneys to

(5) membrane of the choroid plexus of the brain and

promote absorption of these substances into the

other membranes.

blood, as is discussed in later chapters.

The basic mechanism for transport of a substance

through a cellular sheet is (1) active transport through

the cell membrane on one side of the transporting cells

in the sheet, and then (2) either simple diffusion or

facilitated diffusion through the membrane on the

Na⁺

Glucose

opposite side of the cell.

Figure

4-13 shows a mechanism for transport

Na-binding

Glucose-binding

of sodium ions through the epithelial sheet of the

site

intestines, gallbladder, and renal tubules. This figure

shows that the epithelial cells are connected together

tightly at the luminal pole by means of junctions called

“kisses.” The brush border on the luminal surfaces of

the cells is permeable to both sodium ions and water.

Therefore, sodium and water diffuse readily from the

lumen into the interior of the cell. Then, at the basal

and lateral membranes of the cells, sodium ions are

Na⁺

Glucose

actively transported into the extracellular fluid of

the surrounding connective tissue and blood vessels.

Figure 4-12

This creates a high sodium ion concentration gradient

Postulated mechanism for sodium co-transport of glucose.

across these membranes, which in turn causes osmosis

Unit II

Membrane Physiology, Nerve, and Muscle

Brush

Basement

References

border

membrane

Agre P, Kozono D: Aquaporin water channels: molecular

mechanisms for human diseases. FEBS Lett 555:72, 2003.

Benos DJ, Stanton BA: Functional domains within the

Na⁺

degenerin/epithelial sodium channel (Deg/ENaC) super-

Active

family of ion channels. J Physiol 520:631, 1999.

transport

Osmosis

Na⁺

Caplan MJ: Ion pump sorting in polarized renal epithelial

and

cells. Kidney Int 60:427, 2001.

H₂

Decoursey TE: Voltage-gated proton channels and other

Active

Osmosis

proton transfer pathways. Physiol Rev 83:475, 2003.

transport

Active

De Weer P: A century of thinking about cell membranes.

Na⁺

transport

Annu Rev Physiol 62:919, 2000.

Osmosis

Dolphin AC: G protein modulation of voltage-gated calcium

channels. Pharmacol Rev 55:607, 2003.

Diffusion

Jentsch TJ, Stein V, Weinreich F, Zdebik AA: Molecular

structure and physiological function of chloride channels.

Figure 4-13

Physiol Rev 82:503, 2002.

Kaupp UB, Seifert R: Cyclic nucleotide-gated ion channels.

Basic mechanism of active transport across a layer of cells.

Physiol Rev 82:769, 2002.

Kellenberger S, Schild L: Epithelial sodium channel/

degenerin family of ion channels: a variety of functions for

a shared structure. Physiol Rev 82:735, 2002.

MacKinnon R: Potassium channels. FEBS Lett 555:62, 2003.

Peres A, Giovannardi S, Bossi E, Fesce R: Electrophysiolog-

of water as well. Thus, active transport of sodium ions

ical insights into the mechanism of ion-coupled cotrans-

at the basolateral sides of the epithelial cells results in

porters. News Physiol Sci 19:80, 2004.

Philipson KD, Nicoll DA, Ottolia M, et al: The Na⁺/Ca²⁺

transport not only of sodium ions but also of water.

exchange molecule: an overview. Ann N Y Acad Sci 976:1,

These are the mechanisms by which almost all the

2002.

nutrients, ions, and other substances are absorbed into

Rossier BC, Pradervand S, Schild L, Hummler E: Epithelial

the blood from the intestine; they are also the way the

sodium channel and the control of sodium balance: inter-

same substances are reabsorbed from the glomerular

action between genetic and environmental factors. Annu

filtrate by the renal tubules.

Rev Physiol 64:877, 2002.

Throughout this text are numerous examples of the

Russell JM: Sodium-potassium-chloride cotransport. Physiol

different types of transport discussed in this chapter.

Rev 80:211, 2000.

C H A P T E R

Membrane Potentials and

Action Potentials

Electrical potentials exist across the membranes of

virtually all cells of the body. In addition, some cells,

such as nerve and muscle cells, are capable of gen-

erating rapidly changing electrochemical impulses

at their membranes, and these impulses are used to

transmit signals along the nerve or muscle mem-

branes. In still other types of cells, such as glandular

cells, macrophages, and ciliated cells, local changes

in membrane potentials also activate many of the cells’ functions. The present

discussion is concerned with membrane potentials generated both at rest and

during action by nerve and muscle cells.

Basic Physics of Membrane Potentials

Membrane Potentials Caused by Diffusion

“Diffusion Potential” Caused by an Ion Concentration Difference on the Two Sides of the

Membrane. In Figure 5-1A, the potassium concentration is great inside a nerve

fiber membrane but very low outside the membrane. Let us assume that the

membrane in this instance is permeable to the potassium ions but not to any

other ions. Because of the large potassium concentration gradient from inside

toward outside, there is a strong tendency for extra numbers of potassium ions

to diffuse outward through the membrane. As they do so, they carry positive

electrical charges to the outside, thus creating electropositivity outside the

membrane and electronegativity inside because of negative anions that remain

behind and do not diffuse outward with the potassium. Within a millisecond or

so, the potential difference between the inside and outside, called the diffusion

potential, becomes great enough to block further net potassium diffusion to the

exterior, despite the high potassium ion concentration gradient. In the normal

mammalian nerve fiber, the potential difference required is about 94 millivolts,

with negativity inside the fiber membrane.

Figure 5-1B shows the same phenomenon as in Figure 5-1A, but this time

with high concentration of sodium ions outside the membrane and low sodium

inside. These ions are also positively charged. This time, the membrane is highly

permeable to the sodium ions but impermeable to all other ions. Diffusion of

the positively charged sodium ions to the inside creates a membrane potential

of opposite polarity to that in Figure 5-1A, with negativity outside and positiv-

ity inside. Again, the membrane potential rises high enough within milliseconds

to block further net diffusion of sodium ions to the inside; however, this time,

in the mammalian nerve fiber, the potential is about 61 millivolts positive inside

the fiber.

Thus, in both parts of Figure 5-1, we see that a concentration difference of

ions across a selectively permeable membrane can, under appropriate condi-

tions, create a membrane potential. In later sections of this chapter, we show

that many of the rapid changes in membrane potentials observed during nerve

and muscle impulse transmission result from the occurrence of such rapidly

changing diffusion potentials.

Unit II

Membrane Physiology, Nerve, and Muscle

three factors: (1) the polarity of the electrical charge

of each ion, (2) the permeability of the membrane (P)

DIFFUSION POTENTIALS

to each ion, and (3) the concentrations (C) of the

Nerve fiber

(Anions)^-

respective ions on the inside (i) and outside (o) of

the membrane. Thus, the following formula, called the

(Anions)^-

–

Goldman equation, or the Goldman-Hodgkin-Katz

–

equation, gives the calculated membrane potential on

–

K⁺

Na⁺

the inside of the membrane when two univalent posi-

–

tive ions, sodium (Na⁺) and potassium (K⁺), and one

–

univalent negative ion, chloride (Cl^-), are involved.

(- 94 mV)

(+ 61 mV)

–

EMF (millivolts)

Na+i Na

K+i K

=-61◊log

C P ++C P ++C P

Na+o Na

K o K

Let us study the importance and the meaning of this

Figure 5-1

equation. First, sodium, potassium, and chloride ions

are the most important ions involved in the develop-

A, Establishment of a “diffusion” potential across a nerve fiber

ment of membrane potentials in nerve and muscle

membrane, caused by diffusion of potassium ions from inside the

fibers, as well as in the neuronal cells in the nervous

cell to outside through a membrane that is selectively permeable

system. The concentration gradient of each of these

only to potassium. B, Establishment of a “diffusion potential” when

the nerve fiber membrane is permeable only to sodium ions. Note

ions across the membrane helps determine the voltage

that the internal membrane potential is negative when potassium

of the membrane potential.

ions diffuse and positive when sodium ions diffuse because of

Second, the degree of importance of each of the ions

opposite concentration gradients of these two ions.

in determining the voltage is proportional to the mem-

brane permeability for that particular ion. That is, if the

Relation of the Diffusion Potential to the Concentration Differ-

membrane has zero permeability to both potassium

ence—The Nernst Potential. The diffusion potential level

and chloride ions, the membrane potential becomes

across a membrane that exactly opposes the net diffu-

entirely dominated by the concentration gradient of

sion of a particular ion through the membrane is called

sodium ions alone, and the resulting potential will be

the Nernst potential for that ion, a term that was intro-

equal to the Nernst potential for sodium. The same

duced in Chapter 4. The magnitude of this Nernst

holds for each of the other two ions if the membrane

potential is determined by the ratio of the concentra-

should become selectively permeable for either one of

tions of that specific ion on the two sides of the mem-

them alone.

brane. The greater this ratio, the greater the tendency

Third, a positive ion concentration gradient from

for the ion to diffuse in one direction, and therefore

inside the membrane to the outside causes electroneg-

the greater the Nernst potential required to prevent

ativity inside the membrane. The reason for this is that

additional net diffusion. The following equation, called

excess positive ions diffuse to the outside when their

the Nernst equation, can be used to calculate the

concentration is higher inside than outside. This carries

Nernst potential for any univalent ion at normal body

positive charges to the outside but leaves the nondif-

temperature of 98.6°F (37°C):

fusible negative anions on the inside, thus creating

electronegativity on the inside. The opposite effect

Concentration inside

EMF (millivolts) = ± 61log

occurs when there is a gradient for a negative ion. That

Concentration outside

is, a chloride ion gradient from the outside to the inside

where EMF is electromotive force.

causes negativity inside the cell because excess nega-

When using this formula, it is usually assumed that

tively charged chloride ions diffuse to the inside, while

the potential in the extracellular fluid outside the

leaving the nondiffusible positive ions on the outside.

membrane remains at zero potential, and the Nernst

Fourth, as explained later, the permeability of the

potential is the potential inside the membrane. Also,

sodium and potassium channels undergoes rapid

the sign of the potential is positive (+) if the ion dif-

changes during transmission of a nerve impulse,

fusing from inside to outside is a negative ion, and it

whereas the permeability of the chloride channels

is negative (-) if the ion is positive. Thus, when the con-

does not change greatly during this process. Therefore,

centration of positive potassium ions on the inside is

rapid changes in sodium and potassium permeability

10 times that on the outside, the log of 10 is 1, so that

are primarily responsible for signal transmission in

the Nernst potential calculates to be -61 millivolts

nerves, which is the subject of most of the remainder

inside the membrane.

of this chapter.

Calculation of the Diffusion Potential

Measuring the Membrane

When the Membrane Is Permeable to

Potential

Several Different Ions

When a membrane is permeable to several different

The method for measuring the membrane potential is

ions, the diffusion potential that develops depends on

simple in theory but often difficult in practice because

Chapter 5

Membrane Potentials and Action Potentials

Nerve fiber

- + - + - + - + - + - + - + -

+ - + + - - + - + - - + + - +

- + - + - + - + - + - + - + -

+ - + + - - + - + - - + + - +

– + - + - + - + - + - + - + -

—

+ - + + - - + - + - - + + - +

- + - + - + - + - + - + - + -

+ - + + - - + - + - - + + - +

- + - + - + - + - + - + - + -

+ - + + - - + - + - - + + - +

Silver-silver

chloride

+ + + + + + + + + + +

+ + + + +

- - - - - - - - - -

- - - - -

electrode

(- 90

– - - - - - - - -

- - - - - - -

+ + + + + + + + +

mV)+ + + + + + + +

-90

Figure 5-2

Figure 5-3

Measurement of the membrane potential of the nerve fiber using

a microelectrode.

Distribution of positively and negatively charged ions in the extra-

cellular fluid surrounding a nerve fiber and in the fluid inside the

fiber; note the alignment of negative charges along the inside

of the small size of most of the fibers. Figure 5-2 shows

surface of the membrane and positive charges along the outside

a small pipette filled with an electrolyte solution. The

surface. The lower panel displays the abrupt changes in mem-

brane potential that occur at the membranes on the two sides of

pipette is impaled through the cell membrane to

the fiber.

the interior of the fiber. Then another electrode, called

the “indifferent electrode,” is placed in the extracellular

fluid, and the potential difference between the inside

and outside of the fiber is measured using an appropri-

equally small number of positive ions moving from

ate voltmeter. This voltmeter is a highly sophisticated

outside to inside the fiber can reverse the potential from

electronic apparatus that is capable of measuring very

-90 millivolts to as much as +35 millivolts within as little

small voltages despite extremely high resistance to elec-

as 1/10,000 of a second. Rapid shifting of ions in this

trical flow through the tip of the micropipette, which

manner causes the nerve signals discussed in subse-

has a lumen diameter usually less than 1 micrometer

quent sections of this chapter.

and a resistance more than a million ohms. For record-

ing rapid changes in the membrane potential during

Resting Membrane Potential

transmission of nerve impulses, the microelectrode is

connected to an oscilloscope, as explained later in the

of Nerves

chapter.

The lower part of Figure 5-3 shows the electrical

The resting membrane potential of large nerve fibers

potential that is measured at each point in or near the

when not transmitting nerve signals is about

-90

nerve fiber membrane, beginning at the left side of the

millivolts. That is, the potential inside the fiber is 90

figure and passing to the right. As long as the electrode

millivolts more negative than the potential in the extra-

is outside the nerve membrane, the recorded potential

cellular fluid on the outside of the fiber. In the next few

is zero, which is the potential of the extracellular fluid.

Then, as the recording electrode passes through the

paragraphs, we explain all the factors that determine

voltage change area at the cell membrane (called the

the level of this resting potential, but before doing so,

electrical dipole layer), the potential decreases abruptly

we must describe the transport properties of the resting

to -90 millivolts. Moving across the center of the fiber,

nerve membrane for sodium and potassium.

the potential remains at a steady -90-millivolt level but

reverses back to zero the instant it passes through the

Active Transport of Sodium and Potassium Ions Through the

membrane on the opposite side of the fiber.

Membrane—The Sodium-Potassium (Na⁺-K⁺) Pump. First, let

To create a negative potential inside the membrane,

us recall from Chapter 4 that all cell membranes of the

only enough positive ions to develop the electrical

body have a powerful Na⁺-K⁺ that continually pumps

dipole layer at the membrane itself must be transported

sodium ions to the outside of the cell and potassium

outward. All the remaining ions inside the nerve fiber

ions to the inside, as illustrated on the left-hand side in

can be both positive and negative, as shown in the upper

Figure 5-4. Further, note that this is an electrogenic

panel of Figure 5-3. Therefore, an incredibly small

pump because more positive charges are pumped to

number of ions needs to be transferred through the

the outside than to the inside (three Na⁺ ions to the

membrane to establish the normal “resting potential” of

-90 millivolts inside the nerve fiber; this means that only

outside for each two K⁺ ions to the inside), leaving a

about 1/3,000,000 to 1/100,000,000 of the total positive

net deficit of positive ions on the inside; this causes a

charges inside the fiber needs to be transferred. Also, an

negative potential inside the cell membrane.

Unit II

Membrane Physiology, Nerve, and Muscle

Outside

3Na⁺

2K⁺

Na⁺

K⁺

4 mEq/L

K⁺

140 mEq/L

(-94 mV)

Na⁺

K⁺

ATP

Na⁺

K⁺

ADP

K⁺-Na⁺

Na⁺

K⁺

Na⁺-K⁺pump

"leak" channels

142 mEq/L

4 mEq/L

Figure 5-4

Na⁺

K⁺

Functional characteristics of the Na⁺-K⁺ pump and of the K⁺-Na⁺

14 mEq/L

140 mEq/L

(-86 mV)

“leak” channels. ADP, adenosine diphosphate; ATP, adenosine

triphosphate.

(+61 mV)

(-94 mV)

The Na⁺-K⁺ also causes large concentration gradi-

ents for sodium and potassium across the resting nerve

Diffusion

membrane. These gradients are the following:

Na⁺

Na⁺ (outside):

142 mEq/L

pump

Na⁺ (inside):

14 mEq/L

142 mEq/L

14 mEq/L

K⁺ (outside):

4 mEq/L

K⁺ (inside):

140 mEq/L

Diffusion

The ratios of these two respective ions from the inside

to the outside are

K⁺

pump

Na+inside/Na+outside = 0.1

4 mEq/L

140 mEq/L

K+inside/K+outside = 35.0

(-90 mV)

Leakage of Potassium and Sodium Through the Nerve Mem-

brane. The right side of Figure 5-4 shows a channel

(Anions)^-

protein in the nerve membrane through which potas-

sium and sodium ions can leak, called a potassium-

sodium (K⁺-Na⁺) “leak” channel. The emphasis is on

potassium leakage because, on average, the channels

are far more permeable to potassium than to sodium,

Figure 5-5

normally about 100 times as permeable. As discussed

later, this differential in permeability is exceedingly

Establishment of resting membrane potentials in nerve

fibers

under three conditions: A, when the membrane potential is caused

important in determining the level of the normal

entirely by potassium diffusion alone; B, when the membrane

resting membrane potential.

potential is caused by diffusion of both sodium and potassium

ions; and C, when the membrane potential is caused by diffusion

of both sodium and potassium ions plus pumping of both these

Origin of the Normal Resting

ions by the Na⁺-K⁺ pump.

Membrane Potential

Figure 5-5 shows the important factors in the estab-

potential corresponding to this ratio is -94 millivolts

lishment of the normal resting membrane potential of

because the logarithm of 35 is 1.54, and this times -61

-90 millivolts. They are as follows.

millivolts is -94 millivolts. Therefore, if potassium ions

were the only factor causing the resting potential, the

Contribution of the Potassium Diffusion Potential. In Figure

resting potential inside the fiber would be equal to -94

5-5A, we make the assumption that the only move-

millivolts, as shown in the figure.

ment of ions through the membrane is diffusion of

potassium ions, as demonstrated by the open channels

Contribution of Sodium Diffusion Through the Nerve Membrane.

between the potassium symbols

(K⁺) inside and

Figure 5-5B shows the addition of slight permeability

outside the membrane. Because of the high ratio of

of the nerve membrane to sodium ions, caused by the

potassium ions inside to outside, 35:1, the Nernst

minute diffusion of sodium ions through the K⁺-Na⁺

Chapter 5

Membrane Potentials and Action Potentials

leak channels. The ratio of sodium ions from inside to

outside the membrane is 0.1, and this gives a calculated

Nernst potential for the inside of the membrane of

+61 millivolts. But also shown in Figure 5-5B is the

Nernst potential for potassium diffusion of -94 milli-

—

volts. How do these interact with each other, and what

will be the summated potential? This can be answered

by using the Goldman equation described previously.

Silver-silver

Intuitively, one can see that if the membrane is highly

chloride

+ + + +

– - - -

+ + + + +

electrode

permeable to potassium but only slightly permeable to

– - - -

- - - - -

+ + + +

sodium, it is logical that the diffusion of potassium con-

tributes far more to the membrane potential than does

+ + + +

- - - -

- - - - - -

the diffusion of sodium. In the normal nerve fiber, the

+ + + +

- - - -

+ + + + + +

permeability of the membrane to potassium is about

100 times as great as its permeability to sodium. Using

this value in the Goldman equation gives a potential

Overshoot

inside the membrane of -86 millivolts, which is near

+35

the potassium potential shown in the figure.

Contribution of the Na⁺-K⁺ Pump. In Figure

5-5C, the

Na⁺-K⁺ pump is shown to provide an additional con-

tribution to the resting potential. In this figure, there

is continuous pumping of three sodium ions to the

outside for each two potassium ions pumped to the

inside of the membrane. The fact that more sodium

ions are being pumped to the outside than potassium

-90

to the inside causes continual loss of positive charges

Resting

from inside the membrane; this creates an additional

degree of negativity (about -4 millivolts additional) on

0.1 0.2 0.3 0.4 0.5 0.6 0.7

the inside beyond that which can be accounted for by

Milliseconds

diffusion alone. Therefore, as shown in Figure 5-5C,

the net membrane potential with all these factors

operative at the same time is about -90 millivolts.

In summary, the diffusion potentials alone caused by

Figure 5-6

potassium and sodium diffusion would give a mem-

brane potential of about -86 millivolts, almost all of

Typical action potential recorded by the method shown in the

upper panel of the figure.

this being determined by potassium diffusion. Then, an

additional -4 millivolts is contributed to the mem-

brane potential by the continuously acting electro-

genic Na⁺-K⁺ pump, giving a net membrane potential

explosive onset of the action potential and the

of -90 millivolts.

almost equally rapid recovery.

The successive stages of the action potential are as

follows.

Nerve Action Potential

Resting Stage. This is the resting membrane potential

Nerve signals are transmitted by action potentials,

before the action potential begins. The membrane is

which are rapid changes in the membrane potential

said to be “polarized” during this stage because of the

that spread rapidly along the nerve fiber membrane.

-90 millivolts negative membrane potential that is

Each action potential begins with a sudden change

present.

from the normal resting negative membrane potential

to a positive potential and then ends with an almost

Depolarization Stage. At this time, the membrane sud-

equally rapid change back to the negative potential.

denly becomes very permeable to sodium ions, allow-

To conduct a nerve signal, the action potential moves

ing tremendous numbers of positively charged sodium

along the nerve fiber until it comes to the fiber’s

ions to diffuse to the interior of the axon. The normal

end.

“polarized” state of -90 millivolts is immediately neu-

The upper panel of Figure 5-6 shows the changes

tralized by the inflowing positively charged sodium

that occur at the membrane during the action poten-

ions, with the potential rising rapidly in the positive

tial, with transfer of positive charges to the interior of

direction. This is called depolarization. In large nerve

the fiber at its onset and return of positive charges to

fibers, the great excess of positive sodium ions moving

the exterior at its end. The lower panel shows graphi-

to the inside causes the membrane potential to actu-

cally the successive changes in membrane potential

ally “overshoot” beyond the zero level and to become

over a few 10,000ths of a second, illustrating the

somewhat positive. In some smaller fibers, as well as in

Unit II

Membrane Physiology, Nerve, and Muscle

many central nervous system neurons, the potential

Activation

merely approaches the zero level and does not over-

gate

Na⁺

shoot to the positive state.

Repolarization Stage. Within a few 10,000ths of a second

after the membrane becomes highly permeable to

sodium ions, the sodium channels begin to close and

the potassium channels open more than normal.

Inactivation

Then, rapid diffusion of potassium ions to the exterior

gate

re-establishes the normal negative resting mem-

Resting

Activated

Inactivated

brane potential. This is called repolarization of the

(-90 mV)

(-90 to +35 mV)

(+35 to -90 mV,

membrane.

delayed)

To explain more fully the factors that cause both

depolarization and repolarization, we need to describe

the special characteristics of two other types of trans-

port channels through the nerve membrane: the

voltage-gated sodium and potassium channels.

K⁺

Voltage-Gated Sodium and

Resting

Slow activation

(-90 mV)

(+35 to -90 mV)

Potassium Channels

Inside

Figure 5-7

The necessary actor in causing both depolarization

and repolarization of the nerve membrane during the

Characteristics of the voltage-gated sodium (top) and potassium

action potential is the voltage-gated sodium channel. A

(bottom) channels, showing successive activation and inactiva-

voltage-gated potassium channel also plays an impor-

tion of the sodium channels and delayed activation of the potas-

sium channels when the membrane potential is changed from the

tant role in increasing the rapidity of repolarization of

normal resting negative value to a positive value.

the membrane. These two voltage-gated channels are

in addition to the Na⁺-K⁺ pump and the K⁺-Na⁺ leak

channels.

Voltage-Gated Sodium Channel—Activation

conformational change that flips the inactivation gate

and Inactivation of the Channel

to the closed state is a slower process than the con-

The upper panel of Figure 5-7 shows the voltage-gated

formational change that opens the activation gate.

sodium channel in three separate states. This channel

Therefore, after the sodium channel has remained

has two gates—one near the outside of the channel

open for a few 10,000ths of a second, the inactivation

called the activation gate, and another near the inside

gate closes, and sodium ions no longer can pour to the

called the inactivation gate. The upper left of the figure

inside of the membrane. At this point, the membrane

depicts the state of these two gates in the normal

potential begins to recover back toward the resting

resting membrane when the membrane potential is

membrane state, which is the repolarization process.

-90 millivolts. In this state, the activation gate is closed,

Another important characteristic of the sodium

which prevents any entry of sodium ions to the inte-

channel inactivation process is that the inactivation

rior of the fiber through these sodium channels.

gate will not reopen until the membrane potential

returns to or near the original resting membrane

Activation of the Sodium Channel. When the membrane

potential level. Therefore, it usually is not possible for

potential becomes less negative than during the

the sodium channels to open again without the nerve

resting state, rising from -90 millivolts toward zero, it

fiber’s first repolarizing.

finally reaches a voltage—usually somewhere between

-70 and -50 millivolts—that causes a sudden confor-

Voltage-Gated Potassium Channel and

mational change in the activation gate, flipping it all

Its Activation

the way to the open position. This is called the acti-

The lower panel of Figure 5-7 shows the voltage-gated

vated state; during this state, sodium ions can pour

potassium channel in two states: during the resting

inward through the channel, increasing the sodium

state (left) and toward the end of the action potential

permeability of the membrane as much as 500- to

(right). During the resting state, the gate of the potas-

5000-fold.

sium channel is closed, and potassium ions are pre-

vented from passing through this channel to the

Inactivation of the Sodium Channel. The upper right panel

exterior. When the membrane potential rises from

of Figure

5-7 shows a third state of the sodium

-90 millivolts toward zero, this voltage change causes

channel. The same increase in voltage that opens the

a conformational opening of the gate and allows

activation gate also closes the inactivation gate. The

increased potassium diffusion outward through the

inactivation gate, however, closes a few 10,000ths of

channel. However, because of the slight delay in

a second after the activation gate opens. That is, the

opening of the potassium channels, for the most part,

Chapter 5

Membrane Potentials and Action Potentials

they open just at the same time that the sodium chan-

Figure 5-8 shows an experimental apparatus called a

nels are beginning to close because of inactivation.

voltage clamp, which is used to measure flow of ions

Thus, the decrease in sodium entry to the cell and the

through the different channels. In using this apparatus,

two electrodes are inserted into the nerve fiber. One of

simultaneous increase in potassium exit from the cell

these is to measure the voltage of the membrane poten-

combine to speed the repolarization process, leading

tial, and the other is to conduct electrical current into

to full recovery of the resting membrane potential

or out of the nerve fiber. This apparatus is used in the

within another few 10,000ths of a second.

following way: The investigator decides which voltage

he or she wants to establish inside the nerve fiber. The

Research Method for Measuring the Effect of Voltage on Opening

electronic portion of the apparatus is then adjusted to

and Closing of the Voltage-Gated Channels—The

“Voltage

the desired voltage, and this automatically injects either

Clamp.” The original research that led to quantitative

positive or negative electricity through the current elec-

understanding of the sodium and potassium channels

trode at whatever rate is required to hold the voltage,

was so ingenious that it led to Nobel Prizes for the sci-

as measured by the voltage electrode, at the level set by

entists responsible, Hodgkin and Huxley. The essence of

the operator. When the membrane potential is suddenly

these studies is shown in Figures 5-8 and 5-9.

increased by this voltage clamp from -90 millivolts to

zero, the voltage-gated sodium and potassium channels

open, and sodium and potassium ions begin to pour

through the channels. To counterbalance the effect of

these ion movements on the desired setting of the intra-

cellular voltage, electrical current is injected automati-

Amplifier

cally through the current electrode of the voltage clamp

to maintain the intracellular voltage at the required

steady zero level. To achieve this, the current injected

must be equal to but of opposite polarity to the net

Electrode

current flow through the membrane channels. To

in fluid

measure how much current flow is occurring at each

Voltage

Current

instant, the current electrode is connected to an oscillo-

electrode

scope that records the current flow, as demonstrated on

the screen of the oscilloscope in Figure 5-8. Finally, the

investigator adjusts the concentrations of the ions to

other than normal levels both inside and outside the

nerve fiber and repeats the study. This can be done

easily when using large nerve fibers removed from some

Figure 5-8

crustaceans, especially the giant squid axon, which in

“Voltage clamp” method for studying flow of ions through specific

some cases is as large as 1 millimeter in diameter. When

channels.

sodium is the only permeant ion in the solutions inside

and outside the squid axon, the voltage clamp measures

current flow only through the sodium channels. When

potassium is the only permeant ion, current flow only

through the potassium channels is measured.

Another means for studying the flow of ions through

an individual type of channel is to block one type of

channel at a time. For instance, the sodium channels can

Na⁺channel

K⁺channel

be blocked by a toxin called tetrodotoxin by applying it

to the outside of the cell membrane where the sodium

activation gates are located. Conversely, tetraethylam-

monium ion blocks the potassium channels when it is

applied to the interior of the nerve fiber.

Figure 5-9 shows typical changes in conductance of

the voltage-gated sodium and potassium channels when

the membrane potential is suddenly changed by use of

- 90 mV

+10 mV

- 90 mV

the voltage clamp from -90 millivolts to +10 millivolts

Membrane potential

and then, 2 milliseconds later, back to -90 millivolts.

Note the sudden opening of the sodium channels (the

activation stage) within a small fraction of a millisecond

Time (milliseconds)

after the membrane potential is increased to the posi-

tive value. However, during the next millisecond or so,

the sodium channels automatically close (the inactiva-

Figure 5-9

tion stage).

Note the opening (activation) of the potassium chan-

Typical changes in conductance of sodium and potassium ion

nels. These open slowly and reach their full open state

channels when the membrane potential is suddenly increased

only after the sodium channels have almost completely

from the normal resting value of -90 millivolts to a positive value

closed. Further, once the potassium channels open, they

of +10 millivolts for 2 milliseconds. This figure shows that the

remain open for the entire duration of the positive

sodium channels open (activate) and then close

(inactivate)

membrane potential and do not close again until after

before the end of the 2 milliseconds, whereas the potassium chan-

the membrane potential is decreased back to a negative

nels only open (activate), and the rate of opening is much slower

than that of the sodium channels.

value.

Unit II

Membrane Physiology, Nerve, and Muscle

Summary of the Events That Cause

close back to their original status, but again, only after

an additional millisecond or more delay.

the Action Potential

The middle portion of Figure 5-10 shows the ratio

of sodium conductance to potassium conductance at

Figure 5-10 shows in summary form the sequential

each instant during the action potential, and above this

events that occur during and shortly after the action

is the action potential itself. During the early portion

potential. The bottom of the figure shows the changes

of the action potential, the ratio of sodium to potas-

in membrane conductance for sodium and potassium

sium conductance increases more than

1000-fold.

ions. During the resting state, before the action

Therefore, far more sodium ions flow to the interior of

potential begins, the conductance for potassium ions is

the fiber than do potassium ions to the exterior. This

50 to 100 times as great as the conductance for sodium

is what causes the membrane potential to become

ions. This is caused by much greater leakage of potas-

positive at the action potential onset. Then the sodium

sium ions than sodium ions through the leak channels.

channels begin to close and the potassium channels to

However, at the onset of the action potential, the

open, so that the ratio of conductance shifts far in

sodium channels instantaneously become activated

favor of high potassium conductance but low sodium

and allow up to a 5000-fold increase in sodium con-

conductance. This allows very rapid loss of potassium

ductance. Then the inactivation process closes the

ions to the exterior but virtually zero flow of

sodium channels within another fraction of a millisec-

sodium ions to the interior. Consequently, the action

ond. The onset of the action potential also causes

potential quickly returns to its baseline level.

voltage gating of the potassium channels, causing them

to begin opening more slowly a fraction of a millisec-

ond after the sodium channels open. At the end of the

Roles of Other Ions During

action potential, the return of the membrane potential

to the negative state causes the potassium channels to

the Action Potential

Thus far, we have considered only the roles of sodium

and potassium ions in the generation of the action

potential. At least two other types of ions must be con-

sidered: negative anions and calcium ions.

Impermeant Negatively Charged Ions (Anions) Inside the Nerve

Axon. Inside the axon are many negatively charged ions

+ 60

Overshoot

that cannot go through the membrane channels. They

+ 40

+ 20

include the anions of protein molecules and of many

100

organic phosphate compounds, sulfate compounds, and

- 20

so forth. Because these ions cannot leave the interior of

- 40

the axon, any deficit of positive ions inside the mem-

- 60

brane leaves an excess of these impermeant negative

- 80

anions. Therefore, these impermeant negative ions are

-100

responsible for the negative charge inside the fiber

0.1

Positive

when there is a net deficit of positively charged potas-

afterpotential

sium ions and other positive ions.

0.01

0.001

Calcium Ions. The membranes of almost all cells of the

Action potential

100

body have a calcium pump similar to the sodium pump,

Ratio of conductances

and calcium serves along with (or instead of) sodium in

Na⁺

K⁺

some cells to cause most of the action potential. Like

the sodium pump, the calcium pump pumps calcium

ions from the interior to the exterior of the cell mem-

brane (or into the endoplasmic reticulum of the cell),

0.1

creating a calcium ion gradient of about 10,000-fold.

This leaves an internal cell concentration of calcium

0.01

0.005

ions of about 10^-7 molar, in contrast to an external con-

0.5

1.0

1.5

centration of about 10^-3 molar.

Milliseconds

In addition, there are voltage-gated calcium channels.

These channels are slightly permeable to sodium ions as

well as to calcium ions; when they open, both calcium

Figure 5-10

and sodium ions flow to the interior of the fiber. There-

fore, these channels are also called Ca⁺⁺-Na⁺ channels.

Changes in sodium

and potassium conductance during

the

The calcium channels are slow to become activated,

course of the action potential. Sodium conductance increases

requiring 10 to 20 times as long for activation as the

several thousand-fold during the early stages of the action poten-

sodium channels. Therefore, they are called slow chan-

tial, whereas potassium conductance increases only about 30-fold

nels, in contrast to the sodium channels, which are called

during the latter stages of the action potential and for a short

fast channels.

period thereafter. (These curves were constructed from theory pre-

Calcium channels are numerous in both cardiac

sented in papers by Hodgkin and Huxley but transposed from

squid axon to apply to the membrane potentials of large mam-

muscle and smooth muscle. In fact, in some types of

malian nerve fibers.)

smooth muscle, the fast sodium channels are hardly

Chapter 5

Membrane Potentials and Action Potentials

present, so that the action potentials are caused almost

fiber from -90 millivolts up to about -65 millivolts

entirely by activation of slow calcium channels.

usually causes the explosive development of an action

potential. This level of -65 millivolts is said to be the

Increased Permeability of the Sodium Channels When

threshold for stimulation.

There Is a Deficit of Calcium Ions. The concentration of

calcium ions in the extracellular fluid also has a pro-

found effect on the voltage level at which the sodium

Propagation of the

channels become activated. When there is a deficit of

Action Potential

calcium ions, the sodium channels become activated

(opened) by very little increase of the membrane poten-

tial from its normal, very negative level. Therefore, the

In the preceding paragraphs, we discussed the action

nerve fiber becomes highly excitable, sometimes dis-

potential as it occurs at one spot on the membrane.

charging repetitively without provocation rather than

However, an action potential elicited at any one point

remaining in the resting state. In fact, the calcium ion

on an excitable membrane usually excites adjacent

concentration needs to fall only 50 per cent below

portions of the membrane, resulting in propagation of

normal before spontaneous discharge occurs in some

the action potential along the membrane. This mecha-

peripheral nerves, often causing muscle “tetany.” This is

nism is demonstrated in Figure 5-11. Figure 5-11A

sometimes lethal because of tetanic contraction of the

shows a normal resting nerve fiber, and Figure 5-11B

respiratory muscles.

shows a nerve fiber that has been excited in its mid-

The probable way in which calcium ions affect the

portion—that is, the midportion suddenly develops

sodium channels is as follows: These ions appear to bind

to the exterior surfaces of the sodium channel protein

increased permeability to sodium. The arrows show a

molecule. The positive charges of these calcium ions

“local circuit” of current flow from the depolarized

in turn alter the electrical state of the channel protein

areas of the membrane to the adjacent resting mem-

itself, in this way altering the voltage level required to

brane areas. That is, positive electrical charges are

open the sodium gate.

carried by the inward-diffusing sodium ions through

the depolarized membrane and then for several mil-

limeters in both directions along the core of the axon.

Initiation of the Action Potential

These positive charges increase the voltage for a dis-

tance of 1 to 3 millimeters inside the large myelinated

Up to this point, we have explained the changing

sodium and potassium permeability of the membrane,

as well as the development of the action potential

itself, but we have not explained what initiates the

action potential. The answer is quite simple.

+ + + + + + + + + + + + + + + + + + + + + + +

- - - - - - - - - - - - - - - - - - - - - - -

A Positive-Feedback Vicious Cycle Opens the Sodium Channels.

First, as long as the membrane of the nerve fiber

- - - - - - - - - - - - - - - - - - - - - - -

remains undisturbed, no action potential occurs in the

+ + + + + + + + + + + + + + + + + + + + + + +

normal nerve. However, if any event causes enough

initial rise in the membrane potential from -90 milli-

+ + + + + + + + + + + + - - + + + + + + + + +

volts toward the zero level, the rising voltage itself

- - - - - - - - - - - - + + - - - - - - - - -

causes many voltage-gated sodium channels to begin

opening. This allows rapid inflow of sodium ions, which

- - - - - - - - - - - - + + - - - - - - - - -

causes a further rise in the membrane potential, thus

+ + + + + + + + + + + + - - + + + + + + + + +

opening still more voltage-gated sodium channels and

allowing more streaming of sodium ions to the interior

of the fiber. This process is a positive-feedback vicious

+ + + + + + + + + + - - - - + + + + + + + +

cycle that, once the feedback is strong enough, contin-

- - - - - - - - - - + + + + - - - - - - - -

ues until all the voltage-gated sodium channels have

- - - - - - - - - - + + + + - - - - - - - -

become activated (opened). Then, within another frac-

+ + + + + + + + + + - - - - + + + + + + + +

tion of a millisecond, the rising membrane potential

causes closure of the sodium channels as well as

opening of potassium channels, and the action poten-

+ + - - - - - - - - - - - - - - - - - - + +

tial soon terminates.

- - + + + + + + + + + + + + + + + + + + - -

Threshold for Initiation of the Action Potential. An action

- - + + + + + + + + + + + + + + + + + + - -

potential will not occur until the initial rise in mem-

+ + - - - - - - - - - - - - - - - - - - + +

brane potential is great enough to create the vicious

cycle described in the preceding paragraph. This

occurs when the number of Na⁺ ions entering the fiber

becomes greater than the number of K⁺ ions leaving

Figure 5-11

the fiber. A sudden rise in membrane potential of 15

to 30 millivolts usually is required. Therefore, a sudden

Propagation of action potentials in both directions along a con-

increase in the membrane potential in a large nerve

ductive fiber.

Unit II

Membrane Physiology, Nerve, and Muscle

fiber to above the threshold voltage value for initiat-

ing an action potential. Therefore, the sodium channels

in these new areas immediately open, as shown in

Figure 5-11C and D, and the explosive action poten-

tial spreads. These newly depolarized areas produce

still more local circuits of current flow farther along

the membrane, causing progressively more and more

depolarization. Thus, the depolarization process

travels along the entire length of the fiber. This trans-

mission of the depolarization process along a nerve or

muscle fiber is called a nerve or muscle impulse.

At rest

Direction of Propagation. As demonstrated in Figure

5-11, an excitable membrane has no single direction

100

200

300

of propagation, but the action potential travels in all

Impulses per second

directions away from the stimulus—even along all

branches of a nerve fiber—until the entire membrane

has become depolarized.

Figure 5-12

All-or-Nothing Principle. Once an action potential has

Heat production in a nerve fiber at rest and at progressively

been elicited at any point on the membrane of a

increasing rates of stimulation.

normal fiber, the depolarization process travels over

the entire membrane if conditions are right, or it does

not travel at all if conditions are not right. This is called

their original state by the Na⁺-K⁺ pump. Because this

the all-or-nothing principle, and it applies to all normal

pump requires energy for operation, this “recharging”

excitable tissues. Occasionally, the action potential

of the nerve fiber is an active metabolic process, using

reaches a point on the membrane at which it does not

energy derived from the adenosine triphosphate

generate sufficient voltage to stimulate the next area

(ATP) energy system of the cell. Figure 5-12 shows

of the membrane. When this occurs, the spread of

that the nerve fiber produces excess heat during

depolarization stops. Therefore, for continued propa-

recharging, which is a measure of energy expenditure

gation of an impulse to occur, the ratio of action poten-

when the nerve impulse frequency increases.

tial to threshold for excitation must at all times be

A special feature of the Na⁺-K⁺ ATPase pump is that

greater than 1. This “greater than 1” requirement is

its degree of activity is strongly stimulated when excess

called the safety factor for propagation.

sodium ions accumulate inside the cell membrane. In

fact, the pumping activity increases approximately in

proportion to the third power of this intracellular

Re-establishing Sodium and

sodium concentration. That is, as the internal sodium

concentration rises from 10 to 20 mEq/L, the activity

Potassium Ionic Gradients

of the pump does not merely double but increases

After Action Potentials Are

about eightfold. Therefore, it is easy to understand

Completed—Importance

how the “recharging” process of the nerve fiber can be

of Energy Metabolism

set rapidly into motion whenever the concentration

differences of sodium and potassium ions across the

The transmission of each action potential along a

membrane begin to “run down.”

nerve fiber reduces very slightly the concentration

differences of sodium and potassium inside and

Plateau in Some Action

outside the membrane, because sodium ions diffuse to

the inside during depolarization and potassium ions

Potentials

diffuse to the outside during repolarization. For a

single action potential, this effect is so minute that

In some instances, the excited membrane does not

it cannot be measured. Indeed, 100,000 to 50 million

repolarize immediately after depolarization; instead,

impulses can be transmitted by large nerve fibers

the potential remains on a plateau near the peak of the

before the concentration differences reach the point

spike potential for many milliseconds, and only then

that action potential conduction ceases. Even so, with

does repolarization begin. Such a plateau is shown

time, it becomes necessary to re-establish the sodium

in Figure 5-13; one can readily see that the plateau

and potassium membrane concentration differences.

greatly prolongs the period of depolarization. This

This is achieved by action of the Na⁺-K⁺ pump in the

type of action potential occurs in heart muscle fibers,

same way as described previously in the chapter for

where the plateau lasts for as long as 0.2 to 0.3 second

the original establishment of the resting potential. That

and causes contraction of heart muscle to last for this

is, sodium ions that have diffused to the interior of the

same long period.

cell during the action potentials and potassium ions

The cause of the plateau is a combination of several

that have diffused to the exterior must be returned to

factors. First, in heart muscle, two types of channels

Chapter 5

Membrane Potentials and Action Potentials

+60

Rhythmical

Plateau

Potassium

action

+40

+60

conductance

potentials Threshold

+20

+40

+20

-20

-40

- 20

-60

- 40

- 60

-80

-100

Seconds

0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9

Hyperpolarization

Seconds

Figure 5-14

Figure 5-13

Rhythmical action potentials (in millivolts) similar to those recorded

Action potential (in millivolts) from a Purkinje fiber of the heart,

in the rhythmical control center of the heart. Note their relationship

showing a “plateau.”

to potassium conductance and to the state of hyperpolarization.

below a critical value, both of which increase sodium

enter into the depolarization process: (1) the usual

permeability of the membrane.

voltage-activated sodium channels, called fast chan-

nels, and (2) voltage-activated calcium-sodium chan-

Re-excitation Process Necessary for Spontaneous Rhythmicity.

nels, which are slow to open and therefore are called

For spontaneous rhythmicity to occur, the membrane

slow channels. Opening of fast channels causes the

even in its natural state must be permeable enough to

spike portion of the action potential, whereas the slow,

sodium ions (or to calcium and sodium ions through

prolonged opening of the slow calcium-sodium chan-

the slow calcium-sodium channels) to allow automatic

nels mainly allows calcium ions to enter the fiber,

membrane depolarization. Thus, Figure 5-14 shows

which is largely responsible for the plateau portion of

that the “resting” membrane potential in the rhythmi-

the action potential as well.

cal control center of the heart is only -60 to -70 milli-

A second factor that may be partly responsible for

volts. This is not enough negative voltage to keep the

the plateau is that the voltage-gated potassium chan-

sodium and calcium channels totally closed. Therefore,

nels are slower than usual to open, often not opening

the following sequence occurs: (1) some sodium and

very much until the end of the plateau. This delays the

calcium ions flow inward; (2) this increases the mem-

return of the membrane potential toward its normal

brane voltage in the positive direction, which further

negative value of -80 to -90 millivolts.

increases membrane permeability; (3) still more ions

flow inward; and (4) the permeability increases more,

and so on, until an action potential is generated. Then,

RHYTHMICITY OF SOME

at the end of the action potential, the membrane re-

EXCITABLE TISSUES—

polarizes. After another delay of milliseconds or

REPETITIVE DISCHARGE

seconds, spontaneous excitability causes depolariza-

tion again, and a new action potential occurs sponta-

Repetitive self-induced discharges occur normally in

neously. This cycle continues over and over and causes

the heart, in most smooth muscle, and in many of the

self-induced rhythmical excitation of the excitable

neurons of the central nervous system. These rhyth-

tissue.

mical discharges cause (1) the rhythmical beat of the

Why does the membrane of the heart control center

heart, (2) rhythmical peristalsis of the intestines, and

not depolarize immediately after it has become re-

(3) such neuronal events as the rhythmical control of

polarized, rather than delaying for nearly a second

breathing.

before the onset of the next action potential? The

Also, almost all other excitable tissues can discharge

answer can be found by observing the curve labeled

repetitively if the threshold for stimulation of the

“potassium conductance” in Figure 5-14. This shows

tissue cells is reduced low enough. For instance, even

that toward the end of each action potential, and con-

large nerve fibers and skeletal muscle fibers, which

tinuing for a short period thereafter, the membrane

normally are highly stable, discharge repetitively when

becomes excessively permeable to potassium ions. The

they are placed in a solution that contains the drug

excessive outflow of potassium ions carries tremen-

veratrine or when the calcium ion concentration falls

dous numbers of positive charges to the outside of the

Unit II

Membrane Physiology, Nerve, and Muscle

Axon

Myelin

sheath

Schwann cell

cytoplasm

Schwann cell

nucleus

Node of Ranvier

Figure 5-15

Unmyelinated axons

Cross section of a small nerve trunk containing both myelinated

and unmyelinated fibers.

Schwann cell nucleus

Schwann cell cytoplasm

membrane, leaving inside the fiber considerably more

negativity than would otherwise occur. This continues

for nearly a second after the preceding action poten-

Figure 5-16

tial is over, thus drawing the membrane potential

nearer to the potassium Nernst potential. This is a state

Function of the Schwann cell to insulate nerve fibers. A, Wrapping

called hyperpolarization, also shown in Figure 5-14. As

of a Schwann cell membrane around a large axon to form the

long as this state exists, self-re-excitation will not

myelin sheath of the myelinated nerve fiber. B, Partial wrapping of

the membrane and cytoplasm of a Schwann cell around multiple

occur. But the excess potassium conductance (and the

unmyelinated nerve fibers (shown in cross section). (A, Modified

state of hyperpolarization) gradually disappears, as

from Leeson TS, Leeson R: Histology. Philadelphia: WB Saunders,

shown after each action potential is completed in the

1979.)

figure, thereby allowing the membrane potential again

to increase up to the threshold for excitation. Then,

suddenly, a new action potential results, and the

The myelin sheath is deposited around the axon by

process occurs again and again.

Schwann cells in the following manner: The membrane

of a Schwann cell first envelops the axon. Then the

Schwann cell rotates around the axon many times,

Special Characteristics

laying down multiple layers of Schwann cell membrane

of Signal Transmission

containing the lipid substance sphingomyelin. This sub-

stance is an excellent electrical insulator that decreases

in Nerve Trunks

ion flow through the membrane about 5000-fold. At the

Myelinated and Unmyelinated Nerve Fibers. Figure

5-15

juncture between each two successive Schwann cells

shows a cross section of a typical small nerve, revealing

along the axon, a small uninsulated area only 2 to 3

many large nerve fibers that constitute most of the

micrometers in length remains where ions still can flow

cross-sectional area. However, a more careful look

with ease through the axon membrane between the

reveals many more very small fibers lying between

extracellular fluid and the intracellular fluid inside the

the large ones. The large fibers are myelinated, and the

axon. This area is called the node of Ranvier.

small ones are unmyelinated. The average nerve trunk

contains about twice as many unmyelinated fibers as

“Saltatory” Conduction in Myelinated Fibers from Node to Node.

myelinated fibers.

Even though almost no ions can flow through the thick

Figure 5-16 shows a typical myelinated fiber. The

myelin sheaths of myelinated nerves, they can flow with

central core of the fiber is the axon, and the membrane

ease through the nodes of Ranvier. Therefore, action

of the axon is the membrane that actually conducts the

potentials occur only at the nodes. Yet the action poten-

action potential. The axon is filled in its center with axo-

tials are conducted from node to node, as shown in

plasm, which is a viscid intracellular fluid. Surrounding

Figure 5-17; this is called saltatory conduction. That is,

the axon is a myelin sheath that is often much thicker

electrical current flows through the surrounding extra-

than the axon itself. About once every 1 to 3 milli-

cellular fluid outside the myelin sheath as well as

meters along the length of the myelin sheath is a node

through the axoplasm inside the axon from node to

of Ranvier.

node, exciting successive nodes one after another. Thus,

Chapter 5

Membrane Potentials and Action Potentials

Myelin sheath

Axoplasm

Node of Ranvier

+60

Action potentials

+40

+20

Acute

-20

subthreshold

potentials

-40

-60

Threshold

Milliseconds

Figure 5-17

Saltatory conduction along a myelinated axon. Flow of electrical

current from node to node is illustrated by the arrows.

Figure 5-18

Effect of stimuli of increasing voltages to elicit an action potential.

Note development of “acute subthreshold potentials” when the

stimuli are below the threshold value required for eliciting an

the nerve impulse jumps down the fiber, which is the

action potential.

origin of the term “saltatory.”

Saltatory conduction is of value for two reasons. First,

by causing the depolarization process to jump long

Excitation of a Nerve Fiber by a Negatively Charged Metal

intervals along the axis of the nerve fiber, this mecha-

Electrode. The usual means for exciting a nerve or

nism increases the velocity of nerve transmission in

muscle in the experimental laboratory is to apply elec-

myelinated fibers as much as 5- to 50-fold. Second,

tricity to the nerve or muscle surface through two small

saltatory conduction conserves energy for the axon

electrodes, one of which is negatively charged and

because only the nodes depolarize, allowing perhaps

the other positively charged. When this is done, the

100 times less loss of ions than would otherwise be nec-

excitable membrane becomes stimulated at the negative

essary, and therefore requiring little metabolism for re-

electrode.

establishing the sodium and potassium concentration

The cause of this effect is the following: Remember

differences across the membrane after a series of nerve

that the action potential is initiated by the opening of

impulses.

voltage-gated sodium channels. Further, these channels

Still another feature of saltatory conduction in

are opened by a decrease in the normal resting electri-

large myelinated fibers is the following: The excellent

cal voltage across the membrane. That is, negative

insulation afforded by the myelin membrane and the 50-

current from the electrode decreases the voltage on the

fold decrease in membrane capacitance allow repolar-

outside of the membrane to a negative value nearer to

ization to occur with very little transfer of ions.

the voltage of the negative potential inside the fiber.

This decreases the electrical voltage across the mem-

Velocity of Conduction in Nerve Fibers. The velocity of con-

brane and allows the sodium channels to open, result-

duction in nerve fibers varies from as little as 0.25 m/sec

ing in an action potential. Conversely, at the positive

in very small unmyelinated fibers to as great as 100 m/

electrode, the injection of positive charges on the

sec (the length of a football field in 1 second) in very

outside of the nerve membrane heightens the voltage

large myelinated fibers.

difference across the membrane rather than lessening

it. This causes a state of hyperpolarization, which actu-

ally decreases the excitability of the fiber rather than

Excitation—The Process

causing an action potential.

of Eliciting the Action

Threshold for Excitation, and “Acute Local Potentials.” A weak

Potential

negative electrical stimulus may not be able to excite a

Basically, any factor that causes sodium ions to begin to

fiber. However, when the voltage of the stimulus is

diffuse inward through the membrane in sufficient

increased, there comes a point at which excitation does

numbers can set off automatic regenerative opening of

take place. Figure 5-18 shows the effects of successively

the sodium channels. This can result from mechanical

applied stimuli of progressing strength. A very weak

disturbance of the membrane, chemical effects on the

stimulus at point A causes the membrane potential to

membrane, or passage of electricity through the mem-

change from -90 to -85 millivolts, but this is not a suffi-

brane. All these are used at different points in the body

cient change for the automatic regenerative processes

to elicit nerve or muscle action potentials: mechanical

of the action potential to develop. At point B, the stim-

pressure to excite sensory nerve endings in the skin,

ulus is greater, but again, the intensity is still not enough.

chemical neurotransmitters to transmit signals from one

The stimulus does, however, disturb the membrane

neuron to the next in the brain, and electrical current to

potential locally for as long as 1 millisecond or more

transmit signals between successive muscle cells in the

after both of these weak stimuli. These local potential

heart and intestine. For the purpose of understanding

changes are called acute local potentials, and when they

the excitation process, let us begin by discussing the

fail to elicit an action potential, they are called acute

principles of electrical stimulation.

subthreshold potentials.

Unit II

Membrane Physiology, Nerve, and Muscle

At point C in Figure 5-18, the stimulus is even

decrease excitability. For instance, a high extracellular

stronger. Now the local potential has barely reached the

fluid calcium ion concentration decreases membrane

level required to elicit an action potential, called the

permeability to sodium ions and simultaneously reduces

threshold level, but this occurs only after a short “latent

excitability. Therefore, calcium ions are said to be a

period.” At point D, the stimulus is still stronger, the

“stabilizer.”

acute local potential is also stronger, and the action

potential occurs after less of a latent period.

Local Anesthetics. Among the most important stabilizers

Thus, this figure shows that even a very weak stimu-

are the many substances used clinically as local anes-

lus causes a local potential change at the membrane, but

thetics, including procaine and tetracaine. Most of these

the intensity of the local potential must rise to a thresh-

act directly on the activation gates of the sodium chan-

old level before the action potential is set off.

nels, making it much more difficult for these gates to

open, thereby reducing membrane excitability. When

“Refractory Period” After an Action

excitability has been reduced so low that the ratio of

Potential, During Which a New

action potential strength to excitability threshold (called

the “safety factor”) is reduced below 1.0, nerve impulses

Stimulus Cannot Be Elicited

fail to pass along the anesthetized nerves.

A new action potential cannot occur in an excitable fiber

as long as the membrane is still depolarized from the pre-

ceding action potential. The reason for this is that shortly

Recording Membrane

after the action potential is initiated, the sodium channels

Potentials and Action

(or calcium channels, or both) become inactivated, and

Potentials

no amount of excitatory signal applied to these channels

at this point will open the inactivation gates. The only

Cathode Ray Oscilloscope. Earlier in this chapter, we noted

condition that will allow them to reopen is for the mem-

that the membrane potential changes extremely rapidly

brane potential to return to or near the original resting

during the course of an action potential. Indeed, most

membrane potential level. Then, within another small

of the action potential complex of large nerve fibers

fraction of a second, the inactivation gates of the chan-

takes place in less than 1/1000 second. In some figures

nels open, and a new action potential can be initiated.

of this chapter, an electrical meter has been shown

The period during which a second action potential

recording these potential changes. However, it must be

cannot be elicited, even with a strong stimulus, is

understood that any meter capable of recording most

called the absolute refractory period. This period for

action potentials must be capable of responding

large myelinated nerve fibers is about 1/2500 second.

extremely rapidly. For practical purposes, the only

Therefore, one can readily calculate that such a fiber

common type of meter that is capable of responding

can transmit a maximum of about 2500 impulses per

accurately to the rapid membrane potential changes is

second.

the cathode ray oscilloscope.

Figure 5-19 shows the basic components of a cathode

Inhibition of Excitability—

ray oscilloscope. The cathode ray tube itself is composed

“Stabilizers” and Local Anesthetics

basically of an electron gun and a fluorescent screen

against which electrons are fired. Where the electrons

In contrast to the factors that increase nerve excitabil-

hit the screen surface, the fluorescent material glows. If

ity, still others, called membrane-stabilizing factors, can

the electron beam is moved across the screen, the spot

Recorded

action potential

Horizontal

plates

Electron gun

Electron

beam

Plugs

Vertical

Stimulus

plates

Electronic

artifact

Electronic

amplifier

sweep circuit

Electrical

stimulator

Figure 5-19

Nerve

Cathode ray oscilloscope for recording transient

action potentials.

Chapter 5

Membrane Potentials and Action Potentials

of glowing light also moves and draws a fluorescent line

Hodgkin AL: The Conduction of the Nervous Impulse.

on the screen.

Springfield, IL: Charles C Thomas, 1963.

In addition to the electron gun and fluorescent

Hodgkin AL, Huxley AF: Quantitative description of

surface, the cathode ray tube is provided with two sets

membrane current and its application to conduction and

of electrically charged plates—one set positioned on the

excitation in nerve. J Physiol (Lond) 117:500, 1952.

two sides of the electron beam, and the other set posi-

Kleber AG, Rudy Y: Basic mechanisms of cardiac impulse

tioned above and below. Appropriate electronic control

propagation and associated arrhythmias. Physiol Rev

circuits change the voltage on these plates so that the

84:431, 2004.

electron beam can be bent up or down in response to

Lu Z: Mechanism of rectification in inward-rectifier K⁺

electrical signals coming from recording electrodes on

channels. Annu Rev Physiol 66:103, 2004.

nerves. The beam of electrons also is swept horizontally

Matthews GG: Cellular Physiology of Nerve and Muscle.

across the screen at a constant time rate by an internal

Malden, MA: Blackwell Science, 1998.

electronic circuit of the oscilloscope. This gives the

Perez-Reyes E: Molecular physiology of low-voltage-

record shown on the face of the cathode ray tube in

activated T-type calcium channels. Physiol Rev 83:117,

the figure, giving a time base horizontally and voltage

2003.

changes from the nerve electrodes shown vertically.

Poliak S, Peles E: The local differentiation of myelinated

Note at the left end of the record a small stimulus arti-

axons at nodes of Ranvier. Nat Rev Neurosci 12:968, 2003.

fact caused by the electrical stimulus used to elicit the

Pollard TD, Earnshaw WC: Cell Biology. Philadelphia:

nerve action potential. Then further to the right is

Elsevier Science, 2002.

the recorded action potential itself.

Ruff RL: Neurophysiology of the neuromuscular junction:

overview. Ann N Y Acad Sci 998:1, 2003.

Xu-Friedman MA, Regehr WG: Structural contributions to

References

short-term synaptic plasticity. Physiol Rev 84:69, 2004.

Alberts B, Johnson A, Lewis J, et al: Molecular Biology of

the Cell. New York: Garland Science, 2002.

Grillner S: The motor infrastructure: from ion channels to

neuronal networks. Nat Rev Neurosci 4:573, 2003.

C H A P T E R

Contraction of

Skeletal Muscle

About 40 per cent of the body is skeletal muscle,

and perhaps another 10 per cent is smooth and

cardiac muscle. Some of the same basic principles of

contraction apply to all these different types of

muscle. In this chapter, function of skeletal muscle

is considered mainly; the specialized functions of

smooth muscle are discussed in Chapter 8, and

cardiac muscle is discussed in Chapter 9.

Physiologic Anatomy of Skeletal Muscle

Skeletal Muscle Fiber

Figure 6-1 shows the organization of skeletal muscle, demonstrating that all

skeletal muscles are composed of numerous fibers ranging from 10 to 80

micrometers in diameter. Each of these fibers is made up of successively smaller

subunits, also shown in Figure 6-1 and described in subsequent paragraphs.

In most skeletal muscles, each fiber extends the entire length of the muscle.

Except for about 2 per cent of the fibers, each fiber is usually innervated by only

one nerve ending, located near the middle of the fiber.

Sarcolemma. The sarcolemma is the cell membrane of the muscle fiber. The sar-

colemma consists of a true cell membrane, called the plasma membrane, and an

outer coat made up of a thin layer of polysaccharide material that contains

numerous thin collagen fibrils. At each end of the muscle fiber, this surface layer

of the sarcolemma fuses with a tendon fiber, and the tendon fibers in turn collect

into bundles to form the muscle tendons that then insert into the bones.

Myofibrils; Actin and Myosin Filaments. Each muscle fiber contains several hundred

to several thousand myofibrils, which are demonstrated by the many small open

dots in the cross-sectional view of Figure 6-1C. Each myofibril (Figure 6-1D

and E) is composed of about 1500 adjacent myosin filaments and 3000 actin fil-

aments, which are large polymerized protein molecules that are responsible for

the actual muscle contraction. These can be seen in longitudinal view in the elec-

tron micrograph of Figure 6-2 and are represented diagrammatically in Figure

6-1, parts E through L. The thick filaments in the diagrams are myosin, and the

thin filaments are actin.

Note in Figure 6-1E that the myosin and actin filaments partially interdigi-

tate and thus cause the myofibrils to have alternate light and dark bands, as

illustrated in Figure 6-2. The light bands contain only actin filaments and are

called I bands because they are isotropic to polarized light. The dark bands

contain myosin filaments, as well as the ends of the actin filaments where they

overlap the myosin, and are called A bands because they are anisotropic to

polarized light. Note also the small projections from the sides of the myosin

filaments in Figure 6-1E and L. These are cross-bridges. It is the interaction

between these cross-bridges and the actin filaments that causes contraction.

Figure 6-1E also shows that the ends of the actin filaments are attached to a

so-called Z disc. From this disc, these filaments extend in both directions to

Chapter 6

Contraction of Skeletal Muscle

SKELETAL MUSCLE

Muscle

Muscle fasciculus

Muscle fiber

band disc band

band

Myofibril

Sarcomere Z

G-Actin molecules

Myofilaments

F-Actin filament

Figure 6-1

Myosin filament

Organization of skeletal muscle,

from the gross to the molecular

Myosin molecule

level. F, G, H, and I are cross

sections at the levels indicated.

(Drawing by Sylvia Colard

Keene. Modified from Fawcett

DW: Bloom and Fawcett: A Text-

Light

Heavy

book of Histology. Philadelphia:

meromyosin

WB Saunders, 1986.)

interdigitate with the myosin filaments. The Z disc,

beginning to overlap one another. We will see later

which itself is composed of filamentous proteins dif-

that, at this length, the muscle is capable of generating

ferent from the actin and myosin filaments, passes

its greatest force of contraction.

crosswise across the myofibril and also crosswise from

myofibril to myofibril, attaching the myofibrils to one

What Keeps the Myosin and Actin Filaments in Place?

another all the way across the muscle fiber. Therefore,

Titin Filamentous Molecules. The side-by-side rela-

the entire muscle fiber has light and dark bands, as do

tionship between the myosin and actin filaments is dif-

the individual myofibrils. These bands give skeletal and

ficult to maintain. This is achieved by a large number

cardiac muscle their striated appearance.

of filamentous molecules of a protein called titin. Each

The portion of the myofibril (or of the whole muscle

titin molecule has a molecular weight of about 3

fiber) that lies between two successive Z discs is called

million, which makes it one of the largest protein mol-

a sarcomere. When the muscle fiber is contracted, as

ecules in the body. Also, because it is filamentous, it is

shown at the bottom of Figure 6-4, the length of

very springy. These springy titin molecules act as a

the sarcomere is about 2 micrometers. At this length,

framework that holds the myosin and actin filaments

the actin filaments completely overlap the myosin

in place so that the contractile machinery of the sar-

filaments, and the tips of the actin filaments are just

comere will work. There is reason to believe that the

Unit II

Membrane Physiology, Nerve, and Muscle

Figure 6-2

Electron micrograph of muscle myofibrils showing the detailed

Figure 6-3

organization of actin and myosin filaments. Note the mitochondria

lying between the myofibrils.

(From Fawcett DW: The Cell.

Sarcoplasmic reticulum in the extracellular spaces between the

Philadelphia: WB Saunders, 1981.)

myofibrils, showing a longitudinal system paralleling the myofi-

brils. Also shown in cross section are T tubules (arrows) that lead

to the exterior of the fiber membrane and are important for con-

ducting the electrical signal into the center of the muscle fiber.

(From Fawcett DW: The Cell. Philadelphia: WB Saunders, 1981.)

titin molecule itself acts as template for initial forma-

4. Opening of the acetylcholine-gated channels allows

tion of portions of the contractile filaments of the

large quantities of sodium ions to diffuse to the

sarcomere, especially the myosin filaments.

interior of the muscle fiber membrane. This initiates

an action potential at the membrane.

Sarcoplasm. The many myofibrils of each muscle fiber

5. The action potential travels along the muscle fiber

are suspended side by side in the muscle fiber. The

membrane in the same way that action potentials

spaces between the myofibrils are filled with intracel-

travel along nerve fiber membranes.

lular fluid called sarcoplasm, containing large quanti-

6. The action potential depolarizes the muscle

ties of potassium, magnesium, and phosphate, plus

membrane, and much of the action potential

multiple protein enzymes. Also present are tremen-

electricity flows through the center of the muscle

dous numbers of mitochondria that lie parallel to the

fiber. Here it causes the sarcoplasmic reticulum to

release large quantities of calcium ions that have

myofibrils. These supply the contracting myofibrils

been stored within this reticulum.

with large amounts of energy in the form of adenosine

7. The calcium ions initiate attractive forces between

triphosphate (ATP) formed by the mitochondria.

the actin and myosin filaments, causing them to

slide alongside each other, which is the contractile

Sarcoplasmic Reticulum. Also in the sarcoplasm sur-

process.

rounding the myofibrils of each muscle fiber is an

8. After a fraction of a second, the calcium ions are

extensive reticulum (Figure 6-3), called the sarcoplas-

pumped back into the sarcoplasmic reticulum by a

mic reticulum. This reticulum has a special organiza-

Ca⁺⁺ membrane pump, and they remain stored in

tion that is extremely important in controlling muscle

the reticulum until a new muscle action potential

contraction, as discussed in Chapter 7. The very rapidly

comes along; this removal of calcium ions from the

myofibrils causes the muscle contraction to cease.

contracting types of muscle fibers have especially

We now describe the molecular machinery of the

extensive sarcoplasmic reticula.

muscle contractile process.

General Mechanism of Muscle

Contraction

Molecular Mechanism

of Muscle Contraction

The initiation and execution of muscle contraction

occur in the following sequential steps.

Sliding Filament Mechanism of Muscle Contraction. Figure

1. An action potential travels along a motor nerve to

6-4 demonstrates the basic mechanism of muscle con-

its endings on muscle fibers.

traction. It shows the relaxed state of a sarcomere

2. At each ending, the nerve secretes a small amount

(top) and the contracted state (bottom). In the relaxed

of the neurotransmitter substance acetylcholine.

state, the ends of the actin filaments extending from

3. The acetylcholine acts on a local area of the muscle

two successive Z discs barely begin to overlap one

fiber membrane to open multiple “acetylcholine-

gated” channels through protein molecules floating

another. Conversely, in the contracted state, these actin

in the membrane.

filaments have been pulled inward among the myosin

Chapter 6

Contraction of Skeletal Muscle

Head

Tail

Relaxed

Two heavy chains

Light chains

Actin filaments

Contracted

Figure 6-4

Cross-bridges

Hinges

Body

Relaxed and contracted states of a myofibril showing (top) sliding

Myosin filament

of the actin filaments (pink) into the spaces between the myosin

filaments (red), and (bottom) pulling of the Z membranes toward

each other.

Figure 6-5

A, Myosin molecule. B, Combination of many myosin molecules

to form a myosin filament. Also shown are thousands of myosin

filaments, so that their ends overlap one another to

cross-bridges and interaction between the heads of the cross-

their maximum extent. Also, the Z discs have been

bridges with adjacent actin filaments.

pulled by the actin filaments up to the ends of the

myosin filaments. Thus, muscle contraction occurs by a

sliding filament mechanism.

The two heavy chains wrap spirally around each other

But what causes the actin filaments to slide inward

to form a double helix, which is called the tail of the

among the myosin filaments? This is caused by forces

myosin molecule. One end of each of these chains is

generated by interaction of the cross-bridges from

folded bilaterally into a globular polypeptide structure

the myosin filaments with the actin filaments. Under

called a myosin head. Thus, there are two free heads

resting conditions, these forces are inactive, but when

at one end of the double-helix myosin molecule. The

an action potential travels along the muscle fiber,

four light chains are also part of the myosin head, two

this causes the sarcoplasmic reticulum to release large

to each head. These light chains help control the func-

quantities of calcium ions that rapidly surround the

tion of the head during muscle contraction.

myofibrils. The calcium ions in turn activate the forces

The myosin filament is made up of 200 or more indi-

between the myosin and actin filaments, and contrac-

vidual myosin molecules. The central portion of one of

tion begins. But energy is needed for the contractile

these filaments is shown in Figure 6-5B, displaying the

process to proceed. This energy comes from high-

tails of the myosin molecules bundled together to form

energy bonds in the ATP molecule, which is degraded

the body of the filament, while many heads of the

to adenosine diphosphate

(ADP) to liberate the

molecules hang outward to the sides of the body. Also,

energy. In the next few sections, we describe what is

part of the body of each myosin molecule hangs to the

known about the details of these molecular processes

side along with the head, thus providing an arm that

of contraction.

extends the head outward from the body, as shown in

the figure. The protruding arms and heads together are

called cross-bridges. Each cross-bridge is flexible at

Molecular Characteristics of the

two points called hinges—one where the arm leaves

Contractile Filaments

the body of the myosin filament, and the other where

the head attaches to the arm. The hinged arms allow

Myosin Filament. The myosin filament is composed of

the heads either to be extended far outward from the

multiple myosin molecules, each having a molecular

body of the myosin filament or to be brought close to

weight of about 480,000. Figure 6-5A shows an indi-

the body. The hinged heads in turn participate in the

vidual molecule; Figure 6-5B shows the organization

actual contraction process, as discussed in the follow-

of many molecules to form a myosin filament, as well

ing sections.

as interaction of this filament on one side with the ends

The total length of each myosin filament is uniform,

of two actin filaments.

almost exactly 1.6 micrometers. Note, however, that

The myosin molecule (see Figure 6-5A) is composed

there are no cross-bridge heads in the very center of

of six polypeptide chains—two heavy chains, each with

the myosin filament for a distance of about

0.2

a molecular weight of about 200,000, and four light

micrometer because the hinged arms extend away

chains with molecular weights of about 20,000 each.

from the center.

Unit II

Membrane Physiology, Nerve, and Muscle

Now, to complete the picture, the myosin filament

cannot occur between the actin and myosin filaments

itself is twisted so that each successive pair of cross-

to cause contraction.

bridges is axially displaced from the previous pair by

120 degrees. This ensures that the cross-bridges extend

Troponin and Its Role in Muscle Contraction. Attached

in all directions around the filament.

intermittently along the sides of the tropomyosin mol-

ecules are still other protein molecules called troponin.

ATPase Activity of the Myosin Head. Another feature

These are actually complexes of three loosely bound

of the myosin head that is essential for muscle con-

protein subunits, each of which plays a specific role in

traction is that it functions as an ATPase enzyme. As

controlling muscle contraction. One of the subunits

explained later, this property allows the head to cleave

(troponin I) has a strong affinity for actin, another

ATP and to use the energy derived from the ATP’s

(troponin T) for tropomyosin, and a third (troponin C)

high-energy phosphate bond to energize the contrac-

for calcium ions. This complex is believed to attach

tion process.

the tropomyosin to the actin. The strong affinity of the

troponin for calcium ions is believed to initiate the

Actin Filament. The actin filament is also complex.

contraction process, as explained in the next section.

It is composed of three protein components: actin,

tropomyosin, and troponin.

Interaction of One Myosin Filament,

The backbone of the actin filament is a double-

Two Actin Filaments, and Calcium Ions

stranded F-actin protein molecule, represented by the

to Cause Contraction

two lighter-colored strands in Figure 6-6. The two

strands are wound in a helix in the same manner as the

Inhibition of the Actin Filament by the Troponin-Tropomyosin

myosin molecule.

Complex; Activation by Calcium Ions. A pure actin filament

Each strand of the double F-actin helix is composed

without the presence of the troponin-tropomyosin

of polymerized G-actin molecules, each having a

complex (but in the presence of magnesium ions and

molecular weight of about 42,000. Attached to each

ATP) binds instantly and strongly with the heads

one of the G-actin molecules is one molecule of

of the myosin molecules. Then, if the troponin-

ADP. It is believed that these ADP molecules are the

tropomyosin complex is added to the actin filament,

active sites on the actin filaments with which the cross-

the binding between myosin and actin does not take

bridges of the myosin filaments interact to cause

place. Therefore, it is believed that the active sites on

muscle contraction. The active sites on the two F-actin

the normal actin filament of the relaxed muscle are

strands of the double helix are staggered, giving one

inhibited or physically covered by the troponin-

active site on the overall actin filament about every 2.7

tropomyosin complex. Consequently, the sites cannot

nanometers.

attach to the heads of the myosin filaments to cause

Each actin filament is about 1 micrometer long. The

contraction. Before contraction can take place, the

bases of the actin filaments are inserted strongly into

inhibitory effect of the troponin-tropomyosin complex

the Z discs; the ends of the filaments protrude in both

must itself be inhibited.

directions to lie in the spaces between the myosin

This brings us to the role of the calcium ions. In

molecules, as shown in Figure 6-4.

the presence of large amounts of calcium ions, the

inhibitory effect of the troponin-tropomyosin on

Tropomyosin Molecules. The actin filament also con-

the actin filaments is itself inhibited. The mechanism

tains another protein, tropomyosin. Each molecule of

of this is not known, but one suggestion is the follow-

tropomyosin has a molecular weight of 70,000 and a

ing: When calcium ions combine with troponin C, each

length of 40 nanometers. These molecules are wrapped

molecule of which can bind strongly with up to four

spirally around the sides of the F-actin helix. In the

calcium ions, the troponin complex supposedly under-

resting state, the tropomyosin molecules lie on top of

goes a conformational change that in some way tugs

the active sites of the actin strands, so that attraction

on the tropomyosin molecule and moves it deeper into

the groove between the two actin strands. This “uncov-

ers” the active sites of the actin, thus allowing these to

attract the myosin cross-bridge heads and cause con-

Active sites

Troponin complex

traction to proceed. Although this is a hypothetical

mechanism, it does emphasize that the normal relation

between the troponin-tropomyosin complex and actin

is altered by calcium ions, producing a new condition

that leads to contraction.

F-actin

Tropomyosin

Interaction Between the “Activated” Actin Filament and the

Figure 6-6

Myosin Cross-Bridges—The “Walk-Along” Theory of Contrac-

tion. As soon as the actin filament becomes activated

Actin filament, composed of two helical strands of F-actin mole-

by the calcium ions, the heads of the cross-bridges

cules and two strands of tropomyosin molecules that fit in the

from the myosin filaments become attracted to the

grooves between the actin strands. Attached to one end of each

tropomyosin molecule is a troponin complex that initiates

active sites of the actin filament, and this, in some way,

contraction.

causes contraction to occur. Although the precise

Chapter 6

Contraction of Skeletal Muscle

Movement

Active sites

Actin filament

ion, bound to the head. In this state, the

conformation of the head is such that it extends

perpendicularly toward the actin filament but is

Power

not yet attached to the actin.

Hinges

stroke

When the troponin-tropomyosin complex binds

with calcium ions, active sites on the actin filament

are uncovered, and the myosin heads then bind

with these, as shown in Figure 6-7.

The bond between the head of the cross-bridge

Myosin filament

and the active site of the actin filament causes a

conformational change in the head, prompting the

Figure 6-7

head to tilt toward the arm of the cross-bridge.

This provides the power stroke for pulling the

“Walk-along” mechanism for contraction of the muscle.

actin filament. The energy that activates the

power stroke is the energy already stored, like a

“cocked” spring, by the conformational change

manner by which this interaction between the cross-

that occurred in the head when the ATP molecule

bridges and the actin causes contraction is still partly

was cleaved earlier.

theoretical, one hypothesis for which considerable evi-

Once the head of the cross-bridge tilts, this allows

dence exists is the “walk-along” theory (or “ratchet”

release of the ADP and phosphate ion that were

theory) of contraction.

previously attached to the head. At the site of

Figure 6-7 demonstrates this postulated walk-along

release of the ADP, a new molecule of ATP binds.

mechanism for contraction. The figure shows the heads

This binding of new ATP causes detachment of

of two cross-bridges attaching to and disengaging from

the head from the actin.

active sites of an actin filament. It is postulated that

After the head has detached from the actin, the

when a head attaches to an active site, this attach-

new molecule of ATP is cleaved to begin the next

ment simultaneously causes profound changes in the

cycle, leading to a new power stroke. That is,

intramolecular forces between the head and arm of its

the energy again “cocks” the head back to its

cross-bridge. The new alignment of forces causes the

perpendicular condition, ready to begin the new

head to tilt toward the arm and to drag the actin fila-

power stroke cycle.

ment along with it. This tilt of the head is called the

When the cocked head (with its stored energy

power stroke. Then, immediately after tilting, the head

derived from the cleaved ATP) binds with a new

automatically breaks away from the active site. Next,

active site on the actin filament, it becomes

the head returns to its extended direction. In this

uncocked and once again provides a new power

position, it combines with a new active site farther

stroke.

down along the actin filament; then the head tilts again

Thus, the process proceeds again and again until the

to cause a new power stroke, and the actin filament

actin filaments pull the Z membrane up against

moves another step. Thus, the heads of the cross-

the ends of the myosin filaments or until the load on

bridges bend back and forth and step by step walk

the muscle becomes too great for further pulling to

along the actin filament, pulling the ends of two suc-

occur.

cessive actin filaments toward the center of the myosin

filament.

Effect of Amount of Actin and Myosin

Each one of the cross-bridges is believed to operate

Filament Overlap on Tension

independently of all others, each attaching and pulling

in a continuous repeated cycle. Therefore, the greater

Developed by the Contracting Muscle

the number of cross-bridges in contact with the actin

filament at any given time, the greater, theoretically,

Figure 6-8 shows the effect of sarcomere length and

the force of contraction.

amount of myosin-actin filament overlap on the active

tension developed by a contracting muscle fiber. To the

ATP as the Source of Energy for Contraction—Chemical Events

right, shown in black, are different degrees of overlap

in the Motion of the Myosin Heads. When a muscle con-

of the myosin and actin filaments at different sarco-

tracts, work is performed and energy is required. Large

mere lengths. At point D on the diagram, the actin

amounts of ATP are cleaved to form ADP during the

filament has pulled all the way out to the end of the

contraction process; the greater the amount of work

myosin filament, with no actin-myosin overlap. At this

performed by the muscle, the greater the amount of

point, the tension developed by the activated muscle

ATP that is cleaved, which is called the Fenn effect. The

is zero. Then, as the sarcomere shortens and the actin

following sequence of events is believed to be the

filament begins to overlap the myosin filament, the

means by which this occurs:

tension increases progressively until the sarcomere

1. Before contraction begins, the heads of the cross-

length decreases to about 2.2 micrometers. At this

bridges bind with ATP. The ATPase activity of the

point, the actin filament has already overlapped all

myosin head immediately cleaves the ATP but

the cross-bridges of the myosin filament but has not

leaves the cleavage products, ADP plus phosphate

yet reached the center of the myosin filament. With

Unit II

Membrane Physiology, Nerve, and Muscle

Normal range of contraction

B C

100

Tension during

contraction

Increase in tension

during contraction

Tension

before contraction

1/2

Normal

2 x

Length of sarcomere (micrometers)

normal

Length

Figure 6-8

Figure 6-9

Length-tension diagram for a single fully contracted sarcomere,

Relation of muscle length to tension in the muscle both before and

showing maximum strength of contraction when the sarcomere is

during muscle contraction.

2.0 to 2.2 micrometers in length. At the upper right are the rela-

tive positions of the actin and myosin filaments at different sar-

muscle is stretched beyond its normal length—that is,

comere lengths from point A to point D. (Modified from Gordon

AM, Huxley AF, Julian FJ: The length-tension diagram of single

to a sarcomere length greater than about 2.2 microm-

vertebrate striated muscle fibers. J Physiol 171:28P, 1964.)

eters. This is demonstrated by the decreased length of

the arrow in the figure at greater than normal muscle

length.

further shortening, the sarcomere maintains full

tension until point B is reached, at a sarcomere length

of about 2 micrometers. At this point, the ends of the

Relation of Velocity of Contraction

two actin filaments begin to overlap each other in

to Load

addition to overlapping the myosin filaments. As the

A skeletal muscle contracts extremely rapidly when it

sarcomere length falls from 2 micrometers down to

contracts against no load—to a state of full contraction

about 1.65 micrometers, at point A, the strength of

in about 0.1 second for the average muscle. When loads

contraction decreases rapidly. At this point, the two Z

are applied, the velocity of contraction becomes pro-

discs of the sarcomere abut the ends of the myosin fil-

gressively less as the load increases, as shown in Figure

aments. Then, as contraction proceeds to still shorter

6-10. That is, when the load has been increased to equal

sarcomere lengths, the ends of the myosin filaments

the maximum force that the muscle can exert, the veloc-

are crumpled and, as shown in the figure, the strength

ity of contraction becomes zero and no contraction

of contraction approaches zero, but the entire muscle

results, despite activation of the muscle fiber.

has now contracted to its shortest length.

This decreasing velocity of contraction with load is

caused by the fact that a load on a contracting muscle

is a reverse force that opposes the contractile force

Effect of Muscle Length on Force of Contraction in the Whole

caused by muscle contraction. Therefore, the net force

Intact Muscle. The top curve of Figure 6-9 is similar to

that is available to cause velocity of shortening is

that in Figure 6-8, but the curve in Figure 6-9 depicts

correspondingly reduced.

tension of the intact, whole muscle rather than of a

single muscle fiber. The whole muscle has a large

amount of connective tissue in it; also, the sarcomeres

Energetics of Muscle

in different parts of the muscle do not always contract

Contraction

the same amount. Therefore, the curve has somewhat

different dimensions from those shown for the

individual muscle fiber, but it exhibits the same general

Work Output During Muscle

form for the slope in the normal range of contraction,

Contraction

as noted in Figure 6-9.

Note in Figure 6-9 that when the muscle is at its

When a muscle contracts against a load, it performs

normal resting length, which is at a sarcomere length

work. This means that energy is transferred from the

of about 2 micrometers, it contracts upon activation

muscle to the external load to lift an object to a greater

with the approximate maximum force of contraction.

height or to overcome resistance to movement.

However, the increase in tension that occurs during

In mathematical terms, work is defined by the

contraction, called active tension, decreases as the

following equation:

Chapter 6

Contraction of Skeletal Muscle

energy than that of each ATP bond, as is discussed

more fully in Chapters 67 and 72. Therefore, phospho-

creatine is instantly cleaved, and its released energy

causes bonding of a new phosphate ion to ADP to

reconstitute the ATP. However, the total amount of

phosphocreatine in the muscle fiber is also very little—

only about five times as great as the ATP. Therefore,

the combined energy of both the stored ATP and

the phosphocreatine in the muscle is capable of

causing maximal muscle contraction for only 5 to 8

seconds.

The second important source of energy, which is

used to reconstitute both ATP and phosphocreatine,

“glycolysis” of glycogen previously stored in the

muscle cells. Rapid enzymatic breakdown of the glyco-

gen to pyruvic acid and lactic acid liberates energy

Load-opposing contraction (kg)

that is used to convert ADP to ATP; the ATP can

then be used directly to energize additional muscle

contraction and also to re-form the stores of

phosphocreatine.

Figure 6-10

The importance of this glycolysis mechanism is

Relation of load to velocity of contraction in a skeletal muscle

twofold. First, the glycolytic reactions can occur even

with a cross section of 1 square centimeter and a length of 8

in the absence of oxygen, so that muscle contraction

centimeters.

can be sustained for many seconds and sometimes up

to more than a minute, even when oxygen delivery

from the blood is not available. Second, the rate of for-

W=L¥D

mation of ATP by the glycolytic process is about 2.5

in which W is the work output, L is the load, and D is

times as rapid as ATP formation in response to cellu-

the distance of movement against the load. The energy

lar foodstuffs reacting with oxygen. However, so

required to perform the work is derived from the

many end products of glycolysis accumulate in the

chemical reactions in the muscle cells during contrac-

muscle cells that glycolysis also loses its capability to

tion, as described in the following sections.

sustain maximum muscle contraction after about 1

minute.

The third and final source of energy is oxidative

Sources of Energy for Muscle

metabolism. This means combining oxygen with the

Contraction

end products of glycolysis and with various other cel-

lular foodstuffs to liberate ATP. More than 95 per cent

We have already seen that muscle contraction depends

of all energy used by the muscles for sustained, long-

on energy supplied by ATP. Most of this energy is

term contraction is derived from this source. The

required to actuate the walk-along mechanism by

foodstuffs that are consumed are carbohydrates, fats,

which the cross-bridges pull the actin filaments, but

and protein. For extremely long-term maximal muscle

small amounts are required for (1) pumping calcium

activity—over a period of many hours—by far the

ions from the sarcoplasm into the sarcoplasmic retic-

greatest proportion of energy comes from fats, but for

ulum after the contraction is over, and (2) pumping

periods of 2 to 4 hours, as much as one half of the

sodium and potassium ions through the muscle fiber

energy can come from stored carbohydrates.

membrane to maintain appropriate ionic environment

The detailed mechanisms of these energetic

for propagation of muscle fiber action potentials.

processes are discussed in Chapters 67 through 72.

The concentration of ATP in the muscle fiber, about

In addition, the importance of the different mecha-

4 millimolar, is sufficient to maintain full contraction

nisms of energy release during performance of

for only 1 to 2 seconds at most. The ATP is split to form

different sports is discussed in Chapter 84 on sports

ADP, which transfers energy from the ATP molecule

physiology.

to the contracting machinery of the muscle fiber. Then,

as described in Chapter 2, the ADP is rephosphory-

Efficiency of Muscle Contraction. The efficiency of an

engine or a motor is calculated as the percentage of

lated to form new ATP within another fraction of a

energy input that is converted into work instead of heat.

second, which allows the muscle to continue its con-

The percentage of the input energy to muscle (the

traction. There are several sources of the energy for

chemical energy in nutrients) that can be converted into

this rephosphorylation.

work, even under the best conditions, is less than 25 per

The first source of energy that is used to reconsti-

cent, with the remainder becoming heat. The reason for

tute the ATP is the substance phosphocreatine, which

this low efficiency is that about one half of the energy

carries a high-energy phosphate bond similar to the

in foodstuffs is lost during the formation of ATP, and

bonds of ATP. The high-energy phosphate bond of

even then, only 40 to 45 per cent of the energy in the

phosphocreatine has a slightly higher amount of free

ATP itself can later be converted into work.

Unit II

Membrane Physiology, Nerve, and Muscle

Maximum efficiency can be realized only when the

quadriceps muscle, a half million times as large as the

muscle contracts at a moderate velocity. If the muscle

stapedius. Further, the fibers may be as small as 10

contracts slowly or without any movement, small

micrometers in diameter or as large as 80 micrometers.

amounts of maintenance heat are released during con-

Finally, the energetics of muscle contraction vary con-

traction, even though little or no work is performed,

siderably from one muscle to another. Therefore, it is no

thereby decreasing the conversion efficiency to as little

wonder that the mechanical characteristics of muscle

as zero. Conversely, if contraction is too rapid, large pro-

contraction differ among muscles.

portions of the energy are used to overcome viscous

Figure 6-12 shows records of isometric contractions

friction within the muscle itself, and this, too, reduces the

of three types of skeletal muscle: an ocular muscle,

efficiency of contraction. Ordinarily, maximum effi-

which has a duration of isometric contraction of less

ciency is developed when the velocity of contraction is

than 1/40 second; the gastrocnemius muscle, which has

about 30 per cent of maximum.

a duration of contraction of about 1/15 second; and the

soleus muscle, which has a duration of contrac-

tion of about 1/3 second. It is interesting that these dura-

Characteristics of Whole

tions of contraction are adapted to the functions of the

respective muscles. Ocular movements must be

Muscle Contraction

extremely rapid to maintain fixation of the eyes on

Many features of muscle contraction can be demon-

specific objects to provide accuracy of vision. The gas-

strated by eliciting single muscle twitches. This can be

trocnemius muscle must contract moderately rapidly

accomplished by instantaneous electrical excitation of

to provide sufficient velocity of limb movement for

the nerve to a muscle or by passing a short electrical

running and jumping, and the soleus muscle is con-

stimulus through the muscle itself, giving rise to a single,

cerned principally with slow contraction for continual,

sudden contraction lasting for a fraction of a second.

long-term support of the body against gravity.

Isometric Versus Isotonic Contraction. Muscle contraction is

Fast Versus Slow Muscle Fibers. As we discuss more fully in

said to be isometric when the muscle does not shorten

Chapter 84 on sports physiology, every muscle of the

during contraction and isotonic when it does shorten but

body is composed of a mixture of so-called fast and slow

the tension on the muscle remains constant throughout

muscle fibers, with still other fibers gradated between

the contraction. Systems for recording the two types of

these two extremes. The muscles that react rapidly are

muscle contraction are shown in Figure 6-11.

composed mainly of “fast” fibers with only small

In the isometric system, the muscle contracts against

numbers of the slow variety. Conversely, the muscles

a force transducer without decreasing the muscle

that respond slowly but with prolonged contraction are

length, as shown on the right in Figure 6-11. In the iso-

composed mainly of “slow” fibers. The differences

tonic system, the muscle shortens against a fixed load;

between these two types of fibers are as follows.

this is illustrated on the left in the figure, showing a

muscle lifting a pan of weights. The characteristics of

Fast Fibers. (1) Large fibers for great strength of con-

isotonic contraction depend on the load against which

traction. (2) Extensive sarcoplasmic reticulum for rapid

the muscle contracts, as well as the inertia of the load.

release of calcium ions to initiate contraction. (3) Large

However, the isometric system records strictly changes

amounts of glycolytic enzymes for rapid release of

in force of muscle contraction itself. Therefore, the iso-

energy by the glycolytic process. (4) Less extensive

metric system is most often used when comparing the

blood supply because oxidative metabolism is of

functional characteristics of different muscle types.

Characteristics of Isometric Twitches Recorded from Different

Muscles. The human body has many sizes of skeletal

muscles—from the very small stapedius muscle in the

middle ear, measuring only a few millimeters long and

a millimeter or so in diameter, up to the very large

Duration of

depolarization

Soleus

Stimulating

electrodes

Gastrocnemius

Kymograph

Muscle

Ocular

muscle

Electronic force

120

160

200

Weights

transducer

Milliseconds

To electronic

recorder

ISOTONIC SYSTEM

ISOMETRIC SYSTEM

Figure 6-12

Figure 6-11

Duration of isometric contractions for different types of mammalian

skeletal muscles, showing a latent period between the action

Isotonic and isometric systems for recording muscle contractions.

potential (depolarization) and muscle contraction.

Chapter 6

Contraction of Skeletal Muscle

secondary importance. (5) Fewer mitochondria, also

because oxidative metabolism is secondary.

Slow Fibers. (1) Smaller fibers. (2) Also innervated by

smaller nerve fibers. (3) More extensive blood vessel

system and capillaries to supply extra amounts of

Tetanization

oxygen. (4) Greatly increased numbers of mitochondria,

also to support high levels of oxidative metabolism. (5)

Fibers contain large amounts of myoglobin, an iron-

containing protein similar to hemoglobin in red blood

cells. Myoglobin combines with oxygen and stores it

until needed; this also greatly speeds oxygen transport

to the mitochondria. The myoglobin gives the slow

muscle a reddish appearance and the name red muscle,

whereas a deficit of red myoglobin in fast muscle gives

it the name white muscle.

Rate of stimulation (times per second)

Mechanics of Skeletal Muscle

Contraction

Figure 6-13

Motor Unit. Each motoneuron that leaves the spinal cord

Frequency summation and tetanization.

innervates multiple muscle fibers, the number depend-

ing on the type of muscle. All the muscle fibers inner-

vated by a single nerve fiber are called a motor unit. In

Another important feature of multiple fiber summa-

general, small muscles that react rapidly and whose

tion is that the different motor units are driven asyn-

control must be exact have more nerve fibers for fewer

chronously by the spinal cord, so that contraction

muscle fibers (for instance, as few as two or three muscle

alternates among motor units one after the other, thus

fibers per motor unit in some of the laryngeal muscles).

providing smooth contraction even at low frequencies

Conversely, large muscles that do not require fine

of nerve signals.

control, such as the soleus muscle, may have several

hundred muscle fibers in a motor unit. An average

Frequency Summation and Tetanization. Figure 6-13

figure for all the muscles of the body is questionable, but

shows the principles of frequency summation and

a good guess would be about 80 to 100 muscle fibers to

tetanization. To the left are displayed individual twitch

a motor unit.

contractions occurring one after another at low fre-

The muscle fibers in each motor unit are not all

quency of stimulation. Then, as the frequency increases,

bunched together in the muscle but overlap other motor

there comes a point where each new contraction occurs

units in microbundles of 3 to 15 fibers. This interdigita-

before the preceding one is over. As a result, the second

tion allows the separate motor units to contract in

contraction is added partially to the first, so that the

support of one another rather than entirely as individ-

total strength of contraction rises progressively with

ual segments.

increasing frequency. When the frequency reaches a

critical level, the successive contractions eventually

Muscle Contractions of Different Force—Force Summation.

become so rapid that they fuse together, and the whole

Summation means the adding together of individual

muscle contraction appears to be completely smooth

twitch contractions to increase the intensity of overall

and continuous, as shown in the figure. This is called

muscle contraction. Summation occurs in two ways: (1)

tetanization. At a slightly higher frequency, the strength

by increasing the number of motor units contracting

of contraction reaches its maximum, so that any addi-

simultaneously, which is called multiple fiber summa-

tional increase in frequency beyond that point has no

tion, and (2) by increasing the frequency of contraction,

further effect in increasing contractile force. This occurs

which is called frequency summation and can lead to

because enough calcium ions are maintained in the

tetanization.

muscle sarcoplasm, even between action potentials, so

that full contractile state is sustained without allowing

Multiple Fiber Summation. When the central nervous

any relaxation between the action potentials.

system sends a weak signal to contract a muscle, the

smaller motor units of the muscle may be stimulated in

Maximum Strength of Contraction. The maximum strength

preference to the larger motor units. Then, as the

of tetanic contraction of a muscle operating at a normal

strength of the signal increases, larger and larger motor

muscle length averages between 3 and 4 kilograms per

units begin to be excited as well, with the largest motor

square centimeter of muscle, or 50 pounds per square

units often having as much as 50 times the contractile

inch. Because a quadriceps muscle can have as much as

force of the smallest units. This is called the size princi-

16 square inches of muscle belly, as much as 800 pounds

ple. It is important, because it allows the gradations of

of tension may be applied to the patellar tendon. Thus,

muscle force during weak contraction to occur in small

one can readily understand how it is possible for

steps, whereas the steps become progressively greater

muscles to pull their tendons out of their insertions in

when large amounts of force are required. The cause of

bone.

this size principle is that the smaller motor units are

driven by small motor nerve fibers, and the small

Changes in Muscle Strength at the Onset of Contraction—The

motoneurons in the spinal cord are more excitable than

Staircase Effect (Treppe). When a muscle begins to con-

the larger ones, so they naturally are excited first.

tract after a long period of rest, its initial strength of

Unit II

Membrane Physiology, Nerve, and Muscle

contraction may be as little as one half its strength 10

biceps muscle has a cross-sectional area of 6 square

to 50 muscle twitches later. That is, the strength of con-

inches, the maximum force of contraction would be

traction increases to a plateau, a phenomenon called the

about 300 pounds. When the forearm is at right angles

staircase effect, or treppe.

with the upper arm, the tendon attachment of the biceps

Although all the possible causes of the staircase effect

is about 2 inches anterior to the fulcrum at the elbow,

are not known, it is believed to be caused primarily by

and the total length of the forearm lever is about 14

increasing calcium ions in the cytosol because of the

inches. Therefore, the amount of lifting power of the

release of more and more ions from the sarcoplasmic

biceps at the hand would be only one seventh of the 300

reticulum with each successive muscle action potential

pounds of muscle force, or about 43 pounds. When the

and failure of the sarcoplasm to recapture the ions

arm is fully extended, the attachment of the biceps is

immediately.

much less than 2 inches anterior to the fulcrum, and the

force with which the hand can be brought forward is

Skeletal Muscle Tone. Even when muscles are at rest, a

also much less than 43 pounds.

certain amount of tautness usually remains. This is

In short, an analysis of the lever systems of the body

called muscle tone. Because normal skeletal muscle

depends on knowledge of (1) the point of muscle inser-

fibers do not contract without an action potential to

tion, (2) its distance from the fulcrum of the lever, (3)

stimulate the fibers, skeletal muscle tone results entirely

the length of the lever arm, and (4) the position of the

from a low rate of nerve impulses coming from the

lever. Many types of movement are required in the

spinal cord. These, in turn, are controlled partly by

body, some of which need great strength and others

signals transmitted from the brain to the appropriate

of which need large distances of movement. For this

spinal cord anterior motoneurons and partly by signals

reason, there are many different types of muscle; some

that originate in muscle spindles located in the muscle

are long and contract a long distance, and some are

itself. Both of these are discussed in relation to muscle

short but have large cross-sectional areas and can

spindle and spinal cord function in Chapter 54.

provide extreme strength of contraction over short dis-

tances. The study of different types of muscles, lever

Muscle Fatigue. Prolonged and strong contraction of a

systems, and their movements is called kinesiology

muscle leads to the well-known state of muscle fatigue.

and is an important scientific component of human

Studies in athletes have shown that muscle fatigue

physioanatomy.

increases in almost direct proportion to the rate of

“Positioning” of a Body Part by Contraction of Agonist and Antag-

depletion of muscle glycogen. Therefore, fatigue results

onist Muscles on Opposite Sides of a Joint—“Coactivation”

mainly from inability of the contractile and metabolic

of Antagonist Muscles. Virtually all body movements are

processes of the muscle fibers to continue supplying the

caused by simultaneous contraction of agonist and

same work output. However, experiments have also

antagonist muscles on opposite sides of joints. This

shown that transmission of the nerve signal through the

is called coactivation of the agonist and antagonist

neuromuscular junction, which is discussed in Chapter

muscles, and it is controlled by the motor control centers

7, can diminish at least a small amount after intense pro-

of the brain and spinal cord.

longed muscle activity, thus further diminishing muscle

The position of each separate part of the body, such

contraction. Interruption of blood flow through a con-

as an arm or a leg, is determined by the relative degrees

tracting muscle leads to almost complete muscle fatigue

of contraction of the agonist and antagonist sets of

within 1 or 2 minutes because of the loss of nutrient

muscles. For instance, let us assume that an arm or a leg

supply, especially loss of oxygen.

is to be placed in a midrange position. To achieve

this, agonist and antagonist muscles are excited about

Lever Systems of the Body. Muscles operate by applying

equally. Remember that an elongated muscle contracts

tension to their points of insertion into bones, and the

with more force than a shortened muscle, which was

bones in turn form various types of lever systems. Figure

demonstrated in Figure 6-9, showing maximum strength

6-14 shows the lever system activated by the biceps

of contraction at full functional muscle length and

muscle to lift the forearm. If we assume that a large

almost no strength of contraction at half normal length.

Therefore, the elongated muscle on one side of a joint

can contract with far greater force than the shorter

muscle on the opposite side. As an arm or leg moves

toward its midposition, the strength of the longer

muscle decreases, whereas the strength of the shorter

muscle increases until the two strengths equal each

other. At this point, movement of the arm or leg stops.

Thus, by varying the ratios of the degree of activation

of the agonist and antagonist muscles, the nervous

system directs the positioning of the arm or leg.

We learn in Chapter 54 that the motor nervous

system has additional important mechanisms to com-

pensate for different muscle loads when directing this

positioning process.

Remodeling of Muscle

to Match Function

Figure 6-14

All the muscles of the body are continually being

Lever system activated by the biceps muscle.

remodeled to match the functions that are required of

Chapter 6

Contraction of Skeletal Muscle

them. Their diameters are altered, their lengths are

about 2 months, degenerative changes also begin to

altered, their strengths are altered, their vascular sup-

appear in the muscle fibers themselves. If the nerve

plies are altered, and even the types of muscle fibers are

supply to the muscle grows back rapidly, full return

altered at least slightly. This remodeling process is often

of function can occur in as little as 3 months, but from

quite rapid, within a few weeks. Indeed, experiments in

that time onward, the capability of functional return

animals have shown that muscle contractile proteins in

becomes less and less, with no further return of function

some smaller, more active muscles can be replaced in as

after 1 to 2 years.

little as 2 weeks.

In the final stage of denervation atrophy, most of the

muscle fibers are destroyed and replaced by fibrous and

Muscle Hypertrophy and Muscle Atrophy. When the total

fatty tissue. The fibers that do remain are composed of

mass of a muscle increases, this is called muscle hyper-

a long cell membrane with a lineup of muscle cell nuclei

trophy. When it decreases, the process is called muscle

but with few or no contractile properties and little or no

atrophy.

capability of regenerating myofibrils if a nerve does

Virtually all muscle hypertrophy results from an

regrow.

increase in the number of actin and myosin filaments in

The fibrous tissue that replaces the muscle fibers

each muscle fiber, causing enlargement of the individ-

during denervation atrophy also has a tendency to con-

ual muscle fibers; this is called simply fiber hypertrophy.

tinue shortening for many months, which is called con-

Hypertrophy occurs to a much greater extent when the

tracture. Therefore, one of the most important problems

muscle is loaded during the contractile process. Only a

in the practice of physical therapy is to keep atrophying

few strong contractions each day are required to cause

muscles from developing debilitating and disfiguring

significant hypertrophy within 6 to 10 weeks.

contractures. This is achieved by daily stretching of the

The manner in which forceful contraction leads to

muscles or use of appliances that keep the muscles

hypertrophy is not known. It is known, however, that the

stretched during the atrophying process.

rate of synthesis of muscle contractile proteins is far

Recovery of Muscle Contraction in Poliomyelitis: Devel-

greater when hypertrophy is developing, leading also to

opment of Macromotor Units. When some but not all

progressively greater numbers of both actin and myosin

nerve fibers to a muscle are destroyed, as commonly

filaments in the myofibrils, often increasing as much as

occurs in poliomyelitis, the remaining nerve fibers

50 per cent. In turn, some of the myofibrils themselves

branch off to form new axons that then innervate many

have been observed to split within hypertrophying

of the paralyzed muscle fibers. This causes large motor

muscle to form new myofibrils, but how important this

units called macromotor units, which can contain as

is in usual muscle hypertrophy is still unknown.

many as five times the normal number of muscle fibers

Along with the increasing size of myofibrils, the

for each motoneuron coming from the spinal cord. This

enzyme systems that provide energy also increase. This

decreases the fineness of control one has over the

is especially true of the enzymes for glycolysis, allowing

muscles but does allow the muscles to regain varying

rapid supply of energy during short-term forceful

degrees of strength.

muscle contraction.

When a muscle remains unused for many weeks, the

rate of decay of the contractile proteins is more rapid

Rigor Mortis

than the rate of replacement. Therefore, muscle atrophy

occurs.

Several hours after death, all the muscles of the body go

into a state of contracture called “rigor mortis”; that is,

Adjustment of Muscle Length. Another type of hyper-

the muscles contract and become rigid, even without

trophy occurs when muscles are stretched to greater

action potentials. This rigidity results from loss of all the

than normal length. This causes new sarcomeres to be

ATP, which is required to cause separation of the cross-

added at the ends of the muscle fibers, where they attach

bridges from the actin filaments during the relaxation

to the tendons. In fact, new sarcomeres can be added

process. The muscles remain in rigor until the muscle

as rapidly as several per minute in newly developing

proteins deteriorate about 15 to 25 hours later, which

muscle, illustrating the rapidity of this type of

presumably results from autolysis caused by enzymes

hypertrophy.

released from lysosomes. All these events occur more

Conversely, when a muscle continually remains short-

rapidly at higher temperatures.

ened to less than its normal length, sarcomeres at the

ends of the muscle fibers can actually disappear. It is by

these processes that muscles are continually remodeled

to have the appropriate length for proper muscle

References

contraction.

Berchtold MW, Brinkmeier H, Muntener M: Calcium ion

Hyperplasia of Muscle Fibers. Under rare conditions of

in skeletal muscle: its crucial role for muscle function,

extreme muscle force generation, the actual number of

plasticity, and disease. Physiol Rev 80:1215, 2000.

muscle fibers has been observed to increase (but only

Brooks SV: Current topics for teaching skeletal muscle phys-

by a few percentage points), in addition to the fiber

iology. Adv Physiol Educ 27:171, 2003.

hypertrophy process. This increase in fiber number is

Clausen T: Na⁺-K⁺ pump regulation and skeletal muscle con-

called fiber hyperplasia. When it does occur, the mech-

tractility. Physiol Rev 83:1269, 2003.

anism is linear splitting of previously enlarged fibers.

Glass DJ: Molecular mechanisms modulating muscle mass.

Trends Mol Med 8:344, 2003.

Effects of Muscle Denervation. When a muscle loses its

Glass DJ: Signalling pathways that mediate skeletal muscle

nerve supply, it no longer receives the contractile signals

hypertrophy and atrophy. Nat Cell Biol 5:87, 2003.

that are required to maintain normal muscle size.

Gordon AM, Homsher E, Regnier M: Regulation of con-

Therefore, atrophy begins almost immediately. After

traction in striated muscle. Physiol Rev 80:853, 2000.

C H A P T E R

Excitation of Skeletal Muscle:

Neuromuscular Transmission and

Excitation-Contraction Coupling

Transmission of Impulses

from Nerve Endings to

Skeletal Muscle Fibers:

The Neuromuscular

Junction

The skeletal muscle fibers are innervated by large,

myelinated nerve fibers that originate from large motoneurons in the anterior

horns of the spinal cord. As pointed out in Chapter 6, each nerve fiber, after

entering the muscle belly, normally branches and stimulates from three to

several hundred skeletal muscle fibers. Each nerve ending makes a junction,

called the neuromuscular junction, with the muscle fiber near its midpoint. The

action potential initiated in the muscle fiber by the nerve signal travels in both

directions toward the muscle fiber ends. With the exception of about 2 per cent

of the muscle fibers, there is only one such junction per muscle fiber.

Physiologic Anatomy of the Neuromuscular Junction—The Motor End Plate. Figure 7-1A

and B shows the neuromuscular junction from a large, myelinated nerve fiber

to a skeletal muscle fiber. The nerve fiber forms a complex of branching nerve

terminals that invaginate into the surface of the muscle fiber but lie outside the

muscle fiber plasma membrane. The entire structure is called the motor end

plate. It is covered by one or more Schwann cells that insulate it from the

surrounding fluids.

Figure 7-1C shows an electron micrographic sketch of the junction between

a single axon terminal and the muscle fiber membrane. The invaginated mem-

brane is called the synaptic gutter or synaptic trough, and the space between the

terminal and the fiber membrane is called the synaptic space or synaptic cleft.

This space is 20 to 30 nanometers wide. At the bottom of the gutter are numer-

ous smaller folds of the muscle membrane called subneural clefts, which greatly

increase the surface area at which the synaptic transmitter can act.

In the axon terminal are many mitochondria that supply adenosine triphos-

phate (ATP), the energy source that is used for synthesis of an excitatory

transmitter acetylcholine. The acetylcholine in turn excites the muscle

fiber membrane. Acetylcholine is synthesized in the cytoplasm of the terminal,

but it is absorbed rapidly into many small synaptic vesicles, about 300,000

of which are normally in the terminals of a single end plate. In the synaptic

space are large quantities of the enzyme acetylcholinesterase, which destroys

acetylcholine a few milliseconds after it has been released from the synaptic

vesicles.

Secretion of Acetylcholine by the Nerve Terminals

When a nerve impulse reaches the neuromuscular junction, about 125 vesicles

of acetylcholine are released from the terminals into the synaptic space. Some

of the details of this mechanism can be seen in Figure 7-2, which shows an

expanded view of a synaptic space with the neural membrane above and the

muscle membrane and its subneural clefts below.

Unit II

Membrane Physiology, Nerve, and Muscle

Axon

Myelin

sheath

Terminal nerve

branches

Teloglial cell

Myofibrils

Muscle

nuclei

Axon terminal in

Synaptic vesicles

synaptic trough

Figure 7-1

Different views of the motor end

plate. A, Longitudinal section

through the end plate. B, Surface

view of the end plate. C, Electron

micrographic appearance of the

contact point between a single

axon terminal and the muscle

fiber membrane. (Redrawn from

Fawcett DW, as modified from

Couteaux R, in Bloom W, Fawcett

DW: A Textbook of Histology.

Philadelphia: WB Saunders,

Subneural clefts

1986.)

On the inside surface of the neural membrane are

Release

Neural

Vesicles

linear dense bars, shown in cross section in Figure 7-2.

sites

membrane

To each side of each dense bar are protein particles

that penetrate the neural membrane; these are voltage-

Dense bar

gated calcium channels. When an action potential

spreads over the terminal, these channels open and

Calcium

channels

allow calcium ions to diffuse from the synaptic space

to the interior of the nerve terminal. The calcium ions,

Basal lamina

and

in turn, are believed to exert an attractive influence on

acetylcholinesterase

the acetylcholine vesicles, drawing them to the neural

membrane adjacent to the dense bars. The vesicles

Acetylcholine

then fuse with the neural membrane and empty their

receptors

acetylcholine into the synaptic space by the process of

exocytosis.

Subneural cleft

Although some of the aforementioned details are

speculative, it is known that the effective stimulus for

causing acetylcholine release from the vesicles is entry

of calcium ions and that acetylcholine from the vesi-

cles is then emptied through the neural membrane

Muscle

adjacent to the dense bars.

membrane

Figure 7-2

Effect of Acetylcholine on the Postsynaptic Muscle Fiber Mem-

brane to Open Ion Channels. Figure 7-2 also shows many

Release of acetylcholine from synaptic vesicles at the neural

very small acetylcholine receptors in the muscle fiber

membrane of the neuromuscular junction. Note the proximity of

membrane; these are acetylcholine-gated ion channels,

the release sites in the neural membrane to the acetylcholine

receptors in the muscle membrane, at the mouths of the subneural

and they are located almost entirely near the mouths

clefts.

of the subneural clefts lying immediately below the

dense bar areas, where the acetylcholine is emptied

into the synaptic space.

Each receptor is a protein complex that has a total

molecular weight of 275,000. The complex is composed

Chapter 7

Excitation of Skeletal Muscle: Neuromuscular Transmission and Excitation-Contraction Coupling

of five subunit proteins, two alpha proteins and one

In practice, far more sodium ions flow through the

each of beta, delta, and gamma proteins. These protein

acetylcholine channels than any other ions, for two

molecules penetrate all the way through the mem-

reasons. First, there are only two positive ions in large

brane, lying side by side in a circle to form a tubular

concentration: sodium ions in the extracellular fluid,

channel, illustrated in Figure 7-3. The channel remains

and potassium ions in the intracellular fluid. Second,

constricted, as shown in section A of the figure, until

the very negative potential on the inside of the muscle

two acetylcholine molecules attach respectively to the

membrane, -80 to -90 millivolts, pulls the positively

two alpha subunit proteins. This causes a conforma-

charged sodium ions to the inside of the fiber, while

tional change that opens the channel, as shown in

simultaneously preventing efflux of the positively

section B of the figure.

charged potassium ions when they attempt to pass

The opened acetylcholine channel has a diameter of

outward.

about 0.65 nanometer, which is large enough to allow

As shown in Figure 7-3B, the principal effect of

the important positive ions—sodium (Na⁺), potassium

opening the acetylcholine-gated channels is to allow

(K⁺), and calcium (Ca⁺⁺)—to move easily through the

large numbers of sodium ions to pour to the inside of

opening. Conversely, negative ions, such as chloride

the fiber, carrying with them large numbers of positive

ions, do not pass through because of strong negative

charges. This creates a local positive potential change

charges in the mouth of the channel that repel these

inside the muscle fiber membrane, called the end plate

negative ions.

potential. In turn, this end plate potential initiates an

action potential that spreads along the muscle mem-

brane and thus causes muscle contraction.

Destruction of the Released Acetylcholine by Acetyl-

cholinesterase. The acetylcholine, once released into

the synaptic space, continues to activate the acetyl-

choline receptors as long as the acetylcholine persists

–

in the space. However, it is removed rapidly by two

means: (1) Most of the acetylcholine is destroyed

by the enzyme acetylcholinesterase, which is attached

mainly to the spongy layer of fine connective tissue

that fills the synaptic space between the presynaptic

nerve terminal and the postsynaptic muscle mem-

brane. (2) A small amount of acetylcholine diffuses out

of the synaptic space and is then no longer available

to act on the muscle fiber membrane.

The short time that the acetylcholine remains in the

synaptic space—a few milliseconds at most—normally

is sufficient to excite the muscle fiber. Then the rapid

removal of the acetylcholine prevents continued

Na⁺

Ach

muscle re-excitation after the muscle fiber has re-

covered from its initial action potential.

End Plate Potential and Excitation of the Skeletal Muscle Fiber.

The sudden insurgence of sodium ions into the muscle

fiber when the acetylcholine channels open causes the

electrical potential inside the fiber at the local area of

the end plate to increase in the positive direction as

much as 50 to 75 millivolts, creating a local potential

called the end plate potential. Recall from Chapter 5

that a sudden increase in nerve membrane potential

of more than 20 to 30 millivolts is normally sufficient

to initiate more and more sodium channel opening,

thus initiating an action potential at the muscle fiber

membrane.

Figure 7-4 shows the principle of an end plate

potential initiating the action potential. This figure

shows three separate end plate potentials. End plate

Figure 7-3

potentials A and C are too weak to elicit an action

Acetylcholine channel.

Closed state. B,

After acetylcholine

potential, but they do produce weak local end plate

(Ach) has become attached and a conformational change has

voltage changes, as recorded in the figure. By contrast,

opened the channel, allowing sodium ions to enter the muscle

end plate potential B is much stronger and causes

fiber and excite contraction. Note the negative charges at the

enough sodium channels to open so that the self-

channel mouth that prevent passage of negative ions such as

chloride ions.

regenerative effect of more and more sodium ions

Unit II

Membrane Physiology, Nerve, and Muscle

nervous system for which most of the details of chemi-

cal transmission have been worked out. The formation

+ 60

and release of acetylcholine at this junction occur in the

+ 40

following stages:

+ 20

Small vesicles, about 40 nanometers in size, are

formed by the Golgi apparatus in the cell body of

the motoneuron in the spinal cord. These vesicles

- 20

are then transported by axoplasm that “streams”

- 40

through the core of the axon from the central

- 60

cell body in the spinal cord all the way to the

neuromuscular junction at the tips of the peripheral

- 80

nerve fibers. About 300,000 of these small vesicles

-100

collect in the nerve terminals of a single skeletal

muscle end plate.

Acetylcholine is synthesized in the cytosol of the

Milliseconds

nerve fiber terminal but is immediately transported

through the membranes of the vesicles to their

interior, where it is stored in highly concentrated

Figure 7-4

form, about 10,000 molecules of acetylcholine in

each vesicle.

End plate potentials (in millivolts). A, Weakened end plate poten-

When an action potential arrives at the nerve

tial recorded in a curarized muscle, too weak to elicit an action

terminal, it opens many calcium channels in the

potential. B, Normal end plate potential eliciting a muscle action

membrane of the nerve terminal because this

potential. C, Weakened end plate potential caused by botulinum

terminal has an abundance of voltage-gated

toxin that decreases end plate release of acetylcholine, again too

weak to elicit a muscle action potential.

calcium channels. As a result, the calcium ion

concentration inside the terminal membrane

increases about 100-fold, which in turn increases

the rate of fusion of the acetylcholine vesicles with

flowing to the interior of the fiber initiates an action

the terminal membrane about 10,000-fold. This

potential. The weakness of the end plate potential at

fusion makes many of the vesicles rupture, allowing

exocytosis of acetylcholine into the synaptic space.

point A was caused by poisoning of the muscle fiber

About 125 vesicles usually rupture with each

with curare, a drug that blocks the gating action of

action potential. Then, after a few milliseconds, the

acetylcholine on the acetylcholine channels by com-

acetylcholine is split by acetylcholinesterase

peting for the acetylcholine receptor sites. The weak-

into acetate ion and choline, and the choline is

ness of the end plate potential at point C resulted from

reabsorbed actively into the neural terminal to be

the effect of botulinum toxin, a bacterial poison that

reused to form new acetylcholine. This sequence of

decreases the quantity of acetylcholine release by the

events occurs within a period of 5 to 10

nerve terminals.

milliseconds.

The number of vesicles available in the nerve

Safety Factor for Transmission at the Neuromuscular Junction;

ending is sufficient to allow transmission of only a

few thousand nerve-to-muscle impulses. Therefore,

Fatigue of the Junction. Ordinarily, each impulse that

for continued function of the neuromuscular

arrives at the neuromuscular junction causes about

junction, new vesicles need to be re-formed rapidly.

three times as much end plate potential as that

Within a few seconds after each action potential is

required to stimulate the muscle fiber. Therefore, the

over, “coated pits” appear in the terminal nerve

normal neuromuscular junction is said to have a high

membrane, caused by contractile proteins in the

safety factor. However, stimulation of the nerve fiber

nerve ending, especially the protein clathrin, which

at rates greater than 100 times per second for several

is attached to the membrane in the areas of the

minutes often diminishes the number of acetylcholine

original vesicles. Within about 20 seconds, the

vesicles so much that impulses fail to pass into the

proteins contract and cause the pits to break away

muscle fiber. This is called fatigue of the neuromuscu-

to the interior of the membrane, thus forming new

vesicles. Within another few seconds, acetylcholine

lar junction, and it is the same effect that causes fatigue

is transported to the interior of these vesicles, and

of synapses in the central nervous system when the

they are then ready for a new cycle of acetylcholine

synapses are overexcited. Under normal functioning

release.

conditions, measurable fatigue of the neuromuscular

junction occurs rarely, and even then only at the most

exhausting levels of muscle activity.

Drugs That Enhance or

Block Transmission at the

Molecular Biology of

Neuromuscular Junction

Acetylcholine Formation

Drugs That Stimulate the Muscle Fiber by Acetylcholine-Like

and Release

Action. Many compounds, including methacholine, car-

Because the neuromuscular junction is large enough to

bachol, and nicotine, have the same effect on the muscle

be studied easily, it is one of the few synapses of the

fiber as does acetylcholine. The difference between

Chapter 7

Excitation of Skeletal Muscle: Neuromuscular Transmission and Excitation-Contraction Coupling

these drugs and acetylcholine is that the drugs are not

Muscle Action Potential

destroyed by cholinesterase or are destroyed so slowly

that their action often persists for many minutes to

Almost everything discussed in Chapter 5 regarding

several hours. The drugs work by causing localized areas

initiation and conduction of action potentials in nerve

of depolarization of the muscle fiber membrane at the

fibers applies equally to skeletal muscle fibers, except

motor end plate where the acetylcholine receptors

for quantitative differences. Some of the quantitative

are located. Then, every time the muscle fiber recovers

from a previous contraction, these depolarized areas, by

aspects of muscle potentials are the following:

virtue of leaking ions, initiate a new action potential,

1. Resting membrane potential: about -80 to -90

thereby causing a state of muscle spasm.

millivolts in skeletal fibers—the same as in large

myelinated nerve fibers.

Drugs That Stimulate the Neuromuscular Junction by

2. Duration of action potential: 1 to 5 milliseconds in

Inactivating Acetylcholinesterase. Three particularly well-

skeletal muscle—about five times as long as in

known drugs, neostigmine, physostigmine, and

large myelinated nerves.

diisopropyl fluorophosphate, inactivate the acetyl-

3. Velocity of conduction: 3 to 5 m/sec—about 1/13

cholinesterase in the synapses so that it no longer

the velocity of conduction in the large myelinated

hydrolyzes acetylcholine. Therefore, with each succes-

nerve fibers that excite skeletal muscle.

sive nerve impulse, additional acetylcholine accumu-

lates and stimulates the muscle fiber repetitively. This

causes muscle spasm when even a few nerve impulses

reach the muscle. Unfortunately, it also can cause death

Spread of the Action Potential to the

due to laryngeal spasm, which smothers the person.

Interior of the Muscle Fiber by Way of

Neostigmine and physostigmine combine with acetyl-

“Transverse Tubules”

cholinesterase to inactivate the acetylcholinesterase

for up to several hours, after which these drugs are

The skeletal muscle fiber is so large that action poten-

displaced from the acetylcholinesterase so that the

esterase once again becomes active. Conversely, diiso-

tials spreading along its surface membrane cause

propyl fluorophosphate, which has military potential

almost no current flow deep within the fiber. Yet, to

as a powerful “nerve” gas poison, inactivates acetyl-

cause maximum muscle contraction, current must pen-

cholinesterase for weeks, which makes this a particu-

etrate deeply into the muscle fiber to the vicinity of the

larly lethal poison.

separate myofibrils. This is achieved by transmission of

action potentials along transverse tubules (T tubules)

Drugs That Block Transmission at the Neuromuscular Junction. A

that penetrate all the way through the muscle fiber

group of drugs known as curariform drugs can prevent

from one side of the fiber to the other, as illustrated in

passage of impulses from the nerve ending into the

Figure

7-5. The T tubule action potentials cause

muscle. For instance, D-tubocurarine blocks the action

release of calcium ions inside the muscle fiber in the

of acetylcholine on the muscle fiber acetylcholine recep-

tors, thus preventing sufficient increase in permeability

immediate vicinity of the myofibrils, and these calcium

of the muscle membrane channels to initiate an action

ions then cause contraction. This overall process is

potential.

called excitation-contraction coupling.

Myasthenia Gravis

Excitation-Contraction

Coupling

Myasthenia gravis, which occurs in about 1 in every

20,000 persons, causes muscle paralysis because of

inability of the neuromuscular junctions to transmit

Transverse Tubule-Sarcoplasmic

enough signals from the nerve fibers to the muscle

Reticulum System

fibers. Pathologically, antibodies that attack the acetyl-

choline-gated sodium ion transport proteins have been

Figure 7-5 shows myofibrils surrounded by the T

demonstrated in the blood of most patients with

tubule-sarcoplasmic reticulum system. The T tubules

myasthenia gravis. Therefore, it is believed that myas-

thenia gravis is an autoimmune disease in which the

are very small and run transverse to the myofibrils.

patients have developed immunity against their own

They begin at the cell membrane and penetrate all the

acetylcholine-activated ion channels.

way from one side of the muscle fiber to the opposite

Regardless of the cause, the end plate potentials that

side. Not shown in the figure is the fact that these

occur in the muscle fibers are mostly too weak to stimu-

tubules branch among themselves so that they form

late the muscle fibers. If the disease is intense enough,

entire planes of T tubules interlacing among all the

the patient dies of paralysis—in particular, paralysis of

separate myofibrils. Also, where the T tubules originate

the respiratory muscles. The disease usually can be ame-

from the cell membrane, they are open to the exterior

liorated for several hours by administering neostigmine

of the muscle fiber. Therefore, they communicate with

or some other anticholinesterase drug, which allows

the extracellular fluid surrounding the muscle fiber,

larger than normal amounts of acetylcholine to accu-

mulate in the synaptic space. Within minutes, some of

and they themselves contain extracellular fluid in their

these paralyzed people can begin to function almost

lumens. In other words, the T tubules are actually

normally, until a new dose of neostigmine is required a

internal extensions of the cell membrane. Therefore,

few hours later.

when an action potential spreads over a muscle fiber

Unit II

Membrane Physiology, Nerve, and Muscle

Myofibrils

Sarcolemma

Terminal

Triad of the

cisternae

reticulum

Z line

Transverse

tubule

Mitochondrion

Figure 7-5

Transverse

(T) tubule-sarcoplas-

A band

mic reticulum system. Note that

the T tubules communicate with the

outside of the cell membrane, and

deep in the muscle fiber, each T

Sarcoplasmic

tubule lies adjacent to the ends of

reticulum

longitudinal sarcoplasmic reticulum

tubules that surround all sides of

the actual myofibrils that contract.

This illustration was drawn from frog

muscle, which has one T tubule per

Transverse

sarcomere, located at the Z line. A

I band

tubule

similar arrangement is found in

mammalian heart muscle, but

mammalian skeletal muscle has

two T tubules per sarcomere,

located at the A-I band junctions.

(Redrawn from Bloom W, Fawcett

DW: A Textbook of Histology.

Philadelphia: WB Saunders, 1986.

Modified after Peachey LD: J Cell

Biol 25:209, 1965. Drawn by Sylvia

Sarcotubules

Colard Keene.)

membrane, a potential change also spreads along the

sarcoplasm surrounding the myofibrils to cause con-

T tubules to the deep interior of the muscle fiber. The

traction, as discussed in Chapter 6.

electrical currents surrounding these T tubules then

elicit the muscle contraction.

Calcium Pump for Removing Calcium Ions from the Myofibrillar

Figure 7-5 also shows a sarcoplasmic reticulum, in

Fluid After Contraction Occurs. Once the calcium ions

yellow. This is composed of two major parts: (1) large

have been released from the sarcoplasmic tubules and

chambers called terminal cisternae that abut the T

have diffused among the myofibrils, muscle contrac-

tubules, and (2) long longitudinal tubules that sur-

tion continues as long as the calcium ions remain in

round all surfaces of the actual contracting myofibrils.

high concentration. However, a continually active

calcium pump located in the walls of the sarcoplasmic

reticulum pumps calcium ions away from the myofi-

Release of Calcium Ions by the

brils back into the sarcoplasmic tubules. This pump can

Sarcoplasmic Reticulum

concentrate the calcium ions about 10,000-fold inside

the tubules. In addition, inside the reticulum is a

One of the special features of the sarcoplasmic reticu-

protein called calsequestrin that can bind up to 40

lum is that within its vesicular tubules is an excess of

times more calcium.

calcium ions in high concentration, and many of these

ions are released from each vesicle when an action

Excitatory “Pulse” of Calcium Ions. The normal resting

potential occurs in the adjacent T tubule.

state concentration (less than 10-7 molar) of calcium

Figure 7-6 shows that the action potential of the T

ions in the cytosol that bathes the myofibrils is too

tubule causes current flow into the sarcoplasmic re-

little to elicit contraction. Therefore, the troponin-

ticular cisternae where they abut the T tubule. This in

tropomyosin complex keeps the actin filaments inhib-

turn causes rapid opening of large numbers of calcium

ited and maintains a relaxed state of the muscle.

channels through the membranes of the cisternae as

Conversely, full excitation of the T tubule and

well as their attached longitudinal tubules. These

sarcoplasmic reticulum system causes enough re-

channels remain open for a few milliseconds; during

lease of calcium ions to increase the concentration

this time, enough calcium ions are released into the

in the myofibrillar fluid to as high as 2

¥ 10-4 molar

Chapter 7

Excitation of Skeletal Muscle: Neuromuscular Transmission and Excitation-Contraction Coupling

Action potential

Sarcolemma

Calcium pump

ATP

required

Figure 7-6

Ca⁺⁺

Excitation-contraction coupling in

the muscle, showing (1) an action

potential that causes release of

calcium ions from the sarcoplas-

mic reticulum and then

(2) re-

uptake of the calcium ions by a

calcium pump.

Actin filaments

Myosin filaments

concentration, a 500-fold increase, which is about 10

neurophysiological basis and implication for respiratory

times the level required to cause maximum muscle

control. J Appl Physiol 96:407, 2004.

contraction. Immediately thereafter, the calcium pump

Hoch W: Molecular dissection of neuromuscular junction

formation. Trends Neurosci 26:335, 2003.

depletes the calcium ions again. The total duration of

Keesey JC: Clinical evaluation and management of myas-

this calcium “pulse” in the usual skeletal muscle fiber

thenia gravis. Muscle Nerve 29:484, 2004.

lasts about

1/20 of a second, although it may last

Lee C: Conformation, action, and mechanism of action of

several times as long in some fibers and several times

neuromuscular blocking muscle relaxants. Pharmacol Ther

less in others. (In heart muscle, the calcium pulse lasts

98:143, 2003.

about 1/3 of a second because of the long duration of

Leite JF, Rodrigues-Pinguet N, Lester HA: Insights into

the cardiac action potential.)

channel function via channel dysfunction. J Clin Invest

During this calcium pulse, muscle contraction

111:436, 2003.

occurs. If the contraction is to continue without inter-

Payne AM, Delbono O: Neurogenesis of excitation-

ruption for long intervals, a series of calcium pulses

contraction uncoupling in aging skeletal muscle. Exerc

Sport Sci Rev 32:36, 2004.

must be initiated by a continuous series of repetitive

Pette D: Historical perspectives: plasticity of mammalian

action potentials, as discussed in Chapter 6.

skeletal muscle. J Appl Physiol 90:1119, 2001.

Rekling JC, Funk GD, Bayliss DA, et al: Synaptic control of

motoneuronal excitability. Physiol Rev 80:767, 2000.

References

Schiaffino S, Serrano A: Calcineurin signaling and neural

control of skeletal muscle fiber type and size. Trends

Also see references for Chapters 5 and 6.

Pharmacol Sci 23:569, 2002.

Allman BL, Rice CL: Neuromuscular fatigue and aging:

Tang W, Sencer S, Hamilton SL: Calmodulin modulation of

central and peripheral factors. Muscle Nerve 25:785, 2002.

proteins involved in excitation-contraction coupling. Front

Amonof MJ: Electromyography in Clinical Practice. New

Biosci 7:583, 2002.

York: Churchill Livingstone, 1998.

Toyoshima C, Nomura H, Sugita Y: Structural basis of ion

Brown RH Jr: Dystrophin-associated proteins and the mus-

pumping by Ca2+-ATPase of sarcoplasmic reticulum.

cular dystrophies. Annu Rev Med 48:457, 1997.

FEBS Lett 555:106, 2003.

Chaudhuri A, Behan PO: Fatigue in neurological disorders.

Van der Kloot W, Molgo J: Quantal acetylcholine release at

Lancet 363:978, 2004.

the vertebrate neuromuscular junction. Physiol Rev

Engel AG, Ohno K, Shen XM, Sine SM: Congenital myas-

74:899, 1994.

thenic syndromes: multiple molecular targets at the

Vincent A: Unraveling the pathogenesis of myasthenia

neuromuscular junction. Ann N Y Acad Sci 998:138,

gravis. Nat Rev Immunol 10:797, 2002.

2003.

Vincent A, McConville J, Farrugia ME, et al: Antibodies in

Haouzi P, Chenuel B, Huszczuk A: Sensing vascular disten-

myasthenia gravis and related disorders. Ann N Y Acad

sion in skeletal muscle by slow conducting afferent fibers:

Sci 998:324, 2003.

C H A P T E R

Contraction and Excitation

of Smooth Muscle

Contraction of Smooth

Muscle

In Chapters 6 and 7, the discussion was concerned

with skeletal muscle. We now turn to smooth

muscle, which is composed of far smaller fibers—

usually 1 to 5 micrometers in diameter and only 20

to 500 micrometers in length. In contrast, skeletal

muscle fibers are as much as 30 times greater in diameter and hundreds of times

as long. Many of the same principles of contraction apply to smooth muscle as

to skeletal muscle. Most important, essentially the same attractive forces

between myosin and actin filaments cause contraction in smooth muscle as in

skeletal muscle, but the internal physical arrangement of smooth muscle fibers

is very different.

Types of Smooth Muscle

The smooth muscle of each organ is distinctive from that of most other organs

in several ways: (1) physical dimensions, (2) organization into bundles or sheets,

(3) response to different types of stimuli, (4) characteristics of innervation, and

(5) function. Yet, for the sake of simplicity, smooth muscle can generally be

divided into two major types, which are shown in Figure 8-1: multi-unit smooth

muscle and unitary (or single-unit) smooth muscle.

Multi-Unit Smooth Muscle. This type of smooth muscle is composed of discrete,

separate smooth muscle fibers. Each fiber operates independently of the others

and often is innervated by a single nerve ending, as occurs for skeletal muscle

fibers. Further, the outer surfaces of these fibers, like those of skeletal muscle

fibers, are covered by a thin layer of basement membrane-like substance, a

mixture of fine collagen and glycoprotein that helps insulate the separate fibers

from one another.

The most important characteristic of multi-unit smooth muscle fibers is that

each fiber can contract independently of the others, and their control is exerted

mainly by nerve signals. In contrast, a major share of control of unitary smooth

muscle is exerted by non-nervous stimuli. Some examples of multi-unit smooth

muscle are the ciliary muscle of the eye, the iris muscle of the eye, and the pilo-

erector muscles that cause erection of the hairs when stimulated by the sym-

pathetic nervous system.

Unitary Smooth Muscle. The term “unitary” is confusing because it does not mean

single muscle fibers. Instead, it means a mass of hundreds to thousands of

smooth muscle fibers that contract together as a single unit. The fibers usually

are arranged in sheets or bundles, and their cell membranes are adherent to one

another at multiple points so that force generated in one muscle fiber can be

transmitted to the next. In addition, the cell membranes are joined by many gap

junctions through which ions can flow freely from one muscle cell to the next

so that action potentials or simple ion flow without action potentials can travel

Chapter 8

Contraction and Excitation of Smooth Muscle

Adventitia

Actin

filaments

Dense bodies

Medial

muscle fibers

Endothelium

Small artery

Multi-unit smooth muscle

Unitary smooth muscle

Myosin filaments

Figure 8-1

Multi-unit (A) and unitary (B) smooth muscle.

from one fiber to the next and cause the muscle fibers

Cell membrane

to contract together. This type of smooth muscle is also

known as syncytial smooth muscle because of its syn-

cytial interconnections among fibers. It is also called

visceral smooth muscle because it is found in the walls

of most viscera of the body, including the gut, bile

ducts, ureters, uterus, and many blood vessels.

Contractile Mechanism in

Smooth Muscle

Chemical Basis for Smooth

Muscle Contraction

Smooth muscle contains both actin and myosin fila-

Figure 8-2

ments, having chemical characteristics similar to those

Physical structure of smooth muscle. The upper left-hand fiber

of the actin and myosin filaments in skeletal muscle.

shows actin filaments radiating from dense bodies. The lower left-

It does not contain the normal troponin complex

hand fiber and the right-hand diagram demonstrate the relation of

that is required in the control of skeletal muscle con-

myosin filaments to actin filaments.

traction, so the mechanism for control of contraction

is different. This is discussed in detail later in this

chapter.

Chemical studies have shown that actin and myosin

Physical Basis for Smooth Muscle Contraction

filaments derived from smooth muscle interact with

Smooth muscle does not have the same striated

each other in much the same way that they do in skele-

arrangement of actin and myosin filaments as is found

tal muscle. Further, the contractile process is activated

in skeletal muscle. Instead, electron micrographic tech-

by calcium ions, and adenosine triphosphate (ATP) is

niques suggest the physical organization exhibited in

degraded to adenosine diphosphate (ADP) to provide

Figure 8-2. This figure shows large numbers of actin

the energy for contraction.

filaments attached to so-called dense bodies. Some of

There are, however, major differences between the

these bodies are attached to the cell membrane.

physical organization of smooth muscle and that of

Others are dispersed inside the cell. Some of the mem-

skeletal muscle, as well as differences in excitation-

brane dense bodies of adjacent cells are bonded

contraction coupling, control of the contractile process

together by intercellular protein bridges. It is mainly

by calcium ions, duration of contraction, and amount

through these bonds that the force of contraction is

of energy required for contraction.

transmitted from one cell to the next.

Unit II

Membrane Physiology, Nerve, and Muscle

Interspersed among the actin filaments in the

This sparsity of energy utilization by smooth muscle

muscle fiber are myosin filaments. These have a diam-

is exceedingly important to the overall energy

eter more than twice that of the actin filaments. In

economy of the body, because organs such as the intes-

electron micrographs, one usually finds 5 to 10 times

tines, urinary bladder, gallbladder, and other viscera

as many actin filaments as myosin filaments.

often maintain tonic muscle contraction almost

To the right in Figure 8-2 is a postulated structure

indefinitely.

of an individual contractile unit within a smooth

muscle cell, showing large numbers of actin filaments

Slowness of Onset of Contraction and Relaxation of the Total

radiating from two dense bodies; the ends of these

Smooth Muscle Tissue. A typical smooth muscle tissue

filaments overlap a myosin filament located midway

begins to contract 50 to 100 milliseconds after it is

between the dense bodies. This contractile unit is

excited, reaches full contraction about 0.5 second later,

similar to the contractile unit of skeletal muscle, but

and then declines in contractile force in another 1 to

without the regularity of the skeletal muscle structure;

2 seconds, giving a total contraction time of 1 to 3

in fact, the dense bodies of smooth muscle serve the

seconds. This is about 30 times as long as a single

same role as the Z discs in skeletal muscle.

contraction of an average skeletal muscle fiber. But

There is another difference: Most of the myosin fila-

because there are so many types of smooth muscle,

ments have what are called “sidepolar” cross-bridges

contraction of some types can be as short as 0.2 second

arranged so that the bridges on one side hinge in one

or as long as 30 seconds.

direction and those on the other side hinge in the

The slow onset of contraction of smooth muscle,

opposite direction. This allows the myosin to pull an

as well as its prolonged contraction, is caused by

actin filament in one direction on one side while simul-

the slowness of attachment and detachment of the

taneously pulling another actin filament in the oppo-

cross-bridges with the actin filaments. In addition, the

site direction on the other side. The value of this

initiation of contraction in response to calcium ions is

organization is that it allows smooth muscle cells to

much slower than in skeletal muscle, as discussed later.

contract as much as 80 per cent of their length instead

of being limited to less than 30 per cent, as occurs in

Force of Muscle Contraction. Despite the relatively few

skeletal muscle.

myosin filaments in smooth muscle, and despite the

slow cycling time of the cross-bridges, the maximum

Comparison of Smooth Muscle Contraction

force of contraction of smooth muscle is often greater

and Skeletal Muscle Contraction

than that of skeletal muscle—as great as 4 to 6 kg/cm²

Although most skeletal muscles contract and relax

cross-sectional area for smooth muscle, in comparison

rapidly, most smooth muscle contraction is prolonged

with 3 to 4 kilograms for skeletal muscle. This great

tonic contraction, sometimes lasting hours or even

force of smooth muscle contraction results from the

days. Therefore, it is to be expected that both the physi-

prolonged period of attachment of the myosin cross-

cal and the chemical characteristics of smooth muscle

bridges to the actin filaments.

versus skeletal muscle contraction would differ.

Following are some of the differences.

“Latch” Mechanism for Prolonged Holding of Contractions of

Smooth Muscle. Once smooth muscle has developed full

Slow Cycling of the Myosin Cross-Bridges. The rapidity

contraction, the amount of continuing excitation

of cycling of the myosin cross-bridges in smooth

usually can be reduced to far less than the initial

muscle—that is, their attachment to actin, then release

level, yet the muscle maintains its full force of con-

from the actin, and reattachment for the next cycle—

traction. Further, the energy consumed to maintain

is much, much slower in smooth muscle than in skele-

contraction is often minuscule, sometimes as little as

tal muscle; in fact, the frequency is as little as 1/10 to

1/300 the energy required for comparable sustained

1/300 that in skeletal muscle. Yet the fraction of time

skeletal muscle contraction. This is called the “latch”

that the cross-bridges remain attached to the actin fila-

mechanism.

ments, which is a major factor that determines the

The importance of the latch mechanism is that it

force of contraction, is believed to be greatly increased

can maintain prolonged tonic contraction in smooth

in smooth muscle. A possible reason for the slow

muscle for hours with little use of energy. Little con-

cycling is that the cross-bridge heads have far less

tinued excitatory signal is required from nerve fibers

ATPase activity than in skeletal muscle, so that degra-

or hormonal sources.

dation of the ATP that energizes the movements

of the cross-bridge heads is greatly reduced, with

Stress-Relaxation of Smooth Muscle. Another impor-

corresponding slowing of the rate of cycling.

tant characteristic of smooth muscle, especially the vis-

ceral unitary type of smooth muscle of many hollow

Energy Required to Sustain Smooth Muscle Contraction. Only

organs, is its ability to return to nearly its original

1/10 to 1/300 as much energy is required to sustain the

force of contraction seconds or minutes after it has

same tension of contraction in smooth muscle as in

been elongated or shortened. For example, a sudden

skeletal muscle. This, too, is believed to result from the

increase in fluid volume in the urinary bladder, thus

slow attachment and detachment cycling of the cross-

stretching the smooth muscle in the bladder wall,

bridges and because only one molecule of ATP is

causes an immediate large increase in pressure in the

required for each cycle, regardless of its duration.

bladder. However, during the next 15 seconds to a

Chapter 8

Contraction and Excitation of Smooth Muscle

minute or so, despite continued stretch of the bladder

myosin phosphatase, located in the fluids of the

wall, the pressure returns almost exactly back to the

smooth muscle cell, which splits the phosphate from

original level. Then, when the volume is increased by

the regulatory light chain. Then the cycling stops and

another step, the same effect occurs again.

contraction ceases. The time required for relaxation of

Conversely, when the volume is suddenly decreased,

muscle contraction, therefore, is determined to a great

the pressure falls very low at first but then rises back

extent by the amount of active myosin phosphatase in

in another few seconds or minutes to or near to the

the cell.

original level. These phenomena are called stress-

relaxation and reverse stress-relaxation. Their impor-

Possible Mechanism for Regulation of the

tance is that, except for short periods of time, they

Latch Phenomenon

allow a hollow organ to maintain about the same

Because of the importance of the latch phenomenon

amount of pressure inside its lumen despite long-term,

in smooth muscle, and because this phenomenon

large changes in volume.

allows long-term maintenance of tone in many smooth

muscle organs without much expenditure of energy,

many attempts have been made to explain it. Among

Regulation of Contraction

the many mechanisms that have been postulated, one

by Calcium Ions

of the simplest is the following.

When the myosin kinase and myosin phosphatase

As is true for skeletal muscle, the initiating stimulus

enzymes are both strongly activated, the cycling fre-

for most smooth muscle contraction is an increase in

quency of the myosin heads and the velocity of

intracellular calcium ions. This increase can be caused

contraction are great. Then, as the activation of the

in different types of smooth muscle by nerve stimula-

enzymes decreases, the cycling frequency decreases,

tion of the smooth muscle fiber, hormonal stimulation,

but at the same time, the deactivation of these enzymes

stretch of the fiber, or even change in the chemical

allows the myosin heads to remain attached to the

environment of the fiber.

actin filament for a longer and longer proportion of

Yet smooth muscle does not contain troponin, the

the cycling period. Therefore, the number of heads

regulatory protein that is activated by calcium ions

attached to the actin filament at any given time

to cause skeletal muscle contraction. Instead, smooth

remains large. Because the number of heads attached

muscle contraction is activated by an entirely different

to the actin determines the static force of contraction,

mechanism, as follows.

tension is maintained, or “latched”; yet little energy

is used by the muscle, because ATP is not degraded

Combination of Calcium Ions with Calmodulin—Activation of

to ADP except on the rare occasion when a head

Myosin Kinase and Phosphorylation of the Myosin Head. In

detaches.

place of troponin, smooth muscle cells contain a large

amount of another regulatory protein called calmod-

ulin. Although this protein is similar to troponin, it is

Nervous and Hormonal Control

different in the manner in which it initiates contrac-

tion. Calmodulin does this by activating the myosin

of Smooth Muscle Contraction

cross-bridges. This activation and subsequent contrac-

tion occur in the following sequence:

Although skeletal muscle fibers are stimulated exclu-

1. The calcium ions bind with calmodulin.

sively by the nervous system, smooth muscle can be

2. The calmodulin-calcium combination joins with

stimulated to contract by multiple types of signals: by

and activates myosin kinase, a phosphorylating

nervous signals, by hormonal stimulation, by stretch of

enzyme.

the muscle, and in several other ways. The principal

3. One of the light chains of each myosin

reason for the difference is that the smooth muscle

head, called the regulatory chain, becomes

membrane contains many types of receptor proteins

phosphorylated in response to this myosin kinase.

that can initiate the contractile process. Still other

When this chain is not phosphorylated, the

receptor proteins inhibit smooth muscle contraction,

attachment-detachment cycling of the myosin

which is another difference from skeletal muscle.

head with the actin filament does not occur. But

Therefore, in this section, we discuss nervous control

when the regulatory chain is phosphorylated, the

of smooth muscle contraction, followed by hormonal

head has the capability of binding repetitively

control and other means of control.

with the actin filament and proceeding through

the entire cycling process of intermittent “pulls,”

the same as occurs for skeletal muscle, thus

Neuromuscular Junctions

causing muscle contraction.

of Smooth Muscle

Cessation of Contraction—Role of Myosin Phosphatase.

Physiologic Anatomy of Smooth Muscle Neuromuscular Junc-

When the calcium ion concentration falls below a crit-

tions. Neuromuscular junctions of the highly struc-

ical level, the aforementioned processes automatically

tured type found on skeletal muscle fibers do not occur

reverse, except for the phosphorylation of the myosin

in smooth muscle. Instead, the autonomic nerve fibers

head. Reversal of this requires another enzyme,

that innervate smooth muscle generally branch

Unit II

Membrane Physiology, Nerve, and Muscle

autonomic nerves innervating smooth muscle are

acetylcholine and norepinephrine, but they are never

secreted by the same nerve fibers. Acetylcholine is an

excitatory transmitter substance for smooth muscle

fibers in some organs but an inhibitory transmitter for

smooth muscle in other organs. When acetylcholine

excites a muscle fiber, norepinephrine ordinarily

inhibits it. Conversely, when acetylcholine inhibits a

fiber, norepinephrine usually excites it.

Varicosities

But why these different responses? The answer is

that both acetylcholine and norepinephrine excite or

inhibit smooth muscle by first binding with a receptor

protein on the surface of the muscle cell membrane.

Visceral

Multi-unit

Some of the receptor proteins are excitatory receptors,

whereas others are inhibitory receptors. Thus, the type

Figure 8-3

of receptor determines whether the smooth muscle is

inhibited or excited and also determines which of the

Innervation of smooth muscle.

two transmitters, acetylcholine or norepinephrine, is

effective in causing the excitation or inhibition. These

diffusely on top of a sheet of muscle fibers, as shown

receptors are discussed in more detail in Chapter 60 in

in Figure 8-3. In most instances, these fibers do not

relation to function of the autonomic nervous system.

make direct contact with the smooth muscle fiber cell

membranes but instead form so-called diffuse junc-

Membrane Potentials and Action

tions that secrete their transmitter substance into the

matrix coating of the smooth muscle often a few

Potentials in Smooth Muscle

nanometers to a few micrometers away from the

muscle cells; the transmitter substance then diffuses to

Membrane Potentials in Smooth Muscle. The quantitative

the cells. Furthermore, where there are many layers of

voltage of the membrane potential of smooth muscle

muscle cells, the nerve fibers often innervate only the

depends on the momentary condition of the muscle. In

outer layer, and muscle excitation travels from this

the normal resting state, the intracellular potential is

outer layer to the inner layers by action potential con-

usually about -50 to -60 millivolts, which is about 30

duction in the muscle mass or by additional diffusion

millivolts less negative than in skeletal muscle.

of the transmitter substance.

The axons that innervate smooth muscle fibers do

Action Potentials in Unitary Smooth Muscle. Action poten-

not have typical branching end feet of the type in the

tials occur in unitary smooth muscle (such as visceral

motor end plate on skeletal muscle fibers. Instead,

muscle) in the same way that they occur in skeletal

most of the fine terminal axons have multiple vari-

muscle. They do not normally occur in many, if not

cosities distributed along their axes. At these points the

most, multi-unit types of smooth muscle, as discussed

Schwann cells that envelop the axons are interrupted

in a subsequent section.

so that transmitter substance can be secreted through

The action potentials of visceral smooth muscle

the walls of the varicosities. In the varicosities are vesi-

occur in one of two forms: (1) spike potentials or

cles similar to those in the skeletal muscle end plate

(2) action potentials with plateaus.

that contain transmitter substance. But, in contrast to

the vesicles of skeletal muscle junctions, which always

Spike Potentials. Typical spike action potentials, such

contain acetylcholine, the vesicles of the autonomic

as those seen in skeletal muscle, occur in most types of

nerve fiber endings contain acetylcholine in some

unitary smooth muscle. The duration of this type of

fibers and norepinephrine in others—and occasionally

action potential is 10 to 50 milliseconds, as shown in

other substances as well.

Figure 8-4A. Such action potentials can be elicited in

In a few instances, particularly in the multi-unit type

many ways, for example, by electrical stimulation, by

of smooth muscle, the varicosities are separated from

the action of hormones on the smooth muscle, by the

the muscle cell membrane by as little as 20 to 30

action of transmitter substances from nerve fibers, by

nanometers—the same width as the synaptic cleft that

stretch, or as a result of spontaneous generation in the

occurs in the skeletal muscle junction. These are called

muscle fiber itself, as discussed subsequently.

contact junctions, and they function in much the same

way as the skeletal muscle neuromuscular junction; the

Action Potentials with Plateaus. Figure 8-4C shows a

rapidity of contraction of these smooth muscle fibers

smooth muscle action potential with a plateau. The

is considerably faster than that of fibers stimulated by

onset of this action potential is similar to that of the

the diffuse junctions.

typical spike potential. However, instead of rapid

repolarization of the muscle fiber membrane, the repo-

Excitatory and Inhibitory Transmitter Substances Secreted at

larization is delayed for several hundred to as much

the Smooth Muscle Neuromuscular Junction. The most

as 1000 milliseconds (1 second). The importance of

important transmitter substances secreted by the

the plateau is that it can account for the prolonged

Chapter 8

Contraction and Excitation of Smooth Muscle

ions act directly on the smooth muscle contractile

mechanism to cause contraction. Thus, the calcium

performs two tasks at once.

Slow Wave Potentials in Unitary Smooth Muscle, and Sponta-

neous Generation of Action Potentials. Some smooth

muscle is self-excitatory. That is, action potentials arise

+ 20

within the smooth muscle cells themselves without

an extrinsic stimulus. This often is associated with a

- 40

basic slow wave rhythm of the membrane potential.

A typical slow wave in a visceral smooth muscle of

the gut is shown in Figure 8-4B. The slow wave itself

- 60

Slow waves

is not the action potential. That is, it is not a self-

regenerative process that spreads progressively over

the membranes of the muscle fibers. Instead, it is a

100

local property of the smooth muscle fibers that make

Milliseconds

Seconds

up the muscle mass.

The cause of the slow wave rhythm is unknown. One

suggestion is that the slow waves are caused by waxing

and waning of the pumping of positive ions (presum-

ably sodium ions) outward through the muscle fiber

- 25

membrane; that is, the membrane potential becomes

more negative when sodium is pumped rapidly and

- 50

less negative when the sodium pump becomes less

active. Another suggestion is that the conductances of

0.1

0.2

0.3

0.4

the ion channels increase and decrease rhythmically.

Seconds

The importance of the slow waves is that, when they

are strong enough, they can initiate action potentials.

The slow waves themselves cannot cause muscle con-

Figure 8-4

traction, but when the peak of the negative slow wave

potential inside the cell membrane rises in the positive

A, Typical smooth muscle action potential (spike potential) elicited

direction from

-60 to about

-35 millivolts

(the

by an external stimulus. B, Repetitive spike potentials, elicited by

approximate threshold for eliciting action potentials in

slow rhythmical electrical waves that occur spontaneously in the

smooth muscle of the intestinal wall. C, Action potential with a

most visceral smooth muscle), an action potential

plateau, recorded from a smooth muscle fiber of the uterus.

develops and spreads over the muscle mass. Then con-

traction does occur. Figure 8-4B demonstrates this

effect, showing that at each peak of the slow wave, one

contraction that occurs in some types of smooth

or more action potentials occur. These repetitive

muscle, such as the ureter, the uterus under some con-

sequences of action potentials elicit rhythmical con-

ditions, and certain types of vascular smooth muscle.

traction of the smooth muscle mass. Therefore, the

(Also, this is the type of action potential seen in

slow waves are called pacemaker waves. In Chapter 62,

cardiac muscle fibers that have a prolonged period of

we see that this type of pacemaker activity controls the

contraction, as discussed in Chapters 9 and 10.)

rhythmical contractions of the gut.

Importance of Calcium Channels in Generating the

Excitation of Visceral Smooth Muscle by Muscle Stretch.

Smooth Muscle Action Potential. The smooth muscle

When visceral (unitary) smooth muscle is stretched

cell membrane has far more voltage-gated calcium

sufficiently, spontaneous action potentials usually

channels than does skeletal muscle but few voltage-

are generated. They result from a combination of (1)

gated sodium channels. Therefore, sodium participates

the normal slow wave potentials and (2) decrease in

little in the generation of the action potential in most

overall negativity of the membrane potential caused

smooth muscle. Instead, flow of calcium ions to the

by the stretch itself. This response to stretch allows the

interior of the fiber is mainly responsible for the action

gut wall, when excessively stretched, to contract auto-

potential. This occurs in the same self-regenerative

matically and rhythmically. For instance, when the gut

way as occurs for the sodium channels in nerve fibers

is overfilled by intestinal contents, local automatic con-

and in skeletal muscle fibers. However, the calcium

tractions often set up peristaltic waves that move the

channels open many times more slowly than do

contents away from the overfilled intestine, usually in

sodium channels, and they also remain open much

the direction of the anus.

longer. This accounts in large measure for the pro-

longed plateau action potentials of some smooth

Depolarization of Multi-Unit Smooth Muscle

muscle fibers.

Without Action Potentials

Another important feature of calcium ion entry into

The smooth muscle fibers of multi-unit smooth muscle

the cells during the action potential is that the calcium

(such as the muscle of the iris of the eye or the

Unit II

Membrane Physiology, Nerve, and Muscle

piloerector muscle of each hair) normally contract

angiotensin, endothelin, vasopressin, oxytocin, sero-

mainly in response to nerve stimuli. The nerve endings

tonin, and histamine.

secrete acetylcholine in the case of some multi-unit

A hormone causes contraction of a smooth muscle

smooth muscles and norepinephrine in the case of

when the muscle cell membrane contains hormone-

others. In both instances, the transmitter substances

gated excitatory receptors for the respective hormone.

cause depolarization of the smooth muscle membrane,

Conversely, the hormone causes inhibition if the mem-

and this in turn elicits contraction. Action potentials

brane contains inhibitory receptors for the hormone

usually do not develop; the reason is that the fibers are

rather than excitatory receptors.

too small to generate an action potential. (When

action potentials are elicited in visceral unitary smooth

Mechanisms of Smooth Muscle Excitation or Inhibition by Hor-

muscle, 30 to 40 smooth muscle fibers must depolarize

mones or Local Tissue Factors. Some hormone receptors

simultaneously before a self-propagating action poten-

in the smooth muscle membrane open sodium or

tial ensues.) Yet, in small smooth muscle cells, even

calcium ion channels and depolarize the membrane,

without an action potential, the local depolarization

the same as after nerve stimulation. Sometimes action

(called the junctional potential) caused by the nerve

potentials result, or action potentials that are already

transmitter substance itself spreads “electrotonically”

occurring may be enhanced. In other cases, depolari-

over the entire fiber and is all that is needed to cause

zation occurs without action potentials, and this depo-

muscle contraction.

larization allows calcium ion entry into the cell, which

promotes the contraction.

Inhibition, in contrast, occurs when the hormone (or

Effect of Local Tissue Factors and

other tissue factor) closes the sodium and calcium

Hormones to Cause Smooth Muscle

channels to prevent entry of these positive ions; inhi-

Contraction Without Action Potentials

bition also occurs if the normally closed potassium

channels are opened, allowing positive potassium ions

Probably half of all smooth muscle contraction is

to diffuse out of the cell. Both of these actions increase

initiated by stimulatory factors acting directly on

the degree of negativity inside the muscle cell, a

the smooth muscle contractile machinery and without

state called hyperpolarization, which strongly inhibits

action potentials. Two types of non-nervous and

muscle contraction.

non-action potential stimulating factors often

Sometimes smooth muscle contraction or inhibition

involved are (1) local tissue chemical factors and (2)

is initiated by hormones without directly causing any

various hormones.

change in the membrane potential. In these instances,

the hormone may activate a membrane receptor that

Smooth Muscle Contraction in Response to Local Tissue

does not open any ion channels but instead causes an

Chemical Factors. In Chapter 17, we discuss control of

internal change in the muscle fiber, such as release of

contraction of the arterioles, meta-arterioles, and pre-

calcium ions from the intracellular sarcoplasmic re-

capillary sphincters. The smallest of these vessels have

ticulum; the calcium then induces contraction. To

little or no nervous supply. Yet the smooth muscle is

inhibit contraction, other receptor mechanisms are

highly contractile, responding rapidly to changes in

known to activate the enzyme adenylate cyclase or

local chemical conditions in the surrounding intersti-

guanylate cyclase in the cell membrane; the portions of

tial fluid.

the receptors that protrude to the interior of the cells

In the normal resting state, many of these small

are coupled to these enzymes, causing the formation

blood vessels remain contracted. But when extra blood

of cyclic adenosine monophosphate (cAMP) or cyclic

flow to the tissue is needed, multiple factors can relax

guanosine monophosphate (cGMP), so-called second

the vessel wall, thus allowing for increased flow. In this

messengers. The cAMP or cGMP has many effects, one

way, a powerful local feedback control system controls

of which is to change the degree of phosphorylation of

the blood flow to the local tissue area. Some of the

several enzymes that indirectly inhibit contraction.

specific control factors are as follows:

The pump that moves calcium ions from the sar-

1. Lack of oxygen in the local tissues causes smooth

coplasm into the sarcoplasmic reticulum is activated,

muscle relaxation and, therefore, vasodilatation.

as well as the cell membrane pump that moves calcium

2. Excess carbon dioxide causes vasodilatation.

ions out of the cell itself; these effects reduce the

3. Increased hydrogen ion concentration causes

calcium ion concentration in the sarcoplasm, thereby

vasodilatation.

inhibiting contraction.

Adenosine, lactic acid, increased potassium ions,

Smooth muscles have considerable diversity in how

diminished calcium ion concentration, and increased

they initiate contraction or relaxation in response to

body temperature can all cause local vasodilatation.

different hormones, neurotransmitters, and other

substances. In some instances, the same substance

Effects of Hormones on Smooth Muscle Contraction. Most

may cause either relaxation or contraction of smooth

circulating hormones in the blood affect smooth

muscles in different locations. For example, norepi-

muscle contraction to some degree, and some have

nephrine inhibits contraction of smooth muscle in the

profound effects. Among the more important of

intestine but stimulates contraction of smooth muscle

these are norepinephrine, epinephrine, acetylcholine,

in blood vessels.

Chapter 8

Contraction and Excitation of Smooth Muscle

Source of Calcium Ions That Cause

Contraction (1) Through the Cell

Membrane and (2) from the

Sarcoplasmic Reticulum

Although the contractile process in smooth muscle,

as in skeletal muscle, is activated by calcium ions,

the source of the calcium ions differs; the difference

is that the sarcoplasmic reticulum, which provides

virtually all the calcium ions for skeletal muscle con-

traction, is only slightly developed in most smooth

Caveolae

muscle. Instead, almost all the calcium ions that

cause contraction enter the muscle cell from the extra-

cellular fluid at the time of the action potential or

other stimulus. That is, the concentration of calcium

ions in the extracellular fluid is greater than 10-3 molar,

Sarcoplasmic

in comparison with less than 10-7 molar inside the

reticulum

smooth muscle cell; this causes rapid diffusion of

the calcium ions into the cell from the extracellular

fluid when the calcium pores open. The time required

Figure 8-5

for this diffusion to occur averages 200 to 300 mil-

liseconds and is called the latent period before con-

Sarcoplasmic tubules in a large smooth muscle fiber showing their

traction begins. This latent period is about 50 times

relation to invaginations in the cell membrane called caveolae.

as great for smooth muscle as for skeletal muscle

contraction.

of the smooth muscle fiber back into the extra-

Role of the Smooth Muscle Sarcoplasmic Reticulum. Figure

cellular fluid, or into a sarcoplasmic reticulum, if it

8-5 shows a few slightly developed sarcoplasmic

is present. This pump is slow-acting in comparison

tubules that lie near the cell membrane in some larger

with the fast-acting sarcoplasmic reticulum pump in

smooth muscle cells. Small invaginations of the

skeletal muscle. Therefore, a single smooth muscle

cell membrane, called caveolae, abut the surfaces of

contraction often lasts for seconds rather than hun-

these tubules. The caveolae suggest a rudimentary

dredths to tenths of a second, as occurs for skeletal

analog of the transverse tubule system of skeletal

muscle.

muscle. When an action potential is transmitted into

the caveolae, this is believed to excite calcium ion

release from the abutting sarcoplasmic tubules in the

References

same way that action potentials in skeletal muscle

transverse tubules cause release of calcium ions from

Also see references for Chapters 5 and 6.

the skeletal muscle longitudinal sarcoplasmic tubules.

Blaustein MP, Lederer WJ: Sodium/calcium exchange:

In general, the more extensive the sarcoplasmic re-

its physiological implications. Physiol Rev 79:763, 1999.

ticulum in the smooth muscle fiber, the more rapidly

Davis MJ, Hill MA: Signaling mechanisms underlying

it contracts.

the vascular myogenic response. Physiol Rev

79:387,

1999.

Effect on Smooth Muscle Contraction Caused by Changing of

Harnett KM, Biancani P: Calcium-dependent and calcium-

independent contractions in smooth muscles. Am J Med

Extracellular Calcium Ion Concentration. Although chang-

115(Suppl 3A):24S, 2003.

ing the extracellular fluid calcium ion concentration

Horowitz A, Menice CB, Laporte R, Morgan KG: Mecha-

from normal has little effect on the force of contrac-

nisms of smooth muscle contraction. Physiol Rev 76:967,

tion of skeletal muscle, this is not true for most smooth

1996.

muscle. When the extracellular fluid calcium ion con-

Kamm KE, Stull JT: Regulation of smooth muscle contrac-

centration falls to about 1/3 to 1/10 normal, smooth

tile elements by second messengers. Annu Rev Physiol

muscle contraction usually ceases. Therefore, the

51:299, 1989.

force of contraction of smooth muscle usually is

Kuriyama H, Kitamura K, Itoh T, Inoue R: Physiological fea-

highly dependent on extracellular fluid calcium ion

tures of visceral smooth muscle cells, with special refer-

concentration.

ence to receptors and ion channels. Physiol Rev 78:811,

1998.

Lee CH, Poburko D, Kuo KH, et al: Ca2+ oscillations, gradi-

A Calcium Pump Is Required to Cause Smooth Muscle

ents, and homeostasis in vascular smooth muscle. Am J

Relaxation. To cause relaxation of smooth muscle after

Physiol Heart Circ Physiol 282:H1571, 2002.

it has contracted, the calcium ions must be removed

Rybalkin SD, Yan C, Bornfeldt KE, Beavo JA: Cyclic GMP

from the intracellular fluids. This removal is achieved

phosphodiesterases and regulation of smooth muscle

by a calcium pump that pumps calcium ions out

function. Circ Res 93:280, 2003.

C H A P T E R

Heart Muscle; The Heart as

a Pump and Function of the

Heart Valves

With this chapter we begin discussion of the heart

and circulatory system. The heart, shown in Figure

9-1, is actually two separate pumps: a right heart

that pumps blood through the lungs, and a left heart

that pumps blood through the peripheral organs. In

turn, each of these hearts is a pulsatile two-chamber

pump composed of an atrium and a ventricle. Each

atrium is a weak primer pump for the ventricle,

helping to move blood into the ventricle. The ventricles then supply the main

pumping force that propels the blood either (1) through the pulmonary circu-

lation by the right ventricle or (2) through the peripheral circulation by the left

ventricle.

Special mechanisms in the heart cause a continuing succession of heart con-

tractions called cardiac rhythmicity, transmitting action potentials throughout

the heart muscle to cause the heart’s rhythmical beat. This rhythmical control

system is explained in Chapter 10. In this chapter, we explain how the heart

operates as a pump, beginning with the special features of heart muscle itself.

Physiology of Cardiac Muscle

The heart is composed of three major types of cardiac muscle: atrial muscle, ven-

tricular muscle, and specialized excitatory and conductive muscle fibers. The

atrial and ventricular types of muscle contract in much the same way as skele-

tal muscle, except that the duration of contraction is much longer. Conversely,

the specialized excitatory and conductive fibers contract only feebly because

they contain few contractile fibrils; instead, they exhibit either automatic rhyth-

mical electrical discharge in the form of action potentials or conduction of the

action potentials through the heart, providing an excitatory system that controls

the rhythmical beating of the heart.

Physiologic Anatomy of Cardiac Muscle

Figure 9-2 shows a typical histological picture of cardiac muscle, demonstrat-

ing cardiac muscle fibers arranged in a latticework, with the fibers dividing,

recombining, and then spreading again. One also notes immediately from this

figure that cardiac muscle is striated in the same manner as in typical skeletal

muscle. Further, cardiac muscle has typical myofibrils that contain actin and

myosin filaments almost identical to those found in skeletal muscle; these fila-

ments lie side by side and slide along one another during contraction in the

same manner as occurs in skeletal muscle (see Chapter 6). But in other ways,

cardiac muscle is quite different from skeletal muscle, as we shall see.

Cardiac Muscle as a Syncytium. The dark areas crossing the cardiac muscle fibers

in Figure 9-2 are called intercalated discs; they are actually cell membranes that

separate individual cardiac muscle cells from one another. That is, cardiac

muscle fibers are made up of many individual cells connected in series and in

parallel with one another.

103

104

Unit III

The Heart

HEAD AND UPPER EXTREMITY

Plateau

Aorta

+20

Pulmonary artery

- 20

Superior

vena cava

- 40

- 60

Lungs

- 80

Right atrium

-100

Purkinje fiber

Pulmonary

Plateau

Pulmonary

vein

valve

+20

Left atrium

Tricuspid

- 20

Mitral valve

valve

- 40

Aortic valve

- 60

Right ventricle

- 80

Inferior

Left

Ventricular muscle

-100

vena cava

ventricle

Seconds

TRUNK AND LOWER EXTREMITY

Figure 9-1

Figure 9-3

Structure of the heart, and course of blood flow through the heart

Rhythmical action potentials (in millivolts) from a Purkinje fiber

chambers and heart valves.

and from a ventricular muscle fiber, recorded by means of

microelectrodes.

The heart actually is composed of two syncytiums:

the atrial syncytium that constitutes the walls of the

two atria, and the ventricular syncytium that consti-

tutes the walls of the two ventricles. The atria are sepa-

rated from the ventricles by fibrous tissue that

surrounds the atrioventricular (A-V) valvular open-

ings between the atria and ventricles. Normally, poten-

tials are not conducted from the atrial syncytium into

the ventricular syncytium directly through this fibrous

tissue. Instead, they are conducted only by way of a

specialized conductive system called the A-V bundle,

a bundle of conductive fibers several millimeters in

diameter that is discussed in detail in Chapter 10.

This division of the muscle of the heart into two

Figure 9-2

functional syncytiums allows the atria to contract a

short time ahead of ventricular contraction, which is

“Syncytial,” interconnecting nature of cardiac muscle fibers.

important for effectiveness of heart pumping.

At each intercalated disc the cell membranes fuse

Action Potentials in Cardiac Muscle

with one another in such a way that they form perme-

able “communicating” junctions (gap junctions) that

The action potential recorded in a ventricular muscle

allow almost totally free diffusion of ions. Therefore,

fiber, shown in Figure 9-3, averages about 105 milli-

from a functional point of view, ions move with ease

volts, which means that the intracellular potential rises

in the intracellular fluid along the longitudinal axes of

from a very negative value, about

-85 millivolts,

the cardiac muscle fibers, so that action potentials

between beats to a slightly positive value, about +20

travel easily from one cardiac muscle cell to the next,

millivolts, during each beat. After the initial spike, the

past the intercalated discs. Thus, cardiac muscle is a

membrane remains depolarized for about 0.2 second,

syncytium of many heart muscle cells in which the

exhibiting a plateau as shown in the figure, followed at

cardiac cells are so interconnected that when one

the end of the plateau by abrupt repolarization. The

of these cells becomes excited, the action potential

presence of this plateau in the action potential causes

spreads to all of them, spreading from cell to cell

ventricular contraction to last as much as 15 times as

throughout the latticework interconnections.

long in cardiac muscle as in skeletal muscle.

Chapter 9

Heart Muscle; The Heart as a Pump and Function of the Heart Valves

105

What Causes the Long Action Potential and the Plateau? At

is this: Immediately after the onset of the action poten-

this point, we must ask the questions: Why is the action

tial, the permeability of the cardiac muscle membrane

potential of cardiac muscle so long, and why does it

for potassium ions decreases about fivefold, an effect

have a plateau, whereas that of skeletal muscle does

that does not occur in skeletal muscle. This decreased

not? The basic biophysical answers to these questions

potassium permeability may result from the excess

were presented in Chapter 5, but they merit summa-

calcium influx through the calcium channels just

rizing here as well.

noted. Regardless of the cause, the decreased potas-

At least two major differences between the mem-

sium permeability greatly decreases the outflux of

brane properties of cardiac and skeletal muscle

positively charged potassium ions during the action

account for the prolonged action potential and the

potential plateau and thereby prevents early return of

plateau in cardiac muscle. First, the action potential of

the action potential voltage to its resting level. When

skeletal muscle is caused almost entirely by sudden

the slow calcium-sodium channels do close at the end

opening of large numbers of so-called fast sodium

of 0.2 to 0.3 second and the influx of calcium and

channels that allow tremendous numbers of sodium

sodium ions ceases, the membrane permeability for

ions to enter the skeletal muscle fiber from the extra-

potassium ions also increases rapidly; this rapid loss of

cellular fluid. These channels are called “fast” channels

potassium from the fiber immediately returns the

because they remain open for only a few thousandths

membrane potential to its resting level, thus ending

of a second and then abruptly close. At the end of this

the action potential.

closure, repolarization occurs, and the action potential

is over within another thousandth of a second or so.

Velocity of Signal Conduction in Cardiac Muscle. The veloci-

In cardiac muscle, the action potential is caused by

ty of conduction of the excitatory action potential

opening of two types of channels: (1) the same fast

signal along both atrial and ventricular muscle fibers is

sodium channels as those in skeletal muscle and (2)

about 0.3 to 0.5 m/sec, or about ¹/250 the velocity in very

another entirely different population of slow calcium

large nerve fibers and about ¹/10 the velocity in skele-

channels, which are also called calcium-sodium

tal muscle fibers. The velocity of conduction in the

channels. This second population of channels differs

specialized heart conductive system—in the Purkinje

from the fast sodium channels in that they are slower

fibers—is as great as 4 m/sec in most parts of the

to open and, even more important, remain open

system, which allows reasonably rapid conduction of

for several tenths of a second. During this time, a large

the excitatory signal to the different parts of the heart,

quantity of both calcium and sodium ions flows

as explained in Chapter 10.

through these channels to the interior of the cardiac

muscle fiber, and this maintains a prolonged period of

Refractory Period of Cardiac Muscle. Cardiac muscle, like

depolarization, causing the plateau in the action poten-

all excitable tissue, is refractory to restimulation

tial. Further, the calcium ions that enter during this

during the action potential. Therefore, the refractory

plateau phase activate the muscle contractile process,

period of the heart is the interval of time, as shown to

while the calcium ions that cause skeletal muscle con-

the left in Figure 9-4, during which a normal cardiac

traction are derived from the intracellular sarcoplas-

impulse cannot re-excite an already excited area of

mic reticulum.

cardiac muscle. The normal refractory period of the

The second major functional difference between

ventricle is 0.25 to 0.30 second, which is about the

cardiac muscle and skeletal muscle that helps account

duration of the prolonged plateau action potential.

for both the prolonged action potential and its plateau

There is an additional relative refractory period of

Refractory period

Relative refractory

period

Later premature

contraction

Early premature

contraction

Figure 9-4

Force of ventricular heart muscle

contraction, showing also dura-

tion of the refractory period and

relative refractory period, plus the

effect of premature contraction.

Seconds

Note that premature contractions

do not cause wave summation, as

occurs in skeletal muscle.

106

Unit III

The Heart

about 0.05 second during which the muscle is more dif-

tubule system—that is, the availability of calcium ions

ficult than normal to excite but nevertheless can be

to cause cardiac muscle contraction—depends to a

excited by a very strong excitatory signal, as demon-

great extent on the extracellular fluid calcium ion

strated by the early “premature” contraction in the

concentration.

second example of Figure 9-4. The refractory period

(By way of contrast, the strength of skeletal muscle

of atrial muscle is much shorter than that for the ven-

contraction is hardly affected by moderate changes in

tricles (about 0.15 second for the atria compared with

extracellular fluid calcium concentration because

0.25 to 0.30 second for the ventricles).

skeletal muscle contraction is caused almost entirely

by calcium ions released from the sarcoplasmic retic-

Excitation-Contraction Coupling—Function

ulum inside the skeletal muscle fiber itself.)

of Calcium Ions and the Transverse Tubules

At the end of the plateau of the cardiac action

The term “excitation-contraction coupling” refers to

potential, the influx of calcium ions to the interior of

the mechanism by which the action potential causes

the muscle fiber is suddenly cut off, and the calcium

the myofibrils of muscle to contract. This was discussed

ions in the sarcoplasm are rapidly pumped back out of

for skeletal muscle in Chapter 7. Once again, there are

the muscle fibers into both the sarcoplasmic reticulum

differences in this mechanism in cardiac muscle that

and the T tubule-extracellular fluid space. As a result,

have important effects on the characteristics of cardiac

the contraction ceases until a new action potential

muscle contraction.

comes along.

As is true for skeletal muscle, when an action poten-

tial passes over the cardiac muscle membrane, the

Duration of Contraction. Cardiac muscle begins to contract

a few milliseconds after the action potential begins and

action potential spreads to the interior of the cardiac

continues to contract until a few milliseconds after the

muscle fiber along the membranes of the transverse

action potential ends. Therefore, the duration of con-

(T) tubules. The T tubule action potentials in turn act

traction of cardiac muscle is mainly a function of the

on the membranes of the longitudinal sarcoplasmic

duration of the action potential, including the plateau—

tubules to cause release of calcium ions into the

about 0.2 second in atrial muscle and 0.3 second in ven-

muscle sarcoplasm from the sarcoplasmic reticulum. In

tricular muscle.

another few thousandths of a second, these calcium

ions diffuse into the myofibrils and catalyze the chemi-

cal reactions that promote sliding of the actin and

The Cardiac Cycle

myosin filaments along one another; this produces the

muscle contraction.

The cardiac events that occur from the beginning of

Thus far, this mechanism of excitation-contraction

one heartbeat to the beginning of the next are called

coupling is the same as that for skeletal muscle, but

the cardiac cycle. Each cycle is initiated by sponta-

there is a second effect that is quite different. In addi-

neous generation of an action potential in the sinus

tion to the calcium ions that are released into the

node, as explained in Chapter 10. This node is located

sarcoplasm from the cisternae of the sarcoplasmic

in the superior lateral wall of the right atrium near the

reticulum, a large quantity of extra calcium ions also

opening of the superior vena cava, and the action

diffuses into the sarcoplasm from the T tubules them-

potential travels from here rapidly through both atria

selves at the time of the action potential. Indeed,

and then through the A-V bundle into the ventricles.

without this extra calcium from the T tubules, the

Because of this special arrangement of the conducting

strength of cardiac muscle contraction would be

system from the atria into the ventricles, there is a

reduced considerably because the sarcoplasmic re-

delay of more than 0.1 second during passage of the

ticulum of cardiac muscle is less well developed than

cardiac impulse from the atria into the ventricles. This

that of skeletal muscle and does not store enough

allows the atria to contract ahead of ventricular con-

calcium to provide full contraction. Conversely, the T

traction, thereby pumping blood into the ventricles

tubules of cardiac muscle have a diameter 5 times as

before the strong ventricular contraction begins. Thus,

great as that of the skeletal muscle tubules, which

the atria act as primer pumps for the ventricles, and

means a volume 25 times as great. Also, inside the T

the ventricles in turn provide the major source of

tubules is a large quantity of mucopolysaccharides that

power for moving blood through the body’s vascular

are electronegatively charged and bind an abundant

system.

store of calcium ions, keeping these always available

for diffusion to the interior of the cardiac muscle fiber

when a T tubule action potential appears.

Diastole and Systole

The strength of contraction of cardiac muscle

depends to a great extent on the concentration of

The cardiac cycle consists of a period of relaxation

calcium ions in the extracellular fluids. The reason for

called diastole, during which the heart fills with blood,

this is that the openings of the T tubules pass directly

followed by a period of contraction called systole.

through the cardiac muscle cell membrane into the

Figure 9-5 shows the different events during the

extracellular spaces surrounding the cells, allowing the

cardiac cycle for the left side of the heart. The top three

same extracellular fluid that is in the cardiac muscle

curves show the pressure changes in the aorta, left ven-

interstitium to percolate through the T tubules as well.

tricle, and left atrium, respectively. The fourth curve

Consequently, the quantity of calcium ions in the T

depicts the changes in left ventricular volume, the fifth

Chapter 9

Heart Muscle; The Heart as a Pump and Function of the Heart Valves

107

Isovolumic

relaxation

Rapid inflow

Ejection

Atrial systole

Isovolumic

Diastasis

contraction

Aortic valve

120

Aortic

closes

valve

100

opens

Aortic pressure

A-V valve

opens

closes

Atrial pressure

Ventricular pressure

130

Ventricular volume

Electrocardiogram

1st

2nd

3rd

Phonocardiogram

Systole

Diastole

Systole

Figure 9-5

Events of the cardiac cycle for left ventricular function, showing changes in left atrial pressure, left ventricular pressure, aortic pressure,

ventricular volume, the electrocardiogram, and the phonocardiogram.

the electrocardiogram, and the sixth a phonocardio-

About 0.16 second after the onset of the P wave, the

gram, which is a recording of the sounds produced by

QRS waves appear as a result of electrical depolariza-

the heart—mainly by the heart valves—as it pumps. It

tion of the ventricles, which initiates contraction of the

is especially important that the reader study in detail

ventricles and causes the ventricular pressure to begin

this figure and understand the causes of all the events

rising, as also shown in the figure. Therefore, the QRS

shown.

complex begins slightly before the onset of ventricu-

lar systole.

Finally, one observes the ventricular T wave in the

electrocardiogram. This represents the stage of repo-

Relationship of the Electrocardiogram

larization of the ventricles when the ventricular muscle

to the Cardiac Cycle

fibers begin to relax. Therefore, the T wave occurs

slightly before the end of ventricular contraction.

The electrocardiogram in Figure 9-5 shows the P, Q,

R, S, and T waves, which are discussed in Chapters 11,

12, and 13. They are electrical voltages generated by

Function of the Atria as Primer Pumps

the heart and recorded by the electrocardiograph from

the surface of the body.

Blood normally flows continually from the great veins

The P wave is caused by spread of depolarization

into the atria; about 80 per cent of the blood flows

through the atria, and this is followed by atrial con-

directly through the atria into the ventricles even

traction, which causes a slight rise in the atrial pres-

before the atria contract. Then, atrial contraction

sure curve immediately after the electrocardiographic

usually causes an additional 20 per cent filling of the

P wave.

ventricles. Therefore, the atria simply function as

108

Unit III

The Heart

primer pumps that increase the ventricular pumping

causing the A-V valves to close. Then an additional

effectiveness as much as 20 per cent. However, the

0.02 to 0.03 second is required for the ventricle to build

heart can continue to operate under most conditions

up sufficient pressure to push the semilunar (aortic

even without this extra

20 per cent effectiveness

and pulmonary) valves open against the pressures in

because it normally has the capability of pumping 300

the aorta and pulmonary artery. Therefore, during this

to 400 per cent more blood than is required by the

period, contraction is occurring in the ventricles, but

resting body. Therefore, when the atria fail to function,

there is no emptying. This is called the period of iso-

the difference is unlikely to be noticed unless a person

volumic or isometric contraction, meaning that tension

exercises; then acute signs of heart failure occasionally

is increasing in the muscle but little or no shortening

develop, especially shortness of breath.

of the muscle fibers is occurring.

Pressure Changes in the Atria—The a, c, and v Waves. In the

atrial pressure curve of Figure 9-5, three minor pressure

Period of Ejection. When the left ventricular pressure

elevations, called the a, c, and v atrial pressure waves, are

rises slightly above 80 mm Hg (and the right ventricu-

noted.

lar pressure slightly above 8 mm Hg), the ventricular

The a wave is caused by atrial contraction. Ordinarily,

pressures push the semilunar valves open. Immedi-

the right atrial pressure increases 4 to 6 mm Hg during

ately, blood begins to pour out of the ventricles, with

atrial contraction, and the left atrial pressure increases

about 70 per cent of the blood emptying occurring

about 7 to 8 mm Hg.

during the first third of the period of ejection and the

The c wave occurs when the ventricles begin to

remaining 30 per cent emptying during the next two

contract; it is caused partly by slight backflow of blood

into the atria at the onset of ventricular contraction

thirds. Therefore, the first third is called the period of

but mainly by bulging of the A-V valves backward

rapid ejection, and the last two thirds, the period of

toward the atria because of increasing pressure in the

slow ejection.

ventricles.

The v wave occurs toward the end of ventricular

contraction; it results from slow flow of blood into the

Period of Isovolumic (Isometric) Relaxation. At the end of

atria from the veins while the A-V valves are closed

systole, ventricular relaxation begins suddenly, allow-

during ventricular contraction. Then, when ventricular

ing both the right and left intraventricular pressures

contraction is over, the A-V valves open, allowing this

to decrease rapidly. The elevated pressures in the dis-

stored atrial blood to flow rapidly into the ventricles and

tended large arteries that have just been filled with

causing the v wave to disappear.

blood from the contracted ventricles immediately

push blood back toward the ventricles, which snaps the

aortic and pulmonary valves closed. For another 0.03

Function of the Ventricles as Pumps

to 0.06 second, the ventricular muscle continues to

relax, even though the ventricular volume does not

Filling of the Ventricles. During ventricular systole, large

change, giving rise to the period of isovolumic or iso-

amounts of blood accumulate in the right and left atria

metric relaxation. During this period, the intraven-

because of the closed A-V valves. Therefore, as soon

tricular pressures decrease rapidly back to their low

as systole is over and the ventricular pressures fall

diastolic levels. Then the A-V valves open to begin a

again to their low diastolic values, the moderately

new cycle of ventricular pumping.

increased pressures that have developed in the atria

during ventricular systole immediately push the A-V

valves open and allow blood to flow rapidly into the

End-Diastolic Volume, End-Systolic Volume, and Stroke Volume

ventricles, as shown by the rise of the left ventricular

Output. During diastole, normal filling of the ventricles

volume curve in Figure 9-5. This is called the period of

increases the volume of each ventricle to about 110 to

rapid filling of the ventricles.

120 milliliters. This volume is called the end-diastolic

The period of rapid filling lasts for about the first

volume. Then, as the ventricles empty during systole,

third of diastole. During the middle third of diastole,

the volume decreases about 70 milliliters, which is

only a small amount of blood normally flows into the

called the stroke volume output. The remaining volume

ventricles; this is blood that continues to empty into

in each ventricle, about 40 to 50 milliliters, is called the

the atria from the veins and passes through the atria

end-systolic volume. The fraction of the end-diastolic

directly into the ventricles.

volume that is ejected is called the ejection fraction—

During the last third of diastole, the atria contract

usually equal to about 60 per cent.

and give an additional thrust to the inflow of blood

When the heart contracts strongly, the end-systolic

into the ventricles; this accounts for about 20 per cent

volume can be decreased to as little as 10 to 20 milli-

of the filling of the ventricles during each heart cycle.

liters. Conversely, when large amounts of blood flow

into the ventricles during diastole, the ventricular end-

Emptying of the Ventricles During Systole

diastolic volumes can become as great as 150 to 180

milliliters in the healthy heart. By both increasing the

Period of Isovolumic (Isometric) Contraction. Immedi-

end-diastolic volume and decreasing the end-systolic

ately after ventricular contraction begins, the ventric-

volume, the stroke volume output can be increased to

ular pressure rises abruptly, as shown in Figure 9-5,

more than double normal.

Chapter 9

Heart Muscle; The Heart as a Pump and Function of the Heart Valves

109

Function of the Valves

Aortic and Pulmonary Artery Valves. The aortic and pul-

monary artery semilunar valves function quite differ-

Atrioventricular Valves. The A-V valves

(the tricuspid

ently from the A-V valves. First, the high pressures in

and mitral valves) prevent backflow of blood from the

the arteries at the end of systole cause the semilunar

ventricles to the atria during systole, and the semilu-

valves to snap to the closed position, in contrast to the

nar valves (the aortic and pulmonary artery valves)

much softer closure of the A-V valves. Second, because

prevent backflow from the aorta and pulmonary ar-

of smaller openings, the velocity of blood ejection

teries into the ventricles during diastole. These valves,

through the aortic and pulmonary valves is far greater

shown in Figure 9-6 for the left ventricle, close and

than that through the much larger A-V valves. Also,

open passively. That is, they close when a backward

because of the rapid closure and rapid ejection, the

pressure gradient pushes blood backward, and they

edges of the aortic and pulmonary valves are subjected

open when a forward pressure gradient forces blood

to much greater mechanical abrasion than are the

in the forward direction. For anatomical reasons, the

A-V valves. Finally, the A-V valves are supported by

thin, filmy A-V valves require almost no backflow to

the chordae tendineae, which is not true for the semi-

cause closure, whereas the much heavier semilunar

lunar valves. It is obvious from the anatomy of the

valves require rather rapid backflow for a few

aortic and pulmonary valves (as shown for the aortic

milliseconds.

valve at the bottom of Figure 9-6) that they must be

constructed with an especially strong yet very pliable

Function of the Papillary Muscles. Figure 9-6 also

fibrous tissue base to withstand the extra physical

shows papillary muscles that attach to the vanes of the

stresses.

A-V valves by the chordae tendineae. The papillary

muscles contract when the ventricular walls contract,

Aortic Pressure Curve

but contrary to what might be expected, they do not

help the valves to close. Instead, they pull the vanes of

When the left ventricle contracts, the ventricular pres-

the valves inward toward the ventricles to prevent

sure increases rapidly until the aortic valve opens.

their bulging too far backward toward the atria during

Then, after the valve opens, the pressure in the ventri-

ventricular contraction. If a chorda tendinea becomes

cle rises much less rapidly, as shown in Figure 9-5,

ruptured or if one of the papillary muscles becomes

because blood immediately flows out of the ventricle

paralyzed, the valve bulges far backward during ven-

into the aorta and then into the systemic distribution

tricular contraction, sometimes so far that it leaks

arteries.

severely and results in severe or even lethal cardiac

The entry of blood into the arteries causes the walls

incapacity.

of these arteries to stretch and the pressure to increase

to about 120 mm Hg.

Next, at the end of systole, after the left ventricle

stops ejecting blood and the aortic valve closes, the

elastic walls of the arteries maintain a high pressure in

the arteries, even during diastole.

MITRAL VALVE

A so-called incisura occurs in the aortic pressure

Cusp

curve when the aortic valve closes. This is caused by a

short period of backward flow of blood immediately

before closure of the valve, followed by sudden cessa-

Chordae tendineae

tion of the backflow.

After the aortic valve has closed, the pressure in the

aorta decreases slowly throughout diastole because

Papillary muscles

the blood stored in the distended elastic arteries flows

continually through the peripheral vessels back to the

veins. Before the ventricle contracts again, the aortic

pressure usually has fallen to about 80 mm Hg (dias-

tolic pressure), which is two thirds the maximal pres-

sure of 120 mm Hg (systolic pressure) that occurs in

the aorta during ventricular contraction.

Cusp

The pressure curves in the right ventricle and pul-

monary artery are similar to those in the aorta, except

AORTIC VALVE

that the pressures are only about one sixth as great, as

discussed in Chapter 14.

Relationship of the Heart

Sounds to Heart Pumping

Figure 9-6

When listening to the heart with a stethoscope, one does

Mitral and aortic valves (the left ventricular valves).

not hear the opening of the valves because this is a

110

Unit III

The Heart

relatively slow process that normally makes no noise.

However, when the valves close, the vanes of the valves

and the surrounding fluids vibrate under the influence

300

Systolic pressure

of sudden pressure changes, giving off sound that travels

in all directions through the chest.

250

When the ventricles contract, one first hears a sound

caused by closure of the A-V valves. The vibration is low

200

Isovolumic

in pitch and relatively long-lasting and is known as the

relaxation

first heart sound. When the aortic and pulmonary valves

Period of ejection

close at the end of systole, one hears a rapid snap

150

because these valves close rapidly, and the surroundings

Isovolumic

vibrate for a short period. This sound is called the

III

100

contraction

second heart sound. The precise causes of the heart

sounds are discussed more fully in Chapter 23, in rela-

tion to listening to the sounds with the stethoscope.

Diastolic

pressure

100

150

200

250

Work Output of the Heart

Left ventricular volume (ml)

Period of filling

The stroke work output of the heart is the amount of

energy that the heart converts to work during each

heartbeat while pumping blood into the arteries. Minute

work output is the total amount of energy converted to

Figure 9-7

work in 1 minute; this is equal to the stroke work output

Relationship between left ventricular volume and intraventricular

times the heart rate per minute.

pressure during diastole and systole. Also shown by the heavy

Work output of the heart is in two forms. First, by far

red lines is the

“volume-pressure diagram,” demonstrating

the major proportion is used to move the blood from

changes in intraventricular volume and pressure during the

the low-pressure veins to the high-pressure arteries.

normal cardiac cycle. EW, net external work.

This is called volume-pressure work or external work.

Second, a minor proportion of the energy is used to

accelerate the blood to its velocity of ejection through

the aortic and pulmonary valves. This is the kinetic

Until the volume of the noncontracting ventricle rises

energy of blood flow component of the work output.

above about 150 milliliters, the “diastolic” pressure

Right ventricular external work output is normally

does not increase greatly. Therefore, up to this volume,

about one sixth the work output of the left ventricle

blood can flow easily into the ventricle from the atrium.

because of the sixfold difference in systolic pressures

Above 150 milliliters, the ventricular diastolic pressure

that the two ventricles pump. The additional work

increases rapidly, partly because of fibrous tissue in the

output of each ventricle required to create kinetic

heart that will stretch no more and partly because the

energy of blood flow is proportional to the mass of

pericardium that surrounds the heart becomes filled

blood ejected times the square of velocity of ejection.

nearly to its limit.

Ordinarily, the work output of the left ventricle

During ventricular contraction, the “systolic” pres-

required to create kinetic energy of blood flow is only

sure increases even at low ventricular volumes and

about 1 per cent of the total work output of the ventri-

reaches a maximum at a ventricular volume of 150 to

cle and therefore is ignored in the calculation of the

170 milliliters. Then, as the volume increases still

total stroke work output. But in certain abnormal con-

further, the systolic pressure actually decreases under

ditions, such as aortic stenosis, in which blood flows with

some conditions, as demonstrated by the falling systolic

great velocity through the stenosed valve, more than

pressure curve in Figure 9-7, because at these great

50 per cent of the total work output may be required to

volumes, the actin and myosin filaments of the cardiac

create kinetic energy of blood flow.

muscle fibers are pulled apart far enough that the

strength of each cardiac fiber contraction becomes less

than optimal.

Graphical Analysis of Ventricular

Note especially in the figure that the maximum sys-

Pumping

tolic pressure for the normal left ventricle is between

250 and 300 mm Hg, but this varies widely with each

Figure 9-7 shows a diagram that is especially useful in

person’s heart strength and degree of heart stimulation

explaining the pumping mechanics of the left ventricle.

by cardiac nerves. For the normal right ventricle,

The most important components of the diagram are

the maximum systolic pressure is between

60 and

the two curves labeled

“diastolic pressure” and

80 mm Hg.

“systolic pressure.” These curves are volume-pressure

curves.

“Volume-Pressure Diagram” During the Cardiac Cycle; Cardiac

The diastolic pressure curve is determined by filling

Work Output. The red lines in Figure 9-7 form a loop

the heart with progressively greater volumes of blood

called the volume-pressure diagram of the cardiac cycle

and then measuring the diastolic pressure immediately

for normal function of the left ventricle. It is divided into

before ventricular contraction occurs, which is the end-

four phases.

diastolic pressure of the ventricle.

Phase I: Period of filling. This phase in the volume-

The systolic pressure curve is determined by record-

pressure diagram begins at a ventricular volume of

ing the systolic pressure achieved during ventricular

about 45 milliliters and a diastolic pressure near

contraction at each volume of filling.

0 mm Hg. Forty-five milliliters is the amount of

Chapter 9

Heart Muscle; The Heart as a Pump and Function of the Heart Valves

111

blood that remains in the ventricle after the

The importance of the concepts of preload and after-

previous heartbeat and is called the end-systolic

load is that in many abnormal functional states of the

volume. As venous blood flows into the ventricle

heart or circulation, the pressure during filling of the

from the left atrium, the ventricular volume

ventricle

(the preload), the arterial pressure against

normally increases to about 115 milliliters, called

which the ventricle must contract (the afterload), or

the end-diastolic volume, an increase of 70

both are severely altered from normal.

milliliters. Therefore, the volume-pressure diagram

during phase I extends along the line labeled “I,”

with the volume increasing to 115 milliliters and the

Chemical Energy Required

diastolic pressure rising to about 5 mm Hg.

for Cardiac Contraction:

Phase II: Period of isovolumic contraction. During

Oxygen Utilization by

isovolumic contraction, the volume of the ventricle

does not change because all valves are closed.

the Heart

However, the pressure inside the ventricle increases

Heart muscle, like skeletal muscle, uses chemical energy

to equal the pressure in the aorta, at a pressure

to provide the work of contraction. This energy is

value of about 80 mm Hg, as depicted by the arrow

derived mainly from oxidative metabolism of fatty acids

end of the line labeled “II.”

and, to a lesser extent, of other nutrients, especially

Phase III: Period of ejection. During ejection, the

lactate and glucose. Therefore, the rate of oxygen con-

systolic pressure rises even higher because of still

sumption by the heart is an excellent measure of the

more contraction of the ventricle. At the same time,

chemical energy liberated while the heart performs its

the volume of the ventricle decreases because the

work. The different chemical reactions that liberate this

aortic valve has now opened and blood flows out of

energy are discussed in Chapters 67 and 68.

the ventricle into the aorta. Therefore, the curve

labeled “III” traces the changes in volume and

Efficiency of Cardiac Contraction. During heart muscle con-

systolic pressure during this period of ejection.

traction, most of the expended chemical energy is con-

Phase IV: Period of isovolumic relaxation. At the end

verted into heat and a much smaller portion into work

of the period of ejection, the aortic valve closes, and

output. The ratio of work output to total chemical

the ventricular pressure falls back to the diastolic

energy expenditure is called the efficiency of cardiac

pressure level. The line labeled “IV” traces this

contraction, or simply efficiency of the heart. Maximum

decrease in intraventricular pressure without any

efficiency of the normal heart is between 20 and 25 per

change in volume. Thus, the ventricle returns to its

cent. In heart failure, this can decrease to as low as 5 to

starting point, with about 45 milliliters of blood

10 per cent.

left in the ventricle and at an atrial pressure near

0 mm Hg.

Readers well trained in the basic principles of physics

should recognize that the area subtended by this func-

Regulation of Heart Pumping

tional volume-pressure diagram (the tan shaded area,

labeled EW) represents the net external work output of

When a person is at rest, the heart pumps only 4 to 6

the ventricle during its contraction cycle. In experimen-

liters of blood each minute. During severe exercise,

tal studies of cardiac contraction, this diagram is used

the heart may be required to pump four to seven times

for calculating cardiac work output.

this amount. The basic means by which the volume

When the heart pumps large quantities of blood, the

pumped by the heart is regulated are (1) intrinsic

area of the work diagram becomes much larger. That is,

cardiac regulation of pumping in response to changes

it extends far to the right because the ventricle fills with

in volume of blood flowing into the heart and (2)

more blood during diastole, it rises much higher because

control of heart rate and strength of heart pumping by

the ventricle contracts with greater pressure, and it

usually extends farther to the left because the ventricle

the autonomic nervous system.

contracts to a smaller volume—especially if the ventri-

cle is stimulated to increased activity by the sympathetic

nervous system.

Intrinsic Regulation of Heart

Pumping—The Frank-Starling

Mechanism

Concepts of Preload and Afterload. In assessing the contrac-

tile properties of muscle, it is important to specify the

In Chapter 20, we will learn that under most condi-

degree of tension on the muscle when it begins to con-

tions, the amount of blood pumped by the heart each

tract, which is called the preload, and to specify the load

minute is determined almost entirely by the rate of

against which the muscle exerts its contractile force,

blood flow into the heart from the veins, which is called

which is called the afterload.

venous return. That is, each peripheral tissue of the

For cardiac contraction, the preload is usually con-

body controls its own local blood flow, and all the local

sidered to be the end-diastolic pressure when the ven-

tissue flows combine and return by way of the veins to

tricle has become filled.

the right atrium. The heart, in turn, automatically

The afterload of the ventricle is the pressure in the

pumps this incoming blood into the arteries, so that it

artery leading from the ventricle. In Figure 9-7, this cor-

can flow around the circuit again.

responds to the systolic pressure described by the phase

III curve of the volume-pressure diagram. (Sometimes

This intrinsic ability of the heart to adapt to increas-

the afterload is loosely considered to be the resistance

ing volumes of inflowing blood is called the Frank-

in the circulation rather than the pressure.)

Starling mechanism of the heart, in honor of Frank and

112

Unit III

The Heart

Starling, two great physiologists of a century ago. Basi-

work output for that side increases until it reaches the

cally, the Frank-Starling mechanism means that the

limit of the ventricle’s pumping ability.

greater the heart muscle is stretched during filling,

Figure 9-9 shows another type of ventricular func-

the greater is the force of contraction and the greater

tion curve called the ventricular volume output curve.

the quantity of blood pumped into the aorta. Or, stated

The two curves of this figure represent function of the

another way: Within physiologic limits, the heart pumps

two ventricles of the human heart based on data

all the blood that returns to it by the way of the veins.

extrapolated from lower animals. As the right and left

atrial pressures increase, the respective ventricular

What Is the Explanation of the Frank-Starling Mechanism?

volume outputs per minute also increase.

When an extra amount of blood flows into the ventri-

Thus, ventricular function curves are another way of

cles, the cardiac muscle itself is stretched to greater

expressing the Frank-Starling mechanism of the heart.

length. This in turn causes the muscle to contract with

That is, as the ventricles fill in response to higher atrial

increased force because the actin and myosin filaments

pressures, each ventricular volume and strength of

are brought to a more nearly optimal degree of

cardiac muscle contraction increase, causing the

overlap for force generation. Therefore, the ventricle,

heart to pump increased quantities of blood into the

because of its increased pumping, automatically

arteries.

pumps the extra blood into the arteries.

This ability of stretched muscle, up to an optimal

Control of the Heart by the Sympathetic and

length, to contract with increased work output is char-

Parasympathetic Nerves

acteristic of all striated muscle, as explained in Chapter

The pumping effectiveness of the heart also is con-

6, and is not simply a characteristic of cardiac muscle.

trolled by the sympathetic and parasympathetic

In addition to the important effect of lengthening

(vagus) nerves, which abundantly supply the heart, as

the heart muscle, still another factor increases heart

shown in Figure 9-10. For given levels of input atrial

pumping when its volume is increased. Stretch of the

pressure, the amount of blood pumped each minute

right atrial wall directly increases the heart rate by

(cardiac output) often can be increased more than 100

10 to 20 per cent; this, too, helps increase the amount

per cent by sympathetic stimulation. By contrast, the

of blood pumped each minute, although its contribu-

output can be decreased to as low as zero or almost

tion is much less than that of the Frank-Starling

zero by vagal (parasympathetic) stimulation.

mechanism.

Mechanisms of Excitation of the Heart by the Sympathetic

Ventricular Function Curves

Nerves. Strong sympathetic stimulation can increase

One of the best ways to express the functional ability

the heart rate in young adult humans from the normal

of the ventricles to pump blood is by ventricular func-

rate of 70 beats per minute up to 180 to 200 and, rarely,

tion curves, as shown in Figures 9-8 and 9-9. Figure

even 250 beats per minute. Also, sympathetic stimula-

9-8 shows a type of ventricular function curve called

tion increases the force of heart contraction to as much

the stroke work output curve. Note that as the atrial

as double normal, thereby increasing the volume of

pressure for each side of the heart increases, the stroke

blood pumped and increasing the ejection pressure.

Left ventricular

Right ventricular

stroke work

(gram meters)

Right ventricle

Left ventricle

Left mean atrial

Right mean atrial

pressure

(mm Hg)

-4

+12

+16

Atrial pressure (mm Hg)

Figure 9-8

Left and right ventricular function curves recorded from dogs,

Figure 9-9

depicting ventricular stroke work output as a function of left and

right mean atrial pressures. (Curves reconstructed from data in

Approximate normal right and left ventricular volume output

Sarnoff SJ: Myocardial contractility as described by ventricular

curves for the normal resting human heart as extrapolated from

function curves. Physiol Rev 35:107, 1955.)

data obtained in dogs and data from human beings.

Chapter 9

Heart Muscle; The Heart as a Pump and Function of the Heart Valves

113

Sympathetic chains

Maximum sympathetic

Vagi

stimulation

S-A

A-V

node

Normal sympathetic

stimulation

Zero sympathetic

stimulation

(Parasympathetic

Sympathetic

stimulation)

nerves

Figure 9-10

Cardiac sympathetic and parasympathetic nerves. (The vagus

-4

nerves to the heart are parasympathetic nerves.)

Right atrial pressure (mm Hg)

Thus, sympathetic stimulation often can increase the

Figure 9-11

maximum cardiac output as much as twofold to three-

Effect on the cardiac output curve of different degrees of sympa-

fold, in addition to the increased output caused by the

thetic or parasympathetic stimulation.

Frank-Starling mechanism already discussed.

Conversely, inhibition of the sympathetic nerves to

the heart can decrease cardiac pumping to a moderate

extent in the following way: Under normal conditions,

function curves. They are similar to the ventricular

the sympathetic nerve fibers to the heart discharge

function curves of Figure 9-9. However, they represent

continuously at a slow rate that maintains pumping at

function of the entire heart rather than of a single ven-

about 30 per cent above that with no sympathetic stimu-

tricle; they show the relation between right atrial pres-

lation. Therefore, when the activity of the sympathetic

sure at the input of the right heart and cardiac output

nervous system is depressed below normal, this

from the left ventricle into the aorta.

decreases both heart rate and strength of ventricular

The curves of Figure 9-11 demonstrate that at any

muscle contraction, thereby decreasing the level of

given right atrial pressure, the cardiac output increases

cardiac pumping as much as 30 per cent below normal.

during increased sympathetic stimulation and

decreases during increased parasympathetic stimula-

Parasympathetic

(Vagal) Stimulation of the Heart. Strong

tion. These changes in output caused by nerve stimu-

stimulation of the parasympathetic nerve fibers in the

lation result both from changes in heart rate and from

vagus nerves to the heart can stop the heartbeat for a

changes in contractile strength of the heart because

few seconds, but then the heart usually “escapes” and

both change in response to the nerve stimulation.

beats at a rate of 20 to 40 beats per minute as long

as the parasympathetic stimulation continues. In

addition, strong vagal stimulation can decrease the

Effect of Potassium and Calcium Ions

strength of heart muscle contraction by

20 to

on Heart Function

per cent.

The vagal fibers are distributed mainly to the atria

In the discussion of membrane potentials in Chapter

and not much to the ventricles, where the power con-

5, it was pointed out that potassium ions have a

traction of the heart occurs. This explains the effect of

marked effect on membrane potentials, and in Chapter

vagal stimulation mainly to decrease heart rate rather

6 it was noted that calcium ions play an especially

than to decrease greatly the strength of heart contrac-

important role in activating the muscle contractile

tion. Nevertheless, the great decrease in heart rate

process. Therefore, it is to be expected that the con-

combined with a slight decrease in heart contraction

centration of each of these two ions in the extracellu-

strength can decrease ventricular pumping 50 per cent

lar fluids should also have important effects on cardiac

or more.

pumping.

Effect of Sympathetic or Parasympathetic Stimulation on the

Effect of Potassium Ions. Excess potassium in the extra-

Cardiac Function Curve. Figure 9-11 shows four cardiac

cellular fluids causes the heart to become dilated and

114

Unit III

The Heart

flaccid and also slows the heart rate. Large quantities

also can block conduction of the cardiac impulse from

the atria to the ventricles through the A-V bundle.

Normal range

Elevation of potassium concentration to only 8 to

12 mEq/L—two to three times the normal value—can

cause such weakness of the heart and abnormal

rhythm that this can cause death.

These effects result partially from the fact that a

high potassium concentration in the extracellular

fluids decreases the resting membrane potential in

the cardiac muscle fibers, as explained in Chapter 5.

As the membrane potential decreases, the intensity of

the action potential also decreases, which makes con-

100

150

200

250

traction of the heart progressively weaker.

Arterial pressure (mm Hg)

Effect of Calcium Ions. An excess of calcium ions causes

effects almost exactly opposite to those of potassium

Figure 9-12

ions, causing the heart to go toward spastic contrac-

tion. This is caused by a direct effect of calcium ions to

Constancy of cardiac output up to a pressure level of 160 mm Hg.

initiate the cardiac contractile process, as explained

Only when the arterial pressure rises above this normal limit does

earlier in the chapter.

the increasing pressure load cause the cardiac output to fall

Conversely, deficiency of calcium ions causes cardiac

significantly.

flaccidity, similar to the effect of high potassium.

Fortunately, however, calcium ion levels in the blood

normally are regulated within a very narrow range.

the heart at normal systolic arterial pressures (80 to

Therefore, cardiac effects of abnormal calcium con-

140 mm Hg), the cardiac output is determined almost

centrations are seldom of clinical concern.

entirely by the ease of blood flow through the body’s

tissues, which in turn controls venous return of

blood to the heart. This is the principal subject of

Effect of Temperature on

Chapter 20.

Heart Function

Increased body temperature, as occurs when one has

References

fever, causes a greatly increased heart rate, sometimes

to as fast as double normal. Decreased temperature

Bers DM: Cardiac excitation-contraction coupling. Nature

causes a greatly decreased heart rate, falling to as low

415:198, 2002.

as a few beats per minute when a person is near death

Brette F, Orchard C: T-tubule function in mammalian cardiac

from hypothermia in the body temperature range of

myocytes. Circ Res 92:1182, 2003.

60° to

70°F. These effects presumably result from

Brutsaert DL: Cardiac endothelial-myocardial signaling: its

role in cardiac growth, contractile performance, and rhyth-

the fact that heat increases the permeability of the

micity. Physiol Rev 83:59, 2003.

cardiac muscle membrane to ions that control heart

Clancy CE, Kass RS: Defective cardiac ion channels: from

rate, resulting in acceleration of the self-excitation

mutations to clinical syndromes. J Clin Invest 110:1075,

process.

2002.

Contractile strength of the heart often is enhanced

Fozzard HA: Cardiac sodium and calcium channels: a history

temporarily by a moderate increase in temperature, as

of excitatory currents. Cardiovasc Res 55:1, 2002.

occurs during body exercise, but prolonged elevation

Fuchs F, Smith SH: Calcium, cross-bridges, and the Frank-

of temperature exhausts the metabolic systems of the

Starling relationship. News Physiol Sci 16:5, 2001.

heart and eventually causes weakness. Therefore,

Guyton AC: Determination of cardiac output by equating

optimal function of the heart depends greatly on

venous return curves with cardiac response curves. Physiol

Rev 35:123, 1955.

proper control of body temperature by the tempera-

Guyton AC, Jones CE, Coleman TG: Circulatory Physiology:

ture control mechanisms explained in Chapter 73.

Cardiac Output and Its Regulation, 2nd ed. Philadelphia:

WB Saunders, 1973.

Herring N, Danson EJ, Paterson DJ: Cholinergic control of

Increasing the Arterial Pressure Load

heart rate by nitric oxide is site specific. News Physiol Sci

(up to a Limit) Does Not Decrease the

17:202, 2002.

Korzick DH: Regulation of cardiac excitation-contraction

Cardiac Output

coupling: a cellular update. Adv Physiol Educ 27:192, 2003.

Olson EN: A decade of discoveries in cardiac biology. Nat

Note in Figure 9-12 that increasing the arterial pres-

Med 10:467, 2004.

sure in the aorta does not decrease the cardiac output

Page E, Fozzard HA, Solaro JR: Handbook of Physiology,

until the mean arterial pressure rises above about

sec 2: The Cardiovascular System, vol 1: The Heart. New

160 mm Hg. In other words, during normal function of

York: Oxford University Press, 2002.

C H A P T E R

Rhythmical Excitation

of the Heart

The heart is endowed with a special system for (1)

generating rhythmical electrical impulses to cause

rhythmical contraction of the heart muscle and (2)

conducting these impulses rapidly through the

heart. When this system functions normally, the atria

contract about one sixth of a second ahead of ven-

tricular contraction, which allows filling of the ven-

tricles before they pump the blood through the

lungs and peripheral circulation. Another special importance of the system is

that it allows all portions of the ventricles to contract almost simultaneously,

which is essential for most effective pressure generation in the ventricular

chambers.

This rhythmical and conductive system of the heart is susceptible to damage

by heart disease, especially by ischemia of the heart tissues resulting from poor

coronary blood flow. The result is often a bizarre heart rhythm or abnormal

sequence of contraction of the heart chambers, and the pumping effectiveness

of the heart often is affected severely, even to the extent of causing death.

Specialized Excitatory and Conductive System

of the Heart

Figure 10-1 shows the specialized excitatory and conductive system of the heart

that controls cardiac contractions. The figure shows the sinus node (also called

sinoatrial or S-A node), in which the normal rhythmical impulse is generated;

the internodal pathways that conduct the impulse from the sinus node to the

atrioventricular (A-V) node; the A-V node, in which the impulse from the atria

is delayed before passing into the ventricles; the A-V bundle, which conducts

the impulse from the atria into the ventricles; and the left and right bundle

branches of Purkinje fibers, which conduct the cardiac impulse to all parts of

the ventricles.

Sinus (Sinoatrial) Node

The sinus node (also called sinoatrial node) is a small, flattened, ellipsoid strip

of specialized cardiac muscle about 3 millimeters wide, 15 millimeters long, and

1 millimeter thick. It is located in the superior posterolateral wall of the right

atrium immediately below and slightly lateral to the opening of the superior

vena cava. The fibers of this node have almost no contractile muscle filaments

and are each only 3 to 5 micrometers in diameter, in contrast to a diameter of

10 to 15 micrometers for the surrounding atrial muscle fibers. However, the

sinus nodal fibers connect directly with the atrial muscle fibers, so that any

action potential that begins in the sinus node spreads immediately into the atrial

muscle wall.

Automatic Electrical Rhythmicity of the Sinus Fibers

Some cardiac fibers have the capability of self-excitation, a process that can

cause automatic rhythmical discharge and contraction. This is especially true of

116

Chapter 10

Rhythmical Excitation of the Heart

117

fiber for three heartbeats and, by comparison, a single

ventricular muscle fiber action potential. Note that the

“resting membrane potential” of the sinus nodal fiber

between discharges has a negativity of about -55 to

-60 millivolts, in comparison with -85 to -90 millivolts

for the ventricular muscle fiber. The cause of this lesser

negativity is that the cell membranes of the sinus fibers

A-V node

Sinus

are naturally leaky to sodium and calcium ions, and

node

positive charges of the entering sodium and calcium

A-V bundle

ions neutralize much of the intracellular negativity.

Before attempting to explain the rhythmicity of the

Left

sinus nodal fibers, first recall from the discussions of

Internodal

bundle

Chapters 5 and 9 that cardiac muscle has three types

pathways

branch

of membrane ion channels that play important roles in

Right

causing the voltage changes of the action potential.

bundle

They are (1) fast sodium channels, (2) slow sodium-

branch

calcium channels, and (3) potassium channels. Opening

of the fast sodium channels for a few 10,000ths of a

second is responsible for the rapid upstroke spike of

the action potential observed in ventricular muscle,

Figure 10-1

because of rapid influx of positive sodium ions to the

interior of the fiber. Then the “plateau” of the ven-

Sinus node, and the Purkinje system of the heart, showing also

tricular action potential is caused primarily by slower

the A-V node, atrial internodal pathways, and ventricular bundle

opening of the slow sodium-calcium channels, which

branches.

lasts for about 0.3 second. Finally, opening of potas-

sium channels allows diffusion of large amounts of

positive potassium ions in the outward direction

through the fiber membrane and returns the mem-

brane potential to its resting level.

Sinus

But there is a difference in the function of these

nodal fiber

channels in the sinus nodal fiber because the “resting”

Ventricular

potential is much less negative—only -55 millivolts in

muscle fiber

Threshold for

the nodal fiber instead of the -90 millivolts in the ven-

+20

discharge

tricular muscle fiber. At this level of -55 millivolts,

the fast sodium channels mainly have already become

“inactivated,” which means that they have become

blocked. The cause of this is that any time the mem-

- 40

brane potential remains less negative than about -55

millivolts for more than a few milliseconds, the inacti-

vation gates on the inside of the cell membrane that

“Resting

potential”

close the fast sodium channels become closed and

- 80

remain so. Therefore, only the slow sodium-calcium

channels can open (i.e., can become “activated”) and

thereby cause the action potential. As a result, the

Seconds

atrial nodal action potential is slower to develop than

the action potential of the ventricular muscle. Also,

after the action potential does occur, return of the

potential to its negative state occurs slowly as well,

Figure 10-2

rather than the abrupt return that occurs for the

Rhythmical discharge of a sinus nodal fiber. Also, the sinus nodal

ventricular fiber.

action potential is compared with that of a ventricular muscle fiber.

Self-Excitation of Sinus Nodal Fibers. Because of the

high sodium ion concentration in the extracellular

the fibers of the heart’s specialized conducting system,

fluid outside the nodal fiber, as well as a moderate

including the fibers of the sinus node. For this reason,

number of already open sodium channels, positive

the sinus node ordinarily controls the rate of beat

sodium ions from outside the fibers normally tend to

of the entire heart, as discussed in detail later in

leak to the inside. Therefore, between heartbeats,

this chapter. First, let us describe this automatic

influx of positively charged sodium ions causes a slow

rhythmicity.

rise in the resting membrane potential in the positive

direction. Thus, as shown in Figure 10-2, the “resting”

Mechanism of Sinus Nodal Rhythmicity. Figure 10-2 shows

potential gradually rises between each two heartbeats.

action potentials recorded from inside a sinus nodal

When the potential reaches a threshold voltage of

118

Unit III

The Heart

about

-40 millivolts, the sodium-calcium channels

Internodal

become “activated,” thus causing the action potential.

pathways

Transitional fibers

Therefore, basically, the inherent leakiness of the sinus

nodal fibers to sodium and calcium ions causes their

self-excitation.

A-V node

Why does this leakiness to sodium and calcium ions

not cause the sinus nodal fibers to remain depolarized

all the time? The answer is that two events occur

(0.03)

during the course of the action potential to prevent

this. First, the sodium-calcium channels become inac-

Atrioventricular

tivated (i.e., they close) within about 100 to 150 mil-

fibrous tissue

liseconds after opening, and second, at about the same

(0.12)

Penetrating portion

time, greatly increased numbers of potassium channels

of A-V bundle

open. Therefore, influx of positive calcium and sodium

Distal portion of

ions through the sodium-calcium channels ceases,

A-V bundle

while at the same time large quantities of positive

potassium ions diffuse out of the fiber. Both of these

Left bundle branch

Right bundle branch

effects reduce the intracellular potential back to its

negative resting level and therefore terminate the

(0.16)

action potential. Furthermore, the potassium channels

remain open for another few tenths of a second, tem-

porarily continuing movement of positive charges out

of the cell, with resultant excess negativity inside the

Ventricular

fiber; this is called hyperpolarization. The hyperpolar-

septum

ization state initially carries the “resting” membrane

potential down to about -55 to -60 millivolts at the

Figure 10-3

termination of the action potential.

Organization of the A-V node. The numbers represent the interval

Last, we must explain why this new state of hyper-

of time from the origin of the impulse in the sinus node. The values

polarization is not maintained forever. The reason is

have been extrapolated to human beings.

that during the next few tenths of a second after the

action potential is over, progressively more and more

potassium channels close. The inward-leaking sodium

other small bands curve through the anterior, lateral,

and calcium ions once again overbalance the outward

and posterior atrial walls and terminate in the A-V

flux of potassium ions, and this causes the “resting”

node; shown in Figures 10-1 and 10-3, these are called,

potential to drift upward once more, finally reaching

respectively, the anterior, middle, and posterior inter-

the threshold level for discharge at a potential of about

nodal pathways. The cause of more rapid velocity of

-40 millivolts. Then the entire process begins again:

conduction in these bands is the presence of special-

self-excitation to cause the action potential, recovery

ized conduction fibers. These fibers are similar to even

from the action potential, hyperpolarization after the

more rapidly conducting “Purkinje fibers” of the ven-

action potential is over, drift of the “resting” potential

tricles, which will be discussed.

to threshold, and finally re-excitation to elicit another

cycle. This process continues indefinitely throughout a

person’s life.

Atrioventricular Node, and Delay

of Impulse Conduction from the Atria

to the Ventricles

Internodal Pathways and

Transmission of the Cardiac Impulse

The atrial conductive system is organized so that the

Through the Atria

cardiac impulse does not travel from the atria into

the ventricles too rapidly; this delay allows time for the

The ends of the sinus nodal fibers connect directly with

atria to empty their blood into the ventricles before

surrounding atrial muscle fibers. Therefore, action

ventricular contraction begins. It is primarily the A-V

potentials originating in the sinus node travel outward

node and its adjacent conductive fibers that delay this

into these atrial muscle fibers. In this way, the action

transmission into the ventricles.

potential spreads through the entire atrial muscle mass

The A-V node is located in the posterior wall of the

and, eventually, to the A-V node. The velocity of con-

right atrium immediately behind the tricuspid valve,

duction in most atrial muscle is about 0.3 m/sec, but

as shown in Figure 10-1. And Figure 10-3 shows dia-

conduction is more rapid, about 1 m/sec, in several

grammatically the different parts of this node, plus

small bands of atrial fibers. One of these, called the

its connections with the entering atrial internodal

anterior interatrial band, passes through the anterior

pathway fibers and the exiting A-V bundle. The figure

walls of the atria to the left atrium. In addition, three

also shows the approximate intervals of time in

Chapter 10

Rhythmical Excitation of the Heart

119

fractions of a second between initial onset of the

re-entry of cardiac impulses by this route from the

cardiac impulse in the sinus node and its subsequent

ventricles to the atria, allowing only forward conduc-

appearance in the A-V nodal system. Note that the

tion from the atria to the ventricles.

impulse, after traveling through the internodal path-

Furthermore, it should be recalled that everywhere,

ways, reaches the A-V node about 0.03 second after its

except at the A-V bundle, the atrial muscle is sepa-

origin in the sinus node. Then there is a delay of

rated from the ventricular muscle by a continuous

another 0.09 second in the A-V node itself before the

fibrous barrier, a portion of which is shown in Figure

impulse enters the penetrating portion of the A-V

10-3. This barrier normally acts as an insulator to

bundle, where it passes into the ventricles. A final delay

prevent passage of the cardiac impulse between atrial

of another 0.04 second occurs mainly in this penetrat-

and ventricular muscle through any other route

ing A-V bundle, which is composed of multiple small

besides forward conduction through the A-V bundle

fascicles passing through the fibrous tissue separating

itself. (In rare instances, an abnormal muscle bridge

the atria from the ventricles.

does penetrate the fibrous barrier elsewhere besides

Thus, the total delay in the A-V nodal and A-V

at the A-V bundle. Under such conditions, the cardiac

bundle system is about 0.13 second. This, in addition to

impulse can re-enter the atria from the ventricles and

the initial conduction delay of 0.03 second from the

cause a serious cardiac arrhythmia.)

sinus node to the A-V node, makes a total delay of 0.16

second before the excitatory signal finally reaches the

Distribution of the Purkinje Fibers in the Ventricles—The Left

contracting muscle of the ventricles.

and Right Bundle Branches. After penetrating the fibrous

tissue between the atrial and ventricular muscle, the

Cause of the Slow Conduction. The slow conduction in the

distal portion of the A-V bundle passes downward in

transitional, nodal, and penetrating A-V bundle fibers

the ventricular septum for 5 to 15 millimeters toward

is caused mainly by diminished numbers of gap junc-

the apex of the heart, as shown in Figures 10-1 and

tions between successive cells in the conducting path-

10-3. Then the bundle divides into left and right bundle

ways, so that there is great resistance to conduction of

branches that lie beneath the endocardium on the two

excitatory ions from one conducting fiber to the next.

respective sides of the ventricular septum. Each

Therefore, it is easy to see why each succeeding cell is

branch spreads downward toward the apex of the ven-

slow to be excited.

tricle, progressively dividing into smaller branches.

These branches in turn course sidewise around each

ventricular chamber and back toward the base of the

heart. The ends of the Purkinje fibers penetrate about

Rapid Transmission in the Ventricular

one third the way into the muscle mass and finally

Purkinje System

become continuous with the cardiac muscle fibers.

From the time the cardiac impulse enters the bundle

Special Purkinje fibers lead from the A-V node

branches in the ventricular septum until it reaches the

through the A-V bundle into the ventricles. Except for

terminations of the Purkinje fibers, the total elapsed

the initial portion of these fibers where they penetrate

time averages only 0.03 second. Therefore, once the

the A-V fibrous barrier, they have functional charac-

cardiac impulse enters the ventricular Purkinje con-

teristics that are quite the opposite of those of the

ductive system, it spreads almost immediately to the

A-V nodal fibers. They are very large fibers, even

entire ventricular muscle mass.

larger than the normal ventricular muscle fibers, and

they transmit action potentials at a velocity of 1.5 to

4.0 m/sec, a velocity about 6 times that in the usual

ventricular muscle and 150 times that in some of the

Transmission of the Cardiac Impulse

A-V nodal fibers. This allows almost instantaneous

in the Ventricular Muscle

transmission of the cardiac impulse throughout the

entire remainder of the ventricular muscle.

Once the impulse reaches the ends of the Purkinje

The rapid transmission of action potentials by Purk-

fibers, it is transmitted through the ventricular muscle

inje fibers is believed to be caused by a very high level

mass by the ventricular muscle fibers themselves. The

of permeability of the gap junctions at the intercalated

velocity of transmission is now only 0.3 to 0.5 m/sec,

discs between the successive cells that make up the

one sixth that in the Purkinje fibers.

Purkinje fibers. Therefore, ions are transmitted easily

The cardiac muscle wraps around the heart in a

from one cell to the next, thus enhancing the velocity

double spiral, with fibrous septa between the spiraling

of transmission. The Purkinje fibers also have very few

layers; therefore, the cardiac impulse does not neces-

myofibrils, which means that they contract little or not

sarily travel directly outward toward the surface of the

at all during the course of impulse transmission.

heart but instead angulates toward the surface along

the directions of the spirals. Because of this, transmis-

One-Way Conduction Through the A-V Bundle. A special

sion from the endocardial surface to the epicardial

characteristic of the A-V bundle is the inability, except

surface of the ventricle requires as much as another

in abnormal states, of action potentials to travel back-

0.03 second, approximately equal to the time required

ward from the ventricles to the atria. This prevents

for transmission through the entire ventricular portion

120

Unit III

The Heart

of the Purkinje system. Thus, the total time for trans-

Control of Excitation and

mission of the cardiac impulse from the initial bundle

Conduction in the Heart

branches to the last of the ventricular muscle fibers in

the normal heart is about 0.06 second.

The Sinus Node as the Pacemaker

of the Heart

Summary of the Spread of the Cardiac

In the discussion thus far of the genesis and transmis-

Impulse Through the Heart

sion of the cardiac impulse through the heart, we have

noted that the impulse normally arises in the sinus

Figure 10-4 shows in summary form the transmission

node. In some abnormal conditions, this is not the case.

of the cardiac impulse through the human heart. The

A few other parts of the heart can exhibit intrinsic

numbers on the figure represent the intervals of time,

rhythmical excitation in the same way that the sinus

in fractions of a second, that lapse between the origin

nodal fibers do; this is particularly true of the A-V

of the cardiac impulse in the sinus node and its appear-

nodal and Purkinje fibers.

ance at each respective point in the heart. Note that

The A-V nodal fibers, when not stimulated from

the impulse spreads at moderate velocity through the

some outside source, discharge at an intrinsic rhyth-

atria but is delayed more than 0.1 second in the A-V

mical rate of 40 to 60 times per minute, and the Purk-

nodal region before appearing in the ventricular septal

inje fibers discharge at a rate somewhere between

A-V bundle. Once it has entered this bundle, it spreads

15 and 40 times per minute. These rates are in contrast

very rapidly through the Purkinje fibers to the entire

to the normal rate of the sinus node of 70 to 80 times

endocardial surfaces of the ventricles. Then the impulse

per minute.

once again spreads slightly less rapidly through the

The question we must ask is: Why does the sinus

ventricular muscle to the epicardial surfaces.

node rather than the A-V node or the Purkinje fibers

It is extremely important that the student learn in

control the heart’s rhythmicity? The answer derives

detail the course of the cardiac impulse through the

from the fact that the discharge rate of the sinus node

heart and the precise times of its appearance in each

is considerably faster than the natural self-excitatory

separate part of the heart, because a thorough quanti-

discharge rate of either the A-V node or the Purkinje

tative knowledge of this process is essential to the

fibers. Each time the sinus node discharges, its impulse

understanding of electrocardiography, to be discussed

is conducted into both the A-V node and the Purkinje

in Chapters 11 through 13.

fibers, also discharging their excitable membranes. But

the sinus node discharges again before either the A-V

node or the Purkinje fibers can reach their own thresh-

olds for self-excitation. Therefore, the new impulse

from the sinus node discharges both the A-V node and

the Purkinje fibers before self-excitation can occur in

either of these.

Thus, the sinus node controls the beat of the heart

.07

because its rate of rhythmical discharge is faster than

that of any other part of the heart. Therefore, the sinus

.04

.09

.06

node is virtually always the pacemaker of the normal

S-A

.22

heart.

.03

.07

.19

Abnormal Pacemakers—“Ectopic” Pacemaker. Occasionally

some other part of the heart develops a rhythmical dis-

.00

.16

A-V

charge rate that is more rapid than that of the sinus

node. For instance, this sometimes occurs in the A-V

.05

.03

.18

.21

node or in the Purkinje fibers when one of these

.17

becomes abnormal. In either case, the pacemaker of

.07

.17

the heart shifts from the sinus node to the A-V node

.19

or to the excited Purkinje fibers. Under rarer condi-

tions, a place in the atrial or ventricular muscle devel-

.18

ops excessive excitability and becomes the pacemaker.

A pacemaker elsewhere than the sinus node is

.21

called an “ectopic” pacemaker. An ectopic pacemaker

causes an abnormal sequence of contraction of the

.20

different parts of the heart and can cause significant

debility of heart pumping.

Figure 10-4

Another cause of shift of the pacemaker is blockage

of transmission of the cardiac impulse from the sinus

Transmission of the cardiac impulse through the heart, showing

the time of appearance (in fractions of a second after initial

node to the other parts of the heart. The new pace-

appearance at the sinoatrial node) in different parts of the heart.

maker then occurs most frequently at the A-V node or

Chapter 10

Rhythmical Excitation of the Heart

121

in the penetrating portion of the A-V bundle on the

Parasympathetic (Vagal) Stimulation Can Slow or Even Block

way to the ventricles.

Cardiac Rhythm and Conduction—“Ventricular Escape.”

When A-V block occurs—that is, when the cardiac

Stimulation of the parasympathetic nerves to the heart

impulse fails to pass from the atria into the ventricles

(the vagi) causes the hormone acetylcholine to be

through the A-V nodal and bundle system—the atria

released at the vagal endings. This hormone has two

continue to beat at the normal rate of rhythm of the

major effects on the heart. First, it decreases the rate

sinus node, while a new pacemaker usually develops

of rhythm of the sinus node, and second, it decreases

in the Purkinje system of the ventricles and drives the

the excitability of the A-V junctional fibers between

ventricular muscle at a new rate somewhere between

the atrial musculature and the A-V node, thereby

15 and 40 beats per minute. After sudden A-V bundle

slowing transmission of the cardiac impulse into the

block, the Purkinje system does not begin to emit its

ventricles.

intrinsic rhythmical impulses until 5 to 20 seconds later

Weak to moderate vagal stimulation slows the rate

because, before the blockage, the Purkinje fibers had

of heart pumping, often to as little as one half normal.

been “overdriven” by the rapid sinus impulses and,

And strong stimulation of the vagi can stop completely

consequently, are in a suppressed state. During these

the rhythmical excitation by the sinus node or block

5 to 20 seconds, the ventricles fail to pump blood, and

completely transmission of the cardiac impulse from

the person faints after the first 4 to 5 seconds because

the atria into the ventricles through the A-V mode. In

of lack of blood flow to the brain. This delayed pickup

either case, rhythmical excitatory signals are no longer

of the heartbeat is called Stokes-Adams syndrome. If

transmitted into the ventricles. The ventricles stop

the delay period is too long, it can lead to death.

beating for 5 to 20 seconds, but then some point in the

Purkinje fibers, usually in the ventricular septal

portion of the A-V bundle, develops a rhythm of its

Role of the Purkinje System

own and causes ventricular contraction at a rate of

15 to 40 beats per minute. This phenomenon is called

in Causing Synchronous Contraction

ventricular escape.

of the Ventricular Muscle

Mechanism of the Vagal Effects. The acetylcholine

It is clear from our description of the Purkinje system

released at the vagal nerve endings greatly increases

that normally the cardiac impulse arrives at almost all

the permeability of the fiber membranes to potassium

portions of the ventricles within a narrow span of time,

ions, which allows rapid leakage of potassium out of

exciting the first ventricular muscle fiber only 0.03 to

the conductive fibers. This causes increased negativity

0.06 second ahead of excitation of the last ventricular

inside the fibers, an effect called hyperpolarization,

muscle fiber. This causes all portions of the ventricular

which makes this excitable tissue much less excitable,

muscle in both ventricles to begin contracting at

as explained in Chapter 5.

almost the same time and then to continue contract-

In the sinus node, the state of hyperpolarization

ing for about another 0.3 second.

decreases the “resting” membrane potential of the

Effective pumping by the two ventricular chambers

sinus nodal fibers to a level considerably more nega-

requires this synchronous type of contraction. If the

tive than usual, to -65 to -75 millivolts rather than

cardiac impulse should travel through the ventricles

the normal level of -55 to -60 millivolts. Therefore,

slowly, much of the ventricular mass would contract

the initial rise of the sinus nodal membrane potential

before contraction of the remainder, in which case the

caused by inward sodium and calcium leakage

overall pumping effect would be greatly depressed.

requires much longer to reach the threshold potential

Indeed, in some types of cardiac debilities, several of

for excitation. This greatly slows the rate of rhythmic-

which are discussed in Chapters 12 and 13, slow trans-

ity of these nodal fibers. If the vagal stimulation is

mission does occur, and the pumping effectiveness of

strong enough, it is possible to stop entirely the rhyth-

the ventricles is decreased as much as 20 to 30 per cent.

mical self-excitation of this node.

In the A-V node, a state of hyperpolarization caused

by vagal stimulation makes it difficult for the small

Control of Heart Rhythmicity and

atrial fibers entering the node to generate enough elec-

Impulse Conduction by the Cardiac

tricity to excite the nodal fibers. Therefore, the safety

Nerves: The Sympathetic and

factor for transmission of the cardiac impulse through

Parasympathetic Nerves

the transitional fibers into the A-V nodal fibers

decreases. A moderate decrease simply delays con-

The heart is supplied with both sympathetic and

duction of the impulse, but a large decrease blocks

parasympathetic nerves, as shown in Figure 9-10 of

conduction entirely.

Chapter 9. The parasympathetic nerves (the vagi) are

distributed mainly to the S-A and A-V nodes, to a

Effect of Sympathetic Stimulation on Cardiac Rhythm and Con-

lesser extent to the muscle of the two atria, and very

duction. Sympathetic stimulation causes essentially the

little directly to the ventricular muscle. The sympa-

opposite effects on the heart to those caused by vagal

thetic nerves, conversely, are distributed to all parts of

stimulation, as follows: First, it increases the rate of

the heart, with strong representation to the ventricu-

sinus nodal discharge. Second, it increases the rate

lar muscle as well as to all the other areas.

of conduction as well as the level of excitability in all

122

Unit III

The Heart

portions of the heart. Third, it increases greatly the

Gentlesk PJ, Markwood TT, Atwood JE: Chronotropic

force of contraction of all the cardiac musculature,

incompetence in a young adult: case report and literature

both atrial and ventricular, as discussed in Chapter 9.

review. Chest 125:297, 2004.

Huikuri HV, Castellanos A, Myerburg RJ: Sudden death due

In short, sympathetic stimulation increases the

to cardiac arrhythmias. N Engl J Med 345:1473, 2001.

overall activity of the heart. Maximal stimulation

Hume JR, Duan D, Collier ML, et al: Anion transport in

can almost triple the frequency of heartbeat and can

heart. Physiol Rev 80:31, 2000.

increase the strength of heart contraction as much as

James TN: Structure and function of the sinus node, AV node

twofold.

and His bundle of the human heart: part I—structure. Prog

Cardiovasc Dis 45:235, 2002.

Mechanism of the Sympathetic Effect. Stimulation of

James TN: Structure and function of the sinus node, AV node

the sympathetic nerves releases the hormone norepi-

and His bundle of the human heart: part II—function.

nephrine at the sympathetic nerve endings. The precise

Prog Cardiovasc Dis 45:327, 2003.

mechanism by which this hormone acts on cardiac

Kaupp UB, Seifert R: Molecular diversity of pacemaker ion

channels. Annu Rev Physiol 63:235, 2001.

muscle fibers is somewhat unclear, but the belief is

Kléber AG, Rudy Y: Basic mechanisms of cardiac impulse

that it increases the permeability of the fiber mem-

propagation and associated arrhythmias. Physiol Rev

brane to sodium and calcium ions. In the sinus node,

84:431, 2004.

an increase of sodium-calcium permeability causes

Leclercq C, Hare JM: Ventricular resynchronization: current

a more positive resting potential and also causes

state of the art. Circulation 109:296, 2004.

increased rate of upward drift of the diastolic mem-

Mazgalev TN, Ho SY, Anderson RH: Anatomic-

brane potential toward the threshold level for self-

electrophysiological correlations concerning the pathways

excitation, thus accelerating self-excitation and,

for atrioventricular conduction. Circulation

103:2660,

therefore, increasing the heart rate.

2001.

In the A-V node and A-V bundles, increased

Page E, Fozzard HA, Solaro JR: Handbook of Physiology,

sec 2: The Cardiovascular System, vol 1: The Heart. New

sodium-calcium permeability makes it easier for the

York: Oxford University Press, 2002.

action potential to excite each succeeding portion of

Petrashevskaya NN, Koch SE, Bodi I, Schwartz A: Calcium

the conducting fiber bundles, thereby decreasing the

cycling, historic overview and perspectives: role for auto-

conduction time from the atria to the ventricles.

nomic nervous system regulation. J Mol Cell Cardiol

The increase in permeability to calcium ions is at

34:885, 2002.

least partially responsible for the increase in contrac-

Priori SG: Inherited arrhythmogenic diseases: the com-

tile strength of the cardiac muscle under the influence

plexity beyond monogenic disorders. Circ Res 94:140,

of sympathetic stimulation, because calcium ions play

2004.

a powerful role in exciting the contractile process of

Roden DM, Balser JR, George AL Jr, Anderson ME:

the myofibrils.

Cardiac ion channels. Annu Rev Physiol 64:431, 2002.

Schram G, Pourrier M, Melnyk P, Nattel S: Differential dis-

tribution of cardiac ion channel expression as a basis for

regional specialization in electrical function. Circ Res

References

90:939, 2002.

Surawicz B: Electrophysiologic Basis of ECG and Cardiac

Blatter LA, Kockskamper J, Sheehan KA, et al: Local

Arrhythmias. Baltimore: Williams & Wilkins, 1995.

calcium gradients during excitation-contraction coupling

Waldo AL: Mechanisms of atrial fibrillation. J Cardiovasc

and alternans in atrial myocytes. J Physiol 546:19, 2003.

Electrophysiol 14(12 Suppl):S267, 2003.

Ferrier GR, Howlett SE: Cardiac excitation-contraction cou-

Yasuma F, Hayano J: Respiratory sinus arrhythmia: why does

pling: role of membrane potential in regulation of con-

the heartbeat synchronize with respiratory rhythm? Chest

traction. Am J Physiol Heart Circ Physiol 280:H1928, 2001.

125:683, 2004.

C H A P T E R

The Normal Electrocardiogram

When the cardiac impulse passes through the heart,

electrical current also spreads from the heart into

the adjacent tissues surrounding the heart. A small

portion of the current spreads all the way to the

surface of the body. If electrodes are placed on the

skin on opposite sides of the heart, electrical

potentials generated by the current can be recorded;

the recording is known as an electrocardiogram.

A normal electrocardiogram for two beats of the heart is shown in Figure 11-1.

Characteristics of the Normal

Electrocardiogram

The normal electrocardiogram (see Figure 11-1) is composed of a P wave, a

QRS complex, and a T wave. The QRS complex is often, but not always, three

separate waves: the Q wave, the R wave, and the S wave.

The P wave is caused by electrical potentials generated when the atria depo-

larize before atrial contraction begins. The QRS complex is caused by poten-

tials generated when the ventricles depolarize before contraction, that is, as the

depolarization wave spreads through the ventricles. Therefore, both the P wave

and the components of the QRS complex are depolarization waves.

The T wave is caused by potentials generated as the ventricles recover from

the state of depolarization. This process normally occurs in ventricular muscle

0.25 to 0.35 second after depolarization, and the T wave is known as a repolar-

ization wave.

Thus, the electrocardiogram is composed of both depolarization and repo-

larization waves. The principles of depolarization and repolarization are

discussed in Chapter 5. The distinction between depolarization waves and repo-

larization waves is so important in electrocardiography that further clarification

is needed.

Depolarization Waves Versus Repolarization Waves

Figure 11-2 shows a single cardiac muscle fiber in four stages of depolarization

and repolarization, the color red designating depolarization. During depolar-

ization, the normal negative potential inside the fiber reverses and becomes

slightly positive inside and negative outside.

In Figure 11-2A, depolarization, demonstrated by red positive charges inside

and red negative charges outside, is traveling from left to right. The first half of

the fiber has already depolarized, while the remaining half is still polarized.

Therefore, the left electrode on the outside of the fiber is in an area of nega-

tivity, and the right electrode is in an area of positivity; this causes the meter to

record positively. To the right of the muscle fiber is shown a record of changes

in potential between the two electrodes, as recorded by a high-speed recording

meter. Note that when depolarization has reached the halfway mark in Figure

11-2A, the record has risen to a maximum positive value.

123

124

Unit III

The Heart

In Figure 11-2B, depolarization has extended over

Figure 11-2C shows halfway repolarization of the

the entire muscle fiber, and the recording to the right

same muscle fiber, with positivity returning to the

has returned to the zero baseline because both elec-

outside of the fiber. At this point, the left electrode is

trodes are now in areas of equal negativity. The com-

in an area of positivity, and the right electrode is in an

pleted wave is a depolarization wave because it results

area of negativity. This is opposite to the polarity in

from spread of depolarization along the muscle fiber

Figure 11-2A. Consequently, the recording, as shown

membrane.

to the right, becomes negative.

In Figure 11-2D, the muscle fiber has completely

repolarized, and both electrodes are now in areas of

positivity, so that no potential difference is recorded

between them. Thus, in the recording to the right, the

potential returns once more to zero. This completed

Atria Ventricles

negative wave is a repolarization wave because it

results from spread of repolarization along the muscle

RR interval

fiber membrane.

S-T

segment

Relation of the Monophasic Action Potential of Ventricular

Muscle to the QRS and T Waves in the Standard Electrocardio-

gram. The monophasic action potential of ventricular

muscle, discussed in Chapter 10, normally lasts between

0.25 and 0.35 second. The top part of Figure 11-3 shows

P-R

interval

Q-T interval

a monophasic action potential recorded from a micro-

= 0.16 sec

–1

electrode inserted to the inside of a single ventricular

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

muscle fiber. The upsweep of this action potential is

Time (sec)

caused by depolarization, and the return of the poten-

tial to the baseline is caused by repolarization.

Note in the lower half of the figure a simultaneous

Figure 11-1

recording of the electrocardiogram from this same

Normal electrocardiogram.

ventricle, which shows the QRS waves appearing at

- - - - - - -+ + + + + + + + +

- - - - - - - - -

+ + + + + + +

- - - - - - - - -

+ + + + + + +

- - - - - - -+ + + + + + + + +

–

Depolarization

wave

- - - - - - - - - - - - - - - -

+ + + + + + + + + + + + + + + +

– - - - - - - - - - - - - - - -

+ + + + + + + + + - - - - - - -

- - - - - - - - - + + + + + + +

+ + + + + + + + + - - - - - - -

Repolarization

+ + + + + + + + + + + + + + + +

wave

- - - - - - - - - - - - - - - -

Figure 11-2

+ + + + + + + + + + + + + + + +

0.30 second

Recording the depolarization wave (A and B) and

the repolarization wave (C and D) from a cardiac

muscle fiber.

Chapter 11

The Normal Electrocardiogram

125

(the QRS complex), but in many other fibers, it takes

as long as 0.35 second. Thus, the process of ventricular

repolarization extends over a long period, about 0.15

second. For this reason, the T wave in the normal elec-

trocardiogram is a prolonged wave, but the voltage of

the T wave is considerably less than the voltage of the

QRS complex, partly because of its prolonged length.

Voltage and Time Calibration of the

Electrocardiogram

All recordings of electrocardiograms are made with

appropriate calibration lines on the recording paper.

Either these calibration lines are already ruled on the

paper, as is the case when a pen recorder is used, or

they are recorded on the paper at the same time that

the electrocardiogram is recorded, which is the case

with the photographic types of electrocardiographs.

Figure 11-3

As shown in Figure 11-1, the horizontal calibration

lines are arranged so that 10 of the small line divisions

Above, Monophasic action potential from a ventricular muscle

upward or downward in the standard electrocardio-

fiber during normal cardiac function, showing rapid depolarization

gram represent 1 millivolt, with positivity in the upward

and then repolarization occurring slowly during the plateau stage

but rapidly toward the end. Below, Electrocardiogram recorded

direction and negativity in the downward direction.

simultaneously.

The vertical lines on the electrocardiogram are time

calibration lines. Each inch in the horizontal direction

is 1 second, and each inch is usually broken into five

the beginning of the monophasic action potential and

segments by dark vertical lines; the intervals between

the T wave appearing at the end. Note especially that

these dark lines represent 0.20 second. The 0.20 second

no potential is recorded in the electrocardiogram when

intervals are then broken into five smaller intervals by

the ventricular muscle is either completely polarized

thin lines, each of which represents 0.04 second.

or completely depolarized. Only when the muscle is

Normal Voltages in the Electrocardiogram. The recorded

partly polarized and partly depolarized does current

voltages of the waves in the normal electrocardiogram

flow from one part of the ventricles to another part,

depend on the manner in which the electrodes are

and therefore current also flows to the surface of the

applied to the surface of the body and how close the

body to produce the electrocardiogram.

electrodes are to the heart. When one electrode is

placed directly over the ventricles and a second elec-

Relationship of Atrial and Ventricular

trode is placed elsewhere on the body remote from the

heart, the voltage of the QRS complex may be as great

Contraction to the Waves of the

as 3 to 4 millivolts. Even this voltage is small in com-

Electrocardiogram

parison with the monophasic action potential of 110

millivolts recorded directly at the heart muscle mem-

Before contraction of muscle can occur, depolarization

brane. When electrocardiograms are recorded from

must spread through the muscle to initiate the chemi-

electrodes on the two arms or on one arm and one leg,

cal processes of contraction. Refer again to Figure

the voltage of the QRS complex usually is 1.0 to 1.5

11-1; the P wave occurs at the beginning of contrac-

millivolt from the top of the R wave to the bottom of

tion of the atria, and the QRS complex of waves occurs

the S wave; the voltage of the P wave is between 0.1

at the beginning of contraction of the ventricles. The

and 0.3 millivolt; and that of the T wave is between 0.2

ventricles remain contracted until after repolarization

and 0.3 millivolt.

has occurred, that is, until after the end of the T wave.

The atria repolarize about 0.15 to 0.20 second after

P-Q or P-R Interval. The time between the beginning of

termination of the P wave. This is also approxima-

the P wave and the beginning of the QRS complex is

tely when the QRS complex is being recorded in

the interval between the beginning of electrical exci-

the electrocardiogram. Therefore, the atrial repo-

tation of the atria and the beginning of excitation of

larization wave, known as the atrial T wave, is usually

the ventricles. This period is called the P-Q interval.

obscured by the much larger QRS complex. For

The normal P-Q interval is about 0.16 second. (Often

this reason, an atrial T wave seldom is observed in the

this interval is called the P-R interval because the Q

electrocardiogram.

wave is likely to be absent.)

The ventricular repolarization wave is the T wave of

the normal electrocardiogram. Ordinarily, ventricular

Q-T Interval. Contraction of the ventricle lasts almost

muscle begins to repolarize in some fibers about 0.20

from the beginning of the Q wave (or R wave, if

second after the beginning of the depolarization wave

the Q wave is absent) to the end of the T wave. This

126

Unit III

The Heart

interval is called the Q-T interval and ordinarily is

about 0.35 second.

Rate of Heartbeat as Determined from the Electrocardiogram.

The rate of heartbeat can be determined easily from

–

an electrocardiogram because the heart rate is the

reciprocal of the time interval between two successive

–

heartbeats. If the interval between two beats as deter-

mined from the time calibration lines is 1 second, the

+++++

heart rate is 60 beats per minute. The normal interval

+++++++++

++++

++++++

between two successive QRS complexes in the adult

- - - - -

++++++

– - - - - -

- - - - - - - - -

++++

++++++

- - - - - -

- - -

person is about 0.83 second. This is a heart rate of

- - - - - -

- - -

++++++

- - - -

- - - - -

++++++

- - - - - - - - -

+++++

60/0.83 times per minute, or 72 beats per minute.

+++++

- - - - - - - - -

++++++-

- - - - - - - -

++++++

- - - - - - - -

++++++

- - - - - - -

++++++

- - - -

++++++++

- -

++++++

++++

+++++++++++

Methods for Recording

++++++++++

Electrocardiograms

Sometimes the electrical currents generated by the

cardiac muscle during each beat of the heart change

Figure 11-4

electrical potentials and polarities on the respective

Instantaneous potentials develop on the surface of a cardiac

sides of the heart in less than 0.01 second. Therefore,

muscle mass that has been depolarized in its center.

it is essential that any apparatus for recording electro-

cardiograms be capable of responding rapidly to these

changes in potentials.

Before stimulation, all the exteriors of the muscle cells

had been positive and the interiors negative. For

Pen Recorder

reasons presented in Chapter 5 in the discussion of

membrane potentials, as soon as an area of cardiac

Many modern clinical electrocardiographs use com-

syncytium becomes depolarized, negative charges leak

puter-based systems and electronic display, while

to the outsides of the depolarized muscle fibers,

others use a direct pen recorder that writes the elec-

making this part of the surface electronegative, as rep-

trocardiogram with a pen directly on a moving sheet

resented by the negative signs in Figure 11-4. The

of paper. Sometimes the pen is a thin tube connected

remaining surface of the heart, which is still polarized,

at one end to an inkwell, and its recording end is con-

is represented by the positive signs. Therefore, a meter

nected to a powerful electromagnet system that is

connected with its negative terminal on the area of

capable of moving the pen back and forth at high

depolarization and its positive terminal on one of the

speed. As the paper moves forward, the pen records

still-polarized areas, as shown to the right in the figure,

the electrocardiogram. The movement of the pen is con-

records positively.

trolled by appropriate electronic amplifiers connected

Two other electrode placements and meter readings

to electrocardiographic electrodes on the patient.

are also demonstrated in Figure 11-4. These should be

Other pen recording systems use special paper that

studied carefully, and the reader should be able to

does not require ink in the recording stylus. One such

explain the causes of the respective meter readings.

paper turns black when it is exposed to heat; the stylus

Because the depolarization spreads in all directions

itself is made very hot by electrical current flowing

through the heart, the potential differences shown

through its tip. Another type turns black when electri-

in the figure persist for only a few thousandths of

cal current flows from the tip of the stylus through the

a second, and the actual voltage measurements can

paper to an electrode at its back. This leaves a black

be accomplished only with a high-speed recording

line on the paper where the stylus touches.

apparatus.

Flow of Current Around

Flow of Electrical Currents in the

the Heart During the

Chest Around the Heart

Cardiac Cycle

Figure 11-5 shows the ventricular muscle lying within

the chest. Even the lungs, although mostly filled

Recording Electrical Potentials from a

with air, conduct electricity to a surprising extent, and

Partially Depolarized Mass of

fluids in other tissues surrounding the heart conduct

Syncytial Cardiac Muscle

electricity even more easily. Therefore, the heart

is actually suspended in a conductive medium.

Figure 11-4 shows a syncytial mass of cardiac muscle

When one portion of the ventricles depolarizes and

that has been stimulated at its centralmost point.

therefore becomes electronegative with respect to the

Chapter 11

The Normal Electrocardiogram

127

+0.5 mV

Lead I

-0.2 mV

+++

+0.3 mV

+1.2 mV

+0.7 mV

Figure 11-5

Lead II

Lead III

Flow of current

the chest around

partially

depolarized

ventricles.

+1.0 mV

remainder, electrical current flows from the depolar-

Figure 11-6

ized area to the polarized area in large circuitous

routes, as noted in the figure.

Conventional arrangement of electrodes for recording the stan-

It should be recalled from the discussion of the

dard electrocardiographic leads. Einthoven’s triangle is superim-

Purkinje system in Chapter 10 that the cardiac impulse

posed on the chest.

first arrives in the ventricles in the septum and shortly

thereafter spreads to the inside surfaces of the remain-

der of the ventricles, as shown by the red areas and the

negative signs in Figure

11-5. This provides elec-

Thus, in normal heart ventricles, current flows from

tronegativity on the insides of the ventricles and elec-

negative to positive primarily in the direction from

tropositivity on the outer walls of the ventricles, with

the base of the heart toward the apex during almost

electrical current flowing through the fluids surround-

the entire cycle of depolarization, except at the very

ing the ventricles along elliptical paths, as demon-

end. And if a meter is connected to electrodes on

strated by the curving arrows in the figure. If one

the surface of the body as shown in Figure 11-5, the

algebraically averages all the lines of current flow (the

electrode nearer the base will be negative, whereas

elliptical lines), one finds that the average current flow

the electrode nearer the apex will be positive, and

occurs with negativity toward the base of the heart and

the recording meter will show positive recording in the

with positivity toward the apex.

electrocardiogram.

During most of the remainder of the depolarization

process, current also continues to flow in this same

direction, while depolarization spreads from the endo-

Electrocardiographic Leads

cardial surface outward through the ventricular

muscle mass. Then, immediately before depolarization

Three Bipolar Limb Leads

has completed its course through the ventricles, the

average direction of current flow reverses for about

Figure 11-6 shows electrical connections between the

0.01 second, flowing from the ventricular apex toward

patient’s limbs and the electrocardiograph for record-

the base, because the last part of the heart to become

ing electrocardiograms from the so-called standard

depolarized is the outer walls of the ventricles near the

bipolar limb leads. The term “bipolar” means that the

base of the heart.

electrocardiogram is recorded from two electrodes

128

Unit III

The Heart

located on different sides of the heart, in this case, on

Now, note that the sum of the voltages in leads I and

the limbs. Thus, a “lead” is not a single wire connect-

III equals the voltage in lead II; that is,

0.5 plus

ing from the body but a combination of two wires and

0.7 equals 1.2. Mathematically, this principle, called

their electrodes to make a complete circuit between

Einthoven’s law, holds true at any given instant while

the body and the electrocardiograph. The electrocar-

the three “standard” bipolar electrocardiograms are

diograph in each instance is represented by an elec-

being recorded.

trical meter in the diagram, although the actual

electrocardiograph is a high-speed recording meter

Normal Electrocardiograms Recorded from the Three Standard

with a moving paper.

Bipolar Limb Leads. Figure 11-7 shows recordings of the

electrocardiograms in leads I, II, and III. It is obvious

Lead I. In recording limb lead I, the negative terminal

that the electrocardiograms in these three leads are

of the electrocardiograph is connected to the right arm

similar to one another because they all record positive

and the positive terminal to the left arm. Therefore,

P waves and positive T waves, and the major portion

when the point where the right arm connects to the

of the QRS complex is also positive in each

chest is electronegative with respect to the point where

electrocardiogram.

the left arm connects, the electrocardiograph records

On analysis of the three electrocardiograms, it can

positively, that is, above the zero voltage line in the

be shown, with careful measurements and proper

electrocardiogram. When the opposite is true, the elec-

observance of polarities, that at any given instant the

trocardiograph records below the line.

sum of the potentials in leads I and III equals the

potential in lead II, thus illustrating the validity of

Lead II. To record limb lead II, the negative terminal of

Einthoven’s law.

the electrocardiograph is connected to the right arm and

Because the recordings from all the bipolar limb

the positive terminal to the left leg. Therefore, when the

leads are similar to one another, it does not matter

right arm is negative with respect to the left leg, the

greatly which lead is recorded when one wants to

electrocardiograph records positively.

diagnose different cardiac arrhythmias, because diag-

nosis of arrhythmias depends mainly on the time

Lead III. To record limb lead III, the negative terminal

relations between the different waves of the cardiac

of the electrocardiograph is connected to the left arm

cycle. But when one wants to diagnose damage in

and the positive terminal to the left leg. This means that

the ventricular or atrial muscle or in the Purkinje

the electrocardiograph records positively when the left

conducting system, it does matter greatly which leads

arm is negative with respect to the left leg.

are recorded, because abnormalities of cardiac

muscle contraction or cardiac impulse conduction do

Einthoven’s Triangle. In Figure 11-6, the triangle, called

Einthoven’s triangle, is drawn around the area of the

heart. This illustrates that the two arms and the left leg

form apices of a triangle surrounding the heart. The

two apices at the upper part of the triangle represent

the points at which the two arms connect electrically

with the fluids around the heart, and the lower apex is

the point at which the left leg connects with the fluids.

Einthoven’s Law. Einthoven’s law states that if the

electrical potentials of any two of the three bipolar

limb electrocardiographic leads are known at any

given instant, the third one can be determined

mathematically by simply summing the first two (but

note that the positive and negative signs of the

different leads must be observed when making this

summation).

For instance, let us assume that momentarily, as

noted in Figure 11-6, the right arm is -0.2 millivolt

(negative) with respect to the average potential in

the body, the left arm is + 0.3 millivolt (positive), and

III

the left leg is +1.0 millivolt (positive). Observing the

meters in the figure, it can be seen that lead I records

a positive potential of +0.5 millivolt, because this is the

difference between the -0.2 millivolt on the right arm

and the +0.3 millivolt on the left arm. Similarly, lead

III records a positive potential of +0.7 millivolt, and

Figure 11-7

lead II records a positive potential of +1.2 millivolts

because these are the instantaneous potential differ-

Normal electrocardiograms

recorded

from

the

three

standard

ences between the respective pairs of limbs.

electrocardiographic leads.

Chapter 11

The Normal Electrocardiogram

129

3456

V₁

V₂

V₃

V₄

V₅

V₆

5000

ohms

Figure 11-9

5000

ohms

Normal electrocardiograms recorded from the six standard chest

leads.

5000

ohms

aVR

aVL

aVF

Figure 11-8

Connections of the body with the electrocardiograph for record-

ing chest leads. LA, left arm; RA, right arm.

Figure 11-10

Normal electrocardiograms recorded from the three augmented

change the patterns of the electrocardiograms

unipolar limb leads.

markedly in some leads yet may not affect other leads.

Electrocardiographic interpretation of these two

types of conditions—cardiac myopathies and cardiac

electrical potential of the cardiac musculature imme-

arrhythmias—is discussed separately in Chapters 12

diately beneath the electrode. Therefore, relatively

and 13.

minute abnormalities in the ventricles, particularly in

the anterior ventricular wall, can cause marked

changes in the electrocardiograms recorded from indi-

Chest Leads (Precordial Leads)

vidual chest leads.

In leads V₁ and V₂, the QRS recordings of the

Often electrocardiograms are recorded with one elec-

normal heart are mainly negative because, as shown in

trode placed on the anterior surface of the chest

Figure 11-8, the chest electrode in these leads is nearer

directly over the heart at one of the points shown in

to the base of the heart than to the apex, and the base

Figure 11-8. This electrode is connected to the positive

of the heart is the direction of electronegativity during

terminal of the electrocardiograph, and the negative

most of the ventricular depolarization process. Con-

electrode, called the indifferent electrode, is connected

versely, the QRS complexes in leads V₄, V₅, and V₆ are

through equal electrical resistances to the right arm,

mainly positive because the chest electrode in these

left arm, and left leg all at the same time, as also shown

leads is nearer the heart apex, which is the direction

in the figure. Usually six standard chest leads are

of electropositivity during most of depolarization.

recorded, one at a time, from the anterior chest wall,

the chest electrode being placed sequentially at the six

points shown in the diagram. The different recordings

Augmented Unipolar Limb Leads

are known as leads V₁, V₂, V₃, V₄, V₅, and V₆.

Figure 11-9 illustrates the electrocardiograms of the

Another system of leads in wide use is the augmented

healthy heart as recorded from these six standard

unipolar limb lead. In this type of recording, two of

chest leads. Because the heart surfaces are close

the limbs are connected through electrical resistances

to the chest wall, each chest lead records mainly the

to the negative terminal of the electrocardiograph,

C H A P T E R

Electrocardiographic

Interpretation of Cardiac Muscle

and Coronary Blood Flow

Abnormalities: Vectorial Analysis

From the discussion in Chapter 10 of impulse trans-

mission through the heart, it is obvious that any

change in the pattern of this transmission can cause

abnormal electrical potentials around the heart and,

consequently, alter the shapes of the waves in the

electrocardiogram. For this reason, almost all

serious abnormalities of the heart muscle can be

diagnosed by analyzing the contours of the different

waves in the different electrocardiographic leads.

Principles of Vectorial Analysis

of Electrocardiograms

Use of Vectors to Represent Electrical Potentials

Before it is possible to understand how cardiac abnormalities affect the con-

tours of the electrocardiogram, one must first become thoroughly familiar with

the concept of vectors and vectorial analysis as applied to electrical potentials

in and around the heart.

Several times in Chapter 11 it was pointed out that heart current flows in a

particular direction in the heart at a given instant during the cardiac cycle. A

vector is an arrow that points in the direction of the electrical potential gener-

ated by the current flow, with the arrowhead in the positive direction. Also, by

convention, the length of the arrow is drawn proportional to the voltage of the

potential.

“Resultant” Vector in the Heart at Any Given Instant. Figure 12-1 shows, by the shaded

area and the negative signs, depolarization of the ventricular septum and parts

of the apical endocardial walls of the two ventricles. At this instant of heart exci-

tation, electrical current flows between the depolarized areas inside the heart

and the nondepolarized areas on the outside of the heart, as indicated by the

long elliptical arrows. Some current also flows inside the heart chambers directly

from the depolarized areas toward the still polarized areas. Overall, consider-

ably more current flows downward from the base of the ventricles toward the

apex than in the upward direction. Therefore, the summated vector of the gen-

erated potential at this particular instant, called the instantaneous mean vector,

is represented by the long black arrow drawn through the center of the ventri-

cles in a direction from base toward apex. Furthermore, because the summated

current is considerable in quantity, the potential is large, and the vector is long.

Direction of a Vector Is Denoted in Terms of Degrees

When a vector is exactly horizontal and directed toward the person’s left side,

the vector is said to extend in the direction of 0 degrees, as shown in Figure

131

132

Unit III

The Heart

aVF

- --

III

---

aVR

aVL

---

210∞

-30∞

-----

+++

- -

0∞

+ + + +

aVL

aVR

60∞

III

120∞

90∞

Figure 12-1

Mean vector through the partially depolarized ventricles.

Figure 12-3

Axes of the three bipolar and three unipolar leads.

-90∞

+270∞

through the center of Figure 12-2 in the +59-degree

direction. This means that during most of the depolar-

ization wave, the apex of the heart remains positive

-100∞

with respect to the base of the heart, as discussed later

in the chapter.

180∞

0∞

Axis for Each Standard Bipolar Lead

and Each Unipolar Limb Lead

In Chapter 11, the three standard bipolar and the three

120∞

59∞

unipolar limb leads are described. Each lead is actu-

ally a pair of electrodes connected to the body on

opposite sides of the heart, and the direction from neg-

-90∞

ative electrode to positive electrode is called the “axis”

of the lead. Lead I is recorded from two electrodes

placed respectively on the two arms. Because the elec-

trodes lie exactly in the horizontal direction, with

Figure 12-2

the positive electrode to the left, the axis of lead I is

Vectors drawn to represent potentials for several different hearts,

0 degrees.

and the “axis” of the potential (expressed in degrees) for each

In recording lead II, electrodes are placed on the

heart.

right arm and left leg. The right arm connects to the

torso in the upper right-hand corner and the left leg

connects in the lower left-hand corner. Therefore, the

12-2. From this zero reference point, the scale of

direction of this lead is about +60 degrees.

vectors rotates clockwise: when the vector extends

By similar analysis, it can be seen that lead III has

from above and straight downward, it has a direction

an axis of about +120 degrees; lead aVR, +210 degrees;

of +90 degrees; when it extends from the person’s left

aVF, +90 degrees; and aVL -30 degrees. The directions

to right, it has a direction of +180 degrees; and when

of the axes of all these leads are shown in Figure 12-3,

it extends straight upward, it has a direction of -90 (or

which is known as the hexagonal reference system. The

+270) degrees.

polarities of the electrodes are shown by the plus and

In a normal heart, the average direction of the

minus signs in the figure. The reader must learn these

vector during spread of the depolarization wave

axes and their polarities, particularly for the bipolar

through the ventricles, called the mean QRS vector, is

limb leads I, II, and III, to understand the remainder of

about +59 degrees, which is shown by vector A drawn

this chapter.

Chapter 12

Electrocardiographic Interpretation of Cardiac Muscle and Coronary Blood Flow Abnormalities

133

Vectorial Analysis of Potentials

in the electrocardiogram), and the voltage recorded

will be slight, about -0.3 millivolts. This figure demon-

Recorded in Different Leads

strates that when the vector in the heart is in a direc-

tion almost perpendicular to the axis of the lead, the

Now that we have discussed, first, the conventions for

voltage recorded in the electrocardiogram of this lead

representing potentials across the heart by means of

is very low. Conversely, when the heart vector has

vectors and, second, the axes of the leads, it is possible

almost exactly the same axis as the lead axis, essentially

to use these together to determine the instantaneous

the entire voltage of the vector will be recorded.

potential that will be recorded in the electrocardio-

gram of each lead for a given vector in the heart, as

Vectorial Analysis of Potentials in the Three Standard

follows.

Bipolar Limb Leads. In Figure 12-6, vector A depicts the

Figure 12-4 shows a partially depolarized heart;

vector A represents the instantaneous mean direction

of current flow in the ventricles. In this instance, the

direction of the vector is +55 degrees, and the voltage

of the potential, represented by the length of vector A,

is 2 millivolts. In the diagram below the heart, vector

A is shown again, and a line is drawn to represent the

axis of lead I in the 0-degree direction. To determine

how much of the voltage in vector A will be recorded

in lead I, a line perpendicular to the axis of lead I is

drawn from the tip of vector A to the lead I axis, and

a so-called projected vector (B) is drawn along the lead

I axis. The arrow of this projected vector points toward

- I

the positive end of the lead I axis, which means that

the record momentarily being recorded in the electro-

cardiogram of lead I is positive. And the instantaneous

recorded voltage will be equal to the length of B

divided by the length of A times 2 millivolts, or about

1 millivolt.

Figure 12-5 shows another example of vectorial

analysis. In this example, vector A represents the elec-

Figure 12-5

trical potential and its axis at a given instant during

Determination of the projected vector B along the axis of lead I

ventricular depolarization in a heart in which the left

when vector A represents the instantaneous potential in the

side of the heart depolarizes more rapidly than the

ventricles.

right. In this instance, the instantaneous vector has a

direction of 100 degrees, and its voltage is again 2 mil-

livolts. To determine the potential actually recorded in

lead I, we draw a perpendicular line from the tip of

vector A to the lead I axis and find projected vector B.

Vector B is very short and this time in the negative

direction, indicating that at this particular instant, the

III

recording in lead I will be negative (below the zero line

- I

III

Figure 12-4

Figure 12-6

Determination of a projected vector B along the axis of lead I when

Determination of projected vectors in leads I, II, and III when

vector A represents the instantaneous potential in the ventricles.

134

Unit III

The Heart

instantaneous electrical potential of a partially depo-

understood. Each of these analyses should be studied

larized heart. To determine the potential recorded at

in detail by the procedure given here. A short

this instant in the electrocardiogram for each one of

summary of this sequence follows.

the three standard bipolar limb leads, perpendicular

In Figure 12-7A, the ventricular muscle has just

lines

(the dashed lines) are drawn from the tip of

begun to be depolarized, representing an instant about

vector A to the three lines representing the axes of the

0.01 second after the onset of depolarization. At this

three different standard leads, as shown in the figure.

time, the vector is short because only a small portion

The projected vector B depicts the potential recorded

of the ventricles—the septum—is depolarized. There-

at that instant in lead I, projected vector C depicts the

fore, all electrocardiographic voltages are low, as

potential in lead II, and projected vector D depicts the

recorded to the right of the ventricular muscle for each

potential in lead III. In each of these, the record in

of the leads. The voltage in lead II is greater than the

the electrocardiogram is positive—that is, above the

voltages in leads I and III because the heart vector

zero line—because the projected vectors point in the

extends mainly in the same direction as the axis of lead

positive directions along the axes of all the leads.

II.

The potential in lead I (vector B) is about one half that

In Figure 12-7B, which represents about 0.02 second

of the actual potential in the heart (vector A); in lead

after onset of depolarization, the heart vector is long

II (vector C), it is almost equal to that in the heart; and

because much of the ventricular muscle mass has

in lead III (vector D), it is about one third that in the

become depolarized. Therefore, the voltages in all

heart.

electrocardiographic leads have increased.

An identical analysis can be used to determine

In Figure 12-7C, about 0.035 second after onset of

potentials recorded in augmented limb leads, except

depolarization, the heart vector is becoming shorter

that the respective axes of the augmented leads (see

and the recorded electrocardiographic voltages are

Figure 12-3) are used in place of the standard bipolar

lower because the outside of the heart apex is now

limb lead axes used for Figure 12-6.

electronegative, neutralizing much of the positivity on

the other epicardial surfaces of the heart. Also, the axis

of the vector is beginning to shift toward the left side

Vectorial Analysis of the

of the chest because the left ventricle is slightly slower

to depolarize than the right. Therefore, the ratio of the

Normal Electrocardiogram

voltage in lead I to that in lead III is increasing.

In Figure 12-7D, about 0.05 second after onset of

Vectors That Occur at Successive

depolarization, the heart vector points toward the base

Intervals During Depolarization of the

of the left ventricle, and it is short because only a

Ventricles—The QRS Complex

minute portion of the ventricular muscle is still polar-

ized positive. Because of the direction of the vector at

When the cardiac impulse enters the ventricles

this time, the voltages recorded in leads II and III are

through the atrioventricular bundle, the first part of

both negative—that is, below the line—whereas the

the ventricles to become depolarized is the left endo-

voltage of lead I is still positive.

cardial surface of the septum. Then depolarization

In Figure 12-7E, about 0.06 second after onset of

spreads rapidly to involve both endocardial surfaces of

depolarization, the entire ventricular muscle mass is

the septum, as demonstrated by the shaded portion

depolarized, so that no current flows around the heart

of the ventricle in Figure 12-7A. Next, depolarization

and no electrical potential is generated. The vector

spreads along the endocardial surfaces of the remain-

becomes zero, and the voltages in all leads become

der of the two ventricles, as shown in Figure 12-7B and

zero.

C. Finally, it spreads through the ventricular muscle to

Thus, the QRS complexes are completed in the

the outside of the heart, as shown progressively in

three standard bipolar limb leads.

Figure 12-7C, D, and E.

Sometimes the QRS complex has a slight negative

At each stage in Figure 12-7, parts A to E, the

depression at its beginning in one or more of the leads,

instantaneous mean electrical potential of the ventri-

which is not shown in Figure 12-7; this depression is

cles is represented by a red vector superimposed on

the Q wave. When it occurs, it is caused by initial depo-

the ventricle in each figure. Each of these vectors is

larization of the left side of the septum before the right

then analyzed by the method described in the preced-

side, which creates a weak vector from left to right for

ing section to determine the voltages that will be

a fraction of a second before the usual base-to-apex

recorded at each instant in each of the three standard

vector occurs. The major positive deflection shown in

electrocardiographic leads. To the right in each figure

Figure 12-7 is the R wave, and the final negative

is shown progressive development of the electrocar-

deflection is the S wave.

diographic QRS complex. Keep in mind that a positive

vector in a lead will cause recording in the electrocar-

diogram above the zero line, whereas a negative vector

Electrocardiogram During

will cause recording below the zero line.

Repolarization—The T Wave

Before proceeding with further consideration of

vectorial analysis, it is essential that this analysis of the

After the ventricular muscle has become depolarized,

successive normal vectors presented in Figure 12-7 be

about 0.15 second later, repolarization begins and

Chapter 12

Electrocardiographic Interpretation of Cardiac Muscle and Coronary Blood Flow Abnormalities

135

−

III

−

III

−

III

−

III

−

III

−

III

Figure 12-7

Shaded areas of the ventricles are depolarized (-); nonshaded areas are still polarized (+). The ventricular vectors and QRS complexes

0.01 second after onset of ventricular depolarization (A); 0.02 second after onset of depolarization (B); 0.035 second after onset of

depolarization (C); 0.05 second after onset of depolarization (D); and after depolarization of the ventricles is complete, 0.06 second after

onset (E).

proceeds until complete at about 0.35 second.This repo-

flow to the endocardium, thereby slowing repolariza-

larization causes the T wave in the electrocardiogram.

tion in the endocardial areas.

Because the septum and endocardial areas of the

Because the outer apical surfaces of the ventricles

ventricular muscle depolarize first, it seems logical that

repolarize before the inner surfaces, the positive end

these areas should repolarize first as well. However,

of the overall ventricular vector during repolarization

this is not the usual case because the septum and other

is toward the apex of the heart. As a result, the normal

endocardial areas have a longer period of contraction

T wave in all three bipolar limb leads is positive, which

than most of the external surfaces of the heart. There-

is also the polarity of most of the normal QRS complex.

fore, the greatest portion of ventricular muscle mass to

In Figure 12-8, five stages of repolarization of the

repolarize first is the entire outer surface of the ventri-

ventricles are denoted by progressive increase of the

cles, especially near the apex of the heart. The endocar-

white areas—the repolarized areas. At each stage,

dial areas, conversely, normally repolarize last. This

the vector extends from the base of the heart toward

sequence of repolarization is postulated to be caused

the apex until it disappears in the last stage. At

by the high blood pressure inside the ventricles during

first, the vector is relatively small because the area of

contraction, which greatly reduces coronary blood

repolarization is small. Later, the vector becomes

136

Unit III

The Heart

P T

---

III

+ +

III

Figure 12-9

III

Depolarization of the atria and generation of the P wave, showing

the maximum vector through the atria and the resultant vectors in

Figure 12-8

the three standard leads. At the right are the atrial P and T waves.

SA, sinoatrial node.

Generation of the T wave during repolarization of the ventricles,

showing also vectorial analysis of the first stage of repolarization.

The total time from the beginning of the T wave to its end is

approximately 0.15 second.

Repolarization of the Atria—The Atrial T Wave. Spread of

depolarization through the atrial muscle is much

slower than in the ventricles because the atria have no

Purkinje system for fast conduction of the depolariza-

stronger because of greater degrees of repolarization.

tion signal. Therefore, the musculature around the

Finally, the vector becomes weaker again because the

sinus node becomes depolarized a long time before the

areas of depolarization still persisting become so slight

musculature in distal parts of the atria. Because of this,

that the total quantity of current flow decreases. These

the area in the atria that also becomes repolarized first

changes also demonstrate that the vector is greatest

is the sinus nodal region, the area that had originally

when about half the heart is in the polarized state and

become depolarized first. Thus, when repolarization

about half is depolarized.

begins, the region around the sinus node becomes pos-

The changes in the electrocardiograms of the three

itive with respect to the rest of the atria. Therefore, the

standard limb leads during repolarization are noted

atrial repolarization vector is backward to the vector of

under each of the ventricles, depicting the progressive

depolarization. (Note that this is opposite to the effect

stages of repolarization. Thus, over about 0.15 second,

that occurs in the ventricles.) Therefore, as shown to

the period of time required for the whole process to

the right in Figure 12-9, the so-called atrial T wave

take place, the T wave of the electrocardiogram is

follows about 0.15 second after the atrial P wave, but

generated.

this T wave is on the opposite side of the zero refer-

ence line from the P wave; that is, it is normally nega-

tive rather than positive in the three standard bipolar

Depolarization of the Atria—

limb leads.

The P Wave

In the normal electrocardiogram, the atrial T wave

appears at about the same time that the QRS complex

Depolarization of the atria begins in the sinus node

of the ventricles appears. Therefore, it is almost always

and spreads in all directions over the atria. Therefore,

totally obscured by the large ventricular QRS

the point of original electronegativity in the atria is

complex, although in some very abnormal states, it

about at the point of entry of the superior vena cava

does appear in the recorded electrocardiogram.

where the sinus node lies, and the direction of initial

depolarization is denoted by the black vector in Figure

12-9. Furthermore, the vector remains generally in this

Vectorcardiogram

direction throughout the process of normal atrial

depolarization. Because this direction is generally

It has been noted in the discussion up to this point that

in the positive directions of the axes of the three

the vector of current flow through the heart changes

standard bipolar limb leads I, II, and III, the electro-

rapidly as the impulse spreads through the

cardiograms recorded from the atria during depolar-

myocardium. It changes in two aspects: First, the

ization are also usually positive in all three of these

vector increases and decreases in length because of

leads, as shown in Figure 12-9. This record of atrial

increasing and decreasing voltage of the vector.

depolarization is known as the atrial P wave.

Second, the vector changes direction because of

Chapter 12

Electrocardiographic Interpretation of Cardiac Muscle and Coronary Blood Flow Abnormalities

137

III

-60∞

180∞

0∞

III

120∞

59∞

Depolarization

Repolarization

QRS

III

Figure 12-10

QRS and T vectorcardiograms.

Figure 12-11

Plotting the mean electrical axis of the ventricles from two elec-

trocardiographic leads (leads I and III).

changes in the average direction of the electrical

potential from the heart. The so-called vectorcardio-

Mean Electrical Axis

gram depicts these changes at different times during

of the Ventricular QRS—

the cardiac cycle, as shown in Figure 12-10.

In the large vectorcardiogram of Figure 12-10, point

And Its Significance

5 is the zero reference point, and this point is the neg-

ative end of all the successive vectors. While the heart

The vectorcardiogram during ventricular depolariza-

muscle is polarized between heartbeats, the positive

tion

(the QRS vectorcardiogram) shown in Figure

end of the vector remains at the zero point because

12-10 is that of a normal heart. Note from this vec-

there is no vectorial electrical potential. However,

torcardiogram that the preponderant direction of the

as soon as current begins to flow through the ventri-

vectors of the ventricles during depolarization is

cles at the beginning of ventricular depolarization, the

mainly toward the apex of the heart. That is, during

positive end of the vector leaves the zero reference

most of the cycle of ventricular depolarization, the

point.

direction of the electrical potential (negative to posi-

When the septum first becomes depolarized, the

tive) is from the base of the ventricles toward the apex.

vector extends downward toward the apex of the ven-

This preponderant direction of the potential during

tricles, but it is relatively weak, thus generating the first

depolarization is called the mean electrical axis of the

portion of the ventricular vectorcardiogram, as shown

ventricles. The mean electrical axis of the normal

by the positive end of vector

1. As more of the

ventricles is 59 degrees. In many pathological condi-

ventricular muscle becomes depolarized, the vector

tions of the heart, this direction changes markedly—

becomes stronger and stronger, usually swinging

sometimes even to opposite poles of the heart.

slightly to one side. Thus, vector 2 of Figure 12-10 rep-

resents the state of depolarization of the ventricles

about 0.02 second after vector 1. After another 0.02

Determining the Electrical Axis from

second, vector 3 represents the potential, and vector 4

Standard Lead Electrocardiograms

occurs in another 0.01 second. Finally, the ventricles

become totally depolarized, and the vector becomes

Clinically, the electrical axis of the heart usually is esti-

zero once again, as shown at point 5.

mated from the standard bipolar limb lead electrocar-

The elliptical figure generated by the positive ends

diograms rather than from the vectorcardiogram.

of the vectors is called the QRS vectorcardiogram.

Figure 12-11 shows a method for doing this. After

Vectorcardiograms can be recorded on an oscilloscope

recording the standard leads, one determines the net

by connecting body surface electrodes from the neck

potential and polarity of the recordings in leads I and

and lower abdomen to the vertical plates of the oscil-

III. In lead I of Figure 12-11, the recording is positive,

loscope and connecting chest surface electrodes from

and in lead III, the recording is mainly positive but

each side of the heart to the horizontal plates. When

negative during part of the cycle. If any part of a

the vector changes, the spot of light on the oscilloscope

recording is negative, this negative potential is sub-

follows the course of the positive end of the changing

tracted from the positive part of the potential to deter-

vector, thus inscribing the vectorcardiogram on the

mine the net potential for that lead, as shown by the

oscilloscopic screen.

arrow to the right of the QRS complex for lead III.

138

Unit III

The Heart

Then each net potential for leads I and III is plotted

side of the heart than on the other side, and this allows

on the axes of the respective leads, with the base of the

excess generation of electrical potential on that side.

potential at the point of intersection of the axes, as

Second, more time is required for the depolarization

shown in Figure 12-11.

wave to travel through the hypertrophied ventricle

If the net potential of lead I is positive, it is plotted

than through the normal ventricle. Consequently, the

in a positive direction along the line depicting lead I.

normal ventricle becomes depolarized considerably in

Conversely, if this potential is negative, it is plotted in

advance of the hypertrophied ventricle, and this causes

a negative direction. Also, for lead III, the net poten-

a strong vector from the normal side of the heart

tial is placed with its base at the point of intersection,

toward the hypertrophied side, which remains strongly

and, if positive, it is plotted in the positive direction

positively charged. Thus, the axis deviates toward the

along the line depicting lead III. If it is negative, it is

hypertrophied ventricle.

plotted in the negative direction.

To determine the vector of the total QRS ventricu-

Vectorial Analysis of Left Axis Deviation Resulting from

lar mean electrical potential, one draws perpendicular

Hypertrophy of the Left Ventricle. Figure 12-12 shows

lines (the dashed lines in the figure) from the apices of

the three standard bipolar limb lead electrocardio-

leads I and III, respectively. The point of intersection

grams. Vectorial analysis demonstrates left axis devia-

of these two perpendicular lines represents, by vecto-

tion with mean electrical axis pointing in the

rial analysis, the apex of the mean QRS vector in the

-15-degree direction. This is a typical electrocardio-

ventricles, and the point of intersection of the lead I

gram caused by increased muscle mass of the left ven-

and lead III axes represents the negative end of the

tricle. In this instance, the axis deviation was caused by

mean vector. Therefore, the mean QRS vector is drawn

hypertension

(high arterial blood pressure), which

between these two points. The approximate average

caused the left ventricle to hypertrophy so that it could

potential generated by the ventricles during depolar-

pump blood against elevated systemic arterial pres-

ization is represented by the length of this mean QRS

sure. A similar picture of left axis deviation occurs

vector, and the mean electrical axis is represented by

when the left ventricle hypertrophies as a result of

the direction of the mean vector. Thus, the orientation

aortic valvular stenosis, aortic valvular regurgitation, or

of the mean electrical axis of the normal ventricles,

any number of congenital heart conditions in which the

as determined in Figure 12-11, is 59 degrees positive

left ventricle enlarges while the right ventricle remains

(+59 degrees).

relatively normal in size.

Vectorial Analysis of Right Axis Deviation Resulting

Abnormal Ventricular Conditions That

from Hypertrophy of the Right Ventricle. The electro-

Cause Axis Deviation

cardiogram of Figure 12-13 shows intense right axis

deviation, to an electrical axis of 170 degrees, which is

Although the mean electrical axis of the ventricles

averages about 59 degrees, this axis can swing even

in the normal heart from about 20 degrees to about

100 degrees. The causes of the normal variations are

mainly anatomical differences in the Purkinje distri-

bution system or in the musculature itself of different

hearts. However, a number of abnormal conditions of

the heart can cause axis deviation beyond the normal

limits, as follows.

Change in the Position of the Heart in the Chest. If the heart

III

itself is angulated to the left, the mean electrical axis

III

of the heart also shifts to the left. Such shift occurs (1)

at the end of deep expiration, (2) when a person lies

down, because the abdominal contents press upward

against the diaphragm, and (3) quite frequently in

stocky, fat people whose diaphragms normally press

upward against the heart all the time.

Likewise, angulation of the heart to the right causes

the mean electrical axis of the ventricles to shift to the

right. This occurs (1) at the end of deep inspiration,

(2) when a person stands up, and (3) normally in tall,

III

lanky people whose hearts hang downward.

Hypertrophy of One Ventricle. When one ventricle greatly

Figure 12-12

hypertrophies, the axis of the heart shifts toward the

hypertrophied ventricle for two reasons. First, a far

Left axis deviation in a hypertensive heart (hypertrophic left ven-

greater quantity of muscle exists on the hypertrophied

tricle). Note the slightly prolonged QRS complex as well.

Chapter 12

Electrocardiographic Interpretation of Cardiac Muscle and Coronary Blood Flow Abnormalities

139

III

Figure 12-14

Left axis deviation caused by left bundle branch block. Note also

Figure 12-13

the greatly prolonged QRS complex.

High-voltage electrocardiogram in congenital pulmonary valve

stenosis with right ventricular hypertrophy. Intense right axis devi-

blocked, cardiac depolarization spreads through the

ation and a slightly prolonged QRS complex also are seen.

right ventricle two to three times as rapidly as through

the left ventricle. Consequently, much of the left ven-

111 degrees to the right of the normal 59-degree mean

tricle remains polarized for as long as 0.1 second after

ventricular QRS axis. The right axis deviation demon-

the right ventricle has become totally depolarized.

strated in this figure was caused by hypertrophy of the

Thus, the right ventricle becomes electronegative,

right ventricle as a result of congenital pulmonary

whereas the left ventricle remains electropositive

valve stenosis. Right axis deviation also can occur in

during most of the depolarization process, and a strong

other congenital heart conditions that cause hypertro-

vector projects from the right ventricle toward the left

phy of the right ventricle, such as tetralogy of Fallot and

ventricle. In other words, there is intense left axis devi-

interventricular septal defect.

ation of about -50 degrees because the positive end of

the vector points toward the left ventricle. This is

Bundle Branch Block Causes Axis Deviation. Ordinarily, the

demonstrated in Figure 12-14, which shows typical left

lateral walls of the two ventricles depolarize at almost

axis deviation resulting from left bundle branch block.

the same instant because both the left and the right

Because of slowness of impulse conduction when

bundle branches of the Purkinje system transmit the

the Purkinje system is blocked, in addition to axis devi-

cardiac impulse to the two ventricular walls at almost

ation, the duration of the QRS complex is greatly pro-

the same instant. As a result, the potentials generated

longed because of extreme slowness of depolarization

by the two ventricles (on the two opposite sides of the

in the affected side of the heart. One can see this by

heart) almost neutralize each other. But if only one of

observing the excessive widths of the QRS waves in

the major bundle branches is blocked, the cardiac

Figure 12-14. This is discussed in greater detail later in

impulse spreads through the normal ventricle long

the chapter. This extremely prolonged QRS complex

before it spreads through the other. Therefore, depo-

differentiates bundle branch block from axis deviation

larization of the two ventricles does not occur even

caused by hypertrophy.

nearly simultaneously, and the depolarization poten-

tials do not neutralize each other. As a result, axis devi-

Vectorial Analysis of Right Axis Deviation in Right

ation occurs as follows.

Bundle Branch Block. When the right bundle branch

is blocked, the left ventricle depolarizes far more

Vectorial Analysis of Left Axis Deviation in Left Bundle

rapidly than the right ventricle, so that the left side of

Branch Block. When the left bundle branch is

the ventricles becomes electronegative as long as

140

Unit III

The Heart

0.1 second before the right. Therefore, a strong vector

the electrical potentials recorded in the electrocardio-

develops, with its negative end toward the left ventri-

graphic leads are considerably greater than normal, as

cle and its positive end toward the right ventricle. In

shown in Figures 12-12 and 12-13.

other words, intense right axis deviation occurs. Right

axis deviation caused by right bundle branch block is

demonstrated, and its vector is analyzed, in Figure

Decreased Voltage of the

12-15, which shows an axis of about 105 degrees

Electrocardiogram

instead of the normal 59 degrees and a prolonged QRS

complex because of slow conduction.

Decreased Voltage Caused by Cardiac Myopathies. One of

the most common causes of decreased voltage of the

QRS complex is a series of old myocardial artery

Conditions That Cause

infarctions with resultant diminished muscle mass. This

Abnormal Voltages of the QRS

also causes the depolarization wave to move through

the ventricles slowly and prevents major portions of

Complex

the heart from becoming massively depolarized all at

once. Consequently, this condition causes some pro-

Increased Voltage in the Standard

longation of the QRS complex along with the

Bipolar Limb Leads

decreased voltage. Figure 12-16 shows a typical low-

voltage electrocardiogram with prolongation of the

Normally, the voltages in the three standard bipolar

QRS complex, which is common after multiple small

limb leads, as measured from the peak of the R wave

infarctions of the heart have caused local delays of

to the bottom of the S wave, vary between 0.5 and 2.0

impulse conduction and reduced voltages due to loss

millivolts, with lead III usually recording the lowest

of muscle mass throughout the ventricles.

voltage and lead II the highest. However, these rela-

tions are not invariable, even for the normal heart. In

Decreased Voltage Caused by Conditions Surrounding the

general, when the sum of the voltages of all the QRS

Heart. One of the most important causes of decreased

complexes of the three standard leads is greater than

voltage in electrocardiographic leads is fluid in the

4 millivolts, the patient is considered to have a high-

pericardium. Because extracellular fluid conducts elec-

voltage electrocardiogram.

trical currents with great ease, a large portion of the

The cause of high-voltage QRS complexes most

electricity flowing out of the heart is conducted from

often is increased muscle mass of the heart, which

one part of the heart to another through the pericar-

ordinarily results from hypertrophy of the muscle in

dial fluid. Thus, this effusion effectively “short-circuits”

response to excessive load on one part of the heart or

the electrical potentials generated by the heart,

the other. For example, the right ventricle hypertro-

decreasing the electrocardiographic voltages that

phies when it must pump blood through a stenotic pul-

reach the outside surfaces of the body. Pleural effu-

monary valve, and the left ventricle hypertrophies

sion, to a lesser extent, also can “short-circuit” the

when a person has high blood pressure. The increased

electricity around the heart, so that the voltages at the

quantity of muscle causes generation of increased

quantities of electricity around the heart. As a result,

III

I-

III

Figure 12-15

Figure 12-16

Right axis deviation caused by right bundle branch block. Note

Low-voltage electrocardiogram following local damage through-

also the greatly prolonged QRS complex.

out the ventricles caused by previous myocardial infarction.

Chapter 12

Electrocardiographic Interpretation of Cardiac Muscle and Coronary Blood Flow Abnormalities

141

surface of the body and in the electrocardiograms are

ventricular system, with replacement of this muscle by

decreased.

scar tissue, and (2) multiple small local blocks in the

Pulmonary emphysema can decrease the electrocar-

conduction of impulses at many points in the Purkinje

diographic potentials, but by a different method from

system. As a result, cardiac impulse conduction

that of pericardial effusion. In pulmonary emphysema,

becomes irregular, causing rapid shifts in voltages and

conduction of electrical current through the lungs is

axis deviations. This often causes double or even triple

depressed considerably because of excessive quantity

peaks in some of the electrocardiographic leads, such

of air in the lungs. Also, the chest cavity enlarges, and

as those shown in Figure 12-14.

the lungs tend to envelop the heart to a greater extent

than normally. Therefore, the lungs act as an insulator

to prevent spread of electrical voltage from the heart

Current of Injury

to the surface of the body, and this results in decreased

electrocardiographic potentials in the various leads.

Many different cardiac abnormalities, especially those

that damage the heart muscle itself, often cause part

of the heart to remain partially or totally depolarized

all the time. When this occurs, current flows between

Prolonged and Bizarre

the pathologically depolarized and the normally polar-

Patterns of the QRS Complex

ized areas even between heartbeats. This is called a

current of injury. Note especially that the injured part

Prolonged QRS Complex as a Result

of the heart is negative, because this is the part that is

of Cardiac Hypertrophy or Dilatation

depolarized and emits negative charges into the sur-

rounding fluids, whereas the remainder of the heart is

The QRS complex lasts as long as depolarization con-

neutral or positive polarity.

tinues to spread through the ventricles—that is, as long

Some abnormalities that can cause current of injury

as part of the ventricles is depolarized and part is

are (1) mechanical trauma, which sometimes makes

still polarized. Therefore, prolonged conduction of the

the membranes remain so permeable that full repo-

impulse through the ventricles always causes a pro-

larization cannot take place; (2) infectious processes

longed QRS complex. Such prolongation often occurs

that damage the muscle membranes; and (3) ischemia

when one or both ventricles are hypertrophied or

of local areas of heart muscle caused by local coronary

dilated, owing to the longer pathway that the impulse

occlusions, which is by far the most common cause of

must then travel. The normal QRS complex lasts 0.06

current of injury in the heart. During ischemia, not

to 0.08 second, whereas in hypertrophy or dilatation of

enough nutrients from the coronary blood supply are

the left or right ventricle, the QRS complex may be

available to the heart muscle to maintain normal mem-

prolonged to 0.09 to 0.12 second.

brane polarization.

Prolonged QRS Complex Resulting

Effect of Current of Injury on the

from Purkinje System Blocks

QRS Complex

When the Purkinje fibers are blocked, the cardiac

In Figure 12-17, a small area in the base of the left ven-

impulse must then be conducted by the ventricular

tricle is newly infarcted (loss of coronary blood flow).

muscle instead of by way of the Purkinje system. This

Therefore, during the T-P interval—that is, when the

decreases the velocity of impulse conduction to about

normal ventricular muscle is totally polarized—abnor-

one third of normal. Therefore, if complete block of

mal negative current still flows from the infarcted area

one of the bundle branches occurs, the duration of the

at the base of the left ventricle and spreads toward the

QRS complex usually is increased to 0.14 second or

rest of the ventricles. The vector of this “current of

greater.

injury,” as shown in the first heart in the figure, is in a

In general, a QRS complex is considered to be

direction of about 125 degrees, with the base of the

abnormally long when it lasts more than 0.09 second;

vector, the negative end, toward the injured muscle. As

when it lasts more than 0.12 second, the prolongation

shown in the lower portions of the figure, even before

is almost certainly caused by pathological block some-

the QRS complex begins, this vector causes an initial

where in the ventricular conduction system, as shown

record in lead I below the zero potential line, because

by the electrocardiograms for bundle branch block in

the projected vector of the current of injury in lead I

Figures 12-14 and 12-15.

points toward the negative end of the lead I axis. In

lead II, the record is above the line because the pro-

jected vector points more toward the positive terminal

Conditions That Cause Bizarre QRS

of the lead. In lead III, the projected vector points in

Complexes

the same direction as the positive terminal of lead III,

so that the record is positive. Furthermore, because the

Bizarre patterns of the QRS complex most frequently

vector lies almost exactly in the direction of the axis

are caused by two conditions:

(1) destruction of

of lead III, the voltage of the current of injury in lead

cardiac muscle in various areas throughout the

III is much greater than in either lead I or lead II.

142

Unit III

The Heart

Injured area

III

Current

of injury

III

Figure 12-17

Effect of a current of injury on

the electrocardiogram.

As the heart then proceeds through its normal

heart. However, many stray currents exist in the body,

process of depolarization, the septum first becomes

such as currents resulting from “skin potentials” and

depolarized; then the depolarization spreads down to

from differences in ionic concentrations in different

the apex and back toward the bases of the ventricles.

fluids of the body. Therefore, when two electrodes are

The last portion of the ventricles to become totally

connected between the arms or between an arm and a

depolarized is the base of the right ventricle, because

leg, these stray currents make it impossible for one to

the base of the left ventricle is already totally and per-

predetermine the exact zero reference level in the

manently depolarized. By vectorial analysis, the suc-

electrocardiogram. For these reasons, the following

cessive stages of electrocardiogram generation by the

procedure must be used to determine the zero poten-

depolarization wave traveling through the ventricles

tial level: First, one notes the exact point at which the

can be constructed graphically, as demonstrated in the

wave of depolarization just completes its passage

lower part of Figure 12-17.

through the heart, which occurs at the end of the QRS

When the heart becomes totally depolarized, at the

complex. At exactly this point, all parts of the ventri-

end of the depolarization process (as noted by the

cles have become depolarized, including both the

next-to-last stage in Figure 12-17), all the ventricular

damaged parts and the normal parts, so that no current

muscle is in a negative state. Therefore, at this instant

is flowing around the heart. Even the current of injury

in the electrocardiogram, no current flows from the

disappears at this point. Therefore, the potential of the

ventricles to the electrocardiographic electrodes

electrocardiogram at this instant is at zero voltage. This

because now both the injured heart muscle and the

point is known as the “J point” in the electrocardio-

contracting muscle are depolarized.

gram, as shown in Figure 12-18.

Next, as repolarization takes place, all of the heart

Then, for analysis of the electrical axis of the injury

finally repolarizes, except the area of permanent depo-

potential caused by a current of injury, a horizontal

larization in the injured base of the left ventricle. Thus,

line is drawn in the electrocardiogram for each lead at

repolarization causes a return of the current of injury

the level of the J point. This horizontal line is then the

in each lead, as noted at the far right in Figure 12-17.

zero potential level in the electrocardiogram from

which all potentials caused by currents of injury must

be measured.

The J Point—The Zero Reference

Use of the J Point in Plotting Axis of Injury Potential. Figure

Potential for Analyzing Current

12-18 shows electrocardiograms (leads I and III) from

of Injury

an injured heart. Both records show injury potentials.

In other words, the J point of each of these two elec-

One would think that the electrocardiograph

trocardiograms is not on the same line as the T-P

machines for recording electrocardiograms could

segment. In the figure, a horizontal line has been

determine when no current is flowing around the

drawn through the J point to represent the zero

Chapter 12

Electrocardiographic Interpretation of Cardiac Muscle and Coronary Blood Flow Abnormalities

143

voltage level in each of the two recordings. The injury

Coronary Ischemia as a Cause

potential in each lead is the difference between the

of Injury Potential

voltage of the electrocardiogram immediately before

onset of the P wave and the zero voltage level deter-

Insufficient blood flow to the cardiac muscle depresses

mined from the J point. In lead I, the recorded voltage

the metabolism of the muscle for three reasons: (1)

of the injury potential is above the zero potential level

lack of oxygen, (2) excess accumulation of carbon

and is, therefore, positive. Conversely, in lead III, the

dioxide, and

(3) lack of sufficient food nutrients.

injury potential is below the zero voltage level and,

Consequently, repolarization of the muscle membrane

therefore, is negative.

cannot occur in areas of severe myocardial ischemia.

At the bottom in Figure 12-18, the respective injury

Often the heart muscle does not die because the blood

potentials in leads I and III are plotted on the coordi-

flow is sufficient to maintain life of the muscle even

nates of these leads, and the resultant vector of the

though it is not sufficient to cause repolarization of the

injury potential for the whole ventricular muscle mass

membranes. As long as this state exists, an injury

is determined by vectorial analysis as described. In this

potential continues to flow during the diastolic portion

instance, the resultant vector extends from the right

(the T-P portion) of each heart cycle.

side of the ventricles toward the left and slightly

Extreme ischemia of the cardiac muscle occurs after

upward, with an axis of about -30 degrees. If one

coronary occlusion, and a strong current of injury

places this vector for the injury potential directly over

flows from the infarcted area of the ventricles during

the ventricles, the negative end of the vector points

the T-P interval between heartbeats, as shown in

toward the permanently depolarized, “injured” area of

Figures 12-19 and 12-20. Therefore, one of the most

the ventricles. In the example shown in Figure 12-18,

important diagnostic features of electrocardiograms

the injured area would be in the lateral wall of the

recorded after acute coronary thrombosis is the

right ventricle.

current of injury.

This analysis is obviously complex. However, it is

essential that the student go over it again and

Acute Anterior Wall Infarction. Figure

12-19 shows the

again until he or she understands it thoroughly. No

electrocardiogram in the three standard bipolar limb

other aspect of electrocardiographic analysis is more

important.

“J” point

III

I -

III

V₂

Figure 12-18

Figure 12-19

J point as the zero reference potential of the electrocardiograms

for leads I and II. Also, the method for plotting the axis of the injury

Current of injury in acute anterior wall infarction. Note the intense

potential is shown by the lowermost panel.

injury potential in lead V₂.

144

Unit III

The Heart

leads and in one chest lead (lead V₂) recorded from a

also in the chest lead. If a zero potential reference line

patient with acute anterior wall cardiac infarction. The

is drawn through the J point of this lead, it is readily

most important diagnostic feature of this electrocar-

apparent that during the T-P interval, the potential of

diogram is the intense injury potential in chest lead V₂.

the current of injury is positive. This means that the

If one draws a zero horizontal potential line through

positive end of the vector is in the direction of the

the J point of this electrocardiogram, a strong negative

anterior chest wall, and the negative end (injured end

injury potential during the T-P interval is found, which

of the vector) points away from the chest wall. In other

means that the chest electrode over the front of the

words, the current of injury is coming from the back

heart is in an area of strongly negative potential. In

of the heart opposite to the anterior chest wall, which

other words, the negative end of the injury potential

is the reason this type of electrocardiogram is the basis

vector in this heart is against the anterior chest wall.

for diagnosing posterior wall infarction.

This means that the current of injury is emanating

If one analyzes the injury potentials from leads II

from the anterior wall of the ventricles, which diag-

and III of Figure 12-20, it is readily apparent that the

noses this condition as anterior wall infarction.

injury potential is negative in both leads. By vectorial

Analyzing the injury potentials in leads I and III,

analysis, as shown in the figure, one finds that the

one finds a negative potential in lead I and a positive

resultant vector of the injury potential is about -95

potential in lead III. This means that the resultant

degrees, with the negative end pointing downward and

vector of the injury potential in the heart is about +150

the positive end pointing upward. Thus, because the

degrees, with the negative end pointing toward the left

infarct, as indicated by the chest lead, is on the poste-

ventricle and the positive end pointing toward the

rior wall of the heart and, as indicated by the injury

right ventricle. Thus, in this particular electrocardio-

potentials in leads II and III, is in the apical portion of

gram, the current of injury is coming mainly from the

the heart, one would suspect that this infarct is near

left ventricle as well as from the anterior wall of the

the apex on the posterior wall of the left ventricle.

heart. Therefore, one would conclude that this anterior

wall infarction almost certainly is caused by thrombo-

Infarction in Other Parts of the Heart. By the same proce-

sis of the anterior descending branch of the left coro-

dures demonstrated in the preceding discussions of

nary artery.

anterior and posterior wall infarctions, it is possible to

determine the locus of any infarcted area emitting a

Posterior Wall Infarction. Figure 12-20 shows the three

current of injury, regardless of which part of the heart

standard bipolar limb leads and one chest lead (lead

is involved. In making such vectorial analyses, it must

V₂) from a patient with posterior wall infarction. The

be remembered that the positive end of the injury

major diagnostic feature of this electrocardiogram is

potential vector points toward the normal cardiac

muscle, and the negative end points toward the injured

portion of the heart that is emitting the current of injury.

Recovery from Acute Coronary Thrombosis. Figure

12-21

shows a V₃ chest lead from a patient with acute pos-

terior wall infarction, demonstrating changes in the

electrocardiogram from the day of the attack to 1

III

V₂

III

Same day

1 week

2 weeks

1 year

III

Figure 12-21

Recovery of the myocardium after moderate posterior wall infarc-

Figure 12-20

tion, demonstrating disappearance of the injury potential that is

present on the first day after the infarction and still slightly present

Injury potential in acute posterior wall, apical infarction.

at 1 week.

Chapter 12

Electrocardiographic Interpretation of Cardiac Muscle and Coronary Blood Flow Abnormalities

145

week later, 3 weeks later, and finally 1 year later.

Current of Injury in Angina Pectoris. “Angina pectoris”

From this electrocardiogram, one can see that the

means pain from the heart felt in the pectoral regions

injury potential is strong immediately after the

of the upper chest. This pain usually also radiates into

acute attack (T-P segment displaced positively from

the left neck area and down the left arm. The pain typ-

the S-T segment). However, after about 1 week, the

ically is caused by moderate ischemia of the heart.

injury potential has diminished considerably, and after

Usually, no pain is felt as long as the person is quiet,

3 weeks, it is gone. After that, the electrocardiogram

but as soon as he or she overworks the heart, the pain

does not change greatly during the next year. This

appears.

is the usual recovery pattern after acute cardiac

An injury potential sometimes appears in the elec-

infarction of moderate degree, showing that the new

trocardiogram during an attack of severe angina pec-

collateral coronary blood flow develops enough

toris, because the coronary insufficiency becomes great

to re-establish appropriate nutrition to most of the

enough to prevent adequate repolarization of some

infarcted area.

areas of the heart during diastole.

Conversely, in some patients with coronary infarc-

tion, the infarcted area never redevelops adequate

coronary blood supply. Often, some of the heart

Abnormalities in the T Wave

muscle dies, but if the muscle does not die, it will con-

tinue to show an injury potential as long as the

Earlier in the chapter, it was pointed out that the T

ischemia exists, particularly during bouts of exercise

wave is normally positive in all the standard bipolar

when the heart is overloaded.

limb leads and that this is caused by repolarization of

the apex and outer surfaces of the ventricles ahead

Old Recovered Myocardial Infarction. Figure 12-22 shows

of the intraventricular surfaces. That is, the T wave

leads I and III after anterior infarction and leads I and

becomes abnormal when the normal sequence of

III after posterior infarction about 1 year after the

repolarization does not occur. Several factors can

acute heart attack. The records show what might be

change this sequence of repolarization.

called the “ideal” configurations of the QRS complex

in these types of recovered myocardial infarction.

Usually a Q wave has developed at the beginning of

Effect of Slow Conduction of the

the QRS complex in lead I in anterior infarction

Depolarization Wave on the

because of loss of muscle mass in the anterior wall of

Characteristics of the T Wave

the left ventricle, but in posterior infarction, a Q wave

has developed at the beginning of the QRS complex

Referring back to Figure 12-14, note that the QRS

in lead III because of loss of muscle in the posterior

complex is considerably prolonged. The reason for this

apical part of the ventricle.

prolongation is delayed conduction in the left ventricle

These configurations are certainly not found in all

resulting from left bundle branch block. This causes

cases of old cardiac infarction. Local loss of muscle and

the left ventricle to become depolarized about 0.08

local points of cardiac signal conduction block can

second after depolarization of the right ventricle,

cause very bizarre QRS patterns (especially promi-

which gives a strong mean QRS vector to the left.

nent Q waves, for instance), decreased voltage, and

However, the refractory periods of the right and left

QRS prolongation.

ventricular muscle masses are not greatly different

from each other. Therefore, the right ventricle begins

to repolarize long before the left ventricle; this causes

strong positivity in the right ventricle and negativity in

the left ventricle at the time that the T wave is devel-

oping. In other words, the mean axis of the T wave is

now deviated to the right, which is opposite the mean

Posterior

electrical axis of the QRS complex in the same elec-

trocardiogram. Thus, when conduction of the depolar-

ization impulse through the ventricles is greatly

delayed, the T wave is almost always of opposite polar-

ity to that of the QRS complex.

III

Shortened Depolarization in Portions

of the Ventricular Muscle as a Cause

of T Wave Abnormalities

Figure 12-22

If the base of the ventricles should exhibit an abnor-

Electrocardiograms of anterior and posterior wall infarctions that

mally short period of depolarization, that is, a short-

occurred about 1 year previously, showing a Q wave in lead I in

ened action potential, repolarization of the ventricles

anterior wall infarction and a Q wave in lead III in posterior wall

infarction.

would not begin at the apex as it normally does.

146

Unit III

The Heart

Figure 12-23

Inverted T wave resulting from mild ischemia at the apex of the

ventricles.

Figure 12-24

Instead, the base of the ventricles would repolarize

Biphasic T wave caused by digitalis toxicity.

ahead of the apex, and the vector of repolarization

would point from the apex toward the base of the

heart, opposite to the standard vector of repolariza-

inversion, for instance, or a biphasic wave—is often

tion. Consequently, the T wave in all three standard

evidence enough that some portion of the ventricular

leads would be negative rather than the usual positive.

muscle has a period of depolarization out of propor-

Thus, the simple fact that the base of the ventricles has

tion to the rest of the heart, caused by mild to moder-

a shortened period of depolarization is sufficient to

ate coronary insufficiency.

cause marked changes in the T wave, even to the

extent of changing the entire T wave polarity, as shown

Effect of Digitalis on the T Wave. As discussed in Chapter

in Figure 12-23.

22, digitalis is a drug that can be used during coronary

Mild ischemia is by far the most common cause of

insufficiency to increase the strength of cardiac muscle

shortening of depolarization of cardiac muscle,

contraction. But when overdosages of digitalis are

because this increases current flow through the potas-

given, depolarization duration in one part of the ven-

sium channels. When the ischemia occurs in only one

tricles may be increased out of proportion to that of

area of the heart, the depolarization period of this area

other parts. As a result, nonspecific changes, such as T

decreases out of proportion to that in other portions.

wave inversion or biphasic T waves, may occur in one

As a result, definite changes in the T wave can take

or more of the electrocardiographic leads. A biphasic

place. The ischemia might result from chronic, pro-

T wave caused by excessive administration of digitalis

gressive coronary occlusion; acute coronary occlusion;

is shown in Figure 12-24. Therefore, changes in the T

or relative coronary insufficiency that occurs during

wave during digitalis administration are often the ear-

exercise.

liest signs of digitalis toxicity.

One means for detecting mild coronary insufficiency

is to have the patient exercise and to record the elec-

trocardiogram, noting whether changes occur in the T

References

waves. The changes in the T waves need not be spe-

cific, because any change in the T wave in any lead—

See references for Chapter 13.

C H A P T E R

Cardiac Arrhythmias and

Their Electrocardiographic

Interpretation

Some of the most distressing types of heart malfunction

occur not as a result of abnormal heart muscle but

because of abnormal rhythm of the heart. For instance,

sometimes the beat of the atria is not coordinated with

the beat of the ventricles, so that the atria no longer

function as primer pumps for the ventricles.

The purpose of this chapter is to discuss the

physiology of common cardiac arrhythmias and their

effects on heart pumping, as well as their diagnosis by

electrocardiography. The causes of the cardiac arrhythmias are usually one or a com-

bination of the following abnormalities in the rhythmicity-conduction system of the

heart:

1. Abnormal rhythmicity of the pacemaker

2. Shift of the pacemaker from the sinus node to another place in the heart

3. Blocks at different points in the spread of the impulse through the heart

4. Abnormal pathways of impulse transmission through the heart

5. Spontaneous generation of spurious impulses in almost any part of the heart

Abnormal Sinus Rhythms

Tachycardia

The term “tachycardia” means fast heart rate, usually defined in an adult person as

faster than 100 beats per minute. An electrocardiogram recorded from a patient

with tachycardia is shown in Figure 13-1. This electrocardiogram is normal except

that the heart rate, as determined from the time intervals between QRS complexes,

is about 150 per minute instead of the normal 72 per minute.

The general causes of tachycardia include increased body temperature, stimulation

of the heart by the sympathetic nerves, or toxic conditions of the heart.

The heart rate increases about 10 beats per minute for each degree Fahrenheit

(18 beats per degree Celsius) increase in body temperature, up to a body tempera-

ture of about 105°F (40.5°C); beyond this, the heart rate may decrease because of

progressive debility of the heart muscle as a result of the fever. Fever causes tachy-

cardia because increased temperature increases the rate of metabolism of the sinus

node, which in turn directly increases its excitability and rate of rhythm.

Many factors can cause the sympathetic nervous system to excite the heart, as we

discuss at multiple points in this text. For instance, when a patient loses blood and

passes into a state of shock or semishock, sympathetic reflex stimulation of the heart

often increases the heart rate to 150 to 180 beats per minute.

Simple weakening of the myocardium usually increases the heart rate because

the weakened heart does not pump blood into the arterial tree to a normal extent,

and this elicits sympathetic reflexes to increase the heart rate.

Bradycardia

The term “bradycardia” means a slow heart rate, usually defined as fewer than 60

beats per minute. Bradycardia is shown by the electrocardiogram in Figure 13-2.

Bradycardia in Athletes. The athlete’s heart is larger and considerably stronger than

that of a normal person, which allows the athlete’s heart to pump a large stroke

volume output per beat even during periods of rest. When the athlete is at rest,

excessive quantities of blood pumped into the arterial tree with each beat initiate

feedback circulatory reflexes or other effects to cause bradycardia.

147

148

Unit III

The Heart

SA block

Figure 13-4

Figure 13-1

Sinoatrial nodal block, with A-V nodal rhythm during the block

Sinus tachycardia (lead I).

period (lead III).

quiet respiration (left half of the record). Then, during

deep respiration, the heart rate increased and decreased

with each respiratory cycle by as much as 30 per cent.

Sinus arrhythmia can result from any one of many cir-

culatory conditions that alter the strengths of the sym-

pathetic and parasympathetic nerve signals to the heart

sinus node. In the “respiratory” type of sinus arrhyth-

mia, as shown in Figure 13-3, this results mainly from

“spillover” of signals from the medullary respiratory

Figure 13-2

center into the adjacent vasomotor center during inspi-

ratory and expiratory cycles of respiration. The spillover

Sinus bradycardia (lead III).

signals cause alternate increase and decrease in the

number of impulses transmitted through the sympa-

thetic and vagus nerves to the heart.

Abnormal Rhythms That

100

Result from Block of Heart

120

Signals Within the

Intracardiac Conduction

Pathways

Figure 13-3

Sinoatrial Block

Sinus arrhythmia as recorded by a cardiotachometer. To the left is

the record when the subject was breathing normally; to the right,

In rare instances, the impulse from the sinus node is

when breathing deeply.

blocked before it enters the atrial muscle. This phe-

nomenon is demonstrated in Figure 13-4, which shows

sudden cessation of P waves, with resultant standstill of

Vagal Stimulation as a Cause of Bradycardia. Any circulatory

the atria. However, the ventricles pick up a new rhythm,

reflex that stimulates the vagus nerves causes release of

the impulse usually originating spontaneously in the

acetylcholine at the vagal endings in the heart, thus

atrioventricular (A-V) node, so that the rate of the ven-

giving a parasympathetic effect. Perhaps the most strik-

tricular QRS-T complex is slowed but not otherwise

ing example of this occurs in patients with carotid sinus

altered.

syndrome. In these patients, the pressure receptors

(baroreceptors) in the carotid sinus region of the carotid

artery walls are excessively sensitive. Therefore, even

Atrioventricular Block

mild external pressure on the neck elicits a strong

The only means by which impulses ordinarily can pass

baroreceptor reflex, causing intense vagal-acetylcholine

from the atria into the ventricles is through the A-V

effects on the heart, including extreme bradycardia.

bundle, also known as the bundle of His. Conditions that

Indeed, sometimes this reflex is so powerful that it actu-

can either decrease the rate of impulse conduction in

ally stops the heart for 5 to 10 seconds.

this bundle or block the impulse entirely are as follows:

1. Ischemia of the A-V node or A-V bundle fibers

Sinus Arrhythmia

often delays or blocks conduction from the atria to

the ventricles. Coronary insufficiency can cause

Figure 13-3 shows a cardiotachometer recording of the

ischemia of the A-V node and bundle in the same

heart rate, at first during normal and then (in the second

way that it can cause ischemia of the myocardium.

half of the record) during deep respiration. A cardiota-

2. Compression of the A-V bundle by scar tissue or by

chometer is an instrument that records by the height of

calcified portions of the heart can depress or block

successive spikes the duration of the interval between

conduction from the atria to the ventricles.

the successive QRS complexes in the electrocar-

3. Inflammation of the A-V node or A-V bundle

diogram. Note from this record that the heart rate

can depress conductivity from the atria to the

increased and decreased no more than 5 per cent during

ventricles. Inflammation results frequently from

Chapter 13

Cardiac Arrhythmias and Their Electrocardiographic Interpretation

149

Dropped beat

Figure 13-5

Prolonged P-R interval caused by first degree A-V heart block

(lead II).

Figure 13-6

different types of myocarditis, caused, for example,

Second degree A-V block, showing occasional failure of the ven-

by diphtheria or rheumatic fever.

tricles to receive the excitatory signals (lead V₃).

4. Extreme stimulation of the heart by the vagus nerves

in rare instances blocks impulse conduction

through the A-V node. Such vagal excitation

occasionally results from strong stimulation of the

baroreceptors in people with carotid sinus

syndrome, discussed earlier in relation to

bradycardia.

Incomplete Atrioventricular

Heart Block

Figure 13-7

Prolonged P-R (or P-Q) Interval—First Degree Block. The usual

lapse of time between beginning of the P wave and

Complete A-V block (lead II).

beginning of the QRS complex is about 0.16 second

when the heart is beating at a normal rate. This so-

called P-R interval usually decreases in length with

faster heartbeat and increases with slower heartbeat. In

from the atria into the ventricles occurs. In this instance,

general, when the P-R interval increases to greater than

the ventricles spontaneously establish their own signal,

0.20 second, the P-R interval is said to be prolonged, and

usually originating in the A-V node or A-V bundle.

the patient is said to have first degree incomplete heart

Therefore, the P waves become dissociated from the

block.

QRS-T complexes, as shown in Figure 13-7. Note that

Figure 13-5 shows an electrocardiogram with pro-

the rate of rhythm of the atria in this electrocardiogram

longed P-R interval; the interval in this instance is about

is about 100 beats per minute, whereas the rate of ven-

0.30 second instead of the normal 0.20 or less. Thus, first

tricular beat is less than 40 per minute. Furthermore,

degree block is defined as a delay of conduction from

there is no relation between the rhythm of the P waves

the atria to the ventricles but not actual blockage of con-

and that of the QRS-T complexes because the ventri-

duction. The P-R interval seldom increases above 0.35

cles have “escaped” from control by the atria, and they

to 0.45 second because, by that time, conduction through

are beating at their own natural rate, controlled most

the A-V bundle is depressed so much that conduction

often by rhythmical signals generated in the A-V node

stops entirely. One means for determining the severity

or A-V bundle.

of some heart diseases—acute rheumatic heart disease,

for instance—is to measure the P-R interval.

Stokes-Adams Syndrome—Ventricular Escape. In some

patients with A-V block, the total block comes and goes;

Second Degree Block. When conduction through the A-V

that is, impulses are conducted from the atria into the

bundle is slowed enough to increase the P-R interval to

ventricles for a period of time and then suddenly

0.25 to 0.45 second, the action potential sometimes is

impulses are not conducted. The duration of block may

strong enough to pass through the bundle into the ven-

be a few seconds, a few minutes, a few hours, or even

tricles and sometimes is not strong enough. In this

weeks or longer before conduction returns. This condi-

instance, there will be an atrial P wave but no QRS-T

tion occurs in hearts with borderline ischemia of the

wave, and it is said that there are “dropped beats” of the

conductive system.

ventricles. This condition is called second degree heart

Each time A-V conduction ceases, the ventricles often

block.

do not start their own beating until after a delay of 5 to

Figure 13-6 shows P-R intervals of 0.30 second, as

30 seconds. This results from the phenomenon called

well as one dropped ventricular beat as a result of

overdrive suppression. This means that ventricular

failure of conduction from the atria to the ventricles.

excitability is at first in a suppressed state because the

At times, every other beat of the ventricles is

ventricles have been driven by the atria at a rate greater

dropped, so that a “2:1 rhythm” develops, with the atria

than their natural rate of rhythm. However, after a few

beating twice for every single beat of the ventricles. At

seconds, some part of the Purkinje system beyond the

other times, rhythms of 3:2 or 3:1 also develop.

block, usually in the distal part of the A-V node beyond

the blocked point in the node, or in the A-V bundle,

Complete A-V Block (Third Degree Block). When the condi-

begins discharging rhythmically at a rate of 15 to 40

tion causing poor conduction in the A-V node or A-V

times per minute and acting as the pacemaker of the

bundle becomes severe, complete block of the impulse

ventricles. This is called ventricular escape.

150

Unit III

The Heart

Because the brain cannot remain active for more than

areas of ischemia; (2) small calcified plaques at differ-

4 to 7 seconds without blood supply, most patients faint

ent points in the heart, which press against the adjacent

a few seconds after complete block occurs because the

cardiac muscle so that some of the fibers are irritated;

heart does not pump any blood for 5 to 30 seconds,

and (3) toxic irritation of the A-V node, Purkinje

until the ventricles “escape.” After escape, however, the

system, or myocardium caused by drugs, nicotine, or caf-

slowly beating ventricles usually pump enough blood to

feine. Mechanical initiation of premature contractions

allow rapid recovery from the faint and then to sustain

is also frequent during cardiac catheterization; large

the person. These periodic fainting spells are known as

numbers of premature contractions often occur when

the Stokes-Adams syndrome.

the catheter enters the right ventricle and presses

Occasionally the interval of ventricular standstill at

against the endocardium.

the onset of complete block is so long that it becomes

detrimental to the patient’s health or even causes death.

Consequently, most of these patients are provided

Premature Atrial Contractions

with an artificial pacemaker, a small battery-operated

Figure 13-9 shows a single premature atrial contraction.

electrical stimulator planted beneath the skin, with

The P wave of this beat occurred too soon in the heart

electrodes usually connected to the right ventricle. The

cycle; the P-R interval is shortened, indicating that the

pacemaker provides continued rhythmical impulses

ectopic origin of the beat is in the atria near the A-V

that take control of the ventricles.

node. Also, the interval between the premature con-

traction and the next succeeding contraction is slightly

Incomplete Intraventricular Block—

prolonged, which is called a compensatory pause. One

of the reasons for this is that the premature contraction

Electrical Alternans

originated in the atrium some distance from the sinus

Most of the same factors that can cause A-V block can

node, and the impulse had to travel through a consid-

also block impulse conduction in the peripheral ven-

erable amount of atrial muscle before it discharged the

tricular Purkinje system. Figure 13-8 shows the condi-

sinus node. Consequently, the sinus node discharged late

tion known as electrical alternans, which results from

in the premature cycle, and this made the succeeding

partial intraventricular block every other heartbeat.

sinus node discharge also late in appearing.

This electrocardiogram also shows tachycardia (rapid

Premature atrial contractions occur frequently in

heart rate), which is probably the reason the block has

otherwise healthy people. Indeed, they often occur in

occurred, because when the rate of the heart is rapid, it

athletes whose hearts are in very healthy condition.

may be impossible for some portions of the Purkinje

Mild toxic conditions resulting from such factors as

system to recover from the previous refractory period

smoking, lack of sleep, ingestion of too much coffee,

quickly enough to respond during every succeeding

alcoholism, and use of various drugs can also initiate

heartbeat. Also, many conditions that depress the heart,

such contractions.

such as ischemia, myocarditis, or digitalis toxicity, can

cause incomplete intraventricular block, resulting in

Pulse Deficit. When the heart contracts ahead of sched-

electrical alternans.

ule, the ventricles will not have filled with blood nor-

mally, and the stroke volume output during that

contraction is depressed or almost absent. Therefore,

Premature Contractions

the pulse wave passing to the peripheral arteries after a

premature contraction may be so weak that it cannot be

A premature contraction is a contraction of the heart

felt in the radial artery. Thus, a deficit in the number of

before the time that normal contraction would have

radial pulses occurs when compared with the actual

been expected. This condition is also called extrasystole,

number of contractions of the heart.

premature beat, or ectopic beat.

Causes of Premature Contractions. Most premature con-

A-V Nodal or A-V Bundle Premature

tractions result from ectopic foci in the heart, which emit

Contractions

abnormal impulses at odd times during the cardiac

rhythm. Possible causes of ectopic foci are (1) local

Figure

13-10 shows a premature contraction that

originated in the A-V node or in the A-V bundle. The

P wave is missing from the electrocardiographic record

Premature beat

Figure 13-8

Figure 13-9

Partial intraventricular block—“electrical alternans” (lead III).

Atrial premature beat (lead I).

Chapter 13

Cardiac Arrhythmias and Their Electrocardiographic Interpretation

151

ing with normal contractions. PVCs cause specific

effects in the electrocardiogram, as follows:

Premature beat

1. The QRS complex is usually considerably

prolonged. The reason is that the impulse is

conducted mainly through slowly conducting

muscle of the ventricles rather than through the

Purkinje system.

2. The QRS complex has a high voltage for the

following reasons: when the normal impulse passes

through the heart, it passes through both ventricles

nearly simultaneously; consequently, in the normal

heart, the depolarization waves of the two sides

of the heart—mainly of opposite polarity to each

Figure 13-10

other—partially neutralize each other in the

A-V nodal premature contraction (lead III).

electrocardiogram. When a PVC occurs, the

impulse almost always travels in only one direction,

so that there is no such neutralization effect,

and one entire side or end of the ventricles is

depolarized ahead of the other; this causes large

electrical potentials, as shown for the PVCs in

Figure 13-11.

3. After almost all PVCs, the T wave has an electrical

potential polarity exactly opposite to that of the

QRS complex, because the slow conduction of the

impulse through the cardiac muscle causes the

muscle fibers that depolarize first also to repolarize

first.

III

Some PVCs are relatively benign in their effects on

overall pumping by the heart; they can result from such

factors as cigarettes, coffee, lack of sleep, various mild

III

toxic states, and even emotional irritability. Conversely,

many other PVCs result from stray impulses or re-

entrant signals that originate around the borders of

infarcted or ischemic areas of the heart. The presence

of such PVCs is not to be taken lightly. Statistics show

that people with significant numbers of PVCs have a

much higher than normal chance of developing sponta-

neous lethal ventricular fibrillation, presumably initi-

ated by one of the PVCs. This is especially true when

the PVCs occur during the vulnerable period for

causing fibrillation, just at the end of the T wave when

III

the ventricles are coming out of refractoriness, as

explained later in the chapter.

Vector Analysis of the Origin of an Ectopic Premature Ventricular

Figure 13-11

Contraction. In Chapter 12, the principles of vectorial

analysis are explained. Applying these principles, one

Premature ventricular contractions (PVCs) demonstrated by the

can determine from the electrocardiogram in Figure

large abnormal QRS-T complexes (leads II and III). Axis of the

13-11 the point of origin of the PVC as follows: Note

premature contractions is plotted in accordance with the princi-

that the potentials of the premature contractions in

ples of vectorial analysis explained in Chapter 12; this shows the

leads II and III are both strongly positive. Plotting these

origin of the PVC to be near the base of the ventricles.

potentials on the axes of leads II and III and solving by

vectorial analysis for the mean QRS vector in the heart,

one finds that the vector of this premature contraction

of the premature contraction. Instead, the P wave is

has its negative end (origin) at the base of the heart and

superimposed onto the QRS-T complex because the

its positive end toward the apex. Thus, the first portion

cardiac impulse traveled backward into the atria at

of the heart to become depolarized during this prema-

the same time that it traveled forward into the ventri-

ture contraction is near the base of the ventricles, which

cles; this P wave slightly distorts the QRS-T complex,

therefore is the locus of the ectopic focus.

but the P wave itself cannot be discerned as such. In

general, A-V nodal premature contractions have

the same significance and causes as atrial premature

contractions.

Paroxysmal Tachycardia

Some abnormalities in different portions of the heart,

Premature Ventricular Contractions

including the atria, the Purkinje system, or the ventri-

cles, can occasionally cause rapid rhythmical discharge

The electrocardiogram of Figure 13-11 shows a series

of impulses that spread in all directions throughout the

of premature ventricular contractions (PVCs) alternat-

heart. This is believed to be caused most frequently by

152

Unit III

The Heart

Figure 13-12

Atrial paroxysmal tachycardia—onset in middle of record (lead I).

Figure 13-13

Ventricular paroxysmal tachycardia (lead III).

re-entrant circus movement feedback pathways that set

up local repeated self-re-excitation. Because of the

rapid rhythm in the irritable focus, this focus becomes

the pacemaker of the heart.

lar paroxysmal tachycardia has the appearance of a

The term “paroxysmal” means that the heart rate

series of ventricular premature beats occurring one

becomes rapid in paroxysms, with the paroxysm

after another without any normal beats interspersed.

beginning suddenly and lasting for a few seconds, a

Ventricular paroxysmal tachycardia is usually a

few minutes, a few hours, or much longer. Then the

serious condition for two reasons. First, this type of

paroxysm usually ends as suddenly as it began, with

tachycardia usually does not occur unless considerable

the pacemaker of the heart instantly shifting back to

ischemic damage is present in the ventricles. Second,

the sinus node.

ventricular tachycardia frequently initiates the lethal

Paroxysmal tachycardia often can be stopped by elic-

condition of ventricular fibrillation because of rapid

iting a vagal reflex. A type of vagal reflex sometimes

repeated stimulation of the ventricular muscle, as we

elicited for this purpose is to press on the neck in the

discuss in the next section.

regions of the carotid sinuses, which may cause enough

Sometimes intoxication from the heart treatment

of a vagal reflex to stop the paroxysm. Various drugs

drug digitalis causes irritable foci that lead to ventricu-

may also be used. Two drugs frequently used are quini-

lar tachycardia. Conversely, quinidine, which increases

dine and lidocaine, either of which depresses the normal

the refractory period and threshold for excitation of

increase in sodium permeability of the cardiac muscle

cardiac muscle, may be used to block irritable foci

membrane during generation of the action potential,

causing ventricular tachycardia.

thereby often blocking the rhythmical discharge of the

focal point that is causing the paroxysmal attack.

Ventricular Fibrillation

Atrial Paroxysmal Tachycardia

The most serious of all cardiac arrhythmias is ventricu-

lar fibrillation, which, if not stopped within

1 to 3

Figure 13-12 demonstrates in the middle of the record

minutes, is almost invariably fatal. Ventricular fibrilla-

a sudden increase in the heart rate from about 95 to

tion results from cardiac impulses that have gone

about 150 beats per minute. On close study of the elec-

berserk within the ventricular muscle mass, stimulating

trocardiogram during the rapid heartbeat, an inverted P

first one portion of the ventricular muscle, then another

wave is seen before each QRS-T complex, and this P

portion, then another, and eventually feeding back onto

wave is partially superimposed onto the normal T wave

itself to re-excite the same ventricular muscle over and

of the preceding beat. This indicates that the origin

over—never stopping. When this happens, many small

of this paroxysmal tachycardia is in the atrium, but

portions of the ventricular muscle will be contracting at

because the P wave is abnormal in shape, the origin is

the same time, while equally as many other portions will

not near the sinus node.

be relaxing. Thus, there is never a coordinate contrac-

tion of all the ventricular muscle at once, which is

A-V Nodal Paroxysmal Tachycardia. Paroxysmal tachycardia

required for a pumping cycle of the heart. Despite

often results from an aberrant rhythm that involves the

massive movement of stimulatory signals throughout

A-V node. This usually causes almost normal QRS-T

the ventricles, the ventricular chambers neither enlarge

complexes but totally missing or obscured P waves.

nor contract but remain in an indeterminate stage of

Atrial or A-V nodal paroxysmal tachycardia, both of

partial contraction, pumping either no blood or negligi-

which are called supraventricular tachycardias, usually

ble amounts. Therefore, after fibrillation begins, uncon-

occurs in young, otherwise healthy people, and they gen-

sciousness occurs within 4 to 5 seconds for lack of blood

erally grow out of the predisposition to tachycardia

flow to the brain, and irretrievable death of tissues

after adolescence. In general, supraventricular tachy-

begins to occur throughout the body within a few

cardia frightens a person tremendously and may cause

minutes.

weakness during the paroxysm, but only seldom does

Multiple factors can spark the beginning of ventricu-

permanent harm come from the attack.

lar fibrillation—a person may have a normal heartbeat

one moment, but 1 second later, the ventricles are in fib-

Ventricular Paroxysmal Tachycardia

rillation. Especially likely to initiate fibrillation are (1)

sudden electrical shock of the heart, or (2) ischemia of

Figure 13-13 shows a typical short paroxysm of ven-

the heart muscle, of its specialized conducting system,

tricular tachycardia. The electrocardiogram of ventricu-

or both.

Chapter 13

Cardiac Arrhythmias and Their Electrocardiographic Interpretation

153

Phenomenon of Re-entry—“Circus

the refractory state, and the impulse can continue

Movements” as the Basis for

around the circle again and again.

Third, the refractory period of the muscle might

Ventricular Fibrillation

become greatly shortened. In this case, the impulse could

When the normal cardiac impulse in the normal heart

also continue around and around the circle.

has traveled through the extent of the ventricles, it has

All these conditions occur in different pathological

no place to go because all the ventricular muscle is

states of the human heart, as follows: (1) A long pathway

refractory and cannot conduct the impulse farther.

typically occurs in dilated hearts. (2) Decreased rate of

Therefore, that impulse dies, and the heart awaits a new

conduction frequently results from (a) blockage of the

action potential to begin in the atrial sinus node.

Purkinje system, (b) ischemia of the muscle, (c) high

Under some circumstances, however, this normal

blood potassium levels, or (d) many other factors. (3)

sequence of events does not occur. Therefore, let us

A shortened refractory period commonly occurs in

explain more fully the background conditions that can

response to various drugs, such as epinephrine, or after

initiate re-entry and lead to “circus movements,” which

repetitive electrical stimulation. Thus, in many cardiac

in turn cause ventricular fibrillation.

disturbances, re-entry can cause abnormal patterns of

Figure

13-14 shows several small cardiac muscle

cardiac contraction or abnormal cardiac rhythms that

strips cut in the form of circles. If such a strip is stimu-

ignore the pace-setting effects of the sinus node.

lated at the 12 o’clock position so that the impulse travels

in only one direction, the impulse spreads progressively

Chain Reaction Mechanism

around the circle until it returns to the 12 o’clock posi-

tion. If the originally stimulated muscle fibers are still in

of Fibrillation

a refractory state, the impulse then dies out because

In ventricular fibrillation, one sees many separate and

refractory muscle cannot transmit a second impulse. But

small contractile waves spreading at the same time in

there are three different conditions that can cause this

different directions over the cardiac muscle. The re-

impulse to continue to travel around the circle, that is,

entrant impulses in fibrillation are not simply a single

to cause “re-entry” of the impulse into muscle that

impulse moving in a circle, as shown in Figure 13-14.

has already been excited. This is called a

“circus

Instead, they have degenerated into a series of multiple

movement.”

wave fronts that have the appearance of a “chain reac-

First, if the pathway around the circle is too long, by

tion.” One of the best ways to explain this process in

the time the impulse returns to the 12 o’clock position,

fibrillation is to describe the initiation of fibrillation by

the originally stimulated muscle will no longer be

electric shock caused by 60-cycle alternating electric

refractory and the impulse will continue around the

current.

circle again and again.

Second, if the length of the pathway remains constant

Fibrillation Caused by

60-Cycle Alternating Current. At a

but the velocity of conduction becomes decreased

central point in the ventricles of heart A in Figure 13-15,

enough, an increased interval of time will elapse before

60-cycle electrical stimulus is applied through a

the impulse returns to the 12 o’clock position. By this

stimulating electrode. The first cycle of the electrical

time, the originally stimulated muscle might be out of

stimulus causes a depolarization wave to spread in all

directions, leaving all the muscle beneath the electrode

in a refractory state. After about 0.25 second, part of this

muscle begins to come out of the refractory state. Some

portions come out of refractoriness before other

NORMAL PATHWAY

Stimulus

point

Dividing

impulses

Absolutely

refractory

Absolutely

refractory

Relatively

refractory

LONG PATHWAY

Blocked

impulse

Figure 13-14

Figure 13-15

Circus movement, showing annihilation of the impulse in the short

A, Initiation of fibrillation in a heart when patches of refractory mus-

pathway and continued propagation of the impulse in the long

culature are present. B, Continued propagation of fibrillatory

pathway.

impulses in the fibrillating ventricle.

154

Unit III

The Heart

portions. This state of events is depicted in heart A by

many lighter patches, which represent excitable cardiac

muscle, and dark patches, which represent still refrac-

tory muscle. Now, continuing 60-cycle stimuli from the

electrode can cause impulses to travel only in certain

directions through the heart but not in all directions.

Thus, in heart A, certain impulses travel for short dis-

tances, until they reach refractory areas of the heart, and

then are blocked. But other impulses pass between the

refractory areas and continue to travel in the excitable

Figure 13-16

areas. Then, several events transpire in rapid succession,

all occurring simultaneously and eventuating in a state

Ventricular fibrillation (lead II).

of fibrillation.

First, block of the impulses in some directions but suc-

cessful transmission in other directions creates one of

dency toward a regular rhythm of any type. During the

the necessary conditions for a re-entrant signal to

first few seconds of ventricular fibrillation, relatively

develop—that is, transmission of some of the depolar-

large masses of muscle contract simultaneously, and this

ization waves around the heart in only some directions

causes coarse, irregular waves in the electrocardiogram.

but not other directions.

After another few seconds, the coarse contractions of

Second, the rapid stimulation of the heart causes two

the ventricles disappear, and the electrocardiogram

changes in the cardiac muscle itself, both of which pre-

changes into a new pattern of low-voltage, very irregu-

dispose to circus movement: (1) The velocity of conduc-

lar waves. Thus, no repetitive electrocardiographic pat-

tion through the heart muscle decreases, which allows a

tern can be ascribed to ventricular fibrillation. Instead,

longer time interval for the impulses to travel around

the ventricular muscle contracts at as many as 30 to 50

the heart. (2) The refractory period of the muscle is

small patches of muscle at a time, and electrocardio-

shortened, allowing re-entry of the impulse into previ-

graphic potentials change constantly and spasmodically

ously excited heart muscle within a much shorter time

because the electrical currents in the heart flow first in

than normally.

one direction and then in another and seldom repeat

Third, one of the most important features of fibrilla-

any specific cycle.

tion is the division of impulses, as demonstrated in heart

The voltages of the waves in the electrocardiogram

A. When a depolarization wave reaches a refractory

in ventricular fibrillation are usually about 0.5 millivolt

area in the heart, it travels to both sides around the

when ventricular fibrillation first begins, but they

refractory area. Thus, a single impulse becomes two

decay rapidly so that after

20 to

30 seconds, they

impulses. Then, when each of these reaches another

are usually only 0.2 to 0.3 millivolt. Minute voltages of

refractory area, it, too, divides to form two more

0.1 millivolt or less may be recorded for 10 minutes or

impulses. In this way, many new wave fronts are contin-

longer after ventricular fibrillation begins. As already

ually being formed in the heart by progressive chain

pointed out, because no pumping of blood occurs

reactions until, finally, there are many small depolariza-

during ventricular fibrillation, this state is lethal unless

tion waves traveling in many directions at the same

stopped by some heroic therapy, such as immediate

time. Furthermore, this irregular pattern of impulse

electroshock through the heart, as explained in the next

travel causes many circuitous routes for the impulses to

section.

travel, greatly lengthening the conductive pathway, which

is one of the conditions that sustains the fibrillation. It

also results in a continual irregular pattern of patchy

Electroshock Defibrillation

refractory areas in the heart.

of the Ventricles

One can readily see when a vicious circle has been

initiated: More and more impulses are formed; these

Although a moderate alternating-current voltage

cause more and more patches of refractory muscle, and

applied directly to the ventricles almost invariably

the refractory patches cause more and more division of

throws the ventricles into fibrillation, a strong high-

the impulses. Therefore, any time a single area of cardiac

voltage alternating electrical current passed through the

muscle comes out of refractoriness, an impulse is close

ventricles for a fraction of a second can stop fibrillation

at hand to re-enter the area.

by throwing all the ventricular muscle into refractori-

Heart B in Figure 13-15 demonstrates the final state

ness simultaneously. This is accomplished by passing

that develops in fibrillation. Here one can see many

intense current through large electrodes placed on two

impulses traveling in all directions, some dividing and

sides of the heart. The current penetrates most of the

increasing the number of impulses, whereas others are

fibers of the ventricles at the same time, thus stimulat-

blocked by refractory areas. In fact, a single electric

ing essentially all parts of the ventricles simultaneously

shock during this vulnerable period frequently can lead

and causing them all to become refractory. All action

to an odd pattern of impulses spreading multidirection-

potentials stop, and the heart remains quiescent for 3 to

ally around refractory areas of muscle, which will lead

5 seconds, after which it begins to beat again, usually

to fibrillation.

with the sinus node or some other part of the heart

becoming the pacemaker. However, the same re-entrant

focus that had originally thrown the ventricles into fib-

Electrocardiogram in Ventricular

rillation often is still present, in which case fibrillation

Fibrillation

may begin again immediately.

When electrodes are applied directly to the two sides

In ventricular fibrillation, the electrocardiogram is

of the heart, fibrillation can usually be stopped using 110

bizarre (Figure 13-16) and ordinarily shows no ten-

volts of

60-cycle alternating current applied for

0.1

Chapter 13

Cardiac Arrhythmias and Their Electrocardiographic Interpretation

155

second or 1000 volts of direct current applied for a few

Atrial Fibrillation

thousandths of a second. When applied through two

electrodes on the chest wall, as shown in Figure 13-17,

Remember that except for the conducting pathway

the usual procedure is to charge a large electrical

through the A-V bundle, the atrial muscle mass is

capacitor up to several thousand volts and then to cause

separated from the ventricular muscle mass by fibrous

the capacitor to discharge for a few thousandths of a

tissue. Therefore, ventricular fibrillation often occurs

second through the electrodes and through the heart.

without atrial fibrillation. Likewise, fibrillation often

In our laboratory, the heart of a single anesthetized

occurs in the atria without ventricular fibrillation

dog was defibrillated 130 times through the chest wall,

(shown to the right in Figure 13-19).

and the animal lived thereafter in perfectly normal

The mechanism of atrial fibrillation is identical to that

condition.

of ventricular fibrillation, except that the process occurs

only in the atrial muscle mass instead of the ventricular

mass. A frequent cause of atrial fibrillation is atrial

Hand Pumping of the Heart

enlargement resulting from heart valve lesions that

(Cardiopulmonary Resuscitation) as

prevent the atria from emptying adequately into the

ventricles, or from ventricular failure with excess

an Aid to Defibrillation

damming of blood in the atria. The dilated atrial walls

Unless defibrillated within 1 minute after fibrillation

provide ideal conditions of a long conductive pathway

begins, the heart is usually too weak to be revived by

as well as slow conduction, both of which predispose to

defibrillation because of the lack of nutrition from coro-

atrial fibrillation.

nary blood flow. However, it is still possible to revive the

heart by preliminarily pumping the heart by hand

Pumping Characteristics of the Atria During Atrial Fibrillation.

(intermittent hand squeezing) and then defibrillating

For the same reasons that the ventricles will not pump

the heart later. In this way, small quantities of blood are

blood during ventricular fibrillation, neither do the atria

delivered into the aorta and a renewed coronary blood

pump blood in atrial fibrillation. Therefore, the atria

supply develops. Then, after a few minutes of hand

become useless as primer pumps for the ventricles. Even

pumping, electrical defibrillation often becomes possi-

so, blood flows passively through the atria into the

ble. Indeed, fibrillating hearts have been pumped by

ventricles, and the efficiency of ventricular pumping is

hand for as long as 90 minutes followed by successful

decreased only 20 to 30 per cent. Therefore, in contrast

defibrillation.

to the lethality of ventricular fibrillation, a person can

A technique for pumping the heart without opening

live for months or even years with atrial fibrillation,

the chest consists of intermittent thrusts of pressure on

although at reduced efficiency of overall heart pumping.

the chest wall along with artificial respiration. This, plus

defibrillation, is called cardiopulmonary resuscitation,

Electrocardiogram in Atrial Fibrillation. Figure 13-18 shows

or CPR.

the electrocardiogram during atrial fibrillation. Numer-

Lack of blood flow to the brain for more than 5 to

ous small depolarization waves spread in all directions

8 minutes usually causes permanent mental impair-

through the atria during atrial fibrillation. Because the

ment or even destruction of brain tissue. Even if the

waves are weak and many of them are of opposite

heart is revived, the person may die from the effects of

polarity at any given time, they usually almost com-

brain damage or may live with permanent mental

pletely electrically neutralize one another. Therefore, in

impairment.

the electrocardiogram, one can see either no P waves

from the atria or only a fine, high-frequency, very low

voltage wavy record. Conversely, the QRS-T complexes

are normal unless there is some pathology of the ven-

tricles, but their timing is irregular, as explained next.

Several thousand volts

for a few milliseconds

Irregularity of Ventricular Rhythm During Atrial Fibrillation.

When the atria are fibrillating, impulses arrive from the

atrial muscle at the A-V node rapidly but also irregu-

Handle for

larly. Because the A-V node will not pass a second

application

impulse for about 0.35 second after a previous one, at

of pressure

least 0.35 second must elapse between one ventricular

contraction and the next. Then an additional but

Electrode

Figure 13-17

Figure 13-18

Application of electrical current to the chest to stop ventricular

Atrial fibrillation (lead I). The waves that can be seen are ventric-

fibrillation.

ular QRS and T waves.

156

Unit III

The Heart

Figure 13-20

Atrial flutter—2:1 and 3:1 atrial to ventricle rhythm (lead I).

Atrial flutter

Atrial fibrillation

Figure 13-19

Cardiac Arrest

Pathways of impulses in atrial flutter and atrial fibrillation.

A final serious abnormality of the cardiac rhythmicity-

conduction system is cardiac arrest. This results from

cessation of all electrical control signals in the heart.

That is, no spontaneous rhythm remains.

variable interval of 0 to 0.6 second occurs before one of

Cardiac arrest is especially likely to occur during deep

the irregular atrial fibrillatory impulses happens to

anesthesia, when many patients develop severe hypoxia

arrive at the A-V node. Thus, the interval between suc-

because of inadequate respiration. The hypoxia pre-

cessive ventricular contractions varies from a minimum

vents the muscle fibers and conductive fibers from main-

of about 0.35 second to a maximum of about 0.95

taining normal electrolyte concentration differentials

second, causing a very irregular heartbeat. In fact, this

across their membranes, and their excitability may be so

irregularity, demonstrated by the variable spacing of the

affected that the automatic rhythmicity disappears.

heartbeats in the electrocardiogram of Figure 13-18, is

In most instances of cardiac arrest from anesthesia,

one of the clinical findings used to diagnose the condi-

prolonged cardiopulmonary resuscitation

(many

tion. Also, because of the rapid rate of the fibrillatory

minutes or even hours) is quite successful in re-

impulses in the atria, the ventricle is driven at a fast

establishing a normal heart rhythm. In some patients,

heart rate, usually between

125 and 150 beats per

severe myocardial disease can cause permanent or

minute.

semipermanent cardiac arrest, which can cause death.

To treat the condition, rhythmical electrical impulses

Electroshock Treatment of Atrial Fibrillation. In the same

from an implanted electronic cardiac pacemaker have

manner that ventricular fibrillation can be converted

been used successfully to keep patients alive for months

back to a normal rhythm by electroshock, so too can

to years.

atrial fibrillation be converted by electroshock. The pro-

cedure is essentially the same as for ventricular fibrilla-

tion conversion—passage of a single strong electric

References

shock through the heart, which throws the entire heart

into refractoriness for a few seconds; a normal rhythm

Al-Khatib SM, LaPointe NM, Kramer JM, Califf RM: What

often follows if the heart is capable of this.

clinicians should know about the QT interval. JAMA

289:2120, 2003.

Armoundas AA, Tomaselli GF, Esperer HD: Pathophysio-

Atrial Flutter

logical basis and clinical application of T-wave alternans.

Atrial flutter is another condition caused by a circus

J Am Coll Cardiol 40:207, 2002.

movement in the atria. It is different from atrial fibril-

Bigi R, Cortigiani L, Desideri A: Exercise electrocardiogra-

lation, in that the electrical signal travels as a single

phy after acute coronary syndromes: still the first testing

large wave always in one direction around and around

modality? Clin Cardiol 8:390, 2003.

the atrial muscle mass, as shown to the left in Figure

Cheitlin MD, Armstrong WF, Aurigemma GP, et al:

13-19. Atrial flutter causes a rapid rate of contraction of

ACC/AHA/ASE 2003 Guideline update for the clinical

the atria, usually between 200 and 350 beats per minute.

application of echocardiography: summary article. A

However, because one side of the atria is contracting

report of the American College of Cardiology/American

while the other side is relaxing, the amount of blood

Heart Association Task Force on Practice Guidelines

pumped by the atria is slight. Furthermore, the signals

(ACC/AHA/ASE Committee to Update the 1997 Guide-

reach the A-V node too rapidly for all of them to be

lines for the Clinical Application of Echocardiography).

passed into the ventricles, because the refractory

J Am Soc Echocardiogr 16:1091, 2003.

periods of the A-V node and A-V bundle are too long

Cohn PF, Fox KM, Daly C: Silent myocardial ischemia.

to pass more than a fraction of the atrial signals. There-

Circulation 108:1263, 2003.

fore, there are usually two to three beats of the atria for

Falk RH: Atrial fibrillation. N Engl J Med 344:1067, 2001.

every single beat of the ventricles.

Frenneaux MP: Assessing the risk of sudden cardiac death

Figure 13-20 shows a typical electrocardiogram in

in a patient with hypertrophic cardiomyopathy. Heart

atrial flutter. The P waves are strong because of con-

90:570, 2004.

traction of semicoordinate masses of muscle. However,

Greenland P, Gaziano JM: Clinical practice: selecting asymp-

note in the record that a QRS-T complex follows an

tomatic patients for coronary computed tomography or

atrial P wave only once for every two to three beats of

electrocardiographic exercise testing. N Engl J Med

the atria, giving a 2:1 or 3:1 rhythm.

349:465, 2003.

Chapter 13

Cardiac Arrhythmias and Their Electrocardiographic Interpretation

157

Hurst JW: Current status of clinical electrocardiography with

Roden DM: Drug-induced prolongation of the QT interval.

suggestions for the improvement of the interpretive

N Engl J Med 350:1013, 2004.

process. Am J Cardiol 92:1072, 2003.

Swynghedauw B, Baillard C, Milliez P: The long QT interval

Jalife J: Ventricular fibrillation: mechanisms of initiation and

is not only inherited but is also linked to cardiac hyper-

maintenance. Annu Rev Physiol 62:25, 2000.

trophy. J Mol Med 81:336, 2003.

Lee TH, Boucher CA: Clinical practice: noninvasive tests in

Topol EJ: A guide to therapeutic decision-making in patients

patients with stable coronary artery disease. N Engl J Med

with non-ST-segment elevation acute coronary syn-

344:1840, 2001.

dromes. J Am Coll Cardiol 41(4 Suppl S):S123, 2003.

Lehmann MH, Morady F: QT interval: metric for cardiac

Wang K, Asinger RW, Marriott HJ: ST-segment elevation in

prognosis? Am J Med 115:732, 2003.

conditions other than acute myocardial infarction. N Engl

Levy S: Pharmacologic management of atrial fibrillation: cur-

J Med 349:2128, 2003.

rent therapeutic strategies. Am Heart J 141(2 Suppl):S15,

Yan GX, Lankipalli RS, Burke JF, et al: Ventricular repolar-

2001.

ization components on the electrocardiogram: cellular

Marban E: The surprising role of vascular K(ATP)

basis and clinical significance. J Am Coll Cardiol 42:401,

channels in vasospastic angina. J Clin Invest

110:153,

2003.

2002.

Zimetbaum PJ, Josephson ME: Use of the electrocardiogram

Maron BJ: Sudden death in young athletes. N Engl J Med

in acute myocardial infarction. N Engl J Med 348:933,

349:1064, 2003.

2003.

Nattel S: New ideas about atrial fibrillation 50 years on.

Zipes DP, Jalife J: Cardiac Electrophysiology,

3rd ed.

Nature 415:219, 2002.

Philadelphia: WB Saunders, 1999.

C H A P T E R

Overview of the Circulation;

Medical Physics of Pressure,

Flow, and Resistance

The function of the circulation is to service the

needs of the body tissues—to transport nutrients to

the body tissues, to transport waste products away,

to conduct hormones from one part of the body to

another, and, in general, to maintain an appropriate

environment in all the tissue fluids of the body for

optimal survival and function of the cells.

The rate of blood flow through most tissues is

controlled in response to tissue need for nutrients. The heart and circulation in

turn are controlled to provide the necessary cardiac output and arterial pres-

sure to cause the needed tissue blood flow. What are the mechanisms for con-

trolling blood volume and blood flow, and how does this relate to all the other

functions of the circulation? These are some of the topics and questions that we

discuss in this section on the circulation.

Physical Characteristics of the Circulation

The circulation, shown in Figure 14-1, is divided into the systemic circulation

and the pulmonary circulation. Because the systemic circulation supplies blood

flow to all the tissues of the body except the lungs, it is also called the greater

circulation or peripheral circulation.

Functional Parts of the Circulation. Before discussing the details of circulatory func-

tion, it is important to understand the role of each part of the circulation.

The function of the arteries is to transport blood under high pressure to the

tissues. For this reason, the arteries have strong vascular walls, and blood flows

at a high velocity in the arteries.

The arterioles are the last small branches of the arterial system; they act as

control conduits through which blood is released into the capillaries. The arte-

riole has a strong muscular wall that can close the arteriole completely or can,

by relaxing, dilate it severalfold, thus having the capability of vastly altering

blood flow in each tissue bed in response to the need of the tissue.

The function of the capillaries is to exchange fluid, nutrients, electrolytes,

hormones, and other substances between the blood and the interstitial fluid.

To serve this role, the capillary walls are very thin and have numerous minute

capillary pores permeable to water and other small molecular substances.

The venules collect blood from the capillaries, and they gradually coalesce

into progressively larger veins.

The veins function as conduits for transport of blood from the venules back

to the heart; equally important, they serve as a major reservoir of extra blood.

Because the pressure in the venous system is very low, the venous walls are thin.

Even so, they are muscular enough to contract or expand and thereby act as a

controllable reservoir for the extra blood, either a small or a large amount,

depending on the needs of the circulation.

Volumes of Blood in the Different Parts of the Circulation. Figure

14-1 gives an

overview of the circulation and lists the percentage of the total blood volume

161

162

Unit IV The Circulation

Pulmonary circulation-9%

Vessel

Cross-Sectional Area (cm²)

Aorta

2.5

Small arteries

Arterioles

Capillaries

2500

Venules

250

Small veins

Aorta

Venae cavae

Superior

vena cava

Note particularly the much larger cross-sectional

Heart-7%

areas of the veins than of the arteries, averaging about

four times those of the corresponding arteries. This

explains the large storage of blood in the venous

system in comparison with the arterial system.

Because the same volume of blood must flow

Inferior

Systemic

through each segment of the circulation each minute,

vena cava

vessels

Arteries-13%

the velocity of blood flow is inversely proportional to

vascular cross-sectional area. Thus, under resting con-

ditions, the velocity averages about 33 cm/sec in the

Arterioles

aorta but only 1/1000 as rapidly in the capillaries, about

and

0.3 mm/sec. However, because the capillaries have a

capillaries-7%

typical length of only 0.3 to 1 millimeter, the blood

remains in the capillaries for only 1 to 3 seconds. This

short time is surprising because all diffusion of

nutrient food substances and electrolytes that occurs

through the capillary walls must do so in this exceed-

ingly short time.

Veins, venules,

and venous

Pressures in the Various Portions of the Circulation. Because

sinuses-64%

the heart pumps blood continually into the aorta,

the mean pressure in the aorta is high, averaging about

Figure 14-1

100 mm Hg. Also, because heart pumping is pulsatile,

Distribution of blood (in percentage of total blood) in the different

the arterial pressure alternates between a systolic pres-

parts of the circulatory system.

sure level of 120 mm Hg and a diastolic pressure level

of 80 mm Hg, as shown on the left side of Figure 14-2.

As the blood flows through the systemic circulation,

its mean pressure falls progressively to about 0 mm Hg

by the time it reaches the termination of the venae

cavae where they empty into the right atrium of the

heart.

The pressure in the systemic capillaries varies from

as high as 35 mm Hg near the arteriolar ends to as low

in major segments of the circulation. For instance,

as 10 mm Hg near the venous ends, but their average

about 84 per cent of the entire blood volume of the

“functional” pressure in most vascular beds is about

body is in the systemic circulation, and 16 per cent in

17 mm Hg, a pressure low enough that little of the

heart and lungs. Of the 84 per cent in the systemic cir-

plasma leaks through the minute pores of the capillary

culation, 64 per cent is in the veins, 13 per cent in the

walls, even though nutrients can diffuse easily through

arteries, and 7 per cent in the systemic arterioles and

these same pores to the outlying tissue cells.

capillaries. The heart contains 7 per cent of the blood,

Note at the far right side of Figure 14-2 the respec-

and the pulmonary vessels, 9 per cent.

tive pressures in the different parts of the pulmonary

Most surprising is the low blood volume in the cap-

circulation. In the pulmonary arteries, the pressure is

illaries. It is here, however, that the most important

pulsatile, just as in the aorta, but the pressure level is

function of the circulation occurs, diffusion of sub-

far less: pulmonary artery systolic pressure averages

stances back and forth between the blood and the

about 25 mm Hg and diastolic pressure 8 mm Hg, with

tissues. This function is discussed in detail in Chapter

a mean pulmonary arterial pressure of only 16 mm Hg.

16.

The mean pulmonary capillary pressure averages only

7 mm Hg. Yet the total blood flow through the lungs

Cross-Sectional Areas and Velocities of Blood Flow. If all the

each minute is the same as through the systemic cir-

systemic vessels of each type were put side by side,

culation. The low pressures of the pulmonary system

their approximate total cross-sectional areas for the

are in accord with the needs of the lungs, because

average human being would be as follows:

all that is required is to expose the blood in the

Chapter 14

Overview of the Circulation; Medical Physics of Pressure, Flow, and Resistance

163

120

100

Systemic

Pulmonary

Figure 14-2

Normal blood pressures in the different portions of the circulatory system when a person is lying in the horizontal position.

pulmonary capillaries to oxygen and other gases in the

through a tissue, it immediately returns by way of

pulmonary alveoli.

the veins to the heart. The heart responds

automatically to this increased inflow of blood by

pumping it immediately into the arteries from

Basic Theory of Circulatory

whence it had originally come. Thus, the heart acts

Function

as an automaton, responding to the demands of

the tissues. The heart, however, often needs help

Although the details of circulatory function are

in the form of special nerve signals to make it

complex, there are three basic principles that underlie

pump the required amounts of blood flow.

all functions of the system.

In general the arterial pressure is controlled

1. The rate of blood flow to each tissue of the body

independently of either local blood flow control

is almost always precisely controlled in relation to

or cardiac output control. The circulatory

the tissue need. When tissues are active, they need

system is provided with an extensive system for

greatly increased supply of nutrients and

controlling the arterial blood pressure.

therefore much more blood flow than when at

For instance, if at any time the pressure falls

rest—occasionally as much as 20 to 30 times

significantly below the normal level of about

the resting level. Yet the heart normally cannot

100 mm Hg, within seconds a barrage of nervous

increase its cardiac output more than four to

reflexes elicits a series of circulatory changes to

seven times greater than resting levels. Therefore,

raise the pressure back toward normal. The

it is not possible simply to increase blood flow

nervous signals especially (a) increase the force of

everywhere in the body when a particular tissue

heart pumping, (b) cause contraction of the large

demands increased flow. Instead, the microvessels

venous reservoirs to provide more blood to the

of each tissue continuously monitor tissue needs,

heart, and (c) cause generalized constriction of

such as the availability of oxygen and other

most of the arterioles throughout the body so that

nutrients and the accumulation of carbon dioxide

more blood accumulates in the large arteries to

and other tissue waste products, and these in turn

increase the arterial pressure. Then, over more

act directly on the local blood vessels, dilating or

prolonged periods, hours and days, the kidneys

constricting them, to control local blood flow

play an additional major role in pressure control

precisely to that level required for the tissue

both by secreting pressure-controlling hormones

activity. Also, nervous control of the circulation

and by regulating the blood volume.

from the central nervous system provides

Thus, in summary, the needs of the individual tissues

additional help in controlling tissue blood

are served specifically by the circulation. In the

flow.

remainder of this chapter, we begin to discuss the basic

2. The cardiac output is controlled mainly by the

details of the management of tissue blood flow and

sum of all the local tissue flows. When blood flows

control of cardiac output and arterial pressure.

164

Unit IV The Circulation

Interrelationships Among

of time. Ordinarily, blood flow is expressed in milliliters

per minute or liters per minute, but it can be expressed

Pressure, Flow, and

in milliliters per second or in any other unit of flow.

Resistance

The overall blood flow in the total circulation of an

adult person at rest is about 5000 ml/min. This is called

Blood flow through a blood vessel is determined by

the cardiac output because it is the amount of blood

two factors: (1) pressure difference of the blood be-

pumped into the aorta by the heart each minute.

tween the two ends of the vessel, also sometimes called

“pressure gradient” along the vessel, which is the force

Methods for Measuring Blood Flow. Many mechanical and

that pushes the blood through the vessel, and (2) the

mechanoelectrical devices can be inserted in series with

impediment to blood flow through the vessel, which is

a blood vessel or, in some instances, applied to the

called vascular resistance. Figure 14-3 demonstrates

outside of the vessel to measure flow. They are called

these relationships, showing a blood vessel segment

flowmeters.

located anywhere in the circulatory system.

P₁ represents the pressure at the origin of the vessel;

Electromagnetic Flowmeter. One of the most important

at the other end, the pressure is P₂. Resistance occurs

devices for measuring blood flow without opening the

vessel is the electromagnetic flowmeter, the principles

as a result of friction between the flowing blood and

of which are illustrated in Figure 14-4. Figure 14-4A

the intravascular endothelium all along the inside of

shows the generation of electromotive force (electrical

the vessel. The flow through the vessel can be cal-

voltage) in a wire that is moved rapidly in a cross-wise

culated by the following formula, which is called

direction through a magnetic field. This is the well-

Ohm’s law:

known principle for production of electricity by the

electric generator. Figure 14-4B shows that the same

= D

principle applies for generation of electromotive force

in blood that is moving through a magnetic field. In

in which F is blood flow, DP is the pressure difference

this case, a blood vessel is placed between the poles

of a strong magnet, and electrodes are placed on the

(P₁- P₂) between the two ends of the vessel, and R is

two sides of the vessel perpendicular to the magnetic

the resistance. This formula states, in effect, that the

lines of force. When blood flows through the vessel,

blood flow is directly proportional to the pressure dif-

an electrical voltage proportional to the rate of blood

ference but inversely proportional to the resistance.

flow is generated between the two electrodes, and this

Note that it is the difference in pressure between the

is recorded using an appropriate voltmeter or electronic

two ends of the vessel, not the absolute pressure in the

recording apparatus. Figure

14-4C shows an actual

vessel, that determines rate of flow. For example, if

“probe” that is placed on a large blood vessel to record

the pressure at both ends of a vessel is 100 mm Hg and

its blood flow. The probe contains both the strong

yet no difference exists between the two ends, there

magnet and the electrodes.

will be no flow despite the presence of 100 mm Hg

A special advantage of the electromagnetic flowme-

ter is that it can record changes in flow in less than 1/100

pressure.

of a second, allowing accurate recording of pulsatile

Ohm’s law, illustrated in Equation 1, expresses the

changes in flow as well as steady flow.

most important of all the relations that the reader

needs to understand to comprehend the hemodynam-

Ultrasonic Doppler Flowmeter. Another type of flowmeter

ics of the circulation. Because of the extreme impor-

that can be applied to the outside of the vessel and that

tance of this formula, the reader should also become

has many of the same advantages as the electromagnetic

familiar with its other algebraic forms:

flowmeter is the ultrasonic Doppler flowmeter, shown in

Figure 14-5. A minute piezoelectric crystal is mounted

DP = F ¥ R

at one end in the wall of the device. This crystal, when

energized with an appropriate electronic apparatus,

= D

transmits ultrasound at a frequency of several hun-

dred thousand cycles per second downstream along the

flowing blood. A portion of the sound is reflected by the

red blood cells in the flowing blood. The reflected ultra-

Blood Flow

sound waves then travel backward from the blood cells

toward the crystal. These reflected waves have a lower

Blood flow means simply the quantity of blood that

frequency than the transmitted wave because the red

passes a given point in the circulation in a given period

cells are moving away from the transmitter crystal. This

is called the Doppler effect. (It is the same effect that

one experiences when a train approaches and passes by

Pressure gradient

P₁

P₂

while blowing its whistle. Once the whistle has passed

Blood flow

by the person, the pitch of the sound from the whistle

suddenly becomes much lower than when the train is

approaching.)

Resistance

For the flowmeter shown in Figure 14-5, the high-

frequency ultrasound wave is intermittently cut off, and

the reflected wave is received back onto the crystal and

Figure 14-3

amplified greatly by the electronic apparatus. Another

portion of the electronic apparatus determines the

Interrelationships among pressure, resistance, and blood flow.

Chapter 14

Overview of the Circulation; Medical Physics of Pressure, Flow, and Resistance

165

Figure 14-4

Flowmeter of the electromagnetic

type, showing generation of an

electrical voltage in a wire as it

passes through an electromag-

netic field

(A); generation of an

electrical voltage in electrodes on

a blood vessel when the vessel

is placed in a strong magnetic

field and blood flows through

the vessel

(B); and a modern

electromagnetic flowmeter probe

for chronic implantation around

blood vessels (C).

Crystal

Transmitted

Reflected

wave

Figure 14-6

Figure 14-5

A, Two fluids (one dyed red, and the other clear) before flow

Ultrasonic Doppler flowmeter.

begins; B, the same fluids 1 second after flow begins; C, turbu-

lent flow, with elements of the fluid moving in a disorderly pattern.

frequency difference between the transmitted wave and

the reflected wave, thus determining the velocity of

Parabolic Velocity Profile During Laminar Flow. When laminar

blood flow.

flow occurs, the velocity of flow in the center of the

Like the electromagnetic flowmeter, the ultrasonic

vessel is far greater than that toward the outer edges.

Doppler flowmeter is capable of recording rapid, pul-

This is demonstrated in Figure 14-6. In Figure 14-6A, a

satile changes in flow as well as steady flow.

vessel contains two fluids, the one at the left colored by

a dye and the one at the right a clear fluid, but there is

Laminar Flow of Blood in Vessels. When blood flows at a

no flow in the vessel. When the fluids are made to flow,

steady rate through a long, smooth blood vessel, it flows

a parabolic interface develops between them, as shown

in streamlines, with each layer of blood remaining the

1 second later in Figure 14-6B; the portion of fluid adja-

same distance from the vessel wall. Also, the central

cent to the vessel wall has hardly moved, the portion

most portion of the blood stays in the center of the

slightly away from the wall has moved a small distance,

vessel. This type of flow is called laminar flow or stream-

and the portion in the center of the vessel has moved a

line flow, and it is the opposite of turbulent flow, which

long distance. This effect is called the “parabolic profile

is blood flowing in all directions in the vessel and

for velocity of blood flow.”

continually mixing within the vessel, as discussed

The cause of the parabolic profile is the following: The

subsequently.

fluid molecules touching the wall barely move because

166

Unit IV

The Circulation

of adherence to the vessel wall. The next layer of mol-

100 mm Hg pressure

ecules slips over these, the third layer over the second,

the fourth layer over the third, and so forth. Therefore,

the fluid in the middle of the vessel can move rapidly

because many layers of slipping molecules exist

between the middle of the vessel and the vessel wall;

thus, each layer toward the center flows progressively

0 pressure

more rapidly than the outer layers.

Moving sooted

Turbulent Flow of Blood Under Some Conditions. When the rate

paper

of blood flow becomes too great, when it passes by an

Float

obstruction in a vessel, when it makes a sharp turn, or

Anticoagulant

when it passes over a rough surface, the flow may then

solution

become turbulent, or disorderly, rather than streamline

Mercury

(see Figure 14-6C). Turbulent flow means that the blood

flows crosswise in the vessel as well as along the vessel,

usually forming whorls in the blood called eddy cur-

Mercury

rents. These are similar to the whirlpools that one

manometer

frequently sees in a rapidly flowing river at a point of

obstruction.

When eddy currents are present, the blood flows with

much greater resistance than when the flow is stream-

Figure 14-7

line because eddies add tremendously to the overall

friction of flow in the vessel.

Recording arterial pressure with a mercury manometer, a method

The tendency for turbulent flow increases in direct

that has been used in the manner shown for recording pressure

proportion to the velocity of blood flow, the diameter of

throughout the history of physiology.

the blood vessel, and the density of the blood, and is

inversely proportional to the viscosity of the blood, in

accordance with the following equation:

reference for measuring pressure. Actually, blood pres-

n◊d ◊r

Re =

sure means the force exerted by the blood against any

unit area of the vessel wall. When one says that the

pressure in a vessel is 50 mm Hg, one means that the

where Re is Reynolds’ number and is the measure of the

force exerted is sufficient to push a column of mercury

tendency for turbulence to occur, n is the mean velocity

of blood flow (in centimeters/second), d is the vessel

against gravity up to a level 50 mm high. If the pres-

diameter (in centimeters), r is density, and h is the vis-

sure is 100 mm Hg, it will push the column of mercury

cosity

(in poise). The viscosity of blood is normally

up to 100 millimeters.

about 1/30 poise, and the density is only slightly greater

Occasionally, pressure is measured in centimeters of

than 1. When Reynolds’ number rises above 200 to 400,

water (cm H₂O). A pressure of 10 cm H₂O means a

turbulent flow will occur at some branches of vessels but

pressure sufficient to raise a column of water against

will die out along the smooth portions of the vessels.

gravity to a height of 10 centimeters. One millimeter of

However, when Reynolds’ number rises above approx-

mercury pressure equals

1.36 cm water pressure

imately 2000, turbulence will usually occur even in a

because the specific gravity of mercury is 13.6 times

straight, smooth vessel.

that of water, and 1 centimeter is 10 times as great as

Reynolds’ number for flow in the vascular system

even normally rises to 200 to 400 in large arteries; as a

1 millimeter.

result there is almost always some turbulence of flow at

the branches of these vessels. In the proximal portions

High-Fidelity Methods for Measuring Blood Pressure. The

of the aorta and pulmonary artery, Reynolds’ number

mercury in the mercury manometer has so much inertia

can rise to several thousand during the rapid phase of

that it cannot rise and fall rapidly. For this reason, the

ejection by the ventricles; this causes considerable tur-

mercury manometer, although excellent for recording

bulence in the proximal aorta and pulmonary artery

steady pressures, cannot respond to pressure changes

where many conditions are appropriate for turbulence:

that occur more rapidly than about one cycle every 2 to

(1) high velocity of blood flow, (2) pulsatile nature of

3 seconds. Whenever it is desired to record rapidly

the flow, (3) sudden change in vessel diameter, and

changing pressures, some other type of pressure

(4) large vessel diameter. However, in small vessels,

recorder is needed. Figure 14-8 demonstrates the basic

Reynolds’ number is almost never high enough to cause

principles of three electronic pressure transducers com-

turbulence.

monly used for converting blood pressure and/or rapid

changes in pressure into electrical signals and then

recording the electrical signals on a high-speed electri-

cal recorder. Each of these transducers uses a very thin,

Blood Pressure

highly stretched metal membrane that forms one wall

of the fluid chamber. The fluid chamber in turn is con-

Standard Units of Pressure. Blood pressure almost always

nected through a needle or catheter to the blood vessel

is measured in millimeters of mercury

(mm Hg)

in which the pressure is to be measured. When the pres-

because the mercury manometer (shown in Figure

sure is high, the membrane bulges slightly, and when it

14-7) has been used since antiquity as the standard

is low, it returns toward its resting position.

Chapter 14

Overview of the Circulation; Medical Physics of Pressure, Flow, and Resistance

167

any direct means. Instead, resistance must be calcu-

lated from measurements of blood flow and pressure

difference between two points in the vessel. If the

pressure difference between two points is 1 mm Hg

and the flow is 1 ml/sec, the resistance is said to be 1

peripheral resistance unit, usually abbreviated PRU.

Expression of Resistance in CGS Units. Occasionally, a

basic physical unit called the CGS (centimeters, grams,

seconds) unit is used to express resistance. This unit is

dyne seconds/centimeters⁵. Resistance in these units can

be calculated by the following formula:

dyne

sec

1333

mm Hg

R in

¯ =

ml sec

Total Peripheral Vascular Resistance and Total Pulmonary Vas-

cular Resistance. The rate of blood flow through the

entire circulatory system is equal to the rate of blood

pumping by the heart—that is, it is equal to the cardiac

output. In the adult human being, this is approximately

100 ml/sec. The pressure difference from the systemic

arteries to the systemic veins is about 100 mm Hg.

Therefore, the resistance of the entire systemic circu-

lation, called the total peripheral resistance, is about

100/100, or 1 PRU.

In conditions in which all the blood vessels through-

out the body become strongly constricted, the total

peripheral resistance occasionally rises to as high as 4

PRU. Conversely, when the vessels become greatly

dilated, the resistance can fall to as little as 0.2 PRU.

In the pulmonary system, the mean pulmonary arte-

rial pressure averages 16 mm Hg and the mean left

Figure 14-8

atrial pressure averages 2 mm Hg, giving a net pres-

sure difference of 14 mm. Therefore, when the cardiac

Principles of three types of electronic transducers for recording

output is normal at about

100 ml/sec, the total

rapidly changing blood pressures (explained in the text).

pulmonary vascular resistance calculates to be about

0.14 PRU (about one seventh that in the systemic

In Figure 14-8A, a simple metal plate is placed a few

circulation).

hundredths of a centimeter above the membrane. When

the membrane bulges, the membrane comes closer to

the plate, which increases the electrical capacitance

“Conductance” of Blood in a Vessel and Its Relation to Resis-

between these two, and this change in capacitance can

tance. Conductance is a measure of the blood flow

be recorded using an appropriate electronic system.

through a vessel for a given pressure difference. This

In Figure 14-8B, a small iron slug rests on the mem-

is generally expressed in terms of milliliters per second

brane, and this can be displaced upward into a center

per millimeter of mercury pressure, but it can also be

space inside an electrical wire coil. Movement of the

expressed in terms of liters per second per millimeter

iron into the coil increases the inductance of the coil,

of mercury or in any other units of blood flow and

and this, too, can be recorded electronically.

pressure.

Finally, in Figure 14-8C, a very thin, stretched resist-

It is evident that conductance is the exact reciprocal

ance wire is connected to the membrane. When this wire

of resistance in accord with the following equation:

is stretched greatly, its resistance increases; when it is

stretched less, its resistance decreases. These changes,

too, can be recorded by an electronic system.

Conductance

With some of these high-fidelity types of recording

Resistance

systems, pressure cycles up to 500 cycles per second

have been recorded accurately. In common use are

Very Slight Changes in Diameter of a Vessel Can Change Its

recorders capable of registering pressure changes that

Conductance Tremendously! Slight changes in the diame-

occur as rapidly as 20 to 100 cycles per second, in the

ter of a vessel cause tremendous changes in the vessel’s

manner shown on the recording paper in Figure 14-8C.

ability to conduct blood when the blood flow is stream-

lined. This is demonstrated by the experiment illus-

Resistance to Blood Flow

trated in Figure 14-9A, which shows three vessels with

relative diameters of 1, 2, and 4 but with the same pres-

Units of Resistance. Resistance is the impediment to

sure difference of 100 mm Hg between the two ends

blood flow in a vessel, but it cannot be measured by

of the vessels. Although the diameters of these vessels

168

Unit IV The Circulation

Note particularly in this equation that the rate of

blood flow is directly proportional to the fourth power

d = 1

of the radius of the vessel, which demonstrates once

1 ml/min

again that the diameter of a blood vessel (which is equal

P =

d = 2

to twice the radius) plays by far the greatest role of all

16 ml/min

100 mm

factors in determining the rate of blood flow through a

d = 4

vessel.

256 ml/min

Importance of the Vessel Diameter “Fourth Power Law” in

Determining Arteriolar Resistance. In the systemic circula-

tion, about two thirds of the total systemic resistance

to blood flow is arteriolar resistance in the small

arterioles. The internal diameters of the arterioles

Small vessel

range from as little as 4 micrometers to as great as

25 micrometers. However, their strong vascular walls

allow the internal diameters to change tremendously,

Large vessel

often as much as fourfold. From the fourth power law

discussed above that relates blood flow to diameter of

the vessel, one can see that a fourfold increase in vessel

diameter can increase the flow as much as 256-fold.

Figure 14-9

Thus, this fourth power law makes it possible for

the arterioles, responding with only small changes in

A, Demonstration of the effect of vessel diameter on blood flow.

B, Concentric rings of blood flowing at different velocities; the

diameter to nervous signals or local tissue chemical

farther away from the vessel wall, the faster the flow.

signals, either to turn off almost completely the blood

flow to the tissue or at the other extreme to cause a

vast increase in flow. Indeed, ranges of blood flow of

more than 100-fold in separate tissue areas have been

increase only fourfold, the respective flows are 1, 16,

recorded between the limits of maximum arteriolar

and 256 ml/mm, which is a 256-fold increase in flow.

constriction and maximum arteriolar dilatation.

Thus, the conductance of the vessel increases in pro-

portion to the fourth power of the diameter, in accor-

Resistance to Blood Flow in Series and Parallel Vascular Cir-

dance with the following formula:

cuits. Blood pumped by the heart flows from the high

Conductance µ Diameter⁴

pressure part of the systemic circulation (i.e., aorta) to

the low pressure side (i.e., vena cava) through many

Poiseuille’s Law. The cause of this great increase in con-

miles of blood vessels arranged in series and in paral-

ductance when the diameter increases can be explained

lel. The arteries, arterioles, capillaries, venules, and

by referring to Figure 14-9B, which shows cross sections

veins are collectively arranged in series. When blood

of a large and a small vessel. The concentric rings inside

vessels are arranged in series, flow through each blood

the vessels indicate that the velocity of flow in each ring

vessel is the same and the total resistance to blood flow

is different from that in the adjacent rings because of

(R_total) is equal to the sum of the resistances of each

laminar flow, which was discussed earlier in the chapter.

vessel:

That is, the blood in the ring touching the wall of the

vessel is barely flowing because of its adherence to

R =R +R +R +R ...

total

the vascular endothelium. The next ring of blood toward

the center of the vessel slips past the first ring and,

The total peripheral vascular resistance is therefore

therefore, flows more rapidly. The third, fourth, fifth, and

equal to the sum of resistances of the arteries, arteri-

sixth rings likewise flow at progressively increasing

oles, capillaries, venules, and veins. In the example

velocities. Thus, the blood that is near the wall of the

shown in Figure 14-10A, the total vascular resistance

vessel flows extremely slowly, whereas that in the

is equal to the sum of R₁ and R₂.

middle of the vessel flows extremely rapidly.

Blood vessels branch extensively to form parallel

In the small vessel, essentially all the blood is near the

circuits that supply blood to the many organs and

wall, so that the extremely rapidly flowing central

tissues of the body. This parallel arrangement permits

stream of blood simply does not exist. By integrating the

velocities of all the concentric rings of flowing blood and

each tissue to regulate its own blood flow, to a great

multiplying them by the areas of the rings, one can

extent, independently of flow to other tissues.

derive the following formula, known as Poiseuille’s law:

For blood vessels arranged in parallel

(Figure

14-10B), the total resistance to blood flow is expressed

Pr⁴

as:

= D

+ ...

in which F is the rate of blood flow, DP is the pressure

total

R R

difference between the ends of the vessel, r is the radius

of the vessel, l is length of the vessel, and h is viscosity

It is obvious that for a given pressure gradient,

of the blood.

far greater amounts of blood will flow through this

Chapter 14

Overview of the Circulation; Medical Physics of Pressure, Flow, and Resistance

169

R₁

R₂

100

R₂

R₃

R₄

Figure 14-10

Vascular resistances: A, in series and B, in parallel.

parallel system than through any of the individual

blood vessels. Therefore, the total resistance is far less

than the resistance of any single blood vessel. Flow

through each of the parallel vessels in Figure 14-10B

Normal

Anemia

Polycythemia

is determined by the pressure gradient and its own

Figure 14-11

resistance, not the resistance of the other parallel

blood vessels. However, increasing the resistance of

Hematocrits in a healthy (normal) person and in patients with

any of the blood vessels increases the total vascular

anemia and polycythemia.

resistance.

It may seem paradoxical that adding more blood

vessels to a circuit reduces the total vascular resist-

ance. Many parallel blood vessels, however, make it

each of which exerts frictional drag against adjacent

easier for blood to flow through the circuit because

cells and against the wall of the blood vessel.

each parallel vessel provides another pathway, or con-

ductance, for blood flow. The total conductance (C_total)

Hematocrit. The percentage of the blood that is cells is

for blood flow is the sum of the conductance of each

called the hematocrit. Thus, if a person has a hemat-

parallel pathway:

ocrit of 40, this means that 40 per cent of the blood

volume is cells and the remainder is plasma. The hema-

total

C =C +C +C +C ...2

tocrit of men averages about 42, while that of women

For example, brain, kidney, muscle, gastrointestinal,

averages about 38. These values vary tremendously,

skin, and coronary circulations are arranged in paral-

depending on whether the person has anemia, on the

lel, and each tissue contributes to the overall conduc-

degree of bodily activity, and on the altitude at which

tance of the systemic circulation. Blood flow through

the person resides. These changes in hematocrit are

each tissue is a fraction of the total blood flow (cardiac

discussed in relation to the red blood cells and their

output) and is determined by the resistance (the recip-

oxygen transport function in Chapter 32.

rocal of conductance) for blood flow in the tissue, as

Hematocrit is determined by centrifuging blood in

well as the pressure gradient. Therefore, amputation of

a calibrated tube, as shown in Figure 14-11. The cali-

a limb or surgical removal of a kidney also removes a

bration allows direct reading of the percentage of cells.

parallel circuit and reduces the total vascular conduc-

tance and total blood flow (i.e., cardiac output) while

Effect of Hematocrit on Blood Viscosity. The viscosity of

increasing total peripheral vascular resistance.

blood increases drastically as the hematocrit increases,

as shown in Figure 14-12. The viscosity of whole blood

Effect of Blood Hematocrit and Blood

at normal hematocrit is about 3; this means that three

Viscosity on Vascular Resistance and

times as much pressure is required to force whole

Blood Flow

blood as to force water through the same blood vessel.

Note especially that another of the important factors

When the hematocrit rises to 60 or 70, which it often

in Poiseuille’s equation is the viscosity of the blood.

does in polycythemia, the blood viscosity can become

The greater the viscosity, the less the flow in a vessel

as great as 10 times that of water, and its flow through

if all other factors are constant. Furthermore, the vis-

blood vessels is greatly retarded.

cosity of normal blood is about three times as great as

Other factors that affect blood viscosity are the

the viscosity of water.

plasma protein concentration and types of proteins in

But what makes the blood so viscous? It is mainly

the plasma, but these effects are so much less than

the large numbers of suspended red cells in the blood,

the effect of hematocrit that they are not significant

170

Unit IV The Circulation

Sympathetic

Viscosity of whole blood

inhibition

Normal

Viscosity of plasma

Sympathetic

Viscosity of water

stimulation

Critical

closing

pressure

Normal blood

100

120 140 160 180 200

Arterial pressure (mm Hg)

Hematocrit

Figure 14-13

Effect of arterial pressure on blood flow through a blood vessel at

Figure 14-12

different degrees of vascular tone caused by increased or

decreased sympathetic stimulation of the vessel.

Effect of hematocrit on blood viscosity. (Water viscosity = 1.)

considerations in most hemodynamic studies. The vis-

arterial pressure is usually four to six times as great as

cosity of blood plasma is about 1.5 times that of water.

blood flow at 50 mm Hg instead of two times as would

be true if there were no effect of increasing pressure

to increase vascular diameter.

Effects of Pressure on Vascular

Note also in Figure 14-13 the large changes in

Resistance and Tissue Blood Flow

blood flow that can be caused by either increased

or decreased sympathetic nerve stimulation of the

From the discussion thus far, one might expect an

peripheral blood vessels. Thus, as shown in the figure,

increase in arterial pressure to cause a proportionate

inhibition of sympathetic activity greatly dilates the

increase in blood flow through the various tissues of

vessels and can increase the blood flow twofold or

the body. However, the effect of pressure on blood

more. Conversely, very strong sympathetic stimulation

flow is greater than one would expect, as shown by the

can constrict the vessels so much that blood flow occa-

upward curving lines in Figure 14-13. The reason for

sionally decreases to as low as zero for a few seconds

this is that an increase in arterial pressure not only

despite high arterial pressure.

increases the force that pushes blood through the

vessels but also distends the vessels at the same time,

which decreases vascular resistance. Thus, greater

References

pressure increases the flow in both of these ways.

Therefore, for most tissues, blood flow at 100 mm Hg

See references for Chapter 15.

C H A P T E R

Vascular Distensibility and

Functions of the Arterial and

Venous Systems

Vascular Distensibility

A valuable characteristic of the vascular system is

that all blood vessels are distensible. We have seen

one example of this in Chapter 14: When the pres-

sure in blood vessels is increased, this dilates the

blood vessels and therefore decreases their resist-

ance. The result is increased blood flow not only

because of increased pressure but also because of decreased resistance, usually

giving at least twice as much flow increase for each increase in pressure as one

might expect.

Vascular distensibility also plays other important roles in circulatory function.

For example, the distensible nature of the arteries allows them to accommodate

the pulsatile output of the heart and to average out the pressure pulsations. This

provides smooth, continuous flow of blood through the very small blood vessels

of the tissues.

The most distensible by far of all the vessels are the veins. Even slight

increases in venous pressure cause the veins to store 0.5 to 1.0 liter of extra

blood. Therefore, the veins provide a reservoir function for storing large quan-

tities of extra blood that can be called into use whenever required elsewhere in

the circulation.

Units of Vascular Distensibility. Vascular distensibility normally is expressed as the

fractional increase in volume for each millimeter of mercury rise in pressure, in

accordance with the following formula:

Increase in volume

Vascular distensibility

Increase in pressure¥Original volume

That is, if 1 mm Hg causes a vessel that originally contained 10 millimeters of

blood to increase its volume by 1 milliliter, the distensibility would be 0.1 per

mm Hg, or 10 per cent per mm Hg.

Difference in Distensibility of the Arteries and the Veins. Anatomically, the walls

of the arteries are far stronger than those of the veins. Consequently, the arter-

ies, on average, are about eight times less distensible than the veins. That is, a

given increase in pressure causes about eight times as much increase in blood

in a vein as in an artery of comparable size.

In the pulmonary circulation, the pulmonary vein distensibilities are similar

to those of the systemic circulation. But, the pulmonary arteries normally

operate under pressures about one sixth of those in the systemic arterial system,

and their distensibilities are correspondingly greater, about six times the dis-

tensibility of systemic arteries.

Vascular Compliance (or Vascular Capacitance)

In hemodynamic studies, it usually is much more important to know the total

quantity of blood that can be stored in a given portion of the circulation for

each millimeter of mercury pressure rise than to know the distensibilities of the

171

172

Unit IV The Circulation

individual vessels. This value is called the compliance

In the entire systemic venous system, the volume

or capacitance of the respective vascular bed; that is,

normally ranges from 2000 to 3500 milliliters, and a

change of several hundred millimeters in this volume

Increase in volume

is required to change the venous pressure only 3 to

Vascular compliance

Increase in pressure

5 mm Hg. This mainly explains why as much as one

half liter of blood can be transfused into a healthy

Compliance and distensibility are quite different. A

person in only a few minutes without greatly altering

highly distensible vessel that has a slight volume may

function of the circulation.

have far less compliance than a much less distensible

vessel that has a large volume because compliance is

equal to distensibility times volume.

Effect of Sympathetic Stimulation or Sympathetic Inhibition on

The compliance of a systemic vein is about 24 times

the Volume-Pressure Relations of the Arterial and Venous

that of its corresponding artery because it is about 8

Systems. Also shown in Figure 15-1 are the effects that

times as distensible and it has a volume about 3 times

exciting or inhibiting the vascular sympathetic nerves

as great (8

¥ 3 = 24).

has on the volume-pressure curves. It is evident that

increase in vascular smooth muscle tone caused by

sympathetic stimulation increases the pressure at each

Volume-Pressure Curves of the

volume of the arteries or veins, whereas sympathetic

Arterial and Venous Circulations

inhibition decreases the pressure at each volume.

Control of the vessels in this manner by the sympa-

A convenient method for expressing the relation of

thetics is a valuable means for diminishing the

pressure to volume in a vessel or in any portion of the

dimensions of one segment of the circulation, thus

circulation is to use the so-called volume-pressure

transferring blood to other segments. For instance, an

curve. The red and blue solid curves in Figure 15-1

increase in vascular tone throughout the systemic cir-

represent, respectively, the volume-pressure curves

culation often causes large volumes of blood to shift

of the normal systemic arterial system and venous

into the heart, which is one of the principal methods

system, showing that when the arterial system of the

that the body uses to increase heart pumping.

average adult person (including all the large arteries,

Sympathetic control of vascular capacitance is also

small arteries, and arterioles) is filled with about 700

highly important during hemorrhage. Enhancement of

milliliters of blood, the mean arterial pressure is

sympathetic tone, especially to the veins, reduces the

100 mm Hg, but when it is filled with only 400 milli-

vessel sizes enough that the circulation continues to

liters of blood, the pressure falls to zero.

operate almost normally even when as much as 25 per

cent of the total blood volume has been lost.

Delayed Compliance

(Stress-Relaxation) of Vessels

The term “delayed compliance” means that a vessel

exposed to increased volume at first exhibits a large

140

increase in pressure, but progressive delayed stretching

of smooth muscle in the vessel wall allows the pressure

120

to return back toward normal over a period of minutes

Sympathetic stimulation

to hours. This effect is shown in Figure 15-2. In this

100

figure, the pressure is recorded in a small segment of a

Sympathetic inhibition

vein that is occluded at both ends. An extra volume of

blood is suddenly injected until the pressure rises from

5 to 12 mm Hg. Even though none of the blood is

Normal volume

removed after it is injected, the pressure begins to

decrease immediately and approaches about 9 mm Hg

Arterial system

after several minutes. In other words, the volume of

Venous system

blood injected causes immediate elastic distention of the

vein, but then the smooth muscle fibers of the vein begin

to “creep” to longer lengths, and their tensions corre-

500

1000

1500

2000

2500

3000

3500

spondingly decrease. This effect is a characteristic of all

Volume (ml)

smooth muscle tissue and is called stress-relaxation,

which was explained in Chapter 8.

Delayed compliance is a valuable mechanism by

which the circulation can accommodate much extra

blood when necessary, such as after too large a transfu-

Figure 15-1

sion. Delayed compliance in the reverse direction is one

“Volume-pressure curves” of the systemic arterial and venous

of the ways in which the circulation automatically

systems, showing the effects of stimulation or inhibition of the sym-

adjusts itself over a period of minutes or hours to dimin-

pathetic nerves to the circulatory system.

ished blood volume after serious hemorrhage.

Chapter 15

Vascular Distensibility and Functions of the Arterial and Venous Systems

173

Exponential diastolic decline

(may be distorted by

Slow rise

Sharp

reflected wave)

to peak

incisura

+20

- 80

Sharp

upstroke

- 80

Minutes

- 80

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

2.0

Figure 15-2

Seconds

Effect on the intravascular pressure of injecting a volume of blood

into a venous segment and later removing the excess blood,

demonstrating the principle of delayed compliance.

Figure 15-3

Pressure pulse contour recorded from the ascending

aorta.

(Redrawn from Opdyke DF: Fed Proc 11:734, 1952.)

Arterial Pressure Pulsations

With each beat of the heart a new surge of blood fills

the arteries. Were it not for distensibility of the arte-

rial system, all of this new blood would have to flow

160

through the peripheral blood vessels almost instanta-

neously, only during cardiac systole, and no flow would

120

occur during diastole. However, normally the compli-

ance of the arterial tree reduces the pressure pulsa-

Normal

Arteriosclerosis Aortic stenosis

tions to almost no pulsations by the time the blood

160

reaches the capillaries; therefore, tissue blood flow is

mainly continuous with very little pulsation.

120

A typical record of the pressure pulsations at the

root of the aorta is shown in Figure 15-3. In the

healthy young adult, the pressure at the top of each

Normal

pulse, called the systolic pressure, is about 120 mm Hg.

At the lowest point of each pulse, called the diastolic

Patent ductus

pressure, it is about 80 mm Hg. The difference between

arteriosus

Aortic

these two pressures, about 40 mm Hg, is called the

regurgitation

pulse pressure.

Two major factors affect the pulse pressure: (1) the

stroke volume output of the heart and (2) the compli-

ance (total distensibility) of the arterial tree. A third,

Figure 15-4

less important factor is the character of ejection from

Aortic pressure pulse contours in arteriosclerosis, aortic stenosis,

the heart during systole.

patent ductus arteriosus, and aortic regurgitation.

In general, the greater the stroke volume output, the

greater the amount of blood that must be accommo-

dated in the arterial tree with each heartbeat, and,

therefore, the greater the pressure rise and fall during

systole and diastole, thus causing a greater pulse pres-

have become hardened with arteriosclerosis and there-

sure. Conversely, the less the compliance of the arte-

fore are relatively noncompliant.

rial system, the greater the rise in pressure for a given

In effect, then, pulse pressure is determined ap-

stroke volume of blood pumped into the arteries. For

proximately by the ratio of stroke volume output to

instance, as demonstrated by the middle top curves in

compliance of the arterial tree. Any condition of the cir-

Figure 15-4, the pulse pressure in old age sometimes

culation that affects either of these two factors also

rises to as much as twice normal, because the arteries

affects the pulse pressure.

174

Unit IV The Circulation

Abnormal Pressure Pulse Contours

Wave fronts

Some conditions of the circulation also cause abnor-

mal contours of the pressure pulse wave in addition

to altering the pulse pressure. Especially distinctive

among these are aortic stenosis, patent ductus arterio-

sus, and aortic regurgitation, each of which is shown in

Figure 15-4.

In aortic stenosis, the diameter of the aortic valve

opening is reduced significantly, and the aortic pres-

sure pulse is decreased significantly because of dimin-

ished blood flow outward through the stenotic valve.

In patent ductus arteriosus, one half or more of the

blood pumped into the aorta by the left ventricle flows

immediately backward through the wide-open ductus

into the pulmonary artery and lung blood vessels, thus

allowing the diastolic pressure to fall very low before

the next heartbeat.

In aortic regurgitation, the aortic valve is absent or

will not close completely. Therefore, after each heart-

beat, the blood that has just been pumped into the

aorta flows immediately backward into the left ventri-

cle. As a result, the aortic pressure can fall all the way

Figure 15-5

to zero between heartbeats. Also, there is no incisura

in the aortic pulse contour because there is no aortic

Progressive stages in transmission of the pressure pulse along the

valve to close.

aorta.

Transmission of Pressure Pulses

to the Peripheral Arteries

When the heart ejects blood into the aorta during

systole, at first only the proximal portion of the aorta

becomes distended because the inertia of the blood

prevents sudden blood movement all the way to the

Incisura

periphery. However, the rising pressure in the proxi-

Systole

Diastole

mal aorta rapidly overcomes this inertia, and the wave

front of distention spreads farther and farther along

the aorta, as shown in Figure 15-5. This is called trans-

mission of the pressure pulse in the arteries.

Proximal aorta

The velocity of pressure pulse transmission in the

normal aorta is 3 to 5 m/sec; in the large arterial

branches, 7 to 10 m/sec; and in the small arteries, 15 to

35 m/sec. In general, the greater the compliance of

each vascular segment, the slower the velocity, which

Femoral artery

explains the slow transmission in the aorta and the

much faster transmission in the much less compliant

Radial artery

small distal arteries. In the aorta, the velocity of trans-

mission of the pressure pulse is 15 or more times the

velocity of blood flow because the pressure pulse is

simply a moving wave of pressure that involves little

Arteriole

forward total movement of blood volume.

Capillary

Damping of the Pressure Pulses in the Smaller Arteries, Arteri-

oles, and Capillaries. Figure 15-6 shows typical changes

in the contours of the pressure pulse as the pulse

travels into the peripheral vessels. Note especially in

Time (seconds)

the three lower curves that the intensity of pulsation

becomes progressively less in the smaller arteries,

the arterioles, and, especially, the capillaries. In fact,

Figure 15-6

only when the aortic pulsations are extremely large or

the arterioles are greatly dilated can pulsations be

Changes in the pulse pressure contour as the pulse wave travels

observed in the capillaries.

toward the smaller vessels.

Chapter 15

Vascular Distensibility and Functions of the Arterial and Venous Systems

175

This progressive diminution of the pulsations in the

arterial pressure cycle, a sound then is heard with each

periphery is called damping of the pressure pulses. The

pulsation. These sounds are called Korotkoff sounds.

cause of this is twofold: (1) resistance to blood move-

The exact cause of Korotkoff sounds is still

ment in the vessels and (2) compliance of the vessels.

debated, but they are believed to be caused mainly

The resistance damps the pulsations because a small

by blood jetting through the partly occluded vessel.

amount of blood must flow forward at the pulse wave

The jet causes turbulence in the vessel beyond the cuff,

front to distend the next segment of the vessel; the

and this sets up the vibrations heard through the

greater the resistance, the more difficult it is for this to

stethoscope.

occur. The compliance damps the pulsations because

In determining blood pressure by the auscultatory

the more compliant a vessel, the greater the quantity

method, the pressure in the cuff is first elevated well

of blood required at the pulse wave front to cause an

above arterial systolic pressure. As long as this cuff

increase in pressure. Therefore, in effect, the degree of

pressure is higher than systolic pressure, the brachial

damping is almost directly proportional to the product

artery remains collapsed so that no blood jets into the

of resistance times compliance.

lower artery during any part of the pressure cycle.

Therefore, no Korotkoff sounds are heard in the lower

artery. But then the cuff pressure gradually is reduced.

Clinical Methods for Measuring

Just as soon as the pressure in the cuff falls below sys-

Systolic and Diastolic Pressures

tolic pressure, blood begins to slip through the artery

beneath the cuff during the peak of systolic pressure,

It is not reasonable to use pressure recorders that

and one begins to hear tapping sounds from the ante-

require needle insertion into an artery for making

cubital artery in synchrony with the heartbeat. As soon

routine pressure measurements in human patients,

as these sounds begin to be heard, the pressure level

although these are used on occasion when special

indicated by the manometer connected to the cuff is

studies are necessary. Instead, the clinician determines

about equal to the systolic pressure.

systolic and diastolic pressures by indirect means,

As the pressure in the cuff is lowered still more, the

usually by the auscultatory method.

Korotkoff sounds change in quality, having less of the

tapping quality and more of a rhythmical and harsher

Auscultatory Method. Figure 15-7 shows the auscultatory

quality. Then, finally, when the pressure in the cuff falls

method for determining systolic and diastolic arterial

to equal diastolic pressure, the artery no longer closes

pressures. A stethoscope is placed over the antecubital

during diastole, which means that the basic factor

artery and a blood pressure cuff is inflated around the

causing the sounds (the jetting of blood through a

upper arm. As long as the cuff continues to compress

squeezed artery) is no longer present. Therefore, the

the arm with too little pressure to close the brachial

sounds suddenly change to a muffled quality, then dis-

artery, no sounds are heard from the antecubital artery

appear entirely after another 5- to 10-millimeter drop

with the stethoscope. However, when the cuff pressure

in cuff pressure. One notes the manometer pressure

is great enough to close the artery during part of the

when the Korotkoff sounds change to the muffled

quality; this pressure is about equal to the diastolic

pressure. The auscultatory method for determining

systolic and diastolic pressures is not entirely accurate,

Sounds

but it usually gives values within 10 per cent of those

determined by direct catheter measurement from

inside the arteries.

120

100

Normal Arterial Pressures as Measured by the Auscultatory

Method. Figure 15-8 shows the approximate normal

systolic and diastolic arterial pressures at different

ages. The progressive increase in pressure with age

150

results from the effects of aging on the blood pressure

control mechanisms. We shall see in Chapter 19 that

100

the kidneys are primarily responsible for this long-

term regulation of arterial pressure; and it is well

known that the kidneys exhibit definitive changes with

age, especially after the age of 50 years.

A slight extra increase in systolic pressure usually

occurs beyond the age of 60 years. This results from

hardening of the arteries, which itself is an end-stage

result of atherosclerosis. The final effect is a bounding

systolic pressure with considerable increase in pulse

pressure, as previously explained.

Figure 15-7

Auscultatory method for measuring systolic and diastolic arterial

Mean Arterial Pressure. The mean arterial pressure is the

pressures.

average of the arterial pressures measured millisecond

176

Unit IV The Circulation

Right atrial pressure is regulated by a balance

between (1) the ability of the heart to pump blood out

of the right atrium and ventricle into the lungs and (2)

200

the tendency for blood to flow from the peripheral veins

into the right atrium. If the right heart is pumping

150

strongly, the right atrial pressure decreases. Con-

versely, weakness of the heart elevates the right atrial

100

pressure. Also, any effect that causes rapid inflow of

blood into the right atrium from the peripheral veins

elevates the right atrial pressure. Some of the factors

that can increase this venous return (and thereby

increase the right atrial pressure) are (1) increased

blood volume, (2) increased large vessel tone through-

out the body with resultant increased peripheral

Age (years)

venous pressures, and (3) dilatation of the arterioles,

which decreases the peripheral resistance and allows

rapid flow of blood from the arteries into the veins.

The same factors that regulate right atrial pressure

Figure 15-8

also enter into the regulation of cardiac output

because the amount of blood pumped by the heart

Changes in systolic, diastolic, and mean arterial pressures with

depends on both the ability of the heart to pump and

age. The shaded areas show the approximate normal ranges.

the tendency for blood to flow into the heart from the

peripheral vessels. Therefore, we will discuss regula-

by millisecond over a period of time. It is not equal to

tion of right atrial pressure in much more depth in

the average of systolic and diastolic pressure because

Chapter 20 in connection with regulation of cardiac

the arterial pressure remains nearer to diastolic pres-

output.

sure than to systolic pressure during the greater part

The normal right atrial pressure is about 0 mm Hg,

of the cardiac cycle. Therefore, the mean arterial pres-

which is equal to the atmospheric pressure around the

sure is determined about 60 per cent by the diastolic

body. It can increase to 20 to 30 mm Hg under very

pressure and 40 per cent by the systolic pressure. Note

abnormal conditions, such as (1) serious heart failure

in Figure 15-8 that the mean pressure (solid green

or (2) after massive transfusion of blood, which greatly

line) at all ages is nearer to the diastolic pressure than

increases the total blood volume and causes excessive

to the systolic pressure.

quantities of blood to attempt to flow into the heart

from the peripheral vessels.

The lower limit to the right atrial pressure is usually

Veins and Their Functions

about -3 to -5 mm Hg below atmospheric pressure.

This is also the pressure in the chest cavity that sur-

For years, the veins were considered to be nothing

rounds the heart. The right atrial pressure approaches

more than passageways for flow of blood to the heart,

these low values when the heart pumps with excep-

but it has become apparent that they perform other

tional vigor or when blood flow into the heart from the

special functions that are necessary for operation of

peripheral vessels is greatly depressed, such as after

the circulation. Especially important, they are capable

severe hemorrhage.

of constricting and enlarging and thereby storing

either small or large quantities of blood and making

Venous Resistance and Peripheral

this blood available when it is required by the remain-

Venous Pressure

der of the circulation. The peripheral veins can also

Large veins have so little resistance to blood flow when

propel blood forward by means of a so-called venous

they are distended that the resistance then is almost

pump, and they even help to regulate cardiac output,

zero and is of almost no importance. However, as

an exceedingly important function that is described in

shown in Figure 15-9, most of the large veins that enter

detail in Chapter 20.

the thorax are compressed at many points by the sur-

rounding tissues, so that blood flow is impeded at these

points. For instance, the veins from the arms are com-

Venous Pressures—Right Atrial

pressed by their sharp angulations over the first rib.

Pressure (Central Venous Pressure)

Also, the pressure in the neck veins often falls so low

and Peripheral Venous Pressures

that the atmospheric pressure on the outside of the

neck causes these veins to collapse. Finally, veins

To understand the various functions of the veins, it is

coursing through the abdomen are often compressed

first necessary to know something about pressure in

by different organs and by the intra-abdominal pres-

the veins and what determines the pressure.

sure, so that they usually are at least partially collapsed

Blood from all the systemic veins flows into the right

to an ovoid or slitlike state. For these reasons, the

atrium of the heart; therefore, the pressure in the right

large veins do usually offer some resistance to blood

atrium is called the central venous pressure.

flow, and because of this, the pressure in the more

Chapter 15

Vascular Distensibility and Functions of the Arterial and Venous Systems

177

Sagittal sinus

-10 mm

0 mm

Atmospheric

0 mm

pressure

collapse in neck

+ 6 mm

+ 8 mm

Rib collapse

Axillary collapse

Intrathoracic

+ 22 mm

pressure = - 4 mm Hg

+ 35 mm

Abdominal

pressure

collapse

+ 40 mm

Figure 15-9

Compression points that tend to collapse the veins entering the

thorax.

peripheral small veins in a person lying down is usually

+4 to +6 mm Hg greater than the right atrial pressure.

Effect of High Right Atrial Pressure on Peripheral Venous Pres-

+ 90 mm

sure. When the right atrial pressure rises above its

normal value of 0 mm Hg, blood begins to back up in

the large veins. This enlarges the veins, and even the

collapse points in the veins open up when the right

Figure 15-10

atrial pressure rises above +4 to +6 mm Hg. Then, as

Effect of gravitational pressure on the venous pressures through-

the right atrial pressure rises still further, the addi-

out the body in the standing person.

tional increase causes a corresponding rise in periph-

eral venous pressure in the limbs and elsewhere.

Because the heart must be weakened greatly to cause

pressure, but the pressure rises 1 mm Hg for each 13.6

a rise in right atrial pressure as high as +4 to +6 mm

millimeters of distance below the surface. This pres-

Hg, one often finds that the peripheral venous pres-

sure results from the weight of the water and there-

sure is not noticeably elevated even in the early stages

fore is called gravitational pressure or hydrostatic

of heart failure.

pressure.

Gravitational pressure also occurs in the vascular

Effect of Intra-abdominal Pressure on Venous Pressures of the

system of the human being because of weight of the

Leg. The pressure in the abdominal cavity of a recum-

blood in the vessels, as shown in Figure 15-10. When

bent person normally averages about

+6 mm Hg,

a person is standing, the pressure in the right atrium

but it can rise to +15 to +30 mm Hg as a result of

remains about 0 mm Hg because the heart pumps into

pregnancy, large tumors, or excessive fluid

(called

the arteries any excess blood that attempts to accu-

“ascites”) in the abdominal cavity. When the intra-

mulate at this point. However, in an adult who is stand-

abdominal pressure does rise, the pressure in the veins

ing absolutely still, the pressure in the veins of the feet

of the legs must rise above the abdominal pressure

is about +90 mm Hg simply because of the gravita-

before the abdominal veins will open and allow

tional weight of the blood in the veins between

the blood to flow from the legs to the heart. Thus,

the heart and the feet. The venous pressures at other

if the intra-abdominal pressure is

+20 mm Hg, the

levels of the body are proportionately between 0 and

lowest possible pressure in the femoral veins is also

90 mm Hg.

+20 mm Hg.

In the arm veins, the pressure at the level of the top

rib is usually about +6 mm Hg because of compression

Effect of Gravitational Pressure on Venous

of the subclavian vein as it passes over this rib. The

Pressure

gravitational pressure down the length of the arm then

In any body of water that is exposed to air, the pres-

is determined by the distance below the level of this

sure at the surface of the water is equal to atmospheric

rib. Thus, if the gravitational difference between the

178

Unit IV The Circulation

level of the rib and the hand is +29 mm Hg, this grav-

Deep vein

itational pressure is added to the +6 mm Hg pressure

caused by compression of the vein as it crosses the rib,

making a total of +35 mm Hg pressure in the veins of

Perforating

the hand.

vein

The neck veins of a person standing upright collapse

almost completely all the way to the skull because of

Superficial

vein

atmospheric pressure on the outside of the neck. This

collapse causes the pressure in these veins to remain

at zero along their entire extent. The reason for this is

that any tendency for the pressure to rise above this

level opens the veins and allows the pressure to fall

back to zero because of flow of the blood. Conversely,

any tendency for the neck vein pressure to fall below

Valve

zero collapses the veins still more, which further

increases their resistance and again returns the pres-

sure back to zero.

The veins inside the skull, on the other hand, are in

a noncollapsible chamber (the skull cavity) so that

they cannot collapse. Consequently, negative pressure

can exist in the dural sinuses of the head; in the stand-

ing position, the venous pressure in the sagittal sinus

Figure 15-11

at the top of the brain is about -10 mm Hg because of

Venous valves of the leg.

the hydrostatic “suction” between the top of the skull

and the base of the skull. Therefore, if the sagittal sinus

is opened during surgery, air can be sucked immedi-

ately into the venous system; the air may even pass

legs increase to the full gravitational value of 90 mm

downward to cause air embolism in the heart, and

Hg in about 30 seconds. The pressures in the capillar-

death can ensue.

ies also increase greatly, causing fluid to leak from the

circulatory system into the tissue spaces. As a result,

Effect of the Gravitational Factor on Arterial and Other Pres-

the legs swell, and the blood volume diminishes.

sures. The gravitational factor also affects pressures in

Indeed, 10 to 20 per cent of the blood volume can be

the peripheral arteries and capillaries, in addition to its

lost from the circulatory system within the 15 to 30

effects in the veins. For instance, a standing person who

minutes of standing absolutely still, as often occurs

has a mean arterial pressure of 100 mm Hg at the level

when a soldier is made to stand at rigid attention.

of the heart has an arterial pressure in the feet of about

190 mm Hg. Therefore, when one states that the arte-

Venous Valve Incompetence Causes “Varicose” Veins. The

rial pressure is 100 mm Hg, this generally means that

valves of the venous system frequently become

this is the pressure at the gravitational level of the

“incompetent” or sometimes even are destroyed. This

heart but not necessarily elsewhere in the arterial

is especially true when the veins have been over-

vessels.

stretched by excess venous pressure lasting weeks or

months, as occurs in pregnancy or when one stands

Venous Valves and the “Venous Pump”:

most of the time. Stretching the veins increases their

Their Effects on Venous Pressure

cross-sectional areas, but the leaflets of the valves do

Were it not for valves in the veins, the gravitational

not increase in size. Therefore, the leaflets of the valves

pressure effect would cause the venous pressure in the

no longer close completely. When this develops, the

feet always to be about +90 mm Hg in a standing adult.

pressure in the veins of the legs increases greatly

However, every time one moves the legs, one tightens

because of failure of the venous pump; this further

the muscles and compresses the veins in or adjacent to

increases the sizes of the veins and finally destroys the

the muscles, and this squeezes the blood out of the

function of the valves entirely. Thus, the person devel-

veins. But the valves in the veins, shown in Figure

ops “varicose veins,” which are characterized by large,

15-11, are arranged so that the direction of venous

bulbous protrusions of the veins beneath the skin of

blood flow can be only toward the heart. Conse-

the entire leg, particularly the lower leg.

quently, every time a person moves the legs or even

Whenever people with varicose veins stand for more

tenses the leg muscles, a certain amount of venous

than a few minutes, the venous and capillary pressures

blood is propelled toward the heart. This pumping

become very high, and leakage of fluid from the cap-

system is known as the “venous pump” or “muscle

illaries causes constant edema in the legs. The edema

pump,” and it is efficient enough that under ordinary

in turn prevents adequate diffusion of nutritional

circumstances, the venous pressure in the feet of a

materials from the capillaries to the muscle and skin

walking adult remains less than +20 mm Hg.

cells, so that the muscles become painful and weak,

If a person stands perfectly still, the venous pump

and the skin frequently becomes gangrenous and

does not work, and the venous pressures in the lower

ulcerates. The best treatment for such a condition is

Chapter 15

Vascular Distensibility and Functions of the Arterial and Venous Systems

179

continual elevation of the legs to a level at least as high

significant gravitational changes in pressure at this point

as the heart. Tight binders on the legs also can be of

in the following way:

considerable assistance in preventing the edema and

If the pressure at the tricuspid valve rises slightly

above normal, the right ventricle fills to a greater extent

its sequelae.

than usual, causing the heart to pump blood more

rapidly and therefore to decrease the pressure at the tri-

Clinical Estimation of Venous Pressure. The venous pressure

cuspid valve back toward the normal mean value. Con-

often can be estimated by simply observing the degree

versely, if the pressure falls, the right ventricle fails to fill

of distention of the peripheral veins—especially of the

adequately, its pumping decreases, and blood dams up

neck veins. For instance, in the sitting position, the neck

in the venous system until the pressure at the tricuspid

veins are never distended in the normal quietly resting

level again rises to the normal value. In other words,

person. However, when the right atrial pressure be-

the heart acts as a feedback regulator of pressure at the

comes increased to as much as +10 mm Hg, the lower

tricuspid valve.

veins of the neck begin to protrude; and at +15 mm Hg

When a person is lying on his or her back, the tricus-

atrial pressure essentially all the veins in the neck

pid valve is located at almost exactly 60 per cent of the

become distended.

chest thickness in front of the back. This is the zero pres-

sure reference level for a person lying down.

Direct Measurement of Venous Pressure and

Right Atrial Pressure

Venous pressure can also be measured with ease by

inserting a needle directly into a vein and connecting it

Blood Reservoir Function of the Veins

to a pressure recorder. The only means by which right

atrial pressure can be measured accurately is by insert-

As pointed out in Chapter 14, more than 60 per cent

ing a catheter through the peripheral veins and into the

of all the blood in the circulatory system is usually in

right atrium. Pressures measured through such central

the veins. For this reason and also because the veins

venous catheters are used almost routinely in some types

are so compliant, it is said that the venous system

of hospitalized cardiac patients to provide constant

serves as a blood reservoir for the circulation.

assessment of heart pumping ability.

When blood is lost from the body and the arterial

pressure begins to fall, nervous signals are elicited

Pressure Reference Level for Measuring Venous and Other

Circulatory Pressures

from the carotid sinuses and other pressure-sensitive

In discussions up to this point, we often have spoken of

areas of the circulation, as discussed in Chapter 18.

right atrial pressure as being 0 mm Hg and arterial pres-

These in turn elicit nerve signals from the brain and

sure as being 100 mm Hg, but we have not stated the

spinal cord mainly through sympathetic nerves to the

gravitational level in the circulatory system to which this

veins, causing them to constrict. This takes up much of

pressure is referred. There is one point in the circula-

the slack in the circulatory system caused by the lost

tory system at which gravitational pressure factors

blood. Indeed, even after as much as 20 per cent of the

caused by changes in body position of a healthy person

total blood volume has been lost, the circulatory

usually do not affect the pressure measurement by more

system often functions almost normally because of this

than 1 to 2 mm Hg. This is at or near the level of the tri-

variable reservoir function of the veins.

cuspid valve, as shown by the crossed axes in Figure

15-12. Therefore, all circulatory pressure measurements

Specific Blood Reservoirs. Certain portions of the circu-

discussed in this text are referred to this level, which is

called the reference level for pressure measurement.

latory system are so extensive and/or so compliant that

The reason for lack of gravitational effects at the

they are called

“specific blood reservoirs.” These

tricuspid valve is that the heart automatically prevents

include (1) the spleen, which sometimes can decrease

in size sufficiently to release as much as 100 milliliters

of blood into other areas of the circulation; (2) the

Right ventricle

liver, the sinuses of which can release several hundred

milliliters of blood into the remainder of the circula-

tion; (3) the large abdominal veins, which can con-

tribute as much as 300 milliliters; and (4) the venous

plexus beneath the skin, which also can contribute

several hundred milliliters. The heart and the lungs,

Right atrium

although not parts of the systemic venous reservoir

system, must also be considered blood reservoirs. The

heart, for instance, shrinks during sympathetic stimu-

lation and in this way can contribute some 50 to 100

milliliters of blood; the lungs can contribute another

100 to 200 milliliters when the pulmonary pressures

decrease to low values.

Natural reference

point

The Spleen as a Reservoir for Storing Red Blood Cells.

Figure 15-13 shows that the spleen has two separate

Figure 15-12

areas for storing blood: the venous sinuses and the

Reference point for circulatory pressure measurement (located

pulp. The sinuses can swell the same as any other part

near the tricuspid valve).

of the venous system and store whole blood.

180

Unit IV The Circulation

lined with similar cells. These cells function as part of a

cleansing system for the blood, acting in concert with a

similar system of reticuloendothelial cells in the venous

sinuses of the liver. When the blood is invaded by infec-

tious agents, the reticuloendothelial cells of the spleen

rapidly remove debris, bacteria, parasites, and so forth.

Pulp

Also, in many chronic infectious processes, the spleen

enlarges in the same manner that lymph nodes enlarge

Capillaries

and then performs its cleansing function even more

avidly.

Venous sinuses

References

Vein

Artery

Badeer HS: Hemodynamics for medical students. Am J

Physiol (Adv Physiol Educ) 25:44, 2001.

Benetos A, Waeber B, Izzo J, Mitchell G, et al: Influence of

age, risk factors, and cardiovascular and renal disease on

arterial stiffness: clinical applications. Am J Hypertens

Figure 15-13

15:1101, 2002.

Gimbrone MA Jr, Topper JN, Nagel T, et al: Endothelial dys-

Functional structures of the spleen.

(Courtesy of Dr. Don W.

function, hemodynamic forces, and atherogenesis. Ann

Fawcett, Montana.)

N Y Acad Sci 902:230, 2000.

Guyton AC: Arterial Pressure and Hypertension.

Philadelphia: WB Saunders Co, 1980.

In the splenic pulp, the capillaries are so permeable

Guyton AC, Jones CE: Central venous pressure: physiologi-

cal significance and clinical implications. Am Heart J 86:

that whole blood, including the red blood cells, oozes

431, 1973.

through the capillary walls into a trabecular mesh,

Guyton AC, Jones CE, Coleman TG: Circulatory Physiology:

forming the red pulp. The red cells are trapped by the

Cardiac Output and Its Regulation. Philadelphia: WB

trabeculae, while the plasma flows on into the venous

Saunders Co, 1973.

sinuses and then into the general circulation. As a con-

Hall J: Integration and regulation of cardiovascular function.

sequence, the red pulp of the spleen is a special reser-

Am J Physiol (Adv Physiol Educ) 22:s174, 1999.

voir that contains large quantities of concentrated red

Hicks JW, Badeer HS: Gravity and the circulation: “open”

blood cells. These can then be expelled into the general

vs. “closed” systems. Am J Physiol 262:R725-R732, 1992.

circulation whenever the sympathetic nervous system

Jones DW, Appel LJ, Sheps SG, et al: Measuring blood pres-

becomes excited and causes the spleen and its vessels

sure accurately: New and persistent challenges. JAMA

289:1027, 2003.

to contract. As much as 50 milliliters of concentrated

Lakatta EG, Levy D: Arterial and cardiac aging: major

red blood cells can be released into the circulation,

shareholders in cardiovascular disease enterprises. Part I:

raising the hematocrit 1 to 2 per cent.

Aging arteries: a “set up” for vascular disease. Circulation

In other areas of the splenic pulp are islands of white

107:139, 2003.

blood cells, which collectively are called the white pulp.

McAlister FA, Straus SE: Evidence based treatment of

Here lymphoid cells are manufactured similar to those

hypertension. Measurement of blood pressure: an evi-

manufactured in the lymph nodes. They are part of the

dence based review. BMJ 322:908, 2001.

body’s immune system, described in Chapter 34.

O’Brien E, Asmar R, Beilin L, et al: European Society

of Hypertension recommendations for conventional,

Blood-Cleansing Function of the Spleen—Removal of Old Cells

ambulatory and home blood pressure measurement. J

Blood cells passing through the splenic pulp before

Hypertens 21:821, 2003.

entering the sinuses undergo thorough squeezing.

Perloff D, Grim C, Flack J, et al: Human blood pressure

Therefore, it is to be expected that fragile red blood cells

determination by sphygmomanometry. Circulation

would not withstand the trauma. For this reason, many

88:2460, 1993.

of the red blood cells destroyed in the body have their

Rothe CF, Gersting JM: Cardiovascular interactions: an

final demise in the spleen. After the cells rupture, the

interactive tutorial and mathematical model. Am J Physiol

released hemoglobin and the cell stroma are digested

(Adv Physiol Educ) 26:98, 2002.

by the reticuloendothelial cells of the spleen, and the

Safar ME, Levy BI, Struijker-Boudier H: Current perspec-

products of digestion are mainly reused by the body as

tives on arterial stiffness and pulse pressure in hyperten-

nutrients, often for making new blood cells.

sion and cardiovascular diseases. Circulation

107:2864,

2003.

Reticuloendothelial Cells of the Spleen

Verdecchia P, Angeli F, Gattobigio R: Clinical usefulness of

The pulp of the spleen contains many large phagocytic

ambulatory blood pressure monitoring. J Am Soc Nephrol

reticuloendothelial cells, and the venous sinuses are

15(Suppl 1):S30, 2004.

C H A P T E R

The Microcirculation and the

Lymphatic System: Capillary

Fluid Exchange, Interstitial Fluid,

and Lymph Flow

The most purposeful function of the circulation

occurs in the microcirculation: this is transport of

nutrients to the tissues and removal of cell excreta.

The small arterioles control blood flow to each

tissue area, and local conditions in the tissues in turn

control the diameters of the arterioles. Thus, each

tissue, in most instances, controls its own blood flow

in relation to its individual needs, a subject that is

discussed in detail in Chapter 17.

The walls of the capillaries are extremely thin, constructed of single-layer,

highly permeable endothelial cells. Therefore, water, cell nutrients, and cell

excreta can all interchange quickly and easily between the tissues and the cir-

culating blood.

The peripheral circulation of the whole body has about 10 billion capillaries

with a total surface area estimated to be 500 to 700 square meters (about one-

eighth the surface area of a football field). Indeed, it is rare that any single func-

tional cell of the body is more than 20 to 30 micrometers away from a capillary.

Structure of the Microcirculation and

Capillary System

The microcirculation of each organ is organized specifically to serve that organ’s

needs. In general, each nutrient artery entering an organ branches six to eight times

before the arteries become small enough to be called arterioles, which generally

have internal diameters of only 10 to 15 micrometers. Then the arterioles themselves

branch two to five times, reaching diameters of 5 to 9 micrometers at their ends

where they supply blood to the capillaries.

The arterioles are highly muscular, and their diameters can change manyfold. The

metarterioles (the terminal arterioles) do not have a continuous muscular coat, but

smooth muscle fibers encircle the vessel at intermittent points, as shown in Figure

16-1 by the black dots on the sides of the metarteriole.

At the point where each true capillary originates from a metarteriole, a smooth

muscle fiber usually encircles the capillary. This is called the precapillary sphincter.

This sphincter can open and close the entrance to the capillary.

The venules are larger than the arterioles and have a much weaker muscular coat.

Yet it must be remembered that the pressure in the venules is much less than that

in the arterioles, so that the venules still can contract considerably despite the weak

muscle.

This typical arrangement of the capillary bed is not found in all parts of the body;

however, some similar arrangement serves the same purposes. Most important, the

metarterioles and the precapillary sphincters are in close contact with the tissues

they serve. Therefore, the local conditions of the tissues—the concentrations of

nutrients, end products of metabolism, hydrogen ions, and so forth—can cause direct

effects on the vessels in controlling local blood flow in each small tissue area.

Structure of the Capillary Wall. Figure 16-2 shows the ultramicroscopic structure of

typical endothelial cells in the capillary wall as found in most organs of the body,

especially in muscles and connective tissue. Note that the wall is composed of

181

182

Unit IV The Circulation

Metarteriole

Preferential channel

Because the intercellular clefts are located only at

the edges of the endothelial cells, they usually repre-

Arteriole

sent no more than 1/1000 of the total surface area of

Precapillary

sphincter

the capillary wall. Nevertheless, the rate of thermal

motion of water molecules as well as most water-

True capillaries

soluble ions and small solutes is so rapid that all of

these diffuse with ease between the interior and exte-

rior of the capillaries through these “slit-pores,” the

Venule

intercellular clefts.

Also present in the endothelial cells are many

minute plasmalemmal vesicles. These form at one

surface of the cell by imbibing small packets of plasma

Figure 16-1

or extracellular fluid. They can then move slowly

through the endothelial cell. It also has been postu-

Structure of the mesenteric capillary bed. (Redrawn from Zweifach

BW: Factors Regulating Blood Pressure. New York: Josiah Macy,

lated that some of these vesicles coalesce to form

Jr., Foundation, 1950.)

vesicular channels all the way through the endothelial

cell, which is demonstrated to the right in Figure 16-2.

However, careful measurements in laboratory animals

Endothelial

probably have proved that these vesicular forms of

cell

transport are quantitatively of little importance.

Special Types of “Pores” Occur in the Capillaries of Certain

Vesicular

Organs. The “pores” in the capillaries of some organs

channel??

have special characteristics to meet the peculiar needs

of the organs. Some of these characteristics are as

Plasmalemmal

vesicles

follows:

1. In the brain, the junctions between the capillary

endothelial cells are mainly “tight” junctions that

allow only extremely small molecules such as

water, oxygen, and carbon dioxide to pass into or

out of the brain tissues.

Basement

2. In the liver, the opposite is true. The clefts between

Intercellular

membrane

the capillary endothelial cells are wide open, so

cleft

that almost all dissolved substances of the plasma,

including the plasma proteins, can pass from the

Figure 16-2

blood into the liver tissues.

Structure of the capillary wall. Note especially the intercellular cleft

3. The pores of the gastrointestinal capillary

at the junction between adjacent endothelial cells; it is believed

membranes are midway between those of the

that most water-soluble substances diffuse through the capillary

muscles and those of the liver.

membrane along the clefts.

4. In the glomerular tufts of the kidney, numerous

small oval windows called fenestrae penetrate all

the way through the middle of the endothelial

cells, so that tremendous amounts of very small

a unicellular layer of endothelial cells and is sur-

molecular and ionic substances (but not the large

molecules of the plasma proteins) can filter through

rounded by a very thin basement membrane on the

the glomeruli without having to pass through the

outside of the capillary. The total thickness of the cap-

clefts between the endothelial cells.

illary wall is only about 0.5 micrometer. The internal

diameter of the capillary is 4 to 9 micrometers, barely

large enough for red blood cells and other blood cells

Flow of Blood in the

to squeeze through.

Capillaries—Vasomotion

“Pores” in the Capillary Membrane. Studying Figure 16-2,

one sees two very small passageways connecting the

Blood usually does not flow continuously through the

interior of the capillary with the exterior. One of these

capillaries. Instead, it flows intermittently, turning on

is an intercellular cleft, which is the thin-slit, curving

and off every few seconds or minutes. The cause of this

channel that lies at the bottom of the figure between

intermittency is the phenomenon called vasomotion,

adjacent endothelial cells. Each cleft is interrupted

which means intermittent contraction of the metarte-

periodically by short ridges of protein attachments

rioles and precapillary sphincters

(and sometimes

that hold the endothelial cells together, but between

even the very small arterioles as well).

these ridges fluid can percolate freely through the

cleft. The cleft normally has a uniform spacing with a

Regulation of Vasomotion. The most important factor

width of about 6 to 7 nanometers (60 to 70 angstroms),

found thus far to affect the degree of opening and

slightly smaller than the diameter of an albumin

closing of the metarterioles and precapillary sphinc-

protein molecule.

ters is the concentration of oxygen in the tissues. When

Chapter 16

The Microcirculation and the Lymphatic System

183

the rate of oxygen usage by the tissue is great so that

Arterial end

Blood capillary

Venous end

tissue oxygen concentration decreases below normal,

the intermittent periods of capillary blood flow occur

more often, and the duration of each period of flow

lasts longer, thereby allowing the capillary blood to

carry increased quantities of oxygen (as well as other

nutrients) to the tissues. This effect, along with multi-

ple other factors that control local tissue blood flow, is

discussed in Chapter 17.

Average Function of the

Capillary System

Lymphatic

Despite the fact that blood flow through each capillary

capillary

is intermittent, so many capillaries are present in the

tissues that their overall function becomes averaged.

That is, there is an average rate of blood flow through

each tissue capillary bed, an average capillary pressure

within the capillaries, and an average rate of transfer of

Figure 16-3

substances between the blood of the capillaries and the

surrounding interstitial fluid. In the remainder of this

Diffusion of fluid molecules and dissolved substances between

chapter, we will be concerned with these averages,

the capillary and interstitial fluid spaces.

although one must remember that the average func-

tions are, in reality, the functions of literally billions of

individual capillaries, each operating intermittently in

response to local conditions in the tissues.

substances, such as sodium ions and glucose that can

go only through the pores.

Exchange of Water, Nutrients,

Water-Soluble, Non-Lipid-Soluble Substances Diffuse Only

and Other Substances

Through Intercellular

“Pores” in the Capillary Membrane.

Between the Blood and

Many substances needed by the tissues are soluble in

water but cannot pass through the lipid membranes of

Interstitial Fluid

the endothelial cells; such substances include water

molecules themselves, sodium ions, chloride ions, and

Diffusion Through the

glucose. Despite the fact that not more than 1/1000 of

Capillary Membrane

the surface area of the capillaries is represented by the

intercellular clefts between the endothelial cells, the

By far the most important means by which substances

velocity of thermal molecular motion in the clefts is so

are transferred between the plasma and the interstitial

great that even this small area is sufficient to allow

fluid is diffusion. Figure

16-3 demonstrates this

tremendous diffusion of water and water-soluble sub-

process, showing that as the blood flows along the

stances through these cleft-pores. To give one an idea

lumen of the capillary, tremendous numbers of water

of the rapidity with which these substances diffuse, the

molecules and dissolved particles diffuse back and

rate at which water molecules diffuse through the cap-

forth through the capillary wall, providing continual

illary membrane is about 80 times as great as the rate at

mixing between the interstitial fluid and the plasma.

which plasma itself flows linearly along the capillary.

Diffusion results from thermal motion of the water

That is, the water of the plasma is exchanged with

molecules and dissolved substances in the fluid, the

the water of the interstitial fluid 80 times before the

different molecules and ions moving first in one direc-

plasma can flow the entire distance through the

tion and then another, bouncing randomly in every

capillary.

direction.

Effect of Molecular Size on Passage Through the

Lipid-Soluble Substances Can Diffuse Directly Through the Cell

Pores. The width of the capillary intercellular cleft-

Membranes of the Capillary Endothelium. If a substance is

pores, 6 to 7 nanometers, is about 20 times the diame-

lipid soluble, it can diffuse directly through the cell

ter of the water molecule, which is the smallest

membranes of the capillary without having to go

molecule that normally passes through the capillary

through the pores. Such substances include oxygen and

pores. Conversely, the diameters of plasma protein

carbon dioxide. Because these substances can per-

molecules are slightly greater than the width of the

meate all areas of the capillary membrane, their rates

pores. Other substances, such as sodium ions, chloride

of transport through the capillary membrane are

ions, glucose, and urea, have intermediate diameters.

many times faster than the rates for lipid-insoluble

Therefore, the permeability of the capillary pores for

184

Unit IV The Circulation

Table 16-1

Relative Permeability of Skeletal Muscle Capillary Pores to

Different-Sized Molecules

Free fluid

vesicles

Substance

Molecular Weight

Permeability

Water

1.00

Rivulets

NaCl

58.5

0.96

of free

Urea

0.8

fluid

Glucose

180

0.6

Sucrose

342

0.4

Inulin

5,000

0.2

Myoglobin

17,600

0.03

Hemoglobin

68,000

0.01

Albumin

69,000

0.001

Data from Pappenheimer JR: Passage of molecules through capillary walls.

Physiol Rev 33:387, 1953.

Collagen fiber

Proteoglycan

Capillary

bundles

filaments

different substances varies according to their molecu-

Figure 16-4

lar diameters.

Structure of the interstitium. Proteoglycan filaments are every-

Table 16-1 gives the relative permeabilities of the

where in the spaces between the collagen fiber bundles. Free fluid

capillary pores in skeletal muscle for substances com-

vesicles and small amounts of free fluid in the form of rivulets

monly encountered, demonstrating, for instance, that

occasionally also occur.

the permeability for glucose molecules is 0.6 times that

for water molecules, whereas the permeability for

albumin molecules is very, very slight, only 1/1000 that

for water molecules.

to move into the blood and to be carried away from

A word of caution must be issued at this point.

the tissues.

The capillaries in different tissues have extreme dif-

The rates of diffusion through the capillary mem-

ferences in their permeabilities. For instance, the mem-

branes of most nutritionally important substances are

brane of the liver capillary sinusoids is so permeable

so great that only slight concentration differences

that even plasma proteins pass freely through these

suffice to cause more than adequate transport between

walls, almost as easily as water and other substances.

the plasma and interstitial fluid. For instance, the con-

Also, the permeability of the renal glomerular mem-

centration of oxygen in the interstitial fluid immedi-

brane for water and electrolytes is about 500 times the

ately outside the capillary is no more than a few per

permeability of the muscle capillaries, but this is not

cent less than its concentration in the plasma of the

true for the plasma proteins; for these, the capillary

blood, yet this slight difference causes enough oxygen

permeabilities are very slight, as in other tissues and

to move from the blood into the interstitial spaces to

organs. When we study these different organs later in

provide all the oxygen required for tissue metabolism,

this text, it should become clear why some tissues—the

often as much as several liters of oxygen per minute

liver, for instance—require greater degrees of capillary

during very active states of the body.

permeability than others to transfer tremendous

amounts of nutrients between the blood and liver

The Interstitium and

parenchymal cells, and the kidneys to allow filtration

of large quantities of fluid for formation of urine.

Interstitial Fluid

Effect of Concentration Difference on Net Rate of Diffusion

About one sixth of the total volume of the body con-

Through the Capillary Membrane. The “net” rate of diffu-

sists of spaces between cells, which collectively are

sion of a substance through any membrane is propor-

called the interstitium. The fluid in these spaces is the

tional to the concentration difference of the substance

interstitial fluid.

between the two sides of the membrane. That is, the

The structure of the interstitium is shown in Figure

greater the difference between the concentrations of

16-4. It contains two major types of solid structures:

any given substance on the two sides of the capillary

(1) collagen fiber bundles and (2) proteoglycan fila-

membrane, the greater the net movement of the sub-

ments. The collagen fiber bundles extend long dis-

stance in one direction through the membrane. For

tances in the interstitium. They are extremely strong

instance, the concentration of oxygen in capillary

and therefore provide most of the tensional strength

blood is normally greater than in the interstitial fluid.

of the tissues. The proteoglycan filaments, however, are

Therefore, large quantities of oxygen normally move

extremely thin coiled or twisted molecules composed

from the blood toward the tissues. Conversely, the con-

of about 98 per cent hyaluronic acid and 2 per cent

centration of carbon dioxide is greater in the tissues

protein. These molecules are so thin that they can

than in the blood, which causes excess carbon dioxide

never be seen with a light microscope and are difficult

Chapter 16

The Microcirculation and the Lymphatic System

185

to demonstrate even with the electron microscope.

Capillary

Plasma colloid

Nevertheless, they form a mat of very fine reticular fil-

pressure

osmotic pressure

aments aptly described as a “brush pile.”

(Pc)

(Pp)

“Gel” in the Interstitium. The fluid in the interstitium is

derived by filtration and diffusion from the capillaries.

It contains almost the same constituents as plasma

except for much lower concentrations of proteins

Interstitial

Interstitial fluid

because proteins do not pass outward through the

fluid pressure

colloid osmotic pressure

pores of the capillaries with ease. The interstitial fluid

(Pif)

is entrapped mainly in the minute spaces among the

proteoglycan filaments. This combination of proteo-

Figure 16-5

glycan filaments and fluid entrapped within them has

the characteristics of a gel and therefore is called tissue

Fluid pressure and colloid osmotic pressure forces operate at the

capillary membrane, tending to move fluid either outward or

gel.

inward through the membrane pores.

Because of the large number of proteoglycan fila-

ments, it is difficult for fluid to flow easily through the

tissue gel. Instead, it mainly diffuses through the gel;

that is, it moves molecule by molecule from one place

of fluid volume from the blood into the interstitial

to another by kinetic, thermal motion rather than by

spaces.

large numbers of molecules moving together.

Also important is the lymphatic system, which

Diffusion through the gel occurs about 95 to 99 per

returns to the circulation the small amounts of excess

cent as rapidly as it does through free fluid. For the

protein and fluid that leak from the blood into the

short distances between the capillaries and the tissue

interstitial spaces. In the remainder of this chapter, we

cells, this diffusion allows rapid transport through the

discuss the mechanisms that control capillary filtration

interstitium not only of water molecules but also of

and lymph flow function together to regulate the

electrolytes, small molecular weight nutrients, cellular

respective volumes of the plasma and the interstitial

excreta, oxygen, carbon dioxide, and so forth.

fluid.

“Free” Fluid in the Interstitium. Although almost all the

Four Primary Hydrostatic and Colloid Osmotic Forces Determine

fluid in the interstitium normally is entrapped within

Fluid Movement Through the Capillary Membrane. Figure

the tissue gel, occasionally small rivulets of “free” fluid

16-5 shows the four primary forces that determine

and small free fluid vesicles are also present, which

whether fluid will move out of the blood into the inter-

means fluid that is free of the proteoglycan molecules

stitial fluid or in the opposite direction. These forces,

and therefore can flow freely. When a dye is injected

called “Starling forces” in honor of the physiologist

into the circulating blood, it often can be seen to flow

who first demonstrated their importance, are:

through the interstitium in the small rivulets, usually

1. The capillary pressure (Pc), which tends to force

coursing along the surfaces of collagen fibers or sur-

fluid outward through the capillary membrane.

faces of cells.

2. The interstitial fluid pressure (Pif), which tends

The amount of “free” fluid present in normal tissues

to force fluid inward through the capillary

is slight, usually much less than 1 per cent. Conversely,

membrane when Pif is positive but outward when

when the tissues develop edema, these small pockets

Pif is negative.

and rivulets of free fluid expand tremendously until one

3. The capillary plasma colloid osmotic pressure

half or more of the edema fluid becomes freely flowing

(Pp), which tends to cause osmosis of fluid inward

fluid independent of the proteoglycan filaments.

through the capillary membrane.

4. The interstitial fluid colloid osmotic pressure (Pif),

which tends to cause osmosis of fluid outward

Fluid Filtration Across

through the capillary membrane.

Capillaries Is Determined

If the sum of these forces, the net filtration pressure,

is positive, there will be a net fluid filtration across the

by Hydrostatic and Colloid

capillaries. If the sum of the Starling forces is negative,

Osmotic Pressures, and

there will be a net fluid absorption from the intersti-

Capillary Filtration Coefficient

tial spaces into the capillaries. The net filtration pres-

sure (NFP) is calculated as:

The hydrostatic pressure in the capillaries tends to

NFP = Pc - Pif - Pp + Pif

force fluid and its dissolved substances through the

capillary pores into the interstitial spaces. Conversely,

As discussed later, the NFP is slightly positive under

osmotic pressure caused by the plasma proteins

normal conditions, resulting in a net filtration of fluid

(called colloid osmotic pressure) tends to cause fluid

across the capillaries into the interstitial space in most

movement by osmosis from the interstitial spaces

organs. The rate of fluid filtration in a tissue is also

into the blood. This osmotic pressure exerted by

determined by the number and size of the pores in

the plasma proteins normally prevents significant loss

each capillary as well as the number of capillaries in

186

Unit IV The Circulation

which blood is flowing. These factors are usually

expressed together as the capillary filtration coefficient

(K_f). The K_f is therefore a measure of the capacity of

the capillary membranes to filter water for a given

NFP and is usually expressed as ml/min per mm Hg

net filtration pressure.

The rate of capillary fluid filtration is therefore

determined as:

Filtration=K ¥NFP

In the following sections we discuss in detail each

of the forces that determine the rate of capillary fluid

filtration.

Gut

Arterial pressure

Capillary Hydrostatic Pressure

Venous pressure

Two experimental methods have been used to esti-

mate the capillary hydrostatic pressure:

(1) direct

micropipette cannulation of the capillaries, which has

100

given an average mean capillary pressure of about 25

mm Hg, and (2) indirect functional measurement of the

capillary pressure, which has given a capillary pressure

averaging about 17 mm Hg.

Micropipette Method for Measuring Capillary Pressure. To

measure pressure in a capillary by cannulation, a

microscopic glass pipette is thrust directly into the cap-

illary, and the pressure is measured by an appropriate

micromanometer system. Using this method, capillary

Capillary pressure

pressures have been measured in capillaries of

= 17 mm Hg

exposed tissues of animals and in large capillary loops

of the eponychium at the base of the fingernail in

humans. These measurements have given pressures of

30 to 40 mm Hg in the arterial ends of the capillaries,

100

Arterial pressure

- venous pressure

10 to 15 mm Hg in the venous ends, and about 25 mm

Hg in the middle.

Figure 16-6

Isogravimetric Method for Indirectly Measuring “Functional”

Isogravimetric method for measuring capillary pressure.

Capillary Pressure. Figure

16-6 demonstrates an iso-

gravimetric method for indirectly estimating capillary

pressure. This figure shows a section of gut held up by

one arm of a gravimetric balance. Blood is perfused

fluid through the capillary walls would have occurred.

through the blood vessels of the gut wall. When the

Thus, in a roundabout way, the “functional” capillary

arterial pressure is decreased, the resulting decrease in

pressure is measured to be about 17 mm Hg.

capillary pressure allows the osmotic pressure of the

plasma proteins to cause absorption of fluid out of the

Why Is the Functional Capillary Pressure Lower than Capillary

gut wall and makes the weight of the gut decrease. This

Pressure Measured by the Micropipette Method? It is clear

immediately causes displacement of the balance arm.

that the aforementioned two methods do not give the

To prevent this weight decrease, the venous pressure

same capillary pressure. However, the isogravimetric

is increased an amount sufficient to overcome the

method determines the capillary pressure that exactly

effect of decreasing the arterial pressure. In other

balances all the forces tending to move fluid into or

words, the capillary pressure is kept constant while

out of the capillaries. Because such a balance of forces

simultaneously (1) decreasing the arterial pressure

is the normal state, the average functional capillary

and (2) increasing the venous pressure.

pressure must be close to the pressure measured by

In the graph in the lower part of the figure, the

the isogravimetric method. Therefore, one is justified

changes in arterial and venous pressures that exactly

in believing that the true functional capillary pressure

nullify all weight changes are shown. The arterial and

averages about 17 mm Hg.

venous lines meet each other at a value of 17 mm Hg.

It is easy to explain why the cannulation methods

Therefore, the capillary pressure must have remained

give higher pressure values. The most important

at this same level of

17 mm Hg throughout these

reason is that these measurements usually are made

maneuvers; otherwise, either filtration or absorption of

in capillaries whose arterial ends are open and when

Chapter 16

The Microcirculation and the Lymphatic System

187

blood is actively flowing into the capillary. However, it

protruding from its end. The cotton fibers form a “wick”

should be recalled from the earlier discussion of cap-

that makes excellent contact with the tissue fluids and

illary vasomotion that the metarterioles and precapil-

transmits interstitial fluid pressure into the Teflon tube:

the pressure can then be measured from the tube by

lary sphincters normally are closed during a large part

usual manometric means. Pressures measured by this

of the vasomotion cycle. When closed, the pressure in

technique in loose subcutaneous tissue also have been

the capillaries beyond the closures should be almost

negative, usually measuring -1 to -3 mm Hg.

equal to the pressure at the venous ends of the capil-

laries, about

10 mm Hg. Therefore, when averaged

Interstitial Fluid Pressures in Tightly

over a period of time, one would expect the functional

Encased Tissues

mean capillary pressure to be much nearer to the pres-

Some tissues of the body are surrounded by tight

sure in the venous ends of the capillaries than to the

encasements, such as the cranial vault around the

pressure in the arterial ends.

brain, the strong fibrous capsule around the kidney, the

There are two other reasons why the functional cap-

fibrous sheaths around the muscles, and the sclera

illary pressure is less than the values measured by can-

around the eye. In most of these, regardless of the

nulation. First, there are far more capillaries nearer to

method used for measurement, the interstitial fluid

the venules than to the arterioles. Second, the venous

pressures are usually positive. However, these intersti-

capillaries are several times as permeable as the arte-

tial fluid pressures almost invariably are still less than

rial capillaries. Both of these effects further decrease

the pressures exerted on the outsides of the tissues by

the functional capillary pressure to a lower value.

their encasements. For instance, the cerebrospinal fluid

pressure surrounding the brain of an animal lying on

its side averages about +10 mm Hg, whereas the brain

Interstitial Fluid Hydrostatic Pressure

interstitial fluid pressure averages about +4 to +6 mm

Hg. In the kidneys, the capsular pressure surrounding

As is true for the measurement of capillary pressure,

the kidney averages about +13 mm Hg, whereas the

there are several methods for measuring interstitial

reported renal interstitial fluid pressures have averaged

fluid pressure, and each of these gives slightly differ-

about +6 mm Hg. Thus, if one remembers that the

ent values but usually values that are a few millime-

pressure exerted on the skin is atmospheric pressure,

ters of mercury less than atmospheric pressure, that is,

which is considered to be zero pressure, one might for-

values called negative interstitial fluid pressure. The

mulate a general rule that the normal interstitial fluid

methods most widely used have been (1) direct can-

pressure is usually several millimeters of mercury neg-

nulation of the tissues with a micropipette, (2) meas-

ative with respect to the pressure that surrounds each

urement of the pressure from implanted perforated

tissue.

capsules, and (3) measurement of the pressure from a

cotton wick inserted into the tissue.

Is the True Interstitial Fluid Pressure in Loose

Subcutaneous Tissue Subatmospheric?

Measurement of Interstitial Fluid Pressure Using the

The concept that the interstitial fluid pressure is sub-

Micropipette. The same type of micropipette used for

atmospheric in many if not most tissues of the body

measuring capillary pressure can also be used in some

began with clinical observations that could not be

tissues for measuring interstitial fluid pressure. The tip

explained by the previously held concept that intersti-

of the micropipette is about 1 micrometer in diameter,

tial fluid pressure was always positive. Some of the per-

but even this is 20 or more times larger than the sizes

tinent observations are the following:

of the spaces between the proteoglycan filaments of the

1. When a skin graft is placed on a concave surface

interstitium. Therefore, the pressure that is measured is

probably the pressure in a free fluid pocket.

of the body, such as in an eye socket after

The first pressures measured using the micropipette

removal of the eye, before the skin becomes

method ranged from -1 to +2 mm Hg but were usually

attached to the sublying socket, fluid tends to

slightly positive. With experience and improved equip-

collect underneath the graft. Also, the skin

ment for making such measurements, more recent pres-

attempts to shorten, with the result that it tends to

sures have averaged about -2 mm Hg, giving average

pull it away from the concavity. Nevertheless,

pressure values in loose tissues, such as skin, that are

some negative force underneath the skin causes

slightly less than atmospheric pressure.

absorption of the fluid and usually literally pulls

the skin back into the concavity.

Measurement of Interstitial Free Fluid Pressure in Implanted Per-

2. Less than 1 mm Hg of positive pressure is

forated Hollow Capsules. Interstitial free fluid pressure

required to inject tremendous volumes of fluid

measured by this method when using 2-centimeter

into loose subcutaneous tissues, such as beneath

diameter capsules in normal loose subcutaneous tissue

the lower eyelid, in the axillary space, and in the

averages about -6 mm Hg, but with smaller capsules,

the values are not greatly different from the -2 mm Hg

scrotum. Amounts of fluid calculated to be more

measured by the micropipette in Figure 16-7.

than 100 times the amount of fluid normally in the

interstitial space, when injected into these areas,

Measurement of Interstitial Free Fluid Pressure by Means of a

cause no more than about 2 mm Hg of positive

Cotton Wick. Still another method is to insert into a

pressure. The importance of these observations is

tissue a small Teflon tube with about eight cotton fibers

that they show that such tissues do not have

188

Unit IV The Circulation

strong fibers that can prevent the accumulation of

through the capillary pores, it is the proteins of the

fluid. Therefore, some other mechanism, such as a

plasma and interstitial fluids that are responsible for

negative fluid pressure system, must be available

the osmotic pressures on the two sides of the capillary

to prevent such fluid accumulation.

membrane. To distinguish this osmotic pressure from

3. In most natural cavities of the body where there

that which occurs at the cell membrane, it is called

is free fluid in dynamic equilibrium with the

either colloid osmotic pressure or oncotic pressure. The

surrounding interstitial fluids, the pressures that

term “colloid” osmotic pressure is derived from the

have been measured have been negative. Some of

fact that a protein solution resembles a colloidal solu-

these are the following:

tion despite the fact that it is actually a true molecu-

lar solution.

Intrapleural space: -8 mm Hg

Joint synovial spaces: -4 to -6 mm Hg

Normal Values for Plasma Colloid Osmotic Pressure. The

Epidural space: -4 to -6 mm Hg

colloid osmotic pressure of normal human plasma

4. The implanted capsule for measuring the

averages about 28 mm Hg; 19 mm of this is caused by

interstitial fluid pressure can be used to record

molecular effects of the dissolved protein and 9 mm by

dynamic changes in this pressure. The changes are

the Donnan effect—that is, extra osmotic pressure

approximately those that one would calculate to

caused by sodium, potassium, and the other cations

occur (1) when the arterial pressure is increased

held in the plasma by the proteins.

or decreased, (2) when fluid is injected into the

surrounding tissue space, or (3) when a highly

Effect of the Different Plasma Proteins on Colloid Osmotic

Pressure. The plasma proteins are a mixture that con-

concentrated colloid osmotic agent is injected into

tains albumin, with an average molecular weight of

the blood to absorb fluid from the tissue spaces. It

69,000; globulins, 140,000; and fibrinogen, 400,000. Thus,

is not likely that these dynamic changes could be

1 gram of globulin contains only half as many molecules

recorded this accurately unless the capsule

as 1 gram of albumin, and 1 gram of fibrinogen contains

pressure closely approximated the true interstitial

only one sixth as many molecules as 1 gram of albumin.

pressure.

It should be recalled from the discussion of osmotic

pressure in Chapter 4 that osmotic pressure is deter-

Summary—An Average Value for Negative Interstitial Fluid

mined by the number of molecules dissolved in a fluid

Pressure in Loose Subcutaneous Tissue. Although the

rather than by the mass of these molecules. Therefore,

aforementioned different methods give slightly differ-

when corrected for number of molecules rather than

mass, the following chart gives both the relative mass

ent values for interstitial fluid pressure, there currently

concentrations (g/dl) of the different types of proteins

is a general belief among most physiologists that the

in normal plasma and their respective contributions to

true interstitial fluid pressure in loose subcutaneous

the total plasma colloid osmotic pressure (Pp).

tissue is slightly less subatmospheric, averaging about

-3 mm Hg.

Pumping by the Lymphatic System Is the

g/dl

Pp (mm Hg)

Basic Cause of the Negative Interstitial

Albumin

4.5

21.8

Fluid Pressure

Globulins

2.5

6.0

The lymphatic system is discussed later in the chapter,

Fibrinogen

0.3

0.2

but we need to understand here the basic role that this

Total

7.3

28.0

system plays in determining interstitial fluid pressure.

The lymphatic system is a “scavenger” system that

removes excess fluid, excess protein molecules, debris,

Thus, about 80 per cent of the total colloid osmotic

and other matter from the tissue spaces. Normally,

pressure of the plasma results from the albumin frac-

when fluid enters the terminal lymphatic capillaries,

tion, 20 per cent from the globulins, and almost none

the lymph vessel walls automatically contract for a few

from the fibrinogen. Therefore, from the point of view

seconds and pump the fluid into the blood circulation.

of capillary and tissue fluid dynamics, it is mainly

This overall process creates the slight negative pres-

albumin that is important.

sure that has been measured for fluid in the interstitial

spaces.

Interstitial Fluid Colloid

Osmotic Pressure

Plasma Colloid Osmotic Pressure

Although the size of the usual capillary pore is smaller

Proteins in the Plasma Cause Colloid Osmotic Pressure. In the

than the molecular sizes of the plasma proteins, this is

basic discussion of osmotic pressure in Chapter 4, it

not true of all the pores. Therefore, small amounts of

was pointed out that only those molecules or ions that

plasma proteins do leak through the pores into the

fail to pass through the pores of a semiperme-

interstitial spaces.

able membrane exert osmotic pressure. Because the

The total quantity of protein in the entire 12 liters

proteins are the only dissolved constituents in the

of interstitial fluid of the body is slightly greater than

plasma and interstitial fluids that do not readily pass

the total quantity of protein in the plasma itself, but

Chapter 16

The Microcirculation and the Lymphatic System

189

because this volume is four times the volume of

mm Hg

plasma, the average protein concentration of the inter-

stitial fluid is usually only 40 per cent of that in plasma,

Forces tending to move fluid inward:

or about 3 g/dl. Quantitatively, one finds that the

Plasma colloid osmotic pressure

average interstitial fluid colloid osmotic pressure for

total inward force

this concentration of proteins is about 8 mm Hg.

Forces tending to move fluid outward:

Capillary pressure (venous end of capillary)

Negative interstitial free fluid pressure

Interstitial fluid colloid osmotic pressure

Exchange of Fluid Volume Through

total outward force

the Capillary Membrane

Summation of forces:

Inward

Now that the different factors affecting fluid move-

Outward

ment through the capillary membrane have been

net inward force

discussed, it is possible to put all these together to

see how the capillary system maintains normal fluid

Thus, the force that causes fluid to move into the

volume distribution between the plasma and the inter-

capillary,

28 mm Hg, is greater than that opposing

stitial fluid.

reabsorption, 21 mm Hg. The difference, 7 mm Hg, is

The average capillary pressure at the arterial ends

the net reabsorption pressure at the venous ends of the

of the capillaries is 15 to 25 mm Hg greater than at the

capillaries. This reabsorption pressure is considerably

venous ends. Because of this difference, fluid “filters”

less than the filtration pressure at the capillary arterial

out of the capillaries at their arterial ends, but at their

ends, but remember that the venous capillaries are

venous ends fluid is reabsorbed back into the capillar-

more numerous and more permeable than the arterial

ies. Thus, a small amount of fluid actually “flows”

capillaries, so that less reabsorption pressure is

through the tissues from the arterial ends of the cap-

required to cause inward movement of fluid.

illaries to the venous ends. The dynamics of this flow

The reabsorption pressure causes about nine tenths

are as follows.

of the fluid that has filtered out of the arterial ends of

the capillaries to be reabsorbed at the venous ends.

Analysis of the Forces Causing Filtration at the Arterial End of

The remaining one tenth flows into the lymph vessels

the Capillary. The approximate average forces operative

and returns to the circulating blood.

at the arterial end of the capillary that cause movement

through the capillary membrane are shown as follows:

Starling Equilibrium for

Capillary Exchange

mm Hg

E. H. Starling pointed out over a century ago that

Forces tending to move fluid outward:

Capillary pressure (arterial end of capillary)

under normal conditions, a state of near-equilibrium

Negative interstitial free fluid pressure

exists at the capillary membrane. That is, the amount

Interstitial fluid colloid osmotic pressure

of fluid filtering outward from the arterial ends of cap-

total outward force

illaries equals almost exactly the fluid returned to the

Forces tending to move fluid inward:

circulation by absorption. The slight disequilibrium

Plasma colloid osmotic pressure

that does occur accounts for the small amount of fluid

total inward force

that is eventually returned by way of the lymphatics.

Summation of forces:

The following chart shows the principles of the Star-

Outward

ling equilibrium. For this chart, the pressures in the arte-

Inward

rial and venous capillaries are averaged to calculate

net outward force (at arterial end)

mean functional capillary pressure for the entire length

of the capillary. This calculates to be 17.3 mm Hg.

Thus, the summation of forces at the arterial end of

mm Hg

the capillary shows a net filtration pressure of 13 mm

Mean forces tending to move fluid outward:

Hg, tending to move fluid outward through the capil-

Mean capillary pressure

17.3

lary pores.

Negative interstitial free fluid pressure

3.0

This 13 mm Hg filtration pressure causes, on the

Interstitial fluid colloid osmotic pressure

8.0

average, about 1/200 of the plasma in the flowing blood

total outward force

28.3

to filter out of the arterial ends of the capillaries into

Mean force tending to move fluid inward:

the interstitial spaces each time the blood passes

Plasma colloid osmotic pressure

28.0

through the capillaries.

total inward force

28.0

Summation of mean forces:

Analysis of Reabsorption at the Venous End of the Capillary.

Outward

28.3

The low blood pressure at the venous end of the cap-

Inward

28.0

illary changes the balance of forces in favor of absorp-

net outward force

0.3

tion as follows:

190

Unit IV The Circulation

Thus, for the total capillary circulation, we find a

Effect of Abnormal Imbalance of Forces

near-equilibrium between the total outward forces,

at the Capillary Membrane

28.3 mm Hg, and the total inward force, 28.0 mm Hg.

If the mean capillary pressure rises above 17 mm Hg,

This slight imbalance of forces, 0.3 mm Hg, causes

the net force tending to cause filtration of fluid into the

slightly more filtration of fluid into the interstitial

tissue spaces rises. Thus, a 20 mm Hg rise in mean cap-

spaces than reabsorption. This slight excess of filtration

illary pressure causes an increase in net filtration pres-

is called net filtration, and it is the fluid that must be

sure from 0.3 mm Hg to 20.3 mm Hg, which results in

returned to the circulation through the lymphatics. The

68 times as much net filtration of fluid into the inter-

normal rate of net filtration in the entire body is only

stitial spaces as normally occurs. To prevent accumu-

about 2 milliliters per minute.

lation of excess fluid in these spaces would require 68

times the normal flow of fluid into the lymphatic

system, an amount that is 2 to 5 times too much for the

Filtration Coefficient. In the above example, an average

lymphatics to carry away. As a result, fluid will begin

net imbalance of forces at the capillary membranes

to accumulate in the interstitial spaces, and edema will

of 0.3 mm Hg causes net fluid filtration in the entire

result.

body of 2 ml/min. Expressing this for each millimeter

Conversely, if the capillary pressure falls very low,

of mercury imbalance, one finds a net filtration rate

net reabsorption of fluid into the capillaries will occur

of 6.67 milliliters of fluid per minute per millimeter of

instead of net filtration, and the blood volume will

mercury for the entire body. This is called the whole

increase at the expense of the interstitial fluid volume.

body capillary filtration coefficient.

These effects of imbalance at the capillary membrane

The filtration coefficient can also be expressed for

in relation to the development of different kinds of

separate parts of the body in terms of rate of filtration

edema are discussed in Chapter 25.

per minute per millimeter of mercury per 100 grams

of tissue. On this basis, the filtration coefficient of the

average tissue is about 0.01 ml/min/mm Hg/100 g of

Lymphatic System

tissue. But, because of extreme differences in perme-

abilities of the capillary systems in different tissues,

The lymphatic system represents an accessory route

this coefficient varies more than 100-fold among the

through which fluid can flow from the interstitial

different tissues. It is very small in both brain and

spaces into the blood. Most important, the lymphatics

muscle, moderately large in subcutaneous tissue, large

can carry proteins and large particulate matter away

in the intestine, and extreme in the liver and glomeru-

from the tissue spaces, neither of which can be

lus of the kidney where the pores are either numerous

removed by absorption directly into the blood capil-

or wide open. By the same token, the permeation

laries. This return of proteins to the blood from the

of proteins through the capillary membranes varies

interstitial spaces is an essential function without

greatly as well. The concentration of protein in the

which we would die within about 24 hours.

interstitial fluid of muscles is about 1.5 g/dl; in subcu-

taneous tissue, 2 g/dl; in intestine, 4 g/dl; and in liver,

6 g/dl.

Lymph Channels of the Body

Almost all tissues of the body have special lymph chan-

nels that drain excess fluid directly from the interstitial

spaces. The exceptions include the superficial portions

of the skin, the central nervous system, the endomysium

Implanted

Blood

of muscles, and the bones. But, even these tissues have

Skin

capsule

vessels

minute interstitial channels called prelymphatics

through which interstitial fluid can flow; this fluid even-

tually empties either into lymphatic vessels or, in the

case of the brain, into the cerebrospinal fluid and then

directly back into the blood.

Essentially all the lymph vessels from the lower part

of the body eventually empty into the thoracic duct,

which in turn empties into the blood venous system at

the juncture of the left internal jugular vein and left sub-

clavian vein, as shown in Figure 16-8.

Lymph from the left side of the head, the left arm, and

parts of the chest region also enters the thoracic duct

before it empties into the veins.

Lymph from the right side of the neck and head, the

right arm, and parts of the right thorax enters the right

measure

lymph duct (much smaller than the thoracic duct), which

pressure

Fluid filled cavity

empties into the blood venous system at the juncture of

the right subclavian vein and internal jugular vein.

FIGURE 16-7

Perforated capsule method for measuring interstitial fluid

Terminal Lymphatic Capillaries and Their Permeability. Most

pressure.

of the fluid filtering from the arterial ends of blood

Chapter 16

The Microcirculation and the Lymphatic System

191

Cervical nodes

Sentinel node

Subclavian vein

R. lymphatic duct

Thoracic duct

Axillary nodes

Cisterna chyli

Abdominal nodes

Inguinal nodes

Peripheral lymphatics

FIGURE 16-8

Lymphatic system.

capillaries flows among the cells and finally is reab-

in such a way that the overlapping edge is free to flap

sorbed back into the venous ends of the blood capil-

inward, thus forming a minute valve that opens to the

laries; but on the average, about 1/10 of the fluid

interior of the lymphatic capillary. Interstitial fluid,

instead enters the lymphatic capillaries and returns to

along with its suspended particles, can push the valve

the blood through the lymphatic system rather than

open and flow directly into the lymphatic capillary. But

through the venous capillaries. The total quantity of all

this fluid has difficulty leaving the capillary once it has

this lymph is normally only 2 to 3 liters each day.

entered because any backflow closes the flap valve.

The fluid that returns to the circulation by way of

Thus, the lymphatics have valves at the very tips of the

the lymphatics is extremely important because sub-

terminal lymphatic capillaries as well as valves along

stances of high molecular weight, such as proteins,

their larger vessels up to the point where they empty

cannot be absorbed from the tissues in any other way,

into the blood circulation.

although they can enter the lymphatic capillaries

almost unimpeded. The reason for this is a special

structure of the lymphatic capillaries, demonstrated in

Formation of Lymph

Figure 16-9. This figure shows the endothelial cells of

the lymphatic capillary attached by anchoring fila-

Lymph is derived from interstitial fluid that flows into

ments to the surrounding connective tissue. At the

the lymphatics. Therefore, lymph as it first enters the

junctions of adjacent endothelial cells, the edge of one

terminal lymphatics has almost the same composition

endothelial cell overlaps the edge of the adjacent cell

as the interstitial fluid.

192

Unit IV The Circulation

Endothelial cells

Valves

2 times/

7 times/

Anchoring filaments

mm Hg

FIGURE 16-9

-6

-4

-2

Special structure of the lymphatic capillaries that permits passage

P_T (mm Hg)

of substances of high molecular weight into the lymph.

The protein concentration in the interstitial fluid of

FIGURE 16-10

most tissues averages about 2 g/dl, and the protein con-

Relation between interstitial fluid pressure and lymph flow in the

centration of lymph flowing from these tissues is near

leg of a dog. Note that lymph flow reaches a maximum when the

this value. Conversely, lymph formed in the liver has a

interstitial pressure, P_T, rises slightly above atmospheric pressure

protein concentration as high as 6 g/dl, and lymph

(0 mm Hg). (Courtesy Drs. Harry Gibson and Aubrey Taylor.)

formed in the intestines has a protein concentration as

high as 3 to 4 g/dl. Because about two thirds of all

lymph normally is derived from the liver and intes-

tines, the thoracic duct lymph, which is a mixture of

value of -6 mm Hg. Then, as the pressure rises to 0 mm

lymph from all areas of the body, usually has a protein

Hg (atmospheric pressure), flow increases more than

concentration of 3 to 5 g/dl.

20-fold. Therefore, any factor that increases interstitial

The lymphatic system is also one of the major routes

fluid pressure also increases lymph flow if the lymph

for absorption of nutrients from the gastrointestinal

vessels are functioning normally. Such factors include

tract, especially for absorption of virtually all fats in

the following:

food, as discussed in Chapter 65. Indeed, after a fatty

∑ Elevated capillary pressure

meal, thoracic duct lymph sometimes contains as much

∑ Decreased plasma colloid osmotic pressure

as 1 to 2 per cent fat.

∑ Increased interstitial fluid colloid osmotic pressure

Finally, even large particles, such as bacteria, can

∑ Increased permeability of the capillaries

push their way between the endothelial cells of the

All of these cause a balance of fluid exchange at the

lymphatic capillaries and in this way enter the lymph.

blood capillary membrane to favor fluid movement

As the lymph passes through the lymph nodes, these

into the interstitium, thus increasing interstitial fluid

particles are almost entirely removed and destroyed,

volume, interstitial fluid pressure, and lymph flow all

as discussed in Chapter 33.

at the same time.

However, note in Figure 16-10 that when the inter-

stitial fluid pressure becomes 1 or 2 millimeters greater

Rate of Lymph Flow

than atmospheric pressure (greater than 0 mm Hg),

lymph flow fails to rise any further at still higher pres-

About 100 milliliters per hour of lymph flows through

sures. This results from the fact that the increasing

the thoracic duct of a resting human, and approxi-

tissue pressure not only increases entry of fluid into

mately another 20 milliliters flows into the circulation

the lymphatic capillaries but also compresses the

each hour through other channels, making a total esti-

outside surfaces of the larger lymphatics, thus imped-

mated lymph flow of about 120 ml/hr or 2 to 3 liters

ing lymph flow. At the higher pressures, these two

per day.

factors balance each other almost exactly, so that

lymph flow reaches what is called the “maximum

Effect of Interstitial Fluid Pressure on Lymph Flow. Figure

lymph flow rate.” This is illustrated by the upper level

16-10 shows the effect of different levels of interstitial

plateau in Figure 16-10.

fluid pressure on lymph flow as measured in dog legs.

Note that normal lymph flow is very little at intersti-

Lymphatic Pump Increases Lymph Flow. Valves exist in all

tial fluid pressures more negative than the normal

lymph channels; typical valves are shown in Figure

Chapter 16

The Microcirculation and the Lymphatic System

193

Pores

Valves

Lymphatic

capillaries

Collecting

FIGURE 16-11

lymphatic

Structure of lymphatic capillaries

and a collecting lymphatic,

showing also the lymphatic

valves.

16-11 in collecting lymphatics into which the lym-

through the junctions between the endothelial cells.

phatic capillaries empty.

Then, when the tissue is compressed, the pressure

Motion pictures of exposed lymph vessels, both

inside the capillary increases and causes the overlap-

in animals and in human beings, show that when a

ping edges of the endothelial cells to close like valves.

collecting lymphatic or larger lymph vessel becomes

Therefore, the pressure pushes the lymph forward into

stretched with fluid, the smooth muscle in the wall of

the collecting lymphatic instead of backward through

the vessel automatically contracts. Furthermore, each

the cell junctions.

segment of the lymph vessel between successive valves

The lymphatic capillary endothelial cells also

functions as a separate automatic pump. That is, even

contain a few contractile actomyosin filaments. In

slight filling of a segment causes it to contract, and the

some animal tissues (e.g., the bat’s wing) these fila-

fluid is pumped through the next valve into the next

ments have been observed to cause rhythmical con-

lymphatic segment. This fills the subsequent segment,

traction of the lymphatic capillaries in the same way

and a few seconds later it, too, contracts, the process

that many of the small blood and larger lymphatic

continuing all along the lymph vessel until the fluid is

vessels also contract rhythmically. Therefore, it is

finally emptied into the blood circulation. In a very

probable that at least part of lymph pumping results

large lymph vessel such as the thoracic duct, this lym-

from lymph capillary endothelial cell contraction

phatic pump can generate pressures as great as 50 to

in addition to contraction of the larger muscular

100 mm Hg.

lymphatics.

Pumping Caused by External Intermittent Compression

Summary of Factors That Determine Lymph Flow. From the

of the Lymphatics. In addition to the pumping caused

above discussion, one can see that the two primary

by intrinsic intermittent contraction of the lymph

factors that determine lymph flow are (1) the intersti-

vessel walls, any external factor that intermittently

tial fluid pressure and (2) the activity of the lymphatic

compresses the lymph vessel also can cause pumping.

pump. Therefore, one can state that, roughly, the rate

In order of their importance, such factors are:

of lymph flow is determined by the product of intersti-

∑ Contraction of surrounding skeletal muscles

tial fluid pressure times the activity of the lymphatic

∑ Movement of the parts of the body

pump.

∑ Pulsations of arteries adjacent to the lymphatics

∑ Compression of the tissues by objects outside the

body

Role of the Lymphatic System in

The lymphatic pump becomes very active during exer-

Controlling Interstitial Fluid Protein

cise, often increasing lymph flow 10- to 30-fold. Con-

versely, during periods of rest, lymph flow is sluggish,

Concentration, Interstitial Fluid

almost zero.

Volume, and Interstitial Fluid Pressure

Lymphatic Capillary Pump. The terminal lymphatic capil-

It is already clear that the lymphatic system functions

lary is also capable of pumping lymph, in addition to

as an “overflow mechanism” to return to the circula-

the lymph pumping by the larger lymph vessels.

tion excess proteins and excess fluid volume from the

As explained earlier in the chapter, the walls of the

tissue spaces. Therefore, the lymphatic system also

lymphatic capillaries are tightly adherent to the sur-

plays a central role in controlling (1) the concentration

rounding tissue cells by means of their anchoring

of proteins in the interstitial fluids, (2) the volume of

filaments. Therefore, each time excess fluid enters

interstitial fluid, and (3) the interstitial fluid pressure.

the tissue and causes the tissue to swell, the anchoring

Let us explain how these factors interact.

filaments pull on the wall of the lymphatic capillary,

First, remember that small amounts of proteins

and fluid flows into the terminal lymphatic capillary

leak continuously out of the blood capillaries into the

194

Unit IV The Circulation

interstitium. Only minute amounts, if any, of the leaked

condition known as edema occurs, which is discussed

proteins return to the circulation by way of the venous

in Chapter 25.

ends of the blood capillaries. Therefore, these proteins

tend to accumulate in the interstitial fluid, and this in

turn increases the colloid osmotic pressure of the

References

interstitial fluids.

Second, the increasing colloid osmotic pressure in

Aukland K, Reed RK: Interstitial-lymphatic mechanisms in

the control of extracellular fluid volume. Physiol Rev 73:1,

the interstitial fluid shifts the balance of forces at the

1993.

blood capillary membranes in favor of fluid filtration

D’Amico G, Bazzi C: Pathophysiology of proteinuria.

into the interstitium. Therefore, in effect, fluid is

Kidney Int 63:809, 2003.

translocated osmotically outward through the capil-

Dejana E: Endothelial cell-cell junctions: happy together.

lary wall by the proteins and into the interstitium, thus

Nat Rev Mol Cell Biol 5:261, 2004.

increasing both interstitial fluid volume and interstitial

Frank PG, Woodman SE, Park DS, Lisanti MP: Caveolin,

fluid pressure.

caveolae, and endothelial cell function. Arterioscler

Third, the increasing interstitial fluid pressure

Thromb Vasc Biol 23:1161, 2003.

greatly increases the rate of lymph flow, as explained

Gashev AA: Physiologic aspects of lymphatic contractile

previously. This in turn carries away the excess inter-

function: current perspectives. Ann N Y Acad Sci 979:178,

2002.

stitial fluid volume and excess protein that has accu-

Guyton AC: Concept of negative interstitial pressure based

mulated in the spaces.

on pressures in implanted perforated capsules. Circ Res

Thus, once the interstitial fluid protein concentra-

12:399, 1963.

tion reaches a certain level and causes a comparable

Guyton AC: Interstitial fluid pressure: II. Pressure-volume

increase in interstitial fluid volume and interstitial

curves of interstitial space. Circ Res 16:452, 1965.

fluid pressure, the return of protein and fluid by way

Guyton AC, Granger HJ, Taylor AE: Interstitial fluid pres-

of the lymphatic system becomes great enough to

sure. Physiol Rev 51:527, 1971.

balance exactly the rate of leakage of these into the

Guyton AC, Prather J, Scheel K, McGehee J: Interstitial fluid

interstitium from the blood capillaries. Therefore, the

pressure: IV. Its effect on fluid movement through the

quantitative values of all these factors reach a steady

capillary wall. Circ Res 19:1022, 1966.

Guyton AC, Scheel K, Murphree D: Interstitial fluid pres-

state; they will remain balanced at these steady state

sure: III. Its effect on resistance to tissue fluid mobility.

levels until something changes the rate of leakage of

Circ Res 19:412, 1966.

proteins and fluid from the blood capillaries.

Guyton AC, Taylor AE, Granger HJ: Circulatory Physiology

II. Dynamics and Control of the Body Fluids. Philadel-

Significance of Negative Interstitial Fluid

phia: WB Saunders Co, 1975.

Pressure as a Means for Holding the

Michel CC, Curry FE: Microvascular permeability. Physiol

Body Tissues Together

Rev 79:703, 1999.

Traditionally, it has been assumed that the different

Miyasaka M, Tanaka T: Lymphocyte trafficking across high

tissues of the body are held together entirely by

endothelial venules: dogmas and enigmas. Nat Rev

connective tissue fibers. However, at many places in

Immunol 4:360, 2004.

Oliver G: Lymphatic vasculature development. Nat Rev

the body, connective tissue fibers are very weak or

Immunol 4:35, 2004.

even absent. This occurs particularly at points where

Rippe B, Rosengren BI, Carlsson O, Venturoli D:

tissues slide over one another, such as the skin sliding

Transendothelial transport: the vesicle controversy. J Vasc

over the back of the hand or over the face. Yet even

Res 39:375, 2002.

at these places, the tissues are held together by the

Taylor AE, Granger DN: Exchange of macromolecules

negative interstitial fluid pressure, which is actually a

across the microcirculation. In: Renkin EM, Michel CC

partial vacuum. When the tissues lose their negative

(eds): Handbook of Physiology. Sec. 2, Vol. IV. Bethesda:

pressure, fluid accumulates in the spaces and the

American Physiological Society, 1984, p 467.

C H A P T E R

Local and Humoral Control of

Blood Flow by the Tissues

Local Control of Blood

Flow in Response to

Tissue Needs

One of the most fundamental principles of circula-

tory function is the ability of each tissue to control

its own local blood flow in proportion to its meta-

bolic needs.

What are some of the specific needs of the tissues for blood flow? The answer

to this is manyfold, including the following:

1. Delivery of oxygen to the tissues

2. Delivery of other nutrients, such as glucose, amino acids, and fatty acids

3. Removal of carbon dioxide from the tissues

4. Removal of hydrogen ions from the tissues

5. Maintenance of proper concentrations of other ions in the tissues

6. Transport of various hormones and other substances to the different tissues

Certain organs have special requirements. For instance, blood flow to the skin

determines heat loss from the body and in this way helps to control body tem-

perature. Also, delivery of adequate quantities of blood plasma to the kidneys

allows the kidneys to excrete the waste products of the body.

We shall see that most of these factors exert extreme degrees of local blood

flow control.

Variations in Blood Flow in Different Tissues and Organs. Note in Table 17-1 the very

large blood flows in some organs—for example, several hundred milliliters per

minute per 100 grams of thyroid or adrenal gland tissue and a total blood flow

of 1350 ml/min in the liver, which is 95 ml/min/100 g of liver tissue.

Also note the extremely large blood flow through the kidneys—1100 ml/min.

This extreme amount of flow is required for the kidneys to perform their func-

tion of cleansing the blood of waste products.

Conversely, most surprising is the low blood flow to all the inactive muscles

of the body, only a total of 750 ml/min, even though the muscles constitute

between 30 and 40 per cent of the total body mass. In the resting state, the meta-

bolic activity of the muscles is very low, and so also is the blood flow, only

4 ml/min/100 g. Yet, during heavy exercise, muscle metabolic activity can

increase more than 60-fold and the blood flow as much as 20-fold, increasing to

as high as 16,000 ml/min in the body’s total muscle vascular bed (or 80 ml/

min/100 g of muscle).

Importance of Blood Flow Control by the Local Tissues. One might ask the simple ques-

tion: Why not simply allow a very large blood flow all the time through every

tissue of the body, always enough to supply the tissue’s needs whether the activ-

ity of the tissue is little or great? The answer is equally simple: To do this would

require many times more blood flow than the heart can pump.

Experiments have shown that the blood flow to each tissue usually is regu-

lated at the minimal level that will supply the tissue’s requirements— no more,

no less. For instance, in tissues for which the most important requirement is

delivery of oxygen, the blood flow is always controlled at a level only slightly

more than required to maintain full tissue oxygenation but no more than this.

195

196

Unit IV The Circulation

Table 17-1

Blood Flow to Different Organs and Tissues Under Basal

Conditions

Per cent

ml/min

ml/min/100 g

Brain

700

Heart

200

Bronchi

100

Kidneys

1100

360

Liver

1350

Portal

(21)

1050

Arterial

(6)

300

Normal level

Muscle (inactive state)

750

Bone

250

Skin (cool weather)

300

Thyroid gland

160

Adrenal glands

0.5

300

Rate of metabolism (x normal)

Other tissues

3.5

175

1.3

Total

100.0

5000

Based mainly on data compiled by Dr. L. A. Sapirstein.

Figure 17-1

Effect of increasing rate of metabolism on tissue blood flow.

By controlling local blood flow in such an exact way,

the tissues almost never suffer from oxygen nutritional

deficiency, and yet the workload on the heart is kept

(3) in carbon monoxide poisoning (which poisons the

at a minimum.

ability of hemoglobin to transport oxygen), or (4) in

cyanide poisoning (which poisons the ability of the

tissues to use oxygen), the blood flow through the

Mechanisms of Blood

tissues increases markedly. Figure 17-2 shows that as

Flow Control

the arterial oxygen saturation decreases to about 25

per cent of normal, the blood flow through an isolated

Local blood flow control can be divided into two

leg increases about threefold; that is, the blood flow

phases: (1) acute control and (2) long-term control.

increases almost enough, but not quite enough, to

Acute control is achieved by rapid changes in local

make up for the decreased amount of oxygen in the

vasodilation or vasoconstriction of the arterioles,

blood, thus almost maintaining an exact constant

metarterioles, and precapillary sphincters, occurring

supply of oxygen to the tissues.

within seconds to minutes to provide very rapid main-

Total cyanide poisoning of oxygen usage by a local

tenance of appropriate local tissue blood flow.

tissue area can cause local blood flow to increase as

Long-term control, however, means slow, controlled

much as sevenfold, thus demonstrating the extreme

changes in flow over a period of days, weeks, or even

effect of oxygen deficiency to increase blood flow.

months. In general, these long-term changes provide

There are two basic theories for the regulation of

even better control of the flow in proportion to the

local blood flow when either the rate of tissue metab-

needs of the tissues. These changes come about as a

olism changes or the availability of oxygen changes.

result of an increase or decrease in the physical sizes

They are (1) the vasodilator theory and (2) the oxygen

and numbers of actual blood vessels supplying the

lack theory.

tissues.

Vasodilator Theory for Acute Local Blood Flow Regu-

lation—Possible Special Role of Adenosine. Accord-

Acute Control of Local Blood Flow

ing to this theory, the greater the rate of metabolism

or the less the availability of oxygen or some other

Effect of Tissue Metabolism on Local Blood Flow. Figure

nutrients to a tissue, the greater the rate of formation

17-1 shows the approximate quantitative acute effect

of vasodilator substances in the tissue cells. The

on blood flow of increasing the rate of metabolism in

vasodilator substances then are believed to diffuse

a local tissue, such as in a skeletal muscle. Note that an

through the tissues to the precapillary sphincters,

increase in metabolism up to eight times normal

metarterioles, and arterioles to cause dilation. Some of

increases the blood flow acutely about fourfold.

the different vasodilator substances that have been

suggested are adenosine, carbon dioxide, adenosine

Acute Local Blood Flow Regulation When Oxygen Availability

phosphate compounds, histamine, potassium ions, and

Changes. One of the most necessary of the metabolic

hydrogen tons.

nutrients is oxygen. Whenever the availability of

Most of the vasodilator theories assume that the

oxygen to the tissues decreases, such as (1) at high alti-

vasodilator substance is released from the tissue

tude at the top of a high mountain, (2) in pneumonia,

mainly in response to oxygen deficiency. For instance,

Chapter 17

Local and Humoral Control of Blood Flow by the Tissues

197

Precapillary sphincter

Metarteriole

Sidearm capillary

100

Arterial oxygen saturation (per cent)

Figure 17-2

Effect of decreasing arterial oxygen saturation on blood flow

Figure 17-3

through an isolated dog leg.

Diagram of a tissue unit area for explanation of acute local feed-

back control of blood flow, showing a metarteriole passing through

experiments have shown that decreased availability of

the tissue and a sidearm capillary with its precapillary sphincter

oxygen can cause both adenosine and lactic acid (con-

for controlling capillary blood flow.

taining hydrogen ions) to be released into the spaces

between the tissue cells; these substances then cause

intense acute vasodilation and therefore are respon-

sible, or partially responsible, for the local blood flow

several critical facts have made other physiologists

regulation.

favor still another theory, which can be called either

Many physiologists have suggested that the sub-

the oxygen lack theory or, more accurately, the

stance adenosine is the most important of the local

nutrient lack theory (because other nutrients besides

vasodilators for controlling local blood flow. For

oxygen are involved). Oxygen (and other nutrients

example, minute quantities of adenosine are released

as well) is required as one of the metabolic nutrients

from heart muscle cells when coronary blood flow

to cause vascular muscle contraction. Therefore, in the

becomes too little, and this causes enough local vasodi-

absence of adequate oxygen, it is reasonable to

lation in the heart to return coronary blood flow

believe that the blood vessels simply would relax

back to normal. Also, whenever the heart becomes

and therefore naturally dilate. Also, increased utiliza-

more active than normal and the heart’s metabolism

tion of oxygen in the tissues as a result of increased

increases an extra amount, this, too, causes increased

metabolism theoretically could decrease the availabil-

utilization of oxygen, followed by

(1) decreased

ity of oxygen to the smooth muscle fibers in the

oxygen concentration in the heart muscle cells with (2)

local blood vessels, and this, too, would cause local

consequent degradation of adenosine triphosphate

vasodilation.

(ATP), which (3) increases the release of adenosine. It

A mechanism by which the oxygen lack theory

is believed that much of this adenosine leaks out of the

could operate is shown in Figure 17-3. This figure

heart muscle cells to cause coronary vasodilation, pro-

shows a tissue unit, consisting of a metarteriole with a

viding increased coronary blood flow to supply the

single sidearm capillary and its surrounding tissue. At

increased nutrient demands of the active heart.

the origin of the capillary is a precapillary sphincter,

Although research evidence is less clear, many phys-

and around the metarteriole are several other smooth

iologists also have suggested that the same adenosine

muscle fibers. Observing such a tissue under a micro-

mechanism is the most important controller of blood

scope—for example, in a bat’s wing—one sees that the

flow in skeletal muscle and many other tissues as

precapillary sphincters are normally either completely

well as in the heart. The problem with the different

open or completely closed. The number of precapillary

vasodilator theories of local blood flow regulation

sphincters that are open at any given time is roughly

has been the following: It has been difficult to prove

proportional to the requirements of the tissue for

that sufficient quantities of any single vasodilator sub-

nutrition. The precapillary sphincters and metarteri-

stance (including adenosine) are indeed formed in the

oles open and close cyclically several times per minute,

tissues to cause all the measured increase in blood

with the duration of the open phases being propor-

flow. But a combination of several different vasodila-

tional to the metabolic needs of the tissues for oxygen.

tors could increase the blood flow sufficiently.

The cyclical opening and closing is called vasomotion.

Let us explain how oxygen concentration in the

Oxygen Lack Theory for Local Blood Flow Control.

local tissue could regulate blood flow through the area.

Although the vasodilator theory is widely accepted,

Because smooth muscle requires oxygen to remain

198

Unit IV The Circulation

contracted, one might assume that the strength of con-

emphasizes the close connection between local blood

traction of the sphincters would increase with an

flow regulation and delivery of oxygen and other nutri-

increase in oxygen concentration. Consequently, when

ents to the tissues.

the oxygen concentration in the tissue rises above

a certain level, the precapillary and metarteriole

Active Hyperemia. When any tissue becomes highly

sphincters presumably would close until the tissue

active, such as an exercising muscle, a gastrointestinal

cells consume the excess oxygen. But when the excess

gland during a hypersecretory period, or even the

oxygen is gone and the oxygen concentration falls low

brain during rapid mental activity, the rate of blood

enough, the sphincters would open once more to begin

flow through the tissue increases. Here again, by

the cycle again.

simply applying the basic principles of local blood flow

Thus, on the basis of available data, either a

control, one can easily understand this active hyper-

vasodilator substance theory or an oxygen lack theory

emia. The increase in local metabolism causes the cells

could explain acute local blood flow regulation in

to devour tissue fluid nutrients extremely rapidly and

response to the metabolic needs of the tissues.

also to release large quantities of vasodilator sub-

Probably the truth lies in a combination of the two

stances. The result is to dilate the local blood vessels

mechanisms.

and, therefore, to increase local blood flow. In this way,

the active tissue receives the additional nutrients

Possible Role of Other Nutrients Besides Oxygen in Control of

required to sustain its new level of function. As

Local Blood Flow. Under special conditions, it has been

pointed out earlier, active hyperemia in skeletal

shown that lack of glucose in the perfusing blood can

muscle can increase local muscle blood flow as much

cause local tissue vasodilation. Also, it is possible that

as 20-fold during intense exercise.

this same effect occurs when other nutrients, such as

amino acids or fatty acids, are deficient, although this

“Autoregulation” of Blood Flow When the

has not been studied adequately. In addition, vasodi-

Arterial Pressure Changes from Normal—

lation occurs in the vitamin deficiency disease beriberi,

“Metabolic” and “Myogenic” Mechanisms

in which the patient has deficiencies of the vitamin B

In any tissue of the body, an acute increase in arterial

substances thiamine, niacin, and riboflavin. In this

pressure causes immediate rise in blood flow. But,

disease, the peripheral vascular blood flow everywhere

within less than a minute, the blood flow in most

in the body often increases twofold to threefold.

tissues returns almost to the normal level, even though

Because these vitamins all are needed for oxygen-

the arterial pressure is kept elevated. This return of

induced phosphorylation that is required to produce

flow toward normal is called “autoregulation of blood

ATP in the tissue cells, one can well understand how

flow.” After autoregulation has occurred, the local

deficiency of these vitamins might lead to diminished

blood flow in most body tissues will be related to arte-

smooth muscle contractile ability and therefore also

rial pressure approximately in accord with the solid

local vasodilation.

“acute” curve in Figure 17-4. Note that between an

Special Examples of Acute “Metabolic”

Control of Local Blood Flow

The mechanisms that we have described thus far for

local blood flow control are called “metabolic mecha-

2.5

nisms” because all of them function in response to the

Acute

metabolic needs of the tissues. Two additional special

examples of metabolic control of local blood flow are

2.0

reactive hyperemia and active hyperemia.

1.5

Reactive Hyperemia. When the blood supply to a tissue

is blocked for a few seconds to as long an hour or more

1.0

Long-term

and then is unblocked, blood flow through the tissue

usually increases immediately to four to seven times

0.5

normal; this increased flow will continue for a few

seconds if the block has lasted only a few seconds but

sometimes continues for as long as many hours if the

100

150

200

250

blood flow has been stopped for an hour or more. This

Arterial pressure (mm Hg)

phenomenon is called reactive hyperemia.

Reactive hyperemia is another manifestation of the

local “metabolic” blood flow regulation mechanism;

that is, lack of flow sets into motion all of those factors

Figure 17-4

that cause vasodilation. After short periods of vascu-

lar occlusion, the extra blood flow during the reactive

Effect of different levels of arterial pressure on blood flow through

a muscle. The solid red curve shows the effect if the arterial pres-

hyperemia phase lasts long enough to repay almost

sure is raised over a period of a few minutes. The dashed green

exactly the tissue oxygen deficit that has accrued

curve shows the effect if the arterial pressure is raised extremely

during the period of occlusion. This mechanism

slowly over a period of many weeks.

Chapter 17

Local and Humoral Control of Blood Flow by the Tissues

199

arterial pressure of about 70 mm Hg and 175 mm Hg,

operate in a few special areas. They all are discussed

the blood flow increases only 30 per cent even though

throughout this text in relation to specific organs, but

the arterial pressure increases 150 per cent.

two notable ones are as follows:

For almost a century, two views have been proposed

1. In the kidneys, blood flow control is vested mainly

to explain this acute autoregulation mechanism. They

in a mechanism called tubuloglomerular feedback,

in which the composition of the fluid in the early

have been called (1) the metabolic theory and (2) the

distal tubule is detected by an epithelial structure

myogenic theory.

of the distal tubule itself called the macula densa.

The metabolic theory can be understood easily by

This is located where the distal tubule lies adjacent

applying the basic principles of local blood flow regu-

to the afferent and efferent arterioles at the

lation discussed in previous sections. Thus, when the

nephron juxtaglomerular apparatus. When too

arterial pressure becomes too great, the excess flow

much fluid filters from the blood through the

provides too much oxygen and too many other nutri-

glomerulus into the tubular system, appropriate

ents to the tissues. These nutrients (especially oxygen)

feedback signals from the macula densa cause

then cause the blood vessels to constrict and the flow

constriction of the afferent arterioles, in this way

to return nearly to normal despite the increased

reducing both renal blood flow and glomerular

filtration rate back to or near to normal. The

pressure.

details of this mechanism are discussed in

The myogenic theory, however, suggests that still

Chapter 26.

another mechanism not related to tissue metabolism

2. In the brain, in addition to control of blood flow by

explains the phenomenon of autoregulation. This

tissue oxygen concentration, the concentrations of

theory is based on the observation that sudden stretch

carbon dioxide and hydrogen ions play very

of small blood vessels causes the smooth muscle of the

prominent roles. An increase of either or both of

vessel wall to contract for a few seconds. Therefore, it

these dilates the cerebral vessels and allows rapid

has been proposed that when high arterial pressure

washout of the excess carbon dioxide or hydrogen

stretches the vessel, this in turn causes reactive vascu-

ions from the brain tissues. This is important

lar constriction that reduces blood flow nearly back to

because the level of excitability of the brain itself is

highly dependent on exact control of both carbon

normal. Conversely, at low pressures, the degree of

dioxide concentration and hydrogen ion

stretch of the vessel is less, so that the smooth muscle

concentration. This special mechanism for cerebral

relaxes and allows increased flow.

blood flow control is presented in Chapter 61.

The myogenic response is inherent to vascular

smooth muscle and can occur in the absence of neural

or hormonal influences. It is most pronounced in arte-

Mechanism for Dilating Upstream Arteries

rioles but can also be observed in arteries, venules,

When Microvascular Blood Flow Increases—

veins, and even lymphatic vessels. Myogenic contrac-

The Endothelium-Derived Relaxing Factor

tion is initiated by stretch-induced vascular depolar-

(Nitric Oxide)

ization, which then rapidly increases calcium ion entry

The local mechanisms for controlling tissue blood flow

from the extracellular fluid into the cells, causing them

can dilate only the very small arteries and arterioles in

to contract. Changes in vascular pressure may also

each tissue because tissue cell vasodilator substances

open or close other ion channels that influence vascu-

or tissue cell oxygen deficiency can reach only these

lar contraction. The precise mechanisms by which

vessels, not the intermediate and larger arteries back

changes in pressure cause opening or closing of vas-

upstream. Yet, when blood flow through a micro-

cular ion channels are still uncertain, but likely involve

vascular portion of the circulation increases, this sec-

mechanical effects of pressure on extracellular pro-

ondarily entrains another mechanism that does dilate

teins that are tethered to cytoskeleton elements of the

the larger arteries as well. This mechanism is the

vascular wall or to the ion channels themselves.

following:

The myogenic mechanism may be important in pre-

The endothelial cells lining the arterioles and small

venting excessive stretch of blood vessel when blood

arteries synthesize several substances that, when

pressure is increased. However, the importance of

released, can affect the degree of relaxation or con-

the myogenic mechanism in blood flow regulation

traction of the arterial wall. The most important of

is unclear because this pressure sensing mechanism

these is a vasodilator substance called endothelium-

cannot directly detect changes in blood flow in the

derived relaxing factor (EDRF), which is composed

tissue. Indeed metabolic factors appear to override

principally of nitric oxide, which has a half-life in the

the myogenic mechanism in circumstances where the

blood of only 6 seconds. Rapid flow of blood through

metabolic demands of the tissues are significantly

the arteries and arterioles causes shear stress on the

increased, such as during vigorous muscle exercise,

endothelial cells because of viscous drag of the blood

which can cause dramatic increases in skeletal muscle

against the vascular walls. This stress contorts the

blood flow.

endothelial cells in the direction of flow and causes sig-

nificant increase in the release of nitric oxide. The

Special Mechanisms for Acute Blood Flow

nitric oxide then relaxes the blood vessels. This is for-

Control in Specific Tissues

tunate because it increases the diameters of the

Although the general mechanisms for local blood flow

upstream arterial blood vessels whenever microvascu-

control discussed thus far are present in almost all

lar blood flow increases downstream. Without such a

tissues of the body, distinctly different mechanisms

response, the effectiveness of local blood flow control

200

Unit IV The Circulation

would be significantly decreased because a significant

well-established tissues. Therefore, the time required

part of the resistance to blood flow is in the upstream

for long-term regulation to take place may be only

small arteries.

a few days in the neonate or as long as months in

the elderly person. Furthermore, the final degree of

response is much better in younger tissues than in

Long-Term Blood Flow Regulation

older, so that in the neonate, the vascularity will adjust

to match almost exactly the needs of the tissue for

Thus far, most of the mechanisms for local blood flow

blood flow, whereas in older tissues, vascularity fre-

regulation that we have discussed act within a few

quently lags far behind the needs of the tissues.

seconds to a few minutes after the local tissue condi-

Role of Oxygen in Long-Term Regulation. Oxygen is impor-

tions have changed. Yet, even after full activation

tant not only for acute control of local blood flow but

of these acute mechanisms, the blood flow usually

also for long-term control. One example of this is

is adjusted only about three quarters of the way to

increased vascularity in tissues of animals that live at

the exact additional requirements of the tissues.

high altitudes, where the atmospheric oxygen is low. A

For instance, when the arterial pressure suddenly is

second example is that fetal chicks hatched in low

increased from 100 to 150 mm Hg, the blood flow

oxygen have up to twice as much tissue blood vessel

increases almost instantaneously about 100 per cent.

conductivity as is normally true. This same effect is also

Then, within

30 seconds to

2 minutes, the flow

dramatically demonstrated in premature human

decreases back to about 15 per cent above the origi-

babies put into oxygen tents for therapeutic purposes.

nal control value. This illustrates the rapidity of the

The excess oxygen causes almost immediate cessation

acute mechanisms for local blood flow regulation, but

of new vascular growth in the retina of the premature

at the same time, it demonstrates that the regulation is

baby’s eyes and even causes degeneration of some of

still incomplete because there remains an excess 15 per

the small vessels that already have formed. Then when

cent increase in blood flow.

the infant is taken out of the oxygen tent, there is

However, over a period of hours, days, and weeks, a

explosive overgrowth of new vessels to make up for

long-term type of local blood flow regulation develops

the sudden decrease in available oxygen; indeed, there

in addition to the acute regulation. This long-term

is often so much overgrowth that the retinal vessels

regulation gives far more complete regulation. For

grow out from the retina into the eye’s vitreous humor;

instance, in the aforementioned example, if the arte-

and this eventually causes blindness. (This condition is

rial pressure remains at 150 mm Hg indefinitely, within

called retrolental fibroplasia.)

a few weeks the blood flow through the tissues gradu-

ally reapproaches almost exactly the normal flow level.

Importance of Vascular Endothelial Growth

Figure 17-4 shows by the dashed green curve the

Factor in Formation of New Blood Vessels

extreme effectiveness of this long-term local blood

A dozen or more factors that increase growth of new

flow regulation. Note that once the long-term regula-

blood vessels have been found, almost all of which are

tion has had time to occur, long-term changes in arte-

small peptides. Three of those that have been best

rial pressure between 50 and 250 mm Hg have little

characterized are vascular endothelial growth factor

effect on the rate of local blood flow.

(VEGF), fibroblast growth factor, and angiogenin, each

Long-term regulation of blood flow is especially

of which has been isolated from tissues that have inad-

important when the long-term metabolic demands

equate blood supply. Presumably, it is deficiency of

of a tissue change. Thus, if a tissue becomes chroni-

tissue oxygen or other nutrients, or both, that leads to

cally overactive and therefore requires chronically

formation of the vascular growth factors (also called

increased quantities of oxygen and other nutrients, the

“angiogenic factors”).

arterioles and capillary vessels usually increase both in

Essentially all the angiogenic factors promote new

number and size within a few weeks to match the

vessel growth in the same way. They cause new vessels

needs of the tissue—unless the circulatory system has

to sprout from other small vessels. The first step is dis-

become pathological or too old to respond.

solution of the basement membrane of the endothelial

cells at the point of sprouting. This is followed by rapid

Mechanism of Long-Term Regulation—

reproduction of new endothelial cells that stream

Change in “Tissue Vascularity”

outward through the vessel wall in extended cords

The mechanism of long-term local blood flow regula-

directed toward the source of the angiogenic factor.

tion is principally to change the amount of vascularity

The cells in each cord continue to divide and rapidly

of the tissues. For instance, if the metabolism in a

fold over into a tube. Next, the tube connects with

given tissue is increased for a prolonged period,

another tube budding from another donor vessel

vascularity increases; if the metabolism is decreased,

(another arteriole or venule) and forms a capillary

vascularity decreases.

loop through which blood begins to flow. If the flow is

Thus, there is actual physical reconstruction of

great enough, smooth muscle cells eventually invade

the tissue vasculature to meet the needs of the tissues.

the wall, so that some of the new vessels eventually

This reconstruction occurs rapidly (within days) in

grow to be new arterioles or venules or perhaps even

extremely young animals. It also occurs rapidly in new

larger vessels. Thus, angiogenesis explains the manner

growth tissue, such as in scar tissue and cancerous

in which metabolic factors in local tissues can cause

tissue; however, it occurs much more slowly in old,

growth of new vessels.

Chapter 17

Local and Humoral Control of Blood Flow by the Tissues

201

Certain other substances, such as some steroid hor-

metabolic dilation, followed chronically by manifold

mones, have exactly the opposite effect on small blood

growth and enlargement of new vessels over a period

vessels, occasionally even causing dissolution of vas-

of weeks and months.

cular cells and disappearance of vessels. Therefore,

The most important example of the development of

blood vessels can also be made to disappear when not

collateral blood vessels occurs after thrombosis of one

needed.

of the coronary arteries. Almost all people by the age

of 60 years have had at least one of the smaller branch

coronary vessels close. Yet most people do not know

Vascularity Is Determined by Maximum Blood Flow Need, Not

that this has happened because collaterals have devel-

by Average Need. An especially valuable characteristic

oped rapidly enough to prevent myocardial damage. It

of long-term vascular control is that vascularity is

is in those other instances in which coronary insuffi-

determined mainly by the maximum level of blood

ciency occurs too rapidly or too severely for collater-

flow need rather than by average need. For instance,

als to develop that serious heart attacks occur.

during heavy exercise the need for whole body blood

flow often increases to six to eight times the resting

blood flow. This great excess of flow may not be

Humoral Control of the

required for more than a few minutes each day. Nev-

ertheless, even this short need can cause enough

Circulation

VEGF to be formed by the muscles to increase their

vascularity as required. Were it not for this capability,

Humoral control of the circulation means control by

every time that a person attempted heavy exercise, the

substances secreted or absorbed into the body fluids—

muscles would fail to receive the required nutrients,

such as hormones and ions. Some of these substances

especially the required oxygen, so that the muscles

are formed by special glands and transported in

simply would fail to contract.

the blood throughout the entire body. Others are

However, after extra vascularity does develop, the

formed in local tissue areas and cause only local cir-

extra blood vessels normally remain mainly vasocon-

culatory effects. Among the most important of the

stricted, opening to allow extra flow only when ap-

humoral factors that affect circulatory function are the

propriate local stimuli such as oxygen lack, nerve

following.

vasodilatory stimuli, or other stimuli call forth the

required extra flow.

Vasoconstrictor Agents

Norepinephrine and Epinephrine. Norepinephrine is an

Development of Collateral

especially powerful vasoconstrictor hormone; epi-

Circulation—A Phenomenon of Long-

nephrine is less so and in some tissues even causes mild

Term Local Blood Flow Regulation

vasodilation.

(A special example of vasodilation

caused by epinephrine occurs to dilate the coronary

When an artery or a vein is blocked in virtually any

arteries during increased heart activity.)

tissue of the body, a new vascular channel usually

When the sympathetic nervous system is stimulated

develops around the blockage and allows at least

in most or all parts of the body during stress or exer-

partial resupply of blood to the affected tissue. The

cise, the sympathetic nerve endings in the individual

first stage in this process is dilation of small vascular

tissues release norepinephrine, which excites the heart

loops that already connect the vessel above the block-

and contracts the veins and arterioles. In addition,

age to the vessel below. This dilation occurs within the

the sympathetic nerves to the adrenal medullae cause

first minute or two, indicating that the dilation is

these glands to secrete both norepinephrine and epi-

simply a neurogenic or metabolic relaxation of the

nephrine into the blood. These hormones then circu-

muscle fibers of the small vessels involved. After this

late to all areas of the body and cause almost the same

initial opening of collateral vessels, the blood flow

effects on the circulation as direct sympathetic stimu-

often is still less than one quarter that needed to

lation, thus providing a dual system of control: (1)

supply all the tissue needs. However, further opening

direct nerve stimulation and (2) indirect effects of

occurs within the ensuing hours, so that within 1 day

norepinephrine and/or epinephrine in the circulating

as much as half the tissue needs may be met, and

blood.

within a few days often all the tissue needs.

The collateral vessels continue to grow for many

Angiotensin II. Angiotensin II is another powerful vaso-

months thereafter, almost always forming multiple

constrictor substance. As little as one millionth of a

small collateral channels rather than one single large

gram can increase the arterial pressure of a human

vessel. Under resting conditions, the blood flow usually

being 50 mm Hg or more.

returns very near to normal, but the new channels

The effect of angiotensin II is to constrict powerfully

seldom become large enough to supply the blood flow

the small arterioles. If this occurs in an isolated

needed during strenuous tissue activity. Thus, the

tissue area, the blood flow to that area can be

development of collateral vessels follows the usual

severely depressed. However, the real importance of

principles of both acute and long-term local blood flow

angiotensin II is that it normally acts on many of the

control, the acute control being rapid neurogenic and

arterioles of the body at the same time to increase the

202

Unit IV The Circulation

total peripheral resistance, thereby increasing the arte-

kallidin that then is converted by tissue enzymes into

rial pressure. Thus, this hormone plays an integral role

bradykinin. Once formed, bradykinin persists for only

in the regulation of arterial pressure, as is discussed in

a few minutes because it is inactivated by the enzyme

detail in Chapter 19.

carboxypeptidase or by converting enzyme, the same

enzyme that also plays an essential role in activating

Vasopressin. Vasopressin, also called antidiuretic

angiotensin, as discussed in Chapter 19. The activated

hormone, is even more powerful than angiotensin II as

kallikrein enzyme is destroyed by a kallikrein inhibitor

a vasoconstrictor, thus making it one of the body’s

also present in the body fluids.

most potent vascular constrictor substances. It is

Bradykinin causes both powerful arteriolar

formed in nerve cells in the hypothalamus of the brain

dilation and increased capillary permeability. For

(see Chapter 75) but is then transported downward by

instance, injection of 1 microgram of bradykinin into

nerve axons to the posterior pituitary gland, where it

the brachial artery of a person increases blood flow

is finally secreted into the blood.

through the arm as much as sixfold, and even smaller

It is clear that vasopressin could have enormous

amounts injected locally into tissues can cause marked

effects on circulatory function. Yet, normally, only

local edema resulting from increase in capillary pore

minute amounts of vasopressin are secreted, so that

size.

most physiologists have thought that vasopressin plays

There is reason to believe that kinins play special

little role in vascular control. However, experiments

roles in regulating blood flow and capillary leakage of

have shown that the concentration of circulating blood

fluids in inflamed tissues. It also is believed that

vasopressin after severe hemorrhage can rise high

bradykinin plays a normal role to help regulate blood

enough to increase the arterial pressure as much as

flow in the skin as well as in the salivary and gastroin-

60 mm Hg. In many instances, this can, by itself, bring

testinal glands.

the arterial pressure almost back up to normal.

Vasopressin has a major function to increase greatly

Histamine. Histamine is released in essentially every

water reabsorption from the renal tubules back into

tissue of the body if the tissue becomes damaged or

the blood (discussed in Chapter 28), and therefore

inflamed or is the subject of an allergic reaction. Most

to help control body fluid volume. That is why this

of the histamine is derived from mast cells in the

hormone is also called antidiuretic hormone.

damaged tissues and from basophils in the blood.

Histamine has a powerful vasodilator effect on

Endothelin—A Powerful Vasoconstrictor in Damaged Blood

the arterioles and, like bradykinin, has the ability to

Vessels. Still another vasoconstrictor substance that

increase greatly capillary porosity, allowing leakage

ranks along with angiotensin and vasopressin in its

of both fluid and plasma protein into the tissues. In

vasoconstrictor capability is a large 21 amino acid

many pathological conditions, the intense arteriolar

peptide called endothelin, which requires only

dilation and increased capillary porosity produced

nanogram quantities to cause powerful vasoconstric-

by histamine cause tremendous quantities of fluid

tion. This substance is present in the endothelial cells

to leak out of the circulation into the tissues, inducing

of all or most blood vessels. The usual stimulus for

edema. The local vasodilatory and edema-producing

release is damage to the endothelium, such as that

effects of histamine are especially prominent

caused by crushing the tissues or injecting a trauma-

during allergic reactions and are discussed in

tizing chemical into the blood vessel. After severe

Chapter 34.

blood vessel damage, release of local endothelin and

subsequent vasoconstriction helps to prevent exten-

sive bleeding from arteries as large as 5 millimeters in

Vascular Control by Ions and Other

diameter that might have been torn open by crushing

Chemical Factors

injury.

Many different ions and other chemical factors can

either dilate or constrict local blood vessels. Most of

Vasodilator Agents

them have little function in overall regulation of the

circulation, but some specific effects are:

Bradykinin. Several substances called kinins cause pow-

1. An increase in calcium ion concentration causes

erful vasodilation when formed in the blood and tissue

vasoconstriction. This results from the general

fluids of some organs.

effect of calcium to stimulate smooth muscle

The kinins are small polypeptides that are split away

contraction, as discussed in Chapter 8.

by proteolytic enzymes from alpha2-globulins in the

2. An increase in potassium ion concentration causes

plasma or tissue fluids. A proteolytic enzyme of par-

vasodilation. This results from the ability of

ticular importance for this purpose is kallikrein, which

potassium ions to inhibit smooth muscle

is present in the blood and tissue fluids in an inactive

contraction.

form. This inactive kallikrein is activated by macera-

3. An increase in magnesium ion concentration

tion of the blood, by tissue inflammation, or by other

causes powerful vasodilation because magnesium

similar chemical or physical effects on the blood or

ions inhibit smooth muscle contraction.

tissues. As kallikrein becomes activated, it acts imme-

4. An increase in hydrogen ion concentration

diately on alpha2-globulin to release a kinin called

(decrease in pH) causes dilation of the arterioles.

Chapter 17

Local and Humoral Control of Blood Flow by the Tissues

203

Conversely, slight decrease in hydrogen ion

Ferrara N, Gerber HP, LeCouter J: The biology of VEGF and

concentration causes arteriolar constriction.

its receptors. Nat Med 9:669, 2003.

5. Anions that have significant effects on blood

Granger HJ, Guyton AC: Autoregulation of the total sys-

temic circulation following destruction of the central

vessels are acetate and citrate, both of which cause

nervous system in the dog. Circ Res 25:379, 1969.

mild degrees of vasodilation.

Guyton AC, Coleman TG, Granger HJ: Circulation: overall

6. An increase in carbon dioxide concentration

regulation. Annu Rev Physiol 34:13, 1972.

causes moderate vasodilation in most tissues, but

Hall JE, Brands MW, Henegar JR: Angiotensin II and long-

marked vasodilation in the brain. Also, carbon

term arterial pressure regulation: the overriding domi-

dioxide in the blood, acting on the brain

nance of the kidney. J Am Soc Nephrol 10(Suppl 12):S258,

vasomotor center, has an extremely powerful

1999.

indirect effect, transmitted through the

Harder DR, Zhang C, Gebremedhin D: Astrocytes function

sympathetic nervous vasoconstrictor system, to

in matching blood flow to metabolic activity. News Physiol

cause widespread vasoconstriction throughout the

Sci 17:27, 2002.

Hester RL, Hammer LW: Venular-arteriolar communication

body.

in the regulation of blood flow. Am J Physiol Regul Integr

Comp Physiol 282:R1280, 2002.

Iglarz M, Schiffrin EL: Role of endothelin-1 in hypertension.

References

Curr Hypertens Rep 5:144, 2003.

Kerbel R, Folkman J: Clinical translation of angiogenesis

Adair TH, Gay WJ, Montani JP: Growth regulation of the

inhibitors. Nat Rev Cancer 2:727, 2002.

vascular system: evidence for a metabolic hypothesis. Am

Losordo DW, Dimmeler S: Therapeutic angiogenesis and

J Physiol 259:R393, 1990.

vasculogenesis for ischemic disease: Part I: angiogenic

Campbell WB, Gauthier KM: What is new in endothelium-

cytokines. Circulation 109:2487, 2004.

derived hyperpolarizing factors? Curr Opin Nephrol

Renkin EM: Control of microcirculation and blood-tissue

Hypertens 11:177, 2002.

exchange. In: Renkin EM, Michel CC (eds): Handbook of

Chang L, Kaipainen A, Folkman J: Lymphangiogenesis new

Physiology, Sec. 2, Vol. IV. Bethesda: American Physiolog-

mechanisms. Ann N Y Acad Sci 979:111, 2002.

ical Society, 1984, p 627.

Cowley AW Jr, Mori T, Mattson D, Zou AP: Role of renal

Rich S, McLaughlin VV: Endothelin receptor blockers in car-

NO production in the regulation of medullary blood flow.

diovascular disease. Circulation 108:2184, 2003.

Am J Physiol Regul Integr Comp Physiol 284:R1355, 2003.

Roman RJ: P-450 metabolites of arachidonic acid in the

Davis MJ, Hill MA: Signaling mechanisms underlying the

control of cardiovascular function. Physiol Rev 82:131,

vascular myogenic response. Physiol Rev 79:387, 1999.

2002.

Erdös EG, Marcic BM: Kinins, receptors, kininases and

Schnermann J, Levine DZ: Paracrine factors in tubu-

inhibitors—where did they lead us? Biol Chem 382:43,

loglomerular feedback: adenosine, ATP, and nitric oxide.

2001.

Annu Rev Physiol 65:501, 2003.

C H A P T E R

Nervous Regulation of the

Circulation, and Rapid Control

of Arterial Pressure

Nervous Regulation of the

Circulation

As discussed in Chapter 17, adjustment of blood

flow tissue by tissue is mainly the function of local

tissue blood flow control mechanisms. We shall see

in this chapter that nervous control of the circula-

tion has more global functions, such as redistribut-

ing blood flow to different areas of the body, increasing or decreasing pumping

activity by the heart, and, especially, providing very rapid control of systemic

arterial pressure.

The nervous system controls the circulation almost entirely through the auto-

nomic nervous system. The total function of this system is presented in Chapter

60, and this subject was also introduced in Chapter 17. For our present discus-

sion, we need to present still other specific anatomical and functional charac-

teristics, as follows.

Autonomic Nervous System

By far the most important part of the autonomic nervous system for regulating

the circulation is the sympathetic nervous system. The parasympathetic nervous

system also contributes specifically to regulation of heart function, as we shall

see later in the chapter.

Sympathetic Nervous System. Figure

18-1 shows the anatomy of sympathetic

nervous control of the circulation. Sympathetic vasomotor nerve fibers leave

the spinal cord through all the thoracic spinal nerves and through the first one

or two lumbar spinal nerves. They then pass immediately into a sympathetic

chain, one of which lies on each side of the vertebral column. Next, they pass

by two routes to the circulation: (1) through specific sympathetic nerves that

innervate mainly the vasculature of the internal viscera and the heart, as shown

on the right side of Figure 18-1, and (2) almost immediately into peripheral por-

tions of the spinal nerves distributed to the vasculature of the peripheral areas.

The precise pathways of these fibers in the spinal cord and in the sympathetic

chains are discussed more fully in Chapter 60.

Sympathetic Innervation of the Blood Vessels. Figure 18-2 shows distribution

of sympathetic nerve fibers to the blood vessels, demonstrating that in most

tissues all the vessels except the capillaries, precapillary sphincters, and metar-

terioles are innervated.

The innervation of the small arteries and arterioles allows sympathetic stim-

ulation to increase resistance to blood flow and thereby to decrease rate of blood

flow through the tissues.

The innervation of the large vessels, particularly of the veins, makes it possi-

ble for sympathetic stimulation to decrease the volume of these vessels. This can

push blood into the heart and thereby play a major role in regulation of heart

pumping, as we shall see later in this and subsequent chapters.

204

Chapter 18

Nervous Regulation of the Circulation, and Rapid Control of Arterial Pressure

205

Vasomotor center

Blood

vessels

Sympathetic chain

Vagus

Heart

Vasoconstrictor

Cardioinhibitor

Vasodilator

Blood

vessels

Figure 18-1

Anatomy of sympathetic nervous

control of the circulation. Also

shown by the red dashed line is a

vagus nerve that carries parasym-

pathetic signals to the heart.

Sympathetic Nerve Fibers to the Heart. In addition to

Arteries

sympathetic nerve fibers supplying the blood vessels,

sympathetic fibers also go directly to the heart, as

Arterioles

shown in Figure 18-1 and also discussed in Chapter 9.

It should be recalled that sympathetic stimulation

markedly increases the activity of the heart, both

increasing the heart rate and enhancing its strength

Sympathetic

and volume of pumping.

vasoconstriction

Capillaries

Parasympathetic Control of Heart Function, Especially Heart

Rate. Although the parasympathetic nervous system is

exceedingly important for many other autonomic

functions of the body, such as control of multiple gas-

trointestinal actions, it plays only a minor role in

Veins

Venules

regulation of the circulation. Its most important circu-

latory effect is to control heart rate by way of parasym-

Figure 18-2

pathetic nerve fibers to the heart in the vagus

Sympathetic innervation of the systemic circulation.

nerves, shown in Figure 18-1 by the dashed red line

from the brain medulla directly to the heart.

The effects of parasympathetic stimulation on

heart function were discussed in detail in Chapter 9.

206

Unit IV The Circulation

Principally, parasympathetic stimulation causes a

possible to identify certain important areas in this

marked decrease in heart rate and a slight decrease in

center, as follows:

heart muscle contractility.

1. A vasoconstrictor area located bilaterally in the

anterolateral portions of the upper medulla. The

neurons originating in this area distribute their

Sympathetic Vasoconstrictor System and

fibers to all levels of the spinal cord, where they

Its Control by the Central Nervous System

excite preganglionic vasoconstrictor neurons of the

The sympathetic nerves carry tremendous numbers of

sympathetic nervous system.

vasoconstrictor nerve fibers and only a few vasodilator

2. A vasodilator area located bilaterally in the

fibers. The vasoconstrictor fibers are distributed to

anterolateral portions of the lower half of the

essentially all segments of the circulation, but more to

medulla. The fibers from these neurons project

some tissues than others. This sympathetic vasocon-

upward to the vasoconstrictor area just described;

strictor effect is especially powerful in the kidneys,

they inhibit the vasoconstrictor activity of this area,

intestines, spleen, and skin but much less potent in

thus causing vasodilation.

skeletal muscle and the brain.

3. A sensory area located bilaterally in the tractus

solitarius in the posterolateral portions of the

medulla and lower pons. The neurons of this area

Vasomotor Center in the Brain and Its Control of the Vasocon-

receive sensory nerve signals from the circulatory

strictor System. Located bilaterally mainly in the retic-

system mainly through the vagus and

ular substance of the medulla and of the lower third

glossopharyngeal nerves, and output signals from

of the pons, shown in Figures 18-1 and 18-3, is an area

this sensory area then help to control activities of

called the vasomotor center. This center transmits

both the vasoconstrictor and vasodilator areas of

parasympathetic impulses through the vagus nerves to

the vasomotor center, thus providing “reflex”

the heart and transmits sympathetic impulses through

control of many circulatory functions. An example

the spinal cord and peripheral sympathetic nerves

is the baroreceptor reflex for controlling arterial

to virtually all arteries, arterioles, and veins of the

pressure, which we describe later in this chapter.

body.

Although the total organization of the vasomotor

Continuous Partial Constriction of the Blood Vessels Is Nor-

center is still unclear, experiments have made it

mally Caused by Sympathetic Vasoconstrictor Tone. Under

normal conditions, the vasoconstrictor area of the

vasomotor center transmits signals continuously to

the sympathetic vasoconstrictor nerve fibers over the

Reticular

entire body, causing continuous slow firing of these

Motor

substance

Cingulate

fibers at a rate of about one half to two impulses per

second. This continual firing is called sympathetic vaso-

Orbital

Mesencephalon

constrictor tone. These impulses normally maintain a

partial state of contraction in the blood vessels, called

vasomotor tone.

Figure 18-4 demonstrates the significance of vaso-

constrictor tone. In the experiment of this figure,

total spinal anesthesia was administered to an animal.

This blocked all transmission of sympathetic nerve

impulses from the spinal cord to the periphery. As a

result, the arterial pressure fell from 100 to 50 mm Hg,

demonstrating the effect of losing vasoconstrictor tone

throughout the body. A few minutes later, a small

Temporal

amount of the hormone norepinephrine was injected

into the blood

(norepinephrine is the principal

vasoconstrictor hormonal substance secreted at the

Pons

endings of the sympathetic vasoconstrictor nerve

fibers throughout the body). As this injected hormone

Medulla

VASOMOTOR

was transported in the blood to all blood vessels, the

CENTER

vessels once again became constricted, and the arterial

pressure rose to a level even greater than normal for

VASODILATOR

1 to 3 minutes, until the norepinephrine was destroyed.

VASOCONSTRICTOR

Control of Heart Activity by the Vasomotor Center. At the

same time that the vasomotor center is controlling the

amount of vascular constriction, it also controls heart

activity. The lateral portions of the vasomotor center

Figure 18-3

transmit excitatory impulses through the sympathetic

nerve fibers to the heart when there is need to increase

Areas of the brain that play important roles in the nervous regula-

tion of the circulation. The dashed lines represent inhibitory

heart rate and contractility. Conversely, when there is

pathways.

need to decrease heart pumping, the medial portion of

Chapter 18

Nervous Regulation of the Circulation, and Rapid Control of Arterial Pressure

207

150

125

Total spinal

anesthesia

100

Injection of norepinephrine

Figure 18-4

Effect of total spinal anesthesia on

the arterial pressure, showing

Seconds

marked decrease in pressure

resulting from loss of “vasomotor

tone.”

the vasomotor center sends signals to the adjacent

the cingulate gyrus, the amygdala, the septum, and the

dorsal motor nuclei of the vagus nerves, which then

hippocampus can all either excite or inhibit the vaso-

transmit parasympathetic impulses through the vagus

motor center, depending on the precise portions of

nerves to the heart to decrease heart rate and heart

these areas that are stimulated and on the intensity of

contractility. Therefore, the vasomotor center can

stimulus. Thus, widespread basal areas of the brain can

either increase or decrease heart activity. Heart rate

have profound effects on cardiovascular function.

and strength of heart contraction ordinarily increase

when vasoconstriction occurs and ordinarily decrease

Norepinephrine—The Sympathetic Vasoconstrictor Transmitter

when vasoconstriction is inhibited.

Substance. The substance secreted at the endings of the

vasoconstrictor nerves is almost entirely norepineph-

Control of the Vasomotor Center by Higher Nervous Centers.

rine. Norepinephrine acts directly on the alpha adren-

Large numbers of small neurons located throughout

ergic receptors of the vascular smooth muscle to cause

the reticular substance of the pons, mesencephalon,

vasoconstriction, as discussed in Chapter 60.

and diencephalon can either excite or inhibit the

vasomotor center. This reticular substance is shown

Adrenal Medullae and Their Relation to the Sympathetic Vaso-

in Figure 18-3 by the rose-colored area. In general, the

constrictor System. Sympathetic impulses are transmit-

neurons in the more lateral and superior portions

ted to the adrenal medullae at the same time that they

of the reticular substance cause excitation, whereas

are transmitted to the blood vessels. They cause the

the more medial and inferior portions cause inhibition.

medullae to secrete both epinephrine and norepineph-

The hypothalamus plays a special role in controlling

rine into the circulating blood. These two hormones are

the vasoconstrictor system because it can exert either

carried in the blood stream to all parts of the body,

powerful excitatory or inhibitory effects on the vaso-

where they act directly on all blood vessels, usually

motor center. The posterolateral portions of the hypo-

to cause vasoconstriction, but in an occasional tissue

thalamus cause mainly excitation, whereas the anterior

epinephrine causes vasodilation because it also has

portion can cause either mild excitation or inhibition,

a “beta” adrenergic receptor stimulatory effect, which

depending on the precise part of the anterior hypo-

dilates rather than constricts certain vessels, as dis-

thalamus stimulated.

cussed in Chapter 60.

Many parts of the cerebral cortex can also excite or

inhibit the vasomotor center. Stimulation of the motor

Sympathetic Vasodilator System and its Control by the Central

cortex, for instance, excites the vasomotor center

Nervous System. The sympathetic nerves to skeletal

because of impulses transmitted downward into the

muscles carry sympathetic vasodilator fibers as well as

hypothalamus and thence to the vasomotor center.

constrictor fibers. In lower animals such as the cat, these

Also, stimulation of the anterior temporal lobe, the

dilator fibers release acetylcholine, not norepinephrine,

orbital areas of the frontal cortex, the anterior part of

at their endings, although in primates, the vasodilator

208

Unit IV

The Circulation

effect is believed to be caused by epinephrine exciting

3. Finally, the heart itself is directly stimulated by the

specific beta adrenergic receptors in the muscle

autonomic nervous system, further enhancing

vasculature.

cardiac pumping. Much of this is caused by an

The pathway for central nervous system control of

increase in the heart rate, the rate sometimes

the vasodilator system is shown by the dashed lines in

increasing to as great as three times normal. In

Figure 18-3. The principal area of the brain controlling

addition, sympathetic nervous signals have a

this system is the anterior hypothalamus.

significant direct effect to increase contractile

force of the heart muscle, this, too, increasing the

capability of the heart to pump larger volumes of

Possible Unimportance of the Sympathetic Vasodilator System.

blood. During strong sympathetic stimulation, the

It is doubtful that the sympathetic vasodilator system

heart can pump about two times as much blood as

plays an important role in the control of the circulation

under normal conditions. This contributes still more

in the human being because complete block of the sym-

to the acute rise in arterial pressure.

pathetic nerves to the muscles hardly affects the ability

of these muscles to control their own blood flow in

response to their needs. Yet some experiments suggest

Rapidity of Nervous Control of Arterial Pressure. An espe-

that at the onset of exercise, the sympathetic vasodila-

cially important characteristic of nervous control of

tor system might cause initial vasodilation in skeletal

arterial pressure is its rapidity of response, beginning

muscles to allow anticipatory increase in blood flow even

within seconds and often increasing the pressure to

before the muscles require increased nutrients.

two times normal within 5 to 10 seconds. Conversely,

sudden inhibition of nervous cardiovascular stimula-

Emotional Fainting—Vasovagal Syncope. A particularly

tion can decrease the arterial pressure to as little as

interesting vasodilatory reaction occurs in people who

experience intense emotional disturbances that cause

one half normal within 10 to 40 seconds. Therefore,

fainting. In this case, the muscle vasodilator system

nervous control of arterial pressure is by far the most

becomes activated, and at the same time, the vagal car-

rapid of all our mechanisms for pressure control.

dioinhibitory center transmits strong signals to the heart

to slow the heart rate markedly. The arterial pressure

falls rapidly, which reduces blood flow to the brain and

Increase in Arterial Pressure

causes the person to lose consciousness. This overall

effect is called vasovagal syncope. Emotional fainting

During Muscle Exercise and Other

begins with disturbing thoughts in the cerebral cortex.

Types of Stress

The pathway probably then goes to the vasodilatory

center of the anterior hypothalamus next to the vagal

An important example of the ability of the nervous

centers of the medulla, to the heart through the vagus

system to increase the arterial pressure is the increase

nerves, and also through the spinal cord to the sympa-

in pressure that occurs during muscle exercise. During

thetic vasodilator nerves of the muscles.

heavy exercise, the muscles require greatly increased

blood flow. Part of this increase results from local

vasodilation of the muscle vasculature caused by

Role of the Nervous System

increased metabolism of the muscle cells, as explained

in Rapid Control of

in Chapter 17. Additional increase results from simul-

Arterial Pressure

taneous elevation of arterial pressure caused by sym-

pathetic stimulation of the overall circulation during

One of the most important functions of nervous

exercise. In most heavy exercise, the arterial pressure

control of the circulation is its capability to cause rapid

rises about 30 to 40 per cent, which increases blood

increases in arterial pressure. For this purpose, the

flow almost an additional twofold.

entire vasoconstrictor and cardioaccelerator functions

The increase in arterial pressure during exercise

of the sympathetic nervous system are stimulated

results mainly from the following effect: At the same

together. At the same time, there is reciprocal inhibi-

time that the motor areas of the brain become acti-

tion of parasympathetic vagal inhibitory signals to the

vated to cause exercise, most of the reticular activat-

heart. Thus, three major changes occur simultaneously,

ing system of the brain stem is also activated, which

each of which helps to increase arterial pressure. They

includes greatly increased stimulation of the vasocon-

are as follows:

strictor and cardioacceleratory areas of the vasomotor

1. Almost all arterioles of the systemic circulation

center. These increase the arterial pressure instanta-

are constricted. This greatly increases the total

neously to keep pace with the increase in muscle

peripheral resistance, thereby increasing the arterial

activity.

pressure.

In many other types of stress besides muscle exer-

2. The veins especially (but the other large vessels of

cise, a similar rise in pressure can also occur. For

the circulation as well) are strongly constricted.

instance, during extreme fright, the arterial pressure

This displaces blood out of the large peripheral

sometimes rises to as high as double normal within a

blood vessels toward the heart, thus increasing the

few seconds. This is called the alarm reaction, and it

volume of blood in the heart chambers. The stretch

provides an excess of arterial pressure that can imme-

of the heart then causes the heart to beat with far

greater force and therefore to pump increased

diately supply blood to any or all muscles of the body

quantities of blood. This, too, increases the arterial

that might need to respond instantly to cause flight

pressure.

from danger.

Chapter 18

Nervous Regulation of the Circulation, and Rapid Control of Arterial Pressure

209

Reflex Mechanisms for Maintaining

Normal Arterial Pressure

Aside from the exercise and stress functions of the

autonomic nervous system to increase arterial pres-

sure, there are multiple subconscious special nervous

Glossopharyngeal nerve

control mechanisms that operate all the time to main-

tain the arterial pressure at or near normal. Almost

all of these are negative feedback reflex mechanisms,

which we explain in the following sections.

Hering’s nerve

The Baroreceptor Arterial Pressure Control

Carotid body

System—Baroreceptor Reflexes

Carotid sinus

By far the best known of the nervous mechanisms for

arterial pressure control is the baroreceptor reflex.

Basically, this reflex is initiated by stretch receptors,

Vagus nerve

called either baroreceptors or pressoreceptors, located

at specific points in the walls of several large systemic

arteries. A rise in arterial pressure stretches the

baroreceptors and causes them to transmit signals into

the central nervous system. “Feedback” signals are

Aortic baroreceptors

then sent back through the autonomic nervous system

to the circulation to reduce arterial pressure down-

ward toward the normal level.

Physiologic Anatomy of the Baroreceptors and Their Innerva-

tion. Baroreceptors are spray-type nerve endings that

lie in the walls of the arteries; they are stimulated when

Figure 18-5

stretched. A few baroreceptors are located in the wall

of almost every large artery of the thoracic and neck

The baroreceptor system for controlling arterial pressure.

regions; but, as shown in Figure 18-5, baroreceptors

are extremely abundant in (1) the wall of each inter-

nal carotid artery slightly above the carotid bifurca-

tion, an area known as the carotid sinus, and (2) the

wall of the aortic arch.

Figure 18-5 shows that signals from the “carotid

baroreceptors” are transmitted through very small

Hering’s nerves to the glossopharyngeal nerves in

the high neck, and then to the tractus solitarius in the

medullary area of the brain stem. Signals from the

“aortic baroreceptors” in the arch of the aorta are

transmitted through the vagus nerves also to the same

tractus solitarius of the medulla.

= maximum

Response of the Baroreceptors to Pressure. Figure

18-6

shows the effect of different arterial pressure levels on

the rate of impulse transmission in a Hering’s carotid

sinus nerve. Note that the carotid sinus baroreceptors

are not stimulated at all by pressures between 0 and

50 to 60 mm Hg, but above these levels, they respond

160

244

progressively more rapidly and reach a maximum at

Arterial blood pressure (mm Hg)

about 180 mm Hg. The responses of the aortic barore-

ceptors are similar to those of the carotid receptors

except that they operate, in general, at pressure levels

about 30 mm Hg higher.

Figure 18-6

Note especially that in the normal operating range

of arterial pressure, around 100 mm Hg, even a slight

Activation of the baroreceptors at different levels of arterial

change in pressure causes a strong change in the

pressure. DI, change in carotid sinus nerve impulses per second;

baroreflex signal to readjust arterial pressure back

DP, change in arterial blood pressure in mm Hg.

toward normal. Thus, the baroreceptor feedback

mechanism functions most effectively in the pressure

range where it is most needed.

210

Unit IV The Circulation

The baroreceptors respond extremely rapidly to

carotids are occluded. Removal of the occlusion allows

changes in arterial pressure; in fact, the rate of impulse

the pressure in the carotid sinuses to rise, and the

firing increases in the fraction of a second during each

carotid sinus reflex now causes the aortic pressure to

systole and decreases again during diastole. Further-

fall immediately to slightly below normal as a momen-

more, the baroreceptors respond much more to a

tary overcompensation and then return to normal in

rapidly changing pressure than to a stationary pres-

another minute.

sure. That is, if the mean arterial pressure is 150 mm

Hg but at that moment is rising rapidly, the rate of

Function of the Baroreceptors During Changes in Body

impulse transmission may be as much as twice that

Posture. The ability of the baroreceptors to maintain

when the pressure is stationary at 150 mm Hg.

relatively constant arterial pressure in the upper body

is important when a person stands up after having

Circulatory Reflex Initiated by the Baroreceptors. After the

been lying down. Immediately on standing, the arterial

baroreceptor signals have entered the tractus solitar-

pressure in the head and upper part of the body tends

ius of the medulla, secondary signals inhibit the vaso-

to fall, and marked reduction of this pressure could

constrictor center of the medulla and excite the vagal

cause loss of consciousness. However, the falling pres-

parasympathetic center. The net effects are (1) vasodi-

sure at the baroreceptors elicits an immediate reflex,

lation of the veins and arterioles throughout the

resulting in strong sympathetic discharge throughout

peripheral circulatory system and (2) decreased heart

the body. This minimizes the decrease in pressure in

rate and strength of heart contraction. Therefore, exci-

the head and upper body.

tation of the baroreceptors by high pressure in the

arteries reflexly causes the arterial pressure to decrease

Pressure

“Buffer” Function of the Baroreceptor

because of both a decrease in peripheral resistance

Control System. Because the baroreceptor system

and a decrease in cardiac output. Conversely, low pres-

opposes either increases or decreases in arterial pres-

sure has opposite effects, reflexly causing the pressure

sure, it is called a pressure buffer system, and the nerves

to rise back toward normal.

from the baroreceptors are called buffer nerves.

Figure 18-7 shows a typical reflex change in arterial

Figure 18-8 shows the importance of this buffer

pressure caused by occluding the two common carotid

function of the baroreceptors. The upper record in this

arteries. This reduces the carotid sinus pressure; as a

figure shows an arterial pressure recording for 2 hours

result, the baroreceptors become inactive and lose

from a normal dog, and the lower record shows an

their inhibitory effect on the vasomotor center. The

arterial pressure recording from a dog whose barore-

vasomotor center then becomes much more active

ceptor nerves from both the carotid sinuses and the

than usual, causing the aortic arterial pressure to rise

aorta had been removed. Note the extreme variability

and remain elevated during the 10 minutes that the

of pressure in the denervated dog caused by simple

events of the day, such as lying down, standing, excite-

ment, eating, defecation, and noises.

Figure 18-9 shows the frequency distributions of the

mean arterial pressures recorded for a 24-hour day in

both the normal dog and the denervated dog. Note

that when the baroreceptors were functioning nor-

mally the mean arterial pressure remained throughout

the day within a narrow range between

85 and

115 mm Hg—indeed, during most of the day at almost

150

exactly 100 mm Hg. Conversely, after denervation of

the baroreceptors, the frequency distribution curve

became the broad, low curve of the figure, showing

100

that the pressure range increased 2.5-fold, frequently

falling to as low as 50 mm Hg or rising to over 160 mm

Both common

Carotids released

Hg. Thus, one can see the extreme variability of pres-

carotids clamped

sure in the absence of the arterial baroreceptor

system.

In summary, a primary purpose of the arterial

baroreceptor system is to reduce the minute by minute

variation in arterial pressure to about one third that

which would occur were the baroreceptor system not

Minutes

present.

Are the Baroreceptors Important in Long-Term Regulation of

Arterial Pressure? Although the arterial baroreceptors

Figure 18-7

provide powerful moment-to-moment control of

arterial pressure, their importance in long-term

Typical carotid sinus reflex effect on aortic arterial pressure

caused by clamping both common carotids (after the two vagus

blood pressure regulation has been controversial. One

nerves have been cut).

reason that the baroreceptors have been considered

Chapter 18

Nervous Regulation of the Circulation, and Rapid Control of Arterial Pressure

211

NORMAL

200

Normal

100

Denervated

DENERVATED

200

100

150

200

250

Mean arterial pressure (mm Hg)

100

Figure 18-9

Frequency distribution curves of the arterial pressure for a 24-hour

period in a normal dog and in the same dog several weeks after

the baroreceptors had been denervated. (Redrawn from Cowley

Time (min)

AW Jr, Liard JP, Guyton AC: Role of baroreceptor reflex in daily

control of arterial blood pressure and other variables in dogs. Circ

Res 32:564, 1973. By permission of the American Heart Associa-

tion, Inc.)

Figure 18-8

Two-hour records of arterial pressure in a normal dog (above) and

in the same dog (below) several weeks after the baroreceptors

long-term blood pressure regulation, especially by

had been denervated. (Redrawn from Cowley AW Jr, Liard JF,

influencing sympathetic nerve activity of the kidneys.

Guyton AC: Role of baroreceptor reflex in daily control of arterial

For example, with prolonged increases in arterial pres-

blood pressure and other variables in dogs. Circ Res 32:564,

sure, the baroreceptor reflexes may mediate decreases

1973. By permission of the American Heart Association, Inc.)

in renal sympathetic nerve activity that promote

increased excretion of sodium and water by the

kidneys. This, in turn, causes a gradual decrease in

by some physiologists to be relatively unimportant in

blood volume, which helps to restore arterial pressure

chronic regulation of arterial pressure chronically is

toward normal. Thus, long-term regulation of mean

that they tend to reset in 1 to 2 days to the pressure

arterial pressure by the baroreceptors requires

level to which they are exposed. That is, if the arterial

interaction with additional systems, principally the

pressure rises from the normal value of 100 mm Hg to

renal-body fluid-pressure control system (along with

160 mm Hg, a very high rate of baroreceptor impulses

its associated nervous and hormonal mechanisms), dis-

are at first transmitted. During the next few minutes,

cussed in Chapters 19 and 29.

the rate of firing diminishes considerably; then it

diminishes much more slowly during the next 1 to 2

Control of Arterial Pressure by the Carotid and Aortic

days, at the end of which time the rate of firing will

Chemoreceptors—Effect of Oxygen Lack on Arterial Pressure.

have returned to nearly normal despite the fact that

Closely associated with the baroreceptor pressure

the mean arterial pressure still remains at 160 mm Hg.

control system is a chemoreceptor reflex that operates in

Conversely, when the arterial pressure falls to a very

much the same way as the baroreceptor reflex except

low level, the baroreceptors at first transmit no

that chemoreceptors, instead of stretch receptors, initi-

ate the response.

impulses, but gradually, over 1 to 2 days, the rate of

The chemoreceptors are chemosensitive cells sensi-

baroreceptor firing returns toward the control level.

tive to oxygen lack, carbon dioxide excess, and hydro-

This “resetting” of the baroreceptors may attenuate

gen ion excess. They are located in several small

their potency as a control system for correcting dis-

chemoreceptor organs about 2 millimeters in size (two

turbances that tend to change arterial pressure for

carotid bodies, one of which lies in the bifurcation of

longer than a few days at a time. Experimental studies,

each common carotid artery, and usually one to three

however, have suggested that the baroreceptors do

aortic bodies adjacent to the aorta). The chemo-

not completely reset and may therefore contribute to

receptors excite nerve fibers that, along with the

212

Unit IV

The Circulation

baroreceptor fibers, pass through Hering’s nerves and

All these mechanisms that tend to return the blood

the vagus nerves into the vasomotor center of the brain

volume back toward normal after a volume overload act

stem.

indirectly as pressure controllers as well as blood

Each carotid or aortic body is supplied with an

volume controllers because excess volume drives the

abundant blood flow through a small nutrient artery, so

heart to greater cardiac output and leads, therefore, to

that the chemoreceptors are always in close contact

greater arterial pressure. This volume reflex mechanism

with arterial blood. Whenever the arterial pressure falls

is discussed again in Chapter 29, along with other mech-

below a critical level, the chemoreceptors become stim-

anisms of blood volume control.

ulated because diminished blood flow causes decreased

oxygen as well as excess buildup of carbon dioxide and

Atrial Reflex Control of Heart Rate (the Bainbridge Reflex). An

hydrogen ions that are not removed by the slowly

increase in atrial pressure also causes an increase in

flowing blood.

heart rate, sometimes increasing the heart rate as much

The signals transmitted from the chemoreceptors

as 75 per cent. A small part of this increase is caused by

excite the vasomotor center, and this elevates the arterial

a direct effect of the increased atrial volume to stretch

pressure back toward normal. However, this chemo-

the sinus node: it was pointed out in Chapter 10 that

receptor reflex is not a powerful arterial pressure con-

such direct stretch can increase the heart rate as much

troller until the arterial pressure falls below 80 mm Hg.

as 15 per cent. An additional 40 to 60 per cent increase

Therefore, it is at the lower pressures that this reflex

in rate is caused by a nervous reflex called the Bain-

becomes important to help prevent still further fall in

bridge reflex. The stretch receptors of the atria that elicit

pressure.

the Bainbridge reflex transmit their afferent signals

The chemoreceptors are discussed in much more

through the vagus nerves to the medulla of the brain.

detail in Chapter 41 in relation to respiratory control,

Then efferent signals are transmitted back through

in which they play a far more important role than in

vagal and sympathetic nerves to increase heart rate and

pressure control.

strength of heart contraction. Thus, this reflex helps

prevent damming of blood in the veins, atria, and pul-

Atrial and Pulmonary Artery Reflexes That Help Regulate Arterial

monary circulation.

Pressure and Other Circulatory Factors. Both the atria and

the pulmonary arteries have in their walls stretch recep-

Central Nervous System Ischemic

tors called low-pressure receptors. They are similar to

Response—Control of Arterial

the baroreceptor stretch receptors of the large systemic

arteries. These low-pressure receptors play an important

Pressure by the Brain’s Vasomotor

role, especially in minimizing arterial pressure changes

Center in Response to Diminished

in response to changes in blood volume. To give an

Brain Blood Flow

example, if 300 milliliters of blood suddenly are infused

into a dog with allreceptors intact, the arterial pressure

Most nervous control of blood pressure is achieved

rises only about 15 mm Hg. With the arterial barorecep-

by reflexes that originate in the baroreceptors, the

tors denervated, the pressure rises about 40 mm Hg. If

chemoreceptors, and the low-pressure receptors, all of

the low-pressure receptors also are denervated, the pres-

which are located in the peripheral circulation outside

sure rises about 100 mm Hg.

the brain. However, when blood flow to the vasomotor

Thus, one can see that even though the low-pressure

center in the lower brain stem becomes decreased

receptors in the pulmonary artery and in the atria

severely enough to cause nutritional deficiency—that is,

cannot detect the systemic arterial pressure, they do

to cause cerebral ischemia—the vasoconstrictor and

detect simultaneous increases in pressure in the low-

cardioaccelerator neurons in the vasomotor center

pressure areas of the circulation caused by increase in

respond directly to the ischemia and become strongly

volume, and they elicit reflexes parallel to the barore-

excited. When this occurs, the systemic arterial pressure

ceptor reflexes to make the total reflex system more

often rises to a level as high as the heart can possibly

potent for control of arterial pressure.

pump. This effect is believed to be caused by failure of

the slowly flowing blood to carry carbon dioxide away

Atrial Reflexes That Activate the Kidneys—The “Volume Reflex.”

from the brain stem vasomotor center: at low levels of

Stretch of the atria also causes significant reflex dilation

blood flow to the vasomotor center, the local con-

of the afferent arterioles in the kidneys. And still

centration of carbon dioxide increases greatly and

other signals are transmitted simultaneously from the

has an extremely potent effect in stimulating the sym-

atria to the hypothalamus to decrease secretion of

pathetic vasomotor nervous control areas in the brain’s

antidiuretic hormone. The decreased afferent arteriolar

medulla.

resistance in the kidneys causes the glomerular capillary

It is possible that other factors, such as buildup of

pressure to rise, with resultant increase in filtration of

lactic acid and other acidic substances in the vasomotor

fluid into the kidney tubules. The diminution of antidi-

center, also contribute to the marked stimulation and

uretic hormone diminishes the reabsorption of water

elevation in arterial pressure. This arterial pressure ele-

from the tubules. Combination of these two effects—

vation in response to cerebral ischemia is known as the

increase in glomerular filtration and decrease in reab-

central nervous system ischemic response, or simply CNS

sorption of the fluid—increases fluid loss by the kidneys

ischemic response.

and reduces an increased blood volume back toward

The magnitude of the ischemic effect on vasomotor

normal. (We will also see in Chapter 19 that atrial

activity is tremendous: it can elevate the mean arterial

stretch caused by increased blood volume also elicits a

pressure for as long as 10 minutes sometimes to as high

hormonal effect on the kidneys—release of atrial natri-

as 250 mm Hg. The degree of sympathetic vasoconstric-

uretic peptide that adds still further to the excretion of

tion caused by intense cerebral ischemia is often so great

fluid in the urine and return of blood volume toward

that some of the peripheral vessels become totally or

normal.)

almost totally occluded. The kidneys, for instance, often

Chapter 18

Nervous Regulation of the Circulation, and Rapid Control of Arterial Pressure

213

Pen

Arterial

recorder

pressure

Zero

CSF pressure CSF pressure

pressure

raised

reduced

Moving paper

Figure 18-10

“Cushing reaction,” showing a

rapid rise in arterial pressure

Connector to

Arterial

Pressure

subarachnoid

pressure

resulting from increased cere-

bottle

space

brospinal fluid (CSF) pressure.

transducer

entirely cease their production of urine because of renal

Special Features of Nervous

arteriolar constriction in response to the sympathetic

Control of Arterial Pressure

discharge. Therefore, the CNS ischemic response is one

of the most powerful of all the activators of the sympa-

Role of the Skeletal Nerves and

thetic vasoconstrictor system.

Skeletal Muscles in Increasing

Importance of the CNS Ischemic Response as a Regulator of Arte-

Cardiac Output and

rial Pressure. Despite the powerful nature of the CNS

Arterial Pressure

ischemic response, it does not become significant until

the arterial pressure falls far below normal, down to

Although most rapidly acting nervous control of the cir-

60 mm Hg and below, reaching its greatest degree of

culation is effected through the autonomic nervous

stimulation at a pressure of 15 to 20 mm Hg. Therefore,

system, at least two conditions in which the skeletal

it is not one of the normal mechanisms for regulating

nerves and muscles also play major roles in circulatory

arterial pressure. Instead, it operates principally as an

responses are the following.

emergency pressure control system that acts rapidly and

very powerfully to prevent further decrease in arterial

Abdominal Compression Reflex. When a baroreceptor or

pressure whenever blood flow to the brain decreases dan-

chemoreceptor reflex is elicited, nerve signals are trans-

gerously close to the lethal level. It is sometimes called

mitted simultaneously through skeletal nerves to skele-

the “last ditch stand” pressure control mechanism.

tal muscles of the body, particularly to the abdominal

muscles. This compresses all the venous reservoirs of

Cushing Reaction. The so-called Cushing reaction is a

the abdomen, helping to translocate blood out of the

special type of CNS ischemic response that results from

abdominal vascular reservoirs toward the heart. As a

increased pressure of the cerebrospinal fluid around

result, increased quantities of blood are made available

the brain in the cranial vault. For instance, when the

for the heart to pump. This overall response is called the

cerebrospinal fluid pressure rises to equal the arterial

abdominal compression reflex. The resulting effect on

pressure, it compresses the whole brain as well as the

the circulation is the same as that caused by sympathetic

arteries in the brain and cuts off the blood supply to the

vasoconstrictor impulses when they constrict the veins:

brain. This initiates a CNS ischemic response that causes

an increase in both cardiac output and arterial pressure.

the arterial pressure to rise. When the arterial pressure

The abdominal compression reflex is probably much

has risen to a level higher than the cerebrospinal fluid

more important than has been realized in the past

pressure, blood will flow once again into the vessels of

because it is well known that people whose skeletal

the brain to relieve the brain ischemia. Ordinarily, the

muscles have been paralyzed are considerably more

blood pressure comes to a new equilibrium level slightly

prone to hypotensive episodes than are people with

higher than the cerebrospinal fluid pressure, thus allow-

normal skeletal muscles.

ing blood to begin again to flow through the brain. A

typical Cushing reaction is shown in Figure

18-10,

Increased Cardiac Output and Arterial Pressure Caused by

caused in this instance by pumping fluid under pressure

Skeletal Muscle Contraction During Exercise. When the

into the cranial vault around the brain. The Cushing

skeletal muscles contract during exercise, they compress

reaction helps protect the vital centers of the brain from

blood vessels throughout the body. Even anticipation of

loss of nutrition if ever the cerebrospinal fluid pressure

exercise tightens the muscles, thereby compressing

rises high enough to compress the cerebral arteries.

the vessels in the muscles and in the abdomen. The

214

Unit IV

The Circulation

resulting effect is to translocate blood from the periph-

eral vessels into the heart and lungs and, therefore, to

increase the cardiac output. This is an essential effect in

helping to cause the fivefold to sevenfold increase in

200

cardiac output that sometimes occurs in heavy exercise.

100

160

The increase in cardiac output in turn is an essential

120

ingredient in increasing the arterial pressure during

exercise, an increase usually from a normal mean of

100 mm Hg up to 130 to 160 mm Hg.

Respiratory Waves in the

Arterial Pressure

With each cycle of respiration, the arterial pressure

usually rises and falls

4 to 6 mm Hg in a wavelike

Figure 18-11

manner, causing respiratory waves in the arterial pres-

sure. The waves result from several different effects,

A, Vasomotor waves caused by oscillation of the CNS ischemic

some of which are reflex in nature, as follows:

response. B, Vasomotor waves caused by baroreceptor reflex

1. Many of the “breathing signals” that arise in the

oscillation.

respiratory center of the medulla “spill over” into

the vasomotor center with each respiratory cycle.

2. Every time a person inspires, the pressure in the

thoracic cavity becomes more negative than usual,

causing the blood vessels in the chest to expand.

pressure in turn reduces the baroreceptor stimulation

This reduces the quantity of blood returning to the

and allows the vasomotor center to become active once

left side of the heart and thereby momentarily

again, elevating the pressure to a high value. The

decreases the cardiac output and arterial pressure.

response is not instantaneous, and it is delayed until a

3. The pressure changes caused in the thoracic vessels

few seconds later. This high pressure then initiates

by respiration can excite vascular and atrial stretch

another cycle, and the oscillation continues on and on.

receptors.

The chemoreceptor reflex can also oscillate to give the

Although it is difficult to analyze the exact relations

same type of waves. This reflex usually oscillates simul-

of all these factors in causing the respiratory pressure

taneously with the baroreceptor reflex. It probably plays

waves, the net result during normal respiration is usually

the major role in causing vasomotor waves when the

an increase in arterial pressure during the early part

arterial pressure is in the range of 40 to 80 mm Hg

of expiration and a decrease in pressure during the

because in this low range, chemoreceptor control of the

remainder of the respiratory cycle. During deep respi-

circulation becomes powerful, whereas baroreceptor

ration, the blood pressure can rise and fall as much as

control becomes weaker.

20 mm Hg with each respiratory cycle.

Oscillation of the CNS Ischemic Response. The record in

Figure 18-11A resulted from oscillation of the CNS

Arterial Pressure “Vasomotor”

ischemic pressure control mechanism. In this experi-

Waves—Oscillation of Pressure

ment, the cerebrospinal fluid pressure was raised to

Reflex Control Systems

160 mm Hg, which compressed the cerebral vessels and

initiated a CNS ischemic pressure response up to

Often while recording arterial pressure from an animal,

200 mm Hg. When the arterial pressure rose to such a

in addition to the small pressure waves caused by res-

high value, the brain ischemia was relieved and the sym-

piration, some much larger waves are also noted—as

pathetic nervous system became inactive. As a result,

great as 10 to 40 mm Hg at times—that rise and fall

the arterial pressure fell rapidly back to a much lower

more slowly than the respiratory waves. The duration of

value, causing brain ischemia once again. The ischemia

each cycle varies from 26 seconds in the anesthetized

then initiated another rise in pressure. Again the

dog to 7 to 10 seconds in the unanesthetized human.

ischemia was relieved and again the pressure fell. This

These waves are called vasomotor waves or “Mayer

repeated itself cyclically as long as the cerebrospinal

waves.” Such records are demonstrated in Figure 18-11,

fluid pressure remained elevated.

showing the cyclical rise and fall in arterial pressure.

Thus, any reflex pressure control mechanism can

The cause of vasomotor waves is “reflex oscillation”

oscillate if the intensity of “feedback” is strong enough

of one or more nervous pressure control mechanisms,

and if there is a delay between excitation of the pres-

some of which are the following.

sure receptor and the subsequent pressure response.

The vasomotor waves are of considerable theoretical

Oscillation of the Baroreceptor and Chemoreceptor Reflexes.

importance because they show that the nervous reflexes

The vasomotor waves of Figure 18-11B are often seen

that control arterial pressure obey the same principles

in experimental pressure recordings, although usually

as those applicable to mechanical and electrical control

much less intense than shown in the figure. They are

systems. For instance, if the feedback “gain” is too great

caused mainly by oscillation of the baroreceptor reflex.

in the guiding mechanism of an automatic pilot for an

That is, a high pressure excites the baroreceptors;

airplane and there is also delay in response time of the

this then inhibits the sympathetic nervous system and

guiding mechanism, the plane will oscillate from side to

lowers the pressure a few seconds later. The decreased

side instead of following a straight course.

Chapter 18

Nervous Regulation of the Circulation, and Rapid Control of Arterial Pressure

215

References

Hall JE, Hildebrandt DA, Kuo J: Obesity hypertension: role

of leptin and sympathetic nervous system. Am J Hyper-

tens 14:103S, 2001.

Antunes-Rodrigues J, De Castro M, Elias LLK, et al: Neu-

Ketch T, Biaggioni I, Robertson R, Robertson D: Four faces

roendocrine control of body fluid metabolism. Physiol Rev

of baroreflex failure: hypertensive crisis, volatile hyper-

84: 169, 2004.

tension, orthostatic tachycardia, and malignant vagotonia.

Cao WH, Fan W, Morrison SF: Medullary pathways mediat-

Circulation 105:2518, 2002.

ing specific sympathetic responses to activation of dorso-

Krieger EM, Da Silva GJ, Negrao CE: Effects of exercise

medial hypothalamus. Neuroscience 126:229, 2004.

training on baroreflex control of the cardiovascular

Cowley AW Jr, Guyton AC: Baroreceptor reflex contribu-

system. Ann N Y Acad Sci 940:338, 2001.

tion in angiotensin II-induced hypertension. Circulation

Lohmeier TE, Lohmeier JR, Warren S, et al: Sustained acti-

50:61, 1974.

vation of the central baroreceptor pathway in angiotensin

DiBona GF: Peripheral and central interactions between

hypertension. Hypertension 39:550, 2002.

the renin-angiotensin system and the renal sympathetic

Lohmeier TE: The sympathetic nervous system and long-

nerves in control of renal function. Ann N Y Acad Sci

term blood pressure regulation. Am J Hypertens 14:147S,

940:395, 2001.

2001.

DiCarlo SE, Bishop VS: Central baroreflex resetting as a

Malpas SC: What sets the long-term level of sympathetic

means of increasing and decreasing sympathetic outflow

nerve activity: is there a role for arterial baroreceptors?

and arterial pressure. Ann N Y Acad Sci 940:324, 2001.

Am J Physiol Regul Integr Comp Physiol 286:R1, 2004.

Esler M, Lambert G, Brunner-La Rocca HP, et al: Sympa-

Mifflin SW: What does the brain know about blood pressure?

thetic nerve activity and neurotransmitter release in

News Physiol Sci 16:266, 2001.

humans: translation from pathophysiology into clinical

Morrison SF: Differential control of sympathetic outflow.

practice. Acta Physiol Scand 177:275, 2003.

Am J Physiol Regul Integr Comp Physiol 281:R683, 2001.

Floras JS: Arterial baroreceptor and cardiopulmonary reflex

Sved AF, Ito S, Sved JC: Brainstem mechanisms of hyper-

control of sympathetic outflow in human heart failure.

tension: role of the rostral ventrolateral medulla. Curr

Ann N Y Acad Sci 940:500, 2001.

Hypertens Rep 5:262, 2003 .

Felder RB, Francis J, Zhang ZH, et al: Heart failure and the

Thrasher TN: Unloading arterial baroreceptors causes neu-

brain: new perspectives. Am J Physiol Regul Integr Comp

rogenic hypertension. Am J Physiol Regul Integr Comp

Physiol 284:R259, 2003.

Physiol 282:R1044, 2002.

Goldstein DS, Robertson D, Esler M, et al: Dysautonomias:

Zucker IH, Wang W, Pliquett RU, et al: The regulation

clinical disorders of the autonomic nervous system. Ann

of sympathetic outflow in heart failure. The roles of

Intern Med 137:753, 2002.

angiotensin II, nitric oxide, and exercise training. Ann

Guyton AC: Arterial Pressure and Hypertension. Philadel-

N Y Acad Sci 940:431, 2001.

phia: WB Saunders Co, 1980.

C H A P T E R

Dominant Role of the Kidney

in Long-Term Regulation of

Arterial Pressure and in

Hypertension: The Integrated

System for Pressure Control

Short-term control of arterial pressure by the sym-

pathetic nervous system, as discussed in Chapter 18,

occurs primarily through the effects of the nervous

system on total peripheral vascular resistance and

capacitance, and on cardiac pumping ability.

The body, however, also has powerful mecha-

nisms for regulating arterial pressure week

after week and month after month. This long-term

control of arterial pressure is closely intertwined with homeostasis of body fluid

volume, which is determined by the balance between the fluid intake and

output. For long-term survival, fluid intake and output must be precisely bal-

anced, a task that is performed by multiple nervous and hormonal controls, and

by local control systems within the kidneys that regulate their excretion of salt

and water. In this chapter we discuss these renal-body fluid systems that play

a dominant role in long-term blood pressure regulation.

Renal-Body Fluid System for Arterial

Pressure Control

The renal-body fluid system for arterial pressure control is a simple one: When

the body contains too much extracellular fluid, the blood volume and arterial

pressure rise. The rising pressure in turn has a direct effect to cause the kidneys

to excrete the excess extracellular fluid, thus returning the pressure back toward

normal.

In the phylogenetic history of animal development, this renal-body fluid

system for pressure control is a primitive one. It is fully operative in one of the

lowest of vertebrates, the hagfish. This animal has a low arterial pressure, only

8 to 14 mm Hg, and this pressure increases almost directly in proportion to its

blood volume. The hagfish continually drinks sea water, which is absorbed into

its blood, increasing the blood volume as well as the pressure. However, when

the pressure rises too high, the kidney simply excretes the excess volume into

the urine and relieves the pressure. At low pressure, the kidney excretes far less

fluid than is ingested. Therefore, because the hagfish continues to drink, extra-

cellular fluid volume, blood volume, and pressure all build up again to the higher

levels.

Throughout the ages, this primitive mechanism of pressure control has sur-

vived almost exactly as it functions in the hagfish; in the human being, kidney

output of water and salt is just as sensitive to pressure changes as in the hagfish,

if not more so. Indeed, an increase in arterial pressure in the human of only a

few millimeters of mercury can double renal output of water, which is called

pressure diuresis, as well as double the output of salt, which is called pressure

natriuresis.

216

Chapter 19

The Integrated System for Pressure Control

217

4000

3000

2000

1000

80 100 120 140 160 180 200

225

Arterial pressure (mm Hg)

200

175

150

125

Figure 19-1

100

Typical renal urinary output curve measured in a perfused isolated

kidney, showing pressure diuresis when the arterial pressure rises

Infusion period

above normal.

0 10 20 30 40 50 60

120

Time (minutes)

In the human being, the renal-body fluid system for

arterial pressure control, just as in the hagfish, is the

fundamental basis for long-term arterial pressure

Figure 19-2

control. However, through the stages of evolution,

Increases in cardiac output, urinary output, and arterial pressure

multiple refinements have been added to make this

caused by increased blood volume in dogs whose nervous pres-

system much more exact in its control in the human

sure control mechanisms had been blocked. This figure shows

being. An especially important refinement, as we shall

return of arterial pressure to normal after about an hour of fluid

see, has been addition of the renin-angiotensin

loss into the urine. (Courtesy Dr. William Dobbs.)

mechanism.

in cardiac output to about double normal and increase

Quantitation of Pressure Diuresis as

in mean arterial pressure to 205 mm Hg, 115 mm Hg

a Basis for Arterial Pressure Control

above its resting level. Shown by the middle curve is

the effect of this increased arterial pressure on urine

Figure 19-1 shows the approximate average effect of

output, which increased

12-fold. Along with this

different arterial pressure levels on urinary volume

tremendous loss of fluid in the urine, both the cardiac

output by an isolated kidney, demonstrating markedly

output and the arterial pressure returned to normal

increased output of volume as the pressure rises. This

during the subsequent hour. Thus, one sees an extreme

increased urinary output is the phenomenon of pres-

capability of the kidneys to eliminate fluid volume

sure diuresis. The curve in this figure is called a renal

from the body in response to high arterial pressure and

urinary output curve or a renal function curve. In the

in so doing to return the arterial pressure back to

human being, at an arterial pressure of 50 mm Hg, the

normal.

urine output is essentially zero. At 100 mm Hg it is

normal, and at 200 mm Hg it is about six to eight times

Graphical Analysis of Pressure Control by the Renal-Body Fluid

normal. Furthermore, not only does increasing the

Mechanism, Demonstrating an

“Infinite Feedback Gain”

arterial pressure increase urine volume output, but it

Feature. Figure 19-3 shows a graphical method that

causes approximately equal increase in sodium output,

can be used for analyzing arterial pressure control by

which is the phenomenon of pressure natriuresis.

the renal-body fluid system. This analysis is based on

two separate curves that intersect each other: (1) the

An Experiment Demonstrating the Renal-Body Fluid System for

renal output curve for water and salt in response to

Arterial Pressure Control. Figure 19-2 shows the results

rising arterial pressure, which is the same renal output

of a research experiment in dogs in which all the

curve as that shown in Figure 19-1, and (2) the curve

nervous reflex mechanisms for blood pressure control

(or line) that represents the net water and salt intake.

were first blocked. Then the arterial pressure was sud-

Over a long period, the water and salt output must

denly elevated by infusing about 400 milliliters of

equal the intake. Furthermore, the only place on the

blood intravenously. Note the instantaneous increase

graph in Figure 19-3 at which output equals intake is

218

Unit IV The Circulation

Renal output of water and salt

Water and salt intake

Normal

Elevated

pressure

100

150

200

250

Equilibrium point

100

150

250

Elevated

Arterial pressure (mm Hg)

pressure

Normal

Figure 19-3

Analysis of arterial pressure regulation by equating the “renal

output curve” with the “salt and water intake curve.” The equilib-

100

150

200

250

rium point describes the level to which the arterial pressure will

be regulated. (That small portion of the salt and water intake that

Arterial pressure (mm Hg)

is lost from the body through nonrenal routes is ignored in this and

similar figures in this chapter.)

Figure 19-4

Two ways in which the arterial pressure can be increased: A, by

where the two curves intersect, which is called the

shifting the renal output curve in the right-hand direction toward

equilibrium point. Now, let us see what happens if the

a higher pressure level or B, by increasing the intake level of salt

arterial pressure becomes some value that is different

and water.

from that at the equilibrium point.

First, assume that the arterial pressure rises to

150 mm Hg. At this level, the graph shows that renal

output of water and salt is about three times as great

As long as the two curves representing (1) renal

as the intake. Therefore, the body loses fluid, the blood

output of salt and water and (2) intake of salt and

volume decreases, and the arterial pressure decreases.

water remain exactly as they are shown in Figure 19-3,

Furthermore, this “negative balance” of fluid will not

the long-term mean arterial pressure level will always

cease until the pressure falls all the way back exactly

readjust exactly to 100 mm Hg, which is the pressure

to the equilibrium level. Indeed, even when the arte-

level depicted by the equilibrium point of this figure.

rial pressure is only 1 mm Hg greater than the equi-

Furthermore, there are only two ways in which the

librium level, there still is slightly more loss of water

pressure of this equilibrium point can be changed from

and salt than intake, so that the pressure continues to

the 100 mm Hg level. One of these is by shifting the

fall that last

1 mm Hg until the pressure eventually

pressure level of the renal output curve for salt and

returns exactly to the equilibrium point.

water; and the other is by changing the level of the

If the arterial pressure falls below the equilibrium

water and salt intake line. Therefore, expressed simply,

point, the intake of water and salt is greater than the

the two primary determinants of the long-term arte-

output. Therefore, body fluid volume increases, blood

rial pressure level are as follows:

volume increases, and the arterial pressure rises until

1. The degree of pressure shift of the renal output

once again it returns exactly to the equilibrium point.

curve for water and salt

This return of the arterial pressure always exactly

2. The level of the water and salt intake line

back to the equilibrium point is the infinite feedback

Operation of these two determinants in the control

gain principle for control of arterial pressure by the

of arterial pressure is demonstrated in Figure 19-4. In

renal-body fluid mechanism.

Figure 19-4A, some abnormality of the kidneys has

caused the renal output curve to shift 50 mm Hg in the

Two Determinants of the Long-Term Arterial Pressure Level. In

high-pressure direction (to the right). Note that the

Figure 19-3, one can also see that two basic long-term

equilibrium point has also shifted to 50 mm Hg higher

factors determine the long-term arterial pressure level.

than normal. Therefore, one can state that if the renal

This can be explained as follows.

output curve shifts to a new pressure level, so will the

Chapter 19

The Integrated System for Pressure Control

219

arterial pressure follow to this new pressure level

within a few days.

Figure 19-4B shows how a change in the level of salt

and water intake also can change the arterial pressure.

In this case, the intake level has increased fourfold and

the equilibrium point has shifted to a pressure level of

200

160 mm Hg, 60 mm Hg above the normal level. Con-

versely, a decrease in the intake level would reduce the

arterial pressure.

150

Thus, it is impossible to change the long-term mean

arterial pressure level to a new value without changing

one or both of the two basic determinants of long-term

100

arterial pressure—either (1) the level of salt and water

Arterial pressure

intake or (2) the degree of shift of the renal function

curve along the pressure axis. However, if either of

these is changed, one finds the arterial pressure there-

after to be regulated at a new pressure level, at the

pressure level at which the two new curves intersect.

100

120

140

160

Failure of Increased Total Peripheral

Total peripheral resistance

(per cent of normal)

Resistance to Elevate the Long-Term Level

of Arterial Pressure if Fluid Intake and Renal

Function Do Not Change

Now is the chance for the reader to see whether he or

Figure 19-5

she really understands the renal-body fluid mecha-

nism for arterial pressure control. Recalling the basic

Relations of total peripheral resistance to the long-term levels of

arterial pressure and cardiac output in different clinical abnor-

equation for arterial pressure—arterial pressure equals

malities. In these conditions, the kidneys were functioning nor-

cardiac output times total peripheral resistance—it is

mally. Note that changing the whole-body total peripheral

clear that an increase in total peripheral resistance

resistance caused equal and opposite changes in cardiac output

should elevate the arterial pressure. Indeed, when the

but in all cases had no effect on arterial pressure. (Redrawn from

Guyton AC: Arterial Pressure and Hypertension. Philadelphia: WB

total peripheral resistance is acutely increased, the arte-

Saunders Co, 1980.)

rial pressure does rise immediately. Yet if the kidneys

continue to function normally, the acute rise in arterial

pressure usually is not maintained. Instead, the arte-

rial pressure returns all the way to normal within a day

hypertension by shifting the renal function curve to a

or so. Why?

higher pressure level, in the manner shown in Figure

The answer to this is the following: Increasing resist-

19-4A. We see an example of this later in this chapter

ance in the blood vessels everywhere else in the body

when we discuss hypertension caused by vasoconstric-

besides in the kidneys does not change the equilibrium

tor mechanisms. But it is the increase in renal resistance

point for blood pressure control as dictated by the

that is the culprit, not the increased total peripheral

kidneys (see again Figures 19-3 and 19-4). Instead, the

resistance—an important distinction!)

kidneys immediately begin to respond to the high arte-

rial pressure, causing pressure diuresis and pressure

Increased Fluid Volume Can Elevate Arterial

natriuresis. Within hours, large amounts of salt and

Pressure by Increasing Cardiac Output or

water are lost from the body, and this continues until

Total Peripheral Resistance

the arterial pressure returns exactly to the pressure

The overall mechanism by which increased extracellu-

level of the equilibrium point.

lar fluid volume elevates arterial pressure is given in

As proof of this principle that changes in total

the schema of Figure 19-6. The sequential events are

peripheral resistance do not affect the long-term level

(1) increased extracellular fluid volume (2) increases

of arterial pressure if function of the kidneys is still

the blood volume, which (3) increases the mean cir-

normal, carefully study Figure 19-5. This figure shows

culatory filling pressure, which (4) increases venous

the approximate cardiac outputs and the arterial pres-

return of blood to the heart, which

(5) increases

sures in different clinical conditions in which the long-

cardiac output, which (6) increases arterial pressure.

term total peripheral resistance is either much less than

Note especially in this schema the two ways in which

or much greater than normal, but kidney excretion of

an increase in cardiac output can increase the arterial

salt and water is normal. Note in all these different

pressure. One of these is the direct effect of increased

clinical conditions that the arterial pressure is also

cardiac output to increase the pressure, and the other

exactly normal.

is an indirect effect to raise total peripheral vascular

(A word of caution! Many times when the total

resistance through autoregulation of blood flow. The

peripheral resistance increases, this increases the

second effect can be explained as follows.

intrarenal vascular resistance at the same time, which

Referring back to Chapter 17, let us recall that

alters the function of the kidney and can cause

whenever an excess amount of blood flows through a

220

Unit IV

The Circulation

pressure than is an increase in water intake. The reason

for this is that pure water is normally excreted by the

kidneys almost as rapidly as it is ingested, but salt

Increased extracellular fluid volume

is not excreted so easily. As salt accumulates in the

body, it also indirectly increases the extracellular fluid

volume for two basic reasons:

Increased blood volume

1. When there is excess salt in the extracellular fluid,

the osmolality of the fluid increases, and this in

turn stimulates the thirst center in the brain,

Increased mean circulatory filling pressure

making the person drink extra amounts of

water to return the extracellular salt

concentration to normal. This increases the

Increased venous return of blood to the heart

extracellular fluid volume.

2. The increase in osmolality caused by the excess

salt in the extracellular fluid also stimulates the

Increased cardiac output

hypothalamic-posterior pituitary gland secretory

mechanism to secrete increased quantities of

antidiuretic hormone. (This is discussed in Chapter

Autoregulation

28.) The antidiuretic hormone then causes the

kidneys to reabsorb greatly increased quantities

of water from the renal tubular fluid, thereby

Increased total

diminishing the excreted volume of urine but

peripheral resistance

increasing the extracellular fluid volume.

Thus, for these important reasons, the amount of salt

Increased arterial pressure

that accumulates in the body is the main determinant

of the extracellular fluid volume. Because only small

increases in extracellular fluid and blood volume can

often increase the arterial pressure greatly, accumula-

tion of even a small amount of extra salt in the body

Figure 19-6

can lead to considerable elevation of arterial pressure.

Sequential steps by which increased extracellular fluid volume

increases the arterial pressure. Note especially that increased

cardiac output has both a direct effect to increase arterial pres-

sure and an indirect effect by first increasing the total peripheral

Chronic Hypertension (High Blood

resistance.

Pressure) Is Caused by Impaired

Renal Fluid Excretion

tissue, the local tissue vasculature constricts and

When a person is said to have chronic hypertension (or

decreases the blood flow back toward normal. This

“high blood pressure”), it is meant that his or her mean

phenomenon is called “autoregulation,” which means

arterial pressure is greater than the upper range of the

simply regulation of blood flow by the tissue itself.

accepted normal measure. A mean arterial pressure

When increased blood volume increases the cardiac

greater than 110 mm Hg (normal is about 90 mm Hg)

output, the blood flow increases in all tissues of the

is considered to be hypertensive. (This level of mean

body, so that this autoregulation mechanism constricts

pressure occurs when the diastolic blood pressure is

blood vessels all over the body. This in turn increases

greater than about 90 mm Hg and the systolic pressure

the total peripheral resistance.

is greater than about 135 mm Hg.) In severe hyper-

Finally, because arterial pressure is equal to cardiac

tension, the mean arterial pressure can rise to 150

output times total peripheral resistance, the secondary

170 mm Hg, with diastolic pressure as high as

increase in total peripheral resistance that results from

130 mm Hg and systolic pressure occasionally as high

the autoregulation mechanism helps greatly in increas-

as 250 mm Hg.

ing the arterial pressure. For instance, only a 5 to 10

Even moderate elevation of arterial pressure leads

per cent increase in cardiac output can increase the

to shortened life expectancy. At severely high pres-

arterial pressure from the normal mean arterial pres-

sures—mean arterial pressures 50 per cent or more

sure of 100 mm Hg up to 150 mm Hg. In fact, the slight

above normal—a person can expect to live no more

increase in cardiac output is often unmeasurable.

than a few more years unless appropriately treated.

The lethal effects of hypertension are caused mainly

Importance of Salt (NaCl) in the Renal-Body

in three ways:

Fluid Schema for Arterial Pressure Regulation

1. Excess workload on the heart leads to early heart

Although the discussions thus far have emphasized the

failure and coronary heart disease, often causing

importance of volume in regulation of arterial pres-

death as a result of a heart attack.

sure, experimental studies have shown that an increase

2. The high pressure frequently damages a major

in salt intake is far more likely to elevate the arterial

blood vessel in the brain, followed by death of

Chapter 19

The Integrated System for Pressure Control

221

0.9% NaCl

Tap water

0.9% NaCl

150

140

130

120

35-45% of left

Entire right

kidney removed

110

100

Days

Figure 19-7

Average effect on arterial pressure of drinking 0.9 per cent saline solution instead of water in four dogs with 70 per cent of their

renal tissue removed. (Redrawn from Langston JB, Guyton AC, Douglas BH, Dorsett PE: Circ Res 12:508, 1963. By permission of the

American Heart Association, Inc.)

major portions of the brain; this is a cerebral

normal amounts of volume, and within a few days,

infarct. Clinically it is called a “stroke.” Depending

their average arterial pressure rose to about 40 mm Hg

on which part of the brain is involved, a stroke

above normal. After 2 weeks, the dogs were given tap

can cause paralysis, dementia, blindness, or

water again instead of salt solution; the pressure

multiple other serious brain disorders.

returned to normal within 2 days. Finally, at the end of

3. High pressure almost always causes injury in

the experiment, the dogs were given salt solution

the kidneys, producing many areas of renal

again, and this time the pressure rose much more

destruction and, eventually, kidney failure, uremia,

rapidly to an even higher level because the dogs had

and death.

already learned to tolerate the salt solution and there-

Lessons learned from the type of hypertension

fore drank much more. Thus, this experiment demon-

called

“volume-loading hypertension” have been

strates volume-loading hypertension.

crucial in understanding the role of the renal-body

If the reader considers again the basic determinants

fluid volume mechanism for arterial pressure regula-

of long-term arterial pressure regulation, he or she can

tion. Volume-loading hypertension means hyperten-

immediately understand why hypertension occurred in

sion caused by excess accumulation of extracellular

the volume-loading experiment of Figure 19-7. First,

fluid in the body, some examples of which follow.

reduction of the kidney mass to 30 per cent of normal

greatly reduced the ability of the kidneys to excrete

Experimental Volume-Loading Hypertension Caused by Reduced

salt and water. Therefore, salt and water accumulated

Renal Mass Along with Simultaneous Increase in Salt Intake.

in the body and in a few days raised the arterial pres-

Figure 19-7 shows a typical experiment demonstrating

sure high enough to excrete the excess salt and water

volume-loading hypertension in a group of dogs with

intake.

70 per cent of their kidney mass removed. At the first

circled point on the curve, the two poles of one of the

kidneys were removed, and at the second circled point,

Sequential Changes in Circulatory Function During the Devel-

the entire opposite kidney was removed, leaving the

opment of Volume-Loading Hypertension. It is especially

animals with only 30 per cent of normal renal mass.

instructive to study the sequential changes in circula-

Note that removal of this amount of kidney mass

tory function during progressive development of

increased the arterial pressure an average of only 6

volume-loading hypertension. Figure 19-8 shows these

mm Hg. Then, the dogs were given salt solution to

sequential changes. A week or so before the point

drink instead of water. Because salt solution fails to

labeled “0” days, the kidney mass had already been

quench the thirst, the dogs drank two to four times the

decreased to only 30 per cent of normal. Then, at this

222

Unit IV The Circulation

33%

6.0

20%

5.5

5.0

40%

7.0

6.5

6.0

5.5

5.0

33%

-13%

Figure 19-8

150

40%

30%

Progressive changes in important circulatory

140

system variables during the first few weeks of

130

volume-loading hypertension. Note especially the

120

initial increase in cardiac output as the basic

110

cause of the hypertension. Subsequently, the auto-

regulation mechanism returns the cardiac output

almost to normal while simultaneously causing a

Days

secondary increase in total peripheral resistance.

(Modified from Guyton AC: Arterial Pressure and

Hypertension. Philadelphia: WB Saunders Co,

1980.)

point, the intake of salt and water was increased to

Chapter 17 and earlier in this chapter. That is, after the

about six times normal and kept at this high intake

cardiac output had risen to a high level and had initi-

thereafter. The acute effect was to increase extracellu-

ated the hypertension, the excess blood flow through

lar fluid volume, blood volume, and cardiac output to

the tissues then caused progressive constriction of the

20 to 40 per cent above normal. Simultaneously, the

local arterioles, thus returning the local blood flows

arterial pressure began to rise but not nearly so much

in all the body tissues and also the cardiac output

at first as did the fluid volumes and cardiac output. The

almost all the way back to normal, while simultane-

reason for this slower rise in pressure can be discerned

ously causing a secondary increase in total peripheral

by studying the total peripheral resistance curve, which

resistance.

shows an initial decrease in total peripheral resistance.

Note, too, that the extracellular fluid volume and

This decrease was caused by the baroreceptor mecha-

blood volume returned almost all the way back to

nism discussed in Chapter 18, which tried to prevent

normal along with the decrease in cardiac output. This

the rise in pressure. However, after 2 to 4 days, the

resulted from two factors: First, the increase in arteri-

baroreceptors adapted (reset) and were no longer able

olar resistance decreased the capillary pressure, which

to prevent the rise in pressure. At this time, the arte-

allowed the fluid in the tissue spaces to be absorbed

rial pressure had risen almost to its full height because

back into the blood. Second, the elevated arterial

of the increase in cardiac output, even though the total

pressure now caused the kidneys to excrete the excess

peripheral resistance was still almost at the normal

volume of fluid that had initially accumulated in the

level.

body.

After these early acute changes in the circulatory

Last, let us take stock of the final state of the circu-

variables had occurred, more prolonged secondary

lation several weeks after the initial onset of volume

changes occurred during the next few weeks. Espe-

loading. We find the following effects:

cially important was a progressive increase in total

1. Hypertension

peripheral resistance, while at the same time the cardiac

2. Marked increase in total peripheral resistance

3. Almost complete return of the extracellular fluid

output decreased almost all the way back to normal,

volume, blood volume, and cardiac output back to

mainly as a result of the long-term blood flow autoreg-

normal

ulation mechanism that is discussed in detail in

Chapter 19

The Integrated System for Pressure Control

223

Therefore, we can divide volume-loading hyperten-

The Renin-Angiotensin

sion into two separate sequential stages: The first stage

System: Its Role in Pressure

results from increased fluid volume causing increased

Control and in Hypertension

cardiac output. This increase in cardiac output causes

the hypertension. The second stage in volume-loading

Aside from the capability of the kidneys to control

hypertension is characterized by high blood pressure

arterial pressure through changes in extracellular

and high total peripheral resistance but return of the

fluid volume, the kidneys also have another powerful

cardiac output so near to normal that the usual meas-

mechanism for controlling pressure. It is the renin-

uring techniques frequently cannot detect an abnor-

angiotensin system.

mally elevated cardiac output.

Renin is a protein enzyme released by the kidneys

Thus, the increased total peripheral resistance in

when the arterial pressure falls too low. In turn, it

volume-loading hypertension occurs after the hyper-

raises the arterial pressure in several ways, thus

tension has developed and, therefore, is secondary to

helping to correct the initial fall in pressure.

the hypertension rather than being the cause of the

hypertension.

Components of the Renin-Angiotensin

Volume-Loading Hypertension in Patients

Who Have No Kidneys but Are Being

System

Maintained on an Artificial Kidney

When a patient is maintained on an artificial kidney, it

Figure 19-9 shows the functional steps by which the

is especially important to keep the patient’s body fluid

renin-angiotensin system helps to regulate arterial

volume at a normal level—that is, it is important

pressure.

to remove an appropriate amount of water and salt

Renin is synthesized and stored in an inactive form

each time the patient is dialyzed. If this is not done and

called prorenin in the juxtaglomerular cells (JG cells)

extracellular fluid volume is allowed to increase,

of the kidneys. The JG cells are modified smooth

hypertension almost invariably develops in exactly the

muscle cells located in the walls of the afferent

same way as shown in Figure 19-8. That is, the cardiac

output increases at first and causes hypertension. Then

the autoregulation mechanism returns the cardiac

output back toward normal while causing a secondary

increase in total peripheral resistance. Therefore, in

Decreased

the end, the hypertension is a high peripheral resist-

arterial pressure

ance type of hypertension.

Hypertension Caused by

Renin (kidney)

Primary Aldosteronism

Another type of volume-loading hypertension is

Renin substrate

caused by excess aldosterone in the body or, occa-

(angiotensinogen)

sionally, by excesses of other types of steroids. A small

tumor in one of the adrenal glands occasionally

Angiotensin I

secretes large quantities of aldosterone, which is

the condition called “primary aldosteronism.” As dis-

Converting

cussed in Chapter 29, aldosterone increases the rate of

enzyme

(lung)

reabsorption of salt and water by the tubules of the

kidneys, thereby reducing the loss of these in the

urine while at the same time causing an increase in

Angiotensin II

blood volume and extracellular fluid volume. Conse-

Angiotensinase

quently, hypertension occurs. And, if salt intake is

increased at the same time, the hypertension becomes

(Inactivated)

even greater. Furthermore, if the condition persists for

Renal retention

Vasoconstriction

months or years, the excess arterial pressure often

of salt and water

causes pathological changes in the kidneys that make

the kidneys retain even more salt and water in addi-

tion to that caused directly by the aldosterone. There-

fore, the hypertension often finally becomes lethally

Increased arterial pressure

severe.

Here again, in the early stages of this type of hyper-

tension, the cardiac output is increased, but in later

stages, the cardiac output generally returns almost to

Figure 19-9

normal while the total peripheral resistance becomes

secondarily elevated, as explained earlier in the

Renin-angiotensin vasoconstrictor mechanism for arterial pres-

chapter for primary volume-loading hypertension.

sure control.

224

Unit IV The Circulation

arterioles immediately proximal to the glomeruli. When

the arterial pressure falls, intrinsic reactions in the

kidneys themselves cause many of the prorenin mole-

100

With

cules in the JG cells to split and release renin. Most of

renin-angiotensin system

the renin enters the renal blood and then passes out

of the kidneys to circulate throughout the entire body.

However, small amounts of the renin do remain in the

Without

local fluids of the kidney and initiate several intrarenal

renin-angiotensin system

functions.

Renin itself is an enzyme, not a vasoactive sub-

Hemorrhage

stance. As shown in the schema of Figure

19-9,

renin acts enzymatically on another plasma protein,

a globulin called renin substrate (or angiotensinogen),

to release a

10-amino acid peptide, angiotensin I.

Minutes

Angiotensin I has mild vasoconstrictor properties but

not enough to cause significant changes in circulatory

function. The renin persists in the blood for 30 minutes

to 1 hour and continues to cause formation of still

Figure 19-10

more angiotensin I during this entire time.

Pressure-compensating effect of the renin-angiotensin vasocon-

Within a few seconds to minutes after formation of

strictor system after severe hemorrhage. (Drawn from experiments

angiotensin I, two additional amino acids are split

by Dr. Royce Brough.)

from the angiotensin I to form the

8-amino acid

peptide angiotensin II. This conversion occurs almost

entirely in the lungs while the blood flows through the

small vessels of the lungs, catalyzed by an enzyme

called converting enzyme that is present in the

endothelium of the lung vessels.

the system functioning (the system was interrupted

Angiotensin II is an extremely powerful vasocon-

by a renin-blocking antibody). Note that after hemor-

strictor, and it also affects circulatory function in other

rhage—enough to cause acute decrease of the arterial

ways as well. However, it persists in the blood only

pressure to

50 mm Hg—the arterial pressure rose

for 1 or 2 minutes because it is rapidly inactivated by

back to

83 mm Hg when the renin-angiotensin

multiple blood and tissue enzymes collectively called

system was functional. Conversely, it rose to only

angiotensinases.

60 mm Hg when the renin-angiotensin system was

During its persistence in the blood, angiotensin

blocked. This shows that the renin-angiotensin system

II has two principal effects that can elevate arterial

is powerful enough to return the arterial pressure at

pressure. The first of these, vasoconstriction in many

least halfway back to normal within a few minutes

areas of the body, occurs rapidly. Vasoconstriction

after severe hemorrhage. Therefore, sometimes it

occurs intensely in the arterioles and much less so in

can be of lifesaving service to the body, especially in

the veins. Constriction of the arterioles increases the

circulatory shock.

total peripheral resistance, thereby raising the arterial

Note also that the renin-angiotensin vasocon-

pressure, as demonstrated at the bottom of the schema

strictor system requires about 20 minutes to become

in Figure 19-9. Also, the mild constriction of the veins

fully active. Therefore, it is somewhat slower to act

promotes increased venous return of blood to the

for pressure control than are the nervous reflexes

heart, thereby helping the heart pump against the

and the sympathetic norepinephrine-epinephrine

increasing pressure.

system.

The second principal means by which angiotensin

increases the arterial pressure is to decrease excretion

Effect of Angiotensin in the Kidneys to

of both salt and water by the kidneys. This slowly

Cause Renal Retention of Salt and Water—

increases the extracellular fluid volume, which then

An Especially Important Means for

increases the arterial pressure during subsequent

Long-Term Control of Arterial Pressure

hours and days. This long-term effect, acting through

Angiotensin causes the kidneys to retain both salt and

the extracellular fluid volume mechanism, is even

water in two major ways:

more powerful than the acute vasoconstrictor mecha-

1. Angiotensin acts directly on the kidneys to cause

nism in eventually raising the arterial pressure.

salt and water retention.

2. Angiotensin causes the adrenal glands to secrete

Rapidity and Intensity of the

aldosterone, and the aldosterone in turn increases

Vasoconstrictor Pressure Response to

salt and water reabsorption by the kidney tubules.

the Renin-Angiotensin System

Thus, whenever excess amounts of angiotensin cir-

Figure

19-10 shows a typical experiment demon-

culate in the blood, the entire long-term renal-body

strating the effect of hemorrhage on the arterial

fluid mechanism for arterial pressure control auto-

pressure under two separate conditions: (1) with the

matically becomes set to a higher arterial pressure

renin-angiotensin system functioning and (2) without

level than normal.

Chapter 19

The Integrated System for Pressure Control

225

Mechanisms of the Direct Renal Effects of Angiotensin to Cause

Renal Retention of Salt and Water. Angiotensin has several

Angiotensin levels in the blood

direct renal effects that make the kidneys retain salt

(times normal)

and water. One major effect is to constrict the renal

arterioles, thereby diminishing blood flow through

2.5

the kidneys. As a result, less fluid filters through the

glomeruli into the tubules. Also, the slow flow of blood

reduces the pressure in the peritubular capillaries,

which causes rapid reabsorption of fluid from the

tubules. And still a third effect is that angiotensin has

important direct actions on the tubular cells them-

selves to increase tubular reabsorption of sodium and

water. The total result of all these effects is significant,

sometimes decreasing urine output less than one fifth

Equilibrium

of normal.

points

Stimulation of Aldosterone Secretion by Angiotensin, and the

Normal Intake

Effect of Aldosterone in Increasing Salt and Water Retention

by the Kidneys. Angiotensin is also one of the most

powerful stimulators of aldosterone secretion by the

100

120

140

160

adrenal glands, as we shall discuss in relation to body

Arterial pressure (mm Hg)

fluid regulation in Chapter

29 and in relation to

adrenal gland function in Chapter 77. Therefore, when

the renin-angiotensin system becomes activated, the

rate of aldosterone secretion usually also increases;

Figure 19-11

and an important subsequent function of aldosterone

Effect of two angiotensin II levels in the blood on the renal output

is to cause marked increase in sodium reabsorption by

curve, showing regulation of the arterial pressure at an equilibrium

the kidney tubules, thus increasing the total body

point of 75 mm Hg when the angiotensin II level is low and at

extracellular fluid sodium. This increased sodium then

115 mm Hg when the angiotensin II level is high.

causes water retention, as already explained, increas-

ing the extracellular fluid volume and leading second-

arily to still more long-term elevation of the arterial

pressure.

angiotensin to cause renal retention of salt and water

Thus both the direct effect of angiotensin on the

can have a powerful effect in promoting chronic eleva-

kidney and its effect acting through aldosterone are

tion of the arterial pressure.

important in long-term arterial pressure control.

However, research in our own laboratory has sug-

Role of the Renin-Angiotensin System in

gested that the direct effect of angiotensin on the

Maintaining a Normal Arterial Pressure

kidneys is perhaps three or more times as potent as the

Despite Wide Variations in Salt Intake

indirect effect acting through aldosterone—even

One of the most important functions of the renin-

though the indirect effect is the one most widely

angiotensin system is to allow a person to eat either

known.

very small or very large amounts of salt without

causing great changes in either extracellular fluid

Quantitative Analysis of Arterial Pressure Changes Caused by

volume or arterial pressure. This function is explained

Angiotensin. Figure 19-11 shows a quantitative analysis

by the schema in Figure 19-12, which shows that the

of the effect of angiotensin in arterial pressure control.

initial effect of increased salt intake is to elevate the

This figure shows two renal output curves as well as a

extracellular fluid volume and this in turn to elevate

line depicting normal level of sodium intake. The left-

the arterial pressure. Then, the increased arterial pres-

hand renal output curve is that measured in dogs whose

sure causes increased blood flow through the kidneys,

renin-angiotensin system had been blocked by the drug

captopril (which blocks the conversion of angiotensin I

which reduces the rate of secretion of renin to a much

to angiotensin II, the active form of angiotensin). The

lower level and leads sequentially to decreased renal

right-hand curve was measured in dogs infused contin-

retention of salt and water, return of the extracellular

uously with angiotensin II at a level about 2.5 times the

fluid volume almost to normal, and, finally, return of

normal rate of angiotensin formation in the blood. Note

the arterial pressure also almost to normal. Thus, the

the shift of the renal output curve toward higher pres-

renin-angiotensin system is an automatic feedback

sure levels under the influence of angiotensin II. This

mechanism that helps maintain the arterial pressure at

shift is caused by both the direct effects of angiotensin

or near the normal level even when salt intake is

on the kidney and the indirect effect acting through

increased. Or, when salt intake is decreased below

aldosterone secretion, as explained above.

normal, exactly opposite effects take place.

Finally, note the two equilibrium points, one for zero

angiotensin showing an arterial pressure level of 75 mm

To emphasize the efficacy of the renin-angiotensin

Hg, and one for elevated angiotensin showing a

system in controlling arterial pressure, when the

pressure level of 115 mm Hg. Therefore, the effect of

system functions normally, the pressure rises no more

226

Unit IV The Circulation

Increased salt intake

Increased extracellular volume

Increased arterial pressure

Decreased renin and angiotensin

Renal artery constricted

Constriction released

Decreased renal retention of salt and water

Systemic arterial

pressure

200

Return of extracellular volume almost to normal

150

Return of arterial pressure almost to normal

Distal renal arterial

100

pressure

Figure 19-12

Sequential events by which increased salt intake increases the

arterial pressure, but feedback decrease in activity of the renin

angiotensin system returns the arterial pressure almost to the

normal level.

Renin secretion

than 4 to 6 mm Hg in response to as much as a 50-fold

increase in salt intake. Conversely, when the renin-

angiotensin system is blocked, the same increase in salt

Days

intake sometimes causes the pressure to rise 10 times

the normal increase, often as much as 50 to 60 mm Hg.

Figure 19-13

Types of Hypertension in Which

Angiotensin Is Involved: Hypertension

Effect of placing a constricting clamp on the renal artery of one

Caused by a Renin-Secreting Tumor

kidney after the other kidney has been removed. Note the

changes in systemic arterial pressure, renal artery pressure distal

or by Infusion of Angiotensin II

to the clamp, and rate of renin secretion. The resulting hyperten-

sion is called “one-kidney” Goldblatt hypertension.

Occasionally a tumor of the renin-secreting juxta-

glomerular cells (the JG cells) occurs and secretes

tremendous quantities of renin; in turn, equally large

2. By causing the kidneys to retain salt and water;

over a period of days, this, too, causes hypertension

quantities of angiotensin II are formed. In all patients

and is the principal cause of the long-term

in whom this has occurred, severe hypertension has

continuation of the elevated pressure.

developed. Also, when large amounts of angiotensin

are infused continuously for days or weeks into

“One-Kidney” Goldblatt Hypertension. When one kidney is

animals, similar severe long-term hypertension

removed and a constrictor is placed on the renal artery

develops.

of the remaining kidney, as shown in Figure 19-13, the

We have already noted that angiotensin can increase

immediate effect is greatly reduced pressure in the

the arterial pressure in two ways:

renal artery beyond the constrictor, as demonstrated

1. By constricting the arterioles throughout the entire

by the dashed curve in the figure. Then, within seconds

body, thereby increasing the total peripheral

resistance and arterial pressure; this effect occurs

or minutes, the systemic arterial pressure begins to rise

within seconds after one begins to infuse

and continues to rise for several days. The pressure

angiotensin.

usually rises rapidly for the first hour or so, and this is

Chapter 19

The Integrated System for Pressure Control

227

followed by a slower additional rise during the next

Other Types of Hypertension

several days. When the systemic arterial pressure

Caused by Combinations of Volume

reaches its new stable pressure level, the renal arterial

Loading and Vasoconstriction

pressure (the dashed curve in the figure) will have

returned almost all the way back to normal. The hyper-

Hypertension in the Upper Part of the Body Caused by Coarctation

of the Aorta. One out of every few thousand babies is

tension produced in this way is called “one-kidney”

born with pathological constriction or blockage of the

Goldblatt hypertension in honor of Dr. Goldblatt, who

aorta at a point beyond the aortic arterial branches to

first studied the important quantitative features of

the head and arms but proximal to the renal arteries,

hypertension caused by renal artery constriction.

a condition called coarctation of the aorta. When this

The early rise in arterial pressure in Goldblatt

occurs, blood flow to the lower body is carried by mul-

hypertension is caused by the renin-angiotensin vaso-

tiple, small collateral arteries in the body wall, with

constrictor mechanism. That is, because of poor blood

much vascular resistance between the upper aorta and

flow through the kidney after acute constriction of the

the lower aorta. As a consequence, the arterial pressure

renal artery, large quantities of renin are secreted by

in the upper part of the may be 40-50 per cent higher

the kidney, as demonstrated by the lowermost curve in

than that in the lower body.

The mechanism of this upper-body hypertension is

Figure 19-13, and this causes increased angiotensin

almost identical to that of one-kidney Goldblatt hyper-

II and aldosterone in the blood. The angiotensin in

tension. That is, when a constrictor is placed on the aorta

turn raises the arterial pressure acutely. The secretion

above the renal arteries, the blood pressure in both

of renin rises to a peak in an hour or so but returns

kidneys at first falls, renin is secreted, angiotensin and

nearly to normal in 5 to 7 days because the renal arte-

aldosterone are formed, and hypertension occurs in the

rial pressure by that time has also risen back to

upper body. The arterial pressure in the lower body at

normal, so that the kidney is no longer ischemic.

the level of the kidneys rises approximately to normal,

The second rise in arterial pressure is caused by

but high pressure persists in the upper body. The

retention of salt and water by the constricted kidney

kidneys are no longer ischemic, so that secretion of

(that is also stimulated by angiotensin II and aldos-

renin and formation of angiotensin and aldosterone

return to normal. Likewise, in coarctation of the aorta,

terone). In 5 to 7 days, the body fluid volume will have

the arterial pressure in the lower body is usually almost

increased enough to raise the arterial pressure to its

normal, whereas the pressure in the upper body is far

new sustained level. The quantitative value of this sus-

higher than normal.

tained pressure level is determined by the degree of

constriction of the renal artery. That is, the aortic pres-

Role of Autoregulation in the Hypertension Caused by Aortic

sure must rise high enough so that renal arterial pres-

Coarctation. A significant feature of hypertension caused

sure distal to the constrictor is enough to cause normal

by aortic coarctation is that blood flow in the arms,

urine output.

where the pressure may be 40 to 60 per cent above

normal, is almost exactly normal. Also, blood flow in the

“Two-Kidney” Goldblatt Hypertension. Hypertension also

legs, where the pressure is not elevated, is almost exactly

can result when the artery to only one kidney is con-

normal. How could this be, with the pressure in the

stricted while the artery to the other kidney is normal.

upper body 40 to 60 per cent greater than in the lower

This hypertension results from the following mecha-

body? The answer is not that there are differences in

nism: The constricted kidney secretes renin and also

vasoconstrictor substances in the blood of the upper and

retains salt and water because of decreased renal arte-

lower body, because the same blood flows to both areas.

Likewise, the nervous system innervates both areas of

rial pressure in this kidney. Then the “normal” oppo-

the circulation similarly, so that there is no reason to

site kidney retains salt and water because of the renin

believe that there is a difference in nervous control of

produced by the ischemic kidney. This renin causes

the blood vessels. The only reasonable answer is that

formation of angiotension II and aldosterone both of

long-term autoregulation develops so nearly completely

which circulate to the opposite kidney and cause it also

that the local blood flow control mechanisms have com-

to retain salt and water. Thus, both kidneys, but for dif-

pensated almost 100 per cent for the differences in pres-

ferent reasons, become salt and water retainers. Con-

sure. The result is that, in both the high-pressure area

sequently, hypertension develops.

and the low-pressure area, the local blood flow is con-

trolled almost exactly in accord with the needs of the

Hypertension Caused by Diseased Kidneys That Secrete Renin

tissue and not in accord with the level of the pressure.

One of the reasons these observations are so important

Chronically. Often, patchy areas of one or both kidneys

is that they demonstrate how nearly complete the long-

are diseased and become ischemic because of local

term autoregulation process can be.

vascular constrictions, whereas other areas of the

kidneys are normal. When this occurs, almost identical

Hypertension in Preeclampsia (Toxemia of Pregnancy). Approx-

effects occur as in the two-kidney type of Goldblatt

imately 5 to 10 per cent of expectant mothers develop

hypertension. That is, the patchy ischemic kidney

a syndrome called preeclampsia (also called toxemia of

tissue secretes renin, and this in turn, acting through

pregnancy). One of the manifestations of preeclampsia

the formation of angiotensin II, causes the remaining

is hypertension that usually subsides after delivery of

kidney mass also to retain salt and water. Indeed, one

the baby. Although the precise causes of preeclampsia

of the most common causes of renal hypertension,

are not completely understood, ischemia of the placenta

especially in older persons, is such patchy ischemic

and subsequent release by the placenta of toxic factors

kidney disease.

are believed to play a role in causing many of the man-

228

Unit IV

The Circulation

ifestations of this disorder, including hypertension in the

hypertension. In other strains of hypertensive rats,

mother. Substances released by the ischemic placenta,

impaired renal function also has been observed.

in turn, cause dysfunction of vascular endothelial cells

throughout the body, including the blood vessels of the

kidneys. This endothelial dysfunction decreases release of

“Primary (Essential) Hypertension”

nitric oxide and other vasodilator substances, causing

vasoconstriction, decreased rate of fluid filtration from

About 90 to 95 per cent of all people who have hyper-

the glomeruli into the renal tubules, impaired renal-

pressure natriuresis, and development of hypertension.

tension are said to have “primary hypertension,” also

Another pathological abnormality that may con-

widely known as “essential hypertension” by many cli-

tribute to hypertension in preeclampsia is thickening of

nicians. These terms mean simply that the hypertension

the kidney glomerular membranes (perhaps caused by

is of unknown origin, in contrast to those forms of

an autoimmune process), which also reduces the rate of

hypertension that are secondary to known causes, such

glomerular fluid filtration. For obvious reasons, the arte-

as renal artery stenosis. In some patients with primary

rial pressure level required to cause normal formation

hypertension, there is a strong hereditary tendency, the

of urine becomes elevated, and the long-term level of

same as occurs in animal strains of genetic hyperten-

arterial pressure becomes correspondingly elevated.

sion discussed above.

These patients are especially prone to extra degrees of

In most patients, excess weight gain and sedentary

hypertension when they have excess salt intake.

lifestyle appear to play a major role in causing hyper-

Neurogenic Hypertension. Acute neurogenic hypertension

tension. The majority of patients with hypertension

can be caused by strong stimulation of the sympathetic

are overweight, and studies of different populations

nervous system. For instance, when a person becomes

suggest that excess weight gain and obesity may

excited for any reason or at times during states of

account for as much as 65 to 70 percent of the risk

anxiety, the sympathetic system becomes excessively

for developing primary hypertension. Clinical studies

stimulated, peripheral vasoconstriction occurs every-

have clearly shown the value of weight loss for reduc-

where in the body, and acute hypertension ensues.

ing blood pressure in most patients with hypertension.

In fact, new clinical guidelines for treating hyper-

Acute Neurogenic Hypertension Caused by Sectioning the Barore-

tension recommend increased physical activity and

ceptor Nerves. Another type of acute neurogenic hyper-

weight loss as a first step in treating most patients with

tension occurs when the nerves leading from the

hypertension.

baroreceptors are cut or when the tractus solitarius

is destroyed in each side of the medulla oblongata

Some of the characteristics of primary hypertension

(these are the areas where the nerves from the carotid

caused by excess weight gain and obesity include:

and aortic baroreceptors connect in the brain stem).

Cardiac output is increased due, in part, to the

The sudden cessation of normal nerve signals from

additional blood flow required for the extra

the baroreceptors has the same effect on the nervous

adipose tissue. However, blood flow in the heart,

pressure control mechanisms as a sudden reduction

kidneys, gastrointestinal tract, and skeletal muscle

of the arterial pressure in the aorta and carotid arteries.

also increases with weight gain due to increased

That is, loss of the normal inhibitory effect on the

metabolic rate and growth of the organs and tissues

vasomotor center caused by normal baroreceptor

in response to their increased metabolic demands.

nervous signals allows the vasomotor center suddenly

As the hypertension is sustained for many months

to become extremely active and the mean arterial pres-

and years, total peripheral vascular resistance may

sure to increase from 100 mm Hg to as high as 160 mm

be increased.

Hg. The pressure returns to nearly normal within about

Sympathetic nerve activity, especially in the kidneys,

2 days because the response of the vasomotor center to

is increased in overweight patients. The causes of

the absent baroreceptor signal fades away, which is

increased sympathetic activity in obesity are not

called central “resetting” of the baroreceptor pressure

fully understood, but recent studies suggest that

control mechanism. Therefore, the neurogenic hyper-

hormones, such as leptin, released from fat cells

tension caused by sectioning the baroreceptor nerves is

may directly stimulate multiple regions of the

mainly an acute type of hypertension, not a chronic

hypothalamus, which, in turn, have an excitatory

type.

influence on the vasomotor centers of the brain

medulla.

Spontaneous Hereditary Hypertension in Lower Animals. Spon-

Angiotensin II and aldosterone levels are increased

taneous hereditary hypertension has been observed in

two- to threefold in many obese patients. This may

a number of strains of lower animals, including several

be caused partly by increased sympathetic nerve

different strains of rats, at least one strain of rabbits, and

stimulation, which increases renin release by the

at least one strain of dogs. In the strain of rats that has

kidneys and therefore formation of angiotensin II,

been studied to the greatest extent, the Okamoto strain,

which, in turn, stimulates the adrenal gland to

there is evidence that in early development of the

secrete aldosterone.

hypertension, the sympathetic nervous system is con-

The renal-pressure natriuresis mechanism is

siderably more active than in normal rats. However, in

impaired, and the kidneys will not excrete adequate

the late stages of this type of hypertension, two struc-

amounts of salt and water unless the arterial

tural changes have been observed in the nephrons of the

pressure is high or unless kidney function is

kidneys:

(1) increased preglomerular renal arterial

somehow improved. In other words, if the mean

resistance and

(2) decreased permeability of the

arterial pressure in the essential hypertensive

glomerular membranes. These structural changes could

person is 150 mm Hg, acute reduction of the mean

easily be the basis for the long-term continuance of the

arterial pressure artificially to the normal value of

Chapter 19

The Integrated System for Pressure Control

229

100 mm Hg (but without otherwise altering renal

increasing the level of sodium intake. The sodium-

function except for the decreased pressure) will

loading type of curve can be determined by increasing

cause almost total anuria, and the person will retain

the level of sodium intake to a new level every few

salt and water until the pressure rises back to the

days, then waiting for the renal output of sodium to

elevated value of 150 mm Hg. Chronic reductions

come into balance with the intake, and at the same

in arterial pressure with effective antihypertensive

time recording the changes in arterial pressure.

therapies, however, usually do not cause marked

When this procedure is used in essential hyperten-

salt and water retention by the kidneys because

sive patients, two types of curves, shown to the right in

these therapies also improve renal-pressure

natriuresis, as discussed below.

Figure 19-14, can be recorded in essential hyperten-

Experimental studies in obese animals and obese

sive patients, one called (1) nonsalt-sensitive hyperten-

patients suggest that impaired renal-pressure natri-

sion and the other (2) salt-sensitive hypertension. Note

uresis in obesity hypertension is caused mainly by

in both instances that the curves are shifted to the

increased renal tubular reabsorption of salt and

right, to a much higher pressure level than for normal

water due to increased sympathetic nerve activity and

people. Now, let us plot on this same graph (1) a

increased levels of angiotensin II and aldosterone.

normal level of salt intake and (2) a high level of salt

However, if hypertension is not effectively treated,

intake representing 3.5 times the normal intake. In

there may also be vascular damage in the kidneys that

the case of the person with nonsalt-sensitive essential

can reduce the glomerular filtration rate and increase

hypertension, the arterial pressure does not increase

the severity of the hypertension. Eventually uncon-

significantly when changing from normal salt intake

trolled hypertension associated with obesity can lead

to high salt intake. Conversely, in those patients who

to severe vascular injury and complete loss of kidney

have salt-sensitive essential hypertension, the high salt

function.

intake significantly exacerbates the hypertension.

Two additional points should be emphasized: (1)

Graphical Analysis of Arterial Pressure Control in Essential

Salt-sensitivity of blood pressure is not an all-or-none

Hypertension. Figure 19-14 is a graphical analysis of

characteristic—it is a quantitative characteristic, with

essential hypertension. The curves of this figure are

some individuals being more salt-sensitive than others.

called sodium-loading renal function curves because

(2) Salt-sensitivity of blood pressure is not a fixed

the arterial pressure in each instance is increased

characteristic; instead, blood pressure usually becomes

very slowly, over many days or weeks, by gradually

more salt-sensitive as a person ages, especially after 50

or 60 years of age.

The reason for the difference between nonsalt-

sensitive essential hypertension and salt-sensitive

hypertension is presumably related to structural or

functional differences in the kidneys of these two types

of hypertensive patients. For example, salt-sensitive

Normal

hypertension may occur with different types of chronic

Nonsalt-sensitive

renal disease due to gradual loss of the functional units

Salt-sensitive

of the kidneys (the nephrons) or to normal aging as

discussed in Chapter 31. Abnormal function of the

renin-angiotensin system can also cause blood pres-

sure to become salt-sensitive, as discussed previously

in this chapter.

High intake

B¹

Treatment of Essential Hypertension. Current guidelines

for treating hypertension recommend, as a first step,

Essential

Normal

lifestyle modifications that are aimed at increasing

hypertension

physical activity and weight loss in most patients.

Normal intake

Unfortunately, many patients are unable to lose

weight, and pharmacological treatment with antihy-

pertensive drugs must be initiated.

100

150

Two general classes of drugs are used to treat hyper-

tension: (1) vasodilator drugs that increase renal blood

Arterial pressure (mm Hg)

flow and (2) natriuretic or diuretic drugs that decrease

tubular reabsorption of salt and water.

Vasodilator drugs usually cause vasodilation in

many other tissues of the body as well as in the

Figure 19-14

kidneys. Different ones act in one of the following

ways: (1) by inhibiting sympathetic nervous signals to

Analysis of arterial pressure regulation in (1) nonsalt-sensitive

essential hypertension and (2) salt-sensitive essential hyperten-

the kidneys or by blocking the action of the sympa-

sion. (Redrawn from Guyton AC, Coleman TG, Young DB, et al:

thetic transmitter substance on the renal vasculature,

Salt balance and long-term blood pressure control. Annu Rev Med

31:15, 1980. With permission, from the Annual Review of Medi-

(2) by directly relaxing the smooth muscle of the renal

cine, " 1980, by Annual Reviews http://www.AnnualReviews.org.)

vasculature, or

(3) by blocking the action of the

230

Unit IV The Circulation

renin-angiotensin system on the renal vasculature or

renal tubules.

Renin-angiotensin-vasoconstriction

Those drugs that reduce reabsorption of salt and

water by the renal tubules include especially drugs that

•

• !!

block active transport of sodium through the tubular

wall; this blockage in turn also prevents the reabsorp-

tion of water, as explained earlier in the chapter. These

natriuretic or diuretic drugs are discussed in greater

detail in Chapter 31.

Baroreceptors

Summary of the Integrated,

Multifaceted System for

Arterial Pressure Regulation

By now, it is clear that arterial pressure is regulated

not by a single pressure controlling system but instead

0 1530 1 2 4 816321 2 4 816 1 2 4

8 16

•

by several interrelated systems, each of which per-

forms a specific function. For instance, when a person

Seconds Minutes

Hours

Days

bleeds severely so that the pressure falls suddenly, two

Time after sudden change in pressure

problems confront the pressure control system. The

first is survival, that is, to return the arterial pressure

immediately to a high enough level that the person can

live through the acute episode. The second is to return

Figure 19-15

the blood volume eventually to its normal level so that

Approximate potency of various arterial pressure control mecha-

the circulatory system can re-establish full normality,

nisms at different time intervals after onset of a disturbance to the

including return of the arterial pressure all the way

arterial pressure. Note especially the infinite gain (∞) of the renal

back to its normal value, not merely back to a pressure

body fluid pressure control mechanism that occurs after a few

weeks’ time. (Redrawn from Guyton AC: Arterial Pressure and

level required for survival.

Hypertension. Philadelphia: WB Saunders Co, 1980.)

In Chapter 18, we saw that the first line of de-

fense against acute changes in arterial pressure is

the nervous control system. In this chapter, we have

emphasized a second line of defense achieved mainly

(2) to cause increased heart rate and contractility of

by kidney mechanisms for long-term control of arte-

the heart to provide greater pumping capacity by the

rial pressure. However, there are other pieces to the

heart, and (3) to cause constriction of most peripheral

puzzle. Figure 19-15 helps to put these together.

arterioles to impede flow of blood out of the arteries;

Figure

19-15 shows the approximate immediate

all these effects occur almost instantly to raise the

(seconds and minutes) and long-term (hours and days)

arterial pressure back into a survival range.

control responses, expressed as feedback gain, of eight

When the pressure suddenly rises too high, as might

arterial pressure control mechanism. These mecha-

occur in response to rapid overadministration of a

nisms can be divided into three groups: (1) those that

blood transfusion, the same control mechanisms

react rapidly, within seconds or minutes; (2) those that

operate in the reverse direction, again returning the

respond over an intermediate time period, minutes or

pressure back toward normal.

hours; and (3) those that provide long-term arterial

pressure regulation, days, months, and years. Let us see

Pressure Control Mechanisms That Act After Many Minutes.

how they fit together as a total, integrated system for

Several pressure control mechanisms exhibit signifi-

pressure control.

cant responses only after a few minutes following

acute arterial pressure change. Three of these, shown

Rapidly Acting Pressure Control Mechanisms, Acting Within

in Figure 19-15, are (1) the renin-angiotensin vaso-

Seconds or Minutes. The rapidly acting pressure control

constrictor mechanism, (2) stress-relaxation of the

mechanisms are almost entirely acute nervous reflexes

vasculature, and (3) shift of fluid through the tissue

or other nervous responses. Note in Figure 19-15 the

capillary walls in and out of the circulation to readjust

three mechanisms that show responses within seconds.

the blood volume as needed.

They are (1) the baroreceptor feedback mechanism,

We have already described at length the role of the

(2) the central nervous system ischemic mechanism,

renin-angiotensin vasoconstrictor system to provide a

and (3) the chemoreceptor mechanism. Not only do

semi-acute means for increasing the arterial pressure

these mechanisms begin to react within seconds, but

when this is needed. The stress-relaxation mechanism

they are also powerful. After any acute fall in pressure,

is demonstrated by the following example: When the

as might be caused by severe hemorrhage, the nervous

pressure in the blood vessels becomes too high, they

mechanisms combine (1) to cause constriction of the

become stretched and keep on stretching more and

veins and provide transfer of blood into the heart,

more for minutes or hours; as a result, the pressure in

Chapter 19

The Integrated System for Pressure Control

231

the vessels falls toward normal. This continuing stretch

pressure controls, then continues with the sustaining

of the vessels, called stress-relaxation, can serve as an

characteristics of the intermediate pressure controls,

intermediate-term pressure “buffer.”

and, finally, is stabilized at the long-term pressure level

The capillary fluid shift mechanism means simply

by the renal-body fluid mechanism. This long-term

that any time capillary pressure falls too low, fluid is

mechanism in turn has multiple interactions with the

absorbed through the capillary membranes from the

renin-angiotensin-aldosterone system, the nervous

tissues into the circulation, thus building up the blood

system, and several other factors that provide special

volume and increasing the pressure in the circulation.

blood pressure control capabilities for special pur-

Conversely, when the capillary pressure rises too high,

poses.

fluid is lost out of the circulation into the tissues, thus

reducing the blood volume as well as virtually all the

pressures throughout the circulation.

References

These three intermediate mechanisms become

mostly activated within 30 minutes to several hours.

Chobanian AV, Bakris GL, Black HR, et al: Joint National

During this time, the nervous mechanisms usually

Committee on Prevention, Detection, Evaluation, and

Treatment of High Blood Pressure. National High Blood

become less and less effective, which explains the

Pressure Education Program Coordinating Committee.

importance of these non-nervous, intermediate time

Seventh Report of the Joint National Committee on

pressure control measures.

prevention, detection, evaluation, and treatment of high

blood pressure. Hypertension 42:1206, 2003.

Long-Term Mechanisms for Arterial Pressure Regulation. The

Cowley AW J: Long-term control of arterial blood pressure.

goal of this chapter has been to explain the role of the

Physiol Rev 72:231, 1992.

kidneys in long-term control of arterial pressure. To

Granger JP, Alexander BT, Bennett WA, Khalil RA: Patho-

the far right in Figure 19-15 is shown the renal-blood

physiology of pregnancy-induced hypertension. Am J

volume pressure control mechanism (which is the

Hypertens 14:178S, 2001.

same as the renal-body fluid pressure control mecha-

Granger JP, Alexander BT: Abnormal pressure-natriuresis in

hypertension: role of nitric oxide. Acta Physiol Scand

nism), demonstrating that it takes a few hours to begin

168:161, 2000.

showing significant response. Yet it eventually devel-

Guyton AC: Arterial Pressure and Hypertension. Philadel-

ops a feedback gain for control of arterial pressure

phia: WB Saunders Co, 1980.

equal to infinity. This means that this mechanism can

Guyton AC: Blood pressure control—special role of the

eventually return the arterial pressure all the way back,

kidneys and body fluids. Science 252:1813, 1991.

not merely partway back, to that pressure level that

Guyton AC, Coleman TG, Cowley AW Jr, et al: Arterial pres-

provides normal output of salt and water by the

sure regulation: overriding dominance of the kidneys in

kidneys. By now, the reader should be familiar with

long-term regulation and in hypertension. Am J Med

this concept, which has been the major point of this

52:584, 1972.

chapter.

Hall JE: The kidney, hypertension, and obesity. Hypertension

41:625, 2003.

It must also be remembered that many factors can

Hall JE, Brands MW, Henegar JR: Angiotensin II and long-

affect the pressure-regulating level of the renal-body

term arterial pressure regulation: the overriding domi-

fluid mechanism. One of these, shown in Figure 19-15,

nance of the kidney. J Am Soc Nephrol 10(Suppl 12):S258,

is aldosterone. A decrease in arterial pressure leads

1999.

within minutes to an increase in aldosterone secretion,

Hall JE, Guyton AC, Brands MW: Pressure-volume regula-

and over the next hour or days, this plays an important

tion in hypertension. Kidney Int Suppl 55:S35, 1996.

role in modifying the pressure control characteristics

Hall JE, Jones DW, Kuo JJ, et al: Impact of the obesity epi-

of the renal-body fluid mechanism. Especially impor-

demic on hypertension and renal disease. Curr Hypertens

tant is interaction of the renin-angiotensin system with

Rep 5:386, 2003.

the aldosterone and renal fluid mechanisms. For

Lifton RP, Gharavi AG, Geller DS: Molecular mechanisms

of human hypertension. Cell 104:545, 2001.

instance, a person’s salt intake varies tremendously

Manning RD Jr, Hu L, Tan DY, Meng S: Role of abnormal

from one day to another. We have seen in this chapter

nitric oxide systems in salt-sensitive hypertension. Am J

that the salt intake can decrease to as little as 1/10

Hypertens 14:68S, 2001.

normal or can increase to 10 to 15 times normal and

Oparil S, Zaman MA, Calhoun DA: Pathogenesis of hyper-

yet the regulated level of the mean arterial pressure

tension. Ann Intern Med 139:761, 2003.

will change only a few millimeters of mercury if the

O’Shaughnessy KM, Karet FE: Salt handling and hyperten-

renin-angiotensin-aldosterone system is fully opera-

sion. J Clin Invest 113:1075, 2004.

tive. But, without a functional renin-angiotensin-aldos-

Reckelhoff JF: Gender differences in the regulation of blood

terone system, blood pressure becomes very sensitive

pressure. Hypertension 37:1199, 2001.

to changes in salt intake. Thus, arterial pressure control

Rossier BC: Negative regulators of sodium transport in the

kidney: key factors in understanding salt-sensitive hyper-

begins with the lifesaving measures of the nervous

tension? J Clin Invest 111:947, 2003.

C H A P T E R

Cardiac Output, Venous Return,

and Their Regulation

Cardiac output is the quantity of blood pumped into

the aorta each minute by the heart. This is

also the quantity of blood that flows through the

circulation. Cardiac output is perhaps the most

important factor that we have to consider in rela-

tion to the circulation.

Venous return is the quantity of blood flowing

from the veins into the right atrium each minute.

The venous return and the cardiac output must equal each other except for a

few heartbeats at a time when blood is temporarily stored in or removed from

the heart and lungs.

Normal Values for Cardiac Output at Rest and

During Activity

Cardiac output varies widely with the level of activity of the body. The follow-

ing factors, among others, directly affect cardiac output: (1) the basic level of

body metabolism, (2) whether the person is exercising, (3) the person’s age, and

(4) size of the body.

For young, healthy men, resting cardiac output averages about 5.6 L/min.

For women, this value is about 4.9 L/min. When one considers the factor of age

as well—because with increasing age, body activity diminishes—the average

cardiac output for the resting adult, in round numbers, is often stated to be

almost exactly 5 L/min.

Cardiac Index

Experiments have shown that the cardiac output increases approximately in pro-

portion to the surface area of the body. Therefore, cardiac output is frequently stated

in terms of the cardiac index, which is the cardiac output per square meter of body

surface area. The normal human being weighing 70 kilograms has a body surface

area of about 1.7 square meters, which means that the normal average cardiac index

for adults is about 3 L/min/m² of body surface area.

Effect of Age on Cardiac Output. Figure 20-1 shows the cardiac output, expressed

as cardiac index, at different ages. Rising rapidly to a level greater than

4 L/min/m² at age 10 years, the cardiac index declines to about 2.4 L/min/m² at

age 80 years. We will see later in the chapter that the cardiac output is regu-

lated throughout life almost directly in proportion to the overall bodily meta-

bolic activity. Therefore, the declining cardiac index is indicative of declining

activity with age.

Control of Cardiac Output by Venous

Return—Role of the Frank-Starling

Mechanism of the Heart

When one states that cardiac output is controlled by venous return, this means

that it is not the heart itself that is the primary controller of cardiac output.

232

Chapter 20

Cardiac Output, Venous Return, and Their Regulation

233

Cardiac output

and cardiac index

Oxygen

consumption

Dexter

1951

Douglas

1922

Christensen

1931

Donald

1055

200 400 600 800 1000 1200 14001600

Work output during exercise (kg-m/min)

Figure 20-2

Age in years

Effect of increasing levels of exercise to increase cardiac output

(red solid line) and oxygen consumption

(blue dashed line).

(Redrawn from Guyton AC, Jones CE, Coleman TB: Circulatory

Physiology: Cardiac Output and Its Regulation. 2nd ed. Philadel-

Figure 20-1

phia: WB Saunders Co, 1973.)

Cardiac index for the human being (cardiac output per square

meter of surface area) at different ages. (Redrawn from Guyton

Under most normal unstressful conditions, the

AC, Jones CE, Coleman TB: Circulatory Physiology: Cardiac

cardiac output is controlled almost entirely by periph-

Output and Its Regulation. 2nd ed. Philadelphia: WB Saunders Co,

1973.)

eral factors that determine venous return. However,

we shall see later in the chapter that if the returning

blood does become more than the heart can pump,

then the heart becomes the limiting factor that deter-

mines cardiac output.

Instead, it is the various factors of the peripheral cir-

culation that affect flow of blood into the heart from

the veins, called venous return, that are the primary

Cardiac Output Regulation Is the Sum

controllers.

of Blood Flow Regulation in All the

The main reason peripheral factors are usually more

Local Tissues of the Body—Tissue

important than the heart itself in controlling cardiac

output is that the heart has a built-in mechanism that

Metabolism Regulates Most Local

normally allows it to pump automatically whatever

Blood Flow

amount of blood that flows into the right atrium from

the veins. This mechanism, called the Frank-Starling

The venous return to the heart is the sum of all the

law of the heart, was discussed in Chapter 9. Basically,

local blood flows through all the individual tissue

this law states that when increased quantities of blood

segments of the peripheral circulation. Therefore, it

flow into the heart, the increased blood stretches the

follows that cardiac output regulation is the sum of all

walls of the heart chambers. As a result of the stretch,

the local blood flow regulations.

the cardiac muscle contracts with increased force, and

The mechanisms of local blood flow regulation were

this empties the extra blood that has entered from the

discussed in Chapter 17. In most tissues, blood flow

systemic circulation. Therefore, the blood that flows

increases mainly in proportion to each tissue’s metab-

into the heart is automatically pumped without delay

olism. For instance, local blood flow almost always

into the aorta and flows again through the circulation.

increases when tissue oxygen consumption increases;

Another important factor, discussed in Chapter 10,

this effect is demonstrated in Figure 20-2 for different

is that stretching the heart causes the heart to pump

levels of exercise. Note that at each increasing level of

faster—at an increased heart rate. That is, stretch of the

work output during exercise, the oxygen consumption

sinus node in the wall of the right atrium has a direct

and the cardiac output increase in parallel to each

effect on the rhythmicity of the node itself to increase

other.

heart rate as much as 10 to 15 per cent. In addition,

To summarize, cardiac output is determined by the

the stretched right atrium initiates a nervous reflex

sum of all the various factors throughout the body that

called the Bainbridge reflex, passing first to the vaso-

control local blood flow. All the local blood flows

motor center of the brain and then back to the heart

summate to form the venous return, and the heart

by way of the sympathetic nerves and vagi, also to

automatically pumps this returning blood back into

increase the heart rate.

the arteries to flow around the system again.

234

Unit IV The Circulation

200

Hypereffective

150

Normal

100

Hypoeffective

100

120

140

160

Total peripheral resistance

-4

(percentage of normal)

Right atrial pressure (mm Hg)

Figure 20-3

Figure 20-4

Chronic effect of different levels of total peripheral resistance on

cardiac output, showing a reciprocal relationship between total

Cardiac output curves for the normal heart and for hypoeffective

peripheral resistance and cardiac output. (Redrawn from Guyton

and hypereffective hearts. (Redrawn from Guyton AC, Jones CE,

AC: Arterial Pressure and Hypertension. Philadelphia: WB

Coleman TB: Circulatory Physiology: Cardiac Output and Its

Saunders Co, 1980.)

Regulation. 2nd ed. Philadelphia: WB Saunders Co, 1973.)

Effect of Total Peripheral Resistance on the Long-Term Cardiac

Output Level. Figure 20-3 is the same as Figure 19-5.

Figure 20-4 demonstrates the normal cardiac output

It is repeated here to illustrate an extremely important

curve, showing the cardiac output per minute at each

principle in cardiac output control: Under most

level of right atrial pressure. This is one type of cardiac

normal conditions, the long-term cardiac output level

function curve, which was discussed in Chapter 9. Note

varies reciprocally with changes in total peripheral

that the plateau level of this normal cardiac output

resistance. Note in Figure 20-3 that when the total

curve is about 13 L/min, 2.5 times the normal cardiac

peripheral resistance is exactly normal (at the 100 per

output of about 5 L/min. This means that the normal

cent mark in the figure), the cardiac output is also

human heart, functioning without any special stimula-

normal. Then, when the total peripheral resistance

tion, can pump an amount of venous return up to

increases above normal, the cardiac output falls; con-

about 2.5 times the normal venous return before the

versely, when the total peripheral resistance decreases,

heart becomes a limiting factor in the control of

the cardiac output increases. One can easily under-

cardiac output.

stand this by reconsidering one of the forms of Ohm’s

Shown in Figure 20-4 are several other cardiac

law, as expressed in Chapter 14:

output curves for hearts that are not pumping nor-

Arterial Pressure

mally. The uppermost curves are for hypereffective

Cardiac Output

Total Peripheral Resistance

hearts that are pumping better than normal. The low-

ermost curves are for hypoeffective hearts that are

The meaning of this formula, and of Figure 20-3, is

pumping at levels below normal.

simply the following: Any time the long-term level of

total peripheral resistance changes (but no other func-

Factors That Can Cause Hypereffective Heart

tions of the circulation change), the cardiac output

Only two types of factors usually can make the heart

changes quantitatively in exactly the opposite direction.

a better pump than normal. They are (1) nervous stim-

ulation and (2) hypertrophy of the heart muscle.

The Heart Has Limits for the Cardiac

Effect of Nervous Excitation to Increase Heart Pumping. In

Output That It Can Achieve

Chapter 9, we saw that a combination of (1) sympa-

thetic stimulation and (2) parasympathetic inhibition

There are definite limits to the amount of blood that

does two things to increase the pumping effectiveness

the heart can pump, which can be expressed quantita-

of the heart: (1) it greatly increases the heart rate—

tively in the form of cardiac output curves.

sometimes, in young people, from the normal level of

Chapter 20

Cardiac Output, Venous Return, and Their Regulation

235

72 beats/min up to 180 to 200 beats/min—and (2) it

increases the strength of heart contraction (which is

called increased “contractility”) to twice its normal

Dinitrophenol

strength. Combining these two effects, maximal

nervous excitation of the heart can raise the plateau

level of the cardiac output curve to almost twice the

plateau of the normal curve, as shown by the 25-liter

level of the uppermost curve in Figure 20-4.

Increased Pumping Effectiveness Caused by Heart Hypertrophy.

With pressure control

A long-term increased workload, but not so much

Without pressure control

excess load that it damages the heart, causes the heart

muscle to increase in mass and contractile strength in

100

the same way that heavy exercise causes skeletal

muscles to hypertrophy. For instance, it is common for

the hearts of marathon runners to be increased in mass

by 50 to 75 per cent. This increases the plateau level of

the cardiac output curve, sometimes 60 to 100 per cent,

and therefore allows the heart to pump much greater

Minutes

than usual amounts of cardiac output.

When one combines nervous excitation of the heart

and hypertrophy, as occurs in marathon runners, the

total effect can allow the heart to pump as much 30 to

Figure 20-5

40 L/min, about 2¹/₂ times normal; this increased level

Experiment in a dog to demonstrate the importance of nervous

of pumping is one of the most important factors in

maintenance of the arterial pressure as a prerequisite for cardiac

determining the runner’s running time.

output control. Note that with pressure control, the metabolic stim-

ulant dinitrophenol increases cardiac output greatly; without pres-

sure control, the arterial pressure falls and the cardiac output rises

Factors That Cause a Hypoeffective Heart

very little. (Drawn from experiments by Dr. M. Banet.)

Any factor that decreases the heart’s ability to pump

blood causes hypoeffectivity. Some of the factors that

can do this are the following:

However, after autonomic control of the nervous

Coronary artery blockage, causing a “heart

system had been blocked, none of the normal circula-

attack”

tory reflexes for maintaining the arterial pressure

Inhibition of nervous excitation of the heart

could function, and vasodilation of the vessels with

Pathological factors that cause abnormal heart

dinitrophenol (dashed curves) then caused a profound

rhythm or rate of heartbeat

fall in arterial pressure to about one half normal, and

Valvular heart disease

the cardiac output rose only 1.6-fold instead of 4-fold.

Increased arterial pressure against which the

Thus, maintenance of a normal arterial pressure by

heart must pump, such as in hypertension

the nervous reflexes, by mechanisms explained in

Congenital heart disease

Chapter 18, is essential to achieve high cardiac outputs

Myocarditis

when the peripheral tissues dilate their vessels to

Cardiac hypoxia

increase the venous return.

Effect of the Nervous System to Increase the Arterial Pressure

What Is the Role of the

During Exercise. During exercise, intense increase in

Nervous System in Controlling

metabolism in active skeletal muscles acts directly on

Cardiac Output?

the muscle arterioles to relax them and to allow ade-

quate oxygen and other nutrients needed to sustain

Importance of the Nervous System in

muscle contraction. Obviously, this greatly decreases

Maintaining the Arterial Pressure When the

the total peripheral resistance, which normally would

Venous Return and Cardiac Output Increase

decrease the arterial pressure also. However, the

Figure 20-5 shows an important difference in cardiac

nervous system immediately compensates. The same

output control with and without a functioning auto-

brain activity that sends motor signals to the muscles

nomic nervous system. The solid curves demonstrate

sends simultaneous signals into the autonomic nervous

the effect in the normal dog of intense dilation of

centers of the brain to excite circulatory activity,

the peripheral blood vessels caused by administering

causing large vein constriction, increased heart rate,

the drug dinitrophenol, which increased the metabo-

and increased contractility of the heart. All these

lism of virtually all tissues of the body about fourfold.

changes acting together increase the arterial pressure

Note that with nervous control to keep the arterial

above normal, which in turn forces still more blood

pressure from falling, dilating all the peripheral blood

flow through the active muscles.

vessels caused almost no change in arterial pressure

In summary, when local tissue vessels dilate and

but increased the cardiac output almost fourfold.

thereby increase venous return and cardiac output

236

Unit IV The Circulation

above normal, the nervous system plays an exceed-

and at the same time increase the cardiac output to

ingly important role in preventing the arterial pressure

above normal.

from falling to disastrously low levels. In fact, during

Beriberi. This disease is caused by insufficient

quantity of the vitamin thiamine (vitamin B₁) in the

exercise, the nervous system goes even further, pro-

diet. Lack of this vitamin causes diminished ability

viding additional signals to raise the arterial pressure

of the tissues to use some cellular nutrients, and the

even above normal, which serves to increase the

local tissue blood flow mechanisms in turn cause

cardiac output an extra 30 to 100 per cent.

marked compensatory peripheral vasodilation.

Sometimes the total peripheral resistance decreases

to as little as one-half normal. Consequently, the

Pathologically High and

long-term levels of venous return and cardiac

Pathologically Low

output also often increase to twice normal.

Arteriovenous fistula (shunt). Earlier, we pointed

Cardiac Outputs

out that whenever a fistula (also called an AV

In healthy human beings, the cardiac outputs are

shunt) occurs between a major artery and a major

surprisingly constant from one person to another.

vein, tremendous amounts of blood flow directly

However, multiple clinical abnormalities can cause

from the artery into the vein. This, too, greatly

either high or low cardiac outputs. Some of the more

decreases the total peripheral resistance and,

important of these are shown in Figure 20-6.

likewise, increases the venous return and cardiac

output.

Hyperthyroidism. In hyperthyroidism, the

High Cardiac Output Caused

metabolism of most tissues of the body becomes

by Reduced Total Peripheral

greatly increased. Oxygen usage increases, and

Resistance

vasodilator products are released from the tissues.

Therefore, the total peripheral resistance decreases

The left side of Figure 20-6 identifies conditions that

markedly because of the local tissue blood

commonly cause cardiac outputs higher than normal.

flow control reactions throughout the body;

One of the distinguishing features of these conditions is

consequently, the venous return and cardiac output

that they all result from chronically reduced total periph-

often increase to 40 to 80 per cent above normal.

eral resistance. None of them result from excessive

Anemia. In anemia, two peripheral effects greatly

excitation of the heart itself, which we will explain sub-

decrease the total peripheral resistance. One of

sequently. For the present, let us look at some of the

these is reduced viscosity of the blood, resulting

conditions that can decrease the peripheral resistance

from the decreased concentration of red blood

200

175

150

125

Control (young adults)

100

Average 45-year-old adult

Figure 20-6

Cardiac output in different pathological conditions. The numbers in parentheses indicate number of patients studied in each condition.

(Redrawn from Guyton AC, Jones CE, Coleman TB: Circulatory Physiology: Cardiac Output and Its Regulation. 2nd ed. Philadelphia:

WB Saunders Co, 1973.)

Chapter 20

Cardiac Output, Venous Return, and Their Regulation

237

cells. The other is diminished delivery of oxygen to

blood flow needs of the muscles, resulting in

the tissues, which causes local vasodilation. As a

decreases in skeletal muscle blood flow and cardiac

consequence, the cardiac output increases greatly.

output.

Any other factor that decreases the total peripheral

Regardless of the cause of low cardiac output,

resistance chronically also increases the cardiac output.

whether it be a peripheral factor or a cardiac factor, if

ever the cardiac output falls below that level required

for adequate nutrition of the tissues, the person is said

Low Cardiac Output

to suffer circulatory shock. This condition can be lethal

within a few minutes to a few hours. Circulatory shock

Figure 20-6 shows at the far right several conditions that

is such an important clinical problem that it is discussed

cause abnormally low cardiac output. These conditions

in detail in Chapter 24.

fall into two categories: (1) those abnormalities that

cause the pumping effectiveness of the heart to fall too

low and (2) those that cause venous return to fall too

A More Quantitative Analysis

low.

of Cardiac Output Regulation

Decreased Cardiac Output Caused by Cardiac Factors. When-

Our discussion of cardiac output regulation thus far is

ever the heart becomes severely damaged, regardless

adequate for understanding the factors that control

of the cause, its limited level of pumping may fall below

cardiac output in most simple conditions. However, to

that needed for adequate blood flow to the tissues. Some

understand cardiac output regulation in especially

examples of this include (1) severe coronary blood vessel

stressful situations, such as the extremes of exercise,

blockage and consequent myocardial infarction,

(2)

cardiac failure, and circulatory shock, a more complex

severe valvular heart disease, (3) myocarditis, (4) cardiac

quantitative analysis is presented in the following

tamponade, and (5) cardiac metabolic derangements.

sections.

The effects of several of these are shown on the right in

To perform the more quantitative analysis, it is nec-

Figure 20-6, demonstrating the low cardiac outputs that

essary to distinguish separately the two primary factors

result.

concerned with cardiac output regulation:

(1) the

When the cardiac output falls so low that the tissues

pumping ability of the heart, as represented by cardiac

throughout the body begin to suffer nutritional defi-

output curves, and (2) the peripheral factors that affect

ciency, the condition is called cardiac shock. This is dis-

flow of blood from the veins into the heart, as repre-

cussed fully in Chapter 22 in relation to cardiac failure.

sented by venous return curves. Then one can put these

Decrease in Cardiac Output Caused by Non-cardiac Peripheral

curves together in a quantitative way to show how they

Factors—Decreased Venous Return. Anything that inter-

interact with each other to determine cardiac output,

feres with venous return also can lead to decreased

venous return, and right atrial pressure at the same time.

cardiac output. Some of these factors are the following:

Decreased blood volume. By far, the most

common non-cardiac peripheral factor that leads

Cardiac Output Curves Used in the

to decreased cardiac output is decreased blood

Quantitative Analysis

volume, resulting most often from hemorrhage.

It is clear why this condition decreases the cardiac

Some of the cardiac output curves used to depict quan-

output: Loss of blood decreases the filling of the

titative heart pumping effectiveness have already been

vascular system to such a low level that there is not

shown in Figure 20-4. However, an additional set of

enough blood in the peripheral vessels to create

curves is required to show the effect on cardiac output

peripheral vascular pressures high enough to push

caused by changing external pressures on the outside of

the blood back to the heart.

the heart, as explained in the next section.

Acute venous dilation. On some occasions, the

peripheral veins become acutely vasodilated. This

Effect of External Pressure Outside the Heart on Cardiac Output

results most often when the sympathetic nervous

Curves. Figure 20-7 shows the effect of changes in exter-

system suddenly becomes inactive. For instance,

nal cardiac pressure on the cardiac output curve. The

fainting often results from sudden loss of

normal external pressure is equal to the normal

sympathetic nervous system activity, which causes

intrapleural pressure (the pressure in the chest cavity),

the peripheral capacitative vessels, especially the

which is -4 mm Hg. Note in the figure that a rise in

veins, to dilate markedly. This decreases the filling

intrapleural pressure, to -2 mm Hg, shifts the entire

pressure of the vascular system because the blood

cardiac output curve to the right by the same amount.

volume can no longer create adequate pressure

This shift occurs because to fill the cardiac chambers

in the now flaccid peripheral blood vessels. As a

with blood requires an extra 2 mm Hg right atrial pres-

result, the blood “pools” in the vessels and does not

sure to overcome the increased pressure on the outside

return to the heart.

of the heart. Likewise, an increase in intrapleural pres-

Obstruction of the large veins. On rare occasions,

sure to +2 mm Hg requires a 6 mm Hg increase in right

the large veins leading into the heart become

atrial pressure from the normal -4 mm Hg, which shifts

obstructed, so that the blood in the peripheral

the entire cardiac output curve 6 mm Hg to the right.

vessels cannot flow back into the heart.

Some of the factors that can alter the intrapleural

Consequently, the cardiac output falls markedly.

pressure and thereby shift the cardiac output curve are

Decreased tissue mass, especially decreased skeletal

the following:

muscle mass. With normal aging or with prolonged

1. Cyclical changes of intrapleural pressure during

periods of physical inactivity, there is usually a

respiration, which are about ±2 mm Hg during

reduction in the size of the skeletal muscles. This, in

normal breathing but can be as much as

turn, decreases the total oxygen consumption and

±50 mm Hg during strenuous breathing.

238

Unit IV The Circulation

Hypereffective-increased

intrapleural pressure

Normal

Hypoeffective-reduced

intrapleural pressure

-4

+12

Right atrial pressure (mm Hg)

-4

+12

Right atrial pressure (mm Hg)

Figure 20-7

Figure 20-8

Cardiac output curves at different levels of intrapleural pressure

and at different degrees of cardiac tamponade. (Redrawn from

Combinations of two major patterns of cardiac output curves

Guyton AC, Jones CE, Coleman TB: Circulatory Physiology:

showing the effect of alterations in both extracardiac pressure and

Cardiac Output and Its Regulation. 2nd ed. Philadelphia: WB

effectiveness of the heart as a pump. (Redrawn from Guyton AC,

Saunders Co, 1973.)

Jones CE, Coleman TB: Circulatory Physiology: Cardiac Output

and Its Regulation. 2nd ed. Philadelphia: WB Saunders Co, 1973.)

2. Breathing against a negative pressure, which shifts

the curve to a more negative right atrial pressure

three principal factors that affect venous return to the

(to the left).

heart from the systemic circulation. They are as follows:

3. Positive pressure breathing, which shifts the curve to

1. Right atrial pressure, which exerts a backward force

the right.

on the veins to impede flow of blood from the

4. Opening the thoracic cage, which increases the

veins into the right atrium.

intrapleural pressure to 0 mm Hg and shifts the

2. Degree of filling of the systemic circulation

cardiac output curve to the right 4 mm Hg.

(measured by the mean systemic filling pressure),

5. Cardiac tamponade, which means accumulation of

which forces the systemic blood toward the heart

a large quantity of fluid in the pericardial cavity

(this is the pressure measured everywhere in the

around the heart with resultant increase in external

systemic circulation when all flow of blood is

cardiac pressure and shifting of the curve to the

stopped—we discuss this in detail later).

right. Note in Figure 20-7 that cardiac tamponade

3. Resistance to blood flow between the peripheral

shifts the upper parts of the curves farther to the

vessels and the right atrium.

right than the lower parts because the external

These factors can all be expressed quantitatively

“tamponade” pressure rises to higher values as the

by the venous return curve, as we explain in the next

chambers of the heart fill to increased volumes

sections.

during high cardiac output.

Normal Venous Return Curve

Combinations of Different Patterns of Cardiac Output Curves.

In the same way that the cardiac output curve relates

Figure 20-8 shows that the final cardiac output curve can

pumping of blood by the heart to right atrial pressure,

change as a result of simultaneous changes in (a) exter-

the venous return curve relates venous return also to

nal cardiac pressure and (b) effectiveness of the heart as

right atrial pressure—that is, the venous flow of blood

a pump. Thus, by knowing what is happening to the

into the heart from the systemic circulation at different

external pressure as well as to the capability of the heart

levels of right atrial pressure.

as a pump, one can express the momentary ability of the

The curve in Figure 20-9 is the normal venous return

heart to pump blood by a single cardiac output curve.

curve. This curve shows that when heart pumping capa-

bility becomes diminished and causes the right atrial

Venous Return Curves

pressure to rise, the backward force of the rising atrial

pressure on the veins of the systemic circulation

There remains the entire systemic circulation that must

decreases venous return of blood to the heart. If all

be considered before total analysis of cardiac regulation

nervous circulatory reflexes are prevented from acting,

can be achieved. To analyze the function of the systemic

venous return decreases to zero when the right atrial

circulation, we first remove the heart and lungs from the

pressure rises to about +7 mm Hg. Such a slight rise in

circulation of an animal and replace them with a pump

right atrial pressure causes a drastic decrease in venous

and artificial oxygenator system. Then, different factors,

return because the systemic circulation is a distensible

such blood volume, vascular resistances, and central

bag, so that any increase in back pressure causes blood

venous pressure in the right atrium, are altered to

to dam up in this bag instead of returning to the heart.

determine how the systemic circulation operates in

At the same time that the right atrial pressure is rising

different circulatory states. In these studies, one finds

and causing venous stasis, pumping by the heart also

Chapter 20

Cardiac Output, Venous Return, and Their Regulation

239

Plateau

Transitional zone

Mean

systemic

filling

Figure 20-9

pressure

Normal venous return curve. The

plateau is caused by collapse of

the large veins entering the chest

when the right atrial pressure falls

-8

-4

below atmospheric pressure.

Note also that venous return

Right atrial pressure (mm Hg)

becomes zero when the right

atrial pressure rises to equal the

mean systemic filling pressure.

approaches zero because of decreasing venous return.

Both the arterial and the venous pressures come to

equilibrium when all flow in the systemic circulation

ceases at a pressure of 7 mm Hg, which, by definition, is

Strong sympathetic

the mean systemic filling pressure (Psf).

stimulation

Normal circulatory

Plateau in the Venous Return Curve at Negative Atrial

system

Pressures—Caused by Collapse of the Large Veins. When the

Complete sympathetic

right atrial pressure falls below zero—that is, below

inhibition

atmospheric pressure—further increase in venous

Normal volume

return almost ceases. And by the time the right atrial

pressure has fallen to about -2 mm Hg, the venous

return will have reached a plateau. It remains at this

plateau level even though the right atrial pressure falls

to -20 mm Hg, -50 mm Hg, or even further. This plateau

is caused by collapse of the veins entering the chest. Neg-

ative pressure in the right atrium sucks the walls of the

veins together where they enter the chest, which pre-

vents any additional flow of blood from the peripheral

veins. Consequently, even very negative pressures in the

right atrium cannot increase venous return significantly

-0

1000 2000 3000 4000 5000 6000 7000

above that which exists at a normal atrial pressure of

Volume (ml)

0 mm Hg.

Mean Circulatory Filling Pressure and Mean Systemic Filling

Pressure, and Their Effect on Venous Return

Figure 20-10

When heart pumping is stopped by shocking the heart

with electricity to cause ventricular fibrillation or is

Effect of changes in total blood volume on the mean circulatory

stopped in any other way, flow of blood everywhere in

filling pressure (i.e., “volume-pressure curves” for the entire cir-

the circulation ceases a few seconds later. Without blood

culatory system). These curves also show the effects of strong

flow, the pressures everywhere in the circulation

sympathetic stimulation and complete sympathetic inhibition.

become equal. This equilibrated pressure level is called

the mean circulatory filling pressure.

Effect of Sympathetic Nervous Stimulation of the Circulation on

Effect of Blood Volume on Mean Circulatory Filling Pressure.

Mean Circulatory Filling Pressure. The green curve and blue

The greater the volume of blood in the circulation, the

curve in Figure 20-10 show the effects, respectively,

greater is the mean circulatory filling pressure because

of high and low levels of sympathetic nervous activity

extra blood volume stretches the walls of the vascula-

on the mean circulatory filling pressure. Strong sympa-

ture. The red curve in Figure 20-10 shows the approxi-

thetic stimulation constricts all the systemic blood

mate normal effect of different levels of blood volume

vessels as well as the larger pulmonary blood vessels

on the mean circulatory filling pressure. Note that at a

and even the chambers of the heart. Therefore, the

blood volume of about 4000 milliliters, the mean circu-

capacity of the system decreases, so that at each level of

latory filling pressure is close to zero because this is the

blood volume, the mean circulatory filling pressure is

“unstressed volume” of the circulation, but at a volume

increased. At normal blood volume, maximal sympa-

of 5000 milliliters, the filling pressure is the normal value

thetic stimulation increases the mean circulatory filling

of 7 mm Hg. Similarly, at still higher volumes, the mean

pressure from 7 mm Hg to about 2.5 times that value, or

circulatory filling pressure increases almost linearly.

about 17 mm Hg.

240

Unit IV

The Circulation

Conversely, complete inhibition of the sympathetic

Conversely, the lower the mean systemic filling pressure,

nervous system relaxes both the blood vessels and the

the more the curve shifts downward and to the left.

heart, decreasing the mean circulatory filling pressure

To express this another way, the greater the system is

from the normal value of 7 mm Hg down to about 4 mm

filled, the easier it is for blood to flow into the heart.

Hg. Before leaving Figure 20-10, note specifically how

The less the filling, the more difficult it is for blood to

steep the curves are. This means that even slight changes

flow into the heart.

in blood volume or slight changes in the capacity of the

system caused by various levels of sympathetic activity

can have large effects on the mean circulatory filling

“Pressure Gradient for Venous Return”—When This Is Zero, There

pressure.

Is No Venous Return. When the right atrial pressure rises

to equal the mean systemic filling pressure, there is no

Mean Systemic Filling Pressure and Its Relation to Mean Circula-

longer any pressure difference between the peripheral

tory Filling Pressure. The mean systemic filling pressure,

vessels and the right atrium. Consequently, there can no

Psf, is slightly different from the mean circulatory filling

longer be any blood flow from any peripheral vessels

pressure. It is the pressure measured everywhere in the

back to the right atrium. However, when the right atrial

systemic circulation after blood flow has been stopped

pressure falls progressively lower than the mean sys-

by clamping the large blood vessels at the heart, so that

temic filling pressure, the flow to the heart increases

the pressures in the systemic circulation can be meas-

proportionately, as one can see by studying any of the

ured independently from those in the pulmonary circu-

venous return curves in Figure 20-11. That is, the greater

lation. The mean systemic pressure, although almost

the difference between the mean systemic filling pressure

impossible to measure in the living animal, is the impor-

and the right atrial pressure, the greater becomes the

tant pressure for determining venous return. The mean

venous return. Therefore, the difference between these

systemic filling pressure, however, is almost always nearly

two pressures is called the pressure gradient for venous

equal to the mean circulatory filling pressure because the

return.

pulmonary circulation has less than one eighth as much

capacitance as the systemic circulation and only about

one tenth as much blood volume.

Resistance to Venous Return

In the same way that mean systemic filling pressure rep-

Effect on the Venous Return Curve of Changes in Mean Systemic

resents a pressure pushing venous blood from the

Filling Pressure. Figure 20-11 shows the effects on the

periphery toward the heart, there is also resistance to

venous return curve caused by increasing or decreasing

this venous flow of blood. It is called the resistance to

the mean systemic filling pressure (Psf). Note in Figure

venous return. Most of the resistance to venous return

20-11 that the normal mean systemic filling pressure is

occurs in the veins, although some occurs in the arteri-

7 mm Hg. Then, for the uppermost curve in the figure,

oles and small arteries as well.

the mean systemic filling pressure has been increased to

Why is venous resistance so important in determin-

14 mm Hg, and for the lowermost curve, has been

ing the resistance to venous return? The answer is that

decreased to 3.5 mm Hg. These curves demonstrate that

when the resistance in the veins increases, blood begins

the greater the mean systemic filling pressure (which

to be dammed up, mainly in the veins themselves. But

also means the greater the “tightness” with which the

the venous pressure rises very little because the veins

circulatory system is filled with blood) the more the

are highly distensible. Therefore, this rise in venous

venous return curve shifts upward and to the right.

pressure is not very effective in overcoming the resist-

ance, and blood flow into the right atrium decreases

drastically. Conversely, when arteriolar and small artery

resistances increase, blood accumulates in the arteries,

which have a capacitance only 1/30 as great as that of

the veins. Therefore, even slight accumulation of blood

in the arteries raises the pressure greatly—30 times as

much as in the veins—and this high pressure does over-

Psf = 3.5

come much of the increased resistance. Mathematically,

Psf = 7

it turns out that about two thirds of the so-called “resist-

Psf = 14

ance to venous return” is determined by venous resist-

ance, and about one third by the arteriolar and small

artery resistance.

Venous return can be calculated by the following

formula:

-4

+12

Right atrial pressure (mm Hg)

Psf PRA

VR =

RVR

in which VR is venous return, Psf is mean systemic

Figure 20-11

filling pressure, PRA is right atrial pressure, and RVR

is resistance to venous return. In the healthy human

Venous return curves showing the normal curve when the mean

adult, the values for these are as follows: venous return

systemic filling pressure (Psf) is 7 mm Hg, and showing the effect

equals 5 L/min, mean systemic filling pressure equals

of altering the Psf to either

3.5 or 14 mm Hg. (Redrawn from

Guyton AC, Jones CE, Coleman TB: Circulatory Physiology:

7 mm Hg, right atrial pressure equals 0 mm Hg, and

Cardiac Output and Its Regulation. 2nd ed. Philadelphia: WB

resistance to venous return equals 1.4 mm Hg per liter

Saunders Co, 1973.)

of blood flow.

Chapter 20

Cardiac Output, Venous Return, and Their Regulation

241

Normal resistance

¥ resistance

1/2 resistance

1/3 resistance

Psf = 10.5

Psf = 10

Psf = 7

Psf = 2.3

Psf = 7

-4

+12

Right atrial pressure (mm Hg)

-4

Right atrial pressure (mm Hg)

Figure 20-13

Combinations of the major patterns of venous return curves,

showing the effects of simultaneous changes in mean systemic

Figure 20-12

filling pressure

(Psf) and in

“resistance to venous return.”

(Redrawn from Guyton AC, Jones CE, Coleman TB: Circulatory

Venous return curves depicting the effect of altering the “resist-

Physiology: Cardiac Output and Its Regulation. 2nd ed. Philadel-

ance to venous return.” Psf, mean systemic filling pressure.

phia: WB Saunders Co, 1973.)

(Redrawn from Guyton AC, Jones CE, Coleman TB: Circulatory

Physiology: Cardiac Output and Its Regulation. 2nd ed. Philadel-

phia: WB Saunders Co, 1973.)

equal the cardiac output from the heart and (2) the right

atrial pressure is the same for both the heart and the

Effect of Resistance to Venous Return on the Venous Return

systemic circulation.

Curve. Figure 20-12 demonstrates the effect of different

Therefore, one can predict the cardiac output and

levels of resistance to venous return on the venous

right atrial pressure in the following way: (1) Determine

return curve, showing that a decrease in this resistance

the momentary pumping ability of the heart and depict

to one-half normal allows twice as much flow of blood

this in the form of a cardiac output curve; (2) determine

and, therefore, rotates the curve upward to twice as great

the momentary state of flow from the systemic circula-

a slope. Conversely, an increase in resistance to twice

tion into the heart and depict this in the form of a

normal rotates the curve downward to one-half as great

venous return curve; and (3) “equate” these curves

a slope.

against each other, as shown in Figure 20-14.

Note also that when the right atrial pressure rises to

Two curves in the figure depict the normal cardiac

equal the mean systemic filling pressure, venous return

output curve (red line) and the normal venous return

becomes zero at all levels of resistance to venous return

curve (blue line). There is only one point on the graph,

because when there is no pressure gradient to cause

point A, at which the venous return equals the cardiac

flow of blood, it makes no difference what the resistance

output and at which the right atrial pressure is the same

is in the circulation; the flow is still zero. Therefore, the

for both the heart and the systemic circulation. There-

highest level to which the right atrial pressure can rise,

fore, in the normal circulation, the right atrial pressure,

regardless of how much the heart might fail, is equal to

cardiac output, and venous return are all depicted by

the mean systemic filling pressure.

point A, called the equilibrium point, giving a normal

value for cardiac output of 5 liters per minute and a

Combinations of Venous Return Curve Patterns. Figure 20-13

right atrial pressure of 0 mm Hg .

shows effects on the venous return curve caused by

simultaneous changes in mean systemic pressure (Psf)

Effect of Increased Blood Volume on Cardiac Output. A sudden

and resistance to venous return, demonstrating that

increase in blood volume of about 20 per cent increases

both these factors can operate simultaneously.

the cardiac output to about 2.5 to 3 times normal. An

analysis of this effect is shown in Figure 20-14. Imme-

diately on infusing the large quantity of extra blood, the

Analysis of Cardiac Output and

increased filling of the system causes the mean systemic

Right Atrial Pressure, Using

filling pressure (Psf) to increase to 16 mm Hg, which

Simultaneous Cardiac Output and

shifts the venous return curve to the right. At the same

time, the increased blood volume distends the blood

Venous Return Curves

vessels, thus reducing their resistance and thereby

In the complete circulation, the heart and the systemic

reducing the resistance to venous return, which rotates

circulation must operate together. This means that (1)

the curve upward. As a result of these two effects, the

the venous return from the systemic circulation must

venous return curve of Figure 20-14 is shifted to the

242

Unit IV The Circulation

Maximal sympathetic

stimulation

Moderate sympathetic

stimulation

Normal

Spinal anesthesia

Psf = 7

Psf = 16

-4

+12

+16

Right atrial pressure (mm Hg)

-4

+12

+16

Right atrial pressure (mm Hg)

Figure 20-14

The two solid curves demonstrate an analysis of cardiac output

Figure 20-15

and right atrial pressure when the cardiac output (red line) and

venous return (blue line) curves are normal. Transfusion of blood

Analysis of the effect on cardiac output of (1) moderate sympa-

equal to 20 per cent of the blood volume causes the venous return

thetic stimulation (from point A to point C), (2) maximal sympa-

curve to become the dashed curve; as a result, the cardiac output

thetic stimulation (point D), and (3) sympathetic inhibition caused

and right atrial pressure shift from point A to point B. Psf, mean

by total spinal anesthesia (point B). (Redrawn from Guyton AC,

systemic filling pressure.

Jones CE, Coleman TB: Circulatory Physiology: Cardiac Output

and Its Regulation. 2nd ed. Philadelphia: WB Saunders Co, 1973.)

right. This new curve equates with the cardiac output

each other at point A, which represents a normal venous

curve at point B, showing that the cardiac output and

return and cardiac output of 5 L/min and a right atrial

venous return increase 2.5 to 3 times, and that the right

pressure of 0 min Hg. Note in the figure that maximal

atrial pressure rises to about +8 mm Hg.

sympathetic stimulation (green curves) increases the

mean systemic filling pressure to 17 mm Hg (depicted

Further Compensatory Effects Initiated in Response to Increased

by the point at which the venous return curve reaches

Blood Volume. The greatly increased cardiac output

the zero venous return level). And the sympathetic stim-

caused by increased blood volume lasts for only a few

ulation also increases pumping effectiveness of the

minutes because several compensatory effects immedi-

heart by nearly 100 per cent. As a result, the cardiac

ately begin to occur: (1) The increased cardiac output

output rises from the normal value at equilibrium point

increases the capillary pressure so that fluid begins to

A to about double normal at equilibrium point D—and

transude out of the capillaries into the tissues, thereby

yet the right atrial pressure hardly changes. Thus, differ-

returning the blood volume toward normal. (2) The

ent degrees of sympathetic stimulation can increase the

increased pressure in the veins causes the veins to

cardiac output progressively to about twice normal for

continue distending gradually by the mechanism called

short periods of time, until other compensatory effects

stress-relaxation, especially causing the venous blood

occur within seconds or minutes.

reservoirs, such as the liver and spleen, to distend, thus

Effect of Sympathetic Inhibition on Cardiac Output. The sym-

reducing the mean systemic pressure. (3) The excess

pathetic nervous system can be blocked by inducing

blood flow through the peripheral tissues causes

total spinal anesthesia or by using some drug, such as

autoregulatory increase in the peripheral resistance,

hexamethonium, that blocks transmission of nerve

thus increasing the resistance to venous return. These

signals through the autonomic ganglia. The lowermost

factors cause the mean systemic filling pressure to

curves in Figure 20-15 show the effect of sympathetic

return back toward normal and the resistance vessels of

inhibition caused by total spinal anesthesia, demon-

the systemic circulation to constrict. Therefore, gradu-

strating that (1) the mean systemic filling pressure falls

ally, over a period of 10 to 40 minutes, the cardiac output

to about 4 mm Hg and (2) the effectiveness of the heart

returns almost to normal.

as a pump decreases to about 80 per cent of normal. The

cardiac output falls from point A to point B, which is a

Effect of Sympathetic Stimulation on Cardiac Output. Sympa-

decrease to about 60 per cent of normal.

thetic stimulation affects both the heart and the sys-

temic circulation: (1) It makes the heart a stronger pump.

Effect of Opening a Large Arteriovenous Fistula. Figure 20-16

(2) In the systemic circulation, it increases the mean

shows various stages of circulatory changes that occur

systemic filling pressure because of contraction of

after opening a large arteriovenous fistula, that is, after

the peripheral vessels—especially the veins—and it

making an opening directly between a large artery and

increases the resistance to venous return.

a large vein.

In Figure

20-15, the normal cardiac output and

1. The two red curves crossing at point A show the

venous return curves are depicted; these equate with

normal condition.

Chapter 20

Cardiac Output, Venous Return, and Their Regulation

243

Seconds

Figure 20-17

Pulsatile blood flow in the root of the aorta recorded using an elec-

tromagnetic flowmeter.

-4

+12

Right atrial pressure (mm Hg)

4. Point D shows the effect after several more weeks.

By this time, the blood volume has increased

because the slight reduction in arterial pressure and

the sympathetic stimulation have both reduced

Figure 20-16

kidney output of urine. The mean systemic filling

pressure has now risen to +12 mm Hg, shifting the

Analysis of successive changes in cardiac output and right atrial

venous return curve another 3 mm Hg to the right.

pressure in a human being after a large arteriovenous (AV) fistula

Also, the prolonged increased workload on the

is suddenly opened. The stages of the analysis, as shown by the

heart has caused the heart muscle to hypertrophy

equilibrium points, are A, normal conditions; B, immediately after

slightly, raising the level of the cardiac output curve

opening the AV fistula; C, 1 minute or so after the sympathetic

reflexes have become active; and D, several weeks after the blood

still further. Therefore, point D shows a cardiac

volume has increased and the heart has begun to hypertrophy.

output now of almost 20 L/min and a right atrial

(Redrawn from Guyton AC, Jones CE, Coleman TB: Circulatory

pressure of about 6 mm Hg.

Physiology: Cardiac Output and Its Regulation. 2nd ed. Philadel-

phia: WB Saunders Co, 1973.)

Other Analyses of Cardiac Output Regulation. In Chapter 21,

analysis of cardiac output regulation during exercise is

presented, and in Chapter 22, analyses of cardiac output

regulation at various stages of congestive heart failure

The curves crossing at point B show the circulatory

are shown.

condition immediately after opening the large

fistula. The principal effects are (1) a sudden and

precipitous rotation of the venous return curve

Methods for Measuring

upward caused by the large decrease in resistance to

Cardiac Output

venous return when blood is allowed to flow with

almost no impediment directly from the large

In animal experiments, one can cannulate the aorta, pul-

arteries into the venous system, bypassing most

monary artery, or great veins entering the heart and

of the resistance elements of the peripheral

measure the cardiac output using any type of flowme-

circulation, and (2) a slight increase in the level of

ter. An electromagnetic or ultrasonic flowmeter can also

the cardiac output curve because opening the fistula

be placed on the aorta or pulmonary artery to measure

decreases the peripheral resistance and allows

cardiac output.

an acute fall in arterial pressure against which

In the human, except in rare instances, cardiac output

the heart can pump more easily. The net result,

is measured by indirect methods that do not require

depicted by point B, is an increase in cardiac output

surgery. Two of the methods commonly used are the

from 5 L/min up to 13 L/min and an increase in

oxygen Fick method and the indicator dilution method.

right atrial pressure to about +3 mm Hg.

Point C represents the effects about 1 minute later,

after the sympathetic nerve reflexes have restored

Pulsatile Output of the Heart as

the arterial pressure almost to normal and caused

Measured by an Electromagnetic or

two other effects: (1) an increase in the mean

Ultrasonic Flowmeter

systemic filling pressure (because of constriction of

all veins and arteries) from 7 to 9 mm Hg, thus

Figure 20-17 shows a recording in a dog of blood flow

shifting the venous return curve 2 mm Hg to the

in the root of the aorta made using an electromagnetic

right, and (2) further elevation of the cardiac

flowmeter. It demonstrates that the blood flow rises

output curve because of sympathetic nervous

rapidly to a peak during systole, and then at the end of

excitation of the heart. The cardiac output now

systole reverses for a fraction of a second. This reverse

rises to almost 16 L/min, and the right atrial

flow causes the aortic valve to close and the flow to

pressure to about 4 mm Hg.

return to zero.

244

Unit IV The Circulation

Measurement of Cardiac Output Using

Indicator Dilution Method for

the Oxygen Fick Principle

Measuring Cardiac Output

To measure cardiac output by the so-called “indicator

The Fick principle is explained by Figure 20-18. This

dilution method,” a small amount of indicator, such as

figure shows that 200 milliliters of oxygen are being

a dye, is injected into a large systemic vein or, prefer-

absorbed from the lungs into the pulmonary blood

ably, into the right atrium. This passes rapidly through

each minute. It also shows that the blood entering the

the right side of the heart, then through the blood

right heart has an oxygen concentration of 160 milli-

vessels of the lungs, through the left side of the heart

liters per liter of blood, whereas that leaving the left

and, finally, into the systemic arterial system. The con-

heart has an oxygen concentration of 200 milliliters

centration of the dye is recorded as the dye passes

through one of the peripheral arteries, giving a curve as

per liter of blood. From these data, one can calculate

shown in Figure 20-19. In each of these instances, 5 mil-

that each liter of blood passing through the lungs

ligrams of Cardio-Green dye was injected at zero time.

absorbs 40 milliliters of oxygen.

In the top recording, none of the dye passed into the

Because the total quantity of oxygen absorbed into

arterial tree until about 3 seconds after the injection, but

the blood from the lungs each minute is 200 milliliters,

then the arterial concentration of the dye rose rapidly

dividing 200 by 40 calculates a total of five 1-liter por-

to a maximum in about 6 to 7 seconds. After that, the

tions of blood that must pass through the pulmonary

concentration fell rapidly, but before the concentration

circulation each minute to absorb this amount of

reached zero, some of the dye had already circulated all

oxygen. Therefore, the quantity of blood flowing

the way through some of the peripheral systemic vessels

through the lungs each minute is 5 liters, which is also

and returned through the heart for a second time. Con-

sequently, the dye concentration in the artery began to

a measure of the cardiac output. Thus, the cardiac

rise again. For the purpose of calculation, it is necessary

output can be calculated by the following formula:

to extrapolate the early down-slope of the curve to the

zero point, as shown by the dashed portion of each

Cardiac output(L min)

curve. In this way, the extrapolated time-concentration

O absorbed per minute by the lungs(ml min

)

curve of the dye in the systemic artery without recircu-

Arteriovenous O2 difference

(ml L of blood)

lation can be measured in its first portion and estimated

reasonably accurately in its latter portion.

In applying this Fick procedure for measuring

Once the extrapolated time-concentration curve has

cardiac output in the human being, mixed venous

been determined, one then calculates the mean con-

blood is usually obtained through a catheter inserted

centration of dye in the arterial blood for the duration

of the curve. For instance, in the top example of Figure

up the brachial vein of the forearm, through the sub-

20-19, this was done by measuring the area under the

clavian vein, down to the right atrium, and, finally, into

the right ventricle or pulmonary artery. And systemic

arterial blood can then be obtained from any systemic

artery in the body. The rate of oxygen absorption by

the lungs is measured by the rate of disappearance of

oxygen from the respired air, using any type of oxygen

5 mg

meter.

injected

0.5

0.4

0.3

0.2

0.1

LUNGS

5 mg

0.5

injected

0.4

Oxygen used = 200 ml/min

0.3

0.2

0.1

Cardiac output =

O₂=

5000 ml/min

O₂ =

Seconds

160 ml/L

200 ml/L

right heart

left heart

Figure 20-19

Extrapolated dye concentration curves used to calculate two sep-

Figure 20-18

arate cardiac outputs by the dilution method. (The rectangular

areas are the calculated average concentrations of dye in the arte-

Fick principle for determining cardiac output.

rial blood for the durations of the respective extrapolated curves.)

Chapter 20

Cardiac Output, Venous Return, and Their Regulation

245

entire initial and extrapolated curve and then averaging

Guyton AC: Venous return. In: Hamilton WF (ed): Hand-

the concentration of dye for the duration of the curve;

book of Physiology. Sec 2, Vol. 2. Baltimore, Williams &

one can see from the shaded rectangle straddling the

Wilkins, 1963, p 1099.

curve in the upper figure that the average concentration

Guyton AC: Determination of cardiac output by equating

of dye was 0.25 mg/dl of blood and that the duration

venous return curves with cardiac response curves. Physiol

of this average value was 12 seconds. A total of 5 mil-

Rev 35:123, 1955.

ligrams of dye had been injected at the beginning of the

Guyton AC, Coleman TG, Granger HJ: Circulation: overall

experiment. For blood carrying only 0.25 milligram of

regulation. Annu Rev Physiol 34:13, 1972.

dye in each deciliter to carry the entire 5 milligrams of

Guyton AC, Jones CE, Coleman TG: Circulatory Physiology:

dye through the heart and lungs in 12 seconds, a total

Cardiac Output and Its Regulation. Philadelphia: WB

of 20 1-deciliter portions of blood would have passed

Saunders Co, 1973.

through the heart during the 12 seconds, which would

Guyton AC, Lindsey AW, Kaufmann BN: Effect of mean cir-

be the same as a cardiac output of 2 L/12 sec, or

culatory filling pressure and other peripheral circulatory

10 L/min. We leave it to the reader to calculate the

factors on cardiac output. Am J Physiol 180:463-468, 1955.

cardiac output from the bottom extrapolated curve of

Koch WJ, Lefkowitz RJ, Rockman HA: Functional conse-

Figure 20-19. To summarize, the cardiac output can be

quences of altering myocardial adrenergic receptor sig-

determined using the following formula:

naling. Annu Rev Physiol 62:237, 2000.

Rockman HA, Koch WJ, Lefkowitz RJ: Seven-transmem-

brane-spanning receptors and heart function. Nature

Cardiac output(ml min)=

415:206, 2002.

Milligrams of dye injected

Rothe CF: Mean circulatory filling pressure: its meaning and

Ê Average concentration of dyeˆ

ÊDuration ofˆ

measurement. J Appl Physiol 74:499, 1993.

in each milliliter of blood

the curve

Rothe CF: Reflex control of veins and vascular capacitance.

for the duration of the curve

in seconds

Physiol Rev 63:1281, 1983.

Sarnoff SJ, Berglund E: Ventricular function. 1. Starling’s law

of the heart, studied by means of simultaneous right and

left ventricular function curves in the dog. Circulation

References

9:706-718, 1953.

Uemura K, Sugimachi M, Kawada T, et al: A novel frame-

Brengelmann GL: A critical analysis of the view that right

work of circulatory equilibrium. Am J Physiol Heart Circ

atrial pressure determines venous return. J Appl Physiol

Physiol 286:H2376, 2004.

94:849, 2003.

Vatner SF, Braunwald E: Cardiovascular control mecha-

Gaasch WH, Zile MR: Left ventricular diastolic dysfunction

nisms in the conscious state. N Engl J Med 293:970, 1975.

and diastolic heart failure. Annu Rev Med. 55:373, 2004.

C H A P T E R

Muscle Blood Flow and Cardiac

Output During Exercise; the

Coronary Circulation and Ischemic

Heart Disease

In this chapter we consider (1) blood flow to the

skeletal muscles and

(2) coronary blood flow

to the heart. Regulation of each of these is

achieved mainly by local control of vascular

resistance in response to muscle tissue metabolic

needs.

In addition, related subjects are discussed, such as

(1) cardiac output control during exercise, (2) char-

acteristics of heart attacks, and (3) the pain of angina pectoris.

Blood Flow in Skeletal Muscle and Blood Flow

Regulation During Exercise

Very strenuous exercise is one of the most stressful conditions that the normal

circulatory system faces. This is true because there is such a large mass of skele-

tal muscle in the body, all of it requiring large amounts of blood flow. Also, the

cardiac output often must increase in the non-athlete to four to five times

normal, or in the well-trained athlete to six to seven times normal.

Rate of Blood Flow Through the Muscles

During rest, blood flow through skeletal muscle averages 3 to 4 ml/min/100 g of

muscle. During extreme exercise in the well-conditioned athlete, this can increase

15- to 25-fold, rising to 50 to 80 ml/min/100 g of muscle.

Blood Flow During Muscle Contractions. Figure 21-1 shows a record of blood flow

changes in a calf muscle of a human leg during strong rhythmical muscular exer-

cise. Note that the flow increases and decreases with each muscle contraction.

At the end of the contractions, the blood flow remains very high for a few

seconds but then fades toward normal during the next few minutes.

The cause of the lower flow during the muscle contraction phase of exercise

is compression of the blood vessels by the contracted muscle. During strong

tetanic contraction, which causes sustained compression of the blood vessels, the

blood flow can be almost stopped, but this also causes rapid weakening of the

contraction.

Increased Blood Flow in Muscle Capillaries During Exercise. During rest, some muscle

capillaries have little or no flowing blood. But during strenuous exercise, all

the capillaries open. This opening of dormant capillaries diminishes the dis-

tance that oxygen and other nutrients must diffuse from the capillaries to the

contracting muscle fibers and sometimes contributes a twofold to threefold

increased capillary surface area through which oxygen and nutrients can diffuse

from the blood.

246

Chapter 21

Muscle Blood Flow and Cardiac Output During Exercise

247

(in some species of animals) sympathetic vasodilator

nerves as well.

Rhythmic exercise

Sympathetic Vasoconstrictor Nerves. The sympa-

thetic vasoconstrictor nerve fibers secrete norepineph-

rine at their nerve endings. When maximally activated,

this can decrease blood flow through resting muscles

to as little as one half to one third normal. This vaso-

constriction is of physiologic importance in circulatory

shock and during other periods of stress when it is

necessary to maintain a normal or even high arterial

pressure.

Calf

flow

In addition to the norepinephrine secreted at the

sympathetic vasoconstrictor nerve endings, the medul-

lae of the two adrenal glands also secrete large

Minutes

amounts of norepinephrine plus even more epineph-

rine into the circulating blood during strenuous exer-

cise. The circulating norepinephrine acts on the muscle

vessels to cause a vasoconstrictor effect similar to that

Figure 21-1

caused by direct sympathetic nerve stimulation. The

Effects of muscle exercise on blood flow in the calf of a leg during

epinephrine, however, often has a slight vasodilator

strong rhythmical contraction. The blood flow was much less

effect because epinephrine excites more of the beta

during contractions than between contractions. (Adapted from

adrenergic receptors of the vessels, which are vasodila-

Barcroft and Dornhorst: J Physiol 109:402, 1949.)

tor receptors, in contrast to the alpha vasoconstrictor

receptors excited especially by norepinephrine. These

receptors are discussed in Chapter 60.

Control of Blood Flow Through the

Skeletal Muscles

Total Body Circulatory Readjustments

Local Regulation—Decreased Oxygen in Muscle Greatly

During Exercise

Enhances Flow. The tremendous increase in muscle

blood flow that occurs during skeletal muscle activity

Three major effects occur during exercise that are

is caused primarily by chemical effects acting directly

essential for the circulatory system to supply the

on the muscle arterioles to cause dilation. One of the

tremendous blood flow required by the muscles. They

most important chemical effects is reduction of oxygen

are (1) mass discharge of the sympathetic nervous

in the muscle tissues. That is, during muscle activity,

system throughout the body with consequent stimula-

the muscle uses oxygen rapidly, thereby decreasing the

tory effects on the entire circulation, (2) increase in

oxygen concentration in the tissue fluids. This in turn

arterial pressure, and (3) increase in cardiac output.

causes local arteriolar vasodilation both because the

arteriolar walls cannot maintain contraction in the

Effects of Mass Sympathetic Discharge

absence of oxygen and because oxygen deficiency

At the onset of exercise, signals are transmitted not

causes release of vasodilator substances. The most

only from the brain to the muscles to cause muscle

important vasodilator substance is probably adeno-

contraction but also into the vasomotor center to ini-

sine, but experiments have shown that even large

tiate mass sympathetic discharge throughout the body.

amounts of adenosine infused directly into a muscle

Simultaneously, the parasympathetic signals to the

artery cannot sustain vasodilation in skeletal muscle

heart are attenuated. Therefore, three major circula-

for more than about 2 hours.

tory effects result.

Fortunately, even after the muscle blood vessels

First, the heart is stimulated to greatly increased

have become insensitive to the vasodilator effects of

heart rate and increased pumping strength as a result

adenosine, still other vasodilator factors continue to

of the sympathetic drive to the heart plus release of

maintain increased capillary blood flow as long as the

the heart from normal parasympathetic inhibition.

exercise continues. These factors include (1) potassium

Second, most of the arterioles of the peripheral

ions, (2) adenosine triphosphate (ATP), (3) lactic acid,

circulation are strongly contracted, except for the

and (4) carbon dioxide. We still do not know quanti-

arterioles in the active muscles, which are strongly

tatively how great a role each of these plays in in-

vasodilated by the local vasodilator effects in the

creasing muscle blood flow during muscle activity;

muscles as noted above. Thus, the heart is stimulated

this subject was discussed in additional detail in

to supply the increased blood flow required by the

Chapter 17.

muscles, while at the same time blood flow through

most nonmuscular areas of the body is temporarily

Nervous Control of Muscle Blood Flow. In addition to local

reduced, thereby temporarily “lending” their blood

tissue vasodilator mechanisms, skeletal muscles are

supply to the muscles. This accounts for as much as

provided with sympathetic vasoconstrictor nerves and

2 L/min of extra blood flow to the muscles, which is

248

Unit IV The Circulation

exceedingly important when one thinks of a person

running for his life—even a fractional increase in

running speed may make the difference between life

and death. Two of the peripheral circulatory systems,

the coronary and cerebral systems, are spared this vaso-

constrictor effect because both these circulatory areas

have poor vasoconstrictor innervation—fortunately so

because both the heart and the brain are as essential

to exercise as are the skeletal muscles.

Third, the muscle walls of the veins and other capac-

itative areas of the circulation are contracted power-

fully, which greatly increases the mean systemic filling

pressure. As we learned in Chapter 20, this is one of

-4

+12

+16

+20

+24

the most important factors in promoting increase in

venous return of blood to the heart and, therefore, in

Right atrial pressure (mm Hg)

increasing the cardiac output.

Increase in Arterial Pressure During Exercise—

Figure 21-2

An Important Result of Increased

Sympathetic Stimulation

Graphical analysis of change in cardiac output and right atrial

pressure with onset of strenuous exercise. Black curves, normal

One of the most important effects of increased sym-

circulation. Red curves, heavy exercise.

pathetic stimulation in exercise is to increase the arte-

rial pressure. This results from multiple stimulatory

effects, including (1) vasoconstriction of the arterioles

and small arteries in most tissues of the body except

assume, for instance, that the arterial pressure rises

the active muscles, (2) increased pumping activity

30 per cent, a common increase during heavy exercise.

by the heart, and (3) a great increase in mean systemic

This 30 per cent increase causes 30 per cent more force

filling pressure caused mainly by venous contraction.

to push blood through the muscle tissue vessels. But

These effects, working together, virtually always

this is not the only important effect; the extra pressure

increase the arterial pressure during exercise. This

also stretches the walls of the vessels so much that

increase can be as little as 20 mm Hg or as great as

muscle total flow often rises to more than 20 times

80 mm Hg, depending on the conditions under which

normal.

the exercise is performed. When a person performs

exercise under tense conditions but uses only a few

Importance of the Increase in Cardiac Output

muscles, the sympathetic nervous response still occurs

During Exercise

everywhere in the body. In the few active muscles,

Many different physiologic effects occur at the same

vasodilation occurs, but everywhere else in the body

time during exercise to increase cardiac output

the effect is mainly vasoconstriction, often increasing

approximately in proportion to the degree of exercise.

the mean arterial pressure to as high as 170 mm Hg.

In fact, the ability of the circulatory system to provide

Such a condition might occur in a person standing

increased cardiac output for delivery of oxygen and

on a ladder and nailing with a hammer on the ceiling

other nutrients to the muscles during exercise is

above. The tenseness of the situation is obvious.

equally as important as the strength of the muscles

Conversely, when a person performs massive

themselves in setting the limit for continued muscle

whole-body exercise, such as running or swimming,

work. For instance, marathon runners who can

the increase in arterial pressure is often only 20 to

increase their cardiac outputs the most are generally

40 mm Hg. This lack of a large increase in pressure

the same persons who have record-breaking running

results from the extreme vasodilation that occurs

times.

simultaneously in large masses of active muscle.

Graphical Analysis of the Changes in Cardiac Output During

Why Is the Arterial Pressure Increase During Exercise Impor-

Heavy Exercise. Figure 21-2 shows a graphical analysis

tant? When muscles are stimulated maximally in a lab-

of the large increase in cardiac output that occurs

oratory experiment but without allowing the arterial

during heavy exercise. The cardiac output and venous

pressure to rise, muscle blood flow seldom rises more

return curves crossing at point A give the analysis for

than about eightfold. Yet, we know from studies of

the normal circulation; and the curves crossing at point

marathon runners that muscle blood flow can increase

B analyze heavy exercise. Note that the great increase

from as little as 1 L/min for the whole body during rest

in cardiac output requires significant changes in both

to at least 20 L/min during maximal activity. Therefore,

the cardiac output curve and the venous return curve,

it is clear that muscle blood flow can increase much

as follow.

more than occurs in the aforementioned simple labo-

The increased level of the cardiac output curve is

ratory experiment. What is the difference? Mainly, the

easy to understand. It results almost entirely from

arterial pressure rises during normal exercise. Let us

sympathetic stimulation of the heart that causes (1)

Chapter 21

Muscle Blood Flow and Cardiac Output During Exercise

249

increased heart rate, often up to rates as high as 170 to

Aortic valve

190 beats/min, and (2) increased strength of contrac-

tion of the heart, often to as much as twice normal.

Without this increased level of the output curve, the

increase in cardiac output would be limited to the

plateau level of the normal heart, which would be a

Left coronary

maximum increase of cardiac output of only about

artery

2.5-fold rather than the 4-fold that can commonly be

achieved by the untrained runner and the 7-fold that

Right coronary

can be achieved in some marathon runners.

artery

Now study the venous return curves. If no change

occurred from the normal venous return curve, the

cardiac output could hardly rise at all in exercise

because the upper plateau level of the normal venous

return curve is only

6 L/min. Yet two important

changes do occur:

1. The mean systemic filling pressure rises

Figure 21-3

tremendously at the onset of heavy exercise. This

results partly from the sympathetic stimulation

The coronary arteries.

that contracts the veins and other capacitative parts

of the circulation. In addition, tensing of the

abdominal and other skeletal muscles of the body

compresses many of the internal vessels, thus

Physiologic Anatomy of the Coronary

providing more compression of the entire

Blood Supply

capacitative vascular system, causing a still greater

increase in mean systemic filling pressure.

Figure 21-3 shows the heart and its coronary blood

During maximal exercise, these two effects

supply. Note that the main coronary arteries lie on the

together can increase the mean systemic filling

surface of the heart and smaller arteries then pene-

pressure from a normal level of 7 mm Hg to as

trate from the surface into the cardiac muscle mass. It

high as 30 mm Hg.

is almost entirely through these arteries that the heart

2. The slope of the venous return curve rotates

receives its nutritive blood supply. Only the inner 1/10

upward. This is caused by decreased resistance in

millimeter of the endocardial surface can obtain sig-

virtually all the blood vessels in active muscle

nificant nutrition directly from the blood inside the

tissue, which also causes resistance to venous

cardiac chambers, so that this source of muscle nutri-

return to decrease, thus increasing the upward

tion is minuscule.

slope of the venous return curve.

The left coronary artery supplies mainly the anterior

Therefore, the combination of increased mean sys-

and left lateral portions of the left ventricle, whereas

temic filling pressure and decreased resistance to

the right coronary artery supplies most of the right

venous return raises the entire level of the venous

ventricle as well as the posterior part of the left ven-

return curve.

tricle in 80 to 90 per cent of people.

In response to the changes in both the venous return

Most of the coronary venous blood flow from the

curve and the cardiac output curve, the new equilib-

left ventricular muscle returns to the right atrium of

rium point in Figure 21-2 for cardiac output and

the heart by way of the coronary sinus—which is about

right atrial pressure is now point B, in contrast to the

75 per cent of the total coronary blood flow. And most

normal level at point A. Note especially that the right

of the coronary venous blood from the right ventricu-

atrial pressure has hardly changed, having risen only

lar muscle returns through small anterior cardiac veins

1.5 mm Hg. In fact, in a person with a strong heart,

that flow directly into the right atrium, not by way of

the right atrial pressure often falls below normal in

the coronary sinus. A very small amount of coronary

very heavy exercise because of the greatly increased

venous blood also flows back into the heart through

sympathetic stimulation of the heart during exercise.

very minute thebesian veins, which empty directly into

all chambers of the heart.

Coronary Circulation

Normal Coronary Blood Flow

About one third of all deaths in the affluent society of

The resting coronary blood flow in the human being

the Western world result from coronary artery disease,

averages about 225 ml/min, which is about 4 to 5 per

and almost all elderly people have at least some

cent of the total cardiac output.

impairment of the coronary artery circulation. For this

During strenuous exercise, the heart in the young

reason, understanding normal and pathological physi-

adult increases its cardiac output fourfold to seven-

ology of the coronary circulation is one of the most

fold, and it pumps this blood against a higher than

important subjects in medicine.

normal arterial pressure. Consequently, the work

250

Unit IV The Circulation

Epicardial coronary arteries

Cardiac

300

muscle

Subendocardial arterial plexus

200

Figure 21-5

Diagram of the epicardial, intramuscular, and subendocardial

100

coronary vasculature.

the special arrangement of the coronary vessels at dif-

Systole

Diastole

ferent depths in the heart muscle, showing on the outer

surface epicardial coronary arteries that supply most of

the muscle. Smaller, intramuscular arteries derived

from the epicardial arteries penetrate the muscle,

Figure 21-4

supplying the needed nutrients. Lying immediately

beneath the endocardium is a plexus of subendocar-

dial arteries. During systole, blood flow through the

Phasic flow of blood through the coronary capillaries of the human

left ventricle during cardiac systole and diastole (as extrapolated

subendocardial plexus of the left ventricle, where the

from measured flows in dogs).

intramuscular coronary vessels are compressed greatly

by ventricular muscle contraction, tends to be reduced.

output of the heart under severe conditions may

But the extra vessels of the subendocardial plexus nor-

increase sixfold to ninefold. At the same time, the

mally compensate for this. Later in the chapter, we will

coronary blood flow increases threefold to fourfold to

see that this peculiar difference between blood flow in

supply the extra nutrients needed by the heart. This

the epicardial and subendocardial arteries plays an

increase is not as much as the increase in workload,

important role in certain types of coronary ischemia.

which means that the ratio of energy expenditure by

the heart to coronary blood flow increases. Thus, the

“efficiency” of cardiac utilization of energy increases

Control of Coronary Blood Flow

to make up for the relative deficiency of coronary

blood supply.

Local Muscle Metabolism Is the Primary

Controller of Coronary Flow

Phasic Changes in Coronary Blood Flow During Systole and

Blood flow through the coronary system is regulated

Diastole—Effect of Cardiac Muscle Compression. Figure

mostly by local arteriolar vasodilation in response to

21-4 shows the changes in blood flow through the

cardiac muscle need for nutrition. That is, whenever

nutrient capillaries of the left ventricular coronary

the vigor of cardiac contraction is increased, regard-

system in milliliters per minute in the human heart

less of cause, the rate of coronary blood flow also

during systole and diastole, as extrapolated from

increases. Conversely, decreased heart activity is

experiments in lower animals. Note from this diagram

accompanied by decreased coronary flow. This local

that the coronary capillary blood flow in the left ven-

regulation of coronary blood flow is almost identical

tricle muscle falls to a low value during systole, which

to that occurring in many other tissues of the body,

is opposite to flow in vascular beds elsewhere in the

especially in the skeletal muscles all over the body.

body. The reason for this is strong compression of the

left ventricular muscle around the intramuscular

Oxygen Demand as a Major Factor in Local Coronary Blood Flow

vessels during systolic contraction.

Regulation. Blood flow in the coronaries usually is reg-

During diastole, the cardiac muscle relaxes and no

ulated almost exactly in proportion to the need of the

longer obstructs blood flow through the left ventricu-

cardiac musculature for oxygen. Normally, about 70

lar muscle capillaries, so that blood flows rapidly

per cent of the oxygen in the coronary arterial blood

during all of diastole.

is removed as the blood flows through the heart

Blood flow through the coronary capillaries of the

muscle. Because not much oxygen is left, very little

right ventricle also undergoes phasic changes during

additional oxygen can be supplied to the heart mus-

the cardiac cycle, but because the force of contraction

culature unless the coronary blood flow increases. For-

of the right ventricular muscle is far less than that of

tunately, the coronary blood flow does increase almost

the left ventricular muscle, the inverse phasic changes

in direct proportion to any additional metabolic con-

are only partial in contrast to those in the left ventric-

sumption of oxygen by the heart.

ular muscle.

However, the exact means by which increased

oxygen consumption causes coronary dilation has

Epicardial Versus Subendocardial Coronary Blood Flow—Effect

not been determined. It is speculated by many

of Intramyocardial Pressure. Figure

21-5 demonstrates

research workers that a decrease in the oxygen

Chapter 21

Muscle Blood Flow and Cardiac Output During Exercise

251

concentration in the heart causes vasodilator sub-

There is much more extensive sympathetic innerva-

stances to be released from the muscle cells and that

tion of the coronary vessels. In Chapter 60, we see that

these dilate the arterioles. A substance with great

the sympathetic transmitter substances norepineph-

vasodilator propensity is adenosine. In the presence of

rine and epinephrine can have either vascular con-

very low concentrations of oxygen in the muscle cells,

strictor or vascular dilator effects, depending on the

a large proportion of the cell’s ATP degrades to adeno-

presence or absence of constrictor or dilator receptors

sine monophosphate; then small portions of this are

in the blood vessel walls. The constrictor receptors are

further degraded and release adenosine into the tissue

called alpha receptors and the dilator receptors are

fluids of the heart muscle, with resultant increase in

called beta receptors. Both alpha and beta receptors

local coronary blood flow. After the adenosine causes

exist in the coronary vessels. In general, the epicardial

vasodilation, much of it is reabsorbed into the cardiac

coronary vessels have a preponderance of alpha recep-

cells to be reused.

tors, whereas the intramuscular arteries may have a

Adenosine is not the only vasodilator product

preponderance of beta receptors. Therefore, sympa-

that has been identified. Others include adenosine

thetic stimulation can, at least theoretically, cause

phosphate compounds, potassium ions, hydrogen

slight overall coronary constriction or dilation, but

ions, carbon dioxide, bradykinin, and, possibly,

usually constriction. In some people, the alpha vaso-

prostaglandins and nitric oxide.

constrictor effects seem to be disproportionately

Yet, difficulties with the vasodilator hypothesis exist.

severe, and these people can have vasospastic myocar-

First, pharmacologic agents that block or partially

dial ischemia during periods of excess sympathetic

block the vasodilator effect of adenosine do not

drive, often with resultant anginal pain.

prevent coronary vasodilation caused by increased

Metabolic factors—especially myocardial oxygen

heart muscle activity. Second, studies in skeletal

consumption—are the major controllers of myocardial

muscle have shown that continued infusion of adeno-

blood flow. Whenever the direct effects of nervous

sine maintains vascular dilation for only 1 to 3 hours,

stimulation alter the coronary blood flow in the wrong

and yet muscle activity still dilates the local blood

direction, the metabolic control of coronary flow

vessels even when the adenosine can no longer dilate

usually overrides the direct coronary nervous effects

them. Therefore, the other vasodilator mechanisms

within seconds.

listed above must be remembered.

Nervous Control of Coronary Blood Flow

Special Features of Cardiac

Stimulation of the autonomic nerves to the heart can

Muscle Metabolism

affect coronary blood flow both directly and indirectly.

The direct effects result from action of the nervous

The basic principles of cellular metabolism, discussed

transmitter substances acetylcholine from the vagus

in Chapters 67 through 72, apply to cardiac muscle the

nerves and norepinephrine and epinephrine from the

same as for other tissues, but there are some quantita-

sympathetic nerves on the coronary vessels them-

tive differences. Most important, under resting condi-

selves. The indirect effects result from secondary

tions, cardiac muscle normally consumes fatty acids to

changes in coronary blood flow caused by increased or

supply most of its energy instead of carbohydrates

decreased activity of the heart.

(about 70 per cent of the energy is derived from fatty

The indirect effects, which are mostly opposite to

acids). However, as is also true of other tissues, under

the direct effects, play a far more important role in

anaerobic or ischemic conditions, cardiac metabolism

normal control of coronary blood flow. Thus, sympa-

must call on anaerobic glycolysis mechanisms for

thetic stimulation, which releases norepinephrine and

energy. Unfortunately, glycolysis consumes tremen-

epinephrine, increases both heart rate and heart con-

dous quantities of the blood glucose and at the same

tractility as well as increases the rate of metabolism of

time forms large amounts of lactic acid in the cardiac

the heart. In turn, the increased metabolism of the

tissue, which is probably one of the causes of cardiac

heart sets off local blood flow regulatory mechanisms

pain in cardiac ischemic conditions, as discussed later

for dilating the coronary vessels, and the blood flow

in this chapter.

increases approximately in proportion to the meta-

As is true in other tissues, more than 95 per cent of

bolic needs of the heart muscle. In contrast, vagal stim-

the metabolic energy liberated from foods is used to

ulation, with its release of acetylcholine, slows the

form ATP in the mitochondria. This ATP in turn acts

heart and has a slight depressive effect on heart con-

as the conveyer of energy for cardiac muscular con-

tractility. These effects in turn decrease cardiac oxygen

traction and other cellular functions. In severe coro-

consumption and, therefore, indirectly constrict the

nary ischemia, the ATP degrades first to adenosine

coronary arteries.

diphosphate, then to adenosine monophosphate and

adenosine. Because the cardiac muscle cell membrane

Direct Effects of Nervous Stimuli on the Coronary Vasculature.

is slightly permeable to adenosine, much of this

The distribution of parasympathetic

(vagal) nerve

can diffuse from the muscle cells into the circulating

fibers to the ventricular coronary system is not very

blood.

great. However, the acetylcholine released by parasym-

The released adenosine is believed to be one of the

pathetic stimulation has a direct effect to dilate the coro-

substances that causes dilation of the coronary arteri-

nary arteries.

oles during coronary hypoxia, as discussed earlier.

252

Unit IV The Circulation

However, loss of adenosine also has a serious cellular

the flowing blood. Because the plaque presents an

consequence. Within as little as 30 minutes of severe

unsmooth surface, blood platelets adhere to it,

coronary ischemia, as occurs after a myocardial infarct,

fibrin is deposited, and red blood cells become

about one half of the adenine base can be lost from

entrapped to form a blood clot that grows until

the affected cardiac muscle cells. Furthermore, this loss

it occludes the vessel. Or, occasionally, the

can be replaced by new synthesis of adenine at a rate

clot breaks away from its attachment on the

of only 2 per cent per hour. Therefore, once a serious

atherosclerotic plaque and flows to a more

bout of coronary ischemia has persisted for 30 or more

peripheral branch of the coronary arterial tree,

minutes, relief of the ischemia may be too late to save

where it blocks the artery at that point. A

the lives of the cardiac cells. This almost certainly is

thrombus that flows along the artery in this way

one of the major causes of cardiac cellular death

and occludes the vessel more distally is called a

during myocardial ischemia.

coronary embolus.

2. Many clinicians believe that local muscular spasm

of a coronary artery also can occur. The spasm

Ischemic Heart Disease

might result from direct irritation of the smooth

muscle of the arterial wall by the edges of an

The most common cause of death in Western culture

arteriosclerotic plaque, or it might result from

is ischemic heart disease, which results from insuffi-

local nervous reflexes that cause excess coronary

cient coronary blood flow. About 35 per cent of people

vascular wall contraction. The spasm may then

in the United States die of this cause. Some deaths

lead to secondary thrombosis of the vessel.

occur suddenly as a result of acute coronary occlusion

or fibrillation of the heart, whereas other deaths occur

Lifesaving Value of Collateral Circulation in the Heart. The

slowly over a period of weeks to years as a result of

degree of damage to the heart muscle caused either by

progressive weakening of the heart pumping process.

slowly developing atherosclerotic constriction of the

In this chapter, we discuss acute coronary ischemia

coronary arteries or by sudden coronary occlusion is

caused by acute coronary occlusion and myocardial

determined to a great extent by the degree of collat-

infarction. In Chapter 22, we discuss congestive heart

eral circulation that has already developed or that can

failure, the most frequent cause of which is slowly

open within minutes after the occlusion.

increasing coronary ischemia and weakening of the

In a normal heart, almost no large communications

cardiac muscle.

exist among the larger coronary arteries. But many

anastomoses do exist among the smaller arteries

Atherosclerosis as a Cause of Ischemic Heart Disease. The

sized 20 to 250 micrometers in diameter, as shown in

most frequent cause of diminished coronary blood

Figure 21-6.

flow is atherosclerosis. The atherosclerotic process is

When a sudden occlusion occurs in one of the larger

discussed in connection with lipid metabolism in

coronary arteries, the small anastomoses begin to

Chapter 68. Briefly, this process is the following.

In people who have genetic predisposition to ath-

erosclerosis, or in people who eat excessive quantities

of cholesterol and have a sedentary lifestyle, large

Artery

quantities of cholesterol gradually become deposited

beneath the endothelium at many points in arteries

throughout the body. Gradually, these areas of deposit

are invaded by fibrous tissue and frequently become

Vein

calcified. The net result is the development of athero-

sclerotic plaques that actually protrude into the vessel

lumens and either block or partially block blood flow.

A common site for development of atherosclerotic

plaques is the first few centimeters of the major coro-

nary arteries.

Acute Coronary Occlusion

Acute occlusion of a coronary artery most frequently

occurs in a person who already has underlying ath-

erosclerotic coronary heart disease but almost never

in a person with a normal coronary circulation. Acute

Artery

occlusion can result from any one of several effects,

two of which are the following:

1. The atherosclerotic plaque can cause a local blood

clot called a thrombus, which in turn occludes

Vein

the artery. The thrombus usually occurs where the

Figure 21-6

arteriosclerotic plaque has broken through the

endothelium, thus coming in direct contact with

Minute anastomoses in the normal coronary arterial system.

Chapter 21

Muscle Blood Flow and Cardiac Output During Exercise

253

dilate within seconds. But the blood flow through these

Subendocardial Infarction. The subendocardial muscle

minute collaterals is usually less than one half that

frequently becomes infarcted even when there is no

needed to keep alive most of the cardiac muscle that

evidence of infarction in the outer surface portions of

they now supply; the diameters of the collateral vessels

the heart. The reason for this is that the subendocar-

do not enlarge much more for the next 8 to 24 hours.

dial muscle has extra difficulty obtaining adequate

But then collateral flow does begin to increase, dou-

blood flow because the blood vessels in the subendo-

bling by the second or third day and often reaching

cardium are intensely compressed by systolic contrac-

normal or almost normal coronary flow within about

tion of the heart, as explained earlier. Therefore, any

1 month. Because of these developing collateral chan-

condition that compromises blood flow to any area of

nels, many patients recover almost completely from

the heart usually causes damage first in the subendo-

various degrees of coronary occlusion when the area

cardial regions, and the damage then spreads outward

of muscle involved is not too great.

toward the epicardium.

When atherosclerosis constricts the coronary arter-

ies slowly over a period of many years rather than

Causes of Death After Acute

suddenly, collateral vessels can develop at the same

Coronary Occlusion

time while the atherosclerosis becomes more and

more severe. Therefore, the person may never experi-

The most common causes of death after acute

ence an acute episode of cardiac dysfunction. But,

myocardial infarction are (1) decreased cardiac output;

eventually, the sclerotic process develops beyond the

(2) damming of blood in the pulmonary blood vessels

limits of even the collateral blood supply to provide

and then death resulting from pulmonary edema; (3)

the needed blood flow, and sometimes the collateral

fibrillation of the heart; and, occasionally, (4) rupture of

blood vessels themselves develop atherosclerosis.

the heart.

When this occurs, the heart muscle becomes severely

limited in its work output, often so much so that the

Decreased Cardiac Output—Systolic Stretch and Cardiac

heart cannot pump even normally required amounts

Shock. When some of the cardiac muscle fibers are not

of blood flow. This is one of the most common causes

functioning and others are too weak to contract with

of the cardiac failure that occurs in vast numbers of

great force, the overall pumping ability of the affected

older people.

ventricle is proportionately depressed. Indeed, the

overall pumping strength of the infarcted heart is often

Myocardial Infarction

decreased more than one might expect because of a

Immediately after an acute coronary occlusion, blood

phenomenon called systolic stretch, shown in Figure

flow ceases in the coronary vessels beyond the occlu-

21-7. That is, when the normal portions of the ventric-

sion except for small amounts of collateral flow from

ular muscle contract, the ischemic portion of the

surrounding vessels. The area of muscle that has either

muscle, whether this be dead or simply nonfunctional,

zero flow or so little flow that it cannot sustain cardiac

instead of contracting is forced outward by the pres-

muscle function is said to be infarcted. The overall

sure that develops inside the ventricle. Therefore,

process is called a myocardial infarction.

Soon after the onset of the infarction, small amounts

of collateral blood begin to seep into the infarcted area,

and this, combined with progressive dilation of local

blood vessels, causes the area to become overfilled with

stagnant blood. Simultaneously the muscle fibers use

the last vestiges of the oxygen in the blood, causing

the hemoglobin to become totally de-oxygenated.

Therefore, the infarcted area takes on a bluish-brown

Normal contraction

hue, and the blood vessels of the area appear to be

engorged despite lack of blood flow. In later stages, the

vessel walls become highly permeable and leak fluid;

Non-functional

muscle

the local muscle tissue becomes edematous, and the

cardiac muscle cells begin to swell because of dimin-

ished cellular metabolism. Within a few hours of almost

no blood supply, the cardiac muscle cells die.

Cardiac muscle requires about

1.3 milliliters of

oxygen per 100 grams of muscle tissue per minute just

to remain alive. This is in comparison with about 8 mil-

liliters of oxygen per

100 grams delivered to the

Systolic stretch

normal resting left ventricle each minute. Therefore, if

there is even 15 to 30 per cent of normal resting

coronary blood flow, the muscle will not die. In the

central portion of a large infarct, however, where

Figure 21-7

there is almost no collateral blood flow, the muscle

does die.

Systolic stretch in an area of ischemic cardiac muscle.

254

Unit IV The Circulation

much of the pumping force of the ventricle is dissi-

increases the irritability of the cardiac

pated by bulging of the area of nonfunctional cardiac

musculature and, therefore, its likelihood of

muscle.

fibrillating.

When the heart becomes incapable of contracting

Ischemia of the muscle causes an “injury current,”

with sufficient force to pump enough blood into the

which is described in Chapter 12 in relation to

peripheral arterial tree, cardiac failure and death of

electrocardiograms in patients with acute

peripheral tissues ensue as a result of peripheral

myocardial infarction. That is, the ischemic

ischemia. This condition is called coronary shock, car-

musculature often cannot completely repolarize

diogenic shock, cardiac shock, or low cardiac output

its membranes after a heart beat, so that the

failure. It is discussed more fully in the next chapter.

external surface of this muscle remains negative

Cardiac shock almost always occurs when more than

with respect to normal cardiac muscle membrane

40 per cent of the left ventricle is infarcted. And death

potential elsewhere in the heart. Therefore,

occurs in about 85 per cent of patients once they

electric current flows from this ischemic area of

develop cardiac shock.

the heart to the normal area and can elicit

abnormal impulses that can cause fibrillation.

Damming of Blood in the Body’s Venous System. When the

Powerful sympathetic reflexes often develop after

heart is not pumping blood forward, it must be

massive infarction, principally because the heart

damming blood in the atria and in the blood vessels

does not pump an adequate volume of blood into

of the lungs or in the systemic circulation. This leads

the arterial tree. The sympathetic stimulation also

to increased capillary pressures, particularly in the

increases irritability of the cardiac muscle and

lungs.

thereby predisposes to fibrillation.

This damming of blood in the veins often causes

Cardiac muscle weakness caused by the

little difficulty during the first few hours after myocar-

myocardial infarction often causes the ventricle to

dial infarction. Instead, symptoms develop a few days

dilate excessively. This increases the pathway length

later for the following reason: The acutely diminished

for impulse conduction in the heart and frequently

cardiac output leads to diminished blood flow to the

causes abnormal conduction pathways all the way

kidneys. Then, for reasons that are discussed in

around the infarcted area of the cardiac muscle.

Chapter 22. the kidneys fail to excrete enough urine.

Both of these effects predispose to development

This adds progressively to the total blood volume and,

of circus movements because, as discussed in

therefore, leads to congestive symptoms. Consequently,

Chapter 13, excess prolongation of conduction

many patients who seemingly are getting along well

pathways in the ventricles allows impulses to re-

during the first few days after onset of heart failure will

enter muscle that is already recovering from

suddenly develop acute pulmonary edema and often

refractoriness, thereby initiating a “circus

will die within a few hours after appearance of the

movement” cycle of new excitation and causing

initial pulmonary symptoms.

the process to continue on and on.

Fibrillation of the Ventricles After Myocardial Infarction.

Rupture of the Infarcted Area. During the first day or so

Many people who die of coronary occlusion die

after an acute infarct, there is little danger of rupture

because of sudden ventricular fibrillation. The ten-

of the ischemic portion of the heart, but a few days

dency to develop fibrillation is especially great after a

later, the dead muscle fibers begin to degenerate, and

large infarction, but fibrillation can sometimes occur

the heart wall becomes stretched very thin. When this

after small occlusions as well. Indeed, some patients

happens, the dead muscle bulges outward severely

with chronic coronary insufficiency die suddenly from

with each heart contraction, and this systolic stretch

fibrillation without any acute infarction.

becomes greater and greater until finally the heart rup-

There are two especially dangerous periods after

tures. In fact, one of the means used in assessing

coronary infarction during which fibrillation is most

progress of severe myocardial infarction is to record

likely to occur. The first is during the first 10 minutes

by cardiac imaging (i.e., x-rays) whether the degree of

after the infarction occurs. Then there is a short period

systolic stretch is worsening.

of relative safety, followed by a secondary period of

When a ventricle does rupture, loss of blood into the

cardiac irritability beginning 1 hour or so later and

pericardial space causes rapid development of cardiac

lasting for another few hours. Fibrillation can also

tamponade—that is, compression of the heart from the

occur many days after the infarct but less likely so.

outside by blood collecting in the pericardial cavity.

At least four factors enter into the tendency for the

Because of this compression of the heart, blood cannot

heart to fibrillate:

flow into the right atrium, and the patient dies of sud-

1. Acute loss of blood supply to the cardiac muscle

denly decreased cardiac output.

causes rapid depletion of potassium from the

ischemic musculature. This also increases the

potassium concentration in the extracellular

Stages of Recovery from Acute

fluids surrounding the cardiac muscle fibers.

Myocardial Infarction

Experiments in which potassium has been injected

into the coronary system have demonstrated that

The upper left part of Figure 21-8 shows the effects of

an elevated extracellular potassium concentration

acute coronary occlusion in a patient with a small area

Chapter 21

Muscle Blood Flow and Cardiac Output During Exercise

255

Mild

heart recovers either partially or almost completely

Mild

ischemia

within a few months.

Non-

Value of Rest in Treating Myocardial Infarction. The degree

functional

of cardiac cellular death is determined by the degree

of ischemia and the workload on the heart muscle.

When the workload is greatly increased, such as during

exercise, in severe emotional strain, or as a result of

Dead fibers

fatigue, the heart needs increased oxygen and other

Nonfunctional

nutrients for sustaining its life. Furthermore, anasto-

motic blood vessels that supply blood to ischemic

areas of the heart must also still supply the areas of

the heart that they normally supply. When the heart

becomes excessively active, the vessels of the normal

musculature become greatly dilated. This allows most

Dead fibers

Fibrous tissue

of the blood flowing into the coronary vessels to flow

Figure 21-8

through the normal muscle tissue, thus leaving little

blood to flow through the small anastomotic channels

Top, Small and large areas of coronary ischemia. Bottom, Stages

into the ischemic area, so that the ischemic condition

of recovery from myocardial infarction.

worsens. This condition is called the “coronary steal”

syndrome. Consequently, one of the most important

factors in the treatment of a patient with myocardial

of muscle ischemia; to the right is shown a heart with

infarction is observance of absolute body rest during

a large area of ischemia. When the area of ischemia is

the recovery process.

small, little or no death of the muscle cells may occur,

but part of the muscle often does become temporarily

nonfunctional because of inadequate nutrition to

Function of the Heart After Recovery

support muscle contraction.

from Myocardial Infarction

When the area of ischemia is large, some of the

muscle fibers in the center of the area die rapidly,

Occasionally, a heart that has recovered from a large

within 1 to 3 hours where there is total cessation of

myocardial infarction returns almost to full functional

coronary blood supply. Immediately around the dead

capability, but more frequently its pumping capability

area is a nonfunctional area, with failure of contrac-

is permanently decreased below that of a healthy

tion and usually failure of impulse conduction. Then,

heart. This does not mean that the person is necessar-

extending circumferentially around the nonfunctional

ily a cardiac invalid or that the resting cardiac output

area is an area that is still contracting but weakly so

is depressed below normal, because the normal heart

because of mild ischemia.

is capable of pumping 300 to 400 per cent more blood

per minute than the body requires during rest—that is,

Replacement of Dead Muscle by Scar Tissue. In the lower

a normal person has a “cardiac reserve” of 300 to 400

part of Figure 21-8, the various stages of recovery after

per cent. Even when the cardiac reserve is reduced to

a large myocardial infarction are shown. Shortly after

as little as 100 per cent, the person can still perform

the occlusion, the muscle fibers in the center of the

normal activity of a quiet, restful type but not strenu-

ischemic area die. Then, during the ensuing days, this

ous exercise that would overload the heart.

area of dead fibers becomes bigger because many of

the marginal fibers finally succumb to the prolonged

Pain in Coronary Heart Disease

ischemia. At the same time, because of enlargement of

collateral arterial channels supplying the outer rim of

Normally, a person cannot “feel” his or her heart, but

the infarcted area, much of the nonfunctional muscle

ischemic cardiac muscle often does cause pain sensa-

recovers. After a few days to three weeks, most of

tion—sometimes severe pain. Exactly what causes this

the nonfunctional muscle becomes functional again or

pain is not known, but it is believed that ischemia

dies—one or the other. In the meantime, fibrous tissue

causes the muscle to release acidic substances, such as

begins developing among the dead fibers because

lactic acid, or other pain-promoting products, such as

ischemia can stimulate growth of fibroblasts and

histamine, kinins, or cellular proteolytic enzymes, that

promote development of greater than normal quanti-

are not removed rapidly enough by the slowly moving

ties of fibrous tissue. Therefore, the dead muscle tissue

coronary blood flow. The high concentrations of these

is gradually replaced by fibrous tissue. Then, because

abnormal products then stimulate pain nerve endings

it is a general property of fibrous tissue to undergo

in the cardiac muscle, sending pain impulses through

progressive contraction and dissolution, the fibrous

sensory afferent nerve fibers into the central nervous

scar may grow smaller over a period of several months

system.

to a year.

Finally, the normal areas of the heart gradually

Angina Pectoris

hypertrophy to compensate at least partially for the

In most people who develop progressive constriction

lost dead cardiac musculature. By these means, the

of their coronary arteries, cardiac pain, called angina

256

Unit IV The Circulation

pectoris, begins to appear whenever the load on the

procedure may provide the patient with normal sur-

heart becomes too great in relation to the available

vival expectation. Conversely, if the heart has already

coronary blood flow. This pain is usually felt beneath

been severely damaged, the bypass procedure is likely

the upper sternum over the heart, and in addition it is

to be of little value.

often referred to distant surface areas of the body,

most commonly to the left arm and left shoulder but

Coronary Angioplasty. Since the 1980s, a procedure has

also frequently to the neck and even to the side of the

been used to open partially blocked coronary vessels

face. The reason for this distribution of pain is that the

before they become totally occluded. This procedure,

heart originates during embryonic life in the neck, as

called coronary artery angioplasty, is the following:

do the arms. Therefore, both the heart and these

A small balloon-tipped catheter, about 1 millimeter in

surface areas of the body receive pain nerve fibers

diameter, is passed under radiographic guidance into

from the same spinal cord segments.

the coronary system and pushed through the partially

Most people who have chronic angina pectoris feel

occluded artery until the balloon portion of the

pain when they exercise or when they experience

catheter straddles the partially occluded point. Then

emotions that increase metabolism of the heart or

the balloon is inflated with high pressure, which

temporarily constrict the coronary vessels because of

markedly stretches the diseased artery. After this pro-

sympathetic vasoconstrictor nerve signals. The pain

cedure is performed, the blood flow through the vessel

usually lasts for only a few minutes. However, some

often increases threefold to fourfold, and more than

patients have such severe and lasting ischemia that the

three quarters of the patients who undergo the proce-

pain is present all the time. The pain is frequently

dure are relieved of the coronary ischemic symptoms

described as hot, pressing, and constricting; it is of such

for at least several years, although many of the patients

quality that it usually makes the patient stop all unnec-

still eventually require coronary bypass surgery.

essary body activity and come to a complete state of

Still newer procedures for opening atherosclerotic

rest.

coronary arteries are constantly in experimental

development. One of these employs a laser beam from

Treatment with Drugs. Several vasodilator drugs, when

the tip of a coronary artery catheter aimed at the

administered during an acute anginal attack, can

atherosclerotic lesion. The laser literally dissolves the

often give immediate relief from the pain. Commonly

lesion without substantially damaging the rest of

used vasodilators are nitroglycerin and other nitrate

the arterial wall.

drugs.

Another development has been a minute metal

A second class of drugs that are used for prolonged

“sleeve” placed inside a coronary artery dilated by

treatment of angina pectoris is the beta blockers,

angioplasty to hold the artery open, thus preventing its

such as propranolol. These drugs block sympathetic

restenosis.

beta adrenergic receptors, which prevents sympathetic

enhancement of heart rate and cardiac metabolism

during exercise or emotional episodes. Therefore,

References

therapy with a beta blocker decreases the need

of the heart for extra metabolic oxygen during

Casscells W, Nahai M, Willerson JT: Vulnerable atheroscle-

stressful conditions. For obvious reasons, this can also

rotic plaque: a multifocal disease. Circulation 107:2072,

reduce the number of anginal attacks as well as their

2003.

severity.

Cohn PF, Fox KM, Daly C: Silent myocardial ischemia.

Circulation 108:1263, 2003.

Dalal H, Evans PH, Campbell JL: Recent developments in

Surgical Treatment of

secondary prevention and cardiac rehabilitation after

acute myocardial infarction. BMJ 328:693, 2004.

Coronary Disease

Freedman SB, Isner JM: Therapeutic angiogenesis for coro-

nary artery disease. Ann Intern Med 136:54, 2002.

Aortic-Coronary Bypass Surgery. In many patients with

Gehlbach BK, Geppert E: The pulmonary manifestations of

coronary ischemia, the constricted areas of the coro-

left heart failure. Chest 125:669, 2004.

nary arteries are located at only a few discrete points

Guyton AC, Jones CE, Coleman TG: Circulatory Pathology:

blocked by atherosclerotic disease, and the coronary

Cardiac Output and Its Regulation. Philadelphia: WB

vessels elsewhere are normal or almost normal. A sur-

Saunders Co, 1973.

gical procedure was developed in the 1960s, called

Hao H, Gabbiani J, Bochaton-Piallat M: Arterial smooth

aortic-coronary bypass, for removing a section of a

muscle cell heterogeneity: implications for atherosclerosis

subcutaneous vein from an arm or leg and then graft-

and restenosis development. Arterioscler Thromb Vasc

Biol 23:1510, 2003.

ing this vein from the root of the aorta to the side of

Hester RL, Hammer LW: Venular-arteriolar communication

a peripheral coronary artery beyond the atheroscle-

in the regulation of blood flow. Am J Physiol 282:R1280,

rotic blockage point. One to five such grafts are usually

2002.

performed, each of which supplies a peripheral coro-

Hochman JS: Cardiogenic shock complicating acute myocar-

nary artery beyond a block.

dial infarction: expanding the paradigm. Circulation 107:

Anginal pain is relieved in most patients. Also, in

2998, 2003.

patients whose hearts have not become too severely

Joyner MJ, Dietz NM: Sympathetic vasodilation in human

damaged before the operation, the coronary bypass

muscle. Acta Physiol Scand 177:329, 2003.

C H A P T E R

Cardiac Failure

One of the most important ailments that must be

treated by the physician is cardiac failure (“heart

failure”). This can result from any heart condition

that reduces the ability of the heart to pump blood.

The cause usually is decreased contractility of the

myocardium resulting from diminished coronary

blood flow. However, failure can also be caused by

damaged heart valves, external pressure around the

heart, vitamin B deficiency, primary cardiac muscle disease, or any other abnor-

mality that makes the heart a hypoeffective pump. In this chapter, we discuss

mainly cardiac failure caused by ischemic heart disease resulting from partial

blockage of the coronary blood vessels. In Chapter 23, we discuss valvular and

congenital heart disease.

Definition of Cardiac Failure. The term “cardiac failure” means simply failure of

the heart to pump enough blood to satisfy the needs of the body.

Dynamics of the Circulation in Cardiac Failure

Acute Effects of Moderate Cardiac Failure

If a heart suddenly becomes severely damaged, such as by myocardial infarc-

tion, the pumping ability of the heart is immediately depressed. As a result, two

main effects occur: (1) reduced cardiac output and (2) damming of blood in the

veins, resulting in increased venous pressure.

The progressive changes in heart pumping effectiveness at different times

after an acute myocardial infarction are shown graphically in Figure 22-1. The

top curve of this figure shows a normal cardiac output curve. Point A on this

curve is the normal operating point, showing a normal cardiac output under

resting conditions of 5 L/min and a right atrial pressure of 0 mm Hg.

Immediately after the heart becomes damaged, the cardiac output curve

becomes greatly lowered, falling to the lowest curve at the bottom of the graph.

Within a few seconds, a new circulatory state is established at point B rather

than point A, illustrating that the cardiac output has fallen to 2 L/min, about

two-fifths normal, whereas the right atrial pressure has risen to +4 mm Hg

because venous blood returning to the heart from the body is dammed up in

the right atrium. This low cardiac output is still sufficient to sustain life for

perhaps a few hours, but it is likely to be associated with fainting. Fortunately,

this acute stage usually lasts for only a few seconds because sympathetic nerve

reflexes occur immediately and compensate, to a great extent, for the damaged

heart, as follows.

Compensation for Acute Cardiac Failure by Sympathetic Nervous Reflexes. When the

cardiac output falls precariously low, many of the circulatory reflexes discussed

in Chapter 18 are immediately activated. The best known of these is the barore-

ceptor reflex, which is activated by diminished arterial pressure. It is probable

that the chemoreceptor reflex, the central nervous system ischemic response,

and even reflexes that originate in the damaged heart also contribute to activat-

ing the sympathetic nervous system. But whatever the reflexes might be, the

sympathetics become strongly stimulated within a few seconds, and the

258

Chapter 22

Cardiac Failure

259

The sympathetic reflexes become maximally devel-

oped in about 30 seconds. Therefore, a person who has

Normal heart

a sudden, moderate heart attack might experience

Partially recovered heart

nothing more than cardiac pain and a few seconds of

fainting. Shortly thereafter, with the aid of the sympa-

Damaged heart + sympathetic stimulation

thetic reflex compensations, the cardiac output may

Acutely damaged heart

return to a level adequate to sustain the person if he

or she remains quiet, although the pain might persist.

Chronic Stage of Failure—Fluid

Retention Helps to Compensate

Cardiac Output

After the first few minutes of an acute heart attack, a

prolonged semi-chronic state begins, characterized

mainly by two events: (1) retention of fluid by the

kidneys and (2) varying degrees of recovery of the

-4

-2

+10 +12 +14

heart itself over a period of weeks to months, as illus-

Right atrial pressure (mm Hg)

trated by the light green curve in Figure 22-1; this was

also discussed in Chapter 21.

Renal Retention of Fluid and Increase in Blood

Figure 22-1

Volume Occur for Hours to Days

Progressive changes in the cardiac output curve after acute

A low cardiac output has a profound effect on renal

myocardial infarction. Both the cardiac output and right atrial pres-

function, sometimes causing anuria when the cardiac

sure change progressively from point A to point D (illustrated by

output falls to one-half to two-thirds normal. In

the black line) over a period of seconds, minutes, days, and

general, the urine output remains reduced below

weeks.

normal as long as the cardiac output and arterial pres-

sure remain significantly less than normal, and urine

output usually does not return all the way to normal

after an acute heart attack until the cardiac output and

parasympathetic nervous signals to the heart become

arterial pressure rise either all the way back to normal

reciprocally inhibited at the same time.

or almost to normal.

Strong sympathetic stimulation has two major

effects on the circulation: first on the heart itself,

and second on the peripheral vasculature. If all the

Moderate Fluid Retention in Cardiac Failure Can Be Beneficial.

ventricular musculature is diffusely damaged but is

Many cardiologists formerly considered fluid retention

still functional, sympathetic stimulation strengthens

always to have a detrimental effect in cardiac failure.

this damaged musculature. If part of the muscle is non-

But it is now known that a moderate increase in body

functional and part of it is still normal, the normal

fluid and blood volume is an important factor in

muscle is strongly stimulated by sympathetic stimula-

helping to compensate for the diminished pumping

tion, in this way partially compensating for the non-

ability of the heart by increasing the venous return.

functional muscle. Thus, the heart, one way or another,

The increased blood volume increases venous return

becomes a stronger pump. This effect is also demon-

in two ways: First, it increases the mean systemic filling

strated in Figure 22-1, showing after sympathetic com-

pressure, which increases the pressure gradient for

pensation about twofold elevation of the very low

causing venous flow of blood toward the heart. Second,

cardiac output curve.

it distends the veins, which reduces the venous resist-

Sympathetic stimulation also increases venous

ance and allows even more ease of flow of blood to the

return because it increases the tone of most of the

heart.

blood vessels of the circulation, especially the veins,

If the heart is not too greatly damaged, this

raising the mean systemic filling pressure to 12 to 14

increased venous return can often fully compensate

mm Hg, almost 100 per cent above normal. As dis-

for the heart’s diminished pumping ability—enough in

cussed in Chapter 20, this increased filling pressure

fact that even when the heart’s pumping ability is

greatly increases the tendency for blood to flow from

reduced to as low as 40 to 50 per cent of normal, the

the veins back into the heart. Therefore, the damaged

increased venous return can often cause an entirely

heart becomes primed with more inflowing blood than

normal cardiac output as long as the person remains

usual, and the right atrial pressure rises still further,

in a quiet resting state.

which helps the heart to pump still larger quantities of

When the heart’s pumping capability is reduced

blood. Thus, in Figure 22-1, the new circulatory state

still more, blood flow to the kidneys finally becomes

is depicted by point C, showing a cardiac output of

too low for the kidneys to excrete enough salt and

4.2 L/min and a right atrial pressure of 5 mm Hg.

water to equal salt and water intake. Therefore, fluid

260

Unit IV The Circulation

retention begins and continues indefinitely, unless

thetic stimulation gradually abates toward normal for

major therapeutic procedures are used to prevent this.

the following reasons: The partial recovery of the

Furthermore, because the heart is already pumping at

heart can elevate the cardiac output curve the same as

its maximum pumping capacity, this excess fluid no

sympathetic stimulation can. Therefore, as the heart

longer has a beneficial effect on the circulation. Instead,

recovers even slightly, the fast pulse rate, cold skin,

severe edema develops throughout the body, which

and pallor resulting from sympathetic stimulation in

can be very detrimental in itself and can lead to death.

the acute stage of cardiac failure gradually disappear.

Detrimental Effects of Excess Fluid Retention in Severe Cardiac

Summary of the Changes That Occur

Failure. In contrast to the beneficial effects of moder-

After Acute Cardiac Failure—

ate fluid retention in cardiac failure, in severe failure

extreme excesses of fluid can have serious physiologi-

“Compensated Heart Failure”

cal consequences. They include (1) overstretching of

the heart, thus weakening the heart still more; (2)

To summarize the events discussed in the past few sec-

filtration of fluid into the lungs, causing pulmonary

tions describing the dynamics of circulatory changes

edema and consequent deoxygenation of the blood;

after an acute, moderate heart attack, we can divide

and (3) development of extensive edema in most parts

the stages into (1) the instantaneous effect of the

of the body. These detrimental effects of excessive fluid

cardiac damage; (2) compensation by the sympathetic

are discussed in later sections of this chapter.

nervous system, which occurs mainly within the first 30

seconds to 1 minute; and (3) chronic compensations

Recovery of the Myocardium After

resulting from partial heart recovery and renal reten-

Myocardial Infarction

tion of fluid. All these changes are shown graphically

After a heart becomes suddenly damaged as a result

by the black curve in Figure 22-1. The progression of

of myocardial infarction, the natural reparative

this curve shows the normal state of the circulation

processes of the body begin immediately to help

(point A), the state a few seconds after the heart attack

restore normal cardiac function. For instance, a new

but before sympathetic reflexes have occurred (point

collateral blood supply begins to penetrate the periph-

B), the rise in cardiac output toward normal caused

eral portions of the infarcted area of the heart, often

by sympathetic stimulation (point C), and final return

causing much of the heart muscle in the fringe areas

of the cardiac output almost exactly to normal after

to become functional again. Also, the undamaged

several days to several weeks of partial cardiac recov-

portion of the heart musculature hypertrophies, in this

ery and fluid retention (point D). This final state is

way offsetting much of the cardiac damage.

called compensated heart failure.

The degree of recovery depends on the type of

Compensated Heart Failure. Note especially in Figure

cardiac damage, and it varies from no recovery to

22-1 that the maximum pumping ability of the partly

almost complete recovery. After acute myocardial

recovered heart, as depicted by the plateau level of the

infarction, the heart ordinarily recovers rapidly during

light green curve, is still depressed to less than one-half

the first few days and weeks and achieves most of its

normal. This demonstrates that an increase in right

final state of recovery within 5 to 7 weeks, although

atrial pressure can maintain the cardiac output at a

mild degrees of additional recovery can continue for

normal level despite continued weakness of the heart.

months.

Thus many people, especially older people, have

normal resting cardiac outputs but mildly to moder-

The Cardiac Output Curve After Partial Recovery. Figure 22-1

ately elevated right atrial pressures because of various

shows function of the partially recovered heart a week

degrees of “compensated heart failure.” These persons

or so after acute myocardial infarction. By this time,

may not know that they have cardiac damage because

considerable fluid has been retained in the body and

the damage often has occurred a little at a time, and

the tendency for venous return has increased

the compensation has occurred concurrently with the

markedly as well; therefore, the right atrial pressure

progressive stages of damage.

has risen even more. As a result, the state of the cir-

When a person is in compensated heart failure, any

culation is now changed from point C to point D, which

attempt to perform heavy exercise usually causes

shows a normal cardiac output of 5 L/min but right

immediate return of the symptoms of acute failure

atrial pressure increased to 6 mm Hg.

because the heart is not able to increase its pumping

Because the cardiac output has returned to normal,

capacity to the levels required for the exercise. There-

renal output of fluid also returns to normal, and no

fore, it is said that the cardiac reserve is reduced in

further fluid retention occurs, except that the retention

compensated heart failure. This concept of cardiac

of fluid that has already occurred continues to maintain

reserve is discussed more fully later in the chapter.

moderate excesses of fluid. Therefore, except for the

high right atrial pressure represented by point D in

this figure, the person now has essentially normal car-

Dynamics of Severe Cardiac Failure—

diovascular dynamics as long as he or she remains at

Decompensated Heart Failure

rest.

If the heart recovers to a significant extent and if

If the heart becomes severely damaged, no amount of

adequate fluid volume has been retained, the sympa-

compensation, either by sympathetic nervous reflexes

Chapter 22

Cardiac Failure

261

or by fluid retention, can make the excessively weak-

circulation continues to rise; this forces progressively

ened heart pump a normal cardiac output. As a con-

increasing quantities of blood from the person’s

sequence, the cardiac output cannot rise high enough

peripheral veins into the right atrium, thus increasing

to make the kidneys excrete normal quantities of fluid.

the right atrial pressure. After 1 day or so, the state of

Therefore, fluid continues to be retained, the person

the circulation changes in Figure 22-2 from point B to

develops more and more edema, and this state of

point C—the right atrial pressure rising to 7 mm Hg

events eventually leads to death. This is called decom-

and the cardiac output to 4.2 L/min. Note again that

pensated heart failure. Thus, the main cause of decom-

the cardiac output is still not high enough to cause

pensated heart failure is failure of the heart to pump

normal renal output of fluid; therefore, fluid continues

sufficient blood to make the kidneys excrete daily the

to be retained. After another day or so, the right atrial

necessary amounts of fluid.

pressure rises to 9 mm Hg, and the circulatory state

becomes that depicted by point D. Still, the cardiac

Graphical Analysis of Decompensated Heart Failure. Figure

output is not enough to establish normal fluid

22-2 shows greatly depressed cardiac output at differ-

balance.

ent times (points A to F) after the heart has become

After another few days of fluid retention, the right

severely weakened. Point A on this curve represents

atrial pressure has risen still further, but by now,

the approximate state of the circulation before any

cardiac function is beginning to decline toward a lower

compensation has occurred, and point B, the state a

level. This decline is caused by overstretch of the heart,

few minutes later after sympathetic stimulation has

edema of the heart muscle, and other factors that

compensated as much as it can but before fluid reten-

diminish the heart’s pumping performance. It is

tion has begun. At this time, the cardiac output has

now clear that further retention of fluid will be more

risen to 4 L/min and the right atrial pressure has risen

detrimental than beneficial to the circulation. Yet the

to 5 mm Hg. The person appears to be in reasonably

cardiac output still is not high enough to bring about

good condition, but this state will not remain stable

normal renal function, so that fluid retention not

because the cardiac output has not risen high enough

only continues but accelerates because of the falling

to cause adequate kidney excretion of fluid; therefore,

cardiac output (and falling arterial pressure that also

fluid retention continues and can eventually be the

occurs). Consequently, within a few days, the state

cause of death. These events can be explained quanti-

of the circulation has reached point F on the curve,

tatively in the following way.

with the cardiac output now less than 2.5 L/min and

Note the straight line in Figure 22-2, at a cardiac

the right atrial pressure 16 mm Hg. This state has

output level of 5 L/min. This is approximately the crit-

approached or reached incompatibility with life, and

ical cardiac output level that is required in the normal

the patient dies. This state of heart failure in which the

adult person to make the kidneys re-establish normal

failure continues to worsen is called decompensated

fluid balance—that is, for the output of salt and water

heart failure.

to be as great as the intake of these. At any cardiac

Thus, one can see from this analysis that failure of

output below this level, all the fluid-retaining mecha-

the cardiac output (and arterial pressure) to rise to the

nisms discussed in the earlier section remain in play

critical level required for normal renal function results

and the body fluid volume increases progressively.

in (1) progressive retention of more and more fluid,

And because of this progressive increase in fluid

which causes (2) progressive elevation of the mean

volume, the mean systemic filling pressure of the

systemic filling pressure, and (3) progressive elevation

of the right atrial pressure until finally the heart is so

overstretched or so edematous that it cannot pump

even moderate quantities of blood and, therefore, fails

completely. Clinically, one detects this serious condi-

Critical cardiac output level

tion of decompensation principally by the progressing

for normal fluid balance

edema, especially edema of the lungs, which leads

to bubbling rales in the lungs and to dyspnea (air

hunger). All clinicians know that lack of appropriate

5.0

therapy when this state of events occurs leads to rapid

2.5

C D E

death.

Treatment of Decompensation. The decompensation

-4

+12

+16

process can often be stopped by (1) strengthening the

Right atrial pressure (mm Hg)

heart in any one of several ways, especially by admin-

istration of a cardiotonic drug, such as digitalis, so that

the heart becomes strong enough to pump adequate

quantities of blood required to make the kidneys func-

Figure 22-2

tion normally again, or (2) administering diuretic drugs

to increase kidney excretion while at the same time

Greatly depressed cardiac output that indicates decompensated

reducing water and salt intake, which brings about a

heart disease. Progressive fluid retention raises the right atrial

pressure over a period of days, and the cardiac output progresses

balance between fluid intake and output despite low

from point A to point F, until death occurs.

cardiac output.

262

Unit IV The Circulation

Both methods stop the decompensation process by

it can cause death by suffocation in 20 to 30 minutes,

re-establishing normal fluid balance, so that at least as

which we discuss more fully later in the chapter.

much fluid leaves the body as enters it.

Mechanism of Action of the Cardiotonic Drugs Such as

Low-Output Cardiac Failure—

Digitalis. Cardiotonic drugs, such as digitalis, when

Cardiogenic Shock

administered to a person with a healthy heart, have

little effect on increasing the contractile strength of

In many instances after acute heart attacks and

the cardiac muscle. However, when administered to a

often after prolonged periods of slow progressive

person with a chronically failing heart, the same drugs

cardiac deterioration, the heart becomes incapable of

can sometimes increase the strength of the failing

pumping even the minimal amount of blood flow

myocardium as much as 50 to 100 per cent. Therefore,

required to keep the body alive. Consequently, all the

they are one of the mainstays of therapy in chronic

body tissues begin to suffer and even to deteriorate,

heart failure.

often leading to death within a few hours to a few days.

Digitalis and other cardiotonic glycosides are

The picture then is one of circulatory shock, as

believed to strengthen heart contraction by increasing

explained in Chapter

24. Even the cardiovascular

the quantity of calcium ions in muscle fibers. In the

system suffers from lack of nutrition, and it, too (along

failing heart muscle, the sarcoplasmic reticulum fails

with the remainder of the body), deteriorates, thus has-

to accumulate normal quantities of calcium and,

tening death. This circulatory shock syndrome caused

therefore, cannot release enough calcium ions into

by inadequate cardiac pumping is called cardiogenic

the free-fluid compartment of the muscle fibers to

shock or simply cardiac shock. Once a person devel-

cause full contraction of the muscle. One effect of dig-

ops cardiogenic shock, the survival rate is often less

italis is to depress the calcium pump of the cell mem-

than 15 per cent.

brane of the cardiac muscle fibers. This pump normally

pumps calcium ions out of the muscle. However, in the

Vicious Circle of Cardiac Deterioration in Cardiogenic Shock.

case of a failing heart, extra calcium is needed to

The discussion of circulatory shock in Chapter 24

increase the muscle contractile force. Therefore, it is

emphasizes the tendency for the heart to become pro-

usually beneficial to depress the calcium pumping

gressively more damaged when its coronary blood

mechanism a moderate amount using digitalis, allow-

supply is reduced during the course of the shock. That

ing the muscle fiber intracellular calcium level to rise

is, the low arterial pressure that occurs during shock

slightly.

reduces the coronary blood supply even more. This

makes the heart still weaker, which makes the arterial

pressure fall still more, which makes the shock still

Unilateral Left Heart Failure

worse, the process eventually becoming a vicious circle

of cardiac deterioration. In cardiogenic shock caused

In the discussions thus far in this chapter, we have con-

by myocardial infarction, this problem is greatly com-

sidered failure of the heart as a whole. Yet, in a large

pounded by already existing coronary vessel blockage.

number of patients, especially those with early acute

For instance, in a healthy heart, the arterial pres-

failure, left-sided failure predominates over right-

sure usually must be reduced below about 45 mm Hg

sided failure, and in rare instances, the right side fails

before cardiac deterioration sets in. However, in a

without significant failure of the left side. Therefore,

heart that already has a blocked major coronary

we need especially to discuss the special features of

vessel, deterioration sets in when the coronary arterial

unilateral heart failure.

pressure falls below 80 to 90 mm Hg. In other words,

When the left side of the heart fails without con-

even a small decrease in arterial pressure can now

comitant failure of the right side, blood continues to

set off a vicious circle of cardiac deterioration. For

be pumped into the lungs with usual right heart vigor,

this reason, in treating myocardial infarction, it is

whereas it is not pumped adequately out of the lungs

extremely important to prevent even short periods of

by the left heart into the systemic circulation. As

hypotension.

a result, the mean pulmonary filling pressure rises

because of shift of large volumes of blood from the sys-

temic circulation into the pulmonary circulation.

Physiology of Treatment. Often a patient dies of cardio-

As the volume of blood in the lungs increases, the

genic shock before the various compensatory

pulmonary capillary pressure increases, and if this rises

processes can return the cardiac output (and arterial

above a value approximately equal to the colloid

pressure) to a life-sustaining level. Therefore, treat-

osmotic pressure of the plasma, about 28 mm Hg, fluid

ment of this condition is one of the most important

begins to filter out of the capillaries into the lung inter-

problems in the management of acute heart attacks.

stitial spaces and alveoli, resulting in pulmonary

Immediate administration of digitalis is often used

edema.

for strengthening the heart if the ventricular muscle

Thus, among the most important problems of left

shows signs of deterioration. Also, infusion of whole

heart failure are pulmonary vascular congestion and

blood, plasma, or a blood pressure-raising drug is used

pulmonary edema. In severe, acute left heart failure,

to sustain the arterial pressure. If the arterial pressure

pulmonary edema occasionally occurs so rapidly that

can be elevated high enough, the coronary blood flow

Chapter 22

Cardiac Failure

263

often will increase enough to prevent the vicious circle

of 13 mm Hg. Thus, severe acute cardiac failure often

of deterioration. And this allows enough time for

causes a fall in peripheral capillary pressure rather than

appropriate compensatory mechanisms in circulatory

a rise. Therefore, animal experiments, as well as expe-

system to correct the shock.

rience in humans, show that acute cardiac failure

Some success has also been achieved in saving the

almost never causes immediate development of peri-

lives of patients in cardiogenic shock by using one of

pheral edema.

the following procedures: (1) surgically removing the

clot in the coronary artery, often in combination with

Long-Term Fluid Retention by the Kidneys—

coronary bypass graft, or (2) catheterizing the blocked

The Cause of Peripheral Edema in Persisting

coronary artery and infusing either streptokinase or

Heart Failure

tissue-type plasminogen activator enzymes that cause

After the first day or so of overall heart failure or of

dissolution of the clot. The results occasionally are

right-ventricular heart failure, peripheral edema does

astounding when one of these procedures is instituted

begin to occur principally because of fluid retention by

within the first hour of cardiogenic shock but of little,

the kidneys. The retention of fluid increases the mean

if any, benefit after 3 hours.

systemic filling pressure, resulting in increased ten-

dency for blood to return to the heart. This elevates

the right atrial pressure to a still higher value and

Edema in Patients with

returns the arterial pressure back toward normal.

Cardiac Failure

Therefore, the capillary pressure now also rises

markedly, thus causing loss of fluid into the tissues and

Inability of Acute Cardiac Failure to Cause Peripheral Edema.

development of severe edema.

Acute left heart failure can cause terrific and rapid

There are three known causes of the reduced renal

congestion of the lungs, with development of pul-

output of urine during cardiac failure, all of which are

monary edema and even death within minutes to

equally important but in different ways.

hours.

Decreased glomerular filtration. A decrease in

However, either left or right heart failure is very

cardiac output has a tendency to reduce the

slow to cause peripheral edema. This can best be

glomerular pressure in the kidneys because

explained by referring to Figure 22-3. When a previ-

of (1) reduced arterial pressure and (2) intense

ously healthy heart acutely fails as a pump, the aortic

sympathetic constriction of the afferent arterioles

pressure falls and the right atrial pressure rises. As the

of the kidney. As a consequence, except in the

cardiac output approaches zero, these two pressures

mildest degrees of heart failure, the glomerular

approach each other at an equilibrium value of about

filtration rate becomes less than normal. It is

13 mm Hg. Capillary pressure also falls from its normal

clear from the discussion of kidney function in

value of 17 mm Hg to the new equilibrium pressure

Chapters 26 through 29 that even a slight decrease

in glomerular filtration often markedly decreases

urine output. When the cardiac output falls to

about one-half normal, this can result in almost

complete anuria.

Activation of the renin-angiotensin system and

Mean aortic pressure

increased reabsorption of water and salt by the

renal tubules. The reduced blood flow to the

Capillary pressure

kidneys causes marked increase in renin secretion

Right atrial pressure

100

by the kidneys, and this in turn causes the

formation of angiotensin, as described in Chapter

19. The angiotensin in turn has a direct effect on

the arterioles of the kidneys to decrease further

the blood flow through the kidneys, which

especially reduces the pressure in the capillaries

13 mm Hg

surrounding the renal tubules, promoting greatly

increased reabsorption of both water and salt

from the tubules. Therefore, loss of water and salt

into the urine decreases greatly, and large

quantities of salt and water accumulate in the

Normal

1/2 Normal

Zero

blood and interstitial fluids everywhere in the

body.

Cardiac output

Increased aldosterone secretion. In the chronic

stage of heart failure, large quantities of

aldosterone are secreted by the adrenal cortex.

Figure 22-3

This results mainly from the effect of angiotensin

to stimulate aldosterone secretion by the adrenal

Progressive changes in mean aortic pressure, peripheral tissue

cortex. But some of the increase in aldosterone

capillary pressure, and right atrial pressure as the cardiac output

falls from normal to zero.

secretion often results from increased plasma

264

Unit IV The Circulation

potassium. Excess potassium is one of the most

5. The peripheral vasodilation increases venous

powerful stimuli known for aldosterone secretion,

return of blood from the peripheral circulation

and the potassium concentration rises in response

still more.

to reduced renal function in cardiac failure.

6. The increased venous return further increases the

The elevated aldosterone level further increases

damming of the blood in the lungs, leading to still

the reabsorption of sodium from the renal

more transudation of fluid, more arterial oxygen

tubules. This in turn leads to a secondary increase

desaturation, more venous return, and so forth.

in water reabsorption for two reasons: First, as the

Thus, a vicious circle has been established.

sodium is reabsorbed, it reduces the osmotic

Once this vicious circle has proceeded beyond a

pressure in the tubules but increases the osmotic

certain critical point, it will continue until death of the

pressure in the renal interstitial fluids; these

patient unless heroic therapeutic measures are used

changes promote osmosis of water into the blood.

within minutes. The types of heroic therapeutic meas-

Second, the absorbed sodium and anions that go

ures that can reverse the process and save the patient’s

with the sodium, mainly chloride ions, increase

life include the following:

the osmotic concentration of the extracellular

1. Putting tourniquets on both arms and legs to

fluid everywhere in the body. This elicits

sequester much of the blood in the veins and,

antidiuretic hormone secretion by the

therefore, decrease the workload on the left side

hypothalamic-posterior pituitary gland system

of the heart

(discussed in Chapter 29). The antidiuretic

2. Bleeding the patient

hormone in turn promotes still greater increase in

3. Giving a rapidly acting diuretic, such as

tubular reabsorption of water.

furosemide, to cause rapid loss of fluid from the

body

4. Giving the patient pure oxygen to breathe to

Role of Atrial Natriuretic Factor to Delay Onset of Cardiac

reverse the blood oxygen desaturation, the heart

Decompensation. Atrial natriuretic factor

(ANF) is a

deterioration, and the peripheral vasodilation

hormone released by the atrial walls of the heart when

5. Giving the patient a rapidly acting cardiotonic

they become stretched. Because heart failure almost

drug, such as digitalis, to strengthen the heart

always causes excessive increase in both the right and

This vicious circle of acute pulmonary edema can

left atrial pressures that stretch the atrial walls, the cir-

proceed so rapidly that death can occur in 20 minutes

culating levels of ANF in the blood increase fivefold

to 1 hour. Therefore, any procedure that is to be suc-

to tenfold in severe heart failure. The ANF in turn has

cessful must be instituted immediately.

a direct effect on the kidneys to increase greatly their

excretion of salt and water. Therefore, ANF plays a

natural role to help prevent extreme congestive symp-

Cardiac Reserve

toms during cardiac failure. The renal effects of ANF

are discussed in Chapter 29.

The maximum percentage that the cardiac output can

increase above normal is called the cardiac reserve.

Acute Pulmonary Edema in Late-Stage Heart

Thus, in the healthy young adult, the cardiac reserve is

Failure—Another Lethal Vicious Circle

300 to 400 per cent. In athletically trained persons, it

A frequent cause of death in heart failure is acute pul-

is occasionally 500 to 600 per cent. But in heart failure,

monary edema occurring in patients who have already

there is no cardiac reserve. As an example of normal

had chronic heart failure for a long time. When this

reserve, during severe exercise the cardiac output of a

occurs in a person without new cardiac damage, it

healthy young adult can rise to about five times

usually is set off by some temporary overload of the

normal; this is an increase above normal of 400 per

heart, such as might result from a bout of heavy exer-

cent—that is, a cardiac reserve of 400 per cent.

cise, some emotional experience, or even a severe cold.

Any factor that prevents the heart from pumping

The acute pulmonary edema is believed to result from

blood satisfactorily will decrease the cardiac reserve.

the following vicious circle:

This can result from ischemic heart disease, primary

1. A temporarily increased load on the already weak

myocardial disease, vitamin deficiency that affects

left ventricle initiates the vicious circle. Because of

cardiac muscle, physical damage to the myocardium,

limited pumping capacity of the left heart, blood

valvular heart disease, and many other factors, some of

begins to dam up in the lungs.

which are shown in Figure 22-4.

2. The increased blood in the lungs elevates the

pulmonary capillary pressure, and a small amount

Diagnosis of Low Cardiac Reserve—Exercise Test. As long as

of fluid begins to transude into the lung tissues

persons with low cardiac reserve remain in a state of

and alveoli.

rest, they usually will not know that they have heart

3. The increased fluid in the lungs diminishes the

disease. However, a diagnosis of low cardiac reserve

degree of oxygenation of the blood.

usually can be easily made by requiring the person to

4. The decreased oxygen in the blood further

exercise either on a treadmill or by walking up and

weakens the heart and also weakens the arterioles

down steps, either of which requires greatly increased

everywhere in the body, thus causing peripheral

cardiac output. The increased load on the heart rapidly

vasodilation.

uses up the small amount of reserve that is available,

Chapter 22

Cardiac Failure

265

Athlete

Normal

600

500

Normal

Mild

400

valvular

disease

300

Moderate

coronary

200

disease

Diphtheria

Severe

-4

-2

100

coronary

valvular

Right atrial pressure (mm Hg)

thrombosis

disease

Normal

operation

Figure 22-5

Progressive changes in cardiac output and right atrial pressure

during different stages of cardiac failure.

Figure 22-4

Cardiac reserve in different conditions, showing less than zero

reserve for two of the conditions.

and the cardiac output soon fails to rise high enough

circulation. The two curves passing through Point A

to sustain the body’s new level of activity. The acute

are (1) the normal cardiac output curve and (2) the

effects are as follows:

normal venous return curve. As pointed out in Chapter

1. Immediate and sometimes extreme shortness of

20, there is only one point on each of these two curves

breath (dyspnea) resulting from failure of the

at which the circulatory system can operate. This point

heart to pump sufficient blood to the tissues,

is where the two curves cross at point A. Therefore, the

thereby causing tissue ischemia and creating a

normal state of the circulation is a cardiac output and

sensation of air hunger

venous return of 5 L/min and a right atrial pressure of

2. Extreme muscle fatigue resulting from muscle

0 mm Hg.

ischemia, thus limiting the person’s ability to

continue with the exercise

Effect of Acute Heart Attack. During the first few seconds

3. Excessive increase in heart rate because the

after a moderately severe heart attack, the cardiac

nervous reflexes to the heart overreact in an

output curve falls to the lowermost curve. During these

attempt to overcome the inadequate cardiac

few seconds, the venous return curve still has not

output

changed because the peripheral circulatory system is

Exercise tests are part of the armamentarium of the

still operating normally. Therefore, the new state of the

cardiologist. These tests take the place of cardiac

circulation is depicted by point B, where the new

output measurements that cannot be made with ease

cardiac output curve crosses the normal venous return

in most clinical settings.

curve. Thus, the right atrial pressure rises immedi-

ately to 4 mm Hg, whereas the cardiac output falls to

2 L/min.

Quantitative Graphical Method for

Analysis of Cardiac Failure

Effect of Sympathetic Reflexes. Within the next

Although it is possible to understand most general

seconds, the sympathetic reflexes become very active.

principles of cardiac failure using mainly qualitative

They affect both the cardiac output and the venous

logic, as we have done thus far in this chapter, one can

return curves, raising both of them. Sympathetic stim-

grasp the importance of the different factors in cardiac

ulation can increase the plateau level of the cardiac

failure with far greater depth by using more quantita-

output curve as much as 30 to 100 per cent. It can also

tive approaches. One such approach is the graphical

increase the mean systemic filling pressure (depicted

method for analysis of cardiac output regulation intro-

by the point where the venous return curve crosses the

duced in Chapter 20. In the remaining sections of this

zero venous return axis) by several millimeters of

chapter, we analyze several aspects of cardiac failure,

mercury—in this figure, from a normal value of 7 mm

using this graphical technique.

Hg up to 10 mm Hg. This increase in mean systemic

filling pressure shifts the entire venous return curve to

Graphical Analysis of Acute Heart Failure and

the right and upward. The new cardiac output and

Chronic Compensation

venous return curves now equilibrate at point C, that

Figure 22-5 shows cardiac output and venous return

is, at a right atrial pressure of +5 mm Hg and a cardiac

curves for different states of the heart and peripheral

output of 4 L/min.

266

Unit IV The Circulation

Compensation During the Next Few Days. During the

curve to this low level. At point A, the curve at time

ensuing week, the cardiac output and venous return

zero equates with the normal venous return curve to

curves rise further because of (1) some recovery of the

give a cardiac output of about 3 L/min. However, stim-

heart and (2) renal retention of salt and water, which

ulation of the sympathetic nervous system, caused by

raises the mean systemic filling pressure still further—

this low cardiac output, increases the mean systemic

this time up to +12 mm Hg. The two new curves now

filling pressure within 30 seconds from 7 to 10.5 mm

equilibrate at point D. Thus, the cardiac output has

Hg. This shifts the venous return curve upward and to

now returned to normal. The right atrial pressure,

the right to produce the curve labeled “autonomic

however, has risen still further to +6 mm Hg. Because

compensation.” Thus, the new venous return curve

the cardiac output is now normal, renal output is also

equates with the cardiac output curve at point B. The

normal, so that a new state of equilibrated fluid

cardiac output has been improved to a level of 4 L/min

balance has been achieved. The circulatory system will

but at the expense of an additional rise in right atrial

continue to function at point D and remain stable, with

pressure to 5 mm Hg.

a normal cardiac output and an elevated right atrial

The cardiac output of 4 L/min is still too low to cause

pressure, until some additional extrinsic factor changes

the kidneys to function normally. Therefore, fluid con-

either the cardiac output curve or the venous return

tinues to be retained, and the mean systemic filling

curve.

pressure rises from 10.5 to almost 13 mm Hg. Now the

Using this technique for analysis, one can see espe-

venous return curve becomes that labeled “2nd day”

cially the importance of moderate fluid retention and

and equilibrates with the cardiac output curve at point

how it eventually leads to a new stable state of the cir-

C. The cardiac output rises to 4.2 L/min and the right

culation in mild to moderate heart failure. And one

atrial pressure to 7 mm Hg.

can also see the interrelation between mean systemic

During the succeeding days, the cardiac output

filling pressure and cardiac pumping at various

never rises quite high enough to re-establish normal

degrees of heart failure.

renal function. Fluid continues to be retained, the

Note that the events described in Figure 22-5 are

mean systemic filling pressure continues to rise, the

the same as those presented in Figure 22-1, but in

venous return curve continues to shift to the right, and

Figure 22-5, they are presented in a more quantitative

the equilibrium point between the venous return curve

manner.

and the cardiac output curve also shifts progressively

to point D, to point E, and, finally, to point F. The equi-

Graphical Analysis of “Decompensated”

libration process is now on the down slope of the

Cardiac Failure

cardiac output curve, so that further retention of fluid

The black cardiac output curve in Figure 22-6 is the

causes only more severe cardiac edema and a detri-

same as the curve shown in Figure 22-2, a very low

mental effect on cardiac output. The condition accel-

curve that has already reached a degree of recovery as

erates downhill until death occurs.

great as this heart can achieve. In this figure, we have

Thus, “decompensation” results from the fact that

added venous return curves that occur during succes-

the cardiac output curve never rises to the critical level

sive days after the acute fall of the cardiac output

of 5 L/min needed to re-establish normal kidney excre-

tion of fluid that would be required to cause balance

between fluid input and output.

Treatment of Decompensated Heart Disease with Digitalis. Let

us assume that the stage of decompensation has

already reached point E in Figure 22-6, and let us

proceed to the same point E in Figure 22-7. At this

time, digitalis is given to strengthen the heart. This

raises the cardiac output curve to the level shown in

Critical cardiac

Figure 22-7, but there is not an immediate change in

output level

the venous return curve. Therefore, the new cardiac

for normal

fluid balance

output curve equates with the venous return curve at

point G. The cardiac output is now 5.7 L/min, a value

C D

greater than the critical level of 5 liters required to

A B

make the kidneys excrete normal amounts of urine.

Therefore, the kidneys eliminate much more fluid than

-4

-2

normally, causing diuresis, a well-known therapeutic

Right atrial pressure (mm Hg)

effect of digitalis.

The progressive loss of fluid over a period of several

days reduces the mean systemic filling pressure back

down to 11.5 mm Hg, and the new venous return curve

Figure 22-6

becomes the curve labeled “Several days later.” This

curve equates with the cardiac output curve of the

Graphical analysis of decompensated heart disease showing

digitalized heart at point H, at an output of 5 L/min

progressive shift of the venous return curve to the right as a result

of continued fluid retention.

and a right atrial pressure of 4.6 mm Hg. This cardiac

Chapter 22

Cardiac Failure

267

Critical cardiac output

level for normal

fluid balance

Normal

Normal cardiac

venous

output curve

return

curve

-4

-2

Right atrial pressure (mm Hg)

Beriberi

heart

disease

Figure 22-7

-4 -2

Right atrial pressure (mm Hg)

Treatment of decompensated heart disease showing the effect of

digitalis in elevating the cardiac output curve, this in turn causing

increased urine output and progressive shift of the venous return

curve to the left.

Figure 22-8

Graphical analysis of two types of conditions that can cause high-

output cardiac failure:

(1) arteriovenous

(AV) fistula and

(2)

output is precisely that required for normal fluid

beriberi heart disease.

balance. Therefore, no additional fluid will be lost and

none will be gained. Consequently, the circulatory

system has now stabilized, or in other words, the

decompensation of the heart failure has been “com-

pensated.” And to state this another way, the final

steady-state condition of the circulation is defined by

is slightly elevated, and there are mild signs of periph-

the crossing point of three curves: the cardiac output

eral congestion. If the person attempts to exercise, he

curve, the venous return curve, and the critical level

or she will have little cardiac reserve because the heart

for normal fluid balance. The compensatory mecha-

is already being used almost to maximum capacity to

nisms automatically stabilize the circulation when all

pump the extra blood through the arteriovenous

three curves cross at the same point.

fistula. This condition resembles a failure condition

and is called “high-output failure,” but in reality, the

Graphical Analysis of High-Output

heart is overloaded by excess venous return.

Cardiac Failure

Figure 22-8 gives an analysis of two types of high-

Beriberi. Figure 22-8 shows the approximate changes

output cardiac failure. One of these is caused by an

in the cardiac output and venous return curves caused

arteriovenous fistula that overloads the heart because

by beriberi. The decreased level of the cardiac output

of excessive venous return, even though the pumping

curve is caused by weakening of the heart because of

capability of the heart is not depressed. The other is

the avitaminosis (mainly lack of thiamine) that causes

caused by beriberi, in which the venous return is

the beriberi syndrome. The weakening of the heart has

greatly increased because of diminished systemic vas-

decreased the blood flow to the kidneys. Therefore, the

cular resistance, but at the same time, the pumping

kidneys have retained a large amount of extra body

capability of the heart is depressed.

fluid, which in turn has increased the mean systemic

filling pressure (represented by the point where the

Arteriovenous Fistula. The

“normal” curves of Figure

venous return curve now intersects the zero cardiac

22-8 depict the normal cardiac output and normal

output level) from the normal value of 7 mm Hg up to

venous return curves. These equate with each other at

11 mm Hg. This has shifted the venous return curve to

point A, which depicts a normal cardiac output of 5 L/

the right. Finally, the venous return curve has rotated

min and a normal right atrial pressure of 0 mm Hg.

upward from the normal curve because the avita-

Now let us assume that the systemic resistance (the

minosis has dilated the peripheral blood vessels, as

total peripheral resistance) becomes greatly decreased

explained in Chapter 17.

because of opening a large arteriovenous fistula (a

The two blue curves (cardiac output curve and

direct opening between a large artery and a large

venous return curve) intersect with each other at

vein). The venous return curve rotates upward to give

point C, which describes the circulatory condition in

the curve labeled “AV fistula.” This venous return

beriberi, with a right atrial pressure in this instance of

curve equates with the normal cardiac output curve at

9 mm Hg and a cardiac output about 65 per cent above

point B, with a cardiac output of 12.5 L/min and a right

normal; this high cardiac output occurs despite the

atrial pressure of 3 mm Hg. Thus, the cardiac output

weak heart, as demonstrated by the depressed plateau

has become greatly elevated, the right atrial pressure

level of the cardiac output curve.

268

Unit IV The Circulation

References

Lohmeier TE: Neurohumoral regulation of arterial pressure

in hemorrhage and heart failure. Am J Physiol Regul

Integr Comp Physiol 283:R810, 2002.

Andrew P: Diastolic heart failure demystified. Chest 124:744,

Mehra MR, Gheorghiade M, Bonow RO: Mitral regurgita-

2003.

tion in chronic heart failure: more questions than answers?

Braunwald E, Zipes DP, Liby P: A Textbook for Cardiovas-

Curr Cardiol Rep 6:96, 2004.

cular Medicine. 6th Ed. Philadelphia: WB Saunders Co,

McMurray J, Pfeffer MA: New therapeutic options in con-

2001.

gestive heart failure: Part I. Circulation 105:2099, 2002.

Dorn GW 2nd, Molkentin JD: Manipulating cardiac con-

McMurray J, Pfeffer MA: New therapeutic options in con-

tractility in heart failure: data from mice and men. Circu-

gestive heart failure: Part II. Circulation 105:2223, 2002

lation 109:150, 2004.

Pfisterer M: Right ventricular involvement in myocardial

Ducas J, Grech ED: ABC of interventional cardiology. Per-

infarction and cardiogenic shock. Lancet 362:392, 2003.

cutaneous coronary intervention: cardiogenic shock. BMJ

Ruskoaho H: Cardiac hormones as diagnostic tools in heart

326:1450, 2003.

failure. Endocr Rev 24:341, 2003.

Eikelboom J, White H, Yusuf S: The evolving role of direct

Shlipak MG: Pharmacotherapy for heart failure in patients

thrombin inhibitors in acute coronary syndromes. J Am

with renal insufficiency. Ann Intern Med 138:917, 2003.

Coll Cardiol 41(4 Suppl S):70S, 2003.

Sjaastad I, Wasserstrom JA, Sejersted OM: Heart failure—

Floras JS: Sympathetic activation in human heart failure:

a challenge to our current concepts of excitation-

diverse mechanisms, therapeutic opportunities. Acta

contraction coupling. J Physiol 546:33, 2003.

Physiol Scand 177:391, 2003.

Spodick DH: Acute cardiac tamponade. N Engl J Med

Gavras H, Brunner HR: Role of angiotensin and its inhibi-

349:684, 2003.

tion in hypertension, ischemic heart disease, and heart

Zile MR, Brutsaert DL: New concepts in diastolic dysfunc-

failure. Hypertension 37:342, 2001.

tion and diastolic heart failure: Part I: diagnosis, progno-

Gehlbach BK, Geppert E: The pulmonary manifestations of

sis, and measurements of diastolic function. Circulation

left heart failure. Chest 125:669, 2004.

105:1387, 2002.

Guyton AC, Jones CE, Coleman TG: Circulatory Physiology:

Zile MR, Brutsaert DL: New concepts in diastolic dysfunc-

Cardiac Output and Its Regulation. Philadelphia: WB

tion and diastolic heart failure: Part II: causal mechanisms

Saunders Co, 1973.

and treatment. Circulation 105:1503, 2002.

Hochman JS: Cardiogenic shock complicating acute myocar-

dial infarction: expanding the paradigm. Circulation 107:

2998, 2003.

C H A P T E R

Heart Valves and Heart Sounds;

Dynamics of Valvular and

Congenital Heart Defects

Function of the heart valves was discussed in

Chapter 9, where it was pointed out that closing of

the valves causes audible sounds. Ordinarily, no

audible sounds occur when the valves open. In this

chapter, we first discuss the factors that cause the

sounds in the heart under normal and abnormal

conditions. Then we discuss what happens in the

overall circulatory system when valvular or congen-

ital heart defects are present.

Heart Sounds

Normal Heart Sounds

Listening with a stethoscope to a normal heart, one hears a sound usually

described as “lub, dub, lub, dub.” The “lub” is associated with closure of the atrio-

ventricular (A-V) valves at the beginning of systole, and the “dub” is associated

with closure of the semilunar (aortic and pulmonary) valves at the end of

systole. The “lub” sound is called the first heart sound, and the “dub” is called

the second heart sound, because the normal pumping cycle of the heart is con-

sidered to start when the A-V valves close at the onset of ventricular systole.

Causes of the First and Second Heart Sounds. The earliest explanation for the cause

of the heart sounds was that the “slapping” together of the valve leaflets sets

up vibrations. However, this has been shown to cause little, if any, of the sound,

because the blood between the leaflets cushions the slapping effect and pre-

vents significant sound. Instead, the cause is vibration of the taut valves imme-

diately after closure, along with vibration of the adjacent walls of the heart and

major vessels around the heart. That is, in generating the first heart sound, con-

traction of the ventricles first causes sudden backflow of blood against the

A-V valves (the tricuspid and mitral valves), causing them to close and bulge

toward the atria until the chordae tendineae abruptly stop the back bulging.

The elastic tautness of the chordae tendineae and of the valves then causes the

back surging blood to bounce forward again into each respective ventricle. This

causes the blood and the ventricular walls, as well as the taut valves, to vibrate

and causes vibrating turbulence in the blood. The vibrations travel through the

adjacent tissues to the chest wall, where they can be heard as sound by using

the stethoscope.

The second heart sound results from sudden closure of the semilunar valves

at the end of systole. When the semilunar valves close, they bulge backward

toward the ventricles, and their elastic stretch recoils the blood back into the

arteries, which causes a short period of reverberation of blood back and forth

between the walls of the arteries and the semilunar valves, as well as between

these valves and the ventricular walls. The vibrations occurring in the arterial

walls are then transmitted mainly along the arteries. When the vibrations of the

vessels or ventricles come into contact with a “sounding board,” such as the

chest wall, they create sound that can be heard.

269

270

Unit IV The Circulation

Duration and Pitch of the First and Second Heart Sounds. The

third of diastole. A logical but unproved explanation

duration of each of the heart sounds is slightly more

of this sound is oscillation of blood back and forth

than 0.10 second—the first sound about 0.14 second,

between the walls of the ventricles initiated by inrush-

and the second about 0.11 second. The reason for the

ing blood from the atria. This is analogous to running

shorter second sound is that the semilunar valves are

water from a faucet into a paper sack, the inrushing

more taut than the A-V valves, so that they vibrate for

water reverberating back and forth between the walls

a shorter time than do the A-V valves.

of the sack to cause vibrations in its walls. The reason

The audible range of frequency (pitch) in the first

the third heart sound does not occur until the middle

and second heart sounds, as shown in Figure 23-1,

third of diastole is believed to be that in the early part

begins at the lowest frequency the ear can detect,

of diastole, the ventricles are not filled sufficiently to

about 40 cycles/sec, and goes up above 500 cycles/sec.

create even the small amount of elastic tension neces-

When special electronic apparatus is used to record

sary for reverberation. The frequency of this sound is

these sounds, by far a larger proportion of the re-

usually so low that the ear cannot hear it, yet it can

corded sound is at frequencies and sound levels below

often be recorded in the phonocardiogram.

the audible range, going down to 3 to 4 cycles/sec and

peaking at about 20 cycles/sec, as illustrated by the

Atrial Heart Sound (Fourth Heart Sound). An atrial heart

lower shaded area in Figure 23-1. For this reason,

sound can sometimes be recorded in the phonocar-

major portions of the heart sounds can be recorded

diogram, but it can almost never be heard with a

electronically in phonocardiograms even though they

stethoscope because of its weakness and very low

cannot be heard with a stethoscope.

frequency—usually 20 cycles/sec or less. This sound

The second heart sound normally has a higher fre-

occurs when the atria contract, and presumably, it is

quency than the first heart sound for two reasons: (1)

caused by the inrush of blood into the ventricles, which

the tautness of the semilunar valves in comparison

initiates vibrations similar to those of the third heart

with the much less taut A-V valves, and (2) the greater

sound.

elastic coefficient of the taut arterial walls that provide

the principal vibrating chambers for the second sound,

Chest Surface Areas for Auscultation

in comparison with the much looser, less elastic ven-

of Normal Heart Sounds

tricular chambers that provide the vibrating system for

Listening to the sounds of the body, usually with the

the first heart sound. The clinician uses these differ-

aid of a stethoscope, is called auscultation. Figure 23-2

ences to distinguish special characteristics of the two

shows the areas of the chest wall from which the dif-

respective sounds.

ferent heart valvular sounds can best be distinguished.

Although the sounds from all the valves can be heard

Third Heart Sound. Occasionally a weak, rumbling third

from all these areas, the cardiologist distinguishes

heart sound is heard at the beginning of the middle

the sounds from the different valves by a process of

Heart sounds

Inaudible and murmurs

Aortic area

Pulmonic area

100

Speech

area

0.1

Heart sounds

0.01

and murmurs

0.001

0.0001

64 128 256 5121024 2048 4096

Frequency in cycles per second

Figure 23-1

Amplitude of different-frequency vibrations in the heart sounds

and heart murmurs in relation to the threshold of audibility,

Tricuspid area

Mitral area

showing that the range of sounds that can be heard is between

40 and 520 cycles/sec. (Modified from Butterworth JS, Chassin

Figure 23-2

JL, McGrath JJ: Cardiac Auscultation, 2nd ed. New York: Grune

& Stratton, 1960.)

Chest areas from which sound from each valve is best heard.

Chapter 23

Heart Valves and Heart Sounds; Dynamics of Valvular and Congenital Heart Defects

271

Valvular Lesions

1st

2nd

3rd

Atrial

Rheumatic Valvular Lesions

By far the greatest number of valvular lesions results

Normal

from rheumatic fever. Rheumatic fever is an autoim-

mune disease in which the heart valves are likely to be

damaged or destroyed. It is usually initiated by strep-

Aortic stenosis

tococcal toxin in the following manner.

The sequence of events almost always begins with a

preliminary streptococcal infection caused specifically

Mitral regurgitation

by group A hemolytic streptococci. These bacteria ini-

tially cause a sore throat, scarlet fever, or middle ear

infection. But the streptococci also release several dif-

Aortic regurgitation

ferent proteins against which the person’s reticuloen-

dothelial system produces antibodies. The antibodies

Mitral stenosis

react not only with the streptococcal protein but also

with other protein tissues of the body, often causing

severe immunologic damage. These reactions continue

to take place as long as the antibodies persist in the

Patent ductus

blood—1 year or more.

arteriosus

Rheumatic fever causes damage especially in

Diastole

Systole

Diastole

Systole

certain susceptible areas, such as the heart valves. The

degree of heart valve damage is directly correlated

with the concentration and persistence of the anti-

bodies. The principles of immunity that relate to this

Figure 23-3

type of reaction are discussed in Chapter 34, and it is

noted in Chapter 31 that acute glomerular nephritis of

Phonocardiograms from normal and abnormal hearts.

the kidneys has a similar immunologic basis.

In rheumatic fever, large hemorrhagic, fibrinous,

bulbous lesions grow along the inflamed edges of

the heart valves. Because the mitral valve receives

more trauma during valvular action than any of the

elimination. That is, he or she moves the stethoscope

other valves, it is the one most often seriously

from one area to another, noting the loudness of the

damaged, and the aortic valve is second most fre-

sounds in different areas and gradually picking out the

quently damaged. The right heart valves, the tricuspid

sound components from each valve.

and pulmonary valves, are usually affected much less

The areas for listening to the different heart sounds

severely, probably because the low-pressure stresses

are not directly over the valves themselves. The aortic

that act on these valves are slight compared with

area is upward along the aorta because of sound trans-

the high-pressure stresses that act on the left heart

mission up the aorta, and the pulmonic area is upward

valves.

along the pulmonary artery. The tricuspid area is over

the right ventricle, and the mitral area is over the apex

Scarring of the Valves. The lesions of acute rheumatic

of the left ventricle, which is the portion of the heart

fever frequently occur on adjacent valve leaflets simul-

nearest the surface of the chest; the heart is rotated

taneously, so that the edges of the leaflets become

so that the remainder of the left ventricle lies more

stuck together. Then, weeks, months, or years later, the

posteriorly.

lesions become scar tissue, permanently fusing por-

tions of adjacent valve leaflets. Also, the free edges of

Phonocardiogram

the leaflets, which are normally filmy and free-flapping,

If a microphone specially designed to detect low-fre-

often become solid, scarred masses.

quency sound is placed on the chest, the heart sounds

A valve in which the leaflets adhere to one another

can be amplified and recorded by a high-speed record-

so extensively that blood cannot flow through it nor-

ing apparatus. The recording is called a phonocardio-

mally is said to be stenosed. Conversely, when the valve

gram, and the heart sounds appear as waves, as shown

edges are so destroyed by scar tissue that they cannot

schematically in Figure

23-3. Recording A is an

close as the ventricles contract, regurgitation (back-

example of normal heart sounds, showing the vibra-

flow) of blood occurs when the valve should be closed.

tions of the first, second, and third heart sounds and

Stenosis usually does not occur without the coexis-

even the very weak atrial sound. Note specifically that

tence of at least some degree of regurgitation, and vice

the third and atrial heart sounds are each a very low

versa.

rumble. The third heart sound can be recorded in only

one third to one half of all people, and the atrial heart

Other Causes of Valvular Lesions. Stenosis or lack of one

sound can be recorded in perhaps one fourth of all

or more leaflets of a valve also occurs occasionally as

people.

a congenital defect. Complete lack of leaflets is rare;

272

Unit IV The Circulation

congenital stenosis is more common, as is discussed

frequency, so that most of the sound spectrum is below

later in this chapter.

the low-frequency end of human hearing.

During the early part of diastole, a left ventricle with

Heart Murmurs Caused by Valvular Lesions

a stenotic mitral valve has so little blood in it and its

As shown by the phonocardiograms in Figure 23-3,

walls are so flabby that blood does not reverberate

many abnormal heart sounds, known as

“heart

back and forth between the walls of the ventricle. For

murmurs,” occur when there are abnormalities of the

this reason, even in severe mitral stenosis, no murmur

valves, as follows.

may be heard during the first third of diastole. Then,

after partial filling, the ventricle has stretched enough

Systolic Murmur of Aortic Stenosis. In aortic stenosis,

for blood to reverberate, and a low rumbling murmur

blood is ejected from the left ventricle through only a

begins.

small fibrous opening of the aortic valve. Because of

the resistance to ejection, sometimes the blood pres-

Phonocardiograms of Valvular Murmurs. Phonocardio-

sure in the left ventricle rises as high as 300 mm Hg,

grams B, C, D, and E of Figure 23-3 show, respectively,

while the pressure in the aorta is still normal. Thus,

idealized records obtained from patients with aortic

a nozzle effect is created during systole, with blood

stenosis, mitral regurgitation, aortic regurgitation, and

jetting at tremendous velocity through the small

mitral stenosis. It is obvious from these phonocardio-

opening of the valve. This causes severe turbulence of

grams that the aortic stenotic lesion causes the loudest

the blood in the root of the aorta. The turbulent blood

murmur, and the mitral stenotic lesion causes the

impinging against the aortic walls causes intense vibra-

weakest. The phonocardiograms show how the inten-

tion, and a loud murmur (see recording B, Figure 23-3)

sity of the murmurs varies during different portions of

occurs during systole and is transmitted throughout

systole and diastole, and the relative timing of each

the superior thoracic aorta and even into the large

murmur is also evident. Note especially that the

arteries of the neck. This sound is harsh and in severe

murmurs of aortic stenosis and mitral regurgitation

stenosis may be so loud that it can be heard several

occur only during systole, whereas the murmurs of

feet away from the patient. Also, the sound vibrations

aortic regurgitation and mitral stenosis occur only

can often be felt with the hand on the upper chest and

during diastole. If the reader does not understand this

lower neck, a phenomenon known as a “thrill.”

timing, extra review should be undertaken until it is

understood.

Diastolic Murmur of Aortic Regurgitation. In aortic regurgi-

tation, no abnormal sound is heard during systole,

but during diastole, blood flows backward from the

Abnormal Circulatory

high-pressure aorta into the left ventricle, causing

Dynamics in Valvular

a “blowing” murmur of relatively high pitch with a

Heart Disease

swishing quality heard maximally over the left ventri-

cle (see recording D, Figure 23-3). This murmur results

from turbulence of blood jetting backward into the

Dynamics of the Circulation in Aortic

blood already in the low-pressure diastolic left

Stenosis and Aortic Regurgitation

ventricle.

In aortic stenosis, the contracting left ventricle fails to

Systolic Murmur of Mitral Regurgitation. In mitral regurgi-

empty adequately, whereas in aortic regurgitation,

tation, blood flows backward through the mitral valve

blood flows backward into the ventricle from the aorta

into the left atrium during systole. This also causes a

after the ventricle has just pumped the blood into the

high-frequency “blowing,” swishing sound (see record-

aorta. Therefore, in either case, the net stroke volume

ing C, Figure 23-3) similar to that of aortic regurgita-

output of the heart is reduced.

tion but occurring during systole rather than diastole.

Several important compensations take place that

It is transmitted most strongly into the left atrium.

can ameliorate the severity of the circulatory defects.

However, the left atrium is so deep within the chest

Some of these compensations are the following.

that it is difficult to hear this sound directly over the

atrium. As a result, the sound of mitral regurgitation

Hypertrophy of the Left Ventricle. In both aortic stenosis

is transmitted to the chest wall mainly through the left

and aortic regurgitation, the left ventricular muscula-

ventricle to the apex of the heart.

ture hypertrophies because of the increased ventricu-

lar workload.

Diastolic Murmur of Mitral Stenosis. In mitral stenosis,

In regurgitation, the left ventricular chamber also

blood passes with difficulty through the stenosed

enlarges to hold all the regurgitant blood from the

mitral valve from the left atrium into the left ventri-

aorta. Sometimes the left ventricular muscle mass

cle, and because the pressure in the left atrium seldom

increases fourfold to fivefold, creating a tremendously

rises above 30 mm Hg, a large pressure differential

large left side of the heart.

forcing blood from the left atrium into the left ventri-

When the aortic valve is seriously stenosed, the

cle does not develop. Consequently, the abnormal

hypertrophied muscle allows the left ventricle to

sounds heard in mitral stenosis

(see recording E,

develop as much as 400 mm Hg intraventricular pres-

Figure

23-3) are usually weak and of very low

sure at systolic peak.

Chapter 23

Heart Valves and Heart Sounds; Dynamics of Valvular and Congenital Heart Defects

273

In severe aortic regurgitation, sometimes the hyper-

development of serious pulmonary edema. Ordinarily,

trophied muscle allows the left ventricle to pump a

lethal edema does not occur until the mean left atrial

stroke volume output as great as

250 milliliters,

pressure rises above 25 mm Hg and sometimes as high

although as much as three fourths of this blood returns

as 40 mm Hg, because the lung lymphatic vasculature

to the ventricle during diastole, and only one fourth

enlarges manyfold and can carry fluid away from the

flows through the aorta to the body.

lung tissues extremely rapidly.

Increase in Blood Volume. Another effect that helps

Enlarged Left Atrium and Atrial Fibrillation. The high left

compensate for the diminished net pumping by the left

atrial pressure in mitral valvular disease also causes

ventricle is increased blood volume. This results from

progressive enlargement of the left atrium, which

(1) an initial slight decrease in arterial pressure, plus

increases the distance that the cardiac electrical exci-

(2) peripheral circulatory reflexes that the decrease in

tatory impulse must travel in the atrial wall. This

pressure induces. These together diminish renal output

pathway may eventually become so long that it pre-

of urine, causing the blood volume to increase and

disposes to development of excitatory signal circus

the mean arterial pressure to return to normal. Also,

movements, as discussed in Chapter 13. Therefore,

red cell mass eventually increases because of a slight

in late stages of mitral valvular disease, especially in

degree of tissue hypoxia.

mitral stenosis, atrial fibrillation usually occurs. This

The increase in blood volume tends to increase

further reduces the pumping effectiveness of the heart

venous return to the heart. This, in turn, causes the left

and causes further cardiac debility.

ventricle to pump with the extra power required to

overcome the abnormal pumping dynamics.

Compensation in Early Mitral Valvular Disease. As also

occurs in aortic valvular disease and in many types of

Eventual Failure of the Left Ventricle, and

congenital heart disease, the blood volume increases

Development of Pulmonary Edema

in mitral valvular disease principally because of dimin-

In the early stages of aortic stenosis or aortic regurgi-

ished excretion of water and salt by the kidneys. This

tation, the intrinsic ability of the left ventricle to adapt

increased blood volume increases venous return to the

to increasing loads prevents significant abnormalities

heart, thereby helping to overcome the effect of the

in circulatory function in the person during rest, other

cardiac debility. Therefore, after compensation, cardiac

than increased work output required of the left ven-

output may fall only minimally until the late stages of

tricle. Therefore, considerable degrees of aortic steno-

mitral valvular disease, even though the left atrial pres-

sis or aortic regurgitation often occur before the

sure is rising.

person knows that he or she has serious heart disease

As the left atrial pressure rises, blood begins to dam

(such as a resting left ventricular systolic pressure as

up in the lungs, eventually all the way back to the pul-

high as 200 mm Hg in aortic stenosis or a left ventric-

monary artery. In addition, incipient edema of the

ular stroke volume output as high as double normal in

lungs causes pulmonary arteriolar constriction. These

aortic regurgitation).

two effects together increase systolic pulmonary arte-

Beyond a critical stage in these aortic valve lesions,

rial pressure and also right ventricular pressure, some-

the left ventricle finally cannot keep up with the work

times to as high as 60 mm Hg, which is more than

demand. As a consequence, the left ventricle dilates

double normal. This, in turn, causes hypertrophy of the

and cardiac output begins to fall; blood simultaneously

right side of the heart, which partially compensates for

dams up in the left atrium and in the lungs behind the

its increased workload.

failing left ventricle. The left atrial pressure rises pro-

gressively, and at mean left atrial pressures above 25

to 40 mm Hg, serious edema appears in the lungs, as

Circulatory Dynamics During Exercise

discussed in detail in Chapter 38.

in Patients with Valvular Lesions

During exercise, large quantities of venous blood are

Dynamics of Mitral Stenosis and

returned to the heart from the peripheral circulation.

Mitral Regurgitation

Therefore, all the dynamic abnormalities that occur in

the different types of valvular heart disease become

In mitral stenosis, blood flow from the left atrium into

tremendously exacerbated. Even in mild valvular

the left ventricle is impeded, and in mitral regurgita-

heart disease, in which the symptoms may be unrec-

tion, much of the blood that has flowed into the left

ognizable at rest, severe symptoms often develop

ventricle during diastole leaks back into the left atrium

during heavy exercise. For instance, in patients with

during systole rather than being pumped into the

aortic valvular lesions, exercise can cause acute left

aorta. Therefore, either of these conditions reduces net

ventricular failure followed by acute pulmonary

movement of blood from the left atrium into the left

edema. Also, in patients with mitral disease, exercise

ventricle.

can cause so much damming of blood in the lungs that

serious or even lethal pulmonary edema may ensue in

Pulmonary Edema in Mitral Valvular Disease. The buildup

as little as 10 minutes.

of blood in the left atrium causes progressive increase

Even in mild to moderate cases of valvular disease,

in left atrial pressure, and this eventually results in

the patient’s cardiac reserve diminishes in proportion

274

Unit IV The Circulation

to the severity of the valvular dysfunction. That is, the

Head and upper

cardiac output does not increase as much as it should

extremities

Ductus

during exercise. Therefore, the muscles of the body

arteriosus

Aorta

fatigue rapidly because of too little increase in muscle

Right

blood flow.

lung

Left lung

Abnormal Circulatory

Dynamics in Congenital

Heart Defects

Occasionally, the heart or its associated blood vessels

are malformed during fetal life; the defect is called a

congenital anomaly. There are three major types of

Trunk and lower

Pulmonary

Left

congenital anomalies of the heart and its associated

extremities

artery

pulmonary

vessels: (1) stenosis of the channel of blood flow at

artery

some point in the heart or in a closely allied major

Figure 23-4

blood vessel; (2) an anomaly that allows blood to flow

backward from the left side of the heart or aorta to the

Patent ductus arteriosus, showing by the intensity of the pink color

right side of the heart or pulmonary artery, thus failing

that dark venous blood changes into oxygenated blood at differ-

to flow through the systemic circulation—called a left-

ent points in the circulation. The right-hand diagram shows back-

flow of blood from the aorta into the pulmonary artery and then

to-right shunt; and (3) an anomaly that allows blood to

through the lungs for a second time.

flow directly from the right side of the heart into the

left side of the heart, thus failing to flow through the

lungs—called a right-to-left shunt.

The effects of the different stenotic lesions are easily

lungs. This lack of blood flow through the lungs is not

understood. For instance, congenital aortic valve steno-

detrimental to the fetus because the blood is oxy-

sis results in the same dynamic effects as aortic valve

genated by the placenta.

stenosis caused by other valvular lesions, namely, a

tendency to develop serious pulmonary edema and a

Closure of the Ductus Arteriosus After Birth. As soon as a

reduced cardiac output.

baby is born and begins to breathe, the lungs inflate;

Another type of congenital stenosis is coarctation

not only do the alveoli fill with air, but also the resist-

of the aorta, often occurring near the level of the

ance to blood flow through the pulmonary vascular

diaphragm. This causes the arterial pressure in the

tree decreases tremendously, allowing the pulmonary

upper part of the body (above the level of the coarc-

arterial pressure to fall. Simultaneously, the aortic

tation) to be much greater than the pressure in the

pressure rises because of sudden cessation of blood

lower body because of the great resistance to blood

flow from the aorta through the placenta. Thus, the

flow through the coarctation to the lower body; part of

pressure in the pulmonary artery falls, while that in

the blood must go around the coarctation through

the aorta rises. As a result, forward blood flow through

small collateral arteries, as discussed in Chapter 19.

the ductus arteriosus ceases suddenly at birth, and in

fact, blood begins to flow backward through the ductus

from the aorta into the pulmonary artery. This new

Patent Ductus Arteriosus—

state of backward blood flow causes the ductus arte-

A Left-to-Right Shunt

riosus to become occluded within a few hours to a few

days in most babies, so that blood flow through the

During fetal life, the lungs are collapsed, and the

ductus does not persist. The ductus is believed to close

elastic compression of the lungs that keeps the alveoli

because the oxygen concentration of the aortic blood

collapsed keeps most of the lung blood vessels col-

now flowing through it is about twice as high as that

lapsed as well. Therefore, resistance to blood flow

of the blood flowing from the pulmonary artery into

through the lungs is so great that the pulmonary arte-

the ductus during fetal life. The oxygen presumably

rial pressure is high in the fetus. Also, because of low

constricts the muscle in the ductus wall. This is dis-

resistance to blood flow from the aorta through the

cussed further in Chapter 83.

large vessels of the placenta, the pressure in the aorta

Unfortunately, in about 1 of every 5500 babies, the

of the fetus is lower than normal—in fact, lower than

ductus does not close, causing the condition known as

in the pulmonary artery. This causes almost all the pul-

patent ductus arteriosus, which is shown in Figure 23-4.

monary arterial blood to flow through a special artery

present in the fetus that connects the pulmonary artery

Dynamics of the Circulation with a Persistent Patent Ductus.

with the aorta (Figure 23-4), called the ductus arterio-

During the early months of an infant’s life, a patent

sus, thus bypassing the lungs. This allows immediate

ductus usually does not cause severely abnormal func-

recirculation of the blood through the systemic arter-

tion. But as the child grows older, the differential

ies of the fetus without the blood going through the

between the high pressure in the aorta and the lower

Chapter 23

Heart Valves and Heart Sounds; Dynamics of Valvular and Congenital Heart Defects

275

pressure in the pulmonary artery progressively in-

Head and upper

creases, with corresponding increase in backward flow

extremities

of blood from the aorta into the pulmonary artery.

Also, the high aortic blood pressure usually causes the

Right

diameter of the partially open ductus to increase with

lung

time, making the condition even worse.

Left lung

Recirculation Through the Lungs. In an older child

with a patent ductus, one half to two thirds of the aortic

blood flows backward through the ductus into the pul-

monary artery, then through the lungs, and finally back

into the left ventricle and aorta, passing through the

lungs and left side of the heart two or more times for

every one time that it passes through the systemic cir-

Trunk and lower

culation. These people do not show cyanosis until later

extremities

in life, when the heart fails or the lungs become con-

gested. Indeed, early in life, the arterial blood is often

better oxygenated than normal because of the extra

times it passes through the lungs.

Diminished Cardiac and Respiratory Reserve. The

major effects of patent ductus arteriosus on the patient

are decreased cardiac and respiratory reserve. The left

ventricle is pumping about two or more times the

Figure 23-5

normal cardiac output, and the maximum that it can

Tetralogy of Fallot, showing by the intensity of the pink color that

pump after hypertrophy of the heart has occurred is

most of the dark venous blood is shunted from the right ventricle

about four to seven times normal. Therefore, during

into the aorta without passing through the lungs.

exercise, the net blood flow through the remainder of

the body can never increase to the levels required for

strenuous activity. With even moderately strenuous

exercise, the person is likely to become weak and may

Tetralogy of Fallot—

even faint from momentary heart failure.

A Right-to-Left Shunt

The high pressures in the pulmonary vessels caused

by excess flow through the lungs often lead to pul-

Tetralogy of Fallot is shown in Figure 23-5; it is the

monary congestion and pulmonary edema. As a result

most common cause of “blue baby.” Most of the blood

of the excessive load on the heart, and especially

bypasses the lungs, so the aortic blood is mainly unoxy-

because the pulmonary congestion becomes progres-

genated venous blood. In this condition, four abnor-

sively more severe with age, most patients with uncor-

malities of the heart occur simultaneously:

rected patent ductus die from heart disease between

1. The aorta originates from the right ventricle

ages 20 and 40 years.

rather than the left, or it overrides a hole in the

septum, as shown in Figure 23-5, receiving blood

from both ventricles.

Heart Sounds: Machinery Murmur. In a newborn infant

2. The pulmonary artery is stenosed, so that much

with patent ductus arteriosus, occasionally no abnor-

lower than normal amounts of blood pass from

mal heart sounds are heard because the quantity of

the right ventricle into the lungs; instead, most of

reverse blood flow through the ductus may be insuffi-

the blood passes directly into the aorta, thus

cient to cause a heart murmur. But as the baby grows

bypassing the lungs.

older, reaching age 1 to 3 years, a harsh, blowing

3. Blood from the left ventricle flows either through

murmur begins to be heard in the pulmonary artery

a ventricular septal hole into the right ventricle

area of the chest, as shown in recording F, Figure 23-3.

and then into the aorta or directly into the aorta

This sound is much more intense during systole when

that overrides this hole.

the aortic pressure is high and much less intense

4. Because the right side of the heart must pump

during diastole when the aortic pressure falls low, so

large quantities of blood against the high pressure

that the murmur waxes and wanes with each beat of

in the aorta, its musculature is highly developed,

the heart, creating the so-called machinery murmur.

causing an enlarged right ventricle.

Surgical Treatment. Surgical treatment of patent ductus

Abnormal Circulatory Dynamics. It is readily apparent that

arteriosus is extremely simple; one need only ligate the

the major physiological difficulty caused by tetralogy

patent ductus or divide it and then close the two ends.

of Fallot is the shunting of blood past the lungs without

In fact, this was one of the first successful heart sur-

its becoming oxygenated. As much as 75 per cent of

geries ever performed.

the venous blood returning to the heart passes directly

276

Unit IV The Circulation

from the right ventricle into the aorta without becom-

passing the blood between thin membranes or through

ing oxygenated.

thin tubes that are permeable to oxygen and carbon

A diagnosis of tetralogy of Fallot is usually based on

dioxide.

(1) the fact that the baby’s skin is cyanotic (blue); (2)

The different systems have all been fraught with

measurement of high systolic pressure in the right

many difficulties, including hemolysis of the blood,

ventricle, recorded through a catheter; (3) charac-

development of small clots in the blood, likelihood of

teristic changes in the radiological silhouette of the

small bubbles of oxygen or small emboli of antifoam

heart, showing an enlarged right ventricle; and (4)

agent passing into the arteries of the patient, necessity

angiograms (x-ray pictures) showing abnormal blood

for large quantities of blood to prime the entire

flow through the interventricular septal hole and into

system, failure to exchange adequate quantities of

the overriding aorta, but much less flow through the

oxygen, and necessity to use heparin to prevent blood

stenosed pulmonary artery.

coagulation in the extracorporeal system. Heparin also

interferes with adequate hemostasis during the surgi-

cal procedure. Yet despite these difficulties, in the

Surgical Treatment. Tetralogy of Fallot can usually be

hands of experts, patients can be kept alive on artifi-

treated successfully by surgery. The usual operation is

cial heart-lung machines for many hours while opera-

to open the pulmonary stenosis, close the septal defect,

tions are performed on the inside of the heart.

and reconstruct the flow pathway into the aorta. When

surgery is successful, the average life expectancy

increases from only 3 to 4 years to 50 or more years.

Hypertrophy of the Heart

in Valvular and Congenital

Causes of Congenital Anomalies

Heart Disease

One of the most common causes of congenital heart

Hypertrophy of cardiac muscle is one of the most

defects is a viral infection in the mother during the first

important mechanisms by which the heart adapts to

trimester of pregnancy when the fetal heart is being

increased workloads, whether these loads are caused

formed. Defects are particularly prone to develop

by increased pressure against which the heart muscle

when the expectant mother contracts German

must contract or by increased cardiac output that

measles; thus, obstetricians often advise termination of

must be pumped. Some physicians believe that the

pregnancy if German measles occurs in the first

increased strength of contraction of the heart muscle

trimester.

causes the hypertrophy; others believe that the

Some congenital defects of the heart are hereditary,

increased metabolic rate of the muscle is the primary

because the same defect has been known to occur in

stimulus. Regardless of which of these is correct, one

identical twins as well as in succeeding generations.

can calculate approximately how much hypertrophy

Children of patients surgically treated for congenital

will occur in each chamber of the heart by multiplying

heart disease have about a 10 times greater chance of

ventricular output by the pressure against which the

having congenital heart disease than other children do.

ventricle must work, with emphasis on pressure. Thus,

Congenital defects of the heart are also frequently

hypertrophy occurs in most types of valvular and con-

associated with other congenital defects of the baby’s

genital disease, sometimes causing heart weights as

body.

great as 800 grams instead of the normal 300 grams.

Use of Extracorporeal

References

Circulation During

Arad M, Seidman JG, Seidman CE: Phenotypic diversity in

Cardiac Surgery

hypertrophic cardiomyopathy. Hum Mol Genet 11:2499,

2002.

It is almost impossible to repair intracardiac defects

Braunwald E, Seidman CE, Sigwart U: Contemporary eval-

surgically while the heart is still pumping. Therefore,

uation and management of hypertrophic cardiomyopathy.

many types of artificial heart-lung machines have been

Circulation 106:1312, 2002.

developed to take the place of the heart and lungs

Brickner ME, Hillis LD, Lange RA: Congenital heart disease

during the course of operation. Such a system is called

in adults: second of two parts. N Engl J Med 342:334, 2000.

extracorporeal circulation. The system consists princi-

Gottdiener JS: Overview of stress echocardiography: uses,

pally of a pump and an oxygenating device. Almost

advantages, and limitations. Curr Probl Cardiol 28:485,

2003.

any type of pump that does not cause hemolysis of the

Grech ED: Non-coronary percutaneous intervention. BMJ

blood seems to be suitable.

327:97, 2003.

Methods used for oxygenating blood include (1)

Guidelines for the management of patients with valvular

bubbling oxygen through the blood and removing the

heart disease. A report of the American College of Cardi-

bubbles from the blood before passing it back into the

ology/American Heart Association Task Force on Practice

patient, (2) dripping the blood downward over the sur-

Guidelines. Circulation 98:1949, 1998.

faces of plastic sheets in the presence of oxygen, (3)

Hoffman JI, Kaplan S: The incidence of congenital heart

passing the blood over surfaces of rotating discs, or (4)

disease. J Am Coll Cardiol 39:1890, 2002.

C H A P T E R

Circulatory Shock and

Physiology of Its Treatment

Circulatory shock means generalized inadequate

blood flow through the body, to the extent that the

body tissues are damaged because of too little flow,

especially because of too little oxygen and other

nutrients delivered to the tissue cells. Even the car-

diovascular system itself—the heart musculature,

walls of the blood vessels, vasomotor system, and

other circulatory parts—begins to deteriorate, so

that the shock, once begun, is prone to become progressively worse.

Physiologic Causes of Shock

Circulatory Shock Caused by Decreased Cardiac Output

Shock usually results from inadequate cardiac output. Therefore, any condition

that reduces the cardiac output far below normal will likely lead to circulatory

shock. Two types of factors can severely reduce cardiac output:

1. Cardiac abnormalities that decrease the ability of the heart to pump blood.

These include especially myocardial infarction but also toxic states of

the heart, severe heart valve dysfunction, heart arrhythmias, and other

conditions. The circulatory shock that results from diminished cardiac

pumping ability is called cardiogenic shock. This is discussed in detail in

Chapter 22, where it is pointed out that as many as 85 per cent of people

who develop cardiogenic shock do not survive.

2. Factors that decrease venous return also decrease cardiac output because

the heart cannot pump blood that does not flow into it. The most common

cause of decreased venous return is diminished blood volume, but venous

return can also be reduced as a result of decreased vascular tone, especially

of the venous blood reservoirs, or obstruction to blood flow at some point

in the circulation, especially in the venous return pathway to the heart.

Circulatory Shock That Occurs Without Diminished

Cardiac Output

Occasionally, the cardiac output is normal or even greater than normal, yet the

person is in circulatory shock. This can result from (1) excessive metabolism of

the body, so that even a normal cardiac output is inadequate, or (2) abnormal

tissue perfusion patterns, so that most of the cardiac output is passing through

blood vessels besides those that supply the local tissues with nutrition.

The specific causes of shock are discussed later in the chapter. For the present,

it is important to note that all of them lead to inadequate delivery of nutrients

to critical tissues and critical organs and also cause inadequate removal of cellu-

lar waste products from the tissues.

278

Chapter 24

Circulatory Shock and Physiology of Its Treatment

279

What Happens to the Arterial Pressure

in Circulatory Shock?

Arterial

100

pressure

In the minds of many physicians, the arterial pressure

level is the principal measure of adequacy of circula-

tory function. However, the arterial pressure can often

be seriously misleading. At times, a person may be in

Cardiac

severe shock and still have an almost normal arterial

output

pressure because of powerful nervous reflexes that

keep the pressure from falling. At other times, the

arterial pressure can fall to half of normal, but the

person still has normal tissue perfusion and is not in

shock.

In most types of shock, especially shock caused by

Percentage of total blood removed

severe blood loss, the arterial blood pressure decreases

at the same time as the cardiac output decreases,

although usually not as much.

Figure 24-1

Effect of hemorrhage on cardiac output and arterial pressure.

Tissue Deterioration Is the End Result

Shock Caused by

of Circulatory Shock, Whatever

Hypovolemia—Hemorrhagic

the Cause

Shock

Once circulatory shock reaches a critical state of sever-

Hypovolemia means diminished blood volume. Hem-

ity, regardless of its initiating cause, the shock itself

orrhage is the most common cause of hypovolemic

breeds more shock. That is, the inadequate blood flow

shock. Hemorrhage decreases the filling pressure of the

causes the body tissues to begin deteriorating, includ-

circulation and, as a consequence, decreases venous

ing the heart and circulatory system itself. This causes

return. As a result, the cardiac output falls below

an even greater decrease in cardiac output, and a

normal, and shock may ensue.

vicious circle ensues, with progressively increasing cir-

culatory shock, less adequate tissue perfusion, more

shock, and so forth until death. It is with this late stage

Relationship of Bleeding Volume to

of circulatory shock that we are especially concerned,

Cardiac Output and Arterial Pressure

because appropriate physiologic treatment can often

reverse the rapid slide to death.

Figure 24-1 shows the approximate effects on both

cardiac output and arterial pressure of removing blood

from the circulatory system over a period of about 30

minutes. About 10 per cent of the total blood volume

Stages of Shock

can be removed with almost no effect on either arte-

rial pressure or cardiac output, but greater blood loss

Because the characteristics of circulatory shock

usually diminishes the cardiac output first and later the

change with different degrees of severity, shock is

arterial pressure, both of which fall to zero when about

divided into the following three major stages:

35 to 45 per cent of the total blood volume has been

1. A nonprogressive stage (sometimes called

removed.

the compensated stage), in which the normal

circulatory compensatory mechanisms eventually

Sympathetic Reflex Compensations in Shock—Their Special

cause full recovery without help from outside

Value to Maintain Arterial Pressure. The decrease in arte-

therapy.

rial pressure after hemorrhage—as well as decreases

2. A progressive stage, in which, without therapy,

in pressures in the pulmonary arteries and veins in the

the shock becomes steadily worse until death.

thorax—causes powerful sympathetic reflexes (initi-

3. An irreversible stage, in which the shock has

ated mainly by the arterial baroreceptors and other

progressed to such an extent that all forms of

vascular stretch receptors, as explained in Chapter 18).

known therapy are inadequate to save the

These reflexes stimulate the sympathetic vasoconstric-

person’s life, even though, for the moment, the

tor system throughout the body, resulting in three

person is still alive.

important effects: (1) The arterioles constrict in most

Now, let us discuss the stages of circulatory shock

parts of the systemic circulation, thereby increasing

caused by decreased blood volume, which illustrate the

the total peripheral resistance.

(2) The veins and

basic principles. Then we can consider special charac-

venous reservoirs constrict, thereby helping to main-

teristics of shock initiated by other causes.

tain adequate venous return despite diminished blood

280

Unit IV The Circulation

100

III

Figure 24-2

120

180

240

300

360

Time in minutes

Time course of arterial pressure in dogs after dif-

ferent degrees of acute hemorrhage. Each curve

represents average results from six dogs.

volume. (3) Heart activity increases markedly, some-

The sympathetic stimulation does not cause significant

times increasing the heart rate from the normal value

constriction of either the cerebral or the cardiac

of 72 beats/min to as high as 160 to 180 beats/min.

vessels. In addition, in both these vascular beds, local

blood flow autoregulation is excellent, which prevents

Value of the Sympathetic Nervous Reflexes. In the

moderate decreases in arterial pressure from signifi-

absence of the sympathetic reflexes, only 15 to 20 per

cantly decreasing their blood flows. Therefore, blood

cent of the blood volume can be removed over a

flow through the heart and brain is maintained essen-

period of 30 minutes before a person dies; this is in

tially at normal levels as long as the arterial pressure

contrast to a 30 to 40 per cent loss of blood volume

does not fall below about 70 mm Hg, despite the fact

that a person can sustain when the reflexes are intact.

that blood flow in some other areas of the body might

Therefore, the reflexes extend the amount of blood

be decreased to as little as one third to one quarter

loss that can occur without causing death to about

normal by this time because of vasoconstriction.

twice that which is possible in their absence.

Greater Effect of the Sympathetic Nervous Reflexes in

Progressive and Nonprogressive

Maintaining Arterial Pressure than in Maintaining

Hemorrhagic Shock

Cardiac Output. Referring again to Figure 24-1, note

that the arterial pressure is maintained at or near

Figure 24-2 shows an experiment that we performed

normal levels in the hemorrhaging person longer than

in dogs to demonstrate the effects of different degrees

is the cardiac output. The reason for this is that the

of sudden acute hemorrhage on the subsequent course

sympathetic reflexes are geared more for maintaining

of arterial pressure. The dogs were bled rapidly until

arterial pressure than for maintaining output. They

their arterial pressures fell to different levels. Those

increase the arterial pressure mainly by increasing the

dogs whose pressures fell immediately to no lower

total peripheral resistance, which has no beneficial

than 45 mm Hg (groups I, II, and III) all eventually

effect on cardiac output; however, the sympathetic con-

recovered; the recovery occurred rapidly if the pres-

striction of the veins is important to keep venous return

sure fell only slightly (group I) but occurred slowly if

and cardiac output from falling too much, in addition

it fell almost to the 45 mm Hg level (group III). When

to their role in maintaining arterial pressure.

the arterial pressure fell below 45 mm Hg (groups IV,

Especially interesting is the second plateau occur-

V, and VI), all the dogs died, although many of them

ring at about 50 mm Hg in the arterial pressure curve

hovered between life and death for hours before the

of Figure 24-1. This results from activation of the

circulatory system deteriorated to the stage of death.

central nervous system ischemic response, which

This experiment demonstrates that the circulatory

causes extreme stimulation of the sympathetic nervous

system can recover as long as the degree of hemor-

system when the brain begins to suffer from lack of

rhage is no greater than a certain critical amount.

oxygen or from excess buildup of carbon dioxide, as

Crossing this critical threshold by even a few milliliters

discussed in Chapter 18. This effect of the central

of blood loss makes the eventual difference between

nervous system ischemic response can be called the

life and death. Thus, hemorrhage beyond a certain crit-

“last-ditch stand” of the sympathetic reflexes in their

ical level causes shock to become progressive. That is,

attempt to keep the arterial pressure from falling too

the shock itself causes still more shock, and the condi-

low.

tion becomes a vicious circle that eventually leads to

deterioration of the circulation and to death.

Protection of Coronary and Cerebral Blood Flow by

the Reflexes. A special value of the maintenance

Nonprogressive Shock—Compensated Shock

of normal arterial pressure even in the presence of

If shock is not severe enough to cause its own pro-

decreasing cardiac output is protection of blood flow

gression, the person eventually recovers. Therefore,

through the coronary and cerebral circulatory systems.

shock of this lesser degree is called nonprogressive

Chapter 24

Circulatory Shock and Physiology of Its Treatment

281

shock. It is also called compensated shock, meaning

the shock to become progressive. Some of the more

that the sympathetic reflexes and other factors com-

important feedbacks are the following.

pensate enough to prevent further deterioration of the

circulation.

Cardiac Depression. When the arterial pressure falls low

The factors that cause a person to recover from

enough, coronary blood flow decreases below that

moderate degrees of shock are all the negative feed-

required for adequate nutrition of the myocardium.

back control mechanisms of the circulation that

This weakens the heart muscle and thereby decreases

attempt to return cardiac output and arterial pressure

the cardiac output more. Thus, a positive feedback

back to normal levels. They include the following:

cycle has developed, whereby the shock becomes more

Baroreceptor reflexes, which elicit powerful

and more severe.

sympathetic stimulation of the circulation.

Figure 24-4 shows cardiac output curves extrapo-

Central nervous system ischemic response,

lated to the human heart from experiments in dogs,

which elicits even more powerful sympathetic

demonstrating progressive deterioration of the heart

stimulation throughout the body but is not

at different times after the onset of shock. A dog was

activated significantly until the arterial pressure

bled until the arterial pressure fell to 30 mm Hg, and

falls below 50 mm Hg.

the pressure was held at this level by further bleeding

Reverse stress-relaxation of the circulatory system,

or retransfusion of blood as required. Note from the

which causes the blood vessels to contract around

second curve in the figure that there was little deteri-

the diminished blood volume, so that the blood

oration of the heart during the first 2 hours, but by 4

volume that is available more adequately fills the

hours, the heart had deteriorated about 40 per cent;

circulation.

then, rapidly, during the last hour of the experiment

Formation of angiotensin by the kidneys, which

(after 4 hours of low coronary blood pressure), the

constricts the peripheral arteries and also causes

heart deteriorated completely.

decreased output of water and salt by the

Thus, one of the important features of progressive

kidneys, both of which help prevent progression

shock, whether it is hemorrhagic in origin or caused in

of shock.

another way, is eventual progressive deterioration of

Formation of vasopressin (antidiuretic hormone)

the heart. In the early stages of shock, this plays very

by the posterior pituitary gland, which constricts

little role in the condition of the person, partly because

the peripheral arteries and veins and greatly

deterioration of the heart is not severe during the first

increases water retention by the kidneys.

hour or so of shock, but mainly because the heart has

Compensatory mechanisms that return the blood

tremendous reserve capability that normally allows

volume back toward normal, including absorption

it to pump 300 to 400 per cent more blood than is

of large quantities of fluid from the intestinal

required by the body for adequate bodywide tissue

tract, absorption of fluid into the blood capillaries

nutrition. In the latest stages of shock, however, dete-

from the interstitial spaces of the body,

rioration of the heart is probably the most important

conservation of water and salt by the kidneys, and

factor in the final lethal progression of the shock.

increased thirst and increased appetite for salt,

which make the person drink water and eat salty

Vasomotor Failure. In the early stages of shock, various

foods if able.

circulatory reflexes cause intense activity of the

The sympathetic reflexes provide immediate help

sympathetic nervous system. This, as discussed earlier,

toward bringing about recovery because they become

helps delay depression of the cardiac output and

maximally activated within 30 seconds to a minute

especially helps prevent decreased arterial pressure.

after hemorrhage.

However, there comes a point when diminished blood

The angiotensin and vasopressin mechanisms, as

flow to the brain’s vasomotor center depresses the

well as the reverse stress-relaxation that causes

center so much that it, too, becomes progressively less

contraction of the blood vessels and venous reservoirs,

active and finally totally inactive. For instance, com-

all require 10 minutes to 1 hour to respond completely,

plete circulatory arrest to the brain causes, during the

but they aid greatly in increasing the arterial pressure

first 4 to 8 minutes, the most intense of all sympathetic

or increasing the circulatory filling pressure and

discharges, but by the end of 10 to 15 minutes, the vaso-

thereby increasing the return of blood to the heart.

motor center becomes so depressed that no further

Finally, readjustment of blood volume by absorption

evidence of sympathetic discharge can be demon-

of fluid from the interstitial spaces and intestinal tract,

strated. Fortunately, the vasomotor center usually does

as well as oral ingestion and absorption of additional

not fail in the early stages of shock if the arterial

quantities of water and salt, may require from 1 to 48

pressure remains above 30 mm Hg.

hours, but recovery eventually takes place, provided

the shock does not become severe enough to enter the

Blockage of Very Small Vessels—“Sludged Blood.” In time,

progressive stage.

blockage occurs in many of the very small blood

vessels in the circulatory system, and this also causes

“Progressive Shock” Is Caused by a Vicious

the shock to progress. The initiating cause of this

Circle of Cardiovascular Deterioration

blockage is sluggish blood flow in the microvessels.

Figure 24-3 shows some of the positive feedbacks that

Because tissue metabolism continues despite the low

further depress cardiac output in shock, thus causing

flow, large amounts of acid, both carbonic acid and

282

Unit IV The Circulation

Decreased cardiac output

Decreased arterial pressure

Decreased systemic blood flow

Decreased cardiac nutrition

Decreased nutrition of tissues

Intravascular clotting

Decreased nutrition of brain

Decreased nutrition

Tissue ischemia

of vascular system

Decreased vasomotor

activity

Increased

Release of

capillary

toxins

permeability

Vascular dilation

Decreased

Venous pooling

blood volume

of blood

Cardiac depression

Decreased venous return

Figure 24-3

Different types of “positive feedback” that can lead to progression of shock.

lactic acid, continue to empty into the local blood

Release of Toxins by Ischemic Tissue. Throughout the

vessels and greatly increase the local acidity of the

history of research in the field of shock, it has been

blood. This acid, plus other deterioration products

suggested that shock causes tissues to release toxic

from the ischemic tissues, causes local blood aggluti-

substances, such as histamine, serotonin, and tissue

nation, resulting in minute blood clots, leading to very

enzymes, that cause further deterioration of the circu-

small plugs in the small vessels. Even if the vessels do

latory system. Quantitative studies have proved the

not become plugged, an increased tendency for the

significance of at least one toxin, endotoxin, in some

blood cells to stick to one another makes it more dif-

types of shock.

ficult for blood to flow through the microvasculature,

giving rise to the term sludged blood.

Cardiac Depression Caused by Endotoxin. Endotoxin

is released from the bodies of dead gram-negative

Increased Capillary Permeability. After many hours of

bacteria in the intestines. Diminished blood flow to

capillary hypoxia and lack of other nutrients, the

the intestines often causes enhanced formation and

permeability of the capillaries gradually increases,

absorption of this toxic substance. The circulating

and large quantities of fluid begin to transude into the

toxin then causes increased cellular metabolism

tissues. This decreases the blood volume even more,

despite inadequate nutrition of the cells; this has a spe-

with a resultant further decrease in cardiac output,

cific effect on the heart muscle, causing cardiac depres-

making the shock still more severe. Capillary hypoxia

sion. Endotoxin can play a major role in some types

does not cause increased capillary permeability until

of shock, especially “septic shock,” discussed later in

the late stages of prolonged shock.

the chapter.

Chapter 24

Circulatory Shock and Physiology of Its Treatment

283

0 time

2 hours

4 hours

4¹/2 hours

4³/4 hours

5 hours

–4

Right atrial pressure (mm Hg)

Figure 24-4

Cardiac output curves of the heart at different times after hemor-

rhagic shock begins. (These curves are extrapolated to the human

heart from data obtained in dog experiments by Dr. J. W. Crowell.)

Figure 24-5

Necrosis of the central portion of a liver lobule in severe circula-

tory shock. (Courtesy Dr. J. W. Crowell.)

Generalized Cellular Deterioration. As shock becomes

severe, many signs of generalized cellular deteriora-

tion occur throughout the body. One organ especially

Tissue Necrosis in Severe Shock—Patchy Areas of

affected is the liver, as illustrated in Figure 24-5. This

Necrosis Occur Because of Patchy Blood Flows in

occurs mainly because of lack of enough nutrients to

Different Organs. Not all cells of the body are equally

support the normally high rate of metabolism in liver

damaged by shock, because some tissues have better

cells, but also partly because of the extreme exposure

blood supplies than others. For instance, the cells adja-

of the liver cells to any vascular toxin or other abnor-

cent to the arterial ends of capillaries receive better

mal metabolic factor occurring in shock.

nutrition than cells adjacent to the venous ends of the

Among the damaging cellular effects that are

same capillaries. Therefore, one would expect more

known to occur in most body tissues are the following:

nutritive deficiency around the venous ends of capil-

1. Active transport of sodium and potassium

laries than elsewhere. This is precisely the effect that

through the cell membrane is greatly diminished.

Crowell discovered in studying tissue areas in many

As a result, sodium and chloride accumulate in

parts of the body. For instance, Figure 24-5 shows

the cells, and potassium is lost from the cells. In

necrosis in the center of a liver lobule, the portion of

addition, the cells begin to swell.

the lobule that is last to be exposed to the blood as it

2. Mitochondrial activity in the liver cells, as well as

passes through the liver sinusoids.

in many other tissues of the body, becomes

Similar punctate lesions occur in heart muscle,

severely depressed.

although here a definite repetitive pattern, such as

3. Lysosomes in the cells in widespread tissue areas

occurs in the liver, cannot be demonstrated. Never-

begin to break open, with intracellular release of

theless, the cardiac lesions play an important role in

hydrolases that cause further intracellular

leading to the final irreversible stage of shock. Deteri-

deterioration.

orative lesions also occur in the kidneys, especially in

4. Cellular metabolism of nutrients, such as glucose,

the epithelium of the kidney tubules, leading to kidney

eventually becomes greatly depressed in the last

failure and occasionally uremic death several days

stages of shock. The actions of some hormones

later. Deterioration of the lungs also often leads to res-

are depressed as well, including almost 100 per

piratory distress and death several days later—called

cent depression of the action of insulin.

the shock lung syndrome.

All these effects contribute to further deterioration

of many organs of the body, including especially (1)

Acidosis in Shock. Most metabolic derangements that

the liver, with depression of its many metabolic and

occur in shocked tissue can lead to blood acidosis all

detoxification functions; (2) the lungs, with eventual

through the body. This results from poor delivery of

development of pulmonary edema and poor ability to

oxygen to the tissues, which greatly diminishes oxida-

oxygenate the blood; and (3) the heart, thereby further

tive metabolism of the foodstuffs. When this occurs,

depressing its contractility.

the cells obtain most of their energy by the anaerobic

284

Unit IV The Circulation

process of glycolysis, which leads to tremendous quan-

tities of excess lactic acid in the blood. In addition, poor

blood flow through tissues prevents normal removal

100

of carbon dioxide. The carbon dioxide reacts locally

in the cells with water to form high concentrations of

intracellular carbonic acid; this, in turn, reacts with

Progressive

Transfusion

stage

various tissue chemicals to form still other intracellu-

lar acidic substances. Thus, another deteriorative effect

of shock is both generalized and local tissue acidosis,

leading to further progression of the shock itself.

Irreversible shock

120

150

Positive Feedback Deterioration of Tissues

Minutes

in Shock and the Vicious Circle of

Progressive Shock

All the factors just discussed that can lead to further

Figure 24-6

progression of shock are types of positive feedback.

That is, each increase in the degree of shock causes a

Failure of transfusion to prevent death in irreversible shock.

further increase in the shock.

However, positive feedback does not necessarily

lead to a vicious circle. Whether a vicious circle devel-

the heart’s immediate ability to pump blood but, over

ops depends on the intensity of the positive feedback.

a long period, depress heart pumping enough to cause

In mild degrees of shock, the negative feedback mech-

death. Beyond a certain point, so much tissue damage

anisms of the circulation—sympathetic reflexes,

has occurred, so many destructive enzymes have been

reverse stress-relaxation mechanism of the blood

released into the body fluids, so much acidosis has

reservoirs, absorption of fluid into the blood from the

developed, and so many other destructive factors are

interstitial spaces, and others—can easily overcome

now in progress that even a normal cardiac output for

the positive feedback influences and, therefore, cause

a few minutes cannot reverse the continuing deterio-

recovery. But in severe degrees of shock, the deterio-

ration. Therefore, in severe shock, a stage is eventually

rative feedback mechanisms become more and more

reached at which the person will die even though vig-

powerful, leading to such rapid deterioration of the

orous therapy might still return the cardiac output to

circulation that all the normal negative feedback

normal for short periods.

systems of circulatory control acting together cannot

return the cardiac output to normal.

Depletion of Cellular High-Energy Phosphate Reserves in

Considering once again the principles of positive

Irreversible Shock. The high-energy phosphate reserves

feedback and vicious circle discussed in Chapter 1, one

in the tissues of the body, especially in the liver and

can readily understand why there is a critical cardiac

the heart, are greatly diminished in severe degrees of

output level above which a person in shock recovers

shock. Essentially all the creatine phosphate has been

and below which a person enters a vicious circle of cir-

degraded, and almost all the adenosine triphosphate

culatory deterioration that proceeds until death.

has downgraded to adenosine diphosphate, adenosine

monophosphate, and, eventually, adenosine. Then

much of this adenosine diffuses out of the cells into the

Irreversible Shock

circulating blood and is converted into uric acid, a

substance that cannot re-enter the cells to reconstitute

After shock has progressed to a certain stage, transfu-

the adenosine phosphate system. New adenosine can

sion or any other type of therapy becomes incapable

be synthesized at a rate of only about 2 per cent of

of saving the person’s life. The person is then said to

the normal cellular amount an hour, meaning that

be in the irreversible stage of shock. Ironically, even in

once the high-energy phosphate stores of the cells are

this irreversible stage, therapy can, on rare occasions,

depleted, they are difficult to replenish.

return the arterial pressure and even the cardiac

Thus, one of the most devastating end results of

output to normal or near normal for short periods, but

deterioration in shock, and the one that is perhaps

the circulatory system nevertheless continues to dete-

most significant for development of the final state of

riorate, and death ensues in another few minutes to

irreversibility, is this cellular depletion of these high-

few hours.

energy compounds.

Figure 24-6 demonstrates this effect, showing that

transfusion during the irreversible stage can some-

times cause the cardiac output (as well as the arterial

Hypovolemic Shock Caused

pressure) to return to normal. However, the cardiac

by Plasma Loss

output soon begins to fall again, and subsequent trans-

fusions have less and less effect. By this time, multiple

Loss of plasma from the circulatory system, even

deteriorative changes have occurred in the muscle

without loss of red blood cells, can sometimes be

cells of the heart that may not necessarily affect

severe enough to reduce the total blood volume

Chapter 24

Circulatory Shock and Physiology of Its Treatment

285

markedly, causing typical hypovolemic shock similar in

Neurogenic Shock—Increased

almost all details to that caused by hemorrhage. Severe

Vascular Capacity

plasma loss occurs in the following conditions:

1. Intestinal obstruction is often a cause of severely

Shock occasionally results without any loss of blood

reduced plasma volume. Distention of the

volume. Instead, the vascular capacity increases so

intestine in intestinal obstruction partly blocks

much that even the normal amount of blood becomes

venous blood flow in the intestinal walls, which

incapable of filling the circulatory system adequately.

increases intestinal capillary pressure. This in turn

One of the major causes of this is sudden loss of vaso-

causes fluid to leak from the capillaries into the

motor tone throughout the body, resulting especially in

intestinal walls and also into the intestinal lumen.

massive dilation of the veins. The resulting condition

Because the lost fluid has a high protein content,

is known as neurogenic shock.

the result is reduced total blood plasma protein as

The role of vascular capacity in helping to regulate

well as reduced plasma volume.

circulatory function was discussed in Chapter

15,

2. In almost all patients who have severe burns or

where it was pointed out that either an increase in vas-

other denuding conditions of the skin, so much

cular capacity or a decrease in blood volume reduces

plasma is lost through the denuded skin areas

the mean systemic filling pressure, which reduces

that the plasma volume becomes markedly

venous return to the heart. Diminished venous return

reduced.

caused by vascular dilation is called venous pooling of

The hypovolemic shock that results from plasma

blood.

loss has almost the same characteristics as the shock

caused by hemorrhage, except for one additional com-

Causes of Neurogenic Shock. Some neurogenic factors

plicating factor: the blood viscosity increases greatly as

that can cause loss of vasomotor tone include the

a result of increased red blood cell concentration in

following:

the remaining blood, and this exacerbates the slug-

1. Deep general anesthesia often depresses the

gishness of blood flow.

vasomotor center enough to cause vasomotor

Loss of fluid from all fluid compartments of the

paralysis, with resulting neurogenic shock.

body is called dehydration; this, too, can reduce the

2. Spinal anesthesia, especially when this extends all

blood volume and cause hypovolemic shock similar to

the way up the spinal cord, blocks the sympathetic

that resulting from hemorrhage. Some of the causes of

nervous outflow from the nervous system and can

this type of shock are (1) excessive sweating, (2) fluid

be a potent cause of neurogenic shock.

loss in severe diarrhea or vomiting, (3) excess loss of

3. Brain damage is often a cause of vasomotor

fluid by nephrotic kidneys, (4) inadequate intake of

paralysis. Many patients who have had brain

fluid and electrolytes, or (5) destruction of the adrenal

concussion or contusion of the basal regions of

cortices, with loss of aldosterone secretion and conse-

the brain develop profound neurogenic shock.

quent failure of the kidneys to reabsorb sodium,

Also, even though brain ischemia for a few

chloride, and water, which occurs in the absence of

minutes almost always causes extreme vasomotor

the adrenocortical hormone aldosterone.

stimulation, prolonged ischemia (lasting longer

than 5 to 10 minutes) can cause the opposite

effect—total inactivation of the vasomotor

neurons in the brain stem, with consequent

Hypovolemic Shock Caused

development of severe neurogenic shock.

by Trauma

One of the most common causes of circulatory shock

Anaphylactic Shock and

is trauma to the body. Often the shock results simply

from hemorrhage caused by the trauma, but it can also

Histamine Shock

occur even without hemorrhage, because extensive

contusion of the body can damage the capillaries

Anaphylaxis is an allergic condition in which the

sufficiently to allow excessive loss of plasma into the

cardiac output and arterial pressure often decrease

tissues. This results in greatly reduced plasma volume,

drastically. This is discussed in Chapter 34. It results

with resultant hypovolemic shock.

primarily from an antigen-antibody reaction that takes

Various attempts have been made to implicate toxic

place immediately after an antigen to which the person

factors released by the traumatized tissues as one of

is sensitive enters the circulation. One of the principal

the causes of shock after trauma. However, cross-

effects is to cause the basophils in the blood and mast

transfusion experiments into normal animals have

cells in the pericapillary tissues to release histamine or

failed to show significant toxic elements.

a histamine-like substance. The histamine causes (1) an

In summary, traumatic shock seems to result

increase in vascular capacity because of venous dila-

mainly from hypovolemia, although there might also

tion, thus causing a marked decrease in venous return;

be a moderate degree of concomitant neurogenic

(2) dilation of the arterioles, resulting in greatly

shock caused by loss of vasomotor tone, as discussed

reduced arterial pressure; and (3) greatly increased

next.

capillary permeability, with rapid loss of fluid and

286

Unit IV The Circulation

protein into the tissue spaces. The net effect is a great

blood clotting factors to be used up, so that

reduction in venous return and sometimes such

hemorrhaging occurs in many tissues, especially in

serious shock that the person dies within minutes.

the gut wall of the intestinal tract.

Intravenous injection of large amounts of histamine

In early stages of septic shock, the patient usually

causes “histamine shock,” which has characteristics

does not have signs of circulatory collapse but only

almost identical to those of anaphylactic shock.

signs of the bacterial infection. As the infection

becomes more severe, the circulatory system usually

becomes involved either because of direct extension

Septic Shock

of the infection or secondarily as a result of toxins

from the bacteria, with resultant loss of plasma into the

A condition that was formerly known by the popular

infected tissues through deteriorating blood capillary

name “blood poisoning” is now called septic shock

walls. There finally comes a point at which deteriora-

by most clinicians. This refers to a bacterial infection

tion of the circulation becomes progressive in the same

widely disseminated to many areas of the body, with

way that progression occurs in all other types of shock.

the infection being borne through the blood from one

The end stages of septic shock are not greatly differ-

tissue to another and causing extensive damage. There

ent from the end stages of hemorrhagic shock, even

are many varieties of septic shock because of the many

though the initiating factors are markedly different in

types of bacterial infections that can cause it and

the two conditions.

because infection in different parts of the body

produces different effects.

Septic shock is extremely important to the clinician,

Physiology of Treatment

because other than cardiogenic shock, septic shock is

in Shock

the most frequent cause of shock-related death in the

modern hospital.

Replacement Therapy

Some of the typical causes of septic shock include

the following:

Blood and Plasma Transfusion. If a person is in shock

1. Peritonitis caused by spread of infection from the

caused by hemorrhage, the best possible therapy is

uterus and fallopian tubes, sometimes resulting

usually transfusion of whole blood. If the shock is

from instrumental abortion performed under

caused by plasma loss, the best therapy is administra-

unsterile conditions.

tion of plasma; when dehydration is the cause, admin-

2. Peritonitis resulting from rupture of the

istration of an appropriate electrolyte solution can

gastrointestinal system, sometimes caused by

correct the shock.

intestinal disease and sometimes by wounds.

Whole blood is not always available, such as under

3. Generalized bodily infection resulting from

battlefield conditions. Plasma can usually substitute

spread of a skin infection such as streptococcal

adequately for whole blood because it increases the

or staphylococcal infection.

blood volume and restores normal hemodynamics.

4. Generalized gangrenous infection resulting

Plasma cannot restore a normal hematocrit, but the

specifically from gas gangrene bacilli, spreading

human body can usually stand a decrease in hemat-

first through peripheral tissues and finally by way

ocrit to about half of normal before serious con-

of the blood to the internal organs, especially the

sequences result, if cardiac output is adequate.

liver.

Therefore, in emergency conditions, it is reasonable to

5. Infection spreading into the blood from the

use plasma in place of whole blood for treatment of

kidney or urinary tract, often caused by colon

hemorrhagic or most other types of hypovolemic

bacilli.

shock.

Sometimes plasma is unavailable. In these instances,

Special Features of Septic Shock. Because of the multiple

various plasma substitutes have been developed that

types of septic shock, it is difficult to categorize this

perform almost exactly the same hemodynamic func-

condition. Some features often observed are:

tions as plasma. One of these is dextran solution.

1. High fever.

2. Often marked vasodilation throughout the body,

especially in the infected tissues.

Dextran Solution as a Plasma Substitute. The principal

3. High cardiac output in perhaps half of patients,

requirement of a truly effective plasma substitute is

caused by arteriolar dilation in the infected tissues

that it remain in the circulatory system—that is, not

and by high metabolic rate and vasodilation

filter through the capillary pores into the tissue spaces.

elsewhere in the body, resulting from bacterial

In addition, the solution must be nontoxic and must

toxin stimulation of cellular metabolism and from

contain appropriate electrolytes to prevent derange-

high body temperature.

ment of the body’s extracellular fluid electrolytes on

4. Sludging of the blood, caused by red cell

administration.

agglutination in response to degenerating tissues.

To remain in the circulation, the plasma substitute

5. Development of micro-blood clots in widespread

must contain some substance that has a large enough

areas of the body, a condition called disseminated

molecular size to exert colloid osmotic pressure. One

intravascular coagulation. Also, this causes the

of the most satisfactory substances developed for this

Chapter 24

Circulatory Shock and Physiology of Its Treatment

287

purpose is dextran, a large polysaccharide polymer of

the tissues, giving the patient oxygen to breathe can be

glucose. Certain bacteria secrete dextran as a by-

of benefit in many instances. However, this frequently

product of their growth, and commercial dextran can

is far less beneficial than one might expect, because the

be manufactured using a bacterial culture procedure.

problem in most types of shock is not inadequate oxy-

By varying the growth conditions of the bacteria, the

genation of the blood by the lungs but inadequate

molecular weight of the dextran can be controlled to

transport of the blood after it is oxygenated.

the desired value. Dextrans of appropriate molecular

size do not pass through the capillary pores and, there-

Treatment with Glucocorticoids (Adrenal Cortex Hormones That

fore, can replace plasma proteins as colloid osmotic

Control Glucose Metabolism). Glucocorticoids are fre-

agents.

quently given to patients in severe shock for several

Few toxic reactions have been observed when using

reasons: (1) experiments have shown empirically that

purified dextran to provide colloid osmotic pressure;

glucocorticoids frequently increase the strength of the

therefore, solutions containing this substance have

heart in the late stages of shock; (2) glucocorticoids

proved to be a satisfactory substitute for plasma in

stabilize lysosomes in tissue cells and thereby prevent

most fluid replacement therapy.

release of lysosomal enzymes into the cytoplasm of the

cells, thus preventing deterioration from this source;

and (3) glucocorticoids might aid in the metabolism of

Treatment of Shock with

glucose by the severely damaged cells.

Sympathomimetic Drugs—Sometimes

Useful, Sometimes Not

Circulatory Arrest

A sympathomimetic drug is a drug that mimics sym-

pathetic stimulation. These drugs include norepineph-

A condition closely allied to circulatory shock is cir-

rine, epinephrine, and a large number of long-acting

culatory arrest, in which all blood flow stops. This

drugs that have the same effect as epinephrine and

occurs frequently on the surgical operating table as a

norepinephrine.

result of cardiac arrest or ventricular fibrillation.

In two types of shock, sympathomimetic drugs have

Ventricular fibrillation can usually be stopped by

proved to be especially beneficial. The first of these is

strong electroshock of the heart, the basic principles

neurogenic shock, in which the sympathetic nervous

of which are described in Chapter 13.

system is severely depressed. Administering a sympa-

Cardiac arrest often results from too little oxygen in

thomimetic drug takes the place of the diminished

the anesthetic gaseous mixture or from a depressant

sympathetic actions and can often restore full circula-

effect of the anesthesia itself. A normal cardiac rhythm

tory function.

can usually be restored by removing the anesthetic and

The second type of shock in which sympatho-

immediately applying cardiopulmonary resuscitation

mimetic drugs are valuable is anaphylactic shock, in

procedures, while at the same time supplying the

which excess histamine plays a prominent role. The

patient’s lungs with adequate quantities of ventilatory

sympathomimetic drugs have a vasoconstrictor effect

oxygen.

that opposes the vasodilating effect of histamine.

Therefore, either norepinephrine or another sympa-

thomimetic drug is often lifesaving.

Effect of Circulatory Arrest

Sympathomimetic drugs have not proved to be very

on the Brain

valuable in hemorrhagic shock. The reason is that in

this type of shock, the sympathetic nervous system is

A special problem in circulatory arrest is to prevent

almost always maximally activated by the circulatory

detrimental effects in the brain as a result of the arrest.

reflexes already; so much norepinephrine and epi-

In general, more than 5 to 8 minutes of total circula-

nephrine are already circulating in the blood that sym-

tory arrest can cause at least some degree of perma-

pathomimetic drugs have essentially no additional

nent brain damage in more than half of patients.

beneficial effect.

Circulatory arrest for as long as 10 to 15 minutes

almost always permanently destroys significant

amounts of mental power.

Other Therapy

For many years, it was taught that this detrimental

effect on the brain was caused by the acute cerebral

Treatment by the Head-Down Position. When the pressure

hypoxia that occurs during circulatory arrest.

falls too low in most types of shock, especially in

However, experiments have shown that if blood clots

hemorrhagic and neurogenic shock, placing the patient

are prevented from occurring in the blood vessels of

with the head at least 12 inches lower than the feet

the brain, this will also prevent most of the early dete-

helps tremendously in promoting venous return,

rioration of the brain during circulatory arrest. For

thereby also increasing cardiac output. This head-

instance, in animal experiments performed by Crowell,

down position is the first essential step in the treat-

all the blood was removed from the animal’s blood

ment of many types of shock.

vessels at the beginning of circulatory arrest and

Oxygen Therapy. Because the major deleterious effect of

then replaced at the end of circulatory arrest so that

most types of shock is too little delivery of oxygen to

no intravascular blood clotting could occur. In this

288

Unit IV The Circulation

experiment, the brain was usually able to withstand up

Goodnough LT, Shander A: Evolution in alternatives to

to 30 minutes of circulatory arrest without permanent

blood transfusion. Hematol J 4:87, 2003.

brain damage. Also, administration of heparin or strep-

Granger DN, Stokes KY, Shigematsu T, et al: Splanchnic

ischaemia-reperfusion injury: mechanistic insights pro-

tokinase (to prevent blood coagulation) before cardiac

vided by mutant mice. Acta Physiol Scand 173:83, 2001.

arrest was shown to increase the survivability of the

Guyton AC, Jones CE, Coleman TG: Circulatory Physiology:

brain up to two to four times longer than usual.

Cardiac Output and Its Regulation. Philadelphia: WB

It is likely that the severe brain damage that occurs

Saunders, 1973.

from circulatory arrest is caused mainly by permanent

Ledgerwood AM, Lucas CE: A review of studies on the

blockage of many small blood vessels by blood clots,

effects of hemorrhagic shock and resuscitation on the

thus leading to prolonged ischemia and eventual death

coagulation profile. J Trauma 54(5 Suppl):S68, 2003.

of the neurons.

Martin GS, Mannino DM, Eaton S, Moss M: The epidemiol-

ogy of sepsis in the United States from 1979 through 2000.

N Engl J Med 348:1546, 2003.

McLean-Tooke AP, Bethune CA, Fay AC, Spickett GP:

References

Adrenaline in the treatment of anaphylaxis: what is the

evidence? BMJ 327:1332, 2003.

Annane D, Sebille V, Charpentier C, et al: Effect of treat-

Proctor KG: Blood substitutes and experimental models of

ment with low doses of hydrocortisone and fludrocorti-

trauma. J Trauma 54(5 Suppl):S106, 2003.

sone on mortality in patients with septic shock. JAMA

Rivers E, Nguyen B, Havstad S, et al: The Early Goal-

288:862, 2002.

Directed Therapy Collaborative Group. Early goal-

Burry LD, Wax RS: Role of corticosteroids in septic shock.

directed therapy in the treatment of severe sepsis and

Ann Pharmacother 38:464, 2004.

septic shock. N Engl J Med 345:1368, 2001.

Creteur J, Vincent JL: Hemoglobin solutions. Crit Care Med

Toh CH, Dennis M: Disseminated intravascular coagulation:

31(12 Suppl):S698, 2003.

old disease, new hope. BMJ 327:974, 2003.

Crowell JW, Guyton AC: Evidence favoring a cardiac mech-

Wernly JA: Ischemia, reperfusion, and the role of surgery in

anism in irreversible hemorrhagic shock. Am J Physiol

the treatment of cardiogenic shock secondary to acute

201:893, 1961.

myocardial infarction: an interpretative review. J Surg Res

Crowell JW, Smith EE: Oxygen deficit and irreversible

117:6, 2004.

hemorrhagic shock. Am J Physiol 206:313, 1964.

Wilson M, Davis DP, Coimbra R: Diagnosis and monitoring

de Jonge E, Levi M: Effects of different plasma substitutes

of hemorrhagic shock during the initial resuscitation of

on blood coagulation: a comparative review. Crit Care

multiple trauma patients: a review. J Emerg Med 24:413,

Med 29:1261, 2001.

2003.

C H A P T E R

The Body Fluid Compartments:

Extracellular and

Intracellular Fluids;

Interstitial Fluid and Edema

The maintenance of a relatively constant volume

and a stable composition of the body fluids is essen-

tial for homeostasis, as discussed in Chapter 1. Some

of the most common and important problems in

clinical medicine arise because of abnormalities in

the control systems that maintain this constancy of

the body fluids. In this chapter and in the following

chapters on the kidneys, we discuss the overall reg-

ulation of body fluid volume, constituents of the extracellular fluid, acid-base

balance, and control of fluid exchange between extracellular and intracellular

compartments.

Fluid Intake and Output Are Balanced During

Steady-State Conditions

The relative constancy of the body fluids is remarkable because there is con-

tinuous exchange of fluid and solutes with the external environment as well as

within the different compartments of the body. For example, there is a highly

variable fluid intake that must be carefully matched by equal output from the

body to prevent body fluid volumes from increasing or decreasing.

Daily Intake of Water

Water is added to the body by two major sources: (1) it is ingested in the form

of liquids or water in the food, which together normally add about 2100 ml/day

to the body fluids, and (2) it is synthesized in the body as a result of oxidation

of carbohydrates, adding about 200 ml/day. This provides a total water intake

of about 2300 ml/day (Table 25-1). Intake of water, however, is highly variable

among different people and even within the same person on different days,

depending on climate, habits, and level of physical activity.

Daily Loss of Body Water

Insensible Water Loss. Some of the water losses cannot be precisely regulated. For

example, there is a continuous loss of water by evaporation from the respira-

tory tract and diffusion through the skin, which together account for about

700 ml/day of water loss under normal conditions. This is termed insensible

water loss because we are not consciously aware of it, even though it occurs con-

tinually in all living humans.

The insensible water loss through the skin occurs independently of sweating

and is present even in people who are born without sweat glands; the average

water loss by diffusion through the skin is about 300 to 400 ml/day. This loss is

minimized by the cholesterol-filled cornified layer of the skin, which provides a

barrier against excessive loss by diffusion. When the cornified layer becomes

291

292

Unit V The Body Fluids and Kidneys

Table 25-1

OUTPUT

INTAKE

•Kidneys

Daily Intake and Output of Water (ml/day)

•Lungs

•Feces

•Sweat

Plasma

Prolonged,

•Skin

3.0 L

Normal

Heavy Exercise

Capillary membrane

Intake

Fluids ingested

2100

Interstitial

From metabolism

200

fluid

Total intake

2300

11.0 L

Output

Insensible—skin

350

Insensible—lungs

350

650

Cell membrane

Sweat

100

5000

Feces

100

Urine

1400

500

Total output

2300

6600

Intracellular

fluid

denuded, as occurs with extensive burns, the rate of

28.0 L

evaporation can increase as much as 10-fold, to 3 to

5 L/day. For this reason, burn victims must be given

large amounts of fluid, usually intravenously, to

balance fluid loss.

Insensible water loss through the respiratory tract

averages about 300 to 400 ml/day. As air enters the

Figure 25-1

respiratory tract, it becomes saturated with moisture,

to a vapor pressure of about 47 mm Hg, before it is

Summary of body fluid regulation, including the major body fluid

expelled. Because the vapor pressure of the inspired

compartments and the membranes that separate these compart-

ments. The values shown are for an average 70-kilogram person.

air is usually less than 47 mm Hg, water is continuously

lost through the lungs with respiration. In cold

weather, the atmospheric vapor pressure decreases to

nearly 0, causing an even greater loss of water from

20 L/day in a person who has been drinking tremen-

the lungs as the temperature decreases. This explains

dous amounts of water.

the dry feeling in the respiratory passages in cold

This variability of intake is also true for most of the

weather.

electrolytes of the body, such as sodium, chloride, and

potassium. In some people, sodium intake may be as

Fluid Loss in Sweat. The amount of water lost by sweat-

low as 20 mEq/day, whereas in others, sodium intake

ing is highly variable, depending on physical activity

may be as high as 300 to 500 mEq/day. The kidneys are

and environmental temperature. The volume of sweat

faced with the task of adjusting the excretion rate of

normally is about 100 ml/day, but in very hot weather

water and electrolytes to match precisely the intake of

or during heavy exercise, water loss in sweat occa-

these substances, as well as compensating for excessive

sionally increases to 1 to 2 L/hour. This would rapidly

losses of fluids and electrolytes that occur in certain

deplete the body fluids if intake were not also

disease states. In Chapters 26 through 30, we discuss

increased by activating the thirst mechanism discussed

the mechanisms that allow the kidneys to perform

in Chapter 29.

these remarkable tasks.

Water Loss in Feces. Only a small amount of water

(100 ml/day) normally is lost in the feces. This can

Body Fluid Compartments

increase to several liters a day in people with severe

diarrhea. For this reason, severe diarrhea can be life

The total body fluid is distributed mainly between two

threatening if not corrected within a few days.

compartments: the extracellular fluid and the intracel-

lular fluid

(Figure 25-1). The extracellular fluid is

Water Loss by the Kidneys. The remaining water loss from

divided into the interstitial fluid and the blood plasma.

the body occurs in the urine excreted by the kidneys.

There is another small compartment of fluid that is

There are multiple mechanisms that control the rate

referred to as transcellular fluid. This compartment

of urine excretion. In fact, the most important means

includes fluid in the synovial, peritoneal, pericardial,

by which the body maintains a balance between water

and intraocular spaces, as well as the cerebrospinal

intake and output, as well as a balance between intake

fluid; it is usually considered to be a specialized type

and output of most electrolytes in the body, is by con-

of extracellular fluid, although in some cases, its com-

trolling the rates at which the kidneys excrete these

position may differ markedly from that of the plasma

substances. For example, urine volume can be as low

or interstitial fluid. All the transcellular fluids together

as 0.5 L/day in a dehydrated person or as high as

constitute about 1 to 2 liters.

Chapter 25

The Body Fluid Compartments: Extracellular and Intracellular Fluids; Interstitial Fluid and Edema

293

In the average 70-kilogram adult human, the total

chamber of its own, the circulatory system. The blood

body water is about 60 per cent of the body weight, or

volume is especially important in the control of car-

about 42 liters. This percentage can change, depending

diovascular dynamics.

on age, gender, and degree of obesity. As a person

The average blood volume of adults is about 7 per

grows older, the percentage of total body weight that

cent of body weight, or about 5 liters. About 60 per

is fluid gradually decreases. This is due in part to the

cent of the blood is plasma and 40 per cent is red blood

fact that aging is usually associated with an increased

cells, but these percentages can vary considerably in

percentage of the body weight being fat, which

different people, depending on gender, weight, and

decreases the percentage of water in the body. Because

other factors.

women normally have more body fat than men, they

contain slightly less water than men in proportion to

Hematocrit (Packed Red Cell Volume). The hematocrit is

their body weight. Therefore, when discussing the

the fraction of the blood composed of red blood cells,

“average” body fluid compartments, we should realize

as determined by centrifuging blood in a “hematocrit

that variations exist, depending on age, gender, and

tube” until the cells become tightly packed in the

percentage of body fat.

bottom of the tube. It is impossible to completely pack

the red cells together; therefore, about 3 to 4 per cent

of the plasma remains entrapped among the cells, and

Intracellular Fluid Compartment

the true hematocrit is only about 96 per cent of the

measured hematocrit.

About 28 of the 42 liters of fluid in the body are inside

In men, the measured hematocrit is normally about

the 75 trillion cells and are collectively called the intra-

0.40, and in women, it is about 0.36. In severe anemia,

cellular fluid. Thus, the intracellular fluid constitutes

the hematocrit may fall as low as 0.10, a value that is

about 40 per cent of the total body weight in an

barely sufficient to sustain life. Conversely, there are

“average” person.

some conditions in which there is excessive production

The fluid of each cell contains its individual mixture

of red blood cells, resulting in polycythemia. In these

of different constituents, but the concentrations of

conditions, the hematocrit can rise to 0.65.

these substances are similar from one cell to another.

In fact, the composition of cell fluids is remarkably

similar even in different animals, ranging from the

Constituents of Extracellular

most primitive microorganisms to humans. For this

reason, the intracellular fluid of all the different

and Intracellular Fluids

cells together is considered to be one large fluid

compartment.

Comparisons of the composition of the extracellular

fluid, including the plasma and interstitial fluid, and the

intracellular fluid are shown in Figures 25-2 and 25-3

Extracellular Fluid

and in Table 25-2.

Compartment

All the fluids outside the cells are collectively called

Ionic Composition of Plasma and

the extracellular fluid. Together these fluids account for

Interstitial Fluid Is Similar

about 20 per cent of the body weight, or about 14 liters

in a normal 70-kilogram adult. The two largest com-

Because the plasma and interstitial fluid are separated

partments of the extracellular fluid are the interstitial

only by highly permeable capillary membranes, their

fluid, which makes up more than three fourths of the

ionic composition is similar. The most important dif-

extracellular fluid, and the plasma, which makes up

ference between these two compartments is the higher

almost one fourth of the extracellular fluid, or about 3

concentration of protein in the plasma; because the

liters. The plasma is the noncellular part of the blood;

capillaries have a low permeability to the plasma pro-

it exchanges substances continuously with the intersti-

teins, only small amounts of proteins are leaked into

tial fluid through the pores of the capillary mem-

the interstitial spaces in most tissues.

branes. These pores are highly permeable to almost all

Because of the Donnan effect, the concentration of

solutes in the extracellular fluid except the proteins.

positively charged ions (cations) is slightly greater

Therefore, the extracellular fluids are constantly

(about 2 per cent) in the plasma than in the intersti-

mixing, so that the plasma and interstitial fluids have

tial fluid. The plasma proteins have a net negative

about the same composition except for proteins, which

charge and, therefore, tend to bind cations, such as

have a higher concentration in the plasma.

sodium and potassium ions, thus holding extra

amounts of these cations in the plasma along with the

Blood Volume

plasma proteins. Conversely, negatively charged ions

(anions) tend to have a slightly higher concentration

Blood contains both extracellular fluid (the fluid in

in the interstitial fluid compared with the plasma,

plasma) and intracellular fluid (the fluid in the red

because the negative charges of the plasma proteins

blood cells). However, blood is considered to be a sep-

repel the negatively charged anions. For practical

arate fluid compartment because it is contained in a

purposes, however, the concentration of ions in the

Chapter 25

The Body Fluid Compartments: Extracellular and Intracellular Fluids; Interstitial Fluid and Edema

295

interstitial fluid and in the plasma is considered to be

about equal.

Referring again to Figure 25-2, one can see that

the extracellular fluid, including the plasma and the

Indicator Mass A = Volume A x Concentration A

interstitial fluid, contains large amounts of sodium

and chloride ions, reasonably large amounts of bicar-

bonate ions, but only small quantities of potassium,

Indicator Mass A = Indicator Mass B

calcium, magnesium, phosphate, and organic acid ions.

The composition of extracellular fluid is carefully

regulated by various mechanisms, but especially by the

kidneys, as discussed later. This allows the cells to

remain continually bathed in a fluid that contains the

proper concentration of electrolytes and nutrients for

optimal cell function.

Important Constituents of the

Intracellular Fluid

Indicator Mass B = Volume B x Concentration B

Volume B = Indicator Mass B / Concentration B

The intracellular fluid is separated from the extracel-

Figure 25-4

lular fluid by a cell membrane that is highly permeable

to water but not to most of the electrolytes in the body.

Indicator-dilution method for measuring fluid volumes.

In contrast to the extracellular fluid, the intracellu-

lar fluid contains only small quantities of sodium and

chloride ions and almost no calcium ions. Instead, it

tion, one can calculate the unknown volume

contains large amounts of potassium and phosphate

chamber B as

ions plus moderate quantities of magnesium and

sulfate ions, all of which have low concentrations in the

Volume A ¥Concentration A

extracellular fluid. Also, cells contain large amounts of

Volume B=

Concentration B

protein, almost four times as much as in the plasma.

Note that all one needs to know for this calculation

(1) the total amount of substance injected into

Measurement of Fluid

the chamber (the numerator of the equation) and (2)

Volumes in the Different Body

the concentration of the fluid in the chamber after the

substance has been dispersed

(the denominator).

Fluid Compartments—The

For example, if 1 milliliter of a solution containing

Indicator-Dilution Principle

10 mg/ml of dye is dispersed into chamber B and

the final concentration in the chamber is 0.01 mil-

The volume of a fluid compartment in the body can be

ligram for each milliliter of fluid, the unknown volume

measured by placing an indicator substance in the

of the chamber can be calculated as follows:

compartment, allowing it to disperse evenly through-

out the compartment’s fluid, and then analyzing the

10 mg ml

Volume B=

1000

extent to which the substance becomes diluted. Figure

0.01 mg ml

25-4 shows this “indicator-dilution” method of meas-

uring the volume of a fluid compartment, which is

This method can be used to measure the volume of

based on the principle of conservation of mass. This

virtually any compartment in the body as long as (1)

means that the total mass of a substance after disper-

the indicator disperses evenly throughout the com-

sion in the fluid compartment will be the same as the

partment, (2) the indicator disperses only in the com-

total mass injected into the compartment.

partment that is being measured, and (3) the indicator

In the example shown in Figure

25-4, a small

is not metabolized or excreted. Several substances can

amount of dye or other substance contained in the

be used to measure the volume of each of the differ-

syringe is injected into a chamber, and the substance

ent body fluids.

is allowed to disperse throughout the chamber until it

becomes mixed in equal concentrations in all areas.

Determination of Volumes

Then a sample of fluid containing the dispersed sub-

of Specific Body Fluid

stance is removed and the concentration is analyzed

chemically, photoelectrically, or by other means. If

Compartments

none of the substance leaks out of the compartment,

Measurement of Total Body Water. Radioactive water

the total mass of substance in the compartment

(tritium,³H₂O) or heavy water (deuterium,²H₂O) can

(Volume B ¥ Concentration B) will equal the total

be used to measure total body water. These forms of

mass of the substance injected (Volume A ¥ Con-

water mix with the total body water within a few hours

centration A). By simple rearrangement of the equa-

after being injected into the blood, and the dilution

296

Unit V The Body Fluids and Kidneys

volume can also be calculated if one knows the

Table 25-3

hematocrit (the fraction of the total blood volume com-

Measurement of Body Fluid Volumes

posed of cells), using the following equation:

Plasma volume

Volume

Indicators

Total blood volume

1-Hematocrit

Total body water

³H

2O,²H2O, antipyrine

For example, if plasma volume is 3 liters and hemat-

Extracellular fluid

²²Na,¹²⁵I-iothalamate, thiosulfate, inulin

ocrit is 0.40, total blood volume would be calculated as

Intracellular fluid

(Calculated as Total body water -

Extracellular fluid volume)

3 liters

liters

Plasma volume

¹²⁵I-albumin, Evans blue dye (T-1824)

Blood volume

⁵¹Cr-labeled red blood cells, or calculated

Another way to measure blood volume is to inject

as Blood volume = Plasma volume/

into the circulation red blood cells that have been

(1 - Hematocrit)

labeled with radioactive material. After these mix in the

Interstitial fluid

(Calculated as Extracellular fluid

circulation, the radioactivity of a mixed blood sample

volume - Plasma volume)

can be measured, and the total blood volume can be cal-

culated using the dilution principle. A substance fre-

quently used to label the red blood cells is radioactive

From Guyton AC, Hall JE: Human Physiology and Mechanisms of Disease,

6th ed. Philadelphia: WB Saunders, 1997.

chromium (⁵¹Cr), which binds tightly with the red blood

cells.

principle can be used to calculate total body water

(Table 25-3). Another substance that has been used to

Regulation of Fluid Exchange

measure total body water is antipyrine, which is very

lipid soluble and can rapidly penetrate cell membranes

and Osmotic Equilibrium

and distribute itself uniformly throughout the intracel-

Between Intracellular and

lular and extracellular compartments.

Extracellular Fluid

Measurement of Extracellular Fluid Volume. The volume of

extracellular fluid can be estimated using any of several

A frequent problem in treating seriously ill patients is

substances that disperse in the plasma and interstitial

maintaining adequate fluids in one or both of the intra-

fluid but do not readily permeate the cell membrane.

cellular and extracellular compartments. As discussed

They include radioactive sodium, radioactive chloride,

in Chapter 16 and later in this chapter, the relative

radioactive iothalamate, thiosulfate ion, and inulin.

amounts of extracellular fluid distributed between the

When any one of these substances is injected into the

plasma and interstitial spaces are determined mainly

blood, it usually disperses almost completely through-

out the extracellular fluid within 30 to 60 minutes. Some

by the balance of hydrostatic and colloid osmotic

of these substances, however, such as radioactive

forces across the capillary membranes.

sodium, may diffuse into the cells in small amounts.

The distribution of fluid between intracellular and

Therefore, one frequently speaks of the sodium space or

extracellular compartments, in contrast, is determined

the inulin space, instead of calling the measurement the

mainly by the osmotic effect of the smaller solutes—

true extracellular fluid volume.

especially sodium, chloride, and other electrolytes—

acting across the cell membrane. The reason for this is

Calculation of Intracellular Volume. The intracellular

that the cell membranes are highly permeable to water

volume cannot be measured directly. However, it can be

calculated as

but relatively impermeable to even small ions such as

sodium and chloride. Therefore, water moves across

Intracellular volume = Total body water

the cell membrane rapidly, so that the intracellular

- Extracellular volume

fluid remains isotonic with the extracellular fluid.

In the next section, we discuss the interrelations

Measurement of Plasma Volume. To measure plasma

volume, a substance must be used that does not readily

between intracellular and extracellular fluid volumes

penetrate capillary membranes but remains in the vas-

and the osmotic factors that can cause shifts of fluid

cular system after injection. One of the most commonly

between these two compartments.

used substances for measuring plasma volume is serum

albumin labeled with radioactive iodine (¹²⁵I-albumin).

Also, dyes that avidly bind to the plasma proteins, such

Basic Principles of Osmosis

as Evans blue dye (also called T-1824), can be used to

and Osmotic Pressure

measure plasma volume.

The basic principles of osmosis and osmotic pressure

Calculation of Interstitial Fluid Volume. Interstitial fluid

were presented in Chapter 4. Therefore, we review

volume cannot be measured directly, but it can be cal-

culated as

here only the most important aspects of these princi-

ples as they apply to volume regulation.

Interstitial fluid volume = Extracellular fluid volume

Osmosis is the net diffusion of water across a selec-

- Plasma volume

tively permeable membrane from a region of high water

Measurement of Blood Volume. If one measures plasma

concentration to one that has a lower water concentra-

volume using the methods described earlier, blood

tion. When a solute is added to pure water, this reduces

Chapter 25

The Body Fluid Compartments: Extracellular and Intracellular Fluids; Interstitial Fluid and Edema

297

the concentration of water in the mixture. Thus, the

the osmosis. The precise amount of pressure required

higher the solute concentration in a solution, the lower

to prevent the osmosis is called the osmotic pressure.

the water concentration. Further, water diffuses from

Osmotic pressure, therefore, is an indirect measure-

a region of low solute concentration (high water con-

ment of the water and solute concentrations of a solu-

centration) to one with a high solute concentration

tion. The higher the osmotic pressure of a solution,

(low water concentration).

the lower the water concentration and the higher the

Because cell membranes are relatively impermeable

solute concentration of the solution.

to most solutes but highly permeable to water (i.e.,

selectively permeable), whenever there is a higher

Relation Between Osmotic Pressure and Osmolarity. The

concentration of solute on one side of the cell mem-

osmotic pressure of a solution is directly proportional

brane, water diffuses across the membrane toward the

to the concentration of osmotically active particles in

region of higher solute concentration. Thus, if a solute

that solution. This is true regardless of whether the

such as sodium chloride is added to the extracellular

solute is a large molecule or a small molecule. For

fluid, water rapidly diffuses from the cells through the

example, one molecule of albumin with a molecular

cell membranes into the extracellular fluid until the

weight of 70,000 has the same osmotic effect as one

water concentration on both sides of the membrane

molecule of glucose with a molecular weight of 180.

becomes equal. Conversely, if a solute such as sodium

One molecule of sodium chloride, however, has two

chloride is removed from the extracellular fluid, water

osmotically active particles, Na⁺ and Cl^-, and therefore

diffuses from the extracellular fluid through the cell

has twice the osmotic effect of either an albumin mol-

membranes and into the cells. The rate of diffusion of

ecule or a glucose molecule. Thus, the osmotic pressure

water is called the rate of osmosis.

of a solution is proportional to its osmolarity, a

measure of the concentration of solute particles.

Relation Between Moles and Osmoles. Because the water

Expressed mathematically, according to van’t Hoff ’s

concentration of a solution depends on the number of

law, osmotic pressure (p) can be calculated as

solute particles in the solution, a concentration term is

p = CRT

needed to describe the total concentration of solute

particles, regardless of their exact composition. The

where C is the concentration of solutes in osmoles per

total number of particles in a solution is measured in

liter, R is the ideal gas constant, and T is the absolute

osmoles. One osmole (osm) is equal to 1 mole (mol)

temperature in degrees kelvin (273° + centigrade°). If

(6.02

¥ 10²³) of solute particles. Therefore, a solution

p is expressed in millimeters of mercury (mm Hg), the

containing 1 mole of glucose in each liter has a con-

unit of pressure commonly used for biological fluids,

centration of 1 osm/L. If a molecule dissociates into

and T is normal body temperature (273° + 37° =

two ions (giving two particles), such as sodium chlo-

310° kelvin), the value of p calculates to be about

ride ionizing to give chloride and sodium ions, then a

19,300 mm Hg for a solution having a concentration

solution containing 1 mol/L will have an osmolar con-

of 1 osm/L. This means that for a concentration of

centration of 2 osm/L. Likewise, a solution that con-

1 mOsm/L, p is equal to 19.3 mm Hg. Thus, for each

tains 1 mole of a molecule that dissociates into three

milliosmole concentration gradient across the cell

ions, such as sodium sulfate (Na₂SO₄), will contain

membrane, 19.3 mm Hg osmotic pressure is exerted.

3 osm/L. Thus, the term osmole refers to the number

of osmotically active particles in a solution rather than

Calculation of the Osmolarity and Osmotic Pressure of a

to the molar concentration.

Solution. Using van’t Hoff ’s law, one can calculate the

In general, the osmole is too large a unit for express-

potential osmotic pressure of a solution, assuming that

ing osmotic activity of solutes in the body fluids.

the cell membrane is impermeable to the solute.

The term milliosmole (mOsm), which equals 1/1000

For example, the osmotic pressure of a 0.9 per cent

osmole, is commonly used.

sodium chloride solution is calculated as follows: A

0.9 per cent solution means that there is 0.9 gram of

Osmolality and Osmolarity. The osmolal concentration of

sodium chloride per 100 milliliters of solution, or

a solution is called osmolality when the concentration

9 g/L. Because the molecular weight of sodium chlo-

is expressed as osmoles per kilogram of water; it is

ride is 58.5 g/mol, the molarity of the solution is 9 g/L

called osmolarity when it is expressed as osmoles per

divided by 58.5 g/mol, or about 0.154 mol/L. Because

liter of solution. In dilute solutions such as the body

each molecule of sodium chloride is equal to

fluids, these two terms can be used almost synony-

2 osmoles, the osmolarity of the solution is 0.154

¥ 2,

mously because the differences are small. In most

or 0.308 osm/L. Therefore, the osmolarity of this solu-

cases, it is easier to express body fluid quantities in

tion is 308 mOsm/L. The potential osmotic pressure

liters of fluid rather than in kilograms of water. There-

of this solution would therefore be

308 mOsm/L

fore, most of the calculations used clinically and the

¥ 19.3 mm Hg/mOsm/L, or 5944 mm Hg.

calculations expressed in the next several chapters are

This calculation is only an approximation, because

based on osmolarities rather than osmolalities.

sodium and chloride ions do not behave entirely inde-

pendently in solution because of interionic attraction

Osmotic Pressure. Osmosis of water molecules across a

between them. One can correct for these deviations

selectively permeable membrane can be opposed by

from the predictions of van’t Hoff ’s law by using a

applying a pressure in the direction opposite that of

correction factor called the osmotic coefficient. For

298

Unit V The Body Fluids and Kidneys

sodium chloride, the osmotic coefficient is about 0.93.

Therefore, the actual osmolarity of a 0.9 per cent

sodium chloride solution is

308

¥ 0.93, or about

286 mOsm/L. For practical reasons, the osmotic coef-

ficients of different solutes are sometimes neglected in

determining the osmolarity and osmotic pressures of

physiologic solutions.

280 mOsm/L

Osmolarity of the Body Fluids. Turning back to Table 25-2,

ISOTONIC

note the approximate osmolarity of the various osmot-

No change

ically active substances in plasma, interstitial fluid, and

intracellular fluid. Note that about 80 per cent of the

total osmolarity of the interstitial fluid and plasma is

due to sodium and chloride ions, whereas for intracel-

lular fluid, almost half the osmolarity is due to potas-

sium ions, and the remainder is divided among many

other intracellular substances.

As shown in Table 25-2, the total osmolarity of each

200 mOsm/L

360 mOsm/L

of the three compartments is about 300 mOsm/L, with

the plasma being about 1 mOsm/L greater than that

HYPOTONIC

HYPERTONIC

of the interstitial and intracellular fluids. The slight dif-

Cell swells

Cell shrinks

ference between plasma and interstitial fluid is caused

Figure 25-5

by the osmotic effects of the plasma proteins, which

maintain about 20 mm Hg greater pressure in the cap-

Effects of isotonic (A), hypertonic (B), and hypotonic (C) solutions

illaries than in the surrounding interstitial spaces, as

on cell volume.

discussed in Chapter 16.

Corrected Osmolar Activity of the Body Fluids. At the

bottom of Table 25-2 are shown corrected osmolar

potential osmotic pressure that can develop across the

activities of plasma, interstitial fluid, and intracellular

cell membrane is more than 5400 mm Hg. This demon-

fluid. The reason for these corrections is that molecules

strates the large force that can move water across the

and ions in solution exert interionic and intermolecu-

cell membrane when the intracellular and extracellu-

lar attraction or repulsion from one solute molecule to

lar fluids are not in osmotic equilibrium. As a result of

the next, and these two effects can cause, respectively,

these forces, relatively small changes in the concen-

a slight decrease or an increase in the osmotic “activ-

tration of impermeant solutes in the extracellular fluid

ity” of the dissolved substance.

can cause large changes in cell volume.

Total Osmotic Pressure Exerted by the Body Fluids. Table

Isotonic, Hypotonic, and Hypertonic Fluids. The effects of

25-2 also shows the total osmotic pressure in millime-

different concentrations of impermeant solutes in the

ters of mercury that would be exerted by each of the

extracellular fluid on cell volume are shown in Figure

different fluids if it were placed on one side of the cell

25-5. If a cell is placed in a solution of impermeant

membrane with pure water on the other side. Note

solutes having an osmolarity of 282 mOsm/L, the cells

that this total pressure averages about 5443 mm Hg for

will not shrink or swell because the water concentra-

plasma, which is 19.3 times the corrected osmolarity of

tion in the intracellular and extracellular fluids is equal

282 mOsm/L for plasma.

and the solutes cannot enter or leave the cell. Such a

solution is said to be isotonic because it neither shrinks

nor swells the cells. Examples of isotonic solutions

Osmotic Equilibrium Is

include a 0.9 per cent solution of sodium chloride or a

5 per cent glucose solution. These solutions are impor-

Maintained Between

tant in clinical medicine because they can be infused

Intracellular and

into the blood without the danger of upsetting osmotic

Extracellular Fluids

equilibrium between the intracellular and extracellu-

lar fluids.

Large osmotic pressures can develop across the cell

If a cell is placed into a hypotonic solution that has

membrane with relatively small changes in the con-

a lower concentration of impermeant solutes (less than

centrations of solutes in the extracellular fluid. As dis-

282 mOsm/L), water will diffuse into the cell, causing

cussed earlier, for each milliosmole concentration

it to swell; water will continue to diffuse into the cell,

gradient of an impermeant solute (one that will not

diluting the intracellular fluid while also concentrating

permeate the cell membrane), about

19.3 mm Hg

the extracellular fluid until both solutions have about

osmotic pressure is exerted across the cell membrane.

the same osmolarity. Solutions of sodium chloride with

If the cell membrane is exposed to pure water and the

a concentration of less than 0.9 per cent are hypotonic

osmolarity of intracellular fluid is 282 mOsm/L, the

and cause cells to swell.

Chapter 25

The Body Fluid Compartments: Extracellular and Intracellular Fluids; Interstitial Fluid and Edema

299

If a cell is placed in a hypertonic solution having a

1. Water moves rapidly across cell membranes;

higher concentration of impermeant solutes, water will

therefore, the osmolarities of intracellular and

flow out of the cell into the extracellular fluid, con-

extracellular fluids remain almost exactly equal

centrating the intracellular fluid and diluting the extra-

to each other except for a few minutes after a

cellular fluid. In this case, the cell will shrink until the

change in one of the compartments.

two concentrations become equal. Sodium chloride

2. Cell membranes are almost completely

solutions of greater than 0.9 per cent are hypertonic.

impermeable to many solutes; therefore, the

number of osmoles in the extracellular or

Isosmotic, Hyperosmotic, and Hypo-osmotic Fluids. The

intracellular fluid generally remains constant

terms isotonic, hypotonic, and hypertonic refer to

unless solutes are added to or lost from the

whether solutions will cause a change in cell volume.

extracellular compartment.

The tonicity of solutions depends on the concentration

With these basic principles in mind, we can analyze

of impermeant solutes. Some solutes, however, can

the effects of different abnormal fluid conditions on

permeate the cell membrane. Solutions with an osmo-

extracellular and intracellular fluid volumes and

larity the same as the cell are called isosmotic, regard-

osmolarities.

less of whether the solute can penetrate the cell

membrane.

The terms hyperosmotic and hypo-osmotic refer to

Effect of Adding Saline Solution

solutions that have a higher or lower osmolarity,

to the Extracellular Fluid

respectively, compared with the normal extracellular

fluid, without regard for whether the solute permeates

If an isotonic saline solution is added to the extracel-

the cell membrane. Highly permeating substances,

lular fluid compartment, the osmolarity of the extra-

such as urea, can cause transient shifts in fluid volume

cellular fluid does not change; therefore, no osmosis

between the intracellular and extracellular fluids, but

occurs through the cell membranes. The only effect is

given enough time, the concentrations of these sub-

an increase in extracellular fluid volume

(Figure

stances eventually become equal in the two compart-

25-6A). The sodium and chloride largely remain in the

ments and have little effect on intracellular volume

extracellular fluid because the cell membrane behaves

under steady-state conditions.

as though it were virtually impermeable to the sodium

chloride.

Osmotic Equilibrium Between Intracellular and Extracellular

If a hypertonic solution is added to the extracellular

Fluids Is Rapidly Attained. The transfer of fluid across the

fluid, the extracellular osmolarity increases and causes

cell membrane occurs so rapidly that any differences

osmosis of water out of the cells into the extracellular

in osmolarities between these two compartments are

compartment (see Figure 25-6B). Again, almost all the

usually corrected within seconds or, at the most,

added sodium chloride remains in the extracellular

minutes. This rapid movement of water across the cell

compartment, and fluid diffuses from the cells into the

membrane does not mean that complete equilibrium

extracellular space to achieve osmotic equilibrium.

occurs between the intracellular and extracellular

The net effect is an increase in extracellular volume

compartments throughout the whole body within the

(greater than the volume of fluid added), a decrease in

same short period. The reason for this is that fluid

intracellular volume, and a rise in osmolarity in both

usually enters the body through the gut and must be

compartments.

transported by the blood to all tissues before complete

If a hypotonic solution is added to the extracellular

osmotic equilibrium can occur. It usually takes about

fluid, the osmolarity of the extracellular fluid decreases

30 minutes to achieve osmotic equilibrium everywhere

and some of the extracellular water diffuses into the

in the body after drinking water.

cells until the intracellular and extracellular compart-

ments have the same osmolarity (see Figure 25-6C).

Both the intracellular and the extracellular volumes

are increased by the addition of hypotonic fluid,

Volume and Osmolality of

although the intracellular volume increases to a

Extracellular and Intracellular

greater extent.

Fluids in Abnormal States

Calculation of Fluid Shifts and Osmolarities After Infusion

Some of the different factors that can cause extracel-

of Hypertonic Saline. We can calculate the sequential

lular and intracellular volumes to change markedly are

effects of infusing different solutions on extracellular

ingestion of water, dehydration, intravenous infusion

and intracellular fluid volumes and osmolarities. For

of different types of solutions, loss of large amounts of

example, if 2 liters of a hypertonic 3.0 per cent sodium

fluid from the gastrointestinal tract, and loss of abnor-

chloride solution are infused into the extracellular

mal amounts of fluid by sweating or through the

fluid compartment of a 70-kilogram patient whose

kidneys.

initial plasma osmolarity is 280 mOsm/L, what would

One can calculate both the changes in intracellular

be the intracellular and extracellular fluid volumes and

and extracellular fluid volumes and the types of

osmolarities after osmotic equilibrium?

therapy that should be instituted if the following basic

The first step is to calculate the initial conditions,

principles are kept in mind:

including the volume, concentration, and total

300

Unit V The Body Fluids and Kidneys

Intracellular fluid

Extracellular fluid

Normal State

A. Add Isotonic NaCl

300

200

100

Volume (liters)

Figure 25-6

C. Add Hypotonic NaCl

B. Add Hypertonic NaCl

Effect of adding isotonic, hyper-

tonic, and hypotonic solutions

to the extracellular fluid after

osmotic equilibrium. The normal

state is indicated by the solid

lines, and the shifts from normal

are shown by the shaded areas.

The volumes of intracellular and

extracellular fluid compartments

are shown in the abscissa of each

diagram, and the osmolarities of

these compartments are shown

on the ordinates.

milliosmoles in each compartment. Assuming that

would be an additional 2051 milliosmoles of total

extracellular fluid volume is 20 per cent of body weight

solute, yielding a total of 5791 milliosmoles. Because

and intracellular fluid volume is 40 per cent of body

the extracellular compartment now has 16 liters of

weight, the following volumes and concentrations

volume, the concentration can be calculated by divid-

can be calculated.

ing

5791 milliosmoles by 16 liters to yield a con-

centration of 373 mOsm/L. Thus, the following values

Step 1. Initial Conditions

would occur instantly after adding the solution.

Volume

Concentration

Total

Step 2. Instantaneous Effect of Adding 2 Liters of

(Liters)

(mOsm/L)

(mOsm)

3.0 Per Cent Sodium Chloride

Extracellular fluid

280

3,920

Intracellular fluid

280

7,840

Volume

Concentration

Total

Total body fluid

280

11,760

(Liters)

(mOsm/L)

(mOsm)

Extracellular fluid

373

5,971

Intracellular fluid

280

7,840

Next, we calculate the total milliosmoles added to

Total body fluid

No equilibrium

13,811

the extracellular fluid in 2 liters of 3.0 per cent sodium

chloride. A 3.0 per cent solution means that there are

3.0 g/100 ml, or 30 grams of sodium chloride per liter.

In the third step, we calculate the volumes and con-

Because the molecular weight of sodium chloride is

centrations that would occur within a few minutes

about 58.5 g/mol, this means that there is about 0.513

after osmotic equilibrium develops. In this case, the

mole of sodium chloride per liter of solution. For 2

concentrations in the intracellular and extracellular

liters of solution, this would be 1.026 mole of sodium

fluid compartments would be equal and can be calcu-

chloride. Because 1 mole of sodium chloride is about

lated by dividing the total milliosmoles in the body,

equal to 2 osmoles (sodium chloride has two osmoti-

13,811, by the total volume, which is now 44 liters. This

cally active particles per mole), the net effect of adding

yields a concentration of 313.9 mOsm/L. Therefore, all

2 liters of this solution is to add 2051 milliosmoles of

the body fluid compartments will have this same con-

sodium chloride to the extracellular fluid.

centration after osmotic equilibrium. Assuming that

In Step 2, we calculate the instantaneous effect of

no solute or water has been lost from the body and

adding 2051 milliosmoles of sodium chloride to the

that there is no movement of sodium chloride into or

extracellular fluid along with 2 liters of volume. There

out of the cells, we then calculate the volumes of

would be no change in the intracellular fluid concen-

the intracellular and extracellular compartments. The

tration or volume, and there would be no osmotic

intracellular fluid volume is calculated by dividing the

equilibrium. In the extracellular fluid, however, there

total milliosmoles in the intracellular fluid (7840) by

Chapter 25

The Body Fluid Compartments: Extracellular and Intracellular Fluids; Interstitial Fluid and Edema

301

the concentration (313.9 mOsm/L), to yield a volume

After the glucose or other nutrients are metabolized, an

of 24.98 liters. Extracellular fluid volume is calculated

excess of water often remains, especially if additional

by dividing the total milliosmoles in extracellular fluid

fluid is ingested. Ordinarily, the kidneys excrete this in

the form of a very dilute urine. The net result, therefore,

(5971) by the concentration (313.9 mOsm/L), to yield

is the addition of only nutrients to the body.

a volume of 19.02 liters. Again, these calculations are

based on the assumption that the sodium chloride

added to the extracellular fluid remains there and does

not move into the cells.

Clinical Abnormalities of

Fluid Volume Regulation:

Step 3. Effect of Adding 2 Liters of 3.0 Per Cent Sodium

Hyponatremia and

Chloride After Osmotic Equilibrium

Hypernatremia

The primary measurement that is readily available to

Volume

Concentration

Total

the clinician for evaluating a patient’s fluid status is the

(Liters)

(mOsm/L)

(mOsm)

plasma sodium concentration. Plasma osmolarity is not

Extracellular fluid

19.02

313.9

5,971

routinely measured, but because sodium and its associ-

Intracellular fluid

24.98

313.9

7,840

ated anions (mainly chloride) account for more than

Total body fluid

44.0

313.9

13,811

90 per cent of the solute in the extracellular fluid,

plasma sodium concentration is a reasonable indicator

of plasma osmolarity under many conditions. When

Thus, one can see from this example that adding 2

plasma sodium concentration is reduced more than a

liters of a hypertonic sodium chloride solution causes

few milliequivalents below normal (about 142 mEq/L),

more than a 5-liter increase in extracellular fluid

a person is said to have hyponatremia. When plasma

volume while decreasing intracellular fluid volume by

sodium concentration is elevated above normal, a

almost 3 liters.

person is said to have hypernatremia.

This method of calculating changes in intracellular

and extracellular fluid volumes and osmolarities can

be applied to virtually any clinical problem of fluid

Causes of Hyponatremia: Excess

volume regulation. The reader should be familiar with

Water or Loss of Sodium

such calculations because an understanding of the

mathematical aspects of osmotic equilibrium between

Decreased plasma sodium concentration can result

intracellular and extracellular fluid compartments is

from loss of sodium chloride from the extracellular fluid

essential for understanding almost all fluid abnormal-

or addition of excess water to the extracellular fluid

ities of the body and their treatment.

(Table 25-4). A primary loss of sodium chloride usually

results in hypo-osmotic dehydration and is associated

with decreased extracellular fluid volume. Conditions

that can cause hyponatremia owing to loss of sodium

Glucose and Other

chloride include diarrhea and vomiting. Overuse of

Solutions Administered

diuretics that inhibit the ability of the kidneys to con-

for Nutritive Purposes

serve sodium and certain types of sodium-wasting

kidney diseases can also cause modest degrees of

Many types of solutions are administered intravenously

hyponatremia. Finally, Addison’s disease, which results

to provide nutrition to people who cannot otherwise

from decreased secretion of the hormone aldosterone,

take adequate amounts of nutrition. Glucose solutions

impairs the ability of the kidneys to reabsorb sodium

are widely used, and amino acid and homogenized fat

and can cause a modest degree of hyponatremia.

solutions are used to a lesser extent. When these solu-

Hyponatremia can also be associated with excess

tions are administered, their concentrations of osmoti-

water retention, which dilutes the sodium in the extra-

cally active substances are usually adjusted nearly to

cellular fluid, a condition that is referred to as hypo-

isotonicity, or they are given slowly enough that they do

osmotic overhydration. For example, excessive secretion

not upset the osmotic equilibrium of the body fluids.

of antidiuretic hormone, which causes the kidney

Table 25-4

Abnormalities of Body Fluid Volume Regulation: Hyponatremia and Hypernatremia

Plasma Na⁺

Extracellular

Intracellular

Abnormality

Cause

Concentration

Fluid Volume

Hypo-osmotic dehydration

Adrenal insufficiency; overuse of diuretics

≠

Hypo-osmotic overhydration

Excess ADH; bronchogenic tumor

≠

Hyper-osmotic dehydration

Diabetes insipidus; excessive sweating

≠

Hyper-osmotic overhydration

Cushing’s disease; primary aldosteronism

≠

ADH, antidiuretic hormone.

302

Unit V The Body Fluids and Kidneys

tubules to reabsorb more water, can lead to hypona-

cell can no longer be pumped out of the cells, and the

tremia and overhydration.

excess sodium ions inside the cells cause osmosis of

water into the cells. Sometimes this can increase intra-

cellular volume of a tissue area—even of an entire

Causes of Hypernatremia: Water

ischemic leg, for example—to two to three times

Loss or Excess Sodium

normal. When this occurs, it is usually a prelude to

death of the tissue.

Increased plasma sodium concentration, which also

Intracellular edema can also occur in inflamed

causes increased osmolarity, can be due to either loss of

tissues. Inflammation usually has a direct effect on the

water from the extracellular fluid, which concentrates

the sodium ions, or excess sodium in the extracellular

cell membranes to increase their permeability, allow-

fluid. When there is primary loss of water from the

ing sodium and other ions to diffuse into the interior

extracellular fluid, this results in hyperosmotic dehydra-

of the cell, with subsequent osmosis of water into the

tion. This condition can occur from an inability to

cells.

secrete antidiuretic hormone, which is needed for the

kidneys to conserve water. As a result of lack of anti-

diuretic hormone, the kidneys excrete large amounts

Extracellular Edema

of dilute urine

(a disorder referred to as diabetes

insipidus), causing dehydration and increased concen-

Extracellular fluid edema occurs when there is excess

tration of sodium chloride in the extracellular fluid. In

fluid accumulation in the extracellular spaces. There

certain types of renal diseases, the kidneys cannot

are two general causes of extracellular edema: (1)

respond to antidiuretic hormone, also causing a type of

nephrogenic diabetes insipidus. A more common cause

abnormal leakage of fluid from the plasma to the inter-

of hypernatremia associated with decreased extracellu-

stitial spaces across the capillaries, and (2) failure of

lar fluid volume is dehydration caused by water intake

the lymphatics to return fluid from the interstitium

that is less than water loss, as can occur with sweating

back into the blood. The most common clinical cause

during prolonged, heavy exercise.

of interstitial fluid accumulation is excessive capillary

Hypernatremia can also occur as a result of excessive

fluid filtration.

sodium chloride added to the extracellular fluid. This

often results in hyperosmotic overhydration because

Factors That Can Increase Capillary Filtration

excess extracellular sodium chloride is usually associ-

To understand the causes of excessive capillary filtra-

ated with at least some degree of water retention by the

tion, it is useful to review the determinants of capillary

kidneys as well. For example, excessive secretion of the

filtration discussed in Chapter 16. Mathematically, cap-

sodium-retaining hormone aldosterone can cause a mild

illary filtration rate can be expressed as

degree of hypernatremia and overhydration. The reason

that the hypernatremia is not more severe is that

Filtration = K_f ¥ (P_c - P_if - p_c + p_if),

increased aldosterone secretion causes the kidneys to

reabsorb greater amounts of water as well as sodium.

where K_f is the capillary filtration coefficient

(the

Thus, in analyzing abnormalities of plasma sodium

product of the permeability and surface area of the

concentration and deciding on proper therapy, one

capillaries), P_c is the capillary hydrostatic pressure, P_if

should first determine whether the abnormality is

is the interstitial fluid hydrostatic pressure, p_c is the

caused by a primary loss or gain of sodium or a primary

capillary plasma colloid osmotic pressure, and p_if is the

loss or gain of water.

interstitial fluid colloid osmotic pressure. From this

equation, one can see that any one of the following

changes can increase the capillary filtration rate:

Edema: Excess Fluid

∑ Increased capillary filtration coefficient.

in the Tissues

∑ Increased capillary hydrostatic pressure.

∑ Decreased plasma colloid osmotic pressure.

Edema refers to the presence of excess fluid in the

body tissues. In most instances, edema occurs mainly

Lymphatic Blockage Causes Edema

in the extracellular fluid compartment, but it can

When lymphatic blockage occurs, edema can become

involve intracellular fluid as well.

especially severe because plasma proteins that leak

into the interstitium have no other way to be removed.

The rise in protein concentration raises the colloid

Intracellular Edema

osmotic pressure of the interstitial fluid, which draws

even more fluid out of the capillaries.

Two conditions are especially prone to cause intracel-

Blockage of lymph flow can be especially severe

lular swelling: (1) depression of the metabolic systems

with infections of the lymph nodes, such as occurs with

of the tissues, and (2) lack of adequate nutrition to

infection by filaria nematodes. Blockage of the lymph

the cells. For example, when blood flow to a tissue

vessels can occur in certain types of cancer or after

is decreased, the delivery of oxygen and nutrients is

surgery in which lymph vessels are removed or

reduced. If the blood flow becomes too low to main-

obstructed. For example, large numbers of lymph

tain normal tissue metabolism, the cell membrane

vessels are removed during radical mastectomy,

ionic pumps become depressed. When this occurs,

impairing removal of fluid from the breast and arm

sodium ions that normally leak into the interior of the

areas and causing edema and swelling of the tissue

Chapter 25

The Body Fluid Compartments: Extracellular and Intracellular Fluids; Interstitial Fluid and Edema

303

spaces. A few lymph vessels eventually regrow after

factors acting together cause serious generalized extra-

this type of surgery, so that the interstitial edema is

cellular edema.

usually temporary.

In patients with left-sided heart failure but without

significant failure of the right side of the heart, blood is

pumped into the lungs normally by the right side of the

Summary of Causes of

heart but cannot escape easily from the pulmonary

veins to the left side of the heart because this part of the

Extracellular Edema

heart has been greatly weakened. Consequently, all

A large number of conditions can cause fluid accumu-

the pulmonary vascular pressures, including pulmon-

lation in the interstitial spaces by the abnormal leaking

ary capillary pressure, rise far above normal, causing

of fluid from the capillaries or by preventing the lym-

serious and life-threatening pulmonary edema. When

phatics from returning fluid from the interstitium back

untreated, fluid accumulation in the lungs can rapidly

to the circulation. The following is a partial list of con-

progress, causing death within a few hours.

ditions that can cause extracellular edema by these two

types of abnormalities:

Edema Caused by Decreased Kidney Excretion of Salt and Water.

Increased capillary pressure

As discussed earlier, most sodium chloride added to the

A. Excessive kidney retention of salt and water

blood remains in the extracellular compartment, and

1. Acute or chronic kidney failure

only small amounts enter the cells. Therefore, in kidney

2. Mineralocorticoid excess

diseases that compromise urinary excretion of salt and

B. High venous pressure and venous constriction

water, large amounts of sodium chloride and water are

1. Heart failure

added to the extracellular fluid. Most of this salt and

2. Venous obstruction

water leaks from the blood into the interstitial spaces,

3. Failure of venous pumps

but some remains in the blood. The main effects of this

(a) Paralysis of muscles

are to cause (1) widespread increases in interstitial fluid

(b) Immobilization of parts of the body

volume (extracellular edema) and

(2) hypertension

because of the increase in blood volume, as explained

C. Decreased arteriolar resistance

in Chapter 19. As an example, children who develop

1. Excessive body heat

acute glomerulonephritis, in which the renal glomeruli

2. Insufficiency of sympathetic nervous system

are injured by inflammation and therefore fail to filter

3. Vasodilator drugs

adequate amounts of fluid, also develop serious

II.

Decreased plasma proteins

extracellular fluid edema in the entire body; along with

A. Loss of proteins in urine (nephrotic

the edema, these children usually develop severe

syndrome)

hypertension.

B. Loss of protein from denuded skin areas

1. Burns

Edema Caused by Decreased Plasma Proteins. A reduction in

2. Wounds

plasma concentration of proteins because of either

C. Failure to produce proteins

failure to produce normal amounts of proteins or

1. Liver disease (e.g., cirrhosis)

leakage of proteins from the plasma causes the plasma

2. Serious protein or caloric malnutrition

colloid osmotic pressure to fall. This leads to increased

III.

Increased capillary permeability

capillary filtration throughout the body as well as extra-

A. Immune reactions that cause release of

cellular edema.

histamine and other immune products

One of the most important causes of decreased

B. Toxins

plasma protein concentration is loss of proteins in the

C. Bacterial infections

urine in certain kidney diseases, a condition referred to

D. Vitamin deficiency, especially vitamin C

as nephrotic syndrome. Multiple types of renal diseases

E. Prolonged ischemia

can damage the membranes of the renal glomeruli,

F. Burns

causing the membranes to become leaky to the plasma

IV.

Blockage of lymph return

proteins and often allowing large quantities of these

A. Cancer

proteins to pass into the urine. When this loss exceeds

B. Infections (e.g., filaria nematodes)

the ability of the body to synthesize proteins, a reduc-

C. Surgery

tion in plasma protein concentration occurs. Serious

D. Congenital absence or abnormality of

generalized edema occurs when the plasma protein con-

lymphatic vessels

centration falls below 2.5 g/100 ml.

Cirrhosis of the liver is another condition that causes

Edema Caused by Heart Failure. One of the most serious and

a reduction in plasma protein concentration. Cirrhosis

most common causes of edema is heart failure. In heart

means development of large amounts of fibrous tissue

failure, the heart fails to pump blood normally from the

among the liver parenchymal cells. One result is failure

veins into the arteries; this raises venous pressure and

of these cells to produce sufficient plasma proteins,

capillary pressure, causing increased capillary filtration.

leading to decreased plasma colloid osmotic pressure

In addition, the arterial pressure tends to fall, causing

and the generalized edema that goes with this condition.

decreased excretion of salt and water by the kidneys,

Another way that liver cirrhosis causes edema is that

which increases blood volume and further raises capil-

the liver fibrosis sometimes compresses the abdominal

lary hydrostatic pressure to cause still more edema.

portal venous drainage vessels as they pass through the

Also, diminished blood flow to the kidneys stimulates

liver before emptying back into the general circulation.

secretion of renin, causing increased formation of

Blockage of this portal venous outflow raises capillary

angiotensin II and increased secretion of aldosterone,

hydrostatic pressure throughout the gastrointestinal

both of which cause additional salt and water retention

area and further increases filtration of fluid out of

by the kidneys. Thus, in untreated heart failure, all these

the plasma into the intra-abdominal areas. When this

304

Unit V The Body Fluids and Kidneys

occurs, the combined effects of decreased plasma

tissues with relatively small additional increases in

protein concentration and high portal capillary pres-

interstitial fluid hydrostatic pressure. Thus, in the pos-

sures cause transudation of large amounts of fluid and

itive tissue pressure range, this safety factor against

protein into the abdominal cavity, a condition referred

edema is lost because of the large increase in compli-

to as ascites.

ance of the tissues.

Importance of Interstitial Gel in Preventing Fluid Accumulation in

Safety Factors That Normally

the Interstitium. Note in Figure

25-7 that in normal

tissues with negative interstitial fluid pressure, virtually

Prevent Edema

all the fluid in the interstitium is in gel form. That is, the

fluid is bound in a proteoglycan meshwork so that there

Even though many disturbances can cause edema,

are virtually no “free” fluid spaces larger than a few

usually the abnormality must be severe before serious

hundredths of a micrometer in diameter. The impor-

edema develops. The reason for this is that three major

tance of the gel is that it prevents fluid from flowing

safety factors prevent excessive fluid accumulation in

easily through the tissues because of impediment from

the interstitial spaces: (1) low compliance of the inter-

the “brush pile” of trillions of proteoglycan filaments.

stitium when interstitial fluid pressure is in the nega-

Also, when the interstitial fluid pressure falls to very

tive pressure range, (2) the ability of lymph flow

negative values, the gel does not contract greatly

to increase 10- to 50-fold, and (3) washdown of inter-

because the meshwork of proteoglycan filaments offers

an elastic resistance to compression. In the negative

stitial fluid protein concentration, which reduces

fluid pressure range, the interstitial fluid volume does

interstitial fluid colloid osmotic pressure as capillary

not change greatly, regardless of whether the degree of

filtration increases.

suction is only a few millimeters of mercury negative

pressure or 10 to 20 mm Hg negative pressure. In other

Safety Factor Caused by Low Compliance

words, the compliance of the tissues is very low in the

of the Interstitium in the Negative

negative pressure range.

Pressure Range

In Chapter 16, we noted that interstitial fluid hydro-

static pressure in most loose subcutaneous tissues of

the body is slightly less than atmospheric pressure,

averaging about -3 mm Hg. This slight suction in the

tissues helps hold the tissues together. Figure 25-7

Free fluid

Gel fluid

shows the approximate relations between different

levels of interstitial fluid pressure and interstitial fluid

volume, as extrapolated to the human being from

animal studies. Note in Figure 25-7 that as long as the

interstitial fluid pressure is in the negative range, small

changes in interstitial fluid volume are associated with

relatively large changes in interstitial fluid hydrostatic

pressure. Therefore, in the negative pressure range, the

compliance of the tissues, defined as the change in

volume per millimeter of mercury pressure change, is

(High

low.

compliance)

How does the low compliance of the tissues in the

negative pressure range act as a safety factor against

Normal

edema? To answer this question, recall the determi-

nants of capillary filtration discussed previously. When

interstitial fluid hydrostatic pressure increases, this

increased pressure tends to oppose further capillary

(Low compliance)

filtration. Therefore, as long as the interstitial fluid

hydrostatic pressure is in the negative pressure range,

small increases in interstitial fluid volume cause rela-

tively large increases in interstitial fluid hydrostatic

-10

-8

-6

-4

-2

pressure, opposing further filtration of fluid into the

Interstitial free fluid pressure

tissues.

(mm Hg)

Because the normal interstitial fluid hydrostatic

pressure is -3 mm Hg, the interstitial fluid hydrostatic

pressure must increase by about 3 mm Hg before large

Figure 25-7

amounts of fluid will begin to accumulate in the tissues.

Therefore, the safety factor against edema is a change

Relation between interstitial fluid hydrostatic pressure and inter-

stitial fluid volumes, including total volume, free fluid volume, and

of interstitial fluid pressure of about 3 mm Hg.

gel fluid volume, for loose tissues such as skin. Note that signifi-

Once interstitial fluid pressure rises above 0 mm Hg,

cant amounts of free fluid occur only when the interstitial fluid pres-

the compliance of the tissues increases markedly,

sure becomes positive. (Modified from Guyton AC, Granger HJ,

allowing large amounts of fluid to accumulate in the

Taylor AE: Interstitial fluid pressure. Physiol Rev 51:527, 1971.)

Chapter 25

The Body Fluid Compartments: Extracellular and Intracellular Fluids; Interstitial Fluid and Edema

305

By contrast, when interstitial fluid pressure rises to

caused by increased lymph flow has been calculated to

the positive pressure range, there is a tremendous accu-

be about 7 mm Hg.

mulation of free fluid in the tissues. In this pressure

range, the tissues are compliant, allowing large amounts

“Washdown” of the Interstitial Fluid Protein as

of fluid to accumulate with relatively small additional

a Safety Factor Against Edema

increases in interstitial fluid hydrostatic pressure. Most

As increased amounts of fluid are filtered into the

of the extra fluid that accumulates is “free fluid” because

it pushes the brush pile of proteoglycan filaments apart.

interstitium, the interstitial fluid pressure increases,

Therefore, the fluid can flow freely through the tissue

causing increased lymph flow. In most tissues, the

spaces because it is not in gel form. When this occurs,

protein concentration of the interstitium decreases as

the edema is said to be pitting edema because one can

lymph flow is increased, because larger amounts of

press the thumb against the tissue area and push the

protein are carried away than can be filtered out of the

fluid out of the area. When the thumb is removed, a pit

capillaries; the reason for this is that the capillaries

is left in the skin for a few seconds until the fluid flows

are relatively impermeable to proteins, compared

back from the surrounding tissues. This type of edema

with the lymph vessels. Therefore, the proteins are

is distinguished from nonpitting edema, which occurs

“washed out” of the interstitial fluid as lymph flow

when the tissue cells swell instead of the interstitium or

increases.

when the fluid in the interstitium becomes clotted with

fibrinogen so that it cannot move freely within the tissue

Because the interstitial fluid colloid osmotic pres-

spaces.

sure caused by the proteins tends to draw fluid out of

the capillaries, decreasing the interstitial fluid proteins

Importance of the Proteoglycan Filaments as a “Spacer” for the

lowers the net filtration force across the capillaries and

Cells and in Preventing Rapid Flow of Fluid in the Tissues. The

tends to prevent further accumulation of fluid. The

proteoglycan filaments, along with much larger collagen

safety factor from this effect has been calculated to be

fibrils in the interstitial spaces, act as a “spacer” between

about 7 mm Hg.

the cells. Nutrients and ions do not diffuse readily

through cell membranes; therefore, without adequate

spacing between the cells, these nutrients, electrolytes,

Summary of Safety Factors That

and cell waste products could not be rapidly exchanged

Prevent Edema

between the blood capillaries and cells located at a dis-

tance from one another.

Putting together all the safety factors against edema, we

The proteoglycan filaments also prevent fluid from

find the following:

flowing too easily through the tissue spaces. If it were

1. The safety factor caused by low tissue compliance

not for the proteoglycan filaments, the simple act of a

in the negative pressure range is about 3 mm Hg.

person standing up would cause large amounts of inter-

2. The safety factor caused by increased lymph flow is

stitial fluid to flow from the upper body to the lower

about 7 mm Hg.

body. When too much fluid accumulates in the intersti-

3. The safety factor caused by washdown of proteins

tium, as occurs in edema, this extra fluid creates large

from the interstitial spaces is about 7 mm Hg.

channels that allow the fluid to flow readily through the

Therefore, the total safety factor against edema is

interstitium. Therefore, when severe edema occurs in

about 17 mm Hg. This means that the capillary pres-

the legs, the edema fluid often can be decreased by

sure in a peripheral tissue could theoretically rise by

simply elevating the legs.

17 mm Hg, or approximately double the normal value,

Even though fluid does not flow easily through the

before marked edema would occur.

tissues in the presence of the compacted proteoglycan

filaments, different substances within the fluid can

diffuse through the tissues at least 95 per cent as easily

Fluids in the “Potential

as they normally diffuse. Therefore, the usual diffusion

of nutrients to the cells and the removal of waste prod-

Spaces” of the Body

ucts from the cells are not compromised by the proteo-

glycan filaments of the interstitium.

Perhaps the best way to describe a “potential space”

is to list some examples: pleural cavity, pericardial

Increased Lymph Flow as a Safety Factor

cavity, peritoneal cavity, and synovial cavities, includ-

Against Edema

ing both the joint cavities and the bursae. Virtually all

A major function of the lymphatic system is to return

these potential spaces have surfaces that almost touch

to the circulation the fluid and proteins filtered from

each other, with only a thin layer of fluid in between,

the capillaries into the interstitium. Without this con-

and the surfaces slide over each other. To facilitate the

tinuous return of the filtered proteins and fluid to the

sliding, a viscous proteinaceous fluid lubricates the

blood, the plasma volume would be rapidly depleted,

surfaces.

and interstitial edema would occur.

The lymphatics act as a safety factor against edema

Fluid Is Exchanged Between the Capillaries and the Potential

because lymph flow can increase 10- to 50-fold when

Spaces. The surface membrane of a potential space

fluid begins to accumulate in the tissues. This allows

usually does not offer significant resistance to the

the lymphatics to carry away large amounts of fluid

passage of fluids, electrolytes, or even proteins, which

and proteins in response to increased capillary filtra-

all move back and forth between the space and the

tion, preventing the interstitial pressure from rising

interstitial fluid in the surrounding tissue with relative

into the positive pressure range. The safety factor

ease. Therefore, each potential space is in reality a

306

Unit V The Body Fluids and Kidneys

large tissue space. Consequently, fluid in the capillar-

References

ies adjacent to the potential space diffuses not only

into the interstitial fluid but also into the potential

Amiry-Moghaddam M, Ottersen OP: The molecular basis of

space.

water transport in the brain. Nat Rev Neurosci 4:991, 2003.

Aukland K: Why don’t our feet swell in the upright position?

Lymphatic Vessels Drain Protein from the Potential Spaces.

News Physiol Sci 9:214, 1994.

Basnyat B, Murdoch DR: High-altitude illness. Lancet

Proteins collect in the potential spaces because of

361:1967, 2003.

leakage out of the capillaries, similar to the collection

Cho S, Atwood JE: Peripheral edema. Am J Med 113:580,

of protein in the interstitial spaces throughout the

2002.

body. The protein must be removed through lymphat-

Decaux G, Soupart A: Treatment of symptomatic hypona-

ics or other channels and returned to the circulation.

tremia. Am J Med Sci 326:25, 2003.

Each potential space is either directly or indirectly

Drake RE, Doursout MF: Pulmonary edema and elevated

connected with lymph vessels. In some cases, such as

left atrial pressure: four hours and beyond. News Physiol

the pleural cavity and peritoneal cavity, large lymph

Sci 17:223, 2002.

vessels arise directly from the cavity itself.

Gashev AA: Physiologic aspects of lymphatic contractile

function: current perspectives. Ann N Y Acad Sci 979:178,

2002.

Edema Fluid in the Potential Spaces Is Called “Effusion.”

Guyton AC, Granger HJ, Taylor AE: Interstitial fluid pres-

When edema occurs in the subcutaneous tissues adja-

sure. Physiol Rev 51:527, 1971.

cent to the potential space, edema fluid usually collects

Guyton AC, Taylor AE, Granger HJ: Circulatory Physiology

in the potential space as well, and this fluid is called

II: Dynamics and Control of the Body Fluids. Philadel-

effusion. Thus, lymph blockage or any of the multiple

phia: WB Saunders, 1975.

abnormalities that can cause excessive capillary filtra-

Halperin ML, Bohn D: Clinical approach to disorders of salt

tion can cause effusion in the same way that intersti-

and water balance: emphasis on integrative physiology.

tial edema is caused. The abdominal cavity is especially

Crit Care Clin 18:249, 2002.

prone to collect effusion fluid, and in this instance, the

Jussila L, Alitalo K: Vascular growth factors and lymphan-

effusion is called ascites. In serious cases, 20 liters or

giogenesis. Physiol Rev 82:673, 2002.

Matthay MA, Folkesson HG, Clerici C: Lung epithelial fluid

more of ascitic fluid can accumulate.

transport and the resolution of pulmonary edema. Physiol

The other potential spaces, such as the pleural

Rev 82:569, 2002.

cavity, pericardial cavity, and joint spaces, can become

Michel CC: Exchange of fluid and solutes across microvas-

seriously swollen when there is generalized edema.

cular walls. In Seldin DW, Giebisch G (eds): The Kidney—

Also, injury or local infection in any one of the cavi-

Physiology & Pathophysiology,

3rd ed. Philadelphia:

ties often blocks the lymph drainage, causing isolated

Lippincott Williams & Wilkins, 2000.

swelling in the cavity.

Moritz ML, Ayus JC: Disorders of water metabolism in

The dynamics of fluid exchange in the pleural cavity

children: hyponatremia and hypernatremia. Pediatr Rev

are discussed in detail in Chapter 38. These dynamics

23:371, 2002.

are mainly representative of all the other potential

Saaristo A, Karkkainen MJ, Alitalo K: Insights into the

molecular pathogenesis and targeted treatment of lym-

spaces as well. It is especially interesting that the

phedema. Ann N Y Acad Sci 979:94, 2002.

normal fluid pressure in most or all of the potential

Winaver J, Abassi Z, Green J, Skorecki KL: Control of extra-

spaces in the nonedematous state is negative in the

cellular fluid volume and the pathophysiology of edema

same way that this pressure is negative (subatmos-

formation. In Brenner BM, Rector FC (eds): The Kidney,

pheric) in loose subcutaneous tissue. For instance, the

6th ed. Philadelphia: WB Saunders, 2000.

interstitial fluid hydrostatic pressure is normally about

-7 to -8 mm Hg in the pleural cavity, -3 to -5 mm Hg

in the joint spaces, and -5 to -6 mm Hg in the peri-

cardial cavity.

C H A P T E R

Urine Formation by the Kidneys:

I. Glomerular Filtration, Renal

Blood Flow, and Their Control

Multiple Functions of the

Kidneys in Homeostasis

Most people are familiar with one important func-

tion of the kidneys—to rid the body of waste mate-

rials that are either ingested or produced by

metabolism. A second function that is especially

critical is to control the volume and composition of

the body fluids. For water and virtually all electrolytes in the body, the balance

between intake (due to ingestion or metabolic production) and output (due to

excretion or metabolic consumption) is maintained in large part by the kidneys.

This regulatory function of the kidneys maintains the stable environment of the

cells necessary for them to perform their various activities.

The kidneys perform their most important functions by filtering the plasma

and removing substances from the filtrate at variable rates, depending on the

needs of the body. Ultimately, the kidneys “clear” unwanted substances from

the filtrate (and therefore from the blood) by excreting them in the urine while

returning substances that are needed back to the blood.

Although this chapter and the next few chapters focus mainly on the control

of renal excretion, it is important to recognize that the kidneys serve multiple

functions, including the following:

∑ Excretion of metabolic waste products and foreign chemicals

∑ Regulation of water and electrolyte balances

∑ Regulation of body fluid osmolality and electrolyte concentrations

∑ Regulation of arterial pressure

∑ Regulation of acid-base balance

∑ Secretion, metabolism, and excretion of hormones

∑ Gluconeogenesis

Excretion of Metabolic Waste Products, Foreign Chemicals, Drugs, and Hormone Metabo-

lites. The kidneys are the primary means for eliminating waste products of

metabolism that are no longer needed by the body. These products include urea

(from the metabolism of amino acids), creatinine (from muscle creatine), uric

acid (from nucleic acids), end products of hemoglobin breakdown (such as

bilirubin), and metabolites of various hormones. These waste products must be

eliminated from the body as rapidly as they are produced. The kidneys also

eliminate most toxins and other foreign substances that are either produced by

the body or ingested, such as pesticides, drugs, and food additives.

Regulation of Water and Electrolyte Balances. For maintenance of homeostasis, excre-

tion of water and electrolytes must precisely match intake. If intake exceeds

excretion, the amount of that substance in the body will increase. If intake is

less than excretion, the amount of that substance in the body will decrease.

Intake of water and many electrolytes is governed mainly by a person’s eating

and drinking habits, requiring the kidneys to adjust their excretion rates to

match the intake of various substances. Figure 26-1 shows the response of the

kidneys to a sudden 10-fold increase in sodium intake from a low level of

30 mEq/day to a high level of 300 mEq/day. Within 2 to 3 days after raising the

307

308

Unit V The Body Fluids and Kidneys

Regulation of Acid-Base Balance. The kidneys contribute

to acid-base regulation, along with the lungs and body

Sodium

fluid buffers, by excreting acids and by regulating the

retention

body fluid buffer stores. The kidneys are the only

300

Intake

means of eliminating from the body certain types of

acids, such as sulfuric acid and phosphoric acid, gen-

200

erated by the metabolism of proteins.

Excretion

Sodium

100

loss

Regulation of Erythrocyte Production. The kidneys secrete

erythropoietin, which stimulates the production of red

blood cells, as discussed in Chapter 32. One important

stimulus for erythropoietin secretion by the kidneys is

hypoxia. The kidneys normally account for almost all

the erythropoietin secreted into the circulation. In

people with severe kidney disease or who have had

their kidneys removed and have been placed on

hemodialysis, severe anemia develops as a result of

decreased erythropoietin production.

-4

-2

Time (days)

Regulation of

1,25-Dihydroxyvitamin D₃

Production. The

kidneys produce the active form of vitamin D, 1,25-

dihydroxyvitamin D₃ (calcitriol), by hydroxylating this

Figure 26-1

vitamin at the “number 1” position. Calcitriol is essen-

tial for normal calcium deposition in bone and calcium

Effect of increasing sodium intake 10-fold (from 30 to 300 mEq/

day) on urinary sodium excretion and extracellular fluid volume.

reabsorption by the gastrointestinal tract. As discussed

The shaded areas represent the net sodium retention or the net

in Chapter 79, calcitriol plays an important role in

sodium loss, determined from the difference between sodium

calcium and phosphate regulation.

intake and sodium excretion.

Glucose Synthesis. The kidneys synthesize glucose from

amino acids and other precursors during prolonged

fasting, a process referred to as gluconeogenesis. The

sodium intake, renal excretion also increases to about

kidneys’ capacity to add glucose to the blood during

300 mEq/day, so that a balance between intake and

prolonged periods of fasting rivals that of the liver.

output is re-established. However, during the 2 to 3

With chronic kidney disease or acute failure of the

days of renal adaptation to the high sodium intake,

kidneys, these homeostatic functions are disrupted,

there is a modest accumulation of sodium that raises

and severe abnormalities of body fluid volumes and

extracellular fluid volume slightly and triggers hor-

composition rapidly occur. With complete renal

monal changes and other compensatory responses

failure, enough potassium, acids, fluid, and other sub-

that signal the kidneys to increase their sodium

stances accumulate in the body to cause death within

excretion.

a few days, unless clinical interventions such as

The capacity of the kidneys to alter sodium excre-

hemodialysis are initiated to restore, at least partially,

tion in response to changes in sodium intake is enor-

the body fluid and electrolyte balances.

mous. Experimental studies have shown that in many

people, sodium intake can be increased to 1500 mEq/

day (more than 10 times normal) or decreased to

Physiologic Anatomy

10 mEq/day (less than one tenth normal) with rela-

of the Kidneys

tively small changes in extracellular fluid volume or

plasma sodium concentration. This is also true for

General Organization of the Kidneys

water and for most other electrolytes, such as chloride,

potassium, calcium, hydrogen, magnesium, and phos-

and Urinary Tract

phate ions. In the next few chapters, we discuss the spe-

cific mechanisms that permit the kidneys to perform

The two kidneys lie on the posterior wall of the

these amazing feats of homeostasis.

abdomen, outside the peritoneal cavity (Figure 26-2).

Each kidney of the adult human weighs about 150

Regulation of Arterial Pressure. As discussed in Chapter

grams and is about the size of a clenched fist. The

19, the kidneys play a dominant role in long-term reg-

medial side of each kidney contains an indented region

ulation of arterial pressure by excreting variable

called the hilum through which pass the renal artery

amounts of sodium and water. The kidneys also con-

and vein, lymphatics, nerve supply, and ureter, which

tribute to short-term arterial pressure regulation by

carries the final urine from the kidney to the bladder,

secreting vasoactive factors or substances, such as

where it is stored until emptied. The kidney is sur-

renin, that lead to the formation of vasoactive prod-

rounded by a tough, fibrous capsule that protects its

ucts (e.g., angiotensin II).

delicate inner structures.

Chapter 26

Urine Formation by the Kidneys: I. Glomerular Filtration, Renal Blood Flow, and Their Control

309

Minor calyx

Major calyx

Nephron (enlarged)

Papilla

Renal cortex

Renal medulla

Renal pelvis

Renal

Kidney

artery

Renal pyramid

Capsule

Ureter

Kidney

Figure 26-2

Bladder

Urethra

General organization of the

kidneys and the urinary system.

If the kidney is bisected from top to bottom, the two

much lower hydrostatic pressure in the peritubular

major regions that can be visualized are the outer

capillaries (about 13 mm Hg) permits rapid fluid reab-

cortex and the inner region referred to as the medulla.

sorption. By adjusting the resistance of the afferent

The medulla is divided into multiple cone-shaped

and efferent arterioles, the kidneys can regulate the

masses of tissue called renal pyramids. The base of

hydrostatic pressure in both the glomerular and the

each pyramid originates at the border between the

peritubular capillaries, thereby changing the rate of

cortex and medulla and terminates in the papilla,

which projects into the space of the renal pelvis, a

funnel-shaped continuation of the upper end of the

ureter. The outer border of the pelvis is divided into

open-ended pouches called major calyces that extend

downward and divide into minor calyces, which collect

Interlobar

arteries

urine from the tubules of each papilla. The walls of the

Renal artery

calyces, pelvis, and ureter contain contractile elements

that propel the urine toward the bladder, where urine

Arcuate arteries

Segmental

is stored until it is emptied by micturition, discussed in

arteries

later in this chapter.

Interlobular

arterioles

Renal Blood Supply

Blood flow to the two kidneys is normally about 22 per

Efferent

Bowman's

cent of the cardiac output, or 1100 ml/min. The renal

Glomerulus

arteriole

capsule

Proximal tubule

artery enters the kidney through the hilum and then

branches progressively to form the interlobar arteries,

Juxtaglomerular

Cortical

apparatus

arcuate arteries, interlobular arteries (also called radial

collecting tubule

arteries) and afferent arterioles, which lead to the

Afferent

arteriole

Distal tubule

glomerular capillaries, where large amounts of fluid

and solutes (except the plasma proteins) are filtered to

Arcuate

artery

begin urine formation (Figure 26-3). The distal ends of

the capillaries of each glomerulus coalesce to form the

Arcuate

Loop of

efferent arteriole, which leads to a second capillary

vein

Henle

network, the peritubular capillaries, that surrounds the

renal tubules.

Peritubular

The renal circulation is unique in that it has two cap-

capillaries

Collecting duct

illary beds, the glomerular and peritubular capillaries,

which are arranged in series and separated by the

Figure 26-3

efferent arterioles, which help regulate the hydrostatic

pressure in both sets of capillaries. High hydro-

Section of the human kidney showing the

major vessels that

static pressure in the glomerular capillaries (about

supply the blood flow to the kidney and schematic of the micro-

60 mm Hg) causes rapid fluid filtration, whereas a

circulation of each nephron.

310

Unit V The Body Fluids and Kidneys

glomerular filtration, tubular reabsorption, or both in

Proximal tubule

Cortex

response to body homeostatic demands.

Connecting tubule

The peritubular capillaries empty into the vessels of

Distal tubule

the venous system, which run parallel to the arteriolar

Bowman's capsule

vessels and progressively form the interlobular vein,

arcuate vein, interlobar vein, and renal vein, which

Macula densa

Cortical

leaves the kidney beside the renal artery and ureter.

collecting tubule

The Nephron Is the Functional Unit

Loop of Henle:

Medulla

Thick segment of

of the Kidney

ascending limb

Thin segment of

Medullary

Each kidney in the human contains about 1 million

ascending limb

collecting tubule

nephrons, each capable of forming urine. The kidney

Descending limb

cannot regenerate new nephrons. Therefore, with renal

injury, disease, or normal aging, there is a gradual

decrease in nephron number. After age 40, the number

of functioning nephrons usually decreases about 10

Collecting duct

per cent every 10 years; thus, at age 80, many people

have 40 per cent fewer functioning nephrons than they

did at age 40. This loss is not life threatening because

Figure 26-4

adaptive changes in the remaining nephrons allow

Basic tubular segments of the nephron. The relative lengths of the

them to excrete the proper amounts of water,

different tubular segments are not drawn to scale.

electrolytes, and waste products, as discussed in

Chapter 31.

Each nephron contains (1) a tuft of glomerular cap-

illaries called the glomerulus, through which large

amounts of fluid are filtered from the blood, and (2) a

eventually empty into the renal pelvis through the tips

long tubule in which the filtered fluid is converted into

of the renal papillae. In each kidney, there are about

urine on its way to the pelvis of the kidney (see Figure

250 of the very large collecting ducts, each of which

26-3).

collects urine from about 4000 nephrons.

The glomerulus contains a network of branching

and anastomosing glomerular capillaries that, com-

Regional Differences in Nephron Structure: Cortical and

pared with other capillaries, have high hydrostatic

Juxtamedullary Nephrons. Although each nephron has all

pressure (about 60 mm Hg). The glomerular capillar-

the components described earlier, there are some dif-

ies are covered by epithelial cells, and the total

ferences, depending on how deep the nephron lies

glomerulus is encased in Bowman’s capsule. Fluid

within the kidney mass. Those nephrons that have

filtered from the glomerular capillaries flows into

glomeruli located in the outer cortex are called corti-

Bowman’s capsule and then into the proximal tubule,

cal nephrons; they have short loops of Henle that

which lies in the cortex of the kidney (Figure 26-4).

penetrate only a short distance into the medulla

From the proximal tubule, fluid flows into the loop

(Figure 26-5).

of Henle, which dips into the renal medulla. Each loop

About 20 to 30 per cent of the nephrons have

consists of a descending and an ascending limb. The

glomeruli that lie deep in the renal cortex near the

walls of the descending limb and the lower end of the

medulla and are called juxtamedullary nephrons.

ascending limb are very thin and therefore are called

These nephrons have long loops of Henle that dip

the thin segment of the loop of Henle. After the ascend-

deeply into the medulla, in some cases all the way to

ing limb of the loop has returned partway back to the

the tips of the renal papillae.

cortex, its wall becomes much thicker, and it is referred

The vascular structures supplying the jux-

to as the thick segment of the ascending limb.

tamedullary nephrons also differ from those supplying

At the end of the thick ascending limb is a short

the cortical nephrons. For the cortical nephrons, the

segment, which is actually a plaque in its wall, known

entire tubular system is surrounded by an extensive

as the macula densa. As we discuss later, the macula

network of peritubular capillaries. For the jux-

densa plays an important role in controlling nephron

tamedullary nephrons, long efferent arterioles extend

function. Beyond the macula densa, fluid enters the

from the glomeruli down into the outer medulla and

distal tubule, which, like the proximal tubule, lies in the

then divide into specialized peritubular capillaries

renal cortex. This is followed by the connecting tubule

called vasa recta that extend downward into the

and the cortical collecting tubule, which lead to the cor-

medulla, lying side by side with the loops of Henle.

tical collecting duct. The initial parts of 8 to 10 cortical

Like the loops of Henle, the vasa recta return toward

collecting ducts join to form a single larger collecting

the cortex and empty into the cortical veins. This

duct that runs downward into the medulla and

specialized network of capillaries in the medulla plays

becomes the medullary collecting duct. The collecting

an essential role in the formation of a concentrated

ducts merge to form progressively larger ducts that

urine.

Chapter 26

Urine Formation by the Kidneys: I. Glomerular Filtration, Renal Blood Flow, and Their Control

311

Micturition

Although the micturition reflex is an autonomic spinal

cord reflex, it can also be inhibited or facilitated by

Micturition is the process by which the urinary bladder

centers in the cerebral cortex or brain stem.

empties when it becomes filled. This involves two main

steps: First, the bladder fills progressively until the

Physiologic Anatomy and

tension in its walls rises above a threshold level; this

Nervous Connections

elicits the second step, which is a nervous reflex called

the micturition reflex that empties the bladder or, if this

of the Bladder

fails, at least causes a conscious desire to urinate.

The urinary bladder, shown in Figure 26-6, is a smooth

muscle chamber composed of two main parts: (1) the

Cortical

body, which is the major part of the bladder in which

Efferent

nephron

urine collects, and (2) the neck, which is a funnel-shaped

arteriole

extension of the body, passing inferiorly and anteriorly

Afferent

into the urogenital triangle and connecting with the

arteriole

urethra. The lower part of the bladder neck is also called

Juxtamedullary

the posterior urethra because of its relation to the

Interlobar

nephron

urethra.

artery

vein

The smooth muscle of the bladder is called the detru-

sor muscle. Its muscle fibers extend in all directions and,

when contracted, can increase the pressure in the

bladder to 40 to 60 mm Hg. Thus, contraction of the

Thick loop

of Henle

detrusor muscle is a major step in emptying the bladder.

Smooth muscle cells of the detrusor muscle fuse with

Interlobar

Vasa

one another so that low-resistance electrical pathways

artery

recta

exist from one muscle cell to the other. Therefore, an

vein

action potential can spread throughout the detrusor

muscle, from one muscle cell to the next, to cause con-

traction of the entire bladder at once.

On the posterior wall of the bladder, lying immedi-

Collecting

Thin loop

duct

ately above the bladder neck, is a small triangular area

of Henle

called the trigone. At the lowermost apex of the trigone,

the bladder neck opens into the posterior urethra, and

the two ureters enter the bladder at the uppermost

Duct of

angles of the trigone. The trigone can be identified by

Bellini

the fact that its mucosa, the inner lining of the bladder,

is smooth, in contrast to the remaining bladder mucosa,

which is folded to form rugae. Each ureter, as it enters

Figure 26-5

the bladder, courses obliquely through the detrusor

muscle and then passes another 1 to 2 centimeters

Schematic of relations between blood vessels and tubular struc-

tures and differences between cortical and juxtamedullary

beneath the bladder mucosa before emptying into the

nephrons.

bladder.

Ureter

Body

Sympathetics

Trigone

Parasympathetics

Bladder neck

(posterior urethra)

Pudendal

External sphincter

Figure 26-6

Urinary bladder and its innervation.

312

Unit V The Body Fluids and Kidneys

The bladder neck (posterior urethra) is 2 to 3 cen-

thereby forcing urine from the renal pelvis toward the

timeters long, and its wall is composed of detrusor

bladder. The walls of the ureters contain smooth

muscle interlaced with a large amount of elastic tissue.

muscle and are innervated by both sympathetic and

The muscle in this area is called the internal sphincter.

parasympathetic nerves as well as by an intramural

Its natural tone normally keeps the bladder neck and

plexus of neurons and nerve fibers that extends along

posterior urethra empty of urine and, therefore, pre-

the entire length of the ureters. As with other visceral

vents emptying of the bladder until the pressure in the

smooth muscle, peristaltic contractions in the ureter are

main part of the bladder rises above a critical threshold.

enhanced by parasympathetic stimulation and inhibited

Beyond the posterior urethra, the urethra passes

through the urogenital diaphragm, which contains a

by sympathetic stimulation.

layer of muscle called the external sphincter of the

The ureters enter the bladder through the detrusor

bladder. This muscle is a voluntary skeletal muscle, in

muscle in the trigone region of the bladder, as shown

contrast to the muscle of the bladder body and bladder

in Figure 26-6. Normally, the ureters course obliquely

neck, which is entirely smooth muscle. The external

for several centimeters through the bladder wall. The

sphincter muscle is under voluntary control of the

normal tone of the detrusor muscle in the bladder wall

nervous system and can be used to consciously prevent

tends to compress the ureter, thereby preventing back-

urination even when involuntary controls are attempt-

flow of urine from the bladder when pressure builds

ing to empty the bladder.

up in the bladder during micturition or bladder

compression. Each peristaltic wave along the ureter

increases the pressure within the ureter so that the

Innervation of the Bladder

region passing through the bladder wall opens and

The principal nerve supply of the bladder is by way of

allows urine to flow into the bladder.

the pelvic nerves, which connect with the spinal cord

In some people, the distance that the ureter courses

through the sacral plexus, mainly connecting with cord

through the bladder wall is less than normal, so that

segments S-2 and S-3. Coursing through the pelvic

contraction of the bladder during micturition does not

nerves are both sensory nerve fibers and motor nerve

always lead to complete occlusion of the ureter. As a

fibers. The sensory fibers detect the degree of stretch in

result, some of the urine in the bladder is propelled

the bladder wall. Stretch signals from the posterior

backward into the ureter, a condition called vesi-

urethra are especially strong and are mainly re-

coureteral reflux. Such reflux can lead to enlargement

sponsible for initiating the reflexes that cause bladder

of the ureters and, if severe, can increase the pressure

emptying.

The motor nerves transmitted in the pelvic nerves are

in the renal calyces and structures of the renal

parasympathetic fibers. These terminate on ganglion

medulla, causing damage to these regions.

cells located in the wall of the bladder. Short postgan-

glionic nerves then innervate the detrusor muscle.

Pain Sensation in the Ureters, and the Ureterorenal Reflex.

In addition to the pelvic nerves, two other types of

The ureters are well supplied with pain nerve fibers.

innervation are important in bladder function. Most

When a ureter becomes blocked (e.g., by a ureteral

important are the skeletal motor fibers transmitted

stone), intense reflex constriction occurs, associated

through the pudendal nerve to the external bladder

with severe pain. Also, the pain impulses cause a sym-

sphincter. These are somatic nerve fibers that innervate

pathetic reflex back to the kidney to constrict the renal

and control the voluntary skeletal muscle of the sphinc-

arterioles, thereby decreasing urine output from the

ter. Also, the bladder receives sympathetic innervation

from the sympathetic chain through the hypogastric

kidney. This effect is called the ureterorenal reflex and

nerves, connecting mainly with the L-2 segment of the

is important for preventing excessive flow of fluid into

spinal cord. These sympathetic fibers stimulate mainly

the pelvis of a kidney with a blocked ureter.

the blood vessels and have little to do with bladder con-

traction. Some sensory nerve fibers also pass by way of

Filling of the Bladder

the sympathetic nerves and may be important in the

sensation of fullness and, in some instances, pain.

and Bladder Wall Tone;

the Cystometrogram

Transport of Urine from the

Figure 26-7 shows the approximate changes in intra-

vesicular pressure as the bladder fills with urine. When

Kidney Through the Ureters

there is no urine in the bladder, the intravesicular pres-

and into the Bladder

sure is about 0, but by the time 30 to 50 milliliters of

urine has collected, the pressure rises to 5 to 10 cen-

Urine that is expelled from the bladder has essentially

timeters of water. Additional urine—200 to 300 milli-

liters—can collect with only a small additional rise in

the same composition as fluid flowing out of the col-

pressure; this constant level of pressure is caused by

lecting ducts; there are no significant changes in the

intrinsic tone of the bladder wall itself. Beyond 300 to

composition of urine as it flows through the renal

400 milliliters, collection of more urine in the bladder

calyces and ureters to the bladder.

causes the pressure to rise rapidly.

Urine flowing from the collecting ducts into the

Superimposed on the tonic pressure changes during

renal calyces stretches the calyces and increases their

filling of the bladder are periodic acute increases in

inherent pacemaker activity, which in turn initiates

pressure that last from a few seconds to more than a

peristaltic contractions that spread to the renal pelvis

minute. The pressure peaks may rise only a few cen-

and then downward along the length of the ureter,

timeters of water or may rise to more than

100

Chapter 26

Urine Formation by the Kidneys: I. Glomerular Filtration, Renal Blood Flow, and Their Control

313

Thus, the micturition reflex is a single complete cycle

of (1) progressive and rapid increase of pressure, (2) a

period of sustained pressure, and (3) return of the

pressure to the basal tone of the bladder. Once a mic-

turition reflex has occurred but has not succeeded in

Micturition

emptying the bladder, the nervous elements of this

contractions

reflex usually remain in an inhibited state for a few

minutes to 1 hour or more before another micturition

reflex occurs. As the bladder becomes more and more

filled, micturition reflexes occur more and more often

and more and more powerfully.

Once the micturition reflex becomes powerful

enough, it causes another reflex, which passes through

the pudendal nerves to the external sphincter to inhibit

it. If this inhibition is more potent in the brain than the

voluntary constrictor signals to the external sphincter,

urination will occur. If not, urination will not occur

100

200

300

400

until the bladder fills still further and the micturition

Volume (milliliters)

reflex becomes more powerful.

Figure 26-7

Facilitation or Inhibition of Micturition

by the Brain

Normal cystometrogram, showing also acute pressure waves

(dashed spikes) caused by micturition reflexes.

The micturition reflex is a completely autonomic

spinal cord reflex, but it can be inhibited or facilitated

centimeters of water. These pressure peaks are called

by centers in the brain. These centers include (1)

micturition waves in the cystometrogram and are caused

by the micturition reflex.

strong facilitative and inhibitory centers in the brain

stem, located mainly in the pons, and (2) several centers

located in the cerebral cortex that are mainly inhibitory

Micturition Reflex

but can become excitatory.

The micturition reflex is the basic cause of micturi-

Referring again to Figure 26-7, one can see that as the

tion, but the higher centers normally exert final control

bladder fills, many superimposed micturition contrac-

of micturition as follows:

tions begin to appear, as shown by the dashed spikes.

1. The higher centers keep the micturition reflex

They are the result of a stretch reflex initiated by

partially inhibited, except when micturition is

sensory stretch receptors in the bladder wall, especially

desired.

by the receptors in the posterior urethra when this

2. The higher centers can prevent micturition, even

area begins to fill with urine at the higher bladder pres-

if the micturition reflex occurs, by continual tonic

sures. Sensory signals from the bladder stretch recep-

contraction of the external bladder sphincter until

tors are conducted to the sacral segments of the cord

a convenient time presents itself.

through the pelvic nerves and then reflexively back

3. When it is time to urinate, the cortical centers can

again to the bladder through the parasympathetic

facilitate the sacral micturition centers to help

nerve fibers by way of these same nerves.

initiate a micturition reflex and at the same time

When the bladder is only partially filled, these mic-

inhibit the external urinary sphincter so that

turition contractions usually relax spontaneously after

urination can occur.

a fraction of a minute, the detrusor muscles stop con-

Voluntary urination is usually initiated in the fol-

tracting, and pressure falls back to the baseline. As the

lowing way: First, a person voluntarily contracts his or

bladder continues to fill, the micturition reflexes

her abdominal muscles, which increases the pressure

become more frequent and cause greater contractions

in the bladder and allows extra urine to enter the

of the detrusor muscle.

bladder neck and posterior urethra under pressure,

Once a micturition reflex begins, it is “self-regener-

thus stretching their walls. This stimulates the stretch

ative.” That is, initial contraction of the bladder acti-

receptors, which excites the micturition reflex and

vates the stretch receptors to cause a greater increase

simultaneously inhibits the external urethral sphincter.

in sensory impulses to the bladder and posterior

Ordinarily, all the urine will be emptied, with rarely

urethra, which causes a further increase in reflex con-

more than 5 to 10 milliliters left in the bladder.

traction of the bladder; thus, the cycle is repeated again

and again until the bladder has reached a strong

Abnormalities of Micturition

degree of contraction. Then, after a few seconds to

more than a minute, the self-regenerative reflex begins

Atonic Bladder Caused by Destruction of Sensory Nerve Fibers.

to fatigue and the regenerative cycle of the micturition

Micturition reflex contraction cannot occur if the

reflex ceases, permitting the bladder to relax.

sensory nerve fibers from the bladder to the spinal cord

314

Unit V The Body Fluids and Kidneys

are destroyed, thereby preventing transmission of

Afferent

Efferent

stretch signals from the bladder. When this happens, a

arteriole

person loses bladder control, despite intact efferent

1. Filtration

fibers from the cord to the bladder and despite intact

2. Reabsorption

neurogenic connections within the brain. Instead of

3. Secretion

emptying periodically, the bladder fills to capacity and

Glomerular

4. Excretion

capillaries

overflows a few drops at a time through the urethra. This

is called overflow incontinence.

A common cause of atonic bladder is crush injury to

the sacral region of the spinal cord. Certain diseases can

also cause damage to the dorsal root nerve fibers that

Bowman's

capsule

enter the spinal cord. For example, syphilis can cause

constrictive fibrosis around the dorsal root nerve fibers,

destroying them. This condition is called tabes dorsalis,

and the resulting bladder condition is called tabetic

Peritubular

bladder.

capillaries

Automatic Bladder Caused by Spinal Cord Damage Above the

Sacral Region. If the spinal cord is damaged above the

sacral region but the sacral cord segments are still intact,

Renal

typical micturition reflexes can still occur. However,

vein

they are no longer controlled by the brain. During the

first few days to several weeks after the damage to the

cord has occurred, the micturition reflexes are sup-

pressed because of the state of “spinal shock” caused by

Urinary excretion

the sudden loss of facilitative impulses from the brain

Excretion = Filtration - Reabsorption + Secretion

stem and cerebrum. However, if the bladder is emptied

periodically by catheterization to prevent bladder injury

Figure 26-8

caused by overstretching of the bladder, the excitability

Basic kidney processes that determine the composition of the

of the micturition reflex gradually increases until typical

urine. Urinary excretion rate of a substance is equal to the rate at

micturition reflexes return; then, periodic (but unan-

which the substance is filtered minus its reabsorption rate plus the

nounced) bladder emptying occurs.

rate at which it is secreted from the peritubular capillary blood into

Some patients can still control urination in this con-

the tubules.

dition by stimulating the skin (scratching or tickling) in

the genital region, which sometimes elicits a micturition

reflex.

Urine formation begins when a large amount of

Uninhibited Neurogenic Bladder Caused by Lack of Inhibitory

fluid that is virtually free of protein is filtered from the

Signals from the Brain. Another abnormality of micturi-

tion is the so-called uninhibited neurogenic bladder,

glomerular capillaries into Bowman’s capsule. Most

which results in frequent and relatively uncontrolled

substances in the plasma, except for proteins, are freely

micturition. This condition derives from partial damage

filtered, so that their concentration in the glomerular

in the spinal cord or the brain stem that interrupts most

filtrate in Bowman’s capsule is almost the same as in

of the inhibitory signals. Therefore, facilitative impulses

the plasma. As filtered fluid leaves Bowman’s capsule

passing continually down the cord keep the sacral

and passes through the tubules, it is modified by reab-

centers so excitable that even a small quantity of urine

sorption of water and specific solutes back into the

elicits an uncontrollable micturition reflex, thereby pro-

blood or by secretion of other substances from the

moting frequent urination.

peritubular capillaries into the tubules.

Figure 26-9 shows the renal handling of four hypo-

thetical substances. The substance shown in panel A is

Urine Formation Results

freely filtered by the glomerular capillaries but is

from Glomerular Filtration,

neither reabsorbed nor secreted. Therefore, its excre-

tion rate is equal to the rate at which it was filtered.

Tubular Reabsorption, and

Certain waste products in the body, such as creatinine,

Tubular Secretion

are handled by the kidneys in this manner, allowing

excretion of essentially all that is filtered.

The rates at which different substances are excreted

In panel B, the substance is freely filtered but is also

in the urine represent the sum of three renal pro-

partly reabsorbed from the tubules back into the

cesses, shown in Figure 26-8: (1) glomerular filtration,

blood. Therefore, the rate of urinary excretion is less

(2) reabsorption of substances from the renal tubules

than the rate of filtration at the glomerular capillaries.

into the blood, and

(3) secretion of substances

In this case, the excretion rate is calculated as the fil-

from the blood into the renal tubules. Expressed

tration rate minus the reabsorption rate. This is typical

mathematically,

for many of the electrolytes of the body.

Urinary excretion rate = Filtration rate

In panel C, the substance is freely filtered at the

- Reabsorption rate + Secretion rate

glomerular capillaries but is not excreted into the

Chapter 26

Urine Formation by the Kidneys: I. Glomerular Filtration, Renal Blood Flow, and Their Control

315

A. Filtration only

B. Filtration, partial

Filtration, Reabsorption, and

reabsorption

Secretion of Different Substances

Substance A

Substance B

In general, tubular reabsorption is quantitatively more

important than tubular secretion in the formation of

urine, but secretion plays an important role in deter-

mining the amounts of potassium and hydrogen ions

and a few other substances that are excreted in the

urine. Most substances that must be cleared from the

blood, especially the end products of metabolism such

as urea, creatinine, uric acid, and urates, are poorly

reabsorbed and are therefore excreted in large

amounts in the urine. Certain foreign substances and

drugs are also poorly reabsorbed but, in addition, are

Urine

secreted from the blood into the tubules, so that their

excretion rates are high. Conversely, electrolytes, such

C. Filtration, complete

D. Filtration, secretion

reabsorption

as sodium ions, chloride ions, and bicarbonate ions, are

highly reabsorbed, so that only small amounts appear

in the urine. Certain nutritional substances, such as

Substance C

Substance D

amino acids and glucose, are completely reabsorbed

from the tubules and do not appear in the urine even

though large amounts are filtered by the glomerular

capillaries.

Each of the processes—glomerular filtration,

tubular reabsorption, and tubular secretion—is regu-

lated according to the needs of the body. For example,

when there is excess sodium in the body, the rate at

which sodium is filtered increases and a smaller frac-

tion of the filtered sodium is reabsorbed, resulting in

Urine

increased urinary excretion of sodium.

Figure 26-9

For most substances, the rates of filtration and reab-

sorption are extremely large relative to the rates of

Renal handling of four hypothetical substances. A, The substance

excretion. Therefore, subtle adjustments of filtration or

is freely filtered but not reabsorbed. B, The substance is freely fil-

reabsorption can lead to relatively large changes in

tered, but part of the filtered load is reabsorbed back in the blood.

renal excretion. For example, an increase in glomeru-

C, The substance is freely filtered but is not excreted in the urine

because all the filtered substance is reabsorbed from the tubules

lar filtration rate (GFR) of only 10 per cent (from 180

into the blood. D, The substance is freely filtered and is not reab-

to 198 L/day) would raise urine volume 13-fold (from

sorbed but is secreted from the peritubular capillary blood into the

1.5 to 19.5 L/day) if tubular reabsorption remained

renal tubules.

constant. In reality, changes in glomerular filtration

and tubular reabsorption usually act in a coordinated

manner to produce the necessary changes in renal

excretion.

urine because all the filtered substance is reabsorbed

from the tubules back into the blood. This pattern

Why Are Large Amounts of Solutes Filtered and Then Reab-

occurs for some of the nutritional substances in the

sorbed by the Kidneys? One might question the wisdom

blood, such as amino acids and glucose, allowing them

of filtering such large amounts of water and solutes

to be conserved in the body fluids.

and then reabsorbing most of these substances. One

The substance in panel D is freely filtered at the

advantage of a high GFR is that it allows the kidneys

glomerular capillaries and is not reabsorbed, but addi-

to rapidly remove waste products from the body that

tional quantities of this substance are secreted from

depend primarily on glomerular filtration for their

the peritubular capillary blood into the renal tubules.

excretion. Most waste products are poorly reabsorbed

This pattern often occurs for organic acids and bases,

by the tubules and, therefore, depend on a high GFR

permitting them to be rapidly cleared from the blood

for effective removal from the body.

and excreted in large amounts in the urine. The excre-

A second advantage of a high GFR is that it allows

tion rate in this case is calculated as filtration rate plus

all the body fluids to be filtered and processed by the

tubular secretion rate.

kidney many times each day. Because the entire

For each substance in the plasma, a particular com-

plasma volume is only about 3 liters, whereas the GFR

bination of filtration, reabsorption, and secretion

is about 180 L/day, the entire plasma can be filtered

occurs. The rate at which the substance is excreted in

and processed about 60 times each day. This high GFR

the urine depends on the relative rates of these three

allows the kidneys to precisely and rapidly control the

basic renal processes.

volume and composition of the body fluids.

316

Unit V The Body Fluids and Kidneys

Glomerular Filtration—The

Proximal tubule

First Step in Urine Formation

Podocytes

Composition of the Glomerular

Filtrate

Capillary loops

Urine formation begins with filtration of large

amounts of fluid through the glomerular capillaries

Bowman's space

Afferent arteriole

into Bowman’s capsule. Like most capillaries, the

glomerular capillaries are relatively impermeable to

Bowman's capsule

Efferent arteriole

proteins, so that the filtered fluid (called the glomeru-

lar filtrate) is essentially protein-free and devoid of

Slit pores

cellular elements, including red blood cells.

The concentrations of other constituents of the

glomerular filtrate, including most salts and organic

molecules, are similar to the concentrations in the

plasma. Exceptions to this generalization include a few

Epithelium

low-molecular-weight substances, such as calcium and

fatty acids, that are not freely filtered because they are

Basement

partially bound to the plasma proteins. Almost one

membrane

half of the plasma calcium and most of the plasma fatty

acids are bound to proteins, and these bound portions

Endothelium

are not filtered through the glomerular capillaries.

Fenestrations

GFR Is About 20 Per Cent of the

Figure 26-10

Renal Plasma Flow

A, Basic ultrastructure of the glomerular capillaries. B, Cross

section of the glomerular capillary membrane and its major com-

As in other capillaries, the GFR is determined by (1)

ponents: capillary endothelium, basement membrane, and epithe-

the balance of hydrostatic and colloid osmotic forces

lium (podocytes).

acting across the capillary membrane and (2) the cap-

illary filtration coefficient (K_f), the product of the per-

meability and filtering surface area of the capillaries.

The high filtration rate across the glomerular capil-

The glomerular capillaries have a much higher rate of

lary membrane is due partly to its special charac-

filtration than most other capillaries because of a high

teristics. The capillary endothelium is perforated by

glomerular hydrostatic pressure and a large K_f. In the

thousands of small holes called fenestrae, similar to the

average adult human, the GFR is about 125 ml/min, or

fenestrated capillaries found in the liver. Although the

180 L/day. The fraction of the renal plasma flow that is

fenestrations are relatively large, endothelial cells are

filtered (the filtration fraction) averages about 0.2; this

richly endowed with fixed negative charges that hinder

means that about 20 per cent of the plasma flowing

the passage of plasma proteins.

through the kidney is filtered through the glomerular

Surrounding the endothelium is the basement mem-

capillaries. The filtration fraction is calculated as

brane, which consists of a meshwork of collagen and

follows:

proteoglycan fibrillae that have large spaces through

Filtration fraction = GFR/Renal plasma flow

which large amounts of water and small solutes can

filter. The basement membrane effectively prevents

filtration of plasma proteins, in part because of

Glomerular Capillary Membrane

strong negative electrical charges associated with the

proteoglycans.

The glomerular capillary membrane is similar to that

The final part of the glomerular membrane is a layer

of other capillaries, except that it has three (instead

of epithelial cells that line the outer surface of the

of the usual two) major layers: (1) the endothelium of

glomerulus. These cells are not continuous but have

the capillary, (2) a basement membrane, and (3) a layer

long footlike processes (podocytes) that encircle the

of epithelial cells (podocytes) surrounding the outer

outer surface of the capillaries (see Figure 26-10).

surface of the capillary basement membrane (Figure

The foot processes are separated by gaps called

26-10). Together, these layers make up the filtration

slit pores through which the glomerular filtrate moves.

barrier, which, despite the three layers, filters several

The epithelial cells, which also have negative charges,

hundred times as much water and solutes as the usual

provide additional restriction to filtration of plasma

capillary membrane. Even with this high rate of filtra-

proteins. Thus, all layers of the glomerular capillary

tion, the glomerular capillary membrane normally pre-

wall provide a barrier to filtration of plasma

vents filtration of plasma proteins.

proteins.

Chapter 26

Urine Formation by the Kidneys: I. Glomerular Filtration, Renal Blood Flow, and Their Control

317

Table 26-1

Filterability of Substances by Glomerular Capillaries Based

1.0

Polycationic dextran

on Molecular Weight

Neutral dextran

Polyanionic dextran

0.8

Substance

Molecular Weight

Filterability

Water

1.0

0.6

Sodium

1.0

Glucose

180

1.0

Inulin

5,500

1.0

0.4

Myoglobin

17,000

0.75

Albumin

69,000

0.005

0.2

Filterability of Solutes Is Inversely Related to Their

Size. The glomerular capillary membrane is thicker

than most other capillaries, but it is also much more

Effective molecular radius (A)

porous and therefore filters fluid at a high rate. Despite

the high filtration rate, the glomerular filtration barrier

is selective in determining which molecules will filter,

Figure 26-11

based on their size and electrical charge.

Table 26-1 lists the effect of molecular size on fil-

Effect of size and electrical charge of dextran on its filterability by

the glomerular capillaries. A value of 1.0 indicates that the sub-

terability of different molecules. A filterability of 1.0

stance is filtered as freely as water, whereas a value of 0 indicates

means that the substance is filtered as freely as water;

that it is not filtered. Dextrans are polysaccharides that can be

a filterability of 0.75 means that the substance is fil-

manufactured as neutral molecules or with negative or positive

tered only 75 per cent as rapidly as water. Note that

charges and with varying molecular weights.

electrolytes such as sodium and small organic com-

pounds such as glucose are freely filtered. As the

molecular weight of the molecule approaches that of

albumin, the filterability rapidly decreases, approach-

in the urine, a condition known as proteinuria or

ing zero.

albuminuria.

Negatively Charged Large Molecules Are Filtered Less Easily

Than Positively Charged Molecules of Equal Molecular Size.

Determinants of the GFR

The molecular diameter of the plasma protein albumin

is only about 6 nanometers, whereas the pores of

The GFR is determined by (1) the sum of the hydro-

the glomerular membrane are thought to be about

static and colloid osmotic forces across the glomerular

8 nanometers (80 angstroms). Albumin is restricted

membrane, which gives the net filtration pressure, and

from filtration, however, because of its negative charge

(2) the glomerular capillary filtration coefficient,

and the electrostatic repulsion exerted by negative

K_f. Expressed mathematically, the GFR equals the

charges of the glomerular capillary wall proteoglycans.

product of K_f and the net filtration pressure:

Figure 26-11 shows how electrical charge affects the

filtration of different molecular weight dextrans by the

GFR = K_f ¥ Net filtration pressure

glomerulus. Dextrans are polysaccharides that can be

The net filtration pressure represents the sum of the

manufactured as neutral molecules or with negative or

hydrostatic and colloid osmotic forces that either favor

positive charges. Note that for any given molecular

or oppose filtration across the glomerular capillaries

radius, positively charged molecules are filtered much

(Figure 26-12). These forces include (1) hydrostatic

more readily than negatively charged molecules.

pressure inside the glomerular capillaries (glomerular

Neutral dextrans are also filtered more readily than

hydrostatic pressure, P_G), which promotes filtration;

negatively charged dextrans of equal molecular

(2) the hydrostatic pressure in Bowman’s capsule (P_B)

weight. The reason for these differences in filterability

outside the capillaries, which opposes filtration; (3) the

is that the negative charges of the basement mem-

colloid osmotic pressure of the glomerular capillary

brane and the podocytes provide an important means

plasma proteins (p_G), which opposes filtration; and

for restricting large negatively charged molecules,

(4) the colloid osmotic pressure of the proteins in

including the plasma proteins.

Bowman’s capsule (p_B), which promotes filtration.

In certain kidney diseases, the negative charges on

(Under normal conditions, the concentration of

the basement membrane are lost even before there are

protein in the glomerular filtrate is so low that the

noticeable changes in kidney histology, a condition

colloid osmotic pressure of the Bowman’s capsule fluid

referred to as minimal change nephropathy. As a result

is considered to be zero.)

of this loss of negative charges on the basement

The GFR can therefore be expressed as

membranes, some of the lower-molecular-weight

proteins, especially albumin, are filtered and appear

GFR = K_f ¥ (P_G - P_B - p_G + p_B)

318

Unit V The Body Fluids and Kidneys

4.2 ml/min/mm Hg, a value about 400 times as high as

Afferent

Efferent

the K_f of most other capillary systems of the body; the

arteriole

Glomerular

arteriole

average K_f of many other tissues in the body is only

hydrostatic

colloid osmotic

about 0.01 ml/min/mm Hg per 100 grams. This high K_f

pressure

for the glomerular capillaries contributes tremen-

(60 mm Hg)

(32 mm Hg)

dously to their rapid rate of fluid filtration.

Although increased K_f raises GFR and decreased K_f

reduces GFR, changes in K_f probably do not provide

a primary mechanism for the normal day-to-day regu-

lation of GFR. Some diseases, however, lower K_f by

Bowman's

reducing the number of functional glomerular capil-

capsule

laries (thereby reducing the surface area for filtration)

pressure

or by increasing the thickness of the glomerular

(18 mm Hg)

capillary membrane and reducing its hydraulic con-

ductivity. For example, chronic, uncontrolled hyper-

tension and diabetes mellitus gradually reduce K_f by

Glomerular

Bowman's

Glomerular

Net filtration

increasing the thickness of the glomerular capillary

hydrostatic

capsule

pressure

- oncotic

basement membrane and, eventually, by damaging the

pressure

(10 mm Hg)

(60 mm Hg)

(18 mm Hg)

(32 mm Hg)

capillaries so severely that there is loss of capillary

function.

Figure 26-12

Summary of forces causing filtration by the glomerular capillaries.

The values shown are estimates for healthy humans.

Increased Bowman’s Capsule

Hydrostatic Pressure Decreases GFR

Although the normal values for the determinants of

Direct measurements, using micropipettes, of hydro-

GFR have not been measured directly in humans, they

static pressure in Bowman’s capsule and at different

have been estimated in animals such as dogs and rats.

points in the proximal tubule suggest that a reasonable

Based on the results in animals, the approximate

estimate for Bowman’s capsule pressure in humans is

normal forces favoring and opposing glomerular fil-

about 18 mm Hg under normal conditions. Increasing

tration in humans are believed to be as follows (see

the hydrostatic pressure in Bowman’s capsule reduces

Figure 26-12):

GFR, whereas decreasing this pressure raises GFR.

However, changes in Bowman’s capsule pressure nor-

Forces Favoring Filtration (mm Hg)

mally do not serve as a primary means for regulating

Glomerular hydrostatic pressure

GFR.

Bowman’s capsule colloid osmotic pressure

In certain pathological states associated with

obstruction of the urinary tract, Bowman’s capsule

Forces Opposing Filtration (mm Hg)

pressure can increase markedly, causing serious reduc-

Bowman’s capsule hydrostatic pressure

tion of GFR. For example, precipitation of calcium or

Glomerular capillary colloid osmotic pressure

of uric acid may lead to “stones” that lodge in the

Net filtration pressure = 60 - 18 - 32 = +10 mm Hg

urinary tract, often in the ureter, thereby obstructing

outflow of the urinary tract and raising Bowman’s

Some of these values can change markedly under

capsule pressure. This reduces GFR and eventually

different physiologic conditions, whereas others are

can damage or even destroy the kidney unless the

altered mainly in disease states, as discussed later.

obstruction is relieved.

Increased Glomerular Capillary

Filtration Coefficient Increases GFR

Colloid Osmotic Pressure

The K_f is a measure of the product of the hydraulic

Decreases GFR

conductivity and surface area of the glomerular capil-

laries. The K_f cannot be measured directly, but it is

As blood passes from the afferent arteriole through

estimated experimentally by dividing the rate of

the glomerular capillaries to the efferent arterioles,

glomerular filtration by net filtration pressure:

the plasma protein concentration increases about

20 per cent (Figure 26-13). The reason for this is that

K_f = GFR/Net filtration pressure

about one fifth of the fluid in the capillaries filters into

Because total GFR for both kidneys is about 125 ml/

Bowman’s capsule, thereby concentrating the

min and the net filtration pressure is 10 mm Hg, the

glomerular plasma proteins that are not filtered.

normal K_f is calculated to be about 12.5 ml/min/mm

Assuming that the normal colloid osmotic pressure

Hg of filtration pressure. When K_f is expressed per

of plasma entering the glomerular capillaries is

100 grams of kidney weight, it averages about

28 mm Hg, this value usually rises to about 36 mm Hg

Chapter 26

Urine Formation by the Kidneys: I. Glomerular Filtration, Renal Blood Flow, and Their Control

319

Glomerular

150

2000

Filtration

filtration

fraction

rate

Normal

100

1400

Normal

800

Filtration

fraction

Renal blood

flow

200

Afferent

Efferent

Efferent arteriolar resistance

end

Distance along

end

(X normal)

glomerular capillary

250

2000

Figure 26-13

100

Increase in colloid osmotic pressure in plasma flowing through the

1400

glomerular capillary. Normally, about one fifth of the fluid in the

150

Normal

glomerular capillaries filters into Bowman’s capsule, thereby con-

centrating the plasma proteins that are not filtered. Increases in

100

Renal blood

800

the filtration fraction (glomerular filtration rate/renal plasma flow)

Glomerular

flow

increase the rate at which the plasma colloid osmotic pressure

filtration

rises along the glomerular capillary; decreases in the filtration

rate

fraction have the opposite effect.

200

Afferent arteriolar resistance

(X normal)

by the time the blood reaches the efferent end of the

capillaries. Therefore, the average colloid osmotic

pressure of the glomerular capillary plasma proteins

is midway between 28 and 36 mm Hg, or about

Figure 26-14

32 mm Hg.

Effect of change in afferent arteriolar resistance or efferent arteri-

Thus, two factors that influence the glomerular cap-

olar resistance on glomerular filtration rate and renal blood flow.

illary colloid osmotic pressure are

(1) the arterial

plasma colloid osmotic pressure and (2) the fraction

of plasma filtered by the glomerular capillaries (filtra-

tion fraction). Increasing the arterial plasma colloid

osmotic pressure raises the glomerular capillary

Increased Glomerular Capillary

colloid osmotic pressure, which in turn decreases

Hydrostatic Pressure Increases GFR

GFR.

Increasing the filtration fraction also concentrates the

The glomerular capillary hydrostatic pressure has

plasma proteins and raises the glomerular colloid

been estimated to be about 60 mm Hg under normal

osmotic pressure (see Figure 26-13). Because the fil-

conditions. Changes in glomerular hydrostatic pres-

tration fraction is defined as GFR/renal plasma flow,

sure serve as the primary means for physiologic regu-

the filtration fraction can be increased either by raising

lation of GFR. Increases in glomerular hydrostatic

GFR or by reducing renal plasma flow. For example, a

pressure raise GFR, whereas decreases in glomerular

reduction in renal plasma flow with no initial change

hydrostatic pressure reduce GFR.

in GFR would tend to increase the filtration fraction,

Glomerular hydrostatic pressure is determined by

which would raise the glomerular capillary colloid

three variables, each of which is under physiologic

osmotic pressure and tend to reduce GFR. For this

control: (1) arterial pressure,

(2) afferent arteriolar

reason, changes in renal blood flow can influence GFR

resistance, and (3) efferent arteriolar resistance.

independently of changes in glomerular hydrostatic

Increased arterial pressure tends to raise glomeru-

pressure.

lar hydrostatic pressure and, therefore, to increase

With increasing renal blood flow, a lower fraction of

GFR. (However, as discussed later, this effect is

the plasma is initially filtered out of the glomerular

buffered by autoregulatory mechanisms that maintain

capillaries, causing a slower rise in the glomerular

a relatively constant glomerular pressure as blood

capillary colloid osmotic pressure and less inhibitory

pressure fluctuates.)

effect on GFR. Consequently, even with a constant

Increased resistance of afferent arterioles reduces

glomerular hydrostatic pressure, a greater rate of blood

glomerular hydrostatic pressure and decreases GFR.

flow into the glomerulus tends to increase GFR, and a

Conversely, dilation of the afferent arterioles increases

lower rate of blood flow into the glomerulus tends to

both glomerular hydrostatic pressure and GFR

decrease GFR.

(Figure 26-14).

320

Unit V The Body Fluids and Kidneys

Constriction of the efferent arterioles increases the

Renal Blood Flow

resistance to outflow from the glomerular capillaries.

This raises the glomerular hydrostatic pressure, and as

In an average 70-kilogram man, the combined blood

long as the increase in efferent resistance does not

flow through both kidneys is about 1100 ml/min, or

reduce renal blood flow too much, GFR increases

about 22 per cent of the cardiac output. Considering

slightly (see Figure 26-14). However, because efferent

the fact that the two kidneys constitute only about 0.4

arteriolar constriction also reduces renal blood flow,

per cent of the total body weight, one can readily see

the filtration fraction and glomerular colloid osmotic

that they receive an extremely high blood flow com-

pressure increase as efferent arteriolar resistance

pared with other organs.

increases. Therefore, if the constriction of efferent

As with other tissues, blood flow supplies the

arterioles is severe

(more than about a threefold

kidneys with nutrients and removes waste products.

increase in efferent arteriolar resistance), the rise in

However, the high flow to the kidneys greatly exceeds

colloid osmotic pressure exceeds the increase in

this need. The purpose of this additional flow is to

glomerular capillary hydrostatic pressure caused by

supply enough plasma for the high rates of glomeru-

efferent arteriolar constriction. When this occurs, the

lar filtration that are necessary for precise regulation

net force for filtration actually decreases, causing a

of body fluid volumes and solute concentrations. As

reduction in GFR.

might be expected, the mechanisms that regulate renal

Thus, efferent arteriolar constriction has a biphasic

blood flow are closely linked to the control of GFR

effect on GFR. At moderate levels of constriction,

and the excretory functions of the kidneys.

there is a slight increase in GFR, but with severe con-

striction, there is a decrease in GFR. The primary

cause of the eventual decrease in GFR is as follows:

Renal Blood Flow and Oxygen

As efferent constriction becomes severe and as plasma

Consumption

protein concentration increases, there is a rapid, non-

linear increase in colloid osmotic pressure caused by

On a per gram weight basis, the kidneys normally

the Donnan effect; the higher the protein concentra-

consume oxygen at twice the rate of the brain but have

tion, the more rapidly the colloid osmotic pressure

almost seven times the blood flow of the brain. Thus,

rises because of the interaction of ions bound to the

the oxygen delivered to the kidneys far exceeds their

plasma proteins, which also exert an osmotic effect, as

metabolic needs, and the arterial-venous extraction of

discussed in Chapter 16.

oxygen is relatively low compared with that of most

To summarize, constriction of afferent arterioles

other tissues.

reduces GFR. However, the effect of efferent arterio-

A large fraction of the oxygen consumed by the

lar constriction depends on the severity of the con-

kidneys is related to the high rate of active sodium

striction; modest efferent constriction raises GFR, but

reabsorption by the renal tubules. If renal blood flow

severe efferent constriction (more than a threefold

and GFR are reduced and less sodium is filtered, less

increase in resistance) tends to reduce GFR.

sodium is reabsorbed and less oxygen is consumed.

Table 26-2 summarizes the factors that can decrease

Therefore, renal oxygen consumption varies in pro-

GFR.

portion to renal tubular sodium reabsorption, which in

turn is closely related to GFR and the rate of sodium

filtered (Figure 26-15). If glomerular filtration com-

Table 26-2

pletely ceases, renal sodium reabsorption also ceases,

Factors That Can Decrease the Glomerular Filtration Rate

and oxygen consumption decreases to about one

(GFR)

fourth normal. This residual oxygen consumption

reflects the basic metabolic needs of the renal cells.

Physical Determinants* Physiologic/Pathophysiologic Causes

ØK_f

Æ Ø GFR

Renal disease, diabetes mellitus,

Determinants of Renal Blood Flow

hypertension

≠ P_B Æ Ø GFR

Urinary tract obstruction (e.g., kidney

stones)

Renal blood flow is determined by the pressure gradi-

≠ p_G Æ Ø GFR

Ø Renal blood flow, increased plasma

ent across the renal vasculature

(the difference

proteins

between renal artery and renal vein hydrostatic pres-

Ø P_G Æ Ø GFR

sures), divided by the total renal vascular resistance:

ØA_P ÆØP_G

Ø Arterial pressure (has only small effect

due to autoregulation)

(Renal artery pressure Renal vein pressure)

ØR_E ÆØP_G

Ø Angiotensin II (drugs that block

angiotensin II formation)

Total renal vascular resistance

≠R_A ÆØP_G

≠ Sympathetic activity, vasoconstrictor

Renal artery pressure is about equal to systemic

hormones (e.g., norepinephrine,

endothelin)

arterial pressure, and renal vein pressure averages

about 3 to 4 mm Hg under most conditions. As in other

* Opposite changes in the determinants usually increase GFR.

vascular beds, the total vascular resistance through the

K_f, glomerular filtration coefficient; P_B, Bowman’s capsule hydrostatic pres-

kidneys is determined by the sum of the resistances in

sure; p_G, glomerular capillary colloid osmotic pressure; P_G, glomerular capil-

the individual vasculature segments, including the

lary hydrostatic pressure; A_P, systemic arterial pressure; R_E, efferent arteriolar

resistance; R_A, afferent arteriolar resistance.

arteries, arterioles, capillaries, and veins (Table 26-3).

Chapter 26

Urine Formation by the Kidneys: I. Glomerular Filtration, Renal Blood Flow, and Their Control

321

Table 26-3

Approximate Pressures and Vascular Resistances in the Circulation of a Normal Kidney

Pressure in Vessel (mm Hg)

Vessel

Beginning

End

Per Cent of Total Renal Vascular Resistance

Renal artery

100

Interlobar, arcuate, and interlobular arteries

~100

~16

Afferent arteriole

~26

Glomerular capillaries

Efferent arteriole

~43

Peritubular capillaries

~10

Interlobar, interlobular, and arcuate veins

Renal vein

range between 80 and 170 mm Hg, a process called

autoregulation. This capacity for autoregulation occurs

3.0

through mechanisms that are completely intrinsic to

the kidneys, as discussed later in this chapter.

2.5

Blood Flow in the Vasa Recta of the

Renal Medulla Is Very Low Compared

2.0

with Flow in the Renal Cortex

1.5

The outer part of the kidney, the renal cortex, receives

most of the kidney’s blood flow. Blood flow in the renal

medulla accounts for only 1 to 2 per cent of the total

1.0

renal blood flow. Flow to the renal medulla is supplied

by a specialized portion of the peritubular capillary

0.5

system called the vasa recta. These vessels descend into

Basal oxygen consumption

the medulla in parallel with the loops of Henle and

then loop back along with the loops of Henle and

return to the cortex before emptying into the venous

Sodium reabsorption

system. As discussed in Chapter 28, the vasa recta play

(mEq/min per 100 g kidney weight)

an important role in allowing the kidneys to form a

concentrated urine.

Figure 26-15

Physiologic Control of

Glomerular Filtration and

Relationship between oxygen consumption and sodium reab-

Renal Blood Flow

sorption in dog kidneys. (Kramer K, Deetjen P: Relation of renal

oxygen consumption to blood supply and glomerular filtration

during variations of blood pressure. Pflugers Arch Physiol

The determinants of GFR that are most variable and

271:782, 1960.)

subject to physiologic control include the glomerular

hydrostatic pressure and the glomerular capillary

Most of the renal vascular resistance resides in three

colloid osmotic pressure. These variables, in turn, are

major segments: interlobular arteries, afferent arteri-

influenced by the sympathetic nervous system, hor-

oles, and efferent arterioles. Resistance of these vessels

mones and autacoids (vasoactive substances that are

is controlled by the sympathetic nervous system,

released in the kidneys and act locally), and other

various hormones, and local internal renal control

feedback controls that are intrinsic to the kidneys.

mechanisms, as discussed later. An increase in the

resistance of any of the vascular segments of the

kidneys tends to reduce the renal blood flow, whereas

Sympathetic Nervous System

a decrease in vascular resistance increases renal blood

Activation Decreases GFR

flow if renal artery and renal vein pressures remain

constant.

Essentially all the blood vessels of the kidneys, includ-

Although changes in arterial pressure have some

ing the afferent and the efferent arterioles, are richly

influence on renal blood flow, the kidneys have effec-

innervated by sympathetic nerve fibers. Strong activa-

tive mechanisms for maintaining renal blood flow and

tion of the renal sympathetic nerves can constrict the

GFR relatively constant over an arterial pressure

renal arterioles and decrease renal blood flow and

322

Unit V The Body Fluids and Kidneys

GFR. Moderate or mild sympathetic stimulation has

Angiotensin II Constricts Efferent Arterioles. A powerful

little influence on renal blood flow and GFR. For

renal vasoconstrictor, angiotensin II, can be consid-

example, reflex activation of the sympathetic nervous

ered a circulating hormone as well as a locally pro-

system resulting from moderate decreases in pressure

duced autacoid because it is formed in the kidneys

at the carotid sinus baroreceptors or cardiopulmonary

as well as in the systemic circulation. Because

receptors has little influence on renal blood flow or

angiotensin II preferentially constricts efferent arteri-

GFR.

oles, increased angiotensin II levels raise glomerular

The renal sympathetic nerves seem to be most

hydrostatic pressure while reducing renal blood flow.

important in reducing GFR during severe, acute dis-

It should be kept in mind that increased angiotensin

turbances lasting for a few minutes to a few hours,

II formation usually occurs in circumstances associ-

such as those elicited by the defense reaction, brain

ated with decreased arterial pressure or volume

ischemia, or severe hemorrhage. In the healthy resting

depletion, which tend to decrease GFR. In these cir-

person, sympathetic tone appears to have little influ-

cumstances, the increased level of angiotensin II, by

ence on renal blood flow.

constricting efferent arterioles, helps prevent decreases

in glomerular hydrostatic pressure and GFR; at the

same time, though, the reduction in renal blood flow

Hormonal and Autacoid Control

caused by efferent arteriolar constriction contributes

of Renal Circulation

to decreased flow through the peritubular capillaries,

which in turn increases reabsorption of sodium and

There are several hormones and autacoids that can

water, as discussed in Chapter 27.

influence GFR and renal blood flow, as summarized in

Thus, increased angiotensin II levels that occur with

Table 26-4.

a low-sodium diet or volume depletion help preserve

GFR and maintain normal excretion of metabolic

Norepinephrine, Epinephrine, and Endothelin Constrict Renal

waste products such as urea and creatinine that

Blood Vessels and Decrease GFR. Hormones that constrict

depend on glomerular filtration for their excretion; at

afferent and efferent arterioles, causing reductions in

the same time, the angiotensin II-induced constriction

GFR and renal blood flow, include norepinephrine and

of efferent arterioles increases tubular reabsorption of

epinephrine released from the adrenal medulla. In

sodium and water, which helps restore blood volume

general, blood levels of these hormones parallel the

and blood pressure. This effect of angiotensin II in

activity of the sympathetic nervous system; thus, nor-

helping to “autoregulate” GFR is discussed in more

epinephrine and epinephrine have little influence on

detail later in this chapter.

renal hemodynamics except under extreme conditions,

such as severe hemorrhage.

Endothelial-Derived Nitric Oxide Decreases Renal Vascular

Another vasoconstrictor, endothelin, is a peptide

Resistance and Increases GFR. An autacoid that de-

that can be released by damaged vascular endothelial

creases renal vascular resistance and is released by the

cells of the kidneys as well as by other tissues. The

vascular endothelium throughout the body is endothe-

physiologic role of this autacoid is not completely

lial-derived nitric oxide. A basal level of nitric oxide

understood. However, endothelin may contribute to

production appears to be important for maintaining

hemostasis

(minimizing blood loss) when a blood

vasodilation of the kidneys. This allows the kidneys to

vessel is severed, which damages the endothelium

excrete normal amounts of sodium and water. There-

and releases this powerful vasoconstrictor. Plasma

fore, administration of drugs that inhibit this normal

endothelin levels also are increased in certain disease

formation of nitric oxide increases renal vascular

states associated with vascular injury, such as toxemia

resistance and decreases GFR and urinary sodium

of pregnancy, acute renal failure, and chronic uremia,

excretion, eventually causing high blood pressure. In

and may contribute to renal vasoconstriction and

some hypertensive patients, impaired nitric oxide pro-

decreased GFR in some of these pathophysiologic

duction could be the cause of increased renal vaso-

conditions.

constriction and increased blood pressure.

Prostaglandins and Bradykinin Tend to Increase GFR. Hor-

mones and autacoids that cause vasodilation and

Table 26-4

increased renal blood flow and GFR include the

prostaglandins

(PGE₂ and PGI₂) and bradykinin.

Hormones and Autacoids That Influence Glomerular

These substances are discussed in Chapter

17.

Filtration Rate (GFR)

Although these vasodilators do not appear to be of

major importance in regulating renal blood flow or

Hormone or Autacoid

Effect on GFR

GFR in normal conditions, they may dampen the renal

Norepinephrine

vasoconstrictor effects of the sympathetic nerves or

Epinephrine

angiotensin II, especially their effects to constrict the

Endothelin

afferent arterioles.

Angiotensin II

¨Æ (prevents Ø)

By opposing vasoconstriction of afferent arterioles,

Endothelial-derived nitric oxide

≠

Prostaglandins

≠

the prostaglandins may help prevent excessive reduc-

tions in GFR and renal blood flow. Under stressful

Chapter 26

Urine Formation by the Kidneys: I. Glomerular Filtration, Renal Blood Flow, and Their Control

323

conditions, such as volume depletion or after surgery,

arterial pressure to as low as 75 mm Hg or an increase

the administration of nonsteroidal anti-inflammatory

to as high as 160 mm Hg changes GFR only a few

agents, such as aspirin, that inhibit prostaglandin syn-

percentage points. In general, renal blood flow is auto-

thesis may cause significant reductions in GFR.

regulated in parallel with GFR, but GFR is more effi-

ciently autoregulated under certain conditions.

Autoregulation of GFR and

Renal Blood Flow

Importance of GFR Autoregulation

in Preventing Extreme Changes in

Feedback mechanisms intrinsic to the kidneys nor-

Renal Excretion

mally keep the renal blood flow and GFR relatively

constant, despite marked changes in arterial blood

The autoregulatory mechanisms of the kidney are not

pressure. These mechanisms still function in blood-

100 per cent perfect, but they do prevent potentially

perfused kidneys that have been removed from the

large changes in GFR and renal excretion of water and

body, independent of systemic influences. This relative

solutes that would otherwise occur with changes in

constancy of GFR and renal blood flow is referred to

blood pressure. One can understand the quantitative

as autoregulation (Figure 26-16).

importance of autoregulation by considering the rela-

The primary function of blood flow autoregulation

tive magnitudes of glomerular filtration, tubular reab-

in most tissues other than the kidneys is to maintain

sorption, and renal excretion and the changes in renal

the delivery of oxygen and nutrients at a normal level

excretion that would occur without autoregulatory

and to remove the waste products of metabolism,

mechanisms.

despite changes in the arterial pressure. In the kidneys,

Normally, GFR is about 180 L/day and tubular reab-

the normal blood flow is much higher than that

sorption is 178.5 L/day, leaving 1.5 L/day of fluid to be

required for these functions. The major function of

excreted in the urine. In the absence of autoregulation,

autoregulation in the kidneys is to maintain a rela-

a relatively small increase in blood pressure (from 100

tively constant GFR and to allow precise control of

to 125 mm Hg) would cause a similar 25 per cent

renal excretion of water and solutes.

increase in GFR (from about 180 to 225 L/day). If

The GFR normally remains autoregulated (that is,

tubular reabsorption remained constant at 178.5 L/

remains relatively constant), despite considerable

day, this would increase the urine flow to 46.5 L/day

arterial pressure fluctuations that occur during a

(the difference between GFR and tubular reabsorp-

person’s usual activities. For instance, a decrease in

tion)—a total increase in urine of more than 30-fold.

Because the total plasma volume is only about 3 liters,

such a change would quickly deplete the blood

volume.

But in reality, such a change in arterial pressure

1600

160

exerts much less of an effect on urine volume for

two reasons: (1) renal autoregulation prevents large

1200

120

changes in GFR that would otherwise occur, and (2)

there are additional adaptive mechanisms in the renal

800

tubules that allow them to increase their reabsorption

Renal blood flow

rate when GFR rises, a phenomenon referred to as

400

Glomerular filtration

glomerulotubular balance (discussed in Chapter 27).

rate

Even with these special control mechanisms, changes

in arterial pressure still have significant effects on

renal excretion of water and sodium; this is referred to

as pressure diuresis or pressure natriuresis, and it is

crucial in the regulation of body fluid volumes and

arterial pressure, as discussed in Chapters 19 and 29.

Role of Tubuloglomerular Feedback

in Autoregulation of GFR

100

150

200

Arterial pressure

To perform the function of autoregulation, the kidneys

(mm Hg)

have a feedback mechanism that links changes in

sodium chloride concentration at the macula densa

with the control of renal arteriolar resistance. This

Figure 26-16

feedback helps ensure a relatively constant delivery of

sodium chloride to the distal tubule and helps prevent

Autoregulation of renal blood flow and glomerular filtration rate but

lack of autoregulation of urine flow during changes in renal arte-

spurious fluctuations in renal excretion that would

rial pressure.

otherwise occur. In many circumstances, this feedback

324

Unit V The Body Fluids and Kidneys

autoregulates renal blood flow and GFR in parallel.

decreased GFR slows the flow rate in the loop of

However, because this mechanism is specifically

Henle, causing increased reabsorption of sodium and

directed toward stabilizing sodium chloride delivery to

chloride ions in the ascending loop of Henle, thereby

the distal tubule, there are instances when GFR is

reducing the concentration of sodium chloride at the

autoregulated at the expense of changes in renal blood

macula densa cells. This decrease in sodium chloride

flow, as discussed later.

concentration initiates a signal from the macula densa

The tubuloglomerular feedback mechanism has

that has two effects (Figure 26-18): (1) it decreases

two components that act together to control GFR:

resistance to blood flow in the afferent arterioles,

(1) an afferent arteriolar feedback mechanism and (2)

which raises glomerular hydrostatic pressure and helps

an efferent arteriolar feedback mechanism. These

return GFR toward normal, and (2) it increases renin

feedback mechanisms depend on special anatomical

release from the juxtaglomerular cells of the afferent

arrangements of the juxtaglomerular complex (Figure

and efferent arterioles, which are the major storage

26-17).

sites for renin. Renin released from these cells then

The juxtaglomerular complex consists of macula

functions as an enzyme to increase the formation of

densa cells in the initial portion of the distal tubule and

angiotensin I, which is converted to angiotensin II.

juxtaglomerular cells in the walls of the afferent and

Finally, the angiotensin II constricts the efferent arte-

efferent arterioles. The macula densa is a specialized

rioles, thereby increasing glomerular hydrostatic pres-

group of epithelial cells in the distal tubules that comes

sure and returning GFR toward normal.

in close contact with the afferent and efferent arteri-

These two components of the tubuloglomerular

oles. The macula densa cells contain Golgi apparatus,

feedback mechanism, operating together by way of the

which are intracellular secretory organelles directed

special anatomical structure of the juxtaglomerular

toward the arterioles, suggesting that these cells may

apparatus, provide feedback signals to both the affer-

be secreting a substance toward the arterioles.

ent and the efferent arterioles for efficient autoregu-

lation of GFR during changes in arterial pressure.

Decreased Macula Densa Sodium Chloride Causes Dilation of

When both of these mechanisms are functioning

Afferent Arterioles and Increased Renin Release. The

together, the GFR changes only a few percentage

macula densa cells sense changes in volume delivery

points, even with large fluctuations in arterial pressure

to the distal tubule by way of signals that are not com-

between the limits of 75 and 160 mm Hg.

pletely understood. Experimental studies suggest that

Arterial pressure

Glomerular hydrostatic

pressure

Glomerular

epithelium

GFR

Proximal

NaCl

Macula densa

reabsorption

NaCl

Juxtaglomerular

cells

Afferent

Renin

Efferent

arteriole

Angiotensin II

Internal

Macula densa

elastic

lamina

Efferent

Afferent

arteriolar

Smooth

Basement

resistance

muscle

membrane

Distal

fiber

tubule

Figure 26-18

Figure 26-17

Macula densa feedback mechanism for autoregulation

Structure of the juxtaglomerular apparatus, demonstrating its pos-

glomerular hydrostatic pressure and glomerular filtration rate

sible feedback role in the control of nephron function.

(GFR) during decreased renal arterial pressure.

Chapter 26

Urine Formation by the Kidneys: I. Glomerular Filtration, Renal Blood Flow, and Their Control

325

Blockade of Angiotensin II Formation Further Reduces GFR During

The exact mechanisms by which this occurs are still

Renal Hypoperfusion. As discussed earlier, a preferential

not completely understood, but one possible explana-

constrictor action of angiotensin II on efferent arteri-

tion is the following: A high-protein meal increases the

oles helps prevent serious reductions in glomerular

release of amino acids into the blood, which are reab-

hydrostatic pressure and GFR when renal perfusion

sorbed in the proximal tubule. Because amino acids

pressure falls below normal. The administration of

and sodium are reabsorbed together by the proximal

drugs that block the formation of angiotensin II

tubules, increased amino acid reabsorption also stimu-

(angiotensin-converting enzyme inhibitors) or that

lates sodium reabsorption in the proximal tubules. This

block the action of angiotensin II (angiotensin II antag-

decreases sodium delivery to the macula densa, which

onists) causes greater reductions in GFR than usual

elicits a tubuloglomerular feedback-mediated decrease

when the renal arterial pressure falls below normal.

in resistance of the afferent arterioles, as discussed

Therefore, an important complication of using these

earlier. The decreased afferent arteriolar resistance then

drugs to treat patients who have hypertension because

raises renal blood flow and GFR. This increased GFR

of renal artery stenosis (partial blockage of the renal

allows sodium excretion to be maintained at a nearly

artery) is a severe decrease in GFR that can, in

normal level while increasing the excretion of the waste

some cases, cause acute renal failure. Nevertheless,

products of protein metabolism, such as urea.

angiotensin II-blocking drugs can be useful therapeutic

A similar mechanism may also explain the marked

agents in many patients with hypertension, congestive

increases in renal blood flow and GFR that occur with

heart failure, and other conditions, as long as they are

large increases in blood glucose levels in uncontrolled

monitored to ensure that severe decreases in GFR do

diabetes mellitus. Because glucose, like some of the

not occur.

amino acids, is also reabsorbed along with sodium in

the proximal tubule, increased glucose delivery to the

tubules causes them to reabsorb excess sodium along

with glucose. This, in turn, decreases delivery of sodium

Myogenic Autoregulation of Renal

chloride to the macula densa, activating a tubu-

Blood Flow and GFR

loglomerular feedback-mediated dilation of the affer-

ent arterioles and subsequent increases in renal blood

Another mechanism that contributes to the main-

flow and GFR.

tenance of a relatively constant renal blood flow

These examples demonstrate that renal blood flow

and GFR is the ability of individual blood vessels to

and GFR per se are not the primary variables controlled

resist stretching during increased arterial pressure, a

by the tubuloglomerular feedback mechanism. The

phenomenon referred to as the myogenic mechanism.

main purpose of this feedback is to ensure a constant

delivery of sodium chloride to the distal tubule, where

Studies of individual blood vessels (especially small

final processing of the urine takes place. Thus, distur-

arterioles) throughout the body have shown that they

bances that tend to increase reabsorption of sodium

respond to increased wall tension or wall stretch by

chloride at tubular sites before the macula densa tend

contraction of the vascular smooth muscle. Stretch

to elicit increased renal blood flow and GFR, which

of the vascular wall allows increased movement of

helps return distal sodium chloride delivery toward

calcium ions from the extracellular fluid into the cells,

normal so that normal rates of sodium and water excre-

causing them to contract through the mechanisms dis-

tion can be maintained (see Figure 26-18).

cussed in Chapter 8. This contraction prevents overdis-

An opposite sequence of events occurs when proxi-

tention of the vessel and at the same time, by raising

mal tubular reabsorption is reduced. For example, when

vascular resistance, helps prevent excessive increases

the proximal tubules are damaged (which can occur as

a result of poisoning by heavy metals, such as mercury,

in renal blood flow and GFR when arterial pressure

or large doses of drugs, such as tetracyclines), their

increases.

ability to reabsorb sodium chloride is decreased. As a

Although the myogenic mechanism probably oper-

consequence, large amounts of sodium chloride are

ates in most arterioles throughout the body, its impor-

delivered to the distal tubule and, without appropriate

tance in renal blood flow and GFR autoregulation has

compensations, would quickly cause excessive volume

been questioned by some physiologists because this

depletion. One of the important compensatory

pressure-sensitive mechanism has no means of directly

responses appears to be a tubuloglomerular feed-

detecting changes in renal blood flow or GFR per se.

back-mediated renal vasoconstriction that occurs in

response to the increased sodium chloride delivery to

the macula densa in these circumstances. These exam-

Other Factors That Increase Renal

ples again demonstrate the importance of this feedback

Blood Flow and GFR: High Protein

mechanism in ensuring that the distal tubule receives

the proper rate of delivery of sodium chloride, other

Intake and Increased Blood Glucose

tubular fluid solutes, and tubular fluid volume so that

Although renal blood flow and GFR are relatively

appropriate amounts of these substances are excreted

stable under most conditions, there are circumstances in

in the urine.

which these variables change significantly. For example,

a high protein intake is known to increase both renal

blood flow and GFR. With a chronic high-protein diet,

References

such as one that contains large amounts of meat, the

increases in GFR and renal blood flow are due partly to

Beeuwkes R III: The vascular organization of the kidney.

growth of the kidneys. However, GFR and renal blood

Annu Rev Physiol 42:531, 1980.

flow increase 20 to 30 per cent within 1 or 2 hours after

Bell PD, Lapointe JY, Peti-Peterdi J: Macula densa cell sig-

a person eats a high-protein meal.

naling. Annu Rev Physiol 65:481, 2003.

326

Unit V The Body Fluids and Kidneys

Blantz RC, Deng A, Lortie M, et al: The complex role of

Haraldsson B, Sörensson J: Why do we not all have protein-

nitric oxide in the regulation of glomerular ultrafiltration.

uria? An update of our current understanding of the

Kidney Int 61:782, 2002.

glomerular barrier. News Physiol Sci 19:7, 2004.

Cowley AW Jr, Mori T, Mattson D, Zou AP: Role of renal

Kriz W, Kaissling B: Structural organization of the mam-

NO production in the regulation of medullary blood flow.

malian kidney. In Seldin DW, Giebisch G (eds): The

Am J Physiol Regul Integr Comp Physiol 284:R1355,

Kidney—Physiology and Pathophysiology, 3rd ed. New

2003.

York: Raven Press, 2000, pp 587-654.

Davis MJ, Hill MA: Signaling mechanisms underlying

Navar LG, Kobori H, Prieto-Carrasquero M: Intrarenal

the vascular myogenic response. Physiol Rev

79:387,

angiotensin II and hypertension. Curr Hypertens Rep

1999.

5:135, 2003.

Deen WM, Lazzara MJ, Myers BD: Structural determinants

Pallone TL, Zhang Z, Rhinehart K: Physiology of the renal

of glomerular permeability. Am J Physiol Renal Physiol

medullary microcirculation. Am J Physiol Renal Physiol

281:F579, 2001.

284:F253, 2003.

DiBona GF: Neural control of the kidney: past, present, and

Roman RJ: P-450 metabolites of arachidonic acid in the

future. Hypertension 41:621, 2003.

control of cardiovascular function. Physiol Rev 82:131,

Hall JE: Angiotensin II and long-term arterial pressure reg-

2002.

ulation: the overriding dominance of the kidney. J Am Soc

Schnermann J, Levine DZ: Paracrine factors in tubu-

Nephrol 10 (Suppl 12):s258, 1999.

loglomerular feedback: adenosine, ATP, and nitric oxide.

Hall JE, Brands MW: The renin-angiotensin-aldosterone

Annu Rev Physiol 65:501, 2003.

system: renal mechanisms and circulatory homeostasis. In

Whelton A: Renal aspects of treatment with conventional

Seldin DW, Giebisch G (eds): The Kidney—Physiology

nonsteroidal anti-inflammatory drugs versus cyclooxyge-

and Pathophysiology, 3rd ed. New York: Raven Press,

nase-2-specific inhibitors. Am J Med 110 (Suppl 3A):33S,

2000, pp 1009-1046.

2001.

C H A P T E R

Urine Formation by the Kidneys:

II. Tubular Processing of the

Glomerular Filtrate

Reabsorption and Secretion

by the Renal Tubules

As the glomerular filtrate enters the renal tubules,

it flows sequentially through the successive parts of

the tubule—the proximal tubule, the loop of Henle,

the distal tubule, the collecting tubule, and, finally,

the collecting duct—before it is excreted as urine.

Along this course, some substances are selectively reabsorbed from the tubules

back into the blood, whereas others are secreted from the blood into the tubular

lumen. Eventually, the urine that is formed and all the substances in the urine

represent the sum of three basic renal processes—glomerular filtration, tubular

reabsorption, and tubular secretion—as follows:

Urinary excretion = Glomerular filtration - Tubular reabsorption

+ Tubular secretion

For many substances, reabsorption plays a much more important role than

does secretion in determining the final urinary excretion rate. However, secre-

tion accounts for significant amounts of potassium ions, hydrogen ions, and a

few other substances that appear in the urine.

Tubular Reabsorption Is Selective and Quantitatively Large

Table 27-1 shows the renal handling of several substances that are all freely fil-

tered in the kidneys and reabsorbed at variable rates.

The rate at which each of these substances is filtered is calculated as

Filtration = Glomerular filtration rate ¥ Plasma concentration

This calculation assumes that the substance is freely filtered and not bound

to plasma proteins. For example, if plasma glucose concentration is 1 g/L, the

amount of glucose filtered each day is about 180 L/day ¥ 1 g/L, or 180 g/day.

Because virtually none of the filtered glucose is normally excreted, the rate of

glucose reabsorption is also 180 g/day.

From Table 27-1, two things are immediately apparent. First, the processes of

glomerular filtration and tubular reabsorption are quantitatively very large rel-

ative to urinary excretion for many substances. This means that a small change

in glomerular filtration or tubular reabsorption can potentially cause a relatively

large change in urinary excretion. For example, a 10 per cent decrease in tubular

reabsorption, from 178.5 to 160.7 L/day, would increase urine volume from 1.5

to 19.3 L/day (almost a 13-fold increase) if the glomerular filtration rate (GFR)

remained constant. In reality, however, changes in tubular reabsorption and

glomerular filtration are closely coordinated, so that large fluctuations in urinary

excretion are avoided.

Second, unlike glomerular filtration, which is relatively nonselective (that is,

essentially all solutes in the plasma are filtered except the plasma proteins or

substances bound to them), tubular reabsorption is highly selective. Some sub-

stances, such as glucose and amino acids, are almost completely reabsorbed

327

328

Unit V The Body Fluids and Kidneys

Table 27-1

Filtration, Reabsorption, and Excretion Rates of Different Substances by the Kidneys

Amount Filtered

Amount Reabsorbed

Amount Excreted

% of Filtered Load Reabsorbed

Glucose (g/day)

180

100

Bicarbonate (mEq/day)

4,320

4,318

>99.9

Sodium (mEq/day)

25,560

25,410

150

99.4

Chloride (mEq/day)

19,440

19,260

180

99.1

Potassium (mEq/day)

756

664

87.8

Urea (g/day)

46.8

23.4

Creatinine (g/day)

1.8

from the tubules, so that the urinary excretion rate is

FILTRATION

essentially zero. Many of the ions in the plasma, such

Peritubular

Tubular

capillary

cells

as sodium, chloride, and bicarbonate, are also highly

Lumen

reabsorbed, but their rates of reabsorption and urinary

excretion are variable, depending on the needs of the

body. Certain waste products, such as urea and creati-

Paracellular

nine, conversely, are poorly reabsorbed from the

Bulk

path

tubules and excreted in relatively large amounts.

flow

Transcellular

Therefore, by controlling the rate at which they

path

Active

reabsorb different substances, the kidneys regulate the

ATP

excretion of solutes independently of one another, a

Blood

Passive

Solutes

capability that is essential for precise control of the

(diffusion)

composition of body fluids. In this chapter, we discuss

the mechanisms that allow the kidneys to selectively

Osmosis

H₂O

reabsorb or secrete different substances at variable

rates.

REABSORPTION

EXCRETION

Tubular Reabsorption

Figure 27-1

Includes Passive and

Active Mechanisms

Reabsorption of filtered water and solutes from the tubular lumen

across the tubular epithelial cells, through the renal interstitium, and

back into the blood. Solutes are transported through the cells (trans-

For a substance to be reabsorbed, it must first be trans-

cellular route) by passive diffusion or active transport, or between

ported (1) across the tubular epithelial membranes

the cells

(paracellular route) by diffusion. Water is transported

into the renal interstitial fluid and then (2) through the

through the cells and between the tubular cells by osmosis. Trans-

port of water and solutes from the interstitial fluid into the peri-

peritubular capillary membrane back into the blood

tubular capillaries occurs by ultrafiltration (bulk flow).

(Figure 27-1). Thus, reabsorption of water and solutes

includes a series of transport steps. Reabsorption

across the tubular epithelium into the interstitial fluid

includes active or passive transport by way of the same

Active Transport

basic mechanisms discussed in Chapter 4 for transport

across other membranes of the body. For instance,

Active transport can move a solute against an elec-

water and solutes can be transported either through

trochemical gradient and requires energy derived

the cell membranes themselves (transcellular route) or

from metabolism. Transport that is coupled directly to

through the junctional spaces between the cells (para-

an energy source, such as the hydrolysis of adenosine

cellular route). Then, after absorption across the

triphosphate (ATP), is termed primary active trans-

tubular epithelial cells into the interstitial fluid, water

port. A good example of this is the sodium-potassium

and solutes are transported the rest of the way through

ATPase pump that functions throughout most parts of

the peritubular capillary walls into the blood by ultra-

the renal tubule. Transport that is coupled indirectly to

filtration (bulk flow) that is mediated by hydrostatic

an energy source, such as that due to an ion gradient,

and colloid osmotic forces. The peritubular capillaries

is referred to as secondary active transport. Reabsorp-

behave very much like the venous ends of most other

tion of glucose by the renal tubule is an example of

capillaries because there is a net reabsorptive force

secondary active transport. Although solutes can be

that moves the fluid and solutes from the interstitium

reabsorbed by active and/or passive mechanisms by

into the blood.

the tubule, water is always reabsorbed by a passive

Chapter 27

Urine Formation by the Kidneys: II. Tubular Processing of the Glomerular Filtrate

329

(nonactive) physical mechanism called osmosis, which

Peritubular

Tubular

means water diffusion from a region of low solute con-

capillary

epithelial cells

lumen

centration (high water concentration) to one of high

solute concentration (low water concentration).

Solutes Can Be Transported Through Epithelial Cells or Between

Cells. Renal tubular cells, like other epithelial cells, are

ATP

Na⁺

held together by tight junctions. Lateral intercellular

Na⁺

spaces lie behind the tight junctions and separate the

ATP

K⁺

(-3 mv)

epithelial cells of the tubule. Solutes can be reabsorbed

K⁺

or secreted across the cells by way of the transcellular

(-70 mV)

Tight junction

pathway or between the cells by moving across the

tight junctions and intercellular spaces by way of

Brush border

Basal

(luminal

the paracellular pathway. Sodium is a substance that

channels

membrane)

moves through both routes, although most of the

sodium is transported through the transcellular

Interstitial

Basement

Intercellular space

fluid

membrane

pathway. In some nephron segments, especially the

proximal tubule, water is also reabsorbed across the

Figure 27-2

paracellular pathway, and substances dissolved in

the water, especially potassium, magnesium, and chlo-

Basic mechanism for active transport of sodium through the tubular

ride ions, are carried with the reabsorbed fluid

epithelial cell. The sodium-potassium pump transports sodium from

the interior of the cell across the basolateral membrane, creating a

between the cells.

low intracellular sodium concentration and a negative intracellular

electrical potential. The low intracellular sodium concentration and

Primary Active Transport Through the Tubular Membrane Is

the negative electrical potential cause sodium ions to diffuse from

Linked to Hydrolysis of ATP. The special importance of

the tubular lumen into the cell through the brush border.

primary active transport is that it can move solutes

against an electrochemical gradient. The energy for this

active transport comes from the hydrolysis of ATP by

way of membrane-bound ATPase; the ATPase is also

brush border on the luminal side of the membrane

a component of the carrier mechanism that binds and

(the side that faces the tubular lumen) that multiplies

moves solutes across the cell membranes. The primary

the surface area about 20-fold. There are also sodium

active transporters that are known include sodium-

carrier proteins that bind sodium ions on the luminal

potassium ATPase, hydrogen ATPase, hydrogen-

surface of the membrane and release them inside the

potassium ATPase, and calcium ATPase.

cell, providing facilitated diffusion of sodium through

A good example of a primary active transport

the membrane into the cell. These sodium carrier pro-

system is the reabsorption of sodium ions across the

teins are also important for secondary active transport

proximal tubular membrane, as shown in Figure 27-2.

of other substances, such as glucose and amino acids,

On the basolateral sides of the tubular epithelial cell,

as discussed later.

the cell membrane has an extensive sodium-potassium

Thus, the net reabsorption of sodium ions from the

ATPase system that hydrolyzes ATP and uses the

tubular lumen back into the blood involves at least

released energy to transport sodium ions out of the

three steps:

cell into the interstitium. At the same time, potassium

1. Sodium diffuses across the luminal membrane

is transported from the interstitium to the inside of the

(also called the apical membrane) into the cell

cell. The operation of this ion pump maintains low

down an electrochemical gradient established

intracellular sodium and high intracellular potassium

by the sodium-potassium ATPase pump on the

concentrations and creates a net negative charge of

basolateral side of the membrane.

about -70 millivolts within the cell. This pumping of

2. Sodium is transported across the basolateral

sodium out of the cell across the basolateral membrane

membrane against an electrochemical gradient

of the cell favors passive diffusion of sodium across the

by the sodium-potassium ATPase pump.

luminal membrane of the cell, from the tubular lumen

3. Sodium, water, and other substances are

into the cell, for two reasons: (1) There is a concen-

reabsorbed from the interstitial fluid into the

tration gradient favoring sodium diffusion into the cell

peritubular capillaries by ultrafiltration, a passive

because intracellular sodium concentration is low

process driven by the hydrostatic and colloid

(12 mEq/L) and tubular fluid sodium concentration is

osmotic pressure gradients.

high (140 mEq/L). (2) The negative, -70-millivolt,

intracellular potential attracts the positive sodium ions

Secondary Active Reabsorption Through the Tubular Membrane.

from the tubular lumen into the cell.

In secondary active transport, two or more substances

Active reabsorption of sodium by sodium-

interact with a specific membrane protein (a carrier

potassium ATPase occurs in most parts of the tubule.

molecule) and are transported together across the

In certain parts of the nephron, there are additional

membrane. As one of the substances (for instance,

provisions for moving large amounts of sodium into

sodium) diffuses down its electrochemical gradient,

the cell. In the proximal tubule, there is an extensive

the energy released is used to drive another substance

330

Unit V The Body Fluids and Kidneys

Interstitial

Tubular

the simultaneous uphill transport of glucose across the

fluid

cells

lumen

luminal membrane. Thus, this reabsorption of glucose

Co-transport

is referred to as “secondary active transport” because

glucose itself is reabsorbed uphill against a chemical

Glucose

gradient, but it is “secondary” to primary active trans-

port of sodium.

Na⁺

Another important point is that a substance is said

ATP

-70 mV

to undergo “active” transport when at least one of the

K⁺

steps in the reabsorption involves primary or second-

Na⁺

ary active transport, even though other steps in

Amino acids

the reabsorption process may be passive. For glucose

reabsorption, secondary active transport occurs at the

luminal membrane, but passive facilitated diffusion

occurs at the basolateral membrane, and passive

uptake by bulk flow occurs at the peritubular

capillaries.

Na⁺

ATP

-70 mV

Secondary Active Secretion into the Tubules. Some sub-

K⁺

H⁺

stances are secreted into the tubules by secondary

active transport. This often involves counter-transport

of the substance with sodium ions. In counter-

transport, the energy liberated from the downhill

Counter-transport

movement of one of the substances (for example,

sodium ions) enables uphill movement of a second

Figure 27-3

substance in the opposite direction.

Mechanisms of secondary active transport. The upper cell shows the

One example of counter-transport, shown in Figure

co-transport of glucose and amino acids along with sodium ions

27-3, is the active secretion of hydrogen ions coupled

through the apical side of the tubular epithelial cells, followed by

to sodium reabsorption in the luminal membrane of

facilitated diffusion through the basolateral membranes. The lower

the proximal tubule. In this case, sodium entry into the

cell shows the counter-transport of hydrogen ions from the interior

of the cell across the apical membrane and into the tubular lumen;

cell is coupled with hydrogen extrusion from the cell

movement of sodium ions into the cell, down an electrochemical gra-

by sodium-hydrogen counter-transport. This transport

dient established by the sodium-potassium pump on the basolateral

is mediated by a specific protein in the brush border

membrane, provides the energy for transport of the hydrogen ions

of the luminal membrane. As sodium is carried to the

from inside the cell into the tubular lumen.

interior of the cell, hydrogen ions are forced outward

in the opposite direction into the tubular lumen. The

(for instance, glucose) against its electrochemical

basic principles of primary and secondary active trans-

gradient. Thus, secondary active transport does not

port are discussed in additional detail in Chapter 4.

require energy directly from ATP or from other high-

energy phosphate sources. Rather, the direct source of

Pinocytosis—An Active Transport Mechanism for Reabsorption

the energy is that liberated by the simultaneous facil-

of Proteins. Some parts of the tubule, especially the

itated diffusion of another transported substance

proximal tubule, reabsorb large molecules such as

down its own electrochemical gradient.

proteins by pinocytosis. In this process, the protein

Figure 27-3 shows secondary active transport of

attaches to the brush border of the luminal membrane,

glucose and amino acids in the proximal tubule. In

and this portion of the membrane then invaginates to

both instances, a specific carrier protein in the brush

the interior of the cell until it is completely pinched off

border combines with a sodium ion and an amino acid

and a vesicle is formed containing the protein. Once

or a glucose molecule at the same time. These trans-

inside the cell, the protein is digested into its con-

port mechanisms are so efficient that they remove vir-

stituent amino acids, which are reabsorbed through the

tually all the glucose and amino acids from the tubular

basolateral membrane into the interstitial fluid.

lumen. After entry into the cell, glucose and amino

Because pinocytosis requires energy, it is considered a

acids exit across the basolateral membranes by facili-

form of active transport.

tated diffusion, driven by the high glucose and amino

acid concentrations in the cell.

Transport Maximum for Substances That Are Actively Reab-

Although transport of glucose against a chemical

sorbed. For most substances that are actively reab-

gradient does not directly use ATP, the reabsorption

sorbed or secreted, there is a limit to the rate at which

of glucose depends on energy expended by the

the solute can be transported, often referred to as the

primary active sodium-potassium ATPase pump in the

transport maximum. This limit is due to saturation

basolateral membrane. Because of the activity of

of the specific transport systems involved when the

this pump, an electrochemical gradient for facilitated

amount of solute delivered to the tubule (referred to

diffusion of sodium across the luminal membrane is

as tubular load) exceeds the capacity of the carrier

maintained, and it is this downhill diffusion of sodium

proteins and specific enzymes involved in the trans-

to the interior of the cell that provides the energy for

port process.

Chapter 27

Urine Formation by the Kidneys: II. Tubular Processing of the Glomerular Filtrate

331

nephrons have the same transport maximum for

glucose, and some of the nephrons excrete glucose

900

before others have reached their transport maximum.

The overall transport maximum for the kidneys, which

800

is normally about 375 mg/min, is reached when all

nephrons have reached their maximal capacity to reab-

700

Filtered

sorb glucose.

load

The plasma glucose of a healthy person almost

600

never becomes high enough to cause excretion of

Excretion

500

glucose in the urine, even after eating a meal.

However, in uncontrolled diabetes mellitus, plasma

400

glucose may rise to high levels, causing the filtered load

of glucose to exceed the transport maximum and

Transport

300

resulting in urinary glucose excretion. Some of the

maximum Reabsorption

Normal

important transport maximums for substances actively

200

reabsorbed by the tubules are as follows:

100

Threshold

Substance

Transport Maximum

Glucose

375 mg/min

100

200

300

400

500

600

700

800

Phosphate

0.10 mM/min

Plasma glucose concentration

Sulfate

0.06 mM/min

(mg/100 ml)

Amino acids

1.5 mM/min

Urate

15 mg/min

Lactate

75 mg/min

Plasma protein

30 mg/min

Figure 27-4

Relations among the filtered load of glucose, the rate of glucose

Transport Maximums for Substances That Are Actively

reabsorption by the renal tubules, and the rate of glucose excretion

in the urine. The transport maximum is the maximum rate at which

Secreted. Substances that are actively secreted also

glucose can be reabsorbed from the tubules. The threshold for

exhibit transport maximums as follows:

glucose refers to the filtered load of glucose at which glucose first

begins to be excreted in the urine.

Substance

Transport Maximum

The glucose transport system in the proximal tubule

Creatinine

16 mg/min

is a good example. Normally, measurable glucose does

Para-aminohippuric acid

80 mg/min

not appear in the urine because essentially all the fil-

tered glucose is reabsorbed in the proximal tubule.

However, when the filtered load exceeds the capabil-

Substances That Are Actively Transported but Do Not Exhibit a

ity of the tubules to reabsorb glucose, urinary excre-

Transport Maximum. The reason that actively trans-

tion of glucose does occur.

ported solutes often exhibit a transport maximum is

In the adult human, the transport maximum for

that the transport carrier system becomes saturated as

glucose averages about 375 mg/min, whereas the fil-

the tubular load increases. Substances that are passively

tered load of glucose is only about 125 mg/min (GFR

reabsorbed do not demonstrate a transport maximum

¥ plasma glucose = 125 ml/min ¥ 1 mg/ml). With large

because their rate of transport is determined by other

increases in GFR and/or plasma glucose concentration

factors, such as (1) the electrochemical gradient for

that increase the filtered load of glucose above 375 mg/

diffusion of the substance across the membrane, (2)

min, the excess glucose filtered is not reabsorbed and

the permeability of the membrane for the substance,

passes into the urine.

and (3) the time that the fluid containing the substance

Figure 27-4 shows the relation between plasma con-

remains within the tubule. Transport of this type is

centration of glucose, filtered load of glucose, tubular

referred to as gradient-time transport because the rate

transport maximum for glucose, and rate of glucose

of transport depends on the electrochemical gradient

loss in the urine. Note that when the plasma glucose

and the time that the substance is in the tubule, which

concentration is 100 mg/100 mL and the filtered load

in turn depends on the tubular flow rate.

is at its normal level, 125 mg/min, there is no loss of

Some actively transported substances also have char-

glucose in the urine. However, when the plasma con-

acteristics of gradient-time transport. An example is

centration of glucose rises above about 200 mg/100 ml,

sodium reabsorption in the proximal tubule. The

increasing the filtered load to about 250 mg/min, a

main reason that sodium transport in the proximal

small amount of glucose begins to appear in the urine.

tubule does not exhibit a transport maximum is that

This point is termed the threshold for glucose. Note

other factors limit the reabsorption rate besides the

that this appearance of glucose in the urine (at the

maximum rate of active transport. For example, in the

threshold) occurs before the transport maximum is

proximal tubules, the maximum transport capacity of

reached. One reason for the difference between

the basolateral sodium-potassium ATPase pump is

threshold and transport maximum is that not all

usually far greater than the actual rate of net sodium

332

Unit V The Body Fluids and Kidneys

reabsorption. One of the reasons for this is that a sig-

lecting tubule, the tight junctions become far less per-

nificant amount of sodium transported out of the

meable to water and solutes, and the epithelial cells

cell leaks back into the tubular lumen through the

also have a greatly decreased membrane surface area.

epithelial tight junctions. The rate at which this back-

Therefore, water cannot move easily across the tubular

leak occurs depends on several factors, including (1)

membrane by osmosis. However, antidiuretic hormone

the permeability of the tight junctions and (2) the

(ADH) greatly increases the water permeability in the

interstitial physical forces, which determine the rate of

distal and collecting tubules, as discussed later.

bulk flow reabsorption from the interstitial fluid into

Thus, water movement across the tubular epithe-

the peritubular capillaries. Therefore, sodium trans-

lium can occur only if the membrane is permeable to

port in the proximal tubules obeys mainly gradient-

water, no matter how large the osmotic gradient. In the

time transport principles rather than tubular

proximal tubule, the water permeability is always high,

maximum transport characteristics. This means that

and water is reabsorbed as rapidly as the solutes. In

the greater the concentration of sodium in the proxi-

the ascending loop of Henle, water permeability is

mal tubules, the greater its reabsorption rate. Also, the

always low, so that almost no water is reabsorbed,

slower the flow rate of tubular fluid, the greater the

despite a large osmotic gradient. Water permeability in

percentage of sodium that can be reabsorbed from

the last parts of the tubules—the distal tubules, col-

the proximal tubules.

lecting tubules, and collecting ducts—can be high or

In the more distal parts of the nephron, the epithe-

low, depending on the presence or absence of ADH.

lial cells have much tighter junctions and transport

much smaller amounts of sodium. In these segments,

sodium reabsorption exhibits a transport maximum

Reabsorption of Chloride, Urea, and

similar to that for other actively transported substances.

Other Solutes by Passive Diffusion

Furthermore, this transport maximum can be increased

in response to certain hormones, such as aldosterone.

When sodium is reabsorbed through the tubular

epithelial cell, negative ions such as chloride are trans-

ported along with sodium because of electrical poten-

Passive Water Reabsorption

tials. That is, transport of positively charged sodium

by Osmosis Is Coupled Mainly

ions out of the lumen leaves the inside of the lumen

to Sodium Reabsorption

negatively charged, compared with the interstitial

fluid. This causes chloride ions to diffuse passively

When solutes are transported out of the tubule by

through the paracellular pathway. Additional reab-

either primary or secondary active transport, their

sorption of chloride ions occurs because of a chloride

concentrations tend to decrease inside the tubule

concentration gradient that develops when water is

while increasing in the renal interstitium. This creates

reabsorbed from the tubule by osmosis, thereby con-

a concentration difference that causes osmosis of

centrating the chloride ions in the tubular lumen

water in the same direction that the solutes are trans-

(Figure 27-5). Thus, the active reabsorption of sodium

ported, from the tubular lumen to the renal intersti-

is closely coupled to the passive reabsorption of chlo-

tium. Some parts of the renal tubule, especially the

ride by way of an electrical potential and a chloride

proximal tubule, are highly permeable to water, and

concentration gradient.

water reabsorption occurs so rapidly that there is only

a small concentration gradient for solutes across the

tubular membrane.

A large part of the osmotic flow of water occurs

Na⁺ reabsorption

through the so-called tight junctions between the

epithelial cells as well as through the cells themselves.

The reason for this, as already discussed, is that the

junctions between the cells are not as tight as their

H₂O reabsorption

name would imply, and they allow significant diffusion

of water and small ions. This is especially true in the

proximal tubules, which have a high permeability for

water and a smaller but significant permeability to

Lumen

Luminal

Luminal Cl^-

most ions, such as sodium, chloride, potassium,

negative

urea

concentration

potential

concentration

calcium, and magnesium.

As water moves across the tight junctions by

osmosis, it can also carry with it some of the solutes, a

process referred to as solvent drag. And because the

Passive Cl^-

Passive urea

reabsorption of water, organic solutes, and ions is

reabsorption

coupled to sodium reabsorption, changes in sodium

reabsorption significantly influence the reabsorption

Figure 27-5

of water and many other solutes.

In the more distal parts of the nephron, beginning

Mechanisms by which water, chloride, and urea reabsorption are

in the loop of Henle and extending through the col-

coupled with sodium reabsorption.

Chapter 27

Urine Formation by the Kidneys: II. Tubular Processing of the Glomerular Filtrate

333

Chloride ions can also be reabsorbed by secondary

65%

active transport. The most important of the secondary

active transport processes for chloride reabsorption

involves co-transport of chloride with sodium across

Proximal tubule

the luminal membrane.

Urea is also passively reabsorbed from the tubule,

but to a much lesser extent than chloride ions. As

Na⁺, Cl^-, HCO3-, K⁺,

water is reabsorbed from the tubules (by osmosis

H₂O, glucose, amino acids

coupled to sodium reabsorption), urea concentration

in the tubular lumen increases (see Figure 27-5). This

Isosmotic

creates a concentration gradient favoring the reab-

sorption of urea. However, urea does not permeate

H⁺, organic acids, bases

the tubule as readily as water. In some parts of the

nephron, especially the inner medullary collecting

duct, passive urea reabsorption is facilitated by specific

urea transporters. Yet only about one half of the urea

that is filtered by the glomerular capillaries is reab-

Figure 27-6

sorbed from the tubules. The remainder of the urea

passes into the urine, allowing the kidneys to excrete

Cellular ultrastructure and primary transport characteristics of the

proximal tubule. The proximal tubules reabsorb about 65 per cent

large amounts of this waste product of metabolism.

of the filtered sodium, chloride, bicarbonate, and potassium and

Another waste product of metabolism, creatinine, is

essentially all the filtered glucose and amino acids. The proximal

an even larger molecule than urea and is essentially

tubules also secrete organic acids, bases, and hydrogen ions into the

impermeant to the tubular membrane. Therefore,

tubular lumen.

almost none of the creatinine that is filtered is reab-

sorbed, so that virtually all the creatinine filtered by

the glomerulus is excreted in the urine.

tubular cells have an extensive brush border on the

luminal (apical) side of the membrane as well as an

extensive labyrinth of intercellular and basal channels,

Reabsorption and Secretion

all of which together provide an extensive membrane

Along Different Parts of

surface area on the luminal and basolateral sides of the

the Nephron

epithelium for rapid transport of sodium ions and

other substances.

In the previous sections, we discussed the basic princi-

The extensive membrane surface of the epithelial

ples by which water and solutes are transported across

brush border is also loaded with protein carrier mole-

the tubular membrane. With these generalizations in

cules that transport a large fraction of the sodium ions

mind, we can now discuss the different characteristics

across the luminal membrane linked by way of the co-

of the individual tubular segments that enable them to

transport mechanism with multiple organic nutrients

perform their specific excretory functions. Only the

such as amino acids and glucose. The remainder of the

tubular transport functions that are quantitatively

sodium is transported from the tubular lumen into the

most important are discussed, especially as they relate

cell by counter-transport mechanisms, which reabsorb

to the reabsorption of sodium, chloride, and water. In

sodium while secreting other substances into the

subsequent chapters, we discuss the reabsorption and

tubular lumen, especially hydrogen ions. As discussed

secretion of other specific substances in different parts

in Chapter 30, the secretion of hydrogen ions into the

of the tubular system.

tubular lumen is an important step in the removal of

bicarbonate ions from the tubule (by combining H⁺

with the HCO_{3_} to form H₂CO₃, which then dissociates

Proximal Tubular Reabsorption

into H₂O and CO₂).

Although the sodium-potassium ATPase pump pro-

Normally, about 65 per cent of the filtered load of

vides the major force for reabsorption of sodium,

sodium and water and a slightly lower percentage of

chloride, and water throughout the proximal tubule,

filtered chloride are reabsorbed by the proximal

there are some differences in the mechanisms by

tubule before the filtrate reaches the loops of Henle.

which sodium and chloride are transported through

These percentages can be increased or decreased in

the luminal side of the early and late portions of the

different physiologic conditions, as discussed later.

proximal tubular membrane.

In the first half of the proximal tubule, sodium is

Proximal Tubules Have a High Capacity for Active and Passive

reabsorbed by co-transport along with glucose, amino

Reabsorption. The high capacity of the proximal tubule

acids, and other solutes. But in the second half of the

for reabsorption results from its special cellular char-

proximal tubule, little glucose and amino acids remain

acteristics, as shown in Figure

27-6. The proximal

to be reabsorbed. Instead, sodium is now reabsorbed

tubule epithelial cells are highly metabolic and have

mainly with chloride ions. The second half of the prox-

large numbers of mitochondria to support potent

imal tubule has a relatively high concentration of

active transport processes. In addition, the proximal

chloride (around 140 mEq/L) compared with the early

334

Unit V The Body Fluids and Kidneys

Secretion of Organic Acids and Bases by the Proximal Tubule.

The proximal tubule is also an important site for secre-

5.0

tion of organic acids and bases such as bile salts,

Creatinine

oxalate, urate, and catecholamines. Many of these sub-

2.0

stances are the end products of metabolism and must

Urea

Cl^-

be rapidly removed from the body. The secretion of

1.0

these substances into the proximal tubule plus filtra-

Na⁺

Osmolality

tion into the proximal tubule by the glomerular capil-

0.5

laries and the almost total lack of reabsorption by the

tubules, all combined, contribute to rapid excretion in

HCO₃

0.2

the urine.

In addition to the waste products of metabolism, the

0.1

kidneys secrete many potentially harmful drugs or

toxins directly through the tubular cells into the

tubules and rapidly clear these substances from the

Glucose

0.05

blood. In the case of certain drugs, such as penicillin

Amino acids

and salicylates, the rapid clearance by the kidneys

creates a problem in maintaining a therapeutically

0.01

effective drug concentration.

100

Another compound that is rapidly secreted by the

% Total proximal tubule length

proximal tubule is para-aminohippuric acid (PAH).

PAH is secreted so rapidly that the average person

can clear about 90 per cent of the PAH from the

plasma flowing through the kidneys and excrete it in

Figure 27-7

the urine. For this reason, the rate of PAH clearance

can be used to estimate the renal plasma flow, as dis-

Changes in concentrations of different substances in tubular fluid

cussed later.

along the proximal convoluted tubule relative to the concentrations

of these substances in the plasma and in the glomerular filtrate. A

value of 1.0 indicates that the concentration of the substance in the

Solute and Water Transport in the

tubular fluid is the same as the concentration in the plasma. Values

below 1.0 indicate that the substance is reabsorbed more avidly than

Loop of Henle

water, whereas values above 1.0 indicate that the substance is reab-

sorbed to a lesser extent than water or is secreted into the tubules.

The loop of Henle consists of three functionally dis-

tinct segments: the thin descending segment, the thin

proximal tubule (about 105 mEq/L) because when

ascending segment, and the thick ascending segment.

sodium is reabsorbed, it preferentially carries with it

The thin descending and thin ascending segments, as

glucose, bicarbonate, and organic ions in the early

their names imply, have thin epithelial membranes

proximal tubule, leaving behind a solution that has a

with no brush borders, few mitochondria, and minimal

higher concentration of chloride. In the second half of

levels of metabolic activity (Figure 27-8).

the proximal tubule, the higher chloride concentration

The descending part of the thin segment is highly

favors the diffusion of this ion from the tubule lumen

permeable to water and moderately permeable to

through the intercellular junctions into the renal inter-

most solutes, including urea and sodium. The function

stitial fluid.

of this nephron segment is mainly to allow simple dif-

Concentrations of Solutes Along the Proximal Tubule. Figure

fusion of substances through its walls. About 20 per

27-7 summarizes the changes in concentrations of

cent of the filtered water is reabsorbed in the loop of

various solutes along the proximal tubule. Although

Henle, and almost all of this occurs in the thin descend-

the amount of sodium in the tubular fluid decreases

ing limb. The ascending limb, including both the thin

markedly along the proximal tubule, the concentration

and the thick portions, is virtually impermeable to

of sodium (and the total osmolarity) remains relatively

water, a characteristic that is important for concen-

constant because water permeability of the proximal

trating the urine.

tubules is so great that water reabsorption keeps pace

The thick segment of the loop of Henle, which

with sodium reabsorption. Certain organic solutes,

begins about halfway up the ascending limb, has thick

such as glucose, amino acids, and bicarbonate, are

epithelial cells that have high metabolic activity and

much more avidly reabsorbed than water, so that their

are capable of active reabsorption of sodium, chloride,

concentrations decrease markedly along the length of

and potassium (see Figure 27-8). About 25 per cent of

the proximal tubule. Other organic solutes that are less

the filtered loads of sodium, chloride, and potassium

permeant and not actively reabsorbed, such as creati-

are reabsorbed in the loop of Henle, mostly in the

nine, increase their concentration along the proximal

thick ascending limb. Considerable amounts of other

tubule. The total solute concentration, as reflected by

ions, such as calcium, bicarbonate, and magnesium, are

osmolarity, remains essentially the same all along the

also reabsorbed in the thick ascending loop of Henle.

proximal tubule because of the extremely high per-

The thin segment of the ascending limb has a much

meability of this part of the nephron to water.

lower reabsorptive capacity than the thick segment,

Chapter 27

Urine Formation by the Kidneys: II. Tubular Processing of the Glomerular Filtrate

335

Thin descending

Renal

Tubular

loop of Henle

interstitial

Tubular

lumen

fluid

cells

(+8 mV)

Paracellular

Na⁺, K⁺

Mg⁺⁺, Ca⁺⁺

diffusion

H₂O

Na⁺

ATP

H⁺

K⁺

Na⁺

Cl^-

K⁺

2Cl^-

K⁺

Thick ascending

loop of Henle

25%

Loop diuretics

Na⁺, Cl^-, K⁺,

• Furosemide

^-, Mg⁺⁺

Ca⁺⁺, HCO₃

• Ethacrynic acid

• Bumetanide

Hypo-

osmotic

Figure 27-9

H⁺

Mechanisms of sodium, chloride, and potassium transport in the

thick ascending loop of Henle. The sodium-potassium ATPase pump

in the basolateral cell membrane maintains a low intracellular

sodium concentration and a negative electrical potential in the cell.

The 1-sodium, 2-chloride, 1-potassium co-transporter in the luminal

Figure 27-8

membrane transports these three ions from the tubular lumen into

the cells, using the potential energy released by diffusion of sodium

Cellular ultrastructure

and transport characteristics of the thin

down an electrochemical gradient into the cells. Sodium is also

descending loop of Henle (top) and the thick ascending segment of

transported into the tubular cell by sodium-hydrogen counter-trans-

the loop of Henle (bottom). The descending part of the thin segment

port. The positive charge (+8 mV) of the tubular lumen relative to

of the loop of Henle is highly permeable to water and moderately

the interstitial fluid forces cations such as Mg⁺⁺ and Ca⁺⁺ to diffuse

permeable to most solutes but has few mitochondria and little or no

from the lumen to the interstitial fluid via the paracellular pathway.

active reabsorption. The thick ascending limb of the loop of Henle

reabsorbs about 25 per cent of the filtered loads of sodium, chloride,

and potassium, as well as large amounts of calcium, bicarbonate,

and magnesium. This segment also secretes hydrogen ions into the

The thick ascending limb of the loop of Henle is

tubular lumen.

the site of action of the powerful “loop” diuretics

furosemide, ethacrynic acid, and bumetanide, all of

which inhibit the action of the sodium 2-chloride,

and the thin descending limb does not reabsorb sig-

potassium co-transporter. These diuretics are dis-

nificant amounts of any of these solutes.

cussed in Chapter 31.

An important component of solute reabsorption in

There is also significant paracellular reabsorption of

the thick ascending limb is the sodium-potassium

cations, such as Mg⁺⁺, Ca⁺⁺, Na⁺, and K⁺, in the thick

ATPase pump in the epithelial cell basolateral mem-

ascending limb owing to the slight positive charge of

branes. As in the proximal tubule, the reabsorption of

the tubular lumen relative to the interstitial fluid.

other solutes in the thick segment of the ascending

Although the 1-sodium, 2-chloride, 1-potassium co-

loop of Henle is closely linked to the reabsorptive

transporter moves equal amounts of cations and

capability of the sodium-potassium ATPase pump,

anions into the cell, there is a slight backleak of potas-

which maintains a low intracellular sodium concentra-

sium ions into the lumen, creating a positive charge of

tion. The low intracellular sodium concentration in

about +8 millivolts in the tubular lumen. This positive

turn provides a favorable gradient for movement

charge forces cations such as Mg⁺⁺ and Ca⁺⁺ to diffuse

of sodium from the tubular fluid into the cell. In the

from the tubular lumen through the paracellular space

thick ascending loop, movement of sodium across

and into the interstitial fluid.

the luminal membrane is mediated primarily by a

The thick ascending limb also has a sodium-

1-sodium,

2-chloride,

1-potassium co-transporter

hydrogen counter-transport mechanism in its luminal

(Figure 27-9). This co-transport protein carrier in the

cell membrane that mediates sodium reabsorption and

luminal membrane uses the potential energy released

hydrogen secretion in this segment.

by downhill diffusion of sodium into the cell to drive

The thick segment of the ascending loop of Henle is

the reabsorption of potassium into the cell against a

virtually impermeable to water. Therefore, most of the

concentration gradient.

water delivered to this segment remains in the tubule,

336

Unit V The Body Fluids and Kidneys

despite reabsorption of large amounts of solute. The

Late Distal Tubule and Cortical

tubular fluid in the ascending limb becomes very dilute

Collecting Tubule

as it flows toward the distal tubule, a feature that is

important in allowing the kidneys to dilute or concen-

The second half of the distal tubule and the subse-

trate the urine under different conditions, as we

quent cortical collecting tubule have similar functional

discuss much more fully in Chapter 28.

characteristics. Anatomically, they are composed of

two distinct cell types, the principal cells and the inter-

calated cells (Figure 27-11). The principal cells reab-

Distal Tubule

sorb sodium and water from the lumen and secrete

potassium ions into the lumen. The intercalated cells

The thick segment of the ascending limb of the loop

reabsorb potassium ions and secrete hydrogen ions

of Henle empties into the distal tubule. The very first

into the tubular lumen.

portion of the distal tubule forms part of the juxta-

glomerular complex that provides feedback control of

Principal Cells Reabsorb Sodium and Secrete Potassium.

GFR and blood flow in this same nephron. The next

Sodium reabsorption and potassium secretion by the

part of the distal tubule is highly convoluted and has

principal cells depend on the activity of a sodium-

many of the same reabsorptive characteristics of the

potassium ATPase pump in each cell’s basolateral

thick segment of the ascending limb of the loop of

membrane (Figure 27-12). This pump maintains a low

Henle. That is, it avidly reabsorbs most of the ions,

sodium concentration inside the cell and, therefore,

including sodium, potassium, and chloride, but is vir-

favors sodium diffusion into the cell through special

tually impermeable to water and urea. For this reason,

it is referred to as the diluting segment because it also

dilutes the tubular fluid.

Approximately 5 percent of the filtered load of

Early distal tubule

sodium chloride is reabsorbed in the early distal

tubule. The sodium-chloride co-transporter moves

sodium chloride from the tubular lumen into the cell,

and the sodium-potassium ATPase pump transports

Na⁺, Cl^-, Ca⁺⁺, Mg⁺⁺

sodium out of the cell across the basolateral mem-

brane (Figure 27-10). Chloride diffuses out of the cell

into the renal interstitial fluid through chloride chan-

nels in the basolateral membrane. The thiazide diuret-

ics, which are widely used to treat disorders such as

hypertension and heart failure, inhibit the sodium-

chloride co-transporter.

Late distal tubule

and collecting tubule

Principal

Na⁺, Cl^-

cells

Renal

Tubular

interstitial

Tubular

lumen

fluid

cells

(-10mV)

(+ADH) H₂O

K⁺

H⁺

Na⁺

ATP

Na⁺

K⁺

Intercalated

HCO₃

K⁺

cells

Cl^-

Figure 27-11

Cellular ultrastructure and transport characteristics of the early

distal tubule and the late distal tubule and collecting tubule. The

Thiazide diuretics:

early distal tubule has many of the same characteristics as the thick

ascending loop of Henle and reabsorbs sodium, chloride, calcium,

and magnesium but is virtually impermeable to water and urea. The

Figure 27-10

late distal tubules and cortical collecting tubules are composed of

two distinct cell types, the principal cells and the intercalated cells.

Mechanism of sodium chloride transport in the early distal tubule.

The principal cells reabsorb sodium from the lumen and secrete

Sodium and chloride are transported from the tubular lumen into

potassium ions into the lumen. The intercalated cells reabsorb potas-

the cell by a co-transporter that is inhibited by thiazide diuretics.

sium and bicarbonate ions from the lumen and secrete hydrogen

Sodium is pumped out of the cell by sodium-potassium ATPase and

ions into the lumen. The reabsorption of water from this tubular

chloride diffuses into the interstitial fluid via chloride channels.

segment is controlled by the concentration of antidiuretic hormone.

Chapter 27

Urine Formation by the Kidneys: II. Tubular Processing of the Glomerular Filtrate

337

Renal

Tubular

then dissociates into hydrogen ions and bicarbonate

interstitial

Tubular

lumen

ions. The hydrogen ions are then secreted into the

fluid

cells

(-50 mV)

tubular lumen, and for each hydrogen ion secreted, a

bicarbonate ion becomes available for reabsorption

across the basolateral membrane. A more detailed dis-

cussion of this mechanism is presented in Chapter 30.

The intercalated cells can also reabsorb potassium

K⁺

ions.

Na⁺

The functional characteristics of the late distal tubule

ATP

and cortical collecting tubule can be summarized as

K⁺

follows:

The tubular membranes of both segments are

Cl^-

almost completely impermeable to urea, similar

to the diluting segment of the early distal tubule;

thus, almost all the urea that enters these

Aldosterone antagonists

Na⁺ channel blockers

segments passes on through and into the

• Spironolactone

• Amiloride

collecting duct to be excreted in the urine,

• Eplerenone

• Triamterene

although some reabsorption of urea occurs

in the medullary collecting ducts.

Figure 27-12

Both the late distal tubule and the cortical

collecting tubule segments reabsorb sodium ions,

Mechanism of sodium chloride reabsorption and potassium secre-

and the rate of reabsorption is controlled by

tion in the late distal tubules and cortical collecting tubules. Sodium

hormones, especially aldosterone. At the same

enters the cell through special channels and is transported out of the

cell by the sodium-potassium ATPase pump. Aldosterone antago-

time, these segments secrete potassium ions

nists compete with aldosterone for binding sites in the cell and

from the peritubular capillary blood into the

therefore inhibit the effects of aldosterone to stimulate sodium reab-

tubular lumen, a process that is also controlled

sorption and potassium secretion. Sodium channel blockers directly

by aldosterone and by other factors such as

inhibit the entry of sodium into the sodium channels.

the concentration of potassium ions in the body

fluids.

channels. The secretion of potassium by these cells

The intercalated cells of these nephron segments

from the blood into the tubular lumen involves two

avidly secrete hydrogen ions by an active

steps: (1) Potassium enters the cell because of the

hydrogen-ATPase mechanism. This process is

sodium-potassium ATPase pump, which maintains a

different from the secondary active secretion of

high intracellular potassium concentration, and then

hydrogen ions by the proximal tubule because it is

(2) once in the cell, potassium diffuses down its con-

capable of secreting hydrogen ions against a large

centration gradient across the luminal membrane into

concentration gradient, as much as 1000 to 1. This

the tubular fluid.

is in contrast to the relatively small gradient (4- to

The principal cells are the primary sites of action

10-fold) for hydrogen ions that can be achieved

of the potassium-sparing diuretics, including spirono-

by secondary active secretion in the proximal

lactone, eplerenone, amiloride, and triamterene.

tubule. Thus, the intercalated cells play a key role

Aldosterone antagonists compete with aldosterone for

in acid-base regulation of the body fluids.

receptor sites in the principal cells and therefore

The permeability of the late distal tubule and

inhibit the stimulatory effects of aldosterone on

cortical collecting duct to water is controlled by

sodium reabsorption and potassium secretion. Sodium

the concentration of ADH, which is also called

channel blockers directly inhibit the entry of sodium

vasopressin. With high levels of ADH, these

into the sodium channels of the luminal membranes

tubular segments are permeable to water, but

and therefore reduce the amount of sodium that can

in the absence of ADH, they are virtually

be transported across the basolateral membranes by

impermeable to water. This special characteristic

the sodium-potassium ATPase pump. This, in turn,

provides an important mechanism for controlling

decreases transport of potassium into the cells and

the degree of dilution or concentration of the

ultimately reduces potassium secretion into the

urine.

tubular fluid. For this reason the sodium channel

blockers as well as the aldosterone antagonists

decrease urinary excretion of potassium and act as

Medullary Collecting Duct

potassium-sparing diuretics.

Although the medullary collecting ducts reabsorb less

Intercalated Cells Avidly Secrete Hydrogen and Reabsorb Bicar-

than 10 per cent of the filtered water and sodium, they

bonate and Potassium Ions. Hydrogen ion secretion by

are the final site for processing the urine and, there-

the intercalated cells is mediated by a hydrogen-

fore, play an extremely important role in determining

ATPase transport mechanism. Hydrogen is generated

the final urine output of water and solutes.

in this cell by the action of carbonic anhydrase on

The epithelial cells of the collecting ducts are nearly

water and carbon dioxide to form carbonic acid, which

cuboidal in shape with smooth surfaces and relatively

338

Unit V The Body Fluids and Kidneys

Medullary

collecting duct

100.0

50.0

PAH

Urea

20.0

10.0

H⁺

5.0

2.0

1.0

and Na

0.50

Figure 27-13

Cellular ultrastructure and transport characteristics of the

0.20

medullary collecting duct. The medullary collecting ducts actively

reabsorb sodium and secrete hydrogen ions and are permeable to

0.10

urea, which is reabsorbed in these tubular segments. The reabsorp-

HCO₃

tion of water in medullary collecting ducts is controlled by the con-

0.05

centration of antidiuretic hormone.

0.02

Proximal

Loop of

Distal

Collecting

few mitochondria (Figure 27-13). Special characteris-

tubule

Henle

tubule

tics of this tubular segment are as follows:

1. The permeability of the medullary collecting duct

to water is controlled by the level of ADH. With

Figure 27-14

high levels of ADH, water is avidly reabsorbed

into the medullary interstitium, thereby reducing

Changes in average concentrations of different substances at differ-

the urine volume and concentrating most of the

ent points in the tubular system relative to the concentration of that

solutes in the urine.

substance in the plasma and in the glomerular filtrate. A value of 1.0

indicates that the concentration of the substance in the tubular fluid

2. Unlike the cortical collecting tubule, the

is the same as the concentration of that substance in the plasma.

medullary collecting duct is permeable to urea.

Values below 1.0 indicate that the substance is reabsorbed more

Therefore, some of the tubular urea is reabsorbed

avidly than water, whereas values above 1.0 indicate that the sub-

into the medullary interstitium, helping to raise

stance is reabsorbed to a lesser extent than water or is secreted into

the tubules.

the osmolality in this region of the kidneys and

contributing to the kidneys’ overall ability to form

a concentrated urine.

3. The medullary collecting duct is capable of

a substance. If plasma concentration of the substance

secreting hydrogen ions against a large

is assumed to be constant, any change in the ratio

concentration gradient, as also occurs in the

of tubular fluid/plasma concentration rate reflects

cortical collecting tubule. Thus, the medullary

changes in tubular fluid concentration.

collecting duct also plays a key role in regulating

As the filtrate moves along the tubular system, the

acid-base balance.

concentration rises to progressively greater than 1.0 if

more water is reabsorbed than solute, or if there has

been a net secretion of the solute into the tubular fluid.

Summary of Concentrations of

If the concentration ratio becomes progressively less

Different Solutes in the Different

than 1.0, this means that relatively more solute has

Tubular Segments

been reabsorbed than water.

The substances represented at the top of Figure

Whether a solute will become concentrated in the

27-14, such as creatinine, become highly concentrated

tubular fluid is determined by the relative degree of

in the urine. In general, these substances are not

reabsorption of that solute versus the reabsorption of

needed by the body, and the kidneys have become

water. If a greater percentage of water is reabsorbed,

adapted to reabsorb them only slightly or not at all, or

the substance becomes more concentrated. If a greater

even to secrete them into the tubules, thereby excret-

percentage of the solute is reabsorbed, the substance

ing especially great quantities into the urine. Con-

becomes more diluted.

versely, the substances represented toward the bottom

Figure 27-14 shows the degree of concentration of

of the figure, such as glucose and amino acids, are all

several substances in the different tubular segments.

strongly reabsorbed; these are all substances that the

All the values in this figure represent the tubular fluid

body needs to conserve, and almost none of them are

concentration divided by the plasma concentration of

lost in the urine.

Chapter 27

Urine Formation by the Kidneys: II. Tubular Processing of the Glomerular Filtrate

339

Tubular Fluid /Plasma Inulin Concentration Ratio Can Be Used

are not fully understood but may be due partly to

to Measure Water Reabsorption by the Renal Tubules. Inulin,

changes in physical forces in the tubule and surround-

a polysaccharide used to measure GFR, is not reab-

ing renal interstitium, as discussed later. It is clear that

sorbed or secreted by the renal tubules. Changes in

the mechanisms for glomerulotubular balance can

inulin concentration at different points along the renal

occur independently of hormones and can be demon-

tubule, therefore, reflect changes in the amount of

strated in completely isolated kidneys or even in com-

water present in the tubular fluid. For example, the

pletely isolated proximal tubular segments.

tubular fluid/plasma concentration ratio for inulin

The importance of glomerulotubular balance is that

rises to about 3.0 at the end of the proximal tubules,

it helps to prevent overloading of the distal tubular

indicating that inulin concentration in the tubular fluid

segments when GFR increases. Glomerulotubular

3 times greater than in the plasma and in the

balance acts as a second line of defense to buffer the

glomerular filtrate. Since inulin is not secreted or reab-

effects of spontaneous changes in GFR on urine

sorbed from the tubules, a tubular fluid/plasma con-

output. (The first line of defense, discussed earlier,

centration ratio of 3.0 means that only one third of the

includes the renal autoregulatory mechanisms, espe-

water that was filtered remains in the renal tubule and

cially tubuloglomerular feedback, which help prevent

that two thirds of the filtered water has been reab-

changes in GFR.) Working together, the autoregula-

sorbed as the fluid passes through the proximal tubule.

tory and glomerulotubular balance mechanisms

At the end of the collecting ducts, the tubular

prevent large changes in fluid flow in the distal tubules

fluid/plasma inulin concentration ratio rises to about

when the arterial pressure changes or when there

125 (see Figure 27-14), indicating that only 1/125 of

are other disturbances that would otherwise wreak

the filtered water remains in the tubule and that more

havoc with the maintenance of sodium and volume

than 99% has been reabsorbed.

homeostasis.

Peritubular Capillary and Renal

Regulation of Tubular

Interstitial Fluid Physical Forces

Reabsorption

Hydrostatic and colloid osmotic forces govern the rate

Because it is essential to maintain a precise balance

of reabsorption across the peritubular capillaries,

between tubular reabsorption and glomerular filtra-

just as these physical forces control filtration in the

tion, there are multiple nervous, hormonal, and local

glomerular capillaries. Changes in peritubular capil-

control mechanisms that regulate tubular reabsorp-

lary reabsorption can in turn influence the hydrostatic

tion, just as there are for control of glomerular filtra-

and colloid osmotic pressures of the renal interstitium

tion. An important feature of tubular reabsorption is

and, ultimately, reabsorption of water and solutes from

that reabsorption of some solutes can be regulated

the renal tubules.

independently of others, especially through hormonal

control mechanisms.

Normal Values for Physical Forces and Reabsorption Rate. As

the glomerular filtrate passes through the renal

tubules, more than 99 per cent of the water and most

Glomerulotubular Balance—The

of the solutes are normally reabsorbed. Fluid and elec-

Ability of the Tubules to Increase

trolytes are reabsorbed from the tubules into the renal

Reabsorption Rate in Response

interstitium and from there into the peritubular capil-

to Increased Tubular Load

laries. The normal rate of peritubular capillary reab-

sorption is about 124 ml/min.

One of the most basic mechanisms for controlling

Reabsorption across the peritubular capillaries can

tubular reabsorption is the intrinsic ability of the

be calculated as

tubules to increase their reabsorption rate in response

Reabsorption = K_f ¥ Net reabsorptive force

to increased tubular load (increased tubular inflow).

This phenomenon is referred to as glomerulotubular

The net reabsorptive force represents the sum of the

balance. For example, if GFR is increased from 125 ml/

hydrostatic and colloid osmotic forces that either favor

min to 150 ml/min, the absolute rate of proximal

or oppose reabsorption across the peritubular capil-

tubular reabsorption also increases from about 81 ml/

laries. These forces include (1) hydrostatic pressure

min (65 per cent of GFR) to about 97.5 ml/min (65 per

inside the peritubular capillaries (peritubular hydro-

cent of GFR). Thus, glomerulotubular balance refers

static pressure

[P_c]), which opposes reabsorption;

to the fact that the total rate of reabsorption increases

(2) hydrostatic pressure in the renal interstitium (P_if)

as the filtered load increases, even though the

outside the capillaries, which favors reabsorption; (3)

percentage of GFR reabsorbed in the proximal

colloid osmotic pressure of the peritubular capillary

tubule remains relatively constant at about 65 per

plasma proteins (p_c), which favors reabsorption; and

cent.

(4) colloid osmotic pressure of the proteins in the renal

Some degree of glomerulotubular balance also

interstitium (p_if), which opposes reabsorption.

occurs in other tubular segments, especially the loop

Figure 27-15 shows the approximate normal forces

of Henle. The precise mechanisms responsible for this

that favor and oppose peritubular reabsorption.

340

Unit V The Body Fluids and Kidneys

Peritubular

Interstitial

Tubular

raise peritubular capillary hydrostatic pressure and

capillary

fluid

cells

lumen

decrease reabsorption rate. This effect is buffered to

some extent by autoregulatory mechanisms that main-

tain relatively constant renal blood flow as well as

Pif

6 mm Hg

relatively constant hydrostatic pressures in the renal

blood vessels. (2) Increase in resistance of either the

13 mm Hg

πif

afferent or the efferent arterioles reduces peritubular

15 mm Hg

πcc

capillary hydrostatic pressure and tends to increase

32 mm Hg

Bulk

reabsorption rate. Although constriction of the

H₂O

H₂

flow

^O efferent arterioles increases glomerular capillary

hydrostatic pressure, it lowers peritubular capillary

Na⁺

10 mm Hg

ATP

hydrostatic pressure.

Net reabsorption

The second major determinant of peritubular capil-

pressure

lary reabsorption is the colloid osmotic pressure of the

plasma in these capillaries; raising the colloid osmotic

pressure increases peritubular capillary reabsorption.

Figure 27-15

The colloid osmotic pressure of peritubular capillaries

Summary of the hydrostatic and colloid osmotic forces that deter-

is determined by

(1) the systemic plasma colloid

mine fluid reabsorption by the peritubular capillaries. The numeri-

osmotic pressure; increasing the plasma protein con-

cal values shown are estimates of the normal values for humans. The

centration of systemic blood tends to raise peritubular

net reabsorptive pressure is normally about 10 mm Hg, causing fluid

capillary colloid osmotic pressure, thereby increasing

and solutes to be reabsorbed into the peritubular capillaries as they

are transported across the renal tubular cells. ATP, adenosine

reabsorption; and (2) the filtration fraction; the higher

triphosphate; P_c, peritubular capillary hydrostatic pressure; P_if, inter-

the filtration fraction, the greater the fraction of

, peritubular capillary colloid

stitial fluid hydrostatic pressure; p_c

plasma filtered through the glomerulus and, conse-

, interstitial fluid colloid osmotic pressure.

osmotic pressure; p_if

quently, the more concentrated the protein becomes in

the plasma that remains behind. Thus, increasing the

filtration fraction also tends to increase the peritubu-

Because the normal peritubular capillary pressure

lar capillary reabsorption rate. Because filtration frac-

averages about 13 mm Hg and renal interstitial fluid

tion is defined as the ratio of GFR/renal plasma flow,

hydrostatic pressure averages 6 mm Hg, there is a pos-

increased filtration fraction can occur as a result of

itive hydrostatic pressure gradient from the peritubu-

increased GFR or decreased renal plasma flow. Some

lar capillary to the interstitial fluid of about 7 mm Hg,

renal vasoconstrictors, such as angiotensin II, increase

which opposes fluid reabsorption. This is more than

peritubular capillary reabsorption by decreasing renal

counterbalanced by the colloid osmotic pressures that

plasma flow and increasing filtration fraction, as dis-

favor reabsorption. The plasma colloid osmotic pres-

cussed later.

sure, which favors reabsorption, is about 32 mm Hg,

Changes in the peritubular capillary K_f can also

and the colloid osmotic pressure of the interstitium,

influence the reabsorption rate because K_f is a

which opposes reabsorption, is 15 mm Hg, causing a

measure of the permeability and surface area of the

net colloid osmotic force of about 17 mm Hg, favoring

capillaries. Increases in K_f raise reabsorption, whereas

reabsorption. Therefore, subtracting the net hydro-

decreases in K_f lower peritubular capillary reabsorp-

static forces that oppose reabsorption (7 mm Hg) from

tion. K_f remains relatively constant in most physiologic

the net colloid osmotic forces that favor reabsorption

conditions. Table 27-2 summarizes the factors that

(17 mm Hg) gives a net reabsorptive force of about

can influence the peritubular capillary reabsorption

10 mm Hg. This is a high value, similar to that found

rate.

in the glomerular capillaries, but in the opposite

direction.

Renal Interstitial Hydrostatic and Colloid Osmotic Pressures.

The other factor that contributes to the high rate of

Ultimately, changes in peritubular capillary physical

fluid reabsorption in the peritubular capillaries is a

forces influence tubular reabsorption by changing the

large filtration coefficient

(K_f) because of the high

physical forces in the renal interstitium surrounding

hydraulic conductivity and large surface area of the

the tubules. For example, a decrease in the reabsorp-

capillaries. Because the reabsorption rate is normally

tive force across the peritubular capillary membranes,

about 124 ml/min and net reabsorption pressure is

caused by either increased peritubular capillary hydro-

10 mm Hg, K_f normally is about 12.4 ml/min/mm Hg.

static pressure or decreased peritubular capillary

colloid osmotic pressure, reduces the uptake of fluid

Regulation of Peritubular Capillary Physical Forces. The two

and solutes from the interstitium into the peritubular

determinants of peritubular capillary reabsorption

capillaries. This in turn raises renal interstitial fluid

that are directly influenced by renal hemodynamic

hydrostatic pressure and decreases interstitial fluid

changes are the hydrostatic and colloid osmotic pres-

colloid osmotic pressure because of dilution of the

sures of the peritubular capillaries. The peritubular

proteins in the renal interstitium. These changes then

capillary hydrostatic pressure is influenced by the arte-

decrease the net reabsorption of fluid from the renal

rial pressure and resistances of the afferent and efferent

tubules into the interstitium, especially in the proximal

arterioles. (1) Increases in arterial pressure tend to

tubules.

Chapter 27

Urine Formation by the Kidneys: II. Tubular Processing of the Glomerular Filtrate

341

Table 27-2

Normal

Peritubular

Interstitial

Tubular

Lumen

Factors That Can Influence Peritubular Capillary

capillary

fluid

cells

Reabsorption

≠ P_c Æ Ø Reabsorption

P_c

• ØR_A Æ≠P_c

π_c

• ØR_E Æ≠P_c

• ≠ Arterial Pressure Æ ≠ P_c

≠ p_c Æ ≠ Reabsorption

• ≠p_A Æ≠p_c

ATP

• ≠ FF Æ ≠ p_c

Net

≠ K_f Æ ≠ Reabsorption

reabsorption

P_c, peritubular capillary hydrostatic pressure; R_A and R_E, afferent and effer-

ent arteriolar resistances, respectively; p_c, peritubular capillary colloid osmotic

ATP

pressure; p_A, arterial plasma colloid osmotic pressure; FF, filtration fraction;

Backleak

K_f, peritubular capillary filtration coefficient.

The mechanisms by which changes in interstitial

Decreased reabsorption

fluid hydrostatic and colloid osmotic pressures influ-

ence tubular reabsorption can be understood by exam-

P_c

ining the pathways through which solute and water are

π_c

reabsorbed (Figure 27-16). Once the solutes enter the

intercellular channels or renal interstitium by active

transport or passive diffusion, water is drawn from the

ATP

tubular lumen into the interstitium by osmosis. And

Decreased net

once the water and solutes are in the interstitial spaces,

reabsorption

they can either be swept up into the peritubular cap-

illaries or diffuse back through the epithelial junctions

ATP

into the tubular lumen. The so-called tight junctions

Increased

between the epithelial cells of the proximal tubule are

backleak

actually leaky, so that considerable amounts of sodium

can diffuse in both directions through these junctions.

With the normal high rate of peritubular capillary

Figure 27-16

reabsorption, the net movement of water and solutes

Proximal tubular and peritubular capillary

reabsorption under

is into the peritubular capillaries with little backleak

normal conditions (top) and during decreased peritubular capillary

into the lumen of the tubule. However, when peri-

reabsorption (bottom) caused by either increasing peritubular cap-

tubular capillary reabsorption is reduced, there is

illary hydrostatic pressure (P_c) or decreasing peritubular capillary

increased interstitial fluid hydrostatic pressure and a

colloid osmotic pressure (p_c). Reduced peritubular capillary reab-

sorption, in turn, decreases the net reabsorption of solutes and water

tendency for greater amounts of solute and water to

by increasing the amounts of solutes and water that leak back into

backleak into the tubular lumen, thereby reducing the

the tubular lumen through the tight junctions of the tubular epithe-

rate of net reabsorption (refer again to Figure 27-16).

lial cells, especially in the proximal tubule.

The opposite is true when there is increased peri-

tubular capillary reabsorption above the normal level.

An initial increase in reabsorption by the peritubular

Effect of Arterial Pressure on Urine

capillaries tends to reduce interstitial fluid hydrostatic

pressure and raise interstitial fluid colloid osmotic

Output—The Pressure-Natriuresis and

pressure. Both of these forces favor movement of fluid

Pressure-Diuresis Mechanisms

and solutes out of the tubular lumen and into the inter-

stitium; therefore, backleak of water and solutes into

Even small increases in arterial pressure often cause

the tubular lumen is reduced, and net tubular reab-

marked increases in urinary excretion of sodium and

sorption increases.

water, phenomena that are referred to as pressure

Thus, through changes in the hydrostatic and colloid

natriuresis and pressure diuresis. Because of the

osmotic pressures of the renal interstitium, the uptake

autoregulatory mechanisms described in Chapter 26,

of water and solutes by the peritubular capillaries is

increasing the arterial pressure between the limits of

closely matched to the net reabsorption of water and

75 and 160 mm Hg usually has only a small effect on

solutes from the tubular lumen into the interstitium.

renal blood flow and GFR. The slight increase in GFR

Therefore, in general, forces that increase peritubular

that does occur contributes in part to the effect of

capillary reabsorption also increase reabsorption from

increased arterial pressure on urine output. When

the renal tubules. Conversely, hemodynamic changes

GFR autoregulation is impaired, as often occurs in

that inhibit peritubular capillary reabsorption also

kidney disease, increases in arterial pressure cause

inhibit tubular reabsorption of water and solutes.

much larger increases in GFR.

342

Unit V The Body Fluids and Kidneys

A second effect of increased renal arterial pressure

Aldosterone Increases Sodium Reabsorption and Increases

that raises urine output is that it decreases the per-

Potassium Secretion. Aldosterone, secreted by the zona

centage of the filtered load of sodium and water that

glomerulosa cells of the adrenal cortex, is an impor-

is reabsorbed by the tubules. The mechanisms respon-

tant regulator of sodium reabsorption and potassium

sible for this effect include a slight increase in peri-

secretion by the renal tubules. The primary site

tubular capillary hydrostatic pressure, especially in the

of aldosterone action is on the principal cells of the

vasa recta of the renal medulla, and a subsequent

cortical collecting tubule. The mechanism by which

increase in the renal interstitial fluid hydrostatic pres-

aldosterone increases sodium reabsorption while at

sure. As discussed earlier, an increase in the renal

the same time increasing potassium secretion is by

interstitial fluid hydrostatic pressure enhances back-

stimulating the sodium-potassium ATPase pump on

leak of sodium into the tubular lumen, thereby reduc-

the basolateral side of the cortical collecting tubule

ing the net reabsorption of sodium and water and

membrane. Aldosterone also increases the sodium

further increasing the rate of urine output when renal

permeability of the luminal side of the membrane.

arterial pressure rises.

The cellular mechanisms of aldosterone action are

A third factor that contributes to the pressure-

discussed in Chapter 77.

natriuresis and pressure-diuresis mechanisms is

In the absence of aldosterone, as occurs with adrenal

reduced angiotensin II formation. Angiotensin II itself

destruction or malfunction (Addison’s disease), there

increases sodium reabsorption by the tubules; it also

is marked loss of sodium from the body and accumu-

stimulates aldosterone secretion, which further

lation of potassium. Conversely, excess aldosterone

increases sodium reabsorption. Therefore, decreased

secretion, as occurs in patients with adrenal tumors

angiotensin II formation contributes to the decreased

(Conn’s syndrome) is associated with sodium retention

tubular sodium reabsorption that occurs when arterial

and potassium depletion. Although day-to-day regula-

pressure is increased.

tion of sodium balance can be maintained as long as

minimal levels of aldosterone are present, the inabil-

ity to appropriately adjust aldosterone secretion

Hormonal Control of Tubular

greatly impairs the regulation of renal potassium

Reabsorption

excretion and potassium concentration of the body

fluids. Thus, aldosterone is even more important as a

Precise regulation of body fluid volumes and solute

regulator of potassium concentration than it is for

concentrations requires the kidneys to excrete differ-

sodium concentration.

ent solutes and water at variable rates, sometimes

independently of one another. For example, when

Angiotensin II Increases Sodium and Water Reabsorption.

potassium intake is increased, the kidneys must

Angiotensin II is perhaps the body’s most powerful

excrete more potassium while maintaining normal

sodium-retaining hormone. As discussed in Chapter

excretion of sodium and other electrolytes. Likewise,

19, angiotensin II formation increases in circumstances

when sodium intake is changed, the kidneys must

associated with low blood pressure and/or low extra-

appropriately adjust urinary sodium excretion without

cellular fluid volume, such as during hemorrhage or

major changes in excretion of other electrolytes.

loss of salt and water from the body fluids. The

Several hormones in the body provide this specificity

increased formation of angiotensin II helps to return

of tubular reabsorption for different electrolytes and

blood pressure and extracellular volume toward

water. Table 27-3 summarizes some of the most impor-

normal by increasing sodium and water reabsorption

tant hormones for regulating tubular reabsorption,

from the renal tubules through three main effects:

their principal sites of action on the renal tubule, and

1. Angiotensin II stimulates aldosterone secretion,

their effects on solute and water excretion. Some

which in turn increases sodium reabsorption.

of these hormones are discussed in more detail in

2. Angiotensin II constricts the efferent arterioles,

Chapters 28 and 29, but we briefly review their renal

which has two effects on peritubular capillary

tubular actions in the next few paragraphs.

dynamics that raise sodium and water

Table 27-3

Hormones That Regulate Tubular Reabsorption

Hormone

Site of Action

Effects

Aldosterone

Collecting tubule and duct

≠ NaCl, H₂O reabsorption, ≠ K⁺ secretion

Angiotensin II

Proximal tubule, thick ascending loop of Henle/distal

≠ NaCl, H₂O reabsorption, ≠ H⁺ secretion

tubule, collecting tubule

Antidiuretic hormone

Distal tubule/collecting tubule and duct

≠ H₂O reabsorption

Atrial natriuretic peptide

Distal tubule/collecting tubule and duct

Ø NaCl reabsorption

Parathyroid hormone

Proximal tubule, thick ascending loop of

Ø PO4- - - reabsorption, ≠ Ca⁺⁺ reabsorption

Henle/distal tubule

Chapter 27

Urine Formation by the Kidneys: II. Tubular Processing of the Glomerular Filtrate

343

reabsorption. First, efferent arteriolar constriction

distended because of plasma volume expansion,

reduces peritubular capillary hydrostatic pressure,

secrete a peptide called atrial natriuretic peptide.

which increases net tubular reabsorption,

Increased levels of this peptide in turn inhibit the reab-

especially from the proximal tubules. Second,

sorption of sodium and water by the renal tubules,

efferent arteriolar constriction, by reducing renal

especially in the collecting ducts. This decreased

blood flow, raises filtration fraction in the

sodium and water reabsorption increases urinary

glomerulus and increases the concentration of

excretion, which helps to return blood volume back

proteins and the colloid osmotic pressure in

toward normal.

the peritubular capillaries; this increases the

reabsorptive force at the peritubular capillaries

Parathyroid Hormone Increases Calcium Reabsorption.

and raises tubular reabsorption of sodium and

Parathyroid hormone is one of the most important

water.

calcium-regulating hormones in the body. Its principal

3. Angiotensin II directly stimulates sodium

action in the kidneys is to increase tubular reabsorp-

reabsorption in the proximal tubules, the loops of

tion of calcium, especially in the distal tubules and

Henle, the distal tubules, and the collecting tubules.

perhaps also in the loops of Henle. Parathyroid

One of the direct effects of angiotensin II is to

hormone also has other actions, including inhibition of

stimulate the sodium-potassium ATPase pump on

phosphate reabsorption by the proximal tubule and

the tubular epithelial cell basolateral membrane.

stimulation of magnesium reabsorption by the loop of

A second effect is to stimulate sodium-hydrogen

Henle, as discussed in Chapter 29.

exchange in the luminal membrane, especially

in the proximal tubule. Thus, angiotensin II

Sympathetic Nervous System

stimulates sodium transport across both the

luminal and the basolateral surfaces of the

Activation Increases Sodium

epithelial cell membrane in the tubules.

Reabsorption

These multiple actions of angiotensin II cause

marked sodium retention by the kidneys when

Activation of the sympathetic nervous system can

angiotensin II levels are increased.

decrease sodium and water excretion by constricting

the renal arterioles, thereby reducing GFR. Sympa-

ADH Increases Water Reabsorption. The most important

thetic activation also increases sodium reabsorption in

renal action of ADH is to increase the water perme-

the proximal tubule, the thick ascending limb of the

ability of the distal tubule, collecting tubule, and col-

loop of Henle, and perhaps in more distal parts of the

lecting duct epithelia. This effect helps the body to

renal tubule. And finally, sympathetic nervous system

conserve water in circumstances such as dehydration.

stimulation increases renin release and angiotensin II

In the absence of ADH, the permeability of the distal

formation, which adds to the overall effect to increase

tubules and collecting ducts to water is low, causing the

tubular reabsorption and decrease renal excretion of

kidneys to excrete large amounts of dilute urine. Thus,

sodium.

the actions of ADH play a key role in controlling the

degree of dilution or concentration of the urine, as dis-

Use of Clearance Methods

cussed further in Chapters 28 and 75.

ADH binds to specific V₂ receptors in the late distal

to Quantify Kidney Function

tubules, collecting tubules, and collecting ducts,

increasing the formation of cyclic AMP and activating

The rates at which different substances are “cleared”

protein kinases. This, in turn, stimulates the movement

from the plasma provide a useful way of quantitating

of an intracellular protein, called aquaporin-2 (AQP-

the effectiveness with which the kidneys excrete

2), to the luminal side of the cell membranes. The mol-

various substances (Table 27-4). By definition, the

ecules of AQP-2 cluster together and fuse with the cell

renal clearance of a substance is the volume of plasma

membrane by exocytosis to form water channels that

that is completely cleared of the substance by the

permit rapid diffusion of water through the cells. There

kidneys per unit time. This concept is somewhat

are other aquaporins, AQP-3 and AQP-4, in the baso-

abstract because there is no single volume of plasma

lateral side of the cell membrane that provide a path

that is completely cleared of a substance. However,

for water to rapidly exit the cells, although these

renal clearance provides a useful way of quantifying

are not believed to be regulated by ADH. Chronic

the excretory function of the kidneys and, as discussed

increases in ADH levels also increase the formation of

later, can be used to quantify the rate at which blood

AQP-2 protein in the renal tubular cells by stimulat-

flows through the kidneys as well as the basic functions

ing AQP-2 gene transcription. When the concentration

of the kidneys: glomerular filtration, tubular reabsorp-

of ADH decreases, the molecules of AQP-2 are shut-

tion, and tubular secretion.

tled back to the cell cytoplasm, thereby removing the

To illustrate the clearance principle, consider the fol-

water channels from the luminal membrane and

lowing example: If the plasma passing through the

reducing water permeability.

kidneys contains 1 milligram of a substance in each mil-

liliter and if

1 milligram of this substance is also

Atrial Natriuretic Peptide Decreases Sodium and Water

excreted into the urine each minute, then 1 ml/min

Reabsorption. Specific cells of the cardiac atria, when

of the plasma is “cleared” of the substance. Thus,

344

Unit V The Body Fluids and Kidneys

Table 27-4

Use of Clearance to Quantify Kidney Function

Term

Equation

Units

Clearance rate (C_s)

C =U

ml/min

inulin

Glomerular filtration rate (GFR)

GFR

inulin

C_s

Clearance ratio

None

C_inulin

UPAH¥V

Effective renal plasma flow (ERPF)

ERPF =C

PAH

ml/min

PAH

(UPAH¥V

PAH

)

Renal plasma flow (RPF)

RPF

ml/min

PAH

)

PAH

UPAH¥V

PAH

RPF

Renal blood flow (RBF)

RBF

ml/min

1-Hematocrit

Excretion rate

Excretion rate = U_s ¥ V

mg/min, mmol/min, or mEq/min

Reabsorption rate

Reabsorption rate = Filtered load - Excretion rate

mg/min, mmol/min, or mEq/min

= (GFR ¥ P_s) - (U_s ¥ V)

Secretion rate

Secretion rate = Excretion rate - Filtered load

mg/min, mmol/min, or mEq/min

S, a substance; U, urine concentration; V, urine flow rate; P, plasma concentration; PAH, para-aminohippuric acid; P_PAH, renal arterial PAH concentration; E_PAH, PAH

extraction ratio; V_PAH, renal venous PAH concentration.

clearance refers to the volume of plasma that would be

5200. Inulin, which is not produced in the body, is found

necessary to supply the amount of substance excreted

in the roots of certain plants and must be administered

intravenously to a patient to measure GFR.

in the urine per unit time. Stated mathematically,

Figure 27-17 shows the renal handling of inulin. In

C_s ¥ P_s = U_s ¥ V,

this example, the plasma concentration is 1 mg/ml, urine

concentration is 125 mg/ml, and urine flow rate is 1 ml/

where C_s is the clearance rate of a substance s, P_s is the

min. Therefore, 125 mg/min of inulin passes into the

plasma concentration of the substance, U_s is the urine

urine. Then, inulin clearance is calculated as the urine

concentration of that substance, and V is the urine flow

excretion rate of inulin divided by the plasma concen-

rate. Rearranging this equation, clearance can be

tration, which yields a value of 125 ml/min. Thus, 125

expressed as

milliliters of plasma flowing through the kidneys must

be filtered to deliver the inulin that appears in the urine.

C =U

Inulin is not the only substance that can be used for

determining GFR. Other substances that have been

Thus, renal clearance of a substance is calculated from

used clinically to estimate GFR include radioactive

the urinary excretion rate (U_s ¥ V) of that substance

iothalamate and creatinine.

divided by its plasma concentration.

Inulin Clearance Can Be Used

Creatinine Clearance and Plasma

to Estimate GFR

Creatinine Concentration Can Be

Used to Estimate GFR

If a substance is freely filtered (filtered as freely as

water) and is not reabsorbed or secreted by the renal

Creatinine is a by-product of muscle metabolism and is

tubules, then the rate at which that substance is excreted

cleared from the body fluids almost entirely by glomeru-

in the urine (U_s ¥ V) is equal to the filtration rate of the

lar filtration. Therefore, the clearance of creatinine can

substance by the kidneys (GFR ¥ P_s). Thus,

also be used to assess GFR. Because measurement of

creatinine clearance does not require intravenous infu-

GFR ¥ P_s = U_s ¥ V

sion into the patient, this method is much more widely

The GFR, therefore, can be calculated as the clearance

used than inulin clearance for estimating GFR clinically.

of the substance as follows:

However, creatinine clearance is not a perfect marker

Us¥V

of GFR because a small amount of it is secreted by the

GFR

tubules, so that the amount of creatinine excreted

slightly exceeds the amount filtered. There is normally

A substance that fits these criteria is inulin, a polysac-

a slight error in measuring plasma creatinine that

charide molecule with a molecular weight of about

leads to an overestimate of the plasma creatinine

Chapter 27

Urine Formation by the Kidneys: II. Tubular Processing of the Glomerular Filtrate

345

P_inulin = 1 mg/ml

100

Amount filtered = Amount excreted

GFR x P_inulin = U_inulin x V

U_inulin x V

GFR =

P_inulin

GFR = 125 ml/min

U_inulin = 125 mg/ml

V = 1 ml/min

Positive balance

Production

Figure 27-17

Measurement of glomerular filtration rate (GFR) from the renal

clearance of inulin. Inulin is freely filtered by the glomerular cap-

Excretion GFR x P_Creatinine

illaries but is not reabsorbed by the renal tubules. P_inulin, plasma

inulin concentration; U_inulin, urine inulin concentration; V, urine flow

rate.

concentration, and fortuitously, these two errors tend to

cancel each other. Therefore, creatinine clearance pro-

vides a reasonable estimate of GFR.

Days

In some cases, it may not be practical to collect urine

in a patient for measuring creatinine clearance (C_Cr). An

approximation of changes in GFR, however, can be

obtained by simply measuring plasma creatinine con-

Figure 27-18

centration (P_Cr), which is inversely proportional to GFR:

UCr¥V

Effect of reducing glomerular filtration rate (GRF) by 50 per cent

GFRªC

on serum creatinine concentration and on creatinine excretion

rate when the production rate of creatinine remains constant.

P_Creatinine, plasma creatinine concentration.

If GFR suddenly decreases by 50%, the kidneys will

transiently filter and excrete only half as much creati-

nine, causing accumulation of creatinine in the body

fluids and raising plasma concentration. Plasma con-

to the total renal plasma flow. In other words, the

centration of creatinine will continue to rise until the fil-

amount of the substance delivered to the kidneys in

tered load of creatinine (P_Cr ¥ GFR) and creatinine

the blood (renal plasma flow ¥ P_s) would be equal to

excretion (U_Cr ¥ V) return to normal and a balance

the amount excreted in the urine (U_s ¥ V). Thus, renal

between creatinine production and creatinine excretion

plasma flow (RPF) could be calculated as

is reestablished. This will occur when plasma creatinine

increases to approximately twice normal, as shown in

Us¥V

RPF

Figure 27-18. If GFR falls to one-fourth normal, plasma

creatinine would increase to about 4 times normal, and

a decrease of GFR to one-eighth normal would raise

Because the GFR is only about 20 per cent of the

plasma creatinine to 8 times normal. Thus, under steady-

total plasma flow, a substance that is completely cleared

state conditions, the creatinine excretion rate equals the

from the plasma must be excreted by tubular secretion

rate of creatinine production, despite reductions in

as well as glomerular filtration (Figure 27-20). There is

GFR. However, this normal rate of creatinine excretion

no known substance that is completely cleared by the

occurs at the expense of elevated plasma creatinine con-

kidneys. One substance, however, PAH, is about 90 per

centration, as shown in Figure 27-19.

cent cleared from the plasma. Therefore, the clearance

of PAH can be used as an approximation of renal

plasma flow. To be more accurate, one can correct for

PAH Clearance Can Be Used to

the percentage of PAH that is still in the blood when it

Estimate Renal Plasma Flow

leaves the kidneys. The percentage of PAH removed

from the blood is known as the extraction ratio of PAH

Theoretically, if a substance is completely cleared from

and averages about 90 per cent in normal kidneys. In

the plasma, the clearance rate of that substance is equal

diseased kidneys, this extraction ratio may be reduced

346

Unit V The Body Fluids and Kidneys

P_PAH = 0.01 mg/ml

Renal plasma flow

U_PAH x V

PAH

Renal venous

PAH =

Normal

0.001 mg/ml

U_PAH = 5.85 mg/ml

100

125

150

V = 1 ml/min

Glomerular filtration rate

(ml/min)

Figure 27-20

Measurement of renal plasma flow from the renal clearance of para-

aminohippuric acid (PAH). PAH is freely filtered by the glomerular

Figure 27-19

capillaries and is also secreted from the peritubular capillary blood

into the tubular lumen. The amount of PAH in the plasma of the

Approximate relationship between glomerular filtration rate (GFR)

renal artery is about equal to the amount of PAH excreted in

and plasma creatinine concentration under steady-state conditions.

the urine. Therefore, the renal plasma flow can be calculated from

Decreasing GFR by 50 per cent will increase plasma creatinine to

the clearance of PAH (C_PAH). To be more accurate, one can correct

twice normal if creatinine production by the body remains constant.

for the percentage of PAH that is still in the blood when it leaves

the kidneys. P_PAH, arterial plasma PAH concentration; U_PAH, urine

PAH concentration; V, urine flow rate.

because of inability of damaged tubules to secrete PAH

Filtration Fraction Is Calculated

into the tubular fluid.

from GFR Divided by Renal

The calculation of RPF can be demonstrated by the

Plasma Flow

following example: Assume that the plasma concentra-

tion of PAH is 0.01 mg/ml, urine concentration is 5.85

To calculate the filtration fraction, which is the fraction

mg/ml, and urine flow rate is 1 ml/min. PAH clearance

of plasma that filters through the glomerular mem-

can be calculated from the rate of urinary PAH excre-

brane, one must first know the renal plasma flow (PAH

tion (5.85 mg/ml ¥ 1 ml/min) divided by the plasma PAH

clearance) and the GFR (inulin clearance). If renal

concentration (0.01 mg/ml). Thus, clearance of PAH cal-

plasma flow is 650 ml/min and GFR is 125 ml/min, the

culates to be 585 ml/min.

filtration fraction (FF) is calculated as

If the extraction ratio for PAH is 90 per cent, the

actual renal plasma flow can be calculated by dividing

FF = GFR/RPF = 125/650 = 0.19

585 ml/min by 0.9, yielding a value of 650 ml/min. Thus,

total renal plasma flow can be calculated as

Calculation of Tubular Reabsorption

Total renal plasma flow =

or Secretion from Renal Clearances

Clearance of PAH/Extraction ratio of PAH

If the rates of glomerular filtration and renal excretion

The extraction ratio (E_PAH) is calculated as the dif-

of a substance are known, one can calculate whether

ference between the renal arterial PAH (P_PAH) and renal

there is a net reabsorption or a net secretion of that sub-

venous PAH (V_PAH) concentrations, divided by the renal

stance by the renal tubules. For example, if the rate of

arterial PAH concentration:

excretion of the substance (U_s ¥ V) is less than the fil-

PAH

-V

PAH

tered load of the substance (GFR ¥ P_s), then some of

PAH

the substance must have been reabsorbed from the

PAH

renal tubules. Conversely, if the excretion rate of the

One can calculate the total blood flow through the

substance is greater than its filtered load, then the rate

kidneys from the total renal plasma flow and hematocrit

at which it appears in the urine represents the sum of

(the percentage of red blood cells in the blood). If the

the rate of glomerular filtration plus tubular secretion.

hematocrit is 0.45 and the total renal plasma flow is

The following example demonstrates the calculation

650 ml/min, the total blood flow through both kidneys

of tubular reabsorption. Assume the following labora-

is 650/(1 - 0.45), or 1182 ml/min.

tory values for a patient were obtained:

Chapter 27

Urine Formation by the Kidneys: II. Tubular Processing of the Glomerular Filtrate

347

Urine flow rate = 1 ml/min

Féraille E, Doucet A: Sodium-potassium-adenosine-

Urine concentration of sodium (U_Na) = 70 mEq/L

triphosphatase-dependent sodium transport in the

= 70 mEq/ml

kidney: Hormonal control. Physiol Rev 81:345, 2001.

Plasma sodium concentration = 140 mEq/L

Granger JP, Alexander BT, Llinas M: Mechanisms of pres-

= 140 mEq/ml

sure natriuresis. Curr Hypertens Rep 4:152, 2002.

GFR (inulin clearance) = 100 ml/min

Hall JE, Brands MW: The renin-angiotensin-aldosterone

system: renal mechanisms and circulatory homeostasis.

In this example, the filtered sodium load is GFR ¥ P_Na,

In Seldin DW, Giebisch G (eds): The Kidney—Physiology

or 100 ml/min ¥ 140 mEq/ml = 14,000 mEq/min. Urinary

and Pathophysiology, 3rd ed. New York: Raven Press,

sodium excretion (U_Na ¥ urine flow rate) is 70 mEq/min.

2000.

Therefore, tubular reabsorption of sodium is the differ-

Humphreys MH, Valentin J-P: Natriuretic hormonal agents.

ence between the filtered load and urinary excretion, or

In Seldin DW, Giebisch G (eds): The Kidney—Physiology

14,000 mEq/min - 70 mEq/min = 13,930 mEq/min.

and Pathophysiology, 3rd ed. New York: Raven Press,

2000.

Comparisons of Inulin Clearance with Clearances of Different

Kellenberger S, Schild L: Epithelial sodium channel/

Solutes. The following generalizations can be made by

degenerin family of ion channels: A variety of functions

comparing the clearance of a substance with the clear-

for a shared structure. Physiol Rev 82:735, 2002.

ance of inulin, a measure of GFR: (1) if the clearance

Nielsen S, Frøkiær J, Marples D, et al: Aquaporins in the

rate of the substance equals that of inulin, the substance

kidney: from molecules to medicine. Physiol Rev 82:205,

is only filtered and not reabsorbed or secreted; (2) if the

2002.

clearance rate of a substance is less than inulin clear-

Palmer LG, Frindt G: Aldosterone and potassium secretion

ance, the substance must have been reabsorbed by the

by the cortical collecting duct. Kidney Int 57:1324, 2000.

nephron tubules; and (3) if the clearance rate of a sub-

Rahn KH, Heidenreich S, Bruckner D: How to assess

stance is greater than that of inulin, the substance must

glomerular function and damage in humans. J Hypertens

be secreted by the nephron tubules. Listed below are

17:309, 1999.

the approximate clearance rates for some of the sub-

Reeves WB, Andreoli TE: Sodium chloride transport in the

stances normally handled by the kidneys:

loop of Henle, distal convoluted tubule and collecting

duct. In Seldin DW, Giebisch G (eds): The Kidney—Phys-

Substance

Clearance Rate (ml/min)

iology and Pathophysiology, 3rd ed. New York: Raven

Press, 2000.

Glucose

Reilly RF, Ellison DH: Mammalian distal tubule: physiology,

Sodium

0.9

pathophysiology, and molecular anatomy. Physiol Rev

Chloride

1.3

80:277, 2000.

Potassium

12.0

Rossier BC, Praderv S, Schild L, Hummler E: Epithelial

Phosphate

25.0

sodium channel and the control of sodium balance: inter-

Inulin

125.0

Creatinine

140.0

action between genetic and environmental factors. Annu

Rev Physiol 64:877, 2002.

Russell JM: Sodium-potassium-chloride cotransport. Physiol

Rev 80:211, 2000.

Schafer JA: Abnormal regulation of ENaC: syndromes of

References

salt retention and salt wasting by the collecting duct. Am

J Physiol Renal Physiol 283:F221, 2002.

Aronson PS: Ion exchangers mediating NaCl transport in the

Weinstein AM: Mathematical models of renal fluid and elec-

renal proximal tubule. Cell Biochem Biophys 36:147, 2002.

trolyte transport: acknowledging our uncertainty. Am J

Benos DJ, Fuller CM, Shlyonsky VG, et al: Amiloride-

Physiol Renal Physiol 284:F871, 2003.

sensitive Na⁺ channels: insights and outlooks. News

Wright EM: Renal Na(+)-glucose cotransporters. Am J

Physiol Sci 12:55, 1997.

Physiol Renal Physiol 280:F10, 2001.

C H A P T E R

Regulation of Extracellular Fluid

Osmolarity and Sodium

Concentration

For the cells of the body to function properly, they

must be bathed in extracellular fluid with a rela-

tively constant concentration of electrolytes and

other solutes. The total concentration of solutes in

the extracellular fluid—and therefore the osmolar-

ity—is determined by the amount of solute divided

by the volume of the extracellular fluid. Thus, to a

large extent, extracellular fluid sodium concentra-

tion and osmolarity are regulated by the amount of extracellular water. The

body water in turn is controlled by (1) fluid intake, which is regulated by factors

that determine thirst, and (2) renal excretion of water, which is controlled by

multiple factors that influence glomerular filtration and tubular reabsorption.

In this chapter, we discuss specifically (1) the mechanisms that cause the

kidneys to eliminate excess water by excreting a dilute urine; (2) the mecha-

nisms that cause the kidneys to conserve water by excreting a concentrated

urine; (3) the renal feedback mechanisms that control the extracellular fluid

sodium concentration and osmolarity; and (4) the thirst and salt appetite mech-

anisms that determine the intakes of water and salt, which also help to control

extracellular fluid volume, osmolarity, and sodium concentration.

The Kidneys Excrete Excess Water by Forming

a Dilute Urine

The normal kidney has tremendous capability to vary the relative proportions

of solutes and water in the urine in response to various challenges. When there

is excess water in the body and body fluid osmolarity is reduced, the kidney can

excrete urine with an osmolarity as low as 50 mOsm/L, a concentration that is

only about one sixth the osmolarity of normal extracellular fluid. Conversely,

when there is a deficit of water and extracellular fluid osmolarity is high, the

kidney can excrete urine with a concentration of 1200 to 1400 mOsm/L. Equally

important, the kidney can excrete a large volume of dilute urine or a small

volume of concentrated urine without major changes in rates of excretion of

solutes such as sodium and potassium. This ability to regulate water excretion

independently of solute excretion is necessary for survival, especially when fluid

intake is limited.

Antidiuretic Hormone Controls Urine Concentration

There is a powerful feedback system for regulating plasma osmolarity and

sodium concentration that operates by altering renal excretion of water inde-

pendently of the rate of solute excretion. A primary effector of this feedback is

antidiuretic hormone (ADH), also called vasopressin.

When osmolarity of the body fluids increases above normal (that is, the

solutes in the body fluids become too concentrated), the posterior pituitary

gland secretes more ADH, which increases the permeability of the distal tubules

and collecting ducts to water, as discussed in Chapter 27. This allows large

amounts of water to be reabsorbed and decreases urine volume but does not

348

Chapter 28

Regulation of Extracellular Fluid Osmolarity and Sodium Concentration

349

markedly alter the rate of renal excretion of the

However, the total amount of solute excreted remains

solutes.

relatively constant because the urine formed becomes

When there is excess water in the body and extra-

very dilute and urine osmolarity decreases from 600 to

cellular fluid osmolarity is reduced, the secretion of

about 100 mOsm/L. Thus, after ingestion of excess

ADH by the posterior pituitary decreases, thereby

water, the kidney rids the body of the excess water but

reducing the permeability of the distal tubule and col-

does not excrete excess amounts of solutes.

lecting ducts to water, which causes large amounts of

When the glomerular filtrate is initially formed,

dilute urine to be excreted. Thus, the rate of ADH

its osmolarity is about the same as that of plasma

secretion determines, to a large extent, whether the

(300 mOsm/L). To excrete excess water, it is necessary

kidney excretes a dilute or a concentrated urine.

to dilute the filtrate as it passes along the tubule. This

is achieved by reabsorbing solutes to a greater extent

than water, as shown in Figure 28-2, but this occurs

Renal Mechanisms for Excreting a

only in certain segments of the tubular system as

Dilute Urine

follows.

When there is a large excess of water in the body, the

Tubular Fluid Remains Isosmotic in the Proximal Tubule. As

kidney can excrete as much as 20 L/day of dilute urine,

fluid flows through the proximal tubule, solutes and

with a concentration as low as 50 mOsm/L. The kidney

water are reabsorbed in equal proportions, so that

performs this impressive feat by continuing to reab-

little change in osmolarity occurs; that is, the proximal

sorb solutes while failing to reabsorb large amounts of

tubule fluid remains isosmotic to the plasma, with an

water in the distal parts of the nephron, including the

osmolarity of about 300 mOsm/L. As fluid passes down

late distal tubule and the collecting ducts.

the descending loop of Henle, water is reabsorbed by

Figure 28-1 shows the approximate renal responses

osmosis and the tubular fluid reaches equilibrium with

in a human after ingestion of 1 liter of water. Note that

the surrounding interstitial fluid of the renal medulla,

urine volume increases to about six times normal

which is very hypertonic—about two to four times the

within 45 minutes after the water has been drunk.

osmolarity of the original glomerular filtrate. There-

fore, the tubular fluid becomes more concentrated as

it flows into the inner medulla.

Tubular Fluid Becomes Dilute in the Ascending Loop of Henle.

In the ascending limb of the loop of Henle, especially

Drink 1.0 L H₂O

in the thick segment, sodium, potassium, and chloride

800

are avidly reabsorbed. However, this portion of the

Urine

osmolarity

tubular segment is impermeable to water, even in

400

Plasma

osmolarity

NaCl

H₂O

NaCl

300

100

300

NaCl

1.2

400

NaCl

0.6

H₂

NaCl

120

180

600

Time (minutes)

Figure 28-2

Figure 28-1

Formation of a dilute urine when antidiuretic hormone (ADH) levels

Water diuresis in a human after ingestion of 1 liter of water. Note

are very low. Note that in the ascending loop of Henle, the tubular

that after water ingestion, urine volume increases and urine osmo-

fluid becomes very dilute. In the distal tubules and collecting

larity decreases, causing the excretion of a large volume of dilute

tubules, the tubular fluid is further diluted by the reabsorption of

urine; however, the total amount of solute excreted by the kidneys

sodium chloride and the failure to reabsorb water when ADH

remains relatively constant. These responses of the kidneys

levels are very low. The failure to reabsorb water and continued

prevent plasma osmolarity from decreasing markedly during

reabsorption of solutes lead to a large volume of dilute urine.

excess water ingestion.

(Numerical values are in milliosmoles per liter.)

350

Unit V The Body Fluids and Kidneys

the presence of large amounts of ADH. Therefore, the

water produced in the body by metabolism of the food.

tubular fluid becomes more dilute as it flows up the

Animals adapted to aquatic environments, such as the

ascending loop of Henle into the early distal tubule,

beaver, have minimal urine concentrating ability; they

with the osmolarity decreasing progressively to about

can concentrate the urine to only about 500 mOsm/L.

100 mOsm/L by the time the fluid enters the early

distal tubular segment. Thus, regardless of whether

ADH is present or absent, fluid leaving the early distal

Obligatory Urine Volume

tubular segment is hypo-osmotic, with an osmolarity of

The maximal concentrating ability of the kidney dic-

only about one third the osmolarity of plasma.

tates how much urine volume must be excreted each

day to rid the body of waste products of metabolism and

Tubular Fluid in Distal and Collecting Tubules Is Further Diluted

ions that are ingested. A normal 70-kilogram human

in the Absence of ADH. As the dilute fluid in the early

must excrete about 600 milliosmoles of solute each day.

distal tubule passes into the late distal convoluted

If maximal urine concentrating ability is 1200 mOsm/L,

tubule, cortical collecting duct, and collecting duct,

the minimal volume of urine that must be excreted,

called the obligatory urine volume, can be calculated as

there is additional reabsorption of sodium chloride. In

the absence of ADH, this portion of the tubule is also

600 mOsm day

impermeable to water, and the additional reabsorption

= 0.5 L day

1200 mOsm L

of solutes causes the tubular fluid to become even

more dilute, decreasing its osmolarity to as low as

This minimal loss of volume in the urine contributes to

50 mOsm/L. The failure to reabsorb water and the con-

dehydration, along with water loss from the skin, respi-

ratory tract, and gastrointestinal tract, when water is not

tinued reabsorption of solutes lead to a large volume

available to drink.

of dilute urine.

The limited ability of the human kidney to con-

To summarize, the mechanism for forming a dilute

centrate the urine to a maximal concentration of

urine is to continue reabsorbing solutes from the distal

1200 mOsm/L explains why severe dehydration occurs

segments of the tubular system while failing to reab-

if one attempts to drink seawater. Sodium chloride

sorb water. In healthy kidneys, fluid leaving the

concentration in the oceans averages about 3.0 to 3.5

ascending loop of Henle and early distal tubule is

per cent, with an osmolarity between about 1000 and

always dilute, regardless of the level of ADH. In the

1200 mOsm/L. Drinking 1 liter of seawater with a con-

absence of ADH, the urine is further diluted in the late

centration of

1200 mOsm/L would provide a total

distal tubule and collecting ducts, and a large volume

sodium chloride intake of 1200 milliosmoles. If maximal

urine concentrating ability is 1200 mOsm/L, the amount

of dilute urine is excreted.

of urine volume needed to excrete 1200 milliosmoles

would be 1200 milliosmoles divided by 1200 mOsm/L,

or 1.0 liter. Why then does drinking seawater cause

The Kidneys Conserve Water

dehydration? The answer is that the kidney must also

by Excreting a Concentrated

excrete other solutes, especially urea, which contribute

about 600 mOsm/L when the urine is maximally con-

Urine

centrated. Therefore, the maximum concentration of

sodium chloride that can be excreted by the kidneys is

The ability of the kidney to form a urine that is more

about 600 mOsm/L. Thus, for every liter of seawater

concentrated than plasma is essential for survival of

drunk, 2 liters of urine volume would be required to rid

mammals that live on land, including humans. Water is

the body of

1200 milliosmoles of sodium chloride

continuously lost from the body through various

ingested in addition to other solutes such as urea. This

routes, including the lungs by evaporation into the

would result in a net fluid loss of 1 liter for every liter

of seawater drunk, explaining the rapid dehydration

expired air, the gastrointestinal tract by way of the

that occurs in shipwreck victims who drink seawater.

feces, the skin through evaporation and perspiration,

However, a shipwreck victim’s pet Australian hopping

and the kidneys through the excretion of urine. Fluid

mouse could drink with impunity all the seawater it

intake is required to match this loss, but the ability of

wanted.

the kidney to form a small volume of concentrated

urine minimizes the intake of fluid required to main-

tain homeostasis, a function that is especially impor-

Requirements for Excreting a

tant when water is in short supply.

When there is a water deficit in the body, the kidney

Concentrated Urine—High ADH Levels

forms a concentrated urine by continuing to excrete

and Hyperosmotic Renal Medulla

solutes while increasing water reabsorption and

decreasing the volume of urine formed. The human

The basic requirements for forming a concentrated

kidney can produce a maximal urine concentration of

urine are (1) a high level of ADH, which increases the

1200 to 1400 mOsm/L, four to five times the osmolar-

permeability of the distal tubules and collecting ducts

ity of plasma. Some desert animals, such as the Aus-

to water, thereby allowing these tubular segments to

tralian hopping mouse, can concentrate urine to as

avidly reabsorb water, and (2) a high osmolarity of the

high as 10,000 mOsm/L. This allows the mouse to

renal medullary interstitial fluid, which provides the

survive in the desert without drinking water; sufficient

osmotic gradient necessary for water reabsorption to

water can be obtained through the food ingested and

occur in the presence of high levels of ADH.

Chapter 28

Regulation of Extracellular Fluid Osmolarity and Sodium Concentration

351

The renal medullary interstitium surrounding the

Table 28-1

collecting ducts normally is very hyperosmotic, so that

Summary of Tubule Characteristics—Urine Concentration

when ADH levels are high, water moves through the

tubular membrane by osmosis into the renal intersti-

tium; from there it is carried away by the vasa recta

Permeability

Active NaCl

back into the blood. Thus, the urine concentrating

Transport

H₂O

NaCl

Urea

ability is limited by the level of ADH and by the

Proximal tubule

degree of hyperosmolarity of the renal medulla. We

Thin descending limb

discuss the factors that control ADH secretion later,

Thin ascending limb

but for now, what is the process by which renal

Thick ascending limb

Distal tubule

+ADH

medullary interstitial fluid becomes hyperosmotic?

Cortical collecting

+ADH

This process involves the operation of the countercur-

tubule

rent mechanism.

Inner medullary

+ADH

++ADH

The countercurrent mechanism depends on the

collecting duct

special anatomical arrangement of the loops of Henle

and the vasa recta, the specialized peritubular capillar-

0, minimal level of active transport or permeability; +, moderate level of active

transport or permeability; ++, high level of active transport or permeability;

ies of the renal medulla. In the human, about 25 per

+ADH, permeability to water or urea is increased by ADH.

cent of the nephrons are juxtamedullary nephrons,

with loops of Henle and vasa recta that go deeply into

the medulla before returning to the cortex. Some of

far less than the reabsorption of solutes into the

the loops of Henle dip all the way to the tips of the

medullary interstitium

renal papillae that project from the medulla into the

renal pelvis. Paralleling the long loops of Henle are

Special Characteristics of Loop of Henle That Cause Solutes to

the vasa recta, which also loop down into the medulla

Be Trapped in the Renal Medulla. The transport character-

before returning to the renal cortex. And finally, the

istics of the loops of Henle are summarized in Table

collecting ducts, which carry urine through the hyper-

28-1, along with the characteristics of the proximal

osmotic renal medulla before it is excreted, also play

tubules, distal tubules, cortical collecting tubules, and

a critical role in the countercurrent mechanism.

inner medullary collecting ducts.

The most important cause of the high medullary

osmolarity is active transport of sodium and co-

Countercurrent Mechanism

transport of potassium, chloride, and other ions from

Produces a Hyperosmotic Renal

the thick ascending loop of Henle into the interstitium.

Medullary Interstitium

This pump is capable of establishing about a 200-

milliosmole concentration gradient between the

The osmolarity of interstitial fluid in almost all parts

tubular lumen and the interstitial fluid. Because the

of the body is about 300 mOsm/L, which is similar to

thick ascending limb is virtually impermeable to water,

the plasma osmolarity. (As discussed in Chapter 25,

the solutes pumped out are not followed by osmotic

the corrected osmolar activity, which accounts for

flow of water into the interstitium. Thus, the active

intermolecular attraction and repulsion, is about

transport of sodium and other ions out of the thick

282 mOsm/L.) The osmolarity of the interstitial fluid

ascending loop adds solutes in excess of water to the

in the medulla of the kidney is much higher, increas-

renal medullary interstitium. There is some passive

ing progressively to about 1200 to 1400 mOsm/L in the

reabsorption of sodium chloride from the thin ascend-

pelvic tip of the medulla. This means that the renal

ing limb of Henle’s loop, which is also impermeable to

medullary interstitium has accumulated solutes in

water, adding further to the high solute concentration

great excess of water. Once the high solute concentra-

of the renal medullary interstitium.

tion in the medulla is achieved, it is maintained by a

The descending limb of Henle’s loop, in contrast to

balanced inflow and outflow of solutes and water in

the ascending limb, is very permeable to water, and the

the medulla.

tubular fluid osmolarity quickly becomes equal to the

The major factors that contribute to the buildup of

renal medullary osmolarity. Therefore, water diffuses

solute concentration into the renal medulla are as

out of the descending limb of Henle’s loop into the

follows:

interstitium, and the tubular fluid osmolarity gradually

1. Active transport of sodium ions and co-transport

rises as it flows toward the tip of the loop of Henle.

of potassium, chloride, and other ions out of the

thick portion of the ascending limb of the loop

Steps Involved in Causing Hyperosmotic Renal Medullary Inter-

of Henle into the medullary interstitium

stitium. With these characteristics of the loop of Henle

2. Active transport of ions from the collecting ducts

in mind, let us now discuss how the renal medulla

into the medullary interstitium

becomes hyperosmotic. First, assume that the loop of

3. Facilitated diffusion of large amounts of urea

Henle is filled with fluid with a concentration of

from the inner medullary collecting ducts into the

300 mOsm/L, the same as that leaving the proximal

medullary interstitium

tubule (Figure 28-3, step 1). Next, the active pump of

4. Diffusion of only small amounts of water from the

the thick ascending limb on the loop of Henle is turned

medullary tubules into the medullary interstitium,

on, reducing the concentration inside the tubule and

352

Unit V The Body Fluids and Kidneys

300

200

300

200

300

200

300

400

200

400

200

300

400

200

300

400

200

400

200

400

300

400

200

400

200

400

300

150

300

150

300

100

300

350

150

350

150

700

500

Repeat Steps 4-6

400

500

300

500

300

1000

800

400

500

300

500

300

1200

1000

Figure 28-3

Countercurrent multiplier system in the loop of Henle for producing a hyperosmotic renal medulla. (Numerical values are in milliosmoles

per liter.)

raising the interstitial concentration; this pump estab-

hyperosmotic tubular fluid from the descending limb

lishes a 200-mOsm/L concentration gradient between

of the loop of Henle flows into the ascending limb, still

the tubular fluid and the interstitial fluid (step 2). The

more solute is continuously pumped out of the tubules

limit to the gradient is about 200 mOsm/L because

and deposited into the medullary interstitium.

paracellular diffusion of ions back into the tubule

These steps are repeated over and over, with the net

eventually counterbalances transport of ions out of the

effect of adding more and more solute to the medulla

lumen when the 200-mOsm/L concentration gradient

in excess of water; with sufficient time, this process

is achieved.

gradually traps solutes in the medulla and multiplies

Step 3 is that the tubular fluid in the descending limb

the concentration gradient established by the active

of the loop of Henle and the interstitial fluid quickly

pumping of ions out of the thick ascending loop of

reach osmotic equilibrium because of osmosis of water

Henle, eventually raising the interstitial fluid osmolar-

out of the descending limb. The interstitial osmolarity

ity to 1200 to 1400 mOsm/L as shown in step 7.

is maintained at 400 mOsm/L because of continued

Thus, the repetitive reabsorption of sodium chloride

transport of ions out of the thick ascending loop of

by the thick ascending loop of Henle and continued

Henle. Thus, by itself, the active transport of sodium

inflow of new sodium chloride from the proximal

chloride out of the thick ascending limb is capable of

tubule into the loop of Henle is called the countercur-

establishing only a 200-mOsm/L concentration gradi-

rent multiplier. The sodium chloride reabsorbed from

ent, much less than that achieved by the countercur-

the ascending loop of Henle keeps adding to the newly

rent system.

arrived sodium chloride, thus “multiplying” its con-

Step 4 is additional flow of fluid into the loop of

centration in the medullary interstitium.

Henle from the proximal tubule, which causes the

hyperosmotic fluid previously formed in the descend-

Role of Distal Tubule and

ing limb to flow into the ascending limb. Once this fluid

is in the ascending limb, additional ions are pumped

Collecting Ducts in Excreting a

into the interstitium, with water remaining behind,

Concentrated Urine

until a 200-mOsm/L osmotic gradient is established,

with the interstitial fluid osmolarity rising to

When the tubular fluid leaves the loop of Henle and

500 mOsm/L (step 5). Then, once again, the fluid in the

flows into the distal convoluted tubule in the renal

descending limb reaches equilibrium with the hyper-

cortex, the fluid is dilute, with an osmolarity of only

osmotic medullary interstitial fluid (step 6), and as the

about 100 mOsm/L (Figure 28-4). The early distal

Chapter 28

Regulation of Extracellular Fluid Osmolarity and Sodium Concentration

353

H₂O

NaCl

Urea Contributes to Hyperosmotic

NaCl

H₂O

Urea

300

Renal Medullary Interstitium and to a

100

300

Concentrated Urine

300

NaCl

Thus far, we have considered only the contribution of

sodium chloride to the hyperosmotic renal medullary

interstitium. However, urea contributes about

to 50 per cent of the osmolarity (500-600 mOsm/L) of

the renal medullary interstitium when the kidney

600

is forming a maximally concentrated urine. Unlike

sodium chloride, urea is passively reabsorbed from the

NaCl

tubule. When there is water deficit and blood concen-

H₂O

NaCl

trations of ADH are high, large amounts of urea are

Urea

passively reabsorbed from the inner medullary col-

1200

lecting ducts into the interstitium.

The mechanism for reabsorption of urea into the

renal medulla is as follows: As water flows up the

ascending loop of Henle and into the distal and corti-

Figure 28-4

cal collecting tubules, little urea is reabsorbed because

Formation of a concentrated urine when antidiuretic hormone

these segments are impermeable to urea (see Table

(ADH) levels are high. Note that the fluid leaving the loop of Henle

28-1). In the presence of high concentrations of ADH,

is dilute but becomes concentrated as water is absorbed from the

water is reabsorbed rapidly from the cortical col-

distal tubules and collecting tubules. With high ADH levels, the

osmolarity of the urine is about the same as the osmolarity of

lecting tubule and the urea concentration increases

the renal medullary interstitial fluid in the papilla, which is about

rapidly because urea is not very permeant in this part

1200 mOsm/L. (Numerical values are in milliosmoles per liter.)

of the tubule. Then, as the tubular fluid flows into the

inner medullary collecting ducts, still more water reab-

sorption takes place, causing an even higher concen-

tubule further dilutes the tubular fluid because this

tration of urea in the fluid. This high concentration of

segment, like the ascending loop of Henle, actively

urea in the tubular fluid of the inner medullary col-

transports sodium chloride out of the tubule but is rel-

lecting duct causes urea to diffuse out of the tubule

atively impermeable to water.

into the renal interstitium. This diffusion is greatly

As fluid flows into the cortical collecting tubule, the

facilitated by specific urea transporters. One of these

amount of water reabsorbed is critically dependent on

urea transporters, UT-AI, is activated by ADH,

the plasma concentration of ADH. In the absence of

increasing transport of urea out of the inner medullary

ADH, this segment is almost impermeable to water

collecting duct even more when ADH levels are ele-

and fails to reabsorb water but continues to reabsorb

vated. The simultaneous movement of water and urea

solutes and further dilutes the urine. When there is a

out of the inner medullary collecting ducts maintains

high concentration of ADH, the cortical collecting

a high concentration of urea in the tubular fluid and,

tubule becomes highly permeable to water, so that

eventually, in the urine, even though urea is being

large amounts of water are now reabsorbed from the

reabsorbed.

tubule into the cortex interstitium, where it is swept

The fundamental role of urea in contributing to

away by the rapidly flowing peritubular capillaries.

urine concentrating ability is evidenced by the fact that

The fact that these large amounts of water are reab-

people who ingest a high-protein diet, yielding large

sorbed into the cortex, rather than into the renal

amounts of urea as a nitrogenous “waste” product,

medulla, helps to preserve the high medullary intersti-

can concentrate their urine much better than people

tial fluid osmolarity.

whose protein intake and urea production are low.

As the tubular fluid flows along the medullary col-

Malnutrition is associated with a low urea concentra-

lecting ducts, there is further water reabsorption from

tion in the medullary interstitium and considerable

the tubular fluid into the interstitium, but the total

impairment of urine concentrating ability.

amount of water is relatively small compared with that

added to the cortex interstitium. The reabsorbed water

Recirculation of Urea from Collecting Duct to Loop of Henle

is quickly carried away by the vasa recta into the

Contributes to Hyperosmotic Renal Medulla. A person

venous blood. When high levels of ADH are present,

usually excretes about 20 to 50 per cent of the filtered

the collecting ducts become permeable to water, so

load of urea. In general, the rate of urea excretion is

that the fluid at the end of the collecting ducts has

determined mainly by two factors: (1) the concentra-

essentially the same osmolarity as the interstitial fluid

tion of urea in the plasma and (2) the glomerular fil-

of the renal medulla—about 1200 mOsm/L (see Figure

tration rate (GFR). In patients with renal disease who

28-3). Thus, by reabsorbing as much water as possible,

have large reductions of GFR, the plasma urea con-

the kidneys form a highly concentrated urine, excret-

centration increases markedly, returning the filtered

ing normal amounts of solutes in the urine while

urea load and urea excretion rate to the normal level

adding water back to the extracellular fluid and com-

(equal to the rate of urea production), despite the

pensating for deficits of body water.

reduced GFR.

354

Unit V The Body Fluids and Kidneys

back down into the medullary collecting duct again. In

100% remaining

this way, urea can recirculate through these terminal

parts of the tubular system several times before it is

Urea

4.5

Urea

4.5

excreted. Each time around the circuit contributes to

a higher concentration of urea.

100%

remaining

This urea recirculation provides an additional mech-

Cortex

anism for forming a hyperosmotic renal medulla.

Because urea is one of the most abundant waste prod-

50% remaining

ucts that must be excreted by the kidneys, this mech-

Outer

H₂O

anism for concentrating urea before it is excreted is

medulla

essential to the economy of the body fluid when water

is in short supply.

Urea

When there is excess water in the body and low

Inner

levels of ADH, the inner medullary collecting ducts

300

medulla

have a much lower permeability to both water and

urea, and more urea is excreted in the urine.

500

550

Urea

20% remaining

Countercurrent Exchange in the Vasa

Recta Preserves Hyperosmolarity

Figure 28-5

of the Renal Medulla

Recirculation of urea absorbed from the medullary collecting duct

Blood flow must be provided to the renal medulla to

into the interstitial fluid. This urea diffuses into the thin loop of

supply the metabolic needs of the cells in this part of

Henle, and then passes through the distal tubules, and finally

passes back into the collecting duct. The recirculation of urea

the kidney. Without a special medullary blood flow

helps to trap urea in the renal medulla and contributes to the

system, the solutes pumped into the renal medulla by

hyperosmolarity of the renal medulla. The heavy dark lines, from

the countercurrent multiplier system would be rapidly

the thick ascending loop of Henle to the medullary collecting

dissipated.

ducts, indicate that these segments are not very permeable to

There are two special features of the renal

urea. (Numerical values are in milliosmoles per liter of urea during

antidiuresis, when large amounts of antidiuretic hormone are

medullary blood flow that contribute to the preserva-

present. Percentages of the filtered load of urea that remain in the

tion of the high solute concentrations:

tubules are indicated in the boxes.)

1. The medullary blood flow is low, accounting for

less than 5 per cent of the total renal blood flow.

This sluggish blood flow is sufficient to supply

the metabolic needs of the tissues but helps to

In the proximal tubule, 40 to 50 per cent of the fil-

minimize solute loss from the medullary

tered urea is reabsorbed, but even so, the tubular fluid

interstitium.

urea concentration increases because urea is not

2. The vasa recta serve as countercurrent exchangers,

nearly as permeant as water. The concentration of urea

minimizing washout of solutes from the medullary

continues to rise as the tubular fluid flows into the thin

interstitium.

segments of the loop of Henle, partly because of water

The countercurrent exchange mechanism operates as

reabsorption out of the descending loop of Henle but

follows (Figure 28-6): Blood enters and leaves the

also because of some secretion of urea into the thin

medulla by way of the vasa recta at the boundary

loop of Henle from the medullary interstitium (Figure

of the cortex and renal medulla. The vasa recta, like

28-5).

other capillaries, are highly permeable to solutes in

The thick limb of the loop of Henle, the distal

the blood, except for the plasma proteins. As blood

tubule, and the cortical collecting tubule are all rela-

descends into the medulla toward the papillae, it

tively impermeable to urea, and very little urea reab-

becomes progressively more concentrated, partly

sorption occurs in these tubular segments. When the

by solute entry from the interstitium and partly by

kidney is forming a concentrated urine and high levels

loss of water into the interstitium. By the time the

of ADH are present, the reabsorption of water from

blood reaches the tips of the vasa recta, it has a con-

the distal tubule and cortical collecting tubule further

centration of about 1200 mOsm/L, the same as that of

raises the tubular fluid concentration of urea. And as

the medullary interstitium. As blood ascends back

this urea flows into the inner medullary collecting

toward the cortex, it becomes progressively less

duct, the high tubular fluid concentration of urea

concentrated as solutes diffuse back out into the

and specific urea transporters cause urea to diffuse

medullary interstitium and as water moves into the

into the medullary interstitium. A moderate share of

vasa recta.

the urea that moves into the medullary interstitium

Thus, although there is a large amount of fluid and

eventually diffuses into the thin loop of Henle, so that

solute exchange across the vasa recta, there is little net

it passes upward through the ascending loop of Henle,

dilution of the concentration of the interstitial fluid at

the distal tubule, the cortical collecting tubule, and

each level of the renal medulla because of the U shape

Chapter 28

Regulation of Extracellular Fluid Osmolarity and Sodium Concentration

355

Vasa recta

Interstitium

Summary of Urine Concentrating

mOsm/L

Mechanism and Changes in

300

350

300

Osmolarity in Different Segments

Solute

of the Tubules

H₂O

600

Solute

600

The changes in osmolarity and volume of the tubular

600

fluid as it passes through the different parts of the

Solute

nephron are shown in Figure 28-7.

H₂O

800

Solute

800

Proximal Tubule. About

65 per cent of the filtered

900

Solute

electrolytes are reabsorbed in the proximal tubule.

H₂O

1000

Solute

1000

However, the tubular membranes are highly perme-

1000

able to water, so that whenever solutes are reabsorbed,

water also diffuses through the tubular membrane by

1200

osmosis. Therefore, the osmolarity of the fluid remains

about the same as the glomerular filtrate, 300 mOsm/L.

Figure 28-6

Descending Loop of Henle. As fluid flows down the

Countercurrent exchange in the vasa recta. Plasma flowing down

the descending limb of the vasa recta becomes more hyperos-

descending loop of Henle, water is absorbed into the

motic because of diffusion of water out of the blood and diffusion

medulla. The descending limb is highly permeable to

of solutes from the renal interstitial fluid into the blood. In the

water but much less permeable to sodium chloride and

ascending limb of the vasa recta, solutes diffuse back into the

urea. Therefore, the osmolarity of the fluid flowing

interstitial fluid and water diffuses back into the vasa recta. Large

amounts of solutes would be lost from the renal medulla without

through the descending loop gradually increases until

the U shape of the vasa recta capillaries. (Numerical values are

it is equal to that of the surrounding interstitial fluid,

in milliosmoles per liter.)

which is about 1200 mOsm/L when the blood concen-

tration of ADH is high. When a dilute urine is being

formed, owing to low ADH concentrations, the med-

ullary interstitial osmolarity is less than 1200 mOsm/L;

consequently, the descending loop tubular fluid osmo-

of the vasa recta capillaries, which act as countercur-

larity also becomes less concentrated. This is due

rent exchangers. Thus, the vasa recta do not create the

partly to the fact that less urea is absorbed into the

medullary hyperosmolarity, but they do prevent it from

medullary interstitium from the collecting ducts when

being dissipated.

ADH levels are low and the kidney is forming a large

The U-shaped structure of the vessels minimizes

volume of dilute urine.

loss of solute from the interstitium but does not

prevent the bulk flow of fluid and solutes into the

Thin Ascending Loop of Henle. The thin ascending limb is

blood through the usual colloid osmotic and hydro-

essentially impermeable to water but reabsorbs some

static pressures that favor reabsorption in these capil-

sodium chloride. Because of the high concentration of

laries. Thus, under steady-state conditions, the vasa

sodium chloride in the tubular fluid, owing to water

recta carry away only as much solute and water as is

removal from the descending loop of Henle, there is

absorbed from the medullary tubules, and the high

some passive diffusion of sodium chloride from the

concentration of solutes established by the counter-

thin ascending limb into the medullary interstitium.

current mechanism is maintained.

Thus, the tubular fluid becomes more dilute as the

sodium chloride diffuses out of the tubule and water

Increased Medullary Blood Flow Can Reduce Urine Concentrat-

remains in the tubule. Some of the urea absorbed into

ing Ability. Certain vasodilators can markedly increase

the medullary interstitium from the collecting ducts

renal medullary blood flow, thereby “washing out”

also diffuses into the ascending limb, thereby return-

some of the solutes from the renal medulla and reduc-

ing the urea to the tubular system and helping to

ing maximum urine concentrating ability. Large

prevent its washout from the renal medulla. This urea

increases in arterial pressure can also increase the

recycling is an additional mechanism that contributes

blood flow of the renal medulla to a greater extent

to the hyperosmotic renal medulla.

than in other regions of the kidney and tend to wash

out the hyperosmotic interstitium, thereby reducing

urine concentrating ability. As discussed earlier,

Thick Ascending Loop of Henle. The thick part of the

maximum concentrating ability of the kidney is deter-

ascending loop of Henle is also virtually impermeable

mined not only by the level of ADH but also by the

to water, but large amounts of sodium, chloride, potas-

osmolarity of the renal medulla interstitial fluid. Even

sium, and other ions are actively transported from

with maximal levels of ADH, urine concentrating

the tubule into the medullary interstitium. Therefore,

ability will be reduced if medullary blood flow

fluid in the thick ascending limb of the loop of Henle

increases enough to reduce the hyperosmolarity in the

becomes very dilute, falling to a concentration of

renal medulla.

about 100 mOsm/L.

356

Unit V The Body Fluids and Kidneys

0.2 ml

25 ml

1200

900

600

Figure 28-7

8 ml

Changes in osmolarity of the

300

tubular fluid as it passes through

125 ml

44 ml

the different tubular segments in

200

the presence of high levels of

100

antidiuretic hormone (ADH) and

25 ml

20 ml

in the absence of ADH. (Numeri-

Proximal

Loop of Henle

Distal

Collecting

Urine

cal values indicate the approxi-

tubule

mate volumes in milliliters per

and duct

minute or in osmolarities in mil-

liosmoles per liter of fluid flow-

ing along the different tubular

segments.)

Early Distal Tubule. The early distal tubule has proper-

fluid, and because the inner medullary collecting ducts

ties similar to those of the thick ascending loop of

have specific urea transporters that greatly facilitate

Henle, so that further dilution of the tubular fluid

diffusion, much of the highly concentrated urea in

occurs as solutes are reabsorbed while water remains

the ducts diffuses out of the tubular lumen into the

in the tubule.

medullary interstitium. This absorption of the urea

into the renal medulla contributes to the high osmo-

Late Distal Tubule and Cortical Collecting Tubules. In the late

larity of the medullary interstitium and the high con-

distal tubule and cortical collecting tubules, the osmo-

centrating ability of the kidney.

larity of the fluid depends on the level of ADH. With

There are several important points to consider that

high levels of ADH, these tubules are highly perme-

may not be obvious from this discussion. First,

able to water, and significant amounts of water are

although sodium chloride is one of the principal

reabsorbed. Urea, however, is not very permeant in

solutes that contributes to the hyperosmolarity of the

this part of the nephron, resulting in increased urea

medullary interstitium, the kidney can, when needed,

concentration as water is reabsorbed. This allows most

excrete a highly concentrated urine that contains little

of the urea delivered to the distal tubule and collect-

sodium chloride. The hyperosmolarity of the urine in

ing tubule to pass into the inner medullary collecting

these circumstances is due to high concentrations of

ducts, from which it is eventually reabsorbed or

other solutes, especially of waste products such as urea

excreted in the urine. In the absence of ADH, little

and creatinine. One condition in which this occurs is

water is reabsorbed in the late distal tubule and corti-

dehydration accompanied by low sodium intake. As

cal collecting tubule; therefore, osmolarity decreases

discussed in Chapter 29, low sodium intake stimulates

even further because of continued active reabsorption

formation of the hormones angiotensin II and aldos-

of ions from these segments.

terone, which together cause avid sodium reabsorption

from the tubules while leaving the urea and other

Inner Medullary Collecting Ducts. The concentration of

solutes to maintain the highly concentrated urine.

fluid in the inner medullary collecting ducts also

Second, large quantities of dilute urine can be

depends on (1) ADH and (2) the osmolarity of the

excreted without increasing the excretion of sodium.

medullary interstitium established by the countercur-

This is accomplished by decreasing ADH secretion,

rent mechanism. In the presence of large amounts of

which reduces water reabsorption in the more distal

ADH, these ducts are highly permeable to water, and

tubular segments without significantly altering sodium

water diffuses from the tubule into the interstitium

reabsorption.

until osmotic equilibrium is reached, with the tubular

And finally, we should keep in mind that there is

fluid having about the same concentration as the renal

an obligatory urine volume, which is dictated by the

medullary interstitium (1200 to 1400 mOsm/L). Thus,

maximum concentrating ability of the kidney and the

a very concentrated but small volume of urine is pro-

amount of solute that must be excreted. Therefore, if

duced when ADH levels are high. Because water reab-

large amounts of solute must be excreted, they must

sorption increases urea concentration in the tubular

be accompanied by the minimal amount of water

Chapter 28

Regulation of Extracellular Fluid Osmolarity and Sodium Concentration

357

necessary to excrete them. For example, if 1200 mil-

Disorders of Urinary

liosmoles of solute must be excreted each day, this

Concentrating Ability

requires at least 1 liter of urine if maximal urine con-

centrating ability is 1200 mOsm/L.

An impairment in the ability of the kidneys to concen-

trate or dilute the urine appropriately can occur with

one or more of the following abnormalities:

1. Inappropriate secretion of ADH. Either too much

Quantifying Renal Urine

or too little ADH secretion results in abnormal

Concentration and Dilution:

fluid handling by the kidneys.

“Free Water” and

2. Impairment of the countercurrent mechanism. A

hyperosmotic medullary interstitium is required for

Osmolar Clearances

maximal urine concentrating ability. No matter how

The process of concentrating or diluting the urine

much ADH is present, maximal urine concentration

requires the kidneys to excrete water and solutes some-

is limited by the degree of hyperosmolarity of the

what independently. When the urine is dilute, water is

medullary interstitium.

excreted in excess of solutes. Conversely, when the urine

3. Inability of the distal tubule, collecting tubule, and

is concentrated, solutes are excreted in excess of water.

collecting ducts to respond to ADH.

The total clearance of solutes from the blood can be

expressed as the osmolar clearance (C_osm); this is the

Failure to Produce ADH:

“Central” Diabetes Insipidus. An

volume of plasma cleared of solutes each minute, in

inability to produce or release ADH from the posterior

the same way that clearance of a single substance is cal-

pituitary can be caused by head injuries or infections, or

culated:

it can be congenital. Because the distal tubular segments

cannot reabsorb water in the absence of ADH, this con-

osm

dition, called “central” diabetes insipidus, results in the

C =U

osm

formation of a large volume of dilute urine, with urine

volumes that can exceed 15 L/day. The thirst mecha-

where U_osm is the urine osmolarity, V is the urine flow

nisms, discussed later in this chapter, are activated when

rate, and P_osm is the plasma osmolarity. For example, if

excessive water is lost from the body; therefore, as long

plasma osmolarity is 300 mOsm/L, urine osmolarity is

as the person drinks enough water, large decreases in

600 mOsm/L, and urine flow rate is 1 ml/min (0.001 L/

body fluid water do not occur. The primary abnormal-

min), the rate of osmolar excretion is 0.6 mOsm/min

ity observed clinically in people with this condition is

(600 mOsm/L ¥ 0.001 L/min) and osmolar clearance is

the large volume of dilute urine. However, if water

0.6 mOsm/min divided by 300 mOsm/L, or 0.002 L/min

intake is restricted, as can occur in a hospital setting

(2.0 ml/min). This means that 2 milliliters of plasma are

when fluid intake is restricted or the patient is uncon-

being cleared of solute each minute.

scious (for example, because of a head injury), severe

dehydration can rapidly occur.

Relative Rates at Which Solutes and Water Are Excreted Can Be

The treatment for central diabetes insipidus is admin-

Assessed Using the Concept of “Free-Water Clearance.” Free-

istration of a synthetic analog of ADH, desmopressin,

water clearance (C_H

2O) is calculated as the difference

which acts selectively on V₂ receptors to increase water

between water excretion (urine flow rate) and osmolar

permeability in the late distal and collecting tubules.

clearance:

Desmopressin can be given by injection, as a nasal spray,

or orally, and rapidly restores urine output toward

(Uosm¥V)

CH O=V Cosm=V

normal.

osm

)

Thus, the rate of free-water clearance represents the

Inability of the Kidneys to Respond to ADH: “Nephrogenic”

rate at which solute-free water is excreted by the

Diabetes Insipidus. There are circumstances in which

kidneys. When free-water clearance is positive, excess

normal or elevated levels of ADH are present but the

water is being excreted by the kidneys; when free-water

renal tubular segments cannot respond appropriately.

clearance is negative, excess solutes are being removed

This condition is referred to as “nephrogenic” diabetes

from the blood by the kidneys and water is being

insipidus because the abnormality resides in the

conserved.

kidneys. This abnormality can be due to either failure of

Using the example discussed earlier, if urine flow

the countercurrent mechanism to form a hyperosmotic

rate is

1 ml/min and osmolar clearance is 2 ml/min,

renal medullary interstitium or failure of the distal and

free-water clearance would be -1 ml/min. This means

collecting tubules and collecting ducts to respond to

that instead of water being cleared from the kidneys in

ADH. In either case, large volumes of dilute urine are

excess of solutes, the kidneys are actually returning

formed, which tends to cause dehydration unless fluid

water back to the systemic circulation, as occurs during

intake is increased by the same amount as urine volume

water deficits. Thus, whenever urine osmolarity is greater

is increased.

than plasma osmolarity, free-water clearance will be neg-

Many types of renal diseases can impair the concen-

ative, indicating water conservation.

trating mechanism, especially those that damage the

When the kidneys are forming a dilute urine (that is,

renal medulla. Also, impairment of the function of the

urine osmolarity is less than plasma osmolarity), free-

loop of Henle, as occurs with diuretics that inhibit elec-

water clearance will be a positive value, denoting that

trolyte reabsorption by this segment, can compromise

water is being removed from the plasma by the kidneys

urine concentrating ability. And certain drugs, such as

in excess of solutes. Thus, water free of solutes, called

lithium

(used to treat manic-depressive disorders)

“free water,” is being lost from the body and the plasma

and tetracyclines (used as antibiotics), can impair the

is being concentrated when free-water clearance is

ability of the distal nephron segments to respond to

positive.

ADH.

358

Unit V The Body Fluids and Kidneys

Nephrogenic diabetes insipidus can be distinguished

Although multiple mechanisms control the amount

from central diabetes insipidus by administration of

of sodium and water excretion by the kidneys, two

desmopressin, the synthetic analog of ADH. Lack of a

primary systems are especially involved in regulating

prompt decrease in urine volume and an increase in

the concentration of sodium and osmolarity of extra-

urine osmolarity within

2 hours after injection of

cellular fluid: (1) the osmoreceptor-ADH system and

desmopressin is strongly suggestive of nephrogenic dia-

(2) the thirst mechanism.

betes insipidus. The treatment for nephrogenic diabetes

insipidus is to correct, if possible, the underlying renal

disorder. The hypernatremia can also be attenuated by

Osmoreceptor-ADH

a low-sodium diet and administration of a diuretic that

enhances renal sodium excretion, such as a thiazide

Feedback System

diuretic.

Figure

28-8 shows the basic components of the

osmoreceptor-ADH feedback system for control of

Control of Extracellular Fluid

extracellular fluid sodium concentration and osmolar-

Osmolarity and Sodium

ity. When osmolarity (plasma sodium concentration)

Concentration

increases above normal because of water deficit, for

example, this feedback system operates as follows:

Regulation of extracellular fluid osmolarity and

An increase in extracellular fluid osmolarity

sodium concentration are closely linked because

(which in practical terms means an increase in

sodium is the most abundant ion in the extracellular

plasma sodium concentration) causes the special

compartment. Plasma sodium concentration is nor-

nerve cells called osmoreceptor cells, located in

mally regulated within close limits of 140 to 145 mEq/

the anterior hypothalamus near the supraoptic

L, with an average concentration of about 142 mEq/L.

nuclei, to shrink.

Osmolarity averages about

300 mOsm/L

(about

Shrinkage of the osmoreceptor cells causes them

282 mOsm/L when corrected for interionic attraction)

to fire, sending nerve signals to additional nerve

and seldom changes more than ±2 to 3 per cent. As

cells in the supraoptic nuclei, which then relay

discussed in Chapter 25, these variables must be pre-

cisely controlled because they determine the distribu-

tion of fluid between the intracellular and extracellular

compartments.

Water deficit

Estimating Plasma Osmolarity from

Plasma Sodium Concentration

Extracellular osmolarity

In most clinical laboratories, plasma osmolarity is not

routinely measured. However, because sodium and its

Osmoreceptors

associated anions account for about 94 per cent of the

solute in the extracellular compartment, plasma osmo-

ADH secretion

(posterior pituitary)

larity (P_osm) can be roughly approximated as

P_osm = 2.1

¥ Plasma sodium concentration

For instance, with a plasma sodium concentration of

Plasma ADH

142 mEq/L, the plasma osmolarity would be estimated

from the formula above to be about 298 mOsm/L. To

be more exact, especially in conditions associated with

renal disease, the contribution of two other solutes,

H₂O permeability in

glucose and urea, should be included. Such estimates

distal tubules,

collecting ducts

of plasma osmolarity are usually accurate within a few

percentage points of those measured directly.

Normally, sodium ions and associated anions (pri-

marily bicarbonate and chloride) represent about 94

H₂O reabsorption

per cent of the extracellular osmoles, with glucose and

urea contributing about 3 to 5 per cent of the total

osmoles. However, because urea easily permeates

most cell membranes, it exerts little effective osmotic

H₂O excreted

pressure under steady-state conditions. Therefore, the

sodium ions in the extracellular fluid and associated

anions are the principal determinants of fluid move-

Figure 28-8

ment across the cell membrane. Consequently, we can

Osmoreceptor-antidiuretic hormone (ADH) feedback mechanism

discuss the control of osmolarity and control of sodium

for regulating extracellular fluid osmolarity in response to a water

ion concentration at the same time.

deficit.

Chapter 28

Regulation of Extracellular Fluid Osmolarity and Sodium Concentration

359

these signals down the stalk of the pituitary gland

to the posterior pituitary.

3. These action potentials conducted to the posterior

pituitary stimulate the release of ADH, which is

stored in secretory granules (or vesicles) in the

Pituitary

nerve endings.

4. ADH enters the blood stream and is transported

to the kidneys, where it increases the water

Osmoreceptors

permeability of the late distal tubules, cortical

collecting tubules, and medullary collecting ducts.

Baroreceptors

5. The increased water permeability in the distal

Cardiopulmonary

nephron segments causes increased water

Supraoptic

receptors

reabsorption and excretion of a small volume of

neuron

concentrated urine.

Paraventricular

neuron

Thus, water is conserved in the body while sodium and

other solutes continue to be excreted in the urine. This

lobe

causes dilution of the solutes in the extracellular fluid,

Posterior

lobe

thereby correcting the initial excessively concentrated

extracellular fluid.

The opposite sequence of events occurs when the

extracellular fluid becomes too dilute (hypo-osmotic).

ADH

For example, with excess water ingestion and a

decrease in extracellular fluid osmolarity, less ADH is

formed, the renal tubules decrease their permeability

for water, less water is reabsorbed, and a large volume

of dilute urine is formed. This in turn concentrates the

body fluids and returns plasma osmolarity toward

normal.

ADH Synthesis in Supraoptic and

Urine:

decreased flow

Paraventricular Nuclei of the

and concentrated

Hypothalamus and ADH Release

Figure 28-9

from the Posterior Pituitary

Neuroanatomy of the hypothalamus, where antidiuretic hormone

Figure 28-9 shows the neuroanatomy of the hypothal-

(ADH) is synthesized, and the posterior pituitary gland, where

amus and the pituitary gland, where ADH is synthe-

ADH is released.

sized and released. The hypothalamus contains two

types of magnocellular (large) neurons that synthesize

ADH in the supraoptic and paraventricular nuclei of

anteroventral region of the third ventricle, called the

the hypothalamus, about five sixths in the supraoptic

AV3V region. At the upper part of this region is a

nuclei and about one sixth in the paraventricular

structure called the subfornical organ, and at the infe-

nuclei. Both of these nuclei have axonal extensions to

rior part is another structure called the organum vas-

the posterior pituitary. Once ADH is synthesized, it is

culosum of the lamina terminalis. Between these two

transported down the axons of the neurons to their

organs is the median preoptic nucleus, which has mul-

tips, terminating in the posterior pituitary gland. When

tiple nerve connections with the two organs as well as

the supraoptic and paraventricular nuclei are stimu-

with the supraoptic nuclei and the blood pressure

lated by increased osmolarity or other factors, nerve

control centers in the medulla of the brain. Lesions of

impulses pass down these nerve endings, changing

the AV3V region cause multiple deficits in the control

their membrane permeability and increasing calcium

of ADH secretion, thirst, sodium appetite, and blood

entry. ADH stored in the secretory granules (also

pressure. Electrical stimulation of this region or stim-

called vesicles) of the nerve endings is released in

ulation by angiotensin II can alter ADH secretion,

response to increased calcium entry. The released

thirst, and sodium appetite.

ADH is then carried away in the capillary blood of the

In the vicinity of the AV3V region and the supraop-

posterior pituitary into the systemic circulation.

tic nuclei are neuronal cells that are excited by small

Secretion of ADH in response to an osmotic stimu-

increases in extracellular fluid osmolarity; hence, the

lus is rapid, so that plasma ADH levels can increase

term osmoreceptors has been used to describe these

severalfold within minutes, thereby providing a rapid

neurons. These cells send nerve signals to the supraop-

means for altering renal excretion of water.

tic nuclei to control their firing and secretion of ADH.

A second neuronal area important in controlling

It is also likely that they induce thirst in response to

osmolarity and ADH secretion is located along the

increased extracellular fluid osmolarity.

360

Unit V The Body Fluids and Kidneys

Both the subfornical organ and the organum vascu-

losum of the lamina terminalis have vascular supplies

that lack the typical blood-brain barrier that impedes

Isotonic volume depletion

the diffusion of most ions from the blood into the brain

Isovolemic osmotic increase

tissue. This makes it possible for ions and other solutes

to cross between the blood and the local interstitial

P_AVP = 1.3 e^{-0.17 vol.}

fluid in this region. As a result, the osmoreceptors

rapidly respond to changes in osmolarity of the extra-

cellular fluid, exerting powerful control over the secre-

tion of ADH and over thirst, as discussed later.

Cardiovascular Reflex Stimulation

of ADH Release by Decreased

P_AVP = 2.5 D Osm + 2.0

Arterial Pressure and/or Decreased

Blood Volume

ADH release is also controlled by cardiovascular

reflexes that respond to decreases in blood pressure

and/or blood volume, including (1) the arterial barore-

ceptor reflexes and (2) the cardiopulmonary reflexes,

both of which are discussed in Chapter 18. These reflex

pathways originate in high-pressure regions of the cir-

Per cent change

culation, such as the aortic arch and carotid sinus, and

in the low-pressure regions, especially in the cardiac

atria. Afferent stimuli are carried by the vagus and

glossopharyngeal nerves with synapses in the nuclei of

Figure 28-10

the tractus solitarius. Projections from these nuclei

relay signals to the hypothalamic nuclei that control

The effect of increased plasma osmolarity or decreased blood

ADH synthesis and secretion.

volume on the level of plasma (P) antidiuretic hormone (ADH), also

called arginine vasopressin

(AVP).

(Redrawn from Dunn FL,

Thus, in addition to increased osmolarity, two other

Brennan TJ, Nelson AE, Robertson GL: The role of blood osmo-

stimuli increase ADH secretion: (1) decreased arterial

lality and volume in regulating vasopressin secretion in the rat. J

pressure and (2) decreased blood volume. Whenever

Clin Invest 52(12):3212, 1973. By copyright permission of the

blood pressure and blood volume are reduced, such as

American Society of Clinical Investigation.)

occurs during hemorrhage, increased ADH secretion

causes increased fluid reabsorption by the kidneys,

helping to restore blood pressure and blood volume

Table 28-2

toward normal.

Regulation of ADH Secretion

Increase ADH

Decrease ADH

Quantitative Importance of

Cardiovascular Reflexes and

≠ Plasma osmolarity

Ø Plasma osmolarity

Ø Blood volume

≠ Blood volume

Osmolarity in Stimulating

Ø Blood pressure

≠ Blood pressure

ADH Secretion

Nausea

Hypoxia

As shown in Figure 28-10, either a decrease in effec-

Drugs:

tive blood volume or an increase in extracellular fluid

Morphine

Alcohol

osmolarity stimulates ADH secretion. However, ADH

Nicotine

Clonidine (antihypertensive drug)

is considerably more sensitive to small changes in

Cyclophosphamide

Haloperidol (dopamine blocker)

osmolarity than to similar changes in blood volume.

For example, a change in plasma osmolarity of only

1 per cent is sufficient to increase ADH levels. By

greatly enhances the ADH response to increased

contrast, after blood loss, plasma ADH levels do not

osmolarity.

change appreciably until blood volume is reduced by

about 10 per cent. With further decreases in blood

volume, ADH levels rapidly increase. Thus, with severe

Other Stimuli for ADH Secretion

decreases in blood volume, the cardiovascular reflexes

play a major role in stimulating ADH secretion. The

ADH secretion can also be increased or decreased by

usual day-to-day regulation of ADH secretion during

other stimuli to the central nervous system as well as

simple dehydration is effected mainly by changes in

by various drugs and hormones, as shown in Table

plasma osmolarity. Decreased blood volume, however,

28-2. For example, nausea is a potent stimulus for

Chapter 28

Regulation of Extracellular Fluid Osmolarity and Sodium Concentration

361

ADH release, which may increase to as much as 100

Table 28-3

times normal after vomiting. Also, drugs such as nico-

Control of Thirst

tine and morphine stimulate ADH release, whereas

some drugs, such as alcohol, inhibit ADH release. The

marked diuresis that occurs after ingestion of alcohol

Increase Thirst

Decrease Thirst

is due in part to inhibition of ADH release.

≠ Osmolarity

Ø Osmolarity

Ø Blood volume

≠ Blood volume

Ø Blood pressure

≠ Blood pressure

≠ Angiotensin

Ø Angiotensin II

Role of Thirst in Controlling

Dryness of mouth

Gastric distention

Extracellular Fluid Osmolarity

and Sodium Concentration

The kidneys minimize fluid loss during water deficits

through the osmoreceptor-ADH feedback system.

Adequate fluid intake, however, is necessary to coun-

Decreases in extracellular fluid volume and arterial

terbalance whatever fluid loss does occur through

pressure also stimulate thirst by a pathway that is inde-

sweating and breathing and through the gastrointesti-

pendent of the one stimulated by increased plasma

nal tract. Fluid intake is regulated by the thirst mech-

osmolarity. Thus, blood volume loss by hemorrhage

anism, which, together with the osmoreceptor-ADH

stimulates thirst even though there might be no change

mechanism, maintains precise control of extracellular

in plasma osmolarity. This probably occurs because of

fluid osmolarity and sodium concentration.

neutral input from cardiopulmonary and systemic

Many of the same factors that stimulate ADH secre-

arterial baroreceptors in the circulation.

tion also increase thirst, which is defined as the con-

A third important stimulus for thirst is angiotensin II.

scious desire for water.

Studies in animals have shown that angiotensin II acts

on the subfornical organ and on the organum vascu-

losum of the lamina terminalis. These regions are

Central Nervous System Centers

outside the blood-brain barrier, and peptides such as

for Thirst

angiotensin II diffuse into the tissues. Because

angiotensin II is also stimulated by factors associated

Referring again to Figure 28-9, the same area along

with hypovolemia and low blood pressure, its effect on

the anteroventral wall of the third ventricle that pro-

thirst helps to restore blood volume and blood pres-

motes ADH release also stimulates thirst. Located

sure toward normal, along with the other actions

anterolaterally in the preoptic nucleus is another small

of angiotensin II on the kidneys to decrease fluid

area that, when stimulated electrically, causes immedi-

excretion.

ate drinking that continues as long as the stimulation

Dryness of the mouth and mucous membranes of the

lasts. All these areas together are called the thirst

esophagus can elicit the sensation of thirst. As a result,

center.

a thirsty person may receive relief from thirst almost

The neurons of the thirst center respond to injec-

immediately after drinking water, even though the

tions of hypertonic salt solutions by stimulating drink-

water has not been absorbed from the gastrointestinal

ing behavior. These cells almost certainly function as

tract and has not yet had an effect on extracellular

osmoreceptors to activate the thirst mechanism, in

fluid osmolarity.

the same way that the osmoreceptors stimulate ADH

Gastrointestinal and pharyngeal stimuli influence

release.

thirst. For example, in animals that have an esophageal

Increased osmolarity of the cerebrospinal fluid in

opening to the exterior so that water is never absorbed

the third ventricle has essentially the same effect to

into the blood, partial relief of thirst occurs after

promote drinking. It is likely that the organum vascu-

drinking, although the relief is only temporary. Also,

losum of the lamina terminalis, which lies immediately

gastrointestinal distention may partially alleviate

beneath the ventricular surface at the inferior end of

thirst; for instance, simple inflation of a balloon in the

the AV3V region, is intimately involved in mediating

stomach can relieve thirst. However, relief of thirst

this response.

sensations through gastrointestinal or pharyngeal

mechanisms is short-lived; the desire to drink is com-

pletely satisfied only when plasma osmolarity and/or

Stimuli for Thirst

blood volume returns to normal.

The ability of animals and humans to “meter” fluid

Table 28-3 summarizes some of the known stimuli for

intake is important because it prevents overhydration.

thirst. One of the most important is increased extra-

After a person drinks water, 30 to 60 minutes may be

cellular fluid osmolarity, which causes intracellular

required for the water to be reabsorbed and dis-

dehydration in the thirst centers, thereby stimulating

tributed throughout the body. If the thirst sensation

the sensation of thirst. The value of this response is

were not temporarily relieved after drinking water, the

obvious: it helps to dilute extracellular fluids and

person would continue to drink more and more, even-

returns osmolarity toward normal.

tually leading to overhydration and excess dilution of

362

Unit V The Body Fluids and Kidneys

the body fluids. Experimental studies have repeatedly

shown that animals drink almost exactly the amount

necessary to return plasma osmolarity and volume to

152

normal.

Threshold for Osmolar Stimulus

ADH and

148

thirst

of Drinking

systems

blocked

The kidneys must continually excrete at least some

fluid, even in a dehydrated person, to rid the body of

excess solutes that are ingested or produced by metab-

144

olism. Water is also lost by evaporation from the lungs

and the gastrointestinal tract and by evaporation and

Normal

sweating from the skin. Therefore, there is always a

tendency for dehydration, with resultant increased

140

extracellular fluid sodium concentration and osmolar-

ity. When the sodium concentration increases only

about 2 mEq/L above normal, the thirst mechanism is

activated, causing a desire to drink water. This is called

the threshold for drinking. Thus, even small increases

136

in plasma osmolarity are normally followed by water

120

150

180

intake, which restores extracellular fluid osmolarity

Sodium intake (mEq/day)

and volume toward normal. In this way, the extracel-

lular fluid osmolarity and sodium concentration are

precisely controlled.

Figure 28-11

Effect of large changes in sodium intake on extracellular fluid

Integrated Responses of

sodium concentration in dogs under normal conditions (red line)

and after the antidiuretic hormone (ADH) and thirst feedback

Osmoreceptor-ADH and Thirst

systems had been blocked (blue line). Note that control of extra-

Mechanisms in Controlling

cellular fluid sodium concentration is poor in the absence of these

feedback systems. (Courtesy Dr. David B. Young.)

Extracellular Fluid Osmolarity and

Sodium Concentration

Role of Angiotensin II and

In a healthy person, the osmoreceptor-ADH and thirst

Aldosterone in Controlling

mechanisms work in parallel to precisely regulate

Extracellular Fluid Osmolarity and

extracellular fluid osmolarity and sodium concentra-

Sodium Concentration

tion, despite the constant challenges of dehydration.

Even with additional challenges, such as high salt

As discussed in Chapter 27, both angiotensin II and

intake, these feedback systems are able to keep plasma

aldosterone play an important role in regulating sodium

osmolarity reasonably constant. Figure 28-11 shows

reabsorption by the renal tubules. When sodium intake

that an increase in sodium intake to as high as six times

is low, increased levels of these hormones stimulate

normal has only a small effect on plasma sodium con-

sodium reabsorption by the kidneys and, therefore,

prevent large sodium losses, even though sodium intake

centration as long as the ADH and thirst mechanisms

may be reduced to as low as 10 per cent of normal. Con-

are both functioning normally.

versely, with high sodium intake, decreased formation of

When either the ADH or the thirst mechanism fails,

these hormones permits the kidneys to excrete large

the other ordinarily can still control extracellular

amounts of sodium.

osmolarity and sodium concentration with reasonable

Because of the importance of angiotensin II and

effectiveness, as long as there is enough fluid intake

aldosterone in regulating sodium excretion by the

to balance the daily obligatory urine volume and

kidneys, one might mistakenly infer that they also

water losses caused by respiration, sweating, or

play an important role in regulating extracellular fluid

gastrointestinal losses. However, if both the ADH

sodium concentration. Although these hormones

and thirst mechanisms fail simultaneously, plasma

increase the amount of sodium in the extracellular fluid,

they also increase the extracellular fluid volume by

sodium concentration and osmolarity are very poorly

increasing reabsorption of water along with the sodium.

controlled; thus, when sodium intake is increased

Therefore, angiotensin II and aldosterone have little

after blocking the total ADH-thirst system, relatively

effect on sodium concentration, except under extreme

large changes in plasma sodium concentration do

conditions.

occur. In the absence of the ADH-thirst mechanisms,

This relative unimportance of aldosterone in regulat-

no other feedback mechanism is capable of ad-

ing extracellular fluid sodium concentration is shown by

equately regulating plasma sodium concentration and

the experiment of Figure 28-12. This figure shows the

osmolarity.

effect on plasma sodium concentration of changing

Chapter 28

Regulation of Extracellular Fluid Osmolarity and Sodium Concentration

363

reasons for this is that large losses of sodium eventually

cause severe volume depletion and decreased blood

pressure, which can activate the thirst mechanism

through the cardiovascular reflexes. This leads to a

150

further dilution of the plasma sodium concentration,

Normal

even though the increased water intake helps to mini-

140

mize the decrease in body fluid volumes under these

Aldosterone system blocked

conditions.

130

Thus, there are extreme situations in which plasma

sodium concentration may change significantly, even

120

with a functional ADH-thirst mechanism. Even so, the

ADH-thirst mechanism is by far the most powerful

feedback system in the body for controlling extracellu-

110

lar fluid osmolarity and sodium concentration.

100

120

150

180

210

Salt-Appetite Mechanism

Sodium intake (mEq/L)

for Controlling Extracellular

Fluid Sodium Concentration

and Volume

Figure 28-12

Maintenance of normal extracellular fluid volume and

Effect of large changes in sodium intake on extracellular fluid

sodium concentration requires a balance between

sodium concentration in dogs under normal conditions (red line)

sodium excretion and sodium intake. In modern civi-

and after the aldosterone feedback system had been blocked

lizations, sodium intake is almost always greater than

(blue line). Note that sodium concentration is maintained relatively

necessary for homeostasis. In fact, the average sodium

constant over this wide range of sodium intakes, with or without

intake for individuals in industrialized cultures eating

aldosterone feedback control. (Courtesy Dr. David B. Young.)

processed foods usually ranges between

100 and

200 mEq/day, even though humans can survive and

function normally on 10 to 20 mEq/day. Thus, most

sodium intake more than sixfold under two conditions:

people eat far more sodium than is necessary for home-

(1) under normal conditions and (2) after the aldos-

ostasis, and there is evidence that our usual high sodium

terone feedback system has been blocked by removing

intake may contribute to cardiovascular disorders such

the adrenal glands and infusing the animals with aldos-

as hypertension.

terone at a constant rate so that plasma levels could not

Salt appetite is due in part to the fact that animals and

change upward or downward. Note that when sodium

humans like salt and eat it regardless of whether they

intake was increased sixfold, plasma concentration

are salt-deficient. There is also a regulatory component

changed only about 1 to 2 per cent in either case. This

to salt appetite in which there is a behavioral drive to

indicates that even without a functional aldosterone

obtain salt when there is sodium deficiency in the body.

feedback system, plasma sodium concentration can be

This is particularly important in herbivores, which nat-

well regulated. The same type of experiment has been

urally eat a low-sodium diet, but salt craving may also

conducted after blocking angiotensin II formation, with

be important in humans who have extreme deficiency

the same result.

of sodium, such as occurs in Addison’s disease. In this

There are two primary reasons why changes in

instance, there is deficiency of aldosterone secretion,

angiotensin II and aldosterone do not have a major

which causes excessive loss of sodium in the urine and

effect on plasma sodium concentration. First, as dis-

leads to decreased extracellular fluid volume and

cussed earlier, angiotensin II and aldosterone increase

decreased sodium concentration; both of these changes

both sodium and water reabsorption by the renal

elicit the desire for salt.

tubules, leading to increases in extracellular fluid

In general, the two primary stimuli that are believed to

volume and sodium quantity but little change in sodium

increase salt appetite are (1) decreased extracellular fluid

concentrations. Second, as long as the ADH-thirst mech-

sodium concentration and (2) decreased blood volume

anism is functional, any tendency toward increased

or blood pressure, associated with circulatory insuffi-

plasma sodium concentration is compensated for by

ciency. These are the same major stimuli that elicit thirst.

increased water intake or increased plasma ADH secre-

The neuronal mechanism for salt appetite is analo-

tion, which tends to dilute the extracellular fluid back

gous to that of the thirst mechanism. Some of the same

toward normal. The ADH-thirst system far overshad-

neuronal centers in the AV3V region of the brain seem

ows the angiotensin II and aldosterone systems for reg-

to be involved, because lesions in this region frequently

ulating sodium concentration under normal conditions.

affect both thirst and salt appetite simultaneously in

Even in patients with primary aldosteronism, who have

animals. Also, circulatory reflexes elicited by low blood

extremely high levels of aldosterone, the plasma sodium

pressure or decreased blood volume affect both thirst

concentration usually increases only about 3 to 5 mEq/L

and salt appetite at the same time.

above normal.

Under extreme conditions, caused by complete loss of

aldosterone secretion because of adrenalectomy or in

References

patients with Addison’s disease

(severely impaired

secretion or total lack of aldosterone), there is tremen-

Cowley AW Jr, Mori T, Mattson D, Zou AP: Role of renal

dous loss of sodium by the kidneys, which can lead to

NO production in the regulation of medullary blood flow.

reductions in plasma sodium concentration. One of the

Am J Physiol Regul Integr Comp Physiol 284:R1355, 2003.

364

Unit V The Body Fluids and Kidneys

Dwyer TM, Schmidt-Nielsen B: The renal pelvis: machinery

Pallone TL, Turner MR, Edwards A, Jamison RL: Counter-

that concentrates urine in the papilla. News Physiol Sci

current exchange in the renal medulla. Am J Physiol

18:1, 2003.

Regul Integr Comp Physiol 284:R1153, 2003.

Edwards A, Delong MJ, Pallone TL: Interstitial water and

Robertson GL: Vasopressin. In Seldin DW, Giebisch G (eds):

solute recovery by inner medullary vasa recta. Am J

The Kidney—Physiology and Pathophysiology, 3rd ed.

Physiol Renal Physiol 278:F257, 2000.

New York: Raven Press, 2000.

Fitzsimons JT: Angiotensin, thirst, and sodium appetite.

Sands JM, Layton HE: Urine concentrating mechanism and

Physiol Rev 78:583, 1998.

its regulation. In Seldin DW, Giebisch G

(eds): The

Knepper MA, Saidel GM, Hascall VC, Dwyer T: Concentra-

Kidney—Physiology and Pathophysiology, 3rd ed. New

tion of solutes in the renal inner medulla: interstitial

York: Raven Press, 2000.

hyaluronan as a mechano-osmotic transducer. Am J

Sands JM: Molecular mechanisms of urea transport. J Mem-

Physiol Renal Physiol 284:F433, 2003.

brane Biol 191:149, 2003.

Kozono D, Yasui M, King LS, Agre P: Aquaporin water chan-

Stricker EM, Sved AF: Controls of vasopressin secretion and

nels: atomic structure molecular dynamics meet clinical

thirst: similarities and dissimilarities in signals. Physiol

medicine. J Clin Invest 109:1395, 2002.

Behav 77:731, 2002.

McKinley MJ, Johnson AK: The physiological regulation of

Verbalis JG: Diabetes insipidus. Rev Endocr Metab Disord

thirst and fluid intake. News Physiol Sci 19:1, 2004.

4:177, 2003.

Morello JP, Bichet DG: Nephrogenic diabetes insipidus.

Annu Rev Physiol 63:607, 2001.

Nielsen S, Frokiaer J, Marples D, et al: Aquaporins in the

kidney: from molecules to medicine. Physiol Rev 82:205,

2002.

C H A P T E R

Renal Regulation of Potassium,

Calcium, Phosphate, and

Magnesium; Integration

of Renal Mechanisms for

Control of Blood Volume and

Extracellular Fluid Volume

Regulation of Potassium

Excretion and Potassium

Concentration in

Extracellular Fluid

Extracellular fluid potassium concentration nor-

mally is regulated precisely at about 4.2 mEq/L,

seldom rising or falling more than ± 0.3 mEq/L. This precise control is neces-

sary because many cell functions are very sensitive to changes in extracellular

fluid potassium concentration. For instance, an increase in plasma potassium

concentration of only 3 to 4 mEq/L can cause cardiac arrhythmias, and higher

concentrations can lead to cardiac arrest or fibrillation.

A special difficulty in regulating extracellular potassium concentration is the

fact that over 98 per cent of the total body potassium is contained in the cells

and only 2 per cent in the extracellular fluid (Figure 29-1). For a 70-kilogram

adult, who has about 28 liters of intracellular fluid (40 per cent of body weight)

and 14 liters of extracellular fluid (20 per cent of body weight), about 3920 mil-

liequivalents of potassium are inside the cells and only about 59 milliequiva-

lents are in the extracellular fluid. Also, the potassium contained in a single meal

is often as high as 50 milliequivalents, and the daily intake usually ranges

between 50 and 200 mEq/day; therefore, failure to rapidly rid the extracellular

fluid of the ingested potassium could cause life-threatening hyperkalemia

(increased plasma potassium concentration). Likewise, a small loss of potassium

from the extracellular fluid could cause severe hypokalemia (low plasma potas-

sium concentration) in the absence of rapid and appropriate compensatory

responses.

Maintenance of potassium balance depends primarily on excretion by the

kidneys because the amount excreted in the feces is only about 5 to 10 per cent

of the potassium intake. Thus, the maintenance of normal potassium balance

requires the kidneys to adjust their potassium excretion rapidly and precisely

to wide variations in intake, as is also true for most other electrolytes.

Control of potassium distribution between the extracellular and intracellular

compartments also plays an important role in potassium homeostasis. Because

over 98 per cent of the total body potassium is contained in the cells, they can

serve as an overflow site for excess extracellular fluid potassium during hyper-

kalemia or as a source of potassium during hypokalemia. Thus, redistribution

of potassium between the intra- and extracellular fluid compartments pro-

vides a first line of defense against changes in extracellular fluid potassium

concentration.

365

366

Unit V The Body Fluids and Kidneys

plasma potassium concentration after eating a meal is

K⁺ intake

100 mEq/day

much greater than normal. Injections of insulin,

however, can help to correct the hyperkalemia.

Extracellular

Intracellular

fluid K⁺

Aldosterone Increases Potassium Uptake into Cells. Increased

potassium intake also stimulates secretion of aldos-

terone, which increases cell potassium uptake. Excess

4.2 mEq/L

140 mEq/L

x 14 L

x 28 L

aldosterone secretion

(Conn’s syndrome) is almost

invariably associated with hypokalemia, due in part to

movement of extracellular potassium into the cells.

59 m Eq

3920 mEq

Conversely, patients with deficient aldosterone produc-

tion (Addison’s disease) often have clinically significant

hyperkalemia due to accumulation of potassium in

K⁺ output

the extracellular space as well as to renal retention of

Urine 92 mEq/day

potassium.

Feces 8 mEq/day

100 mEq/day

b-Adrenergic Stimulation Increases Cellular Uptake of Potassium.

Figure 29-1

Increased secretion of catecholamines, especially epi-

nephrine, can cause movement of potassium from the

Normal potassium intake, distribution of potassium in the body

extracellular to the intracellular fluid, mainly by activa-

fluids, and potassium output from the body.

tion of b₂-adrenergic receptors. Treatment of hyperten-

sion with b-adrenergic receptor blockers, such as

propranolol, causes potassium to move out of the cells

and creates a tendency toward hyperkalemia.

Table 29-1

Factors That Can Alter Potassium Distribution Between the

Acid-Base Abnormalities Can Cause Changes in Potassium Distri-

Intra- and Extracellular Fluid

bution. Metabolic acidosis increases extracellular potas-

sium concentration, in part by causing loss of potassium

from the cells, whereas metabolic alkalosis decreases

Factors That Shift K⁺ into Cells

Factors That Shift K⁺ Out of Cells

extracellular fluid potassium concentration. Although

(Decrease Extracellular [K⁺])

(Increase Extracellular [K⁺])

the mechanisms responsible for the effect of hydrogen

• Insulin

• Insulin deficiency (diabetes

ion concentration on potassium internal distribution are

• Aldosterone

mellitus)

not completely understood, one effect of increased

• b-adrenergic stimulation

• Aldosterone deficiency

hydrogen ion concentration is to reduce the activity

• Alkalosis

(Addison’s disease)

of the sodium-potassium adenosine triphosphatase

• b-adrenergic blockade

(ATPase) pump. This in turn decreases cellular uptake

• Acidosis

of potassium and raises extracellular potassium

• Cell lysis

concentration.

• Strenuous exercise

• Increased extracellular fluid

osmolarity

Cell Lysis Causes Increased Extracellular Potassium Concentra-

tion. As cells are destroyed, the large amounts of potas-

sium contained in the cells are released into the

extracellular compartment. This can cause significant

hyperkalemia if large amounts of tissue are destroyed,

Regulation of Internal Potassium

as occurs with severe muscle injury or with red blood

Distribution

cell lysis.

After ingestion of a normal meal, extracellular fluid

Strenuous Exercise Can Cause Hyperkalemia by Releasing Potas-

potassium concentration would rise to a lethal level if

sium from Skeletal Muscle. During prolonged exercise,

the ingested potassium did not rapidly move into the

potassium is released from skeletal muscle into the

cells. For example, absorption of 40 milliequivalents of

extracellular fluid. Usually the hyperkalemia is mild, but

it may be clinically significant after heavy exercise in

potassium (the amount contained in a meal rich in veg-

patients treated with b-adrenergic blockers or in indi-

etables and fruit) into an extracellular fluid volume of

viduals with insulin deficiency. In rare instances, hyper-

14 liters would raise plasma potassium concentration

kalemia after exercise may be severe enough to cause

by about 2.9 mEq/L if all the potassium remained in

cardiac arrhythmias and sudden death.

the extracellular compartment. Fortunately, most of

the ingested potassium rapidly moves into the cells

Increased Extracellular Fluid Osmolarity Causes Redistribution of

until the kidneys can eliminate the excess. Table 29-1

Potassium from the Cells to Extracellular Fluid. Increased

summarizes some of the factors that can influence the

extracellular fluid osmolarity causes osmotic flow of

distribution of potassium between the intra- and extra-

water out of the cells. The cellular dehydration increases

cellular compartments.

intracellular potassium concentration, thereby pro-

moting diffusion of potassium out of the cells and

Insulin Stimulates Potassium Uptake into Cells. One of the

increasing extracellular fluid potassium concentration.

most important factors that increase cell potassium

Decreased extracellular fluid osmolarity has the oppo-

uptake after a meal is insulin. In people who have

site effect. In diabetes mellitus, large increases in plasma

insulin deficiency owing to diabetes mellitus, the rise in

glucose raise extracellular osmolarity, causing cell

Chapter 29

Renal Regulation; Integration of Renal Mechanisms

367

dehydration and movement of potassium from the cells

segments, potassium can at times be reabsorbed or at

into the extracellular fluid.

other times be secreted, depending on the needs of the

body. With a normal potassium intake of 100 mEq/day,

the kidneys must excrete about 92 mEq/day (the

Overview of Renal Potassium

remaining 8 milliequivalents are lost in the feces).

Excretion

About one third (31 mEq/day) of this amount of

potassium is secreted into the distal and collecting

Potassium excretion is determined by the sum of three

tubules.

renal processes: (1) the rate of potassium filtration

With high potassium intakes, the required extra

(GFR multiplied by the plasma potassium concentra-

excretion of potassium is achieved almost entirely by

tion), (2) the rate of potassium reabsorption by the

increasing the secretion of potassium into the distal

tubules, and (3) the rate of potassium secretion by

and collecting tubules. In fact, with extremely high

the tubules. The normal rate of potassium filtration is

potassium diets, the rate of potassium excretion can

about 756 mEq/day (GFR, 180 L/day multiplied by

exceed the amount of potassium in the glomerular fil-

plasma potassium, 4.2 mEq/L); this rate of filtration is

trate, indicating a powerful mechanism for secreting

usually relatively constant because of the autoregula-

potassium.

tory mechanisms for GFR discussed previously and

When potassium intake is reduced below normal,

the precision with which plasma potassium concentra-

the secretion rate of potassium in the distal and

tion is regulated. Severe decreases in GFR in certain

collecting tubules decreases, causing a reduction in

renal diseases, however, can cause serious potassium

urinary potassium secretion. With extreme reductions

accumulation and hyperkalemia.

in potassium intake, there is net reabsorption of potas-

Figure 29-2 summarizes the tubular handling of

sium in the distal segments of the nephron, and potas-

potassium under normal conditions. About 65 per cent

sium excretion can fall to 1 per cent of the potassium

of the filtered potassium is reabsorbed in the proximal

in the glomerular filtrate (to less than 10 mEq/day).

tubule. Another 25 to 30 per cent of the filtered potas-

With potassium intakes below this level, severe

sium is reabsorbed in the loop of Henle, especially in

hypokalemia can develop.

the thick ascending part where potassium is actively

Thus, most of the day-to-day regulation of potas-

co-transported along with sodium and chloride. In

sium excretion occurs in the late distal and cortical

both the proximal tubule and the loop of Henle, a rel-

collecting tubules, where potassium can be either

atively constant fraction of the filtered potassium load

reabsorbed or secreted, depending on the needs of the

is reabsorbed. Changes in potassium reabsorption in

body. In the next section, we consider the basic mech-

these segments can influence potassium excretion, but

anisms of potassium secretion and the factors that reg-

most of the day-to-day variation of potassium excre-

ulate this process.

tion is not due to changes in reabsorption in the prox-

imal tubule or loop of Henle.

Potassium Secretion by Principal

Most Daily Variation in Potassium Excretion Is Caused by

Cells of Late Distal and Cortical

Changes in Potassium Secretion in Distal and Collecting

Collecting Tubules

Tubules. The most important sites for regulating potas-

sium excretion are the principal cells of the late distal

The cells in the late distal and cortical collecting

tubules and cortical collecting tubules. In these tubular

tubules that secrete potassium are called principal cells

65%

(491 mEq/day)

(31 mEq/day)

756 mEq/day

(180 L/day x 4.2 mEq/L)

27%

Figure 29-2

(204 mEq/day)

Renal tubular sites of potassium reabsorp-

tion and secretion. Potassium is reab-

sorbed in the proximal tubule and in the

ascending loop of Henle, so that only about

8 per cent of the filtered load is delivered to

the distal tubule. Secretion of potassium

into the late distal tubules and collecting

ducts adds to the amount delivered, so that

the daily excretion is about 12 per cent of

the potassium filtered at the glomerular

capillaries. The percentages indicate how

much of the filtered load is reabsorbed or

secreted into the different tubular seg-

12%

ments.

(92 mEq/day)

368

Unit V The Body Fluids and Kidneys

Renal

Principal

Tubular

reabsorption occurs through the intercalated cells;

interstitial

cells

lumen

although this reabsorptive process is not completely

fluid

understood, one mechanism believed to contribute

is a hydrogen-potassium ATPase transport mechanism

located in the luminal membrane. This transporter reab-

Na⁺

sorbs potassium in exchange for hydrogen ions secreted

into the tubular lumen, and the potassium then diffuses

Na⁺

through the basolateral membrane of the cell into the

ATP

blood. This transporter is necessary to allow potassium

K⁺

reabsorption during extracellular fluid potassium deple-

tion, but under normal conditions it plays a small role

in controlling the excretion of potassium.

K⁺

Summary of Factors That Regulate

Potassium Secretion: Plasma

0 mV

-70 mV

-50 mV

Potassium Concentration,

Aldosterone, Tubular Flow Rate, and

Figure 29-3

Hydrogen Ion Concentration

Mechanisms of potassium secretion and sodium reabsorption by

Because normal regulation of potassium excretion

the principal cells of the late distal and collecting tubules.

occurs mainly as a result of changes in potassium

secretion by the principal cells of the late distal and

collecting tubules, we will discuss the primary factors

and make up about 90 per cent of the epithelial cells

that influence secretion by these cells. The most impor-

in these regions. Figure 29-3 shows the basic cellular

tant factors that stimulate potassium secretion by the

mechanisms of potassium secretion by the principal

principal cells include (1) increased extracellular fluid

cells.

potassium concentration, (2) increased aldosterone,

Secretion of potassium from the blood into the

and (3) increased tubular flow rate.

tubular lumen is a two-step process, beginning with

One factor that decreases potassium secretion is

uptake from the interstitium into the cell by the

increased hydrogen ion concentration (acidosis).

sodium-potassium ATPase pump in the basolateral

membrane of the cell; this pump moves sodium out of

Increased Extracellular Fluid Potassium Concentration Stimu-

the cell into the interstitium and at the same time

lates Potassium Secretion. The rate of potassium secre-

moves potassium to the interior of the cell. The second

tion in the late distal and cortical collecting tubules is

step of the process is passive diffusion of potassium

directly stimulated by increased extracellular fluid

from the interior of the cell into the tubular fluid. The

potassium concentration, leading to increases in potas-

sodium-potassium ATPase pump creates a high intra-

sium excretion, as shown in Figure 29-4. This effect

cellular potassium concentration, which provides the

is especially pronounced when extracellular fluid

driving force for passive diffusion of potassium from

potassium concentration rises above about 4.1 mEq/L,

the cell into the tubular lumen. The luminal membrane

slightly less than the normal concentration. Increased

of the principal cells is highly permeable to potassium.

plasma potassium concentration, therefore, serves as

One reason for this high permeability is that there are

one of the most important mechanisms for increasing

special channels that are specifically permeable to

potassium secretion and regulating extracellular fluid

potassium ions, thus allowing these ions to diffuse

potassium ion concentration.

across the membrane.

There are three mechanisms by which increased

extracellular fluid potassium concentration raises

Control of Potassium Secretion by Principal Cells. The

potassium secretion: (1) Increased extracellular fluid

primary factors that control potassium secretion by the

potassium concentration stimulates the sodium-

principal cells of the late distal and cortical collecting

potassium ATPase pump, thereby increasing potas-

tubules are (1) the activity of the sodium-potassium

sium uptake across the basolateral membrane. This in

ATPase pump, (2) the electrochemical gradient for

turn increases intracellular potassium ion concentra-

potassium secretion from the blood to the tubular

tion, causing potassium to diffuse across the luminal

lumen, and (3) the permeability of the luminal mem-

membrane into the tubule. (2) Increased extracellular

brane for potassium. These three determinants of

potassium concentration increases the potassium gra-

potassium secretion are in turn regulated by the

dient from the renal interstitial fluid to the interior of

factors discussed later.

the epithelial cell; this reduces backleakage of potas-

sium ions from inside the cells through the basolateral

Intercalated Cells Can Reabsorb Potassium During Potassium

membrane. (3) Increased potassium concentration

Depletion. In circumstances associated with severe

potassium depletion, there is a cessation of potassium

stimulates aldosterone secretion by the adrenal cortex,

secretion and actually a net reabsorption of potas-

which further stimulates potassium secretion, as dis-

sium in the late distal and collecting tubules. This

cussed next.

Chapter 29

Renal Regulation; Integration of Renal Mechanisms

369

Effect of aldosterone

Effect of extracellular

K⁺ concentration

3.0

3.5

4.0

4.5

5.0

5.5

6.0

6.5

Serum potassium concentration (mEq/L)

Plasma aldosterone (times normal)

Extracellular potassium concentration

(mEq/L)

Figure 29-5

Effect of extracellular fluid potassium ion concentration on plasma

aldosterone concentration. Note that small changes in potassium

Figure 29-4

concentration cause large changes in aldosterone concentration.

Effect of plasma aldosterone concentration (red line) and extra-

cellular potassium ion concentration (black line) on the rate of

urinary potassium excretion. These factors stimulate potassium

secretion by the principal cells of the cortical collecting tubules.

(Drawn from data in Young DB, Paulsen AW: Interrelated effects

Ald.

of aldosterone and plasma potassium on potassium excretion. Am

J Physiol 244:F28, 1983.)

K⁺

concentration

K⁺

Aldosterone Stimulates Potassium Secretion. In Chapter 27,

Aldosterone

we discuss the fact that aldosterone stimulates active

concentration

reabsorption of sodium ions by the principal cells of

K⁺ excretion

the late distal tubules and collecting ducts. This effect

is mediated through a sodium-potassium ATPase

K⁺

excretion

pump that transports sodium outward through the

Ald.

basolateral membrane of the cell and into the blood at

the same time that it pumps potassium into the cell.

K⁺intake

Thus, aldosterone also has a powerful effect to control

the rate at which the principal cells secrete potassium.

A second effect of aldosterone is to increase the per-

Figure 29-6

meability of the luminal membrane for potassium,

further adding to the effectiveness of aldosterone in

Basic feedback mechanism for control of extracellular fluid potas-

stimulating potassium secretion. Therefore, aldos-

sium concentration by aldosterone (Ald.).

terone has a powerful effect to increase potassium

excretion, as shown in Figure 29-4.

The effect of potassium ion concentration to stimu-

Increased Extracellular Potassium Ion Concentration Stimu-

late aldosterone secretion is part of a powerful feed-

lates Aldosterone Secretion. In negative feedback control

back system for regulating potassium excretion, as

systems, the factor that is controlled usually has a

shown in Figure 29-6. In this feedback system, an

feedback effect on the controller. In the case of the

increase in plasma potassium concentration stimulates

aldosterone-potassium control system, the rate of

aldosterone secretion and, therefore, increases the

aldosterone secretion by the adrenal gland is con-

blood level of aldosterone (block 1). The increase in

trolled strongly by extracellular fluid potassium ion

blood aldosterone then causes a marked increase in

concentration. Figure 29-5 shows that an increase in

potassium excretion by the kidneys (block 2). The

plasma potassium concentration of about 3 mEq/L can

increased potassium excretion then reduces the extra-

increase plasma aldosterone concentration from

cellular fluid potassium concentration back toward

nearly 0 to as high as 60 ng/100 ml, a concentration

normal (blocks 3 and 4). Thus, this feedback mecha-

almost 10 times normal.

nism acts synergistically with the direct effect of

370

Unit V The Body Fluids and Kidneys

K⁺ intake

4.8

Plasma K⁺

4.6

concentration

Aldosterone

4.4

K+ secretion

Normal

Cortical collecting

tubules

4.2

Aldosterone

4.0

system

blocked

K⁺ excretion

3.8

Figure 29-7

120

150

180

210

Primary mechanisms by which high potassium intake raises

Potassium intake (mEq/day)

potassium excretion. Note that increased plasma potassium con-

centration directly raises potassium secretion by the cortical col-

lecting tubules and indirectly increases potassium secretion by

raising plasma aldosterone concentration.

Figure 29-8

Effect of large changes in potassium intake on extracellular fluid

potassium concentration under normal conditions (red line) and

increased extracellular potassium concentration to

after the aldosterone feedback had been blocked (blue line). Note

elevate potassium excretion when potassium intake is

that after blockade of the aldosterone system, regulation of potas-

raised (Figure 29-7).

sium concentration was greatly impaired. (Courtesy Dr. David B.

Young.)

Blockade of Aldosterone Feedback System Greatly Impairs

Control of Potassium Concentration. In the absence of

aldosterone secretion, as occurs in patients with

impairment of potassium regulation is observed in

Addison’s disease, renal secretion of potassium is

humans with poorly functioning aldosterone feedback

impaired, thus causing extracellular fluid potassium

systems, such as occurs in patients with either primary

concentration to rise to dangerously high levels. Con-

aldosteronism (too much aldosterone) or Addison’s

versely, with excess aldosterone secretion (primary

disease (too little aldosterone).

aldosteronism), potassium secretion becomes greatly

increased, causing potassium loss by the kidneys and

Increased Distal Tubular Flow Rate Stimulates Potassium

thus leading to hypokalemia.

Secretion. A rise in distal tubular flow rate, as occurs

The special quantitative importance of the aldos-

with volume expansion, high sodium intake, or diuretic

terone feedback system in controlling potassium con-

drug treatment, stimulates potassium secretion. Con-

centration is shown in Figure 29-8. In this experiment,

versely, a decrease in distal tubular flow rate, as caused

potassium intake was increased almost sevenfold in

by sodium depletion, reduces potassium secretion.

dogs under two conditions: (1) under normal condi-

The mechanism for the effect of high-volume flow

tions and (2) after the aldosterone feedback system

rate is as follows: When potassium is secreted into the

had been blocked by removing the adrenal glands and

tubular fluid, the luminal concentration of potassium

placing the animals on a fixed rate of aldosterone infu-

increases, thereby reducing the driving force for potas-

sion so that plasma aldosterone concentration could

sium diffusion across the luminal membrane. With

neither increase nor decrease.

increased tubular flow rate, the secreted potassium is

Note that in the normal animals, a sevenfold

continuously flushed down the tubule, so that the rise

increase in potassium intake caused only a slight in-

in tubular potassium concentration becomes mini-

crease in potassium concentration, from 4.2 to 4.3 mEq/

mized. Therefore, net potassium secretion is stimu-

L. Thus, when the aldosterone feedback system is

lated by increased tubular flow rate.

functioning normally, potassium concentration is pre-

The effect of increased tubular flow rate is especially

cisely controlled, despite large changes in potassium

important in helping to preserve normal potassium

intake.

excretion during changes in sodium intake. For

When the aldosterone feedback system was

example, with a high sodium intake, there is decreased

blocked, the same increases in potassium intake

aldosterone secretion, which by itself would tend to

caused a much larger increase in potassium concen-

decrease the rate of potassium secretion and, there-

tration, from 3.8 to almost 4.7 mEq/L. Thus, control of

fore, reduce urinary excretion of potassium. However,

potassium concentration is greatly impaired when the

the high distal tubular flow rate that occurs with a high

aldosterone feedback system is blocked. A similar

sodium intake tends to increase potassium secretion

Chapter 29

Renal Regulation; Integration of Renal Mechanisms

371

to a loss of potassium, whereas acute acidosis leads to

Na⁺ intake

decreased potassium excretion.

Proximal

Control of Renal Calcium

Aldosterone

GFR

tubular Na⁺

reabsorption

Excretion and Extracellular

Calcium Ion Concentration

Distal tubular

The mechanisms for regulating calcium ion concen-

flow rate

tration are discussed in detail in Chapter 79, along with

the endocrinology of the calcium-regulating hormones

parathyroid hormone (PTH) and calcitonin. There-

K+ secretion

fore, calcium ion regulation is discussed only briefly in

Cortical collecting

this chapter.

ducts

Extracellular fluid calcium ion concentration

normally remains tightly controlled within a few

percentage points of its normal level,

2.4 mEq/L.

When calcium ion concentration falls to low levels

Unchanged K⁺

excretion

(hypocalcemia), the excitability of nerve and muscle

cells increases markedly and can in extreme cases

result in hypocalcemic tetany. This is characterized by

Figure 29-9

spastic skeletal muscle contractions. Hypercalcemia

Effect of high sodium intake on renal excretion of potassium. Note

(increased calcium concentration) depresses neuromus-

that a high-sodium diet decreases plasma aldosterone, which

cular excitability and can lead to cardiac arrhythmias.

tends to decrease potassium secretion by the cortical collecting

About 50 per cent of the total calcium in the plasma

tubules. However, the high-sodium diet simultaneously increases

(5 mEq/L) exists in the ionized form, which is the form

fluid delivery to the cortical collecting duct, which tends to

that has biological activity at cell membranes. The

increase potassium secretion. The opposing effects of a high-

sodium diet counterbalance each other, so that there is little

remainder is either bound to the plasma proteins

change in potassium excretion.

(about 40 per cent) or complexed in the non-ionized

form with anions such as phosphate and citrate (about

10 per cent).

(Figure 29-9), as discussed in the previous paragraph.

Changes in plasma hydrogen ion concentration can

Therefore, the two effects of high sodium intake,

influence the degree of calcium binding to plasma pro-

decreased aldosterone secretion and the high tubular

teins. With acidosis, less calcium is bound to the plasma

flow rate, counterbalance each other, so that there is

proteins. Conversely, in alkalosis, a greater amount of

little change in potassium excretion. Likewise, with a

calcium is bound to the plasma proteins. Therefore,

low sodium intake, there is little change in potassium

patients with alkalosis are more susceptible to hypocal-

excretion because of the counterbalancing effects of

cemic tetany.

increased aldosterone secretion and decreased tubular

As with other substances in the body, the intake of

flow rate on potassium secretion.

calcium must be balanced with the net loss of calcium

over the long term. Unlike ions such as sodium and

Acute Acidosis Decreases Potassium Secretion. Acute

chloride, however, a large share of calcium excretion

increases in hydrogen ion concentration of the extra-

occurs in the feces. The usual rate of dietary calcium

cellular fluid

(acidosis) reduce potassium secretion,

intake is about 1000 mg/day, with about 900 mg/day of

whereas decreased hydrogen ion concentration (alka-

calcium excreted in the feces. Under certain condi-

losis) increases potassium secretion. The primary

tions, fecal calcium excretion can exceed calcium

mechanism by which increased hydrogen ion concen-

ingestion because calcium can also be secreted into

tration inhibits potassium secretion is by reducing the

the intestinal lumen. Therefore, the gastrointestinal

activity of the sodium-potassium ATPase pump. This

tract and the regulatory mechanisms that influence

in turn decreases intracellular potassium concentra-

intestinal calcium absorption and secretion play a

tion and subsequent passive diffusion of potassium

major role in calcium homeostasis, as discussed in

across the luminal membrane into the tubule.

Chapter 79.

Almost all the calcium in the body (99 per cent) is

With more prolonged acidosis, lasting over a period of

stored in the bone, with only about 1 per cent in the

several days, there is an increase in urinary potassium

extracellular fluid and 0.1 per cent in the intracellular

excretion. The mechanism for this effect is due in part

fluid. The bone, therefore, acts as a large reservoir

to an effect of chronic acidosis to inhibit proximal

for storing calcium and as a source of calcium when

tubular sodium chloride and water reabsorption, which

extracellular fluid calcium concentration tends to

increases distal volume delivery, thereby stimulating

the secretion of potassium. This effect overrides

decrease.

the inhibitory effect of hydrogen ions on the sodium-

One of the most important regulators of bone uptake

potassium ATPase pump. Thus, chronic acidosis leads

and release of calcium is PTH. When extracellular fluid

372

Unit V The Body Fluids and Kidneys

proteins or complexed with anions such as phosphate.

[Ca⁺⁺]

Therefore, only about

50 per cent of the plasma

calcium can be filtered at the glomerulus. Normally,

about 99 per cent of the filtered calcium is reabsorbed

by the tubules, with only about 1 per cent of the fil-

Vitamin D₃

PTH

tered calcium being excreted. About 65 per cent of the

activation

filtered calcium is reabsorbed in the proximal tubule,

25 to 30 per cent is reabsorbed in the loop of Henle,

and 4 to 9 per cent is reabsorbed in the distal and col-

lecting tubules. This pattern of reabsorption is similar

Intestinal Ca⁺⁺

Renal Ca⁺⁺

Ca⁺⁺release

reabsorption

from bones

to that for sodium.

As is true with the other ions, calcium excretion is

adjusted to meet the body’s needs. With an increase in

Figure 29-10

calcium intake, there is also increased renal calcium

Compensatory responses to decreased plasma ionized calcium

excretion, although much of the increase of calcium

concentration mediated by parathyroid hormone

(PTH) and

intake is eliminated in the feces. With calcium deple-

vitamin D.

tion, calcium excretion by the kidneys decreases as a

result of enhanced tubular reabsorption.

One of the primary controllers of renal tubular

calcium concentration falls below normal, the parathy-

calcium reabsorption is PTH. With increased levels of

roid glands are directly stimulated by the low calcium

PTH, there is increased calcium reabsorption in the

levels to promote increased secretion of PTH. This

thick ascending loops of Henle and distal tubules,

hormone then acts directly on the bones to increase

which reduces urinary excretion of calcium. Con-

the resorption of bone salts (release of salts from the

versely, reduction of PTH promotes calcium excretion

bones) and, therefore, to release large amounts of

by decreasing reabsorption in the loops of Henle and

calcium into the extracellular fluid, thereby returning

distal tubules.

calcium levels back toward normal. When calcium ion

In the proximal tubule, calcium reabsorption usually

concentration is elevated, PTH secretion decreases, so

parallels sodium and water reabsorption. Therefore,

that almost no bone resorption now occurs; instead,

in instances of extracellular volume expansion or

excess calcium is deposited in the bones because of

increased arterial pressure—both of which decrease

new bone formation. Thus, the day-to-day regulation

proximal sodium and water reabsorption—there is

of calcium ion concentration is mediated in large part

also reduction in calcium reabsorption and, con-

by the effect of PTH on bone resorption.

sequently, increased urinary excretion of calcium.

The bones, however, do not have an inexhaustible

Conversely, with extracellular volume contraction or

supply of calcium. Therefore, over the long term, the

decreased blood pressure, calcium excretion decreases

intake of calcium must be balanced with calcium

primarily because of increased proximal tubular

excretion by the gastrointestinal tract and the kidneys.

reabsorption.

The most important regulator of calcium reabsorption

Another factor that influences calcium reabsorption

at both of these sites is PTH. Thus, PTH regulates

is the plasma concentration of phosphate. An increase

plasma calcium concentration through three main

in plasma phosphate stimulates PTH, which increases

effects: (1) by stimulating bone resorption; (2) by stim-

calcium reabsorption by the renal tubules, thereby

ulating activation of vitamin D, which then increases

reducing calcium excretion. The opposite occurs with

intestinal reabsorption of calcium; and (3) by directly

reduction in plasma phosphate concentration.

increasing renal tubular calcium reabsorption (Figure

Calcium reabsorption is also stimulated by meta-

29-10). The control of gastrointestinal calcium reab-

bolic acidosis and inhibited by metabolic alkalosis.

sorption and calcium exchange in the bones is dis-

Most of the effect of hydrogen ion concentration on

cussed elsewhere, and the remainder of this section

calcium excretion results from changes in calcium

focuses on the mechanisms that control renal calcium

reabsorption in the distal tubule.

excretion.

A summary of the factors that are known to influ-

ence calcium excretion by the renal tubules is shown

in Table 29-2.

Control of Calcium Excretion

by the Kidneys

Regulation of Renal Phosphate

Because calcium is both filtered and reabsorbed in the

Excretion

kidneys but not secreted, the rate of renal calcium

excretion is calculated as

Phosphate excretion by the kidneys is controlled

primarily by an overflow mechanism that can be

Renal calcium excretion = Calcium filtered

explained as follows: The renal tubules have a normal

- Calcium reabsorbed

transport maximum for reabsorbing phosphate of

Only about 50 per cent of the plasma calcium is

about

0.1 mM/min. When less than this amount

ionized, with the remainder being bound to the plasma

of phosphate is present in the glomerular filtrate,

Chapter 29

Renal Regulation; Integration of Renal Mechanisms

373

normally excrete about 10 to 15 per cent of the mag-

Table 29-2

nesium in the glomerular filtrate.

Factors That Alter Renal Calcium Excretion

Renal excretion of magnesium can increase

markedly during magnesium excess or can decrease to

Ø Calcium Excretion

≠ Calcium Excretion

almost nil during magnesium depletion. Because mag-

nesium is involved in many biochemical processes in

≠ Parathyroid hormone (PTH)

Ø PTH

Ø Extracellular fluid volume

≠ Extracellular fluid volume

the body, including activation of many enzymes, its

Ø Blood pressure

≠ Blood pressure

concentration must be closely regulated.

≠ Plasma phosphate

Ø Plasma phosphate

Regulation of magnesium excretion is achieved

Metabolic acidosis

Metabolic alkalosis

mainly by changing tubular reabsorption. The proxi-

Vitamin D

mal tubule usually reabsorbs only about 25 per cent of

the filtered magnesium. The primary site of reabsorp-

tion is the loop of Henle, where about 65 per cent of

the filtered load of magnesium is reabsorbed. Only a

essentially all the filtered phosphate is reabsorbed.

small amount (usually less than 5 per cent) of the

When more than this is present, the excess is excreted.

filtered magnesium is reabsorbed in the distal and

Therefore, phosphate normally begins to spill into the

collecting tubules.

urine when its concentration in the extracellular fluid

The mechanisms that regulate magnesium excretion

rises above a threshold of about 0.8 mM/L, which gives

are not well understood, but the following distur-

a tubular load of phosphate of about 0.1 mM/min,

bances lead to increased magnesium excretion: (1)

assuming a GFR of 125 ml/min. Because most people

increased extracellular fluid magnesium concentra-

ingest large quantities of phosphate in milk products

tion,

(2) extracellular volume expansion, and

(3)

and meat, the concentration of phosphate is usually

increased extracellular fluid calcium concentration.

maintained above 1 mM/L, a level at which there is

continual excretion of phosphate into the urine.

Changes in tubular phosphate reabsorption can also

Integration of Renal

influence phosphate excretion. For instance, a diet low

in phosphate can, over time, increase the reabsorptive

Mechanisms for Control

transport maximum for phosphate, thereby reducing

of Extracellular Fluid

the tendency for phosphate to spill over into the urine.

PTH can play a significant role in regulating phos-

Extracellular fluid volume is determined mainly by the

phate concentration through two effects: (1) PTH

balance between intake and output of water and salt.

promotes bone resorption, thereby dumping large

In most cases, salt and fluid intakes are dictated by a

amounts of phosphate ions into the extracellular fluid

person’s habits rather than by physiologic control

from the bone salts, and (2) PTH decreases the trans-

mechanisms. Therefore, the burden of extracellular

port maximum for phosphate by the renal tubules,

volume regulation is usually placed on the kidneys,

so that a greater proportion of the tubular phosphate

which must adapt their excretion of salt and water to

is lost in the urine. Thus, whenever plasma PTH is

match intake of salt and water under steady-state

increased, tubular phosphate reabsorption is decreased

conditions.

and more phosphate is excreted. These interrelations

In discussing the regulation of extracellular fluid

among phosphate, PTH, and calcium are discussed in

volume, we also consider the factors that regulate the

more detail in Chapter 79.

amount of sodium chloride in the extracellular fluid,

because changes in extracellular fluid sodium chloride

content usually cause parallel changes in extracellular

Control of Renal Magnesium

fluid volume, provided the antidiuretic hormone

Excretion and Extracellular

(ADH)-thirst mechanisms are also operative. When

the ADH-thirst mechanisms are functioning normally,

Magnesium Ion Concentration

a change in the amount of sodium chloride in the

extracellular fluid is matched by a similar change in

More than one half of the body’s magnesium is stored

the amount of extracellular water, so that osmolality

in the bones. Most of the rest resides within the cells,

and sodium concentration are maintained relatively

with less than 1 per cent located in the extracellular

constant.

fluid. Although the total plasma magnesium concen-

tration is about 1.8 mEq/L, more than one half of this

is bound to plasma proteins. Therefore, the free

Sodium Excretion Is Precisely

ionized concentration of magnesium is only about

0.8 mEq/L.

Matched to Intake Under Steady-State

The normal daily intake of magnesium is about 250

Conditions

to 300 mg/day, but only about one half of this intake is

absorbed by the gastrointestinal tract. To maintain

An important consideration in overall control of

magnesium balance, the kidneys must excrete this

sodium excretion—or excretion of any electrolyte, for

absorbed magnesium, about one half the daily intake

that matter—is that under steady-state conditions,

of magnesium, or 125 to 150 mg/day. The kidneys

excretion by the kidneys is determined by intake. To

374

Unit V The Body Fluids and Kidneys

maintain life, a person must, over the long term,

compensations: (1) increased tubular reabsorption of

excrete almost precisely the amount of sodium

much of the extra sodium chloride filtered, called

ingested. Therefore, even with disturbances that cause

glomerulotubular balance, and (2) macula densa feed-

major changes in kidney function, balance between

back, in which increased sodium chloride delivery to

intake and output of sodium usually is restored within

the distal tubule causes afferent arteriolar constriction

a few days.

and return of GFR toward normal. Likewise, abnor-

If disturbances of kidney function are not too

malities of tubular reabsorption in the proximal tubule

severe, sodium balance may be achieved mainly by

or loop of Henle are partially compensated for by

intrarenal adjustments with minimal changes in extra-

these same intrarenal feedbacks.

cellular fluid volume or other systemic adjustments.

Because neither of these two mechanisms operates

But when perturbations to the kidneys are severe and

perfectly to restore distal sodium chloride delivery all

intrarenal compensations are exhausted, systemic

the way back to normal, changes in either GFR or

adjustments must be invoked, such as changes in blood

tubular reabsorption can lead to significant changes in

pressure, changes in circulating hormones, and alter-

urine sodium and water excretion. When this happens,

ations of sympathetic nervous system activity. These

other feedback mechanisms come into play, such as

adjustments are costly in terms of overall homeostasis

changes in blood pressure and changes in various

because they cause other changes throughout the

hormones, that eventually return sodium excretion to

body that may, in the long run, be damaging. These

equal sodium intake. In the next few sections, we

compensations, however, are necessary because a

review how these mechanisms operate together to

sustained imbalance between fluid and electrolyte

control sodium and water balance and in so doing act

intake and excretion would quickly lead to accumula-

also to control extracellular fluid volume. We should

tion or loss of electrolytes and fluid, causing cardio-

keep in mind, however, that all these feedback mech-

vascular collapse within a few days. Thus, one can view

anisms control renal excretion of sodium and water by

the systemic adjustments that occur in response to

altering either GFR or tubular reabsorption.

abnormalities of kidney function as a necessary trade-

off that brings electrolyte and fluid excretion back in

balance with intake.

Importance of Pressure

Natriuresis and Pressure

Diuresis in Maintaining Body

Sodium Excretion Is Controlled by

Sodium and Fluid Balance

Altering Glomerular Filtration or

Tubular Sodium Reabsorption Rates

One of the most basic and powerful mechanisms for

control of blood volume and extracellular fluid

The two variables that influence sodium and water

volume, as well as for the maintenance of sodium and

excretion are the rates of filtration and the rates of

fluid balance, is the effect of blood pressure on sodium

reabsorption:

and water excretion—called the pressure natriuresis

and pressure diuresis mechanisms, respectively. As

Excretion = Glomerular filtration - Tubular

discussed in Chapter 19, this feedback between the

reabsorption

kidneys and the circulatory system also plays a domi-

GFR normally is about 180 L/day, tubular reab-

nant role in long-term blood pressure regulation.

sorption is

178.5 L/day, and urine excretion is 1.5

Pressure diuresis refers to the effect of increased

L/day. Thus, small changes in GFR or tubular reab-

blood pressure to raise urinary volume excretion,

sorption potentially can cause large changes in renal

whereas pressure natriuresis refers to the rise in

excretion. For example, a 5 per cent increase in GFR

sodium excretion that occurs with elevated blood pres-

(to 189 L/day) would cause a 9 L/day increase in urine

sure. Because pressure diuresis and natriuresis usually

volume, if tubular compensations did not occur; this

occur in parallel, we refer to these mechanisms simply

would quickly cause catastrophic changes in body fluid

as “pressure natriuresis” in the following discussion.

volumes. Similarly, small changes in tubular reabsorp-

Figure 29-11 shows the effect of arterial pressure on

tion, in the absence of compensatory adjustments of

urinary sodium output. Note that acute increases in

GFR, would also lead to dramatic changes in urine

blood pressure of 30 to 50 mm Hg cause a twofold to

volume and sodium excretion. Tubular reabsorption

threefold increase in urinary sodium output. This

and GFR usually are regulated precisely, so that excre-

effect is independent of changes in activity of the sym-

tion by the kidneys can be exactly matched to intake

pathetic nervous system or of various hormones, such

of water and electrolytes.

as angiotensin II, ADH, or aldosterone, because pres-

Even with disturbances that alter GFR or tubular

sure natriuresis can be demonstrated in an isolated

reabsorption, changes in urinary excretion are mini-

kidney that has been removed from the influence of

mized by various buffering mechanisms. For example,

these factors. With chronic increases in blood pressure,

if the kidneys become greatly vasodilated and GFR

the effectiveness of pressure natriuresis is greatly

increases (as can occur with certain drugs or high

enhanced because the increased blood pressure also,

fever), this raises sodium chloride delivery to the

after a short time delay, suppresses renin release and,

tubules, which in turn leads to at least two intrarenal

therefore, decreases formation of angiotensin II and

Chapter 29

Renal Regulation; Integration of Renal Mechanisms

375

aldosterone. As discussed previously, decreased levels

ates to maintain balance between fluid intake and

of angiotensin II and aldosterone inhibit renal tubular

output, as shown in Figure 29-12. This is the same

reabsorption of sodium, thereby amplifying the direct

mechanism that is discussed in Chapter 19 for arterial

effects of increased blood pressure to raise sodium and

pressure control. The extracellular fluid volume, blood

water excretion.

volume, cardiac output, arterial pressure, and urine

output are all controlled at the same time as separate

parts of this basic feedback mechanism.

Pressure Natriuresis and Diuresis Are

During changes in sodium and fluid intake, this feed-

Key Components of a Renal-Body

back mechanism helps to maintain fluid balance and

to minimize changes in blood volume, extracellular

Fluid Feedback for Regulating Body

fluid volume, and arterial pressure as follows:

Fluid Volumes and Arterial Pressure

An increase in fluid intake (assuming that sodium

accompanies the fluid intake) above the level of

The effect of increased blood pressure to raise urine

urine output causes a temporary accumulation of

output is part of a powerful feedback system that oper-

fluid in the body.

As long as fluid intake exceeds urine output, fluid

accumulates in the blood and interstitial spaces,

causing parallel increases in blood volume and

extracellular fluid volume. As discussed later, the

actual increases in these variables are usually

Chronic

small because of the effectiveness of this

Acute

feedback.

An increase in blood volume raises mean

circulatory filling pressure.

An increase in mean circulatory filling pressure

raises the pressure gradient for venous return.

An increased pressure gradient for venous return

elevates cardiac output.

An increased cardiac output raises arterial

80 100 120 140 160 180 200

pressure.

Arterial pressure (mm Hg)

An increased arterial pressure increases urine

output by way of pressure diuresis. The steepness

of the normal pressure natriuresis relation

Figure 29-11

indicates that only a slight increase in blood

pressure is required to raise urinary excretion

Acute and chronic effects of arterial pressure on sodium output

severalfold.

by the kidneys (pressure natriuresis). Note that chronic increases

The increased fluid excretion balances the

in arterial pressure cause much greater increases in sodium

output than those measured during acute increases in arterial

increased intake, and further accumulation of fluid

pressure.

is prevented.

Nonrenal

Fluid

fluid loss

intake

Arterial

Rate of change of

Extracellular

pressure

extracellular

fluid volume

Total peripheral

Arterial pressure

Blood

resistance

volume

Figure 29-12

Basic renal-body fluid feedback

Cardiac

Venous

Mean circulatory

mechanism for control of

output

return

filling pressure

blood volume, extracellular fluid

volume, and arterial pressure.

Solid lines indicate positive

effects, and dashed lines indicate

Heart strength

Vascular

negative effects.

capacity

376

Unit V The Body Fluids and Kidneys

pressure causes a large change in urine output. These

factors work together to provide effective feedback

control of blood volume.

Blood volume

The same control mechanisms operate whenever

there is a loss of whole blood because of hemorrhage.

Normal range

In this case, fluid is retained by the kidneys, and other

Death

parallel processes occur to reconstitute the red blood

cells and plasma proteins in the blood. If abnormali-

ties of red blood cell volume remain, such as occurs

when there is deficiency of erythropoietin or other

factors needed to stimulate red blood cell production,

the plasma volume will simply make up the difference,

and the overall blood volume will return essentially to

normal despite the low red blood cell mass.

Daily fluid intake

(water and electrolytes) (L/day)

Distribution of Extracellular

Fluid Between the Interstitial

Figure 29-13

Spaces and Vascular System

Approximate effect of changes in daily fluid intake on blood

volume. Note that blood volume remains relatively constant in the

From Figure 29-12 it is apparent that blood volume

normal range of daily fluid intakes.

and extracellular fluid volume are usually controlled

in parallel with each other. Ingested fluid initially goes

into the blood, but it rapidly becomes distributed

Thus, the renal-body fluid feedback mechanism

between the interstitial spaces and the plasma. There-

operates to prevent continuous accumulation of salt

fore, blood volume and extracellular fluid volume

and water in the body during increased salt and water

usually are controlled simultaneously.

intake. As long as kidney function is normal and the

There are circumstances, however, in which the dis-

pressure diuresis mechanism is operating effectively,

tribution of extracellular fluid between the interstitial

large changes in salt and water intake can be accom-

spaces and blood can vary greatly. As discussed in

modated with only slight changes in blood volume,

Chapter 25, the principal factors that can cause accu-

extracellular fluid volume, cardiac output, and arterial

mulation of fluid in the interstitial spaces include (1)

pressure.

increased capillary hydrostatic pressure, (2) decreased

The opposite sequence of events occurs when fluid

plasma colloid osmotic pressure, (3) increased perme-

intake falls below normal. In this case, there is a ten-

ability of the capillaries, and (4) obstruction of lym-

dency toward decreased blood volume and extracellu-

phatic vessels. In all these conditions, an unusually high

lar fluid volume, as well as reduced arterial pressure.

proportion of the extracellular fluid becomes distrib-

Even a small decrease in blood pressure causes a

uted to the interstitial spaces.

large decrease in urine output, thereby allowing fluid

Figure 29-14 shows the normal distribution of fluid

balance to be maintained with minimal changes in

between the interstitial spaces and the vascular system

blood pressure, blood volume, or extracellular fluid

and the distribution that occurs in edema states. When

volume. The effectiveness of this mechanism in pre-

small amounts of fluid accumulate in the blood as a

venting large changes in blood volume is demon-

result of either too much fluid intake or a decrease in

strated in Figure 29-13, which shows that changes in

renal output of fluid, about 20 to 30 per cent of it stays

blood volume are almost imperceptible despite large

in the blood and increases the blood volume. The

variations in daily intake of water and electrolytes,

remainder is distributed to the interstitial spaces.

except when intake becomes so low that it is not suf-

When the extracellular fluid volume rises more than

ficient to make up for fluid losses caused by evapora-

30 to 50 per cent above normal, almost all the addi-

tion or other inescapable losses.

tional fluid goes into the interstitial spaces and little

remains in the blood. This occurs because once the

interstitial fluid pressure rises from its normally nega-

Precision of Blood Volume and

tive value to become positive, the tissue interstitial

Extracellular Fluid Volume Regulation

spaces become compliant, and large amounts of fluid

then pour into the tissues without interstitial fluid

By studying Figure 29-12, one can see why the blood

pressure rising much more. In other words, the safety

volume remains almost exactly constant despite

factor against edema, owing to a rising interstitial

extreme changes in daily fluid intake. The reason for

fluid pressure that counteracts fluid accumulation in

this is the following: (1) a slight change in blood

the tissues, is lost once the tissues become highly

volume causes a marked change in cardiac output, (2)

compliant.

a slight change in cardiac output causes a large change

Thus, under normal conditions, the interstitial

in blood pressure, and (3) a slight change in blood

spaces act as an “overflow” reservoir for excess fluid,

Chapter 29

Renal Regulation; Integration of Renal Mechanisms

377

Sympathetic Nervous System

Control of Renal Excretion: Arterial

Edema

Baroreceptor and Low-Pressure

Stretch Receptor Reflexes

Normal value

Because the kidneys receive extensive sympathetic

innervation, changes in sympathetic activity can alter

renal sodium and water excretion as well as regulation

Death

of extracellular fluid volume under some conditions.

For example, when blood volume is reduced by hem-

orrhage, the pressures in the pulmonary blood vessels

and other low-pressure regions of the thorax decrease,

causing reflex activation of the sympathetic nervous

system. This in turn increases renal sympathetic nerve

Extracellular fluid volume (liters)

activity, which has several effects to decrease sodium

and water excretion: (1) constriction of the renal arte-

rioles, with resultant decreased GFR; (2) increased

Figure 29-14

tubular reabsorption of salt and water; and (3) stimu-

lation of renin release and increased angiotensin II

Approximate relation between extracellular fluid volume and blood

and aldosterone formation, both of which further

volume, showing a nearly linear relation in the normal range but

increase tubular reabsorption. And if the reduction in

also showing the failure of blood volume to continue rising when

the extracellular fluid volume becomes excessive. When this

blood volume is great enough to lower systemic arte-

occurs, the additional extracellular fluid volume resides in the

rial pressure, further activation of the sympathetic

interstitial spaces, and edema results.

nervous system occurs because of decreased stretch of

the arterial baroreceptors located in the carotid sinus

and aortic arch. All these reflexes together play an

important role in the rapid restitution of blood volume

that occurs in acute conditions such as hemorrhage.

sometimes increasing in volume 10 to 30 liters. This

Also, reflex inhibition of renal sympathetic activity

causes edema, as explained in Chapter 25, but it also

may contribute to the rapid elimination of excess fluid

acts as an important overflow release valve for the cir-

in the circulation that occurs after eating a meal that

culation, protecting the cardiovascular system against

contains large amounts of salt and water.

dangerous overload that could lead to pulmonary

edema and cardiac failure.

To summarize, extracellular fluid volume and blood

Role of Angiotensin II In Controlling

volume are controlled simultaneously, but the quanti-

Renal Excretion

tative amounts of fluid distribution between the

interstitium and the blood depend on the physical

One of the body’s most powerful controllers of sodium

properties of the circulation and the interstitial spaces

excretion is angiotensin II. Changes in sodium and

as well as on the dynamics of fluid exchange through

fluid intake are associated with reciprocal changes in

the capillary membranes.

angiotensin II formation, and this in turn contributes

greatly to the maintenance of body sodium and fluid

Nervous and Hormonal

balances. That is, when sodium intake is elevated

above normal, renin secretion is decreased, causing

Factors Increase the

decreased angiotensin II formation. Because

Effectiveness of Renal-Body

angiotensin II has several important effects in increas-

Fluid Feedback Control

ing tubular reabsorption of sodium, as explained in

Chapter 27, a reduced level of angiotensin II decreases

In Chapter 27, we discuss the nervous and hormonal

tubular reabsorption of sodium and water, thus

factors that influence GFR and tubular reabsorption

increasing the kidneys’ excretion of sodium and water.

and, therefore, renal excretion of salt and water. These

The net result is to minimize the rise in extracellular

nervous and hormonal mechanisms usually act in

fluid volume and arterial pressure that would other-

concert with the pressure natriuresis and pressure

wise occur when sodium intake increases.

diuresis mechanisms, making them more effective in

Conversely, when sodium intake is reduced below

minimizing the changes in blood volume, extracellular

normal, increased levels of angiotensin II cause

fluid volume, and arterial pressure that occur in

sodium and water retention and oppose reductions in

response to day-to-day challenges. However, abnor-

arterial blood pressure that would otherwise occur.

malities of kidney function or of the various nervous

Thus, changes in activity of the renin-angiotensin

and hormonal factors that influence the kidneys can

system act as a powerful amplifier of the pressure

lead to serious changes in blood pressure and body

natriuresis mechanism for maintaining stable blood

fluid volumes, as discussed later.

pressures and body fluid volumes.

378

Unit V The Body Fluids and Kidneys

Angiotensin blockade

Normal

High angiotensin II

Figure 29-15

Effect of excessive angiotensin II

formation and effect of blocking

angiotensin II formation on the

renal-pressure natriuresis curve. Note

that high levels of angiotensin II for-

mation decrease the slope of pressure

100

120

140

160

natriuresis, making blood pressure

Arterial pressure (mm Hg)

very sensitive to changes in sodium

intake. Blockade of angiotensin II for-

mation shifts pressure natriuresis to

lower blood pressures.

Importance of Angiotensin II in Increasing Effectiveness of

lowering effects in hypertensive patients of the

Pressure Natriuresis. The importance of angiotensin II

angiotensin-converting enzyme inhibitors and

in making the pressure natriuresis mechanism more

angiotensin II receptor antagonists.

effective is shown in Figure 29-15. Note that when the

angiotensin control of natriuresis is fully functional,

Excessive Angiotensin II Does Not Cause Large Increases in

the pressure natriuresis curve is steep (normal curve),

Extracellular Fluid Volume Because Increased Arterial Pressure

indicating that only minor changes in blood pressure

Counterbalances Angiotensin-Mediated Sodium Retention.

are needed to increase sodium excretion when sodium

Although angiotensin II is one of the most powerful

intake is raised.

sodium- and water-retaining hormones in the body,

In contrast, when angiotensin levels cannot be

neither a decrease nor an increase in circulating

decreased in response to increased sodium intake

angiotensin II has a large effect on extracellular fluid

(high angiotensin II curve), as occurs in some hyper-

volume or blood volume. The reason for this is

tensive patients who have impaired ability to decrease

that with large increases in angiotensin II levels, as

renin secretion, the pressure natriuresis curve is not

occurs with a renin-secreting tumor of the kidney,

nearly as steep. Therefore, when sodium intake is

the high angiotensin II levels initially cause sodium

raised, much greater increases in arterial pressure are

and water retention by the kidneys and a small

needed to increase sodium excretion and maintain

increase in extracellular fluid volume. This also initi-

sodium balance. For example, in most people, a 10-fold

ates a rise in arterial pressure that quickly increases

increase in sodium intake causes an increase of only a

kidney output of sodium and water, thereby overcom-

few millimeters of mercury in arterial pressure,

ing the sodium- and water-retaining effects of the

whereas in subjects who cannot suppress angiotensin

angiotensin II and re-establishing a balance between

II formation appropriately in response to excess

intake and output of sodium at a higher blood pres-

sodium, the same rise in sodium intake causes blood

sure. Conversely, after blockade of angiotensin II for-

pressure to rise as much as 50 mm Hg. Thus, the inabil-

mation, as occurs when an angiotensin-converting

ity to suppress angiotensin II formation when there is

enzyme inhibitor is administered, there is initial loss of

excess sodium reduces the slope of pressure natriure-

sodium and water, but the fall in blood pressure offsets

sis and makes arterial pressure very salt sensitive, as

this effect, and sodium excretion is once again restored

discussed in Chapter 19.

to normal.

The use of drugs to block the effects of angiotensin

II has proved to be important clinically for improv-

ing the kidneys’ ability to excrete salt and water.

Role of Aldosterone in Controlling

When angiotensin II formation is blocked with an

Renal Excretion

angiotensin-converting enzyme inhibitor (see Figure

29-15) or an angiotensin II receptor antagonist, the

Aldosterone increases sodium reabsorption, especially

renal-pressure natriuresis curve is shifted to lower

in the cortical collecting tubules. The increased sodium

pressures; this indicates an enhanced ability of the

reabsorption is also associated with increased water

kidneys to excrete sodium because normal levels of

reabsorption and potassium secretion. Therefore, the

sodium excretion can now be maintained at reduced

net effect of aldosterone is to make the kidneys retain

arterial pressures. This shift of pressure natriuresis

sodium and water but to increase potassium excretion

provides the basis for the chronic blood pressure-

in the urine.

Chapter 29

Renal Regulation; Integration of Renal Mechanisms

379

The function of aldosterone in regulating sodium

Conversely, when there is excess extracellular volume,

balance is closely related to that described for

decreased ADH levels reduce reabsorption of water by

angiotensin II. That is, with reduction in sodium intake,

the kidneys, thus helping to rid the body of the excess

the increased angiotensin II levels that occur stimulate

volume.

aldosterone secretion, which in turn contributes to the

reduction in urinary sodium excretion and, therefore,

Excess ADH Secretion Usually Causes Only Small Increases in

to the maintenance of sodium balance. Conversely,

Extracellular Fluid Volume but Large Decreases in Sodium Con-

with high sodium intake, suppression of aldosterone

centration. Although ADH is important in regulating

formation decreases tubular reabsorption, allowing

extracellular fluid volume, excessive levels of ADH

the kidneys to excrete larger amounts of sodium. Thus,

seldom cause large increases in arterial pressure or

changes in aldosterone formation also aid the pressure

extracellular fluid volume. Infusion of large amounts

natriuresis mechanism in maintaining sodium balance

of ADH into animals initially causes renal retention of

during variations in salt intake.

water and a 10 to 15 per cent increase in extracellular

fluid volume. As the arterial pressure rises in response

During Chronic Oversecretion of Aldosterone, Kidneys

to this increased volume, much of the excess volume

“Escape” from Sodium Retention as Arterial Pressure Rises.

is excreted because of the pressure diuresis mecha-

Although aldosterone has powerful effects on sodium

nism. After several days of ADH infusion, the blood

reabsorption, when there is excessive infusion of

volume and extracellular fluid volume are elevated no

aldosterone or excessive formation of aldosterone, as

more than 5 to 10 per cent, and the arterial pressure is

occurs in patients with tumors of the adrenal gland

also elevated by less than 10 mm Hg. The same is true

(Conn’s syndrome), the increased sodium reabsorp-

for patients with inappropriate ADH syndrome, in

tion and decreased sodium excretion by the kidneys

which ADH levels may be elevated severalfold.

are transient. After 1 to 3 days of sodium and water

Thus, high levels of ADH do not cause major

retention, the extracellular fluid volume rises by about

increases of either body fluid volume or arterial pres-

10 to 15 per cent and there is a simultaneous increase

sure, although high ADH levels can cause severe reduc-

in arterial blood pressure. When the arterial pressure

tions in extracellular sodium ion concentration. The

rises sufficiently, the kidneys “escape” from the sodium

reason for this is that increased water reabsorption by

and water retention and thereafter excrete amounts of

the kidneys dilutes the extracellular sodium, and at the

sodium equal to the daily intake, despite continued

same time, the small increase in blood pressure that

presence of high levels of aldosterone. The primary

does occur causes loss of sodium from the extracellu-

reason for the escape is the pressure natriuresis and

lar fluid in the urine through pressure natriuresis.

diuresis that occur when the arterial pressure rises.

In patients who have lost their ability to secrete

In patients with adrenal insufficiency who do not

ADH because of destruction of the supraoptic nuclei,

secrete enough aldosterone (Addison’s disease), there

the urine volume may become 5 to 10 times normal.

is increased excretion of sodium and water, reduction

This is almost always compensated for by ingestion of

in extracellular fluid volume, and a tendency toward

enough water to maintain fluid balance. If free access

low blood pressure. In the complete absence of aldos-

to water is prevented, the inability to secrete ADH

terone, the volume depletion may be severe unless the

may lead to marked reductions in blood volume and

person is allowed to eat large amounts of salt and

arterial pressure.

drink large amounts of water to balance the increased

urine output of salt and water.

Role of Atrial Natriuretic Peptide

in Controlling Renal Excretion

Role of ADH in Controlling Renal

Water Excretion

Thus far, we have discussed mainly the role of sodium-

and water-retaining hormones in controlling extracel-

As discussed in Chapter 28, ADH plays an important

lular fluid volume. However, several different natri-

role in allowing the kidneys to form a small volume of

uretic hormones may also contribute to volume

concentrated urine while excreting normal amounts of

regulation. One of the most important of the natri-

salt. This effect is especially important during water

uretic hormones is a peptide referred to as atrial natri-

deprivation, which strongly elevates plasma levels of

uretic peptide (ANP), released by the cardiac atrial

ADH that in turn increase water reabsorption by the

muscle fibers. The stimulus for release of this peptide

kidneys and help to minimize the decreases in extra-

appears to be overstretch of the atria, which can result

cellular fluid volume and arterial pressure that would

from excess blood volume. Once released by the

otherwise occur. Water deprivation for 24 to 48 hours

cardiac atria, ANP enters the circulation and acts on

normally causes only a small decrease in extracellular

the kidneys to cause small increases in GFR and

fluid volume and arterial pressure. However, if the

decreases in sodium reabsorption by the collecting

effects of ADH are blocked with a drug that antago-

ducts. These combined actions of ANP lead to

nizes the action of ADH to promote water reabsorp-

increased excretion of salt and water, which helps to

tion in the distal and collecting tubules, the same

compensate for the excess blood volume.

period of water deprivation causes a substantial fall in

Changes in ANP levels probably help to minimize

both extracellular fluid volume and arterial pressure.

changes in blood volume during various disturbances,

380

Unit V The Body Fluids and Kidneys

such as increased salt and water intake. However,

systems leads to an increase in sodium excretion when

excessive production of ANP or even complete lack of

sodium intake is increased. The opposite changes take

ANP does not cause major changes in blood volume

place when sodium intake is reduced below normal

because these effects can easily be overcome by small

levels.

changes in blood pressure, acting through pressure

natriuresis. For example, infusions of large amounts of

ANP initially raise urine output of salt and water and

Conditions That Cause

cause slight decreases in blood volume. In less than 24

Large Increases in Blood

hours, this effect is overcome by a slight decrease in

Volume and Extracellular

blood pressure that returns urine output toward

Fluid Volume

normal, despite continued excess of ANP.

Despite the powerful regulatory mechanisms that main-

tain blood volume and extracellular fluid volume rea-

sonably constant, there are abnormal conditions that

Integrated Responses to

can cause large increases in both of these variables.

Changes in Sodium Intake

Almost all of these conditions result from circulatory

abnormalities.

The integration of the different control systems that

regulate sodium and fluid excretion under normal

Increased Blood Volume and

conditions can be summarized by examining the

Extracellular Fluid Volume Caused

homeostatic responses to progressive increases in

by Heart Diseases

dietary sodium intake. As discussed previously, the

kidneys have an amazing capability to match their

In congestive heart failure, blood volume may increase

excretion of salt and water to intakes that can range

15 to 20 per cent, and extracellular fluid volume some-

from as low as one tenth of normal to as high as 10

times increases by 200 per cent or more. The reason for

times normal.

this can be understood by re-examination of Figure

29-12. Initially, heart failure reduces cardiac output and,

consequently, decreases arterial pressure. This in turn

High Sodium Intake Suppresses Antinatriuretic Systems and

activates multiple sodium-retaining systems, especially

Activates Natriuretic Systems. As sodium intake is

the renin-angiotensin, aldosterone, and sympathetic

increased, sodium output initially lags slightly behind

nervous systems. In addition, the low blood pressure

intake. The time delay results in a small increase in the

itself causes the kidneys to retain salt and water. There-

cumulative sodium balance, which causes a slight

fore, the kidneys retain volume in an attempt to return

increase in extracellular fluid volume. It is mainly this

the arterial pressure and cardiac output toward normal.

small increase in extracellular fluid volume that trig-

Indeed, if the heart failure is not too severe, the rise in

gers various mechanisms in the body to increase

blood volume can often return cardiac output and arte-

rial pressure virtually all the way to normal, and sodium

sodium excretion. These mechanisms include the

excretion will eventually increase back to normal,

following:

although there will remain excess extracellular fluid

1. Activation of low pressure receptor reflexes that

volume and blood volume to keep the weakened heart

originate from the stretch receptors of the right

pumping adequately. However, if the heart is greatly

atrium and the pulmonary blood vessels. Signals

weakened, arterial pressure will not be able to increase

from the stretch receptors go to the brain stem

enough to restore urine output to normal. When this

and there inhibit sympathetic nerve activity to the

occurs, the kidneys continue to retain volume until the

kidneys to decrease tubular sodium reabsorption.

person develops severe circulatory congestion and

This mechanism is most important in the first few

eventually dies of pulmonary edema.

hours—or perhaps the first day—after a large

In myocardial failure, heart valvular disease, and

congenital abnormalities of the heart, an important

increase in salt and water intake.

circulatory compensation is an increase in blood

2. Small increases in arterial pressure, caused by

volume, which helps to return cardiac output and blood

volume expansion, raise sodium excretion through

pressure to normal. This allows even the weakened

pressure natriuresis.

heart to maintain a life-sustaining level of cardiac

3. Suppression of angiotensin II formation, caused by

output.

increased arterial pressure and extracellular fluid

volume expansion, decreases tubular sodium

reabsorption by eliminating the normal effect of

Increased Blood Volume Caused by

angiotensin II to increase sodium reabsorption.

Increased Capacity of Circulation

Also, reduced angiotensin II decreases

Any condition that increases vascular capacity will also

aldosterone secretion, thus further reducing

cause the blood volume to increase to fill this extra

tubular sodium reabsorption.

capacity. An increase in vascular capacity initially

4. Stimulation of natriuretic systems, especially ANP,

reduces mean circulatory filling pressure (see Figure

contributes further to increased sodium excretion.

29-12), which leads to decreased cardiac output and

Thus, the combined activation of natriuretic systems

decreased arterial pressure. The fall in pressure causes

and suppression of sodium- and water-retaining

salt and water retention by the kidneys until the blood

Chapter 29

Renal Regulation; Integration of Renal Mechanisms

381

volume increases sufficiently to fill the extra capacity.

into the tissues of the body. The net result is massive

For example, in pregnancy the increased vascular capac-

fluid retention by the kidneys until tremendous extra-

ity of the uterus, placenta, and other enlarged organs

cellular edema occurs unless treatment is instituted to

of the woman’s body regularly increases the blood

restore the plasma proteins.

volume 15 to 25 per cent. Similarly, in patients who

have large varicose veins of the legs, which in rare

instances may hold up to an extra liter of blood,

Liver Cirrhosis—Decreased

the blood volume simply increases to fill the extra

Synthesis of Plasma Proteins

vascular capacity. In these cases, salt and water are

by the Liver and Sodium Retention

retained by the kidneys until the total vascular bed is

filled enough to raise blood pressure to the level

by the Kidneys

required to balance renal output of fluid with daily

A similar sequence of events occurs in cirrhosis of the

intake of fluid.

liver as in nephrotic syndrome, except that in liver cir-

rhosis, the reduction in plasma protein concentration

results from destruction of the liver cells, thus reducing

the ability of the liver to synthesize enough plasma

Conditions That Cause

proteins. Cirrhosis is also associated with large amounts

Large Increases in

of fibrous tissue in the liver structure, which greatly

Extracellular Fluid

impedes the flow of portal blood through the liver.

This in turn raises capillary pressure throughout the

Volume but with Normal

portal vascular bed, which also contributes to the

Blood Volume

leakage of fluid and proteins into the peritoneal cavity,

a condition called ascites. Once fluid and protein are lost

There are several conditions in which extracellular fluid

from the circulation, the renal responses are similar to

volume becomes markedly increased but blood volume

those observed in other conditions associated with

remains normal or even slightly reduced. These condi-

decreased plasma volume. That is, the kidneys continue

tions are usually initiated by leakage of fluid and protein

to retain salt and water until plasma volume and arte-

into the interstitium, which tends to decrease the blood

rial pressure are restored to normal. In some cases,

volume. The kidneys’ response to these conditions is

plasma volume may actually increase above normal

similar to the response after hemorrhage. That is, the

because of increased vascular capacity in cirrhosis;

kidneys retain salt and water in an attempt to restore

the high pressures in the portal circulation can

blood volume toward normal. Much of the extra fluid,

greatly distend veins and therefore increase vascular

however, leaks into the interstitium, causing further

capacity.

edema.

References

Nephrotic Syndrome—Loss of

Plasma Proteins in Urine and

Antunes-Rodrigues J, de Castro M, Elias LL, et al: Neu-

Sodium Retention by the Kidneys

roendocrine control of body fluid metabolism. Physiol Rev

84:169, 2004.

The general mechanisms that lead to extracellular

Cowley AW Jr: Long-term control of arterial pressure.

edema are reviewed in Chapter 25. One of the most

Physiol Rev 72:231, 1992.

important clinical causes of edema is the so-called

Fitzsimmons JT: Physiology and pathophysiology of thirst

nephrotic syndrome. In nephrotic syndrome, the

and salt appetite. In Seldin DW, Giebisch G (eds): The

glomerular capillaries leak large amounts of protein

Kidney—Physiology and Pathophysiology, 3rd ed. New

into the filtrate and the urine because of an increased

York: Raven Press, 2000, pp 1153-1174.

permeability of the glomerulus. Thirty to 50 grams of

Giebisch GH: A trail of research on potassium. Kidney Int

plasma protein can be lost in the urine each day, some-

62:1498, 2002.

times causing the plasma protein concentration to fall

Giebisch G, Hebert SC, Wang WH: New aspects of renal

to less than one-third normal. As a consequence of the

potassium transport. Pflugers Arch 446:289, 2003.

decreased plasma protein concentration, the plasma

Granger JP, Alexander BT, Llinas M: Mechanisms of pres-

colloid osmotic pressure falls to low levels. This causes

sure natriuresis. Curr Hypertens Rep 4:15, 2002.

the capillaries all over the body to filter large amounts

Guise TA, Mundy GR: Disorders of calcium metabolism. In

of fluid into the various tissues, which in turn causes

Seldin DW, Giebisch G (eds): The Kidney—Physiology

edema and decreases the plasma volume.

and Pathophysiology, 3rd ed. New York: Raven Press,

Renal sodium retention in nephrotic syndrome

2000, pp 1811-1840.

occurs through multiple mechanisms activated by

Guyton AC: Blood pressure control—special role of the

leakage of protein and fluid from the plasma into the

kidneys and body fluids. Science 252:1813, 1991.

interstitial fluid, including activation of various sodium-

Hall JE, Brands MW: The renin-angiotensin-aldosterone

retaining systems such as the renin-angiotensin system,

system: renal mechanisms and circulatory homeostasis. In

aldosterone, and possibly the sympathetic nervous

Seldin DW, Giebisch G (eds): The Kidney—Physiology

system. The kidneys continue to retain sodium and

and Pathophysiology, 3rd ed. New York: Raven Press,

water until plasma volume is restored nearly to normal.

2000, pp 1009-1046.

However, because of the large amount of sodium and

Hall JE: Angiotensin II and long-term arterial pressure reg-

water retention, the plasma protein concentration

ulation: the overriding dominance of the kidney. J Am Soc

becomes further diluted, causing still more fluid to leak

Nephrol 10(Suppl 12):s258, 1999.

C H A P T E R

Regulation of Acid-Base Balance

Regulation of hydrogen ion (H⁺) balance is similar

in some ways to the regulation of other ions in the

body. For instance, to achieve homeostasis, there

must be a balance between the intake or production

of H⁺ and the net removal of H⁺ from the body. And,

as is true for other ions, the kidneys play a key role

in regulating H⁺ removal. However, precise control

of extracellular fluid H⁺ concentration involves

much more than simple elimination of H⁺ by the kidneys. There are also multi-

ple acid-base buffering mechanisms involving the blood, cells, and lungs that are

essential in maintaining normal H⁺ concentrations in both the extracellular and

the intracellular fluid.

In this chapter, the various mechanisms that contribute to the regulation of

H⁺ concentration are discussed, with special emphasis on the control of renal

H⁺ secretion and renal reabsorption, production, and excretion of bicarbonate

ions (HCO_3-), one of the key components of acid-base control systems in the

body fluids.

Hydrogen Ion Concentration Is

Precisely Regulated

Precise H⁺ regulation is essential because the activities of almost all enzyme

systems in the body are influenced by H⁺ concentration. Therefore, changes in

hydrogen concentration alter virtually all cell and body functions.

Compared with other ions, the H⁺ concentration of the body fluids normally

is kept at a low level. For example, the concentration of sodium in extracellu-

lar fluid (142 mEq/L) is about 3.5 million times as great as the normal concen-

tration of H⁺, which averages only 0.00004 mEq/L. Equally important, the

normal variation in H⁺ concentration in extracellular fluid is only about one mil-

lionth as great as the normal variation in sodium ion (Na⁺) concentration. Thus,

the precision with which H⁺ is regulated emphasizes its importance to the

various cell functions.

Acids and Bases—Their Definitions

and Meanings

A hydrogen ion is a single free proton released from a hydrogen atom. Molecules

containing hydrogen atoms that can release hydrogen ions in solutions are referred

to as acids. An example is hydrochloric acid (HCl), which ionizes in water to form

hydrogen ions (H⁺) and chloride ions (Cl^-). Likewise, carbonic acid (H₂CO₃) ionizes

in water to form H⁺ and bicarbonate ions (HCO_3-).

A base is an ion or a molecule that can accept an H⁺. For example, HCO_3- is a

base because it can combine with H⁺ to form H₂CO₃. Likewise, HPO4= is a base

because it can accept an H⁺ to form H₂PO_4-. The proteins in the body also function

as bases, because some of the amino acids that make up proteins have net negative

charges that readily accept H⁺. The protein hemoglobin in the red blood cells and

proteins in the other cells of the body are among the most important of the body’s

bases.

The terms base and alkali are often used synonymously. An alkali is a molecule

formed by the combination of one or more of the alkaline metals—sodium, potas-

sium, lithium, and so forth—with a highly basic ion such as a hydroxyl ion (OH^-).

383

384

Unit V The Body Fluids and Kidneys

The base portion of these molecules reacts quickly with

Table 30-1

H⁺ to remove it from solution; they are, therefore,

typical bases. For similar reasons, the term alkalosis

pH and H⁺ Concentration of Body Fluids

refers to excess removal of H⁺ from the body fluids, in

contrast to the excess addition of H⁺, which is referred

H⁺ Concentration (mEq/L)

to as acidosis.

Extracellular fluid

Strong and Weak Acids and Bases. A strong acid is one that

Arterial blood

4.0

¥ 10^-5

7.40

Venous blood

4.5

¥ 10^-5

7.35

rapidly dissociates and releases especially large

Interstitial fluid

4.5

¥ 10^-5

7.35

amounts of H⁺ in solution. An example is HCl. Weak

acids have less tendency to dissociate their ions and,

Intracellular fluid

¥ 10^-3 to 4

¥ 10^-5

6.0 to 7.4

therefore, release H⁺ with less vigor. An example is

Urine

¥ 10^-2 to 1

¥ 10^-5

4.5 to 8.0

H₂CO₃. A strong base is one that reacts rapidly and

Gastric HCl

160

0.8

strongly with H⁺ and, therefore, quickly removes these

from a solution. A typical example is OH^-, which reacts

with H⁺ to form water (H₂O). A typical weak base is

HCO_3- because it binds with H⁺ much more weakly than

does OH^-. Most of the acids and bases in the extracel-

The pH of urine can range from 4.5 to 8.0, depending

lular fluid that are involved in normal acid-base regula-

on the acid-base status of the extracellular fluid. As dis-

tion are weak acids and bases. The most important ones

cussed later, the kidneys play a major role in correcting

that we discuss in detail are H₂CO₃ and bicarbonate

abnormalities of extracellular fluid H⁺ concentration by

base.

excreting acids or bases at variable rates.

An extreme example of an acidic body fluid is the

Normal Hydrogen Ion Concentration and pH of Body Fluids

HCl secreted into the stomach by the oxyntic (parietal)

and Changes That Occur in Acidosis and Alkalosis. As dis-

cells of the stomach mucosa, as discussed in Chapter 64.

cussed earlier, the blood H⁺ concentration is normally

The H⁺ concentration in these cells is about 4 million

maintained within tight limits around a normal value

times greater than the hydrogen concentration in blood,

of about 0.00004 mEq/L (40 nEq/L). Normal variations

with a pH of 0.8.

are only about

3 to

5 nEq/L, but under extreme

In the remainder of this chapter, we discuss the reg-

conditions, the H⁺ concentration can vary from as low

ulation of extracellular fluid H⁺ concentration.

as 10 nEq/L to as high as 160 nEq/L without causing

death.

Because H⁺ concentration normally is low, and

Defenses Against Changes in

because these small numbers are cumbersome, it is cus-

tomary to express H⁺ concentration on a logarithm

Hydrogen Ion Concentration:

scale, using pH units. pH is related to the actual H⁺ con-

Buffers, Lungs, and Kidneys

centration by the following formula (H⁺ concentration

[H⁺] is expressed in equivalents per liter):

There are three primary systems that regulate the H⁺

concentration in the body fluids to prevent acidosis or

pH=log

[

]

alkalosis: (1) the chemical acid-base buffer systems of

[

H⁺

]=-lo

the body fluids, which immediately combine with acid

For example, the normal

[H⁺] is

40 nEq/L

or base to prevent excessive changes in H⁺ concentra-

(0.00000004 Eq/L). Therefore, the normal pH is

tion; (2) the respiratory center, which regulates the

removal of CO₂ (and, therefore, H₂CO₃) from the

pH = -log [0.00000004]

extracellular fluid; and

(3) the kidneys, which can

pH = 7.4

excrete either acid or alkaline urine, thereby readjust-

From this formula, one can see that pH is inversely

ing the extracellular fluid H⁺ concentration toward

related to the H⁺ concentration; therefore, a low pH

normal during acidosis or alkalosis.

corresponds to a high H⁺ concentration, and a high pH

When there is a change in H⁺ concentration, the

corresponds to a low H⁺ concentration.

buffer systems of the body fluids react within a fraction

The normal pH of arterial blood is 7.4, whereas the

of a second to minimize these changes. Buffer systems

pH of venous blood and interstitial fluids is about 7.35

do not eliminate H⁺ from or add them to the body

because of the extra amounts of carbon dioxide (CO₂)

released from the tissues to form H₂CO₃ in these fluids

but only keep them tied up until balance can be re-

(Table 30-1). Because the normal pH of arterial blood

established.

is 7.4, a person is considered to have acidosis when the

The second line of defense, the respiratory system,

pH falls below this value and to have alkalosis when the

also acts within a few minutes to eliminate CO₂and,

pH rises above 7.4. The lower limit of pH at which a

therefore, H₂CO₃ from the body.

person can live more than a few hours is about 6.8, and

These first two lines of defense keep the H⁺ con-

the upper limit is about 8.0.

centration from changing too much until the more

Intracellular pH usually is slightly lower than plasma

slowly responding third line of defense, the kidneys,

pH because the metabolism of the cells produces acid,

can eliminate the excess acid or base from the body.

especially H₂CO₃. Depending on the type of cells, the

Although the kidneys are relatively slow to respond

pH of intracellular fluid has been estimated to range

between 6.0 and 7.4. Hypoxia of the tissues and poor

compared with the other defenses, over a period of

blood flow to the tissues can cause acid accumulation

hours to several days, they are by far the most power-

and decreased intracellular pH.

ful of the acid-base regulatory systems.

Chapter 30

Regulation of Acid-Base Balance

385

Buffering of Hydrogen Ions

Now, putting the entire system together, we have the

following:

in the Body Fluids

ææ

CO +H O

H CO

H++HCO

A buffer is any substance that can reversibly bind H⁺.

The general form of the buffering reaction is

Because of the weak dissociation of H₂CO₃, the H⁺

Buffer+H

H Buffer

concentration is extremely small.

In this example, a free H⁺ combines with the buffer to

When a strong acid such as HCl is added to the

form a weak acid (H buffer) that can either remain as

bicarbonate buffer solution, the increased H⁺ released

an unassociated molecule or dissociate back to buffer

from the acid (HCl Æ H⁺ + Cl^-) is buffered by HCO_3-.

and H⁺. When the H⁺ concentration increases, the

reaction is forced to the right, and more H⁺ binds to

≠H⁺ + HCO_3- Æ H₂CO₃ Æ CO₂ + H₂O

the buffer, as long as buffer is available. Conversely,

As a result, more H₂CO₃ is formed, causing increased

when the H⁺ concentration decreases, the reaction

CO₂ and H₂O production. From these reactions, one

shifts toward the left, and H⁺ is released from the

can see that H⁺ from the strong acid HCl reacts with

buffer. In this way, changes in H⁺ concentration are

HCO_3- to form the very weak acid H₂CO₃, which in

minimized.

turn forms CO₂ and H₂O. The excess CO₂ greatly stim-

The importance of the body fluid buffers can be

ulates respiration, which eliminates the CO₂ from the

quickly realized if one considers the low concentration

extracellular fluid.

of H⁺ in the body fluids and the relatively large

The opposite reactions take place when a strong

amounts of acids produced by the body each day. For

base, such as sodium hydroxide (NaOH), is added to

example, about 80 milliequivalents of hydrogen is

the bicarbonate buffer solution.

either ingested or produced each day by metabolism,

whereas the H⁺ concentration of the body fluids nor-

NaOH + H₂CO₃ Æ NaHCO₃ + H₂O

mally is only about 0.00004 mEq/L. Without buffering,

In this case, the OH^- from the NaOH combines with

the daily production and ingestion of acids would

H₂CO₃ to form additional HCO_3-.Thus, the weak base

cause huge changes in body fluid H⁺ concentration.

NaHCO₃ replaces the strong base NaOH. At the same

The action of acid-base buffers can perhaps best be

time, the concentration of H₂CO₃ decreases (because

explained by considering the buffer system that is

it reacts with NaOH), causing more CO₂ to combine

quantitatively the most important in the extracellular

with H₂O to replace the H₂CO₃.

fluid—the bicarbonate buffer system.

CO +H O

H CO

≠HCO +H

Bicarbonate Buffer System

NaOH

The net result, therefore, is a tendency for the CO₂

The bicarbonate buffer system consists of a water solu-

levels in the blood to decrease, but the decreased CO₂

tion that contains two ingredients: (1) a weak acid,

in the blood inhibits respiration and decreases the rate

H₂CO₃, and (2) a bicarbonate salt, such as NaHCO₃.

of CO₂ expiration. The rise in blood HCO_3- that occurs

H₂CO₃ is formed in the body by the reaction of CO₂

is compensated for by increased renal excretion of

with H₂O.

HCO_3-.

carbonic

anhydrase

CO +H O

H CO

ææ

Quantitative Dynamics of the

This reaction is slow, and exceedingly small amounts

Bicarbonate Buffer System

of H₂CO₃ are formed unless the enzyme carbonic

All acids, including H₂CO₃, are ionized to some extent.

anhydrase is present. This enzyme is especially abun-

From mass balance considerations, the concentrations

dant in the walls of the lung alveoli, where CO₂ is

of H⁺ and HCO_3- are proportional to the concentration

released; carbonic anhydrase is also present in the

of H₂CO₃.

epithelial cells of the renal tubules, where CO₂ reacts

with H₂O to form H₂CO₃.

H2CO

HCO

H₂CO₃ ionizes weakly to form small amounts of H⁺

For any acid, the concentration of the acid relative

and HCO_3-.

to its dissociated ions is defined by the dissociation

constant K¢.

H C2

H++HCO

HCO

The second component of the system, bicarbonate

K¢=

(1)

H2CO

salt, occurs predominantly as sodium bicarbonate

(NaHCO₃) in the extracellular fluid. NaHCO₃

This equation indicates that in an H₂CO₃ solution, the

ionizes almost completely to form HCO_3- and Na⁺, as

amount of free H⁺ is equal to

follows:

H2CO

H+=K¢¥

(2)

NaHCO

Na++HCO

HCO

386

Unit V The Body Fluids and Kidneys

The concentration of undissociated H₂CO₃ cannot be

toward alkalosis. An increase in PCO₂ causes the pH to

measured in solution because it rapidly dissociates into

decrease, shifting the acid-base balance toward acidosis.

CO₂ and H₂O or to H⁺ and HCO_3-. However, the CO₂

The Henderson-Hasselbalch equation, in addition to

dissolved in the blood is directly proportional to the

defining the determinants of normal pH regulation and

amount of undissociated H₂CO₃. Therefore, equation 2

acid-base balance in the extracellular fluid, provides

can be rewritten as

insight into the physiologic control of acid and base

composition of the extracellular fluid. As discussed

H+=K

(3)

later, the bicarbonate concentration is regulated mainly

HCO₃

by the kidneys, whereas the PCO₂ in extracellular fluid is

controlled by the rate of respiration. By increasing the

The dissociation constant (K) for equation 3 is only

rate of respiration, the lungs remove CO₂ from the

about ¹/₄₀₀ of the dissociation constant (K¢) of equation

plasma, and by decreasing respiration, the lungs elevate

2 because the proportionality ratio between H₂CO₃ and

PCO₂. Normal physiologic acid-base homeostasis results

CO₂ is 1:400.

from the coordinated efforts of both of these organs, the

Equation 3 is written in terms of the total amount of

lungs and the kidneys, and acid-base disorders occur

CO₂ dissolved in solution. However, most clinical labo-

when one or both of these control mechanisms are

ratories measure the blood CO₂ tension (PCO₂) rather

impaired, thus altering either the bicarbonate concen-

than the actual amount of CO₂. Fortunately, the amount

tration or the PCO₂ of extracellular fluid.

of CO₂ in the blood is a linear function of PCO₂ times

When disturbances of acid-base balance result from

the solubility coefficient for CO₂; under physiologic

a primary change in extracellular fluid bicarbonate con-

conditions, the solubility coefficient for CO₂

centration, they are referred to as metabolic acid-base

0.03 mmol/mm Hg at body temperature. This means that

disorders. Therefore, acidosis caused by a primary

0.03 millimole of H₂CO₃ is present in the blood for each

decrease in bicarbonate concentration is termed meta-

millimeter of mercury PCO₂ measured. Therefore, equa-

bolic acidosis, whereas alkalosis caused by a primary

tion 3 can be rewritten as

increase in bicarbonate concentration is called meta-

(0.03

Pco

)

bolic alkalosis. Acidosis caused by an increase in PCO₂

H+=K

(4)

is called respiratory acidosis, whereas alkalosis caused

HCO

by a decrease in PCO2 is termed respiratory alkalosis.

Henderson-Hasselbalch Equation. As discussed earlier, it is

Bicarbonate Buffer System Titration Curve. Figure 30-1 shows

customary to express H⁺ concentration in pH units

the changes in pH of the extracellular fluid when the

rather than in actual concentrations. Recall that pH is

ratio of HCO_3- to CO₂ in extracellular fluid is altered.

defined as pH = -log H⁺.

When the concentrations of these two components are

The dissociation constant can be expressed in a

equal, the right-hand portion of equation 8 becomes the

similar manner.

log of 1, which is equal to 0. Therefore, when the two

components of the buffer system are equal, the pH of

pK = -log K

the solution is the same as the pK (6.1) of the bicar-

Therefore, we can express the H⁺ concentration in

bonate buffer system. When base is added to the system,

equation 4 in pH units by taking the negative logarithm

part of the dissolved CO₂ is converted into HCO_3-,

of that equation, which yields

causing an increase in the ratio of HCO_3- to CO₂ and

increasing the pH, as is evident from the Henderson-

(0 03

Pco

)

Hasselbalch equation. When acid is added, it is buffered

-log H

=-log

-log

(5)

HCO₃

Therefore,

(0 03

Pco

)

-log

(6)

HCO₃

100

Normal

Rather than work with a negative logarithm, we can

operating

change the sign of the logarithm and invert the numer-

point in body

ator and denominator in the last term, using the law of

logarithms to yield

HCO

pK+

log

(7)

(0 03

Pco

)

For the bicarbonate buffer system, the pK is 6.1, and

equation 7 can be written as

HCO

log

(8)

100

0 03

Pco

Equation 8 is the Henderson-Hasselbalch equation,

and with it, one can calculate the pH of a solution if

the molar concentration of HCO_3- and the PCO₂ are

Figure 30-1

known.

From the Henderson-Hasselbalch equation, it is

Titration curve for bicarbonate buffer system showing the pH of

apparent that an increase in HCO_3- concentration

extracellular fluid when the percentages of buffer in the form of

causes the pH to rise, shifting the acid-base balance

HCO3- and CO₂ (or H₂CO₃) are altered.

Chapter 30

Regulation of Acid-Base Balance

387

by HCO_3-, which is then converted into dissolved CO₂,

HCl + Na₂HPO₄ Æ NaH₂PO₄ + NaCl

decreasing the ratio of HCO_3- to CO₂ and decreasing

The result of this reaction is that the strong acid, HCl,

the pH of the extracellular fluid.

is replaced by an additional amount of a weak acid,

“Buffer Power” Is Determined by the Amount and Relative Con-

NaH₂PO₄, and the decrease in pH is minimized.

centrations of the Buffer Components. From the titration

When a strong base, such as NaOH, is added to the

curve in Figure 30-1, several points are apparent. First,

buffer system, the OH^- is buffered by the H₂PO_4- to

the pH of the system is the same as the pK when each

form additional amounts of HPO4= + H₂O.

of the components (HCO_3- and CO₂) constitutes 50 per

cent of the total concentration of the buffer system.

NaOH + NaH₂PO₄ Æ Na₂HPO₄ + H₂O

Second, the buffer system is most effective in the central

In this case, a strong base, NaOH, is traded for a weak

part of the curve, where the pH is near the pK of the

base, NaH₂PO₄, causing only a slight increase in

system. This means that the change in pH for any given

pH.

amount of acid or base added to the system is least when

The phosphate buffer system has a pK of 6.8, which

the pH is near the pK of the system. The buffer system

is still reasonably effective for 1.0 pH unit on either side

is not far from the normal pH of 7.4 in the body fluids;

of the pK, which for the bicarbonate buffer system

this allows the system to operate near its maximum

extends from a pH of about 5.1 to 7.1 units. Beyond

buffering power. However, its concentration in the

these limits, the buffering power rapidly diminishes.

extracellular fluid is low, only about 8 per cent of the

And when all the CO₂ has been converted into HCO₃

concentration of the bicarbonate buffer. Therefore,

or when all the HCO_3- has been converted into CO₂, the

the total buffering power of the phosphate system in

system has no more buffering power.

the extracellular fluid is much less than that of the

The absolute concentration of the buffers is also an

bicarbonate buffering system.

important factor in determining the buffer power of a

In contrast to its rather insignificant role as an extra-

system. With low concentrations of the buffers, only a

cellular buffer, the phosphate buffer is especially

small amount of acid or base added to the solution

changes the pH considerably.

important in the tubular fluids of the kidneys, for two

reasons: (1) phosphate usually becomes greatly con-

Bicarbonate Buffer System Is the Most Important Extracellular

centrated in the tubules, thereby increasing the buffer-

Buffer. From the titration curve shown in Figure 30-1,

ing power of the phosphate system, and (2) the tubular

one would not expect the bicarbonate buffer system to

fluid usually has a considerably lower pH than

be powerful, for two reasons: First, the pH of the extra-

the extracellular fluid does, bringing the operating

cellular fluid is about 7.4, whereas the pK of the bicar-

range of the buffer closer to the pK (6.8) of the

bonate buffer system is 6.1. This means that there is

system.

about 20 times as much of the bicarbonate buffer

The phosphate buffer system is also important in

system in the form of HCO_3- as in the form of dis-

buffering intracellular fluid because the concentration

solved CO₂. For this reason, this system operates on

of phosphate in this fluid is many times that in the

the portion of the buffering curve where the slope is

extracellular fluid. Also, the pH of intracellular fluid is

low and the buffering power is poor. Second, the con-

lower than that of extracellular fluid and therefore is

centrations of the two elements of the bicarbonate

usually closer to the pK of the phosphate buffer

system, CO₂ and HCO_3-, are not great.

system compared with the extracellular fluid.

Despite these characteristics, the bicarbonate buffer

system is the most powerful extracellular buffer in the

body. This apparent paradox is due mainly to the fact

Proteins: Important

that the two elements of the buffer system, HCO_3- and

Intracellular Buffers

CO₂, are regulated, respectively, by the kidneys and the

lungs, as discussed later. As a result of this regulation,

Proteins are among the most plentiful buffers in the

the pH of the extracellular fluid can be precisely con-

body because of their high concentrations, especially

trolled by the relative rate of removal and addition of

within the cells.

HCO_3- by the kidneys and the rate of removal of CO₂

The pH of the cells, although slightly lower than in

by the lungs.

the extracellular fluid, nevertheless changes approxi-

mately in proportion to extracellular fluid pH changes.

There is a slight amount of diffusion of H⁺

and HCO₃

Phosphate Buffer System

through the cell membrane, although these ions

require several hours to come to equilibrium with the

Although the phosphate buffer system is not impor-

extracellular fluid, except for rapid equilibrium that

tant as an extracellular fluid buffer, it plays a major

occurs in the red blood cells. CO₂, however, can rapidly

role in buffering renal tubular fluid and intracellular

diffuse through all the cell membranes. This diffusion

fluids.

of the elements of the bicarbonate buffer system causes

The main elements of the phosphate buffer system

the pH in intracellular fluid to change when there are

are H₂PO_4- and HPO4=. When a strong acid such as

changes in extracellular pH. For this reason, the buffer

HCl is added to a mixture of these two substances, the

systems within the cells help prevent changes in the

hydrogen is accepted by the base HPO4= and con-

pH of extracellular fluid but may take several hours to

verted to H₂PO_4-.

become maximally effective.

388

Unit V The Body Fluids and Kidneys

In the red blood cell, hemoglobin (Hb) is an impor-

flowing blood transports it to the lungs, where it dif-

tant buffer, as follows:

fuses into the alveoli and then is transferred to the

atmosphere by pulmonary ventilation. About 1.2 mol/

H⁺ + Hb

HHb

L of dissolved CO₂ normally is in the extracellular

Approximately 60 to 70 per cent of the total chemi-

fluid, corresponding to a Pco₂ of 40 mm Hg.

cal buffering of the body fluids is inside the cells, and

If the rate of metabolic formation of CO₂ increases,

most of this results from the intracellular proteins.

the Pco₂ of the extracellular fluid is likewise increased.

However, except for the red blood cells, the slowness

Conversely, a decreased metabolic rate lowers the

with which H⁺ and HCO_3- move through the cell mem-

Pco₂. If the rate of pulmonary ventilation is increased,

branes often delays for several hours the maximum

CO₂ is blown off from the lungs, and the Pco₂ in the

ability of the intracellular proteins to buffer extracel-

extracellular fluid decreases. Therefore, changes in

lular acid-base abnormalities.

either pulmonary ventilation or the rate of CO₂ for-

In addition to the high concentration of proteins in

mation by the tissues can change the extracellular fluid

the cells, another factor that contributes to their

Pco₂.

buffering power is the fact that the pKs of many of

these protein systems are fairly close to 7.4.

Increasing Alveolar Ventilation

Decreases Extracellular Fluid

Isohydric Principle: All Buffers

Hydrogen Ion Concentration and

in a Common Solution Are

Raises pH

in Equilibrium with the Same

Hydrogen Ion Concentration

If the metabolic formation of CO₂ remains constant,

We have been discussing buffer systems as though they

the only other factor that affects Pco₂in extracellular

operated individually in the body fluids. However, they

fluid is the rate of alveolar ventilation. The higher the

all work together, because H⁺ is common to the reac-

alveolar ventilation, the lower the Pco₂; conversely, the

tions of all the systems. Therefore, whenever there is a

lower the alveolar ventilation rate, the higher the Pco₂.

change in H⁺ concentration in the extracellular fluid, the

As discussed previously, when CO₂

concentration

balance of all the buffer systems changes at the same

increases, the H₂CO₃ concentration and H⁺ concentra-

time. This phenomenon is called the isohydric principle

tion also increase, thereby lowering extracellular

and is illustrated by the following formula:

fluid pH.

Figure

30-2 shows the approximate changes in

H+=K

K ¥HA

blood pH that are caused by increasing or decreasing

the rate of alveolar ventilation. Note that increasing

K₁, K₂, K₃ are the dissociation constants of three

alveolar ventilation to about twice normal raises the

respective acids, HA₁, HA₂, HA₃, and A₁, A₂, A₃ are the

pH of the extracellular fluid by about 0.23. If the pH

concentrations of the free negative ions that constitute

of the body fluids is 7.40 with normal alveolar ventila-

the bases of the three buffer systems.

tion, doubling the ventilation rate raises the pH to

The implication of this principle is that any condition

that changes the balance of one of the buffer systems

also changes the balance of all the others because the

buffer systems actually buffer one another by shifting

H⁺ back and forth between them.

+0.3

+0.2

Respiratory Regulation

+0.1

of Acid-Base Balance

Normal

The second line of defense against acid-base distur-

-0.1

bances is control of extracellular fluid CO₂ concentra-

-0.2

tion by the lungs. An increase in ventilation eliminates

-0.3

CO₂ from extracellular fluid, which, by mass action,

reduces the H⁺ concentration. Conversely, decreased

-0.4

ventilation increases CO₂, thus also increasing H⁺ con-

-0.5

centration in the extracellular fluid.

0.5

1.0

1.5

2.0

2.5

Rate of alveolar ventilation

(normal = 1)

Pulmonary Expiration of CO₂

Balances Metabolic Formation of CO₂

Figure 30-2

CO₂ is formed continually in the body by intracellular

metabolic processes. After it is formed, it diffuses from

Change in extracellular fluid pH caused by increased or

the cells into the interstitial fluids and blood, and the

decreased rate of alveolar ventilation, expressed as times normal.

Chapter 30

Regulation of Acid-Base Balance

389

about 7.63. Conversely, a decrease in alveolar ventila-

Feedback Control of Hydrogen Ion Concentration by the Respi-

tion to one fourth normal reduces the pH by 0.45. That

ratory System. Because increased H⁺ concentration

is, if the pH is 7.4 at a normal alveolar ventilation,

stimulates respiration, and because increased alveolar

reducing the ventilation to one fourth normal reduces

ventilation decreases the H⁺ concentration, the respi-

the pH to 6.95. Because the alveolar ventilation rate

ratory system acts as a typical negative feedback con-

can change markedly, from as low as 0 to as high as 15

troller of H⁺ concentration.

times normal, one can easily understand how much the

≠[H⁺] Æ ≠Alveolar ventilation

pH of the body fluids can be changed by the respira-

tory system.

ØPCO₂

Increased Hydrogen Ion

That is, whenever the H⁺ concentration increases

above normal, the respiratory system is stimulated,

Concentration Stimulates

and alveolar ventilation increases. This decreases the

Alveolar Ventilation

PCO₂ in extracellular fluid and reduces H⁺ concentra-

tion back toward normal. Conversely, if H⁺ concen-

Not only does the alveolar ventilation rate influence

tration falls below normal, the respiratory center

H⁺ concentration by changing the Pco₂ of the body

becomes depressed, alveolar ventilation decreases, and

fluids, but the H⁺ concentration affects the rate of

H⁺ concentration increases back toward normal.

alveolar ventilation. Thus, Figure 30-3 shows that the

alveolar ventilation rate increases four to five times

Efficiency of Respiratory Control of Hydrogen Ion Concen-

normal as the pH decreases from the normal value of

tration. Respiratory control cannot return the H⁺

7.4 to the strongly acidic value of 7.0. Conversely, when

concentration all the way back to normal when a dis-

plasma pH rises above 7.4, this causes a decrease in the

turbance outside the respiratory system has altered

ventilation rate. As one can see from the graph, the

pH. Ordinarily, the respiratory mechanism for con-

change in ventilation rate per unit pH change is much

trolling H⁺ concentration has an effectiveness between

greater at reduced levels of pH (corresponding to ele-

50 and 75 per cent, corresponding to a feedback gain

vated H⁺ concentration) compared with increased

of 1 to 3. That is, if the H⁺ concentration is suddenly

levels of pH. The reason for this is that as the alveolar

increased by adding acid to the extracellular fluid and

ventilation rate decreases, owing to an increase in pH

pH falls from 7.4 to 7.0, the respiratory system can

(decreased H⁺ concentration), the amount of oxygen

return the pH to a value of about 7.2 to 7.3. This

added to the blood decreases and the partial pressure

response occurs within 3 to 12 minutes.

of oxygen (PO₂) in the blood also decreases, which

stimulates the ventilation rate. Therefore, the respira-

Buffering Power of the Respiratory System. Respiratory reg-

tory compensation for an increase in pH is not nearly

ulation of acid-base balance is a physiologic type of

as effective as the response to a marked reduction in

buffer system because it acts rapidly and keeps the H

pH.

concentration from changing too much until the slowly

responding kidneys can eliminate the imbalance. In

general, the overall buffering power of the respiratory

system is one to two times as great as the buffering

power of all other chemical buffers in the extracellu-

lar fluid combined. That is, one to two times as much

acid or base can normally be buffered by this mecha-

nism as by the chemical buffers.

Impairment of Lung Function Can Cause Respiratory Acidosis.

We have discussed thus far the role of the normal res-

piratory mechanism as a means of buffering changes

in H⁺ concentration. However, abnormalities of respi-

ration can also cause changes in H⁺ concentration. For

example, an impairment of lung function, such as

severe emphysema, decreases the ability of the lungs

to eliminate CO₂; this causes a buildup of CO₂ in the

extracellular fluid and a tendency toward respiratory

acidosis. Also, the ability to respond to metabolic aci-

7.0

7.1

7.2

7.3

7.4

7.5

7.6

dosis is impaired because the compensatory reduc-

pH of arterial blood

tions in PCO₂ that would normally occur by means of

increased ventilation are blunted. In these circum-

stances, the kidneys represent the sole remaining phys-

iologic mechanism for returning pH toward normal

Figure 30-3

after the initial chemical buffering in the extracellular

Effect of blood pH on the rate of alveolar ventilation.

fluid has occurred.

390

Unit V The Body Fluids and Kidneys

Renal Control of

body of the nonvolatile acids produced each day, for a

total of 4400 milliequivalents of H⁺ secreted into the

Acid-Base Balance

tubular fluid each day.

When there is a reduction in the extracellular fluid

The kidneys control acid-base balance by excreting

H⁺ concentration (alkalosis), the kidneys fail to reab-

either an acidic or a basic urine. Excreting an acidic

sorb all the filtered bicarbonate, thereby increasing the

urine reduces the amount of acid in extracellular fluid,

excretion of bicarbonate. Because HCO_3- normally

whereas excreting a basic urine removes base from the

buffers hydrogen in the extracellular fluid, this loss of

extracellular fluid.

bicarbonate is the same as adding an H⁺ to the extra-

The overall mechanism by which the kidneys

cellular fluid. Therefore, in alkalosis, the removal of

excrete acidic or basic urine is as follows: Large

HCO_3- raises the extracellular fluid H⁺ concentration

numbers of HCO_3- are filtered continuously into the

back toward normal.

tubules, and if they are excreted into the urine, this

In acidosis, the kidneys do not excrete bicarbonate

removes base from the blood. Large numbers of H⁺ are

into the urine but reabsorb all the filtered bicarbonate

also secreted into the tubular lumen by the tubular

and produce new bicarbonate, which is added back to

epithelial cells, thus removing acid from the blood. If

the extracellular fluid. This reduces the extracellular

more H⁺ is secreted than HCO_3- is filtered, there will

fluid H⁺ concentration back toward normal.

be a net loss of acid from the extracellular fluid. Con-

Thus, the kidneys regulate extracellular fluid H⁺ con-

versely, if more HCO_3- is filtered than H⁺ is secreted,

centration through three fundamental mechanisms: (1)

there will be a net loss of base.

secretion of H⁺, (2) reabsorption of filtered HCO3-, and

As discussed previously, each day the body produces

(3) production of new HCO3-. All these processes are

about 80 milliequivalents of nonvolatile acids, mainly

accomplished through the same basic mechanism, as

from the metabolism of proteins. These acids are called

discussed in the next few sections.

nonvolatile because they are not H₂CO₃ and, there-

fore, cannot be excreted by the lungs. The primary

mechanism for removal of these acids from the body

is renal excretion. The kidneys must also prevent the

Secretion of Hydrogen Ions

loss of bicarbonate in the urine, a task that is quanti-

and Reabsorption of

tatively more important than the excretion of non-

Bicarbonate Ions by the

volatile acids. Each day the kidneys filter about 4320

milliequivalents of bicarbonate (180 L/day ¥ 24 mEq/

Renal Tubules

L); under normal conditions, almost all this is reab-

sorbed from the tubules, thereby conserving the

Hydrogen ion secretion and bicarbonate reabsorption

primary buffer system of the extracellular fluid.

occur in virtually all parts of the tubules except the

As discussed later, both the reabsorption of bicar-

descending and ascending thin limbs of the loop of

bonate and the excretion of H⁺ are accomplished

Henle. Figure 30-4 summarizes bicarbonate reabsorp-

through the process of H⁺ secretion by the tubules.

tion along the tubule. Keep in mind that for each bicar-

Because the HCO_3- must react with a secreted H⁺ to

bonate reabsorbed, an H⁺ must be secreted.

form H₂CO₃ before it can be reabsorbed, 4320 mil-

About 80 to 90 per cent of the bicarbonate reab-

liequivalents of H⁺ must be secreted each day just to

sorption (and H⁺ secretion) occurs in the proximal

reabsorb the filtered bicarbonate. Then an additional

tubule, so that only a small amount of bicarbonate

80 milliequivalents of H⁺ must be secreted to rid the

flows into the distal tubules and collecting ducts. In the

85%

(3672 mEq/day)

4320 mEq/day

10%

(432 mEq/day)

>4.9%

(215 mEq/day)

Figure 30-4

Reabsorption of bicarbonate in differ-

ent segments of the renal tubule. The

percentages of the filtered load of

bicarbonate absorbed by the various

tubular segments are shown, as well

as the number of milliequivalents

reabsorbed per day under normal

(1 mEq/day)

conditions.

Chapter 30

Regulation of Acid-Base Balance

391

thick ascending loop of Henle, another 10 per cent of

process begins when CO₂ either diffuses into the

the filtered bicarbonate is reabsorbed, and the remain-

tubular cells or is formed by metabolism in the tubular

der of the reabsorption takes place in the distal tubule

epithelial cells. CO₂, under the influence of the enzyme

and collecting duct. As discussed previously, the mech-

carbonic anhydrase, combines with H₂O to form

anism by which bicarbonate is reabsorbed also

H₂CO₃, which dissociates into HCO_3- and H⁺. The H⁺

involves tubular secretion of H⁺, but different tubular

is secreted from the cell into the tubular lumen by

segments accomplish this task differently.

sodium-hydrogen counter-transport. That is, when an

Na⁺ moves from the lumen of the tubule to the inte-

rior of the cell, it first combines with a carrier protein

Hydrogen Ions Are Secreted

in the luminal border of the cell membrane; at the

by Secondary Active Transport

same time, an H⁺ in the interior of the cells combines

with the carrier protein. The Na⁺ moves into the cell

in the Early Tubular Segments

down a concentration gradient that has been estab-

lished by the sodium-potassium ATPase pump in the

The epithelial cells of the proximal tubule, the thick

basolateral membrane. The gradient for Na⁺ move-

segment of the ascending loop of Henle, and the early

ment into the cell then provides the energy for moving

distal tubule all secrete H⁺ into the tubular fluid

H⁺ in the opposite direction from the interior of the

by sodium-hydrogen counter-transport, as shown in

cell to the tubular lumen.

Figure 30-5. This secondary active secretion of H⁺

The HCO_3- generated in the cell (when H⁺ dissoci-

is coupled with the transport of Na⁺ into the cell at

ates from H₂CO₃) then moves downhill across the

the luminal membrane by the sodium-hydrogen

basolateral membrane into the renal interstitial fluid

exchanger protein, and the energy for H⁺ secretion

and the peritubular capillary blood. The net result is

against a concentration gradient is derived from the

that for every H⁺ secreted into the tubular lumen, an

sodium gradient favoring Na⁺ movement into the cell.

HCO_3- enters the blood.

This gradient is established by the sodium-potassium

adenosine triphosphatase (ATPase) pump in the baso-

lateral membrane. More than 90 per cent of the bicar-

bonate is reabsorbed in this manner, requiring about

Filtered Bicarbonate Ions Are

3900 milliequivalents of H⁺ to be secreted each day by

Reabsorbed by Interaction with

the tubules. This mechanism, however, does not estab-

Hydrogen Ions in the Tubules

lish a very high H⁺ concentration in the tubular fluid;

the tubular fluid becomes very acidic only in the col-

Bicarbonate ions do not readily permeate the luminal

lecting tubules and collecting ducts.

membranes of the renal tubular cells; therefore,

Figure 30-5 shows how the process of H⁺ secretion

HCO_3- that is filtered by the glomerulus cannot be

achieves bicarbonate reabsorption. The secretory

directly reabsorbed. Instead, HCO_3- is reabsorbed by

a special process in which it first combines with H⁺ to

form H₂CO₃, which eventually becomes CO₂ and H₂O,

as shown in Figure 30-5.

Renal

Tubular

This reabsorption of HCO_3- is initiated by a reaction

interstitial

Tubular cells

lumen

in the tubules between HCO_3- filtered at the glomeru-

fluid

Na⁺+ HCO3-

lus and H⁺ secreted by the tubular cells. The H₂CO₃

formed then dissociates into CO₂ and H₂O. The CO₂

can move easily across the tubular membrane; there-

Na⁺

fore, it instantly diffuses into the tubular cell, where it

ATP

K⁺

H⁺

recombines with H₂O, under the influence of carbonic

HCO3- + H⁺

anhydrase, to generate a new H₂CO₃ molecule. This

H₂CO

H₂CO₃ in turn dissociates to form HCO_3- and H⁺; the

H₂CO₃

HCO_3- then diffuses through the basolateral mem-

Carbonic

brane into the interstitial fluid and is taken up into the

anhydrase

peritubular capillary blood. The transport of HCO₃

H₂O

across the basolateral membrane is facilitated by

CO₂ + H₂O

two mechanisms: (1) Na⁺-HCO_3- co-transport and (2)

Cl^--HCO_3- exchange.

Thus, each time an H⁺ is formed in the tubular epithe-

Figure 30-5

lial cells, an HCO

^- is also formed and released back

into the blood. The net effect of these reactions is

Cellular mechanisms for (1) active secretion of hydrogen ions into

the renal tubule; (2) tubular reabsorption of bicarbonate ions by

“reabsorption” of HCO_3- from the tubules, although

combination with hydrogen ions to form carbonic acid, which dis-

the HCO_3- that actually enters the extracellular fluid

sociates to form carbon dioxide and water; and (3) sodium ion

is not the same as that filtered into the tubules. The

reabsorption in exchange for hydrogen ions secreted. This pattern

reabsorption of filtered HCO_3- does not result in net

of hydrogen ion secretion occurs in the proximal tubule, the thick

secretion of H⁺ because the secreted H⁺ combines with

ascending segment of the loop of Henle, and the early distal

tubule.

the filtered HCO_3- and is therefore not excreted.

392

Unit V The Body Fluids and Kidneys

Bicarbonate Ions Are “Titrated” Against Hydrogen Ions in the

Renal

Tubular

Tubules. Under normal conditions, the rate of tubular

interstitial

Tubular cells

lumen

H⁺ secretion is about 4400 mEq/day, and the rate of fil-

fluid

tration by HCO_3- is about 4320 mEq/day. Thus, the

quantities of these two ions entering the tubules are

Cl^-

almost equal, and they combine with each other to

form CO₂ and H₂O. Therefore, it is said that HCO₃

HCO₃- + H⁺

H⁺

and H⁺ normally “titrate” each other in the tubules.

ATP

The titration process is not quite exact because there

H₂CO₃

is usually a slight excess of H⁺ in the tubules to be

Carbonic

excreted in the urine. This excess H⁺ (about 80 mEq/

anhydrase

day) rids the body of nonvolatile acids produced by

H₂O

metabolism. As discussed later, most of this H⁺ is

CO₂

not excreted as free H⁺ but rather in combination with

other urinary buffers, especially phosphate and

ammonia.

When there is an excess of HCO_3- over H⁺ in the

Figure 30-6

urine, as occurs in metabolic alkalosis, the excess

Primary active secretion of hydrogen ions through the luminal

HCO_3- cannot be reabsorbed; therefore, the excess

membrane of the intercalated epithelial cells of the late distal and

HCO_3- is left in the tubules and eventually excreted

collecting tubules. Note that one bicarbonate ion is absorbed for

into the urine, which helps correct the metabolic

each hydrogen ion secreted, and a chloride ion is passively

alkalosis.

secreted along with the hydrogen ion.

In acidosis, there is excess H⁺ relative to HCO_3-,

causing complete reabsorption of the bicarbonate;

the excess H⁺ passes into the urine. The excess H⁺ is

buffered in the tubules by phosphate and ammonia

instead of by counter-transport, as occurs in the early

and eventually excreted as salts. Thus, the basic mech-

parts of the nephron.

anism by which the kidneys correct either acidosis or

Although the secretion of H⁺ in the late distal tubule

alkalosis is incomplete titration of H⁺ against HCO_3-,

and collecting tubules accounts for only about 5 per

leaving one or the other to pass into the urine and be

cent of the total H⁺ secreted, this mechanism is impor-

removed from the extracellular fluid.

tant in forming a maximally acidic urine. In the prox-

imal tubules, H⁺ concentration can be increased only

Primary Active Secretion of Hydrogen

about threefold to fourfold, and the tubular fluid pH

Ions in the Intercalated Cells of Late

can be reduced to only about 6.7, although large

amounts of H⁺ are secreted by this nephron segment.

Distal and Collecting Tubules

However, H⁺ concentration can be increased as much

as 900-fold in the collecting tubules. This decreases the

Beginning in the late distal tubules and continuing

pH of the tubular fluid to about 4.5, which is the lower

through the remainder of the tubular system, the

limit of pH that can be achieved in normal kidneys.

tubular epithelium secretes H⁺ by primary active

transport. The characteristics of this transport are dif-

ferent from those discussed for the proximal tubule,

Combination of Excess

loop of Henle, and early distal tubule.

The mechanism for primary active H⁺ secretion is

Hydrogen Ions with Phosphate

shown in Figure 30-6. It occurs at the luminal mem-

and Ammonia Buffers in

brane of the tubular cell, where H⁺ is transported

the Tubule—A Mechanism

directly by a specific protein, a hydrogen-transporting

for Generating “New”

ATPase. The energy required for pumping the H⁺ is

derived from the breakdown of ATP to adenosine

Bicarbonate Ions

diphosphate.

Primary active secretion of H⁺ occurs in a special

When H⁺ is secreted in excess of the bicarbonate fil-

type of cell called the intercalated cells of the late distal

tered into the tubular fluid, only a small part of the

tubule and in the collecting tubules. Hydrogen ion

excess H⁺ can be excreted in the ionic form (H⁺) in the

secretion in these cells is accomplished in two steps:

urine. The reason for this is that the minimal urine pH

(1) the dissolved CO₂ in this cell combines with H₂O

is about 4.5, corresponding to an H⁺ concentration

to form H₂CO₃, and (2) the H₂CO₃ then dissociates

of 10^-4.5 mEq/L, or 0.03 mEq/L. Thus, for each liter of

into HCO_3-, which is reabsorbed into the blood, plus

urine formed, a maximum of only about 0.03 mil-

H⁺, which is secreted into the tubule by means of the

liequivalent of free H⁺ can be excreted. To excrete the

hydrogen-ATPase mechanism. For each H⁺ secreted,

80 milliequivalents of nonvolatile acid formed by

an HCO_3- is reabsorbed, similar to the process in the

metabolism each day, about 2667 liters of urine would

proximal tubules. The main difference is that H⁺ moves

have to be excreted if the H⁺ remained free in

across the luminal membrane by an active H⁺ pump

solution.

Chapter 30

Regulation of Acid-Base Balance

393

The excretion of large amounts of H⁺ (on occasion

Renal

Tubular

interstitial

lumen

as much as 500 mEq/day) in the urine is accomplished

Tubular cells

fluid

Na⁺+ NaHPO4-

primarily by combining the H⁺ with buffers in the

tubular fluid. The most important buffers are phos-

phate buffer and ammonia buffer. There are other

Na⁺

weak buffer systems, such as urate and citrate, that are

ATP

much less important.

K⁺

H⁺+ NaHPO4-

HCO3-

HCO₃- + H⁺

When H⁺ is titrated in the tubular fluid with HCO_3-,

this results in the reabsorption of one HCO_3- for each

H⁺ secreted, as discussed earlier. But when there are

H₂CO₃

NaH₂PO₄

excess H⁺ in the urine, they combine with buffers other

³ Carbonic

anhydrase

than HCO_3-, and this results in the generation of new

H₂O

HCO_3- that can also enter the blood. Thus, when there

CO₂

is excess H⁺ in the extracellular fluid, the kidneys not

CO₂

only reabsorb all the filtered HCO_3- but also generate

new HCO_3-, thereby helping to replenish the HCO3

Figure 30-7

lost from the extracellular fluid in acidosis. In the next

two sections, we discuss the mechanisms by which

Buffering of secreted hydrogen ions by filtered phosphate

phosphate and ammonia buffers contribute to the gen-

(NaHPO4-). Note that a new bicarbonate ion is returned to the

eration of new HCO_3-.

blood for each NaHPO4- that reacts with a secreted hydrogen ion.

Phosphate Buffer System Carries

HCO3- to the blood. This demonstrates one of the

Excess Hydrogen Ions into the Urine

mechanisms by which the kidneys are able to replen-

and Generates New Bicarbonate

ish the extracellular fluid stores of HCO_3-.

Under normal conditions, much of the filtered phos-

phate is reabsorbed, and only about 30 to 40 mEq/day

The phosphate buffer system is composed of HPO₄

and H₂PO_4-. Both become concentrated in the tubular

is available for buffering H⁺. Therefore, much of the

fluid because of their relatively poor reabsorption and

buffering of excess H⁺ in the tubular fluid in acidosis

because of the reabsorption of water from the tubular

occurs through the ammonia buffer system.

fluid. Therefore, although phosphate is not an impor-

tant extracellular fluid buffer, it is much more effective

Excretion of Excess Hydrogen Ions

as a buffer in the tubular fluid.

Another factor that makes phosphate important as

and Generation of New Bicarbonate

a tubular buffer is the fact that the pK of this system

by the Ammonia Buffer System

is about 6.8. Under normal conditions, the urine is

slightly acidic, and the urine pH is near the pK of the

A second buffer system in the tubular fluid that is even

phosphate buffer system. Therefore, in the tubules, the

more important quantitatively than the phosphate

phosphate buffer system normally functions near its

buffer system is composed of ammonia (NH₃) and the

most effective range of pH.

ammonium ion (NH4+). Ammonium ion is synthesized

Figure 30-7 shows the sequence of events by which

from glutamine, which comes mainly from the metab-

H⁺ is excreted in combination with phosphate buffer

olism of amino acids in the liver. The glutamine deliv-

and the mechanism by which new bicarbonate is added

ered to the kidneys is transported into the epithelial

to the blood. The process of H⁺ secretion into the

cells of the proximal tubules, thick ascending limb of

tubules is the same as described earlier. As long as

the loop of Henle, and distal tubules (Figure 30-8).

there is excess HCO_3- in the tubular fluid, most of the

Once inside the cell, each molecule of glutamine is

secreted H⁺ combines with HCO_3-. However, once all

metabolized in a series of reactions to ultimately form

the HCO_3- has been reabsorbed and is no longer avail-

two NH4+ and two HCO_3-. The NH4+ is secreted into

able to combine with H⁺, any excess H⁺ can combine

the tubular lumen by a counter-transport mechanism

with HPO4= and other tubular buffers. After the H⁺

in exchange for sodium, which is reabsorbed. The

combines with HPO4= to form H₂PO_4-, it can be

HCO_3- is transported across the basolateral mem-

excreted as a sodium salt (NaH₂PO₄), carrying with it

brane, along with the reabsorbed Na⁺, into the inter-

the excess hydrogen.

stitial fluid and is taken up by the peritubular

There is one important difference in this sequence

capillaries. Thus, for each molecule of glutamine

of H⁺ excretion from that discussed previously. In this

metabolized in the proximal tubules, two NH4+ are

case, the HCO_3- that is generated in the tubular cell

secreted into the urine and two HCO_3- are reabsorbed

and enters the peritubular blood represents a net gain

into the blood. The HCO

^- generated by this process

of HCO_3- by the blood, rather than merely a replace-

constitutes new bicarbonate.

ment of filtered HCO_3-. Therefore, whenever an H⁺

In the collecting tubules, the addition of NH4+ to the

secreted into the tubular lumen combines with a buffer

tubular fluids occurs through a different mechanism

other than HCO

^-, the net effect is addition of a new

(Figure 30-9). Here, H⁺ is secreted by the tubular

394

Unit V The Body Fluids and Kidneys

Renal

Tubular

An increase in extracellular fluid H⁺ concentration

Proximal

interstitial

lumen

tubular cells

stimulates renal glutamine metabolism and, therefore,

fluid

increases the formation of NH4+ and new HCO_3- to be

used in H⁺ buffering; a decrease in H⁺ concentration

has the opposite effect.

Under normal conditions, the amount of H⁺ elimi-

Glutamine

nated by the ammonia buffer system accounts for

about 50 per cent of the acid excreted and 50 per cent

Cl^-

of the new HCO_3- generated by the kidneys. However,

2HCO3-

2NH4+

with chronic acidosis, the rate of NH4+ excretion can

increase to as much as 500 mEq/day. Therefore, with

chronic acidosis, the dominant mechanism by which

NH4+

+ Cl^-

acid is eliminated is excretion of NH4+. This also pro-

Na⁺

vides the most important mechanism for generating

new bicarbonate during chronic acidosis.

Figure 30-8

Quantifying Renal

Production and secretion of ammonium ion (NH4+) by proximal

Acid-Base Excretion

tubular cells. Glutamine is metabolized in the cell, yielding NH₄

and bicarbonate. The NH4+ is secreted into the lumen by a

sodium-NH4+ pump. For each glutamine molecule metabolized,

Based on the principles discussed earlier, we can quan-

two NH4+ are produced and secreted and two HCO3- are returned

to the blood.

titate the kidneys’ net excretion of acid or net addition

or elimination of bicarbonate from the blood as

follows.

Renal

Tubular

Bicarbonate excretion is calculated as the urine flow

Collecting

interstitial

lumen

rate multiplied by urinary bicarbonate concentration.

tubular cells

fluid

This number indicates how rapidly the kidneys are

removing HCO_3- from the blood (which is the same as

adding an H⁺ to the blood). In alkalosis, the loss of

Na⁺

NH₃

HCO_3- helps return the plasma pH toward normal.

ATP

K⁺

Cl^-

The amount of new bicarbonate contributed to

HCO3- + H⁺

ATP

the blood at any given time is equal to the amount of

H⁺

H⁺ secreted that ends up in the tubular lumen with

H₂CO

nonbicarbonate urinary buffers. As discussed previ-

Carbonic

NH₄+ + Cl^-

ously, the primary sources of nonbicarbonate urinary

anhydrase

buffers are NH4+ and phosphate. Therefore, the

H₂O

CO₂

amount of HCO_3- added to the blood (and H⁺ excreted

by NH4+) is calculated by measuring NH4+

excretion (urine flow rate multiplied by urinary NH4+

concentration).

Figure 30-9

The rest of the nonbicarbonate, non-NH4+ buffer

excreted in the urine is measured by determining a

Buffering of hydrogen ion secretion by ammonia (NH₃) in the col-

value known as titratable acid. The amount of titrat-

lecting tubules. Ammonia diffuses into the tubular lumen, where it

reacts with secreted hydrogen ions to form NH4+, which is then

able acid in the urine is measured by titrating the urine

excreted. For each NH4+ excreted, a new HCO3- is formed in the

with a strong base, such as NaOH, to a pH of 7.4, the

tubular cells and returned to the blood.

pH of normal plasma, and the pH of the glomerular

filtrate. This titration reverses the events that occurred

in the tubular lumen when the tubular fluid was

membrane into the lumen, where it combines with

titrated by excreted H⁺. Therefore, the number of mil-

NH₃ to form NH4+, which is then excreted. The col-

liequivalents of NaOH required to return the urinary

lecting ducts are permeable to NH₃, which can easily

pH to 7.4 equals the number of milliequivalents of H⁺

diffuse into the tubular lumen. However, the luminal

added to the tubular fluid that combined with phos-

membrane of this part of the tubules is much less per-

phate and other organic buffers. The titratable acid

meable to NH4+; therefore, once the H⁺ has reacted

measurement does not include H⁺ in association with

with NH₃ to form NH4+, the NH4+ is trapped in the

NH4+, because the pK of the ammonia-ammonium

tubular lumen and eliminated in the urine. For each

reaction is 9.2, and titration with NaOH to a pH of 7.4

NH4+ excreted, a new HCO3- is generated and added to

does not remove the H⁺ from NH4+.

the blood.

Thus, the net acid excretion by the kidneys can be

assessed as

Chronic Acidosis Increases NH4+ Excretion. One of the most

important features of the renal ammonium-ammonia

Net acid excretion = NH4+ excretion + Urinary

buffer system is that it is subject to physiologic control.

titratable acid - Bicarbonate excretion

Chapter 30

Regulation of Acid-Base Balance

395

The reason we subtract bicarbonate excretion is that

Table 30-2

the loss of HCO_3- is the same as the addition of H⁺ to

Factors That Increase or Decrease H⁺

Secretion and HCO₃

the blood. To maintain acid-base balance, the net acid

Reabsorption by the Renal Tubules

excretion must equal the nonvolatile acid production

in the body. In acidosis, the net acid excretion increases

markedly, especially because of increased NH4+ excre-

Increase H⁺ Secretion and

Decrease H⁺ Secretion and

HCO_3- Reabsorption

tion, thereby removing acid from the blood. The net

acid excretion also equals the rate of net HCO_3- addi-

≠ PCO₂

Ø PCO₂

tion to the blood. Therefore, in acidosis, there is a net

≠ H⁺, Ø HCO_3-

ØH⁺, ≠ HCO3

addition of HCO3- back to the blood as more NH4+ and

Ø Extracellular fluid volume

≠ Extracellular fluid volume

urinary titratable acid are excreted.

In alkalosis, titratable acid and NH4+ excretion drop

≠ Angiotensin II

Ø Angiotensin II

to 0, whereas HCO_3- excretion increases. Therefore, in

≠ Aldosterone

Ø Aldosterone

alkalosis, there is a negative net acid secretion. This

Hypokalemia

Hyperkalemia

means that there is a net loss of HCO_3- from the blood

(which is the same as adding H⁺ to the blood) and that

no new HCO_3- is generated by the kidneys.

A special factor that can increase H⁺ secretion under

some pathophysiologic conditions is excessive aldos-

terone secretion. Aldosterone stimulates the secretion

Regulation of Renal Tubular Hydrogen

of H⁺ by the intercalated cells of the collecting duct.

Ion Secretion

Therefore, oversecretion of aldosterone, as occurs in

Conn’s syndrome, can cause excessive secretion of H⁺

As discussed earlier, H⁺ secretion by the tubular

into the tubular fluid and, consequently, increased

epithelium is necessary for both HCO_3- reabsorption

amounts of bicarbonate added back to the blood. This

and generation of new HCO_3- associated with titrat-

usually causes alkalosis in patients with excessive

able acid formation. Therefore, the rate of H⁺ secre-

aldosterone secretion.

tion must be carefully regulated if the kidneys are to

The tubular cells usually respond to a decrease in H⁺

effectively perform their functions in acid-base home-

concentration (alkalosis) by reducing H⁺ secretion.

ostasis. Under normal conditions, the kidney tubules

The decreased H⁺ secretion results from decreased

must secrete at least enough H⁺ to reabsorb almost all

extracellular PCO₂, as occurs in respiratory alkalosis, or

the HCO_3- that is filtered, and there must be enough

from a decrease in H⁺ concentration per se, as occurs

H⁺

left over to be excreted as titratable acid or NH₄

in both respiratory and metabolic alkalosis.

to rid the body of the nonvolatile acids produced each

Table 30-2 summarizes the major factors that influ-

day from metabolism.

ence H⁺ secretion and HCO_3- reabsorption. Some of

In alkalosis, tubular secretion of H⁺ must be reduced

these are not directly related to the regulation of acid-

to a level that is too low to achieve complete HCO₃

base balance. For example, H⁺ secretion is coupled

–

reabsorption, enabling the kidneys to increase HCO₃

to Na⁺ reabsorption by the Na⁺-H⁺ exchanger in the

excretion. In this condition, titratable acid and

proximal tubule and thick ascending loop of Henle.

ammonia are not excreted because there is no excess

Therefore, factors that stimulate Na⁺ reabsorption,

H⁺ available to combine with nonbicarbonate buffers;

such as decreased extracellular fluid volume, may also

therefore, there is no new HCO_3- added to the

secondarily increase H⁺ secretion.

urine in alkalosis. During acidosis, the tubular H⁺

Extracellular fluid volume depletion stimulates

secretion must be increased sufficiently to reabsorb

sodium reabsorption by the renal tubules and

all the filtered HCO_3- and still have enough H⁺ left

increases H⁺ secretion and HCO_3- reabsorption

over to excrete large amounts of NH4+ and titratable

through multiple mechanisms, including (1) increased

acid, thereby contributing large amounts of new

angiotensin II levels, which directly stimulate the activ-

HCO_3- to the total body extracellular fluid. The

ity of the Na⁺-H⁺ exchanger in the renal tubules, and

most important stimuli for increasing H⁺ secretion by

(2) increased aldosterone levels, which stimulate H⁺

the tubules in acidosis are (1) an increase in PCO₂

secretion by the intercalated cells of the cortical col-

of the extracellular fluid and (2) an increase in H⁺

lecting tubules. Therefore, extracellular fluid volume

concentration of the extracellular fluid

(decreased

depletion tends to cause alkalosis due to excess H⁺

pH).

secretion and HCO_3- reabsorption.

The tubular cells respond directly to an increase in

Changes in plasma potassium concentration can

PCO₂ of the blood, as occurs in respiratory acidosis,

also influence H⁺ secretion, with hypokalemia stimu-

with an increase in the rate of H⁺ secretion as follows:

lating and hyperkalemia inhibiting H⁺ secretion in the

The increased PCO₂ raises the PCO₂ of the tubular cells,

proximal tubule. A decreased plasma potassium con-

causing increased formation of H⁺ in the tubular

centration tends to increase the H⁺ concentration in

cells, which in turn stimulates the secretion of H⁺. The

the renal tubular cells. This, in turn, stimulates H⁺

second factor that stimulates H⁺ secretion is an

secretion and HCO_3- reabsorption and leads to alka-

increase in extracellular fluid H⁺ concentration

losis. Hyperkalemia decreases H⁺

secretion and HCO₃

(decreased pH).

reabsorption and tends to cause acidosis.

396

Unit V The Body Fluids and Kidneys

Renal Correction of Acidosis—

Table 30-3

Increased Excretion of

Characteristics of Primary Acid-Base Disturbances

Hydrogen Ions and Addition

of Bicarbonate Ions to the

pH H⁺

PCO₂

HCO₃

Extracellular Fluid

Normal

7.4

40 mEq/L

40 mm Hg

24 mEq/L

Respiratory acidosis

≠

≠≠

≠

Now that we have described the mechanisms by which

Respiratory alkalosis

≠ Ø

ØØ

the kidneys secrete H⁺ and reabsorb HCO_3-, we can

explain how the kidneys readjust the pH of the extra-

Metabolic acidosis

≠

ØØ

cellular fluid when it becomes abnormal.

Metabolic alkalosis

≠ Ø

≠

≠≠

Referring to equation

8, the Henderson-

Hasselbalch equation, we can see that acidosis occurs

The primary event is indicated by the double arrows (≠≠ or ØØ). Note that

respiratory acid-base disorders are initiated by an increase or decrease in

when the ratio of HCO_3- to CO₂ in the extracellular

PCO₂, whereas metabolic disorders are initiated by an increase or decrease in

fluid decreases, thereby decreasing pH. If this ratio

HCO_3-.

decreases because of a fall in HCO_3-, the acidosis is

referred to as metabolic acidosis. If the pH falls

respiratory and metabolic alkalosis, which are dis-

because of an increase in PCO₂, the acidosis is referred

cussed in the next section. Note that in respiratory

to as respiratory acidosis.

acidosis, there is a reduction in pH, an increase in

extracellular fluid H⁺ concentration, and an increase in

Acidosis Decreases the Ratio of

PCO₂, which is the initial cause of the acidosis. The

HCO3-/H⁺ in Renal Tubular Fluid

compensatory response is an increase in plasma

HCO3-, caused by the addition of new bicarbonate to

Both respiratory and metabolic acidosis cause a

the extracellular fluid by the kidneys. The rise in HCO₃

decrease in the ratio of HCO_3- to H⁺ in the renal

helps offset the increase in PCO₂, thereby returning the

tubular fluid. As a result, there is an excess of H⁺ in the

plasma pH toward normal.

renal tubules, causing complete reabsorption of HCO₃

In metabolic acidosis, there is also a decrease in pH

and still leaving additional H⁺ available to combine

and a rise in extracellular fluid H⁺ concentration.

with the urinary buffers NH4+ and HPO4=. Thus, in aci-

However, in this case, the primary abnormality is a

dosis, the kidneys reabsorb all the filtered HCO_3- and

decrease in plasma HCO_3-. The primary compensa-

contribute new HCO_3-

through the formation of NH₄

tions include increased ventilation rate, which reduces

and titratable acid.

PCO₂, and renal compensation, which, by adding new

In metabolic acidosis, an excess of H⁺

over HCO

bicarbonate to the extracellular fluid, helps minimize

occurs in the tubular fluid primarily because of

the initial fall in extracellular HCO3- concentration.

decreased filtration of HCO

^-. This decreased filtration

of HCO_3- is caused mainly by a decrease in the extra-

cellular fluid concentration of HCO_3-.

Renal Correction of

In respiratory acidosis, the excess H⁺ in the tubular

Alkalosis—Decreased Tubular

fluid is due mainly to the rise in extracellular fluid

Secretion of Hydrogen Ions

PCO₂, which stimulates H⁺ secretion.

and Increased Excretion

As discussed previously, with chronic acidosis,

regardless of whether it is respiratory or metabolic,

of Bicarbonate Ions

there is an increase in the production of NH4+, which

further contributes to the excretion of H⁺ and the addi-

The compensatory responses to alkalosis are basically

tion of new HCO_3- to the extracellular fluid. With

opposite to those that occur in acidosis. In alkalosis,

severe chronic acidosis, as much as 500 mEq/day of H⁺

the ratio of HCO_3- to CO₂ in the extracellular fluid

can be excreted in the urine, mainly in the form of

increases, causing a rise in pH

(a decrease in H⁺

NH4+; this, in turn, contributes up to 500 mEq/day of

concentration), as is evident from the Henderson-

new HCO_3- that is added to the blood.

Hasselbalch equation.

Thus, with chronic acidosis, the increased secretion

of H⁺ by the tubules helps eliminate excess H⁺ from

the body and increases the quantity of HCO_3- in the

Alkalosis Increases the Ratio of

extracellular fluid. This increases the bicarbonate part

HCO3-/H⁺ in Renal Tubular Fluid

of the bicarbonate buffer system, which, in accordance

with the Henderson-Hasselbalch equation, helps raise

Regardless of whether the alkalosis is caused by meta-

the extracellular pH and corrects the acidosis. If the

bolic or respiratory abnormalities, there is still an

acidosis is metabolically mediated, additional com-

increase in the ratio of HCO_3- to H⁺ in the renal

pensation by the lungs causes a reduction in PCO₂, also

tubular fluid. The net effect of this is an excess of

helping to correct the acidosis.

HCO_3- that cannot be reabsorbed from the tubules

Table 30-3 summarizes the characteristics associ-

and is, therefore, excreted in the urine. Thus, in alka-

ated with respiratory and metabolic acidosis as well as

losis, HCO_3- is removed from the extracellular fluid by

Chapter 30

Regulation of Acid-Base Balance

397

renal excretion, which has the same effect as adding an

In respiratory acidosis, the compensatory responses

H⁺ to the extracellular fluid. This helps return the H⁺

available are (1) the buffers of the body fluids and (2)

concentration and pH back toward normal.

the kidneys, which require several days to compensate

for the disorder.

Table 30-3 shows the overall characteristics of res-

piratory and metabolic alkalosis. In respiratory alkalo-

sis, there is an increase in extracellular fluid pH and a

Respiratory Alkalosis Results

decrease in H⁺ concentration. The cause of the alkalo-

from Increased Ventilation and

sis is a decrease in plasma PCO₂ , caused by hyperventi-

Decreased PCO₂

lation. The reduction in PCO₂ then leads to a decrease

in the rate of H⁺ secretion by the renal tubules. The

Respiratory alkalosis is caused by overventilation by

decrease in H⁺ secretion reduces the amount of H⁺ in

the lungs. Rarely does this occur because of physical

the renal tubular fluid. Consequently, there is not

pathological conditions. However, a psychoneurosis can

enough H⁺ to react with all the HCO_3- that is filtered.

occasionally cause overbreathing to the extent that a

Therefore, the HCO_3- that cannot react with H⁺ is not

person becomes alkalotic.

A physiologic type of respiratory alkalosis occurs

reabsorbed and is excreted in the urine. This results in

when a person ascends to high altitude. The low oxygen

a decrease in plasma HCO_3- concentration and cor-

content of the air stimulates respiration, which causes

rection of the alkalosis. Therefore, the compensatory

excess loss of CO₂ and development of mild respiratory

response to a primary reduction in PCO₂ in respiratory

alkalosis. Again, the major means for compensation are

alkalosis is a reduction in plasma HCO3- concentration,

the chemical buffers of the body fluids and the ability

caused by increased renal excretion of HCO3-.

of the kidneys to increase HCO_3- excretion.

In metabolic alkalosis, there is also an increase in

plasma pH and a decrease in H⁺ concentration.

Metabolic Acidosis Results from

The cause of metabolic alkalosis, however, is a rise in

the extracellular fluid HCO_3- concentration. This is

Decreased Extracellular Fluid

partly compensated for by a reduction in the respira-

Bicarbonate Concentration

tion rate, which increases PCO₂ and helps return the

The term metabolic acidosis refers to all other types of

extracellular fluid pH toward normal. In addition, the

acidosis besides those caused by excess CO₂ in the body

increase in HCO_3- concentration in the extracellular

fluids. Metabolic acidosis can result from several general

fluid leads to an increase in the filtered load of HCO_3-,

causes: (1) failure of the kidneys to excrete metabolic

which in turn causes an excess of HCO_3- over H⁺

acids normally formed in the body, (2) formation of

secreted in the renal tubular fluid. The excess HCO₃

excess quantities of metabolic acids in the body, (3)

in the tubular fluid fails to be reabsorbed because

addition of metabolic acids to the body by ingestion or

there is no H⁺ to react with, and it is excreted in the

infusion of acids, and (4) loss of base from the body

urine. In metabolic alkalosis, the primary compensa-

fluids, which has the same effect as adding an acid to the

body fluids. Some specific conditions that cause meta-

tions are decreased ventilation, which raises PCO₂ , and

bolic acidosis are the following.

increased renal HCO3- excretion, which helps compen-

sate for the initial rise in extracellular fluid HCO₃

Renal Tubular Acidosis. This type of acidosis results from

concentration.

a defect in renal secretion of H⁺ or in reabsorption of

HCO_3-, or both. These disorders are generally of two

types: (1) impairment of renal tubular HCO_3- reab-

Clinical Causes of

sorption, causing loss of HCO_3- in the urine, or (2)

Acid-Base Disorders

inability of the renal tubular H⁺ secretory mechanism to

establish a normal acidic urine, causing the excretion of

Respiratory Acidosis Is Caused

an alkaline urine. In these cases, inadequate amounts of

by Decreased Ventilation and

titratable acid and NH4+ are excreted, so that there is

Increased PCO₂

net accumulation of acid in the body fluids. Some causes

of renal tubular acidosis include chronic renal failure,

From the previous discussion, it is obvious that any

insufficient aldosterone secretion (Addison’s disease),

factor that decreases the rate of pulmonary ventilation

and several hereditary and acquired disorders that

also increases the PCO₂ of extracellular fluid. This causes

impair tubular function, such as Fanconi’s syndrome.

an increase in H₂CO₃ and H⁺ concentration, thus re-

sulting in acidosis. Because the acidosis is caused by

Diarrhea. Severe diarrhea is probably the most frequent

an abnormality in respiration, it is called respiratory

cause of metabolic acidosis. The cause of this acidosis is

acidosis.

the loss of large amounts of sodium bicarbonate into the

Respiratory acidosis can occur from pathological

feces. The gastrointestinal secretions normally contain

conditions that damage the respiratory centers or

large amounts of bicarbonate, and diarrhea results in

that decrease the ability of the lungs to eliminate CO₂.

the loss of HCO_3- from the body, which has the same

For example, damage to the respiratory center in the

effect as losing large amounts of bicarbonate in the

medulla oblongata can lead to respiratory acidosis. Also,

urine. This form of metabolic acidosis is particularly

obstruction of the passageways of the respiratory tract,

serious and can cause death, especially in young

pneumonia, emphysema, or decreased pulmonary mem-

children.

brane surface area, as well as any factor that interferes

with the exchange of gases between the blood and the

Vomiting of Intestinal Contents. Vomiting of gastric con-

alveolar air, can cause respiratory acidosis.

tents alone would cause loss of acid and a tendency

398

Unit V The Body Fluids and Kidneys

toward alkalosis because the stomach secretions are

Vomiting of Gastric Contents. Vomiting of the gastric con-

highly acidic. However, vomiting large amounts from

tents alone, without vomiting of the lower gastrointesti-

deeper in the gastrointestinal tract, which sometimes

nal contents, causes loss of the HCl secreted by the

occurs, causes loss of bicarbonate and results in meta-

stomach mucosa. The net result is a loss of acid from the

bolic acidosis in the same way that diarrhea causes

extracellular fluid and development of metabolic alka-

acidosis.

losis. This type of alkalosis occurs especially in neonates

who have pyloric obstruction caused by hypertrophied

Diabetes Mellitus. Diabetes mellitus is caused by lack of

pyloric sphincter muscles.

insulin secretion by the pancreas (type I diabetes) or

by insufficient insulin secretion to compensate for

Ingestion of Alkaline Drugs. A common cause of metabolic

decreased sensitivity to the effects of insulin (type II

alkalosis is ingestion of alkaline drugs, such as sodium

diabetes). In the absence of sufficient insulin, the normal

bicarbonate, for the treatment of gastritis or peptic

use of glucose for metabolism is prevented. Instead,

ulcer.

some of the fats are split into acetoacetic acid, and this

is metabolized by the tissues for energy in place of

glucose. With severe diabetes mellitus, blood acetoacetic

Treatment of Acidosis

acid levels can rise very high, causing severe metabolic

acidosis. In an attempt to compensate for this acidosis,

or Alkalosis

large amounts of acid are excreted in the urine, some-

The best treatment for acidosis or alkalosis is to correct

times as much as 500 mmol/day.

the condition that caused the abnormality. This is often

Ingestion of Acids. Rarely are large amounts of acids

difficult, especially in chronic diseases that cause

ingested in normal foods. However, severe metabolic

impaired lung function or kidney failure. In these cir-

acidosis occasionally results from the ingestion of

cumstances, various agents can be used to neutralize the

certain acidic poisons. Some of these include acetylsali-

excess acid or base in the extracellular fluid.

cylics (aspirin) and methyl alcohol (which forms formic

To neutralize excess acid, large amounts of sodium

acid when it is metabolized).

bicarbonate can be ingested by mouth. The sodium

bicarbonate is absorbed from the gastrointestinal tract

Chronic Renal Failure. When kidney function declines

into the blood and increases the bicarbonate portion of

markedly, there is a buildup of the anions of weak acids

the bicarbonate buffer system, thereby increasing pH

in the body fluids that are not being excreted by the

toward normal. Sodium bicarbonate can also be infused

kidneys. In addition, the decreased glomerular filtration

intravenously, but because of the potentially dangerous

rate reduces the excretion of phosphates and NH4+,

physiologic effects of such treatment, other substances

which reduces the amount of bicarbonate added back

are often used instead, such as sodium lactate and

to the body fluids. Thus, chronic renal failure can be

sodium gluconate. The lactate and gluconate portions of

associated with severe metabolic acidosis.

the molecules are metabolized in the body, leaving the

sodium in the extracellular fluid in the form of sodium

Metabolic Alkalosis Is Caused

bicarbonate and thereby increasing the pH of the fluid

by Increased Extracellular Fluid

toward normal.

For the treatment of alkalosis, ammonium chloride

Bicarbonate Concentration

can be administered by mouth. When the ammonium

When there is excess retention of HCO_3- or loss of H⁺

chloride is absorbed into the blood, the ammonia

from the body, this results in metabolic alkalosis. Meta-

portion is converted by the liver into urea. This

bolic alkalosis is not nearly as common as metabolic aci-

reaction liberates HCl, which immediately reacts with

dosis, but some of the causes of metabolic alkalosis are

the buffers of the body fluids to shift the H⁺ concentra-

as follows.

tion in the acidic direction. Ammonium chloride

occasionally is infused intravenously, but NH4+ is

Administration of Diuretics

(Except the Carbonic Anhydrase

highly toxic, and this procedure can be dan-

Inhibitors). All diuretics cause increased flow of fluid

gerous. Another substance used occasionally is lysine

along the tubules, usually causing increased flow in the

monohydrochloride.

distal and collecting tubules. This leads to increased

reabsorption of Na⁺ from these parts of the nephrons.

Because the sodium reabsorption here is coupled with

Clinical Measurements and

H⁺ secretion, the enhanced sodium reabsorption also

Analysis of Acid-Base

leads to an increase in H⁺ secretion and an increase in

bicarbonate reabsorption. These changes lead to the

Disorders

development of alkalosis, characterized by increased

Appropriate therapy of acid-base disorders requires

extracellular fluid bicarbonate concentration.

proper diagnosis. The simple acid-base disorders

Excess Aldosterone. When large amounts of aldosterone

described previously can be diagnosed by analyzing

are secreted by the adrenal glands, a mild metabolic

three measurements from an arterial blood sample: pH,

alkalosis develops. As discussed previously, aldosterone

plasma bicarbonate concentration, and PCO₂.

promotes extensive reabsorption of Na⁺ from the distal

The diagnosis of simple acid-base disorders involves

and collecting tubules and at the same time stimulates

several steps, as shown in Figure

30-10. By exam-

the secretion of H⁺ by the intercalated cells of the col-

ining the pH, one can determine whether the disorder

lecting tubules. This increased secretion of H⁺ leads to

is acidosis or alkalosis. A pH less than 7.4 indicates

its increased excretion by the kidneys and, therefore,

acidosis, whereas a pH greater than

7.4 indicates

metabolic alkalosis.

alkalosis.

Chapter 30

Regulation of Acid-Base Balance

399

Complex Acid-Base Disorders and

Arterial blood sample

Use of the Acid-Base Nomogram

for Diagnosis

<7.4

>7.4

In some instances, acid-base disorders are not accom-

pH?

panied by appropriate compensatory responses. When

this occurs, the abnormality is referred to as a mixed

acid-base disorder. This means that there are two or

Acidosis

Alkalosis

more underlying causes for the acid-base disturbance.

For example, a patient with low pH would be catego-

HCO₃

Pco₂

HCO₃

Pco₂

rized as acidotic. If the disorder was metabolically medi-

<24 mEq/L

>40 mm Hg

>24 mEq/L

<40 mm Hg

ated, this would also be accompanied by a low plasma

Metabolic

Respiratory

Metabolic

Respiratory

HCO_3- concentration and, after appropriate respiratory

compensation, a low PCO₂. However, if the low plasma

pH and low HCO_3- concentration are associated with

elevated PCO₂, one would suspect a respiratory compo-

Respiratory

Renal

Respiratory

Renal

nent to the acidosis as well as a metabolic component.

compensation

Therefore, this disorder would be categorized as a

Pco₂

HCO₃

Pco₂

HCO₃

mixed acidosis. This could occur, for example, in a

<40 mm Hg

>24 mEq/L

>40 mm Hg

<24 mEq/L

patient with acute HCO_3- loss from the gastrointestinal

tract because of diarrhea (metabolic acidosis) who also

Figure 30-10

has emphysema (respiratory acidosis).

A convenient way to diagnose acid-base disorders is

Analysis of simple acid-base disorders. If the compensatory

to use an acid-base nomogram, as shown in Figure

responses are markedly different from those shown at the bottom

30-11. This diagram can be used to determine the type

of the figure, one should suspect a mixed acid-base disorder.

of acidosis or alkalosis, as well as its severity. In this

acid-base diagram, pH, HCO_3- concentration, and PCO₂

values intersect according to the Henderson-Hassel-

balch equation. The central open circle shows normal

values and the deviations that can still be considered

within the normal range. The shaded areas of the

The second step is to examine the plasma PCO₂ and

diagram show the 95 per cent confidence limits for the

HCO_3- concentration. The normal value for PCO₂ is

normal compensations to simple metabolic and respira-

about 40 mm Hg, and for HCO_3-, it is 24 mEq/L. If the

tory disorders.

disorder has been characterized as acidosis and the

When using this diagram, one must assume that suf-

plasma PCO₂ is increased, there must be a respiratory

ficient time has elapsed for a full compensatory

component to the acidosis. After renal compensation,

response, which is 6 to 12 hours for the ventilatory com-

the plasma HCO_3- concentration in respiratory acidosis

pensations in primary metabolic disorders and 3 to 5

would tend to increase above normal. Therefore, the

days for the metabolic compensations in primary respi-

expected values for a simple respiratory acidosis would

ratory disorders. If a value is within the shaded area, this

be reduced plasma pH, increased PCO₂ , and increased

suggests that there is a simple acid-base disturbance.

plasma HCO_3- concentration after partial renal

Conversely, if the values for pH, bicarbonate, or PCO₂

compensation.

lie outside the shaded area, this suggests that there may

For metabolic acidosis, there would also be a decrease

be a mixed acid-base disorder.

in plasma pH. However, with metabolic acidosis, the

It is important to recognize that an acid-base value

primary abnormality is a decrease in plasma HCO₃

within the shaded area does not always mean that there

concentration. Therefore, if a low pH is associated with

is a simple acid-base disorder. With this reservation in

a low HCO_3-concentration, there must be a metabolic

mind, the acid-base diagrams can be used as a quick

component to the acidosis. In simple metabolic acidosis,

means of determining the specific type and severity of

the PCO₂ is reduced because of partial respiratory com-

an acid-base disorder.

pensation, in contrast to respiratory acidosis, in which

For example, assume that the arterial plasma from a

PCO₂ is increased. Therefore, in simple metabolic acido-

patient yields the following values: pH 7.30, plasma

sis, one would expect to find a low pH, a low plasma

HCO_3- concentration 12.0 mEq/L, and plasma PCO₂

HCO3- concentration, and a reduction in PCO₂ after

25 mm Hg. With these values, one can look at the

partial respiratory compensation.

diagram and find that this represents a simple metabolic

The procedures for categorizing the types of alkalo-

acidosis, with appropriate respiratory compensation

sis involve the same basic steps. First, alkalosis implies

that reduces the PCO₂ from its normal value of 40 mm

that there is an increase in plasma pH. If the increase in

Hg to 25 mm Hg.

pH is associated with decreased PCO₂, there must be a

A second example would be a patient with the fol-

respiratory component to the alkalosis. If the rise in pH

lowing values: pH 7.15, plasma HCO_3- concentration

is associated with increased HCO_3-, there must be a

7 mEq/L, and plasma PCO₂ 50 mm Hg. In this example,

metabolic component to the alkalosis. Therefore, in

the patient is acidotic, and there appears to be a meta-

simple respiratory alkalosis, one would expect to find

bolic component because the plasma HCO_3- concentra-

increased pH, decreased PCO₂ , and decreased HCO₃

tion is lower than the normal value of 24 mEq/L.

concentration in the plasma. In simple metabolic alkalo-

However, the respiratory compensation that would

sis, one would expect to find increased pH, increased

normally reduce PCO₂ is absent, and PCO₂ is slightly

plasma HCO3-, and increased PCO₂.

increased above the normal value of 40 mm Hg. This is

400

Unit V The Body Fluids and Kidneys

120

100 90

110

Pco₂ (mm Hg)

Metabolic

Chronic

alkalosis

respiratory

acidosis

Acute

respiratory

Figure 30-11

acidosis

Acid-base nomogram showing

arterial blood pH, arterial plasma

HCO3-, and PCO₂

values. The

Normal

central open circle shows the

Acute

approximate limits for acid-base

respiratory

status in normal people. The

alkalosis

shaded areas in the nomogram

show the approximate limits

Metabolic

Chronic

for the normal compensations

acidosis

respiratory

caused by simple metabolic and

alkalosis

Pco₂ (mm Hg)

respiratory disorders. For values

lying outside the shaded areas,

one should suspect a mixed acid-

7.00

7.10

7.20

7.30

7.40

7.50

7.60

7.70

7.80

base disorder.

(Adapted from

Cogan MG, Rector FC Jr: Acid-

Arterial blood pH

Base Disorders in the Kidney, 3rd

ed. Philadelphia: WB Saunders,

1986.)

consistent with a mixed acid-base disturbance con-

Table 30-4

sisting of metabolic acidosis as well as a respiratory

component.

Metabolic Acidosis Associated with Normal or Increased

The acid-base diagram serves as a quick way to assess

Plasma Anion Gap

the type and severity of disorders that may be con-

tributing to abnormal pH, PCO₂ , and plasma bicarbon-

Increased Anion Gap

Normal Anion Gap

ate concentrations. In a clinical setting, the patient’s

(Normochloremia)

(Hyperchloremia)

history and other physical findings also provide impor-

tant clues concerning causes and treatment of the acid-

Diabetes mellitus (ketoacidosis)

Diarrhea

Lactic acidosis

Renal tubular acidosis

base disorders.

Chronic renal failure

Carbonic anhydrase inhibitors

Aspirin (acetylsalicylic acid)

Addison’s disease

poisoning

Use of Anion Gap to Diagnose

Methanol poisoning

Acid-Base Disorders

Ethylene glycol poisoning

Starvation

The concentrations of anions and cations in plasma

must be equal to maintain electrical neutrality. There-

fore, there is no real

“anion gap” in the plasma.

However, only certain cations and anions are routinely

dosis, the plasma HCO_3- is reduced. If the plasma

measured in the clinical laboratory. The cation normally

sodium concentration is unchanged, the concentration

measured is Na⁺, and the anions are usually Cl^- and

of anions (either Cl^- or an unmeasured anion) must

HCO_3-. The “anion gap” (which is only a diagnostic

increase to maintain electroneutrality. If plasma Cl^-

concept) is the difference between unmeasured anions

increases in proportion to the fall in plasma HCO_3-, the

and unmeasured cations, and is estimated as

anion gap will remain normal, and this is often referred

to as hyperchloremic metabolic acidosis.

Plasma anion gap = [Na⁺] - [HCO_3-] - [Cl^-]

If the decrease in plasma HCO_3- is not accompanied

= 144 - 24 - 108 = 10 mEq/L

by increased Cl^-, there must be increased levels of

The anion gap will increase if unmeasured anions rise

unmeasured anions and therefore an increase in the cal-

or if unmeasured cations fall. The most important

culated anion gap. Metabolic acidosis caused by excess

unmeasured cations include calcium, magnesium, and

nonvolatile acids (besides HCl), such as lactic acid or

potassium, and the major unmeasured anions are

ketoacids, is associated with an increased plasma anion

albumin, phosphate, sulfate, and other organic anions.

gap because the fall in HCO_3- is not matched by an

Usually the unmeasured anions exceed the unmeasured

equal increase in Cl^-. Some examples of metabolic aci-

cations, and the anion gap ranges between

8 and

dosis associated with a normal or increased anion gap

16 mEq/L.

are shown in Table 30-4. By calculating the anion gap,

The plasma anion gap is used mainly in diagnosing

one can narrow some of the potential causes of meta-

different causes of metabolic acidosis. In metabolic aci-

bolic acidosis.

Chapter 30

Regulation of Acid-Base Balance

401

References

Karet FE: Inherited distal renal tubular acidosis. J Am Soc

Nephrol 13:2178, 2002.

Laffey JG, Kavanagh BP: Hypocapnia. N Engl J Med 347:43,

Alpern RJ: Renal acidification mechanisms. In Brenner BM

2002.

(ed): The Kidney, 6th ed. Philadelphia: WB Saunders, 2000,

Lemann J Jr, Bushinsky DA, Hamm LL: Bone buffering of

pp 455-519.

acid and base in humans. Am J Physiol Renal Physiol

Capasso G, Unwin R, Rizzo M, et al: Bicarbonate transport

285:F811, 2003.

along the loop of Henle: molecular mechanisms and reg-

Madias NE, Adrogue HJ: Cross-talk between two organs:

ulation. J Nephrol 15(Suppl 5):S88, 2002.

how the kidney responds to disruption of acid-base

Decoursey TE: Voltage-gated proton channels and other

balance by the lung. Nephron Physiol 93:61, 2003.

proton transfer pathways. Physiol Rev 83:475, 2003.

Wagner CA, Geibel JP: Acid-base transport in the collecting

Gennari FJ, Maddox DA: Renal regulation of acid-base

duct. J Nephrol 15(Suppl 5):S112, 2002.

homeostasis. In Seldin DW, Giebisch G

(eds): The

Wesson DE, Alpern RJ, Seldin DW: Clinical syndromes of

Kidney—Physiology and Pathophysiology, 3rd ed. New

metabolic alkalosis. In Seldin DW, Giebisch G (eds): The

York: Raven Press, 2000, pp 2015-2054.

Kidney—Physiology and Pathophysiology, 3rd ed. New

Good DW: Ammonium transport by the thick ascending

York: Raven Press, 2000, pp 2055-2072.

limb of Henle’s loop. Ann Rev Physiol 56:623, 1994.

White NH: Management of diabetic ketoacidosis. Rev

Igarashi I, Sekine T, Inatomi J, Seki G: Unraveling the molec-

Endocr Metab Disord 4:343, 2003.

ular pathogenesis of isolated proximal renal tubular aci-

dosis. J Am Soc Nephrol 13:2171, 2002.

C H A P T E R

Kidney Diseases and Diuretics

Diuretics and Their

Mechanisms of Action

A diuretic is a substance that increases the rate of urine

volume output, as the name implies. Most diuretics also

increase urinary excretion of solutes, especially sodium

and chloride. In fact, most diuretics that are used clin-

ically act by decreasing the rate of sodium reabsorption

from the tubules, which causes natriuresis (increased

sodium output), which in turn causes diuresis (increased water output). That is, in

most cases, increased water output occurs secondary to inhibition of tubular

sodium reabsorption, because sodium remaining in the tubules acts osmotically to

decrease water reabsorption. Because the renal tubular reabsorption of many

solutes, such as potassium, chloride, magnesium, and calcium, is also influenced sec-

ondarily by sodium reabsorption, many diuretics raise renal output of these solutes

as well.

The most common clinical use of diuretics is to reduce extracellular fluid volume,

especially in diseases associated with edema and hypertension. As discussed in

Chapter 25, loss of sodium from the body mainly decreases extracellular fluid

volume; therefore, diuretics are most often administered in clinical conditions in

which extracellular fluid volume is expanded.

Some diuretics can increase urine output more than 20-fold within a few minutes

after they are administered. However, the effect of most diuretics on renal output

of salt and water subsides within a few days (Figure 31-1). This is due to activation

of other compensatory mechanisms initiated by decreased extracellular fluid

volume. For example, a decrease in extracellular fluid volume often reduces arterial

pressure and glomerular filtration rate (GFR) and increases renin secretion and

angiotensin II formation; all these responses, together, eventually override the

chronic effects of the diuretic on urine output. Thus, in the steady state, urine output

becomes equal to intake, but only after reductions in arterial pressure and extra-

cellular fluid volume have occurred, relieving the hypertension or edema that

prompted the use of diuretics in the first place.

The many diuretics available for clinical use have different mechanisms of action

and, therefore, inhibit tubular reabsorption at different sites along the renal

nephron. The general classes of diuretics and their mechanisms of action are shown

in Table 31-1.

Osmotic Diuretics Decrease Water Reabsorption

by Increasing Osmotic Pressure of Tubular Fluid

Injection into the blood stream of substances that are not easily reabsorbed by the

renal tubules, such as urea, mannitol, and sucrose, causes a marked increase in the

concentration of osmotically active molecules in the tubules. The osmotic pressure

of these solutes then greatly reduces water reabsorption, flushing large amounts of

tubular fluid into the urine.

Large volumes of urine are also formed in certain diseases associated with excess

solutes that fail to be reabsorbed from the tubular fluid. For example, when the

blood glucose concentration rises to high levels in diabetes mellitus, the increased

filtered load of glucose into the tubules exceeds their capacity to reabsorb glucose

(i.e., exceeds their transport maximum for glucose). Above a plasma glucose con-

centration of about 250 mg/dl, little of the extra glucose is reabsorbed by the tubules;

instead, the excess glucose remains in the tubules, acts as an osmotic diuretic, and

causes rapid loss of fluid into the urine. In patients with diabetes mellitus, the high

402

Chapter 31

Kidney Diseases and Diuretics

403

urine output is balanced by a high level of fluid intake

owing to activation of the thirst mechanism.

Diuretic therapy

“Loop” Diuretics Decrease Active

Sodium-Chloride-Potassium

200

Reabsorption in the Thick

Excretion

Ascending Loop of Henle

Furosemide, ethacrynic acid, and bumetanide are power-

100

ful diuretics that decrease active reabsorption in the

thick ascending limb of the loop of Henle by blocking

Intake

the

1-sodium, 2-chloride, 1-potassium co-transporter

located in the luminal membrane of the epithelial cells.

These diuretics are among the most powerful of the clin-

ically used diuretics.

By blocking active sodium-chloride-potassium co-

15.0

transport in the luminal membrane of the loop of Henle,

the loop diuretics raise urine output of sodium, chloride,

14.0

potassium, and other electrolytes, as well as water, for

two reasons: (1) they greatly increase the quantities of

solutes delivered to the distal parts of the nephrons, and

13.0

these act as osmotic agents to prevent water reabsorp-

tion as well; and (2) they disrupt the countercurrent

multiplier system by decreasing absorption of ions from

the loop of Henle into the medullary interstitium,

-4

-2

thereby decreasing the osmolarity of the medullary

Time (days)

interstitial fluid. Because of this effect, loop diuretics

impair the ability of the kidneys to either concentrate

or dilute the urine. Urinary dilution is impaired because

the inhibition of sodium and chloride reabsorption in

Figure 31-1

the loop of Henle causes more of these ions to be

excreted along with increased water excretion. Urinary

Sodium excretion and extracellular fluid volume during diuretic

concentration is impaired because the renal medullary

administration. The immediate increase in sodium excretion is

interstitial fluid concentration of these ions, and there-

accompanied by a decrease in extracellular fluid volume. If

fore renal medullary osmolarity, is reduced. Conse-

sodium intake is held constant, compensatory mechanisms will

quently, reabsorption of fluid from the collecting ducts

eventually return sodium excretion to equal sodium intake, thus

is decreased, so that the maximal concentrating ability

re-establishing sodium balance.

of the kidneys is also greatly reduced. In addition,

decreased renal medullary interstitial fluid osmolarity

reduces absorption of water from the descending loop

of Henle. Because of these multiple effects, 20 to 30 per

cent of the glomerular filtrate may be delivered into

the urine, causing, under acute conditions, urine output

to be as great as 25 times normal for at least a few

minutes.

Table 31-1

Classes of Diuretics, Their Mechanisms of Action, and Tubular Sites of Action

Class of Diuretic

Mechanism of Action

Tubular Site of Action

Osmotic diuretics (mannitol)

Inhibit water and solute reabsorption by increasing

Mainly proximal tubules

osmolarity of tubular fluid

Loop diuretics (furosemide, bumetanide)

Inhibit Na⁺-K⁺-Cl^- co-transport in luminal membrane

Thick ascending loop of Henle

Thiazide diuretics (hydrochlorothiazide,

Inhibit Na⁺-Cl^- co-transport in luminal membrane

Early distal tubules

chlorthalidone)

Carbonic anhydrase inhibitors

Inhibit H⁺ secretion and HCO_3- reabsorption, which

Proximal tubules

(acetazolamide)

reduces Na⁺ reabsorption

Aldosterone antagonists

Inhibit action of aldosterone on tubular receptor,

Collecting tubules

(spironolactone, eplerenone)

decrease Na⁺ reabsorption, and decrease

K⁺ secretion

Sodium channel blockers

Block entry of Na⁺ into Na⁺ channels of luminal

Collecting tubules

(triamterene, amiloride)

membrane, decrease Na⁺ reabsorption, and

decrease K⁺ secretion

404

Unit V The Body Fluids and Kidneys

Thiazide Diuretics Inhibit Sodium-

Diuretics That Block Sodium

Chloride Reabsorption in the Early

Channels in the Collecting Tubules

Distal Tubule

Decrease Sodium Reabsorption

The thiazide derivatives, such as chlorothiazide, act

Amiloride and triamterene also inhibit sodium reab-

mainly on the early distal tubules to block the sodium-

sorption and potassium secretion in the collecting

chloride co-transporter in the luminal membrane of the

tubules, similar to the effects of spironolactone.

tubular cells. Under favorable conditions, these agents

However, at the cellular level, these drugs act directly

cause 5 to 10 per cent of the glomerular filtrate to pass

to block the entry of sodium into the sodium channels

into the urine. This is about the same amount of sodium

of the luminal membrane of the collecting tubule

normally reabsorbed by the distal tubules.

epithelial cells. Because of this decreased sodium entry

into the epithelial cells, there is also decreased sodium

transport across the cells’ basolateral membranes and,

therefore, decreased activity of the sodium-potassium-

Carbonic Anhydrase Inhibitors

adenosine triphosphatase pump. This decreased activity

Block Sodium-Bicarbonate

reduces the transport of potassium into the cells and

ultimately decreases the secretion of potassium into the

Reabsorption in the Proximal

tubular fluid. For this reason, the sodium channel block-

Tubules

ers are also potassium-sparing diuretics and decrease

the urinary excretion rate of potassium.

Acetazolamide inhibits the enzyme carbonic anhydrase,

which is critical for the reabsorption of bicarbonate in

the proximal tubule, as discussed in Chapter 30. Car-

Kidney Diseases

bonic anhydrase is abundant in the proximal tubule, the

primary site of action of carbonic anhydrase inhibitors.

Some carbonic anhydrase is also present in other

Diseases of the kidneys are among the most important

tubular cells, such as in the intercalated cells of the col-

causes of death and disability in many countries

lecting tubule.

throughout the world. For example, in 2004, more than

Because hydrogen ion secretion and bicarbonate

20 million adults in the United States were estimated

reabsorption in the proximal tubules are coupled to

to have chronic kidney disease.

sodium reabsorption through the sodium-hydrogen ion

Severe kidney diseases can be divided into two main

counter-transport mechanism in the luminal membrane,

categories: (1) acute renal failure, in which the kidneys

decreasing bicarbonate reabsorption also reduces

abruptly stop working entirely or almost entirely but

sodium reabsorption. The blockage of sodium and

may eventually recover nearly normal function, and

bicarbonate reabsorption from the tubular fluid causes

these ions to remain in the tubules and act as an osmotic

(2) chronic renal failure, in which there is progressive

diuretic. Predictably, a disadvantage of the carbonic

loss of function of more and more nephrons that grad-

anhydrase inhibitors is that they cause some degree of

ually decreases overall kidney function. Within these

acidosis because of the excessive loss of bicarbonate

two general categories, there are many specific kidney

ions in the urine.

diseases that can affect the kidney blood vessels,

glomeruli, tubules, renal interstitium, and parts of the

urinary tract outside the kidney, including the ureters

and bladder. In this chapter, we discuss specific physi-

Competitive Inhibitors of

ologic abnormalities that occur in a few of the more

Aldosterone Decrease Sodium

important types of kidney diseases.

Reabsorption from and Potassium

Secretion into the Cortical

Collecting Tubule

Acute Renal Failure

Spironolactone and eplerenone are aldosterone antago-

The causes of acute renal failure can be divided into

nists that compete with aldosterone for receptor sites

three main categories:

in the cortical collecting tubule epithelial cells and,

1. Acute renal failure resulting from decreased

therefore, can decrease the reabsorption of sodium and

secretion of potassium in this tubular segment. As a con-

blood supply to the kidneys; this condition is

sequence, sodium remains in the tubules and acts as an

often referred to as prerenal acute renal failure

osmotic diuretic, causing increased excretion of water as

to reflect the fact that the abnormality occurs

well as sodium. Because these drugs also block the

in a system before the kidneys. This can be a

effect of aldosterone to promote potassium secretion in

consequence of heart failure with reduced cardiac

the tubules, they decrease the excretion of potassium.

output and low blood pressure or conditions

Aldosterone antagonists also cause movement of potas-

associated with diminished blood volume and low

sium from the cells to the extracellular fluid. In some

blood pressure, such as severe hemorrhage.

instances, this causes extracellular fluid potassium con-

2. Intrarenal acute renal failure resulting from

centration to increase excessively. For this reason,

abnormalities within the kidney itself, including

spironolactone and other aldosterone inhibitors are

referred to as potassium-sparing diuretics. Many of the

those that affect the blood vessels, glomeruli, or

other diuretics cause loss of potassium in the urine, in

tubules.

contrast to the aldosterone antagonists, which “spare”

3. Postrenal acute renal failure, resulting from

the loss of potassium.

obstruction of the urinary collecting system

Chapter 31

Kidney Diseases and Diuretics

405

anywhere from the calyces to the outflow from

Table 31-2

the bladder. The most common causes of

Some Causes of Prerenal Acute Renal Failure

obstruction of the urinary tract outside the kidney

are kidney stones, caused by precipitation of

calcium, urate, or cystine.

Intravascular volume depletion

Hemorrhage (trauma, surgery, postpartum, gastrointestinal)

Diarrhea or vomiting

Prerenal Acute Renal Failure

Burns

Cardiac failure

Caused by Decreased Blood Flow

Myocardial infarction

to the Kidney

Valvular damage

Peripheral vasodilation and resultant hypotension

The kidneys normally receive an abundant blood supply

Anaphylactic shock

of about 1100 ml/min, or about 20 to 25 per cent of the

Anesthesia

cardiac output. The main purpose of this high blood flow

Sepsis, severe infections

to the kidneys is to provide enough plasma for the high

Primary renal hemodynamic abnormalities

rates of glomerular filtration needed for effective regu-

Renal artery stenosis, embolism, or thrombosis of renal artery

or vein

lation of body fluid volumes and solute concentrations.

Therefore, decreased renal blood flow is usually accom-

panied by decreased GFR and decreased urine output

of water and solutes. Consequently, conditions that

Table 31-3

acutely diminish blood flow to the kidneys usually cause

oliguria, which refers to diminished urine output below

Some Causes of Intrarenal Acute Renal Failure

the level of intake of water and solutes. This causes accu-

mulation of water and solutes in the body fluids. If renal

Small vessel and/or glomerular injury

blood flow is markedly reduced, total cessation of urine

Vasculitis (polyarteritis nodosa)

output can occur, a condition referred to as anuria.

Cholesterol emboli

As long as renal blood flow does not fall below about

Malignant hypertension

20 to 25 per cent of normal, acute renal failure can

Acute glomerulonephritis

usually be reversed if the cause of the ischemia is cor-

Tubular epithelial injury (tubular necrosis)

rected before damage to the renal cells has occurred.

Acute tubular necrosis due to ischemia

Acute tubular necrosis due to toxins (heavy metals, ethylene

Unlike some tissues, the kidney can endure a relatively

glycol, insecticides, poison mushrooms, carbon tetrachloride)

large reduction in blood flow before actual damage to

Renal interstitial injury

the renal cells occurs. The reason for this is that as renal

Acute pyelonephritis

blood flow is reduced, the GFR and the amount of

Acute allergic interstitial nephritis

sodium chloride filtered by the glomeruli (as well as

the filtration rate of water and other electrolytes) are

reduced. This decreases the amount of sodium chloride

that must be reabsorbed by the tubules, which uses most

acute renal failure can be further divided into

(1)

of the energy and oxygen consumed by the normal

conditions that injure the glomerular capillaries or

kidney. Therefore, as renal blood flow and GFR fall,

other small renal vessels, (2) conditions that damage the

the requirement for renal oxygen consumption is also

renal tubular epithelium, and (3) conditions that cause

reduced. As the GFR approaches zero, oxygen con-

damage to the renal interstitium. This type of classifica-

sumption of the kidney approaches the rate that is

tion refers to the primary site of injury, but because the

required to keep the renal tubular cells alive even when

renal vasculature and tubular system are functionally

they are not reabsorbing sodium. When blood flow is

interdependent, damage to the renal blood vessels can

reduced below this basal requirement, which is usually

lead to tubular damage, and primary tubular damage

less than 20 to 25 per cent of the normal renal blood

can lead to damage of the renal blood vessels. Causes

flow, the renal cells start to become hypoxic, and further

of intrarenal acute renal failure are listed in Table 31-3.

decreases in renal blood flow, if prolonged, will cause

damage or even death of the renal cells, especially the

Acute Renal Failure Caused by Glomerulonephritis. Acute

tubular epithelial cells. If the cause of prerenal acute

glomerulonephritis is a type of intrarenal acute renal

renal failure is not corrected and ischemia of the kidney

failure usually caused by an abnormal immune reaction

persists longer than a few hours, this type of renal failure

that damages the glomeruli. In about 95 per cent of the

can evolve into intrarenal acute renal failure, as dis-

patients with this disease, damage to the glomeruli

cussed later. Acute reduction of renal blood flow is a

occurs 1 to 3 weeks after an infection elsewhere in the

common cause of acute renal failure in hospitalized

body, usually caused by certain types of group A beta

patients. Table 31-2 shows some of the common causes

streptococci. The infection may have been a streptococ-

of decreased renal blood flow and prerenal acute renal

cal sore throat, streptococcal tonsillitis, or even strepto-

failure.

coccal infection of the skin. It is not the infection itself

that damages the kidneys. Instead, over a few weeks, as

antibodies develop against the streptococcal antigen,

Intrarenal Acute Renal Failure

the antibodies and antigen react with each other to form

Caused by Abnormalities

an insoluble immune complex that becomes entrapped

Within the Kidney

in the glomeruli, especially in the basement membrane

portion of the glomeruli.

Abnormalities that originate within the kidney and that

Once the immune complex has deposited in the

abruptly diminish urine output fall into the general cat-

glomeruli, many of the cells of the glomeruli begin to

egory of intrarenal acute renal failure. This category of

proliferate, but mainly the mesangial cells that lie

406

Unit V The Body Fluids and Kidneys

between the endothelium and the epithelium. In addi-

acute renal failure even when the kidneys’ blood supply

tion, large numbers of white blood cells become

and other functions are initially normal. If the urine

entrapped in the glomeruli. Many of the glomeruli

output of only one kidney is diminished, no major

become blocked by this inflammatory reaction, and

change in body fluid composition will occur because the

those that are not blocked usually become excessively

contralateral kidney can increase its urine output suffi-

permeable, allowing both protein and red blood cells to

ciently to maintain relatively normal levels of extracel-

leak from the blood of the glomerular capillaries into

lular electrolytes and solutes as well as normal

the glomerular filtrate. In severe cases, either total or

extracellular fluid volume. With this type of renal

almost complete renal shutdown occurs.

failure, normal kidney function can be restored if the

The acute inflammation of the glomeruli usually sub-

basic cause of the problem is corrected within a few

sides in about 2 weeks, and in most patients, the kidneys

hours. But chronic obstruction of the urinary tract,

return to almost normal function within the next few

lasting for several days or weeks, can lead to irreversible

weeks to few months. Sometimes, however, many of the

kidney damage. Some of the causes of postrenal acute

glomeruli are destroyed beyond repair, and in a small

failure include (1) bilateral obstruction of the ureters or

percentage of patients, progressive renal deterioration

renal pelvises caused by large stones or blood clots, (2)

continues indefinitely, leading to chronic renal failure, as

bladder obstruction, and (3) obstruction of the urethra.

described in a subsequent section of this chapter.

Tubular Necrosis as a Cause of Acute Renal Failure. Another

cause of intrarenal acute renal failure is tubular necro-

Physiologic Effects of Acute

sis, which means destruction of epithelial cells in the

tubules. Some common causes of tubular necrosis are

Renal Failure

(1) severe ischemia and inadequate supply of oxygen

and nutrients to the tubular epithelial cells and (2)

A major physiologic effect of acute renal failure is

poisons, toxins, or medications that destroy the tubular

retention in the blood and extracellular fluid of water,

epithelial cells.

waste products of metabolism, and electrolytes. This

Acute Tubular Necrosis Caused by Severe Renal

can lead to water and salt overload, which in turn can

Ischemia. Severe ischemia of the kidney can result from

lead to edema and hypertension. Excessive retention

circulatory shock or any other disturbance that severely

of potassium, however, is often a more serious threat

impairs the blood supply to the kidney. If the ischemia

to patients with acute renal failure, because increases

is severe enough to seriously impair the delivery of

in plasma potassium concentration (hyperkalemia) to

nutrients and oxygen to the renal tubular epithelial

more than about 8 mEq/L (only twice normal) can be

cells, and if the insult is prolonged, damage or eventual

fatal. Because the kidneys are also unable to excrete

destruction of the epithelial cells can occur. When this

sufficient hydrogen ions, patients with acute renal

happens, tubular cells “slough off ” and plug many of the

nephrons, so that there is no urine output from the

failure develop metabolic acidosis, which in itself can

blocked nephrons; the affected nephrons often fail to

be lethal or can aggravate the hyperkalemia.

excrete urine even when renal blood flow is restored to

In the most severe cases of acute renal failure, com-

normal, as long as the tubules remain plugged. The most

plete anuria occurs. The patient will die in 8 to 14 days

common causes of ischemic damage to the tubular

unless kidney function is restored or unless an artifi-

epithelium are the prerenal causes of acute renal failure

cial kidney is used to rid the body of the excessive

associated with circulatory shock, as discussed earlier in

retained water, electrolytes, and waste products of

this chapter.

metabolism. Other effects of diminished urine output,

Acute Tubular Necrosis Caused by Toxins or Medications.

as well as treatment with an artificial kidney, are dis-

There is a long list of renal poisons and medications that

cussed in the next section in relation to chronic renal

can damage the tubular epithelium and cause acute renal

failure.

failure. Some of these are carbon tetrachloride, heavy

metals (such as mercury and lead), ethylene glycol (which

is a major component in antifreeze), various insecticides,

various medications

(such as tetracyclines) used as

Chronic Renal Failure:

antibiotics, and cis-platinum, which is used in treating

An Irreversible Decrease

certain cancers. Each of these substances has a specific

toxic action on the renal tubular epithelial cells, causing

in the Number of Functional

death of many of them. As a result, the epithelial cells

Nephrons

slough away from the basement membrane and plug the

tubules. In some instances, the basement membrane also

Chronic renal failure results from progressive and irre-

is destroyed. If the basement membrane remains intact,

new tubular epithelial cells can grow along the surface

versible loss of large numbers of functioning nephrons.

of the membrane, so that the tubule repairs itself within

Serious clinical symptoms often do not occur until the

10 to 20 days.

number of functional nephrons falls to at least 70 to

75 per cent below normal. In fact, relatively normal

blood concentrations of most electrolytes and normal

Postrenal Acute Renal Failure

body fluid volumes can still be maintained until the

Caused by Abnormalities of the

number of functioning nephrons decreases below 20

Lower Urinary Tract

to 25 per cent of normal.

Multiple abnormalities in the lower urinary tract can

Table 31-4 gives some of the most important causes

block or partially block urine flow and therefore lead to

of chronic renal failure. In general, chronic renal

Chapter 31

Kidney Diseases and Diuretics

407

Table 31-4

Primary

kidney disease

Some Causes of Chronic Renal Failure

Metabolic disorders

Nephron

Diabetes mellitus

number

Obesity

Amyloidosis

Hypertension

Renal vascular disorders

Atherosclerosis

Nephrosclerosis-hypertension

Immunologic disorders

Glomerulonephritis

Hypertrophy

Polyarteritis nodosa

Glomerular

and vasodilation

Lupus erythematosus

sclerosis

of surviving

Infections

nephrons

Pyelonephritis

Tuberculosis

Arterial

Primary tubular disorders

pressure

Nephrotoxins (analgesics, heavy metals)

Urinary tract obstruction

Renal calculi

Glomerular

Hypertrophy of prostate

pressure

Urethral constriction

and/or

Congenital disorders

filtration

Polycystic disease

Congenital absence of kidney tissue (renal hypoplasia)

Figure 31-2

Vicious circle that can occur with primary kidney disease. Loss of

nephrons because of disease may increase pressure and flow in

the surviving glomerular capillaries, which in turn may eventually

failure, like acute renal failure, can occur because of

injure these “normal” capillaries as well, thus causing progressive

disorders of the blood vessels, glomeruli, tubules, renal

sclerosis and eventual loss of these glomeruli.

interstitium, and lower urinary tract. Despite the wide

variety of diseases that can lead to chronic renal

failure, the end result is essentially the same—a

The cause of this additional injury is not known, but

decrease in the number of functional nephrons.

some investigators believe that it may be related in

part to increased pressure or stretch of the remaining

glomeruli, which occurs as a result of functional

Vicious Circle of Chronic Renal

vasodilation or increased blood pressure; the chronic

Failure Leading to End-Stage

increase in pressure and stretch of the small arterioles

Renal Disease

and glomeruli are believed to cause sclerosis of these

vessels (replacement of normal tissue with connective

In many cases, an initial insult to the kidney leads to

tissue). These sclerotic lesions can eventually obliter-

progressive deterioration of kidney function and

ate the glomerulus, leading to further reduction in

further loss of nephrons to the point where the person

kidney function, further adaptive changes in the

must be placed on dialysis treatment or transplanted

remaining nephrons, and a slowly progressing vicious

with a functional kidney to survive. This condition is

circle that eventually terminates in end-stage renal

referred to as end-stage renal disease.

disease

(Figure

31-2). The only proven method

Studies in laboratory animals have shown that sur-

of slowing down this progressive loss of kidney func-

gical removal of large portions of the kidney initially

tion is to lower arterial pressure and glomerular

causes adaptive changes in the remaining nephrons

hydrostatic pressure, especially by using drugs such

that lead to increased blood flow, increased GFR, and

as angiotensin-converting enzyme inhibitors or

increased urine output in the surviving nephrons. The

angiotensin II antagonists.

exact mechanisms responsible for these changes are

Table 31-5 gives the most common causes of end-

not well understood but involve hypertrophy (growth

stage renal disease. In the early

1980s, glomeru-

of the various structures of the surviving nephrons) as

lonephritis in all its various forms was believed to be

well as functional changes that decrease vascular

the most common initiating cause of end-stage renal

resistance and tubular reabsorption in the surviving

disease. In recent years, diabetes mellitus and hyper-

nephrons. These adaptive changes permit a person to

tension have become recognized as the leading causes

excrete normal amounts of water and solutes even

of end-stage renal disease, together accounting for

when kidney mass is reduced to 20 to 25 per cent of

approximately 70 per cent of all chronic renal failure.

normal. Over a period of several years, however, the

Excessive weight gain (obesity) appears to be the

renal functional changes may lead to further injury of

most important risk factor for the two main causes of

the remaining nephrons, particularly to the glomeruli

end-stage renal disease—diabetes and hypertension.

of these nephrons.

As discussed in Chapter 78, type II diabetes, which is

408

Unit V The Body Fluids and Kidneys

Table 31-5

Most Common Causes of End-Stage Renal Disease (ESRD)

2.5

Cause

Percentage of Total ESRD Patients

2.0

Diabetes mellitus

Hypertension

1.5

Glomerulonephritis

Polycystic kidney disease

Other/unknown

1.0

0.5

closely linked to obesity, accounts for approximately

0.0

90 per cent of all diabetes mellitus. Excess weight gain

is also a major cause of essential hypertension,

Age (years)

accounting for as much as 65 to 75 per cent of the risk

for developing hypertension in adults. In addition to

causing renal injury through diabetes and hyperten-

sion, obesity may have additive or synergistic effects

Figure 31-3

to worsen renal function in patients with pre-existing

kidney disease.

Effect of aging on the number of functional glomeruli.

Injury to the Renal Vasculature as a

in both renal blood flow and GFR. Even in “normal”

Cause of Chronic Renal Failure

people, kidney plasma flow and GFR decrease by 40 to

50 per cent by age 80.

Many types of vascular lesions can lead to renal

The frequency and severity of nephrosclerosis and

ischemia and death of kidney tissue. The most common

glomerulosclerosis are greatly increased by concurrent

of these are (1) atherosclerosis of the larger renal arter-

hypertension or diabetes mellitus. In fact, diabetes mel-

ies, with progressive sclerotic constriction of the vessels;

litus and hypertension are the two most important

(2) fibromuscular hyperplasia of one or more of the

causes of end-stage renal disease, as discussed previ-

large arteries, which also causes occlusion of the vessels;

ously. Thus, benign nephrosclerosis in association with

and (3) nephrosclerosis, caused by sclerotic lesions of

severe hypertension can lead to a rapidly progressing

the smaller arteries, arterioles, and glomeruli.

malignant nephrosclerosis. The characteristic histologi-

Atherosclerotic or hyperplastic lesions of the large

cal features of malignant nephrosclerosis include large

arteries frequently affect one kidney more than the

amounts of fibrinoid deposits in the arterioles and pro-

other and, therefore, cause unilaterally diminished

gressive thickening of the vessels, with severe ischemia

kidney function. As discussed in Chapter 19, hyperten-

occurring in the affected nephrons. For unknown

sion often occurs when the artery of one kidney is

reasons, the incidence of malignant nephrosclerosis and

constricted while the artery of the other kidney is

severe glomerulosclerosis is significantly higher in

still normal, a condition analogous to “two-kidney”

blacks than in whites of similar ages who have similar

Goldblatt hypertension.

degrees of severity of hypertension or diabetes.

Benign nephrosclerosis, the most common form of

kidney disease, is seen to at least some extent in about

70 per cent of postmortem examinations in people who

Injury to the Glomeruli as a Cause

die after the age of 60. This type of vascular lesion

of Chronic Renal Failure—

occurs in the smaller interlobular arteries and in the

Glomerulonephritis

afferent arterioles of the kidney. It is believed to begin

with leakage of plasma through the intimal membrane

Chronic glomerulonephritis can be caused by several

of these vessels. This causes fibrinoid deposits to

diseases that cause inflammation and damage to the

develop in the medial layers of these vessels, followed

capillary loops in the glomeruli of the kidneys. In con-

by progressive thickening of the vessel wall that even-

trast to the acute form of this disease, chronic glomeru-

tually constricts the vessels and, in some cases, occludes

lonephritis is a slowly progressive disease that often

them. Because there is essentially no collateral circula-

leads to irreversible renal failure. It may be a primary

tion among the smaller renal arteries, occlusion of one

kidney disease, following acute glomerulonephritis, or it

or more of them causes destruction of a comparable

may be secondary to systemic diseases, such as lupus

number of nephrons. Therefore, much of the kidney

erythematosus.

tissue becomes replaced by small amounts of fibrous

In most cases, chronic glomerulonephritis begins with

tissue. When sclerosis occurs in the glomeruli, the injury

accumulation of precipitated antigen-antibody com-

is referred to as glomerulosclerosis.

plexes in the glomerular membrane. In contrast to acute

Nephrosclerosis and glomerulosclerosis occur to

glomerulonephritis, streptococcal infections account for

some extent in most people after the fourth decade of

only a small percentage of patients with the chronic

life, causing about a 10 per cent decrease in the number

form of glomerulonephritis. The results of the accumu-

of functional nephrons each

10 years after age

lation of antigen-antibody complex in the glomerular

(Figure

31-3). This loss of glomeruli and overall

membranes are inflammation, progressive thickening of

nephron function is reflected by a progressive decrease

the membranes, and eventual invasion of the glomeruli

Chapter 31

Kidney Diseases and Diuretics

409

by fibrous tissue. In the later stages of the disease, the

large quantities of plasma proteins into the urine. In

glomerular capillary filtration coefficient becomes

some instances, this occurs without evidence of other

greatly reduced because of decreased numbers of filter-

major abnormalities of kidney function, but more often

ing capillaries in the glomerular tufts and because of

it is associated with some degree of renal failure.

thickened glomerular membranes. In the final stages of

The cause of the protein loss in the urine is increased

the disease, many glomeruli are replaced by fibrous

permeability of the glomerular membrane. Therefore,

tissue and are, therefore, unable to filter fluid.

any disease that increases the permeability of this mem-

brane can cause the nephrotic syndrome. Such diseases

include (1) chronic glomerulonephritis, which affects

Injury to the Renal Interstitium as a

primarily the glomeruli and often causes greatly

Cause of Chronic Renal Failure—

increased permeability of the glomerular membrane;

Pyelonephritis

(2) amyloidosis, which results from deposition of an

abnormal proteinoid substance in the walls of the blood

Primary or secondary disease of the renal interstitium

vessels and seriously damages the basement membrane

is referred to as interstitial nephritis. In general, this can

of the glomeruli; and (3) minimal change nephrotic syn-

result from vascular, glomerular, or tubular damage that

drome, which is associated with no major abnormality

destroys individual nephrons, or it can involve primary

in the glomerular capillary membrane that can be

damage to the renal interstitium by poisons, drugs, and

detected with light microscopy. As discussed in Chapter

bacterial infections.

26, minimal change nephropathy has been found to

Renal interstitial injury caused by bacterial infec-

be associated with loss of the negative charges that are

tion is called pyelonephritis. The infection can result

normally present in the glomerular capillary basement

from different types of bacteria but especially from

membrane. Immunologic studies have also shown

Escherichia coli that originate from fecal contamination

abnormal immune reactions in some cases, suggesting

of the urinary tract. These bacteria reach the kidneys

that the loss of the negative charges may have resulted

either by way of the blood stream or, more commonly,

from antibody attack on the membrane. Loss of normal

by ascension from the lower urinary tract by way of the

negative charges in the basement membrane of the

ureters to the kidneys.

glomerular capillaries allows proteins, especially

Although the normal bladder is able to clear bacteria

albumin, to pass through the glomerular membrane

readily, there are two general clinical conditions that

with ease because the negative charges in the basement

may interfere with the normal flushing of bacteria from

membrane normally repel the negatively charged

the bladder: (1) the inability of the bladder to empty

plasma proteins.

completely, leaving residual urine in the bladder, and

Minimal change nephropathy can occur in adults, but

(2) the existence of obstruction of urine outflow. With

more frequently it occurs in children between the ages

impaired ability to flush bacteria from the bladder, the

of 2 and 6 years. Increased permeability of the glomeru-

bacteria multiply and the bladder becomes inflamed, a

lar capillary membrane occasionally allows as much as

condition termed cystitis. Once cystitis has occurred, it

40 grams of plasma protein loss into the urine each day,

may remain localized without ascending to the kidney,

which is an extreme amount for a young child. There-

or in some people, bacteria may reach the renal pelvis

fore, the child’s plasma protein concentration often falls

because of a pathological condition in which urine is

below 2 g/dl, and the colloid osmotic pressure falls from

propelled up one or both of the ureters during micturi-

a normal value of 28 to less than 10 mm Hg. As a con-

tion. This condition is called vesicoureteral reflux and is

sequence of this low colloid osmotic pressure in the

due to the failure of the bladder wall to occlude the

plasma, large amounts of fluid leak from the capillaries

ureter during micturition; as a result, some of the urine

all over the body into most of the tissues, causing severe

is propelled upward toward the kidney, carrying with it

edema, as discussed in Chapter 25.

bacteria that can reach the renal pelvis and renal

medulla, where they can initiate the infection and

inflammation associated with pyelonephritis.

Nephron Function in Chronic

Pyelonephritis begins in the renal medulla and there-

Renal Failure

fore usually affects the function of the medulla more

than it affects the cortex, at least in the initial stages.

Because one of the primary functions of the medulla is

Loss of Functional Nephrons Requires the Surviving Nephrons

to provide the countercurrent mechanism for concen-

to Excrete More Water and Solutes. It would be reasonable

trating urine, patients with pyelonephritis frequently

to suspect that decreasing the number of functional

have markedly impaired ability to concentrate the urine.

nephrons, which reduces the GFR, would also cause

With long-standing pyelonephritis, invasion of the

major decreases in renal excretion of water and

kidneys by bacteria not only causes damage to the renal

solutes. Yet patients who have lost as much as 75 per

medulla interstitium but also results in progressive

cent of their nephrons are able to excrete normal

damage of renal tubules, glomeruli, and other structures

amounts of water and electrolytes without serious

throughout the kidney. Consequently, large parts of

accumulation of any of these in the body fluids.

functional renal tissue are lost, and chronic renal failure

can develop.

Further reduction in the number of nephrons,

however, leads to electrolyte and fluid retention, and

death usually ensues when the number of nephrons

Nephrotic Syndrome—Excretion

falls below 5 to 10 per cent of normal.

of Protein in the Urine Because of

In contrast to the electrolytes, many of the waste

Increased Glomerular Permeability

products of metabolism, such as urea and creatinine,

Many patients with kidney disease develop the

accumulate almost in proportion to the number of

nephrotic syndrome, which is characterized by loss of

nephrons that have been destroyed. The reason for this

410

Unit V The Body Fluids and Kidneys

100

Glomerular filtration rate

(percentage of normal)

Positive balance

Production

Figure 31-5

Excretion GFR x P_Creatinine

Representative patterns of adaptation for different types of solutes

in chronic renal failure. Curve A shows the approximate changes

in the plasma concentrations of solutes such as creatinine and

urea that are filtered and poorly reabsorbed. Curve B shows the

approximate concentrations for solutes such as phosphate and

urate. Curve C shows the approximate concentrations for solutes

Days

such as sodium and chloride.

Some solutes, such as phosphate, urate, and hydro-

Figure 31-4

gen ions, are often maintained near the normal range

Effect of reducing glomerular filtration rate (GFR) by 50 per cent

until GFR falls below 20 to 30 per cent of normal.

on serum creatinine concentration and on creatinine excretion rate

Thereafter, the plasma concentrations of these sub-

when the production rate of creatinine remains constant.

stances rise, but not in proportion to the fall in GFR,

as shown in curve B of Figure 31-5. Maintenance of

is that substances such as creatinine and urea depend

relatively constant plasma concentrations of these

largely on glomerular filtration for their excretion, and

solutes as GFR declines is accomplished by excreting

they are not reabsorbed as avidly as the electrolytes.

progressively larger fractions of the amounts of these

Creatinine, for example, is not reabsorbed at all, and

solutes that are filtered at the glomerular capillaries;

the excretion rate is equal to the rate at which it is

this occurs by decreasing the rate of tubular reab-

filtered.

sorption or, in some instances, by increasing tubular

secretion rates.

Creatinine filtration rate

In the case of sodium and chloride ions, their plasma

= GFR ¥ Plasma creatinine concentration

concentrations are maintained virtually constant

= Creatinine excretion rate

even with severe decreases in GFR (see curve C of

Therefore, if GFR decreases, the creatinine excre-

Figure

31-5). This is accomplished by greatly de-

tion rate also transiently decreases, causing accumula-

creasing tubular reabsorption of these electrolytes.

tion of creatinine in the body fluids and raising plasma

For example, with a 75 per cent loss of functional

concentration until the excretion rate of creatinine

nephrons, each surviving nephron must excrete four

returns to normal—the same rate at which creatinine

times as much sodium and four times as much volume

is produced in the body (Figure 31-4). Thus, under

as under normal conditions (Table 31-6).

steady-state conditions, the creatinine excretion rate

Part of this adaptation occurs because of increased

equals the rate of creatinine production, despite reduc-

blood flow and increased GFR in each of the surviv-

tions in GFR; however, this normal rate of creatinine

ing nephrons, owing to hypertrophy of the blood

excretion occurs at the expense of elevated plasma

vessels and glomeruli, as well as functional changes

creatinine concentration, as shown in curve A of

that cause the blood vessels to vasodilate. Even with

Figure 31-5.

large decreases in the total GFR, normal rates of renal

Chapter 31

Kidney Diseases and Diuretics

411

Table 31-6

Total Kidney Excretion and Excretion per Nephron in

1.050

Renal Failure

1.040

75% Loss of

Normal

Nephrons

1.030

Isosthenuria

Number of nephrons

2,000,000

500,000

Total GFR (ml/min)

125

Single nephron GFR (nl/min)

62.5

1.020

Volume excreted for all

1.5

nephrons (ml/min)

Glomerular filtrate specific gravity

1.010

Volume excreted per nephron

0.75

3.0

(nl/min)

1.000

2,000,000 1,500,000 1,000,000

500,000

GFR, glomerular filtration rate.

Number of nephrons in both kidneys

excretion can still be maintained by decreasing the

rate at which the tubules reabsorb water and solutes.

Figure 31-6

Isosthenuria—Inability of the Kidney to Concentrate or Dilute

Development of isosthenuria in a patient with decreased numbers

the Urine. One important effect of the rapid rate of

of functional nephrons.

tubular flow that occurs in the remaining nephrons of

diseased kidneys is that the renal tubules lose their

ability to concentrate or dilute the urine. The concen-

trating ability of the kidney is impaired mainly because

(1) the rapid flow of tubular fluid through the collect-

ing ducts prevents adequate water reabsorption, and

(2) the rapid flow through both the loop of Henle and

the collecting ducts prevents the countercurrent mech-

anism from operating effectively to concentrate the

medullary interstitial fluid solutes. Therefore, as pro-

gressively more nephrons are destroyed, the maximum

concentrating ability of the kidney declines, and urine

Normal

osmolarity and specific gravity (a measure of the total

solute concentration) approach the osmolarity and

specific gravity of the glomerular filtrate, as shown in

Figure 31-6.

The diluting mechanism in the kidney is also

Kidney shutdown

impaired when the number of nephrons decreases

because the rapid flushing of fluid through the loops

Days

of Henle and the high load of solutes such as urea

cause a relatively high solute concentration in the

tubular fluid of this part of the nephron. As a conse-

quence, the diluting capacity of the kidney is impaired,

Figure 31-7

and the minimal urine osmolality and specific gravity

approach those of the glomerular filtrate. Because the

Effect of kidney failure on extracellular fluid constituents. NPN,

nonprotein nitrogens.

concentrating mechanism becomes impaired to a

greater extent than does the diluting mechanism in

chronic renal failure, an important clinical test of renal

function is to determine how well the kidneys can

of different substances in the extracellular fluid are

concentrate urine when a person’s water intake is

approximately those shown in Figure 31-7. Important

restricted for 12 or more hours.

effects include (1) generalized edema resulting from

water and salt retention, (2) acidosis resulting from

failure of the kidneys to rid the body of normal acidic

Effects of Renal Failure on the Body

products, (3) high concentration of the nonprotein nitro-

Fluids—Uremia

gens—especially urea, creatinine, and uric acid—result-

ing from failure of the body to excrete the metabolic

The effect of complete renal failure on the body fluids

end products of proteins, and (4) high concentrations of

depends on (1) water and food intake and (2) the

other substances excreted by the kidney, including

degree of impairment of renal function. Assuming that

phenols, sulfates, phosphates, potassium, and guanidine

a person with complete renal failure continues to ingest

bases. This total condition is called uremia because of

the same amounts of water and food, the concentrations

the high concentration of urea in the body fluids.

412

Unit V The Body Fluids and Kidneys

Water Retention and Development of Edema in Renal Failure. If

Osteomalacia in Chronic Renal Failure Caused by Decreased

water intake is restricted immediately after acute renal

Production of Active Vitamin D and by Phosphate Retention by

failure begins, the total body fluid content may become

the Kidneys. Prolonged renal failure also causes osteo-

only slightly increased. If fluid intake is not limited and

malacia, a condition in which the bones are partially

the patient drinks in response to the normal thirst mech-

absorbed and, therefore, become greatly weakened. An

anisms, the body fluids begin to increase immediately

important cause of this condition is the following:

and rapidly.

Vitamin D must be converted by a two-stage process,

With chronic partial kidney failure, accumulation of

first in the liver and then in the kidneys, into 1,25-

fluid may not be severe, as long as salt and fluid intake

dihydroxycholecalciferol before it is able to promote

are not excessive, until kidney function falls to 25 per

calcium absorption from the intestine. Therefore,

cent of normal or lower. The reason for this, as discussed

serious damage to the kidney greatly reduces the blood

previously, is that the surviving nephrons excrete larger

concentration of active vitamin D, which in turn

amounts of salt and water. Even the small fluid reten-

decreases intestinal absorption of calcium and the avail-

tion that does occur, along with increased secretion of

ability of calcium to the bones.

renin and angiotensin II that usually occurs in ischemic

Another important cause of demineralization of the

kidney disease, often causes severe hypertension in

skeleton in chronic renal failure is the rise in serum

chronic renal failure. Almost all patients with kidney

phosphate concentration that occurs as a result of

function so reduced as to require dialysis to preserve life

decreased GFR. This rise in serum phosphate causes

develop hypertension. In most of these patients, severe

increased binding of phosphate with calcium in the

reduction of salt intake or removal of extracellular fluid

plasma, thus decreasing the plasma serum ionized

by dialysis can control the hypertension. The remaining

calcium concentration, which in turn stimulates parathy-

patients continue to have hypertension even after

roid hormone secretion. This secondary hyperparathy-

excess sodium has been removed by dialysis. In this

roidism then stimulates the release of calcium from

group, removal of the ischemic kidneys usually corrects

bones, causing further demineralization of the bones.

the hypertension (as long as fluid retention is prevented

by dialysis) because it removes the source of excessive

renin secretion and subsequent increased angiotensin II

Hypertension and Kidney Disease

formation.

As discussed earlier in this chapter, hypertension can

exacerbate injury to the glomeruli and blood vessels of

Uremia—Increase in Urea and Other Nonprotein Nitrogens

the kidneys and is a major cause of end-stage renal

(Azotemia). The nonprotein nitrogens include urea, uric

disease. Conversely, abnormalities of kidney function

acid, creatinine, and a few less important compounds.

can cause hypertension, as discussed in detail in Chapter

These, in general, are the end products of protein

19. Thus, the relation between hypertension and kidney

metabolism and must be removed from the body to

disease can, in some instances, propagate a vicious

ensure continued normal protein metabolism in the

circle: primary kidney damage leads to increased blood

cells. The concentrations of these, particularly of urea,

pressure, which in turn causes further damage to the

can rise to as high as 10 times normal during 1 to 2

kidneys, further increases in blood pressure, and so

weeks of total renal failure. With chronic renal failure,

forth, until end-stage renal disease develops.

the concentrations rise approximately in proportion to

Not all types of kidney disease cause hypertension,

the degree of reduction in functional nephrons. For this

because damage to certain portions of the kidney cause

reason, measuring the concentrations of these sub-

uremia without hypertension. Nevertheless, some types

stances, especially of urea and creatinine, provides an

of renal damage are particularly prone to cause hyper-

important means for assessing the degree of renal

tension. A classification of kidney disease relative

failure.

to hypertensive or nonhypertensive effects is the

following.

Acidosis in Renal Failure. Each day the body normally pro-

duces about 50 to 80 millimoles more metabolic acid

Renal Lesions That Reduce the Ability of the Kidneys to Excrete

than metabolic alkali. Therefore, when the kidneys fail

Sodium and Water Promote Hypertension. Renal lesions that

to function, acid accumulates in the body fluids. The

decrease the ability of the kidneys to excrete sodium

buffers of the body fluids normally can buffer 500 to

and water almost invariably cause hypertension. There-

1000 millimoles of acid without lethal increases in extra-

fore, lesions that either decrease GFR or increase

cellular fluid hydrogen ion concentration, and the phos-

tubular reabsorption usually lead to hypertension of

phate compounds in the bones can buffer an additional

varying degrees. Some specific types of renal abnormal-

few thousand millimoles of hydrogen ion. However,

ities that can cause hypertension are as follows:

when this buffering power is used up, the blood pH falls

1. Increased renal vascular resistance, which reduces

drastically, and the patient will become comatose and

renal blood flow and GFR. An example is

die if the pH falls below about 6.8.

hypertension caused by renal artery stenosis.

2. Decreased glomerular capillary filtration coefficient,

Anemia in Chronic Renal Failure Caused by Decreased Erythro-

which reduces GFR. An example of this is chronic

poietin Secretion. Patients with severe chronic renal

glomerulonephritis, which causes inflammation and

failure almost always develop anemia. The most im-

thickening of the glomerular capillary membranes,

portant cause of this is decreased renal secretion of

thereby reducing the glomerular capillary filtration

erythropoietin, which stimulates the bone marrow to

coefficient.

produce red blood cells. If the kidneys are seriously

3. Excessive tubular sodium reabsorption. An example

damaged, they are unable to form adequate quantities

is hypertension caused by excessive aldosterone

of erythropoietin, which leads to diminished red blood

secretion, which increases sodium reabsorption

cell production and consequent anemia.

mainly in the cortical collecting tubules.

Chapter 31

Kidney Diseases and Diuretics

413

Once hypertension has developed, renal excretion of

Specific Tubular Disorders

sodium and water returns to normal because the high

arterial pressure causes pressure natriuresis and pres-

In Chapter 27, we point out that several mechanisms are

sure diuresis, so that intake and output of sodium

responsible for transporting different individual sub-

and water become balanced once again. Even when

stances across the tubular epithelial membranes. In

there are large increases in renal vascular resistance or

Chapter 3, we also point out that each cellular enzyme

decreases in the glomerular capillary coefficient, the

and each carrier protein is formed in response to a

GFR may still return to nearly normal levels after the

respective gene in the nucleus. If any required gene

arterial blood pressure rises. Likewise, when tubular

happens to be absent or abnormal, the tubules may be

reabsorption is increased, as occurs with excessive

deficient in one of the appropriate carrier proteins or

aldosterone secretion, the urinary excretion rate is ini-

one of the enzymes needed for solute transport by the

tially reduced but then returns to normal as arterial

renal tubular epithelial cells. For this reason, many

pressure rises. Thus, after hypertension develops, there

hereditary tubular disorders occur because of the trans-

may be no sign of impaired excretion of sodium and

port of individual substances or groups of substances

water other than the hypertension. As explained in

through the tubular membrane. In addition, damage to

Chapter 19, normal excretion of sodium and water at an

the tubular epithelial membrane by toxins or ischemia

elevated arterial pressure means that pressure natriure-

can cause important renal tubular disorders.

sis and pressure diuresis have been reset to a higher

arterial pressure.

Renal Glycosuria—Failure of the Kidneys to Reabsorb Glucose.

In this condition, the blood glucose concentration may

Hypertension Caused by Patchy Renal Damage and Increased

be normal, but the transport mechanism for tubular

Renal Secretion of Renin. If one part of the kidney is

reabsorption of glucose is greatly limited or absent.

ischemic and the remainder is not ischemic, such as

Consequently, despite a normal blood glucose level,

occurs when one renal artery is severely constricted, the

large amounts of glucose pass into the urine each day.

ischemic renal tissue secretes large quantities of renin.

Because diabetes mellitus is also associated with the

This secretion leads to the formation of angiotensin II,

presence of glucose in the urine, renal glycosuria, which

which can cause hypertension. The most likely sequence

is a relatively benign condition, must be ruled out before

of events in causing this hypertension, as discussed in

making a diagnosis of diabetes mellitus.

Chapter 19, is

(1) the ischemic kidney tissue itself

excretes less than normal amounts of water and salt; (2)

Aminoaciduria—Failure of the Kidneys to Reabsorb Amino Acids.

the renin secreted by the ischemic kidney, and subse-

Some amino acids share mutual transport systems for

quent increased angiotensin II formation, affects the

reabsorption, whereas other amino acids have their own

nonischemic kidney tissue, causing it also to retain salt

distinct transport systems. Rarely, a condition called

and water; and (3) excess salt and water cause hyper-

generalized aminoaciduria results from deficient reab-

tension in the usual manner.

sorption of all amino acids; more frequently, deficiencies

A similar type of hypertension can result when patchy

of specific carrier systems may result in (1) essential

areas of one or both kidneys become ischemic as a

cystinuria, in which large amounts of cystine fail to be

result of arteriosclerosis or vascular injury in specific

reabsorbed and often crystallize in the urine to form

portions of the kidneys. When this occurs, the ischemic

renal stones; (2) simple glycinuria, in which glycine fails

nephrons excrete less salt and water but secrete greater

to be reabsorbed; or (3) beta-aminoisobutyricaciduria,

amounts of renin, which causes increased angiotensin

which occurs in about 5 per cent of all people but appar-

II formation. The high levels of angiotensin II then

ently has no major clinical significance.

impair the ability of the surrounding otherwise normal

nephrons to excrete sodium and water. As a result,

Renal Hypophosphatemia—Failure of the Kidneys to Reabsorb

hypertension develops, which restores the overall

Phosphate. In renal hypophosphatemia, the renal

excretion of sodium and water by the kidney, so that

tubules fail to reabsorb large enough quantities of phos-

balance between intake and output of salt and water

phate ions when the phosphate concentration of the

is maintained, but at the expense of high blood

body fluids falls very low. This condition usually does

pressure.

not cause serious immediate abnormalities, because

the phosphate concentration of the extracellular fluid

Kidney Diseases That Cause Loss of Entire Nephrons Lead to Renal

can vary widely without causing major cellular dys-

Failure But May Not Cause Hypertension. Loss of large

function. Over a long period, a low phosphate level

numbers of whole nephrons, such as occurs with the loss

causes diminished calcification of the bones, causing the

of one kidney and part of another kidney, almost always

person to develop rickets. This type of rickets is refrac-

leads to renal failure if the amount of kidney tissue lost

tory to vitamin D therapy, in contrast to the rapid

is great enough. If the remaining nephrons are normal

response of the usual type of rickets, as discussed in

and the salt intake is not excessive, this condition might

Chapter 79.

not cause clinically significant hypertension, because

even a slight rise in blood pressure will raise the GFR

and decrease tubular sodium reabsorption sufficiently

Renal Tubular Acidosis—Failure of the Tubules to Secrete Hydro-

to promote enough water and salt excretion in the urine,

gen Ions. In this condition, the renal tubules are unable

even with the few nephrons that remain intact.

to secrete adequate amounts of hydrogen ions. As a

However, a patient with this type of abnormality may

result, large amounts of sodium bicarbonate are contin-

become severely hypertensive if additional stresses are

ually lost in the urine. This causes a continued state of

imposed, such as eating a large amount of salt. In this

metabolic acidosis, as discussed in Chapter 30. This type

case, the kidneys simply cannot clear adequate quanti-

of renal abnormality can be caused by hereditary dis-

ties of salt with the small number of functioning

orders, or it can occur as a result of widespread injury

nephrons that remain.

to the renal tubules.

414

Unit V The Body Fluids and Kidneys

Nephrogenic Diabetes Insipidus—Failure of the Kidneys to

Respond to Antidiuretic Hormone. Occasionally, the renal

tubules do not respond to antidiuretic hormone, causing

large quantities of dilute urine to be excreted. As long

as the person is supplied with plenty of water, this con-

Semipermeable

Flowing

dition seldom causes severe difficulty. However, when

membrane

blood

adequate quantities of water are not available, the

person rapidly becomes dehydrated.

Fanconi’s Syndrome—A Generalized Reabsorptive Defect of the

Waste Water

Flowing

Renal Tubules. Fanconi’s syndrome is usually associated

products

dialysate

with increased urinary excretion of virtually all amino

acids, glucose, and phosphate. In severe cases, other

manifestations are also observed, such as (1) failure

to reabsorb sodium bicarbonate, which results in

metabolic acidosis; (2) increased excretion of potassium

Bubble

Blood out

and sometimes calcium; and (3) nephrogenic diabetes

trap

insipidus.

There are multiple causes of Fanconi’s syndrome,

Dialyzer

which results from a generalized inability of the renal

tubular cells to transport various substances. Some of

these causes include (1) hereditary defects in cell trans-

Blood in

port mechanisms, (2) toxins or drugs that injure the

Dialysate

renal tubular epithelial cells, and (3) injury to the renal

out

tubular cells as a result of ischemia. The proximal

tubular cells are especially affected in Fanconi’s syn-

drome caused by tubular injury, because these cells

reabsorb and secrete many of the drugs and toxins that

can cause damage.

Treatment of Renal Failure

by Dialysis with an

Artificial Kidney

Fresh dialyzing

Constant

Used dialyzing

solution

temperature

solution

Severe loss of kidney function, either acutely or chron-

bath

ically, is a threat to life and requires removal of toxic

waste products and restoration of body fluid volume

Figure 31-8

and composition toward normal. This can be accom-

Principles of dialysis with an artificial kidney.

plished by dialysis with an artificial kidney. In certain

types of acute renal failure, an artificial kidney may be

used to tide the patient over until the kidneys resume

their function. If the loss of kidney function is irre-

fluid back into the plasma. If the concentration of a sub-

versible, it is necessary to perform dialysis chronically

stance is greater in the plasma than in the dialyzing

to maintain life. In the United States alone, nearly

fluid, there will be a net transfer of the substance from

300,000 people with irreversible renal failure or even

the plasma into the dialyzing fluid.

total kidney removal are being maintained by dialysis

The rate of movement of solute across the dialyzing

with artificial kidneys. Because dialysis cannot maintain

membrane depends on (1) the concentration gradient

completely normal body fluid composition and cannot

of the solute between the two solutions, (2) the per-

replace all the multiple functions performed by the

meability of the membrane to the solute, (3) the surface

kidneys, the health of patients maintained on artificial

area of the membrane, and (4) the length of time

kidneys usually remains significantly impaired. A better

that the blood and fluid remain in contact with the

treatment for permanent loss of kidney function is to

membrane.

restore functional kidney tissue by means of a kidney

Thus, the maximum rate of solute transfer occurs ini-

transplant.

tially when the concentration gradient is greatest (when

dialysis is begun) and slows down as the concentration

Basic Principles of Dialysis. The basic principle of the arti-

gradient is dissipated. In a flowing system, as is the case

ficial kidney is to pass blood through minute blood

with “hemodialysis,” in which blood and dialysate fluid

channels bounded by a thin membrane. On the other

flow through the artificial kidney, the dissipation of the

side of the membrane is a dialyzing fluid into which

concentration gradient can be reduced and diffusion of

unwanted substances in the blood pass by diffusion.

solute across the membrane can be optimized by

Figure 31-8 shows the components of one type of arti-

increasing the flow rate of the blood, the dialyzing fluid,

ficial kidney in which blood flows continually between

or both.

two thin membranes of cellophane; outside the mem-

In normal operation of the artificial kidney, blood

brane is a dialyzing fluid. The cellophane is porous

flows continually or intermittently back into the vein.

enough to allow the constituents of the plasma, except

The total amount of blood in the artificial kidney at any

the plasma proteins, to diffuse in both directions—from

one time is usually less than 500 milliliters, the rate of

plasma into the dialyzing fluid or from the dialyzing

flow may be several hundred milliliters per minute, and

Chapter 31

Kidney Diseases and Diuretics

415

at a rate of 100 to 225 ml/min, which shows that at least

Table 31-7

for the excretion of urea, the artificial kidney can func-

Comparison of Dialyzing Fluid with Normal and Uremic

tion about twice as rapidly as two normal kidneys

Plasma

together, whose urea clearance is only 70 ml/min. Yet

the artificial kidney is used for only 4 to 6 hours per day,

three times a week. Therefore, the overall plasma clear-

Normal

Dialyzing

Uremic

Constituent

Plasma

Fluid

Plasma

ance is still considerably limited when the artificial

kidney replaces the normal kidneys. Also, it is important

Electrolytes (mEq/L)

to keep in mind that the artificial kidney cannot replace

Na⁺

142

133

142

some of the other functions of the kidneys, such as

K⁺

1.0

secretion of erythropoietin, which is necessary for red

Ca⁺⁺

3.0

blood cell production.

Mg⁺⁺

1.5

Cl^-

107

105

107

HCO_3-

35.7

Lactate^-

1.2

References

HPO4=

Urate^-

0.3

Andreoli TE (ed): Cecil’s Essentials of Medicine, 6th ed.

Sulfate⁼

0.5

Philadelphia: WB Saunders, 2004.

Nonelectrolytes

Glucose

100

125

100

Fishbane SA, Scribner BH: Blood pressure control in dialy-

Urea

200

sis patients. Semin Dial 15:144, 2002.

Creatinine

Hall JE: The kidney, hypertension, and obesity. Hypertension

41:625, 2003.

Hall JE, Henegar JR, Dwyer TM, et al: Is obesity a major

cause of chronic renal disease? Adv Ren Replace Ther

the total diffusion surface area is between 0.6 and 2.5

11:41, 2004.

square meters. To prevent coagulation of the blood in

Hostetter TH: Prevention of the development and progres-

the artificial kidney, a small amount of heparin is infused

sion of renal disease. J Am Soc Nephrol 14(Suppl 2):S144,

into the blood as it enters the artificial kidney. In addi-

2003.

tion to diffusion of solutes, mass transfer of solutes and

Levey AS, Beto JA, Coronado BE, et al: Controlling the epi-

water can be produced by applying a hydrostatic pres-

demic of cardiovascular disease in chronic renal disease.

sure to force the fluid and solutes across the membranes

What do we know? What do we need to learn? Where do

of the dialyzer; such filtration is called bulk flow.

we go from here? National Kidney Foundation Task Force

on Cardiovascular Disease. Am J Kidney Dis 32:853, 1998.

Dialyzing Fluid. Table 31-7 compares the constituents in

Luke RG: Chronic renal failure. In: Goldman F, Bennett JC

a typical dialyzing fluid with those in normal plasma and

(eds): Cecil Textbook of Medicine, 21st ed. Philadelphia:

uremic plasma. Note that the concentrations of ions and

WB Saunders, 2000, pp 571-578.

other substances in dialyzing fluid are not the same as

Mitch WE: Acute renal failure. In: Goldman F, Bennett JC

the concentrations in normal plasma or in uremic

(eds): Cecil Textbook of Medicine, 21st ed. Philadelphia:

plasma. Instead, they are adjusted to levels that are

WB Saunders, 2000, pp 567-570.

needed to cause appropriate movement of water and

Molitoris BA: Transitioning to therapy in ischemic acute

solutes through the membrane during dialysis.

renal failure. J Am Soc Nephrol 14:265, 2003.

Note that there is no phosphate, urea, urate, sulfate,

Sarnak MJ, Levey AS, Schoolwerth AC, et al: Kidney disease

or creatinine in the dialyzing fluid; however, these are

as a risk factor for development of cardiovascular disease.

present in high concentrations in the uremic blood.

Hypertension 42:1050, 2003.

Therefore, when a uremic patient is dialyzed, these sub-

Schrier RW: Atlas of Diseases of the Kidney. http://

stances are lost in large quantities into the dialyzing

www.kidneyatlas.org/.

fluid.

Shankar SS, Brater DC: Loop diuretics: from the Na-K-2Cl

The effectiveness of the artificial kidney can be

transporter to clinical use. Am J Physiol Renal Physiol

expressed in terms of the amount of plasma that is

284:F11, 2003.

cleared of different substances each minute, which, as

Singri N, Ahya SN, Levin ML: Acute renal failure. JAMA

discussed in Chapter

27, is the primary means for

289:747, 2003.

expressing the functional effectiveness of the kidneys

United States Renal Data System. http://www.usrds.org/.

themselves to rid the body of unwanted substances.

Wilcox CS: New insights into diuretic use in patients with

Most artificial kidneys can clear urea from the plasma

chronic renal disease. J Am Soc Nephrol 13:798, 2002.

C H A P T E R

Red Blood Cells, Anemia,

and Polycythemia

With this chapter we begin discussing the blood cells

and cells of the macrophage system and lymphatic

system. We first present the functions of red blood

cells, which are the most abundant cells of the blood

and are necessary for the delivery of oxygen to the

tissues.

Red Blood Cells (Erythrocytes)

The major function of red blood cells, also known as erythrocytes, is to trans-

port hemoglobin, which in turn carries oxygen from the lungs to the tissues. In

some lower animals, hemoglobin circulates as free protein in the plasma, not

enclosed in red blood cells. When it is free in the plasma of the human being,

about 3 per cent of it leaks through the capillary membrane into the tissue

spaces or through the glomerular membrane of the kidney into the glomerular

filtrate each time the blood passes through the capillaries. Therefore, for hemo-

globin to remain in the human blood stream, it must exist inside red blood cells.

The red blood cells have other functions besides transport of hemoglobin.

For instance, they contain a large quantity of carbonic anhydrase, an enzyme

that catalyzes the reversible reaction between carbon dioxide (CO₂) and water

to form carbonic acid (H₂CO₃), increasing the rate of this reaction several thou-

sandfold. The rapidity of this reaction makes it possible for the water of the

blood to transport enormous quantities of CO₂ in the form of bicarbonate ion

(HCO_3-) from the tissues to the lungs, where it is reconverted to CO₂ and

expelled into the atmosphere as a body waste product. The hemoglobin in the

cells is an excellent acid-base buffer (as is true of most proteins), so that the red

blood cells are responsible for most of the acid-base buffering power of whole

blood.

Shape and Size of Red Blood Cells. Normal red blood cells, shown in Figure 32-3,

are biconcave discs having a mean diameter of about 7.8 micrometers and

a thickness of 2.5 micrometers at the thickest point and 1 micrometer or less

in the center. The average volume of the red blood cell is 90 to 95 cubic

micrometers.

The shapes of red blood cells can change remarkably as the cells squeeze

through capillaries. Actually, the red blood cell is a “bag” that can be deformed

into almost any shape. Furthermore, because the normal cell has a great excess

of cell membrane for the quantity of material inside, deformation does not

stretch the membrane greatly and, consequently, does not rupture the cell, as

would be the case with many other cells.

Concentration of Red Blood Cells in the Blood. In normal men, the average number

of red blood cells per cubic millimeter is 5,200,000 (±300,000); in normal women,

it is 4,700,000 (±300,000). Persons living at high altitudes have greater numbers

of red blood cells. This is discussed later.

Quantity of Hemoglobin in the Cells. Red blood cells have the ability to concentrate

hemoglobin in the cell fluid up to about 34 grams in each 100 milliliters of cells.

419

420

Unit VI Blood Cells, Immunity, and Blood Clotting

The concentration does not rise above this value,

most red cells continue to be produced in the marrow

because this is the metabolic limit of the cell’s hemo-

of the membranous bones, such as the vertebrae,

globin-forming mechanism. Furthermore, in normal

sternum, ribs, and ilia. Even in these bones, the marrow

people, the percentage of hemoglobin is almost always

becomes less productive as age increases.

near the maximum in each cell. However, when hemo-

globin formation is deficient, the percentage of hemo-

Genesis of Blood Cells

globin in the cells may fall considerably below this

Pluripotential Hematopoietic Stem Cells, Growth Inducers, and

value, and the volume of the red cell may also decrease

Differentiation Inducers. The blood cells begin their lives

because of diminished hemoglobin to fill the cell.

in the bone marrow from a single type of cell called

When the hematocrit (the percentage of blood that

the pluripotential hematopoietic stem cell, from which

is cells—normally, 40 to 45 per cent) and the quantity

all the cells of the circulating blood are eventually

of hemoglobin in each respective cell are normal, the

derived. Figure 32-2 shows the successive divisions of

whole blood of men contains an average of 15 grams

the pluripotential cells to form the different circulat-

of hemoglobin per 100 milliliters of cells; for women,

ing blood cells. As these cells reproduce, a small

it contains an average of 14 grams per 100 milliliters.

portion of them remains exactly like the original

As discussed in connection with blood transport of

pluripotential cells and is retained in the bone marrow

oxygen in Chapter 40, each gram of pure hemoglobin

to maintain a supply of these, although their numbers

is capable of combining with 1.34 milliliters of oxygen.

diminish with age. Most of the reproduced cells,

Therefore, in a normal man, a maximum of about 20

however, differentiate to form the other cell types

milliliters of oxygen can be carried in combination

shown to the right in Figure 32-2. The intermediate-

with hemoglobin in each 100 milliliters of blood, and

stage cells are very much like the pluripotential

in a normal woman, 19 milliliters of oxygen can be

stem cells, even though they have already become

carried.

committed to a particular line of cells and are called

committed stem cells.

The different committed stem cells, when grown in

Production of Red Blood Cells

culture, will produce colonies of specific types of blood

cells. A committed stem cell that produces erythro-

Areas of the Body That Produce Red Blood Cells. In the early

cytes is called a colony-forming unit-erythrocyte, and

weeks of embryonic life, primitive, nucleated red blood

the abbreviation CFU-E is used to designate this type

cells are produced in the yolk sac. During the middle

of stem cell. Likewise, colony-forming units that form

trimester of gestation, the liver is the main organ for

granulocytes and monocytes have the designation

production of red blood cells, but reasonable numbers

CFU-GM, and so forth.

are also produced in the spleen and lymph nodes. Then,

Growth and reproduction of the different stem

during the last month or so of gestation and after birth,

cells are controlled by multiple proteins called growth

red blood cells are produced exclusively in the bone

inducers. Four major growth inducers have been

marrow.

described, each having different characteristics. One of

As demonstrated in Figure 32-1, the bone marrow

these, interleukin-3, promotes growth and reproduc-

of essentially all bones produces red blood cells until

tion of virtually all the different types of committed

a person is 5 years old. The marrow of the long bones,

stem cells, whereas the others induce growth of only

except for the proximal portions of the humeri and

specific types of cells.

tibiae, becomes quite fatty and produces no more red

The growth inducers promote growth but not dif-

blood cells after about age 20 years. Beyond this age,

ferentiation of the cells. This is the function of another

set of proteins called differentiation inducers. Each of

these causes one type of committed stem cell to dif-

ferentiate one or more steps toward a final adult blood

cell.

100

Formation of the growth inducers and differentia-

tion inducers is itself controlled by factors outside the

bone marrow. For instance, in the case of erythrocytes

(red blood cells), exposure of the blood to low oxygen

for a long time results in growth induction, differenti-

ation, and production of greatly increased numbers of

Rib

erythrocytes, as discussed later in the chapter. In the

case of some of the white blood cells, infectious

5 10 15 20

diseases cause growth, differentiation, and eventual

Age (years)

formation of specific types of white blood cells that are

needed to combat each infection.

Stages of Differentiation of Red Blood Cells

Figure 32-1

The first cell that can be identified as belonging to the

red blood cell series is the proerythroblast, shown at

Relative rates of red blood cell production in the bone marrow of

different bones at different ages.

the starting point in Figure 32-3. Under appropriate

422

Unit VI Blood Cells, Immunity, and Blood Clotting

stimulation, large numbers of these cells are formed

from the CFU-E stem cells.

Once the proerythroblast has been formed, it

Hematopoietic Stem Cells

divides multiple times, eventually forming many

Kidney

mature red blood cells. The first-generation cells are

called basophil erythroblasts because they stain with

Proerythroblasts

basic dyes; the cell at this time has accumulated very

Erythropoietin

little hemoglobin. In the succeeding generations, as

shown in Figure 32-3, the cells become filled with

Red Blood Cells

hemoglobin to a concentration of about 34 per cent,

Decreases

the nucleus condenses to a small size, and its final

remnant is absorbed or extruded from the cell. At the

Tissue Oxygenation

same time, the endoplasmic reticulum is also reab-

sorbed. The cell at this stage is called a reticulocyte

because it still contains a small amount of basophilic

Decreases

material, consisting of remnants of the Golgi appara-

tus, mitochondria, and a few other cytoplasmic

organelles. During this reticulocyte stage, the cells pass

Factors that decrease

oxygenation

from the bone marrow into the blood capillaries by

1. Low blood volume

diapedesis (squeezing through the pores of the capil-

2. Anemia

lary membrane).

3. Low hemoglobin

The remaining basophilic material in the reticulo-

4. Poor blood flow

cyte normally disappears within 1 to 2 days, and the

5. Pulmonary disease

cell is then a mature erythrocyte. Because of the short

life of the reticulocytes, their concentration among all

the red cells of the blood is normally slightly less than

1 per cent.

Figure 32-4

Function of the erythropoietin mechanism to increase production

Regulation of Red Blood Cell Production—Role

of red blood cells when tissue oxygenation decreases.

of Erythropoietin

The total mass of red blood cells in the circulatory

system is regulated within narrow limits, so that (1) an

adequate number of red cells is always available to

can also increase the rate of red cell production. This

provide sufficient transport of oxygen from the lungs

is especially apparent in prolonged cardiac failure and

to the tissues, yet (2) the cells do not become so numer-

in many lung diseases, because the tissue hypoxia

ous that they impede blood flow. What we know about

resulting from these conditions increases red cell pro-

this control mechanism is diagrammed in Figure 32-4

duction, with a resultant increase in hematocrit and

and is as follows.

usually total blood volume as well.

Tissue Oxygenation Is the Most Essential Regulator of Red

Erythropoietin Stimulates Red Cell Production, and Its Forma-

Blood Cell Production. Any condition that causes the

tion Increases in Response to Hypoxia. The principal stim-

quantity of oxygen transported to the tissues to

ulus for red blood cell production in low oxygen states

decrease ordinarily increases the rate of red blood cell

is a circulating hormone called erythropoietin, a gly-

production. Thus, when a person becomes extremely

coprotein with a molecular weight of about 34,000. In

anemic as a result of hemorrhage or any other condi-

the absence of erythropoietin, hypoxia has little or no

tion, the bone marrow immediately begins to produce

effect in stimulating red blood cell production. But

large quantities of red blood cells. Also, destruction of

when the erythropoietin system is functional, hypoxia

major portions of the bone marrow by any means,

causes a marked increase in erythropoietin produc-

especially by x-ray therapy, causes hyperplasia of the

tion, and the erythropoietin in turn enhances red

remaining bone marrow, thereby attempting to supply

blood cell production until the hypoxia is relieved.

the demand for red blood cells in the body.

At very high altitudes, where the quantity of oxygen

Role of the Kidneys in Formation of Erythropoietin. In

in the air is greatly decreased, insufficient oxygen is

the normal person, about 90 per cent of all erythro-

transported to the tissues, and red cell production is

poietin is formed in the kidneys; the remainder is

greatly increased. In this case, it is not the concentra-

formed mainly in the liver. It is not known exactly

tion of red blood cells in the blood that controls red

where in the kidneys the erythropoietin is formed.

cell production but the amount of oxygen transported

One likely possibility is that the renal tubular epithe-

to the tissues in relation to tissue demand for oxygen.

lial cells secrete the erythropoietin, because anemic

Various diseases of the circulation that cause

blood is unable to deliver enough oxygen from the

decreased blood flow through the peripheral vessels,

peritubular capillaries to the highly oxygen-consuming

and particularly those that cause failure of oxygen

tubular cells, thus stimulating erythropoietin pro-

absorption by the blood as it passes through the lungs,

duction.

Chapter 32

Red Blood Cells, Anemia, and Polycythemia

423

At times, hypoxia in other parts of the body, but

building blocks of DNA. Therefore, lack of either

not in the kidneys, stimulates kidney erythropoietin

vitamin B₁₂ or folic acid causes abnormal and dimin-

secretion, which suggests that there might be some

ished DNA and, consequently, failure of nuclear

nonrenal sensor that sends an additional signal to the

maturation and cell division. Furthermore, the ery-

kidneys to produce this hormone. In particular, both

throblastic cells of the bone marrow, in addition to

norepinephrine and epinephrine and several of the

failing to proliferate rapidly, produce mainly larger

prostaglandins stimulate erythropoietin production.

than normal red cells called macrocytes, and the cell

When both kidneys are removed from a person or

itself has a flimsy membrane and is often irregular,

when the kidneys are destroyed by renal disease, the

large, and oval instead of the usual biconcave disc.

person invariably becomes very anemic because the 10

These poorly formed cells, after entering the circulat-

per cent of the normal erythropoietin formed in other

ing blood, are capable of carrying oxygen normally, but

tissues (mainly in the liver) is sufficient to cause only

their fragility causes them to have a short life, one half

one third to one half the red blood cell formation

to one third normal. Therefore, it is said that deficiency

needed by the body.

of either vitamin B₁₂ or folic acid causes maturation

failure in the process of erythropoiesis.

Effect of Erythropoietin in Erythrogenesis. When an

animal or a person is placed in an atmosphere of low

Maturation Failure Caused by Poor Absorption of Vitamin

oxygen, erythropoietin begins to be formed within

B₁₂

from the Gastrointestinal Tract—Pernicious Anemia. A

minutes to hours, and it reaches maximum production

common cause of red blood cell maturation failure is

within 24 hours. Yet almost no new red blood cells

failure to absorb vitamin B₁₂ from the gastrointestinal

appear in the circulating blood until about 5 days later.

tract. This often occurs in the disease pernicious

From this fact, as well as other studies, it has been

anemia, in which the basic abnormality is an atrophic

determined that the important effect of erythropoietin

gastric mucosa that fails to produce normal gastric

is to stimulate the production of proerythroblasts from

secretions. The parietal cells of the gastric glands

hematopoietic stem cells in the bone marrow. In ad-

secrete a glycoprotein called intrinsic factor, which

dition, once the proerythroblasts are formed, the

combines with vitamin B₁₂ in food and makes the B₁₂

erythropoietin causes these cells to pass more rapidly

available for absorption by the gut. It does this in the

through the different erythroblastic stages than they

following way: (1) Intrinsic factor binds tightly with

normally do, further speeding up the production of

the vitamin B₁₂. In this bound state, the B₁₂ is protected

new red blood cells. The rapid production of cells con-

from digestion by the gastrointestinal secretions. (2)

tinues as long as the person remains in a low oxygen

Still in the bound state, intrinsic factor binds to specific

state or until enough red blood cells have been pro-

receptor sites on the brush border membranes of the

duced to carry adequate amounts of oxygen to the

mucosal cells in the ileum. (3) Then, vitamin B₁₂ is

tissues despite the low oxygen; at this time, the rate of

transported into the blood during the next few hours

erythropoietin production decreases to a level that will

by the process of pinocytosis, carrying intrinsic factor

maintain the required number of red cells but not an

and the vitamin together through the membrane. Lack

excess.

of intrinsic factor, therefore, causes diminished avail-

In the absence of erythropoietin, few red blood

ability of vitamin B₁₂because of faulty absorption of

cells are formed by the bone marrow. At the other

the vitamin.

extreme, when large quantities of erythropoietin

Once vitamin B₁₂ has been absorbed from the gas-

are formed available, and if there is plenty of iron and

trointestinal tract, it is first stored in large quantities in

other required nutrients available, the rate of red

the liver, then released slowly as needed by the bone

blood cell production can rise to perhaps 10 or more

marrow. The minimum amount of vitamin B₁₂ required

times normal. Therefore, the erythropoietin mecha-

each day to maintain normal red cell maturation is

nism for controlling red blood cell production is a

only 1 to 3 micrograms, and the normal storage in the

powerful one.

liver and other body tissues is about 1000 times this

amount. Therefore, 3 to 4 years of defective B₁₂ absorp-

tion are usually required to cause maturation failure

Maturation of Red Blood Cells—Requirement

anemia.

for Vitamin B₁₂ (Cyanocobalamin) and

Folic Acid

Because of the continuing need to replenish red blood

Failure of Maturation Caused by Deficiency of Folic Acid

cells, the erythropoietic cells of the bone marrow are

(Pteroylglutamic Acid). Folic acid is a normal constituent

among the most rapidly growing and reproducing cells

of green vegetables, some fruits, and meats (especially

in the entire body. Therefore, as would be expected,

liver). However, it is easily destroyed during cooking.

their maturation and rate of production are affected

Also, people with gastrointestinal absorption abnor-

greatly by a person’s nutritional status.

malities, such as the frequently occurring small intes-

Especially important for final maturation of the red

tinal disease called sprue, often have serious difficulty

blood cells are two vitamins, vitamin B

12 and folic acid.

absorbing both folic acid and vitamin B₁₂. Therefore,

Both of these are essential for the synthesis of DNA,

in many instances of maturation failure, the cause is

because each in a different way is required for the for-

deficiency of intestinal absorption of both folic acid

mation of thymidine triphosphate, one of the essential

and vitamin B₁₂.

424

Unit VI Blood Cells, Immunity, and Blood Clotting

2 succinyl-CoA + 2 glycine

II.

4 pyrrole

protoporphyrin IX

(pyrrole)

III.

protoporphyrin IX + Fe⁺⁺

heme

IV.

heme + polypeptide

hemoglobin chain (a or b)

2 a chains + 2 b chains

hemoglobin A

Figure 32-5

Formation of hemoglobin.

Formation of Hemoglobin

Synthesis of hemoglobin begins in the proerythro-

CH₂

blasts and continues even into the reticulocyte stage of

the red blood cells. Therefore, when reticulocytes leave

CH₃

the bone marrow and pass into the blood stream, they

CH₂

continue to form minute quantities of hemoglobin for

H₃C

O₂

another day or so until they become mature erythro-

^(-)N

cytes.

Figure 32-5 shows the basic chemical steps in the

formation of hemoglobin. First, succinyl-CoA, formed

N^(-)

in the Krebs metabolic cycle (as explained in Chapter

67), binds with glycine to form a pyrrole molecule. In

H₃C

CH₃

turn, four pyrroles combine to form protoporphyrin

IX, which then combines with iron to form the heme

molecule. Finally, each heme molecule combines with

CH₂

a long polypeptide chain, a globin synthesized by

ribosomes, forming a subunit of hemoglobin called a

CH₂

hemoglobin chain (Figure 32-6). Each chain has a

molecular weight of about 16,000; four of these in turn

COOH

bind together loosely to form the whole hemoglobin

Polypepitide

molecule.

(hemoglobin chain-a or b)

There are several slight variations in the different

subunit hemoglobin chains, depending on the amino

acid composition of the polypeptide portion. The dif-

ferent types of chains are designated alpha chains, beta

Figure 32-6

chains, gamma chains, and delta chains. The most

common form of hemoglobin in the adult human

Basic structure of the hemoglobin molecule, showing one of the

being, hemoglobin A, is a combination of two alpha

four heme chains that bind together to form the hemoglobin

molecule.

chains and two beta chains. Hemoglobin A has a

molecular weight of 64,458.

Because each hemoglobin chain has a heme pros-

thetic group containing an atom of iron, and because

one point in each of the two beta chains. When this

there are four hemoglobin chains in each hemoglobin

type of hemoglobin is exposed to low oxygen, it forms

molecule, one finds four iron atoms in each hemoglo-

elongated crystals inside the red blood cells that are

bin molecule; each of these can bind loosely with one

sometimes 15 micrometers in length. These make it

molecule of oxygen, making a total of four molecules

almost impossible for the cells to pass through many

of oxygen (or eight oxygen atoms) that can be trans-

small capillaries, and the spiked ends of the crystals are

ported by each hemoglobin molecule.

likely to rupture the cell membranes, leading to sickle

The types of hemoglobin chains in the hemoglobin

cell anemia.

molecule determine the binding affinity of the hemo-

globin for oxygen. Abnormalities of the chains can

Combination of Hemoglobin with Oxygen. The most impor-

alter the physical characteristics of the hemoglobin

tant feature of the hemoglobin molecule is its ability

molecule as well. For instance, in sickle cell anemia, the

to combine loosely and reversibly with oxygen. This

amino acid valine is substituted for glutamic acid at

ability is discussed in detail in Chapter 40 in relation

Chapter 32

Red Blood Cells, Anemia, and Polycythemia

425

to respiration, because the primary function of hemo-

globulin, apotransferrin, to form transferrin, which is

globin in the body is to combine with oxygen in the

then transported in the plasma. The iron is loosely

lungs and then to release this oxygen readily in the

bound in the transferrin and, consequently, can be

peripheral tissue capillaries, where the gaseous tension

released to any tissue cell at any point in the body.

of oxygen is much lower than in the lungs.

Excess iron in the blood is deposited especially in the

Oxygen does not combine with the two positive

liver hepatocytes and less in the reticuloendothelial

bonds of the iron in the hemoglobin molecule. Instead,

cells of the bone marrow.

it binds loosely with one of the so-called coordination

In the cell cytoplasm, iron combines mainly with

bonds of the iron atom. This is an extremely loose

a protein, apoferritin, to form ferritin. Apoferritin

bond, so that the combination is easily reversible. Fur-

has a molecular weight of about

460,000, and

thermore, the oxygen does not become ionic oxygen

varying quantities of iron can combine in clusters of

but is carried as molecular oxygen (composed of two

iron radicals with this large molecule; therefore,

oxygen atoms) to the tissues, where, because of the

ferritin may contain only a small amount of iron or a

loose, readily reversible combination, it is released into

large amount. This iron stored as ferritin is called

the tissue fluids still in the form of molecular oxygen

storage iron.

rather than ionic oxygen.

Smaller quantities of the iron in the storage pool are

in an extremely insoluble form called hemosiderin.

This is especially true when the total quantity of iron

Iron Metabolism

in the body is more than the apoferritin storage pool

can accommodate. Hemosiderin collects in cells in the

Because iron is important for the formation not only

form of large clusters that can be observed micro-

of hemoglobin but also of other essential elements in

scopically as large particles. In contrast, ferritin parti-

the body (e.g., myoglobin, cytochromes, cytochrome

cles are so small and dispersed that they usually can

oxidase, peroxidase, catalase), it is important to under-

be seen in the cell cytoplasm only with the electron

stand the means by which iron is utilized in the body.

microscope.

The total quantity of iron in the body averages 4 to 5

When the quantity of iron in the plasma falls low,

grams, about 65 per cent of which is in the form of

some of the iron in the ferritin storage pool is removed

hemoglobin. About 4 per cent is in the form of myo-

easily and transported in the form of transferrin in the

globin, 1 per cent is in the form of the various heme

plasma to the areas of the body where it is needed. A

compounds that promote intracellular oxidation, 0.1

unique characteristic of the transferrin molecule is that

per cent is combined with the protein transferrin in the

it binds strongly with receptors in the cell membranes

blood plasma, and 15 to 30 per cent is stored for later

of erythroblasts in the bone marrow. Then, along with

use, mainly in the reticuloendothelial system and liver

its bound iron, it is ingested into the erythroblasts by

parenchymal cells, principally in the form of ferritin.

endocytosis. There the transferrin delivers the iron

directly to the mitochondria, where heme is synthe-

Transport and Storage of Iron. Transport, storage, and

sized. In people who do not have adequate quantities

metabolism of iron in the body are diagrammed in

of transferrin in their blood, failure to transport iron

Figure 32-7 and can be explained as follows: When

to the erythroblasts in this manner can cause severe

iron is absorbed from the small intestine, it immedi-

hypochromic anemia—that is, red cells that contain

ately combines in the blood plasma with a beta

much less hemoglobin than normal.

Bilirubin (excreted)

Tissues

Ferritin

Hemosiderin

Macrophages

Heme

Free

Degrading hemoglobin

Enzymes

iron

Free iron

Hemoglobin

Transferrin-Fe

Red Cells

Plasma

Blood loss - 0.7 mg Fe Fe⁺⁺ absorbed Fe excreted-0.6 mg daily

daily in menses

(small intestine)

Figure 32-7

Iron transport and metabolism.

426

Unit VI Blood Cells, Immunity, and Blood Clotting

When red blood cells have lived their life span and

progressively less active, and the cells become more

are destroyed, the hemoglobin released from the cells

and more fragile, presumably because their life

is ingested by monocyte-macrophage cells. There,

processes wear out.

iron is liberated and is stored mainly in the ferritin

Once the red cell membrane becomes fragile, the

pool to be used as needed for the formation of new

cell ruptures during passage through some tight spot

hemoglobin.

of the circulation. Many of the red cells self-destruct

in the spleen, where they squeeze through the red pulp

Daily Loss of Iron. A man excretes about 0.6 milligram

of the spleen. There, the spaces between the structural

of iron each day, mainly into the feces. Additional

trabeculae of the red pulp, through which most of the

quantities of iron are lost when bleeding occurs. For a

cells must pass, are only 3 micrometers wide, in com-

woman, additional menstrual loss of blood brings long-

parison with the 8-micrometer diameter of the red

term iron loss to an average of about 1.3 mg/day.

cell. When the spleen is removed, the number of old

abnormal red cells circulating in the blood increases

Absorption of Iron from the Intestinal Tract

considerably.

Iron is absorbed from all parts of the small intestine,

mostly by the following mechanism. The liver secretes

Destruction of Hemoglobin. When red blood cells burst

moderate amounts of apotransferrin into the bile,

and release their hemoglobin, the hemoglobin is

which flows through the bile duct into the duodenum.

phagocytized almost immediately by macrophages in

Here, the apotransferrin binds with free iron and also

many parts of the body, but especially by the Kupffer

with certain iron compounds, such as hemoglobin and

cells of the liver and macrophages of the spleen and

myoglobin from meat, two of the most important

bone marrow. During the next few hours to days, the

sources of iron in the diet. This combination is called

macrophages release iron from the hemoglobin and

transferrin. It, in turn, is attracted to and binds with

pass it back into the blood, to be carried by transfer-

receptors in the membranes of the intestinal epithelial

rin either to the bone marrow for the production of

cells. Then, by pinocytosis, the transferrin molecule,

new red blood cells or to the liver and other tissues for

carrying its iron store, is absorbed into the epithelial

storage in the form of ferritin. The porphyrin portion

cells and later released into the blood capillaries

of the hemoglobin molecule is converted by the

beneath these cells in the form of plasma transferrin.

macrophages, through a series of stages, into the bile

Iron absorption from the intestines is extremely

pigment bilirubin, which is released into the blood and

slow, at a maximum rate of only a few milligrams per

later removed from the body by secretion through the

day. This means that even when tremendous quantities

liver into the bile; this is discussed in relation to liver

of iron are present in the food, only small proportions

function in Chapter 70.

can be absorbed.

Regulation of Total Body Iron by Controlling Rate of Absorption.

Anemias

When the body has become saturated with iron so that

essentially all apoferritin in the iron storage areas is

Anemia means deficiency of hemoglobin in the blood,

already combined with iron, the rate of additional iron

which can be caused by either too few red blood cells

absorption from the intestinal tract becomes greatly

or too little hemoglobin in the cells. Some types of

decreased. Conversely, when the iron stores have

anemia and their physiologic causes are the following.

become depleted, the rate of absorption can acceler-

ate probably five or more times normal. Thus, total

Blood Loss Anemia. After rapid hemorrhage, the body

body iron is regulated mainly by altering the rate of

replaces the fluid portion of the plasma in 1 to 3 days,

absorption.

but this leaves a low concentration of red blood cells.

If a second hemorrhage does not occur, the red blood

cell concentration usually returns to normal within 3

Life Span and Destruction of Red

to 6 weeks.

Blood Cells

In chronic blood loss, a person frequently cannot

absorb enough iron from the intestines to form hemo-

When red blood cells are delivered from the bone

globin as rapidly as it is lost. Red cells are then pro-

marrow into the circulatory system, they normally cir-

duced that are much smaller than normal and have too

culate an average of 120 days before being destroyed.

little hemoglobin inside them, giving rise to microcytic,

Even though mature red cells do not have a nucleus,

hypochromic anemia, which is shown in Figure 32-3.

mitochondria, or endoplasmic reticulum, they do have

cytoplasmic enzymes that are capable of metabolizing

Aplastic Anemia. Bone marrow aplasia means lack of

glucose and forming small amounts of adenosine

functioning bone marrow. For instance, a person

triphosphate. These enzymes also (1) maintain pliabil-

exposed to gamma ray radiation from a nuclear bomb

ity of the cell membrane, (2) maintain membrane

blast can sustain complete destruction of bone

transport of ions, (3) keep the iron of the cells’ hemo-

marrow, followed in a few weeks by lethal anemia.

globin in the ferrous form rather than ferric form, and

Likewise, excessive x-ray treatment, certain industrial

(4) prevent oxidation of the proteins in the red cells.

chemicals, and even drugs to which the person might

Even so, the metabolic systems of old red cells become

be sensitive can cause the same effect.

Chapter 32

Red Blood Cells, Anemia, and Polycythemia

427

Megaloblastic Anemia. Based on the earlier discussions

Rh-positive cells fragile, leading to rapid rupture and

of vitamin B₁₂, folic acid, and intrinsic factor from the

causing the child to be born with serious anemia. This

stomach mucosa, one can readily understand that loss

is discussed in Chapter 35 in relation to the Rh factor

of any one of these can lead to slow reproduction of

of blood. The extremely rapid formation of new red

erythroblasts in the bone marrow. As a result, the red

cells to make up for the destroyed cells in erythro-

cells grow too large, with odd shapes, and are called

blastosis fetalis causes a large number of early blast

megaloblasts. Thus, atrophy of the stomach mucosa,

forms of red cells to be released from the bone marrow

as occurs in pernicious anemia, or loss of the entire

into the blood.

stomach after surgical total gastrectomy can lead to

megaloblastic anemia. Also, patients who have intes-

tinal sprue, in which folic acid, vitamin B₁₂, and other

Effects of Anemia on Function of the

vitamin B compounds are poorly absorbed, often

Circulatory System

develop megaloblastic anemia. Because in these states

the erythroblasts cannot proliferate rapidly enough to

The viscosity of the blood, which was discussed in

form normal numbers of red blood cells, those red cells

Chapter 14, depends almost entirely on the blood con-

that are formed are mostly oversized, have bizarre

centration of red blood cells. In severe anemia, the

shapes, and have fragile membranes. These cells

blood viscosity may fall to as low as 1.5 times that of

rupture easily, leaving the person in dire need of an

water rather than the normal value of about 3. This

adequate number of red cells.

decreases the resistance to blood flow in the periph-

eral blood vessels, so that far greater than normal

Hemolytic Anemia. Different abnormalities of the red

quantities of blood flow through the tissues and return

blood cells, many of which are hereditarily acquired,

to the heart, thereby greatly increasing cardiac output.

make the cells fragile, so that they rupture easily as

Moreover, hypoxia resulting from diminished trans-

they go through the capillaries, especially through the

port of oxygen by the blood causes the peripheral

spleen. Even though the number of red blood cells

tissue blood vessels to dilate, allowing a further

formed may be normal, or even much greater than

increase in the return of blood to the heart and

normal in some hemolytic diseases, the life span of the

increasing the cardiac output to a still higher level—

fragile red cell is so short that the cells are destroyed

sometimes three to four times normal. Thus, one of the

faster than they can be formed, and serious anemia

major effects of anemia is greatly increased cardiac

results. Some of these types of anemia are the

output, as well as increased pumping workload on the

following.

heart.

In hereditary spherocytosis, the red cells are very

The increased cardiac output in anemia partially

small and spherical rather than being biconcave discs.

offsets the reduced oxygen-carrying effect of the

These cells cannot withstand compression forces

anemia, because even though each unit quantity of

because they do not have the normal loose, baglike cell

blood carries only small quantities of oxygen, the rate

membrane structure of the biconcave discs. On passing

of blood flow may be increased enough so that almost

through the splenic pulp and some other tight vas-

normal quantities of oxygen are actually delivered to

cular beds, they are easily ruptured by even slight

the tissues. However, when a person with anemia

compression.

begins to exercise, the heart is not capable of pumping

In sickle cell anemia, which is present in 0.3 to 1.0

much greater quantities of blood than it is already

per cent of West African and American blacks, the cells

pumping. Consequently, during exercise, which

have an abnormal type of hemoglobin called hemo-

greatly increases tissue demand for oxygen, extreme

globin S, containing faulty beta chains in the hemo-

tissue hypoxia results, and acute cardiac failure

globin molecule, as explained earlier in the chapter.

ensues.

When this hemoglobin is exposed to low concentra-

tions of oxygen, it precipitates into long crystals inside

the red blood cell. These crystals elongate the cell and

Polycythemia

give it the appearance of a sickle rather than a bicon-

cave disc. The precipitated hemoglobin also damages

Secondary Polycythemia. Whenever the tissues become

the cell membrane, so that the cells become highly

hypoxic because of too little oxygen in the breathed

fragile, leading to serious anemia. Such patients fre-

air, such as at high altitudes, or because of failure of

quently experience a vicious circle of events called a

oxygen delivery to the tissues, such as in cardiac

sickle cell disease “crisis,” in which low oxygen tension

failure, the blood-forming organs automatically

in the tissues causes sickling, which leads to ruptured

produce large quantities of extra red blood cells. This

red cells, which causes a further decrease in oxygen

condition is called secondary polycythemia, and the

tension and still more sickling and red cell destruction.

red cell count commonly rises to 6 to 7 million/mm³,

Once the process starts, it progresses rapidly, eventu-

about 30 per cent above normal.

ating in a serious decrease in red blood cells within a

A common type of secondary polycythemia, called

few hours and, often, death.

physiologic polycythemia, occurs in natives who live at

In erythroblastosis fetalis, Rh-positive red blood

altitudes of 14,000 to 17,000 feet, where the atmos-

cells in the fetus are attacked by antibodies from

pheric oxygen is very low. The blood count is generally

an Rh-negative mother. These antibodies make the

6 to 7 million/mm³; this allows these people to perform

428

Unit VI Blood Cells, Immunity, and Blood Clotting

reasonably high levels of continuous work even in a

increase peripheral resistance and, thereby, increase

rarefied atmosphere.

arterial pressure. Beyond certain limits, however, these

regulations fail, and hypertension develops.

Polycythemia Vera

(Erythremia). In addition to those

The color of the skin depends to a great extent on

people who have physiologic polycythemia, others

the quantity of blood in the skin subpapillary venous

have a pathological condition known as polycythemia

plexus. In polycythemia vera, the quantity of blood in

vera, in which the red blood cell count may be 7 to 8

this plexus is greatly increased. Further, because the

million/mm³ and the hematocrit may be 60 to 70 per

blood passes sluggishly through the skin capillaries

cent instead of the normal 40 to 45 per cent. Poly-

before entering the venous plexus, a larger than

cythemia vera is caused by a genetic aberration in the

normal quantity of hemoglobin is deoxygenated. The

hemocytoblastic cells that produce the blood cells. The

blue color of all this deoxygenated hemoglobin masks

blast cells no longer stop producing red cells when too

the red color of the oxygenated hemoglobin. There-

many cells are already present. This causes excess pro-

fore, a person with polycythemia vera ordinarily has a

duction of red blood cells in the same manner that a

ruddy complexion with a bluish (cyanotic) tint to the

breast tumor causes excess production of a specific

skin.

type of breast cell. It usually causes excess production

of white blood cells and platelets as well.

In polycythemia vera, not only does the hematocrit

References

increase, but the total blood volume also increases, on

some occasions to almost twice normal. As a result, the

Alayash AI: Oxygen therapeutics: can we tame haemoglo-

entire vascular system becomes intensely engorged. In

bin? Nat Rev Drug Discov 3:152, 2004.

Brissot P, Troadec MB, Loreal O: The clinical relevance of

addition, many blood capillaries become plugged by

new insights in iron transport and metabolism. Curr

the viscous blood; the viscosity of the blood in poly-

Hematol Rep 3:107, 2004.

cythemia vera sometimes increases from the normal of

Claster S, Vichinsky EP: Managing sickle cell disease. BMJ

3 times the viscosity of water to 10 times that of water.

327:1151, 2003.

Fandrey J: Oxygen-dependent and tissue-specific regulation

of erythropoietin gene expression. Am J Physiol Regul

Effect of Polycythemia on Function of

Integr Comp Physiol 286:R977, 2004.

Hallberg L: Perspectives on nutritional iron deficiency. Annu

the Circulatory System

Rev Nutr 21:1, 2001.

Hentze MW, Muckenthaler MU, Andrews NC: Balancing

Because of the greatly increased viscosity of the blood

acts: molecular control of mammalian iron metabolism.

in polycythemia, blood flow through the peripheral

Cell 117:285, 2004.

blood vessels is often very sluggish. In accordance with

Lappin T: The cellular biology of erythropoietin receptors.

the factors that regulate return of blood to the heart,

Oncologist 8(Suppl 1):15, 2003.

as discussed in Chapter 20, increasing blood viscosity

Maxwell P: HIF-1: an oxygen response system with special

decreases the rate of venous return to the heart. Con-

relevance to the kidney. J Am Soc Nephrol 14:2712, 2003.

versely, the blood volume is greatly increased in poly-

Persons DA: Update on gene therapy for hemoglobin disor-

cythemia, which tends to increase venous return.

ders. Curr Opin Mol Ther 5:508, 2003.

Pietrangelo A: Hereditary hemochromatosis—a new look at

Actually, the cardiac output in polycythemia is not far

an old disease. N Engl J Med 350:2383, 2004.

from normal, because these two factors more or less

Shah S, Vega R: Hereditary spherocytosis. Pediatr Rev

neutralize each other.

25:168, 2004.

The arterial pressure is also normal in most people

Tefferi A: A contemporary approach to the diagnosis and

with polycythemia, although in about one third of

management of polycythemia vera. Curr Hematol Rep

them, the arterial pressure is elevated. This means that

2:237, 2003.

the blood pressure-regulating mechanisms can usually

Trigg ME: Hematopoietic stem cells. Pediatrics

113(4

offset the tendency for increased blood viscosity to

Suppl):1051, 2004.

C H A P T E R

Resistance of the Body

to Infection: I. Leukocytes,

Granulocytes, the

Monocyte-Macrophage System,

and Inflammation

Our bodies are exposed continually to bacteria,

viruses, fungi, and parasites, all of which occur

normally and to varying degrees in the skin, the

mouth, the respiratory passageways, the intestinal

tract, the lining membranes of the eyes, and even the

urinary tract. Many of these infectious agents are

capable of causing serious abnormal physiologic

function or even death if they invade the deeper

tissues. In addition, we are exposed intermittently to other highly infectious bac-

teria and viruses besides those that are normally present, and these can cause

acute lethal diseases such as pneumonia, streptococcal infection, and typhoid

fever.

Our bodies have a special system for combating the different infectious and

toxic agents. This is comprised of blood leukocytes (white blood cells) and tissue

cells derived from leukocytes. These cells work together in two ways to prevent

disease: (1) by actually destroying invading bacteria or viruses by phagocytosis,

and (2) by forming antibodies and sensitized lymphocytes, one or both of which

may destroy or inactivate the invader. This chapter is concerned with the first

of these methods, and Chapter 34 with the second.

Leukocytes (White Blood Cells)

The leukocytes, also called white blood cells, are the mobile units of the body’s

protective system. They are formed partially in the bone marrow (granulocytes

and monocytes and a few lymphocytes) and partially in the lymph tissue (lym-

phocytes and plasma cells). After formation, they are transported in the blood

to different parts of the body where they are needed.

The real value of the white blood cells is that most of them are specifically

transported to areas of serious infection and inflammation, thereby providing a

rapid and potent defense against infectious agents. As we see later, the granu-

locytes and monocytes have a special ability to “seek out and destroy” a foreign

invader.

General Characteristics of Leukocytes

Types of White Blood Cells. Six types of white blood cells are normally present in

the blood. They are polymorphonuclear neutrophils, polymorphonuclear

eosinophils, polymorphonuclear basophils, monocytes, lymphocytes, and, occa-

sionally, plasma cells. In addition, there are large numbers of platelets, which are

fragments of another type of cell similar to the white blood cells found in the

bone marrow, the megakaryocyte. The first three types of cells, the polymor-

phonuclear cells, all have a granular appearance, as shown in cell numbers 7,

429

430

Unit VI Blood Cells, Immunity, and Blood Clotting

Genesis of Myelocytes

Genesis of Lymphocytes

Figure 33-1

Genesis of white blood cells. The

different cells of the myelocyte

series are

1, myeloblast;

promyelocyte; 3, megakaryocyte;

4, neutrophil myelocyte; 5, young

neutrophil metamyelocyte;

“band” neutrophil metamyelocyte;

7, polymorphonuclear neutrophil;

8, eosinophil myelocyte;

eosinophil metamyelocyte;

10,

polymorphonuclear

eosinophil;

11, basophil myelocyte; 12, poly-

morphonuclear basophil;

13-16,

stages of monocyte formation.

10, and 12 in Figure 33-1, for which reason they are

Diapedesis

called granulocytes, or, in clinical terminology, “polys,”

because of the multiple nuclei.

The granulocytes and monocytes protect the body

against invading organisms mainly by ingesting

them—that is, by phagocytosis. The lymphocytes and

plasma cells function mainly in connection with the

Chemotaxis

immune system; this is discussed in Chapter 34. Finally,

source

the function of platelets is specifically to activate the

blood clotting mechanism, which is discussed in

Chapter 36.

Concentrations of the Different White Blood Cells in the Blood.

The adult human being has about 7000 white blood

Increased

cells per microliter of blood (in comparison with 5

permeability

million red blood cells). Of the total white blood cells,

Chemotactic

Margination

substance

the normal percentages of the different types are

approximately the following:

Figure 33-2

Movement of neutrophils by diapedesis through capillary pores

Polymorphonuclear neutrophils

62.0%

and by chemotaxis toward an area of tissue damage.

Polymorphonuclear eosinophils

2.3%

Polymorphonuclear basophils

0.4%

Monocytes

5.3%

Lymphocytes

30.0%

chapter. Aside from those cells committed to form red

blood cells, two major lineages of white blood cells are

formed, the myelocytic and the lymphocytic lineages.

The number of platelets, which are only cell frag-

The left side of Figure 33-1 shows the myelocytic

ments, in each microliter of blood is normally about

lineage, beginning with the myeloblast; the right

300,000.

shows the lymphocytic lineage, beginning with the

lymphoblast.

Genesis of the White Blood Cells

The granulocytes and monocytes are formed only

in the bone marrow. Lymphocytes and plasma cells

Early differentiation of the pluripotential hematopoi-

are produced mainly in the various lymphogenous

etic stem cell into the different types of committed

tissues—especially the lymph glands, spleen, thymus,

stem cells is shown in Figure 32-2 in the previous

tonsils, and various pockets of lymphoid tissue

Chapter 33

Resistance of the Body to Infection: I. Leukocytes, Granulocytes, the Monocyte-Macrophage System

431

elsewhere in the body, such as in the bone marrow and

other injurious agents. The neutrophils are mature

in so-called Peyer’s patches underneath the epithelium

cells that can attack and destroy bacteria even in the

in the gut wall.

circulating blood. Conversely, the tissue macrophages

The white blood cells formed in the bone marrow

begin life as blood monocytes, which are immature

are stored within the marrow until they are needed in

cells while still in the blood and have little ability to

the circulatory system. Then, when the need arises,

fight infectious agents at that time. However, once they

various factors cause them to be released

(these

enter the tissues, they begin to swell—sometimes

factors are discussed later). Normally, about three

increasing their diameters as much as fivefold—to as

times as many white blood cells are stored in the

great as 60 to 80 micrometers, a size that can barely be

marrow as circulate in the entire blood. This represents

seen with the naked eye. These cells are now called

about a 6-day supply of these cells.

macrophages, and they are extremely capable of com-

The lymphocytes are mostly stored in the various

bating intratissue disease agents.

lymphoid tissues, except for a small number that are

temporarily being transported in the blood.

White Blood Cells Enter the Tissue Spaces by Diapedesis.

As shown in Figure 33-1, megakaryocytes (cell 3)

Neutrophils and monocytes can squeeze through the

are also formed in the bone marrow. These megakary-

pores of the blood capillaries by diapedesis. That is,

ocytes fragment in the bone marrow; the small frag-

even though a pore is much smaller than a cell, a small

ments, known as platelets (or thrombocytes), then pass

portion of the cell slides through the pore at a time;

into the blood. They are very important in the initia-

the portion sliding through is momentarily constricted

tion of blood clotting.

to the size of the pore, as shown in Figure 33-2.

White Blood Cells Move Through Tissue Spaces by Ameboid

Life Span of the White Blood Cells

Motion. Both neutrophils and macrophages can move

through the tissues by ameboid motion, described in

The life of the granulocytes after being released from

Chapter 2. Some cells move at velocities as great as

the bone marrow is normally 4 to 8 hours circulating

40 mm/min, a distance as great as their own length

in the blood and another 4 to 5 days in tissues where

each minute.

they are needed. In times of serious tissue infection,

this total life span is often shortened to only a few

White Blood Cells Are Attracted to Inflamed Tissue Areas by

hours because the granulocytes proceed even more

Chemotaxis. Many different chemical substances in the

rapidly to the infected area, perform their functions,

tissues cause both neutrophils and macrophages to

and, in the process, are themselves destroyed.

move toward the source of the chemical. This phe-

The monocytes also have a short transit time, 10 to

nomenon, shown in Figure 33-2, is known as chemo-

20 hours in the blood, before wandering through the

taxis. When a tissue becomes inflamed, at least a dozen

capillary membranes into the tissues. Once in the

different products are formed that can cause chemo-

tissues, they swell to much larger sizes to become tissue

taxis toward the inflamed area. They include (1) some

macrophages, and, in this form, can live for months

of the bacterial or viral toxins, (2) degenerative prod-

unless destroyed while performing phagocytic func-

ucts of the inflamed tissues themselves, (3) several

tions. These tissue macrophages are the basis of the

reaction products of the

“complement complex”

tissue macrophage system, discussed in greater detail

(discussed in Chapter 34) activated in inflamed tissues,

later, which provides continuing defense against

and (4) several reaction products caused by plasma

infection.

clotting in the inflamed area, as well as other

Lymphocytes enter the circulatory system continu-

substances.

ally, along with drainage of lymph from the lymph

As shown in Figure 33-2, chemotaxis depends on

nodes and other lymphoid tissue. After a few hours,

the concentration gradient of the chemotactic sub-

they pass out of the blood back into the tissues by dia-

stance. The concentration is greatest near the source,

pedesis. Then, still later, they re-enter the lymph and

which directs the unidirectional movement of the

return to the blood again and again; thus, there is con-

white cells. Chemotaxis is effective up to 100 microm-

tinual circulation of lymphocytes through the body.

eters away from an inflamed tissue. Therefore, because

The lymphocytes have life spans of weeks or months;

almost no tissue area is more than 50 micrometers

this life span depends on the body’s need for these

away from a capillary, the chemotactic signal can easily

cells.

move hordes of white cells from the capillaries into the

The platelets in the blood are replaced about once

inflamed area.

every 10 days; in other words, about 30,000 platelets

are formed each day for each microliter of blood.

Phagocytosis

Neutrophils and Macrophages

The most important function of the neutrophils and

Defend Against Infections

macrophages is phagocytosis, which means cellular

ingestion of the offending agent. Phagocytes must be

It is mainly the neutrophils and tissue macrophages

selective of the material that is phagocytized; other-

that attack and destroy invading bacteria, viruses, and

wise, normal cells and structures of the body might be

432

Unit VI Blood Cells, Immunity, and Blood Clotting

ingested. Whether phagocytosis will occur depends

and digestion of the phagocytized particle begins

especially on three selective procedures.

immediately.

First, most natural structures in the tissues have

Both neutrophils and macrophages contain an

smooth surfaces, which resist phagocytosis. But if the

abundance of lysosomes filled with proteolytic

surface is rough, the likelihood of phagocytosis is

enzymes especially geared for digesting bacteria

increased.

and other foreign protein matter. The lysosomes of

Second, most natural substances of the body have

macrophages (but not of neutrophils) also contain

protective protein coats that repel the phagocytes.

large amounts of lipases, which digest the thick lipid

Conversely, most dead tissues and foreign particles

membranes possessed by some bacteria such as the

have no protective coats, which makes them subject to

tuberculosis bacillus.

phagocytosis.

Third, the immune system of the body (described in

Both Neutrophils and Macrophages Can Kill Bacteria. In

detail in Chapter 34) develops antibodies against infec-

addition to the digestion of ingested bacteria in

tious agents such as bacteria. The antibodies then

phagosomes, neutrophils and macrophages contain

adhere to the bacterial membranes and thereby make

bactericidal agents that kill most bacteria even when

the bacteria especially susceptible to phagocytosis. To

the lysosomal enzymes fail to digest them. This is espe-

do this, the antibody molecule also combines with the

cially important, because some bacteria have protec-

C3 product of the complement cascade, which is an

tive coats or other factors that prevent their

additional part of the immune system discussed in the

destruction by digestive enzymes. Much of the killing

next chapter. The C3 molecules, in turn, attach to

effect results from several powerful oxidizing agents

receptors on the phagocyte membrane, thus initiating

formed by enzymes in the membrane of the phago-

phagocytosis. This selection and phagocytosis process

some or by a special organelle called the peroxisome.

is called opsonization.

These oxidizing agents include large quantities of

superoxide

(O_2-), hydrogen peroxide

(H₂O₂), and

Phagocytosis by Neutrophils. The neutrophils entering

hydroxyl ions (-OH^-), all of which are lethal to most

the tissues are already mature cells that can immedi-

bacteria, even in small quantities. Also, one of the

ately begin phagocytosis. On approaching a particle to

lysosomal enzymes, myeloperoxidase, catalyzes the

be phagocytized, the neutrophil first attaches itself to

reaction between H₂O₂ and chloride ions to form

the particle and then projects pseudopodia in all direc-

hypochlorite, which is exceedingly bactericidal.

tions around the particle. The pseudopodia meet one

Some bacteria, however, notably the tuberculosis

another on the opposite side and fuse. This creates an

bacillus, have coats that are resistant to lysosomal

enclosed chamber that contains the phagocytized par-

digestion and also secrete substances that partially

ticle. Then the chamber invaginates to the inside of the

resist the killing effects of the neutrophils and

cytoplasmic cavity and breaks away from the outer cell

macrophages. These bacteria are responsible for

membrane to form a free-floating phagocytic vesicle

many of the chronic diseases, an example of which is

(also called a phagosome) inside the cytoplasm. A

tuberculosis.

single neutrophil can usually phagocytize 3 to 20 bac-

teria before the neutrophil itself becomes inactivated

and dies.

Monocyte-Macrophage Cell

System (Reticuloendothelial

Phagocytosis by Macrophages. Macrophages are the end-

stage product of monocytes that enter the tissues from

System)

the blood. When activated by the immune system as

described in Chapter 34, they are much more power-

In the preceding paragraphs, we described the

ful phagocytes than neutrophils, often capable of

macrophages mainly as mobile cells that are capable

phagocytizing as many as 100 bacteria. They also have

of wandering through the tissues. However, after

the ability to engulf much larger particles, even whole

entering the tissues and becoming macrophages,

red blood cells or, occasionally, malarial parasites,

another large portion of monocytes becomes attached

whereas neutrophils are not capable of phagocytizing

to the tissues and remains attached for months or even

particles much larger than bacteria. Also, after digest-

years until they are called on to perform specific local

ing particles, macrophages can extrude the residual

protective functions. They have the same capabilities

products and often survive and function for many

as the mobile macrophages to phagocytize large

more months.

quantities of bacteria, viruses, necrotic tissue, or other

foreign particles in the tissue. And, when appropriately

Once Phagocytized, Most Particles Are Digested by Intracellu-

stimulated, they can break away from their attach-

lar Enzymes. Once a foreign particle has been phagocy-

ments and once again become mobile macrophages

tized, lysosomes and other cytoplasmic granules in

that respond to chemotaxis and all the other stimuli

the neutrophil or macrophage immediately come in

related to the inflammatory process. Thus, the body has

contact with the phagocytic vesicle, and their mem-

a widespread “monocyte-macrophage system” in vir-

branes fuse, thereby dumping many digestive enzymes

tually all tissue areas.

and bactericidal agents into the vesicle. Thus, the

The total combination of monocytes, mobile

phagocytic vesicle now becomes a digestive vesicle,

macrophages, fixed tissue macrophages, and a few

Chapter 33

Resistance of the Body to Infection: I. Leukocytes, Granulocytes, the Monocyte-Macrophage System

433

specialized endothelial cells in the bone marrow,

Large numbers of macrophages line the lymph

spleen, and lymph nodes is called the reticuloendothe-

sinuses, and if any particles enter the sinuses by way

lial system. However, all or almost all these cells orig-

of the lymph, the macrophages phagocytize them and

inate from monocytic stem cells; therefore, the

prevent general dissemination throughout the body.

reticuloendothelial system is almost synonymous with

the monocyte-macrophage system. Because the term

Alveolar Macrophages in the Lungs. Another route by

reticuloendothelial system is much better known

which invading organisms frequently enter the body

in medical literature than the term monocyte-

is through the lungs. Large numbers of tissue

macrophage system, it should be remembered as a

macrophages are present as integral components of

generalized phagocytic system located in all tissues,

the alveolar walls. They can phagocytize particles that

especially in those tissue areas where large quantities

become entrapped in the alveoli. If the particles are

of particles, toxins, and other unwanted substances

digestible, the macrophages can also digest them and

must be destroyed.

release the digestive products into the lymph. If the

particle is not digestible, the macrophages often form

Tissue Macrophages in the Skin and Subcutaneous Tissues (His-

a “giant cell” capsule around the particle until such

tiocytes). Although the skin is mainly impregnable to

time—if ever—that it can be slowly dissolved. Such

infectious agents, this is no longer true when the skin

capsules are frequently formed around tuberculosis

is broken. When infection begins in a subcutaneous

bacilli, silica dust particles, and even carbon particles.

tissue and local inflammation ensues, local tissue

macrophages can divide in situ and form still more

Macrophages

(Kupffer Cells) in the Liver Sinusoids. Still

macrophages. Then they perform the usual functions

another favorite route by which bacteria invade the

of attacking and destroying the infectious agents, as

body is through the gastrointestinal tract. Large

described earlier.

numbers of bacteria from ingested food constantly

pass through the gastrointestinal mucosa into the

Macrophages in the Lymph Nodes. Essentially no particu-

portal blood. Before this blood enters the general cir-

late matter that enters the tissues, such as bacteria, can

culation, it passes through the sinusoids of the liver;

be absorbed directly through the capillary membranes

these sinusoids are lined with tissue macrophages

into the blood. Instead, if the particles are not

called Kupffer cells, shown in Figure 33-4. These cells

destroyed locally in the tissues, they enter the lymph

form such an effective particulate filtration system that

and flow to the lymph nodes located intermittently

almost none of the bacteria from the gastrointestinal

along the course of the lymph flow. The foreign parti-

tract succeeds in passing from the portal blood into the

cles are then trapped in these nodes in a meshwork of

general systemic circulation. Indeed, motion pictures

sinuses lined by tissue macrophages.

of phagocytosis by Kupffer cells have demonstrated

Figure 33-3 illustrates the general organization of

phagocytosis of a single bacterium in less than ¹/₁₀₀ of a

the lymph node, showing lymph entering through the

second.

lymph node capsule by way of afferent lymphatics,

then flowing through the nodal medullary sinuses, and

finally passing out the hilus into efferent lymphatics

that eventually empty into the venous blood.

Afferent lymphatics

Primary

nodule

Capsule

Valve

Subcapsular

sinus

Lymph in

medullary

sinuses

Germinal

center

Hilus

Medullary cord

Efferent lymphatics

Kupffer cells

Figure 33-3

Figure 33-4

Functional diagram of a lymph node. (Redrawn from Ham AW:

Kupffer cells lining the liver sinusoids, showing phagocytosis of

Histology, 6th ed. Philadelphia: JB Lippincott, 1969.) (Modified

India ink particles into the cytoplasm of the Kupffer cells.

from Gartner LP, Hiatt JL: Color Textbook of Histology, 2nd ed.

(Redrawn from Copenhaver WM, et al: Bailey’s Textbook of His-

Philadelphia, WB Saunders, 2001.)

tology, 10th ed. Baltimore: Williams & Wilkins, 1971.)

434

Unit VI Blood Cells, Immunity, and Blood Clotting

Macrophages of the Spleen and Bone Marrow. If an invad-

and cause dramatic secondary changes in the sur-

ing organism succeeds in entering the general circula-

rounding uninjured tissues. This entire complex of

tion, there are other lines of defense by the tissue

tissue changes is called inflammation.

macrophage system, especially by macrophages of the

Inflammation is characterized by (1) vasodilation of

spleen and bone marrow. In both these tissues,

the local blood vessels, with consequent excess local

macrophages have become entrapped by the reticular

blood flow; (2) increased permeability of the capillar-

meshwork of the two organs, and when foreign parti-

ies, allowing leakage of large quantities of fluid into

cles come in contact with these macrophages, they are

the interstitial spaces; (3) often clotting of the fluid in

phagocytized.

the interstitial spaces because of excessive amounts of

The spleen is similar to the lymph nodes, except that

fibrinogen and other proteins leaking from the capil-

blood, instead of lymph, flows through the tissue

laries; (4) migration of large numbers of granulocytes

spaces of the spleen. Figure 33-5 shows a small periph-

and monocytes into the tissue; and (5) swelling of the

eral segment of spleen tissue. Note that a small artery

tissue cells. Some of the many tissue products that

penetrates from the splenic capsule into the splenic

cause these reactions are histamine, bradykinin, sero-

pulp and terminates in small capillaries. The capillar-

tonin, prostaglandins, several different reaction prod-

ies are highly porous, allowing whole blood to pass out

ucts of the complement system (described in Chapter

of the capillaries into cords of red pulp. The blood then

34), reaction products of the blood clotting system, and

gradually squeezes through the trabecular meshwork

multiple substances called lymphokines that are

of these cords and eventually returns to the circulation

released by sensitized T cells (part of the immune

through the endothelial walls of the venous sinuses.

system; also discussed in Chapter 34). Several of these

The trabeculae of the red pulp are lined with vast

substances strongly activate the macrophage system,

numbers of macrophages, and the venous sinuses are

and within a few hours, the macrophages begin to

also lined with macrophages. This peculiar passage of

devour the destroyed tissues. But at times, the

blood through the cords of the red pulp provides an

macrophages also further injure the still-living tissue

exceptional means of phagocytizing unwanted debris

cells.

in the blood, including especially old and abnormal red

blood cells.

“Walling-Off” Effect of Inflammation. One of the first

results of inflammation is to “wall off ” the area of

injury from the remaining tissues. The tissue spaces

Inflammation: Role of

and the lymphatics in the inflamed area are blocked

Neutrophils and Macrophages

by fibrinogen clots so that after a while, fluid barely

flows through the spaces. This walling-off process

Inflammation

delays the spread of bacteria or toxic products.

The intensity of the inflammatory process is usually

When tissue injury occurs, whether caused by bacteria,

proportional to the degree of tissue injury. For

trauma, chemicals, heat, or any other phenomenon,

instance, when staphylococci invade tissues, they

multiple substances are released by the injured tissues

release extremely lethal cellular toxins. As a result,

inflammation develops rapidly—indeed, much more

rapidly than the staphylococci themselves can multi-

ply and spread. Therefore, local staphylococcal in-

fection is characteristically walled off rapidly and

prevented from spreading through the body. Strepto-

cocci, in contrast, do not cause such intense local tissue

destruction. Therefore, the walling-off process devel-

ops slowly over many hours, while many streptococci

Pulp

reproduce and migrate. As a result, streptococci often

have a far greater tendency to spread through the

Capillaries

body and cause death than do staphylococci, even

though staphylococci are far more destructive to the

Venous sinuses

tissues.

Vein

Artery

Macrophage and Neutrophil

Responses During Inflammation

Tissue Macrophage Is a First Line of Defense Against Infection.

Within minutes after inflammation begins, the

Figure 33-5

macrophages already present in the tissues, whether

histiocytes in the subcutaneous tissues, alveolar

Functional structures of the spleen.

(Modified from Bloom W,

macrophages in the lungs, microglia in the brain, or

Fawcett DW: A Textbook of Histology, 10th ed. Philadelphia: WB

Saunders, 1975.)

others, immediately begin their phagocytic actions.

Chapter 33

Resistance of the Body to Infection: I. Leukocytes, Granulocytes, the Monocyte-Macrophage System

435

When activated by the products of infection and

come to dominate the phagocytic cells of the inflamed

inflammation, the first effect is rapid enlargement of

area because of greatly increased bone marrow pro-

each of these cells. Next, many of the previously sessile

duction of new monocytes, as explained later.

macrophages break loose from their attachments

As already pointed out, macrophages can phagocy-

and become mobile, forming the first line of defense

tize far more bacteria (about five times as many) and

against infection during the first hour or so. The

far larger particles, including even neutrophils them-

numbers of these early mobilized macrophages often

selves and large quantities of necrotic tissue, than can

are not great, but they are lifesaving.

neutrophils. Also, the macrophages play an important

role in initiating the development of antibodies, as we

Neutrophil Invasion of the Inflamed Area Is a Second Line of

discuss in Chapter 34.

Defense. Within the first hour or so after inflammation

begins, large numbers of neutrophils begin to invade

Increased Production of Granulocytes and Monocytes by the

the inflamed area from the blood. This is caused by

Bone Marrow Is a Fourth Line of Defense. The fourth line of

products from the inflamed tissues that initiate the fol-

defense is greatly increased production of both gran-

lowing reactions: (1) They alter the inside surface of

ulocytes and monocytes by the bone marrow. This

the capillary endothelium, causing neutrophils to stick

results from stimulation of the granulocytic and mono-

to the capillary walls in the inflamed area. This effect

cytic progenitor cells of the marrow. However, it

is called margination and is shown in Figure 33-2. (2)

takes 3 to 4 days before newly formed granulocytes

They cause the intercellular attachments between the

and monocytes reach the stage of leaving the bone

endothelial cells of the capillaries and small venules

marrow. If the stimulus from the inflamed tissue con-

to loosen, allowing openings large enough for neu-

tinues, the bone marrow can continue to produce these

trophils to pass by diapedesis directly from the blood

cells in tremendous quantities for months and even

into the tissue spaces. (3) Other products of inflam-

years, sometimes at a rate 20 to 50 times normal.

mation then cause chemotaxis of the neutrophils

toward the injured tissues, as explained earlier.

Feedback Control of the Macrophage and

Thus, within several hours after tissue damage

Neutrophil Responses

begins, the area becomes well supplied with neu-

Although more than two dozen factors have been

trophils. Because the blood neutrophils are already

implicated in control of the macrophage response to

mature cells, they are ready to immediately begin their

inflammation, five of these are believed to play domi-

scavenger functions for killing bacteria and removing

nant roles. They are shown in Figure 33-6 and consist

foreign matter.

of (1) tumor necrosis factor (TNF), (2) interleukin-1

(IL-1),

(3) granulocyte-monocyte colony-stimulating

Acute Increase in Number of Neutrophils in the Blood—“Neu-

factor (GM-CSF), (4) granulocyte colony-stimulating

trophilia.” Also within a few hours after the onset of

factor (G-CSF), and (5) monocyte colony-stimulating

acute, severe inflammation, the number of neutrophils

factor (M-CSF). These factors are formed by activated

in the blood sometimes increases fourfold to five-

macrophage cells in the inflamed tissues and in smaller

fold—from a normal of 4000 to 5000 to 15,000 to

quantities by other inflamed tissue cells.

25,000 neutrophils per microliter. This is called neu-

The cause of the increased production of granulo-

trophilia, which means an increase in the number of

cytes and monocytes by the bone marrow is mainly

neutrophils in the blood. Neutrophilia is caused by

the three colony-stimulating factors, one of which,

products of inflammation that enter the blood stream,

GM-CSF, stimulates both granulocyte and monocyte

are transported to the bone marrow, and there act on

production; the other two, G-CSF and M-CSF, stimu-

the stored neutrophils of the marrow to mobilize these

late granulocyte and monocyte production, respec-

into the circulating blood. This makes even more neu-

tively. This combination of TNF, IL-1, and colony-stim-

trophils available to the inflamed tissue area.

ulating factors provides a powerful feedback mecha-

nism that begins with tissue inflammation and

Second Macrophage Invasion into the Inflamed Tissue Is a Third

proceeds to formation of large numbers of defensive

Line of Defense. Along with the invasion of neutrophils,

white blood cells that help remove the cause of the

monocytes from the blood enter the inflamed tissue

inflammation.

and enlarge to become macrophages. However, the

number of monocytes in the circulating blood is low:

Formation of Pus

also, the storage pool of monocytes in the bone

When neutrophils and macrophages engulf large

marrow is much less than that of neutrophils. There-

numbers of bacteria and necrotic tissue, essentially

fore, the buildup of macrophages in the inflamed tissue

all the neutrophils and many, if not most, of the

area is much slower than that of neutrophils, requiring

macrophages eventually die. After several days, a

several days to become effective. Furthermore, even

cavity is often excavated in the inflamed tissues that

after invading the inflamed tissue, monocytes are still

contains varying portions of necrotic tissue, dead neu-

immature cells, requiring 8 hours or more to swell to

trophils, dead macrophages, and tissue fluid. This

much larger sizes and develop tremendous quantities

mixture is commonly known as pus. After the infec-

of lysosomes; only then do they acquire the full capac-

tion has been suppressed, the dead cells and necrotic

ity of tissue macrophages for phagocytosis. Yet, after

tissue in the pus gradually autolyze over a period of

several days to several weeks, the macrophages finally

days, and the end products are eventually absorbed

436

Unit VI Blood Cells, Immunity, and Blood Clotting

INFLAMMATION

and kill many of them. They do so in several ways: (1)

by releasing hydrolytic enzymes from their granules,

which are modified lysosomes; (2) probably by also

releasing highly reactive forms of oxygen that are

especially lethal to parasites; and (3) by releasing from

the granules a highly larvacidal polypeptide called

Activated

TNF

major basic protein.

macrophage

IL-1

In a few areas of the world, another parasitic disease

that causes eosinophilia is trichinosis. This results from

invasion of the body’s muscles by the Trichinella par-

Endothelial cells,

asite (“pork worm”) after a person eats undercooked

fibroblasts,

infested pork.

TNF

lymphocytes

Eosinophils also have a special propensity to collect

IL-1

in tissues in which allergic reactions occur, such as in

GM-CSF

the peribronchial tissues of the lungs in people with

G-CSF

GM-CSF

asthma and in the skin after allergic skin reactions.

M-CSF

G-CSF

This is caused at least partly by the fact that many mast

M-CSF

cells and basophils participate in allergic reactions, as

we discuss in the next paragraph. The mast cells and

basophils release an eosinophil chemotactic factor that

causes eosinophils to migrate toward the inflamed

allergic tissue. The eosinophils are believed to detox-

Bone marrow

ify some of the inflammation-inducing substances

released by the mast cells and basophils and probably

also to phagocytize and destroy allergen-antibody

complexes, thus preventing excess spread of the local

inflammatory process.

Granulocytes

Monocytes/macrophages

Basophils

Figure 33-6

Control of bone marrow production of granulocytes and mono-

The basophils in the circulating blood are similar to

cyte-macrophages in response to multiple growth factors released

the large tissue mast cells located immediately outside

from activated macrophages in an inflamed tissue. G-CSF, gran-

many of the capillaries in the body. Both mast cells and

ulocyte colony-stimulating factor; GM-CSF, granulocyte-monocyte

basophils liberate heparin into the blood, a substance

colony-stimulating factor; IL-1, interleukin-1; M-CSF, monocyte

colony-stimulating factor; TNF, tumor necrosis factor.

that can prevent blood coagulation.

The mast cells and basophils also release histamine,

as well as smaller quantities of bradykinin and

into the surrounding tissues and lymph until most of

serotonin. Indeed, it is mainly the mast cells in

the evidence of tissue damage is gone.

inflamed tissues that release these substances during

inflammation.

The mast cells and basophils play an exceedingly

Eosinophils

important role in some types of allergic reactions

because the type of antibody that causes allergic reac-

The eosinophils normally constitute about 2 per cent

tions, the immunoglobulin E (IgE) type (see Chapter

of all the blood leukocytes. Eosinophils are weak

34), has a special propensity to become attached to

phagocytes, and they exhibit chemotaxis, but in com-

mast cells and basophils. Then, when the specific

parison with the neutrophils, it is doubtful that the

antigen for the specific IgE antibody subsequently

eosinophils are significant in protecting against the

reacts with the antibody, the resulting attachment of

usual types of infection.

antigen to antibody causes the mast cell or basophil

Eosinophils, however, are often produced in large

to rupture and release exceedingly large quantities of

numbers in people with parasitic infections, and they

histamine, bradykinin, serotonin, heparin, slow-reacting

migrate in large numbers into tissues diseased by par-

substance of anaphylaxis, and a number of lysosomal

asites. Although most parasites are too large to be

enzymes. These cause local vascular and tissue reac-

phagocytized by eosinophils or any other phagocytic

tions that cause many, if not most, of the allergic man-

cells, eosinophils attach themselves to the parasites by

ifestations. These reactions are discussed in greater

way of special surface molecules and release sub-

detail in Chapter 34.

stances that kill many of the parasites. For instance,

one of the most widespread infections is schistosomi-

asis, a parasitic infection found in as many as one third

Leukopenia

of the population of some Third World countries; the

parasite can invade any part of the body. Eosinophils

A clinical condition known as leukopenia occasionally

attach themselves to the juvenile forms of the parasite

occurs in which the bone marrow produces very few

Chapter 33

Resistance of the Body to Infection: I. Leukocytes, Granulocytes, the Monocyte-Macrophage System

437

white blood cells, leaving the body unprotected against

extramedullary tissues—especially in the lymph nodes,

many bacteria and other agents that might invade the

spleen, and liver.

tissues.

In myelogenous leukemia, the cancerous process

Normally, the human body lives in symbiosis with

occasionally produces partially differentiated cells,

many bacteria, because all the mucous membranes of

resulting in what might be called neutrophilic

the body are constantly exposed to large numbers of

leukemia, eosinophilic leukemia, basophilic leukemia,

bacteria. The mouth almost always contains various

or monocytic leukemia. More frequently, however, the

spirochetal, pneumococcal, and streptococcal bacteria,

leukemia cells are bizarre and undifferentiated and

and these same bacteria are present to a lesser extent

not identical to any of the normal white blood cells.

in the entire respiratory tract. The distal gastrointesti-

Usually, the more undifferentiated the cell, the more

nal tract is especially loaded with colon bacilli. Fur-

acute is the leukemia, often leading to death within a

thermore, one can always find bacteria on the surfaces

few months if untreated. With some of the more dif-

of the eyes, urethra, and vagina. Any decrease in the

ferentiated cells, the process can be chronic, some-

number of white blood cells immediately allows inva-

times developing slowly over 10 to 20 years. Leukemic

sion of adjacent tissues by bacteria that are already

cells, especially the very undifferentiated cells, are

present.

usually nonfunctional for providing the normal pro-

Within 2 days after the bone marrow stops produc-

tection against infection.

ing white blood cells, ulcers may appear in the mouth

and colon, or the person might develop some form of

severe respiratory infection. Bacteria from the ulcers

Effects of Leukemia on the Body

rapidly invade surrounding tissues and the blood.

Without treatment, death often ensues in less than a

The first effect of leukemia is metastatic growth of

week after acute total leukopenia begins.

leukemic cells in abnormal areas of the body.

Irradiation of the body by x-rays or gamma rays, or

Leukemic cells from the bone marrow may reproduce

exposure to drugs and chemicals that contain benzene

so greatly that they invade the surrounding bone,

or anthracene nuclei, is likely to cause aplasia of the

causing pain and, eventually, a tendency for bones to

bone marrow. Indeed, some common drugs, such as

fracture easily.

chloramphenicol (an antibiotic), thiouracil (used to

Almost all leukemias eventually spread to the

treat thyrotoxicosis), and even various barbiturate

spleen, lymph nodes, liver, and other vascular regions,

hypnotics, on very rare occasions cause leukopenia,

regardless of whether the origin of the leukemia is in

thus setting off the entire infectious sequence of this

the bone marrow or the lymph nodes. Common effects

malady.

in leukemia are the development of infection, severe

After moderate irradiation injury to the bone

anemia, and a bleeding tendency caused by thrombo-

marrow, some stem cells, myeloblasts, and hemocyto-

cytopenia

(lack of platelets). These effects result

blasts may remain undestroyed in the marrow and are

mainly from displacement of the normal bone marrow

capable of regenerating the bone marrow, provided

and lymphoid cells by the nonfunctional leukemic

sufficient time is available. A patient properly treated

cells.

with transfusions, plus antibiotics and other drugs to

Finally, perhaps the most important effect of

ward off infection, usually develops enough new bone

leukemia on the body is excessive use of metabolic

marrow within weeks to months for blood cell con-

substrates by the growing cancerous cells. The

centrations to return to normal.

leukemic tissues reproduce new cells so rapidly that

tremendous demands are made on the body reserves

for foodstuffs, specific amino acids, and vitamins. Con-

The Leukemias

sequently, the energy of the patient is greatly depleted,

and excessive utilization of amino acids by the

Uncontrolled production of white blood cells can be

leukemic cells causes especially rapid deterioration of

caused by cancerous mutation of a myelogenous or

the normal protein tissues of the body. Thus, while the

lymphogenous cell. This causes leukemia, which is

leukemic tissues grow, other tissues become debili-

usually characterized by greatly increased numbers

tated. After metabolic starvation has continued long

of abnormal white blood cells in the circulating

enough, this alone is sufficient to cause death.

blood.

References

Types of Leukemia. Leukemias are divided into two

general types: lymphocytic leukemias and myeloge-

Alexander JS, Granger DN: Lymphocyte trafficking medi-

nous leukemias. The lymphocytic leukemias are caused

ated by vascular adhesion protein-1: implications for

by cancerous production of lymphoid cells, usually

immune targeting and cardiovascular disease. Circ Res

beginning in a lymph node or other lymphocytic tissue

86:1190, 2000.

and spreading to other areas of the body. The second

Blander JM, Medzhitov R: Regulation of phagosome matu-

type of leukemia, myelogenous leukemia, begins by

ration by signals from toll-like receptors. Science 304:1014,

cancerous production of young myelogenous cells in

2004.

the bone marrow and then spreads throughout the

Bleakley M, Riddell SR: Molecules and mechanisms of the

body so that white blood cells are produced in many

graft-versus-leukaemia effect. Nat Rev Cancer 4:371, 2004.

438

Unit VI Blood Cells, Immunity, and Blood Clotting

Ferrajoli A, O’Brien SM: Treatment of chronic lymphocytic

Ossovskaya VS, Bunnett NW: Protease-activated receptors:

leukemia. Semin Oncol 31(Suppl 4):60, 2004.

contribution to physiology and disease. Physiol Rev

Heasman SJ, Giles KM, Ward C, et al: Glucocorticoid-

84:579, 2004.

mediated regulation of granulocyte apoptosis and

Park JE, Barbul A: Understanding the role of immune reg-

macrophage phagocytosis of apoptotic cells: implications

ulation in wound healing. Am J Surg 187:11S, 2004.

for the resolution of inflammation. J Endocrinol 178:29,

Pui CH, Relling MV, Downing JR: Acute lymphoblastic

2003.

leukemia. N Engl J Med 350:1535, 2004.

Kunkel EJ, Butcher EC: Plasma-cell homing. Nat Rev

Roufosse F, Cogan E, Goldman M: The hypereosinophilic

Immunol 3:822, 2003.

syndrome revisited. Annu Rev Med 54:169, 2003.

Kvietys PR, Sandig M: Neutrophil diapedesis: paracellular or

von Herrath MG, Harrison LC: Regulatory lymphocytes:

transcellular? News Physiol Sci 16:15, 2001.

antigen-induced regulatory T cells in autoimmunity. Nat

Ley K, Kansas GS: Selectins in T-cell recruitment to non-

Rev Immunol 3:223, 2003.

lymphoid tissues and sites of inflammation. Nat Rev

Werner S, Grose R: Regulation of wound healing by growth

Immunol 4:325, 2004.

factors and cytokines. Physiol Rev 83:835, 2003.

Moser B, Wolf M, Walz A, Loetscher P: Chemokines: multi-

Zullig S, Hengartner MO: Cell biology: tickling macro-

ple levels of leukocyte migration control. Trends Immunol

phages, a serious business. Science 304:1123, 2004.

25:75, 2004.

Muller WA: Leukocyte-endothelial-cell interactions in

leukocyte transmigration and the inflammatory response.

Trends Immunol 24:327, 2003.

C H A P T E R

Resistance of the Body to

Infection: II. Immunity and Allergy

Innate Immunity

The human body has the ability to resist almost all

types of organisms or toxins that tend to damage the

tissues and organs. This capability is called immu-

nity. Much of immunity is acquired immunity that

does not develop until after the body is first

attacked by a bacterium, virus, or toxin, often

requiring weeks or months to develop the immunity. An additional portion of

immunity results from general processes, rather than from processes directed

at specific disease organisms. This is called innate immunity. It includes the

following:

1. Phagocytosis of bacteria and other invaders by white blood cells and cells

of the tissue macrophage system, as described in Chapter 33.

2. Destruction of swallowed organisms by the acid secretions of the stomach

and the digestive enzymes.

3. Resistance of the skin to invasion by organisms.

4. Presence in the blood of certain chemical compounds that attach to

foreign organisms or toxins and destroy them. Some of these compounds

are (1) lysozyme, a mucolytic polysaccharide that attacks bacteria and

causes them to dissolute; (2) basic polypeptides, which react with and

inactivate certain types of gram-positive bacteria; (3) the complement

complex that is described later, a system of about 20 proteins that can be

activated in various ways to destroy bacteria; and (4) natural killer

lymphocytes that can recognize and destroy foreign cells, tumor cells, and

even some infected cells.

This innate immunity makes the human body resistant to such diseases as

some paralytic viral infections of animals, hog cholera, cattle plague, and dis-

temper—a viral disease that kills a large percentage of dogs that become

afflicted with it. Conversely, many lower animals are resistant or even immune

to many human diseases, such as poliomyelitis, mumps, human cholera, measles,

and syphilis, which are very damaging or even lethal to human beings.

Acquired (Adaptive) Immunity

In addition to its generalized innate immunity, the human body has the ability

to develop extremely powerful specific immunity against individual invading

agents such as lethal bacteria, viruses, toxins, and even foreign tissues from other

animals. This is called acquired or adaptive immunity. Acquired immunity is

caused by a special immune system that forms antibodies and/or activated lym-

phocytes that attack and destroy the specific invading organism or toxin. It is

with this acquired immunity mechanism and some of its associated reactions—

especially the allergies—that this chapter is concerned.

Acquired immunity can often bestow extreme protection. For instance,

certain toxins, such as the paralytic botulinum toxin or the tetanizing toxin of

tetanus, can be protected against in doses as high as 100,000 times the amount

that would be lethal without immunity. This is the reason the treatment process

known as immunization is so important in protecting human beings against

439

440

Unit VI Blood Cells, Immunity, and Blood Clotting

disease and against toxins, as explained in the course

the gastrointestinal tract, thymus, and bone marrow.

of this chapter.

The lymphoid tissue is distributed advantageously in

the body to intercept invading organisms or toxins

before they can spread too widely.

Basic Types of Acquired Immunity

In most instances, the invading agent first enters the

tissue fluids and then is carried by way of lymph vessels

Two basic but closely allied types of acquired immu-

to the lymph node or other lymphoid tissue. For

nity occur in the body. In one of these the body

instance, the lymphoid tissue of the gastrointestinal

develops circulating antibodies, which are globulin

walls is exposed immediately to antigens invading

molecules in the blood plasma that are capable of

from the gut. The lymphoid tissue of the throat and

attacking the invading agent. This type of immunity is

pharynx (the tonsils and adenoids) is well located to

called humoral immunity or B-cell immunity (because

intercept antigens that enter by way of the upper res-

B lymphocytes produce the antibodies). The second

piratory tract. The lymphoid tissue in the lymph nodes

type of acquired immunity is achieved through the

is exposed to antigens that invade the peripheral

formation of large numbers of activated T lymphocytes

tissues of the body. And, finally, the lymphoid tissue of

that are specifically crafted in the lymph nodes to

the spleen, thymus, and bone marrow plays the specific

destroy the foreign agent. This type of immunity is

role of intercepting antigenic agents that have suc-

called cell-mediated immunity or T-cell immunity

ceeded in reaching the circulating blood.

(because the activated lymphocytes are T lympho-

cytes). We shall see shortly that both the antibodies

Two Types of Lymphocytes Promote “Cell-Mediated” Immunity

and the activated lymphocytes are formed in the lym-

“Humoral” Immunity—the T and the B Lymphocytes.

phoid tissues of the body. Let us discuss the initiation

Although most lymphocytes in normal lymphoid

of the immune process by antigens.

tissue look alike when studied under the microscope,

these cells are distinctly divided into two major

populations. One of the populations, the T lympho-

Both Types of Acquired Immunity Are

cytes, is responsible for forming the activated lympho-

Initiated by Antigens

cytes that provide “cell-mediated” immunity, and the

other population, the B lymphocytes, is responsible

Because acquired immunity does not develop until

for forming antibodies that provide

“humoral”

after invasion by a foreign organism or toxin, it is clear

immunity.

that the body must have some mechanism for recog-

Both types of lymphocytes are derived originally in

nizing this invasion. Each toxin or each type of organ-

the embryo from pluripotent hematopoietic stem cells

ism almost always contains one or more specific

that form lymphocytes as one of their most important

chemical compounds in its makeup that are different

offspring as they differentiate. Almost all of the lym-

from all other compounds. In general, these are pro-

phocytes that are formed eventually end up in the

teins or large polysaccharides, and it is they that initi-

lymphoid tissue, but before doing so, they are further

ate the acquired immunity. These substances are called

differentiated or “preprocessed” in the following ways.

antigens (antibody generations).

The lymphocytes that are destined to eventually

For a substance to be antigenic, it usually must have

form activated T lymphocytes first migrate to and are

a high molecular weight, 8000 or greater. Furthermore,

preprocessed in the thymus gland, and thus they are

the process of antigenicity usually depends on regu-

called

“T” lymphocytes to designate the role of

larly recurring molecular groups, called epitopes, on

the thymus. They are responsible for cell-mediated

the surface of the large molecule. This also explains

immunity.

why proteins and large polysaccharides are almost

The other population of lymphocytes—the B lym-

always antigenic, because both of these have this ster-

phocytes that are destined to form antibodies—are

eochemical characteristic.

preprocessed in the liver during midfetal life and in the

bone marrow in late fetal life and after birth. This pop-

ulation of cells was first discovered in birds, which have

Lymphocytes Are Responsible for

a special preprocessing organ called the bursa of Fabri-

Acquired Immunity

cius. For this reason, these lymphocytes are called “B”

lymphocytes to designate the role of the bursa, and

Acquired immunity is the product of the body’s lym-

they are responsible for humoral immunity. Figure

phocytes. In people who have a genetic lack of lym-

34-1 shows the two lymphocyte systems for the for-

phocytes or whose lymphocytes have been destroyed

mation, respectively, of (1) the activated T lympho-

by radiation or chemicals, no acquired immunity can

cytes and (2) the antibodies.

develop. And within days after birth, such a person

dies of fulminating bacterial infection unless treated

by heroic measures. Therefore, it is clear that the lym-

Preprocessing of the T and B

phocytes are essential to survival of the human being.

Lymphocytes

The lymphocytes are located most extensively in the

lymph nodes, but they are also found in special lym-

Although all lymphocytes in the body originate from

phoid tissues such as the spleen, submucosal areas of

lymphocyte-committed stem cells of the embryo, these

Chapter 34

Resistance of the Body to Infection: II. Immunity and Allergy

441

Cell-Mediated Immunity

Thymus

Activated T

Antigen

lymphocytes

T lymphocytes

Lymph node

B lymphocytes

Figure 34-1

Stem cell

Formation of antibodies and sen-

Antigen

Plasma

Antibodies

sitized lymphocytes by a lymph

cells

node in response to antigens.

This figure also shows the origin

Fetal liver,

of thymic (T) and bursal (B) lym-

bone marrow

phocytes that respectively are

responsible for the cell-mediated

Humoral Immunity

and humoral immune processes.

stem cells themselves are incapable of forming directly

Most of the preprocessing of T lymphocytes in the

either activated T lymphocytes or antibodies. Before

thymus occurs shortly before birth of a baby and for a

they can do so, they must be further differentiated in

few months after birth. Beyond this period, removal of

appropriate processing areas as follows.

the thymus gland diminishes (but does not eliminate)

the T-lymphocytic immune system. However, removal

Thymus Gland Preprocesses the T Lymphocytes. The T lym-

of the thymus several months before birth can prevent

phocytes, after origination in the bone marrow, first

development of all cell-mediated immunity. Because

migrate to the thymus gland. Here they divide rapidly

this cellular type of immunity is mainly responsible for

and at the same time develop extreme diversity for

rejection of transplanted organs, such as hearts and

reacting against different specific antigens. That is, one

kidneys, one can transplant organs with much less like-

thymic lymphocyte develops specific reactivity against

lihood of rejection if the thymus is removed from an

one antigen. Then the next lymphocyte develops speci-

animal a reasonable time before its birth.

ficity against another antigen. This continues until

there are thousands of different types of thymic lym-

Liver and Bone Marrow Preprocess the B Lymphocytes. Much

phocytes with specific reactivities against many thou-

less is known about the details for preprocessing B

sands of different antigens. These different types of

lymphocytes than for preprocessing T lymphocytes. In

preprocessed T lymphocytes now leave the thymus

the human being, B lymphocytes are known to be pre-

and spread by way of the blood throughout the body

processed in the liver during midfetal life and in the

to lodge in lymphoid tissue everywhere.

bone marrow during late fetal life and after birth.

The thymus also makes certain that any T lympho-

B lymphocytes are different from T lymphocytes in

cytes leaving the thymus will not react against proteins

two ways: First, instead of the whole cell developing

or other antigens that are present in the body’s

reactivity against the antigen, as occurs for the T lym-

own tissues; otherwise, the T lymphocytes would be

phocytes, the B lymphocytes actively secrete antibod-

lethal to the person’s own body in only a few days.

ies that are the reactive agents. These agents are large

The thymus selects which T lymphocytes will be

protein molecules that are capable of combining with

released by first mixing them with virtually all the spe-

and destroying the antigenic substance, which is

cific “self-antigens” from the body’s own tissues. If a T

explained elsewhere in this chapter and in Chapter

lymphocyte reacts, it is destroyed and phagocytized

33. Second, the B lymphocytes have even greater

instead of being released. This happens to as many as

diversity than the T lymphocytes, thus forming many

90 per cent of the cells. Thus, the only cells that are

millions of types of B-lymphocyte antibodies with dif-

finally released are those that are nonreactive against

ferent specific reactivities. After preprocessing, the B

the body’s own antigens—they react only against anti-

lymphocytes, like the T lymphocytes, migrate to lym-

gens from an outside source, such as from a bacterium,

phoid tissue throughout the body, where they lodge

a toxin, or even transplanted tissue from another

near but slightly removed from the T-lymphocyte

person.

areas.

442

Unit VI Blood Cells, Immunity, and Blood Clotting

T Lymphocytes and B-Lymphocyte

in random combinations, in this way finally forming

whole genes.

Antibodies React Highly Specifically

Because there are several hundred types of gene

Against Specific Antigens—Role of

segments, as well as millions of different combinations

Lymphocyte Clones

in which the segments can be arranged in single cells,

one can understand the millions of different cell gene

When specific antigens come in contact with T and B

types that can occur. For each functional T or B lym-

lymphocytes in the lymphoid tissue, certain of the T

phocyte that is finally formed, the gene structure codes

lymphocytes become activated to form activated T

for only a single antigen specificity. These mature cells

cells, and certain of the B lymphocytes become acti-

then become the highly specific T and B cells that

vated to form antibodies. The activated T cells and

spread to and populate the lymphoid tissue.

antibodies in turn react highly specifically against the

particular types of antigens that initiated their devel-

Mechanism for Activating a Clone

opment. The mechanism of this specificity is the

of Lymphocytes

following.

Each clone of lymphocytes is responsive to only a

single type of antigen (or to several similar antigens

Millions of Specific Types of Lymphocytes Are Stored in the

that have almost exactly the same stereochemical

Lymphoid Tissue. Millions of different types of pre-

characteristics). The reason for this is the following: In

formed B lymphocytes and preformed T lymphocytes

the case of the B lymphocytes, each of these has on the

that are capable of forming highly specific types of

surface of its cell membrane about 100,000 antibody

antibodies or T cells have been stored in the lymph

molecules that will react highly specifically with

tissue, as explained earlier. Each of these preformed

only one specific type of antigen. Therefore, when

lymphocytes is capable of forming only one type of

the appropriate antigen comes along, it immediately

antibody or one type of T cell with a single type of

attaches to the antibody in the cell membrane;

specificity. And only the specific type of antigen with

this leads to the activation process, which we describe

which it can react can activate it. Once the specific lym-

in more detail subsequently. In the case of the T

phocyte is activated by its antigen, it reproduces wildly,

lymphocytes, molecules similar to antibodies, called

forming tremendous numbers of duplicate lympho-

surface receptor proteins (or T-cell markers), are on

cytes. If it is a B lymphocyte, its progeny will eventu-

the surface of the T-cell membrane, and these, too,

ally secrete the specific type of antibody that then

are highly specific for one specified activating

circulates throughout the body. If it is a T lymphocyte,

antigen.

its progeny are specific sensitized T cells that are

released into the lymph and then carried to the blood

and circulated through all the tissue fluids and back

Role of Macrophages in the Activation Process. Aside from

into the lymph, sometimes circulating around and

the lymphocytes in lymphoid tissue, literally millions

around in this circuit for months or years.

of macrophages are also present in the same tissue.

All the different lymphocytes that are capable of

These line the sinusoids of the lymph nodes, spleen,

forming one specificity of antibody or T cell are called

and other lymphoid tissue, and they lie in apposition

a clone of lymphocytes. That is, the lymphocytes in

to many of the lymph node lymphocytes. Most invad-

each clone are alike and are derived originally from

ing organisms are first phagocytized and partially

one or a few early lymphocytes of its specific type.

digested by the macrophages, and the antigenic prod-

ucts are liberated into the macrophage cytosol. The

macrophages then pass these antigens by cell-to-cell

Origin of the Many Clones

contact directly to the lymphocytes, thus leading to

activation of the specified lymphocytic clones. The

of Lymphocytes

macrophages, in addition, secrete a special activating

substance that promotes still further growth and

Only several hundred to a few thousand genes code

reproduction of the specific lymphocytes. This sub-

for the millions of different types of antibodies and T

stance is called interleukin-1.

lymphocytes. At first, it was a mystery how it was pos-

sible for so few genes to code for the millions of dif-

ferent specificities of antibody molecules or T cells that

Role of the T Cells in Activation of the B Lymphocytes. Most

can be produced by the lymphoid tissue, especially

antigens activate both T lymphocytes and B lympho-

when one considers that a single gene is usually nec-

cytes at the same time. Some of the T cells that are

essary for the formation of each different type of

formed, called helper cells, secrete specific substances

protein. This mystery has now been solved.

(collectively called lymphokines) that activate the

The whole gene for forming each type of T cell or B

specific B lymphocytes. Indeed, without the aid of

cell is never present in the original stem cells from

these helper T cells, the quantity of antibodies formed

which the functional immune cells are formed. Instead,

by the B lymphocytes is usually slight. We will discuss

there are only “gene segments”—actually, hundreds of

this cooperative relationship between helper T cells

such segments—but not whole genes. During prepro-

and B cells again after we have an opportunity

cessing of the respective T- and B-cell lymphocytes,

to describe the mechanisms of the T-cell system of

these gene segments become mixed with one another

immunity.

Chapter 34

Resistance of the Body to Infection: II. Immunity and Allergy

443

Specific Attributes of the

B-Lymphocyte System—Humoral

Immunity and the Antibodies

128

Secondary

Primary

Formation of Antibodies by Plasma Cells. Before exposure

to a specific antigen, the clones of B lymphocytes

remain dormant in the lymphoid tissue. On entry of a

foreign antigen, macrophages in the lymphoid tissue

phagocytize the antigen and then present it to adjacent

B lymphocytes. In addition, the antigen is presented to

T cells at the same time, and activated helper T cells

are formed. These helper cells also contribute to

extreme activation of the B lymphocytes, as we discuss

more fully later.

Those B lymphocytes specific for the antigen imme-

diately enlarge and take on the appearance of

Weeks

lymphoblasts. Some of the lymphoblasts further dif-

ferentiate to form plasmablasts, which are precursors

of plasma cells. In the plasmablasts, the cytoplasm

Figure 34-2

expands and the rough endoplasmic reticulum vastly

proliferates. The plasmablasts then begin to divide at

Time course of the antibody response in the circulating blood to

a rate of about once every 10 hours for about nine divi-

a primary injection of antigen and to a secondary injection several

sions, giving in 4 days a total population of about 500

months later.

cells for each original plasmablast. The mature plasma

cell then produces gamma globulin antibodies at an

extremely rapid rate—about

2000 molecules per

second for each plasma cell. In turn, the antibodies are

increased potency and duration of the secondary

secreted into the lymph and carried to the circulating

response explain why immunization is usually accom-

blood. This process continues for several days or weeks

plished by injecting antigen in multiple doses with

until finally exhaustion and death of the plasma cells

periods of several weeks or several months between

occur.

injections.

Formation of “Memory” Cells—Difference Between Primary

Nature of the Antibodies

Response and Secondary Response. A few of the lym-

The antibodies are gamma globulins called immuno-

phoblasts formed by activation of a clone of B lym-

globulins (abbreviated as Ig), and they have molecu-

phocytes do not go on to form plasma cells but instead

lar weights between 160,000 and 970,000. They usually

form moderate numbers of new B lymphocytes similar

constitute about 20 per cent of all the plasma proteins.

to those of the original clone. In other words, the B-

All the immunoglobulins are composed of combi-

cell population of the specifically activated clone

nations of light and heavy polypeptide chains. Most are

becomes greatly enhanced, and the new B lympho-

a combination of two light and two heavy chains,

cytes are added to the original lymphocytes of the

as shown in Figure

34-3. However, some of the

same clone. They also circulate throughout the body to

immunoglobulins have combinations of as many as

populate all the lymphoid tissue; immunologically,

10 heavy and 10 light chains, which gives rise to

however, they remain dormant until activated once

high-molecular-weight immunoglobulins. Yet, in all

again by a new quantity of the same antigen. These

immunoglobulins, each heavy chain is paralleled by a

lymphocytes are called memory cells. Subsequent

light chain at one of its ends, thus forming a heavy-light

exposure to the same antigen will cause a much more

pair, and there are always at least 2 and as many as 10

rapid and much more potent antibody response this

such pairs in each immunoglobulin molecule.

second time around, because there are many more

Figure 34-3 shows by the circled area a designated

memory cells than there were original B lymphocytes

end of each light and heavy chain, called the variable

of the specific clone.

portion; the remainder of each chain is called the con-

Figure

34-2 shows the differences between the

stant portion. The variable portion is different for each

primary response for forming antibodies that occurs on

specificity of antibody, and it is this portion that

first exposure to a specific antigen and the secondary

attaches specifically to a particular type of antigen. The

response that occurs after second exposure to the same

constant portion of the antibody determines other

antigen. Note the 1-week delay in the appearance of

properties of the antibody, establishing such factors as

the primary response, its weak potency, and its short

diffusivity of the antibody in the tissues, adherence of

life. The secondary response, by contrast, begins

the antibody to specific structures within the tissues,

rapidly after exposure to the antigen (often within

attachment to the complement complex, the ease with

hours), is far more potent, and forms antibodies for

which the antibodies pass through membranes, and

many months rather than for only a few weeks. The

other biological properties of the antibody.

444

Unit VI Blood Cells, Immunity, and Blood Clotting

Antigen-binding sites

Variable portion

Antigen

Antibodies

S • S

Light

S • S

chain

Constant portion

Heavy

chain

Figure 34-3

Structure of the typical IgG antibody, showing it to be composed

of two heavy polypeptide chains and two light polypeptide chains.

Figure 34-4

The antigen binds at two different sites on the variable portions of

the chains.

Binding of antigen molecules to one another by bivalent

antibodies.

Specificity of Antibodies. Each antibody is specific for a

in allergy. The IgM class is also interesting because

particular antigen; this is caused by its unique struc-

a large share of the antibodies formed during the

tural organization of amino acids in the variable por-

primary response are of this type. These antibodies

tions of both the light and heavy chains. The amino

have 10 binding sites that make them exceedingly

acid organization has a different steric shape for each

effective in protecting the body against invaders, even

antigen specificity, so that when an antigen comes in

though there are not many IgM antibodies.

contact with it, multiple prosthetic groups of the

antigen fit as a mirror image with those of the anti-

Mechanisms of Action of Antibodies

body, thus allowing rapid and tight bonding between

Antibodies act mainly in two ways to protect the body

the antibody and the antigen. When the antibody is

against invading agents: (1) by direct attack on the

highly specific, there are so many bonding sites that the

invader and (2) by activation of the “complement

antibody-antigen coupling is exceedingly strong, held

system” that then has multiple means of its own for

together by (1) hydrophobic bonding, (2) hydrogen

destroying the invader.

bonding, (3) ionic attractions, and (4) van der Waals

forces. It also obeys the thermodynamic mass action

Direct Action of Antibodies on Invading Agents. Figure 34-4

law.

shows antibodies (designated by the red Y-shaped

bars) reacting with antigens (designated by the shaded

K = Concentration of bound antibody-antigen

objects). Because of the bivalent nature of the anti-

Concentration of antibody

bodies and the multiple antigen sites on most invad-

Concentration of antigen

ing agents, the antibodies can inactivate the invading

K_a is called the affinity constant and is a measure of

agent in one of several ways, as follows:

how tightly the antibody binds with the antigen.

1. Agglutination, in which multiple large particles

Note, especially, in Figure 34-3 that there are two

with antigens on their surfaces, such as bacteria or

variable sites on the illustrated antibody for attach-

red cells, are bound together into a clump

ment of antigens, making this type of antibody biva-

2. Precipitation, in which the molecular complex of

lent. A small proportion of the antibodies, which

soluble antigen (such as tetanus toxin) and

consist of combinations of up to 10 light and 10 heavy

antibody becomes so large that it is rendered

chains, have as many as 10 binding sites.

insoluble and precipitates

3. Neutralization, in which the antibodies cover the

Classes of Antibodies. There are five general classes of

toxic sites of the antigenic agent

antibodies, respectively named IgM, IgG, IgA, IgD,

4. Lysis, in which some potent antibodies are

and IgE. Ig stands for immunoglobulin, and the other

occasionally capable of directly attacking

five respective letters designate the respective classes.

membranes of cellular agents and thereby cause

For the purpose of our present limited discussion,

rupture of the agent

two of these classes of antibodies are of particular

These direct actions of antibodies attacking the anti-

importance: IgG, which is a bivalent antibody and con-

genic invaders often are not strong enough to play a

stitutes about 75 per cent of the antibodies of the

major role in protecting the body against the invader.

normal person, and IgE, which constitutes only a small

Most of the protection comes through the amplifying

percentage of the antibodies but is especially involved

effects of the complement system described next.

Chapter 34

Resistance of the Body to Infection: II. Immunity and Allergy

445

Antigen-antibody complex

Opsonization of bacteria

Activate mast

cells and basophils

C4 + C2

C42 + C4a

Chemotaxis of

C3b + C3a

white blood cells

C5b + C5a

Micro-organism +

B and D

C6 + C7

C5b67

Figure 34-5

Cascade of reactions during

C8 + C9

C5b6789

activation of the classic pathway

of complement.

(Modified from

Alexander JW, Good RA: Funda-

Lysis of cells

mentals of Clinical Immunology.

Philadelphia: WB Saunders,

1977.)

Complement System for Antibody Action

to engulf the bacteria to which the antigen-

“Complement” is a collective term that describes a

antibody complexes are attached. This process is

system of about 20 proteins, many of which are enzyme

called opsonization. It often enhances the number

precursors. The principal actors in this system are 11

of bacteria that can be destroyed by many

proteins designated C1 through C9, B, and D, shown

hundredfold.

in Figure 34-5. All these are present normally among

Lysis. One of the most important of all the

the plasma proteins in the blood as well as among the

products of the complement cascade is the lytic

proteins that leak out of the capillaries into the tissue

complex, which is a combination of multiple

spaces. The enzyme precursors are normally inactive,

complement factors and designated C5b6789.

but they can be activated mainly by the so-called

This has a direct effect of rupturing the cell

classic pathway.

membranes of bacteria or other invading

organisms.

Classic Pathway. The classic pathway is initiated by an

Agglutination. The complement products also

antigen-antibody reaction. That is, when an antibody

change the surfaces of the invading organisms,

binds with an antigen, a specific reactive site on the

causing them to adhere to one another, thus

“constant” portion of the antibody becomes uncov-

promoting agglutination.

ered, or “activated,” and this in turn binds directly with

Neutralization of viruses. The complement

the C1 molecule of the complement system, setting

enzymes and other complement products can

into motion a “cascade” of sequential reactions, shown

attack the structures of some viruses and thereby

in Figure 34-5, beginning with activation of the proen-

render them nonvirulent.

zyme C1 itself. The C1 enzymes that are formed then

Chemotaxis. Fragment C5a initiates chemotaxis of

activate successively increasing quantities of enzymes in

neutrophils and macrophages, thus causing large

the later stages of the system, so that from a small

numbers of these phagocytes to migrate into the

beginning, an extremely large “amplified” reaction

tissue area adjacent to the antigenic agent.

occurs. Multiple end products are formed, as shown to

Activation of mast cells and basophils. Fragments

the right in the figure, and several of these cause

C3a, C4a, and C5a activate mast cells and

important effects that help to prevent damage to the

basophils, causing them to release histamine,

body’s tissues caused by the invading organism or

heparin, and several other substances into the

toxin. Among the more important effects are the

local fluids. These substances in turn cause

following:

increased local blood flow, increased leakage of

1. Opsonization and phagocytosis. One of the

fluid and plasma protein into the tissue, and other

products of the complement cascade, C3b,

local tissue reactions that help inactivate or

strongly activates phagocytosis by both

immobilize the antigenic agent. The same factors

neutrophils and macrophages, causing these cells

play a major role in inflammation (which was

446

Unit VI Blood Cells, Immunity, and Blood Clotting

discussed in Chapter 33) and in allergy, as we

discuss later.

T cell

7. Inflammatory effects. In addition to inflammatory

effects caused by activation of the mast cells and

basophils, several other complement products

T-cell receptor

Cell-cell

contribute to local inflammation. These products

adhesion

Foreign protein

cause (1) the already increased blood flow to

proteins

MHC protein

increase still further, (2) the capillary leakage of

proteins to be increased, and (3) the interstitial

fluid proteins to coagulate in the tissue spaces,

thus preventing movement of the invading

organism through the tissues.

Antigen-

Special Attributes of the

presenting

T-Lymphocyte System-Activated

cell

T Cells and Cell-Mediated Immunity

Figure 34-6

Release of Activated T Cells from Lymphoid Tissue and Forma-

Activation of T cells requires interaction of T-cell receptors with an

tion of Memory Cells. On exposure to the proper antigen,

antigen (foreign protein) that is transported to the surface of the

as presented by adjacent macrophages, the T lympho-

antigen-presenting cell by a major histocompatibility complex

cytes of a specific lymphocyte clone proliferate and

(MHC) protein. Cell-to-cell adhesion proteins enable the T cell

to bind to the antigen-presenting cell long enough to become

release large numbers of activated, specifically react-

activated.

ing T cells in ways that parallel antibody release by

activated B cells. The principal difference is that

instead of releasing antibodies, whole activated T cells

to present antigens to T cells. Interaction of cell adhe-

are formed and released into the lymph. These then

sion proteins is critical in permitting the T cells to bind

pass into the circulation and are distributed through-

to antigen-presenting cells long enough to become

out the body, passing through the capillary walls into

activated.

the tissue spaces, back into the lymph and blood once

The MHC proteins are encoded by a large group of

again, and circulating again and again throughout the

genes called the major histocompatibility complex

body, sometimes lasting for months or even years.

(MHC). The MHC proteins bind peptide fragments

Also, T-lymphocyte memory cells are formed in the

of antigen proteins that are degraded inside antigen-

same way that B memory cells are formed in the anti-

presenting cells and then transport them to the cell

body system. That is, when a clone of T lymphocytes is

surface. There are two types of MHC proteins: (1)

activated by an antigen, many of the newly formed

MHC I proteins, which present antigens to cytotoxic T

lymphocytes are preserved in the lymphoid tissue to

cells, and (2) MHC II proteins, which present antigens

become additional T lymphocytes of that specific

to T helper cells. The specific functions of cytotoxic and

clone; in fact, these memory cells even spread through-

helper T cells are discussed later.

out the lymphoid tissue of the entire body. Therefore,

The antigens on the surface of antigen-presenting

on subsequent exposure to the same antigen anywhere

cells bind with receptor molecules on the surfaces of T

in the body, release of activated T cells occurs far more

cells in the same way that they bind with plasma

rapidly and much more powerfully than had occurred

protein antibodies. These receptor molecules are com-

during first exposure.

posed of a variable unit similar to the variable portion

of the humoral antibody, but its stem section is firmly

Antigen-Presenting Cells, MHC Proteins, and Antigen Recep-

bound to the cell membrane of the T lymphocyte.

tors on the T Lymphocytes. T-cell responses are extremely

There are as many as 100,000 receptor sites on a single

antigen specific, like the antibody responses of B cells,

T cell.

and are at least as important as antibodies in de-

fending against infection. In fact, acquired immune

responses usually require assistance from T cells to

Several Types of T Cells and Their

begin the process, and T cells play a major role in actu-

Different Functions

ally helping to eliminate invading pathogens.

Although B lymphocytes recognize intact antigens,

It has become clear that there are multiple types of T

T lymphocytes respond to antigens only when they are

cells. They are classified into three major groups: (1)

bound to specific molecules called MHC proteins on

helper T cells, (2) cytotoxic T cells, and (3) suppressor

the surface of antigen-presenting cells in the lymphoid

T cells. The functions of each of these are distinct.

tissues

(Figure

34-6). The three major types of

antigen-presenting cells are macrophages, B lympho-

Helper T Cells—Their Role in Overall

cytes, and dendritic cells. The dendritic cells, the most

Regulation of Immunity

potent of the antigen-presenting cells, are located

The helper T cells are by far the most numerous of the

throughout the body, and their only known function is

T cells, usually constituting more than three quarters

Chapter 34

Resistance of the Body to Infection: II. Immunity and Allergy

447

lethal effects of AIDS. Some of the specific regulatory

functions are the following.

PrPreprocesr

sor

arareas

Antigen

Stimulation of Growth and Proliferation of Cytotoxic T

Cells and Suppressor T Cells. In the absence of helper

T cells, the clones for producing cytotoxic T cells and

Processed

MHC

suppressor T cells are activated only slightly by most

antigen

antigens. The lymphokine interleukin-2 has an espe-

Interleukin-1

cially strong stimulatory effect in causing growth and

Antigen-specific receptor

proliferation of both cytotoxic and suppressor T cells.

In addition, several of the other lymphokines have less

Cytotoxic

T cells

potent effects.

Helper

T cells

Stimulation of B-Cell Growth and Differentiation to

Form Plasma Cells and Antibodies. The direct actions

of antigen to cause B-cell growth, proliferation, for-

mation of plasma cells, and secretion of antibodies are

also slight without the “help” of the helper T cells.

Lymphokines!!

Suppressor

Almost all the interleukins participate in the B-cell

T cells

response, but especially interleukins 4, 5, and 6. In fact,

these three interleukins have such potent effects on

the B cells that they have been called B-cell stimulat-

Proliferation

Differentiation

ing factors or B-cell growth factors.

Plasma

cells

IgM

Activation of the Macrophage System. The lym-

phokines also affect the macrophages. First, they slow

IgG

or stop the migration of the macrophages after they

Antigen

have been chemotactically attracted into the inflamed

IgA

tissue area, thus causing great accumulation of

B cell

IgE

macrophages. Second, they activate the macrophages

to cause far more efficient phagocytosis, allowing them

Figure 34-7

to attack and destroy increasing numbers of invading

bacteria or other tissue-destroying agents.

Regulation of the immune system, emphasizing a pivotal role of

the helper T cells. MHC, major histocompatibility complex.

Feedback Stimulatory Effect on the Helper Cells Them-

selves. Some of the lymphokines, especially inter-

of all of them. As their name implies, they help in the

leukin-2, have a direct positive feedback effect in

functions of the immune system, and they do so in

stimulating activation of the helper T cells themselves.

many ways. In fact, they serve as the major regulator

This acts as an amplifier by further enhancing the

of virtually all immune functions, as shown in Figure

helper cell response as well as the entire immune

34-7. They do this by forming a series of protein medi-

response to an invading antigen.

ators, called lymphokines, that act on other cells of the

immune system as well as on bone marrow cells.

Cytotoxic T Cells

Among the important lymphokines secreted by the

The cytotoxic T cell is a direct-attack cell that is

helper T cells are the following:

capable of killing micro-organisms and, at times, even

some of the body’s own cells. For this reason, these

Interleukin-2

cells are called killer cells. The receptor proteins on the

Interleukin-3

surfaces of the cytotoxic cells cause them to bind

Interleukin-4

tightly to those organisms or cells that contain the

Interleukin-5

appropriate binding-specific antigen. Then, they kill

Interleukin-6

the attacked cell in the manner shown in Figure 34-8.

Granulocyte-monocyte colony-stimulating factor

After binding, the cytotoxic T cell secretes hole-

Interferon-g

forming proteins, called perforins, that literally punch

round holes in the membrane of the attacked cell.

Specific Regulatory Functions of the Lymphokines. In the

Then fluid flows rapidly into the cell from the intersti-

absence of the lymphokines from the helper T cells,

tial space. In addition, the cytotoxic T cell releases

the remainder of the immune system is almost para-

cytotoxic substances directly into the attacked cell.

lyzed. In fact, it is the helper T cells that are inactivated

Almost immediately, the attacked cell becomes greatly

or destroyed by the acquired immunodeficiency syn-

swollen, and it usually dissolves shortly thereafter.

drome (AIDS) virus, which leaves the body almost

Especially important, these cytotoxic killer cells can

totally unprotected against infectious disease, there-

pull away from the victim cells after they have

fore leading to the now well-known debilitating and

punched holes and delivered cytotoxic substances and

448

Unit VI Blood Cells, Immunity, and Blood Clotting

as being distinctive from bacteria or viruses, and the

Cytotoxic

person’s immunity system forms few antibodies or

T cells

activated T cells against his or her own antigens.

(killer cells)

Cytotoxic

Most Tolerance Results from Clone Selection During Prepro-

and

digestive

cessing. It is believed that most tolerance develops

enzymes

during preprocessing of T lymphocytes in the thymus

and of B lymphocytes in the bone marrow. The reason

for this belief is that injecting a strong antigen into a

fetus while the lymphocytes are being preprocessed in

these two areas prevents development of clones of

lymphocytes in the lymphoid tissue that are specific for

the injected antigen. Experiments have shown that

Attacked

Specific

specific immature lymphocytes in the thymus, when

Antigen

cell

binding

exposed to a strong antigen, become lymphoblastic,

receptors

proliferate considerably, and then combine with the

stimulating antigen—an effect that is believed to cause

Antigen

the cells themselves to be destroyed by the thymic

epithelial cells before they can migrate to and colonize

Figure 34-8

the total body lymphoid tissue.

It is believed that during the preprocessing of lym-

Direct destruction of an invading cell by sensitized lymphocytes

phocytes in the thymus and bone marrow, all or most

(cytotoxic T cells).

of those clones of lymphocytes that are specific to

damage the body’s own tissues are self-destroyed

because of their continual exposure to the body’s

antigens.

then move on to kill more cells. Indeed, some of these

cells persist for months in the tissues.

Failure of the Tolerance Mechanism Causes Autoimmune Dis-

Some of the cytotoxic T cells are especially lethal to

eases. Sometimes people lose their immune tolerance

tissue cells that have been invaded by viruses because

of their own tissues. This occurs to a greater extent the

many virus particles become entrapped in the mem-

older a person becomes. It usually occurs after destruc-

branes of the tissue cells and attract T cells in response

tion of some of the body’s own tissues, which releases

to the viral antigenicity. The cytotoxic cells also play

considerable quantities of

“self-antigens” that cir-

an important role in destroying cancer cells, heart

culate in the body and presumably cause acquired

transplant cells, or other types of cells that are foreign

immunity in the form of either activated T cells or

to the person’s own body.

antibodies.

Several specific diseases that result from autoim-

Suppressor T Cells

munity include (1) rheumatic fever, in which the body

Much less is known about the suppressor T cells than

becomes immunized against tissues in the joints and

about the others, but they are capable of suppressing

heart, especially the heart valves, after exposure to a

the functions of both cytotoxic and helper T cells. It is

specific type of streptococcal toxin that has an epitope

believed that these suppressor functions serve the

in its molecular structure similar to the structure of

purpose of preventing the cytotoxic cells from causing

some of the body’s own self-antigens; (2) one type of

excessive immune reactions that might be damaging to

glomerulonephritis, in which the person becomes

the body’s own tissues. For this reason, the suppressor

immunized against the basement membranes of

cells are classified, along with the helper T cells, as reg-

glomeruli; (3) myasthenia gravis, in which immunity

ulatory T cells. It is probable that the suppressor T-cell

develops against the acetylcholine receptor proteins of

system plays an important role in limiting the ability

the neuromuscular junction, causing paralysis; and (4)

of the immune system to attack a person’s own body

lupus erythematosus, in which the person becomes

tissues, called immune tolerance, as we discuss in the

immunized against many different body tissues at the

next section.

same time, a disease that causes extensive damage and

often rapid death.

Tolerance of the Acquired Immunity

System to One’s Own Tissues—Role

Immunization by Injection of Antigens

of Preprocessing in the Thymus and

Bone Marrow

Immunization has been used for many years to

produce acquired immunity against specific diseases. A

If a person should become immune to his or her own

person can be immunized by injecting dead organisms

tissues, the process of acquired immunity would

that are no longer capable of causing disease but that

destroy the individual’s own body. The immune mech-

still have some of their chemical antigens. This type of

anism normally “recognizes” a person’s own tissues

immunization is used to protect against typhoid fever,

Chapter 34

Resistance of the Body to Infection: II. Immunity and Allergy

449

whooping cough, diphtheria, and many other types of

diffuse from the circulating blood in large numbers

bacterial diseases.

into the skin to respond to the poison ivy toxin. And,

Immunity can be achieved against toxins that have

at the same time, these T cells elicit a cell-mediated

been treated with chemicals so that their toxic nature

type of immune reaction. Remembering that this type

has been destroyed even though their antigens for

of immunity can cause release of many toxic sub-

causing immunity are still intact. This procedure is

stances from the activated T cells as well as extensive

used in immunizing against tetanus, botulism, and

invasion of the tissues by macrophages along with

other similar toxic diseases.

their subsequent effects, one can well understand that

And, finally, a person can be immunized by being

the eventual result of some delayed-reaction allergies

infected with live organisms that have been “attenu-

can be serious tissue damage. The damage normally

ated.” That is, these organisms either have been grown

occurs in the tissue area where the instigating antigen

in special culture media or have been passed through

is present, such as in the skin in the case of poison ivy,

a series of animals until they have mutated enough

or in the lungs to cause lung edema or asthmatic

that they will not cause disease but do still carry spe-

attacks in the case of some airborne antigens.

cific antigens required for immunization. This proce-

dure is used to protect against poliomyelitis, yellow

fever, measles, smallpox, and many other viral diseases.

Allergies in the “Allergic” Person,

Who Has Excess IgE Antibodies

Passive Immunity

Some people have an “allergic” tendency. Their aller-

gies are called atopic allergies because they are caused

Thus far, all the acquired immunity we have discussed

by a nonordinary response of the immune system. The

has been active immunity. That is, the person’s own

allergic tendency is genetically passed from parent to

body develops either antibodies or activated T cells in

child and is characterized by the presence of large

response to invasion of the body by a foreign antigen.

quantities of IgE antibodies in the blood. These anti-

However, temporary immunity can be achieved in a

bodies are called reagins or sensitizing antibodies to

person without injecting any antigen. This is done by

distinguish them from the more common IgG anti-

infusing antibodies, activated T cells, or both obtained

bodies. When an allergen

(defined as an antigen

from the blood of someone else or from some other

that reacts specifically with a specific type of IgE

animal that has been actively immunized against the

reagin antibody) enters the body, an allergen-reagin

antigen.

reaction lakes place, and a subsequent allergic reaction

Antibodies last in the body of the recipient for 2 to

occurs.

3 weeks, and during that time, the person is protected

A special characteristic of the IgE antibodies (the

against the invading disease. Activated T cells last for

reagins) is a strong propensity to attach to mast cells

a few weeks if transfused from another person but

and basophils. Indeed, a single mast cell or basophil

only for a few hours to a few days if transfused

can bind as many as half a million molecules of IgE

from an animal. Such transfusion of antibodies or T

antibodies. Then, when an antigen (an allergen) that

lymphocytes to confer immunity is called passive

has multiple binding sites binds with several IgE anti-

immunity.

bodies that are already attached to a mast cell or

basophil, this causes immediate change in the mem-

brane of the mast cell or basophil, perhaps resulting

ALLERGY AND

from a physical effect of the antibody molecules to

HYPERSENSITIVITY

contort the cell membrane. At any rate, many of the

mast cells and basophils rupture; others release special

An important undesirable side effect of immunity is

agents immediately or shortly thereafter, including his-

the development, under some conditions, of allergy or

tamine, protease, slow-reacting substance of anaphy-

other types of immune hypersensitivity. There are

laxis

(which is a mixture of toxic leukotrienes),

several types of allergy and other hypersensitivities,

eosinophil chemotactic substance, neutrophil chemo-

some of which occur only in people who have a spe-

tactic substance, heparin, and platelet activating factors.

cific allergic tendency.

These substances cause such effects as dilation of the

local blood vessels; attraction of eosinophils and neu-

trophils to the reactive site; increased permeability of

Allergy Caused by Activated T Cells:

the capillaries with loss of fluid into the tissues; and

Delayed-Reaction Allergy

contraction of local smooth muscle cells. Therefore,

several different tissue responses can occur, depend-

Delayed-reaction allergy is caused by activated T cells

ing on the type of tissue in which the allergen-reagin

and not by antibodies. In the case of poison ivy, the

reaction occurs. Among the different types of allergic

toxin of poison ivy in itself does not cause much harm

reactions caused in this manner are the following.

to the tissues. However, on repeated exposure, it does

cause the formation of activated helper and cytotoxic

Anaphylaxis. When a specific allergen is injected

T cells. Then, after subsequent exposure to the poison

directly into the circulation, the allergen can react with

ivy toxin, within a day or so, the activated T cells

basophils of the blood and mast cells in the tissues

450

Unit VI Blood Cells, Immunity, and Blood Clotting

located immediately outside the small blood vessels

not appear to be the major factor eliciting the asth-

if the basophils and mast cells have been sensitized

matic reaction.

by attachment of IgE reagins. Therefore, a widespread

allergic reaction occurs throughout the vascular

system and closely associated tissues. This is called

References

anaphylaxis. Histamine is released into the circulation

and causes body-wide vasodilation as well as increased

Abreu MT, Arditi M: Innate immunity and toll-like recep-

permeability of the capillaries with resultant marked

tors: clinical implications of basic science research. J

loss of plasma from the circulation. An occasional

Pediatr 144(4):421, 2004.

person who experiences this reaction dies of circula-

Albert ML: Death-defying immunity: do apoptotic cells

tory shock within a few minutes unless treated with

influence antigen processing and presentation? Nat Rev

epinephrine to oppose the effects of the histamine.

Immunol 4:223, 2004.

Also released from the activated basophils and mast

Alberts B, Johnson A, Lewis J, et al: Molecular Biology of

cells is a mixture of leukotrienes called slow-reacting

the Cell. New York: Garland Science, 2002.

substance of anaphylaxis. These leukotrienes can cause

Cheroutre H, Madakamutil L: Acquired and natural

memory T cells join forces at the mucosal front line. Nat

spasm of the smooth muscle of the bronchioles, elicit-

Rev Immunol 4:290, 2004.

ing an asthma-like attack, sometimes causing death by

Cooper MA, Pommering TL, Koranyi K: Primary immuno-

suffocation.

deficiencies. Am Fam Physician 68:2001, 2003.

Cossart P, Sansonetti PJ: Bacterial invasion: the paradigms

Urticaria. Urticaria results from antigen entering spe-

of enteroinvasive pathogens. Science 304:242, 2004.

cific skin areas and causing localized anaphylactoid

Eisenbarth GS, Gottlieb PA: Autoimmune polyendocrine

reactions. Histamine released locally causes (1) vasodi-

syndromes. N Engl J Med. 350:2068, 2004.

lation that induces an immediate red flare and (2)

Figdor CG, de Vries IJ, Lesterhuis WJ, Melief CJ: Dendritic

increased local permeability of the capillaries that

cell immunotherapy: mapping the way. Nat Med 10:475,

leads to local circumscribed areas of swelling of the

2004.

Frossi B, De Carli M, Pucillo C: The mast cell: an antenna of

skin within another few minutes. The swellings are

the microenvironment that directs the immune response.

commonly called hives. Administration of antihista-

J Leukoc Biol 75:579, 2004.

mine drugs to a person before exposure will prevent

Grossman Z, Min B, Meier-Schellersheim M, Paul WE: Con-

the hives.

comitant regulation of T-cell activation and homeostasis.

Nat Rev Immunol 4:387, 2004.

Hay Fever. In hay fever, the allergen-reagin reaction

Kupper TS, Fuhlbrigge RC: Immune surveillance in the skin:

occurs in the nose. Histamine released in response to

mechanisms and clinical consequences. Nat Rev Immunol

the reaction causes local intranasal vascular dilation,

4:211, 2004.

with resultant increased capillary pressure as well as

La Cava A, Matarese G: The weight of leptin in immunity.

increased capillary permeability. Both these effects

Nat Rev Immunol 4:371, 2004.

Linton PJ, Dorshkind K: Age-related changes in lymphocyte

cause rapid fluid leakage into the nasal cavities and

development and function. Nat Immunol 5:133, 2004.

into associated deeper tissues of the nose; and the

MacGlashan D Jr: Histamine: a mediator of inflammation. J

nasal linings become swollen and secretory. Here

Allergy Clin Immunol 112(4 Suppl):S53, 2003.

again, use of antihistamine drugs can prevent this

McGeady SJ: Immunocompetence and allergy. Pediatrics

swelling reaction. But other products of the allergen-

113(4 Suppl):1107, 2004.

reagin reaction can still cause irritation of the nose,

Nikolich-Zugich J, Slifka MK, Messaoudi I: The many impor-

eliciting the typical sneezing syndrome.

tant facets of T-cell repertoire diversity. Nat Rev Immunol

4:123, 2004 .

Asthma. Asthma often occurs in the “allergic” type of

Petrie HT: Cell migration and the control of post-natal T-cell

person. In such a person, the allergen-reagin reaction

lymphopoiesis in the thymus. Nat Rev Immunol 3:859,

2003.

occurs in the bronchioles of the lungs. Here, an impor-

Scott CC, Botelho RJ, Grinstein S: Phagosome maturation:

tant product released from the mast cells is believed

a few bugs in the system. J Membr Biol 193:137, 2003.

to be the slow-reacting substance of anaphylaxis, which

Theoharides TC, Cochrane DE: Critical role of mast cells in

causes spasm of the bronchiolar smooth muscle. Con-

inflammatory diseases and the effect of acute stress. J Neu-

sequently, the person has difficulty breathing until the

roimmunol 146:1, 2004.

reactive products of the allergic reaction have been

Vivier E, Anfossi N: Inhibitory NK-cell receptors on T cells:

removed. Administration of antihistaminics has less

witness of the past, actors of the future. Nat Rev Immunol

effect on the course of asthma because histamine does

4:190, 2004.

C H A P T E R

Blood Types; Transfusion; Tissue

and Organ Transplantation

Antigenicity Causes Immune

Reactions of Blood

When blood transfusions from one person to

another were first attempted, immediate or delayed

agglutination and hemolysis of the red blood cells

often occurred, resulting in typical transfusion reac-

tions that frequently led to death. Soon it was dis-

covered that the bloods of different people have different antigenic and immune

properties, so that antibodies in the plasma of one blood will react with anti-

gens on the surfaces of the red cells of another blood type. If proper precau-

tions are taken, one can determine ahead of time whether the antibodies

and antigens present in the donor and recipient bloods will cause a transfusion

reaction.

Multiplicity of Antigens in the Blood Cells. At least 30 commonly occurring antigens

and hundreds of other rare antigens, each of which can at times cause antigen-

antibody reactions, have been found in human blood cells, especially on the sur-

faces of the cell membranes. Most of the antigens are weak and therefore are

of importance principally for studying the inheritance of genes to establish

parentage.

Two particular types of antigens are much more likely than the others to

cause blood transfusion reactions. They are the O-A-B system of antigens and

the Rh system.

O-A-B Blood Types

A and B Antigens—Agglutinogens

Two antigens—type A and type B—occur on the surfaces of the red blood cells

in a large proportion of human beings. It is these antigens (also called agglu-

tinogens because they often cause blood cell agglutination) that cause most

blood transfusion reactions. Because of the way these agglutinogens are inher-

ited, people may have neither of them on their cells, they may have one, or they

may have both simultaneously.

Major O-A-B Blood Types. In transfusing blood from one person to another, the

bloods of donors and recipients are normally classified into four major O-A-B

blood types, as shown in Table 35-1, depending on the presence or absence of

the two agglutinogens, the A and B agglutinogens. When neither A nor B agglu-

tinogen is present, the blood is type O. When only type A agglutinogen is

present, the blood is type A. When only type B agglutinogen is present, the blood

is type B. When both A and B agglutinogens are present, the blood is type AB.

Genetic Determination of the Agglutinogens. Two genes, one on each of two paired

chromosomes, determine the O-A-B blood type. These genes can be any one of

three types but only one type on each of the two chromosomes: type O, type A,

451

452

Unit VI Blood Cells, Immunity, and Blood Clotting

Table 35-1

Blood Types with Their Genotypes and Their Constituent

Agglutinogens and Agglutinins

Anti-A agglutinins in

groups B and O blood

Anti-B agglutinins in

Genotypes

Blood Types

Agglutinogens

Agglutinins

400

groups A and O blood

—

Anti-A and

Anti-B

300

OA or AA

Anti-B

OB or BB

Anti-A

A and B

—

200

or type B. The type O gene is either functionless or

100

almost functionless, so that it causes no significant type

O agglutinogen on the cells. Conversely, the type A

and type B genes do cause strong agglutinogens on the

10 20 30 40 50 60 70 80 90 100

cells.

Age of person (years)

The six possible combinations of genes, as shown in

Table 35-1, are OO, OA, OB, AA, BB, and AB. These

combinations of genes are known as the genotypes,

and each person is one of the six genotypes.

One can also observe from Table 35-1 that a person

Figure 35-1

with genotype OO produces no agglutinogens, and

Average titers of anti-A and anti-B agglutinins in the plasmas of

therefore the blood type is O. A person with genotype

people with different blood types.

OA or AA produces type A agglutinogens and there-

fore has blood type A. Genotypes OB and BB give

type B blood, and genotype AB gives type AB blood.

when type A agglutinogens are not present in the cells,

and anti-B agglutinins when type B agglutinogens are

Relative Frequencies of the Different Blood Types.

not in the cells. Figure 35-1 shows the changing titers

The prevalence of the different blood types among one

of the anti-A and anti-B agglutinins at different ages.

group of persons studied was approximately:

A maximum titer is usually reached at 8 to 10 years

of age, and this gradually declines throughout the

47%

41%

remaining years of life.

Origin of Agglutinins in the Plasma. The agglutinins are

gamma globulins, as are almost all antibodies, and they

It is obvious from these percentages that the O and

are produced by the same bone marrow and lymph

A genes occur frequently, whereas the B gene is

gland cells that produce antibodies to any other anti-

infrequent.

gens. Most of them are IgM and IgG immunoglobulin

molecules.

But why are these agglutinins produced in people

Agglutinins

who do not have the respective agglutinogens in their

red blood cells? The answer to this is that small

When type A agglutinogen is not present in a person’s

amounts of type A and B antigens enter the body in

red blood cells, antibodies known as anti-A agglutinins

food, in bacteria, and in other ways, and these sub-

develop in the plasma. Also, when type B agglutino-

stances initiate the development of the anti-A and

gen is not present in the red blood cells, antibodies

anti-B agglutinins.

known as anti-B agglutinins develop in the plasma.

For instance, infusion of group A antigen into a

Thus, referring once again to Table 35-1, note that

recipient having a non-A blood type causes a typical

type O blood, although containing no agglutinogens,

immune response with formation of greater quantities

does contain both anti-A and anti-B agglutinins; type

of anti-A agglutinins than ever. Also, the neonate has

A blood contains type A agglutinogens and anti-B

few, if any, agglutinins, showing that agglutinin forma-

agglutinins; type B blood contains type B agglutino-

tion occurs almost entirely after birth.

gens and anti-A agglutinins. Finally, type AB blood

contains both A and B agglutinogens but no

agglutinins.

Agglutination Process In Transfusion

Reactions

Titer of the Agglutinins at Different Ages. Immediately after

birth, the quantity of agglutinins in the plasma is

When bloods are mismatched so that anti-A or anti-B

almost zero. Two to 8 months after birth, an infant

plasma agglutinins are mixed with red blood cells that

begins to produce agglutinins—anti-A agglutinins

contain A or B agglutinogens, respectively, the red

Chapter 35

Blood Types; Transfusion; Tissue and Organ Transplantation

453

cells agglutinate as a result of the agglutinins’ attach-

O red blood cells have no agglutinogens and therefore

ing themselves to the red blood cells. Because the

do not react with either the anti-A or the anti-B agglu-

agglutinins have two binding sites (IgG type) or 10

tinins. Type A blood has A agglutinogens and there-

binding sites (IgM type), a single agglutinin can attach

fore agglutinates with anti-A agglutinins. Type B

to two or more red blood cells at the same time,

blood has B agglutinogens and agglutinates with

thereby causing the cells to be bound together by the

anti-B agglutinins. Type AB blood has both A and B

agglutinin. This causes the cells to clump, which is the

agglutinogens and agglutinates with both types of

process of “agglutination.” Then these clumps plug

agglutinins.

small blood vessels throughout the circulatory system.

During ensuing hours to days, either physical distor-

tion of the cells or attack by phagocytic white blood

Rh Blood Types

cells destroys the membranes of the agglutinated cells,

releasing hemoglobin into the plasma, which is called

Along with the O-A-B blood type system, the Rh

“hemolysis” of the red blood cells.

blood type system is also important when transfusing

blood. The major difference between the O-A-B

Acute Hemolysis Occurs in Some Transfusion Reactions.

system and the Rh system is the following: In the

Sometimes, when recipient and donor bloods are mis-

O-A-B system, the plasma agglutinins responsible for

matched, immediate hemolysis of red cells occurs in

causing transfusion reactions develop spontaneously,

the circulating blood. In this case, the antibodies cause

whereas in the Rh system, spontaneous agglutinins

lysis of the red blood cells by activating the comple-

almost never occur. Instead, the person must first be

ment system, which releases proteolytic enzymes (the

massively exposed to an Rh antigen, such as by trans-

lytic complex) that rupture the cell membranes, as

fusion of blood containing the Rh antigen, before

described in Chapter

34. Immediate intravascular

enough agglutinins to cause a significant transfusion

hemolysis is far less common than agglutination fol-

reaction will develop.

lowed by delayed hemolysis, because not only does

there have to be a high titer of antibodies for lysis to

Rh Antigens—“Rh-Positive” and

“Rh-Negative” People.

occur, but also a different type of antibody seems to

There are six common types of Rh antigens, each of

be required, mainly the IgM antibodies; these anti-

which is called an Rh factor. These types are desig-

bodies are called hemolysins.

nated C, D, E, c, d, and e. A person who has a C antigen

does not have the c antigen, but the person missing the

C antigen always has the c antigen. The same is true

Blood Typing

for the D-d and E-e antigens. Also, because of the

manner of inheritance of these factors, each person has

Before giving a transfusion to a person, it is necessary

one of each of the three pairs of antigens.

to determine the blood type of the recipient’s blood

The type D antigen is widely prevalent in the

and the blood type of the donor blood so that the

population and considerably more antigenic than

bloods can be appropriately matched. This is called

the other Rh antigens. Anyone who has this type of

blood typing and blood matching, and these are per-

antigen is said to be Rh positive, whereas a person who

formed in the following way: The red blood cells are

does not have type D antigen is said to be Rh negative.

first separated from the plasma and diluted with saline.

However, it must be noted that even in Rh-negative

One portion is then mixed with anti-A agglutinin and

people, some of the other Rh antigens can still cause

another portion with anti-B agglutinin. After several

transfusion reactions, although the reactions are

minutes, the mixtures are observed under a micro-

usually much milder.

scope. If the red blood cells have become clumped—

About 85 per cent of all white people are Rh posi-

that is, “agglutinated”—one knows that an antibody-

tive and 15 per cent, Rh negative. In American blacks,

antigen reaction has resulted.

the percentage of Rh-positives is about 95, whereas in

Table 35-2 lists the presence (+) or absence (-) of

African blacks, it is virtually 100 per cent.

agglutination of the four types of red blood cells. Type

Table 35-2

Rh Immune Response

Blood Typing, Showing Agglutination of Cells of the

Different Blood Types with Anti-A or Anti-B Agglutinins

Formation of Anti-Rh Agglutinins. When red blood cells

in the Sera

containing Rh factor are injected into a person whose

blood does not contain the Rh factor—that is, into

Red Blood Cell Types

Sera

an Rh-negative person—anti-Rh agglutinins develop

Anti-A

Anti-B

slowly, reaching maximum concentration of agglu-

tinins about 2 to 4 months later. This immune response

occurs to a much greater extent in some people than

in others. With multiple exposures to the Rh factor,

an Rh-negative person eventually becomes strongly

“sensitized” to Rh factor.

454

Unit VI Blood Cells, Immunity, and Blood Clotting

Characteristics of Rh Transfusion Reactions. If an Rh-

passed from the baby’s bone marrow into the circula-

negative person has never before been exposed to Rh-

tory system, and it is because of the presence of these

positive blood, transfusion of Rh-positive blood into

nucleated blastic red blood cells that the disease is

that person will likely cause no immediate reaction.

called erythroblastosis fetalis.

However, anti-Rh antibodies can develop in sufficient

Although the severe anemia of erythroblastosis

quantities during the next 2 to 4 weeks to cause agglu-

fetalis is usually the cause of death, many children who

tination of those transfused cells that are still circulat-

barely survive the anemia exhibit permanent mental

ing in the blood. These cells are then hemolyzed by the

impairment or damage to motor areas of the brain

tissue macrophage system. Thus, a delayed transfusion

because of precipitation of bilirubin in the neuronal

reaction occurs, although it is usually mild. On subse-

cells, causing destruction of many, a condition called

quent transfusion of Rh-positive blood into the same

kernicterus.

person, who is now already immunized against the Rh

factor, the transfusion reaction is greatly enhanced and

Treatment of the Erythroblastotic Neonate. One treatment

can be immediate and as severe as a transfusion reac-

for erythroblastosis fetalis is to replace the neonate’s

tion caused by mismatched type A or B blood.

blood with Rh-negative blood. About 400 milliliters of

Rh-negative blood is infused over a period of 1.5 or

Erythroblastosis Fetalis (“Hemolytic Disease

more hours while the neonate’s own Rh-positive blood

of the Newborn”)

is being removed. This procedure may be repeated

Erythroblastosis fetalis is a disease of the fetus and

several times during the first few weeks of life, mainly

newborn child characterized by agglutination and

to keep the bilirubin level low and thereby prevent

phagocytosis of the fetus’s red blood cells. In most

kernicterus. By the time these transfused Rh-negative

instances of erythroblastosis fetalis, the mother is Rh

cells are replaced with the infant’s own Rh-positive

negative and the father Rh positive. The baby has

cells, a process that requires 6 or more weeks, the anti-

inherited the Rh-positive antigen from the father, and

Rh agglutinins that had come from the mother will

the mother develops anti-Rh agglutinins from expo-

have been destroyed.

sure to the fetus’s Rh antigen. In turn, the mother’s

agglutinins diffuse through the placenta into the fetus

Prevention of Erythroblastosis Fetalis. The D antigen of

and cause red blood cell agglutination.

the Rh blood group system is the primary culprit in

causing immunization of an Rh-negative mother to

Incidence of the Disease. An Rh-negative mother having

an Rh-positive fetus. In the 1970’s, a dramatic reduc-

her first Rh-positive child usually does not develop

tion in the incidence of erythroblastosis fetalis was

sufficient anti-Rh agglutinins to cause any harm.

achieved with the development of Rh immunoglobu-

However, about 3 per cent of second Rh-positive

lin globin, an anti-D antibody that is administered to

babies exhibit some signs of erythroblastosis fetalis;

the expectant mother starting at 28 to 30 weeks of

about 10 per cent of third babies exhibit the disease;

gestation. The anti-D antibody is also administered to

and the incidence rises progressively with subsequent

Rh-negative women who deliver Rh-positive babies to

pregnancies.

prevent sensitization of the mothers to the D antigen.

This greatly reduces the risk of developing large

Effect of the Mother’s Antibodies on the Fetus. After anti-

amounts of D antibodies during the second pregnancy.

Rh antibodies have formed in the mother, they diffuse

The mechanism by which Rh immunoglobulin

slowly through the placental membrane into the

globin prevents sensitization of the D antigen is not

fetus’s blood. There they cause agglutination of the

completely understood, but one effect of the anti-D

fetus’s blood. The agglutinated red blood cells subse-

antibody is to inhibit antigen-induced B lymphocyte

quently hemolyze, releasing hemoglobin into the

antibody production in the expectant mother. The

blood. The fetus’s macrophages then convert the

administered anti-D antibody also attaches to D-

hemoglobin into bilirubin, which causes the baby’s

antigen sites on Rh-positive fetal red blood cells that

skin to become yellow (jaundiced). The antibodies can

may cross the placenta and enter the circulation of

also attack and damage other cells of the body.

the expectant mother, thereby interfering with the

immune response to the D antigen.

Clinical Picture of Erythroblastosis. The jaundiced, ery-

throblastotic newborn baby is usually anemic at birth,

and the anti-Rh agglutinins from the mother usually

Transfusion Reactions Resulting

circulate in the infant’s blood for another

1 to 2

from Mismatched Blood Types

months after birth, destroying more and more red

blood cells.

If donor blood of one blood type is transfused into a

The hematopoietic tissues of the infant attempt to

recipient who has another blood type, a transfusion

replace the hemolyzed red blood cells. The liver and

reaction is likely to occur in which the red blood cells

spleen become greatly enlarged and produce red

of the donor blood are agglutinated. It is rare that the

blood cells in the same manner that they normally do

transfused blood causes agglutination of the recipient’s

during the middle of gestation. Because of the rapid

cells, for the following reason: The plasma portion of

production of red cells, many early forms of red blood

the donor blood immediately becomes diluted by all

cells, including many nucleated blastic forms, are

the plasma of the recipient, thereby decreasing the

Chapter 35

Blood Types; Transfusion; Tissue and Organ Transplantation

455

titer of the infused agglutinins to a level usually too

its own additional complement of antigens. Conse-

low to cause agglutination. Conversely, the small

quently, foreign cells transplanted anywhere into the

amount of infused blood does not significantly dilute

body of a recipient can produce immune reactions. In

the agglutinins in the recipient’s plasma. Therefore, the

other words, most recipients are just as able to resist

recipient’s agglutinins can still agglutinate the mis-

invasion by foreign tissue cells as to resist invasion by

matched donor cells.

foreign bacteria or red cells.

As explained earlier, all transfusion reactions even-

tually cause either immediate hemolysis resulting from

Autografts, Isografts, Allografts, and Xenografts. A trans-

hemolysins or later hemolysis resulting from phagocy-

plant of a tissue or whole organ from one part of the

tosis of agglutinated cells. The hemoglobin released

same animal to another part is called an autograft;

from the red cells is then converted by the phagocytes

from one identical twin to another, an isograft; from

into bilirubin and later excreted in the bile by the liver,

one human being to another or from any animal to

as discussed in Chapter 70. The concentration of biliru-

another animal of the same species, an allograft; and

bin in the body fluids often rises high enough to cause

from a lower animal to a human being or from an

jaundice—that is, the person’s internal tissues and skin

animal of one species to one of another species, a

become colored with yellow bile pigment. But if liver

xenograft.

function is normal, the bile pigment will be excreted

into the intestines by way of the liver bile, so that jaun-

Transplantation of Cellular Tissues. In the case of auto-

dice usually does not appear in an adult person unless

grafts and isografts, cells in the transplant contain vir-

more than 400 milliliters of blood is hemolyzed in less

tually the same types of antigens as in the tissues of

than a day.

the recipient and will almost always continue to live

normally and indefinitely if an adequate blood supply

Acute Kidney Shutdown After Transfusion Reactions. One of

is provided.

the most lethal effects of transfusion reactions is

At the other extreme, in the case of xenografts,

kidney failure, which can begin within a few minutes

immune reactions almost always occur, causing death

to few hours and continue until the person dies of

of the cells in the graft within 1 day to 5 weeks after

renal failure.

transplantation unless some specific therapy is used to

The kidney shutdown seems to result from three

prevent the immune reactions.

causes: First, the antigen-antibody reaction of the

Some of the different cellular tissues and organs that

transfusion reaction releases toxic substances from the

have been transplanted as allografts, either experi-

hemolyzing blood that cause powerful renal vasocon-

mentally or for therapeutic purposes, from one person

striction. Second, loss of circulating red cells in the

to another are skin, kidney, heart, liver, glandular

recipient, along with production of toxic substances

tissue, bone marrow, and lung. With proper “matching”

from the hemolyzed cells and from the immune reac-

of tissues between persons, many kidney allografts

tion, often causes circulatory shock. The arterial blood

have been successful for at least 5 to 15 years, and allo-

pressure falls very low, and renal blood flow and urine

graft liver and heart transplants for 1 to 15 years.

output decrease. Third, if the total amount of free

hemoglobin released into the circulating blood is

greater than the quantity that can bind with “hapto-

Attempts to Overcome Immune

globin” (a plasma protein that binds small amounts of

Reactions in Transplanted Tissue

hemoglobin), much of the excess leaks through the

glomerular membranes into the kidney tubules. If this

Because of the extreme potential importance of trans-

amount is still slight, it can be reabsorbed through the

planting certain tissues and organs, serious attempts

tubular epithelium into the blood and will cause no

have been made to prevent antigen-antibody reactions

harm; if it is great, then only a small percentage is reab-

associated with transplantation. The following specific

sorbed. Yet water continues to be reabsorbed, causing

procedures have met with some degrees of clinical or

the tubular hemoglobin concentration to rise so high

experimental success.

that the hemoglobin precipitates and blocks many of

the kidney tubules. Thus, renal vasoconstriction, circu-

Tissue Typing—The HLA Complex of Antigens

latory shock, and renal tubular blockage together

The most important antigens for causing graft rejec-

cause acute renal shutdown. If the shutdown is com-

tion are a complex called the HLA antigens. Six of

plete and fails to resolve, the patient dies within a week

these antigens are present on the tissue cell mem-

to 12 days, as explained in Chapter 31, unless treated

branes of each person, but there are about 150 dif-

with an artificial kidney.

ferent HLA antigens to choose from. Therefore, this

represents more than a trillion possible combinations.

Consequently, it is virtually impossible for two

Transplantation of Tissues

persons, except in the case of identical twins, to have

and Organs

the same six HLA antigens. Development of signifi-

cant immunity against any one of these antigens can

Most of the different antigens of red blood cells that

cause graft rejection.

cause transfusion reactions are also widely present

The HLA antigens occur on the white blood cells as

in other cells of the body, and each bodily tissue has

well as on the tissue cells. Therefore, tissue typing for

456

Unit VI Blood Cells, Immunity, and Blood Clotting

these antigens is done on the membranes of lympho-

in an immunosuppressed person, presumably because

cytes that have been separated from the person’s

the immune system is important in destroying many

blood. The lymphocytes are mixed with appropriate

early cancer cells before they can begin to proliferate.

antisera and complement; after incubation, the cells

To summarize, transplantation of living tissues in

are tested for membrane damage, usually by testing

human beings has had very limited but important

the rate of trans-membrane uptake by the lymphocytic

success. When someone does finally succeed in block-

cells of a special dye.

ing the immune response of the recipient without at

Some of the HLA antigens are not severely anti-

the same time destroying the recipient’s specific immu-

genic, for which reason a precise match of some

nity for disease, the story will change overnight.

antigens between donor and recipient is not always

essential to allow allograft acceptance. Therefore, by

obtaining the best possible match between donor and

References

recipient, the grafting procedure has become far less

hazardous. The best success has been with tissue-type

Alayash AI: Oxygen therapeutics: can we tame haemoglo-

matches between siblings and between parent and

bin? Nat Rev Drug Discov 3:152, 2004.

child. The match in identical twins is exact, so that

Altomonte M, Fonsatti E, Visintin A, Maio M: Targeted

transplants between identical twins are almost never

therapy of solid malignancies via HLA class II antigens: a

new biotherapeutic approach? Oncogene 22:6564, 2003.

rejected because of immune reactions.

Avent ND, Reid ME: The Rh blood group system: a review.

Blood 95:375, 2000.

Prevention of Graft Rejection by Suppressing

Bowman J: Thirty-five years of Rh prophylaxis. Transfusion

the Immune System

43:1661, 2003.

If the immune system were completely suppressed,

Goodnough LT, Shander A: Evolution in alternatives to

graft rejection would not occur. In fact, in an occa-

blood transfusion. Hematol J 4:87, 2003.

sional person who has serious depression of the

Gottstein R, Cooke RW: Systematic review of intravenous

immune system, grafts can be successful without the

immunoglobulin in haemolytic disease of the newborn.

use of significant therapy to prevent rejection. But in

Arch Dis Child Fetal Neonatal Ed 88:F6, 2003.

the normal person, even with the best possible tissue

Heeger PS: T-cell allorecognition and transplant rejection: a

summary and update. Am J Transplant 3:525, 2003.

typing, allografts seldom resist rejection for more than

Horn KD: The classification, recognition and significance

a few days or weeks without use of specific therapy to

of polyagglutination in transfusion medicine. Blood Rev

suppress the immune system. Furthermore, because

13:36, 1999.

the T cells are mainly the portion of the immune

Miller J, Mathew JM, Esquenazi V: Toward tolerance to

system important for killing grafted cells, their sup-

human organ transplants: a few additional corollaries and

pression is much more important than suppression of

questions. Transplantation 77:940, 2004.

plasma antibodies. Some of the therapeutic agents that

Ricordi C, Strom TB: Clinical islet transplantation: advances

have been used for this purpose include the following:

and immunological challenges. Nat Rev Immunol 4:259,

1. Glucocorticoid hormones isolated from adrenal

2004.

cortex glands (or drugs with glucocorticoid-like

Schroeder RA, Marroquin CE, Kuo PC: Tolerance and

the “Holy Grail” of transplantation. J Surg Res 111:109,

activity), which suppress the growth of all

2003.

lymphoid tissue and, therefore, decrease

Schulak JA: Steroid immunosuppression in kidney trans-

formation of antibodies and T cells.

plantation: a passing era. J Surg Res 117:154, 2004.

2. Various drugs that have a toxic effect on the

Spahn DR, Pasch T: Physiological properties of blood sub-

lymphoid system and, therefore, block formation

stitutes. News Physiol Sci 16:38, 2001.

of antibodies and T cells, especially the drug

Strober S, Lowsky RJ, Shizuru JA, et al: Approaches to trans-

azathioprine.

plantation tolerance in humans. Transplantation 77:932,

3. Cyclosporine, which has a specific inhibitory effect

2004.

on the formation of helper T cells and, therefore,

Sumpter TL, Wilkes DS: Role of autoimmunity in organ allo-

is especially efficacious in blocking the T-cell

graft rejection: a focus on immunity to type V collagen

in the pathogenesis of lung transplant rejection. Am J

rejection reaction. This has proved to be one of

Physiol Lung Cell Mol Physiol 286:L1129, 2004.

the most valuable of all the drugs because it does

Telen MJ: Red blood cell surface adhesion molecules: their

not depress some other portions of the immune

possible roles in normal human physiology and disease.

system.

Semin Hematol 37:130, 2000.

Use of these agents often leaves the person unpro-

Trigg ME: Hematopoietic stem cells. Pediatrics

113(4

tected from infectious disease; therefore, sometimes

Suppl):1051, 2004.

bacterial and viral infections become rampant. In addi-

Triulzi DJ: Specialized transfusion support for solid organ

tion, the incidence of cancer is several times as great

transplantation. Curr Opin Hematol 9:527, 2002.

C H A P T E R

Hemostasis and Blood Coagulation

Events in Hemostasis

The term hemostasis means prevention of blood

loss. Whenever a vessel is severed or ruptured,

hemostasis is achieved by several mechanisms: (1)

vascular constriction, (2) formation of a platelet

plug, (3) formation of a blood clot as a result of

blood coagulation, and

(4) eventual growth of

fibrous tissue into the blood clot to close the hole in the vessel permanently.

Vascular Constriction

Immediately after a blood vessel has been cut or ruptured, the trauma to the

vessel wall itself causes the smooth muscle in the wall to contract; this instan-

taneously reduces the flow of blood from the ruptured vessel. The contraction

results from (1) local myogenic spasm, (2) local autacoid factors from the trau-

matized tissues and blood platelets, and (3) nervous reflexes. The nervous

reflexes are initiated by pain nerve impulses or other sensory impulses that orig-

inate from the traumatized vessel or nearby tissues. However, even more vaso-

constriction probably results from local myogenic contraction of the blood

vessels initiated by direct damage to the vascular wall. And, for the smaller

vessels, the platelets are responsible for much of the vasoconstriction by releas-

ing a vasoconstrictor substance, thromboxane A

The more severely a vessel is traumatized, the greater the degree of vascular

spasm. The spasm can last for many minutes or even hours, during which time

the processes of platelet plugging and blood coagulation can take place.

Formation of the Platelet Plug

If the cut in the blood vessel is very small—indeed, many very small vascular

holes do develop throughout the body each day—the cut is often sealed by a

platelet plug, rather than by a blood clot. To understand this, it is important that

we first discuss the nature of platelets themselves.

Physical and Chemical Characteristics of Platelets

Platelets (also called thrombocytes) are minute discs 1 to 4 micrometers in diam-

eter. They are formed in the bone marrow from megakaryocytes, which are

extremely large cells of the hematopoietic series in the marrow; the megakary-

ocytes fragment into the minute platelets either in the bone marrow or soon

after entering the blood, especially as they squeeze through capillaries. The

normal concentration of platelets in the blood is between 150,000 and 300,000

per microliter.

Platelets have many functional characteristics of whole cells, even though

they do not have nuclei and cannot reproduce. In their cytoplasm are such active

factors as (1) actin and myosin molecules, which are contractile proteins similar

to those found in muscle cells, and still another contractile protein, throm-

bosthenin, that can cause the platelets to contract; (2) residuals of both the

endoplasmic reticulum and the Golgi apparatus that synthesize various enzymes

and especially store large quantities of calcium ions; (3) mitochondria and

457

458

Unit VI Blood Cells, Immunity, and Blood Clotting

enzyme systems that are capable of forming adenosine

important for closing minute ruptures in very small

triphosphate

(ATP) and adenosine diphosphate

blood vessels that occur many thousands of times

(ADP);

(4)

enzyme systems that synthesize

daily. Indeed, multiple small holes through the

prostaglandins, which are local hormones that cause

endothelial cells themselves are often closed by

many vascular and other local tissue reactions; (5) an

platelets actually fusing with the endothelial cells to

important protein called fibrin-stabilizing factor, which

form additional endothelial cell membrane. A person

we discuss later in relation to blood coagulation; and

who has few blood platelets develops each day liter-

(6) a growth factor that causes vascular endothelial

ally thousands of small hemorrhagic areas under the

cells, vascular smooth muscle cells, and fibroblasts to

skin and throughout the internal tissues, but this does

multiply and grow, thus causing cellular growth that

not occur in the normal person.

eventually helps repair damaged vascular walls.

The cell membrane of the platelets is also important.

On its surface is a coat of glycoproteins that repulses

Blood Coagulation in the

adherence to normal endothelium and yet causes

Ruptured Vessel

adherence to injured areas of the vessel wall, especially

to injured endothelial cells and even more so to any

The third mechanism for hemostasis is formation of

exposed collagen from deep within the vessel wall. In

the blood clot. The clot begins to develop in 15 to 20

addition, the platelet membrane contains large

seconds if the trauma to the vascular wall has been

amounts of phospholipids that activate multiple stages

severe, and in 1 to 2 minutes if the trauma has been

in the blood-clotting process, as we discuss later.

minor. Activator substances from the traumatized vas-

Thus, the platelet is an active structure. It has a half-

cular wall, from platelets, and from blood proteins

life in the blood of 8 to 12 days, so that over several

adhering to the traumatized vascular wall initiate the

weeks its functional processes run out. Then it is

clotting process. The physical events of this process are

eliminated from the circulation mainly by the tissue

shown in Figure 36-1, and Table 36-1 lists the most

macrophage system. More than one half of the

important of the clotting factors.

platelets are removed by macrophages in the spleen,

Within 3 to 6 minutes after rupture of a vessel, if the

where the blood passes through a latticework of tight

vessel opening is not too large, the entire opening or

trabeculae.

broken end of the vessel is filled with clot. After 20

minutes to an hour, the clot retracts; this closes the

Mechanism of the Platelet Plug

vessel still further. Platelets also play an important role

Platelet repair of vascular openings is based on several

in this clot retraction, as is discussed later.

important functions of the platelet itself. When

platelets come in contact with a damaged vascular

surface, especially with collagen fibers in the vascular

Fibrous Organization or Dissolution

wall, the platelets themselves immediately change

of the Blood Clot

their own characteristics drastically. They begin to

swell; they assume irregular forms with numerous irra-

Once a blood clot has formed, it can follow one of two

diating pseudopods protruding from their surfaces;

courses: (1) It can become invaded by fibroblasts,

their contractile proteins contract forcefully and cause

the release of granules that contain multiple active

factors; they become sticky so that they adhere to col-

lagen in the tissues and to a protein called von Wille-

brand factor that leaks into the traumatized tissue

from the plasma; they secrete large quantities of ADP;

1. Severed vessel

2. Platelets agglutinate

and their enzymes form thromboxane A

2. The ADP

and thromboxane in turn act on nearby platelets to

activate them as well, and the stickiness of these addi-

tional platelets causes them to adhere to the original

activated platelets.

Therefore, at the site of any opening in a blood

vessel wall, the damaged vascular wall activates suc-

3. Fibrin appears

4. Fibrin clot forms

cessively increasing numbers of platelets that them-

selves attract more and more additional platelets, thus

forming a platelet plug. This is at first a loose plug, but

it is usually successful in blocking blood loss if the vas-

cular opening is small. Then, during the subsequent

process of blood coagulation, fibrin threads form.

5. Clot retraction occurs

These attach tightly to the platelets, thus constructing

an unyielding plug.

Figure 36-1

Clotting process in a traumatized blood vessel. (Modified from

Importance of the Platelet Mechanism for Closing Vascular

Seegers WH: Hemostatic Agents, 1948. Courtesy of Charles C

Holes. The platelet-plugging mechanism is extremely

Thomas, Publisher, Ltd., Springfield, IL.)

Chapter 36

Hemostasis and Blood Coagulation

459

Table 36-1

Prothrombin

Clotting Factors in Blood and Their Synonyms

Prothrombin

Ca⁺⁺

Clotting Factor

Synonyms

activator

Fibrinogen

Factor I

Thrombin

Prothrombin

Factor II

Tissue factor

Factor III; tissue thromboplastin

Calcium

Factor IV

Factor V

Proaccelerin; labile factor; Ac-globulin

Fibrinogen

Fibrinogen monomer

(Ac-G)

Ca⁺⁺

Factor VII

Serum prothrombin conversion

accelerator (SPCA); proconvertin;

Fibrin fibers

stable factor

Factor VIII

Antihemophilic factor (AHF);

Thrombin activated

antihemophilic globulin (AHG);

fibrin-stabilizing

antihemophilic factor A

factor

Factor IX

Plasma thromboplastin component

(PTC); Christmas factor;

Cross-linked fibrin fibers

antihemophilic factor B

Factor X

Stuart factor; Stuart-Prower factor

Factor XI

Plasma thromboplastin antecedent

(PTA); antihemophilic factor C

Figure 36-2

Factor XII

Hageman factor

Factor XIII

Fibrin-stabilizing factor

Schema for conversion of prothrombin to thrombin and polymer-

Prekallikrein

Fletcher factor

ization of fibrinogen to form fibrin fibers.

High-molecular-weight

Fitzgerald factor; HMWK

kininogen

(high-molecular-weight) kininogen

Platelets

three essential steps: (1) In response to rupture of the

vessel or damage to the blood itself, a complex cascade

of chemical reactions occurs in the blood involving

which subsequently form connective tissue all through

more than a dozen blood coagulation factors. The net

the clot, or (2) it can dissolve. The usual course for a

result is formation of a complex of activated sub-

clot that forms in a small hole of a vessel wall is inva-

stances collectively called prothrombin activator. (2)

sion by fibroblasts, beginning within a few hours after

The prothrombin activator catalyzes conversion of

the clot is formed (which is promoted at least partially

prothrombin into thrombin. (3) The thrombin acts as

by growth factor secreted by platelets). This continues

an enzyme to convert fibrinogen into fibrin fibers that

to complete organization of the clot into fibrous tissue

enmesh platelets, blood cells, and plasma to form the

within about 1 to 2 weeks.

clot.

Conversely, when excess blood has leaked into the

Let us discuss first the mechanism by which the

tissues and tissue clots have occurred where they are

blood clot itself is formed, beginning with conversion

not needed, special substances within the clot itself

of prothrombin to thrombin; then we will come back

usually become activated. These function as enzymes

to the initiating stages in the clotting process by which

to dissolve the clot, as discussed later in the chapter.

prothrombin activator is formed.

Mechanism of Blood

Conversion of Prothrombin

Coagulation

to Thrombin

Basic Theory. More than 50 important substances that

First, prothrombin activator is formed as a result of

cause or affect blood coagulation have been found in

rupture of a blood vessel or as a result of damage

the blood and in the tissues—some that promote coag-

to special substances in the blood. Second, the pro-

ulation, called procoagulants, and others that inhibit

thrombin activator, in the presence of sufficient

coagulation, called anticoagulants. Whether blood will

amounts of ionic Ca⁺⁺, causes conversion of pro-

coagulate depends on the balance between these two

thrombin to thrombin (Figure 36-2). Third, the throm-

groups of substances. In the blood stream, the anti-

bin causes polymerization of fibrinogen molecules into

coagulants normally predominate, so that the blood

fibrin fibers within another 10 to 15 seconds. Thus, the

does not coagulate while it is circulating in the blood

rate-limiting factor in causing blood coagulation is

vessels. But when a vessel is ruptured, procoagulants

usually the formation of prothrombin activator and

from the area of tissue damage become “activated”

not the subsequent reactions beyond that point,

and override the anticoagulants, and then a clot does

because these terminal steps normally occur rapidly to

develop.

form the clot itself.

Platelets also play an important role in the con-

General Mechanism. All research workers in the field of

version of prothrombin to thrombin because much

blood coagulation agree that clotting takes place in

of the prothrombin first attaches to prothrombin

460

Unit VI Blood Cells, Immunity, and Blood Clotting

receptors on the platelets already bound to the

This involves a substance called fibrin-stabilizing

damaged tissue.

factor that is present in small amounts in normal

plasma globulins but is also released from platelets

Prothrombin and Thrombin. Prothrombin is a plasma

entrapped in the clot. Before fibrin-stabilizing factor

protein, an alpha2-globulin, having a molecular weight

can have an effect on the fibrin fibers, it must itself be

of 68,700. It is present in normal plasma in a concen-

activated. The same thrombin that causes fibrin for-

tration of about 15 mg/dl. It is an unstable protein that

mation also activates the fibrin-stabilizing factor.

can split easily into smaller compounds, one of which

Then this activated substance operates as an enzyme

is thrombin, which has a molecular weight of 33,700,

to cause covalent bonds between more and more of the

almost exactly one half that of prothrombin.

fibrin monomer molecules, as well as multiple cross-

Prothrombin is formed continually by the liver, and

linkages between adjacent fibrin fibers, thus adding

it is continually being used throughout the body for

tremendously to the three-dimensional strength of the

blood clotting. If the liver fails to produce prothrom-

fibrin meshwork.

bin, in a day or so prothrombin concentration in

the plasma falls too low to provide normal blood

Blood Clot. The clot is composed of a meshwork of

coagulation.

fibrin fibers running in all directions and entrapping

Vitamin K is required by the liver for normal for-

blood cells, platelets, and plasma. The fibrin fibers also

mation of prothrombin as well as for formation of a

adhere to damaged surfaces of blood vessels; there-

few other clotting factors. Therefore, either lack of

fore, the blood clot becomes adherent to any vascular

vitamin K or the presence of liver disease that pre-

opening and thereby prevents further blood loss.

vents normal prothrombin formation can decrease the

prothrombin level so low that a bleeding tendency

Clot Retraction—Serum. Within a few minutes after a

results.

clot is formed, it begins to contract and usually

expresses most of the fluid from the clot within 20 to

60 minutes. The fluid expressed is called serum because

Conversion of Fibrinogen to Fibrin—

all its fibrinogen and most of the other clotting factors

Formation of the Clot

have been removed; in this way, serum differs from

plasma. Serum cannot clot because it lacks these

Fibrinogen. Fibrinogen is a high-molecular-weight

factors.

protein (MW = 340,000) that occurs in the plasma in

Platelets are necessary for clot retraction to occur.

quantities of 100 to 700 mg/dl. Fibrinogen is formed in

Therefore, failure of clot retraction is an indication

the liver, and liver disease can decrease the concen-

that the number of platelets in the circulating blood

tration of circulating fibrinogen, as it does the concen-

might be low. Electron micrographs of platelets in

tration of prothrombin, pointed out above.

blood clots show that they become attached to the

Because of its large molecular size, little fibrinogen

fibrin fibers in such a way that they actually bond

normally leaks from the blood vessels into the inter-

different fibers together. Furthermore, platelets

stitial fluids, and because fibrinogen is one of the essen-

entrapped in the clot continue to release procoagulant

tial factors in the coagulation process, interstitial fluids

substances, one of the most important of which is

ordinarily do not coagulate. Yet, when the permeabil-

fibrin-stabilizing factor, which causes more and more

ity of the capillaries becomes pathologically increased,

cross-linking bonds between adjacent fibrin fibers. In

fibrinogen does then leak into the tissue fluids in suf-

addition, the platelets themselves contribute directly

ficient quantities to allow clotting of these fluids in

to clot contraction by activating platelet throm-

much the same way that plasma and whole blood can

bosthenin, actin, and myosin molecules, which are all

clot.

contractile proteins in the platelets and cause strong

contraction of the platelet spicules attached to the

Action of Thrombin on Fibrinogen to Form Fibrin. Thrombin

fibrin. This also helps compress the fibrin meshwork

is a protein enzyme with weak proteolytic capabilities.

into a smaller mass. The contraction is activated and

It acts on fibrinogen to remove four low-molecular-

accelerated by thrombin as well as by calcium ions

weight peptides from each molecule of fibrinogen,

released from calcium stores in the mitochondria,

forming one molecule of fibrin monomer that has the

endoplasmic reticulum, and Golgi apparatus of the

automatic capability to polymerize with other fibrin

platelets.

monomer molecules to form fibrin fibers. Therefore,

As the clot retracts, the edges of the broken blood

many fibrin monomer molecules polymerize within

vessel are pulled together, thus contributing still

seconds into long fibrin fibers that constitute the retic-

further to the ultimate state of hemostasis.

ulum of the blood clot.

In the early stages of polymerization, the fibrin

monomer molecules are held together by weak non-

Vicious Circle of Clot Formation

covalent hydrogen bonding, and the newly forming

fibers are not cross-linked with one another; therefore,

Once a blood clot has started to develop, it normally

the resultant clot is weak and can be broken apart with

extends within minutes into the surrounding blood.

ease. But another process occurs during the next few

That is, the clot itself initiates a vicious circle (positive

minutes that greatly strengthens the fibrin reticulum.

feedback) to promote more clotting. One of the most

Chapter 36

Hemostasis and Blood Coagulation

461

important causes of this is the fact that the proteolytic

Prothrombin activator is generally considered to be

action of thrombin allows it to act on many of the

formed in two ways, although, in reality, the two ways

other blood-clotting factors in addition to fibrinogen.

interact constantly with each other: (1) by the extrin-

For instance, thrombin has a direct proteolytic effect

sic pathway that begins with trauma to the vascular

on prothrombin itself, tending to convert this into still

wall and surrounding tissues and (2) by the intrinsic

more thrombin, and it acts on some of the blood-clot-

pathway that begins in the blood itself.

ting factors responsible for formation of prothrombin

In both the extrinsic and the intrinsic pathways, a

activator. (These effects, discussed in subsequent para-

series of different plasma proteins called blood-

graphs, include acceleration of the actions of Factors

clotting factors play major roles. Most of these are inac-

VIII, IX, X, XI, and XII and aggregation of platelets.)

tive forms of proteolytic enzymes. When converted to

Once a critical amount of thrombin is formed, a vicious

the active forms, their enzymatic actions cause the suc-

circle develops that causes still more blood clotting

cessive, cascading reactions of the clotting process.

and more and more thrombin to be formed; thus,

Most of the clotting factors, which are listed in Table

the blood clot continues to grow until blood leakage

36-1, are designated by Roman numerals. To indicate

ceases.

the activated form of the factor, a small letter “a” is

added after the Roman numeral, such as Factor VIIIa

to indicate the activated state of Factor VIII.

Initiation of Coagulation: Formation

of Prothrombin Activator

Extrinsic Pathway for Initiating Clotting

The extrinsic pathway for initiating the formation of

Now that we have discussed the clotting process itself,

prothrombin activator begins with a traumatized vas-

we must turn to the more complex mechanisms that

cular wall or traumatized extravascular tissues that

initiate clotting in the first place. These mechanisms

come in contact with the blood. This leads to the fol-

are set into play by (1) trauma to the vascular wall and

lowing steps, as shown in Figure 36-3:

adjacent tissues, (2) trauma to the blood, or (3) contact

1. Release of tissue factor. Traumatized tissue

of the blood with damaged endothelial cells or with

releases a complex of several factors called tissue

collagen and other tissue elements outside the blood

factor or tissue thromboplastin. This factor is

vessel. In each instance, this leads to the formation of

composed especially of phospholipids from the

prothrombin activator, which then causes prothrombin

membranes of the tissue plus a lipoprotein

conversion to thrombin and all the subsequent clotting

complex that functions mainly as a proteolytic

steps.

enzyme.

(1)

Tissue trauma

Tissue factor

(2)

Vll

VIIa

Activated X (Xa)

Ca⁺⁺

Prothrombin

(3)

Activator

Platelet

phospholipids

Prothrombin

Thrombin

Ca⁺⁺

Figure 36-3

Extrinsic pathway for initiating blood clotting.

462

Unit VI Blood Cells, Immunity, and Blood Clotting

2. Activation of Factor X—role of Factor VII and

accelerator of prothrombin activation. Thus, in the

tissue factor. The lipoprotein complex of tissue

final prothrombin activator complex, activated

factor further complexes with blood coagulation

Factor X is the actual protease that causes

Factor VII and, in the presence of calcium ions,

splitting of prothrombin to form thrombin;

acts enzymatically on Factor X to form activated

activated Factor V greatly accelerates this

Factor X (Xa).

protease activity, and platelet phospholipids act as

3. Effect of activated Factor X (Xa) to form

a vehicle that further accelerates the process. Note

prothrombin activator—role of Factor V. The

especially the positive feedback effect of thrombin,

activated Factor X combines immediately with

acting through Factor V, to accelerate the entire

tissue phospholipids that are part of tissue factor

process once it begins.

or with additional phospholipids released from

platelets as well as with Factor V to form the

Intrinsic Pathway for Initiating Clotting

complex called prothrombin activator. Within a

The second mechanism for initiating formation of pro-

few seconds, in the presence of calcium ions

thrombin activator, and therefore for initiating clot-

(Ca⁺⁺), this splits prothrombin to form thrombin,

ting, begins with trauma to the blood itself or exposure

and the clotting process proceeds as already

of the blood to collagen from a traumatized blood

explained. At first, the Factor V in the

vessel wall. Then the process continues through the

prothrombin activator complex is inactive, but

series of cascading reactions shown in Figure 36-4.

once clotting begins and thrombin begins to form,

1. Blood trauma causes (1) activation of Factor XII

the proteolytic action of thrombin activates Factor

and (2) release of platelet phospholipids. Trauma

V. This then becomes an additional strong

to the blood or exposure of the blood to vascular

Blood trauma or

contact with collagen

(1)

XII

Activated XII (XIIa)

(HMW kininogen, prekallikrein)

(2)

Activated XI (XIa)

Ca⁺⁺

(3)

Activated IX (IXa)

VIII

Thrombin

VIIIa

Ca⁺⁺

(4)

Activated X (Xa)

Platelet

(5)

phospholipids

Thrombin

Ca⁺⁺

Prothrombin

Activator

Platelet

phospholipids

Prothrombin

Thrombin

Ca⁺⁺

Figure 36-4

Intrinsic pathway

for

initiating

blood clotting.

Chapter 36

Hemostasis and Blood Coagulation

463

wall collagen alters two important clotting factors

Interaction Between the Extrinsic

in the blood: Factor XII and the platelets. When

and Intrinsic Pathways—Summary

Factor XII is disturbed, such as by coming into

of Blood-Clotting Initiation

contact with collagen or with a wettable surface

It is clear from the schemas of the intrinsic and extrin-

such as glass, it takes on a new molecular

sic systems that after blood vessels rupture, clotting

configuration that converts it into a proteolytic

occurs by both pathways simultaneously. Tissue factor

enzyme called “activated Factor XII.”

initiates the extrinsic pathway, whereas contact of

Simultaneously, the blood trauma also damages

Factor XII and platelets with collagen in the vascular

the platelets because of adherence to either

wall initiates the intrinsic pathway.

collagen or a wettable surface (or by damage

An especially important difference between the

in other ways), and this releases platelet

extrinsic and intrinsic pathways is that the extrinsic

phospholipids that contain the lipoprotein called

pathway can be explosive; once initiated, its speed of

platelet factor 3, which also plays a role in

completion to the final clot is limited only by the

subsequent clotting reactions.

amount of tissue factor released from the traumatized

Activation of Factor XI. The activated Factor XII

tissues and by the quantities of Factors X, VII, and V

acts enzymatically on Factor XI to activate this

in the blood. With severe tissue trauma, clotting can

factor as well, which is the second step in the

occur in as little as 15 seconds. The intrinsic pathway

intrinsic pathway. This reaction also requires

is much slower to proceed, usually requiring 1 to 6

HMW (high-molecular-weight) kininogen and is

minutes to cause clotting.

accelerated by prekallikrein.

Activation of Factor IX by activated Factor XI.

Prevention of Blood Clotting

The activated Factor XI then acts enzymatically

on Factor IX to activate this factor also.

in the Normal Vascular System—

Activation of Factor X—role of Factor VIII.

Intravascular Anticoagulants

The activated Factor IX, acting in concert with

activated Factor VIII and with the platelet

Endothelial Surface Factors. Probably the most important

phospholipids and factor 3 from the traumatized

factors for preventing clotting in the normal vascular

platelets, activates Factor X. It is clear that when

system are (1) the smoothness of the endothelial cell

either Factor VIII or platelets are in short supply,

surface, which prevents contact activation of the intrin-

this step is deficient. Factor VIII is the factor that

sic clotting system; (2) a layer of glycocalyx on the

is missing in a person who has classic hemophilia,

endothelium

(glycocalyx is a mucopolysaccharide

for which reason it is called antihemophilic factor.

adsorbed to the surfaces of the endothelial cells),

Platelets are the clotting factor that is lacking in

which repels clotting factors and platelets, thereby pre-

the bleeding disease called thrombocytopenia.

venting activation of clotting; and (3) a protein bound

Action of activated Factor X to form prothrombin

with the endothelial membrane, thrombomodulin,

activator—role of Factor V. This step in the

which binds thrombin. Not only does the binding of

intrinsic pathway is the same as the last step in

thrombin with thrombomodulin slow the clotting

the extrinsic pathway. That is, activated Factor X

process by removing thrombin, but the thrombomod-

combines with Factor V and platelet or tissue

ulin-thrombin complex also activates a plasma protein,

phospholipids to form the complex called

protein C, that acts as an anticoagulant by inactivating

prothrombin activator. The prothrombin activator

activated Factors V and VIII.

in turn initiates within seconds the cleavage of

When the endothelial wall is damaged, its smooth-

prothrombin to form thrombin, thereby setting

ness and its glycocalyx-thrombomodulin layer are lost,

into motion the final clotting process, as described

which activates both Factor XII and the platelets,

earlier.

thus setting off the intrinsic pathway of clotting. If

Factor XII and platelets come in contact with the

Role of Calcium Ions in the Intrinsic and

subendothelial collagen, the activation is even more

Extrinsic Pathways

powerful.

Except for the first two steps in the intrinsic pathway,

calcium ions are required for promotion or accelera-

Antithrombin Action of Fibrin and Antithrombin III. Among

tion of all the blood-clotting reactions. Therefore, in

the most important anticoagulants in the blood itself

the absence of calcium ions, blood clotting by either

are those that remove thrombin from the blood. The

pathway does not occur.

most powerful of these are (1) the fibrin fibers that

In the living body, the calcium ion concentration

themselves are formed during the process of clotting

seldom falls low enough to significantly affect the

and (2) an alpha-globulin called antithrombin III or

kinetics of blood clotting. But, when blood is removed

antithrombin-heparin cofactor.

from a person, it can be prevented from clotting by

While a clot is forming, about 85 to 90 per cent of

reducing the calcium ion concentration below the

the thrombin formed from the prothrombin becomes

threshold level for clotting, either by deionizing the

adsorbed to the fibrin fibers as they develop. This helps

calcium by causing it to react with substances such as

prevent the spread of thrombin into the remaining

citrate ion or by precipitating the calcium with sub-

blood and, therefore, prevents excessive spread of the

stances such as oxalate ion.

clot.

464

Unit VI Blood Cells, Immunity, and Blood Clotting

The thrombin that does not adsorb to the fibrin

is trapped in the clot along with other plasma proteins.

fibers soon combines with antithrombin III, which

This will not become plasmin or cause lysis of the clot

further blocks the effect of the thrombin on the fi-

until it is activated. The injured tissues and vascular

brinogen and then also inactivates the thrombin itself

endothelium very slowly release a powerful activator

during the next 12 to 20 minutes.

called tissue plasminogen activator (t-PA) that a few

days later, after the clot has stopped the bleeding,

Heparin. Heparin is another powerful anticoagulant,

eventually converts plasminogen to plasmin, which in

but its concentration in the blood is normally low, so

turn removes the remaining unnecessary blood clot. In

that only under special physiologic conditions does

fact, many small blood vessels in which blood flow has

it have significant anticoagulant effects. However,

been blocked by clots are reopened by this mecha-

heparin is used widely as a pharmacological agent in

nism. Thus, an especially important function of the

medical practice in much higher concentrations to

plasmin system is to remove minute clots from millions

prevent intravascular clotting.

of tiny peripheral vessels that eventually would

The heparin molecule is a highly negatively charged

become occluded were there no way to clear them.

conjugated polysaccharide. By itself, it has little or no

anticoagulant properties, but when it combines with

antithrombin III, the effectiveness of antithrombin III

Conditions That Cause

for removing thrombin increases by a hundredfold to

Excessive Bleeding in

a thousandfold, and thus it acts as an anticoagulant.

Therefore, in the presence of excess heparin, removal

Human Beings

of free thrombin from the circulating blood by

antithrombin III is almost instantaneous.

Excessive bleeding can result from deficiency of any

The complex of heparin and antithrombin III

one of the many blood-clotting factors. Three particu-

removes several other activated coagulation factors in

lar types of bleeding tendencies that have been studied

addition to thrombin, further enhancing the effective-

to the greatest extent are discussed here: bleeding

ness of anticoagulation. The others include activated

caused by (1) vitamin K deficiency, (2) hemophilia, and

Factors XII, XI, X, and IX.

(3) thrombocytopenia (platelet deficiency).

Heparin is produced by many different cells of the

body, but especially large quantities are formed by the

basophilic mast cells located in the pericapillary con-

Decreased Prothrombin, Factor VII,

nective tissue throughout the body. These cells contin-

Factor IX, and Factor X Caused

ually secrete small quantities of heparin that diffuse

by Vitamin K Deficiency

into the circulatory system. The basophil cells of the

blood, which are functionally almost identical to the

With few exceptions, almost all the blood-clotting

mast cells, release small quantities of heparin into

factors are formed by the liver. Therefore, diseases of

the plasma.

the liver such as hepatitis, cirrhosis, and acute yellow

Mast cells are abundant in tissue surrounding the

atrophy can sometimes depress the clotting system so

capillaries of the lungs and to a lesser extent capillar-

greatly that the patient develops a severe tendency to

ies of the liver. It is easy to understand why large quan-

bleed.

tities of heparin might be needed in these areas

Another cause of depressed formation of clotting

because the capillaries of the lungs and liver receive

factors by the liver is vitamin K deficiency. Vitamin K

many embolic clots formed in slowly flowing venous

is necessary for liver formation of five of the impor-

blood; sufficient formation of heparin prevents further

tant clotting factors: prothrombin, Factor VII, Factor

growth of the clots.

IX, Factor X, and protein C. In the absence of vitamin

K, subsequent insufficiency of these coagulation

factors in the blood can lead to serious bleeding ten-

Lysis of Blood Clots—Plasmin

dencies.

Vitamin K is continually synthesized in the intes-

The plasma proteins contain a euglobulin called

tinal tract by bacteria, so that vitamin K deficiency

plasminogen (or profibrinolysin) that, when activated,

seldom occurs in the normal person as a result of

becomes a substance called plasmin (or fibrinolysin).

vitamin K absence from the diet (except in neonates

Plasmin is a proteolytic enzyme that resembles trypsin,

before they establish their intestinal bacterial flora).

the most important proteolytic digestive enzyme of

However, in gastrointestinal disease, vitamin K defi-

pancreatic secretion. Plasmin digests fibrin fibers and

ciency often occurs as a result of poor absorption of

some other protein coagulants such as fibrinogen,

fats from the gastrointestinal tract. The reason is that

Factor V, Factor VIII, prothrombin, and Factor XII.

vitamin K is fat-soluble and ordinarily is absorbed into

Therefore, whenever plasmin is formed, it can cause

the blood along with the fats.

lysis of a clot by destroying many of the clotting

One of the most prevalent causes of vitamin K defi-

factors, thereby sometimes even causing hypocoagula-

ciency is failure of the liver to secrete bile into the gas-

bility of the blood.

trointestinal tract (which occurs either as a result of

Activation of Plasminogen to Form Plasmin: Then Lysis of Clots.

obstruction of the bile ducts or as a result of liver

When a clot is formed, a large amount of plasminogen

disease). Lack of bile prevents adequate fat digestion

Chapter 36

Hemostasis and Blood Coagulation

465

and absorption and, therefore, depresses vitamin K

with thrombocytopenia have a tendency to bleed, as

absorption as well. Thus, liver disease often causes

do hemophiliacs, except that the bleeding is usually

decreased production of prothrombin and some other

from many small venules or capillaries, rather than

clotting factors both because of poor vitamin K

from larger vessels as in hemophilia. As a result, small

absorption and because of the diseased liver cells.

punctate hemorrhages occur throughout all the body

Because of this, vitamin K is injected into all surgical

tissues. The skin of such a person displays many small,

patients with liver disease or with obstructed bile ducts

purplish blotches, giving the disease the name throm-

before performing the surgical procedure. Ordinarily,

bocytopenic purpura. As stated earlier, platelets are

if vitamin K is given to a deficient patient 4 to 8 hours

especially important for repair of minute breaks in

before the operation and the liver parenchymal cells

capillaries and other small vessels.

are at least one-half normal in function, sufficient

Ordinarily, bleeding will not occur until the number

clotting factors will be produced to prevent excessive

of platelets in the blood falls below 50,000/ml, rather

bleeding during the operation.

than the normal 150,000 to 300,000. Levels as low as

10,000/ml are frequently lethal.

Even without making specific platelet counts in the

Hemophilia

blood, sometimes one can suspect the existence of

thrombocytopenia if the person’s blood fails to retract,

Hemophilia is a bleeding disease that occurs almost

because, as pointed out earlier, clot retraction is nor-

exclusively in males. In 85 per cent of cases, it is caused

mally dependent on release of multiple coagulation

by an abnormality or deficiency of Factor VIII; this

factors from the large numbers of platelets entrapped

type of hemophilia is called hemophilia A or classic

in the fibrin mesh of the clot.

hemophilia. About 1 of every 10,000 males in the

Most people with thrombocytopenia have the

United States has classic hemophilia. In the other 15

disease known as idiopathic thrombocytopenia, which

per cent of hemophilia patients, the bleeding tendency

means thrombocytopenia of unknown cause. In most

is caused by deficiency of Factor IX. Both of these

of these people, it has been discovered that for

factors are transmitted genetically by way of the

unknown reasons, specific antibodies have formed and

female chromosome. Therefore, almost never will a

react against the platelets themselves to destroy them.

woman have hemophilia because at least one of her

Relief from bleeding for 1 to 4 days can often be

two X chromosomes will have the appropriate genes.

effected in a patient with thrombocytopenia by

If one of her X chromosomes is deficient, she will be

giving fresh whole blood transfusions that contain

a hemophilia carrier, transmitting the disease to half of

large numbers of platelets. Also, splenectomy is often

her male offspring and transmitting the carrier state to

helpful, sometimes effecting almost complete cure

half of her female offspring.

because the spleen normally removes large numbers

The bleeding trait in hemophilia can have various

of platelets from the blood.

degrees of severity, depending on the character of the

genetic deficiency. Bleeding usually does not occur

except after trauma, but in some patients, the degree

of trauma required to cause severe and prolonged

Thromboembolic Conditions

bleeding may be so mild that it is hardly noticeable.

in the Human Being

For instance, bleeding can often last for days after

extraction of a tooth.

Thrombi and Emboli. An abnormal clot that develops in

Factor VIII has two active components, a large com-

a blood vessel is called a thrombus. Once a clot has

ponent with a molecular weight in the millions and a

developed, continued flow of blood past the clot is

smaller component with a molecular weight of about

likely to break it away from its attachment and cause

230,000. The smaller component is most important in

the clot to flow with the blood; such freely flowing clots

the intrinsic pathway for clotting, and it is deficiency

are known as emboli. Also, emboli that originate in

of this part of Factor VIII that causes classic hemo-

large arteries or in the left side of the heart can flow

philia. Another bleeding disease with somewhat dif-

peripherally and plug arteries or arterioles in the

ferent characteristics, called von Willebrand’s disease,

brain, kidneys, or elsewhere. Emboli that originate in

results from loss of the large component.

the venous system or in the right side of the heart gen-

When a person with classic hemophilia experiences

erally flow into the lungs to cause pulmonary arterial

severe prolonged bleeding, almost the only therapy

embolism.

that is truly effective is injection of purified Factor

VIII. The cost of Factor VIII is high, and its availabil-

ity is limited because it can be gathered only from

Cause of Thromboembolic Conditions. The causes of throm-

human blood and only in extremely small quantities.

boembolic conditions in the human being are usually

twofold: (1) Any roughened endothelial surface of a

vessel—as may be caused by arteriosclerosis, infection,

Thrombocytopenia

or trauma—is likely to initiate the clotting process. (2)

Blood often clots when it flows very slowly through

Thrombocytopenia means the presence of very low

blood vessels, where small quantities of thrombin and

numbers of platelets in the circulating blood. People

other procoagulants are always being formed.

466

Unit VI Blood Cells, Immunity, and Blood Clotting

Use of t-PA in Treating Intravascular Clots. Genetically

clotting factors are removed by the widespread clot-

engineered t-PA

(tissue plasminogen activator) is

ting that too few procoagulants remain to allow

available. When delivered directly to a thrombosed

normal hemostasis of the remaining blood.

area through a catheter, it is effective in activating

plasminogen to plasmin, which in turn can dissolve

some intravascular clots. For instance, if used within

Anticoagulants for

the first hour or so after thrombotic occlusion of a

Clinical Use

coronary artery, the heart is often spared serious

damage.

In some thromboembolic conditions, it is desirable to

delay the coagulation process. Various anticoagulants

have been developed for this purpose. The ones most

Femoral Venous Thrombosis and

useful clinically are heparin and the coumarins.

Massive Pulmonary Embolism

Because clotting almost always occurs when blood

Heparin as an Intravenous

flow is blocked for many hours in any vessel of the

Anticoagulant

body, the immobility of patients confined to bed plus

the practice of propping the knees with pillows often

Commercial heparin is extracted from several differ-

causes intravascular clotting because of blood stasis in

ent animal tissues and prepared in almost pure form.

one or more of the leg veins for hours at a time. Then

Injection of relatively small quantities, about 0.5 to

the clot grows, mainly in the direction of the slowly

1 mg/kg of body weight, causes the blood-clotting time

moving venous blood, sometimes growing the entire

to increase from a normal of about 6 minutes to 30 or

length of the leg veins and occasionally even up into

more minutes. Furthermore, this change in clotting

the common iliac vein and inferior vena cava. Then,

time occurs instantaneously, thereby immediately pre-

about 1 time out of every 10, a large part of the clot

venting or slowing further development of a throm-

disengages from its attachments to the vessel wall and

boembolic condition.

flows freely with the venous blood through the right

The action of heparin lasts about 1.5 to 4 hours. The

side of the heart and into the pulmonary arteries to

injected heparin is destroyed by an enzyme in the

cause massive blockage of the pulmonary arteries,

blood known as heparinase.

called massive pulmonary embolism. If the clot is large

enough to occlude both of the pulmonary arteries at

the same time, immediate death ensues. If only one

Coumarins as Anticoagulants

pulmonary artery is blocked, death may not occur, or

the embolism may lead to death a few hours to several

When a coumarin, such as warfarin, is given to a

days later because of further growth of the clot within

patient, the plasma levels of prothrombin and Factors

the pulmonary vessels. But, again, t-PA therapy can be

VII, IX, and X, all formed by the liver, begin to fall,

a lifesaver.

indicating that warfarin has a potent depressant effect

on liver formation of these compounds. Warfarin

causes this effect by competing with vitamin K for

Disseminated Intravascular

reactive sites in the enzymatic processes for formation

Coagulation

of prothrombin and the other three clotting factors,

thereby blocking the action of vitamin K.

Occasionally the clotting mechanism becomes acti-

After administration of an effective dose of war-

vated in widespread areas of the circulation, giving rise

farin, the coagulant activity of the blood decreases to

to the condition called disseminated intravascular

about 50 per cent of normal by the end of 12 hours and

coagulation. This often results from the presence of

to about 20 per cent of normal by the end of 24 hours.

large amounts of traumatized or dying tissue in the

In other words, the coagulation process is not blocked

body that releases great quantities of tissue factor into

immediately but must await the natural consumption

the blood. Frequently, the clots are small but numer-

of the prothrombin and the other affected coagulation

ous, and they plug a large share of the small periph-

factors already present in the plasma. Normal coagu-

eral blood vessels. This occurs especially in patients

lation usually returns 1 to 3 days after discontinuing

with widespread septicemia, in which either circulat-

coumarin therapy.

ing bacteria or bacterial toxins—especially endotox-

ins—activate the clotting mechanisms. Plugging of

small peripheral vessels greatly diminishes delivery of

Prevention of Blood Coagulation

oxygen and other nutrients to the tissues—a situation

Outside the Body

that leads to or exacerbates circulatory shock. It is

partly for this reason that septicemic shock is lethal in

Although blood removed from the body and held in a

85 per cent or more of patients.

glass test tube normally clots in about 6 minutes, blood

A peculiar effect of disseminated intravascular

collected in siliconized containers often does not clot

coagulation is that the patient on occasion begins

for 1 hour or more. The reason for this delay is that

to bleed. The reason for this is that so many of the

preparing the surfaces of the containers with silicone

Chapter 36

Hemostasis and Blood Coagulation

467

prevents contact activation of platelets and Factor XII,

collect blood in a chemically clean glass test tube and

the two principal factors that initiate the intrinsic clot-

then to tip the tube back and forth about every 30

ting mechanism. Conversely, untreated glass contain-

seconds until the blood has clotted. By this method,

ers allow contact activation of the platelets and Factor

the normal clotting time is 6 to 10 minutes. Procedures

XII, with rapid development of clots.

using multiple test tubes have also been devised for

Heparin can be used for preventing coagulation of

determining clotting time more accurately.

blood outside the body as well as in the body. Heparin

Unfortunately, the clotting time varies widely,

is especially used in surgical procedures in which the

depending on the method used for measuring it, so it

blood must be passed through a heart-lung machine

is no longer used in many clinics. Instead, measure-

or artificial kidney machine and then back into the

ments of the clotting factors themselves are made,

person.

using sophisticated chemical procedures.

Various substances that decrease the concentration

of calcium ions in the blood can also be used for pre-

venting blood coagulation outside the body. For

Prothrombin Time

instance, a soluble oxalate compound mixed in a very

small quantity with a sample of blood causes precipi-

Prothrombin time gives an indication of the concen-

tation of calcium oxalate from the plasma and thereby

tration of prothrombin in the blood. Figure 36-5 shows

decreases the ionic calcium level so much that blood

the relation of prothrombin concentration to pro-

coagulation is blocked.

thrombin time. The method for determining pro-

Any substance that deionizes the blood calcium will

thrombin time is the following.

prevent coagulation. The negatively charged citrate ion

Blood removed from the patient is immediately

is especially valuable for this purpose, mixed with

oxalated so that none of the prothrombin can change

blood usually in the form of sodium, ammonium, or

into thrombin. Then, a large excess of calcium ion and

potassium citrate. The citrate ion combines with

tissue factor is quickly mixed with the oxalated blood.

calcium in the blood to cause an un-ionized calcium

The excess calcium nullifies the effect of the oxalate,

compound, and the lack of ionic calcium prevents

and the tissue factor activates the prothrombin-to-

coagulation. Citrate anticoagulants have an important

thrombin reaction by means of the extrinsic clotting

advantage over the oxalate anticoagulants because

pathway. The time required for coagulation to take

oxalate is toxic to the body, whereas moderate quan-

place is known as the prothrombin time. The shortness

tities of citrate can be injected intravenously. After

of the time is determined mainly by prothrombin con-

injection, the citrate ion is removed from the blood

centration. The normal prothrombin time is about 12

within a few minutes by the liver and is polymerized

seconds. In each laboratory, a curve relating pro-

into glucose or metabolized directly for energy.

thrombin concentration to prothrombin time, such as

Consequently, 500 milliliters of blood that has been

rendered incoagulable by citrate can ordinarily be

transfused into a recipient within a few minutes

without dire consequences. But if the liver is damaged

or if large quantities of citrated blood or plasma are

100

given too rapidly (within fractions of a minute), the

citrate ion may not be removed quickly enough, and

the citrate can, under these conditions, greatly depress

the level of calcium ion in the blood, which can result

in tetany and convulsive death.

Blood Coagulation Tests

50.0

Bleeding Time

When a sharp-pointed knife is used to pierce the tip

25.0

of the finger or lobe of the ear, bleeding ordinarily lasts

for 1 to 6 minutes. The time depends largely on the

12.5

depth of the wound and the degree of hyperemia in

6.25

the finger or ear lobe at the time of the test. Lack of

any one of several of the clotting factors can prolong

the bleeding time, but it is especially prolonged by lack

Prothrombin time

(seconds)

of platelets.

Clotting Time

Figure 36-5

Many methods have been devised for determining

Relation of prothrombin concentration in the blood to “prothrom-

blood clotting times. The one most widely used is to

bin time.”

468

Unit VI Blood Cells, Immunity, and Blood Clotting

that shown in Figure 36-5, is drawn for the method

Levi M: Current understanding of disseminated intravascu-

used so that the prothrombin in the blood can be quan-

lar coagulation. Br J Haematol 124:567, 2004.

tified.

Lindsberg PJ, Kaste M: Thrombolysis for acute stroke. Curr

Opin Neurol 16:73, 2003.

Tests similar to that for prothrombin time have been

Moake JL: Thrombotic microangiopathies. N Engl J Med

devised to determine the quantities of other blood

347:589, 2002.

clotting factors. In each of these tests, excesses of

Roberts HR, Monroe DM, Escobar MA: Current concepts

calcium ions and all the other factors besides the one

of hemostasis: implications for therapy. Anesthesiology

being tested are added to oxalated blood all at once.

100:722, 2004.

Then the time required for coagulation is determined

Saenko EL, Ananyeva NM, Shima M, et al: The future of

in the same manner as for prothrombin time. If the

recombinant coagulation factors. J Thromb Haemost

factor being tested is deficient, the coagulation time is

1:922, 2003.

prolonged. The time itself can then be used to quanti-

Solum NO: Procoagulant expression in platelets and defects

tate the concentration of the factor.

leading to clinical disorders. Arterioscler Thromb Vasc

Biol 19:2841, 1999.

Toh CH, Dennis M: Disseminated intravascular coagulation:

old disease, new hope. BMJ 327:974, 2003.

References

Tsai HM: Advances in the pathogenesis, diagnosis, and treat-

ment of thrombotic thrombocytopenic purpura. J Am Soc

Brass LF: Thrombin and platelet activation. Chest 124(3

Nephrol 14:1072, 2003.

Suppl):18S, 2003.

Tsai HM: Platelet activation and the formation of the

Caprini JA, Glase CJ, Anderson CB, Hathaway K: Labora-

platelet plug: deficiency of ADAMTS13 causes thrombotic

tory markers in the diagnosis of venous thromboem-

thrombocytopenic purpura. Arterioscler Thromb Vasc

bolism. Circulation 109(12 Suppl 1):I4, 2004.

Biol 23:388, 2003.

Dorsam RT, Kunapuli SP: Central role of the P2Y12 recep-

VandenDriessche T, Collen D, Chuah MK: Gene therapy for

tor in platelet activation. J Clin Invest 113:340, 2004.

the hemophilias. J Thromb Haemost 1:1550, 2003.

Fisher M, Brott TG: Emerging therapies for acute ischemic

Vesely SK, Perdue JJ, Rizvi MA, et al: Management of adult

stroke: new therapies on trial. Stroke 34:359, 2003.

patients with persistent idiopathic thrombocytopenic

Geddis AE, Kaushansky K: Inherited thrombocytopenias:

purpura following splenectomy: a systematic review. Ann

toward a molecular understanding of disorders of platelet

Intern Med 140:112, 2004.

production. Curr Opin Pediatr 16:15, 2004.

White RH, Ginsberg JS: Low-molecular-weight heparins: are

Kahn SR, Ginsberg JS: Relationship between deep venous

they all the same? Br J Haematol 121:12, 2003.

thrombosis and the postthrombotic syndrome. Arch

Intern Med 164:17, 2004.

Koreth R, Weinert C, Weisdorf DJ, Key NS: Measurement of

bleeding severity: a critical review. Transfusion 44:605,

2004.

C H A P T E R

Pulmonary Ventilation

The goals of respiration are to provide oxygen to

the tissues and to remove carbon dioxide. To

achieve these goals, respiration can be divided into

four major functions: (1) pulmonary ventilation,

which means the inflow and outflow of air between

the atmosphere and the lung alveoli; (2) diffusion

of oxygen and carbon dioxide between the alveoli

and the blood; (3) transport of oxygen and carbon

dioxide in the blood and body fluids to and from the body’s tissue cells; and

(4) regulation of ventilation and other facets of respiration. This chapter is a

discussion of pulmonary ventilation, and the subsequent five chapters

cover other respiratory functions plus the physiology of special respiratory

abnormalities.

Mechanics of Pulmonary Ventilation

Muscles That Cause Lung Expansion and Contraction

The lungs can be expanded and contracted in two ways: (1) by downward and

upward movement of the diaphragm to lengthen or shorten the chest cavity,

and (2) by elevation and depression of the ribs to increase and decrease the

anteroposterior diameter of the chest cavity. Figure 37-1 shows these two

methods.

Normal quiet breathing is accomplished almost entirely by the first method,

that is, by movement of the diaphragm. During inspiration, contraction of the

diaphragm pulls the lower surfaces of the lungs downward. Then, during expi-

ration, the diaphragm simply relaxes, and the elastic recoil of the lungs, chest

wall, and abdominal structures compresses the lungs and expels the air. During

heavy breathing, however, the elastic forces are not powerful enough to cause

the necessary rapid expiration, so that extra force is achieved mainly by con-

traction of the abdominal muscles, which pushes the abdominal contents

upward against the bottom of the diaphragm, thereby compressing the lungs.

The second method for expanding the lungs is to raise the rib cage. This

expands the lungs because, in the natural resting position, the ribs slant down-

ward, as shown on the left side of Figure 37-1, thus allowing the sternum to fall

backward toward the vertebral column. But when the rib cage is elevated, the

ribs project almost directly forward, so that the sternum also moves forward,

away from the spine, making the anteroposterior thickness of the chest about

20 per cent greater during maximum inspiration than during expiration. There-

fore, all the muscles that elevate the chest cage are classified as muscles of inspi-

ration, and those muscles that depress the chest cage are classified as muscles

of expiration. The most important muscles that raise the rib cage are the exter-

nal intercostals, but others that help are the (1) sternocleidomastoid muscles,

which lift upward on the sternum; (2) anterior serrati, which lift many of the

ribs; and (3) scaleni, which lift the first two ribs.

The muscles that pull the rib cage downward during expiration are mainly

the (1) abdominal recti, which have the powerful effect of pulling downward on

the lower ribs at the same time that they and other abdominal muscles also com-

press the abdominal contents upward against the diaphragm, and (2) internal

intercostals.

471

472

Unit VII

Respiration

Increased

vertical diameter

Increased

Elevated

Lung volume

A-P diameter

rib cage

0.50

External

intercostals

contracted

0.25

Internal

intercostals

relaxed

Diaphragmatic

Abdominals

contraction

Alveolar pressure

contracted

EXPIRATION

INSPIRATION

Figure 37-1

-2

Contraction and expansion of the thoracic cage during expiration

Transpulmonary pressure

and inspiration, demonstrating diaphragmatic contraction, func-

tion of the intercostal muscles, and elevation and depression of

-4

the rib cage.

-6

Figure 37-1 also shows the mechanism by which the

Pleural pressure

-8

external and internal intercostals act to cause inspira-

tion and expiration. To the left, the ribs during

Inspiration

Expiration

expiration are angled downward, and the external

intercostals are elongated forward and downward. As

they contract, they pull the upper ribs forward in rela-

tion to the lower ribs, and this causes leverage on the

ribs to raise them upward, thereby causing inspiration.

Figure 37-2

The internal intercostals function exactly in the oppo-

Changes in lung volume, alveolar pressure, pleural pressure, and

site manner, functioning as expiratory muscles because

transpulmonary pressure during normal breathing.

they angle between the ribs in the opposite direction

and cause opposite leverage.

is about -5 centimeters of water, which is the amount

Movement of Air In and Out of the

of suction required to hold the lungs open to their

Lungs and the Pressures

resting level. Then, during normal inspiration, expan-

That Cause the Movement

sion of the chest cage pulls outward on the lungs with

greater force and creates more negative pressure, to an

The lung is an elastic structure that collapses like a

average of about -7.5 centimeters of water.

balloon and expels all its air through the trachea when-

These relationships between pleural pressure and

ever there is no force to keep it inflated. Also, there

changing lung volume are demonstrated in Figure

are no attachments between the lung and the walls of

37-2, showing in the lower panel the increasing nega-

the chest cage, except where it is suspended at its hilum

tivity of the pleural pressure from -5 to -7.5 during

from the mediastinum. Instead, the lung “floats” in the

inspiration and in the upper panel an increase in lung

thoracic cavity, surrounded by a thin layer of pleural

volume of 0.5 liter. Then, during expiration, the events

fluid that lubricates movement of the lungs within the

are essentially reversed.

cavity. Further, continual suction of excess fluid into

lymphatic channels maintains a slight suction between

Alveolar Pressure

the visceral surface of the lung pleura and the parietal

Alveolar pressure is the pressure of the air inside the

pleural surface of the thoracic cavity. Therefore, the

lung alveoli. When the glottis is open and no air is

lungs are held to the thoracic wall as if glued there,

flowing into or out of the lungs, the pressures in all

except that they are well lubricated and can slide

parts of the respiratory tree, all the way to the alveoli,

freely as the chest expands and contracts.

are equal to atmospheric pressure, which is considered

to be zero reference pressure in the airways—that is,

Pleural Pressure and Its Changes

0 centimeters water pressure. To cause inward flow of

During Respiration

air into the alveoli during inspiration, the pressure in

Pleural pressure is the pressure of the fluid in the thin

the alveoli must fall to a value slightly below atmos-

space between the lung pleura and the chest wall

pheric pressure (below 0). The second curve (labeled

pleura. As noted earlier, this is normally a slight

“alveolar pressure”) of Figure 37-2 demonstrates that

suction, which means a slightly negative pressure. The

during normal inspiration, alveolar pressure decreases

normal pleural pressure at the beginning of inspiration

to about -1 centimeter of water. This slight negative

Chapter 37

Pulmonary Ventilation

473

pressure is enough to pull 0.5 liter of air into the lungs

between successive steps. The two curves are called,

in the 2 seconds required for normal quiet inspiration.

respectively, the inspiratory compliance curve and the

During expiration, opposite pressures occur: The

expiratory compliance curve, and the entire diagram is

alveolar pressure rises to about +1 centimeter of water,

called the compliance diagram of the lungs.

and this forces the 0.5 liter of inspired air out of the

The characteristics of the compliance diagram are

lungs during the 2 to 3 seconds of expiration.

determined by the elastic forces of the lungs. These can

be divided into two parts: (1) elastic forces of the lung

Transpulmonary Pressure. Finally, note in Figure 37-2 the

tissue itself and (2) elastic forces caused by surface

difference between the alveolar pressure and the

tension of the fluid that lines the inside walls of the

pleural pressure. This is called the transpulmonary

alveoli and other lung air spaces.

pressure. It is the pressure difference between that in

The elastic forces of the lung tissue are determined

the alveoli and that on the outer surfaces of the lungs,

mainly by elastin and collagen fibers interwoven

and it is a measure of the elastic forces in the lungs

among the lung parenchyma. In deflated lungs, these

that tend to collapse the lungs at each instant of res-

fibers are in an elastically contracted and kinked state;

piration, called the recoil pressure.

then, when the lungs expand, the fibers become

stretched and unkinked, thereby elongating and exert-

Compliance of the Lungs

ing even more elastic force.

The extent to which the lungs will expand for each unit

The elastic forces caused by surface tension are

increase in transpulmonary pressure (if enough time is

much more complex. The significance of surface

allowed to reach equilibrium) is called the lung com-

tension is shown in Figure 37-4, which compares the

pliance. The total compliance of both lungs together in

compliance diagram of the lungs when filled with

the normal adult human being averages about 200 mil-

saline solution and when filled with air. When the lungs

liliters of air per centimeter of water transpulmonary

are filled with air, there is an interface between the

pressure. That is, every time the transpulmonary pres-

alveolar fluid and the air in the alveoli. In the case of

sure increases 1 centimeter of water, the lung volume,

the saline solution-filled lungs, there is no air-fluid

after 10 to 20 seconds, will expand 200 milliliters.

interface; therefore, the surface tension effect is not

present—only tissue elastic forces are operative in the

Compliance Diagram of the Lungs. Figure 37-3 is a diagram

saline solution-filled lung.

relating lung volume changes to changes in transpul-

Note that transpleural pressures required to expand

monary pressure. Note that the relation is different for

air-filled lungs are about three times as great as those

inspiration and expiration. Each curve is recorded by

required to expand saline solution-filled lungs. Thus,

changing the transpulmonary pressure in small steps

one can conclude that the tissue elastic forces tending

and allowing the lung volume to come to a steady level

to cause collapse of the air-filled lung represent only

about one third of the total lung elasticity, whereas the

Saline-filled

Air-filled

0.50

Expiration

0.25

Inspiration

-2

-4

-6

-8

-4

-5

-6

Pleural pressure (cm H₂O)

Figure 37-4

Figure 37-3

Comparison of the compliance diagrams of saline-filled and air-

Compliance diagram in a healthy person. This diagram shows

filled lungs when the alveolar pressure is maintained at atmos-

compliance of the lungs alone.

pheric pressure (0 cm H₂O) and pleural pressure is changed.

474

Unit VII

Respiration

fluid-air surface tension forces in the alveoli represent

Surface tension

Pressure

about two thirds.

Radius of alveolus

The fluid-air surface tension elastic forces of the

For the average-sized alveolus with a radius of about

lungs also increase tremendously when the substance

100 micrometers and lined with normal surfactant, this

called surfactant is not present in the alveolar fluid. Let

calculates to be about 4 centimeters of water pressure

us now discuss surfactant and its relation to the surface

(3 mm Hg). If the alveoli were lined with pure water

tension forces.

without any surfactant, the pressure would calculate to

be about 18 centimeters of water pressure, 4.5 times as

Surfactant, Surface Tension, and Collapse

great. Thus, one sees how important surfactant is in

of the Alveoli

reducing alveolar surface tension and therefore also

reducing the effort required by the respiratory muscles

to expand the lungs.

Principle of Surface Tension. When water forms a surface

with air, the water molecules on the surface of the

Effect of Alveolar Radius on the Pressure Caused by Surface

water have an especially strong attraction for one

Tension. Note from the preceding formula that the pres-

another. As a result, the water surface is always

sure generated as a result of surface tension in the

attempting to contract. This is what holds raindrops

alveoli is inversely affected by the radius of the alveo-

together: that is, there is a tight contractile membrane

lus, which means that the smaller the alveolus, the

of water molecules around the entire surface of the

greater the alveolar pressure caused by the surface

raindrop. Now let us reverse these principles and see

tension. Thus, when the alveoli have half the normal

what happens on the inner surfaces of the alveoli.

radius (50 instead of 100 micrometers), the pressures

noted earlier are doubled. This is especially significant

Here, the water surface is also attempting to contract.

in small premature babies, many of whom have alveoli

This results in an attempt to force the air out of the

with radii less than one quarter that of an adult person.

alveoli through the bronchi and, in doing so, causes the

Further, surfactant does not normally begin to be

alveoli to try to collapse. The net effect is to cause an

secreted into the alveoli until between the sixth and

elastic contractile force of the entire lungs, which is

seventh months of gestation, and in some cases, even

called the surface tension elastic force.

later than that. Therefore, many premature babies have

little or no surfactant in the alveoli when they are born,

and their lungs have an extreme tendency to collapse,

Surfactant and Its Effect on Surface Tension. Surfactant is a

sometimes as great as six to eight times that in a normal

surface active agent in water, which means that it

adult person. This causes the condition called respira-

greatly reduces the surface tension of water. It is

tory distress syndrome of the newborn. It is fatal if

secreted by special surfactant-secreting epithelial cells

not treated with strong measures, especially properly

called type II alveolar epithelial cells, which constitute

applied continuous positive pressure breathing.

about 10 per cent of the surface area of the alveoli.

These cells are granular, containing lipid inclusions

that are secreted in the surfactant into the alveoli.

Effect of the Thoracic Cage

Surfactant is a complex mixture of several

on Lung Expansibility

phospholipids, proteins, and ions. The most important

components are the phospholipid dipalmitoylphos-

Thus far, we have discussed the expansibility of the

phatidylcholine, surfactant apoproteins, and calcium

lungs alone, without considering the thoracic cage. The

ions. The dipalmitoylphosphatidylcholine, along with

thoracic cage has its own elastic and viscous charac-

several less important phospholipids, is responsible

teristics, similar to those of the lungs; even if the lungs

for reducing the surface tension. It does this by not

were not present in the thorax, muscular effort would

dissolving uniformly in the fluid lining the alveolar

still be required to expand the thoracic cage.

surface. Instead, part of the molecule dissolves,

while the remainder spreads over the surface of the

Compliance of the Thorax and the

water in the alveoli. This surface has from one

Lungs Together

twelfth to one half the surface tension of a pure water

The compliance of the entire pulmonary system (the

surface.

lungs and thoracic cage together) is measured while

In quantitative terms, the surface tension of differ-

expanding the lungs of a totally relaxed or paralyzed

ent water fluids is approximately the following: pure

person. To do this, air is forced into the lungs a little at

water, 72 dynes/cm; normal fluids lining the alveoli but

a time while recording lung pressures and volumes. To

without surfactant, 50 dynes/cm; normal fluids lining

inflate this total pulmonary system, almost twice as

the alveoli and with normal amounts of surfactant

much pressure is needed as to inflate the same lungs

included, between 5 and 30 dynes/cm.

after removal from the chest cage. Therefore, the com-

pliance of the combined lung-thorax system is almost

Pressure in Occluded Alveoli Caused by Surface Tension. If the

exactly one half that of the lungs alone—110 milliliters

air passages leading from the alveoli of the lungs are

blocked, the surface tension in the alveoli tends to col-

of volume per centimeter of water pressure for

lapse the alveoli. This creates positive pressure in the

the combined system, compared with 200 ml/cm for

alveoli, attempting to push the air out. The amount of

the lungs alone. Furthermore, when the lungs are

pressure generated in this way in an alveolus can be cal-

expanded to high volumes or compressed to low

culated from the following formula:

volumes, the limitations of the chest become extreme;

Chapter 37

Pulmonary Ventilation

475

when near these limits, the compliance of the com-

bined lung-thorax system can be less than one fifth

that of the lungs alone.

“Work” of Breathing

Floating

drum

We have already pointed out that during normal quiet

breathing, all respiratory muscle contraction occurs

Oxygen

Recording

chamber

drum

during inspiration; expiration is almost entirely a

passive process caused by elastic recoil of the lungs and

chest cage. Thus, under resting conditions, the respira-

Water

Mouthpiece

tory muscles normally perform “work” to cause inspi-

Counterbalancing

ration but not to cause expiration.

weight

The work of inspiration can be divided into three

fractions: (1) that required to expand the lungs against

the lung and chest elastic forces, called compliance work

or elastic work; (2) that required to overcome the vis-

cosity of the lung and chest wall structures, called tissue

Figure 37-5

resistance work; and (3) that required to overcome

airway resistance to movement of air into the lungs,

Spirometer.

called airway resistance work.

Energy Required for Respiration. During normal quiet respi-

The tidal volume is the volume of air inspired or

ration, only 3 to 5 per cent of the total energy expended

expired with each normal breath; it amounts to

by the body is required for pulmonary ventilation. But

during heavy exercise, the amount of energy required

about 500 milliliters in the adult male.

can increase as much as 50-fold, especially if the person

The inspiratory reserve volume is the extra volume

has any degree of increased airway resistance or de-

of air that can be inspired over and above the

creased pulmonary compliance. Therefore, one of the

normal tidal volume when the person inspires

major limitations on the intensity of exercise that can

with full force; it is usually equal to about

be performed is the person’s ability to provide enough

3000 milliliters.

muscle energy for the respiratory process alone.

The expiratory reserve volume is the maximum

extra volume of air that can be expired by

forceful expiration after the end of a normal

Pulmonary Volumes

tidal expiration; this normally amounts to about

and Capacities

1100 milliliters.

The residual volume is the volume of air

Recording Changes in Pulmonary

remaining in the lungs after the most forceful

Volume—Spirometry

expiration; this volume averages about

1200 milliliters.

A simple method for studying pulmonary ventilation

is to record the volume movement of air into and out

Pulmonary Capacities

of the lungs, a process called spirometry. A typical

In describing events in the pulmonary cycle, it is

basic spirometer is shown in Figure 37-5. It consists of

sometimes desirable to consider two or more of the

a drum inverted over a chamber of water, with the

volumes together. Such combinations are called pul-

drum counterbalanced by a weight. In the drum is a

monary capacities. To the right in Figure 37-6 are listed

breathing gas, usually air or oxygen; a tube connects

the important pulmonary capacities, which can be

the mouth with the gas chamber. When one breathes

described as follows:

into and out of the chamber, the drum rises and falls,

1. The inspiratory capacity equals the tidal volume

and an appropriate recording is made on a moving

plus the inspiratory reserve volume. This is the

sheet of paper.

amount of air (about 3500 milliliters) a person can

Figure 37-6 shows a spirogram indicating changes in

breathe in, beginning at the normal expiratory

lung volume under different conditions of breathing.

level and distending the lungs to the maximum

For ease in describing the events of pulmonary venti-

amount.

lation, the air in the lungs has been subdivided in this

2. The functional residual capacity equals the

diagram into four volumes and four capacities, which

expiratory reserve volume plus the residual

are the average for a young adult man.

volume. This is the amount of air that remains in

the lungs at the end of normal expiration (about

Pulmonary Volumes

2300 milliliters).

To the left in Figure 37-6 are listed four pulmonary

3. The vital capacity equals the inspiratory reserve

lung volumes that, when added together, equal the

volume plus the tidal volume plus the expiratory

maximum volume to which the lungs can be expanded.

reserve volume. This is the maximum amount of

The significance of each of these volumes is the

air a person can expel from the lungs after first

following:

filling the lungs to their maximum extent and then

476

Unit VII Respiration

6000

Inspiration

5000

Inspiratory

Vital

Total lung

reserve

capacity

4000

volume

Tidal

3000

volume

2000

Expiratory

Functional

reserve volume

residual

capacity

1000

Residual

Expiration

volume

Figure 37-6

Time

Diagram showing respiratory excursions during

normal breathing and during maximal inspiration

and maximal expiration.

expiring to the maximum extent (about

Determination of Functional

4600 milliliters).

Residual Capacity, Residual

4. The total lung capacity is the maximum volume to

Volume, and Total Lung Capacity—

which the lungs can be expanded with the greatest

Helium Dilution Method

possible effort (about 5800 milliliters); it is equal

to the vital capacity plus the residual volume.

The functional residual capacity (FRC), which is the

All pulmonary volumes and capacities are about 20

volume of air that remains in the lungs at the end of

each normal expiration, is important to lung function.

to 25 per cent less in women than in men, and they are

Because its value changes markedly in some types of

greater in large and athletic people than in small and

pulmonary disease, it is often desirable to measure this

asthenic people.

capacity. The spirometer cannot be used in a direct way

to measure the functional residual capacity, because the

air in the residual volume of the lungs cannot be expired

Abbreviations and Symbols Used

into the spirometer, and this volume constitutes about

in Pulmonary Function Studies

one half of the functional residual capacity. To measure

functional residual capacity, the spirometer must be

Spirometry is only one of many measurement proce-

used in an indirect manner, usually by means of a

dures that the pulmonary physician uses daily. Many of

helium dilution method, as follows.

these measurement procedures depend heavily on

A spirometer of known volume is filled with air mixed

mathematical computations. To simplify these calcula-

with helium at a known concentration. Before breath-

tions as well as the presentation of pulmonary function

ing from the spirometer, the person expires normally. At

data, a number of abbreviations and symbols have

the end of this expiration, the remaining volume in the

become standardized. The more important of these are

lungs is equal to the functional residual capacity. At this

given in Table 37-1. Using these symbols, we present

point, the subject immediately begins to breathe from

here a few simple algebraic exercises showing some of

the spirometer, and the gases of the spirometer mix with

the interrelations among the pulmonary volumes and

the gases of the lungs. As a result, the helium becomes

capacities; the student should think through and verify

diluted by the functional residual capacity gases, and the

these interrelations.

volume of the functional residual capacity can be cal-

VC = IRV + V_T + ERV

culated from the degree of dilution of the helium, using

VC = IC + ERV

the following formula:

TLC = VC + RV

ÊCi

TLC = IC + FRC

FRC

-1

Spir

FRC = ERV + RV

Cf_He

Chapter 37

Pulmonary Ventilation

477

Table 37-1

Abbreviations and Symbols for Pulmonary Function

V_T

tidal volume

P_B

atmospheric pressure

FRC

functional residual capacity

Palv

alveolar pressure

ERV

expiratory reserve volume

Ppl

pleural pressure

residual volume

P^O2

partial pressure of oxygen

inspiratory capacity

PCO₂

partial pressure of carbon dioxide

IRV

inspiratory reserve volume

PN₂

partial pressure of nitrogen

TLC

total lung capacity

PaO₂

partial pressure of oxygen in arterial blood

vital capacity

PaCO₂

partial pressure of carbon dioxide in arterial blood

Raw

resistance of the airways to flow of air into

PAO₂

partial pressure of oxygen in alveolar gas

the lung

compliance

PACO₂

partial pressure of carbon dioxide in alveolar gas

V_D

volume of dead space gas

PAH₂O

partial pressure of water in alveolar gas

V_A

volume of alveolar gas

respiratory exchange ratio

VI.

inspired volume of ventilation per minute

cardiac output

expired volume of ventilation per minute

shunt flow

VA.

alveolar ventilation per minute

CaO₂

concentration of oxygen in arterial blood

rate of oxygen uptake per minute

¯o₂

concentration of oxygen in mixed venous blood

co2

amount of carbon dioxide eliminated per

SO₂

percentage saturation of hemoglobin with oxygen

minute

Vco

rate of carbon monoxide uptake per minute

SaO₂

percentage saturation of hemoglobin with oxygen

in arterial blood

Dlo₂

diffusing capacity of the lungs for oxygen

Dl_CO

diffusing capacity of the lungs for carbon

monoxide

where FRC is functional residual capacity, Ci_He is initial

greater than 200 L/min, or more than 30 times normal.

concentration of helium in the spirometer, Cf_He is final

Most people cannot sustain more than one half to two

concentration of helium in the spirometer, and Vi_Spir is

thirds these values for longer than 1 minute.

initial volume of the spirometer.

Once the FRC has been determined, the residual

volume (RV) can be determined by subtracting expira-

Alveolar Ventilation

tory reserve volume (ERV), as measured by normal

spirometry, from the FRC. Also, the total lung capacity

(TLC) can be determined by adding the inspiratory

The ultimate importance of pulmonary ventilation is

capacity (IC) to the FRC. That is,

to continually renew the air in the gas exchange areas

of the lungs, where air is in proximity to the pulmonary

RV = FRC - ERV

blood. These areas include the alveoli, alveolar sacs,

and

alveolar ducts, and respiratory bronchioles. The rate at

which new air reaches these areas is called alveolar

TLC = FRC + IC

ventilation.

Minute Respiratory Volume

“Dead Space” and Its Effect

Equals Respiratory Rate

on Alveolar Ventilation

Times Tidal Volume

Some of the air a person breathes never reaches the

The minute respiratory volume is the total amount of

gas exchange areas but simply fills respiratory pas-

new air moved into the respiratory passages each

sages where gas exchange does not occur, such as the

minute; this is equal to the tidal volume times the res-

nose, pharynx, and trachea. This air is called dead space

piratory rate per minute. The normal tidal volume is

air because it is not useful for gas exchange.

about 500 milliliters, and the normal respiratory rate

On expiration, the air in the dead space is expired

is about 12 breaths per minute. Therefore, the minute

first, before any of the air from the alveoli reaches the

respiratory volume averages about 6 L/min. A person

atmosphere. Therefore, the dead space is very disad-

can live for a short period with a minute respiratory

vantageous for removing the expiratory gases from the

volume as low as 1.5 L/min and a respiratory rate of

lungs.

only 2 to 4 breaths per minute.

The respiratory rate occasionally rises to 40 to 50

Measurement of the Dead Space Volume. A simple method

per minute, and the tidal volume can become as great

for measuring dead space volume is demonstrated by

as the vital capacity, about 4600 milliliters in a young

the graph in Figure 37-7. In making this measurement,

adult man. This can give a minute respiratory volume

the subject suddenly takes a deep breath of oxygen. This

478

Unit VII

Respiration

Anatomic Versus Physiologic Dead Space. The method just

described for measuring the dead space measures the

volume of all the space of the respiratory system other

than the alveoli and their other closely related gas

exchange areas; this space is called the anatomic dead

concentration

space. On occasion, some of the alveoli themselves are

nonfunctional or only partially functional because of

absent or poor blood flow through the adjacent pul-

monary capillaries. Therefore, from a functional point of

view, these alveoli must also be considered dead space.

When the alveolar dead space is included in the total

measurement of dead space, this is called the physio-

logic dead space, in contradistinction to the anatomic

dead space. In a normal person, the anatomic and phys-

iologic dead spaces are nearly equal because all alveoli

are functional in the normal lung, but in a person with

100

200

300

400

500

partially functional or nonfunctional alveoli in some

Air expired (ml)

parts of the lungs, the physiologic dead space may be as

much as 10 times the volume of the anatomic dead

space, or 1 to 2 liters. These problems are discussed

further in Chapter 39 in relation to pulmonary gaseous

exchange and in Chapter 42 in relation to certain pul-

Figure 37-7

monary diseases.

Record of the changes in nitrogen concentration in the expired air

after a single previous inspiration of pure oxygen. This record can

be used to calculate dead space, as discussed in the text.

Rate of Alveolar Ventilation

Alveolar ventilation per minute is the total volume of

new air entering the alveoli and adjacent gas exchange

fills the entire dead space with pure oxygen. Some

areas each minute. It is equal to the respiratory rate

oxygen also mixes with the alveolar air but does not

times the amount of new air that enters these areas

completely replace this air. Then the person expires

with each breath.

through a rapidly recording nitrogen meter, which

makes the record shown in the figure. The first portion

A = Freq • (VT - VD)

of the expired air comes from the dead space regions of

whereV_A is the volume of alveolar ventilation per

the respiratory passageways, where the air has been

minute, Freq is the frequency of respiration per

completely replaced by oxygen. Therefore, in the early

minute, V_T is the tidal volume, and V_D is the physio-

part of the record, only oxygen appears, and the nitro-

logic dead space volume.

gen concentration is zero. Then, when alveolar air

begins to reach the nitrogen meter, the nitrogen con-

Thus, with a normal tidal volume of 500 milliliters, a

centration rises rapidly, because alveolar air containing

normal dead space of 150 milliliters, and a respiratory

large amounts of nitrogen begins to mix with the dead

rate of 12 breaths per minute, alveolar ventilation

space air. After still more air has been expired, all the

equals 12

¥ (500 - 150), or 4200 ml/min.

dead space air has been washed from the passages, and

Alveolar ventilation is one of the major factors

only alveolar air remains. Therefore, the recorded nitro-

determining the concentrations of oxygen and carbon

gen concentration reaches a plateau level equal to its

dioxide in the alveoli. Therefore, almost all discussions

concentration in the alveoli, as shown to the right in the

of gaseous exchange in the following chapters on the

figure. With a little thought, the student can see that the

respiratory system emphasize alveolar ventilation.

gray area represents the air that has no nitrogen in it;

this area is a measure of the volume of dead space air.

For exact quantification, the following equation is used:

Functions of the Respiratory

Gray area ¥ V

Passageways

Pink area+Gray area

Trachea, Bronchi, and Bronchioles

where V_D is dead space air and V_E is the total volume

of expired air.

Figure 37-8 shows the respiratory system, demonstrat-

Let us assume, for instance, that the gray area on the

ing especially the respiratory passageways. The air is dis-

graph is 30 square centimeters, the pink area is 70

tributed to the lungs by way of the trachea, bronchi, and

square centimeters, and the total volume expired is 500

bronchioles.

milliliters. The dead space would be

One of the most important problems in all the respi-

ratory passageways is to keep them open and allow easy

500, or

150

passage of air to and from the alveoli. To keep the

30+

trachea from collapsing, multiple cartilage rings extend

about five sixths of the way around the trachea. In the

Normal Dead Space Volume. The normal dead space air in

walls of the bronchi, less extensive curved cartilage

a young adult man is about 150 milliliters. This increases

plates also maintain a reasonable amount of rigidity yet

slightly with age.

allow sufficient motion for the lungs to expand and

Chapter 37

Pulmonary Ventilation

479

Conchae

CO₂

O₂

Alveolus

Epiglottis

O₂

Glottis

Pharynx

CO₂

Larynx, vocal

Esophagus

cords

Pulmonary

Trachea

capillary

Pulmonary arteries

Pulmonary veins

Alveoli

Figure 37-8

Respiratory passages.

contract. These plates become progressively less exten-

are easily occluded by (1) muscle contraction in their

sive in the later generations of bronchi and are gone in

walls, (2) edema occurring in the walls, or (3) mucus col-

the bronchioles, which usually have diameters less than

lecting in the lumens of the bronchioles.

1.5 millimeters. The bronchioles are not prevented from

collapsing by the rigidity of their walls. Instead, they are

Nervous and Local Control of the Bronchiolar Musculature—

kept expanded mainly by the same transpulmonary

“Sympathetic” Dilation of the Bronchioles. Direct control of

pressures that expand the alveoli. That is, as the alveoli

the bronchioles by sympathetic nerve fibers is relatively

enlarge, the bronchioles also enlarge, but not as much.

weak because few of these fibers penetrate to the

central portions of the lung. However, the bronchial tree

Muscular Wall of the Bronchi and Bronchioles and Its Control. In

is very much exposed to norepinephrine and epineph-

all areas of the trachea and bronchi not occupied by car-

rine released into the blood by sympathetic stimulation

tilage plates, the walls are composed mainly of smooth

of the adrenal gland medullae. Both these hormones—

muscle. Also, the walls of the bronchioles are almost

especially epinephrine, because of its greater stimula-

entirely smooth muscle, with the exception of the most

tion of beta-adrenergic receptors—cause dilation of the

terminal bronchiole, called the respiratory bronchiole,

bronchial tree.

which is mainly pulmonary epithelium and underlying

fibrous tissue plus a few smooth muscle fibers. Many

Parasympathetic Constriction of the Bronchioles. A few

obstructive diseases of the lung result from narrowing

parasympathetic nerve fibers derived from the vagus

of the smaller bronchi and larger bronchioles, often

nerves penetrate the lung parenchyma. These nerves

because of excessive contraction of the smooth muscle

secrete acetylcholine and, when activated, cause mild

itself.

to moderate constriction of the bronchioles. When a

disease process such as asthma has already caused some

Resistance to Airflow in the Bronchial Tree. Under normal

bronchiolar constriction, superimposed parasympa-

respiratory conditions, air flows through the respiratory

thetic nervous stimulation often worsens the condition.

passageways so easily that less than 1 centimeter of

When this occurs, administration of drugs that block the

water pressure gradient from the alveoli to the atmos-

effects of acetylcholine, such as atropine, can sometimes

phere is sufficient to cause enough airflow for quiet

relax the respiratory passages enough to relieve the

breathing. The greatest amount of resistance to airflow

obstruction.

occurs not in the minute air passages of the terminal

Sometimes the parasympathetic nerves are also acti-

bronchioles but in some of the larger bronchioles and

vated by reflexes that originate in the lungs. Most of

bronchi near the trachea. The reason for this high resist-

these begin with irritation of the epithelial membrane

ance is that there are relatively few of these larger

of the respiratory passageways themselves, initiated by

bronchi in comparison with the approximately 65,000

noxious gases, dust, cigarette smoke, or bronchial infec-

parallel terminal bronchioles, through each of which

tion. Also, a bronchiolar constrictor reflex often occurs

only a minute amount of air must pass.

when microemboli occlude small pulmonary arteries.

Yet in disease conditions, the smaller bronchioles

often play a far greater role in determining airflow

Local Secretory Factors Often Cause Bronchiolar Constriction.

resistance because of their small size and because they

Several substances formed in the lungs themselves are

480

Unit VII

Respiration

often quite active in causing bronchiolar constriction.

invaginate inward, so that the exploding air actually

Two of the most important of these are histamine and

passes through bronchial and tracheal slits. The rapidly

slow reactive substance of anaphylaxis. Both of these are

moving air usually carries with it any foreign matter that

released in the lung tissues by mast cells during allergic

is present in the bronchi or trachea.

reactions, especially those caused by pollen in the air.

Therefore, they play key roles in causing the airway

Sneeze Reflex

obstruction that occurs in allergic asthma; this is espe-

The sneeze reflex is very much like the cough reflex,

cially true of the slow reactive substance of anaphylaxis.

except that it applies to the nasal passageways instead

The same irritants that cause parasympathetic con-

of the lower respiratory passages. The initiating stimu-

strictor reflexes of the airways—smoke, dust, sulfur

lus of the sneeze reflex is irritation in the nasal pas-

dioxide, and some of the acidic elements in smog—often

sageways; the afferent impulses pass in the fifth cranial

act directly on the lung tissues to initiate local, non-

nerve to the medulla, where the reflex is triggered. A

nervous reactions that cause obstructive constriction of

series of reactions similar to those for the cough reflex

the airways.

takes place; however, the uvula is depressed, so that

large amounts of air pass rapidly through the nose, thus

Mucus Lining the Respiratory Passageways, and Action of Cilia

helping to clear the nasal passages of foreign matter.

to Clear the Passageways

All the respiratory passages, from the nose to the ter-

minal bronchioles, are kept moist by a layer of mucus

Normal Respiratory Functions

that coats the entire surface. The mucus is secreted

of the Nose

partly by individual mucous goblet cells in the epithe-

lial lining of the passages and partly by small submu-

As air passes through the nose, three distinct normal

cosal glands. In addition to keeping the surfaces moist,

respiratory functions are performed by the nasal cavi-

the mucus traps small particles out of the inspired air

ties: (1) the air is warmed by the extensive surfaces of

and keeps most of these from ever reaching the alveoli.

the conchae and septum, a total area of about 160

The mucus itself is removed from the passages in the

square centimeters (see Figure 37-8); (2) the air is

following manner.

almost completely humidified even before it passes

The entire surface of the respiratory passages, both in

beyond the nose; and (3) the air is partially filtered.

the nose and in the lower passages down as far as the

These functions together are called the air conditioning

terminal bronchioles, is lined with ciliated epithelium,

function of the upper respiratory passageways. Ordi-

with about 200 cilia on each epithelial cell. These cilia

narily, the temperature of the inspired air rises to within

beat continually at a rate of 10 to 20 times per second

1°F of body temperature and to within 2 to 3 per cent

by the mechanism explained in Chapter 2, and the direc-

of full saturation with water vapor before it reaches the

tion of their

“power stroke” is always toward the

trachea. When a person breathes air through a tube

pharynx. That is, the cilia in the lungs beat upward,

directly into the trachea (as through a tracheostomy),

whereas those in the nose beat downward. This contin-

the cooling and especially the drying effect in the lower

ual beating causes the coat of mucus to flow slowly, at a

lung can lead to serious lung crusting and infection.

velocity of a few millimeters per minute, toward the

pharynx. Then the mucus and its entrapped particles are

Filtration Function of the Nose. The hairs at the entrance to

either swallowed or coughed to the exterior.

the nostrils are important for filtering out large par-

ticles. Much more important, though, is the removal

Cough Reflex

of particles by turbulent precipitation. That is, the air

The bronchi and trachea are so sensitive to light touch

passing through the nasal passageways hits many

that very slight amounts of foreign matter or other

obstructing vanes: the conchae (also called turbinates,

causes of irritation initiate the cough reflex. The larynx

because they cause turbulence of the air), the septum,

and carina (the point where the trachea divides into the

and the pharyngeal wall. Each time air hits one of these

bronchi) are especially sensitive, and the terminal bron-

obstructions, it must change its direction of movement.

chioles and even the alveoli are sensitive to corrosive

The particles suspended in the air, having far more mass

chemical stimuli such as sulfur dioxide gas or chlorine

and momentum than air, cannot change their direction

gas. Afferent nerve impulses pass from the respiratory

of travel as rapidly as the air can. Therefore, they con-

passages mainly through the vagus nerves to the

tinue forward, striking the surfaces of the obstructions,

medulla of the brain. There, an automatic sequence of

and are entrapped in the mucous coating and trans-

events is triggered by the neuronal circuits of the

ported by the cilia to the pharynx to be swallowed.

medulla, causing the following effect.

First, up to

2.5 liters of air are rapidly inspired.

Size of Particles Entrapped in the Respiratory Passages.

Second, the epiglottis closes, and the vocal cords shut

The nasal turbulence mechanism for removing particles

tightly to entrap the air within the lungs. Third, the

from air is so effective that almost no particles larger

abdominal muscles contract forcefully, pushing against

than 6 micrometers in diameter enter the lungs through

the diaphragm while other expiratory muscles, such as

the nose. This size is smaller than the size of red blood

the internal intercostals, also contract forcefully. Conse-

cells.

quently, the pressure in the lungs rises rapidly to as

Of the remaining particles, many that are between 1

much as 100 mm Hg or more. Fourth, the vocal cords

and 5 micrometers settle in the smaller bronchioles as a

and the epiglottis suddenly open widely, so that air

result of gravitational precipitation. For instance, termi-

under this high pressure in the lungs explodes outward.

nal bronchiolar disease is common in coal miners

Indeed, sometimes this air is expelled at velocities

because of settled dust particles. Some of the still

ranging from 75 to 100 miles per hour. Importantly, the

smaller particles (smaller than 1 micrometer in diame-

strong compression of the lungs collapses the bronchi

ter) diffuse against the walls of the alveoli and adhere

and trachea by causing their noncartilaginous parts to

to the alveolar fluid. But many particles smaller than 0.5

Chapter 37

Pulmonary Ventilation

481

Thyroid

cartilage

Thyroarytenoid

muscle

Vocal

ligament

Lateral

Full

Gentle

Intermediate position-

Figure 37-9

cricoarytenoid

abduction

loud whisper

muscle

A, Anatomy of the larynx.

B, Laryngeal function in phona-

tion, showing the positions of the

Arytenoid

vocal cords during different

cartilage

Posterior

types of phonation.

(Modified

cricoarytenoid

Stage

Phonation

Transverse

from Greene MC: The Voice and

muscle

whisper

arytenoid

Its Disorders,

4th ed. Philadel-

muscle

phia: JB Lippincott, 1980.)

micrometer in diameter remain suspended in the alve-

ligament is attached to the vocal processes of two ary-

olar air and are expelled by expiration. For instance, the

tenoid cartilages. The thyroid cartilage and the arytenoid

particles of cigarette smoke are about 0.3 micrometer.

cartilages articulate from below with another cartilage

Almost none of these particles are precipitated in the

not shown in Figure 37-9, the cricoid cartilage.

respiratory passageways before they reach the alveoli.

The vocal cords can be stretched by either forward

Unfortunately, up to one third of them do precipitate in

rotation of the thyroid cartilage or posterior rotation of

the alveoli by the diffusion process, with the balance

the arytenoid cartilages, activated by muscles stretching

remaining suspended and expelled in the expired air.

from the thyroid cartilage and arytenoid cartilages to

Many of the particles that become entrapped in

the cricoid cartilage. Muscles located within the vocal

the alveoli are removed by alveolar macrophages, as

cords lateral to the vocal ligaments, the thyroarytenoid

explained in Chapter 33, and others are carried away by

muscles, can pull the arytenoid cartilages toward the

the lung lymphatics. An excess of particles can cause

thyroid cartilage and, therefore, loosen the vocal cords.

growth of fibrous tissue in the alveolar septa, leading to

Also, slips of these muscles within the vocal cords can

permanent debility.

change the shapes and masses of the vocal cord edges,

sharpening them to emit high-pitched sounds and blunt-

ing them for the more bass sounds.

Vocalization

Finally, several other sets of small laryngeal muscles

lie between the arytenoid cartilages and the cricoid car-

Speech involves not only the respiratory system but

tilage and can rotate these cartilages inward or outward

also (1) specific speech nervous control centers in the

or pull their bases together or apart to give the various

cerebral cortex, which are discussed in Chapter 57; (2)

configurations of the vocal cords shown in Figure 37-9B.

respiratory control centers of the brain; and (3) the

articulation and resonance structures of the mouth and

Articulation and Resonance. The three major organs of

nasal cavities. Speech is composed of two mechanical

articulation are the lips, tongue, and soft palate. They

functions:

(1) phonation, which is achieved by the

need not be discussed in detail because we are all famil-

larynx, and (2) articulation, which is achieved by the

iar with their movements during speech and other

structures of the mouth.

vocalizations.

The resonators include the mouth, the nose and asso-

ciated nasal sinuses, the pharynx, and even the chest

Phonation. The larynx, shown in Figure 37-9A, is espe-

cavity. Again, we are all familiar with the resonating

cially adapted to act as a vibrator. The vibrating element

qualities of these structures. For instance, the function

is the vocal folds, commonly called the vocal cords. The

of the nasal resonators is demonstrated by the change

vocal cords protrude from the lateral walls of the larynx

in voice quality when a person has a severe cold that

toward the center of the glottis; they are stretched and

blocks the air passages to these resonators.

positioned by several specific muscles of the larynx

itself.

Figure 37-9B shows the vocal cords as they are seen

when looking into the glottis with a laryngoscope.

References

During normal breathing, the cords are wide open to

allow easy passage of air. During phonation, the cords

Carr MJ, Undem BJ: Bronchopulmonary afferent nerves.

move together so that passage of air between them will

Respirology 8:291, 2003.

cause vibration. The pitch of the vibration is determined

Coulson FR, Fryer AD: Muscarinic acetylcholine receptors

mainly by the degree of stretch of the cords, but also by

and airway diseases. Pharmacol Ther 98:59, 2003.

how tightly the cords are approximated to one another

Daniels CB, Orgeig S: Pulmonary surfactant: the key to the

and by the mass of their edges.

evolution of air breathing. News Physiol Sci 18:151, 2003.

Figure 37-9A shows a dissected view of the vocal

Foster WM: Mucociliary transport and cough in humans.

folds after removal of the mucous epithelial lining.

Pulm Pharmacol Ther 15:277, 2002.

Immediately inside each cord is a strong elastic ligament

Haitsma JJ, Papadakos PJ, Lachmann B: Surfactant therapy

called the vocal ligament. This is attached anteriorly to

for acute lung injury/acute respiratory distress syndrome.

the large thyroid cartilage, which is the cartilage that

Curr Opin Crit Care 10:18, 2004.

projects forward from the anterior surface of the neck

Hilaire G, Duron B: Maturation of the mammalian respira-

and is called the “Adam’s apple.” Posteriorly, the vocal

tory system. Physiol Rev 79:325, 1999.

482

Unit VII Respiration

Lai-Fook SJ: Pleural mechanics and fluid exchange. Physiol

Powell FL, Hopkins SR: Comparative physiology of lung

Rev 84:385, 2004.

complexity: implications for gas exchange. News Physiol

Mason RJ, Greene K, Voelker DR: Surfactant protein A and

Sci 19:55, 2004.

surfactant protein D in health and disease. Am J Physiol

Sant’Ambrogio G, Widdicombe J: Reflexes from airway

Lung Cell Mol Physiol 275:L1, 1998.

rapidly adapting receptors. Respir Physiol 125:33, 2001.

Massaro D, Massaro GD: Pulmonary alveoli: formation, the

Uhlig S, Taylor AE: Methods in Pulmonary Research. Basel:

“call for oxygen,” and other regulators. Am J Physiol Lung

Birkhauser Verlag, 1998.

Cell Mol Physiol 282:L345, 2002.

West JB: Respiratory Physiology. New York: Oxford Uni-

Maxfield RA: New and emerging minimally invasive

versity Press, 1996.

techniques for lung volume reduction. Chest

125:777,

West JB: Why doesn’t the elephant have a pleural space?

2004.

News Physiol Sci 17:47, 2002.

McConnell AK, Romer LM: Dyspnoea in health and

Widdicombe J: Neuroregulation of cough: implications for

obstructive pulmonary disease: the role of respiratory

drug therapy. Curr Opin Pharmacol 2:256, 2002.

muscle function and training. Sports Med 34:117, 2004.

Wright JR: Pulmonary surfactant: a front line of lung host

Paton JF, Dutschmann M: Central control of upper airway

defense. J Clin Invest 111:1453, 2003.

resistance regulating respiratory airflow in mammals.

Zeitels SM, Healy GB: Laryngology and phonosurgery.

J Anat 201:319, 2002.

N Engl J Med 349:882, 2003.

C H A P T E R

Pulmonary Circulation,

Pulmonary Edema, Pleural Fluid

Some aspects of blood flow distribution and other

hemodynamics are particular to the pulmonary cir-

culation and are especially important for gas

exchange in the lungs. The present discussion is con-

cerned with these special features of the pulmonary

circulation.

Physiologic Anatomy of the Pulmonary

Circulatory System

Pulmonary Vessels. The pulmonary artery extends only 5 centimeters beyond the apex

of the right ventricle and then divides into right and left main branches that supply

blood to the two respective lungs.

The pulmonary artery is thin, with a wall thickness one third that of the aorta.

The pulmonary arterial branches are very short, and all the pulmonary arteries, even

the smaller arteries and arterioles, have larger diameters than their counterpart sys-

temic arteries. This, combined with the fact that the vessels are thin and distensible,

gives the pulmonary arterial tree a large compliance, averaging almost 7 ml/mm Hg,

which is similar to that of the entire systemic arterial tree. This large compliance

allows the pulmonary arteries to accommodate the stroke volume output of the

right ventricle.

The pulmonary veins, like the pulmonary arteries, are also short. They immedi-

ately empty their effluent blood into the left atrium, to be pumped by the left heart

through the systemic circulation.

Bronchial Vessels. Blood also flows to the lungs through small bronchial arteries that

originate from the systemic circulation, amounting to about 1 to 2 per cent of the

total cardiac output. This bronchial arterial blood is oxygenated blood, in contrast

to the partially deoxygenated blood in the pulmonary arteries. It supplies the sup-

porting tissues of the lungs, including the connective tissue, septa, and large and

small bronchi. After this bronchial and arterial blood has passed through the sup-

porting tissues, it empties into the pulmonary veins and enters the left atrium, rather

than passing back to the right atrium. Therefore, the flow into the left atrium and

the left ventricular output are about 1 to 2 per cent greater than the right ventric-

ular output.

Lymphatics. Lymph vessels are present in all the supportive tissues of the lung, begin-

ning in the connective tissue spaces that surround the terminal bronchioles, cours-

ing to the hilum of the lung, and thence mainly into the right thoracic lymph duct.

Particulate matter entering the alveoli is partly removed by way of these channels,

and plasma protein leaking from the lung capillaries is also removed from the lung

tissues, thereby helping to prevent pulmonary edema.

Pressures in the Pulmonary System

Pressure Pulse Curve in the Right Ventricle. The pressure pulse curves of the right

ventricle and pulmonary artery are shown in the lower portion of Figure 38-1.

These curves are contrasted with the much higher aortic pressure curve shown

in the upper portion of the figure. The systolic pressure in the right ventricle of

the normal human being averages about 25 mm Hg, and the diastolic pressure

483

484

Unit VII

Respiration

normal human being, the diastolic pulmonary arterial

pressure is about 8 mm Hg, and the mean pulmonary

arterial pressure is 15 mm Hg.

Aortic pressure curve

120

Pulmonary Capillary Pressure. The mean pulmonary cap-

illary pressure, as diagrammed in Figure 38-2, is about

7 mm Hg. The importance of this low capillary pres-

sure is discussed in detail later in the chapter in rela-

tion to fluid exchange functions of the pulmonary

capillaries.

Right ventricular curve

Left Atrial and Pulmonary Venous Pressures. The mean

Pulmonary artery curve

pressure in the left atrium and the major pulmonary

veins averages about

2 mm Hg in the recumbent

human being, varying from as low as 1 mm Hg to as

high as 5 mm Hg. It usually is not feasible to measure

a human being’s left atrial pressure using a direct

Seconds

measuring device because it is difficult to pass a

catheter through the heart chambers into the left

atrium. However, the left atrial pressure can often be

estimated with moderate accuracy by measuring the

so-called pulmonary wedge pressure. This is achieved

Figure 38-1

by inserting a catheter first through a peripheral vein

to the right atrium, then through the right side of the

Pressure pulse contours in the right ventricle, pulmonary artery,

and aorta.

heart and through the pulmonary artery into one of

the small branches of the pulmonary artery, finally

pushing the catheter until it wedges tightly in the small

branch.

The pressure measured through the catheter, called

the “wedge pressure,” is about 5 mm Hg. Because all

blood flow has been stopped in the small wedged

artery, and because the blood vessels extending

beyond this artery make a direct connection with the

Pulmonary

pulmonary capillaries, this wedge pressure is usually

capillaries

Left

atrium

only 2 to 3 mm Hg greater than the left atrial pressure.

When the left atrial pressure rises to high values,

the pulmonary wedge pressure also rises. Therefore,

wedge pressure measurements can be used to clinically

study changes in pulmonary capillary pressure and

Pulmonary

Left

artery

capillaries

atrium

left atrial pressure in patients with congestive heart

failure.

Figure 38-2

Blood Volume of the Lungs

Pressures in the different vessels of the lungs. D, diastolic; M,

The blood volume of the lungs is about 450 milliliters,

mean; S, systolic; red curve, arterial pulsations.

about 9 per cent of the total blood volume of the entire

circulatory system. Approximately 70 milliliters of this

pulmonary blood volume is in the pulmonary capil-

averages about 0 to 1 mm Hg, values that are only one

laries, and the remainder is divided about equally

fifth those for the left ventricle.

between the pulmonary arteries and the veins.

Pressures in the Pulmonary Artery. During systole, the

Lungs as a Blood Reservoir. Under various physiological

pressure in the pulmonary artery is essentially equal

and pathological conditions, the quantity of blood in

to the pressure in the right ventricle, as also shown

the lungs can vary from as little as one half normal up

in Figure 38-1. However, after the pulmonary valve

to twice normal. For instance, when a person blows out

closes at the end of systole, the ventricular pressure

air so hard that high pressure is built up in the lungs—

falls precipitously, whereas the pulmonary arterial

such as when blowing a trumpet—as much as 250 mil-

pressure falls more slowly as blood flows through the

liliters of blood can be expelled from the pulmonary

capillaries of the lungs.

circulatory system into the systemic circulation.

As shown in Figure 38-2, the systolic pulmonary

Also, loss of blood from the systemic circulation by

arterial pressure averages about

25 mm Hg in the

hemorrhage can be partly compensated for by the

Chapter 38

Pulmonary Circulation, Pulmonary Edema, Pleural Fluid

485

automatic shift of blood from the lungs into the sys-

Effect of Hydrostatic

temic vessels.

Pressure Gradients in the

Lungs on Regional

Shift of Blood Between the Pulmonary and Systemic

Pulmonary Blood Flow

Circulatory Systems as a Result of Cardiac Pathology.

Failure of the left side of the heart or increased resist-

In Chapter 15, it was pointed out that the blood pres-

ance to blood flow through the mitral valve as a result

sure in the foot of a standing person can be as much as

90 mm Hg greater than the pressure at the level of the

of mitral stenosis or mitral regurgitation causes blood

heart. This is caused by hydrostatic pressure—that is, by

to dam up in the pulmonary circulation, sometimes

the weight of the blood itself in the blood vessels. The

increasing the pulmonary blood volume as much as

same effect, but to a lesser degree, occurs in the lungs.

100 per cent and causing large increases in the pul-

In the normal, upright adult, the lowest point in the

monary vascular pressures. Because the volume of the

lungs is about 30 centimeters below the highest point.

systemic circulation is about nine times that of the pul-

This represents a 23 mm Hg pressure difference, about

monary system, a shift of blood from one system to the

15 mm Hg of which is above the heart and 8 below. That

other affects the pulmonary system greatly but usually

is, the pulmonary arterial pressure in the uppermost

has only mild systemic circulatory effects.

portion of the lung of a standing person is about 15 mm

Hg less than the pulmonary arterial pressure at the level

of the heart, and the pressure in the lowest portion of

the lungs is about 8 mm Hg greater. Such pressure dif-

Blood Flow Through the Lungs

ferences have profound effects on blood flow through

and Its Distribution

the different areas of the lungs. This is demonstrated by

the lower curve in Figure 38-3, which depicts blood flow

The blood flow through the lungs is essentially equal

per unit of lung tissue at different levels of the lung in

the upright person. Note that in the standing position at

to the cardiac output. Therefore, the factors that

rest, there is little flow in the top of the lung but about

control cardiac output—mainly peripheral factors,

five times as much flow in the bottom. To help explain

as discussed in Chapter 20—also control pulmonary

these differences, one often describes the lung as being

blood flow. Under most conditions, the pulmonary

divided into three zones, as shown in Figure 38-4.

vessels act as passive, distensible tubes that enlarge

In each zone, the patterns of blood flow are quite

with increasing pressure and narrow with decreasing

different.

pressure. For adequate aeration of the blood to

occur, it is important for the blood to be distributed to

Zones 1, 2, and 3 of Pulmonary

those segments of the lungs where the alveoli are

Blood Flow

best oxygenated. This is achieved by the following

mechanism.

The capillaries in the alveolar walls are distended by the

blood pressure inside them, but simultaneously, they are

Effect of Diminished Alveolar Oxygen on Local Alveolar Blood

Flow—Automatic Control of Pulmonary Blood Flow Distribution.

When the concentration of oxygen in the air of the

alveoli decreases below normal—especially when it

falls below 70 per cent of normal (below 73 mm Hg

Po₂)—the adjacent blood vessels constrict, with the

vascular resistance increasing more than fivefold at

extremely low oxygen levels. This is opposite to the

effect observed in systemic vessels, which dilate rather

than constrict in response to low oxygen. It is believed

that the low oxygen concentration causes some yet

undiscovered vasoconstrictor substance to be released

from the lung tissue; this substance promotes con-

striction of the small arteries and arterioles. It has been

Exercise

suggested that this vasoconstrictor might be secreted

Standing at rest

by the alveolar epithelial cells when they become

hypoxic.

This effect of low oxygen on pulmonary vascular

Top

Middle

Bottom

resistance has an important function: to distribute

Lung level

blood flow where it is most effective. That is, if some

alveoli are poorly ventilated so that their oxygen con-

centration becomes low, the local vessels constrict. This

causes the blood to flow through other areas of the

Figure 38-3

lungs that are better aerated, thus providing an auto-

Blood flow at different levels in the lung of an upright person at

matic control system for distributing blood flow to the

rest and during exercise. Note that when the person is at rest, the

pulmonary areas in proportion to their alveolar

blood flow is very low at the top of the lungs; most of the flow is

oxygen pressures.

through the bottom of the lung.

486

Unit VII

Respiration

during cardiac systole. Conversely, during diastole, the

ZONE 1

8 mm Hg diastolic pressure at the level of the heart is

not sufficient to push the blood up the 15 mm Hg hydro-

Artery

PALV

Vein

static pressure gradient required to cause diastolic cap-

illary flow. Therefore, blood flow through the apical part

of the lung is intermittent, with flow during systole but

cessation of flow during diastole; this is called zone 2

Ppc

blood flow. Zone 2 blood flow begins in the normal

lungs about 10 centimeters above the midlevel of the

ZONE 2

heart and extends from there to the top of the lungs.

In the lower regions of the lungs, from about 10 cen-

timeters above the level of the heart all the way to the

Artery

PALV

Vein

bottom of the lungs, the pulmonary arterial pressure

during both systole and diastole remains greater than

the zero alveolar air pressure. Therefore, there is con-

Ppc

tinuous flow through the alveolar capillaries, or zone 3

blood flow. Also, when a person is lying down, no part

of the lung is more than a few centimeters above the

ZONE 3

level of the heart. In this case, blood flow in a normal

person is entirely zone 3 blood flow, including the lung

Artery

PALV

Vein

apices.

Zone 1 Blood Flow Occurs Only Under Abnormal Conditions.

Ppc

Zone 1 blood flow, which is blood flow at no time during

the cardiac cycle, occurs when either the pulmonary sys-

tolic arterial pressure is too low or the alveolar pressure

is too high to allow flow. For instance, if an upright

Figure 38-4

person is breathing against a positive air pressure so

Mechanics of blood flow in the three blood flow zones of the lung:

that the intra-alveolar air pressure is at least 10 mm Hg

zone 1, no flow—alveolar air pressure (PALV) is greater than arte-

greater than normal but the pulmonary systolic blood

rial pressure; zone 2, intermittent flow—systolic arterial pressure

pressure is normal, one would expect zone 1 blood

rises higher than alveolar air pressure, but diastolic arterial pres-

flow—no blood flow—in the lung apices. Another

sure falls below alveolar air pressure; and zone 3, continuous

instance in which zone 1 blood flow occurs is in an

flow—arterial pressure and pulmonary capillary pressure (Ppc)

upright person whose pulmonary systolic arterial pres-

remain greater than alveolar air pressure at all times.

sure is exceedingly low, as might occur after severe

blood loss.

compressed by the alveolar air pressure on their out-

Effect of Exercise on Blood Flow Through the Different Parts of

sides. Therefore, any time the lung alveolar air pressure

the Lungs. Referring again to Figure 38-3, one sees that

becomes greater than the capillary blood pressure,

the blood flow in all parts of the lung increases during

the capillaries close and there is no blood flow. Under

exercise. The increase in flow in the top of the lung may

different normal and pathological lung conditions, one

be 700 to 800 per cent, whereas the increase in the lower

may find any one of three possible zones of pulmonary

part of the lung may be no more than 200 to 300 per

blood flow, as follows:

cent. The reason for these differences is that the pul-

Zone 1: No blood flow during all portions of the

monary vascular pressures rise enough during exercise

cardiac cycle because the local alveolar capillary

to convert the lung apices from a zone 2 pattern into a

pressure in that area of the lung never rises higher

zone 3 pattern of flow.

than the alveolar air pressure during any part of the

cardiac cycle

Effect of Increased Cardiac Output

Zone 2: Intermittent blood flow only during the pul-

monary arterial pressure peaks because the systolic

on Pulmonary Blood Flow and

pressure is then greater than the alveolar air pres-

Pulmonary Arterial Pressure During

sure, but the diastolic pressure is less than the alve-

Heavy Exercise

olar air pressure

Zone 3: Continuous blood flow because the alveolar

capillary pressure remains greater than alveolar air

During heavy exercise, blood flow through the lungs

pressure during the entire cardiac cycle

increases fourfold to sevenfold. This extra flow is

Normally, the lungs have only zones 2 and 3 blood

accommodated in the lungs in three ways: (1) by

flow—zone 2 (intermittent flow) in the apices, and zone

increasing the number of open capillaries, sometimes

3 (continuous flow) in all the lower areas. For example,

as much as threefold; (2) by distending all the capil-

when a person is in the upright position, the pulmonary

laries and increasing the rate of flow through each

arterial pressure at the lung apex is about 15 mm Hg

capillary more than twofold; and (3) by increasing the

less than the pressure at the level of the heart. There-

pulmonary arterial pressure. In the normal person, the

fore, the apical systolic pressure is only

10 mm Hg

first two changes decrease pulmonary vascular resist-

(25 mm Hg at heart level minus 15 mm Hg hydrostatic

ance so much that the pulmonary arterial pressure

pressure difference). This 10 mm Hg apical blood pres-

sure is greater than the zero alveolar air pressure, so that

rises very little, even during maximum exercise; this

blood flows through the pulmonary apical capillaries

effect is shown in Figure 38-5.

Chapter 38

Pulmonary Circulation, Pulmonary Edema, Pleural Fluid

487

above 30 mm Hg, causing similar increases in capillary

pressure, pulmonary edema is likely to develop, as we

discuss later in the chapter.

Pulmonary Capillary Dynamics

Normal value

Exchange of gases between the alveolar air and the

pulmonary capillary blood is discussed in the next

chapter. However, it is important for us to note here

that the alveolar walls are lined with so many capil-

laries that, in most places, the capillaries almost touch

one another side by side. Therefore, it is often said that

the capillary blood flows in the alveolar walls as a

“sheet of flow,” rather than in individual capillaries.

Pulmonary Capillary Pressure. No direct measurements

Cardiac output (L/min)

of pulmonary capillary pressure have ever been

made. However, “isogravimetric” measurement of pul-

monary capillary pressure, using a technique described

in Chapter 16, has given a value of 7 mm Hg. This is

Figure 38-5

probably nearly correct, because the mean left atrial

pressure is about 2 mm Hg and the mean pulmonary

Effect on mean pulmonary arterial pressure caused by increasing

the cardiac output during exercise.

arterial pressure is only

15 mm Hg, so the mean

pulmonary capillary pressure must lie somewhere

between these two values.

The ability of the lungs to accommodate greatly

Length of Time Blood Stays in the Pulmonary Capillaries.

increased blood flow during exercise without increas-

From histological study of the total cross-sectional

ing the pulmonary arterial pressure conserves the

area of all the pulmonary capillaries, it can be calcu-

energy of the right side of the heart. This ability also

lated that when the cardiac output is normal, blood

prevents a significant rise in pulmonary capillary pres-

passes through the pulmonary capillaries in about 0.8

sure, thus also preventing the development of pul-

second. When the cardiac output increases, this can

monary edema.

shorten to as little as 0.3 second. The shortening would

be much greater were it not for the fact that additional

capillaries, which normally are collapsed, open up to

Function of the Pulmonary Circulation

accommodate the increased blood flow. Thus, in only

When the Left Atrial Pressure Rises

a fraction of a second, blood passing through the

as a Result of Left-Sided Heart Failure

alveolar capillaries becomes oxygenated and loses its

excess carbon dioxide.

The left atrial pressure in a healthy person almost

never rises above +6 mm Hg, even during the most

Capillary Exchange of Fluid in the

strenuous exercise. These small changes in left atrial

Lungs, and Pulmonary Interstitial

pressure have virtually no effect on pulmonary circu-

latory function because this merely expands the pul-

Fluid Dynamics

monary venules and opens up more capillaries so that

blood continues to flow with almost equal ease from

The dynamics of fluid exchange across the lung capil-

the pulmonary arteries.

lary membranes are qualitatively the same as for

When the left side of the heart fails, however, blood

peripheral tissues. However, quantitatively, there are

begins to dam up in the left atrium. As a result, the

important differences, as follows:

left atrial pressure can rise on occasion from its normal

1. The pulmonary capillary pressure is low, about

value of

1 to

5 mm Hg all the way up to 40 to

7 mm Hg, in comparison with a considerably

50 mm Hg. The initial rise in atrial pressure, up to

higher functional capillary pressure in the

about 7 mm Hg, has very little effect on pulmonary cir-

peripheral tissues of about 17 mm Hg.

culatory function. But when the left atrial pressure

2. The interstitial fluid pressure in the lung is

rises to greater than 7 or 8 mm Hg, further increases

slightly more negative than that in the peripheral

in left atrial pressure above these levels cause almost

subcutaneous tissue. (This has been measured in

equally great increases in pulmonary arterial pressure,

two ways: by a micropipette inserted into the

thus causing a concomitant increased load on the right

pulmonary interstitium, giving a value of about

heart. Any increase in left atrial pressure above 7 or

-5 mm Hg, and by measuring the absorption

8 mm Hg increases the capillary pressure almost

pressure of fluid from the alveoli, giving a value of

equally as much. When the left atrial pressure has risen

about -8 mm Hg.)

488

Unit VII

Respiration

3. The pulmonary capillaries are relatively leaky to

pressure at the pulmonary capillary membrane; this

protein molecules, so that the colloid osmotic

can be calculated as follows:

pressure of the pulmonary interstitial fluid is

about 14 mm Hg, in comparison with less than

mm Hg

half this value in the peripheral tissues.

4. The alveolar walls are extremely thin, and the

Total outward force

+29

Total inward force

-28

alveolar epithelium covering the alveolar surfaces

MEAN FILTRATION PRESSURE

is so weak that it can be ruptured by any positive

pressure in the interstitial spaces greater than

alveolar air pressure (greater than 0 mm Hg),

This filtration pressure causes a slight continual flow

which allows dumping of fluid from the interstitial

of fluid from the pulmonary capillaries into the inter-

spaces into the alveoli.

stitial spaces, and except for a small amount that evap-

Now let us see how these quantitative differences

orates in the alveoli, this fluid is pumped back to the

affect pulmonary fluid dynamics.

circulation through the pulmonary lymphatic system.

Interrelations Between Interstitial Fluid Pressure and Other

Negative Pulmonary Interstitial Pressure and the Mechanism

Pressures in the Lung. Figure 38-6 shows a pulmonary

for Keeping the Alveoli “Dry.” One of the most important

capillary, a pulmonary alveolus, and a lymphatic capil-

problems in lung function is to understand why the

lary draining the interstitial space between the blood

alveoli do not normally fill with fluid. One’s first incli-

capillary and the alveolus. Note the balance of forces

nation is to think that the alveolar epithelium is strong

at the blood capillary membrane, as follows:

enough and continuous enough to keep fluid from

leaking out of the interstitial spaces into the alveoli.

This is not true, because experiments have shown

mm Hg

that there are always openings between the alveolar

Forces tending to cause movement of fluid outward from the

epithelial cells through which even large protein mol-

capillaries and into the pulmonary interstitium:

ecules, as well as water and electrolytes, can pass.

Capillary pressure

However, if one remembers that the pulmonary cap-

Interstitial fluid colloid osmotic pressure

Negative interstitial fluid pressure

illaries and the pulmonary lymphatic system normally

TOTAL OUTWARD FORCE

maintain a slight negative pressure in the interstitial

spaces, it is clear that whenever extra fluid appears

Forces tending to cause absorption of fluid into the capillaries:

Plasma colloid osmotic pressure

in the alveoli, it will simply be sucked mechanically

TOTAL INWARD FORCE

into the lung interstitium through the small openings

between the alveolar epithelial cells. Then the excess

fluid is either carried away through the pulmonary

Thus, the normal outward forces are slightly greater

lymphatics or absorbed into the pulmonary capillaries.

than the inward forces, providing a mean filtration

Thus, under normal conditions, the alveoli are kept

“dry,” except for a small amount of fluid that seeps

from the epithelium onto the lining surfaces of the

Pressures Causing Fluid Movement

alveoli to keep them moist.

CAPILLARY

ALVEOLUS

Pulmonary Edema

Pulmonary edema occurs in the same way that edema

Hydrostatic

occurs elsewhere in the body. Any factor that causes the

-8

pressure

-8

(Surface

pulmonary interstitial fluid pressure to rise from the

tension

negative range into the positive range will cause rapid

at pore)

Osmotic

filling of the pulmonary interstitial spaces and alveoli

pressure

- 28

- 14

with large amounts of free fluid.

The most common causes of pulmonary edema are as

Net

(0)

(Evaporation)

(+1)

follows:

pressure

-5

1. Left-sided heart failure or mitral valve disease, with

consequent great increases in pulmonary venous

-4

pressure and pulmonary capillary pressure and

flooding of the interstitial spaces and alveoli.

2. Damage to the pulmonary blood capillary

Lymphatic pump

membranes caused by infections such as

pneumonia or by breathing noxious substances

Figure 38-6

such as chlorine gas or sulfur dioxide gas. Each of

these causes rapid leakage of both plasma proteins

Hydrostatic and osmotic forces at the capillary (left) and alveolar

and fluid out of the capillaries and into both the

membrane (right) of the lungs. Also shown is the tip end of a lym-

lung interstitial spaces and the alveoli.

phatic vessel (center) that pumps fluid from the pulmonary inter-

stitial spaces. (Modified from Guyton AC, Taylor AE, Granger HJ:

Circulatory Physiology II: Dynamics and Control of the Body

“Pulmonary Edema Safety Factor.” Experiments in animals

Fluids. Philadelphia: WB Saunders, 1975.)

have shown that the pulmonary capillary pressure nor-

Chapter 38

Pulmonary Circulation, Pulmonary Edema, Pleural Fluid

489

Figure 38-7

x x

Rate of fluid loss into the lung tissues when the left

atrial pressure (and pulmonary capillary pressure)

Left atrial pressure (mm Hg)

is increased. (From Guyton AC, Lindsey AW: Effect

of elevated left atrial pressure and decreased

plasma protein concentration on the development

of pulmonary edema. Circ Res 7:649, 1959.)

mally must rise to a value at least equal to the colloid

which the pulmonary capillary pressure occasionally

osmotic pressure of the plasma inside the capillaries

does rise to 50 mm Hg, death frequently ensues in less

before significant pulmonary edema will occur. To give

than 30 minutes from acute pulmonary edema.

an example, Figure 38-7 shows how different levels of

left atrial pressure increase the rate of pulmonary

edema formation in dogs. Remember that every time

Fluid in the Pleural Cavity

the left atrial pressure rises to high values, the pul-

monary capillary pressure rises to a level 1 to 2 mm Hg

When the lungs expand and contract during normal

greater than the left atrial pressure. In these experi-

breathing, they slide back and forth within the pleural

ments, as soon as the left atrial pressure rose above

cavity. To facilitate this, a thin layer of mucoid fluid lies

23 mm Hg (causing the pulmonary capillary pressure to

between the parietal and visceral pleurae.

rise above 25 mm Hg), fluid began to accumulate in the

Figure 38-8 shows the dynamics of fluid exchange in

lungs. This fluid accumulation increased even more

the pleural space. The pleural membrane is a porous,

rapidly with further increases in capillary pressure. The

mesenchymal, serous membrane through which small

plasma colloid osmotic pressure during these experi-

amounts of interstitial fluid transude continually into

ments was equal to this 25 mm Hg critical pressure

the pleural space. These fluids carry with them tissue

level. Therefore, in the human being, whose normal

proteins, giving the pleural fluid a mucoid characteris-

plasma colloid osmotic pressure is 28 mm Hg, one can

tic, which is what allows extremely easy slippage of the

predict that the pulmonary capillary pressure must

moving lungs.

rise from the normal level of 7 mm Hg to more than

The total amount of fluid in each pleural cavity is nor-

28 mm Hg to cause pulmonary edema, giving an acute

mally slight, only a few milliliters. Whenever the quan-

safety factor against pulmonary edema of 21 mm Hg.

tity becomes more than barely enough to begin flowing

in the pleural cavity, the excess fluid is pumped away by

Safety Factor in Chronic Conditions. When the pul-

lymphatic vessels opening directly from the pleural

monary capillary pressure remains elevated chronically

cavity into (1) the mediastinum, (2) the superior surface

(for at least 2 weeks), the lungs become even more

of the diaphragm, and (3) the lateral surfaces of the

resistant to pulmonary edema because the lymph

parietal pleura. Therefore, the pleural space—the space

vessels expand greatly, increasing their capability of car-

between the parietal and visceral pleurae—is called a

rying fluid away from the interstitial spaces perhaps as

potential space because it normally is so narrow that it

much as 10-fold. Therefore, in patients with chronic

is not obviously a physical space.

mitral stenosis, pulmonary capillary pressures of 40 to

45 mm Hg have been measured without the develop-

“Negative Pressure” in Pleural Fluid. A negative force is

ment of lethal pulmonary edema.

always required on the outside of the lungs to keep the

lungs expanded. This is provided by negative pressure

Rapidity of Death in Acute Pulmonary Edema. When the pul-

in the normal pleural space. The basic cause of this neg-

monary capillary pressure rises even slightly above the

ative pressure is pumping of fluid from the space by the

safety factor level, lethal pulmonary edema can occur

lymphatics (which is also the basis of the negative pres-

within hours, or even within 20 to 30 minutes if the cap-

sure found in most tissue spaces of the body). Because

illary pressure rises 25 to 30 mm Hg above the safety

the normal collapse tendency of the lungs is about

factor level. Thus, in acute left-sided heart failure, in

-4 mm Hg, the pleural fluid pressure must always be at

490

Unit VII

Respiration

(3) greatly reduced plasma colloid osmotic pressure,

Venous system

thus allowing excessive transudation of fluid; and (4)

infection or any other cause of inflammation of the sur-

Lymphatics

faces of the pleural cavity, which breaks down the cap-

illary membranes and allows rapid dumping of both

plasma proteins and fluid into the cavity.

Artery

References

Gehlbach BK, Geppert E: The pulmonary manifestations of

left heart failure. Chest 125:669, 2004.

Guazzi M: Alveolar-capillary membrane dysfunction in

heart failure: evidence of a pathophysiologic role. Chest

124:1090, 2003.

Guyton AC, Lindsey AW: Effect of elevated left atrial pres-

sure and decreased plasma protein concentration on the

Vein

development of pulmonary edema. Circ Res 7:649, 1959.

Guyton AC, Parker JC, Taylor AE, et al: Forces governing

water movement in the lung. In: Fishman AP, Renkin EM

(eds): Pulmonary Edema. Baltimore: Waverly Press, 1979,

p 65.

Figure 38-8

Guyton AC, Taylor AE, Granger HJ: Circulatory Physiology.

II. Dynamics and Control of the Body Fluids. Philadel-

Dynamics of fluid exchange in the intrapleural space.

phia: WB Saunders, 1975.

Hoschele S, Mairbaurl H: Alveolar flooding at high altitude:

failure of reabsorption? News Physiol Sci 18:55, 2003.

least as negative as

-4 mm Hg to keep the lungs

Lai-Fook SJ: Pleural mechanics and fluid exchange. Physiol

expanded. Actual measurements have shown that the

Rev 84:385, 2004.

pressure is usually about -7 mm Hg, which is a few mil-

Matalon S, Hardiman KM, Jain L, et al: Regulation of ion

limeters of mercury more negative than the collapse

channel structure and function by reactive oxygen-

pressure of the lungs. Thus, the negativity of the pleural

nitrogen species. Am J Physiol Lung Cell Mol Physiol

fluid keeps the normal lungs pulled against the parietal

285:L1184, 2003.

pleura of the chest cavity, except for an extremely thin

Miserocchi G, Negrini D, Passi A, De Luca G: Development

layer of mucoid fluid that acts as a lubricant.

of lung edema: interstitial fluid dynamics and molecular

structure. News Physiol Sci 16:66, 2001.

Pleural Effusion. Pleural effusion means the collection of

Schoene RB: Limits of human lung function at high altitude.

large amounts of free fluid in the pleural space. The effu-

J Exp Biol 204:3121, 2001.

sion is analogous to edema fluid in the tissues and can

Taylor AE, Guyton AC, Bishop VS: Permeability of the alve-

be called “edema of the pleural cavity.” The causes of

olar membrane to solutes. Circ Res 16:353, 1965.

the effusion are the same as the causes of edema in

Wallace J: Update in pulmonary diseases. Ann Intern Med

other tissues (discussed in Chapter 25), including (1)

139:499, 2003.

blockage of lymphatic drainage from the pleural cavity;

West JB: Respiratory Physiology—The Essentials, 5th ed.

(2) cardiac failure, which causes excessively high periph-

Baltimore: Williams & Wilkins, 1994.

eral and pulmonary capillary pressures, leading to

West JB: Invited review: pulmonary capillary stress failure.

excessive transudation of fluid into the pleural cavity;

J Appl Physiol 89:2483, 2000.

C H A P T E R

Physical Principles of Gas

Exchange; Diffusion of Oxygen

and Carbon Dioxide Through

the Respiratory Membrane

After the alveoli are ventilated with fresh air, the

next step in the respiratory process is diffusion of

oxygen from the alveoli into the pulmonary blood

and diffusion of carbon dioxide in the opposite

direction, out of the blood. The process of diffusion

is simply the random motion of molecules inter-

twining their way in all directions through

the respiratory membrane and adjacent fluids.

However, in respiratory physiology, one is concerned not only with the basic

mechanism by which diffusion occurs but also with the rate at which it occurs;

this is a much more complex problem, requiring a deeper understanding of the

physics of diffusion and gas exchange.

Physics of Gas Diffusion and Gas

Partial Pressures

Molecular Basis of Gas Diffusion

All the gases of concern in respiratory physiology are simple molecules that are free

to move among one another, which is the process called “diffusion.” This is also true

of gases dissolved in the fluids and tissues of the body.

For diffusion to occur, there must be a source of energy. This is provided by the

kinetic motion of the molecules themselves. Except at absolute zero temperature,

all molecules of all matter are continually undergoing motion. For free molecules

that are not physically attached to others, this means linear movement at high veloc-

ity until they strike other molecules. Then they bounce away in new directions and

continue until striking other molecules again. In this way, the molecules move

rapidly and randomly among one another.

Net Diffusion of a Gas in One Direction—Effect of a Concentration Gradient. If a gas chamber

or a solution has a high concentration of a particular gas at one end of the chamber

and a low concentration at the other end, as shown in Figure 39-1, net diffusion of

the gas will occur from the high-concentration area toward the low-concentration

area. The reason is obvious: There are far more molecules at end A of the chamber

to diffuse toward end B than there are molecules to diffuse in the opposite direc-

tion. Therefore, the rates of diffusion in each of the two directions are proportion-

ately different, as demonstrated by the lengths of the arrows in the figure.

Gas Pressures in a Mixture of Gases—“Partial Pressures”

of Individual Gases

Pressure is caused by multiple impacts of moving molecules against a surface. There-

fore, the pressure of a gas acting on the surfaces of the respiratory passages and

alveoli is proportional to the summated force of impact of all the molecules of that

gas striking the surface at any given instant. This means that the pressure is directly

proportional to the concentration of the gas molecules.

491

492

Unit VII

Respiration

When partial pressure is expressed in atmospheres

Dissolved gas molecules

(1 atmosphere pressure equals 760 mm Hg) and con-

centration is expressed in volume of gas dissolved in

each volume of water, the solubility coefficients for

important respiratory gases at body temperature are the

following:

Oxygen

0.024

Carbon dioxide

0.57

Carbon monoxide

0.018

Nitrogen

0.012

Figure 39-1

Helium

0.008

Diffusion of oxygen from one end of a chamber (A) to the other

(B). The difference between the lengths of the arrows represents

From this table, one can see that carbon dioxide is

net diffusion.

more than 20 times as soluble as oxygen. Therefore, the

partial pressure of carbon dioxide (for a given concen-

In respiratory physiology, one deals with mixtures of

tration) is less than one twentieth that exerted by

gases, mainly of oxygen, nitrogen, and carbon dioxide.

oxygen.

The rate of diffusion of each of these gases is directly

proportional to the pressure caused by that gas alone,

Diffusion of Gases Between the Gas Phase in the Alveoli and the

which is called the partial pressure of that gas. The

Dissolved Phase in the Pulmonary Blood. The partial pressure

concept of partial pressure can be explained as follows.

of each gas in the alveolar respiratory gas mixture tends

Consider air, which has an approximate composition

to force molecules of that gas into solution in the blood

of 79 per cent nitrogen and 21 per cent oxygen. The

of the alveolar capillaries. Conversely, the molecules of

total pressure of this mixture at sea level averages

the same gas that are already dissolved in the blood

760 mm Hg. It is clear from the preceding description of

are bouncing randomly in the fluid of the blood, and

the molecular basis of pressure that each gas contributes

some of these bouncing molecules escape back into the

to the total pressure in direct proportion to its concen-

alveoli. The rate at which they escape is directly pro-

tration. Therefore, 79 per cent of the 760 mm Hg is

portional to their partial pressure in the blood.

caused by nitrogen (600 mm Hg) and 21 per cent by

But in which direction will net diffusion of the gas

oxygen (160 mm Hg). Thus, the “partial pressure” of

occur? The answer is that net diffusion is determined by

nitrogen in the mixture is 600 mm Hg, and the “partial

the difference between the two partial pressures. If the

pressure” of oxygen is 160 mm Hg; the total pressure is

partial pressure is greater in the gas phase in the alveoli,

760 mm Hg, the sum of the individual partial pressures.

as is normally true for oxygen, then more molecules will

The partial pressures of individual gases in a mixture are

diffuse into the blood than in the other direction. Alter-

designated by the symbols Po₂, Pco₂, Pn₂, Ph₂o, Phe, and

natively, if the partial pressure of the gas is greater in

so forth.

the dissolved state in the blood, which is normally true

for carbon dioxide, then net diffusion will occur toward

the gas phase in the alveoli.

Pressures of Gases Dissolved in

Water and Tissues

Vapor Pressure of Water

Gases dissolved in water or in body tissues also exert

pressure, because the dissolved gas molecules are

When nonhumidified air is breathed into the respiratory

moving randomly and have kinetic energy. Further,

passageways, water immediately evaporates from the

when the gas dissolved in fluid encounters a surface,

surfaces of these passages and humidifies the air. This

such as the membrane of a cell, it exerts its own partial

results from the fact that water molecules, like the dif-

pressure in the same way that a gas in the gas phase

ferent dissolved gas molecules, are continually escaping

does. The partial pressures of the separate dissolved

from the water surface into the gas phase. The partial

gases are designated the same as the partial pressures

pressure that the water molecules exert to escape

in the gas state, that is, Po₂, Pco₂, Pn₂, Phe, and so forth.

through the surface is called the vapor pressure of the

water. At normal body temperature, 37°C, this vapor

Factors That Determine the Partial Pressure of a Gas Dissolved in

pressure is 47 mm Hg. Therefore, once the gas mixture

a Fluid. The partial pressure of a gas in a solution is

has become fully humidified—that is, once it is in “equi-

determined not only by its concentration but also by the

librium” with the water—the partial pressure of the

solubility coefficient of the gas. That is, some types of

water vapor in the gas mixture is 47 mm Hg. This partial

molecules, especially carbon dioxide, are physically or

pressure, like the other partial pressures, is designated

chemically attracted to water molecules, whereas others

Ph₂o.

are repelled. When molecules are attracted, far more of

The vapor pressure of water depends entirely on the

them can be dissolved without building up excess partial

temperature of the water. The greater the temperature,

pressure within the solution. Conversely, in the case of

the greater the kinetic activity of the molecules and,

those that are repelled, high partial pressure will

therefore, the greater the likelihood that the water mol-

develop with fewer dissolved molecules. These relations

ecules will escape from the surface of the water into the

are expressed by the following formula, which is Henry’s

gas phase. For instance, the water vapor pressure at

law:

0°C is 5 mm Hg, and at 100°C it is 760 mm Hg. But the

most important value to remember is the vapor pres-

Concentration of dissolved gas

sure at body temperature, 47 mm Hg; this value appears

Partial pressure

Solubility coefficient

in many of our subsequent discussions.

Chapter 39

Physical Principles of Gas Exchange; Diffusion of Oxygen and Carbon Dioxide

493

Diffusion of Gases Through

pathway, A is the cross-sectional area of the pathway, S

Fluids—Pressure Difference Causes

is the solubility of the gas, d is the distance of diffusion,

and MW is the molecular weight of the gas.

Net Diffusion

It is obvious from this formula that the characteristics

Now, let us return to the problem of diffusion. From the

of the gas itself determine two factors of the formula:

preceding discussion, it is clear that when the partial

solubility and molecular weight. Together, these two

pressure of a gas is greater in one area than in another

factors determine the diffusion coefficient of the gas,

area, there will be net diffusion from the high-pressure

which is proportional to S/

. That is, the relative

area toward the low-pressure area. For instance, re-

rates at which different gases at the same partial pres-

turning to Figure 39-1, one can readily see that the mol-

sure levels will diffuse are proportional to their diffu-

ecules in the area of high pressure, because of their

sion coefficients. Assuming that the diffusion coefficient

greater number, have a greater statistical chance of

for oxygen is 1, the relative diffusion coefficients for dif-

moving randomly into the area of low pressure than

ferent gases of respiratory importance in the body fluids

do molecules attempting to go in the other direction.

are as follows:

However, some molecules do bounce randomly from

the area of low pressure toward the area of high pres-

Oxygen

1.0

sure. Therefore, the net diffusion of gas from the area of

Carbon dioxide

20.3

high pressure to the area of low pressure is equal to the

Carbon monoxide

0.81

number of molecules bouncing in this forward direction

Nitrogen

0.53

minus the number bouncing in the opposite direction;

Helium

0.95

this is proportional to the gas partial pressure difference

between the two areas, called simply the pressure dif-

ference for causing diffusion.

Diffusion of Gases Through Tissues

The gases that are of respiratory importance are all

Quantifying the Net Rate of Diffusion in Fluids. In addition to

highly soluble in lipids and, consequently, are highly

the pressure difference, several other factors affect the

soluble in cell membranes. Because of this, the major

rate of gas diffusion in a fluid. They are (1) the solubil-

limitation to the movement of gases in tissues is the rate

ity of the gas in the fluid, (2) the cross-sectional area of

at which the gases can diffuse through the tissue water

the fluid, (3) the distance through which the gas must

instead of through the cell membranes. Therefore, dif-

diffuse, (4) the molecular weight of the gas, and (5) the

fusion of gases through the tissues, including through

temperature of the fluid. In the body, the last of these

the respiratory membrane, is almost equal to the diffu-

factors, the temperature, remains reasonably constant

sion of gases in water, as given in the preceding list.

and usually need not be considered.

The greater the solubility of the gas, the greater the

number of molecules available to diffuse for any given

partial pressure difference. The greater the cross-

Composition of Alveolar

sectional area of the diffusion pathway, the greater the

Air—Its Relation to

total number of molecules that diffuse. Conversely,

Atmospheric Air

the greater the distance the molecules must diffuse, the

longer it will take the molecules to diffuse the entire dis-

tance. Finally, the greater the velocity of kinetic move-

Alveolar air does not have the same concentrations of

ment of the molecules, which is inversely proportional

gases as atmospheric air by any means, which can

to the square root of the molecular weight, the greater

readily be seen by comparing the alveolar air compo-

the rate of diffusion of the gas. All these factors can be

sition in Table 39-1 with that of atmospheric air. There

expressed in a single formula, as follows:

are several reasons for the differences. First, the alve-

olar air is only partially replaced by atmospheric air

P¥A ¥S

Dµ

with each breath. Second, oxygen is constantly being

absorbed into the pulmonary blood from the alveolar

in which D is the diffusion rate, DP is the partial pres-

air. Third, carbon dioxide is constantly diffusing from

sure difference between the two ends of the diffusion

the pulmonary blood into the alveoli. And fourth, dry

Table 39-1

Partial Pressures of Respiratory Gases as They Enter and Leave the Lungs (at Sea Level)

Atmospheric Air*

Humidified Air

Alveolar Air

Expired Air

(mm Hg)

N₂

597.0

(78.62%)

563.4

(74.09%)

569.0

(74.9%)

566.0

(74.5%)

O₂

159.0

(20.84%)

149.3

(19.67%)

104.0

(13.6%)

120.0

(15.7%)

CO₂

0.3

(0.04%)

0.3

(0.04%)

40.0

(5.3%)

27.0

(3.6%)

H₂O

3.7

(0.50%)

47.0

(6.20%)

47.0

(6.2%)

47.0

(6.2%)

TOTAL

760.0

(100.0%)

760.0

(100.0%)

760.0

(100.0%)

760.0

(100.0%)

* On an average cool, clear day.

494

Unit VII

Respiration

atmospheric air that enters the respiratory passages is

gas still has not been completely removed from the

humidified even before it reaches the alveoli.

alveoli.

Figure 39-3 demonstrates graphically the rate at

Humidification of the Air in the Respiratory Passages. Table

which excess gas in the alveoli is normally removed,

39-1 shows that atmospheric air is composed almost

showing that with normal alveolar ventilation, about

entirely of nitrogen and oxygen; it normally contains

one half the gas is removed in 17 seconds. When a

almost no carbon dioxide and little water vapor.

person’s rate of alveolar ventilation is only one half

However, as soon as the atmospheric air enters the res-

normal, one half the gas is removed in 34 seconds, and

piratory passages, it is exposed to the fluids that cover

when the rate of ventilation is twice normal, one half

the respiratory surfaces. Even before the air enters the

is removed in about 8 seconds.

alveoli, it becomes (for all practical purposes) totally

humidified.

Importance of the Slow Replacement of Alveolar Air. The slow

The partial pressure of water vapor at a normal

replacement of alveolar air is of particular importance

body temperature of 37°C is 47 mm Hg, which is there-

in preventing sudden changes in gas concentrations in

fore the partial pressure of water vapor in the alveo-

the blood. This makes the respiratory control mecha-

lar air. Because the total pressure in the alveoli

nism much more stable than it would be otherwise, and

cannot rise to more than the atmospheric pressure

it helps prevent excessive increases and decreases in

(760 mm Hg at sea level), this water vapor simply

tissue oxygenation, tissue carbon dioxide concentra-

dilutes all the other gases in the inspired air. Table 39-1

tion, and tissue pH when respiration is temporarily

also shows that humidification of the air dilutes the

interrupted.

oxygen partial pressure at sea level from an average

of 159 mm Hg in atmospheric air to 149 mm Hg in the

humidified air, and it dilutes the nitrogen partial pres-

Oxygen Concentration and Partial

sure from 597 to 563 mm Hg.

Pressure in the Alveoli

Oxygen is continually being absorbed from the alveoli

Rate at Which Alveolar Air Is Renewed

into the blood of the lungs, and new oxygen is contin-

by Atmospheric Air

ually being breathed into the alveoli from the atmos-

phere. The more rapidly oxygen is absorbed, the lower

In Chapter 37, it was pointed out that the average male

its concentration in the alveoli becomes; conversely,

functional residual capacity of the lungs (the volume

the more rapidly new oxygen is breathed into the

of air remaining in the lungs at the end of normal expi-

alveoli from the atmosphere, the higher its concentra-

ration) measures about 2300 milliliters. Yet only 350

tion becomes. Therefore, oxygen concentration in the

milliliters of new air is brought into the alveoli with

alveoli, and its partial pressure as well, is controlled by

each normal inspiration, and this same amount of old

(1) the rate of absorption of oxygen into the blood and

alveolar air is expired. Therefore, the volume of alve-

(2) the rate of entry of new oxygen into the lungs by

olar air replaced by new atmospheric air with each

the ventilatory process.

breath is only one seventh of the total, so that multi-

ple breaths are required to exchange most of the alve-

olar air. Figure 39-2 shows this slow rate of renewal of

the alveolar air. In the first alveolus of the figure, an

excess amount of a gas is present in the alveoli, but

note that even at the end of 16 breaths, the excess

100

1st breath

2nd breath

3rd breath

Time (seconds)

4th breath

8th breath

12th breath

16th breath

Figure 39-2

Figure 39-3

Expiration of a gas from an alveolus with successive breaths.

Rate of removal of excess gas from alveoli.

Chapter 39

Physical Principles of Gas Exchange; Diffusion of Oxygen and Carbon Dioxide

495

Upper limit at maximum ventilation

150

250 ml O₂/min

125

100

Normal alveolar PO

1000 ml O₂/min

Figure 39-4

Alveolar ventilation (L/min)

Effect of alveolar ventilation on the alveolar PO

2 at

two rates of oxygen absorption from the alveoli—

250 ml/min and 1000 ml/min. Point A is the normal

operating point.

Figure 39-4 shows the effect of both alveolar venti-

lation and rate of oxygen absorption into the blood on

the alveolar partial pressure of oxygen (Po₂). One

175

curve represents oxygen absorption at a rate of

150

250 ml/min, and the other curve represents a rate of

1000 ml/min. At a normal ventilatory rate of 4.2 L/min

125

and an oxygen consumption of 250 ml/min, the normal

800 ml CO₂/min

operating point in Figure 39-4 is point A. The figure

100

also shows that when 1000 milliliters of oxygen is being

absorbed each minute, as occurs during moderate

exercise, the rate of alveolar ventilation must increase

Normal alveolar PCO₂

fourfold to maintain the alveolar Po₂ at the normal

value of 104 mm Hg.

200 ml CO₂/min

Another effect shown in Figure 39-4 is that an

extremely marked increase in alveolar ventilation can

never increase the alveolar Po₂ above 149 mm Hg as

Alveolar ventilation (L/min)

long as the person is breathing normal atmospheric

air at sea level pressure, because this is the maximum

Po₂ in humidified air at this pressure. If the person

breathes gases that contain partial pressures of oxygen

Figure 39-5

higher than 149 mm Hg, the alveolar Po₂ can approach

these higher pressures at high rates of ventilation.

Effect of alveolar ventilation on the alveolar PCO₂ at two rates of

carbon dioxide excretion from the blood—800 ml/min and 200 ml/

min. Point A is the normal operating point.

CO₂ Concentration and Partial

Pressure in the Alveoli

to the rate of carbon dioxide excretion, as represented

Carbon dioxide is continually being formed in the

by the fourfold elevation of the curve (when 800

body and then carried in the blood to the alveoli; it is

milliliters of CO₂ are excreted per minute). Second,

continually being removed from the alveoli by venti-

the alveolar PCO₂ decreases in inverse proportion to

lation. Figure 39-5 shows the effects on the alveolar

alveolar ventilation. Therefore, the concentrations and

partial pressure of carbon dioxide (Pco₂) of both alve-

partial pressures of both oxygen and carbon dioxide in

olar ventilation and two rates of carbon dioxide excre-

the alveoli are determined by the rates of absorption

tion,

200 and 800 ml/min. One curve represents a

or excretion of the two gases and by the amount of

normal rate of carbon dioxide excretion of 200 ml/min.

alveolar ventilation.

At the normal rate of alveolar ventilation of 4.2 L/min,

the operating point for alveolar Pco₂ is at point A in

Expired Air

Figure 39-5—that is, 40 mm Hg.

Two other facts are also evident from Figure 39-5:

Expired air is a combination of dead space air and alve-

First, the alveolar PCO₂ increases directly in proportion

olar air; its overall composition is therefore determined

496

Unit VII Respiration

160

140

120

Oxygen (PO₂)

100

Dead

Alveolar air

space

and dead

Alveolar air

air

space air

Carbon dioxide (PCO₂)

100

200

300

400

500

Figure 39-6

Milliliters of air expired

Oxygen and carbon dioxide partial pressures in the

various portions of normal expired air.

by (1) the amount of the expired air that is dead space

air and (2) the amount that is alveolar air. Figure 39-6

shows the progressive changes in oxygen and carbon

dioxide partial pressures in the expired air during the

course of expiration. The first portion of this air, the

Terminal bronchiole

dead space air from the respiratory passageways, is

typical humidified air, as shown in Table 39-1. Then, pro-

gressively more and more alveolar air becomes mixed

with the dead space air until all the dead space air has

finally been washed out and nothing but alveolar air is

Respiratory bronchiole

expired at the end of expiration. Therefore, the method

Alveolar

of collecting alveolar air for study is simply to collect

duct

Alveoli

Atrium

a sample of the last portion of the expired air after

forceful expiration has removed all the dead space

air.

Normal expired air, containing both dead space air

and alveolar air, has gas concentrations and partial

pressures approximately as shown in Table 39-1—that

is, concentrations between those of alveolar air and

humidified atmospheric air.

Diffusion of Gases Through

the Respiratory Membrane

Alveolar sacs

Respiratory Unit. Figure 39-7 shows the respiratory unit

(also called “respiratory lobule”), which is composed

of a respiratory bronchiole, alveolar ducts, atria, and

alveoli. There are about 300 million alveoli in the two

lungs, and each alveolus has an average diameter of

Figure 39-7

about 0.2 millimeter. The alveolar walls are extremely

Respiratory unit. (Redrawn from Miller WS: The Lung. Springfield,

thin, and between the alveoli is an almost solid

Ill: Charles C Thomas, 1947.)

network of interconnecting capillaries, shown in

Figure 39-8. Indeed, because of the extensiveness of

the capillary plexus, the flow of blood in the alveolar

and the pulmonary blood occurs through the mem-

wall has been described as a “sheet” of flowing blood.

branes of all the terminal portions of the lungs, not

Thus, it is obvious that the alveolar gases are in very

merely in the alveoli themselves. All these membranes

close proximity to the blood of the pulmonary capil-

are collectively known as the respiratory membrane,

laries. Further, gas exchange between the alveolar air

also called the pulmonary membrane.

Chapter 39

Physical Principles of Gas Exchange; Diffusion of Oxygen and Carbon Dioxide

497

Epithelial

Alveolar

basement

epithelium

membrane

Fluid and

surfactant

layer

Alveolus

Capillary

Diffusion

Oxygen

Diffusion

Carbon dioxide

Alveolus

Red blood

Interstitial space

cell

Capillaries

Lymphatic

Alveolus

vessel

Capillary endothelium

Interstitial space

Capillary basement membrane

Figure 39-9

Perivascular

Ultrastructure of the alveolar respiratory membrane, shown in

Vein

Artery

interstitial space

cross section.

Alveolus

5. A capillary basement membrane that in many

places fuses with the alveolar epithelial basement

membrane

Figure 39-8

6. The capillary endothelial membrane

Despite the large number of layers, the overall

A, Surface view of capillaries in an alveolar wall. B, Cross-sec-

tional view of alveolar walls and their vascular supply. (A, From

thickness of the respiratory membrane in some areas

Maloney JE, Castle BL: Pressure-diameter relations of capillaries

is as little as 0.2 micrometer, and it averages about 0.6

and small blood vessels in frog lung. Respir Physiol 7:150, 1969.

Reproduced by permission of ASP Biological and Medical Press,

micrometer, except where there are cell nuclei. From

North-Holland Division.)

histological studies, it has been estimated that the total

surface area of the respiratory membrane is about 70

square meters in the normal adult human male. This is

Respiratory Membrane. Figure 39-9 shows the ultrastruc-

equivalent to the floor area of a 25-by-30-foot room.

ture of the respiratory membrane drawn in cross

The total quantity of blood in the capillaries of the

section on the left and a red blood cell on the right. It

lungs at any given instant is 60 to 140 milliliters. Now

also shows the diffusion of oxygen from the alveolus

imagine this small amount of blood spread over the

into the red blood cell and diffusion of carbon dioxide

entire surface of a 25-by-30-foot floor, and it is easy

in the opposite direction. Note the following different

to understand the rapidity of the respiratory exchange

layers of the respiratory membrane:

of oxygen and carbon dioxide.

1. A layer of fluid lining the alveolus and containing

The average diameter of the pulmonary capillaries

surfactant that reduces the surface tension of the

is only about 5 micrometers, which means that red

alveolar fluid

blood cells must squeeze through them. The red blood

2. The alveolar epithelium composed of thin

cell membrane usually touches the capillary wall, so

epithelial cells

that oxygen and carbon dioxide need not pass through

3. An epithelial basement membrane

significant amounts of plasma as they diffuse between

4. A thin interstitial space between the alveolar

the alveolus and the red cell. This, too, increases the

epithelium and the capillary membrane

rapidity of diffusion.

498

Unit VII

Respiration

Factors That Affect the Rate

pressure of the gas in the blood represents the number

of molecules that attempt to escape from the blood

of Gas Diffusion Through the

in the opposite direction. Therefore, the difference

Respiratory Membrane

between these two pressures is a measure of the net

tendency for the gas molecules to move through the

Referring to the earlier discussion of diffusion of gases

membrane. When the partial pressure of a gas in the

in water, one can apply the same principles and math-

alveoli is greater than the pressure of the gas in

ematical formulas to diffusion of gases through the

the blood, as is true for oxygen, net diffusion from the

respiratory membrane. Thus, the factors that deter-

alveoli into the blood occurs; when the pressure of the

mine how rapidly a gas will pass through the mem-

gas in the blood is greater than the partial pressure in

brane are (1) the thickness of the membrane, (2) the

the alveoli, as is true for carbon dioxide, net diffusion

surface area of the membrane, (3) the diffusion coeffi-

from the blood into the alveoli occurs.

cient of the gas in the substance of the membrane, and

(4) the partial pressure difference of the gas between

the two sides of the membrane.

Diffusing Capacity of the

The thickness of the respiratory membrane occa-

Respiratory Membrane

sionally increases—for instance, as a result of edema

fluid in the interstitial space of the membrane and in

The ability of the respiratory membrane to exchange

the alveoli—so that the respiratory gases must then

a gas between the alveoli and the pulmonary blood

diffuse not only through the membrane but also

is expressed in quantitative terms by the respiratory

through this fluid. Also, some pulmonary diseases

membrane’s diffusing capacity, which is defined as

cause fibrosis of the lungs, which can increase the

the volume of a gas that will diffuse through the mem-

thickness of some portions of the respiratory mem-

brane each minute for a partial pressure difference of

brane. Because the rate of diffusion through the mem-

1 mm Hg. All the factors discussed earlier that affect

brane is inversely proportional to the thickness of the

diffusion through the respiratory membrane can affect

membrane, any factor that increases the thickness to

this diffusing capacity.

more than two to three times normal can interfere sig-

nificantly with normal respiratory exchange of gases.

Diffusing Capacity for Oxygen. In the average young man,

The surface area of the respiratory membrane can be

the diffusing capacity for oxygen under resting condi-

greatly decreased by many conditions. For instance,

tions averages 21 ml/min/mm Hg. In functional terms,

removal of an entire lung decreases the total surface

what does this mean? The mean oxygen pressure

area to one half normal. Also, in emphysema, many of

difference across the respiratory membrane during

the alveoli coalesce, with dissolution of many alveolar

normal, quiet breathing is about 11 mm Hg. Multipli-

walls. Therefore, the new alveolar chambers are much

cation of this pressure by the diffusing capacity (11

larger than the original alveoli, but the total surface

21) gives a total of about 230 milliliters of oxygen dif-

area of the respiratory membrane is often decreased

fusing through the respiratory membrane each minute;

as much as fivefold because of loss of the alveolar

this is equal to the rate at which the resting body uses

walls. When the total surface area is decreased to

oxygen.

about one third to one fourth normal, exchange of

gases through the membrane is impeded to a signifi-

Change in Oxygen Diffusing Capacity During Exercise.

cant degree, even under resting conditions, and during

During strenuous exercise or other conditions that

competitive sports and other strenuous exercise, even

greatly increase pulmonary blood flow and alveolar

the slightest decrease in surface area of the lungs can

ventilation, the diffusing capacity for oxygen increases

be a serious detriment to respiratory exchange of

in young men to a maximum of about 65 ml/min/

gases.

mm Hg, which is three times the diffusing capacity

The diffusion coefficient for transfer of each gas

under resting conditions. This increase is caused by

through the respiratory membrane depends on the

several factors, among which are (1) opening up of

gas’s solubility in the membrane and, inversely, on the

many previously dormant pulmonary capillaries or

square root of the gas’s molecular weight. The rate

extra dilation of already open capillaries, thereby

of diffusion in the respiratory membrane is almost

increasing the surface area of the blood into which the

exactly the same as that in water, for reasons explained

oxygen can diffuse; and (2) a better match between

earlier. Therefore, for a given pressure difference,

the ventilation of the alveoli and the perfusion of the

carbon dioxide diffuses about 20 times as rapidly as

alveolar capillaries with blood, called the ventilation-

oxygen. Oxygen diffuses about twice as rapidly as

perfusion ratio, which is explained in detail later in

nitrogen.

this chapter. Therefore, during exercise, oxygenation of

The pressure difference across the respiratory mem-

the blood is increased not only by increased alveolar

brane is the difference between the partial pressure of

ventilation but also by greater diffusing capacity of

the gas in the alveoli and the partial pressure of the

the respiratory membrane for transporting oxygen into

gas in the pulmonary capillary blood. The partial pres-

the blood.

sure represents a measure of the total number of mol-

ecules of a particular gas striking a unit area of the

Diffusing Capacity for Carbon Dioxide. The diffusing capac-

alveolar surface of the membrane in unit time, and the

ity for carbon dioxide has never been measured

Chapter 39

Physical Principles of Gas Exchange; Diffusion of Oxygen and Carbon Dioxide

499

because of the following technical difficulty: Carbon

capacity by such a direct procedure, except on an exper-

dioxide diffuses through the respiratory membrane so

imental basis.

rapidly that the average Pco₂ in the pulmonary blood

To obviate the difficulties encountered in measuring

oxygen diffusing capacity directly, physiologists usually

is not far different from the Pco₂ in the alveoli—the

measure carbon monoxide diffusing capacity instead

average difference is less than 1 mm Hg—and with the

and then calculate the oxygen diffusing capacity from

available techniques, this difference is too small to be

this. The principle of the carbon monoxide method is

measured.

the following: A small amount of carbon monoxide is

Nevertheless, measurements of diffusion of other

breathed into the alveoli, and the partial pressure of the

gases have shown that the diffusing capacity varies

carbon monoxide in the alveoli is measured from appro-

directly with the diffusion coefficient of the particular

priate alveolar air samples. The carbon monoxide pres-

gas. Because the diffusion coefficient of carbon dioxide

sure in the blood is essentially zero, because hemoglobin

is slightly more than 20 times that of oxygen, one

combines with this gas so rapidly that its pressure never

would expect a diffusing capacity for carbon dioxide

has time to build up. Therefore, the pressure difference

of carbon monoxide across the respiratory membrane is

under resting conditions of about 400 to 450 ml/min/

equal to its partial pressure in the alveolar air sample.

mm Hg and during exercise of about 1200 to 1300 ml/

Then, by measuring the volume of carbon monoxide

min/mm Hg. Figure 39-10 compares the measured or

absorbed in a short period and dividing this by the

calculated diffusing capacities of carbon monoxide,

alveolar carbon monoxide partial pressure, one can

oxygen, and carbon dioxide at rest and during exercise,

determine accurately the carbon monoxide diffusing

showing the extreme diffusing capacity of carbon

capacity.

dioxide and the effect of exercise on the diffusing

To convert carbon monoxide diffusing capacity to

capacity of each of these gases.

oxygen diffusing capacity, the value is multiplied by a

factor of

1.23 because the diffusion coefficient for

Measurement of Diffusing Capacity—The Carbon Monoxide

oxygen is 1.23 times that for carbon monoxide. Thus,

Method. The oxygen diffusing capacity can be calculated

the average diffusing capacity for carbon monoxide

from measurements of (1) alveolar Po₂, (2) Po₂ in the

in young men at rest is 17 ml/min/mm Hg, and the

pulmonary capillary blood, and (3) the rate of oxygen

diffusing capacity for oxygen is

1.23 times this, or

uptake by the blood. However, measuring the Po₂ in the

21 ml/min/mm Hg.

pulmonary capillary blood is so difficult and so impre-

cise that it is not practical to measure oxygen diffusing

Effect of the Ventilation-

Perfusion Ratio on Alveolar

Gas Concentration

In the early part of this chapter, we learned that two

1300

Resting

factors determine the Po₂ and the Pco₂ in the alveoli: (1)

1200

the rate of alveolar ventilation and (2) the rate of trans-

Exercise

fer of oxygen and carbon dioxide through the respira-

1100

tory membrane. These earlier discussions made the

assumption that all the alveoli are ventilated equally

1000

and that blood flow through the alveolar capillaries is

the same for each alveolus. However, even normally to

900

some extent, and especially in many lung diseases, some

800

areas of the lungs are well ventilated but have almost

no blood flow, whereas other areas may have excellent

700

blood flow but little or no ventilation. In either of these

conditions, gas exchange through the respiratory mem-

600

brane is seriously impaired, and the person may suffer

severe respiratory distress despite both normal total

500

ventilation and normal total pulmonary blood flow, but

400

with the ventilation and blood flow going to different

parts of the lungs. Therefore, a highly quantitative

300

concept has been developed to help us understand res-

piratory exchange when there is imbalance between

200

alveolar ventilation and alveolar blood flow. This

concept is called the ventilation-perfusion ratio.

100

In quantitativ.e te.rms, the .entilation-perfusion ratio

is expressed as V

a/Q. When V

a (a.veolar ventilation) is

normal for a given alveolus and Q

(blood flow) is also

O₂

CO₂

normal.for.the same alveolus, the ventilation-perfusion

ratio (V

a/Q.

) is also said to be normal. When t .e venti-

lation (V

a) is .ero., yet there is still perfusion (Q) of the

alveolus, the V

a/Q

is zero. Or, at t.e other extreme,

Figure 39-10

when t.here is adequ.ate.ventilation (V

a) but zero perfu-

Diffusing capacities

for carbon monoxide, oxygen, and carbon

sion (Q), the ratio V

a/Q

is infinity. At a ratio of either

dioxide in the normal lungs under resting conditions and during

zero or infinity, there is no exchange of gases through

exercise.

the respiratory membrane of the affected alveoli, which

500

Unit VII

Respiration

explains the importance of this concept. Therefore, let

us explain the respiratory consequences of these two

extremes.

v VA /Q = 0

VA /Q = Normal

Alveolar Oxygen and .arb.n Dioxide Partial Pressures When VA/Q

(PO = 40)

Equals Zero. When V

a/Q

is equal to zero—that is, without

(PCO = 45)

any alveolar ventilation—the air in the alveolus

Normal alveolar

comes to equilibrium with the blood oxygen and carbon

air

dioxide because these gases diffuse between the blood

(PO = 104)

and the alveolar air. Because the blood that perfuses

(PCO = 40)

the capillaries is venous blood returning to the lungs

from the systemic circulation, it is the gases in this

(PO₂

= 149)

VA /Q = ∞

blood with which the alveolar gases equilibrate. In

(PCO = 0)

Chapter 40, we will learn that the normal venous blood

(v¯ ) has a Po2 of 40 mm Hg and a Pco2 of 45 mm Hg.

100

120

140

160

Therefore, these are also the normal partial pressures of

PO₂(mm Hg)

these two gases in alveoli that have blood flow but no

ventilation.

Alveolar Oxygen and Carbon Dioxide Partial Pressures When VA/Q

Figure 39-11

Equals Infinity. .Th . effect on the alveolar gas partial pres-

sures when V

a/Q

equa.ls i.nfinity is entirely different

Normal PO₂-PCO₂, VA/Q

diagram.

from the effect when V

a/Q

equals zero because now

there is no capillary blood flow to carry oxygen away or

to bring carbon dioxide to the alveoli. Therefore, instead

Concept of “Physiologic Shunt”

of the alveolar gases coming to equilibrium with the

(When VA/Q

Is Below Normal)

venous blood, the alveolar air becomes equal to the

humidified inspired air. That is, the air that is inspired

Whenever Va/Q

is below normal, there is inadequate

loses no oxygen to the blood and gains no carbon

ventilation to provide the oxygen needed to fully oxy-

dioxide from the blood. And because normal inspired

genate the blood flowing through the alveolar capil-

and humidified air has a Po₂ of 149 mm Hg and a Pco₂

laries. Therefore, a certain fraction of the venous

of 0 mm Hg, these will be the partial pressures of these

blood passing through the pulmonary capillaries does

two gases in the alveoli.

not become oxygenated. This fraction is called shunted

blood. Also, some additional blood flows through

Gas Exchange and Alveolar Partial Pressures When VA/Q

bronchial vessels rather than through alveolar capillar-

Normal. When there is both normal alveolar ventilation

ies, normally about 2 per cent of the cardiac output; this,

and normal alveolar capillary blood flow (normal alve-

too, is unoxygenated, shunted blood.

olar perfusion), exchange of oxygen and carbon dioxide

The total quantitative amount of shunted blood per

through the respiratory membrane is nearly optimal,

minute is called the physiologic shunt. This physiologic

and alveolar Po₂ is normally at a level of 104 mm Hg,

shunt is measured in clinical pulmonary function labo-

which lies between that of the inspired air (149 mm Hg)

ratories by analyzing the concentration of oxygen in

and that of venous blood

(40 mm Hg). Likewise,

both mixed venous blood and arterial blood, along with

alveolar Pco₂ lies between two extremes; it is normally

simultaneous measurement of cardiac output. From

40 mm Hg, in contrast to 45 mm Hg in venous blood and

these values, the physiologic shunt can be calculated by

0 mm Hg in inspired air. Thus, under normal conditions,

the following equation:

the alveolar air Po₂ averages 104 mm Hg and the Pco₂

averages 40 mm Hg.

Qps

-Ca

-Cv

PO₂-PCO₂, VA/Q

Diagram

in which.Qps is the physiologic shunt blood flow per

minute, Qt is cardiac output per minute, Ci is the con-O

The concepts presented in the preceding sections can be

centration of oxygen in the arterial blood if there is an

shown in graphical form, .s .emonstrated in Figure

“ideal” ventilation-perfusion ratio, Ca is the measured_O

39-11, called the Po₂-Pco₂, V

a/Q

diagram. The curve in

concentration of oxygen in the arterial blood, and C

¯_O

the diagram represents all possib.e .o2 and Pco2 com-

is the measured concentration of oxygen in the mixed

b.ina.tions between the limits of V

a/Q

equals zero and

venous blood.

a/Q

equals infinity when the gas pressures in the

The greater the physiologic shunt, the greater the

venous blood are normal and the person is breathing

amount of blood that fails to be oxygenated as it passes

air at sea-level p.res.ure. Thus, point v¯ is the plot of Po2

through the lungs.

and Pco₂ when V

a/Q

equals zero. At this point, the Po₂

is 40 mm Hg and the Pco₂ is 45 mm Hg, which are the

values in normal venous blood.

Concept of the “Physiologic Dead

At the other end of the curve, when Va/ Qequals infin-

Space” (When VA/Q

Is Greater

ity, point I represents inspired air, showing Po₂ to be 149

Than Normal)

mm Hg while Pco₂ is zero. Also plotted on the curve

i. th.e point that represents normal alveolar air when

When ventilation of some of the alveoli is great but

a/Q

is normal. At this point, Po₂ is 104 mm Hg and

alveolar blood flow is low, there is far more available

Pco₂ is 40 mm Hg.

oxygen in the alveoli than can be transported away from

Chapter 39

Physical Principles of Gas Exchange; Diffusion of Oxygen and Carbon Dioxide

501

the alveoli by the flowing blood. Thus, the ventilation of

t.wo.abnormalities occur in smokers to cause abnormal

these alveoli is said to be wasted. The ventilation of the

a/Q. First, because many of the small bronchioles are

anatomical dead space areas of the respiratory pas-

obstructed, the alveoli b.eyo.nd the obstructions are

sageways is also wasted. The sum of these two types of

unventilated, causing a V

a/Q

that approaches zero.

wasted ventilation is called the physiologic dead space.

Second, in those areas of the lung where the alveolar

This is measured in the clinical pulmonary function lab-

walls have been mainly destroyed but there is still

oratory by making appropriate blood and expiratory

alveolar ventilation, most of the ventilation is wasted

gas measurements and using the following equation,

because of inadequate blood flow to transport the blood

called the Bohr equation:

gases.

Thus, in chronic obstructive lung disease, some areas

phys

-Pe

of the lung exhibit serious physiologic shunt, and other

Pa_CO

areas exhibit serious physiologic dead space. Both these

conditions tremendously decrease the effectiveness of

in which Vd_phys is the physiologic dead space, Vt is the

the lungs as gas exchange organs, sometimes reducing

tidal volume, Pa

is the partial pressure of carbon

CO₂

their effectiveness to as little as one tenth normal. In

dioxide in the arterial blood, and

is the average

PeCO2

fact, this is the most prevalent cause of pulmonary dis-

partial pressure of carbon dioxide in the entire expired

ability today.

air.

When the physiologic dead space is great, much of the

work of ventilation is wasted effort because so much of

the ventilating air never reaches the blood.

References

Abnormalities of Ventilation-

Albert R, Spiro S, Jett J: Comprehensive Respiratory Medi-

Perfusion Ratio

cine. Philadelphia: Mosby, 2002.

Cole RP: CO₂ and lung mechanical or gas exchange func-

tion. Crit Care Med 32:1240, 2004.

Abnormal VA/Q

in the Upper and Lower Normal Lung. In a

Guazzi M: Alveolar-capillary membrane dysfunction in

normal person in the upright position, both pulmonary

heart failure: evidence of a pathophysiologic role. Chest

capillary blood flow and alveolar ventilation are con-

124:1090, 2003.

siderably less in the upper part of the lung than in the

Hsia CC: Recruitment of lung diffusing capacity: update of

lower part; however, blood flow is decreased consider-

concept and application. Chest 122:1774, 2002.

ably more.th.n ventilation is. Therefore, at the top of

Knight DA, Holgate ST: The airway epithelium: structural

the lung, V

a/Q

is as much as 2.5 times as great as the

and functional properties in health and disease. Respirol-

ideal value, which causes a moderate degree of physio-

ogy 8:432, 2003.

logic dead space in this area of the lung.

Otis AB: Quantitative relationships in steady-state gas

At the other extreme, in the bottom of the lung, there

exchange. In: Fenn WQ, Rahn H (eds): Handbook of Phys-

is slig.tly.too little ventilation in relation to blood flow,

iology. Sec 3, Vol 1. Baltimore: Williams & Wilkins, 1964,

with V

a/Q

as low as 0.6 times the ideal value. In this

p 681.

area, a small fraction of the blood fails to become

Parker JC, Townsley MI: Evaluation of lung injury in rats and

normally oxygenated, and this represents a physiologic

mice. Am J Physiol Lung Cell Mol Physiol 286:L231, 2004.

shunt.

Powell FL, Hopkins SR: Comparative physiology of lung

In both extremes, inequalities of ventilation and

complexity: implications for gas exchange. News Physiol

perfusion decrease slightly the lung’s effectiveness

Sci 19:55, 2004.

for exchanging oxygen and carbon dioxide. However,

Rahn H, Farhi EE: Ventilation, perfusion, and gas

during exercise, blood flow to the upper part of the lung

exchange—the Va/Q concept. In: Fenn WO, Rahn H (eds):

increases markedly, so that far less physiologic dead

Handbook of Physiology. Sec 3, Vol 1. Baltimore: Williams

space occurs, and the effectiveness of gas exchange now

& Wilkins, 1964, p 125.

approaches optimum.

Uhlig S, Taylor AE: Methods in Pulmonary Research. Basel:

Birkhauser Verlag, 1998.

Abnormal VA/Q

in Chronic Obstructive Lung Disease. Most

West JB: Pulmonary Physiology and Pathophysiology: An

people who smoke for many years develop various

Integrated, Case-Based Approach. Philadelphia: Lippin-

degrees of bronchial obstruction; in a large share of

cott Williams & Wilkins, 2001.

these persons, this condition eventually becomes so

West JB: Pulmonary Physiology—The Essentials. Baltimore:

severe that they develop serious alveolar air trapping

Lippincott Williams & Wilkins, 2003.

and resultant emphysema. The emphysema in turn

Williams MC: Alveolar type I cells: molecular phenotype and

causes many of the alveolar walls to be destroyed. Thus,

development. Annu Rev Physiol 65:669, 2003.

C H A P T E R

Transport of Oxygen and Carbon

Dioxide in Blood and Tissue Fluids

Once oxygen has diffused from the alveoli into

the pulmonary blood, it is transported to the

peripheral tissue capillaries almost entirely in com-

bination with hemoglobin. The presence of hemo-

globin in the red blood cells allows the blood to

transport 30 to 100 times as much oxygen as could

be transported in the form of dissolved oxygen in

the water of the blood.

In the body’s tissue cells, oxygen reacts with various foodstuffs to form large

quantities of carbon dioxide. This carbon dioxide enters the tissue capillaries

and is transported back to the lungs. Carbon dioxide, like oxygen, also combines

with chemical substances in the blood that increase carbon dioxide transport

15- to 20-fold.

The purpose of this chapter is to present both qualitatively and quantitatively

the physical and chemical principles of oxygen and carbon dioxide transport in

the blood and tissue fluids.

Transport of Oxygen from the Lungs to the

Body Tissues

In Chapter 39, we pointed out that gases can move from one point to another

by diffusion and that the cause of this movement is always a partial pressure

difference from the first point to the next. Thus, oxygen diffuses from the alveoli

into the pulmonary capillary blood because the oxygen partial pressure (Po₂)

in the alveoli is greater than the Po₂ in the pulmonary capillary blood. In the

other tissues of the body, a higher Po₂ in the capillary blood than in the tissues

causes oxygen to diffuse into the surrounding cells.

Conversely, when oxygen is metabolized in the cells to form carbon dioxide,

the intracellular carbon dioxide pressure (Pco₂) rises to a high value, which

causes carbon dioxide to diffuse into the tissue capillaries. After blood flows to

the lungs, the carbon dioxide diffuses out of the blood into the alveoli, because

the Pco₂ in the pulmonary capillary blood is greater than that in the alveoli.

Thus, the transport of oxygen and carbon dioxide by the blood depends on both

diffusion and the flow of blood. We now consider quantitatively the factors

responsible for these effects.

Diffusion of Oxygen from the Alveoli to the Pulmonary

Capillary Blood

The top part of Figure 40-1 shows a pulmonary alveolus adjacent to a pul-

monary capillary, demonstrating diffusion of oxygen molecules between the

alveolar air and the pulmonary blood. The Po₂ of the gaseous oxygen in the

alveolus averages 104 mm Hg, whereas the Po₂ of the venous blood entering the

pulmonary capillary at its arterial end averages only 40 mm Hg because a large

amount of oxygen was removed from this blood as it passed through the periph-

eral tissues. Therefore, the initial pressure difference that causes oxygen to

diffuse into the pulmonary capillary is 104 - 40, or 64 mm Hg. In the graph at

502

Chapter 40

Transport of Oxygen and Carbon Dioxide in Blood and Tissue Fluids

503

Mixed with

Alveolus PO

2 = 104 mm Hg

pulmonary

shunt blood

100

Systemic

Pulmonary Capillary

venous

PO2 = 40 mm Hg

PO2 = 104 mm Hg

blood

Arterial End

Venous End

Pulmonary

Systemic

capillaries

arterial

capillaries

venous

110

Alveolar oxygen partial pressure

blood

100

Figure 40-2

Changes in PO₂ in the pulmonary capillary blood, systemic arte-

rial blood, and systemic capillary blood, demonstrating the effect

of “venous admixture.”

Figure 40-1

Therefore, during exercise, even with a shortened time

Uptake of oxygen by the pulmonary capillary blood. (The curve in

of exposure in the capillaries, the blood can still

this figure was constructed from data in Milhorn HT Jr, Pulley PE

become fully oxygenated, or nearly so.

Jr: A theoretical study of pulmonary capillary gas exchange and

venous admixture. Biophys J 8:337, 1968.)

Transport of Oxygen in the

Arterial Blood

the bottom of the figure, the curve shows the rapid rise

in blood Po₂ as the blood passes through the capillary;

About 98 per cent of the blood that enters the left

the blood Po₂ rises almost to that of the alveolar air by

atrium from the lungs has just passed through the alve-

the time the blood has moved a third of the distance

olar capillaries and has become oxygenated up to a Po₂

through the capillary, becoming almost 104 mm Hg.

of about 104 mm Hg. Another 2 per cent of the blood

has passed from the aorta through the bronchial cir-

Uptake of Oxygen by the Pulmonary Blood During Exercise.

culation, which supplies mainly the deep tissues of the

During strenuous exercise, a person’s body may

lungs and is not exposed to lung air. This blood flow is

require as much as 20 times the normal amount of

called “shunt flow,” meaning that blood is shunted past

oxygen. Also, because of increased cardiac output

the gas exchange areas. On leaving the lungs, the Po₂

during exercise, the time that the blood remains in the

of the shunt blood is about that of normal systemic

pulmonary capillary may be reduced to less than one

venous blood, about

40 mm Hg. When this blood

half normal. Yet, because of the great safety factor for

combines in the pulmonary veins with the oxygenated

diffusion of oxygen through the pulmonary mem-

blood from the alveolar capillaries, this so-called

brane, the blood still becomes almost saturated with

venous admixture of blood causes the Po₂ of the blood

oxygen by the time it leaves the pulmonary capillaries.

entering the left heart and pumped into the aorta to

This can be explained as follows.

fall to about 95 mm Hg. These changes in blood Po₂ at

First, it was pointed out in Chapter 39 that the dif-

different points in the circulatory system are shown in

fusing capacity for oxygen increases almost threefold

Figure 40-2.

during exercise; this results mainly from increased

surface area of capillaries participating in the diffusion

Diffusion of Oxygen from the

and also from a more nearly ideal ventilation-perfu-

sion ratio in the upper part of the lungs.

Peripheral Capillaries into the

Second, note in the curve of Figure 40-1 that under

Tissue Fluid

nonexercising conditions, the blood becomes almost

saturated with oxygen by the time it has passed

When the arterial blood reaches the peripheral tissues,

through one third of the pulmonary capillary, and little

its Po₂ in the capillaries is still 95 mm Hg. Yet, as shown

additional oxygen normally enters the blood during

in Figure 40-3, the Po₂ in the interstitial fluid that sur-

the latter two thirds of its transit. That is, the blood

rounds the tissue cells averages only 40 mm Hg. Thus,

normally stays in the lung capillaries about three

there is a tremendous initial pressure difference that

times as long as necessary to cause full oxygenation.

causes oxygen to diffuse rapidly from the capillary

504

Unit VII

Respiration

In summary, tissue Po₂ is determined by a balance

Arterial end

Venous end

between (1) the rate of oxygen transport to the tissues

40 mm Hg

of capillary

in the blood and (2) the rate at which the oxygen is used

by the tissues.

PO2 = 95 mm Hg

23 mm Hg

PO₂

= 40 mm Hg

Diffusion of Oxygen from the

Peripheral Capillaries to the

Figure 40-3

Tissue Cells

Diffusion of oxygen from a tissue capillary to the cells. (PO₂

interstitial fluid = 40 mm Hg, and in tissue cells = 23 mm Hg.)

Oxygen is always being used by the cells. Therefore,

the intracellular Po₂

in the peripheral tissue cells

remains lower than the Po₂ in the peripheral capillar-

ies. Also, in many instances, there is considerable phys-

ical distance between the capillaries and the cells.

100

Upper limit of infinite blood flow

Therefore, the normal intracellular Po₂ ranges from

as low as 5 mm Hg to as high as 40 mm Hg, averaging

(by direct measurement in lower animals) 23 mm Hg.

Because only 1 to 3 mm Hg of oxygen pressure is

normally required for full support of the chemical

processes that use oxygen in the cell, one can see that

even this low intracellular Po₂ of 23 mm Hg is more

than adequate and provides a large safety factor.

Diffusion of Carbon Dioxide from

the Peripheral Tissue Cells into the

100

200

300

400

500

600

700

Capillaries and from the Pulmonary

Blood flow (per cent of normal)

Capillaries into the Alveoli

When oxygen is used by the cells, virtually all of it

becomes carbon dioxide, and this increases the intra-

Figure 40-4

cellular Pco₂; because of this high tissue cell Pco₂,

Effect of blood flow and rate of oxygen consumption on tissue PO₂.

carbon dioxide diffuses from the cells into the tissue

capillaries and is then carried by the blood to the lungs.

In the lungs, it diffuses from the pulmonary capillaries

blood into the tissues—so rapidly that the capillary Po₂

into the alveoli and is expired.

falls almost to equal the 40 mm Hg pressure in the

Thus, at each point in the gas transport chain, carbon

interstitium. Therefore, the Po₂ of the blood leaving

dioxide diffuses in the direction exactly opposite to the

the tissue capillaries and entering the systemic veins is

diffusion of oxygen. Yet there is one major difference

also about 40 mm Hg.

between diffusion of carbon dioxide and of oxygen:

carbon dioxide can diffuse about 20 times as rapidly as

Effect of Rate of Blood Flow on Interstitial Fluid PO

2. If the

oxygen. Therefore, the pressure differences required to

blood flow through a particular tissue is increased,

cause carbon dioxide diffusion are, in each instance, far

greater quantities of oxygen are transported into the

less than the pressure differences required to cause

tissue, and the tissue Po₂

becomes correspondingly

oxygen diffusion. The CO₂ pressures are approxi-

higher. This is shown in Figure 40-4. Note that an

mately the following:

increase in flow to 400 per cent of normal increases

1. Intracellular Pco₂, 46 mm Hg; interstitial Pco₂,

the Po₂ from 40 mm Hg (at point A in the figure) to

66 mm Hg (at point B). However, the upper limit to

45 mm Hg. Thus, there is only a 1 mm Hg pressure

which the Po₂ can rise, even with maximal blood flow, is

differential, as shown in Figure 40-5.

95 mm Hg, because this is the oxygen pressure in the

2. Pco₂ of the arterial blood entering the tissues,

arterial blood. Conversely, if blood flow through the

40 mm Hg; Pco₂ of the venous blood leaving the

tissue decreases, the tissue Po₂ also decreases, as shown

tissues, 45 mm Hg. Thus, as shown in Figure 40-5,

at point C.

the tissue capillary blood comes almost exactly

to equilibrium with the interstitial Pco₂

Effect of Rate of Tissue Metabolism on Interstitial Fluid PO

2. If

45 mm Hg.

the cells use more oxygen for metabolism than nor-

3. Pco₂ of the blood entering the pulmonary

mally, this reduces the interstitial fluid Po₂. Figure 40-4

capillaries at the arterial end, 45 mm Hg; Pco₂ of

also demonstrates this effect, showing reduced intersti-

tial fluid Po₂ when the cellular oxygen consumption is

the alveolar air, 40 mm Hg. Thus, only a 5 mm Hg

increased, and increased Po₂

when consumption is

pressure difference causes all the required carbon

decreased.

dioxide diffusion out of the pulmonary capillaries

Chapter 40

Transport of Oxygen and Carbon Dioxide in Blood and Tissue Fluids

505

Arterial end

Venous end

of capillary

45 mm Hg

of capillary

120

PCO₂ = 40 mm Hg

46 mm Hg

PCO₂ = 45 mm Hg

100

Figure 40-5

normal metabolism

Uptake of carbon dioxide by the blood in the tissue capillaries.

(PCO₂

in tissue cells

= 46 mm Hg, and in interstitial fluid

Normal metabolism

45 mm Hg.)

Lower limit of infinite blood flow

¹/4 normal metabolism

Alveolus PCO

2 = 40 mm Hg

100

200

300

400

500

600

Blood flow (per cent of normal)

Pulmonary Capillary

PCO2 = 45 mm Hg

PCO

2 = 40 mm Hg

Arterial End

Venous End

Figure 40-7

Effect of blood flow and metabolic rate on peripheral tissue PCO₂.

Pco₂ from the normal value of 45 mm Hg to

41 mm Hg, down to a level almost equal to the

Pco₂ in the arterial blood (40 mm Hg) entering

Pulmonary capillary blood

the tissue capillaries.

Alveolar carbon dioxide partial pressure

2. Note also that a 10-fold increase in tissue

metabolic rate greatly elevates the interstitial fluid

Pco₂ at all rates of blood flow, whereas decreasing

the metabolism to one quarter normal causes the

Figure 40-6

interstitial fluid Pco₂ to fall to about 41 mm Hg,

closely approaching that of the arterial blood,

Diffusion of carbon dioxide from the pulmonary blood into the alve-

40 mm Hg.

olus. (This curve was constructed from data in Milhorn HT Jr,

Pulley PE Jr: A theoretical study of pulmonary capillary gas

exchange and venous admixture. Biophys J 8:337, 1968.)

Role of Hemoglobin in Oxygen

Transport

into the alveoli. Furthermore, as shown in Figure

40-6, the Pco₂ of the pulmonary capillary blood

Normally, about 97 per cent of the oxygen transported

falls to almost exactly equal the alveolar Pco₂ of

from the lungs to the tissues is carried in chemical

40 mm Hg before it has passed more than about

combination with hemoglobin in the red blood cells.

one third the distance through the capillaries. This

The remaining 3 per cent is transported in the dis-

is the same effect that was observed earlier for

solved state in the water of the plasma and blood cells.

oxygen diffusion, except that it is in the opposite

Thus, under normal conditions, oxygen is carried to the

direction.

tissues almost entirely by hemoglobin.

Effect of Rate of Tissue Metabolism and Tissue Blood Flow on

Reversible Combination of Oxygen

Interstitial PCO₂. Tissue capillary blood flow and tissue

metabolism affect the Pco₂ in ways exactly opposite to

with Hemoglobin

their effect on tissue Po₂. Figure 40-7 shows these

effects, as follows:

The chemistry of hemoglobin is presented in Chapter

1. A decrease in blood flow from normal (point A)

32, where it was pointed out that the oxygen molecule

to one quarter normal (point B) increases

combines loosely and reversibly with the heme portion

peripheral tissue Pco₂ from the normal value of

of hemoglobin. When Po₂ is high, as in the pulmonary

45 mm Hg to an elevated level of 60 mm Hg.

capillaries, oxygen binds with the hemoglobin, but

Conversely, increasing the blood flow to six

when Po₂ is low, as in the tissue capillaries, oxygen is

times normal (point C) decreases the interstitial

released from the hemoglobin. This is the basis for

506

Unit VII Respiration

100

Oxygenated blood

leaving the lungs

Reduced blood returning

from tissues

100

110

120

130

140

Pressure of oxygen in blood (PO₂) (mm Hg)

Figure 40-8

Oxygen-hemoglobin dissociation curve.

almost all oxygen transport from the lungs to the

tissues.

Oxygen-Hemoglobin Dissociation Curve. Figure 40-8 shows

the oxygen-hemoglobin dissociation curve, which

demonstrates a progressive increase in the percentage

of hemoglobin bound with oxygen as blood Po₂

increases, which is called the per cent saturation of

hemoglobin. Because the blood leaving the lungs and

entering the systemic arteries usually has a Po₂ of

about 95 mm Hg, one can see from the dissociation

curve that the usual oxygen saturation of systemic arte-

rial blood averages 97 per cent. Conversely, in normal

venous blood returning from the peripheral tissues, the

Po₂ is about 40 mm Hg, and the saturation of hemo-

100

120

140

globin averages 75 per cent.

Pressure of oxygen in blood (PO₂) (mm Hg)

Maximum Amount of Oxygen That Can Combine with the

Hemoglobin of the Blood. The blood of a normal person

contains about 15 grams of hemoglobin in each 100

Figure 40-9

milliliters of blood, and each gram of hemoglobin can

bind with a maximum of 1.34 milliliters of oxygen (1.39

Effect of blood PO₂ on the quantity of oxygen bound with hemo-

globin in each 100 milliliters of blood.

milliliters when the hemoglobin is chemically pure, but

impurities such as methemoglobin reduce this). There-

fore, 15 times 1.34 equals 20.1, which means that, on

average, the 15 grams of hemoglobin in 100 milliliters

systemic arterial blood, which is 97 per cent saturated,

of blood can combine with a total of almost exactly 20

is about 19.4 milliliters per 100 milliliters of blood. This

milliliters of oxygen if the hemoglobin is 100 per cent

is shown in Figure 40-9. On passing through the tissue

saturated. This is usually expressed as 20 volumes per

capillaries, this amount is reduced, on average, to

cent. The oxygen-hemoglobin dissociation curve for

14.4 milliliters (Po₂ of 40 mm Hg, 75 per cent saturated

the normal person can also be expressed in terms of

hemoglobin). Thus, under normal conditions, about 5

volume per cent of oxygen, as shown by the far right

milliliters of oxygen are transported from the lungs to

scale in Figure 40-8, instead of per cent saturation of

the tissues by each 100 milliliters of blood flow.

hemoglobin.

Transport of Oxygen During Strenuous Exercise. During

Amount of Oxygen Released from the Hemoglobin When Sys-

heavy exercise, the muscle cells use oxygen at a rapid

temic Arterial Blood Flows Through the Tissues. The total

rate, which, in extreme cases, can cause the muscle

quantity of oxygen bound with hemoglobin in normal

interstitial fluid Po₂ to fall from the normal 40 mm Hg

Chapter 40

Transport of Oxygen and Carbon Dioxide in Blood and Tissue Fluids

507

to as low as 15 mm Hg. At this low pressure, only 4.4

because of (1) the steep slope of the dissociation curve

milliliters of oxygen remain bound with the hemoglo-

and (2) the increase in tissue blood flow caused by the

bin in each 100 milliliters of blood, as shown in Figure

decreased Po₂; that is, a very small fall in Po₂ causes

40-9. Thus, 19.4 - 4.4, or 15 milliliters, is the quantity

large amounts of extra oxygen to be released from the

of oxygen actually delivered to the tissues by each 100

hemoglobin. It can be seen, then, that the hemoglobin

milliliters of blood flow. Thus, three times as much

in the blood automatically delivers oxygen to the

oxygen as normal is delivered in each volume of blood

tissues at a pressure that is held rather tightly between

that passes through the tissues. And keep in mind that

about 15 and 40 mm Hg.

the cardiac output can increase to six to seven times

normal in well-trained marathon runners. Thus, multi-

When Atmospheric Oxygen Concentration Changes Markedly,

plying the increase in cardiac output (six- to sevenfold)

the Buffer Effect of Hemoglobin Still Maintains Almost Constant

by the increase in oxygen transport in each volume of

Tissue PO₂. The normal Po₂

in the alveoli is about

blood (threefold) gives a 20-fold increase in oxygen

104 mm Hg, but as one ascends a mountain or ascends

transport to the tissues. We see later in the chapter

in an airplane, the Po₂ can easily fall to less than half

that several other factors facilitate delivery of oxygen

this amount. Alternatively, when one enters areas of

into muscles during exercise, so that muscle tissue Po₂

compressed air, such as deep in the sea or in pressur-

often falls very little below normal even during very

ized chambers, the Po₂ may rise to 10 times this level.

strenuous exercise.

Even so, the tissue Po₂ changes little.

It can be seen from the oxygen-hemoglobin dissoci-

Utilization Coefficient. The percentage of the blood that

ation curve in Figure 40-8 that when the alveolar Po₂

gives up its oxygen as it passes through the tissue cap-

is decreased to as low as 60 mm Hg, the arterial hemo-

illaries is called the utilization coefficient. The normal

globin is still 89 per cent saturated with oxygen—only

value for this is about 25 per cent, as is evident from

8 per cent below the normal saturation of 97 per cent.

the preceding discussion—that is, 25 per cent of the

Further, the tissues still remove about 5 milliliters of

oxygenated hemoglobin gives its oxygen to the tissues.

oxygen from each 100 milliliters of blood passing

During strenuous exercise, the utilization coefficient in

through the tissues; to remove this oxygen, the Po₂

the entire body can increase to 75 to 85 per cent. And

of the venous blood falls to 35 mm Hg—only 5 mm Hg

in local tissue areas where blood flow is extremely

below the normal value of 40 mm Hg. Thus, the tissue

slow or the metabolic rate is very high, utilization

Po₂ hardly changes, despite the marked fall in alveolar

coefficients approaching

100 per cent have been

Po₂ from 104 to 60 mm Hg.

recorded—that is, essentially all the oxygen is given to

Conversely, when the alveolar Po₂ rises as high as

the tissues.

500 mm Hg, the maximum oxygen saturation of

hemoglobin can never rise above 100 per cent, which

is only 3 per cent above the normal level of 97 per cent.

Effect of Hemoglobin to “Buffer” the

Only a small amount of additional oxygen dissolves in

Tissue PO₂

the fluid of the blood, as will be discussed subse-

quently. Then, when the blood passes through the

Although hemoglobin is necessary for the transport of

tissue capillaries and loses several milliliters of oxygen

oxygen to the tissues, it performs another function

to the tissues, this reduces the Po₂ of the capillary

essential to life. This is its function as a “tissue oxygen

blood to a value only a few millimeters greater than

buffer” system. That is, the hemoglobin in the blood is

the normal 40 mm Hg. Consequently, the level of alve-

mainly responsible for stabilizing the oxygen pressure

olar oxygen may vary greatly—from 60 to more than

in the tissues. This can be explained as follows.

500 mm Hg Po₂—and still the Po₂ in the peripheral

tissues does not vary more than a few millimeters from

Role of Hemoglobin in Maintaining Nearly Constant PO₂ in the

normal, demonstrating beautifully the tissue “oxygen

Tissues. Under basal conditions, the tissues require

buffer” function of the blood hemoglobin system.

about 5 milliliters of oxygen from each 100 milliliters

of blood passing through the tissue capillaries. Refer-

ring back to the oxygen-hemoglobin dissociation curve

Factors That Shift the Oxygen-

in Figure 40-9, one can see that for the normal 5 mil-

Hemoglobin Dissociation Curve—

liliters of oxygen to be released per 100 milliliters of

blood flow, the Po₂ must fall to about 40 mm Hg.

Their Importance for Oxygen

Therefore, the tissue Po₂ normally cannot rise above

Transport

this 40 mm Hg level, because if it did, the amount of

oxygen needed by the tissues would not be released

The oxygen-hemoglobin dissociation curves of Figures

from the hemoglobin. In this way, the hemoglobin nor-

40-8 and

40-9 are for normal, average blood.

mally sets an upper limit on the oxygen pressure in the

However, a number of factors can displace the disso-

tissues at about 40 mm Hg.

ciation curve in one direction or the other in the

Conversely, during heavy exercise, extra amounts of

manner shown in Figure 40-10. This figure shows

oxygen (as much as 20 times normal) must be deliv-

that when the blood becomes slightly acidic, with the

ered from the hemoglobin to the tissues. But this can

pH decreasing from the normal value of 7.4 to 7.2, the

be achieved with little further decrease in tissue Po₂

oxygen-hemoglobin dissociation curve shifts, on

508

Unit VII

Respiration

oxygen-hemoglobin dissociation curve to the left and

upward. Therefore, the quantity of oxygen that binds

with the hemoglobin at any given alveolar Po₂

becomes considerably increased, thus allowing greater

100

oxygen transport to the tissues.

Effect of BPG to Shift the Oxygen-Hemoglobin Dissociation

Curve. The normal BPG in the blood keeps the

oxygen-hemoglobin dissociation curve shifted slightly

Shift to right:

to the right all the time. In hypoxic conditions that

(1) Increased hydrogen ions

(2) Increased CO₂

last longer than a few hours, the quantity of BPG in

(3) Increased temperature

the blood increases considerably, thus shifting the

(4) Increased BPG

oxygen-hemoglobin dissociation curve even farther to

the right. This causes oxygen to be released to the

tissues at as much as 10 mm Hg higher tissue oxygen

pressure than would be the case without this increased

0 10 20 30 40 50 60 70 80 90100110

120130

140

BPG. Therefore, under some conditions, the BPG

Pressure of oxygen in blood (PO₂) (mm Hg)

mechanism can be important for adaptation to

hypoxia, especially to hypoxia caused by poor tissue

blood flow.

Shift of the Dissociation Curve During Exercise. During exer-

Figure 40-10

cise, several factors shift the dissociation curve con-

Shift of the oxygen-hemoglobin dissociation curve to the right

siderably to the right, thus delivering extra amounts

caused by an increase in hydrogen ion concentration (decrease

of oxygen to the active, exercising muscle fibers. The

in pH). BPG, 2,3-biphosphoglycerate.

exercising muscles, in turn, release large quantities of

carbon dioxide; this and several other acids released

by the muscles increase the hydrogen ion concentra-

average, about 15 per cent to the right. Conversely, an

tion in the muscle capillary blood. In addition, the tem-

increase in pH from the normal 7.4 to 7.6 shifts the

perature of the muscle often rises 2° to 3°C, which can

curve a similar amount to the left.

increase oxygen delivery to the muscle fibers even

In addition to pH changes, several other factors are

more. All these factors act together to shift the oxygen-

known to shift the curve. Three of these, all of which

hemoglobin dissociation curve of the muscle capillary

shift the curve to the right, are (1) increased carbon

blood considerably to the right. This right-hand shift

dioxide concentration, (2) increased blood tempera-

of the curve forces oxygen to be released from the

ture, and (3) increased 2,3-biphosphoglycerate (BPG),

blood hemoglobin to the muscle at Po₂ levels as great

a metabolically important phosphate compound

as 40 mm Hg, even when 70 per cent of the oxygen has

present in the blood in different concentrations under

already been removed from the hemoglobin. Then, in

different metabolic conditions.

the lungs, the shift occurs in the opposite direction,

allowing the pickup of extra amounts of oxygen from

Increased Delivery of Oxygen to the Tissues When Carbon

the alveoli.

Dioxide and Hydrogen Ions Shift the Oxygen-Hemoglobin Disso-

ciation Curve—The Bohr Effect. A shift of the oxygen-

hemoglobin dissociation curve to the right in response

Metabolic Use of Oxygen by the Cells

to increases in blood carbon dioxide and hydrogen

ions has a significant effect by enhancing the release

Effect of Intracellular PO₂ on Rate of Oxygen Usage. Only

of oxygen from the blood in the tissues and enhancing

a minute level of oxygen pressure is required in the

oxygenation of the blood in the lungs. This is called the

cells for normal intracellular chemical reactions to

Bohr effect, which can be explained as follows: As the

take place. The reason for this is that the respiratory

blood passes through the tissues, carbon dioxide dif-

enzyme systems of the cell, which are discussed in

fuses from the tissue cells into the blood. This increases

Chapter 67, are geared so that when the cellular Po₂ is

the blood Po_2, which in turn raises the blood H₂CO₃

more than 1 mm Hg, oxygen availability is no longer a

(carbonic acid) and the hydrogen ion concentration.

limiting factor in the rates of the chemical reactions.

These effects shift the oxygen-hemoglobin dissocia-

Instead, the main limiting factor is the concentration

tion curve to the right and downward, as shown in

of adenosine diphosphate (ADP) in the cells. This

Figure 40-10, forcing oxygen away from the hemoglo-

effect is demonstrated in Figure 40-11, which shows

bin and therefore delivering increased amounts of

the relation between intracellular Po₂ and the rate of

oxygen to the tissues.

oxygen usage at different concentrations of ADP. Note

Exactly the opposite effects occur in the lungs,

that whenever the intracellular Po₂ is above 1 mm Hg,

where carbon dioxide diffuses from the blood into

the rate of oxygen usage becomes constant for any

the alveoli. This reduces the blood Pco₂ and decreases

given concentration of ADP in the cell. Conversely,

the hydrogen ion concentration, shifting the

when the ADP concentration is altered, the rate of

Chapter 40

Transport of Oxygen and Carbon Dioxide in Blood and Tissue Fluids

509

oxygen that can be transported to the tissue in each

100 milliliters of blood and (2) the rate of blood flow.

If the rate of blood flow falls to zero, the amount of

ADP = 1¹/2 normal

available oxygen also falls to zero. Thus, there are

1.5

times when the rate of blood flow through a tissue

can be so low that tissue Po₂ falls below the critical

1 mm Hg required for intracellular metabolism. Under

ADP = Normal resting level

these conditions, the rate of tissue usage of oxygen

1.0

is blood flow limited. Neither diffusion-limited nor

blood flow-limited oxygen states can continue for

long, because the cells receive less oxygen than is

required to continue the life of the cells.

ADP =

¹/2 normal

0.5

Transport of Oxygen in the

Dissolved State

At the normal arterial Po₂ of 95 mm Hg, about 0.29 mil-

liliter of oxygen is dissolved in every 100 milliliters of

water in the blood, and when the Po₂ of the blood falls

Intracellular PO₂(mm Hg)

to the normal 40 mm Hg in the tissue capillaries, only

0.12 milliliter of oxygen remains dissolved. In other

words, 0.17 milliliter of oxygen is normally transported

in the dissolved state to the tissues by each 100 milli-

liters of arterial blood flow. This compares with almost

Figure 40-11

5 milliliters of oxygen transported by the red cell hemo-

Effect of intracellular adenosine diphosphate (ADP) and PO₂ on

globin. Therefore, the amount of oxygen transported to

rate of oxygen usage by the cells. Note that as long as the intra-

the tissues in the dissolved state is normally slight, only

cellular PO₂

remains above 1 mm Hg, the controlling factor for the

about 3 per cent of the total, as compared with 97 per

rate of oxygen usage is the intracellular concentration of ADP.

cent transported by the hemoglobin.

During strenuous exercise, when hemoglobin release

of oxygen to the tissues increases another threefold, the

oxygen usage changes in proportion to the change in

relative quantity of oxygen transported in the dissolved

ADP concentration.

state falls to as little as 1.5 per cent. But if a person

As explained in Chapter 3, when adenosine triphos-

breathes oxygen at very high alveolar Po₂ levels, the

amount transported in the dissolved state can become

phate (ATP) is used in the cells to provide energy, it is

much greater, sometimes so much so that a serious

converted into ADP. The increasing concentration

excess of oxygen occurs in the tissues, and “oxygen poi-

of ADP increases the metabolic usage of oxygen as

soning” ensues. This often leads to brain convulsions

it combines with the various cell nutrients, releasing

and even death, as discussed in detail in Chapter 44

energy that reconverts the ADP back to ATP. Under

in relation to the high-pressure breathing of oxygen

normal operating conditions, the rate of oxygen usage

among deep-sea divers.

by the cells is controlled ultimately by the rate of energy

expenditure within the cells—that is, by the rate at which

ADP is formed from ATP.

Combination of Hemoglobin with

Carbon Monoxide—Displacement

Effect of Diffusion Distance from the Capillary to the Cell on

of Oxygen

Oxygen Usage. Tissue cells are seldom more than 50

Carbon monoxide combines with hemoglobin at the

micrometers away from a capillary, and oxygen nor-

same point on the hemoglobin molecule as does oxygen;

mally can diffuse readily enough from the capillary to

it can therefore displace oxygen from the hemoglobin,

the cell to supply all the required amounts of oxygen

thereby decreasing the oxygen carrying capacity of

for metabolism. However, occasionally, cells are

blood. Further, it binds with about 250 times as much

located farther from the capillaries, and the rate of

tenacity as oxygen, which is demonstrated by the carbon

oxygen diffusion to these cells can become so low that

monoxide-hemoglobin dissociation curve in Figure

intracellular Po₂ falls below the critical level required

40-12. This curve is almost identical to the oxygen-

to maintain maximal intracellular metabolism. Thus,

hemoglobin dissociation curve, except that the carbon

under these conditions, oxygen usage by the cells is

monoxide partial pressures, shown on the abscissa, are

at a level ¹/₂₅₀ of those for the oxygen-hemoglobin dis-

said to be diffusion limited and is no longer deter-

sociation curve of Figure 40-8. Therefore, a carbon

mined by the amount of ADP formed in the cells.

monoxide partial pressure of only 0.4 mm Hg in the

But this almost never occurs, except in pathological

alveoli,¹/₂₅₀that of normal alveolar oxygen (100 mm Hg

states.

Po₂), allows the carbon monoxide to compete equally

with the oxygen for combination with the hemoglobin

Effect of Blood Flow on Metabolic Use of Oxygen. The total

and causes half the hemoglobin in the blood to become

amount of oxygen available each minute for use in

bound with carbon monoxide instead of with oxygen.

any given tissue is determined by (1) the quantity of

Therefore, a carbon monoxide pressure of only

510

Unit VII

Respiration

Capillary

Interstitial

Red blood cell

100

fluid

Cell

Hgb • CO

Carbonic

Hgb

anhydrase

H₂CO₃

H₂O +

CO₂

HCO3- +

H⁺

H₂O

Hgb

CO₂

H₂O

HHgb

CO₂transported as:

1. CO₂

HCO₃

2. Hgb • CO₂

= 23%

3. HCO₃

= 70%

Plasma

0.1

0.2

0.3

0.4

Gas pressure of carbon monoxide (mm Hg)

Figure 40-13

Transport of carbon dioxide in the blood.

Figure 40-12

dioxide in the blood has a lot to do with the acid-base

Carbon monoxide-hemoglobin dissociation curve. Note the

balance of the body fluids, which is discussed in

extremely low carbon monoxide pressures at which carbon

Chapter

30. Under normal resting conditions, an

monoxide combines with hemoglobin.

average of 4 milliliters of carbon dioxide is transported

from the tissues to the lungs in each 100 milliliters of

0.6 mm Hg (a volume concentration of less than one

blood.

part per thousand in air) can be lethal.

Even though the oxygen content of blood is greatly

reduced in carbon monoxide poisoning, the Po₂ of the

Chemical Forms in Which Carbon

blood may be normal. This makes exposure to carbon

Dioxide Is Transported

monoxide especially dangerous, because the blood is

bright red and there are no obvious signs of hypoxemia,

To begin the process of carbon dioxide transport,

such as a bluish color of the fingertips or lips (cyanosis).

carbon dioxide diffuses out of the tissue cells in the

Also, Po₂ is not reduced, and the feedback mechanism

dissolved molecular carbon dioxide form. On entering

that usually stimulates increased respiration rate in

response to lack of oxygen (usually reflected by a low

the tissue capillaries, the carbon dioxide initiates a host

Po₂) is absent. Because the brain is one of the first

of almost instantaneous physical and chemical reac-

organs affected by lack of oxygen, the person may

tions, shown in Figure 40-13, which are essential for

become disoriented and unconscious before becoming

carbon dioxide transport.

aware of the danger.

A patient severely poisoned with carbon monoxide

Transport of Carbon Dioxide in the Dissolved State. A small

can be treated by administering pure oxygen, because

portion of the carbon dioxide is transported in the dis-

oxygen at high alveolar pressure can displace carbon

solved state to the lungs. Recall that the Pco₂ of venous

monoxide rapidly from its combination with hemoglo-

blood is

45 mm Hg and that of arterial blood is

bin. The patient can also benefit from simultaneous

40 mm Hg. The amount of carbon dioxide dissolved in

administration of 5 per cent carbon dioxide, because

this strongly stimulates the respiratory center, which

the fluid of the blood at 45 mm Hg is about 2.7 ml/dl

increases alveolar ventilation and reduces the alveolar

(2.7 volumes per cent). The amount dissolved at

carbon monoxide. With intensive oxygen and carbon

40 mm Hg is about 2.4 milliliters, or a difference of 0.3

dioxide therapy, carbon monoxide can be removed from

milliliter. Therefore, only about 0.3 milliliter of carbon

the blood as much as 10 times as rapidly as without

dioxide is transported in the dissolved form by each

therapy.

100 milliliters of blood flow. This is about 7 per cent of

all the carbon dioxide normally transported.

Transport of Carbon Dioxide

Transport of Carbon Dioxide in the Form of Bicarbonate Ion

in the Blood

Reaction of Carbon Dioxide with Water in the Red

Blood Cells—Effect of Carbonic Anhydrase. The dis-

Transport of carbon dioxide by the blood is not nearly

solved carbon dioxide in the blood reacts with water

as problematical as transport of oxygen is, because

to form carbonic acid. This reaction would occur

even in the most abnormal conditions, carbon dioxide

much too slowly to be of importance were it not for

can usually be transported in far greater quantities

the fact that inside the red blood cells is a protein

than oxygen can be. However, the amount of carbon

enzyme called carbonic anhydrase, which catalyzes the

Chapter 40

Transport of Oxygen and Carbon Dioxide in Blood and Tissue Fluids

511

reaction between carbon dioxide and water and accel-

dioxide with water inside the red blood cells, it is

erates its reaction rate about 5000-fold. Therefore,

doubtful that under normal conditions this carbamino

instead of requiring many seconds or minutes to occur,

mechanism transports more than 20 per cent of the

as is true in the plasma, the reaction occurs so rapidly

total carbon dioxide.

in the red blood cells that it reaches almost complete

equilibrium within a very small fraction of a second.

This allows tremendous amounts of carbon dioxide to

Carbon Dioxide Dissociation Curve

react with the red blood cell water even before the

blood leaves the tissue capillaries.

The curve shown in Figure 40-14—called the carbon

dioxide dissociation curve—depicts the dependence

Dissociation of Carbonic Acid into Bicarbonate and

of total blood carbon dioxide in all its forms on Pco₂.

Hydrogen Ions. In another fraction of a second, the

Note that the normal blood Pco₂ ranges between the

carbonic acid formed in the red cells (H₂CO₃) disso-

limits of 40 mm Hg in arterial blood and 45 mm Hg in

ciates into hydrogen and bicarbonate ions (H⁺ and

venous blood, which is a very narrow range. Note also

HCO_3-). Most of the hydrogen ions then combine with

that the normal concentration of carbon dioxide in the

the hemoglobin in the red blood cells, because the

blood in all its different forms is about 50 volumes per

hemoglobin protein is a powerful acid-base buffer. In

cent, but only 4 volumes per cent of this is exchanged

turn, many of the bicarbonate ions diffuse from the red

during normal transport of carbon dioxide from the

cells into the plasma, while chloride ions diffuse into

tissues to the lungs. That is, the concentration rises to

the red cells to take their place. This is made possible

about 52 volumes per cent as the blood passes through

by the presence of a special bicarbonate-chloride

the tissues and falls to about 48 volumes per cent as it

carrier protein in the red cell membrane that shuttles

passes through the lungs.

these two ions in opposite directions at rapid veloci-

ties. Thus, the chloride content of venous red blood

cells is greater than that of arterial red cells, a phe-

When Oxygen Binds with

nomenon called the chloride shift.

Hemoglobin, Carbon Dioxide Is

The reversible combination of carbon dioxide with

Released (the Haldane Effect)

water in the red blood cells under the influence of car-

to Increase CO₂ Transport

bonic anhydrase accounts for about 70 per cent of the

carbon dioxide transported from the tissues to the

Earlier in the chapter, it was pointed out that an

lungs. Thus, this means of transporting carbon dioxide

increase in carbon dioxide in the blood causes oxygen

is by far the most important. Indeed, when a carbonic

to be displaced from the hemoglobin (the Bohr effect),

anhydrase inhibitor (acetazolamide) is administered

which is an important factor in increasing oxygen

to an animal to block the action of carbonic anhydrase

transport. The reverse is also true: binding of oxygen

in the red blood cells, carbon dioxide transport from

with hemoglobin tends to displace carbon dioxide

the tissues becomes so poor that the tissue Pco₂ can be

from the blood. Indeed, this effect, called the Haldane

made to rise to 80 mm Hg instead of the normal

effect, is quantitatively far more important in

45 mm Hg.

Transport of Carbon Dioxide in Combination with Hemoglobin

and Plasma Proteins—Carbaminohemoglobin. In addition to

reacting with water, carbon dioxide reacts directly with

amine radicals of the hemoglobin molecule to form

the compound carbaminohemoglobin (CO₂Hgb). This

combination of carbon dioxide and hemoglobin is a

reversible reaction that occurs with a loose bond, so

that the carbon dioxide is easily released into the

alveoli, where the Pco₂ is lower than in the pulmonary

capillaries.

A small amount of carbon dioxide also reacts in the

same way with the plasma proteins in the tissue capil-

laries. This is much less significant for the transport of

carbon dioxide because the quantity of these proteins

in the blood is only one fourth as great as the quantity

of hemoglobin.

10 20 30

50 60

100

110

120

The quantity of carbon dioxide that can be carried

Gas pressure of carbon dioxide (mm Hg)

from the peripheral tissues to the lungs by carbamino

combination with hemoglobin and plasma proteins is

about 30 per cent of the total quantity transported—

that is, normally about 1.5 milliliters of carbon dioxide

Figure 40-14

in each 100 milliliters of blood. However, because this

reaction is much slower than the reaction of carbon

Carbon dioxide dissociation curve.

512

Unit VII

Respiration

falls to 48 volumes per cent (point B). This represents

an additional

2 volumes per cent loss of carbon

dioxide. Thus, the Haldane effect approximately

doubles the amount of carbon dioxide released from

the blood in the lungs and approximately doubles the

pickup of carbon dioxide in the tissues.

PO2 = 40 mm Hg

Change in Blood Acidity During

Carbon Dioxide Transport

PO2 = 100 mm Hg

The carbonic acid formed when carbon dioxide enters

the blood in the peripheral tissues decreases the blood

pH. However, reaction of this acid with the acid-base

buffers of the blood prevents the hydrogen ion concen-

tration from rising greatly (and the pH from falling

greatly). Ordinarily, arterial blood has a pH of about

PCO₂

7.41, and as the blood acquires carbon dioxide in the

tissue capillaries, the pH falls to a venous value of about

7.37. In other words, a pH change of 0.04 unit takes

place. The reverse occurs when carbon dioxide is

Figure 40-15

released from the blood in the lungs, with the pH rising

to the arterial value of 7.41 once again. In heavy exer-

Portions of the carbon dioxide dissociation curve when the PO₂ is

cise or other conditions of high metabolic activity, or

100 mm Hg or 40 mm Hg. The arrow represents the Haldane

when blood flow through the tissues is sluggish, the

effect on the transport of carbon dioxide, as discussed in the text.

decrease in pH in the tissue blood (and in the tissues

themselves) can be as much as 0.50, about 12 times

normal, thus causing significant tissue acidosis.

promoting carbon dioxide transport than is the Bohr

effect in promoting oxygen transport.

Respiratory Exchange Ratio

The Haldane effect results from the simple fact that

The discerning student will have noted that normal

the combination of oxygen with hemoglobin in the

transport of oxygen from the lungs to the tissues by each

lungs causes the hemoglobin to become a stronger

100 milliliters of blood is about 5 milliliters, whereas

acid. This displaces carbon dioxide from the blood and

normal transport of carbon dioxide from the tissues

into the alveoli in two ways: (1) The more highly acidic

to the lungs is about 4 milliliters. Thus, under normal

hemoglobin has less tendency to combine with carbon

resting conditions, only about

82 per cent as much

dioxide to form carbaminohemoglobin, thus displacing

carbon dioxide is expired from the lungs as oxygen is

much of the carbon dioxide that is present in the car-

taken up by the lungs. The ratio of carbon dioxide

bamino form from the blood. (2) The increased acidity

output to oxygen uptake is called the respiratory

of the hemoglobin also causes it to release an excess

exchange ratio (R). That is,

of hydrogen ions, and these bind with bicarbonate

ions to form carbonic acid; this then dissociates into

R= Rate of carbon dioxide output

Rate of oxygen uptake

water and carbon dioxide, and the carbon dioxide is

released from the blood into the alveoli and, finally,

The value for R changes under different metabolic

into the air.

conditions. When a person is using exclusively carbohy-

drates for body metabolism, R rises to 1.00. Conversely,

Figure 40-15 demonstrates quantitatively the signif-

when a person is using exclusively fats for metabolic

icance of the Haldane effect on the transport of carbon

energy, the R level falls to as low as 0.7. The reason

dioxide from the tissues to the lungs. This figure shows

for this difference is that when oxygen is metabolized

small portions of two carbon dioxide dissociation

with carbohydrates, one molecule of carbon dioxide is

curves: (1) when the Po₂ is 100 mm Hg, which is the

formed for each molecule of oxygen consumed; when

case in the blood capillaries of the lungs, and (2) when

oxygen reacts with fats, a large share of the oxygen

the Po₂ is 40 mm Hg, which is the case in the tissue cap-

combines with hydrogen atoms from the fats to form

illaries. Point A shows that the normal Pco₂

water instead of carbon dioxide. In other words, when

45 mm Hg in the tissues causes 52 volumes per cent of

fats are metabolized, the respiratory quotient of the

carbon dioxide to combine with the blood. On enter-

chemical reactions in the tissues is about 0.70 instead of

1.00. (The tissue respiratory quotient is discussed in

ing the lungs, the Pco₂ falls to 40 mm Hg and the Po₂

Chapter 71.) For a person on a normal diet consuming

rises to 100 mm Hg. If the carbon dioxide dissociation

average amounts of carbohydrates, fats, and proteins,

curve did not shift because of the Haldane effect, the

the average value for R is considered to be 0.825.

carbon dioxide content of the blood would fall only to

50 volumes per cent, which would be a loss of only 2

volumes per cent of carbon dioxide. However, the

References

increase in Po₂ in the lungs lowers the carbon dioxide

dissociation curve from the top curve to the lower

Albert R, Spiro S, Jett J: Comprehensive Respiratory Medi-

curve of the figure, so that the carbon dioxide content

cine. Philadelphia: Mosby, 2002.

Chapter 40

Transport of Oxygen and Carbon Dioxide in Blood and Tissue Fluids

513

Dempsey JA, Wagner PD: Exercise-induced arterial hypox-

Richardson RS: Oxygen transport and utilization: an inte-

emia. J Appl Physiol 87:1997, 1999.

gration of the muscle systems. Adv Physiol Educ 27:183,

Geers C, Gros G: Carbon dioxide transport and carbonic

2003.

anhydrase in blood and muscle. Physiol Rev

80:681,

Roy TK, Popel AS: Theoretical predictions of end-capillary

2000.

Po₂ in muscles of athletic and nonathletic animals at

Henry RP, Swenson ER: The distribution and physiological

Vo₂max. Am J Physiol 271:H721, 1996.

significance of carbonic anhydrase in vertebrate gas

Spahn DR, Pasch T: Physiological properties of blood sub-

exchange organs. Respir Physiol 121:1, 2000.

stitutes. News Physiol Sci 16:38, 2001.

Jones AM, Koppo K, Burnley M: Effects of prior exercise on

Tsai AG, Johnson PC, Intaglietta M: Oxygen gradients in the

metabolic and gas exchange responses to exercise. Sports

microcirculation. Physiol Rev 83:933, 2003.

Med 33:949, 2003.

Wagner PD: Diffusive resistance to O₂ transport in muscle.

Nikinmaa M: Membrane transport and control of

Acta Physiol Scand 168:609, 2000.

hemoglobin-oxygen affinity in nucleated erythrocytes.

West JB: Pulmonary Physiology and Pathophysiology: An

Physiol Rev 72:301, 1992.

Integrated, Case-Based Approach. Philadelphia: Lippin-

Piiper J: Perfusion, diffusion and their heterogeneities limit-

cott Williams & Wilkins, 2001.

ing blood-tissue O₂ transfer in muscle. Acta Physiol Scand

West JB: Pulmonary Physiology—The Essentials. Baltimore:

168:603, 2000.

Lippincott Williams & Wilkins, 2003.

C H A P T E R

Regulation of Respiration

The nervous system normally adjusts the rate of

alveolar ventilation almost exactly to the demands

of the body so that the oxygen pressure (Po₂) and

carbon dioxide pressure (Pco₂) in the arterial blood

are hardly altered even during heavy exercise and

most other types of respiratory stress. This chapter

describes the function of this neurogenic system for

regulation of respiration.

Respiratory Center

The respiratory center is composed of several groups of neurons located bilat-

erally in the medulla oblongata and pons of the brain stem, as shown in Figure

41-1. It is divided into three major collections of neurons: (1) a dorsal respira-

tory group, located in the dorsal portion of the medulla, which mainly causes

inspiration; (2) a ventral respiratory group, located in the ventrolateral part of

the medulla, which mainly causes expiration; and (3) the pneumotaxic center,

located dorsally in the superior portion of the pons, which mainly controls rate

and depth of breathing. The dorsal respiratory group of neurons plays the most

fundamental role in the control of respiration. Therefore, let us discuss its func-

tion first.

Dorsal Respiratory Group of Neurons—Its Control

of Inspiration and of Respiratory Rhythm

The dorsal respiratory group of neurons extends most of the length of the

medulla. Most of its neurons are located within the nucleus of the tractus soli-

tarius, although additional neurons in the adjacent reticular substance of the

medulla also play important roles in respiratory control. The nucleus of the

tractus solitarius is the sensory termination of both the vagal and the glos-

sopharyngeal nerves, which transmit sensory signals into the respiratory center

from (1) peripheral chemoreceptors, (2) baroreceptors, and (3) several types of

receptors in the lungs.

Rhythmical Inspiratory Discharges from the Dorsal Respiratory Group. The basic rhythm

of respiration is generated mainly in the dorsal respiratory group of neurons.

Even when all the peripheral nerves entering the medulla have been sectioned

and the brain stem transected both above and below the medulla, this group of

neurons still emits repetitive bursts of inspiratory neuronal action potentials. The

basic cause of these repetitive discharges is unknown. In primitive animals,

neural networks have been found in which activity of one set of neurons excites

a second set, which in turn inhibits the first. Then, after a period of time, the

mechanism repeats itself, continuing throughout the life of the animal. There-

fore, most respiratory physiologists believe that some similar network of

neurons is present in the human being, located entirely within the medulla; it

probably involves not only the dorsal respiratory group but adjacent areas of

the medulla as well, and is responsible for the basic rhythm of respiration.

Inspiratory “Ramp” Signal. The nervous signal that is transmitted to the inspira-

tory muscles, mainly the diaphragm, is not an instantaneous burst of action

514

Chapter 41

Regulation of Respiration

515

or more seconds, thus filling the lungs with a great

excess of air.

The function of the pneumotaxic center is primarily

to limit inspiration. This has a secondary effect of

Pneumotaxic center

increasing the rate of breathing, because limitation

of inspiration also shortens expiration and the entire

Inhibits

Fourth ventricle

period of each respiration. A strong pneumotaxic

signal can increase the rate of breathing to 30 to 40

? Apneustic center

breaths per minute, whereas a weak pneumotaxic

Dorsal respiratory

signal may reduce the rate to only 3 to 5 breaths per

Ventral respiratory

group (inspiration)

group (expiration

minute.

and inspiration)

Ventral Respiratory Group of

Vagus and

glossopharyngeal

Respiratory motor

Neurons—Functions in Both

pathways

Inspiration and Expiration

Figure 41-1

Located in each side of the medulla, about 5 millime-

Organization of the respiratory center.

ters anterior and lateral to the dorsal respiratory group

of neurons, is the ventral respiratory group of neurons,

found in the nucleus ambiguus rostrally and the

nucleus retroambiguus caudally. The function of this

potentials. Instead, in normal respiration, it begins

neuronal group differs from that of the dorsal respi-

weakly and increases steadily in a ramp manner for

ratory group in several important ways:

about 2 seconds. Then it ceases abruptly for approxi-

The neurons of the ventral respiratory group

mately the next 3 seconds, which turns off the excita-

remain almost totally inactive during normal quiet

tion of the diaphragm and allows elastic recoil of the

respiration. Therefore, normal quiet breathing is

lungs and the chest wall to cause expiration. Next, the

caused only by repetitive inspiratory signals from

inspiratory signal begins again for another cycle; this

the dorsal respiratory group transmitted mainly to

cycle repeats again and again, with expiration occur-

the diaphragm, and expiration results from elastic

ring in between. Thus, the inspiratory signal is a ramp

recoil of the lungs and thoracic cage.

signal. The obvious advantage of the ramp is that it

There is no evidence that the ventral respiratory

causes a steady increase in the volume of the lungs

neurons participate in the basic rhythmical

during inspiration, rather than inspiratory gasps.

oscillation that controls respiration.

There are two qualities of the inspiratory ramp that

When the respiratory drive for increased

are controlled, as follows:

pulmonary ventilation becomes greater than

1. Control of the rate of increase of the ramp signal,

normal, respiratory signals spill over into the

so that during heavy respiration, the ramp

ventral respiratory neurons from the basic

increases rapidly and therefore fills the lungs

oscillating mechanism of the dorsal respiratory

rapidly.

area. As a consequence, the ventral respiratory

2. Control of the limiting point at which the ramp

area contributes extra respiratory drive as well.

suddenly ceases. This is the usual method for

Electrical stimulation of a few of the neurons in

controlling the rate of respiration; that is, the

the ventral group causes inspiration, whereas

earlier the ramp ceases, the shorter the duration

stimulation of others causes expiration. Therefore,

of inspiration. This also shortens the duration of

these neurons contribute to both inspiration and

expiration. Thus, the frequency of respiration is

expiration. They are especially important in

increased.

providing the powerful expiratory signals to the

abdominal muscles during very heavy expiration.

A Pneumotaxic Center Limits the

Thus, this area operates more or less as an

overdrive mechanism when high levels of

Duration of Inspiration and Increases

pulmonary ventilation are required, especially

the Respiratory Rate

during heavy exercise.

A pneumotaxic center, located dorsally in the nucleus

parabrachialis of the upper pons, transmits signals to

Lung Inflation Signals Limit

the inspiratory area. The primary effect of this center

Inspiration—The Hering-Breuer

is to control the “switch-off” point of the inspiratory

ramp, thus controlling the duration of the filling phase

Inflation Reflex

of the lung cycle. When the pneumotaxic signal is

strong, inspiration might last for as little as 0.5 second,

In addition to the central nervous system respiratory

thus filling the lungs only slightly; when the pneumo-

control mechanisms operating entirely within the

taxic signal is weak, inspiration might continue for 5

brain stem, sensory nerve signals from the lungs also

516

Unit VII

Respiration

help control respiration. Most important, located in

Direct Chemical Control of

the muscular portions of the walls of the bronchi and

Respiratory Center Activity by Carbon

bronchioles throughout the lungs are stretch receptors

Dioxide and Hydrogen Ions

that transmit signals through the vagi into the dorsal

respiratory group of neurons when the lungs become

Chemosensitive Area of the Respiratory Center. We have dis-

overstretched. These signals affect inspiration in much

cussed mainly three areas of the respiratory center:

the same way as signals from the pneumotaxic center;

the dorsal respiratory group of neurons, the ventral

that is, when the lungs become overly inflated, the

respiratory group, and the pneumotaxic center. It

stretch receptors activate an appropriate feedback

is believed that none of these is affected directly by

response that “switches off” the inspiratory ramp and

changes in blood carbon dioxide concentration or

thus stops further inspiration. This is called the Hering-

hydrogen ion concentration. Instead, an additional

Breuer inflation reflex. This reflex also increases the

neuronal area, a chemosensitive area, shown in Figure

rate of respiration, as is true for signals from the pneu-

41-2, is located bilaterally, lying only 0.2 millimeter

motaxic center.

beneath the ventral surface of the medulla. This area

In human beings, the Hering-Breuer reflex probably

is highly sensitive to changes in either blood Pco₂ or

is not activated until the tidal volume increases to

hydrogen ion concentration, and it in turn excites the

more than three times normal (greater than about 1.5

other portions of the respiratory center.

liters per breath). Therefore, this reflex appears to be

mainly a protective mechanism for preventing excess

Excitation of the Chemosensitive Neurons by

lung inflation rather than an important ingredient in

Hydrogen Ions Is Likely the Primary Stimulus

normal control of ventilation.

The sensor neurons in the chemosensitive area are

especially excited by hydrogen ions; in fact, it is

believed that hydrogen ions may be the only impor-

Control of Overall Respiratory

tant direct stimulus for these neurons. However,

Center Activity

hydrogen ions do not easily cross the blood-brain

barrier. For this reason, changes in hydrogen ion con-

Up to this point, we have discussed the basic mecha-

centration in the blood have considerably less effect

nisms for causing inspiration and expiration, but it is

in stimulating the chemosensitive neurons than do

also important to know how the intensity of the respi-

changes in blood carbon dioxide, even though carbon

ratory control signals is increased or decreased to

dioxide is believed to stimulate these neurons second-

match the ventilatory needs of the body. For example,

arily by changing the hydrogen ion concentration, as

during heavy exercise, the rates of oxygen usage and

explained in the following section.

carbon dioxide formation are often increased to as

much as 20 times normal, requiring commensurate

Carbon Dioxide Stimulates the

increases in pulmonary ventilation. The major purpose

Chemosensitive Area

of the remainder of this chapter is to discuss this

Although carbon dioxide has little direct effect in

control of ventilation in accord with the respiratory

stimulating the neurons in the chemosensitive area, it

needs of the body.

Chemical Control

of Respiration

Chemosensitive

The ultimate goal of respiration is to maintain proper

area

concentrations of oxygen, carbon dioxide, and hydro-

gen ions in the tissues. It is fortunate, therefore, that

respiratory activity is highly responsive to changes in

each of these.

Inspiratory area

H⁺

+ HCO₃

Excess carbon dioxide or excess hydrogen ions in

the blood mainly act directly on the respiratory center

itself, causing greatly increased strength of both the

H₂CO₃

inspiratory and the expiratory motor signals to the

respiratory muscles.

Oxygen, in contrast, does not have a significant

CO₂ + H₂O

direct effect on the respiratory center of the brain in

controlling respiration. Instead, it acts almost entirely

Figure 41-2

on peripheral chemoreceptors located in the carotid

and aortic bodies, and these in turn transmit appropri-

Stimulation of the brain stem inspiratory area by signals from the

chemosensitive area located bilaterally in the medulla, lying only

ate nervous signals to the respiratory center for

a fraction of a millimeter beneath the ventral medullary surface.

control of respiration.

Note also that hydrogen ions stimulate the chemosensitive area,

Let us discuss first the stimulation of the respiratory

but carbon dioxide in the fluid gives rise to most of the hydrogen

center itself by carbon dioxide and hydrogen ions.

ions.

Chapter 41

Regulation of Respiration

517

does have a potent indirect effect. It does this by react-

ing with the water of the tissues to form carbonic acid,

which dissociates into hydrogen and bicarbonate ions;

the hydrogen ions then have a potent direct stimula-

tory effect on respiration. These reactions are shown

in Figure 41-2.

Why does blood carbon dioxide have a more potent

effect in stimulating the chemosensitive neurons than

do blood hydrogen ions? The answer is that the blood-

brain barrier is not very permeable to hydrogen ions,

but carbon dioxide passes through this barrier almost

as if the barrier did not exist. Consequently, whenever

the blood Pco₂ increases, so does the Pco₂ of both the

interstitial fluid of the medulla and the cerebrospinal

fluid. In both these fluids, the carbon dioxide immedi-

ately reacts with the water to form new hydrogen ions.

Thus, paradoxically, more hydrogen ions are released

into the respiratory chemosensitive sensory area of the

medulla when the blood carbon dioxide concentration

PCO₂

increases than when the blood hydrogen ion concen-

tration increases. For this reason, respiratory center

activity is increased very strongly by changes in blood

100

carbon dioxide, a fact that we subsequently discuss

PCO₂ (mm Hg)

quantitatively.

7.6

7.5

7.4

7.3

7.2

7.1

7.0

6.9

Decreased Stimulatory Effect of Carbon Dioxide After the First

1 to 2 Days. Excitation of the respiratory center by

carbon dioxide is great the first few hours after the

blood carbon dioxide first increases, but then it grad-

Figure 41-3

ually declines over the next 1 to 2 days, decreasing to

about one fifth the initial effect. Part of this decline

Effects of increased arterial blood PCO₂ and decreased arterial pH

results from renal readjustment of the hydrogen ion

(increased hydrogen ion concentration) on the rate of alveolar

concentration in the circulating blood back toward

ventilation.

normal after the carbon dioxide first increases the

hydrogen concentration. The kidneys achieve this by

Unimportance of Oxygen for Control of the

increasing the blood bicarbonate, which binds with the

Respiratory Center

hydrogen ions in the blood and cerebrospinal fluid to

Changes in oxygen concentration have virtually no

reduce their concentrations. But even more important,

direct effect on the respiratory center itself to alter

over a period of hours, the bicarbonate ions also

respiratory drive (although oxygen changes do have

slowly diffuse through the blood-brain and blood-

an indirect effect, acting through the peripheral

cerebrospinal fluid barriers and combine directly with

chemoreceptors, as explained in the next section).

the hydrogen ions adjacent to the respiratory neurons

We learned in Chapter 40 that the hemoglobin-

as well, thus reducing the hydrogen ions back to near

oxygen buffer system delivers almost exactly normal

normal. A change in blood carbon dioxide concentra-

amounts of oxygen to the tissues even when the pul-

tion therefore has a potent acute effect on controlling

monary Po₂ changes from a value as low as 60 mm Hg

respiratory drive but only a weak chronic effect after

up to a value as high as 1000 mm Hg. Therefore, except

a few days’ adaptation.

under special conditions, adequate delivery of oxygen

can occur despite changes in lung ventilation ranging

Quantitative Effects of Blood PCO₂

from slightly below one half normal to as high as 20 or

and Hydrogen Ion Concentration on

more times normal. This is not true for carbon dioxide,

Alveolar Ventilation

because both the blood and tissue Pco₂

changes

Figure

41-3 shows quantitatively the approximate

inversely with the rate of pulmonary ventilation; thus,

effects of blood Pco₂ and blood pH (which is an

the processes of animal evolution have made carbon

inverse logarithmic measure of hydrogen ion concen-

dioxide the major controller of respiration, not

tration) on alveolar ventilation. Note especially the

oxygen.

very marked increase in ventilation caused by an

Yet, for those special conditions in which the tissues

increase in Pco₂ in the normal range between 35 and

get into trouble for lack of oxygen, the body has a

75 mm Hg. This demonstrates the tremendous effect

special mechanism for respiratory control located in

that carbon dioxide changes have in controlling respi-

the peripheral chemoreceptors, outside the brain res-

ration. By contrast, the change in respiration in the

piratory center; this mechanism responds when the

normal blood pH range between 7.3 and 7.5 is less than

blood oxygen falls too low, mainly below a Po₂ of

one tenth as great.

70 mm Hg, as explained in the next section.

518

Unit VII

Respiration

Peripheral Chemoreceptor

are exposed at all times to arterial blood, not venous

blood, and their Po₂s are arterial Po₂s.

System for Control of

Respiratory Activity—Role of

Stimulation of the Chemoreceptors by Decreased Arterial

Oxygen in Respiratory Control

Oxygen. When the oxygen concentration in the arterial

blood falls below normal, the chemoreceptors become

In addition to control of respiratory activity by the res-

strongly stimulated. This is demonstrated in Figure

piratory center itself, still another mechanism is avail-

41-5, which shows the effect of different levels of arte-

able for controlling respiration. This is the peripheral

rial Po₂ on the rate of nerve impulse transmission from

chemoreceptor system, shown in Figure 41-4. Special

a carotid body. Note that the impulse rate is particu-

nervous chemical receptors, called chemoreceptors, are

larly sensitive to changes in arterial Po₂ in the range of

located in several areas outside the brain. They are

60 down to 30 mm Hg, a range in which hemoglobin

especially important for detecting changes in oxygen

saturation with oxygen decreases rapidly.

in the blood, although they also respond to a lesser

extent to changes in carbon dioxide and hydrogen ion

Effect of Carbon Dioxide and Hydrogen Ion Concentration on

concentrations. The chemoreceptors transmit nervous

Chemoreceptor Activity. An increase in either carbon

signals to the respiratory center in the brain to help

dioxide concentration or hydrogen ion concentration

regulate respiratory activity.

also excites the chemoreceptors and, in this way,

Most of the chemoreceptors are in the carotid

indirectly increases respiratory activity. However, the

bodies. However, a few are also in the aortic bodies,

direct effects of both these factors in the respiratory

shown in the lower part of Figure 41-4, and a very few

center itself are so much more powerful than their

are located elsewhere in association with other arter-

effects mediated through the chemoreceptors (about

ies of the thoracic and abdominal regions.

seven times as powerful) that, for practical purposes,

The carotid bodies are located bilaterally in the

the indirect effects of carbon dioxide and hydrogen

bifurcations of the common carotid arteries. Their

ions through the chemoreceptors do not need to be

afferent nerve fibers pass through Hering’s nerves to

considered. Yet there is one difference between the

the glossopharyngeal nerves and then to the dorsal

peripheral and central effects of carbon dioxide: the

respiratory area of the medulla. The aortic bodies are

stimulation by way of the peripheral chemoreceptors

located along the arch of the aorta; their afferent

occurs as much as five times as rapidly as central stim-

nerve fibers pass through the vagi, also to the dorsal

ulation, so that the peripheral chemoreceptors might

medullary respiratory area.

be especially important in increasing the rapidity of

Each of the chemoreceptor bodies receives its own

response to carbon dioxide at the onset of exercise.

special blood supply through a minute artery directly

from the adjacent arterial trunk. Further, blood flow

Basic Mechanism of Stimulation of the Chemoreceptors by

through these bodies is extreme, 20 times the weight

Oxygen Deficiency. The exact means by which low Po₂

of the bodies themselves each minute. Therefore, the

excites the nerve endings in the carotid and aortic

percentage of oxygen removed from the flowing blood

bodies is still unknown. However, these bodies have

is virtually zero. This means that the chemoreceptors

Medulla

Glossopharyngeal nerve

800

Vagus nerve

600

Carotid body

400

200

100

200

300

400

500

Aortic bodies

Arterial PO₂ (mm Hg)

Figure 41-4

Figure 41-5

Respiratory control by peripheral chemoreceptors in the carotid

Effect of arterial PO₂ on impulse rate from the carotid body of a

and aortic bodies.

cat.

Chapter 41

Regulation of Respiration

519

multiple highly characteristic glandular-like cells,

period of hours, they breathe much more deeply and

called glomus cells, that synapse directly or indirectly

therefore can withstand far lower atmospheric oxygen

with the nerve endings. Some investigators have sug-

concentrations than when they ascend rapidly. This is

gested that these glomus cells might function as the

called acclimatization.

chemoreceptors and then stimulate the nerve endings.

The reason for acclimatization is that, within 2 to 3

But other studies suggest that the nerve endings them-

days, the respiratory center in the brain stem loses

selves are directly sensitive to the low Po₂.

about four fifths of its sensitivity to changes in Pco₂

and hydrogen ions. Therefore, the excess ventilatory

Effect of Low Arterial PO₂ to Stimulate

blow-off of carbon dioxide that normally would inhibit

Alveolar Ventilation When Arterial Carbon

an increase in respiration fails to occur, and low

Dioxide and Hydrogen Ion Concentrations

oxygen can drive the respiratory system to a much

Remain Normal

higher level of alveolar ventilation than under acute

Figure 41-6 shows the effect of low arterial Po₂ on

conditions. Instead of the 70 per cent increase in ven-

alveolar ventilation when the Pco₂ and the hydrogen

tilation that might occur after acute exposure to low

ion concentration are kept constant at their normal

oxygen, the alveolar ventilation often increases 400

levels. In other words, in this figure, only the ventila-

to 500 per cent after 2 to 3 days of low oxygen; this

tory drive due to the effect of low oxygen on the

helps immensely in supplying additional oxygen to the

chemoreceptors is active. The figure shows almost no

mountain climber.

effect on ventilation as long as the arterial Po₂ remains

greater than 100 mm Hg. But at pressures lower than

100 mm Hg, ventilation approximately doubles when

Composite Effects of PCO₂, pH, and

the arterial Po₂ falls to 60 mm Hg and can increase as

PO₂ on Alveolar Ventilation

much as fivefold at very low Po₂s. Under these condi-

tions, low arterial Po₂ obviously drives the ventilatory

Figure 41-7 gives a quick overview of the manner in

process quite strongly.

which the chemical factors Po₂, Pco₂, and pH—

together—affect alveolar ventilation. To understand

Chronic Breathing of Low Oxygen Stimulates

this diagram, first observe the four red curves.

Respiration Even More—The Phenomenon

These curves were recorded at different levels of

of “Acclimatization”

arterial Po₂—40 mm Hg, 50 mm Hg, 60 mm Hg, and

Mountain climbers have found that when they ascend

100 mm Hg. For each of these curves, the Pco₂ was

a mountain slowly, over a period of days rather than a

changed from lower to higher levels. Thus, this

PO₂ (mm Hg)

pH = 7.4

pH = 7.3

5040

50 60

100

PCO₂

Ventilation

160 140 120 100

Arterial PO₂ (mm Hg)

Alveolar PCO₂ (mm Hg)

Figure 41-6

The lower curve demonstrates the effect of different levels of arte-

Figure 41-7

rial PO₂ on alveolar ventilation, showing a sixfold increase in ven-

tilation as the PO₂ decreases from the normal level of 100 mm Hg

Composite diagram showing the interrelated effects of PCO₂, PO₂,

to 20 mm Hg. The upper line shows that the arterial PCO₂ was kept

and pH on alveolar ventilation. (Drawn from data in Cunningham

at a constant level during the measurements of this study; pH also

DJC, Lloyd BB: The Regulation of Human Respiration. Oxford:

was kept constant.

Blackwell Scientific Publications, 1963.)

520

Unit VII

Respiration

“family” of red curves represents the combined effects

to transmit at the same time collateral impulses into

of alveolar Pco₂ and Po₂ on ventilation.

the brain stem to excite the respiratory center. This is

Now observe the green curves. The red curves were

analogous to the stimulation of the vasomotor center

measured at a blood pH of 7.4; the green curves were

of the brain stem during exercise that causes a simul-

measured at a pH of 7.3. We now have two families of

taneous increase in arterial pressure.

curves representing the combined effects of Pco₂ and

Actually, when a person begins to exercise, a large

Po₂ on ventilation at two different pH values. Still

share of the total increase in ventilation begins imme-

other families of curves would be displaced to the right

diately on initiation of the exercise, before any blood

at higher pHs and displaced to the left at lower pHs.

chemicals have had time to change. It is likely that

Thus, using this diagram, one can predict the level of

most of the increase in respiration results from neuro-

alveolar ventilation for most combinations of alveolar

genic signals transmitted directly into the brain stem

Pco₂, alveolar Po₂, and arterial pH.

respiratory center at the same time that signals go to

the body muscles to cause muscle contraction.

Regulation of Respiration

Interrelation Between Chemical Factors and Nervous: Factors

During Exercise

in the Control of Respiration During Exercise. When a

person exercises, direct nervous signals presumably

In strenuous exercise, oxygen consumption and carbon

stimulate the respiratory center almost the proper

dioxide formation can increase as much as 20-fold. Yet,

amount to supply the extra oxygen required for exer-

as illustrated in Figure 41-8, in the healthy athlete,

cise and to blow off extra carbon dioxide. Occasion-

alveolar ventilation ordinarily increases almost exactly

ally, however, the nervous respiratory control signals

in step with the increased level of oxygen metabolism.

are either too strong or too weak. Then chemical

The arterial Po₂, Pco₂, and pH remain almost exactly

factors play a significant role in bringing about the

normal.

final adjustment of respiration required to keep the

In trying to analyze what causes the increased ven-

oxygen, carbon dioxide, and hydrogen ion concentra-

tilation during exercise, one is tempted to ascribe this

tions of the body fluids as nearly normal as possible.

to increases in blood carbon dioxide and hydrogen

This is demonstrated in Figure 41-9, which shows in

ions, plus a decrease in blood oxygen. However, this is

the lower curve changes in alveolar ventilation during

questionable, because measurements of arterial Pco₂,

a 1-minute period of exercise and in the upper curve

pH, and Po₂ show that none of these values changes

changes in arterial Pco₂. Note that at the onset of exer-

significantly during exercise, so that none of them

cise, the alveolar ventilation increases instantaneously,

becomes abnormal enough to stimulate respiration.

without an initial increase in arterial Pco₂. In fact, this

Therefore, the question must be asked: What causes

intense ventilation during exercise? At least one effect

seems to be predominant. The brain, on transmitting

motor impulses to the exercising muscles, is believed

120

110

Exercise

100

Moderate

Severe

exercise

Minutes

1.0

2.0

3.0

4.0

O₂ consumption (L/min)

Figure 41-9

Changes in alveolar ventilation (bottom curve) and arterial PCO₂

Figure 41-8

(top curve) during a 1-minute period of exercise and also after ter-

mination of exercise. (Extrapolated to the human being from data

Effect of exercise on oxygen consumption and ventilatory rate.

in dogs in Bainton CR: Effect of speed vs grade and shivering on

(From Gray JS: Pulmonary Ventilation and Its Physiological Regu-

ventilation in dogs during active exercise. J Appl Physiol 33:778,

lation. Springfield, Ill: Charles C Thomas, 1950.)

1972.)

Chapter 41

Regulation of Respiration

521

the rate of carbon dioxide release, thus keeping arte-

rial Pco₂ near its normal value. The upper curve of

Figure 41-10 also shows that if, during exercise, the

arterial Pco₂ does change from its normal value of

140

40 mm Hg, it has an extra stimulatory effect on venti-

lation at a Pco₂ greater than 40 mm Hg and a depres-

120

sant effect at a Pco₂ less than 40 mm Hg.

Possibility That the Neurogenic Factor for Control of Ventila-

100

tion During Exercise Is a Learned Response. Many experi-

ments suggest that the brain’s ability to shift the

ventilatory response curve during exercise, as shown

in Figure 41-10, is at least partly a learned response.

That is, with repeated periods of exercise, the brain

becomes progressively more able to provide the

proper signals required to keep the blood Pco₂ at its

normal level. Also, there is reason to believe that even

Exercise

the cerebral cortex is involved in this learning, because

Resting

experiments that block only the cortex also block the

Normal

learned response.

100

Arterial PCO₂ (mm Hg)

Other Factors That

Affect Respiration

Voluntary Control of Respiration. Thus far, we have dis-

Figure 41-10

cussed the involuntary system for the control of respi-

ration. However, we all know that for short periods of

Approximate effect of maximum exercise in an athlete to shift the

time, respiration can be controlled voluntarily and that

alveolar PCO₂-ventilation response curve to a level much higher

than normal. The shift, believed to be caused by neurogenic

one can hyperventilate or hypoventilate to such an

factors, is almost exactly the right amount to maintain arterial PCO₂

extent that serious derangements in Pco₂, pH, and Po₂

at the normal level of 40 mm Hg both in the resting state and

can occur in the blood.

during heavy exercise.

Effect of Irritant Receptors in the Airways. The epithelium of

the trachea, bronchi, and bronchioles is supplied with

increase in ventilation is usually great enough so that

sensory nerve endings called pulmonary irritant recep-

at first it actually decreases arterial Pco₂ below normal,

tors that are stimulated by many incidents. These cause

as shown in the figure. The presumed reason that the

coughing and sneezing, as discussed in Chapter 39. They

ventilation forges ahead of the buildup of blood

may also cause bronchial constriction in such diseases

carbon dioxide is that the brain provides an “anticipa-

as asthma and emphysema.

tory” stimulation of respiration at the onset of exer-

cise, causing extra alveolar ventilation even before it

Function of Lung

“J Receptors.” A few sensory nerve

is needed. However, after about 30 to 40 seconds,

endings have been described in the alveolar walls in

juxtaposition to the pulmonary capillaries—hence the

the amount of carbon dioxide released into the blood

name “J receptors.” They are stimulated especially when

from the active muscles approximately matches the

the pulmonary capillaries become engorged with blood

increased rate of ventilation, and the arterial Pco₂

or when pulmonary edema occurs in such conditions as

returns essentially to normal even as the exercise con-

congestive heart failure. Although the functional role of

tinues, as shown toward the end of the 1-minute period

the J receptors is not clear, their excitation may give the

of exercise in the figure.

person a feeling of dyspnea.

Figure 41-10 summarizes the control of respiration

during exercise in still another way, this time more

Effect of Brain Edema. The activity of the respiratory

quantitatively. The lower curve of this figure shows the

center may be depressed or even inactivated by acute

effect of different levels of arterial Pco₂ on alveolar

brain edema resulting from brain concussion. For

ventilation when the body is at rest—that is, not exer-

instance, the head might be struck against some solid

cising. The upper curve shows the approximate shift of

object, after which the damaged brain tissues swell,

compressing the cerebral arteries against the cranial

this ventilatory curve caused by neurogenic drive from

vault and thus partially blocking cerebral blood supply.

the respiratory center that occurs during heavy exer-

Occasionally, respiratory depression resulting from

cise. The points indicated on the two curves show the

brain edema can be relieved temporarily by intravenous

arterial Pco₂ first in the resting state and then in the

injection of hypertonic solutions such as highly concen-

exercising state. Note in both instances that the Pco₂

trated mannitol solution. These solutions osmotically

is at the normal level of 40 mm Hg. In other words, the

remove some of the fluids of the brain, thus relieving

neurogenic factor shifts the curve about 20-fold in the

intracranial pressure and sometimes re-establishing res-

upward direction, so that ventilation almost matches

piration within a few minutes.

522

Unit VII

Respiration

Anesthesia. Perhaps the most prevalent cause of respi-

carbon dioxide and oxygen. Therefore, normally, the

ratory depression and respiratory arrest is overdosage

lungs cannot build up enough extra carbon dioxide or

with anesthetics or narcotics. For instance, sodium pen-

depress the oxygen sufficiently in a few seconds to cause

tobarbital depresses the respiratory center considerably

the next cycle of the periodic breathing. But under two

more than many other anesthetics, such as halothane. At

separate conditions, the damping factors can be over-

one time, morphine was used as an anesthetic, but this

ridden, and Cheyne-Stokes breathing does occur:

drug is now used only as an adjunct to anesthetics

When a long delay occurs for transport of blood

because it greatly depresses the respiratory center while

from the lungs to the brain, changes in carbon

having less ability to anesthetize the cerebral cortex.

dioxide and oxygen in the alveoli can continue

for many more seconds than usual. Under these

conditions, the storage capacities of the alveoli and

Periodic Breathing

pulmonary blood for these gases are exceeded;

then, after a few more seconds, the periodic

An abnormality of respiration called periodic breathing

respiratory drive becomes extreme, and Cheyne-

occurs in a number of disease conditions. The person

Stokes breathing begins. This type of Cheyne-

breathes deeply for a short interval and then breathes

Stokes breathing often occurs in patients with

slightly or not at all for an additional interval, with the

severe cardiac failure because blood flow is slow,

cycle repeating itself over and over. One type of peri-

thus delaying the transport of blood gases from the

odic breathing, Cheyne-Stokes breathing, is character-

lungs to the brain. In fact, in patients with chronic

ized by slowly waxing and waning respiration occur-

heart failure, Cheyne-Stokes breathing can

ring about every 40 to 60 seconds, as illustrated in Figure

sometimes occur on and off for months.

41-11.

A second cause of Cheyne-Stokes breathing is

increased negative feedback gain in the respiratory

Basic Mechanism of Cheyne-Stokes Breathing. The basic

control areas. This means that a change in blood

cause of Cheyne-Stokes breathing is the following:

carbon dioxide or oxygen causes a far greater

When a person overbreathes, thus blowing off too much

change in ventilation than normally. For instance,

carbon dioxide from the pulmonary blood while at the

instead of the normal 2- to 3-fold increase in

same time increasing blood oxygen, it takes several

ventilation that occurs when the Pco₂ rises

seconds before the changed pulmonary blood can be

3 mm Hg, the same 3 mm Hg rise might increase

transported to the brain and inhibit the excess ventila-

ventilation 10- to 20-fold. The brain feedback

tion. By this time, the person has already overventilated

tendency for periodic breathing is now strong

for an extra few seconds. Therefore, when the overven-

enough to cause Cheyne-Stokes breathing without

tilated blood finally reaches the brain respiratory

extra blood flow delay between the lungs and

center, the center becomes depressed an excessive

brain. This type of Cheyne-Stokes breathing occurs

amount. Then the opposite cycle begins. That is, carbon

mainly in patients with brain damage. The brain

dioxide increases and oxygen decreases in the alveoli.

damage often turns off the respiratory drive

Again, it takes a few seconds before the brain can

entirely for a few seconds; then an extra intense

respond to these new changes. When the brain does

increase in blood carbon dioxide turns it back on

respond, the person breathes hard once again, and the

with great force. Cheyne-Stokes breathing of this

cycle repeats.

type is frequently a prelude to death from brain

The basic cause of Cheyne-Stokes breathing occurs

malfunction.

in everyone. However, under normal conditions, this

Typical records of changes in pulmonary and respira-

mechanism is highly “damped.” That is, the fluids of the

tory center Pco₂ during Cheyne-Stokes breathing are

blood and the respiratory center control areas have

shown in Figure 41-11. Note that the Pco₂ of the

large amounts of dissolved and chemically bound

pulmonary blood changes in advance of the Pco₂ of

the respiratory neurons. But the depth of respiration

corresponds with the Pco₂ in the brain, not with the

Pco₂ in the pulmonary blood where the ventilation is

occurring.

Depth of

respiration

Sleep Apnea

The term apnea means absence of spontaneous breath-

PCO₂ of

Respiratory

ing. Occasional apneas occur during normal sleep, but

respiratory

center excited

in persons with sleep apnea, the frequency and duration

neurons

are greatly increased, with episodes of apnea lasting for

10 seconds or longer and occurring 300 to 500 times

each night. Sleep apneas can be caused by obstruction

PCO₂ of

of the upper airways, especially the pharynx, or by

lung blood

impaired central nervous system respiratory drive.

Obstructive Sleep Apnea Is Caused by Blockage of the Upper

Airway. The muscles of the pharynx normally keep this

Figure 41-11

passage open to allow air to flow into the lungs during

Cheyne-Stokes breathing, showing changing PCO₂ in the pul-

inspiration. During sleep, these muscles usually relax,

monary blood (red line) and delayed changes in the PCO₂ of the

but the airway passage remains open enough to permit

fluids of the respiratory center (blue line).

adequate airflow. Some individuals have an especially

Chapter 41

Regulation of Respiration

523

narrow passage, and relaxation of these muscles during

stimulatory effects of carbon dioxide and hydrogen ions.

sleep causes the pharynx to completely close so that air

Patients with this disease are extremely sensitive to

cannot flow into the lungs.

even small doses of sedatives or narcotics, which further

In persons with sleep apnea, loud snoring and labored

reduce the responsiveness of the respiratory centers to

breathing occur soon after falling asleep. The snoring

the stimulatory effects of carbon dioxide. Medications

proceeds, often becoming louder, and is then inter-

that stimulate the respiratory centers can sometimes be

rupted by a long silent period during which no breath-

helpful, but ventilation with CPAP at night is usually

ing

(apnea) occurs. These periods of apnea result

necessary.

in significant decreases in Po₂ and increases in Pco₂,

which greatly stimulate respiration. This, in turn, causes

sudden attempts to breathe, which result in loud snorts

References

and gasps followed by snoring and repeated episodes of

apnea. The periods of apnea and labored breathing are

Dean JB, Ballantyne D, Cardone DL, et al: Role of gap junc-

repeated several hundred times during the night, result-

tions in CO₂ chemoreception and respiratory control. Am

ing in fragmented, restless sleep. Therefore, patients

J Physiol Lung Cell Mol Physiol 283:L665, 2002.

with sleep apnea usually have excessive daytime drowsi-

Dutschmann M, Paton JF: Inhibitory synaptic mechanisms

ness as well as other disorders, including increased sym-

regulating upper airway patency. Respir Physiol Neuro-

pathetic activity, high heart rates, pulmonary and

biol 131:57, 2002.

systemic hypertension, and a greatly elevated risk for

Feldman JL, Mitchell GS, Nattie EE: Breathing: rhythmicity,

cardiovascular disease.

plasticity, chemosensitivity. Annu Rev Neurosci 26:239,

Obstructive sleep apnea most commonly occurs in

2003.

older, obese persons in whom there is increased fat dep-

Forster HV: Plasticity in the control of breathing following

osition in the soft tissues of the pharynx or compression

sensory denervation. J Appl Physiol 94:784, 2003.

of the pharynx due to excessive fat masses in the neck.

Hilaire G, Pasaro R: Genesis and control of the respiratory

In a few individuals, sleep apnea may be associated with

rhythm in adult mammals. News Physiol Sci 18:23, 2003.

nasal obstruction, a very large tongue, enlarged tonsils,

Howard RS, Rudd AG, Wolfe CD, Williams AJ: Pathophysi-

or certain shapes of the palate that greatly increase

ological and clinical aspects of breathing after stroke. Post-

resistance to the flow of air to the lungs during inspira-

grad Med J 77:700, 2001.

tion. The most common treatments of obstructive sleep

Jordan D: Central nervous pathways and control of the

apnea include (1) surgery to remove excess fat tissue

airways. Respir Physiol 125:67, 2001.

at the back of the throat (a procedure called uvu-

Kara T, Narkiewicz K, Somers VK: Chemoreflexes—physi-

lopalatopharyngoplasty), to remove enlarged tonsils or

ology and clinical implications. Acta Physiol Scand 177:

adenoids, or to create an opening in the trachea (tra-

377, 2003.

cheostomy) to bypass the obstructed airway during

Morris KF, Baekey DM, Nuding SC, et al: Neural network

sleep, and (2) nasal ventilation with continuous positive

plasticity in respiratory control. J Appl Physiol 94:1242,

airway pressure (CPAP).

2003.

Mortola JP, Frappell PB: Ventilatory responses to changes in

“Central” Sleep Apnea Occurs When the Neural Drive to Respira-

temperature in mammals and other vertebrates. Annu Rev

tory Muscles Is Transiently Abolished. In a few persons

Physiol 62:847, 2000.

with sleep apnea, the central nervous system drive to

Richerson GB: Serotonergic neurons as carbon dioxide

the ventilatory muscles transiently ceases. Disorders

sensors that maintain pH homeostasis. Nat Rev Neurosci

that can cause cessation of the ventilatory drive during

5:449, 2004.

sleep include damage to the central respiratory centers

Semenza GL: O₂-regulated gene expression: transcriptional

or abnormalities of the respiratory neuromuscular appa-

control of cardiorespiratory physiology by HIF-1. J Appl

ratus. Patients affected by central sleep apnea may have

Physiol 96:1173, 2004.

decreased ventilation when they are awake, although

Sharp FR, Bernaudin M: HIF1 and oxygen sensing in the

they are fully capable of normal voluntary breathing.

brain. Nat Rev Neurosci 5:437, 2004.

During sleep, their breathing disorders usually worsen,

Taylor EW, Jordan D, Coote JH: Central control of the car-

resulting in more frequent episodes of apnea that

diovascular and respiratory systems and their interactions

decrease Po₂ and increase Pco₂until a critical level is

in vertebrates. Physiol Rev 79:855, 1999.

reached that eventually stimulates respiration. These

West JB: Pulmonary Physiology—The Essentials. Baltimore:

transient instabilities of respiration cause restless sleep

Lippincott Williams & Wilkins, 2003.

and clinical features similar to those observed in

Wolk R, Shamsuzzaman AS, Somers VK: Obesity, sleep

obstructive sleep apnea.

apnea, and hypertension. Hypertension 42:1067, 2003.

In most patients, the cause of central sleep apnea is

Young T, Skatrud J, Peppard PE: Risk factors for obstructive

unknown, although instability of the respiratory drive

sleep apnea in adults. JAMA 291:2013, 2004.

can result from strokes or other disorders that make the

Zuperku EJ, McCrimmon DR: Gain modulation of respira-

respiratory centers of the brain less responsive to the

tory neurons. Respir Physiol Neurobiol 131:121, 2002.

C H A P T E R

Respiratory Insufficiency—

Pathophysiology, Diagnosis,

Oxygen Therapy

Diagnosis and treatment of most respiratory disor-

ders depend heavily on understanding the basic

physiologic principles of respiration and gas

exchange. Some respiratory diseases result from

inadequate ventilation. Others result from abnor-

malities of diffusion through the pulmonary mem-

brane or abnormal blood transport of gases

between the lungs and tissues. Therapy is often

entirely different for these diseases, so it is no longer satisfactory simply to make

a diagnosis of “respiratory insufficiency.”

Useful Methods for Studying Respiratory Abnormalities

In the previous few chapters, we have discussed a number of methods for study-

ing respiratory abnormalities, including measuring vital capacity, tidal air, func-

tional residual capacity, dead space, physiologic shunt, and physiologic dead

space. This array of measurements is only part of the armamentarium of the

clinical pulmonary physiologist. Some other interesting tools are described here.

Study of Blood Gases and Blood pH

Among the most fundamental of all tests of pulmonary performance are deter-

minations of the blood Po₂, CO₂, and pH. It is often important to make these

measurements rapidly as an aid in determining appropriate therapy for acute

respiratory distress or acute abnormalities of acid-base balance. Several simple

and rapid methods have been developed to make these measurements within

minutes, using no more than a few drops of blood. They are the following.

Determination of Blood pH. Blood pH is measured using a glass pH electrode of

the type used in all chemical laboratories. However, the electrodes used for this

purpose are miniaturized. The voltage generated by the glass electrode is a

direct measure of pH, and this is generally read directly from a voltmeter scale,

or it is recorded on a chart.

Determination of Blood CO₂. A glass electrode pH meter can also be used to deter-

mine blood CO₂ in the following way: When a weak solution of sodium bicar-

bonate is exposed to carbon dioxide gas, the carbon dioxide dissolves in the

solution until an equilibrium state is established. In this equilibrium state, the

pH of the solution is a function of the carbon dioxide and bicarbonate ion con-

centrations in accordance with the Henderson-Hasselbalch equation that is

explained in Chapter 30; that is,

HCO

= 6.1 + log

When the glass electrode is used to measure CO₂ in blood, a miniature glass

electrode is surrounded by a thin plastic membrane. In the space between the

electrode and plastic membrane is a solution of sodium bicarbonate of known

524

Chapter 42

Respiratory Insufficiency—Pathophysiology, Diagnosis, Oxygen Therapy

525

concentration. Blood is then superfused onto the outer

surface of the plastic membrane, allowing carbon

dioxide to diffuse from the blood into the bicarbonate

solution. Only a drop or so of blood is required. Next,

the pH is measured by the glass electrode, and the CO₂

500

is calculated by use of the above formula.

400

Determination of Blood PO₂. The concentration of oxygen

in a fluid can be measured by a technique called

polarography. Electric current is made to flow

300

between a small negative electrode and the solution.

If the voltage of the electrode is more than -0.6 volt

200

different from the voltage of the solution, oxygen will

deposit on the electrode. Furthermore, the rate of

100

Total lung

Residual

current flow through the electrode will be directly pro-

capacity

volume

portional to the concentration of oxygen (and there-

fore to PO₂ as well). In practice, a negative platinum

electrode with a surface area of about 1 square mil-

Lung volume (liters)

limeter is used, and this is separated from the blood

by a thin plastic membrane that allows diffusion of

oxygen but not diffusion of proteins or other sub-

stances that will “poison” the electrode.

Figure 42-1

Often all three of the measuring devices for pH,

CO₂, and Po₂ are built into the same apparatus, and all

A, Collapse of the respiratory passageway during maximum expi-

these measurements can be made within a minute or

ratory effort, an effect that limits expiratory flow rate. B, Effect of

lung volume on the maximum expiratory air flow, showing

so using a single, droplet-size sample of blood. Thus,

decreasing maximum expiratory air flow as the lung volume

changes in the blood gases and pH can be followed

becomes smaller.

almost moment by moment at the bedside.

Therefore, beyond a critical degree of expiratory force,

Measurement of Maximum

a maximum expiratory flow has been reached.

Expiratory Flow

Figure 42-1B shows the effect of different degrees

of lung collapse (and therefore of bronchiolar collapse

In many respiratory diseases, particularly in asthma,

as well) on the maximum expiratory flow. The curve

the resistance to airflow becomes especially great

recorded in this section shows the maximum expira-

during expiration, sometimes causing tremendous dif-

tory flow at all levels of lung volume after a healthy

ficulty in breathing. This has led to the concept called

person first inhales as much air as possible and then

maximum expiratory flow, which can be defined as

expires with maximum expiratory effort until he or she

follows: When a person expires with great force, the

can expire at no greater rate. Note that the person

expiratory airflow reaches a maximum flow beyond

quickly reaches a maximum expiratory airflow of more

which the flow cannot be increased any more even

than 400 L/min. But regardless of how much addi-

with greatly increased additional force. This is the

tional expiratory effort the person exerts, this is still

maximum expiratory flow. The maximum expiratory

the maximum flow rate that he or she can achieve.

flow is much greater when the lungs are filled with a

Note also that as the lung volume becomes smaller,

large volume of air than when they are almost empty.

the maximum expiratory flow rate also becomes less.

These principles can be understood by referring to

The main reason for this is that in the enlarged lung

Figure 42-1.

the bronchi and bronchioles are held open partially by

Figure 42-1A shows the effect of increased pressure

way of elastic pull on their outsides by lung structural

applied to the outsides of the alveoli and air passage-

elements; however, as the lung becomes smaller, these

ways caused by compressing the chest cage. The arrows

structures are relaxed, so that the bronchi and bron-

indicate that the same pressure compresses the

chioles are collapsed more easily by external chest

outsides of both the alveoli and the bronchioles. There-

pressure, thus progressively reducing the maximum

fore, not only does this pressure force air from

expiratory flow rate as well.

the alveoli toward the bronchioles, but it also tends

to collapse the bronchioles at the same time, which

Abnormalities of the Maximum Expiratory Flow-Volume Curve.

will oppose movement of air to the exterior. Once

Figure 42-2 shows the normal maximum expiratory

the bronchioles have almost completely collapsed,

flow-volume curve, along with two additional flow-

further expiratory force can still greatly increase the

volume curves recorded in two types of lung diseases:

alveolar pressure, but it also increases the degree of

constricted lungs and partial airway obstruction. Note

bronchiolar collapse and airway resistance by an equal

that the constricted lungs have both reduced total lung

amount, thus preventing further increase in flow.

capacity (TLC) and reduced residual volume (RV).

526

Unit VII Respiration

500

Normal

NORMAL

Maximum

Airway obstruction

400

inspiration

Constricted lungs

300

FEV₁

FVC

200

FEV₁/FVC%

= 80%

100

TLC

AIRWAY OBSTRUCTION

Lung volume (liters)

FEV₁

FEV

1/FVC%

FVC

Figure 42-2

= 47%

Effect of two respiratory abnormalities—constricted lungs and

airway obstruction—-on the maximum expiratory flow-volume

Seconds

curve. TLC, total lung capacity; RV, residual volume.

Furthermore, because the lung cannot expand to a

Figure 42-3

normal maximum volume, even with the greatest pos-

sible expiratory effort, the maximal expiratory flow

Recordings during the forced vital capacity maneuver: A, in a

cannot rise to equal that of the normal curve. Con-

healthy person and B, in a person with partial airway obstruction.

stricted lung diseases include fibrotic diseases of the

(The “zero” on the volume scale is residual volume.)

lung itself, such as tuberculosis and silicosis, and dis-

eases that constrict the chest cage, such as kyphosis,

scoliosis, and fibrotic pleurisy.

spirometer with maximum expiratory effort as rapidly

In diseases with airway obstruction, it is usually

and as completely as possible. The total distance of the

much more difficult to expire than to inspire because

downslope of the lung volume record represents the

the closing tendency of the airways is greatly increased

FVC, as shown in the figure.

by the extra positive pressure required in the chest

Now, study the difference between the two records

to cause expiration. By contrast, the extra negative

(1) for normal lungs and (2) for partial airway obstruc-

pleural pressure that occurs during inspiration actually

tion. The total volume changes of the FVCs are not

“pulls” the airways open at the same time that it

greatly different, indicating only a moderate difference

expands the alveoli. Therefore, air tends to enter the

in basic lung volumes in the two persons. There is,

lung easily but then becomes trapped in the lungs.

however, a major difference in the amounts of air that

Over a period of months or years, this effect increases

these persons can expire each second, especially during

both the TLC and the RV, as shown by the green curve

the first second. Therefore, it is customary to compare

in Figure 42-2. Also, because of the obstruction of the

the recorded forced expiratory volume during the first

airways and because they collapse more easily than

second (FEV₁) with the normal. In the normal person

normal airways, the maximum expiratory flow rate is

(see Figure 42-3A), the percentage of the FVC that is

greatly reduced.

expired in the first second divided by the total FVC

The classic disease that causes severe airway

(FEV₁/FVC%) is 80 per cent. However, note in Figure

obstruction is asthma. Serious airway obstruction also

42-3B that, with airway obstruction, this value

occurs in some stages of emphysema.

decreased to only

47 per cent. In serious airway

obstruction, as often occurs in acute asthma, this can

decrease to less than 20 per cent.

Forced Expiratory Vital Capacity and

Forced Expiratory Volume

Physiologic Peculiarities

Another exceedingly useful clinical pulmonary test,

of Specific Pulmonary

and one that is also simple, is to make a record on a

spirometer of the forced expiratory vital capacity

Abnormalities

(FVC). Such a record is shown in Figure 42-3A for a

person with normal lungs and in Figure 42-3B for a

Chronic Pulmonary Emphysema

person with partial airway obstruction. In performing

the FVC maneuver, the person first inspires maximally

The term pulmonary emphysema literally means

to the total lung capacity, then exhales into the

excess air in the lungs. However, this term is usually

Chapter 42

Respiratory Insufficiency—Pathophysiology, Diagnosis, Oxygen Therapy

527

used to describe complex obstructive and destructive

process of the lungs caused by many years of smoking.

It results from the following major pathophysiologic

changes in the lungs:

1. Chronic infection, caused by inhaling smoke or

other substances that irritate the bronchi and

bronchioles. The chronic infection seriously

deranges the normal protective mechanisms of the

airways, including partial paralysis of the cilia of

the respiratory epithelium, an effect caused by

nicotine. As a result, mucus cannot be moved

easily out of the passageways. Also, stimulation

of excess mucus secretion occurs, which further

exacerbates the condition. Too, inhibition of the

alveolar macrophages occurs, so that they become

less effective in combating infection.

2. The infection, excess mucus, and inflammatory

edema of the bronchiolar epithelium together

cause chronic obstruction of many of the smaller

airways.

3. The obstruction of the airways makes it especially

difficult to expire, thus causing entrapment of

air in the alveoli and overstretching them. This,

combined with the lung infection, causes marked

destruction of as much as 50 to 80 per cent of the

alveolar walls. Therefore, the final picture of the

emphysematous lung is that shown in Figures

42-4 (top) and 42-5.

The physiologic effects of chronic emphysema are

extremely varied, depending on the severity of the

disease and the relative degrees of bronchiolar ob-

Figure 42-4

struction versus lung parenchymal destruction. Among

the different abnormalities are the following:

Contrast of the emphysematous lung (top figure) with the normal

The bronchiolar obstruction increases airway

lung (bottom figure), showing extensive alveolar destruction in

resistance and results in greatly increased work of

emphysema. (Reproduced with permission of Patricia Delaney

and the Department of Anatomy, The Medical College of

breathing. It is especially difficult for the person

Wisconsin.)

to move air through the bronchioles during

expiration because the compressive force on the

outside of the lung not only compresses the

alveoli but also compresses the bronchioles,

which further increases their resistance during

turn overloads the right side of the heart and

expiration.

frequently causes right-sided heart failure.

The marked loss of alveolar walls greatly

Chronic emphysema usually progresses slowly over

decreases the diffusing capacity of the lung, which

many years. The person develops both hypoxia and

reduces the ability of the lungs to oxygenate the

hypercapnia because of hypoventilation of many

blood and remove carbon dioxide from the blood.

alveoli plus loss of alveolar walls. The net result of

The obstructive process is frequently much worse

all these effects is severe, prolonged, devastating air

in some parts of the lungs than in other parts,

hunger that can last for years until the hypoxia and

so that some portions of the lungs are well

hypercapnia cause death—a high penalty to pay for

ventilated, while other portions are poorly

smoking.

ventilated. This often causes extremely abnormal

v.ent.lation-perfusion ratios, with a very low

Va/Q

in some parts (physiologic shunt), resul.ing

Pneumonia

in poor aeration of the blood, and very high Va/Q

in other parts (physiologic dead space), resulting

The term pneumonia includes any inflammatory con-

in wasted ventilation, both effects occurring in the

dition of the lung in which some or all of the alveoli

same lungs.

are filled with fluid and blood cells, as shown in Figure

Loss of large portions of the alveolar walls also

42-5. A common type of pneumonia is bacterial pneu-

decreases the number of pulmonary capillaries

monia, caused most frequently by pneumococci.

through which blood can pass. As a result, the

This disease begins with infection in the alveoli; the

pulmonary vascular resistance often increases

pulmonary membrane becomes inflamed and highly

markedly, causing pulmonary hypertension. This in

porous so that fluid and even red and white blood cells

528

Unit VII Respiration

Fluid and blood cells

Confluent alveoli

Edema

Normal

Pneumonia

Emphysema

Figure 42-5

Lung alveolar changes in pneumonia and emphysema.

leak out of the blood into the alveoli. Thus, the infected

Pulmonary arterial blood

alveoli become progressively filled with fluid and cells,

60% saturated with O₂

and the infection spreads by extension of bacteria or

virus from alveolus to alveolus. Eventually, large areas

of the lungs, sometimes whole lobes or even a whole

lung, become “consolidated,” which means that they

Pneumonia

are filled with fluid and cellular debris.

In pneumonia, the gas exchange functions of the

lungs change in different stages of the disease. In early

stages, the pneumonia process might well be localized

to only one lung, with alveolar ventilation reduced

Left

Right

pulmonary

while blood flow through the lung continues normally.

pulmonary

vein

60%

This results in two major pulmonary abnormalities: (1)

vein

97%

saturated

reduction in the total available surface area of the res-

piratory membrane and (2) decreased ventilation-

Aorta:

perfusion ratio. Both these effects cause hypoxemia

Blood 1/2 = 97%

(low blood oxygen) and hypercapnia

(high blood

1/2 = 60%

carbon dioxide).

Mean

= 78%

Figure

42-6 shows the effect of the decreased

ventilation-perfusion ratio in pneumonia, showing that

Figure 42-6

the blood passing through the aerated lung becomes

Effect of pneumonia on percentage saturation of oxygen in the

97 per cent saturated with oxygen, whereas that

pulmonary artery, the right and left pulmonary veins, and the aorta.

passing through the unaerated lung is about 60 per

cent saturated. Therefore, the average saturation of the

blood pumped by the left heart into the aorta is only

about 78 per cent, which is far below normal.

is pliable enough, this will lead simply to collapse of

the alveoli. However, if the lung is rigid because of

Atelectasis

fibrotic tissue and cannot collapse, absorption of air

from the alveoli creates very negative pressures within

Atelectasis means collapse of the alveoli. It can occur

the alveoli, which pull fluid out of the pulmonary cap-

in localized areas of a lung or in an entire lung. Its most

illaries into the alveoli, thus causing the alveoli to fill

common causes are (1) total obstruction of the airway

completely with edema fluid. This almost always is the

or (2) lack of surfactant in the fluids lining the alveoli.

effect that occurs when an entire lung becomes

atelectatic, a condition called massive collapse of the

Airway Obstruction. The airway obstruction type of

lung.

atelectasis usually results from (1) blockage of many

The effects on overall pulmonary function caused by

small bronchi with mucus or (2) obstruction of a major

massive collapse (atelectasis) of an entire lung are

bronchus by either a large mucus plug or some solid

shown in Figure 42-7. Collapse of the lung tissue not

object such as a tumor. The air entrapped beyond the

only occludes the alveoli but also almost always

block is absorbed within minutes to hours by the blood

increases the resistance to blood flow through the pul-

flowing in the pulmonary capillaries. If the lung tissue

monary vessels of the collapsed lung. This resistance

Chapter 42

Respiratory Insufficiency—Pathophysiology, Diagnosis, Oxygen Therapy

529

Pulmonary arterial blood

Asthma

60% saturated with O₂

Asthma is characterized by spastic contraction of the

smooth muscle in the bronchioles, which partially

obstructs the bronchioles and causes extremely diffi-

cult breathing. It occurs in 3 to 5 per cent of all people

Atelectasis

at some time in life.

The usual cause of asthma is contractile hypersensi-

tivity of the bronchioles in response to foreign sub-

stances in the air. In about 70 per cent of patients

Left

younger than age 30 years, the asthma is caused by

Right

pulmonary

allergic hypersensitivity, especially sensitivity to plant

vein 60%

vein

97%

pollens. In older people, the cause is almost always

saturated-

saturated

hypersensitivity to nonallergenic types of irritants in

flow 1/5 normal

the air, such as irritants in smog.

Aorta:

The allergic reaction that occurs in the allergic type

Blood 5/6 = 97%

of asthma is believed to occur in the following way: The

1/6 = 60%

Mean saturation

typical allergic person has a tendency to form abnor-

= 91%

mally large amounts of IgE antibodies, and these anti-

bodies cause allergic reactions when they react with the

Figure 42-7

specific antigens that have caused them to develop in

the first place, as explained in Chapter 34. In asthma,

Effect of atelectasis on aortic blood oxygen saturation.

these antibodies are mainly attached to mast cells that

are present in the lung interstitium in close association

with the bronchioles and small bronchi. When the asth-

matic person breathes in pollen to which he or she is

increase occurs partially because of the lung collapse

sensitive (that is, to which the person has developed

itself, which compresses and folds the vessels as the

IgE antibodies), the pollen reacts with the mast cell-

volume of the lung decreases. In addition, hypoxia in

attached antibodies and causes the mast cells to release

the collapsed alveoli causes additional vasoconstric-

several different substances. Among them are

(a)

tion, as explained in Chapter 38.

histamine, (b) slow-reacting substance of anaphylaxis

Because of the vascular constriction, blood flow

(which is a mixture of leukotrienes), (c) eosinophilic

through the atelectatic lung becomes slight. Fortu-

chemotactic factor, and (d) bradykinin. The combined

nately, most of the blood is routed through the venti-

effects of all these factors, especially the slow-reacting

lated lung and therefore becomes well aerated. In the

substance of anaphylaxis, are to produce (1) localized

situation shown in Figure 42-7, five sixths of the blood

edema in the walls of the small bronchioles, as well as

passes through the aerated lung and only one sixth

secretion of thick mucus into the bronchiolar lumens,

through the unaerated lung. As a result, the overall

and (2) spasm of the bronchiolar smooth muscle.

ventilation-perfusion ratio is only moderately com-

Therefore, the airway resistance increases greatly.

promised, so that the aortic blood has only mild

As discussed earlier in this chapter, the bronchiolar

oxygen desaturation despite total loss of ventilation in

diameter becomes more reduced during expiration

an entire lung.

than during inspiration in asthma, caused by bronchi-

olar collapse during expiratory effort that compresses

Lack of “Surfactant” as a Cause of Lung Collapse. The secre-

the outsides of the bronchioles. Because the bronchi-

tion and function of surfactant in the alveoli were

oles of the asthmatic lungs are already partially

discussed in Chapter 37. It was pointed out that the

occluded, further occlusion resulting from the external

surfactant is secreted by special alveolar epithelial

pressure creates especially severe obstruction during

cells into the fluids that coat the inside surface of the

expiration. That is, the asthmatic person often can

alveoli. The surfactant in turn decreases the surface

inspire quite adequately but has great difficulty expir-

tension in the alveoli 2- to 10-fold, which normally

ing. Clinical measurements show (1) greatly reduced

plays a major role in preventing alveolar collapse.

maximum expiratory rate and (2) reduced timed expi-

However, in a number of conditions, such as in hyaline

ratory volume. Also, all of this together results in

membrane disease (also called respiratory distress syn-

dyspnea, or “air hunger,” which is discussed later in

drome), which often occurs in newborn premature

this chapter.

babies, the quantity of surfactant secreted by the

The functional residual capacity and residual volume

alveoli is so greatly depressed that the surface tension

of the lung become especially increased during the

of the alveolar fluid becomes several times normal.

acute asthmatic attack because of the difficulty in

This causes a serious tendency for the lungs of these

expiring air from the lungs. Also, over a period of

babies to collapse or to become filled with fluid. As

years, the chest cage becomes permanently enlarged,

explained in Chapter 37, many of these infants die of

causing a “barrel chest,” and both the functional resid-

suffocation when large portions of the lungs become

ual capacity and lung residual volume become perma-

atelectatic.

nently increased.

530

Unit VII

Respiration

Tuberculosis

b. Diminished cellular metabolic capacity for using

oxygen, because of toxicity, vitamin deficiency, or

In tuberculosis, the tubercle bacilli cause a peculiar

other factors

tissue reaction in the lungs, including (1) invasion of

This classification of the types of hypoxia is mainly

the infected tissue by macrophages and (2) “walling

self-evident from the discussions earlier in the chapter.

off ” of the lesion by fibrous tissue to form the so-called

Only one of the types of hypoxia in the classification

tubercle. This walling-off process helps to limit further

needs further elaboration: this is the hypoxia caused

transmission of the tubercle bacilli in the lungs and

by inadequate capability of the body’s tissue cells to

therefore is part of the protective process against

use oxygen.

extension of the infection. However, in about 3 per

cent of all people who develop tuberculosis, if

Inadequate Tissue Capability to Use Oxygen. The classic

untreated, the walling-off process fails and tubercle

cause of inability of the tissues to use oxygen is cyanide

bacilli spread throughout the lungs, often causing

poisoning, in which the action of the enzyme

extreme destruction of lung tissue with formation of

cytochrome oxidase is completely blocked by the

large abscess cavities.

cyanide—to such an extent that the tissues simply

Thus, tuberculosis in its late stages is characterized

cannot use oxygen even when plenty is available. Also,

by many areas of fibrosis throughout the lungs, as well

deficiencies of some of the tissue cellular oxidative

as reduced total amount of functional lung tissue.

enzymes or of other elements in the tissue oxidative

These effects cause (1) increased “work” on the part

system can lead to this type of hypoxia. A special

of the respiratory muscles to cause pulmonary venti-

example occurs in the disease beriberi, in which several

lation and reduced vital capacity and breathing capac-

important steps in tissue utilization of oxygen and

ity; (2) reduced total respiratory membrane surface area

formation of carbon dioxide are compromised because

and increased thickness of the respiratory membrane,

of vitamin B deficiency.

causing progressively diminished pulmonary diffusing

capacity; and (3) abnormal ventilation-perfusion ratio

Effects of Hypoxia on the Body. Hypoxia, if severe enough,

in the lungs, further reducing overall pulmonary diffu-

can cause death of cells throughout the body, but in

sion of oxygen and carbon dioxide.

less severe degrees it causes principally (1) depressed

mental activity, sometimes culminating in coma, and

(2) reduced work capacity of the muscles. These effects

Hypoxia and Oxygen Therapy

are specifically discussed in Chapter 43 in relation to

high-altitude physiology.

Almost any of the conditions discussed in the past

few sections of this chapter can cause serious degrees

of bodywide cellular hypoxia. Sometimes, oxygen

Oxygen Therapy in Different Types

therapy is of great value; other times, it is of moderate

of Hypoxia

value; and, at still other times, it is of almost no value.

Therefore, it is important to understand the different

Oxygen can be administered by

(1) placing the

types of hypoxia; then we can discuss the physiologic

patient’s head in a “tent” that contains air fortified

principles of oxygen therapy. The following is a

with oxygen, (2) allowing the patient to breathe either

descriptive classification of the causes of hypoxia:

pure oxygen or high concentrations of oxygen from

1. Inadequate oxygenation of the blood in the lungs

a mask, or

(3) administering oxygen through an

because of extrinsic reasons

intranasal tube.

a. Deficiency of oxygen in the atmosphere

Recalling the basic physiologic principles of the

b. Hypoventilation (neuromuscular disorders)

different types of hypoxia, one can readily decide

2. Pulmonary disease

when oxygen therapy will be of value and, if so, how

a. Hypoventilation caused by increased airway

valuable.

resistance or decreased pulmonary compliance

In atmospheric hypoxia, oxygen therapy can com-

b. Abnormal alveolar ventilation-perfusion ratio

pletely correct the depressed oxygen level in the

(including either increased physiologic dead

inspired gases and, therefore, provide 100 per cent

space or increased physiologic shunt)

effective therapy.

c. Diminished respiratory membrane diffusion

In hypoventilation hypoxia, a person breathing 100

3. Venous-to-arterial shunts

(“right-to-left” cardiac

per cent oxygen can move five times as much oxygen

shunts)

into the alveoli with each breath as when breathing

4. Inadequate oxygen transport to the tissues by the

normal air. Therefore, here again oxygen therapy can

blood

be extremely beneficial. (However, this provides no

a. Anemia or abnormal hemoglobin

benefit for the excess blood carbon dioxide also caused

b. General circulatory deficiency

by the hypoventilation.)

c. Localized circulatory deficiency

(peripheral,

In hypoxia caused by impaired alveolar membrane

cerebral, coronary vessels)

diffusion, essentially the same result occurs as in

d. Tissue edema

hypoventilation hypoxia, because oxygen therapy can

5. Inadequate tissue capability of using oxygen

increase the Po₂ in the lung alveoli from the normal

a. Poisoning of cellular oxidation enzymes

value of about 100 mm Hg to as high as 600 mm Hg.

Chapter 42

Respiratory Insufficiency—Pathophysiology, Diagnosis, Oxygen Therapy

531

dark blue-purple color that is transmitted through the

skin.

300

In general, definite cyanosis appears whenever the

arterial blood contains more than 5 grams of deoxy-

genated hemoglobin in each 100 milliliters of blood. A

Alveolar PO₂ with tent therapy

person with anemia almost never becomes cyanotic

Normal alveolar PO

200

because there is not enough hemoglobin for 5 grams

Pulmonary edema + O₂therapy

to be deoxygenated in 100 milliliters of arterial blood.

Pulmonary edema with no therapy

Conversely, in a person with excess red blood cells, as

occurs in polycythemia vera, the great excess of avail-

100

able hemoglobin that can become deoxygenated leads

frequently to cyanosis, even under otherwise normal

Capillary blood

conditions.

Arterial end

Venous end

Blood in pulmonary capillary

Hypercapnia

Hypercapnia means excess carbon dioxide in the body

fluids.

Figure 42-8

One might suspect, on first thought, that any respi-

ratory condition that causes hypoxia would also cause

Absorption of oxygen into the pulmonary capillary blood in pul-

hypercapnia. However, hypercapnia usually occurs

monary edema with and without oxygen tent therapy.

in association with hypoxia only when the hypoxia

is caused by hypoventilation or circulatory deficiency.

The reasons for this are the following.

This raises the oxygen pressure gradient for diffusion

Hypoxia caused by too little oxygen in the air, too

of oxygen from the alveoli to the blood from the

little hemoglobin, or poisoning of the oxidative

normal value of 60 mm Hg to as high as 560 mm Hg,

enzymes has to do only with the availability of oxygen

an increase of more than 800 per cent. This highly ben-

or use of oxygen by the tissues. Therefore, it is readily

eficial effect of oxygen therapy in diffusion hypoxia is

understandable that hypercapnia is not a concomitant

demonstrated in Figure 42-8, which shows that the

of these types of hypoxia.

pulmonary blood in this patient with pulmonary

In hypoxia resulting from poor diffusion through

edema picks up oxygen three to four times as rapidly

the pulmonary membrane or through the tissues,

as would occur with no therapy.

serious hypercapnia usually does not occur at the same

In hypoxia caused by anemia, abnormal hemoglobin

time because carbon dioxide diffuses

20 times as

transport of oxygen, circulatory deficiency, or physio-

rapidly as oxygen. If hypercapnia does begin to occur,

logic shunt, oxygen therapy is of much less value

this immediately stimulates pulmonary ventilation,

because normal oxygen is already available in the

which corrects the hypercapnia but not necessarily the

alveoli. The problem instead is that one or more of the

hypoxia.

mechanisms for transporting oxygen from the lungs to

Conversely, in hypoxia caused by hypoventilation,

the tissues is deficient. Even so, a small amount of

carbon dioxide transfer between the alveoli and the

extra oxygen, between 7 and 30 per cent, can be trans-

atmosphere is affected as much as is oxygen transfer.

ported in the dissolved state in the blood when alveo-

Hypercapnia then occurs along with the hypoxia. And

lar oxygen is increased to maximum even though the

in circulatory deficiency, diminished flow of blood

amount transported by the hemoglobin is hardly

decreases carbon dioxide removal from the tissues,

altered. This small amount of extra oxygen may be the

resulting in tissue hypercapnia in addition to tissue

difference between life and death.

hypoxia. However, the transport capacity of the blood

In the different types of hypoxia caused by inade-

for carbon dioxide is more than three times that for

quate tissue use of oxygen, there is abnormality neither

oxygen, so that the resulting tissue hypercapnia is

of oxygen pickup by the lungs nor of transport to the

much less than the tissue hypoxia.

tissues. Instead, the tissue metabolic enzyme system is

When the alveolar Pco₂ rises above about 60 to

simply incapable of using the oxygen that is delivered.

75 mm Hg, an otherwise normal person by then is

Therefore, oxygen therapy is of hardly any measura-

breathing about as rapidly and deeply as he or she

ble benefit.

can, and “air hunger,” also called dyspnea, becomes

severe.

If the Pco₂rises to 80 to 100 mm Hg, the person

Cyanosis

becomes lethargic and sometimes even semicomatose.

Anesthesia and death can result when the Pco₂ rises

The term cyanosis means blueness of the skin, and its

to 120 to 150 mm Hg. At these higher levels of Pco₂,

cause is excessive amounts of deoxygenated hemoglo-

the excess carbon dioxide now begins to depress res-

bin in the skin blood vessels, especially in the capil-

piration rather than stimulate it, thus causing a vicious

laries. This deoxygenated hemoglobin has an intense

circle: (1) more carbon dioxide, (2) further decrease in

532

Unit VII

Respiration

respiration,

(3) then more carbon dioxide, and so

forth—culminating rapidly in a respiratory death.

Dyspnea

Mechanism

for applying

positive and

Dyspnea means mental anguish associated with inabil-

negative

ity to ventilate enough to satisfy the demand for air. A

pressure

common synonym is air hunger.

At least three factors often enter into the develop-

ment of the sensation of dyspnea. They are (1) abnor-

Positive

Negative

mality of respiratory gases in the body fluids, especially

pressure

hypercapnia and, to a much less extent, hypoxia; (2)

valve

the amount of work that must be performed by the res-

piratory muscles to provide adequate ventilation; and

(3) state of mind.

A person becomes very dyspneic especially from

excess buildup of carbon dioxide in the body fluids. At

times, however, the levels of both carbon dioxide and

oxygen in the body fluids are normal, but to attain this

normality of the respiratory gases, the person has to

breathe forcefully. In these instances, the forceful

activity of the respiratory muscles frequently gives the

person a sensation of dyspnea.

Leather diaphragm

Finally, the person’s respiratory functions may be

normal and still dyspnea may be experienced because

Figure 42-9

of an abnormal state of mind. This is called neurogenic

A, Resuscitator. B, Tank respirator.

dyspnea or emotional dyspnea. For instance, almost

anyone momentarily thinking about the act of breath-

ing may suddenly start taking breaths a little more

deeply than ordinarily because of a feeling of mild

dyspnea. This feeling is greatly enhanced in people

who have a psychological fear of not being able to

receive a sufficient quantity of air, such as on entering

and the head protruding through a flexible but airtight

small or crowded rooms.

collar. At the end of the tank opposite the patient’s

head a motor-driven leather diaphragm moves back

and forth with sufficient excursion to raise and lower

Artificial Respiration

the pressure inside the tank. As the leather diaphragm

moves inward, positive pressure develops around the

Resuscitator. Many types of respiratory resuscitators

body and causes expiration; as the diaphragm moves

are available, and each has its own characteristic prin-

outward, negative pressure causes inspiration. Check

ciples of operation. The resuscitator shown in Figure

valves on the respirator control the positive and

42-9A consists of a tank supply of oxygen or air; a

negative pressures. Ordinarily these pressures are

mechanism for applying intermittent positive pressure

adjusted so that the negative pressure that causes

and, with some machines, negative pressure as well;

inspiration falls to -10 to -20 cm H₂O and the positive

and a mask that fits over the face of the patient or a

pressure rises to 0 to +5 cm H₂O.

connector for joining the equipment to an endotra-

cheal tube. This apparatus forces air through the mask

Effect of the Resuscitator and the Tank Respirator on Venous

or endotracheal tube into the lungs of the patient

Return. When air is forced into the lungs under posi-

during the positive-pressure cycle of the resuscitator

tive pressure by a resuscitator, or when the pressure

and then usually allows the air to flow passively out of

around the patient’s body is reduced by the tank

the lungs during the remainder of the cycle.

respirator, the pressure inside the lungs becomes

Earlier resuscitators often caused damage to the

greater than pressure everywhere else in the body.

lungs because of excessive positive pressure. Their

Flow of blood into the chest and heart from the

usage was at one time greatly decried. However, resus-

peripheral veins becomes impeded. As a result, use

citators now have adjustable positive-pressure limits

of excessive pressures with either the resuscitator or

that are commonly set at 12 to 15 cm H₂O pressure for

the tank respirator can reduce the cardiac output—

normal lungs (but sometimes much higher for non-

sometimes to lethal levels. For instance, continuous

compliant lungs).

exposure for more than a few minutes to greater than

30 mm Hg positive pressure in the lungs can cause

Tank Respirator (the “Iron-Lung”). Figure 42-9B shows the

death because of inadequate venous return to the

tank respirator with a patient’s body inside the tank

heart.

Chapter 42

Respiratory Insufficiency—Pathophysiology, Diagnosis, Oxygen Therapy

533

References

Page S, Ammit AJ, Black JL, Armour CL: Human mast cell

and airway smooth muscle cell interactions: implications

for asthma. Am J Physiol Lung Cell Mol Physiol 281:

Albert R, Spiro S, Jett J: Comprehensive Respiratory Medi-

L1313, 2001.

cine. Philadelphia: Mosby, 2002.

Rodrigo GJ, Rodrigo C, Hall JB: Acute asthma in adults: a

Barnes PJ, Adcock IM: How do corticosteroids work in

review. Chest 125:1081, 2004.

asthma? Ann Intern Med 139:359, 2003.

Schwiebert LM: Cystic fibrosis, gene therapy, and lung

Basu S, Fenton MJ: Toll-like receptors: function and roles in

inflammation: for better or worse? Am J Physiol Lung Cell

lung disease. Am J Physiol Lung Cell Mol Physiol 286:

Mol Physiol 286:L715, 2004.

L887, 2004.

Sin DD, McAlister FA, Man SF, Anthonisen NR: Contem-

Cardoso WV: Molecular regulation of lung development.

porary management of chronic obstructive pulmonary

Annu Rev Physiol 63:471, 2001.

disease: scientific review. JAMA 290:2301, 2003.

Carter EP, Garat C, Imamura M: Continual emerging roles

Wardlaw AJ, Brightling CE, Green R, et al: New insights

of HO-1: protection against airway inflammation. Am J

into the relationship between airway inflammation and

Physiol Lung Cell Mol Physiol 287:L24, 2004.

asthma. Clin Sci (Lond) 103:201, 2002.

Dwyer TM: Cigarette smoke-induced airway inflammation

West JB: Pulmonary Physiology and Pathophysiology: An

as sampled by the expired breath condensate. Am J Med

Integrated, Case-Based Approach. Philadelphia: Lippin-

Sci 326:174, 2003.

cott Williams & Wilkins, 2001.

Knight DA, Holgate ST: The airway epithelium: structural

Whitsett JA, Weaver TE: Hydrophobic surfactant proteins

and functional properties in health and disease. Respirol-

in lung function and disease. N Engl J Med 347:2141,

ogy 8:432, 2003.

2002.

McConnell AK, Romer LM: Dyspnoea in health and

Wills-Karp M, Ewart SL: Time to draw breath: asthma-

obstructive pulmonary disease: the role of respiratory

susceptibility genes are identified. Nat Rev Genet 5:376,

muscle function and training. Sports Med 34:117, 2004.

2004.

Naureckas ET, Solway J: Clinical practice. Mild asthma.

N Engl J Med 345:1257, 2001.

C H A P T E R

Aviation, High-Altitude,

and Space Physiology

As we have ascended to higher and higher altitudes

in aviation, mountain climbing, and space vehicles,

it has become progressively more important to

understand the effects of altitude and low gas pres-

sures (as well as several other factors—acceleratory

forces, weightlessness, and so forth) on the human

body. This chapter deals with these problems.

Effects of Low Oxygen Pressure on the Body

Barometric Pressures at Different Altitudes. Table 43-1 gives the approximate baro-

metric and oxygen pressures at different altitudes, showing that at sea level, the

barometric pressure is 760 mm Hg; at 10,000 feet, only 523 mm Hg; and at

50,000 feet, 87 mm Hg. This decrease in barometric pressure is the basic cause

of all the hypoxia problems in high-altitude physiology because, as the baro-

metric pressure decreases, the atmospheric oxygen partial pressure decreases

proportionately, remaining at all times slightly less than 21 per cent of the total

barometric pressure—Po₂ at sea level about 159 mm Hg, but at 50,000 feet only

18 mm Hg.

Alveolar PO₂ at Different Elevations

Carbon Dioxide and Water Vapor Decrease the Alveolar Oxygen. Even at high altitudes,

carbon dioxide is continually excreted from the pulmonary blood into the

alveoli. Also, water vaporizes into the inspired air from the respiratory surfaces.

These two gases dilute the oxygen in the alveoli, thus reducing the oxygen con-

centration. Water vapor pressure in the alveoli remains 47 mm Hg as long as

the body temperature is normal, regardless of altitude.

In the case of carbon dioxide, during exposure to very high altitudes, the alve-

olar Pco₂ falls from the sea-level value of 40 mm Hg to lower values. In the

acclimatized person, who increases his or her ventilation about fivefold, the Pco₂

falls to about 7 mm Hg because of increased respiration.

Now let us see how the pressures of these two gases affect the alveolar

oxygen. For instance, assume that the barometric pressure falls from the normal

sea-level value of 760 mm Hg to 253 mm Hg, which is the usual measured value

at the top of 29,028-foot Mount Everest. Forty-seven millimeters of mercury of

this must be water vapor, leaving only 206 mm Hg for all the other gases. In the

acclimatized person, 7 mm of the 206 mm Hg must be carbon dioxide, leaving

only 199 mm Hg. If there were no use of oxygen by the body, one fifth of this

199 mm Hg would be oxygen and four fifths would be nitrogen; that is, the Po₂

in the alveoli would be 40 mm Hg. However, some of this remaining alveolar

oxygen is continually being absorbed into the blood, leaving about 35 mm Hg

oxygen pressure in the alveoli. At the summit of Mount Everest, only the best

of acclimatized people can barely survive when breathing air. But the effect is

very different when the person is breathing pure oxygen, as we see in the fol-

lowing discussions.

537

538

Unit VIII

Aviation, Space, and Deep-Sea Diving Physiology

Table 43-1

Effects of Acute Exposure to Low Atmospheric Pressures on Alveolar Gas Concentrations and Arterial Oxygen Saturation*

Breathing Air

Breathing Pure Oxygen

Arterial

Barometric

PO₂ in

PCO₂ in

PO₂ in

Oxygen

PCO₂ in

PO₂ in

Oxygen

Pressure

Air

Alveoli

Saturation

Alveoli

Saturation

Altitude (ft)

(mm Hg)

(%)

(mm Hg)

(%)

760

159

40 (40)

104 (104)

97 (97)

673

100

10,000

523

110

36 (23)

67 (77)

90 (92)

436

100

20,000

349

24 (10)

40 (53)

73 (85)

262

100

30,000

226

24 (7)

18 (30)

24 (38)

139

40,000

141

50,000

* Numbers in parentheses are acclimatized values.

Alveolar PO₂ at Different Altitudes. The fifth column of

Table 43-1 shows the approximate Po₂s in the alveoli

at different altitudes when one is breathing air for both

Breathing pure oxygen

the unacclimatized and the acclimatized person. At sea

Breathing air

level, the alveolar Po₂is 104 mm Hg; at 20,000 feet alti-

100

tude, it falls to about 40 mm Hg in the unacclimatized

person but only to 53 mm Hg in the acclimatized. The

difference between these two is that alveolar ventila-

tion increases much more in the acclimatized person

than in the unacclimatized person, as we discuss later.

Saturation of Hemoglobin with Oxygen at Different Altitudes.

Figure 43-1 shows arterial blood oxygen saturation at

different altitudes while a person is breathing air and

while breathing oxygen. Up to an altitude of about

10,000 feet, even when air is breathed, the arterial

oxygen saturation remains at least as high as 90 per

cent. Above 10,000 feet, the arterial oxygen saturation

Altitude (thousands of feet)

falls rapidly, as shown by the blue curve of the figure,

until it is slightly less than 70 per cent at 20,000 feet

and much less at still higher altitudes.

Figure 43-1

Effect of high altitude on arterial oxygen saturation when breath-

Effect of Breathing Pure Oxygen on

ing air and when breathing pure oxygen.

Alveolar PO₂ at Different Altitudes

breathing pure oxygen in an unpressurized airplane

When a person breathes pure oxygen instead of air,

can ascend to far higher altitudes than one breathing

most of the space in the alveoli formerly occupied by

air. For instance, the arterial saturation at 47,000 feet

nitrogen becomes occupied by oxygen. At 30,000 feet,

when one is breathing oxygen is about 50 per cent and

an aviator could have an alveolar Po₂ as high as

is equivalent to the arterial oxygen saturation at 23,000

139 mm Hg instead of the 18 mm Hg when breathing

feet when one is breathing air. In addition, because an

air (see Table 43-1).

unacclimatized person usually can remain conscious

The red curve of Figure 43-1 shows arterial blood

until the arterial oxygen saturation falls to 50 per cent,

hemoglobin oxygen saturation at different altitudes

for short exposure times the ceiling for an aviator in

when one is breathing pure oxygen. Note that the sat-

an unpressurized airplane when breathing air is about

uration remains above 90 per cent until the aviator

23,000 feet and when breathing pure oxygen is about

ascends to about 39,000 feet; then it falls rapidly to

47,000 feet, provided the oxygen-supplying equipment

about 50 per cent at about 47,000 feet.

operates perfectly.

The “Ceiling” When Breathing Air

and When Breathing Oxygen in an

Acute Effects of Hypoxia

Unpressurized Airplane

Comparing the two arterial blood oxygen satura-

Some of the important acute effects of hypoxia in the

tion curves in Figure 43-1, one notes that an aviator

unacclimatized person breathing air, beginning at an

Chapter 43

Aviation, High-Altitude, and Space Physiology

539

altitude of about 12,000 feet, are drowsiness, lassitude,

An important mechanism for the gradual decrease

mental and muscle fatigue, sometimes headache, occa-

in bicarbonate concentration is compensation by the

sionally nausea, and sometimes euphoria. These effects

kidneys for the respiratory alkalosis, as discussed in

progress to a stage of twitchings or seizures above

Chapter 30. The kidneys respond to decreased Pco₂

18,000 feet and end, above 23,000 feet in the unaccli-

by reducing hydrogen ion secretion and increasing

matized person, in coma, followed shortly thereafter

bicarbonate excretion. This metabolic compensation

by death.

for the respiratory alkalosis gradually reduces plasma

One of the most important effects of hypoxia is

and cerebrospinal fluid bicarbonate concentration and

decreased mental proficiency, which decreases judg-

pH toward normal and removes part of the inhibitory

ment, memory, and performance of discrete motor

effect on respiration of low hydrogen ion concentra-

movements. For instance, if an unacclimatized aviator

tion. Thus, the respiratory centers are much more

stays at 15,000 feet for 1 hour, mental proficiency ordi-

responsive to the peripheral chemoreceptor stimulus

narily falls to about 50 per cent of normal, and after

caused by the hypoxia after the kidneys compensate

18 hours at this level it falls to about 20 per cent of

for the alkalosis.

normal.

Increase in Red Blood Cells and Hemoglobin Concentration

During Acclimatization. As discussed in Chapter

32,

Acclimatization to Low PO₂

hypoxia is the principal stimulus for causing an

increase in red blood cell production. Ordinarily, when

A person remaining at high altitudes for days, weeks,

a person remains exposed to low oxygen for weeks at

or years becomes more and more acclimatized to the

a time, the hematocrit rises slowly from a normal value

low Po₂, so that it causes fewer deleterious effects on

of 40 to 45 to an average of about 60, with an average

the body. And it becomes possible for the person to

increase in whole blood hemoglobin concentration

work harder without hypoxic effects or to ascend to

from normal of 15 g/dl to about 20 g/dl.

still higher altitudes.

In addition, the blood volume also increases, often

The principal means by which acclimatization comes

by 20 to 30 per cent, and this increase times the

about are (1) a great increase in pulmonary ventila-

increased blood hemoglobin concentration gives an

tion, (2) increased numbers of red blood cells, (3)

increase in total body hemoglobin of 50 or more per

increased diffusing capacity of the lungs, (4) increased

cent.

vascularity of the peripheral tissues, and (5) increased

ability of the tissue cells to use oxygen despite low Po₂.

Increased Diffusing Capacity After Acclimatization. It will

be recalled that the normal diffusing capacity for

Increased Pulmonary Ventilation—Role of Arterial Chemore-

oxygen through the pulmonary membrane is about

ceptors. Immediate exposure to low Po₂ stimulates the

21 ml/mm Hg/min, and this diffusing capacity can

arterial chemoreceptors, and this increases alveolar

increase as much as threefold during exercise. A

ventilation to a maximum of about 1.65 times normal.

similar increase in diffusing capacity occurs at high

Therefore, compensation occurs within seconds for the

altitude.

high altitude, and it alone allows the person to rise

Part of the increase results from increased pul-

several thousand feet higher than would be possible

monary capillary blood volume, which expands the

without the increased ventilation. Then, if the person

capillaries and increases the surface area through

remains at very high altitude for several days, the

which oxygen can diffuse into the blood. Another part

chemoreceptors increase ventilation still more, up to

results from an increase in lung air volume, which

about five times normal.

expands the surface area of the alveolar-capillary

The immediate increase in pulmonary ventilation on

interface still more. A final part results from an

rising to a high altitude blows off large quantities of

increase in pulmonary arterial blood pressure; this

carbon dioxide, reducing the Pco₂and increasing the

forces blood into greater numbers of alveolar capil-

pH of the body fluids. These changes inhibit the brain

laries than normally—especially in the upper parts

stem respiratory center and thereby oppose the effect

of the lungs, which are poorly perfused under usual

of low PO₂ to stimulate respiration by way of the

conditions.

peripheral arterial chemoreceptors in the carotid and

aortic bodies. But during the ensuing 2 to 5 days, this

Peripheral Circulatory System Changes During Acclimatiza-

inhibition fades away, allowing the respiratory center

tion—Increased Tissue Capillarity. The cardiac output

to respond with full force to the peripheral chemore-

often increases as much as 30 per cent immediately

ceptor stimulus from hypoxia, and ventilation in-

after a person ascends to high altitude but then

creases to about five times normal.

decreases back toward normal over a period of weeks

The cause of this fading inhibition is believed to be

as the blood hematocrit increases, so that the amount

mainly a reduction of bicarbonate ion concentration in

of oxygen transported to the peripheral body tissues

the cerebrospinal fluid as well as in the brain tissues.

remains about normal.

This in turn decreases the pH in the fluids surround-

Another circulatory adaptation is growth of

ing the chemosensitive neurons of the respiratory

increased numbers of systemic circulatory capillaries

center, thus increasing the respiratory stimulatory

in the nonpulmonary tissues, which is called in-

activity of the center.

creased tissue capillarity (or angiogenesis). This occurs

540

Unit VIII

Aviation, Space, and Deep-Sea Diving Physiology

especially in animals born and bred at high altitudes

but less so in animals that later in life become exposed

to high altitude.

Mountain dwellers

In active tissues exposed to chronic hypoxia, the

(15,000 ft)

increase in capillarity is especially marked. For

(Arterial values)

instance, capillary density in right ventricular muscle

increases markedly because of the combined effects

of hypoxia and excess workload on the right ventricle

Sea-level dwellers

caused by pulmonary hypertension at high altitude.

(Venous values)

Cellular Acclimatization. In animals native to altitudes of

13,000 to 17,000 feet, cell mitochondria and cellular

oxidative enzyme systems are slightly more plentiful

than in sea-level inhabitants. Therefore, it is presumed

that the tissue cells of high altitude-acclimatized

human beings also can use oxygen more effectively

than can their sea-level counterparts.

100

120

140

Pressure of oxygen in blood (PO₂) (mm Hg)

Natural Acclimatization

of Native Human Beings Living

at High Altitudes

Figure 43-2

Many native human beings in the Andes and in the

Oxygen-hemoglobin dissociation curves for blood of high-altitude

Himalayas live at altitudes above 13,000 feet—one

residents

(red curve) and sea-level residents

(blue curve),

showing the respective arterial and venous PO₂ levels and oxygen

group in the Peruvian Andes lives at an altitude of

contents as recorded in their native surroundings. (Data from

17,500 feet and works a mine at an altitude of 19,000

Oxygen-dissociation curves for bloods of high-altitude and sea-

feet. Many of these natives are born at these altitudes

level residents. PAHO Scientific Publication No. 140, Life at High

and live there all their lives. In all aspects of acclima-

Altitudes, 1966.)

tization, the natives are superior to even the best-

acclimatized lowlanders, even though the lowlanders

might also have lived at high altitudes for 10 or more

years. Acclimatization of the natives begins in infancy.

not only skeletal muscles but also cardiac muscles.

The chest size, especially, is greatly increased, whereas

In general, work capacity is reduced in direct pro-

the body size is somewhat decreased, giving a high

portion to the decrease in maximum rate of oxygen

ratio of ventilatory capacity to body mass. In addition,

uptake that the body can achieve.

their hearts, which from birth onward pump extra

To give an idea of the importance of acclimatization

amounts of cardiac output, are considerably larger

in increasing work capacity, consider this: The work

than the hearts of lowlanders.

capacities as per cent of normal for unacclimatized and

Delivery of oxygen by the blood to the tissues is also

acclimatized people at an altitude of 17,000 feet are as

highly facilitated in these natives. For instance, Figure

follows:

43-2 shows oxygen-hemoglobin dissociation curves for

natives who live at sea level and for their counterparts

who live at 15,000 feet. Note that the arterial oxygen

Work capacity

Po₂ in the natives at high altitude is only 40 mm Hg,

(per cent of normal)

but because of the greater quantity of hemoglobin,

Unacclimatized

the quantity of oxygen in their arterial blood is greater

Acclimatized for 2 months

than that in the blood of the natives at the lower

Native living at 13,200 feet but working at

altitude. Note also that the venous Po₂ in the high-

17,000 feet

altitude natives is only 15 mm Hg less than the venous

Po₂ for the lowlanders, despite the very low arterial

Thus, naturally acclimatized native persons can

Po₂, indicating that oxygen transport to the tissues is

achieve a daily work output even at high altitude

exceedingly effective in the naturally acclimatized

almost equal to that of a lowlander at sea level, but

high-altitude natives.

even well-acclimatized lowlanders can almost never

achieve this result.

Reduced Work Capacity at

High Altitudes and Positive Effect

of Acclimatization

Acute Mountain Sickness and

High-Altitude Pulmonary Edema

In addition to the mental depression caused by

hypoxia, as discussed earlier, the work capacity of all

A small percentage of people who ascend rapidly to

muscles is greatly decreased in hypoxia. This includes

high altitudes become acutely sick and can die if not

Chapter 43

Aviation, High-Altitude, and Space Physiology

541

given oxygen or removed to a low altitude. The sick-

Effects of Acceleratory Forces

ness begins from a few hours up to about 2 days after

on the Body in Aviation and

ascent. Two events frequently occur:

1. Acute cerebral edema. This is believed to result

Space Physiology

from local vasodilation of the cerebral blood

vessels, caused by the hypoxia. Dilation of the

Because of rapid changes in velocity and direction of

arterioles increases blood flow into the capillaries,

motion in airplanes or spacecraft, several types of

thus increasing capillary pressure, which in turn

acceleratory forces affect the body during flight. At the

causes fluid to leak into the cerebral tissues.

beginning of flight, simple linear acceleration occurs;

The cerebral edema can then lead to severe

at the end of flight, deceleration; and every time the

disorientation and other effects related to cerebral

vehicle turns, centrifugal acceleration.

dysfunction.

2. Acute pulmonary edema. The cause of this is still

unknown, but a suggested answer is the following:

The severe hypoxia causes the pulmonary arterioles

Centrifugal Acceleratory Forces

to constrict potently, but the constriction is much

greater in some parts of the lungs than in other

When an airplane makes a turn, the force of cen-

parts, so that more and more of the pulmonary

trifugal acceleration is determined by the following

blood flow is forced through fewer and fewer still

relation:

unconstricted pulmonary vessels. The postulated

result is that the capillary pressure in these areas of

f =

the lungs becomes especially high and local edema

occurs. Extension of the process to progressively

more areas of the lungs leads to spreading

in which f is centrifugal acceleratory force, m is the

pulmonary edema and severe pulmonary

mass of the object, v is velocity of travel, and r is radius

dysfunction that can be lethal. Allowing the person

of curvature of the turn. From this formula, it is

to breathe oxygen usually reverses the process

obvious that as the velocity increases, the force of

within hours.

centrifugal acceleration increases in proportion to the

square of the velocity. It is also obvious that the force

of acceleration is directly proportional to the sharpness

of the turn (the less the radius).

Chronic Mountain Sickness

Measurement of Acceleratory Force—“G.” When an

Occasionally, a person who remains at high altitude

aviator is simply sitting in his seat, the force with which

too long develops chronic mountain sickness, in which

he is pressing against the seat results from the pull of

the following effects occur: (1) the red cell mass and

gravity and is equal to his weight. The intensity of this

hematocrit become exceptionally high, (2) the pul-

force is said to be +1 G because it is equal to the pull

monary arterial pressure becomes elevated even more

of gravity. If the force with which he presses against

than the normal elevation that occurs during acclima-

the seat becomes five times his normal weight during

tization, (3) the right side of the heart becomes greatly

pull-out from a dive, the force acting on the seat is

enlarged, (4) the peripheral arterial pressure begins to

+5 G.

fall, (5) congestive heart failure ensues, and (6) death

If the airplane goes through an outside loop so that

often follows unless the person is removed to a lower

the person is held down by his seat belt, negative G is

altitude.

applied to his body; if the force with which he is held

The causes of this sequence of events are probably

down by his belt is equal to the weight of his body, the

threefold: First, the red cell mass becomes so great that

negative force is -1 G.

the blood viscosity increases severalfold; this increased

viscosity tends to decrease tissue blood flow so that

Effects of Centrifugal Acceleratory Force on the Body—

oxygen delivery also begins to decrease. Second, the

(Positive G)

pulmonary arterioles become vasoconstricted because

Effects on the Circulatory System. The most impor-

of the lung hypoxia. This results from the hypoxic

tant effect of centrifugal acceleration is on the circu-

vascular constrictor effect that normally operates to

latory system, because blood is mobile and can be

divert blood flow from low-oxygen to high-oxygen

translocated by centrifugal forces.

alveoli, as explained in Chapter 38. But because all the

When an aviator is subjected to positive G, blood is

alveoli are now in the low-oxygen state, all the arteri-

centrifuged toward the lowermost part of the body.

oles become constricted, the pulmonary arterial pres-

Thus, if the centrifugal acceleratory force is +5 G and

sure rises excessively, and the right side of the heart

the person is in an immobilized standing position,

fails. Third, the alveolar arteriolar spasm diverts much

the pressure in the veins of the feet becomes greatly

of the blood flow through nonalveolar pulmonary

increased (to about 450 mm Hg). In the sitting posi-

vessels, thus causing an excess of pulmonary shunt

tion, the pressure becomes nearly 300 mm Hg. And, as

blood flow where the blood is poorly oxygenated; this

pressure in the vessels of the lower body increases,

further compounds the problem. Most of these people

these vessels passively dilate so that a major portion

recover within days or weeks when they are moved to

of the blood from the upper body is translocated into

a lower altitude.

the lower vessels. Because the heart cannot pump

542

Unit VIII

Aviation, Space, and Deep-Sea Diving Physiology

cranium show less tendency for rupture than would be

expected for the following reason: The cerebrospinal

fluid is centrifuged toward the head at the same time

that blood is centrifuged toward the cranial vessels,

100

and the greatly increased pressure of the cerebrospinal

fluid acts as a cushioning buffer on the outside of the

brain to prevent intracerebral vascular rupture.

Because the eyes are not protected by the cranium,

intense hyperemia occurs in them during strong nega-

tive G. As a result, the eyes often become temporarily

Time from start of G to symptoms

blinded with “red-out.”

(sec)

Protection of the Body Against Centrifugal Acceleratory

Forces. Specific procedures and apparatus have been

Figure 43-3

developed to protect aviators against the circulatory

collapse that might occur during positive G. First, if

Changes in systolic (top of curve) and diastolic (bottom of curve)

arterial pressures after abrupt and continuing exposure of a sitting

the aviator tightens his or her abdominal muscles to

person to an acceleratory force from top to bottom of 3.3. G. (Data

an extreme degree and leans forward to compress the

from Martin EE, Henry JP: Effects of time and temperature upon

abdomen, some of the pooling of blood in the large

tolerance to positive acceleration. J Aviation Med 22:382, 1951.)

vessels of the abdomen can be prevented, there-

by delaying the onset of blackout. Also, special “anti-

G” suits have been devised to prevent pooling of blood

unless blood returns to it, the greater the quantity of

in the lower abdomen and legs. The simplest of these

blood “pooled” in this way in the lower body, the less

applies positive pressure to the legs and abdomen by

that is available for the cardiac output.

inflating compression bags as the G increases. Theo-

Figure

43-3 shows the changes in systolic and

retically, a pilot submerged in a tank or suit of water

diastolic arterial pressures (top and bottom curves,

might experience little effect of G forces on the circu-

respectively) in the upper body when a centrifugal

lation because the pressures developed in the water

acceleratory force of +3.3 G is suddenly applied to a

pressing on the outside of the body during centrifugal

sitting person. Note that both these pressures fall

acceleration would almost exactly balance the forces

below 22 mm Hg for the first few seconds after the

acting in the body. However, the presence of air in

acceleration begins but then return to a systolic pres-

the lungs still allows displacement of the heart, lung

sure of about 55 mm Hg and a diastolic pressure of

tissues, and diaphragm into seriously abnormal posi-

20 mm Hg within another 10 to 15 seconds. This sec-

tions despite submersion in water. Therefore, even if

ondary recovery is caused mainly by activation of the

this procedure were used, the limit of safety almost

baroreceptor reflexes.

certainly would still be less than 10 G.

Acceleration greater than 4 to 6 G causes “black-

out” of vision within a few seconds and unconscious-

ness shortly thereafter. If this great degree of

Effects of Linear Acceleratory Forces

acceleration is continued, the person will die.

on the Body

Effects on the Vertebrae. Extremely high acceleratory

forces for even a fraction of a second can fracture the

Acceleratory Forces in Space Travel. Unlike an airplane, a

vertebrae. The degree of positive acceleration that the

spacecraft cannot make rapid turns; therefore, cen-

average person can withstand in the sitting position

trifugal acceleration is of little importance except

before vertebral fracture occurs is about 20 G.

when the spacecraft goes into abnormal gyrations.

However, blast-off acceleration and landing decelera-

Negative G. The effects of negative G on the body are

tion can be tremendous; both of these are types

less dramatic acutely but possibly more damaging per-

of linear acceleration, one positive and the other

manently than the effects of positive G. An aviator can

negative.

usually go through outside loops up to negative accel-

Figure 43-4 shows an approximate profile of accel-

eratory forces of -4 to -5 G without causing perma-

eration during blast-off in a three-stage spacecraft,

nent harm, although causing intense momentary

demonstrating that the first-stage booster causes accel-

hyperemia of the head. Occasionally, psychotic distur-

eration as high as 9 G, and the second-stage booster as

bances lasting for 15 to 20 minutes occur as a result of

high as 8 G. In the standing position, the human body

brain edema.

could not withstand this much acceleration, but in a

Occasionally, negative G forces can be so great

semireclining position transverse to the axis of acceler-

(-20 G, for instance) and centrifugation of the blood

ation, this amount of acceleration can be withstood

into the head is so great that the cerebral blood pres-

with ease despite the fact that the acceleratory forces

sure reaches 300 to 400 mm Hg, sometimes causing

continue for as long as several minutes at a time.

small vessels on the surface of the head and in the

Therefore, we see the reason for the reclining seats

brain to rupture. However, the vessels inside the

used by astronauts.

Chapter 43

Aviation, High-Altitude, and Space Physiology

543

other words, the speed of landing is about 20 feet per

second, and the force of impact against the earth is

1/81 the impact force without a parachute. Even so,

the force of impact is still great enough to cause con-

siderable damage to the body unless the parachutist

is properly trained in landing. Actually, the force of

impact with the earth is about the same as that which

would be experienced by jumping without a parachute

from a height of about 6 feet. Unless forewarned, the

parachutist will be tricked by his senses into striking

the earth with extended legs, and this will result in

tremendous deceleratory forces along the skeletal axis

of the body, resulting in fracture of his pelvis, verte-

brae, or leg. Consequently, the trained parachutist

First

Second

Space

strikes the earth with knees bent but muscles taut to

booster

ship

cushion the shock of landing.

Minutes

“Artificial Climate” in the

Sealed Spacecraft

Figure 43-4

Because there is no atmosphere in outer space, an arti-

Acceleratory forces during takeoff of a spacecraft.

ficial atmosphere and climate must be produced in a

spacecraft. Most important, the oxygen concentration

must remain high enough and the carbon dioxide con-

Problems also occur during deceleration when the

centration low enough to prevent suffocation. In some

spacecraft re-enters the atmosphere. A person travel-

earlier space missions, a capsule atmosphere contain-

ing at Mach 1 (the speed of sound and of fast air-

ing pure oxygen at about 260 mm Hg pressure was

planes) can be safely decelerated in a distance of about

used, but in the modern space shuttle, gases about

0.12 mile, whereas a person traveling at a speed of

equal to those in normal air are used, with four times

Mach 100 (a speed possible in interplanetary space

as much nitrogen as oxygen and a total pressure of

travel) would require a distance of about 10,000 miles

760 mm Hg. The presence of nitrogen in the mixture

for safe deceleration. The principal reason for this dif-

greatly diminishes the likelihood of fire and explosion.

ference is that the total amount of energy that must

It also protects against development of local patches

be dispelled during deceleration is proportional to

of lung atelectasis that often occur when breathing

the square of the velocity, which alone increases the

pure oxygen because oxygen is absorbed rapidly when

required distance for decelerations between Mach 1

small bronchi are temporarily blocked by mucous

versus Mach 100 about 10,000-fold. But in addition to

plugs.

this, a human being can withstand far less deceleration

For space travel lasting more than several months,

if the period of deceleration lasts for a long time than

it is impractical to carry along an adequate oxygen

for a short time. Therefore, deceleration must be

supply. For this reason, recycling techniques have been

accomplished much more slowly from high velocities

proposed for use of the same oxygen over and over

than is necessary at lower velocities.

again. Some recycling processes depend on purely

physical procedures, such as electrolysis of water to

Deceleratory Forces Associated with Parachute Jumps.

release oxygen. Others depend on biological methods,

When the parachuting aviator leaves the airplane, his

such as use of algae with their large store of chloro-

velocity of fall is at first exactly 0 feet per second.

phyll to release oxygen from carbon dioxide by the

However, because of the acceleratory force of gravity,

process of photosynthesis. A completely satisfactory

within 1 second his velocity of fall is 32 feet per second

system for recycling has yet to be achieved.

(if there is no air resistance); in 2 seconds it is 64 feet

per second; and so on. As the velocity of fall increases,

the air resistance tending to slow the fall also increases.

Weightlessness in Space

Finally, the deceleratory force of the air resistance

exactly balances the acceleratory force of gravity, so

A person in an orbiting satellite or a nonpropelled

that after falling for about 12 seconds, the person will

spacecraft experiences weightlessness, or a state of

be falling at a “terminal velocity” of 109 to 119 miles

near-zero G force, which is sometimes called micro-

per hour (175 feet per second). If the parachutist has

gravity. That is, the person is not drawn toward the

already reached terminal velocity before opening his

bottom, sides, or top of the spacecraft but simply floats

parachute, an “opening shock load” of up to 1200

inside its chambers. The cause of this is not failure of

pounds can occur on the parachute shrouds.

gravity to pull on the body, because gravity from any

The usual-sized parachute slows the fall of the para-

nearby heavenly body is still active. However, the

chutist to about one ninth the terminal velocity. In

gravity acts on both the spacecraft and the person at

544

Unit VIII

Aviation, Space, and Deep-Sea Diving Physiology

the same time, so that both are pulled with exactly the

upright or perform normal daily activities after return-

same acceleratory forces and in the same direction.

ing to the full gravity of Earth. Astronauts returning

For this reason, the person simply is not attracted

from space flights lasting 4 to 6 months are also sus-

toward any specific wall of the spacecraft.

ceptible to bone fractures and may require several

weeks before they return to pre-flight cardiovascular,

Physiologic Problems of Weightlessness (Microgravity). The

bone, and muscle fitness. As space flights become

physiologic problems of weightlessness have not

longer in preparation for possible human exploration

proved to be of much significance, as long as the period

of other planets, such as Mars, the effects of prolonged

of weightlessness is not too long. Most of the problems

microgravity could pose a very serious threat to astro-

that do occur are related to three effects of the weight-

nauts after they land, especially in the event of an

lessness: (1) motion sickness during the first few days

emergency landing. Therefore, considerable research

of travel, (2) translocation of fluids within the body

effort has been directed toward developing counter-

because of failure of gravity to cause normal hydro-

measures, in addition to exercise, that can prevent or

static pressures, and (3) diminished physical activity

more effectively attenuate these changes. One such

because no strength of muscle contraction is required

countermeasure that is being tested is the application

to oppose the force of gravity.

of intermittent

“artificial gravity” caused by short

Almost 50 per cent of astronauts experience motion

periods (e.g., 1 hour each day) of centrifugal accelera-

sickness, with nausea and sometimes vomiting, during

tion of the astronauts while they sit in specially

the first 2 to 5 days of space travel. This probably

designed short-arm centrifuges that create forces of up

results from an unfamiliar pattern of motion signals

to 2 to 3 G.

arriving in the equilibrium centers of the brain, and at

the same time lack of gravitational signals.

The observed effects of prolonged stay in space

References

are the following: (1) decrease in blood volume, (2)

decrease in red blood cell mass, (3) decrease in muscle

Adams GR, Caiozzo VJ, Baldwin KM: Skeletal muscle

strength and work capacity, (4) decrease in maximum

unweighting: spaceflight and ground-based models. J Appl

cardiac output, and (5) loss of calcium and phosphate

Physiol 95:2185, 2003.

from the bones, as well as loss of bone mass. Most of

Alfrey CP, Udden MM, Leach-Huntoon C, et al: Control of

these same effects also occur in people who lie in bed

red blood cell mass in spaceflight. J Appl Physiol 81:98,

for an extended period of time. For this reason, exer-

1996.

cise programs are carried out by astronauts during

Basnyat B, Murdoch DR: High-altitude illness. Lancet

361:1967, 2003.

prolonged space missions.

Convertino VA: Mechanisms of microgravity induced ortho-

In previous space laboratory expeditions in which

static intolerance: implications for effective countermea-

the exercise program had been less vigorous, the astro-

sures. J Gravit Physiol 9:1, 2002.

nauts had severely decreased work capacities for the

Eckberg DL: Bursting into space: alterations of sympathetic

first few days after returning to earth. They also had a

control by space travel. Acta Physiol Scand 177:299, 2003.

tendency to faint (and still do, to some extent) when

Hackett PH, Roach RC: High-altitude illness. N Engl J Med

they stood up during the first day or so after return to

345:107, 2001.

gravity because of diminished blood volume and

Harm DL, Jennings RT, Meck JV, et al: Gender issues related

diminished responses of the arterial pressure control

to spaceflight: a NASA perspective. J Appl Physiol

mechanisms.

91:2374, 2001.

Hochachka PW, Beatty CL, Burelle Y, et al: The lactate

paradox in human high-altitude physiological perform-

Cardiovascular, Muscle, and Bone “Deconditioning” During

ance. News Physiol Sci 17:122, 2002.

Prolonged Exposure to Weightlessness. During very long

Hoschele S, Mairbaurl H: Alveolar flooding at high altitude:

space flights and prolonged exposure to microgravity,

failure of reabsorption? News Physiol Sci 18:55, 2003.

gradual “deconditioning” effects occur on the cardio-

Hultgren HN: High-altitude pulmonary edema: current con-

vascular system, skeletal muscles, and bone despite rig-

cepts. Annu Rev Med 47:267, 1996.

orous exercise during the flight. Studies of astronauts

Rupert JL, Hochachka PW: Genetic approaches to under-

on space flights lasting several months have shown that

standing human adaptation to altitude in the Andes. J Exp

they may lose as much 1.0 percent of their bone mass

Biol 204(Pt 18):3151, 2001.

each month even though they continue to exercise.

Smith SM, Heer M: Calcium and bone metabolism during

space flight. Nutrition 18:849, 2002.

Substantial atrophy of cardiac and skeletal muscles

West JB: Climbing Mount Everest without oxygen. News

also occurs during prolonged exposure to a micro-

Physiol Sci 1:25, 1986.

gravity environment.

West JB: Man in space. News Physiol Sci 1:198, 1986.

One of the most serious effects is cardiovascular

West JB: High Life—History of High-Altitude Physiology

“deconditioning”, which includes decreased work

and Medicine. Bethesda, MD: American Physiological

capacity, reduced blood volume, impaired barorecep-

Society, 1998.

tor reflexes, and reduced orthostatic tolerance. These

Zhang LF: Vascular adaptation to microgravity: what have

changes greatly limit the astronauts’ ability to stand

we learned? J Appl Physiol 91:2415, 2001.

C H A P T E R

Physiology of Deep-Sea Diving

and Other Hyperbaric Conditions

When human beings descend beneath the sea, the

pressure around them increases tremendously. To

keep the lungs from collapsing, air must be supplied

at very high pressure to keep them inflated. This

exposes the blood in the lungs also to extremely

high alveolar gas pressure, a condition called hyper-

barism. Beyond certain limits, these high pressures

can cause tremendous alterations in body physiol-

ogy and can be lethal.

Relationship of Pressure to Sea Depth. A column of seawater 33 feet deep exerts the

same pressure at its bottom as the pressure of the atmosphere above the sea.

Therefore, a person 33 feet beneath the ocean surface is exposed to 2 atmos-

pheres pressure, 1 atmosphere of pressure caused by the weight of the air above

the water and the second atmosphere by the weight of the water itself. At 66

feet the pressure is 3 atmospheres, and so forth, in accord with the table in

Figure 44-1.

Effect of Sea Depth on the Volume of Gases-Boyle’s Law. Another important effect of

depth is compression of gases to smaller and smaller volumes. The lower part

of Figure 44-1 shows a bell jar at sea level containing 1 liter of air. At 33 feet

beneath the sea, where the pressure is 2 atmospheres, the volume has been com-

pressed to only one-half liter, and at 8 atmospheres (233 feet) to one-eighth

liter. Thus, the volume to which a given quantity of gas is compressed is inversely

proportional to the pressure. This is a principle of physics called Boyle’s law,

which is extremely important in diving physiology because increased pressure

can collapse the air chambers of the diver’s body, especially the lungs, and often

causes serious damage.

Many times in this chapter it is necessary to refer to actual volume versus

sea-level volume. For instance, we might speak of an actual volume of 1 liter at

a depth of 300 feet; this is the same quantity of air as a sea-level volume of

10 liters.

Effect of High Partial Pressures of Individual

Gases on the Body

The individual gases to which a diver is exposed when breathing air are nitro-

gen, oxygen, and carbon dioxide; each of these at times can cause significant

physiologic effects at high pressures.

Nitrogen Narcosis at High Nitrogen Pressures

About four fifths of the air is nitrogen. At sea-level pressure, the nitrogen has

no significant effect on bodily function, but at high pressures it can cause varying

degrees of narcosis. When the diver remains beneath the sea for an hour or

more and is breathing compressed air, the depth at which the first symptoms of

mild narcosis appear is about 120 feet. At this level the diver begins to exhibit

545

546

Unit VIII

Aviation, Space, and Deep-Sea Diving Physiology

Depth (feet)

Atmosphere(s)

Sea level

100

133

166

200

300

400

Oxygen-hemoglobin dissociation curve

500

1 liter

Total O₂ in blood

Sea level

Combined with

Oxygen

hemoglobin

poisoning

Dissolved in

¹/2 liter

water of blood

33 ft

Normal alveolar

oxygen pressure

¹/4 liter

100 ft

760

1560

2280

3040

Oxygen partial pressure in lungs (mm Hg)

Figure 44-2

Quantity of oxygen dissolved in the fluid of the blood and in com-

bination with hemoglobin at very high PO₂s.

Oxygen Toxicity at High Pressures

Effect of Very High PO₂ on Blood Oxygen Transport. When the

233 ft

¹/8 liter

Po₂ in the blood rises above 100 mm Hg, the amount

of oxygen dissolved in the water of the blood increases

markedly. This is shown in Figure 44-2, which depicts

the same oxygen-hemoglobin dissociation curve as

that shown in Chapter 40 but with the alveolar Po₂

Figure 44-1

extended to more than 3000 mm Hg. Also depicted by

the lowest curve in the figure is the volume of oxygen

Effect of sea depth on pressure (top table) and on gas volume

(bottom).

dissolved in the fluid of the blood at each Po₂ level.

Note that in the normal range of alveolar Po₂ (below

120 mm Hg), almost none of the total oxygen in the

joviality and to lose many of his or her cares. At 150

blood is accounted for by dissolved oxygen, but as the

to 200 feet, the diver becomes drowsy. At 200 to 250

oxygen pressure rises into the thousands of millime-

feet, his or her strength wanes considerably, and the

ters of mercury, a large portion of the total oxygen is

diver often becomes too clumsy to perform the work

then dissolved in the water of the blood, in addition to

required. Beyond 250 feet (8.5 atmospheres pressure),

that bound with hemoglobin.

the diver usually becomes almost useless as a result of

nitrogen narcosis if he or she remains at these depths

Effect of High Alveolar PO₂ on Tissue PO₂. Let us assume that

too long.

the Po₂ in the lungs is about 3000 mm Hg (4 atmos-

Nitrogen narcosis has characteristics similar to those

pheres pressure). Referring to Figure 44-2, one finds

of alcohol intoxication, and for this reason it has

that this represents a total oxygen content in each 100

frequently been called “raptures of the depths.” The

milliliters of blood of about 29 volumes per cent, as

mechanism of the narcotic effect is believed to be the

demonstrated by point A in the figure—this means

same as that of most other gas anesthetics. That is, it

20 volumes per cent bound with hemoglobin and 9

dissolves in the fatty substances in neuronal mem-

volumes per cent dissolved in the blood water. As this

branes and, because of its physical effect on altering

blood passes through the tissue capillaries and the

ionic conductance through the membranes, reduces

tissues use their normal amount of oxygen, about

neuronal excitability.

5 milliliters from each 100 milliliters of blood, the

Chapter 44

Physiology of Deep-Sea Diving and Other Hyperbaric Conditions

547

oxygen content on leaving the tissue capillaries is still

Therefore, most of the acute lethal effects of acute

24 volumes per cent (point B in the figure). At this

oxygen toxicity are caused by brain dysfunction.

point, the Po₂ is approximately 1200 mm Hg, which

means that oxygen is delivered to the tissues at this

Chronic Oxygen Poisoning Causes Pulmonary Disabil-

extremely high pressure instead of at the normal value

ity. A person can be exposed to only 1 atmosphere

of 40 mm Hg. Thus, once the alveolar Po₂ rises above

pressure of oxygen almost indefinitely without devel-

a critical level, the hemoglobin-oxygen buffer mecha-

oping the acute oxygen toxicity of the nervous system

nism (discussed in Chapter 40) is no longer capable

just described. However, after only about 12 hours of

of keeping the tissue Po₂ in the normal, safe range

1 atmosphere oxygen exposure, lung passageway con-

between 20 and 60 mm Hg.

gestion, pulmonary edema, and atelectasis caused by

damage to the linings of the bronchi and alveoli begin

Acute Oxygen Poisoning. The extremely high tissue Po₂

to develop. The reason for this effect in the lungs but

that occurs when oxygen is breathed at very high alve-

not in other tissues is that the air spaces of the lungs

olar oxygen pressure can be detrimental to many of

are directly exposed to the high oxygen pressure, but

the body’s tissues. For instance, breathing oxygen at

oxygen is delivered to the other body tissues at almost

4 atmospheres pressure of oxygen (Po₂ = 3040 mm Hg)

normal Po₂because of the hemoglobin-oxygen buffer

will cause brain seizures followed by coma in most

system.

people within 30 to 60 minutes. The seizures often

occur without warning and, for obvious reasons, are

likely to be lethal to divers submerged beneath the

Carbon Dioxide Toxicity at Great

sea.

Depths in the Sea

Other symptoms encountered in acute oxygen poi-

soning include nausea, muscle twitchings, dizziness,

If the diving gear is properly designed and functions

disturbances of vision, irritability, and disorientation.

properly, the diver has no problem due to carbon

Exercise greatly increases the diver’s susceptibility to

dioxide toxicity because depth alone does not increase

oxygen toxicity, causing symptoms to appear much

the carbon dioxide partial pressure in the alveoli. This

earlier and with far greater severity than in the resting

is true because depth does not increase the rate of

person.

carbon dioxide production in the body, and as long as

the diver continues to breathe a normal tidal volume

Excessive Intracellular Oxidation as a Cause of

and expires the carbon dioxide as it is formed, alveo-

Nervous System Oxygen Toxicity—“Oxidizing Free

lar carbon dioxide pressure will be maintained at a

Radicals.” Molecular oxygen (O₂) has little capability

normal value.

of oxidizing other chemical compounds. Instead, it

In certain types of diving gear, however, such as the

must first be converted into an “active” form of

diving helmet and some types of rebreathing appara-

oxygen. There are several forms of active oxygen

tuses, carbon dioxide can build up in the dead space

called oxygen free radicals. One of the most important

air of the apparatus and be rebreathed by the diver.

of these is the superoxide free radical O_{2_}, and another

Up to an alveolar carbon dioxide pressure (Pco₂) of

is the peroxide radical in the form of hydrogen perox-

about 80 mm Hg, twice that in normal alveoli, the

ide. Even when the tissue Po₂ is normal at the level of

diver usually tolerates this buildup by increasing the

40 mm Hg, small amounts of free radicals are contin-

minute respiratory volume a maximum of 8- to 11-fold

ually being formed from the dissolved molecular

to compensate for the increased carbon dioxide.

oxygen. Fortunately, the tissues also contain multiple

Beyond

80-mm Hg alveolar Pco₂, the situation

enzymes that rapidly remove these free radicals,

becomes intolerable, and eventually the respiratory

including peroxidases, catalases, and superoxide dis-

center begins to be depressed, rather than excited,

mutases. Therefore, so long as the hemoglobin-oxygen

because of the negative tissue metabolic effects of high

buffering mechanism maintains a normal tissue Po₂,

Pco₂. The diver’s respiration then begins to fail rather

the oxidizing free radicals are removed rapidly enough

than to compensate. In addition, the diver develops

that they have little or no effect in the tissues.

severe respiratory acidosis, and varying degrees of

Above a critical alveolar Po₂

(above about

lethargy, narcosis, and finally even anesthesia, as dis-

atmospheres Po₂), the hemoglobin-oxygen buffering

cussed in Chapter 42.

mechanism fails, and the tissue Po₂ can then rise to

hundreds or thousands of millimeters of mercury. At

these high levels, the amounts of oxidizing free radi-

Decompression of the Diver After

cals literally swamp the enzyme systems designed to

Excess Exposure to High Pressure

remove them, and now they can have serious destruc-

tive and even lethal effects on the cells. One of the

When a person breathes air under high pressure for a

principal effects is to oxidize the polyunsaturated fatty

long time, the amount of nitrogen dissolved in the

acids that are essential components of many of the cell

body fluids increases. The reason for this is the fol-

membranes. Another effect is to oxidize some of the

lowing: Blood flowing through the pulmonary capil-

cellular enzymes, thus damaging severely the cellular

laries becomes saturated with nitrogen to the same

metabolic systems. The nervous tissues are especially

high pressure as that in the alveolar breathing mixture.

susceptible because of their high lipid content.

And over several more hours, enough nitrogen is

548

Unit VIII

Aviation, Space, and Deep-Sea Diving Physiology

carried to all the tissues of the body to raise their tissue

Pressure Outside Body

Pn₂ also to equal the Pn₂ in the breathing air.

Before

After sudden

Because nitrogen is not metabolized by the body, it

decompression

remains dissolved in all the body tissues until the nitro-

O₂ = 1044 mm Hg

O₂ = 159 mm Hg

gen pressure in the lungs is decreased back to some

N₂ = 3956

N₂ = 601

lower level, at which time the nitrogen can be removed

Total = 5000 mm Hg

Total = 760 mm Hg

by the reverse respiratory process; however, this

removal often takes hours to occur and is the source

of multiple problems collectively called decompression

sickness.

Volume of Nitrogen Dissolved in the Body Fluids at Different

Depths. At sea level, almost exactly 1 liter of nitrogen

is dissolved in the entire body. Slightly less than one

half of this is dissolved in the water of the body and a

Body

little more than one half in the fat of the body. This is

Gaseous pressure

in the body fluids

true because nitrogen is five times as soluble in fat as

H₂O = 47 mm Hg

in water.

CO₂ = 40

After the diver has become saturated with nitrogen,

O₂

= 60

O₂

= 60

the sea-level volume of nitrogen dissolved in the body

N₂

= 3918

N₂

= 3918

at different depths is as follows:

Total = 4065

Feet

Liters

Figure 44-3

Gaseous pressures both inside and outside the body, showing (A)

saturation of the body to high gas pressures when breathing air

100

at a total pressure of 5000 mm Hg, and (B) the great excesses of

200

intra-body pressures that are responsible for bubble formation in

300

the tissues when the lung intra-alveolar pressure body is

suddenly returned from

5000 mm Hg to normal pressure of

760 mm Hg.

Several hours are required for the gas pressures of

nitrogen in all the body tissues to come nearly to equi-

librium with the gas pressure of nitrogen in the alveoli.

nitrogen pressure

(Pn₂

= 3918 mm Hg), about 6.5

The reason for this is that the blood does not flow

times the normal amount of nitrogen in the tissues.

rapidly enough and the nitrogen does not diffuse

As long as the diver remains deep beneath the sea, the

rapidly enough to cause instantaneous equilibrium.

pressure against the outside of his or her body

The nitrogen dissolved in the water of the body comes

(5000 mm Hg) compresses all the body tissues suffi-

to almost complete equilibrium in less than 1 hour, but

ciently to keep the excess nitrogen gas dissolved. But

the fat tissue, requiring five times as much transport of

when the diver suddenly rises to sea level (Figure

nitrogen and having a relatively poor blood supply,

44-3B), the pressure on the outside of the body

reaches equilibrium only after several hours. For this

becomes only 1 atmosphere (760 mm Hg), while the

reason, if a person remains at deep levels for only a

gas pressure inside the body fluids is the sum of the

few minutes, not much nitrogen dissolves in the body

pressures of water vapor, carbon dioxide, oxygen, and

fluids and tissues, whereas if the person remains at a

nitrogen, or a total of 4065 mm Hg, 97 per cent of

deep level for several hours, both the body water and

which is caused by the nitrogen. Obviously, this total

body fat become saturated with nitrogen.

value of 4065 mm Hg is far greater than the 760 mm

Hg pressure on the outside of the body. Therefore, the

Decompression Sickness (Synonyms: Bends, Compressed Air

gases can escape from the dissolved state and form

Sickness, Caisson Disease, Diver’s Paralysis, Dysbarism).

If a

actual bubbles, composed almost entirely of nitrogen,

diver has been beneath the sea long enough that large

both in the tissues and in the blood where they plug

amounts of nitrogen have dissolved in his or her body

many small blood vessels. The bubbles may not appear

and the diver then suddenly comes back to the surface

for many minutes to hours, because sometimes the

of the sea, significant quantities of nitrogen bubbles

gases can remain dissolved in the “supersaturated”

can develop in the body fluids either intracellularly or

state for hours before bubbling.

extracellularly and can cause minor or serious damage

in almost any area of the body, depending on the

Symptoms of Decompression Sickness

(“Bends”).

number and sizes of bubbles formed; this is called

The symptoms of decompression sickness are caused

decompression sickness.

by gas bubbles blocking many blood vessels in

The principles underlying bubble formation are

different tissues. At first, only the smallest vessels

shown in Figure 44-3. In Figure 44-3A, the diver’s

are blocked by minute bubbles, but as the bubbles

tissues have become equilibrated to a high dissolved

coalesce, progressively larger vessels are affected.

Chapter 44

Physiology of Deep-Sea Diving and Other Hyperbaric Conditions

549

Tissue ischemia and sometimes tissue death are the

level near that at which they will be working. This

result.

keeps the tissues and fluids of the body saturated with

In most people with decompression sickness, the

the gases to which they will be exposed while diving.

symptoms are pain in the joints and muscles of the legs

Then, when they return to the same tank after

and arms, affecting 85 to 90 per cent of those persons

working, there are no significant changes in pressure,

who develop decompression sickness. The joint pain

so that decompression bubbles do not occur.

accounts for the term “bends” that is often applied to

In very deep dives, especially during saturation

this condition.

diving, helium is usually used in the gas mixture

In 5 to 10 per cent of people with decompression

instead of nitrogen for three reasons: (1) it has only

sickness, nervous system symptoms occur, ranging

about one fifth the narcotic effect of nitrogen; (2) only

from dizziness in about 5 per cent to paralysis or col-

about one half as much volume of helium dissolves in

lapse and unconsciousness in as many as 3 per cent.

the body tissues as nitrogen, and the volume that does

The paralysis may be temporary, but in some instances,

dissolve diffuses out of the tissues during decompres-

damage is permanent.

sion several times as rapidly as does nitrogen, thus

Finally, about 2 per cent of people with decompres-

reducing the problem of decompression sickness; and

sion sickness develop “the chokes,” caused by massive

(3) the low density of helium (one seventh the density

numbers of microbubbles plugging the capillaries of

of nitrogen) keeps the airway resistance for breathing

the lungs; this is characterized by serious shortness of

at a minimum, which is very important because highly

breath, often followed by severe pulmonary edema

compressed nitrogen is so dense that airway resistance

and, occasionally, death.

can become extreme, sometimes making the work of

breathing beyond endurance.

Nitrogen Elimination from the Body; Decompression Tables. If

Finally, in very deep dives it is important to reduce

a diver is brought to the surface slowly, enough of the

the oxygen concentration in the gaseous mixture

dissolved nitrogen can usually be eliminated by expi-

because otherwise oxygen toxicity would result. For

ration through the lungs to prevent decompression

instance, at a depth of 700 feet (22 atmospheres of

sickness. About two thirds of the total nitrogen is lib-

pressure), a 1 per cent oxygen mixture will provide all

erated in 1 hour and about 90 per cent in 6 hours.

the oxygen required by the diver, whereas a 21 per

Decompression tables have been prepared by the

cent mixture of oxygen (the percentage in air) deliv-

U.S. Navy that detail procedures for safe decompres-

ers a Po₂ to the lungs of more than 4 atmospheres,

sion. To give the student an idea of the decompression

a level very likely to cause seizures in as little as

process, a diver who has been breathing air and has

30 minutes.

been on the sea bottom for 60 minutes at a depth of

190 feet is decompressed according to the following

Scuba (Self-Contained

schedule:

Underwater Breathing

10 minutes at 50 feet depth

17 minutes at 40 feet depth

Apparatus) Diving

19 minutes at 30 feet depth

50 minutes at 20 feet depth

Before the 1940s, almost all diving was done using a

84 minutes at 10 feet depth

diving helmet connected to a hose through which air

Thus, for a work period on the bottom of only

was pumped to the diver from the surface. Then, in

1 hour, the total time for decompression is about

1943, Jacques Cousteau popularized a self-contained

3 hours.

underwater breathing apparatus, known as the SCUBA

apparatus. The type of SCUBA apparatus used in

Tank Decompression and Treatment of Decompression Sick-

more than 99 per cent of all sports and commercial

ness. Another procedure widely used for decompres-

diving is the open-circuit demand system shown in

sion of professional divers is to put the diver into a

Figure 44-4. This system consists of the following com-

pressurized tank and then to lower the pressure grad-

ponents: (1) one or more tanks of compressed air or

ually back to normal atmospheric pressure, using

some other breathing mixture, (2) a first-stage “reduc-

essentially the same time schedule as noted above.

ing” valve for reducing the very high pressure from the

Tank decompression is even more important for

tanks to a low pressure level, (3) a combination inhala-

treating people in whom symptoms of decompression

tion “demand” valve and exhalation valve that allows

sickness develop minutes or even hours after they

air to be pulled into the lungs with slight negative pres-

have returned to the surface. In this case, the diver

sure of breathing and then to be exhaled into the sea

is recompressed immediately to a deep level. Then

at a pressure level slightly positive to the surrounding

decompression is carried out over a period several

water pressure, and (4) a mask and tube system with

times as long as the usual decompression period.

small “dead space.”

The demand system operates as follows: The first-

“Saturation Diving” and Use of Helium-Oxygen Mixtures in Deep

stage reducing valve reduces the pressure from the

Dives. When divers must work at very deep levels—

tanks so that the air delivered to the mask has a pres-

between 250 feet and nearly 1000 feet—they fre-

sure only a few mm Hg greater than the surrounding

quently live in a large compression tank for days or

water pressure. The breathing mixture does not

weeks at a time, remaining compressed at a pressure

flow continually into the mask. Instead, with each

550

Unit VIII

Aviation, Space, and Deep-Sea Diving Physiology

devices, especially when using helium, theoretically

can allow escape from as deep as 600 feet or perhaps

more.

One of the major problems of escape is prevention

Mask

of air embolism. As the person ascends, the gases in

the lungs expand and sometimes rupture a pulmonary

Hose

blood vessel, forcing the gases to enter the vessel and

cause air embolism of the circulation. Therefore, as the

person ascends, he or she must make a special effort

Demand valve

to exhale continually.

First stage

valve

Health Problems in the Submarine Internal Environment.

Except for escape, submarine medicine generally

centers around several engineering problems to keep

hazards out of the internal environment. First, in

atomic submarines, there exists the problem of ra-

diation hazards, but with appropriate shielding, the

amount of radiation received by the crew submerged

beneath the sea has been less than normal radiation

received above the surface of the sea from cosmic rays.

Second, poisonous gases on occasion escape into the

atmosphere of the submarine and must be controlled

rapidly. For instance, during several weeks’ submer-

gence, cigarette smoking by the crew can liberate

enough carbon monoxide, if not removed rapidly,

Air cylinders

to cause carbon monoxide poisoning. And, on occa-

sion, even freon gas has been found to diffuse out of

refrigeration systems in sufficient quantity to cause

toxicity.

Figure 44-4

Open-circuit demand type of SCUBA apparatus.

Hyperbaric Oxygen Therapy

The intense oxidizing properties of high-pressure

inspiration, slight extra negative pressure in the

oxygen

(hyperbaric oxygen) can have valuable

demand valve of the mask pulls the diaphragm of the

therapeutic effects in several important clinical

valve open, and this automatically releases air from

conditions. Therefore, large pressure tanks are now

the tank into the mask and lungs. In this way, only the

available in many medical centers into which patients

amount of air needed for inhalation enters the mask.

can be placed and treated with hyperbaric oxygen.

Then, on expiration, the air cannot go back into the

The oxygen is usually administered at Po₂s of 2 to

tank but instead is expired into the sea.

3 atmospheres of pressure through a mask or intra-

The most important problem in use of the self-

tracheal tube, whereas the gas around the body is

contained underwater breathing apparatus is the

normal air compressed to the same high-pressure

limited amount of time one can remain beneath the

level.

sea surface; for instance, only a few minutes are possi-

It is believed that the same oxidizing free radicals

ble at a 200-foot depth. The reason for this is that

responsible for oxygen toxicity are also responsible for

tremendous airflow from the tanks is required to wash

at least some of the therapeutic benefits. Some of the

carbon dioxide out of the lungs—the greater the

conditions in which hyperbaric oxygen therapy has

depth, the greater the airflow in terms of quantity of

been especially beneficial follow.

air per minute that is required, because the volumes

Probably the most successful use of hyperbaric

have been compressed to small sizes.

oxygen has been for treatment of gas gangrene. The

bacteria that cause this condition, clostridial organ-

isms, grow best under anaerobic conditions and

Special Physiologic Problems

stop growing at oxygen pressures greater than about

in Submarines

70 mm Hg. Therefore, hyperbaric oxygenation of the

tissues can frequently stop the infectious process

Escape from Submarines. Essentially the same problems

entirely and thus convert a condition that formerly was

encountered in deep-sea diving are often met in rela-

almost 100 per cent fatal into one that is cured in most

tion to submarines, especially when it is necessary

instances by early treatment with hyperbaric therapy.

to escape from a submerged submarine. Escape is

Other conditions in which hyperbaric oxygen

possible from as deep as 300 feet without using any

therapy has been either valuable or possibly valuable

apparatus. However, proper use of rebreathing

include decompression sickness, arterial gas embolism,

C H A P T E R

Organization of the Nervous

System, Basic Functions of

Synapses, “Transmitter Substances”

The nervous system is unique in the vast complex-

ity of thought processes and control actions it can

perform. It receives each minute literally millions of

bits of information from the different sensory

nerves and sensory organs and then integrates all

these to determine responses to be made by the

body.

However, before beginning this discussion of the

nervous system, the reader should review Chapters 5 and 7, which present the

principles of membrane potentials and transmission of signals in nerves and

through neuromuscular junctions.

General Design of the Nervous System

Central Nervous System Neuron: The Basic

Functional Unit

The central nervous system contains more than 100 billion neurons. Figure 45-1

shows a typical neuron of a type found in the brain motor cortex. Incoming

signals enter this neuron through synapses located mostly on the neuronal den-

drites, but also on the cell body. For different types of neurons, there may be

only a few hundred or as many as 200,000 such synaptic connections from input

fibers. Conversely, the output signal travels by way of a single axon leaving the

neuron. Then, this axon has many separate branches to other parts of the

nervous system or peripheral body.

A special feature of most synapses is that the signal normally passes only in

the forward direction (from the axon of a preceding neuron to dendrites on cell

membranes of subsequent neurons). This forces the signal to travel in required

directions for performing specific nervous functions.

Sensory Part of the Nervous System—Sensory Receptors

Most activities of the nervous system are initiated by sensory experience

exciting sensory receptors, whether visual receptors in the eyes, auditory

receptors in the ears, tactile receptors on the surface of the body, or other

kinds of receptors. This sensory experience can either cause immediate reaction

from the brain, or memory of the experience can be stored in the brain

for minutes, weeks, or years and determine bodily reactions at some future

date.

Figure 45-2 shows the somatic portion of the sensory system, which transmits

sensory information from the receptors of the entire body surface and from

some deep structures. This information enters the central nervous system

through peripheral nerves and is conducted immediately to multiple sensory

areas in (1) the spinal cord at all levels; (2) the reticular substance of the

medulla, pons, and mesencephalon of the brain; (3) the cerebellum; (4) the thal-

amus; and (5) areas of the cerebral cortex.

555

556

Unit IX The Nervous System: A. General Principles and Sensory Physiology

Somesthetic areas

Motor cortex

Dendrites

Thalamus

Brain

Bulboreticular

Pons

formation

Cell body

Cerebellum

Medulla

Skin

Spinal cord

Pain, cold,

warmth (Free

nerve ending)

Pressure

(Pacinian corpuscle)

(Expanded tip

receptor)

Touch

(Meissner's corpuscle)

Muscle spindle

Axon

Golgi tendon

apparatus

Muscle

Kinesthetic receptor

Synapses

Joint

Spinal cord

Second-order

neurons

Figure 45-2

Somatosensory axis of the nervous system.

Figure 45-1

Structure of a large neuron in the brain, showing its important func-

trolling smooth muscles, glands, and other internal

tional parts.

(Redrawn from Guyton AC: Basic Neuroscience:

bodily systems; this is discussed in Chapter 60.

Anatomy and Physiology. Philadelphia: WB Saunders Co, 1987.)

Note in Figure 45-3 that the skeletal muscles can be

controlled from many levels of the central nervous

system, including (1) the spinal cord; (2) the reticular

substance of the medulla, pons, and mesencephalon;

Motor Part of the Nervous System—

(3) the basal ganglia; (4) the cerebellum; and (5) the

Effectors

motor cortex. Each of these areas plays its own spe-

cific role, the lower regions concerned primarily with

The most important eventual role of the nervous

automatic, instantaneous muscle responses to sensory

system is to control the various bodily activities. This

stimuli, and the higher regions with deliberate

is achieved by controlling (1) contraction of appropri-

complex muscle movements controlled by the thought

ate skeletal muscles throughout the body, (2) contrac-

processes of the brain.

tion of smooth muscle in the internal organs, and

(3) secretion of active chemical substances by both

Processing of Information—

exocrine and endocrine glands in many parts of the

body. These activities are collectively called motor

“Integrative” Function of the

functions of the nervous system, and the muscles and

Nervous System

glands are called effectors because they are the actual

anatomical structures that perform the functions dic-

One of the most important functions of the nervous

tated by the nerve signals.

system is to process incoming information in such a

Figure 45-3 shows the “skeletal” motor nerve axis of

way that appropriate mental and motor responses will

the nervous system for controlling skeletal muscle con-

occur. More than 99 per cent of all sensory informa-

traction. Operating parallel to this axis is another

tion is discarded by the brain as irrelevant and unim-

system, called the autonomic nervous system, for con-

portant. For instance, one is ordinarily unaware of the

Chapter 45

Organization of the Nervous System, Basic Functions of Synapses, “Transmitter Substances”

557

Motor nerve

Motor

system can control synaptic transmission, sometimes

to muscles

area

opening the synapses for transmission and at other

times closing them. In addition, some postsynaptic

Caudate

neurons respond with large numbers of output

nucleus

impulses, and others respond with only a few. Thus, the

synapses perform a selective action, often blocking

weak signals while allowing strong signals to pass, but

at other times selecting and amplifying certain weak

signals, and often channeling these signals in many

directions rather than only one direction.

Thalamus

Storage of Information—Memory

Putamen

Globus pallidus

Only a small fraction of even the most important

Subthalamic nucleus

sensory information usually causes immediate motor

response. But much of the information is stored for

Bulboreticular formation

Cerebellum

future control of motor activities and for use in

the thinking processes. Most storage occurs in the

cerebral cortex, but even the basal regions of the

brain and the spinal cord can store small amounts of

information.

The storage of information is the process we call

memory, and this, too, is a function of the synapses.

Gamma motor fiber

That is, each time certain types of sensory signals pass

Alpha motor fiber

through sequences of synapses, these synapses become

more capable of transmitting the same type of signal

the next time, a process called facilitation. After the

sensory signals have passed through the synapses a

Muscle spindle

large number of times, the synapses become so facili-

tated that signals generated within the brain itself can

Figure 45-3

also cause transmission of impulses through the same

sequences of synapses, even when the sensory input is

Skeletal motor nerve axis of the nervous system.

not excited. This gives the person a perception of expe-

riencing the original sensations, although the percep-

tions are only memories of the sensations.

parts of the body that are in contact with clothing, as

We know little about the precise mechanisms by

well as of the seat pressure when sitting. Likewise,

which long-term facilitation of synapses occurs in the

attention is drawn only to an occasional object in one’s

memory process, but what is known about this and

field of vision, and even the perpetual noise of our sur-

other details of the sensory memory process are dis-

roundings is usually relegated to the subconscious.

cussed in Chapter 57.

But, when important sensory information excites

Once memories have been stored in the nervous

the mind, it is immediately channeled into proper inte-

system, they become part of the brain processing

grative and motor regions of the brain to cause desired

mechanism for future “thinking.” That is, the thinking

responses. This channeling and processing of informa-

processes of the brain compare new sensory experi-

tion is called the integrative function of the nervous

ences with stored memories; the memories then help

system. Thus, if a person places a hand on a hot stove,

to select the important new sensory information and

the desired instantaneous response is to lift the hand.

to channel this into appropriate memory storage areas

And other associated responses follow, such as moving

for future use or into motor areas to cause immediate

the entire body away from the stove, and perhaps even

bodily responses.

shouting with pain.

Major Levels of Central

Role of Synapses in Processing Information. The synapse

is the junction point from one neuron to the next.

Nervous System Function

Later in this chapter, we will discuss the details of

synaptic function. However, it is important to point out

The human nervous system has inherited special func-

here that synapses determine the directions that the

tional capabilities from each stage of human evolu-

nervous signals will spread through the nervous

tionary development. From this heritage, three major

system. Some synapses transmit signals from one

levels of the central nervous system have specific func-

neuron to the next with ease, whereas others transmit

tional characteristics: (1) the spinal cord level, (2) the

signals only with difficulty. Also, facilitatory and

lower brain or subcortical level, and (3) the higher

inhibitory signals from other areas in the nervous

brain or cortical level.

558

Unit IX The Nervous System: A. General Principles and Sensory Physiology

Spinal Cord Level

system performs specific functions. But it is the cortex

that opens a world of stored information for use by the

We often think of the spinal cord as being only a

mind.

conduit for signals from the periphery of the body to

the brain, or in the opposite direction from the brain

Comparison of the

back to the body. This is far from the truth. Even after

the spinal cord has been cut in the high neck region,

Nervous System with

many highly organized spinal cord functions still

a Computer

occur. For instance, neuronal circuits in the cord can

When computers were first developed, it soon became

cause (1) walking movements, (2) reflexes that with-

apparent that these machines have many features in

draw portions of the body from painful objects, (3)

common with the nervous system. First, all computers

reflexes that stiffen the legs to support the body

have input circuits that are comparable to the sensory

against gravity, and (4) reflexes that control local blood

portion of the nervous system, and output circuits that

vessels, gastrointestinal movements, or urinary excre-

are comparable to the motor portion of the nervous

tion. In fact, the upper levels of the nervous system

system.

often operate not by sending signals directly to the

In simple computers, the output signals are controlled

periphery of the body but by sending signals to

directly by the input signals, operating in a manner

similar to that of simple reflexes of the spinal cord. In

the control centers of the cord, simply “commanding”

more complex computers, the output is determined both

the cord centers to perform their functions.

by input signals and by information that has already

been stored in memory in the computer, which is anal-

ogous to the more complex reflex and processing mech-

Lower Brain or Subcortical Level

anisms of our higher nervous system. Furthermore,

as computers become even more complex, it is neces-

Many, if not most, of what we call subconscious activ-

sary to add still another unit, called the central process-

ities of the body are controlled in the lower areas

ing unit, that determines the sequence of all operations.

of the brain—in the medulla, pons, mesencephalon,

This unit is analogous to the control mechanisms in our

hypothalamus, thalamus, cerebellum, and basal

brain that direct our attention first to one thought or

sensation or motor activity, then to another, and so

ganglia. For instance, subconscious control of arterial

forth, until complex sequences of thought or action take

pressure and respiration is achieved mainly in the

place.

medulla and pons. Control of equilibrium is a com-

Figure 45-4 is a simple block diagram of a computer.

bined function of the older portions of the cerebellum

Even a rapid study of this diagram demonstrates its sim-

and the reticular substance of the medulla, pons, and

ilarity to the nervous system. The fact that the basic

mesencephalon. Feeding reflexes, such as salivation

components of the general-purpose computer are anal-

and licking of the lips in response to the taste of food,

ogous to those of the human nervous system demon-

are controlled by areas in the medulla, pons, mesen-

strates that the brain is basically a computer that

cephalon, amygdala, and hypothalamus. And many

continuously collects sensory information and uses this

emotional patterns, such as anger, excitement, sexual

along with stored information to compute the daily

course of bodily activity.

response, reaction to pain, and reaction to pleasure,

can still occur after destruction of much of the cere-

bral cortex.

Higher Brain or Cortical Level

Problem

After the preceding account of the many nervous

system functions that occur at the cord and lower brain

Input

Output

Answer

levels, one may ask, what is left for the cerebral cortex

to do? The answer to this is complex, but it begins with

the fact that the cerebral cortex is an extremely large

memory storehouse. The cortex never functions alone

Procedure

Initial

Result of

but always in association with lower centers of the

for solution

data

operations

Information

nervous system.

storage

Without the cerebral cortex, the functions of the

lower brain centers are often imprecise. The vast store-

Central

Computational

house of cortical information usually converts these

processing unit

unit

functions to determinative and precise operations.

Finally, the cerebral cortex is essential for most of

our thought processes, but it cannot function by itself.

In fact, it is the lower brain centers, not the cortex,

Figure 45-4

that initiate wakefulness in the cerebral cortex, thus

opening its bank of memories to the thinking machin-

Block diagram of a general-purpose computer, showing the basic

ery of the brain. Thus, each portion of the nervous

components and their interrelations.

Chapter 45

Organization of the Nervous System, Basic Functions of Synapses, “Transmitter Substances”

559

Central Nervous System

Think for a moment about the extreme importance

of the one-way conduction mechanism. It allows

Synapses

signals to be directed toward specific goals. Indeed, it

is this specific transmission of signals to discrete and

Every medical student is aware that information is

highly focused areas both within the nervous system

transmitted in the central nervous system mainly in the

and at the terminals of the peripheral nerves that

form of nerve action potentials, called simply “nerve

allows the nervous system to perform its myriad func-

impulses,” through a succession of neurons, one after

tions of sensation, motor control, memory, and many

another. However, in addition, each impulse (1) may

others.

be blocked in its transmission from one neuron to the

next, (2) may be changed from a single impulse into

repetitive impulses, or

(3) may be integrated with

Physiologic Anatomy of the Synapse

impulses from other neurons to cause highly intricate

patterns of impulses in successive neurons. All these

Figure 45-5 shows a typical anterior motor neuron in

functions can be classified as synaptic functions of

the anterior horn of the spinal cord. It is composed of

neurons.

three major parts: the soma, which is the main body of

the neuron; a single axon, which extends from the

soma into a peripheral nerve that leaves the spinal

Types of Synapses—Chemical

cord; and the dendrites, which are great numbers of

and Electrical

branching projections of the soma that extend as

much as 1 millimeter into the surrounding areas of the

There are two major types of synapses: (1) the chemi-

cord.

cal synapse and (2) the electrical synapse.

As many as 10,000 to 200,000 minute synaptic knobs

Almost all the synapses used for signal transmission

called presynaptic terminals lie on the surfaces of the

in the central nervous system of the human being are

dendrites and soma of the motor neuron, about 80 to

chemical synapses. In these, the first neuron secretes at

95 per cent of them on the dendrites and only 5 to 20

its nerve ending synapse a chemical substance called a

per cent on the soma. These presynaptic terminals are

neurotransmitter (or often called simply transmitter

the ends of nerve fibrils that originate from many

substance), and this transmitter in turn acts on recep-

other neurons. Later, it will become evident that many

tor proteins in the membrane of the next neuron to

excite the neuron, inhibit it, or modify its sensitivity in

some other way. More than 40 important transmitter

substances have been discovered thus far. Some of

the best known are acetylcholine, norepinephrine,

epinephrine, histamine, gamma-aminobutyric acid

(GABA), glycine, serotonin, and glutamate.

Electrical synapses, in contrast, are characterized by

direct open fluid channels that conduct electricity from

one cell to the next. Most of these consist of small

protein tubular structures called gap junctions that

Dendrites

allow free movement of ions from the interior of one

cell to the interior of the next. Such junctions were dis-

cussed in Chapter 4. Only a few examples of gap junc-

tions have been found in the central nervous system.

Axon

However, it is by way of gap junctions and other

similar junctions that action potentials are transmitted

from one smooth muscle fiber to the next in visceral

smooth muscle (Chapter 8) and from one cardiac

Soma

muscle cell to the next in cardiac muscle (Chapter 10).

“One-Way” Conduction at Chemical Synapses. Chemical

synapses have one exceedingly important characteris-

tic that makes them highly desirable for transmitting

most nervous system signals: they always transmit

the signals in one direction: that is, from the neuron

that secretes the transmitter substance, called the

presynaptic neuron, to the neuron on which the trans-

mitter acts, called the postsynaptic neuron. This is the

principle of one-way conduction at chemical synapses,

Figure 45-5

and it is quite different from conduction through elec-

trical synapses, which often transmit signals in either

Typical anterior motor neuron, showing presynaptic terminals on

direction.

the neuronal soma and dendrites. Note also the single axon.

560

Unit IX The Nervous System: A. General Principles and Sensory Physiology

of these presynaptic terminals are excitatory—that is,

which in turn supplies the energy for synethesizing

they secrete a transmitter substance that excites the

new transmitter substance.

postsynaptic neuron. But other presynaptic terminals

When an action potential spreads over a presynap-

are inhibitory—they secrete a transmitter substance

tic terminal, depolarization of its membrane causes

that inhibits the postsynaptic neuron.

a small number of vesicles to empty into the cleft.

Neurons in other parts of the cord and brain differ

The released transmitter in turn causes an immediate

from the anterior motor neuron in (1) the size of the

change in permeability characteristics of the postsy-

cell body; (2) the length, size, and number of dendrites,

naptic neuronal membrane, and this leads to excitation

ranging in length from almost zero to many centime-

or inhibition of the postsynaptic neuron, depending on

ters; (3) the length and size of the axon; and (4) the

the neuronal receptor characteristics.

number of presynaptic terminals, which may range

from only a few to as many as 200,000. These differ-

Mechanism by Which an Action Potential

ences make neurons in different parts of the nervous

Causes Transmitter Release from the

system react differently to incoming synaptic signals

Presynaptic Terminals—Role of Calcium Ions

and, therefore, perform many different functions.

The membrane of the presynaptic terminal is called

the presynaptic membrane. It contains large numbers

Presynaptic Terminals. Electron microscopic studies of

of voltage-gated calcium channels. When an action

the presynaptic terminals show that they have varied

potential depolarizes the presynaptic membrane,

anatomical forms, but most resemble small round or

these calcium channels open and allow large numbers

oval knobs and, therefore, are sometimes called termi-

of calcium ions to flow into the terminal. The quantity

nal knobs, boutons, end-feet, or synaptic knobs.

of transmitter substance that is then released from

Figure

45-6 illustrates the basic structure of a

the terminal into the synaptic cleft is directly related

synapse, showing a single presynaptic terminal on the

to the number of calcium ions that enter. The precise

membrane surface of a postsomatic neuron. The presy-

mechanism by which the calcium ions cause this

naptic terminal is separated from the postsynaptic

release is not known, but it is believed to be the

neuronal soma by a synaptic cleft having a width

following.

usually of 200 to 300 angstroms. The terminal has

When the calcium ions enter the presynaptic termi-

two internal structures important to the excitatory or

nal, it is believed that they bind with special protein

inhibitory function of the synapse: the transmitter vesi-

molecules on the inside surface of the presynaptic

cles and the mitochondria. The transmitter vesicles

membrane, called release sites. This binding in turn

contain the transmitter substance that, when released

causes the release sites to open through the mem-

into the synaptic cleft, either excites or inhibits the

brane, allowing a few transmitter vesicles to release

postsynaptic neuron—excites if the neuronal mem-

their transmitter into the cleft after each single action

brane contains excitatory receptors, inhibits if the

potential. For those vesicles that store the neurotrans-

membrane contains inhibitory receptors. The mito-

mitter acetylcholine, between 2000 and 10,000 mole-

chondria provide adenosine triphosphate

(ATP),

cules of acetylcholine are present in each vesicle, and

there are enough vesicles in the presynaptic terminal

to transmit from a few hundred to more than 10,000

action potentials.

Action of the Transmitter Substance

on the Postsynaptic Neuron—Function of

“Receptor Proteins”

The membrane of the postsynaptic neuron contains

Transmitter vesicles

large numbers of receptor proteins, also shown in

Figure 45-6. The molecules of these receptors have

two important components: (1) a binding component

Mitochondria

that protrudes outward from the membrane into the

synaptic cleft—here it binds the neurotransmitter

coming from the presynaptic terminal—and (2) an

Presynaptic

terminal

ionophore component that passes all the way through

the postsynaptic membrane to the interior of the post-

synaptic neuron. The ionophore in turn is one of two

Receptor

types: (1) an ion channel that allows passage of speci-

proteins

fied types of ions through the membrane or (2) a

Synaptic cleft

(200-300

“second messenger” activator that is not an ion channel

angstroms)

Soma of neuron

but instead is a molecule that protrudes into the cell

cytoplasm and activates one or more substances inside

the postsynaptic neuron. These substances in turn

Figure 45-6

serve as “second messengers” to increase or decrease

Physiologic anatomy of the synapse.

specific cellular functions.

Chapter 45

Organization of the Nervous System, Basic Functions of Synapses, “Transmitter Substances”

561

Ion Channels. The ion channels in the postsynaptic neu-

the process of memory—require prolonged changes in

ronal membrane are usually of two types: (1) cation

neurons for seconds to months after the initial trans-

channels that most often allow sodium ions to pass

mitter substance is gone. The ion channels are not suit-

when opened, but sometimes allow potassium and/or

able for causing prolonged postsynaptic neuronal

calcium ions as well, and (2) anion channels that allow

changes because these channels close within millisec-

mainly chloride ions to pass but also minute quantities

onds after the transmitter substance is no longer

of other anions.

present. However, in many instances, prolonged post-

The cation channels that conduct sodium ions are

synaptic neuronal excitation or inhibition is achieved

lined with negative charges. These charges attract the

by activating a “second messenger” chemical system

positively charged sodium ions into the channel when

inside the postsynaptic neuronal cell itself, and then it

the channel diameter increases to a size larger than

is the second messenger that causes the prolonged

that of the hydrated sodium ion. But those same neg-

effect.

ative charges repel chloride ions and other anions and

There are several types of second messenger

prevent their passage.

systems. One of the most common types uses a group

For the anion channels, when the channel diameters

of proteins called G-proteins. Figure 45-7 shows in the

become large enough, chloride ions pass into the

upper left corner a membrane receptor protein. A

channels and on through to the opposite side, whereas

G-protein is attached to the portion of the receptor

sodium, potassium, and calcium cations are blocked,

that protrudes into the interior of the cell. The

mainly because their hydrated ions are too large to

G-protein in turn consists of three components: an

pass.

alpha (a) component that is the activator portion of

We will learn later that when cation channels open

the G-protein, and beta (b) and gamma (g) compo-

and allow positively charged sodium ions to enter, the

nents that are attached to the alpha component and

positive electrical charges of the sodium ions will in

also to the inside of the cell membrane adjacent to the

turn excite this neuron. Therefore, a transmitter sub-

receptor protein. On activation by a nerve impulse, the

stance that opens cation channels is called an excita-

alpha portion of the G-protein separates from the beta

tory transmitter. Conversely, opening anion channels

and gamma portions and then is free to move within

allows negative electrical charges to enter, which

the cytoplasm of the cell.

inhibits the neuron. Therefore, transmitter substances

Inside the cytoplasm, the separated alpha compo-

that open these channels are called inhibitory

nent performs one or more of multiple functions,

transmitters.

depending on the specific characteristic of each type

When a transmitter substance activates an ion

of neuron. Shown in Figure 45-7 are four changes that

channel, the channel usually opens within a fraction of

can occur. They are as follows:

a millisecond; when the transmitter substance is no

1. Opening specific ion channels through the

longer present, the channel closes equally rapidly. The

postsynaptic cell membrane. Shown in the upper

opening and closing of ion channels provide a means

right of the figure is a potassium channel that is

for very rapid control of postsynaptic neurons.

opened in response to the G-protein; this channel

often stays open for a prolonged time, in contrast

“Second Messenger” System in the Postsynaptic Neuron.

to rapid closure of directly activated ion channels

Many functions of the nervous system—for instance,

that do not use the second messenger system.

Transmitter substance

Receptor

Potassium

protein

channel

Figure 45-7

Membrane

Opens

enzyme

“Second messenger” system by

G-protein

channel

K⁺

which a transmitter substance from

an initial neuron can activate a

second neuron by first releasing

“G-protein” into the second

neuron’s cytoplasm. Four subse-

quent possible effects of the

G-protein are shown, including 1,

Activates one or

ATP

GTP

opening an ion channel in the

Activates gene

Activates

more intracellular

membrane of the second neuron;

transcription

enzymes

2, activating an enzyme system in

cAMP

cGMP

the neuron’s membrane; 3, activat-

ing an intracellular enzyme system;

and/or 4, causing gene transcrip-

Specific cellular

Proteins and

tion in the second neuron.

chemical activators

structural changes

562

Unit IX The Nervous System: A. General Principles and Sensory Physiology

2. Activation of cyclic adenosine monophosphate

excitatory membrane receptors or decrease the

(cAMP) or cyclic guanosine monophosphate

number of inhibitory membrane receptors.

(cGMP) in the neuronal cell. Recall that either

cyclic AMP or cyclic GMP can activate highly

Inhibition

specific metabolic machinery in the neuron and,

1. Opening of chloride ion channels through the

therefore, can initiate any one of many chemical

postsynaptic neuronal membrane. This allows

results, including long-term changes in cell

rapid diffusion of negatively charged chloride ions

structure itself, which in turn alters long-term

from outside the postsynaptic neuron to the

excitability of the neuron.

inside, thereby carrying negative charges inward

3. Activation of one or more intracellular enzymes.

and increasing the negativity inside, which is

The G-protein can directly activate one or more

inhibitory.

intracellular enzymes. In turn the enzymes can

2. Increase in conductance of potassium ions out of

cause any one of many specific chemical functions

the neuron. This allows positive ions to diffuse to

in the cell.

the exterior, which causes increased negativity

4. Activation of gene transcription. This is one of the

inside the neuron; this is inhibitory.

most important effects of activation of the second

3. Activation of receptor enzymes that inhibit cellular

messenger systems because gene transcription

metabolic functions that increase the number of

can cause formation of new proteins within the

inhibitory synaptic receptors or decrease the

neuron, thereby changing its metabolic machinery

number of excitatory receptors.

or its structure. Indeed, it is well known that

structural changes of appropriately activated

neurons do occur, especially in long-term memory

Chemical Substances That Function

processes.

as Synaptic Transmitters

It is clear that activation of second messenger

systems within the neuron, whether they be of the

More than 50 chemical substances have been proved

G-protein type or of other types, is extremely impor-

or postulated to function as synaptic transmitters.

tant for changing the long-term response characteris-

Many of them are listed in Tables 45-1 and 45-2, which

tics of different neuronal pathways. We will return to

give two groups of synaptic transmitters. One group

this subject in more detail in Chapter 57 when we

comprises small-molecule, rapidly acting transmitters.

discuss memory functions of the nervous system.

The other is made up of a large number of neuropep-

tides of much larger molecular size that are usually

Excitatory or Inhibitory Receptors in the

much more slowly acting.

Postsynaptic Membrane

The small-molecule, rapidly acting transmitters are

Some postsynaptic receptors, when activated, cause

the ones that cause most acute responses of the

excitation of the postsynaptic neuron, and others cause

nervous system, such as transmission of sensory signals

inhibition. The importance of having inhibitory as well

to the brain and of motor signals back to the muscles.

as excitatory types of receptors is that this gives an

The neuropeptides, in contrast, usually cause more

additional dimension to nervous function, allowing

prolonged actions, such as long-term changes in

restraint of nervous action as well as excitation.

numbers of neuronal receptors, long-term opening or

The different molecular and membrane mechanisms

closure of certain ion channels, and possibly even long-

used by the different receptors to cause excitation or

term changes in numbers of synapses or sizes of

inhibition include the following.

synapses.

Excitation

1. Opening of sodium channels to allow large

numbers of positive electrical charges to flow to the

Table 45-1

interior of the postsynaptic cell. This raises the

Small-Molecule, Rapidly Acting Transmitters

intracellular membrane potential in the positive

direction up toward the threshold level for

Class I

excitation. It is by far the most widely used means

Acetylcholine

for causing excitation.

Class II: The Amines

2. Depressed conduction through chloride or

Norepinephrine

potassium channels, or both. This decreases the

Epinephrine

diffusion of negatively charged chloride ions to

Dopamine

Serotonin

the inside of the postsynaptic neuron or decreases

Histamine

the diffusion of positively charged potassium ions

Class III: Amino Acids

to the outside. In either instance, the effect is to

Gamma-aminobutyric acid (GABA)

make the internal membrane potential more

Glycine

Glutamate

positive than normal, which is excitatory.

Aspartate

3. Various changes in the internal metabolism of the

Class IV

postsynaptic neuron to excite cell activity or, in

Nitric oxide (NO)

some instances, to increase the number of

Chapter 45

Organization of the Nervous System, Basic Functions of Synapses, “Transmitter Substances”

563

membrane still contains appropriate enzyme proteins

Table 45-2

or transport proteins required for synthesizing and/or

Neuropeptide, Slowly Acting Transmitters or Growth

concentrating new transmitter substance inside the

Factors

vesicle.

Acetylcholine is a typical small-molecule transmit-

Hypothalamic-releasing hormones

ter that obeys the principles of synthesis and release

Thyrotropin-releasing hormone

stated earlier. This transmitter substance is synthesized

Luteinizing hormone-releasing hormone

in the presynaptic terminal from acetyl coenzyme A

Somatostatin (growth hormone inhibitory factor)

Pituitary peptides

and choline in the presence of the enzyme choline

Adrenocorticotropic hormone (ACTH)

acetyltransferase. Then it is transported into its specific

b-Endorphin

vesicles. When the vesicles later release the acetyl-

a-Melanocyte-stimulating hormone

choline into the synaptic cleft during synaptic neu-

Prolactin

Luteinizing hormone

ronal signal transmission, the acetylcholine is rapidly

Thyrotropin

split again to acetate and choline by the enzyme

Growth hormone

cholinesterase, which is present in the proteoglycan

Vasopressin

reticulum that fills the space of the synaptic cleft. And

Oxytocin

then again, inside the presynaptic terminal, the vesi-

Peptides that act on gut and brain

Leucine enkephalin

cles are recycled; choline is actively transported back

Methionine enkephalin

into the terminal to be used again for synthesis of new

Substance P

acetylcholine.

Gastrin

Cholecystokinin

Vasoactive intestinal polypeptide (VIP)

Characteristics of Some of the More Important Small-Molecule

Nerve growth factor

Transmitters. The most important of the small-molecule

Brain-derived neurotropic factor

transmitters are the following.

Neurotensin

Acetylcholine is secreted by neurons in many areas

Insulin

of the nervous system but specifically by (1) the ter-

Glucagon

From other tissues

minals of the large pyramidal cells from the motor

Angiotensin II

cortex, (2) several different types of neurons in the

Bradykinin

basal ganglia, (3) the motor neurons that innervate the

Carnosine

skeletal muscles,

(4) the preganglionic neurons of

Sleep peptides

Calcitonin

the autonomic nervous system, (5) the postganglionic

neurons of the parasympathetic nervous system, and

(6) some of the postganglionic neurons of the sympa-

thetic nervous system. In most instances, acetylcholine

Small-Molecule, Rapidly Acting Transmitters

has an excitatory effect; however, it is known to have

In most cases, the small-molecule types of transmitters

inhibitory effects at some peripheral parasympathetic

are synthesized in the cytosol of the presynaptic ter-

nerve endings, such as inhibition of the heart by the

minal and are absorbed by means of active transport

vagus nerves.

into the many transmitter vesicles in the terminal.

Norepinephrine is secreted by the terminals of many

Then, each time an action potential reaches the presy-

neurons whose cell bodies are located in the brain

naptic terminal, a few vesicles at a time release their

stem and hypothalamus. Specifically, norepinephrine-

transmitter into the synaptic cleft. This usually occurs

secreting neurons located in the locus ceruleus in the

within a millisecond or less by the mechanism

pons send nerve fibers to widespread areas of the brain

described earlier. The subsequent action of the small-

to help control overall activity and mood of the mind,

molecule type of transmitter on the membrane recep-

such as increasing the level of wakefulness. In most of

tors of the postsynaptic neuron usually also occurs

these areas, norepinephrine probably activates excita-

within another millisecond or less. Most often the

tory receptors, but in a few areas, it activates inhibitory

effect is to increase or decrease conductance through

receptors instead. Norepinephrine is also secreted by

ion channels; an example is to increase sodium con-

most postganglionic neurons of the sympathetic

ductance, which causes excitation, or to increase potas-

nervous system, where it excites some organs but

sium or chloride conductance, which causes inhibition.

inhibits others.

Dopamine is secreted by neurons that originate in

Recycling of the Small-Molecule Types of Vesicles. The vesi-

the substantia nigra. The termination of these neurons

cles that store and release small-molecule transmitters

is mainly in the striatal region of the basal ganglia. The

are continually recycled and used over and over again.

effect of dopamine is usually inhibition.

After they fuse with the synaptic membrane and open

Glycine is secreted mainly at synapses in the

to release their transmitter substance, the vesicle mem-

spinal cord. It is believed to always act as an inhibitory

brane at first simply becomes part of the synaptic

transmitter.

membrane. However, within seconds to minutes, the

GABA (gamma-aminobutyric acid) is secreted by

vesicle portion of the membrane invaginates back to

nerve terminals in the spinal cord, cerebellum, basal

the inside of the presynaptic terminal and pinches

ganglia, and many areas of the cortex. It is believed

off to form a new vesicle. And the new vesicular

always to cause inhibition.

564

Unit IX The Nervous System: A. General Principles and Sensory Physiology

Glutamate is secreted by the presynaptic terminals

as potent as the small-molecule transmitters. Another

in many of the sensory pathways entering the central

important characteristic of the neuropeptides is that

nervous system, as well as in many areas of the cere-

they often cause much more prolonged actions. Some

bral cortex. It probably always causes excitation.

of these actions include prolonged closure of calcium

Serotonin is secreted by nuclei that originate in the

channels, prolonged changes in the metabolic machin-

median raphe of the brain stem and project to many

ery of cells, prolonged changes in activation or deacti-

brain and spinal cord areas, especially to the dorsal

vation of specific genes in the cell nucleus, and/or

horns of the spinal cord and to the hypothalamus.

prolonged alterations in numbers of excitatory or

Serotonin acts as an inhibitor of pain pathways in the

inhibitory receptors. Some of these effects last for

cord, and an inhibitor action in the higher regions of

days, but others perhaps for months or years. Our

the nervous system is believed to help control the

knowledge of the functions of the neuropeptides is

mood of the person, perhaps even to cause sleep.

only beginning to develop.

Nitric oxide is especially secreted by nerve terminals

in areas of the brain responsible for long-term behav-

ior and for memory. Therefore, this transmitter system

Electrical Events During

might in the future explain some behavior and

Neuronal Excitation

memory functions that thus far have defied under-

standing. Nitric oxide is different from other small-

The electrical events in neuronal excitation have been

molecule transmitters in its mechanism of formation

studied especially in the large motor neurons of the

in the presynaptic terminal and in its actions on the

anterior horns of the spinal cord. Therefore, the events

postsynaptic neuron. It is not preformed and stored in

described in the next few sections pertain essentially

vesicles in the presynaptic terminal as are other trans-

to these neurons. Except for quantitative differences,

mitters. Instead, it is synthesized almost instantly as

they apply to most other neurons of the nervous

needed, and it then diffuses out of the presynaptic

system as well.

terminals over a period of seconds rather than being

released in vesicular packets. Next, it diffuses into

Resting Membrane Potential of the Neuronal Soma. Figure

postsynaptic neurons nearby. In the postsynaptic

45-8 shows the soma of a spinal motor neuron, indi-

neuron, it usually does not greatly alter the membrane

cating a resting membrane potential of about -65 mil-

potential but instead changes intracellular metabolic

livolts. This is somewhat less negative than the -90

functions that modify neuronal excitability for

millivolts found in large peripheral nerve fibers and in

seconds, minutes, or perhaps even longer.

skeletal muscle fibers; the lower voltage is important

because it allows both positive and negative control

Neuropeptides

of the degree of excitability of the neuron. That is,

The neuropeptides are an entirely different class of

decreasing the voltage to a less negative value makes

transmitters that are synthesized differently and

the membrane of the neuron more excitable, whereas

whose actions are usually slow and in other ways quite

increasing this voltage to a more negative value makes

different from those of the small-molecule transmit-

the neuron less excitable. This is the basis for the two

ters. The neuropeptides are not synthesized in the

cytosol of the presynaptic terminals. Instead, they are

synthesized as integral parts of large-protein mole-

cules by ribosomes in the neuronal cell body.

The protein molecules then enter the spaces inside

Dendrite

the endoplasmic reticulum of the cell body and subse-

quently inside the Golgi apparatus, where two changes

occur: First, the neuropeptide-forming protein is enzy-

matically split into smaller fragments, some of which

are either the neuropeptide itself or a precursor of it.

Na⁺: 142 mEq/L

14 mEq/L

(Pumps)

Second, the Golgi apparatus packages the neuropep-

K⁺: 4.5 mEq/L

120 mEq/L

tide into minute transmitter vesicles that are released

-65

Axon

into the cytoplasm. Then the transmitter vesicles are

8 mEq/L

transported all the way to the tips of the nerve fibers

Cl^-: 107 mEq/L

by axonal streaming of the axon cytoplasm, traveling

Pump

at the slow rate of only a few centimeters per day.

Finally, these vesicles release their transmitter at the

Axon hillock

neuronal terminals in response to action potentials in

the same manner as for small-molecule transmitters.

However, the vesicle is autolyzed and is not reused.

Because of this laborious method of forming the

neuropeptides, much smaller quantities of them are

Figure 45-8

usually released than of the small-molecule transmit-

Distribution of sodium, potassium, and chloride ions across the

ters. This is partly compensated for by the fact that the

neuronal somal membrane; origin of the intrasomal membrane

neuropeptides are generally a thousand or more times

potential.

Chapter 45

Organization of the Nervous System, Basic Functions of Synapses, “Transmitter Substances”

565

modes of function of the neuron—either excitation or

-65 that actually exists. Therefore, because of the high

inhibition—as explained in detail in the next sections.

intracellular potassium ion concentration, there is a

net tendency for potassium ions to diffuse to the

Concentration Differences of Ions Across the Neuronal

outside of the neuron, but this is opposed by continual

Somal Membrane. Figure 45-8 also shows the concen-

pumping of these potassium ions back to the

tration differences across the neuronal somal mem-

interior.

brane of the three ions that are most important for

Finally, the chloride ion gradient, 107 mEq/L outside

neuronal function: sodium ions, potassium ions, and

and 8 mEq/L inside, yields a Nernst potential of -70

chloride ions. At the top, the sodium ion concentra-

millivolts inside the neuron, which is only slightly more

tion is shown to be high in the extracellular fluid

negative than the actual measured value of -65 milli-

(142 mEq/L) but low inside the neuron (14 mEq/L).

volts. Therefore, chloride ions tend to leak very slightly

This sodium concentration gradient is caused by a

to the interior of the neuron, but those few that do leak

strong somal membrane sodium pump that continually

are moved back to the exterior, perhaps by an active

pumps sodium out of the neuron.

chloride pump.

The figure also shows that potassium ion concentra-

Keep these three Nernst potentials in mind and

tion is high inside the neuronal soma (120 mEq/L) but

remember the direction in which the different ions

low in the extracellular fluid (4.5 mEq/L). It shows that

tend to diffuse because this information is important

there is a potassium pump (the other half of the Na⁺-

in understanding both excitation and inhibition of the

K⁺ pump) that pumps potassium to the interior.

neuron by synapse activation or inactivation of ion

Figure 45-8 shows the chloride ion to be of high con-

channels.

centration in the extracellular fluid but low concentra-

tion inside the neuron. It also shows that the membrane

Uniform Distribution of Electrical Potential Inside the

is quite permeable to chloride ions and that there may

Soma. The interior of the neuronal soma contains a

be a weak chloride pump. Yet most of the reason

highly conductive electrolytic solution, the intracellu-

for the low concentration of chloride ions inside the

lar fluid of the neuron. Furthermore, the diameter of

neuron is the -65 millivolts in the neuron. That is, this

the neuronal soma is large (from 10 to 80 microme-

negative voltage repels the negatively charged chlo-

ters), causing almost no resistance to conduction of

ride ions, forcing them outward through the pores until

electric current from one part of the somal interior to

the concentration is much less inside the membrane

another part. Therefore, any change in potential in any

than outside.

part of the intrasomal fluid causes an almost exactly

Let us recall at this point what we learned in Chap-

equal change in potential at all other points inside the

ters 4 and 5 about the relation of ionic concentration

soma (that is, as long as the neuron is not transmitting

differences to membrane potentials. It will be recalled

an action potential). This is an important principle,

that an electrical potential across the cell membrane

because it plays a major role in “summation” of signals

can oppose movement of ions through a membrane if

entering the neuron from multiple sources, as we shall

the potential is of proper polarity and magnitude. A

see in subsequent sections of this chapter.

potential that exactly opposes movement of an ion is

called the Nernst potential for that ion; the equation

Effect of Synaptic Excitation on the Postsynaptic Membrane—

for this is the following:

Excitatory Postsynaptic Potential. Figure 45-9A shows the

resting neuron with an unexcited presynaptic terminal

Concentration inside

EMF (mV)=±

¥logÊ

resting on its surface. The resting membrane potential

Ë Concentration outside¯

everywhere in the soma is -65 millivolts.

where EMF is the Nernst potential in millivolts on the

Figure 45-9B shows a presynaptic terminal that has

inside of the membrane. The potential will be negative

secreted an excitatory transmitter into the cleft

(-) for positive ions and positive (+) for negative ions.

between the terminal and the neuronal somal mem-

Now, let us calculate the Nernst potential that will

brane. This transmitter acts on the membrane excita-

exactly oppose the movement of each of the three sep-

tory receptor to increase the membrane’s permeability

arate ions: sodium, potassium, and chloride.

to Na⁺. Because of the large sodium concentration

For the sodium concentration difference shown in

gradient and large electrical negativity inside the

Figure 45-8, 142 mEq/L on the exterior and 14 mEq/L

neuron, sodium ions diffuse rapidly to the inside of the

on the interior, the membrane potential that will

membrane.

exactly oppose sodium ion movement through the

The rapid influx of positively charged sodium ions

sodium channels calculates to be

+61 millivolts.

to the interior neutralizes part of the negativity of the

However, the actual membrane potential is -65 milli-

resting membrane potential. Thus, in Figure 45-9B, the

volts, not +61 millivolts. Therefore, those sodium ions

resting membrane potential has increased in the posi-

that leak to the interior are immediately pumped back

tive direction from -65 to -45 millivolts. This positive

to the exterior by the sodium pump, thus maintaining

increase in voltage above the normal resting neuronal

the -65 millivolt negative potential inside the neuron.

potential—that is, to a less negative value—is called

For potassium ions, the concentration gradient is

the excitatory postsynaptic potential

(or EPSP),

120 mEq/L inside the neuron and 4.5 mEq/L outside.

because if this potential rises high enough in the pos-

This calculates to a Nernst potential of -86 millivolts

itive direction, it will elicit an action potential in the

inside the neuron, which is more negative than the

postsynaptic neuron, thus exciting it. (In this case, the

566

Unit IX The Nervous System: A. General Principles and Sensory Physiology

times as great a concentration of voltage-gated sodium

channels as does the soma and, therefore, can gener-

ate an action potential with much greater ease than

can the soma. The EPSP that will elicit an action

-65 mV

potential in the axon initial segment is between +10

and +20 millivolts. This is in contrast to the +30 or +40

millivolts or more required on the soma.

Resting Neuron

Once the action potential begins, it travels periph-

erally along the axon and usually also backward over

Initial segment

the soma. In some instances, it travels backward into

of axon

Excitatory

the dendrites, too, but not into all of them, because

they, like the neuronal soma, have very few voltage-

-45 mV

gated sodium channels and therefore frequently

cannot generate action potentials at all. Thus, in Figure

45-9B, the threshold for excitation of the neuron is

Na⁺

shown to be about -45 millivolts, which represents an

influx

Excited Neuron

Spread of

EPSP of +20 millivolts—that is, 20 millivolts more pos-

action potential

itive than the normal resting neuronal potential of

Cl^- influx

-65 millivolts.

Inhibitory

-70 mV

Electrical Events During Neuronal

Inhibition

K⁺

efflux

Inhibited Neuron

Effect of Inhibitory Synapses on the Postsynaptic Membrane—

Inhibitory Postsynaptic Potential. The inhibitory synapses

Figure 45-9

open mainly chloride channels, allowing easy passage

of chloride ions. Now, to understand how the

Three states of a neuron. A, Resting neuron, with a normal intra-

inhibitory synapses inhibit the postsynaptic neuron,

neuronal potential of -65 millivolts. B, Neuron in an excited state,

with a less negative intraneuronal potential (-45 millivolts) caused

we must recall what we learned about the Nernst

by sodium influx. C, Neuron in an inhibited state, with a more neg-

potential for chloride ions. We calculated the Nernst

ative intraneuronal membrane potential (-70 millivolts) caused by

potential for chloride ions to be about -70 millivolts.

potassium ion efflux, chloride ion influx, or both.

This potential is more negative than the -65 millivolts

normally present inside the resting neuronal mem-

brane. Therefore, opening the chloride channels

EPSP is +20 millivolts—that is, 20 millivolts more pos-

will allow negatively charged chloride ions to move

itive than the resting value.)

from the extracellular fluid to the interior, which

However, we must issue a word of warning. Dis-

will make the interior membrane potential more

charge of a single presynaptic terminal can never

negative than normal, approaching the -70 millivolt

increase the neuronal potential from -65 millivolts

level.

all the way up to -45 millivolts. An increase of this

Opening potassium channels will allow positively

magnitude requires simultaneous discharge of many

charged potassium ions to move to the exterior, and

terminals—about 40 to 80 for the usual anterior motor

this will also make the interior membrane potential

neuron—at the same time or in rapid succession. This

more negative than usual. Thus, both chloride influx

occurs by a process called summation, which is dis-

and potassium efflux increase the degree of intracel-

cussed in detail in the next sections.

lular negativity, which is called hyperpolarization. This

inhibits the neuron because the membrane potential is

Generation of Action Potentials in the Initial Segment of the

even more negative than the normal intracellular

Axon Leaving the Neuron—Threshold for Excitation. When

potential. Therefore, an increase in negativity beyond

the EPSP rises high enough in the positive direction,

the normal resting membrane potential level is called

there comes a point at which this initiates an action

an inhibitory postsynaptic potential (IPSP).

potential in the neuron. However, the action potential

Figure 45-9C shows the effect on the membrane

does not begin adjacent to the excitatory synapses.

potential caused by activation of inhibitory synapses,

Instead, it begins in the initial segment of the axon

allowing chloride influx into the cell and/or potassium

where the axon leaves the neuronal soma. The main

efflux out of the cell, with the membrane potential

reason for this point of origin of the action potential

decreasing from its normal value of -65 millivolts to

is that the soma has relatively few voltage-gated

the more negative value of -70 millivolts. This mem-

sodium channels in its membrane, which makes it dif-

brane potential is

5 millivolts more negative than

ficult for the EPSP to open the required number of

normal and is therefore an IPSP of -5 millivolts, which

sodium channels to elicit an action potential. Con-

inhibits transmission of the nerve signal through the

versely, the membrane of the initial segment has seven

synapse.

Chapter 45

Organization of the Nervous System, Basic Functions of Synapses, “Transmitter Substances”

567

Presynaptic Inhibition

required for the excess positive charges to leak out of

In addition to inhibition caused by inhibitory synapses

the excited neuron and to re-establish the normal

operating at the neuronal membrane, which is called

resting membrane potential.

postsynaptic inhibition, another type of inhibition

Precisely the opposite effect occurs for an IPSP; that

often occurs at the presynaptic terminals before the

is, the inhibitory synapse increases the permeability of

signal ever reaches the synapse. This type of inhibition,

the membrane to potassium or chloride ions, or both,

called presynaptic inhibition, occurs in the following

for 1 to 2 milliseconds, and this decreases the intra-

way.

neuronal potential to a more negative value than

Presynaptic inhibition is caused by release of an

normal, thereby creating the IPSP. This potential also

inhibitory substance onto the outsides of the presy-

dies away in about 15 milliseconds.

naptic nerve fibrils before their own endings terminate

Other types of transmitter substances can excite or

on the postsynaptic neuron. In most instances, the

inhibit the postsynaptic neuron for much longer

inhibitory transmitter substance is GABA (gamma-

periods—for hundreds of milliseconds or even for

aminobutyric acid). This has a specific effect of

seconds, minutes, or hours. This is especially true for

opening anion channels, allowing large numbers of

some of the neuropeptide types of transmitter

chloride ions to diffuse into the terminal fibril. The

substances.

negative charges of these ions inhibit synaptic trans-

mission because they cancel much of the excitatory

“Spatial Summation” in Neurons—

effect of the positively charged sodium ions that also

Threshold for Firing

enter the terminal fibrils when an action potential

Excitation of a single presynaptic terminal on the

arrives.

surface of a neuron almost never excites the neuron.

Presynaptic inhibition occurs in many of the sensory

The reason for this is that sufficient transmitter sub-

pathways in the nervous system. In fact, adjacent

stance is released by a single terminal to cause an

sensory nerve fibers often mutually inhibit one

EPSP usually no greater than 0.5 to 1 millivolt, instead

another, which minimizes sideways spread and mixing

of the 10 to 20 millivolts normally required to reach

of signals in sensory tracts. We discuss the importance

threshold for excitation. However, many presynaptic

of this phenomenon more fully in subsequent chapters.

terminals are usually stimulated at the same time.

Even though these terminals are spread over wide

Time Course of Postsynaptic Potentials

areas of the neuron, their effects can still summate;

When an excitatory synapse excites the anterior motor

that is, they can add to one another until neuronal exci-

neuron, the neuronal membrane becomes highly per-

tation does occur. The reason for this is the following:

meable to sodium ions for 1 to 2 milliseconds. During

It was pointed out earlier that a change in potential at

this very short time, enough sodium ions diffuse

any single point within the soma will cause the poten-

rapidly to the interior of the postsynaptic motor

tial to change everywhere inside the soma almost

neuron to increase its intraneuronal potential by a few

exactly equally. This is true because of the very high

millivolts, thus creating the excitatory postsynaptic

electrical conductivity inside the large neuronal cell

potential (EPSP) shown by the blue and green curves

body. Therefore, for each excitatory synapse that dis-

of Figure 45-10. This potential then slowly declines

charges simultaneously, the total intrasomal potential

over the next 15 milliseconds because this is the time

becomes more positive by 0.5 to 1.0 millivolt. When

16 synapses firing

+20

8 synapses firing

Action potential

4 synapses firing

–20

-40

Excitatory postsynaptic

potential

Figure 45-10

-60

Excitatory postsynaptic potentials, showing that

Resting membrane potential

simultaneous firing of only a few synapses will not

- 80

cause sufficient summated potential to elicit an

action potential, but that simultaneous firing of

Milliseconds

many synapses will raise the summated potential

to threshold for excitation and cause a superim-

posed action potential.

568

Unit IX The Nervous System: A. General Principles and Sensory Physiology

the EPSP becomes great enough, the threshold for

ronal soma. And these dendrites can receive signals

firing will be reached and an action potential will

from a large spatial area around the motor neuron.

develop spontaneously in the initial segment of the

This provides a vast opportunity for summation of

axon. This is demonstrated in Figure

45-10. The

signals from many separate presynaptic nerve fibers.

bottom postsynaptic potential in the figure was caused

It is also important that between 80 and 95 per cent

by simultaneous stimulation of 4 synapses; the next

of all the presynaptic terminals of the anterior motor

higher potential was caused by stimulation of

neuron terminate on dendrites, in contrast to only 5 to

synapses; finally, a still higher EPSP was caused by

20 per cent terminating on the neuronal soma. There-

stimulation of 16 synapses. In this last instance, the

fore, the preponderant share of the excitation is pro-

firing threshold had been reached, and an action

vided by signals transmitted by way of the dendrites.

potential was generated in the axon.

This effect of summing simultaneous postsynaptic

Most Dendrites Cannot Transmit Action Potentials—But They

potentials by activating multiple terminals on widely

Can Transmit Signals Within the Same Neuron by Electrotonic

spaced areas of the neuronal membrane is called

Conduction. Most dendrites fail to transmit action

spatial summation.

potentials because their membranes have relatively

few voltage-gated sodium channels, and their thresh-

“Temporal Summation”

olds for excitation are too high for action potentials to

Each time a presynaptic terminal fires, the released

occur. Yet they do transmit electrotonic current down

transmitter substance opens the membrane channels

the dendrites to the soma. Transmission of electrotonic

for at most a millisecond or so. But the changed post-

current means direct spread of electrical current by ion

synaptic potential lasts up to 15 milliseconds after the

conduction in the fluids of the dendrites but without

synaptic membrane channels have already closed.

generation of action potentials. Stimulation (or inhibi-

Therefore, a second opening of the same channels can

tion) of the neuron by this current has special charac-

increase the postsynaptic potential to a still greater

teristics, as follows.

level, and the more rapid the rate of stimulation, the

greater the postsynaptic potential becomes. Thus, suc-

Decrement of Electrotonic Conduction in the Den-

cessive discharges from a single presynaptic terminal,

drites—Greater Excitatory

(or Inhibitory) Effect by

if they occur rapidly enough, can add to one another;

Synapses Located Near the Soma. In Figure 45-11,

that is, they can “summate.” This type of summation is

multiple excitatory and inhibitory synapses are shown

called temporal summation.

stimulating the dendrites of a neuron. On the two den-

drites to the left, there are excitatory effects near the

Simultaneous Summation of Inhibitory and Excitatory Postsy-

tip ends; note the high levels of excitatory postsynap-

naptic Potentials. If an IPSP is tending to decrease the

tic potentials at these ends—that is, note the less neg-

membrane potential to a more negative value while an

ative membrane potentials at these points. However, a

EPSP is tending to increase the potential at the same

time, these two effects can either completely or par-

tially nullify each other. Thus, if a neuron is being

excited by an EPSP, an inhibitory signal from another

source can often reduce the postsynaptic potential to

less than threshold value for excitation, thus turning

off the activity of the neuron.

-40

“Facilitation” of Neurons

-50

-75

Often the summated postsynaptic potential is excita-

-70

tory but has not risen high enough to reach the thresh-

-60

old for firing by the postsynaptic neuron. When this

happens, the neuron is said to be facilitated. That is, its

membrane potential is nearer the threshold for firing

-40

-60 mV

-40

-50 -60

than normal, but not yet at the firing level. Conse-

-30

-70 -75

quently, another excitatory signal entering the neuron

from some other source can then excite the neuron

very easily. Diffuse signals in the nervous system often

do facilitate large groups of neurons so that they can

respond quickly and easily to signals arriving from

other sources.

Figure 45-11

Special Functions of Dendrites

for Exciting Neurons

Stimulation of a neuron by presynaptic terminals located on den-

drites, showing, especially, decremental conduction of excitatory

(E) electrotonic potentials in the two dendrites to the left and inhi-

Large Spatial Field of Excitation of the Dendrites. The den-

bition (I) of dendritic excitation in the dendrite that is uppermost.

drites of the anterior motor neurons often extend 500

A powerful effect of inhibitory synapses at the initial segment of

to 1000 micrometers in all directions from the neu-

the axon is also shown.

Chapter 45

Organization of the Nervous System, Basic Functions of Synapses, “Transmitter Substances”

569

large share of the excitatory postsynaptic potential is

Relation of State of Excitation of the

lost before it reaches the soma. The reason is that the

Neuron to Rate of Firing

dendrites are long, and their membranes are thin and

at least partially permeable to potassium and chloride

ions, making them “leaky” to electric current. There-

“Excitatory State.” The “excitatory state” of a neuron is

fore, before the excitatory potentials can reach the

defined as the summated degree of excitatory drive to

soma, a large share of the potential is lost by leakage

the neuron. If there is a higher degree of excitation

through the membrane. This decrease in membrane

than inhibition of the neuron at any given instant, then

potential as it spreads electrotonically along dendrites

it is said that there is an excitatory state. Conversely, if

toward the soma is called decremental conduction.

there is more inhibition than excitation, then it is said

The farther the excitatory synapse is from the soma

that there is an inhibitory state.

of the neuron, the greater will be the decrement, and

When the excitatory state of a neuron rises above

the less will be excitatory signal reaching the soma.

the threshold for excitation, the neuron will fire repet-

Therefore, those synapses that lie near the soma have

itively as long as the excitatory state remains at that

far more effect in causing neuron excitation or inhibi-

level. Figure 45-12 shows responses of three types of

tion than those that lie far away from the soma.

neurons to varying levels of excitatory state. Note that

neuron 1 has a low threshold for excitation, whereas

Summation of Excitation and Inhibition in Dendrites. The

neuron 3 has a high threshold. But note also that

uppermost dendrite of Figure 45-11 is shown to be

neuron 2 has the lowest maximum frequency of dis-

stimulated by both excitatory and inhibitory synapses.

charge, whereas neuron 3 has the highest maximum

At the tip of the dendrite is a strong excitatory post-

frequency.

synaptic potential, but nearer the soma are two

Some neurons in the central nervous system fire

inhibitory synapses acting on the same dendrite. These

continuously because even the normal excitatory

inhibitory synapses provide a hyperpolarizing voltage

state is above the threshold level. Their frequency of

that completely nullifies the excitatory effect and

firing can usually be increased still more by further

indeed transmits a small amount of inhibition by elec-

increasing their excitatory state. The frequency can be

trotonic conduction toward the soma. Thus, dendrites

decreased, or firing can even be stopped, by superim-

can summate excitatory and inhibitory postsynaptic

posing an inhibitory state on the neuron. Thus, dif-

potentials in the same way that the soma can. Also

ferent neurons respond differently, have different

shown in the figure are several inhibitory synapses

thresholds for excitation, and have widely differing

located directly on the axon hillock and initial axon

maximum frequencies of discharge. With a little imag-

segment. This location provides especially powerful

ination, one can readily understand the importance of

inhibition because it has the direct effect of increasing

having different neurons with these many types of

the threshold for excitation at the very point where the

response characteristics to perform the widely varying

action potential is normally generated.

functions of the nervous system.

600

Neuron 1

Neuron 2

500

Neuron 3

400

300

200

Threshold

100

Figure 45-12

Excitatory state (arbitrary units)

Response characteristics of different types of

neurons to different levels of excitatory state.

570

Unit IX The Nervous System: A. General Principles and Sensory Physiology

Some Special Characteristics

neuronal excitability, presumably by reducing the

threshold for excitation of neurons.

of Synaptic Transmission

Strychnine is one of the best known of all agents that

increase excitability of neurons. However, it does not

Fatigue of Synaptic Transmission. When excitatory

do this by reducing the threshold for excitation of

synapses are repetitively stimulated at a rapid rate, the

the neurons; instead, it inhibits the action of some nor-

number of discharges by the postsynaptic neuron is at

mally inhibitory transmitter substances, especially the

first very great, but the firing rate becomes progres-

inhibitory effect of glycine in the spinal cord. Therefore,

sively less in succeeding milliseconds or seconds. This

the effects of the excitatory transmitters become over-

whelming, and the neurons become so excited that they

is called fatigue of synaptic transmission.

go into rapidly repetitive discharge, resulting in severe

Fatigue is an exceedingly important characteristic of

tonic muscle spasms.

synaptic function because when areas of the nervous

Most anesthetics increase the neuronal membrane

system become overexcited, fatigue causes them to

threshold for excitation and thereby decrease synaptic

lose this excess excitability after awhile. For example,

transmission at many points in the nervous system.

fatigue is probably the most important means by which

Because many of the anesthetics are especially lipid-

the excess excitability of the brain during an epileptic

soluble, it has been reasoned that some of them might

seizure is finally subdued so that the seizure ceases.

change the physical characteristics of the neuronal

Thus, the development of fatigue is a protective mech-

membranes, making them less responsive to excitatory

anism against excess neuronal activity. This is dis-

agents.

cussed further in the description of reverberating

neuronal circuits in Chapter 46.

Synaptic Delay. During transmission of a neuronal signal

The mechanism of fatigue is mainly exhaustion or

from a presynaptic neuron to a postsynaptic neuron, a

partial exhaustion of the stores of transmitter sub-

certain amount of time is consumed in the process of

stance in the presynaptic terminals. The excitatory ter-

(1) discharge of the transmitter substance by the presy-

naptic terminal, (2) diffusion of the transmitter to the

minals on many neurons can store enough excitatory

postsynaptic neuronal membrane, (3) action of the

transmitter to cause only about 10,000 action poten-

transmitter on the membrane receptor, (4) action of

tials, and the transmitter can be exhausted in only a

the receptor to increase the membrane permeability,

few seconds to a few minutes of rapid stimulation. Part

and (5) inward diffusion of sodium to raise the excita-

of the fatigue process probably results from two other

tory postsynaptic potential to a high enough level to

factors as well: (1) progressive inactivation of many of

elicit an action potential. The minimal period of time

the postsynaptic membrane receptors and (2) slow

required for all these events to take place, even when

development of abnormal concentrations of ions

large numbers of excitatory synapses are stimulated

inside the postsynaptic neuronal cell.

simultaneously, is about 0.5 millisecond. This is called

the synaptic delay. Neurophysiologists can measure the

minimal delay time between an input volley of impulses

Effect of Acidosis or Alkalosis on Synaptic Transmission. Most

into a pool of neurons and the consequent output volley.

neurons are highly responsive to changes in pH of

From the measure of delay time, one can then estimate

the surrounding interstitial fluids. Normally, alkalosis

the number of series neurons in the circuit.

greatly increases neuronal excitability. For instance, a

rise in arterial blood pH from the 7.4 norm to 7.8 to

8.0 often causes cerebral epileptic seizures because of

increased excitability of some or all of the cerebral

References

neurons. This can be demonstrated especially well by

asking a person who is predisposed to epileptic seizures

Albright TD, Jessell TM, Kandell ER, Posner MI: Progress

to overbreathe. The overbreathing blows off carbon

in the neural sciences in the century after Cajal (and the

dioxide and therefore elevates the pH of the blood

mysteries that remain). Ann N Y Acad Sci 929:11, 2001.

momentarily, but even this short time can often precip-

Boehning D, Snyder SH: Novel neural modulators. Annu

itate an epileptic attack.

Rev Neurosci 26:105, 2003.

Conversely, acidosis greatly depresses neuronal activ-

Brasnjo G, Otis TS: Glycine transporters not only take out

ity; a fall in pH from 7.4 to below 7.0 usually causes a

the garbage, they recycle. Neuron 40:667, 2003.

comatose state. For instance, in very severe diabetic or

Cowley MA, Cone RD, Enriori P, et al: Electrophysiological

uremic acidosis, coma virtually always develops.

actions of peripheral hormones on melanocortin neurons.

Ann N Y Acad Sci 994:175, 2003.

Effect of Hypoxia on Synaptic Transmission. Neuronal

Engelman HS, MacDermott AB: Presynaptic inotropic

excitability is also highly dependent on an adequate

receptors and control of transmitter release. Nat Rev Neu-

supply of oxygen. Cessation of oxygen for only a few

rosci 5:135, 2004.

seconds can cause complete inexcitability of some

Girault JA, Greengard P: The neurobiology of dopamine

neurons. This is observed when the brain’s blood flow is

signaling. Arch Neurol 61:641, 2004.

temporarily interrupted, because within 3 to 7 seconds,

Haines DE: Fundamental Neuroscience. New York:

the person becomes unconscious.

Churchill Livingstone, 1997.

Haines DE, Lancon JA: Review of Neuroscience. New York:

Effect of Drugs on Synaptic Transmission. Many drugs are

Churchill Livingstone, 2003.

known to increase the excitability of neurons, and

Kandel ER: The molecular biology of memory storage: a dia-

others are known to decrease excitability. For instance,

logue between genes and synapses. Science 294:1030, 2001.

caffeine, theophylline, and theobromine, which are

Kandel ER, Schwartz JH, Jessell TM: Principles of Neural

found in coffee, tea, and cocoa, respectively, all increase

Science, 4th ed. New York: McGraw-Hill, 2000.

Chapter 45

Organization of the Nervous System, Basic Functions of Synapses, “Transmitter Substances”

571

Magee JC: Dendritic integration of excitatory synaptic input.

Schmolesky MT, Weber JT, De Zeeuw CI, Hansel C: The

Nat Rev Neurosci 1:181, 2000.

making of a complex spike: ionic composition and plastic-

Migliore M, Shepherd GM: Emerging rules for the distribu-

ity. Ann N Y Acad Sci 978:359, 2002.

tions of active dendritic conductances. Nat Rev Neurosci

Semyanov A, Walker MC, Kullmann DM, Silver RA:

3:362, 2002.

Tonically active GABA A receptors: modulating gain and

Muller D, Nikonenko I: Dynamic presynaptic varicosities: a

maintaining the tone. Trends Neurosci 27:262, 2004.

role in activity-dependent synaptogenesis. Trends Neu-

Stern JE: Nitric oxide and homeostatic control: an intercel-

rosci 26:573, 2003.

lular signaling molecule contributing to autonomic and

Nicholls DG, Budd SL: Mitochondria and neuronal survival.

neuroendocrine integration? Prog Biophys Mol Biol 84:

Physiol Rev 80:315, 2000.

197, 2004.

Nimchinsky EA, Sabatin BL, Svoboda K: Structure and

Timofeev I, Steriade M: Neocortical seizures: initiation,

function of dendritic spines. Annu Rev Physiol 64:313,

development and cessation. Neuroscience 123:299, 2004.

2002.

Tsay D, Yuste RL: On the electrical function of dendritic

Prast H, Philippu A: Nitric oxide as modulator of neuronal

spines. Trends Neurosci 27:77, 2004.

function. Prog Neurobiol 64:51, 2001.

West AR, Floresco SB, Charara A, et al: Electrophysiologi-

Reid CA, Bekkers JM, Clements JD: Presynaptic Ca2+ chan-

cal interactions between striatal glutamatergic and

nels: a functional patchwork. Trends Neurosci 26:683, 2003.

dopaminergic systems. Ann N Y Acad Sci 1003:53, 2003.

Robinson RB, Siegelbaum SA: Hyperpolarization-activated

Williams SR, Stuart GJ: Role of dendritic synapse location

cation currents: from molecules to physiological function.

in the control of action potential output. Trends Neurosci

Annu Rev Physiol 65:453, 2003.

26:147, 2003.

Ruff RL: Neurophysiology of the neuromuscular junction:

Zucker RS, Regehr WG: Short-term synaptic plasticity.

overview. Ann N Y Acad Sci 998:1, 2003.

Annu Rev Physiol 64:355, 2002.

C H A P T E R

Sensory Receptors, Neuronal

Circuits for Processing Information

Input to the nervous system is provided by sensory

receptors that detect such sensory stimuli as touch,

sound, light, pain, cold, and warmth. The purpose of

this chapter is to discuss the basic mechanisms by

which these receptors change sensory stimuli into

nerve signals that are then conveyed to and

processed in the central nervous system.

Types of Sensory Receptors and the Sensory

Stimuli They Detect

Table 46-1 lists and classifies most of the body’s sensory receptors. This table

shows that there are five basic types of sensory receptors: (1) mechanorecep-

tors, which detect mechanical compression or stretching of the receptor or of

tissues adjacent to the receptor; (2) thermoreceptors, which detect changes in

temperature, some receptors detecting cold and others warmth; (3) nociceptors

(pain receptors), which detect damage occurring in the tissues, whether physi-

cal damage or chemical damage; (4) electromagnetic receptors, which detect light

on the retina of the eye; and (5) chemoreceptors, which detect taste in the

mouth, smell in the nose, oxygen level in the arterial blood, osmolality of the

body fluids, carbon dioxide concentration, and perhaps other factors that make

up the chemistry of the body.

In this chapter, we discuss the function of a few specific types of receptors,

primarily peripheral mechanoreceptors, to illustrate some of the principles by

which receptors operate. Other receptors are discussed in other chapters in rela-

tion to the sensory systems that they subserve. Figure 46-1 shows some of the

types of mechanoreceptors found in the skin or in deep tissues of the body.

Differential Sensitivity of Receptors

The first question that must be answered is, how do two types of sensory recep-

tors detect different types of sensory stimuli? The answer is, by “differential sen-

sitivities.” That is, each type of receptor is highly sensitive to one type of stimulus

for which it is designed and yet is almost nonresponsive to other types of sensory

stimuli. Thus, the rods and cones of the eyes are highly responsive to light but

are almost completely nonresponsive to normal ranges of heat, cold, pressure

on the eyeballs, or chemical changes in the blood. The osmoreceptors of the

supraoptic nuclei in the hypothalamus detect minute changes in the osmolality

of the body fluids but have never been known to respond to sound. Finally, pain

receptors in the skin are almost never stimulated by usual touch or pressure

stimuli but do become highly active the moment tactile stimuli become severe

enough to damage the tissues.

Modality of Sensation—The “Labeled Line” Principle

Each of the principal types of sensation that we can experience—pain, touch,

sight, sound, and so forth—is called a modality of sensation. Yet despite the

fact that we experience these different modalities of sensation, nerve fibers

572

Chapter 46

Sensory Receptors, Neuronal Circuits for Processing Information

573

Table 46-1

Classification of Sensory Receptors

Mechanoreceptors

Skin tactile sensibilities (epidermis and dermis)

Free nerve endings

Expanded tip endings

Free nerve

Expanded tip

Tactile hair

Merkel’s discs

endings

receptor

Plus several other variants

Spray endings

Ruffini’s endings

Encapsulated endings

Meissner’s corpuscles

Krause’s corpuscles

Hair end-organs

Deep tissue sensibilities

Free nerve endings

Expanded tip endings

Spray endings

Pacinian

Meissner’s

Krause’s

Ruffini’s endings

corpuscle

Encapsulated endings

Pacinian corpuscles

Plus a few other variants

Muscle endings

Muscle spindles

Golgi tendon receptors

Hearing

Sound receptors of cochlea

Equilibrium

Vestibular receptors

Arterial pressure

Ruffini’s

Golgi tendon

Muscle

Baroreceptors of carotid sinuses and aorta

end-organ

apparatus

spindle

II.

Thermoreceptors

Cold

Figure 46-1

Cold receptors

Warmth

Several types of somatic sensory nerve endings.

Warm receptors

III.

Nociceptors

Pain

Free nerve endings

IV.

Electromagnetic receptors

Vision

Rods

Cones

transmit only impulses. Therefore, how is it that

V. Chemoreceptors

different nerve fibers transmit different modalities of

Taste

sensation?

Receptors of taste buds

The answer is that each nerve tract terminates at a

Smell

Receptors of olfactory epithelium

specific point in the central nervous system, and

Arterial oxygen

the type of sensation felt when a nerve fiber is stimu-

Receptors of aortic and carotid bodies

lated is determined by the point in the nervous system

Osmolality

to which the fiber leads. For instance, if a pain fiber

Neurons in or near supraoptic nuclei

Blood CO₂

is stimulated, the person perceives pain regardless

Receptors in or on surface of medulla and in aortic and

of what type of stimulus excites the fiber. The stimulus

carotid bodies

can be electricity, overheating of the fiber, crushing

Blood glucose, amino acids, fatty acids

of the fiber, or stimulation of the pain nerve ending

Receptors in hypothalamus

by damage to the tissue cells. In all these instances,

the person perceives pain. Likewise, if a touch fiber is

stimulated by electrical excitation of a touch receptor

or in any other way, the person perceives touch

Transduction of Sensory

because touch fibers lead to specific touch areas in

Stimuli into Nerve Impulses

the brain. Similarly, fibers from the retina of the eye

terminate in the vision areas of the brain, fibers from

Local Electrical Currents at Nerve

the ear terminate in the auditory areas of the brain,

and temperature fibers terminate in the temperature

Endings—Receptor Potentials

areas.

This specificity of nerve fibers for transmitting only

All sensory receptors have one feature in common.

one modality of sensation is called the labeled line

Whatever the type of stimulus that excites the recep-

principle.

tor, its immediate effect is to change the membrane

574

Unit IX The Nervous System: A. General Principles and Sensory Physiology

electrical potential of the receptor. This change in

receptor potential rises above the threshold level, the

potential is called a receptor potential.

greater becomes the action potential frequency.

Mechanisms of Receptor Potentials. Different receptors

Receptor Potential of the Pacinian Corpuscle—

can be excited in one of several ways to cause recep-

An Example of Receptor Function

tor potentials: (1) by mechanical deformation of the

The student should at this point restudy the anatomi-

receptor, which stretches the receptor membrane and

cal structure of the pacinian corpuscle shown in Figure

opens ion channels; (2) by application of a chemical to

46-1. Note that the corpuscle has a central nerve fiber

the membrane, which also opens ion channels; (3) by

extending through its core. Surrounding this are mul-

change of the temperature of the membrane, which

tiple concentric capsule layers, so that compression

alters the permeability of the membrane; or (4) by the

anywhere on the outside of the corpuscle will elongate,

effects of electromagnetic radiation, such as light on a

indent, or otherwise deform the central fiber.

retinal visual receptor, which either directly or indi-

Now study Figure 46-3, which shows only the

rectly changes the receptor membrane characteristics

central fiber of the pacinian corpuscle after all capsule

and allows ions to flow through membrane channels.

layers but one have been removed. The tip of the

It will be recognized that these four means of exciting

central fiber inside the capsule is unmyelinated, but

receptors correspond in general with the different

the fiber does become myelinated (the blue sheath

types of known sensory receptors. In all instances, the

shown in the figure) shortly before leaving the cor-

basic cause of the change in membrane potential is a

puscle to enter a peripheral sensory nerve.

change in membrane permeability of the receptor,

The figure also shows the mechanism by which a

which allows ions to diffuse more or less readily

receptor potential is produced in the pacinian corpus-

through the membrane and thereby to change the

cle. Observe the small area of the terminal fiber that

transmembrane potential.

has been deformed by compression of the corpuscle,

and note that ion channels have opened in the mem-

Maximum Receptor Potential Amplitude. The maximum

brane, allowing positively charged sodium ions to

amplitude of most sensory receptor potentials is about

diffuse to the interior of the fiber. This creates

100 millivolts, but this level occurs only at an extremely

increased positivity inside the fiber, which is the

high intensity of sensory stimulus. This is about the

“receptor potential.” The receptor potential in turn

same maximum voltage recorded in action potentials

induces a local circuit of current flow, shown by the

and is also the change in voltage when the membrane

arrows, that spreads along the nerve fiber. At the first

becomes maximally permeable to sodium ions.

node of Ranvier, which itself lies inside the capsule of

the pacinian corpuscle, the local current flow depolar-

Relation of the Receptor Potential to Action Potentials. When

izes the fiber membrane at this node, which then sets

the receptor potential rises above the threshold for

off typical action potentials that are transmitted along

eliciting action potentials in the nerve fiber attached

the nerve fiber toward the central nervous system.

to the receptor, then action potentials occur, as illus-

trated in Figure 46-2. Note also that the more the

Relation Between Stimulus Intensity and the Receptor Poten-

tial. Figure 46-4 shows the changing amplitude of the

receptor potential caused by progressively stronger

mechanical compression

(increasing

“stimulus

strength”) applied experimentally to the central core

of a pacinian corpuscle. Note that the amplitude

Action potentials

+30

Action

Receptor potential

potential

Deformed

-30

area

++++++++++

+++++

+ +

-- - -

+ + + +

Receptor potential

+ +

-60

Threshold

+ +

-- - -

+ + + +

++++++

++++++++++

-90

Resting membrane potential

Node of

Ranvier

100

120

140

Milliseconds

Figure 46-3

Figure 46-2

Excitation of a sensory nerve fiber by a receptor potential pro-

duced in a pacinian corpuscle. (Modified from Loëwenstein WR:

Typical relation between receptor potential and action potentials

Excitation and inactivation in a receptor membrane. Ann N Y Acad

when the receptor potential rises above threshold level.

Sci 94:510, 1961.)

Chapter 46

Sensory Receptors, Neuronal Circuits for Processing Information

575

Joint capsule receptors

100

Muscle spindle

250

Hair receptor

Pacinian corpuscle

200

150

100

Seconds

100

Figure 46-5

Stimulus strength

(per cent)

Adaptation of different types of receptors, showing rapid adapta-

tion of some receptors and slow adaptation of others.

Figure 46-4

within a second or so, whereas some joint capsule and

Relation of amplitude of receptor potential to strength of a

muscle spindle receptors adapt slowly.

mechanical stimulus applied to a pacinian corpuscle. (Data from

Furthermore, some sensory receptors adapt to a far

Loëwenstein WR: Excitation and inactivation in a receptor mem-

greater extent than others. For example, the pacinian

brane. Ann N Y Acad Sci 94:510, 1961.)

corpuscles adapt to “extinction” within a few hun-

dredths of a second, and the receptors at the bases of

the hairs adapt to extinction within a second or more.

increases rapidly at first but then progressively less

It is probable that all other mechanoreceptors eventu-

rapidly at high stimulus strength.

ally adapt almost completely, but some require hours

In turn, the frequency of repetitive action potentials

or days to do so, for which reason they are called “non-

transmitted from sensory receptors increases approx-

adapting” receptors. The longest measured time for

imately in proportion to the increase in receptor

complete adaptation of a mechanoreceptor is about

potential. Putting this principle together with the data

2 days, which is the adaptation time for many caro-

in Figure 46-4, one can see that very intense stimula-

tid and aortic baroreceptors. Conversely, some of

tion of the receptor causes progressively less and less

the nonmechanoreceptors—the chemoreceptors and

additional increase in numbers of action potentials.

pain receptors, for instance—probably never adapt

This is an exceedingly important principle that is appli-

completely.

cable to almost all sensory receptors. It allows the

receptor to be sensitive to very weak sensory experi-

Mechanisms by Which Receptors Adapt. The mechanism of

ence and yet not reach a maximum firing rate until the

receptor adaptation is different for each type of recep-

sensory experience is extreme. This allows the recep-

tor, in much the same way that development of a

tor to have an extreme range of response, from very

receptor potential is an individual property. For

weak to very intense.

instance, in the eye, the rods and cones adapt by chang-

ing the concentrations of their light-sensitive chemi-

cals (which is discussed in Chapter 50).

Adaptation of Receptors

In the case of the mechanoreceptors, the receptor

that has been studied in greatest detail is the pacinian

Another characteristic of all sensory receptors is that

corpuscle. Adaptation occurs in this receptor in two

they adapt either partially or completely to any con-

ways. First, the pacinian corpuscle is a viscoelastic

stant stimulus after a period of time. That is, when a

structure so that when a distorting force is suddenly

continuous sensory stimulus is applied, the receptor

applied to one side of the corpuscle, this force is

responds at a high impulse rate at first and then at a

instantly transmitted by the viscous component of the

progressively slower rate until finally the rate of action

corpuscle directly to the same side of the central nerve

potentials decreases to very few or often to none at all.

fiber, thus eliciting a receptor potential. However,

Figure

46-5 shows typical adaptation of certain

within a few hundredths of a second, the fluid within

types of receptors. Note that the pacinian corpuscle

the corpuscle redistributes, so that the receptor poten-

adapts extremely rapidly and hair receptors adapt

tial is no longer elicited. Thus, the receptor potential

576

Unit IX The Nervous System: A. General Principles and Sensory Physiology

appears at the onset of compression but disappears

status is taking place, one can predict in one’s mind the

within a small fraction of a second even though the

state of the body a few seconds or even a few minutes

compression continues.

later. For instance, the receptors of the semicircular

The second mechanism of adaptation of the pacin-

canals in the vestibular apparatus of the ear detect the

ian corpuscle, but a much slower one, results from a

rate at which the head begins to turn when one runs

process called accommodation, which occurs in the

around a curve. Using this information, a person can

nerve fiber itself. That is, even if by chance the central

predict how much he or she will turn within the next

core fiber should continue to be distorted, the tip of

2 seconds and can adjust the motion of the legs ahead

the nerve fiber itself gradually becomes “accommo-

of time to keep from losing balance. Likewise, recep-

dated” to the stimulus. This probably results from

tors located in or near the joints help detect the rates

progressive “inactivation” of the sodium channels in

of movement of the different parts of the body. For

the nerve fiber membrane, which means that sodium

instance, when one is running, information from the

current flow through the channels causes them gradu-

joint rate receptors allows the nervous system to

ally to close, an effect that seems to occur for all

predict where the feet will be during any precise frac-

or most cell membrane sodium channels, as was

tion of the next second. Therefore, appropriate motor

explained in Chapter 5.

signals can be transmitted to the muscles of the legs to

Presumably, these same two general mechanisms of

make any necessary anticipatory corrections in posi-

adaptation apply also to the other types of mechano-

tion so that the person will not fall. Loss of this pre-

receptors. That is, part of the adaptation results from

dictive function makes it impossible for the person to

readjustments in the structure of the receptor itself,

run.

and part from an electrical type of accommodation in

the terminal nerve fibril.

Nerve Fibers That Transmit

Slowly Adapting Receptors Detect Continuous Stimulus

Different Types of Signals,

Strength—The “Tonic” Receptors. Slowly adapting recep-

and Their Physiologic

tors continue to transmit impulses to the brain as long

Classification

as the stimulus is present (or at least for many minutes

or hours). Therefore, they keep the brain constantly

Some signals need to be transmitted to or from the

apprised of the status of the body and its relation to

central nervous system extremely rapidly; otherwise,

its surroundings. For instance, impulses from the

the information would be useless. An example of this is

the sensory signals that apprise the brain of the momen-

muscle spindles and Golgi tendon apparatuses allow

tary positions of the legs at each fraction of a second

the nervous system to know the status of muscle con-

during running. At the other extreme, some types of

traction and load on the muscle tendon at each instant.

sensory information, such as that depicting prolonged,

Other slowly adapting receptors include (1) recep-

aching pain, do not need to be transmitted rapidly, so

tors of the macula in the vestibular apparatus, (2) pain

that slowly conducting fibers will suffice. As shown in

receptors, (3) baroreceptors of the arterial tree, and (4)

Figure 46-6, nerve fibers come in all sizes between 0.5

chemoreceptors of the carotid and aortic bodies.

and 20 micrometers in diameter—the larger the diame-

Because the slowly adapting receptors can continue

ter, the greater the conducting velocity. The range of

to transmit information for many hours, they are called

conducting velocities is between 0.5 and 120 m/sec.

tonic receptors.

General Classification of Nerve Fibers. Shown in Figure 46-6

Rapidly Adapting Receptors Detect Change in Stimulus

is a “general classification” and a “sensory nerve classi-

fication” of the different types of nerve fibers. In the

Strength—The

“Rate Receptors,”

“Movement Receptors,”

general classification, the fibers are divided into types A

“Phasic Receptors.” Receptors that adapt rapidly

and C, and the type A fibers are further subdivided into

cannot be used to transmit a continuous signal because

a, b, g, and d fibers.

these receptors are stimulated only when the stimulus

Type A fibers are the typical large and medium-sized

strength changes. Yet they react strongly while a

myelinated fibers of spinal nerves. Type C fibers are the

change is actually taking place. Therefore, these recep-

small unmyelinated nerve fibers that conduct impulses

tors are called rate receptors, movement receptors, or

at low velocities. The C fibers constitute more than one

phasic receptors. Thus, in the case of the pacinian cor-

half of the sensory fibers in most peripheral nerves as

puscle, sudden pressure applied to the tissue excites

well as all the postganglionic autonomic fibers.

this receptor for a few milliseconds, and then its exci-

The sizes, velocities of conduction, and functions of

the different nerve fiber types are also given in Figure

tation is over even though the pressure continues. But

46-6. Note that a few large myelinated fibers can trans-

later, it transmits a signal again when the pressure is

mit impulses at velocities as great as

120 m/sec, a

released. In other words, the pacinian corpuscle is

distance in 1 second that is longer than a football field.

exceedingly important in apprising the nervous system

Conversely, the smallest fibers transmit impulses as

of rapid tissue deformations, but it is useless for trans-

slowly as 0.5 m/sec, requiring about 2 seconds to go from

mitting information about constant conditions in the

the big toe to the spinal cord.

body.

Alternative Classification Used by Sensory Physiologists.

Importance of the Rate Receptors—Their Predictive Function.

Certain recording techniques have made it possible to

If one knows the rate at which some change in bodily

separate the type Aa fibers into two subgroups; yet

Chapter 46

Sensory Receptors, Neuronal Circuits for Processing Information

577

Myelinated

Unmyelinated

Diameter (micrometers)

2.0

0.5

Conduction velocity (m/sec.)

120

6 2.0

0.5

General classification

Sensory nerve classification

III

Sensory functions

Muscle spindle

(primary ending)

(secondary ending)

Muscle tendon

(Golgi tendon organ)

Hair receptors

Vibration

(pacinian corpuscle)

High discrimination touch

Crude touch

(Meissner's expanded tips)

and pressure

Deep pressure

Tickle

and touch

Pricking pain

Aching pain

Cold

Warmth

Motor function

Skeletal muscle

Muscle spindle

Sympathetic

(type Aa)

(type Ag)

(type C)

1 2.0

0.5

Figure 46-6

Nerve fiber diameter (micrometers)

Physiologic classifications and functions of nerve

fibers.

these same recording techniques cannot

distinguish

Group III

easily between Ab and Ag fibers. Therefore, the fol-

Fibers carrying temperature, crude touch, and pricking

lowing classification is frequently used by sensory

pain sensations (average about 3 micrometers in diame-

physiologists:

ter; they are d-type A fibers in the general classification).

Group IV

Group Ia

Unmyelinated fibers carrying pain, itch, temperature,

Fibers from the annulospiral endings of muscle spindles

and crude touch sensations (0.5 to 2 micrometers in

(average about 17 microns in diameter; these are a-type

diameter; they are type C fibers in the general classifi-

A fibers in the general classification).

cation).

Group Ib

Fibers from the Golgi tendon organs (average about 16

Transmission of Signals

micrometers in diameter; these also are a-type A

of Different Intensity in

fibers).

Nerve Tracts—Spatial and

Temporal Summation

Group II

Fibers from most discrete cutaneous tactile receptors

and from the flower-spray endings of the muscle spin-

One of the characteristics of each signal that always

dles (average about 8 micrometers in diameter; these

must be conveyed is signal intensity—for instance, the

are b- and g-type A fibers in the general classification).

intensity of pain. The different gradations of intensity

578

Unit IX The Nervous System: A. General Principles and Sensory Physiology

can be transmitted either by using increasing numbers

stimulus, with only a single nerve fiber in the middle

of parallel fibers or by sending more action potentials

of the bundle stimulated strongly (represented by the

along a single fiber. These two mechanisms are called,

red-colored fiber), whereas several adjacent fibers are

respectively, spatial summation and temporal

stimulated weakly (half-red fibers). The other two

summation.

views of the nerve cross section show the effect of a

moderate stimulus and a strong stimulus, with pro-

Spatial Summation. Figure 46-7 shows the phenomenon

gressively more fibers being stimulated. Thus, the

of spatial summation, whereby increasing signal

stronger signals spread to more and more fibers. This

strength is transmitted by using progressively greater

is the phenomenon of spatial summation.

numbers of fibers. This figure shows a section of skin

innervated by a large number of parallel pain fibers.

Temporal Summation. A second means for transmitting

Each of these arborizes into hundreds of minute free

signals of increasing strength is by increasing the fre-

nerve endings that serve as pain receptors. The entire

quency of nerve impulses in each fiber, which is called

cluster of fibers from one pain fiber frequently covers

temporal summation. Figure 46-8 demonstrates this,

an area of skin as large as 5 centimeters in diameter.

showing in the upper part a changing strength of signal

This area is called the receptor field of that fiber. The

and in the lower part the actual impulses transmitted

number of endings is large in the center of the field but

by the nerve fiber.

diminishes toward the periphery. One can also see

from the figure that the arborizing fibrils overlap those

from other pain fibers. Therefore, a pinprick of the skin

Transmission and Processing

usually stimulates endings from many different pain

of Signals in Neuronal Pools

fibers simultaneously. When the pinprick is in the

center of the receptive field of a particular pain fiber,

The central nervous system is composed of thousands

the degree of stimulation of that fiber is far greater

to millions of neuronal pools; some of these contain

than when it is in the periphery of the field, because

few neurons, while others have vast numbers. For

the number of free nerve endings in the middle of the

instance, the entire cerebral cortex could be consid-

field is much greater than at the periphery.

ered to be a single large neuronal pool. Other neuronal

Thus, the lower part of Figure 46-7 shows three

pools include the different basal ganglia and the

views of the cross section of the nerve bundle leading

specific nuclei in the thalamus, cerebellum, mesen-

from the skin area. To the left is the effect of a weak

cephalon, pons, and medulla. Also, the entire dorsal

gray matter of the spinal cord could be considered one

long pool of neurons.

Each neuronal pool has its own special organization

that causes it to process signals in its own unique way,

Nerve

Skin

Time

Weak

Moderate

Strong

stimulus

Figure 46-8

Figure 46-7

Translation of signal strength into a frequency-modulated series

of nerve impulses, showing the strength of signal (above) and the

Pattern of stimulation of pain fibers in a nerve leading from an area

separate nerve impulses (below). This is an example of temporal

of skin pricked by a pin. This is an example of spatial summation.

summation.

Chapter 46

Sensory Receptors, Neuronal Circuits for Processing Information

579

thus allowing the total consortium of pools to achieve

excitatory presynaptic terminal almost never causes an

the multitude of functions of the nervous system. Yet

action potential in a postsynaptic neuron. Instead,

despite their differences in function, the pools also

large numbers of input terminals must discharge on

have many similar principles of function, described in

the same neuron either simultaneously or in rapid suc-

the following pages.

cession to cause excitation. For instance, in Figure

46-9, let us assume that six terminals must discharge

almost simultaneously to excite any one of the

Relaying of Signals Through

neurons. If the student counts the number of terminals

Neuronal Pools

on each one of the neurons from each input fiber, he

or she will see that input fiber 1 has more than enough

Organization of Neurons for Relaying Signals. Figure 46-9 is

terminals to cause neuron a to discharge. The stimulus

a schematic diagram of several neurons in a neuronal

from input fiber 1 to this neuron is said to be an

pool, showing “input” fibers to the left and “output”

excitatory stimulus; it is also called a suprathreshold

fibers to the right. Each input fiber divides hundreds

stimulus because it is above the threshold required for

to thousands of times, providing a thousand or more

excitation.

terminal fibrils that spread into a large area in the pool

Input fiber 1 also contributes terminals to neurons

to synapse with dendrites or cell bodies of the neurons

b and c, but not enough to cause excitation. Never-

in the pool. The dendrites usually also arborize and

theless, discharge of these terminals makes both these

spread hundreds to thousands of micrometers in the

neurons more likely to be excited by signals arriving

pool.

through other incoming nerve fibers. Therefore, the

The neuronal area stimulated by each incoming

stimuli to these neurons are said to be subthreshold,

nerve fiber is called its stimulatory field. Note in Figure

and the neurons are said to be facilitated.

46-9 that large numbers of the terminals from each

Similarly, for input fiber 2, the stimulus to neuron d

input fiber lie on the nearest neuron in its “field,” but

is a suprathreshold stimulus, and the stimuli to neurons

progressively fewer terminals lie on the neurons

b and c are subthreshold, but facilitating, stimuli.

farther away.

Figure 46-9 represents a highly condensed version

of a neuronal pool because each input nerve fiber

Threshold and Subthreshold Stimuli—Excitation or Facilitation.

usually provides massive numbers of branching termi-

From the discussion of synaptic function in Chapter

nals to hundreds or thousands of neurons in its distri-

45,

will

recalled

that

discharge

single

bution “field,” as shown in Figure 46-10. In the central

portion of the field in this figure, designated by the

circled area, all the neurons are stimulated by the

incoming fiber. Therefore, this is said to be the dis-

charge zone of the incoming fiber, also called the

excited zone or liminal zone. To each side, the neurons

are facilitated but not excited, and these areas are

called the facilitated zone, also called the subthreshold

zone or subliminal zone.

Inhibition of a Neuronal Pool. We must also remember

that some incoming fibers inhibit neurons, rather than

exciting them. This is the opposite of facilitation, and

the entire field of the inhibitory branches is called the

inhibitory zone. The degree of inhibition in the center

of this zone is great because of large numbers of

endings in the center; it becomes progressively less

toward its edges.

Facilitated zone

Input nerve

Discharge zone

fiber

Facilitated zone

Figure 46-9

Figure 46-10

Basic organization of a neuronal pool.

“Discharge” and “facilitated” zones of a neuronal pool.

580

Unit IX The Nervous System: A. General Principles and Sensory Physiology

Source

Convergence from

single source

multiple sources

Divergence in same tract

Divergence in multiple tracts

Figure 46-12

Figure 46-11

“Convergence” of multiple input fibers onto a single neuron.

A, Multiple input fibers from a single source. B, Input fibers from

“Divergence” in neuronal pathways. A, Divergence within a

multiple separate sources.

pathway to cause “amplification” of the signal. B, Divergence into

multiple tracts to transmit the signal to separate areas.

Convergence can also result from input signals (exci-

Divergence of Signals Passing Through

tatory or inhibitory) from multiple sources, as shown

Neuronal Pools

in Figure 46-12B. For instance, the interneurons of the

Often it is important for weak signals entering a neu-

spinal cord receive converging signals from (1) periph-

ronal pool to excite far greater numbers of nerve fibers

eral nerve fibers entering the cord, (2) propriospinal

leaving the pool. This phenomenon is called diver-

fibers passing from one segment of the cord to

gence. Two major types of divergence occur and have

another, (3) corticospinal fibers from the cerebral

entirely different purposes.

cortex, and (4) several other long pathways descend-

An amplifying type of divergence is shown in Figure

ing from the brain into the spinal cord. Then the signals

46-11A. This means simply that an input signal spreads

from the interneurons converge on the anterior motor

to an increasing number of neurons as it passes

neurons to control muscle function.

through successive orders of neurons in its path. This

Such convergence allows summation of information

type of divergence is characteristic of the corticospinal

from different sources, and the resulting response is a

pathway in its control of skeletal muscles, with a single

summated effect of all the different types of informa-

large pyramidal cell in the motor cortex capable, under

tion. Convergence is one of the important means by

highly facilitated conditions, of exciting as many as

which the central nervous system correlates, sum-

10,000 muscle fibers.

mates, and sorts different types of information.

The second type of divergence, shown in Figure

46-11B, is divergence into multiple tracts. In this case,

Neuronal Circuit with Both Excitatory and

the signal is transmitted in two directions from the

Inhibitory Output Signals

pool. For instance, information transmitted up the

Sometimes an incoming signal to a neuronal pool

dorsal columns of the spinal cord takes two courses in

causes an output excitatory signal going in one direc-

the lower part of the brain: (1) into the cerebellum and

tion and at the same time an inhibitory signal going

(2) on through the lower regions of the brain to the

elsewhere. For instance, at the same time that an exci-

thalamus and cerebral cortex. Likewise, in the thala-

tatory signal is transmitted by one set of neurons in the

mus, almost all sensory information is relayed both

spinal cord to cause forward movement of a leg, an

into still deeper structures of the thalamus and at the

inhibitory signal is transmitted through a separate set

same time to discrete regions of the cerebral cortex.

of neurons to inhibit the muscles on the back of the

leg so that they will not oppose the forward move-

Convergence of Signals

ment. This type of circuit is characteristic for control-

Convergence means signals from multiple inputs

ling all antagonistic pairs of muscles, and it is called the

uniting to excite a single neuron. Figure 46-12A shows

reciprocal inhibition circuit.

convergence from a single source. That is, multiple ter-

Figure 46-13 shows the means by which the inhibi-

minals from a single incoming fiber tract terminate on

tion is achieved. The input fiber directly excites the

the same neuron. The importance of this is that

excitatory output pathway, but it stimulates an inter-

neurons are almost never excited by an action poten-

mediate inhibitory neuron (neuron 2), which secretes

tial from a single input terminal. But action potentials

a different type of transmitter substance to inhibit the

converging on the neuron from multiple terminals

second output pathway from the pool. This type of

provide enough spatial summation to bring the neuron

circuit is also important in preventing overactivity in

to the threshold required for discharge.

many parts of the brain.

Chapter 46

Sensory Receptors, Neuronal Circuits for Processing Information

581

Excitatory synapse

Input

Output

Input fiber

Excitation

Inhibition

Input

Output

Inhibitory synapse

Figure 46-13

Facilitation

Inhibitory circuit. Neuron 2 is an inhibitory neuron.

Input

Output

Prolongation of a Signal by a

Neuronal Pool—“Afterdischarge”

Thus far, we have considered signals that are merely

relayed through neuronal pools. However, in many

instances, a signal entering a pool causes a prolonged

output discharge, called afterdischarge, lasting a

few milliseconds to as long as many minutes after

the incoming signal is over. The most important

Inhibition

mechanisms by which afterdischarge occurs are the

following.

Input

Output

Synaptic Afterdischarge. When excitatory synapses dis-

charge on the surfaces of dendrites or soma of a

neuron, a postsynaptic electrical potential develops in

the neuron and lasts for many milliseconds, especially

when some of the long-acting synaptic transmitter sub-

stances are involved. As long as this potential lasts, it

can continue to excite the neuron, causing it to trans-

mit a continuous train of output impulses, as was

explained in Chapter 45. Thus, as a result of this synap-

tic “afterdischarge” mechanism alone, it is possible for

Figure 46-14

a single instantaneous input signal to cause a sustained

signal output (a series of repetitive discharges) lasting

Reverberatory circuits of increasing complexity.

for many milliseconds.

Reverberatory (Oscillatory) Circuit as a Cause of Signal Prolon-

intensity and frequency of reverberation, whereas an

gation. One of the most important of all circuits in the

inhibitory signal depresses or stops the reverberation.

entire nervous system is the reverberatory, or oscilla-

Figure 46-14D shows that most reverberating path-

tory, circuit. Such circuits are caused by positive feed-

ways are constituted of many parallel fibers. At each

back within the neuronal circuit that feeds back to

cell station, the terminal fibrils spread widely. In such

re-excite the input of the same circuit. Consequently,

a system, the total reverberating signal can be either

once stimulated, the circuit may discharge repetitively

weak or strong, depending on how many parallel nerve

for a long time.

fibers are momentarily involved in the reverberation.

Several possible varieties of reverberatory circuits

are shown in Figure 46-14. The simplest, shown in

Characteristics of Signal Prolongation from a Rever-

Figure 46-14A, involves only a single neuron. In this

beratory Circuit. Figure 46-15 shows output signals

case, the output neuron simply sends a collateral nerve

from a typical reverberatory circuit. The input stimu-

fiber back to its own dendrites or soma to restimulate

lus may last only 1 millisecond or so, and yet the output

itself. Although this type of circuit probably is not an

can last for many milliseconds or even minutes. The

important one, theoretically, once the neuron dis-

figure demonstrates that the intensity of the output

charges, the feedback stimuli could keep the neuron

signal usually increases to a high value early in rever-

discharging for a protracted time thereafter.

beration and then decreases to a critical point, at which

Figure 46-14B shows a few additional neurons in the

it suddenly ceases entirely. The cause of this sudden

feedback circuit, which causes a longer delay between

cessation of reverberation is fatigue of synaptic junc-

initial discharge and the feedback signal. Figure

tions in the circuit. Fatigue beyond a certain critical

46-14C shows a still more complex system in which

level lowers the stimulation of the next neuron in the

both facilitatory and inhibitory fibers impinge on the

circuit below threshold level so that the circuit feed-

reverberating circuit. A facilitatory signal enhances the

back is suddenly broken.

582

Unit IX The Nervous System: A. General Principles and Sensory Physiology

Inhibited

Output

Normal

Excitation

Facilitated

Inhibition

Time

Figure 46-15

Figure 46-16

Typical pattern of the output signal from a reverberatory circuit

after a single input stimulus, showing the effects of facilitation and

Continuous output from either a reverberating circuit or a pool of

inhibition.

intrinsically discharging neurons. This figure also shows the effect

of excitatory or inhibitory input signals.

The duration of the total signal before cessation can

also be controlled by signals from other parts of the

brain that inhibit or facilitate the circuit. Almost these

of reverberation. Note that an excitatory input signal

exact patterns of output signals are recorded from the

greatly increases the output signal, whereas an

motor nerves exciting a muscle involved in a flexor

inhibitory input signal greatly decreases the output.

reflex after pain stimulation of the foot (as shown later

Those students who are familiar with radio trans-

in Figure 46-18).

mitters will recognize this to be a carrier wave type of

information transmission. That is, the excitatory and

Continuous Signal Output from Some

inhibitory control signals are not the cause of the

Neuronal Circuits

output signal, but they do control its changing level of

Some neuronal circuits emit output signals continu-

intensity. Note that this carrier wave system allows a

ously, even without excitatory input signals. At least

decrease in signal intensity as well as an increase,

two mechanisms can cause this effect: (1) continuous

whereas up to this point, the types of information

intrinsic neuronal discharge and (2) continuous rever-

transmission we have discussed have been mainly pos-

beratory signals.

itive information rather than negative information.

This type of information transmission is used by the

Continuous Discharge Caused by Intrinsic Neuronal Excitabil-

autonomic nervous system to control such functions as

ity. Neurons, like other excitable tissues, discharge

vascular tone, gut tone, degree of constriction of the

repetitively if their level of excitatory membrane

iris in the eye, and heart rate. That is, the nerve exci-

potential rises above a certain threshold level. The

tatory signal to each of these can be either increased

membrane potentials of many neurons even normally

or decreased by accessory input signals into the rever-

are high enough to cause them to emit impulses con-

berating neuronal pathway.

tinually. This occurs especially in many of the neurons

of the cerebellum, as well as in most of the interneu-

Rhythmical Signal Output

rons of the spinal cord. The rates at which these cells

Many neuronal circuits emit rhythmical output

emit impulses can be increased by excitatory signals or

signals—for instance, a rhythmical respiratory signal

decreased by inhibitory signals; inhibitory signals often

originates in the respiratory centers of the medulla and

can decrease the rate of firing to zero.

pons. This respiratory rhythmical signal continues

throughout life. Other rhythmical signals, such as those

Continuous Signals Emitted from Reverberating Circuits as

that cause scratching movements by the hind leg of a

a Means for Transmitting Information. A reverberating

dog or the walking movements of any animal, require

circuit that does not fatigue enough to stop reverber-

input stimuli into the respective circuits to initiate the

ation is a source of continuous impulses. And excita-

rhythmical signals.

tory impulses entering the reverberating pool can

All or almost all rhythmical signals that have been

increase the output signal, whereas inhibition can

studied experimentally have been found to result from

decrease or even extinguish the signal.

reverberating circuits or a succession of sequential

Figure 46-16 shows a continuous output signal from

reverberating circuits that feed excitatory or inhibitory

a pool of neurons. The pool may be emitting impulses

signals in a circular pathway from one neuronal pool

because of intrinsic neuronal excitability or as a result

to the next.

Chapter 46

Sensory Receptors, Neuronal Circuits for Processing Information

583

Flexor reflexes-decremental responses

Stimulus

Seconds

Increasing carotid

body stimulation

Figure 46-18

Figure 46-17

Successive flexor reflexes showing fatigue of conduction through

the reflex pathway.

The rhythmical output of summated nerve impulses from the

respiratory center, showing that progressively increasing stimula-

tion of the carotid body increases both the intensity and the fre-

quency of the phrenic nerve signal to the diaphragm to increase

Inhibitory Circuits as a Mechanism for

respiration.

Stabilizing Nervous System Function

Two types of inhibitory circuits in widespread areas

of the brain help prevent excessive spread of signals:

Excitatory or inhibitory signals can also increase

(1) inhibitory feedback circuits that return from the

or decrease the amplitude of the rhythmical signal

termini of pathways back to the initial excitatory

output. Figure 46-17, for instance, shows changes in

neurons of the same pathways—these circuits occur in

the respiratory signal output in the phrenic nerve.

virtually all sensory nervous pathways and inhibit

When the carotid body is stimulated by arterial oxygen

either the input neurons or the intermediate neurons

deficiency, both the frequency and the amplitude of

in the sensory pathway when the termini become

the respiratory rhythmical output signal increase

overly excited; and (2) some neuronal pools that exert

progressively.

gross inhibitory control over widespread areas of the

brain—for instance, many of the basal ganglia exert

inhibitory influences throughout the muscle control

Instability and Stability

system.

of Neuronal Circuits

Almost every part of the brain connects either directly

Synaptic Fatigue as a Means for

or indirectly with every other part, and this creates a

Stabilizing the Nervous System

serious problem. If the first part excites the second, the

second the third, the third the fourth, and so on until

Synaptic fatigue means simply that synaptic transmis-

finally the signal re-excites the first part, it is clear that

sion becomes progressively weaker the more pro-

an excitatory signal entering any part of the brain

longed and more intense the period of excitation.

would set off a continuous cycle of re-excitation of all

Figure 46-18 shows three successive records of a flexor

parts. If this should occur, the brain would be inun-

reflex elicited in an animal caused by inflicting pain in

dated by a mass of uncontrolled reverberating

the footpad of the paw. Note in each record that the

signals—signals that would be transmitting no infor-

strength of contraction progressively “decrements”—

mation but, nevertheless, would be consuming the cir-

that is, its strength diminishes; much of this effect is

cuits of the brain so that none of the informational

caused by fatigue of synapses in the flexor reflex

signals could be transmitted. Such an effect occurs in

circuit. Furthermore, the shorter the interval between

widespread areas of the brain during epileptic seizures.

successive flexor reflexes, the less the intensity of the

How does the central nervous system prevent this

subsequent reflex response.

from happening all the time? The answer lies mainly

in two basic mechanisms that function throughout the

Automatic Short-Term Adjustment of Pathway Sensitivity by the

central nervous system: (1) inhibitory circuits and (2)

Fatigue Mechanism. Now let us apply this phenomenon

fatigue of synapses.

of fatigue to other pathways in the brain. Those that

584

Unit IX The Nervous System: A. General Principles and Sensory Physiology

are overused usually become fatigued, so that their

Baev KV: Biological Neural Networks. Boston: Birkhauser,

sensitivities decrease. Conversely, those that are

1998.

underused become rested, and their sensitivities

Basar E: Brain Function and Oscillations. Berlin: Springer,

1998.

increase. Thus, fatigue and recovery from fatigue con-

Fain GL, Matthews HR, Cornwall MC, Koutalos Y: Adapta-

stitute an important short-term means of moderating

tion in vertebrate photoreceptors. Physiol Rev 81:117,

the sensitivities of the different nervous system cir-

2001.

cuits. These help to keep the circuits operating in a

Gandevia SC: Spinal and supraspinal factors in human

range of sensitivity that allows effective function.

muscle fatigue. Physiol Rev 81:1725, 2001.

Gebhart GF: Descending modulation of pain. Neurosci

Long-Term Changes in Synaptic Sensitivity Caused by Automatic

Biobehav Rev 27:729, 2004.

Downregulation or Upregulation of Synaptic Receptors. The

Hamill OP, Martinac B: Molecular basis of mechanotrans-

long-term sensitivities of synapses can be changed

duction in living cells. Physiol Rev 81:685, 2001.

tremendously by upregulating the number of receptor

Ivry RB, Robertson LC: The Two Sides of Perception. Cam-

bridge, MA: MIT Press, 1998.

proteins at the synaptic sites when there is underac-

Kandel ER, Schwartz JH, Jessell TM: Principles of Neural

tivity, and downregulating the receptors when there is

Science, 4th ed. New York: McGraw-Hill, 2000.

overactivity. The mechanism for this is the following:

Krupa B, Liu G: Does the fusion pore contribute to synap-

Receptor proteins are being formed constantly by the

tic plasticity? Trends Neurosci 27:62, 2004.

endoplasmic reticular-Golgi apparatus system and are

McLachlan EM: Transmission of signals through sympa-

constantly being inserted into the receptor neuron

thetic ganglia—modulation, integration or simply distri-

synaptic membrane. However, when the synapses are

bution? Acta Physiol Scand 177:227, 2003.

overused so that excesses of transmitter substance

Mombaerts P: Genes and ligands for odorant, vomeronasal

combine with the receptor proteins, many of these

and taste receptors. Nat Rev Neurosci 5:263, 2004.

receptors are inactivated and removed from the synap-

Palmer MJ, von Gersdorff H: Phasic transmitter release from

tonic neurons. Neuron 35:600, 2002.

tic membrane.

Pearson KG: Neural adaptation in the generation of rhyth-

It is indeed fortunate that upregulation and down-

mic behavior. Annu Rev Physiol 62:723, 2000.

regulation of receptors, as well as other control mech-

Renteria RC, Johnson J, Copenhagen DR: Need rods? Get

anisms for adjusting synaptic sensitivity, continually

glycine receptors and taurine. Neuron 41:839, 2004.

adjust the sensitivity in each circuit to almost the exact

Richerson GB, Wu Y: Dynamic equilibrium of neurotrans-

level required for proper function. Think for a moment

mitter transporters: not just for reuptake anymore. J

how serious it would be if the sensitivities of only a few

Neurophysiol 90:1363, 2003.

of these circuits were abnormally high; one might then

Schwartz EA: Transport-mediated synapses in the retina.

expect almost continual muscle cramps, seizures, psy-

Physiol Rev 82:875, 2002.

chotic disturbances, hallucinations, mental tension,

Shen K: Molecular mechanisms of target specificity during

synapse formation. Curr Opin Neurobiol 14:83, 2004.

or other nervous disorders. But fortunately, the auto-

Williams JT, Christie MJ, Manzoni O: Cellular and synaptic

matic controls normally readjust the sensitivities of the

adaptations mediating opioid dependence. Physiol Rev

circuits back to controllable ranges of reactivity any

81:299, 2001.

time the circuits begin to be too active or too

depressed.

References

Buzsaki G: Large-scale recording of neuronal ensembles.

Nat Neurosci 7:446, 2004.

C H A P T E R

Somatic Sensations: I. General

Organization, the Tactile and

Position Senses

The somatic senses are the nervous mechanisms that

collect sensory information from all over the body.

These senses are in contradistinction to the special

senses, which mean specifically vision, hearing,

smell, taste, and equilibrium.

CLASSIFICATION OF SOMATIC SENSES

The somatic senses can be classified into three physiologic types: (1) the

mechanoreceptive somatic senses, which include both tactile and position sensa-

tions that are stimulated by mechanical displacement of some tissue of the body;

(2) the thermoreceptive senses, which detect heat and cold; and (3) the pain

sense, which is activated by any factor that damages the tissues.

This chapter deals with the mechanoreceptive tactile and position senses.

Chapter 48 discusses the thermoreceptive and pain senses. The tactile senses

include touch, pressure, vibration, and tickle senses, and the position senses

include static position and rate of movement senses.

Other Classifications of Somatic Sensations. Somatic sensations are also often

grouped together in other classes, as follows.

Exteroreceptive sensations are those from the surface of the body. Proprio-

ceptive sensations are those having to do with the physical state of the body,

including position sensations, tendon and muscle sensations, pressure sensations

from the bottom of the feet, and even the sensation of equilibrium (which is

often considered a “special” sensation rather than a somatic sensation).

Visceral sensations are those from the viscera of the body; in using this term,

one usually refers specifically to sensations from the internal organs.

Deep sensations are those that come from deep tissues, such as from fasciae,

muscles, and bone. These include mainly “deep” pressure, pain, and vibration.

Detection and Transmission of

Tactile Sensations

Interrelations Among the Tactile Sensations of Touch, Pressure, and Vibration. Although

touch, pressure, and vibration are frequently classified as separate sensations,

they are all detected by the same types of receptors. There are three

principal differences among them: (1) touch sensation generally results from

stimulation of tactile receptors in the skin or in tissues immediately beneath the

skin; (2) pressure sensation generally results from deformation of deeper

tissues; and

(3) vibration sensation results from rapidly repetitive sensory

signals, but some of the same types of receptors as those for touch and pressure

are used.

Tactile Receptors. There are at least six entirely different types of tactile recep-

tors, but many more similar to these also exist. Some were shown in Figure 46-1

of the previous chapter; their special characteristics are the following.

585

586

Unit IX The Nervous System: A. General Principles and Sensory Physiology

First, some free nerve endings, which are found

causes the epithelium at this point to protrude

everywhere in the skin and in many other tissues, can

outward, thus creating a dome and constituting an

detect touch and pressure. For instance, even light

extremely sensitive receptor. Also note that the entire

contact with the cornea of the eye, which contains no

group of Merkel’s discs is innervated by a single large

other type of nerve ending besides free nerve endings,

myelinated nerve fiber (type Ab). These receptors,

can nevertheless elicit touch and pressure sensations.

along with the Meissner’s corpuscles discussed earlier,

Second, a touch receptor with great sensitivity is the

play extremely important roles in localizing touch

Meissner’s corpuscle (illustrated in Figure 46-1), an

sensations to specific surface areas of the body and in

elongated encapsulated nerve ending of a large (type

determining the texture of what is felt.

Ab) myelinated sensory nerve fiber. Inside the capsu-

Fourth, slight movement of any hair on the body

lation are many branching terminal nerve filaments.

stimulates a nerve fiber entwining its base. Thus, each

These corpuscles are present in the nonhairy parts of

hair and its basal nerve fiber, called the hair end-organ,

the skin and are particularly abundant in the finger-

are also a touch receptor. This receptor adapts readily

tips, lips, and other areas of the skin where one’s ability

and, like Meissner’s corpuscles, detects mainly

(a)

to discern spatial locations of touch sensations is

movement of objects on the surface of the body or (b)

highly developed. Meissner’s corpuscles adapt in a

initial contact with the body.

fraction of a second after they are stimulated, which

Fifth, located in the deeper layers of the skin and

means that they are particularly sensitive to movement

also in still deeper internal tissues are many Ruffini’s

of objects over the surface of the skin as well as to low-

end-organs, which are multibranched, encapsulated

frequency vibration.

endings, as shown in Figure 46-1. These endings adapt

Third, the fingertips and other areas that contain

very slowly and, therefore, are important for signaling

large numbers of Meissner’s corpuscles usually also

continuous states of deformation of the tissues, such as

contain large numbers of expanded tip tactile receptors,

heavy prolonged touch and pressure signals. They are

one type of which is Merkel’s discs, shown in Figure

also found in joint capsules and help to signal the

47-1. The hairy parts of the skin also contain moder-

degree of joint rotation.

ate numbers of expanded tip receptors, even though

Sixth, pacinian corpuscles, which were discussed in

they have almost no Meissner’s corpuscles. These

detail in Chapter 46, lie both immediately beneath the

receptors differ from Meissner’s corpuscles in that

skin and deep in the fascial tissues of the body. They

they transmit an initially strong but partially adapting

are stimulated only by rapid local compression of the

signal and then a continuing weaker signal that adapts

tissues because they adapt in a few hundredths of a

only slowly. Therefore, they are responsible for giving

second. Therefore, they are particularly important for

steady-state signals that allow one to determine con-

detecting tissue vibration or other rapid changes in the

tinuous touch of objects against the skin.

mechanical state of the tissues.

Merkel’s discs are often grouped together in a

receptor organ called the Iggo dome receptor, which

Transmission of Tactile Signals in Peripheral Nerve Fibers.

projects upward against the underside of the epithe-

Almost all specialized sensory receptors, such as

lium of the skin, as also shown in Figure 47-1. This

Meissner’s corpuscles, Iggo dome receptors, hair

Figure 47-1

Iggo dome receptor. Note the

multiple numbers of Merkel’s

discs connecting to a single large

myelinated fiber and abutting

tightly the undersurface of the

epithelium.

(From Iggo A, Muir

AR: The structure and function of

a slowly adapting touch corpus-

10 mm

cle in hairy skin. J Physiol 200:

763, 1969.)

Chapter 47

Somatic Sensations: I. General Organization, the Tactile and Position Senses

587

receptors, pacinian corpuscles, and Ruffini’s endings,

Sensory Pathways for

transmit their signals in type Ab nerve fibers that have

Transmitting Somatic

transmission velocities ranging from 30 to 70 m/sec.

Signals into the Central

Conversely, free nerve ending tactile receptors trans-

mit signals mainly by way of the small type Ad myeli-

Nervous System

nated fibers that conduct at velocities of only 5 to

30 m/sec.

Some tactile free nerve endings transmit by way of

Almost all sensory information from the somatic seg-

type C unmyelinated fibers at velocities from a frac-

ments of the body enters the spinal cord through the

tion of a meter up to 2 m/sec; these send signals into

dorsal roots of the spinal nerves. However, from

the spinal cord and lower brain stem, probably sub-

the entry point into the cord and then to the brain, the

serving mainly the sensation of tickle.

sensory signals are carried through one of two alter-

Thus, the more critical types of sensory signals—

native sensory pathways: (1) the dorsal column-medial

those that help to determine precise localization on

lemniscal system or (2) the anterolateral system. These

the skin, minute gradations of intensity, or rapid

two systems come back together partially at the level

changes in sensory signal intensity—are all transmit-

of the thalamus.

ted in more rapidly conducting types of sensory nerve

The dorsal column-medial lemniscal system, as its

fibers. Conversely, the cruder types of signals, such as

name implies, carries signals upward to the medulla of

crude pressure, poorly localized touch, and especially

the brain mainly in the dorsal columns of the cord.

tickle, are transmitted by way of much slower, very

Then, after the signals synapse and cross to the oppo-

small nerve fibers that require much less space in the

site side in the medulla, they continue upward through

nerve bundle than the fast fibers.

the brain stem to the thalamus by way of the medial

lemniscus.

Conversely, signals in the anterolateral system,

Detection of Vibration

immediately after entering the spinal cord from the

dorsal spinal nerve roots, synapse in the dorsal

All tactile receptors are involved in detection of vibra-

horns of the spinal gray matter, then cross to the oppo-

tion, although different receptors detect different fre-

site side of the cord and ascend through the anterior

quencies of vibration. Pacinian corpuscles can detect

and lateral white columns of the cord. They terminate

signal vibrations from 30 to 800 cycles per second

at all levels of the lower brain stem and in the

because they respond extremely rapidly to minute and

thalamus.

rapid deformations of the tissues, and they also trans-

The dorsal column-medial lemniscal system is com-

mit their signals over type Ab nerve fibers, which can

posed of large, myelinated nerve fibers that transmit

transmit as many as 1000 impulses per second. Low-

signals to the brain at velocities of 30 to 110 m/sec,

frequency vibrations from 2 up to 80 cycles per second,

whereas the anterolateral system is composed of

in contrast, stimulate other tactile receptors, especially

smaller myelinated fibers that transmit signals at

Meissner’s corpuscles, which are less rapidly adapting

velocities ranging from a few meters per second up to

than pacinian corpuscles.

40 m/sec.

Another difference between the two systems is

that the dorsal column-medial lemniscal system has a

TICKLE AND ITCH

high degree of spatial orientation of the nerve fibers

with respect to their origin, while the anterolateral

Neurophysiologic studies have demonstrated the exis-

system has much less spatial orientation. These

tence of very sensitive, rapidly adapting mechano-

differences immediately characterize the types of

receptive free nerve endings that elicit only the tickle

sensory information that can be transmitted by the

and itch sensations. Furthermore, these endings are

two systems. That is, sensory information that must

found almost exclusively in superficial layers of the

be transmitted rapidly and with temporal and

skin, which is also the only tissue from which the tickle

spatial fidelity is transmitted mainly in the dorsal

and itch sensations usually can be elicited. These sen-

column-medial lemniscal system; that which does not

sations are transmitted by very small type C, unmyeli-

need to be transmitted rapidly or with great spatial

nated fibers similar to those that transmit the aching,

fidelity is transmitted mainly in the anterolateral

slow type of pain.

system.

The purpose of the itch sensation is presumably to

The anterolateral system has a special capability

call attention to mild surface stimuli such as a flea

that the dorsal system does not have: the ability to

crawling on the skin or a fly about to bite, and the

transmit a broad spectrum of sensory modalities—

elicited signals then activate the scratch reflex or other

pain, warmth, cold, and crude tactile sensations;

maneuvers that rid the host of the irritant. Itch can

most of these are discussed in detail in Chapter 48.

be relieved by scratching if this removes the irritant

The dorsal system is limited to discrete types of

or if the scratch is strong enough to elicit pain. The

mechanoreceptive sensations.

pain signals are believed to suppress the itch signals

With this differentiation in mind, we can now

in the cord by lateral inhibition, as described in

list the types of sensations transmitted in the two

Chapter 48.

systems.

588

Unit IX The Nervous System: A. General Principles and Sensory Physiology

Dorsal Column-Medial

then upward in the dorsal column, proceeding by way

Lemniscal System

of the dorsal column pathway all the way to the brain.

The lateral branch enters the dorsal horn of the cord

1. Touch sensations requiring a high degree of

gray matter, then divides many times to provide termi-

localization of the stimulus

nals that synapse with local neurons in the intermediate

2. Touch sensations requiring transmission of fine

and anterior portions of the cord gray matter. These

gradations of intensity

local neurons in turn serve three functions: (1) A major

3. Phasic sensations, such as vibratory sensations

share of them give off fibers that enter the dorsal

4. Sensations that signal movement against the skin

columns of the cord and then travel upward to the brain.

5. Position sensations from the joints

(2) Many of the fibers are very short and terminate

6. Pressure sensations having to do with fine degrees

locally in the spinal cord gray matter to elicit local spinal

of judgment of pressure intensity

cord reflexes, which are discussed in Chapter 54. (3)

Others give rise to the spinocerebellar tracts, which we

will discuss in Chapter 56 in relation to the function of

Anterolateral System

the cerebellum.

1. Pain

The Dorsal Column-Medial Lemniscal Pathway. Note in Figure

2. Thermal sensations, including both warmth and

47-3 that nerve fibers entering the dorsal columns

cold sensations

pass uninterrupted up to the dorsal medulla, where

3. Crude touch and pressure sensations capable only

they synapse in the dorsal column nuclei (the cuneate

of crude localizing ability on the surface of the

and gracile nuclei). From there, second-order neurons

body

4. Tickle and itch sensations

5. Sexual sensations

Cortex

Transmission in the

Dorsal Column-Medial

Lemniscal System

Anatomy of the Dorsal

Column-Medial Lemniscal System

On entering the spinal cord through the spinal nerve

dorsal roots, the large myelinated fibers from the spe-

cialized mechanoreceptors divide almost immediately

Internal

capsule

to form a medial branch and a lateral branch, shown by

the right-hand fiber entering through the spinal root in

Ventrobasal

Figure 47-2. The medial branch turns medially first and

complex

of thalamus

Spinal nerve

Lamina marginalis

Substantia gelatinosa

Dorsal

Medulla oblongata

Tract of

Lissauer

column

Medial lemniscus

Spinocervical

tract

Dorsal column nuclei

Dorsal

III

spinocerebellar

Ascending branches of

tract

dorsal root fibers

Spinal cord

VII

Ventral

Spinocervical tract

VIII

spinocerebellar

tract

Dorsal root and spinal

Anterolateral

ganglion

spinothalamic

pathway

Figure 47-3

Figure 47-2

The dorsal column-medial lemniscal pathway for transmitting crit-

Cross section of the spinal cord, showing the anatomy of the cord

ical types of tactile signals. (Modified from Ranson SW, Clark SL:

gray matter and of ascending sensory tracts in the white columns

Anatomy of the Nervous System. Philadelphia: WB Saunders Co,

of the spinal cord.

1959.)

Chapter 47

Somatic Sensations: I. General Organization, the Tactile and Position Senses

589

decussate immediately to the opposite side of the brain

medial areas of the complex. Because of the crossing

stem and continue upward through the medial lemnisci

of the medial lemnisci in the medulla, the left side of

to the thalamus. In this pathway through the brain stem,

the body is represented in the right side of the thala-

each medial lemniscus is joined by additional fibers

mus, and the right side of the body in the left side of

from the sensory nuclei of the trigeminal nerve; these

the thalamus.

fibers subserve the same sensory functions for the head

that the dorsal column fibers subserve for the body.

In the thalamus, the medial lemniscal fibers terminate

Somatosensory Cortex

in the thalamic sensory relay area, called the ventrobasal

complex. From the ventrobasal complex, third-order

nerve fibers project, as shown in Figure 47-4, mainly to

Before discussing the role of the cerebral cortex in

the postcentral gyrus of the cerebral cortex, which is

somatic sensation, we need to give an orientation to

called somatic sensory area I (as shown in Figure 47-6,

the various areas of the cortex. Figure 47-5 is a map

these fibers also project to a smaller area in the lateral

of the human cerebral cortex, showing that it is divided

parietal cortex called somatic sensory area II).

into about 50 distinct areas called Brodmann’s areas

based on histological structural differences. This map

Spatial Orientation of the Nerve Fibers in the

is important because virtually all neurophysiologists

Dorsal Column-Medial Lemniscal System

and neurologists use it to refer by number to many of

One of the distinguishing features of the dorsal

the different functional areas of the human cortex.

column-medial lemniscal system is a distinct spatial

Note in the figure the large central fissure (also

orientation of nerve fibers from the individual parts of

called central sulcus) that extends horizontally across

the body that is maintained throughout. For instance,

the brain. In general, sensory signals from all modali-

in the dorsal columns of the spinal cord, the fibers from

ties of sensation terminate in the cerebral cortex

the lower parts of the body lie toward the center of the

immediately posterior to the central fissure. And,

cord, whereas those that enter the cord at progres-

generally, the anterior half of the parietal lobe is

sively higher segmental levels form successive layers

concerned almost entirely with reception and inter-

laterally.

pretation of somatosensory signals. But the posterior

In the thalamus, distinct spatial orientation is still

half of the parietal lobe provides still higher levels of

maintained, with the tail end of the body represented

interpretation.

by the most lateral portions of the ventrobasal

Visual signals terminate in the occipital lobe, and

complex and the head and face represented by the

auditory signals in the temporal lobe.

Conversely, that portion of the cerebral cortex ante-

rior to the central fissure and constituting the poste-

rior half of the frontal lobe is called the motor cortex

POSTCENTRAL GYRUS

and is devoted almost entirely to control of muscle

Lower extremity

Trunk

contractions and body movements. A major share of

this motor control is in response to somatosensory

Upper

extremity

Central fissure

Face

Ventrobasal complex of thalamus

MESENCEPHALON

Spinothalamic tract

Lateral fissure

Medial lemniscus

Figure 47-4

Figure 47-5

Projection of the dorsal column-medial lemniscal system through

the thalamus to the somatosensory cortex. (Modified from Brodal

Structurally distinct areas, called Brodmann’s areas, of the human

A: Neurological Anatomy in Relation to Clinical Medicine. New

cerebral cortex. Note specifically areas 1, 2, and 3, which consti-

York: Oxford University Press, 1969, by permission of Oxford

tute primary somatosensory area I, and areas 5 and 7, which con-

University Press.)

stitute the somatosensory association area.

590

Unit IX The Nervous System: A. General Principles and Sensory Physiology

Somatosensory

area I

Thigh

Somatosensory

Thorax

area II

Neck

Shoulder

Hand

Fingers

Tongue

Leg

Abdomen

Arm

Face

Upper lip

Lips

Lower lip

Teeth, gums, and jaw

Tongue

Figure 47-6

Pharynx

Two somatosensory cortical areas, somatosensory areas I and II.

Intra-abdominal

Figure 47-7

signals received from the sensory portions of the

cortex, which keep the motor cortex informed at each

Representation of the different areas of the body in somatosen-

instant about the positions and motions of the differ-

sory area I of the cortex. (From Penfield W, Rasmussen T: Cere-

ent body parts.

bral Cortex of Man: A Clinical Study of Localization of Function.

New York: Hafner, 1968.)

Somatosensory Areas I and II. Figure 47-6 shows two sep-

arate sensory areas in the anterior parietal lobe called

somatosensory area I and somatosensory area II. The

postcentral gyrus of the human cerebral cortex (in

reason for this division into two areas is that a distinct

Brodmann’s areas 3, 1, and 2).

and separate spatial orientation of the different

Figure 47-7 shows a cross section through the brain

parts of the body is found in each of these two

at the level of the postcentral gyrus, demonstrating

areas. However, somatosensory area I is so much

representations of the different parts of the body in

more extensive and so much more important than

separate regions of somatosensory area I. Note,

somatosensory area II that in popular usage, the term

however, that each lateral side of the cortex receives

“somatosensory cortex” almost always means area I.

sensory information almost exclusively from the oppo-

Somatosensory area I has a high degree of localiza-

site side of the body.

tion of the different parts of the body, as shown by the

Some areas of the body are represented by large

names of virtually all parts of the body in Figure 47-6.

areas in the somatic cortex—the lips the greatest of all,

By contrast, localization is poor in somatosensory area

followed by the face and thumb—whereas the trunk

II, although roughly, the face is represented anteriorly,

and lower part of the body are represented by rela-

the arms centrally, and the legs posteriorly.

tively small areas. The sizes of these areas are directly

Little is known about the function of somatosensory

proportional to the number of specialized sensory

area II. It is known that signals enter this area from

receptors in each respective peripheral area of the

the brain stem, transmitted upward from both sides of

body. For instance, a great number of specialized nerve

the body. In addition, many signals come secondarily

endings are found in the lips and thumb, whereas only

from somatosensory area I as well as from other

a few are present in the skin of the body trunk.

sensory areas of the brain, even from the visual and

Note also that the head is represented in the most

auditory areas. Projections from somatosensory area I

lateral portion of somatosensory area I, and the lower

are required for function of somatosensory area II.

part of the body is represented medially.

However, removal of parts of somatosensory area II

has no apparent effect on the response of neurons in

Layers of the Somatosensory Cortex and

somatosensory area I. Thus, much of what we know

Their Function

about somatic sensation appears to be explained by

The cerebral cortex contains six layers of neurons,

the functions of somatosensory area I.

beginning with layer I next to the brain surface and

extending progressively deeper to layer VI, shown in

Spatial Orientation of Signals from Different Parts of the Body

Figure 47-8. As would be expected, the neurons in

in Somatosensory Area I. Somatosensory area I lies

each layer perform functions different from those

immediately behind the central fissure, located in the

in other layers. Some of these functions are:

Chapter 47

Somatic Sensations: I. General Organization, the Tactile and Position Senses

591

The Sensory Cortex Is Organized in Vertical

Columns of Neurons; Each Column Detects a

Different Sensory Spot on the Body with a

Specific Sensory Modality

Functionally, the neurons of the somatosensory cortex

are arranged in vertical columns extending all the way

through the six layers of the cortex, each column

having a diameter of 0.3 to 0.5 millimeter and con-

III

taining perhaps 10,000 neuronal cell bodies. Each of

these columns serves a single specific sensory modal-

ity, some columns responding to stretch receptors

around joints, some to stimulation of tactile hairs,

others to discrete localized pressure points on the skin,

and so forth. At layer IV, where the input sensory

signals first enter the cortex, the columns of neurons

function almost entirely separately from one another.

At other levels of the columns, interactions occur that

initiate analysis of the meanings of the sensory signals.

In the most anterior 5 to 10 millimeters of the post-

central gyrus, located deep in the central fissure in

VIa

Brodmann’s area 3a, an especially large share of the

vertical columns respond to muscle, tendon, and joint

stretch receptors. Many of the signals from these

sensory columns then spread anteriorly, directly to

VIb

the motor cortex located immediately forward of the

central fissure. These signals play a major role in

controlling the effluent motor signals that activate

sequences of muscle contraction.

As one moves posteriorly in somatosensory area I,

Figure 47-8

more and more of the vertical columns respond to

Structure of the cerebral cortex, showing I, molecular layer; II,

slowly adapting cutaneous receptors, and then still

external granular layer; III, layer of small pyramidal cells; IV, inter-

farther posteriorly, greater numbers of the columns are

nal granular layer; V, large pyramidal cell layer; and VI, layer of

sensitive to deep pressure.

fusiform or polymorphic cells. (From Ranson SW, Clark SL [after

In the most posterior portion of somatosensory area

Brodmann]: Anatomy of the Nervous System. Philadelphia: WB

Saunders, 1959.)

I, about 6 per cent of the vertical columns respond only

when a stimulus moves across the skin in a particular

direction. Thus, this is a still higher order of interpre-

1. The incoming sensory signal excites neuronal

tation of sensory signals; the process becomes even

layer IV first; then the signal spreads toward the

more complex as the signals spread farther backward

surface of the cortex and also toward deeper

from somatosensory area I into the parietal cortex, an

layers.

area called the somatosensory association area, as we

2. Layers I and II receive diffuse, nonspecific input

discuss subsequently.

signals from lower brain centers that facilitate

specific regions of the cortex; this system is

Functions of Somatosensory Area I

described in Chapter 57. This input mainly

Widespread bilateral excision of somatosensory area I

controls the overall level of excitability of the

causes loss of the following types of sensory judgment:

respective regions stimulated.

1. The person is unable to localize discretely the

3. The neurons in layers II and III send axons to

different sensations in the different parts of the

related portions of the cerebral cortex on the

body. However, he or she can localize these

opposite side of the brain through the corpus

sensations crudely, such as to a particular hand, to

callosum.

a major level of the body trunk, or to one of the

4. The neurons in layers V and VI send axons to the

legs. Thus, it is clear that the brain stem, thalamus,

deeper parts of the nervous system. Those in layer

or parts of the cerebral cortex not normally

V are generally larger and project to more distant

considered to be concerned with somatic

areas, such as to the basal ganglia, brain stem,

sensations can perform some degree of

and spinal cord where they control signal

localization.

transmission. From layer VI, especially large

2. The person is unable to judge critical degrees of

numbers of axons extend to the thalamus,

pressure against the body.

providing signals from the cerebral cortex that

3. The person is unable to judge the weights of

interact with and help to control the excitatory

objects.

levels of incoming sensory signals entering the

4. The person is unable to judge shapes or forms of

thalamus.

objects. This is called astereognosis.

592

Unit IX The Nervous System: A. General Principles and Sensory Physiology

5. The person is unable to judge texture of materials

because this type of judgment depends on highly

critical sensations caused by movement of the

Strong stimulus

fingers over the surface to be judged.

Note that in the list nothing has been said about loss

of pain and temperature sense. In specific absence

of only somatosensory area I, appreciation of these

sensory modalities is still preserved both in quality and

Moderate

stimulus

intensity. But the sensations are poorly localized, indi-

cating that pain and temperature localization depend

greatly on the topographical map of the body in

somatosensory area I to localize the source.

Weak

stimulus

Somatosensory Association Areas

Brodmann’s areas 5 and 7 of the cerebral cortex,

Cortex

located in the parietal cortex behind somatosensory

area I (see Figure 47-5), play important roles in deci-

phering deeper meanings of the sensory information

in the somatosensory areas. Therefore, these areas are

called somatosensory association areas.

Electrical stimulation in a somatosensory associa-

Thalamus

tion area can occasionally cause an awake person to

experience a complex body sensation, sometimes even

the “feeling” of an object such as a knife or a ball.

Therefore, it seems clear that the somatosensory asso-

ciation area combines information arriving from mul-

Dorsal column nuclei

tiple points in the primary somatosensory area to

decipher its meaning. This also fits with the anatomi-

cal arrangement of the neuronal tracts that enter the

somatosensory association area because it receives

Single-point stimulus on skin

signals from (1) somatosensory area I, (2) the ven-

trobasal nuclei of the thalamus, (3) other areas of the

thalamus, (4) the visual cortex, and (5) the auditory

cortex.

Figure 47-9

Transmission of a pinpoint stimulus signal to the cerebral cortex.

Effect of Removing the Somatosensory Association Area—

Amorphosynthesis. When the somatosensory association

area is removed on one side of the brain, the person

organization of the neuronal circuit of the spinal cord

loses ability to recognize complex objects and complex

dorsal column pathway, demonstrating that at each

forms felt on the opposite side of the body. In addi-

synaptic stage, divergence occurs. The upper curves of

tion, he or she loses most of the sense of form of his

the figure show that the cortical neurons that discharge

or her own body or body parts on the opposite side.

to the greatest extent are those in a central part of the

In fact, the person is mainly oblivious to the opposite

cortical “field” for each respective receptor. Thus, a

side of the body—that is, forgets that it is there.

weak stimulus causes only the centralmost neurons to

Therefore, he or she also often forgets to use the other

fire. A stronger stimulus causes still more neurons to

side for motor functions as well. Likewise, when

fire, but those in the center discharge at a considerably

feeling objects, the person tends to recognize only

more rapid rate than do those farther away from the

one side of the object and forgets that the other side

center.

even exists. This complex sensory deficit is called

amorphosynthesis.

Two-Point Discrimination. A method frequently used to

test tactile discrimination is to determine a person’s

so-called “two-point” discriminatory ability. In this

Overall Characteristics of Signal

test, two needles are pressed lightly against the skin at

Transmission and Analysis

the same time, and the person determines whether two

in the Dorsal Column-Medial

points of stimulus are felt or one point. On the tips of

Lemniscal System

the fingers, a person can distinguish two separate

points even when the needles are as close together as

Basic Neuronal Circuit in the Dorsal Column-Medial Lemniscal

1 to 2 millimeters. However, on the person’s back,

System. The lower part of Figure 47-9 shows the basic

the needles must usually be as far apart as 30 to 70

Chapter 47

Somatic Sensations: I. General Organization, the Tactile and Position Senses

593

excitatory signal, short lateral pathways transmit

inhibitory signals to the surrounding neurons. That is,

these signals pass through additional interneurons that

secrete an inhibitory transmitter.

The importance of lateral inhibition is that it blocks

lateral spread of the excitatory signals and, therefore,

increases the degree of contrast in the sensory pattern

perceived in the cerebral cortex.

In the case of the dorsal column system, lateral

inhibitory signals occur at each synaptic level—for

instance, in

(1) the dorsal column nuclei of the

medulla, (2) the ventrobasal nuclei of the thalamus,

and (3) the cortex itself. At each of these levels, the

lateral inhibition helps to block lateral spread of the

excitatory signal. As a result, the peaks of excitation

stand out, and much of the surrounding diffuse stimu-

Cortex

lation is blocked. This effect is demonstrated by the

two red curves in Figure 47-10, showing complete

separation of the peaks when the intensity of lateral

inhibition is great.

Two adjacent points

Transmission of Rapidly Changing and Repetitive Sensations.

strongly stimulated

The dorsal column system also is of particular impor-

tance in apprising the sensorium of rapidly changing

peripheral conditions. Based on recorded action

potentials, this system can recognize changing stimuli

Figure 47-10

that occur in as little as 1/400 of a second.

Transmission of signals to the cortex from two adjacent pinpoint

stimuli. The blue curve represents the pattern of cortical stimula-

Vibratory Sensation. Vibratory signals are rapidly

tion without “surround” inhibition, and the two red curves repre-

repetitive and can be detected as vibration up to 700

sent the pattern when “surround” inhibition does occur.

cycles per second. The higher-frequency vibratory

signals originate from the pacinian corpuscles in the

millimeters before two separate points can be

skin and deeper tissues, but lower-frequency signals

detected. The reason for this difference is the different

(below about 200 per second) can originate from

numbers of specialized tactile receptors in the two

Meissner’s corpuscles as well. These signals are trans-

areas.

mitted only in the dorsal column pathway. For this

Figure 47-10 shows the mechanism by which the

reason, application of vibration (e.g., from a “tuning

dorsal column pathway (as well as all other sensory

fork”) to different peripheral parts of the body is an

pathways) transmits two-point discriminatory infor-

important tool used by neurologists for testing func-

mation. This figure shows two adjacent points on the

tional integrity of the dorsal columns.

skin that are strongly stimulated as well as the areas

of the somatosensory cortex (greatly enlarged) that

are excited by signals from the two stimulated points.

Interpretation of Sensory

The blue curve shows the spatial pattern of cortical

Stimulus Intensity

excitation when both skin points are stimulated simul-

The ultimate goal of most sensory stimulation is to

taneously. Note that the resultant zone of excitation

apprise the psyche of the state of the body and its sur-

has two separate peaks. These two peaks, separated by

roundings. Therefore, it is important that we discuss

a valley, allow the sensory cortex to detect the pres-

briefly some of the principles related to transmission of

ence of two stimulatory points, rather than a single

sensory stimulus intensity to the higher levels of the

point. The capability of the sensorium to distinguish

nervous system.

this presence of two points of stimulation is strongly

The first question that comes to mind is, how is it pos-

influenced by another mechanism, lateral inhibition, as

sible for the sensory system to transmit sensory experi-

explained in the next section.

ences of tremendously varying intensities? For instance,

the auditory system can detect the weakest possible

whisper but can also discern the meanings of an explo-

Effect of Lateral Inhibition (Also Called Surround Inhibition) to

sive sound, even though the sound intensities of these

Increase the Degree of Contrast in the Perceived Spatial

two experiences can vary more than 10 billion times; the

Pattern. As pointed out in Chapter 46, virtually every

eyes can see visual images with light intensities that vary

sensory pathway, when excited, gives rise simultane-

as much as a half million times; and the skin can detect

ously to lateral inhibitory signals; these spread to the

pressure differences of 10,000 to 100,000 times.

sides of the excitatory signal and inhibit adjacent

As a partial explanation of these effects, Figure 46-4

neurons. For instance, consider an excited neuron

in the previous chapter shows the relation of the recep-

in a dorsal column nucleus. Aside from the central

tor potential produced by the pacinian corpuscle to the

594

Unit IX The Nervous System: A. General Principles and Sensory Physiology

intensity of the sensory stimulus. At low stimulus inten-

Fechner principle is still a good one to remember,

sity, slight changes in intensity increase the potential

because it emphasizes that the greater the background

markedly, whereas at high levels of stimulus intensity,

sensory intensity, the greater an additional change must

further increases in receptor potential are slight. Thus,

be for the psyche to detect the change.

the pacinian corpuscle is capable of accurately measur-

ing extremely minute changes in stimulus at low-

Power Law. Another attempt by physiopsychologists to

intensity levels, but at high-intensity levels, the change

find a good mathematical relation is the following

in stimulus must be much greater to cause the same

formula, known as the power law.

amount of change in receptor potential.

Interpreted signal strength = K • (Stimulus - k)^y

The transduction mechanism for detecting sound by

the cochlea of the ear demonstrates still another

In this formula, the exponent y and the constants K and

method for separating gradations of stimulus intensity.

k are different for each type of sensation.

When sound stimulates a specific point on the basilar

When this power law relation is plotted on a graph

membrane, weak sound stimulates only those hair cells

using double logarithmic coordinates, as shown in

at the point of maximum sound vibration. But as the

Figure 47-11, and when appropriate quantitative values

sound intensity increases, many more hair cells in each

for the constants y, K, and k are found, a linear relation

direction farther away from the maximum vibratory

can be attained between interpreted stimulus strength

point also become stimulated. Thus, signals are trans-

and actual stimulus strength over a large range for

mitted over progressively increasing numbers of nerve

almost any type of sensory perception.

fibers, which is another mechanism by which stimulus

intensity is transmitted to the central nervous system.

This mechanism, plus the direct effect of stimulus inten-

Position Senses

sity on impulse rate in each nerve fiber, as well as several

other mechanisms, makes it possible for some sensory

The position senses are frequently also called proprio-

systems to operate reasonably faithfully at stimulus

ceptive senses. They can be divided into two subtypes:

intensity levels changing as much as millions of times.

(1) static position sense, which means conscious per-

Importance of the Tremendous Intensity Range of Sensory

ception of the orientation of the different parts of

Reception. Were it not for the tremendous intensity

the body with respect to one another, and (2) rate of

range of sensory reception that we can experience, the

movement sense, also called kinesthesia or dynamic

various sensory systems would more often than not be

proprioception.

operating in the wrong range. This is demonstrated by

the attempts of most people, when taking photographs

Position Sensory Receptors. Knowledge of position, both

with a camera, to adjust the light exposure without using

static and dynamic, depends on knowing the degrees

a light meter. Left to intuitive judgment of light inten-

of angulation of all joints in all planes and their rates

sity, a person almost always overexposes the film on

of change. Therefore, multiple different types of recep-

bright days and greatly underexposes the film at twi-

tors help to determine joint angulation and are used

light. Yet, that person’s own eyes are capable of dis-

criminating with great detail visual objects in bright

sunlight or at twilight; the camera cannot do this without

very special manipulation because of the narrow criti-

cal range of light intensity required for proper exposure

of film.

500

200

Judgment of Stimulus Intensity

Weber-Fechner Principle—Detection of

“Ratio” of Stimulus

100

Strength. In the mid-1800s, Weber first and Fechner later

proposed the principle that gradations of stimulus

strength are discriminated approximately in proportion

to the logarithm of stimulus strength. That is, a person

already holding 30 grams weight in his or her hand can

barely detect an additional 1-gram increase in weight.

And, when already holding 300 grams, he or she can

barely detect a 10-gram increase in weight. Thus, in this

instance, the ratio of the change in stimulus strength

required for detection remains essentially constant,

100

1000

10,000

about 1 to 30, which is what the logarithmic principle

Stimulus strength (arbitrary units)

means. To express this mathematically.

Interpreted signal strength = Log (Stimulus)

+ Constant

Figure 47-11

More recently, it has become evident that the Weber-

Fechner principle is quantitatively accurate only for

Graphical demonstration of the “power law” relation between

higher intensities of visual, auditory, and cutaneous

actual stimulus strength and strength that the psyche interprets it

sensory experience and applies only poorly to most

to be. Note that the power law does not hold at either very weak

other types of sensory experience. Yet the Weber-

or very strong stimulus strengths.

Chapter 47

Somatic Sensations: I. General Organization, the Tactile and Position Senses

595

together for position sense. Both skin tactile receptors

maximally stimulated when the joint is at full rotation

and deep receptors near the joints are used. In the

and (2) those maximally stimulated when the joint is

case of the fingers, where skin receptors are in great

at minimal rotation. Thus, the signals from the indi-

abundance, as much as half of position recognition is

vidual joint receptors are used to tell the psyche how

believed to be detected through the skin receptors.

much each joint is rotated.

Conversely, for most of the larger joints of the body,

deep receptors are more important.

For determining joint angulation in mid ranges of

Transmission of Less Critical

motion, among the most important receptors are the

Sensory Signals in the

muscle spindles. They are also exceedingly important

in helping to control muscle movement, as we shall see

Anterolateral Pathway

in Chapter 54. When the angle of a joint is changing,

some muscles are being stretched while others are

The anterolateral pathway for transmitting sensory

loosened, and the net stretch information from the

signals up the spinal cord and into the brain, in con-

spindles is transmitted into the computational system

trast to the dorsal column pathway, transmits sensory

of the spinal cord and higher regions of the dorsal

signals that do not require highly discrete localization

column system for deciphering joint angulations.

of the signal source and do not require discrimination

At the extremes of joint angulation, stretch of the

of fine gradations of intensity. These types of signals

ligaments and deep tissues around the joints is an addi-

include pain, heat, cold, crude tactile, tickle, itch, and

tional important factor in determining position. Types

sexual sensations. In Chapter 48, pain and temperature

of sensory endings used for this are the pacinian cor-

sensations will be discussed specifically.

puscles, Ruffini’s endings, and receptors similar to the

Golgi tendon receptors found in muscle tendons.

Anatomy of the

The pacinian corpuscles and muscle spindles are

Anterolateral Pathway

especially adapted for detecting rapid rates of change.

It is likely that these are the receptors most responsi-

The spinal cord anterolateral fibers originate mainly in

ble for detecting rate of movement.

dorsal horn laminae I, IV, V, and VI (see Figure 47-2).

These laminae are where many of the dorsal root

Processing of Position Sense Information in the Dorsal

sensory nerve fibers terminate after entering the cord.

Column-Medial Lemniscal Pathway. Referring to Figure

As shown in Figure 47-13, the anterolateral fibers

47-12, one sees that thalamic neurons responding

cross immediately in the anterior commissure of the

to joint rotation are of two categories:

(1) those

cord to the opposite anterior and lateral white columns,

where they turn upward toward the brain by way of the

anterior spinothalamic and lateral spinothalamic tracts.

The upper terminus of the two spinothalamic tracts is

mainly twofold: (1) throughout the reticular nuclei of the

brain stem and (2) in two different nuclear complexes

of the thalamus, the ventrobasal complex and the

100

intralaminar nuclei. In general, the tactile signals are

transmitted mainly into the ventrobasal complex, ter-

minating in some of the same thalamic nuclei where the

dorsal column tactile signals terminate. From here, the

signals are transmitted to the somatosensory cortex

along with the signals from the dorsal columns.

Conversely, only a small fraction of the pain signals

project directly to the ventrobasal complex of the thal-

amus. Instead, most pain signals terminate in the retic-

ular nuclei of the brain stem and from there are relayed

to the intralaminar nuclei of the thalamus where the

pain signals are further processed, as discussed in

greater detail in Chapter 48.

Characteristics of Transmission in the Anterolateral Pathway.

In general, the same principles apply to transmission

100

120

140

160

180

in the anterolateral pathway as in the dorsal

Degrees

column-medial lemniscal system, except for the fol-

lowing differences: (1) the velocities of transmission

are only one third to one half those in the dorsal

Figure 47-12

column-medial lemniscal system, ranging between 8

and 40 m/sec; (2) the degree of spatial localization of

Typical responses of five different thalamic neurons in the thala-

signals is poor; (3) the gradations of intensities are also

mic ventrobasal complex when the knee joint is moved through

far less accurate, most of the sensations being recog-

its range of motion. (Data from Mountcastle VB, Poggie GF, Werner

G: The relation of thalamic cell response to peripheral stimuli

nized in 10 to 20 gradations of strength, rather than as

varied over an intensive continuum. J Neurophysiol 26:807, 1963.)

many as 100 gradations for the dorsal column system;

596

Unit IX

The Nervous System: A. General Principles and Sensory Physiology

Cortex

Internal

capsule

Ventrobasal

T10

and intralaminar

T10

T12

nuclei of the

Mesencephalon

T11

thalamus

T12

Medial lemniscus

S4&5

Medulla oblongata

Lateral

division of the

anterolateral

pathway

Spinal cord

division of the

Dorsal root and spinal

anterolateral

ganglion

pathway

Figure 47-13

Figure 47-14

Anterior and lateral divisions of the anterolateral sensory pathway.

Dermatomes. (Modified from Grinker RR, Sahs AL: Neurology, 6th

ed. Springfield, IL: Charles C Thomas, 1966. Courtesy of Charles

C Thomas, Publisher, Ltd., Springfield, Illinois.)

and (4) the ability to transmit rapidly changing or

rapidly repetitive signals is poor.

Thus, it is evident that the anterolateral system is a

cruder type of transmission system than the dorsal

column-medial lemniscal system. Even so, certain

modalities of sensation are transmitted only in this

does return. Therefore, it must be assumed that the thal-

system and not at all in the dorsal column-medial lem-

amus (as well as other lower centers) has a slight ability

niscal system. They are pain, temperature, tickle, itch,

to discriminate tactile sensation, even though the thala-

and sexual sensations, in addition to crude touch and

mus normally functions mainly to relay this type of

pressure.

information to the cortex.

Conversely, loss of the somatosensory cortex has little

effect on one’s perception of pain sensation and only

Some Special Aspects of

a moderate effect on the perception of temperature.

Somatosensory Function

Therefore, there is much reason to believe that the

lower brain stem, the thalamus, and other associated

Function of the Thalamus

basal regions of the brain play dominant roles in dis-

crimination of these sensibilities. It is interesting that

in Somatic Sensation

these sensibilities appeared very early in the phyloge-

When the somatosensory cortex of a human being is

netic development of animals, whereas the critical

destroyed, that person loses most critical tactile sensi-

tactile sensibilities and the somatosensory cortex were

bilities, but a slight degree of crude tactile sensibility

late developments.

Chapter 47

Somatic Sensations: I. General Organization, the Tactile and Position Senses

597

Cortical Control of Sensory

Chen R, Cohen LG, Hallett M: Nervous system reorganiza-

Sensitivity—“Corticofugal” Signals

tion following injury. Neuroscience 111(4):761, 2002.

Cohen YE, Andersen RA: A common reference frame for

In addition to somatosensory signals transmitted from

movement plans in the posterior parietal cortex. Nat Rev

the periphery to the brain, corticofugal signals are trans-

Neurosci 3:553, 2002.

mitted in the backward direction from the cerebral

Craig AD: Pain mechanisms: labeled lines versus conver-

cortex to the lower sensory relay stations of the thala-

gence in central processing. Annu Rev Neurosci 26:1, 2003.

mus, medulla, and spinal cord; they control the intensity

Foeller E, Feldman DE: Synaptic basis for developmental

of sensitivity of the sensory input.

plasticity in somatosensory cortex. Curr Opin Neurobiol

Corticofugal signals are almost entirely inhibitory, so

14:89, 2004.

that when sensory input intensity becomes too great, the

Haines DE: Fundamental Neuroscience. New York:

corticofugal signals automatically decrease transmission

Churchill Livingstone, 1997.

in the relay nuclei. This does two things: First, it

Haines DE, Lancon JA: Review of Neuroscience. New York:

decreases lateral spread of the sensory signals into adja-

Churchill Livingstone, 2003.

cent neurons and, therefore, increases the degree of

Ivry RB, Spencer RM: The neural representation of time.

sharpness in the signal pattern. Second, it keeps the

Curr Opin Neurobiol 14:225, 2004.

sensory system operating in a range of sensitivity that is

Janig W, Baron R: Complex regional pain syndrome: mystery

not so low that the signals are ineffectual nor so high

explained? Lancet Neurol 2:687, 2003.

that the system is swamped beyond its capacity to dif-

Jeannerod M: The mechanism of self-recognition in humans.

ferentiate sensory patterns. This principle of corticofu-

Behav Brain Res 142:1, 2003.

gal sensory control is used by all sensory systems, not

Johnson KO: The roles and functions of cutaneous

only the somatic system, as explained in subsequent

mechanoreceptors. Curr Opin Neurobiol 11:455, 2001.

chapters.

Kandel ER, Schwartz JH, Jessell TM: Principles of Neural

Science, 4th ed. New York: McGraw-Hill, 2000.

Lumb BM: Hypothalamic and midbrain circuitry that dis-

Segmental Fields of Sensation—

tinguishes between escapable and inescapable pain. News

The Dermatomes

Physiol Sci 19:22, 2004.

Maravita A, Spence C, Driver J: Multisensory integration

Each spinal nerve innervates a “segmental field” of the

and the body schema: close to hand and within reach. Curr

skin called a dermatome. The different dermatomes are

Biol 13:R531, 2003.

shown in Figure 47-14. They are shown in the figure as

Pears S, Jackson SR: Cognitive neuroscience: vision and

if there were distinct borders between the adjacent der-

touch are constant companions. Curr Biol 14:R349, 2004.

matomes, which is far from true because much overlap

Petersen CC: The barrel cortex—integrating molecular, cel-

exists from segment to segment.

lular and systems physiology. Pflugers Arch 447:126, 2003.

The figure shows that the anal region of the body lies

Pouget A, Deneve S, Duhamel JR: A computational per-

in the dermatome of the most distal cord segment, der-

spective on the neural basis of multisensory spatial repre-

matome S5. In the embryo, this is the tail region and the

sentations. Nat Rev Neurosci 3:741, 2002.

most distal portion of the body. The legs originate

Sommer MA: The role of the thalamus in motor control.

embryologically from the lumbar and upper sacral seg-

Curr Opin Neurobiol 13:663, 2003.

ments (L2 to S3), rather than from the distal sacral seg-

Suga N, Ma X: Multiparametric corticofugal modulation and

ments, which is evident from the dermatomal map. One

plasticity in the auditory system. Nat Rev Neurosci 4:783,

can use a dermatomal map as shown in Figure 47-14 to

2003.

determine the level in the spinal cord at which a cord

Thaut MH: Neural basis of rhythmic timing networks in the

injury has occurred when the peripheral sensations are

human brain. Ann N Y Acad Sci 999:364, 2003.

disturbed by the injury.

References

Bosco G, Poppele RE: Proprioception from a spinocerebel-

lar perspective. Physiol Rev 81:539, 2001.

C H A P T E R

Somatic Sensations:

II. Pain, Headache, and

Thermal Sensations

Many, if not most, ailments of the body cause pain.

Furthermore, the ability to diagnose different dis-

eases depends to a great extent on a physician’s

knowledge of the different qualities of pain. For

these reasons, the first part of this chapter is devoted

mainly to pain and to the physiologic bases of some

associated clinical phenomena.

Pain Is a Protective Mechanism. Pain occurs whenever any tissues are being

damaged, and it causes the individual to react to remove the pain stimulus. Even

such simple activities as sitting for a long time on the ischia can cause tissue

destruction because of lack of blood flow to the skin where it is compressed by

the weight of the body. When the skin becomes painful as a result of the

ischemia, the person normally shifts weight subconsciously. But a person who

has lost the pain sense, as after spinal cord injury, fails to feel the pain and, there-

fore, fails to shift. This soon results in total breakdown and desquamation of the

skin at the areas of pressure.

Types of Pain and Their Qualities—Fast Pain

and Slow Pain

Pain has been classified into two major types: fast pain and slow pain. Fast pain

is felt within about 0.1 second after a pain stimulus is applied, whereas slow pain

begins only after 1 second or more and then increases slowly over many seconds

and sometimes even minutes. During the course of this chapter, we shall see

that the conduction pathways for these two types of pain are different and that

each of them has specific qualities.

Fast pain is also described by many alternative names, such as sharp pain,

pricking pain, acute pain, and electric pain. This type of pain is felt when a needle

is stuck into the skin, when the skin is cut with a knife, or when the skin is acutely

burned. It is also felt when the skin is subjected to electric shock. Fast-sharp

pain is not felt in most deeper tissues of the body.

Slow pain also goes by many names, such as slow burning pain, aching pain,

throbbing pain, nauseous pain, and chronic pain. This type of pain is usually

associated with tissue destruction. It can lead to prolonged, unbearable suffer-

ing. It can occur both in the skin and in almost any deep tissue or organ.

Pain Receptors and Their Stimulation

Pain Receptors Are Free Nerve Endings. The pain receptors in the skin and other

tissues are all free nerve endings. They are widespread in the superficial layers

of the skin as well as in certain internal tissues, such as the periosteum, the arte-

rial walls, the joint surfaces, and the falx and tentorium in the cranial vault. Most

other deep tissues are only sparsely supplied with pain endings; nevertheless,

any widespread tissue damage can summate to cause the slow-chronic-aching

type of pain in most of these areas.

598

Chapter 48

Somatic Sensations: II. Pain, Headache, and Thermal Sensations

599

Three Types of Stimuli Excite Pain Receptors—Mechanical,

Thermal, and Chemical. Pain can be elicited by multiple

types of stimuli. They are classified as mechanical,

thermal, and chemical pain stimuli. In general, fast pain

is elicited by the mechanical and thermal types of

stimuli, whereas slow pain can be elicited by all three

types.

Some of the chemicals that excite the chemical type

of pain are bradykinin, serotonin, histamine, potassium

ions, acids, acetylcholine, and proteolytic enzymes. In

addition, prostaglandins and substance P enhance the

sensitivity of pain endings but do not directly excite

them. The chemical substances are especially impor-

tant in stimulating the slow, suffering type of pain that

occurs after tissue injury.

Nonadapting Nature of Pain Receptors. In contrast to most

other sensory receptors of the body, pain receptors

adapt very little and sometimes not at all. In fact,

under some conditions, excitation of pain fibers

Temperature (∞C)

becomes progressively greater, especially so for

slow-aching-nauseous pain, as the pain stimulus

continues. This increase in sensitivity of the pain recep-

tors is called hyperalgesia. One can readily understand

Figure 48-1

the importance of this failure of pain receptors to

adapt, because it allows the pain to keep the person

Distribution curve obtained from a large number of persons

apprised of a tissue-damaging stimulus as long as it

showing the minimal skin temperature that will cause pain. (Mod-

ified from Hardy DJ: Nature of pain. J Clin Epidemiol 4:22, 1956.)

persists.

Rate of Tissue Damage as a Stimulus

for Pain

Tissue Ischemia as a Cause of Pain. When blood flow to a

tissue is blocked, the tissue often becomes very painful

The average person begins to perceive pain when the

within a few minutes. The greater the rate of metabo-

skin is heated above 45°C, as shown in Figure 48-1.

lism of the tissue, the more rapidly the pain appears.

This is also the temperature at which the tissues begin

For instance, if a blood pressure cuff is placed around

to be damaged by heat; indeed, the tissues are even-

the upper arm and inflated until the arterial blood flow

tually destroyed if the temperature remains above this

ceases, exercise of the forearm muscles sometimes

level indefinitely. Therefore, it is immediately apparent

can cause muscle pain within 15 to 20 seconds. In the

that pain resulting from heat is closely correlated

absence of muscle exercise, the pain may not appear

with the rate at which damage to the tissues is occur-

for 3 to 4 minutes even though the muscle blood flow

ring and not with the total damage that has already

remains zero.

occurred.

One of the suggested causes of pain during ischemia

The intensity of pain is also closely correlated with

is accumulation of large amounts of lactic acid in the

the rate of tissue damage from causes other than heat,

tissues, formed as a consequence of anaerobic metab-

such as bacterial infection, tissue ischemia, tissue con-

olism (metabolism without oxygen). It is also proba-

tusion, and so forth.

ble that other chemical agents, such as bradykinin and

proteolytic enzymes, are formed in the tissues because

Special Importance of Chemical Pain Stimuli During Tissue

of cell damage and that these, in addition to lactic acid,

Damage. Extracts from damaged tissue cause intense

stimulate the pain nerve endings.

pain when injected beneath the normal skin. Most of

the chemicals listed earlier that excite the chemical

Muscle Spasm as a Cause of Pain. Muscle spasm is also

pain receptors can be found in these extracts. One

a common cause of pain, and it is the basis of many

chemical that seems to be more painful than others is

clinical pain syndromes. This pain probably results

bradykinin. Many researchers have suggested that

partially from the direct effect of muscle spasm in

bradykinin might be the agent most responsible for

stimulating mechanosensitive pain receptors, but it

causing pain following tissue damage. Also, the inten-

might also result from the indirect effect of muscle

sity of the pain felt correlates with the local increase

spasm to compress the blood vessels and cause

in potassium ion concentration or the increase in pro-

ischemia. Also, the spasm increases the rate of metab-

teolytic enzymes that directly attack the nerve endings

olism in the muscle tissue, thus making the relative

and excite pain by making the nerve membranes more

ischemia even greater, creating ideal conditions for the

permeable to ions.

release of chemical pain-inducing substances.

600

Unit IX The Nervous System: A. General Principles and Sensory Physiology

Dual Pathways for

C Ad

Transmission of Pain

Spinal

Fast-sharp

Signals into the Central

nerve

pain fibers

Nervous System

Tract of

Lissauer

III

Even though all pain receptors are free nerve endings,

these endings use two separate pathways for transmit-

ting pain signals into the central nervous system. The

two pathways mainly correspond to the two types of

VII

pain—a fast-sharp pain pathway and a slow-chronic

VIII

pain pathway.

Lamina

marginalis

Peripheral Pain Fibers—“Fast” and “Slow” Fibers. The fast-

Substantia

Slow-chronic

sharp pain signals are elicited by either mechanical

gelatinosa

pain fibers

Anterolateral

or thermal pain stimuli; they are transmitted in the

pathway

peripheral nerves to the spinal cord by small type Ad

fibers at velocities between 6 and 30 m/sec. Conversely,

Figure 48-2

the slow-chronic type of pain is elicited mostly by

Transmission of both “fast-sharp” and “slow-chronic” pain signals

chemical types of pain stimuli but sometimes by

into and through the spinal cord on their way to the brain.

persisting mechanical or thermal stimuli. This slow-

chronic pain is transmitted to the spinal cord by type

C fibers at velocities between 0.5 and 2 m/sec.

Because of this double system of pain innervation,

To: Somatosensory areas

a sudden painful stimulus often gives a “double” pain

sensation: a fast-sharp pain that is transmitted to the

Thalamus

brain by the Ad fiber pathway, followed a second or so

later by a slow pain that is transmitted by the C fiber

Intralaminar

pathway. The sharp pain apprises the person rapidly of

nuclei

a damaging influence and, therefore, plays an impor-

Ventrobasal

complex and

tant role in making the person react immediately to

posterior

remove himself or herself from the stimulus. The slow

nuclear

pain tends to become greater over time. This sensation

group

"Slow" Pain

eventually produces the intolerable suffering of long-

Fibers

continued pain and makes the person keep trying to

"Fast" Pain

Fibers

relieve the cause of the pain.

Reticular

On entering the spinal cord from the dorsal spinal

formation

roots, the pain fibers terminate on relay neurons in the

dorsal horns. Here again, there are two systems for

processing the pain signals on their way to the brain,

as shown in Figures 48-2 and 48-3.

Pain tracts

Dual Pain Pathways in the

Cord and Brain Stem—The

Neospinothalamic Tract and the

Paleospinothalamic Tract

Figure 48-3

On entering the spinal cord, the pain signals take two

Transmission of pain signals into the brain stem, thalamus, and

pathways to the brain, through (1) the neospinothala-

cerebral cortex by way of the fast pricking pain pathway and the

mic tract and (2) the paleospinothalamic tract.

slow burning pain pathway.

Neospinothalamic Tract for Fast Pain. The fast type Ad

pain fibers transmit mainly mechanical and acute

thermal pain. They terminate mainly in lamina I

Termination of the Neospinothalamic Tract in the Brain

(lamina marginalis) of the dorsal horns, as shown in

Stem and Thalamus. A few fibers of the neospinothal-

Figure 48-2, and there excite second-order neurons of

amic tract terminate in the reticular areas of the brain

the neospinothalamic tract. These give rise to long

stem, but most pass all the way to the thalamus without

fibers that cross immediately to the opposite side of

interruption, terminating in the ventrobasal complex

the cord through the anterior commissure and then

along with the dorsal column-medial lemniscal tract

turn upward, passing to the brain in the anterolateral

for tactile sensations, as was discussed in Chapter 47.

columns.

A few fibers also terminate in the posterior nuclear

Chapter 48

Somatic Sensations: II. Pain, Headache, and Thermal Sensations

601

group of the thalamus. From these thalamic areas, the

Projection of the Paleospinothalamic Pathway (Slow-

signals are transmitted to other basal areas of the brain

Chronic Pain Signals) into the Brain Stem and Thala-

as well as to the somatosensory cortex.

mus. The slow-chronic paleospinothalamic pathway

terminates widely in the brain stem, in the large

shaded area shown in Figure 48-3. Only one tenth to

Capability of the Nervous System to Localize Fast Pain

one fourth of the fibers pass all the way to the thala-

in the Body. The fast-sharp type of pain can be local-

mus. Instead, most terminate in one of three areas: (1)

ized much more exactly in the different parts of the

the reticular nuclei of the medulla, pons, and mesen-

body than can slow-chronic pain. However, when only

cephalon; (2) the tectal area of the mesencephalon

pain receptors are stimulated, without the simultane-

deep to the superior and inferior colliculi; or (3) the

ous stimulation of tactile receptors, even fast pain may

periaqueductal gray region surrounding the aqueduct

be poorly localized, often only within 10 centimeters

of Sylvius. These lower regions of the brain appear to

or so of the stimulated area. Yet when tactile receptors

be important for feeling the suffering types of pain,

that excite the dorsal column-medial lemniscal system

because animals whose brains have been sectioned

are simultaneously stimulated, the localization can be

above the mesencephalon to block pain signals from

nearly exact.

reaching the cerebrum still evince undeniable evi-

dence of suffering when any part of the body is trau-

Glutamate, the Probable Neurotransmitter of the Type

matized. From the brain stem pain areas, multiple

Ad Fast Pain Fibers. It is believed that glutamate is the

short-fiber neurons relay the pain signals upward into

neurotransmitter substance secreted in the spinal cord

the intralaminar and ventrolateral nuclei of the thala-

at the type Ad pain nerve fiber endings. This is one of

mus and into certain portions of the hypothalamus and

the most widely used excitatory transmitters in the

other basal regions of the brain.

central nervous system, usually having a duration of

action lasting for only a few milliseconds.

Very Poor Capability of the Nervous System to Local-

ize Precisely the Source of Pain Transmitted in the

Paleospinothalamic Pathway for Transmitting Slow-Chronic

Slow-Chronic Pathway. Localization of pain transmit-

Pain. The paleospinothalamic pathway is a much older

ted by way of the paleospinothalamic pathway is poor.

system and transmits pain mainly from the peripheral

For instance, slow-chronic pain can usually be local-

slow-chronic type C pain fibers, although it does trans-

ized only to a major part of the body, such as to one

mit some signals from type Ad fibers as well. In this

arm or leg but not to a specific point on the arm or leg.

pathway, the peripheral fibers terminate in the spinal

This is in keeping with the multisynaptic, diffuse con-

cord almost entirely in laminae II and III of the dorsal

nectivity of this pathway. It explains why patients often

horns, which together are called the substantia gelati-

have serious difficulty in localizing the source of some

nosa, as shown by the lateral most dorsal root type C

chronic types of pain.

fiber in Figure 48-2. Most of the signals then pass

through one or more additional short fiber neurons

Function of the Reticular Formation, Thalamus, and Cerebral

within the dorsal horns themselves before entering

Cortex in the Appreciation of Pain. Complete removal of

mainly lamina V, also in the dorsal horn. Here the last

the somatic sensory areas of the cerebral cortex does

neurons in the series give rise to long axons that mostly

not destroy an animal’s ability to perceive pain. There-

join the fibers from the fast pain pathway, passing first

fore, it is likely that pain impulses entering the brain

through the anterior commissure to the opposite side

stem reticular formation, the thalamus, and other

of the cord, then upward to the brain in the anterolat-

lower brain centers cause conscious perception of

eral pathway.

pain. This does not mean that the cerebral cortex has

nothing to do with normal pain appreciation; electri-

Substance P, the Probable Slow-Chronic Neurotrans-

cal stimulation of cortical somatosensory areas does

mitter of Type C Nerve Endings. Research experi-

cause a human being to perceive mild pain from about

ments suggest that type C pain fiber terminals entering

3 per cent of the points stimulated. However, it is

the spinal cord secrete both glutamate transmitter and

believed that the cortex plays an especially important

substance P transmitter. The glutamate transmitter

role in interpreting pain quality, even though pain per-

acts instantaneously and lasts for only a few millisec-

ception might be principally the function of lower

onds. Substance P is released much more slowly, build-

centers.

ing up in concentration over a period of seconds or

even minutes. In fact, it has been suggested that the

Special Capability of Pain Signals to Arouse Overall Brain

“double” pain sensation one feels after a pinprick

Excitability. Electrical stimulation in the reticular areas

might result partly from the fact that the glutamate

of the brain stem and in the intralaminar nuclei of the

transmitter gives a faster pain sensation, whereas the

thalamus, the areas where the slow-suffering type of

substance P transmitter gives a more lagging sensa-

pain terminates, has a strong arousal effect on nervous

tion. Regardless of the yet unknown details, it seems

activity throughout the entire brain. In fact, these two

clear that glutamate is the neurotransmitter most

areas constitute part of the brain’s principal “arousal

involved in transmitting fast pain into the central

system,” which is discussed in Chapter 59. This explains

nervous system, and substance P is concerned with

why it is almost impossible for a person to sleep when

slow-chronic pain.

he or she is in severe pain.

602

Unit IX The Nervous System: A. General Principles and Sensory Physiology

Surgical Interruption of Pain Pathways. When a person has

severe and intractable pain (sometimes resulting from

Third

rapidly spreading cancer), it is necessary to relieve the

ventricle

pain. To do this, the pain nervous pathways can be cut

at any one of several points. If the pain is in the lower

Periventricular

Aqueduct

nuclei

part of the body, a cordotomy in the thoracic region of

the spinal cord often relieves the pain for a few weeks

Periaqueductal gray

Mesencephalon

to a few months. To do this, the spinal cord on the side

opposite to the pain is partially cut in its anterolateral

quadrant to interrupt the anterolateral sensory pathway.

Enkephalin neurons

A cordotomy, however, is not always successful in

relieving pain, for two reasons. First, many pain fibers

Fourth

Pons

from the upper part of the body do not cross to the

ventricle

Raphe magnus

opposite side of the spinal cord until they have reached

nucleus

the brain, so that the cordotomy does not transect these

fibers. Second, pain frequently returns several months

Medulla

later, partly as a result of sensitization of other pathways

that normally are too weak to be effectual (e.g., sparse

pathways in the dorsolateral cord). Another experi-

Serotonergic

mental operative procedure to relieve pain has been to

neurons

cauterize specific pain areas in the intralaminar nuclei

in the thalamus, which often relieves suffering types of

pain while leaving intact one’s appreciation of “acute”

pain, an important protective mechanism.

Pain fibers

Enkephalin

neurons

Presynaptic

Pain Suppression

pain inhibition

(“Analgesia”) System in the

Anterolateral

Brain and Spinal Cord

somatosensory tract

The degree to which a person reacts to pain varies

Figure 48-4

tremendously. This results partly from a capability of

the brain itself to suppress input of pain signals to the

Analgesia system of the brain and spinal cord, showing (1) inhi-

nervous system by activating a pain control system,

bition of incoming pain signals at the cord level and (2) presence

of enkephalin-secreting neurons that suppress pain signals in

called an analgesia system.

both the cord and the brain stem.

The analgesia system is shown in Figure 48-4. It

consists of three major components: (1) The periaque-

ductal gray and periventricular areas of the mesen-

cephalon and upper pons surround the aqueduct of

periventricular nuclei and from the periaqueductal

Sylvius and portions of the third and fourth ventricles.

gray area secrete enkephalin at their endings. Thus, as

Neurons from these areas send signals to (2) the raphe

shown in Figure 48-4, the endings of many fibers in

magnus nucleus, a thin midline nucleus located in

the raphe magnus nucleus release enkephalin when

the lower pons and upper medulla, and the nucleus

stimulated.

reticularis paragigantocellularis, located laterally in

Fibers originating in this area send signals to the

the medulla. From these nuclei, second-order signals

dorsal horns of the spinal cord to secrete serotonin at

are transmitted down the dorsolateral columns in the

their endings. The serotonin causes local cord neurons

spinal cord to (3) a pain inhibitory complex located in

to secrete enkephalin as well. The enkephalin is

the dorsal horns of the spinal cord. At this point, the

believed to cause both presynaptic and postsynaptic

analgesia signals can block the pain before it is relayed

inhibition of incoming type C and type Ad pain fibers

to the brain.

where they synapse in the dorsal horns.

Electrical stimulation either in the periaqueductal

Thus, the analgesia system can block pain signals at

gray area or in the raphe magnus nucleus can suppress

the initial entry point to the spinal cord. In fact, it can

many strong pain signals entering by way of the dorsal

also block many local cord reflexes that result from

spinal roots. Also, stimulation of areas at still higher

pain signals, especially withdrawal reflexes described

levels of the brain that excite the periaqueductal gray

in Chapter 54.

area can also suppress pain. Some of these areas are

(1) the periventricular nuclei in the hypothalamus, lying

adjacent to the third ventricle, and (2) to a lesser

Brain’s Opiate System—Endorphins

extent, the medial forebrain bundle, also in the hypo-

and Enkephalins

thalamus.

Several transmitter substances are involved in the

More than 35 years ago it was discovered that injec-

analgesia system; especially involved are enkephalin

tion of minute quantities of morphine either into the

and serotonin. Many nerve fibers derived from the

periventricular nucleus around the third ventricle or

Chapter 48

Somatic Sensations: II. Pain, Headache, and Thermal Sensations

603

into the periaqueductal gray area of the brain stem

been reported in some instances. Also, pain relief has

causes an extreme degree of analgesia. In subsequent

been reported to last for as long as 24 hours after only

studies, it has been found that morphine-like agents,

a few minutes of stimulation.

mainly the opiates, also act at many other points in the

analgesia system, including the dorsal horns of the

Referred Pain

spinal cord. Because most drugs that alter excitability

of neurons do so by acting on synaptic receptors, it was

Often a person feels pain in a part of the body that is

assumed that the “morphine receptors” of the analge-

fairly remote from the tissue causing the pain. This is

sia system must be receptors for some morphine-like

called referred pain. For instance, pain in one of the

neurotransmitter that is naturally secreted in the

visceral organs often is referred to an area on the body

brain. Therefore, an extensive search was undertaken

surface. Knowledge of the different types of referred

for the natural opiate of the brain. About a dozen such

pain is important in clinical diagnosis because in many

opiate-like substances have now been found at differ-

visceral ailments the only clinical sign is referred pain.

ent points of the nervous system; all are breakdown

products of three large protein molecules: pro-

Mechanism of Referred Pain. Figure 48-5 shows the prob-

opiomelanocortin, proenkephalin, and prodynorphin.

able mechanism by which most pain is referred. In the

Among the more important of these opiate-like

figure, branches of visceral pain fibers are shown to

substances are b-endorphin, met-enkephalin, leu-

synapse in the spinal cord on the same second-order

enkephalin, and dynorphin.

neurons (1 and 2) that receive pain signals from the

The two enkephalins are found in the brain stem

skin. When the visceral pain fibers are stimulated, pain

and spinal cord, in the portions of the analgesia system

signals from the viscera are conducted through at least

described earlier, and b-endorphin is present in both

some of the same neurons that conduct pain signals

the hypothalamus and the pituitary gland. Dynorphin

from the skin, and the person has the feeling that the

is found mainly in the same areas as the enkephalins,

sensations originate in the skin itself.

but in much lower quantities.

Thus, although the fine details of the brain’s opiate

system are not understood, activation of the analgesia

Visceral Pain

system by nervous signals entering the periaqueductal

gray and periventricular areas, or inactivation of pain

In clinical diagnosis, pain from the different viscera of

pathways by morphine-like drugs, can almost totally

the abdomen and chest is one of the few criteria that

suppress many pain signals entering through the

can be used for diagnosing visceral inflammation, vis-

ceral infectious disease, and other visceral ailments.

peripheral nerves.

Often, the viscera have sensory receptors for no other

modalities of sensation besides pain. Also, visceral pain

differs from surface pain in several important aspects.

Inhibition of Pain Transmission

One of the most important differences between

by Simultaneous Tactile

surface pain and visceral pain is that highly localized

Sensory Signals

types of damage to the viscera seldom cause severe

pain. For instance, a surgeon can cut the gut entirely in

Another important event in the saga of pain control was

two in a patient who is awake without causing signifi-

the discovery that stimulation of large type Ab sensory

cant pain. Conversely, any stimulus that causes diffuse

fibers from peripheral tactile receptors can depress

stimulation of pain nerve endings throughout a viscus

transmission of pain signals from the same body area.

causes pain that can be severe. For instance, ischemia

This presumably results from local lateral inhibition in

the spinal cord. It explains why such simple maneuvers

as rubbing the skin near painful areas is often effective

in relieving pain. And it probably also explains why lin-

iments are often useful for pain relief.

This mechanism and the simultaneous psychogenic

excitation of the central analgesia system are probably

also the basis of pain relief by acupuncture.

Treatment of Pain by Electrical

Stimulation

Several clinical procedures have been developed for

suppressing pain by electrical stimulation. Stimulating

electrodes are placed on selected areas of the skin or,

on occasion, implanted over the spinal cord, supposedly

Visceral

Skin nerve

to stimulate the dorsal sensory columns.

nerve fibers

fibers

In some patients, electrodes have been placed stereo-

taxically in appropriate intralaminar nuclei of the thal-

amus or in the periventricular or periaqueductal area of

Figure 48-5

the diencephalon. The patient can then personally

control the degree of stimulation. Dramatic relief has

Mechanism of referred pain and referred hyperalgesia.

604

Unit IX The Nervous System: A. General Principles and Sensory Physiology

caused by occluding the blood supply to a large area of

“Parietal Pain” Caused by

gut stimulates many diffuse pain fibers at the same time

Visceral Disease

and can result in extreme pain.

When a disease affects a viscus, the disease process

often spreads to the parietal peritoneum, pleura, or

Causes of True Visceral Pain

pericardium. These parietal surfaces, like the skin, are

supplied with extensive pain innervation from the

Any stimulus that excites pain nerve endings in diffuse

peripheral spinal nerves. Therefore, pain from the pari-

areas of the viscera can cause visceral pain. Such stimuli

etal wall overlying a viscus is frequently sharp. An

include ischemia of visceral tissue, chemical damage to

example can emphasize the difference between this

the surfaces of the viscera, spasm of the smooth muscle

pain and true visceral pain: a knife incision through the

of a hollow viscus, excess distention of a hollow viscus,

parietal peritoneum is very painful, whereas a similar

and stretching of the connective tissue surrounding or

cut through the visceral peritoneum or through a gut

within the viscus. Essentially all visceral pain that orig-

wall is not very painful, if painful at all.

inates in the thoracic and abdominal cavities is trans-

mitted through small type C pain fibers and, therefore,

can transmit only the chronic-aching-suffering type of

Localization of Visceral Pain—

pain.

“Visceral” and the “Parietal” Pain

Transmission Pathways

Ischemia. Ischemia causes visceral pain in the same way

that it does in other tissues, presumably because of the

Pain from the different viscera is frequently difficult to

formation of acidic metabolic end products or tissue-

localize, for a number of reasons. First, the patient’s

degenerative products such as bradykinin, proteolytic

brain does not know from firsthand experience that the

enzymes, or others that stimulate pain nerve endings.

different internal organs exist; therefore, any pain that

originates internally can be localized only generally.

Second, sensations from the abdomen and thorax are

Chemical Stimuli. On occasion, damaging substances leak

transmitted through two pathways to the central

from the gastrointestinal tract into the peritoneal cavity.

nervous system—the true visceral pathway and the pari-

For instance, proteolytic acidic gastric juice often leaks

etal pathway. True visceral pain is transmitted via pain

through a ruptured gastric or duodenal ulcer. This juice

sensory fibers within the autonomic nerve bundles, and

causes widespread digestion of the visceral peritoneum,

the sensations are referred to surface areas of the body

thus stimulating broad areas of pain fibers. The pain is

often far from the painful organ. Conversely, parietal

usually excruciatingly severe.

sensations are conducted directly into local spinal

nerves from the parietal peritoneum, pleura, or peri-

Spasm of a Hollow Viscus. Spasm of a portion of the gut,

cardium, and these sensations are usually localized

the gallbladder, a bile duct, a ureter, or any other hollow

directly over the painful area.

viscus can cause pain, possibly by mechanical stimula-

tion of the pain nerve endings. Or the spasm might cause

Localization of Referred Pain Transmitted via Visceral Pathways.

diminished blood flow to the muscle, combined with the

When visceral pain is referred to the surface of the body,

muscle’s increased metabolic need for nutrients, thus

the person generally localizes it in the dermatomal

causing severe pain.

segment from which the visceral organ originated in the

Often pain from a spastic viscus occurs in the form of

embryo, not necessarily where the visceral organ now

cramps, with the pain increasing to a high degree of

lies. For instance, the heart originated in the neck and

severity and then subsiding. This process continues

upper thorax, so that the heart’s visceral pain fibers pass

intermittently, once every few minutes. The intermittent

upward along the sympathetic sensory nerves and enter

cycles result from periods of contraction of smooth

the spinal cord between segments C-3 and T-5. There-

muscle. For instance, each time a peristaltic wave travels

fore, as shown in Figure 48-6, pain from the heart is

along an overly excitable spastic gut, a cramp occurs.

referred to the side of the neck, over the shoulder, over

The cramping type of pain frequently occurs in appen-

the pectoral muscles, down the arm, and into the sub-

dicitis, gastroenteritis, constipation, menstruation, par-

sternal area of the upper chest. These are the areas of

turition, gallbladder disease, or ureteral obstruction.

the body surface that send their own somatosensory

nerve fibers into the C-3 to T-5 cord segments. Most fre-

quently, the pain is on the left side rather than on the

Overdistention of a Hollow Viscus. Extreme overfilling of a

right because the left side of the heart is much more fre-

hollow viscus also can result in pain, presumably

quently involved in coronary disease than the right.

because of overstretch of the tissues themselves.

The stomach originated approximately from the

Overdistention can also collapse the blood vessels that

seventh to ninth thoracic segments of the embryo.

encircle the viscus or that pass into its wall, thus perhaps

Therefore, stomach pain is referred to the anterior epi-

promoting ischemic pain.

gastrium above the umbilicus, which is the surface area

of the body subserved by the seventh through ninth tho-

Insensitive Viscera. A few visceral areas are almost com-

racic segments. Figure 48-6 shows several other surface

pletely insensitive to pain of any type. These include the

areas to which visceral pain is referred from other

parenchyma of the liver and the alveoli of the lungs. Yet

organs, representing in general the areas in the embryo

the liver capsule is extremely sensitive to both direct

from which the respective organs originated.

trauma and stretch, and the bile ducts are also sensitive

to pain. In the lungs, even though the alveoli are insen-

Parietal Pathway for Transmission of Abdominal and Thoracic

sitive, both the bronchi and the parietal pleura are very

Pain. Pain from the viscera is frequently localized to two

sensitive to pain.

surface areas of the body at the same time because of

Chapter 48

Somatic Sensations: II. Pain, Headache, and Thermal Sensations

605

Heart

T-10

Esophagus

L-1

Stomach

Liver and

gallbladder

Pylorus

Umbilicus

Appendix and

small intestine

Right kidney

Visceral pain

Left kidney

Colon

Parietal pain

Ureter

Figure 48-6

Figure 48-7

Surface areas of referred pain from different visceral organs.

Visceral and parietal transmission of

pain

signals from the

appendix.

Herpes Zoster (Shingles)

the dual transmission of pain through the referred vis-

Occasionally herpesvirus infects a dorsal root ganglion.

ceral pathway and the direct parietal pathway. Thus,

This causes severe pain in the dermatomal segment sub-

Figure 48-7 shows dual transmission from an inflamed

served by the ganglion, thus eliciting a segmental type

appendix. Pain impulses pass first from the appendix

of pain that circles halfway around the body. The disease

through visceral pain fibers located within sympathetic

is called herpes zoster, or “shingles,” because of a skin

nerve bundles, and then into the spinal cord at about

eruption that often ensues.

T-10 or T-11; this pain is referred to an area around the

The cause of the pain is presumably infection of the

umbilicus and is of the aching, cramping type. Pain

pain neuronal cells in the dorsal root ganglion by the

impulses also often originate in the parietal peritoneum

virus. In addition to causing pain, the virus is carried by

where the inflamed appendix touches or is adherent to

neuronal cytoplasmic flow outward through the neu-

the abdominal wall. These cause pain of the sharp type

ronal peripheral axons to their cutaneous origins. Here

directly over the irritated peritoneum in the right lower

the virus causes a rash that vesiculates within a few days

quadrant of the abdomen.

and then crusts over within another few days, all of this

occurring within the dermatomal area served by the

infected dorsal root.

Some Clinical Abnormalities

of Pain and Other

Somatic Sensations

Tic Douloureux

Lancinating pain occasionally occurs in some people

Hyperalgesia

over one side of the face in the sensory distribution area

A pain nervous pathway sometimes becomes exces-

(or part of the area) of the fifth or ninth nerves; this phe-

sively excitable; this gives rise to hyperalgesia, which

nomenon is called tic douloureux (or trigeminal neural-

means hypersensitivity to pain. Possible causes of hyper-

gia or glossopharyngeal neuralgia). The pain feels like

algesia are (1) excessive sensitivity of the pain receptors

sudden electrical shocks, and it may appear for only a

themselves, which is called primary hyperalgesia, and

few seconds at a time or may be almost continuous.

(2) facilitation of sensory transmission, which is called

Often it is set off by exceedingly sensitive trigger areas

secondary hyperalgesia.

on the surface of the face, in the mouth, or inside the

An example of primary hyperalgesia is the extreme

throat—almost always by a mechanoreceptive stimulus

sensitivity of sunburned skin, which results from

rather than a pain stimulus. For instance, when the

sensitization of the skin pain endings by local tissue

patient swallows a bolus of food, as the food touches a

products from the burn—perhaps histamine, perhaps

tonsil, it might set off a severe lancinating pain in the

prostaglandins, perhaps others. Secondary hyperalgesia

mandibular portion of the fifth nerve.

frequently results from lesions in the spinal cord or the

The pain of tic douloureux can usually be blocked by

thalamus. Several of these lesions are discussed in sub-

surgically cutting the peripheral nerve from the hyper-

sequent sections.

sensitive area. The sensory portion of the fifth nerve is

606

Unit IX The Nervous System: A. General Principles and Sensory Physiology

often sectioned immediately inside the cranium, where

result from pain stimuli arising inside the cranium, but

the motor and sensory roots of the fifth nerve separate

others result from pain arising outside the cranium, such

from each other, so that the motor portions, which are

as from the nasal sinuses.

needed for many jaw movements, can be spared while

the sensory elements are destroyed. This operation

leaves the side of the face anesthetic, which in itself may

Headache of Intracranial Origin

be annoying. Furthermore, sometimes the operation is

Pain-Sensitive Areas in Cranial Vault. The brain tissues

unsuccessful, indicating that the lesion that causes the

themselves are almost totally insensitive to pain. Even

pain might be in the sensory nucleus in the brain stem

cutting or electrically stimulating the sensory areas

and not in the peripheral nerves.

of the cerebral cortex only occasionally causes pain;

instead, it causes prickly types of paresthesias on the

Brown-Séquard Syndrome

area of the body represented by the portion of the

sensory cortex stimulated. Therefore, it is likely that

If the spinal cord is transected entirely, all sensations

much or most of the pain of headache is not caused by

and motor functions distal to the segment of transection

damage within the brain itself.

are blocked, but if the spinal cord is transected on only

Conversely, tugging on the venous sinuses around the

one side, the Brown-Séquard syndrome occurs. The

brain, damaging the tentorium, or stretching the dura at

effects of such transection can be predicted from a

the base of the brain can cause intense pain that is rec-

knowledge of the cord fiber tracts shown in Figure 48-8.

ognized as headache. Also, almost any type of trauma-

All motor functions are blocked on the side of the tran-

tizing, crushing, or stretching stimulus to the blood

section in all segments below the level of the transec-

vessels of the meninges can cause headache. An espe-

tion. Yet only some of the modalities of sensation are

cially sensitive structure is the middle meningeal artery,

lost on the transected side, and others are lost on the

and neurosurgeons are careful to anesthetize this artery

opposite side. The sensations of pain, heat, and cold—

specifically when performing brain operations under

sensations served by the spinothalamic pathway—are

local anesthesia.

lost on the opposite side of the body in all dermatomes

two to six segments below the level of the transection.

Areas of the Head to Which Intracranial Headache Is Referred.

By contrast, the sensations that are transmitted only in

Stimulation of pain receptors in the cerebral vault

the dorsal and dorsolateral columns—kinesthetic and

above the tentorium, including the upper surface of the

position sensations, vibration sensation, discrete local-

tentorium itself, initiates pain impulses in the cerebral

ization, and two-point discrimination—are lost on the

portion of the fifth nerve and, therefore, causes referred

side of the transection in all dermatomes below the level

headache to the front half of the head in the surface

of the transection. Discrete “light touch” is impaired

areas supplied by this somatosensory portion of the fifth

on the side of the transection because the principal

cranial nerve, as shown in Figure 48-9.

pathway for the transmission of light touch, the dorsal

Conversely, pain impulses from beneath the

column, is transected. That is, the fibers in this column

tentorium enter the central nervous system mainly

do not cross to the opposite side until they reach the

through the glossopharyngeal, vagal, and second cervi-

medulla of the brain. “Crude touch,” which is poorly

cal nerves, which also supply the scalp above, behind,

localized, still persists because of partial transmission in

and slightly below the ear. Subtentorial pain stimuli

the opposite spinothalamic tract.

cause “occipital headache” referred to the posterior

part of the head.

Headache

Headaches are a type of pain referred to the surface of

the head from deep head structures. Some headaches

Cerebral vault

Brain stem and

headaches

cerebellar vault

headaches

Fasciculus gracilis

Fasciculus cuneatus

Lateral

Dorsal

corticospinal

spinocerebellar

Nasal sinus

Rubrospinal

and eye

Lateral

headaches

spinothalamic

Olivospinal

Ventral

spinocerebellar

Tectospinal

Spinotectal

Ventral

corticospinal

Vestibulospinal

Ventral spinothalamic

Descending

Ascending

Tracts

Figure 48-8

Figure 48-9

Cross section of the spinal cord, showing principal ascending

tracts on the right and principal descending tracts on the left.

Areas of headache resulting from different causes.

Chapter 48

Somatic Sensations: II. Pain, Headache, and Thermal Sensations

607

Types of Intracranial Headache

absorbed toxic products or from changes in the circula-

Headache of Meningitis. One of the most severe

tory system resulting from loss of fluid into the gut.

headaches of all is that resulting from meningitis, which

causes inflammation of all the meninges, including the

sensitive areas of the dura and the sensitive areas

Extracranial Types of Headache

around the venous sinuses. Such intense damage can

Headache Resulting from Muscle Spasm. Emotional tension

cause extreme headache pain referred over the entire

often causes many of the muscles of the head, especially

head.

those muscles attached to the scalp and the neck

Headache Caused by Low Cerebrospinal Fluid Pressure.

muscles attached to the occiput, to become spastic, and

Removing as little as 20 milliliters of fluid from the

it is postulated that this is one of the common causes of

spinal canal, particularly if the person remains in an

headache. The pain of the spastic head muscles suppos-

upright position, often causes intense intracranial

edly is referred to the overlying areas of the head and

headache. Removing this quantity of fluid removes part

gives one the same type of headache as intracranial

of the flotation for the brain that is normally provided

lesions do.

by the cerebrospinal fluid. The weight of the brain

stretches and otherwise distorts the various dural

Headache Caused by Irritation of Nasal and Accessory Nasal

surfaces and thereby elicits the pain that causes the

Structures. The mucous membranes of the nose and

headache.

nasal sinuses are sensitive to pain, but not intensely so.

Nevertheless, infection or other irritative processes in

Migraine Headache. Migraine headache is a special type

widespread areas of the nasal structures often summate

of headache that is thought to result from abnormal vas-

and cause headache that is referred behind the eyes or,

cular phenomena, although the exact mechanism is

in the case of frontal sinus infection, to the frontal sur-

unknown. Migraine headaches often begin with various

faces of the forehead and scalp, as shown in Figure 48-9.

prodromal sensations, such as nausea, loss of vision in

Also, pain from the lower sinuses, such as from the max-

part of the field of vision, visual aura, and other types

illary sinuses, can be felt in the face.

of sensory hallucinations. Ordinarily, the prodromal

symptoms begin 30 minutes to

1 hour before the

Headache Caused by Eye Disorders. Difficulty in focusing

beginning of the headache. Any theory that explains

one’s eyes clearly may cause excessive contraction of

migraine headache must also explain the prodromal

the eye ciliary muscles in an attempt to gain clear vision.

symptoms.

Even though these muscles are extremely small, it is

One of the theories of the cause of migraine

believed that tonic contraction of them can cause retro-

headaches is that prolonged emotion or tension causes

orbital headache. Also, excessive attempts to focus

reflex vasospasm of some of the arteries of the head,

the eyes can result in reflex spasm in various facial

including arteries that supply the brain. The vasospasm

and extraocular muscles, which is a possible cause of

theoretically produces ischemia of portions of the brain,

headache.

and this is responsible for the prodromal symptoms.

A second type of headache that originates in the eyes

Then, as a result of the intense ischemia, something

occurs when the eyes are exposed to excessive irradia-

happens to the vascular walls, perhaps exhaustion of

tion by light rays, especially ultraviolet light. Looking at

smooth muscle contraction, to allow the blood vessels

the sun or the arc of an arc-welder for even a few

to become flaccid and incapable of maintaining vascu-

seconds may result in headache that lasts from 24 to 48

lar tone for 24 to 48 hours. The blood pressure in the

hours. The headache sometimes results from “actinic”

vessels causes them to dilate and pulsate intensely, and

irritation of the conjunctivae, and the pain is referred to

it is postulated that the excessive stretching of the walls

the surface of the head or retro-orbitally. However,

of the arteries—including some extracranial arteries,

focusing intense light from an arc or the sun on the

such as the temporal artery—causes the actual pain

retina can also burn the retina, and this could be the

of migraine headaches. Other theories of the cause

cause of the headache.

of migraine headaches include spreading cortical de-

pression, psychological abnormalities, and vasospasm

caused by excess local potassium in the cerebral extra-

Thermal Sensations

cellular fluid.

There may be a genetic predisposition to migraine

headaches, because a positive family history for

Thermal Receptors and

migraine has been reported in 65 to 90 per cent of cases.

Their Excitation

Migraine headaches also occur about twice as fre-

quently in women as in men.

The human being can perceive different gradations of

Alcoholic Headache. As many people have experi-

cold and heat, from freezing cold to cold to cool to

enced, a headache usually follows an alcoholic binge. It

indifferent to warm to hot to burning hot.

is most likely that alcohol, because it is toxic to tissues,

Thermal gradations are discriminated by at least

directly irritates the meninges and causes the intracra-

three types of sensory receptors: cold receptors,

nial pain.

warmth receptors, and pain receptors. The pain recep-

tors are stimulated only by extreme degrees of heat or

Headache Caused by Constipation. Constipation causes

cold and, therefore, are responsible, along with the

headache in many people. Because it has been shown

cold and warmth receptors, for “freezing cold” and

that constipation headache can occur in people whose

pain sensory tracts in the spinal cord have been cut, we

“burning hot” sensations.

know that this headache is not caused by nervous

The cold and warmth receptors are located imme-

impulses from the colon. Therefore, it may result from

diately under the skin at discrete separated spots. In

608

Unit IX The Nervous System: A. General Principles and Sensory Physiology

most areas of the body, there are 3 to 10 times as many

out slightly above

40°C. Above about

30°C, the

cold spots as warmth spots, and the number in differ-

warmth receptors begin to be stimulated, but these

ent areas of the body varies from 15 to 25 cold spots

also fade out at about 49°C. Finally, at around 45°C,

per square centimeter in the lips to 3 to 5 cold spots

the heat-pain fibers begin to be stimulated by heat and,

per square centimeter in the finger to less than 1 cold

paradoxically, some of the cold fibers begin to be stim-

spot per square centimeter in some broad surface

ulated again, possibly because of damage to the cold

areas of the trunk.

endings caused by the excessive heat.

Although the existence of distinctive warmth nerve

One can understand from Figure 48-10 that a

endings is quite certain, based on psychological tests,

person determines the different gradations of thermal

they have not been identified histologically. They are

sensations by the relative degrees of stimulation of the

presumed to be free nerve endings, because warmth

different types of endings. One can also understand

signals are transmitted mainly over type C nerve fibers

why extreme degrees of both cold and heat can be

at transmission velocities of only 0.4 to 2 m/sec.

painful and why both these sensations, when intense

Conversely, a definitive cold receptor has been iden-

enough, may give almost the same quality of sensa-

tified. It is a special, small type Ad myelinated nerve

tion—that is, freezing cold and burning hot sensations

ending that branches a number of times, the tips of

feel almost alike.

which protrude into the bottom surfaces of basal epi-

dermal cells. Signals are transmitted from these recep-

Stimulatory Effects of Rising and Falling Temperature—Adap-

tors via type Ad nerve fibers at velocities of about

tation of Thermal Receptors. When a cold receptor is sud-

20 m/sec. Some cold sensations are believed to be

denly subjected to an abrupt fall in temperature, it

transmitted in type C nerve fibers as well, which sug-

becomes strongly stimulated at first, but this stimula-

gests that some free nerve endings also might function

tion fades rapidly during the first few seconds and pro-

as cold receptors.

gressively more slowly during the next 30 minutes or

more. In other words, the receptor “adapts” to a great

Stimulation of Thermal Receptors—Sensations of Cold, Cool,

extent, but never 100 per cent.

Indifferent, Warm, and Hot. Figure

48-10 shows the

Thus, it is evident that the thermal senses respond

effects of different temperatures on the responses of

markedly to changes in temperature, in addition to

four types of nerve fibers: (1) a pain fiber stimulated

being able to respond to steady states of temperature.

by cold, (2) a cold fiber, (3) a warmth fiber, and (4) a

This means that when the temperature of the skin is

pain fiber stimulated by heat. Note especially that

actively falling, a person feels much colder than when

these fibers respond differently at different levels of

the temperature remains cold at the same level. Con-

temperature. For instance, in the very cold region, only

versely, if the temperature is actively rising, the person

the cold-pain fibers are stimulated (if the skin becomes

feels much warmer than he or she would at the same

even colder, so that it nearly freezes or actually does

temperature if it were constant. The response to

freeze, these fibers cannot be stimulated). As the tem-

changes in temperature explains the extreme degree

perature rises to +10° to 15°C, the cold-pain impulses

of heat one feels on first entering a tub of hot water

cease, but the cold receptors begin to be stimulated,

and the extreme degree of cold felt on going from a

reaching peak stimulation at about 24°C and fading

heated room to the out-of-doors on a cold day.

Freezing

Indiffer-

Burning

Cold

Cool

Warm

Hot

cold

ent

hot

Cold-pain

Cold-receptors

Warmth receptors

Heat-pain

Figure 48-10

Temperature (∞C)

Discharge frequencies at different skin tempera-

tures of a cold-pain fiber, a cold fiber, a warmth

fiber, and a heat-pain fiber.

Chapter 48

Somatic Sensations: II. Pain, Headache, and Thermal Sensations

609

Mechanism of Stimulation of

being reduces but does not abolish the ability to dis-

Thermal Receptors

tinguish gradations of temperature.

It is believed that the cold and warmth receptors are

stimulated by changes in their metabolic rates, and

that these changes result from the fact that tempera-

References

ture alters the rate of intracellular chemical reactions

more than twofold for each 10°C change. In other

Almeida TF, Roizenblatt S, Tufik S: Afferent pain pathways:

words, thermal detection probably results not from

a neuroanatomical review. Brain Res 1000:40, 2004.

direct physical effects of heat or cold on the nerve

Ballantyne JC, Mao J: Opioid therapy for chronic pain.

N Engl J Med 349:1943, 2003.

endings but from chemical stimulation of the endings

Borsook D, Becerra L: Pain imaging: future applications to

as modified by temperature.

integrative clinical and basic neurobiology. Adv Drug

Deliv Rev 55:967, 2003.

Spatial Summation of Thermal Sensations. Because the

Bromm B: Brain images of pain. News Physiol Sci 16:244,

number of cold or warm endings in any one surface

2001.

area of the body is slight, it is difficult to judge grada-

Bruera E, Kim HN: Cancer pain. JAMA 290:2476, 2003.

tions of temperature when small skin areas are stimu-

Cervero F, Laird JM: Role of ion channels in mechanisms

lated. However, when a large skin area is stimulated

controlling gastrointestinal pain pathways. Curr Opin

all at once, the thermal signals from the entire area

Pharmacol 3:608, 2003.

summate. For instance, rapid changes in temperature

Costigan M, Woolf CJ: No DREAM, no pain: closing the

spinal gate. Cell 108:297, 2002.

as little as 0.01°C can be detected if this change affects

Gebhart GF: Descending modulation of pain. Neurosci

the entire surface of the body simultaneously. Con-

Biobehav Rev 27:729, 2004.

versely, temperature changes 100 times as great often

Haines DE: Fundamental Neuroscience. New York:

will not be detected when the affected skin area is only

Churchill Livingstone, 1997.

1 square centimeter in size.

Haines DE, Lancon JA: Review of Neuroscience. New York:

Churchill Livingstone, 2003.

Jordt SE, McKemy DD, Julius D: Lessons from peppers and

Transmission of Thermal Signals

peppermint: the molecular logic of thermosensation. Curr

in the Nervous System

Opin Neurobiol 13:487, 2003.

Kandel ER, Schwartz JH, Jessell TM: Principles of Neural

Science, 4th ed. New York: McGraw-Hill, 2000.

In general, thermal signals are transmitted in pathways

Kors EE, Vanmolkot KR, Haan J, et al: Recent findings in

parallel to those for pain signals. On entering the

headache genetics. Curr Opin Neurol 17:283, 2004.

spinal cord, the signals travel for a few segments

Mendell JR, Sahenk Z: Clinical practice: painful sensory

upward or downward in the tract of Lissauer and then

neuropathy. N Engl J Med 348:1243, 2003.

terminate mainly in laminae I, II, and III of the dorsal

Montell C: Thermosensation: hot findings make TRPNs very

horns—the same as for pain. After a small amount of

cool. Curr Biol 13:R476, 2003.

processing by one or more cord neurons, the signals

Sanchez-del-Rio M, Reuter U: Migraine aura: new informa-

enter long, ascending thermal fibers that cross to the

tion on underlying mechanisms. Curr Opin Neurol 17:289,

opposite anterolateral sensory tract and terminate in

2004.

Schaible HG, Ebersberger A, Von Banchet GS: Mechanisms

both (1) the reticular areas of the brain stem and (2)

of pain in arthritis. Ann N Y Acad Sci 966:343, 2002.

the ventrobasal complex of the thalamus.

Silberstein SD: Migraine. Lancet 363:381, 2004.

A few thermal signals are also relayed to the cere-

Vogt BA: Knocking out the DREAM to study pain. N Engl

bral somatic sensory cortex from the ventrobasal

J Med 347:362, 2002.

complex. Occasionally a neuron in cortical somatic

Watkins LR, Maier SF: Beyond neurons: evidence that

sensory area I has been found by microelectrode

immune and glial cells contribute to pathological pain

studies to be directly responsive to either cold or warm

states. Physiol Rev 82:981, 2002.

stimuli on a specific area of the skin. However, removal

Zubrzycka M, Janecka A: Substance P: transmitter of noci-

of the entire cortical postcentral gyrus in the human

ception (minireview). Endocr Regul 34:195, 2000.

C H A P T E R

The Eye: I. Optics of Vision

Physical Principles

of Optics

Before it is possible to understand the optical

system of the eye, the student must first be thor-

oughly familiar with the basic principles of optics,

including the physics of light refraction, focusing,

depth of focus, and so forth. A brief review of these

physical principles is presented; then the optics of the eye is discussed.

Refraction of Light

Refractive Index of a Transparent Substance. Light rays travel through air at a velocity of

about 300,000 km/sec, but they travel much slower through transparent solids

and liquids. The refractive index of a transparent substance is the ratio of the

velocity of light in air to the velocity in the substance. The refractive index of air

itself is 1.00. Thus, if light travels through a particular type of glass at a velocity of

200,000 km/sec, the refractive index of this glass is 300,000 divided by 200,000, or

1.50.

Refraction of Light Rays at an Interface Between Two Media with Different Refractive Indices.

When light rays traveling forward in a beam (as shown in Figure 49-1A) strike an

interface that is perpendicular to the beam, the rays enter the second medium

without deviating from their course. The only effect that occurs is decreased veloc-

ity of transmission and shorter wavelength, as shown in the figure by the shorter

distances between wave fronts.

If the light rays pass through an angulated interface as shown in Figure 49-1B,

the rays bend if the refractive indices of the two media are different from each other.

In this particular figure, the light rays are leaving air, which has a refractive index

of 1.00, and are entering a block of glass having a refractive index of 1.50. When the

beam first strikes the angulated interface, the lower edge of the beam enters the

glass ahead of the upper edge. The wave front in the upper portion of the beam con-

tinues to travel at a velocity of 300,000 km/sec, while that which entered the glass

travels at a velocity of 200,000 km/sec. This causes the upper portion of the wave

front to move ahead of the lower portion, so that the wave front is no longer ver-

tical but angulated to the right. Because the direction in which light travels is always

perpendicular to the plane of the wave front, the direction of travel of the light beam

bends downward.

This bending of light rays at an angulated interface is known as refraction. Note

particularly that the degree of refraction increases as a function of (1) the ratio of

the two refractive indices of the two transparent media and (2) the degree of angu-

lation between the interface and the entering wave front.

Application of Refractive Principles to Lenses

Convex Lens Focuses Light Rays. Figure 49-2 shows parallel light rays entering a convex

lens. The light rays passing through the center of the lens strike the lens exactly per-

pendicular to the lens surface and, therefore, pass through the lens without being

refracted. Toward either edge of the lens, however, the light rays strike a progres-

sively more angulated interface. The outer rays bend more and more toward the

center, which is called convergence of the rays. Half the bending occurs when

the rays enter the lens, and half as they exit from the opposite side. (At this time,

the student should pause and analyze why the rays bend toward the center on

leaving the lens.) Finally, if the lens has exactly the proper curvature, parallel light

613

614

Unit X The Nervous System: B. The Special Senses

Wave fronts

Glass

Light from

distant source

Figure 49-1

Figure 49-3

Light rays entering a glass surface perpendicular to the light rays

Bending of light rays at each surface of a concave spherical lens,

(A) and a glass surface angulated to the light rays (B). This figure

showing that parallel light rays are diverged.

demonstrates that the distance between waves after they enter

the glass is shortened to about two thirds that in air. It also shows

that light rays striking an angulated glass surface are bent.

Light from

Focal length

distant source

Figure 49-2

Bending of light rays at each surface of a convex spherical lens,

showing that parallel light rays are focused to a focal point.

rays passing through each part of the lens will be bent

exactly enough so that all the rays will pass through a

single point, which is called the focal point.

Concave Lens Diverges Light Rays. Figure 49-3 shows the

effect of a concave lens on parallel light rays. The rays

that enter the center of the lens strike an interface that

is perpendicular to the beam and, therefore, do not

refract. The rays at the edge of the lens enter the lens

ahead of the rays in the center. This is opposite to the

effect in the convex lens, and it causes the peripheral

light rays to diverge from the light rays that pass through

the center of the lens. Thus, the concave lens diverges

light rays, but the convex lens converges light rays.

Cylindrical Lens Bends Light Rays in Only One Plane—Comparison

with Spherical Lenses. Figure 49-4 shows both a convex

spherical lens and a convex cylindrical lens. Note that

the cylindrical lens bends light rays from the two sides

of the lens but not from the top or the bottom. That is,

Figure 49-4

bending occurs in one plane but not the other. Thus, par-

allel light rays are bent to a focal line. Conversely, light

A, Point focus of parallel light rays by a spherical convex lens.

rays that pass through the spherical lens are refracted

B, Line focus of parallel light rays by a cylindrical convex lens.

Chapter 49

The Eye: I. Optics of Vision

615

at all edges of the lens (in both planes) toward the

Focal Length of a Lens

central ray, and all the rays come to a focal point.

The cylindrical lens is well demonstrated by a test

The distance beyond a convex lens at which parallel rays

tube full of water. If the test tube is placed in a beam of

converge to a common focal point is called the focal

sunlight and a piece of paper is brought progressively

length of the lens. The diagram at the top of Figure 49-6

closer to the opposite side of the tube, a certain distance

demonstrates this focusing of parallel light rays.

will be found at which the light rays come to a focal line.

In the middle diagram, the light rays that enter the

The spherical lens is demonstrated by an ordinary mag-

convex lens are not parallel but are diverging because

nifying glass. If such a lens is placed in a beam of sun-

the origin of the light is a point source not far away from

light and a piece of paper is brought progressively closer

the lens itself. Because these rays are diverging outward

to the lens, the light rays will impinge on a common

from the point source, it can be seen from the diagram

focal point at an appropriate distance.

that they do not focus at the same distance away from

Concave cylindrical lenses diverge light rays in only

the lens as do parallel rays. In other words, when rays

one plane in the same manner that convex cylindrical

of light that are already diverging enter a convex lens,

lenses converge light rays in one plane.

the distance of focus on the other side of the lens is

farther from the lens than is the focal length of the lens

Combination of Two Cylindrical Lenses at Right Angles

for parallel rays.

Equals a Spherical Lens. Figure

49-5B shows two

The bottom diagram of Figure 49-6 shows light rays

convex cylindrical lenses at right angles to each other.

that are diverging toward a convex lens that has far

The vertical cylindrical lens converges the light rays that

greater curvature than that of the other two lenses in

pass through the two sides of the lens, and the horizon-

the figure. In this diagram, the distance from the lens at

tal lens converges the top and bottom rays. Thus, all the

which the light rays come to focus is exactly the same

light rays come to a single-point focus. In other words,

as that from the lens in the first diagram, in which the

two cylindrical lenses crossed at right angles to each other

lens is less convex but the rays entering it are parallel.

perform the same function as one spherical lens of the

This demonstrates that both parallel rays and diverging

same refractive power.

rays can be focused at the same distance beyond a lens,

provided the lens changes its convexity.

The relation of focal length of the lens, distance of the

point source of light, and distance of focus is expressed

by the following formula:

a b

Line focus

in which f is the focal length of the lens for parallel rays,

a is the distance of the point source of light from the

lens, and b is the distance of focus on the other side of

the lens.

Point source of light

Light from distant source

Focal

points

Point source

Point source of light

Point focus

Figure 49-6

Figure 49-5

The two upper lenses of this figure have the same focal length,

A, Focusing of light from a point source to a line focus by a cylin-

but the light rays entering the top lens are parallel, whereas those

drical lens. B, Two cylindrical convex lenses at right angles to

entering the middle lens are diverging; the effect of parallel versus

each other, demonstrating that one lens converges light rays in

diverging rays on the focal distance is shown. The bottom lens

one plane and the other lens converges light rays in the plane at

has far more refractive power than either of the other two lenses

a right angle. The two lenses combined give the same point focus

(i.e., has a much shorter focal length), demonstrating that the

as that obtained with a single spherical convex lens.

stronger the lens is, the nearer to the lens the point focus is.

616

Unit X The Nervous System: B. The Special Senses

Point sources

Focal points

Figure 49-7

A, Two point sources of light

focused at two separate points on

opposite sides of the lens. B, For-

mation of an image by a convex

spherical lens.

Formation of an Image by a

The refractive power of concave lenses cannot be

Convex Lens

stated in terms of the focal distance beyond the lens

because the light rays diverge, rather than focus to a

Figure

49-7A shows a convex lens with two point

point. However, if a concave lens diverges light rays at

sources of light to the left. Because light rays pass

the same rate that a 1-diopter convex lens converges

through the center of a convex lens without being

them, the concave lens is said to have a dioptric strength

refracted in either direction, the light rays from each

of -1. Likewise, if the concave lens diverges light rays as

point source of light are shown to come to a point focus

much as a +10-diopter lens converges them, this lens is

on the opposite side of the lens directly in line with the

said to have a strength of -10 diopters.

point source and the center of the lens.

Concave lenses “neutralize” the refractive power of

Any object in front of the lens is, in reality, a mosaic

convex lenses. Thus, placing a 1-diopter concave lens

of point sources of light. Some of these points are very

immediately in front of a 1-diopter convex lens results

bright, some are very weak, and they vary in color. Each

in a lens system with zero refractive power.

point source of light on the object comes to a separate

The strengths of cylindrical lenses are computed in

point focus on the opposite side of the lens in line with

the same manner as the strengths of spherical lenses,

the lens center. If a white sheet of paper is placed at the

except that the axis of the cylindrical lens must be stated

focus distance from the lens, one can see an image of

in addition to its strength. If a cylindrical lens focuses

the object, as demonstrated in Figure 49-7B. However,

this image is upside down with respect to the original

object, and the two lateral sides of the image are

reversed. This is the method by which the lens of a

camera focuses images on film.

diopter

Measurement of the Refractive

Power of a Lens—“Diopter”

The more a lens bends light rays, the greater is its

“refractive power.” This refractive power is measured in

diopters

terms of diopters. The refractive power in diopters of a

convex lens is equal to 1 meter divided by its focal

length. Thus, a spherical lens that converges parallel

light rays to a focal point 1 meter beyond the lens has

a refractive power of +1 diopter, as shown in Figure

diopters

49-8. If the lens is capable of bending parallel light rays

twice as much as a lens with a power of +1 diopter, it is

said to have a strength of +2 diopters, and the light rays

1 meter

come to a focal point 0.5 meter beyond the lens. A lens

capable of converging parallel light rays to a focal point

Figure 49-8

only 10 centimeters (0.10 meter) beyond the lens has a

refractive power of +10 diopters.

Effect of lens strength on the focal distance.

Chapter 49

The Eye: I. Optics of Vision

617

parallel light rays to a line focus 1 meter beyond the

The total refractive power of the internal lens of the

lens, it has a strength of +1 diopter. Conversely, if a cylin-

eye, as it normally lies in the eye surrounded by fluid

drical lens of a concave type diverges light rays as much

on each side, is only 20 diopters, about one third the

as a +1-diopter cylindrical lens converges them, it has a

total refractive power of the eye. But the importance

strength of -1 diopter. If the focused line is horizontal,

of the internal lens is that, in response to nervous

its axis is said to be 0 degrees. If it is vertical, its axis is

signals from the brain, its curvature can be increased

90 degrees.

markedly to provide “accommodation,” which is dis-

cussed later in the chapter.

Optics of the Eye

Formation of an Image on the Retina. In the same manner

that a glass lens can focus an image on a sheet of paper,

The Eye as a Camera

the lens system of the eye can focus an image on the

retina. The image is inverted and reversed with respect

The eye, shown in Figure 49-9, is optically equivalent

to the object. However, the mind perceives objects in

to the usual photographic camera. It has a lens system,

the upright position despite the upside-down orienta-

a variable aperture system (the pupil), and a retina

tion on the retina because the brain is trained to con-

that corresponds to the film. The lens system of the eye

sider an inverted image as the normal.

is composed of four refractive interfaces: (1) the inter-

face between air and the anterior surface of the

cornea, (2) the interface between the posterior surface

Mechanism of “Accommodation”

of the cornea and the aqueous humor, (3) the interface

between the aqueous humor and the anterior surface

In children, the refractive power of the lens of the eye

of the lens of the eye, and (4) the interface between

can be increased voluntarily from 20 diopters to about

the posterior surface of the lens and the vitreous

34 diopters; this in an “accommodation” of 14 diopters.

humor. The internal index of air is 1; the cornea, 1.38;

To do this, the shape of the lens is changed from that

the aqueous humor, 1.33; the crystalline lens

(on

of a moderately convex lens to that of a very convex

average), 1.40; and the vitreous humor, 1.34.

lens. The mechanism is as follows.

In a young person, the lens is composed of a strong

Reduced Eye. If all the refractive surfaces of the eye are

elastic capsule filled with viscous, proteinaceous, but

algebraically added together and then considered to

transparent fluid. When the lens is in a relaxed state

be one single lens, the optics of the normal eye may be

with no tension on its capsule, it assumes an almost

simplified and represented schematically as a “reduced

spherical shape, owing mainly to the elastic retraction

eye.” This is useful in simple calculations. In the

of the lens capsule. However, as shown in Figure

reduced eye, a single refractive surface is considered

49-10, about 70 suspensory ligaments attach radially

to exist, with its central point 17 millimeters in front of

around the lens, pulling the lens edges toward the

the retina and a total refractive power of 59 diopters

when the lens is accommodated for distant vision.

About two thirds of the 59 diopters of refractive

power of the eye is provided by the anterior surface of

Cornea

Meridional

the cornea (not by the eye lens). The principal reason

fibers

Sclera

for this is that the refractive index of the cornea is

markedly different from that of air, while the refrac-

tive index of the eye lens is not greatly different

from the indices of the aqueous humor and vitreous

humor.

Suspensory

ligaments

Choroid

Sclerocorneal

Circular

Total refractive power = 59 diopters

junction

fibers

Image

Object

Ciliary muscle

Suspensory

Lens

ligaments

Vitreous

Lens

Aqueous

Cornea

Air

humor

1.40

humor

1.38

1.00

1.34

1.33

Figure 49-9

Figure 49-10

The eye as a camera. The numbers are the refractive indices.

Mechanism of accommodation (focusing).

618

Unit X The Nervous System: B. The Special Senses

outer circle of the eyeball. These ligaments are con-

To see clearly both in the distance and nearby, an

stantly tensed by their attachments at the anterior

older person must wear bifocal glasses with the upper

border of the choroid and retina. The tension on the

segment focused for far-seeing and the lower segment

ligaments causes the lens to remain relatively flat

focused for near-seeing (e.g., for reading).

under normal conditions of the eye.

However, also located at the lateral attachments of

the lens ligaments to the eyeball is the ciliary muscle,

Pupillary Diameter

which itself has two separate sets of smooth muscle

fibers—meridional fibers and circular fibers. The

The major function of the iris is to increase the amount

meridional fibers extend from the peripheral ends of

of light that enters the eye during darkness and to

the suspensory ligaments to the corneoscleral junction.

decrease the amount of light that enters the eye in day-

When these muscle fibers contract, the peripheral

light. The reflexes for controlling this mechanism are

insertions of the lens ligaments are pulled medially

considered in the discussion of the neurology of the

toward the edges of the cornea, thereby releasing the

eye in Chapter 51.

ligaments’ tension on the lens. The circular fibers are

The amount of light that enters the eye through the

arranged circularly all the way around the ligament

pupil is proportional to the area of the pupil or to the

attachments so that when they contract, a sphincter-

square of the diameter of the pupil. The pupil of the

like action occurs, decreasing the diameter of the circle

human eye can become as small as about 1.5 millime-

of ligament attachments; this also allows the ligaments

ters and as large as 8 millimeters in diameter. The

to pull less on the lens capsule.

quantity of light entering the eye can change about 30-

Thus, contraction of either set of smooth muscle

fold as a result of changes in pupillary aperture.

fibers in the ciliary muscle relaxes the ligaments to the

lens capsule, and the lens assumes a more spherical

“Depth of Focus” of the Lens System Increases with Decreas-

shape, like that of a balloon, because of the natural

ing Pupillary Diameter. Figure 49-11 shows two eyes that

elasticity of the lens capsule.

are exactly alike except for the diameters of the pupil-

lary apertures. In the upper eye, the pupillary aperture

Accommodation Is Controlled by Parasympathetic Nerves.

is small, and in the lower eye, the aperture is large. In

The ciliary muscle is controlled almost entirely by

front of each of these two eyes are two small point

parasympathetic nerve signals transmitted to the eye

sources of light; light from each passes through the

through the third cranial nerve from the third nerve

pupillary aperture and focuses on the retina. Conse-

nucleus in the brain stem, as explained in Chapter 51.

quently, in both eyes, the retina sees two spots of light

Stimulation of the parasympathetic nerves contracts

in perfect focus. It is evident from the diagrams,

both sets of ciliary muscle fibers, which relaxes the lens

however, that if the retina is moved forward or back-

ligaments, thus allowing the lens to become thicker

ward to an out-of-focus position, the size of each spot

and increase its refractive power. With this increased

will not change much in the upper eye, but in the lower

refractive power, the eye focuses on objects nearer

eye the size of each spot will increase greatly, becom-

than when the eye has less refractive power. Conse-

ing a “blur circle.” In other words, the upper lens

quently, as a distant object moves toward the eye, the

system has far greater depth of focus than the bottom

number of parasympathetic impulses impinging on

lens system. When a lens system has great depth of

the ciliary muscle must be progressively increased for

focus, the retina can be displaced considerably from

the eye to keep the object constantly in focus. (Sym-

the focal plane or the lens strength can change con-

pathetic stimulation has an additional effect in relax-

siderably from normal and the image will still remain

ing the ciliary muscle, but this effect is so weak that it

plays almost no role in the normal accommodation

mechanism; the neurology of this is discussed in

Chapter 51.)

Point sources of light

Presbyopia. As a person grows older, the lens grows

larger and thicker and becomes far less elastic, partly

because of progressive denaturation of the lens pro-

Lens

teins. The ability of the lens to change shape decreases

Focal point

with age. The power of accommodation decreases

Lens

from about 14 diopters in a child to less than 2 diopters

by the time a person reaches 45 to 50 years; it then

decreases to essentially 0 diopters at age 70 years.

Point sources of light

Thereafter, the lens remains almost totally nonaccom-

modating, a condition known as “presbyopia.”

Once a person has reached the state of presbyopia,

each eye remains focused permanently at an almost

Figure 49-11

constant distance; this distance depends on the physi-

cal characteristics of each person’s eyes. The eyes can

Effect of small (top) and large (bottom) pupillary apertures on

no longer accommodate for both near and far vision.

“depth of focus.”

Chapter 49

The Eye: I. Optics of Vision

619

nearly in sharp focus, whereas when a lens system has

much accommodative power left, and objects closer

a “shallow” depth of focus, moving the retina only

and closer to the eye can also be focused sharply until

slightly away from the focal plane causes extreme blur-

the ciliary muscle has contracted to its limit. In old age,

when the lens becomes “presbyopic,” a farsighted

ring.

person is often unable to accommodate the lens suffi-

The greatest possible depth of focus occurs when the

ciently to focus even distant objects, much less near

pupil is extremely small. The reason for this is that,

objects.

with a very small aperture, almost all the rays pass

through the center of the lens, and the central most

Myopia

(Nearsightedness). In myopia, or

“nearsighted-

rays are always in focus, as explained earlier.

ness,” when the ciliary muscle is completely relaxed, the

light rays coming from distant objects are focused in

front of the retina, as shown in the bottom panel of

Errors of Refraction

Figure 49-12. This is usually due to too long an eyeball,

but it can result from too much refractive power in the

Emmetropia (Normal Vision). As shown in Figure 49-12, the

lens system of the eye.

eye is considered to be normal, or “emmetropic,” if par-

No mechanism exists by which the eye can decrease

allel light rays from distant objects are in sharp focus on

the strength of its lens to less than that which exists

the retina when the ciliary muscle is completely relaxed.

when the ciliary muscle is completely relaxed. A myopic

This means that the emmetropic eye can see all distant

person has no mechanism by which to focus distant

objects clearly with its ciliary muscle relaxed. However,

objects sharply on the retina. However, as an object

to focus objects at close range, the eye must contract its

moves nearer to the person’s eye, it finally gets close

ciliary muscle and thereby provide appropriate degrees

enough that its image can be focused. Then, when the

of accommodation.

object comes still closer to the eye, the person can use

the mechanism of accommodation to keep the image

Hyperopia

(Farsightedness). Hyperopia, which is also

focused clearly. A myopic person has a definite limiting

known as “farsightedness,” is usually due to either an

“far point” for clear vision.

eyeball that is too short or, occasionally, a lens system

that is too weak. In this condition, as seen in the middle

Correction of Myopia and Hyperopia by Use of Lenses.

panel of Figure 49-12, parallel light rays are not bent

It will be recalled that light rays passing through a

sufficiently by the relaxed lens system to come to focus

concave lens diverge. If the refractive surfaces of the eye

by the time they reach the retina. To overcome this

have too much refractive power, as in myopia, this

abnormality, the ciliary muscle must contract to increase

excessive refractive power can be neutralized by placing

the strength of the lens. By using the mechanism of

in front of the eye a concave spherical lens, which will

accommodation, a farsighted person is capable of focus-

diverge rays. Such correction is demonstrated in the

ing distant objects on the retina. If the person has used

upper diagram of Figure 49-13.

only a small amount of strength in the ciliary muscle to

Conversely, in a person who has hyperopia—that is,

accommodate for the distant objects, he or she still has

someone who has too weak a lens system—the abnor-

mal vision can be corrected by adding refractive power

using a convex lens in front of the eye. This correction

is demonstrated in the lower diagram of Figure 49-13.

One usually determines the strength of the concave

or convex lens needed for clear vision by “trial and

error”—that is, by trying first a strong lens and then a

Emmetropia

Hyperopia

Myopia

Figure 49-12

Figure 49-13

Parallel light rays focus on the retina in emmetropia, behind the

Correction of myopia with a concave lens, and correction of hyper-

retina in hyperopia, and in front of the retina in myopia.

opia with a convex lens.

620

Unit X The Nervous System: B. The Special Senses

stronger or weaker lens until the one that gives the best

astigmatism, the usual procedure is to find a spherical

visual acuity is found.

lens by trial and error that corrects the focus in one of

the two planes of the astigmatic lens. Then an additional

Astigmatism

cylindrical lens is used to correct the remaining error

Astigmatism is a refractive error of the eye that causes

in the remaining plane. To do this, both the axis and

the visual image in one plane to focus at a different dis-

the strength of the required cylindrical lens must be

tance from that of the plane at right angles. This most

determined.

often results from too great a curvature of the cornea

There are several methods for determining the axis

in one plane of the eye. An example of an astigmatic

of the abnormal cylindrical component of the lens

lens would be a lens surface like that of an egg lying

system of an eye. One of these methods is based on the

sidewise to the incoming light. The degree of curvature

use of parallel black bars of the type shown in Figure

in the plane through the long axis of the egg is not

49-15. Some of these parallel bars are vertical, some

nearly as great as the degree of curvature in the plane

horizontal, and some at various angles to the vertical

through the short axis.

and horizontal axes. After placing various spherical

Because the curvature of the astigmatic lens along

lenses in front of the astigmatic eye, a strength of lens

one plane is less than the curvature along the other

is usually found that causes sharp focus of one set of

plane, light rays striking the peripheral portions of the

parallel bars but does not correct the fuzziness of the

lens in one plane are not bent nearly as much as the rays

set of bars at right angles to the sharp bars. It can be

striking the peripheral portions of the other plane. This

shown from the physical principles of optics discussed

is demonstrated in Figure

49-14, which shows rays

earlier in this chapter that the axis of the out-of-focus

of light originating from a point source and passing

cylindrical component of the optical system is parallel

through an oblong, astigmatic lens. The light rays in the

to the bars that are fuzzy. Once this axis is found, the

vertical plane, indicated by plane BD, are refracted

examiner tries progressively stronger and weaker posi-

greatly by the astigmatic lens because of the greater cur-

tive or negative cylindrical lenses, the axes of which

vature in the vertical direction than in the horizontal

are placed in line with the out-of-focus bars, until the

direction. By contrast, the light rays in the horizontal

patient sees all the crossed bars with equal clarity. When

plane, indicated by plane AC, are not bent nearly as

this has been accomplished, the examiner directs the

much as the light rays in vertical plane BD. It is obvious

optician to grind a special lens combining both the

that light rays passing through an astigmatic lens do not

spherical correction and the cylindrical correction at

all come to a common focal point, because the light rays

the appropriate axis.

passing through one plane focus far in front of those

passing through the other plane.

Correction of Optical Abnormalities by Use of Contact Lenses

The accommodative power of the eye can never

Glass or plastic contact lenses can be inserted that fit

compensate for astigmatism because, during accommo-

snugly against the anterior surface of the cornea. These

dation, the curvature of the eye lens changes approxi-

lenses are held in place by a thin layer of tear fluid that

mately equally in both planes; therefore, in astigmatism,

fills the space between the contact lens and the anterior

each of the two planes requires a different degree of

eye surface.

accommodation. Thus, without the aid of glasses, a

A special feature of the contact lens is that it nullifies

person with astigmatism never sees in sharp focus.

almost entirely the refraction that normally occurs at

the anterior surface of the cornea. The reason for this is

Correction of Astigmatism with a Cylindrical Lens. One

may consider an astigmatic eye as having a lens system

made up of two cylindrical lenses of different strengths

and placed at right angles to each other. To correct for

Point source

of light

A B

Focal line

Plane AC

for plane BD

Plane BD

(less refractive

(more refractive

power)

Focal line

for plane AC

Figure 49-14

Figure 49-15

Astigmatism, demonstrating that light rays focus at one focal dis-

tance in one focal plane (plane AC) and at another focal distance

Chart composed of parallel black bars at different angular orien-

in the plane at a right angle (plane BD).

tations for determining the axis of astigmatism.

Chapter 49

The Eye: I. Optics of Vision

621

that the tears between the contact lens and the cornea

have a refractive index almost equal to that of the

cornea, so that the anterior surface of the cornea no

longer plays a significant role in the eye’s optical system.

Instead, the outer surface of the contact lens plays the

major role. Thus, the refraction of this surface of the

contact lens substitutes for the cornea’s usual refraction.

2 µm

1 mm

This is especially important in people whose eye refrac-

tive errors are caused by an abnormally shaped cornea,

such as those who have an odd-shaped, bulging

cornea—a condition called keratoconus. Without the

contact lens, the bulging cornea causes such severe

17 mm

10 meters

abnormality of vision that almost no glasses can correct

the vision satisfactorily; when a contact lens is used,

however, the corneal refraction is neutralized, and

normal refraction by the outer surface of the contact

Figure 49-16

lens is substituted.

The contact lens has several other advantages as well,

Maximum visual acuity for two point sources of light.

including (1) the lens turns with the eye and gives a

broader field of clear vision than glasses do, and (2) the

contact lens has little effect on the size of the object the

The normal visual acuity of the human eye for dis-

person sees through the lens, whereas lenses placed 1

centimeter or so in front of the eye do affect the size of

criminating between point sources of light is about 25

the image, in addition to correcting the focus.

seconds of arc. That is, when light rays from two sepa-

rate points strike the eye with an angle of at least 25

Cataracts

seconds between them, they can usually be recognized

“Cataracts” are an especially common eye abnormality

as two points instead of one. This means that a person

that occurs mainly in older people. A cataract is a cloudy

with normal visual acuity looking at two bright pin-

or opaque area or areas in the lens. In the early stage of

point spots of light 10 meters away can barely distin-

cataract formation, the proteins in some of the lens

guish the spots as separate entities when they are 1.5

fibers become denatured. Later, these same proteins

to 2 millimeters apart.

coagulate to form opaque areas in place of the normal

The fovea is less than 0.5 millimeter (less than 500

transparent protein fibers.

When a cataract has obscured light transmission so

micrometers) in diameter, which means that maximum

greatly that it seriously impairs vision, the condition can

visual acuity occurs in less than 2 degrees of the visual

be corrected by surgical removal of the lens. When this

field. Outside this foveal area, the visual acuity

is done, the eye loses a large portion of its refractive

becomes progressively poorer, decreasing more than

power, which must be replaced by a powerful convex

10-fold as the periphery is approached. This is caused

lens in front of the eye; usually, however, an artificial

by the connection of more and more rods and cones

plastic lens is implanted in the eye in place of the

to each optic nerve fiber in the nonfoveal,

removed lens.

more peripheral parts of the retina, as discussed in

Chapter 51.

Visual Acuity

Clinical Method for Stating Visual Acuity. The chart for

testing eyes usually consists of letters of different sizes

Theoretically, light from a distant point source, when

placed 20 feet away from the person being tested. If

focused on the retina, should be infinitely small.

the person can see well the letters of a size that he or

However, because the lens system of the eye is never

she should be able to see at 20 feet, the person is said

perfect, such a retinal spot ordinarily has a total diam-

to have 20/20 vision—that is, normal vision. If the

eter of about 11 micrometers, even with maximal res-

person can see only letters that he or she should be

olution of the normal eye optical system. The spot is

able to see at 200 feet, the person is said to have 20/200

brightest in its center and shades off gradually toward

vision. In other words, the clinical method for express-

the edges, as shown by the two-point images in

ing visual acuity is to use a mathematical fraction that

Figure 49-16.

expresses the ratio of two distances, which is also the

The average diameter of the cones in the fovea of

ratio of one’s visual acuity to that of a person with

the retina—the central part of the retina, where vision

normal visual acuity.

is most highly developed—is about 1.5 micrometers,

which is one seventh the diameter of the spot of light.

Determination of Distance

Nevertheless, because the spot of light has a bright

center point and shaded edges, a person can normally

of an Object from the Eye—

distinguish two separate points if their centers lie as

“Depth Perception”

much as 2 micrometers apart on the retina, which is

slightly greater than the width of a foveal cone. This

A person normally perceives distance by three major

discrimination between points is also shown in Figure

means: (1) the sizes of the images of known objects on

49-16.

the retina, (2) the phenomenon of moving parallax,

622

Unit X The Nervous System: B. The Special Senses

and (3) the phenomenon of stereopsis. This ability to

determine distance is called depth perception.

Object of known

distance and size

Determination of Distance by Sizes of Retinal Images of Known

Objects. If one knows that a person being viewed is 6

1. Size of image

feet tall, one can determine how far away the person

is simply by the size of the person’s image on the

retina. One does not consciously think about the size,

Unknown

but the brain has learned to calculate automatically

object

from image sizes the distances of objects when the

dimensions are known.

Determination of Distance by Moving Parallax. Another

2. Stereopsis

important means by which the eyes determine distance

Figure 49-17

is that of moving parallax. If an individual looks off

into the distance with the eyes completely still, he or

Perception of distance (1) by the size of the image on the retina

she perceives no moving parallax, but when the person

and (2) as a result of stereopsis.

moves his or her head to one side or the other, the

images of close-by objects move rapidly across the

retinas, while the images of distant objects remain

the lens system of the eye. After passing through the

almost completely stationary. For instance, by moving

lens system, they are parallel with one another because

the head 1 inch to the side when the object is only 1

the retina is located one focal length distance behind

inch in front of the eye, the image moves almost all the

the lens system. Then, when these parallel rays pass into

way across the retinas, whereas the image of an object

an emmetropic eye of another person, they focus again

to a point focus on the retina of the second person,

200 feet away from the eyes does not move percepti-

because his or her retina is also one focal length dis-

bly. Thus, by using this mechanism of moving parallax,

tance behind the lens. Any spot of light on the retina of

one can tell the relative distances of different objects

the observed eye projects to a focal spot on the retina

even though only one eye is used.

of the observing eye. Thus, if the retina of one person is

made to emit light, the image of his or her retina will be

Determination of Distance by Stereopsis—Binocular Vision.

focused on the retina of the observer, provided the two

Another method by which one perceives parallax is

eyes are emmetropic and are simply looking into each

that of “binocular vision.” Because one eye is a little

other.

more than 2 inches to one side of the other eye, the

To make an ophthalmoscope, one need only devise a

images on the two retinas are different from each

means for illuminating the retina to be examined. Then,

the reflected light from that retina can be seen by the

other. For instance, an object 1 inch in front of the nose

observer simply by putting the two eyes close to each

forms an image on the left side of the retina of the left

other. To illuminate the retina of the observed eye, an

eye but on the right side of the retina of the right eye,

angulated mirror or a segment of a prism is placed in

whereas a small object 20 feet in front of the nose has

front of the observed eye in such a manner, as shown in

its image at closely corresponding points in the centers

Figure 49-18, that light from a bulb is reflected into the

of the two retinas. This type of parallax is demon-

observed eye. Thus, the retina is illuminated through the

strated in Figure 49-17, which shows the images of a

pupil, and the observer sees into the subject’s pupil by

red spot and a yellow square actually reversed on the

looking over the edge of the mirror or prism or through

two retinas because they are at different distances in

an appropriately designed prism.

front of the eyes. This gives a type of parallax that is

present all the time when both eyes are being used. It

is almost entirely this binocular parallax (or stereop-

Observed eye

Observer’s eye

sis) that gives a person with two eyes far greater ability

Mirror

to judge relative distances when objects are nearby

than a person who has only one eye. However, stere-

opsis is virtually useless for depth perception at dis-

tances beyond 50 to 200 feet.

Illuminate retina

Corrective lens in

Ophthalmoscope

showing blood

turret

(- 4 diopters

vessel

for normal eyes)

The ophthalmoscope is an instrument through which an

Collimating lens

observer can look into another person’s eye and see the

retina with clarity. Although the ophthalmoscope

appears to be a relatively complicated instrument, its

principles are simple. The basic components are shown

in Figure 49-18 and can be explained as follows.

Figure 49-18

If a bright spot of light is on the retina of an

emmetropic eye, light rays from this spot diverge toward

Optical system of the ophthalmoscope.

Chapter 49

The Eye: I. Optics of Vision

623

It is clear that these principles apply only to people

Formation of Aqueous Humor

with completely emmetropic eyes. If the refractive

by the Ciliary Body

power of either the observed eye or the observer’s eye

is abnormal, it is necessary to correct the refractive

Aqueous humor is formed in the eye at an average rate

power for the observer to see a sharp image of the

of 2 to 3 microliters each minute. Essentially all of it is

observed retina. The usual ophthalmoscope has a series

secreted by the ciliary processes, which are linear folds

of very small lenses mounted on a turret so that the

projecting from the ciliary body into the space behind

turret can be rotated from one lens to another until the

the iris where the lens ligaments and ciliary muscle

correction for abnormal refraction is made by selecting

attach to the eyeball. A cross section of these ciliary

a lens of appropriate strength. In normal young adults,

processes is shown in Figure 49-20, and their relation to

natural accommodative reflexes occur that cause an

the fluid chambers of the eye can be seen in Figure

approximate +2-diopter increase in strength of the lens

49-19. Because of their folded architecture, the total

of each eye. To correct for this, it is necessary that

surface area of the ciliary processes is about 6 square

the lens turret be rotated to approximately -4-diopter

centimeters in each eye—a large area, considering the

correction.

small size of the ciliary body. The surfaces of these

processes are covered by highly secretory epithelial

cells, and immediately beneath them is a highly vascu-

Fluid System of the Eye—

lar area.

Aqueous humor is formed almost entirely as an active

Intraocular Fluid

secretion by the epithelium of the ciliary processes.

The eye is filled with intraocular fluid, which maintains

Secretion begins with active transport of sodium ions

sufficient pressure in the eyeball to keep it distended.

into the spaces between the epithelial cells. The sodium

Figure 49-19 demonstrates that this fluid can be divided

ions pull chloride and bicarbonate ions along with them

into two portions—aqueous humor, which lies in front

to maintain electrical neutrality. Then all these ions

of the lens, and vitreous humor, which is between the

together cause osmosis of water from the blood capil-

posterior surface of the lens and the retina. The aqueous

laries lying below into the same epithelial intercellular

humor is a freely flowing fluid, whereas the vitreous

spaces, and the resulting solution washes from the

humor, sometimes called the vitreous body, is a gelati-

spaces of the ciliary processes into the anterior chamber

nous mass held together by a fine fibrillar network com-

of the eye. In addition, several nutrients are transported

posed primarily of greatly elongated proteoglycan

across the epithelium by active transport or facilitated

molecules. Both water and dissolved substances can

diffusion; they include amino acids, ascorbic acid, and

diffuse slowly in the vitreous humor, but there is little

glucose.

flow of fluid.

Aqueous humor is continually being formed and

reabsorbed. The balance between formation and reab-

Outflow of Aqueous Humor

sorption of aqueous humor regulates the total volume

from the Eye

and pressure of the intraocular fluid.

After aqueous humor is formed by the ciliary processes,

it first flows, as shown in Figure 49-19, through the pupil

into the anterior chamber of the eye. From here, the fluid

flows anterior to the lens and into the angle between the

Aqueous humor Iris

Flow of fluid

Spaces of Fontana

Ciliary processes

Formation

of aqueous

Canal of Schlemm

of aqueous

humor

Ciliary body

Lens

Diffusion of

fluid and other

Vitreous

constituents

humor

Filtration and

diffusion at

retinal vessels

Ciliary muscle

Vascular layer

Optic nerve

Figure 49-20

Figure 49-19

Anatomy of the ciliary processes. Aqueous humor is formed on

Formation and flow of fluid in the eye.

surfaces.

624

Unit X The Nervous System: B. The Special Senses

Pressure applied

Cornea

Central plunger

Canal of Schlemm

Trabeculae

Aqueous veins

Iris

Footplate

Blood veins

Sclera

Figure 49-21

Intraocular pressure

Anatomy of the iridocorneal angle, showing the system for outflow

of aqueous humor from the eyeball into the conjunctival veins.

Figure 49-22

Principles of the tonometer.

cornea and the iris, then through a meshwork of trabec-

ulae, finally entering the canal of Schlemm, which

empties into extraocular veins. Figure 49-21 demon-

trabeculae through which the fluid must percolate on its

strates the anatomical structures at this iridocorneal

way from the lateral angles of the anterior chamber to

angle, showing that the spaces between the trabeculae

the wall of the canal of Schlemm. These trabeculae have

extend all the way from the anterior chamber to the

minute openings of only 2 to 3 micrometers. The rate of

canal of Schlemm. The canal of Schlemm is a thin-

fluid flow into the canal increases markedly as the pres-

walled vein that extends circumferentially all the way

sure rises. At about 15 mm Hg in the normal eye, the

around the eye. Its endothelial membrane is so porous

amount of fluid leaving the eye by way of the canal of

that even large protein molecules, as well as small par-

Schlemm usually averages 2.5 ml/min and equals the

ticulate matter up to the size of red blood cells, can pass

inflow of fluid from the ciliary body. The pressure nor-

from the anterior chamber into the canal of Schlemm.

mally remains at about this level of 15 mm Hg.

Even though the canal of Schlemm is actually a venous

blood vessel, so much aqueous humor normally flows

Mechanism for Cleansing the Trabecular Spaces and Intraocular

into it that it is filled only with aqueous humor rather

Fluid. When large amounts of debris are present in the

than with blood. The small veins that lead from the canal

aqueous humor, as occurs after hemorrhage into the eye

of Schlemm to the larger veins of the eye usually contain

or during intraocular infection, the debris is likely to

only aqueous humor, and they are called aqueous veins.

accumulate in the trabecular spaces leading from the

anterior chamber to the canal of Schlemm; this debris

Intraocular Pressure

can prevent adequate reabsorption of fluid from the

anterior chamber, sometimes causing “glaucoma,” as

The average normal intraocular pressure is about

explained subsequently. However, on the surfaces of the

15 mm Hg, with a range from 12 to 20 mm Hg.

trabecular plates are large numbers of phagocytic cells.

Immediately outside the canal of Schlemm is a layer of

Tonometry. Because it is impractical to pass a needle into

interstitial gel that contains large numbers of reticu-

a patient’s eye to measure intraocular pressure, this

loendothelial cells that have an extremely high capacity

pressure is measured clinically by using a “tonometer,”

for engulfing debris and digesting it into small molecu-

the principle of which is shown in Figure 49-22. The

lar substances that can then be absorbed. Thus, this

cornea of the eye is anesthetized with a local anesthetic,

phagocytic system keeps the trabecular spaces cleaned.

and the footplate of the tonometer is placed on the

The surface of the iris and other surfaces of the eye

cornea. A small force is then applied to a central

behind the iris are covered with an epithelium that is

plunger, causing the part of the cornea beneath the

capable of phagocytizing proteins and small particles

plunger to be displaced inward. The amount of dis-

from the aqueous humor, thereby helping to maintain a

placement is recorded on the scale of the tonometer,

clear fluid.

and this is calibrated in terms of intraocular pressure.

“Glaucoma,” a Principal Cause of Blindness. Glaucoma is one

Regulation of Intraocular Pressure. Intraocular pressure

of the most common causes of blindness. It is a disease

remains constant in the normal eye, usually within

of the eye in which the intraocular pressure becomes

±2 mm Hg of its normal level, which averages about

pathologically high, sometimes rising acutely to 60 to

15 mm Hg. The level of this pressure is determined

70 mm Hg. Pressures above 25 to 30 mm Hg can cause

mainly by the resistance to outflow of aqueous humor

loss of vision when maintained for long periods.

from the anterior chamber into the canal of Schlemm.

Extremely high pressures can cause blindness within

This outflow resistance results from the meshwork of

days or even hours. As the pressure rises, the axons of

Chapter 49

The Eye: I. Optics of Vision

625

the optic nerve are compressed where they leave the

Congdon NG, Friedman DS, Lietman T: Important causes of

eyeball at the optic disc. This compression is believed to

visual impairment in the world today. JAMA 290:2057,

block axonal flow of cytoplasm from the retinal neu-

2003.

ronal cell bodies into the optic nerve fibers leading to

Corbett JJ: The bedside and office neuro-ophthalmology

the brain. The result is lack of appropriate nutrition of

examination. Semin Neurol 23:63, 2003.

the fibers, which eventually causes death of the involved

Doane JF: Accommodating intraocular lenses. Curr Opin

fibers. It is possible that compression of the retinal

Ophthalmol 15:16, 2004.

artery, which enters the eyeball at the optic disc, also

Farr AK, Guyton DL: Strabismus after retinal detachment

adds to the neuronal damage by reducing nutrition to

surgery. Curr Opin Ophthalmol 11:207, 2000.

the retina.

Gilmartin B: Myopia: precedents for research in the twenty-

In most cases of glaucoma, the abnormally high pres-

first century. Clin Exp Ophthalmol 32:305, 2004.

sure results from increased resistance to fluid outflow

Guyton DL: Sights and Sounds in Ophthalmology: Ocular

through the trabecular spaces into the canal of Schlemm

Motility and Binocular Vision. St Louis: CV Mosby,

at the iridocorneal junction. For instance, in acute

1989.

eye inflammation, white blood cells and tissue debris

Khaw PT, Shah P, Elkington AR: Glaucoma—1: diagnosis.

can block these trabecular spaces and cause an acute

BMJ 328:97, 2004.

increase in intraocular pressure. In chronic conditions,

Krag S, Andreassen TT: Mechanical properties of the human

especially in older individuals, fibrous occlusion of the

lens capsule. Prog Retin Eye Res 22:749, 2003.

trabecular spaces appears to be the likely culprit.

Mathias RT, Rae JL, Baldo GJ: Physiological properties of

Glaucoma can sometimes be treated by placing drops

the normal lens. Physiol Rev 77:21, 1997.

in the eye that contain a drug that diffuses into the

McBrien NA, Gentle A: Role of the sclera in the develop-

eyeball and reduces the secretion or increases the

ment and pathological complications of myopia. Prog

absorption of aqueous humor. When drug therapy fails,

Retin Eye Res 22:307, 2003.

operative techniques to open the spaces of the trabec-

O’Shea J, Walsh V: Visual awareness: the eye fields have it?

ulae or to make channels to allow fluid to flow directly

Curr Biol 14:R279, 2004.

from the fluid space of the eyeball into the subconjunc-

Schaeffel F, Simon P, Feldkaemper M, et al: Molecular

tival space outside the eyeball can often effectively

biology of myopia. Clin Exp Optom 86:295, 2003.

reduce the pressure.

Schwartz K, Budenz D: Current management of glaucoma.

Curr Opin Ophthalmol 15:119, 2004.

Smith G: The optical properties of the crystalline lens and

their significance. Clin Exp Optom 86:3, 2003.

References

Smith G, Atchison DA: The Eye and Visual Optical Instru-

ments. Cambridge: Cambridge University Press, 1997.

Buisseret P: Influence of extraocular muscle proprioception

Weinreb RN, Khaw PT: Primary open-angle glaucoma.

on vision. Physiol Rev 75:323, 1995.

Lancet 363:1711, 2004.

C H A P T E R

The Eye: II. Receptor and

Neural Function of the Retina

The retina is the light-sensitive portion of the eye

that contains (1) the cones, which are responsible

for color vision, and (2) the rods, which are mainly

responsible for black and white vision and vision in

the dark. When either rods or cones are excited,

signals are transmitted first through successive

layers of neurons in the retina itself and, finally, into

optic nerve fibers and the cerebral cortex. The

purpose of this chapter is to explain the mechanisms by which the rods and

cones detect light and color and convert the visual image into optic nerve

signals.

Anatomy and Function of the Structural

Elements of the Retina

Layers of the Retina. Figure 50-1 shows the functional components of the retina which

are arranged in layers from the outside to the inside as follows: (1) pigmented layer,

(2) layer of rods and cones projecting to the pigment, (3) outer nuclear layer con-

taining the cell bodies of the rods and cones, (4) outer plexiform layer, (5) inner

nuclear layer, (6) inner plexiform layer, (7) ganglionic layer, (8) layer of optic nerve

fibers, and (9) inner limiting membrane.

After light passes through the lens system of the eye and then through the vitre-

ous humor, it enters the retina from the inside (see Figure 50-1); that is, it passes first

through the ganglion cells and then through the plexiform and nuclear layers before

it finally reaches the layer of rods and cones located all the way on the outer edge

of the retina. This distance is a thickness of several hundred micrometers; visual

acuity is decreased by this passage through such nonhomogeneous tissue. However,

in the central foveal region of the retina, as discussed subsequently, the inside layers

are pulled aside to decrease this loss of acuity.

Foveal Region of the Retina and Its Importance in Acute Vision. The fovea is a minute area

in the center of the retina, shown in Figure 50-2, occupying a total area a little more

than 1 square millimeter; it is especially capable of acute and detailed vision. The

central fovea, only 0.3 millimeter in diameter, is composed almost entirely of cones;

these cones have a special structure that aids their detection of detail in the visual

image. That is, the foveal cones have especially long and slender bodies, in con-

tradistinction to the much fatter cones located more peripherally in the retina. Also,

in the foveal region, the blood vessels, ganglion cells, inner nuclear layer of cells,

and plexiform layers are all displaced to one side rather than resting directly on top

of the cones. This allows light to pass unimpeded to the cones.

Rods and Cones. Figure 50-3 is a diagrammatic representation of the essential com-

ponents of a photoreceptor (either a rod or a cone). As shown in Figure 50-4, the

outer segment of the cone is conical in shape. In general, the rods are narrower and

longer than the cones, but this is not always the case. In the peripheral portions of

the retina, the rods are 2 to 5 micrometers in diameter, whereas the cones are 5 to

8 micrometers in diameter; in the central part of the retina, in the fovea, there are

rods, and the cones are slender and have a diameter of only 1.5 micrometers.

To the right in Figure 50-3 are labeled the major functional segments of either a

rod or a cone: (1) the outer segment, (2) the inner segment, (3) the nucleus, and (4)

the synaptic body. The light-sensitive photochemical is found in the outer segment.

In the case of the rods, this is rhodopsin; in the cones, it is one of three “color”

626

Chapter 50

The Eye: II. Receptor and Neural Function of the Retina

627

Pigmented layer

Rod

Cone

Outer nuclear layer

Outer plexiform

Distal

layer

Vertical

Horizontal cell

Bipolar

pathway

Bipolar

Lateral pathway

cell

Inner nuclear layer

Amacrine

cell

Amacrine cell

Proximal

Inner plexiform

layer

Ganglion cell

Ganglion cell layer

To optic nerve

Stratum opticum

Figure 50-1

Inner limiting

Layers of retina.

DIRECTION OF LIGHT

membrane

Figure 50-2

Photomicrograph of the macula and of the fovea in its center. Note that the inner layers of the retina are pulled to the side to decrease

interference with light transmission. (From Fawcett DW: Bloom and Fawcett: A Textbook of Histology, 11th ed. Philadelphia: WB Saunders,

1986; courtesy H. Mizoguchi.)

photochemicals, usually called simply color pigments,

proteins. The concentrations of these photosensitive

that function almost exactly the same as rhodopsin

pigments in the discs are so great that the pigments

except for differences in spectral sensitivity.

themselves constitute about 40 per cent of the entire

Note in the outer segments of the rods and cones in

mass of the outer segment.

Figures 50-3 and 50-4 the large numbers of discs. Each

The inner segment of the rod or cone contains the

of the discs is actually an infolded shelf of cell mem-

usual cytoplasm with cytoplasmic organelles. Particu-

brane. There are as many as 1000 discs in each rod or

larly important are the mitochondria; as explained later,

cone.

these mitochondria play the important role of provid-

Both rhodopsin and the color pigments are conju-

ing energy for function of the photoreceptors.

gated proteins. They are incorporated into the mem-

The synaptic body is the portion of the rod or cone

branes of the discs in the form of transmembrane

that connects with subsequent neuronal cells, the

628

Unit X The Nervous System: B. The Special Senses

lighting of the retina rather than the normal contrast

between dark and light spots required for formation of

precise images.

The importance of melanin in the pigment layer is

Membrane shelves

Outer segment

well illustrated by its absence in albinos, people who are

lined with rhodopsin

hereditarily lacking in melanin pigment in all parts of

or color pigment

their bodies. When an albino enters a bright room, light

that impinges on the retina is reflected in all directions

inside the eyeball by the unpigmented surfaces of

the retina and by the underlying sclera, so that a

Mitochondria

single discrete spot of light that would normally

excite only a few rods or cones is reflected everywhere

Inner segment

and excites many receptors. Therefore, the visual acuity

of albinos, even with the best optical correction, is

seldom better than 20/100 to 20/200 rather than the

normal 20/20 values.

The pigment layer also stores large quantities of

Outer limiting

vitamin A. This vitamin A is exchanged back and forth

membrane

through the cell membranes of the outer segments of

Nucleus

the rods and cones, which themselves are embedded in

the pigment. We show later that vitamin A is an impor-

tant precursor of the photosensitive chemicals of the

rods and cones.

Synaptic body

Blood Supply of the Retina—The Central Retinal Artery and the

Choroid. The nutrient blood supply for the internal

Figure 50-3

layers of the retina is derived from the central retinal

artery, which enters the eyeball through the center of

the optic nerve and then divides to supply the entire

Schematic drawing of the functional parts of the rods and cones.

inside retinal surface. Thus, the inner layers of the retina

have their own blood supply independent of the other

structures of the eye.

However, the outermost layer of the retina is adher-

ent to the choroid, which is also a highly vascular tissue

lying between the retina and the sclera. The outer layers

of the retina, especially the outer segments of the rods

and cones, depend mainly on diffusion from the choroid

blood vessels for their nutrition, especially for their

oxygen.

Retinal Detachment. The neural retina occasionally

detaches from the pigment epithelium. In some instances,

the cause of such detachment is injury to the eyeball

that allows fluid or blood to collect between the neural

retina and the pigment epithelium. Detachment is occa-

sionally caused by contracture of fine collagenous fibrils

in the vitreous humor, which pull areas of the retina

toward the interior of the globe.

Partly because of diffusion across the detachment gap

and partly because of the independent blood supply

to the neural retina through the retinal artery, the

detached retina can resist degeneration for days and can

become functional again if it is surgically replaced in its

Figure 50-4

normal relation with the pigment epithelium. If it is not

Membranous structures of the outer segments of a rod (left) and

replaced soon, however, the retina will be destroyed and

a cone (right). (Courtesy Dr. Richard Young.)

will be unable to function even after surgical repair.

horizontal and bipolar cells, that represent the next

Photochemistry of Vision

stages in the vision chain.

Both rods and cones contain chemicals that decom-

Pigment Layer of the Retina. The black pigment melanin in

pose on exposure to light and, in the process, excite the

the pigment layer prevents light reflection throughout

nerve fibers leading from the eye. The light-sensitive

the globe of the eyeball; this is extremely important for

chemical in the rods is called rhodopsin; the light-

clear vision. This pigment performs the same function

in the eye as the black coloring inside the bellows of a

sensitive chemicals in the cones, called cone pigments

camera. Without it, light rays would be reflected in all

or color pigments, have compositions only slightly dif-

directions within the eyeball and would cause diffuse

ferent from that of rhodopsin.

Chapter 50

The Eye: II. Receptor and Neural Function of the Retina

629

In this section, we discuss principally the photo-

is extremely unstable and decays in nanoseconds to

chemistry of rhodopsin, but the same principles can be

lumirhodopsin. This then decays in microseconds

applied to the cone pigments.

to metarhodopsin I, then in about a millisecond to

metarhodopsin II, and finally, much more slowly (in

seconds), into the completely split products scotopsin

Rhodopsin-Retinal Visual Cycle, and

and all-trans retinal.

Excitation of the Rods

It is the metarhodopsin II, also called activated

rhodopsin, that excites electrical changes in the rods,

Rhodopsin and Its Decomposition by Light Energy. The outer

and the rods then transmit the visual image into the

segment of the rod that projects into the pigment layer

central nervous system in the form of optic nerve

of the retina has a concentration of about 40 per cent

action potential, as we discuss later.

of the light-sensitive pigment called rhodopsin, or

visual purple. This substance is a combination of the

Re-formation of Rhodopsin. The first stage in re-formation

protein scotopsin and the carotenoid pigment retinal

of rhodopsin, as shown in Figure 50-5, is to reconvert

(also called “retinene”). Furthermore, the retinal is a

the all-trans retinal into 11-cis retinal. This process

particular type called 11-cis retinal. This cis form of

requires metabolic energy and is catalyzed by the

retinal is important because only this form can bind

enzyme retinal isomerase. Once the 11-cis retinal is

with scotopsin to synthesize rhodopsin.

formed, it automatically recombines with the scotopsin

When light energy is absorbed by rhodopsin, the

to re-form rhodopsin, which then remains stable until

rhodopsin begins to decompose within a very small

its decomposition is again triggered by absorption of

fraction of a second, as shown at the top of Figure

light energy.

50-5. The cause of this is photoactivation of electrons

in the retinal portion of the rhodopsin, which leads to

Role of Vitamin A for Formation of Rhodopsin. Note in

instantaneous change of the cis form of retinal into an

Figure 50-5 that there is a second chemical route by

all-trans form that still has the same chemical structure

which all-trans retinal can be converted into 11-cis

as the cis form but has a different physical structure—

retinal. This is by conversion of the all-trans retinal first

a straight molecule rather than an angulated molecule.

into all-trans retinol, which is one form of vitamin A.

Because the three-dimensional orientation of the

Then the all-trans retinol is converted into

11-cis

reactive sites of the all-trans retinal no longer fits

retinol under the influence of the enzyme isomerase.

with the orientation of the reactive sites on the protein

Finally, the

11-cis retinol is converted into

11-cis

scotopsin, the all-trans retinal begins to pull

retinal, which combines with scotopsin to form new

away from the scotopsin. The immediate product is

rhodopsin.

bathorhodopsin, which is a partially split combination

Vitamin A is present both in the cytoplasm of the

of the all-trans retinal and scotopsin. Bathorhodopsin

rods and in the pigment layer of the retina. Therefore,

vitamin A is normally always available to form new

retinal when needed. Conversely, when there is excess

retinal in the retina, it is converted back into vitamin

Light energy

A, thus reducing the amount of light-sensitive pigment

Rhodopsin

Bathorhodopsin

in the retina. We shall see later that this interconver-

(p sec)

(nsec)

sion between retinal and vitamin A is especially impor-

tant in long-term adaptation of the retina to different

Lumirhodopsin

light intensities.

(µsec)

Night Blindness. Night blindness occurs in any person

Metarhodopsin I

with severe vitamin A deficiency. The simple reason for

(minutes)

(msec)

this is that without vitamin A, the amounts of retinal and

rhodopsin that can be formed are severely depressed.

This condition is called night blindness because the

Metarhodopsin II

(sec)

amount of light available at night is too little to permit

adequate vision in vitamin A-deficient persons.

For night blindness to occur, a person usually must

Scotopsin

remain on a vitamin A-deficient diet for months,

because large quantities of vitamin A are normally

Isomerase

11-cis retinal

all-trans retinal

stored in the liver and can be made available to the eyes.

Once night blindness develops, it can sometimes be

Isomerase

reversed in less than 1 hour by intravenous injection of

11-cis retinol

all-trans retinol

vitamin A.

(Vitamin A)

Excitation of the Rod When Rhodopsin

Figure 50-5

Is Activated by Light

Rhodopsin-retinal visual cycle in the rod, showing decomposition

of rhodopsin during exposure to light and subsequent slow re-

The Rod Receptor Potential Is Hyperpolarizing, Not Depolariz-

formation of rhodopsin by the chemical processes.

ing. When the rod is exposed to light, the resulting

630

Unit X The Nervous System: B. The Special Senses

receptor potential is different from the receptor poten-

there is reduced electronegativity inside the membrane

tials in almost all other sensory receptors. That is, exci-

of the rod, measuring about -40 millivolts rather than

tation of the rod causes increased negativity of the

the usual -70 to -80 millivolts found in most sensory

intrarod membrane potential, which is a state of hyper-

receptors.

polarization, meaning that there is more negativity

Then, when the rhodopsin in the outer segment

than normal inside the rod membrane. This is exactly

of the rod is exposed to light, the rhodopsin begins

opposite to the decreased negativity

(the process

to decompose, and this decreases the outer segment

of “depolarization”) that occurs in almost all other

membrane conductance of sodium to the interior of

sensory receptors.

the rod, even though sodium ions continue to be

But how does activation of rhodopsin cause hyper-

pumped outward through the membrane of the inner

polarization? The answer is that when rhodopsin

segment. Thus, more sodium ions now leave the rod

decomposes, it decreases the rod membrane conduc-

than leak back in. Because they are positive ions, their

tance for sodium ions in the outer segment of the rod.

loss from inside the rod creates increased negativity

This causes hyperpolarization of the entire rod mem-

inside the membrane, and the greater the amount of

brane in the following way.

light energy striking the rod, the greater the elec-

Figure 50-6 shows movement of sodium ions in a

tronegativity becomes—that is, the greater is the

complete electrical circuit through the inner and outer

degree of hyperpolarization. At maximum light inten-

segments of the rod. The inner segment continually

sity, the membrane potential approaches -70 to -80

pumps sodium from inside the rod to the outside,

millivolts, which is near the equilibrium potential for

thereby creating a negative potential on the inside of

potassium ions across the membrane.

the entire cell. However, the outer segment of the rod,

where the photoreceptor discs are located, is entirely

Duration of the Receptor Potential, and Logarithmic

different; here, the rod membrane, in the dark state,

Relation of the Receptor Potential to Light Intensity.

is very leaky to sodium ions. Therefore, positively

When a sudden pulse of light strikes the retina, the

charged sodium ions continually leak back to the

transient hyperpolarization that occurs in the rods—

inside of the rod and thereby neutralize much of the

that is, the receptor potential that occurs—reaches a

negativity on the inside of the entire cell. Thus, under

peak in about 0.3 second and lasts for more than a

normal dark conditions, when the rod is not excited,

second. In cones, the change occurs four times as fast

as in the rods. A visual image impinged on the rods

of the retina for only one millionth of a second can

sometimes cause the sensation of seeing the image for

longer than a second.

Another characteristic of the receptor potential is

Leakage current

that it is approximately proportional to the logarithm

decreased by

decomposing

of the light intensity. This is exceedingly important,

Na⁺

rhodopsin

because it allows the eye to discriminate light intensi-

ties through a range many thousand times as great as

would be possible otherwise.

Sodium

current

Mechanism by Which Rhodopsin Decomposition

Decreases Membrane Sodium Conductance—The

Excitation

“Cascade.” Under optimal conditions,

a single photon of light, the smallest possible quantal

unit of light energy, can cause a measurable receptor

Na⁺

potential in a rod of about 1 millivolt. Only 30 photons

Sodium

of light will cause half saturation of the rod. How

pump

can such a small amount of light cause such great

excitation? The answer is that the photoreceptors

have an extremely sensitive chemical cascade that

amplifies the stimulatory effects about a millionfold,

as follows:

1. The photon activates an electron in the 11-cis

retinal portion of the rhodopsin; this leads to the

formation of metarhodopsin II, which is the active

form of rhodopsin, as already discussed and

- -

shown in Figure 50-5.

2. The activated rhodopsin functions as an enzyme to

Figure 50-6

activate many molecules of transducin, a protein

present in an inactive form in the membranes of

Theoretical basis for generation of a “hyperpolarization receptor

the discs and cell membrane of the rod.

potential” caused by rhodopsin decomposition, which decreases

the flow of positively charged sodium ions into the outer segment

3. The activated transducin activates many more

of the rod.

molecules of phosphodiesterase.

Chapter 50

The Eye: II. Receptor and Neural Function of the Retina

631

4. Activated phosphodiesterase is another enzyme;

it immediately hydrolyzes many molecules of

Blue

Green Red

cyclic guanosine monophosphate (cGMP), thus

cone

Rods

cone

destroying it. Before being destroyed, the cGMP

100

had been bound with the sodium channel protein

of the rod’s outer membrane in a way that

“splints” it in the open state. But in light, when

phosphodiesterase hydrolyzes the cGMP, this

removes the splinting and allows the sodium

channels to close. Several hundred channels

close for each originally activated molecule of

rhodopsin. Because the sodium flux through

each of these channels has been extremely rapid,

400

500

600

700

flow of more than a million sodium ions is

Wavelength (nanometers)

blocked by the channel closure before the

Violet

Blue

Green

Yellow

Orange

Red

channel opens again. This diminution of sodium

ion flow is what excites the rod, as already

discussed.

5. Within about a second, another enzyme,

Figure 50-7

rhodopsin kinase, which is always present in

the rod, inactivates the activated rhodopsin

Light absorption by the pigment of the rods and by the pigments

of the three color-receptive cones of the human retina. (Drawn

(the metarhodopsin II), and the entire cascade

from curves recorded by Marks WB, Dobelle WH, MacNichol EF

reverses back to the normal state with open

Jr: Visual pigments of single primate cones. Science 143:1181,

sodium channels.

1964, and by Brown PK, Wald G: Visual pigments in single rods

Thus, the rods have developed an important chemi-

and cones of the human retina: direct measurements reveal mech-

anisms of human night and color vision. Science 144:45, 1964.

cal cascade that amplifies the effect of a single photon

" 1964 by the American Association for the Advancement of

of light to cause movement of millions of sodium ions.

Science.)

This explains the extreme sensitivity of the rods under

dark conditions.

The cones are about 30 to 300 times less sensitive

Automatic Regulation of

than the rods, but even this allows color vision at

any intensity of light greater than extremely dim

Retinal Sensitivity—Light and

twilight.

Dark Adaptation

Photochemistry of Color Vision by the Cones

Light and Dark Adaptation. If a person has been in bright

It was pointed out at the outset of this discussion that

light for hours, large portions of the photochemicals in

the photochemicals in the cones have almost exactly

both the rods and the cones will have been reduced to

the same chemical composition as that of rhodopsin

retinal and opsins. Furthermore, much of the retinal of

in the rods. The only difference is that the protein por-

both the rods and the cones will have been converted

tions, or the opsins—called photopsins in the cones—

into vitamin A. Because of these two effects, the con-

are slightly different from the scotopsin of the rods.

centrations of the photosensitive chemicals remaining

The retinal portion of all the visual pigments is exactly

in the rods and cones are considerably reduced, and

the same in the cones as in the rods. The color-

the sensitivity of the eye to light is correspondingly

sensitive pigments of the cones, therefore, are combi-

reduced. This is called light adaptation.

nations of retinal and photopsins.

Conversely, if a person remains in darkness for a

In the discussion of color vision later in the chapter,

long time, the retinal and opsins in the rods and cones

it will become evident that only one of three types of

are converted back into the light-sensitive pigments.

color pigments is present in each of the different cones,

Furthermore, vitamin A is converted back into retinal

thus making the cones selectively sensitive to different

to give still more light-sensitive pigments, the final

colors: blue, green, or red. These color pigments

limit being determined by the amount of opsins in the

are called, respectively, blue-sensitive pigment, green-

rods and cones to combine with the retinal. This is

sensitive pigment, and red-sensitive pigment. The

called dark adaptation.

absorption characteristics of the pigments in the three

Figure 50-8 shows the course of dark adaptation

types of cones show peak absorbencies at light wave-

when a person is exposed to total darkness after

lengths of 445, 535, and 570 nanometers, respectively.

having been exposed to bright light for several hours.

These are also the wavelengths for peak light sensitiv-

Note that the sensitivity of the retina is very low on

ity for each type of cone, which begins to explain how

first entering the darkness, but within 1 minute, the

the retina differentiates the colors. The approximate

sensitivity has already increased 10-fold—that is, the

absorption curves for these three pigments are shown

retina can respond to light of one tenth the previously

in Figure 50-7. Also shown is the absorption curve

required intensity. At the end of 20 minutes, the sensi-

for the rhodopsin of the rods, with a peak at 505

tivity has increased about 6000-fold, and at the end of

nanometers.

40 minutes, about 25,000-fold.

632

Unit X The Nervous System: B. The Special Senses

contrast to the many minutes to hours required for full

adaptation by the photochemicals.

100,000

Value of Light and Dark Adaptation in Vision. Between the

limits of maximal dark adaptation and maximal light

10,000

adaptation, the eye can change its sensitivity to light

as much as 500,000 to 1 million times, the sensitivity

automatically adjusting to changes in illumination.

1000

Because registration of images by the retina

Rod adaptation

requires detection of both dark and light spots in the

image, it is essential that the sensitivity of the retina

100

always be adjusted so that the receptors respond to the

lighter areas but not to the darker areas. An example

of maladjustment of retinal adaptation occurs when a

Cone adaptation

person leaves a movie theater and enters the bright

sunlight. Then, even the dark spots in the images seem

exceedingly bright, and as a consequence, the entire

visual image is bleached, having little contrast among

Minutes in dark

its different parts. This is poor vision, and it remains

poor until the retina has adapted sufficiently so that

the darker areas of the image no longer stimulate the

Figure 50-8

receptors excessively.

Conversely, when a person first enters darkness, the

Dark adaptation, demonstrating the relation of cone adaptation to

sensitivity of the retina is usually so slight that even

rod adaptation.

the light spots in the image cannot excite the retina.

After dark adaptation, the light spots begin to regis-

ter. As an example of the extremes of light and dark

The resulting curve of Figure 50-8 is called the dark

adaptation, the intensity of sunlight is about 10 billion

adaptation curve. Note, however, the inflection in the

times that of starlight, yet the eye can function both in

curve. The early portion of the curve is caused by adap-

bright sunlight after light adaptation and in starlight

tation of the cones, because all the chemical events of

after dark adaptation.

vision, including adaptation, occur about four times as

rapidly in cones as in rods. However, the cones do not

achieve anywhere near the same degree of sensitivity

Color Vision

change in darkness as the rods do. Therefore, despite

rapid adaptation, the cones cease adapting after only

From the preceding sections, we have learned that dif-

a few minutes, while the slowly adapting rods continue

ferent cones are sensitive to different colors of light.

to adapt for many minutes and even hours, their sen-

This section is a discussion of the mechanisms by

sitivity increasing tremendously. In addition, still more

which the retina detects the different gradations of

sensitivity of the rods is caused by neuronal signal con-

color in the visual spectrum.

vergence of 100 or more rods onto a single ganglion

cell in the retina; these rods summate to increase their

sensitivity, as discussed later in the chapter.

Tricolor Mechanism of Color

Detection

Other Mechanisms of Light and Dark Adaptation. In addition

to adaptation caused by changes in concentrations of

All theories of color vision are based on the well-

rhodopsin or color photochemicals, the eye has two

known observation that the human eye can detect

other mechanisms for light and dark adaptation. The

almost all gradations of colors when only red, green,

first of these is a change in pupillary size, as discussed

and blue monochromatic lights are appropriately

in Chapter 49. This can cause adaptation of approxi-

mately 30-fold within a fraction of a second, because of

mixed in different combinations.

changes in the amount of light allowed through the

pupillary opening.

Spectral Sensitivities of the Three Types of Cones. On the

The other mechanism is neural adaptation, involving

basis of color vision tests, the spectral sensitivities of

the neurons in the successive stages of the visual chain

the three types of cones in humans have proved to be

in the retina itself and in the brain. That is, when light

essentially the same as the light absorption curves for

intensity first increases, the signals transmitted by the

the three types of pigment found in the cones. These

bipolar cells, horizontal cells, amacrine cells, and gan-

curves are shown in Figure 50-7 and slightly differ-

glion cells are all intense. However, most of these signals

ently in Figure 50-9. They can explain most of the phe-

decrease rapidly at different stages of transmission in

nomena of color vision.

the neural circuit. Although the degree of adaptation is

only a fewfold rather than the many thousandfold that

occurs during adaptation of the photochemical system,

Interpretation of Color in the Nervous System. Refer-

neural adaptation occurs in a fraction of a second, in

ring to Figure

50-9, one can see that an orange

Chapter 50

The Eye: II. Receptor and Neural Function of the Retina

633

from green and is therefore said to have red-green color

blindness.

Blue

Green Red

A person with loss of red cones is called a protanope;

cone

cone cone

100

the overall visual spectrum is noticeably shortened at

the long wavelength end because of a lack of the red

cones. A color-blind person who lacks green cones is

called a deuteranope; this person has a perfectly normal

visual spectral width because red cones are available to

detect the long wavelength red color.

Red-green color blindness is a genetic disorder that

occurs almost exclusively in males. That is, genes in the

female X chromosome code for the respective cones.

Yet color blindness almost never occurs in females

because at least one of the two X chromosomes almost

400

500

600

700

always has a normal gene for each type of cone. Because

Wavelength (nanometers)

the male has only one X chromosome, a missing gene

Violet

Blue

Green

Yellow

Orange

Red

can lead to color blindness.

Because the X chromosome in the male is always

inherited from the mother, never from the father, color

blindness is passed from mother to son, and the mother

Figure 50-9

is said to be a color blindness carrier; this is true in about

8 per cent of all women.

Demonstration of the degree of stimulation of the different color-

sensitive cones by monochromatic lights of four colors: blue,

Blue Weakness. Only rarely are blue cones missing,

green, yellow, and orange.

although sometimes they are underrepresented, which

is a genetically inherited state giving rise to the phe-

nomenon called blue weakness.

monochromatic light with a wavelength of

580

nanometers stimulates the red cones to a stimulus

Color Test Charts. A rapid method for determining color

blindness is based on the use of spot charts such as those

value of about 99 (99 per cent of the peak stimulation

shown in Figure 50-10. These charts are arranged with

at optimum wavelength); it stimulates the green cones

a confusion of spots of several different colors. In the

to a stimulus value of about 42, but the blue cones not

top chart, the person with normal color vision reads

at all. Thus, the ratios of stimulation of the three types

“74,” whereas the red-green color-blind person reads

of cones in this instance are

99:42:0. The nervous

“21.” In the bottom chart, the person with normal color

system interprets this set of ratios as the sensation of

vision reads “42,” whereas the red-blind person reads

orange. Conversely, a monochromatic blue light with a

“2,” and the green-blind person reads “4.”

wavelength of

450 nanometers stimulates the red

If one studies these charts while at the same time

cones to a stimulus value of 0, the green cones to a

observing the spectral sensitivity curves of the different

value of 0, and the blue cones to a value of 97. This set

cones depicted in Figure 50-9, it can be readily under-

stood how excessive emphasis can be placed on spots of

of ratios—0:0:97—is interpreted by the nervous

certain colors by color-blind people.

system as blue. Likewise, ratios of 83:83:0 are inter-

preted as yellow, and 31:67:36 as green.

Neural Function of the Retina

Perception of White Light. About equal stimulation of

all the red, green, and blue cones gives one the sensa-

Neural Circuitry of the Retina

tion of seeing white. Yet there is no single wavelength

of light corresponding to white; instead, white is a com-

Figure

50-1 shows the tremendous complexity of

bination of all the wavelengths of the spectrum. Fur-

neural organization in the retina. To simplify this,

thermore, the perception of white can be achieved by

Figure 50-11 presents the essentials of the retina’s

stimulating the retina with a proper combination of

neural connections, showing at the left the circuit in

only three chosen colors that stimulate the respective

the peripheral retina and at the right the circuit in the

types of cones about equally.

foveal retina. The different neuronal cell types are as

follows:

Color Blindness

1. The photoreceptors themselves—the rods and

cones—which transmit signals to the outer

Red-Green Color Blindness. When a single group of color-

plexiform layer, where they synapse with bipolar

receptive cones is missing from the eye, the person is

cells and horizontal cells

unable to distinguish some colors from others. For

2. The horizontal cells, which transmit signals

instance, one can see in Figure 50-9 that green, yellow,

horizontally in the outer plexiform layer from the

orange, and red colors, which are the colors between the

rods and cones to bipolar cells

wavelengths of 525 and 675 nanometers, are normally

distinguished from one another by the red and green

3. The bipolar cells, which transmit signals vertically

cones. If either of these two cones is missing, the person

from the rods, cones, and horizontal cells to the

cannot use this mechanism for distinguishing these four

inner plexiform layer, where they synapse with

colors; the person is especially unable to distinguish red

ganglion cells and amacrine cells

634

Unit X The Nervous System: B. The Special Senses

Figure 50-10

Two Ishihara charts. Upper: In this chart, the normal person

reads “74,” but the red-green color-blind person reads “21.”

Lower: In this chart, the red-blind person (protanope) reads

“2,” but the green-blind person (deuteranope) reads “4.” The

normal person reads “42.” (Reproduced from Ishihara’s Tests

for Colour Blindness. Tokyo: Kanehara & Co., but tests for

color blindness cannot be conducted with this material. For

accurate testing, the original plates should be used.)

4. The amacrine cells, which transmit signals in two

A sixth type of neuronal cell in the retina, not very

directions, either directly from bipolar cells to

prominent and not shown in the figure, is the inter-

ganglion cells or horizontally within the inner

plexiform cell. This cell transmits signals in the retro-

plexiform layer from axons of the bipolar cells to

grade direction from the inner plexiform layer to the

dendrites of the ganglion cells or to other

outer plexiform layer. These signals are inhibitory and

amacrine cells

are believed to control lateral spread of visual signals

5. The ganglion cells, which transmit output signals

by the horizontal cells in the outer plexiform layer.

from the retina through the optic nerve into the

Their role may be to help control the degree of con-

brain

trast in the visual image.

Chapter 50

The Eye: II. Receptor and Neural Function of the Retina

635

Neurotransmitters Released by Retinal Neurons. Not all the

neurotransmitter chemical substances used for synap-

Pigment layer

tic transmission in the retina have been entirely delin-

eated. However, both the rods and the cones release

Cones

glutamate at their synapses with the bipolar cells.

Histological and pharmacological studies have shown

Rods

there to be many types of amacrine cells secreting at

least eight types of transmitter substances, including

Rod nuclei

gamma-aminobutyric acid, glycine, dopamine, acetyl-

choline, and indolamine, all of which normally function

as inhibitory transmitters. The transmitters of the

bipolar, horizontal, and interplexiform cells are

Horizontal

Bipolar

unclear, but at least some of the horizontal cells

cells

release inhibitory transmitters.

Transmission of Most Signals Occurs in the Retinal Neurons by

Amacrine

cells

Electrotonic Conduction, Not by Action Potentials. The only

retinal neurons that always transmit visual signals by

Ganglion

means of action potentials are the ganglion cells, and

cells

they send their signals all the way to the brain through

the optic nerve. Occasionally, action potentials have

also been recorded in amacrine cells, although the

Figure 50-11

importance of these action potentials is questionable.

Otherwise, all the retinal neurons conduct their visual

Neural organization of the retina: peripheral area to the left, foveal

area to the right.

signals by electrotonic conduction, which can be

explained as follows.

Electrotonic conduction means direct flow of elec-

The Visual Pathway from the Cones to the Ganglion Cells Func-

tric current, not action potentials, in the neuronal cyto-

tions Differently from the Rod Pathway. As is true for many

plasm and nerve axons from the point of excitation all

of our other sensory systems, the retina has both an

the way to the output synapses. Even in the rods and

old type of vision based on rod vision and a new type

cones, conduction from their outer segments, where

of vision based on cone vision. The neurons and nerve

the visual signals are generated, to the synaptic bodies

fibers that conduct the visual signals for cone vision

is by electrotonic conduction. That is, when hyperpo-

are considerably larger than those that conduct the

larization occurs in response to light in the outer

visual signals for rod vision, and the signals are con-

segment of a rod or a cone, almost the same degree of

ducted to the brain two to five times as rapidly. Also,

hyperpolarization is conducted by direct electric

the circuitry for the two systems is slightly different, as

current flow in the cytoplasm all the way to the synap-

follows.

tic body, and no action potential is required. Then,

To the right in Figure 50-11 is the visual pathway

when the transmitter from a rod or cone stimulates a

from the foveal portion of the retina, representing the

bipolar cell or horizontal cell, once again the signal is

new, fast cone system. This shows three neurons in

transmitted from the input to the output by direct elec-

the direct pathway: (1) cones, (2) bipolar cells, and (3)

tric current flow, not by action potentials.

ganglion cells. In addition, horizontal cells transmit

The importance of electrotonic conduction is that it

inhibitory signals laterally in the outer plexiform layer,

allows graded conduction of signal strength. Thus, for

and amacrine cells transmit signals laterally in the

the rods and cones, the strength of the hyperpolariz-

inner plexiform layer.

ing output signal is directly related to the intensity of

To the left in Figure 50-11 are the neural connec-

illumination; the signal is not all or none, as would be

tions for the peripheral retina, where both rods and

the case for each action potential.

cones are present. Three bipolar cells are shown; the

middle of these connects only to rods, representing the

Lateral Inhibition to Enhance Visual Contrast—

type of visual system present in many lower animals.

Function of the Horizontal Cells

The output from the bipolar cell passes only to

The horizontal cells, shown in Figure 50-11, connect

amacrine cells, which relay the signals to the ganglion

laterally between the synaptic bodies of the rods and

cells. Thus, for pure rod vision, there are four neurons

cones, as well as connecting with the dendrites of the

in the direct visual pathway: (1) rods, (2) bipolar

bipolar cells. The outputs of the horizontal cells are

cells,

(3) amacrine cells, and

(4) ganglion cells.

always inhibitory. Therefore, this lateral connection

Also, horizontal and amacrine cells provide lateral

provides the same phenomenon of lateral inhibition

connectivity.

that is important in all other sensory systems—that is,

The other two bipolar cells shown in the peripheral

helping to ensure transmission of visual patterns with

retinal circuitry of Figure 50-11 connect with both rods

proper visual contrast. This phenomenon is demon-

and cones; the outputs of these bipolar cells pass both

strated in Figure 50-12, which shows a minute spot of

directly to ganglion cells and by way of amacrine cells.

light focused on the retina. The visual pathway from

636

Unit X The Nervous System: B. The Special Senses

positive signals and the other half to transmit negative

signals. We shall see later that both positive and nega-

tive signals are used in transmitting visual information

to the brain.

Another important aspect of this reciprocal relation

Light beam

between depolarizing and hyperpolarizing bipolar

cells is that it provides a second mechanism for

lateral inhibition, in addition to the horizontal cell

mechanism. Because depolarizing and hyperpolarizing

Excited area

bipolar cells lie immediately against each other, this

provides a mechanism for separating contrast borders

in the visual image, even when the border lies exactly

Neither excited

between two adjacent photoreceptors. In contrast, the

nor inhibited

horizontal cell mechanism for lateral inhibition oper-

ates over a much greater distance.

Inhibited area

Amacrine Cells and Their Functions

About 30 types of amacrine cells have been identified

by morphological or histochemical means. The func-

tions of about half a dozen types of amacrine cells have

Figure 50-12

been characterized, and all of them are different. One

type of amacrine cell is part of the direct pathway

Excitation and inhibition of a retinal area caused by a small beam

of light, demonstrating the principle of lateral inhibition.

for rod vision—that is, from rod to bipolar cells to

amacrine cells to ganglion cells.

Another type of amacrine cell responds strongly at

the centralmost area where the light strikes is excited,

the onset of a continuing visual signal, but the response

whereas an area to the side is inhibited. In other words,

dies rapidly.

instead of the excitatory signal spreading widely in the

Other amacrine cells respond strongly at the offset

retina because of spreading dendritic and axonal trees

of visual signals, but again, the response dies quickly.

in the plexiform layers, transmission through the hor-

Still other amacrine cells respond when a light is

izontal cells puts a stop to this by providing lateral

turned either on or off, signaling simply a change in

inhibition in the surrounding areas. This is essential to

illumination, irrespective of direction.

allow high visual accuracy in transmitting contrast

Still another type of amacrine cell responds to

borders in the visual image.

movement of a spot across the retina in a specific

Some of the amacrine cells probably provide addi-

direction; therefore, these amacrine cells are said to be

tional lateral inhibition and further enhancement of

directional sensitive.

visual contrast in the inner plexiform layer of the

In a sense, then, many or most amacrine cells are

retina as well.

interneurons that help analyze visual signals before

they ever leave the retina.

Excitation of Some Bipolar Cells and

Inhibition of Others—The Depolarizing

and Hyperpolarizing Bipolar Cells

Ganglion Cells and Optic Nerve Fibers

Two types of bipolar cells provide opposing excitatory

and inhibitory signals in the visual pathway: (1) the

Each retina contains about 100 million rods and 3

depolarizing bipolar cell and (2) the hyperpolarizing

million cones; yet the number of ganglion cells is only

bipolar cell. That is, some bipolar cells depolarize

about 1.6 million. Thus, an average of 60 rods and 2

when the rods and cones are excited, and others

cones converge on each ganglion cell and the optic

hyperpolarize.

nerve fiber leading from the ganglion cell to the brain.

There are two possible explanations for this differ-

However, major differences exist between the

ence. One explanation is that the two bipolar cells are

peripheral retina and the central retina. As one

of entirely different types—one responding by depo-

approaches the fovea, fewer rods and cones converge

larizing in response to the glutamate neurotransmitter

on each optic fiber, and the rods and cones also

released by the rods and cones, and the other respond-

become more slender. These effects progressively

ing by hyperpolarizing. The other possibility is that one

increase the acuity of vision in the central retina. In

of the bipolar cells receives direct excitation from the

the center, in the central fovea, there are only slender

rods and cones, whereas the other receives its signal

cones—about 35,000 of them—and no rods. Also, the

indirectly through a horizontal cell. Because the hori-

number of optic nerve fibers leading from this part of

zontal cell is an inhibitory cell, this would reverse the

the retina is almost exactly equal to the number of

polarity of the electrical response.

cones, as shown to the right in Figure 50-11. This

Regardless of the mechanism for the two types of

explains the high degree of visual acuity in the central

bipolar responses, the importance of this phenomenon

retina in comparison with the much poorer acuity

is that it allows half the bipolar cells to transmit

peripherally.

Chapter 50

The Eye: II. Receptor and Neural Function of the Retina

637

Another difference between the peripheral and

of a second. These ganglion cells presumably apprise

central portions of the retina is the much greater sen-

the central nervous system almost instantaneously

sitivity of the peripheral retina to weak light. This

when a new visual event occurs anywhere in the visual

results partly from the fact that rods are 30 to 300

field, but without specifying with great accuracy the

times more sensitive to light than cones are, but it is

location of the event, other than to give appropriate

further magnified by the fact that as many as 200 rods

clues that make the eyes move toward the exciting

converge on a single optic nerve fiber in the more

vision.

peripheral portions of the retina, so that signals from

the rods summate to give even more intense stimula-

tion of the peripheral ganglion cells and their optic

Excitation of the Ganglion Cells

nerve fibers.

Spontaneous, Continuous Action Potentials in the Ganglion

Three Types of Retinal Ganglion Cells and

Cells. It is from the ganglion cells that the long fibers

Their Respective Fields

of the optic nerve lead into the brain. Because of the

There are three distinct types of ganglion cells, desig-

distance involved, the electrotonic method of conduc-

nated W, X, and Y cells. Each of these serves a differ-

tion employed in the rods, cones, and bipolar cells

ent function.

within the retina is no longer appropriate; therefore,

ganglion cells transmit their signals by means of repet-

Transmission of Rod Vision by the W Cells. The W cells, con-

itive action potentials instead. Furthermore, even

stituting about 40 per cent of all the ganglion cells, are

when unstimulated, they still transmit continuous im-

small, having a diameter less than 10 micrometers, and

pulses at rates varying between 5 and 40 per second.

they transmit signals in their optic nerve fibers at the

The visual signals, in turn, are superimposed onto this

slow velocity of only 8 m/sec. These ganglion cells

background ganglion cell firing.

receive most of their excitation from rods, transmitted

by way of small bipolar cells and amacrine cells. They

Transmission of Changes in Light Intensity—The On-Off

have broad fields in the peripheral retina because the

Response. As noted previously, many ganglion cells are

dendrites of the ganglion cells spread widely in the

specifically excited by changes in light intensity. This is

inner plexiform layer, receiving signals from broad

demonstrated by the records of nerve impulses in

areas.

Figure 50-13. The upper panel shows rapid impulses

On the basis of histology as well as physiologic

for a fraction of a second when a light is first turned

experiments, the W cells seem to be especially sensi-

on, but decreasing rapidity in the next fraction of a

tive for detecting directional movement in the field of

second. The lower tracing is from a ganglion cell

vision, and they are probably important for much of

located lateral to the spot of light; this cell is markedly

our crude rod vision under dark conditions.

inhibited when the light is turned on because of lateral

inhibition. Then, when the light is turned off, opposite

Transmission of the Visual Image and Color by the X Cells. The

effects occur. Thus, these records are called “on-off ”

most numerous of the ganglion cells are the X cells,

and “off-on” responses. The opposite directions of

representing 55 per cent of the total. They are of

these responses to light are caused, respectively, by the

medium diameter, between 10 and 15 micrometers,

depolarizing and hyperpolarizing bipolar cells, and the

and transmit signals in their optic nerve fibers at about

transient nature of the responses is probably at least

14 m/sec.

partly generated by the amacrine cells, many of which

The X cells have small fields because their dendrites

have similar transient responses themselves.

do not spread widely in the retina. Because of this,

This capability of the eyes to detect change in light

their signals represent discrete retinal locations. There-

intensity is strongly developed in both the peripheral

fore, it is mainly through the X cells that the fine

details of the visual image are transmitted. Also,

because every X cell receives input from at least one

off

cone, X cell transmission is probably responsible for

all color vision.

Excitation

Function of the Y Cells to Transmit Instantaneous Changes in

the Visual Image. The Y cells are the largest of all, up to

35 micrometers in diameter, and they transmit their

signals to the brain at 50 m/sec or faster. They are the

Lateral inhibition

least numerous of all the ganglion cells, representing

Figure 50-13

only 5 per cent of the total. Also, they have broad den-

dritic fields, so that signals are picked up by these cells

Responses of a ganglion cell to light in (1) an area excited by a

from widespread retinal areas.

spot of light and (2) an area adjacent to the excited spot; the gan-

The Y ganglion cells respond, like many of the

glion cell in this area is inhibited by the mechanism of lateral

inhibition.

(Modified from Granit R: Receptors and Sensory

amacrine cells, to rapid changes in the visual image—

Perception: A Discussion of Aims, Means, and Results of Electro-

either rapid movement or rapid change in light inten-

physiological Research into the Process of Reception. New

sity—sending bursts of signals for only small fractions

Haven, Conn: Yale University Press, 1955.)

638

Unit X The Nervous System: B. The Special Senses

retina and the central retina. For instance, a minute

gnat flying across the field of vision is instantaneously

detected. Conversely, the same gnat sitting quietly

remains below the threshold of visual detection.

Transmission of Signals Depicting Contrasts

in the Visual Scene—The Role of

Lateral Inhibition

Many ganglion cells respond mainly to contrast

borders in the scene. Because this seems to be the

Excitation

major means by which the pattern of a scene is trans-

mitted to the brain, let us explain how this process

occurs.

When flat light is applied to the entire retina—that

is, when all the photoreceptors are stimulated equally

by the incident light—the contrast type of ganglion cell

is neither stimulated nor inhibited. The reason for this

Inhibition

is that signals transmitted directly from the photore-

ceptors through depolarizing bipolar cells are excita-

tory, while the signals transmitted laterally through

hyperpolarizing bipolar cells as well as through

horizontal cells are mainly inhibitory. Thus, the direct

excitatory signal through one pathway is likely to be

neutralized by inhibitory signals through lateral path-

ways. One circuit for this is demonstrated in Figure

50-14, which shows at the top three photoreceptors.

The central receptor excites a depolarizing bipolar

cell. The two receptors on each side are connected

to the same bipolar cell through inhibitory horizontal

cells that neutralize the direct excitatory signal if

all three receptors are stimulated simultaneously by

Figure 50-14

light.

Now, let us examine what happens when a contrast

Typical arrangement of rods, horizontal cells (H), a bipolar cell (B),

and a ganglion cell (G) in the retina, showing excitation at the

border occurs in the visual scene. Referring again to

synapses between the rods and the bipolar cell and horizontal

Figure 50-14, assume that the central photoreceptor is

cells, but inhibition from the horizontal cells to the bipolar cell.

stimulated by a bright spot of light while one of the

two lateral receptors is in the dark. The bright spot of

light excites the direct pathway through the bipolar

cell. The fact that one of the lateral photoreceptors is

in the dark causes one of the horizontal cells to remain

unstimulated. Therefore, this cell does not inhibit

type. For instance, this frequently occurs for the red

the bipolar cell, and this allows extra excitation of the

and green cones, with red causing excitation and green

bipolar cell. Thus, where visual contrasts occur, the

causing inhibition, or vice versa.

signals through the direct and lateral pathways accen-

The same type of reciprocal effect occurs between

tuate one another.

blue cones on the one hand and a combination

In summary, the mechanism of lateral inhibition

of red and green cones (both of which are excited

functions in the eye in the same way that it functions

by yellow) on the other hand, giving a reciprocal

in most other sensory systems—to provide contrast

excitation-inhibition relation between the blue and

detection and enhancement.

yellow colors.

The mechanism of this opposing effect of colors is

Transmission of Color Signals by the

the following: One color type of cone excites the gan-

Ganglion Cells

glion cell by the direct excitatory route through a

A single ganglion cell may be stimulated by several

depolarizing bipolar cell, whereas the other color type

cones or by only a few. When all three types of cones—

inhibits the ganglion cell by the indirect inhibitory

the red, blue, and green types—stimulate the same

route through a hyperpolarizing bipolar cell.

ganglion cell, the signal transmitted through the gan-

The importance of these color-contrast mechanisms

glion cell is the same for any color of the spectrum.

is that they represent a means by which the retina itself

Therefore, the signal from the ganglion cell plays no

begins to differentiate colors. Thus, each color-contrast

role in the detection of different colors. Instead, it is a

type of ganglion cell is excited by one color but inhib-

“white” signal.

ited by the “opponent” color. Therefore, color analysis

Conversely, some of the ganglion cells are excited by

begins in the retina and is not entirely a function of

only one color type of cone but inhibited by a second

the brain.

Chapter 50

The Eye: II. Receptor and Neural Function of the Retina

639

References

Gegenfurtner KR, Kiper DC: Color vision. Annu Rev

Neurosci 26:181, 2003.

Hardie RC: Phototransduction: shedding light on transloca-

Arshavsky V: Like night and day: rods and cones have dif-

tion. Curr Biol 13:R775, 2003.

ferent pigment regeneration pathways. Neuron 36:1, 2002.

Hendee WA, Wells PNT: The Perception of Visual Informa-

Backharis W, Kliegl R, Werner JS: Color Vision. Berlin:

tion. New York: Springer, 1997.

Walter de Gruyter, 1998.

Kolb H, Nelson R, Ahnelt P, Cuenca N: Cellular organiza-

Berger JW, Fine SL, Maguire MG: Age-Related Macular

tion of the vertebrate retina. Prog Brain Res 131:3, 2001.

Degeneration. St Louis: Mosby, 1999.

Masland RH: The fundamental plan of the retina. Nat

Berson DM: Strange vision: ganglion cells as circadian pho-

Neurosci 4:877, 2001.

toreceptors. Trends Neurosci 26:314, 2003.

Michaelides M, Hunt DM, Moore AT: The cone dysfunction

Burr D, Ross J: Vision: the world through picket fences. Curr

syndromes. Br J Ophthalmol 88:291, 2004.

Biol 14:R381, 2004.

Neitz M, Neitz J: Molecular genetics of color vision and color

Calkins DJ: Seeing with S cones. Prog Retin Eye Res 20:255,

vision defects. Arch Ophthalmol 118:691, 2000.

2001.

Schwartz EA: Transport-mediated synapses in the retina.

Dacey DM, Packer OS: Colour coding in the primate retina:

Physiol Rev 82:875, 2002.

diverse cell types and cone-specific circuitry. Curr Opin

Taylor WR, Vaney DI: New directions in retinal research.

Neurobiol 13:421, 2003.

Trends Neurosci 26:379, 2003.

Fain GL, Matthews HR, Cornwall MC, Koutalos Y: Adapta-

Thompson DA, Gal A: Vitamin A metabolism in the retinal

tion in vertebrate photoreceptors. Physiol Rev 81:117,

pigment epithelium: genes, mutations, and diseases. Prog

2001.

Retin Eye Res 22:683, 2003.

Garriga P, Manyosa J: The eye photoreceptor protein

Zarbin MA: Current concepts in the pathogenesis of age-

rhodopsin: structural implications for retinal disease.

related macular degeneration. Arch Ophthalmol 122:598,

FEBS Lett 528:17, 2002.

2004.

Gegenfurtner KR: Cortical mechanisms of colour vision. Nat

Rev Neurosci 4:563, 2003.

C H A P T E R

The Eye: III. Central

Neurophysiology of Vision

Visual Pathways

Figure 51-1 shows the principal visual pathways

from the two retinas to the visual cortex. The visual

nerve signals leave the retinas through the optic

nerves. At the optic chiasm, the optic nerve fibers

from the nasal halves of the retinas cross to the

opposite sides, where they join the fibers from the

opposite temporal retinas to form the optic tracts. The fibers of each optic tract

then synapse in the dorsal lateral geniculate nucleus of the thalamus, and from

there, geniculocalcarine fibers pass by way of the optic radiation (also called the

geniculocalcarine tract) to the primary visual cortex in the calcarine fissure area

of the medial occipital lobe.

Visual fibers also pass to several older areas of the brain: (1) from the optic

tracts to the suprachiasmatic nucleus of the hypothalamus, presumably to

control circadian rhythms that synchronize various physiologic changes of the

body with night and day; (2) into the pretectal nuclei in the midbrain, to elicit

reflex movements of the eyes to focus on objects of importance and to activate

the pupillary light reflex; (3) into the superior colliculus, to control rapid direc-

tional movements of the two eyes; and (4) into the ventral lateral geniculate

nucleus of the thalamus and surrounding basal regions of the brain, presumably

to help control some of the body’s behavioral functions.

Thus, the visual pathways can be divided roughly into an old system

to the midbrain and base of the forebrain and a new system for direct trans-

mission of visual signals into the visual cortex located in the occipital lobes. In

human beings, the new system is responsible for perception of virtually all

aspects of visual form, colors, and other conscious vision. Conversely, in many

primitive animals, even visual form is detected by the older system, using the

superior colliculus in the same manner that the visual cortex is used in

mammals.

Function of the Dorsal Lateral Geniculate Nucleus

of the Thalamus

The optic nerve fibers of the new visual system terminate in the dorsal lateral

geniculate nucleus, located at the dorsal end of the thalamus and also called

simply the lateral geniculate body, as shown in Figure 51-1. The dorsal lateral

geniculate nucleus serves two principal functions: First, it relays visual infor-

mation from the optic tract to the visual cortex by way of the optic radiation

(also called the geniculocalcarine tract). This relay function is so accurate that

there is exact point-to-point transmission with a high degree of spatial fidelity

all the way from the retina to the visual cortex.

It will be recalled that half the fibers in each optic tract after passing the optic

chiasm are derived from one eye and half from the other eye, representing cor-

responding points on the two retinas. However, the signals from the two eyes

are kept apart in the dorsal lateral geniculate nucleus. This nucleus is composed

of six nuclear layers. Layers II, III, and V (from ventral to dorsal) receive signals

from the lateral half of the ipsilateral retina, whereas layers I, IV, and VI receive

signals from the medial half of the retina of the opposite eye. The respective

retinal areas of the two eyes connect with neurons that are superimposed over

640

Chapter 51

The Eye: III. Central Neurophysiology of Vision

641

Lateral geniculate body

Optic tract

Calcarine fissure

Optic radiation

Optic chiasm

Optic nerve

Secondary

visual areas

Left eye

Primary

visual cortex

Superior

Visual cortex

colliculus

Macula

20∞

60∞

90∞

Figure 51-2

Right eye

Visual cortex in the calcarine fissure area of the medial occipital

cortex.

Figure 51-1

Motor cortex Somatosensory area I

Form,

Principal visual pathways from the eyes to the visual cortex. (Mod-

3-D position,

ified from Polyak SL: The Retina. Chicago: University of Chicago,

motion

1941.)

one another in the paired layers, and similar parallel

transmission is preserved all the way to the visual

cortex.

The second major function of the dorsal lateral

geniculate nucleus is to “gate” the transmission of

signals to the visual cortex—that is, to control how

much of the signal is allowed to pass to the cortex. The

nucleus receives gating control signals from two major

Visual

Secondary

Primary

sources: (1) corticofugal fibers returning in a backward

detail,

visual

direction from the primary visual cortex to the lateral

color

cortex

geniculate nucleus, and (2) reticular areas of the mes-

Figure 51-3

encephalon. Both of these are inhibitory and, when

stimulated, can turn off transmission through selected

Transmission of visual signals from the primary visual cortex into

portions of the dorsal lateral geniculate nucleus. It is

secondary visual areas on the lateral surfaces of the occipital and

assumed that both of these gating circuits help high-

parietal cortices. Note that the signals representing form, third-

light the visual information that is allowed to pass.

dimensional position, and motion are transmitted mainly into the

superior portions of the occipital lobe and posterior portions of the

Finally, the dorsal lateral geniculate nucleus is

parietal lobe. By contrast, the signals for visual detail and color

divided in another way: (1) Layers I and II are called

are transmitted mainly into the anteroventral portion of the occip-

magnocellular layers because they contain large

ital lobe and the ventral portion of the posterior temporal lobe.

neurons. These receive their input almost entirely from

the large type Y retinal ganglion cells. This magnocel-

lular system provides a rapidly conducting pathway to

Organization and Function

the visual cortex. However, this system is color blind,

transmitting only black-and-white information. Also,

of the Visual Cortex

its point-to-point transmission is poor because there

are not many Y ganglion cells, and their dendrites

Figures 51-2 and 51-3 show the visual cortex located

spread widely in the retina. (2) Layers III through VI

primarily on the medial aspect of the occipital lobes.

are called parvocellular layers because they contain

Like the cortical representations of the other sensory

large numbers of small to medium-sized neurons.

systems, the visual cortex is divided into a primary

These neurons receive their input almost entirely from

visual cortex and secondary visual areas.

the type X retinal ganglion cells that transmit color

and convey accurate point-to-point spatial informa-

Primary Visual Cortex. The primary visual cortex (see

tion, but at only a moderate velocity of conduction

Figure 51-2) lies in the calcarine fissure area, extend-

rather than at high velocity.

ing forward from the occipital pole on the medial

642

Unit X The Nervous System: B. The Special Senses

aspect of each occipital cortex. This area is the termi-

nus of direct visual signals from the eyes. Signals from

the macular area of the retina terminate near the

occipital pole, as shown in Figure 51-2, while signals

from the more peripheral retina terminate at or in con-

centric half circles anterior to the pole but still along

III

the calcarine fissure on the medial occipital lobe. The

upper portion of the retina is represented superiorly

(a)

and the lower portion inferiorly.

(b)

Color

Note in the figure the especially large area that rep-

“blobs”

resents the macula. It is to this region that the retinal

(ca)

fovea transmits its signals. The fovea is responsible for

the highest degree of visual acuity. Based on retinal

(cb)

area, the fovea has several hundred times as much rep-

resentation in the primary visual cortex as do the most

peripheral portions of the retina.

The primary visual cortex is also called visual area

I. Still another name is the striate cortex because this

area has a grossly striated appearance.

Secondary Visual Areas of the Cortex. The secondary visual

LGN

(magnocellular)

(parvocellular)

areas, also called visual association areas, lie lateral,

anterior, superior, and inferior to the primary visual

cortex. Most of these areas also fold outward over the

Retinal

lateral surfaces of the occipital and parietal cortex, as

"Y"

"X"

shown in Figure 51-3. Secondary signals are transmit-

ganglion

ted to these areas for analysis of visual meanings. For

instance, on all sides of the primary visual cortex is

Fast, Black and White

Very Accurate, Color

Brodmann’s area 18 (see Figure 51-3), which is where

virtually all signals from the primary visual cortex pass

Figure 51-4

next. Therefore, Brodmann’s area 18 is called visual

area II, or simply V-2. The other, more distant second-

Six layers of the primary visual cortex. The connections shown on

the left side of the figure originate in the magnocellular layers of

ary visual areas have specific designations—V-3, V-4,

the lateral geniculate nucleus (LGN) and transmit rapidly chang-

and so forth—up to more than a dozen areas. The

ing black-and-white visual signals. The pathways to the right orig-

importance of all these areas is that various aspects

inate in the parvocellular layers (layers III through VI) of the LGN;

of the visual image are progressively dissected and

they transmit signals that depict accurate spatial detail as well as

analyzed.

color. Note especially the areas of the visual cortex called “color

blobs,” which are necessary for detection of color.

Layered Structure of the Primary

Vertical Neuronal Columns in the Visual Cortex. The visual

Visual Cortex

cortex is organized structurally into several million

vertical columns of neuronal cells, each column having

Like almost all other portions of the cerebral cortex,

a diameter of 30 to 50 micrometers. The same vertical

the primary visual cortex has six distinct layers, as

columnar organization is found throughout the cere-

shown in Figure 51-4. Also, as is true for the other

bral cortex for the other senses as well (and also in the

sensory systems, the geniculocalcarine fibers terminate

motor and analytical cortical regions). Each column

mainly in layer IV. But this layer, too, is organized into

represents a functional unit. One can roughly calculate

subdivisions. The rapidly conducted signals from the Y

that each of the visual vertical columns has perhaps

retinal ganglion cells terminate in layer IVca, and

1000 or more neurons.

from there they are relayed vertically both outward

After the optic signals terminate in layer IV, they are

toward the cortical surface and inward toward deeper

further processed as they spread both outward and

levels.

inward along each vertical column unit. This process-

The visual signals from the medium-sized optic

ing is believed to decipher separate bits of visual infor-

nerve fibers, derived from the X ganglion cells in the

mation at successive stations along the pathway. The

retina, also terminate in layer IV, but at points differ-

signals that pass outward to layers I, II, and III even-

ent from the Y signals. They terminate in layers IVa

tually transmit signals for short distances laterally in

and IVcb, the shallowest and deepest portions of layer

the cortex. Conversely, the signals that pass inward to

IV, shown to the right in Figure 51-4. From there, these

layers V and VI excite neurons that transmit signals

signals are transmitted vertically both toward the

much greater distances.

surface of the cortex and to deeper layers. It is these

X ganglion pathways that transmit the accurate point-

“Color Blobs” in the Visual Cortex. Interspersed among the

to-point type of vision as well as color vision.

primary visual columns as well as among the columns

Chapter 51

The Eye: III. Central Neurophysiology of Vision

643

of some of the secondary visual areas are special

into secondary visual areas of the inferior, ventral, and

column-like areas called color blobs. They receive

medial regions of the occipital and temporal cortex,

lateral signals from adjacent visual columns and are

show the principal pathway for analysis of visual

activated specifically by color signals. Therefore, it is

detail. Separate portions of this pathway specifically

presumed that these blobs are the primary areas for

dissect out color as well. Therefore, this pathway is

deciphering color.

concerned with such visual feats as recognizing letters,

reading, determining the texture of surfaces, deter-

Interaction of Visual Signals from the Two Separate Eyes.

mining detailed colors of objects, and deciphering

Recall that the visual signals from the two separate

from all this information what the object is and what

eyes are relayed through separate neuronal layers in

it means.

the lateral geniculate nucleus. These signals still

remain separated from each other when they arrive in

layer IV of the primary visual cortex. In fact, layer IV

Neuronal Patterns of

is interlaced with stripes of neuronal columns, each

Stimulation During Analysis

stripe about 0.5 millimeter wide; the signals from one

of the Visual Image

eye enter the columns of every other stripe, alter-

nating with signals from the second eye. This cortical

Analysis of Contrasts in the Visual Image. If a person looks

area deciphers whether the respective areas of the

at a blank wall, only a few neurons in the primary

two visual images from the two separate eyes are “in

visual cortex will be stimulated, regardless of whether

the illumination of the wall is bright or weak. There-

ding points from the two retinas fit with each other. In

fore, the question must be asked, What does the

turn, the deciphered information is used to adjust the

primary visual cortex detect? To answer this, let us now

directional gaze of the separate eyes so that they will

place on the wall a large solid cross, as shown to the

fuse with each other (be brought into “register”). The

left in Figure 51-5. To the right is shown the spatial

information observed about degree of register of

pattern of the most excited neurons in the visual

images from the two eyes also allows a person to dis-

cortex. Note that the areas of maximum excitation

tinguish the distance of objects by the mechanism of

occur along the sharp borders of the visual pattern.

stereopsis.

Thus, the visual signal in the primary visual cortex is

concerned mainly with contrasts in the visual scene,

Two Major Pathways for Analysis of

rather than with noncontrasting areas. We saw in

Visual Information—(1) The Fast

Chapter 50 that this is true of most of the retinal gan-

glion cells as well, because equally stimulated adjacent

“Position” and “Motion” Pathway;

retinal receptors mutually inhibit one another. But at

(2) The Accurate Color Pathway

any border in the visual scene where there is a change

from dark to light or light to dark, mutual inhibition

Figure 51-3 shows that after leaving the primary visual

does not occur, and the intensity of stimulation of most

cortex, the visual information is analyzed in two major

neurons is proportional to the gradient of contrast—

pathways in the secondary visual areas.

that is, the greater the sharpness of contrast and the

greater the intensity difference between light and dark

1. Analysis of Third-Dimensional Position, Gross Form, and

areas, the greater the degree of stimulation.

Motion of Objects. One of the analytical pathways,

demonstrated in Figure 51-3 by the black arrows, ana-

Visual Cortex Also Detects Orientation of Lines and Borders—

lyzes the third-dimensional positions of visual objects

“Simple” Cells. The visual cortex detects not only the

in the space around the body. This pathway also ana-

existence of lines and borders in the different areas of

lyzes the gross physical form of the visual scene as well

the retinal image but also the direction of orientation

as motion in the scene. In other words, this pathway

tells where every object is during each instant and

whether it is moving. After leaving the primary visual

cortex, the signals flow generally into the posterior

midtemporal area and upward into the broad occipi-

toparietal cortex. At the anterior border of the parietal

cortex, the signals overlap with signals from the pos-

terior somatic association areas that analyze three-

dimensional aspects of somatosensory signals. The

signals transmitted in this position-form-motion

pathway are mainly from the large Y optic nerve fibers

of the retinal Y ganglion cells, transmitting rapid

signals but depicting only black and white with no

Retinal image

Cortical stimulation

color.

Figure 51-5

2. Analysis of Visual Detail and Color. The red arrows in

Pattern of excitation that occurs in the visual cortex in response

Figure 51-3, passing from the primary visual cortex

to a retinal image of a dark cross.

644

Unit X The Nervous System: B. The Special Senses

of each line or border—that is, whether it is vertical or

However, psychological studies demonstrate that such

horizontal or lies at some degree of inclination. This is

“blind” people can still, at times, react subconsciously

believed to result from linear organizations of mutu-

to changes in light intensity, to movement in the visual

ally inhibiting cells that excite second-order neurons

scene, or, rarely, even to some gross patterns of vision.

when inhibition occurs all along a line of cells where

These reactions include turning the eyes, turning the

there is a contrast edge. Thus, for each such orienta-

head, and avoidance. This vision is believed to be sub-

tion of a line, specific neuronal cells are stimulated. A

served by neuronal pathways that pass from the optic

line oriented in a different direction excites a different

tracts mainly into the superior colliculi and other por-

set of cells. These neuronal cells are called simple cells.

tions of the older visual system.

They are found mainly in layer IV of the primary

visual cortex.

Fields of Vision; Perimetry

Detection of Line Orientation When a Line Is Displaced Later-

The field of vision is the visual area seen by an eye at a

ally or Vertically in the Visual Field—“Complex” Cells. As

given instant. The area seen to the nasal side is called

the visual signal progresses farther away from layer IV,

the nasal field of vision, and the area seen to the lateral

some neurons respond to lines that are oriented in the

side is called the temporal field of vision.

same direction but are not position-specific. That is,

To diagnose blindness in specific portions of the

even if a line is displaced moderate distances laterally

retina, one charts the field of vision for each eye by a

process called perimetry. This is done by having the

or vertically in the field, the same few neurons will still

subject look with one eye closed and the other eye

be stimulated if the line has the same direction. These

looking toward a central spot directly in front of the eye.

cells are called complex cells.

Then a small dot of light or a small object is moved back

and forth in all areas of the field of vision, and the

Detection of Lines of Specific Lengths, Angles, or Other Shapes.

subject indicates when the spot of light or object can be

Some neurons in the outer layers of the primary visual

seen and when it cannot. Thus, the field of vision for the

columns, as well as neurons in some secondary visual

left eye is plotted as shown in Figure 51-6. In all perime-

areas, are stimulated only by lines or borders of spe-

try charts, a blind spot caused by lack of rods and cones

cific lengths, by specific angulated shapes, or by images

in the retina over the optic disc is found about 15

that have other characteristics. That is, these neurons

degrees lateral to the central point of vision, as shown

in the figure.

detect still higher orders of information from the

visual scene. Thus, as one goes farther into the analyt-

Abnormalities in the Fields of Vision. Occasionally, blind

ical pathway of the visual cortex, progressively more

spots are found in portions of the field of vision other

characteristics of each visual scene are deciphered.

than the optic disc area. Such blind spots are called sco-

tomata; they frequently are caused by damage to the

optic nerve resulting from glaucoma (too much fluid

Detection of Color

pressure in the eyeball), from allergic reactions in the

retina, or from toxic conditions such as lead poisoning

Color is detected in much the same way that lines are

or excessive use of tobacco.

detected: by means of color contrast. For instance, a

red area is often contrasted against a green area, a blue

area against a red area, or a green area against a yellow

area. All these colors can also be contrasted against a

105

Left

Right

white area within the visual scene. In fact, this con-

120

trasting against white is believed to be mainly respon-

135

sible for the phenomenon called “color constancy”;

that is, when the color of an illuminating light changes,

150

the color of the “white” changes with the light, and

appropriate computation in the brain allows red to be

165

interpreted as red even though the illuminating light

has changed the color entering the eyes.

180

70 6050 4030 20

102030 4050 6070

The mechanism of color contrast analysis depends

on the fact that contrasting colors, called “opponent

Optic

colors,” excite specific neuronal cells. It is presumed

disc

195

345

that the initial details of color contrast are detected by

simple cells, whereas more complex contrasts are

330

210

detected by complex and hypercomplex cells.

225

315

Effect of Removing the Primary

240

300

255

285

Visual Cortex

270

Figure 51-6

Removal of the primary visual cortex in the human

being causes loss of conscious vision, that is, blindness.

Perimetry chart, showing the field of vision for the left eye.

Chapter 51

The Eye: III. Central Neurophysiology of Vision

645

Still another condition that can be diagnosed by

superior and inferior recti, and (3) the superior and

perimetry is retinitis pigmentosa. In this disease, por-

inferior obliques. The medial and lateral recti contract

tions of the retina degenerate, and excessive melanin

to move the eyes from side to side. The superior and

pigment deposits in the degenerated areas. Retinitis pig-

inferior recti contract to move the eyes upward or

mentosa usually causes blindness in the peripheral field

downward. The oblique muscles function mainly to

of vision first and then gradually encroaches on the

rotate the eyeballs to keep the visual fields in the

central areas.

upright position.

Effect of Lesions in the Optic Pathway on the Fields of

Vision. Destruction of an entire optic nerve causes

Neural Pathways for Control of Eye Movements. Figure 51-7

blindness of the affected eye.

also shows brain stem nuclei for the third, fourth, and

Destruction of the optic chiasm prevents the crossing

sixth cranial nerves and their connections with the

of impulses from the nasal half of each retina to the

peripheral nerves to the ocular muscles. Shown, too,

opposite optic tract. Therefore, the nasal half of each

are interconnections among the brain stem nuclei by

retina is blinded, which means that the person is blind

way of the nerve tract called the medial longitudinal

in the temporal field of vision for each eye because the

fasciculus. Each of the three sets of muscles to each

image of the field of vision is inverted on the retina by

eye is reciprocally innervated so that one muscle of the

the optical system of the eye; this condition is called

bitemporal hemianopsia. Such lesions frequently result

pair relaxes while the other contracts.

from tumors of the pituitary gland pressing upward

Figure 51-8 demonstrates cortical control of the

from the sella turcica on the bottom of the optic chiasm.

oculomotor apparatus, showing spread of signals from

Interruption of an optic tract denervates the corre-

visual areas in the occipital cortex through occipito-

sponding half of each retina on the same side as the

tectal and occipitocollicular tracts to the pretectal and

lesion; as a result, neither eye can see objects to the

superior colliculus areas of the brain stem. From both

opposite side of the head. This condition is known as

the pretectal and the superior colliculus areas, the ocu-

homonymous hemianopsia.

lomotor control signals pass to the brain stem nuclei

of the oculomotor nerves. Strong signals are also trans-

mitted from the body’s equilibrium control centers in

Eye Movements and

the brain stem into the oculomotor system (from the

Their Control

vestibular nuclei by way of the medial longitudinal

fasciculus).

To make full use of the visual abilities of the eyes,

almost equally as important as interpretation of the

visual signals from the eyes is the cerebral control

Fixation Movements of the Eyes

system for directing the eyes toward the object to be

viewed.

Perhaps the most important movements of the eyes

are those that cause the eyes to “fix” on a discrete

Muscular Control of Eye Movements. The eye movements

portion of the field of vision. Fixation movements are

are controlled by three pairs of muscles, shown in

controlled by two neuronal mechanisms. The first of

Figure 51-7: (1) the medial and lateral recti, (2) the

these allows a person to move the eyes voluntarily to

find the object on which he or she wants to fix the

vision; this is called the voluntary fixation mechanism.

The second is an involuntary mechanism that holds the

Superior rectus

eyes firmly on the object once it has been found; this

Inferior oblique

is called the involuntary fixation mechanism.

The voluntary fixation movements are controlled by

a cortical field located bilaterally in the premotor cor-

Superior oblique

tical regions of the frontal lobes, as shown in Figure

Inferior rectus

51-8. Bilateral dysfunction or destruction of these

Medial rectus

areas makes it difficult or almost impossible for a

person to “unlock” the eyes from one point of fixation

and move them to another point. It is usually neces-

sary to blink the eyes or put a hand over the eyes for

a short time, which then allows the eyes to be moved.

N.III

Nuclei

Conversely, the fixation mechanism that causes the

eyes to “lock” on the object of attention once it is

N.IV

found is controlled by secondary visual areas in the

Lateral

occipital cortex, located mainly anterior to the primary

rectus

Medial

visual cortex. When this fixation area is destroyed

longitudinal

N.VI

bilaterally in an animal, the animal has difficulty

fasciculus

keeping its eyes directed toward a given fixation point

or may become totally unable to do so.

Figure 51-7

To summarize, posterior “involuntary” occipital cor-

Extraocular muscles of the eye and their innervation.

tical eye fields automatically “lock” the eyes on a given

646

Unit X The Nervous System: B. The Special Senses

Voluntary fixation

area

Involuntary

fixation

area

Visual

association

areas

Primary

visual cortex

Occipitotectal and

occipitocollicular tracts

Frontotectal tract

Pretectal nuclei

Visceral nucleus III nerve

Superior colliculus

Oculomotor nucleus

III nerve

Trochlear nucleus

Abducens nucleus

IV nerve

VI nerve

Vestibular nuclei

Figure 51-8

Medial longitudinal

Neural pathways for control of

conjugate movement of the eyes.

spot of the visual field and thereby prevent movement

These drifting and flicking motions are demon-

of the image across the retinas. To unlock this visual

strated in Figure 51-9, which shows by the dashed lines

fixation, voluntary signals must be transmitted from

the slow drifting across the fovea and by the solid lines

cortical “voluntary” eye fields located in the frontal

the flicks that keep the image from leaving the foveal

cortices.

region. This involuntary fixation capability is mostly

lost when the superior colliculi are destroyed.

Mechanism of Involuntary Locking Fixation—Role of the Supe-

rior Colliculi. The involuntary locking type of fixation

Saccadic Movement of the Eyes—A Mechanism of Successive

discussed in the previous section results from a nega-

Fixation Points. When a visual scene is moving contin-

tive feedback mechanism that prevents the object of

ually before the eyes, such as when a person is riding

attention from leaving the foveal portion of the retina.

in a car, the eyes fix on one highlight after another in

The eyes normally have three types of continuous but

the visual field, jumping from one to the next at a rate

almost imperceptible movements: (1) a continuous

of two to three jumps per second. The jumps are called

tremor at a rate of 30 to 80 cycles per second caused

saccades, and the movements are called opticokinetic

by successive contractions of the motor units in the

movements. The saccades occur so rapidly that no

ocular muscles, (2) a slow drift of the eyeballs in one

more than 10 per cent of the total time is spent in

direction or another, and (3) sudden flicking move-

moving the eyes, with 90 per cent of the time being

ments that are controlled by the involuntary fixation

allocated to the fixation sites. Also, the brain sup-

mechanism.

presses the visual image during saccades, so that the

When a spot of light has become fixed on the foveal

person is not conscious of the movements from point

region of the retina, the tremulous movements cause

to point.

the spot to move back and forth at a rapid rate across

the cones, and the drifting movements cause the spot

Saccadic Movements During Reading. During the

to drift slowly across the cones. Each time the spot

process of reading, a person usually makes several sac-

drifts as far as the edge of the fovea, a sudden reflex

cadic movements of the eyes for each line. In this case,

reaction occurs, producing a flicking movement that

the visual scene is not moving past the eyes, but the

moves the spot away from this edge back toward the

eyes are trained to move by means of several succes-

center of the fovea. Thus, an automatic response moves

sive saccades across the visual scene to extract the

the image back toward the central point of vision.

important information. Similar saccades occur when a

Chapter 51

The Eye: III. Central Neurophysiology of Vision

647

directional movement of the eyes, the superior colli-

culi also have topological maps of somatic sensations

from the body and acoustic signals from the ears.

The optic nerve fibers from the eyes to the colliculi

that are responsible for these rapid turning move-

ments are branches from the rapidly conducting Y

fibers, with one branch going to the visual cortex and

the other going to the superior colliculi. (The superior

colliculi and other regions of the brain stem are also

strongly supplied with visual signals transmitted in

Voluntary

type W optic nerve fibers. These represent the oldest

movement to

fixation site

visual pathway, but their function is unclear.)

In addition to causing the eyes to turn toward a

visual disturbance, signals are relayed from the supe-

rior colliculi through the medial longitudinal fascicu-

Figure 51-9

lus to other levels of the brain stem to cause turning

of the whole head and even of the whole body toward

Movements of a spot of light on the fovea, showing sudden “flick-

ing” eye movements that move the spot back toward the center

the direction of the disturbance. Other types of non-

of the fovea whenever it drifts to the foveal edge. (The dashed

visual disturbances, such as strong sounds or even

lines represent slow drifting movements, and the solid lines rep-

stroking of the side of the body, cause similar turning

resent sudden flicking movements.) (Modified from Whitteridge D:

of the eyes, head, and body, but only if the superior col-

Central control of the eye movements. In Field J, Magoun HW, Hall

VE (eds): Handbook of Physiology. vol. 2, sec. 1. Washington, DC,

liculi are intact. Therefore, the superior colliculi play a

American Physiological Society, 1960.)

global role in orienting the eyes, head, and body with

respect to external disturbances, whether they are

person observes a painting, except that the saccades

visual, auditory, or somatic.

occur in upward, sideways, downward, and angulated

directions one after another from one highlight of the

painting to another, and so forth.

“Fusion” of the Visual Images from

the Two Eyes

Fixation on Moving Objects—“Pursuit Movement.” The eyes

can also remain fixed on a moving object, which is

To make the visual perceptions more meaningful, the

called pursuit movement. A highly developed cortical

visual images in the two eyes normally fuse with each

mechanism automatically detects the course of move-

other on “corresponding points” of the two retinas.

ment of an object and then rapidly develops a similar

The visual cortex plays an important role in fusion. It

course of movement for the eyes. For instance, if an

was pointed out earlier in the chapter that correspon-

object is moving up and down in a wavelike form at a

ding points of the two retinas transmit visual signals to

rate of several times per second, the eyes at first may

different neuronal layers of the lateral geniculate

be unable to fixate on it. However, after a second or

body, and these signals in turn are relayed to parallel

so, the eyes begin to jump by means of saccades in

neurons in the visual cortex. Interactions occur

approximately the same wavelike pattern of move-

between these cortical neurons to cause interference

ment as that of the object. Then, after another few

excitation in specific neurons when the two visual

seconds, the eyes develop progressively smoother

images are not “in register”—that is, are not precisely

movements and finally follow the wave movement

“fused.” This excitation presumably provides the

almost exactly. This represents a high degree of auto-

signal that is transmitted to the oculomotor apparatus

matic subconscious computational ability by the

to cause convergence or divergence or rotation of the

pursuit system for controlling eye movements.

eyes so that fusion can be re-established. Once the cor-

responding points of the two retinas are in register,

Superior Colliculi Are Mainly Responsible

excitation of the specific “interference” neurons in the

for Turning the Eyes and Head Toward a

visual cortex disappears.

Visual Disturbance

Even after the visual cortex has been destroyed, a

Neural Mechanism of Stereopsis for Judging

sudden visual disturbance in a lateral area of the visual

Distances of Visual Objects

field often causes immediate turning of the eyes in that

In Chapter 49, it is pointed out that because the two

direction. This does not occur if the superior colliculi

eyes are more than 2 inches apart, the images on the

have also been destroyed. To support this function, the

two retinas are not exactly the same. That is, the right

various points of the retina are represented topo-

eye sees a little more of the right-hand side of the

graphically in the superior colliculi in the same way as

object, and the left eye a little more of the left-hand

in the primary visual cortex, although with less accu-

side, and the closer the object, the greater the dispar-

racy. Even so, the principal direction of a flash of light

ity. Therefore, even when the two eyes are fused with

in a peripheral retinal field is mapped by the colliculi,

each other, it is still impossible for all corresponding

and secondary signals are transmitted to the oculo-

points in the two visual images to be exactly in regis-

motor nuclei to turn the eyes. To help in this

ter at the same time. Furthermore, the nearer the

648

Unit X The Nervous System: B. The Special Senses

object is to the eyes, the less the degree of register. This

Autonomic Control of

degree of nonregister provides the neural mechanism

Accommodation and

for stereopsis, an important mechanism for judging

Pupillary Aperture

the distances of visual objects up to about 200 feet

(60 meters).

Autonomic Nerves to the Eyes. The eye is innervated by

The neuronal cellular mechanism for stereopsis is

both parasympathetic and sympathetic nerve fibers, as

based on the fact that some of the fiber pathways from

shown in Figure 51-11. The parasympathetic pregan-

the retinas to the visual cortex stray 1 to 2 degrees on

glionic fibers arise in the Edinger-Westphal nucleus

each side of the central pathway. Therefore, some optic

(the visceral nucleus portion of the third cranial nerve)

pathways from the two eyes are exactly in register for

and then pass in the third nerve to the ciliary ganglion,

objects 2 meters away; still another set of pathways is

which lies immediately behind the eye. There, the pre-

in register for objects 25 meters away. Thus, the dis-

ganglionic fibers synapse with postganglionic parasym-

tance is determined by which set or sets of pathways

pathetic neurons, which in turn send fibers through

are excited by nonregister or register. This phenome-

ciliary nerves into the eyeball. These nerves excite (1)

non is called depth perception, which is another name

the ciliary muscle that controls focusing of the eye lens

for stereopsis.

and (2) the sphincter of the iris that constricts the

Strabismus

pupil.

Strabismus, also called squint or cross-eye, means lack

The sympathetic innervation of the eye originates in

of fusion of the eyes in one or more of the visual coor-

the intermediolateral horn cells of the first thoracic

dinates: horizontal, vertical, or rotational. The basic

segment of the spinal cord. From there, sympathetic

types of strabismus are shown in Figure 51-10: (1) hor-

fibers enter the sympathetic chain and pass upward to

izontal strabismus, (2) torsional strabismus, and (3) ver-

the superior cervical ganglion, where they synapse

tical strabismus. Combinations of two or even all three

with postganglionic neurons. Postganglionic sympa-

of the different types of strabismus often occur.

thetic fibers from these then spread along the surfaces

Strabismus is often caused by abnormal “set” of the

of the carotid artery and successively smaller arteries

fusion mechanism of the visual system. That is, in a

young child’s early efforts to fixate the two eyes on the

until they reach the eye. There, the sympathetic fibers

same object, one of the eyes fixates satisfactorily while

the other fails do so, or they both fixate satisfactorily but

never simultaneously. Soon the patterns of conjugate

movements of the eyes become abnormally “set” in the

neuronal control pathways themselves, so that the eyes

never fuse.

Suppression of the Visual Image from a Repressed Eye. In a few

patients with strabismus, the eyes alternate in fixing on

Edinger-

the object of attention. In other patients, one eye alone

Pretectal

Westphal

Ciliary

is used all the time, and the other eye becomes repressed

region

nucleus

ganglion

and is never used for precise vision. The visual acuity of

the repressed eye develops only slightly, sometimes

N.III

N.II

remaining 20/400 or less. If the dominant eye then

becomes blinded, vision in the repressed eye can

develop only to a slight extent in adults but far more in

young children. This demonstrates that visual acuity is

highly dependent on proper development of central

nervous system synaptic connections from the eyes. In

Carotid plexus

Pons

fact, even anatomically, the numbers of neuronal con-

nections diminish in the visual cortex areas that would

Superior cervical

normally receive signals from the repressed eye.

sympathetic

ganglion

Cervical

sympathetic

trunk

Upper thoracic segments

of spinal cord

Horizontal

Torsional

Vertical

Figure 51-11

strabismus

Autonomic innervation of the eye, showing also the reflex arc of

Figure 51-10

the light reflex. (Modified from Ranson SW, Clark SL: Anatomy of

the Nervous System: Its Development and Function, 10th ed.

Basic types of strabismus.

Philadelphia: WB Saunders, 1959.)

Chapter 51

The Eye: III. Central Neurophysiology of Vision

649

innervate the radial fibers of the iris (which open the

The brain cortical areas that control accommoda-

pupil) as well as several extraocular muscles of the eye,

tion closely parallel those that control fixation move-

which are discussed subsequently in relation to

ments of the eyes, with analysis of the visual signals in

Horner’s syndrome.

Brodmann’s cortical areas 18 and 19 and transmission

of motor signals to the ciliary muscle through the

pretectal area in the brain stem, then through the

Control of Accommodation

Edinger-Westphal nucleus, and finally by way of

(Focusing the Eyes)

parasympathetic nerve fibers to the eyes.

The accommodation mechanism—that is, the mecha-

nism that focuses the lens system of the eye—is essen-

Control of Pupillary Diameter

tial for a high degree of visual acuity. Accommodation

results from contraction or relaxation of the eye ciliary

Stimulation of the parasympathetic nerves also excites

muscle. Contraction causes increased refractive power

the pupillary sphincter muscle, thereby decreasing the

of the lens, as explained in Chapter 49, and relaxation

pupillary aperture; this is called miosis. Conversely,

causes decreased power. How does a person adjust

stimulation of the sympathetic nerves excites the

accommodation to keep the eyes in focus all the time?

radial fibers of the iris and causes pupillary dilation,

Accommodation of the lens is regulated by a nega-

called mydriasis.

tive feedback mechanism that automatically adjusts

the refractive power of the lens to achieve the highest

Pupillary Light Reflex. When light is shone into the eyes,

degree of visual acuity. When the eyes have been

the pupils constrict, a reaction called the pupillary light

focused on some far object and must then suddenly

reflex. The neuronal pathway for this reflex is demon-

focus on a near object, the lens usually accommodates

strated by the upper two black traces in Figure 51-11.

for best acuity of vision within less than 1 second.

When light impinges on the retina, a few of the result-

Although the precise control mechanism that causes

ing impulses pass from the optic nerves to the pretec-

this rapid and accurate focusing of the eye is unclear,

tal nuclei. From here, secondary impulses pass to the

some of the known features are the following.

Edinger-Westphal nucleus and, finally, back through

First, when the eyes suddenly change distance of the

parasympathetic nerves to constrict the sphincter of the

fixation point, the lens changes its strength in the

iris. Conversely, in darkness, the reflex becomes inhib-

proper direction to achieve a new state of focus within

ited, which results in dilation of the pupil.

a fraction of a second. Second, different types of

The function of the light reflex is to help the eye

clues help to change the lens strength in the proper

adapt extremely rapidly to changing light conditions,

direction:

as explained in Chapter 50. The limits of pupillary

Chromatic aberration appears to be important.

diameter are about 1.5 millimeters on the small side

That is, red light rays focus slightly posteriorly to

and 8 millimeters on the large side. Therefore, because

blue light rays because the lens bends blue rays

light brightness on the retina increases with the square

more than red rays. The eyes appear to be able to

of pupillary diameter, the range of light and dark adap-

detect which of these two types of rays is in better

tation that can be brought about by the pupillary reflex

focus, and this clue relays information to the

is about 30 to 1—that is, up to as much as 30 times

accommodation mechanism whether to make the

change in the amount of light entering the eye.

lens stronger or weaker.

When the eyes fixate on a near object, the eyes

Pupillary Reflexes or Reactions in Central Nervous System

must converge. The neural mechanisms for

Disease. A few central nervous system diseases damage

convergence cause a simultaneous signal to

nerve transmission of visual signals from the retinas to

the Edinger-Westphal nucleus, thus sometimes blocking

strengthen the lens of the eye.

the pupillary reflexes. Such blocks frequently occur as a

Because the fovea lies in a hollowed-out depression

result of central nervous system syphilis, alcoholism,

that is slightly deeper than the remainder of the

encephalitis, and so forth. The block usually occurs in the

retina, the clarity of focus in the depth of the fovea

pretectal region of the brain stem, although it can result

is different from the clarity of focus on the edges. It

from destruction of some small fibers in the optic

has been suggested that this also gives clues about

nerves.

which way the strength of the lens needs to be

The final nerve fibers in the pathway through the pre-

changed.

tectal area to the Edinger-Westphal nucleus are mostly

It has been found that the degree of

of the inhibitory type. When their inhibitory effect is

accommodation of the lens oscillates slightly all

lost, the nucleus becomes chronically active, causing the

pupils to remain mostly constricted, in addition to their

the time at a frequency up to twice per second.

failure to respond to light.

The visual image becomes clearer when the

Yet the pupils can constrict a little more if the

oscillation of the lens strength is changing in

Edinger-Westphal nucleus is stimulated through some

the appropriate direction and becomes poorer

other pathway. For instance, when the eyes fixate on a

when the lens strength is changing in the wrong

near object, the signals that cause accommodation of

direction. This could give a rapid clue as to which

the lens and those that cause convergence of the two

way the strength of the lens needs to change to

eyes cause a mild degree of pupillary constriction at

provide appropriate focus.

the same time. This is called the pupillary reaction to

650

Unit X The Nervous System: B. The Special Senses

accommodation. A pupil that fails to respond to light

Crawford JD, Martinez-Trujillo JC, Klier EM: Neural control

but does respond to accommodation and is also very

of three-dimensional eye and head movements. Curr Opin

small (an Argyll Robertson pupil) is an important diag-

Neurobiol 13:655, 2003.

nostic sign of central nervous system disease—often

Dacey DM: Parallel pathways for spectral coding in primate

syphilis.

retina. Annu Rev Neurosci 23:743, 2000.

Demer JL: The orbital pulley system: a revolution in con-

Horner’s Syndrome. The sympathetic nerves to the eye are

cepts of orbital anatomy. Ann N Y Acad Sci 956:17, 2002.

occasionally interrupted. Interruption frequently occurs

Derrington AM, Webb BS: Visual system: how is the retina

in the cervical sympathetic chain. This causes the clini-

wired up to the cortex? Curr Biol 14:R14, 2004.

cal condition called Horner’s syndrome, which consists

Ferster D, Miller KD: Neural mechanisms of orientation

of the following effects: First, because of interruption of

selectivity in the visual cortex. Annu Rev Neurosci 23:441,

sympathetic nerve fibers to the pupillary dilator muscle,

2000.

the pupil remains persistently constricted to a smaller

Hendee WA, Wells PNT: The Perception of Visual Informa-

diameter than the pupil of the opposite eye. Second, the

tion. New York: Springer, 1997.

superior eyelid droops because it is normally main-

Hikosaka O, Takikawa Y, Kawagoe R: Role of the basal

tained in an open position during waking hours partly

ganglia in the control of purposive saccadic eye move-

by contraction of smooth muscle fibers embedded in the

ments. Physiol Rev 80:953, 2000.

superior eyelid and innervated by the sympathetics.

Kastner S, Ungerleider LG: Mechanisms of visual attention

Therefore, destruction of the sympathetic nerves makes

in the human cortex. Annu Rev Neurosci 23:315, 2000.

it impossible to open the superior eyelid as widely as

Krauzlis RJ: Recasting the smooth pursuit eye movement

normally. Third, the blood vessels on the corresponding

system. J Neurophysiol 91:591, 2004.

side of the face and head become persistently dilated.

Leigh RJ, Lee DS: The Neurology of Eye Movements. New

Fourth, sweating (which requires sympathetic nerve

York: Oxford University Press, 1999.

signals) cannot occur on the side of the face and head

Mante V, Carandini M: Visual cortex: seeing motion. Curr

affected by Horner’s syndrome.

Biol 13:R906, 2003.

Martinez-Conde S, Macknik SL, Hubel DH: The role of

fixational eye movements in visual perception. Nat Rev

References

Neurosci 5:229, 2004.

Munoz DP, Everling S: Look away: the anti-saccade task and

the voluntary control of eye movement. Nat Rev Neurosci

Backharis W, Kliegl R, Werner JS: Color Vision. Berlin:

5:218, 2004.

Walter de Gruyter, 1998.

Pierrot-Deseilligny C, Milea D, Muri RM: Eye movement

Becker W, Reubel H, Mergner T: Current Oculomotor

control by the cerebral cortex. Curr Opin Neurol 17:17,

Research. New York: Plenum Press, 1999.

2004.

Burr D: Eye movements: keeping vision stable. Curr Biol

Treue S: Visual attention: the where, what, how and why of

14:R195, 2004.

saliency. Curr Opin Neurobiol 13:428, 2003.

Buttner-Ennever JA, Eberhorn A, Horn AK: Motor and

van Wezel RJ, van der Smagt MJ: Motion processing: how

sensory innervation of extraocular eye muscles. Ann N Y

low can you go? Curr Biol 13:R840, 2003.

Acad Sci 1004:40, 2003.

Chalupa LM, Gunhan E: Development of on and off retinal

pathways and retinogeniculate projections. Prog Retin

Eye Res 23:31, 2004.

C H A P T E R

The Sense of Hearing

This chapter describes the mechanisms by which the

ear receives sound waves, discriminates their fre-

quencies, and transmits auditory information into

the central nervous system, where its meaning is

deciphered.

Tympanic Membrane and the Ossicular System

Conduction of Sound from the Tympanic Membrane

to the Cochlea

Figure 52-1 shows the tympanic membrane (commonly called the eardrum) and

the ossicles, which conduct sound from the tympanic membrane through the

middle ear to the cochlea (the inner ear). Attached to the tympanic membrane

is the handle of the malleus. The malleus is bound to the incus by minute liga-

ments, so that whenever the malleus moves, the incus moves with it. The oppo-

site end of the incus articulates with the stem of the stapes, and the faceplate of

the stapes lies against the membranous labyrinth of the cochlea in the opening

of the oval window.

The tip end of the handle of the malleus is attached to the center of the tym-

panic membrane, and this point of attachment is constantly pulled by the tensor

tympani muscle, which keeps the tympanic membrane tensed. This allows sound

vibrations on any portion of the tympanic membrane to be transmitted to the

ossicles, which would not be true if the membrane were lax.

The ossicles of the middle ear are suspended by ligaments in such a way that

the combined malleus and incus act as a single lever, having its fulcrum approx-

imately at the border of the tympanic membrane.

The articulation of the incus with the stapes causes the stapes to push forward

on the oval window and on the cochlear fluid on the other side of window every

time the tympanic membrane moves inward, and to pull backward on the fluid

every time the malleus moves outward.

“Impedance Matching” by the Ossicular System. The amplitude of movement of the

stapes faceplate with each sound vibration is only three fourths as much as the

amplitude of the handle of the malleus. Therefore, the ossicular lever system

does not increase the movement distance of the stapes, as is commonly believed.

Instead, the system actually reduces the distance but increases the force of

movement about 1.3 times. In addition, the surface area of the tympanic mem-

brane is about 55 square millimeters, whereas the surface area of the stapes

averages 3.2 square millimeters. This 17-fold difference times the 1.3-fold ratio

of the lever system causes about 22 times as much total force to be exerted on

the fluid of the cochlea as is exerted by the sound waves against the tympanic

membrane. Because fluid has far greater inertia than air does, it is easily under-

stood that increased amounts of force are needed to cause vibration in the fluid.

Therefore, the tympanic membrane and ossicular system provide impedance

matching between the sound waves in air and the sound vibrations in the fluid

of the cochlea. Indeed, the impedance matching is about 50 to 75 per cent of

perfect for sound frequencies between 300 and 3000 cycles per second, which

allows utilization of most of the energy in the incoming sound waves.

651

652

Unit X The Nervous System: B. The Special Senses

Malleus

Basilar

Spiral organ

membrane of Corti

Stapes

Incus

Spiral

Vestibular membrane

Scala tympani

ligament

Scala vestibuli

Stria

Cochlear

vascularis

nerve

Auditory canal

Spiral

ganglion

Cochlea

Round

Tympanic membrane

window

Oval window

Scala media

Figure 52-1

Spiral ganglion

Cochlear nerve

Scala tympani

Tympanic membrane, ossicular system of the middle ear, and

inner ear.

Figure 52-2

Cochlea. (Redrawn from Gray H, Goss CM [eds]: Gray’s Anatomy

In the absence of the ossicular system and tympanic

of the Human Body. Philadelphia: Lea & Febiger, 1948.)

membrane, sound waves can still travel directly

through the air of the middle ear and enter the cochlea

at the oval window. However, the sensitivity for

hearing is then 15 to 20 decibels less than for ossicu-

Transmission of Sound Through Bone

lar transmission—equivalent to a decrease from a

medium to a barely perceptible voice level.

Because the inner ear, the cochlea, is embedded in a

bony cavity in the temporal bone, called the bony

Attenuation of Sound by Contraction of the Tensor Tympani and

labyrinth, vibrations of the entire skull can cause fluid

Stapedius Muscles. When loud sounds are transmitted

vibrations in the cochlea itself. Therefore, under appro-

through the ossicular system and from there into the

priate conditions, a tuning fork or an electronic vibra-

central nervous system, a reflex occurs after a latent

tor placed on any bony protuberance of the skull, but

period of only 40 to 80 milliseconds to cause contrac-

especially on the mastoid process near the ear, causes

tion of the stapedius muscle and, to a lesser extent, the

the person to hear the sound. However, the energy

tensor tympani muscle. The tensor tympani muscle

available even in loud sound in the air is not sufficient

pulls the handle of the malleus inward while the

to cause hearing via bone conduction unless a special

stapedius muscle pulls the stapes outward. These two

electromechanical sound-amplifying device is applied

forces oppose each other and thereby cause the entire

to the bone.

ossicular system to develop increased rigidity, thus

greatly reducing the ossicular conduction of low-

frequency sound, mainly frequencies below

1000

Cochlea

cycles per second.

This attenuation reflex can reduce the intensity of

Functional Anatomy of the Cochlea

lower-frequency sound transmission by 30 to 40 deci-

bels, which is about the same difference as that

The cochlea is a system of coiled tubes, shown in

between a loud voice and a whisper. The function of

Figure 52-1 and in cross section in Figures 52-2 and

this mechanism is believed to be twofold:

52-3. It consists of three tubes coiled side by side: (1)

1. To protect the cochlea from damaging vibrations

the scala vestibuli, (2) the scala media, and (3) the scala

caused by excessively loud sound.

tympani. The scala vestibuli and scala media are sepa-

2. To mask low-frequency sounds in loud

rated from each other by Reissner’s membrane (also

environments. This usually removes a major share

called the vestibular membrane), shown in Figure 52-3;

of the background noise and allows a person to

the scala tympani and scala media are separated from

concentrate on sounds above 1000 cycles per

each other by the basilar membrane. On the surface of

second, where most of the pertinent information

the basilar membrane lies the organ of Corti, which

in voice communication is transmitted.

contains a series of electromechanically sensitive

Another function of the tensor tympani and

cells, the hair cells. They are the receptive end organs

stapedius muscles is to decrease a person’s hearing

that generate nerve impulses in response to sound

sensitivity to his or her own speech. This effect is acti-

vibrations.

vated by collateral nerve signals transmitted to these

Figure 52-4 diagrams the functional parts of the

muscles at the same time that the brain activates the

uncoiled cochlea for conduction of sound vibrations.

voice mechanism.

First, note that Reissner’s membrane is missing from

Chapter 52

The Sense of Hearing

653

Tectorial membrane

Reissner's membrane

Scala vestibuli

Stria vascularis

Spiral limbus

Scala media

Spiral

prominence

Organ of Corti

Figure 52-3

Spiral ganglion

Section through one of the turns

Basilar membrane

of the cochlea. (Drawn by Sylvia

Colard Keene. From Fawcett DW:

Bloom & Fawcett: A Textbook of

Histology, 11th ed. Philadelphia:

Scala tympani

WB Saunders, 1986.)

Oval

Scala vestibuli

Basilar Membrane and Resonance in the Cochlea. The

window

and scala media

basilar membrane is a fibrous membrane that sepa-

Stapes

rates the scala media from the scala tympani. It

contains 20,000 to 30,000 basilar fibers that project

from the bony center of the cochlea, the modiolus,

toward the outer wall. These fibers are stiff, elastic,

reedlike structures that are fixed at their basal ends

Round

in the central bony structure of the cochlea (the modi-

Scala

Basilar

Helicotrema

window

tympani

membrane

olus) but are not fixed at their distal ends, except

that the distal ends are embedded in the loose basilar

Figure 52-4

membrane. Because the fibers are stiff and free at

one end, they can vibrate like the reeds of a

Movement of fluid in the cochlea after forward thrust of the stapes.

harmonica.

The lengths of the basilar fibers increase progres-

sively beginning at the oval window and going from

this figure. This membrane is so thin and so easily

the base of the cochlea to the apex, increasing from a

moved that it does not obstruct the passage of sound

length of about 0.04 millimeter near the oval and

vibrations from the scala vestibuli into the scala media.

round windows to 0.5 millimeter at the tip of the

Therefore, as far as fluid conduction of sound is con-

cochlea

(the

“helicotrema”), a

12-fold increase in

cerned, the scala vestibuli and scala media are con-

length.

sidered to be a single chamber. (The importance of

The diameters of the fibers, however, decrease from

Reissner’s membrane is to maintain a special kind of

the oval window to the helicotrema, so that their

fluid in the scala media that is required for normal

overall stiffness decreases more than 100-fold. As a

function of the sound-receptive hair cells, as discussed

result, the stiff, short fibers near the oval window of the

later in the chapter.)

cochlea vibrate best at a very high frequency, while the

Sound vibrations enter the scala vestibuli from the

long, limber fibers near the tip of the cochlea vibrate

faceplate of the stapes at the oval window. The face-

best at a low frequency.

plate covers this window and is connected with the

Thus, high-frequency resonance of the basilar mem-

window’s edges by a loose annular ligament so that it

brane occurs near the base, where the sound waves

can move inward and outward with the sound vibra-

enter the cochlea through the oval window. But low-

tions. Inward movement causes the fluid to move

frequency resonance occurs near the helicotrema,

forward in the scala vestibuli and scala media, and

mainly because of the less stiff fibers but also because

outward movement causes the fluid to move back-

of increased “loading” with extra masses of fluid that

ward.

must vibrate along the cochlear tubules.

654

Unit X The Nervous System: B. The Special Senses

Transmission of Sound Waves in the

before it reaches its resonant point and dies, a

medium-frequency sound wave travels about halfway

Cochlea—“Traveling Wave”

and then dies, and a very low frequency sound wave

travels the entire distance along the membrane.

When the foot of the stapes moves inward against the

Another feature of the traveling wave is that it

oval window, the round window must bulge outward

travels fast along the initial portion of the basilar

because the cochlea is bounded on all sides by bony

membrane but becomes progressively slower as it goes

walls. The initial effect of a sound wave entering at the

farther into the cochlea. The cause of this is the high

oval window is to cause the basilar membrane at

coefficient of elasticity of the basilar fibers near the

the base of the cochlea to bend in the direction of the

oval window and a progressively decreasing coefficient

round window. However, the elastic tension that is

farther along the membrane. This rapid initial trans-

built up in the basilar fibers as they bend toward the

mission of the wave allows the high-frequency sounds

round window initiates a fluid wave that “travels”

to travel far enough into the cochlea to spread out and

along the basilar membrane toward the helicotrema,

separate from one another on the basilar membrane.

as shown in Figure 52-5. Figure 52-5A shows move-

Without this, all the high-frequency waves would be

ment of a high-frequency wave down the basilar mem-

bunched together within the first millimeter or so of

brane; Figure 52-5B, a medium-frequency wave; and

the basilar membrane, and their frequencies could not

Figure 52-5C, a very low frequency wave. Movement

be discriminated from one another.

of the wave along the basilar membrane is compara-

ble to the movement of a pressure wave along the arte-

Amplitude Pattern of Vibration of the Basilar Mem-

rial walls, which is discussed in Chapter 15; it is also

brane. The dashed curves of Figure 52-6A show the

comparable to a wave that travels along the surface of

position of a sound wave on the basilar membrane

a pond.

when the stapes (a) is all the way inward, (b) has

moved back to the neutral point, (c) is all the way

Pattern of Vibration of the Basilar Membrane for Different

outward, and (d) has moved back again to the neutral

Sound Frequencies. Note in Figure 52-5 the different

point but is moving inward. The shaded area around

patterns of transmission for sound waves of different

these different waves shows the extent of vibration of

frequencies. Each wave is relatively weak at the outset

the basilar membrane during a complete vibratory

but becomes strong when it reaches that portion of the

cycle. This is the amplitude pattern of vibration of

basilar membrane that has a natural resonant fre-

the basilar membrane for this particular sound

quency equal to the respective sound frequency. At

frequency.

this point, the basilar membrane can vibrate back and

Figure 52-6B shows the amplitude patterns of vibra-

forth with such ease that the energy in the wave is dis-

tion for different frequencies, demonstrating that the

sipated. Consequently, the wave dies at this point and

fails to travel the remaining distance along the basilar

membrane. Thus, a high-frequency sound wave travels

only a short distance along the basilar membrane

High frequency

Frequency

8000

4000

2000

1000

600

400

200

Medium frequency

Distance from stapes (millimeters)

Figure 52-6

Low frequency

A, Amplitude pattern of vibration of the basilar membrane for

Figure 52-5

a medium-frequency sound. B, Amplitude patterns for sounds of

frequencies between 200 and 8000 cycles per second, showing

“Traveling waves” along the basilar membrane for high-,

the points of maximum amplitude on the basilar membrane for the

medium-, and low-frequency sounds.

different frequencies.

Chapter 52

The Sense of Hearing

655

maximum amplitude for sound at 8000 cycles per

of the organ of Corti to the spiral ganglion and to the

second occurs near the base of the cochlea, whereas

cochlear nerve is shown in Figure 52-2.

that for frequencies less than 200 cycles per second is

all the way at the tip of the basilar membrane near the

Excitation of the Hair Cells. Note in Figure

52-7 that

helicotrema, where the scala vestibuli opens into the

minute hairs, or stereocilia, project upward from the

scala tympani.

hair cells and either touch or are embedded in the

The principal method by which sound frequencies

surface gel coating of the tectorial membrane, which

are discriminated from one another is based on the

lies above the stereocilia in the scala media. These hair

“place” of maximum stimulation of the nerve fibers

cells are similar to the hair cells found in the macula

from the organ of Corti lying on the basilar membrane,

and cristae ampullaris of the vestibular apparatus,

as explained in the next section.

which are discussed in Chapter 55. Bending of the

hairs in one direction depolarizes the hair cells, and

bending in the opposite direction hyperpolarizes them.

Function of the Organ of Corti

This in turn excites the auditory nerve fibers synaps-

ing with their bases.

The organ of Corti, shown in Figures 52-2, 52-3, and

Figure 52-8 shows the mechanism by which vibra-

52-7, is the receptor organ that generates nerve

tion of the basilar membrane excites the hair endings.

impulses in response to vibration of the basilar mem-

The outer ends of the hair cells are fixed tightly in a

brane. Note that the organ of Corti lies on the surface

rigid structure composed of a flat plate, called the retic-

of the basilar fibers and basilar membrane. The actual

ular lamina, supported by triangular rods of Corti,

sensory receptors in the organ of Corti are two spe-

which are attached tightly to the basilar fibers. The

cialized types of nerve cells called hair cells—a single

basilar fibers, the rods of Corti, and the reticular

row of internal (or “inner”) hair cells, numbering about

lamina move as a rigid unit.

3500 and measuring about 12 micrometers in diame-

Upward movement of the basilar fiber rocks the

ter, and three or four rows of external (or “outer”) hair

reticular lamina upward and inward toward the modi-

cells, numbering about 12,000 and having diameters

olus. Then, when the basilar membrane moves down-

of only about 8 micrometers. The bases and sides of

ward, the reticular lamina rocks downward and

the hair cells synapse with a network of cochlea

outward. The inward and outward motion causes the

nerve endings. Between 90 and 95 per cent of these

hairs on the hair cells to shear back and forth against

endings terminate on the inner hair cells, which

the tectorial membrane. Thus, the hair cells are excited

emphasizes their special importance for the detection

whenever the basilar membrane vibrates.

of sound.

The nerve fibers stimulated by the hair cells lead to

Auditory Signals Are Transmitted Mainly by the Inner Hair Cells.

the spiral ganglion of Corti, which lies in the modiolus

Even though there are three to four times as many

(center) of the cochlea. The spiral ganglion neuronal

outer hair cells as inner hair cells, about 90 per cent of

cells send axons—a total of about 30,000—into the

the auditory nerve fibers are stimulated by the inner

cochlear nerve and then into the central nervous

cells rather than by the outer cells. Yet, despite this, if

system at the level of the upper medulla. The relation

the outer cells are damaged while the inner cells

remain fully functional, a large amount of hearing

loss occurs. Therefore, it has been proposed that the

outer hair cells in some way control the sensitivity

of the inner hair cells at different sound pitches, a

Tectorial membrane

Inner hair cells

Outer hair cells

Reticular lamina

Hairs Tectorial membrane

Basilar fiber

Rods of Corti

Spiral ganglion

Modiolus

Cochlear nerve

Figure 52-7

Figure 52-8

Organ of Corti, showing especially the hair cells and the tectorial

Stimulation of the hair cells by to-and-fro movement of the hairs

membrane pressing against the projecting hairs.

projecting into the gel coating of the tectorial membrane.

656

Unit X The Nervous System: B. The Special Senses

phenomenon called “tuning” of the receptor system.

the hair cells. Furthermore, the hair cells have a nega-

In support of this concept, a large number of retro-

tive intracellular potential of -70 millivolts with respect

grade nerve fibers pass from the brain stem to the

to the perilymph but -150 millivolts with respect to the

endolymph at their upper surfaces where the hairs

vicinity of the outer hair cells. Stimulating these nerve

project through the reticular lamina and into the

fibers can actually cause shortening of the outer hair

endolymph. It is believed that this high electrical poten-

cells and possibly also change their degree of stiffness.

tial at the tips of the stereocilia sensitizes the cell an

These effects suggest a retrograde nervous mechanism

extra amount, thereby increasing its ability to respond

for control of the ear’s sensitivity to different sound

to the slightest sound.

pitches, activated through the outer hair cells.

Hair Cell Receptor Potentials and Excitation of Auditory Nerve

Determination of Sound Frequency—

Fibers. The stereocilia (the “hairs” protruding from the

The “Place” Principle

ends of the hair cells) are stiff structures because each

has a rigid protein framework. Each hair cell has about

From earlier discussions in this chapter, it is apparent

100 stereocilia on its apical border. These become pro-

that low-frequency sounds cause maximal activation

gressively longer on the side of the hair cell away from

of the basilar membrane near the apex of the cochlea,

the modiolus, and the tops of the shorter stereocilia are

and high-frequency sounds activate the basilar mem-

attached by thin filaments to the back sides of their

brane near the base of the cochlea. Intermediate-

adjacent longer stereocilia. Therefore, whenever the

frequency sounds activate the membrane at inter-

cilia are bent in the direction of the longer ones, the

mediate distances between the two extremes.

tips of the smaller stereocilia are tugged outward from

Furthermore, there is spatial organization of the nerve

the surface of the hair cell. This causes a mechanical

fibers in the cochlear pathway, all the way from the

transduction that opens 200 to 300 cation-conducting

cochlea to the cerebral cortex. Recording of signals in

channels, allowing rapid movement of positively

the auditory tracts of the brain stem and in the audi-

charged potassium ions from the surrounding scala

tory receptive fields of the cerebral cortex shows that

media fluid into the stereocilia, which causes depolar-

specific brain neurons are activated by specific sound

ization of the hair cell membrane.

frequencies. Therefore, the major method used by

Thus, when the basilar fibers bend toward the scala

the nervous system to detect different sound frequen-

vestibuli, the hair cells depolarize, and in the opposite

cies is to determine the positions along the basilar

direction they hyperpolarize, thereby generating an

membrane that are most stimulated. This is called

alternating hair cell receptor potential. This, in turn,

the place principle for the determination of sound

stimulates the cochlear nerve endings that synapse

frequency.

with the bases of the hair cells. It is believed that a

Yet, referring again to Figure 52-6, one can see that

rapidly acting neurotransmitter is released by the hair

the distal end of the basilar membrane at the heli-

cells at these synapses during depolarization. It is pos-

cotrema is stimulated by all sound frequencies below

sible that the transmitter substance is glutamate, but

200 cycles per second. Therefore, it has been difficult

this is not certain.

to understand from the place principle how one can

differentiate between low sound frequencies in the

Endocochlear Potential. To explain even more fully the

range from 200 down to 20. It is postulated that these

electrical potentials generated by the hair cells, we need

low frequencies are discriminated mainly by the so-

to explain another electrical phenomenon called the

called volley or frequency principle. That is, low-

endocochlear potential: The scala media is filled with a

frequency sounds, from 20 to 1500 to 2000 cycles per

fluid called endolymph, in contradistinction to the peri-

second, can cause volleys of nerve impulses synchro-

lymph present in the scala vestibuli and scala tympani.

nized at the same frequencies, and these volleys are

The scala vestibuli and scala tympani communicate

transmitted by the cochlear nerve into the cochlear

directly with the subarachnoid space around the brain,

so that the perilymph is almost identical with cere-

nuclei of the brain. It is further suggested that the

brospinal fluid. Conversely, the endolymph that fills

cochlear nuclei can distinguish the different frequen-

the scala media is an entirely different fluid secreted by

cies of the volleys. In fact, destruction of the entire

the stria vascularis, a highly vascular area on the outer

apical half of the cochlea, which destroys the basilar

wall of the scala media. Endolymph contains a high

membrane where all lower-frequency sounds are nor-

concentration of potassium and a low concentration

mally detected, does not totally eliminate discrimina-

of sodium, which is exactly opposite to the contents of

tion of the lower-frequency sounds.

perilymph.

An electrical potential of about +80 millivolts exists

all the time between endolymph and perilymph, with

Determination of Loudness

positivity inside the scala media and negativity outside.

This is called the endocochlear potential, and it is gen-

Loudness is determined by the auditory system in at

erated by continual secretion of positive potassium ions

least three ways.

into the scala media by the stria vascularis.

First, as the sound becomes louder, the amplitude of

The importance of the endocochlear potential is that

the tops of the hair cells project through the reticular

vibration of the basilar membrane and hair cells also

lamina and are bathed by the endolymph of the scala

increases, so that the hair cells excite the nerve endings

media, whereas perilymph bathes the lower bodies of

at more rapid rates.

Chapter 52

The Sense of Hearing

657

Second, as the amplitude of vibration increases, it

causes more and more of the hair cells on the fringes

of the resonating portion of the basilar membrane to

Vibration

Sound

become stimulated, thus causing spatial summation of

100

Pricking

impulses—that is, transmission through many nerve

(in middle ear)

fibers rather than through only a few.

Third, the outer hair cells do not become stimulated

Tactual

significantly until vibration of the basilar membrane

threshold

reaches high intensity, and stimulation of these cells

presumably apprises the nervous system that the

Threshold

–20

of hearing

sound is loud.

-40

-60

Reference

Detection of Changes in Loudness—The Power Law. As

- 80

pressure = -73.8

pointed out in Chapter 46, a person interprets changes

in intensity of sensory stimuli approximately in pro-

5 10 20

100

500

2000

10,000

Frequency

portion to an inverse power function of the actual

intensity. In the case of sound, the interpreted sensa-

tion changes approximately in proportion to the cube

root of the actual sound intensity. To express this

Figure 52-9

another way, the ear can discriminate differences in

Relation of the threshold of hearing and of somesthetic percep-

sound intensity from the softest whisper to the loudest

tion (pricking and tactual threshold) to the sound energy level at

possible noise, representing an approximately 1 trillion

each sound frequency.

times increase in sound energy or 1 million times

increase in amplitude of movement of the basilar

membrane. Yet the ear interprets this much difference

in sound level as approximately a 10,000-fold change.

to 5000 cycles per second; only with intense sounds can

Thus, the scale of intensity is greatly “compressed” by

the complete range of 20 to 20,000 cycles be achieved.

the sound perception mechanisms of the auditory

In old age, this frequency range is usually shortened to

system. This allows a person to interpret differences in

50 to 8000 cycles per second or less, as discussed later in

sound intensities over an extremely wide range—a far

the chapter.

wider range than would be possible were it not for

compression of the intensity scale.

Central Auditory Mechanisms

Decibel Unit. Because of the extreme changes in sound

Auditory Nervous Pathways

intensities that the ear can detect and discriminate,

sound intensities are usually expressed in terms of the

Figure 52-10 shows the major auditory pathways. It

logarithm of their actual intensities. A 10-fold increase

shows that nerve fibers from the spiral ganglion of

in sound energy is called 1 bel, and 0.1 bel is called 1

Corti enter the dorsal and ventral cochlear nuclei

decibel. One decibel represents an actual increase in

located in the upper part of the medulla. At this point,

sound energy of 1.26 times.

all the fibers synapse, and second-order neurons pass

Another reason for using the decibel system to

mainly to the opposite side of the brain stem to ter-

express changes in loudness is that, in the usual sound

minate in the superior olivary nucleus. A few second-

intensity range for communication, the ears can barely

order fibers also pass to the superior olivary nucleus

distinguish an approximately

1-decibel change in

on the same side. From the superior olivary nucleus,

sound intensity.

the auditory pathway passes upward through the

lateral lemniscus. Some of the fibers terminate in the

Threshold for Hearing Sound at Different Frequencies. Figure

52-9 shows the pressure thresholds at which sounds of

nucleus of the lateral lemniscus, but many bypass this

different frequencies can barely be heard by the ear.

nucleus and travel on to the inferior colliculus, where

This figure demonstrates that a 3000-cycle-per-second

all or almost all the auditory fibers synapse. From

sound can be heard even when its intensity is as low as

there, the pathway passes to the medial geniculate

70 decibels below 1 dyne/cm² sound pressure level,

nucleus, where all the fibers do synapse. Finally, the

which is one ten-millionth microwatt per square cen-

pathway proceeds by way of the auditory radiation to

timeter. Conversely, a 100-cycle-per-second sound can

the auditory cortex, located mainly in the superior

be detected only if its intensity is 10,000 times as great

gyrus of the temporal lobe.

as this.

Several important points should be noted. First,

signals from both ears are transmitted through the

Frequency Range of Hearing. The frequencies of sound that

pathways of both sides of the brain, with a prepon-

a young person can hear are between 20 and 20,000

cycles per second. However, referring again to Figure

derance of transmission in the contralateral pathway.

52-9, we see that the sound range depends to a great

In at least three places in the brain stem, crossing over

extent on loudness. If the loudness is 60 decibels below

occurs between the two pathways: (1) in the trapezoid

1 dyne/cm² sound pressure level, the sound range is 500

body, (2) in the commissure between the two nuclei of

658

Unit X

The Nervous System: B. The Special Senses

vermis of the cerebellum, which is also activated instan-

taneously in the event of a sudden noise.

Third, a high degree of spatial orientation is main-

tained in the fiber tracts from the cochlea all the way

to the cortex. In fact, there are three spatial patterns for

termination of the different sound frequencies in the

cochlear nuclei, two patterns in the inferior colliculi,

one precise pattern for discrete sound frequencies in

the auditory cortex, and at least five other less precise

patterns in the auditory cortex and auditory associa-

tion areas.

Firing Rates at Different Levels of the Auditory Pathways. Single

Primary

nerve fibers entering the cochlear nuclei from the audi-

auditry

cortex

tory nerve can fire at rates up to at least 1000 per

second, the rate being determined mainly by the loud-

Midbrain

Medial

ness of the sound. At sound frequencies up to 2000 to

geniculate

4000 cycles per second, the auditory nerve impulses are

nucleus

often synchronized with the sound waves, but they do

not necessarily occur with every wave.

In the auditory tracts of the brain stem, the firing is

Inferior

usually no longer synchronized with the sound fre-

colliculus

quency, except at sound frequencies below 200 cycles

Midbrain

per second. Above the level of the inferior colliculi, even

this synchronization is mainly lost. These findings

demonstrate that the sound signals are not transmitted

unchanged directly from the ear to the higher levels of

the brain; instead, information from the sound signals

begins to be dissected from the impulse traffic at levels

Nucleus of

as low as the cochlear nuclei. We will have more to say

the lateral

about this later, especially in relation to perception of

Pons

lemniscus

direction from which sound comes.

Function of the Cerebral Cortex

in Hearing

Pons

The projection area of auditory signals to the cerebral

Superior

cortex is shown in Figure 52-11, which demonstrates

olivary

Dorsal

nuclei

that the auditory cortex lies principally on the

acoustic

supratemporal plane of the superior temporal gyrus but

stria

Intermediate

also extends onto the lateral side of the temporal lobe,

acoustic

Cochlear

over much of the insular cortex, and even onto the

site

nuclei

lateral portion of the parietal operculum.

Medulla

Two separate subdivisions are shown in Figure

N. VIlI

52-11: the primary auditory cortex and the auditory

Trapezoid

body

association cortex (also called the secondary auditory

cortex). The primary auditory cortex is directly excited

by projections from the medial geniculate body,

Figure 52-10

whereas the auditory association areas are excited

secondarily by impulses from the primary auditory

Auditory nervous pathways. (Modified from Brodal A: The auditory

cortex as well as by some projections from thalamic

system. In Neurological Anatomy in Relation to Clinical Medicine,

association areas adjacent to the medial geniculate

3rd ed. New York: Oxford University Press, 1981.)

body.

Sound Frequency Perception in the Primary Auditory Cortex.

the lateral lemnisci, and (3) in the commissure con-

At least six tonotopic maps have been found in the

necting the two inferior colliculi.

primary auditory cortex and auditory association

Second, many collateral fibers from the auditory

areas. In each of these maps, high-frequency sounds

tracts pass directly into the reticular activating system

excite neurons at one end of the map, whereas low-

of the brain stem. This system projects diffusely

frequency sounds excite neurons at the opposite end.

upward in the brain stem and downward into the

In most, the low-frequency sounds are located anteri-

spinal cord and activates the entire nervous system in

orly, as shown in Figure 52-11, and the high-frequency

response to loud sounds. Other collaterals go to the

sounds are located posteriorly. This is not true for all

Chapter 52

The Sense of Hearing

659

in Chapter 46 in relation to mechanisms for transmit-

Low

High

ting information in nerves. That is, stimulation of the

frequency

cochlea at one frequency inhibits sound frequencies

on both sides of this primary frequency; this is

caused by collateral fibers angling off the primary

signal pathway and exerting inhibitory influences on

adjacent pathways. The same effect has been demon-

strated to be important in sharpening patterns of

somesthetic images, visual images, and other types of

sensations.

Many of the neurons in the auditory cortex, espe-

Association

Primary

cially in the auditory association cortex, do not respond

only to specific sound frequencies in the ear. It is

believed that these neurons

“associate” different

sound frequencies with one another or associate sound

information with information from other sensory

areas of the cortex. Indeed, the parietal portion of the

auditory association cortex partly overlaps somatosen-

sory area II, which could provide an easy opportunity

Association

for the association of auditory information with

somatosensory information.

Primary

Discrimination of Sound “Patterns” by the Auditory Cortex.

Complete bilateral removal of the auditory cortex

does not prevent a cat or monkey from detecting

sounds or reacting in a crude manner to sounds.

However, it does greatly reduce or sometimes

even abolish the animal’s ability to discriminate dif-

Figure 52-11

ferent sound pitches and especially patterns of sound.

For instance, an animal that has been trained to rec-

Auditory cortex.

ognize a combination or sequence of tones, one fol-

lowing the other in a particular pattern, loses this

ability when the auditory cortex is destroyed; further-

more, the animal cannot relearn this type of response.

the maps. The question one must ask is, Why does the

Therefore, the auditory cortex is especially important

auditory cortex have so many different tonotopic

in the discrimination of tonal and sequential sound

maps? The answer, presumably, is that each of the sep-

patterns.

arate areas dissects out some specific feature of the

Destruction of both primary auditory cortices in

sounds. For instance, one of the large maps in the

the human being greatly reduces one’s sensitivity

primary auditory cortex almost certainly discriminates

for hearing. Destruction of one side only slightly

the sound frequencies themselves and gives the person

reduces hearing in the opposite ear; it does not cause

the psychic sensation of sound pitches. Another map

deafness in the ear because of many crossover con-

is probably used to detect the direction from which the

nections from side to side in the auditory neural

sound comes. Other auditory cortex areas detect

pathway. However, it does affect one’s ability to

special qualities, such as the sudden onset of sounds,

localize the source of a sound, because comparative

or perhaps special modulations, such as noise versus

signals in both cortices are required for the localiza-

pure frequency sounds.

tion function.

The frequency range to which each individual

Lesions that affect the auditory association areas

neuron in the auditory cortex responds is much

but not the primary auditory cortex do not decrease a

narrower than that in the cochlear and brain stem

person’s ability to hear and differentiate sound tones

relay nuclei. Referring back to Figure 52-6B, note that

or even to interpret at least simple patterns of sound.

the basilar membrane near the base of the cochlea is

However, he or she is often unable to interpret the

stimulated by sounds of all frequencies, and in the

meaning of the sound heard. For instance, lesions in

cochlear nuclei, this same breadth of sound represen-

the posterior portion of the superior temporal gyrus,

tation is found. Yet, by the time the excitation has

which is called Wernicke’s area and is part of the audi-

reached the cerebral cortex, most sound-responsive

tory association cortex, often make it impossible for a

neurons respond to only a narrow range of frequen-

person to interpret the meanings of words even though

cies rather than to a broad range. Therefore, some-

he or she hears them perfectly well and can even

where along the pathway, processing mechanisms

repeat them. These functions of the auditory associa-

“sharpen” the frequency response. It is believed that

tion areas and their relation to the overall intellectual

this sharpening effect is caused mainly by the phe-

functions of the brain are discussed in more detail in

nomenon of lateral inhibition, which is discussed

Chapter 57.

660

Unit X The Nervous System: B. The Special Senses

Determination of the Direction from

lag; those in between respond to intermediate time

lags. Thus, a spatial pattern of neuronal stimulation

Which Sound Comes

develops in the medial superior olivary nucleus, with

sound from directly in front of the head stimulating

A person determines the horizontal direction from

one set of olivary neurons maximally and sounds from

which sound comes by two principal means: (1) the

different side angles stimulating other sets of neurons

time lag between the entry of sound into one ear and

on opposite sides. This spatial orientation of signals is

its entry into the opposite ear, and (2) the difference

then transmitted to the auditory cortex, where sound

between the intensities of the sounds in the two ears.

direction is determined by the locus of the maximally

The first mechanism functions best at frequencies

stimulated neurons. It is believed that all these signals

below 3000 cycles per second, and the second mecha-

for determining sound direction are transmitted

nism operates best at higher frequencies because the

through a different pathway and excite a different

head is a greater sound barrier at these frequencies.

locus in the cerebral cortex from the transmission

The time lag mechanism discriminates direction much

pathway and termination locus for tonal patterns of

more exactly than the intensity mechanism because it

sound.

does not depend on extraneous factors but only on the

This mechanism for detection of sound direction

exact interval of time between two acoustical signals.

indicates again how specific information in sensory

If a person is looking straight toward the source of the

signals is dissected out as the signals pass through

sound, the sound reaches both ears at exactly the same

different levels of neuronal activity. In this case, the

instant, whereas if the right ear is closer to the sound

“quality” of sound direction is separated from the

than the left ear is, the sound signals from the right ear

“quality” of sound tones at the level of the superior

enter the brain ahead of those from the left ear.

olivary nuclei.

The two aforementioned mechanisms cannot tell

whether the sound is emanating from in front of or

behind the person or from above or below. This dis-

Centrifugal Signals from the

crimination is achieved mainly by the pinnae of the

Central Nervous System to Lower

two ears. The shape of the pinna changes the quality

Auditory Centers

of the sound entering the ear, depending on the direc-

tion from which the sound comes. It does this by

Retrograde pathways have been demonstrated at each

emphasizing specific sound frequencies from the dif-

level of the auditory nervous system from the cortex to

ferent directions.

the cochlea in the ear itself. The final pathway is mainly

from the superior olivary nucleus to the sound-receptor

Neural Mechanisms for Detecting Sound Direction. Destruc-

hair cells in the organ of Corti.

tion of the auditory cortex on both sides of the brain,

These retrograde fibers are inhibitory. Indeed, direct

whether in human beings or in lower mammals, causes

stimulation of discrete points in the olivary nucleus has

loss of almost all ability to detect the direction from

been shown to inhibit specific areas of the organ of

Corti, reducing their sound sensitivities 15 to 20 deci-

which sound comes. Yet the neural analyses for this

bels. One can readily understand how this could allow

detection process begin in the superior olivary nuclei

a person to direct his or her attention to sounds of par-

in the brain stem, even though the neural pathways all

ticular qualities while rejecting sounds of other quali-

the way from these nuclei to the cortex are required

ties. This is readily demonstrated when one listens to a

for interpretation of the signals. The mechanism is

single instrument in a symphony orchestra.

believed to be the following.

The superior olivary nucleus is divided into two sec-

tions: (1) the medial superior olivary nucleus and (2)

Hearing Abnormalities

the lateral superior olivary nucleus. The lateral nucleus

is concerned with detecting the direction from which

Types of Deafness

the sound is coming, presumably by simply comparing

Deafness is usually divided into two types: (1) that

the difference in intensities of the sound reaching the

caused by impairment of the cochlea or impairment of

two ears and sending an appropriate signal to the audi-

the auditory nerve, which is usually classified as “nerve

tory cortex to estimate the direction.

deafness,” and (2) that caused by impairment of the

The medial superior olivary nucleus, however, has a

physical structures of the ear that conduct sound

specific mechanism for detecting the time lag between

itself to the cochlea, which is usually called “conduction

acoustical signals entering the two ears. This nucleus

deafness.”

contains large numbers of neurons that have two

If either the cochlea or the auditory nerve is

destroyed, the person becomes permanently deaf.

major dendrites, one projecting to the right and the

However, if the cochlea and nerve are still intact but the

other to the left. The acoustical signal from the right

tympanum-ossicular system has been destroyed or

ear impinges on the right dendrite, and the signal from

ankylosed (“frozen” in place by fibrosis or calcification),

the left ear impinges on the left dendrite. The intensity

sound waves can still be conducted into the cochlea by

of excitation of each neuron is highly sensitive to a

means of bone conduction from a sound generator

specific time lag between the two acoustical signals

applied to the skull over the ear.

from the two ears. The neurons near one border of the

nucleus respond maximally to a short time lag, while

Audiometer. To determine the nature of hearing dis-

those near the opposite border respond to a long time

abilities, the “audiometer” is used. Simply an earphone

Chapter 52

The Sense of Hearing

661

-10

Normal

* X

X Air conduction

* ^{Bone conduction}

100

250

500

1000

2000

4000

8000

125

250

500

1000

2000

4000

8000

Frequency

Figure 52-12

Figure 52-13

Audiogram of the old-age type of nerve deafness.

Audiogram of air conduction deafness resulting from middle ear

sclerosis.

connected to an electronic oscillator capable of emitting

pure tones ranging from low frequencies to high fre-

Audiogram for Middle Ear Conduction Deafness. A

quencies, the instrument is calibrated so that zero-

common type of deafness is caused by fibrosis in the

intensity-level sound at each frequency is the loudness

middle ear following repeated infection or by fibrosis

that can barely be heard by the normal ear. A calibrated

that occurs in the hereditary disease called otosclerosis.

volume control can increase the loudness above the

In either case, the sound waves cannot be transmitted

zero level. If the loudness must be increased to 30 deci-

easily through the ossicles from the tympanic mem-

bels above normal before it can be heard, the person is

brane to the oval window. Figure 52-13 shows an audio-

said to have a hearing loss of 30 decibels at that partic-

gram from a person with “middle ear air conduction

ular frequency.

deafness.” In this case, bone conduction is essentially

In performing a hearing test using an audiometer, one

normal, but conduction through the ossicular system is

tests about 8 to 10 frequencies covering the auditory

greatly depressed at all frequencies, but more so at low

spectrum, and the hearing loss is determined for each of

frequencies. In some instances of conduction deafness,

these frequencies. Then the so-called audiogram is

the faceplate of the stapes becomes “ankylosed” by

plotted, as shown in Figures 52-12 and 52-13, depicting

bone overgrowth to the edges of the oval window. In

hearing loss at each of the frequencies in the auditory

this case, the person becomes totally deaf for ossicular

spectrum. The audiometer, in addition to being

conduction but can regain almost normal hearing by the

equipped with an earphone for testing air conduction

surgical removal of the stapes and its replacement with

by the ear, is equipped with a mechanical vibrator for

a minute Teflon or metal prosthesis that transmits the

testing bone conduction from the mastoid process of the

sound from the incus to the oval window.

skull into the cochlea.

Audiogram in Nerve Deafness. In nerve deafness—

References

which includes damage to the cochlea, the auditory

nerve, or the central nervous system circuits from the

ear—the person has decreased or total loss of ability to

Brugge J: Central Auditory Processing and Neural Model-

hear sound as tested by both air conduction and bone

ing. New York: Plenum Press, 1998.

conduction. An audiogram depicting partial nerve deaf-

Eatock RA: Auditory physiology: listening with K⁺ channels.

ness is shown in Figure 52-12. In this figure, the deaf-

Curr Biol 13:R767, 2003.

ness is mainly for high-frequency sound. Such deafness

Fettiplace R, Ricci AJ: Adaptation in auditory hair cells. Curr

could be caused by damage to the base of the cochlea.

Opin Neurobiol 13:446, 2003.

This type of deafness occurs to some extent in almost

Frolenkov GI, Belyantseva IA, Friedman TB, Griffith AJ:

all older people.

Genetic insights into the morphogenesis of inner ear hair

Other patterns of nerve deafness frequently occur as

cells. Nat Rev Genet 5:489, 2004.

follows: (1) deafness for low-frequency sounds caused

Geisler CD: From Sound to Synapse: Physiology of the

by excessive and prolonged exposure to very loud

Mammalian Ear. New York: Oxford University Press,

sounds (a rock band or a jet airplane engine), because

1998.

low-frequency sounds are usually louder and more dam-

Gillespie PG, Cyr JL: Myosin-1c, the hair cell’s adaptation

aging to the organ of Corti, and (2) deafness for all

motor. Annu Rev Physiol 66:521, 2004.

frequencies caused by drug sensitivity of the organ of

Griffiths TD, Warren JD, Scott SK, et al: Cortical processing

Corti—in particular, sensitivity to some antibiotics such

of complex sound: a way forward? Trends Neurosci 27:181,

as streptomycin, kanamycin, and chloramphenicol.

2004.

662

Unit X The Nervous System: B. The Special Senses

Grothe B: New roles for synaptic inhibition in sound local-

Scott SK, Johnsrude IS: The neuroanatomical and functional

ization. Nat Rev Neurosci 4:540, 2003.

organization of speech perception. Trends Neurosci 26:

Joris PX, Schreiner CE, Rees A: Neural processing of ampli-

100, 2003.

tude-modulated sounds. Physiol Rev 84:541, 2004.

Semple MN, Scott BH: Cortical mechanisms in hearing. Curr

McDermott BM Jr, Lopez-Schier H: Inner ear: Ca²⁺ you feel

Opin Neurobiol 13:167, 2003.

the noise? Curr Biol 14:R231, 2004.

Suga N, Ma X: Multiparametric corticofugal modulation and

Minor LB, Schessel DA, Carey JP: Meniere’s disease. Curr

plasticity in the auditory system. Nat Rev Neurosci 4:783,

Opin Neurol 17:9, 2004.

2003.

Rauschecker JP, Shannon RV: Sending sound to the brain.

Syka J: Plastic changes in the central auditory system after

Science 295:1025, 2002.

hearing loss, restoration of function, and during learning.

Read HL, Winer JA, Schreiner CE: Functional architecture

Physiol Rev 82:601, 2002.

of auditory cortex. Curr Opin Neurobiol 12:433, 2002.

Trainor LJ, Shahin A, Roberts LE: Effects of musical train-

Robles L, Ruggero MA: Mechanics of the mammalian

ing on the auditory cortex in children. Ann N Y Acad Sci

cochlea. Physiol Rev 81:1305, 2001.

999:506, 2003.

Santos-Sacchi J: New tunes from Corti’s organ: the outer hair

Weinberger NM: Specific long-term memory traces in

cell boogie rules. Curr Opin Neurobiol 13:459, 2003.

primary auditory cortex. Nat Rev Neurosci 5:279, 2004.

Schreiner CE, Read HL, Sutter ML: Modular organization

of frequency integration in primary auditory cortex. Annu

Rev Neurosci 23:501, 2000.

C H A P T E R

The Chemical Senses—

Taste and Smell

The senses of taste and smell allow us to separate

undesirable or even lethal foods from those that are

pleasant to eat and nutritious. The sense of smell

also allows animals to recognize the proximity of

other animals or even individuals among animals.

Finally, both senses are strongly tied to primitive

emotional and behavioral functions of our nervous

systems.

Sense of Taste

Taste is mainly a function of the taste buds in the mouth, but it is common expe-

rience that one’s sense of smell also contributes strongly to taste perception. In

addition, the texture of food, as detected by tactual senses of the mouth, and

the presence of substances in the food that stimulate pain endings, such as

pepper, greatly alter the taste experience. The importance of taste lies in the

fact that it allows a person to select food in accord with desires and often in

accord with the body tissues’ metabolic need for specific substances.

Primary Sensations of Taste

The identities of the specific chemicals that excite different taste receptors are

not all known. Even so, psychophysiologic and neurophysiologic studies have

identified at least 13 possible or probable chemical receptors in the taste cells,

as follows: 2 sodium receptors, 2 potassium receptors, 1 chloride receptor,

1 adenosine receptor, 1 inosine receptor, 2 sweet receptors, 2 bitter receptors,

1 glutamate receptor, and 1 hydrogen ion receptor.

For practical analysis of taste, the aforementioned receptor capabilities have

also been grouped into five general categories called the primary sensations of

taste. They are sour, salty, sweet, bitter, and “umami.”

A person can perceive hundreds of different tastes. They are all supposed to

be combinations of the elementary taste sensations, just as all the colors we can

see are combinations of the three primary colors, as described in Chapter 50.

Sour Taste. The sour taste is caused by acids, that is, by the hydrogen ion con-

centration, and the intensity of this taste sensation is approximately propor-

tional to the logarithm of the hydrogen ion concentration. That is, the more acidic

the food, the stronger the sour sensation becomes.

Salty Taste. The salty taste is elicited by ionized salts, mainly by the sodium ion

concentration. The quality of the taste varies somewhat from one salt to

another, because some salts elicit other taste sensations in addition to saltiness.

The cations of the salts, especially sodium cations, are mainly responsible for

the salty taste, but the anions also contribute to a lesser extent.

Sweet Taste. The sweet taste is not caused by any single class of chemicals. Some

of the types of chemicals that cause this taste include sugars, glycols, alcohols,

aldehydes, ketones, amides, esters, some amino acids, some small proteins,

663

664

Unit X The Nervous System: B. The Special Senses

Table 53-1

Relative Taste Indices of Different Substances

Sour Substances

Index

Bitter Substances

Index

Sweet Substances

Index

Salty Substances

Index

Hydrochloric acid

Quinine

Sucrose

NaCl

Formic acid

1.1

Brucine

1-Propoxy-2-amino-

5000

NaF

Chloracetic acid

0.9

Strychnine

3.1

4-nitrobenzene

CaCl₂

Acetylacetic acid

0.85

Nicotine

1.3

Saccharin

675

NaBr

0.4

Lactic acid

0.85

Phenylthiourea

0.9

Chloroform

NaI

0.35

Tartaric acid

0.7

Caffeine

0.4

Fructose

1.7

LiCl

0.4

Malic acid

0.6

Veratrine

0.2

Alanine

1.3

NH₄Cl

2.5

Potassium H tartrate

0.58

Pilocarpine

0.16

Glucose

0.8

KCl

0.6

Acetic acid

0.55

Atropine

0.13

Maltose

0.45

Citric acid

0.46

Cocaine

0.02

Galactose

0.32

Carbonic acid

0.06

Morphine

0.02

Lactose

0.3

From Pfaffman C: Handbook of Physiology. Sec I, Vol 1. Baltimore: Williams & Wilkins, 1959, p. 507.

sulfonic acids, halogenated acids, and inorganic salts of

Threshold for Taste

lead and beryllium. Note specifically that most of the

The threshold for stimulation of the sour taste by

substances that cause a sweet taste are organic chem-

hydrochloric acid averages 0.0009 N; for stimulation of

icals. It is especially interesting that slight changes in

the salty taste by sodium chloride, 0.01 M; for the sweet

the chemical structure, such as addition of a simple

taste by sucrose, 0.01 M; and for the bitter taste by

radical, can often change the substance from sweet to

quinine, 0.000008 M. Note especially how much more

bitter.

sensitive is the bitter taste sense than all the others,

which would be expected, because this sensation pro-

Bitter Taste. The bitter taste, like the sweet taste, is not

vides an important protective function against many

caused by any single type of chemical agent. Here

dangerous toxins in food.

again, the substances that give the bitter taste are

Table 53-1 gives the relative taste indices (the recip-

almost entirely organic substances. Two particular

rocals of the taste thresholds) of different substances.

classes of substances are especially likely to cause

In this table, the intensities of four of the primary sen-

bitter taste sensations: (1) long-chain organic sub-

sations of taste are referred, respectively, to the inten-

stances that contain nitrogen, and (2) alkaloids. The

sities of the taste of hydrochloric acid, quinine, sucrose,

alkaloids include many of the drugs used in medicines,

and sodium chloride, each of which is arbitrarily

such as quinine, caffeine, strychnine, and nicotine.

chosen to have a taste index of 1.

Some substances that at first taste sweet have a

bitter aftertaste. This is true of saccharin, which makes

Taste Blindness. Some people are taste blind for certain

this substance objectionable to some people.

substances, especially for different types of thiourea

The bitter taste, when it occurs in high intensity,

compounds. A substance used frequently by psycholo-

usually causes the person or animal to reject the food.

gists for demonstrating taste blindness is phenylthio-

This is undoubtedly an important function of the bitter

carbamide, for which about 15 to 30 per cent of all

taste sensation, because many deadly toxins found in

people exhibit taste blindness; the exact percentage

poisonous plants are alkaloids, and virtually all of

depends on the method of testing and the concentra-

these cause intensely bitter taste, usually followed by

tion of the substance.

rejection of the food.

Umami Taste. Umami is a Japanese word (meaning

Taste Bud and Its Function

“delicious”) designating a pleasant taste sensation that

is qualitatively different from sour, salty, sweet, or

Figure 53-1 shows a taste bud, which has a diameter

bitter. Umami is the dominant taste of food contain-

of about ¹/₃₀ millimeter and a length of about ¹/₁₆ mil-

ing L-glutamate, such as meat extracts and aging

limeter. The taste bud is composed of about 50 modi-

cheese, and some physiologists consider it to be a sep-

fied epithelial cells, some of which are supporting cells

arate, fifth category of primary taste stimuli.

called sustentacular cells and others of which are taste

A taste receptor for L-glutamate may be related to

cells. The taste cells are continually being replaced by

one of the glutamate receptors expressed in neuronal

mitotic division of surrounding epithelial cells, so that

synapses of the brain. However, the precise molecular

some taste cells are young cells. Others are mature

mechanisms responsible for umami taste are still

cells that lie toward the center of the bud; these soon

unclear.

break up and dissolve. The life span of each taste cell

Chapter 53

The Chemical Senses—Taste and Smell

665

Stratified

stimuli, as well as by a few other taste stimuli that do

squamous

not fit into the “primary” categories.

epithelium

Mechanism of Stimulation of Taste Buds

Nerve fibers

Receptor Potential. The membrane of the taste cell,

Microvilli

like that of most other sensory receptor cells, is nega-

tively charged on the inside with respect to the outside.

Pore

Application of a taste substance to the taste hairs

causes partial loss of this negative potential—that is,

the taste cell becomes depolarized. In most instances,

the decrease in potential, within a wide range, is

Taste cells

approximately proportional to the logarithm of con-

centration of the stimulating substance. This change in

Subepithelial

electrical potential in the taste cell is called the recep-

connective

tor potential for taste.

tissue

The mechanism by which most stimulating sub-

stances react with the taste villi to initiate the recep-

Figure 53-1

tor potential is by binding of the taste chemical to a

Taste bud.

protein receptor molecule that lies on the outer

surface of the taste receptor cell near to or protruding

through a villus membrane. This, in turn, opens ion

is about 10 days in lower mammals but is unknown for

channels, which allows positively charged sodium ions

humans.

or hydrogen ions to enter and depolarize the normal

The outer tips of the taste cells are arranged around

negativity of the cell. Then the taste chemical itself is

a minute taste pore, shown in Figure 53-1. From the tip

gradually washed away from the taste villus by the

of each taste cell, several microvilli, or taste hairs, pro-

saliva, which removes the stimulus.

trude outward into the taste pore to approach the

The type of receptor protein in each taste villus

cavity of the mouth. These microvilli provide the

determines the type of taste that will be perceived.

receptor surface for taste.

For sodium ions and hydrogen ions, which elicit salty

Interwoven around the bodies of the taste cells is a

and sour taste sensations, respectively, the receptor

branching terminal network of taste nerve fibers that

proteins open specific ion channels in the apical mem-

are stimulated by the taste receptor cells. Some of

branes of the taste cells, thereby activating the recep-

these fibers invaginate into folds of the taste cell mem-

tors. However, for the sweet and bitter taste sensations,

branes. Many vesicles form beneath the cell membrane

the portions of the receptor protein molecules that

near the fibers. It is believed that these vesicles contain

protrude through the apical membranes activate

a neurotransmitter substance that is released through

second-messenger transmitter substances inside the

the cell membrane to excite the nerve fiber endings in

taste cells, and these second messengers cause intra-

response to taste stimulation.

cellular chemical changes that elicit the taste signals.

Location of the Taste Buds. The taste buds are found on

Generation of Nerve Impulses by the Taste Bud. On

three types of papillae of the tongue, as follows: (1)

first application of the taste stimulus, the rate of dis-

A large number of taste buds are on the walls of

charge of the nerve fibers from taste buds rises to a

the troughs that surround the circumvallate papillae,

peak in a small fraction of a second but then adapts

which form a V line on the surface of the posterior

within the next few seconds back to a lower, steady

tongue. (2) Moderate numbers of taste buds are on the

level as long as the taste stimulus remains. Thus, a

fungiform papillae over the flat anterior surface of the

strong immediate signal is transmitted by the taste

tongue. (3) Moderate numbers are on the foliate papil-

nerve, and a weaker continuous signal is transmitted

lae located in the folds along the lateral surfaces of

as long as the taste bud is exposed to the taste

the tongue. Additional taste buds are located on the

stimulus.

palate, and a few are found on the tonsillar pillars, on

the epiglottis, and even in the proximal esophagus.

Adults have 3000 to 10,000 taste buds, and children

Transmission of Taste Signals into the

have a few more. Beyond the age of 45 years, many

Central Nervous System

taste buds degenerate, causing the taste sensation to

become progressively less critical in old age.

Figure 53-2 shows the neuronal pathways for trans-

mission of taste signals from the tongue and pharyn-

Specificity of Taste Buds for a Primary Taste Stimulus. Micro-

geal region into the central nervous system. Taste

electrode studies from single taste buds show that each

impulses from the anterior two thirds of the tongue

taste bud usually responds mostly to one of the five

pass first into the lingual nerve, then through the

primary taste stimuli when the taste substance is in low

chorda tympani into the facial nerve, and finally into

concentration. But at high concentration, most buds

the tractus solitarius in the brain stem. Taste sensations

can be excited by two or more of the primary taste

from the circumvallate papillae on the back of the

666

Unit X

The Nervous System: B. The Special Senses

glands to help control the secretion of saliva during the

Gustatory cortex

ingestion and digestion of food.

(anterior insula-

frontal operculum)

Adaptation of Taste. Everyone is familiar with the fact

that taste sensations adapt rapidly, often almost com-

pletely within a minute or so of continuous stimula-

tion. Yet, from electrophysiologic studies of taste nerve

fibers, it is clear that adaptation of the taste buds them-

selves usually accounts for no more than about half of

this. Therefore, the final extreme degree of adaptation

that occurs in the sensation of taste almost certainly

Ventral posterior

occurs in the central nervous system itself, although

medial nucleus of

thalamus

the mechanism and site of this are not known. At any

Geniculate

rate, it is a mechanism different from that of most

Chorda

ganglion

other sensory systems, which adapt almost entirely at

tympani

Tongue

the receptors.

N. VII

Nucleus of

Taste Preference and Control

N. IX

solitary tract

Glossopharyngeal

Petrosal

of the Diet

ganglion

Gustatory

N. X

area

Taste preference simply means that an animal will

choose certain types of food in preference to others,

Nodose

and the animal automatically uses this to help control

ganglion

the type of diet it eats. Furthermore, its taste prefer-

ences often change in accord with the body’s need for

Pharynx

certain specific substances.

The following experiments demonstrate this ability

of animals to choose food in accord with the needs

Figure 53-2

of their bodies. First, adrenalectomized, salt-depleted

Transmission of taste signals into the central nervous system.

animals automatically select drinking water with a

high concentration of sodium chloride in preference to

pure water, and this is often sufficient to supply the

needs of the body and prevent salt-depletion death.

tongue and from other posterior regions of the mouth

Second, an animal given injections of excessive

and throat are transmitted through the glossopharyn-

amounts of insulin develops a depleted blood sugar,

geal nerve also into the tractus solitarius, but at a

and the animal automatically chooses the sweetest

slightly more posterior level. Finally, a few taste signals

food from among many samples. Third, calcium-

are transmitted into the tractus solitarius from the base

depleted parathyroidectomized animals automatically

of the tongue and other parts of the pharyngeal region

choose drinking water with a high concentration of

by way of the vagus nerve.

calcium chloride.

All taste fibers synapse in the posterior brain stem

The same phenomena are also observed in everyday

in the nuclei of the tractus solitarius. These nuclei send

life. For instance, the “salt licks” of desert regions are

second-order neurons to a small area of the ventral

known to attract animals from far and wide. Also,

posterior medial nucleus of the thalamus, located

human beings reject any food that has an unpleasant

slightly medial to the thalamic terminations of the

affective sensation, which in many instances protects

facial regions of the dorsal column-medial lemniscal

our bodies from undesirable substances.

system. From the thalamus, third-order neurons are

The phenomenon of taste preference almost cer-

transmitted to the lower tip of the postcentral gyrus in

tainly results from some mechanism located in the

the parietal cerebral cortex, where it curls deep into the

central nervous system and not from a mechanism in

sylvian fissure, and into the adjacent opercular insular

the taste receptors themselves, although it is true that

area. This lies slightly lateral, ventral, and rostral to the

the receptors often become sensitized in favor of a

area for tongue tactile signals in cerebral somatic area

needed nutrient. An important reason for believing

I. From this description of the taste pathways, it is

that taste preference is mainly a central nervous

evident that they closely parallel the somatosensory

system phenomenon is that previous experience with

pathways from the tongue.

unpleasant or pleasant tastes plays a major role in

determining one’s taste preferences. For instance, if a

Taste Reflexes Integrated in the Brain Stem. From the

person becomes sick soon after eating a particular type

tractus solitarius, many taste signals are transmitted

of food, the person generally develops a negative taste

within the brain stem itself directly into the superior

preference, or taste aversion, for that particular food

and inferior salivatory nuclei, and these areas transmit

thereafter; the same effect can be demonstrated in

signals to the submandibular, sublingual, and parotid

lower animals.

Chapter 53

The Chemical Senses—Taste and Smell

667

Olfactory tract

membrane are many small Bowman’s glands that

secrete mucus onto the surface of the olfactory

Olfactory bulb

membrane.

Mitral cell

Stimulation of the Olfactory Cells

Bowman’s

Glomerulus

gland

Mechanism of Excitation of the Olfactory Cells. The portion

of each olfactory cell that responds to the olfactory

chemical stimuli is the olfactory cilia. The odorant sub-

stance, on coming in contact with the olfactory mem-

Sustentacular

brane surface, first diffuses into the mucus that covers

cells

the cilia. Then it binds with receptor proteins in the

Olfactory cell

membrane of each cilium. Each receptor protein is

actually a long molecule that threads its way through

the membrane about seven times, folding inward and

Olfactory cilia

outward. The odorant binds with the portion of the

receptor protein that folds to the outside. The inside

Mucus layer

of the folding protein, however, is coupled to a so-

Figure 53-3

called G-protein, itself a combination of three sub-

units. On excitation of the receptor protein, an alpha

Organization of the olfactory membrane and olfactory bulb, and

subunit breaks away from the G-protein and immedi-

connections to the olfactory tract.

ately activates adenylyl cyclase, which is attached to

the inside of the ciliary membrane near the receptor

cell body. The activated cyclase, in turn, converts many

Sense of Smell

molecules of intracellular adenosine triphosphate into

cyclic adenosine monophosphate (cAMP). Finally, this

Smell is the least understood of our senses. This results

cAMP activates another nearby membrane protein, a

partly from the fact that the sense of smell is a sub-

gated sodium ion channel, that opens its “gate” and

jective phenomenon that cannot be studied with ease

allows large numbers of sodium ions to pour through

in lower animals. Another complicating problem is

the membrane into the receptor cell cytoplasm. The

that the sense of smell is poorly developed in human

sodium ions increase the electrical potential in the pos-

beings in comparison with the sense of smell in many

itive direction inside the cell membrane, thus exciting

lower animals.

the olfactory neuron and transmitting action poten-

tials into the central nervous system by way of the

olfactory nerve.

Olfactory Membrane

The importance of this mechanism for activating

olfactory nerves is that it greatly multiplies the excita-

The olfactory membrane, the histology of which is

tory effect of even the weakest odorant. To summarize:

shown in Figure 53-3, lies in the superior part of each

(1) Activation of the receptor protein by the odorant

nostril. Medially, the olfactory membrane folds down-

substance activates the G-protein complex. (2) This, in

ward along the surface of the superior septum; later-

turn, activates multiple molecules of adenylyl cyclase

ally, it folds over the superior turbinate and even over

inside the olfactory cell membrane. (3) This causes the

a small portion of the upper surface of the middle

formation of many times more molecules of cAMP. (4)

turbinate. In each nostril, the olfactory membrane has

Finally, the cAMP opens still many times more sodium

a surface area of about 2.4 square centimeters.

ion channels. Therefore, even the most minute con-

centration of a specific odorant initiates a cascading

Olfactory Cells. The receptor cells for the smell sensa-

effect that opens extremely large numbers of sodium

tion are the olfactory cells (see Figure 53-3), which are

channels. This accounts for the exquisite sensitivity of

actually bipolar nerve cells derived originally from the

the olfactory neurons to even the slightest amount of

central nervous system itself. There are about 100

odorant.

million of these cells in the olfactory epithelium inter-

In addition to the basic chemical mechanism by

spersed among sustentacular cells, as shown in Figure

which the olfactory cells are stimulated, several phys-

53-3. The mucosal end of the olfactory cell forms a

ical factors affect the degree of stimulation. First, only

knob from which 4 to 25 olfactory hairs (also called

volatile substances that can be sniffed into the nostrils

olfactory cilia), measuring 0.3 micrometer in diameter

can be smelled. Second, the stimulating substance

and up to 200 micrometers in length, project into the

must be at least slightly water soluble so that it can

mucus that coats the inner surface of the nasal cavity.

pass through the mucus to reach the olfactory cilia.

These projecting olfactory cilia form a dense mat in

Third, it is helpful for the substance to be at least

the mucus, and it is these cilia that react to odors in

slightly lipid soluble, presumably because lipid con-

the air and stimulate the olfactory cells, as discussed

stituents of the cilium itself are a weak barrier to

later. Spaced among the olfactory cells in the olfactory

non-lipid-soluble odorants.

668

Unit X The Nervous System: B. The Special Senses

Membrane Potentials and Action Potentials in Olfactory Cells.

of at least 100 primary sensations of smell—a marked

The membrane potential inside unstimulated olfactory

contrast to only three primary sensations of color

cells, as measured by microelectrodes, averages about

detected by the eyes and only four or five primary

-55 millivolts. At this potential, most of the cells gen-

sensations of taste detected by the tongue. Further

erate continuous action potentials at a very slow rate,

support for the many primary sensations of smell is

varying from once every 20 seconds up to two or three

that people have been found who have odor blindness

per second.

for single substances; such discrete odor blindness has

Most odorants cause depolarization of the olfactory

been identified for more than 50 different substances.

cell membrane, decreasing the negative potential in

It is presumed that odor blindness for each substance

the cell from the normal level of -55 millivolts to -30

represents lack of the appropriate receptor protein in

millivolts or less—that is, changing the voltage in the

olfactory cells for that particular substance.

positive direction. Along with this, the number of

action potentials increases to 20 to 30 per second,

“Affective Nature of Smell.” Smell, even more so than

which is a high rate for the minute olfactory nerve

taste, has the affective quality of either pleasantness or

fibers.

unpleasantness. Because of this, smell is probably even

Over a wide range, the rate of olfactory nerve

more important than taste for the selection of food.

impulses changes approximately in proportion to the

Indeed, a person who has previously eaten food that

logarithm of the stimulus strength, which demon-

disagreed with him or her is often nauseated by the

strates that the olfactory receptors obey principles

smell of that same food on a second occasion.

of transduction similar to those of other sensory

Conversely, perfume of the right quality can wreak

receptors.

havoc with human emotions. In addition, in some

lower animals, odors are the primary excitant of sexual

Adaptation. The olfactory receptors adapt about 50 per

drive.

cent in the first second or so after stimulation. There-

after, they adapt very little and very slowly. Yet we all

Threshold for Smell. One of the principal characteristics

know from our own experience that smell sensations

of smell is the minute quantity of stimulating agent in

adapt almost to extinction within a minute or so after

the air that can elicit a smell sensation. For instance,

entering a strongly odorous atmosphere. Because this

the substance methylmercaptan can be smelled when

psychological adaptation is far greater than the degree

only one 25 trillionth of a gram is present in each mil-

of adaptation of the receptors themselves, it is almost

liliter of air. Because of this very low threshold, this

certain that most of the additional adaptation occurs

substance is mixed with natural gas to give the gas an

within the central nervous system. This seems to be

odor that can be detected when even small amounts

true for the adaptation of taste sensations as well.

of gas leak from a pipeline.

A postulated neuronal mechanism for the adapta-

tion is the following: Large numbers of centrifugal

Gradations of Smell Intensities. Although the threshold

nerve fibers pass from the olfactory regions of the

concentrations of substances that evoke smell are

brain backward along the olfactory tract and terminate

extremely slight, for many (if not most) odorants, con-

on special inhibitory cells in the olfactory bulb, the

centrations only 10 to 50 times above the threshold

granule cells. It has been postulated that after the onset

evoke maximum intensity of smell. This is in contrast

of an olfactory stimulus, the central nervous system

to most other sensory systems of the body, in which the

quickly develops strong feedback inhibition to sup-

ranges of intensity discrimination are tremendous—

press relay of the smell signals through the olfactory

for example, 500,000 to 1 in the case of the eyes and

bulb.

1 trillion to 1 in the case of the ears. This difference

might be explained by the fact that smell is concerned

Search for the Primary Sensations of Smell

more with detecting the presence or absence of

In the past, most physiologists were convinced that the

odors rather than with quantitative detection of their

many smell sensations are subserved by a few rather

intensities.

discrete primary sensations, in the same way that

vision and taste are subserved by a few select primary

sensations. Based on psychological studies, one at-

tempt to classify these sensations is the following:

Transmission of Smell Signals into

1. Camphoraceous

the Central Nervous System

2. Musky

3. Floral

The olfactory portions of the brain were among the

4. Pepperminty

first brain structures developed in primitive animals,

5. Ethereal

and much of the remainder of the brain developed

6. Pungent

around these olfactory beginnings. In fact, part of

7. Putrid

the brain that originally subserved olfaction later

It is certain that this list does not represent the true

evolved into the basal brain structures that control

primary sensations of smell. In recent years, multiple

emotions and other aspects of human behavior; this is

clues, including specific studies of the genes that

the system we call the limbic system, discussed in

encode for the receptor proteins, suggest the existence

Chapter 58.

Chapter 53

The Chemical Senses—Taste and Smell

669

Transmission of Olfactory Signals into the Olfactory Bulb. The

Hypothalamus

Medial olfactory area

olfactory bulb is shown in Figure 53-4. The olfactory

nerve fibers leading backward from the bulb are called

Prefrontal

cranial nerve I, or the olfactory tract. However,

cortex

in reality, both the tract and the bulb are an anterior

Olfactory

outgrowth of brain tissue from the base of the brain;

tract

the bulbous enlargement at its end, the olfactory bulb,

lies over the cribriform plate, separating the brain

Mitral

cavity from the upper reaches of the nasal cavity.

cell

The cribriform plate has multiple small perforations

through which an equal number of small nerves

Olfactory

pass upward from the olfactory membrane in the

bulb

nasal cavity to enter the olfactory bulb in the cranial

Orbito-

Olfactory

cavity. Figure 53-3 demonstrates the close relation

frontal

nerve

between the olfactory cells in the olfactory membrane

Lateral

cortex

and the olfactory bulb, showing short axons from

olfactory

area

the olfactory cells terminating in multiple globular

Temporal

Brain stem Hippocampus

structures within the olfactory bulb called glomeruli.

cortex

Each bulb has several thousand such glomeruli,

each of which is the terminus for about 25,000 axons

Figure 53-4

from olfactory cells. Each glomerulus also is the ter-

minus for dendrites from about 25 large mitral cells

Neural connections of the olfactory system.

and about 60 smaller tufted cells, the cell bodies of

which lie in the olfactory bulb superior to the

glomeruli. These dendrites receive synapses from the

olfactory cell neurons, and the mitral and tufted cells

send axons through the olfactory tract to transmit

olfactory signals to higher levels in the central nervous

primitive responses to olfaction, such as licking the

system.

lips, salivation, and other feeding responses caused by

Some research has suggested that different

the smell of food or by primitive emotional drives

glomeruli respond to different odors. It is possible that

associated with smell. Conversely, removal of the

specific glomeruli are the real clue to the analysis of

lateral areas abolishes the more complicated olfactory

different odor signals transmitted into the central

conditioned reflexes.

nervous system.

The Less Old Olfactory System—The Lateral Olfactory Area.

The Very Old, the Less Old, and the

The lateral olfactory area is composed mainly of the

Newer Olfactory Pathways into the

prepyriform and pyriform cortex plus the cortical

Central Nervous System

portion of the amygdaloid nuclei. From these areas,

The olfactory tract enters the brain at the anterior

signal pathways pass into almost all portions of the

junction between the mesencephalon and cerebrum;

limbic system, especially into less primitive portions

there, the tract divides into two pathways, as shown in

such as the hippocampus, which seem to be most

Figure 53-4, one passing medially into the medial

important for learning to like or dislike certain foods

olfactory area of the brain stem, and the other passing

depending on one’s experiences with them. For

laterally into the lateral olfactory area. The medial

instance, it is believed that this lateral olfactory

olfactory area represents a very old olfactory system,

area and its many connections with the limbic behav-

whereas the lateral olfactory area is the input to (1) a

ioral system cause a person to develop an absolute

less old olfactory system and (2) a newer system.

aversion to foods that have caused nausea and

vomiting.

The Very Old Olfactory System—The Medial Olfactory Area.

An important feature of the lateral olfactory area is

The medial olfactory area consists of a group of nuclei

that many signal pathways from this area also feed

located in the midbasal portions of the brain immedi-

directly into an older part of the cerebral cortex called

ately anterior to the hypothalamus. Most conspicuous

the paleocortex in the anteromedial portion of the tem-

are the septal nuclei, which are midline nuclei that feed

poral lobe. This is the only area of the entire cerebral

into the hypothalamus and other primitive portions

cortex where sensory signals pass directly to the cortex

of the brain’s limbic system. This is the brain area

without passing first through the thalamus.

most concerned with basic behavior (described in

Chapter 58).

The Newer Pathway. A newer olfactory pathway has now

The importance of this medial olfactory area is best

been found that passes through the thalamus, passing

understood by considering what happens in animals

to the dorsomedial thalamic nucleus and then to the

when the lateral olfactory areas on both sides of the

lateroposterior quadrant of the orbitofrontale cortex.

brain are removed and only the medial system

Based on studies in monkeys, this newer system prob-

remains. The answer is that this hardly affects the more

ably helps in the conscious analysis of odor.

670

Unit X The Nervous System: B. The Special Senses

Summary. Thus, there appear to be a very old olfactory

Herness MS, Gilbertson TA: Cellular mechanisms of taste

system that subserves the basic olfactory reflexes, a

transduction. Annu Rev Physiol 61:873, 1999.

less old system that provides automatic but partially

Levine AS, Kotz CM, Gosnell BA: Sugars and fats: the neu-

robiology of preference. J Nutr 133:831S, 2003.

learned control of food intake and aversion to toxic

Lledo PM, Gheusi G: Olfactory processing in a changing

and unhealthy foods, and a newer system that is com-

brain. Neuroreport 14:1655, 2003.

parable to most of the other cortical sensory systems

Lowe G: Electrical signaling in the olfactory bulb. Curr Opin

and is used for conscious perception and analysis of

Neurobiol 13:476, 2003.

olfaction.

Margolskee RF: Molecular mechanisms of bitter and sweet

taste transduction. J Biol Chem 277:1, 2002.

Centrifugal Control of Activity in the Olfactory Bulb by the

Matthews HR, Reisert J: Calcium, the two-faced messenger

Central Nervous System. Many nerve fibers that originate

of olfactory transduction and adaptation. Curr Opin Neu-

in the olfactory portions of the brain pass from the

robiol 13:469, 2003.

brain in the outward direction into the olfactory tract

Menini A, Lagostena L, Boccaccio A: Olfaction: from

odorant molecules to the olfactory cortex. News Physiol

to the olfactory bulb (i.e., “centrifugally” from the

Sci 19:101, 2004.

brain to the periphery). These terminate on a large

Mombaerts P: Genes and ligands for odorant, vomeronasal

number of small granule cells located among the mitral

and taste receptors. Nat Rev Neurosci 5:263, 2004.

and tufted cells in the olfactory bulb. The granule cells

Mombaerts P: Odorant receptor gene choice in olfactory

send inhibitory signals to the mitral and tufted cells. It

sensory neurons: the one receptor-one neuron hypothesis

is believed that this inhibitory feedback might be a

revisited. Curr Opin Neurobiol 14:31, 2004.

means for sharpening one’s specific ability to distin-

Montmayeur JP, Matsunami H: Receptors for bitter and

guish one odor from another.

sweet taste. Curr Opin Neurobiol 12:366, 2002.

Reed RR: The contribution of signaling pathways to olfac-

tory organization and development. Curr Opin Neurobiol

References

13:482, 2003.

Ronnett GV, Moon C: G proteins and olfactory signal trans-

duction. Annu Rev Physiol 64:189, 2002.

Bermudez-Rattoni F: Molecular mechanisms of taste-recog-

Sewards TV: Dual separate pathways for sensory and

nition memory. Nat Rev Neurosci 5:209, 2004.

hedonic aspects of taste. Brain Res Bull 62:271, 2004.

Dohlman HG: G proteins and pheromone signaling. Annu

Smith DV, Margolskee RF: Making sense of taste. Sci Am

Rev Physiol 64:129, 2002.

284:32, 2001.

Gibson AD, Garbers DL: Guanylyl cyclases as a family of

putative odorant receptors. Annu Rev Neurosci 23:417,

2000.

C H A P T E R

Motor Functions of the Spinal

Cord; the Cord Reflexes

We have already noted that sensory information is

integrated at all levels of the nervous system and

causes appropriate motor responses that begin in

the spinal cord with relatively simple muscle

reflexes, extend into the brain stem with more com-

plicated responses, and finally extend to the cere-

brum, where the most complicated muscle skills are

controlled.

In this chapter, we discuss the control of muscle function by the spinal cord.

Without the special neuronal circuits of the cord, even the most complex motor

control systems in the brain could not cause any purposeful muscle movement.

To give an example, there is no neuronal circuit anywhere in the brain that

causes the specific to-and-fro movement of the legs that is required in walking.

Instead, the circuits for these movements are in the cord, and the brain simply

sends command signals to the spinal cord to set into motion the walking process.

Let us not belittle the role of the brain, however, because the brain gives

directions that control the sequential cord activities—to promote turning move-

ments when they are required, to lean the body forward during acceleration, to

change the movements from walking to jumping as needed, and to monitor con-

tinuously and control equilibrium. All this is done through “analytical” and

“command” signals generated in the brain. But it also requires the many neu-

ronal circuits of the spinal cord that are the objects of the commands. These

circuits provide all but a small fraction of the direct control of the muscles.

Spinal Animal and the Decerebrate Animal. Two types of experimental preparations have

been especially useful in studying spinal cord function: (1) the spinal animal, in

which the spinal cord is transected, frequently in the neck so that most of the cord

still remains functional, and (2) the decerebrate animal, in which the brain stem is

transected in the middle to lower part of the mesencephalon.

Immediately after preparation of a spinal animal, most spinal cord function below

the level of transection is severely depressed. After a few hours in rats and cats or

a few days to weeks in monkeys, most of the intrinsic spinal cord functions return

to nearly normal and provide a suitable experimental preparation for research

study.

In the decerebrate animal, the brain stem is transected at the middle to lower mes-

encephalic level, which blocks normal inhibitory signals from the higher control

centers of the brain to the pontile and vestibular muscle control nuclei. This allows

these nuclei to become tonically active, transmitting facilitatory signals to most of

the spinal cord motor control circuits. The result is that the spinal cord motor

reflexes become very excitable and, therefore, easy to activate by even the slightest

sensory input signals to the cord. Using this preparation, one can study the intrin-

sic excitatory motor functions of the cord itself.

Organization of the Spinal Cord

for Motor Functions

The cord gray matter is the integrative area for the cord reflexes. Figure 54-1

shows the typical organization of the cord gray matter in a single cord segment.

Sensory signals enter the cord almost entirely through the sensory (posterior)

roots. After entering the cord, every sensory signal travels to two separate

673

674

Unit XI The Nervous System: C. Motor and Integrative Neurophysiology

Sensory root

Motor

Sensory Motor

Solitary cell

14 mm

5 mm

17 mm

8 mm

5 mm

External basal cells

Corticospinal tract

Alpha motor

Sheath Primary

Extrafusal

Interneurons

ending

fibers

Gamma motor

Fluid

Secondary Intrafusal

Anterior motor

ending

cavity

ending

fibers

neurons

1 cm

Figure 54-2

Muscle spindle, showing its relation to the large extrafusal skele-

tal muscle fibers. Note also both motor and sensory innervation of

Motor root

the muscle spindle.

Figure 54-1

Connections of peripheral sensory fibers and corticospinal fibers

Gamma Motor Neurons. Along with the alpha motor

with the interneurons and anterior motor neurons of the spinal

cord.

neurons, which excite contraction of the skeletal

muscle fibers, about one half as many much smaller

gamma motor neurons are located in the spinal cord

anterior horns. These gamma motor neurons transmit

destinations: (1) One branch of the sensory nerve ter-

impulses through much smaller type A gamma (Ag)

minates almost immediately in the gray matter of the

motor nerve fibers, averaging 5 micrometers in diam-

cord and elicits local segmental cord reflexes and other

eter, which go to small, special skeletal muscle fibers

local effects. (2) Another branch transmits signals to

called intrafusal fibers, shown in Figure 54-2. These

higher levels of the nervous system—to higher levels

fibers constitute the middle of the muscle spindle,

in the cord itself, to the brain stem, or even to the cere-

which helps control basic muscle “tone,” as discussed

bral cortex, as described in earlier chapters.

later in this chapter.

Each segment of the spinal cord (at the level of

each spinal nerve) has several million neurons in its

Interneurons. Interneurons are present in all areas of

gray matter. Aside from the sensory relay neurons

the cord gray matter—in the dorsal horns, the anterior

discussed in Chapters 47 and 48, the other neurons

horns, and the intermediate areas between them, as

are of two types: (1) anterior motor neurons and (2)

shown in Figure 54-1. These cells are about 30 times

interneurons.

as numerous as the anterior motor neurons. They are

small and highly excitable, often exhibiting sponta-

Anterior Motor Neurons. Located in each segment of the

neous activity and capable of firing as rapidly as 1500

anterior horns of the cord gray matter are several

times per second. They have many interconnections

thousand neurons that are 50 to 100 per cent larger

with one another, and many of them also synapse

than most of the others and are called anterior motor

directly with the anterior motor neurons, as shown

neurons. They give rise to the nerve fibers that leave

in Figure

54-1. The interconnections among the

the cord by way of the anterior roots and directly

interneurons and anterior motor neurons are respon-

innervate the skeletal muscle fibers. The neurons are

sible for most of the integrative functions of the spinal

of two types, alpha motor neurons and gamma motor

cord that are discussed in the remainder of this

neurons.

chapter.

Essentially all the different types of neuronal cir-

Alpha Motor Neurons. The alpha motor neurons give

cuits described in Chapter

46 are found in the

rise to large type A alpha (Aa) motor nerve fibers,

interneuron pool of cells of the spinal cord, including

averaging 14 micrometers in diameter; these fibers

diverging, converging, repetitive-discharge, and other

branch many times after they enter the muscle and

types of circuits. In this chapter, we examine many

innervate the large skeletal muscle fibers. Stimulation

applications of these different circuits in the perform-

of a single alpha nerve fiber excites anywhere from

ance of specific reflex acts by the spinal cord.

three to several hundred skeletal muscle fibers, which

Only a few incoming sensory signals from the spinal

are collectively called the motor unit. Transmission of

nerves or signals from the brain terminate directly on

nerve impulses into skeletal muscles and their stimu-

the anterior motor neurons. Instead, almost all these

lation of the muscle motor units are discussed in

signals are transmitted first through interneurons,

Chapters 6 and 7.

where they are appropriately processed. Thus, in

Chapter 54

Motor Functions of the Spinal Cord; the Cord Reflexes

675

Figure 54-1, the corticospinal tract from the brain is

The signals from these two receptors are either

shown to terminate almost entirely on spinal interneu-

entirely or almost entirely for the purpose of intrinsic

rons, where the signals from this tract are combined

muscle control. They operate almost completely at a

with signals from other spinal tracts or spinal nerves

subconscious level. Even so, they transmit tremendous

before finally converging on the anterior motor

amounts of information not only to the spinal cord but

neurons to control muscle function.

also to the cerebellum and even to the cerebral cortex,

helping each of these portions of the nervous system

Renshaw Cell Inhibitory System. Also located in the anterior

function to control muscle contraction.

horns of the spinal cord, in close association with the

motor neurons, are a large number of small neurons

called Renshaw cells. Almost immediately after the

Receptor Function of the

anterior motor neuron axon leaves the body of the

Muscle Spindle

neuron, collateral branches from the axon pass to adja-

cent Renshaw cells. These are inhibitory cells that trans-

mit inhibitory signals to the surrounding motor neurons.

Structure and Motor Innervation of the Muscle Spindle. The

Thus, stimulation of each motor neuron tends to inhibit

organization of the muscle spindle is shown in Figure

adjacent motor neurons, an effect called lateral inhibi-

54-2. Each spindle is 3 to 10 millimeters long. It is built

tion. This effect is important for the following major

around 3 to 12 very small intrafusal muscle fibers that

reason: The motor system uses this lateral inhibition to

are pointed at their ends and attached to the glycoca-

focus, or sharpen, its signals in the same way that the

lyx of the surrounding large extrafusal skeletal muscle

sensory system uses the same principle—that is, to allow

fibers.

unabated transmission of the primary signal in the

Each intrafusal muscle fiber is a very small skeletal

desired direction while suppressing the tendency for

muscle fiber. However, the central region of each

signals to spread laterally.

of these fibers—that is, the area midway between

Multisegmental Connections from One Spinal Cord Level

its two ends—has few or no actin and myosin fila-

to Other Levels—Propriospinal Fibers

ments. Therefore, this central portion does not contract

More than half of all the nerve fibers that ascend and

when the ends do. Instead, it functions as a sensory

descend in the spinal cord are propriospinal fibers.

receptor, as described later. The end portions that

These fibers run from one segment of the cord to

do contract are excited by small gamma motor nerve

another. In addition, as the sensory fibers enter the cord

fibers that originate from small type A gamma motor

from the posterior cord roots, they bifurcate and branch

neurons in the anterior horns of the spinal cord,

both up and down the spinal cord; some of the branches

as described earlier. These gamma motor nerve fibers

transmit signals to only a segment or two, while others

are also called gamma efferent fibers, in contradistinc-

transmit signals to many segments. These ascending and

tion to the large alpha efferent fibers (type A alpha

descending propriospinal fibers of the cord provide

pathways for the multisegmental reflexes described

nerve fibers) that innervate the extrafusal skeletal

later in this chapter, including reflexes that coordinate

muscle.

simultaneous movements in the forelimbs and hind

limbs.

Sensory Innervation of the Muscle Spindle. The receptor

portion of the muscle spindle is its central portion. In

this area, the intrafusal muscle fibers do not have

Muscle Sensory Receptors—

myosin and actin contractile elements. As shown in

Figure 54-2 and in more detail in Figure 54-3, sensory

Muscle Spindles and Golgi

fibers originate in this area. They are stimulated by

Tendon Organs—And Their

stretching of this midportion of the spindle. One can

Roles in Muscle Control

readily see that the muscle spindle receptor can be

excited in two ways:

Proper control of muscle function requires not only

1. Lengthening the whole muscle stretches the

excitation of the muscle by spinal cord anterior motor

midportion of the spindle and, therefore, excites

neurons but also continuous feedback of sensory

the receptor.

information from each muscle to the spinal cord, indi-

2. Even if the length of the entire muscle does not

cating the functional status of each muscle at each

change, contraction of the end portions of the

instant. That is, what is the length of the muscle, what

spindle’s intrafusal fibers stretches the midportion

is its instantaneous tension, and how rapidly is its

of the spindle and therefore excites the receptor.

length or tension changing? To provide this informa-

Two types of sensory endings are found in this

tion, the muscles and their tendons are supplied abun-

central receptor area of the muscle spindle. They are

dantly with two special types of sensory receptors: (1)

the primary ending and the secondary ending.

muscle spindles (see Figure 54-2), which are distrib-

uted throughout the belly of the muscle and send

Primary Ending. In the center of the receptor area, a

information to the nervous system about muscle

large sensory nerve fiber encircles the central portion

length or rate of change of length, and (2) Golgi

of each intrafusal fiber, forming the so-called primary

tendon organs (see Figure 54-7), which are located in

ending or annulospiral ending. This nerve fiber is a

the muscle tendons and transmit information about

type Ia fiber averaging 17 micrometers in diameter,

tendon tension or rate of change of tension.

and it transmits sensory signals to the spinal cord at a

676

Unit XI The Nervous System: C. Motor and Integrative Neurophysiology

Dynamic g fiber Static g fiber

Group Ia fiber

several minutes if the muscle spindle itself remains

(efferent)

(primary afferent)

stretched.

Plate

Group II fiber

ending

(secondary

Response of the Primary Ending (but Not the Sec-

efferent)

ondary Ending) to Rate of Change of Receptor

Nuclear bag fiber

Length—“Dynamic” Response. When the length of

(intrafusal muscle)

the spindle receptor increases suddenly, the primary

Nuclear chain fiber

ending (but not the secondary ending) is stimulated

(intrafusal muscle)

especially powerfully. This excess stimulus of the

Trail ending

primary ending is called the dynamic response, which

means that the primary ending responds extremely

Figure 54-3

actively to a rapid rate of change in spindle length.

Details of nerve connections from the nuclear bag and nuclear

Even when the length of a spindle receptor increases

chain muscle spindle fibers. (Modified from Stein RB: Peripheral

only a fraction of a micrometer, if this increase occurs

control of movement. Physiol Rev 54:225, 1974.)

in a fraction of a second, the primary receptor trans-

mits tremendous numbers of excess impulses to the

large

17-micrometer sensory nerve fiber, but only

while the length is actually increasing. As soon as the

length stops increasing, this extra rate of impulse dis-

velocity of 70 to 120 m/sec, as rapidly as any type of

charge returns to the level of the much smaller static

nerve fiber in the entire body.

response that is still present in the signal.

Conversely, when the spindle receptor shortens,

Secondary Ending. Usually one but sometimes two

exactly opposite sensory signals occur. Thus, the

smaller sensory nerve fibers—type II fibers with an

primary ending sends extremely strong, either positive

average diameter of 8 micrometers—innervate the

or negative, signals to the spinal cord to apprise it of

receptor region on one or both sides of the primary

any change in length of the spindle receptor.

ending, as shown in Figures

54-2 and 54-3. This

sensory ending is called the secondary ending; some-

Control of Intensity of the Static and Dynamic Responses by the

times it encircles the intrafusal fibers in the same way

Gamma Motor Nerves. The gamma motor nerves to the

that the type Ia fiber does, but often it spreads like

muscle spindle can be divided into two types: gamma-

branches on a bush.

dynamic (gamma-d) and gamma-static (gamma-s). The

first of these excites mainly the nuclear bag intrafusal

Division of the Intrafusal Fibers into Nuclear Bag and Nuclear

fibers, and the second excites mainly the nuclear chain

Chain Fibers—Dynamic and Static Responses of the Muscle

intrafusal fibers. When the gamma-d fibers excite the

Spindle. There are also two types of muscle spindle

nuclear bag fibers, the dynamic response of the muscle

intrafusal fibers: (1) nuclear bag muscle fibers (one to

spindle becomes tremendously enhanced, whereas the

three in each spindle), in which several muscle fiber

static response is hardly affected. Conversely, stimula-

nuclei are congregated in expanded “bags” in the

tion of the gamma-s fibers, which excite the nuclear

central portion of the receptor area, as shown by the

chain fibers, enhances the static response while having

top fiber in Figure 54-3, and (2) nuclear chain fibers

little influence on the dynamic response. Subsequent

(three to nine), which are about half as large in diam-

paragraphs illustrate that these two types of muscle

eter and half as long as the nuclear bag fibers and have

spindle responses are important in different types of

nuclei aligned in a chain throughout the receptor area,

muscle control.

as shown by the bottom fiber in the figure. The primary

sensory nerve ending

(the

17-micrometer sensory

Continuous Discharge of the Muscle Spindles Under Normal

fiber) is excited by both the nuclear bag intrafusal

Conditions. Normally, particularly when there is some

fibers and the nuclear chain fibers. Conversely, the sec-

degree of gamma nerve excitation, the muscle spindles

ondary ending (the 8-micrometer sensory fiber) is

emit sensory nerve impulses continuously. Stretching

usually excited only by nuclear chain fibers. These rela-

the muscle spindles increases the rate of firing,

tions are shown in Figure 54-3.

whereas shortening the spindle decreases the rate of

firing. Thus, the spindles can send to the spinal cord

Response of Both the Primary and the Secondary

either positive signals—that is, increased numbers of

Endings to the Length of the Receptor—“Static”

impulses to indicate stretch of a muscle—or negative

Response. When the receptor portion of the muscle

signals—below-normal numbers of impulses to indi-

spindle is stretched slowly, the number of impulses

cate that the muscle is unstretched.

transmitted from both the primary and the secondary

endings increases almost directly in proportion to the

degree of stretching, and the endings continue to trans-

Muscle Stretch Reflex

mit these impulses for several minutes. This effect is

called the static response of the spindle receptor,

The simplest manifestation of muscle spindle function

meaning simply that both the primary and secondary

is the muscle stretch reflex. Whenever a muscle is

endings continue to transmit their signals for at least

stretched suddenly, excitation of the spindles causes

Chapter 54

Motor Functions of the Spinal Cord; the Cord Reflexes

677

Stimulus

(8 per second)

Sensory nerve

Motor nerve

Muscle spindle

Seconds

Stretch reflex

Figure 54-5

Figure 54-4

Muscle contraction caused by a spinal cord signal under two con-

Neuronal circuit of the stretch reflex.

ditions: curve A, in a normal muscle, and curve B, in a muscle

whose muscle spindles were denervated by section of the poste-

rior roots of the cord 82 days previously. Note the smoothing effect

reflex contraction of the large skeletal muscle fibers of

of the muscle spindle reflex in curve A. (Modified from Creed RS,

the stretched muscle and also of closely allied syner-

et al: Reflex Activity of the Spinal Cord. New York: Oxford Univer-

gistic muscles.

sity Press, 1932.)

Neuronal Circuitry of the Stretch Reflex. Figure

54-4

demonstrates the basic circuit of the muscle spindle

stretch reflex, showing a type Ia proprioceptor nerve

fiber originating in a muscle spindle and entering a

secondary endings. The importance of the static stretch

dorsal root of the spinal cord. A branch of this fiber

reflex is that it causes the degree of muscle contraction

then goes directly to the anterior horn of the cord gray

to remain reasonably constant, except when the

matter and synapses with anterior motor neurons that

person’s nervous system specifically wills otherwise.

send motor nerve fibers back to the same muscle from

which the muscle spindle fiber originated. Thus, this is

“Damping” Function of the Dynamic and Static

a monosynaptic pathway that allows a reflex signal to

Stretch Reflexes

return with the shortest possible time delay back to the

An especially important function of the stretch reflex

muscle after excitation of the spindle. Most type II

is its ability to prevent oscillation or jerkiness of body

fibers from the muscle spindle terminate on multiple

movements. This is a damping, or smoothing, function,

interneurons in the cord gray matter, and these trans-

as explained in the following paragraph.

mit delayed signals to the anterior motor neurons or

serve other functions.

Damping Mechanism in Smoothing Muscle Contraction.

Signals from the spinal cord are often transmitted to a

Dynamic Stretch Reflex and Static Stretch Reflexes. The

muscle in an unsmooth form, increasing in intensity for

stretch reflex can be divided into two components: the

a few milliseconds, then decreasing in intensity, then

dynamic stretch reflex and the static stretch reflex.

changing to another intensity level, and so forth. When

The dynamic stretch reflex is elicited by the potent

the muscle spindle apparatus is not functioning satis-

dynamic signal transmitted from the primary sensory

factorily, the muscle contraction is jerky during the

endings of the muscle spindles, caused by rapid stretch

course of such a signal. This effect is demonstrated in

or unstretch. That is, when a muscle is suddenly

Figure 54-5. In curve A, the muscle spindle reflex of

stretched or unstretched, a strong signal is transmitted

the excited muscle is intact. Note that the contraction

to the spinal cord; this causes an instantaneous strong

is relatively smooth, even though the motor nerve to

reflex contraction (or decrease in contraction) of the

the muscle is excited at a slow frequency of only 8

same muscle from which the signal originated. Thus,

signals per second. Curve B illustrates the same exper-

the reflex functions to oppose sudden changes in muscle

iment in an animal whose muscle spindle sensory

length.

nerves had been sectioned 3 months earlier. Note the

The dynamic stretch reflex is over within a fraction

unsmooth muscle contraction. Thus, curve A graphi-

of a second after the muscle has been stretched (or

cally demonstrates the damping mechanism’s ability to

unstretched) to its new length, but then a weaker static

smooth muscle contractions, even though the primary

stretch reflex continues for a prolonged period there-

input signals to the muscle motor system may them-

after. This reflex is elicited by the continuous static

selves be jerky. This effect can also be called a signal

receptor signals transmitted by both primary and

averaging function of the muscle spindle reflex.

678

Unit XI The Nervous System: C. Motor and Integrative Neurophysiology

Role of the Muscle Spindle

joint also increases, producing tight, tense muscles

opposing each other at the joint. The net effect is that

in Voluntary Motor Activity

the position of the joint becomes strongly stabilized,

and any force that tends to move the joint from its

To emphasize the importance of the gamma efferent

current position is opposed by highly sensitized stretch

system, one needs to recognize that 31 per cent of all

reflexes operating on both sides of the joint.

the motor nerve fibers to the muscle are the small type

Any time a person must perform a muscle function

A gamma efferent fibers rather than large type A

that requires a high degree of delicate and exact posi-

alpha motor fibers. Whenever signals are transmitted

tioning, excitation of the appropriate muscle spindles

from the motor cortex or from any other area of the

by signals from the bulboreticular facilitatory region

brain to the alpha motor neurons, in most instances the

of the brain stem stabilizes the positions of the major

gamma motor neurons are stimulated simultaneously,

joints. This aids tremendously in performing the

an effect called coactivation of the alpha and gamma

additional detailed voluntary movements (of fingers

motor neurons. This causes both the extrafusal skele-

or other body parts) required for intricate motor

tal muscle fibers and the muscle spindle intrafusal

procedures.

muscle fibers to contract at the same time.

The purpose of contracting the muscle spindle intra-

fusal fibers at the same time that the large skeletal

Clinical Applications of the

muscle fibers contract is twofold: First, it keeps the

Stretch Reflex

length of the receptor portion of the muscle spindle

from changing during the course of the whole muscle

Almost every time a clinician performs a physical exam-

contraction. Therefore, coactivation keeps the muscle

ination on a patient, he or she elicits multiple stretch

spindle reflex from opposing the muscle contraction.

reflexes. The purpose is to determine how much back-

ground excitation, or “tone,” the brain is sending to the

Second, it maintains the proper damping function of

spinal cord. This reflex is elicited as follows.

the muscle spindle, regardless of any change in muscle

length. For instance, if the muscle spindle did not con-

Knee Jerk and Other Muscle Jerks. Clinically, a method used

tract and relax along with the large muscle fibers,

to determine the sensitivity of the stretch reflexes is to

the receptor portion of the spindle would sometimes

elicit the knee jerk and other muscle jerks. The knee jerk

be flail and sometimes be overstretched, in neither

can be elicited by simply striking the patellar tendon

instance operating under optimal conditions for

with a reflex hammer; this instantaneously stretches the

spindle function.

quadriceps muscle and excites a dynamic stretch reflex

that causes the lower leg to “jerk” forward. The upper

part of Figure 54-6 shows a myogram from the quadri-

Brain Areas for Control of the Gamma

ceps muscle recorded during a knee jerk.

Motor System

Similar reflexes can be obtained from almost any

The gamma efferent system is excited specifically by

muscle of the body either by striking the tendon of the

signals from the bulboreticular facilitatory region of

muscle or by striking the belly of the muscle itself. In

the brain stem and, secondarily, by impulses transmit-

other words, sudden stretch of muscle spindles is all that

ted into the bulboreticular area from (1) the cerebel-

is required to elicit a dynamic stretch reflex.

lum, (2) the basal ganglia, and (3) the cerebral cortex.

The muscle jerks are used by neurologists to assess

the degree of facilitation of spinal cord centers. When

Little is known about the precise mechanisms of

control of the gamma efferent system. However,

because the bulboreticular facilitatory area is par-

ticularly concerned with antigravity contractions, and

because the antigravity muscles have an especially

Patellar tendon struck

high density of muscle spindles, emphasis is given to

the importance of the gamma efferent mechanism for

Knee jerk

damping the movements of the different body parts

during walking and running.

Muscle Spindle System Stabilizes Body

Position During Tense Action

One of the most important functions of the muscle

Ankle clonus

spindle system is to stabilize body position during

tense motor action. To do this, the bulboreticular facil-

200

400

600

800

itatory region and its allied areas of the brain stem

Milliseconds

transmit excitatory signals through the gamma nerve

fibers to the intrafusal muscle fibers of the muscle

spindles. This shortens the ends of the spindles and

stretches the central receptor regions, thus increasing

Figure 54-6

their signal output. However, if the spindles on both

Myograms recorded from the quadriceps muscle during elicita-

sides of each joint are activated at the same time, reflex

tion of the knee jerk (above) and from the gastrocnemius muscle

excitation of the skeletal muscles on both sides of the

during ankle clonus (below).

Chapter 54

Motor Functions of the Spinal Cord; the Cord Reflexes

679

large numbers of facilitatory impulses are being trans-

mitted from the upper regions of the central nervous

Nerve fiber (16 mm)

system into the cord, the muscle jerks are greatly exag-

gerated. Conversely, if the facilitatory impulses are

depressed or abrogated, the muscle jerks are consider-

ably weakened or absent. These reflexes are used most

frequently in determining the presence or absence of

muscle spasticity caused by lesions in the motor areas

of the brain or diseases that excite the bulboreticular

Tendon

facilitatory area of the brain stem. Ordinarily, large

lesions in the motor areas of the cerebral cortex but not

in the lower motor control areas (especially lesions

Muscle

caused by strokes or brain tumors) cause greatly exag-

gerated muscle jerks in the muscles on the opposite side

Figure 54-7

of the body.

Golgi tendon organ.

Clonus—Oscillation of Muscle Jerks. Under some condi-

tions, the muscle jerks can oscillate, a phenomenon

proportional to the muscle tension

(the static

called clonus (see lower myogram, Figure 54-6). Oscil-

response). Thus, Golgi tendon organs provide the

lation can be explained particularly well in relation to

ankle clonus, as follows.

nervous system with instantaneous information on the

If a person standing on the tip ends of the feet sud-

degree of tension in each small segment of each

denly drops his or her body downward and stretches

muscle.

the gastrocnemius muscles, stretch reflex impulses are

transmitted from the muscle spindles into the spinal

Transmission of Impulses from the Tendon Organ into the

cord. These impulses reflexively excite the stretched

Central Nervous System. Signals from the tendon organ

muscle, which lifts the body up again. After a fraction

are transmitted through large, rapidly conducting type

of a second, the reflex contraction of the muscle dies out

Ib nerve fibers that average 16 micrometers in diame-

and the body falls again, thus stretching the spindles a

ter, only slightly smaller than those from the primary

second time. Again, a dynamic stretch reflex lifts the

endings of the muscle spindle. These fibers, like those

body, but this too dies out after a fraction of a second,

and the body falls once more to begin a new cycle. In

from the primary spindle endings, transmit signals

this way, the stretch reflex of the gastrocnemius muscle

both into local areas of the cord and, after synapsing

continues to oscillate, often for long periods; this is

in a dorsal horn of the cord, through long fiber path-

clonus.

ways such as the spinocerebellar tracts into the cere-

Clonus ordinarily occurs only when the stretch reflex

bellum and through still other tracts to the cerebral

is highly sensitized by facilitatory impulses from the

cortex. The local cord signal excites a single inhibitory

brain. For instance, in a decerebrate animal, in which the

interneuron that inhibits the anterior motor neuron.

stretch reflexes are highly facilitated, clonus develops

This local circuit directly inhibits the individual muscle

readily. To determine the degree of facilitation of the

without affecting adjacent muscles. The relation

spinal cord, neurologists test patients for clonus by sud-

between signals to the brain and function of the cere-

denly stretching a muscle and applying a steady stretch-

ing force to it. If clonus occurs, the degree of facilitation

bellum and other parts of the brain for muscle control

is certain to be high.

is discussed in Chapter 56.

Inhibitory Nature of the Tendon Reflex and

Golgi Tendon Reflex

Its Importance

When the Golgi tendon organs of a muscle tendon are

Golgi Tendon Organ Helps Control Muscle Tension. The Golgi

stimulated by increased tension in the connecting

tendon organ, shown in Figure 54-7, is an encapsulated

muscle, signals are transmitted to the spinal cord to

sensory receptor through which muscle tendon fibers

cause reflex effects in the respective muscle. This reflex

pass. About 10 to 15 muscle fibers are usually con-

is entirely inhibitory. Thus, this reflex provides a nega-

nected to each Golgi tendon organ, and the organ is

tive feedback mechanism that prevents the develop-

stimulated when this small bundle of muscle fibers is

ment of too much tension on the muscle.

“tensed” by contracting or stretching the muscle. Thus,

When tension on the muscle and, therefore, on the

the major difference in excitation of the Golgi tendon

tendon becomes extreme, the inhibitory effect from

organ versus the muscle spindle is that the spindle

the tendon organ can be so great that it leads to a

detects muscle length and changes in muscle length,

sudden reaction in the spinal cord that causes instan-

whereas the tendon organ detects muscle tension as

taneous relaxation of the entire muscle. This effect is

reflected by the tension in itself.

called the lengthening reaction; it is probably a pro-

The tendon organ, like the primary receptor of the

tective mechanism to prevent tearing of the muscle or

muscle spindle, has both a dynamic response and a

avulsion of the tendon from its attachments to the

static response, responding intensely when the muscle

bone. We know, for instance, that direct electrical stim-

tension suddenly increases (the dynamic response) but

ulation of muscles in the laboratory, which cannot be

settling down within a fraction of a second to a lower

opposed by this negative reflex, can occasionally cause

level of steady-state firing that is almost directly

such destructive effects.

680

Unit XI The Nervous System: C. Motor and Integrative Neurophysiology

Possible Role of the Tendon Reflex to Equalize Contractile

RECIPROCAL INHIBITION

Force Among the Muscle Fibers. Another likely function

of the Golgi tendon reflex is to equalize contractile

forces of the separate muscle fibers. That is, those fibers

that exert excess tension become inhibited by the

reflex, whereas those that exert too little tension

become more excited because of absence of reflex

Excited

inhibition. This spreads the muscle load over all the

Inhibited

fibers and prevents damage in isolated areas of

a muscle where small numbers of fibers might be

overloaded.

Excited

Polysynaptic

Function of the Muscle Spindles and

circuit

Golgi Tendon Organs in Conjunction

with Motor Control from Higher Levels

Painful

of the Brain

stimulus

from hand

Although we have emphasized the function of the

muscle spindles and Golgi tendon organs in spinal

cord control of motor function, these two sensory

organs also apprise the higher motor control centers

of instantaneous changes taking place in the muscles.

For instance, the dorsal spinocerebellar tracts carry

instantaneous information from both the muscle

FLEXOR

CROSSED EXTENSOR

spindles and the Golgi tendon organs directly to the

REFLEX

cerebellum at conduction velocities approaching

Figure 54-8

120 m/sec, the most rapid conduction anywhere in the

brain or spinal cord. Additional pathways transmit

Flexor reflex, crossed extensor reflex, and reciprocal inhibition.

similar information into the reticular regions of the

brain stem and, to a lesser extent, all the way to the

for the flexor reflex. In this instance, a painful stimu-

motor areas of the cerebral cortex. As discussed in

lus is applied to the hand; as a result, the flexor muscles

Chapters 55 and 56, the information from these recep-

of the upper arm become excited, thus withdrawing

tors is crucial for feedback control of motor signals

the hand from the painful stimulus.

that originate in all these areas.

The pathways for eliciting the flexor reflex do not

pass directly to the anterior motor neurons but instead

pass first into the spinal cord interneuron pool of

Flexor Reflex and the

neurons and only secondarily to the motor neurons.

Withdrawal Reflexes

The shortest possible circuit is a three- or four-neuron

pathway; however, most of the signals of the reflex tra-

In the spinal or decerebrate animal, almost any type

verse many more neurons and involve the following

of cutaneous sensory stimulus from a limb is likely to

basic types of circuits: (1) diverging circuits to spread

cause the flexor muscles of the limb to contract,

the reflex to the necessary muscles for withdrawal; (2)

thereby withdrawing the limb from the stimulating

circuits to inhibit the antagonist muscles, called recip-

object. This is called the flexor reflex.

rocal inhibition circuits; and (3) circuits to cause after-

In its classic form, the flexor reflex is elicited most

discharge lasting many fractions of a second after the

powerfully by stimulation of pain endings, such as by

stimulus is over.

a pinprick, heat, or a wound, for which reason it is also

Figure 54-9 shows a typical myogram from a flexor

called a nociceptive reflex, or simply a pain reflex. Stim-

muscle during a flexor reflex. Within a few milliseconds

ulation of touch receptors can also elicit a weaker and

after a pain nerve begins to be stimulated, the flexor

less prolonged flexor reflex.

response appears. Then, in the next few seconds, the

If some part of the body other than one of the limbs

reflex begins to fatigue, which is characteristic of essen-

is painfully stimulated, that part will similarly be with-

tially all complex integrative reflexes of the spinal

drawn from the stimulus, but the reflex may not be con-

cord. Finally, after the stimulus is over, the contraction

fined to flexor muscles, even though it is basically the

of the muscle returns toward the baseline, but because

same type of reflex. Therefore, the many patterns of

of afterdischarge, it takes many milliseconds for this

these reflexes in the different areas of the body are

to occur. The duration of afterdischarge depends on

called withdrawal reflexes.

the intensity of the sensory stimulus that elicited the

reflex; a weak tactile stimulus causes almost no after-

Neuronal Mechanism of the Flexor Reflex. The left-hand

discharge, but after a strong pain stimulus, the after-

portion of Figure 54-8 shows the neuronal pathways

discharge may last for a second or more.

Chapter 54

Motor Functions of the Spinal Cord; the Cord Reflexes

681

Fatigue

Afterdischarge

Duration of

stimulus

Afterdischarge

Duration of stimulus

Seconds

Figure 54-9

Figure 54-10

Myogram of the flexor reflex showing rapid onset of the reflex,

Myogram of a crossed extensor reflex showing slow onset but pro-

an interval of fatigue, and, finally, afterdischarge after the input

longed afterdischarge.

stimulus is over.

This is called the crossed extensor reflex. Extension of

the opposite limb can push the entire body away from

The afterdischarge that occurs in the flexor reflex

the object causing the painful stimulus in the with-

almost certainly results from both types of repetitive

drawn limb.

discharge circuits discussed in Chapter 46. Electro-

physiologic studies indicate that immediate afterdis-

Neuronal Mechanism of the Crossed Extensor Reflex. The

charge, lasting for about 6 to 8 milliseconds, results

right-hand portion of Figure 54-8 shows the neuronal

from repetitive firing of the excited interneurons

circuit responsible for the crossed extensor reflex,

themselves. Also, prolonged afterdischarge occurs

demonstrating that signals from sensory nerves cross

after strong pain stimuli, almost certainly resulting

to the opposite side of the cord to excite extensor

from recurrent pathways that initiate oscillation in

muscles. Because the crossed extensor reflex usually

reverberating interneuron circuits. These, in turn,

does not begin until 200 to 500 milliseconds after onset

transmit impulses to the anterior motor neurons,

of the initial pain stimulus, it is certain that many

sometimes for several seconds after the incoming

interneurons are involved in the circuit between the

sensory signal is over.

incoming sensory neuron and the motor neurons of

Thus, the flexor reflex is appropriately organized to

the opposite side of the cord responsible for the

withdraw a pained or otherwise irritated part of the

crossed extension. After the painful stimulus is

body from a stimulus. Further, because of afterdis-

removed, the crossed extensor reflex has an even

charge, the reflex can hold the irritated part away from

longer period of afterdischarge than does the flexor

the stimulus for 0.1 to 3 seconds after the irritation is

reflex. Again, it is presumed that this prolonged after-

over. During this time, other reflexes and actions of the

discharge results from reverberating circuits among

central nervous system can move the entire body away

the interneuronal cells.

from the painful stimulus.

Figure 54-10 shows a typical myogram recorded

from a muscle involved in a crossed extensor reflex.

Pattern of Withdrawal. The pattern of withdrawal that

This demonstrates the relatively long latency before

results when the flexor reflex is elicited depends on

the reflex begins and the long afterdischarge at the end

which sensory nerve is stimulated. Thus, a pain stimu-

of the stimulus. The prolonged afterdischarge is of

lus on the inward side of the arm elicits not only

benefit in holding the pained area of the body away

contraction of the flexor muscles of the arm but also

from the painful object until other nervous reactions

contraction of abductor muscles to pull the arm

cause the entire body to move away.

outward. In other words, the integrative centers of

the cord cause those muscles to contract that can

most effectively remove the pained part of the body

Reciprocal Inhibition and

away from the object causing the pain. Although this

principle, called the principle of “local sign,” applies to

Reciprocal Innervation

any part of the body, it is especially applicable to the

limbs because of their highly developed flexor reflexes.

In the previous paragraphs, we pointed out several

times that excitation of one group of muscles is often

associated with inhibition of another group. For

Crossed Extensor Reflex

instance, when a stretch reflex excites one muscle, it

often simultaneously inhibits the antagonist muscles.

About 0.2 to 0.5 second after a stimulus elicits a flexor

This is the phenomenon of reciprocal inhibition, and

reflex in one limb, the opposite limb begins to extend.

the neuronal circuit that causes this reciprocal relation

682

Unit XI The Nervous System: C. Motor and Integrative Neurophysiology

raise itself to the standing position. This is called

the cord righting reflex. Such a reflex demonstrates

that some relatively complex reflexes associated with

Duration of inhibitory stimulus

posture are integrated in the spinal cord. Indeed, an

animal with a well-healed transected thoracic cord

between the levels for forelimb and hindlimb innerva-

tion can right itself from the lying position and even

walk using its hindlimbs in addition to its forelimbs.

Duration of flexor reflex stimulus

In the case of an opossum with a similar transection

of the thoracic cord, the walking movements of

the hindlimbs are hardly different from those in a

Seconds

normal opossum—except that the hindlimb walking

movements are not synchronized with those of the

forelimbs.

Figure 54-11

Stepping and Walking Movements

Myogram of a flexor reflex showing reciprocal inhibition caused

Rhythmical Stepping Movements of a Single Limb. Rhythmi-

by an inhibitory stimulus from a stronger flexor reflex on the oppo-

site side of the body.

cal stepping movements are frequently observed in the

limbs of spinal animals. Indeed, even when the lumbar

portion of the spinal cord is separated from the

remainder of the cord and a longitudinal section is

is called reciprocal innervation. Likewise, reciprocal

made down the center of the cord to block neuronal

relations often exist between the muscles on the two

connections between the two sides of the cord and

sides of the body, as exemplified by the flexor and

between the two limbs, each hindlimb can still perform

extensor muscle reflexes described earlier.

individual stepping functions. Forward flexion of the

Figure 54-11 shows a typical example of reciprocal

limb is followed a second or so later by backward

inhibition. In this instance, a moderate but prolonged

extension. Then flexion occurs again, and the cycle is

flexor reflex is elicited from one limb of the body;

repeated over and over.

while this reflex is still being elicited, a stronger flexor

This oscillation back and forth between flexor and

reflex is elicited in the limb on the opposite side of the

extensor muscles can occur even after the sensory

body. This stronger reflex sends reciprocal inhibitory

nerves have been cut, and it seems to result mainly

signals to the first limb and depresses its degree of

from mutually reciprocal inhibition circuits within the

flexion. Finally, removal of the stronger reflex allows

matrix of the cord itself, oscillating between the

the original reflex to reassume its previous intensity.

neurons controlling agonist and antagonist muscles.

The sensory signals from the footpads and from the

position sensors around the joints play a strong role in

Reflexes of Posture and

controlling foot pressure and frequency of stepping

Locomotion

when the foot is allowed to walk along a surface. In

fact, the cord mechanism for control of stepping can

Postural and Locomotive Reflexes

be even more complex. For instance, if the top of the

of the Cord

foot encounters an obstruction during forward thrust,

the forward thrust will stop temporarily; then, in rapid

Positive Supportive Reaction. Pressure on the footpad of

sequence, the foot will be lifted higher and proceed

a decerebrate animal causes the limb to extend against

forward to be placed over the obstruction. This is the

the pressure applied to the foot. Indeed, this reflex

stumble reflex. Thus, the cord is an intelligent walking

is so strong that if an animal whose spinal cord has

controller.

been transected for several months—that is, after the

reflexes have become exaggerated—is placed on its

Reciprocal Stepping of Opposite Limbs. If the lumbar spinal

feet, the reflex often stiffens the limbs sufficiently to

cord is not split down its center, every time stepping

support the weight of the body. This reflex is called the

occurs in the forward direction in one limb, the oppo-

positive supportive reaction.

site limb ordinarily moves backward. This effect results

The positive supportive reaction involves a complex

from reciprocal innervation between the two limbs.

circuit in the interneurons similar to the circuits

responsible for the flexor and cross extensor reflexes.

Diagonal Stepping of All Four Limbs—“Mark Time” Reflex. If

The locus of the pressure on the pad of the foot deter-

a well-healed spinal animal (with spinal transection in

mines the direction in which the limb will extend; pres-

the neck above the forelimb area of the cord) is held

sure on one side causes extension in that direction, an

up from the floor and its legs are allowed to dangle, as

effect called the magnet reaction. This helps keep an

shown in Figure 54-12, the stretch on the limbs occa-

animal from falling to that side.

sionally elicits stepping reflexes that involve all four

limbs. In general, stepping occurs diagonally between

Cord “Righting” Reflexes. When a spinal animal is laid on

the forelimbs and hindlimbs. This diagonal response is

its side, it will make incoordinate movements trying to

another manifestation of reciprocal innervation, this

Chapter 54

Motor Functions of the Spinal Cord; the Cord Reflexes

683

Spinal Cord Reflexes That

Cause Muscle Spasm

In human beings, local muscle spasm is often observed.

In many, if not most, instances, localized pain is the

cause of the local spasm.

Muscle Spasm Resulting from a Broken Bone. One type of

clinically important spasm occurs in muscles that sur-

round a broken bone. This results from pain impulses

initiated from the broken edges of the bone, which

cause the muscles that surround the area to contract

tonically. Pain relief obtained by injecting a local anes-

thetic at the broken edges of the bone relieves the

spasm; a deep general anesthetic of the entire body, such

as ether anesthesia, also relieves the spasm. One of

Figure 54-12

these two anesthetic procedures is often necessary

before the spasm can be overcome sufficiently for the

Diagonal stepping movements exhibited by a spinal animal.

two ends of the bone to be set back into their appro-

priate positions.

Abdominal Muscle Spasm in Peritonitis. Another type of

local spasm caused by cord reflexes is abdominal spasm

resulting from irritation of the parietal peritoneum by

time occurring the entire distance up and down the

peritonitis. Here again, relief of the pain caused by the

cord between the forelimbs and hindlimbs. Such a

peritonitis allows the spastic muscle to relax. The same

walking pattern is called a mark time reflex.

type of spasm often occurs during surgical operations;

for instance, during abdominal operations, pain im-

Galloping Reflex. Another type of reflex that occasion-

pulses from the parietal peritoneum often cause the

ally develops in a spinal animal is the galloping reflex,

abdominal muscles to contract extensively, sometimes

in which both forelimbs move backward in unison

extruding the intestines through the surgical wound. For

while both hindlimbs move forward. This often occurs

this reason, deep anesthesia is usually required for intra-

abdominal operations.

when almost equal stretch or pressure stimuli are

applied to the limbs on both sides of the body at the

Muscle Cramps. Still another type of local spasm is the

same time; unequal stimulation elicits the diagonal

typical muscle cramp. Electromyographic studies indi-

walking reflex. This is in keeping with the normal pat-

cate that the cause of at least some muscle cramps is as

terns of walking and galloping, because in walking,

follows: Any local irritating factor or metabolic abnor-

only one forelimb and one hindlimb at a time are stim-

mality of a muscle, such as severe cold, lack of blood

ulated, which would predispose the animal to continue

flow, or overexercise, can elicit pain or other sensory

walking. Conversely, when the animal strikes the

signals transmitted from the muscle to the spinal cord,

ground during galloping, both forelimbs and both

which in turn cause reflex feedback muscle contraction.

hindlimbs are stimulated about equally; this predis-

The contraction is believed to stimulate the same

sensory receptors even more, which causes the spinal

poses the animal to keep galloping and, therefore, con-

cord to increase the intensity of contraction. Thus, pos-

tinues this pattern of motion.

itive feedback develops, so that a small amount of initial

irritation causes more and more contraction until a full-

blown muscle cramp ensues.

Scratch Reflex

An especially important cord reflex in some animals is

the scratch reflex, which is initiated by itch or tickle sen-

Autonomic Reflexes in the

sation. It involves two functions: (1) a position sense that

Spinal Cord

allows the paw to find the exact point of irritation on

the surface of the body, and (2) a to-and-fro scratching

Many types of segmental autonomic reflexes are inte-

movement.

grated in the spinal cord, most of which are discussed in

The position sense of the scratch reflex is a highly

other chapters. Briefly, these include (1) changes in vas-

developed function. If a flea is crawling as far forward

cular tone resulting from changes in local skin heat (see

as the shoulder of a spinal animal, the hind paw can still

Chapter 73); (2) sweating, which results from localized

find its position, even though 19 muscles in the limb

heat on the surface of the body (see Chapter 73); (3)

must be contracted simultaneously in a precise pattern

intestinointestinal reflexes that control some motor

to bring the paw to the position of the crawling flea. To

functions of the gut (see Chapter 62); (4) peritoneoin-

make the reflex even more complicated, when the flea

testinal reflexes that inhibit gastrointestinal motility in

crosses the midline, the first paw stops scratching and

response to peritoneal irritation (see Chapter 66); and

the opposite paw begins the to-and-fro motion and

(5) evacuation reflexes for emptying the full bladder

eventually finds the flea.

(see Chapter 31) or the colon (see Chapter 63). In addi-

The to-and-fro movement, like the stepping move-

tion, all the segmental reflexes can at times be elicited

ments of locomotion, involves reciprocal innervation

simultaneously in the form of the so-called mass reflex,

circuits that cause oscillation.

described next.

684

Unit XI The Nervous System: C. Motor and Integrative Neurophysiology

Mass Reflex. In a spinal animal or human being, some-

stretch reflexes, followed in order by the

times the spinal cord suddenly becomes excessively

progressively more complex reflexes: flexor reflexes,

active, causing massive discharge in large portions of the

postural antigravity reflexes, and remnants of

cord. The usual stimulus that causes this is a strong pain

stepping reflexes.

stimulus to the skin or excessive filling of a viscus, such

3. The sacral reflexes for control of bladder and colon

as overdistention of the bladder or the gut. Regardless

evacuation are suppressed in human beings for the

of the type of stimulus, the resulting reflex, called the

first few weeks after cord transection, but in most

mass reflex, involves large portions or even all of the

cases they eventually return. These effects are

cord. The effects are (1) a major portion of the body’s

discussed in Chapters 31 and 66.

skeletal muscles goes into strong flexor spasm; (2) the

colon and bladder are likely to evacuate; (3) the arte-

rial pressure often rises to maximal values, sometimes

References

to a systolic pressure well over 200 mm Hg; and (4) large

areas of the body break out into profuse sweating.

Buffelli M, Busetto G, Bidoia C, et al: Activity-dependent

Because the mass reflex can last for minutes, it pre-

synaptic competition at mammalian neuromuscular junc-

sumably results from activation of great numbers of

tions. News Physiol Sci 19:85, 2004.

reverberating circuits that excite large areas of the cord

Chen HH, Hippenmeyer S, Arber S, Frank E: Development

at once. This is similar to the mechanism of epileptic

of the monosynaptic stretch reflex circuit. Curr Opin

seizures, which involve reverberating circuits that occur

Neurobiol 13:96, 2003.

in the brain instead of in the cord.

Dietz V: Proprioception and locomotor disorders. Nat Rev

Neurosci 3:781, 2002.

Dietz V: Spinal cord pattern generators for locomotion. Clin

Spinal Cord Transection and

Neurophysiol 114:1379, 2003.

Spinal Shock

Dobkin BH, Havton LA: Basic advances and new avenues

in therapy of spinal cord injury. Annu Rev Med 55:255,

When the spinal cord is suddenly transected in the

2004.

upper neck, at first, essentially all cord functions, includ-

Duysens J, Clarac F, Cruse H: Load-regulating mechanisms

ing the cord reflexes, immediately become depressed to

in gait and posture: comparative aspects. Physiol Rev

the point of total silence, a reaction called spinal shock.

80:83, 2000.

The reason for this is that normal activity of the cord

Garwicz M: Spinal reflexes provide motor error signals to

neurons depends to a great extent on continual tonic

cerebellar modules—relevance for motor coordination.

excitation by the discharge of nerve fibers entering the

Brain Res Brain Res Rev 40:152, 2002.

cord from higher centers, particularly discharge trans-

Glover JC: Development of specific connectivity between

mitted through the reticulospinal tracts, vestibulospinal

premotor neurons and motoneurons in the brain stem and

tracts, and corticospinal tracts.

spinal cord. Physiol Rev 80:615, 2000.

After a few hours to a few weeks, the spinal neurons

Grillner S: The motor infrastructure: from ion channels to

gradually regain their excitability. This seems to be a

neuronal networks. Nat Rev Neurosci 4:573, 2003.

natural characteristic of neurons everywhere in the

Grillner S: Muscle twitches during sleep shape the precise

nervous system—that is, after they lose their source of

muscles of the withdrawal reflex. Trends Neurosci 27:169,

facilitatory impulses, they increase their own natural

2004.

degree of excitability to make up at least partially for

Guthrie S: Neuronal development: putting motor neurons in

the loss. In most nonprimates, excitability of the cord

their place. Curr Biol 14:R166, 2004.

centers returns essentially to normal within a few hours

Haines DE: Fundamental Neuroscience. New York:

to a day or so, but in human beings, the return is often

Churchill Livingstone, 1997.

delayed for several weeks and occasionally is never

Haines DE, Lancon JA: Review of Neuroscience. New York:

complete; conversely, sometimes recovery is excessive,

Churchill Livingstone, 2003.

with resultant hyperexcitability of some or all cord

Helms AW, Johnson JE: Specification of dorsal spinal cord

functions.

interneurons. Curr Opin Neurobiol 13:42, 2003.

Some of the spinal functions specifically affected

Jankowska E: Spinal interneuronal systems: identification,

during or after spinal shock are the following:

multifunctional character and reconfigurations in

1. At onset of spinal shock, the arterial blood

mammals. J Physiol 533:31, 2001.

pressure falls instantly and drastically—sometimes

Jankowska E, Hammar I: Spinal interneurons: how can

to as low as 40 mm Hg—thus demonstrating that

studies in animals contribute to the understanding of

sympathetic nervous system activity becomes

spinal interneuronal systems in man? Brain Res Brain Res

blocked almost to extinction. The pressure

Rev 40:19, 2002.

ordinarily returns to normal within a few days, even

Kandel ER, Schwartz JH, Jessell TM: Principles of Neural

in human beings.

Science, 4th ed. New York: McGraw-Hill, 2000.

2. All skeletal muscle reflexes integrated in the spinal

Marder E, Bucher D: Central pattern generators and the

cord are blocked during the initial stages of shock.

control of rhythmic movements. Curr Biol 11:R986, 2001.

In lower animals, a few hours to a few days are

Marder E, Prinz AA: Current compensation in neuronal

required for these reflexes to return to normal;

homeostasis. Neuron 37:2, 2003.

in human beings, 2 weeks to several months are

Pearson KG: Generating the walking gait: role of sensory

sometimes required. In both animals and

feedback. Prog Brain Res 143:123, 2004.

humans, some reflexes may eventually become

Rekling JC, Funk GD, Bayliss DA, et al: Synaptic control of

hyperexcitable, particularly if a few facilitatory

motoneuronal excitability. Physiol Rev 80:767, 2000.

pathways remain intact between the brain and the

Rossignol S, Bouyer L, Barthelemy D, et al: Recovery of

cord while the remainder of the spinal cord is

locomotion in the cat following spinal cord lesions. Brain

transected. The first reflexes to return are the

Res Brain Res Rev 40:257, 2002.

C H A P T E R

Cortical and Brain Stem Control

of Motor Function

In this chapter, we discuss control of body move-

ments by the cerebral cortex and brain stem.

Most “voluntary” movements initiated by the

cerebral cortex are achieved when the cortex acti-

vates “patterns” of function stored in lower brain

areas—the cord, brain stem, basal ganglia, and cere-

bellum. These lower centers, in turn, send specific

control signals to the muscles.

For a few types of movements, however, the cortex has almost a direct

pathway to the anterior motor neurons of the cord, bypassing some motor

centers on the way. This is especially true for control of the fine dexterous move-

ments of the fingers and hands. This chapter and Chapter 56 explain the inter-

play among the different motor areas of the brain and spinal cord to provide

overall synthesis of voluntary motor function.

MOTOR CORTEX AND CORTICOSPINAL TRACT

Figure 55-1 shows the functional areas of the cerebral cortex. Anterior to the

central cortical sulcus, occupying approximately the posterior one third of

the frontal lobes, is the motor cortex. Posterior to the central sulcus is the

somatosensory cortex (an area discussed in detail in earlier chapters), which

feeds the motor cortex many of the signals that initiate motor activities.

The motor cortex itself is divided into three subareas, each of which has its

own topographical representation of muscle groups and specific motor func-

tions: (1) the primary motor cortex, (2) the premotor area, and (3) the supple-

mentary motor area.

Primary Motor Cortex

The primary motor cortex, shown in Figure 55-1, lies in the first convolution of

the frontal lobes anterior to the central sulcus. It begins laterally in the sylvian

fissure, spreads superiorly to the uppermost portion of the brain, and then dips

deep into the longitudinal fissure. (This area is the same as area 4 in Brodmann’s

classification of the brain cortical areas, shown in Figure 47-5.)

Figure 55-1 lists the approximate topographical representations of the dif-

ferent muscle areas of the body in the primary motor cortex, beginning with the

face and mouth region near the sylvian fissure; the arm and hand area, in the

midportion of the primary motor cortex; the trunk, near the apex of the brain;

and the leg and foot areas, in the part of the primary motor cortex that dips into

the longitudinal fissure. This topographical organization is demonstrated even

more graphically in Figure 55-2, which shows the degrees of representation of

the different muscle areas as mapped by Penfield and Rasmussen. This mapping

was done by electrically stimulating the different areas of the motor cortex in

human beings who were undergoing neurosurgical operations. Note that more

than one half of the entire primary motor cortex is concerned with controlling

the muscles of the hands and the muscles of speech. Point stimulation in these

hand and speech motor areas on rare occasion causes contraction of a single

685

686

Unit XI The Nervous System: C. Motor and Integrative Neurophysiology

Motor

Sensory

Premotor Area

Primary

motor

Somatic

The premotor area, also shown in Figure 55-1, lies 1

Supplementary

cortex

area 1

to 3 centimeters anterior to the primary motor cortex,

area

Somatic

extending inferiorly into the sylvian fissure and supe-

Legs

association

riorly into the longitudinal fissure, where it abuts

area

Feet

the supplementary motor area, which has functions

similar to those of the premotor area. The topograph-

Trunk

ical organization of the premotor cortex is roughly the

Arm

same as that of the primary motor cortex, with the

Hand

mouth and face areas located most laterally; as one

Face

moves upward, the hand, arm, trunk, and leg areas are

encountered.

Mouth

Nerve signals generated in the premotor area cause

much more complex “patterns” of movement than

the discrete patterns generated in the primary motor

cortex. For instance, the pattern may be to position

the shoulders and arms so that the hands are properly

Premotor

area

oriented to perform specific tasks. To achieve these

results, the most anterior part of the premotor area

Figure 55-1

first develops a “motor image” of the total muscle

movement that is to be performed. Then, in the poste-

Motor and somatosensory functional areas of the cerebral cortex.

rior premotor cortex, this image excites each succes-

The numbers 4, 5, 6, and 7 are Brodmann’s cortical areas, as

explained in Chapter 47.

sive pattern of muscle activity required to achieve the

image. This posterior part of the premotor cortex sends

its signals either directly to the primary motor cortex

to excite specific muscles or, often, by way of the basal

ganglia and thalamus back to the primary motor

cortex. Thus, the premotor cortex, basal ganglia, thal-

amus, and primary motor cortex constitute a complex

overall system for the control of complex patterns of

coordinated muscle activity.

Supplementary Motor Area

The supplementary motor area has yet another topo-

graphical organization for the control of motor func-

Lips

tion. It lies mainly in the longitudinal fissure but

extends a few centimeters onto the superior frontal

cortex. Contractions elicited by stimulating this area

are often bilateral rather than unilateral. For instance,

Mastication

stimulation frequently leads to bilateral grasping

Salivation

movements of both hands simultaneously; these

movements are perhaps rudiments of the hand func-

tions required for climbing. In general, this area func-

tions in concert with the premotor area to provide

body-wide attitudinal movements, fixation movements

Figure 55-2

of the different segments of the body, positional

movements of the head and eyes, and so forth, as back-

Degree of representation of the different muscles of the body in

ground for the finer motor control of the arms and

the motor cortex. (Redrawn from Penfield W, Rasmussen T: The

Cerebral Cortex of Man: A Clinical Study of Localization of Func-

hands by the premotor area and primary motor cortex.

tion. New York: Hafner, 1968.)

Some Specialized Areas of Motor

muscle; most often, stimulation contracts a group of

muscles instead. To express this in another way, exci-

Control Found in the Human

tation of a single motor cortex neuron usually excites

Motor Cortex

a specific movement rather than one specific muscle.

To do this, it excites a “pattern” of separate muscles,

Neurosurgeons have found a few highly specialized

each of which contributes its own direction and

motor regions of the human cerebral cortex (shown in

strength of muscle movement.

Figure 55-3) that control specific motor functions.

Chapter 55

Cortical and Brain Stem Control of Motor Function

687

Supplemental

Primary

Area for Hand Skills. In the premotor area immediately

and premotor

motor

anterior to the primary motor cortex for the hands and

areas

cortex

fingers is a region neurosurgeons have identified as

important for “hand skills.” That is, when tumors or

other lesions cause destruction in this area, hand

movements become uncoordinated and nonpurpose-

ful, a condition called motor apraxia.

Hand skills

Head rotation

Choice

Transmission of Signals from the

Contralateral

Lips

of words

Vocalization

Motor Cortex to the Muscles

eye movements

Jaw

Tongue

Swallowing

Eye

Motor signals are transmitted directly from the cortex

Chewing

fixation

to the spinal cord through the corticospinal tract and

indirectly through multiple accessory pathways that

Word formation

involve the basal ganglia, cerebellum, and various

(Broca’s area)

nuclei of the brain stem. In general, the direct pathways

are concerned more with discrete and detailed move-

ments, especially of the distal segments of the limbs,

Figure 55-3

particularly the hands and fingers.

Representation of the different muscles of the body in the motor

Corticospinal (Pyramidal) Tract

cortex and location of other cortical areas responsible for specific

The most important output pathway from the motor

types of motor movements.

cortex is the corticospinal tract, also called the pyram-

idal tract, shown in Figure 55-4. The corticospinal tract

originates about 30 per cent from the primary motor

cortex, 30 per cent from the premotor and supple-

These regions have been localized either by electrical

mentary motor areas, and

40 per cent from the

stimulation or by noting the loss of motor function

somatosensory areas posterior to the central sulcus.

when destructive lesions occur in specific cortical

After leaving the cortex, it passes through the pos-

areas. Some of the more important regions are the

terior limb of the internal capsule

(between the

following.

caudate nucleus and the putamen of the basal ganglia)

and then downward through the brain stem, forming

Broca’s Area and Speech. Figure 55-3 shows a premotor

the pyramids of the medulla. The majority of the

area labeled

“word formation” lying immediately

pyramidal fibers then cross in the lower medulla to the

anterior to the primary motor cortex and immediately

opposite side and descend into the lateral corticospinal

above the sylvian fissure. This region is called Broca’s

tracts of the cord, finally terminating principally on the

area. Damage to it does not prevent a person from

interneurons in the intermediate regions of the cord

vocalizing, but it does make it impossible for the

gray matter; a few terminate on sensory relay neurons

person to speak whole words rather than uncoordi-

in the dorsal horn, and a very few terminate directly

nated utterances or an occasional simple word such as

on the anterior motor neurons that cause muscle

“no” or “yes.” A closely associated cortical area also

contraction.

causes appropriate respiratory function, so that respi-

A few of the fibers do not cross to the opposite side

ratory activation of the vocal cords can occur simulta-

in the medulla but pass ipsilaterally down the cord in

neously with the movements of the mouth and tongue

the ventral corticospinal tracts. Many if not most of

during speech. Thus, the premotor neuronal activities

these fibers eventually cross to the opposite side of the

related to speech are highly complex.

cord either in the neck or in the upper thoracic region.

These fibers may be concerned with control of bilat-

“Voluntary” Eye Movement Field. In the premotor area

eral postural movements by the supplementary motor

immediately above Broca’s area is a locus for control-

cortex.

ling voluntary eye movements. Damage to this area

The most impressive fibers in the pyramidal tract are

prevents a person from voluntarily moving the eyes

a population of large myelinated fibers with a mean

toward different objects. Instead, the eyes tend to lock

diameter of 16 micrometers. These fibers originate

involuntarily onto specific objects, an effect controlled

from giant pyramidal cells, called Betz cells, that are

by signals from the occipital visual cortex, as explained

found only in the primary motor cortex. The Betz cells

in Chapter 51. This frontal area also controls eyelid

are about 60 micrometers in diameter, and their fibers

movements such as blinking.

transmit nerve impulses to the spinal cord at a veloc-

ity of about 70 m/sec, the most rapid rate of transmis-

Head Rotation Area. Slightly higher in the motor associ-

sion of any signals from the brain to the cord. There

ation area, electrical stimulation elicits head rotation.

are about 34,000 of these large Betz cell fibers in each

This area is closely associated with the eye movement

corticospinal tract. The total number of fibers in each

field; it directs the head toward different objects.

corticospinal tract is more than 1 million, so these large

688

Unit XI

The Nervous System: C. Motor and Integrative Neurophysiology

3. A moderate number of motor fibers pass to red

Motor cortex

nuclei of the midbrain. From these, additional fibers

pass down the cord through the rubrospinal tract.

4. A moderate number of motor fibers deviate into

the reticular substance and vestibular nuclei of the

brain stem; from there, signals go to the cord by

way of reticulospinal and vestibulospinal tracts,

and others go to the cerebellum by way of

reticulocerebellar and vestibulocerebellar tracts.

Posterior limb of internal

5. A tremendous number of motor fibers synapse

capsule

in the pontile nuclei, which give rise to the

pontocerebellar fibers, carrying signals into the

cerebellar hemispheres.

6. Collaterals also terminate in the inferior olivary

nuclei, and from there, secondary olivocerebellar

Genu of corpus callosum

fibers transmit signals to multiple areas of the

cerebellum.

Thus, the basal ganglia, brain stem, and cerebellum all

receive strong motor signals from the corticospinal

system every time a signal is transmitted down the

Basis pedunculi of

spinal cord to cause a motor activity.

mesencephalon

Incoming Fiber Pathways to the

Motor Cortex

Longitudinal fascicles

The functions of the motor cortex are controlled mainly

of pons

by nerve signals from the somatosensory system but

also, to some degree, from other sensory systems such

as hearing and vision. Once the sensory information is

received, the motor cortex operates in association with

the basal ganglia and cerebellum to excite an appropri-

ate course of motor action. The more important incom-

ing fiber pathways to the motor cortex are the following:

Pyramid of medulla

1. Subcortical fibers from adjacent regions of

oblongata

the cerebral cortex, especially from (a) the

somatosensory areas of the parietal cortex, (b) the

adjacent areas of the frontal cortex anterior to

Lateral corticospinal tract

the motor cortex, and (c) the visual and auditory

cortices.

Ventral corticospinal tract

2. Subcortical fibers that arrive through the corpus

callosum from the opposite cerebral hemisphere.

Figure 55-4

These fibers connect corresponding areas of the

cortices in the two sides of the brain.

Pyramidal tract. (Modified from Ranson SW, Clark SL: Anatomy of

3. Somatosensory fibers that arrive directly from the

the Nervous System. Philadelphia: WB Saunders, 1959.)

ventrobasal complex of the thalamus. These relay

mainly cutaneous tactile signals and joint and

fibers represent only 3 per cent of the total. The other

muscle signals from the peripheral body.

97 per cent are mainly fibers smaller than 4 microme-

4. Tracts from the ventrolateral and ventroanterior

ters in diameter that conduct background tonic signals

nuclei of the thalamus, which in turn receive signals

from the cerebellum and basal ganglia. These tracts

to the motor areas of the cord.

provide signals that are necessary for coordination

among the motor control functions of the motor

Other Fiber Pathways from the Motor Cortex

cortex, basal ganglia, and cerebellum.

The motor cortex gives rise to large numbers of addi-

5. Fibers from the intralaminar nuclei of the thalamus.

tional, mainly small fibers that go to deep regions in the

These fibers control the general level of excitability

cerebrum and brain stem, including the following:

of the motor cortex in the same way they control

1. The axons from the giant Betz cells send short

the general level of excitability of most other

collaterals back to the cortex itself. These

regions of the cerebral cortex.

collaterals are believed to inhibit adjacent regions

of the cortex when the Betz cells discharge, thereby

“sharpening” the boundaries of the excitatory

signal.

Red Nucleus Serves as an Alternative

2. A large number of fibers pass from the motor

Pathway for Transmitting Cortical

cortex into the caudate nucleus and putamen. From

Signals to the Spinal Cord

there, additional pathways extend into the brain

stem and spinal cord, as discussed in the next

chapter, mainly to control body postural muscle

The red nucleus, located in the mesencephalon, func-

contractions.

tions in close association with the corticospinal tract.

Chapter 55

Cortical and Brain Stem Control of Motor Function

689

the corticospinal fibers are destroyed but the corti-

Motor

corubrospinal pathway is intact, discrete movements

cortex

can still occur, except that the movements for fine

Corticorubral

control of the fingers and hands are considerably

tract

impaired. Wrist movements are still functional, which

is not the case when the corticorubrospinal pathway is

also blocked.

Therefore, the pathway through the red nucleus to

the spinal cord is associated with the corticospinal

system. Further, the rubrospinal tract lies in the lateral

columns of the spinal cord, along with the corti-

cospinal tract, and terminates on the interneurons and

motor neurons that control the more distal muscles of

Red nucleus

the limbs. Therefore, the corticospinal and rubrospinal

Interpositus

tracts together are called the lateral motor system

nucleus

Reticular formation

of the cord, in contradistinction to a vestibuloreticu-

Dentate

lospinal system, which lies mainly medially in the cord

nucleus

Rubrospinal tract

and is called the medial motor system of the cord, as

Cerebellum

discussed later in this chapter.

“Extrapyramidal” System

Figure 55-5

The term extrapyramidal motor system is widely used in

Corticorubrospinal pathway for motor control, showing also the

clinical circles to denote all those portions of the brain

relation of this pathway to the cerebellum.

and brain stem that contribute to motor control but are

not part of the direct corticospinal-pyramidal system.

These include pathways through the basal ganglia, the

reticular formation of the brain stem, the vestibular

As shown in Figure 55-5, it receives a large number of

nuclei, and often the red nuclei. This is such an all-

direct fibers from the primary motor cortex through

inclusive and diverse group of motor control areas that

it is difficult to ascribe specific neurophysiologic func-

the corticorubral tract, as well as branching fibers from

tions to the so-called extrapyramidal system as a whole.

the corticospinal tract as it passes through the mesen-

For this reason, the term “extrapyramidal” is being used

cephalon. These fibers synapse in the lower portion of

less often both clinically and physiologically.

the red nucleus, the magnocellular portion, which con-

tains large neurons similar in size to the Betz cells in

the motor cortex. These large neurons then give rise to

Excitation of the Spinal Cord Motor

the rubrospinal tract, which crosses to the opposite

side in the lower brain stem and follows a course

Control Areas by the Primary Motor

immediately adjacent and anterior to the corticospinal

Cortex and Red Nucleus

tract into the lateral columns of the spinal cord.

The rubrospinal fibers terminate mostly on the

Vertical Columnar Arrangement of the Neurons in the Motor

interneurons of the intermediate areas of the cord gray

Cortex. In Chapters 47 and 51, we pointed out that the

matter, along with the corticospinal fibers, but some of

cells in the somatosensory cortex and visual cortex are

the rubrospinal fibers terminate directly on anterior

organized in vertical columns of cells. In like manner,

motor neurons, along with some corticospinal fibers.

the cells of the motor cortex are organized in vertical

The red nucleus also has close connections with the

columns a fraction of a millimeter in diameter, with

cerebellum, similar to the connections between the

thousands of neurons in each column.

motor cortex and the cerebellum.

Each column of cells functions as a unit, usually

stimulating a group of synergistic muscles, but some-

Function of the Corticorubrospinal System. The magnocel-

times stimulating just a single muscle. Also, each

lular portion of the red nucleus has a somatographic

column has six distinct layers of cells, as is true

representation of all the muscles of the body, as is true

throughout nearly all the cerebral cortex. The pyram-

of the motor cortex. Therefore, stimulation of a single

idal cells that give rise to the corticospinal fibers all lie

point in this portion of the red nucleus causes con-

in the fifth layer of cells from the cortical surface. Con-

traction of either a single muscle or a small group of

versely, the input signals all enter by way of layers 2

muscles. However, the fineness of representation of

through 4. And the sixth layer gives rise mainly to

the different muscles is far less developed than in the

fibers that communicate with other regions of the cere-

motor cortex. This is especially true in human beings,

bral cortex itself.

who have relatively small red nuclei.

The corticorubrospinal pathway serves as an acces-

Function of Each Column of Neurons. The neurons of

sory route for transmission of relatively discrete

each column operate as an integrative processing

signals from the motor cortex to the spinal cord. When

system, using information from multiple input sources

690

Unit XI The Nervous System: C. Motor and Integrative Neurophysiology

to determine the output response from the column. In

Sensory neurons

addition, each column can function as an amplifying

system to stimulate large numbers of pyramidal fibers

Propriospinal tract

to the same muscle or to synergistic muscles simulta-

Interneurons

neously. This is important, because stimulation of a

single pyramidal cell can seldom excite a muscle.

Corticospinal tract

Usually, 50 to 100 pyramidal cells need to be excited

from pyramidal cells

of cortex

simultaneously or in rapid succession to achieve defin-

itive muscle contraction.

Rubrospinal tract

Reticulospinal tract

Dynamic and Static Signals Transmitted by the Py-

ramidal Neurons. If a strong signal is sent to a muscle

Anterior motor

neuron

to cause initial rapid contraction, then a much weaker

continuing signal can maintain the contraction for long

Motor nerve

periods thereafter. This is the usual manner in which

Tectospinal and

excitation is provided to cause muscle contractions. To

reticulospinal tracts

do this, each column of cells excites two populations

Vestibulospinal and

of pyramidal cell neurons, one called dynamic neurons

reticulospinal tracts

and the other static neurons. The dynamic neurons are

Figure 55-6

excessively excited for a short period at the beginning

of a contraction, causing the initial rapid development

Convergence of different motor control pathways on the anterior

of force. Then the static neurons fire at a much slower

motor neurons.

rate, but they continue firing at this slow rate to main-

tain the force of contraction as long as the contraction

is required.

excitation of the muscles and, therefore, increase the

The neurons of the red nucleus have similar

tightness of the hand grasp.

dynamic and static characteristics, except that a

greater percentage of dynamic neurons is in the red

Stimulation of the Spinal Motor Neurons

nucleus and a greater percentage of static neurons is

Figure 55-6 shows a cross section of a spinal cord

in the primary motor cortex. This may be related to the

segment demonstrating (1) multiple motor and senso-

fact that the red nucleus is closely allied with the cere-

rimotor control tracts entering the cord segment and

bellum, and the cerebellum plays an important role in

(2) a representative anterior motor neuron in the

rapid initiation of muscle contraction, as explained in

middle of the anterior horn gray matter. The corti-

the next chapter.

cospinal tract and the rubrospinal tract lie in the dorsal

portions of the lateral white columns. Their fibers ter-

Somatosensory Feedback to the Motor

minate mainly on interneurons in the intermediate

Cortex Helps Control the Precision of

area of the cord gray matter.

Muscle Contraction

In the cervical enlargement of the cord where the

When nerve signals from the motor cortex cause a

hands and fingers are represented, large numbers of

muscle to contract, somatosensory signals return all

both corticospinal and rubrospinal fibers also termi-

the way from the activated region of the body to the

nate directly on the anterior motor neurons, thus

neurons in the motor cortex that are initiating the

allowing a direct route from the brain to activate

action. Most of these somatosensory signals arise in (1)

muscle contraction. This is in keeping with the fact that

the muscle spindles, (2) the tendon organs of the

the primary motor cortex has an extremely high

muscle tendons, or (3) the tactile receptors of the skin

degree of representation for fine control of hand,

overlying the muscles. These somatic signals often

finger, and thumb actions.

cause positive feedback enhancement of the muscle

contraction in the following ways: In the case of the

Patterns of Movement Elicited by Spinal Cord Centers. From

muscle spindles, if the fusimotor muscle fibers in the

Chapter 54, recall that the spinal cord can provide

spindles contract more than the large skeletal muscle

certain specific reflex patterns of movement in

fibers contract, the central portions of the spindles

response to sensory nerve stimulation. Many of these

become stretched and, therefore, excited. Signals from

same patterns are also important when the cord’s ante-

these spindles then return rapidly to the pyramidal

rior motor neurons are excited by signals from the

cells in the motor cortex to signal them that the large

brain. For example, the stretch reflex is functional at

muscle fibers have not contracted enough. The pyram-

all times, helping to damp any oscillations of the motor

idal cells further excite the muscle, helping its con-

movements initiated from the brain, and probably also

traction to catch up with the contraction of the muscle

providing at least part of the motive power required

spindles. In the case of the tactile receptors, if the

to cause muscle contractions when the intrafusal fibers

muscle contraction causes compression of the skin

of the muscle spindles contract more than the large

against an object, such as compression of the fingers

skeletal muscle fibers do, thus eliciting reflex “servo-

around an object being grasped, the signals from

assist” stimulation of the muscle, in addition to the

the skin receptors can, if necessary, cause further

direct stimulation by the corticospinal fibers.

Chapter 55

Cortical and Brain Stem Control of Motor Function

691

Also, when a brain signal excites a muscle, it usually

Role of the Brain Stem in

is not necessary to transmit an inverse signal to relax

Controlling Motor Function

the antagonist muscle at the same time; this is achieved

by the reciprocal innervation circuit that is always

The brain stem consists of the medulla, pons, and mes-

present in the cord for coordinating the function of

encephalon. In one sense, it is an extension of the

antagonistic pairs of muscles.

spinal cord upward into the cranial cavity, because it

Finally, other cord reflex mechanisms, such as

contains motor and sensory nuclei that perform motor

withdrawal, stepping and walking, scratching, and

and sensory functions for the face and head regions in

postural mechanisms, can each be activated by

the same way that the spinal cord performs these func-

“command” signals from the brain. Thus, simple

tions from the neck down. But in another sense, the

command signals from the brain can initiate many

brain stem is its own master because it provides many

normal motor activities, particularly for such functions

special control functions, such as the following:

as walking and attaining different postural attitudes of

1. Control of respiration

the body.

2. Control of the cardiovascular system

3. Partial control of gastrointestinal function

Effect of Lesions in the Motor Cortex or in the Corticospinal

4. Control of many stereotyped movements of the

Pathway—The “Stroke”

body

The motor control system can be damaged by the

5. Control of equilibrium

common abnormality called a “stroke.” This is caused

6. Control of eye movements

either by a ruptured blood vessel that hemorrhages into

the brain or by thrombosis of one of the major arteries

Finally, the brain stem serves as a way station for

supplying the brain. In either case, the result is loss of

“command signals” from higher neural centers. In the

blood supply to the cortex or to the corticospinal tract

following sections, we discuss the role of the brain stem

where it passes through the internal capsule between

in controlling whole-body movement and equilibrium.

the caudate nucleus and the putamen. Also, experiments

Especially important for these purposes are the brain

have been performed in animals to selectively remove

stem’s reticular nuclei and vestibular nuclei.

different parts of the motor cortex.

Removal of the Primary Motor Cortex

(Area Pyramidalis).

Support of the Body Against Gravity—

Removal of a portion of the primary motor cortex—the

Roles of the Reticular and

area that contains the giant Betz pyramidal cells—

causes varying degrees of paralysis of the represented

Vestibular Nuclei

muscles. If the sublying caudate nucleus and adjacent

premotor and supplementary motor areas are not

Figure 55-7 shows the locations of the reticular and

damaged, gross postural and limb “fixation” movements

vestibular nuclei in the brain stem.

can still occur, but there is loss of voluntary control of

discrete movements of the distal segments of the limbs,

especially of the hands and fingers. This does not mean

that the hand and finger muscles themselves cannot con-

tract; rather, the ability to control the fine movements is

gone. From these observations, one can conclude that

the area pyramidalis is essential for voluntary initiation

of finely controlled movements, especially of the hands

and fingers.

Pontine reticular

nuclei

Muscle Spasticity Caused by Lesions That Damage Large Areas

Adjacent to the Motor Cortex. The primary motor cortex

normally exerts a continual tonic stimulatory effect on

the motor neurons of the spinal cord; when this stimu-

latory effect is removed, hypotonia results. Most lesions

Vestibular nuclei

of the motor cortex, especially those caused by a stroke,

involve not only the primary motor cortex but also adja-

cent parts of the brain such as the basal ganglia. In these

instances, muscle spasm almost invariably occurs in the

Medullary reticular

afflicted muscle areas on the opposite side of the body

nuclei

(because the motor pathways cross to the opposite

side). This spasm results mainly from damage to acces-

sory pathways from the nonpyramidal portions of the

motor cortex. These pathways normally inhibit the

vestibular and reticular brain stem motor nuclei. When

these nuclei cease their state of inhibition (i.e., are “dis-

inhibited”), they become spontaneously active and

cause excessive spastic tone in the involved muscles, as

we discuss more fully later in the chapter. This is the

Figure 55-7

spasticity that normally accompanies a “stroke” in a

human being.

Locations of the reticular and vestibular nuclei in the brain stem.

692

Unit XI The Nervous System: C. Motor and Integrative Neurophysiology

Excitatory-Inhibitory Antagonism Between

signals from the pontine reticular system, so that under

Pontine and Medullary Reticular Nuclei

normal conditions, the body muscles are not abnor-

The reticular nuclei are divided into two major groups:

mally tense.

(1) pontine reticular nuclei, located slightly posteriorly

Yet some signals from higher areas of the brain can

and laterally in the pons and extending into the mes-

“disinhibit” the medullary system when the brain

encephalon, and (2) medullary reticular nuclei, which

wishes to excite the pontine system to cause standing.

extend through the entire medulla, lying ventrally and

At other times, excitation of the medullary reticular

medially near the midline. These two sets of nuclei

system can inhibit antigravity muscles in certain por-

function mainly antagonistically to each other, with

tions of the body to allow those portions to perform

the pontine exciting the antigravity muscles and the

special motor activities. The excitatory and inhibitory

medullary relaxing these same muscles.

reticular nuclei constitute a controllable system that is

manipulated by motor signals from the cerebral cortex

Pontine Reticular System. The pontine reticular nuclei

and elsewhere to provide necessary background

transmit excitatory signals downward into the cord

muscle contractions for standing against gravity and to

through the pontine reticulospinal tract in the anterior

inhibit appropriate groups of muscles as needed so

column of the cord, as shown in Figure 55-8. The fibers

that other functions can be performed.

of this pathway terminate on the medial anterior

motor neurons that excite the axial muscles of the

Role of the Vestibular Nuclei to Excite the

body, which support the body against gravity—that is,

Antigravity Muscles

the muscles of the vertebral column and the extensor

All the vestibular nuclei, shown in Figure 55-7, func-

muscles of the limbs.

tion in association with the pontine reticular nuclei to

The pontine reticular nuclei have a high degree of

control the antigravity muscles. The vestibular nuclei

natural excitability. In addition, they receive strong

transmit strong excitatory signals to the antigravity

excitatory signals from the vestibular nuclei, as well as

muscles by way of the lateral and medial vestibu-

from deep nuclei of the cerebellum. Therefore, when

lospinal tracts in the anterior columns of the spinal

the pontine reticular excitatory system is unopposed

cord, as shown in Figure 55-8. Without this support of

by the medullary reticular system, it causes powerful

the vestibular nuclei, the pontine reticular system

excitation of antigravity muscles throughout the body,

would lose much of its excitation of the axial anti-

so much so that four-legged animals can be placed in

gravity muscles.

a standing position, supporting the body against

The specific role of the vestibular nuclei, however,

gravity without any signals from higher levels of the

is to selectively control the excitatory signals to the dif-

brain.

ferent antigravity muscles to maintain equilibrium in

response to signals from the vestibular apparatus. We

Medullary Reticular System. The medullary reticular

discuss this more fully later in the chapter.

nuclei transmit inhibitory signals to the same anti-

gravity anterior motor neurons by way of a different

The Decerebrate Animal Develops Spastic Rigidity

tract, the medullary reticulospinal tract, located in the

When the brain stem of an animal is sectioned below

lateral column of the cord, as also shown in Figure

the midlevel of the mesencephalon, but the pontine and

55-8. The medullary reticular nuclei receive strong

medullary reticular systems as well as the vestibular

system are left intact, the animal develops a condition

input collaterals from (1) the corticospinal tract, (2)

called decerebrate rigidity. This rigidity does not occur

the rubrospinal tract, and (3) other motor pathways.

in all muscles of the body but does occur in the anti-

These normally activate the medullary reticular

gravity muscles—the muscles of the neck and trunk and

inhibitory system to counterbalance the excitatory

the extensors of the legs.

The cause of decerebrate rigidity is blockage of nor-

mally strong input to the medullary reticular nuclei

from the cerebral cortex, the red nuclei, and the basal

ganglia. Lacking this input, the medullary reticular

inhibitor system becomes nonfunctional; full overactiv-

ity of the pontine excitatory system occurs, and rigidity

Medullary reticulospinal

develops. We shall see later that other causes of rigidity

tract

occur in other neuromotor diseases, especially lesions of

the basal ganglia.

Vestibular Sensations and

Lateral vestibulospinal

tract

Maintenance of Equilibrium

Medial vestibulospinal tract

Pontine reticulospinal tract

Vestibular Apparatus

Figure 55-8

The vestibular apparatus, shown in Figure 55-9, is the

Vestibulospinal and reticulospinal tracts descending in the spinal

cord to excite (solid lines) or inhibit (dashed lines) the anterior

sensory organ for detecting sensations of equilibrium.

motor neurons that control the body’s axial musculature.

It is encased in a system of bony tubes and chambers

Chapter 55

Cortical and Brain Stem Control of Motor Function

693

Ampullae

Kinocilium

Utricle

Maculae and

Stereocilia

statoconia

Semi-

Filamentous

circular

attachments

canals

Ductus

Saccule

Posterior

cochlearis

Crista ampullaris

Ductus endolymphaticus

MEMBRANOUS LABYRINTH

Gelatinous

Statoconia

mass of

cupula

Gelatinous

Hair tufts

layer

Hair tufts

Hair

Hair cells

cells

Nerve fibers

Nerve

fibers

Sustentacular cells

Nerve fiber

CRISTA AMPULLARIS AND MACULA

Figure 55-9

Membranous labyrinth, and organization of the crista ampullaris

and the macula.

Figure 55-10

Hair cell of the equilibrium apparatus and its synapses with the

vestibular nerve.

located in the petrous portion of the temporal bone,

called the bony labyrinth. Within this system are mem-

branous tubes and chambers called the membranous

of the utricle and plays an important role in deter-

labyrinth. The membranous labyrinth is the functional

mining orientation of the head when the head is

part of the vestibular apparatus.

upright. Conversely, the macula of the saccule is

The top of Figure 55-9 shows the membranous

located mainly in a vertical plane and signals head

labyrinth. It is composed mainly of the cochlea (ductus

orientation when the person is lying down.

cochlearis); three semicircular canals; and two large

Each macula is covered by a gelatinous layer in

chambers, the utricle and saccule. The cochlea is the

which many small calcium carbonate crystals called

major sensory organ for hearing (see Chapter 52) and

statoconia are embedded. Also in the macula are thou-

has little to do with equilibrium. However, the semi-

sands of hair cells, one of which is shown in Figure

circular canals, the utricle, and the saccule are all inte-

55-10; these project cilia up into the gelatinous layer.

gral parts of the equilibrium mechanism.

The bases and sides of the hair cells synapse with

sensory endings of the vestibular nerve.

“Maculae”—Sensory Organs of the Utricle and Saccule for

The calcified statoconia have a specific gravity two

Detecting Orientation of the Head with Respect to Gravity.

to three times the specific gravity of the surrounding

Located on the inside surface of each utricle and

fluid and tissues. The weight of the statoconia bends

saccule, shown in the top diagram of Figure 55-9, is a

the cilia in the direction of gravitational pull.

small sensory area slightly over 2 millimeters in diam-

eter called a macula. The macula of the utricle lies

Directional Sensitivity of the Hair Cells—Kinocilium. Each

mainly in the horizontal plane on the inferior surface

hair cell has 50 to 70 small cilia called stereocilia, plus

694

Unit XI The Nervous System: C. Motor and Integrative Neurophysiology

one large cilium, the kinocilium, as shown in Figure

55-10. The kinocilium is always located to one side,

and the stereocilia become progressively shorter

toward the other side of the cell. Minute filamentous

attachments, almost invisible even to the electron

microscope, connect the tip of each stereocilium to the

Cupula

next longer stereocilium and, finally, to the kinocilium.

Cristae

Because of these attachments, when the stereocilia and

Ampulla

ampullaris

kinocilium bend in the direction of the kinocilium, the

filamentous attachments tug in sequence on the ster-

eocilia, pulling them outward from the cell body. This

opens several hundred fluid channels in the neuronal

cell membrane around the bases of the stereocilia,

and these channels are capable of conducting large

numbers of positive ions. Therefore, positive ions pour

into the cell from the surrounding endolymphatic

Hair cells

fluid, causing receptor membrane depolarization. Con-

Nerve

versely, bending the pile of stereocilia in the opposite

direction (backward to the kinocilium) reduces the

tension on the attachments; this closes the ion chan-

nels, thus causing receptor hyperpolarization.

Under normal resting conditions, the nerve fibers

Figure 55-11

leading from the hair cells transmit continuous nerve

impulses at a rate of about 100 per second. When the

Movement of the cupula and its embedded hairs at the onset of

rotation.

stereocilia are bent toward the kinocilium, the impulse

traffic increases, often to several hundred per second;

conversely, bending the cilia away from the kinocilium

decreases the impulse traffic, often turning it off com-

cupula. When a person’s head begins to rotate in any

pletely. Therefore, as the orientation of the head in

direction, the inertia of the fluid in one or more of the

space changes and the weight of the statoconia bends

semicircular ducts causes the fluid to remain station-

the cilia, appropriate signals are transmitted to the

ary while the semicircular duct rotates with the head.

brain to control equilibrium.

This causes fluid to flow from the duct and through the

In each macula, each of the hair cells is oriented in

ampulla, bending the cupula to one side, as demon-

a different direction so that some of the hair cells are

strated by the position of the colored cupula in Figure

stimulated when the head bends forward, some are

55-11. Rotation of the head in the opposite direction

stimulated when it bends backward, others are stimu-

causes the cupula to bend to the opposite side.

lated when it bends to one side, and so forth. There-

Into the cupula are projected hundreds of cilia from

fore, a different pattern of excitation occurs in the

hair cells located on the ampullary crest. The kinocilia

macular nerve fibers for each orientation of the head

of these hair cells are all oriented in the same direc-

in the gravitational field. It is this

“pattern” that

tion in the cupula, and bending the cupula in that

apprises the brain of the head’s orientation in space.

direction causes depolarization of the hair cells,

whereas bending it in the opposite direction hyperpo-

Semicircular Ducts. The three semicircular ducts in each

larizes the cells. Then, from the hair cells, appropriate

vestibular apparatus, known as the anterior, posterior,

signals are sent by way of the vestibular nerve to

and lateral

(horizontal) semicircular ducts, are

apprise the central nervous system of a change in rota-

arranged at right angles to one another so that they

tion of the head and the rate of change in each of the

represent all three planes in space. When the head is

three planes of space.

bent forward about 30 degrees, the lateral semicircu-

lar ducts are approximately horizontal with respect

to the surface of the earth; the anterior ducts are in

Function of the Utricle and Saccule in

vertical planes that project forward and 45 degrees

the Maintenance of Static Equilibrium

outward, whereas the posterior ducts are in

vertical planes that project backward and 45 degrees

It is especially important that the hair cells are all ori-

outward.

ented in different directions in the maculae of the utri-

Each semicircular duct has an enlargement at one

cles and saccules, so that with different positions of the

of its ends called the ampulla, and the ducts and

head, different hair cells become stimulated. The “pat-

ampulla are filled with a fluid called endolymph. Flow

terns” of stimulation of the different hair cells apprise

of this fluid through one of the ducts and through its

the brain of the position of the head with respect to

ampulla excites the sensory organ of the ampulla in

the pull of gravity. In turn, the vestibular, cerebellar,

the following manner: Figure 55-11 shows in each

and reticular motor nerve systems of the brain excite

ampulla a small crest called a crista ampullaris. On top

appropriate postural muscles to maintain proper

of this crista is a loose gelatinous tissue mass, the

equilibrium.

Chapter 55

Cortical and Brain Stem Control of Motor Function

695

This utricle and saccule system functions extremely

effectively for maintaining equilibrium when the head

is in the near-vertical position. Indeed, a person

400

Rotation

can determine as little as half a degree of dysequilib-

rium when the body leans from the precise upright

position.

300

Tonic

Detection of Linear Acceleration by the Utricle and Saccule

200

level of

Maculae. When the body is suddenly thrust forward—

discharge

Stop rotation

that is, when the body accelerates—the statoconia,

100

which have greater mass inertia than the surrounding

fluid, fall backward on the hair cell cilia, and informa-

Begin rotation

tion of dysequilibrium is sent into the nervous centers,

causing the person to feel as though he or she were

Seconds

falling backward. This automatically causes the person

to lean forward until the resulting anterior shift of the

statoconia exactly equals the tendency for the stato-

conia to fall backward because of the acceleration. At

Figure 55-12

this point, the nervous system senses a state of proper

Response of a hair cell when a semicircular canal is stimulated

equilibrium and leans the body forward no farther.

first by the onset of head rotation and then by stopping rotation.

Thus, the maculae operate to maintain equilibrium

during linear acceleration in exactly the same manner

as they operate during static equilibrium.

The maculae do not operate for the detection of

another 5 to 20 seconds, the cupula slowly returns to

linear velocity. When runners first begin to run, they

its resting position in the middle of the ampulla

must lean far forward to keep from falling backward

because of its own elastic recoil.

because of initial acceleration, but once they have

When the rotation suddenly stops, exactly opposite

achieved running speed, if they were running in a

effects take place: The endolymph continues to rotate

vacuum, they would not have to lean forward. When

while the semicircular duct stops. This time, the cupula

running in air, they lean forward to maintain equilib-

bends in the opposite direction, causing the hair cell to

rium only because of air resistance against their

stop discharging entirely. After another few seconds,

bodies; in this instance, it is not the maculae that make

the endolymph stops moving and the cupula gradually

them lean but air pressure acting on pressure end-

returns to its resting position, thus allowing hair cell

organs in the skin, which initiate appropriate equilib-

discharge to return to its normal tonic level, as shown

rium adjustments to prevent falling.

to the right in Figure 55-12. Thus, the semicircular

duct transmits a signal of one polarity when the head

begins to rotate and of opposite polarity when it stops

Detection of Head Rotation by the

rotating.

Semicircular Ducts

“Predictive” Function of the Semicircular Duct System in the

When the head suddenly begins to rotate in any direc-

Maintenance of Equilibrium. Because the semicircular

tion (called angular acceleration), the endolymph in

ducts do not detect that the body is off balance in the

the semicircular ducts, because of its inertia, tends to

forward direction, in the side direction, or in the back-

remain stationary while the semicircular ducts turn.

ward direction, one might ask: What is the semicircu-

This causes relative fluid flow in the ducts in the direc-

lar ducts’ function in the maintenance of equilibrium?

tion opposite to head rotation.

All they detect is that the person’s head is beginning

Figure 55-12 shows a typical discharge signal from

or stopping to rotate in one direction or another.

a single hair cell in the crista ampullaris when an

Therefore, the function of the semicircular ducts is not

animal is rotated for 40 seconds, demonstrating that

to maintain static equilibrium or to maintain equilib-

(1) even when the cupula is in its resting position, the

rium during steady directional or rotational move-

hair cell emits a tonic discharge of about 100 impulses

ments. Yet loss of function of the semicircular ducts

per second; (2) when the animal begins to rotate, the

does cause a person to have poor equilibrium when

hairs bend to one side and the rate of discharge

attempting to perform rapid, intricate changing body

increases greatly; and

(3) with continued rotation,

movements.

the excess discharge of the hair cell gradually

We can explain the function of the semicircular

subsides back to the resting level during the next few

ducts best by the following illustration: If a person is

seconds.

running forward rapidly and then suddenly begins to

The reason for this adaptation of the receptor is that

turn to one side, he or she will fall off balance a frac-

within the first few seconds of rotation, back resistance

tion of a second later unless appropriate corrections

to the flow of fluid in the semicircular duct and past

are made ahead of time. But the maculae of the utricle

the bent cupula causes the endolymph to begin rotat-

and saccule cannot detect that he or she is off balance

ing as rapidly as the semicircular canal itself; then, in

until after this has occurred. The semicircular ducts,

696

Unit XI The Nervous System: C. Motor and Integrative Neurophysiology

however, will have already detected that the person is

Proprioceptive and Exteroceptive Information from Other Parts

turning, and this information can easily apprise the

of the Body. Proprioceptive information from parts of

the body other than the neck is also important in the

central nervous system of the fact that the person will

maintenance of equilibrium. For instance, pressure

fall off balance within the next fraction of a second or

sensations from the footpads tell one

(1) whether

so unless some anticipatory correction is made.

weight is distributed equally between the two feet and

In other words, the semicircular duct mechanism

(2) whether weight on the feet is more forward or

predicts that dysequilibrium is going to occur and

backward.

thereby causes the equilibrium centers to make appro-

Exteroceptive information is especially necessary for

priate anticipatory preventive adjustments. In this way,

the maintenance of equilibrium when a person is

the person need not fall off balance at all before he or

running. The air pressure against the front of the body

she begins to correct the situation.

signals that a force is opposing the body in a direction

Removal of the flocculonodular lobes of the cere-

different from that caused by gravitational pull; as a

result, the person leans forward to oppose this.

bellum prevents normal detection of semicircular duct

signals but has less effect on detecting macular signals.

Importance of Visual Information in the Maintenance of Equilib-

It is especially interesting that the cerebellum serves

rium. After destruction of the vestibular apparatus, and

as a “predictive” organ for most rapid movements of

even after loss of most proprioceptive information from

the body, as well as for those having to do with equi-

the body, a person can still use the visual mechanisms

librium. These other functions of the cerebellum are

reasonably effectively for maintaining equilibrium.

discussed in the following chapter.

Even a slight linear or rotational movement of the body

instantaneously shifts the visual images on the retina,

and this information is relayed to the equilibrium

Vestibular Mechanisms for

centers. Some people with bilateral destruction of the

vestibular apparatus have almost normal equilibrium as

Stabilizing the Eyes

long as their eyes are open and all motions are per-

When a person changes his or her direction of move-

formed slowly. But when moving rapidly or when the

ment rapidly or even leans the head sideways, forward,

eyes are closed, equilibrium is immediately lost.

or backward, it would be impossible to maintain a stable

image on the retinas unless the person had some auto-

Neuronal Connections of the Vestibular Apparatus with the

matic control mechanism to stabilize the direction of the

Central Nervous System

eyes’ gaze. In addition, the eyes would be of little use in

Figure 55-13 shows the connections in the hindbrain of

detecting an image unless they remained “fixed” on

the vestibular nerve. Most of the vestibular nerve fibers

each object long enough to gain a clear image. Fortu-

terminate in the brain stem in the vestibular nuclei,

nately, each time the head is suddenly rotated, signals

which are located approximately at the junction of the

from the semicircular ducts cause the eyes to rotate in

medulla and the pons. Some fibers pass directly to the

a direction equal and opposite to the rotation of the

brain stem reticular nuclei without synapsing and also

head. This results from reflexes transmitted through the

to the cerebellar fastigial, uvular, and flocculonodular

vestibular nuclei and the medial longitudinal fasciculus

lobe nuclei. The fibers that end in the brain stem

to the oculomotor nuclei. These reflexes are described

vestibular nuclei synapse with second-order neurons

in Chapter 51.

that also send fibers into the cerebellum, the vestibu-

lospinal tracts, the medial longitudinal fasciculus, and

Other Factors Concerned

with Equilibrium

Fastigial

Medial longitudinal

Dentate nucleus

nucleus

fasciculus

Neck Proprioceptors. The vestibular apparatus detects the

orientation and movement only of the head. Therefore,

it is essential that the nervous centers also receive

Red

appropriate information about the orientation of the

nucleus

head with respect to the body. This information is trans-

Reticular

mitted from the proprioceptors of the neck and body

substance

directly to the vestibular and reticular nuclei in the

Fastigioreticular

brain stem and indirectly by way of the cerebellum.

tract

Among the most important proprioceptive informa-

tion needed for the maintenance of equilibrium is that

Vestibular nucleus

transmitted by joint receptors of the neck. When the

Vestibular nerve

head is leaned in one direction by bending the neck,

Flocculonodular

impulses from the neck proprioceptors keep the signals

lobe

originating in the vestibular apparatus from giving the

Vestibulospinal tract

person a sense of dysequilibrium. They do this by trans-

Rubrospinal tract

mitting signals that exactly oppose the signals transmit-

Recticulospinal

tract

ted from the vestibular apparatus. However, when the

entire body leans in one direction, the impulses from the

Figure 55-13

vestibular apparatus are not opposed by signals from

the neck proprioceptors; therefore, in this case, the

Connections of vestibular nerves through the vestibular nuclei (the

person does perceive a change in equilibrium status of

large oval white area) with other areas of the central nervous

the entire body.

system.

Chapter 55

Cortical and Brain Stem Control of Motor Function

697

other areas of the brain stem, particularly the reticular

objects with movements of the eyes and head. Also,

nuclei.

placing pressure on the upper anterior parts of their legs

The primary pathway for the equilibrium reflexes

causes them to pull to the sitting position. It is clear that

begins in the vestibular nerves, where the nerves are

many of the stereotyped motor functions of the human

excited by the vestibular apparatus. The pathway then

being are integrated in the brain stem.

passes to the vestibular nuclei and cerebellum. Next,

signals are sent into the reticular nuclei of the brain

stem, as well as down the spinal cord by way of the

References

vestibulospinal and reticulospinal tracts. The signals to

the cord control the interplay between facilitation and

Alitto HJ, Usrey WM: Corticothalamic feedback and sensory

inhibition of the many antigravity muscles, thus auto-

processing. Curr Opin Neurobiol 13:440, 2003.

matically controlling equilibrium.

Angelaki DE, Dickman JD: Gravity or translation: central

The flocculonodular lobes of the cerebellum are espe-

processing of vestibular signals to detect motion or tilt. J

cially concerned with dynamic equilibrium signals from

Vestib Res 13:245, 2003.

the semicircular ducts. In fact, destruction of these lobes

Barmack NH: Central vestibular system: vestibular nuclei

results in almost exactly the same clinical symptoms as

and posterior cerebellum. Brain Res Bull 60:511, 2003.

destruction of the semicircular ducts themselves. That is,

Blake DT, Byl NN, Merzenich MM: Representation of the

severe injury to either the lobes or the ducts causes loss

hand in the cerebral cortex. Behav Brain Res 135:179,

of dynamic equilibrium during rapid changes in direc-

2002.

tion of motion but does not seriously disturb equilib-

Boyle R: Vestibulospinal control of reflex and voluntary

rium under static conditions. It is believed that the uvula

head movement. Ann N Y Acad Sci 942:364, 2001.

of the cerebellum plays a similar important role in static

Cullen KE, Roy JE: Signal processing in the vestibular

equilibrium.

system during active versus passive head movements. J

Signals transmitted upward in the brain stem from

Neurophysiol 91:1919, 2004.

both the vestibular nuclei and the cerebellum by way of

Garwicz M: Spinal reflexes provide motor error signals to

the medial longitudinal fasciculus cause corrective

cerebellar modules—relevance for motor coordination.

movements of the eyes every time the head rotates, so

Brain Res Brain Res Rev 40:152, 2002.

that the eyes remain fixed on a specific visual object.

Johansen-Berg H: Motor physiology: a brain of two halves.

Signals also pass upward (either through this same tract

Curr Biol 13:R802, 2003.

or through reticular tracts) to the cerebral cortex, ter-

Raineteau O, Schwab ME: Plasticity of motor systems after

minating in a primary cortical center for equilibrium

incomplete spinal cord injury. Nat Rev Neurosci 2:263,

located in the parietal lobe deep in the sylvian fissure

2001.

on the opposite side of the fissure from the auditory

Raphael Y, Altschuler RA: Structure and innervation of the

area of the superior temporal gyrus. These signals

cochlea. Brain Res Bull 60:397, 2003.

apprise the psyche of the equilibrium status of the body.

Robles L, Ruggero MA: Mechanics of the mammalian

cochlea. Physiol Rev 81:1305, 2001.

Salenius S, Hari R: Synchronous cortical oscillatory activity

Functions of Brain Stem

during motor action. Curr Opin Neurobiol 13:678, 2003.

Nuclei in Controlling

Sanes JN: Neocortical mechanisms in motor learning. Curr

Subconscious, Stereotyped

Opin Neurobiol 13:225, 2003.

Schieber MH: Motor control: basic units of cortical output?

Movements

Curr Biol 14:R353, 2004.

Rarely, a baby is born without brain structures above

Scott SH: The role of primary motor cortex in goal-directed

the mesencephalic region, a condition called anen-

movements: insights from neurophysiological studies on

cephaly. Some of these babies have been kept alive for

non-human primates. Curr Opin Neurobiol 13:671, 2003.

many months. They are able to perform some stereo-

Umilta MA: Frontal cortex: goal-relatedness and the corti-

typed movements for feeding, such as suckling, extru-

cal motor system. Curr Biol 14:R204, 2004.

sion of unpleasant food from the mouth, and moving the

Yates BJ, Miller AD, Lucot JB: Physiological basis and phar-

hands to the mouth to suck the fingers. In addition, they

macology of motion sickness: an update. Brain Res Bull

can yawn and stretch. They can cry and can follow

47:395, 1998.

C H A P T E R

Contributions of the Cerebellum

and Basal Ganglia to Overall

Motor Control

Aside from the areas in the cerebral cortex that

stimulate muscle contraction, two other brain struc-

tures are also essential for normal motor function.

They are the cerebellum and the basal ganglia. Yet

neither of these two can control muscle function by

themselves. Instead, they always function in associa-

tion with other systems of motor control.

Basically, the cerebellum plays major roles in the

timing of motor activities and in rapid, smooth progression from one muscle

movement to the next. It also helps to control intensity of muscle contraction

when the muscle load changes, as well as controlling necessary instantaneous

interplay between agonist and antagonist muscle groups.

The basal ganglia help to plan and control complex patterns of muscle move-

ment, controlling relative intensities of the separate movements, directions of

movements, and sequencing of multiple successive and parallel movements for

achieving specific complicated motor goals. This chapter explains the basic

mechanisms of function of the cerebellum and basal ganglia and discusses the

overall brain mechanisms for achieving intricate coordination of total motor

activity.

Cerebellum and Its Motor Functions

The cerebellum, illustrated in Figures 56-1 and 56-2, has long been called a

silent area of the brain, principally because electrical excitation of the cerebel-

lum does not cause any conscious sensation and rarely causes any motor move-

ment. Removal of the cerebellum, however, does cause body movements to

become highly abnormal. The cerebellum is especially vital during rapid mus-

cular activities such as running, typing, playing the piano, and even talking. Loss

of this area of the brain can cause almost total incoordination of these activi-

ties even though its loss causes paralysis of no muscles.

But how is it that the cerebellum can be so important when it has no direct

ability to cause muscle contraction? The answer is that it helps to sequence

the motor activities and also monitors and makes corrective adjustments in the

body’s motor activities while they are being executed so that they will conform to

the motor signals directed by the cerebral motor cortex and other parts of the

brain.

The cerebellum receives continuously updated information about the desired

sequence of muscle contractions from the brain motor control areas; it also

receives continuous sensory information from the peripheral parts of the body,

giving sequential changes in the status of each part of the body—its position,

rate of movement, forces acting on it, and so forth. The cerebellum then com-

pares the actual movements as depicted by the peripheral sensory feedback

information with the movements intended by the motor system. If the two do

not compare favorably, then instantaneous subconscious corrective signals are

transmitted back into the motor system to increase or decrease the levels of

activation of specific muscles.

The cerebellum also aids the cerebral cortex in planning the next sequential

movement a fraction of a second in advance while the current movement is still

698

Chapter 56

Contributions of the Cerebellum and Basal Ganglia to Overall Motor Control

699

Posterior lobe

Anterior lobe

Pons

Medulla

Flocculonodular

lobe

Figure 56-1

Anatomical lobes of the cerebellum as seen from the lateral side.

Figure 56-3

Somatosensory projection areas in the cerebellar cortex.

Hemisphere Vermis

lobe

controlling body equilibrium, as discussed in Chapter

55.

Longitudinal Functional Divisions of the Anterior and Posterior

Lobes. From a functional point of view, the anterior and

posterior lobes are organized not by lobes but along the

longitudinal axis, as demonstrated in Figure 56-2, which

Posterior

shows a posterior view of the human cerebellum after

lobe

the lower end of the posterior cerebellum has been

rolled downward from its normally hidden position.

Note down the center of the cerebellum a narrow band

called the vermis, separated from the remainder of the

cerebellum by shallow grooves. In this area, most cere-

Flocculonodular

Lateral zone

bellar control functions for muscle movements of the

Vermis

lobe

of hemisphere

axial body, neck, shoulders, and hips are located.

Intermediate zone

To each side of the vermis is a large, laterally pro-

of hemisphere

truding cerebellar hemisphere, and each of these hemi-

spheres is divided into an intermediate zone and a lateral

Figure 56-2

zone.

The intermediate zone of the hemisphere is con-

Functional parts of the cerebellum as seen from the posteroinfe-

cerned with controlling muscle contractions in the distal

rior view, with the inferiormost portion of the cerebellum rolled

outward to flatten the surface.

portions of the upper and lower limbs, especially the

hands and fingers and feet and toes.

The lateral zone of the hemisphere operates at a

much more remote level because this area joins with the

being executed, thus helping the person to progress

cerebral cortex in the overall planning of sequential

smoothly from one movement to the next. Also, it

motor movements. Without this lateral zone, most dis-

learns by its mistakes—that is, if a movement does not

crete motor activities of the body lose their appropriate

occur exactly as intended, the cerebellar circuit learns

timing and sequencing and therefore become incoordi-

to make a stronger or weaker movement the next time.

nate, as we discuss more fully later.

To do this, changes occur in the excitability of appro-

priate cerebellar neurons, thus bringing subsequent

Topographical Representation of the Body in the Vermis and Inter-

muscle contractions into better correspondence with the

mediate Zones. In the same manner that the cerebral

sensory cortex, motor cortex, basal ganglia, red nuclei,

intended movements.

and reticular formation all have topographical repre-

sentations of the different parts of the body, so also is

Anatomical Functional Areas

this true for the vermis and intermediate zones of the

cerebellum. Figure 56-3 shows two such representa-

of the Cerebellum

tions. Note that the axial portions of the body lie in the

Anatomically, the cerebellum is divided into three lobes

vermis part of the cerebellum, whereas the limbs and

by two deep fissures, as shown in Figures 56-1 and 56-2:

facial regions lie in the intermediate zones. These topo-

(1) the anterior lobe, (2) the posterior lobe, and (3) the

graphical representations receive afferent nerve signals

flocculonodular lobe. The flocculonodular lobe is the

from all the respective parts of the body as well as from

oldest of all portions of the cerebellum; it developed

corresponding topographical motor areas in the cere-

along with (and functions with) the vestibular system in

bral cortex and brain stem. In turn, they send motor

700

Unit XI The Nervous System: C. Motor and Integrative Neurophysiology

signals back to the same respective topographical areas

originate in the vestibular apparatus itself and others

of the cerebral motor cortex, as well as to topographi-

from the brain stem vestibular nuclei—almost all of

cal areas of the red nucleus and reticular formation in

these terminate in the flocculonodular lobe and fastigial

the brain stem.

nucleus of the cerebellum; and (3) reticulocerebellar

Note that the large lateral portions of the cerebellar

fibers, which originate in different portions of the brain

hemispheres do not have topographical representations

stem reticular formation and terminate in the midline

of the body. These areas of the cerebellum receive their

cerebellar areas (mainly in the vermis).

input signals almost exclusively from the cerebral

cortex, especially from the premotor areas of the frontal

Afferent Pathways from the Periphery. The cerebellum also

cortex and from the somatosensory and other sensory

receives important sensory signals directly from the

association areas of the parietal cortex. It is believed

peripheral parts of the body mainly through four tracts

that this connectivity with the cerebral cortex allows the

on each side, two of which are located dorsally in the

lateral portions of the cerebellar hemispheres to play

cord and two ventrally. The two most important of these

important roles in planning and coordinating the body’s

tracts are shown in Figure 56-5: the dorsal spinocere-

rapid sequential muscular activities that occur one after

bellar tract and the ventral spinocerebellar tract. The

another within fractions of a second.

dorsal tract enters the cerebellum through the inferior

cerebellar peduncle and terminates in the vermis and

intermediate zones of the cerebellum on the same side

Neuronal Circuit of the Cerebellum

as its origin. The ventral tract enters the cerebellum

through the superior cerebellar peduncle, but it termi-

The human cerebellar cortex is actually a large folded

nates in both sides of the cerebellum.

sheet, about 17 centimeters wide by 120 centimeters

The signals transmitted in the dorsal spinocerebellar

long, with the folds lying crosswise, as shown in Figures

tracts come mainly from the muscle spindles and to a

56-2 and 56-3. Each fold is called a folium. Lying deep

lesser extent from other somatic receptors throughout

beneath the folded mass of cerebellar cortex are deep

the body, such as Golgi tendon organs, large tactile

cerebellar nuclei.

receptors of the skin, and joint receptors. All these

signals apprise the cerebellum of the momentary status

Input Pathways to the Cerebellum

of (1) muscle contraction, (2) degree of tension on the

Afferent Pathways from Other Parts of the Brain. The basic

muscle tendons, (3) positions and rates of movement

input pathways to the cerebellum are shown in Figure

of the parts of the body, and (4) forces acting on the

56-4. An extensive and important afferent pathway is

surfaces of the body.

the corticopontocerebellar pathway, which originates in

Conversely, the ventral spinocerebellar tracts receive

the cerebral motor and premotor cortices and also in the

less information from the peripheral receptors. Instead,

cerebral somatosensory cortex. It passes by way of the

they are excited mainly by motor signals arriving in the

pontile nuclei and pontocerebellar tracts mainly to

anterior horns of the spinal cord from (1) the brain

the lateral divisions of the cerebellar hemispheres on

through the corticospinal and rubrospinal tracts and (2)

the opposite side of the brain from the cerebral areas.

the internal motor pattern generators in the cord itself.

In addition, important afferent tracts originate in

Thus, this ventral fiber pathway tells the cerebellum

each side of the brain stem; they include (1) an exten-

sive olivocerebellar tract, which passes from the inferior

olive to all parts of the cerebellum and is excited in the

olive by fibers from the cerebral motor cortex, basal

Superior cerebellar peduncle

Ventral spinocerebellar tract

ganglia, widespread areas of the reticular formation, and

spinal cord; (2) vestibulocerebellar fibers, some of which

Cerebellum

Anterior Superior cerebellar

lobe

peduncle

Inferior cerebellar peduncle

Ventral

spinocerebellar

Medulla oblongata

tract

Dorsal external arcuate fiber

Cerebropontile

tract

Ventral spinocerebellar tract

Pontocerebellar

tract

Middle cerebellar

Spinal cord

peduncle

Posterior

Vestibulocerebellar tract

lobe

Dorsal spinocerebellar tract

Olivocerebellar and

Flocculonodular

reticulocerebellar tract

lobe

Inferior cerebellar peduncle

Ventral spinocerebellar tract

Dorsal spinocerebellar tract

Clark’s cells

Figure 56-4

Figure 56-5

Principal afferent tracts to the cerebellum.

Spinocerebellar tracts.

Chapter 56

Contributions of the Cerebellum and Basal Ganglia to Overall Motor Control

701

which motor signals have arrived at the anterior horns;

Dentate

Cerebellothalamocortical

this feedback is called the efference copy of the anterior

tract

horn motor drive.

To thalamus

The spinocerebellar pathways can transmit impulses

Red nucleus

at velocities up to 120 m/sec, which is the most rapid

conduction in any pathway in the central nervous

system. This extremely rapid conduction is important

Reticulum of

for instantaneous apprisal of the cerebellum of changes

mesencephalon

in peripheral muscle actions.

In addition to signals from the spinocerebellar tracts,

Superior cerebellar

signals are transmitted into the cerebellum from the

peduncle

body periphery through the spinal dorsal columns to the

Fastigioreticular tract

dorsal column nuclei of the medulla and then relayed

Fastigial nucleus

to the cerebellum. Likewise, signals are transmitted up

the spinal cord through the spinoreticular pathway to

Fastigioreticular tract

the reticular formation of the brain stem and also

Paleocerebellum

through the spino-olivary pathway to the inferior

olivary nucleus. Then signals are relayed from both of

Figure 56-6

these areas to the cerebellum. Thus, the cerebellum con-

tinually collects information about the movements and

Principal efferent tracts from the cerebellum.

positions of all parts of the body even though it is oper-

ating at a subconscious level.

mainly the reciprocal contractions of agonist and

Output Signals from the Cerebellum

antagonist muscles in the peripheral portions of the

Deep Cerebellar Nuclei and the Efferent Pathways. Located

limbs, especially in the hands, fingers, and thumbs.

deep in the cerebellar mass on each side are three deep

A pathway that begins in the cerebellar cortex of

cerebellar nuclei—the dentate, interposed, and fastigial.

the lateral zone of the cerebellar hemisphere and

(The vestibular nuclei in the medulla also function in

then passes to the dentate nucleus, next to the

some respects as if they were deep cerebellar nuclei

ventrolateral and ventroanterior nuclei of the

because of their direct connections with the cortex of

thalamus, and, finally, to the cerebral cortex. This

the flocculonodular lobe.) All the deep cerebellar nuclei

pathway plays an important role in helping

receive signals from two sources: (1) the cerebellar

coordinate sequential motor activities initiated by

cortex and (2) the deep sensory afferent tracts to the

the cerebral cortex.

cerebellum.

Each time an input signal arrives in the cerebellum,

Functional Unit of the Cerebellar Cortex—

it divides and goes in two directions: (1) directly to one

The Purkinje Cell and the Deep Nuclear Cell

of the cerebellar deep nuclei and (2) to a corresponding

The cerebellum has about 30 million nearly identical

area of the cerebellar cortex overlying the deep nucleus.

functional units, one of which is shown to the left in

Then, a fraction of a second later, the cerebellar cortex

Figure 56-7. This functional unit centers on a single,

relays an inhibitory output signal to the deep nucleus.

very large Purkinje cell (30 million of which are in

Thus, all input signals that enter the cerebellum even-

the cerebellar cortex) and on a corresponding deep

tually end in the deep nuclei in the form of initial exci-

tatory signals followed a fraction of a second later by

nuclear cell.

inhibitory signals. From the deep nuclei, output signals

To the top and right in Figure 56-7, the three major

leave the cerebellum and are distributed to other parts

layers of the cerebellar cortex are shown: the molecu-

of the brain.

lar layer, Purkinje cell layer, and granule cell layer.

The general plan of the major efferent pathways

Beneath these cortical layers, in the center of the cere-

leading out of the cerebellum is shown in Figure 56-6

bellar mass, are the deep cerebellar nuclei that send

and consists of the following:

output signals to other parts of the nervous system.

1. A pathway that originates in the midline structures

of the cerebellum (the vermis) and then passes

Neuronal Circuit of the Functional Unit. Also shown in the

through the fastigial nuclei into the medullary and

left half of Figure 56-7 is the neuronal circuit of the

pontile regions of the brain stem. This circuit

functions in close association with the equilibrium

functional unit, which is repeated with little variation

apparatus and brain stem vestibular nuclei to

30 million times in the cerebellum. The output from

control equilibrium, and also in association with the

the functional unit is from a deep nuclear cell. This cell

reticular formation of the brain stem to control the

is continually under both excitatory and inhibitory

postural attitudes of the body. It was discussed in

influences. The excitatory influences arise from direct

detail in Chapter 55 in relation to equilibrium.

connections with afferent fibers that enter the cere-

2. A pathway that originates in (1) the intermediate

bellum from the brain or the periphery. The inhibitory

zone of the cerebellar hemisphere and then passes

influence arises entirely from the Purkinje cell in the

through (2) the interposed nucleus to (3) the

cortex of the cerebellum.

ventrolateral and ventroanterior nuclei of the

The afferent inputs to the cerebellum are mainly of

thalamus and then to (4) the cerebral cortex, to (5)

several midline structures of the thalamus and then

two types, one called the climbing fiber type and the

to (6) the basal ganglia and (7) the red nucleus and

other called the mossy fiber type.

reticular formation of the upper portion of the

The climbing fibers all originate from the inferior

brain stem. This complex circuit helps to coordinate

olives of the medulla. There is one climbing fiber for

702

Unit XI The Nervous System: C. Motor and Integrative Neurophysiology

Purkinje Cells and Deep Nuclear Cells Fire Continuously Under

Molecular

layer

Normal Resting Conditions. One characteristic of both

Purkinje

Purkinje cells and deep nuclear cells is that normally

Purkinje

cell

cell layer

both of them fire continuously; the Purkinje cell fires

at about 50 to 100 action potentials per second, and

Climbing

Granule

fiber

cell layer

the deep nuclear cells at much higher rates. Further-

Inhibition

Deep

Granule

more, the output activity of both these cells can be

nuclear

cells

Deep

modulated upward or downward.

cell

nuclei

Excitation

Mossy

fiber

Balance Between Excitation and Inhibition at the Deep Cere-

Input

bellar Nuclei. Referring again to the circuit of Figure

Input

(all other afferents)

56-7, one should note that direct stimulation of the

(inferior olive)

deep nuclear cells by both the climbing and the mossy

Output

fibers excites them. By contrast, signals arriving from

the Purkinje cells inhibit them. Normally, the balance

Figure 56-7

between these two effects is slightly in favor of exci-

tation, so that, under quiet conditions, output from the

The left side of this figure shows the basic neuronal circuit of the

deep nuclear cell remains relatively constant at a mod-

cerebellum, with excitatory neurons shown in red and the Purkinje

erate level of continuous stimulation.

cell (an inhibitory neuron) shown in black. To the right is shown

the physical relationship of the deep cerebellar nuclei to the cere-

In execution of a rapid motor movement, the

bellar cortex with its three layers.

initiating signal from the cerebral motor cortex or

brain stem at first greatly increases deep nuclear

cell excitation. Then, another few milliseconds later,

feedback inhibitory signals from the Purkinje cell

about 5 to 10 Purkinje cells. After sending branches to

circuit arrive. In this way, there is first a rapid excita-

several deep nuclear cells, the climbing fiber continues

tory signal sent by the deep nuclear cells into the

all the way to the outer layers of the cerebellar cortex,

motor output pathway to enhance the motor move-

where it makes about 300 synapses with the soma

ment, but this is followed within another small fraction

and dendrites of each Purkinje cell. This climbing

of a second by an inhibitory signal. This inhibitory

fiber is distinguished by the fact that a single impulse

signal resembles a

“delay-line” negative feedback

in it will always cause a single, prolonged (up to 1

signal of the type that is effective in providing

second), peculiar type of action potential in each

damping. That is, when the motor system is excited,

Purkinje cell with which it connects, beginning with

a negative feedback signal occurs after a short delay

a strong spike and followed by a trail of weakening

to stop the muscle movement from overshooting its

secondary spikes. This action potential is called the

mark. Otherwise, oscillation of the movement would

complex spike.

occur.

The mossy fibers are all the other fibers that enter

the cerebellum from multiple sources: from the higher

Other Inhibitory Cells in the Cerebellum. In addition to the

brain, brain stem, and spinal cord. These fibers also

deep nuclear cells, granule cells, and Purkinje cells, two

send collaterals to excite the deep nuclear cells. Then

other types of neurons are located in the cerebellum:

they proceed to the granule cell layer of the cortex,

basket cells and stellate cells. These are inhibitory cells

where they too synapse with hundreds to thousands of

with short axons. Both the basket cells and the stellate

granule cells. In turn, the granule cells send very, very

cells are located in the molecular layer of the cerebel-

small axons, less than 1 micrometer in diameter, up to

lar cortex, lying among and stimulated by the small

the molecular layer on the outer surface of the cere-

parallel fibers. These cells in turn send their axons at

bellar cortex. Here the axons divide into two branches

right angles across the parallel fibers and cause lateral

that extend 1 to 2 millimeters in each direction paral-

inhibition of adjacent Purkinje cells, thus sharpening

lel to the folia. There are many millions of these par-

the signal in the same manner that lateral inhibition

allel nerve fibers because there are some 500 to 1000

sharpens contrast of signals in many other neuronal

granule cells for every 1 Purkinje cell. It is into this

circuits of the nervous system.

molecular layer that the dendrites of the Purkinje cells

project and 80,000 to 200,000 of the parallel fibers

Turn-On/Turn-Off and Turn-Off/Turn-On Output

synapse with each Purkinje cell.

Signals from the Cerebellum

The mossy fiber input to the Purkinje cell is quite

The typical function of the cerebellum is to help

different from the climbing fiber input because their

provide rapid turn-on signals for the agonist muscles

synaptic connections are weak, so that large numbers

and simultaneous reciprocal turn-off signals for the

of mossy fibers must be stimulated simultaneously to

antagonist muscles at the onset of a movement. Then

excite the Purkinje cell. Furthermore, activation

on approaching termination of the movement, the

usually takes the form of a much weaker short-

cerebellum is mainly responsible for timing and exe-

duration Purkinje cell action potential called a simple

cuting the turn-off signals to the agonists and turn-on

spike, rather than the prolonged complex action

signals to the antagonists. Although the exact details

potential caused by climbing fiber input.

are not fully known, one can speculate from the basic

Chapter 56

Contributions of the Cerebellum and Basal Ganglia to Overall Motor Control

703

cerebellar circuit of Figure 56-7 how this might work,

are still to be determined; they, too, could play roles in

as follows.

the initial inhibition of the antagonist muscles at onset

Let us suppose that the turn-on/turn-off pattern of

of a movement and subsequent excitation at the end

agonist/antagonist contraction at the onset of move-

of a movement.

ment begins with signals from the cerebral cortex.

All these mechanisms are still partly speculation.

These signals pass through noncerebellar brain stem

They are presented here especially to illustrate ways

and cord pathways directly to the agonist muscle to

by which the cerebellum could cause exaggerated turn-

begin the initial contraction.

on and turn-off signals, controlling the agonist and

At the same time, parallel signals are sent by way of

antagonist muscles, and controlling the timing as well.

the pontile mossy fibers into the cerebellum. One

branch of each mossy fiber goes directly to deep

The Purkinje Cells “Learn” to Correct Motor

nuclear cells in the dentate or other deep cerebellar

Errors—Role of the Climbing Fibers

nuclei; this instantly sends an excitatory signal back

The degree to which the cerebellum supports onset

into the cerebral corticospinal motor system, either by

and offset of muscle contractions, as well as timing of

way of return signals through the thalamus to the cere-

contractions, must be learned by the cerebellum. Typ-

bral cortex or by way of neuronal circuitry in the brain

ically, when a person first performs a new motor act,

stem, to support the muscle contraction signal that had

the degree of motor enhancement by the cerebellum

already been begun by the cerebral cortex. As a con-

at the onset of contraction, the degree or inhibition at

sequence, the turn-on signal, after a few milliseconds,

the end of contraction, and the timing of these are

becomes even more powerful than it was at the start

almost always incorrect for precise performance of the

because it becomes the sum of both the cortical

movement. But after the act has been performed many

and the cerebellar signals. This is the normal effect

times, the individual events become progressively

when the cerebellum is intact, but in the absence of the

more precise, sometimes requiring only a few move-

cerebellum, the secondary extra supportive signal is

ments before the desired result is achieved, but at

missing. This cerebellar support makes the turn-on

other times requiring hundreds of movements.

muscle contraction much stronger than it would be if

How do these adjustments come about? The exact

the cerebellum did not exist.

answer is not known, although it is known that sensi-

Now, what causes the turn-off signal for the agonist

tivity levels of cerebellar circuits themselves progres-

muscles at the termination of the movement? Remem-

sively adapt during the training process. Especially,

ber that all mossy fibers have a second branch that

the sensitivity of the Purkinje cells to respond to the

transmits signals by way of the granule cells to the

granule cell excitation becomes altered. Furthermore,

cerebellar cortex and eventually, by way of “parallel”

this sensitivity change is brought about by signals from

fibers, to the Purkinje cells. The Purkinje cells in turn

the climbing fibers entering the cerebellum from the

inhibit the deep nuclear cells. This pathway passes

inferior olivary complex.

through some of the smallest, slowest-conducting

Under resting conditions, the climbing fibers fire

nerve fibers in the nervous system: that is, the parallel

about once per second. But each time they do fire, they

fibers of the cerebellar cortical molecular layer, which

cause extreme depolarization of the entire dendritic

have diameters of only a fraction of a millimeter. Also,

tree of the Purkinje cell, lasting for up to a second.

the signals from these fibers are weak so that they

During this time, the Purkinje cell fires with one initial

require a finite period of time to build up enough exci-

strong output spike followed by a series of diminish-

tation in the dendrites of the Purkinje cell to excite it.

ing spikes. When a person performs a new movement

But once the Purkinje cell is excited, it in turn sends a

for the first time, feedback signals from the muscle and

strong inhibitory signal to the same deep nuclear cell

joint proprioceptors will usually denote to the cere-

that had originally turned on the movement. There-

bellum how much the actual movement fails to match

fore, this helps to turn off the movement after a short

the intended movement. And the climbing fiber signals

time.

in some way alter long-term sensitivity of the Purkinje

Thus, one can see how the complete cerebellar

cells. Over a period of time, this change in sensitivity,

circuit could cause a rapid turn-on agonist muscle con-

along with other possible “learning” functions of the

traction at the beginning of a movement and yet cause

cerebellum, is believed to make the timing and other

also a precisely timed turn-off of the same agonist con-

aspects of cerebellar control of movements approach

traction after a given time period.

perfection. When this has been achieved, the climbing

Now let us speculate on the circuit for the antago-

fibers no longer need to send “error” signals to the

nist muscles. Most important, remember that through-

cerebellum to cause further change.

out the spinal cord there are reciprocal agonist/

antagonist circuits for virtually every movement that

the cord can initiate. Therefore, these circuits are part

Function of the Cerebellum in Overall

of the basis for antagonist turn-off at the onset of

Motor Control

movement and then turn-on at termination of move-

ment, mirroring whatever occurs in the agonist

The nervous system uses the cerebellum to coordinate

muscles. But we must remember, too, that the cere-

motor control functions at three levels, as follows:

bellum contains several other types of inhibitory cells

1. The vestibulocerebellum. This consists principally

besides Purkinje cells. The functions of some of these

of the small flocculonodular cerebellar lobes (that

704

Unit XI The Nervous System: C. Motor and Integrative Neurophysiology

lie under the posterior cerebellum) and adjacent

brain at the same time that the movements actually

portions of the vermis. It provides neural circuits

occur. How, then, is it possible for the brain to know

for most of the body’s equilibrium movements.

when to stop a movement and to perform the next

2. The spinocerebellum. This consists of most of the

sequential act, especially when the movements are

vermis of the posterior and anterior cerebellum

performed rapidly? The answer is that the signals from

plus the adjacent intermediate zones on both

the periphery tell the brain how rapidly and in which

sides of the vermis. It provides the circuitry for

directions the body parts are moving. It is then the

coordinating mainly movements of the distal

function of the vestibulocerebellum to calculate in

portions of the limbs, especially the hands and

advance from these rates and directions where the

fingers.

different parts will be during the next few milliseconds.

3. The cerebrocerebellum. This consists of the large

The results of these calculations are the key to the

lateral zones of the cerebellar hemispheres, lateral

brain’s progression to the next sequential movement.

to the intermediate zones. It receives virtually all

Thus, during control of equilibrium, it is presumed

its input from the cerebral motor cortex and

that information from both the body periphery and the

adjacent premotor and somatosensory cortices of

vestibular apparatus is used in a typical feedback

the cerebrum. It transmits its output information

control circuit to provide anticipatory correction of

in the upward direction back to the brain,

postural motor signals necessary for maintaining equi-

functioning in a feedback manner with the

librium even during extremely rapid motion, including

cerebral cortical sensorimotor system to plan

rapidly changing directions of motion.

sequential voluntary body and limb movements,

planning these as much as tenths of a second in

Spinocerebellum—Feedback Control of Distal

advance of the actual movements. This is called

Limb Movements by Way of the Intermediate

development of “motor imagery” of movements

Cerebellar Cortex and the Interposed Nucleus

to be performed.

As shown in Figure 56-8, the intermediate zone of

each cerebellar hemisphere receives two types of

Vestibulocerebellum—Its Function in

information when a movement is performed: (1) infor-

Association with the Brain Stem and

mation from the cerebral motor cortex and from

Spinal Cord to Control Equilibrium and

the midbrain red nucleus, telling the cerebellum the

Postural Movements

intended sequential plan of movement for the next few

The vestibulocerebellum originated phylogenetically

fractions of a second, and (2) feedback information

at about the same time that the vestibular apparatus

in the inner ear developed. Furthermore, as discussed

in Chapter 55, loss of the flocculonodular lobes and

adjacent portions of the vermis of the cerebellum,

Motor cortex

which constitute the vestibulocerebellum, causes

extreme disturbance of equilibrium and postural

movements.

We still must ask the question, what role does the

vestibulocerebellum play in equilibrium that cannot

be provided by other neuronal machinery of the brain

Red nucleus

Thalamus

stem? A clue is the fact that in people with vestibulo-

cerebellar dysfunction, equilibrium is far more dis-

turbed during performance of rapid motions than

during stasis, especially so when these movements

Intermediate

involve changes in direction of movement and stimu-

zone of

Mesencephalon,

late the semicircular ducts. This suggests that the

cerebellum

pons, and medulla

vestibulocerebellum is especially important in con-

trolling balance between agonist and antagonist

muscle contractions of the spine, hips, and shoulders

during rapid changes in body positions as required by

Corticospinal tract

the vestibular apparatus.

Spinocerebellar

One of the major problems in controlling balance is

tract

Reticulospinal

the amount of time required to transmit position

and rubrospinal

signals and velocity of movement signals from the dif-

tracts

ferent parts of the body to the brain. Even when the

most rapidly conducting sensory pathways are used, up

Muscles

to 120 m/sec in the spinocerebellar afferent tracts, the

delay for transmission from the feet to the brain is still

15 to 20 milliseconds. The feet of a person running

Figure 56-8

rapidly can move as much as 10 inches during that

time. Therefore, it is never possible for return signals

Cerebral and cerebellar control of voluntary movements, involving

from the peripheral parts of the body to reach the

especially the intermediate zone of the cerebellum.

Chapter 56

Contributions of the Cerebellum and Basal Ganglia to Overall Motor Control

705

from the peripheral parts of the body, especially from

pendular elements that have inertia must have

the distal proprioceptors of the limbs, telling the cere-

damping circuits built into the mechanisms. For motor

bellum what actual movements result.

control by the nervous system, the cerebellum pro-

After the intermediate zone of the cerebellum has

vides most of this damping function.

compared the intended movements with the actual

movements, the deep nuclear cells of the interposed

Cerebellar Control of Ballistic Movements. Most rapid

nucleus send corrective output signals (1) back to the

movements of the body, such as the movements of the

cerebral motor cortex through relay nuclei in the thal-

fingers in typing, occur so rapidly that it is not possi-

amus and (2) to the magnocellular portion (the lower

ble to receive feedback information either from the

portion) of the red nucleus that gives rise to the

periphery to the cerebellum or from the cerebellum

rubrospinal tract. The rubrospinal tract in turn joins

back to the motor cortex before the movements are

the corticospinal tract in innervating the lateral most

over. These movements are called ballistic movements,

motor neurons in the anterior horns of the spinal cord

meaning that the entire movement is preplanned and

gray matter, the neurons that control the distal parts

set into motion to go a specific distance and then to

of the limbs, particularly the hands and fingers.

stop. Another important example is the saccadic move-

This part of the cerebellar motor control system pro-

ments of the eyes, in which the eyes jump from one

vides smooth, coordinate movements of the agonist

position to the next when reading or when looking at

and antagonist muscles of the distal limbs for per-

successive points along a road as a person is moving

forming acute purposeful patterned movements. The

in a car.

cerebellum seems to compare the “intentions” of the

Much can be understood about the function of the

higher levels of the motor control system, as transmit-

cerebellum by studying the changes that occur in these

ted to the intermediate cerebellar zone through the

ballistic movements when the cerebellum is removed.

corticopontocerebellar tract, with the “performance”

Three major changes occur: (1) The movements are

by the respective parts of the body, as transmitted

slow to develop and do not have the extra onset surge

back to the cerebellum from the periphery. In fact,

that the cerebellum usually provides, (2) the force

the ventral spinocerebellar tract even transmits back

developed is weak, and (3) the movements are slow to

to the cerebellum an “efference” copy of the actual

turn off, usually allowing the movement to go well

motor control signals that reach the anterior motor

beyond the intended mark. Therefore, in the absence

neurons, and this, too, is integrated with the signals

of the cerebellar circuit, the motor cortex has to think

arriving from the muscle spindles and other proprio-

extra hard to turn ballistic movements on and again

ceptor sensory organs, transmitted principally in the

has to think hard and take extra time to turn the

dorsal spinocerebellar tract. We learned earlier that

movement off. Thus, the automatism of ballistic move-

similar comparator signals also go to the inferior

ments is lost.

olivary complex; if the signals do not compare favor-

If one considers once again the circuitry of the cere-

ably, the olivary-Purkinje cell system along with pos-

bellum as described earlier, one sees that it is beauti-

sibly other cerebellar learning mechanisms eventually

fully organized to perform this biphasic, first excitatory

corrects the motions until they perform the desired

and then delayed inhibitory function that is required

function.

for preplanned rapid ballistic movements. One also

sees that the built-in timing circuits of the cerebellar

Function of the Cerebellum to Prevent Overshoot of Movements

cortex are fundamental to this particular ability of the

and to “Damp” Movements. Almost all movements of the

cerebellum.

body are “pendular.” For instance, when an arm is

moved, momentum develops, and the momentum

Cerebrocerebellum—Function of the

must be overcome before the movement can be

Large Lateral Zone of the Cerebellar

stopped. Because of momentum, all pendular move-

Hemisphere to Plan, Sequence, and Time

ments have a tendency to overshoot. If overshooting

Complex Movements

does occur in a person whose cerebellum has been

In human beings, the lateral zones of the two cerebel-

destroyed, the conscious centers of the cerebrum even-

lar hemispheres are highly developed and greatly

tually recognize this and initiate a movement in the

enlarged. This goes along with human abilities to plan

reverse direction attempting to bring the arm to its

and perform intricate sequential patterns of move-

intended position. But the arm, by virtue of its momen-

ment, especially with the hands and fingers, and to

tum, overshoots once more in the opposite direction,

speak. Yet the large lateral zones of the cerebellar

and appropriate corrective signals must again be insti-

hemispheres have no direct input of information from

tuted. Thus, the arm oscillates back and forth past its

the peripheral parts of the body. Also, almost all com-

intended point for several cycles before it finally fixes

munication between these lateral cerebellar areas and

on its mark. This effect is called an action tremor, or

the cerebral cortex is not with the primary cerebral

intention tremor.

motor cortex itself but instead with the premotor area

But, if the cerebellum is intact, appropriate learned,

and primary and association somatosensory areas.

subconscious signals stop the movement precisely at

Even so, destruction of the lateral zones of the cere-

the intended point, thereby preventing the overshoot

bellar hemispheres along with their deep nuclei, the

as well as the tremor. This is the basic characteristic

dentate nuclei, can lead to extreme incoordination of

of a damping system. All control systems regulating

complex purposeful movements of the hands, fingers,

706

Unit XI The Nervous System: C. Motor and Integrative Neurophysiology

and feet and of the speech apparatus. This has been

body. For instance, the rates of progression of both

difficult to understand because of lack of direct com-

auditory and visual phenomena can be predicted by

munication between this part of the cerebellum and

the brain, but both of these require cerebellar partici-

the primary motor cortex. However, experimental

pation. As an example, a person can predict from

studies suggest that these portions of the cerebellum

the changing visual scene how rapidly he or she is

are concerned with two other important but indirect

approaching an object. A striking experiment that

aspects of motor control: (1) the planning of sequen-

demonstrates the importance of the cerebellum in this

tial movements and (2) the “timing” of the sequential

ability is the effects of removing the large lateral por-

movements.

tions of the cerebellum in monkeys. Such a monkey

occasionally charges the wall of a corridor and literally

Planning of Sequential Movements. The planning of

bashes its brains because it is unable to predict when

sequential movements requires that the lateral zones

it will reach the wall.

of the hemispheres communicate with both the pre-

We are only now beginning to learn about these

motor and the sensory portions of the cerebral cortex,

extramotor predictive functions of the cerebellum. It

and it requires two-way communication between these

is quite possible that the cerebellum provides a “time-

cerebral cortex areas with corresponding areas of the

base,” perhaps using time-delay circuits, against which

basal ganglia. It seems that the “plan” of sequential

signals from other parts of the central nervous system

movements actually begins in the sensory and premo-

can be compared; it is often stated that the cerebellum

tor areas of the cerebral cortex, and from there the

is particularly helpful in interpreting rapidly changing

plan is transmitted to the lateral zones of the cerebel-

spatiotemporal relations in sensory information.

lar hemispheres. Then, amid much two-way traffic

between cerebellum and cerebral cortex, appropriate

motor signals provide transition from one sequence of

Clinical Abnormalities of

movements to the next.

the Cerebellum

An exceedingly interesting observation that sup-

An important feature of clinical cerebellar abnormali-

ports this view is that many neurons in the cerebellar

ties is that destruction of small portions of the lateral

dentate nuclei display the activity pattern for the

cerebellar cortex seldom causes detectable abnormali-

sequential movement that is yet to come while the

ties in motor function. In fact, several months after as

present movement is still occurring. Thus, the lateral

much as one half of the lateral cerebellar cortex on one

cerebellar zones appear to be involved not with what

side of the brain has been removed, if the deep cere-

movement is happening at a given moment but with

bellar nuclei are not removed along with the cortex, the

what will be happening during the next sequential

motor functions of the animal appear to be almost

movement a fraction of a second or perhaps even

normal as long as the animal performs all movements

seconds later.

slowly. Thus, the remaining portions of the motor

control system are capable of compensating tremen-

To summarize, one of the most important features

dously for loss of parts of the cerebellum.

of normal motor function is one’s ability to progress

Therefore, to cause serious and continuing dysfunc-

smoothly from one movement to the next in orderly

tion of the cerebellum, the cerebellar lesion usually

succession. In the absence of the large lateral zones of

must involve one or more of the deep cerebellar

the cerebellar hemispheres, this capability is seriously

nuclei—the dentate, interposed, or fastigial nuclei.

disturbed for rapid movements.

Dysmetria and Ataxia. Two of the most important symp-

Timing Function. Another important function of the

toms of cerebellar disease are dysmetria and ataxia. As

lateral zones of the cerebellar hemispheres is to

pointed out previously, in the absence of the cerebel-

provide appropriate timing for each succeeding move-

lum, the subconscious motor control system cannot

predict how far movements will go. Therefore, the

ment. In the absence of these cerebellar zones, one

movements ordinarily overshoot their intended mark;

loses the subconscious ability to predict ahead of time

then the conscious portion of the brain overcompen-

how far the different parts of the body will move in a

sates in the opposite direction for the succeeding com-

given time. Without this timing capability, the person

pensatory movement. This effect is called dysmetria, and

becomes unable to determine when the next sequen-

it results in uncoordinated movements that are called

tial movement needs to begin. As a result, the suc-

ataxia. Dysmetria and ataxia can also result from lesions

ceeding movement may begin too early or, more likely,

in the spinocerebellar tracts because feedback informa-

too late. Therefore, lesions in the lateral zones of the

tion from the moving parts of the body to the cerebel-

cerebellum cause complex movements (such as those

lum is essential for cerebellar timing of movement

required for writing, running, or even talking) to

termination.

become incoordinate and lacking ability to progress in

Past Pointing. Past pointing means that in the absence

orderly sequence from one movement to the next.

of the cerebellum, a person ordinarily moves the hand

Such cerebellar lesions are said to cause failure of

or some other moving part of the body considerably

smooth progression of movements.

beyond the point of intention. This results from the

fact that normally the cerebellum initiates most of the

Extramotor Predictive Functions of the Cerebrocerebellum.

motor signal that turns off a movement after it is

The cerebrocerebellum (the large lateral lobes) also

begun; if the cerebellum is not available to do this, the

helps to “time” events other than movements of the

movement ordinarily goes beyond the intended mark.

Chapter 56

Contributions of the Cerebellum and Basal Ganglia to Overall Motor Control

707

Longitudinal fissure

Caudate nucleus

Tail of caudate

POSTERIOR

Figure 56-9

Thalamus

Anatomical relations of the basal

ganglia to the cerebral cortex and

thalamus, shown in three-dimen-

sional view. (Redrawn from Guyton

LATERAL

AC: Basic Neuroscience: Anatomy

Putamen and

Fibers to and from

and Physiology. Philadelphia: WB

globus pallidus

spinal cord in

Saunders Co, 1992.)

internal capsule

Therefore, past pointing is actually a manifestation of

Cerebellar Nystagmus. Cerebellar nystagmus is tremor of

dysmetria.

the eyeballs that occurs usually when one attempts to

fixate the eyes on a scene to one side of the head. This

Failure of Progression

off-center type of fixation results in rapid, tremulous

Dysdiadochokinesia. When the motor control system

movements of the eyes rather than steady fixation, and

fails to predict where the different parts of the body will

it is another manifestation of failure of damping by the

be at a given time, it “loses” perception of the parts

cerebellum. It occurs especially when the flocculonodu-

during rapid motor movements. As a result, the suc-

lar lobes of the cerebellum are damaged; in this instance

ceeding movement may begin much too early or much

it is also associated with loss of equilibrium because of

too late, so that no orderly “progression of movement”

dysfunction of the pathways through the flocculonodu-

can occur. One can demonstrate this readily by having

lar cerebellum from the semicircular ducts.

a patient with cerebellar damage turn one hand upward

and downward at a rapid rate. The patient rapidly

Hypotonia. Loss of the deep cerebellar nuclei, particu-

“loses” all perception of the instantaneous position of

larly of the dentate and interposed nuclei, causes

the hand during any portion of the movement. As a

decreased tone of the peripheral body musculature on

result, a series of stalled attempted but jumbled move-

the side of the cerebellar lesion. The hypotonia results

ments occurs instead of the normal coordinate upward

from loss of cerebellar facilitation of the motor cortex

and downward motions. This is called dysdiadochokine-

and brain stem motor nuclei by tonic signals from the

sia.

deep cerebellar nuclei.

Dysarthria. Another example in which failure of pro-

gression occurs is in talking because the formation of

Basal Ganglia—Their Motor

words depends on rapid and orderly succession of indi-

Functions

vidual muscle movements in the larynx, mouth, and res-

piratory system. Lack of coordination among these and

The basal ganglia, like the cerebellum, constitute

inability to adjust in advance either the intensity of

sound or duration of each successive sound causes

another accessory motor system that functions usually

jumbled vocalization, with some syllables loud, some

not by itself but in close association with the cerebral

weak, some held for long intervals, some held for short

cortex and corticospinal motor control system. In fact,

intervals, and resultant speech that is often unintelligi-

the basal ganglia receive most of their input signals

ble. This is called dysarthria.

from the cerebral cortex itself and also return almost

all their output signals back to the cortex.

Intention Tremor. When a person who has lost the cere-

Figure 56-9 shows the anatomical relations of the

bellum performs a voluntary act, the movements tend

basal ganglia to other structures of the brain. On each

to oscillate, especially when they approach the intended

side of the brain, these ganglia consist of the caudate

mark, first overshooting the mark and then vibrating

nucleus, putamen, globus pallidus, substantia nigra,

back and forth several times before settling on the

mark. This reaction is called an intention tremor or an

and subthalamic nucleus. They are located mainly

action tremor, and it results from cerebellar overshoot-

lateral to and surrounding the thalamus, occupying a

ing and failure of the cerebellar system to “damp” the

large portion of the interior regions of both cerebral

motor movements.

hemispheres. Note also that almost all motor and

708

Unit XI The Nervous System: C. Motor and Integrative Neurophysiology

sensory nerve fibers connecting the cerebral cortex

Function of the Basal Ganglia in

and spinal cord pass through the space that lies

Executing Patterns of Motor Activity—

between the major masses of the basal ganglia, the

The Putamen Circuit

caudate nucleus and the putamen. This space is called

the internal capsule of the brain. It is important for our

One of the principal roles of the basal ganglia in motor

current discussion because of the intimate association

control is to function in association with the corti-

between the basal ganglia and the corticospinal system

cospinal system to control complex patterns of motor

for motor control.

activity. An example is the writing of letters of the

alphabet. When there is serious damage to the basal

Neuronal Circuitry of the Basal Ganglia. The anatomical

ganglia, the cortical system of motor control can no

connections between the basal ganglia and the other

longer provide these patterns. Instead, one’s writing

brain elements that provide motor control are

becomes crude, as if one were learning for the first

complex, as shown in Figure 56-10. To the left is shown

time how to write.

the motor cortex, thalamus, and associated brain stem

Other patterns that require the basal ganglia are

and cerebellar circuitry. To the right is the major cir-

cutting paper with scissors, hammering nails, shooting

cuitry of the basal ganglia system, showing the tremen-

a basketball through a hoop, passing a football, throw-

dous interconnections among the basal ganglia

ing a baseball, the movements of shoveling dirt, most

themselves plus extensive input and output pathways

aspects of vocalization, controlled movements of the

between the other motor regions of the brain and the

eyes, and virtually any other of our skilled movements,

basal ganglia.

most of them performed subconsciously.

In the next few sections we will concentrate espe-

cially on two major circuits, the putamen circuit and the

Neural Pathways of the Putamen Circuit. Figure

56-11

caudate circuit.

shows the principal pathways through the basal

ganglia for executing learned patterns of movement.

They begin mainly in the premotor and supplementary

areas of the motor cortex and in the somatosensory

areas of the sensory cortex. Next they pass to the

Premotor and

putamen (mainly bypassing the caudate nucleus), then

supplemental motor

to the internal portion of the globus pallidus, next to

association areas

the ventroanterior and ventrolateral relay nuclei of

the thalamus, and finally return to the cerebral primary

Motor cortex

motor cortex and to portions of the premotor and sup-

plementary cerebral areas closely associated with the

Caudate

primary motor cortex. Thus, the putamen circuit has its

nucleus

Thalamus

Putamen

Premotor and

supplemental

Primary motor

Prefrontal

Somatosensory

Subthalamus

Globus

pallidus

Substantia nigra

Red nucleus

Ventroanterior and

Cerebellum

Inferior olive

ventrolateral

nuclei of thalamus

Caudate

Putamen

Reticular formation

Subthalamus

Globus

Muscles

pallidus

Substantia nigra

internal/external

Figure 56-10

Figure 56-11

Relation of the basal ganglial circuitry to the corticospinal-

Putamen circuit through the basal ganglia for subconscious exe-

cerebellar system for movement control.

cution of learned patterns of movement.

Chapter 56

Contributions of the Cerebellum and Basal Ganglia to Overall Motor Control

709

inputs mainly from those parts of the brain adjacent to

Premotor and

the primary motor cortex but not much from the

supplemental

Primary motor

Prefrontal

primary motor cortex itself. Then its outputs do go

Somatosensory

mainly back to the primary motor cortex or closely

associated premotor and supplementary cortex. Func-

tioning in close association with this primary putamen

circuit are ancillary circuits that pass from the

putamen through the external globus pallidus, the sub-

thalamus, and the substantia nigra—finally returning

to the motor cortex by way of the thalamus.

Abnormal Function in the Putamen Circuit: Athetosis, Hemibal-

Ventroanterior and

lismus, and Chorea. How does the putamen circuit func-

ventrolateral

tion to help execute patterns of movement? The

nuclei of thalamus

Caudate

answer is poorly known. However, when a portion of

the circuit is damaged or blocked, certain patterns of

Putamen

movement become severely abnormal. For instance,

Subthalamus

lesions in the globus pallidus frequently lead to spon-

Globus

taneous and often continuous writhing movements of

pallidus

a hand, an arm, the neck, or the face—movements

Substantia nigra

internal/external

called athetosis.

A lesion in the subthalamus often leads to sudden

Figure 56-12

flailing movements of an entire limb, a condition called

hemiballismus.

Caudate circuit through the basal ganglia for cognitive planning

Multiple small lesions in the putamen lead to flick-

of sequential and parallel motor patterns to achieve specific con-

ing movements in the hands, face, and other parts of

scious goals.

the body, called chorea.

Lesions of the substantia nigra lead to the common

and extremely severe disease of rigidity, akinesia, and

tremors known as Parkinson’s disease, which we

ventroanterior and ventrolateral thalamus, and finally

discuss in more detail later.

back to the prefrontal, premotor, and supplementary

motor areas of the cerebral cortex, but with almost

none of the returning signals passing directly to the

Role of the Basal Ganglia for

primary motor cortex. Instead, the returning signals go

Cognitive Control of Sequences of

to those accessory motor regions in the premotor and

supplementary motor areas that are concerned with

Motor Patterns—The Caudate Circuit

putting together sequential patterns of movement

lasting 5 or more seconds instead of exciting individ-

The term cognition means the thinking processes of

ual muscle movements.

the brain, using both sensory input to the brain plus

A good example of this would be a person seeing a

information already stored in memory. Most of our

lion approach and then responding instantaneously

motor actions occur as a consequence of thoughts gen-

and automatically by (1) turning away from the lion,

erated in the mind, a process called cognitive control

(2) beginning to run, and (3) even attempting to climb

of motor activity. The caudate nucleus plays a major

a tree. Without the cognitive functions, the person

role in this cognitive control of motor activity.

might not have the instinctive knowledge, without

The neural connections between the caudate

thinking for too long a time, to respond quickly and

nucleus and the corticospinal motor control system,

appropriately. Thus, cognitive control of motor activity

shown in Figure 56-12, are somewhat different from

determines subconsciously, and within seconds, which

those of the putamen circuit. Part of the reason for this

patterns of movement will be used together to achieve

is that the caudate nucleus, as shown in Figure 56-9,

a complex goal that might itself last for many seconds.

extends into all lobes of the cerebrum, beginning ante-

riorly in the frontal lobes, then passing posteriorly

through the parietal and occipital lobes, and finally

Function of the Basal Ganglia to

curving forward again like the letter “C” into the tem-

poral lobes. Furthermore, the caudate nucleus receives

Change the Timing and to Scale the

large amounts of its input from the association areas

Intensity of Movements

of the cerebral cortex overlying the caudate nucleus,

mainly areas that also integrate the different types of

Two important capabilities of the brain in controlling

sensory and motor information into usable thought

movement are (1) to determine how rapidly the move-

patterns.

ment is to be performed and (2) to control how large

After the signals pass from the cerebral cortex to

the movement will be. For instance, a person may write

the caudate nucleus, they are next transmitted to the

the letter “a” slowly or rapidly. Also, he or she may

internal globus pallidus, then to the relay nuclei of the

write a small “a” on a piece of paper or a large “a” on

710

Unit XI The Nervous System: C. Motor and Integrative Neurophysiology

a chalkboard. Regardless of the choice, the propor-

conjectured in the last few sections is analytical deduc-

tional characteristics of the letter remain nearly the

tion rather than proven fact.

same.

In patients with severe lesions of the basal ganglia,

these timing and scaling functions are poor; in fact,

Functions of Specific

sometimes they are nonexistent. Here again, the basal

Neurotransmitter Substances in the

ganglia do not function alone; they function in close

Basal Ganglial System

association with the cerebral cortex. One especially

important cortical area is the posterior parietal cortex,

Figure 56-14 demonstrates the interplay of several

which is the locus of the spatial coordinates for motor

specific neurotransmitters that are known to function

control of all parts of the body as well as for the rela-

within the basal ganglia, showing (1) dopamine path-

tion of the body and its parts to all its surroundings.

ways from the substantia nigra to the caudate nucleus

Figure 56-13 shows the way in which a person lacking

and putamen, (2) gamma-aminobutyric acid (GABA)

a left posterior parietal cortex might draw the face of

pathways from the caudate nucleus and putamen to

another human being, providing proper proportions

the globus pallidus and substantia nigra, (3) acetyl-

for the right side of the face but almost ignoring the

choline pathways from the cortex to the caudate

left side (which is in his or her right field of vision).

nucleus and putamen, and (4) multiple general path-

Also, such a person will try always to avoid using his

ways from the brain stem that secrete norepinephrine,

or her right arm, right hand, or other portions of his or

serotonin, enkephalin, and several other neurotrans-

her right body for the performance of tasks, almost not

mitters in the basal ganglia as well as in other parts of

knowing that these parts of his or her body exist.

the cerebrum. In addition to all these are multiple glu-

Because the caudate circuit of the basal ganglial

tamate pathways that provide most of the excitatory

system functions mainly with association areas of the

signals

(not shown in the figure) that balance out

cerebral cortex such as the posterior parietal cortex,

the large numbers of inhibitory signals transmitted

presumably the timing and scaling of movements are

especially by the dopamine, GABA, and serotonin

functions of this caudate cognitive motor control

inhibitory transmitters. We will have more to say about

circuit. However, our understanding of function in the

some of these neurotransmitter and hormonal systems

basal ganglia is still so imprecise that much of what is

in subsequent sections when we discuss diseases of the

basal ganglia, as well as in subsequent chapters when

we discuss behavior, sleep, wakefulness, and functions

of the autonomic nervous system.

For the present, it should be remembered that

the neurotransmitter GABA always functions as an

inhibitory agent. Therefore, GABA neurons in the

feedback loops from the cortex through the basal

From cortex

Caudate nucleus

Ach

Putamen

GABA

Globus

pallidus

Substantia

nigra

Dopamine

From brain stem

1. Norepinephrine

2. Serotonin

3. Enkephalin

Figure 56-13

Figure 56-14

Typical drawing that might be made by a person who has severe

Neuronal pathways that secrete different types of neurotransmit-

damage in his or her left parietal cortex where the spatial coordi-

ter substances in the basal ganglia. Ach, acetylcholine; GABA,

nates of the right field of vision are stored.

gamma-aminobutyric acid.

Chapter 56

Contributions of the Cerebellum and Basal Ganglia to Overall Motor Control

711

ganglia and then back to the cortex make virtually

and akinesia. The reason for this is believed to be that

all these loops negative feedback loops, rather than

L-dopa is converted in the brain into dopamine, and the

positive feedback loops, thus lending stability to the

dopamine then restores the normal balance between

inhibition and excitation in the caudate nucleus and

motor control systems. Dopamine also functions as an

putamen. Administration of dopamine itself does not

inhibitory neurotransmitter in most parts of the brain,

have the same effect because dopamine has a chemical

so that it, too, undoubtedly functions as a stabilizer

structure that will not allow it to pass through the blood-

under some conditions.

brain barrier, even though the slightly different struc-

ture of L-dopa does allow it to pass.

Clinical Syndromes Resulting from

Treatment with l-Deprenyl. Another treatment for

Damage to the Basal Ganglia

Parkinson’s disease is the drug L-deprenyl. This drug

Aside from athetosis and hemiballismus, which have

inhibits monoamine oxidase, which is responsible for

already been mentioned in relation to lesions in the

destruction of most of the dopamine after it has been

globus pallidus and subthalamus, two other major dis-

secreted. Therefore, any dopamine that is released

eases result from damage in the basal ganglia. These are

remains in the basal ganglial tissues for a longer time.

Parkinson’s disease and Huntington’s disease.

In addition, for reasons not understood, this treatment

helps to slow destruction of the dopamine-secreting

Parkinson’s Disease

neurons in the substantia nigra. Therefore, appropriate

Parkinson’s disease, known also as paralysis agitans,

combinations of L-dopa therapy along with L-deprenyl

results from widespread destruction of that portion of

therapy usually provide much better treatment than use

the substantia nigra (the pars compacta) that sends

of one of these drugs alone.

dopamine-secreting nerve fibers to the caudate nucleus

and putamen. The disease is characterized by (1) rigid-

Treatment with Transplanted Fetal Dopamine Cells.

ity of much of the musculature of the body, (2) invol-

Transplantation of dopamine-secreting cells

(cells

untary tremor of the involved areas even when the

obtained from the brains of aborted fetuses) into the

person is resting at a fixed rate of 3 to 6 cycles per

caudate nuclei and putamen has been used with some

second, and (3) serious difficulty in initiating movement,

short-term success to treat Parkinson’s disease.

called akinesia.

However, the cells do not live for more than a few

The causes of these abnormal motor effects are

months. If persistence could be achieved, perhaps this

unknown. However, the dopamine secreted in the

would become the treatment of the future.

caudate nucleus and putamen is an inhibitory transmit-

ter; therefore, destruction of the dopaminergic neurons

Treatment by Destroying Part of the Feedback Circuitry

in the substantia nigra of the parkinsonian patient the-

in the Basal Ganglia. Because abnormal signals from

oretically would allow the caudate nucleus and putamen

the basal ganglia to the motor cortex cause most of the

to become overly active and possibly cause continuous

abnormalities in Parkinson’s disease, multiple attempts

output of excitatory signals to the corticospinal motor

have been made to treat these patients by blocking

control system. These signals could overly excite

these signals surgically. For a number of years, surgical

many or all of the muscles of the body, thus leading to

lesions were made in the ventrolateral and ventroante-

rigidity.

rior nuclei of the thalamus, which blocked part of the

Some of the feedback circuits might easily oscillate

feedback circuit from the basal ganglia to the cortex;

because of high feedback gains after loss of their inhi-

variable degrees of success were achieved—as well as

bition, leading to the tremor of Parkinson’s disease. This

sometimes serious neurological damage. In monkeys

tremor is quite different from that of cerebellar disease

with Parkinson’s disease, lesions placed in the subthal-

because it occurs during all waking hours and therefore

amus have been used, sometimes with surprisingly good

is an involuntary tremor, in contradistinction to cere-

results.

bellar tremor, which occurs only when the person per-

forms intentionally initiated movements and therefore

Huntington’s Disease (Huntington’s Chorea)

is called intention tremor.

Huntington’s disease is a hereditary disorder that

The akinesia that occurs in Parkinson’s disease is often

usually begins causing symptoms at age 30 to 40 years.

much more distressing to the patient than are the symp-

It is characterized at first by flicking movements in indi-

toms of muscle rigidity and tremor, because to perform

vidual muscles and then progressive severe distortional

even the simplest movement in severe parkinsonism, the

movements of the entire body. In addition, severe

person must exert the highest degree of concentration.

dementia develops along with the motor dysfunctions.

The mental effort, even mental anguish, that is necessary

The abnormal movements of Huntington’s disease

to make the desired movements is often at the limit of

are believed to be caused by loss of most of the cell

the patient’s willpower. Then, when the movements do

bodies of the GABA-secreting neurons in the caudate

occur, they are usually stiff and staccato in character

nucleus and putamen and of acetylcholine-secreting

instead of smooth. The cause of this akinesia is still spec-

neurons in many parts of the brain. The axon terminals

ulative. However, dopamine secretion in the limbic

of the GABA neurons normally inhibit portions of the

system, especially in the nucleus accumbens, is often

globus pallidus and substantia nigra. This loss of inhibi-

decreased along with its decrease in the basal ganglia. It

tion is believed to allow spontaneous outbursts of

has been suggested that this might reduce the psychic

globus pallidus and substantia nigra activity that cause

drive for motor activity so greatly that akinesia results.

the distortional movements.

The dementia in Huntington’s disease probably does

Treatment with l-Dopa. Administration of the drug L-

not result from the loss of GABA neurons but from the

dopa to patients with Parkinson’s disease usually ame-

loss of acetylcholine-secreting neurons, perhaps espe-

liorates many of the symptoms, especially the rigidity

cially in the thinking areas of the cerebral cortex.

712

Unit XI The Nervous System: C. Motor and Integrative Neurophysiology

The abnormal gene that causes Huntington’s disease

Associated Functions of the Cerebellum. The cerebellum

has been found; it has a many-times-repeating codon,

functions with all levels of muscle control. It functions

CAG, that codes for multiple extra glutamine amino

with the spinal cord especially to enhance the stretch

acids in the molecular structure of an abnormal neu-

reflex, so that when a contracting muscle encounters

ronal cell protein called huntingtin that causes the symp-

an unexpectedly heavy load, a long stretch reflex signal

toms. How this protein causes the disease effects is now

transmitted all the way through the cerebellum and

the question for major research effort.

back again to the cord strongly enhances the load-

resisting effect of the basic stretch reflex.

At the brain stem level, the cerebellum functions to

Integration of the Many

make the postural movements of the body—especially

Parts of the Total Motor

the rapid movements required by the equilibrium

Control System

system—smooth and continuous and without abnor-

mal oscillations.

Finally, we need to summarize as best we can what is

At the cerebral cortex level, the cerebellum oper-

known about overall control of movement. To do this,

ates in association with the cortex to provide many

let us first give a synopsis of the different levels of

accessory motor functions, especially to provide extra

control.

motor force for turning on muscle contraction rapidly

at the start of a movement. Near the end of each move-

ment, the cerebellum turns on antagonist muscles at

Spinal Level

exactly the right time and with proper force to stop the

movement at the intended point. Furthermore, there

Programmed in the spinal cord are local patterns of

is good physiologic evidence that all aspects of this

movement for all muscle areas of the body—for

turn-on/turn-off patterning by the cerebellum can be

instance, programmed withdrawal reflexes that pull

learned with experience.

any part of the body away from a source of pain. The

The cerebellum functions with the cerebral cortex at

cord is the locus also of complex patterns of rhythmi-

still another level of motor control: it helps to program

cal motions such as to-and-fro movement of the limbs

in advance muscle contractions that are required for

for walking, plus reciprocal motions on opposite sides

smooth progression from a present rapid movement in

of the body or of the hindlimbs versus the forelimbs

one direction to the next rapid movement in another

in four-legged animals.

direction, all this occurring in a fraction of a second.

All these programs of the cord can be commanded

The neural circuit for this passes from the cerebral

into action by higher levels of motor control, or they

cortex to the large lateral zones of the cerebellar hemi-

can be inhibited while the higher levels take over

spheres and then back to the cerebral cortex.

control.

The cerebellum functions mainly when muscle

movements have to be rapid. Without the cerebellum,

slow and calculated movements can still occur, but it

Hindbrain Level

is difficult for the corticospinal system to achieve rapid

and changing intended movements to execute a par-

The hindbrain provides two major functions for

ticular goal or especially to progress smoothly from

general motor control of the body: (1) maintenance of

one rapid movement to the next.

axial tone of the body for the purpose of standing and

(2) continuous modification of the degrees of tone in

the different muscles in response to information from

Associated Functions of the Basal Ganglia. The basal

the vestibular apparatuses for the purpose of main-

ganglia are essential to motor control in ways entirely

taining body equilibrium.

different from those of the cerebellum. Their most

important functions are (1) to help the cortex execute

subconscious but learned patterns of movement and (2)

Motor Cortex Level

to help plan multiple parallel and sequential patterns

of movement that the mind must put together to

The motor cortex system provides most of the acti-

accomplish a purposeful task.

vating motor signals to the spinal cord. It functions

The types of motor patterns that require the basal

partly by issuing sequential and parallel commands

ganglia include those for writing all the different

that set into motion various cord patterns of motor

letters of the alphabet, for throwing a ball, and for

action. It can also change the intensities of the differ-

typing. Also, the basal ganglia are required to modify

ent patterns or modify their timing or other charac-

these patterns for writing small or writing very large,

teristics. When needed, the corticospinal system can

thus controlling dimensions of the patterns.

bypass the cord patterns, replacing them with higher-

At a still higher level of control is another combined

level patterns from the brain stem or cerebral cortex.

cerebral and basal ganglia circuit, beginning in the

The cortical patterns usually are complex; also, they

thinking processes of the cerebrum to provide overall

can be “learned,” whereas cord patterns are mainly

sequential steps of action for responding to each new

determined by heredity and are said to be “hard

situation, such as planning one’s immediate motor

wired.”

response to an assailant who hits the person in the face

Chapter 56

Contributions of the Cerebellum and Basal Ganglia to Overall Motor Control

713

or one’s sequential response to an unexpectedly fond

de Zeeuw CI, Strata P, Voogd J: The Cerebellum: From Struc-

embrace.

ture to Control. Amsterdam: Elsevier, 1997.

Elble RJ: Origins of tremor. Lancet 355:1113, 2000.

Garwicz M, Ekerot C-F, Jorntell H: Organizational principles

What Drives Us to Action?

of cerebellar neuronal circuitry. News Physiol Sci 13:26,

1998.

Gibson AR, Horn KM, Pong M: Inhibitory control of olivary

What is it that arouses us from inactivity and sets into

discharge. Ann N Y Acad Sci 978:219, 2002.

play our trains of movement? We are beginning to

Goodale MA, Westwood DA: An evolving view of duplex

learn about the motivational systems of the brain.

vision: separate but interacting cortical pathways for

Basically, the brain has an older core located beneath,

perception and action. Curr Opin Neurobiol

14:203,

anterior, and lateral to the thalamus—including the

2004.

hypothalamus, amygdala, hippocampus, septal region

Ito M: Cerebellar long-term depression: characterization,

anterior to the hypothalamus and thalamus, and even

signal transduction, and functional roles. Physiol Rev

old regions of the thalamus and cerebral cortex them-

81:1143, 2001.

selves—all of which function together to initiate most

Kandel ER, Schwartz JH, Jessell TM: Principles of Neural

Science, 4th ed. New York: McGraw-Hill, 2000.

motor and other functional activities of the brain.

Keifer J, Houk JC: Motor function of the cerebel-

These areas are collectively called the limbic system

lorubrospinal system. Physiol Rev 74:509, 1994.

of the brain. We discuss this system in detail in

Li JY, Plomann M, Brundin P: Huntington’s disease: a synap-

Chapter 58.

topathy? Trends Mol Med 9:414, 2003.

Obeso JA, Rodriguez-Oroz M, Marin C, et al: The origin

of motor fluctuations in Parkinson’s disease: importance

References

of dopaminergic innervation and basal ganglia circuits.

Neurology 62(1 Suppl 1):S17, 2004.

Albin RL: Dominant ataxias and Friedreich ataxia: an

Ohyama T, Medina JF, Nores WL, Mauk MD: Trying to

update. Curr Opin Neurol 16:507, 2003.

understand the cerebellum well enough to build one. Ann

Barnham KJ, Masters CL, Bush AI: Neurodegenerative dis-

N Y Acad Sci 978:425, 2002.

eases and oxidative stress. Nat Rev Drug Discov 3:205,

Olanow CW: The scientific basis for the current treatment of

2004.

Parkinson’s disease. Annu Rev Med 55:41, 2004.

Brooks VB, Thach WT: Cerebellar control of posture and

Samii A, Nutt JG, Ransom BR: Parkinson’s disease. Lancet

movement. In: Handbook of Physiology, Sec. 1, Vol. II.

363:1783, 2004.

Bethesda: American Physiological Society, 1981, p 877.

Schweighofer N, Doya K, Kuroda S: Cerebellar aminergic

DeKosky ST, Marek K: Looking backward to move forward:

neuromodulation: towards a functional understanding.

early detection of neurodegenerative disorders. Science

Brain Res Brain Res Rev 44:103, 2004.

302:830, 2003.

Sethi KD: Tremor. Curr Opin Neurol 16:481, 2003.

C H A P T E R

Cerebral Cortex, Intellectual

Functions of the Brain, Learning

and Memory

It is ironic that of all the parts of the brain, we know

least about the functions of the cerebral cortex,

even though it is by far the largest portion of the

nervous system. But we do know the effects of

damage or specific stimulation in various portions

of the cortex. In the first part of this chapter, the

facts known about cortical function are discussed;

then basic theories of neuronal mechanisms

involved in thought processes, memory, analysis of sensory information, and so

forth are presented briefly.

Physiologic Anatomy of the Cerebral Cortex

The functional part of the cerebral cortex is a thin layer of neurons covering the

surface of all the convolutions of the cerebrum. This layer is only 2 to 5 millimeters

thick, with a total area of about one quarter of a square meter. The total cerebral

cortex contains about 100 billion neurons.

Figure 57-1 shows the typical histological structure of the neuronal surface of the

cerebral cortex, with its successive layers of different types of neurons. Most of the

neurons are of three types: (1) granular (also called stellate), (2) fusiform, and (3)

pyramidal, the last named for their characteristic pyramidal shape.

The granular neurons generally have short axons and, therefore, function mainly

as interneurons that transmit neural signals only short distances within the cortex

itself. Some are excitatory, releasing mainly the excitatory neurotransmitter gluta-

mate; others are inhibitory and release mainly the inhibitory neurotransmitter

gamma-aminobutyric acid (GABA). The sensory areas of the cortex as well as the

association areas between sensory and motor areas have large concentrations of

these granule cells, suggesting a high degree of intracortical processing of incoming

sensory signals within the sensory areas and association areas.

The pyramidal and fusiform cells give rise to almost all the output fibers from the

cortex. The pyramidal cells are larger and more numerous than the fusiform cells.

They are the source of the long, large nerve fibers that go all the way to the spinal

cord. They also give rise to most of the large subcortical association fiber bundles

that pass from one major part of the brain to another.

To the right in Figure 57-1 is shown the typical organization of nerve fibers within

the different layers of the cerebral cortex. Note particularly the large number of

horizontal fibers that extend between adjacent areas of the cortex, but note also the

vertical fibers that extend to and from the cortex to lower areas of the brain and

some all the way to the spinal cord or to distant regions of the cerebral cortex

through long association bundles.

The functions of the specific layers of the cerebral cortex are discussed in Chap-

ters 47 and 51. By way of review, let us recall that most incoming specific sensory

signals from the body terminate in cortical layer IV. Most of the output signals leave

the cortex through neurons located in layers V and VI; the very large fibers to the

brain stem and cord arise generally in layer V; and the tremendous numbers of fibers

to the thalamus arise in layer VI. Layers I, II, and III perform most of the intra-

cortical association functions, with especially large numbers of neurons in layers II

and III making short horizontal connections with adjacent cortical areas.

Anatomical and Functional Relations of the Cerebral Cortex to the Thalamus and Other Lower

Centers. All areas of the cerebral cortex have extensive to-and-fro efferent

and afferent connections with deeper structures of the brain. It is especially

714

Chapter 57

Cerebral Cortex, Intellectual Functions of the Brain, Learning and Memory

715

N. dorsalis

N. lateralis

medialis

posterior

III

Med. geniculate

body indeterminate

Lat.

geniculate

body

Figure 57-2

Areas of the cerebral cortex that connect with specific portions of

the thalamus.

VIa

Supplementary

motor synergies

VIb

Hand

skills

Elaboration

Figure 57-1

of thought

Speech

Structure of the cerebral cortex, showing: I, molecular layer; II,

external granular layer; III, layer of pyramidal cells; IV, internal

Speech

Bilateral

granular layer; V, large pyramidal cell layer; and VI, layer of fusiform

vision

or polymorphic cells. (Redrawn from Ranson SW, Clark SL [after

Brodmann]: Anatomy of the Nervous System. Philadelphia: WB

Saunders Co, 1959.)

Contralateral

vision

Figure 57-3

Functional areas of the human cerebral cortex as determined by

important to emphasize the relation between the cere-

electrical stimulation of the cortex during neurosurgical operations

bral cortex and the thalamus. When the thalamus is

and by neurological examinations of patients with destroyed corti-

cal regions. (Redrawn from Penfield W, Rasmussen T: The Cerebral

damaged along with the cortex, the loss of cerebral

Cortex of Man: A Clinical Study of Localization of Function. New

function is far greater than when the cortex alone is

York: Hafner Co, 1968.)

damaged because thalamic excitation of the cortex is

necessary for almost all cortical activity.

Figure 57-2 shows the areas of the cerebral cortex

that connect with specific parts of the thalamus. These

Functions of Specific

connections act in two directions, both from the thala-

Cortical Areas

mus to the cortex and then from the cortex back to

essentially the same area of the thalamus. Further-

Studies in human beings by neurosurgeons, neurolo-

more, when the thalamic connections are cut, the func-

gists, and neuropathologists have shown that different

tions of the corresponding cortical area become almost

cerebral cortical areas have separate functions. Figure

entirely lost. Therefore, the cortex operates in close

57-3 is a map of some of these functions as determined

association with the thalamus and can almost be con-

by Penfield and Rasmussen from electrical stimulation

sidered both anatomically and functionally a unit with

of the cortex in awake patients or during neurological

the thalamus: for this reason, the thalamus and the

examination of patients after portions of the cortex

cortex together are sometimes called the thalamocor-

had been removed. The electrically stimulated patients

tical system. Almost all pathways from the sensory

told their thoughts evoked by the stimulation, and

receptors and sensory organs to the cortex pass

sometimes they experienced movements. Occasionally

through the thalamus, with the principal exception of

they spontaneously emitted a sound or even a word or

some sensory pathways of olfaction.

gave some other evidence of the stimulation.

716

Unit XI The Nervous System: C. Motor and Integrative Neurophysiology

Primary somatic

association areas are (1) the parieto-occipitotemporal

Supplemental

Primary motor

association area, (2) the prefrontal association area,

Secondary somatic

and premotor

and (3) the limbic association area. Following are

explanations of the functions of these areas.

Secondary

visual

Parieto-occipitotemporal Association Area. This association

Parieto-

area lies in the large parietal and occipital cortical

Prefrontal

occipito-

space bounded by the somatosensory cortex anteri-

Association

temporal

orly, the visual cortex posteriorly, and the auditory

Area

Association

cortex laterally. As would be expected, it provides a

Area

high level of interpretative meaning for signals from

all the surrounding sensory areas. However, even the

Limbic

parieto-occipitotemporal association area has its own

Association

Primary

functional subareas, which are shown in Figure 57-5.

Area

visual

Primary

Secondary

auditory

1. Analysis of the Spatial Coordinates of the Body. An

area beginning in the posterior parietal cortex and

Figure 57-4

extending into the superior occipital cortex provides

continuous analysis of the spatial coordinates of all

Locations of major association areas of the cerebral cortex, as well

parts of the body as well as of the surroundings

as primary and secondary motor and sensory areas.

of the body. This area receives visual sensory informa-

tion from the posterior occipital cortex and simulta-

neous somatosensory information from the anterior

parietal cortex. From all this information, it computes

Putting large amounts of information together from

the coordinates of the visual, auditory, and body

many different sources gives a more general map, as

surroundings.

shown in Figure 57-4. This figure shows the major

primary and secondary premotor and supplementary

2. Area for Language Comprehension. The major area

motor areas of the cortex as well as the major primary

for language comprehension, called Wernicke’s area,

and secondary sensory areas for somatic sensation,

lies behind the primary auditory cortex in the posterior

vision, and hearing, all of which are discussed in earlier

part of the superior gyrus of the temporal lobe. We

chapters. The primary motor areas have direct con-

discuss this area much more fully later; it is the most

nections with specific muscles for causing discrete

important region of the entire brain for higher intel-

muscle movements. The primary sensory areas detect

lectual function because almost all such intellectual

specific sensations—visual, auditory, or somatic—

functions are language based.

transmitted directly to the brain from peripheral

sensory organs.

3. Area for Initial Processing of Visual Language

The secondary areas make sense out of the signals

(Reading). Posterior to the language comprehension

in the primary areas. For instance, the supplementary

area, lying mainly in the anterolateral region of the

and premotor areas function along with the primary

occipital lobe, is a visual association area that feeds

motor cortex and basal ganglia to provide “patterns”

visual information conveyed by words read from a

of motor activity. On the sensory side, the secondary

book into Wernicke’s area, the language comprehen-

sensory areas, located within a few centimeters of the

sion area. This so-called angular gyrus area is needed

primary areas, begin to analyze the meanings of the

to make meaning out of the visually perceived words.

specific sensory signals, such as (1) interpretation of

In its absence, a person can still have excellent

the shape or texture of an object in one’s hand; (2)

language comprehension through hearing but not

interpretation of color, light intensity, directions of

through reading.

lines and angles, and other aspects of vision; and (3)

interpretations of the meanings of sound tones and

4. Area for Naming Objects. In the most lateral por-

sequence of tones in the auditory signals.

tions of the anterior occipital lobe and posterior tem-

poral lobe is an area for naming objects. The names are

learned mainly through auditory input, whereas the

Association Areas

physical natures of the objects are learned mainly

through visual input. In turn, the names are essential

Figure 57-4 also shows several large areas of the cere-

for both auditory and visual language comprehension

bral cortex that do not fit into the rigid categories of

(functions performed in Wernicke’s area located imme-

primary and secondary motor and sensory areas. These

diately superior to the auditory “names” region and

areas are called association areas because they receive

anterior to the visual word processing area).

and analyze signals simultaneously from multiple

regions of both the motor and sensory cortices as well

Prefrontal Association Area. In Chapter 56, we learned

as from subcortical structures. Yet even the association

that the prefrontal association area functions in close

areas have their specializations. The most important

association with the motor cortex to plan complex

Chapter 57

Cerebral Cortex, Intellectual Functions of the Brain, Learning and Memory

717

Motor

Somato-

Spatial

sensory

coordinates

Planning complex

of body and

movements and

surroundings

elaboration of

thoughts

Visual

Word

Language

processing

formation

comprehension

of words

Auditory

intelligence

Broca‘s

Area

Behavior,

Vision

Figure 57-5

emotions,

Naming of

motivation

objects

Map of specific functional areas in

the cerebral cortex, showing espe-

cially Wernicke’s and Broca’s

areas for language comprehension

Limbic

Wernicke‘s

and speech production, which in 95

Association

Area

per cent of all people are located

Area

in the left hemisphere.

patterns and sequences of motor movements. To aid in

association cortex, as we discuss more fully later in the

this function, it receives strong input through a

chapter.

massive subcortical bundle of nerve fibers connecting

An especially interesting discovery is the following:

the parieto-occipitotemporal association area with the

When a person has already learned one language and

prefrontal association area. Through this bundle, the

then learns a new language, the area in the brain where

prefrontal cortex receives much preanalyzed sensory

the new language is stored is slightly removed from the

information, especially information on the spatial

storage area for the first language. If both languages

coordinates of the body that is necessary for planning

are learned simultaneously, they are stored together in

effective movements. Much of the output from the

the same area of the brain.

prefrontal area into the motor control system passes

Limbic Association Area. Figures 57-4 and 57-5 show still

through the caudate portion of the basal ganglia-

another association area called the limbic association

thalamic feedback circuit for motor planning, which

area. This area is found in the anterior pole of the tem-

provides many of the sequential and parallel compo-

poral lobe, in the ventral portion of the frontal lobe,

nents of movement stimulation.

and in the cingulate gyrus lying deep in the longitu-

The prefrontal association area is also essential to

dinal fissure on the midsurface of each cerebral

carrying out “thought” processes in the mind. This pre-

hemisphere. It is concerned primarily with behavior,

sumably results from some of the same capabilities of

emotions, and motivation. We will learn in Chapter 58

the prefrontal cortex that allow it to plan motor activ-

that the limbic cortex is part of a much more extensive

ities. It seems to be capable of processing nonmotor as

system, the limbic system, that includes a complex set

well as motor information from widespread areas of

of neuronal structures in the midbasal regions of the

the brain and therefore to achieve nonmotor types of

brain. This limbic system provides most of the emo-

thinking as well as motor types. In fact, the prefrontal

tional drives for activating other areas of the brain and

association area is frequently described simply as

even provides motivational drive for the process of

important for elaboration of thoughts, and it is said to

learning itself.

store on a short-term basis “working memories” that

are used to combine new thoughts while they are

Area for Recognition of Faces

entering the brain.

An interesting type of brain abnormality called

prosophenosia is inability to recognize faces. This

Broca’s Area. A special region in the frontal cortex,

occurs in people who have extensive damage on the

called Broca’s area, provides the neural circuitry for

medial undersides of both occipital lobes and along

word formation. This area, shown in Figure 57-5, is

the medioventral surfaces of the temporal lobes, as

located partly in the posterior lateral prefrontal cortex

shown in Figure 57-6. Loss of these face recognition

and partly in the premotor area. It is here that plans

areas, strangely enough, results in little other abnor-

and motor patterns for expressing individual words or

mality of brain function.

even short phrases are initiated and executed. This

One wonders why so much of the cerebral cortex

area also works in close association with Wernicke’s

should be reserved for the simple task of face recog-

language comprehension center in the temporal

nition. Most of our daily tasks involve associations

718

Unit XI The Nervous System: C. Motor and Integrative Neurophysiology

Facial

recognition area

Motor

Primary

Somatic

Interpretative

Prefrontal

areas

Somatic

area

Broca's

speech

area

Visual

interpretative

Auditory

areas

interpretative

Primary

areas

visual

Wernicke‘s area

Temporal

Frontal

lobe

Figure 57-7

Organization of the somatic auditory and visual association areas

Figure 57-6

into a general mechanism for interpretation of sensory experience.

All of these feed also into Wernicke’s area, located in the postero-

Facial recognition areas located on the underside of the brain in the

superior portion of the temporal lobe. Note also the prefrontal area

medial occipital and temporal lobes. (Redrawn from Geschwind N:

and Broca’s speech area in the frontal lobe.

Specializations of the human brain. Sci Am 241:180, 1979. " 1979 by

to read words from the printed page but be unable to

recognize the thought that is conveyed.

with other people, and one can see the importance of

Electrical stimulation in Wernicke’s area of a con-

this intellectual function.

scious person occasionally causes a highly complex

The occipital portion of this facial recognition area

thought. This is particularly true when the stimulation

is contiguous with the visual cortex, and the temporal

electrode is passed deep enough into the brain to

portion is closely associated with the limbic system

approach the corresponding connecting areas of the

that has to do with emotions, brain activation, and

thalamus. The types of thoughts that might be experi-

control of one’s behavioral response to the environ-

enced include complicated visual scenes that one

ment, as we see in Chapter 58.

might remember from childhood, auditory hallucina-

tions such as a specific musical piece, or even a state-

ment made by a specific person. For this reason, it is

Comprehensive Interpretative

believed that activation of Wernicke’s area can call

Function of the Posterior Superior

forth complicated memory patterns that involve more

Temporal Lobe—“Wernicke’s Area”

than one sensory modality even though most of the

(a General Interpretative Area)

individual memories may be stored elsewhere. This

belief is in accord with the importance of Wernicke’s

The somatic, visual, and auditory association areas all

area in interpreting the complicated meanings of dif-

meet one another in the posterior part of the superior

ferent patterns of sensory experiences.

temporal lobe, shown in Figure 57-7, where the tem-

poral, parietal, and occipital lobes all come together.

Angular Gyrus—Interpretation of Visual Information. The

This area of confluence of the different sensory inter-

angular gyrus is the most inferior portion of the pos-

pretative areas is especially highly developed in the

terior parietal lobe, lying immediately behind Wer-

dominant side of the brain—the left side in almost all

nicke’s area and fusing posteriorly into the visual areas

right-handed people—and it plays the greatest single

of the occipital lobe as well. If this region is destroyed

role of any part of the cerebral cortex for the higher

while Wernicke’s area in the temporal lobe is still

comprehension levels of brain function that we call

intact, the person can still interpret auditory experi-

intelligence. Therefore, this region has been called by

ences as usual, but the stream of visual experiences

different names suggestive of an area that has almost

passing into Wernicke’s area from the visual cortex is

global importance: the general interpretative area, the

mainly blocked. Therefore, the person may be able to

gnostic area, the knowing area, the tertiary association

see words and even know that they are words but not

area, and so forth. It is best known as Wernicke’s area

be able to interpret their meanings. This is the condi-

in honor of the neurologist who first described its

tion called dyslexia, or word blindness.

special significance in intellectual processes.

Let us again emphasize the global importance of

After severe damage in Wernicke’s area, a person

Wernicke’s area for processing most intellectual

might hear perfectly well and even recognize different

functions of the brain. Loss of this area in an

words but still be unable to arrange these words into

adult usually leads thereafter to a lifetime of almost

a coherent thought. Likewise, the person may be able

demented existence.

Chapter 57

Cerebral Cortex, Intellectual Functions of the Brain, Learning and Memory

719

Concept of the Dominant Hemisphere

Role of Language in the Function of

The general interpretative functions of Wernicke’s

Wernicke’s Area and in Intellectual Functions

area and the angular gyrus, as well as the functions

A major share of our sensory experience is converted

of the speech and motor control areas, are usually

into its language equivalent before being stored in the

much more highly developed in one cerebral

memory areas of the brain and before being processed

hemisphere than in the other. Therefore, this hemi-

for other intellectual purposes. For instance, when we

sphere is called the dominant hemisphere. In about 95

read a book, we do not store the visual images of

per cent of all people, the left hemisphere is the dom-

the printed words but instead store the words them-

inant one.

selves or their conveyed thoughts often in language

Even at birth, the area of the cortex that will even-

form.

tually become Wernicke’s area is as much as 50 per

The sensory area of the dominant hemisphere for

cent larger in the left hemisphere than in the right in

interpretation of language is Wernicke’s area, and this

more than one half of neonates. Therefore, it is easy

is closely associated with both the primary and sec-

to understand why the left side of the brain might

ondary hearing areas of the temporal lobe. This close

become dominant over the right side. However, if for

relation probably results from the fact that the first

some reason this left side area is damaged or removed

introduction to language is by way of hearing. Later

in very early childhood, the opposite side of the brain

in life, when visual perception of language through

will usually develop dominant characteristics.

the medium of reading develops, the visual informa-

A theory that can explain the capability of one

tion conveyed by written words is then presumably

hemisphere to dominate the other hemisphere is the

channeled through the angular gyrus, a visual associa-

following.

tion area, into the already developed Wernicke’s lan-

The attention of the “mind” seems to be directed

guage interpretative area of the dominant temporal

to one principal thought at a time. Presumably,

lobe.

because the left posterior temporal lobe at birth is

usually slightly larger than the right, the left side

normally begins to be used to a greater extent

Functions of the Parieto-

than the right. Thereafter, because of the tendency to

occipitotemporal Cortex in the

direct one’s attention to the better developed region,

Nondominant Hemisphere

the rate of learning in the cerebral hemisphere that

gains the first start increases rapidly, whereas in the

When Wernicke’s area in the dominant hemisphere of

opposite, less-used side, learning remains slight.

an adult person is destroyed, the person normally loses

Therefore, the left side normally becomes dominant

almost all intellectual functions associated with lan-

over the right.

guage or verbal symbolism, such as the ability to read,

In about 95 per cent of all people, the left temporal

the ability to perform mathematical operations, and

lobe and angular gyrus become dominant, and in the

even the ability to think through logical problems.

remaining 5 per cent, either both sides develop simul-

Many other types of interpretative capabilities, some

taneously to have dual function, or, more rarely, the

of which use the temporal lobe and angular gyrus

right side alone becomes highly developed, with full

regions of the opposite hemisphere, are retained.

dominance.

Psychological studies in patients with damage to the

As discussed later in the chapter, the premotor

nondominant hemisphere have suggested that this

speech area (Broca’s area), located far laterally in the

hemisphere may be especially important for under-

intermediate frontal lobe, is also almost always domi-

standing and interpreting music, nonverbal visual

nant on the left side of the brain. This speech area is

experiences (especially visual patterns), spatial rela-

responsible for formation of words by exciting simul-

tions between the person and their surroundings, the

taneously the laryngeal muscles, respiratory muscles,

significance of “body language” and intonations of

and muscles of the mouth.

people’s voices, and probably many somatic experi-

The motor areas for controlling hands are also

ences related to use of the limbs and hands. Thus, even

dominant in the left side of the brain in about 9 of

though we speak of the “dominant” hemisphere, this

10 persons, thus causing right-handedness in most

is primarily for language-based intellectual functions;

people.

the so-called nondominant hemisphere might actually

Although the interpretative areas of the temporal

be dominant for some other types of intelligence.

lobe and angular gyrus, as well as many of the motor

areas, are usually highly developed in only the left

hemisphere, these areas receive sensory information

from both hemispheres and are capable also of con-

Higher Intellectual Functions of the

trolling motor activities in both hemispheres. For this

Prefrontal Association Areas

purpose, they use mainly fiber pathways in the corpus

callosum for communication between the two hemi-

For years, it has been taught that the prefrontal cortex

spheres. This unitary, cross-feeding organization pre-

is the locus of “higher intellect” in the human being,

vents interference between the two sides of the brain;

principally because the main difference between the

such interference could create havoc with both mental

brains of monkeys and of human beings is the great

thoughts and motor responses.

prominence of the human prefrontal areas. Yet, efforts

720

Unit XI The Nervous System: C. Motor and Integrative Neurophysiology

to show that the prefrontal cortex is more important

prefrontal association areas have the capability of

in higher intellectual functions than other portions of

calling forth information from widespread areas of the

the brain have not been successful. Indeed, destruction

brain and using this information to achieve deeper

of the language comprehension area in the posterior

thought patterns for attaining goals. If these goals

superior temporal lobe (Wernicke’s area) and the

include motor action, so be it. If they do not, then

adjacent angular gyrus region in the dominant hemi-

the thought processes attain intellectual analytical

sphere causes much more harm to the intellect than

goals.

does destruction of the prefrontal areas. The prefrontal

Although people without prefrontal cortices can

areas do, however, have less definable but nevertheless

still think, they show little concerted thinking in logical

important intellectual functions of their own. These

sequence for longer than a few seconds or a minute or

functions can best be explained by describing what

so at most. One of the results is that people without

happens to patients in whom the prefrontal areas have

prefrontal cortices are easily distracted from their

become nonfunctional, as follows.

central theme of thought, whereas people with func-

Several decades ago, before the advent of modern

tioning prefrontal cortices can drive themselves to

drugs for treating psychiatric conditions, it was found

completion of their thought goals irrespective of

that some patients could receive significant relief from

distractions.

severe psychotic depression by severing the neuronal

connections between the prefrontal areas of the brain

Elaboration of Thought, Prognostication, and Performance of

and the remainder of the brain, that is, by a procedure

Higher Intellectual Functions by the Prefrontal Areas—Concept

called prefrontal lobotomy. This was done by inserting

of a “Working Memory.” Another function that has been

a blunt, thin-bladed knife through a small opening in

ascribed to the prefrontal areas by psychologists and

the lateral frontal skull on each side of the head and

neurologists is elaboration of thought. This means

slicing the brain at the back edge of the prefrontal

simply an increase in depth and abstractness of the dif-

lobes from top to bottom. Subsequent studies in these

ferent thoughts put together from multiple sources of

patients showed the following mental changes:

information. Psychological tests have shown that pre-

1. The patients lost their ability to solve complex

frontal lobectomized lower animals presented with

problems.

successive bits of sensory information fail to keep

2. They became unable to string together sequential

track of these bits even in temporary memory, proba-

tasks to reach complex goals.

bly because they are distracted so easily that they

3. They became unable to learn to do several

cannot hold thoughts long enough for memory storage

parallel tasks at the same time.

to take place.

4. Their level of aggressiveness was decreased,

This ability of the prefrontal areas to keep track of

sometimes markedly, and, in general, they lost

many bits of information simultaneously and to cause

ambition.

recall of this information instantaneously as it is

5. Their social responses were often inappropriate

needed for subsequent thoughts is called the brain’s

for the occasion, often including loss of morals

“working memory.” This could well explain the many

and little reticence in relation to sex and

functions of the brain that we associate with higher

excretion.

intelligence. In fact, studies have shown that the pre-

6. The patients could still talk and comprehend

frontal areas are divided into separate segments for

language, but they were unable to carry through

storing different types of temporary memory, such as

any long trains of thought, and their moods

one area for storing shape and form of an object or a

changed rapidly from sweetness to rage to

part of the body and another for storing movement.

exhilaration to madness.

By combining all these temporary bits of working

7. The patients could also still perform most of the

memory, we have the abilities to (1) prognosticate; (2)

usual patterns of motor function that they had

plan for the future; (3) delay action in response to

performed throughout life, but often without

incoming sensory signals so that the sensory informa-

purpose.

tion can be weighed until the best course of response

From this information, let us try to piece together a

is decided; (4) consider the consequences of motor

coherent understanding of the function of the pre-

actions before they are performed; (5) solve compli-

frontal association areas.

cated mathematical, legal, or philosophical problems;

(6) correlate all avenues of information in diagnosing

Decreased Aggressiveness and Inappropriate Social Re-

rare diseases; and (7) control our activities in accord

sponses. These two characteristics probably result

with moral laws.

from loss of the ventral parts of the frontal lobes on

the underside of the brain. As explained earlier and

Function of the Brain in

shown in Figures 57-4 and 57-5, this area is part of the

Communication—Language

limbic association cortex, rather than of the prefrontal

association cortex. This limbic area helps to control

Input and Language Output

behavior, which is discussed in detail in Chapter 58.

One of the most important differences between human

beings and lower animals is the facility with which

Inability to Progress Toward Goals or to Carry Through Sequen-

human beings can communicate with one another. Fur-

tial Thoughts. We learned earlier in this chapter that the

thermore, because neurological tests can easily assess

Chapter 57

Cerebral Cortex, Intellectual Functions of the Brain, Learning and Memory

721

These effects are called, respectively, auditory receptive

SPEAKING A HEARD WORD

Motor cortex

Arcuate fasciculus

aphasia and visual receptive aphasia or, more commonly,

word deafness and word blindness (also called dyslexia).

Wernicke’s Aphasia and Global Aphasia. Some people

are capable of understanding either the spoken word or

the written word but are unable to interpret the thought

that is expressed. This results most frequently when

Wernicke’s area in the posterior superior temporal gyrus

in the dominant hemisphere is damaged or destroyed.

Therefore, this type of aphasia is called Wernicke’s

aphasia.

When the lesion in Wernicke’s area is widespread and

extends (1) backward into the angular gyrus region, (2)

inferiorly into the lower areas of the temporal lobe, and

(3) superiorly into the superior border of the sylvian

Broca’s area

fissure, the person is likely to be almost totally

demented for language understanding or communica-

Wernicke’s area

tion and therefore is said to have global aphasia.

Primary auditory area

Motor Aspects of Communication. The process of speech

SPEAKING A WRITTEN WORD

Motor cortex

involves two principal stages of mentation: (1) forma-

tion in the mind of thoughts to be expressed as well

as choice of words to be used and then (2) motor

control of vocalization and the actual act of vocalization

itself.

The formation of thoughts and even most choices of

words are the function of sensory association areas of

the brain. Again, it is Wernicke’s area in the posterior

part of the superior temporal gyrus that is most impor-

tant for this ability. Therefore, a person with either Wer-

nicke’s aphasia or global aphasia is unable to formulate

the thoughts that are to be communicated. Or, if the

lesion is less severe, the person may be able to formu-

late the thoughts but unable to put together appropri-

ate sequences of words to express the thought. The

person sometimes is even fluent with words but the

Broca’s area

Primary

words are jumbled.

visual area

Wernicke’s area Angular gyrus

Loss of Broca’s Area Causes Motor Aphasia. Sometimes

a person is capable of deciding what he or she wants to

Figure 57-8

say but cannot make the vocal system emit words

instead of noises. This effect, called motor aphasia,

Brain pathways for (top) perceiving a heard word and then speak-

results from damage to Broca’s speech area, which lies

ing the same word, and (bottom) perceiving a written word and then

in the prefrontal and premotor facial region of the cere-

speaking the same word. (Redrawn from Geschwind N: Specializa-

tions of the human brain. Sci Am 241:180, 1979. " 1979 by Scientific

bral cortex—about 95 per cent of the time in the left

hemisphere, as shown in Figures 57-5 and 57-8. There-

fore, the skilled motor patterns for control of the larynx,

lips, mouth, respiratory system, and other accessory

muscles of speech are all initiated from this area.

the ability of a person to communicate with others, we

know more about the sensory and motor systems

Articulation. Finally, we have the act of articulation,

related to communication than about any other

which means the muscular movements of the mouth,

segment of brain cortex function. Therefore, we will

tongue, larynx, vocal cords, and so forth that are respon-

review, with the help of anatomical maps of neural path-

sible for the intonations, timing, and rapid changes in

ways in Figure 57-8, function of the cortex in commu-

intensities of the sequential sounds. The facial and laryn-

nication. From this, one will see immediately how the

geal regions of the motor cortex activate these muscles,

principles of sensory analysis and motor control apply

and the cerebellum, basal ganglia, and sensory cortex all

to this art.

help to control the sequences and intensities of muscle

There are two aspects to communication: first, the

contractions, making liberal use of basal ganglial and

sensory aspect (language input), involving the ears and

cerebellar feedback mechanisms described in Chapters

eyes, and, second, the motor aspect (language output),

55 and 56. Destruction of any of these regions can cause

involving vocalization and its control.

either total or partial inability to speak distinctly.

Sensory Aspects of Communication. We noted earlier in the

Summary. Figure 57-8 shows two principal pathways for

chapter that destruction of portions of the auditory or

communication. The upper half of the figure shows the

visual association areas of the cortex can result in inabil-

pathway involved in hearing and speaking. This

ity to understand the spoken word or the written word.

sequence is the following: (1) reception in the primary

722

Unit XI The Nervous System: C. Motor and Integrative Neurophysiology

auditory area of the sound signals that encode the

Thus, one of the functions of the corpus callosum

words; (2) interpretation of the words in Wernicke’s

and the anterior commissure is to make information

area; (3) determination, also in Wernicke’s area, of the

stored in the cortex of one hemisphere available to

thoughts and the words to be spoken; (4) transmission

corresponding cortical areas of the opposite hemi-

of signals from Wernicke’s area to Broca’s area by way

sphere. Important examples of such cooperation

of the arcuate fasciculus; (5) activation of the skilled

between the two hemispheres are the following.

motor programs in Broca’s area for control of word for-

Cutting the corpus callosum blocks transfer

mation; and (6) transmission of appropriate signals into

of information from Wernicke’s area of the

the motor cortex to control the speech muscles.

The lower figure illustrates the comparable steps in

dominant hemisphere to the motor cortex on

reading and then speaking in response. The initial recep-

the opposite side of the brain. Therefore, the

tive area for the words is in the primary visual area

intellectual functions of Wernicke’s area, located

rather than in the primary auditory area. Then the infor-

in the left hemisphere, lose control over the right

mation passes through early stages of interpretation in

motor cortex that initiates voluntary motor

the angular gyrus region and finally reaches its full level

functions of the left hand and arm, even though

of recognition in Wernicke’s area. From here, the

the usual subconscious movements of the left

sequence is the same as for speaking in response to the

hand and arm are normal.

spoken word.

Cutting the corpus callosum prevents transfer of

somatic and visual information from the right

hemisphere into Wernicke’s area in the left

Function of the Corpus

dominant hemisphere. Therefore, somatic and

Callosum and Anterior

visual information from the left side of the body

Commissure to Transfer

frequently fails to reach this general interpretative

Thoughts, Memories, Training,

area of the brain and therefore cannot be used for

decision making.

and Other Information

Finally, people whose corpus callosum is

Between the Two Cerebral

completely sectioned have two entirely separate

Hemispheres

conscious portions of the brain. For example, in a

teenage boy with a sectioned corpus callosum,

Fibers in the corpus callosum provide abundant bi-

only the left half of his brain could understand

directional neural connections between most of the

both the written word and the spoken word

respective cortical areas of the two cerebral hemi-

because the left side was the dominant

spheres except for the anterior portions of the tempo-

hemisphere. Conversely, the right side of the brain

ral lobes; these temporal areas, including especially

could understand the written word but not the

the amygdala, are interconnected by fibers that pass

spoken word. Furthermore, the right cortex could

through the anterior commissure.

elicit a motor action response to the written word

Because of the tremendous number of fibers in the

without the left cortex ever knowing why the

corpus callosum, it was assumed from the beginning

response was performed.

that this massive structure must have some important

The effect was quite different when an emotional

function to correlate activities of the two cerebral

response was evoked in the right side of the brain:

hemispheres. However, when the corpus callosum was

In this case, a subconscious emotional response

destroyed in laboratory animals, it was at first difficult

occurred in the left side of the brain as well. This

to discern deficits in brain function. Therefore, for a

undoubtedly occurred because the areas of the

long time, the function of the corpus callosum was a

two sides of the brain for emotions, the anterior

mystery.

temporal cortices and adjacent areas, were still

Properly designed psychological experiments have

communicating with each other through the

now demonstrated extremely important functions for

anterior commissure that was not sectioned. For

the corpus callosum and anterior commissure. These

instance, when the command “kiss” was written

functions can best be explained by describing one of

for the right half of his brain to see, the boy

the experiments: A monkey is first prepared by cutting

immediately and with full emotion said, “No way!”

the corpus callosum and splitting the optic chiasm lon-

This response required function of Wernicke’s

gitudinally, so that signals from each eye can go only

area and the motor areas for speech in the left

to the cerebral hemisphere on the side of the eye. Then

hemisphere because these left-side areas were

the monkey is taught to recognize different objects

necessary to speak the words “No way!” But when

with its right eye while its left eye is covered. Next,

questioned why he said this, the boy could not

the right eye is covered and the monkey is tested

explain. Thus, the two halves of the brain have

to determine whether its left eye can recognize the

independent capabilities for consciousness, memory

same objects. The answer to this is that the left eye

storage, communication, and control of motor

cannot recognize the objects. However, on repeating

activities. The corpus callosum is required for the

the same experiment in another monkey with the optic

two sides to operate cooperatively at the superficial

chiasm split but the corpus callosum intact, it is found

subconscious level, and the anterior commissure

invariably that recognition in one hemisphere of the

plays an important additional role in unifying the

brain creates recognition in the opposite hemisphere.

emotional responses of the two sides of the brain.

Chapter 57

Cerebral Cortex, Intellectual Functions of the Brain, Learning and Memory

723

Thoughts, Consciousness,

Experiments in lower animals have demonstrated

that memory traces can occur at all levels of the

and Memory

nervous system. Even spinal cord reflexes can change

at least slightly in response to repetitive cord activa-

Our most difficult problem in discussing conscious-

tion, and these reflex changes are part of the memory

ness, thoughts, memory, and learning is that we do not

process. Also, long-term memories result from

know the neural mechanisms of a thought and we

changed synaptic conduction in lower brain centers.

know little about the mechanisms of memory. We

However, most memory that we associate with intel-

know that destruction of large portions of the cerebral

lectual processes is based on memory traces in the

cortex does not prevent a person from having

cerebral cortex.

thoughts, but it does reduce the depth of the thoughts

and also the degree of awareness of the surroundings.

Positive and Negative Memory—“Sensitization” or “Habitua-

Each thought certainly involves simultaneous

tion” of Synaptic Transmission. Although we often think

signals in many portions of the cerebral cortex, thala-

of memories as being positive recollections of previous

mus, limbic system, and reticular formation of the

thoughts or experiences, probably the greater share

brain stem. Some crude thoughts probably depend

of our memories are negative memories, not positive.

almost entirely on lower centers; the thought of pain

That is, our brain is inundated with sensory informa-

is probably a good example because electrical stimu-

tion from all our senses. If our minds attempted

lation of the human cortex seldom elicits anything

to remember all this information, the memory capacity

more than mild pain, whereas stimulation of certain

of the brain would be exceeded within minutes. Fortu-

areas of the hypothalamus, amygdala, and mesen-

nately, the brain has the capability to learn to ignore

cephalon can cause excruciating pain. Conversely, a

information that is of no consequence.This results from

type of thought pattern that does require large

inhibition of the synaptic pathways for this type of

involvement of the cerebral cortex is that of vision,

information; the resulting effect is called habituation.

because loss of the visual cortex causes complete

This is a type of negative memory.

inability to perceive visual form or color.

Conversely, for incoming information that causes

We might formulate a provisional definition of a

important consequences such as pain or pleasure, the

thought in terms of neural activity as follows: A

brain has a different automatic capability of enhanc-

thought results from a “pattern” of stimulation of

ing and storing the memory traces. This is positive

many parts of the nervous system at the same time,

memory. It results from facilitation of the synaptic

probably involving most importantly the cerebral

pathways, and the process is called memory sensitiza-

cortex, thalamus, limbic system, and upper reticular

tion. We will learn later that special areas in the basal

formation of the brain stem. This is called the holistic

limbic regions of the brain determine whether infor-

theory of thoughts. The stimulated areas of the limbic

mation is important or unimportant and make the sub-

system, thalamus, and reticular formation are believed

conscious decision whether to store the thought as a

to determine the general nature of the thought, giving

sensitized memory trace or to suppress it.

it such qualities as pleasure, displeasure, pain, comfort,

crude modalities of sensation, localization to gross

Classification of Memories. We know that some memo-

areas of the body, and other general characteristics.

ries last for only a few seconds, whereas others last for

However, specific stimulated areas of the cerebral

hours, days, months, or years. For the purpose of dis-

cortex determine discrete characteristics of the

cussing these, let us use a common classification of

thought, such as (1) specific localization of sensations

memories that divides memories into (1) short-term

on the surface of the body and of objects in the fields

memory, which includes memories that last for

of vision, (2) the feeling of the texture of silk, (3) visual

seconds or at most minutes unless they are converted

recognition of the rectangular pattern of a concrete

into longer-term memories; (2) intermediate long-term

block wall, and (4) other individual characteristics that

memories, which last for days to weeks but then fade

enter into one’s overall awareness of a particular

away; and (3) long-term memory, which, once stored,

instant. Consciousness can perhaps be described as our

can be recalled up to years or even a lifetime later.

continuing stream of awareness of either our sur-

In addition to this general classification of memo-

roundings or our sequential thoughts.

ries, we also discussed earlier (in connection with the

prefrontal lobes) another type of memory, called

“working memory,” that includes mainly short-term

Memory—Roles of Synaptic

memory that is used during the course of intellectual

Facilitation and Synaptic Inhibition

reasoning but is terminated as each stage of the

problem is resolved.

Physiologically, memories are stored in the brain by

Memories are frequently classified according to the

changing the basic sensitivity of synaptic transmission

type of information that is stored. One of these classi-

between neurons as a result of previous neural activ-

fications divides memory into declarative memory and

ity. The new or facilitated pathways are called memory

skill memory, as follows:

traces. They are important because once the traces are

1. Declarative memory basically means memory of

established, they can be selectively activated by the

the various details of an integrated thought, such

thinking mind to reproduce the memories.

as memory of an important experience that

724

Unit XI The Nervous System: C. Motor and Integrative Neurophysiology

includes (1) memory of the surroundings, (2)

Noxious

memory of time relationships, (3) memory of

stimulus

causes of the experience, (4) memory of the

Facilitator

meaning of the experience, and (5) memory of

terminal

one’s deductions that were left in the person’s

Serotonin

mind.

Sensory

2. Skill memory is frequently associated with motor

stimulus

activities of the person’s body, such as all the skills

developed for hitting a tennis ball, including

cAMP

Sensory

automatic memories to (1) sight the ball, (2)

terminal

calculate the relationship and speed of the ball to

the racquet, and (3) deduce rapidly the motions of

Calcium

the body, the arms, and the racquet required to hit

channels

ions

the ball as desired—all of these activated instantly

based on previous learning of the game of

Figure 57-9

tennis—then moving on to the next stroke of the

Memory system that has been discovered in the snail Aplysia.

game while forgetting the details of the previous

stroke.

memories lasting from a few minutes up to 3 weeks in

the large snail Aplysia. In this figure, there are two

Short-Term Memory

synaptic terminals. One terminal is from a sensory

input neuron and terminates directly on the surface of

Short-term memory is typified by one’s memory of 7

the neuron that is to be stimulated; this is called the

to 10 numerals in a telephone number (or 7 to 10 other

sensory terminal. The other terminal is a presynaptic

discrete facts) for a few seconds to a few minutes at a

ending that lies on the surface of the sensory terminal,

time but lasting only as long as the person continues

and it is called the facilitator terminal. When the

to think about the numbers or facts.

sensory terminal is stimulated repeatedly but without

Many physiologists have suggested that this short-

stimulation of the facilitator terminal, signal transmis-

term memory is caused by continual neural activity

sion at first is great, but it becomes less and less intense

resulting from nerve signals that travel around and

with repeated stimulation until transmission almost

around a temporary memory trace in a circuit of rever-

ceases. This phenomenon is habituation, as was

berating neurons. It has not yet been possible to prove

explained previously. It is a type of negative memory

this theory. Another possible explanation of short-

that causes the neuronal circuit to lose its response to

term memory is presynaptic facilitation or inhibition.

repeated events that are insignificant.

This occurs at synapses that lie on terminal nerve

Conversely, if a noxious stimulus excites the facili-

fibrils immediately before these fibrils synapse with a

tator terminal at the same time that the sensory ter-

subsequent neuron. The neurotransmitter chemicals

minal is stimulated, then instead of the transmitted

secreted at such terminals frequently cause facilitation

signal into the postsynaptic neuron becoming pro-

or inhibition lasting for seconds up to several minutes.

gressively weaker, the ease of transmission becomes

Circuits of this type could lead to short-term memory.

stronger and stronger; and it will remain strong for

minutes, hours, days, or, with more intense training, up

to about 3 weeks even without further stimulation of

Intermediate Long-Term Memory

the facilitator terminal. Thus, the noxious stimulus

causes the memory pathway through the sensory

Intermediate long-term memories may last for many

terminal to become facilitated for days or weeks

minutes or even weeks. They will eventually be lost

thereafter. It is especially interesting that even after

unless the memory traces are activated enough to

habituation has occurred, this pathway can be con-

become more permanent; then they are classified as

verted back to a facilitated pathway with only a few

long-term memories. Experiments in primitive animals

noxious stimuli.

have demonstrated that memories of the intermediate

long-term type can result from temporary chemical or

Molecular Mechanism of Intermediate Memory

physical changes, or both, in either the synapse presy-

Mechanism for Habituation. At the molecular level,

naptic terminals or the synapse postsynaptic mem-

the habituation effect in the sensory terminal results

brane, changes that can persist for a few minutes up to

from progressive closure of calcium channels through

several weeks. These mechanisms are so important

the terminal membrane, though the cause of this

that they deserve special description.

calcium channel closure is not fully known. Neverthe-

less, much smaller than normal amounts of calcium

Memory Based on Chemical Changes in

ions can diffuse into the habituated terminal, and

the Presynaptic Terminal or Postsynaptic

much less sensory terminal transmitter is therefore

Neuronal Membrane

released because calcium entry is the principal stim-

Figure 57-9 shows a mechanism of memory studied

ulus for transmitter release

(as was discussed in

especially by Kandel and his colleagues that can cause

Chapter 45).

Chapter 57

Cerebral Cortex, Intellectual Functions of the Brain, Learning and Memory

725

Mechanism for Facilitation. In the case of facilitation,

Structural Changes Occur in Synapses During

at least part of the molecular mechanism is believed

the Development of Long-Term Memory

to be the following:

Electron microscopic pictures taken from invertebrate

Stimulation of the facilitator presynaptic terminal

animals have demonstrated multiple physical struc-

at the same time that the sensory terminal is

tural changes in many synapses during development of

stimulated causes serotonin release at the

long-term memory traces. The structural changes will

facilitator synapse on the surface of the sensory

not occur if a drug is given that blocks DNA stimula-

terminal.

tion of protein replication in the presynaptic neuron;

The serotonin acts on serotonin receptors in the

nor will the permanent memory trace develop. There-

sensory terminal membrane, and these receptors

fore, it appears that development of true long-term

activate the enzyme adenyl cyclase inside the

memory depends on physically restructuring the

membrane. And, finally, the adenyl cyclase causes

synapses themselves in a way that changes their sensi-

formation of cyclic adenosine monophosphate

tivity for transmitting nervous signals.

(cAMP) also inside the sensory presynaptic

The most important of the physical structural

terminal.

changes that occur are the following:

The cyclic AMP activates a protein kinase that

1. Increase in vesicle release sites for secretion of

causes phosphorylation of a protein that itself is

transmitter substance.

part of the potassium channels in the sensory

2. Increase in number of transmitter vesicles

synaptic terminal membrane; this in turn blocks

released.

the channels for potassium conductance. The

3. Increase in number of presynaptic terminals.

blockage can last for minutes up to several

4. Changes in structures of the dendritic spines that

weeks.

permit transmission of stronger signals.

Lack of potassium conductance causes a greatly

Thus, in several different ways, the structural capa-

prolonged action potential in the synaptic

bility of synapses to transmit signals appears to

terminal because flow of potassium ions out of the

increase during establishment of true long-term

terminal is necessary for rapid recovery from the

memory traces.

action potential.

Number of Neurons and Their Connectivities

The prolonged action potential causes prolonged

Often Change Significantly During Learning

activation of the calcium channels, allowing

During the first few weeks, months, and perhaps even

tremendous quantities of calcium ions to enter the

year or so of life, many parts of the brain produce a

sensory synaptic terminal. These calcium ions

great excess of neurons, and the neurons send out

cause greatly increased transmitter release by the

numerous axon branches to make connections with

synapse, thereby markedly facilitating synaptic

other neurons. If the new axons fail to connect with

transmission to the subsequent neuron.

appropriate subsequent neurons, muscle cells, or gland

Thus, in a very indirect way, the associative effect of

cells, the new axons themselves will dissolute within a

stimulating the facilitator terminal at the same time

few weeks. Thus, the number of neuronal connections

that the sensory terminal is stimulated causes pro-

is determined by specific nerve growth factors released

longed increase in excitatory sensitivity of the sensory

retrogradely from the stimulated cells. Furthermore,

terminal, and this establishes the memory trace. Studies

when insufficient connectivity occurs, the entire

by Byrne and colleagues, also in the snail Aplysia, have

neuron that is sending out the axon branches might

suggested still another mechanism of synaptic memory.

eventually disappear.

Their studies have shown that stimuli from separate

Therefore, soon after birth, there is a principle of

sources acting on a single neuron, under appropriate

“use it or lose it” that governs the final number of

conditions, can cause long-term changes in membrane

neurons and their connectivities in respective parts of

properties of the post-synaptic neuron instead of in the

the human nervous system. This is a type of learning.

presynaptic neuronal membrane, but leading to essen-

For example, if one eye of a newborn animal is covered

tially the same memory effects.

for many weeks after birth, neurons in alternate stripes

of the cerebral visual cortex—neurons normally con-

nected to the covered eye—will degenerate, and the

Long-Term Memory

covered eye will remain either partially or totally blind

for the remainder of life. Until recently, it was believed

There is no obvious demarcation between the more

that very little “learning” is achieved in adult human

prolonged types of intermediate long-term memory

beings and animals by modification of numbers of

and true long-term memory. The distinction is one of

neurons in the memory circuits; however, recent

degree. However, long-term memory is generally

research suggests that even adults use this mechanism

believed to result from actual structural changes,

to at least some extent.

instead of only chemical changes, at the synapses, and

these enhance or suppress signal conduction. Again,

let us recall experiments in primitive animals (where

Consolidation of Memory

the nervous systems are much easier to study) that

have aided immensely in understanding possible

For short-term memory to be converted into long-term

mechanisms of long-term memory.

memory that can be recalled weeks or years later, it

726

Unit XI The Nervous System: C. Motor and Integrative Neurophysiology

must become “consolidated.” That is, the short-term

removed for the treatment of epilepsy in a few

memory if activated repeatedly will initiate chemical,

patients. This procedure does not seriously affect the

physical, and anatomical changes in the synapses that

person’s memory for information stored in the brain

are responsible for the long-term type of memory. This

before removal of the hippocampi. However, after

process requires 5 to 10 minutes for minimal consoli-

removal, these people have virtually no capability

dation and 1 hour or more for strong consolidation.

thereafter for storing verbal and symbolic types of

For instance, if a strong sensory impression is made on

memories (declarative types of memory) in long-term

the brain but is then followed within a minute or so by

memory, or even in intermediate memory lasting

an electrically induced brain convulsion, the sensory

longer than a few minutes. Therefore, these people are

experience will not be remembered. Likewise, brain

unable to establish new long-term memories of those

concussion, sudden application of deep general

types of information that are the basis of intelligence.

anesthesia, or any other effect that temporarily

This is called anterograde amnesia.

blocks the dynamic function of the brain can prevent

But why are the hippocampi so important in helping

consolidation.

the brain to store new memories? The probable

Consolidation and the time required for it to occur

answer is that the hippocampi are among the most

can probably be explained by the phenomenon of

important output pathways from the “reward” and

rehearsal of the short-term memory as follows.

“punishment” areas of the limbic system, as explained

in Chapter 58. Sensory stimuli or thoughts that cause

Rehearsal Enhances the Transference of Short-Term Memory

pain or aversion excite the limbic punishment centers,

into Long-Term Memory. Psychological studies have

and stimuli that cause pleasure, happiness, or sense of

shown that rehearsal of the same information again

reward excite the limbic reward centers. All these

and again in the mind accelerates and potentiates the

together provide the background mood and motiva-

degree of transfer of short-term memory into long-

tions of the person. Among these motivations is the

term memory and therefore accelerates and enhances

drive in the brain to remember those experiences and

consolidation. The brain has a natural tendency to

thoughts that are either pleasant or unpleasant. The

rehearse newfound information, especially newfound

hippocampi especially and to a lesser degree the dorsal

information that catches the mind’s attention. There-

medial nuclei of the thalamus, another limbic struc-

fore, over a period of time, the important features of

ture, have proved especially important in making the

sensory experiences become progressively more and

decision about which of our thoughts are important

more fixed in the memory stores. This explains why a

enough on a basis of reward or punishment to be

person can remember small amounts of information

worthy of memory.

studied in depth far better than large amounts of infor-

mation studied only superficially. It also explains why

Retrograde Amnesia—Inability to Recall Memories from the

a person who is wide awake can consolidate memories

Past. When retrograde amnesia occurs, the degree of

far better than a person who is in a state of mental

amnesia for recent events is likely to be much greater

fatigue.

than for events of the distant past. The reason for this

difference is probably that the distant memories have

New Memories Are Codified During Consolidation. One of the

been rehearsed so many times that the memory traces

most important features of consolidation is that new

are deeply engrained, and elements of these memories

memories are codified into different classes of infor-

are stored in widespread areas of the brain.

mation. During this process, similar types of informa-

In some people who have hippocampal lesions,

tion are pulled from the memory storage bins and used

some degree of retrograde amnesia occurs along with

to help process the new information. The new and old

anterograde amnesia, which suggests that these two

are compared for similarities and differences, and part

types of amnesia are at least partially related and

of the storage process is to store the information about

that hippocampal lesions can cause both. However,

these similarities and differences, rather than to store

damage in some thalamic areas may lead specifically

the new information unprocessed. Thus, during con-

to retrograde amnesia without causing significant

solidation, the new memories are not stored randomly

anterograde amnesia. A possible explanation of this is

in the brain but are stored in direct association with

that the thalamus may play a role in helping the person

other memories of the same type. This is necessary if

“search” the memory storehouses and thus “read out”

one is to be able to “search” the memory store at a

the memories. That is, the memory process not only

later date to find the required information.

requires the storing of memories but also an ability to

search and find the memory at a later date. The possi-

Role of Specific Parts of the Brain in the

ble function of the thalamus in this process is discussed

Memory Process

further in Chapter 58.

Hippocampus Promotes Storage of Memories—Anterograde

Hippocampi Are Not Important in Reflexive Learning. People

Amnesia After Hippocampal Lesions. The hippocampus is

with hippocampal lesions usually do not have difficulty

the most medial portion of the temporal lobe cortex,

in learning physical skills that do not involve verbal-

where it folds first medially underneath the brain and

ization or symbolic types of intelligence. For instance,

then upward into the lower, inside surface of the

these people can still learn the rapid hand and

lateral ventricle. The two hippocampi have been

physical skills required in many types of sports. This

Chapter 57

Cerebral Cortex, Intellectual Functions of the Brain, Learning and Memory

727

type of learning is called skill learning or reflexive

Hamann S, Canli T: Individual differences in emotion pro-

learning; it depends on physically repeating the

cessing. Curr Opin Neurobiol 14:233, 2004.

required tasks over and over again, rather than on

Kandel ER: The molecular biology of memory storage: a

dialogue between genes and synapses. Science 294:1030,

symbolical rehearsing in the mind.

2001.

Kandel ER, Schwartz JH, Jessell TM: Principles of Neural

Science, 4th ed. New York: McGraw-Hill, 2000.

References

LeDoux JE: Emotion, memory and the brain: the neural

routes underlying the formation of memories about prim-

Baddeley A: Working memory: looking back and looking

itive emotional experiences, such as fear, have been

forward. Nat Rev Neurosci 4:829, 2003.

traced. Sci Am June: 50, 1994.

Blank T, Nijholt I, Spiess J: Molecular determinants mediat-

Leuner B, Shors TJ: New spines, new memories. Mol Neuro-

ing effects of acute stress on hippocampus-dependent

biol 29:117, 2004.

synaptic plasticity and learning. Mol Neurobiol 29:131,

Lynch MA: Long-term potentiation and memory. Physiol

2004.

Rev 84:87, 2004.

Bookheimer S: Functional MRI of language: new

Miller BL, Cummings JL: The Human Frontal Lobes. New

approaches to understanding the cortical organization of

York: Guilford Press, 1998.

semantic processing. Annu Rev Neurosci 25:151, 2002.

Nakazawa K, McHugh TJ, Wilson MA, Tonegawa S: NMDA

Conlon R, Hobson JA: Understanding the Human Mind.

receptors, place cells and hippocampal spatial memory.

New York: John Wiley, 1999.

Nat Rev Neurosci 5:361, 2004.

Dash PK, Hebert AE, Runyan JD: A unified theory for

Phelps EA: Human emotion and memory: interactions of the

systems and cellular memory consolidation. Brain Res

amygdala and hippocampal complex. Curr Opin Neuro-

Brain Res Rev 45:30, 2004.

biol 14:198, 2004.

Dick P, Katsuyuki S: The prefrontal cortex and working

Sah P, Faber ES, Lopez De Armentia M, Power J: The amyg-

memory: physiology and brain imaging. Curr Opin Neu-

daloid complex: anatomy and physiology. Physiol Rev

robiol 14:163, 2004.

83:803, 2003.

Dudai Y: The neurobiology of consolidations, or, how stable

Shors TJ: Memory traces of trace memories: neurogenesis,

is the engram? Annu Rev Psychol 55:51, 2004.

synaptogenesis and awareness. Trends Neurosci 27:250,

Ehrlich YM: Molecular and Cellular Mechanisms of Neu-

2004.

ronal Plasticity. New York: Plenum Press, 1998.

Wixted JT: The psychology and neuroscience of forgetting.

Guillery RW: Branching thalamic afferents link action and

Annu Rev Psychol 55:235, 2004.

perception. J Neurophysiol 90:539, 2003.

Haines DE: Fundamental Neuroscience. New York:

Churchill Livingstone, 1997.

C H A P T E R

Behavioral and Motivational

Mechanisms of the Brain—The

Limbic System and the

Hypothalamus

Control of behavior is a function of the entire

nervous system. Even the wakefulness and sleep

cycle discussed in Chapter 59 is one of our most

important behavioral patterns.

In this chapter, we deal first with those mecha-

nisms that control levels of activity in the different

parts of the brain. Then we discuss the causes of

motivational drives, especially motivational control

of the learning process and feelings of pleasure and punishment. These func-

tions of the nervous system are performed mainly by the basal regions of the

brain, which together are loosely called the limbic system, meaning the “border”

system.

Activating-Driving Systems of the Brain

Without continuous transmission of nerve signals from the lower brain into the

cerebrum, the cerebrum becomes useless. In fact, severe compression of the

brain stem at the juncture between the mesencephalon and cerebrum, as some-

times results from a pineal tumor, often causes the person to go into unremit-

ting coma lasting for the remainder of his or her life.

Nerve signals in the brain stem activate the cerebral part of the brain in two

ways: (1) by directly stimulating a background level of neuronal activity in wide

areas of the brain and (2) by activating neurohormonal systems that release

specific facilitory or inhibitory hormone-like neurotransmitter substances into

selected areas of the brain.

Control of Cerebral Activity by Continuous Excitatory

Signals from the Brain Stem

Reticular Excitatory Area of the Brain Stem

Figure 58-1 shows a general system for controlling the level of activity of the

brain. The central driving component of this system is an excitatory area located

in the reticular substance of the pons and mesencephalon. This area is also known

by the name bulboreticular facilitory area. We also discuss this area in Chapter

55 because it is the same brain stem reticular area that transmits facilitory

signals downward to the spinal cord to maintain tone in the antigravity muscles

and to control levels of activity of the spinal cord reflexes. In addition to these

downward signals, this area also sends a profusion of signals in the upward direc-

tion. Most of these go first to the thalamus, where they excite a different set of

neurons that transmit nerve signals to all regions of the cerebral cortex as well

as to multiple subcortical areas.

The signals passing through the thalamus are of two types. One type is rapidly

transmitted action potentials that excite the cerebrum for only a few millisec-

onds. These originate from large neuronal cell bodies that lie throughout the

728

Chapter 58

Behavioral and Motivational Mechanisms of the Brain—The Limbic System and the Hypothalamus

729

Thalamus

nerves enter the pons. These nerves are the highest

nerves entering the brain that transmit significant

numbers of somatosensory signals into the brain.

When all these input sensory signals are gone, the level

of activity in the brain excitatory area diminishes

abruptly, and the brain proceeds instantly to a state

of greatly reduced activity, approaching a permanent

state of coma. But when the brain stem is transected

below the fifth nerves, which leaves much input of

sensory signals from the facial and oral regions, the

coma is averted.

Increased Activity of the Excitatory Area Caused by Feedback

Signals Returning from the Cerebral Cortex. Not only do

excitatory signals pass to the cerebral cortex from

Excitatory area

the bulboreticular excitatory area of the brain stem,

but feedback signals also return from the cerebral

5th Cranial nerve

cortex back to this same area. Therefore, any time

the cerebral cortex becomes activated by either

brain thought processes or motor processes, signals

Inhibitory area

are sent from the cortex to the brain stem excitatory

area, which in turn sends still more excitatory signals

to the cortex. This helps to maintain the level of

excitation of the cerebral cortex or even to enhance it.

This is a general mechanism of positive feedback that

allows any beginning activity in the cerebral cortex to

support still more activity, thus leading to an “awake”

Figure 58-1

mind.

Excitatory-activating

system

of the brain. Also shown is

Thalamus Is a Distribution Center That Controls Activity in Spe-

inhibitory area in the medulla that can inhibit or depress the acti-

vating system.

cific Regions of the Cortex. As pointed out in Chapter 57

and shown in Figure 57-2, almost every area of the

cerebral cortex connects with its own highly specific

brain stem reticular area. Their nerve endings release

area in the thalamus. Therefore, electrical stimulation

the neurotransmitter substance acetylcholine, which

of a specific point in the thalamus generally activates

serves as an excitatory agent, lasting for only a few mil-

its own specific small region of the cortex. Further-

liseconds before it is destroyed.

more, signals regularly reverberate back and forth

The second type of excitatory signal originates from

between the thalamus and the cerebral cortex, the

large numbers of small neurons spread throughout the

thalamus exciting the cortex and the cortex then re-

brain stem reticular excitatory area. Again, most of

exciting the thalamus by way of return fibers. It has

these pass to the thalamus, but this time through small,

been suggested that the thinking process establishes

slowly conducting fibers that synapse mainly in the

long-term memories by activating such back-and-forth

intralaminar nuclei of the thalamus and in the reticu-

reverberation of signals.

lar nuclei over the surface of the thalamus. From here,

Can the thalamus also function to call forth specific

additional small fibers are distributed everywhere in

memories from the cortex or to activate specific

the cerebral cortex. The excitatory effect caused by

thought processes? Proof of this is still lacking, but the

this system of fibers can build up progressively for

thalamus does have appropriate neuronal circuitry for

many seconds to a minute or more, which suggests that

these purposes.

its signals are especially important for controlling

longer-term background excitability level of the brain.

A Reticular Inhibitory Area Located in the

Lower Brain Stem

Excitation of the Excitatory Area by Peripheral Sensory Signals.

Figure 58-1 shows still another area that is important

The level of activity of the excitatory area in the brain

in controlling brain activity. This is the reticular

stem, and therefore the level of activity of the entire

inhibitory area, located medially and ventrally in the

brain, is determined to a great extent by the number

medulla. In Chapter 55, we learned that this area can

and type of sensory signals that enter the brain from

inhibit the reticular facilitory area of the upper brain

the periphery. Pain signals in particular increase activ-

stem and thereby decrease activity in the superior por-

ity in this excitatory area and therefore strongly excite

tions of the brain as well. One of the mechanisms for

the brain to attention.

this is to excite serotonergic neurons; these in turn

The importance of sensory signals in activating the

secrete the inhibitory neurohormone serotonin at

excitatory area is demonstrated by the effect of cutting

crucial points in the brain; we will discuss this in more

the brain stem above the point where the fifth cerebral

detail later.

730

Unit XI The Nervous System: C. Motor and Integrative Neurophysiology

Neurohormonal Control of

as an excitatory hormone, whereas serotonin usually is

inhibitory, and dopamine is excitatory in some areas

Brain Activity

but inhibitory in others. As would be expected, these

three systems have different effects on levels of

Aside from direct control of brain activity by specific

excitability in different parts of the brain. The norepi-

transmission of nerve signals from the lower brain

nephrine system spreads to virtually every area of the

areas to the cortical regions of the brain, still another

brain, whereas the serotonin and dopamine systems

physiologic mechanism is very often used to control

are directed much more to specific brain regions—

brain activity. This is to secrete excitatory or inhibitory

the dopamine system mainly into the basal ganglial

neurotransmitter hormonal agents into the substance

regions and the serotonin system more into the

of the brain. These neurohormones often persist for

midline structures.

minutes or hours and thereby provide long periods of

control, rather than just instantaneous activation or

Neurohormonal Systems in the Human Brain. Figure 58-3

inhibition.

shows the brain stem areas in the human brain for acti-

Figure 58-2 shows three neurohormonal systems

vating four neurohormonal systems, the same three

that have been mapped in detail in the rat brain: (1) a

discussed for the rat and one other, the acetylcholine

norepinephrine system, (2) a dopamine system, and (3)

system. Some of the specific functions of these are as

a serotonin system. Norepinephrine usually functions

follows:

1. The locus ceruleus and the norepinephrine system.

The locus ceruleus is a small area located

Cerebellum

bilaterally and posteriorly at the juncture between

the pons and mesencephalon. Nerve fibers

from this area spread throughout the brain, the

same as shown for the rat in the top frame of

Figure 58-2, and they secrete norepinephrine. The

norepinephrine generally excites the brain to

increased activity. However, it has inhibitory

effects in a few brain areas because of inhibitory

Brain stem

receptors at certain neuronal synapses. In Chapter

Olfactory

59, we will see that this system probably plays an

region

Basal brain areas

important role in causing dreaming, thus leading

Locus cerulus

to a type of sleep called rapid eye movement

NOREPINEPHRINE

sleep (REM sleep).

2. The substantia nigra and the dopamine system.

The substantia nigra is discussed in Chapter 56 in

Frontal

cortex

Cingulate

cortex

Caudate nucleus

To diencephalon

and cerebrum

DOPAMINE

Mesencephalon

Substantia nigra

(dopamine)

To cerebellum

Gigantocellular

neurons of

reticular formation

Pons

(acetylcholine)

Locus ceruleus

(norepinephrine)

Medulla

Nuclei of the raphe

(serotonin)

Midline nuclei

SEROTONIN

To cord

Figure 58-2

Figure 58-3

Three neurohormonal systems that have been mapped in the rat

brain: a norepinephrine system, a dopamine system, and a sero-

Multiple centers in the brain stem, the neurons of which secrete

tonin system. (Adapted from Kelly, after Cooper, Bloom, and Roth,

different transmitter substances (specified in parentheses). These

in Kandel ER, Schwartz JH: Principles of Neural Science, 2nd ed.

neurons send control signals upward into the diencephalon and

New York: Elsevier, 1985.)

cerebrum and downward into the spinal cord.

Chapter 58

Behavioral and Motivational Mechanisms of the Brain—The Limbic System and the Hypothalamus

731

relation to the basal ganglia. It lies anteriorly in

limbic system, the term limbic system has been

the superior mesencephalon, and its neurons send

expanded to mean the entire neuronal circuitry that

nerve endings mainly to the caudate nucleus and

controls emotional behavior and motivational drives.

putamen of the cerebrum, where they secrete

A major part of the limbic system is the hypothala-

dopamine. Other neurons located in adjacent

mus, with its related structures. In addition to their

regions also secrete dopamine, but they send their

roles in behavioral control, these areas control many

endings into more ventral areas of the brain,

internal conditions of the body, such as body temper-

especially to the hypothalamus and the limbic

ature, osmolality of the body fluids, and the drives to

system. The dopamine is believed to act as an

eat and drink and to control body weight. These inter-

inhibitory transmitter in the basal ganglia, but

nal functions are collectively called vegetative func-

in some other areas of the brain it is possibly

tions of the brain, and their control is closely related

excitatory. Also, remember from Chapter 56 that

to behavior.

destruction of the dopaminergic neurons in the

substantia nigra is the basic cause of Parkinson’s

Functional Anatomy of the

disease.

Limbic System; Key Position

The raphe nuclei and the serotonin system. In

the midline of the pons and medulla are several

of the Hypothalamus

thin nuclei called the raphe nuclei. Many of the

neurons in these nuclei secrete serotonin. They

Figure 58-4 shows the anatomical structures of the

send fibers into the diencephalon and a few fibers

limbic system, demonstrating that they are an inter-

to the cerebral cortex; still other fibers descend to

connected complex of basal brain elements. Located

the spinal cord. The serotonin secreted at the cord

in the middle of all these is the extremely small hypo-

fiber endings has the ability to suppress pain,

thalamus, which from a physiologic point of view is one

which was discussed in Chapter 48. The serotonin

of the central elements of the limbic system. Figure

released in the diencephalon and cerebrum almost

58-5 illustrates schematically this key position of the

certainly plays an essential inhibitory role to help

hypothalamus in the limbic system and shows sur-

cause normal sleep, as we discuss in Chapter 59.

rounding it other subcortical structures of the limbic

The gigantocellular neurons of the reticular

system, including the septum, the paraolfactory area,

excitatory area and the acetylcholine system.

the anterior nucleus of the thalamus, portions of the

Earlier we discussed the gigantocellular neurons

basal ganglia, the hippocampus, and the amygdala.

(the giant cells) in the reticular excitatory area of

And surrounding the subcortical limbic areas is the

the pons and mesencephalon. The fibers from

limbic cortex, composed of a ring of cerebral cortex in

these large cells divide immediately into two

each side of the brain (1) beginning in the orbitofrontal

branches, one passing upward to the higher levels

area on the ventral surface of the frontal lobes, (2)

of the brain and the other passing downward

extending upward into the subcallosal gyrus, (3) then

through the reticulospinal tracts into the spinal

over the top of the corpus callosum onto the medial

cord. The neurohormone secreted at their

aspect of the cerebral hemisphere in the cingulate

terminals is acetylcholine. In most places,

gyrus, and finally (4) passing behind the corpus callo-

the acetylcholine functions as an excitatory

sum and downward onto the ventromedial surface of

neurotransmitter. Activation of these

the temporal lobe to the parahippocampal gyrus and

acetylcholine neurons leads to an acutely awake

uncus.

and excited nervous system.

Thus, on the medial and ventral surfaces of each

cerebral hemisphere is a ring of mostly paleocortex

Other Neurotransmitters and Neurohormonal Substances

that surrounds a group of deep structures intimately

Secreted in the Brain. Without describing their function,

associated with overall behavior and emotions. In turn,

the following is a list of still other neurohormonal

this ring of limbic cortex functions as a two-way com-

substances that function either at specific synapses or

munication and association linkage between the neo-

by release into the fluids of the brain: enkephalins,

cortex and the lower limbic structures.

gamma-aminobutyric acid, glutamate, vasopressin,

Many of the behavioral functions elicited from the

adrenocorticotropic hormone, epinephrine, histamine,

hypothalamus and other limbic structures are also

endorphins, angiotensin II, and neurotensin. Thus,

mediated through the reticular nuclei in the brain stem

there are multiple neurohormonal systems in the

and their associated nuclei. It was pointed out in

brain, the activation of each of which plays its own role

Chapter 55 as well as earlier in this chapter that stim-

in controlling a different quality of brain function.

ulation of the excitatory portion of this reticular for-

mation can cause high degrees of cerebral excitability

while also increasing the excitability of much of the

Limbic System

spinal cord synapses. In Chapter 60, we will see that

most of the hypothalamic signals for controlling the

The word “limbic” means “border.” Originally, the

autonomic nervous system are also transmitted

term “limbic” was used to describe the border struc-

through synaptic nuclei located in the brain stem.

tures around the basal regions of the cerebrum, but as

An important route of communication between

we have learned more about the functions of the

the limbic system and the brain stem is the medial

732

Unit XI The Nervous System: C. Motor and Integrative Neurophysiology

Cingulate gyrus and cingulum

Stria medullaris

thalami

Indusium griseum

Body of fornix

and longitudinal striae

Dorsal fornix

Septum pellucidum

(supracommissural septum)

Anterior nuclear

Mamillothalamic

group of thalamus

tract

Anterior commissure

Mamillotegmental

tract

Subcallosal gyrus

Isthmus

Paraterminal gyrus

(precommissural

septum)

Gyrus

fasciolaris

Orbitofrontal cortex

Fimbria

Prehippocampal rudiment

of fornix

Paraolfactory area

Stria terminalis

Olfactory bulb

Connecting spinal cord

HYPOTHALAMUS

Column of fornix

Hippocampus

(postcommissural fornix)

Dentate gyrus

Uncus

Amygdaloid body

Parahippocampal gyrus

Mamillary body

Figure 58-4

Anatomy of the limbic system, shown in the dark pink area. (Redrawn from Warwick R, Williams PL: Gray’s Anatomy, 35th Br. ed. London:

Longman Group Ltd, 1973.)

short pathways among the reticular formation of the

brain stem, thalamus, hypothalamus, and most other

Cingulate gyrus

contiguous areas of the basal brain.

Portions

Subcallosal

Hypothalamus, a Major

Septum

of basal

nuclei of

gyrus

area

Control Headquarters for the

ganglia

thalamus

Limbic System

Paraolfactory

Hypothalamus

Orbitofrontal

area

cortex

The hypothalamus, despite its very small size of only a

Hippocampus

few cubic centimeters, has two-way communicating

Uncus

Amygdala

pathways with all levels of the limbic system. In turn,

it and its closely allied structures send output signals

in three directions: (1) backward and downward to the

Parahippocampal gyrus

brain stem, mainly into the reticular areas of the mes-

encephalon, pons, and medulla and from these areas

into the peripheral nerves of the autonomic nervous

Figure 58-5

system; (2) upward toward many higher areas of the

diencephalon and cerebrum, especially to the anterior

Limbic system, showing the key position of the hypothalamus.

thalamus and limbic portions of the cerebral cortex;

and (3) into the hypothalamic infundibulum to control

or partially control most of the secretory functions of

forebrain bundle, which extends from the septal and

both the posterior and the anterior pituitary glands.

orbitofrontal regions of the cerebral cortex downward

Thus, the hypothalamus, which represents less than

through the middle of the hypothalamus to the brain

1 per cent of the brain mass, is one of the most impor-

stem reticular formation. This bundle carries fibers in

tant of the control pathways of the limbic system. It

both directions, forming a trunk line communication

controls most of the vegetative and endocrine func-

system. A second route of communication is through

tions of the body as well as many aspects of emotional

Chapter 58

Behavioral and Motivational Mechanisms of the Brain—The Limbic System and the Hypothalamus

733

POSTERIOR

Dorsomedial nucleus

Paraventricular nucleus

(GI stimulation)

(Oxytocin release)

(Water conservation)

Medial preoptic area

Posterior hypothalamus

(Bladder contraction)

(Increased blood pressure)

HYPOTHALAMUS

(Decreased heart rate)

(Pupillary dilation)

(Decreased blood pressure)

(Shivering)

Perifornical nucleus

Posterior preoptic and

(Hunger)

anterior hypothalamic areas

(Increased blood pressure)

(Body temperature regulation)

(Rage)

(Panting)

(Sweating)

Ventromedial nucleus

(Thyrotropin inhibition)

(Satiety)

(Neuroendocrine control)

Optic chiasm (Optic nerve)

Supraoptic nucleus

Mamillary body

(Vasopressin release)

(Feeding reflexes)

Arcuate nucleus and periventricular zone

Infundibulum

Figure 58-6

(Neuroendocrine control)

Control centers of the hypothala-

Lateral hypothalamic area (not shown)

mus (sagittal view).

(Thirst and hunger)

behavior. Let us discuss first the vegetative and

endocrine control functions and then return to the

Thalamus

behavioral functions of the hypothalamus to see how

Paraventricular

these operate together.

Periventricular

Dorsomedial

Fornix

Vegetative and Endocrine Control

hypothalamic

Lateral

Functions of the Hypothalamus

hypothalamic

Optic

tract

Supraoptic

The different hypothalamic mechanisms for control-

ling multiple functions of the body are so important

that they are discussed in multiple chapters through-

Arcuate

Ventromedial

out this text. For instance, the role of the hypothala-

mus to help regulate arterial pressure is discussed in

Figure 58-7

Chapter 18, thirst and water conservation in Chapter

29, temperature regulation in Chapter

73, and

Coronal view of the hypothalamus, showing the mediolateral posi-

endocrine control in Chapter 75. To illustrate the

tions of the respective hypothalamic nuclei.

organization of the hypothalamus as a functional unit,

let us summarize the more important of its vegetative

activation of fiber tracts leading from or to control

and endocrine functions here as well.

nuclei located elsewhere. With this caution in mind, we

Figures 58-6 and 58-7 show enlarged sagittal and

can give the following general description of the veg-

coronal views of the hypothalamus, which represents

etative and control functions of the hypothalamus.

only a small area in Figure 58-4. Take a few minutes

to study these diagrams, especially to see in Figure

Cardiovascular Regulation. Stimulation of different areas

58-6 the multiple activities that are excited or inhib-

throughout the hypothalamus can cause every known

ited when respective hypothalamic nuclei are stimu-

type of neurogenic effect on the cardiovascular system,

lated. In addition to the centers shown in Figure 58-6,

including increased arterial pressure, decreased arterial

a large lateral hypothalamic area (shown in Figure

pressure, increased heart rate, and decreased heart rate.

58-7) is present on each side of the hypothalamus. The

In general, stimulation in the posterior and lateral hypo-

thalamus increases the arterial pressure and heart rate,

lateral areas are especially important in controlling

whereas stimulation in the preoptic area often has oppo-

thirst, hunger, and many of the emotional drives.

site effects, causing a decrease in both heart rate and

A word of caution must be issued for studying these

arterial pressure. These effects are transmitted mainly

diagrams because the areas that cause specific activi-

through specific cardiovascular control centers in the

ties are not nearly as accurately localized as suggested

reticular regions of the pons and medulla.

in the figures. Also, it is not known whether the effects

noted in the figures result from stimulation of specific

Regulation of Body Temperature. The anterior portion of the

control nuclei or whether they result merely from

hypothalamus, especially the preoptic area, is concerned

734

Unit XI The Nervous System: C. Motor and Integrative Neurophysiology

with regulation of body temperature. An increase in the

overactive, so that it has a voracious appetite, resulting

temperature of the blood flowing through this area

eventually in tremendous obesity. Another area of the

increases the activity of temperature-sensitive neurons,

hypothalamus that enters into overall control of gas-

while a decrease in temperature decreases their activ-

trointestinal activity is the mamillary bodies; these

ity. In turn, these neurons control mechanisms for

control at least partially the patterns of many feeding

increasing or decreasing body temperature, as discussed

reflexes, such as licking the lips and swallowing.

in Chapter 73.

Hypothalamic Control of Endocrine Hormone Secretion by the

Regulation of Body Water. The hypothalamus regulates

Anterior Pituitary Gland. Stimulation of certain areas of the

body water in two ways: (1) by creating the sensation of

hypothalamus also causes the anterior pituitary gland to

thirst, which makes the animal or person drink water,

secrete its endocrine hormones. This subject is discussed

and (2) by controlling the excretion of water into the

in detail in Chapter 74 in relation to neural control of

urine. An area called the thirst center is located in the

the endocrine glands. Briefly, the basic mechanisms are

lateral hypothalamus. When the fluid electrolytes in

the following.

either this center or closely allied areas become too

The anterior pituitary gland receives its blood supply

concentrated, the animal develops an intense desire to

mainly from blood that flows first through the lower

drink water; it will search out the nearest source of

part of the hypothalamus and then through the anterior

water and drink enough to return the electrolyte con-

pituitary vascular sinuses. As the blood courses through

centration of the thirst center to normal.

the hypothalamus before reaching the anterior pitu-

Control of renal excretion of water is vested mainly

itary, specific releasing and inhibitory hormones are

in the supraoptic nuclei. When the body fluids become

secreted into the blood by various hypothalamic nuclei.

too concentrated, the neurons of these areas become

These hormones are then transported via the blood

stimulated. Nerve fibers from these neurons project

to the anterior pituitary gland, where they act on the

downward through the infundibulum of the hypothala-

glandular cells to control release of specific anterior

mus into the posterior pituitary gland, where the nerve

pituitary hormones.

endings secrete the hormone antidiuretic hormone (also

called vasopressin). This hormone is then absorbed into

Summary. A number of areas of the hypothalamus

the blood and transported to the kidneys where it acts

control specific vegetative and endocrine functions.

on the collecting ducts of the kidneys to cause increased

These areas are still poorly delimited, so much so that

reabsorption of water. This decreases loss of water into

the specification given above of different areas for dif-

the urine but allows continuing excretion of electrolytes,

ferent hypothalamic functions is partially tentative.

thus decreasing the concentration of the body fluids

back toward normal. These functions are presented in

Chapter 28.

Behavioral Functions of the

Regulation of Uterine Contractility and of Milk Ejection from the

Hypothalamus and Associated

Breasts. Stimulation of the paraventricular nuclei causes

Limbic Structures

their neuronal cells to secrete the hormone oxytocin.

This in turn causes increased contractility of the uterus

Effects Caused by Stimulation. In addition to the vegeta-

as well as contraction of the myoepithelial cells sur-

tive and endocrine functions of the hypothalamus,

rounding the alveoli of the breasts, which then causes

stimulation of or lesions in the hypothalamus often

the alveoli to empty their milk through the nipples.

have profound effects on emotional behavior of

At the end of pregnancy, especially large quantities of

oxytocin are secreted, and this secretion helps to

animals and human beings.

promote labor contractions that expel the baby. Then,

In animals, some of the behavioral effects of stimu-

whenever the baby suckles the mother’s breast, a reflex

lation are the following:

signal from the nipple to the posterior hypothalamus

1. Stimulation in the lateral hypothalamus not only

also causes oxytocin release, and the oxytocin now per-

causes thirst and eating, as discussed above, but

forms the necessary function of contracting the ductules

also increases the general level of activity of the

of the breast, thereby expelling milk through the nipples

animal, sometimes leading to overt rage and

so that the baby can nourish itself. These functions are

fighting, as discussed subsequently.

discussed in Chapter 82.

2. Stimulation in the ventromedial nucleus

and surrounding areas mainly causes effects

Gastrointestinal and Feeding Regulation. Stimulation of

several areas of the hypothalamus causes an animal to

opposite to those caused by lateral hypothalamic

experience extreme hunger, a voracious appetite, and an

stimulation—that is, a sense of satiety, decreased

intense desire to search for food. One area associated

eating, and tranquility.

with hunger is the lateral hypothalamic area. Con-

3. Stimulation of a thin zone of periventricular

versely, damage to this area on both sides of the hypo-

nuclei, located immediately adjacent to the third

thalamus causes the animal to lose desire for food,

ventricle (or also stimulation of the central gray

sometimes causing lethal starvation.

area of the mesencephalon that is continuous with

A center that opposes the desire for food, called the

this portion of the hypothalamus), usually leads to

satiety center, is located in the ventromedial nuclei.

fear and punishment reactions.

When this center is stimulated electrically, an animal

4. Sexual drive can be stimulated from several

that is eating food suddenly stops eating and shows

complete indifference to food. However, if this area is

areas of the hypothalamus, especially the most

destroyed bilaterally, the animal cannot be satiated;

anterior and most posterior portions of the

instead, its hypothalamic hunger centers become

hypothalamus.

Chapter 58

Behavioral and Motivational Mechanisms of the Brain—The Limbic System and the Hypothalamus

735

Effects Caused by Hypothalamic Lesions. Lesions in the

hypothalamus, in general, cause effects opposite to

those caused by stimulation. For instance:

1. Bilateral lesions in the lateral hypothalamus will

decrease drinking and eating almost to zero, often

leading to lethal starvation. These lesions cause

extreme passivity of the animal as well, with loss

of most of its overt drives.

2. Bilateral lesions of the ventromedial areas of the

hypothalamus cause effects that are mainly

opposite to those caused by lesions of the lateral

hypothalamus: excessive drinking and eating as

well as hyperactivity and often continuous

savagery along with frequent bouts of extreme

rage on the slightest provocation.

Stimulation or lesions in other regions of the limbic

system, especially in the amygdala, the septal area,

and areas in the mesencephalon, often cause effects

similar to those elicited from the hypothalamus. We

will discuss some of these in more detail later.

Figure 58-8

“Reward” and “Punishment” Function

Technique for localizing reward and punishment centers in the

of the Limbic System

brain of a monkey.

From the discussion thus far, it is already clear that

several limbic structures are particularly concerned

stimuli giving a sense of reward and stronger ones a

with the affective nature of sensory sensations—that is,

sense of punishment. Less potent reward centers,

whether the sensations are pleasant or unpleasant.

which are perhaps secondary to the major ones in the

These affective qualities are also called reward or pun-

hypothalamus, are found in the septum, the amygdala,

ishment, or satisfaction or aversion. Electrical stimula-

certain areas of the thalamus and basal ganglia, and

tion of certain limbic areas pleases or satisfies the

extending downward into the basal tegmentum of the

animal, whereas electrical stimulation of other regions

mesencephalon.

causes terror, pain, fear, defense, escape reactions,

and all the other elements of punishment. The degrees

Punishment Centers

of stimulation of these two oppositely responding

The apparatus shown in Figure 58-8 can also be

systems greatly affect the behavior of the animal.

connected so that the stimulus to the brain continues

all the time except when the lever is pressed. In this

Reward Centers

case, the animal will not press the lever to turn the

Figure 58-8 shows a technique that has been used for

stimulus off when the electrode is in one of the reward

localizing specific reward and punishment areas of the

areas; but when it is in certain other areas, the animal

brain. In this figure, a lever is placed at the side of

immediately learns to turn it off. Stimulation in these

the cage and is arranged so that depressing the lever

areas causes the animal to show all the signs of

makes electrical contact with a stimulator. Electrodes

displeasure, fear, terror, pain, punishment, and even

are placed successively at different areas in the brain

sickness.

so that the animal can stimulate the area by pressing

By means of this technique, the most potent areas

the lever. If stimulating the particular area gives the

for punishment and escape tendencies have been

animal a sense of reward, then it will press the lever

found in the central gray area surrounding the aque-

again and again, sometimes as much as hundreds or

duct of Sylvius in the mesencephalon and extending

even thousands of times per hour. Furthermore, when

upward into the periventricular zones of the hypo-

offered the choice of eating some delectable food as

thalamus and thalamus. Less potent punishment areas

opposed to the opportunity to stimulate the reward

are found in some locations in the amygdala and hip-

center, the animal often chooses the electrical

pocampus. It is particularly interesting that stimulation

stimulation.

in the punishment centers can frequently inhibit the

By using this procedure, the major reward centers

reward and pleasure centers completely, demonstrat-

have been found to be located along the course of the

ing that punishment and fear can take precedence over

medial forebrain bundle, especially in the lateral and

pleasure and reward.

ventromedial nuclei of the hypothalamus. It is strange

that the lateral nucleus should be included among the

Rage—Its Association with

reward areas—indeed, it is one of the most potent of

Punishment Centers

all—because even stronger stimuli in this area can

An emotional pattern that involves the punish-

cause rage. But this is true in many areas, with weaker

ment centers of the hypothalamus and other limbic

736

Unit XI The Nervous System: C. Motor and Integrative Neurophysiology

structures, and has also been well characterized, is the

If the stimulus does cause either reward or punish-

rage pattern, described as follows.

ment rather than indifference, the cerebral cortical

Strong stimulation of the punishment centers of

response becomes progressively more and more

the brain, especially in the periventricular zone of the

intense during repeated stimulation instead of fading

hypothalamus and in the lateral hypothalamus, causes

away, and the response is said to be reinforced. An

the animal to (1) develop a defense posture, (2) extend

animal builds up strong memory traces for sensations

its claws, (3) lift its tail, (4) hiss, (5) spit, (6) growl, and

that are either rewarding or punishing but, conversely,

(7) develop piloerection, wide-open eyes, and dilated

develops complete habituation to indifferent sensory

pupils. Furthermore, even the slightest provocation

stimuli.

causes an immediate savage attack. This is approxi-

It is evident that the reward and punishment centers

mately the behavior that one would expect from an

of the limbic system have much to do with selecting

animal being severely punished, and it is a pattern of

the information that we learn, usually throwing away

behavior that is called rage.

more than 99 per cent of it and selecting less than 1

Fortunately, in the normal animal, the rage phe-

per cent for retention.

nomenon is held in check mainly by inhibitory signals

from the ventromedial nuclei of the hypothalamus. In

addition, portions of the hippocampi and anterior

Specific Functions of Other

limbic cortex, especially in the anterior cingulate

gyri and subcallosal gyri, help suppress the rage

Parts of the Limbic System

phenomenon.

Functions of the Hippocampus

Placidity and Tameness. Exactly the opposite emotional

The hippocampus is the elongated portion of the cere-

behavior patterns occur when the reward centers are

bral cortex that folds inward to form the ventral

stimulated: placidity and tameness.

surface of much of the inside of the lateral ventricle.

One end of the hippocampus abuts the amygdaloid

nuclei, and along its lateral border it fuses with the

Importance of Reward or Punishment

parahippocampal gyrus, which is the cerebral cortex

in Behavior

on the ventromedial outside surface of the temporal

lobe.

Almost everything that we do is related in some way

The hippocampus (and its adjacent temporal and

to reward and punishment. If we are doing something

parietal lobe structures, all together called the hip-

that is rewarding, we continue to do it; if it is punish-

pocampal formation) has numerous but mainly indi-

ing, we cease to do it. Therefore, the reward and pun-

rect connections with many portions of the cerebral

ishment centers undoubtedly constitute one of the

cortex as well as with the basal structures of the limbic

most important of all the controllers of our bodily

system—the amygdala, the hypothalamus, the septum,

activities, our drives, our aversions, our motivations.

and the mamillary bodies. Almost any type of sensory

experience causes activation of at least some part of

Effect of Tranquilizers on the Reward or Punishment Centers.

the hippocampus, and the hippocampus in turn dis-

Administration of a tranquilizer, such as chlorpro-

tributes many outgoing signals to the anterior thala-

mazine, usually inhibits both the reward and the pun-

mus, hypothalamus, and other parts of the limbic

ishment centers, thereby decreasing the affective

system, especially through the fornix, a major commu-

reactivity of the animal. Therefore, it is presumed that

nicating pathway. Thus, the hippocampus is an addi-

tranquilizers function in psychotic states by suppress-

tional channel through which incoming sensory signals

ing many of the important behavioral areas of the

can initiate behavioral reactions for different pur-

hypothalamus and its associated regions of the limbic

poses. As in other limbic structures, stimulation of dif-

brain.

ferent areas in the hippocampus can cause almost any

of the different behavioral patterns such as pleasure,

Importance of Reward or Punishment

rage, passivity, or excess sex drive.

in Learning and Memory—Habituation

Another feature of the hippocampus is that it can

Versus Reinforcement

become hyperexcitable. For instance, weak electrical

Animal experiments have shown that a sensory expe-

stimuli can cause focal epileptic seizures in small areas

rience that causes neither reward nor punishment is

of the hippocampi. These often persist for many

hardly remembered at all. Electrical recordings from

seconds after the stimulation is over, suggesting that

the brain show that a newly experienced sensory stim-

the hippocampi can perhaps give off prolonged output

ulus almost always excites multiple areas in the cere-

signals even under normal functioning conditions.

bral cortex. But, if the sensory experience does not

During hippocampal seizures, the person experiences

elicit a sense of either reward or punishment, repeti-

various psychomotor effects, including olfactory,

tion of the stimulus over and over leads to almost com-

visual, auditory, tactile, and other types of hallucina-

plete extinction of the cerebral cortical response. That

tions that cannot be suppressed as long as the seizure

is, the animal becomes habituated to that specific

persists even though the person has not lost con-

sensory stimulus and thereafter ignores it.

sciousness and knows these hallucinations to be

Chapter 58

Behavioral and Motivational Mechanisms of the Brain—The Limbic System and the Hypothalamus

737

unreal. Probably one of the reasons for this hyper-

In lower animals, the amygdala is concerned to a great

excitability of the hippocampi is that they have a dif-

extent with olfactory stimuli and their interrelations

ferent type of cortex from that elsewhere in the

with the limbic brain. Indeed, it is pointed out in

Chapter 53 that one of the major divisions of the olfac-

cerebrum, having only three nerve cell layers in some

tory tract terminates in a portion of the amygdala

of its areas instead of the six layers found elsewhere.

called the corticomedial nuclei, which lies immediately

beneath the cerebral cortex in the olfactory pyriform

Role of the Hippocampus in Learning

area of the temporal lobe. In the human being, another

Effect of Bilateral Removal of the Hippocampi—Inability to

portion of the amygdala, the basolateral nuclei, has

Learn. Portions of the hippocampi have been surgically

become much more highly developed than the olfactory

removed bilaterally in a few human beings for treat-

portion and plays important roles in many behavioral

ment of epilepsy. These people can recall most previ-

activities not generally associated with olfactory stimuli.

ously learned memories satisfactorily. However, they

The amygdala receives neuronal signals from all por-

often can learn essentially no new information that is

tions of the limbic cortex, as well as from the neocortex

of the temporal, parietal, and occipital lobes—especially

based on verbal symbolism. In fact, they often cannot

from the auditory and visual association areas. Because

even learn the names of people with whom they come

of these multiple connections, the amygdala has been

in contact every day. Yet they can remember for a

called the “window” through which the limbic system

moment or so what transpires during the course of

sees the place of the person in the world. In turn, the

their activities. Thus, they are capable of short-term

amygdala transmits signals (1) back into these same cor-

memory for seconds up to a minute or two, although

tical areas,

(2) into the hippocampus, (3) into the

their ability to establish memories lasting longer than

septum, (4) into the thalamus, and (5) especially into the

a few minutes is either completely or almost com-

hypothalamus.

pletely abolished. This is the phenomenon called

anterograde amnesia that was discussed in Chapter 57.

Effects of Stimulating the Amygdala. In general, stimulation

in the amygdala can cause almost all the same effects as

those elicited by direct stimulation of the hypothalamus,

Theoretical Function of the Hippocampus in Learning. The

plus other effects. Effects initiated from the amygdala

hippocampus originated as part of the olfactory

and then sent through the hypothalamus include (1)

cortex. In many lower animals, this cortex plays essen-

increases or decreases in arterial pressure, (2) increases

tial roles in determining whether the animal will eat

or decreases in heart rate, (3) increases or decreases in

a particular food, whether the smell of a particular

gastrointestinal motility and secretion, (4) defecation or

object suggests danger, or whether the odor is sexually

micturition, (5) pupillary dilation or, rarely, constriction,

inviting, thus making decisions that are of life-or-death

(6) piloerection, and (7) secretion of various anterior

importance. Very early in evolutionary development of

pituitary hormones, especially the gonadotropins and

the brain, the hippocampus presumably became a crit-

adrenocorticotropic hormone.

ical decision-making neuronal mechanism, determin-

Aside from these effects mediated through the hypo-

thalamus, amygdala stimulation can also cause several

ing the importance of the incoming sensory signals.

types of involuntary movement. These include (1) tonic

Once this critical decision-making capability had been

movements, such as raising the head or bending the

established, presumably the remainder of the brain

body; (2) circling movements; (3) occasionally clonic,

also began to call on the hippocampus for decision

rhythmical movements; and (4) different types of move-

making. Therefore, if the hippocampus signals that a

ments associated with olfaction and eating, such as

neuronal input is important, the information is likely

licking, chewing, and swallowing.

to be committed to memory.

In addition, stimulation of certain amygdaloid nuclei

Thus, a person rapidly becomes habituated to indif-

can cause a pattern of rage, escape, punishment, severe

ferent stimuli but learns assiduously any sensory expe-

pain, and fear similar to the rage pattern elicited from

rience that causes either pleasure or pain. But what is

the hypothalamus, as described earlier. Stimulation of

other amygdaloid nuclei can give reactions of reward

the mechanism by which this occurs? It has been sug-

and pleasure.

gested that the hippocampus provides the drive that

Finally, excitation of still other portions of the amyg-

causes translation of short-term memory into long-

dala can cause sexual activities that include erection,

term memory—that is, the hippocampus transmits

copulatory movements, ejaculation, ovulation, uterine

some signal or signals that seem to make the mind

activity, and premature labor.

rehearse over and over the new information until per-

manent storage takes place. Whatever the mechanism,

Effects of Bilateral Ablation of the Amygdala—The Klüver-Bucy

without the hippocampi, consolidation of long-term

Syndrome. When the anterior parts of both temporal

memories of the verbal or symbolic thinking type is

lobes are destroyed in a monkey, this removes not only

poor or does not take place.

portions of temporal cortex but also of the amygdalas

that lie inside these parts of the temporal lobes. This

causes changes in behavior called the Klüver-Bucy syn-

Functions of the Amygdala

drome, which is demonstrated by an animal that (1) is

not afraid of anything, (2) has extreme curiosity about

The amygdala is a complex of multiple small nuclei

everything, (3) forgets rapidly, (4) has a tendency to

located immediately beneath the cerebral cortex of the

place everything in its mouth and sometimes even tries

medial anterior pole of each temporal lobe. It has abun-

to eat solid objects, and (5) often has a sex drive so

dant bidirectional connections with the hypothalamus

strong that it attempts to copulate with immature

as well as with other areas of the limbic system.

animals, animals of the wrong sex, or even animals of a

738

Unit XI The Nervous System: C. Motor and Integrative Neurophysiology

different species. Although similar lesions in human

and olfactory behavioral associations. In the parahip-

beings are rare, afflicted people respond in a manner not

pocampal gyri, there is a tendency for complex auditory

too different from that of the monkey.

associations as well as complex thought associations

derived from Wernicke’s area of the posterior temporal

Overall Function of the Amygdalas. The amygdalas seem to

lobe. In the middle and posterior cingulate cortex, there

be behavioral awareness areas that operate at a semi-

is reason to believe that sensorimotor behavioral asso-

conscious level. They also seem to project into the

ciations occur.

limbic system one’s current status in relation to both

surroundings and thoughts. On the basis of this infor-

mation, the amygdala is believed to make the person’s

References

behavioral response appropriate for each occasion.

Adell A, Celada P, Abellan MT, Artigas F: Origin and func-

Function of the Limbic Cortex

tional role of the extracellular serotonin in the midbrain

raphe nuclei. Brain Res Brain Res Rev 39:154, 2002.

The most poorly understood portion of the limbic

Bechara A, Damasio H, Damasio AR: Role of the amygdala

system is the ring of cerebral cortex called the limbic

in decision-making. Ann N Y Acad Sci 985:356, 2003.

cortex that surrounds the subcortical limbic structures.

Blank T, Nijholt I, Spiess J: Molecular determinants mediat-

This cortex functions as a transitional zone through

ing effects of acute stress on hippocampus-dependent

which signals are transmitted from the remainder of the

synaptic plasticity and learning. Mol Neurobiol 29:131,

brain cortex into the limbic system and also in the oppo-

2004.

site direction. Therefore, the limbic cortex in effect

Bouret SG, Simerly RB: Leptin and development of hypo-

functions as a cerebral association area for control of

thalamic feeding circuits. Endocrinology 145:2621, 2004.

behavior.

Conlon R, Hobson JA: Understanding the Human Mind.

Stimulation of the different regions of the limbic

New York: John Wiley, 1999.

cortex has failed to give any real idea of their functions.

Denton DA, McKinley MJ, Weisinger RS: Hypothalamic

However, as is true of so many other portions of the

integration of body fluid regulation. Proc Natl Acad Sci

limbic system, essentially all behavioral patterns can be

U S A 93:7397, 1996.

elicited by stimulation of specific portions of the limbic

Drevets WC: Neuroimaging abnormalities in the amygdala

cortex. Likewise, ablation of some limbic cortical areas

in mood disorders. Ann N Y Acad Sci 985:420, 2003

can cause persistent changes in an animal’s behavior, as

Gerashchenko D, Shiromani PJ: Different neuronal pheno-

follows.

types in the lateral hypothalamus and their role in sleep

and wakefulness. Mol Neurobiol 29:41, 2004.

Ablation of the Anterior Temporal Cortex. When the anterior

Guillery RW: Branching thalamic afferents link action and

temporal cortex is ablated bilaterally, the amygdalas are

perception. J Neurophysiol 90:539, 2003.

almost invariably damaged as well. This was discussed

Haines DE: Fundamental Neuroscience. New York:

earlier in this chapter; it was pointed out that the

Churchill Livingstone, 1997.

Klüver-Bucy syndrome occurs. The animal especially

Holland PC, Gallagher M: Amygdala—frontal interactions

develops consummatory behavior: it investigates any

and reward expectancy. Curr Opin Neurobiol 14:148, 2004.

and all objects, has intense sex drives toward inappro-

Joels M, Verkuyl JM, Van Riel E: Hippocampal and hypo-

priate animals or even inanimate objects, and loses all

thalamic function after chronic stress. Ann N Y Acad Sci

fear—and thus develops tameness as well.

1007:367, 2003.

Kandel ER, Schwartz JH, Jessell TM: Principles of Neural

Ablation of the Posterior Orbital Frontal Cortex. Bilateral

Science, 4th ed. New York: McGraw-Hill, 2000.

removal of the posterior portion of the orbital frontal

Kelley AE: Ventral striatal control of appetitive motivation:

cortex often causes an animal to develop insomnia asso-

role in ingestive behavior and reward-related learning.

ciated with intense motor restlessness, becoming unable

Neurosci Biobehav Rev 27:765, 2004.

to sit still and moving about continuously.

LeDoux JE: Emotion circuits in the brain. Annu Rev Neu-

rosci 23:155, 2000.

Ablation of the Anterior Cingulate Gyri and Subcallosal Gyri. The

Lumb BM: Hypothalamic and midbrain circuitry that dis-

anterior cingulate gyri and the subcallosal gyri are the

tinguishes between escapable and inescapable pain. News

portions of the limbic cortex that communicate between

Physiol Sci 19:22, 2004.

the prefrontal cerebral cortex and the subcortical limbic

Morris JF, Ludwig M: Magnocellular dendrites: prototypic

structures. Destruction of these gyri bilaterally releases

receiver/transmitters. J Neuroendocrinol 16:403, 2004.

the rage centers of the septum and hypothalamus from

Phelps EA: Human emotion and memory: interactions of the

prefrontal inhibitory influence. Therefore, the animal

amygdala and hippocampal complex. Curr Opin Neuro-

can become vicious and much more subject to fits of

biol 14:198, 2004.

rage than normally.

Sah P, Faber ES, Lopez De Armentia M, Power J: The amyg-

daloid complex: anatomy and physiology. Physiol Rev

Summary. Until further information is available, it is

83:803, 2003.

perhaps best to state that the cortical regions of the

van den Pol AN: Weighing the role of hypothalamic feeding

limbic system occupy intermediate associative positions

neurotransmitters. Neuron 40:1059, 2003.

between the functions of the specific areas of the cere-

Vann SD, Aggleton JP: The mammillary bodies: two memory

bral cortex and functions of the subcortical limbic struc-

systems in one? Nat Rev Neurosci 5:35, 2004.

tures for control of behavioral patterns. Thus, in the

Wild B, Rodden FA, Grodd W, Ruch W: Neural correlates of

anterior temporal cortex, one especially finds gustatory

laughter and humour. Brain 126:2121, 2003.

C H A P T E R

States of Brain Activity—Sleep,

Brain Waves, Epilepsy, Psychoses

All of us are aware of the many different states

of brain activity, including sleep, wakefulness,

extreme excitement, and even different levels of

mood such as exhilaration, depression, and fear. All

these states result from different activating

or inhibiting forces generated usually within the

brain itself. In Chapter 58, we began a partial dis-

cussion of this subject when we described different

systems that are capable of activating large portions of the brain. In this chapter,

we present brief surveys of specific states of brain activity, beginning with

sleep.

Sleep

Sleep is defined as unconsciousness from which the person can be aroused by

sensory or other stimuli. It is to be distinguished from coma, which is uncon-

sciousness from which the person cannot be aroused. There are multiple stages

of sleep, from very light sleep to very deep sleep; sleep researchers also divide

sleep into two entirely different types of sleep that have different qualities, as

follows.

Two Types of Sleep. During each night, a person goes through stages of two types

of sleep that alternate with each other. They are called (1) slow-wave sleep,

because in this type of sleep the brain waves are very strong and very low fre-

quency, as we discuss later, and (2) rapid eye movement sleep (REM sleep),

because in this type of sleep the eyes undergo rapid movements despite the fact

that the person is still asleep.

Most sleep during each night is of the slow-wave variety; this is the deep,

restful sleep that the person experiences during the first hour of sleep after

having been awake for many hours. REM sleep, on the other hand, occurs in

episodes that occupy about 25 per cent of the sleep time in young adults; each

episode normally recurs about every 90 minutes. This type of sleep is not so

restful, and it is usually associated with vivid dreaming.

Slow-Wave Sleep

Most of us can understand the characteristics of deep slow-wave sleep by

remembering the last time we were kept awake for more than 24 hours and

then the deep sleep that occurred during the first hour after going to sleep. This

sleep is exceedingly restful and is associated with decrease in both peripheral

vascular tone and many other vegetative functions of the body. For instance,

there are 10 to 30 per cent decreases in blood pressure, respiratory rate, and

basal metabolic rate.

Although slow-wave sleep is frequently called “dreamless sleep,” dreams and

sometimes even nightmares do occur during slow-wave sleep. The difference

between the dreams that occur in slow-wave sleep and those that occur in REM

sleep is that those of REM sleep are associated with more bodily muscle

activity, and the dreams of slow-wave sleep usually are not remembered. That

739

740

Unit XI The Nervous System: C. Motor and Integrative Neurophysiology

is, during slow-wave sleep, consolidation of the dreams

Neuronal Centers, Neurohumoral Substances,

in memory does not occur.

and Mechanisms That Can Cause Sleep—

A Possible Specific Role for Serotonin

Stimulation of several specific areas of the brain

REM Sleep (Paradoxical Sleep,

can produce sleep with characteristics near those

Desynchronized Sleep)

of natural sleep. Some of these areas are the

following:

In a normal night of sleep, bouts of REM sleep lasting

The most conspicuous stimulation area for causing

5 to 30 minutes usually appear on the average every

almost natural sleep is the raphe nuclei in the

90 minutes. When the person is extremely sleepy, each

lower half of the pons and in the medulla. These

bout of REM sleep is short, and it may even be absent.

nuclei are a thin sheet of special neurons located

Conversely, as the person becomes more rested

in the midline. Nerve fibers from these nuclei

through the night, the durations of the REM bouts

spread locally in the brain stem reticular

increase.

formation and also upward into the thalamus,

There are several important characteristics of REM

hypothalamus, most areas of the limbic system,

sleep:

and even the neocortex of the cerebrum. In

1. It is usually associated with active dreaming and

addition, fibers extend downward into the spinal

active bodily muscle movements.

cord, terminating in the posterior horns where

2. The person is even more difficult to arouse by

they can inhibit incoming sensory signals,

sensory stimuli than during deep slow-wave sleep,

including pain, as discussed in Chapter 48. It is

and yet people usually awaken spontaneously in

also known that many nerve endings of fibers

the morning during an episode of REM sleep.

from these raphe neurons secrete serotonin.

3. Muscle tone throughout the body is exceedingly

When a drug that blocks the formation of

depressed, indicating strong inhibition of the

serotonin is administered to an animal, the animal

spinal muscle control areas.

often cannot sleep for the next several days.

4. Heart rate and respiratory rate usually become

Therefore, it has been assumed that serotonin is a

irregular, which is characteristic of the dream

transmitter substance associated with production

state.

of sleep.

5. Despite the extreme inhibition of the peripheral

Stimulation of some areas in the nucleus of the

muscles, irregular muscle movements do occur.

tractus solitarius can also cause sleep. This nucleus

These are in addition to the rapid movements of

is the termination in the medulla and pons for

the eyes.

visceral sensory signals entering by way of the

6. The brain is highly active in REM sleep, and

vagus and glossopharyngeal nerves.

overall brain metabolism may be increased as

Stimulation of several regions in the diencephalon

much as 20 per cent. The electroencephalogram

can also promote sleep, including (1) the rostral

(EEG) shows a pattern of brain waves similar to

part of the hypothalamus, mainly in the

those that occur during wakefulness. This type of

suprachiasmal area, and (2) an occasional area in

sleep is also called paradoxical sleep because it is

the diffuse nuclei of the thalamus.

a paradox that a person can still be asleep despite

marked activity in the brain.

Lesions in Sleep-Promoting Centers Can Cause Intense Wake-

In summary, REM sleep is a type of sleep in which

fulness. Discrete lesions in the raphe nuclei lead to a

the brain is quite active. However, the brain activity is

high state of wakefulness. This is also true of bilateral

not channeled in the proper direction for the person

lesions in the medial rostral suprachiasmal area in the

to be fully aware of his or her surroundings, and there-

anterior hypothalamus. In both instances, the excita-

fore the person is truly asleep.

tory reticular nuclei of the mesencephalon and upper

pons seem to become released from inhibition, thus

causing the intense wakefulness. Indeed, sometimes

Basic Theories of Sleep

lesions of the anterior hypothalamus can cause such

intense wakefulness that the animal actually dies of

Sleep Is Believed to Be Caused by an Active Inhibitory Process.

exhaustion.

An earlier theory of sleep was that the excitatory areas

of the upper brain stem, the reticular activating system,

simply fatigued during the waking day and became

Other Possible Transmitter Substances Related to Sleep.

inactive as a result. This was called the passive theory

Experiments have shown that the cerebrospinal fluid

of sleep. An important experiment changed this view

as well as the blood or urine of animals that have been

to the current belief that sleep is caused by an active

kept awake for several days contains a substance or

inhibitory process: it was discovered that transecting

substances that will cause sleep when injected into the

the brain stem at the level of the midpons creates a

brain ventricular system of another animal. One likely

brain whose cortex never goes to sleep. In other words,

substance has been identified as muramyl peptide, a

there seems to be some center located below the mid-

low-molecular-weight substance that accumulates in

pontile level of the brain stem that is required to cause

the cerebrospinal fluid and urine in animals kept

sleep by inhibiting other parts of the brain.

awake for several days. When only micrograms of this

Chapter 59

States of Brain Activity—Sleep, Brain Waves, Epilepsy, Psychoses

741

sleep-producing substance are injected into the third

Physiologic Effects of Sleep

ventricle, almost natural sleep occurs within a few

minutes, and the animal may stay asleep for several

Sleep causes two major types of physiologic effects:

hours. Another substance that has similar effects in

first, effects on the nervous system itself, and second,

causing sleep is a nonapeptide isolated from the blood

effects on other functional systems of the body. The

of sleeping animals. And still a third sleep factor, not

nervous system effects seem to be by far the more

yet identified molecularly, has been isolated from the

important because any person who has a transected

neuronal tissues of the brain stem of animals kept

spinal cord in the neck (and therefore has no sleep-

awake for days. It is possible that prolonged wakeful-

wakefulness cycle below the transection) shows no

ness causes progressive accumulation of a sleep factor

harmful effects in the body beneath the level of

or factors in the brain stem or in the cerebrospinal

transection that can be attributed directly to a sleep-

fluid that lead to sleep.

wakefulness cycle.

Lack of sleep certainly does, however, affect the

functions of the central nervous system. Prolonged

Possible Cause of REM Sleep. Why slow-wave sleep is

wakefulness is often associated with progressive mal-

broken periodically by REM sleep is not understood.

function of the thought processes and sometimes even

However, drugs that mimic the action of acetylcholine

causes abnormal behavioral activities.

increase the occurrence of REM sleep. Therefore, it

We are all familiar with the increased sluggishness

has been postulated that the large acetylcholine-

of thought that occurs toward the end of a prolonged

secreting neurons in the upper brain stem reticular for-

wakeful period, but in addition, a person can become

mation might, through their extensive efferent fibers,

irritable or even psychotic after forced wakefulness.

activate many portions of the brain. This theoretically

Therefore, we can assume that sleep in multiple ways

could cause the excess activity that occurs in certain

restores both normal levels of brain activity and

brain regions in REM sleep, even though the signals

normal “balance” among the different functions of the

are not channeled appropriately in the brain to cause

central nervous system. This might be likened to the

normal conscious awareness that is characteristic of

“rezeroing” of electronic analog computers after pro-

wakefulness.

longed use, because computers of this type gradually

lose their “baseline” of operation; it is reasonable to

Cycle Between Sleep and Wakefulness

assume that the same effect occurs in the central

The preceding discussions have merely identified

nervous system because overuse of some brain areas

neuronal areas, transmitters, and mechanisms that are

during wakefulness could easily throw these areas out

related to sleep. They have not explained the cyclical,

of balance with the remainder of the nervous system.

reciprocal operation of the sleep-wakefulness cycle.

We might postulate that the principal value of sleep

There is as yet no explanation. Therefore, we can let

is to restore natural balances among the neuronal

our imaginations run wild and suggest the following

centers. The specific physiologic functions of sleep

possible mechanism for causing the sleep-wakefulness

remain a mystery, and they are the subject of much

cycle.

research.

When the sleep centers are not activated, the mes-

encephalic and upper pontile reticular activating

nuclei are released from inhibition, which allows the

Brain Waves

reticular activating nuclei to become spontaneously

active. This in turn excites both the cerebral cortex and

Electrical recordings from the surface of the brain or

the peripheral nervous system, both of which send

even from the outer surface of the head demonstrate

numerous positive feedback signals back to the same

that there is continuous electrical activity in the brain.

Both the intensity and the patterns of this electrical

reticular activating nuclei to activate them still further.

activity are determined by the level of excitation of dif-

Therefore, once wakefulness begins, it has a natural

ferent parts of the brain resulting from sleep, wakeful-

tendency to sustain itself because of all this positive

ness, or brain diseases such as epilepsy or even

feedback activity.

psychoses. The undulations in the recorded electrical

Then, after the brain remains activated for many

potentials, shown in Figure 59-1, are called brain waves,

hours, even the neurons themselves in the activating

and the entire record is called an EEG (electroen-

system presumably become fatigued. Consequently,

cephalogram).

the positive feedback cycle between the mesen-

The intensities of brain waves recorded from the

cephalic reticular nuclei and the cerebral cortex fades,

surface of the scalp range from 0 to 200 microvolts, and

and the sleep-promoting effects of the sleep centers

their frequencies range from once every few seconds to

50 or more per second. The character of the waves is

take over, leading to rapid transition from wakefulness

dependent on the degree of activity in respective parts

back to sleep.

of the cerebral cortex, and the waves change markedly

This overall theory could explain the rapid transi-

between the states of wakefulness and sleep and coma.

tions from sleep to wakefulness and from wakefulness

Much of the time, the brain waves are irregular, and

to sleep. It could also explain arousal, the insomnia

no specific pattern can be discerned in the EEG. At

that occurs when a person’s mind becomes preoccu-

other times, distinct patterns do appear, some of which

pied with a thought, and the wakefulness that is pro-

are characteristic of specific abnormalities of the brain

duced by bodily physical activity.

such as epilepsy, which is discussed later.

742

Unit XI The Nervous System: C. Motor and Integrative Neurophysiology

Alpha

Eyes open

Eyes closed

Beta

Figure 59-2

Theta

Replacement of the alpha rhythm by an asynchronous, low-

voltage beta rhythm when the eyes are opened.

50 mV

Delta

1 sec

Origin of Brain Waves

The discharge of a single neuron or single nerve fiber

in the brain can never be recorded from the surface of

Figure 59-1

the head. Instead, many thousands or even millions of

neurons or fibers must fire synchronously; only then will

Different types of brain waves in the normal electro-

the potentials from the individual neurons or fibers

encephalogram.

summate enough to be recorded all the way through the

skull. Thus, the intensity of the brain waves from the

scalp is determined mainly by the numbers of neurons

In normal healthy people, most waves in the EEG can

and fibers that fire in synchrony with one another, not

be classified as alpha, beta, theta, and delta waves, which

by the total level of electrical activity in the brain. In

are shown in Figure 59-1.

fact, strong nonsynchronous nerve signals often nullify

Alpha waves are rhythmical waves that occur at fre-

one another in the recorded brain waves because of

quencies between 8 and 13 cycles per second and are

opposing polarities. This is demonstrated in Figure 59-2,

found in the EEGs of almost all normal adult people

which shows, when the eyes were closed, synchronous

when they are awake and in a quiet, resting state of

discharge of many neurons in the cerebral cortex at a

cerebration. These waves occur most intensely in the oc-

frequency of about 12 per second, thus causing alpha

cipital region but can also be recorded from the parietal

waves. Then, when the eyes were opened, the activity of

and frontal regions of the scalp. Their voltage usually is

the brain increased greatly, but synchronization of the

about 50 microvolts. During deep sleep, the alpha waves

signals became so little that the brain waves mainly nul-

disappear.

lified one another, and the resultant effect was very low

When the awake person’s attention is directed to

voltage waves of generally high but irregular frequency,

some specific type of mental activity, the alpha waves

the beta waves.

are replaced by asynchronous, higher-frequency but

lower-voltage beta waves. Figure 59-2 shows the effect

Origin of Alpha Waves. Alpha waves will not occur in the

on the alpha waves of simply opening the eyes in bright

cerebral cortex without cortical connections with the

light and then closing the eyes. Note that the visual sen-

thalamus. Conversely, stimulation in the nonspecific

sations cause immediate cessation of the alpha waves

layer of reticular nuclei that surround the thalamus or

and that these are replaced by low-voltage, asynchro-

in “diffuse” nuclei deep inside the thalamus often sets

nous beta waves.

up electrical waves in the thalamocortical system at a

Beta waves occur at frequencies greater than 14 cycles

frequency between 8 and 13 per second, which is the

per second and as high as 80 cycles per second. They are

natural frequency of the alpha waves. Therefore, it is

recorded mainly from the parietal and frontal regions

believed that the alpha waves result from spontaneous

during specific activation of these parts of the brain.

feedback oscillation in this diffuse thalamocortical

Theta waves have frequencies between 4 and 7 cycles

system, possibly including the reticular activating

per second. They occur normally in the parietal and

system in the brain stem as well. This oscillation pre-

temporal regions in children, but they also occur during

sumably causes both the periodicity of the alpha waves

emotional stress in some adults, particularly during dis-

and the synchronous activation of literally millions of

appointment and frustration. Theta waves also occur in

cortical neurons during each wave.

many brain disorders, often in degenerative brain states.

Delta waves include all the waves of the EEG with

Origin of Delta Waves. Transection of the fiber tracts from

frequencies less than 3.5 cycles per second, and they

the thalamus to the cerebral cortex, which blocks thal-

often have voltages two to four times greater than most

amic activation of the cortex and thereby eliminates the

other types of brain waves. They occur in very deep

alpha waves, nevertheless does not block delta waves in

sleep, in infancy, and in serious organic brain disease.

the cortex. This indicates that some synchronizing mech-

They also occur in the cortex of animals that have had

anism can occur in the cortical neuronal system by

subcortical transections separating the cerebral cortex

itself—mainly independent of lower structures in the

from the thalamus. Therefore, delta waves can occur

brain—to cause the delta waves.

strictly in the cortex independent of activities in lower

Delta waves also occur during deep slow-wave sleep;

regions of the brain.

this suggests that the cortex then is mainly released

Chapter 59

States of Brain Activity—Sleep, Brain Waves, Epilepsy, Psychoses

743

Figure 59-3

Effect of varying degrees of cere-

Stupor

Sleep Psychomotor

Infants Relaxation Attention

Grand mal

bral activity on the basic rhythm

of the electroencephalogram.

Surgical

Slow component

Deteriorated epileptics Fright Fast component

(Redrawn from Gibbs FA, Gibbs

anesthesia

of petit mal

EL: Atlas of Electroencephalogra-

Confusion

phy, 2nd ed, Vol I: Methodology

and Controls. " 1974. Reprinted

1 second

by permission of Prentice-Hall,

Inc., Upper Saddle River, NJ.)

from the activating influences of the thalamus and other

lower centers.

Alert wakefulness (beta waves)

Effect of Varying Levels of

Cerebral Activity on the Frequency

of the EEG

Quiet wakefulness (alpha waves)

There is a general correlation between level of cerebral

activity and average frequency of the EEG rhythm, the

Stage 1 sleep (low voltage and spindles)

average frequency increasing progressively with higher

degrees of activity. This is demonstrated in Figure 59-3,

50 mV

which shows the existence of delta waves in stupor,

Stages 2 and 3 sleep (theta waves)

surgical anesthesia, and deep sleep; theta waves in

psychomotor states and in infants; alpha waves during

relaxed states; and beta waves during periods of intense

mental activity. During periods of mental activity, the

Stage 4 slow wave sleep (delta waves)

waves usually become asynchronous rather than syn-

chronous, so that the voltage falls considerably, despite

markedly increased cortical activity, as shown in

REM sleep (beta waves)

Figure 59-2.

1 sec

Changes in the EEG at Different

Stages of Wakefulness and Sleep

Figure 59-4

Figure 59-4 shows EEG patterns from a typical person

in different stages of wakefulness and sleep. Alert wake-

Progressive change in the characteristics of the brain waves

fulness is characterized by high-frequency beta waves,

during different stages of wakefulness and sleep.

whereas quiet wakefulness is usually associated with

alpha waves, as demonstrated by the first two EEGs of

the figure.

Slow-wave sleep is divided into four stages. In the first

central nervous system. A person who is predisposed to

stage, a stage of very light sleep, the voltage of the EEG

epilepsy has attacks when the basal level of excitability

waves becomes very low; this is broken by “sleep spin-

of the nervous system (or of the part that is susceptible

dles,” that is, short spindle-shaped bursts of alpha waves

to the epileptic state) rises above a certain critical

that occur periodically. In stages 2, 3, and 4 of slow-wave

threshold. As long as the degree of excitability is held

sleep, the frequency of the EEG becomes progressively

below this threshold, no attack occurs.

slower until it reaches a frequency of only 1 to 3 waves

Epilepsy can be classified into three major types:

per second in stage 4; these are delta waves.

grand mal epilepsy, petit mal epilepsy, and focal epilepsy.

Finally, the bottom record in Figure 59-4 shows the

EEG during REM sleep. It is often difficult to tell the

difference between this brain wave pattern and that of

Grand Mal Epilepsy

an awake, active person. The waves are irregular and

high-frequency, which are normally suggestive of desyn-

Grand mal epilepsy is characterized by extreme neu-

chronized nervous activity as found in the awake state.

ronal discharges in all areas of the brain—in the cere-

Therefore, REM sleep is frequently called desynchro-

bral cortex, in the deeper parts of the cerebrum, and

nized sleep because there is lack of synchrony in the

even in the brain stem. Also, discharges transmitted all

firing of the neurons, despite significant brain activity.

the way into the spinal cord sometimes cause general-

ized tonic seizures of the entire body, followed toward

the end of the attack by alternating tonic and spasmodic

Epilepsy

muscle contractions called tonic-clonic seizures. Often

the person bites or “swallows” his or her tongue and

Epilepsy (also called “seizures”) is characterized by

may have difficulty breathing, sometimes to the extent

uncontrolled excessive activity of either part or all of the

that cyanosis occurs. Also, signals transmitted from the

744

Unit XI The Nervous System: C. Motor and Integrative Neurophysiology

Even in people who are not genetically predisposed,

certain types of traumatic lesions in almost any part of

the brain can cause excess excitability of local brain

100 mV

areas, as we discuss shortly; these, too, sometimes trans-

mit signals into the activating systems of the brain to

elicit grand mal seizures.

Grand mal

What Stops the Grand Mal Attack? The cause of the extreme

neuronal overactivity during a grand mal attack is pre-

50 mV

sumed to be massive simultaneous activation of many

reverberating neuronal pathways throughout the brain.

Presumably, the major factor that stops the attack after

Petit mal

a few minutes is neuronal fatigue. A second factor is

probably active inhibition by inhibitory neurons that

50 mV

have been activated by the attack.

Psychomotor

Petit Mal Epilepsy

Petit mal epilepsy almost certainly involves the thala-

mocortical brain activating system. It is usually charac-

Figure 59-5

terized by

3 to

30 seconds of unconsciousness

(or

diminished consciousness) during which time the

Electroencephalograms in different types of epilepsy.

person has twitch-like contractions of muscles usually in

the head region, especially blinking of the eyes; this is

followed by return of consciousness and resumption of

previous activities. This total sequence is called the

brain to the viscera frequently cause urination and defe-

absence syndrome or absence epilepsy. The patient

cation.

may have one such attack in many months or, in rare

The usual grand mal seizure lasts from a few seconds

instances, may have a rapid series of attacks, one after

to 3 to 4 minutes. It is also characterized by postseizure

the other. The usual course is for the petit mal attacks

depression of the entire nervous system; the person

to appear first during late childhood and then to disap-

remains in stupor for 1 to many minutes after the

pear by the age of 30. On occasion, a petit mal epilep-

seizure attack is over, and then often remains severely

tic attack will initiate a grand mal attack.

fatigued and asleep for hours thereafter.

The brain wave pattern in petit mal epilepsy is

The top recording of Figure 59-5 shows a typical

demonstrated by the middle recording of Figure 59-5,

EEG from almost any region of the cortex during the

which is typified by a spike and dome pattern. The spike

tonic phase of a grand mal attack. This demonstrates

and dome can be recorded over most or all of the cere-

that high-voltage, high-frequency discharges occur over

bral cortex, showing that the seizure involves much

the entire cortex. Furthermore, the same type of dis-

or most of the thalamocortical activating system of

charge occurs on both sides of the brain at the same

the brain. In fact, animal studies suggest that it results

time, demonstrating that the abnormal neuronal cir-

from oscillation of

(1) inhibitory thalamic reticular

cuitry responsible for the attack strongly involves the

neurons

(which are inhibitory gamma-aminobutyric

basal regions of the brain that drive the two halves of

acid [GABA]-producing neurons) and (2) excitatory

the cerebrum simultaneously.

thalamocortical and corticothalamic neurons.

In laboratory animals and even in human beings,

grand mal attacks can be initiated by administering a

neuronal stimulant such as the drug pentylenetetrazol,

Focal Epilepsy

or they can be caused by insulin hypoglycemia, or by

passage of alternating electrical current directly through

Focal epilepsy can involve almost any local part of the

the brain. Electrical recordings from the thalamus as

brain, either localized regions of the cerebral cortex or

well as from the reticular formation of the brain stem

deeper structures of both the cerebrum and brain stem.

during the grand mal attack show typical high-voltage

Most often, focal epilepsy results from some localized

activity in both of these areas similar to that recorded

organic lesion or functional abnormality, such as (1) scar

from the cerebral cortex. Presumably, therefore, a grand

tissue in the brain that pulls on the adjacent neuronal

mal attack involves not only abnormal activation of the

tissue, (2) a tumor that compresses an area of the brain,

thalamus and cerebral cortex but also abnormal activa-

(3) a destroyed area of brain tissue, or (4) congenitally

tion in the subthalamic brain stem portions of the brain

deranged local circuitry.

activating system itself.

Lesions such as these can promote extremely rapid

discharges in the local neurons; when the discharge rate

What Initiates a Grand Mal Attack? Most people who have

rises above several hundred per second, synchronous

grand mal attacks have hereditary predisposition to

waves begin to spread over adjacent cortical regions.

epilepsy, a predisposition that occurs in about 1 of every

These waves presumably result from localized reverber-

50 to 100 persons. In such people, factors that can

ating circuits that gradually recruit adjacent areas of the

increase the excitability of the abnormal “epilepto-

cortex into the epileptic discharge zone. The process

genic” circuitry enough to precipitate attacks include

spreads to adjacent areas at a rate as slow as a few mil-

(1) strong emotional stimuli, (2) alkalosis caused by

limeters a minute to as fast as several centimeters per

overbreathing, (3) drugs, (4) fever, and (5) loud noises

second. When such a wave of excitation spreads over the

or flashing lights.

motor cortex, it causes progressive “march” of muscle

Chapter 59

States of Brain Activity—Sleep, Brain Waves, Epilepsy, Psychoses

745

contractions throughout the opposite side of the body,

neurotransmitters.) Depressed patients experience

beginning most characteristically in the mouth region

symptoms of grief, unhappiness, despair, and misery.

and marching progressively downward to the legs but at

In addition, they often lose their appetite and sex

other times marching in the opposite direction. This is

drive and have severe insomnia. Often associated with

called jacksonian epilepsy.

these is a state of psychomotor agitation despite the

A focal epileptic attack may remain confined to a

depression.

single area of the brain, but in many instances, the

Moderate numbers of norepinephrine-secreting

strong signals from the convulsing cortex excite the

neurons are located in the brain stem, especially in

mesencephalic portion of the brain activating system so

the locus ceruleus. These neurons send fibers upward

greatly that a grand mal epileptic attack ensues as well.

to most parts of the brain limbic system, thalamus,

Another type of focal epilepsy is the so-called psy-

and cerebral cortex. Also, many serotonin-producing

chomotor seizure, which may cause (1) a short period of

neurons located in the midline raphe nuclei of the lower

amnesia; (2) an attack of abnormal rage; (3) sudden

pons and medulla send fibers to many areas of the

anxiety, discomfort, or fear; and/or (4) a moment of

limbic system and to some other areas of the brain.

incoherent speech or mumbling of some trite phrase.

A principal reason for believing that depres-

Sometimes the person cannot remember his or her

sion might be caused by diminished activity of

activities during the attack, but at other times, he or she

norepinephrine- and serotonin-secreting neurons is that

is conscious of everything that he or she is doing but

drugs that block secretion of norepinephrine and sero-

unable to control it. Attacks of this type frequently

tonin, such as reserpine, frequently cause depression.

involve part of the limbic portion of the brain, such as

Conversely, about 70 per cent of depressive patients can

the hippocampus, the amygdala, the septum, and/or por-

be treated effectively with drugs that increase the exci-

tions of the temporal cortex.

tatory effects of norepinephrine and serotonin at the

The lowest tracing of Figure 59-5 demonstrates a

nerve endings—for instance, (1) monoamine oxidase

typical EEG during a psychomotor seizure, showing a

inhibitors, which block destruction of norepinephrine

low-frequency rectangular wave with a frequency

and serotonin once they are formed; and (2) tricyclic

between 2 and 4 per second and with occasional super-

antidepressants, such as imipramine and amitriptyline,

imposed 14-per-second waves.

which block reuptake of norepinephrine and serotonin

by nerve endings so that these transmitters remain

Surgical Excision of Epileptic Foci Can Often Prevent Seizures.

active for longer periods after secretion.

The EEG can be used to localize abnormal spiking

Mental depression can be treated by electroconvul-

waves originating in areas of organic brain disease that

sive therapy—commonly called “shock therapy.” In this

predispose to focal epileptic attacks. Once such a focal

therapy, electrical current is passed through the brain to

point is found, surgical excision of the focus frequently

cause a generalized seizure similar to that of an epilep-

prevents future attacks.

tic attack. This has been shown to enhance norepine-

phrine activity.

Some patients with mental depression alternate

between depression and mania, which is called either

Psychotic Behavior and

bipolar disorder or manic-depressive psychosis, and a

Dementia—Roles of Specific

few people exhibit only mania without the depressive

Neurotransmitter Systems

episodes. Drugs that diminish the formation or action of

norepinephrine and serotonin, such as lithium com-

Clinical studies of patients with different psychoses or

pounds, can be effective in treating the manic phase of

different types of dementia have suggested that many

the condition.

of these conditions result from diminished function of

It is presumed that the norepinephrine and serotonin

neurons that secrete a specific neurotransmitter. Use of

systems normally provide drive to the limbic areas of

appropriate drugs to counteract loss of the respective

the brain to increase a person’s sense of well-being, to

neurotransmitter has been successful in treating some

create happiness, contentment, good appetite, appropri-

patients.

ate sex drive, and psychomotor balance—although too

In Chapter 56, we discussed the cause of Parkinson’s

much of a good thing can cause mania. In support of this

disease. This disease results from loss of neurons in the

concept is the fact that pleasure and reward centers of

substantia nigra whose nerve endings secrete dopamine

the hypothalamus and surrounding areas receive large

in the caudate nucleus and putamen. Also in Chapter

numbers of nerve endings from the norepinephrine and

56, we pointed out that in Huntington’s disease, loss of

serotonin systems.

GABA-secreting neurons and acetylcholine-secreting

neurons is associated with specific abnormal motor pat-

terns plus dementia occurring in the same patient.

Schizophrenia—Possible

Exaggerated Function of Part of the

Dopamine System

Depression and Manic-Depressive

Psychoses—Decreased Activity of

Schizophrenia comes in many varieties. One of the most

the Norepinephrine and Serotonin

common types is seen in the person who hears voices

Neurotransmitter Systems

and has delusions of grandeur, intense fear, or other

types of feelings that are unreal. Many schizophrenics

Much evidence has accumulated suggesting that mental

(1) are highly paranoid, with a sense of persecution from

depression psychosis, which occurs in about 8 million

outside sources; (2) may develop incoherent speech, dis-

people in the United States, might be caused by dimin-

sociation of ideas, and abnormal sequences of thought;

ished formation in the brain of norepinephrine or sero-

and (3) are often withdrawn, sometimes with abnormal

tonin, or both. (New evidence has implicated still other

posture and even rigidity.

746

Unit XI The Nervous System: C. Motor and Integrative Neurophysiology

There are reasons to believe that schizophrenia

behavioral disturbances in the later stages of the

results from one or more of three possibilities: (1) mul-

disease. Patients with Alzheimer’s disease usually

tiple areas in the cerebral cortex prefrontal lobes in

require continuous care within a few years after the

which neural signals have become blocked or where

disease begins.

processing of the signals becomes dysfunctional because

Alzheimer’s disease is the most common form of

many synapses normally excited by the neurotransmit-

dementia in the elderly and about 5 million people in

ter glutamate lose their responsiveness to this transmit-

the United States are estimated to be afflicted by this

ter; (2) excessive excitement of a group of neurons that

disorder. The percentage of persons with Alzheimer’s

secrete dopamine in the behavioral centers of the brain,

disease approximately doubles with every five years of

including in the frontal lobes; and/or (3) abnormal func-

age, with about 1 percent of 60-year-olds and about 30

tion of a crucial part of the brain’s limbic behavioral

percent of 85-year-olds having the disease.

control system centered around the hippocampus.

The reason for believing that the prefrontal lobes are

Alzheimer’s Disease Is Associated with Accumulation of Brain

involved in schizophrenia is that a schizophrenic-like

Beta-Amyloid Peptide. Pathologically, one finds increased

pattern of mental activity can be induced in monkeys by

amounts of beta-amyloid peptide in the brains of

making multiple minute lesions in widespread areas of

patients with Alzheimer’s disease. The peptide accumu-

the prefrontal lobes.

lates in amyloid plaques, which range in diameter from

Dopamine has been implicated as a possible cause of

10 micrometers to several hundred micrometers and are

schizophrenia because many patients with Parkinson’s

found in widespread areas of the brain, including in the

disease develop schizophrenic-like symptoms when

cerebral cortex, hippocampus, basal ganglia, thalamus,

they are treated with the drug called L-dopa. This drug

and even the cerebellum. Thus, Alzheimer’s disease

releases dopamine in the brain, which is advantageous

appears to be a metabolic degenerative disease.

for treating Parkinson’s disease, but at the same time it

A key role for excess accumulation of beta-amyloid

depresses various portions of the prefrontal lobes and

peptide in the pathogenesis of Alzheimer’s disease is

other related areas.

suggested by the following observations: (1) all cur-

It has been suggested that in schizophrenia excess

rently known mutations associated with Alzheimer’s

dopamine is secreted by a group of dopamine-secreting

disease increase the production of beta-amyloid

neurons whose cell bodies lie in the ventral tegmentum

peptide; (2) patients with trisomy 21 (Down syndrome)

of the mesencephalon, medial and superior to the sub-

have three copies of the gene for amyloid precursor

stantia nigra. These neurons give rise to the so-called

protein and develop neurological characteristics of

mesolimbic dopaminergic system that projects nerve

Alzheimer’s disease by midlife; (3) patients who have

fibers and dopamine secretion into the medial and ante-

abnormality of a gene that controls apolipoprotein E, a

rior portions of the limbic system, especially into the

blood protein that transports cholesterol to the tissues,

hippocampus, amygdala, anterior caudate nucleus, and

have accelerated deposition of amyloid and greatly

portions of the prefrontal lobes. All of these are pow-

increased risk for Alzheimer’s disease; (4) transgenic

erful behavioral control centers.

mice that overproduce the human amyloid precursor

An even more compelling reason for believing that

protein have learning and memory deficits in associa-

schizophrenia might be caused by excess production of

tion with the accumulation of amyloid plaques; and (5)

dopamine is that many drugs that are effective in treat-

generation of anti-amyloid antibodies in humans with

ing schizophrenia—such as chlorpromazine, haloperi-

Alzheimer’s disease appears to attenuate the disease

dol, and thiothixene—-all either decrease secretion of

process.

dopamine at dopaminergic nerve endings or decrease

the effect of dopamine on subsequent neurons.

Vascular Disorders May Contribute to Progression of Alzheimer’s

Finally, possible involvement of the hippocampus in

Disease. There is also accumulating evidence that

schizophrenia was discovered recently when it was

cerebrovascular disease caused by hypertension and

learned that in schizophrenia, the hippocampus is often

atherosclerosis may play a role in Alzheimer’s disease.

reduced in size, especially in the dominant hemisphere.

Cerebrovascular disease is the second most common

cause of acquired cognitive impairment and dementia

and likely contributes to cognitive decline in

Alzheimer’s Disease—Amyloid

Alzheimer’s disease. In fact, many of the common risk

Plaques and Depressed Memory

factors for cerebrovascular disease, such as hyperten-

sion, diabetes, and hyperlipidemia, are also recognized

Alzheimer’s disease is defined as premature aging of the

to greatly increase the risk for developing Alzheimer’s

brain, usually beginning in mid-adult life and progress-

disease.

ing rapidly to extreme loss of mental powers—similar

to that seen in very, very old age. The clinical features

of Alzheimer’s disease include (1) an amnesic type of

memory impairment, (2) deterioration of language, and

References

(3) visuospatial deficits. Motor and sensory abnormali-

ties, gait disturbances, and seizures are uncommon until

Aldrich MS: Sleep Medicine: Normal Sleep and Its Disor-

the late phases of the disease. One consistent finding in

ders. New York: Oxford University Press, 1999.

Alzheimer’s disease is loss of neurons in that part of the

Beardsley T: Waking up. Sci Am Jul 18, 1996.

limbic pathway that drives the memory process. Loss of

Bryant PA, Trinder J, Curtis N: Sick and tired: does sleep

this memory function is devastating.

have a vital role in the immune system? Nat Rev Immunol

Alzheimer’s disease is a progressive and fatal neu-

4:457, 2004.

rodegenerative disorder that results in impairment of

Casserly I, Topol E: Convergence of atherosclerosis and

the person’s ability to perform activities of daily living

Alzheimer’s disease: inflammation, cholesterol, and mis-

as well as a variety of neuropsychiatric symptoms and

folded proteins. Lancet 363:1139, 2004.

Chapter 59

States of Brain Activity—Sleep, Brain Waves, Epilepsy, Psychoses

747

Cummings JL: Alzheimer’s disease. N Engl J Med 351:56,

Iadecola C: Neurovascular regulation in the normal brain

2004.

and in Alzheimer’s disease. Nat Rev Neurosci 5:347-360,

de la Torre JC: Is Alzheimer’s disease a neurodegenerative

2004.

or a vascular disorder? Data, dogma, and dialectics. Lancet

LaRoche SM, Helmers SL: The new antiepileptic drugs: sci-

Neurol 3:184, 2004.

entific review. JAMA 291:605, 2004.

George AL Jr: Molecular basis of inherited epilepsy. Arch

McCormick DA, Contreras D: On the cellular and network

Neurol 61:473, 2004.

bases of epileptic seizures. Annu Rev Physiol

63:815,

Gerashchenko D, Shiromani PJ: Different neuronal pheno-

2001.

types in the lateral hypothalamus and their role in sleep

Noebels JL: The biology of epilepsy genes. Annu Rev Neu-

and wakefulness. Mol Neurobiol 29:41, 2004.

rosci 26:599, 2003.

Golde TE: Alzheimer disease therapy: can the amyloid

Selkoe DJ: Alzheimer disease: mechanistic understanding

cascade be halted? J Clin Invest 111:11, 2003.

predicts novel therapies. Ann Intern Med 140:627, 2004.

Gourfinkel-An I, Baulac S, Nabbout R, et al: Monogenic

Selkoe DJ: Alzheimer’s disease: genes, proteins, and therapy.

idiopathic epilepsies. Lancet Neurol 3:209, 2004.

Physiol Rev 81:741, 2001.

Greene R, Siegel J: Sleep: a functional enigma. Neuromo-

Steinlein OK: Genetic mechanisms that underlie epilepsy.

lecular Med 5:59, 2004.

Nat Rev Neurosci 5:400-408, 2004.

Heller HC, Ruby NF: Sleep and circadian rhythms in mam-

malian torpor. Annu Rev Physiol 66:275, 2004.

C H A P T E R

The Autonomic Nervous System

and the Adrenal Medulla

The portion of the nervous system that controls

most visceral functions of the body is called the

autonomic nervous system. This system helps to

control arterial pressure, gastrointestinal motility,

gastrointestinal secretion, urinary bladder empty-

ing, sweating, body temperature, and many other

activities, some of which are controlled almost

entirely and some only partially by the autonomic

nervous system.

One of the most striking characteristics of the autonomic nervous system is

the rapidity and intensity with which it can change visceral functions. For

instance, within 3 to 5 seconds it can increase the heart rate to twice normal,

and within 10 to 15 seconds the arterial pressure can be doubled; or, at the other

extreme, the arterial pressure can be decreased low enough within 10 to 15

seconds to cause fainting. Sweating can begin within seconds, and the urinary

bladder may empty involuntarily, also within seconds.

General Organization of the Autonomic

Nervous System

The autonomic nervous system is activated mainly by centers located in the

spinal cord, brain stem, and hypothalamus. Also, portions of the cerebral cortex,

especially of the limbic cortex, can transmit signals to the lower centers and in

this way influence autonomic control.

The autonomic nervous system also often operates by means of visceral

reflexes. That is, subconscious sensory signals from a visceral organ can enter

the autonomic ganglia, the brain stem, or the hypothalamus and then return

subconscious reflex responses directly back to the visceral organ to control its

activities.

The efferent autonomic signals are transmitted to the various organs of the

body through two major subdivisions called the sympathetic nervous system and

the parasympathetic nervous system, the characteristics and functions of which

follow.

Physiologic Anatomy of the Sympathetic Nervous System

Figure 60-1 shows the general organization of the peripheral portions of the sym-

pathetic nervous system. Shown specifically in the figure are (1) one of the two

paravertebral sympathetic chains of ganglia that are interconnected with the spinal

nerves on the side of the vertebral column, (2) two prevertebral ganglia (the celiac

and hypogastric), and (3) nerves extending from the ganglia to the different inter-

nal organs.

The sympathetic nerve fibers originate in the spinal cord along with spinal nerves

between cord segments T-1 and L-2 and pass first into the sympathetic chain and

then to the tissues and organs that are stimulated by the sympathetic nerves.

Preganglionic and Postganglionic Sympathetic Neurons

The sympathetic nerves are different from skeletal motor nerves in the following

way: Each sympathetic pathway from the cord to the stimulated tissue is composed

748

Chapter 60

The Autonomic Nervous System and the Adrenal Medulla

749

Posterior root

Spinal nerve

Eye

Intermedio-

White ramus

lateral horn

Gray ramus

Piloerector

muscle

Sympathetic chain

Heart

T-1

Sweat

Bronchi

Anterior root

gland

Preganglionic nerve

fiber

Peripheral ganglion

Blood

Celiac

Postganglionic nerve

vessel

ganglion

fibers

Pylorus

Effector endings

L-1

Sensory endings

Adrenal

Gut

medulla

Kidney

Ureter

Figure 60-2

Nerve connections between the spinal cord, spinal nerves, sym-

Intestine

pathetic chain, and peripheral sympathetic nerves.

Ileocecal valve

Sympathetic Nerve Fibers in the Skeletal Nerves. Some of the

Hypogastric plexus

Anal sphincter

postganglionic fibers pass back from the sympathetic

Detrusor

chain into the spinal nerves through gray rami at all

levels of the cord, as shown in Figure 60-2. These sym-

Trigone

pathetic fibers are all very small type C fibers, and they

extend to all parts of the body by way of the skeletal

Figure 60-1

nerves. They control the blood vessels, sweat glands, and

Sympathetic nervous system. The black dashed lines represent

piloerector muscles of the hairs. About 8 per cent of the

postganglionic fibers in the gray rami leading from the sympa-

fibers in the average skeletal nerve are sympathetic

thetic chains into spinal nerves for distribution to blood vessels,

fibers, a fact that indicates their great importance.

sweat glands, and piloerector muscles.

Segmental Distribution of the Sympathetic Nerve Fibers. The

of two neurons, a preganglionic neuron and a postgan-

sympathetic pathways that originate in the different

glionic neuron, in contrast to only a single neuron in the

segments of the spinal cord are not necessarily distrib-

skeletal motor pathway. The cell body of each pregan-

uted to the same part of the body as the somatic spinal

glionic neuron lies in the intermediolateral horn of the

nerve fibers from the same segments. Instead, the sym-

spinal cord; its fiber passes, as shown in Figure 60-2,

pathetic fibers from cord segment T-1 generally pass up

through an anterior root of the cord into the corre-

the sympathetic chain to terminate in the head; from T-2

sponding spinal nerve.

to terminate in the neck; from T-3, T-4, T-5, and T-6

Immediately after the spinal nerve leaves the spinal

into the thorax; from T-7, T-8, T-9, T-10, and T-11 into

canal, the preganglionic sympathetic fibers leave the

the abdomen; and from T-12, L-1, and L-2 into the legs.

spinal nerve and pass through a white ramus into one of

This distribution is only approximate and overlaps

the ganglia of the sympathetic chain. Then the course

greatly.

of the fibers can be one of the following three: (1) It

The distribution of sympathetic nerves to each organ

can synapse with postganglionic sympathetic neurons

is determined partly by the locus in the embryo from

in the ganglion that it enters; (2) it can pass upward

which the organ originated. For instance, the heart

or downward in the chain and synapse in one of the

receives many sympathetic nerve fibers from the neck

other ganglia of the chain; or (3) it can pass for variable

portion of the sympathetic chain because the heart orig-

distances through the chain and then through one

inated in the neck of the embryo before translocating

of the sympathetic nerves radiating outward from the

into the thorax. Likewise, the abdominal organs receive

chain, finally synapsing in a peripheral sympathetic

most of their sympathetic innervation from the lower

ganglion.

thoracic spinal cord segments because most of the prim-

The postganglionic sympathetic neuron thus origi-

itive gut originated in this area.

nates either in one of the sympathetic chain ganglia

or in one of the peripheral sympathetic ganglia.

Special Nature of the Sympathetic Nerve Endings in the Adrenal

From either of these two sources, the postganglionic

Medullae. Preganglionic sympathetic nerve fibers pass,

fibers then travel to their destinations in the various

without synapsing, all the way from the intermedio-

organs.

lateral horn cells of the spinal cord, through the

750

Unit XI The Nervous System: C. Motor and Integrative Neurophysiology

sympathetic chains, then through the splanchnic nerves,

esophagus, stomach, entire small intestine, proximal half

and finally into the two adrenal medullae. There they

of the colon, liver, gallbladder, pancreas, kidneys, and

end directly on modified neuronal cells that secrete epi-

upper portions of the ureters.

nephrine and norepinephrine into the blood stream.

Parasympathetic fibers in the third cranial nerve go to

These secretory cells embryologically are derived from

the pupillary sphincter and ciliary muscle of the eye.

nervous tissue and are actually themselves postgan-

Fibers from the seventh cranial nerve pass to the

glionic neurons; indeed, they even have rudimentary

lacrimal, nasal, and submandibular glands. And fibers

nerve fibers, and it is the endings of these fibers that

from the ninth cranial nerve go to the parotid gland.

secrete the adrenal hormones epinephrine and

The sacral parasympathetic fibers are in the pelvic

norepinephrine.

nerves, which pass through the spinal nerve sacral

plexus on each side of the cord at the S-2 and S-3 levels.

These fibers then distribute to the descending colon,

Physiologic Anatomy of the

rectum, urinary bladder, and lower portions of the

Parasympathetic Nervous System

ureters. Also, this sacral group of parasympathetics sup-

plies nerve signals to the external genitalia to cause

The parasympathetic nervous system is shown in Figure

erection.

60-3, demonstrating that parasympathetic fibers leave

the central nervous system through cranial nerves III,

Preganglionic and Postganglionic Parasympathetic Neurons.

VII, IX, and X; additional parasympathetic fibers leave

The parasympathetic system, like the sympathetic, has

the lowermost part of the spinal cord through the

both preganglionic and postganglionic neurons.

second and third sacral spinal nerves and occasionally

However, except in the case of a few cranial parasym-

the first and fourth sacral nerves. About 75 per cent of

pathetic nerves, the preganglionic fibers pass uninter-

all parasympathetic nerve fibers are in the vagus nerves

rupted all the way to the organ that is to be controlled.

(cranial nerve X), passing to the entire thoracic and

In the wall of the organ are located the postganglionic

abdominal regions of the body. Therefore, a physiologist

neurons. The preganglionic fibers synapse with these,

speaking of the parasympathetic nervous system often

and very, very short postganglionic fibers, a fraction of

thinks mainly of the two vagus nerves. The vagus nerves

a millimeter to several centimeters in length, leave the

supply parasympathetic

nerves

to the heart, lungs,

neurons to innervate the tissues of the organ. This loca-

tion of the parasympathetic postganglionic neurons in

the visceral organ itself is quite different from the

arrangement of the sympathetic ganglia, because the

cell bodies of the sympathetic postganglionic neurons

Ciliary ganglion

are almost always located in the ganglia of the sympa-

Ciliary muscles of eye

thetic chain or in various other discrete ganglia in the

III

abdomen, rather than in the excited organ itself.

Pupillary sphincter

Sphenopalatine ganglion

VII

Lacrimal glands

Nasal glands

Basic Characteristics

Submandibular ganglion

of Sympathetic and

Submandibular gland

Parasympathetic Function

Otic ganglion

Parotid gland

Cholinergic and Adrenergic Fibers—

Heart

Secretion of Acetylcholine or

Norepinephrine

The sympathetic and parasympathetic nerve fibers

Stomach

secrete mainly one or the other of two synaptic trans-

mitter substances, acetylcholine or norepinephrine.

Pylorus

Those fibers that secrete acetylcholine are said to be

cholinergic. Those that secrete norepinephrine are said

Colon

to be adrenergic, a term derived from adrenalin, which

is an alternate name for epinephrine.

Small intestine

All preganglionic neurons are cholinergic in both

Sacral

the sympathetic and the parasympathetic nervous

systems. Acetylcholine or acetylcholine-like sub-

Ileocecal valve

stances, when applied to the ganglia, will excite both

Anal sphincter

sympathetic and parasympathetic postganglionic

neurons. Either all or almost all of the postganglionic

Bladder

neurons of the parasympathetic system are also cholin-

Detrusor

ergic. Conversely, most of the postganglionic sym-

Trigone

pathetic neurons are adrenergic. However, the

postganglionic sympathetic nerve fibers to the sweat

Figure 60-3

glands, to the piloerector muscles of the hairs, and to

Parasympathetic nervous system.

a very few blood vessels are cholinergic.

Chapter 60

The Autonomic Nervous System and the Adrenal Medulla

751

Thus, the terminal nerve endings of the parasympa-

Synthesis of Acetylcholine, Its Destruction After Secretion, and

thetic system all or virtually all secrete acetylcholine.

Its Duration of Action. Acetylcholine is synthesized in the

Almost all of the sympathetic nerve endings secrete

terminal endings and varicosities of the cholinergic

norepinephrine, but a few secrete acetylcholine. These

nerve fibers where it is stored in vesicles in highly con-

hormones in turn act on the different organs to cause

centrated form until it is released. The basic chemical

respective parasympathetic or sympathetic effects.

reaction of this synthesis is the following:

Therefore, acetylcholine is called a parasympathetic

choline acetyl-

transferase

transmitter and norepinephrine is called a sympathetic

Acetyl-CoA+Choline

ææ

æææÆAcetylcholine

transmitter.

The molecular structures of acetylcholine and nor-

Once acetylcholine is secreted into a tissue by a

epinephrine are the following:

cholinergic nerve ending, it persists in the tissue for a

few seconds while it performs its nerve signal trans-

mitter function. Then it is split into an acetate ion and

choline, catalyzed by the enzyme acetylcholinesterase

CH₃

that is bound with collagen and glycosaminoglycans in

the local connective tissue. This is the same mechanism

O CH₂

CH₂

for acetylcholine signal transmission and subsequent

CH₃

acetylcholine destruction that occurs at the neuro-

CH₃

muscular junctions of skeletal nerve fibers. The choline

Acetylcholine

that is formed is then transported back into the ter-

minal nerve ending, where it is used again and again

for synthesis of new acetylcholine.

Synthesis of Norepinephrine, Its Removal, and Its Duration of

Action. Synthesis of norepinephrine begins in the axo-

plasm of the terminal nerve endings of adrenergic

CH₂

NH₂

nerve fibers but is completed inside the secretory vesi-

cles. The basic steps are the following:

hydroxylation

Tyrosineæ

ææææÆDopa

Norepinephrine

decarboxylation

Dopaæ

ææææÆDopamine

3. Transport of dopamine into the vesicles

Mechanisms of Transmitter Secretion and

hydroxylation

Dopamine

ææææÆNorepinephrine

Subsequent Removal of the Transmitter

at the Postganglionic Endings

In the adrenal medulla, this reaction goes still one

step further to transform about 80 per cent of the nor-

Secretion of Acetylcholine and Norepinephrine by Postgan-

epinephrine into epinephrine, as follows:

glionic Nerve Endings. A few of the postganglionic

methylation

Norepinephrine

æææÆEpinephrine

autonomic nerve endings, especially those of the

parasympathetic nerves, are similar to but much

After secretion of norepinephrine by the terminal

smaller than those of the skeletal neuromuscular junc-

nerve endings, it is removed from the secretory site in

tion. However, many of the parasympathetic nerve

three ways: (1) reuptake into the adrenergic nerve

fibers and almost all the sympathetic fibers merely

endings themselves by an active transport process—

touch the effector cells of the organs that they inner-

accounting for removal of 50 to 80 per cent of the

vate as they pass by; or in some instances, they termi-

secreted norepinephrine; (2) diffusion away from the

nate in connective tissue located adjacent to the cells

nerve endings into the surrounding body fluids and

that are to be stimulated. Where these filaments touch

then into the blood—accounting for removal of most

or pass over or near the cells to be stimulated, they

of the remaining norepinephrine; and (3) destruction

usually have bulbous enlargements called varicosities;

of small amounts by tissue enzymes (one of these

it is in these varicosities that the transmitter vesicles of

enzymes is monoamine oxidase, which is found in the

acetylcholine or norepinephrine are synthesized and

nerve endings, and another is catechol-O-methyl trans-

stored. Also in the varicosities are large numbers of

ferase, which is present diffusely in all tissues).

mitochondria that supply adenosine triphosphate,

Ordinarily, the norepinephrine secreted directly into

which is required to energize acetylcholine or norepi-

a tissue remains active for only a few seconds, demon-

nephrine synthesis.

strating that its reuptake and diffusion away from the

When an action potential spreads over the terminal

tissue are rapid. However, the norepinephrine and

fibers, the depolarization process increases the perme-

epinephrine secreted into the blood by the adrenal

ability of the fiber membrane to calcium ions, allowing

medullae remain active until they diffuse into some

these ions to diffuse into the nerve terminals or nerve

tissue, where they can be destroyed by catechol-O-

varicosities. The calcium ions in turn cause the termi-

methyl transferase; this occurs mainly in the liver.

nals or varicosities to empty their contents to the exte-

Therefore, when secreted into the blood, both norepi-

rior. Thus, the transmitter substance is secreted.

nephrine and epinephrine remain very active for 10 to

752

Unit XI The Nervous System: C. Motor and Integrative Neurophysiology

30 seconds; but their activity declines to extinction

are likely to be entirely different from those in other

over 1 to several minutes.

organs.

Two Principal Types of Acetylcholine

Receptors on the Effector Organs

Receptors—Muscarinic and Nicotinic

Receptors

Before an acetylcholine, norepinephrine, or epineph-

Acetylcholine activates mainly two types of receptors.

rine secreted at an autonomic nerve ending can stim-

They are called muscarinic and nicotinic receptors. The

ulate an effector organ, it must first bind with specific

reason for these names is that muscarine, a poison

receptors on the effector cells. The receptor is on the

from toadstools, activates only muscarinic receptors

outside of the cell membrane, bound as a prosthetic

and will not activate nicotinic receptors, whereas nico-

group to a protein molecule that penetrates all the way

tine activates only nicotinic receptors; acetylcholine

through the cell membrane. When the transmitter sub-

activates both of them.

stance binds with the receptor, this causes a confor-

Muscarinic receptors are found on all effector cells

mational change in the structure of the protein

that are stimulated by the postganglionic cholinergic

molecule. In turn, the altered protein molecule excites

neurons of either the parasympathetic nervous system

or inhibits the cell, most often by (1) causing a change

or the sympathetic system.

in cell membrane permeability to one or more ions or

Nicotinic receptors are found in the autonomic

(2) activating or inactivating an enzyme attached to

ganglia at the synapses between the preganglionic and

the other end of the receptor protein where it pro-

postganglionic neurons of both the sympathetic and

trudes into the interior of the cell.

parasympathetic systems. (Nicotinic receptors are also

present at many nonautonomic nerve endings—for

Excitation or Inhibition of the Effector Cell by Changing Its

instance, at the neuromuscular junctions in skeletal

Membrane Permeability. Because the receptor protein

muscle [discussed in Chapter 7].)

is an integral part of the cell membrane, a conforma-

An understanding of the two types of receptors is

tional change in structure of the receptor protein

especially important because specific drugs are fre-

often opens or closes an ion channel through the

quently used as medicine to stimulate or block one or

interstices of the protein molecule, thus altering the

the other of the two types of receptors.

permeability of the cell membrane to various ions.

For instance, sodium and/or calcium ion channels

Adrenergic Receptors—Alpha and

frequently become opened and allow rapid influx of

Beta Receptors

the respective ions into the cell, usually depolarizing

There are also two major types of adrenergic recep-

the cell membrane and exciting the cell. At other

tors, alpha receptors and beta receptors. (The beta

times, potassium channels are opened, allowing potas-

receptors in turn are divided into beta₁ and beta₂ recep-

sium ions to diffuse out of the cell, and this usually

tors because certain chemicals affect only certain beta

inhibits the cell because loss of electropositive

receptors. Also, there is a division of alpha receptors

potassium ions creates hypernegativity inside the cell.

into alpha₁ and alpha₂ receptors.)

In some cells, the changed intracellular ion environ-

Norepinephrine and epinephrine, both of which are

ment will cause an internal cell action, such as a direct

secreted into the blood by the adrenal medulla,

effect of calcium ions to promote smooth muscle

have slightly different effects in exciting the alpha and

contraction.

beta receptors. Norepinephrine excites mainly alpha

receptors but excites the beta receptors to a lesser

Receptor Action by Altering Intracellular “Second Messenger”

extent as well. Conversely, epinephrine excites both

Enzymes. Another way a receptor often functions is to

types of receptors approximately equally. Therefore,

activate or inactivate an enzyme (or other intracellu-

the relative effects of norepinephrine and epinephrine

lar chemical) inside the cell. The enzyme often is

on different effector organs are determined by the

attached to the receptor protein where the receptor

types of receptors in the organs. If they are all

protrudes into the interior of the cell. For instance,

beta receptors, epinephrine will be the more effective

binding of norepinephrine with its receptor on the

excitant.

outside of many cells increases the activity of the

Table 60-1 gives the distribution of alpha and beta

enzyme adenylyl cyclase on the inside of the cell, and

receptors in some of the organs and systems controlled

this causes formation of cyclic adenosine monophos-

by the sympathetics. Note that certain alpha functions

phate (cAMP). The cAMP in turn can initiate any one

are excitatory, whereas others are inhibitory. Likewise,

of many different intracellular actions, the exact effect

certain beta functions are excitatory and others are

depending on the chemical machinery of the effector

inhibitory. Therefore, alpha and beta receptors are not

cell.

necessarily associated with excitation or inhibition but

It is easy to understand how an autonomic trans-

simply with the affinity of the hormone for the recep-

mitter substance can cause inhibition in some organs

tors in the given effector organ.

or excitation in others. This is usually determined by

A synthetic hormone chemically similar to epi-

the nature of the receptor protein in the cell mem-

nephrine and norepinephrine, isopropyl norepineph-

brane and the effect of receptor binding on its con-

rine, has an extremely strong action on beta receptors

formational state. In each organ, the resulting effects

but essentially no action on alpha receptors.

Chapter 60

The Autonomic Nervous System and the Adrenal Medulla

753

Focusing of the lens is controlled almost entirely by

Table 60-1

the parasympathetic nervous system. The lens is nor-

Adrenergic Receptors and Function

mally held in a flattened state by intrinsic elastic tension

of its radial ligaments. Parasympathetic excitation con-

tracts the ciliary muscle, which is a ringlike body of

Alpha Receptor

Beta Receptor

smooth muscle fibers that encircles the outside ends

Vasoconstriction

Vasodilation (b₂)

of the lens radial ligaments. This contraction releases

Iris dilation

Cardioacceleration (b₁)

the tension on the ligaments and allows the lens to

Intestinal relaxation

Increased myocardial

become more convex, causing the eye to focus on

strength (b₁)

objects near at hand. The detailed focusing mechanism

Intestinal sphincter contraction

Intestinal relaxation (b₂)

is discussed in Chapters 49 and 51 in relation to func-

Uterus relaxation (b₂)

tion of the eyes.

Pilomotor contraction

Bronchodilation (b₂)

Bladder sphincter contraction

Calorigenesis (b₂)

Glycogenolysis (b₂)

Glands of the Body. The nasal, lacrimal, salivary, and many

Lipolysis (b₁)

gastrointestinal glands are strongly stimulated by the

Bladder wall relaxation (b₂)

parasympathetic nervous system, usually resulting in

copious quantities of watery secretion. The glands of

the alimentary tract most strongly stimulated by the

parasympathetics are those of the upper tract, especially

those of the mouth and stomach. On the other hand, the

glands of the small and large intestines are controlled

Excitatory and Inhibitory

principally by local factors in the intestinal tract itself

Actions of Sympathetic and

and by the intestinal enteric nervous system and much

Parasympathetic Stimulation

less by the autonomic nerves.

Sympathetic stimulation has a direct effect on most

Table 60-2 lists the effects on different visceral func-

alimentary gland cells to cause formation of a concen-

tions of the body caused by stimulating either the

trated secretion that contains high percentages of

enzymes and mucus. But it also causes vasoconstriction

parasympathetic nerves or the sympathetic nerves.

of the blood vessels that supply the glands and in this

From this table, it can be seen again that sympathetic

way sometimes reduces their rates of secretion.

stimulation causes excitatory effects in some organs but

The sweat glands secrete large quantities of sweat

inhibitory effects in others. Likewise, parasympathetic

when the sympathetic nerves are stimulated, but no

stimulation causes excitation in some but inhibition in

effect is caused by stimulating the parasympathetic

others. Also, when sympathetic stimulation excites a

nerves. However, the sympathetic fibers to most sweat

particular organ, parasympathetic stimulation some-

glands are cholinergic

(except for a few adrenergic

times inhibits it, demonstrating that the two systems

fibers to the palms and soles), in contrast to almost all

occasionally act reciprocally to each other. But most

other sympathetic fibers, which are adrenergic. Further-

organs are dominantly controlled by one or the other

more, the sweat glands are stimulated primarily by

centers in the hypothalamus that are usually considered

of the two systems.

to be parasympathetic centers. Therefore, sweating

There is no generalization one can use to explain

could be called a parasympathetic function, even though

whether sympathetic or parasympathetic stimulation

it is controlled by nerve fibers that anatomically are dis-

will cause excitation or inhibition of a particular organ.

tributed through the sympathetic nervous system.

Therefore, to understand sympathetic and parasympa-

The apocrine glands in the axillae secrete a thick,

thetic function, one must learn all the separate func-

odoriferous secretion as a result of sympathetic stimu-

tions of these two nervous systems on each organ, as

lation, but they do not respond to parasympathetic stim-

listed in Table 60-2. Some of these functions need to

ulation. This secretion actually functions as a lubricant

be clarified in still greater detail, as follows.

to allow easy sliding motion of the inside surfaces under

the shoulder joint. The apocrine glands, despite their

close embryological relation to sweat glands, are acti-

Effects of Sympathetic and

vated by adrenergic fibers rather than by cholinergic

Parasympathetic Stimulation

fibers and are also controlled by the sympathetic centers

of the central nervous system rather than by the

on Specific Organs

parasympathetic centers.

Eyes. Two functions of the eyes are controlled by the

autonomic nervous system. They are (1) the pupillary

Intramural Nerve Plexus of the Gastrointestinal System. The

opening and (2) the focus of the lens.

gastrointestinal system has its own intrinsic set of nerves

Sympathetic stimulation contracts the meridional

known as the intramural plexus or the intestinal enteric

fibers of the iris that dilate the pupil, whereas parasym-

nervous system, located in the walls of the gut. Also, both

pathetic stimulation contracts the circular muscle of the

parasympathetic and sympathetic stimulation originat-

iris to constrict the pupil.

ing in the brain can affect gastrointestinal activity

The parasympathetics that control the pupil are

mainly by increasing or decreasing specific actions in

reflexly stimulated when excess light enters the eyes,

the gastrointestinal intramural plexus. Parasympathetic

which is explained in Chapter 51; this reflex reduces the

stimulation, in general, increases overall degree of activ-

pupillary opening and decreases the amount of light

ity of the gastrointestinal tract by promoting peristalsis

that strikes the retina. Conversely, the sympathetics

and relaxing the sphincters, thus allowing rapid propul-

become stimulated during periods of excitement and

sion of contents along the tract. This propulsive effect

increase pupillary opening at these times.

is associated with simultaneous increases in rates of

754

Unit XI The Nervous System: C. Motor and Integrative Neurophysiology

Table 60-2

Autonomic Effects on Various Organs of the Body

Organ

Effect of Sympathetic Stimulation

Effect of Parasympathetic Stimulation

Eye

Pupil

Dilated

Constricted

Ciliary muscle

Slight relaxation (far vision)

Constricted (near vision)

Glands

Vasoconstriction and slight secretion

Stimulation of copious secretion (containing many enzymes for

Nasal

enzyme-secreting glands)

Lacrimal

Parotid

Submandibular

Gastric

Pancreatic

Sweat glands

Copious sweating (cholinergic)

Sweating on palms of hands

Apocrine glands

Thick, odoriferous secretion

None

Blood vessels

Most often constricted

Most often little or no effect

Heart

Muscle

Increased rate

Slowed rate

Increased force of contraction

Decreased force of contraction (especially of atria)

Coronaries

Dilated (b₂); constricted (a)

Dilated

Lungs

Bronchi

Dilated

Constricted

Blood vessels

Mildly constricted

? Dilated

Gut

Lumen

Decreased peristalsis and tone

Increased peristalsis and tone

Sphincter

Increased tone (most times)

Relaxed (most times)

Liver

Glucose released

Slight glycogen synthesis

Gallbladder and bile ducts

Relaxed

Contracted

Kidney

Decreased output and renin secretion

None

Bladder

Detrusor

Relaxed (slight)

Contracted

Trigone

Contracted

Relaxed

Penis

Ejaculation

Erection

Systemic arterioles

Abdominal viscera

Constricted

None

Muscle

Constricted (adrenergic a)

None

Dilated (adrenergic b₂)

Dilated (cholinergic)

Skin

Constricted

None

Blood

Coagulation

Increased

None

Glucose

Increased

None

Lipids

Increased

None

Basal metabolism

Increased up to 100%

None

Adrenal medullary secretion

Increased

None

Mental activity

Increased

None

Piloerector muscles

Contracted

None

Skeletal muscle

Increased glycogenolysis

None

Increased strength

Fat cells

Lipolysis

None

secretion by many of the gastrointestinal glands,

thetic stimulation increases the effectiveness of the

described earlier.

heart as a pump, as required during heavy exercise,

Normal function of the gastrointestinal tract is not

whereas parasympathetic stimulation decreases heart

very dependent on sympathetic stimulation. However,

pumping, allowing the heart to rest between bouts of

strong sympathetic stimulation inhibits peristalsis and

strenuous activity.

increases the tone of the sphincters. The net result is

greatly slowed propulsion of food through the tract and

Systemic Blood Vessels. Most systemic blood vessels, espe-

sometimes decreased secretion as well—even to the

cially those of the abdominal viscera and skin of the

extent of sometimes causing constipation.

limbs, are constricted by sympathetic stimulation.

Parasympathetic stimulation has almost no effects on

Heart. In general, sympathetic stimulation increases the

most blood vessels except to dilate vessels in certain

overall activity of the heart. This is accomplished by

restricted areas, such as in the blush area of the face.

increasing both the rate and force of heart contraction.

Under some conditions, the beta function of the sym-

Parasympathetic stimulation causes mainly opposite

pathetics causes vascular dilation instead of the usual

effects—decreased heart rate and strength of contrac-

sympathetic vascular constriction, but this occurs rarely

tion. To express these effects in another way, sympa-

except after drugs have paralyzed the sympathetic alpha

Chapter 60

The Autonomic Nervous System and the Adrenal Medulla

755

vasoconstrictor effects, which, in blood vessels, are

greater effect in stimulating the beta receptors, has a

usually far dominant over the beta effects.

greater effect on cardiac stimulation than does nor-

epinephrine. Second, epinephrine causes only weak

Effect of Sympathetic and Parasympathetic Stimulation on Arter-

constriction of the blood vessels in the muscles, in com-

ial Pressure. The arterial pressure is determined by two

parison with much stronger constriction caused by

factors: propulsion of blood by the heart and resistance

norepinephrine. Because the muscle vessels represent

to flow of blood through the peripheral blood vessels.

a major segment of the vessels of the body, this differ-

Sympathetic stimulation increases both propulsion by

ence is of special importance because norepinephrine

the heart and resistance to flow, which usually causes a

marked acute increase in arterial pressure but often very

greatly increases the total peripheral resistance and

little change in long-term pressure unless the sympa-

elevates arterial pressure, whereas epinephrine raises

thetics stimulate the kidneys to retain salt and water at

the arterial pressure to a lesser extent but increases the

the same time.

cardiac output more.

Conversely, moderate parasympathetic stimulation

A third difference between the actions of epineph-

via the vagal nerves decreases pumping by the heart but

rine and norepinephrine relates to their effects on

has virtually no effect on vascular peripheral resistance.

tissue metabolism. Epinephrine has 5 to 10 times as

Therefore, the usual effect is a slight decrease in arte-

great a metabolic effect as norepinephrine. Indeed, the

rial pressure. But very strong vagal parasympathetic

epinephrine secreted by the adrenal medullae can

stimulation can almost stop or occasionally actually stop

increase the metabolic rate of the whole body often to

the heart entirely for a few seconds and cause tempo-

rary loss of all or most arterial pressure.

as much as 100 per cent above normal, in this way

increasing the activity and excitability of the body. It

Effects of Sympathetic and Parasympathetic Stimulation on Other

also increases the rates of other metabolic activities,

Functions of the Body. Because of the great importance of

such as glycogenolysis in the liver and muscle, and

the sympathetic and parasympathetic control systems,

glucose release into the blood.

they are discussed many times in this text in relation

In summary, stimulation of the adrenal medullae

to multiple body functions. In general, most of the

causes release of the hormones epinephrine and nor-

entodermal structures, such as the ducts of the liver,

epinephrine, which together have almost the same

gallbladder, ureter, urinary bladder, and bronchi, are

effects throughout the body as direct sympathetic

inhibited by sympathetic stimulation but excited by

stimulation, except that the effects are greatly pro-

parasympathetic stimulation. Sympathetic stimulation

also has multiple metabolic effects such as release of

longed, lasting 2 to 4 minutes after the stimulation is

glucose from the liver, increase in blood glucose con-

over.

centration, increase in glycogenolysis in both liver and

muscle, increase in skeletal muscle strength, increase in

Value of the Adrenal Medullae to the Function of the Sympa-

basal metabolic rate, and increase in mental activity.

thetic Nervous System. Epinephrine and norepinephrine

Finally, the sympathetics and parasympathetics are

are almost always released by the adrenal medullae at

involved in execution of the male and female sexual

the same time that the different organs are stimulated

acts, as explained in Chapters 80 and 81.

directly by generalized sympathetic activation. There-

fore, the organs are actually stimulated in two ways:

Function of the Adrenal Medullae

directly by the sympathetic nerves and indirectly by

the adrenal medullary hormones. The two means

Stimulation of the sympathetic nerves to the adrenal

of stimulation support each other, and either can, in

medullae causes large quantities of epinephrine and

most instances, substitute for the other. For instance,

norepinephrine to be released into the circulating

destruction of the direct sympathetic pathways to

blood, and these two hormones in turn are carried in

the different body organs does not abrogate sympa-

the blood to all tissues of the body. On the average,

thetic excitation of the organs because norepinephrine

about 80 per cent of the secretion is epinephrine and

and epinephrine are still released into the circulating

20 per cent is norepinephrine, although the relative

blood and indirectly cause stimulation. Likewise,

proportions can change considerably under different

loss of the two adrenal medullae usually has little

physiologic conditions.

effect on the operation of the sympathetic nervous

The circulating epinephrine and norepinephrine

system because the direct pathways can still perform

have almost the same effects on the different organs

almost all the necessary duties. Thus, the dual mecha-

as the effects caused by direct sympathetic stimulation,

nism of sympathetic stimulation provides a safety

except that the effects last 5 to 10 times as long because

factor, one mechanism substituting for the other if it is

both of these hormones are removed from the blood

missing.

slowly over a period of 2 to 4 minutes.

Another important value of the adrenal medullae

The circulating norepinephrine causes constriction

is the capability of epinephrine and norepinephrine

of essentially all the blood vessels of the body; it also

to stimulate structures of the body that are not

causes increased activity of the heart, inhibition of the

innervated by direct sympathetic fibers. For instance,

gastrointestinal tract, dilation of the pupils of the eyes,

the metabolic rate of every cell of the body is increased

and so forth.

by these hormones, especially by epinephrine,

Epinephrine causes almost the same effects as those

even though only a small proportion of all the cells

caused by norepinephrine, but the effects differ in the

in the body are innervated directly by sympathetic

following respects: First, epinephrine, because of its

fibers.

756

Unit XI The Nervous System: C. Motor and Integrative Neurophysiology

Relation of Stimulus Rate

Effect of Loss of Sympathetic or Parasympathetic Tone After

Denervation. Immediately after a sympathetic or

to Degree of Sympathetic and

parasympathetic nerve is cut, the innervated organ

Parasympathetic Effect

loses its sympathetic or parasympathetic tone. In the

case of the blood vessels, for instance, cutting the sym-

A special difference between the autonomic nervous

pathetic nerves results within 5 to 30 seconds in almost

system and the skeletal nervous system is that only a

maximal vasodilation. However, over minutes, hours,

low frequency of stimulation is required for full acti-

days, or weeks, intrinsic tone in the smooth muscle of

vation of autonomic effectors. In general, only one

the vessels increases—that is, increased tone caused by

nerve impulse every few seconds suffices to maintain

increased smooth muscle contractile force that is not

normal sympathetic or parasympathetic effect, and full

the result of sympathetic stimulation but of chemical

activation occurs when the nerve fibers discharge 10 to

adaptations in the smooth muscle fibers themselves.

20 times per second. This compares with full activation

This intrinsic tone eventually restores almost normal

in the skeletal nervous system at 50 to 500 or more

vasoconstriction.

impulses per second.

Essentially the same effects occur in most other

effector organs whenever sympathetic or parasympa-

thetic tone is lost. That is, intrinsic compensation soon

Sympathetic and

develops to return the function of the organ almost to

Parasympathetic “Tone”

its normal basal level. However, in the parasympa-

thetic system, the compensation sometimes requires

Normally, the sympathetic and parasympathetic

many months. For instance, loss of parasympathetic

systems are continually active, and the basal rates of

tone to the heart after cardiac vagotomy increases the

activity are known, respectively, as sympathetic tone

heart rate to 160 beats per minute in a dog, and this

and parasympathetic tone.

will still be partially elevated 6 months later.

The value of tone is that it allows a single nervous

system both to increase and to decrease the activity of

Denervation Supersensitivity of

a stimulated organ. For instance, sympathetic tone nor-

Sympathetic and Parasympathetic

mally keeps almost all the systemic arterioles con-

Organs After Denervation

stricted to about one half their maximum diameter.

By increasing the degree of sympathetic stimulation

During the first week or so after a sympathetic or

above normal, these vessels can be constricted even

parasympathetic nerve is destroyed, the innervated

more; conversely, by decreasing the stimulation below

organ becomes more sensitive to injected norepineph-

normal, the arterioles can be dilated. If it were not for

rine or acetylcholine, respectively. This effect is demon-

the continual background sympathetic tone, the sym-

strated in Figure

60-4, showing blood flow in the

pathetic system could cause only vasoconstriction,

forearm before removal of the sympathetics to be about

never vasodilation.

200 ml/min; a test dose of norepinephrine causes only a

slight depression in flow lasting a minute or so. Then the

Another interesting example of tone is the back-

stellate ganglion is removed, and normal sympathetic

ground

“tone” of the parasympathetics in the

tone is lost. At first, the blood flow rises markedly

gastrointestinal tract. Surgical removal of the parasym-

because of the lost vascular tone, but over a period of

pathetic supply to most of the gut by cutting the vagus

days to weeks the blood flow returns much of the way

nerves can cause serious and prolonged gastric and

back toward normal because of progressive increase in

intestinal “atony” with resulting blockage of much of

the normal gastrointestinal propulsion and consequent

serious constipation, thus demonstrating that

parasympathetic tone to the gut is normally very much

required. This tone can be decreased by the brain,

400

thereby inhibiting gastrointestinal motility, or it can be

increased, thereby promoting increased gastrointesti-

nal activity.

Effect of same

Normal

200

test dose of

Stellate

norepinephrine

Tone Caused by Basal Secretion of Epinephrine and Norepi-

ganglionectomy

nephrine by the Adrenal Medullae. The normal resting

Effect of test dose

rate of secretion by the adrenal medullae is about

of norepinephrine

0.2 mg/kg/min of epinephrine and about 0.05 mg/kg/min

of norepinephrine. These quantities are considerable—

Weeks

indeed, enough to maintain the blood pressure almost

up to normal even if all direct sympathetic pathways to

the cardiovascular system are removed. Therefore, it is

obvious that much of the overall tone of the sympa-

Figure 60-4

thetic nervous system results from basal secretion of

Effect of sympathectomy on blood flow in the arm, and effect of a

epinephrine and norepinephrine in addition to the tone

test dose of norepinephrine before and after sympathectomy,

resulting from direct sympathetic stimulation.

showing supersensitization of the vasculature to norepinephrine.

Chapter 60

The Autonomic Nervous System and the Adrenal Medulla

757

intrinsic tone of the vascular musculature itself, thus

bladder and relaxation of the urinary sphincters,

partially compensating for the loss of sympathetic tone.

thereby promoting micturition.

Then, another test dose of norepinephrine is adminis-

Also important are the sexual reflexes, which are ini-

tered, and the blood flow decreases much more than

tiated both by psychic stimuli from the brain and by

before, demonstrating that the blood vessels have

stimuli from the sexual organs. Impulses from these

become about two to four times as responsive to nor-

sources converge on the sacral cord and, in the male,

epinephrine as previously. This phenomenon is called

result first in erection, mainly a parasympathetic func-

denervation supersensitivity. It occurs in both sympa-

tion, and then ejaculation, partially a sympathetic

thetic and parasympathetic organs but to far greater

function.

extent in some organs than in others, occasionally

Other autonomic control functions include reflex

increasing the response more than 10-fold.

contributions to the regulation of pancreatic secretion,

gallbladder emptying, kidney excretion of urine, sweat-

Mechanism of Denervation Supersensitivity. The cause of

ing, blood glucose concentration, and many other vis-

denervation supersensitivity is only partially known.

ceral functions, all of which are discussed in detail at

Part of the answer is that the number of receptors in

other points in this text.

the postsynaptic membranes of the effector cells

increases—sometimes manyfold—when norepineph-

rine or acetylcholine is no longer released at the

Stimulation of Discrete

synapses, a process called “up-regulation” of the recep-

tors. Therefore, when a dose of the hormone is now

Organs in Some Instances and

injected into the circulating blood, the effector reaction

Mass Stimulation in Other

is vastly enhanced.

Instances by the Sympathetic

and Parasympathetic Systems

Autonomic Reflexes

Sympathetic System Often Responds by Mass Discharge. In

Many visceral functions of the body are regulated by

many instances, almost all portions of the sympathetic

autonomic reflexes. Throughout this text, the functions

nervous system discharge simultaneously as a com-

of these reflexes are discussed in relation to individual

plete unit, a phenomenon called mass discharge. This

organ systems; to illustrate their importance, a few are

frequently occurs when the hypothalamus is activated

presented here briefly.

by fright or fear or severe pain. The result is a wide-

Cardiovascular Autonomic Reflexes. Several reflexes in the

spread reaction throughout the body called the alarm

cardiovascular system help to control especially the

or stress response, which we shall discuss shortly.

arterial blood pressure and the heart rate. One of these

At other times, activation occurs in isolated portions

is the baroreceptor reflex, which is described in Chapter

of the sympathetic nervous system. The most impor-

18 along with other cardiovascular reflexes. Briefly,

tant of these are the following: (1) During the process

stretch receptors called baroreceptors are located in the

of heat regulation, the sympathetics control sweating

walls of several major arteries, including especially the

and blood flow in the skin without affecting other

internal carotid arteries and the arch of the aorta. When

organs innervated by the sympathetics.

(2) Many

these become stretched by high pressure, signals are

“local reflexes” involving sensory afferent fibers travel

transmitted to the brain stem, where they inhibit the

centrally in the peripheral nerves to the sympathetic

sympathetic impulses to the heart and blood vessels and

excite the parasympathetics; this allows the arterial

ganglia and spinal cord and cause highly localized

pressure to fall back toward normal.

reflex responses. For instance, heating a local skin area

causes local vasodilation and enhanced local sweating,

Gastrointestinal Autonomic Reflexes. The uppermost part of

whereas cooling causes opposite effects. (3) Many of

the gastrointestinal tract and the rectum are controlled

the sympathetic reflexes that control gastrointestinal

principally by autonomic reflexes. For instance, the

functions operate by way of nerve pathways that do

smell of appetizing food or the presence of food in

not even enter the spinal cord, merely passing from the

the mouth initiates signals from the nose and mouth

gut mainly to the paravertebral ganglia, and then back

to the vagal, glossopharyngeal, and salivatory nuclei

to the gut through sympathetic nerves to control

of the brain stem. These in turn transmit signals through

motor or secretory activity.

the parasympathetic nerves to the secretory glands of

the mouth and stomach, causing secretion of digestive

juices sometimes even before food enters the mouth.

Parasympathetic System Usually Causes Specific Localized

When fecal matter fills the rectum at the other end

Responses. In contrast to the common mass discharge

of the alimentary canal, sensory impulses initiated by

response of the sympathetic system, control functions

stretching the rectum are sent to the sacral portion of

by the parasympathetic system are much more likely

the spinal cord, and a reflex signal is transmitted back

to be highly specific. For instance, parasympathetic

through the sacral parasympathetics to the distal parts

cardiovascular reflexes usually act only on the heart to

of the colon; these result in strong peristaltic contrac-

increase or decrease its rate of beating. Likewise, other

tions that cause defecation.

parasympathetic reflexes cause secretion mainly by

the mouth glands, or in other instances secretion is

Other Autonomic Reflexes. Emptying of the urinary bladder

is controlled in the same way as emptying the rectum;

mainly by the stomach glands. Finally, the rectal emp-

stretching of the bladder sends impulses to the sacral

tying reflex does not affect other parts of the bowel to

cord, and this in turn causes reflex contraction of the

a major extent.

758

Unit XI The Nervous System: C. Motor and Integrative Neurophysiology

Yet there is often association between closely allied

parasympathetic functions. For instance, although sali-

vary secretion can occur independently of gastric

secretion, these two also often occur together, and

Heat control

pancreatic secretion frequently occurs at the same

Sympathetic

Parasympathetic

time. Also, the rectal emptying reflex often initiates a

urinary bladder emptying reflex, resulting in simulta-

Water

neous emptying of both the bladder and the rectum.

balance

Conversely, the bladder emptying reflex can help ini-

Feeding

tiate rectal emptying.

control

Urinary bladder control

Hypothalamus

“Alarm” or “Stress” Response of the

Pneumotaxic center

Adenohypophysis

Sympathetic Nervous System

Cardiac acceleration

Mamillary body

and vasoconstriction

When large portions of the sympathetic nervous

Pons

Cardiac slowing

system discharge at the same time—that is, a mass dis-

charge—this increases in many ways the ability of the

Respiratory center

Medulla

body to perform vigorous muscle activity. Let us sum-

marize these ways:

1. Increased arterial pressure

2. Increased blood flow to active muscles concurrent

Figure 60-5

with decreased blood flow to organs such as the

Autonomic control areas in the brain stem and hypothalamus.

gastrointestinal tract and the kidneys that are not

needed for rapid motor activity

3. Increased rates of cellular metabolism throughout

the body

4. Increased blood glucose concentration

many special nuclei (Figure 60-5), control different

5. Increased glycolysis in the liver and in muscle

autonomic functions such as arterial pressure, heart

6. Increased muscle strength

rate, glandular secretion in the gastrointestinal tract,

7. Increased mental activity

gastrointestinal peristalsis, and degree of contraction

8. Increased rate of blood coagulation

of the urinary bladder. Control of each of these is dis-

The sum of these effects permits a person to

cussed at appropriate points in this text. Suffice it to

perform far more strenuous physical activity than

point out here that the most important factors con-

would otherwise be possible. Because either mental or

trolled in the brain stem are arterial pressure, heart rate,

physical stress can excite the sympathetic system, it is

and respiratory rate. Indeed, transection of the brain

frequently said that the purpose of the sympathetic

stem above the midpontine level allows basal control

system is to provide extra activation of the body in

of arterial pressure to continue as before but prevents

states of stress: this is called the sympathetic stress

its modulation by higher nervous centers such as the

response.

hypothalamus. Conversely, transection immediately

The sympathetic system is especially strongly acti-

below the medulla causes the arterial pressure to fall

vated in many emotional states. For instance, in the

to less than one-half normal.

state of rage, which is elicited to a great extent by stim-

Closely associated with the cardiovascular regula-

ulating the hypothalamus, signals are transmitted

tory centers in the brain stem are the medullary and

downward through the reticular formation of the brain

pontine centers for regulation of respiration, which are

stem and into the spinal cord to cause massive sym-

discussed in Chapter 41. Although this is not consid-

pathetic discharge; most aforementioned sympathetic

ered to be an autonomic function, it is one of the invol-

events ensue immediately. This is called the sympa-

untary functions of the body.

thetic alarm reaction. It is also called the fight or flight

reaction because an animal in this state decides almost

Control of Brain Stem Autonomic Centers by Higher Areas.

instantly whether to stand and fight or to run. In either

Signals from the hypothalamus and even from the

event, the sympathetic alarm reaction makes the

cerebrum can affect the activities of almost all the

animal’s subsequent activities vigorous.

brain stem autonomic control centers. For instance,

stimulation in appropriate areas mainly of the poste-

rior hypothalamus can activate the medullary cardio-

Medullary, Pontine, and

vascular control centers strongly enough to increase

Mesencephalic Control of the

arterial pressure to more than twice normal. Likewise,

Autonomic Nervous System

other hypothalamic centers control body temperature,

increase or decrease salivation and gastrointes-

Many neuronal areas in the brain stem reticular sub-

tinal activity, and cause bladder emptying. To some

stance and along the course of the tractus solitarius of

extent, therefore, the autonomic centers in the brain

the medulla, pons, and mesencephalon, as well as in

stem act as relay stations for control activities

Chapter 60

The Autonomic Nervous System and the Adrenal Medulla

759

initiated at higher levels of the brain, especially in the

autonomic ganglia. They are discussed in a later

hypothalamus.

section, but an important drug for blockade of both

In Chapters 58 and 59, it is pointed out also that

sympathetic and parasympathetic transmission

through the ganglia is hexamethonium.

many of our behavioral responses are mediated

through (1) the hypothalamus, (2) the reticular areas

of the brain stem, and (3) the autonomic nervous

Drugs That Act on Cholinergic

system. Indeed, some higher areas of the brain can

Effector Organs

alter function of the whole autonomic nervous system

or of portions of it strongly enough to cause severe

Parasympathomimetic Drugs

(Cholinergic Drugs). Acetyl-

autonomic-induced disease such as peptic ulcer of the

choline injected intravenously usually does not cause

stomach or duodenum, constipation, heart palpitation,

exactly the same effects throughout the body as

or even heart attack.

parasympathetic stimulation because most of the acetyl-

choline is destroyed by cholinesterase in the blood and

body fluids before it can reach all the effector organs.

Yet a number of other drugs that are not so rapidly

Pharmacology of the

destroyed can produce typical widespread parasympa-

Autonomic Nervous System

thetic effects, and they are called parasympathomimetic

drugs.

Drugs That Act on Adrenergic

Two commonly used parasympathomimetic drugs are

Effector Organs—

pilocarpine and methacholine. They act directly on the

muscarinic type of cholinergic receptors.

Sympathomimetic Drugs

From the foregoing discussion, it is obvious that intra-

Drugs That Have a Parasympathetic Potentiating Effect—Anti-

venous injection of norepinephrine causes essentially

cholinesterase Drugs. Some drugs do not have a direct

the same effects throughout the body as sympathetic

effect on parasympathetic effector organs but do poten-

stimulation. Therefore, norepinephrine is called a

tiate the effects of the naturally secreted acetylcholine

sympathomimetic or adrenergic drug. Epinephrine and

at the parasympathetic endings. They are the same drugs

methoxamine are also sympathomimetic drugs, and

as those discussed in Chapter 7 that potentiate the effect

there are many others. They differ from one another in

of acetylcholine at the neuromuscular junction. They

the degree to which they stimulate different sympa-

include neostigmine, pyridostigmine, and ambenonium.

thetic effector organs and in their duration of action.

These drugs inhibit acetylcholinesterase, thus prevent-

Norepinephrine and epinephrine have actions as short

ing rapid destruction of the acetylcholine liberated at

as 1 to 2 minutes, whereas the actions of some other

parasympathetic nerve endings. As a consequence, the

commonly used sympathomimetic drugs last for 30

quantity of acetylcholine increases with successive

minutes to 2 hours.

stimuli, and the degree of action also increases.

Important drugs that stimulate specific adrenergic

receptors but not others are phenylephrine

(alpha

Drugs That Block Cholinergic Activity at Effector Organs—

receptors), isoproterenol (beta receptors), and albuterol

Antimuscarinic Drugs. Atropine and similar drugs, such as

(only beta

receptors).

homatropine and scopolamine, block the action of

acetylcholine on the muscarinic type of cholinergic effec-

Drugs That Cause Release of Norepinephrine from Nerve Endings.

tor organs. These drugs do not affect the nicotinic action

Certain drugs have an indirect sympathomimetic action

of acetylcholine on the postganglionic neurons or on

instead of directly exciting adrenergic effector organs.

skeletal muscle.

These drugs include ephedrine, tyramine, and ampheta-

mine. Their effect is to cause release of norepinephrine

from its storage vesicles in the sympathetic nerve

Drugs That Stimulate or Block

endings. The released norepinephrine in turn causes the

Sympathetic and Parasympathetic

sympathetic effects.

Postganglionic Neurons

Drugs That Block Adrenergic Activity. Adrenergic activity

Drugs That Stimulate Autonomic Postganglionic Neurons. The

can be blocked at several points in the stimulatory

preganglionic neurons of both the parasympathetic and

process, as follows:

the sympathetic nervous systems secrete acetylcholine

1. The synthesis and storage of norepinephrine in the

at their endings, and this acetylcholine in turn stimulates

sympathetic nerve endings can be prevented. The

the postganglionic neurons. Furthermore, injected

best known drug that causes this effect is reserpine.

acetylcholine can also stimulate the postganglionic

2. Release of norepinephrine from the sympathetic

neurons of both systems, thereby causing at the same

endings can be blocked. This is caused by

time both sympathetic and parasympathetic effects

guanethidine.

throughout the body.

3. The sympathetic alpha receptors can be blocked.

Nicotine is another drug that can stimulate postgan-

Two drugs that cause this effect are

glionic neurons in the same manner as acetylcholine

phenoxybenzamine and phentolamine.

because the membranes of these neurons all contain the

4. The sympathetic beta receptors can be blocked.

nicotinic type of acetylcholine receptor. Therefore, drugs

A drug that blocks beta₁ and beta₂ receptors is

that cause autonomic effects by stimulating postgan-

propranolol. One that blocks mainly beta₁

glionic neurons are called nicotinic drugs. Some other

receptors is metoprolol.

drugs, such as methacholine, have both nicotinic and

5. Sympathetic activity can be blocked by drugs that

muscarinic actions, whereas pilocarpine has only mus-

block transmission of nerve impulses through the

carinic actions.

760

Unit XI The Nervous System: C. Motor and Integrative Neurophysiology

Nicotine excites both the sympathetic and parasym-

DiBona GF, Kopp UC: Neural control of renal function.

pathetic postganglionic neurons at the same time,

Physiol Rev 77:75, 1997.

resulting in strong sympathetic vasoconstriction in the

Gibbins IL, Jobling P, Morris JL: Functional organization

abdominal organs and limbs but at the same time result-

of peripheral vasomotor pathways. Acta Physiol Scand

ing in parasympathetic effects such as increased gas-

177:237, 2003.

trointestinal activity and, sometimes, slowing of the

Goldstein DS: Catecholamines and stress. Endocr Regul

heart.

37:69, 2003.

Goldstein DS, Robertson D, Esler M, et al: Dysautonomias:

Ganglionic Blocking Drugs. Many important drugs block

clinical disorders of the autonomic nervous system. Ann

impulse transmission from the autonomic preganglionic

Intern Med 137:753, 2002.

neurons to the postganglionic neurons, including

Hall JE, Hildebrandt DA, Kuo J: Obesity hypertension: role

tetraethyl ammonium ion, hexamethonium ion, and pen-

of leptin and sympathetic nervous system. Am J Hyper-

tolinium. These drugs block acetylcholine stimulation of

tens 14:103S, 2001.

the postganglionic neurons in both the sympathetic and

Hirst GD, Ward SM: Interstitial cells: involvement in rhyth-

the parasympathetic systems simultaneously. They are

micity and neural control of gut smooth muscle. J Physiol

often used for blocking sympathetic activity but seldom

550:337, 2003.

for blocking parasympathetic activity because their

Koch WJ, Lefkowitz RJ, Rockman HA: Functional conse-

effects of sympathetic blockade usually far overshadow

quences of altering myocardial adrenergic receptor sig-

the effects of parasympathetic blockade. The ganglionic

naling. Annu Rev Physiol 62:237, 2000.

blocking drugs especially can reduce the arterial pres-

Lefkowitz RJ, Rockman HA, Koch WJ: Catecholamines,

sure in many patients with hypertension, but these drugs

cardiac beta-adrenergic receptors, and heart failure.

are not very useful clinically because their effects are

Circulation 101:1634, 2000.

difficult to control.

Lohmeier TE: The sympathetic nervous system and long-

term blood pressure regulation. Am J Hypertens 14:147S,

2001.

References

Saper CB: The central autonomic nervous system: conscious

visceral perception and autonomic pattern generation.

Annu Rev Neurosci 25:433, 2002.

Andresen MC, Doyle MW, Jin YH, Bailey TW: Cellular

Taylor EW, Jordan D, Coote JH: Central control of the car-

mechanisms of baroreceptor integration at the nucleus

diovascular and respiratory systems and their interactions

tractus solitarius. Ann N Y Acad Sci 940:132, 2001

in vertebrates. Physiol Rev 79:855, 1999.

Chang HY, Mashimo H, Goyal RK: Musings on the wan-

Wanamaker CP, Christianson JC, Green WN: Regulation of

derer: what’s new in our understanding of vago-vagal

nicotinic acetylcholine receptor assembly. Ann N Y Acad

reflex? IV. Current concepts of vagal efferent projections

Sci 998:66, 2003.

to the gut. Am J Physiol Gastrointest Liver Physiol

Wess J: Novel insights into muscarinic acetylcholine recep-

284:G357, 2003.

tor function using gene targeting technology. Trends Phar-

Dajas-Bailador F, Wonnacott S: Nicotinic acetylcholine

macol Sci 24:414, 2003.

receptors and the regulation of neuronal signalling. Trends

Pharmacol Sci 25:317, 2004.

Dampney RA, Horiuchi J, Tagawa T, et al: Medullary and

supramedullary mechanisms regulating sympathetic vaso-

motor tone. Acta Physiol Scand 177:209, 2003.

C H A P T E R

Cerebral Blood Flow,

Cerebrospinal Fluid, and Brain

Metabolism

Thus far, we have discussed the function of the brain as

if it were independent of its blood flow, its metabolism,

and its fluids. However, this is far from true because

abnormalities of any of these can profoundly affect

brain function. For instance, total cessation of blood

flow to the brain causes unconsciousness within 5 to 10

seconds. This occurs because lack of oxygen delivery to

the brain cells shuts down most metabolism in these

cells. Also, on a longer time scale, abnormalities of the

cerebrospinal fluid, either its composition or its fluid pressure, can have equally

severe effects on brain function.

Cerebral Blood Flow

Normal Rate of Cerebral Blood Flow

Normal blood flow through the brain of the adult person averages 50 to 65 milli-

liters per 100 grams of brain tissue per minute. For the entire brain, this amounts to

750 to 900 ml/min, or 15 per cent of the resting cardiac output.

Regulation of Cerebral Blood Flow

As in most other vascular areas of the body, cerebral blood flow is highly related to

metabolism of the tissue. At least three metabolic factors have potent effects in con-

trolling cerebral blood flow: (1) carbon dioxide concentration, (2) hydrogen ion con-

centration, and (3) oxygen concentration.

Increase of Cerebral Blood Flow in Response to Excess Carbon Dioxide or Excess Hydrogen Ion

Concentration. An increase in carbon dioxide concentration in the arterial blood per-

fusing the brain greatly increases cerebral blood flow. This is demonstrated in Figure

61-1, which shows that a 70 per cent increase in arterial PCO₂ approximately doubles

cerebral blood flow.

Carbon dioxide is believed to increase cerebral blood flow by combining first with

water in the body fluids to form carbonic acid, with subsequent dissociation of this

acid to form hydrogen ions. The hydrogen ions then cause vasodilation of the cere-

bral vessels—the dilation being almost directly proportional to the increase in

hydrogen ion concentration up to a blood flow limit of about twice normal.

Any other substance that increases the acidity of the brain tissue, and therefore

increases hydrogen ion concentration, will likewise increase cerebral blood flow.

Such substances include lactic acid, pyruvic acid, and any other acidic material

formed during the course of tissue metabolism.

Importance of Cerebral Blood Flow Control by Carbon Dioxide and Hydrogen Ions. Increased

hydrogen ion concentration greatly depresses neuronal activity. Therefore, it is for-

tunate that an increase in hydrogen ion concentration also causes an increase in

blood flow, which in turn carries hydrogen ions, carbon dioxide, and other acid-

forming substances away from the brain tissues. Loss of carbon dioxide removes

carbonic acid from the tissues; this, along with removal of other acids, reduces the

hydrogen ion concentration back toward normal. Thus, this mechanism helps main-

tain a constant hydrogen ion concentration in the cerebral fluids and thereby helps

to maintain a normal, constant level of neuronal activity.

Oxygen Deficiency as a Regulator of Cerebral Blood Flow. Except during periods of intense

brain activity, the rate of utilization of oxygen by the brain tissue remains within

761

762

Unit XI The Nervous System: C. Motor and Integrative Neurophysiology

2.0

140

1.6

130

120

1.2

Light shining

110

in eyes

Normal

100

0.8

0.5

1.0

1.5

Minutes

0.4

100

Arterial Pco₂

Figure 61-2

Increase in blood flow to the occipital regions of a cat’s brain when

Figure 61-1

light is shined into its eyes.

Relationship between arterial PCO₂ and cerebral blood flow.

opposite side of the brain. Reading a book increases the

blood flow, especially in the visual areas of the occipital

narrow limits—almost exactly 3.5 (± 0.2) milliliters of

cortex and in the language perception areas of the tem-

oxygen per 100 grams of brain tissue per minute. If

poral cortex. This measuring procedure can also be used

blood flow to the brain ever becomes insufficient to

for localizing the origin of epileptic attacks because

supply this needed amount of oxygen, the oxygen defi-

local brain blood flow increases acutely and markedly

ciency mechanism for causing vasodilation immediately

at the focal point of each attack.

causes vasodilation, returning the brain blood flow and

Demonstrating the effect of local neuronal activity on

transport of oxygen to the cerebral tissues to near

cerebral blood flow, Figure 61-2 shows a typical increase

normal. Thus, this local blood flow regulatory mecha-

in occipital blood flow recorded in a cat’s brain when

nism is almost exactly the same in the brain as in coro-

intense light is shined into its eyes for one-half minute.

nary blood vessels, in skeletal muscle, and in most other

circulatory areas of the body.

Autoregulation of Cerebral Blood Flow When the Arterial Pressure

Experiments have shown that a decrease in cerebral

Changes. Cerebral blood flow is

“autoregulated”

tissue PO₂ below about 30 mm Hg (normal value is 35 to

extremely well between arterial pressure limits of 60

40 mm Hg) immediately begins to increase cerebral

and 140 mm Hg. That is, mean arterial pressure can be

blood flow. This is fortuitous because brain function

decreased acutely to as low as 60 mm Hg or increased

becomes deranged at not much lower values of PO₂,

to as high as 140 mm Hg without significant change in

especially so at PO₂ levels below 20 mm Hg. Even coma

cerebral blood flow. And, in people who have hyper-

can result at these low levels. Thus, the oxygen mecha-

tension, autoregulation of cerebral blood flow occurs

nism for local regulation of cerebral blood flow is a very

even when the mean arterial pressure rises to as high as

important protective response against diminished cere-

160 to 180 mm Hg. This is demonstrated in Figure 61-3,

bral neuronal activity and, therefore, against derange-

which shows cerebral blood flow measured both in

ment of mental capability.

persons with normal blood pressure and in hypertensive

and hypotensive patients. Note the extreme constancy

Measurement of Cerebral Blood Flow, and Effect of Brain Activ-

of cerebral blood flow between the limits of 60 and

ity on the Flow. A method has been developed to record

180 mm Hg mean arterial pressure. But, if the arterial

blood flow in as many as 256 isolated segments of the

pressure falls below 60 mm Hg, cerebral blood flow then

human cerebral cortex simultaneously. To do this, a

does become severely decreased.

radioactive substance, such as radioactive xenon, is

injected into the carotid artery; then the radioactivity of

Role of the Sympathetic Nervous System in Controlling Cerebral

each segment of the cortex is recorded as the radioac-

Blood Flow. The cerebral circulatory system has strong

tive substance passes through the brain tissue. For this

sympathetic innervation that passes upward from the

purpose, 256 small radioactive scintillation detectors are

superior cervical sympathetic ganglia in the neck and

pressed against the surface of the cortex. The rapidity

then into the brain along with the cerebral arteries. This

of rise and decay of radioactivity in each tissue segment

innervation supplies both the large brain arteries and

is a direct measure of the rate of blood flow through that

the arteries that penetrate into the substance of the

segment.

brain. However, transection of the sympathetic nerves

Using this technique, it has become clear that blood

or mild to moderate stimulation of them usually causes

flow in each individual segment of the brain changes as

very little change in cerebral blood flow because the

much as 100 to 150 per cent within seconds in response

blood flow autoregulation mechanism can override the

to changes in local neuronal activity. For instance,

nervous effects.

simply making a fist of the hand causes an immedi-

When mean arterial pressure rises acutely to an

ate increase in blood flow in the motor cortex of the

exceptionally high level, such as during strenuous

Chapter 61

Cerebral Blood Flow, Cerebrospinal Fluid, and Brain Metabolism

763

Cerebral “Stroke” Occurs When

Cerebral Blood Vessels Are Blocked

Almost all elderly people have blockage of some small

arteries in the brain, and as many as 10 per cent even-

tually have enough blockage to cause serious distur-

bance of brain function, a condition called a “stroke.”

Most strokes are caused by arteriosclerotic plaques

that occur in one or more of the feeder arteries to the

brain. The plaques can activate the clotting mechanism

of the blood, causing a blood clot to occur and block

blood flow in the artery, thereby leading to acute loss of

brain function in a localized area.

In about one quarter of people who develop strokes,

high blood pressure makes one of the blood vessels

Hypotension

Hypertension

burst; hemorrhage then occurs, compressing the local

100

150

brain tissue and further compromising its functions. The

Mean arterial blood pressure (mm Hg)

neurological effects of a stroke are determined by the

brain area affected. One of the most common types of

stroke is blockage of the middle cerebral artery that sup-

plies the midportion of one brain hemisphere. For

instance, if the middle cerebral artery is blocked on the

Figure 61-3

left side of the brain, the person is likely to become

almost totally demented because of lost function in

Effect of differences in mean arterial pressure, from hypotensive

Wernicke’s speech comprehension area in the left cere-

to hypertensive level, on cerebral blood flow in different human

beings.

(Modified from Lassen NA: Cerebral blood flow and

bral hemisphere, and he or she also becomes unable to

oxygen consumption in man. Physiol Rev 39:183, 1959.)

speak words because of loss of Broca’s motor area for

word formation. In addition, loss of function of neural

motor control areas of the left hemisphere can create

spastic paralysis of most muscles on the opposite side of

the body.

In a similar manner, blockage of a posterior cerebral

exercise or during other states of excessive circulatory

artery will cause infarction of the occipital pole of the

activity, the sympathetic nervous system normally con-

hemisphere on the same side as the blockage, which

stricts the large- and intermediate-sized brain arteries

causes loss of vision in both eyes in the half of the retina

enough to prevent the high pressure from reaching the

on the same side as the stroke lesion. Especially devas-

smaller brain blood vessels. This is important in pre-

tating are strokes that involve the blood supply to the

venting vascular hemorrhages into the brain—that is,

midbrain because this can block nerve conduction in

for preventing the occurrence of “cerebral stroke.”

major pathways between the brain and spinal cord,

causing both sensory and motor abnormalities.

Cerebral Microcirculation

As is true for almost all other tissues of the body, the

Cerebrospinal Fluid System

number of blood capillaries in the brain is greatest

where the metabolic needs are greatest. The overall

The entire cerebral cavity enclosing the brain and spinal

metabolic rate of the brain gray matter where the neu-

cord has a capacity of about 1600 to 1700 milliliters;

ronal cell bodies lie is about four times as great as that

about 150 milliliters of this capacity is occupied by cere-

of white matter; correspondingly, the number of capil-

brospinal fluid and the remainder by the brain and cord.

laries and rate of blood flow are also about four times

This fluid, as shown in Figure 61-4, is present in the ven-

as great in the gray matter.

tricles of the brain, in the cisterns around the outside of

An important structural characteristic of the brain

the brain, and in the subarachnoid space around both the

capillaries is that they are much less “leaky” than the

brain and the spinal cord. All these chambers are con-

blood capillaries in almost any other tissue of the body.

nected with one another, and the pressure of the fluid

One reason for this is that the capillaries are supported

is maintained at a surprisingly constant level.

on all sides by “glial feet,” which are small projections

from the surrounding glial cells that abut against all sur-

faces of the capillaries and provide physical support to

prevent overstretching of the capillaries in case of high

Cushioning Function of the

capillary blood pressure.

Cerebrospinal Fluid

The walls of the small arterioles leading to the brain

capillaries become greatly thickened in people who

A major function of the cerebrospinal fluid is to cushion

develop high blood pressure, and these arterioles

the brain within its solid vault. The brain and the cere-

remain significantly constricted all the time to prevent

brospinal fluid have about the same specific gravity

transmission of the high pressure to the capillaries. We

(only about 4 per cent different), so that the brain

shall see later in the chapter that whenever these

simply floats in the fluid. Therefore, a blow to the head,

systems for protecting against transudation of fluid into

if it is not too intense, moves the entire brain simulta-

the brain break down, serious brain edema ensues,

neously with the skull, causing no one portion of the

which can lead rapidly to coma and death.

brain to be momentarily contorted by the blow.

764

Unit XI The Nervous System: C. Motor and Integrative Neurophysiology

Lateral

Arachnoidal

ventricles

villi

Foramen

of Monro

Choroid

Artery

plexuses

Ependyma

Vein

Third

ventricle

Tentorium

cerebelli

Taenia

Aqueduct

fornicis

of Sylvius

Fourth

ventricle

Tela

Foramen of

choroides

Luschka

Magendie

Taenia

choroidea

Figure 61-4

Blood vessel

The arrows show the pathway of cerebrospinal fluid flow from the

choroid plexuses in the lateral ventricles to the arachnoidal villi

Ependyma

protruding into the dural sinuses.

Villus epithelium

Contrecoup. When a blow to the head is extremely

Villus connective tissue

severe, it may not damage the brain on the side of the

head where the blow is struck but on the opposite side.

This phenomenon is known as “contrecoup,” and the

Figure 61-5

reason for this effect is the following: When the blow is

struck, the fluid on the struck side is so incompressible

Choroid plexus in a lateral ventricle.

that as the skull moves, the fluid pushes the brain at the

same time in unison with the skull. On the side oppo-

site to the area that is struck, the sudden movement of

from the third ventricle, it flows downward along the

the whole skull causes the skull to pull away from the

aqueduct of Sylvius into the fourth ventricle, where still

brain momentarily because of the brain’s inertia, creat-

another minute amount of fluid is added. Finally, the

ing for a split second a vacuum space in the cranial vault

fluid passes out of the fourth ventricle through three

in the area opposite to the blow. Then, when the skull is

small openings, two lateral foramina of Luschka and a

no longer being accelerated by the blow, the vacuum

midline foramen of Magendie, entering the cisterna

suddenly collapses and the brain strikes the inner

magna, a fluid space that lies behind the medulla and

surface of the skull.

beneath the cerebellum.

The poles and the inferior surfaces of the frontal and

The cisterna magna is continuous with the subarach-

temporal lobes, where the brain comes into contact with

noid space that surrounds the entire brain and spinal

bony protuberances in the base of the skull, are often

cord. Almost all the cerebrospinal fluid then flows

the sites of injury and contusions (bruises) after a severe

upward from the cisterna magna through the subarach-

blow to the head, such as that experienced by a boxer.

noid spaces surrounding the cerebrum. From here, the

If the contusion occurs on the same side as the impact

fluid flows into and through multiple arachnoidal villi

injury, it is a coup injury; if it occurs on the opposite side,

that project into the large sagittal venous sinus and

the contusion is a contrecoup injury.

other venous sinuses of the cerebrum. Thus, any extra

fluid empties into the venous blood through pores of

these villi.

Formation, Flow, and Absorption

of Cerebrospinal Fluid

Secretion by the Choroid Plexus. The choroid plexus, a

section of which is shown in Figure 61-5, is a cauliflower-

Cerebrospinal fluid is formed at a rate of about 500 mil-

like growth of blood vessels covered by a thin layer of

liliters each day, which is three to four times as much as

epithelial cells. This plexus projects into (1 and 2) the

the total volume of fluid in the entire cerebrospinal fluid

temporal horn of each lateral ventricle, (3) the posterior

system. About two thirds or more of this fluid originates

portion of the third ventricle, and (4) the roof of the

as secretion from the choroid plexuses in the four ven-

fourth ventricle.

tricles, mainly in the two lateral ventricles. Additional

Secretion of fluid into the ventricles by the choroid

small amounts of fluid are secreted by the ependymal

plexus depends mainly on active transport of sodium

surfaces of all the ventricles and by the arachnoidal

ions through the epithelial cells lining the outside of the

membranes; and a small amount comes from the brain

plexus. The sodium ions in turn pull along large amounts

itself through the perivascular spaces that surround the

of chloride ions as well because the positive charge of

blood vessels passing through the brain.

the sodium ion attracts the chloride ion’s negative

The arrows in Figure 61-4 show that the main chan-

charge. The two of these together increase the quantity

nels of fluid flow from the choroid plexuses and then

of osmotically active sodium chloride in the cere-

through the cerebrospinal fluid system. The fluid

brospinal fluid, which then causes almost immediate

secreted in the lateral ventricles passes first into the third

osmosis of water through the membrane, thus providing

ventricle; then, after addition of minute amounts of fluid

the fluid of the secretion.

Chapter 61

Cerebral Blood Flow, Cerebrospinal Fluid, and Brain Metabolism

765

Less important transport processes move small

lar spaces, in effect, are a specialized lymphatic system

amounts of glucose into the cerebrospinal fluid and both

for the brain.

potassium and bicarbonate ions out of the cerebrospinal

In addition to transporting fluid and proteins, the

fluid into the capillaries. Therefore, the resulting char-

perivascular spaces transport extraneous particulate

acteristics of the cerebrospinal fluid become the follow-

matter out of the brain. For instance, whenever infec-

ing: osmotic pressure, approximately equal to that of

tion occurs in the brain, dead white blood cells and

plasma; sodium ion concentration, also approximately

other infectious debris are carried away through the

equal to that of plasma; chloride ion, about 15 per cent

perivascular spaces.

greater than in plasma; potassium ion, approximately 40

per cent less; and glucose, about 30 per cent less.

Cerebrospinal Fluid Pressure

Absorption of Cerebrospinal Fluid Through the Arachnoidal Villi.

The normal pressure in the cerebrospinal fluid system

The arachnoidal villi are microscopic fingerlike inward

when one is lying in a horizontal position averages 130

projections of the arachnoidal membrane through the

millimeters of water (10 mm Hg), although this may be

walls and into the venous sinuses. Conglomerates of

as low as 65 millimeters of water or as high as 195 mil-

these villi form macroscopic structures called arach-

limeters of water even in the normal healthy person.

noidal granulations that can be seen protruding into the

sinuses. The endothelial cells covering the villi have

been shown by electron microscopy to have vesicular

Regulation of Cerebrospinal Fluid Pressure by the Arachnoidal

passages directly through the bodies of the cells large

Villi. The normal rate of cerebrospinal fluid formation

enough to allow relatively free flow of (1) cerebrospinal

remains very nearly constant, so that changes in fluid

fluid, (2) dissolved protein molecules, and (3) even par-

formation are seldom a factor in pressure control. Con-

ticles as large as red and white blood cells into the

versely, the arachnoidal villi function like “valves” that

venous blood.

allow cerebrospinal fluid and its contents to flow readily

into the blood of the venous sinuses while not allowing

Perivascular Spaces and Cerebrospinal Fluid. The large arter-

blood to flow backward in the opposite direction. Nor-

ies and veins of the brain lie on the surface of the brain

mally, this valve action of the villi allows cerebrospinal

but their ends penetrate inward, carrying with them a

fluid to begin to flow into the blood when cerebrospinal

layer of pia mater, the membrane that covers the brain,

fluid pressure is about 1.5 mm Hg greater than the pres-

as shown in Figure 61-6. The pia is only loosely adher-

sure of the blood in the venous sinuses. Then, if the cere-

ent to the vessels, so that a space, the perivascular space,

brospinal fluid pressure rises still higher, the valves open

exists between it and each vessel. Therefore, perivascu-

more widely, so that under normal conditions, the cere-

lar spaces follow both the arteries and the veins into the

brospinal fluid pressure almost never rises more than a

brain as far as the arterioles and venules go.

few millimeters of mercury higher than the pressure in

the cerebral venous sinuses.

Lymphatic Function of the Perivascular Spaces. As is true

Conversely, in disease states, the villi sometimes

elsewhere in the body, a small amount of protein leaks

become blocked by large particulate matter, by fibrosis,

out of the brain capillaries into the interstitial spaces of

or by excesses of blood cells that have leaked into the

the brain. Because no true lymphatics are present in

cerebrospinal fluid in brain diseases. Such blockage can

brain tissue, excess protein in the brain tissue leaves the

cause high cerebrospinal fluid pressure, as follows.

tissue flowing with fluid through the perivascular spaces

into the subarachnoid spaces. On reaching the sub-

High Cerebrospinal Fluid Pressure in Pathological Conditions of

arachnoid spaces, the protein then flows with the cere-

the Brain. Often a large brain tumor elevates the cere-

brospinal fluid, to be absorbed through the arachnoidal

brospinal fluid pressure by decreasing reabsorption of

villi into the large cerebral veins. Therefore, perivascu-

the cerebrospinal fluid back into the blood. As a result,

the cerebrospinal fluid pressure can rise to as much as

500 millimeters of water (37 mm Hg) or about four

times normal.

The cerebrospinal fluid pressure also rises consider-

Arachnoid membrane

ably when hemorrhage or infection occurs in the cranial

Arachnoid trabecula

vault. In both these conditions, large numbers of red

and/or white blood cells suddenly appear in the cere-

Subarachnoid space

brospinal fluid, and they can cause serious blockage of

the small absorption channels through the arachnoidal

Pia mater

villi. This also sometimes elevates the cerebrospinal

fluid pressure to 400 to 600 millimeters of water (about

Perivascular space

four times normal).

Blood vessel

Some babies are born with high cerebrospinal fluid

pressure. This is often caused by abnormally high resist-

ance to fluid reabsorption through the arachnoidal villi,

Brain tissue

resulting either from too few arachnoidal villi or from

villi with abnormal absorptive properties. This is dis-

cussed later in connection with hydrocephalus.

Figure 61-6

Measurement of Cerebrospinal Fluid Pressure. The usual pro-

cedure for measuring cerebrospinal fluid pressure is

Drainage of a perivascular space into the subarachnoid space.

(Redrawn from Ranson SW, Clark SL: Anatomy of the Nervous

very simple and is the following: First, the person lies

System. Philadelphia: WB Saunders Co, 1959.)

exactly horizontally on his or her side so that the fluid

766

Unit XI The Nervous System: C. Motor and Integrative Neurophysiology

pressure in the spinal canal is equal to the pressure in

extent inside the ventricles. This will also cause the head

the cranial vault. A spinal needle is then inserted into

to swell tremendously if it occurs in infancy when the

the lumbar spinal canal below the lower end of the cord,

skull is still pliable and can be stretched, and it can

and the needle is connected to a vertical glass tube that

damage the brain at any age. A therapy for many types

is open to the air at its top. The spinal fluid is allowed

of hydrocephalus is surgical placement of a silicone tube

to rise in the tube as high as it will. If it rises to a level

shunt all the way from one of the brain ventricles to the

136 millimeters above the level of the needle, the pres-

peritoneal cavity where the excess fluid can be absorbed

sure is said to be 136 millimeters of water pressure or,

into the blood.

dividing this by 13.6, which is the specific gravity of

mercury, about 10 mm Hg pressure.

Blood-Cerebrospinal Fluid and

High Cerebrospinal Fluid Pressure Causes Edema of the Optic

Blood-Brain Barriers

Disc—Papilledema. Anatomically, the dura of the brain

It has already been pointed out that the concentrations

extends as a sheath around the optic nerve and then

of several important constituents of cerebrospinal fluid

connects with the sclera of the eye. When the pressure

are not the same as in extracellular fluid elsewhere

rises in the cerebrospinal fluid system, it also rises inside

in the body. Furthermore, many large molecular sub-

the optic nerve sheath. The retinal artery and vein

stances hardly pass at all from the blood into the cere-

pierce this sheath a few millimeters behind the eye and

brospinal fluid or into the interstitial fluids of the brain,

then pass along with the optic nerve fibers into the eye

even though these same substances pass readily into

itself. Therefore, (1) high cerebrospinal fluid pressure

the usual interstitial fluids of the body. Therefore, it is

pushes fluid first into the optic nerve sheath and then

said that barriers, called the blood-cerebrospinal fluid

along the spaces between the optic nerve fibers to the

barrier and the blood-brain barrier, exist between the

interior of the eyeball; (2) the high pressure decreases

blood and the cerebrospinal fluid and brain fluid,

outward fluid flow in the optic nerves, causing accumu-

respectively.

lation of excess fluid in the optic disc at the center of

Barriers exist both at the choroid plexus and at the

the retina; and

(3) the pressure in the sheath also

tissue capillary membranes in essentially all areas of the

impedes flow of blood in the retinal vein, thereby

brain parenchyma except in some areas of the hypothal-

increasing the retinal capillary pressure throughout the

amus, pineal gland, and area postrema, where substances

eye, which results in still more retinal edema.

diffuse with greater ease into the tissue spaces. The ease

The tissues of the optic disc are much more distensi-

of diffusion in these areas is important because they

ble than those of the remainder of the retina, so that the

have sensory receptors that respond to specific changes

disc becomes far more edematous than the remainder

in the body fluids, such as changes in osmolality and in

of the retina and swells into the cavity of the eye. The

glucose concentration, as well as receptors for peptide

swelling of the disc can be observed with an ophthal-

hormones that regulate thirst, such as angiotensin II.

moscope and is called papilledema. Neurologists can

The blood-brain barrier also has specific carrier mole-

estimate the cerebrospinal fluid pressure by assessing

cules that facilitate transport of hormones, such as

the extent to which the edematous optic disc protrudes

leptin, from the blood into the hypothalamus where

into the eyeball.

they bind to specific receptors that control other func-

tions such as appetite and sympathetic nervous system

Obstruction to Flow of

activity.

In general, the blood-cerebrospinal fluid and blood-

Cerebrospinal Fluid Can

brain barriers are highly permeable to water, carbon

Cause Hydrocephalus

dioxide, oxygen, and most lipid-soluble substances

such as alcohol and anesthetics; slightly permeable to

“Hydrocephalus” means excess water in the cranial

electrolytes such as sodium, chloride, and potassium;

vault. This condition is frequently divided into commu-

and almost totally impermeable to plasma proteins and

nicating hydrocephalus and noncommunicating hydro-

most non-lipid-soluble large organic molecules. There-

cephalus. In communicating hydrocephalus fluid flows

fore, the blood-cerebrospinal fluid and blood-brain bar-

readily from the ventricular system into the subarach-

riers often make it impossible to achieve effective

noid space, whereas in noncommunicating hydro-

concentrations of therapeutic drugs, such as protein

cephalus fluid flow out of one or more of the ventricles

antibodies and non-lipid-soluble drugs, in the cere-

is blocked.

brospinal fluid or parenchyma of the brain.

Usually the noncommunicating type of hydro-

The cause of the low permeability of the blood-

cephalus is caused by a block in the aqueduct of Sylvius,

cerebrospinal fluid and blood-brain barriers is the

resulting from atresia (closure) before birth in many

manner in which the endothelial cells of the brain tissue

babies or from blockage by a brain tumor at any age.

capillaries are joined to one another. They are joined by

As fluid is formed by the choroid plexuses in the two

so-called tight junctions. That is, the membranes of the

lateral and the third ventricles, the volumes of these

adjacent endothelial cells are tightly fused rather than

three ventricles increase greatly. This flattens the brain

having large slit-pores between them, as is the case for

into a thin shell against the skull. In neonates, the

most other capillaries of the body.

increased pressure also causes the whole head to swell

because the skull bones have not yet fused.

The communicating type of hydrocephalus is usually

Brain Edema

caused by blockage of fluid flow in the subarachnoid

spaces around the basal regions of the brain or by block-

One of the most serious complications of abnormal

age of the arachnoidal villi where the fluid is normally

cerebral fluid dynamics is the development of brain

absorbed into the venous sinuses. Fluid therefore col-

edema. Because the brain is encased in a solid cranial

lects both on the outside of the brain and to a lesser

vault, accumulation of extra edema fluid compresses the

Chapter 61

Cerebral Blood Flow, Cerebrospinal Fluid, and Brain Metabolism

767

blood vessels, often causing seriously decreased blood

breaking down glucose and glycogen but without com-

flow and destruction of brain tissue.

bining these with oxygen. This delivers energy only at

The usual cause of brain edema is either greatly

the expense of consuming tremendous amounts of

increased capillary pressure or damage to the capillary

glucose and glycogen. However, it does keep the tissues

wall that makes the wall leaky to fluid. A very common

alive.

cause is a serious blow to the head, leading to brain con-

The brain is not capable of much anaerobic metabo-

cussion, in which the brain tissues and capillaries are

lism. One of the reasons for this is the high metabolic

traumatized so that capillary fluid leaks into the trau-

rate of the neurons, so that most neuronal activity

matized tissues.

depends on second-by-second delivery of oxygen from

Once brain edema begins, it often initiates two vicious

the blood. Putting these factors together, one can under-

circles because of the following positive feedbacks:

stand why sudden cessation of blood flow to the brain

(1) Edema compresses the vasculature. This in turn

or sudden total lack of oxygen in the blood can cause

decreases blood flow and causes brain ischemia. The

unconsciousness within 5 to 10 seconds.

ischemia in turn causes arteriolar dilation with still

further increase in capillary pressure. The increased cap-

Under Normal Conditions Most Brain Energy Is Supplied by

illary pressure then causes more edema fluid, so that the

Glucose. Under normal conditions, almost all the energy

edema becomes progressively worse. (2) The decreased

used by the brain cells is supplied by glucose derived

cerebral blood flow also decreases oxygen delivery. This

from the blood. As is true for oxygen, most of this is

increases the permeability of the capillaries, allowing

derived minute by minute and second by second from

still more fluid leakage. It also turns off the sodium

the capillary blood, with a total of only about a 2-minute

pumps of the neuronal tissue cells, thus allowing these

supply of glucose normally stored as glycogen in the

cells to swell in addition.

neurons at any given time.

Once these two vicious circles have begun, heroic

A special feature of glucose delivery to the neurons

measures must be used to prevent total destruction of

is that its transport into the neurons through the cell

the brain. One such measure is to infuse intravenously

membrane is not dependent on insulin, even though

a concentrated osmotic substance, such as a very con-

insulin is required for glucose transport into most other

centrated mannitol solution. This pulls fluid by osmosis

body cells. Therefore, in patients who have serious dia-

from the brain tissue and breaks up the vicious circles.

betes with essentially zero secretion of insulin, glucose

Another procedure is to remove fluid quickly from the

still diffuses readily into the neurons—which is most

lateral ventricles of the brain by means of ventricular

fortunate in preventing loss of mental function in

needle puncture, thereby relieving the intracerebral

diabetic patients. Yet, when a diabetic patient is

pressure.

overtreated with insulin, the blood glucose concentra-

tion can fall extremely low because the excess insulin

causes almost all the glucose in the blood to be trans-

Brain Metabolism

ported rapidly into the vast numbers of insulin-sensitive

non-neural cells throughout the body, especially into

Like other tissues, the brain requires oxygen and food

muscle and liver cells. When this happens, not enough

nutrients to supply its metabolic needs. However, there

glucose is left in the blood to supply the neurons prop-

are special peculiarities of brain metabolism that

erly, and mental function does then become seriously

require mention.

deranged, leading sometimes to coma and even more

often to mental imbalances and psychotic distur-

Total Brain Metabolic Rate and Metabolic Rate of Neurons.

bances—all caused by overtreatment with insulin.

Under resting but awake conditions, the metabolism of

the brain accounts for about 15 per cent of the total

metabolism in the body, even though the mass of the

References

brain is only 2 per cent of the total body mass. There-

fore, under resting conditions, brain metabolism per unit

Anderson CM, Nedergaard M: Astrocyte-mediated control

mass of tissue is about 7.5 times the average metabo-

of cerebral microcirculation. Trends Neurosci

26:340,

lism in non-nervous system tissues.

2003.

Most of this excess metabolism of the brain occurs in

Antunes-Rodrigues J, de Castro M, Elias LL, et al: Neu-

the neurons, not in the glial supportive tissues. The

roendocrine control of body fluid metabolism. Physiol Rev

major need for metabolism in the neurons is to pump

84:169, 2004.

ions through their membranes, mainly to transport

Burmester T, Hankeln T: Neuroglobin: a respiratory protein

sodium and calcium ions to the outside of the neuronal

of the nervous system. News Physiol Sci 19:110, 2004.

membrane and potassium ions to the interior. Each time

Chesler M: Regulation and modulation of pH in the brain.

a neuron conducts an action potential, these ions move

Physiol Rev 83:1183, 2003.

through the membranes, increasing the need for addi-

Duelli R, Kuschinsky W: Brain glucose transporters: rela-

tional membrane transport to restore proper ionic con-

tionship to local energy demand. News Physiol Sci 16:71,

centration differences across the neuron membranes.

2001.

Therefore, during excessive brain activity, neuronal

Faraci FM: Vascular protection. Stroke 34:327, 2003.

metabolism can increase as much as 100 to 150 per cent.

Faraci FM, Heistad DD: Regulation of the cerebral circula-

tion: role of endothelium and potassium channels. Physiol

Special Requirement of the Brain for Oxygen—Lack of Significant

Rev 78:53, 1998.

Anaerobic Metabolism. Most tissues of the body can live

Ganong WF: Circumventricular organs: definition and role

without oxygen for several minutes and some for as long

in the regulation of endocrine and autonomic function.

as 30 minutes. During this time, the tissue cells obtain

Clin Exp Pharmacol Physiol 27:422, 2000.

their energy through processes of anaerobic metab-

Gore JC: Principles and practice of functional MRI of the

olism, which means release of energy by partially

human brain. J Clin Invest 112:4, 2003.

C H A P T E R

General Principles of

Gastrointestinal Function—

Motility, Nervous Control, and

Blood Circulation

The alimentary tract provides the body with a con-

tinual supply of water, electrolytes, and nutrients. To

achieve this requires (1) movement of food through

the alimentary tract; (2) secretion of digestive juices

and digestion of the food; (3) absorption of water,

various electrolytes, and digestive products;

(4)

circulation of blood through the gastrointestinal

organs to carry away the absorbed substances; and

(5) control of all these functions by local, nervous, and hormonal systems.

Figure 62-1 shows the entire alimentary tract. Each part is adapted to its spe-

cific functions: some to simple passage of food, such as the esophagus; others to

temporary storage of food, such as the stomach; and others to digestion and

absorption, such as the small intestine. In this chapter, we discuss the basic prin-

ciples of function in the entire alimentary tract; in the following chapters, we

will discuss the specific functions of different segments of the tract.

General Principles of Gastrointestinal Motility

Physiologic Anatomy of the Gastrointestinal Wall

Figure 62-2 shows a typical cross section of the intestinal wall, including the fol-

lowing layers from outer surface inward: (1) the serosa, (2) a longitudinal muscle

layer, (3) a circular muscle layer, (4) the submucosa, and (5) the mucosa. In addi-

tion, sparse bundles of smooth muscle fibers, the mucosal muscle, lie in the

deeper layers of the mucosa. The motor functions of the gut are performed by

the different layers of smooth muscle.

The general characteristics of smooth muscle and its function are discussed

in Chapter 8, which should be reviewed as a background for the following sec-

tions of this chapter. The specific characteristics of smooth muscle in the gut are

the following.

Gastrointestinal Smooth Muscle Functions as a Syncytium. The individual smooth

muscle fibers in the gastrointestinal tract are 200 to 500 micrometers in length

and 2 to 10 micrometers in diameter, and they are arranged in bundles of as

many as 1000 parallel fibers. In the longitudinal muscle layer, the bundles extend

longitudinally down the intestinal tract; in the circular muscle layer, they extend

around the gut.

Within each bundle, the muscle fibers are electrically connected with one

another through large numbers of gap junctions that allow low-resistance move-

ment of ions from one muscle cell to the next. Therefore, electrical signals that

initiate muscle contractions can travel readily from one fiber to the next within

each bundle but more rapidly along the length of the bundle than sideways.

Each bundle of smooth muscle fibers is partly separated from the next by

loose connective tissue, but the muscle bundles fuse with one another at many

771

772

Unit XII Gastrointestinal Physiology

Spikes

Depolarization

Parotid gland

-10

Mouth

-20

Slow

Salivary glands

waves

-30

Stimulation by

-40

Esophagus

1. Norepinephrine

-50

2. Sympathetics

-60

Resting

Stimulation by

-70

1. Stretch

Hyperpolarization

2. Acetylcholine

3. Parasympathetics

Seconds

Liver

Stomach

Gallbladder

Pancreas

Duodenum

Figure 62-3

Transverse

Jejunum

colon

Membrane potentials in intestinal smooth muscle. Note the slow

Ascending

Descending

waves, the spike potentials, total depolarization, and hyperpolar-

colon

ization, all of which occur under different physiologic conditions

of the intestine.

Ileum

Anus

on the excitability of the muscle; sometimes it stops

after only a few millimeters and at other times it

travels many centimeters or even the entire length and

Figure 62-1

breadth of the intestinal tract.

Also, a few connections exist between the longitu-

Alimentary tract.

dinal and circular muscle layers, so that excitation of

one of these layers often excites the other as well.

Serosa

Electrical Activity of Gastrointestinal

Circular muscle

Smooth Muscle

Longitudinal

The smooth muscle of the gastrointestinal tract is

muscle

excited by almost continual slow, intrinsic electrical

Submucosa

activity along the membranes of the muscle fibers.

Meissner's

This activity has two basic types of electrical waves: (1)

nerve plexus

slow waves and (2) spikes, both of which are shown

Mucosa

in Figure 62-3. In addition, the voltage of the resting

Epithelial

membrane potential of the gastrointestinal smooth

lining

muscle can be made to change to different levels, and

Mucosal

this too can have important effects in controlling

muscle

motor activity of the gastrointestinal tract.

Mucosal gland

Slow Waves. Most gastrointestinal contractions occur

Myenteric nerve

rhythmically, and this rhythm is determined mainly by

plexus

the frequency of so-called “slow waves” of smooth

Submucosal gland

muscle membrane potential. These waves, shown in

Figure 62-3, are not action potentials. Instead, they are

Mesentery

slow, undulating changes in the resting membrane

potential. Their intensity usually varies between 5 and

Figure 62-2

15 millivolts, and their frequency ranges in different

Typical cross section of the gut.

parts of the human gastrointestinal tract from 3 to 12

per minute: about 3 in the body of the stomach, as

much as 12 in the duodenum, and about 8 or 9 in the

points, so that in reality each muscle layer represents

terminal ileum. Therefore, the rhythm of contraction

a branching latticework of smooth muscle bundles.

of the body of the stomach usually is about 3 per

Therefore, each muscle layer functions as a syncytium;

minute, of the duodenum about 12 per minute, and of

that is, when an action potential is elicited anywhere

the ileum 8 to 9 per minute.

within the muscle mass, it generally travels in all direc-

The precise cause of the slow waves is not com-

tions in the muscle. The distance that it travels depends

pletely understood, although they appear to be caused

Chapter 62

General Principles of Gastrointestinal Function—Motility, Nervous Control, and Blood Circulation

773

by complex interactions among the smooth muscle

which is called depolarization of the membrane, the

cells and specialized cells, called the interstitial cells of

muscle fibers become more excitable. When the poten-

Cajal, that are believed to act as electrical pacemakers

tial becomes more negative, which is called hyperpo-

for smooth muscle cells. These interstitial cells form a

larization, the fibers become less excitable.

network with each other and are interposed between

Factors that depolarize the membrane—that is,

the smooth muscle layers, with synaptic-like contacts

make it more excitable—are (1) stretching of the

to smooth muscle cells. The interstitial cells of Cajal

muscle, (2) stimulation by acetylcholine, (3) stimula-

undergo cyclic changes in membrane potential due

tion by parasympathetic nerves that secrete acetyl-

to unique ion channels that periodically open and

choline at their endings, and (4) stimulation by several

produce inward (pacemaker) currents that may gen-

specific gastrointestinal hormones.

erate slow wave activity.

Important factors that make the membrane poten-

The slow waves usually do not by themselves cause

tial more negative—that is, hyperpolarize the mem-

muscle contraction in most parts of the gastrointesti-

brane and make the muscle fibers less excitable—are

nal tract, except perhaps in the stomach. Instead, they

(1) the effect of norepinephrine or epinephrine on the

mainly excite the appearance of intermittent spike

fiber membrane and (2) stimulation of the sympathetic

potentials, and the spike potentials in turn actually

nerves that secrete mainly norepinephrine at their

excite the muscle contraction.

endings.

Spike Potentials. The spike potentials are true action

Calcium Ions and Muscle Contraction. Smooth muscle con-

potentials. They occur automatically when the resting

traction occurs in response to entry of calcium ions

membrane potential of the gastrointestinal smooth

into the muscle fiber. As explained in Chapter 8,

muscle becomes more positive than about -40 milli-

calcium ions, acting through a calmodulin control

volts (the normal resting membrane potential in the

mechanism, activate the myosin filaments in the fiber,

smooth muscle fibers of the gut is between -50 and

causing attractive forces to develop between the

-60 millivolts). Thus, note in Figure 62-3 that each time

myosin filaments and the actin filaments, thereby

the peaks of the slow waves temporarily become more

causing the muscle to contract.

positive than -40 millivolts, spike potentials appear on

The slow waves do not cause calcium ions to enter

these peaks. The higher the slow wave potential rises,

the smooth muscle fiber (only sodium ions). Therefore,

the greater the frequency of the spike potentials,

the slow waves by themselves usually cause no muscle

usually ranging between 1 and 10 spikes per second.

contraction. Instead, it is during the spike potentials,

The spike potentials last 10 to 40 times as long in gas-

generated at the peaks of the slow waves, that signifi-

trointestinal muscle as the action potentials in large

cant quantities of calcium ions do enter the fibers and

nerve fibers, each gastrointestinal spike lasting as long

cause most of the contraction.

as 10 to 20 milliseconds.

Another important difference between the action

Tonic Contraction of Some Gastrointestinal Smooth Muscle.

potentials of the gastrointestinal smooth muscle and

Some smooth muscle of the gastrointestinal tract

those of nerve fibers is the manner in which they are

exhibits tonic contraction as well as or instead of rhyth-

generated. In nerve fibers, the action potentials are

mical contractions. Tonic contraction is continuous, not

caused almost entirely by rapid entry of sodium ions

associated with the basic electrical rhythm of the slow

through sodium channels to the interior of the fibers.

waves but often lasting several minutes or even hours.

In gastrointestinal smooth muscle fibers, the channels

The tonic contraction often increases or decreases in

responsible for the action potentials are somewhat dif-

intensity but continues.

ferent; they allow especially large numbers of calcium

Tonic contraction is sometimes caused by con-

ions to enter along with smaller numbers of sodium

tinuous repetitive spike potentials—the greater the

ions and therefore are called calcium-sodium channels.

frequency, the greater the degree of contraction. At

These channels are much slower to open and close

other times, tonic contraction is caused by hormones

than are the rapid sodium channels of large nerve

or other factors that bring about continuous partial

fibers. The slowness of opening and closing of the

depolarization of the smooth muscle membrane

calcium-sodium channels accounts for the long dura-

without causing action potentials. A third cause of

tion of the action potentials. Also, the movement of

tonic contraction is continuous entry of calcium ions

large amounts of calcium ions to the interior of the

into the interior of the cell brought about in ways not

muscle fiber during the action potential plays a special

associated with changes in membrane potential. The

role in causing the intestinal muscle fibers to contract,

details of these mechanisms are still unclear.

as we discuss shortly.

Changes in Voltage of the Resting Membrane Potential. In

Neural Control of

addition to the slow waves and spike potentials, the

Gastrointestinal Function—

baseline voltage level of the smooth muscle resting

membrane potential also can change. Under normal

Enteric Nervous System

conditions, the resting membrane potential averages

about -56 millivolts, but multiple factors can change

The gastrointestinal tract has a nervous system all its

this level. When the potential becomes less negative,

own called the enteric nervous system. It lies entirely

774

Unit XII Gastrointestinal Physiology

Sympathetic

Parasympathetic

To prevertebral

ganglia, spinal

(mainly postganglionic)

(preganglionic)

cord, and brain

stem

Myenteric

plexus

Figure 62-4

Neural control of the gut wall, showing (1)

Submucosal

the myenteric and submucosal plexuses

plexus

(black fibers); (2) extrinsic control of these

plexuses by the sympathetic and

parasympathetic nervous systems

(red

Sensory

fibers); and

(3) sensory fibers passing

neurons

from the luminal epithelium and gut wall

to the enteric plexuses, then to the pre-

Epithelium

vertebral ganglia of the spinal cord and

directly to the spinal cord and brain stem

(dashed fibers).

in the wall of the gut, beginning in the esophagus and

Differences Between the Myenteric

extending all the way to the anus. The number of

and Submucosal Plexuses

neurons in this enteric system is about 100 million,

almost exactly equal to the number in the entire spinal

cord. This highly developed enteric nervous system is

The myenteric plexus consists mostly of a linear chain

especially important in controlling gastrointestinal

of many interconnecting neurons that extends the

movements and secretion.

entire length of the gastrointestinal tract. A section of

The enteric nervous system is composed mainly of

this chain is shown in Figure 62-4.

two plexuses, shown in Figure 62-4: (1) an outer plexus

Because the myenteric plexus extends all the way

lying between the longitudinal and circular muscle

along the intestinal wall and because it lies between

layers, called the myenteric plexus or Auerbach’s

the longitudinal and circular layers of intestinal

plexus, and (2) an inner plexus, called the submucosal

smooth muscle, it is concerned mainly with controlling

plexus or Meissner’s plexus, that lies in the submucosa.

muscle activity along the length of the gut. When this

The nervous connections within and between these

plexus is stimulated, its principal effects are

(1)

two plexuses are also shown in Figure 62-4.

increased tonic contraction, or “tone,” of the gut wall,

The myenteric plexus controls mainly the gastroin-

(2) increased intensity of the rhythmical contractions,

testinal movements, and the submucosal plexus con-

(3) slightly increased rate of the rhythm of contraction,

trols mainly gastrointestinal secretion and local blood

and (4) increased velocity of conduction of excitatory

flow.

waves along the gut wall, causing more rapid move-

Note especially in Figure 62-4 the extrinsic sympa-

ment of the gut peristaltic waves.

thetic and parasympathetic fibers that connect to both

The myenteric plexus should not be considered

the myenteric and submucosal plexuses. Although the

entirely excitatory because some of its neurons are

enteric nervous system can function on its own, inde-

inhibitory; their fiber endings secrete an inhibitory

pendently of these extrinsic nerves, stimulation by the

transmitter, possibly vasoactive intestinal polypeptide

parasympathetic and sympathetic systems can greatly

or some other inhibitory peptide. The resulting

enhance or inhibit gastrointestinal functions, as we

inhibitory signals are especially useful for inhibiting

discuss later.

some of the intestinal sphincter muscles that impede

Also shown in Figure

62-4 are sensory nerve

movement of food along successive segments of the

endings that originate in the gastrointestinal epithe-

gastrointestinal tract, such as the pyloric sphincter,

lium or gut wall and send afferent fibers to both

which controls emptying of the stomach into the duo-

plexuses of the enteric system, as well as (1) to the pre-

denum, and the sphincter of the ileocecal valve, which

vertebral ganglia of the sympathetic nervous system,

controls emptying from the small intestine into the

(2) to the spinal cord, and (3) in the vagus nerves all

cecum.

the way to the brain stem. These sensory nerves can

The submucosal plexus, in contrast to the myenteric

elicit local reflexes within the gut wall itself and still

plexus, is mainly concerned with controlling function

other reflexes that are relayed to the gut from either

within the inner wall of each minute segment of the

the prevertebral ganglia or the basal regions of the

intestine. For instance, many sensory signals originate

brain.

from the gastrointestinal epithelium and are then

Chapter 62

General Principles of Gastrointestinal Function—Motility, Nervous Control, and Blood Circulation

775

integrated in the submucosal plexus to help control

Sympathetic Innervation. The sympathetic fibers to the

local intestinal secretion, local absorption, and local

gastrointestinal tract originate in the spinal cord

contraction of the submucosal muscle that causes

between segments T-5 and L-2. Most of the pregan-

various degrees of infolding of the gastrointestinal

glionic fibers that innervate the gut, after leaving the

mucosa.

cord, enter the sympathetic chains that lie lateral to the

spinal column, and many of these fibers then pass on

through the chains to outlying ganglia such as to the

Types of Neurotransmitters Secreted

celiac ganglion and various mesenteric ganglia. Most of

by Enteric Neurons

the postganglionic sympathetic neuron bodies are in

these ganglia, and postganglionic fibers then spread

In an attempt to understand better the multiple func-

through postganglionic sympathetic nerves to all parts

tions of the gastrointestinal enteric nervous system,

of the gut.. The sympathetics innervate essentially all

research workers the world over have identified a

of the gastrointestinal tract, rather than being more

dozen or more different neurotransmitter substances

extensive nearest the oral cavity and anus as is true of

that are released by the nerve endings of different

the parasympathetics. The sympathetic nerve endings

types of enteric neurons. Two of them with which we

secrete mainly norepinephrine but also small amounts

are already familiar are (1) acetylcholine and (2) nor-

of epinephrine.

epinephrine. Others are (3) adenosine triphosphate,

In general, stimulation of the sympathetic nervous

(4) serotonin, (5) dopamine, (6) cholecystokinin, (7)

system inhibits activity of the gastrointestinal tract,

substance P,

(8) vasoactive intestinal polypeptide,

causing many effects opposite to those of the

(9) somatostatin,

(10) leu-enkephalin,

(11) met-

parasympathetic system. It exerts its effects in two

enkephalin, and (12) bombesin. The specific functions

ways: (1) to a slight extent by direct effect of secreted

of many of these are not known well enough to justify

norepinephrine to inhibit intestinal tract smooth

discussion here, other than to point out the following.

muscle (except the mucosal muscle, which it excites)

Acetylcholine most often excites gastrointestinal

and (2) to a major extent by an inhibitory effect of

activity. Norepinephrine almost always inhibits gas-

norepinephrine on the neurons of the entire enteric

trointestinal activity. This is also true of epinephrine,

nervous system.

which reaches the gastrointestinal tract mainly by way

Strong stimulation of the sympathetic system can

of the blood after it is secreted by the adrenal medul-

inhibit motor movements of the gut so greatly that this

lae into the circulation. The other aforementioned

literally can block movement of food through the gas-

transmitter substances are a mixture of excitatory and

trointestinal tract.

inhibitory agents, some of which we will discuss in the

following chapter.

Afferent Sensory Nerve Fibers from the Gut

Many afferent sensory nerve fibers innervate the gut.

Autonomic Control of the

Some of them have their cell bodies in the enteric

Gastrointestinal Tract

nervous system itself and some in the dorsal root

Parasympathetic Innervation. The parasympathetic sup-

ganglia of the spinal cord. These sensory nerves can be

ply to the gut is divided into cranial and sacral divi-

stimulated by (1) irritation of the gut mucosa, (2)

sions, which were discussed in Chapter 60.

excessive distention of the gut, or (3) presence of spe-

Except for a few parasympathetic fibers to the

cific chemical substances in the gut. Signals trans-

mouth and pharyngeal regions of the alimentary tract,

mitted through the fibers can then cause excitation or,

the cranial parasympathetic nerve fibers are almost

under other conditions, inhibition of intestinal move-

entirely in the vagus nerves. These fibers provide

ments or intestinal secretion.

extensive innervation to the esophagus, stomach, and

In addition, other sensory signals from the gut go all

pancreas and somewhat less to the intestines down

the way to multiple areas of the spinal cord and

through the first half of the large intestine.

even the brain stem. For example, 80 per cent of the

The sacral parasympathetics originate in the second,

nerve fibers in the vagus nerves are afferent rather

third, and fourth sacral segments of the spinal cord and

than efferent. These afferent fibers transmit sensory

pass through the pelvic nerves to the distal half of the

signals from the gastrointestinal tract into the brain

large intestine and all the way to the anus. The sig-

medulla, which in turn initiates vagal reflex signals that

moidal, rectal, and anal regions are considerably better

return to the gastrointestinal tract to control many of

supplied with parasympathetic fibers than are the

its functions.

other intestinal areas. These fibers function especially

to execute the defecation reflexes, discussed in

Gastrointestinal Reflexes

Chapter 63.

The anatomical arrangement of the enteric nervous

The postganglionic neurons of the gastrointestinal

system and its connections with the sympathetic and

parasympathetic system are located mainly in the

parasympathetic systems support three types of gas-

myenteric and submucosal plexuses. Stimulation of

trointestinal reflexes that are essential to gastroin-

these parasympathetic nerves causes general increase

testinal control. They are the following:

in activity of the entire enteric nervous system. This

1. Reflexes that are integrated entirely within the gut

in turn enhances activity of most gastrointestinal

wall enteric nervous system. These include reflexes

functions.

that control much gastrointestinal secretion,

776

Unit XII Gastrointestinal Physiology

peristalsis, mixing contractions, local inhibitory

of the duodenum in response to acidic gastric juice

effects, and so forth.

emptying into the duodenum from the pylorus of the

2. Reflexes from the gut to the prevertebral

stomach. Secretin has a mild effect on motility of the

sympathetic ganglia and then back to the

gastrointestinal tract and acts to promote pancreatic

gastrointestinal tract. These reflexes transmit

secretion of bicarbonate which in turn helps to neu-

signals long distances to other areas of the

tralize the acid in the small intestine.

gastrointestinal tract, such as signals from the

Gastric inhibitory peptide is secreted by the mucosa

stomach to cause evacuation of the colon (the

of the upper small intestine, mainly in response to fatty

gastrocolic reflex), signals from the colon and

acids and amino acids but to a lesser extent in response

small intestine to inhibit stomach motility and

to carbohydrate. It has a mild effect in decreasing

stomach secretion (the enterogastric reflexes), and

motor activity of the stomach and therefore slows

reflexes from the colon to inhibit emptying of ileal

emptying of gastric contents into the duodenum when

contents into the colon (the colonoileal reflex).

the upper small intestine is already overloaded with

3. Reflexes from the gut to the spinal cord or brain

food products.

stem and then back to the gastrointestinal tract.

Motilin is secreted by the upper duodenum during

These include especially (1) reflexes from the

fasting, and the only known function of this hormone

stomach and duodenum to the brain stem and

is to increase gastrointestinal motility. Motilin is

back to the stomach—by way of the vagus

released cyclically and stimulates waves of gastroin-

nerves—to control gastric motor and secretory

testinal motility called interdigestive myoelectric com-

activity; (2) pain reflexes that cause general

plexes that move through the stomach and small

inhibition of the entire gastrointestinal tract; and

intestine every 90 minutes in a fasted person. Motilin

(3) defecation reflexes that travel from the colon

secretion is inhibited after ingestion by mechanisms

and rectum to the spinal cord and back again

that are not fully understood.

to produce the powerful colonic, rectal, and

abdominal contractions required for defecation

Functional Types of

(the defecation reflexes).

Movements in the

Gastrointestinal Tract

Hormonal Control of

Gastrointestinal Motility

Two types of movements occur in the gastrointestinal

tract: (1) propulsive movements, which cause food to

In Chapter 64, we discuss the extreme importance of

move forward along the tract at an appropriate rate

several hormones for controlling gastrointestinal

to accommodate digestion and absorption, and (2)

secretion. Most of these same hormones also affect

mixing movements, which keep the intestinal contents

motility in some parts of the gastrointestinal

thoroughly mixed at all times.

tract. Although the motility effects are usually less

important than the secretory effects of the hormones,

some of the more important of them are the

Propulsive Movements—Peristalsis

following.

Gastrin is secreted by the “G” cells of the antrum of

The basic propulsive movement of the gastrointestinal

the stomach in response to stimuli associated with

tract is peristalsis, which is illustrated in Figure 62-5.

ingestion of a meal, such as distention of the stomach,

A contractile ring appears around the gut and then

the products of proteins, and gastrin releasing peptide,

moves forward; this is analogous to putting one’s

which is released by the nerves of the gastric mucosa

fingers around a thin distended tube, then constricting

during vagal stimulation. The primary actions of

the fingers and sliding them forward along the tube.

gastrin are (1) stimulation of gastric acid secretion and

Any material in front of the contractile ring is moved

(2) stimulation of growth of the gastric mucosa.

forward.

Cholecystokinin is secreted by

“I” cells in the

Peristalsis is an inherent property of many syncytial

mucosa of the duodenum and jejunum mainly in

smooth muscle tubes; stimulation at any point in the

response to digestive products of fat, fatty acids,

gut can cause a contractile ring to appear in the circu-

and monoglycerides in the intestinal contents. This

lar muscle, and this ring then spreads along the gut

hormone strongly contracts the gallbladder, expelling

tube. (Peristalsis also occurs in the bile ducts, glandu-

bile into the small intestine where the bile in turn plays

lar ducts, ureters, and many other smooth muscle tubes

important roles in emulsifying fatty substances, allow-

of the body.)

ing them to be digested and absorbed. Cholecystokinin

The usual stimulus for intestinal peristalsis is disten-

also inhibits stomach contraction moderately. There-

tion of the gut. That is, if a large amount of food col-

fore, at the same time that this hormone causes emp-

lects at any point in the gut, the stretching of the gut

tying of the gallbladder, it also slows the emptying of

wall stimulates the enteric nervous system to contract

food from the stomach to give adequate time for diges-

the gut wall 2 to 3 centimeters behind this point, and

tion of the fats in the upper intestinal tract.

a contractile ring appears that initiates a peristaltic

Secretin was the first gastrointestinal hormone dis-

movement. Other stimuli that can initiate peristalsis

covered and is secreted by the “S” cells in the mucosa

include chemical or physical irritation of the epithelial

Chapter 62

General Principles of Gastrointestinal Function—Motility, Nervous Control, and Blood Circulation

777

Peristaltic contraction

Vena cava

Leading wave of distention

Hepatic artery

Hepatic vein

Hepatic

sinuses

Aorta

Zero time

5 seconds later

Figure 62-5

Splenic

Peristalsis.

vein

Portal

vein

lining in the gut. Also, strong parasympathetic nervous

signals to the gut will elicit strong peristalsis.

Intestinal vein

Intestinal artery

Function of the Myenteric Plexus in Peristalsis. Peristalsis

occurs only weakly or not at all in any portion of the

gastrointestinal tract that has congenital absence of

the myenteric plexus. Also, it is greatly depressed or

Capillary

completely blocked in the entire gut when a person is

treated with atropine to paralyze the cholinergic nerve

Figure 62-6

endings of the myenteric plexus. Therefore, effectual

peristalsis requires an active myenteric plexus.

Splanchnic circulation.

Directional Movement of Peristaltic Waves Toward the Anus.

Peristalsis, theoretically, can occur in either direction

especially true when forward progression of the intes-

from a stimulated point, but it normally dies out

tinal contents is blocked by a sphincter, so that a

rapidly in the orad direction while continuing for a

peristaltic wave can then only churn the intestinal con-

considerable distance toward the anus. The exact cause

tents, rather than propelling them forward. At other

of this directional transmission of peristalsis has never

times, local intermittent constrictive contractions occur

been ascertained, although it probably results mainly

every few centimeters in the gut wall. These constric-

from the fact that the myenteric plexus itself is “polar-

tions usually last only 5 to 30 seconds; then new con-

ized” in the anal direction, which can be explained as

strictions occur at other points in the gut, thus

follows.

“chopping” and “shearing” the contents first here and

then there. These peristaltic and constrictive move-

Peristaltic Reflex and the “Law of the Gut.” When a

ments are modified in different parts of the gastroin-

segment of the intestinal tract is excited by distention

testinal tract for proper propulsion and mixing, as

and thereby initiates peristalsis, the contractile ring

discussed for each portion of the tract in Chapter 63.

causing the peristalsis normally begins on the orad side

of the distended segment and moves toward the dis-

tended segment, pushing the intestinal contents in the

Gastrointestinal Blood Flow—

anal direction for 5 to 10 centimeters before dying out.

At the same time, the gut sometimes relaxes several

“Splanchnic Circulation”

centimeters downstream toward the anus, which is

called “receptive relaxation,” thus allowing the food to

The blood vessels of the gastrointestinal system are

be propelled more easily anally than orad.

part of a more extensive system called the splanchnic

This complex pattern does not occur in the absence

circulation, shown in Figure 62-6. It includes the blood

of the myenteric plexus. Therefore, the complex is

flow through the gut itself plus blood flows through the

called the myenteric reflex or the peristaltic reflex. The

spleen, pancreas, and liver. The design of this system is

peristaltic reflex plus the anal direction of movement

such that all the blood that courses through the gut,

of the peristalsis is called the “law of the gut.”

spleen, and pancreas then flows immediately into the

liver by way of the portal vein. In the liver, the blood

passes through millions of minute liver sinusoids and

Mixing Movements

finally leaves the liver by way of hepatic veins that

empty into the vena cava of the general circulation.

Mixing movements differ in different parts of the ali-

This flow of blood through the liver, before it empties

mentary tract. In some areas, the peristaltic contrac-

into the vena cava, allows the reticuloendothelial cells

tions themselves cause most of the mixing. This is

that line the liver sinusoids to remove bacteria and

778

Unit XII Gastrointestinal Physiology

other particulate matter that might enter the blood

On entering the wall of the gut, the arteries branch

from the gastrointestinal tract, thus preventing direct

and send smaller arteries circling in both directions

transport of potentially harmful agents into the

around the gut, with the tips of these arteries meeting

remainder of the body.

on the side of the gut wall opposite the mesenteric

The nonfat, water-soluble nutrients absorbed from

attachment. From the circling arteries, still much

the gut (such as carbohydrates and proteins) are trans-

smaller arteries penetrate into the intestinal wall and

ported in the portal venous blood to the same liver

spread (1) along the muscle bundles, (2) into the intes-

sinusoids. Here, both the reticuloendothelial cells and

tinal villi, and (3) into submucosal vessels beneath the

the principal parenchymal cells of the liver, the hepatic

epithelium to serve the secretory and absorptive func-

cells, absorb and store temporarily from one half to

tions of the gut.

three quarters of the nutrients. Also, much chemical

Figure 62-8 shows the special organization of the

intermediary processing of these nutrients occurs in

blood flow through an intestinal villus, including a

the liver cells. We discuss these nutritional functions of

small arteriole and venule that interconnect with a

the liver in Chapters 67 through 71. Almost all of the

system of multiple looping capillaries. The walls of the

fats absorbed from the intestinal tract are not carried

arterioles are highly muscular and are highly active in

in the portal blood but instead are absorbed into the

controlling villus blood flow.

intestinal lymphatics and then conducted to the sys-

temic circulating blood by way of the thoracic duct,

Effect of Gut Activity and Metabolic

bypassing the liver.

Factors on Gastrointestinal

Blood Flow

Anatomy of the Gastrointestinal

Blood Supply

Under normal conditions, the blood flow in each area

of the gastrointestinal tract, as well as in each layer of

Figure 62-7 shows the general plan of the arterial

the gut wall, is directly related to the level of local

blood supply to the gut, including the superior mesen-

activity. For instance, during active absorption of nutri-

teric and inferior mesenteric arteries supplying the

ents, blood flow in the villi and adjacent regions of the

walls of the small and large intestines by way of an

submucosa is increased as much as eightfold. Likewise,

arching arterial system. Not shown in the figure is the

blood flow in the muscle layers of the intestinal wall

celiac artery, which provides a similar blood supply to

increases with increased motor activity in the gut. For

the stomach.

instance, after a meal, the motor activity, secretory

Aorta

Transverse

colon

Branch of

Middle colic

inferior

mesenteric

Ascending

colon

Superior

Right colic

mesenteric

Descending

colon

Ileocolic

Jejunum

Jejunal

Ileal

Figure 62-7

Arterial blood supply to the intes-

tines through the mesenteric

Ileum

web.

Chapter 62

General Principles of Gastrointestinal Function—Motility, Nervous Control, and Blood Circulation

779

100 per cent; therefore, the increased mucosal and gut

wall metabolic rate during gut activity probably lowers

the oxygen concentration enough to cause much of the

vasodilation. The decrease in oxygen can also lead to

as much as a fourfold increase of adenosine, a well-

known vasodilator that could be responsible for much

of the increased flow.

Thus, the increased blood flow during increased gas-

Central lacteal

trointestinal activity is probably a combination of

many of the aforementioned factors plus still others

yet undiscovered.

Blood capillaries

“Countercurrent” Blood Flow in the Villi. Note in Figure

62-8 that the arterial flow into the villus and the

venous flow out of the villus are in directions opposite

to each other, and that the vessels lie in close apposi-

tion to each other. Because of this vascular arrange-

ment, much of the blood oxygen diffuses out of the

arterioles directly into the adjacent venules without

ever being carried in the blood to the tips of the villi.

As much as 80 per cent of the oxygen may take this

short-circuit route and therefore not be available for

Vein

local metabolic functions of the villi. The reader will

recognize that this type of countercurrent mechanism

in the villi is analogous to the countercurrent mecha-

nism in the vasa recta of the kidney medulla, discussed

in detail in Chapter 28.

Artery

Under normal conditions, this shunting of oxygen

from the arterioles to the venules is not harmful to the

villi, but in disease conditions in which blood flow to

the gut becomes greatly curtailed, such as in circula-

tory shock, the oxygen deficit in the tips of the villi can

become so great that the villus tip or even the whole

Figure 62-8

villus suffers ischemic death and can disintegrate.

Microvasculature of the villus, showing a countercurrent arrange-

Therefore, for this reason and others, in many gas-

ment of blood flow in the arterioles and venules.

trointestinal diseases the villi become seriously

blunted, leading to greatly diminished intestinal

absorptive capacity.

activity, and absorptive activity all increase; likewise,

the blood flow increases greatly but then decreases

back to the resting level over another 2 to 4 hours.

Nervous Control of Gastrointestinal

Possible Causes of the Increased Blood Flow During Gastroin-

Blood Flow

testinal Activity. Although the precise cause or causes

of the increased blood flow during increased gastroin-

Stimulation of the parasympathetic nerves going to the

testinal activity are still unclear, some facts are known.

stomach and lower colon increases local blood flow at

First, several vasodilator substances are released

the same time that it increases glandular secretion.

from the mucosa of the intestinal tract during the

This increased flow probably results secondarily from

digestive process. Most of these are peptide hormones,

the increased glandular activity and not as a direct

including cholecystokinin, vasoactive intestinal peptide,

effect of the nervous stimulation.

gastrin, and secretin. These same hormones control

Sympathetic stimulation, by contrast, has a direct

specific motor and secretory activities of the gut, as we

effect on essentially all the gastrointestinal tract to

will see in Chapters 63 and 64.

cause intense vasoconstriction of the arterioles with

Second, some of the gastrointestinal glands also

greatly decreased blood flow. After a few minutes of

release into the gut wall two kinins, kallidin and

this vasoconstriction, the flow often returns almost to

bradykinin, at the same time that they secrete their

normal by means of a mechanism called “autoregula-

secretions into the lumen. These kinins are powerful

tory escape.” That is, the local metabolic vasodilator

vasodilators that are believed to cause much of the

mechanisms that are elicited by ischemia become pre-

increased mucosal vasodilation that occurs along with

potent over the sympathetic vasoconstriction and,

secretion.

therefore, redilate the arterioles, thus causing return of

Third, decreased oxygen concentration in the gut

necessary nutrient blood flow to the gastrointestinal

wall can increase intestinal blood flow at least 50 to

glands and muscle.

780

Unit XII Gastrointestinal Physiology

Importance of Nervous Depression of Gastrointestinal Blood

Hocker M: Molecular mechanisms of gastrin-dependent

Flow When Other Parts of the Body Need Extra Blood Flow. A

gene regulation. Ann N Y Acad Sci 1014:97, 2004.

major value of sympathetic vasoconstriction in the gut

Huizinga JD: Physiology and pathophysiology of the inter-

stitial cell of Cajal: from bench to bedside. II. Gastric

is that it allows shut-off of gastrointestinal and other

motility: lessons from mutant mice on slow waves and

splanchnic blood flow for short periods of time during

innervation. Am J Physiol Gastrointest Liver Physiol

heavy exercise, when increased flow is needed by the

281:G1129, 2001.

skeletal muscle and heart. Also, in circulatory shock,

Inui A, Asakawa A, Bowers CY, et al: Ghrelin, appetite, and

when all the body’s vital tissues are in danger of cel-

gastric motility: the emerging role of the stomach as an

lular death for lack of blood flow—especially the brain

endocrine organ. FASEB J 18:439, 2004.

and the heart—sympathetic stimulation can decrease

Johnson LR: Gastrointestinal Physiology, 6th ed. St. Louis:

splanchnic blood flow to very little for many hours.

Mosby, 2001.

Sympathetic stimulation also causes strong vaso-

Lammers WJ, Slack JR: Of slow waves and spike patches.

constriction of the large-volume intestinal and mesen-

News Physiol Sci 16:138, 2001.

Moran TH, Kinzig KP: Gastrointestinal satiety signals II.

teric veins. This decreases the volume of these veins,

Cholecystokinin. Am J Physiol Gastrointest Liver Physiol

thereby displacing large amounts of blood into other

286:G183, 2004.

parts of the circulation. In hemorrhagic shock or other

Powley TL, Phillips RJ: Musings on the wanderer: what’s new

states of low blood volume, this mechanism can

in our understanding of vago-vagal reflexes? I. Morphol-

provide as much as 200 to 400 milliliters of extra blood

ogy and topography of vagal afferents innervating the GI

to sustain the general circulation.

tract. Am J Physiol Gastrointest Liver Physiol 283:G1217,

2002.

Rehfeld JF: The new biology of gastrointestinal hormones.

References

Physiol Rev 78:1087, 1998.

Sanders KM, Ordog T, Ward SM: Physiology and patho-

Adelson DW, Million M: Tracking the moveable feast:

physiology of the interstitial cells of Cajal: from bench to

sonomicrometry and gastrointestinal motility. News

bedside. IV. Genetic and animal models of GI motility dis-

Physiol Sci 19:27, 2004.

orders caused by loss of interstitial cells of Cajal. Am J

Daniel EE: Physiology and pathophysiology of the intersti-

Physiol Gastrointest Liver Physiol 282:G747, 2002.

tial cell of Cajal: from bench to bedside. III. Interaction of

Smith GP: Satiation: From Gut to Brain. New York: Oxford

interstitial cells of Cajal with neuromediators: an interim

University Press, 1998.

assessment. Am J Physiol Gastrointest Liver Physiol

Thomas RP, Hellmich MR, Townsend CM Jr, Evers

281:G1329, 2001.

BM: Role of gastrointestinal hormones in the proliferation

Furness JB, Jones C, Nurgali K, Clerc N: Intrinsic primary

of normal and neoplastic tissues. Endocr Rev 24:571,

afferent neurons and nerve circuits within the intestine.

2003.

Prog Neurobiol 72:143, 2004.

Woods SC: Gastrointestinal satiety signals I. An overview of

Hansen MB: The enteric nervous system II: gastrointestinal

gastrointestinal signals that influence food intake. Am J

functions. Pharmacol Toxicol 92:249-57, 2003.

Physiol Gastrointest Liver Physiol 286:G7, 2004

Hobson AR, Aziz Q: Central nervous system processing of

human visceral pain in health and disease. News Physiol

Sci 18:109, 2003.

C H A P T E R

Propulsion and Mixing of

Food in the Alimentary Tract

For food to be processed optimally in the alimen-

tary tract, the time that it remains in each part of the

tract is critical. Also, appropriate mixing must be

provided. Yet because the requirements for mixing

and propulsion are quite different at each stage of

processing, multiple automatic nervous and hor-

monal feedback mechanisms control the timing of

each of these so that they will occur optimally, not

too rapidly, not too slowly.

The purpose of this chapter is to discuss these movements, especially the auto-

matic mechanisms of this control.

Ingestion of Food

The amount of food that a person ingests is determined principally by intrinsic

desire for food called hunger. The type of food that a person preferentially seeks

is determined by appetite. These mechanisms in themselves are extremely

important automatic regulatory systems for maintaining an adequate nutri-

tional supply for the body; they are discussed in Chapter 71 in relation to nutri-

tion of the body. The current discussion of food ingestion is confined to the

mechanics of ingestion, especially mastication and swallowing.

Mastication (Chewing)

The teeth are admirably designed for chewing, the anterior teeth (incisors) pro-

viding a strong cutting action and the posterior teeth (molars), a grinding action.

All the jaw muscles working together can close the teeth with a force as great

as 55 pounds on the incisors and 200 pounds on the molars.

Most of the muscles of chewing are innervated by the motor branch of the

fifth cranial nerve, and the chewing process is controlled by nuclei in the brain

stem. Stimulation of specific reticular areas in the brain stem taste centers will

cause rhythmical chewing movements. Also, stimulation of areas in the hypo-

thalamus, amygdala, and even the cerebral cortex near the sensory areas for

taste and smell can often cause chewing.

Much of the chewing process is caused by a chewing reflex, which may be

explained as follows: The presence of a bolus of food in the mouth at first ini-

tiates reflex inhibition of the muscles of mastication, which allows the lower jaw

to drop. The drop in turn initiates a stretch reflex of the jaw muscles that leads

to rebound contraction. This automatically raises the jaw to cause closure of the

teeth, but it also compresses the bolus again against the linings of the mouth,

which inhibits the jaw muscles once again, allowing the jaw to drop and rebound

another time; this is repeated again and again.

Chewing is important for digestion of all foods, but especially important for

most fruits and raw vegetables because these have indigestible cellulose mem-

branes around their nutrient portions that must be broken before the food can

be digested. Also, chewing aids the digestion of food for still another simple

reason: Digestive enzymes act only on the surfaces of food particles; therefore,

781

782

Unit XII Gastrointestinal Physiology

the rate of digestion is absolutely dependent on the

epithelial swallowing receptor areas all around the

total surface area exposed to the digestive secretions.

opening of the pharynx, especially on the tonsillar

In addition, grinding the food to a very fine particulate

pillars, and impulses from these pass to the brain stem

consistency prevents excoriation of the gastrointesti-

to initiate a series of automatic pharyngeal muscle

nal tract and increases the ease with which food is

contractions as follows:

emptied from the stomach into the small intestine,

The soft palate is pulled upward to close the

then into all succeeding segments of the gut.

posterior nares, to prevent reflux of food into the

nasal cavities.

The palatopharyngeal folds on each side of the

Swallowing (Deglutition)

pharynx are pulled medially to approximate each

other. In this way, these folds form a sagittal

Swallowing is a complicated mechanism, principally

slit through which the food must pass into the

because the pharynx subserves respiration as well as

posterior pharynx. This slit performs a selective

swallowing. The pharynx is converted for only a few

action, allowing food that has been masticated

seconds at a time into a tract for propulsion of food.

sufficiently to pass with ease. Because this stage of

It is especially important that respiration not be com-

swallowing lasts less than 1 second, any large

promised because of swallowing.

object is usually impeded too much to pass into

In general, swallowing can be divided into (1) a vol-

the esophagus.

untary stage, which initiates the swallowing process; (2)

The vocal cords of the larynx are strongly

a pharyngeal stage, which is involuntary and consti-

approximated, and the larynx is pulled upward

tutes passage of food through the pharynx into the

and anteriorly by the neck muscles. These actions,

esophagus; and (3) an esophageal stage, another invol-

combined with the presence of ligaments that

untary phase that transports food from the pharynx to

prevent upward movement of the epiglottis, cause

the stomach.

the epiglottis to swing backward over the opening

of the larynx. All these effects acting together

Voluntary Stage of Swallowing. When the food is ready for

prevent passage of food into the nose and

swallowing, it is “voluntarily” squeezed or rolled pos-

trachea. Most essential is the tight approximation

teriorly into the pharynx by pressure of the tongue

of the vocal cords, but the epiglottis helps to

upward and backward against the palate, as shown in

prevent food from ever getting as far as the vocal

Figure

63-1. From here on, swallowing becomes

cords. Destruction of the vocal cords or of the

entirely—or almost entirely—automatic and ordinar-

muscles that approximate them can cause

ily cannot be stopped.

strangulation.

The upward movement of the larynx also pulls

Pharyngeal Stage of Swallowing. As the bolus of food

up and enlarges the opening to the esophagus.

enters the posterior mouth and pharynx, it stimulates

At the same time, the upper 3 to 4 centimeters

of the esophageal muscular wall, called the

upper esophageal sphincter (also called the

Vagus

Glossopharyngeal

pharyngoesophageal sphincter) relaxes, thus

nerve

allowing food to move easily and freely from the

posterior pharynx into the upper esophagus.

Trigeminal nerve

Between swallows, this sphincter remains strongly

contracted, thereby preventing air from going

Swallowing

into the esophagus during respiration. The

center

upward movement of the larynx also lifts the

Medulla

glottis out of the main stream of food flow, so

Bolus of food

that the food mainly passes on each side of the

Uvula

epiglottis rather than over its surface; this adds

Pharynx

still another protection against entry of food into

Epiglottis

the trachea.

Once the larynx is raised and the

Vocal cords

pharyngoesophageal sphincter becomes relaxed,

Esophagus

the entire muscular wall of the pharynx contracts,

beginning in the superior part of the pharynx,

then spreading downward over the middle and

inferior pharyngeal areas, which propels the food

Peristalsis

by peristalsis into the esophagus.

To summarize the mechanics of the pharyngeal

stage of swallowing: The trachea is closed, the esoph-

agus is opened, and a fast peristaltic wave initiated by

the nervous system of the pharynx forces the bolus of

Figure 63-1

food into the upper esophagus, the entire process

Swallowing mechanism.

occurring in less than 2 seconds.

Chapter 63

Propulsion and Mixing of Food in the Alimentary Tract

783

Nervous Initiation of the Pharyngeal Stage of Swallow-

the esophagus itself by the retained food; these waves

ing. The most sensitive tactile areas of the posterior

continue until all the food has emptied into the

mouth and pharynx for initiating the pharyngeal stage

stomach. The secondary peristaltic waves are initiated

of swallowing lie in a ring around the pharyngeal

partly by intrinsic neural circuits in the myenteric

opening, with greatest sensitivity on the tonsillar

nervous system and partly by reflexes that begin in the

pillars. Impulses are transmitted from these areas

pharynx and are then transmitted upward through

through the sensory portions of the trigeminal and

vagal afferent fibers to the medulla and back again to

glossopharyngeal nerves into the medulla oblongata,

the esophagus through glossopharyngeal and vagal

either into or closely associated with the tractus soli-

efferent nerve fibers.

tarius, which receives essentially all sensory impulses

The musculature of the pharyngeal wall and upper

from the mouth.

third of the esophagus is striated muscle. Therefore, the

The successive stages of the swallowing process

peristaltic waves in these regions are controlled by

are then automatically initiated in orderly sequence

skeletal nerve impulses from the glossopharyngeal and

by neuronal areas of the reticular substance of the

vagus nerves. In the lower two thirds of the esophagus,

medulla and lower portion of the pons. The sequence

the musculature is smooth muscle, but this portion of

of the swallowing reflex is the same from one swallow

the esophagus is also strongly controlled by the vagus

to the next, and the timing of the entire cycle also

nerves acting through connections with the esophageal

remains constant from one swallow to the next. The

myenteric nervous system. When the vagus nerves to

areas in the medulla and lower pons that control

the esophagus are cut, the myenteric nerve plexus of

swallowing are collectively called the deglutition or

the esophagus becomes excitable enough after several

swallowing center.

days to cause strong secondary peristaltic waves even

The motor impulses from the swallowing center to

without support from the vagal reflexes. Therefore,

the pharynx and upper esophagus that cause swallow-

even after paralysis of the brain stem swallowing

ing are transmitted successively by the 5th, 9th, 10th,

reflex, food fed by tube or in some other way into the

and 12th cranial nerves and even a few of the superior

esophagus still passes readily into the stomach.

cervical nerves.

In summary, the pharyngeal stage of swallowing is

Receptive Relaxation of the Stomach. When the

principally a reflex act. It is almost always initiated by

esophageal peristaltic wave approaches toward the

voluntary movement of food into the back of the

stomach, a wave of relaxation, transmitted through

mouth, which in turn excites involuntary pharyngeal

myenteric inhibitory neurons, precedes the peristalsis.

sensory receptors to elicit the swallowing reflex.

Furthermore, the entire stomach and, to a lesser

extent, even the duodenum become relaxed as this

Effect of the Pharyngeal Stage of Swallowing on Res-

wave reaches the lower end of the esophagus and

piration. The entire pharyngeal stage of swallowing

thus are prepared ahead of time to receive the food

usually occurs in less than 6 seconds, thereby inter-

propelled into the esophagus during the swallowing

rupting respiration for only a fraction of a usual res-

act.

piratory cycle. The swallowing center specifically

inhibits the respiratory center of the medulla during

Function of the Lower Esophageal Sphincter (Gastro-

this time, halting respiration at any point in its cycle to

esophageal Sphincter). At the lower end of the esoph-

allow swallowing to proceed. Yet, even while a person

agus, extending upward about 3 centimeters above its

is talking, swallowing interrupts respiration for such a

juncture with the stomach, the esophageal circular

short time that it is hardly noticeable.

muscle functions as a broad lower esophageal sphinc-

ter, also called the gastroesophageal sphincter. This

Esophageal Stage of Swallowing. The esophagus functions

sphincter normally remains tonically constricted with

primarily to conduct food rapidly from the pharynx to

an intraluminal pressure at this point in the esophagus

the stomach, and its movements are organized specif-

of about 30 mm Hg, in contrast to the midportion of

ically for this function.

the esophagus, which normally remains relaxed. When

The esophagus normally exhibits two types of peri-

a peristaltic swallowing wave passes down the esoph-

staltic movements: primary peristalsis and secondary

agus, there is

“receptive relaxation” of the lower

peristalsis. Primary peristalsis is simply continuation of

esophageal sphincter ahead of the peristaltic wave,

the peristaltic wave that begins in the pharynx and

which allows easy propulsion of the swallowed food

spreads into the esophagus during the pharyngeal

into the stomach. Rarely, the sphincter does not relax

stage of swallowing. This wave passes all the way from

satisfactorily, resulting in a condition called achalasia,

the pharynx to the stomach in about 8 to 10 seconds.

which is discussed in Chapter 66.

Food swallowed by a person who is in the upright posi-

The stomach secretions are highly acidic and

tion is usually transmitted to the lower end of the

contain many proteolytic enzymes. The esophageal

esophagus even more rapidly than the peristaltic wave

mucosa, except in the lower one eighth of the esoph-

itself, in about 5 to 8 seconds, because of the additional

agus, is not capable of resisting for long the digestive

effect of gravity pulling the food downward.

action of gastric secretions. Fortunately, the tonic con-

If the primary peristaltic wave fails to move into the

striction of the lower esophageal sphincter helps to

stomach all the food that has entered the esophagus,

prevent significant reflux of stomach contents into the

secondary peristaltic waves result from distention of

esophagus except under very abnormal conditions.

784

Unit XII Gastrointestinal Physiology

Additional Prevention of Esophageal Reflux by Valve-

and the oldest food lying nearest the outer wall of the

like Closure of the Distal End of the Esophagus.

stomach. Normally, when food stretches the stomach,

Another factor that helps to prevent reflux is a valve-

a “vagovagal reflex” from the stomach to the brain

like mechanism of a short portion of the esophagus

stem and then back to the stomach reduces the tone

that extends slightly into the stomach. Increased intra-

in the muscular wall of the body of the stomach so that

abdominal pressure caves the esophagus inward at this

the wall bulges progressively outward, accommodating

point. Thus, this valvelike closure of the lower esoph-

greater and greater quantities of food up to a limit in

agus helps to prevent high intra-abdominal pressure

the completely relaxed stomach of 0.8 to 1.5 liters. The

from forcing stomach contents backward into the

pressure in the stomach remains low until this limit is

esophagus. Otherwise, every time we walked, coughed,

approached.

or breathed hard, we might expel stomach acid into the

esophagus.

Mixing and Propulsion of Food in the

Stomach—The Basic Electrical

Motor Functions of the

Rhythm of the Stomach Wall

Stomach

The digestive juices of the stomach are secreted by

The motor functions of the stomach are threefold: (1)

gastric glands, which are present in almost the entire

storage of large quantities of food until the food can

wall of the body of the stomach except along a narrow

be processed in the stomach, duodenum, and lower

strip on the lesser curvature of the stomach. These

intestinal tract; (2) mixing of this food with gastric

secretions come immediately into contact with that

secretions until it forms a semifluid mixture called

portion of the stored food lying against the mucosal

chyme; and (3) slow emptying of the chyme from the

surface of the stomach. As long as food is in the

stomach into the small intestine at a rate suitable for

stomach, weak peristaltic constrictor waves, called

proper digestion and absorption by the small intestine.

mixing waves, begin in the mid- to upper portions of

Figure

63-2 shows the basic anatomy of the

the stomach wall and move toward the antrum about

stomach. Anatomically, the stomach is usually divided

once every 15 to 20 seconds. These waves are initiated

into two major parts: (1) the body and (2) the antrum.

by the gut wall basic electrical rhythm, which was dis-

Physiologically, it is more appropriately divided into

cussed in Chapter 62, consisting of electrical “slow

(1) the “orad” portion, comprising about the first two

waves” that occur spontaneously in the stomach wall.

thirds of the body, and (2) the “caudad” portion, com-

As the constrictor waves progress from the body of the

prising the remainder of the body plus the antrum.

stomach into the antrum, they become more intense,

some becoming extremely intense and providing pow-

erful peristaltic action potential-driven constrictor

Storage Function of the Stomach

rings that force the antral contents under higher and

higher pressure toward the pylorus.

As food enters the stomach, it forms concentric circles

These constrictor rings also play an important role

of the food in the orad portion of the stomach, the

in mixing the stomach contents in the following way:

newest food lying closest to the esophageal opening

Each time a peristaltic wave passes down the antral

wall toward the pylorus, it digs deeply into the food

contents in the antrum. Yet the opening of the pylorus

Esophagus

is still small enough that only a few milliliters or less

Fundus

of antral contents are expelled into the duodenum

with each peristaltic wave. Also, as each peristaltic

wave approaches the pylorus, the pyloric muscle itself

Cardia

often contracts, which further impedes emptying

through the pylorus. Therefore, most of the antral con-

tents are squeezed upstream through the peristaltic

ring toward the body of the stomach, not through the

Angular

pylorus. Thus, the moving peristaltic constrictive ring,

notch

Pyloric

combined with this upstream squeezing action, called

Pylorus sphincter

Body

“retropulsion,” is an exceedingly important mixing

mechanism in the stomach.

Chyme. After food in the stomach has become thor-

oughly mixed with the stomach secretions, the result-

ing mixture that passes down the gut is called chyme.

The degree of fluidity of the chyme leaving the

Duodenum

Antrum

Rugae

stomach depends on the relative amounts of food,

water, and stomach secretions and on the degree of

Figure 63-2

digestion that has occurred. The appearance of chyme

Physiologic anatomy of the stomach.

is that of a murky semifluid or paste.

Chapter 63

Propulsion and Mixing of Food in the Alimentary Tract

785

Hunger Contractions. Besides the peristaltic contractions

and other fluids to empty from the stomach into the

that occur when food is present in the stomach,

duodenum with ease. Conversely, the constriction

another type of intense contractions, called hunger

usually prevents passage of food particles until they

contractions, often occurs when the stomach has been

have become mixed in the chyme to almost fluid con-

empty for several hours or more. They are rhythmical

sistency. The degree of constriction of the pylorus is

peristaltic contractions in the body of the stomach.

increased or decreased under the influence of nervous

When the successive contractions become extremely

and humoral reflex signals from both the stomach and

strong, they often fuse to cause a continuing tetanic

the duodenum, as discussed shortly.

contraction that sometimes lasts for 2 to 3 minutes.

Hunger contractions are most intense in young,

healthy people who have high degrees of gastroin-

Regulation of Stomach Emptying

testinal tonus; they are also greatly increased by the

person’s having lower than normal levels of blood

The rate at which the stomach empties is regulated by

sugar. When hunger contractions occur in the stomach,

signals from both the stomach and the duodenum.

the person sometimes experiences mild pain in the pit

However, the duodenum provides by far the more

of the stomach, called hunger pangs. Hunger pangs

potent of the signals, controlling the emptying of

usually do not begin until 12 to 24 hours after the last

chyme into the duodenum at a rate no greater than the

ingestion of food; in starvation, they reach their great-

rate at which the chyme can be digested and absorbed

est intensity in 3 to 4 days and gradually weaken in

in the small intestine.

succeeding days.

Gastric Factors That Promote Emptying

Effect of Gastric Food Volume on Rate of Emptying. Increased

Stomach Emptying

food volume in the stomach promotes increased emp-

tying from the stomach. But this increased emptying

Stomach emptying is promoted by intense peristaltic

does not occur for the reasons that one would expect.

contractions in the stomach antrum. At the same time,

It is not increased storage pressure of the food in the

emptying is opposed by varying degrees of resistance

stomach that causes the increased emptying because,

to passage of chyme at the pylorus.

in the usual normal range of volume, the increase

in volume does not increase the pressure much.

Intense Antral Peristaltic Contractions During Stomach Empty-

However, stretching of the stomach wall does elicit

ing—“Pyloric Pump.” Most of the time, the rhythmical

local myenteric reflexes in the wall that greatly accen-

stomach contractions are weak and function mainly to

tuate activity of the pyloric pump and at the same time

cause mixing of food and gastric secretions. However,

inhibit the pylorus.

for about 20 per cent of the time while food is in the

stomach, the contractions become intense, beginning

Effect of the Hormone Gastrin on Stomach Emptying. In

in midstomach and spreading through the caudad

Chapter 64, we shall see that stomach wall stretch and

stomach no longer as weak mixing contractions but as

the presence of certain types of foods in the stomach—

strong peristaltic, very tight ringlike constrictions that

particularly digestive products of meat—elicit release

can cause stomach emptying. As the stomach becomes

of a hormone called gastrin from the antral mucosa.

progressively more and more empty, these constric-

This has potent effects to cause secretion of highly

tions begin farther and farther up the body of the

acidic gastric juice by the stomach glands. Gastrin also

stomach, gradually pinching off the food in the body

has mild to moderate stimulatory effects on motor

of the stomach and adding this food to the chyme in

functions in the body of the stomach. Most important,

the antrum. These intense peristaltic contractions

it seems to enhance the activity of the pyloric pump.

often create 50 to 70 centimeters of water pressure,

Thus, it, too, probably promotes stomach emptying.

which is about six times as powerful as the usual

mixing type of peristaltic waves.

Powerful Duodenal Factors That Inhibit

When pyloric tone is normal, each strong peristaltic

Stomach Emptying

wave forces up to several milliliters of chyme into the

Inhibitory Effect of Enterogastric Nervous Reflexes from the

duodenum. Thus, the peristaltic waves, in addition to

Duodenum. When food enters the duodenum, multiple

causing mixing in the stomach, also provide a pumping

nervous reflexes are initiated from the duodenal wall

action called the “pyloric pump.”

that pass back to the stomach to slow or even stop

stomach emptying if the volume of chyme in the duo-

Role of the Pylorus in Controlling Stomach Emptying. The

denum becomes too much. These reflexes are medi-

distal opening of the stomach is the pylorus. Here the

ated by three routes: (1) directly from the duodenum

thickness of the circular wall muscle becomes 50 to 100

to the stomach through the enteric nervous system

per cent greater than in the earlier portions of the

in the gut wall, (2) through extrinsic nerves that go to

stomach antrum, and it remains slightly tonically con-

the prevertebral sympathetic ganglia and then back

tracted almost all the time. Therefore, the pyloric cir-

through inhibitory sympathetic nerve fibers to the

cular muscle is called the pyloric sphincter.

stomach, and (3) probably to a slight extent through

Despite normal tonic contraction of the pyloric

the vagus nerves all the way to the brain stem, where

sphincter, the pylorus usually is open enough for water

they inhibit the normal excitatory signals transmitted

786

Unit XII Gastrointestinal Physiology

to the stomach through the vagi. All these parallel

hormone acts as an inhibitor to block increased

reflexes have two effects on stomach emptying: first,

stomach motility caused by gastrin.

they strongly inhibit the “pyloric pump” propulsive

Other possible inhibitors of stomach emptying are

contractions, and second, they increase the tone of the

the hormones secretin and gastric inhibitory peptide

pyloric sphincter.

(GIP). Secretin is released mainly from the duodenal

The types of factors that are continually monitored

mucosa in response to gastric acid passed from the

in the duodenum and that can initiate enterogastric

stomach through the pylorus. GIP has a general but

inhibitory reflexes include the following:

weak effect of decreasing gastrointestinal motility.

1. The degree of distention of the duodenum

GIP is released from the upper small intestine in

2. The presence of any degree of irritation of the

response mainly to fat in the chyme, but to a lesser

duodenal mucosa

extent to carbohydrates as well. Although GIP does

3. The degree of acidity of the duodenal chyme

inhibit gastric motility under some conditions, its effect

4. The degree of osmolality of the chyme

at physiologic concentrations is probably mainly to

5. The presence of certain breakdown products in

stimulate secretion of insulin by the pancreas.

the chyme, especially breakdown products of

These hormones are discussed at greater length

proteins and perhaps to a lesser extent of fats

elsewhere in this text, especially in Chapter 64 in rela-

The enterogastric inhibitory reflexes are especially

tion to control of gallbladder emptying and control of

sensitive to the presence of irritants and acids in the

rate of pancreatic secretion.

duodenal chyme, and they often become strongly acti-

In summary, hormones, especially CCK, can inhibit

vated within as little as 30 seconds. For instance, when-

gastric emptying when excess quantities of chyme,

ever the pH of the chyme in the duodenum falls below

especially acidic or fatty chyme, enter the duodenum

about 3.5 to 4, the reflexes frequently block further

from the stomach.

release of acidic stomach contents into the duodenum

until the duodenal chyme can be neutralized by pan-

Summary of the Control of Stomach Emptying

creatic and other secretions.

Emptying of the stomach is controlled only to a mod-

Breakdown products of protein digestion also elicit

erate degree by stomach factors such as the degree

inhibitory enterogastric reflexes; by slowing the rate of

of filling in the stomach and the excitatory effect of

stomach emptying, sufficient time is ensured for ade-

gastrin on stomach peristalsis. Probably the more

quate protein digestion in the duodenum and small

important control of stomach emptying resides in

intestine.

inhibitory feedback signals from the duodenum,

Finally, either hypotonic or hypertonic fluids (espe-

including both enterogastric inhibitory nervous feed-

cially hypertonic) elicit the inhibitory reflexes. Thus,

back reflexes and hormonal feedback by CCK. These

too rapid flow of nonisotonic fluids into the small

feedback inhibitory mechanisms work together to

intestine is prevented, thereby also preventing rapid

slow the rate of emptying when (1) too much chyme

changes in electrolyte concentrations in the whole-

is already in the small intestine or (2) the chyme is

body extracellular fluid during absorption of the intes-

excessively acidic, contains too much unprocessed

tinal contents.

protein or fat, is hypotonic or hypertonic, or is irritat-

ing. In this way, the rate of stomach emptying is limited

Hormonal Feedback from the Duodenum Inhibits Gastric Emp-

to that amount of chyme that the small intestine can

tying—Role of Fats and the Hormone Cholecystokinin. Not

process.

only do nervous reflexes from the duodenum to the

stomach inhibit stomach emptying, but hormones

released from the upper intestine do so as well. The

Movements of the

stimulus for releasing these inhibitory hormones is

Small Intestine

mainly fats entering the duodenum, although other

types of foods can increase the hormones to a lesser

The movements of the small intestine, like those else-

degree.

where in the gastrointestinal tract, can be divided into

On entering the duodenum, the fats extract several

mixing contractions and propulsive contractions. To a

different hormones from the duodenal and jejunal

great extent, this separation is artificial because essen-

epithelium, either by binding with “receptors” on

tially all movements of the small intestine cause at

the epithelial cells or in some other way. In turn, the

least some degree of both mixing and propulsion. The

hormones are carried by way of the blood to the

usual classification of these processes is the following.

stomach, where they inhibit the pyloric pump and at

the same time increase the strength of contraction of

the pyloric sphincter. These effects are important

Mixing Contractions (Segmentation

because fats are much slower to be digested than most

Contractions)

other foods.

Precisely which hormones cause the hormonal

When a portion of the small intestine becomes dis-

feedback inhibition of the stomach is not fully clear.

tended with chyme, stretching of the intestinal wall

The most potent appears to be cholecystokinin (CCK),

elicits localized concentric contractions spaced at

which is released from the mucosa of the jejunum in

intervals along the intestine and lasting a fraction of a

response to fatty substances in the chyme. This

minute. The contractions cause “segmentation” of the

Chapter 63

Propulsion and Mixing of Food in the Alimentary Tract

787

averages only 1 cm/min. This means that 3 to 5 hours

are required for passage of chyme from the pylorus to

Regularly spaced

the ileocecal valve.

Control of Peristalsis by Nervous and Hormonal Signals. Peri-

Isolated

staltic activity of the small intestine is greatly increased

after a meal. This is caused partly by the beginning

entry of chyme into the duodenum causing stretch of

the duodenal wall, but also by a so-called gastroenteric

Irregularly spaced

reflex that is initiated by distention of the stomach and

conducted principally through the myenteric plexus

from the stomach down along the wall of the small

Weak regularly spaced

intestine.

In addition to the nervous signals that may affect

Figure 63-3

small intestinal peristalsis, several hormonal factors

also affect peristalsis. They include gastrin, CCK,

Segmentation movements of the small intestine.

insulin, motilin, and serotonin, all of which enhance

intestinal motility and are secreted during various

phases of food processing. Conversely, secretin and

small intestine, as shown in Figure 63-3. That is, they

glucagon inhibit small intestinal motility. The physio-

divide the intestine into spaced segments that have the

logic importance of each of these hormonal factors for

appearance of a chain of sausages. As one set of seg-

controlling motility is still questionable.

mentation contractions relaxes, a new set often begins,

The function of the peristaltic waves in the small

but the contractions this time occur mainly at new

intestine is not only to cause progression of chyme

points between the previous contractions. Therefore,

toward the ileocecal valve but also to spread out the

the segmentation contractions “chop” the chyme two

chyme along the intestinal mucosa. As the chyme

to three times per minute, in this way promoting pro-

enters the intestines from the stomach and elicits peri-

gressive mixing of the food with secretions of the small

stalsis, this immediately spreads the chyme along the

intestine.

intestine; and this process intensifies as additional

The maximum frequency of the segmentation con-

chyme enters the duodenum. On reaching the ileoce-

tractions in the small intestine is determined by the

cal valve, the chyme is sometimes blocked for several

frequency of electrical slow waves in the intestinal wall,

hours until the person eats another meal; at that time,

which is the basic electrical rhythm described in

a gastroileal reflex intensifies peristalsis in the ileum

Chapter 62. Because this frequency normally is not

and forces the remaining chyme through the ileocecal

over 12 per minute in the duodenum and proximal

valve into the cecum of the large intestine.

jejunum, the maximum frequency of the segmentation

contractions in these areas is also about 12 per minute,

Propulsive Effect of the Segmentation Movements. The seg-

but this occurs only under extreme conditions of stim-

mentation movements, although lasting for only a few

ulation. In the terminal ileum, the maximum frequency

seconds at a time, often also travel 1 centimeter or so

is usually 8 to 9 contractions per minute.

in the anal direction and during that time help propel

The segmentation contractions become exceedingly

the food down the intestine. The difference between

weak when the excitatory activity of the enteric

the segmentation and the peristaltic movements is not

nervous system is blocked by the drug atropine. There-

as great as might be implied by their separation into

fore, even though it is the slow waves in the smooth

these two classifications.

muscle itself that cause the segmentation contractions,

these contractions are not effective without back-

Peristaltic Rush. Although peristalsis in the small

ground excitation mainly from the myenteric nerve

intestine is normally weak, intense irritation of the

plexus.

intestinal mucosa, as occurs in some severe cases of

infectious diarrhea, can cause both powerful and rapid

peristalsis, called the peristaltic rush. This is initiated

Propulsive Movements

partly by nervous reflexes that involve the autonomic

nervous system and brain stem and partly by intrinsic

Peristalsis in the Small Intestine. Chyme is propelled

enhancement of the myenteric plexus reflexes within

through the small intestine by peristaltic waves. These

the gut wall itself. The powerful peristaltic contractions

can occur in any part of the small intestine, and they

travel long distances in the small intestine within

move toward the anus at a velocity of 0.5 to 2.0 cm/sec,

minutes, sweeping the contents of the intestine into the

faster in the proximal intestine and slower in the ter-

colon and thereby relieving the small intestine of irri-

minal intestine. They normally are very weak and

tative chyme and excessive distention.

usually die out after traveling only 3 to 5 centimeters,

very rarely farther than 10 centimeters, so that forward

Movements Caused by the Muscularis Mucosae and Muscle Fibers

movement of the chyme is very slow, so slow in fact

of the Villi. The muscularis mucosae can cause short

that net movement along the small intestine normally

folds to appear in the intestinal mucosa. In addition,

788

Unit XII Gastrointestinal Physiology

individual fibers from this muscle extend into the intes-

Feedback Control of the Ileocecal Sphincter. The degree of

tinal villi and cause them to contract intermittently. The

contraction of the ileocecal sphincter and the intensity

mucosal folds increase the surface area exposed to the

of peristalsis in the terminal ileum are controlled sig-

chyme, thereby increasing absorption. Also, contrac-

nificantly by reflexes from the cecum. When the cecum

tions of the villi—shortening, elongating, and shorten-

is distended, contraction of the ileocecal sphincter

ing again—“milk” the villi, so that lymph flows freely

becomes intensified and ileal peristalsis is inhibited,

from the central lacteals of the villi into the lymphatic

both of which greatly delay emptying of additional

system. These mucosal and villous contractions are ini-

chyme into the cecum from the ileum. Also, any irri-

tiated mainly by local nervous reflexes in the submu-

cosal nerve plexus that occur in response to chyme in

tant in the cecum delays emptying. For instance, when

the small intestine.

a person has an inflamed appendix, the irritation of

this vestigial remnant of the cecum can cause such

intense spasm of the ileocecal sphincter and partial

Function of the Ileocecal Valve

paralysis of the ileum that these effects together block

emptying of the ileum into the cecum. The reflexes

A principal function of the ileocecal valve is to prevent

from the cecum to the ileocecal sphincter and ileum

backflow of fecal contents from the colon into the

are mediated both by way of the myenteric plexus in

small intestine. As shown in Figure 63-4, the ileocecal

the gut wall itself and of the extrinsic autonomic

valve itself protrudes into the lumen of the cecum and

nerves, especially by way of the prevertebral sympa-

therefore is forcefully closed when excess pressure

thetic ganglia.

builds up in the cecum and tries to push cecal contents

backward against the valve lips. The valve usually can

resist reverse pressure of at least 50 to 60 centimeters

Movements of the Colon

of water.

In addition, the wall of the ileum for several cen-

The principal functions of the colon are (1) absorption

timeters immediately upstream from the ileocecal

of water and electrolytes from the chyme to form solid

valve has a thickened circular muscle called the ileo-

feces and (2) storage of fecal matter until it can be

cecal sphincter. This sphincter normally remains mildly

expelled. The proximal half of the colon, shown in

constricted and slows emptying of ileal contents into

Figure 63-5, is concerned principally with absorption,

the cecum. However, immediately after a meal, a gas-

and the distal half with storage. Because intense colon

troileal reflex (described earlier) intensifies peristalsis

wall movements are not required for these functions,

in the ileum, and emptying of ileal contents into the

the movements of the colon are normally very slug-

cecum proceeds.

gish. Yet in a sluggish manner, the movements still

Resistance to emptying at the ileocecal valve pro-

have characteristics similar to those of the small intes-

longs the stay of chyme in the ileum and thereby

tine and can be divided once again into mixing move-

facilitates absorption. Normally, only 1500 to 2000 mil-

ments and propulsive movements.

liliters of chyme empty into the cecum each day.

Mixing Movements—“Haustrations.” In the same manner

that segmentation movements occur in the small

intestine, large circular constrictions occur in the large

Pressure and chemical

Semi-

irritation relax sphincter

mush

and excite peristalsis

Mush

Semifluid

Fluidity of contents

Colon

promotes emptying

Poor motility causes

greater absorption, and

Valve

Fluid

hard feces in transverse

colon causes

Semi-

constipation

solid

Ileum

Ileocecal

valve

Ileocecal sphincter

Pressure or chemical irritation

in cecum inhibits peristalsis

Solid

Excess motility causes

of ileum and excites sphincter

less absorption and

diarrhea or loose feces

Figure 63-4

Figure 63-5

Emptying at the ileocecal valve.

Absorptive and storage functions of the large intestine.

Chapter 63

Propulsion and Mixing of Food in the Alimentary Tract

789

intestine. At each of these constrictions, about 2.5 cen-

to the colon have been removed; therefore, the reflexes

timeters of the circular muscle contracts, sometimes

almost certainly are transmitted by way of the auto-

constricting the lumen of the colon almost to occlu-

nomic nervous system.

sion. At the same time, the longitudinal muscle of the

Irritation in the colon can also initiate intense mass

colon, which is aggregated into three longitudinal

movements. For instance, a person who has an ulcer-

strips called the teniae coli, contracts. These combined

ated condition of the colon mucosa (ulcerative colitis)

contractions of the circular and longitudinal strips of

frequently has mass movements that persist almost all

muscle cause the unstimulated portion of the large

the time.

intestine to bulge outward into baglike sacs called

haustrations.

Each haustration usually reaches peak intensity in

Defecation

about 30 seconds and then disappears during the next

60 seconds. They also at times move slowly toward the

Most of the time, the rectum is empty of feces. This

anus during contraction, especially in the cecum and

results partly from the fact that a weak functional

ascending colon, and thereby provide a minor amount

sphincter exists about 20 centimeters from the anus

of forward propulsion of the colonic contents. After

at the juncture between the sigmoid colon and the

another few minutes, new haustral contractions occur

rectum. There is also a sharp angulation here that con-

in other areas nearby. Therefore, the fecal material in

tributes additional resistance to filling of the rectum.

the large intestine is slowly dug into and rolled over in

When a mass movement forces feces into the

much the same manner that one spades the earth. In

rectum, the desire for defecation occurs immediately,

this way, all the fecal material is gradually exposed to

including reflex contraction of the rectum and relax-

the mucosal surface of the large intestine, and fluid and

ation of the anal sphincters.

dissolved substances are progressively absorbed until

Continual dribble of fecal matter through the anus

only 80 to 200 milliliters of feces are expelled each day.

is prevented by tonic constriction of (1) an internal

anal sphincter, a several-centimeters-long thickening

Propulsive Movements—“Mass Movements.” Much of the

of the circular smooth muscle that lies immediately

propulsion in the cecum and ascending colon results

inside the anus, and (2) an external anal sphincter, com-

from the slow but persistent haustral contractions,

posed of striated voluntary muscle that both surrounds

requiring as many as 8 to 15 hours to move the chyme

the internal sphincter and extends distal to it. The

from the ileocecal valve through the colon, while the

external sphincter is controlled by nerve fibers in the

chyme itself becomes fecal in quality, a semisolid slush

pudendal nerve, which is part of the somatic nervous

instead of semifluid.

system and therefore is under voluntary, conscious

From the cecum to the sigmoid, mass movements

or at least subconscious control; subconsciously,

can, for many minutes at a time, take over the propul-

the external sphincter is usually kept continuously

sive role. These movements usually occur only one to

constricted unless conscious signals inhibit the

three times each day, in many people especially for

constriction.

about 15 minutes during the first hour after eating

breakfast.

Defecation Reflexes. Ordinarily, defecation is initiated

A mass movement is a modified type of peristalsis

by defecation reflexes. One of these reflexes is an intrin-

characterized by the following sequence of events:

sic reflex mediated by the local enteric nervous system

First, a constrictive ring occurs in response to a dis-

in the rectal wall. This can be described as follows:

tended or irritated point in the colon, usually in the

When feces enter the rectum, distention of the rectal

transverse colon. Then, rapidly, the 20 or more cen-

wall initiates afferent signals that spread through the

timeters of colon distal to the constrictive ring lose their

myenteric plexus to initiate peristaltic waves in the

haustrations and instead contract as a unit, propelling

descending colon, sigmoid, and rectum, forcing feces

the fecal material in this segment en masse further

toward the anus. As the peristaltic wave approaches

down the colon. The contraction develops progres-

the anus, the internal anal sphincter is relaxed by

sively more force for about 30 seconds, and relaxation

inhibitory signals from the myenteric plexus; if the

occurs during the next 2 to 3 minutes. Then, another

external anal sphincter is also consciously, voluntarily

mass movement occurs, this time perhaps farther along

relaxed at the same time, defecation occurs.

the colon.

The intrinsic myenteric defecation reflex function-

A series of mass movements usually persists for 10

ing by itself normally is relatively weak. To be effec-

to 30 minutes. Then they cease but return perhaps a

tive in causing defecation, it usually must be fortified

half day later. When they have forced a mass of feces

by another type of defecation reflex, a parasympathetic

into the rectum, the desire for defecation is felt.

defecation reflex that involves the sacral segments of

the spinal cord, shown in Figure 63-6. When the nerve

Initiation of Mass Movements by Gastrocolic and Duo-

endings in the rectum are stimulated, signals are trans-

denocolic Reflexes. Appearance of mass movements

mitted first into the spinal cord and then reflexly back

after meals is facilitated by gastrocolic and duodeno-

to the descending colon, sigmoid, rectum, and anus by

colic reflexes. These reflexes result from distention of

way of parasympathetic nerve fibers in the pelvic

the stomach and duodenum. They occur either not at

nerves. These parasympathetic signals greatly intensify

all or hardly at all when the extrinsic autonomic nerves

the peristaltic waves as well as relax the internal anal

790

Unit XII Gastrointestinal Physiology

Descending

discussed in this chapter, several other important

From

colon

nervous reflexes also can affect the overall degree of

conscious

bowel activity. They are the peritoneointestinal reflex,

cortex

Afferent

renointestinal reflex, and vesicointestinal reflex.

nerve

The peritoneointestinal reflex results from irritation

fibers

of the peritoneum; it strongly inhibits the excitatory

Parasympathetic

enteric nerves and thereby can cause intestinal paral-

nerve fibers

ysis, especially in patients with peritonitis. The reno-

(pelvic nerves)

intestinal and vesicointestinal reflexes inhibit intestinal

activity as a result of kidney or bladder irritation.

Sigmoid

References

Skeletal

colon

motor nerve

Rectum

Adelson DW, Million M: Tracking the moveable feast:

sonomicrometry and gastrointestinal motility. News

External anal sphincter

Physiol Sci 19:27, 2004.

Internal anal sphincter

Chelimsky G, Chelimsky TC: Evaluation and treatment of

autonomic disorders of the gastrointestinal tract. Semin

Figure 63-6

Neurol 23:453, 2003.

Cooke HJ, Wunderlich J, Christofi FL: “The force be with

Afferent and efferent pathways of the parasympathetic mecha-

you”: ATP in gut mechanosensory transduction. News

nism for enhancing the defecation reflex.

Physiol Sci 18:43, 2003.

De Giorgio R, Guerrini S, Barbara G, et al: Inflammatory

neuropathies of the enteric nervous system. Gastroen-

terology 126:1872, 2004.

Gonella J, Bouvier M, Blanquet F: Extrinsic nervous control

sphincter, thus converting the intrinsic myenteric defe-

of motility of small and large intestines and related sphinc-

cation reflex from a weak effort into a powerful

ters. Physiol Rev 67:902, 1987.

process of defecation that is sometimes effective in

Hall KE: Aging and neural control of the GI tract. II. Neural

emptying the large bowel all the way from the splenic

control of the aging gut: can an old dog learn new tricks?

flexure of the colon to the anus.

Am J Physiol Gastrointest Liver Physiol 283:G827, 2002.

Defecation signals entering the spinal cord initiate

Hansen MB: Neurohumoral control of gastrointestinal

other effects, such as taking a deep breath, closure of

motility. Physiol Res 52:1, 2003.

the glottis, and contraction of the abdominal wall

Hatoum OA, Miura H, Binion DG: The vascular contribu-

tion in the pathogenesis of inflammatory bowel disease.

muscles to force the fecal contents of the colon down-

Am J Physiol Heart Circ Physiol 285:H1791, 2003.

ward and at the same time cause the pelvic floor to

Jensen RT: Involvement of cholecystokinin/gastrin-related

relax downward and pull outward on the anal ring to

peptides and their receptors in clinical gastrointestinal dis-

evaginate the feces.

orders. Pharmacol Toxicol 91:333, 2002.

When it becomes convenient for the person to defe-

Johnson LR: Gastrointestinal Physiology, 6th ed. St. Louis:

cate, the defecation reflexes can purposely be activated

Mosby, 2001.

by taking a deep breath to move the diaphragm down-

Kirkup AJ, Brunsden AM, Grundy D: Receptors and trans-

ward and then contracting the abdominal muscles to

mission in the brain-gut axis: potential for novel therapies.

increase the pressure in the abdomen, thus forcing

I. Receptors on visceral afferents. Am J Physiol Gastroin-

fecal contents into the rectum to cause new reflexes.

test Liver Physiol 280:G787, 2001.

Laroux FS, Pavlick KP, Wolf RE, Grisham MB: Dysregula-

Reflexes initiated in this way are almost never as effec-

tion of intestinal mucosal immunity: implications in

tive as those that arise naturally, for which reason

inflammatory bowel disease. News Physiol Sci 16:272,

people who too often inhibit their natural reflexes are

2001.

likely to become severely constipated.

Orr WC, Chen CL: Aging and neural control of the GI tract:

In newborn babies and in some people with tran-

IV. Clinical and physiological aspects of gastrointestinal

sected spinal cords, the defecation reflexes cause auto-

motility and aging. Am J Physiol Gastrointest Liver

matic emptying of the lower bowel at inconvenient

Physiol 283:G1226, 2002.

times during the day because of lack of conscious

Rao SS: Pathophysiology of adult fecal incontinence. Gas-

control exercised through voluntary contraction or

troenterology 126(1 Suppl 1):S14, 2004.

relaxation of the external anal sphincter.

Sanders KM, Ordog T, Koh SD, Ward SM:A Novel Pace-

maker Mechanism Drives Gastrointestinal Rhythmicity.

News Physiol Sci 15:291, 2000.

Takahashi T: Pathophysiological significance of neuronal

Other Autonomic Reflexes

nitric oxide synthase in the gastrointestinal tract. J Gas-

That Affect Bowel Activity

troenterol 38:421, 2003.

Timmons S, Liston R, Moriarty KJ: Functional dyspepsia:

Aside from the duodenocolic, gastrocolic, gastroileal,

motor abnormalities, sensory dysfunction, and therapeutic

enterogastric, and defecation reflexes that have been

options. Am J Gastroenterol 99:739, 2004.

C H A P T E R

Secretory Functions of the

Alimentary Tract

Throughout the gastrointestinal tract, secretory

glands subserve two primary functions: First, diges-

tive enzymes are secreted in most areas of the ali-

mentary tract, from the mouth to the distal end of

the ileum. Second, mucous glands, from the mouth

to the anus, provide mucus for lubrication and pro-

tection of all parts of the alimentary tract.

Most digestive secretions are formed only in

response to the presence of food in the alimentary tract, and the quantity

secreted in each segment of the tract is almost exactly the amount needed for

proper digestion. Furthermore, in some portions of the gastrointestinal tract,

even the types of enzymes and other constituents of the secretions are varied in

accordance with the types of food present. The purpose of this chapter, there-

fore, is to describe the different alimentary secretions, their functions, and reg-

ulation of their production.

General Principles of Alimentary

Tract Secretion

Anatomical Types of Glands

Several types of glands provide the different types of alimentary tract secretions.

First, on the surface of the epithelium in most parts of the gastrointestinal tract are

billions of single-cell mucous glands called simply mucous cells or sometimes goblet

cells because they look like goblets. They function mainly in response to local irri-

tation of the epithelium: they extrude mucus directly onto the epithelial surface to

act as a lubricant that also protects the surfaces from excoriation and digestion.

Second, many surface areas of the gastrointestinal tract are lined by pits that rep-

resent invaginations of the epithelium into the submucosa. In the small intestine,

these pits, called crypts of Lieberkühn, are deep and contain specialized secretory

cells. One of these cells is shown in Figure 64-1.

Third, in the stomach and upper duodenum are large numbers of deep tubular

glands. A typical tubular gland can be seen in Figure 64-4, which shows an acid- and

pepsinogen-secreting gland of the stomach (oxyntic gland).

Fourth, also associated with the alimentary tract are several complex glands—the

salivary glands, pancreas, and liver—that provide secretions for digestion or emul-

sification of food. The liver has a highly specialized structure that is discussed in

Chapter 70. The salivary glands and the pancreas are compound acinous glands of

the type shown in Figure 64-2. These glands lie outside the walls of the alimentary

tract and, in this, differ from all other alimentary glands. They contain millions of

acini lined with secreting glandular cells; these acini feed into a system of ducts that

finally empty into the alimentary tract itself.

Basic Mechanisms of Stimulation of the Alimentary

Tract Glands

Effect of Contact of Food with the Epithelium—Function of Enteric Nervous Stimuli. The

mechanical presence of food in a particular segment of the gastrointestinal tract

usually causes the glands of that region and often of adjacent regions to secrete

791

792

Unit XII Gastrointestinal Physiology

Nerve

Endoplasmic Golgi

secretion. This is especially true of the glands in the

Capillary

fiber

reticulum apparatus

upper portion of the tract (innervated by the glos-

sopharyngeal and vagus parasympathetic nerves)

such as the salivary glands, esophageal glands, gastric

Secretion

glands, pancreas, and Brunner’s glands in the duode-

num. It is also true of some glands in the distal portion

of the large intestine, innervated by pelvic parasym-

pathetic nerves. Secretion in the remainder of the

small intestine and in the first two thirds of the large

intestine occurs mainly in response to local neural and

hormonal stimuli in each segment of the gut.

Sympathetic Stimulation. Stimulation of the sympa-

thetic nerves going to the gastrointestinal tract causes

a slight to moderate increase in secretion by some

Basement

Mitochondria Ribosomes

Zymogen

of the local glands. But sympathetic stimulation also

membrane

granules

results in constriction of the blood vessels that supply

Figure 64-1

the glands. Therefore, sympathetic stimulation can

have a dual effect: First, sympathetic stimulation alone

Typical function of a glandular cell for formation and secretion of

usually slightly increases secretion. But, second, if

enzymes and other secretory substances.

parasympathetic or hormonal stimulation is already

causing copious secretion by the glands, superimposed

sympathetic stimulation usually reduces the secretion,

sometimes significantly so, mainly because of vaso-

Primary secretion:

constrictive reduction of the blood supply.

1. Ptyalin

2. Mucus

3. Extracellular fluid

Regulation of Glandular Secretion by Hormones. In the

stomach and intestine, several different gastrointestinal

hormones help regulate the volume and character of

the secretions. These hormones are liberated from the

gastrointestinal mucosa in response to the presence of

Na⁺ active absorption

food in the lumen of the gut. The hormones then are

Cl^- passive absorption

absorbed into the blood and carried to the glands,

K⁺ active secretion

where they stimulate secretion. This type of stimula-

HCO3- secretion

tion is particularly valuable to increase the output of

gastric juice and pancreatic juice when food enters the

stomach or duodenum.

Chemically, the gastrointestinal hormones are

polypeptides or polypeptide derivatives.

Saliva

Figure 64-2

Basic Mechanism of Secretion

Formation and secretion of saliva by a submandibular salivary

by Glandular Cells

gland.

Secretion of Organic Substances. Although all the

basic mechanisms by which glandular cells function

moderate to large quantities of juices. Part of this local

are not known, experimental evidence points to the

effect, especially the secretion of mucus by mucous

following principles of secretion, as shown in Figure

cells, results from direct contact stimulation of the

64-1.

surface glandular cells by the food.

1. The nutrient material needed for formation of

In addition, local epithelial stimulation also acti-

the secretion must first diffuse or be actively

vates the enteric nervous system of the gut wall. The

transported by the blood in the capillaries into the

types of stimuli that do this are (1) tactile stimulation,

base of the glandular cell.

(2) chemical irritation, and (3) distention of the gut

2. Many mitochondria located inside the glandular

wall. The resulting nervous reflexes stimulate both the

cell near its base use oxidative energy to form

mucous cells on the gut epithelial surface and the deep

adenosine triphosphate (ATP).

glands in the gut wall to increase their secretion.

3. Energy from the ATP, along with appropriate

substrates provided by the nutrients, is then used

Autonomic Stimulation of Secretion

to synthesize the organic secretory substances;

Parasympathetic Stimulation. Stimulation of the

this synthesis occurs almost entirely in the

parasympathetic nerves to the alimentary tract almost

endoplasmic reticulum and Golgi complex of the

invariably increases the rates of alimentary glandular

glandular cell. Ribosomes adherent to the

Chapter 64

Secretory Functions of the Alimentary Tract

793

reticulum are specifically responsible for

through the membrane to the interior of the cell, thus

formation of the proteins that are secreted.

leading to secretion.

4. The secretory materials are transported through

Although this mechanism for secretion is still partly

the tubules of the endoplasmic reticulum, passing

theoretical, it does explain how it would be possible

in about 20 minutes all the way to the vesicles of

for nerve impulses to regulate secretion. Hormones

the Golgi complex.

acting on the cell membrane are believed also to cause

5. In the Golgi complex, the materials are modified,

similar secretory results to those caused by nervous

added to, concentrated, and discharged into the

stimulation.

cytoplasm in the form of secretory vesicles, which

are stored in the apical ends of the secretory cells.

6. These vesicles remain stored until nervous or

Lubricating and Protective

hormonal control signals cause the cells to

Properties of Mucus, and

extrude the vesicular contents through the cells’

Importance of Mucus in the

surface. This probably occurs in the following

Gastrointestinal Tract

way: The control signal first increases the cell

Mucus is a thick secretion composed mainly of water,

membrane permeability to calcium ions, and

electrolytes, and a mixture of several glycoproteins,

calcium enters the cell. The calcium in turn causes

which themselves are composed of large polysaccha-

many of the vesicles to fuse with the apical cell

rides bound with much smaller quantities of protein.

membrane. Then the apical cell membrane breaks

Mucus is slightly different in different parts of the gas-

open, thus emptying the vesicles to the exterior;

trointestinal tract, but everywhere it has several im-

this process is called exocytosis.

portant characteristics that make it both an excellent

lubricant and a protectant for the wall of the gut. First,

Water and Electrolyte Secretion. A second necessity for

mucus has adherent qualities that make it adhere tightly

glandular secretion is secretion of sufficient water and

to the food or other particles and to spread as a thin film

electrolytes to go along with the organic substances.

over the surfaces. Second, it has sufficient body that

it coats the wall of the gut and prevents actual contact

The following is a postulated method by which

of most food particles with the mucosa. Third, mucus

nervous stimulation causes water and salts to pass

has a low resistance for slippage, so that the particles

through the glandular cells in great profusion, washing

can slide along the epithelium with great ease. Fourth,

the organic substances through the secretory border of

mucus causes fecal particles to adhere to one another

the cells at the same time:

to form the feces that are expelled during a bowel move-

1. Nerve stimulation has a specific effect on the

ment. Fifth, mucus is strongly resistant to digestion by

basal portion of the cell membrane to cause active

the gastrointestinal enzymes. And sixth, the glycopro-

transport of chloride ions to the cell interior.

teins of mucus have amphoteric properties, which

2. The resulting increase in electronegativity induced

means that they are capable of buffering small amounts

inside the cell by excess negatively charged

of either acids or alkalies; also, mucus often contains

moderate quantities of bicarbonate ions which specifi-

chloride ions then causes positive ions such as

cally neutralize acids.

sodium ions also to move through the cell

In summary, mucus has the ability to allow easy slip-

membrane to the interior of the cell.

page of food along the gastrointestinal tract and to

3. Now, the new excess of both negative and

prevent excoriative or chemical damage to the epithe-

positive ions inside the cell creates an osmotic

lium. A person becomes acutely aware of the lubricat-

force that causes osmosis of water to the interior,

ing qualities of mucus when the salivary glands fail to

thereby increasing cell volume and hydrostatic

secrete saliva, because then it is difficult to swallow solid

pressure inside the cell, causing the cell itself to

food even when it is eaten along with large amounts of

swell.

water.

4. The pressure in the cell then initiates minute

openings of the secretory border of the cell,

causing flushing of water, electrolytes, and organic

Secretion of Saliva

materials out of the secretory end of the glandular

cell.

Salivary Glands; Characteristics of Saliva. The principal

In support of these secretory processes have been

glands of salivation are the parotid, submandibular,

the following findings: First, the nerve endings on glan-

and sublingual glands; in addition, there are many very

dular cells are principally on the bases of the cells.

small buccal glands. Daily secretion of saliva normally

Second, microelectrode studies show that the normal

ranges between 800 and 1500 milliliters, as shown by

electrical potential across the membrane at the base of

the average value of 1000 milliliters in Table 64-1.

the cell is between 30 and 40 millivolts, with negativ-

Saliva contains two major types of protein secretion:

ity on the interior and positivity on the exterior.

(1) a serous secretion that contains ptyalin

(an

Parasympathetic stimulation increases this polariza-

a-amylase), which is an enzyme for digesting starches,

tion voltage to values some 10 and 20 millivolts more

and (2) mucus secretion that contains mucin for lubri-

negative than normal. This increase in polarization

cating and for surface protective purposes.

voltage lasts for 1 second or longer after the nerve

The parotid glands secrete almost entirely the

signal has arrived, indicating that it is caused by move-

serous type of secretion, while the submandibular and

ment of negative ions

(presumably chloride ions)

sublingual glands secrete both serous secretion and

794

Unit XII Gastrointestinal Physiology

as in plasma; and the concentration of bicarbonate

Table 64-1

ions is 50 to 70 mEq/L, about two to three times that

Daily Secretion of Intestinal Juices

of plasma.

During maximal salivation, the salivary ionic con-

Daily Volume (ml)

centrations change considerably because the rate of

formation of primary secretion by the acini can

Saliva

1000

6.0-7.0

Gastric secretion

1500

1.0-3.5

increase as much as 20-fold. This acinar secretion

Pancreatic secretion

1000

8.0-8.3

then flows through the ducts so rapidly that the ductal

Bile

1000

7.8

reconditioning of the secretion is considerably

Small intestine secretion

1800

7.5-8.0

reduced. Therefore, when copious quantities of saliva

Brunner’s gland secretion

200

8.0-8.9

are being secreted, the sodium chloride concentration

Large intestinal secretion

200

7.5-8.0

rises only to one half or two thirds that of plasma, and

Total

6700

the potassium concentration rises to only four times

that of plasma.

Function of Saliva for Oral Hygiene. Under basal awake con-

ditions, about 0.5 milliliter of saliva, almost entirely of

mucus. The buccal glands secrete only mucus. Saliva

the mucous type, is secreted each minute; but during

has a pH between 6.0 and 7.0, a favorable range for

sleep, secretion becomes very little. This secretion plays

the digestive action of ptyalin.

an exceedingly important role for maintaining healthy

oral tissues. The mouth is loaded with pathogenic bac-

Secretion of Ions in Saliva. Saliva contains especially

teria that can easily destroy tissues and cause dental

large quantities of potassium and bicarbonate ions.

caries. Saliva helps prevent the deteriorative processes

Conversely, the concentrations of both sodium and

in several ways.

chloride ions are several times less in saliva than in

First, the flow of saliva itself helps wash away patho-

plasma. One can understand these special concentra-

genic bacteria as well as food particles that provide their

metabolic support.

tions of ions in the saliva from the following descrip-

Second, saliva contains several factors that destroy

tion of the mechanism for secretion of saliva.

bacteria. One of these is thiocyanate ions and another

Figure 64-2 shows secretion by the submandibular

is several proteolytic enzymes—most important,

gland, a typical compound gland that contains acini

lysozyme—that (a) attack the bacteria, (b) aid the thio-

and salivary ducts. Salivary secretion is a two-stage

cyanate ions in entering the bacteria where these ions

operation: the first stage involves the acini, and the

in turn become bactericidal, and (c) digest food parti-

second, the salivary ducts. The acini secrete a primary

cles, thus helping further to remove the bacterial meta-

secretion that contains ptyalin and/or mucin in a solu-

bolic support.

tion of ions in concentrations not greatly different

Third, saliva often contains significant amounts of

from those of typical extracellular fluid. As the

protein antibodies that can destroy oral bacteria, includ-

ing some that cause dental caries. In the absence of

primary secretion flows through the ducts, two major

salivation, oral tissues often become ulcerated and oth-

active transport processes take place that markedly

erwise infected, and caries of the teeth can become

modify the ionic composition of the fluid in the saliva.

rampant.

First, sodium ions are actively reabsorbed from all

the salivary ducts and potassium ions are actively

secreted in exchange for the sodium. Therefore, the

Nervous Regulation of Salivary

sodium ion concentration of the saliva becomes

greatly reduced, whereas the potassium ion concen-

Secretion

tration becomes increased. However, there is excess

sodium reabsorption over potassium secretion, and

Figure 64-3 shows the parasympathetic nervous path-

this creates electrical negativity of about -70 millivolts

ways for regulating salivation, demonstrating that the

in the salivary ducts; this in turn causes chloride ions

salivary glands are controlled mainly by parasympa-

to be reabsorbed passively. Therefore, the chloride ion

thetic nervous signals all the way from the superior and

concentration in the salivary fluid falls to a very low

inferior salivatory nuclei in the brain stem.

level, matching the ductal decrease in sodium ion

The salivatory nuclei are located approximately at

concentration.

the juncture of the medulla and pons and are excited

Second, bicarbonate ions are secreted by the ductal

by both taste and tactile stimuli from the tongue and

epithelium into the lumen of the duct. This is at least

other areas of the mouth and pharynx. Many taste

partly caused by passive exchange of bicarbonate for

stimuli, especially the sour taste (caused by acids),

chloride ions, but it may also result partly from an

elicit copious secretion of saliva—often 8 to 20 times

active secretory process.

the basal rate of secretion. Also, certain tactile stimuli,

The net result of these transport processes is that

such as the presence of smooth objects in the mouth

under resting conditions, the concentrations of sodium

(e.g., a pebble), cause marked salivation, whereas

and chloride ions in the saliva are only about 15 mEq/

rough objects cause less salivation and occasionally

L each, about one seventh to one tenth their concen-

even inhibit salivation.

trations in plasma. Conversely, the concentration of

Salivation can also be stimulated or inhibited by

potassium ions is about 30 mEq/L, seven times as great

nervous signals arriving in the salivatory nuclei from

Chapter 64

Secretory Functions of the Alimentary Tract

795

Surface

Tractus

Superior and inferior

epithelium

solitarius

salivatory nuclei

Submandibular gland

Mucous neck

Submandibular

cells

ganglion

Oxyntic

Facial

(or parietal)

nerve

cells

Chorda

Peptic

tympani

(or chief)

Sublingual gland

cells

Parotid

gland

Otic ganglion Taste and

tactile stimuli

Figure 64-4

Glossopharyngeal

nerve

Oxyntic gland from the body of the stomach.

Tongue

Figure 64-3

Esophageal Secretion

The esophageal secretions are entirely mucous in char-

Parasympathetic nervous regulation of salivary secretion.

acter and principally provide lubrication for swallowing.

The main body of the esophagus is lined with many

simple mucous glands. At the gastric end and to a lesser

extent in the initial portion of the esophagus, there

higher centers of the central nervous system. For

are also many compound mucous glands. The mucus

instance, when a person smells or eats favorite foods,

secreted by the compound glands in the upper esopha-

salivation is greater than when disliked food is smelled

gus prevents mucosal excoriation by newly entering

or eaten. The appetite area of the brain, which partially

food, whereas the compound glands located near the

esophagogastric junction protect the esophageal wall

regulates these effects, is located in proximity to the

from digestion by acidic gastric juices that often reflux

parasympathetic centers of the anterior hypothalamus,

from the stomach back into the lower esophagus.

and it functions to a great extent in response to signals

Despite this protection, a peptic ulcer at times can still

from the taste and smell areas of the cerebral cortex

occur at the gastric end of the esophagus.

or amygdala.

Salivation also occurs in response to reflexes origi-

nating in the stomach and upper small intestines—par-

Gastric Secretion

ticularly when irritating foods are swallowed or when

a person is nauseated because of some gastrointestinal

Characteristics of the Gastric

abnormality. The saliva, when swallowed, helps to

Secretions

remove the irritating factor in the gastrointestinal tract

by diluting or neutralizing the irritant substances.

In addition to mucus-secreting cells that line the entire

Sympathetic stimulation can also increase salivation

surface of the stomach, the stomach mucosa has two

a slight amount, much less so than does parasympa-

important types of tubular glands: oxyntic glands (also

thetic stimulation. The sympathetic nerves originate

called gastric glands) and pyloric glands. The oxyntic

from the superior cervical ganglia and travel along the

(acid-forming) glands secrete hydrochloric acid,

surfaces of the blood vessel walls to the salivary

pepsinogen, intrinsic factor, and mucus. The pyloric

glands.

glands secrete mainly mucus for protection of the

A secondary factor that also affects salivary secre-

pyloric mucosa from the stomach acid. They also

tion is the blood supply to the glands because secretion

secrete the hormone gastrin.

always requires adequate nutrients from the blood.

The oxyntic glands are located on the inside surfaces

The parasympathetic nerve signals that induce copious

of the body and fundus of the stomach, constituting the

salivation also moderately dilate the blood vessels. In

proximal 80 per cent of the stomach. The pyloric

addition, salivation itself directly dilates the blood

glands are located in the antral portion of the stomach,

vessels, thus providing increased salivatory gland

the distal 20 per cent of the stomach.

nutrition as needed by the secreting cells. Part of this

additional vasodilator effect is caused by kallikrein

Secretions from the Oxyntic (Gastric) Glands

secreted by the activated salivary cells, which in turn

A typical stomach oxyntic gland is shown in Figure

acts as an enzyme to split one of the blood proteins,

64-4. It is composed of three types of cells: (1) mucous

an alpha2-globulin, to form bradykinin, a strong

neck cells, which secrete mainly mucus; (2) peptic

vasodilator.

(or chief) cells, which secrete large quantities of

796

Unit XII Gastrointestinal Physiology

pepsinogen; and (3) parietal (or oxyntic) cells, which

demonstrating that it contains large branching intra-

secrete hydrochloric acid and intrinsic factor. Secretion

cellular canaliculi. The hydrochloric acid is formed at

of hydrochloric acid by the parietal cells involves

the villus-like projections inside these canaliculi and is

special mechanisms, as follows.

then conducted through the canaliculi to the secretory

end of the cell.

Basic Mechanism of Hydrochloric Acid Secretion. When

Different suggestions for the chemical mechanism

stimulated, the parietal cells secrete an acid solution

of hydrochloric acid formation have been offered.

that contains about 160 millimoles of hydrochloric acid

One of these, shown in Figure 64-6, consists of the

per liter, which is almost exactly isotonic with the body

following steps:

fluids. The pH of this acid is about 0.8, demonstrating

Chloride ion is actively transported from the

its extreme acidity. At this pH, the hydrogen ion con-

cytoplasm of the parietal cell into the lumen of

centration is about 3 million times that of the arterial

the canaliculus, and sodium ions are actively

blood. To concentrate the hydrogen ions this tre-

transported out of the canaliculus into the

mendous amount requires more than 1500 calories of

cytoplasm of the parietal cell. These two effects

energy per liter of gastric juice.

together create a negative potential of -40 to -70

Figure

64-5 shows schematically the functional

millivolts in the canaliculus, which in turn causes

structure of a parietal cell (also called oxyntic cell),

diffusion of positively charged potassium ions

and a small number of sodium ions from the

cell cytoplasm into the canaliculus. Thus, in

effect, mainly potassium chloride and much

smaller amounts of sodium chloride enter the

Mucous

canaliculus.

neck cells

Water becomes dissociated into hydrogen ions

and hydroxyl ions in the cell cytoplasm. The

hydrogen ions are then actively secreted into the

canaliculus in exchange for potassium ions: this

active exchange process is catalyzed by H⁺,K⁺-

Oxyntic

ATPase. In addition, the sodium ions are actively

(parietal)

reabsorbed by a separate sodium pump. Thus,

Secretion

cell

most of the potassium and sodium ions that had

diffused into the canaliculus are reabsorbed into

Canaliculi

the cell cytoplasm, and hydrogen ions take their

place in the canaliculus, giving a strong solution

of hydrochloric acid in the canaliculus. The

hydrochloric acid is then secreted outward

through the open end of the canaliculus into the

lumen of the gland.

Water passes into the canaliculus by osmosis

because of extra ions secreted into the canaliculus.

Thus, the final secretion from the canaliculus

Figure 64-5

contains water, hydrochloric acid at a

concentration of about 150 to 160 mEq/L,

Schematic anatomy of the canaliculi in a parietal (oxyntic) cell.

Extracellular fluid

Parietal cell

Lumen of canaliculus

CO₂

H₂O

H⁺ (155 mEq/L)

HCO3-

CO₂ + OH^- + H⁺

K⁺

K⁺ (15 mEq/L)

Na⁺

(3 mEq/L)

Figure 64-6

Postulated mechanism for secre-

Cl^- (173 mEq/L)

Cl^-

tion of hydrochloric acid.

(The

points labeled “P” indicate active

(Osmosis)

pumps, and the dashed lines

H₂O

represent free diffusion and

osmosis.)

Chapter 64

Secretory Functions of the Alimentary Tract

797

potassium chloride at a concentration of 15 mEq/

Surface Mucous Cells

L, and a small amount of sodium chloride.

4. Finally, carbon dioxide, either formed during

The entire surface of the stomach mucosa between

metabolism in the cell or entering the cell from

glands has a continuous layer of a special type of

the blood, combines under the influence of

mucous cells called simply “surface mucous cells.”

carbonic anhydrase with the hydroxyl ions (from

They secrete large quantities of a very viscid mucus

step 2) to form bicarbonate ions. These then

that coats the stomach mucosa with a gel layer of

diffuse out of the cell cytoplasm into the

mucus often more than

1 millimeter thick, thus

extracellular fluid in exchange for chloride ions

providing a major shell of protection for the stomach

that enter the cell from the extracellular fluid and

wall as well as contributing to lubrication of food

are later secreted into the canaliculus.

transport.

Another characteristic of this mucus is that it is alka-

line. Therefore, the normal underlying stomach wall is

Secretion and Activation of Pepsinogen. Several slightly

not directly exposed to the highly acidic, proteolytic

different types of pepsinogen are secreted by

stomach secretion. Even the slightest contact with

the peptic and mucous cells of the gastric glands.

food or any irritation of the mucosa directly stimulates

Even so, all the pepsinogens perform the same

the surface mucous cells to secrete additional quanti-

functions.

ties of this thick, alkaline, viscid mucus.

When pepsinogen is first secreted, it has no diges-

tive activity. However, as soon as it comes in contact

with hydrochloric acid, it is activated to form active

Stimulation of Gastric Acid Secretion

pepsin. In this process, the pepsinogen molecule,

having a molecular weight of about 42,500, is split to

Parietal Cells of the Oxyntic Glands Are the Only Cells That

form a pepsin molecule, having a molecular weight of

Secrete Hydrochloric Acid. The parietal cells, located deep

about 35,000.

in the oxyntic glands of the main body of the stomach,

Pepsin functions as an active proteolytic enzyme in

are the only cells that secrete hydrochloric acid. As

a highly acid medium (optimum pH 1.8 to 3.5), but

noted earlier in the chapter, the acidity of the fluid

above a pH of about 5 it has almost no proteolytic

secreted by these cells can be very great, with pH as

activity and becomes completely inactivated in a short

low as 0.8. However, secretion of this acid is under con-

time. Hydrochloric acid is as necessary as pepsin for

tinuous control by both endocrine and nervous signals.

protein digestion in the stomach; this is discussed

Furthermore, the parietal cells operate in close associ-

further in Chapter 65.

ation with another type of cell called enterochromaf-

fin-like cells (ECL cells), the primary function of which

is to secrete histamine.

Secretion of Intrinsic Factor. The substance intrinsic factor,

The ECL cells lie in the deep recesses of the oxyntic

essential for absorption of vitamin B₁₂ in the ileum, is

glands and therefore release histamine in direct

secreted by the parietal cells along with the secretion of

contact with the parietal cells of the glands. The rate

hydrochloric acid. When the acid-producing parietal

of formation and secretion of hydrochloric acid by the

cells of the stomach are destroyed, which frequently

parietal cells is directly related to the amount of his-

occurs in chronic gastritis, the person develops not only

tamine secreted by the ECL cells. In turn, the ECL

achlorhydria (lack of stomach acid secretion) but often

also pernicious anemia because of failure of maturation

cells can be stimulated to secrete histamine in several

of the red blood cells in the absence of vitamin B₁₂ stim-

different ways: (1) Probably the most potent mecha-

ulation of the bone marrow. This is discussed in detail

nism for stimulating histamine secretion is by the hor-

in Chapter 32.

monal substance gastrin, which is formed almost

entirely in the antral portion of the stomach mucosa

in response to proteins in the foods being digested.

(2) In addition, the ECL cells can be stimulated by

Pyloric Glands—Secretion of Mucus

(a) acetylcholine released from stomach vagal nerve

and Gastrin

endings and (b) probably also by hormonal substances

secreted by the enteric nervous system of the stomach

The pyloric glands are structurally similar to the

wall. Let us discuss first the gastrin mechanism for

oxyntic glands but contain few peptic cells and almost

control of the ECL cells and their subsequent control

no parietal cells. Instead, they contain mostly mucous

of parietal cell secretion of hydrochloric acid.

cells that are identical with the mucous neck cells of

the oxyntic glands. These cells secrete a small amount

Stimulation of Acid Secretion by Gastrin. Gastrin is itself a

of pepsinogen, as discussed earlier, and an especially

hormone secreted by gastrin cells, also called G cells.

large amount of thin mucus that helps to lubricate

These cells are located in the pyloric glands in the

food movement, as well as to protect the stomach wall

distal end of the stomach. Gastrin is a large polypep-

from digestion by the gastric enzymes. The pyloric

tide secreted in two forms: a large form called G-34,

glands also secrete the hormone gastrin, which plays a

which contains 34 amino acids, and a smaller form,

key role in controlling gastric secretion, as we discuss

G-17, which contains 17 amino acids. Although both of

shortly.

these are important, the smaller is more abundant.

798

Unit XII Gastrointestinal Physiology

When meats or other protein-containing foods

Cephalic Phase. The cephalic phase of gastric secretion

reach the antral end of the stomach, some of the pro-

occurs even before food enters the stomach, especially

teins from these foods have a special stimulatory effect

while it is being eaten. It results from the sight, smell,

thought, or taste of food, and the greater the appetite,

on the gastrin cells in the pyloric glands to cause

the more intense is the stimulation. Neurogenic signals

release of gastrin into the digestive juices of the

that cause the cephalic phase of gastric secretion origi-

stomach. The vigorous mixing of the gastric juices

nate in the cerebral cortex and in the appetite centers

transports the gastrin rapidly to the ECL cells in the

of the amygdala and hypothalamus. They are trans-

body of the stomach, causing release of histamine

mitted through the dorsal motor nuclei of the vagi and

directly into the deep oxyntic glands. The histamine

thence through the vagus nerves to the stomach. This

then acts quickly to stimulate gastric hydrochloric acid

phase of secretion normally accounts for about 20 per

secretion.

cent of the gastric secretion associated with eating a

meal.

Regulation of Pepsinogen Secretion

Gastric Phase. Once food enters the stomach, it excites

(1) long vagovagal reflexes from the stomach to the

brain and back to the stomach, (2) local enteric reflexes,

Regulation of pepsinogen secretion by the peptic cells

and (3) the gastrin mechanism, all of which in turn cause

in the oxyntic glands is much less complex than regu-

secretion of gastric juice during several hours while food

lation of acid secretion; it occurs in response to two

remains in the stomach. The gastric phase of secretion

types of signals: (1) stimulation of the peptic cells by

accounts for about 70 per cent of the total gastric secre-

acetylcholine released from the vagus nerves or from

tion associated with eating a meal and therefore

the gastric enteric nervous plexus, and (2) stimulation

accounts for most of the total daily gastric secretion of

of peptic cell secretion in response to acid in the

about 1500 milliliters.

stomach. The acid probably does not stimulate the

peptic cells directly but instead elicits additional

Intestinal Phase. The presence of food in the upper

portion of the small intestine, particularly in the duo-

enteric nervous reflexes that support the original

denum, will continue to cause stomach secretion of

nervous signals to the peptic cells. Therefore, the rate

small amounts of gastric juice, probably partly because

of secretion of pepsinogen, the precursor of the

of small amounts of gastrin released by the duodenal

enzyme pepsin that causes protein digestion, is

mucosa.

strongly influenced by the amount of acid in the

stomach. In people who have lost the ability to secrete

normal amounts of acid, secretion of pepsinogen is

Inhibition of Gastric Secretion

also decreased, even though the peptic cells may

by Other Post-Stomach

otherwise appear to be normal.

Intestinal Factors

Phases of Gastric Secretion

Although intestinal chyme slightly stimulates gastric

secretion during the early intestinal phase of stomach

Gastric secretion is said to occur in three “phases” (as

secretion, it paradoxically inhibits gastric secretion at

shown in Figure 64-7): a cephalic phase, a gastric phase,

other times. This inhibition results from at least two

and an intestinal phase.

influences.

Vagal center

of medulla

Cephalic phase via vagus

Parasympathetics excite

pepsin and acid production

Secretory

Food

fiber

Gastric phase:

1. Local nervous

Afferent

Vagus

Local nerve

secretory reflexes

fibers

trunk

plexus

2. Vagal reflexes

3. Gastrin-histamine

stimulation

Circulatory system

Gastrin

Intestinal phase:

1. Nervous mechanisms

Figure 64-7

2. Hormonal mechanisms

Small bowel

Phases of gastric secretion and their regulation.

Chapter 64

Secretory Functions of the Alimentary Tract

799

1. The presence of food in the small intestine initiates

Pancreatic Secretion

a reverse enterogastric reflex, transmitted through

the myenteric nervous system as well as through

The pancreas, which lies parallel to and beneath the

extrinsic sympathetic and vagus nerves, that inhibits

stomach (illustrated in Figure 64-10), is a large com-

stomach secretion. This reflex can be initiated by

pound gland with most of its internal structure similar

distending the small bowel, by the presence of acid

to that of the salivary glands shown in Figure 64-2. The

in the upper intestine, by the presence of protein

breakdown products, or by irritation of the mucosa.

pancreatic digestive enzymes are secreted by pancre-

This is part of the complex mechanism discussed in

atic acini, and large volumes of sodium bicarbonate

Chapter 63 for slowing stomach emptying when the

solution are secreted by the small ductules and larger

intestines are already filled.

ducts leading from the acini. The combined product of

2. The presence of acid, fat, protein breakdown

enzymes and sodium bicarbonate then flows through

products, hyperosmotic or hypo-osmotic fluids, or

a long pancreatic duct that normally joins the hepatic

any irritating factor in the upper small intestine

duct immediately before it empties into the duodenum

causes release of several intestinal hormones. One

through the papilla of Vater, surrounded by the sphinc-

of these is secretin, which is especially important

ter of Oddi.

for control of pancreatic secretion. However,

Pancreatic juice is secreted most abundantly in

secretin opposes stomach secretion. Three other

hormones—gastric inhibitory peptide, vasoactive

response to the presence of chyme in the upper por-

intestinal polypeptide, and somatostatin—also have

tions of the small intestine, and the characteristics of

slight to moderate effects in inhibiting gastric

the pancreatic juice are determined to some extent by

secretion.

the types of food in the chyme. (The pancreas also

The functional purpose of inhibitory gastric secretion

secretes insulin, but this is not secreted by the same

by intestinal factors is presumably to slow passage of

pancreatic tissue that secretes intestinal pancreatic

chyme from the stomach when the small intestine is

juice. Instead, insulin is secreted directly into the

already filled or already overactive. In fact, the entero-

blood—not into the intestine—by the islets of Langer-

gastric inhibitory reflexes plus inhibitory hormones

hans that occur in islet patches throughout the pan-

usually also reduce stomach motility at the same time

creas. These are discussed in detail in Chapter 78.)

that they reduce gastric secretion, as was discussed in

Chapter 63.

Pancreatic Digestive Enzymes

Gastric Secretion During the Interdigestive Period. The

stomach secretes a few milliliters of gastric juice each

Pancreatic secretion contains multiple enzymes for

hour during the “interdigestive period,” when little or

digesting all of the three major types of food: proteins,

no digestion is occurring anywhere in the gut. The secre-

carbohydrates, and fats. It also contains large quanti-

tion that does occur usually is almost entirely of the

ties of bicarbonate ions, which play an important role

nonoxyntic type, composed mainly of mucus but little

pepsin and almost no acid.

in neutralizing the acidity of the chyme emptied from

Unfortunately, emotional stimuli frequently increase

the stomach into the duodenum.

interdigestive gastric secretion

(highly peptic and

The most important of the pancreatic enzymes for

acidic) to 50 milliliters or more per hour, in very much

digesting proteins are trypsin, chymotrypsin, and car-

the same way that the cephalic phase of gastric secre-

boxypolypeptidase. By far the most abundant of these

tion excites secretion at the onset of a meal. This

is trypsin.

increase of secretion in response to emotional stimuli is

Trypsin and chymotrypsin split whole and partially

believed to be one of the causative factors in develop-

digested proteins into peptides of various sizes but do

ment of peptic ulcers, as discussed in Chapter 66.

not cause release of individual amino acids. However,

carboxypolypeptidase does split some peptides into

individual amino acids, thus completing digestion of

Chemical Composition of Gastrin and

some proteins all the way to the amino acid state.

Other Gastrointestinal Hormones

The pancreatic enzyme for digesting carbohydrates

is pancreatic amylase, which hydrolyzes starches, glyco-

Gastrin, cholecystokinin, and secretin are all large

gen, and most other carbohydrates (except cellulose)

polypeptides with approximate molecular weights,

to form mostly disaccharides and a few trisaccharides.

respectively, of 2000, 4200, and 3400. The terminal five

The main enzymes for fat digestion are (1) pancre-

amino acids in the gastrin and cholecystokinin molec-

atic lipase, which is capable of hydrolyzing neutral fat

ular chains are the same. The functional activity of

into fatty acids and monoglycerides; (2) cholesterol

gastrin resides in the terminal four amino acids, and

esterase, which causes hydrolysis of cholesterol esters;

the activity for cholecystokinin resides in the terminal

and (3) phospholipase, which splits fatty acids from

eight amino acids. All the amino acids in the secretin

phospholipids.

molecule are essential.

When first synthesized in the pancreatic cells, the

A synthetic gastrin, composed of the terminal four

proteolytic digestive enzymes are in the inactive

amino acids of natural gastrin plus the amino acid

forms trypsinogen, chymotrypsinogen, and procar-

alanine, has all the same physiologic properties as

boxypolypeptidase, which are all inactive enzymati-

the natural gastrin. This synthetic product is called

cally. They become activated only after they are

pentagastrin.

secreted into the intestinal tract. Trypsinogen is

800

Unit XII Gastrointestinal Physiology

activated by an enzyme called enterokinase, which is

secreted by the intestinal mucosa when chyme comes

Blood

Lumen

in contact with the mucosa. Also, trypsinogen can be

Ductule cells

autocatalytically activated by trypsin that has already

been formed from previously secreted trypsinogen.

Chymotrypsinogen is activated by trypsin to form chy-

motrypsin, and procarboxypolypeptidase is activated

Na⁺

in a similar manner.

H⁺

HCO₃

HCO3-

(Active

transport)

(Active

Secretion of Trypsin Inhibitor Prevents Digestion of the

H₂CO₃

transport)

Pancreas Itself. It is important that the proteolytic

(Carbonic

anhydrase)

enzymes of the pancreatic juice not become activated

H₂O

until after they have been secreted into the intestine

CO₂

because the trypsin and the other enzymes would

digest the pancreas itself. Fortunately, the same cells

H₂O

that secrete proteolytic enzymes into the acini of the

pancreas secrete simultaneously another substance

called trypsin inhibitor. This substance is formed in the

cytoplasm of the glandular cells, and it prevents acti-

Figure 64-8

vation of trypsin both inside the secretory cells and in

the acini and ducts of the pancreas. And, because it is

Secretion of isosmotic sodium bicarbonate solution by the pan-

trypsin that activates the other pancreatic proteolytic

creatic ductules and ducts.

enzymes, trypsin inhibitor prevents activation of the

others as well.

When the pancreas becomes severely damaged or

when a duct becomes blocked, large quantities of pan-

ions (HCO_{3_} and H⁺). Then the bicarbonate ions

creatic secretion sometimes become pooled in the

are actively transported in association with

damaged areas of the pancreas. Under these condi-

sodium ions (Na⁺) through the luminal border of

tions, the effect of trypsin inhibitor is often over-

the cell into the lumen of the duct.

whelmed, in which case the pancreatic secretions

2. The hydrogen ions formed by dissociation of

rapidly become activated and can literally digest the

carbonic acid inside the cell are exchanged for

entire pancreas within a few hours, giving rise to the

sodium ions through the blood border of the

condition called acute pancreatitis. This sometimes is

cell by a secondary active transport process.

lethal because of accompanying circulatory shock;

This supplies the sodium ions (Na⁺) that are

even if not lethal, it usually leads to a subsequent life-

transported through the luminal border into the

time of pancreatic insufficiency.

pancreatic duct lumen to provide electrical

neutrality for the secreted bicarbonate ions.

3. The overall movement of sodium and bicarbonate

Secretion of Bicarbonate Ions

ions from the blood into the duct lumen creates

an osmotic pressure gradient that causes osmosis

Although the enzymes of the pancreatic juice are

of water also into the pancreatic duct, thus

secreted entirely by the acini of the pancreatic glands,

forming an almost completely isosmotic

the other two important components of pancreatic

bicarbonate solution.

juice, bicarbonate ions and water, are secreted mainly

by the epithelial cells of the ductules and ducts that

lead from the acini. When the pancreas is stimulated

Regulation of Pancreatic Secretion

to secrete copious quantities of pancreatic juice, the

bicarbonate ion concentration can rise to as high as

Basic Stimuli That Cause Pancreatic Secretion

145 mEq/L, a value about five times that of bicarbon-

Three basic stimuli are important in causing pancre-

ate ions in the plasma. This provides a large quantity

atic secretion:

of alkali in the pancreatic juice that serves to neutral-

1. Acetylcholine, which is released from the

ize the hydrochloric acid emptied into the duodenum

parasympathetic vagus nerve endings and from

from the stomach.

other cholinergic nerves in the enteric nervous

The basic steps in the cellular mechanism for secret-

system

ing sodium bicarbonate solution into the pancreatic

2. Cholecystokinin, which is secreted by the

ductules and ducts are shown in Figure 64-8. They are

duodenal and upper jejunal mucosa when food

the following:

enters the small intestine

1. Carbon dioxide diffuses to the interior of the

3. Secretin, which is also secreted by the duodenal

cell from the blood and, under the influence of

and jejunal mucosa when highly acid food enters

carbonic anhydrase, combines with water to form

the small intestine

carbonic acid (H₂CO₃). The carbonic acid in turn

The first two of these stimuli, acetylcholine and

dissociates into bicarbonate ions and hydrogen

cholecystokinin, stimulate the acinar cells of the

Chapter 64

Secretory Functions of the Alimentary Tract

801

pancreas, causing production of large quantities of

Secretin in turn causes the pancreas to secrete large

pancreatic digestive enzymes but relatively small

quantities of fluid containing a high concentration of

quantities of water and electrolytes to go with the

bicarbonate ion (up to 145 mEq/L) but a low concen-

enzymes. Without the water, most of the enzymes

tration of chloride ion. The secretin mechanism is

remain temporarily stored in the acini and ducts until

especially important for two reasons: First, secretin

more fluid secretion comes along to wash them into

begins to be released from the mucosa of the small

the duodenum. Secretin, in contrast to the first two

intestine when the pH of the duodenal contents falls

basic stimuli, stimulates secretion of large quantities of

below 4.5 to 5.0, and its release increases greatly as the

water solution of sodium bicarbonate by the pancre-

pH falls to 3.0. This immediately causes copious secre-

atic ductal epithelium.

tion of pancreatic juice containing abundant amounts

of sodium bicarbonate. The net result is then the fol-

Multiplicative Effects of Different Stimuli. When all the dif-

lowing reaction in the duodenum:

ferent stimuli of pancreatic secretion occur at once, the

total secretion is far greater than the sum of the secre-

HCl+NaHCO ÆNaCl+H CO

tions caused by each one separately. Therefore, the

Then the carbonic acid immediately dissociates

various stimuli are said to “multiply,” or “potentiate,”

into carbon dioxide and water. The carbon dioxide

one another. Thus, pancreatic secretion normally

is absorbed into the blood and expired through the

results from the combined effects of the multiple basic

lungs, thus leaving a neutral solution of sodium chlo-

stimuli, not from one alone.

ride in the duodenum. In this way, the acid contents

emptied into the duodenum from the stomach become

Phases of Pancreatic Secretion

neutralized, so that further peptic digestive activity by

Pancreatic secretion occurs in three phases, the same

the gastric juices in the duodenum is immediately

as for gastric secretion: the cephalic phase, the gastric

blocked. Because the mucosa of the small intestine

phase, and the intestinal phase. Their characteristics are

cannot withstand the digestive action of acid gastric

as follows.

juice, this is an essential protective mechanism to

prevent development of duodenal ulcers, as is dis-

Cephalic and Gastric Phases. During the cephalic phase

cussed in further detail in Chapter 66.

of pancreatic secretion, the same nervous signals from

Bicarbonate ion secretion by the pancreas provides

the brain that cause secretion in the stomach also

an appropriate pH for action of the pancreatic diges-

cause acetylcholine release by the vagal nerve endings

tive enzymes, which function optimally in a slightly

in the pancreas. This causes moderate amounts of

alkaline or neutral medium, at a pH of 7.0 to 8.0.

enzymes to be secreted into the pancreatic acini,

Fortunately, the pH of the sodium bicarbonate secre-

accounting for about 20 per cent of the total secretion

tion averages 8.0.

of pancreatic enzymes after a meal. But little of the

secretion flows immediately through the pancreatic

ducts into the intestine because only small amounts of

Cholecystokinin—Its Contribution to Control of Diges-

water and electrolytes are secreted along with the

tive Enzyme Secretion by the Pancreas. The presence

enzymes.

of food in the upper small intestine also causes a

During the gastric phase, the nervous stimulation of

second hormone, cholecystokinin, a polypeptide con-

enzyme secretion continues, accounting for another 5

taining 33 amino acids, to be released from yet another

to 10 per cent of pancreatic enzymes secreted after a

group of cells, the I cells, in the mucosa of the duode-

meal. But, again, only small amounts reach the duo-

num and upper jejunum. This release of cholecys-

denum because of continued lack of significant fluid

tokinin results especially from the presence of

secretion.

proteoses and peptones (products of partial protein

digestion) and long-chain fatty acids in the chyme

Intestinal Phase. After chyme leaves the stomach and

coming from the stomach.

enters the small intestine, pancreatic secretion

Cholecystokinin, like secretin, passes by way of the

becomes copious, mainly in response to the hormone

blood to the pancreas but instead of causing sodium

secretin.

bicarbonate secretion causes mainly secretion of still

much more pancreatic digestive enzymes by the acinar

Secretin Stimulates Secretion of Copious Quantities of

cells. This effect is similar to that caused by vagal stim-

Bicarbonate Ions—Neutralization of Acidic Stomach

ulation but even more pronounced, accounting for 70

Chyme. Secretin is a polypeptide, containing 27 amino

to 80 per cent of the total secretion of the pancreatic

acids (molecular weight about 3400), present in an

digestive enzymes after a meal.

inactive form, prosecretin, in so-called S cells in the

The differences between the pancreatic stimulatory

mucosa of the duodenum and jejunum. When acid

effects of secretin and cholecystokinin are shown in

chyme with pH less than 4.5 to 5.0 enters the duode-

Figure 64-9, which demonstrates (1) intense sodium

num from the stomach, it causes duodenal mucosal

bicarbonate secretion in response to acid in the duo-

release and activation of secretin, which is then

denum, stimulated by secretin, (2) a dual effect in

absorbed into the blood. The one truly potent con-

response to soap (a fat), and (3) intense digestive

stituent of chyme that causes this secretin release is the

enzyme secretion (when peptones enter the duode-

hydrochloric acid from the stomach.

num) stimulated by cholecystokinin.

802

Unit XII Gastrointestinal Physiology

Acid from stomach

releases secretin from

wall of duodenum;

Water and

fats and amino acids

NaHCO₃

cause release of

Enzymes

cholecystokinin

Common

bile duct

Vagal

stimulation

releases

enzymes

into acini

Secretin causes

copious secretion

Secretin and

of pancreatic fluid

cholecystokinin

and bicarbonate;

absorbed into

cholecystokinin

blood stream

causes secretion

HCI

Soap

Peptone

of enzymes

Figure 64-10

Figure 64-9

Regulation of pancreatic secretion.

Sodium bicarbonate (NaHCO₃), water, and enzyme secretion by

the pancreas, caused by the presence of acid (HCl), fat (soap),

or peptone solutions in the duodenum.

(2) Next, the bile flows in the canaliculi toward the

interlobular septa, where the canaliculi empty into ter-

Figure

64-10 summarizes the more important

minal bile ducts and then into progressively larger

factors in the regulation of pancreatic secretion. The

ducts, finally reaching the hepatic duct and common

total amount secreted each day is about 1 liter.

bile duct. From these the bile either empties directly

into the duodenum or is diverted for minutes up to

several hours through the cystic duct into the gall-

Secretion of Bile by the Liver;

bladder, shown in Figure 64-11.

Functions of the Biliary Tree

In its course through the bile ducts, a second portion

of liver secretion is added to the initial bile. This addi-

One of the many functions of the liver is to secrete bile,

tional secretion is a watery solution of sodium and

normally between 600 and 1000 ml/day. Bile serves two

bicarbonate ions secreted by secretory epithelial cells

important functions:

that line the ductules and ducts. This second secretion

First, bile plays an important role in fat digestion

sometimes increases the total quantity of bile by as

and absorption, not because of any enzymes in the bile

much as an additional 100 per cent. The second secre-

that cause fat digestion, but because bile acids in the

tion is stimulated especially by secretin, which causes

bile do two things: (1) they help to emulsify the large

release of additional quantities of bicarbonate ions to

fat particles of the food into many minute particles,

supplement the bicarbonate ions in pancreatic secre-

the surface of which can then be attacked by lipase

tion (for neutralizing acid that empties into the duo-

enzymes secreted in pancreatic juice, and (2) they aid

denum from the stomach).

in absorption of the digested fat end products through

the intestinal mucosal membrane.

Storing and Concentrating Bile in the Gallbladder. Bile is

Second, bile serves as a means for excretion of

secreted continually by the liver cells, but most of it is

several important waste products from the blood.

normally stored in the gallbladder until needed in the

These include especially bilirubin, an end product of

duodenum. The maximum volume that the gallbladder

hemoglobin destruction, and excesses of cholesterol.

can hold is only 30 to 60 milliliters. Nevertheless, as

much as 12 hours of bile secretion (usually about 450

milliliters) can be stored in the gallbladder because

Physiologic Anatomy of

water, sodium, chloride, and most other small elec-

Biliary Secretion

trolytes are continually absorbed through the gall-

bladder mucosa, concentrating the remaining bile

Bile is secreted in two stages by the liver: (1) The initial

constituents that contain the bile salts, cholesterol,

portion is secreted by the principal functional cells of

lecithin, and bilirubin.

the liver, the hepatocytes; this initial secretion contains

Most of this gallbladder absorption is caused by

large amounts of bile acids, cholesterol, and other

active transport of sodium through the gallbladder

organic constituents. It is secreted into minute bile

epithelium, and this is followed by secondary absorp-

canaliculi that originate between the hepatic cells.

tion of chloride ions, water, and most other diffusible

Chapter 64

Secretory Functions of the Alimentary Tract

803

Vagal stimulation

Secretin via

Bile acids via blood

causes weak

blood stream

stimulate parenchymal

contraction of

stimulates

secretion

gallbladder

liver ductal

Stomach

secretion

Liver

Acid

Bile stored and

concentrated up

to 15 times in

Pancreas

gallbladder

Sphincter of

Duodenum

Oddi

Cholecystokinin via blood stream causes:

Figure 64-11

1. Gallbladder contraction

2. Relaxation of sphincter of Oddi

Liver secretion and gallbladder emptying.

constituents. Bile is normally concentrated in this way

Table 64-2

about 5-fold, but it can be concentrated up to a

Composition of Bile

maximum of 20-fold.

Composition of Bile. Table 64-2 gives the composition of

Liver Bile

Gallbladder Bile

bile when it is first secreted by the liver and then after

Water

97.5 g/dl

92 g/dl

it has been concentrated in the gallbladder. This table

Bile salts

1.1 g/dl

6 g/dl

shows that by far the most abundant substances

Bilirubin

0.04 g/dl

0.3 g/dl

secreted in the bile are bile salts, which account for

Cholesterol

0.1 g/dl

0.3 to 0.9 g/dl

Fatty acids

0.12 g/dl

0.3 to 1.2 g/dl

about one half of the total solutes also in the bile. Also

Lecithin

0.04 g/dl

0.3 g/dl

secreted or excreted in large concentrations are biliru-

Na⁺

145.04 mEq/L

130 mEq/L

bin, cholesterol, lecithin, and the usual electrolytes of

K⁺

5 mEq/L

12 mEq/L

plasma.

Ca⁺⁺

5 mEq/L

23 mEq/L

Cl^-

100 mEq/L

25 mEq/L

In the concentrating process in the gallbladder,

HCO3-

28 mEq/L

10 mEq/L

water and large portions of the electrolytes (except

calcium ions) are reabsorbed by the gallbladder

mucosa; essentially all other constituents, especially

the bile salts and the lipid substances cholesterol and

lecithin, are not reabsorbed and, therefore, become

This is the same cholecystokinin discussed earlier that

highly concentrated in the gallbladder bile.

causes increased secretion of digestive enzymes by the

acinar cells of the pancreas. The stimulus for cholecys-

Emptying of the Gallbladder—Stimulatory Role of Cholecys-

tokinin entry into the blood from the duodenal

tokinin. When food begins to be digested in the upper

mucosa is mainly the presence of fatty foods in the

gastrointestinal tract, the gallbladder begins to empty,

duodenum.

especially when fatty foods reach the duodenum about

In addition to cholecystokinin, the gallbladder is

30 minutes after a meal. The mechanism of gallblad-

stimulated less strongly by acetylcholine-secreting

der emptying is rhythmical contractions of the wall of

nerve fibers from both the vagi and the intestinal

the gallbladder, but effective emptying also requires

enteric nervous system. They are the same nerves that

simultaneous relaxation of the sphincter of Oddi,

promote motility and secretion in other parts of the

which guards the exit of the common bile duct into the

upper gastrointestinal tract.

duodenum.

In summary, the gallbladder empties its store of con-

By far the most potent stimulus for causing the gall-

centrated bile into the duodenum mainly in response

bladder contractions is the hormone cholecystokinin.

to the cholecystokinin stimulus that itself is initiated

804

Unit XII Gastrointestinal Physiology

mainly by fatty foods. When fat is not in the food,

bile salts is called the enterohepatic circulation of bile

the gallbladder empties poorly, but when significant

salts.

quantities of fat are present, the gallbladder normally

The quantity of bile secreted by the liver each day is

highly dependent on the availability of bile salts—the

empties completely in about 1 hour. Figure 64-11 sum-

greater the quantity of bile salts in the enterohepatic cir-

marizes the secretion of bile, its storage in the gall-

culation (usually a total of only about 2.5 grams), the

bladder, and its ultimate release from the bladder to

greater the rate of bile secretion. Indeed, ingestion of

the duodenum.

supplemental bile salts can increase bile secretion by

several hundred milliliters per day.

If a bile fistula empties the bile salts to the exterior

Function of Bile Salts in Fat Digestion

for several days to several weeks so that they cannot be

reabsorbed from the ileum, the liver increases its pro-

and Absorption

duction of bile salts 6- to 10-fold, which increases the

rate of bile secretion most of the way back to normal.

The liver cells synthesize about 6 grams of bile salts

This demonstrates that the daily rate of liver bile salt

daily. The precursor of the bile salts is cholesterol,

secretion is actively controlled by the availability (or

which is either present in the diet or synthesized in the

lack of availability) of bile salts in the enterohepatic

liver cells during the course of fat metabolism. The

circulation.

cholesterol is first converted to cholic acid or che-

nodeoxycholic acid in about equal quantities. These

Role of Secretin in Helping to Control Bile Secretion. In addi-

acids in turn combine principally with glycine and to a

tion to the strong stimulating effect of bile acids to cause

bile secretion, the hormone secretin that also stimulates

lesser extent with taurine to form glyco- and tauro-

pancreatic secretion increases bile secretion, sometimes

conjugated bile acids. The salts of these acids, mainly

more than doubling its secretion for several hours after

sodium salts, are then secreted in the bile.

a meal. This increase in secretion is almost entirely

The bile salts have two important actions in the

secretion of a sodium bicarbonate-rich watery solution

intestinal tract:

by the epithelial cells of the bile ductules and ducts, and

First, they have a detergent action on the fat parti-

not increased secretion by the liver parenchymal cells

cles in the food. This decreases the surface tension of

themselves. The bicarbonate in turn passes into the

the particles and allows agitation in the intestinal tract

small intestine and joins the bicarbonate from the pan-

to break the fat globules into minute sizes. This is

creas in neutralizing the hydrochloric acid from the

called the emulsifying or detergent function of bile

stomach. Thus, the secretin feedback mechanism for

neutralizing duodenal acid operates not only through its

salts.

effects on pancreatic secretion but also to a lesser extent

Second, and even more important than the emulsi-

through its effect on secretion by the liver ductules and

fying function, bile salts help in the absorption of

ducts.

(1) fatty acids, (2) monoglycerides, (3) cholesterol, and

(4) other lipids from the intestinal tract. They do this

by forming very small physical complexes with these

Liver Secretion of Cholesterol and

lipids; the complexes are called micelles, and they are

Gallstone Formation

semi-soluble in the chyme because of the electrical

charges of the bile salts. The intestinal lipids are

Bile salts are formed in the hepatic cells from choles-

“ferried” in this form to the intestinal mucosa, where

terol in the blood plasma. In the process of secreting the

they are then absorbed into the blood, as will be

bile salts, about 1 to 2 grams of cholesterol are removed

from the blood plasma and secreted into the bile each

described in detail in Chapter 65. Without the presence

day.

of bile salts in the intestinal tract, up to 40 per cent of

Cholesterol is almost completely insoluble in pure

the ingested fats are lost into the feces, and the person

water, but the bile salts and lecithin in bile combine

often develops a metabolic deficit because of this

physically with the cholesterol to form ultramicroscopic

nutrient loss.

micelles in the form of a colloidal solution, as explained

in more detail in Chapter 65. When the bile becomes

Enterohepatic Circulation of Bile Salts. About 94 per cent of

concentrated in the gallbladder, the bile salts and

the bile salts are reabsorbed into the blood from the

lecithin become concentrated along with the choles-

small intestine, about one half of this by diffusion

terol, which keeps the cholesterol in solution.

through the mucosa in the early portions of the small

Under abnormal conditions, the cholesterol may pre-

intestine and the remainder by an active transport

cipitate in the gallbladder, resulting in the formation of

process through the intestinal mucosa in the distal

cholesterol gallstones, as shown in Figure 64-12. The

ileum. They then enter the portal blood and pass back

amount of cholesterol in the bile is determined partly

to the liver. On reaching the liver, on first passage

by the quantity of fat that the person eats, because liver

through the venous sinusoids these salts are absorbed

cells synthesize cholesterol as one of the products of fat

almost entirely back into the hepatic cells and then are

metabolism in the body. For this reason, people on a

resecreted into the bile.

high-fat diet over a period of years are prone to the

In this way, about 94 per cent of all the bile salts are

development of gallstones.

recirculated into the bile, so that on the average these

Inflammation of the gallbladder epithelium, often

salts make the entire circuit some 17 times before being

resulting from low-grade chronic infection, may also

carried out in the feces. The small quantities of bile salts

change the absorptive characteristics of the gallbladder

lost into the feces are replaced by new amounts formed

mucosa, sometimes allowing excessive absorption of

continually by the liver cells. This recirculation of the

water and bile salts but leaving behind the cholesterol

Chapter 64

Secretory Functions of the Alimentary Tract

805

Causes of gallstones:

1. Too much absorption of water

from bile

2. Too much absorption of bile

acids from bile

Mucous goblet

3. Too much cholesterol in bile

Stones

cell

4. Inflammation of epithelium

Liver

Epithelial cell

Hepatic duct

Gallbladder

Stones

Course followed by bile:

Cystic duct

1. During rest

2. During digestion

Paneth cell

Common bile duct

Sphincter of Oddi

Figure 64-13

Papilla of Vater

Pancreatic duct

A crypt of Lieberkühn, found in all parts of the small intestine

between the villi, which secretes almost pure extracellular fluid.

Duodenum

Figure 64-12

area of the gastrointestinal tract to be the site of peptic

Formation of gallstones.

ulcers in about 50 per cent of ulcer patients.

in the bladder in progressively greater concentrations.

Secretion of Intestinal Digestive

Then the cholesterol begins to precipitate, first forming

Juices by the Crypts of Lieberkühn

many small crystals of cholesterol on the surface of

the inflamed mucosa, but then progressing to large

Located over the entire surface of the small intestine

gallstones.

are small pits called crypts of Lieberkühn, one of which

is illustrated in Figure 64-13. These crypts lie between

the intestinal villi. The surfaces of both the crypts and

Secretions of the

the villi are covered by an epithelium composed of two

Small Intestine

types of cells: (1) a moderate number of goblet cells,

which secrete mucus that lubricates and protects the

Secretion of Mucus by Brunner’s

intestinal surfaces, and (2) a large number of entero-

Glands in the Duodenum

cytes, which, in the crypts, secrete large quantities of

water and electrolytes and, over the surfaces of adja-

An extensive array of compound mucous glands,

cent villi, reabsorb the water and electrolytes along

called Brunner’s glands, is located in the wall of the

with end products of digestion.

first few centimeters of the duodenum, mainly

The intestinal secretions are formed by the entero-

between the pylorus of the stomach and the papilla of

cytes of the crypts at a rate of about 1800 ml/day. These

Vater where pancreatic secretion and bile empty into

secretions are almost pure extracellular fluid and have

the duodenum. These glands secrete large amounts of

a slightly alkaline pH in the range of 7.5 to 8.0. The

alkaline mucus in response to (1) tactile or irritating

secretions also are rapidly reabsorbed by the villi. This

stimuli on the duodenal mucosa; (2) vagal stimulation,

flow of fluid from the crypts into the villi supplies a

which causes increased Brunner’s glands secretion

watery vehicle for absorption of substances from

concurrently with increase in stomach secretion; and

chyme when it comes in contact with the villi. Thus, the

(3) gastrointestinal hormones, especially secretin.

primary function of the small intestine is to absorb

The function of the mucus secreted by Brunner’s

nutrients and their digestive products into the blood.

glands is to protect the duodenal wall from digestion

by the highly acid gastric juice emptying from the

Mechanism of Secretion of the Watery Fluid. The exact

stomach. In addition, the mucus contains a large excess

mechanism that controls the marked secretion of

of bicarbonate ions, which add to the bicarbonate ions

watery fluid by the crypts of Lieberkühn is not known.

from pancreatic secretion and liver bile in neutralizing

It is believed to involve at least two active secretory

the hydrochloric acid entering the duodenum from the

processes: (1) active secretion of chloride ions into the

stomach.

crypts and (2) active secretion of bicarbonate ions. The

Brunner’s glands are inhibited by sympathetic stim-

secretion of both of these ions causes electrical drag

ulation; therefore, such stimulation in very excitable

as well of positively charged sodium ions through the

persons is likely to leave the duodenal bulb unpro-

membrane and into the secreted fluid. Finally, all these

tected and is perhaps one of the factors that cause this

ions together cause osmotic movement of water.

806

Unit XII Gastrointestinal Physiology

Digestive Enzymes in the Small Intestinal Secretion. When

Mucus in the large intestine protects the intestinal

secretions of the small intestine are collected without

wall against excoriation, but in addition, it provides an

cellular debris, they have almost no enzymes. The en-

adherent medium for holding fecal matter together.

terocytes of the mucosa, especially those that cover the

Furthermore, it protects the intestinal wall from the

villi, do contain digestive enzymes that digest specific

great amount of bacterial activity that takes place

food substances while they are being absorbed through

inside the feces, and, finally, the mucus plus the alka-

the epithelium. These enzymes are the following:

linity of the secretion

(pH of 8.0 caused by large

(1) several peptidases for splitting small peptides into

amounts of sodium bicarbonate) provides a barrier to

amino acids, (2) four enzymes—sucrase, maltase, iso-

keep acids formed in the feces from attacking the

maltase, and lactase—for splitting disaccharides into

intestinal wall.

monosaccharides, and (3) small amounts of intestinal

lipase for splitting neutral fats into glycerol and fatty

Diarrhea Caused by Excess Secretion of Water and Electrolytes

acids.

in Response to Irritation. Whenever a segment of the

The epithelial cells deep in the crypts of Lieberkühn

large intestine becomes intensely irritated, as occurs

continually undergo mitosis, and new cells migrate

when bacterial infection becomes rampant during

along the basement membrane upward out of the

enteritis, the mucosa secretes extra large quantities of

crypts toward the tips of the villi, thus continually

water and electrolytes in addition to the normal viscid

replacing the villus epithelium and also forming new

alkaline mucus. This acts to dilute the irritating factors

digestive enzymes. As the villus cells age, they are

and to cause rapid movement of the feces toward the

finally shed into the intestinal secretions. The life cycle

anus. The result is diarrhea, with loss of large quanti-

of an intestinal epithelial cell is about 5 days. This rapid

ties of water and electrolytes. But the diarrhea also

growth of new cells also allows rapid repair of excori-

washes away irritant factors, which promotes earlier

ations that occur in the mucosa.

recovery from the disease than might otherwise occur.

Regulation of Small Intestine

References

Secretion—Local Stimuli

Barrett KE, Keely SJ: Chloride secretion by the intestinal

By far the most important means for regulating small

epithelium: molecular basis and regulatory aspects. Annu

intestine secretion are local enteric nervous reflexes,

Rev Physiol 62:535, 2000.

especially reflexes initiated by tactile or irritative

Chiang JY: Bile acid regulation of hepatic physiology: III.

stimuli from the chyme in the intestines.

Bile acids and nuclear receptors. Am J Physiol Gastroin-

test Liver Physiol 284:G349, 2003.

Dockray GJ, Varro A, Dimaline R, Wang T: The gastrins: their

Secretions of the

production and biological activities. Annu Rev Physiol

63:119, 2001.

Large Intestine

Dockray GJ, Varro A, Dimaline R: Gastric endocrine cells:

gene expression, processing, and targeting of active prod-

Mucus Secretion. The mucosa of the large intestine, like

ucts. Physiol Rev 76:767,1996.

that of the small intestine, has many crypts of

Flemstrom G, Isenberg JI: Gastroduodenal mucosal alkaline

Lieberkühn; however, unlike the small intestine, there

secretion and mucosal protection. News Physiol Sci 16:23,

are no villi. The epithelial cells contain almost no

2001.

enzymes. Instead, they consist mainly of mucous cells

Fuchs M: Bile acid regulation of hepatic physiology: III. Reg-

that secrete only mucus. The great preponderance of

ulation of bile acid synthesis: past progress and future

secretion in the large intestine is mucus. This mucus

challenges. Am J Physiol Gastrointest Liver Physiol

284:G551, 2003.

contains moderate amounts of bicarbonate ions

Hocker M: Molecular mechanisms of gastrin-dependent

secreted by a few non-mucus-secreting epithelial cells.

gene regulation. Ann N Y Acad Sci 1014:97, 2004.

The rate of secretion of mucus is regulated principally

Jass JR, Walsh MD: Altered mucin expression in the gas-

by direct, tactile stimulation of the epithelial cells

trointestinal tract: a review. J Cell Mol Med 5:327, 2001.

lining the large intestine and by local nervous reflexes

Johnson LR: Gastrointestinal Physiology, 6th ed. St. Louis:

to the mucous cells in the crypts of Lieberkühn.

Mosby, 2001.

Stimulation of the pelvic nerves from the spinal

Kidd JF, Thorn P: Intracellular Ca²⁺ and Cl^- channel activa-

cord, which carry parasympathetic innervation to the

tion in secretory cells. Annu Rev Physiol 62:493, 2000.

distal one half to two thirds of the large intestine, also

Lee MG, Ahn W, Lee JA, Kim JY, et al: Coordination of pan-

can cause marked increase in mucus secretion. This

creatic HCO_{_} secretion by protein-protein interaction

between membrane transporters. JOP 2(4 Suppl):203,

occurs along with increase in peristaltic motility of the

2001.

colon, which was discussed in Chapter 63.

Marve GM: Nerves and hormones interact to control gall-

During extreme parasympathetic stimulation, often

bladder function. News Physiol Sci 13:64, 1998.

caused by emotional disturbances, so much mucus can

Portincasa P, Di Ciaula A, vanBerge-Henegouwen GP:

occasionally be secreted into the large intestine that

Smooth muscle function and dysfunction in gallbladder

the person has a bowel movement of ropy mucus as

disease. Curr Gastroenterol Rep 6:151, 2004.

often as every 30 minutes; this mucus often contains

Russell DW: The enzymes, regulation, and genetics of bile

little or no fecal material.

acid synthesis. Annu Rev Biochem 72:137, 2003.

C H A P T E R

Digestion and Absorption in the

Gastrointestinal Tract

The major foods on which the body lives (with the

exception of small quantities of substances such as

vitamins and minerals) can be classified as carbo-

hydrates, fats, and proteins. They generally cannot be

absorbed in their natural forms through the gas-

trointestinal mucosa and, for this reason, are useless

as nutrients without preliminary digestion. There-

fore, this chapter discusses, first, the processes by

which carbohydrates, fats, and proteins are digested into small enough com-

pounds for absorption and, second, the mechanisms by which the digestive end

products as well as water, electrolytes, and other substances are absorbed.

Digestion of the Various Foods by Hydrolysis

Hydrolysis of Carbohydrates. Almost all the carbohydrates of the diet are either

large polysaccharides or disaccharides, which are combinations of monosaccha-

rides bound to one another by condensation. This means that a hydrogen ion

(H⁺) has been removed from one of the monosaccharides, and a hydroxyl ion

(-OH) has been removed from the next one. The two monosaccharides then

combine with each other at these sites of removal, and the hydrogen and

hydroxyl ions combine to form water (H₂O).

When carbohydrates are digested, the above process is reversed and the car-

bohydrates are converted into monosaccharides. Specific enzymes in the diges-

tive juices of the gastrointestinal tract return the hydrogen and hydroxyl ions

from water to the polysaccharides and thereby separate the monosaccharides

from each other. This process, called hydrolysis, is the following (in which

R≤-R¢ is a disaccharide):

R¢¢

¢+

ædigestiveÆR¢¢

-R

H O

enzyme

Hydrolysis of Fats. Almost the entire fat portion of the diet consists of triglyc-

erides (neutral fats), which are combinations of three fatty acid molecules con-

densed with a single glycerol molecule. During condensation, three molecules

of water are removed.

Digestion of the triglycerides consists of the reverse process: the fat-

digesting enzymes return three molecules of water to the triglyceride molecule

and thereby split the fatty acid molecules away from the glycerol. Here again,

the digestive process is one of hydrolysis.

Hydrolysis of Proteins. Proteins are formed from multiple amino acids that are

bound together by peptide linkages. At each linkage, a hydroxyl ion has been

removed from one amino acid and a hydrogen ion has been removed from the

succeeding one; thus, the successive amino acids in the protein chain are also

bound together by condensation, and digestion occurs by the reverse effect:

hydrolysis. That is, the proteolytic enzymes return hydrogen and hydroxyl ions

from water molecules to the protein molecules to split them into their con-

stituent amino acids.

808

Chapter 65

Digestion and Absorption in the Gastrointestinal Tract

809

Therefore, the chemistry of digestion is simple

pH of the medium falls below about 4.0. Nevertheless,

because, in the case of all three major types of food,

on the average, before food and its accompanying

the same basic process of hydrolysis is involved. The

saliva do become completely mixed with the gastric

only difference lies in the types of enzymes required

secretions, as much as 30 to 40 per cent of the starches

to promote the hydrolysis reactions for each type of

will have been hydrolyzed mainly to form maltose.

food.

All the digestive enzymes are proteins. Their secre-

Digestion of Carbohydrates in the Small Intestine

tion by the different gastrointestinal glands was dis-

Digestion by Pancreatic Amylase. Pancreatic secre-

cussed in Chapter 64.

tion, like saliva, contains a large quantity of a-amylase

that is almost identical in its function with the

a-amylase of saliva but is several times as powerful.

Digestion of Carbohydrates

Therefore, within 15 to 30 minutes after the chyme

empties from the stomach into the duodenum and

Carbohydrate Foods of the Diet. Only three major sources

mixes with pancreatic juice, virtually all the carbohy-

of carbohydrates exist in the normal human diet. They

drates will have become digested.

are sucrose, which is the disaccharide known popularly

In general, the carbohydrates are almost totally con-

as cane sugar; lactose, which is a disaccharide found

verted into maltose and/or other very small glucose

in milk; and starches, which are large polysaccharides

polymers before passing beyond the duodenum or

present in almost all nonanimal foods, particularly in

upper jejunum.

potatoes and the different types of grains. Other car-

bohydrates ingested to a slight extent are amylose,

glycogen, alcohol, lactic acid, pyruvic acid, pectins, dex-

Hydrolysis of Disaccharides and Small Glucose Polymers

trins, and minor quantities of carbohydrate derivatives

into Monosaccharides by Intestinal Epithelial Enzymes. The

in meats.

enterocytes lining the villi of the small intestine

The diet also contains a large amount of cellulose,

contain four enzymes (lactase, sucrase, maltase, and

which is a carbohydrate. However, no enzymes

a-dextrinase), which are capable of splitting the disac-

capable of hydrolyzing cellulose are secreted in the

charides lactose, sucrose, and maltose, plus other small

human digestive tract. Consequently, cellulose cannot

glucose polymers, into their constituent monosaccha-

be considered a food for humans.

rides. These enzymes are located in the enterocytes cov-

ering the intestinal microvilli brush border, so that the

Digestion of Carbohydrates in the Mouth and Stomach. When

disaccharides are digested as they come in contact with

food is chewed, it is mixed with saliva, which contains

these enterocytes.

the digestive enzyme ptyalin (an a-amylase) secreted

Lactose splits into a molecule of galactose and a

mainly by the parotid glands. This enzyme hydrolyzes

molecule of glucose. Sucrose splits into a molecule of

starch into the disaccharide maltose and other small

fructose and a molecule of glucose. Maltose and other

polymers of glucose that contain three to nine glucose

small glucose polymers all split into multiple molecules

molecules, as shown in Figure 65-1. However, the food

of glucose. Thus, the final products of carbohydrate

remains in the mouth only a short time, so that prob-

digestion are all monosaccharides. They are all water

ably not more than 5 per cent of all the starches will

soluble and are absorbed immediately into the portal

have become hydrolyzed by the time the food is

blood.

swallowed.

In the ordinary diet, which contains far more

However, starch digestion sometimes continues in

starches than all other carbohydrates combined,

the body and fundus of the stomach for as long as 1

glucose represents more than 80 per cent of the final

hour before the food becomes mixed with the stomach

products of carbohydrate digestion, and galactose and

secretions. Then activity of the salivary amylase is

fructose each seldom more than 10 per cent.

blocked by acid of the gastric secretions because the

The major steps in carbohydrate digestion are sum-

amylase is essentially nonactive as an enzyme once the

marized in Figure 65-1.

Starches

Ptyalin (saliva)-20-40%

Pancreatic amylase-50-80%

Maltose and 3 to 9 glucose polymers Lactose

Sucrose

Lactase

Sucrase

Maltase and a-dextrinase

(intestine)

Glucose

Galactose

Fructose

Figure 65-1

Digestion of carbohydrates.

810

Unit XII Gastrointestinal Physiology

Digestion of Proteins

Proteins of the Diet. The dietary proteins are chemically

Pepsin

Proteoses

Proteins

Peptones

long chains of amino acids bound together by peptide

Polypeptides

linkages. A typical linkage is the following:

Trypsin, chymotrypsin, carboxypolypeptidase,

proelastase

Polypeptides

Peptidases

Amino acids

R CH C

OH + H

CH COOH

Amino acids

Figure 65-2

NH₂

Digestion of proteins.

R CH

C N

CH COOH + H₂O

Digestion of Proteins by Pancreatic Secretions. Most

protein digestion occurs in the upper small intestine,

in the duodenum and jejunum, under the influence

of proteolytic enzymes from pancreatic secretion.

Immediately on entering the small intestine from the

The characteristics of each protein are determined

stomach, the partial breakdown products of the

by the types of amino acids in the protein molecule

protein foods are attacked by major proteolytic

and by the sequential arrangements of these amino

pancreatic enzymes: trypsin, chymotrypsin, carboxy-

acids. The physical and chemical characteristics of dif-

polypeptidase, and proelastase, as shown in Figure

ferent proteins important in human tissues are dis-

65-2.

cussed in Chapter 69.

Both trypsin and chymotrypsin split protein mole-

cules into small polypeptides; carboxypolypeptidase

Digestion of Proteins in the Stomach.

Pepsin, the important

then cleaves individual amino acids from the carboxyl

peptic enzyme of the stomach, is most active at a pH

ends of the polypeptides. Proelastase, in turn, is con-

of 2.0 to 3.0 and is inactive at a pH above about 5.0.

verted into elastase, which then digests elastin fibers

Consequently, for this enzyme to cause digestive

that partially hold meats together.

action on protein, the stomach juices must be acidic.

Only a small percentage of the proteins are digested

As explained in Chapter 64, the gastric glands secrete

all the way to their constituent amino acids by the

a large quantity of hydrochloric acid. This hydrochlo-

pancreatic juices. Most remain as dipeptides and

ric acid is secreted by the parietal (oxyntic) cells in the

tripeptides.

glands at a pH of about 0.8, but by the time it is mixed

with the stomach contents and with secretions from

Digestion of Peptides by Peptidases in the Enterocytes That

the nonoxyntic glandular cells of the stomach, the pH

Line the Small Intestinal Villi. The last digestive stage of

then averages around 2.0 to 3.0, a highly favorable

the proteins in the intestinal lumen is achieved by the

range of acidity for pepsin activity.

enterocytes that line the villi of the small intestine,

One of the important features of pepsin digestion is

mainly in the duodenum and jejunum. These cells have

its ability to digest the protein collagen, an albuminoid

a brush border that consists of hundreds of microvilli

type of protein that is affected little by other digestive

projecting from the surface of each cell. In the mem-

enzymes. Collagen is a major constituent of the inter-

brane of each of these microvilli are multiple pepti-

cellular connective tissue of meats; therefore, for the

dases that protrude through the membranes to the

digestive enzymes of the digestive tract to penetrate

exterior, where they come in contact with the intestinal

meats and digest the other meat proteins, it is first nec-

fluids.

essary that the collagen fibers be digested. Conse-

Two types of peptidase enzymes are especially

quently, in persons who lack pepsin in the stomach

important, aminopolypeptidase and several dipepti-

juices, the ingested meats are less well penetrated by

dases. They succeed in splitting the remaining larger

the other digestive enzymes and, therefore, may be

polypeptides into tripeptides and dipeptides and a few

poorly digested.

into amino acids. Both the amino acids plus the dipep-

As shown in Figure 65-2, pepsin only initiates the

tides and tripeptides are easily transported through

process of protein digestion, usually providing only 10

the microvillar membrane to the interior of the

to 20 per cent of the total protein digestion to convert

enterocyte.

the protein to proteoses, peptones, and a few polypep-

Finally, inside the cytosol of the enterocyte are mul-

tides. This splitting of proteins occurs as a result of

tiple other peptidases that are specific for the remain-

hydrolysis at the peptide linkages between amino

ing types of linkages between amino acids. Within

acids.

minutes, virtually all the last dipeptides and tripeptides

Chapter 65

Digestion and Absorption in the Gastrointestinal Tract

811

Instead, essentially all fat digestion occurs in the small

intestine as follows.

CH₃

(CH₂)₁₆

C O CH₂

Emulsification of Fat by Bile Acids and Lecithin. The

first step in fat digestion is physically to break the fat

globules into very small sizes so that the water-soluble

Lipase

CH₃

(CH₂)₁₆

O CH + 2H₂O

digestive enzymes can act on the globule surfaces. This

process is called emulsification of the fat, and it begins

by agitation in the stomach to mix the fat with the

CH₃

(CH₂)₁₆

C O CH₂

products of stomach digestion.

(Tristearin)

Then, most of the emulsification occurs in the duo-

denum under the influence of bile, the secretion from

HO CH₂

the liver that does not contain any digestive enzymes.

CH₃

(CH₂)₁₆

C O

CH + 2CH₃

(CH₂)₁₆

C OH

However, bile does contain a large quantity of bile salts

as well as the phospholipid lecithin. Both of these,

HO CH₂

but especially the lecithin, are extremely important for

(2-Monoglyceride)

(Stearic acid)

emulsification of the fat. The polar parts (the points

where ionization occurs in water) of the bile salts and

lecithin molecules are highly soluble in water, whereas

Figure 65-3

most of the remaining portions of their molecules are

highly soluble in fat. Therefore, the fat-soluble por-

Hydrolysis of neutral fat catalyzed by lipase.

tions of these liver secretions dissolve in the surface

layer of the fat globules, with the polar portions pro-

jecting. The polar projections, in turn, are soluble in the

surrounding watery fluids, which greatly decreases the

are digested to the final stage to form single amino

interfacial tension of the fat and makes it soluble as

acids; these then pass on through to the other side of

well.

the enterocyte and thence into the blood.

When the interfacial tension of a globule of non-

More than 99 per cent of the final protein digestive

miscible fluid is low, this nonmiscible fluid, on agita-

products that are absorbed are individual amino acids,

tion, can be broken up into many very minute particles

with only rare absorption of peptides and very, very

far more easily than it can when the interfacial tension

rare absorption of whole protein molecules. Even

is great. Consequently, a major function of the bile

these very few absorbed molecules of whole protein

salts and lecithin, especially the lecithin, in the bile is

can sometimes cause serious allergic or immunologic

to make the fat globules readily fragmentable by agi-

disturbances, as discussed in Chapter 34.

tation with the water in the small bowel. This action is

the same as that of many detergents that are widely

used in household cleaners for removing grease.

Digestion of Fats

Each time the diameters of the fat globules are sig-

nificantly decreased as a result of agitation in the small

Fats of the Diet. By far the most abundant fats of the

intestine, the total surface area of the fat increases

diet are the neutral fats, also known as triglycerides,

manyfold. Because the average diameter of the fat

each molecule of which is composed of a glycerol

particles in the intestine after emulsification has

nucleus and three fatty acid side chains, as shown in

occurred is less than 1 micrometer, this represents an

Figure 65-3. Neutral fat is a major constituent in food

increase of as much as 1000-fold in total surface areas

of animal origin but much, much less so in food of

of the fats caused by the emulsification process.

plant origin.

The lipase enzymes are water-soluble compounds

In the usual diet are also small quantities of phos-

and can attack the fat globules only on their surfaces.

pholipids, cholesterol, and cholesterol esters. The phos-

Consequently, it can be readily understood how impor-

pholipids and cholesterol esters contain fatty acid and

tant this detergent function of bile salts and lecithin is

therefore can be considered fats themselves. Choles-

for digestion of fats.

terol, however, is a sterol compound that contains no

fatty acid, but it does exhibit some of the physical and

Digestion of Triglycerides by Pancreatic Lipase. By far the

chemical characteristics of fats; plus, it is derived from

most important enzyme for digestion of the triglyc-

fats and is metabolized similarly to fats. Therefore,

erides is pancreatic lipase, present in enormous quan-

cholesterol is considered, from a dietary point of view,

tities in pancreatic juice, enough to digest within 1

a fat.

minute all triglycerides that it can reach. In addition,

the enterocytes of the small intestine contain still more

Digestion of Fats in the Intestine. A small amount of

lipase, known as enteric lipase, but this is usually not

triglycerides is digested in the stomach by lingual lipase

needed.

that is secreted by lingual glands in the mouth and

swallowed with the saliva. This amount of digestion is

End Products of Fat Digestion. Most of the triglyc-

less than

10 per cent and generally unimportant.

erides of the diet are split by pancreatic lipase into

812

Unit XII Gastrointestinal Physiology

(Bile + Agitation)

Fat

Emulsified fat

Villi

Pancreatic lipase

Emulsified fat

Fatty acids and

Food

2-monoglycerides

movement

Figure 65-4

Digestion of fats.

Valvulae

conniventes

free fatty acids and

2-monoglycerides, as shown in

Figure 65-4.

Role of Bile Salts to Accelerate Fat Digestion—Formation of

Figure 65-5

Micelles. The hydrolysis of triglycerides is a highly

reversible process; therefore, accumulation of mono-

Longitudinal section of the small intestine, showing the valvulae

conniventes covered by villi.

glycerides and free fatty acids in the vicinity of digest-

ing fats quickly blocks further digestion. But the bile

salts play the additional important role of removing

the monoglycerides and free fatty acids from the vicin-

The bile salt micelles play the same role in “ferry-

ity of the digesting fat globules almost as rapidly as

ing” free cholesterol and phospholipid molecule diges-

these end products of digestion are formed. This

tates that they play in “ferrying” monoglycerides and

occurs in the following way.

free fatty acids. Indeed, essentially no cholesterol is

Bile salts, when in high enough concentration in

absorbed without this function of the micelles.

water, have the propensity to form micelles, which are

small spherical, cylindrical globules 3 to 6 nanometers

in diameter composed of 20 to 40 molecules of bile

Basic Principles of

salt. These develop because each bile salt molecule is

Gastrointestinal Absorption

composed of a sterol nucleus that is highly fat-soluble

and a polar group that is highly water-soluble. The

It is suggested that the reader review the basic princi-

sterol nucleus encompasses the fat digestate, forming

ples of transport of substances through cell mem-

a small fat globule in the middle of a resulting micelle,

branes discussed in detail in Chapter 4. The following

with polar groups of bile salts projecting outward to

paragraphs present specialized applications of these

cover the surface of the micelle. Because these polar

transport processes during gastrointestinal absorption.

groups are negatively charged, they allow the entire

micelle globule to dissolve in the water of the diges-

tive fluids and to remain in stable solution until the fat

Anatomical Basis of Absorption

is absorbed into the blood.

The bile salt micelles also act as a transport medium

The total quantity of fluid that must be absorbed each

to carry the monoglycerides and free fatty acids, both

day by the intestines is equal to the ingested fluid

of which would otherwise be relatively insoluble, to

(about 1.5 liters) plus that secreted in the various gas-

the brush borders of the intestinal epithelial cells.

trointestinal secretions (about 7 liters). This comes to

There the monoglycerides and free fatty acids are

a total of 8 to 9 liters. All but about 1.5 liters of this is

absorbed into the blood, as discussed later, but the bile

absorbed in the small intestine, leaving only 1.5 liters

salts themselves are released back into the chyme to

to pass through the ileocecal valve into the colon each

be used again and again for this “ferrying” process.

day.

The stomach is a poor absorptive area of the gas-

Digestion of Cholesterol Esters and Phospholipids. Most cho-

trointestinal tract because it lacks the typical villus

lesterol in the diet is in the form of cholesterol esters,

type of absorptive membrane, and also because the

which are combinations of free cholesterol and one

junctions between the epithelial cells are tight junc-

molecule of fatty acid. Phospholipids also contain fatty

tions. Only a few highly lipid-soluble substances,

acid within their molecules. Both the cholesterol esters

such as alcohol and some drugs like aspirin, can be

and the phospholipids are hydrolyzed by two other

absorbed in small quantities.

lipases in the pancreatic secretion that free the fatty

acids—the enzyme cholesterol ester hydrolase to

Absorptive Surface of the Small Intestinal Mucosa Villi.

hydrolyze the cholesterol ester, and phospholipase A₂

Figure 65-5 demonstrates the absorptive surface of the

to hydrolyze the phospholipid.

small intestinal mucosa, showing many folds called

Chapter 65

Digestion and Absorption in the Gastrointestinal Tract

813

Central

Brush

Basement

lacteal

border

membrane

Blood

capillaries

Venules

Arteriole

Central

lacteal

Figure 65-6

Vein

Functional organization of the

Capillaries

villus. A, Longitudinal section.

Artery

B, Cross section showing a base-

ment membrane beneath the

epithelial cells and a brush

border at the other ends of these

cells.

valvulae conniventes (or folds of Kerckring), which

Figure 65-6B shows a cross section of the villus, and

increase the surface area of the absorptive mucosa

Figure 65-7 shows many small pinocytic vesicles, which

about threefold. These folds extend circularly most of

are pinched-off portions of infolded enterocyte mem-

the way around the intestine and are especially well

brane forming vesicles of absorbed fluids that have

developed in the duodenum and jejunum, where they

been entrapped. Small amounts of substances are

often protrude as much as 8 millimeters into the

absorbed by this physical process of pinocytosis.

lumen.

Extending from the epithelial cell body into each

Also located on the epithelial surface of the small

microvillus of the brush border are multiple actin fila-

intestine all the way down to the ileocecal valve are

ments that contract rhythmically to cause continual

literally millions of small villi. These project about 1

movement of the microvilli, keeping them constantly

millimeter from the surface of the mucosa, as shown

exposed to new quantities of intestinal fluid.

on the surfaces of the valvulae conniventes in Figure

65-5 and in individual detail in Figure 65-6. The villi

lie so close to one another in the upper small intestine

Absorption in the

that they touch in most areas, but their distribution is

Small Intestine

less profuse in the distal small intestine. The presence

of villi on the mucosal surface enhances the total

Absorption from the small intestine each day consists

absorptive area another 10-fold.

of several hundred grams of carbohydrates, 100 or

Finally, each intestinal epithelial cell on each villus

is characterized by a brush border, consisting of as

many as 1000 microvilli 1 micrometer in length and 0.1

micrometer in diameter protruding into the intestinal

chyme; these microvilli are shown in the electron

micrograph in Figure 65-7. This increases the surface

area exposed to the intestinal materials at least

another 20-fold.

Thus, the combination of the folds of Kerckring, the

villi, and the microvilli increases the total absorptive

area of the mucosa perhaps

1000-fold, making a

tremendous total area of 250 or more square meters

for the entire small intestine—about the surface area

of a tennis court.

Figure

65-6A shows in longitudinal section the

general organization of the villus, emphasizing (1) the

Figure 65-7

advantageous arrangement of the vascular system for

Brush border of a gastrointestinal epithelial cell, showing also

absorption of fluid and dissolved material into the

absorbed pinocytic vesicles, mitochondria, and endoplasmic

portal blood and (2) the arrangement of the “central

reticulum lying immediately beneath the brush border. (Courtesy

lacteal” lymph vessel for absorption into the lymph.

Dr. William Lockwood.)

814

Unit XII Gastrointestinal Physiology

more grams of fat, 50 to 100 grams of amino acids, 50

to 100 grams of ions, and 7 to 8 liters of water. The

absorptive capacity of the normal small intestine is far

H₂O

greater than this: as much as several kilograms of car-

H₂O

bohydrates per day, 500 grams of fat per day, 500 to

700 grams of proteins per day, and 20 or more liters of

water per day. The large intestine can absorb still addi-

H₂O

Active transport

tional water and ions, although very few nutrients.

Diffusion

Osmosis

Na (142 mEq/L)

(50 mEq/L)

Absorption of Water

H₂O

Isosmotic Absorption. Water is transported through the

H₂O

intestinal membrane entirely by diffusion. Further-

more, this diffusion obeys the usual laws of osmosis.

Therefore, when the chyme is dilute enough, water is

absorbed through the intestinal mucosa into the blood

Figure 65-8

of the villi almost entirely by osmosis.

Absorption of sodium through the intestinal epithelium. Note also

Conversely, water can also be transported in the

osmotic absorption of water—that is, water

“follows” sodium

opposite direction—from plasma into the chyme. This

through the epithelial membrane.

occurs especially when hyperosmotic solutions are dis-

charged from the stomach into the duodenum. Within

minutes, sufficient water usually will be transferred by

osmosis to make the chyme isosmotic with the plasma.

passively “dragged” by the positive electrical charges

of the sodium ions.

Active transport of sodium through the basolateral

Absorption of Ions

membranes of the cell reduces the sodium concentra-

tion inside the cell to a low value (about 50 mEq/L),

Active Transport of Sodium. Twenty to 30 grams of sodium

as also shown in Figure 65-8. Because the sodium con-

are secreted in the intestinal secretions each day.

centration in the chyme is normally about 142 mEq/L

In addition, the average person eats 5 to 8 grams of

(that is, about equal to that in plasma), sodium moves

sodium each day. Therefore, to prevent net loss of

down this steep electrochemical gradient from the

sodium into the feces, the intestines must absorb 25 to

chyme through the brush border of the epithelial cell

35 grams of sodium each day, which is equal to about

into the epithelial cell cytoplasm. This provides still

one seventh of all the sodium present in the body.

more sodium ions to be transported by the epithelial

Whenever significant amounts of intestinal secre-

cells into the paracellular spaces.

tions are lost to the exterior, as in extreme diarrhea,

the sodium reserves of the body can sometimes be

Osmosis of the Water. The next step in the transport

depleted to lethal levels within hours. Normally,

process is osmosis of water into the paracellular

however, less than 0.5 per cent of the intestinal sodium

spaces. This occurs because a large osmotic gradient

is lost in the feces each day because it is rapidly

has been created by the elevated concentration of ions

absorbed through the intestinal mucosa. Sodium also

in the paracellular space. Much of this osmosis occurs

plays an important role in helping to absorb sugars

through the tight junctions between the apical borders

and amino acids, as we shall see in subsequent

of the epithelial cells, but much also occurs through the

discussions.

cells themselves. And osmotic movement of water

The basic mechanism of sodium absorption from the

creates flow of fluid into and through the paracellular

intestine is shown in Figure 65-8. The principles of this

spaces and, finally, into the circulating blood of the

mechanism, discussed in Chapter 4, are also essentially

villus.

the same as for absorption of sodium from the

gallbladder and renal tubules as discussed in Chapter

Aldosterone Greatly Enhances Sodium Absorption. When a

27.

person becomes dehydrated, large amounts of aldos-

The motive power for sodium absorption is pro-

terone almost always are secreted by the cortices of

vided by active transport of sodium from inside the

the adrenal glands. Within 1 to 3 hours this aldosterone

epithelial cells through the basal and side walls of

causes increased activation of the enzyme and trans-

these cells into paracellular spaces. This is demon-

port mechanisms for all aspects of sodium absorption

strated by the heavy red arrows in Figure 65-8. This

by the intestinal epithelium. And the increased sodium

active transport obeys the usual laws of active trans-

absorption in turn causes secondary increases in

port: it requires energy, and the energy process is cat-

absorption of chloride ions, water, and some other

alyzed by appropriate adenosine triphosphatase

substances.

enzymes in the cell membrane (see Chapter 4). Part of

This effect of aldosterone is especially important in

the sodium is absorbed along with chloride ions; in

the colon because it allows virtually no loss of sodium

fact, the negatively charged chloride ions are mainly

chloride in the feces and also little water loss. Thus, the

Chapter 65

Digestion and Absorption in the Gastrointestinal Tract

815

function of aldosterone in the intestinal tract is the

Extreme diarrheal secretion is initiated by entry of

same as that achieved by aldosterone in the renal

a subunit of cholera toxin into the epithelial cells.

tubules, which also serves to conserve sodium chloride

This stimulates formation of excess cyclic adenosine

monophosphate, which opens tremendous numbers of

and water in the body when a person becomes

chloride channels, allowing chloride ions to flow rapidly

dehydrated.

from inside the cell into the intestinal crypts. In turn, this

is believed to activate a sodium pump that pumps

Absorption of Chloride Ions in the Duodenum and Jejunum. In

sodium ions into the crypts to go along with the chlo-

the upper part of the small intestine, chloride ion

ride ions. Finally, all this extra sodium chloride causes

absorption is rapid and occurs mainly by diffusion—

extreme osmosis of water from the blood, thus provid-

that is, absorption of sodium ions through the epithe-

ing rapid flow of fluid along with the salt. All this excess

lium creates electronegativity in the chyme and

fluid washes away most of the bacteria and is of value

in combating the disease, but too much of a good thing

electropositivity in the paracellular spaces between

can be lethal because of serious dehydration of the

the epithelial cells. Then chloride ions move along this

whole body that might ensue. In most instances, the life

electrical gradient to “follow” the sodium ions.

of a cholera victim can be saved by administration of

tremendous amounts of sodium chloride solution to

Absorption of Bicarbonate Ions in the Duodenum and Jejunum.

make up for the loss.

Often large quantities of bicarbonate ions must be

reabsorbed from the upper small intestine because

Absorption of Other Ions. Calcium ions are actively

large amounts of bicarbonate ions have been secreted

absorbed into the blood especially from the duode-

into the duodenum in both pancreatic secretion and

num, and the amount of calcium ion absorption is very

bile. The bicarbonate ion is absorbed in an indirect way

exactly controlled to supply exactly the daily need of

as follows: When sodium ions are absorbed, moderate

the body for calcium. One important factor controlling

amounts of hydrogen ions are secreted into the lumen

calcium absorption is parathyroid hormone secreted

of the gut in exchange for some of the sodium. These

by the parathyroid glands, and another is vitamin D.

hydrogen ions in turn combine with the bicarbonate

Parathyroid hormone activates vitamin D, and the

ions to form carbonic acid (H₂CO₃), which then disso-

activated vitamin D in turn greatly enhances

ciates to form water and carbon dioxide. The water

calcium absorption. These effects are discussed in

remains as part of the chyme in the intestines, but the

Chapter 79.

carbon dioxide is readily absorbed into the blood and

Iron ions are also actively absorbed from the small

subsequently expired through the lungs. Thus, this is

intestine. The principles of iron absorption and regu-

so-called “active absorption of bicarbonate ions.” It is

lation of its absorption in proportion to the body’s

the same mechanism that occurs in the tubules of the

need for iron, especially for the formation of hemo-

kidneys.

globin, are discussed in Chapter 32.

Potassium, magnesium, phosphate, and probably still

Secretion of Bicarbonate Ions in the Ileum

other ions can also be actively absorbed through the

and Large Intestine—Simultaneous Absorption

intestinal mucosa. In general, the monovalent ions are

of Chloride Ions

absorbed with ease and in great quantities. Conversely,

The epithelial cells on the surfaces of the villi in the

bivalent ions are normally absorbed in only small

ileum as well as on all surfaces of the large intestine

amounts; for example, maximum absorption of

have a special capability of secreting bicarbonate ions

calcium ions is only 1/50 as great as the normal absorp-

in exchange for absorption of chloride ions. This is

tion of sodium ions. Fortunately, only small quantities

important because it provides alkaline bicarbonate

of the bivalent ions are normally required daily by the

ions that neutralize acid products formed by bacteria

body.

in the large intestine.

Absorption of Nutrients

Extreme Secretion of Chloride Ions, Sodium Ions, and Water from

the Large Intestine Epithelium in Some Types of Diarrhea. Deep

Absorption of Carbohydrates

in the spaces between the intestinal epithelial folds are

Essentially all the carbohydrates in the food are

immature epithelial cells that continually divide to form

new epithelial cells. These in turn spread outward over

absorbed in the form of monosaccharides; only a small

the luminal surfaces of the intestines. While still in the

fraction are absorbed as disaccharides and almost

deep folds, the epithelial cells secrete sodium chloride

none as larger carbohydrate compounds. By far

and water into the intestinal lumen. This secretion in

the most abundant of the absorbed monosaccharides

turn is reabsorbed by the older epithelial cells outside

is glucose, usually accounting for more than 80 per cent

the folds, thus providing flow of water for absorbing

of carbohydrate calories absorbed. The reason for

intestinal digestates.

this is that glucose is the final digestion product of our

The toxins of cholera and of some other types of diar-

most abundant carbohydrate food, the starches. The

rheal bacteria can stimulate the fold secretion so greatly

remaining 20 per cent of absorbed monosaccharides

that this secretion often becomes much greater than can

are composed almost entirely of galactose and fruc-

be reabsorbed, thus sometimes causing loss of 5 to 10

liters of water and sodium chloride as diarrhea each day.

tose, the galactose derived from milk and the fructose

Within 1 to 5 days, many severely affected patients die

as one of the monosaccharides digested from cane

from this loss of fluid alone.

sugar.

816

Unit XII Gastrointestinal Physiology

Virtually all the monosaccharides are absorbed by

microvillus membrane with a specific transport protein

an active transport process. Let us first discuss the

that requires sodium binding before transport can

absorption of glucose.

occur. After binding, the sodium ion then moves down

its electrochemical gradient to the interior of the cell

Glucose Is Transported by a Sodium Co-Transport Mechanism.

and pulls the amino acid or peptide along with it. This

In the absence of sodium transport through the intes-

is called co-transport (or secondary active transport)

tinal membrane, virtually no glucose can be absorbed.

of the amino acids and peptides. A few amino acids do

The reason is that glucose absorption occurs in a co-

not require this sodium co-transport mechanism but

transport mode with active transport of sodium.

instead are transported by special membrane trans-

There are two stages in the transport of sodium

port proteins in the same way that fructose is trans-

through the intestinal membrane. First is active trans-

ported, by facilitated diffusion.

port of sodium ions through the basolateral mem-

At least five types of transport proteins for trans-

branes of the intestinal epithelial cells into the blood,

porting amino acids and peptides have been found in

thereby depleting sodium inside the epithelial cells.

the luminal membranes of intestinal epithelial cells.

Second, decrease of sodium inside the cells causes

This multiplicity of transport proteins is required

sodium from the intestinal lumen to move through the

because of the diverse binding properties of different

brush border of the epithelial cells to the cell interiors

amino acids and peptides.

by a process of facilitated diffusion. That is, a sodium

ion combines with a transport protein, but the trans-

Absorption of Fats

port protein will not transport the sodium to the inte-

Earlier in this chapter, it was pointed out that when

rior of the cell until the protein itself also combines

fats are digested to form monoglycerides and free fatty

with some other appropriate substance such as

acids, both of these digestive end products first become

glucose. Fortunately, intestinal glucose also combines

dissolved in the central lipid portions of bile micelles.

simultaneously with the same transport protein, and

Because the molecular dimensions of these micelles

then both the sodium ion and glucose molecule are

are only 3 to 6 nanometers in diameter, and because

transported together to the interior of the cell. Thus,

of their highly charged exterior, they are soluble in

the low concentration of sodium inside the cell liter-

chyme. In this form, the monoglycerides and free fatty

ally “drags” sodium to the interior of the cell and along

acids are carried to the surfaces of the microvilli of the

with it the glucose at the same time. Once inside the

intestinal cell brush border and then penetrate into the

epithelial cell, other transport proteins and enzymes

recesses among the moving, agitating microvilli. Here,

cause facilitated diffusion of the glucose through the

both the monoglycerides and fatty acids diffuse imme-

cell’s basolateral membrane into the paracellular

diately out of the micelles and into the interior of

space and from there into the blood.

the epithelial cells, which is possible because the lipids

To summarize, it is the initial active transport of

are also soluble in the epithelial cell membrane. This

sodium through the basolateral membranes of the

leaves the bile micelles still in the chyme, where they

intestinal epithelial cells that provides the eventual

function again and again to help absorb still more

motive force for moving glucose also through the

monoglycerides and fatty acids.

membranes.

Thus, the micelles perform a “ferrying” function that

is highly important for fat absorption. In the presence

Absorption of Other Monosaccharides. Galactose is trans-

of an abundance of bile micelles, about 97 per cent of

ported by almost exactly the same mechanism as

the fat is absorbed; in the absence of the bile micelles,

glucose. Conversely, fructose transport does not occur

only 40 to 50 per cent can be absorbed.

by the sodium co-transport mechanism. Instead, fruc-

After entering the epithelial cell, the fatty acids and

tose is transported by facilitated diffusion all the way

monoglycerides are taken up by the cell’s smooth

through the intestinal epithelium but not coupled with

endoplasmic reticulum; here, they are mainly used to

sodium transport.

form new triglycerides that are subsequently released

Much of the fructose, on entering the cell, becomes

in the form of chylomicrons through the base of the

phosphorylated, then converted to glucose, and finally

epithelial cell, to flow upward through the thoracic

transported in the form of glucose the rest of the way

lymph duct and empty into the circulating blood.

into the blood. Because fructose is not co-transported

with sodium, its overall rate of transport is only about

Direct Absorption of Fatty Acids into the Portal Blood. Small

one half that of glucose or galactose.

quantities of short- and medium-chain fatty acids, such

as those from butterfat, are absorbed directly into the

Absorption of Proteins

portal blood rather than being converted into triglyc-

As explained earlier in the chapter, most proteins,

erides and absorbed by way of the lymphatics. The

after digestion, are absorbed through the luminal

cause of this difference between short- and long-chain

membranes of the intestinal epithelial cells in the form

fatty acid absorption is that the short-chain fatty acids

of dipeptides, tripeptides, and a few free amino acids.

are more water-soluble and mostly are not recon-

The energy for most of this transport is supplied by a

verted into triglycerides by the endoplasmic reticulum.

sodium co-transport mechanism in the same way that

This allows direct diffusion of these short-chain fatty

sodium co-transport of glucose occurs. That is, most

acids from the intestinal epithelial cells directly into

peptide or amino acid molecules bind in the cell’s

the capillary blood of the intestinal villi.

Chapter 65

Digestion and Absorption in the Gastrointestinal Tract

817

Absorption in the Large

source of energy is significant, although it is of negligi-

ble importance in human beings.

Intestine: Formation of Feces

Other substances formed as a result of bacterial activ-

, thiamine, riboflavin, and

ity are vitamin K, vitamin B

About 1500 milliliters of chyme normally pass through

various gases that contribute to flatus in the colon, espe-

the ileocecal valve into the large intestine each day.

cially carbon dioxide, hydrogen gas, and methane.

Most of the water and electrolytes in this chyme are

The bacteria-formed vitamin K is especially important

absorbed in the colon, usually leaving less than 100

because the amount of this vitamin in the daily ingested

milliliters of fluid to be excreted in the feces. Also,

foods is normally insufficient to maintain adequate

blood coagulation.

essentially all the ions are absorbed, leaving only 1 to

5 milliequivalents each of sodium and chloride ions to

be lost in the feces.

Composition of the Feces. The feces normally are about

Most of the absorption in the large intestine occurs

three-fourths water and one-fourth solid matter that

itself is composed of about 30 per cent dead bacteria, 10

in the proximal one half of the colon, giving this

to 20 per cent fat, 10 to 20 per cent inorganic matter, 2

portion the name absorbing colon, whereas the distal

3 per cent protein, and

30 per cent undigested

colon functions principally for feces storage until a

roughage from the food and dried constituents of diges-

propitious time for feces excretion and is therefore

tive juices, such as bile pigment and sloughed epithelial

called the storage colon.

cells. The brown color of feces is caused by stercobilin

and urobilin, derivatives of bilirubin. The odor is caused

Absorption and Secretion of Electrolytes and Water. The

principally by products of bacterial action; these prod-

mucosa of the large intestine, like that of the small

ucts vary from one person to another, depending on

intestine, has a high capability for active absorption of

each person’s colonic bacterial flora and on the type of

food eaten. The actual odoriferous products include

sodium, and the electrical potential gradient created

indole, skatole, mercaptans, and hydrogen sulfide.

by absorption of the sodium causes chloride absorp-

tion as well. The tight junctions between the epithelial

cells of the large intestinal epithelium are much tighter

than those of the small intestine. This prevents signif-

References

icant amounts of back-diffusion of ions through these

junctions, thus allowing the large intestinal mucosa to

Adibi SA: Regulation of expression of the intestinal

oligopeptide transporter (Pept-1) in health and disease.

absorb sodium ions far more completely—that is,

Am J Physiol Gastrointest Liver Physiol 285:G779, 2003.

against a much higher concentration gradient—than

Barrett KE, Keely SJ: Chloride secretion by the intestinal

can occur in the small intestine. This is especially true

epithelium: molecular basis and regulatory aspects. Annu

when large quantities of aldosterone are available

Rev Physiol 62:535, 2000.

because aldosterone greatly enhances sodium trans-

Daniel H: Molecular and integrative physiology of intestinal

port capability.

peptide transport. Annu Rev Physiol 66:361, 2004.

In addition, as occurs in the distal portion of the

Farhadi A, Banan A, Fields J, Keshavarzian A: Intestinal

small intestine, the mucosa of the large intestine

barrier: an interface between health and disease. J Gas-

secretes bicarbonate ions while it simultaneously

troenterol Hepatol 18:479, 2003.

absorbs an equal number of chloride ions in an

Ferraris RP, Diamond J: Regulation of intestinal sugar trans-

port. Physiol Rev 77:257, 1997.

exchange transport process that has already been

Field M: Intestinal ion transport and the pathophysiology of

described. The bicarbonate helps neutralize the acidic

diarrhea. J Clin Invest 111:931, 2003.

end products of bacterial action in the large intestine.

Greig E, Sandle GI: Diarrhea in ulcerative colitis. The role

Absorption of sodium and chloride ions creates an

of altered colonic sodium transport. Ann N Y Acad Sci

osmotic gradient across the large intestinal mucosa,

915:327, 2000.

which in turn causes absorption of water.

Hershberg RM: The epithelial cell cytoskeleton and intra-

cellular trafficking. V. Polarized compartmentalization of

Maximum Absorption Capacity of the Large Intestine. The

antigen processing and Toll-like receptor signaling in

large intestine can absorb a maximum of 5 to 8 liters

intestinal epithelial cells. Am J Physiol Gastrointest Liver

of fluid and electrolytes each day. When the total quan-

Physiol 283:G833, 2002.

Johnson LR: Gastrointestinal Physiology, 6th ed. St. Louis:

tity entering the large intestine through the ileocecal

Mosby, 2001.

valve or by way of large intestine secretion exceeds

Kullak-Ublick GA, Stieger B, Meier PJ: Enterohepatic bile

this amount, the excess appears in the feces as diar-

salt transporters in normal physiology and liver disease.

rhea. As noted earlier in the chapter, toxins from

Gastroenterology 126:322, 2004.

cholera or certain other bacterial infections often

Kunzelmann K, Mall M: Electrolyte transport in the mam-

cause the crypts in the terminal ileum and in the large

malian colon: mechanisms and implications for disease.

intestine to secrete 10 or more liters of fluid each day,

Physiol Rev 82:245, 2002.

leading to severe and sometimes lethal diarrhea.

Meier PJ, Stieger B: Bile salt transporters. Annu Rev Physiol

64:635, 2002.

Bacterial Action in the Colon. Numerous bacteria, especially

Pacha J: Development of intestinal transport function in

colon bacilli, are present even normally in the absorbing

mammals. Physiol Rev 80:1633, 2000.

colon. They are capable of digesting small amounts of

Pappenheimer JR: Intestinal absorption of hexoses and

cellulose, in this way providing a few calories of extra

amino acids: from apical cytosol to villus capillaries. J

nutrition for the body. In herbivorous animals, this

Membr Biol 184:233, 2001.

C H A P T E R

Physiology of Gastrointestinal

Disorders

Effective therapy for most gastrointestinal disorders

depends on a basic knowledge of gastrointestinal phys-

iology. The purpose of this chapter, therefore, is to

discuss a few representative types of gastrointestinal

malfunction that have special physiologic bases or

consequences.

Disorders of Swallowing and of the Esophagus

Paralysis of the Swallowing Mechanism. Damage to the 5th, 9th, or 10th cerebral nerve

can cause paralysis of significant portions of the swallowing mechanism. Also, a few

diseases, such as poliomyelitis or encephalitis, can prevent normal swallowing by

damaging the swallowing center in the brain stem. Finally, paralysis of the swal-

lowing muscles, as occurs in muscle dystrophy or in failure of neuromuscular trans-

mission in myasthenia gravis or botulism, can also prevent normal swallowing.

When the swallowing mechanism is partially or totally paralyzed, the abnormal-

ities that can occur include (1) complete abrogation of the swallowing act so

that swallowing cannot occur, (2) failure of the glottis to close so that food passes

into the lungs instead of the esophagus, and (3) failure of the soft palate and

uvula to close the posterior nares so that food refluxes into the nose during

swallowing.

One of the most serious instances of paralysis of the swallowing mechanism

occurs when patients are under deep anesthesia. Often, while on the operating table,

they vomit large quantities of materials from the stomach into the pharynx; then,

instead of swallowing the materials again, they simply suck them into the trachea

because the anesthetic has blocked the reflex mechanism of swallowing. As a result,

such patients occasionally choke to death on their own vomitus.

Achalasia and Megaesophagus. Achalasia is a condition in which the lower esophageal

sphincter fails to relax during swallowing. As a result, food swallowed into the

esophagus then fails to pass from the esophagus into the stomach. Pathological

studies have shown damage in the neural network of the myenteric plexus in the

lower two thirds of the esophagus. As a result, the musculature of the lower esoph-

agus remains spastically contracted, and the myenteric plexus has lost its ability to

transmit a signal to cause “receptive relaxation” of the gastroesophageal sphincter

as food approaches this sphincter during swallowing.

When achalasia becomes severe, the esophagus often cannot empty the swallowed

food into the stomach for many hours, instead of the few seconds that is the normal

time. Over months and years, the esophagus becomes tremendously enlarged until

it often can hold as much as 1 liter of food, which often becomes putridly infected

during the long periods of esophageal stasis. The infection may also cause ulcera-

tion of the esophageal mucosa, sometimes leading to severe substernal pain or even

rupture and death. Considerable benefit can be achieved by stretching the lower

end of the esophagus by means of a balloon inflated on the end of a swallowed

esophageal tube. Antispasmotic drugs (drugs that relax smooth muscle) can also be

helpful.

Disorders of the Stomach

Gastritis—Inflammation of the Gastric Mucosa. Mild to moderate chronic gastritis is

exceedingly common in the population as a whole, especially in the middle to later

years of adult life.

819

820

Unit XII Gastrointestinal Physiology

The inflammation of gastritis may be only superficial

bines with vitamin B₁₂ in the stomach and protects it

and therefore not very harmful, or it can penetrate

from being digested and destroyed as it passes into the

deeply into the gastric mucosa, in many long-standing

small intestine. Then, when the intrinsic factor-vitamin

cases causing almost complete atrophy of the gastric

B₁₂ complex reaches the terminal ileum, the intrinsic

mucosa. In a few cases, gastritis can be acute and severe,

factor binds with receptors on the ileal epithelial

with ulcerative excoriation of the stomach mucosa by

surface. This in turn makes it possible for the vitamin

the stomach’s own peptic secretions.

B₁₂ to be absorbed.

Research suggests that much gastritis is caused

In the absence of intrinsic factor, only about 1/50 of

by chronic bacterial infection of the gastric mucosa.

the vitamin B₁₂

is absorbed. And, without intrinsic

This often can be treated successfully by an intensive

factor, an adequate amount of vitamin B₁₂ is not made

regimen of antibacterial therapy.

available from the foods to cause young, newly forming

In addition, certain ingested irritant substances can be

red blood cells to mature in the bone marrow. The result

especially damaging to the protective gastric mucosal

is pernicious anemia. This is discussed in more detail in

barrier—that is, to the mucous glands and to the tight

Chapter 32.

epithelial junctions between the gastric lining cells—

often leading to severe acute or chronic gastritis. Two of

the most common of these substances are excesses of

Peptic Ulcer

alcohol or aspirin.

A peptic ulcer is an excoriated area of stomach or intes-

tinal mucosa caused principally by the digestive action

Gastric Barrier and Its Penetration in Gastritis. Absorp-

of gastric juice or upper small intestinal secretions.

tion of food from the stomach directly into the blood is

Figure 66-1 shows the points in the gastrointestinal tract

normally slight. This low level of absorption is mainly

at which peptic ulcers most frequently occur, demon-

caused by two specific features of the gastric mucosa:

strating that the most frequent site is within a few

(1) it is lined with highly resistant mucous cells that

centimeters of the pylorus. In addition, peptic ulcers fre-

secrete a viscid and adherent mucus and (2) it has tight

quently occur along the lesser curvature of the antral

junctions between the adjacent epithelial cells. These

end of the stomach or, more rarely, in the lower end of

two together plus other impediments to gastric absorp-

the esophagus where stomach juices frequently reflux.

tion are called the “gastric barrier.”

A type of peptic ulcer called a marginal ulcer also often

The gastric barrier normally is resistant enough to dif-

occurs wherever a surgical opening such as a gastro-

fusion so that even the highly concentrated hydrogen

jejunostomy has been made between the stomach and

ions of the gastric juice, averaging about 100,000 times

the jejunum of the small intestine.

the concentration of hydrogen ions in plasma, seldom

diffuse even to the slightest extent through the lining

Basic Cause of Peptic Ulceration. The usual cause of peptic

mucus as far as the epithelial membrane itself. In gas-

ulceration is an imbalance between the rate of secretion

tritis, the permeability of the barrier is greatly increased.

of gastric juice and the degree of protection afforded by

The hydrogen ions do then diffuse into the stomach

(1) the gastroduodenal mucosal barrier and (2) the neu-

epithelium, creating additional havoc and leading to a

tralization of the gastric acid by duodenal juices. It will

vicious circle of progressive stomach mucosal damage

be recalled that all areas normally exposed to gastric

and atrophy. It also makes the mucosa susceptible to

juice are well supplied with mucous glands, beginning

digestion by the peptic digestive enzymes, thus fre-

with compound mucous glands in the lower esophagus

quently resulting in gastric ulcer.

plus the mucous cell coating of the stomach mucosa, the

mucous neck cells of the gastric glands, the deep pyloric

Gastric Atrophy. In many people who have chronic gas-

glands that secrete mainly mucus, and, finally, the glands

tritis, the mucosa gradually becomes more and more

of Brunner of the upper duodenum, which secrete a

atrophic until little or no gastric gland digestive secre-

highly alkaline mucus.

tion remains. It is also believed that some people

In addition to the mucus protection of the mucosa,

develop autoimmunity against the gastric mucosa, this

the duodenum is protected by the alkalinity of the small

also leading eventually to gastric atrophy. Loss of the

stomach secretions in gastric atrophy leads to achlorhy-

Cardia

dria and, occasionally, to pernicious anemia.

Causes:

Achlorhydria

(and Hypochlorhydria). Achlorhydria

1. High acid and peptic content

means simply that the stomach fails to secrete

2. Irritation

hydrochloric acid; it is diagnosed when the pH of the

3. Poor blood supply

gastric secretions fails to decrease below

6.5 after

4. Poor secretion of mucus

Ulcer

maximal stimulation. Hypochlorhydria means dimin-

5. Infection, H. pylori

sites

ished acid secretion. When acid is not secreted, pepsin

also usually is not secreted; even when it is, the lack of

Pylorus

acid prevents it from functioning because pepsin

requires an acid medium for activity.

Marginal

Pernicious Anemia in Gastric Atrophy. Pernicious

ulcer

anemia is a common accompaniment of gastric atrophy

and achlorhydria. Normal gastric secretions contain a

glycoprotein called intrinsic factor, secreted by the same

parietal cells that secrete hydrochloric acid. Intrinsic

Figure 66-1

factor must be present for adequate absorption of

vitamin B₁₂ from the ileum. That is, intrinsic factor com-

Peptic ulcer. H. pylori, Helicobacter pylori.

Chapter 66

Physiology of Gastrointestinal Disorders

821

intestinal secretions. Especially important is pancreatic

changed immensely. Initial reports are that almost all

secretion, which contains large quantities of sodium

patients with peptic ulceration can be treated effectively

bicarbonate that neutralize the hydrochloric acid of the

by two measures: (1) use of antibiotics along with other

gastric juice, thus also inactivating pepsin and prevent-

agents to kill infectious bacteria and (2) administration

ing digestion of the mucosa. In addition, large amounts

of an acid-suppressant drug, especially ranitidine, an

of bicarbonate ions are provided in (1) the secretions of

antihistaminic that blocks the stimulatory effect of his-

the large Brunner’s glands in the first few centimeters

tamine on gastric gland histamine₂

receptors, thus

of the duodenal wall and (2) in bile coming from the

reducing gastric acid secretion by 70 to 80 per cent.

liver.

In the past, before these approaches to peptic ulcer

Finally, two feedback control mechanisms normally

therapy were developed, it was often necessary to

ensure that this neutralization of gastric juices is com-

remove as much as four fifths of the stomach, thus

plete, as follows:

reducing stomach acid-peptic juices enough to cure

1. When excess acid enters the duodenum, it reflexly

most patients. Another therapy was to cut the two vagus

inhibits gastric secretion and peristalsis in the

nerves that supply parasympathetic stimulation to the

stomach, both by nervous reflexes and by hormonal

gastric glands. This blocked almost all secretion of acid

feedback from the duodenum, thereby decreasing

and pepsin and often cured the ulcer or ulcers within 1

the rate of gastric emptying.

week after the operation was performed. However,

2. The presence of acid in the small intestine liberates

much of the basal stomach secretion returned after a

secretin from the intestinal mucosa, which then

few months, and in many patients the ulcer also

passes by way of the blood to the pancreas to

returned.

promote rapid secretion of pancreatic juice. This

The newer physiologic approaches to therapy may

juice also contains a high concentration of sodium

prove to be miraculous. Even so, in a few instances, the

bicarbonate, thus making still more sodium

patient’s condition is so severe—including massive

bicarbonate available for neutralization of the acid.

bleeding from the ulcer—that heroic operative proce-

Therefore, a peptic ulcer can be caused in either of

dures often must still be used.

two ways: (1) excess secretion of acid and pepsin by the

gastric mucosa or (2) diminished ability of the gastro-

duodenal mucosal barrier to protect against the diges-

Disorders of the

tive properties of the stomach acid-pepsin secretion.

Small Intestine

Specific Causes of Peptic Ulcer in

Abnormal Digestion of Food in the

the Human Being

Small Intestine—Pancreatic Failure

Bacterial Infection by Helicobacter pylori Breaks Down the Gas-

A serious cause of abnormal digestion is failure of the

troduodenal Mucosal Barrier. Many peptic ulcer patients

pancreas to secrete pancreatic juice into the small intes-

have been found to have chronic infection of the ter-

tine. Lack of pancreatic secretion frequently occurs (1)

minal portions of the gastric mucosa and initial portions

in pancreatitis (which is discussed later), (2) when the

of the duodenal mucosa, infection most often caused by

pancreatic duct is blocked by a gallstone at the papilla

the bacterium Helicobacter pylori. Once this infection

of Vater, or (3) after the head of the pancreas has been

begins, it can last a lifetime unless it is eradicated by

removed because of malignancy.

antibacterial therapy. Furthermore, the bacterium is

Loss of pancreatic juice means loss of trypsin, chy-

capable of penetrating the mucosal barrier both by

motrypsin, carboxypolypeptidase, pancreatic amylase,

virtue of its physical capability to burrow through the

pancreatic lipase, and still a few other digestive

barrier and by releasing bacterial digestive enzymes

enzymes. Without these enzymes, as much as 60 per cent

that liquefy the barrier. As a result, the strong acidic

of the fat entering the small intestine may be unab-

digestive juices of the stomach secretions can then pen-

sorbed, as well as one third to one half of the proteins

etrate into the underlying epithelium and literally digest

and carbohydrates. As a result, large portions of the

the gastrointestinal wall, thus leading to peptic

ingested food cannot be used for nutrition, and copious,

ulceration.

fatty feces are excreted.

Other Causes of Ulceration. In many people who have

Pancreatitis. Pancreatitis means inflammation of the

peptic ulcer in the initial portion of the duodenum, the

pancreas, and this can occur in the form of either acute

rate of gastric acid secretion is greater than normal,

pancreatitis or chronic pancreatitis.

sometimes as much as twice normal. Although part of

The most common cause of pancreatitis is drinking

this increased secretion may be stimulated by bacterial

excess alcohol, and the second most common cause is

infection, studies in both animals and human beings

blockage of the papilla of Vater by a gallstone; the two

have shown that excess secretion of gastric juices for

together account for more than 90 per cent of all cases.

any reason (for instance, even in psychic disturbances)

When a gallstone blocks the papilla of Vater, this blocks

may cause peptic ulceration.

the main secretory duct from the pancreas as well as the

Other factors that predispose to ulcers include (1)

common bile duct. The pancreatic enzymes are then

smoking, presumably because of increased nervous

dammed up in the ducts and acini of the pancreas. Even-

stimulation of the stomach secretory glands; (2) alcohol,

tually, so much trypsinogen accumulates that it over-

because it tends to break down the mucosal barrier; and

comes the trypsin inhibitor in the secretions, and a small

(3) aspirin and other non-steroidal anti-inflammatory

quantity of trypsinogen becomes activated to form

drugs that also have a strong propensity for breaking

trypsin. Once this happens, the trypsin activates still

down this barrier.

more trypsinogen as well as chymotrypsinogen and car-

Physiology of Treatment. Since discovery of the bacterial

boxypolypeptidase, resulting in a vicious circle until

infectious basis for much peptic ulceration, therapy has

most of the proteolytic enzymes in the pancreatic ducts

822

Unit XII Gastrointestinal Physiology

and acini become activated. These enzymes rapidly

of dry, hard feces in the descending colon that accumu-

digest large portions of the pancreas itself, sometimes

late because of over-absorption of fluid. Any pathology

completely and permanently destroying the ability of

of the intestines that obstructs movement of intestinal

the pancreas to secrete digestive enzymes.

contents, such as tumors, adhesions that constrict the

intestines, or ulcers, can cause constipation. A frequent

functional cause of constipation is irregular bowel

Malabsorption by the Small

habits that have developed through a lifetime of inhibi-

Intestinal Mucosa—Sprue

tion of the normal defecation reflexes.

Infants are seldom constipated, but part of their train-

Occasionally, nutrients are not adequately absorbed

ing in the early years of life requires that they learn to

from the small intestine even though the food has

control defecation; this control is effected by inhibiting

become well digested. Several diseases can cause

the natural defecation reflexes. Clinical experience

decreased absorption by the mucosa; they are often

shows that if one does not allow defecation to occur

classified together under the general term “sprue.” Mal-

when the defecation reflexes are excited or if one over-

absorption also can occur when large portions of the

uses laxatives to take the place of natural bowel func-

small intestine have been removed.

tion, the reflexes themselves become progressively less

strong over months or years, and the colon becomes

Nontropical Sprue. One type of sprue, called variously

atonic. For this reason, if a person establishes regular

idiopathic sprue, celiac disease (in children), or gluten

bowel habits early in life, usually defecating in the

enteropathy, results from the toxic effects of gluten

morning after breakfast when the gastrocolic and duo-

present in certain types of grains, especially wheat and

denocolic reflexes cause mass movements in the large

rye. Only some people are susceptible to this effect, but

intestine, the development of constipation in later life is

in those who are susceptible, gluten has a direct destruc-

much less likely.

tive effect on intestinal enterocytes. In milder forms of

Constipation can also result from spasm of a small

the disease, only the microvilli of the absorbing entero-

segment of the sigmoid colon. It should be recalled that

cytes on the villi are destroyed, thus decreasing the

motility even normally is weak in the large intestine, so

absorptive surface area as much as twofold. In the more

that even a slight degree of spasm is often capable of

severe forms, the villi themselves become blunted or

causing serious constipation. After the constipation has

disappear altogether, thus still further reducing the

continued for several days and excess feces have accu-

absorptive area of the gut. Removal of wheat and rye

mulated above a spastic sigmoid colon, excessive

flour from the diet frequently results in cure within

colonic secretions often then lead to a day or so of diar-

weeks, especially in children with this disease.

rhea. After this, the cycle begins again, with repeated

bouts of alternating constipation and diarrhea.

Tropical Sprue. A different type of sprue called tropical

sprue frequently occurs in the tropics and can often be

Megacolon. Occasionally, constipation is so severe that

treated with antibacterial agents. Even though no spe-

bowel movements occur only once every several days

cific bacterium has been implicated as the cause, it is

or sometimes only once a week. This allows tremendous

believed that this variety of sprue is usually caused by

quantities of fecal matter to accumulate in the colon,

inflammation of the intestinal mucosa resulting from

causing the colon sometimes to distend to a diameter of

unidentified infectious agents.

3 to 4 inches. The condition is called megacolon, or

Hirschsprung’s disease.

Malabsorption in Sprue. In the early stages of sprue, intes-

A frequent cause of megacolon is lack of or deficiency

tinal absorption of fat is more impaired than absorption

of ganglion cells in the myenteric plexus in a segment

of other digestive products. The fat that appears in the

of the sigmoid colon. As a consequence, neither defeca-

stools is almost entirely in the form of salts of fatty acids

tion reflexes nor strong peristaltic motility can occur in

rather than undigested fat, demonstrating that the

this area of the large intestine. The sigmoid itself

problem is one of absorption, not of digestion. In fact,

becomes small and almost spastic while feces accumu-

the condition is frequently called steatorrhea, which

late proximal to this area, causing megacolon in the

means simply excess fats in the stools.

ascending, transverse, and descending colons.

In very severe cases of sprue, in addition to malab-

sorption of fats there is also impaired absorption of pro-

teins, carbohydrates, calcium, vitamin K, folic acid, and

Diarrhea

vitamin B

12. As a result, the person suffers (1) severe

nutritional deficiency, often developing wasting of the

Diarrhea results from rapid movement of fecal matter

body; (2) osteomalacia (demineralization of the bones

through the large intestine. Several causes of diarrhea

because of lack of calcium); (3) inadequate blood coag-

with important physiologic sequelae are the following.

ulation caused by lack of vitamin K; and (4) macrocytic

anemia of the pernicious anemia type, owing to dimin-

Enteritis. Enteritis means inflammation usually caused

ished vitamin B

and folic acid absorption.

either by a virus or by bacteria in the intestinal tract. In

usual infectious diarrhea, the infection is most extensive

in the large intestine and the distal end of the ileum.

Disorders of the

Everywhere the infection is present, the mucosa

becomes extensively irritated, and its rate of secretion

Large Intestine

becomes greatly enhanced. In addition, motility of the

Constipation

intestinal wall usually increases manyfold. As a result,

large quantities of fluid are made available for washing

Constipation means slow movement of feces through the

the infectious agent toward the anus, and at the same

large intestine; it is often associated with large quantities

time strong propulsive movements propel this fluid

Chapter 66

Physiology of Gastrointestinal Disorders

823

forward. This is an important mechanism for ridding the

injury. But, because the cord defecation reflex can still

intestinal tract of a debilitating infection.

occur, a small enema to excite action of this cord reflex,

Of special interest is diarrhea caused by cholera (and

usually given in the morning shortly after a meal, can

less often by other bacteria such as some pathogenic

often cause adequate defecation. In this way, people

colon bacilli). As explained in Chapter 65, cholera toxin

with spinal cord injuries that do not destroy the conus

directly stimulates excessive secretion of electrolytes

medullaris of the spinal cord can usually control their

and fluid from the crypts of Lieberkühn in the distal

bowel movements each day.

ileum and colon. The amount can be 10 to 12 liters

per day, although the colon can usually reabsorb a

maximum of only 6 to 8 liters per day. Therefore, loss of

General Disorders of the

fluid and electrolytes can be so debilitating within

Gastrointestinal Tract

several days that death can ensue.

The most important physiologic basis of therapy in

Vomiting

cholera is to replace the fluid and electrolytes as rapidly

as they are lost, mainly by giving the patient intravenous

Vomiting is the means by which the upper gastroin-

solutions. With proper therapy, along with the use of

testinal tract rids itself of its contents when almost any

antibiotics, almost no cholera patients die, but without

part of the upper tract becomes excessively irritated,

therapy, as many as 50 per cent do.

overdistended, or even overexcitable. Excessive disten-

tion or irritation of the duodenum provides an espe-

Psychogenic Diarrhea. Everyone is familiar with the diar-

cially strong stimulus for vomiting.

rhea that accompanies periods of nervous tension, such

The sensory signals that initiate vomiting originate

as during examination time or when a soldier is about

mainly from the pharynx, esophagus, stomach, and

to go into battle. This type of diarrhea, called psy-

upper portions of the small intestines. And the nerve

chogenic emotional diarrhea, is caused by excessive

impulses are transmitted, as shown in Figure 66-2, by

stimulation of the parasympathetic nervous system,

both vagal and sympathetic afferent nerve fibers to mul-

which greatly excites both (1) motility and (2) excess

secretion of mucus in the distal colon. These two effects

added together can cause marked diarrhea.

Apomorphine, morphine

Ulcerative Colitis. Ulcerative colitis is a disease in which

Chemoreceptor

extensive areas of the walls of the large intestine

trigger zone

become inflamed and ulcerated. The motility of the

ulcerated colon is often so great that mass movements

“Vomiting center”

occur much of the day rather than for the usual 10 to

30 minutes. Also, the colon’s secretions are greatly

enhanced. As a result, the patient has repeated diarrheal

bowel movements.

The cause of ulcerative colitis is unknown. Some cli-

nicians believe that it results from an allergic or immune

Vagal

destructive effect, but it also could result from chronic

afferents

bacterial infection not yet understood. Whatever the

cause, there is a strong hereditary tendency for suscep-

tibility to ulcerative colitis. Once the condition has pro-

gressed very far, the ulcers seldom will heal until an

ileostomy is performed to allow the small intestinal con-

tents to drain to the exterior rather than to pass through

the colon. Even then the ulcers sometimes fail to heal,

Sympathetic afferents

and the only solution might be surgical removal of the

entire colon.

Paralysis of Defecation in Spinal

Cord Injuries

From Chapter 63 it will be recalled that defecation is

normally initiated by accumulating feces in the rectum,

which causes a spinal cord-mediated defecation reflex

passing from the rectum to the conus medullaris of the

spinal cord and then back to the descending colon,

sigmoid, rectum, and anus.

When the spinal cord is injured somewhere between

the conus medullaris and the brain, the voluntary

portion of the defecation act is blocked while the basic

Figure 66-2

cord reflex for defecation is still intact. Nevertheless,

loss of the voluntary aid to defecation—that is, loss of

Neutral connections of the “vomiting center.” This so-called vom-

the increased abdominal pressure and relaxation of the

iting center includes multiple sensory, motor, and control nuclei

voluntary anal sphincter—often makes defecation a dif-

mainly in the medullary and pontile reticular formation but also

ficult process in the person with this type of upper cord

extending into the spinal cord.

824

Unit XII Gastrointestinal Physiology

tiple distributed nuclei in the brain stem that all

Also, it is well known that rapidly changing direction

together are called the “vomiting center.” From here,

or rhythm of motion of the body can cause certain

motor impulses that cause the actual vomiting are trans-

people to vomit. The mechanism for this is the follow-

mitted from the vomiting center by way of the 5th, 7th,

ing: The motion stimulates receptors in the vestibular

9th, 10th, and 12th cranial nerves to the upper gastroin-

labyrinth of the inner ear, and from here impulses are

testinal tract, through vagal and sympathetic nerves to

transmitted mainly by way of the brain stem vestibular

the lower tract, and through spinal nerves to the

nuclei into the cerebellum, then to the chemoreceptor

diaphragm and abdominal muscles.

trigger zone, and finally to the vomiting center to cause

vomiting.

Antiperistalsis, the Prelude to Vomiting. In the early stages

of excessive gastrointestinal irritation or overdistention,

antiperistalsis begins to occur often many minutes

Nausea

before vomiting appears. Antiperistalsis means peristal-

Everyone has experienced the sensation of nausea and

sis up the digestive tract rather than downward. This

knows that it is often a prodrome of vomiting. Nausea

may begin as far down in the intestinal tract as the

is the conscious recognition of subconscious excitation

ileum, and the antiperistaltic wave travels backward up

in an area of the medulla closely associated with or part

the intestine at a rate of 2 to 3 cm/sec; this process

of the vomiting center, and it can be caused by (1) irri-

can actually push a large share of the lower small intes-

tative impulses coming from the gastrointestinal tract,

tine contents all the way back to the duodenum

(2) impulses that originate in the lower brain associated

and stomach within 3 to 5 minutes. Then, as these upper

with motion sickness, or (3) impulses from the cerebral

portions of the gastrointestinal tract, especially the duo-

cortex to initiate vomiting. Vomiting occasionally occurs

denum, become overly distended, this distention

without the prodromal sensation of nausea, indicating

becomes the exciting factor that initiates the actual

that only certain portions of the vomiting center are

vomiting act.

associated with the sensation of nausea.

At the onset of vomiting, strong intrinsic contractions

occur in both the duodenum and the stomach, along

with partial relaxation of the esophageal-stomach

Gastrointestinal Obstruction

sphincter, thus allowing vomitus to begin moving from

the stomach into the esophagus. From here, a specific

The gastrointestinal tract can become obstructed at

vomiting act involving the abdominal muscles takes

almost any point along its course, as shown in Figure

over and expels the vomitus to the exterior, as explained

66-3. Some common causes of obstruction are (1)

in the next paragraph.

cancer, (2) fibrotic constriction resulting from ulceration

or from peritoneal adhesions, (3) spasm of a segment of

Vomiting Act. Once the vomiting center has been suffi-

the gut, and (4) paralysis of a segment of the gut.

ciently stimulated and the vomiting act instituted, the

The abnormal consequences of obstruction de-

first effects are (1) a deep breath, (2) raising of the hyoid

pend on the point in the gastrointestinal tract that

bone and larynx to pull the upper esophageal sphincter

becomes obstructed. If the obstruction occurs at the

open, (3) closing of the glottis to prevent vomitus flow

pylorus, which results often from fibrotic constriction

into the lungs, and (4) lifting of the soft palate to close

after peptic ulceration, persistent vomiting of stomach

the posterior nares. Next comes a strong downward con-

contents occurs. This depresses bodily nutrition; it

traction of the diaphragm along with simultaneous con-

also causes excessive loss of hydrogen ions from the

traction of all the abdominal wall muscles. This squeezes

stomach and can result in various degrees of whole-

the stomach between the diaphragm and the abdominal

body alkalosis.

muscles, building the intragastric pressure to a high

If the obstruction is beyond the stomach, antiperi-

level. Finally, the lower esophageal sphincter relaxes

staltic reflux from the small intestine causes intestinal

completely, allowing expulsion of the gastric contents

juices to flow backward into the stomach, and these

upward through the esophagus.

Thus, the vomiting act results from a squeezing action

of the muscles of the abdomen associated with simulta-

Obstruction at pylorus

Causes

neous contraction of the stomach wall and opening of

causes acid vomitus

1. Cancer

the esophageal sphincters so that the gastric contents

2. Ulcer

can be expelled.

Obstruction below

3. Spasm

duodenum causes

4. Paralytic ileus

“Chemoreceptor Trigger Zone” in the Brain Medulla for Initiation

neutral or basic

5. Adhesions

vomitus

of Vomiting by Drugs or by Motion Sickness. Aside from the

vomiting initiated by irritative stimuli in the gastroin-

High obstruction

testinal tract itself, vomiting can also be caused by

causes extreme

nervous signals arising in areas of the brain. This is par-

vomiting

ticularly true for a small area located bilaterally on the

floor of the fourth ventricle called the chemoreceptor

trigger zone for vomiting. Electrical stimulation of this

Low obstruction

area can initiate vomiting; but, more important, admin-

causes extreme

istration of certain drugs, including apomorphine, mor-

constipation with

phine, and some digitalis derivatives, can directly

less vomiting

stimulate this chemoreceptor trigger zone and initiate

vomiting. Destruction of this area blocks this type of

Figure 66-3

vomiting but does not block vomiting resulting from

irritative stimuli in the gastrointestinal tract itself.

Obstruction in different parts of the gastrointestinal tract.

Chapter 66

Physiology of Gastrointestinal Disorders

825

juices are vomited along with the stomach secretions. In

References

this instance, the person loses large amounts of water

and electrolytes, so that he or she becomes severely

Berkes J, Viswanathan VK, Savkovic SD, Hecht G: Intestinal

dehydrated, but the loss of acid from the stomach and

epithelial responses to enteric pathogens: effects on the

base from the small intestine may be approximately

tight junction barrier, ion transport, and inflammation.

equal, so that little change in acid-base balance occurs.

Gut 52:439, 2003.

If the obstruction is near the distal end of the large

Blaser MJ, Atherton JC: Helicobacter pylori persistence:

intestine, feces can accumulate in the colon for a week

biology and disease. J Clin Invest 113:321, 2004.

or more. The patient develops an intense feeling of con-

Dierkes J, Ebert M, Malfertheiner P, Luley C: Helicobacter

stipation, but at first vomiting is not severe. After the

pylori infection, vitamin B₁₂ and homocysteine. A review.

large intestine has become completely filled and it

Dig Dis 21:237, 2003.

finally becomes impossible for additional chyme to

Egan LJ, Sandborn WJ: Advances in the treatment of

move from the small intestine into the large intestine,

Crohn’s disease. Gastroenterology 126:1574, 2004.

severe vomiting does then occur. Prolonged obstruction

Elson CO: Genes, microbes, and T cells—new therapeutic

of the large intestine can finally causes rupture of the

targets in Crohn’s disease. N Engl J Med 346(8):614, 2002.

intestine itself or dehydration and circulatory shock

Itzkowitz SH, Yio X: Inflammation and cancer. IV. Colorec-

resulting from the severe vomiting.

tal cancer in inflammatory bowel disease: the role of

inflammation. Am J Physiol Gastrointest Liver Physiol

287:G7, 2004

Gases in the Gastrointestinal

Johnson LR: Gastrointestinal Physiology, 6th ed. St. Louis:

Tract; “Flatus”

Mosby, 2001.

Kapadia CR: Gastric atrophy, metaplasia, and dysplasia: a

Gases, called flatus, can enter the gastrointestinal tract

clinical perspective. J Clin Gastroenterol 36(5 Suppl):S29,

from three sources: (1) swallowed air, (2) gases formed

2003

in the gut as a result of bacterial action, or (3) gases that

Kunzelmann K, Mall M: Electrolyte transport in the mam-

diffuse from the blood into the gastrointestinal tract.

malian colon: mechanisms and implications for disease.

Most gases in the stomach are mixtures of nitrogen and

Physiol Rev 82:245, 2002.

oxygen derived from swallowed air. In the typical

Laroux FS, Pavlick KP, Wolf RE, Grisham MB: Dysregula-

person these gases are expelled by belching. Only small

tion of intestinal mucosal immunity: implications in

amounts of gas normally occur in the small intestine,

inflammatory bowel disease. News Physiol Sci 16:272,

and much of this gas is air that passes from the stomach

2001.

into the intestinal tract.

Larson DW, Pemberton JH: Current concepts and contro-

In the large intestine, most of the gases are derived

versies in surgery for IBD. Gastroenterology 126:1611,

from bacterial action, including especially carbon

2004.

dioxide, methane, and hydrogen. When methane and

Ming SC, Goldman H: Pathology of the Gastrointestinal

hydrogen become suitably mixed with oxygen, an actual

Tract. Baltimore: Williams and Wilkins, 1998.

explosive mixture is sometimes formed. Use of the elec-

Podolsky DK: Inflammatory bowel disease. N Engl J Med

tric cautery during sigmoidoscopy has been known to

347:417, 2002.

cause a mild explosion.

Puri P, Shinkai T: Pathogenesis of Hirschsprung’s disease and

Certain foods are known to cause greater expulsion

its variants: recent progress. Semin Pediatr Surg 13:18,

of flatus through the anus than others—beans, cabbage,

2004.

onion, cauliflower, corn, and certain irritant foods

Spirt MJ: Stress-related mucosal disease: risk factors and

such as vinegar. Some of these foods serve as a

prophylactic therapy. Clin Ther 26:197, 2004.

suitable medium for gas-forming bacteria, especially

Suerbaum S, Michetti P: Helicobacter pylori infection.

unabsorbed fermentable types of carbohydrates. For

N Engl J Med 347(15):1175, 2002.

instance, beans contain an indigestible carbohydrate

Wolfe MM, Lichtenstein DR, Singh G: Gastrointestinal tox-

that passes into the colon and becomes a superior food

icity of nonsteroidal antiinflammatory drugs. N Engl J

for colonic bacteria. But in other instances, excess expul-

Med 340(24):1888, 1999.

sion of gas results from irritation of the large intestine,

Wood JD: Neuropathophysiology of irritable bowel syn-

which promotes rapid peristaltic expulsion of gases

drome. J Clin Gastroenterol 35(1 Suppl):S11, 2002.

through the anus before they can be absorbed.

Wright EM, Martin MG, Turk E: Intestinal absorption in

The amount of gases entering or forming in the large

health and disease—sugars. Best Pract Res Clin Gas-

intestine each day averages 7 to 10 liters, whereas the

troenterol 17:943, 2003.

average amount expelled through the anus is usually

only about 0.6 liter. The remainder is normally absorbed

into the blood through the intestinal mucosa and

expelled through the lungs.

C H A P T E R

Metabolism of Carbohydrates,

and Formation of Adenosine

Triphosphate

The next few chapters deal with metabolism in the

body, which means the chemical processes that make it

possible for the cells to continue living. It is not the

purpose of this textbook to present the chemical details

of all the various cellular reactions, because this lies in

the discipline of biochemistry. Instead, these chapters

are devoted to (1) a review of the principal chemical

processes of the cell and (2) an analysis of their physio-

logic implications, especially the manner in which they

fit into the overall concept of homeostasis.

Release of Energy from Foods, and the Concept of

“Free Energy”

A great proportion of the chemical reactions in the cells is concerned with making

the energy in foods available to the various physiologic systems of the cell. For

instance, energy is required for muscle activity, secretion by the glands, maintenance

of membrane potentials by the nerve and muscle fibers, synthesis of substances

in the cells, absorption of foods from the gastrointestinal tract, and many other

functions.

Coupled Reactions. All the energy foods—carbohydrates, fats, and proteins—can be

oxidized in the cells, and during this process, large amounts of energy are released.

These same foods can also be burned with pure oxygen outside the body in an actual

fire, also releasing large amounts of energy; in this case, however, the energy is

released suddenly, all in the form of heat. The energy needed by the physiologic

processes of the cells is not heat but energy to cause mechanical movement in the

case of muscle function, to concentrate solutes in the case of glandular secretion,

and to effect other functions. To provide this energy, the chemical reactions must be

“coupled” with the systems responsible for these physiologic functions. This cou-

pling is accomplished by special cellular enzyme and energy transfer systems, some

of which are explained in this and subsequent chapters.

“Free Energy.” The amount of energy liberated by complete oxidation of a food is

called the free energy of oxidation of the food, and this is generally represented by

the symbol DG. Free energy is usually expressed in terms of calories per mole of

substance. For instance, the amount of free energy liberated by complete oxidation

of 1 mole (180 grams) of glucose is 686,000 calories.

Role of Adenosine Triphosphate in Metabolism

Adenosine triphosphate

(ATP) is an essential link between energy-utilizing

and energy-producing functions of the body (Figure 67-1). For this reason, ATP

has been called the energy currency of the body, and it can be gained and spent

repeatedly.

Energy derived from the oxidation of carbohydrates, proteins, and fats is used to

convert adenosine diphosphate (ADP) to ATP, which is then consumed by the

various reactions of the body that are necessary for (1) active transport of mole-

cules across cell membranes; (2) contraction of muscles and performance of

mechanical work; (3) various synthetic reactions that create hormones, cell mem-

branes, and many other essential molecules of the body; (4) conduction of nerve

impulses; (5) cell division and growth; and (6) many other physiologic functions that

are necessary to maintain and propagate life.

829

830

Unit XIII

Metabolism and Temperature Regulation

ATP is a labile chemical compound that is present in

The interconversions among ATP, ADP, and AMP are

all cells. It has the chemical structure shown in Figure

the following:

67-2. From this formula, it can be seen that ATP is a

combination of adenine, ribose, and three phosphate

-12,000 cal

ADP

-12,000 cal

ADP

radicals. The last two phosphate radicals are connected

ATP

with the remainder of the molecule by high-energy

bonds, which are indicated by the symbol ~.

+12,000 cal

PO₃

+12,000 cal

2PO₃

The amount of free energy in each of these high-

energy bonds per mole of ATP is about 7300 calories

ATP is present everywhere in the cytoplasm and

under standard conditions and about 12,000 calories

nucleoplasm of all cells, and essentially all the physio-

under the usual conditions of temperature and concen-

logic mechanisms that require energy for operation

trations of the reactants in the body. Therefore, in the

obtain it directly from ATP (or another similar high-

body, removal of each of the last two phosphate radicals

energy compound—guanosine triphosphate [GTP]). In

liberates about 12,000 calories of energy. After loss of

turn, the food in the cells is gradually oxidized, and the

one phosphate radical from ATP, the compound

released energy is used to form new ATP, thus always

becomes ADP, and after loss of the second phosphate

maintaining a supply of this substance. All these energy

radical, it becomes adenosine monophosphate (AMP).

transfers take place by means of coupled reactions.

The principal purpose of this chapter is to explain

how the energy from carbohydrates can be used to form

ATP in the cells. Normally, 90 per cent or more of all

the carbohydrates utilized by the body are used for this

purpose.

Energy production

•Proteins

Central Role of Glucose in

•Carbohydrates

Oxidation

•Fats

Carbohydrate Metabolism

As explained in Chapter 65, the final products of car-

bohydrate digestion in the alimentary tract are almost

entirely glucose, fructose, and galactose—with glucose

ADP + P_i

ATP

representing, on average, about 80 per cent of these.

After absorption from the intestinal tract, much of the

fructose and almost all the galactose are rapidly con-

verted into glucose in the liver. Therefore, little fructose

Energy utilization

and galactose are present in the circulating blood.

•Active ion transport

•Muscle contraction

Glucose thus becomes the final common pathway for the

•Synthesis of molecules

transport of almost all carbohydrates to the tissue cells.

•Cell division and growth

In liver cells, appropriate enzymes are available to

promote interconversions among the monosaccha-

rides—glucose, fructose, and galactose—as shown in

Figure 67-3. Furthermore, the dynamics of the reactions

are such that when the liver releases the monosaccha-

Figure 67-1

rides back into the blood, the final product is almost

Adenosine triphosphate (ATP) as the central link between energy-

entirely glucose. The reason for this is that the liver cells

producing and energy-utilizing systems of the body. ADP, adeno-

contain large amounts of glucose phosphatase. There-

sine diphosphate; P_i, inorganic phosphate.

fore, glucose-6-phosphate can be degraded to glucose

NH₂

Adenine

Triphosphate

O P

O ~

~ P

O^-

Ribose

C C

Figure 67-2

OH OH

Chemical structure of adenosine

triphosphate (ATP).

Chapter 67

Metabolism of Carbohydrates, and Formation of Adenosine Triphosphate

831

The transport of glucose through the membranes of

most tissue cells is quite different from that which

Cell membrane

occurs through the gastrointestinal membrane or

through the epithelium of the renal tubules. In both

these cases, the glucose is transported by the mechanism

ATP

Galactose

Galactose-1-phosphate

of active sodium-glucose co-transport, in which active

transport of sodium provides energy for absorbing

glucose against a concentration difference. This sodium

co-transport mechanism functions only in certain

Uridine diphosphate galactose

special epithelial cells that are specifically adapted for

active absorption of glucose. At other cell membranes,

glucose is transported only from higher concentration

Uridine diphosphate glucose

toward lower concentration by facilitated diffusion,

made possible by the special binding properties of mem-

Glycogen

brane glucose carrier protein. The details of facilitated

diffusion for cell membrane transport are presented in

Glucose-1-phosphate

Chapter 4.

ATP

Insulin Increases Facilitated

Glucose

Glucose-6-phosphate

Diffusion of Glucose

The rate of glucose transport as well as transport of

some other monosaccharides is greatly increased by

insulin. When large amounts of insulin are secreted by

ATP

Fructose

Fructose-6-phosphate

the pancreas, the rate of glucose transport into most

cells increases to 10 or more times the rate of transport

when no insulin is secreted. Conversely, the amounts of

Glycolysis

glucose that can diffuse to the insides of most cells of

the body in the absence of insulin, with the exception

of liver and brain cells, are far too little to supply the

amount of glucose normally required for energy metab-

Figure 67-3

olism.

In effect, the rate of carbohydrate utilization by most

Interconversions of the three major monosaccharides—glucose,

cells is controlled by the rate of insulin secretion from

fructose, and galactose—in liver cells.

the pancreas. The functions of insulin and its control of

carbohydrate metabolism are discussed in detail in

Chapter 78.

and phosphate, and the glucose can then be transported

through the liver cell membrane back into the blood.

Once again, it should be emphasized that usually

Phosphorylation of Glucose

more than 95 per cent of all the monosaccharides that

circulate in the blood are the final conversion product,

Immediately on entry into the cells, glucose combines

glucose.

with a phosphate radical in accordance with the follow-

ing reaction:

Transport of Glucose

glucokinase or hexokinase

Glucoseæ

ææææææææ ÆGlucose-6-phosphate

Through the Cell Membrane

ATP

Before glucose can be used by the body’s tissue cells, it

This phosphorylation is promoted mainly by the

must be transported through the tissue cell membrane

enzyme glucokinase in the liver and by hexokinase in

into the cellular cytoplasm. However, glucose cannot

most other cells. The phosphorylation of glucose is

easily diffuse through the pores of the cell membrane

almost completely irreversible except in the liver cells,

because the maximum molecular weight of particles

the renal tubular epithelial cells, and the intestinal

that can diffuse readily is about 100, and glucose has a

epithelial cells; in these cells, another enzyme, glucose

molecular weight of 180. Yet glucose does pass to the

phosphatase, is also available, and when this is activated,

interior of the cells with a reasonable degree of freedom

it can reverse the reaction. In most tissues of the body,

by the mechanism of facilitated diffusion. The principles

phosphorylation serves to capture the glucose in the

of this type of transport are discussed in Chapter 4. Basi-

cell. That is, because of its almost instantaneous binding

cally, they are the following. Penetrating through the

with phosphate, the glucose will not diffuse back out,

lipid matrix of the cell membrane are large numbers of

except from those special cells, especially liver cells, that

protein carrier molecules that can bind with glucose. In

have phosphatase.

this bound form, the glucose can be transported by the

carrier from one side of the membrane to the other side

and then released. Therefore, if the concentration of

Glycogen Is Stored in Liver

glucose is greater on one side of the membrane than on

and Muscle

the other side, more glucose will be transported from

the high-concentration area to the low-concentration

After absorption into a cell, glucose can be used imme-

area than in the opposite direction.

diately for release of energy to the cell, or it can be

832

Unit XIII

Metabolism and Temperature Regulation

stored in the form of glycogen, which is a large polymer

Removal of Stored Glycogen—

of glucose.

Glycogenolysis

All cells of the body are capable of storing at least

some glycogen, but certain cells can store large amounts,

Glycogenolysis means the breakdown of the cell’s

especially liver cells, which can store up to 5 to 8 per

stored glycogen to re-form glucose in the cells. The

cent of their weight as glycogen, and muscle cells, which

glucose can then be used to provide energy. Glycogenol-

can store up to 1 to 3 per cent glycogen. The glycogen

ysis does not occur by reversal of the same chemical

molecules can be polymerized to almost any molecular

reactions that form glycogen; instead, each succeeding

weight, with the average molecular weight being

glucose molecule on each branch of the glycogen

million or greater; most of the glycogen precipitates in

polymer is split away by phosphorylation, catalyzed by

the form of solid granules.

the enzyme phosphorylase.

This conversion of the monosaccharides into a high-

Under resting conditions, the phosphorylase is in an

molecular-weight precipitated compound

(glycogen)

inactive form, so that glycogen will remain stored. When

makes it possible to store large quantities of carbohy-

it is necessary to re-form glucose from glycogen, the

drates without significantly altering the osmotic pres-

phosphorylase must first be activated. This can be

sure of the intracellular fluids. High concentrations of

accomplished in several ways, including the following

low-molecular-weight soluble monosaccharides would

two.

play havoc with the osmotic relations between intracel-

lular and extracellular fluids.

Activation of Phosphorylase by Epinephrine or by Glucagon. Two

hormones, epinephrine and glucagon, can activate phos-

Glycogenesis—The Process

phorylase and thereby cause rapid glycogenolysis. The

of Glycogen Formation

initial effect of each of these hormones is to promote

the formation of cyclic AMP in the cells, which then

The chemical reactions for glycogenesis are shown in

initiates a cascade of chemical reactions that activates

Figure 67-4. From this figure, it can be seen that glucose-

the phosphorylase. This is discussed in detail in Chapter

6-phosphate can become glucose-1-phosphate; this is

78.

converted to uridine diphosphate glucose, which is

Epinephrine is released by the adrenal medullae

finally converted into glycogen. Several specific

when the sympathetic nervous system is stimulated.

enzymes are required to cause these conversions, and

Therefore, one of the functions of the sympathetic

any monosaccharide that can be converted into glucose

nervous system is to increase the availability of glucose

can enter into the reactions. Certain smaller com-

for rapid energy metabolism. This function of epineph-

pounds, including lactic acid, glycerol, pyruvic acid, and

rine occurs markedly in both liver cells and muscle,

some deaminated amino acids, can also be converted

thereby contributing, along with other effects of sym-

into glucose or closely allied compounds and then con-

pathetic stimulation, to preparing the body for action,

verted into glycogen.

as discussed fully in Chapter 60.

Glucagon is a hormone secreted by the alpha cells

of the pancreas when the blood glucose concentration

falls too low. It stimulates formation of cyclic AMP

mainly in the liver cells, and this in turn promotes

conversion of liver glycogen into glucose and its

release into the blood, thereby elevating the blood

Cell membrane

glucose concentration. The function of glucagon in

blood glucose regulation is discussed more fully in

Chapter 78.

Glycogen

Uridine diphosphate glucose

(phosphorylase)

Release of Energy from the

Glucose Molecule by the

Glucose-1-phosphate

Glycolytic Pathway

Because complete oxidation of 1 gram-molecule of

Glucose

(glucokinase)

glucose releases

686,000 calories of energy and

Blood

Glucose-6-phosphate

only 12,000 calories of energy are required to form 1

glucose

(phosphatase)

gram-molecule of ATP, energy would be wasted if

glucose were decomposed all at once into water and

carbon dioxide while forming only a single ATP mole-

Glycolysis

cule. Fortunately, all cells of the body contain special

protein enzymes that cause the glucose molecule to split

a little at a time in many successive steps, so that its

energy is released in small packets to form one mole-

cule of ATP at a time, forming a total of 38 moles of

Figure 67-4

ATP for each mole of glucose metabolized by the cells.

The next sections describe the basic principles of

Chemical reactions of glycogenesis and glycogenolysis, showing

the processes by which the glucose molecule is pro-

also interconversions between blood glucose and liver glycogen.

(The phosphatase required for the release of glucose from the cell

gressively dissected and its energy released to form

is present in liver cells but not in most other cells.)

ATP.

Chapter 67

Metabolism of Carbohydrates, and Formation of Adenosine Triphosphate

833

Glycolysis and the Formation

ATP molecules by the entire glycolytic process is only 2

of Pyruvic Acid

moles for each mole of glucose utilized. This amounts to

24,000 calories of energy that becomes transferred to

By far the most important means of releasing energy

ATP, but during glycolysis, a total of 56,000 calories of

from the glucose molecule is initiated by glycolysis. The

energy were lost from the original glucose, giving an

end products of glycolysis are then oxidized to provide

overall efficiency for ATP formation of only 43 per cent.

energy. Glycolysis means splitting of the glucose mole-

The remaining 57 per cent of the energy is lost in the

cule to form two molecules of pyruvic acid.

form of heat.

Glycolysis occurs by 10 successive chemical reactions,

shown in Figure 67-5. Each step is catalyzed by at least

one specific protein enzyme. Note that glucose is first

Conversion of Pyruvic Acid

converted into fructose-1,6-diphosphate and then split

to Acetyl Coenzyme A

into two three-carbon-atom molecules, glyceraldehyde-

3-phosphate, each of which is then converted through

The next stage in the degradation of glucose is a two-

five additional steps into pyruvic acid.

step conversion of the two pyruvic acid molecules from

Figure 67-5 into two molecules of acetyl coenzyme

Formation of ATP During Glycolysis. Despite the many chem-

A (acetyl-CoA), in accordance with the following

ical reactions in the glycolytic series, only a small

reaction:

portion of the free energy in the glucose molecule is

released at most steps. However, between the

1,3-

diphosphoglyceric acid and the 3-phosphoglyceric acid

stages, and again between the phosphoenolpyruvic acid

and the pyruvic acid stages, the packets of energy

2CH₃

C COOH

2CoA SH

released are greater than 12,000 calories per mole, the

(Pyruvic acid)

(Coenzyme A)

amount required to form ATP, and the reactions are

coupled in such a way that ATP is formed. Thus, a total

of 4 moles of ATP were formed for each mole of fruc-

tose-1,6-diphosphate that is split into pyruvic acid.

Yet 2 moles of ATP were required to phosphorylate

2CH₃

C S CoA + 2CO₂ + 4H

the original glucose to form fructose-1,6-diphosphate

(Acetyl-CoA)

before glycolysis could begin. Therefore, the net gain in

From this reaction, it can be seen that two carbon

dioxide molecules and four hydrogen atoms are

released, while the remaining portions of the two

Glucose

pyruvic acid molecules combine with coenzyme A, a

ATP

ADP

derivative of the vitamin pantothenic acid, to form two

Glucose-6-phosphate

molecules of acetyl-CoA. In this conversion, no ATP is

formed, but up to six molecules of ATP are formed

when the four released hydrogen atoms are later oxi-

Fructose-6-phosphate

dized, as discussed later.

ATP

ADP

Fructose-1,6-diphosphate

Citric Acid Cycle (Krebs Cycle)

Dihydroxyacetone phosphate

The next stage in the degradation of the glucose mole-

cule is called the citric acid cycle (also called the tricar-

2 (Glyceraldehyde-3-phosphate)

boxylic acid cycle or Krebs cycle). This is a sequence of

chemical reactions in which the acetyl portion of acetyl-

CoA is degraded to carbon dioxide and hydrogen

2 (1,3-Diphosphoglyceric acid)

atoms. These reactions all occur in the matrix of the

2ADP

+2ATP

mitochondrion. The released hydrogen atoms add to

the number of these atoms that will subsequently be

2 (3-Phosphoglyceric acid)

oxidized

(as discussed later), releasing tremendous

amounts of energy to form ATP.

2 (2-Phosphoglyceric acid)

Figure 67-6 shows the different stages of the chemi-

cal reactions in the citric acid cycle. The substances to

the left are added during the chemical reactions, and the

2 (Phosphoenolpyruvic acid)

products of the chemical reactions are shown to the

2ADP

2ATP

right. Note at the top of the column that the cycle begins

2 (Pyruvic acid)

with oxaloacetic acid, and at the bottom of the chain of

reactions, oxaloacetic acid is formed again. Thus, the

Net reaction per molecule of glucose:

Glucose + 2ADP + 2PO4-

2 Pyruvic acid + 2ATP + 4H

cycle can continue over and over.

In the initial stage of the citric acid cycle, acetyl-CoA

combines with oxaloacetic acid to form citric acid. The

coenzyme A portion of the acetyl-CoA is released and

Figure 67-5

can be used again and again for the formation of still

Sequence of chemical reactions responsible for glycolysis.

more quantities of acetyl-CoA from pyruvic acid. The

834

Unit XIII

Metabolism and Temperature Regulation

acetyl portion, however, becomes an integral part of the

citric acid molecule. During the successive stages of the

CH₃

CO CoA

COOH

citric acid cycle, several molecules of water are added,

(Acetyl coenzyme A)

as shown on the left in the figure, and carbon dioxide

H₂C COOH

and hydrogen atoms are released at other stages in the

(Oxaloacetic acid)

cycle, as shown on the right in the figure.

H₂O

CoA

The net results of the entire citric acid cycle are given

H₂C COOH

in the explanation at the bottom of Figure 67-6, demon-

HOC COOH

strating that for each molecule of glucose originally

metabolized, 2 acetyl-CoA molecules enter into the

H₂C COOH

citric acid cycle, along with 6 molecules of water. These

(Citric acid)

are then degraded into 4 carbon dioxide molecules, 16

H₂O

hydrogen atoms, and 2 molecules of coenzyme A. Two

H₂C COOH

molecules of ATP are formed, as follows.

COOH

Formation of ATP in the Citric Acid Cycle. Not a great amount

of energy is released during the citric acid cycle itself; in

HC COOH

(cis-Aconitic acid)

only one of the chemical reactions—during the change

from a-ketoglutaric acid to succinic acid—is a molecule

of ATP formed. Thus, for each molecule of glucose

H₂C COOH

metabolized, two acetyl-CoA molecules pass through

HC COOH

the citric acid cycle, each forming a molecule of ATP, or

a total of two molecules of ATP formed.

HOC COOH

Function of Dehydrogenases and Nicotinamide Adenine Dinu-

(Isocitric acid)

cleotide in Causing Release of Hydrogen Atoms in the Citric Acid

Cycle. As already noted at several points in this discus-

H₂C COOH

sion, hydrogen atoms are released during different

chemical reactions of the citric acid cycle—4 hydrogen

HC COOH

atoms during glycolysis, 4 during formation of acetyl-

CoA from pyruvic acid, and 16 in the citric acid cycle;

COOH

this makes a total of 24 hydrogen atoms released for each

(Oxalosuccinic acid)

original molecule of glucose. However, the hydrogen

atoms are not simply turned loose in the intracellular

H₂C COOH

fluid. Instead, they are released in packets of two, and

H₂C

in each instance, the release is catalyzed by a specific

protein enzyme called a dehydrogenase. Twenty of the

COOH

24 hydrogen atoms immediately combine with nicoti-

(a-Ketoglutaric acid)

namide adenine dinucleotide (NAD⁺), a derivative of

H₂O

CO₂

the vitamin niacin, in accordance with the following

ADP

reaction:

H₂C COOH

ATP

C COOH

H₂

(Succinic acid)

Substrate

+ NAD+ dehydrogenase

HC COOH

HOOC CH

(Fumaric acid)

NADH + H⁺ + Substrate

This reaction will not occur without intermediation of

COOH

the specific dehydrogenase or without the availability of

NAD⁺ to act as a hydrogen carrier. Both the free hydro-

H₂C COOH

gen ion and the hydrogen bound with NAD⁺ subse-

(Malic acid)

quently enter into multiple oxidative chemical reactions

that form tremendous quantities of ATP, as discussed

COOH

later.

The remaining four hydrogen atoms released during

C COOH

H₂

the breakdown of glucose—the four released during the

(Oxaloacetic acid)

citric acid cycle between the succinic and fumaric acid

Net reaction per molecule of glucose:

stages—combine with a specific dehydrogenase but are

O + 2ADP

2 Acetyl-CoA + 6H₂

not subsequently released to NAD⁺. Instead, they pass

4CO₂ + 16H + 2CoA + 2ATP

directly from the dehydrogenase into the oxidative

process.

Figure 67-6

Function of Decarboxylases in Causing Release of Carbon Dioxide.

Referring again to the chemical reactions of the

Chemical reactions of the citric acid cycle, showing the release of

citric acid cycle, as well as to those for the formation of

carbon dioxide and a number of hydrogen atoms during the cycle.

Chapter 67

Metabolism of Carbohydrates, and Formation of Adenosine Triphosphate

835

acetyl-CoA from pyruvic acid, we find that there are

this sequence of oxidative reactions, tremendous

three stages in which carbon dioxide is released. To

quantities of energy are released to form ATP. Forma-

cause the release of carbon dioxide, other specific

tion of ATP in this manner is called oxidative phospho-

protein enzymes, called decarboxylases, split the carbon

rylation. This occurs entirely in the mitochondria by a

dioxide away from the substrate. The carbon dioxide is

highly specialized process called the chemiosmotic

then dissolved in the body fluids and transported to the

mechanism.

lungs, where it is expired from the body (see Chapter

40).

Chemiosmotic Mechanism of the

Mitochondria to Form ATP

Formation of Large Quantities

Ionization of Hydrogen, the Electron Transport Chain, and Forma-

of ATP by Oxidation of Hydrogen

tion of Water. The first step in oxidative phosphorylation

(the Process of Oxidative

in the mitochondria is to ionize the hydrogen atoms that

Phosphorylation)

have been removed from the food substrates. As

described earlier, these hydrogen atoms are removed in

Despite all the complexities of (1) glycolysis, (2) the

pairs: one immediately becomes a hydrogen ion, H⁺; the

citric acid cycle, (3) dehydrogenation, and (4) decar-

other combines with NAD⁺ to form NADH. The upper

boxylation, pitifully small amounts of ATP are formed

portion of Figure 67-7 shows the subsequent fate of the

during all these processes—only two ATP molecules in

NADH and H⁺. The initial effect is to release the other

the glycolysis scheme and another two in the citric acid

hydrogen atom from the NADH to form another hydro-

cycle for each molecule of glucose metabolized. Instead,

gen ion, H⁺; this process also reconstitutes NAD⁺ that

almost 90 per cent of the total ATP created through

will be reused again and again.

glucose metabolism is formed during subsequent oxi-

The electrons that are removed from the hydrogen

dation of the hydrogen atoms that were released at

atoms to cause the hydrogen ionization immediately

early stages of glucose degradation. Indeed, the princi-

enter an electron transport chain of electron acceptors

pal function of all these earlier stages is to make the

that are an integral part of the inner membrane (the

hydrogen of the glucose molecule available in forms

shelf membrane) of the mitochondrion. The electron

that can be oxidized.

acceptors can be reversibly reduced or oxidized by

Oxidation of hydrogen is accomplished, as illustrated

accepting or giving up electrons. The important

in Figure 67-7, by a series of enzymatically catalyzed

members of this electron transport chain include flavo-

reactions in the mitochondria. These reactions (1) split

protein, several iron sulfide proteins, ubiquinone, and

each hydrogen atom into a hydrogen ion and an elec-

cytochromes B, C1, C, A, and A3. Each electron is shut-

tron and (2) use the electrons eventually to combine dis-

tled from one of these acceptors to the next until it

solved oxygen of the fluids with water molecules to form

finally reaches cytochrome A3, which is called

hydroxyl ions. Then the hydrogen and hydroxyl ions

cytochrome oxidase because it is capable of giving up

combine with each other to form water. During

two electrons and thus reducing elemental oxygen to

form ionic oxygen, which then combines with hydrogen

Food substrate

ions to form water.

Thus, Figure 67-7 shows the transport of electrons

through the electron chain and then their ultimate

NADH +

H⁺

use by cytochrome oxidase to cause the formation

of water molecules. During the transport of these elec-

H⁺

FMN

^-2e

trons through the electron transport chain, energy is

2H⁺

FeS

NAD⁺

released that is used to cause the synthesis of ATP, as

follows.

FeS

2H⁺

C₁

H₂O

Pumping of Hydrogen Ions into the Outer Chamber of the Mito-

chondrion, Caused by the Electron Transport Chain. As the

electrons pass through the electron transport chain,

large amounts of energy are released. This energy is

2e + 1/2 O₂

used to pump hydrogen ions from the inner matrix of

6H⁺

the mitochondrion (to the right in Figure 67-7) into the

ATP

outer chamber between the inner and outer mitochon-

ATPase

drial membranes (to the left). This creates a high con-

centration of positively charged hydrogen ions in this

3 ADP

ADP

Facilitated

chamber; it also creates a strong negative electrical

Diffusion

diffusion

potential in the inner matrix.

3 ATP

Outer

Inner

Formation of ATP. The next step in oxidative phosphory-

membrane

lation is to convert ADP into ATP. This occurs in con-

junction with a large protein molecule that protrudes all

Figure 67-7

the way through the inner mitochondrial membrane

Mitochondrial chemiosmotic mechanism of oxidative phosphory-

and projects with a knoblike head into the inner mito-

lation for forming large quantities of ATP. This figure shows the

chondrial matrix. This molecule is an ATPase, the phys-

relationship of the oxidative and phosphorylation steps at the outer

ical nature of which is shown in Figure 67-7. It is called

and inner membranes of the mitochondrion.

ATP synthetase.

836

Unit XIII

Metabolism and Temperature Regulation

The high concentration of positively charged hydro-

Control of Energy Release from

gen ions in the outer chamber and the large electrical

Stored Glycogen When the Body

potential difference across the inner membrane cause

Needs Additional Energy: Effect

the hydrogen ions to flow into the inner mitochondrial

of ATP and ADP Cell Concentrations

matrix through the substance of the ATPase molecule. In

doing so, energy derived from this hydrogen ion flow is

in Controlling the Rate of Glycolysis

used by ATPase to convert ADP into ATP by combin-

Continual release of energy from glucose when energy

ing ADP with a free ionic phosphate radical (Pi), thus

is not needed by the cells would be an extremely waste-

adding another high-energy phosphate bond to the

ful process. Instead, glycolysis and the subsequent oxi-

molecule.

dation of hydrogen atoms are continually controlled in

The final step in the process is transfer of ATP from

accordance with the cells’ need for ATP. This control is

the inside of the mitochondrion back to the cell cyto-

accomplished by multiple feedback control mechanisms

plasm. This occurs by facilitated diffusion outward

within the chemical schemata. Among the more impor-

through the inner membrane and then by simple dif-

tant of these are the effects of cell concentrations of

fusion through the permeable outer mitochondrial

both ADP and ATP in controlling the rates of chemical

membrane. In turn, ADP is continually transferred in

reactions in the energy metabolism sequence.

the other direction for continual conversion into ATP.

One important way in which ATP helps control

For each two electrons that pass through the entire elec-

energy metabolism is to inhibit the enzyme phospho-

tron transport chain (representing the ionization of

fructokinase. Because this enzyme promotes the forma-

two hydrogen atoms), up to three ATP molecules are

tion of fructose-1,6-diphosphate, one of the initial steps

synthesized.

in the glycolytic series of reactions, the net effect of

excess cellular ATP is to slow or even stop glycolysis,

which in turn stops most carbohydrate metabolism.

Summary of ATP Formation During

Conversely, ADP (and AMP as well) causes the oppo-

the Breakdown of Glucose

site change in this enzyme, greatly increasing its activ-

ity. Whenever ATP is used by the tissues for energizing

We can now determine the total number of ATP mole-

a major fraction of almost all intracellular chemical

cules that, under optimal conditions, can be formed by

reactions, this reduces the ATP inhibition of the enzyme

the energy from one molecule of glucose.

phosphofructokinase and at the same time increases its

1. During glycolysis, four molecules of ATP are

activity as a result of the excess ADP formed. Thus, the

formed, and two are expended to cause the initial

glycolytic process is set in motion, and the total cellular

phosphorylation of glucose to get the process

store of ATP is replenished.

going. This gives a net gain of two molecules of

Another control linkage is the citrate ion formed in

ATP.

the citric acid cycle. An excess of this ion also strongly

2. During each revolution of the citric acid cycle,

inhibits phosphofructokinase, thus preventing the

one molecule of ATP is formed. However, because

glycolytic process from getting ahead of the citric

each glucose molecule splits into two pyruvic acid

acid cycle’s ability to use the pyruvic acid formed during

molecules, there are two revolutions of the cycle

glycolysis.

for each molecule of glucose metabolized, giving

A third way by which the ATP-ADP-AMP system

a net production of two more molecules of

controls carbohydrate metabolism, as well as control-

ATP.

ling energy release from fats and proteins, is the fol-

3. During the entire schema of glucose breakdown, a

lowing: Referring back to the various chemical reactions

total of 24 hydrogen atoms are released during

for energy release, we see that if all the ADP in the

glycolysis and during the citric acid cycle. Twenty of

cell has already been converted into ATP, additional

these atoms are oxidized in conjunction with the

ATP simply cannot be formed. As a result, the entire

chemiosmotic mechanism shown in Figure 67-7,

sequence involved in the use of foodstuffs—glucose,

with the release of three ATP molecules per two

fats, and proteins—to form ATP is stopped. Then, when

atoms of hydrogen metabolized. This gives an

ATP is used by the cell to energize the different phy-

additional 30 ATP molecules.

siologic functions in the cell, the newly formed ADP and

4. The remaining four hydrogen atoms are released

AMP turn on the energy processes again, and ADP and

by their dehydrogenase into the chemiosmotic

AMP are almost instantly returned to the ATP state. In

oxidative schema in the mitochondrion beyond the

this way, essentially a full store of ATP is automatically

first stage of Figure 67-7. Two ATP molecules are

maintained, except during extreme cellular activity, such

usually released for every two hydrogen atoms

as very strenuous exercise.

oxidized, thus giving a total of four more ATP

molecules.

Now, adding all the ATP molecules formed, we

find a maximum of 38 ATP molecules formed for each

Anaerobic Release of Energy—

molecule of glucose degraded to carbon dioxide

“Anaerobic Glycolysis”

and water. Thus, 456,000 calories of energy can be stored

in the form of ATP, whereas

686,000 calories are

Occasionally, oxygen becomes either unavailable or

released during the complete oxidation of each gram-

insufficient, so that oxidative phosphorylation cannot

molecule of glucose. This represents an overall

take place. Yet even under these conditions, a small

maximum efficiency of energy transfer of 66 per cent.

amount of energy can still be released to the cells by the

The remaining 34 per cent of the energy becomes heat

glycolysis stage of carbohydrate degradation, because

and, therefore, cannot be used by the cells to perform

the chemical reactions for the breakdown of glucose to

specific functions.

pyruvic acid do not require oxygen.

Chapter 67

Metabolism of Carbohydrates, and Formation of Adenosine Triphosphate

837

This process is extremely wasteful of glucose, because

occurs in the liver, but a small amount can also occur in

only 24,000 calories of energy are used to form ATP for

other tissues.

each molecule of glucose metabolized, which represents

only a little over 3 per cent of the total energy in the

Use of Lactic Acid by the Heart for Energy. Heart muscle

glucose molecule. Nevertheless, this release of glycolytic

is especially capable of converting lactic acid to pyruvic

energy to the cells, which is called anaerobic energy, can

acid and then using the pyruvic acid for energy. This

be a lifesaving measure for up to a few minutes when

occurs to a great extent during heavy exercise, when

oxygen becomes unavailable.

large amounts of lactic acid are released into the blood

from the skeletal muscles and consumed as an extra

Formation of Lactic Acid During Anaerobic Glycolysis Allows

energy source by the heart.

Release of Extra Anaerobic Energy. The law of mass action

states that as the end products of a chemical reaction

build up in a reacting medium, the rate of the reaction

Release of Energy from

decreases, approaching zero. The two end products of

Glucose by the Pentose

the glycolytic reactions (see Figure 67-5) are (1) pyruvic

Phosphate Pathway

acid and (2) hydrogen atoms combined with NAD⁺ to

form NADH and H⁺. The buildup of either or both of

In almost all the body’s muscles, essentially all the car-

these would stop the glycolytic process and prevent

bohydrates utilized for energy are degraded to pyruvic

further formation of ATP. When their quantities begin

acid by glycolysis and then oxidized. However, this gly-

to be excessive, these two end products react with each

colytic scheme is not the only means by which glucose

other to form lactic acid, in accordance with the fol-

can be degraded and used to provide energy. A second

lowing equation:

important mechanism for the breakdown and oxidation

of glucose is called the pentose phosphate pathway (or

phosphogluconate pathway), which is responsible for as

much as 30 per cent of the glucose breakdown in the

lactic

liver and even more than this in fat cells.

dehydrogenase

This pathway is especially important because it can

C COOH

NADH

H+

provide energy independently of all the enzymes of the

(Pyruvic acid)

citric acid cycle and therefore is an alternative pathway

for energy metabolism when certain enzymatic abnor-

malities occur in cells. It has a special capacity for pro-

viding energy to multiple cellular synthetic processes.

CH₃

C COOH

NAD+

Release of Carbon Dioxide and Hydrogen by Means of the Pentose

Phosphate Pathway. Figure 67-8 shows most of the basic

chemical reactions in the pentose phosphate pathway. It

demonstrates that glucose, during several stages of con-

(Lactic acid)

version, can release one molecule of carbon dioxide and

four atoms of hydrogen, with the resultant formation

Thus, under anaerobic conditions, the major portion

of a five-carbon sugar, D-ribulose. This substance can

of the pyruvic acid is converted into lactic acid, which

change progressively into several other five-, four-,

diffuses readily out of the cells into the extracellular

seven-, and three-carbon sugars. Finally, various combi-

fluids and even into the intracellular fluids of other

nations of these sugars can resynthesize glucose.

less active cells. Therefore, lactic acid represents a type

However, only five molecules of glucose are resynthe-

of “sinkhole” into which the glycolytic end products

sized for every six molecules of glucose that initially enter

can disappear, thus allowing glycolysis to proceed far

into the reactions. That is, the pentose phosphate

longer than would otherwise be possible. Indeed, gly-

pathway is a cyclical process in which one molecule of

colysis could proceed for only a few seconds without

glucose is metabolized for each revolution of the cycle.

this conversion. Instead, it can proceed for several

Thus, by repeating the cycle again and again, all the

minutes, supplying the body with considerable extra

glucose can eventually be converted into carbon dioxide

quantities of ATP, even in the absence of respiratory

and hydrogen, and the hydrogen can enter the oxidative

oxygen.

phosphorylation pathway to form ATP; more often,

however, it is used for the synthesis of fat or other sub-

Reconversion of Lactic Acid to Pyruvic Acid When Oxygen

stances, as follows.

Becomes Available Again. When a person begins to breathe

oxygen again after a period of anaerobic metabolism,

Use of Hydrogen to Synthesize Fat; the Function of Nicotinamide

the lactic acid is rapidly reconverted to pyruvic acid and

Adenine Dinucleotide Phosphate. The hydrogen released

NADH plus H⁺. Large portions of these are immedi-

during the pentose phosphate cycle does not combine

ately oxidized to form large quantities of ATP. This

with NAD⁺ as in the glycolytic pathway but combines

excess ATP then causes as much as three fourths of the

with nicotinamide adenine dinucleotide phosphate

remaining excess pyruvic acid to be converted back into

(NADP⁺), which is almost identical to NAD⁺ except

glucose.

for an extra phosphate radical, P. This difference is

Thus, the large amount of lactic acid that forms during

extremely significant, because only hydrogen bound

anaerobic glycolysis is not lost from the body because,

with NADP⁺ in the form of NADPH can be used for

when oxygen is available again, the lactic acid can be

the synthesis of fats from carbohydrates (as discussed

either reconverted to glucose or used directly for

in Chapter 68) and for the synthesis of some other

energy. By far the greatest portion of this reconversion

substances.

838

Unit XIII

Metabolism and Temperature Regulation

Formation of Carbohydrates

from Proteins and Fats—

Glucose-6-phosphate

“Gluconeogenesis”

6-Phosphoglucono-d-lactone

When the body’s stores of carbohydrates decrease

below normal, moderate quantities of glucose can be

formed from amino acids and the glycerol portion of fat.

6-Phosphogluconic acid

This process is called gluconeogenesis.

Gluconeogenesis is especially important in prevent-

3-Keto-6-phosphogluconic acid

ing an excessive reduction in the blood glucose concen-

CO₂

tration during fasting. Glucose is the primary substrate

for energy in tissues such as the brain and the red blood

D-Ribulose-5-phosphate

H₂O

cells, and adequate amounts of glucose must be present

in the blood for several hours between meals. The liver

D-Xylulose-5-phosphate

plays a key role in maintaining blood glucose levels

during fasting by converting its stored glycogen to

D-Ribose-5-phosphate

glucose (glycogenolysis) and by synthesizing glucose,

mainly from lactate and amino acids (gluconeogenesis).

Approximately 25 per cent of the liver’s glucose pro-

D-Sedoheptulose-7-phosphate

duction during fasting is from gluconeogenesis, helping

to provide a steady supply of glucose to the brain.

D-Glyceraldehyde-3-phosphate

During prolonged fasting, the kidneys also synthesize

considerable amounts of glucose from amino acids and

other precursors.

Fructose-6-phosphate

About 60 per cent of the amino acids in the body pro-

teins can be converted easily into carbohydrates; the

Erythrose-4-phosphate

remaining 40 per cent have chemical configurations that

make this difficult or impossible. Each amino acid is

Net reaction:

converted into glucose by a slightly different chemical

Glucose + 12NADP⁺ + 6H₂O

6CO₂ + 12H + 12NADPH

process. For instance, alanine can be converted directly

into pyruvic acid simply by deamination; the pyruvic

acid is then converted into glucose or stored glycogen.

Several of the more complicated amino acids can be

Figure 67-8

converted into different sugars that contain three-,

four-, five-, or seven-carbon atoms; they can then enter

Pentose phosphate pathway for glucose metabolism.

the phosphogluconate pathway and eventually form

glucose. Thus, by means of deamination plus several

simple interconversions, many of the amino acids can

become glucose. Similar interconversions can change

glycerol into glucose or glycogen.

When the glycolytic pathway for using glucose

becomes slowed because of cellular inactivity, the

Regulation of Gluconeogenesis. Diminished carbohydrates

pentose phosphate pathway remains operative (mainly

in the cells and decreased blood sugar are the basic

in the liver) to break down any excess glucose that con-

stimuli that increase the rate of gluconeogenesis. Dimin-

tinues to be transported into the cells, and NADPH

ished carbohydrates can directly reverse many of the

becomes abundant to help convert acetyl-CoA, also

glycolytic and phosphogluconate reactions, thus allow-

derived from glucose, into long fatty acid chains. This is

ing the conversion of deaminated amino acids and

another way in which energy in the glucose molecule is

glycerol into carbohydrates. In addition, the hormone

used other than for the formation of ATP—in this

cortisol is especially important in this regulation, as

instance, for the formation and storage of fat in the body.

follows.

Glucose Conversion to Glycogen

Effect of Corticotropin and Glucocorticoids on Gluco-

or Fat

neogenesis. When normal quantities of carbohydrates

are not available to the cells, the adenohypophysis,

When glucose is not immediately required for energy,

for reasons not completely understood, begins to

the extra glucose that continually enters the cells is

secrete increased quantities of the hormone corti-

either stored as glycogen or converted into fat. Glucose

cotropin. This stimulates the adrenal cortex to produce

is preferentially stored as glycogen until the cells have

large quantities of glucocorticoid hormones, especially

stored as much glycogen as they can—an amount suffi-

cortisol. In turn, cortisol mobilizes proteins from

cient to supply the energy needs of the body for only 12

essentially all cells of the body, making these available

to 24 hours.

in the form of amino acids in the body fluids. A high

When the glycogen-storing cells (primarily liver and

proportion of these immediately become deaminated

muscle cells) approach saturation with glycogen, the

in the liver and provide ideal substrates for conversion

additional glucose is converted into fat in liver and fat

into glucose. Thus, one of the most important means

cells and is stored as fat in the fat cells. Other steps

by which gluconeogenesis is promoted is through

in the chemistry of this conversion are discussed in

the release of glucocorticoids from the adrenal

Chapter 68.

cortex.

Chapter 67

Metabolism of Carbohydrates, and Formation of Adenosine Triphosphate

839

Blood Glucose

Jiang G, Zhang BB: Glucagon and regulation of glucose

metabolism. Am J Physiol Endocrinol Metab 284:E671,

The normal blood glucose concentration in a person

2003.

who has not eaten a meal within the past 3 to 4 hours

Jungas RL, Halperin ML, Brosnan JT: Quantitative analysis

is about 90 mg/dl. After a meal containing large amounts

of amino acid oxidation and related gluconeogenesis in

of carbohydrates, this level seldom rises above 140 mg/

humans. Physiol Rev 72:419, 1992.

dl unless the person has diabetes mellitus, which is dis-

Krebs HA: The tricarboxylic acid cycle. Harvey Lect 44:165,

cussed in Chapter 78.

1948-1949.

The regulation of blood glucose concentration is inti-

Kunji ER: The role and structure of mitochondrial carriers.

mately related to the pancreatic hormones insulin and

FEBS Lett 564:239, 2004.

glucagon; this subject is discussed in detail in Chapter

Lam TK, Carpentier A, Lewis GF, et al: Mechanisms of

78 in relation to the functions of these hormones.

the free fatty acid-induced increase in hepatic glucose

production. Am J Physiol Endocrinol Metab 284:E863,

2003.

References

Mills DA, Ferguson-Miller S: Understanding the mechanism

of proton movement linked to oxygen reduction in

Barrett EJ: Insulin’s effect on glucose production: direct or

cytochrome c oxidase: lessons from other proteins. FEBS

indirect? J Clin Invest 111:434, 2003.

Lett 545:47, 2003.

Barthel A, Schmoll D: Novel concepts in insulin regulation

Pilkis SJ, Granner DK: Molecular physiology of the regula-

of hepatic gluconeogenesis. Am J Physiol Endocrinol

tion of hepatic gluconeogenesis and glycolysis. Annu Rev

Metab 285:E685, 2003.

Physiol 54:885, 1992.

Ceulemans H, Bollen M: Functional diversity of protein

Roden M, Bernroider E: Hepatic glucose metabolism in

phosphatase-1, a cellular economizer and reset button.

humans—its role in health and disease. Best Pract Res

Physiol Rev 84:1, 2004.

Clin Endocrinol Metab 17:365, 2003.

Duchen MR: Roles of mitochondria in health and disease.

Ronquist G, Waldenstrom A: Imbalance of plasma mem-

Diabetes 53(Suppl 1):S96, 2004.

brane ion leak and pump relationship as a new aetiologi-

Ferrer JC, Favre C, Gomis RR, et al: Control of glycogen

cal basis of certain disease states. J Intern Med 254:517,

deposition. FEBS Lett 546:127, 2003.

2003.

Gleeson TT: Post-exercise lactate metabolism: a comparative

Spriet LL, Watt MJ: Regulatory mechanisms in the interac-

review of sites, pathways, and regulation. Annu Rev

tion between carbohydrate and lipid oxidation during

Physiol 58:565, 1996.

exercise. Acta Physiol Scand 178:443, 2003.

Gunter TE, Yule DI, Gunter KK, et al: Calcium and mito-

Wolfsdorf JI, Weinstein DA: Glycogen storage diseases. Rev

chondria. FEBS Lett 567:96, 2004.

Endocr Metab Disord 4:95, 2003.

Jackson JB: Proton translocation by transhydrogenase.

FEBS Lett 545:18, 2003.

C H A P T E R

Lipid Metabolism

Several chemical compounds in food and in the

body are classified as lipids. They include (1) neutral fat,

also known as triglycerides;

(2) phospholipids;

(3) cholesterol; and (4) a few others of less importance.

Chemically, the basic lipid moiety of the triglycerides

and the phospholipids is fatty acids, which are simply

long-chain hydrocarbon organic acids. A typical fatty

acid, palmitic acid, is the following: CH₃(CH₂)₁₄COOH.

Although cholesterol does not contain fatty acid, its

sterol nucleus is synthesized from portions of fatty acid molecules, thus giving it

many of the physical and chemical properties of other lipid substances.

The triglycerides are used in the body mainly to provide energy for the different

metabolic processes, a function they share almost equally with the carbohydrates.

However, some lipids, especially cholesterol, the phospholipids, and small amounts

of triglycerides, are used to form the membranes of all cells of the body and to

perform other cellular functions.

Basic Chemical Structure of Triglycerides (Neutral Fat). Because most of this chapter deals

with the utilization of triglycerides for energy, the following typical structure of the

triglyceride molecule must be understood.

CH₃—(CH₂)₁₆—COO—CH₂

CH₃—(CH₂)₁₆—COO—CH

CH₃—(CH₂)₁₆—COO—CH₂

Tristearin

Note that three long-chain fatty acid molecules are bound with one molecule of

glycerol. The three fatty acids most commonly present in the triglycerides of the

human body are (1) stearic acid (shown in the tristearin example above), which has

an 18-carbon chain and is fully saturated with hydrogen atoms; (2) oleic acid, which

also has an 18-carbon chain but has one double bond in the middle of the chain;

and (3) palmitic acid, which has 16 carbon atoms and is fully saturated.

Transport of Lipids in the Body Fluids

Transport of Triglycerides and Other Lipids from the

Gastrointestinal Tract by Lymph—The Chylomicrons

As explained in Chapter 65, almost all the fats in the diet, with the principal excep-

tion of a few short-chain fatty acids, are absorbed from the intestines into the intes-

tinal lymph. During digestion, most triglycerides are split into monoglycerides and

fatty acids. Then, while passing through the intestinal epithelial cells, the mono-

glycerides and fatty acids are resynthesized into new molecules of triglycerides that

enter the lymph as minute, dispersed droplets called chylomicrons, whose diame-

ters are between 0.08 and 0.6 micron. A small amount of apoprotein B is adsorbed

to the outer surfaces of the chylomicrons. This leaves the remainder of the protein

molecules projecting into the surrounding water and thereby increases the suspen-

sion stability of the chylomicrons in the lymph fluid and prevents their adherence

to the lymphatic vessel walls.

Most of the cholesterol and phospholipids absorbed from the gastrointestinal

tract enter the chylomicrons. Thus, although the chylomicrons are composed prin-

cipally of triglycerides, they also contain about 9 per cent phospholipids, 3 per cent

cholesterol, and 1 per cent apoprotein B. The chylomicrons are then transported

upward through the thoracic duct and emptied into the circulating venous blood at

the juncture of the jugular and subclavian veins.

840

Chapter 68

Lipid Metabolism

841

Removal of the Chylomicrons

1. Despite the minute amount of free fatty acid in

from the Blood

the blood, its rate of “turnover” is extremely

rapid: half the plasma fatty acid is replaced by

About 1 hour after a meal that contains large quantities

new fatty acid every 2 to 3 minutes. One can

of fat, the chylomicron concentration in the plasma may

calculate that at this rate, almost all the normal

rise to 1 to 2 per cent of the total plasma, and because

energy requirements of the body can be provided

of the large size of the chylomicrons, the plasma appears

by the oxidation of transported free fatty acids,

turbid and sometimes yellow. However, the chylomi-

without using any carbohydrates or proteins for

crons have a half-life of less than 1 hour, so the plasma

energy.

becomes clear again within a few hours. The fat of the

2. Conditions that increase the rate of utilization

chylomicrons is removed mainly in the following way.

of fat for cellular energy also increase the free

fatty acid concentration in the blood; in fact, the

Chylomicron Triglycerides Are Hydrolyzed by Lipoprotein Lipase,

concentration sometimes increases fivefold to

and Fat Is Stored in Adipose Tissue and Liver Cells. Most of the

eightfold. Such a large increase occurs especially in

chylomicrons are removed from the circulating blood as

cases of starvation and in diabetes; in both these

they pass through the capillaries of adipose tissue or the

conditions, the person derives little or no metabolic

liver. Both adipose tissue and the liver contain large

energy from carbohydrates.

quantities of the enzyme lipoprotein lipase. This enzyme

Under normal conditions, only about 3 molecules of

is especially active in the capillary endothelium, where

fatty acid combine with each molecule of albumin, but

it hydrolyzes the triglycerides of chylomicrons as they

as many as 30 fatty acid molecules can combine with a

come in contact with the endothelial wall, thus releas-

single albumin molecule when the need for fatty acid

ing fatty acids and glycerol.

transport is extreme. This shows how variable the rate

The fatty acids, being highly miscible with the mem-

of lipid transport can be under different physiologic

branes of the cells, immediately diffuse into the fat cells

conditions.

of the adipose tissue and into the liver cells. Once inside

these cells, the fatty acids are again synthesized into

triglycerides, with new glycerol being supplied by the

Lipoproteins—Their Special

metabolic processes of the storage cells, as discussed

Function in Transporting

later in the chapter. The lipase also causes hydrolysis of

phospholipids; this, too, releases fatty acids to be stored

Cholesterol and Phospholipids

in the cells in the same way.

In the postabsorptive state, after all the chylomicrons

have been removed from the blood, more than 95

“Free Fatty Acids” Are Transported

per cent of all the lipids in the plasma are in the

in the Blood in Combination

form of lipoprotein. These are small particles—much

with Albumin

smaller than chylomicrons, but qualitatively similar

in composition—containing triglycerides, cholesterol,

When fat that has been stored in the adipose tissue is to

phospholipids, and protein. The total concentration

be used elsewhere in the body to provide energy, it must

of lipoproteins in the plasma averages about 700 mg

first be transported from the adipose tissue to the other

per 100 ml of plasma—that is, 700 mg/dl. This can be

tissue. It is transported mainly in the form of free fatty

broken down into the following individual lipoprotein

acids. This is achieved by hydrolysis of the triglycerides

constituents:

back into fatty acids and glycerol.

At least two classes of stimuli play important roles

mg/dl of plasma

in promoting this hydrolysis. First, when the amount

of glucose available to the fat cell is inadequate, one of

Cholesterol

180

the glucose breakdown products, a-glycerophosphate, is

Phospholipids

160

Triglycerides

160

also available in insufficient quantities. Because this

Protein

200

substance is required to maintain the glycerol portion

of triglycerides, the result is hydrolysis of triglycerides.

Second, a hormone-sensitive cellular lipase can be acti-

Types of Lipoproteins. Aside from the chylomicrons, which

vated by several hormones from the endocrine glands,

are themselves very large lipoproteins, there are four

and this also promotes rapid hydrolysis of triglycerides.

major types of lipoproteins, classified by their densities

This is discussed later in the chapter.

as measured in the ultracentrifuge: (1) very low density

On leaving fat cells, fatty acids ionize strongly in the

lipoproteins, which contain high concentrations of

plasma, and the ionic portion combines immediately

triglycerides and moderate concentrations of both cho-

with albumin molecules of the plasma proteins. Fatty

lesterol and phospholipids;

(2) intermediate-density

acids bound in this manner are called free fatty acids

lipoproteins, which are very low density lipoproteins

or nonesterified fatty acids, to distinguish them from

from which a share of the triglycerides has been

other fatty acids in the plasma that exist in the form

removed, so that the concentrations of cholesterol and

of (1) esters of glycerol, (2) cholesterol, or (3) other

phospholipids are increased; (3) low-density lipopro-

substances.

teins, which are derived from intermediate-density

The concentration of free fatty acids in the plasma

lipoproteins by the removal of almost all the triglyc-

under resting conditions is about 15 mg/dl, which is a

erides, leaving an especially high concentration of

total of only 0.45 gram of fatty acids in the entire circu-

cholesterol and a moderately high concentration of

latory system. Strangely enough, even this small amount

phospholipids; and (4) high-density lipoproteins, which

accounts for almost all the transport of fatty acids from

contain a high concentration of protein (about 50 per

one part of the body to another for the following

cent) but much smaller concentrations of cholesterol

reasons:

and phospholipids.

842

Unit XIII

Metabolism and Temperature Regulation

Formation and Function of Lipoproteins. Almost all the

can be used for energy; (2) synthesize triglycerides,

lipoproteins are formed in the liver, which is also where

mainly from carbohydrates, but to a lesser extent from

most of the plasma cholesterol, phospholipids, and

proteins as well; and (3) synthesize other lipids from

triglycerides are synthesized. In addition, small quanti-

fatty acids, especially cholesterol and phospholipids.

ties of high-density lipoproteins are synthesized in the

Large quantities of triglycerides appear in the liver

intestinal epithelium during the absorption of fatty

(1) during the early stages of starvation, (2) in diabetes

acids from the intestines.

mellitus, and (3) in any other condition in which fat

The primary function of the lipoproteins is to trans-

instead of carbohydrates is being used for energy. In

port their lipid components in the blood. The very low

these conditions, large quantities of triglycerides are

density lipoproteins transport triglycerides synthesized

mobilized from the adipose tissue, transported as free

in the liver mainly to the adipose tissue, whereas the

fatty acids in the blood, and redeposited as triglycerides

other lipoproteins are especially important in the dif-

in the liver, where the initial stages of much of fat degra-

ferent stages of phospholipid and cholesterol transport

dation begin. Thus, under normal physiologic condi-

from the liver to the peripheral tissues or from the

tions, the total amount of triglycerides in the liver is

periphery back to the liver. Later in the chapter, we

determined to a great extent by the overall rate at which

discuss in more detail special problems of cholesterol

lipids are being used for energy.

transport in relation to the disease atherosclerosis, which

The liver cells, in addition to containing triglycerides,

is associated with the development of fatty lesions on

contain large quantities of phospholipids and choles-

the insides of arterial walls.

terol, which are continually synthesized by the liver.

Also, the liver cells are much more capable than other

tissues of desaturating fatty acids, so that liver triglyc-

Fat Deposits

erides normally are much more unsaturated than the

triglycerides of adipose tissue. This capability of the liver

Adipose Tissue

to desaturate fatty acids is functionally important to all

tissues of the body, because many structural elements of

Large quantities of fat are stored in two major tissues

all cells contain reasonable quantities of unsaturated

of the body, the adipose tissue and the liver. The adipose

fats, and their principal source is the liver. This desatu-

tissue is usually called fat deposits, or simply tissue fat.

ration is accomplished by a dehydrogenase in the liver

The major function of adipose tissue is storage of

cells.

triglycerides until they are needed to provide energy

elsewhere in the body. A subsidiary function is to

provide heat insulation for the body, as discussed in

Use of Triglycerides

Chapter 73.

for Energy: Formation

Fat Cells

(Adipocytes). The fat cells

(adipocytes) of

of Adenosine Triphosphate

adipose tissue are modified fibroblasts that store almost

About 40 per cent of the calories in a typical American

pure triglycerides in quantities as great as 80 to 95 per

diet are derived from fats, which is almost equal to the

cent of the entire cell volume. Triglycerides inside the

calories derived from carbohydrates. Therefore, the use

fat cells are generally in a liquid form. When the tissues

of fats by the body for energy is as important as the use

are exposed to prolonged cold, the fatty acid chains of

of carbohydrates is. In addition, many of the carbohy-

the cell triglycerides, over a period of weeks, become

drates ingested with each meal are converted into

either shorter or more unsaturated to decrease their

triglycerides, then stored, and used later in the form of

melting point, thereby always allowing the fat to remain

fatty acids released from the triglycerides for energy.

in a liquid state. This is particularly important, because

only liquid fat can be hydrolyzed and transported from

Hydrolysis of Triglycerides. The first stage in using triglyc-

the cells.

erides for energy is their hydrolysis into fatty acids and

Fat cells can synthesize very small amounts of fatty

glycerol. Then, both the fatty acids and the glycerol are

acids and triglycerides from carbohydrates; this function

transported in the blood to the active tissues, where they

supplements the synthesis of fat in the liver, as discussed

will be oxidized to give energy. Almost all cells—with

later in the chapter.

some exceptions, such as brain tissue and red blood

cells—can use fatty acids for energy.

Exchange of Fat Between the Adipose Tissue and the Blood—

Glycerol, on entering the active tissue, is immediately

Tissue Lipases. As discussed earlier, large quantities of

changed by intracellular enzymes into glycerol-3-

lipases are present in adipose tissue. Some of these

phosphate, which enters the glycolytic pathway for

enzymes catalyze the deposition of cell triglycerides

glucose breakdown and is thus used for energy. Before

from the chylomicrons and lipoproteins. Others, when

the fatty acids can be used for energy, they must be

activated by hormones, cause splitting of the triglyc-

processed further in the following way.

erides of the fat cells to release free fatty acids. Because

of the rapid exchange of fatty acids, the triglycerides in

Entry of Fatty Acids into Mitochondria. Degradation and oxi-

fat cells are renewed about once every 2 to 3 weeks,

dation of fatty acids occur only in the mitochondria.

which means that the fat stored in the tissues today is

Therefore, the first step for the use of fatty acids is

not the same fat that was stored last month, thus empha-

their transport into the mitochondria. This is a carrier-

sizing the dynamic state of storage fat.

mediated process that uses carnitine as the carrier sub-

stance. Once inside the mitochondria, fatty acids split

Liver Lipids

away from carnitine and are degraded and oxidized.

The principal functions of the liver in lipid metabolism

Degradation of Fatty Acids to Acetyl Coenzyme A by Beta-

are to (1) degrade fatty acids into small compounds that

Oxidation. The fatty acid molecule is degraded in the

Chapter 68

Lipid Metabolism

843

Thiokinase

(1) RCH₂CH₂CH₂COOH + CoA + ATP

RCH₂CH₂CH₂COCoA + AMP + Pyrophosphate

(Fatty acid)

(Fatty acyl-CoA)

Acyl dehydrogenase

(2) RCH₂CH₂CH₂COCoA + FAD

RCH₂CH=CHCOCoA + FADH₂

(Fatty acyl-CoA)

Enoyl hydrase

(3) RCH₂CH=CHCOCoA + H₂O

RCH₂CHOHCH₂COCoA

b-Hydroxyacyl

(4) RCH2CHOHCH2COCoA + NAD+

RCH₂COCH₂COCoA + NADH + H⁺

dehydrogenase

Thiolase

(5) RCH

RCH₂COCoA + CH₃COCoA

2COCH2COCoA + CoA

(Fatty acyl-CoA) (Acetyl-CoA)

Figure 68-1

Beta-oxidation of fatty acids to yield acetyl coenzyme A.

mitochondria by progressive release of two-carbon seg-

Thus, after initial degradation of fatty acids to acetyl-

ments in the form of acetyl coenzyme A (acetyl-CoA).

CoA, their final breakdown is precisely the same as that

This process, which is shown in Figure 68-1, is called the

of the acetyl-CoA formed from pyruvic acid during the

beta-oxidation process for degradation of fatty acids.

metabolism of glucose. And the extra hydrogen atoms

To understand the essential steps in the beta-

are also oxidized by the same chemiosmotic oxidative

oxidation process, note that in equation 1 the first step

system of the mitochondria that is used in carbohydrate

is combination of the fatty acid molecule with coenzyme

oxidation, liberating large amounts of adenosine

A (CoA) to form fatty acyl-CoA. In equations 2, 3, and

triphosphate (ATP).

4, the beta carbon (the second carbon from the right) of

the fatty acyl-CoA binds with an oxygen molecule—that

Tremendous Amounts of ATP Are Formed by Oxidation of Fatty

is, the beta carbon becomes oxidized.

Acids. In Figure 68-1, note that the 4 separate hydrogen

Then, in equation

5, the right-hand two-carbon

atoms released each time a molecule of acetyl-CoA is

portion of the molecule is split off to release acetyl-CoA

split from the fatty acid chain are released in the forms

into the cell fluid. At the same time, another CoA mol-

FADH₂, NADH, and H⁺. Therefore, for every stearic

ecule binds at the end of the remaining portion of the

fatty acid molecule that is split to form 9 acetyl-CoA

fatty acid molecule, and this forms a new fatty acyl-CoA

molecules, 32 extra hydrogen atoms are removed. In

molecule; this time, however, the molecule is two carbon

addition, for each of the 9 molecules of acetyl-CoA that

atoms shorter because of the loss of the first acetyl-CoA

are subsequently degraded by the citric acid cycle, 8

from its terminal end.

more hydrogen atoms are removed, making another 72

Next, this shorter fatty acyl-CoA enters into equation

hydrogens. This makes a total of 104 hydrogen atoms

2 and progresses through equations 3, 4, and 5 to release

eventually released by the degradation of each stearic

still another acetyl-CoA molecule, thus shortening the

acid molecule. Of this group, 34 are removed from

original fatty acid molecule by another two carbons. In

the degrading fatty acids by flavoproteins, and 70 are

addition to the released acetyl-CoA molecules, four

removed by nicotinamide adenine dinucleotide (NAD⁺)

atoms of hydrogen are released from the fatty acid mol-

as NADH and H⁺.

ecule at the same time, entirely separate from the

These two groups of hydrogen atoms are oxidized in

acetyl-CoA.

the mitochondria, as discussed in Chapter 67, but they

enter the oxidative system at different points, so that

Oxidation of Acetyl-CoA. The acetyl-CoA molecules

1 molecule of ATP is synthesized for each of the 34

formed by beta-oxidation of fatty acids in the mito-

flavoprotein hydrogens, and 1.5 molecules of ATP are

chondria enter immediately into the citric acid cycle (see

synthesized for each of the 70 NADH and H⁺ hydro-

Chapter 67), combining first with oxaloacetic acid to

gens. This makes 34 plus 105, or a total of 139 molecules

form citric acid, which then is degraded into carbon

of ATP formed by the oxidation of hydrogen derived

dioxide and hydrogen atoms. The hydrogen is subse-

from each molecule of stearic acid. Another 9 molecules

quently oxidized by the chemiosmotic oxidative system

of ATP are formed in the citric acid cycle itself (sepa-

of the mitochondria, which was also explained in

rate from the ATP released by the oxidation of hydro-

Chapter 67. The net reaction in the citric acid cycle for

gen), one for each of the

9 acetyl-CoA molecules

each molecule of acetyl-CoA is the following:

metabolized. Thus, a total of 148 molecules of ATP are

formed during the complete oxidation of 1 molecule of

CH3COCo-A + Oxaloacetic acid+ 3H2O + ADP

stearic acid. However, two high-energy bonds are con-

Citric acid cycle

sumed in the initial combination of CoA with the stearic

æææææææÆ

acid molecule, making a net gain of 146 molecules of

2CO2+ 8H + HCo-A + ATP + Oxaloacetic acid

ATP.

844

Unit XIII

Metabolism and Temperature Regulation

Formation of Acetoacetic Acid

carbohydrates are metabolized—in starvation and with

in the Liver and Its Transport

a high-fat diet because carbohydrates are not available,

and in diabetes because insulin is not available to cause

in the Blood

glucose transport into the cells.

A large share of the initial degradation of fatty acids

When carbohydrates are not used for energy, almost

occurs in the liver, especially when excessive amounts

all the energy of the body must come from metabolism

of lipids are being used for energy. However, the liver

of fats. We shall see later in the chapter that the unavail-

uses only a small proportion of the fatty acids for its own

ability of carbohydrates automatically increases the rate

intrinsic metabolic processes. Instead, when the fatty

of removal of fatty acids from adipose tissues; in addi-

acid chains have been split into acetyl-CoA, two mole-

tion, several hormonal factors—such as increased secre-

cules of acetyl-CoA condense to form one molecule of

tion of glucocorticoids by the adrenal cortex, increased

acetoacetic acid, which is then transported in the blood

secretion of glucagon by the pancreas, and decreased

to the other cells throughout the body, where it is used

secretion of insulin by the pancreas—further enhance

for energy. The chemical processes are the following:

the removal of fatty acids from the fat tissues. As a

result, tremendous quantities of fatty acids become

available (1) to the peripheral tissue cells to be used for

liver cells

2CH3COCo-A + H2O

æææææÆ¨ææææ æ

energy and (2) to the liver cells, where much of the fatty

other cells

acids is converted to ketone bodies.

Acetyl

CoA

The ketone bodies pour out of the liver to be carried

CH3COCH2COOH

2HCo-A

to the cells. For several reasons, the cells are limited in

the amount of ketone bodies that can be oxidized; the

Acetoacetic acid

most important reason is the following: One of the prod-

ucts of carbohydrate metabolism is the oxaloacetate that

Part of the acetoacetic acid is also converted into

is required to bind with acetyl-CoA before it can be

b-hydroxybutyric acid, and minute quantities are

processed in the citric acid cycle. Therefore, deficiency

converted into acetone in accord with the following

of oxaloacetate derived from carbohydrates limits the

reactions:

entry of acetyl-CoA into the citric acid cycle, and when

there is a simultaneous outpouring of large quantities

of acetoacetic acid and other ketone bodies from the

liver, the blood concentrations of acetoacetic acid and

CH₃

C CH₂

C OH

b-hydroxybutyric acid sometimes rise to as high as

20 times normal, thus leading to extreme acidosis, as

Acetoacetic acid

explained in Chapter 30.

+ 2H

The acetone that is formed during ketosis is a volatile

-CO₂

substance, some of which is blown off in small quanti-

ties in the expired air of the lungs. This gives the breath

an acetone smell that is frequently used as a diagnostic

criterion of ketosis.

CH₃

CH CH₂

C OH

CH₃

C CH₃

b-Hydroxybutyric acid

Acetone

Adaptation to a High-Fat Diet. When changing slowly from

a carbohydrate diet to an almost completely fat diet, a

person’s body adapts to use far more acetoacetic acid

The acetoacetic acid, b-hydroxybutyric acid, and

than usual, and in this instance, ketosis normally does

acetone diffuse freely through the liver cell membranes

not occur. For instance, the Inuit (Eskimos), who some-

and are transported by the blood to the peripheral

times live almost entirely on a fat diet, do not develop

tissues. Here they again diffuse into the cells, where

ketosis. Undoubtedly, several factors, none of which is

reverse reactions occur and acetyl-CoA molecules are

clear, enhance the rate of acetoacetic acid metabolism

formed. These in turn enter the citric acid cycle and are

by the cells. After a few weeks, even the brain cells,

oxidized for energy, as already explained.

which normally derive almost all their energy from

Normally, the acetoacetic acid and b-hydroxybutyric

glucose, can derive 50 to 75 per cent of their energy from

acid that enter the blood are transported so rapidly to

fats.

the tissues that their combined concentration in the

plasma seldom rises above 3 mg/dl. Yet despite this

small concentration in the blood, large quantities are

Synthesis of Triglycerides

actually transported, as is also true for free fatty acid

from Carbohydrates

transport. The rapid transport of both these substances

results from their high solubility in the membranes of

Whenever a greater quantity of carbohydrates enters

the target cells, which allows almost instantaneous dif-

the body than can be used immediately for energy or

fusion into the cells.

can be stored in the form of glycogen, the excess is

rapidly converted into triglycerides and stored in this

Ketosis in Starvation, Diabetes, and Other Diseases. The con-

form in the adipose tissue.

centrations of acetoacetic acid, b-hydroxybutyric acid,

In human beings, most triglyceride synthesis occurs in

and acetone occasionally rise to levels many times

the liver, but minute quantities are also synthesized in

normal in the blood and interstitial fluids; this condition

the adipose tissue itself. The triglycerides formed in the

is called ketosis, because acetoacetic acid is a keto acid.

liver are transported mainly in very low density lipopro-

The three compounds are called ketone bodies. Ketosis

teins to the adipose tissue, where they are stored.

occurs especially in starvation, in diabetes mellitus, and

sometimes even when a person’s diet is composed

Conversion of Acetyl-CoA into Fatty Acids. The first step

almost entirely of fat. In all these states, essentially no

in the synthesis of triglycerides is conversion of

Chapter 68

Lipid Metabolism

845

carbohydrates into acetyl-CoA. As explained in

Efficiency of Carbohydrate Conversion into Fat. During triglyc-

Chapter 67, this occurs during the normal degradation

eride synthesis, only about 15 per cent of the original

of glucose by the glycolytic system. Because fatty acids

energy in the glucose is lost in the form of heat; the

are actually large polymers of acetic acid, it is easy to

remaining 85 per cent is transferred to the stored

understand how acetyl-CoA can be converted into fatty

triglycerides.

acids. However, the synthesis of fatty acids from acetyl-

CoA is not achieved by simply reversing the oxidative

Importance of Fat Synthesis and Storage. Fat synthesis from

degradation described earlier. Instead, this occurs by the

carbohydrates is especially important for two reasons:

two-step process shown in Figure 68-2, using malonyl-

1. The ability of the different cells of the body to

CoA and NADPH as the principal intermediates in the

store carbohydrates in the form of glycogen is

polymerization process.

generally slight; a maximum of only a few hundred

grams of glycogen can be stored in the liver, the

Combination of Fatty Acids with a-Glycerophosphate to Form

skeletal muscles, and all other tissues of the body

Triglycerides. Once the synthesized fatty acid chains have

put together. In contrast, many kilograms of fat

grown to contain 14 to 18 carbon atoms, they bind with

can be stored. Therefore, fat synthesis provides a

glycerol to form triglycerides. The enzymes that cause

means by which the energy of excess ingested

this conversion are highly specific for fatty acids with

carbohydrates (and proteins) can be stored for

chain lengths of 14 carbon atoms or greater, a factor that

later use. Indeed, the average person has almost

controls the physical quality of the triglycerides stored

150 times as much energy stored in the form of fat

in the body.

as stored in the form of carbohydrate.

As shown in Figure 68-3, the glycerol portion of

2. Each gram of fat contains almost two and a half

triglycerides is furnished by a-glycerophosphate, which

times the calories of energy contained by each

is another product derived from the glycolytic scheme

gram of glycogen. Therefore, for a given weight

of glucose degradation. This mechanism is discussed in

gain, a person can store several times as much

Chapter 67.

energy in the form of fat as in the form of

carbohydrate, which is exceedingly important when

an animal must be highly motile to survive.

Failure to Synthesize Fats from Carbohydrates in the Absence of

Insulin. When no insulin is available, as occurs in serious

Step 1:

diabetes mellitus, fats are poorly synthesized, if at all,

+ ATP

CH₃COCoA + CO₂

for the following reasons: First, when insulin is not avail-

(Acetyl-CoA carboxylase)

able, glucose does not enter the fat and liver cells satis-

factorily, so that little of the acetyl-CoA and NADPH

COOH

needed for fat synthesis can be derived from glucose.

Second, lack of glucose in the fat cells greatly reduces

+ ADP + PO_4-3

the availability of a-glycerophosphate, which also

makes it difficult for the tissues to form triglycerides.

CoA

Malonyl-CoA

Synthesis of Triglycerides

Step 2:

from Proteins

1 Acetyl-CoA + Malonyl-CoA + 16NADPH + 16H⁺

1 Steric acid + 8CO₂ + 9CoA + 16NADP⁺+ 7H₂

Many amino acids can be converted into acetyl-CoA, as

discussed in Chapter 69. The acetyl-CoA can then be

synthesized into triglycerides. Therefore, when people

Figure 68-2

have more proteins in their diets than their tissues can

use as proteins, a large share of the excess is stored as

Synthesis of fatty acids.

fat.

Glucose

Pentose

Glycolytic

phosphate

pathway

a-Glycerophosphate + Acetyl-CoA + NADH + H⁺

NADPH + H⁺

Fatty acids

Figure 68-3

Triglycerides

Overall schema for synthesis of

triglycerides from glucose.

846

Unit XIII

Metabolism and Temperature Regulation

Regulation of Energy

Probably the most dramatic increase that occurs in fat

utilization is that observed during heavy exercise. This

Release from Triglycerides

results almost entirely from release of epinephrine and

Carbohydrates Are Preferred over Fats for Energy When Excess

norepinephrine by the adrenal medullae during exer-

Carbohydrates Are Available. When excess quantities of

cise, as a result of sympathetic stimulation. These two

carbohydrates are available in the body, carbohydrates

hormones directly activate hormone-sensitive triglyc-

are used preferentially over triglycerides for energy.

eride lipase, which is present in abundance in the fat

There are several reasons for this “fat-sparing” effect of

cells, and this causes rapid breakdown of triglycerides

carbohydrates. One of the most important is the fol-

and mobilization of fatty acids. Sometimes the free fatty

lowing: The fats in adipose tissue cells are present in two

acid concentration in the blood of an exercising person

forms: stored triglycerides and small quantities of free

rises as much as eightfold, and the use of these fatty

fatty acids. They are in constant equilibrium with each

acids by the muscles for energy is correspondingly

other. When excess quantities of a-glycerophosphate are

increased. Other types of stress that activate the sym-

present (which occurs when excess carbohydrates are

pathetic nervous system can also increase fatty acid

available), the excess a-glycerophosphate binds the

mobilization and utilization in a similar manner.

free fatty acids in the form of stored triglycerides. As a

Stress also causes large quantities of corticotropin to

result, the equilibrium between free fatty acids and

be released by the anterior pituitary gland, and this

triglycerides shifts toward the stored triglycerides;

causes the adrenal cortex to secrete extra quantities of

consequently, only minute quantities of fatty acids

glucocorticoids. Both corticotropin and glucocorticoids

are available to be used for energy. Because a-

activate either the same hormone-sensitive triglyceride

glycerophosphate is an important product of glucose

lipase as that activated by epinephrine and norepi-

metabolism, the availability of large amounts of glucose

nephrine or a similar lipase. When corticotropin and

automatically inhibits the use of fatty acids for energy.

glucocorticoids are secreted in excessive amounts for

Second, when carbohydrates are available in excess,

long periods, as occurs in the endocrine condition called

fatty acids are synthesized more rapidly than they are

Cushing’s disease, fats are frequently mobilized to such

degraded. This effect is caused partially by the large

a great extent that ketosis results. Corticotropin and

quantities of acetyl-CoA formed from the carbohy-

glucocorticoids are then said to have a ketogenic effect.

drates and by the low concentration of free fatty acids

Growth hormone has an effect similar to but weaker

in the adipose tissue, thus creating conditions appropri-

than that of corticotropin and glucocorticoids in

ate for the conversion of acetyl-CoA into fatty acids.

activating hormone-sensitive lipase. Therefore, growth

An even more important effect that promotes the

hormone can also have a mild ketogenic effect.

conversion of carbohydrates to fats is the following: The

Finally, thyroid hormone causes rapid mobilization

first step, which is the rate-limiting step, in the synthesis

of fat, which is believed to result indirectly from an

of fatty acids is carboxylation of acetyl-CoA to form

increased overall rate of energy metabolism in all cells

malonyl-CoA. The rate of this reaction is controlled

of the body under the influence of this hormone. The

primarily by the enzyme acetyl-CoA carboxylase, the

resulting reduction in acetyl-CoA and other intermedi-

activity of which is accelerated in the presence of inter-

ates of both fat and carbohydrate metabolism in the

mediates of the citric acid cycle. When excess carbohy-

cells is a stimulus to fat mobilization.

drates are being used, these intermediates increase,

The effects of the different hormones on metabolism

automatically causing increased synthesis of fatty acids.

are discussed further in the chapters dealing with each

Thus, an excess of carbohydrates in the diet not only

hormone.

acts as a fat-sparer but also increases fat stores. In fact,

all the excess carbohydrates not used for energy or

stored in the small glycogen deposits of the body are

Obesity

converted to fat for storage.

Obesity means deposition of excess fat in the body. This

subject is discussed in Chapter 71 in relation to dietary

Acceleration of Fat Utilization for Energy in the Absence of Car-

balances, but briefly, it is caused by the ingestion of

bohydrates. All the fat-sparing effects of carbohydrates

greater amounts of food than can be used by the body

are lost and actually reversed when carbohydrates are

for energy. The excess food, whether fats, carbohydrates,

not available. The equilibrium shifts in the opposite

or proteins, is then stored almost entirely as fat in the

direction, and fat is mobilized from the adipose cells and

adipose tissue, to be used later for energy.

used for energy in place of carbohydrates.

Strains of rats have been found in which hereditary

Also important are several hormonal changes that

obesity occurs. In at least one of these, the obesity is

take place to promote rapid fatty acid mobilization from

caused by ineffective mobilization of fat from the

adipose tissue. Among the most important of these is

adipose tissue by tissue lipase, while synthesis and

a marked decrease in pancreatic secretion of insulin

storage of fat continue normally. Such a one-way

caused by the absence of carbohydrates. This not only

process causes progressive enhancement of the fat

reduces the rate of glucose utilization by the tissues

stores, resulting in severe obesity.

but also decreases fat storage, which further shifts the

equilibrium in favor of fat metabolism in place of

carbohydrates.

Phospholipids and

Hormonal Regulation of Fat Utilization. At least seven of

Cholesterol

the hormones secreted by the endocrine glands have

significant effects on fat utilization. Some important

Phospholipids

hormonal effects on fat metabolism—in addition to

insulin lack, discussed in the previous paragraph—are

The major types of body phospholipids are lecithins,

noted here.

cephalins, and sphingomyelin; their typical chemical

Chapter 68

Lipid Metabolism

847

CH₃

(CH₂)₇

CH CH

(CH₂)₇

CH₃

(CH₂)

CH₃

(CH₂)₁₆

CH₃

H₂C

CH₂

N⁺

CH₃

A lecithin

Figure 68-5

(CH₂)₇

CH CH

(CH₂)₇

Cholesterol.

(CH₂)₁₆

CH₃

rate of fat metabolism because, when triglycerides are

deposited in the liver, the rate of phospholipid forma-

tion increases. Also, certain specific chemical substances

H₂C

CH₂

N⁺H3

are needed for the formation of some phospholipids.

For instance, choline, either obtained in the diet or syn-

thesized in the body, is needed for the formation of

A cephalin

lecithin, because choline is the nitrogenous base of the

lecithin molecule. Also, inositol is needed for the for-

CH₃

mation of some cephalins.

(CH₂)₁₂

Specific Uses of Phospholipids. Several functions of the

phospholipids are the following:

(1) Phospholipids

are an important constituent of lipoproteins in the

blood and are essential for the formation and function

of most of these; in their absence, serious abnormalities

of transport of cholesterol and other lipids can occur.

(CH₂)₁₆

CH₃

(2) Thromboplastin, which is needed to initiate the clot-

ting process, is composed mainly of one of the cephalins.

(3) Large quantities of sphingomyelin are present in the

O CH₂

CH₂

N⁺

nervous system; this substance acts as an electrical insu-

CH₃

lator in the myelin sheath around nerve fibers. (4) Phos-

pholipids are donors of phosphate radicals when these

Sphingomyelin

radicals are needed for different chemical reactions in

the tissues. (5) Perhaps the most important of all the

functions of phospholipids is participation in the for-

mation of structural elements—mainly membranes—in

Figure 68-4

cells throughout the body, as discussed in the next

Typical phospholipids.

section of this chapter in connection with a similar func-

tion for cholesterol.

formulas are shown in Figure

68-4. Phospholipids

Cholesterol

always contain one or more fatty acid molecules and

one phosphoric acid radical, and they usually contain a

Cholesterol, the formula of which is shown in Figure

nitrogenous base. Although the chemical structures of

68-5, is present in the diets of all people, and it can be

phospholipids are somewhat variant, their physical

absorbed slowly from the gastrointestinal tract into the

properties are similar because they are all lipid soluble,

intestinal lymph. It is highly fat soluble but only slightly

transported in lipoproteins, and used throughout the

soluble in water. It is specifically capable of forming

body for various structural purposes, such as in cell

esters with fatty acids. Indeed, about 70 per cent of the

membranes and intracellular membranes.

cholesterol in the lipoproteins of the plasma is in the

form of cholesterol esters.

Formation of Phospholipids. Phospholipids are synthesized

in essentially all cells of the body, although certain cells

Formation of Cholesterol. Besides the cholesterol absorbed

have a special ability to form great quantities of them.

each day from the gastrointestinal tract, which is called

Probably 90 per cent are formed in the liver cells; sub-

exogenous cholesterol, an even greater quantity is

stantial quantities are also formed by the intestinal

formed in the cells of the body, called endogenous cho-

epithelial cells during lipid absorption from the gut.

lesterol. Essentially all the endogenous cholesterol that

The rate of phospholipid formation is governed to

circulates in the lipoproteins of the plasma is formed by

some extent by the usual factors that control the overall

the liver, but all other cells of the body form at least

848

Unit XIII

Metabolism and Temperature Regulation

some cholesterol, which is consistent with the fact that

A large amount of cholesterol is precipitated in the

many of the membranous structures of all cells are par-

corneum of the skin. This, along with other lipids, makes

tially composed of this substance.

the skin highly resistant to the absorption of water-

The basic structure of cholesterol is a sterol nucleus.

soluble substances and to the action of many chemical

This is synthesized entirely from multiple molecules of

agents, because cholesterol and the other skin lipids are

acetyl-CoA. In turn, the sterol nucleus can be modified

highly inert to acids and to many solvents that might

by means of various side chains to form (1) cholesterol;

otherwise easily penetrate the body. Also, these lipid

(2) cholic acid, which is the basis of the bile acids formed

substances help prevent water evaporation from the

in the liver; and (3) many important steroid hormones

skin; without this protection, the amount of evaporation

secreted by the adrenal cortex, the ovaries, and the

can be 5 to 10 liters per day (as occurs in burn patients

testes (these hormones are discussed in later chapters).

who have lost their skin) instead of the usual 300 to

400 milliliters.

Factors That Affect Plasma Cholesterol Concentration—Feed-

back Control of Body Cholesterol. Among the important

Cellular Structural Functions of

factors that affect plasma cholesterol concentration are

Phospholipids and Cholesterol—

the following:

An increase in the amount of cholesterol ingested

Especially for Membranes

each day increases the plasma concentration

The previously mentioned uses of phospholipids and

slightly. However, when cholesterol is ingested,

cholesterol are of only minor importance in comparison

the rising concentration of cholesterol inhibits the

with their function of forming specialized structures,

most essential enzyme for endogenous synthesis

mainly membranes, in all cells of the body. In

of cholesterol, 3-hydroxy-3-methylglutaryl CoA

Chapter 2, it was pointed out that large quantities of

reductase, thus providing an intrinsic feedback

phospholipids and cholesterol are present in both the

control system to prevent an excessive increase

cell membrane and the membranes of the internal

in plasma cholesterol concentration. As a result,

organelles of all cells. It is also known that the ratio

plasma cholesterol concentration usually is not

of membrane cholesterol to phospholipids is especially

changed upward or downward more than ±15 per

important in determining the fluidity of the cell

cent by altering the amount of cholesterol in the

membranes.

diet, although the response of individuals differs

For membranes to be formed, substances that are not

markedly.

soluble in water must be available. In general, the only

A highly saturated fat diet increases blood

substances in the body that are not soluble in water

cholesterol concentration 15 to 25 per cent. This

(besides the inorganic substances of bone) are the lipids

results from increased fat deposition in the liver,

and some proteins. Thus, the physical integrity of cells

which then provides increased quantities of

everywhere in the body is based mainly on phospho-

acetyl-CoA in the liver cells for the production

lipids, cholesterol, and certain insoluble proteins. The

of cholesterol. Therefore, to decrease the blood

polar charges on the phospholipids also reduce the

cholesterol concentration, it is usually just as

interfacial tension between the cell membranes and

important, if not more important, to maintain a diet

the surrounding fluids.

low in saturated fat as to maintain a diet low in

Another fact that indicates the importance of phos-

cholesterol.

pholipids and cholesterol for the formation of structural

Ingestion of fat containing highly unsaturated fatty

elements of the cells is the slow turnover rates of

acids usually depresses the blood cholesterol

these substances in most nonhepatic tissues—turnover

concentration a slight to moderate amount. The

rates measured in months or years. For instance, their

mechanism of this effect is unknown, despite the

function in brain cells to provide memory processes

fact that this observation is the basis of much

is related mainly to their indestructible physical

present-day dietary strategy.

properties.

Lack of insulin or thyroid hormone increases the

blood cholesterol concentration, whereas excess

thyroid hormone decreases the concentration.

Atherosclerosis

These effects are probably caused mainly by

changes in the degree of activation of specific

Atherosclerosis is a disease of the large and intermedi-

enzymes responsible for the metabolism of lipid

ate-sized arteries in which fatty lesions called athero-

substances.

matous plaques develop on the inside surfaces of the

arterial walls. Arteriosclerosis, in contrast, is a general

Specific Uses of Cholesterol in the Body. By far the most

term that refers to thickened and stiffened blood vessels

abundant nonmembranous use of cholesterol in the

of all sizes.

body is to form cholic acid in the liver. As much as 80

One abnormality that can be measured very early

per cent of cholesterol is converted into cholic acid. As

in blood vessels that later become atherosclerotic is

explained in Chapter 70, this is conjugated with other

damage to the vascular endothelium. This, in turn,

substances to form bile salts, which promote digestion

increases the expression of adhesion molecules on

and absorption of fats.

endothelial cells and decreases their ability to release

A small quantity of cholesterol is used by (1) the

nitric oxide and other substances that help prevent

adrenal glands to form adrenocortical hormones, (2)

adhesion of macromolecules, platelets, and monocytes

the ovaries to form progesterone and estrogen, and (3)

to the endothelium. After damage to the vascular

the testes to form testosterone. These glands can

endothelium occurs, circulating monocytes and lipids

also synthesize their own sterols and then form hor-

(mostly low-density lipoproteins) begin to accumulate

mones from them, as discussed in the chapters on

at the site of injury (Figure 68-6A). The monocytes cross

endocrinology.

the endothelium, enter the intima of the vessel wall, and

Chapter 68

Lipid Metabolism

849

Blood monocyte

Monocyte

adhered to

Arterial

epithelium

lumen

Monocyte

migrating

into intima

Macrophage

foam cell

Damaged

Adhesion

endothelium

molecule

Growth/

inflammatory

Arterial

factors

intima

Receptor

Lipid

droplets

Lipoprotein

particle

Endothelium

Intima Media

Normal

Smooth

artery

muscle

cells

Adventitia

Small

plaque

Thrombosis

of a ruptured

plaque

Large

plaque

Figure 68-6

Development of atherosclerotic plaque. A, Attachment of a monocyte to an adhesion molecule on a damaged endothelial cell of an artery.

The monocyte then migrates through the endothelium into the intimal layer of the arterial wall and is transformed into a macrophage. The

macrophage then ingests and oxidizes lipoprotein molecules, becoming a macrophage foam cell. The foam cells release substances that

cause inflammation and growth of the intimal layer. B, Additional accumulation of macrophages and growth of the intima cause the plaque

to grow larger and accumulate lipids. Eventually, the plaque could occlude the vessel or rupture, causing the blood in the artery to coag-

ulate and form a thrombus. (Modified from Libby P: Inflammation in atherosclerosis. Nature 420:868, 2002.)

differentiate to become macrophages, which then

arterial wall. The lipid deposits plus the cellular prolif-

ingest and oxidize the accumulated lipoproteins,

eration can become so large that the plaque bulges into

giving the macrophages a foamlike appearance. These

the lumen of the artery and greatly reduces blood

macrophage foam cells then aggregate on the blood

flow, sometimes completely occluding the vessel. Even

vessel and form a visible fatty streak.

without occlusion, the fibroblasts of the plaque eventu-

With time, the fatty streaks grow larger and coalesce,

ally deposit extensive amounts of dense connective

and the surrounding fibrous and smooth muscle tissues

tissue; sclerosis

(fibrosis) becomes so great that the

proliferate to form larger and larger plaques (see Figure

arteries become stiff and unyielding. Still later, calcium

68-6B). Also, the macrophages release substances that

salts often precipitate with the cholesterol and other

cause inflammation and further proliferation of smooth

lipids of the plaques, leading to bony-hard calcifications

muscle and fibrous tissue on the inside surfaces of the

that can make the arteries rigid tubes. Both of these

850

Unit XIII

Metabolism and Temperature Regulation

later stages of the disease are called “hardening of the

high-density to low-density lipoproteins, the likelihood

arteries.”

of developing atherosclerosis is greatly reduced.

Atherosclerotic arteries lose most of their distensi-

bility, and because of the degenerative areas in their

Other Major Risk Factors

walls, they are easily ruptured. Also, where the plaques

protrude into the flowing blood, their rough surfaces

for Atherosclerosis

can cause blood clots to develop, with resultant throm-

In some people with perfectly normal levels of choles-

bus or embolus formation (see Chapter 36), leading to

terol and lipoproteins, atherosclerosis still develops.

a sudden blockage of all blood flow in the artery.

Some of the factors that are known to predispose to ath-

Almost half of all deaths in the United States and

erosclerosis are (1) physical inactivity and obesity, (2)

Europe are due to vascular disease. About two thirds of

diabetes mellitus, (3) hypertension, (4) hyperlipidemia,

these deaths are caused by thrombosis of one or more

and (5) cigarette smoking.

coronary arteries. The remaining one third are caused

Hypertension, for example, increases the risk for

by thrombosis or hemorrhage of vessels in other organs

atherosclerotic coronary artery disease by at least

of the body, especially the brain (causing strokes), but

twofold. Likewise, a person with diabetes mellitus has,

also the kidneys, liver, gastrointestinal tract, limbs, and

on average, more than a twofold increased risk of devel-

so forth.

oping coronary artery disease. When hypertension and

diabetes mellitus occur together, the risk for coronary

artery disease is increased by more than eightfold. And

Basic Causes of Atherosclerosis—

when hypertension, diabetes mellitus, and hyperlipemia

The Roles of Cholesterol

are all present, the risk for atherosclerotic coronary

and Lipoproteins

artery disease is increased almost 20-fold, suggesting

that these factors interact in a synergistic manner to

Increased Low-Density Lipoproteins. An important factor

increase the risk of developing atherosclerosis. In many

in causing atherosclerosis is a high blood plasma con-

overweight and obese patients, these three risk factors

centration of cholesterol in the form of low-density

do occur together, greatly increasing their risk for

lipoproteins. The plasma concentration of these high-

atherosclerosis, which in turn may lead to heart attack,

cholesterol low-density lipoproteins is increased by

stroke, and kidney disease.

several factors, including eating highly saturated fat in

In early and middle adulthood, men are more likely

the daily diet, obesity, and physical inactivity. To a lesser

to develop atherosclerosis than are women of compa-

extent, eating excess cholesterol may also raise plasma

rable age, suggesting that male sex hormones might be

levels of low-density lipoproteins.

atherogenic or, conversely, that female sex hormones

An interesting example occurs in rabbits, which

might be protective.

normally have low plasma cholesterol concentrations

Some of these factors cause atherosclerosis by

because of their vegetarian diet. Simply feeding these

increasing the concentration of low-density lipoproteins

animals large quantities of cholesterol as part of their

in the plasma. Others, such as hypertension, lead to

daily diet leads to serious atherosclerotic plaques

atherosclerosis by causing damage to the vascular en-

throughout their arterial systems.

dothelium and other changes in the vascular tissues that

predispose to cholesterol deposition.

Familial Hypercholesterolemia. This is a disease in which

To add to the complexity of atherosclerosis, experi-

the person inherits defective genes for the formation of

mental studies suggest that excess blood levels of iron

low-density lipoprotein receptors on the membrane sur-

can lead to atherosclerosis, perhaps by forming free rad-

faces of the body’s cells. In the absence of these recep-

icals in the blood that damage the vessel walls. About

tors, the liver cannot absorb either intermediate-density

one quarter of all people have a special type of low-

or low-density lipoproteins. Without this absorption, the

density lipoprotein called lipoprotein(a), containing an

cholesterol machinery of the liver cells goes on a

additional protein, apoprotein(a), that almost doubles

rampage, producing new cholesterol; it is no longer

the incidence of atherosclerosis. The precise mecha-

responsive to the feedback inhibition of too much

nisms of these atherogenic effects have yet to be

plasma cholesterol. As a result, the number of very low

discovered.

density lipoproteins released by the liver into the

plasma increases immensely.

Prevention of Atherosclerosis

Patients with full-blown familial hypercholes-

terolemia have blood cholesterol concentrations of 600

The most important measures to protect against the

to 1000 mg/dl, levels that are four to six times normal.

development of atherosclerosis and its progression to

Many of these people die before age 20 because of

serious vascular disease are (1) maintaining a healthy

myocardial infarction or other sequelae of atheroscle-

weight, being physically active, and eating a diet that

rotic blockage of blood vessels throughout the body.

contains mainly unsaturated fat with a low cholesterol

content; (2) preventing hypertension by maintaining a

Role of High-Density Lipoproteins in Preventing Atherosclerosis.

healthy diet and being physically active, or effectively

Much less is known about the function of high-density

controlling blood pressure with antihypertensive drugs

lipoproteins compared with that of low-density lipopro-

if hypertension does develop; (3) effectively controlling

teins. It is believed that high-density lipoproteins can

blood glucose with insulin treatment or other drugs if

actually absorb cholesterol crystals that are beginning

diabetes develops; and (4) avoiding cigarette smoking.

to be deposited in arterial walls. Whether this mecha-

Several types of drugs that lower plasma lipids and

nism is true or not, high-density lipoproteins do help

cholesterol have proved to be valuable in preventing

protect against the development of atherosclerosis.

atherosclerosis. Most of the cholesterol formed in the

Consequently, when a person has a high ratio of

liver is converted into bile acids and secreted in this

Chapter 68

Lipid Metabolism

851

form into the duodenum; then, more than 90 per cent of

Fromenty B, Robin MA, Igoudjil A, et al: The ins and outs

these same bile acids is reabsorbed in the terminal ileum

of mitochondrial dysfunction in NASH. Diabetes Metab

and used over and over again in the bile. Therefore, any

30:121, 2004.

agent that combines with the bile acids in the gastroin-

Gotto AM Jr, Brinton EA: Assessing low levels of high-

testinal tract and prevents their reabsorption into the

density lipoprotein cholesterol as a risk factor in coronary

circulation can decrease the total bile acid pool in the

heart disease: a working group report and update. J Am

circulating blood. This causes far more of the liver cho-

Coll Cardiol 43:717, 2004.

lesterol to be converted into new bile acids. Thus, simply

Grundy SM, Brewer HB Jr, Cleeman JI, et al: Definition of

eating oat bran, which binds bile acids and is a con-

metabolic syndrome: report of the National Heart, Lung,

stituent of many breakfast cereals, increases the pro-

and Blood Institute/American Heart Association confer-

portion of liver cholesterol that forms new bile acids

ence on scientific issues related to definition. Circulation

rather than forming new low-density lipoproteins and

109:433, 2004.

atherogenic plaques. Resin agents can also be used to

Haemmerle G, Zimmermann R, Zechner R: Letting lipids

bind bile acids in the gut and increase their fecal excre-

go: hormone-sensitive lipase. Curr Opin Lipidol 14:289,

tion, thereby reducing cholesterol synthesis by the liver.

2003.

Another group of drugs called statins competitively

Havel RJ, Hamilton RL: Hepatic catabolism of remnant

inhibits hydroxymethylglutaryl-coenzyme A

(HMG-

lipoproteins: where the action is. Arterioscler Thromb Vasc

CoA) reductase, a rate-limiting enzyme in the synthesis

Biol 24:213, 2004.

of cholesterol. This inhibition decreases cholesterol syn-

Hilgemann DW: Getting ready for the decade of the lipids.

thesis and increases low-density lipoprotein receptors in

Annu Rev Physiol 65:697, 2003.

the liver, usually causing a 25 to 50 per cent reduction

Horton JD, Goldstein JL, Brown MS: SREBPs: activators of

in plasma levels of low-density lipoproteins. The statins

the complete program of cholesterol and fatty acid syn-

may also have other beneficial effects that help prevent

thesis in the liver. J Clin Invest 109:1125, 2002.

atherosclerosis, such as attenuating vascular inflamma-

LaRosa JC, Gotto AM Jr: Past, present, and future standards

tion. These drugs are now widely used to treat patients

for management of dyslipidemia. Am J Med 116(Suppl

who have increased plasma cholesterol levels.

6A):3S, 2004.

In general, studies show that for each

1 mg/dl

Libby P: Inflammation in atherosclerosis. Nature 420:868,

decrease in low-density lipoprotein cholesterol in the

2002.

plasma, there is about a 2 per cent decrease in mortal-

Osterud B, Bjorklid E: Role of monocytes in atherogenesis.

ity from atherosclerotic heart disease. Therefore, appro-

Physiol Rev 83:1069, 2003.

priate preventive measures are valuable in decreasing

Rinaldo P, Matern D, Bennett MJ: Fatty acid oxidation dis-

heart attacks.

orders. Annu Rev Physiol 64:477, 2002.

Roden M: How free fatty acids inhibit glucose utilization in

human skeletal muscle. News Physiol Sci 19:92, 2004.

References

Ruderman NB, Saha AK, Kraegen EW: Malonyl CoA, AMP-

activated protein kinase, and adiposity. Endocrinology

144:5166, 2003.

Assmann G, Nofer JR: Atheroprotective effects of high-

Schonbeck U, Libby P: Inflammation, immunity, and HMG-

density lipoproteins. Annu Rev Med 54:321, 2003.

CoA reductase inhibitors: statins as antiinflammatory

Brown MS, Goldstein JL: A proteolytic pathway that con-

agents? Circulation 109(21 Suppl 1):II18, 2004.

trols the cholesterol content of membranes, cells, and

Spriet LL, Watt MJ: Regulatory mechanisms in the interac-

blood. Proc Natl Acad Sci U S A 96:11041, 1999.

tion between carbohydrate and lipid oxidation during

Casserly I, Topol E: Convergence of atherosclerosis and

exercise. Acta Physiol Scand 178:443, 2003.

Alzheimer’s disease: inflammation, cholesterol, and mis-

Unger RH: The physiology of cellular liporegulation. Annu

folded proteins. Lancet 363:1139, 2004.

Rev Physiol 65:333, 2003.

Fielding BA, Frayn KN: Lipid metabolism. Curr Opin

Lipidol 14:389, 2003.

C H A P T E R

Protein Metabolism

About three quarters of the body solids are proteins.

These include structural proteins, enzymes, nucleopro-

teins, proteins that transport oxygen, proteins of the

muscle that cause muscle contraction, and many other

types that perform specific intracellular and extracellu-

lar functions throughout the body.

The basic chemical properties that explain proteins’

diverse functions are so extensive that they

constitute a major portion of the entire discipline of

biochemistry. For this reason, the current discussion is confined to a few specific

aspects of protein metabolism that are important as background for other discus-

sions in this text.

Basic Properties

Amino Acids

The principal constituents of proteins are amino acids, 20 of which are present in

the body proteins in significant quantities. Figure 69-1 shows the chemical formu-

las of these 20 amino acids, demonstrating that they all have two features in

common: each amino acid has an acidic group (—COOH) and a nitrogen atom

attached to the molecule, usually represented by the amino group (—NH₂).

Peptide Linkages and Peptide Chains. In proteins, the amino acids are aggregated into

long chains by means of peptide linkages. The chemical nature of this linkage is

demonstrated by the following reaction:

NH₂

H NH

R CH CO OH + R' CH COOH

NH₂

R CH CO

NH + H₂O

CH COOH

Note in this reaction that the nitrogen of the amino radical of one amino acid

bonds with the carbon of the carboxyl radical of the other amino acid. A hydrogen

ion is released from the amino radical, and a hydroxyl ion is released from the car-

boxyl radical; these two combine to form a molecule of water. After the peptide

linkage has been formed, an amino radical and a carboxyl radical are still at oppo-

site ends of the new, longer molecule. Each of these radicals is capable of combin-

ing with additional amino acids to form a peptide chain. Some complicated protein

molecules have many thousand amino acids combined by peptide linkages, and even

the smallest protein molecule usually has more than 20 amino acids combined by

peptide linkages. The average is about 400 amino acids.

Other Linkages in Protein Molecules. Some protein molecules are composed of several

peptide chains rather than a single chain, and these chains are bound to one another

852

854

Unit XIII

Metabolism and Temperature Regulation

by other linkages, often by hydrogen bonding between

Renal Threshold for Amino Acids. In the kidneys, the

the CO and NH radicals of the peptides, as follows:

different amino acids can be actively reabsorbed

through the proximal tubular epithelium, which

removes them from the glomerular filtrate and returns

them to the blood if they should filter into the renal

H N

tubules through the glomerular membranes. However,

as is true of other active transport mechanisms in the

CH R'

renal tubules, there is an upper limit to the rate at which

each type of amino acid can be transported. For this

reason, when the concentration of a particular type

N H

O C

of amino acid becomes too high in the plasma and

glomerular filtrate, the excess that cannot be actively

reabsorbed is lost into the urine.

Many peptide chains are coiled or folded, and the suc-

cessive coils or folds are held in a tight spiral or in other

shapes by similar hydrogen bonding and other forces.

Storage of Amino Acids as Proteins

in the Cells

Transport and Storage

Almost immediately after entry into tissue cells, amino

acids combine with one another by peptide linkages,

of Amino Acids

under the direction of the cell’s messenger RNA and

ribosomal system, to form cellular proteins. Therefore,

Blood Amino Acids

the concentration of free amino acids inside the cells

The normal concentration of amino acids in the blood

usually remains low. Thus, storage of large quantities

is between 35 and 65 mg/dl. This is an average of about

of free amino acids does not occur in the cells; instead,

2 mg/dl for each of the 20 amino acids, although some

they are stored mainly in the form of actual proteins.

are present in far greater amounts than others. Because

But many of these intracellular proteins can be rapidly

the amino acids are relatively strong acids, they exist

decomposed again into amino acids under the influence

in the blood principally in the ionized state, resulting

of intracellular lysosomal digestive enzymes; these

from the removal of one hydrogen atom from the NH₂

amino acids can then be transported back out of the

radical. They actually account for 2 to 3 milliequivalents

cell into the blood. Special exceptions to this reversal

of the negative ions in the blood. The precise distribu-

process are the proteins in the chromosomes of the

tion of the different amino acids in the blood depends

nucleus and the structural proteins such as collagen

to some extent on the types of proteins eaten, but

and muscle contractile proteins; these proteins do not

the concentrations of at least some individual amino

participate significantly in this reverse digestion and

acids are regulated by selective synthesis in the differ-

transport back out of the cells.

ent cells.

Some tissues of the body participate in the storage

of amino acids to a greater extent than others. For

instance, the liver, which is a large organ and has special

Fate of Amino Acids Absorbed from the Gastrointestinal Tract.

systems for processing amino acids, can store large

The products of protein digestion and absorption in the

quantities of rapidly exchangeable proteins; this is also

gastrointestinal tract are almost entirely amino acids;

true to a lesser extent of the kidneys and the intestinal

only rarely are polypeptides or whole protein molecules

mucosa.

absorbed from the digestive tract into the blood. Imme-

diately after a meal, the amino acid concentration in a

Release of Amino Acids from the Cells as a Means of Regulating

person’s blood rises, but the increase is usually only a

Plasma Amino Acid Concentration. Whenever plasma amino

few milligrams per deciliter, for two reasons: First,

acid concentrations fall below normal levels, the

protein digestion and absorption are usually extended

required amino acids are transported out of the cells to

over 2 to 3 hours, which allows only small quantities of

replenish their supply in the plasma. In this way, the

amino acids to be absorbed at a time. Second, after

plasma concentration of each type of amino acid is main-

entering the blood, the excess amino acids are absorbed

tained at a reasonably constant value. Later, it is noted

within 5 to 10 minutes by cells throughout the body,

that some of the hormones secreted by the endocrine

especially by the liver. Therefore, almost never do large

glands are able to alter the balance between tissue pro-

concentrations of amino acids accumulate in the blood

teins and circulating amino acids. For instance, growth

and tissue fluids. Nevertheless, the turnover rate of the

hormone and insulin increase the formation of tissue

amino acids is so rapid that many grams of proteins can

proteins, whereas adrenocortical glucocorticoid hor-

be carried from one part of the body to another in the

mones increase the concentration of plasma amino acids.

form of amino acids each hour.

Reversible Equilibrium Between the Proteins in Different Parts of

Active Transport of Amino Acids into the Cells. The molecules

the Body. Because cellular proteins in the liver (and, to

of all the amino acids are much too large to diffuse

a much less extent, in other tissues) can be synthesized

readily through the pores of the cell membranes. There-

rapidly from plasma amino acids, and because many of

fore, significant quantities of amino acids can move

these proteins can be degraded and returned to the

either inward or outward through the membranes only

plasma almost as rapidly, there is constant interchange

by facilitated transport or active transport using carrier

and equilibrium between the plasma amino acids and

mechanisms. The nature of some of the carrier mecha-

labile proteins in virtually all cells of the body. For

nisms is still poorly understood, but a few are discussed

instance, if any particular tissue requires proteins, it can

in Chapter 4.

synthesize new proteins from the amino acids of the

Chapter 69

Protein Metabolism

855

blood; in turn, the blood amino acids are replenished by

throughout the body to build cellular proteins wherever

degradation of proteins from other cells of the body,

needed. In this way, the plasma proteins function as a

especially from the liver cells. These effects are particu-

labile protein storage medium and represent a readily

larly noticeable in relation to protein synthesis in cancer

available source of amino acids whenever a particular

cells. Cancer cells are often prolific users of amino acids;

tissue requires them.

therefore, the proteins of the other cells can become

markedly depleted.

Reversible Equilibrium Between the Plasma Proteins and the

Tissue Proteins. There is a constant state of equilibrium,

Upper Limit for the Storage of Proteins. Each particular type

as shown in Figure 69-2, among the plasma proteins, the

of cell has an upper limit with regard to the amount of

amino acids of the plasma, and the tissue proteins. It has

proteins it can store. After all the cells have reached

been estimated from radioactive tracer studies that

their limits, the excess amino acids still in the circulation

normally about 400 grams of body protein are synthe-

are degraded into other products and used for energy,

sized and degraded each day as part of the continual

as discussed subsequently, or they are converted to fat

state of flux of amino acids. This demonstrates the

or glycogen and stored in these forms.

general principle of reversible exchange of amino acids

among the different proteins of the body. Even during

starvation or severe debilitating diseases, the ratio of

Functional Roles of the

total tissue proteins to total plasma proteins in the body

remains relatively constant at about 33:1.

Plasma Proteins

Because of this reversible equilibrium between

The major types of protein present in the plasma are

plasma proteins and the other proteins of the body, one

albumin, globulin, and fibrinogen.

of the most effective therapies for severe, acute whole-

A major function of albumin is to provide colloid

body protein deficiency is intravenous transfusion of

osmotic pressure in the plasma, which prevents plasma

plasma protein. Within a few days, or sometimes within

loss from the capillaries, as discussed in Chapter 16.

hours, the amino acids of the administered protein are

The globulins perform a number of enzymatic func-

distributed throughout the cells of the body to form new

tions in the plasma, but equally important, they are prin-

proteins where they are needed.

cipally responsible for the body’s both natural and

acquired immunity against invading organisms, dis-

Essential and Nonessential

cussed in Chapter 34.

Amino Acids

Fibrinogen polymerizes into long fibrin threads

during blood coagulation, thereby forming blood clots

Ten of the amino acids normally present in animal pro-

that help repair leaks in the circulatory system, dis-

teins can be synthesized in the cells, whereas the other

cussed in Chapter 36.

10 either cannot be synthesized or are synthesized in

quantities too small to supply the body’s needs. This

Formation of the Plasma Proteins. Essentially all the

second group of amino acids that cannot be synthesized

albumin and fibrinogen of the plasma proteins, as well

is called the essential amino acids. Use of the word

as 50 to 80 per cent of the globulins, are formed in the

“essential” does not mean that the other 10 “nonessen-

liver. The remainder of the globulins are formed almost

tial” amino acids are not required for the formation of

entirely in the lymphoid tissues. They are mainly the

proteins, but only that the others are not essential in the

gamma globulins that constitute the antibodies used in

diet because they can be synthesized in the body.

the immune system.

Synthesis of the nonessential amino acids depends

The rate of plasma protein formation by the liver can

mainly on the formation of appropriate a-keto acids,

be extremely high, as much as 30 g/day. Certain disease

conditions cause rapid loss of plasma proteins; severe

burns that denude large surface areas of the skin can

Tissue cells

Liver cells

cause the loss of several liters of plasma through the

denuded areas each day. The rapid production of plasma

proteins by the liver is valuable in preventing death in

such states. Occasionally, a person with severe renal

Proteins

Amino

Proteins

disease loses as much as 20 grams of plasma protein in

Amino acids

acids

the urine each day for months, and it is continually

replaced mainly by liver production of the required

proteins.

Amino acids

Blood

Plasma proteins

In cirrhosis of the liver, large amounts of fibrous tissue

develop among the liver parenchymal cells, causing a

reduction in their ability to synthesize plasma proteins.

As discussed in Chapter 25, this leads to decreased

plasma colloid osmotic pressure, which causes general-

Imbibed plasma protein

ized edema.

Plasma Proteins as a Source of Amino Acids for the Tissues.

When the tissues become depleted of proteins, the

Reticuloendothelial cell

plasma proteins can act as a source of rapid replace-

ment. Indeed, whole plasma proteins can be imbibed in

Figure 69-2

toto by tissue macrophages through the process of

pinocytosis; once in these cells, they are split into amino

Reversible equilibrium among the tissue proteins, plasma pro-

acids that are transported back into the blood and used

teins, and plasma amino acids.

856

Unit XIII

Metabolism and Temperature Regulation

NH₂

CH₂

CH COOH

CH₃

C COOH

Transaminase

(Glutamine)

(Pyruvic acid)

NH₂

CH₂

COOH

CH₃

C COOH

Figure 69-3

(a-Ketoglutamic acid)

(Alanine)

Synthesis of alanine from pyruvic

acid by transamination.

which are the precursors of the respective amino acids.

Note from this schema that the amino group from the

For instance, pyruvic acid, which is formed in large

amino acid is transferred to a-ketoglutaric acid, which

quantities during the glycolytic breakdown of glucose,

then becomes glutamic acid. The glutamic acid can then

is the keto acid precursor of the amino acid alanine.

transfer the amino group to still other substances or

Then, by the process of transamination, an amino

release it in the form of ammonia (NH₃). In the process

radical is transferred to the a-keto acid, and the keto

of losing the amino group, the glutamic acid once again

oxygen is transferred to the donor of the amino radical.

becomes a-ketoglutaric acid, so that the cycle can be

This reaction is shown in Figure 69-3. Note in this figure

repeated again and again. To initiate this process, the

that the amino radical is transferred to the pyruvic acid

excess amino acids in the cells, especially in the liver,

from another chemical that is closely allied to the amino

induce the activation of large quantities of aminotrans-

acids, glutamine. Glutamine is present in the tissues in

ferases, the enzymes responsible for initiating most

large quantities, and one of its principal functions is to

deamination.

serve as an amino radical storehouse. In addition, amino

radicals can be transferred from asparagine, glutamic

Urea Formation by the Liver. The ammonia released

acid, and aspartic acid.

during deamination of amino acids is removed from the

Transamination is promoted by several enzymes,

blood almost entirely by conversion into urea; two mol-

among which are the aminotransferases, which are deriv-

ecules of ammonia and one molecule of carbon dioxide

atives of pyridoxine, one of the B vitamins (B₆). Without

combine in accordance with the following net reaction:

this vitamin, the amino acids are synthesized only poorly,

2 NH₃ + CO₂ Æ H₂N—C—NH₂ + H₂O

and protein formation cannot proceed normally.

Use of Proteins for Energy

Essentially all urea formed in the human body is syn-

thesized in the liver. In the absence of the liver or in

Once the cells are filled to their limits with stored

serious liver disease, ammonia accumulates in the

protein, any additional amino acids in the body fluids are

blood. This is extremely toxic, especially to the brain,

degraded and used for energy or are stored mainly as fat

often leading to a state called hepatic coma.

or secondarily as glycogen. This degradation occurs

The stages in the formation of urea are essentially the

almost entirely in the liver, and it begins with deamina-

following:

tion, which is explained in the following section.

Ornithine + CO₂ + NH₃

Deamination. Deamination means removal of the amino

Citrulline

groups from the amino acids. This occurs mainly by

-H₂O

transamination, which means transfer of the amino

NH₃

group to some acceptor substance, which is the reverse

-H₂O

of the transamination explained earlier in relation to the

synthesis of amino acids.

Arginine

The greatest amount of deamination occurs by the

following transamination schema:

(Arginase)

+ H₂O

Urea

a-Ketoglutaric acid + Amino acid

After its formation, the urea diffuses from the liver cells

into the body fluids and is excreted by the kidneys.

Glutamic acid + a-Keto acid

Oxidation of Deaminated Amino Acids. Once amino acids

have been deaminated, the resulting keto acids can, in

most instances, be oxidized to release energy for meta-

bolic purposes. This usually involves two successive

+ NAD+ + H₂O

processes: (1) the keto acid is changed into an appro-

priate chemical substance that can enter the citric acid

NADH + H⁺ + NH₃

cycle, and (2) this substance is degraded by the cycle and

Chapter 69

Protein Metabolism

857

used for energy in the same manner that acetyl coen-

Hormonal Regulation

zyme A (acetyl-CoA) derived from carbohydrate and

of Protein Metabolism

lipid metabolism is used, as explained in Chapters 67

and 68. In general, the amount of adenosine triphos-

Growth Hormone Increases the Synthesis of Cellular Proteins.

phate (ATP) formed for each gram of protein that is

Growth hormone causes the tissue proteins to increase.

oxidized is slightly less than that formed for each gram

The precise mechanism by which this occurs is not

of glucose oxidized.

known, but it is believed to result mainly from increased

transport of amino acids through the cell membranes or

acceleration of the DNA and RNA transcription and

Gluconeogenesis and Ketogenesis. Certain deaminated

translation processes for protein synthesis.

amino acids are similar to the substrates normally used

by the cells, mainly the liver cells, to synthesize glucose

Insulin Is Necessary for Protein Synthesis. Total lack of

or fatty acids. For instance, deaminated alanine is

insulin reduces protein synthesis to almost zero. The

pyruvic acid. This can be converted into either glucose

mechanism by which this occurs is also unknown, but

or glycogen. Alternatively, it can be converted into

insulin does accelerate the transport of some amino

acetyl-CoA, which can then be polymerized into fatty

acids into cells, which could be the stimulus to protein

acids. Also, two molecules of acetyl-CoA can condense

synthesis. Also, insulin increases the availability of

to form acetoacetic acid, which is one of the ketone

glucose to the cells, so that the need for amino acids for

bodies, as explained in Chapter 68.

energy is correspondingly reduced.

The conversion of amino acids into glucose or glyco-

gen is called gluconeogenesis, and the conversion of

Glucocorticoids Increase Breakdown of Most Tissue Proteins.

amino acids into keto acids or fatty acids is called keto-

The glucocorticoids secreted by the adrenal cortex

genesis. Of the 20 deaminated amino acids, 18 have

decrease the quantity of protein in most tissues while

chemical structures that allow them to be converted into

increasing the amino acid concentration in the plasma,

glucose, and 19 of them can be converted into fatty

as well as increasing both liver proteins and plasma pro-

acids.

teins. It is believed that the glucocorticoids act by

increasing the rate of breakdown of extrahepatic pro-

teins, thereby making increased quantities of amino

acids available in the body fluids. This supposedly allows

Obligatory Degradation of Proteins

the liver to synthesize increased quantities of hepatic

When a person eats no proteins, a certain proportion of

cellular proteins and plasma proteins.

body proteins is degraded into amino acids and then

deaminated and oxidized. This involves 20 to 30 grams

Testosterone Increases Protein Deposition in Tissues. Testos-

of protein each day, which is called the obligatory

terone, the male sex hormone, causes increased deposi-

loss of proteins. Therefore, to prevent net loss of

tion of protein in tissues throughout the body, especially

protein from the body, one must ingest a minimum

the contractile proteins of the muscles (30 to 50 per cent

of 20 to 30 grams of protein each day; to be on the

increase). The mechanism of this effect is unknown, but

safe side, a minimum of 60 to 75 grams is usually

it is definitely different from the effect of growth

recommended.

hormone, in the following way: Growth hormone causes

The ratios of the different amino acids in the dietary

tissues to continue growing almost indefinitely, whereas

protein must be about the same as the ratios in the body

testosterone causes the muscles and, to a much lesser

tissues if the entire dietary protein is to be fully usable

extent, some other protein tissues to enlarge for only

to form new proteins in the tissues. If one particular type

several months. Once the muscles and other protein

of essential amino acid is low in concentration, the

tissues have reached a maximum, despite continued

others become unusable because cells synthesize either

administration of testosterone, further protein deposi-

whole proteins or none at all, as explained in Chapter 3

tion ceases.

in relation to protein synthesis. The unusable amino

acids are deaminated and oxidized. A protein that has

Estrogen. Estrogen, the principal female sex hormone,

a ratio of amino acids different from that of the average

also causes some deposition of protein, but its effect

body protein is called a partial protein or incomplete

is relatively insignificant in comparison with that of

protein, and such a protein is less valuable for nutrition

testosterone.

than is a complete protein.

Thyroxine. Thyroxine increases the rate of metabolism of

all cells and, as a result, indirectly affects protein metab-

Effect of Starvation on Protein Degradation. Except for the 20

olism. If insufficient carbohydrates and fats are avail-

to 30 grams of obligatory protein degradation each day,

able for energy, thyroxine causes rapid degradation of

the body uses almost entirely carbohydrates or fats

proteins and uses them for energy. Conversely, if ade-

for energy, as long as they are available. However,

quate quantities of carbohydrates and fats are available

after several weeks of starvation, when the quantities

and excess amino acids are also available in the extra-

of stored carbohydrates and fats begin to run out, the

cellular fluid, thyroxine can actually increase the rate of

amino acids of the blood are rapidly deaminated and

protein synthesis. In growing animals or human beings,

oxidized for energy. From this point on, the proteins

deficiency of thyroxine causes growth to be greatly

of the tissues degrade rapidly—as much as 125 grams

inhibited because of lack of protein synthesis. In

daily—and, as a result, cellular functions deteriorate

essence, it is believed that thyroxine has little specific

precipitously. Because carbohydrate and fat utilization

effect on protein metabolism but does have an

for energy normally occurs in preference to protein

important general effect by increasing the rates of

utilization, carbohydrates and fats are called protein

both normal anabolic and normal catabolic protein

sparers.

reactions.

858

Unit XIII

Metabolism and Temperature Regulation

References

Kuhn CM: Anabolic steroids. Recent Prog Horm Res 57:411,

2002.

Layman DK, Baum JI: Dietary protein impact on glycemic

Altenberg GA: The engine of ABC proteins. News Physiol

control during weight loss. J Nutr 134:968S, 2004.

Sci 18:191, 2003.

Mann GE, Yudilevich DL, Sobrevia L: Regulation of amino

Caldwell J: Pharmacogenetics and individual variation in

acid and glucose transporters in endothelial and smooth

the range of amino acid adequacy: the biological aspects.

muscle cells. Physiol Rev 83:183, 2003.

J Nutr 134(6 Suppl):1600S, 2004.

Meijer AJ: Amino acids as regulators and components of

Daniel H: Molecular and integrative physiology of intestinal

nonproteinogenic pathways. J Nutr 133(6 Suppl 1):2057S,

peptide transport. Annu Rev Physiol 66:361, 2004.

2003.

Deves R, Boyd CA: Transporters for cationic amino acids in

Moriwaki H, Miwa Y, Tajika M, et al: Branched-chain amino

animal cells: discovery, structure, and function. Physiol

acids as a protein- and energy-source in liver cirrhosis.

Rev 78:487, 1998.

Biochem Biophys Res Commun 313:405, 2004.

Fukagawa NK, Galbraith RA: Advancing age and other

Pencharz PB, Ball RO: Amino acid needs for early growth

factors influencing the balance between amino acid

and development. J Nutr 134(6 Suppl):1566S, 2004.

requirements and toxicity. J Nutr

134(6 Suppl):1569S,

Prod’homme M, Rieu I, Balage M, et al: Insulin and amino

2004.

acids both strongly participate to the regulation of protein

Jans DA, Hubner S: Regulation of protein transport to the

metabolism. Curr Opin Clin Nutr Metab Care 7:71, 2004.

nucleus: central role of phosphorylation. Physiol Rev

Tessari P: Protein metabolism in liver cirrhosis: from albumin

76:651, 1996.

to muscle myofibrils. Curr Opin Clin Nutr Metab Care

Kadowaki M, Kanazawa T: Amino acids as regulators of pro-

6:79, 2003.

teolysis. J Nutr 133(6 Suppl 1):2052S, 2003.

van de Poll MC, Soeters PB, Deutz NE, et al: Renal metab-

Kimball SR, Jefferson LS: Regulation of global and specific

olism of amino acids: its role in interorgan amino acid

mRNA translation by oral administration of branched-

exchange. Am J Clin Nutr 79:185, 2004.

chain amino acids. Biochem Biophys Res Commun

313:423, 2004.

C H A P T E R

The Liver as an Organ

The liver performs many different functions yet is also

a discrete organ, and many of its functions interrelate

with one another. This becomes especially evident in

abnormalities of the liver, because many of its functions

are disturbed simultaneously. The purpose of this

chapter is to summarize the liver’s different functions,

including

(1) filtration and storage of blood;

(2)

metabolism of carbohydrates, proteins, fats, hormones,

and foreign chemicals; (3) formation of bile; (4) storage

of vitamins and iron; and (5) formation of coagulation factors.

Physiologic Anatomy of the Liver

The liver is the largest organ in the body, contributing about 2 per cent of the total

body weight, or about 1.5 kg in the average adult human. The basic functional unit

of the liver is the liver lobule, which is a cylindrical structure several millimeters in

length and 0.8 to 2 millimeters in diameter. The human liver contains 50,000 to

100,000 individual lobules.

The liver lobule, shown in cut-away format in Figure 70-1, is constructed around

a central vein that empties into the hepatic veins and then into the vena cava. The

lobule itself is composed principally of many liver cellular plates (two of which are

shown in Figure 70-1) that radiate from the central vein like spokes in a wheel. Each

hepatic plate is usually two cells thick, and between the adjacent cells lie small bile

canaliculi that empty into bile ducts in the fibrous septa separating the adjacent liver

lobules.

In the septa are small portal venules that receive their blood mainly from the

venous outflow of the gastrointestinal tract by way of the portal vein. From these

venules blood flows into flat, branching hepatic sinusoids that lie between the

hepatic plates and then into the central vein. Thus, the hepatic cells are exposed con-

tinuously to portal venous blood.

Hepatic arterioles are also present in the interlobular septa. These arterioles

supply arterial blood to the septal tissues between the adjacent lobules, and many

of the small arterioles also empty directly into the hepatic sinusoids, most frequently

emptying into those located about one third the distance from the interlobular

septa, as shown in Figure 70-1.

In addition to the hepatic cells, the venous sinusoids are lined by two other types

of cell: (1) typical endothelial cells and (2) large Kupffer cells (also called reticu-

loendothelial cells), which are resident macrophages that line the sinusoids and are

capable of phagocytizing bacteria and other foreign matter in the hepatic sinus

blood.

The endothelial lining of the sinusoids has extremely large pores, some of which

are almost 1 micrometer in diameter. Beneath this lining, lying between the

endothelial cells and the hepatic cells, are narrow tissue spaces called the spaces of

Disse, also known as the perisinusoidal spaces. The millions of spaces of Disse

connect with lymphatic vessels in the interlobular septa. Therefore, excess fluid in

these spaces is removed through the lymphatics. Because of the large pores in the

endothelium, substances in the plasma move freely into the spaces of Disse. Even

large portions of the plasma proteins diffuse freely into these spaces.

Hepatic Vascular and Lymph Systems

The function of the hepatic vascular system is discussed in Chapter 15 in connec-

tion with the portal veins and can be summarized as follows.

859

860

Unit XIII

Metabolism and Temperature Regulation

Central

The Liver Functions as

vein

a Blood Reservoir

Because the liver is an expandable organ, large quanti-

Liver cell plate

ties of blood can be stored in its blood vessels. Its

Sinusoids

normal blood volume, including both that in the hepatic

Space of Disse

Kupffer cell

veins and that in the hepatic sinuses, is about 450 milli-

Terminal

Bile canaliculi

liters, or almost 10 per cent of the body’s total blood

lymphatics

volume. When high pressure in the right atrium causes

backpressure in the liver, the liver expands, and 0.5 to 1

Lymphatic

liter of extra blood is occasionally stored in the hepatic

duct

Portal

veins and sinuses. This occurs especially in cardiac

vein

failure with peripheral congestion, which is discussed in

Hepatic

Chapter 22. Thus, in effect, the liver is a large, expand-

artery

able, venous organ capable of acting as a valuable blood

reservoir in times of excess blood volume and capable

Bile duct

of supplying extra blood in times of diminished blood

volume.

Figure 70-1

Basic structure of a liver lobule, showing the liver cellular plates,

The Liver Has Very High

the blood vessels, the bile-collecting system, and the lymph flow

system composed of the spaces of Disse and the interlobular

Lymph Flow

lymphatics. (Modified from Guyton AC, Taylor AE, Granger HJ:

Circulatory Physiology. Vol 2: Dynamics and Control of the Body

Because the pores in the hepatic sinusoids are very

Fluids. Philadelphia: WB Saunders, 1975.)

permeable and allow ready passage of both fluid and

proteins into the spaces of Disse, the lymph draining

from the liver usually has a protein concentration of

about 6 g/dl, which is only slightly less than the protein

Blood Flows Through the Liver from

concentration of plasma. Also, the extreme permeabil-

ity of the liver sinusoid epithelium allows large quanti-

the Portal Vein and Hepatic Artery

ties of lymph to form. Therefore, about half of all the

The Liver Has High Blood Flow and Low Vascular Resistance.

lymph formed in the body under resting conditions

About 1050 milliliters of blood flows from the portal

arises in the liver.

vein into the liver sinusoids each minute, and an addi-

tional 300 milliliters flows into the sinusoids from the

High Hepatic Vascular Pressures Can Cause Fluid Transudation

hepatic artery, the total averaging about 1350 ml/min.

into the Abdominal Cavity from the Liver and Portal Capillaries—

This amounts to 27 per cent of the resting cardiac

Ascites. When the pressure in the hepatic veins rises

output.

only 3 to 7 mm Hg above normal, excessive amounts of

The pressure in the portal vein leading into the liver

fluid begin to transude into the lymph and leak through

averages about

9 mm Hg, and the pressure in the

the outer surface of the liver capsule directly into the

hepatic vein leading from the liver into the vena cava

abdominal cavity. This fluid is almost pure plasma, con-

normally averages almost exactly 0 mm Hg. This small

taining 80 to 90 per cent as much protein as normal

pressure difference, only 9 mm Hg, shows that the resist-

plasma. At vena caval pressures of 10 to 15 mm Hg,

ance to blood flow through the hepatic sinusoids is nor-

hepatic lymph flow increases to as much as 20 times

mally very low, especially when one considers that about

normal, and the “sweating” from the surface of the liver

1350 milliliters of blood flows by this route each minute.

can be so great that it causes large amounts of free fluid

in the abdominal cavity, which is called ascites. Block-

Cirrhosis of the Liver Greatly Increases Resistance to Blood Flow.

age of portal flow through the liver also causes high

When liver parenchymal cells are destroyed, they are

capillary pressures in the entire portal vascular system

replaced with fibrous tissue that eventually contracts

of the gastrointestinal tract, resulting in edema of

around the blood vessels, thereby greatly impeding the

the gut wall and transudation of fluid through the serosa

flow of portal blood through the liver. This disease

of the gut into the abdominal cavity. This, too, can cause

process is known as cirrhosis of the liver. It results most

ascites.

commonly from alcoholism, but it can also follow inges-

tion of poisons such as carbon tetrachloride, viral dis-

eases such as infectious hepatitis, obstruction of the bile

Regulation of Liver Mass—

ducts, and infectious processes in the bile ducts.

Regeneration

The portal system is also occasionally blocked by a

large clot that develops in the portal vein or its major

The liver possesses a remarkable ability to restore itself

branches. When the portal system is suddenly blocked,

after significant hepatic tissue loss from either partial

the return of blood from the intestines and spleen

hepatectomy or acute liver injury, as long as the injury

through the liver portal blood flow system to the sys-

is uncomplicated by viral infection or inflammation.

temic circulation is tremendously impeded, resulting in

Partial hepatectomy, in which up to 70 per cent of the

portal hypertension and increasing the capillary pres-

liver is removed, causes the remaining lobes to enlarge

sure in the intestinal wall to 15 to 20 mm Hg above

and restore the liver to its original size. This regenera-

normal. The patient often dies within a few hours

tion is remarkably rapid and requires only 5 to 7 days

because of excessive loss of fluid from the capillaries

in rats. During liver regeneration, hepatocytes are esti-

into the lumens and walls of the intestines.

mated to replicate once or twice, and after the original

Chapter 70

The Liver as an Organ

861

size and volume of the liver are achieved, the hepato-

Carbohydrate Metabolism

cytes revert to their usual quiescent state.

Control of this rapid regeneration of the liver is still

In carbohydrate metabolism, the liver performs the fol-

poorly understood, but hepatocyte growth factor (HGF)

lowing functions, as summarized from Chapter 67:

appears to be an important factor causing liver cell divi-

1. Storage of large amounts of glycogen

sion and growth. HGF is produced by mesenchymal

2. Conversion of galactose and fructose to glucose

cells in the liver and in other tissues, but not by hepa-

3. Gluconeogenesis

tocytes. Blood levels of HGF rise more than 20-fold

4. Formation of many chemical compounds from

after partial hepatectomy, but mitogenic responses are

intermediate products of carbohydrate metabolism

usually found only in the liver after these operations,

The liver is especially important for maintaining a

suggesting that HGF may be activated only in the

normal blood glucose concentration. Storage of glyco-

affected organ. Other growth factors, especially epider-

gen allows the liver to remove excess glucose from the

mal growth factor, and cytokines such as tumor necro-

blood, store it, and then return it to the blood when the

sis factor and interleukin-6 may also be involved in

blood glucose concentration begins to fall too low. This

stimulating regeneration of liver cells.

is called the glucose buffer function of the liver. In a

After the liver has returned to its original size, the

person with poor liver function, blood glucose concen-

process of hepatic cell division is terminated. Again,

tration after a meal rich in carbohydrates may rise two

the factors involved are not well understood, although

to three times as much as in a person with normal liver

transforming growth factor-b, a cytokine secreted by

function.

hepatic cells, is a potent inhibitor of liver cell prolifera-

Gluconeogenesis in the liver is also important in

tion and has been suggested as the main terminator of

maintaining a normal blood glucose concentration,

liver regeneration.

because gluconeogenesis occurs to a significant extent

Physiologic experiments indicate that liver growth is

only when the glucose concentration falls below normal.

closely regulated by some unknown signal related to

In such a case, large amounts of amino acids and glyc-

body size, so that an optimal liver-to-body weight ratio

erol from triglycerides are converted into glucose,

is maintained for optimal metabolic function. In liver

thereby helping to maintain a relatively normal blood

diseases associated with fibrosis, inflammation, or viral

glucose concentration.

infections, however, the regenerative process of the liver

is severely impaired, and liver function deteriorates.

Fat Metabolism

Although most cells of the body metabolize fat, certain

Hepatic Macrophage System Serves

aspects of fat metabolism occur mainly in the liver.

a Blood-Cleansing Function

Specific functions of the liver in fat metabolism, as

summarized from Chapter 68, are the following:

Blood flowing through the intestinal capillaries picks up

1. Oxidation of fatty acids to supply energy for other

many bacteria from the intestines. Indeed, a sample of

body functions

blood taken from the portal veins before it enters the

2. Synthesis of large quantities of cholesterol,

liver almost always grows colon bacilli when cultured,

phospholipids, and most lipoproteins

whereas growth of colon bacilli from blood in the sys-

3. Synthesis of fat from proteins and carbohydrates

temic circulation is extremely rare.

To derive energy from neutral fats, the fat is first split

Special high-speed motion pictures of the action of

into glycerol and fatty acids; then the fatty acids are split

Kupffer cells, the large phagocytic macrophages that

by beta-oxidation into two-carbon acetyl radicals that

line the hepatic venous sinuses, have demonstrated that

form acetyl coenzyme A (acetyl-CoA). This can enter

these cells efficiently cleanse blood as it passes through

the citric acid cycle and be oxidized to liberate tremen-

the sinuses; when a bacterium comes into momentary

dous amounts of energy. Beta-oxidation can take place

contact with a Kupffer cell, in less than 0.01 second the

in all cells of the body, but it occurs especially rapidly

bacterium passes inward through the wall of the Kupffer

in the hepatic cells. The liver itself cannot use all the

cell to become permanently lodged therein until it is

acetyl-CoA that is formed; instead, it is converted by the

digested. Probably less than 1 per cent of the bacteria

condensation of two molecules of acetyl-CoA into

entering the portal blood from the intestines succeeds

acetoacetic acid, a highly soluble acid that passes from

in passing through the liver into the systemic

the hepatic cells into the extracellular fluid and is then

circulation.

transported throughout the body to be absorbed by

other tissues. These tissues reconvert the acetoacetic

acid into acetyl-CoA and then oxidize it in the usual

Metabolic Functions

manner. Thus, the liver is responsible for a major part

of the Liver

of the metabolism of fats.

About 80 per cent of the cholesterol synthesized in

The liver is a large, chemically reactant pool of cells that

the liver is converted into bile salts, which are secreted

have a high rate of metabolism, sharing substrates and

into the bile; the remainder is transported in the

energy from one metabolic system to another, process-

lipoproteins and carried by the blood to the tissue cells

ing and synthesizing multiple substances that are trans-

everywhere in the body. Phospholipids are likewise syn-

ported to other areas of the body, and performing

thesized in the liver and transported principally in the

myriad other metabolic functions. For these reasons, a

lipoproteins. Both cholesterol and phospholipids are

major share of the entire discipline of biochemistry is

used by the cells to form membranes, intracellular

devoted to the metabolic reactions in the liver. But here,

structures, and multiple chemical substances that are

let us summarize those metabolic functions that are

important to cellular function.

especially important in understanding the integrated

Almost all the fat synthesis in the body from carbo-

physiology of the body.

hydrates and proteins also occurs in the liver. After fat

862

Unit XIII

Metabolism and Temperature Regulation

is synthesized in the liver, it is transported in the

known as an excellent source of certain vitamins in the

lipoproteins to the adipose tissue to be stored.

treatment of patients. The vitamin stored in greatest

quantity in the liver is vitamin A, but large quantities of

Protein Metabolism

vitamin D and vitamin B₁₂ are normally stored as well.

Sufficient quantities of vitamin A can be stored to

The body cannot dispense with the liver’s contribution

prevent vitamin A deficiency for as long as 10 months.

to protein metabolism for more than a few days without

Sufficient vitamin D can be stored to prevent deficiency

death ensuing. The most important functions of the liver

for 3 to 4 months, and enough vitamin B₁₂ can be stored

in protein metabolism, as summarized from Chapter 69,

to last for at least 1 year and maybe several years.

are the following:

1. Deamination of amino acids

The Liver Stores Iron as Ferritin. Except for the iron in the

2. Formation of urea for removal of ammonia from

hemoglobin of the blood, by far the greatest proportion

the body fluids

of iron in the body is stored in the liver in the form of

3. Formation of plasma proteins

ferritin. The hepatic cells contain large amounts of a

4. Interconversions of the various amino acids and

protein called apoferritin, which is capable of combin-

synthesis of other compounds from amino acids

ing reversibly with iron. Therefore, when iron is avail-

Deamination of amino acids is required before they

able in the body fluids in extra quantities, it combines

can be used for energy or converted into carbohydrates

with apoferritin to form ferritin and is stored in this

or fats. A small amount of deamination can occur in the

form in the hepatic cells until needed elsewhere. When

other tissues of the body, especially in the kidneys, but

the iron in the circulating body fluids reaches a low

this is much less important than the deamination of

level, the ferritin releases the iron. Thus, the apoferritin-

amino acids by the liver.

ferritin system of the liver acts as a blood iron buffer, as

Formation of urea by the liver removes ammonia

well as an iron storage medium. Other functions of the

from the body fluids. Large amounts of ammonia are

liver in relation to iron metabolism and red blood cell

formed by the deamination process, and additional

formation are considered in Chapter 32.

amounts are continually formed in the gut by bacteria

and then absorbed into the blood. Therefore, if the liver

The Liver Forms a Large Proportion of the Blood Substances Used

does not form urea, the plasma ammonia concentration

in Coagulation. Substances formed in the liver that are

rises rapidly and results in hepatic coma and death.

used in the coagulation process include fibrinogen, pro-

Indeed, even greatly decreased blood flow through the

thrombin, accelerator globulin, Factor VII, and several

liver—as occurs occasionally when a shunt develops

other important factors. Vitamin K is required by the

between the portal vein and the vena cava—can cause

metabolic processes of the liver for the formation of

excessive ammonia in the blood, an extremely toxic

several of these substances, especially prothrombin and

condition.

Factors VII, IX, and X. In the absence of vitamin K, the

Essentially all the plasma proteins, with the exception

concentrations of all these decrease markedly, and this

of part of the gamma globulins, are formed by the

almost prevents blood coagulation.

hepatic cells. This accounts for about 90 per cent of all

the plasma proteins. The remaining gamma globulins

The Liver Removes or Excretes Drugs, Hormones, and Other Sub-

are the antibodies formed mainly by plasma cells in the

stances. The active chemical medium of the liver is well

lymph tissue of the body. The liver can form plasma pro-

known for its ability to detoxify or excrete into the bile

teins at a maximum rate of 15 to 50 g/day. Therefore,

many drugs, including sulfonamides, penicillin, ampi-

even if as much as half the plasma proteins are lost from

cillin, and erythromycin.

the body, they can be replenished in 1 or 2 weeks.

In a similar manner, several of the hormones secreted

It is particularly interesting that plasma protein

by the endocrine glands are either chemically altered or

depletion causes rapid mitosis of the hepatic cells and

excreted by the liver, including thyroxine and essentially

growth of the liver to a larger size; these effects are

all the steroid hormones, such as estrogen, cortisol, and

coupled with rapid output of plasma proteins until the

aldosterone. Liver damage can lead to excess accumu-

plasma concentration returns to normal. With chronic

lation of one or more of these hormones in the body

liver disease (e.g., cirrhosis), plasma proteins, such as

fluids and therefore cause overactivity of the hormonal

albumin, may fall to very low levels, causing generalized

systems.

edema and ascites, as explained in Chapter 29.

Finally, one of the major routes for excreting calcium

Among the most important functions of the liver is

from the body is secretion by the liver into the bile,

its ability to synthesize certain amino acids and to

which then passes into the gut and is lost in the feces.

synthesize other important chemical compounds from

amino acids. For instance, the so-called nonessential

amino acids can all be synthesized in the liver. To do

Measurement of Bilirubin

this, a keto acid having the same chemical composition

in the Bile as a Clinical

(except at the keto oxygen) as that of the amino acid to

Diagnostic Tool

be formed is synthesized. Then an amino radical is trans-

ferred through several stages of transamination from an

The formation of bile by the liver and the function of

available amino acid to the keto acid to take the place

the bile salts in the digestive and absorptive processes

of the keto oxygen.

of the intestinal tract are discussed in Chapters 64 and

65. In addition, many substances are excreted in the bile

Other Metabolic Functions

and then eliminated in the feces. One of these is the

greenish yellow pigment bilirubin. This is a major end

of the Liver

product of hemoglobin degradation, as pointed out in

The Liver Is a Storage Site for Vitamins. The liver has a par-

Chapter 32. However, it also provides an exceedingly

ticular propensity for storing vitamins and has long been

valuable tool for diagnosing both hemolytic blood

Chapter 70

The Liver as an Organ

863

Plasma

Fragile red blood cells

Reticuloendothelial

system

Free bilirubin (protein-bound)

Liver

Urobilinogen

Liver

Kidneys

Absorbed

Conjugated bilirubin

Urobilinogen

Bacterial

Oxidation

action

Urobilin

Urobilinogen

Stercobilinogen

Oxidation

Stercobilin

Intestinal Contents

Urine

Figure 70-2

Bilirubin formation and excretion.

diseases and various types of liver diseases. Therefore,

forms, the bilirubin is excreted from the hepatocytes by

while referring to Figure 70-2, let us explain this.

an active transport process into the bile canaliculi and

Briefly, when the red blood cells have lived out their

then into the intestines.

life span (on average, 120 days) and have become too

fragile to exist in the circulatory system, their cell

Formation and Fate of Urobilinogen. Once in the intestine,

membranes rupture, and the released hemoglobin is

about half of the “conjugated” bilirubin is converted by

phagocytized by tissue macrophages (also called the

bacterial action into the substance urobilinogen, which

reticuloendothelial system) throughout the body. The

is highly soluble. Some of the urobilinogen is reab-

hemoglobin is first split into globin and heme, and

sorbed through the intestinal mucosa back into the

the heme ring is opened to give (1) free iron, which is

blood. Most of this is re-excreted by the liver back into

transported in the blood by transferrin, and

(2) a

the gut, but about 5 per cent is excreted by the kidneys

straight chain of four pyrrole nuclei, which is the sub-

into the urine. After exposure to air in the urine, the uro-

strate from which bilirubin will eventually be formed.

bilinogen becomes oxidized to urobilin; alternatively, in

The first substance formed is biliverdin, but this is

the feces, it becomes altered and oxidized to form ster-

rapidly reduced to free bilirubin, which is gradually

cobilin. These interrelations of bilirubin and the other

released from the macrophages into the plasma. The

bilirubin products are shown in Figure 70-2.

free bilirubin immediately combines strongly with

plasma albumin and is transported in this combination

throughout the blood and interstitial fluids. Even when

Jaundice—Excess Bilirubin in the

bound with plasma protein, this bilirubin is still called

Extracellular Fluid

“free bilirubin” to distinguish it from “conjugated biliru-

bin,” which is discussed later.

Jaundice refers to a yellowish tint to the body tissues,

Within hours, the free bilirubin is absorbed through

including a yellowness of the skin as well as the deep

the hepatic cell membrane. In passing to the inside of

tissues. The usual cause of jaundice is large quantities of

the liver cells, it is released from the plasma albumin and

bilirubin in the extracellular fluids, either free bilirubin

soon thereafter conjugated about 80 per cent with glu-

or conjugated bilirubin. The normal plasma concentra-

curonic acid to form bilirubin glucuronide, about 10 per

tion of bilirubin, which is almost entirely the free form,

cent with sulfate to form bilirubin sulfate, and about 10

averages 0.5 mg/dl of plasma. In certain abnormal con-

per cent with a multitude of other substances. In these

ditions, this can rise to as high as 40 mg/dl, and much of

864

Unit XIII

Metabolism and Temperature Regulation

it can become the conjugated type. The skin usually

often possible to differentiate among multiple types of

begins to appear jaundiced when the concentration rises

hemolytic diseases and liver diseases, as well as to deter-

to about three times normal—that is, above 1.5 mg/dl.

mine the severity of the disease.

The common causes of jaundice are (1) increased

destruction of red blood cells, with rapid release of

bilirubin into the blood, and (2) obstruction of the bile

References

ducts or damage to the liver cells so that even the usual

amounts of bilirubin cannot be excreted into the gas-

Alison MR, Vig P, Russo F, et al: Hepatic stem cells: from

trointestinal tract. These two types of jaundice are

inside and outside the liver? Cell Prolif 37:1, 2004.

called, respectively, hemolytic jaundice and obstructive

Angulo P: Nonalcoholic fatty liver disease. N Engl J Med

jaundice. They differ from each other in the following

346:1221, 2002.

ways.

Ankoma-Sey V: Hepatic regeneration—revisiting the myth

of Prometheus. News Physiol Sci 14:149, 1999.

Hemolytic Jaundice Is Caused by Hemolysis of Red Blood Cells.

Barthel A, Schmoll D: Novel concepts in insulin regulation

In hemolytic jaundice, the excretory function of the liver

of hepatic gluconeogenesis. Am J Physiol Endocrinol

is not impaired, but red blood cells are hemolyzed so

Metab 285:E685, 2003.

rapidly that the hepatic cells simply cannot excrete the

Bauer M: Heme oxygenase in liver transplantation: heme

bilirubin as quickly as it is formed. Therefore, the

catabolism and metabolites in the search of function.

plasma concentration of free bilirubin rises to above-

Hepatology 38:286, 2003.

normal levels. Likewise, the rate of formation of uro-

Black D, Lyman S, Heider TR, Behrns KE: Molecular and

bilinogen in the intestine is greatly increased, and much

cellular features of hepatic regeneration. J Surg Res

of this is absorbed into the blood and later excreted in

117:306, 2004.

the urine.

Bonder CS, Kubes P: The future of GI and liver research:

editorial perspectives. II. Modulating leukocyte recruit-

Obstructive Jaundice Is Caused by Obstruction of Bile Ducts or

ment to splanchnic organs to reduce inflammation. Am J

Liver Disease. In obstructive jaundice, caused either by

Physiol Gastrointest Liver Physiol 284:G729, 2003.

obstruction of the bile ducts (which most often occurs

Crispe IN: Hepatic T cells and liver tolerance. Nat Rev

when a gallstone or cancer blocks the common bile

Immunol 3:51, 2003.

duct) or by damage to the hepatic cells (which occurs in

Diehl AM: Nonalcoholic steatosis and steatohepatitis. IV.

hepatitis), the rate of bilirubin formation is normal, but

Nonalcoholic fatty liver disease abnormalities in

the bilirubin formed cannot pass from the blood into the

macrophage function and cytokines. Am J Physiol Gas-

intestines. The free bilirubin still enters the liver cells

trointest Liver Physiol 282:G1, 2002.

and becomes conjugated in the usual way. This conju-

Gines P, Cardenas A, Arroyo V, Rodes J: Management of

gated bilirubin is then returned to the blood, probably

cirrhosis and ascites. N Engl J Med 350:1646, 2004.

by rupture of the congested bile canaliculi and direct

Gines P, Guevara M, Arroyo V, Rodes J: Hepatorenal syn-

emptying of the bile into the lymph leaving the liver.

drome. Lancet 362:1819, 2003.

Thus, most of the bilirubin in the plasma becomes the

Iredale JP: Cirrhosis: new research provides a basis for

conjugated type rather than the free type.

rational and targeted treatments. BMJ 327:143, 2003.

Koniaris LG, McKillop IH, Schwartz SI, Zimmers TA: Liver

Diagnostic Differences Between Hemolytic and Obstructive

regeneration. J Am Coll Surg 197:634, 2003.

Jaundice. Chemical laboratory tests can be used to dif-

Li MK, Crawford JM: The pathology of cholestasis. Semin

ferentiate between free and conjugated bilirubin in the

Liver Dis 24:21, 2004.

plasma. In hemolytic jaundice, almost all the bilirubin is

Portincasa P, Moschetta A, Mazzone A, et al: Water handling

in the “free” form; in obstructive jaundice, it is mainly

and aquaporins in bile formation: recent advances and

in the “conjugated” form. A test called the van den

research trends. J Hepatol 39:864, 2003.

Bergh reaction can be used to differentiate between the

Ramadori G, Saile B: Mesenchymal cells in the liver—one

two.

cell type or two? Liver 22:283, 2002.

When there is total obstruction of bile flow, no biliru-

Reichen J: The role of the sinusoidal endothelium in liver

bin can reach the intestines to be converted into uro-

function. News Physiol Sci 14:117, 1999.

bilinogen by bacteria. Therefore, no urobilinogen is

Sands JM: Mammalian urea transporters. Annu Rev Physiol

reabsorbed into the blood, and none can be excreted by

65:543, 2003.

the kidneys into the urine. Consequently, in total

Schoemaker MH, Moshage H: Defying death: the hepato-

obstructive jaundice, tests for urobilinogen in the urine

cyte’s survival kit. Clin Sci (Lond) 107:13, 2004.

are completely negative. Also, the stools become clay

Schrier RW, Gurevich AK, Cadnapaphornchai MA: Patho-

colored owing to a lack of stercobilin and other bile

genesis and management of sodium and water retention

pigments.

in cardiac failure and cirrhosis. Semin Nephrol 21:157,

Another major difference between free and conju-

2001.

gated bilirubin is that the kidneys can excrete small

Su GL: Lipopolysaccharides in liver injury: molecular mech-

quantities of the highly soluble conjugated bilirubin

anisms of Kupffer cell activation. Am J Physiol Gastroin-

but not the albumin-bound free bilirubin. Therefore,

test Liver Physiol 283:G256, 2002.

in severe obstructive jaundice, significant quantities of

Trauner M, Boyer JL: Bile salt transporters: molecular char-

conjugated bilirubin appear in the urine. This can be

acterization, function, and regulation. Physiol Rev 83:633,

demonstrated simply by shaking the urine and observ-

2003.

ing the foam, which turns an intense yellow. Thus,

Wolkoff AW, Cohen DE: Bile acid regulation of hepatic

by understanding the physiology of bilirubin excretion

physiology. I. Hepatocyte transport of bile acids. Am J

by the liver and by the use of a few simple tests, it is

Physiol Gastrointest Liver Physiol 284:G175, 2003.

C H A P T E R

Dietary Balances; Regulation of

Feeding; Obesity and Starvation;

Vitamins and Minerals

Energy Intake and Output

Are Balanced Under Steady-

State Conditions

Intake of carbohydrates, fats, and proteins provides

energy that can be used to perform various body

functions or stored for later use. Stability of body

weight and composition over long periods requires that a person’s energy intake

and energy expenditure be balanced. When a person is overfed and energy

intake persistently exceeds expenditure, most of the excess energy is stored as

fat, and body weight increases; conversely, loss of body mass and starvation

occur when energy intake is insufficient to meet the body’s metabolic needs.

Because different foods contain different proportions of proteins, carbohy-

drates, fats, minerals, and vitamins, appropriate balances must also be main-

tained among these constituents so that all segments of the body’s metabolic

systems can be supplied with the requisite materials. This chapter discusses the

mechanisms by which food intake is regulated in accordance with the body’s

metabolic needs and some of the problems of maintaining balance among the

different types of foods.

Dietary Balances

Energy Available in Foods

The energy liberated from each gram of carbohydrate as it is oxidized to carbon

dioxide and water is 4.1 Calories (1 Calorie equals 1 kilocalorie), and that liberated

from fat is 9.3 Calories. The energy liberated from metabolism of the average dietary

protein as each gram is oxidized to carbon dioxide, water, and urea is 4.35 Calories.

Also, these substances vary in the average percentages that are absorbed from the

gastrointestinal tract: about 98 per cent of carbohydrate, 95 per cent of fat, and 92

per cent of protein. Therefore, the average physiologically available energy in each

gram of these three foodstuffs is as follows:

Calories

Carbohydrate

Fat

Protein

Average Americans receive about 15 per cent of their energy from protein, 40

per cent from fat, and 45 per cent from carbohydrate. In most non-Western coun-

tries, the quantity of energy derived from carbohydrates far exceeds that derived

from both proteins and fats. Indeed, in some parts of the world where meat is scarce,

the energy received from fats and proteins combined may be no greater than 15 to

20 per cent.

Table 71-1 gives the compositions of selected foods, demonstrating especially the

high proportions of fat and protein in meat products and the high proportion of car-

bohydrate in most vegetable and grain products. Fat is deceptive in the diet because

it usually exists as 100 per cent fat, whereas both proteins and carbohydrates are

mixed in watery media so that each of these normally represents less than 25 per

865

866

Unit XIII

Metabolism and Temperature Regulation

Table 71-1

Protein, Fat, and Carbohydrate Content of Different Foods

Food

% Protein

% Fat

% Carbohydrate

Fuel Value per 100 Grams (Calories)

Apples

0.3

0.4

14.9

Asparagus

2.2

0.2

3.9

Bacon, fat

6.2

76.0

0.7

712

broiled

25.0

55.0

1.0

599

Beef (average)

17.5

22.0

1.0

268

Beets, fresh

1.6

0.1

9.6

Bread, white

9.0

3.6

49.8

268

Butter

0.6

81.0

0.4

733

Cabbage

1.4

0.2

5.3

Carrots

1.2

0.3

9.3

Cashew nuts

19.6

47.2

26.4

609

Cheese, cheddar, American

23.9

32.3

1.7

393

Chicken, total edible

21.6

2.7

1.0

111

Chocolate

5.5

52.9

18.0

570

Corn (maize)

10.0

4.3

73.4

372

Haddock

17.2

0.3

0.5

Lamb, leg (average)

18.0

17.5

1.0

230

Milk, fresh whole

3.5

3.9

4.9

Molasses

0.0

60.0

240

Oatmeal, dry, uncooked

14.2

7.4

68.2

396

Oranges

0.9

0.2

11.2

Peanuts

26.9

44.2

23.6

600

Peas, fresh

6.7

0.4

17.7

101

Pork, ham

15.2

31.0

1.0

340

Potatoes

2.0

0.1

19.1

Spinach

2.3

0.3

3.2

Strawberries

0.8

0.6

8.1

Tomatoes

1.0

0.3

4.0

Tuna, canned

24.2

10.8

0.5

194

Walnuts, English

15.0

64.4

15.6

702

cent of the weight. Therefore, the fat of one pat of butter

two substances, and little is derived from proteins.

mixed with an entire helping of potato sometimes con-

Therefore, both carbohydrates and fats are said to

tains as much energy as the potato itself.

be protein sparers. Conversely, in starvation, after the

carbohydrates and fats have been depleted, the

Average Daily Requirement for Protein Is

30 to

50 Grams.

body’s protein stores are consumed rapidly for energy,

Twenty to 30 grams of the body proteins are degraded

sometimes at rates approaching several hundred

and used to produce other body chemicals daily. There-

grams per day rather than the normal daily rate of 30

fore, all cells must continue to form new proteins to take

to 50 grams.

the place of those that are being destroyed, and a supply

of protein is needed in the diet for this purpose. An

average person can maintain normal stores of protein,

Methods for Determining Metabolic

provided the daily intake is above 30 to 50 grams.

Utilization of Proteins,

Some proteins have inadequate quantities of certain

Carbohydrates, and Fats

essential amino acids and therefore cannot be used to

replace the degraded proteins. Such proteins are called

Nitrogen Excretion Can Be Used to Assess Protein Metabolism.

partial proteins, and when they are present in large

The average protein contains about 16 per cent nitro-

quantities in the diet, the daily protein requirement is

gen. During metabolism of the protein, about 90 per

much greater than normal. In general, proteins derived

cent of this nitrogen is excreted in the urine in the form

from animal foodstuffs are more complete than are pro-

of urea, uric acid, creatinine, and other less important

teins derived from vegetable and grain sources. For

nitrogen products. The remaining 10 per cent is excreted

example, the protein of corn has almost no tryptophan,

in the feces. Therefore, the rate of protein breakdown in

one of the essential amino acids. Therefore, individuals

the body can be estimated by measuring the amount of

in economically disadvantaged countries who consume

nitrogen in the urine, then adding 10 per cent for the

cornmeal as the principal source of protein sometimes

nitrogen excreted in the feces, and multiplying by 6.25

develop the protein-deficiency syndrome called kwashi-

(i.e., 100/16) to determine the total amount of protein

orkor, which consists of failure to grow, lethargy,

metabolism in grams per day. Thus, excretion of 8 grams

depressed mentality, and edema caused by low plasma

of nitrogen in the urine each day means that there has

protein concentration.

been about 55 grams of protein breakdown. If the daily

intake of protein is less than the daily breakdown of

Carbohydrates and Fats Act as “Protein Sparers.” When the

protein, the person is said to have a negative nitrogen

diet contains an abundance of carbohydrates and

balance, which means that his or her body stores of

fats, almost all the body’s energy is derived from these

protein are decreasing daily.

Chapter 71

Dietary Balances; Regulation of Feeding; Obesity and Starvation; Vitamins and Minerals

867

“Respiratory Quotient” Is the Ratio of CO₂

Production to O₂

functional systems of the cells, and much of this is

Utilization and Can Be Used to Estimate Fat and Carbohydrate

eventually converted to heat, which is generated as a

Utilization. When carbohydrates are metabolized with

result of protein metabolism, muscle activity, and

oxygen, exactly one carbon dioxide molecule is formed

activities of the various organs and tissues of the body.

for each molecule of oxygen consumed. This ratio of

Excess energy intake is stored mainly as fat, whereas

carbon dioxide output to oxygen usage is called the

a deficit of energy intake causes loss of total body

respiratory quotient, so the respiratory quotient for

mass until energy expenditure eventually equals

carbohydrates is 1.0.

When fat is oxidized in the body’s cells, an average of

energy intake or death occurs.

70 carbon dioxide molecules are formed for each 100

Although there is considerable variability in the

molecules of oxygen consumed. The respiratory quo-

amount of energy storage (i.e., fat mass) in different

tient for the metabolism of fat averages 0.70. When pro-

individuals, maintenance of an adequate energy supply

teins are oxidized by the cells, the average respiratory

is necessary for survival. Therefore, the body is

quotient is 0.80. The reason that the respiratory quo-

endowed with powerful physiologic control systems

tients for fats and proteins are lower than that for

that help maintain adequate energy intake. Deficits of

carbohydrates is that a large share of the oxygen metab-

energy stores, for example, rapidly activate multiple

olized with these foods is required to combine with the

mechanisms that cause hunger and drive a person to

excess hydrogen atoms present in their molecules, so

seek food. In athletes and laborers, energy expenditure

that less carbon dioxide is formed in relation to the

oxygen used.

for the high level of muscle activity may be as high as

Now let us see how one can make use of the respira-

6000 to 7000 Calories per day, compared with only

tory quotient to determine the relative utilization of dif-

about 2000 Calories per day for sedentary individuals.

ferent foods by the body. First, it will be recalled from

Thus, a large energy expenditure associated with phys-

Chapter 39 that the output of carbon dioxide by the

ical work usually stimulates equally large increases in

lungs divided by the uptake of oxygen during the same

caloric intake.

period is called the respiratory exchange ratio. Over a

What are the physiologic mechanisms that sense

period of 1 hour or more, the respiratory exchange ratio

changes in energy balance and influence the quest

exactly equals the average respiratory quotient of the

for food? Maintenance of adequate energy supply in

metabolic reactions throughout the body. If a person has

the body is so critical that there are multiple short-

a respiratory quotient of 1.0, he or she is metabolizing

almost entirely carbohydrates, because the respiratory

term and long-term control systems that regulate not

quotients for both fat and protein metabolism are con-

only food intake but also energy expenditure and

siderably less than 1.0. Likewise, when the respiratory

energy stores. In the next few sections we describe

quotient is about 0.70, the body is metabolizing almost

some of these control systems and their operation

entirely fats, to the exclusion of carbohydrates and

in physiologic conditions, as well as in obesity and

proteins. And, finally, if we ignore the normally small

starvation.

amount of protein metabolism, respiratory quotients

between 0.70 and 1.0 describe the approximate ratios of

carbohydrate to fat metabolism. To be more exact, one

Neural Centers Regulate Food Intake

can first determine the protein utilization by measuring

nitrogen excretion and then, using the appropriate

mathematical formula, calculate almost exactly the uti-

The sensation of hunger is associated with a craving

lization of the three foodstuffs.

for food and several other several physiologic effects,

Some of the important findings from studies of respi-

such as rhythmical contractions of the stomach and

ratory quotients are the following:

restlessness, which cause the person to search for an

1. Immediately after a meal, almost all the food

adequate food supply. A person’s appetite is a desire

that is metabolized is carbohydrates, so that the

for food, often of a particular type, and is useful in

respiratory quotient at that time approaches 1.0.

helping to choose the quality of the food to be eaten.

2. About 8 to 10 hours after a meal, the body has

If the quest for food is successful, the feeling of satiety

already used up most of its readily available

occurs. Each of these feelings is influenced by envi-

carbohydrates, and the respiratory quotient

ronmental and cultural factors, as well as by physio-

approaches that for fat metabolism, about 0.70.

3. In untreated diabetes mellitus, little carbohydrate

logic controls that influence specific centers of the

can be used by the body’s cells under any

brain, especially the hypothalamus.

conditions, because insulin is required for this.

Therefore, when diabetes is severe, most of the

The Hypothalamus Contains Hunger and Satiety Centers.

time the respiratory quotient remains near that for

Several neuronal centers of the hypothalamus partici-

fat metabolism, 0.70.

pate in the control of food intake. The lateral nuclei of

the hypothalamus serve as a feeding center, and stimu-

lation of this area causes an animal to eat voraciously

Regulation of Food Intake and

(hyperphagia). Conversely, destruction of the lateral

Energy Storage

hypothalamus causes lack of desire for food and

progressive inanition, a condition characterized by

Stability of the body’s total mass and composition over

marked weight loss, muscle weakness, and decreased

long periods requires that energy intake match energy

metabolism. The lateral hypothalamic feeding center

expenditure. As discussed in Chapter 72, only about 27

operates by exciting the motor drives to search for

per cent of the energy ingested normally reaches the

food.

868

Unit XIII

Metabolism and Temperature Regulation

The ventromedial nuclei of the hypothalamus serve

as the satiety center. This center is believed to give a

sense of nutritional satisfaction that inhibits the

Hypothalamus

feeding center. Electrical stimulation of this region can

cause complete satiety, and even in the presence

of highly appetizing food, the animal refuses to eat

(aphagia). Conversely, destruction of the ventromedial

nuclei causes voracious and continued eating until the

animal becomes extremely obese, sometimes as large

as four times normal.

The paraventricular, dorsomedial, and arcuate nuclei

of the hypothalamus also play a major role in regulat-

ing food intake. For example, lesions of the paraven-

tricular nuclei often cause excessive eating, whereas

Vagus nerve

lesions of the dorsomedial nuclei usually depress

eating behavior. As discussed later, the arcuate nuclei

are the sites in the hypothalamus where multiple hor-

mones released from the gastrointestinal tract and

adipose tissue converge to regulate food intake as well

as energy expenditure.

There is much chemical cross-talk among the

neurons on the hypothalamus, and together, these

centers coordinate the processes that control eating

behavior and the perception of satiety. These nuclei

Stomach

of the hypothalamus also influence the secretion of

several hormones that are important in regulating

Leptin

Ghrelin

energy balance and metabolism, including those from

the thyroid and adrenal glands, as well as the pancre-

Insulin

atic islet cells.

CCK

The hypothalamus receives neural signals from the

gastrointestinal tract that provide sensory information

PYY

about stomach filling, chemical signals from nutrients

Large intestine

Small intestine

in the blood (glucose, amino acids, and fatty acids) that

signify satiety, signals from gastrointestinal hormones,

Figure 71-1

signals from hormones released by adipose tissue,

and signals from the cerebral cortex (sight, smell,

Feedback mechanisms for control of food intake. Stretch recep-

and taste) that influence feeding behavior. Some of

tors in the stomach activate sensory afferent pathways in the

vagus nerve and inhibit food intake. Peptide YY (PYY), cholecys-

these inputs to the hypothalamus are shown in Figure

tokinin (CCK), and insulin are gastrointestinal hormones that are

71-1.

released by the ingestion of food and suppress further feeding.

The hypothalamic feeding and satiety centers have

Ghrelin is released by the stomach, especially during fasting, and

a high density of receptors for neurotransmitters and

stimulates appetite. Leptin is a hormone produced in increasing

amounts by fat cells as they increase in size; it inhibits food intake.

hormones that influence feeding behavior. A few of

the many substances that have been shown to alter

appetite and feeding behavior in experimental studies

are listed in Table 71-2 and are generally categorized

As discussed later, these neurons appear to be the

as (1) orexigenic substances that stimulate feeding, or

major targets for the actions of several hormones that

(2) anorexigenic substances that inhibit feeding.

regulate appetite, including leptin, insulin, cholecys-

tokinin (CCK), and ghrelin. In fact, the neurons of the

Neurons and Neurotransmitters in the Hypothalamus That Stim-

arcuate nuclei appear to be a site of convergence of

ulate or Inhibit Feeding. There are two distinct types of

many of the nervous and peripheral signals that regu-

neurons in the arcuate nuclei of the hypothalamus that

late energy stores.

are especially important as controllers of both appetite

The POMC neurons release a-MSH, which then

and energy expenditure

(Figure

71-2):

(1) pro-

acts on melanocortin receptors found especially in

opiomelanocortin (POMC) neurons that produce a-

neurons of the paraventricular nuclei. Although there

melanocyte-stimulating hormone (a-MSH) together

are at least five subtypes of melanocortin receptor

with cocaine- and amphetamine-related transcript

(MCR), MCR-3 and MCR-4 are especially important

(CART), and (2) neurons that produce the orexigenic

in regulating food intake and energy balance. Activa-

substances neuropeptide Y (NPY) and agouti-related

tion of these receptors reduces food intake while

protein (AGRP). Activation of the POMC neurons

increasing energy expenditure. Conversely, inhibition

decreases food intake and increases energy expendi-

of MCR-3 and MCR-4 greatly increases food intake

ture, whereas activation of the NPY-AGRP neurons

and decreases energy expenditure. The effect of MCR

increases food intake and reduces energy expenditure.

activation to increase energy expenditure appears to

Chapter 71

Dietary Balances; Regulation of Feeding; Obesity and Starvation; Vitamins and Minerals

869

Table 71-2

Neurotransmitters and Hormones That Influence Feeding and Satiety Centers in the Hypothalamus

Decrease Feeding (Anorexigenic)

Increase Feeding (Orexigenic)

a-Melanocyte-stimulating hormone (a-MSH)

Neuropeptide Y (NPY)

Leptin

Agouti-related protein (AGRP)

Serotonin

Melanin-concentrating hormone (MCH)

Norepinephrine

Orexins A and B

Corticotropin-releasing hormone

Endorphins

Insulin

Galanin (GAL)

Cholecystokinin (CCK)

Amino acids (glutamate and g-aminobutyric acid)

Glucagon-like peptide (GLP)

Cortisol

Cocaine- and amphetamine-regulated transcript (CART)

Ghrelin

Peptide YY (PYY)

Food intake

Neurons

Neuron

of PVN

Y₁r

MCR-4

a-MSH

To nucleus

tractus solitarius

Food

(NTS)

intake

•Sympathetic activity

Food

•Energy expenditure

intake

AGRP/

Y₁r

NPY

Arcuate

nucleus

MCR-3

POMC/

CART

Third

ventricle

LepR

MCR-3

a-MSH

LepR

Insulin,

Ghrelin

leptin,

CCK

Figure 71-2

Control of energy balance by two types of neurons of the arcuate nuclei: (1) pro-opiomelanocortin (POMC) neurons that release a-

melanocyte-stimulating hormone (a-MSH) and cocaine- and amphetamine-regulated transcript (CART), decreasing food intake and

increasing energy expenditure; and (2) neurons that produce agouti-related protein (AGRP) and neuropeptide Y (NPY), increasing food

intake and reducing energy expenditure. a-MSH released by POMC neurons stimulates melanocortin receptors (MCR-3 and MCR-4) in

the paraventricular nuclei (PVN), which then activate neuronal pathways that project to the nucleus tractus solitarius (NTS) and increase

sympathetic activity and energy expenditure. AGRP acts as an antagonist of MCR-4. Insulin, leptin, and cholecystokinin (CCK) are hor-

mones that inhibit AGRP-NPY neurons and stimulate adjacent POMC-CART neurons, thereby reducing food intake. Ghrelin, a hormone

secreted from the stomach, activates AGRP-NPY neurons and stimulates food intake. LepR, leptin receptor; Y₁R, neuropeptide Y1

receptor. (Redrawn from Barsh GS, Schwartz MW: Nature Rev Genetics 3:589, 2002).

be mediated, at least in part, by activation of neuronal

associated with extreme obesity. In fact, mutations of

pathways that project from the paraventricular nuclei

MCR-4 represent the most common known mono-

to the nucleus tractus solitarius and stimulate sympa-

genic (single-gene) cause of human obesity, and some

thetic nervous system activity.

studies suggest that MCR-4 mutations may account for

The hypothalamic melanocortin system plays a pow-

as much as 5 to 6 percent of early-onset severe obesity

erful role in regulating energy stores of the body, and

in children. In contrast, excessive activation of the

defective signaling of the melanocortin pathway is

melanocortin system reduces appetite. Some studies

870

Unit XIII

Metabolism and Temperature Regulation

suggest that this activation may play a role in causing

Short-Term Regulation of Food Intake

the anorexia associated with severe infections or

When a person is driven by hunger to eat voraciously

cancer tumors.

and rapidly, what turns off the eating when he or she

AGRP released from the orexigenic neurons of the

has eaten enough? There has not been enough time for

hypothalamus is a natural antagonist of MCR-3 and

changes in the body’s energy stores to occur, and

MCR-4 and probably increases feeding by inhibiting

it takes hours for enough nutritional factors to be

the effects of a-MSH to stimulate melanocortin recep-

absorbed into the blood to cause the necessary inhibi-

tors (see Figure 71-2). Although the role of AGRP in

tion of eating. Yet it is important that the person not

normal physiologic control of food intake is unclear,

overeat and that he or she eat an amount of food that

excessive formation of AGRP in mice and humans,

approximates nutritional needs. The following are

due to gene mutations, is associated with excessive

several types of rapid feedback signals that are impor-

feeding and obesity.

tant for these purposes.

NPY is also released from orexigenic neurons of the

arcuate nuclei. When energy stores of the body are

Gastrointestinal Filling Inhibits Feeding. When the gas-

low, orexigenic neurons are activated to release NPY,

trointestinal tract becomes distended, especially the

which stimulates appetite. At the same time, firing of

stomach and the duodenum, stretch inhibitory signals

the POMC neurons is reduced, thereby decreasing the

are transmitted mainly by way of the vagi to suppress

activity of the melanocortin pathway and further stim-

the feeding center, thereby reducing the desire for

ulating appetite.

food (Fig. 71-1).

Neural Centers That Influence the Mechanical Process of

Feeding. Another aspect of feeding is the mechanical

Gastrointestinal Hormonal Factors Suppress Feeding. Chole-

act of the feeding process itself. If the brain is sec-

cystokinin is released mainly in response to fat enter-

tioned below the hypothalamus but above the mesen-

ing the duodenum and has a direct effect on the

cephalon, the animal can still perform the basic

feeding centers to reduce subsequent eating. Studies in

mechanical features of the feeding process. It can sali-

experimental animals suggest that CCK may decrease

vate, lick its lips, chew food, and swallow. Therefore,

feeding mainly by activation of the melanocortin

the actual mechanics of feeding are controlled by

pathway in the hypothalamus.

centers in the brain stem. The function of the other

Peptide YY (PYY) is secreted from the entire gas-

centers in feeding, then, is to control the quantity of

trointestinal tract, but especially from the ileum and

food intake and to excite these centers of feeding

colon. Food intake stimulates release of PYY, with

mechanics to activity.

blood concentrations rising to peak levels 1 to 2 hours

Neural centers higher than the hypothalamus also

after ingesting a meal. These peak levels of PYY are

play important roles in the control of feeding, partic-

influenced by the number of calories ingested and the

ularly in the control of appetite. These centers include

composition of the food, with higher levels of PYY

the amygdala and the prefrontal cortex, which are

observed after meals with a high fat content. Although

closely coupled with the hypothalamus. It will be

injections of PYY into mice have been shown to

recalled from the discussion of the sense of smell in

decrease food intake for 12 hours or more, the impor-

Chapter 53 that portions of the amygdala are a major

tance of this gastrointestinal hormone in regulating

part of the olfactory nervous system. Destructive

appetite in humans is still unclear.

lesions in the amygdala have demonstrated that some

For reasons that are not entirely understood, the

of its areas increase feeding, whereas others inhibit

presence of food in the intestines stimulates them to

feeding. In addition, stimulation of some areas of the

secrete glucagon-like peptide, which in turn enhances

amygdala elicits the mechanical act of feeding. An

glucose-dependent insulin production and secretion

important effect of destruction of the amygdala on

from the pancreas. Glucagon-like peptide and insulin

both sides of the brain is a “psychic blindness” in the

both tend to suppress appetite. Thus, eating a meal

choice of foods. In other words, the animal (and pre-

stimulates the release of several gastrointestinal hor-

sumably the human being as well) loses or at least par-

mones that may induce satiety and reduce further

tially loses the appetite control that determines the

intake of food (see Fig. 71-1).

type and quality of food it eats.

Ghrelin—a Gastrointestinal Hormone—Increases Feeding.

Ghrelin is a hormone released mainly by the oxyntic

Factors That Regulate Quantity

cells of the stomach but also, to a much less extent, by

of Food Intake

the intestine. Blood levels of ghrelin rise during

fasting, peak just before eating, and then fall rapidly

Regulation of the quantity of food intake can be

after a meal, suggesting a possible role in stimulating

divided into short-term regulation, which is concerned

feeding. Also, administration of ghrelin increases food

primarily with preventing overeating at each meal, and

intake in experimental animals, further supporting

long-term regulation, which is concerned primarily

the possibility that it may be an orexigenic hormone.

with maintenance of normal quantities of energy

However, its physiologic role in humans is still

stores in the body.

uncertain.

Chapter 71

Dietary Balances; Regulation of Feeding; Obesity and Starvation; Vitamins and Minerals

871

Oral Receptors Meter Food Intake. When an animal with

system. This is important, because increased food

an esophageal fistula is fed large quantities of food,

intake in a cold animal (1) increases its metabolic rate

even though this food is immediately lost again to the

and (2) provides increased fat for insulation, both of

exterior, the degree of hunger is decreased after a

which tend to correct the cold state.

reasonable quantity of food has passed through the

mouth. This effect occurs despite the fact that the gas-

Feedback Signals from Adipose Tissue Regulate Food Intake.

trointestinal tract does not become the least bit filled.

Most of the stored energy in the body consists of fat,

Therefore, it is postulated that various “oral factors”

the amount of which can vary considerably in differ-

related to feeding, such as chewing, salivation, swal-

ent individuals. What regulates this energy reserve, and

lowing, and tasting, “meter” the food as it passes

why is there so much variability among individuals?

through the mouth, and after a certain amount has

Recent studies suggest that the hypothalamus

passed, the hypothalamic feeding center becomes

senses energy storage through the actions of leptin, a

inhibited. However, the inhibition caused by this

peptide hormone released from adipocytes. When the

metering mechanism is considerably less intense and

amount of adipose tissue increases (signaling excess

of shorter duration, usually lasting for only 20 to 40

energy storage), the adipocytes produce increased

minutes, than is the inhibition caused by gastrointesti-

amounts of leptin, which is released into the blood.

nal filling.

Leptin then circulates to the brain, where it moves

across the blood-brain barrier by facilitated diffusion

Intermediate and Long-Term Regulation

and occupies leptin receptors at multiple sites in the

of Food Intake

hypothalamus, especially the POMC neurons of the

An animal that has been starved for a long time and

arcuate nuclei and neurons of the paraventricular

is then presented with unlimited food eats a far greater

nuclei.

quantity than does an animal that has been on a

Stimulation of leptin receptors in these hypothala-

regular diet. Conversely, an animal that has been force-

mic nuclei initiates multiple actions that decrease fat

fed for several weeks eats very little when allowed to

storage, including

(1) decreased production in the

eat according to its own desires. Thus, the feeding

hypothalamus of appetite stimulators, such as NPY

control mechanism of the body is geared to the nutri-

and AGRP; (2) activation of POMC neurons, causing

tional status of the body.

release of a-MSH and activation of melanocortin

receptors; (3) increased production in the hypothala-

Effect of Blood Concentrations of Glucose, Amino Acids, and

mus of substances, such as corticotropin-releasing

Lipids on Hunger and Feeding. It has long been known that

hormone, that decrease food intake; (4) increased

a decrease in blood glucose concentration causes

sympathetic nerve activity (through neural projections

hunger, which has led to the so-called glucostatic

from the hypothalamus to the vasomotor centers),

theory of hunger and feeding regulation. Similar

which increases metabolic rate and energy expendi-

studies have demonstrated the same effect for blood

ture; and (5) decreased insulin secretion by the pan-

amino acid concentration and blood concentration of

creatic beta cells, which decreases energy storage.

breakdown products of lipids such as the keto acids

Thus, leptin may be an important means by which

and some fatty acids, leading to the aminostatic and

the adipose tissue signals the brain that enough energy

lipostatic theories of regulation. That is, when the avail-

has been stored and that intake of food is no longer

ability of any of the three major types of food

necessary.

decreases, the desire for feeding is increased, eventu-

In mice or humans with mutations that render their

ally returning the blood metabolite concentrations

fat cells unable to produce leptin or mutations that

back toward normal.

cause defective leptin receptors in the hypothalamus,

Neurophysiologic studies of function in specific

marked hyperphagia and morbid obesity occur. In

areas of the brain also support the glucostatic, amino-

most obese humans, however, there does not appear

static, and lipostatic theories, by the following obser-

to be a deficiency of leptin production, because plasma

vations: (1) A rise in blood glucose level increases the

leptin levels increase in proportion with increasing

rate of firing of glucoreceptor neurons in the satiety

adiposity. Therefore, some physiologists believe that

center in the ventromedial and paraventricular nuclei of

obesity may be associated with leptin resistance; that

the hypothalamus. (2) The same increase in blood

is, leptin receptors or post-receptor signaling pathways

glucose level simultaneously decreases the firing of glu-

normally activated by leptin may be defective in obese

cosensitive neurons in the hunger center of the lateral

people, who continue to eat despite very high levels of

hypothalamus. In addition, some amino acids and lipid

leptin.

substances affect the rates of firing of these same

Another explanation for the failure of leptin to

neurons or other closely associated neurons.

prevent increasing adiposity in obese individuals is

that there are many redundant systems that control

Temperature Regulation and Food Intake. When an animal

feeding behavior, as well as social and cultural factors

is exposed to cold, it tends to increase feeding; when

that can cause continued excess food intake even in

it is exposed to heat, it tends to decrease its caloric

the presence of high levels of leptin.

intake. This is caused by interaction within the hypo-

thalamus between the temperature-regulating system

Summary of Long-Term Regulation. Even though our

(see Chapter

73) and the food intake-regulating

information on the different feedback factors in

872

Unit XIII

Metabolism and Temperature Regulation

long-term feeding regulation is imprecise, we can

liver and other tissues of the body often accumulate sig-

make the following general statement: When the

nificant amounts of lipids in obese persons. The meta-

energy stores of the body fall below normal, the

bolic processes involved in fat storage were discussed in

Chapter 68.

feeding centers of the hypothalamus and other areas

It was previously believed that the number of

of the brain become highly active, and the person

adipocytes could increase substantially only during

exhibits increased hunger as well as searching for food;

infancy and childhood and that excess energy intake

conversely, when the energy stores (mainly the fat

in children led to hyperplastic obesity, associated with

stores) are already abundant, the person usually loses

increased numbers of adipocytes and only small

the sensation of hunger and develops a state of satiety.

increases in adipocyte size. In contrast, obesity devel-

oping in adults was thought to increase only adipocyte

Importance of Having Both Long- and Short-

size, resulting in hypertrophic obesity. Recent studies,

Term Regulatory Systems for Feeding

however, have shown that new adipocytes can differen-

The long-term regulatory system for feeding, which

tiate from fibroblast-like preadipocytes at any period of

life and that the development of obesity in adults is

includes all the nutritional energy feedback mecha-

accompanied by increased numbers, as well as increased

nisms, helps maintain constant stores of nutrients in

size, of adipocytes. An extremely obese person may have

the tissues, preventing them from becoming too low or

as many as four times as many adipocytes, each con-

too high. The short-term regulatory stimuli serve two

taining twice as much lipid, as a lean person.

other purposes. First, they tend to make the person eat

Once a person has become obese and a stable weight

smaller quantities at each eating session, thus allowing

is obtained, energy intake once again equals energy

food to pass through the gastrointestinal tract at a

output. For a person to lose weight, energy intake must

steadier pace, so that its digestive and absorptive

be less than energy expenditure.

mechanisms can work at optimal rates rather than

becoming periodically overburdened. Second, they

help prevent the person from eating amounts at each

Decreased Physical Activity and

meal that would be too much for the metabolic storage

Abnormal Feeding Regulation as

systems once all the food has been absorbed.

Causes of Obesity

The causes of obesity are complex. Although genes

Obesity

play an important role in determining food intake and

energy metabolism, lifestyle and environmental factors

Obesity can be defined as an excess of body fat. A sur-

may play the dominant role in many obese people. The

rogate marker for body fat content is the body mass

rapid increase in the prevalence of obesity in the past

index (BMI), which is calculated as:

20 to 30 years emphasizes the important role of lifestyle

and environmental factors, because genetic changes

BMI = Weight in kg/Height m²

could not have occurred so rapidly.

In clinical terms, a BMI between 25 and 29.9 kg/m²is

called overweight, and a BMI greater than 30 kg/m² is

Sedentary Lifestyle Is a Major Cause of Obesity. Regular phys-

called obese. BMI is not a direct estimate of adiposity

ical activity and physical training are known to increase

and does not take into account the fact that some indi-

muscle mass and decrease body fat mass, whereas

viduals have a high BMI due to a large muscle mass. A

inadequate physical activity is typically associated

better way to define obesity is to actually measure the

with decreased muscle mass and increased adiposity.

percentage of total body fat. Obesity is usually defined

For example, studies have shown a close association

as 25 per cent or greater total body fat in men and 35

between sedentary behaviors, such as prolonged televi-

per cent or greater in women. Although percentage of

sion watching, and obesity.

body fat can be estimated with various methods, such as

About 25 to 30 per cent of the energy used each day

measuring skin-fold thickness, bioelectrical impedance,

by the average person goes into muscular activity, and

or underwater weighing, these methods are rarely used

in a laborer, as much as 60 to 70 per cent is used in this

in clinical practice, where BMI is commonly used to

way. In obese people, increased physical activity usually

assess obesity.

increases energy expenditure more than food intake,

The prevalence of obesity in children and adults in

resulting in significant weight loss. Even a single episode

the United States and in many other industrialized

of strenuous exercise may increase basal energy expen-

countries is rapidly increasing, rising by more than 30

diture for several hours after the physical activity is

per cent over the past decade. Approximately 64 per

stopped. Because muscular activity is by far the most

cent of adults in the United States are overweight, and

important means by which energy is expended in the

nearly 33 per cent of adults are obese.

body, increased physical activity is often an effective

means of reducing fat stores.

Obesity Results from Greater Energy Intake than Energy Expendi-

ture. When greater quantities of energy (in the form of

Abnormal Feeding Behavior Is an Important Cause of Obesity.

food) enter the body than are expended, the body

Although powerful physiologic mechanisms regulate

weight increases, and most of the excess energy is stored

food intake, there are also important environmental and

as fat. Therefore, excessive adiposity (obesity) is caused

psychological factors that can cause abnormal feeding

by energy intake in excess of energy output. For each

behavior, excessive energy intake, and obesity.

9.3 Calories of excess energy that enter the body,

approximately 1 gram of fat is stored.

Environmental, Social, and Psychological Factors Con-

Fat is stored mainly in adipocytes in subcutaneous

tribute to Abnormal Feeding. As discussed previously,

tissue and in the intraperitoneal cavity, although the

the importance of environmental factors is evident from

Chapter 71

Dietary Balances; Regulation of Feeding; Obesity and Starvation; Vitamins and Minerals

873

the rapid increase in the prevalence of obesity in most

Genes can contribute to obesity by causing abnor-

industrialized countries, which has coincided with an

malities of (1) one or more of the pathways that regu-

abundance of high-energy foods (especially fatty foods)

late the feeding centers and (2) energy expenditure and

and sedentary lifestyles.

fat storage. Three of the monogenic (single-gene) causes

Psychological factors may contribute to obesity in

of obesity are

(1) mutations of MCR-4, the most

some people. For example, people often gain large

common monogenic form of obesity discovered thus

amounts of weight during or after stressful situations,

far; (2) congenital leptin deficiency caused by mutations

such as the death of a parent, a severe illness, or even

of the leptin gene, which are very rare; and (3) muta-

mental depression. It seems that eating can be a means

tions of the leptin receptor, also very rare. All these

of releasing tension.

monogenic forms of obesity account for only a very

small percentage of obesity. It is likely that many gene

Childhood Overnutrition as a Possible Cause of Obesity.

variations interact with environmental factors to influ-

One factor that may contribute to obesity is the preva-

ence the amount and distribution of body fat.

lent idea that healthy eating habits require three meals

a day and that each meal must be filling. Many young

children are forced into this habit by overly solicitous

Treatment of Obesity

parents, and the children continue to practice it

throughout life.

Treatment of obesity depends on decreasing energy

The rate of formation of new fat cells is especially

input below energy expenditure and creating a sus-

rapid in the first few years of life, and the greater the

tained negative energy balance until the desired weight

rate of fat storage, the greater the number of fat cells.

loss is achieved. In other words, this means either reduc-

The number of fat cells in obese children is often as

ing energy intake or increasing energy expenditure. The

much as three times that in normal children. Therefore,

current National Institutes of Health (NIH) guidelines

it has been suggested that overnutrition of children—

recommend a decrease in caloric intake of 500 kilo-

especially in infancy and, to a lesser extent, during the

calories per day for overweight and moderately obese

later years of childhood—can lead to a lifetime of

persons (BMI greater than 25 but less than 35 kg/m²) to

obesity.

achieve a weight loss of approximately 1 pound each

week. A more aggressive energy deficit of 500 to 1000

kilocalories per day is recommended for persons with

Neurogenic Abnormalities as a Cause of Obesity. We pre-

BMIs greater than 35 kg/m². Typically, such an energy

viously pointed out that lesions in the ventromedial

deficit, if it can be achieved and sustained, will cause a

nuclei of the hypothalamus cause an animal to eat

weight loss of about 1 to 2 pounds per week, or about a

excessively and become obese. People with hypophysial

10 per cent weight loss after 6 months. For most people

tumors that encroach on the hypothalamus often

attempting to lose weight, increasing physical activity is

develop progressive obesity, demonstrating that obesity

also an important component of successful long-term

in human beings, too, can result from damage to the

weight loss.

hypothalamus.

To decrease energy intake, most reducing diets are

Although hypothalamic damage is almost never

designed to contain large quantities of “bulk,” which is

found in obese people, it is possible that the functional

generally made up of non-nutritive cellulose substances.

organization of the hypothalamic or other neurogenic

This bulk distends the stomach and thereby partially

feeding centers in obese individuals is different from

appeases hunger. In most lower animals, such a proce-

that in nonobese persons. Also, there may be abnor-

dure simply makes the animal increase its food intake

malities of neurotransmitters or receptor mechanisms in

even more, but human beings can often fool themselves

the neural pathways of the hypothalamus that control

because their food intake is sometimes controlled as

feeding. In support of this theory, an obese person who

much by habit as by hunger. As pointed out later in con-

has reduced to normal weight by strict dietary measures

nection with starvation, it is important to prevent

usually develops intense hunger that is demonstrably

vitamin deficiencies during the dieting period.

far greater than that of a normal person. This indicates

Various drugs for decreasing the degree of hunger

that the “set-point” of an obese person’s feeding control

have been used in the treatment of obesity. The most

system is at a much higher level of nutrient storage than

widely used drugs are amphetamines (or amphetamine

that of a nonobese person.

derivatives), which directly inhibit the feeding centers

Studies in experimental animals also indicate that

in the brain. One drug for treating obesity is sibu-

when food intake is restricted in obese animals, there

tramine, a sympathomimetic that reduces food intake

are marked neurotransmitter changes in the hypothala-

and increases energy expenditure. The danger in using

mus that greatly increase hunger and oppose weight

these drugs is that they simultaneously overexcite the

loss. Some of these changes include increased formation

central nervous system, making the person nervous and

of orexigenic neurotransmitters such as NPY and

elevating the blood pressure. Also, a person soon adapts

decreased formation of anorexic substances such as

to the drug, so that weight reduction is usually no

leptin and a-MSH.

greater than 5 to 10 per cent.

Another group of drugs works by altering lipid

Genetic Factors as a Cause of Obesity. Obesity definitely

metabolism. For example, orlistat, a lipase inhibitor,

runs in families. Yet it has been difficult to determine

reduces the intestinal digestion of fat. This causes a

the precise role of genetics in contributing to obesity,

portion of the ingested fat to be lost in the feces and

because family members generally share many of the

therefore reduces energy absorption. However, fecal fat

same eating habits and physical activity patterns.

loss may cause unpleasant gastrointestinal side effects,

Current evidence, however, suggests that 20 to 25 per

as well as loss of fat-soluble vitamins in the feces.

cent of cases of obesity may be caused by genetic

Significant weight loss can be achieved in many obese

factors.

persons with increased physical activity. The more

874

Unit XIII

Metabolism and Temperature Regulation

exercise one gets, the greater the daily energy expendi-

Several inflammatory cytokines, including tumor

ture and the more rapidly the obesity disappears.

necrosis factor-a , interleukin-6, interleukin-1b, and a

Therefore, forced exercise is often an essential part of

proteolysis-inducing factor, have been shown to cause

treatment. The current clinical guidelines for the treat-

anorexia and cachexia. Most of these inflammatory

ment of obesity recommend that the first step be

cytokines appear to mediate anorexia by activation of

lifestyle modifications that include increased physical

the melanocortin system in the hypothalamus. The

activity combined with a reduction in caloric intake. For

precise mechanisms by which cytokines or tumor prod-

morbidly obese patients with BMIs greater than 40, or

ucts interact with the melanocortin pathway to decrease

for patients with BMIs greater than 35 and conditions

food intake are still unclear, but blockade of the hypo-

such as hypertension or type II diabetes that predispose

thalamic melanocortin receptors appears to almost

them to other serious diseases, various surgical proce-

completely prevent their anorexic and cachectic effects

dures can be used to decrease the fat mass of the body

in experimental animals. Additional research, however,

or to decrease the amount of food that can be eaten at

is needed to better understand the pathophysiologic

each meal.

mechanisms of anorexia and cachexia in cancer patients

Two of the most common surgical procedures used in

and to develop therapeutic agents to improve their

the United States to treat morbid obesity are gastric

nutritional status and survival.

bypass surgery and gastric banding surgery. Gastric

bypass surgery involves construction of a small pouch in

the proximal part of the stomach that is then connected

Starvation

to the jejunum with a section of small bowel of varying

Depletion of Food Stores in the Body Tissues During Starvation.

lengths; the pouch is separated from the remaining part

Even though the tissues preferentially use carbohydrate

of the stomach with staples. Gastric banding surgery

for energy over both fat and protein, the quantity of car-

involves placing an adjustable band around the stomach

bohydrate normally stored in the entire body is only a

near its upper end; this also creates a small stomach

few hundred grams (mainly glycogen in the liver and

pouch that restricts the amount of food that can be

muscles), and it can supply the energy required for body

eaten at each meal. Although these surgical procedures

functions for perhaps half a day. Therefore, except for

generally produce substantial weight loss in obese

the first few hours of starvation, the major effects are

patients, they are major operations, and their long-

progressive depletion of tissue fat and protein. Because

term effects on overall health and mortality are still

fat is the prime source of energy (100 times as much fat

uncertain.

energy is stored in the normal person as carbohydrate

energy), the rate of fat depletion continues unabated, as

shown in Figure 71-3, until most of the fat stores in the

Inanition, Anorexia, and

body are gone.

Cachexia

Protein undergoes three phases of depletion: rapid

depletion at first, then greatly slowed depletion, and,

Inanition is the opposite of obesity and is characterized

finally, rapid depletion again shortly before death. The

by extreme weight loss. It can be caused by inadequate

initial rapid depletion is caused by the use of easily

availability of food or by pathophysiologic conditions

mobilized protein for direct metabolism or for conver-

that greatly decrease the desire for food, including psy-

sion to glucose and then metabolism of glucose mainly

chogenic disturbances, hypothalamic abnormalities,

by the brain. After the readily mobilized protein stores

and factors released from peripheral tissues. In many

have been depleted during the early phase of starvation,

instances, especially in those with serious diseases such

as cancer, the reduced desire for food may be associated

with increased energy expenditure, causing serious

weight loss.

Anorexia can be defined as a reduction in food intake

caused primarily by diminished appetite, as opposed to

the literal definition of “not eating.” This definition

emphasizes the important role of central neural mech-

anisms in the pathophysiology of anorexia in diseases

Protein

such as cancer, when other common problems, such as

pain and nausea, may also cause a person to consume

less food. Anorexia nervosa is an abnormal psychic state

in which a person loses all desire for food and even

Fat

becomes nauseated by food; as a result, severe inanition

occurs.

Cachexia is a metabolic disorder of increased energy

expenditure leading to weight loss greater than that

caused by reduced food intake alone. Anorexia and

cachexia often occur together in many types of cancer

Carbohydrate

or in the

“wasting syndrome” observed in patients

with acquired immunodeficiency syndrome (AIDS) and

Weeks of starvation

chronic inflammatory disorders. Almost all types of

cancer cause both anorexia and cachexia, and more than

half of cancer patients develop anorexia-cachexia syn-

drome during the course of their disease.

Figure 71-3

Central neural and peripheral factors are believed to

contribute to cancer-induced anorexia and cachexia.

Effect of starvation on the food stores of the body.

Chapter 71

Dietary Balances; Regulation of Feeding; Obesity and Starvation; Vitamins and Minerals

875

the remaining protein is not so easily removed. At this

major extent in the liver. For instance, the quantity of

time, the rate of gluconeogenesis decreases to one third

vitamin A stored in the liver may be sufficient to main-

to one fifth its previous rate, and the rate of depletion

tain a person for 5 to 10 months without any intake of

of protein becomes greatly decreased. The lessened

vitamin A. The quantity of vitamin D stored in the liver

availability of glucose then initiates a series of events

is usually sufficient to maintain a person for 2 to 4

that leads to excessive fat utilization and conversion of

months without any additional intake of vitamin D.

some of the fat breakdown products to ketone bodies,

The storage of most water-soluble vitamins is rela-

producing the state of ketosis, which is discussed in

tively slight. This applies especially to most vitamin B

Chapter 68. The ketone bodies, like glucose, can cross

compounds. When a person’s diet is deficient in vitamin

the blood-brain barrier and can be used by the brain

B compounds, clinical symptoms of the deficiency can

cells for energy. Therefore, about two thirds of the

sometimes be recognized within a few days (except for

brain’s energy is now derived from these ketone bodies,

vitamin B₁₂, which can last in the liver in a bound form

principally from beta-hydroxybutyrate. This sequence

for a year or longer). Absence of vitamin C, another

of events leads to at least partial preservation of the

water-soluble vitamin, can cause symptoms within a few

protein stores of the body.

weeks and can cause death from scurvy in 20 to 30

There finally comes a time when the fat stores are

weeks.

almost depleted, and the only remaining source of

energy is protein. At that time, the protein stores once

again enter a stage of rapid depletion. Because proteins

Vitamin A

are also essential for the maintenance of cellular func-

Vitamin A occurs in animal tissues as retinol. This

tion, death ordinarily ensues when the proteins of the

vitamin does not occur in foods of vegetable origin, but

body have been depleted to about half their normal

provitamins for the formation of vitamin A do occur in

level.

abundance in many vegetable foods. These are the

yellow and red carotenoid pigments, which, because

Vitamin Deficiencies in Starvation. The stores of some of the

their chemical structures are similar to that of vitamin

vitamins, especially the water-soluble vitamins—the

A, can be changed into vitamin A in the liver.

vitamin B group and vitamin C—do not last long during

starvation. Consequently, after a week or more of

Vitamin A Deficiency Causes “Night Blindness” and Abnormal

starvation, mild vitamin deficiencies usually begin to

Epithelial Cell Growth. One basic function of vitamin A is

appear, and after several weeks, severe vitamin defi-

its use in the formation of the retinal pigments of the

ciencies can occur. These deficiencies can add to the

eye, which is discussed in Chapter 50. Vitamin A is

debility that leads to death.

needed to form the visual pigments and, therefore, to

prevent night blindness.

Vitamin A is also necessary for normal growth of

Vitamins

most cells of the body and especially for normal growth

Daily Requirements of Vitamins. A vitamin is an organic

and proliferation of the different types of epithelial

compound needed in small quantities for normal

cells. When vitamin A is lacking, the epithelial structures

metabolism that cannot be manufactured in the cells of

of the body tend to become stratified and keratinized.

the body. Lack of vitamins in the diet can cause impor-

Vitamin A deficiency manifests itself by (1) scaliness of

tant metabolic deficits. Table 71-3 lists the amounts

the skin and sometimes acne; (2) failure of growth of

of important vitamins required daily by the average

young animals, including cessation of skeletal growth;

person. These requirements vary considerably, depend-

(3) failure of reproduction, associated especially with

ing on such factors as body size, rate of growth, amount

atrophy of the germinal epithelium of the testes and

of exercise, and pregnancy.

sometimes with interruption of the female sexual cycle;

and (4) keratinization of the cornea, with resultant

Storage of Vitamins in the Body. Vitamins are stored to a

corneal opacity and blindness.

slight extent in all cells. Some vitamins are stored to a

In vitamin A deficiency, the damaged epithelial struc-

tures often become infected, for example, the conjunc-

tivae of the eyes, the linings of the urinary tract, and the

respiratory passages. Vitamin A has been called an

Table 71-3

“anti-infection” vitamin.

Required Daily Amounts of Vitamins

Thiamine (Vitamin B₁)

Vitamin

Amount

Thiamine operates in the metabolic systems of the body

5000 IU

principally as thiamine pyrophosphate; this compound

Thiamine

1.5 mg

functions as a cocarboxylase, operating mainly in con-

Riboflavin

1.8 mg

junction with a protein decarboxylase for decarboxyla-

Niacin

20 mg

tion of pyruvic acid and other a-keto acids, as discussed

Ascorbic acid

45 mg

in Chapter 67.

400 IU

Thiamine deficiency (beriberi) causes decreased uti-

15 IU

lization of pyruvic acid and some amino acids by the

70 mg

tissues, but increased utilization of fats. Thus, thiamine

Folic acid

0.4 mg

B₁₂

3 mg

is specifically needed for the final metabolism of carbo-

Pyridoxine

2 mg

hydrates and many amino acids. The decreased utiliza-

Pantothenic acid

Unknown

tion of these nutrients is responsible for many debilities

associated with thiamine deficiency.

876

Unit XIII

Metabolism and Temperature Regulation

Thiamine Deficiency Causes Lesions of the Central and Peripheral

In the early stages of niacin deficiency, simple phys-

Nervous Systems. The central nervous system normally

iologic changes such as muscle weakness and poor glan-

depends almost entirely on the metabolism of carbohy-

dular secretion may occur, but in severe niacin

drates for its energy. In thiamine deficiency, the utiliza-

deficiency, actual tissue death ensues. Pathological

tion of glucose by nervous tissue may be decreased 50

lesions appear in many parts of the central nervous

to 60 per cent and is replaced by the utilization of

system, and permanent dementia or many types of psy-

ketone bodies derived from fat metabolism. The neu-

choses may result. Also, the skin develops a cracked,

ronal cells of the central nervous system frequently

pigmented scaliness in areas that are exposed to

show chromatolysis and swelling during thiamine defi-

mechanical irritation or sun irradiation; thus, it appears

ciency, changes that are characteristic of neuronal

that in persons with niacin deficiency, the skin is unable

cells with poor nutrition. These changes can disrupt

to repair irritative damage.

communication in many portions of the central nervous

Niacin deficiency causes intense irritation and

system.

inflammation of the mucous membranes of the mouth

Thiamine deficiency can cause degeneration of myelin

and other portions of the gastrointestinal tract, result-

sheaths of nerve fibers in both the peripheral nerves and

ing in many digestive abnormalities that can lead to

the central nervous system. Lesions in the peripheral

widespread gastrointestinal hemorrhage in severe cases.

nerves frequently cause them to become extremely irri-

It is possible that this results from generalized depres-

table, resulting in “polyneuritis,” characterized by pain

sion of metabolism in the gastrointestinal epithelium

radiating along the course of one or many peripheral

and failure of appropriate epithelial repair.

nerves. Also, fiber tracts in the cord can degenerate to

The clinical entity called pellagra and the canine

such an extent that paralysis occasionally results; even

disease called black tongue are caused mainly by niacin

in the absence of paralysis, the muscles atrophy, result-

deficiency. Pellagra is greatly exacerbated in people on

ing in severe weakness.

a corn diet, because corn is deficient in the amino acid

tryptophan, which can be converted in limited quanti-

Thiamine Deficiency Weakens the Heart and Causes Peripheral

ties to niacin in the body.

Vasodilation. A person with severe thiamine deficiency

eventually develops cardiac failure because of weak-

Riboflavin (Vitamin B₂)

ened cardiac muscle. Further, the venous return of

blood to the heart may be increased to as much as two

Riboflavin normally combines in the tissues with phos-

times normal. This occurs because thiamine deficiency

phoric acid to form two coenzymes, flavin mononu-

causes peripheral vasodilation throughout the circula-

cleotide (FMN) and flavin adenine dinucleotide (FAD).

tory system, presumably as a result of decreased release

They operate as hydrogen carriers in important oxida-

of metabolic energy in the tissues, leading to local vas-

tive systems of the mitochondria. NAD, operating

cular dilation. The cardiac effects of thiamine deficiency

in association with specific dehydrogenases, usually

are due partly to high blood flow into the heart and

accepts hydrogen removed from various food substrates

partly to primary weakness of the cardiac muscle.

and then passes the hydrogen to FMN or FAD; finally,

Peripheral edema and ascites also occur to a major

the hydrogen is released as an ion into the mitochon-

extent in some people with thiamine deficiency, mainly

drial matrix to become oxidized by oxygen (described

because of cardiac failure.

in Chapter 67).

Deficiency of riboflavin in experimental animals

Thiamine Deficiency Causes Gastrointestinal Tract Disturbances.

causes severe dermatitis, vomiting, diarrhea, muscle

Among the gastrointestinal symptoms of thiamine defi-

spasticity that finally becomes muscle weakness, coma

ciency are indigestion, severe constipation, anorexia,

and decline in body temperature, and then death. Thus,

gastric atony, and hypochlorhydria. All these effects pre-

severe riboflavin deficiency can cause many of the same

sumably result from failure of the smooth muscle and

effects as a lack of niacin in the diet; presumably, the

glands of the gastrointestinal tract to derive sufficient

debilities that result in each instance are due to gener-

energy from carbohydrate metabolism.

ally depressed oxidative processes within the cells.

The overall picture of thiamine deficiency, including

In the human being, there are no known cases of

polyneuritis, cardiovascular symptoms, and gastro-

riboflavin deficiency severe enough to cause the marked

intestinal disorders, is frequently referred to as

debilities noted in experimental animals, but mild

beriberi—especially when the cardiovascular symptoms

riboflavin deficiency is probably common. Such defi-

predominate.

ciency causes digestive disturbances, burning sensations

of the skin and eyes, cracking at the corners of the

mouth, headaches, mental depression, forgetfulness, and

so on.

Niacin

Although the manifestations of riboflavin deficiency

Niacin, also called nicotinic acid, functions in the body

are usually relatively mild, this deficiency frequently

as coenzymes in the form of nicotinamide adenine

occurs in association with deficiency of thiamine, niacin,

dinucleotide (NAD) and nicotinamide adenine dinu-

or both. Many deficiency syndromes, including pellagra,

cleotide phosphate

(NADP). These coenzymes are

beriberi, sprue, and kwashiorkor, are probably due to a

hydrogen acceptors; they combine with hydrogen atoms

combined deficiency of a number of vitamins, as well as

as they are removed from food substrates by many types

other aspects of malnutrition.

of dehydrogenases. The typical operation of both these

coenzymes is presented in Chapter 67. When a defi-

Vitamin B₁₂

ciency of niacin exists, the normal rate of dehydrogena-

tion cannot be maintained; therefore, oxidative delivery

Several cobalamin compounds that possess the common

of energy from the foodstuffs to the functioning ele-

prosthetic group shown next exhibit so-called vitamin

ments of all cells cannot occur at normal rates.

B₁₂ activity.

Chapter 71

Dietary Balances; Regulation of Feeding; Obesity and Starvation; Vitamins and Minerals

877

Pyridoxine (Vitamin B₆)

Pyridoxine exists in the form of pyridoxal phosphate in

the cells and functions as a coenzyme for many chemi-

cal reactions related to amino acid and protein metab-

olism. Its most important role is that of coenzyme in the

transamination process for the synthesis of amino acids.

As a result, pyridoxine plays many key roles in metab-

olism, especially protein metabolism. Also, it is believed

to act in the transport of some amino acids across cell

membranes.

Note that this prosthetic group contains cobalt, which

has bonds similar to those of iron in the hemoglobin

molecule. It is likely that the cobalt atom functions in

much the same way that the iron atom functions to

combine reversibly with other substances.

CH₂

Vitamin B₁₂ Deficiency Causes Pernicious Anemia. Vitamin B₁₂

performs several metabolic functions, acting as a hydro-

H₂C

gen acceptor coenzyme. Its most important function is

to act as a coenzyme for reducing ribonucleotides to

CH₃

deoxyribonucleotides, a step that is necessary in the

replication of genes. This could explain the major func-

Pyridoxine

tions of vitamin B₁₂: (1) promotion of growth and (2)

promotion of red blood cell formation and maturation.

This red cell function is described in detail in Chapter

Dietary lack of pyridoxine in lower animals can cause

32 in relation to pernicious anemia, a type of anemia

dermatitis, decreased rate of growth, development of

caused by failure of red blood cell maturation when

fatty liver, anemia, and evidence of mental deteriora-

vitamin B₁₂ is deficient.

tion. Rarely, in children, pyridoxine deficiency has been

known to cause seizures, dermatitis, and gastrointestinal

Vitamin B₁₂ Deficiency Causes Demyelination of the Large Nerve

disturbances such as nausea and vomiting.

Fibers of the Spinal Cord. The demyelination of nerve

fibers in people with vitamin B₁₂ deficiency occurs espe-

cially in the posterior columns, and occasionally the

Pantothenic Acid

lateral columns, of the spinal cord. As a result, many

people with pernicious anemia have loss of peripheral

Pantothenic acid mainly is incorporated in the body into

sensation and, in severe cases, even become paralyzed.

coenzyme A (CoA), which has many metabolic roles in

The usual cause of vitamin B₁₂ deficiency is not lack

the cells. Two of these discussed at length in Chapters

of this vitamin in the food but deficiency of formation

67 and 68 are (1) conversion of decarboxylated pyruvic

of intrinsic factor, which is normally secreted by the

acid into acetyl-CoA before its entry into the citric acid

parietal cells of the gastric glands and is essential for

cycle, and (2) degradation of fatty acid molecules into

absorption of vitamin B₁₂ by the ileal mucosa. This is dis-

multiple molecules of acetyl-CoA. Thus, lack of pan-

cussed in Chapters 32 and 66.

tothenic acid can lead to depressed metabolism of both

carbohydrates and fats.

Deficiency of pantothenic acid in lower animals can

Folic Acid (Pteroylglutamic Acid)

cause retarded growth, failure of reproduction, graying

of the hair, dermatitis, fatty liver, and hemorrhagic

Several pteroylglutamic acids exhibit the “folic acid

adrenocortical necrosis. In the human being, no definite

effect.” Folic acid functions as a carrier of hydroxy-

deficiency syndrome has been proved, presumably

methyl and formyl groups. Perhaps its most important

because of the wide occurrence of this vitamin in almost

use in the body is in the synthesis of purines and thymine,

all foods and because small amounts can probably be

which are required for formation of DNA. Therefore,

synthesized in the body. This does not mean that pan-

folic acid, like vitamin B₁₂, is required for replication of

tothenic acid is not of value in the metabolic systems of

the cellular genes. This may explain one of the most

the body; indeed, it is perhaps as necessary as any other

important functions of folic acid—to promote growth.

vitamin.

Indeed, when it is absent from the diet, an animal grows

very little.

Folic acid is an even more potent growth promoter

Ascorbic Acid (Vitamin C)

than vitamin B₁₂ and, like vitamin B₁₂, is important

for the maturation of red blood cells, as discussed

Ascorbic Acid Deficiency Weakens Collagen Fibers Throughout

in Chapter 32. However, vitamin B₁₂ and folic acid

the Body. Ascorbic acid is essential for activating the

each perform specific and different chemical functions

enzyme prolyl hydroxylase, which promotes the hydrox-

in promoting growth and maturation of red blood

ylation step in the formation of hydroxyproline, an inte-

cells. One of the significant effects of folic acid

gral constituent of collagen. Without ascorbic acid, the

deficiency is the development of macrocytic anemia,

collagen fibers that are formed in virtually all tissues of

almost identical to that which occurs in pernicious

the body are defective and weak. Therefore, this vitamin

anemia. This often can be treated effectively with folic

is essential for the growth and strength of the fibers in

acid alone.

subcutaneous tissue, cartilage, bone, and teeth.

878

Unit XIII

Metabolism and Temperature Regulation

Ascorbic Acid Deficiency Causes Scurvy. Deficiency of ascor-

absence of vitamin E, the quantity of unsaturated fats

bic acid for 20 to 30 weeks, which occurred frequently

in the cells becomes diminished, causing abnormal

during long ship voyages in the past, causes scurvy. One

structure and function of such cellular organelles as

of the most important effects of scurvy is failure of

the mitochondria, the lysosomes, and even the cell

wounds to heal. This is caused by failure of the cells to

membrane.

deposit collagen fibrils and intercellular cement sub-

stances. As a result, healing of a wound may require

several months instead of the several days ordinarily

Vitamin K

necessary.

Vitamin K is necessary for the formation by the liver of

Lack of ascorbic acid also causes cessation of bone

prothrombin, Factor VII (proconvertin), Factor IX, and

growth. The cells of the growing epiphyses continue to

Factor X, all of which are important in blood coagula-

proliferate, but no new collagen is laid down between

tion. Therefore, when vitamin K deficiency occurs, blood

the cells, and the bones fracture easily at the point of

clotting is retarded. The function of this vitamin and

growth because of failure to ossify. Also, when an

its relation to some of the anticoagulants, such as

already ossified bone fractures in a person with ascor-

dicumarol, are presented in greater detail in Chapter 35.

bic acid deficiency, the osteoblasts cannot form new

Several compounds, both natural and synthetic,

bone matrix. Consequently, the fractured bone does not

exhibit vitamin K activity. Because vitamin K is synthe-

heal.

sized by bacteria in the colon, it is rare for a person to

The blood vessel walls become extremely fragile in

have a bleeding tendency because of vitamin K defi-

scurvy because of (1) failure of the endothelial cells to

ciency in the diet. However, when the bacteria of the

be cemented together properly and (2) failure to form

colon are destroyed by the administration of large quan-

the collagen fibrils normally present in vessel walls.

tities of antibiotic drugs, vitamin K deficiency occurs

The capillaries are especially likely to rupture, and as

rapidly because of the paucity of this compound in the

a result, many small petechial hemorrhages occur

normal diet.

throughout the body. The hemorrhages beneath the

skin cause purpuric blotches, sometimes over the entire

body. To test for ascorbic acid deficiency, one can

Mineral Metabolism

produce such petechial hemorrhages by inflating a

blood pressure cuff over the upper arm; this occludes

The functions of many of the minerals, such as sodium,

the venous return of blood, the capillary pressure rises,

potassium, and chloride, are presented at appropriate

and red blotches occur on the forearm if the ascorbic

points in the text. Only specific functions of minerals

acid deficiency is sufficiently severe.

not covered elsewhere are mentioned here. The body

In extreme scurvy, the muscle cells sometimes frag-

content of the most important minerals is listed in Table

ment; lesions of the gums occur, with loosening of the

71-4, and the daily requirements of these are given in

teeth; infections of the mouth develop; and vomiting of

Table 71-5.

blood, bloody stools, and cerebral hemorrhage can all

occur. Finally, high fever often develops before death.

Magnesium. Magnesium is about one sixth as plentiful in

cells as potassium. Magnesium is required as a catalyst

for many intracellular enzymatic reactions, particularly

Vitamin D

those related to carbohydrate metabolism.

The extracellular fluid magnesium concentration is

Vitamin D increases calcium absorption from the gas-

slight, only 1.8 to 2.5 mEq/L. Increased extracellular

trointestinal tract and helps control calcium deposition in

concentration of magnesium depresses nervous system

the bone. The mechanism by which vitamin D increases

activity as well as skeletal muscle contraction. This latter

calcium absorption is mainly to promote active trans-

effect can be blocked by the administration of calcium.

port of calcium through the epithelium of the ileum. In

Low magnesium concentration causes increased irri-

particular, it increases the formation of a calcium-

tability of the nervous system, peripheral vasodilation,

binding protein in the intestinal epithelial cells that aids

in calcium absorption. The specific functions of vitamin

D in relation to overall body calcium metabolism and

bone formation are presented in Chapter 79.

Table 71-4

Average Content of a 70-Kilogram Man

Vitamin E

Constituent

Amount (grams)

Several related compounds exhibit so-called vitamin E

activity. Only rare instances of proved vitamin E defi-

Water

41,400

ciency have occurred in human beings. In experimental

Fat

12,600

animals, lack of vitamin E can cause degeneration of the

Protein

12,600

germinal epithelium in the testis and, therefore, can

Carbohydrate

300

cause male sterility. Lack of vitamin E can also cause

Sodium

resorption of a fetus after conception in the female.

Potassium

150

Calcium

1,160

Because of these effects of vitamin E deficiency, vitamin

Magnesium

E is sometimes called the “antisterility vitamin.” Defi-

Chloride

ciency of vitamin E prevents normal growth and some-

Phosphorus

670

times causes degeneration of the renal tubular cells and

Sulfur

112

the muscle cells.

Iron

Vitamin E is believed to play a protective role in the

Iodine

0.014

prevention of oxidation of unsaturated fats. In the

Chapter 71

Dietary Balances; Regulation of Feeding; Obesity and Starvation; Vitamins and Minerals

879

with the formation and function of thyroid hormone; as

Table 71-5

shown in Table 71-4, the entire body contains an

Average Required Daily Amounts of Minerals for Adults

average of only 14 milligrams. Iodine is essential for the

formation of thyroxine and triiodothyronine, the two

thyroid hormones that are essential for maintenance of

Mineral

Amount

normal metabolic rates in all cells of the body.

Sodium

3.0 g

Potassium

1.0 g

Zinc. Zinc is an integral part of many enzymes, one of

Chloride

3.5 g

the most important of which is carbonic anhydrase,

Calcium

1.2 g

present in especially high concentration in the red blood

Phosphorus

1.2 g

cells. This enzyme is responsible for rapid combination

Iron

18.0 mg

of carbon dioxide with water in the red blood cells of

Iodine

150.0 mg

the peripheral capillary blood and for rapid release of

Magnesium

0.4 g

carbon dioxide from the pulmonary capillary blood into

Cobalt

Unknown

Copper

Unknown

the alveoli. Carbonic anhydrase is also present to a

Manganese

Unknown

major extent in the gastrointestinal mucosa, the tubules

Zinc

15 mg

of the kidney, and the epithelial cells of many glands of

the body. Consequently, zinc in small quantities is essen-

tial for the performance of many reactions related to

carbon dioxide metabolism.

Zinc is also a component of lactic dehydrogenase and

and cardiac arrhythmias, especially after acute myocar-

is therefore important for the interconversions between

dial infarction.

pyruvic acid and lactic acid. Finally, zinc is a component

of some peptidases and is important for the digestion of

Calcium. Calcium is present in the body mainly in the

proteins in the gastrointestinal tract.

form of calcium phosphate in the bone. This subject is

discussed in detail in Chapter 79, as is the calcium

Fluorine. Fluorine does not seem to be a necessary

content of extracellular fluid. Excess quantities of

element for metabolism, but the presence of a small

calcium ions in extracellular fluid can cause the heart to

quantity of fluorine in the body during the period of life

stop in systole and can act as a mental depressant. At

when the teeth are being formed subsequently protects

the other extreme, low levels of calcium can cause spon-

against caries. Fluorine does not make the teeth them-

taneous discharge of nerve fibers, resulting in tetany, as

selves stronger but has a poorly understood effect in

discussed in Chapter 79.

suppressing the cariogenic process. It has been sug-

gested that fluorine is deposited in the hydroxyapatite

Phosphorus. Phosphate is the major anion of intracellular

crystals of the tooth enamel and combines with and

fluid. Phosphates have the ability to combine reversibly

therefore blocks the functions of various trace metals

with many coenzyme systems and with multiple other

that are necessary for activation of the bacterial

compounds that are necessary for the operation of

enzymes that cause caries. Therefore, when fluorine is

metabolic processes. Many important reactions of phos-

present, the enzymes remain inactive and cause no

phates have been catalogued at other points in this text,

caries.

especially in relation to the functions of adenosine

Excessive intake of fluorine causes fluorosis, which

triphosphate, adenosine diphosphate, phosphocreatine,

manifests in its mild state by mottled teeth and in its

and so forth. Also, bone contains a tremendous amount

more severe state by enlarged bones. It has been pos-

of calcium phosphate, which is discussed in Chapter 79.

tulated that in this condition, fluorine combines with

trace metals in some of the metabolic enzymes, includ-

Iron. The function of iron in the body, especially in rela-

ing the phosphatases, so that various metabolic systems

tion to the formation of hemoglobin, is discussed in

become partially inactivated. According to this theory,

Chapter 32. Two thirds of the iron in the body is in the

the mottled teeth and enlarged bones are due to ab-

form of hemoglobin, although smaller quantities are

normal enzyme systems in the odontoblasts and

present in other forms, especially in the liver and the

osteoblasts. Even though the mottled teeth are highly

bone marrow. Electron carriers containing iron (espe-

resistant to the development of caries, the structural

cially the cytochromes) are present in the mitochondria

strength of these teeth may be considerably lessened by

of all cells of the body and are essential for most of the

the mottling process.

oxidation that occurs in the cells. Therefore, iron is

absolutely essential for both the transport of oxygen to

the tissues and the operation of oxidative systems within

References

the tissue cells, without which life would cease within a

few seconds.

Barsh GS, Schwartz MW: Genetic approaches to studying

energy balance: perception and integration. Nat Rev

Important Trace Elements in the Body. A few elements are

Genet 3:589, 2002.

present in the body in such small quantities that they

Coll AP, Farooqi IS, Challis BG, et al: Proopiomelanocortin

are called trace elements. The amounts of these elements

and energy balance: insights from human and murine

in foods are also usually minute. Yet without any one of

genetics. J Clin Endocrinol Metab 89:2557, 2004.

them, a specific deficiency syndrome is likely to develop.

Cowley MA, Cone RD, Enriori P, et al: Electrophysiological

Three of the most important are iodine, zinc, and

actions of peripheral hormones on melanocortin neurons.

fluorine.

Ann N Y Acad Sci 994:175, 2003.

Iodine. The best known of the trace elements is iodine.

Cowley MA, Grove KL: Ghrelin—satisfying a hunger for the

This element is discussed in Chapter 76 in connection

mechanism. Endocrinology 145:2604, 2004.

880

Unit XIII

Metabolism and Temperature Regulation

da Silva AA, Kuo JJ, Hall JE: Role of hypothalamic

Lucock M: Is folic acid the ultimate functional food compo-

melanocortin 3/4-receptors in mediating chronic cardio-

nent for disease prevention? BMJ 328:211, 2004.

vascular, renal, and metabolic actions of leptin. Hyperten-

National Institutes of Health: Clinical Guidelines on the

sion 43:1312, 2004.

Identification, Evaluation, and Treatment of Overweight

Davy KP, Hall JE: Obesity and hypertension: two epidemics

and Obesity in Adults: The Evidence Report. Bethesda

or one? Am J Physiol Regul Integr Comp Physiol

MD: National Heart, Lung, and Blood Institute and

286:R803, 2004.

National Institute of Diabetes and Digestive and Kidney

Druce MR, Small CJ, Bloom SR: Gut peptides regulating

Diseases,

1998. Available at: http://www.nhlbi.nih.gov/

satiety. Endocrinology 145:2660, 2004.

guidelines/index.htm.

Dutta A, Dutta SK: Vitamin E and its role in the prevention

O’Rahilly S, Farooqi IS, Yeo GS, Challis BG: Human

of atherosclerosis and carcinogenesis: a review. J Am Coll

obesity—lessons from monogenic disorders. Endocrinol-

Nutr 22:258, 2003.

ogy 144:3757, 2003.

Flier JS: Obesity wars: molecular progress confronts an

Powers HJ: Riboflavin (vitamin B₂) and health. Am J Clin

expanding epidemic. Cell 116:337, 2004.

Nutr 77:1352, 2003.

Fraser PD, Bramley PM: The biosynthesis and nutritional

Ravussin E: Cellular sensors of feast and famine. J Clin

uses of carotenoids. Prog Lipid Res 43:228, 2004.

Invest 109:1537, 2002.

Friedman JM, Halaas JL: Leptin and the regulation of body

Rindi G, Laforenza U: Thiamine intestinal transport and

weight in mammals. Nature 395:763, 1998.

related issues: recent aspects. Proc Soc Exp Biol Med

Grundy SM: Obesity, metabolic syndrome, and cardiovascu-

224:246, 2000.

lar disease. J Clin Endocrinol Metab 89:2595, 2004.

Ross SA, McCaffery PJ, Drager UC, De Luca LM: Retinoids

Hall JE, Henegar JR, Dwyer TM, et al: Is obesity a major

in embryonal development. Physiol Rev 80:1021, 2000.

cause of chronic kidney disease? Adv Ren Replace Ther

Said HM: Recent advances in carrier-mediated intestinal

11:41, 2004.

absorption of water-soluble vitamins. Annu Rev Physiol

Hall JE, Jones DW: What can we do about the “epidemic”

66:419, 2004.

of obesity. Am J Hypertens 15:657, 2002.

Seeley R, Woods S: Monitoring of stored and available fuel

Hall JE, Jones DW, Kuo JJ, et al: Impact of the obesity epi-

by the CNS: implications for obesity. Nat Rev Neurosci 4:

demic on hypertension and renal disease. Curr Hypertens

901, 2003.

Rep 5:386, 2003.

Stanley S, Wynne K, Bloom S: Gastrointestinal satiety

Jequier E, Tappy L: Regulation of body weight in humans.

signals. III. Glucagon-like peptide

1, oxyntomodulin,

Physiol Rev 79:451, 1999.

peptide YY, and pancreatic polypeptide. Am J Physiol

Jones G, Strugnell SA, DeLuca HF: Current understanding

Gastrointest Liver Physiol 286:G693, 2004.

of the molecular actions of vitamin D. Physiol Rev

Wisse BE, Schwartz MW, Cummings DE: Melanocortin sig-

78:1193, 1998.

naling and anorexia in chronic disease states. Ann N Y

Kershaw EE, Flier JS: Adipose tissue as an endocrine organ.

Acad Sci 994:275, 2003.

J Clin Endocrinol Metab 89:2548, 2004.

Woods SC: Gastrointestinal satiety signals. I. An overview of

Korner J, Aronne LJ: Pharmacological approaches to weight

gastrointestinal signals that influence food intake. Am J

reduction: therapeutic targets. J Clin Endocrinol Metab

Physiol Gastrointest Liver Physiol 286:G7, 2004.

89:2616, 2004.

Wynne K, Stanley S, Bloom S: The gut and regulation of body

Korner J, Leibel RL: To eat or not to eat—how the gut talks

weight. J Clin Endocrinol Metab 89:2576, 2004.

to the brain. N Engl J Med 349:926, 2003.

Kuo JJ, Silva AA, Hall JE: Hypothalamic melanocortin

receptors and chronic regulation of arterial pressure and

renal function. Hypertension 41:768, 2003.

C H A P T E R

Energetics and Metabolic Rate

Adenosine Triphosphate

(ATP) Functions as

an “Energy Currency”

in Metabolism

In the past few chapters, we have pointed out that car-

bohydrates, fats, and proteins can all be used by cells to

synthesize large quantities of adenosine triphosphate

(ATP), which can be used as an energy source for almost all other cellular func-

tions. For this reason, ATP has been called an energy “currency” in cell metabolism.

Indeed, the transfer of energy from foodstuffs to most functional systems of the cells

can be done only through this medium of ATP (or the similar nucleotide guanosine

triphosphate, GTP). Many of the attributes of ATP are presented in Chapter 2.

An attribute of ATP that makes it highly valuable as an energy currency is the

large quantity of free energy (about 7300 calories, or 7.3 Calories [kilocalories], per

mole under standard conditions, but as much as 12,000 calories under physiologic

conditions) vested in each of its two high-energy phosphate bonds. The amount of

energy in each bond, when liberated by decomposition of ATP, is enough to cause

almost any step of any chemical reaction in the body to take place if appropriate

energy transfer is achieved. Some chemical reactions that require ATP energy use

only a few hundred of the available 12,000 calories, and the remainder of this energy

is lost in the form of heat.

ATP Is Generated by Combustion of Carbohydrates, Fats, and Proteins. In previous chapters,

we discussed the transfer of energy from various foods to ATP. To summarize, ATP

is produced from

1. Combustion of carbohydrates—mainly glucose, but also smaller amounts of

other sugars such as fructose; this occurs in the cytoplasm of the cell through

the anaerobic process of glycolysis and in the cell mitochondria through the

aerobic citric acid (Krebs) cycle.

2. Combustion of fatty acids in the cell mitochondria by beta-oxidation.

3. Combustion of proteins, which requires hydrolysis to their component amino

acids and degradation of the amino acids to intermediate compounds of the

citric acid cycle and then to acetyl coenzyme A and carbon dioxide.

ATP Energizes the Synthesis of Most Important Cellular Components. Among the most impor-

tant intracellular processes that require ATP energy is the formation of peptide link-

ages between amino acids during the synthesis of proteins. The different peptide

linkages, depending on which types of amino acids are linked, require from 500 to

5000 calories of energy per mole. It will be recalled from the discussion of protein

synthesis in Chapter 3 that four high-energy phosphate bonds are expended during

the cascade of reactions required to form each peptide linkage. This provides a total

of 48,000 calories of energy, which is far more than the 500 to 5000 calories even-

tually stored in each of the peptide linkages.

ATP energy is also used in the synthesis of glucose from lactic acid and in the syn-

thesis of fatty acids from acetyl coenzyme A. In addition, ATP energy is used for the

synthesis of cholesterol, phospholipids, the hormones, and almost all other substances

of the body. Even the urea excreted by the kidneys requires ATP to cause its

formation from ammonia. One might wonder about the advisability of expending

energy to form urea, which is simply discarded by the body. However, remembering

the extreme toxicity of ammonia in the body fluids, one can see the value of this reac-

tion, which keeps the ammonia concentration of the body fluids at a low level.

ATP Energizes Muscle Contraction. Muscle contraction will not occur without energy

from ATP. Myosin, one of the important contractile proteins of the muscle fiber, acts

as an enzyme to cause breakdown of ATP into adenosine diphosphate (ADP), thus

881

882

Unit XIII

Metabolism and Temperature Regulation

releasing the energy required to cause contraction. Only

CH₃

a small amount of ATP is normally degraded in muscles

when muscle contraction is not occurring, but this rate

HOOC CH

P OH

of ATP usage can rise to at least 150 times the resting

level during short bursts of maximal contraction. The

postulated mechanism by which ATP energy is used to

cause muscle contraction is discussed in Chapter 6.

and the functional cellular systems, but it can transfer

ATP Energizes Active Transport Across Membranes. In

energy interchangeably with ATP. When extra amounts

Chapters 4, 27, and 65, active transport of electrolytes

of ATP are available in the cell, much of its energy is

and various nutrients across cell membranes and from

used to synthesize phosphocreatine, thus building up

the renal tubules and gastrointestinal tract into the

this storehouse of energy. Then, when the ATP begins

blood is discussed. In each instance, we noted that active

to be used up, the energy in the phosphocreatine is

transport of most electrolytes and substances such as

transferred rapidly back to ATP and then to the func-

glucose, amino acids, and acetoacetate can occur against

tional systems of the cells. This reversible interrelation

an electrochemical gradient, even though the natural

between ATP and phosphocreatine is demonstrated by

diffusion of the substances would be in the opposite

the following equation:

direction. To oppose the electrochemical gradient

Phosphocreatine + ADP

requires energy, which is provided by ATP.

Ø≠

ATP + Creatine

ATP Energizes Glandular Secretion. The same principles

Note particularly that the higher energy level of the

apply to glandular secretion as to the absorption of

high-energy phosphate bond in phosphocreatine (1000

substances against concentration gradients, because

to 1500 calories per mole greater than that in ATP)

energy is required to concentrate substances as they are

causes the reaction between phosphocreatine and ADP

secreted by the glandular cells. In addition, energy is

to proceed rapidly toward the formation of new ATP

required to synthesize the organic compounds to be

every time even the slightest amount of ATP expends

secreted.

its energy elsewhere. Therefore, the slightest usage of

ATP by the cells calls forth the energy from the phos-

ATP Energizes Nerve Conduction. The energy used during

phocreatine to synthesize new ATP. This effect keeps

propagation of a nerve impulse is derived from

the concentration of ATP at an almost constant high

the potential energy stored in the form of concentration

level as long as any phosphocreatine remains. For this

differences of ions across the membranes. That is, a

reason, we can call the ATP-phosphocreatine system an

high concentration of potassium inside the fiber and a

ATP “buffer” system. One can readily understand the

low concentration outside the fiber constitute a type

importance of keeping the concentration of ATP nearly

of energy storage. Likewise, a high concentration

constant, because the rates of almost all the metabolic

of sodium on the outside of the membrane and a low

reactions in the body depend on this constancy.

concentration on the inside represent another store

of energy. The energy needed to pass each action

Anaerobic Versus Aerobic Energy

potential along the fiber membrane is derived from

this energy storage, with small amounts of potassium

Anaerobic energy means energy that can be derived

transferring out of the cell and sodium into the cell

from foods without the simultaneous utilization of

during each of the action potentials. However, active

oxygen; aerobic energy means energy that can be

transport systems energized by ATP then retransport

derived from foods only by oxidative metabolism. In the

the ions back through the membrane to their former

discussions in Chapters 67 through 69, it is noted that

positions.

carbohydrates, fats, and proteins can all be oxidized to

cause synthesis of ATP. However, carbohydrates are the

only significant foods that can be used to provide energy

Phosphocreatine Functions as an

without the utilization of oxygen; this energy release

Accessory Storage Depot for

occurs during glycolytic breakdown of glucose or glyco-

gen to pyruvic acid. For each mole of glucose that is split

Energy and as an “ATP Buffer”

into pyruvic acid, 2 moles of ATP are formed. However,

Despite the paramount importance of ATP as a cou-

when stored glycogen in a cell is split to pyruvic acid,

pling agent for energy transfer, this substance is not the

each mole of glucose in the glycogen gives rise to 3

most abundant store of high-energy phosphate bonds in

moles of ATP. The reason for this difference is that free

the cells. Phosphocreatine, which also contains high-

glucose entering the cell must be phosphorylated by

energy phosphate bonds, is three to eight times as

using 1 mole of ATP before it can begin to be split; this

abundant. Also, the high-energy bond (~) of phospho-

is not true of glucose derived from glycogen because it

creatine contains about 8500 calories per mole under

comes from the glycogen already in the phosphorylated

standard conditions and as much as 13,000 calories per

state, without the additional expenditure of ATP. Thus,

mole under conditions in the body (37°C and low con-

the best source of energy under anaerobic conditions is

centrations of the reactants). This is slightly greater than

the stored glycogen of the cells.

the 12,000 calories per mole in each of the two high-

energy phosphate bonds of ATP. The formula for crea-

Anaerobic Energy Utilization During Hypoxia. One of the prime

tinine phosphate is the following:

examples of anaerobic energy utilization occurs in acute

Unlike ATP, phosphocreatine cannot act as a direct

hypoxia. When a person stops breathing, there is already

coupling agent for energy transfer between the foods

a small amount of oxygen stored in the lungs and an

Chapter 72

Energetics and Metabolic Rate

883

additional amount stored in the hemoglobin of the

Oxygen Debt Is the Extra Consumption of Oxygen After Completion

blood. This oxygen is sufficient to keep the metabolic

of Strenuous Exercise. After a period of strenuous exer-

processes functioning for only about 2 minutes. Contin-

cise, a person continues to breathe hard and to consume

ued life beyond this time requires an additional source

large amounts of oxygen for at least a few minutes and

of energy. This can be derived for another minute or so

sometimes for as long as 1 hour thereafter. This addi-

from glycolysis—that is, the glycogen of the cells split-

tional oxygen is used (1) to reconvert the lactic acid that

ting into pyruvic acid, and the pyruvic acid becoming

has accumulated during exercise back into glucose, (2)

lactic acid, which diffuses out of the cells, as described

to reconvert adenosine monophosphate and ADP to

in Chapter 67.

ATP, (3) to reconvert creatine and phosphate to phos-

phocreatine, (4) to re-establish normal concentrations

Anaerobic Energy Utilization During Strenuous Bursts of Activity

of oxygen bound with hemoglobin and myoglobin, and

Is Derived Mainly from Glycolysis. Skeletal muscles can

(5) to raise the concentration of oxygen in the lungs to

perform extreme feats of strength for a few seconds but

its normal level. This extra consumption of oxygen after

are much less capable during prolonged activity. Most

exercise is over is called repaying the oxygen debt.

of the extra energy required during these bursts of activ-

The principle of oxygen debt is discussed further in

ity cannot come from the oxidative processes because

Chapter 84 in relation to sports physiology; the ability

they are too slow to respond. Instead, the extra energy

of a person to build up an oxygen debt is especially

comes from anaerobic sources: (1) ATP already present

important in many types of athletics.

in the muscle cells, (2) phosphocreatine in the cells, and

(3) anaerobic energy released by glycolytic breakdown

of glycogen to lactic acid.

Summary of Energy Utilization

The maximum amount of ATP in muscle is only about

by the Cells

5 mmol/L of intracellular fluid, and this amount can

maintain maximum muscle contraction for no more

With the background of the past few chapters and of the

than a second or so. The amount of phosphocreatine in

preceding discussion, we can now synthesize a compos-

the cells is three to eight times this amount, but even by

ite picture of overall energy utilization by the cells, as

using all the phosphocreatine, maximum contraction

shown in Figure 72-1. This figure demonstrates the

can be maintained for only 5 to 10 seconds.

anaerobic utilization of glycogen and glucose to form

Release of energy by glycolysis can occur much more

ATP and the aerobic utilization of compounds derived

rapidly than can oxidative release of energy. Conse-

from carbohydrates, fats, proteins, and other substances

quently, most of the extra energy required during stren-

to form additional ATP. In turn, ATP is in reversible

uous activity that lasts for more than 5 to 10 seconds but

equilibrium with phosphocreatine in the cells, and

less than 1 to 2 minutes is derived from anaerobic gly-

because larger quantities of phosphocreatine are

colysis. As a result, the glycogen content of muscles

present in the cells than ATP, much of the cells’ stored

during strenuous bouts of exercise is reduced, whereas

energy is in this energy storehouse.

the lactic acid concentration of the blood rises. After the

Energy from ATP can be used by the different func-

exercise is over, oxidative metabolism is used to recon-

tioning systems of the cells to provide for synthesis

vert about four fifths of the lactic acid into glucose;

and growth, muscle contraction, glandular secretion,

the remainder becomes pyruvic acid and is degraded

nerve impulse conduction, active absorption, and other

and oxidized in the citric acid cycle. The reconversion

cellular activities. If greater amounts of energy are

to glucose occurs principally in the liver cells, and

demanded for cellular activities than can be provided

the glucose is then transported in the blood back to the

by oxidative metabolism, the phosphocreatine store-

muscles, where it is stored once more in the form of

house is used first, and then anaerobic breakdown of

glycogen.

glycogen follows rapidly. Thus, oxidative metabolism

Glycogen

Energy for

Glucose

1. Synthesis and growth

2. Muscular contraction

ATP

3. Glandular secretion

4. Nerve conduction

Lactic acid

Pyruvic acid

5. Active absorption

6. Etc.

Acetyl-CoA

Deaminated

Phosphocreatine

Figure 72-1

amino acids

Overall schema of energy trans-

AMP

fer from foods to the adenylic

Other substrates

acid system and then to the

functional elements of the cells.

(Modified from Soskin S, Levine

CO₂ + H₂O

Creatine + PO₄

R: Carbohydrate Metabolism.

Chicago: University of Chicago

Press, 1946, 1952.)

884

Unit XIII

Metabolism and Temperature Regulation

cannot deliver bursts of extreme energy to the cells

reabsorption, because the transport enzymes are satu-

nearly as rapidly as the anaerobic processes can, but at

rated. Under these conditions, the rate of reabsorption

slower rates of usage, the oxidative processes can con-

of the glucose is limited by the concentration of the

tinue as long as energy stores (mainly fat) exist.

transport enzymes in the proximal tubular cells, not by

the concentration of the glucose itself.

Control of Energy Release

Role of Substrate Concentration in Regulation of Meta-

bolic Reactions. Note also in Figure 72-2 that when the

in the Cell

substrate concentration becomes low enough that only

Rate Control of Enzyme-Catalyzed Reactions. Before dis-

a small portion of the enzyme is required in the reac-

cussing the control of energy release in the cell, it is nec-

tion, the rate of the reaction becomes directly propor-

essary to consider the basic principles of rate control of

tional to the substrate concentration as well as the

enzymatically catalyzed chemical reactions, which are

enzyme concentration. This is the relationship seen in

the types of reactions that occur almost universally

the absorption of substances from the intestinal tract

throughout the body.

and renal tubules when their concentrations are low.

The mechanism by which an enzyme catalyzes a

chemical reaction is for the enzyme first to combine

Rate Limitation in a Series of Reactions. Almost all chemical

loosely with one of the substrates of the reaction. This

reactions of the body occur in series, with the product

alters the bonding forces on the substrate sufficiently so

of one reaction acting as a substrate for the next reac-

that it can react with other substances. Therefore, the

tion, and so on. Therefore, the overall rate of a complex

rate of the overall chemical reaction is determined by

series of chemical reactions is determined mainly by the

both the concentration of the enzyme and the concen-

rate of reaction of the slowest step in the series. This is

tration of the substrate that binds with the enzyme. The

called the rate-limiting step in the entire series.

basic equation expressing this concept is as follows:

K1¥[Enzyme]¥[Substrate]

ADP Concentration as a Rate-Controlling Factor in Energy

Rate of reaction

Release. Under resting conditions, the concentration of

K2+[Substrate]

ADP in the cells is extremely slight, so that the chemi-

This is called the Michaelis-Menten equation. Figure

cal reactions that depend on ADP as one of the sub-

72-2 shows the application of this equation.

strates are quite slow. They include all the oxidative

metabolic pathways that release energy from food, as

Role of Enzyme Concentration in Regulation of Metabolic

well as essentially all other pathways for the release of

Reactions. Figure 72-2 shows that when the substrate is

energy in the body. Thus, ADP is a major rate-limiting

present in high concentration, as shown in the right half

factor for almost all energy metabolism of the body.

of the figure, the rate of a chemical reaction is deter-

When the cells become active, regardless of the type

mined almost entirely by the concentration of the

of activity, ATP is converted into ADP, increasing the

enzyme. Thus, as the enzyme concentration increases

concentration of ADP in direct proportion to the degree

from an arbitrary value of 1 up to 2, 4, or 8, the rate of

of activity of the cell. This ADP then automatically

the reaction increases proportionately, as demonstrated

increases the rates of all the reactions for the metabolic

by the rising levels of the curves. As an example, when

release of energy from food. Thus, by this simple

large quantities of glucose enter the renal tubules in a

process, the amount of energy released in the cell is con-

person with diabetes mellitus—that is, the substrate

trolled by the degree of activity of the cell. In the

glucose is in great excess in the tubules—further

absence of cellular activity, the release of energy stops

increases in tubular glucose have little effect on glucose

because all the ADP soon becomes ATP.

Metabolic Rate

The metabolism of the body simply means all the chem-

ical reactions in all the cells of the body, and the meta-

bolic rate is normally expressed in terms of the rate of

heat liberation during chemical reactions.

Heat Is the End Product of Almost All the Energy Released in the

Body. In discussing many of the metabolic reactions in

the preceding chapters, we noted that not all the energy

in foods is transferred to ATP; instead, a large portion

of this energy becomes heat. On average, 35 per cent of

the energy in foods becomes heat during ATP forma-

tion. Then, still more energy becomes heat as it is trans-

ferred from ATP to the functional systems of the cells,

Substrate concentration

so that even under optimal conditions, no more than 27

per cent of all the energy from food is finally used by

the functional systems.

Even when 27 per cent of the energy reaches the func-

tional systems of the cells, most of this eventually

Figure 72-2

becomes heat. For example, when proteins are syn-

Effect of substrate and enzyme concentrations on the rate of

thesized, large portions of ATP are used to form the

enzyme-catalyzed reaction.

peptide linkages, and this stores energy in these link-

Chapter 72

Energetics and Metabolic Rate

885

ages. But there is also continuous turnover of proteins—

Indirect Calorimetry—The

“Energy Equivalent” of Oxygen.

some being degraded while others are being formed.

Because more than 95 per cent of the energy expended

When proteins are degraded, the energy stored in the

in the body is derived from reactions of oxygen with the

peptide linkages is released in the form of heat into the

different foods, the whole-body metabolic rate can also

body.

be calculated with a high degree of accuracy from the

Another example is the energy used for muscle activ-

rate of oxygen utilization. When 1 liter of oxygen is

ity. Much of this energy simply overcomes the viscosity

metabolized with glucose, 5.01 Calories of energy are

of the muscles themselves or of the tissues so that the

released; when metabolized with starches, 5.06 Calories

limbs can move. This viscous movement causes friction

are released; with fat, 4.70 Calories; and with protein,

within the tissues, which generates heat.

4.60 Calories.

Consider also the energy expended by the heart in

Using these figures, it is striking how nearly equiva-

pumping blood. The blood distends the arterial system,

lent are the quantities of energy liberated per liter of

and this distention itself represents a reservoir of poten-

oxygen, regardless of the type of food being metabo-

tial energy. As the blood flows through the peripheral

lized. For the average diet, the quantity of energy liber-

vessels, the friction of the different layers of blood

ated per liter of oxygen used in the body averages about

flowing over one another and the friction of the blood

4.825 Calories. This is called the energy equivalent of

against the walls of the vessels turn all this energy into

oxygen; using this energy equivalent, one can calculate

heat.

with a high degree of precision the rate of heat libera-

Essentially all the energy expended by the body is

tion in the body from the quantity of oxygen used in a

eventually converted into heat. The only significant

given period of time.

exception occurs when the muscles are used to perform

If a person metabolizes only carbohydrates during

some form of work outside the body. For instance, when

the period of the metabolic rate determination, the cal-

the muscles elevate an object to a height or propel the

culated quantity of energy liberated, based on the value

body up steps, a type of potential energy is created by

for the average energy equivalent of oxygen (4.825

raising a mass against gravity. But when external expen-

Calories/L), would be about 4 per cent too little. Con-

diture of energy is not taking place, all the energy

versely, if the person obtains most energy from fat, the

released by the metabolic processes eventually becomes

calculated value would be about 4 per cent too great.

body heat.

Energy Metabolism—

The Calorie. To discuss the metabolic rate of the body

Factors That Influence

and related subjects intelligently, it is necessary to use

some unit for expressing the quantity of energy released

Energy Output

from the different foods or expended by the different

As discussed in Chapter 71, energy intake is balanced

functional processes of the body. Most often, the Calorie

with energy output in healthy adults who maintain a

is the unit used for this purpose. It will be recalled that

stable body weight. About 45 per cent of daily energy

1 calorie—spelled with a small “c” and often called a

intake is derived from carbohydrates,

40 per cent

gram calorie—is the quantity of heat required to raise

from fats, and 15 per cent from proteins in the average

the temperature of 1 gram of water 1°C. The calorie is

American diet. Energy output can also be partitioned

much too small a unit when referring to energy in the

into several measurable components, including energy

body. Consequently, the Calorie—sometimes spelled

used for (1) performing essential metabolic functions of

with a capital “C” and often called a kilocalorie, which

the body (the “basal” metabolic rate); (2) performing

is equivalent to 1000 calories—is the unit ordinarily

various physical activities; (3) digesting, absorbing, and

used in discussing energy metabolism.

processing food; and (4) maintaining body temperature.

Measurement of the Whole-Body

Overall Energy Requirements

Metabolic Rate

for Daily Activities

Direct Calorimetry Measures Heat Liberated from the Body.

An average man who weighs 70 kilograms and lies in

Because a person ordinarily is not performing any

bed all day uses about 1650 Calories of energy. The

external work, the whole-body metabolic rate can be

process of eating and digesting food increases the

determined by simply measuring the total quantity of

amount of energy used each day by an additional 200

heat liberated from the body in a given time.

or more Calories, so that the same man lying in bed and

In determining the metabolic rate by direct calorime-

eating a reasonable diet requires a dietary intake of

try, one measures the quantity of heat liberated from the

about 1850 Calories per day. If he sits in a chair all day

body in a large, specially constructed calorimeter. The

without exercising, his total energy requirement reaches

subject is placed in an air chamber that is so well insu-

2000 to 2250 Calories. Therefore, the approximate daily

lated that no heat can leak through the walls of the

energy requirement for a very sedentary man perform-

chamber. Heat formed by the subject’s body warms the

ing only essential functions is 2000 Calories.

air of the chamber. However, the air temperature within

The amount of energy used to perform daily physical

the chamber is maintained at a constant level by forcing

activities is normally about 25 per cent of the total

the air through pipes in a cool water bath. The rate of

energy expenditure, but it can vary markedly in differ-

heat gain by the water bath, which can be measured with

ent individuals, depending on the type and amount of

an accurate thermometer, is equal to the rate at which

physical activity. For example, walking up stairs requires

heat is liberated by the subject’s body.

about 17 times as much energy as lying in bed asleep.

Direct calorimetry is physically difficult to perform

In general, over a 24-hour period, a person performing

and is used only for research purposes.

heavy labor can achieve a maximal rate of energy uti-

886

Unit XIII

Metabolism and Temperature Regulation

lization as great as 6000 to 7000 Calories, or as much as

reason, BMR is usually corrected for differences in

3.5 times the energy used under conditions of no phys-

body size by expressing it as Calories per hour per

ical activity.

square meter of body surface area, calculated from

height and weight. The average values for males and

females of different ages are shown in Figure 72-4.

Basal Metabolic Rate (BMR)—

Much of the decline in BMR with increasing age is

The Minimum Energy Expenditure

probably related to loss of muscle mass and replace-

for the Body to Exist

ment of muscle with adipose tissue, which has a lower

rate of metabolism. Likewise, slightly lower BMRs in

Even when a person is at complete rest, considerable

women, compared with men, are due partly to their

energy is required to perform all the chemical reactions

lower percentage of muscle mass and higher percentage

of the body. This minimum level of energy required

of adipose tissue. However, there are other factors that

to exist is called the basal metabolic rate (BMR) and

can influence the BMR, as discussed next.

accounts for about 50 to 70 per cent of the daily energy

expenditure in most sedentary individuals (Figure 72-3).

Thyroid Hormone Increases Metabolic Rate. When the thyroid

Because the level of physical activity is highly vari-

gland secretes maximal amounts of thyroxine, the meta-

able among different individuals, measurement of

bolic rate sometimes rises 50 to 100 per cent above

the BMR provides a useful means of comparing one

normal. Conversely, total loss of thyroid secretion

person’s metabolic rate with that of another. The usual

decreases the metabolic rate to 40 to 60 per cent of

method for determining BMR is to measure the rate of

normal. As discussed in Chapter 76, thyroxine increases

oxygen utilization over a given period of time under the

the rates of the chemical reactions of many cells in the

following conditions:

body and therefore increases metabolic rate. Adapta-

1. The person must not have eaten food for at least 12

tion of the thyroid gland—with increased secretion in

hours.

cold climates and decreased secretion in hot climates—

2. The BMR is determined after a night of restful

contributes to the differences in BMRs among people

sleep.

living in different geographical zones; for example,

3. No strenuous activity is performed for at least 1

people living in arctic regions have BMRs 10 to 20 per

hour before the test.

cent higher than those of persons living in tropical

4. All psychic and physical factors that cause

regions.

excitement must be eliminated.

5. The temperature of the air must be comfortable

Male Sex Hormone Increases Metabolic Rate. The male sex

and between 68° and 80°F.

hormone testosterone can increase the metabolic rate

6. No physical activity is permitted during the test.

about 10 to 15 per cent. The female sex hormones may

The BMR normally averages about 65 to 70 Calories

increase the BMR a small amount, but usually not

per hour in an average 70-kilogram man. Although

enough to be significant. Much of this effect of the male

much of the BMR is accounted for by essential activi-

sex hormone is related to its anabolic effect to increase

ties of the central nervous system, heart, kidneys, and

skeletal muscle mass.

other organs, the variations in BMR among different

individuals are related mainly to differences in the

amount of skeletal muscle and body size.

Growth Hormone Increases Metabolic Rate. Growth hormone

Skeletal muscle, even under resting conditions,

can increase the metabolic rate 15 to 20 per cent as a

accounts for 20 to 30 per cent of the BMR. For this

result of direct stimulation of cellular metabolism.

100

Purposeful physical activity (25%)

Nonexercise activity (7%)

Thermic effect of food (8%)

Arousal

Males

Basal

Sleeping

metabolic

Females

metabolic

rate (60%)

rate

Age (years)

Figure 72-3

Figure 72-4

Components of energy expenditure.

Normal basal metabolic rates at different ages for each sex.

Chapter 72

Energetics and Metabolic Rate

887

Fever Increases Metabolic Rate. Fever, regardless of its

Even in sedentary individuals who perform little or

cause, increases the chemical reactions of the body by

no daily exercise or physical work, significant energy

an average of about 120 per cent for every 10°C rise

is spent on spontaneous physical activity required

in temperature. This is discussed in more detail in

to maintain muscle tone and body posture and on other

Chapter 73.

nonexercise activities such as

“fidgeting.” Together,

these nonexercise activities account for about 7 per cent

Sleep Decreases Metabolic Rate. The metabolic rate

of a person’s daily energy usage.

decreases 10 to 15 per cent below normal during sleep.

This fall is due to two principal factors: (1) decreased

tone of the skeletal musculature during sleep and (2)

Energy Used for Processing Food—

decreased activity of the central nervous system.

Thermogenic Effect of Food

Malnutrition Decreases Metabolic Rate. Prolonged malnutri-

After a meal is ingested, the metabolic rate increases as

tion can decrease the metabolic rate 20 to 30 per cent,

a result of the different chemical reactions associated

presumably due to the paucity of food substances in the

with digestion, absorption, and storage of food in the

cells. In the final stages of many disease conditions, the

body. This is called the thermogenic effect of food,

inanition that accompanies the disease causes a marked

because these processes require energy and generate

decrease in metabolic rate, to the extent that the body

heat.

temperature may fall several degrees shortly before

After a meal that contains a large quantity of carbo-

death.

hydrates or fats, the metabolic rate usually increases

about 4 per cent. However, after a high-protein meal,

the metabolic rate usually begins rising within an hour,

Energy Used for Physical Activities

reaching a maximum of about 30 per cent above normal,

and this lasts for 3 to 12 hours. This effect of protein on

The factor that most dramatically increases metabolic

the metabolic rate is called the specific dynamic action

rate is strenuous exercise. Short bursts of maximal

of protein. The thermogenic effect of food accounts for

muscle contraction in a single muscle can liberate as

about 8 per cent of the total daily energy expenditure

much as 100 times its normal resting amount of heat for

in many persons.

a few seconds. For the entire body, maximal muscle

exercise can increase the overall heat production of the

body for a few seconds to about 50 times normal, or to

Energy Used for Nonshivering

about 20 times normal for more sustained exercise in a

Thermogenesis—Role of

well-trained individual.

Sympathetic Stimulation

Table 72-1 shows the energy expenditure during dif-

ferent types of physical activity for a 70-kilogram man.

Although physical work and the thermogenic effect of

Because of the great variation in the amount of physi-

food cause liberation of heat, these mechanisms are not

cal activity among individuals, this component of energy

aimed primarily at regulation of body temperature.

expenditure is the most important reason for the dif-

Shivering provides a regulated means of producing heat

ferences in caloric intake required to maintain energy

by increasing muscle activity in response to cold stress,

balance. However, in industrialized countries where

as discussed in Chapter

73. Another mechanism,

food supplies are plentiful, such as the United States,

nonshivering thermogenesis, can also produce heat in

caloric intake periodically exceeds energy expenditure,

response to cold stress. This type of thermogenesis is

and the excess energy is stored mainly as fat. This under-

stimulated by sympathetic nervous system activation,

scores the importance of maintaining a proper level of

which releases norepinephrine and epinephrine, which

physical activity to prevent excess fat stores and obesity.

in turn increase metabolic activity and heat generation.

In certain types of fat tissue, called brown fat, sym-

pathetic nervous stimulation causes liberation of large

amounts of heat. This type of fat contains large numbers

of mitochondria and many small globules of fat instead

Table 72-1

of one large fat globule. In these cells, the process of

Energy Expenditure During Different Types of Activity for a

oxidative phosphorylation in the mitochondria is mainly

70-Kilogram Man

“uncoupled.” That is, when the cells are stimulated by

the sympathetic nerves, the mitochondria produce a

large amount of heat but almost no ATP, so that almost

Form of Activity

Calories per Hour

all the released oxidative energy immediately becomes

Sleeping

heat.

Awake lying still

A neonate has a considerable number of brown fat

Sitting at rest

100

cells, and maximal sympathetic stimulation can increase

Standing relaxed

105

the child’s metabolism more than 100 per cent. The mag-

Dressing and undressing

118

nitude of this type of thermogenesis in an adult human,

Typewriting rapidly

140

who has virtually no brown fat, is probably less than 15

Walking slowly (2.6 miles per hour)

200

per cent, although this might increase significantly after

Carpentry, metalworking, industrial painting

240

Sawing wood

480

cold adaptation.

Swimming

500

Nonshivering thermogenesis may also serve as a

Running (5.3 miles per hour)

570

buffer against obesity. Recent studies indicate that

Walking up stairs rapidly

1100

sympathetic nervous system activity is increased in

obese persons who have a persistent excess caloric

Extracted from data compiled by Professor M. S. Rose.

intake. The mechanism responsible for sympathetic acti-

888

Unit XIII

Metabolism and Temperature Regulation

vation in obese persons is uncertain, but it may be medi-

MD: National Heart, Lung, and Blood Institute and

ated partly through the effects of increased leptin, which

National Institute of Diabetes and Digestive and Kidney

activates pro-opiomelanocortin neurons in the hypo-

Diseases.

1998. Available at: http://www.nhlbi.nih.gov/

thalamus. Sympathetic stimulation, by increasing ther-

guidelines/index.htm

mogenesis, helps to limit excess weight gain.

Robidoux J, Martin TL, Collins S: Beta-adrenergic receptors

and regulation of energy expenditure: a family affair.

Annu Rev Pharmacol Toxicol 44:297, 2004.

References

Rousset S, Alves-Guerra MC, Mozo J, et al: The biology of

mitochondrial uncoupling proteins. Diabetes

53(Suppl

Argyropoulos G, Harper ME: Uncoupling proteins and ther-

1):S130, 2004.

moregulation. J Appl Physiol 92:2187, 2002.

Seals DR, Bell C: Chronic sympathetic activation: conse-

Cannon B, Nedergaard J: Brown adipose tissue: function and

quence and cause of age-associated obesity? Diabetes

physiological significance. Physiol Rev 84:277, 2004.

53:276, 2004.

Chakravarthy MV, Booth FW: Eating, exercise, and “thrifty”

Silva JE: The thermogenic effect of thyroid hormone and its

genotypes: connecting the dots toward an evolutionary

clinical implications. Ann Intern Med 139:205, 2003.

understanding of modern chronic diseases. J Appl Physiol

van Marken Lichtenbelt WD, Daanen HA: Cold-induced

96:3, 2004.

metabolism. Curr Opin Clin Nutr Metab Care 6:469, 2003.

Evans RM, Barish GD, Wang YX: PPARs and the complex

Westerterp KR: Limits to sustainable human metabolic rate.

journey to obesity. Nat Med 10:355, 2004.

J Exp Biol 204:3183, 2001.

Levine JA: Nonexercise activity thermogenesis (NEAT):

Westerterp KR: Impacts of vigorous and non-vigorous activ-

environment and biology. Am J Physiol Endocrinol Metab

ity on daily energy expenditure. Proc Nutr Soc 62:645,

286:E675, 2004.

2003.

Livingstone MB, Black AE: Markers of the validity of

Wilson MM, Morley JE: Aging and energy balance. J Appl

reported energy intake. J Nutr 133(Suppl 3):895S, 2003.

Physiol 95:1728, 2003.

Lowell BB, Bachman ES: Beta-adrenergic receptors, diet-

Winder WW: Energy-sensing and signaling by AMP-acti-

induced thermogenesis, and obesity. J Biol Chem

vated protein kinase in skeletal muscle. J Appl Physiol

278:29385, 2003.

91:1017, 2001.

Morrison SF: Central pathways controlling brown adipose

Yen PM: Physiological and molecular basis of thyroid

tissue thermogenesis. News Physiol Sci 19:67, 2004.

hormone action. Physiol Rev 81:1097, 2001.

National Institutes of Health: Clinical Guidelines on the

Identification, Evaluation, and Treatment of Overweight

and Obesity in Adults: The Evidence Report. Bethesda,

C H A P T E R

Body Temperature, Temperature

Regulation, and Fever

Normal Body Temperatures

Core Temperature and Skin Temperature. The tempera-

ture of the deep tissues of the body—the “core” of

the body—remains very constant, within

±1°F

(±0.6°C), day in and day out, except when a person

develops a febrile illness. Indeed, a nude person can

be exposed to temperatures as low as 55°F or as

high as 130°F in dry air and still maintain an almost constant core temperature.

The mechanisms for regulating body temperature represent a beautifully

designed control system. The purpose of this chapter is to discuss this system as

it operates in health and in disease.

The skin temperature, in contrast to the core temperature, rises and falls

with the temperature of the surroundings. The skin temperature is the im-

portant temperature when we refer to the skin’s ability to lose heat to the

surroundings.

Normal Core Temperature. No single core temperature can be considered normal,

because measurements in many healthy people have shown a range of normal

temperatures measured orally, as shown in Figure 73-1, from less than 97°F

(36°C) to over 99.5°F (37.5°C). The average normal core temperature is gener-

ally considered to be between 98.0° and 98.6°F when measured orally and about

1°F higher when measured rectally.

The body temperature increases during exercise and varies with temperature

extremes of the surroundings, because the temperature regulatory mechanisms

are not perfect. When excessive heat is produced in the body by strenuous

exercise, the temperature can rise temporarily to as high as 101° to 104°F. Con-

versely, when the body is exposed to extreme cold, the temperature can often

fall to values below 96°F.

Body Temperature Is Controlled by Balancing

Heat Production Against Heat Loss

When the rate of heat production in the body is greater than the rate at which

heat is being lost, heat builds up in the body and the body temperature rises.

Conversely, when heat loss is greater, both body heat and body temperature

decrease. Most of the remainder of this chapter is concerned with this balance

between heat production and heat loss and the mechanisms by which the body

controls each of these.

Heat Production

Heat production is a principal by-product of metabolism. In Chapter 72, which

summarizes body energetics, we discuss the different factors that determine the

rate of heat production, called the metabolic rate of the body. The most impor-

tant of these factors are listed again here: (1) basal rate of metabolism of all

the cells of the body; (2) extra rate of metabolism caused by muscle activity,

889

890

Unit XIII

Metabolism and Temperature Regulation

including muscle contractions caused by shivering; (3)

tissues to the skin, where it is lost to the air and other

extra metabolism caused by the effect of thyroxine

surroundings. Therefore, the rate at which heat is lost

(and, to a less extent, other hormones, such as growth

is determined almost entirely by two factors: (1) how

hormone and testosterone) on the cells; (4) extra

rapidly heat can be conducted from where it is pro-

metabolism caused by the effect of epinephrine, nor-

duced in the body core to the skin and (2) how rapidly

epinephrine, and sympathetic stimulation on the cells;

heat can then be transferred from the skin to the sur-

(5) extra metabolism caused by increased chemical

roundings. Let us begin by discussing the system that

activity in the cells themselves, especially when the cell

insulates the core from the skin surface.

temperature increases; and

(6) extra metabolism

needed for digestion, absorption, and storage of food

Insulator System of the Body

(thermogenic effect of food).

The skin, the subcutaneous tissues, and especially the

fat of the subcutaneous tissues act together as a heat

insulator for the body. The fat is important because it

Heat Loss

conducts heat only one third as readily as other tissues.

When no blood is flowing from the heated internal

Most of the heat produced in the body is generated in

organs to the skin, the insulating properties of the

the deep organs, especially in the liver, brain, and

normal male body are about equal to three quarters

heart, and in the skeletal muscles during exercise. Then

the insulating properties of a usual suit of clothes. In

this heat is transferred from the deeper organs and

women, this insulation is even better.

The insulation beneath the skin is an effective

means of maintaining normal internal core tempera-

ture, even though it allows the temperature of the skin

Oral

-F

-C

Rectal

to approach the temperature of the surroundings.

104

Blood Flow to the Skin from the Body Core

Provides Heat Transfer

Hard exercise

Blood vessels are distributed profusely beneath the

102

skin. Especially important is a continuous venous

Emotion or

Hard work, emotion

moderate exercise

plexus that is supplied by inflow of blood from the skin

A few normal adults

100

A few normal adults

capillaries, shown in Figure 73-2. In the most exposed

Many active children

areas of the body—the hands, feet, and ears—blood is

Usual range

also supplied to the plexus directly from the small

of normal

arteries through highly muscular arteriovenous

anastomoses.

Early morning

The rate of blood flow into the skin venous plexus

Cold weather, etc.

can vary tremendously—from barely above zero to as

great as 30 per cent of the total cardiac output. A high

rate of skin flow causes heat to be conducted from the

core of the body to the skin with great efficiency,

Figure 73-1

whereas reduction in the rate of skin flow can decrease

the heat conduction from the core to very little.

Estimated range of body “core” temperature in normal people.

(Redrawn from DuBois EF: Fever. Springfield, IL: Charles C

Figure 73-3 shows quantitatively the effect of envi-

Thomas, 1948.)

ronmental air temperature on conductance of heat

Epidermis

Capillaries

Dermis

Arteries

Veins

Venous plexus

Subcutaneous tissue

Arteriovenous

anastomosis

Figure 73-2

Artery

Skin circulation.

Chapter 73

Body Temperature, Temperature Regulation, and Fever

891

Walls

Evaporation (22%)

Vasodilated

Radiation (60%)

heat waves

Conduction to air (15%)

Air currents

(convection)

Conduction to

objects (3%)

Vasoconstricted

Figure 73-4

Mechanisms of heat loss from the body.

100

110

120

Environmental temperature (°F)

have wavelengths of 5 to 20 micrometers, 10 to 30

times the wavelengths of light rays. All objects that are

not at absolute zero temperature radiate such rays. The

Figure 73-3

human body radiates heat rays in all directions. Heat

rays are also being radiated from the walls of rooms

Effect of changes in the environmental temperature on heat con-

ductance from the body core to the skin surface. (Modified from

and other objects toward the body. If the temperature

Benzinger TH: Heat and Temperature Fundamentals of Medical

of the body is greater than the temperature of the sur-

Physiology. New York: Dowden, Hutchinson & Ross, 1980.)

roundings, a greater quantity of heat is radiated from

the body than is radiated to the body.

from the core to the skin surface and then conductance

Conduction. As shown in Figure

73-4, only minute

into the air, demonstrating an approximate eightfold

quantities of heat, about 3 per cent, are normally lost

increase in heat conductance between the fully vaso-

from the body by direct conduction from the surface

constricted state and the fully vasodilated state.

of the body to solid objects, such as a chair or a bed.

Therefore, the skin is an effective controlled “heat

Loss of heat by conduction to air, however, represents

radiator” system, and the flow of blood to the skin is a

a sizable proportion of the body’s heat loss (about 15

most effective mechanism for heat transfer from the

per cent) even under normal conditions.

body core to the skin.

It will be recalled that heat is actually the kinetic

energy of molecular motion, and the molecules of

Control of Heat Conduction to the Skin by the Sympathetic

the skin are continually undergoing vibratory motion.

Nervous System. Heat conduction to the skin by the

Much of the energy of this motion can be transferred

blood is controlled by the degree of vasoconstriction

to the air if the air is colder than the skin, thus increas-

of the arterioles and the arteriovenous anastomoses

ing the velocity of the air molecules’ motion. Once the

that supply blood to the venous plexus of the skin. This

temperature of the air adjacent to the skin equals the

vasoconstriction is controlled almost entirely by the

temperature of the skin, no further loss of heat occurs

sympathetic nervous system in response to changes in

in this way, because now an equal amount of heat is

body core temperature and changes in environmental

conducted from the air to the body. Therefore, con-

temperature. This is discussed later in the chapter in

duction of heat from the body to the air is self-limited

connection with control of body temperature by the

unless the heated air moves away from the skin, so that

hypothalamus.

new, unheated air is continually brought in contact

with the skin, a phenomenon called air convection.

Basic Physics of How Heat Is Lost from the

Skin Surface

Convection. The removal of heat from the body by con-

The various methods by which heat is lost from the

vection air currents is commonly called heat loss by

skin to the surroundings are shown in Figure 73-4.

convection. Actually, the heat must first be conducted

They include radiation, conduction, and evaporation,

to the air and then carried away by the convection air

which are explained next.

currents.

A small amount of convection almost always occurs

Radiation. As shown in Figure 73-4, in a nude person

around the body because of the tendency for air adja-

sitting inside at normal room temperature, about 60

cent to the skin to rise as it becomes heated. There-

per cent of total heat loss is by radiation.

fore, in a nude person seated in a comfortable room

Loss of heat by radiation means loss in the form of

without gross air movement, about 15 per cent of his

infrared heat rays, a type of electromagnetic wave.

or her total heat loss occurs by conduction to the air

Most infrared heat rays that radiate from the body

and then by air convection away from the body.

892

Unit XIII

Metabolism and Temperature Regulation

Cooling Effect of Wind. When the body is exposed to

suit of clothes decreases the rate of heat loss to about

wind, the layer of air immediately adjacent to the skin

half that from the nude body, but arctic-type clothing

is replaced by new air much more rapidly than normally,

can decrease this heat loss to as little as one sixth.

and heat loss by convection increases accordingly. The

About half the heat transmitted from the skin to the

cooling effect of wind at low velocities is about propor-

clothing is radiated to the clothing instead of being

tional to the square root of the wind velocity. For

conducted across the small intervening space. There-

instance, a wind of 4 miles per hour is about twice as

fore, coating the inside of clothing with a thin layer of

effective for cooling as a wind of 1 mile per hour.

gold, which reflects radiant heat back to the body,

Conduction and Convection of Heat from a Person Sus-

makes the insulating properties of clothing far more

pended in Water. Water has a specific heat several thou-

effective than otherwise. Using this technique, clothing

sand times as great as that of air, so that each unit

for use in the arctic can be decreased in weight by

portion of water adjacent to the skin can absorb far

about half.

greater quantities of heat than air can. Also, heat con-

The effectiveness of clothing in maintaining body

ductivity in water is very great in comparison with that

temperature is almost completely lost when the cloth-

in air. Consequently, it is impossible for the body to heat

ing becomes wet, because the high conductivity of

a thin layer of water next to the body to form an “insu-

water increases the rate of heat transmission through

lator zone” as occurs in air. Therefore, the rate of heat

loss to water is usually many times greater than the rate

cloth

20-fold or more. Therefore, one of the most

of heat loss to air.

important factors for protecting the body against cold

in arctic regions is extreme caution against allowing

Evaporation. When water evaporates from the body

the clothing to become wet. Indeed, one must be

surface, 0.58 Calorie (kilocalorie) of heat is lost for

careful not to become overheated even temporarily,

each gram of water that evaporates. Even when a

because sweating in one’s clothes makes them much

person is not sweating, water still evaporates insensi-

less effective thereafter as an insulator.

bly from the skin and lungs at a rate of about 600 to

700 ml/day. This causes continual heat loss at a rate of

Sweating and Its Regulation by the Autonomic

16 to 19 Calories per hour. This insensible evaporation

Nervous System

through the skin and lungs cannot be controlled for

Stimulation of the anterior hypothalamus-preoptic

purposes of temperature regulation because it results

area in the brain either electrically or by excess heat

from continual diffusion of water molecules through

causes sweating. The nerve impulses from this area

the skin and respiratory surfaces. However, loss of heat

that cause sweating are transmitted in the autonomic

by evaporation of sweat can be controlled by regulat-

pathways to the spinal cord and then through sympa-

ing the rate of sweating, which is discussed later in the

thetic outflow to the skin everywhere in the body.

chapter.

It should be recalled from the discussion of the

autonomic nervous system in Chapter 60 that the

Evaporation Is a Necessary Cooling Mechanism at Very High

sweat glands are innervated by cholinergic nerve

Air Temperatures. As long as skin temperature is greater

fibers (fibers that secrete acetylcholine but that run

than the temperature of the surroundings, heat can be

in the sympathetic nerves along with the adrenergic

lost by radiation and conduction. But when the tem-

fibers). These glands can also be stimulated to

perature of the surroundings becomes greater than that

some extent by epinephrine or norepinephrine circu-

of the skin, instead of losing heat, the body gains heat

by both radiation and conduction. Under these condi-

lating in the blood, even though the glands themselves

tions, the only means by which the body can rid itself of

do not have adrenergic innervation. This is important

heat is by evaporation.

during exercise, when these hormones are secreted by

Therefore, anything that prevents adequate evapo-

the adrenal medullae and the body needs to lose

ration when the surrounding temperature is higher

excessive amounts of heat produced by the active

than the skin temperature will cause the internal body

muscles.

temperature to rise. This occurs occasionally in human

beings who are born with congenital absence of sweat

Mechanism of Sweat Secretion. In Figure 73-5, the sweat

glands. These people can stand cold temperatures as

gland is shown to be a tubular structure consisting of

well as normal people can, but they are likely to die of

two parts: (1) a deep subdermal coiled portion that

heatstroke in tropical zones because without the evap-

secretes the sweat, and (2) a duct portion that passes

orative refrigeration system, they cannot prevent a rise

outward through the dermis and epidermis of the skin.

in body temperature when the air temperature is

As is true of so many other glands, the secretory

above that of the body.

portion of the sweat gland secretes a fluid called the

primary secretion or precursor secretion; the concen-

Effect of Clothing on Conductive Heat Loss. Clothing

trations of constituents in the fluid are then modified

entraps air next to the skin in the weave of the cloth,

as the fluid flows through the duct.

thereby increasing the thickness of the so-called

The precursor secretion is an active secretory

private zone of air adjacent to the skin and also

product of the epithelial cells lining the coiled portion

decreasing the flow of convection air currents. Conse-

of the sweat gland. Cholinergic sympathetic nerve

quently, the rate of heat loss from the body by con-

fibers ending on or near the glandular cells elicit the

duction and convection is greatly depressed. A usual

secretion.

Chapter 73

Body Temperature, Temperature Regulation, and Fever

893

Pore

duct may reabsorb only slightly more than half the

sodium chloride; the concentrations of sodium and

chloride ions are then (in an unacclimatized person) a

maximum of about 50 to 60 mEq/L, slightly less than

half the concentrations in plasma. Furthermore, the

sweat flows through the glandular tubules so rapidly

that little of the water is reabsorbed. Therefore, the

other dissolved constituents of sweat are only moder-

ately increased in concentration—urea is about twice

that in the plasma, lactic acid about 4 times, and potas-

Duct

sium about 1.2 times.

Absorption, mainly

There is a significant loss of sodium chloride in the

sodium and chloride ions

sweat when a person is unacclimatized to heat. There

is much less electrolyte loss, despite increased sweat-

ing capacity, once a person has become acclimatized,

as follows.

Acclimatization of the Sweating Mechanism to Heat—Role

of Aldosterone. Although a normal, unacclimatized

Gland

person seldom produces more than about 1 liter of

sweat per hour, when this person is exposed to hot

Primary

weather for 1 to 6 weeks, he or she begins to sweat

secretion,

mainly

more profusely, often increasing maximum sweat pro-

protein-

duction to as much as 2 to 3 L/hour. Evaporation of

free

this much sweat can remove heat from the body at a

filtrate

rate more than 10 times the normal basal rate of heat

production. This increased effectiveness of the sweat-

ing mechanism is caused by a change in the internal

Sympathetic

sweat gland cells themselves to increase their sweating

nerve

capability.

Also associated with acclimatization is a further

Figure 73-5

decrease in the concentration of sodium chloride in

Sweat gland innervated by an acetylcholine-secreting sympa-

the sweat, which allows progressively better conserva-

thetic nerve. A primary protein-free secretion is formed by the

tion of body salt. Most of this effect is caused by

glandular portion, but most of the electrolytes are reabsorbed in

increased secretion of aldosterone by the adrenocor-

the duct, leaving a dilute, watery secretion.

tical glands, which results from a slight decrease in

sodium chloride concentration in the extracellular

fluid and plasma. An unacclimatized person who

The composition of the precursor secretion is

sweats profusely often loses 15 to 30 grams of salt each

similar to that of plasma, except that it does not

day for the first few days. After 4 to 6 weeks of acclima-

contain plasma proteins. The concentration of sodium

tization, the loss is usually 3 to 5 g/day.

is about

142 mEq/L and that of chloride is about

104 mEq/L, with much smaller concentrations of the

Loss of Heat by Panting

Many lower animals have little ability to lose heat from

other solutes of plasma. As this precursor solution

the surfaces of their bodies, for two reasons: (1) the sur-

flows through the duct portion of the gland, it is mod-

faces are usually covered with fur, and (2) the skin of

ified by reabsorption of most of the sodium and chlo-

most lower animals is not supplied with sweat glands,

ride ions. The degree of this reabsorption depends on

which prevents most of the evaporative loss of heat

the rate of sweating, as follows.

from the skin. A substitute mechanism, the panting

When the sweat glands are stimulated only slightly,

mechanism, is used by many lower animals as a means

the precursor fluid passes through the duct slowly. In

of dissipating heat.

this instance, essentially all the sodium and chloride

The phenomenon of panting is “turned on” by the

ions are reabsorbed, and the concentration of each

thermoregulator centers of the brain. That is, when the

falls to as low as 5 mEq/L. This reduces the osmotic

blood becomes overheated, the hypothalamus initiates

neurogenic signals to decrease the body temperature.

pressure of the sweat fluid to such a low level that most

One of these signals initiates panting. The actual panting

of the water is also reabsorbed, which concentrates

process is controlled by a panting center that is associ-

most of the other constituents. Therefore, at low rates

ated with the pneumotaxic respiratory center located in

of sweating, such constituents as urea, lactic acid, and

the pons.

potassium ions are usually very concentrated.

When an animal pants, it breathes in and out rapidly,

Conversely, when the sweat glands are strongly

so that large quantities of new air from the exterior

stimulated by the sympathetic nervous system, large

come in contact with the upper portions of the respira-

amounts of precursor secretion are formed, and the

tory passages; this cools the blood in the respiratory

894

Unit XIII

Metabolism and Temperature Regulation

passage mucosa as a result of water evaporation from

Role of the Anterior Hypothalamic-Preoptic

the mucosal surfaces, especially evaporation of saliva

Area in Thermostatic Detection

from the tongue. Yet panting does not increase the alve-

of Temperature

olar ventilation more than is required for proper control

Experiments have been performed in which minute

of the blood gases, because each breath is extremely

areas in the brain of an animal have been either heated

shallow; therefore, most of the air that enters the alveoli

or cooled by use of a thermode. This small, needle-like

is dead-space air mainly from the trachea and not from

device is heated by electrical means or by passing hot

the atmosphere.

water through it, or it is cooled by cold water. The

principal areas in the brain where heat or cold from

a thermode affects body temperature control are the

Regulation of Body

preoptic and anterior hypothalamic nuclei of the

Temperature—Role of the

hypothalamus.

Hypothalamus

Using the thermode, the anterior hypothalamic-

preoptic area has been found to contain large numbers

Figure 73-6 shows what happens to the body “core”

of heat-sensitive neurons as well as about one third

temperature of a nude person after a few hours’ expo-

as many cold-sensitive neurons. These neurons are

sure to dry air ranging from 30° to 160°F. The precise

believed to function as temperature sensors for con-

dimensions of this curve depend on the wind move-

trolling body temperature. The heat-sensitive neurons

ment of the air, the amount of moisture in the air, and

increase their firing rate 2- to 10-fold in response to a

even the nature of the surroundings. In general, a nude

10°C increase in body temperature. The cold-sensitive

person in dry air between 55° and 130°F is capable of

neurons, by contrast, increase their firing rate when the

maintaining a normal body core temperature some-

body temperature falls.

where between 97° and 100°F.

When the preoptic area is heated, the skin all over

The temperature of the body is regulated almost

the body immediately breaks out in a profuse sweat,

entirely by nervous feedback mechanisms, and almost

while the skin blood vessels over the entire body

all these operate through temperature-regulating

become greatly dilated. This is an immediate reaction

centers located in the hypothalamus. For these feed-

to cause the body to lose heat, thereby helping to

back mechanisms to operate, there must also be

return the body temperature toward the normal level.

temperature detectors to determine when the body

In addition, any excess body heat production is inhib-

temperature becomes either too high or too low.

ited. Therefore, it is clear that the hypothalamic-

preoptic area has the capability to serve as a ther-

mostatic body temperature control center.

Detection of Temperature by Receptors in the

Skin and Deep Body Tissues

Although the signals generated by the temperature

receptors of the hypothalamus are extremely power-

ful in controlling body temperature, receptors in other

120

parts of the body play additional roles in temperature

regulation. This is especially true of temperature

110

receptors in the skin and in a few specific deep tissues

of the body.

100

It will be recalled from the discussion of sensory

receptors in Chapter 48 that the skin is endowed

with both cold and warmth receptors. There are far

more cold receptors than warmth receptors—in fact,

10 times as many in many parts of the skin. Therefore,

peripheral detection of temperature mainly concerns

detecting cool and cold instead of warm temperatures.

When the skin is chilled over the entire body, imme-

diate reflex effects are invoked and begin to increase

the temperature of the body in several ways: (1) by

providing a strong stimulus to cause shivering, with a

110

130

150

170

resultant increase in the rate of body heat production;

Atmospheric temperature (°F)

(2) by inhibiting the process of sweating, if this is

already occurring; and (3) by promoting skin vaso-

constriction to diminish loss of body heat from the

Figure 73-6

skin.

Deep body temperature receptors are found mainly

Effect of high and low atmospheric temperatures of several hours’

in the spinal cord, in the abdominal viscera, and in or

duration on the internal body “core” temperature. Note that the

around the great veins in the upper abdomen and

internal body temperature remains stable despite wide changes

in atmospheric temperature.

thorax. These deep receptors function differently from

Chapter 73

Body Temperature, Temperature Regulation, and Fever

895

the skin receptors because they are exposed to the

body core temperature rather than the body surface

temperature. Yet, like the skin temperature receptors,

they detect mainly cold rather than warmth. It is prob-

Heat production

able that both the skin and the deep body receptors

Evaporative heat loss

are concerned with preventing hypothermia—that is,

preventing low body temperature.

Posterior Hypothalamus Integrates the Central

and Peripheral Temperature Sensory Signals

Even though many temperature sensory signals arise

in peripheral receptors, these signals contribute to

body temperature control mainly through the hypo-

thalamus. The area of the hypothalamus that they

stimulate is located bilaterally in the posterior hypo-

thalamus approximately at the level of the mammil-

lary bodies. The temperature sensory signals from the

anterior hypothalamic-preoptic area are also trans-

mitted into this posterior hypothalamic area. Here the

signals from the preoptic area and the signals from

36.4

36.6

36.8

37.0

37.2

37.4

37.6

elsewhere in the body are combined and integrated to

Head temperature (°C)

control the heat-producing and heat-conserving reac-

tions of the body.

Figure 73-7

Neuronal Effector Mechanisms

Effect of hypothalamic temperature on evaporative heat loss from

the body and on heat production caused primarily by muscle

That Decrease or Increase Body

activity and shivering. This figure demonstrates the extremely crit-

Temperature

ical temperature level at which increased heat loss begins and

heat production reaches a minimum stable level.

When the hypothalamic temperature centers detect

that the body temperature is either too high or too

low, they institute appropriate temperature-decreasing

or temperature-increasing procedures. The reader is

probably familiar with most of these from personal

Temperature-Increasing Mechanisms When the

experience, but special features are the following.

Body Is Too Cold

When the body is too cold, the temperature control

Temperature-Decreasing Mechanisms

system institutes exactly opposite procedures. They

When the Body Is Too Hot

are:

The temperature control system uses three important

1. Skin vasoconstriction throughout the body.

mechanisms to reduce body heat when the body tem-

This is caused by stimulation of the posterior

perature becomes too great:

hypothalamic sympathetic centers.

1. Vasodilation of skin blood vessels. In almost all

2. Piloerection. Piloerection means hairs “standing

areas of the body, the skin blood vessels become

on end.” Sympathetic stimulation causes the

intensely dilated. This is caused by inhibition

arrector pili muscles attached to the hair follicles

of the sympathetic centers in the posterior

to contract, which brings the hairs to an upright

hypothalamus that cause vasoconstriction. Full

stance. This is not important in human beings, but

vasodilation can increase the rate of heat transfer

in lower animals, upright projection of the hairs

to the skin as much as eightfold.

allows them to entrap a thick layer of “insulator

2. Sweating. The effect of increased body

air” next to the skin, so that transfer of heat to

temperature to cause sweating is demonstrated by

the surroundings is greatly depressed.

the blue curve in Figure 73-7, which shows a

3. Increase in thermogenesis (heat production). Heat

sharp increase in the rate of evaporative heat

production by the metabolic systems is increased

loss resulting from sweating when the body core

by promoting shivering, sympathetic excitation of

temperature rises above the critical level of 37°C

heat production, and thyroxine secretion. These

(98.6°F). An additional 1°C increase in body

methods of increasing heat require additional

temperature causes enough sweating to remove 10

explanation, which follows.

times the basal rate of body heat production.

3. Decrease in heat production. The mechanisms that

Hypothalamic Stimulation of Shivering. Located in the

cause excess heat production, such as shivering

dorsomedial portion of the posterior hypothalamus

and chemical thermogenesis, are strongly

near the wall of the third ventricle is an area called

inhibited.

the primary motor center for shivering. This area is

896

Unit XIII

Metabolism and Temperature Regulation

normally inhibited by signals from the heat center in

of the hypothalamic portal veins to the anterior pitu-

the anterior hypothalamic-preoptic area but is excited

itary gland, where it stimulates secretion of thyroid-

by cold signals from the skin and spinal cord. There-

stimulating hormone.

fore, as shown by the sudden increase in “heat pro-

Thyroid-stimulating hormone in turn stimulates

duction” (see the red curve in Figure 73-7), this center

increased output of thyroxine by the thyroid gland, as

becomes activated when the body temperature falls

explained in Chapter

76. The increased thyroxine

even a fraction of a degree below a critical tempera-

increases the rate of cellular metabolism throughout

ture level. It then transmits signals that cause shiver-

the body, which is yet another mechanism of chemical

ing through bilateral tracts down the brain stem, into

thermogenesis. This increase in metabolism does not

the lateral columns of the spinal cord, and finally to

occur immediately but requires several weeks’ expo-

the anterior motor neurons. These signals are non-

sure to cold to make the thyroid gland hypertrophy

rhythmical and do not cause the actual muscle shaking.

and reach its new level of thyroxine secretion.

Instead, they increase the tone of the skeletal muscles

Exposure of animals to extreme cold for several

throughout the body by facilitating the activity of the

weeks can cause their thyroid glands to increase in size

anterior motor neurons. When the tone rises above a

20 to 40 per cent. However, human beings seldom

certain critical level, shivering begins. This probably

allow themselves to be exposed to the same degree of

results from feedback oscillation of the muscle spindle

cold as that to which animals are often subjected.

stretch reflex mechanism, which is discussed in

Therefore, we still do not know, quantitatively, how

Chapter 54. During maximum shivering, body heat

important the thyroid mechanism of adaptation to

production can rise to four to five times normal.

cold is in the human being.

Isolated measurements have shown that military

Sympathetic “Chemical” Excitation of Heat Production. As

personnel residing for several months in the arctic

pointed out in Chapter 72, an increase in either sym-

develop increased metabolic rates; some Inuit

pathetic stimulation or circulating norepinephrine and

(Eskimos) also have abnormally high basal metabolic

epinephrine in the blood can cause an immediate

rates. Further, the continuous stimulatory effect of

increase in the rate of cellular metabolism. This effect

cold on the thyroid gland may explain the much higher

is called chemical thermogenesis. It results at least par-

incidence of toxic thyroid goiters in people who live in

tially from the ability of norepinephrine and epineph-

cold climates than in those who live in warm climates.

rine to uncouple oxidative phosphorylation, which

means that excess foodstuffs are oxidized and thereby

release energy in the form of heat but do not cause

Concept of a “Set-Point”

adenosine triphosphate to be formed.

for Temperature Control

The degree of chemical thermogenesis that occurs

in an animal is almost directly proportional to the

In the example of Figure 73-7, it is clear that at a crit-

amount of brown fat in the animal’s tissues. This is a

ical body core temperature of about 37.1°C (98.8∞F),

type of fat that contains large numbers of special

drastic changes occur in the rates of both heat loss and

mitochondria where uncoupled oxidation occurs, as

heat production. At temperatures above this level, the

described in Chapter 72; these cells are supplied by

rate of heat loss is greater than that of heat produc-

strong sympathetic innervation.

tion, so the body temperature falls and approaches the

Acclimatization greatly affects the intensity of

37.1°C level. At temperatures below this level, the rate

chemical thermogenesis; some animals, such as rats,

of heat production is greater than that of heat loss, so

that have been exposed to a cold environment for

the body temperature rises and again approaches the

several weeks exhibit a 100 to 500 per cent increase in

37.1°C level. This crucial temperature level is called

heat production when acutely exposed to cold, in con-

the “set-point” of the temperature control mechanism.

trast to the unacclimatized animal, which responds

That is, all the temperature control mechanisms con-

with an increase of perhaps one third as much. This

tinually attempt to bring the body temperature back

increased thermogenesis also leads to a corresponding

to this set-point level.

increase in food intake.

In adult human beings, who have almost no brown

Feedback Gain for Body Temperature Control. Let us recall

fat, it is rare for chemical thermogenesis to increase

the discussion of feedback gain of control systems pre-

the rate of heat production more than 10 to 15 per

sented in Chapter 1. Feedback gain is a measure of the

cent. However, in infants, who do have a small amount

effectiveness of a control system. In the case of body

of brown fat in the interscapular space, chemical ther-

temperature control, it is important for the internal

mogenesis can increase the rate of heat production 100

core temperature to change as little as possible, even

per cent, which is probably an important factor in

though the environmental temperature might change

maintaining normal body temperature in neonates.

greatly from day to day or even hour to hour. The feed-

back gain of the temperature control system is equal

Increased Thyroxine Output as a Long-Term Cause of Increased

to the ratio of the change in environmental tempera-

Heat Production. Cooling the anterior hypothalamic-

ture to the change in body core temperature minus

preoptic area also increases production of the neu-

1.0

(see Chapter 1 for this formula). Experiments

rosecretory hormone thyrotropin-releasing hormone

have shown that the body temperature of humans

by the hypothalamus. This hormone is carried by way

changes about 1°C for each 25° to 30°C change in

Chapter 73

Body Temperature, Temperature Regulation, and Fever

897

environmental temperature. Therefore, the feedback

temperature was high, sweating began at a lower

gain of the total mechanism for body temperature

hypothalamic temperature than when the skin tem-

control averages about 27 (28/1.0 - 1.0 = 27), which is

perature was low. One can readily understand the

an extremely high gain for a biological control system

value of such a system, because it is important that

(the baroreceptor arterial pressure control system, for

sweating be inhibited when the skin temperature is

instance, has a feedback gain of less than 2).

low; otherwise, the combined effect of low skin

temperature and sweating could cause far too much

Skin Temperature Can Slightly Alter the

loss of body heat.

Set-Point for Core Temperature Control

A similar effect occurs in shivering, as shown in

The critical temperature set-point in the hypothalamus

Figure 73-9. That is, when the skin becomes cold,

above which sweating begins and below which shiver-

it drives the hypothalamic centers to the shivering

ing begins is determined mainly by the degree of activ-

threshold even when the hypothalamic temperature

ity of the heat temperature receptors in the anterior

itself is still on the hot side of normal. Here again, one

hypothalamic-preoptic area. However, temperature

can understand the value of the control system,

signals from the peripheral areas of the body, espe-

because a cold skin temperature would soon lead to a

cially from the skin and certain deep body tissues

deeply depressed body temperature unless heat pro-

(spinal cord and abdominal viscera), also contribute

duction were increased. Thus, a cold skin temperature

slightly to body temperature regulation. But how do

actually “anticipates” a fall in internal body tempera-

they contribute? The answer is that they alter the set-

ture and prevents this.

point of the hypothalamic temperature control center.

This effect is shown in Figures 73-8 and 73-9.

Figure 73-8 demonstrates the effect of different skin

Behavioral Control of Body

temperatures on the set-point for sweating, showing

Temperature

that the set-point increases as the skin temperature

decreases. Thus, for the person represented in this

Aside from the subconscious mechanisms for

figure, the hypothalamic set-point increased from

body temperature control, the body has another

36.7°C when the skin temperature was higher than

temperature-control mechanism that is even more

33°C to a set-point of 37.4°C when the skin tempera-

potent. This is behavioral control of temperature, which

ture had fallen to 29°C. Therefore, when the skin

Skin temperature (20°)

20°

33°C

22°

39°C

24°

Shivering

26°

Skin temperature

28°

Sweating

32°C

30°

31°C

Set-point

31°

30°C

Basal heat

Set-point

29°C

production

Insensible

evaporation

36.0 36.2 36.4

36.6

36.8

37.0 37.2 37.4

36.6

36.8

37.0

37.2

37.4

37.6

Internal head temperature (°C)

Figure 73-8

Figure 73-9

Effect of changes in the internal head temperature on the rate of

evaporative heat loss from the body. Note that the skin tempera-

heat production by the body. Note that the skin temperature

ture determines the set-point level at which sweating begins.

determines the set-point level at which shivering begins.

(Courtesy Dr. T. H. Benzinger.)

898

Unit XIII

Metabolism and Temperature Regulation

can be explained as follows: Whenever the internal

body temperature becomes too high, signals from the

-F

-C

temperature-controlling areas in the brain give the

Upper limit

person a psychic sensation of being overheated. Con-

Temperature

114

of survival?

regulation

versely, whenever the body becomes too cold, signals

seriously

110

Heatstroke

from the skin and probably also from some deep body

impaired

Brain lesions

receptors elicit the feeling of cold discomfort. There-

106

Fever therapy

Temperature

fore, the person makes appropriate environmental

regulation

102

Febrile disease

adjustments to re-establish comfort, such as moving

efficient in

and hard exercise

into a heated room or wearing well-insulated clothing

febrile disease,

Usual range

health, and work

in freezing weather. This is a much more powerful

of normal

system of body temperature control than most

Temperature

regulation

physiologists have acknowledged in the past. Indeed,

impaired

this is the only really effective mechanism to prevent

body heat control breakdown in severely cold

Temperature

environments.

regulation

Lower limit

lost

of survival?

Local Skin Temperature Reflexes

When a person places a foot under a hot lamp and

leaves it there for a short time, local vasodilation and

Figure 73-10

mild local sweating occur. Conversely, placing the foot

in cold water causes local vasoconstriction and local ces-

Body temperatures under different conditions. (Redrawn from

sation of sweating. These reactions are caused by local

DuBois EF: Fever. Springfield, IL: Charles C Thomas, 1948.)

effects of temperature directly on the blood vessels and

also by local cord reflexes conducted from skin recep-

tors to the spinal cord and back to the same skin area

brain tumors, and environmental conditions that may

and the sweat glands. The intensity of these local effects

terminate in heatstroke.

is, in addition, controlled by the central brain tempera-

ture controller, so that their overall effect is propor-

Resetting the Hypothalamic Temperature-

tional to the hypothalamic heat control signal times the

local signal. Such reflexes can help prevent excessive

Regulating Center in Febrile Diseases—

heat exchange from locally cooled or heated portions of

Effect of Pyrogens

the body.

Many proteins, breakdown products of proteins, and

certain other substances, especially lipopolysaccharide

Regulation of Internal Body Temperature Is Impaired by Cutting

toxins released from bacterial cell membranes, can

the Spinal Cord. After cutting the spinal cord in the neck

cause the set-point of the hypothalamic thermostat to

above the sympathetic outflow from the cord, regulation

rise. Substances that cause this effect are called pyro-

of body temperature becomes extremely poor because

gens. Pyrogens released from toxic bacteria or those

the hypothalamus can no longer control either skin

released from degenerating body tissues cause fever

blood flow or the degree of sweating anywhere in the

during disease conditions. When the set-point of the

body. This is true even though the local temperature

reflexes originating in the skin, spinal cord, and intra-

hypothalamic temperature-regulating center becomes

abdominal receptors still exist. These reflexes are

higher than normal, all the mechanisms for raising the

extremely weak in comparison with hypothalamic

body temperature are brought into play, including heat

control of body temperature.

conservation and increased heat production. Within a

In people with this condition, body temperature

few hours after the set-point has been increased, the

must be regulated principally by the patient’s psychic

body temperature also approaches this level, as shown

response to cold and hot sensations in the head region—

in Figure 73-11.

that is, by behavioral control of clothing and by moving

into an appropriate warm or cold environment.

Mechanism of Action of Pyrogens in Causing Fever—Role of

Interleukin-1. Experiments in animals have shown that

some pyrogens, when injected into the hypothalamus,

Abnormalities of Body

can act directly and immediately on the hypothalamic

Temperature Regulation

temperature-regulating center to increase its set-point.

Other pyrogens function indirectly and may require

Fever

several hours of latency before causing their effects.

This is true of many of the bacterial pyrogens, espe-

Fever, which means a body temperature above the

cially the endotoxins from gram-negative bacteria.

usual range of normal, can be caused by abnormalities

When bacteria or breakdown products of bacteria

in the brain itself or by toxic substances that affect the

are present in the tissues or in the blood, they are

temperature-regulating centers. Some causes of fever

phagocytized by the blood leukocytes, by tissue

(and also of subnormal body temperatures) are pre-

macrophages, and by large granular killer lymphocytes.

sented in Figure 73-10. They include bacterial diseases,

All these cells digest the bacterial products and then

Chapter 73

Body Temperature, Temperature Regulation, and Fever

899

the normal level to higher than normal (as a result of

tissue destruction, pyrogenic substances, or dehydra-

tion), the body temperature usually takes several hours

Set-point

suddenly

Setting of the thermostat

to reach the new temperature set-point.

105

raised to

Actual body temperature

Figure 73-11 demonstrates the effect of suddenly

high value

increasing the temperature set-point to a level of 103°F.

104

Because the blood temperature is now less than the set-

Crisis

103

point of the hypothalamic temperature controller, the

usual responses that cause elevation of body tempera-

Vasodilation

102

ture occur. During this period, the person experiences

Sweating

chills and feels extremely cold, even though his or her

101

Chills:

Set-point

body temperature may already be above normal. Also,

1. Vasoconstriction

suddenly

100

2. Piloerection

reduced to

the skin becomes cold because of vasoconstriction,

3. Epinephrine

low value

and the person shivers. Chills can continue until the

secretion

body temperature reaches the hypothalamic set-point

4. Shivering

of 103°F. Then the person no longer experiences chills

but instead feels neither cold nor hot. As long as the

factor that is causing the higher set-point of the hypo-

Time in hours

thalamic temperature controller is present, the body

temperature is regulated more or less in the normal

manner, but at the high temperature set-point level.

Figure 73-11

Crisis, or “Flush.” If the factor that is causing the high

temperature is removed, the set-point of the hypothal-

Effects of changing the set-point of the hypothalamic temperature

amic temperature controller will be reduced to a lower

controller.

value—perhaps even back to the normal level, as shown

in Figure 73-11. In this instance, the body temperature

release the substance interleukin-1—also called leuko-

is still

103°F, but the hypothalamus is attempting

cyte pyrogen or endogenous pyrogen—into the body

to regulate the temperature to 98.6°F. This situation

fluids. The interleukin-1, on reaching the hypothala-

is analogous to excessive heating of the anterior

mus, immediately activates the processes to produce

hypothalamic-preoptic area, which causes intense

sweating and the sudden development of hot skin

fever, sometimes increasing the body temperature a

because of vasodilation everywhere. This sudden change

noticeable amount in only 8 to 10 minutes. As little as

of events in a febrile state is known as the “crisis” or,

one ten-millionth of a gram of endotoxin lipopolysac-

more appropriately, the “flush.” In the days before the

charide from bacteria, acting in concert with the blood

advent of antibiotics, the crisis was always anxiously

leukocytes, tissue macrophages, and killer lympho-

awaited, because once this occurred, the doctor

cytes, can cause fever. The amount of interleukin-1 that

assumed that the patient’s temperature would soon

is formed in response to lipopolysaccharide to cause

begin falling.

fever is only a few nanograms.

Several experiments have suggested that inter-

Heatstroke

leukin-1 causes fever by first inducing the formation of

The upper limit of air temperature that one can stand

one of the prostaglandins, mainly prostaglandin E₂, or

depends almost entirely on whether the air is dry or wet.

If the air is dry and sufficient convection air currents are

a similar substance, which acts in the hypothalamus to

flowing to promote rapid evaporation from the body, a

elicit the fever reaction. When prostaglandin forma-

person can withstand several hours of air temperature

tion is blocked by drugs, the fever is either completely

at 130°F. Conversely, if the air is 100 per cent humidi-

abrogated or at least reduced. In fact, this may be the

fied or if the body is in water, the body temperature

explanation for the manner in which aspirin reduces

begins to rise whenever the environmental temperature

fever, because aspirin impedes the formation of

rises above about 94°F. If the person is performing

prostaglandins from arachidonic acid. Drugs such as

heavy work, the critical environmental temperature

aspirin that reduce fever are called antipyretics.

above which heatstroke is likely to occur may be as low

as 85° to 90°F.

Fever Caused by Brain Lesions. When a brain surgeon

When the body temperature rises beyond a critical

temperature, into the range of 105° to 108°F, the person

operates in the region of the hypothalamus, severe

is likely to develop heatstroke. The symptoms include

fever almost always occurs; rarely, the opposite effect,

dizziness, abdominal distress sometimes accompanied

hypothermia, occurs, demonstrating both the potency

by vomiting, sometimes delirium, and eventually loss of

of the hypothalamic mechanisms for body tempera-

consciousness if the body temperature is not soon

ture control and the ease with which abnormalities of

decreased. These symptoms are often exacerbated by a

the hypothalamus can alter the set-point of tempera-

degree of circulatory shock brought on by excessive loss

ture control. Another condition that frequently causes

of fluid and electrolytes in the sweat.

prolonged high temperature is compression of the

The hyperpyrexia itself is also exceedingly damaging

hypothalamus by a brain tumor.

to the body tissues, especially the brain, and is respon-

sible for many of the effects. In fact, even a few minutes

Characteristics of Febrile Conditions

of very high body temperature can sometimes be

Chills. When the set-point of the hypothalamic

fatal. For this reason, many authorities recommend

temperature-control center is suddenly changed from

immediate treatment of heatstroke by placing the

900

Unit XIII

Metabolism and Temperature Regulation

person in a cold water bath. Because this often induces

Cold-Induced Vasodilation Is a Final Protection Against

uncontrollable shivering, with a considerable increase in

Frostbite at Almost Freezing Temperatures. When the

the rate of heat production, others have suggested that

temperature of tissues falls almost to freezing, the

sponge or spray cooling of the skin is likely to be

smooth muscle in the vascular wall becomes paralyzed

more effective for rapidly decreasing the body core

because of the cold itself, and sudden vasodilation

temperature.

occurs, often manifested by a flush of the skin. This

mechanism helps prevent frostbite by delivering warm

Harmful Effects of High Temperature. The pathological find-

blood to the skin. This mechanism is far less developed

ings in a person who dies of hyperpyrexia are local

in humans than in most lower animals that live in the

hemorrhages and parenchymatous degeneration of cells

cold all the time.

throughout the entire body, but especially in the brain.

Once neuronal cells are destroyed, they can never be

Artificial Hypothermia. It is easy to decrease the tempera-

replaced. Also, damage to the liver, kidneys, and other

ture of a person by first administering a strong sedative

organs can often be severe enough that failure of one

to depress the reactivity of the hypothalamic tempera-

or more of these organs eventually causes death, but

ture controller and then cooling the person with ice or

sometimes not until several days after the heatstroke.

cooling blankets until the temperature falls. The tem-

Acclimatization to Heat. It can be extremely important

perature can then be maintained below 90°F for several

to acclimatize people to extreme heat. Examples of

days to a week or more by continual sprinkling of cool

people requiring acclimatization are soldiers on duty

water or alcohol on the body. Such artificial cooling has

in the tropics and miners working in the 2-mile-deep

been used during heart surgery so that the heart can be

gold mines of South Africa, where the temperature

stopped artificially for many minutes at a time. Cooling

approaches body temperature and the humidity

to this extent does not cause tissue damage, but it does

approaches 100 per cent. A person exposed to heat for

slow the heart and greatly depresses cell metabolism,

several hours each day while performing a reasonably

so that the body’s cells can survive 30 minutes to more

heavy workload will develop increased tolerance to hot

than 1 hour without blood flow during the surgical

and humid conditions in 1 to 3 weeks.

procedure.

Among the most important physiological changes

that occur during this acclimatization process are an

approximately twofold increase in the maximum rate of

References

sweating, an increase in plasma volume, and diminished

loss of salt in the sweat and urine to almost none; the

Aronoff DM, Neilson EG: Antipyretics: mechanisms of

last two effects result from increased secretion of aldos-

action and clinical use in fever suppression. Am J Med

terone by the adrenal glands.

111:304, 2001.

Blatteis CM, Li S, Li Z, et al: Signaling the brain in systemic

inflammation: the role of complement. Front Biosci 9:915,

Exposure of the Body to

2004.

Extreme Cold

Boulant JA: Hypothalamic neurons. Mechanisms of sensi-

tivity to temperature. Ann N Y Acad Sci 856:108, 1998.

Unless treated immediately, a person exposed to ice

Conti B, Tabarean I, Andrei C, Bartfai T: Cytokines and

water for 20 to 30 minutes ordinarily dies because of

fever. Front Biosci 9:1433, 2004.

heart standstill or heart fibrillation. By that time, the

Florez-Duquet M, McDonald RB: Cold-induced thermoreg-

internal body temperature will have fallen to about

ulation and biological aging. Physiol Rev 78:339, 1998.

77°F. If warmed rapidly by the application of external

Gourine AV, Dale N, Gourine VN, Spyer KM: Fever in sys-

heat, the person’s life can often be saved.

temic inflammation: roles of purines. Front Biosci 9:1011,

Loss of Temperature Regulation at Low Temperatures. As noted

2004.

in Figure 73-10, once the body temperature has fallen

Hildebrand F, Giannoudis PV, van Griensven M, et al:

below about 85°F, the ability of the hypothalamus to

Pathophysiologic changes and effects of hypothermia on

regulate temperature is lost; it is greatly impaired even

outcome in elective surgery and trauma patients. Am J

when the body temperature falls below about 94°F. Part

Surg 187:363, 2004.

of the reason for this diminished temperature regula-

Ivanov AI, Romanovsky AA: Prostaglandin E₂ as a media-

tion is that the rate of chemical heat production in each

tor of fever: synthesis and catabolism. Front Biosci 9:1977,

cell is depressed almost twofold for each 10°F decrease

2004.

in body temperature. Also, sleepiness develops (later

Katschinski DM: On heat and cells and proteins. News

followed by coma), which depresses the activity of the

Physiol Sci 19:11, 2004.

central nervous system heat control mechanisms and

Kenney WL, Munce TA: Aging and human temperature reg-

prevents shivering.

ulation. J Appl Physiol 95:2598, 2003.

Kozak W, Kluger MJ, Tesfaigzi J, et al: Molecular mechanisms

Frostbite. When the body is exposed to extremely low

of fever and endogenous antipyresis. Ann N Y Acad Sci

temperatures, surface areas can freeze; the freezing is

917:121, 2000.

called frostbite. This occurs especially in the lobes of the

Leon LR: Cytokine regulation of fever: studies using gene

ears and in the digits of the hands and feet. If the freeze

knockout mice. J Appl Physiol 92:2648, 2002.

has been sufficient to cause extensive formation of ice

McDermott MF: Genetic clues to understanding periodic

crystals in the cells, permanent damage usually results,

fevers, and possible therapies. Trends Mol Med 8:550,

such as permanent circulatory impairment as well as

2002.

local tissue damage. Often gangrene follows thawing,

Morrison SF: Central pathways controlling brown adipose

and the frostbitten areas must be removed surgically.

tissue thermogenesis. News Physiol Sci 19:67, 2004.

C H A P T E R

Introduction to Endocrinology

Coordination of Body

Functions by Chemical

Messengers

The multiple activities of the cells, tissues, and

organs of the body are coordinated by the interplay

of several types of chemical messenger systems:

1. Neurotransmitters are released by axon terminals of neurons into the

synaptic junctions and act locally to control nerve cell functions.

2. Endocrine hormones are released by glands or specialized cells into the

circulating blood and influence the function of cells at another location in

the body.

3. Neuroendocrine hormones are secreted by neurons into the circulating

blood and influence the function of cells at another location in the body.

4. Paracrines are secreted by cells into the extracellular fluid and affect

neighboring cells of a different type.

5. Autocrines are secreted by cells into the extracellular fluid and affect the

function of the same cells that produced them by binding to cell surface

receptors.

6. Cytokines are peptides secreted by cells into the extracellular fluid and can

function as autocrines, paracrines, or endocrine hormones. Examples of

cytokines include the interleukins and other lymphokines that are secreted

by helper cells and act on other cells of the immune system (see Chapter

34). Cytokine hormones (e.g., leptin) produced by adipocytes are

sometimes called adipokines.

In the next few chapters, we discuss mainly the endocrine and neuroendocrine

hormone systems, keeping in mind that many of the body’s chemical messen-

ger systems interact with one another to maintain homeostasis. For example,

the adrenal medullae and the pituitary gland secrete their hormones primarily

in response to neural stimuli. The neuroendocrine cells, located in the hypo-

thalamus, have axons that terminate in the posterior pituitary gland and median

eminence and secrete several neurohormones, including antidiuretic hormone

(ADH), oxytocin, and hypophysiotropic hormones, which control the secretion

of anterior pituitary hormones.

The endocrine hormones are carried by the circulatory system to cells

throughout the body, including the nervous system in some cases, where they

bind with receptors and initiate many reactions. Some endocrine hormones

affect many different types of cells of the body; for example, growth hormone

(from the anterior pituitary gland) causes growth in most parts of the body, and

thyroxine (from the thyroid gland) increases the rate of many chemical reac-

tions in almost all the body’s cells.

Other hormones affect only specific target tissues, because only these tissues

have receptors for the hormone. For example, adrenocorticotropic hormone

(ACTH) from the anterior pituitary gland specifically stimulates the adrenal

cortex, causing it to secrete adrenocortical hormones, and the ovarian hormones

have specific effects on the female sex organs as well as on the secondary sexual

characteristics of the female body.

Figure 74-1 shows the anatomical loci of the major endocrine glands and

endocrine tissues of the body, except for the placenta, which is an additional

source of the sex hormones. Table 74-1 provides an overview of the different

hormone systems and their most important actions.

905

906

Unit XIV Endocrinology and Reproduction

Chemical Structure and

Hypothalamus

Synthesis of Hormones

There are three general classes of hormones:

Pineal gland

1. Proteins and polypeptides, including hormones

Pituitary gland

secreted by the anterior and posterior pituitary

gland, the pancreas (insulin and glucagon), the

parathyroid gland (parathyroid hormone), and

many others (see Table 74-1).

2. Steroids secreted by the adrenal cortex (cortisol

Parathyroid glands

and aldosterone), the ovaries (estrogen and

(behind thyroid gland)

Thyroid gland

progesterone), the testes (testosterone), and the

Thymus gland

placenta (estrogen and progesterone).

3. Derivatives of the amino acid tyrosine, secreted

by the thyroid (thyroxine and triiodothyronine)

and the adrenal medullae (epinephrine and

norepinephrine). There are no known

polysaccharides or nucleic acid hormones.

Polypeptide and Protein Hormones Are Stored in Secretory Vesi-

cles Until Needed. Most of the hormones in the body

Stomach

are polypeptides and proteins. These hormones range

in size from small peptides with as few as 3 amino

Adrenal

glands

acids

(thyrotropin-releasing hormone) to proteins

with almost 200 amino acids (growth hormone and

Pancreas

Adipose

prolactin). In general, polypeptides with 100 or more

Kidney

tissue

amino acids are called proteins, and those with fewer

than 100 amino acids are referred to as peptides.

Small

Protein and peptide hormones are synthesized on

intestine

the rough end of the endoplasmic reticulum of the dif-

ferent endocrine cells, in the same fashion as most

other proteins (Figure 74-2). They are usually synthe-

sized first as larger proteins that are not biologically

Ovaries

active

(preprohormones) and are cleaved to form

(female)

smaller prohormones in the endoplasmic reticulum.

These are then transferred to the Golgi apparatus for

packaging into secretory vesicles. In this process,

enzymes in the vesicles cleave the prohormones to

Testes (male)

produce smaller, biologically active hormones and

inactive fragments. The vesicles are stored within the

Figure 74-1

cytoplasm, and many are bound to the cell membrane

until their secretion is needed. Secretion of the hor-

Anatomical loci of the principal endocrine glands and tissues of

mones (as well as the inactive fragments) occurs when

the body.

the secretory vesicles fuse with the cell membrane and

the granular contents are extruded into the interstitial

fluid or directly into the blood stream by exocytosis.

In many cases, the stimulus for exocytosis is an

increase in cytosolic calcium concentration caused by

The multiple hormone systems play a key role in

depolarization of the plasma membrane. In other

regulating almost all body functions, including metab-

instances, stimulation of an endocrine cell surface

olism, growth and development, water and electrolyte

receptor causes increased cyclic adenosine monophos-

balance, reproduction, and behavior. For instance,

phate (cAMP) and subsequently activation of protein

without growth hormone, a person would be a dwarf.

kinases that initiate secretion of the hormone. The

Without thyroxine and triiodothyronine from the

peptide hormones are water soluble, allowing them to

thyroid gland, almost all the chemical reactions of the

enter the circulatory system easily, where they are

body would become sluggish, and the person would

carried to their target tissues.

become sluggish as well. Without insulin from the pan-

creas, the body’s cells could use little of the food car-

Steroid Hormones Are Usually Synthesized from Cholesterol and

bohydrates for energy. And without the sex hormones,

Are Not Stored. The chemical structure of steroid hor-

sexual development and sexual functions would be

mones is similar to that of cholesterol, and in most

absent.

instances they are synthesized from cholesterol itself.

Chapter 74

Introduction to Endocrinology

907

Table 74-1

Endocrine Glands, Hormones, and Their Functions and Structure

Chemical

Gland/Tissue

Hormones

Major Functions

Structure

Hypothalamus

Thyrotropin-releasing hormone (TRH)

Stimulates secretion of TSH and prolactin

Peptide

(Chapter 75)

Corticotropin-releasing hormone (CRH)

Causes release of ACTH

Peptide

Growth hormone-releasing hormone (GHRH)

Causes release of growth hormone

Peptide

Growth hormone inhibitory hormone (GHIH)

Inhibits release of growth hormone

Peptide

(somatostatin)

Gonadotropin-releasing hormone (GnRH)

Causes release of LH and FSH

Dopamine or prolactin-inhibiting factor (PIF)

Inhibits release of prolactin

Amine

Anterior pituitary

Growth hormone

Stimulates protein synthesis and overall growth

Peptide

(Chapter 75)

of most cells and tissues

Thyroid-stimulating hormone (TSH)

Stimulates synthesis and secretion of thyroid

Peptide

hormones (thyroxine and triiodothyronine)

Adrenocorticotropic hormone (ACTH)

Stimulates synthesis and secretion of adrenocortical

Peptide

hormones (cortisol, androgens, and aldosterone)

Prolactin

Promotes development of the female breasts and

Peptide

secretion of milk

Follicle-stimulating hormone (FSH)

Causes growth of follicles in the ovaries and sperm

Peptide

maturation in Sertoli cells of testes

Luteinizing hormone (LH)

Stimulates testosterone synthesis in Leydig cells of

Peptide

testes; stimulates ovulation, formation of corpus

luteum, and estrogen and progesterone synthesis

in ovaries

Posterior pituitary

Antidiuretic hormone (ADH) (also called

Increases water reabsorption by the kidneys and

Peptide

(Chapter 75)

vasopressin)

causes vasoconstriction and increased blood

pressure

Oxytocin

Stimulates milk ejection from breasts and uterine

Peptide

contractions

Thyroid

Thyroxine (T₄) and triiodothyronine (T₃)

Increases the rates of chemical reactions in most

Amine

(Chapter 76)

cells, thus increasing body metabolic rate

Calcitonin

Promotes deposition of calcium in the bones and

Peptide

decreases extracellular fluid calcium ion

concentration

Adrenal cortex

Cortisol

Has multiple metabolic functions for controlling

Steroid

(Chapter 77)

metabolism of proteins, carbohydrates, and fats;

also has anti-inflammatory effects

Aldosterone

Increases renal sodium reabsorption, potassium

Steroid

secretion, and hydrogen ion secretion

Adrenal medulla

Norepinephrine, epinephrine

Same effects as sympathetic stimulation

Amine

(Chapter 60)

Pancreas

Insulin (b cells)

Promotes glucose entry in many cells, and in

Peptide

(Chapter 78)

this way controls carbohydrate metabolism

Glucagon (a cells)

Increases synthesis and release of glucose from

Peptide

the liver into the body fluids

Parathyroid

Parathyroid hormone (PTH)

Controls serum calcium ion concentration by

Peptide

(Chapter 79)

increasing calcium absorption by the gut and

kidneys and releasing calcium from bones

Testes

Testosterone

Promotes development of male reproductive

Steroid

(Chapter 80)

system and male secondary sexual characteristics

Ovaries

Estrogens

Promotes growth and development of female

Steroid

(Chapter 81)

reproductive system, female breasts, and female

secondary sexual characteristics

Progesterone

Stimulates secretion of “uterine milk” by the uterine

Steroid

endometrial glands and promotes development of

secretory apparatus of breasts

Placenta

Human chorionic gonadotropin (HCG)

Promotes growth of corpus luteum and secretion of

Peptide

(Chapter 82)

estrogens and progesterone by corpus luteum

Human somatomammotropin

Probably helps promote development of some

Peptide

fetal tissues as well as the mother’s breasts

Estrogens

See actions of estrogens from ovaries

Steroid

Progesterone

See actions of progesterone from ovaries

Steroid

Kidney

Renin

Catalyzes conversion of angiotensinogen to

Peptide

(Chapter 26)

angiotensin I (acts as an enzyme)

1,25-Dihydroxycholecalciferol

Increases intestinal absorption of calcium and bone

Steroid

mineralization

Erythropoietin

Increases erythrocyte production

Peptide

Heart

Atrial natriuretic peptide (ANP)

Increases sodium excretion by kidneys, reduces

Peptide

(Chapter 22)

blood pressure

Stomach

Gastrin

Stimulates HCl secretion by parietal cells

Peptide

(Chapter 64)

Small intestine

Secretin

Stimulates pancreatic acinar cells to release

Peptide

(Chapter 64)

bicarbonate and water

Cholecystokinin (CCK)

Stimulates gallbladder contraction and release of

Peptide

pancreatic enzymes

Adipocytes

Leptin

Inhibits appetite, stimulates thermogenesis

Peptide

(Chapter 71)

908

Unit XIV

Endocrinology and Reproduction

Nucleus

DNA

CH₂OH

O CH2OH

C O

Transcription

Synthesis

mRNA

Cortisol

Aldosterone

Translation

Endoplasmic

reticulum

Packaging

Testosterone

Estradiol

Golgi

apparatus

Figure 74-3

Chemical structures of several steroid hormones.

Secretory

Storage

vesicles

Ca⁺⁺

hormones are then released into the blood stream.

cAMP

After entering the blood, most of the thyroid hor-

mones combine with plasma proteins, especially thy-

Secretion

roxine-binding globulin, which slowly releases the

Extracellular

Stimulus

hormones to the target tissues.

fluid

Epinephrine and norepinephrine are formed in the

Figure 74-2

adrenal medulla, which normally secretes about four

times more epinephrine than norepinephrine. Cate-

Synthesis and secretion of peptide hormones. The stimulus for

cholamines are taken up into preformed vesicles and

hormone secretion often involves changes in intracellular calcium

stored until secreted. Similar to the protein hormones

or changes in cyclic adenosine monophosphate (cAMP) in the

cell.

stored in secretory granules, catecholamines are also

released from adrenal medullary cells by exocytosis.

Once the catecholamines enter the circulation, they

They are lipid soluble and consist of three cyclohexyl

can exist in the plasma in free form or in conjugation

rings and one cyclopentyl ring combined into a single

with other substances.

structure (Figure 74-3).

Although there is usually very little hormone

Hormone Secretion, Transport,

storage in steroid-producing endocrine cells, large

stores of cholesterol esters in cytoplasm vacuoles can

and Clearance from the Blood

be rapidly mobilized for steroid synthesis after a stim-

ulus. Much of the cholesterol in steroid-producing cells

Onset of Hormone Secretion After a Stimulus, and Duration of

comes from the plasma, but there is also de novo

Action of Different Hormones. Some hormones, such as

synthesis of cholesterol in steroid-producing cells.

norepinephrine and epinephrine, are secreted within

Because the steroids are highly lipid soluble, once they

seconds after the gland is stimulated, and they may

are synthesized, they simply diffuse across the cell

develop full action within another few seconds to

membrane and enter the interstitial fluid and then the

minutes; the actions of other hormones, such as thy-

blood.

roxine or growth hormone, may require months for

full effect. Thus, each of the different hormones has its

Amine Hormones Are Derived from Tyrosine. The two groups

own characteristic onset and duration of action—each

of hormones derived from tyrosine, the thyroid and

tailored to perform its specific control function.

the adrenal medullary hormones, are formed by the

actions of enzymes in the cytoplasmic compartments

Concentrations of Hormones in the Circulating Blood, and Hor-

of the glandular cells. The thyroid hormones are

monal Secretion Rates. The concentrations of hormones

synthesized and stored in the thyroid gland and incor-

required to control most metabolic and endocrine

porated into macromolecules of the protein thy-

functions are incredibly small. Their concentrations in

roglobulin, which is stored in large follicles within

the blood range from as little as 1 picogram (which is

the thyroid gland. Hormone secretion occurs when

one millionth of one millionth of a gram) in each mil-

the amines are split from thyroglobulin, and the free

liliter of blood up to at most a few micrograms (a few

Chapter 74

Introduction to Endocrinology

909

millionths of a gram) per milliliter of blood. Similarly,

of neural pathways involved in controlling hormone

the rates of secretion of the various hormones are

release.

extremely small, usually measured in micrograms or

milligrams per day. We shall see later in this chapter

that highly specialized mechanisms are available in the

Transport of Hormones in the Blood

target tissues that allow even these minute quantities

of hormones to exert powerful control over the phys-

Water-soluble hormones

(peptides and cate-

iological systems.

cholamines) are dissolved in the plasma and trans-

ported from their sites of synthesis to target tissues,

where they diffuse out of the capillaries, into the inter-

Feedback Control of

stitial fluid, and ultimately to target cells.

Hormone Secretion

Steroid and thyroid hormones, in contrast, circulate

in the blood mainly bound to plasma proteins. Usually

Negative Feedback Prevents Overactivity of Hormone Systems.

less than 10 per cent of steroid or thyroid hormones in

Although the plasma concentrations of many hor-

the plasma exist free in solution. For example, more

mones fluctuate in response to various stimuli that

than 99 per cent of the thyroxine in the blood is bound

occur throughout the day, all hormones studied thus

to plasma proteins. However, protein-bound hor-

far appear to be closely controlled. In most instances,

mones cannot easily diffuse across the capillaries and

this control is exerted through negative feedback mech-

gain access to their target cells and are therefore bio-

anisms that ensure a proper level of hormone activity

logically inactive until they dissociate from plasma

at the target tissue. After a stimulus causes release of

proteins.

the hormone, conditions or products resulting from the

The relatively large amounts of hormones bound to

action of the hormone tend to suppress its further

proteins serve as reservoirs, replenishing the concen-

release. In other words, the hormone (or one of its

tration of free hormones when they are bound to

products) has a negative feedback effect to prevent

target receptors or lost from the circulation. Binding

oversecretion of the hormone or overactivity at the

of hormones to plasma proteins greatly slows their

target tissue.

clearance from the plasma.

The controlled variable is often not the secretory

rate of the hormone itself but the degree of activity of

the target tissue. Therefore, only when the target tissue

“Clearance” of Hormones

activity rises to an appropriate level will feedback

from the Blood

signals to the endocrine gland become powerful

enough to slow further secretion of the hormone.

Two factors can increase or decrease the concentration

Feedback regulation of hormones can occur at all

of a hormone in the blood. One of these is the rate of

levels, including gene transcription and translation

hormone secretion into the blood. The second is

steps involved in the synthesis of hormones and steps

the rate of removal of the hormone from the blood,

involved in processing hormones or releasing stored

which is called the metabolic clearance rate. This

hormones.

is usually expressed in terms of the number of milli-

liters of plasma cleared of the hormone per minute.

Surges of Hormones Can Occur with Positive Feedback. In a

To calculate this clearance rate, one measures (1)

few instances, positive feedback occurs when the bio-

the rate of disappearance of the hormone from the

logical action of the hormone causes additional secre-

plasma per minute and (2) the concentration of the

tion of the hormone. One example of this is the surge

hormone in each milliliter of plasma. Then, the meta-

of luteinizing hormone (LH) that occurs as a result of

bolic clearance rate is calculated by the following

the stimulatory effect of estrogen on the anterior pitu-

formula:

itary before ovulation. The secreted LH then acts on

Metabolic clearance rate = Rate of disappearance

the ovaries to stimulate additional secretion of estro-

of hormone from the plasma/Concentration of

gen, which in turn causes more secretion of LH. Even-

hormone in each milliliter of plasma

tually, LH reaches an appropriate concentration, and

typical negative feedback control of hormone secre-

The usual procedure for making this measurement

tion is then exerted.

is the following: A purified solution of the hormone to

be measured is tagged with a radioactive substance.

Cyclical Variations Occur in Hormone Release. Superim-

Then the radioactive hormone is infused at a constant

posed on the negative and positive feedback control

rate into the blood stream until the radioactive con-

of hormone secretion are periodic variations in

centration in the plasma becomes steady. At this time,

hormone release that are influenced by seasonal

the rate of disappearance of the radioactive hormone

changes, various stages of development and aging, the

from the plasma equals the rate at which it is infused,

diurnal (daily) cycle, and sleep. For example, the secre-

which gives one the rate of disappearance. At the same

tion of growth hormone is markedly increased during

time, the plasma concentration of the radioactive

the early period of sleep but is reduced during the later

hormone is measured using a standard radioactive

stages of sleep. In many cases, these cyclical variations

counting procedure. Then, using the formula just cited,

in hormone secretion are due to changes in activity

the metabolic clearance rate is calculated.

910

Unit XIV Endocrinology and Reproduction

Hormones are “cleared” from the plasma in several

2. In the cell cytoplasm. The primary receptors for

ways, including

(1) metabolic destruction by the

the different steroid hormones are found mainly

tissues, (2) binding with the tissues, (3) excretion by the

in the cytoplasm.

liver into the bile, and (4) excretion by the kidneys into

3. In the cell nucleus. The receptors for the thyroid

the urine. For certain hormones, a decreased metabolic

hormones are found in the nucleus and are

clearance rate may cause an excessively high concen-

believed to be located in direct association with

tration of the hormone in the circulating body fluids.

one or more of the chromosomes.

For instance, this occurs for several of the steroid hor-

mones when the liver is diseased, because these hor-

The Number and Sensitivity of Hormone Receptors Are Regu-

mones are conjugated mainly in the liver and then

lated. The number of receptors in a target cell usually

“cleared” into the bile.

does not remain constant from day to day, or even

Hormones are sometimes degraded at their target

from minute to minute. The receptor proteins them-

cells by enzymatic processes that cause endocytosis of

selves are often inactivated or destroyed during the

the cell membrane hormone-receptor complex; the

course of their function, and at other times they

hormone is then metabolized in the cell, and the recep-

are reactivated or new ones are manufactured by

tors are usually recycled back to the cell membrane.

the protein-manufacturing mechanism of the cell.

Most of the peptide hormones and catecholamines

For instance, increased hormone concentration and

are water soluble and circulate freely in the blood.

increased binding with its target cell receptors some-

They are usually degraded by enzymes in the blood

times cause the number of active receptors to

and tissues and rapidly excreted by the kidneys and

decrease. This down-regulation of the receptors can

liver, thus remaining in the blood for only a short time.

occur as a result of (1) inactivation of some of the

For example, the half-life of angiotensin II circulating

receptor molecules, (2) inactivation of some of the

in the blood is less than a minute.

intracellular protein signaling molecules, (3) tempo-

Hormones that are bound to plasma proteins are

rary sequestration of the receptor to the inside of the

cleared from the blood at much slower rates and may

cell, away from the site of action of hormones that

remain in the circulation for several hours or even

interact with cell membrane receptors, (4) destruction

days. The half-life of adrenal steroids in the circulation,

of the receptors by lysosomes after they are internal-

for example, ranges between 20 and 100 minutes,

ized, or (5) decreased production of the receptors. In

whereas the half-life of the protein-bound thyroid hor-

each case, receptor down-regulation decreases the

mones may be as long as 1 to 6 days.

target tissue’s responsiveness to the hormone.

Some hormones cause up-regulation of receptors

and intracellular signaling proteins; that is, the stimu-

lating hormone induces greater than normal formation

Mechanisms of Action

of receptor or intracellular signaling molecules by the

of Hormones

protein-manufacturing machinery of the target cell, or

greater availability of the receptor for interaction with

Hormone Receptors and Their

the hormone. When this occurs, the target tissue

Activation

becomes progressively more sensitive to the stimulat-

ing effects of the hormone.

The first step of a hormone’s action is to bind to spe-

cific receptors at the target cell. Cells that lack recep-

tors for the hormones do not respond. Receptors

Intracellular Signaling After Hormone

for some hormones are located on the target cell

Receptor Activation

membrane, whereas other hormone receptors are

located in the cytoplasm or the nucleus. When the

Almost without exception, a hormone affects its target

hormone combines with its receptor, this usually initi-

tissues by first forming a hormone-receptor complex.

ates a cascade of reactions in the cell, with each stage

This alters the function of the receptor itself, and the

becoming more powerfully activated so that even

activated receptor initiates the hormonal effects. To

small concentrations of the hormone can have a large

explain this, let us give a few examples of the different

effect.

types of interactions.

Hormonal receptors are large proteins, and each cell

that is to be stimulated usually has some 2000 to

Ion Channel-Linked Receptors. Virtually all the neuro-

100,000 receptors. Also, each receptor is usually highly

transmitter substances, such as acetylcholine and

specific for a single hormone; this determines the type

norepinephrine, combine with receptors in the postsy-

of hormone that will act on a particular tissue. The

naptic membrane. This almost always causes a change

target tissues that are affected by a hormone are those

in the structure of the receptor, usually opening or

that contain its specific receptors.

closing a channel for one or more ions. Some of these

The locations for the different types of hormone

ion channel-linked receptors open (or close) channels

receptors are generally the following:

for sodium ions, others for potassium ions, others for

1. In or on the surface of the cell membrane. The

calcium ions, and so forth. The altered movement of

membrane receptors are specific mostly for the

these ions through the channels causes the subsequent

protein, peptide, and catecholamine hormones.

effects on the postsynaptic cells. Although a few

Chapter 74

Introduction to Endocrinology

911

hormones may exert some of their actions through

such as adenylyl cyclase or phospholipase C, which

activation of ion channel receptors, most hormones

alters cell function.

that open or close ions channels do this indirectly by

The signaling event is rapidly terminated when the

coupling with G protein-linked or enzyme-linked

hormone is removed and the a subunit inactivates

receptors, as discussed next.

itself by converting its bound GTP to GDP; then the

a subunit once again combines with the b and g sub-

G Protein-Linked Hormone Receptors. Many hormones

units to form an inactive, membrane-bound trimeric G

activate receptors that indirectly regulate the activity

protein.

of target proteins (e.g., enzymes or ion channels) by

Some hormones are coupled to inhibitory G pro-

coupling with groups of cell membrane proteins called

teins

(denoted G_i proteins), whereas others are

heterotrimeric GTP-binding proteins

(G proteins)

coupled to stimulatory G proteins (denoted G_s pro-

(Figure 74-4). There are more than 1000 known G

teins). Thus, depending on the coupling of a hormone

protein-coupled receptors, all of which have seven

receptor to an inhibitory or stimulatory G protein, a

transmembrane segments that loop in and out of the

hormone can either increase or decrease the activity

cell membrane. Some parts of the receptor that pro-

of intracellular enzymes. This complex system of cell

trude into the cell cytoplasm (especially the cytoplas-

membrane G proteins provides a vast array of poten-

mic tail of the receptor) are coupled to G proteins that

tial cell responses to different hormones in the various

include three (i.e., trimeric) parts—the a, b, and g sub-

target tissues of the body.

units. When the ligand (hormone) binds to the extra-

cellular part of the receptor, a conformational change

Enzyme-Linked Hormone Receptors. Some receptors,

occurs in the receptor that activates the G proteins and

when activated, function directly as enzymes or are

induces intracellular signals that either (1) open or

closely associated with enzymes that they activate.

close cell membrane ion channels or (2) change the

These enzyme-linked receptors are proteins that pass

activity of an enzyme in the cytoplasm of the cell.

through the membrane only once, in contrast to the

The trimeric G proteins are named for their ability

seven-transmembrane G protein-coupled receptors.

to bind guanosine nucleotides. In their inactive state,

Enzyme-linked receptors have their hormone-binding

the a, b, and g subunits of G proteins form a complex

site on the outside of the cell membrane and their cat-

that binds guanosine diphosphate (GDP) on the a

alytic or enzyme-binding site on the inside. When the

subunit. When the receptor is activated, it undergoes

hormone binds to the extracellular part of the recep-

a conformational change that causes the GDP-bound

tor, an enzyme immediately inside the cell membrane

trimeric G protein to associate with the cytoplasmic

is activated

(or occasionally inactivated). Although

part of the receptor and to exchange GDP for guano-

many enzyme-linked receptors have intrinsic enzyme

sine triphosphate (GTP). Displacement of GDP by

activity, others rely on enzymes that are closely asso-

GTP causes the a subunit to dissociate from the

ciated with the receptor to produce changes in cell

trimeric complex and to associate with other intracel-

function.

lular signaling proteins; these proteins, in turn, alter

One example of an enzyme-linked receptor is the

the activity of ion channels or intracellular enzymes

leptin receptor

(Figure 74-5). Leptin is a hormone

Hormone

Receptor

Extracellular

fluid

Cytoplasm

GDP

G-protein

GTP activated

GTP

(inactive)

target protein

G-protein

(enzyme)

(active)

Figure 74-4

Mechanism of activation of a G protein-coupled receptor. When the hormone activates the receptor, the inactive a, b, and g G protein

complex associates with the receptor and is activated, with an exchange of guanosine triphosphate (GTP) for guanosine diphosphate

(GDP). This causes the a subunit (to which the GTP is bound) to dissociate from the b and g subunits of the G protein and to interact with

membrane-bound target proteins (enzymes) that initiate intracellular signals.

912

Unit XIV Endocrinology and Reproduction

whereas other actions occur more slowly and require

Leptin

synthesis of new proteins.

Another example, one widely used in hormonal

control of cell function, is for the hormone to bind

Leptin receptor

with a special transmembrane receptor, which then

becomes the activated enzyme adenylyl cyclase at the

Jak2

end that protrudes to the interior of the cell. This

cyclase catalyzes the formation of cAMP, which has a

Stat3

Activation

multitude of effects inside the cell to control cell activ-

of enzymes

ity, as discussed in greater detail later. cAMP is called

a second messenger because it is not the hormone itself

that directly institutes the intracellular changes;

instead, the cAMP serves as a second messenger to

Physiological

cause these effects.

effects

For a few peptide hormones, such as atrial natri-

Stat3

uretic peptide

(ANP), cyclic guanosine monophos-

phate (cGMP), which is only slightly different from

Stat3

Translation

cAMP, serves in a similar manner as a second

messenger.

Intracellular Hormone Receptors and Activation of Genes.

Target gene

mRNA

Several hormones, including adrenal and gonadal

steroid hormones, thyroid hormones, retinoid hor-

mones, and vitamin D, bind with protein receptors

Figure 74-5

inside the cell rather than in the cell membrane.

Because these hormones are lipid soluble, they readily

An enzyme-linked receptor—the leptin receptor. The receptor

cross the cell membrane and interact with receptors in

exists as a homodimer (two identical parts), and leptin binds to

the cytoplasm or nucleus. The activated hormone-

the extracellular part of the receptor, causing phosphorylation and

activation of the intracellular associated janus kinase 2 (JAK2).

receptor complex then binds with a specific regulatory

This causes phosphorylation of signal transducer and activator of

(promoter) sequence of the DNA called the hormone

transcription (STAT) proteins, which then activates the transcrip-

response element, and in this manner either activates

tion of target genes and the synthesis of proteins. JAK2 phos-

or represses transcription of specific genes and for-

phorylation also activates several other enzyme systems that

mation of messenger RNA (mRNA) (Figure 74-6).

mediate some of the more rapid effects of leptin.

Therefore, minutes, hours, or even days after the

hormone has entered the cell, newly formed proteins

appear in the cell and become the controllers of new

or altered cellular functions.

secreted by fat cells and has many physiological

Many different tissues have identical intracellular

effects, but it is especially important in regulating

hormone receptors, but the genes that the receptors

appetite and energy balance, as discussed in Chapter

regulate are different in the various tissues. An intra-

71. The leptin receptor is a member of a large family

cellular receptor can activate a gene response only if

of cytokine receptors that do not themselves contain

the appropriate combination of gene regulatory pro-

enzymatic activity but signal through associated

teins is present, and many of these regulatory proteins

enzymes. In the case of the leptin receptor, one of the

are tissue specific. Thus, the responses of different

signaling pathways occurs through a tyrosine kinase of

tissues to a hormone are determined not only by the

the janus kinase (JAK) family, JAK2. The leptin recep-

specificity of the receptors but also by the genes that

tor exists as a dimer (i.e., in two parts), and binding of

the receptor regulates.

leptin to the extracellular part of the receptor alters its

conformation, enabling phosphorylation and activa-

tion of the intracellular associated JAK2 molecules.

Second Messenger Mechanisms

The activated JAK2 molecules then phosphorylate

for Mediating Intracellular

other tyrosine residues within the leptin receptor-

JAK2 complex to mediate intracellular signaling. The

Hormonal Functions

intracellular signals include phosphorylation of signal

transducer and activator of transcription (STAT) pro-

We noted earlier that one of the means by which hor-

teins, which activates transcription by leptin target

mones exert intracellular actions is to stimulate for-

genes to initiate protein synthesis. Phosphorylation of

mation of the second messenger cAMP inside the cell

JAK2 also leads to activation of other intracellular

membrane. The cAMP then causes subsequent intra-

enzyme pathways such as mitogen-activated protein

cellular effects of the hormone. Thus, the only direct

kinases

(MAPK) and phosphatidylinositol 3-kinase

effect that the hormone has on the cell is to activate a

(PI3K). Some of the effects of leptin occur rapidly as

single type of membrane receptor. The second mes-

a result of activation of these intracellular enzymes,

senger does the rest.

Chapter 74

Introduction to Endocrinology

913

Lipophilic hormone

Extracellular fluid

Diffusion

Nucleus

Target cell

Proteins

DNA

Nuclear

Figure 74-6

receptor

Mechanisms of interaction of

Ribosome

lipophilic hormones, such as

steroids, with intracellular recep-

Cytoplasmic

mRNA

tors in target cells. After the

receptor

Hormone

hormone binds to the receptor in

receptor

mRNA

the cytoplasm or in the nucleus,

Hormone

complex

the hormone-receptor complex

response

binds to the hormone response

element

Nuclear envelope

element (promoter) on the DNA.

This either activates or inhibits

Nuclear pore

gene transcription, formation of

messenger RNA (mRNA), and

protein synthesis.

Table 74-2

Some Hormones That Use the Adenylyl Cyclase-cAMP

Extracellular

Hormone

Second Messenger System

fluid

Adrenocorticotropic hormone (ACTH)

Angiotensin II (epithelial cells)

Calcitonin

Catecholamines (b receptors)

Corticotropin-releasing hormone (CRH)

Cytoplasm

Follicle-stimulating hormone (FSH)

Glucagon

Human chorionic gonadotropin (HCG)

Luteinizing hormone (LH)

Adenylyl

Parathyroid hormone (PTH)

GTP

cyclase

Secretin

Somatostatin

Thyroid-stimulating hormone (TSH)

cAMP

ATP

Vasopressin (V₂ receptor, epithelial cells)

Active

Inactive

cAMP-

dependent

protein

cAMP is not the only second messenger used by the

kinase

different hormones. Two other especially important

ones are (1) calcium ions and associated calmodulin

Protein - PO4 + ADP

Protein + ATP

and

(2) products of membrane phospholipid

breakdown.

Cell’s response

Adenylyl Cyclase-cAMP Second

Figure 74-7

Messenger System

Table 74-2 shows a few of the many hormones that use

Cyclic adenosine monophosphate (cAMP) mechanism by which

many hormones exert their control of cell function. ADP, adeno-

the adenylyl cyclase-cAMP mechanism to stimulate

sine diphosphate; ATP, adenosine triphosphate.

their target tissues, and Figure 74-7 shows the adeny-

lyl

cyclase-cAMP second messenger system

itself. Binding of the hormones with the receptor

the conversion of a small amount of cytoplasmic

allows coupling of the receptor to a G protein. If the

adenosine triphosphate (ATP) into cAMP inside the

G protein stimulates the adenylyl cyclase-cAMP

cell. This then activates cAMP-dependent protein

system, it is called a G_s protein, denoting a stimulatory

kinase, which phosphorylates specific proteins in the

G protein. Stimulation of adenylyl cyclase, a mem-

cell, triggering biochemical reactions that ultimately

brane-bound enzyme, by the G_s protein then catalyzes

lead to the cell’s response to the hormone.

914

Unit XIV Endocrinology and Reproduction

Once cAMP is formed inside the cell, it usually acti-

reticulum, and the calcium ions then have their own

vates a cascade of enzymes. That is, first one enzyme is

second messenger effects, such as smooth muscle con-

activated, which activates a second enzyme, which acti-

traction and changes in cell secretion.

vates a third, and so forth. The importance of this

DAG, the other lipid second messenger, activates

mechanism is that only a few molecules of activated

the enzyme protein kinase C (PKC), which then phos-

adenylyl cyclase immediately inside the cell mem-

phorylates a large number of proteins, leading to the

brane can cause many more molecules of the next

cell’s response

(Figure 74-8). In addition to these

enzyme to be activated, which can cause still more

effects, the lipid portion of DAG is arachidonic acid,

molecules of the third enzyme to be activated, and

which is the precursor for the prostaglandins and other

so forth. In this way, even the slightest amount of

local hormones that cause multiple effects in tissues

hormone acting on the cell surface can initiate a pow-

throughout the body.

erful cascading activating force for the entire cell.

If binding of the hormone to its receptors is coupled

Calcium-Calmodulin Second

to an inhibitory G protein

(denoted G_i protein),

Messenger System

adenylyl cyclase will be inhibited, reducing the forma-

Another second messenger system operates in

tion of cAMP and ultimately leading to an inhibitory

response to the entry of calcium into the cells. Calcium

action in the cell. Thus, depending on the coupling of

entry may be initiated by (1) changes in membrane

the hormone receptor to an inhibitory or a stimulatory

potential that open calcium channels or (2) a hormone

G protein, a hormone can either increase or decrease

interacting with membrane receptors that open

the concentration of cAMP and phosphorylation of

calcium channels.

key proteins inside the cell.

On entering a cell, calcium ions bind with the

The specific action that occurs in response to

protein calmodulin. This protein has four calcium sites,

increases or decreases of cAMP in each type of target

and when three or four of these sites have bound with

cell depends on the nature of the intracellular machin-

calcium, the calmodulin changes its shape and initiates

ery—some cells have one set of enzymes, and other

multiple effects inside the cell, including activation

cells have other enzymes. Therefore, different func-

or inhibition of protein kinases. Activation

tions are elicited in different target cells, such as initi-

ating synthesis of specific intracellular chemicals,

causing muscle contraction or relaxation, initiating

secretion by the cells, and altering cell permeability.

Thus, a thyroid cell stimulated by cAMP forms the

Peptide

metabolic hormones thyroxine and triiodothyronine,

hormone

whereas the same cAMP in an adrenocortical cell

causes secretion of the adrenocortical steroid hor-

Extracellular fluid

mones. In epithelial cells of the renal tubules, cAMP

increases their permeability to water.

Receptor

The Cell Membrane Phospholipid Second

Messenger System

G protein

Some hormones activate transmembrane receptors

that activate the enzyme phospholipase C attached to

Cell

membrane

the inside projections of the receptors (Table 74-3).

This enzyme catalyzes the breakdown of some phos-

Phospholipase C

pholipids in the cell membrane, especially phos-

DAG + IP₃

PIP₂

phatidylinositol biphosphate (PIP

2), into two different

second messenger products: inositol triphosphate

(IP

3) and diacylglycerol

(DAG). The IP₃ mobilizes

Cytoplasm

calcium ions from mitochondria and the endoplasmic

Active

Inactive

protein

kinase C

Table 74-3

Some Hormones That Use the Phospholipase C Second

Protein - PO₄

Protein

Ca⁺⁺

Messenger System

Endoplasmic reticulum

Angiotensin II (vascular smooth muscle)

Cell’s response

Catecholamines (a receptors)

Gonadotropin-releasing hormone (GnRH)

Figure 74-8

Growth hormone-releasing hormone (GHRH)

Oxytocin

The cell membrane phospholipid second messenger system by

Thyroid-releasing hormone (TRH)

which some hormones exert their control of cell function. DAG,

Vasopressin (V₁ receptor, vascular smooth muscle)

diacylglycerol; IP₃, inositol triphosphate; PIP₂, phosphatidylinosi-

tol biphosphate.

Chapter 74

Introduction to Endocrinology

915

calmodulin-dependent protein kinases causes, via

nucleus. To accomplish this, these hormones first bind

phosphorylation, activation or inhibition of proteins

directly with receptor proteins in the nucleus itself;

involved in the cell’s response to the hormone. For

these receptors are probably protein molecules

example, one specific function of calmodulin is to acti-

located within the chromosomal complex, and they

vate myosin kinase, which acts directly on the myosin

likely control the function of the genetic promoters or

of smooth muscle to cause smooth muscle contraction.

operators, as explained in Chapter 3.

The normal calcium ion concentration in most cells

Two important features of thyroid hormone func-

of the body is 10-8 to 10-7 mol/L, which is not enough

tion in the nucleus are the following:

to activate the calmodulin system. But when the

1. They activate the genetic mechanisms for the

calcium ion concentration rises to 10-6 to 10-5 mol/L,

formation of many types of intracellular

enough binding occurs to cause all the intracellular

proteins—probably 100 or more. Many of these

actions of calmodulin. This is almost exactly the same

are enzymes that promote enhanced intracellular

amount of calcium ion change that is required in skele-

metabolic activity in virtually all cells of the body.

tal muscle to activate troponin C, which causes skele-

2. Once bound to the intranuclear receptors, the

tal muscle contraction, as explained in Chapter 7. It is

thyroid hormones can continue to express their

interesting that troponin C is similar to calmodulin in

control functions for days or even weeks.

both function and protein structure.

Measurement of Hormone

Hormones That Act Mainly on the

Concentrations in the Blood

Genetic Machinery of the Cell

Most hormones are present in the blood in extremely

Steroid Hormones Increase Protein Synthesis

minute quantities; some concentrations are as low as

Another means by which hormones act—specifically,

one billionth of a milligram (1 picogram) per milliliter.

the steroid hormones secreted by the adrenal cortex,

Therefore, it was very difficult to measure these con-

ovaries, and testes—is to cause synthesis of proteins in

centrations by the usual chemical means. An extremely

the target cells. These proteins then function as

sensitive method, however, was developed about 40

enzymes, transport proteins, or structural proteins,

years ago that revolutionized the measurement of hor-

which in turn provide other functions of the cells.

mones, their precursors, and their metabolic end prod-

The sequence of events in steroid function is essen-

ucts. This method is called radioimmunoassay.

tially the following:

1. The steroid hormone diffuses across the cell

membrane and enters the cytoplasm of the cell,

Radioimmunoassay

where it binds with a specific receptor protein.

2. The combined receptor protein-hormone then

The method of performing radioimmunoassay is as

diffuses into or is transported into the nucleus.

follows. First, an antibody that is highly specific for the

3. The combination binds at specific points on the

hormone to be measured is produced.

DNA strands in the chromosomes, which activates

Second, a small quantity of this antibody is (1)

the transcription process of specific genes to form

mixed with a quantity of fluid from the animal con-

mRNA.

taining the hormone to be measured and (2) mixed

4. The mRNA diffuses into the cytoplasm, where it

simultaneously with an appropriate amount of purified

promotes the translation process at the ribosomes

standard hormone that has been tagged with a

to form new proteins.

radioactive isotope. However, one specific condition

To give an example, aldosterone, one of the hor-

must be met: There must be too little antibody to bind

mones secreted by the adrenal cortex, enters the cyto-

completely both the radioactively tagged hormone

plasm of renal tubular cells, which contain a specific

and the hormone in the fluid to be assayed. Therefore,

aldosterone receptor protein. Therefore, in these cells,

the natural hormone in the assay fluid and the radio-

the sequence of events cited earlier ensues. After

active standard hormone compete for the binding sites

about 45 minutes, proteins begin to appear in the renal

of the antibody. In the process of competing, the quan-

tubular cells and promote sodium reabsorption from

tity of each of the two hormones, the natural and the

the tubules and potassium secretion into the tubules.

radioactive, that binds is proportional to its concen-

Thus, the full action of the steroid hormone is charac-

tration in the assay fluid.

teristically delayed for at least

45 minutes—up to

Third, after binding has reached equilibrium, the

several hours or even days. This is in marked contrast

antibody-hormone complex is separated from the

to the almost instantaneous action of some of the

remainder of the solution, and the quantity of radio-

peptide and amino acid-derived hormones, such as

active hormone bound in this complex is measured by

vasopressin and norepinephrine.

radioactive counting techniques. If a large amount of

radioactive hormone has bound with the antibody, it is

Thyroid Hormones Increase Gene

clear that there was only a small amount of natural

Transcription in the Cell Nucleus

hormone to compete with the radioactive hormone,

The thyroid hormones thyroxine and triiodothyronine

and therefore the concentration of the natural

cause increased transcription by specific genes in the

hormone in the assayed fluid was small. Conversely, if

916

Unit XIV Endocrinology and Reproduction

100

AB₁

Figure 74-10

128

Aldosterone concentration in

Basic principles of the enzyme-linked immunosorbent assay

test sample (ng/d)

(ELISA) for measuring the concentration of a hormone (H). AB

and AB2 are antibodies that recognize the hormone at different

binding sites, and AB₃ is an antibody that recognizes AB₂. E is an

enzyme linked to AB₃ that catalyzes the formation of a colored

Figure 74-9

fluorescent product (P) from a substrate (S). The amount of the

product is measured using optical methods and is proportional to

“Standard curve” for radioimmunoassay of aldosterone. (Courtesy

the amount of hormone in the well if there are excess antibodies

Dr. Manis Smith.)

in the well.

detected by colorimetric or fluorescent optical

only a small amount of radioactive hormone has

methods.

bound, it is clear that there was a large amount of

Because each molecule of enzyme catalyzes the

natural hormone to compete for the binding sites.

formation of many thousands of product molecules,

Fourth, to make the assay highly quantitative, the

even very small amounts of hormone molecules can be

radioimmunoassay procedure is also performed for

detected. In contrast to competitive radioimmuno-

“standard” solutions of untagged hormone at several

assay methods, ELISA methods use excess antib-

concentration levels. Then a

“standard curve” is

odies so that all hormone molecules are captured in

plotted, as shown in Figure 74-9. By comparing the

antibody-hormone complexes. Therefore, the amount

radioactive counts recorded from the

“unknown”

of hormone present in the sample or in the standard

assay procedures with the standard curve, one can

is proportional to the amount of product formed.

determine within an error of 10 to 15 per cent the con-

The ELISA method has become widely used in clin-

centration of the hormone in the “unknown” assayed

ical laboratories because

(1) it does not employ

fluid. As little as billionths or even trillionths of a gram

radioactive isotopes, (2) much of the assay can be auto-

of hormone can often be assayed in this way.

mated using 96-well plates, and (3) it has proved to be

a cost-effective and accurate method for assessing

hormone levels.

Enzyme-Linked Immunosorbent

Assay (ELISA)

References

Enzyme-linked immunosorbent assays (ELISAs) can

be used to measure almost any protein, including hor-

Alberts B, Johnson A, Lewis J, et al: Molecular Biology of

mones. This test combines the specificity of antibodies

the Cell. New York: Garland Science, 2002.

with the sensitivity of simple enzyme assays. Figure

Aranda A, Pascual A: Nuclear hormone receptors and gene

74-10 shows the basic elements of this method, which

expression. Physiol Rev 81:1269, 2001.

Clark AJ, Baig AH, Noon L, et al: Expression, desensitiza-

is often performed on plastic plates that each have 96

tion, and internalization of the ACTH receptor (MC2R).

small wells. Each well is coated with an antibody (AB₁)

Ann N Y Acad Sci 994:111, 2003.

that is specific for the hormone being assayed. Samples

Katzmann DJ, Odorizzi G, Emr SD: Receptor downregula-

or standards are added to each of the wells, followed

tion and multivesicular-body sorting. Nat Rev Mol Cell

by a second antibody (AB₂) that is also specific for the

Biol 3:893, 2002.

hormone but binds to a different site of the hormone

Kelly MJ, Qiu J, Ronnekleiv OK: Estrogen modulation of G-

molecule. A third antibody (AB₃) is added that recog-

protein-coupled receptor activation of potassium channels

nizes AB₂and is coupled to an enzyme that converts

in the central nervous system. Ann N Y Acad Sci 1007:6,

a suitable substrate to a product that can be easily

2003.

Chapter 74

Introduction to Endocrinology

917

Kuhn M: Structure, regulation, and function of mammalian

Pires-daSilva A, Sommer RJ: The evolution of signaling

membrane guanylyl cyclase receptors, with a focus on

pathways in animal development. Nat Rev Genet 4:39,

guanylyl cyclase-A. Circ Res 93:700, 2003.

2003.

Larsen PR, Kronenberg HM, Melmed S, Polonsky KS:

Privalsky ML: The role of corepressors in transcriptional

Williams Textbook of Endocrinolog, 10th ed. Philadelphia:

regulation by nuclear hormone receptors. Annu Rev

WB Saunders, 2003.

Physiol 66:315, 2004.

Lösel RM, Falkenstein E, Feuring M, et al: Nongenomic

Spat A, Hunyady L: Control of aldosterone secretion: a

steroid action: controversies, questions, and answers.

model for convergence in cellular signaling pathways.

Physiol Rev 83:965, 2003.

Physiol Rev 84:489, 2004.

Morris AJ, Malbon CC: Physiological regulation of G

Spiegel AM, Weinstein LS: Inherited diseases involving G

protein-linked signaling. Physiol Rev 79:1373, 1999.

proteins and G protein-coupled receptors. Annu Rev Med

Nadal A, Diaz M, Valverde MA: The estrogen trinity: mem-

55:27, 2004.

brane, cytosolic, and nuclear effects. News Physiol Sci

Tasken K, Aandahl EM: Localized effects of cAMP medi-

16:251, 2001.

ated by distinct routes of protein kinase A. Physiol Rev

Nagaich AK, Rayasam GV, Martinez ED, et al: Subnuclear

84:137, 2004.

trafficking and gene targeting by steroid receptors. Ann

Vasudevan N, Ogawa S, Pfaff D: Estrogen and thyroid

N Y Acad Sci 1024:213, 2004.

hormone receptor interactions: physiological flexibility by

Olson TS, Ley K: Chemokines and chemokine receptors in

molecular specificity. Physiol Rev 82:923, 2002.

leukocyte trafficking. Am J Physiol Regul Integr Comp

Yen PM: Physiological and molecular basis of thyroid

Physiol 283:R7, 2002.

hormone action. Physiol Rev 81:1097, 2001.

O’Shea JJ, Pesu M, Borie DC, Changelian PS: A new modal-

ity for immunosuppression: targeting the JAK/STAT

pathway. Nat Rev Drug Discov 3:555, 2004.

C H A P T E R

Pituitary Hormones and Their

Control by the Hypothalamus

Pituitary Gland and

Its Relation to the

Hypothalamus

Pituitary Gland: Two Distinct Parts-The Anterior and Poste-

rior Lobes. The pituitary gland (Figure 75-1), also

called the hypophysis, is a small gland—about 1 cen-

timeter in diameter and 0.5 to 1 gram in weight—

that lies in the sella turcica, a bony cavity at the base of the brain, and is

connected to the hypothalamus by the pituitary (or hypophysial) stalk. Physio-

logically, the pituitary gland is divisible into two distinct portions: the anterior

pituitary, also known as the adenohypophysis, and the posterior pituitary, also

known as the neurohypophysis. Between these is a small, relatively avascular

zone called the pars intermedia, which is almost absent in the human being but

is much larger and much more functional in some lower animals.

Embryologically, the two portions of the pituitary originate from different

sources—the anterior pituitary from Rathke’s pouch, which is an embryonic

invagination of the pharyngeal epithelium, and the posterior pituitary from a

neural tissue outgrowth from the hypothalamus. The origin of the anterior pitu-

itary from the pharyngeal epithelium explains the epithelioid nature of its cells,

and the origin of the posterior pituitary from neural tissue explains the pres-

ence of large numbers of glial-type cells in this gland.

Six important peptide hormones plus several less important ones are secreted

by the anterior pituitary, and two important peptide hormones are secreted

by the posterior pituitary. The hormones of the anterior pituitary play major

roles in the control of metabolic functions throughout the body, as shown in

Figure 75-2.

• Growth hormone promotes growth of the entire body by affecting protein

formation, cell multiplication, and cell differentiation.

• Adrenocorticotropin (corticotropin) controls the secretion of some of the

adrenocortical hormones, which affect the metabolism of glucose, proteins,

and fats.

• Thyroid-stimulating hormone (thyrotropin) controls the rate of secretion of

thyroxine and triiodothyronine by the thyroid gland, and these hormones

control the rates of most intracellular chemical reactions in the body.

• Prolactin promotes mammary gland development and milk production.

• Two separate gonadotropic hormones, follicle-stimulating hormone and

luteinizing hormone, control growth of the ovaries and testes, as well as

their hormonal and reproductive activities.

The two hormones secreted by the posterior pituitary play other roles.

• Antidiuretic hormone (also called vasopressin) controls the rate of water

excretion into the urine, thus helping to control the concentration of water

in the body fluids.

• Oxytocin helps express milk from the glands of the breast to the nipples

during suckling and possibly helps in the delivery of the baby at the end of

gestation.

Anterior Pituitary Gland Contains Several Different Cell Types That Synthesize and Secrete

Hormones. Usually, there is one cell type for each major hormone formed in the

918

Chapter 75

Pituitary Hormones and Their Control by the Hypothalamus

919

Hypothalamus

Gamma

Alpha

Epsilon (e)

Delta (d)

(g) cell

Sinusoid

(a) cell acidophil cell basophil cell

Hypophysial stalk

Posterior pituitary

Anterior pituitary

Pars intermedia

Beta (b) cell

Figure 75-1

Figure 75-3

Pituitary gland.

Cellular structure of the anterior pituitary gland. (Redrawn from

Guyton AC: Physiology of the Human Body, 6th ed. Philadelphia:

Saunders College Publishing, 1984.)

3. Thyrotropes—thyroid-stimulating hormone (TSH)

Thyroid

4. Gonadotropes—gonadotropic hormones, which

gland

include both luteinizing hormone (LH) and follicle-

stimulating hormone (FSH)

Growth

5. Lactotropes—prolactin (PRL)

About 30 to 40 per cent of the anterior pituitary cells

are somatotropes that secrete growth hormone, and

Increases blood

about 20 per cent are corticotropes that secrete ACTH.

glucose level

ACH

Each of the other cell types accounts for only 3 to 5 per

cent of the total; nevertheless, they secrete powerful

hormones for controlling thyroid function, sexual func-

Corticotropin

Promotes secretion

tions, and milk secretion by the breasts.

of insulin

Somatotropes stain strongly with acid dyes and are

pituitary

Adrenal cortex

therefore called acidophils. Thus, pituitary tumors that

gland

Follicle

secrete large quantities of human growth hormone are

stimulating

called acidophilic tumors.

Pancreas

Luteinizing

Posterior Pituitary Hormones Are Synthesized by Cell Bodies in

Ovary

the Hypothalamus. The bodies of the cells that secrete

the posterior pituitary hormones are not located in the

Prolactin

pituitary gland itself but are large neurons, called mag-

Mammary

nocellular neurons, located in the supraoptic and par-

gland

aventricular nuclei of the hypothalamus. The hormones

are then transported in the axoplasm of the neurons’

nerve fibers passing from the hypothalamus to the pos-

Figure 75-2

terior pituitary gland. This is discussed more fully later

in the chapter.

Metabolic functions of the anterior pituitary hormones. ACH,

adrenal corticosteroid hormones.

Hypothalamus Controls

anterior pituitary gland. With special stains attached to

Pituitary Secretion

high-affinity antibodies that bind with the distinctive

hormones, at least five cell types can be differentiated

Almost all secretion by the pituitary is controlled by

(Figure 75-3). Table 75-1 provides a summary of these

either hormonal or nervous signals from the hypo-

cell types, the hormones they produce, and their physio-

logical actions. These five cell types are:

thalamus. Indeed, when the pituitary gland is removed

1. Somatotropes—human growth hormone (hGH)

from its normal position beneath the hypothalamus

2. Corticotropes—adrenocorticotropin (ACTH)

and transplanted to some other part of the body, its

920

Unit XIV Endocrinology and Reproduction

Table 75-1

Cells and Hormones of the Anterior Pituitary Gland and Their Physiological Functions

Cell

Hormone

Chemistry

Physiological Actions

Somatotropes

Growth hormone (GH;

Single chain of 191 amino acids

Stimulates body growth; stimulates

somatotropin)

secretion of IGF-1; stimulates lipolysis;

inhibits actions of insulin on

carbohydrate and lipid metabolism

Corticotropes

Adrenocorticotropic hormone

Single chain of 39 amino acids

Stimulates production of glucocorticoids

(ACTH; corticotropin)

and androgens by the adrenal cortex;

maintains size of zona fasciculata and

zona reticularis of cortex

Thyrotropes

Thyroid-stimulating hormone

Glycoprotein of two subunits,

Stimulates production of thyroid

(TSH; thyrotropin)

a (89 amino acids) and

hormones by thyroid follicular cells;

b (112 amino acids)

maintains size of follicular cells

Gonadotropes

Follicle-stimulating hormone

Glycoprotein of two subunits,

Stimulates development of ovarian

(FSH)

a (89 amino acids) and

follicles; regulates spermatogenesis in

b (112 amino acids)

the testis

Luteinizing hormone (LH)

Glycoprotein of two subunits,

Causes ovulation and formation of the

a (89 amino acids) and

corpus luteum in the ovary; stimulates

b (115 amino acids)

production of estrogen and progesterone

by the ovary; stimulates testosterone

production by the testis

Lactotropes,

Prolactin (PRL)

Single chain of 198 amino

Stimulates milk secretion and production

Mammotropes

acids

IGF, insulin-like

growth factor

rates of secretion of the different hormones (except

Hypothalamus

for prolactin) fall to very low levels.

Secretion from the posterior pituitary is controlled

by nerve signals that originate in the hypothalamus

and terminate in the posterior pituitary. In contrast,

secretion by the anterior pituitary is controlled by hor-

Optic chiasm

mones called hypothalamic releasing and hypothala-

Mamillary body

Artery

mic inhibitory hormones (or factors) secreted within

Primary capillary

the hypothalamus itself and then conducted, as shown

Median eminence

plexus

in Figure

75-4, to the anterior pituitary through

Hypothalamic-

minute blood vessels called hypothalamic-hypophysial

hypophysial

portal vessels. In the anterior pituitary, these releasing

portal vessels

and inhibitory hormones act on the glandular cells to

Posterior pituitary

Sinuses

control their secretion. This system of control is dis-

gland

cussed in the next section of this chapter.

Anterior pituitary

gland

The hypothalamus receives signals from many

Vein

sources in the nervous system. Thus, when a person is

exposed to pain, a portion of the pain signal is trans-

Figure 75-4

mitted into the hypothalamus. Likewise, when a

person experiences some powerful depressing or excit-

Hypothalamic-hypophysial portal system.

ing thought, a portion of the signal is transmitted into

the hypothalamus. Olfactory stimuli denoting pleasant

or unpleasant smells transmit strong signal compo-

Hypothalamic-Hypophysial Portal

nents directly and through the amygdaloid nuclei into

Blood Vessels of the Anterior

the hypothalamus. Even the concentrations of nutri-

ents, electrolytes, water, and various hormones in the

Pituitary Gland

blood excite or inhibit various portions of the hypo-

thalamus. Thus, the hypothalamus is a collecting center

The anterior pituitary is a highly vascular gland with

for information concerning the internal well-being

extensive capillary sinuses among the glandular cells.

of the body, and much of this information is used

Almost all the blood that enters these sinuses passes

to control secretions of the many globally important

first through another capillary bed in the lower

pituitary hormones.

hypothalamus. The blood then flows through small

Chapter 75

Pituitary Hormones and Their Control by the Hypothalamus

921

hypothalamic-hypophysial portal blood vessels into the

called somatostatin, which inhibits release of

anterior pituitary sinuses. Figure 75-4 shows the low-

growth hormone

ermost portion of the hypothalamus, called the median

4. Gonadotropin-releasing hormone (GnRH), which

eminence, which connects inferiorly with the pituitary

causes release of the two gonadotropic hormones,

stalk. Small arteries penetrate into the substance

luteinizing hormone and follicle-stimulating

of the median eminence and then additional small

hormone

vessels return to its surface, coalescing to form the

5. Prolactin inhibitory hormone (PIH), which causes

hypothalamic-hypophysial portal blood vessels. These

inhibition of prolactin secretion

pass downward along the pituitary stalk to supply

There are some additional hypothalamic hormones,

blood to the anterior pituitary sinuses.

including one that stimulates prolactin secretion and

perhaps others that inhibit release of the anterior pitu-

Hypothalamic Releasing and Inhibitory Hormones Are Secreted

itary hormones. Each of the more important hypo-

into the Median Eminence. Special neurons in the hypo-

thalamic hormones is discussed in detail as the specific

thalamus synthesize and secrete the hypothalamic

hormonal systems controlled by them are presented in

releasing and inhibitory hormones that control secre-

this and subsequent chapters.

tion of the anterior pituitary hormones. These neurons

originate in various parts of the hypothalamus and

Specific Areas in the Hypothalamus Control Secretion of Spe-

send their nerve fibers to the median eminence and

cific Hypothalamic Releasing and Inhibitory Hormones. All or

tuber cinereum, an extension of hypothalamic tissue

most of the hypothalamic hormones are secreted at

into the pituitary stalk.

nerve endings in the median eminence before being

The endings of these fibers are different from most

transported to the anterior pituitary gland. Electrical

endings in the central nervous system, in that their

stimulation of this region excites these nerve endings

function is not to transmit signals from one neuron to

and, therefore, causes release of essentially all the

another but rather to secrete the hypothalamic releas-

hypothalamic hormones. However, the neuronal cell

ing and inhibitory hormones into the tissue fluids.

bodies that give rise to these median eminence nerve

These hormones are immediately absorbed into the

endings are located in other discrete areas of the hypo-

hypothalamic-hypophysial portal system and carried

thalamus or in closely related areas of the basal brain.

directly to the sinuses of the anterior pituitary gland.

The specific loci of the neuronal cell bodies that form

the different hypothalamic releasing or inhibitory

Hypothalamic Releasing and Inhibitory Hormones Control Ante-

hormones are still poorly known, so that it would be

rior Pituitary Secretion. The function of the releasing and

misleading to attempt delineation here.

inhibitory hormones is to control secretion of the ante-

rior pituitary hormones. For most of the anterior pitu-

itary hormones, it is the releasing hormones that are

Physiological Functions

important, but for prolactin, a hypothalamic inhibitory

of Growth Hormone

hormone probably exerts more control. The major

hypothalamic releasing and inhibitory hormones are

All the major anterior pituitary hormones, except for

summarized in Table 75-2 and are the following:

growth hormone, exert their principal effects by stim-

1. Thyrotropin-releasing hormone (TRH), which

ulating target glands, including thyroid gland, adrenal

causes release of thyroid-stimulating hormone

cortex, ovaries, testicles, and mammary glands. The

2. Corticotropin-releasing hormone (CRH), which

functions of each of these pituitary hormones are so

causes release of adrenocorticotropin

intimately concerned with the functions of the respec-

3. Growth hormone-releasing hormone (GHRH),

tive target glands that, except for growth hormone,

which causes release of growth hormone, and

their functions are discussed in subsequent chapters

growth hormone inhibitory hormone (GHIH), also

along with the target glands. Growth hormone, in

Table 75-2

Hypothalamic Releasing and Inhibitory Hormones That Control Secretion of the Anterior Pituitary Gland

Hormone

Structure

Primary Action on Anterior Pituitary

Thyrotropin-releasing hormone (TRH)

Peptide of 3 amino acids

Stimulates secretion of TSH by thyrotropes

Gonadotropin-releasing hormone (GnRH)

Single chain of 10 amino acids

Stimulates secretion of FSH and LH by gonadotropes

Corticotropin-releasing hormone (CRH)

Single chain of 41 amino acids

Stimulates secretion of ACTH by corticotropes

Growth hormone-releasing hormone

Single chain of 44 amino acids

Stimulates secretion of growth hormone by somatotropes

(GHRH)

Growth hormone inhibitory hormone

Single chain of 14 amino acids

Inhibits secretion of growth hormone by somatotropes

(somatostatin)

Prolactin-inhibiting hormone (PIH)

Dopamine (a catecholamine)

Inhibits secretion of prolactin by lactotropes

ACTH, adrenocorticotropic hormone; FSH, follicle-stimulating hormone; LH, luteinizing hormone; TSH, thyroid-stimulating hormone.

922

Unit XIV Endocrinology and Reproduction

contrast to other hormones, does not function through

including (1) increased rate of protein synthesis in

a target gland but exerts its effects directly on all or

most cells of the body; (2) increased mobilization of

almost all tissues of the body.

fatty acids from adipose tissue, increased free fatty

acids in the blood, and increased use of fatty acids for

energy; and (3) decreased rate of glucose utilization

Growth Hormone Promotes Growth

throughout the body. Thus, in effect, growth hormone

of Many Body Tissues

enhances body protein, uses up fat stores, and con-

serves carbohydrates.

Growth hormone, also called somatotropic hormone

or somatotropin, is a small protein molecule that con-

Growth Hormone Promotes Protein Deposition

tains

191 amino acids in a single chain and has a

in Tissues

molecular weight of 22,005. It causes growth of almost

Although the precise mechanisms by which growth

all tissues of the body that are capable of growing. It

hormone increases protein deposition are not known,

promotes increased sizes of the cells and increased

a series of different effects are known, all of which

mitosis, with development of greater numbers of cells

could lead to enhanced protein deposition.

and specific differentiation of certain types of cells

such as bone growth cells and early muscle cells.

Enhancement of Amino Acid Transport Through the Cell Mem-

Figure 75-5 shows typical weight charts of two

branes. Growth hormone directly enhances transport

growing littermate rats, one of which received daily

of at least some and perhaps most amino acids through

injections of growth hormone and the other of which

the cell membranes to the interior of the cells. This

did not receive growth hormone. This figure shows

increases the amino acid concentrations in the cells

marked enhancement of growth in the rat given

and is presumed to be at least partly responsible for

growth hormone—in the early days of life and even

the increased protein synthesis. This control of amino

after the two rats reached adulthood. In the early

acid transport is similar to the effect of insulin in con-

stages of development, all organs of the treated rat

trolling glucose transport through the membrane, as

increased proportionately in size; after adulthood was

discussed in Chapters 67 and 78.

reached, most of the bones stopped lengthening, but

many of the soft tissues continued to grow. This results

Enhancement of RNA Translation to Cause Protein Synthesis by

from the fact that once the epiphyses of the long bones

the Ribosomes. Even when the amino acid concentra-

have united with the shafts, further lengthening of

tions are not increased in the cells, growth hormone

bone cannot occur, even though most other tissues of

still increases RNA translation, causing protein to be

the body can continue to grow throughout life.

synthesized in greater amounts by the ribosomes in the

cytoplasm.

Growth Hormone Has Several

Increased Nuclear Transcription of DNA to Form RNA. Over

Metabolic Effects

more prolonged periods (24 to 48 hours), growth

hormone also stimulates the transcription of DNA in

Aside from its general effect in causing growth, growth

the nucleus, causing the formation of increased quan-

hormone has multiple specific metabolic effects,

tities of RNA. This promotes more protein synthesis

and promotes growth if sufficient energy, amino acids,

vitamins, and other requisites for growth are available.

In the long run, this may be the most important func-

500

tion of growth hormone.

Injected daily with

growth hormone

Decreased Catabolism of Protein and Amino Acids. In addi-

400

tion to the increase in protein synthesis, there is a

decrease in the breakdown of cell protein. A probable

300

reason for this is that growth hormone also mobilizes

Control

large quantities of free fatty acids from the adipose

200

tissue, and these are used to supply most of the energy

for the body’s cells, thus acting as a potent “protein

200

sparer.”

Summary. Growth hormone enhances almost all facets

100

200

300

400

500

600

of amino acid uptake and protein synthesis by cells,

Days

while at the same time reducing the breakdown of

proteins.

Growth Hormone Enhances Fat Utilization

Figure 75-5

for Energy

Comparison of weight gain of a rat injected daily with growth

Growth hormone has a specific effect in causing

hormone with that of a normal littermate.

the release of fatty acids from adipose tissue and,

Chapter 75

Pituitary Hormones and Their Control by the Hypothalamus

923

therefore, increasing the concentration of fatty acids in

tive. Part of this requirement for carbohydrates and

the body fluids. In addition, in tissues throughout the

insulin is to provide the energy needed for the metab-

body, growth hormone enhances the conversion of

olism of growth, but there seem to be other effects as

fatty acids to acetyl coenzyme A (acetyl-CoA) and its

well. Especially important is insulin’s ability to

subsequent utilization for energy. Therefore, under

enhance the transport of some amino acids into cells,

the influence of growth hormone, fat is used for

in the same way that it stimulates glucose transport.

energy in preference to the use of carbohydrates and

proteins.

Growth hormone’s ability to promote fat utilization,

Growth Hormone Stimulates Cartilage

together with its protein anabolic effect, causes an

and Bone Growth

increase in lean body mass. However, mobilization of

fat by growth hormone requires several hours to occur,

Although growth hormone stimulates increased de-

whereas enhancement of protein synthesis can begin

position of protein and increased growth in almost

in minutes under the influence of growth hormone.

all tissues of the body, its most obvious effect is to

increase growth of the skeletal frame. This results from

“Ketogenic” Effect of Growth Hormone. Under the influ-

multiple effects of growth hormone on bone, including

ence of excessive amounts of growth hormone, fat

(1) increased deposition of protein by the chondro-

mobilization from adipose tissue sometimes becomes

cytic and osteogenic cells that cause bone growth,

so great that large quantities of acetoacetic acid are

(2) increased rate of reproduction of these cells,

formed by the liver and released into the body fluids,

and (3) a specific effect of converting chondrocytes

thus causing ketosis. This excessive mobilization of fat

into osteogenic cells, thus causing deposition of new

from the adipose tissue also frequently causes a fatty

bone.

liver.

There are two principal mechanisms of bone

growth. First, in response to growth hormone stimula-

Growth Hormone Decreases

tion, the long bones grow in length at the epiphyseal

Carbohydrate Utilization

cartilages, where the epiphyses at the ends of the bone

Growth hormone causes multiple effects that

are separated from the shaft. This growth first causes

influence carbohydrate metabolism, including

(1)

deposition of new cartilage, followed by its conversion

decreased glucose uptake in tissues such as skeletal

into new bone, thus elongating the shaft and pushing

muscle and fat, (2) increased glucose production by

the epiphyses farther and farther apart. At the same

the liver, and (3) increased insulin secretion.

time, the epiphyseal cartilage itself is progressively

Each of these changes results from growth

used up, so that by late adolescence, no additional epi-

hormone-induced “insulin resistance,” which attenu-

physeal cartilage remains to provide for further long

ates insulin’s actions to stimulate the uptake and uti-

bone growth. At this time, bony fusion occurs between

lization of glucose in skeletal muscle and fat and to

the shaft and the epiphysis at each end, so that no

inhibit gluconeogenesis (glucose production) by the

further lengthening of the long bone can occur.

liver; this leads to increased blood glucose concentra-

Second, osteoblasts in the bone periosteum and in

tion and a compensatory increase in insulin secretion.

some bone cavities deposit new bone on the surfaces

For these reasons, growth hormone’s effects are called

of older bone. Simultaneously, osteoclasts in the bone

diabetogenic, and excess secretion of growth hormone

(discussed in detail in Chapter 79) remove old bone.

can produce metabolic disturbances very similar to

When the rate of deposition is greater than that of

those found in patients with type II

(non-insulin-

resorption, the thickness of the bone increases. Growth

dependent) diabetes, who are also very resistant to the

hormone strongly stimulates osteoblasts. Therefore, the

metabolic effects of insulin.

bones can continue to become thicker throughout life

We do not know the precise mechanism by which

under the influence of growth hormone; this is espe-

growth hormone causes insulin resistance and

cially true for the membranous bones. For instance, the

decreased glucose utilization by the cells. However,

jaw bones can be stimulated to grow even after ado-

growth hormone-induced increases in blood concen-

lescence, causing forward protrusion of the chin and

trations of fatty acids may impair insulin’s actions on

lower teeth. Likewise, the bones of the skull can grow

tissue glucose utilization. Experimental studies indi-

in thickness and give rise to bony protrusions over the

cate that raising blood levels of fatty acids above

eyes.

normal rapidly decreases the sensitivity of the liver

and skeletal muscle to insulin’s effects on carbohy-

drate metabolism.

Growth Hormone Exerts Much

of Its Effect Through Intermediate

Necessity of Insulin and Carbohydrate for the Growth-

Substances Called “Somatomedins”

Promoting Action of Growth Hormone. Growth hormone

fails to cause growth in an animal that lacks a pan-

(Also Called “Insulin-Like

creas; it also fails to cause growth if carbohydrates are

Growth Factors”)

excluded from the diet. This shows that adequate

insulin activity and adequate availability of carbohy-

When growth hormone is supplied directly to cartilage

drates are necessary for growth hormone to be effec-

chondrocytes cultured outside the body, proliferation

924

Unit XIV Endocrinology and Reproduction

or enlargement of the chondrocytes usually fails to

occur. Yet growth hormone injected into the intact

animal does cause proliferation and growth of the

Sleep

same cells.

In brief, it has been found that growth hormone

Strenuous

causes the liver

(and, to a much less extent,

exercise

other tissues) to form several small proteins

called somatomedins that have the potent effect of

increasing all aspects of bone growth. Many of the

somatomedin effects on growth are similar to the

effects of insulin on growth. Therefore, the somato-

medins are also called insulin-like growth factors

(IGFs).

8 am

4 am

8 pm

4 am

8 am

At least four somatomedins have been isolated,

Noon

Midnight

but by far the most important of these is somatomedin

C (also called IGF-I). The molecular weight of

somatomedin C is about 7500, and its concentration in

the plasma closely follows the rate of growth hormone

Figure 75-6

secretion.

Typical variations in growth hormone secretion throughout the day,

The pygmies of Africa have a congenital inability to

demonstrating the especially powerful effect of strenuous exercise

synthesize significant amounts of somatomedin C.

and also the high rate of growth hormone secretion that occurs

Therefore, even though their plasma concentration of

during the first few hours of deep sleep.

growth hormone is either normal or high, they have

diminished amounts of somatomedin C in the plasma;

this apparently accounts for the small stature of these

Regulation of Growth

people. Some other dwarfs

(e.g., the Lévi-Lorain

Hormone Secretion

dwarf) also have this problem.

It has been postulated that most, if not all, of the

For many years it was believed that growth hormone

growth effects of growth hormone result from

was secreted primarily during the period of growth but

somatomedin C and other somatomedins, rather

then disappeared from the blood at adolescence. This

than from direct effects of growth hormone on the

has proved to be untrue. After adolescence, secretion

bones and other peripheral tissues. Even so, experi-

decreases slowly with aging, finally falling to about 25

ments have demonstrated that injection of growth

per cent of the adolescent level in very old age.

hormone directly into the epiphyseal cartilages of

Growth hormone is secreted in a pulsatile pattern,

bones of living animals causes the specific growth

increasing and decreasing. The precise mechanisms

of these cartilage areas, and the amount of growth

that control secretion of growth hormone are not fully

hormone required for this is minute. Some aspects

understood, but several factors related to a person’s

of the somatomedin hypothesis are still questionable.

state of nutrition or stress are known to stimulate

One possibility is that growth hormone can cause

secretion: (1) starvation, especially with severe protein

the formation of enough somatomedin C in the

deficiency; (2) hypoglycemia or low concentration of

local tissue to cause local growth. It is also possible

fatty acids in the blood; (3) exercise; (4) excitement; and

that growth hormone itself is directly responsible

(5) trauma. Growth hormone also characteristically

for increased growth in some tissues and that the

increases during the first 2 hours of deep sleep, as

somatomedin mechanism is an alternative means of

shown in Figure 75-6. Table 75-3 summarizes some of

increasing growth but not always a necessary

the factors that are known to influence growth

one.

hormone secretion.

The normal concentration of growth hormone in the

plasma of an adult is between 1.6 and 3 ng/ml; in a

Short Duration of Action of Growth Hormone but Prolonged

child or adolescent, it is about 6 ng/ml. These values

Action of Somatomedin C. Growth hormone attaches only

often increase to as high as 50 ng/ml after depletion of

weakly to the plasma proteins in the blood. Therefore,

the body stores of proteins or carbohydrates during

it is released from the blood into the tissues rapidly,

prolonged starvation.

having a half-time in the blood of less than 20 minutes.

Under acute conditions, hypoglycemia is a far more

By contrast, somatomedin C attaches strongly to a

potent stimulator of growth hormone secretion than is

carrier protein in the blood that, like somatomedin C,

an acute decrease in protein intake. Conversely, in

is produced in response to growth hormone. As a

chronic conditions, growth hormone secretion seems

result, somatomedin C is released only slowly from the

to correlate more with the degree of cellular protein

blood to the tissues, with a half-time of about 20 hours.

depletion than with the degree of glucose insufficiency.

This greatly prolongs the growth-promoting effects of

For instance, the extremely high levels of growth

the bursts of growth hormone secretion shown in

hormone that occur during starvation are closely

Figure 75-6.

related to the amount of protein depletion.

Chapter 75

Pituitary Hormones and Their Control by the Hypothalamus

925

hormone concentration. The third and fourth columns

Table 75-3

show the levels after treatment with protein supple-

Factors That Stimulate or Inhibit Secretion of

ments for 3 and 25 days, respectively, with a concomi-

Growth Hormone

tant decrease in the hormone.

These results demonstrate that under severe condi-

Stimulate Growth Hormone

Inhibit Growth Hormone

tions of protein malnutrition, adequate calories alone

Secretion

are not sufficient to correct the excess production of

Decreased blood glucose

Increased blood glucose

growth hormone. The protein deficiency must also be

Decreased blood free fatty

Increased blood free fatty

corrected before the growth hormone concentration

acids

will return to normal.

Starvation or fasting, protein

Aging

deficiency

Obesity

Trauma, stress, excitement

Growth hormone inhibitory

Role of the Hypothalamus, Growth

Exercise

hormone (somatostatin)

Hormone-Releasing Hormone, and

Testosterone, estrogen

Growth hormone (exogenous)

Somatostatin in the Control of Growth

Deep sleep ( stages II and IV)

Somatomedins (insulin-like

Hormone Secretion

Growth hormone-releasing

growth factors)

From the preceding description of the many factors

hormone

that can affect growth hormone secretion, one can

readily understand the perplexity of physiologists as

they attempt to unravel the mysteries of regulation of

growth hormone secretion. It is known that growth

hormone secretion is controlled by two factors

secreted in the hypothalamus and then transported to

the anterior pituitary gland through the hypothalamic-

hypophysial portal vessels. They are growth

hormone-releasing hormone and growth hormone

inhibitory hormone (also called somatostatin). Both of

these are polypeptides; GHRH is composed of 44

amino acids, and somatostatin is composed of

amino acids.

The part of the hypothalamus that causes secretion

of GHRH is the ventromedial nucleus; this is the

same area of the hypothalamus that is sensitive to

blood glucose concentration, causing satiety in hyper-

glycemic states and hunger in hypoglycemic states. The

secretion of somatostatin is controlled by other nearby

areas of the hypothalamus. Therefore, it is reasonable

Protein

Carbohydrate

Protein

to believe that some of the same signals that modify a

deficiency

treatment

(kwashiorkor)

(3 days)

(25 days)

person’s behavioral feeding instincts also alter the rate

of growth hormone secretion.

In a similar manner, hypothalamic signals depicting

emotions, stress, and trauma can all affect hypothala-

Figure 75-7

mic control of growth hormone secretion. In fact,

experiments have shown that catecholamines,

Effect of extreme protein deficiency on the plasma concentration

of growth hormone in the disease kwashiorkor. Also shown is the

dopamine, and serotonin, each of which is released by

failure of carbohydrate treatment but the effectiveness of protein

a different neuronal system in the hypothalamus, all

treatment in lowering growth hormone concentration. (Drawn from

increase the rate of growth hormone secretion.

data in Pimstone BL, Barbezat G, Hansen JD, Murray P: Studies

Most of the control of growth hormone secretion

on growth hormone secretion in protein-calorie malnutrition. Am J

Clin Nutr 21:482, 1968.)

is probably mediated through GHRH rather than

through the inhibitory hormone somatostatin. GHRH

stimulates growth hormone secretion by attaching to

specific cell membrane receptors on the outer surfaces

Figure 75-7 demonstrates the effect of protein defi-

of the growth hormone cells in the pituitary gland. The

ciency on plasma growth hormone and then the effect

receptors activate the adenylyl cyclase system inside

of adding protein to the diet. The first column shows

the cell membrane, increasing the intracellular level of

very high levels of growth hormone in children with

cyclic adenosine monophosphate (cAMP). This has

extreme protein deficiency during the protein malnu-

both a short-term and a long-term effect. The short-

trition condition called kwashiorkor; the second

term effect is to increase calcium ion transport into the

column shows the levels in the same children after 3

cell; within minutes, this causes fusion of the growth

days of treatment with more than adequate quantities

hormone secretory vesicles with the cell membrane

of carbohydrates in their diets, demonstrating that

and release of the hormone into the blood. The long-

the carbohydrates did not lower the plasma growth

term effect is to increase transcription in the nucleus

926

Unit XIV Endocrinology and Reproduction

by the genes to stimulate the synthesis of new growth

only in the one species or, at most, closely related

hormone.

species. For this reason, growth hormone prepared from

When growth hormone is administered directly into

lower animals (except, to some extent, from primates)

is not effective in human beings. Therefore, the growth

the blood of an animal over a period of hours, the rate

hormone of the human being is called human growth

of endogenous growth hormone secretion decreases.

hormone to distinguish it from the others.

This demonstrates that growth hormone secretion is

In the past, because growth hormone had to be pre-

subject to typical negative feedback control, as is true

pared from human pituitary glands, it was difficult to

for essentially all hormones. The nature of this feed-

obtain sufficient quantities to treat patients with growth

back mechanism and whether it is mediated mainly

hormone deficiency, except on an experimental basis.

through inhibition of GHRH or enhancement of

However, human growth hormone can now be synthe-

somatostatin, which inhibits growth hormone secre-

sized by Escherichia coli bacteria as a result of success-

tion, are uncertain.

ful application of recombinant DNA technology.

In summary, our knowledge of the regulation of

Therefore, this hormone is now available in sufficient

quantities for treatment purposes. Dwarfs who have

growth hormone secretion is not sufficient to describe

pure growth hormone deficiency can be completely

a composite picture. Yet, because of the extreme secre-

cured if treated early in life. Human growth hormone

tion of growth hormone during starvation and its

may prove to be beneficial in other metabolic disorders

important long-term effect to promote protein syn-

because of its widespread metabolic functions.

thesis and tissue growth, we can propose the follow-

ing: the major long-term controller of growth hormone

Panhypopituitarism in the Adult. Panhypopituitarism first

secretion is the long-term state of nutrition of the

occurring in adulthood frequently results from one of

tissues themselves, especially their level of protein

three common abnormalities. Two tumorous conditions,

nutrition. That is, nutritional deficiency or excess tissue

craniopharyngiomas or chromophobe tumors, may

need for cellular proteins—for instance, after a severe

compress the pituitary gland until the functioning

bout of exercise when the muscles’ nutritional status

anterior pituitary cells are totally or almost totally

destroyed. The third cause is thrombosis of the pituitary

has been taxed—in some way increases the rate of

blood vessels. This abnormality occasionally occurs

growth hormone secretion. Growth hormone, in turn,

when a new mother develops circulatory shock after the

promotes synthesis of new proteins while at the same

birth of her baby.

time conserving the proteins already present in the

The general effects of adult panhypopituitarism are

cells.

(1) hypothyroidism, (2) depressed production of gluco-

corticoids by the adrenal glands, and (3) suppressed

secretion of the gonadotropic hormones so that sexual

Abnormalities of Growth

functions are lost. Thus, the picture is that of a lethargic

Hormone Secretion

person (from lack of thyroid hormones) who is gaining

weight (because of lack of fat mobilization by growth,

Panhypopituitarism. This term means decreased secretion

adrenocorticotropic, adrenocortical, and thyroid hor-

of all the anterior pituitary hormones. The decrease in

mones) and has lost all sexual functions. Except for the

secretion may be congenital (present from birth), or it

abnormal sexual functions, the patient can usually be

may occur suddenly or slowly at any time during life,

treated satisfactorily by administering adrenocortical

most often resulting from a pituitary tumor that

and thyroid hormones.

destroys the pituitary gland.

Gigantism. Occasionally, the

acidophilic,

growth

Dwarfism. Most instances of dwarfism result from gener-

hormone-producing cells of the anterior pituitary gland

alized deficiency of anterior pituitary secretion (panhy-

become excessively active, and sometimes even aci-

popituitarism) during childhood. In general, all the

dophilic tumors occur in the gland. As a result, large

physical parts of the body develop in appropriate pro-

quantities of growth hormone are produced. All body

portion to one another, but the rate of development is

tissues grow rapidly, including the bones. If the condi-

greatly decreased. A child who has reached the age of

tion occurs before adolescence, before the epiphyses of

10 years may have the bodily development of a child

the long bones have become fused with the shafts,

aged 4 to 5 years, and the same person at age 20 years

height increases so that the person becomes a giant—

may have the bodily development of a child aged 7 to

up to 8 feet tall.

10 years.

The giant ordinarily has hyperglycemia, and the beta

A person with panhypopituitary dwarfism does not

cells of the islets of Langerhans in the pancreas are

pass through puberty and never secretes sufficient

prone to degenerate because they become overactive

quantities of gonadotropic hormones to develop adult

owing to the hyperglycemia. Consequently, in about 10

sexual functions. In one third of such dwarfs, however,

per cent of giants, full-blown diabetes mellitus eventu-

only growth hormone is deficient; these persons do

ally develops.

mature sexually and occasionally reproduce. In one type

In most giants, panhypopituitarism eventually devel-

of dwarfism (the African pygmy and the Lévi-Lorain

ops if they remain untreated, because the gigantism is

dwarf), the rate of growth hormone secretion is normal

usually caused by a tumor of the pituitary gland that

or high, but there is a hereditary inability to form

grows until the gland itself is destroyed. This eventual

somatomedin C, which is a key step for the promotion

general deficiency of pituitary hormones usually causes

of growth by growth hormone.

death in early adulthood. However, once gigantism is

Treatment with Human Growth Hormone. Growth hor-

diagnosed, further effects can often be blocked by

mones from different species of animals are sufficiently

microsurgical removal of the tumor or by irradiation of

different from one another that they will cause growth

the pituitary gland.

Chapter 75

Pituitary Hormones and Their Control by the Hypothalamus

927

Figure 75-8

Acromegalic patient.

Acromegaly. If an acidophilic tumor occurs after adoles-

ng/ml

cence—that is, after the epiphyses of the long bones

have fused with the shafts—the person cannot grow

5 to 20 years

taller, but the bones can become thicker and the soft

20 to 40 years

tissues can continue to grow. This condition, shown in

40 to 70 years

1.6

Figure 75-8, is known as acromegaly. Enlargement is

especially marked in the bones of the hands and feet

and in the membranous bones, including the cranium,

nose, bosses on the forehead, supraorbital ridges, lower

Thus, it is highly possible that some of the normal

jawbone, and portions of the vertebrae, because their

aging effects result from diminished growth hormone

growth does not cease at adolescence. Consequently,

secretion. In fact, multiple tests of growth hormone

the lower jaw protrudes forward, sometimes as much as

therapy in older people have demonstrated three

half an inch, the forehead slants forward because of

important effects that suggest antiaging actions: (1)

excess development of the supraorbital ridges, the

increased protein deposition in the body, especially in

nose increases to as much as twice normal size, the feet

the muscles; (2) decreased fat deposits; and (3) a feeling

require size 14 or larger shoes, and the fingers become

of increased energy.

extremely thickened so that the hands are almost twice

normal size. In addition to these effects, changes in the

vertebrae ordinarily cause a hunched back, which is

known clinically as kyphosis. Finally, many soft tissue

Posterior Pituitary Gland

organs, such as the tongue, the liver, and especially the

and Its Relation to the

kidneys, become greatly enlarged.

Hypothalamus

Possible Role of Decreased Growth Hormone Secretion

in Causing Changes Associated with Aging

The posterior pituitary gland, also called the neurohy-

In people who have lost the ability to secrete growth

pophysis, is composed mainly of glial-like cells called

hormone, some features of the aging process accelerate.

pituicytes. The pituicytes do not secrete hormones; they

For instance, a 50-year-old person who has been without

act simply as a supporting structure for large numbers

growth hormone for many years may have the appear-

of terminal nerve fibers and terminal nerve endings

ance of a person aged 65. The aged appearance seems

from nerve tracts that originate in the supraoptic and

to result mainly from decreased protein deposition in

paraventricular nuclei of the hypothalamus, as shown

most tissues of the body and increased fat deposition in

in Figure 75-9. These tracts pass to the neurohypoph-

its place. The physical and physiological effects are

ysis through the pituitary stalk (hypophysial stalk). The

increased wrinkling of the skin, diminished rates of

nerve endings are bulbous knobs that contain many

function of some of the organs, and diminished muscle

mass and strength.

secretory granules. These endings lie on the surfaces of

As one ages, the average plasma concentration of

capillaries, where they secrete two posterior pituitary

growth hormone in an otherwise normal person

hormones:

(1) antidiuretic hormone

(ADH), also

changes approximately as follows:

called vasopressin, and (2) oxytocin.

928

Unit XIV Endocrinology and Reproduction

except that in vasopressin, phenylalanine and arginine

Paraventricular

Supraoptic

nucleus

replace isoleucine and leucine of the oxytocin molecule.

nucleus

The similarity of the molecules explains their partial

functional similarities.

Optic chiasm

Physiological Functions of ADH

Mamillary body

The injection of extremely minute quantities of

Hypothalamic-

ADH—as small as 2 nanograms—can cause decreased

hypophysial

tract

excretion of water by the kidneys (antidiuresis). This

antidiuretic effect is discussed in detail in Chapter 28.

Briefly, in the absence of ADH, the collecting tubules

Posterior pituitary

and ducts become almost impermeable to water, which

prevents significant reabsorption of water and there-

Anterior pituitary

fore allows extreme loss of water into the urine, also

causing extreme dilution of the urine. Conversely, in

the presence of ADH, the permeability of the collect-

Figure 75-9

ing ducts and tubules to water increases greatly and

allows most of the water to be reabsorbed as the

Hypothalamic control of the posterior pituitary.

tubular fluid passes through these ducts, thereby con-

serving water in the body and producing very concen-

trated urine.

If the pituitary stalk is cut above the pituitary gland

The precise mechanism by which ADH acts on the

but the entire hypothalamus is left intact, the posterior

collecting ducts to increase their permeability is only

pituitary hormones continue to be secreted normally,

partially known. Without ADH, the luminal mem-

after a transient decrease for a few days; they are then

branes of the tubular epithelial cells of the collecting

secreted by the cut ends of the fibers within the hypo-

ducts are almost impermeable to water. However,

thalamus and not by the nerve endings in the poste-

immediately inside the cell membrane are a large

rior pituitary. The reason for this is that the hormones

number of special vesicles that have highly water-

are initially synthesized in the cell bodies of the

permeable pores called aquaporins. When ADH acts

supraoptic and paraventricular nuclei and are then

on the cell, it first combines with membrane receptors

transported in combination with “carrier” proteins

that activate adenylyl cyclase and cause the formation

called neurophysins down to the nerve endings in the

of cAMP inside the tubular cell cytoplasm. This causes

posterior pituitary gland, requiring several days to

phosphorylation of elements in the special vesicles,

reach the gland.

which then causes the vesicles to insert into the apical

ADH is formed primarily in the supraoptic nuclei,

cell membranes, thus providing many areas of high

whereas oxytocin is formed primarily in the paraven-

water permeability. All this occurs within

5 to 10

tricular nuclei. Each of these nuclei can synthesize

minutes. Then, in the absence of ADH, the entire

about one sixth as much of the second hormone as of

process reverses in another 5 to 10 minutes. Thus, this

its primary hormone.

process temporarily provides many new pores that

When nerve impulses are transmitted downward

allow free diffusion of water from the tubular fluid

along the fibers from the supraoptic or paraventri-

through the tubular epithelial cells and into the renal

cular nuclei, the hormone is immediately released

interstitial fluid. Water is then absorbed from the col-

from the secretory granules in the nerve endings by

lecting tubules and ducts by osmosis, as explained in

the usual secretory mechanism of exocytosis and is

Chapter 28 in relation to the urine-concentrating

absorbed into adjacent capillaries. Both the neuro-

mechanism of the kidneys.

physin and the hormone are secreted together, but

because they are only loosely bound to each other, the

Regulation of ADH Production

hormone separates almost immediately. The neuro-

Osmotic Regulation. When a concentrated electrolyte

physin has no known function after leaving the nerve

solution is injected into the artery that supplies the

terminals.

hypothalamus, the ADH neurons in the supraoptic and

paraventricular nuclei immediately transmit impulses

Chemical Structures of ADH

into the posterior pituitary to release large quantities

and Oxytocin

of ADH into the circulating blood, sometimes increas-

ing the ADH secretion to as high as 20 times normal.

Both oxytocin and ADH (vasopressin) are polypep-

Conversely, injection of a dilute solution into this

tides, each containing nine amino acids. Their amino

artery causes cessation of the impulses and therefore

acid sequences are the following:

almost total cessation of ADH secretion. Thus, the con-

Vasopressin: Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-

centration of ADH in the body fluids can change from

GlyNH

Oxytocin: Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-GlyNH₂

small amounts to large amounts, or vice versa, in only

Note that these two hormones are almost identical

a few minutes.

Chapter 75

Pituitary Hormones and Their Control by the Hypothalamus

929

The precise way that the osmotic concentration of

indicating a possible effect of oxytocin during delivery.

the extracellular fluid controls ADH secretion is not

(2) The amount of oxytocin in the plasma increases

clear. Yet somewhere in or near the hypothalamus

during labor, especially during the last stage. (3) Stim-

are modified neuron receptors called osmoreceptors.

ulation of the cervix in a pregnant animal elicits

When the extracellular fluid becomes too concen-

nervous signals that pass to the hypothalamus and

trated, fluid is pulled by osmosis out of the osmore-

cause increased secretion of oxytocin. These effects

ceptor cell, decreasing its size and initiating

and this possible mechanism for aiding in the birth

appropriate nerve signals in the hypothalamus to

process are discussed in much more detail in Chapter

cause additional ADH secretion. Conversely, when the

82.

extracellular fluid becomes too dilute, water moves by

Oxytocin Aids in Milk Ejection by the Breasts. Oxytocin also

osmosis in the opposite direction, into the cell, and this

plays an especially important role in lactation—a role

decreases the signal for ADH secretion. Although

that is far better understood than its role in delivery.

some researchers place these osmoreceptors in the

In lactation, oxytocin causes milk to be expressed from

hypothalamus itself (possibly even in the supraoptic

the alveoli into the ducts of the breast so that the baby

nuclei), others believe that they are located in the

can obtain it by suckling.

organum vasculosum, a highly vascular structure in the

This mechanism works as follows: The suckling stim-

anteroventral wall of the third ventricle.

ulus on the nipple of the breast causes signals to be

Regardless of the mechanism, concentrated body

transmitted through sensory nerves to the oxytocin

fluids stimulate the supraoptic nuclei, whereas dilute

neurons in the paraventricular and supraoptic nuclei

body fluids inhibit them. A feedback control system is

in the hypothalamus, which causes release of oxytocin

available to control the total osmotic pressure of the

by the posterior pituitary gland. The oxytocin is then

body fluids.

carried by the blood to the breasts, where it causes

Further details on the role of ADH in controlling

contraction of myoepithelial cells that lie outside of

renal function and body fluid osmolality are presented

and form a latticework surrounding the alveoli of the

in Chapter 28.

mammary glands. In less than a minute after the begin-

ning of suckling, milk begins to flow. This mechanism

Vasoconstrictor and Pressor Effects of ADH,

is called milk letdown or milk ejection. It is discussed

and Increased ADH Secretion Caused by Low

further in Chapter 82 in relation to the physiology of

Blood Volume

lactation.

Whereas minute concentrations of ADH cause

increased water conservation by the kidneys, higher

References

concentrations of ADH have a potent effect of con-

stricting the arterioles throughout the body and there-

Antunes-Rodrigues J, de Castro M, Elias LL, et al: Neu-

fore increasing the arterial pressure. For this reason,

roendocrine control of body fluid metabolism. Physiol Rev

ADH has another name, vasopressin.

84:169, 2004.

One of the stimuli for causing intense ADH secre-

Besser GM, Thorner MO: Comprehensive Clinical

tion is decreased blood volume. This occurs especially

Endocrinology,

3rd ed. Philadelphia: Mosby, Elsevier

strongly when the blood volume decreases 15 to 25 per

Science Limited, 2002.

cent or more; the secretory rate then sometimes rises

Burbach JP, Luckman SM, Murphy D, Gainer H: Gene

to as high as 50 times normal. The cause of this is the

regulation in the magnocellular hypothalamo-

following.

neurohypophysial system. Physiol Rev 81:1197, 2001.

The atria have stretch receptors that are excited by

Butler AA, Le Roith D: Control of growth by the somatropic

overfilling. When excited, they send signals to the brain

axis: growth hormone and the insulin-like growth factors

have related and independent roles. Annu Rev Physiol

to inhibit ADH secretion. Conversely, when the recep-

63:141, 2001.

tors are unexcited as a result of underfilling, the oppo-

Cummings DE, Merriam GR: Growth hormone therapy in

site occurs, with greatly increased ADH secretion.

adults. Annu Rev Med 54:513, 2003.

Decreased stretch of the baroreceptors of the carotid,

Dattani M, Preece M: Growth hormone deficiency and

aortic, and pulmonary regions also stimulates ADH

related disorders: insights into causation, diagnosis, and

secretion. For further details about this blood volume-

treatment. Lancet 363:1977, 2004.

pressure feedback mechanism, refer to Chapter 28.

Dunn AJ, Swiergiel AH, Palamarchouk V: Brain circuits

involved in corticotropin-releasing factor-norepinephrine

interactions during stress. Ann N Y Acad Sci 1018:25, 2004.

Oxytocic Hormone

Edmondson SR, Thumiger SP, Werther GA, Wraight CJ: Epi-

dermal homeostasis: the role of the growth hormone and

insulin-like growth factor systems. Endocr Rev 24:737,

Oxytocin Causes Contraction of the Pregnant Uterus. The

2003.

hormone oxytocin, in accordance with its name, pow-

Eugster EA, Pescovitz OH: Gigantism. J Clin Endocrinol

erfully stimulates contraction of the pregnant uterus,

Metab 84:4379, 1999.

especially toward the end of gestation. Therefore,

Freeman ME, Kanyicska B, Lerant A, Nagy G: Prolactin:

many obstetricians believe that this hormone is at least

structure, function, and regulation of secretion. Physiol

partially responsible for causing birth of the baby. This

Rev 80:1523, 2000.

is supported by the following facts: (1) In a hypophy-

Gimpl G, Fahrenholz F: The oxytocin receptor system: struc-

sectomized animal, the duration of labor is prolonged,

ture, function, and regulation. Physiol Rev 81:629, 2001.

C H A P T E R

Thyroid Metabolic Hormones

The thyroid gland, located immediately below the

larynx on each side of and anterior to the trachea,

is one of the largest of the endocrine glands,

normally weighing 15 to 20 grams in adults. The

thyroid secretes two major hormones, thyroxine and

triiodothyronine, commonly called T₄ and T₃, respec-

tively. Both of these hormones profoundly increase

the metabolic rate of the body. Complete lack of

thyroid secretion usually causes the basal metabolic rate to fall 40 to 50 per cent

below normal, and extreme excesses of thyroid secretion can increase the basal

metabolic rate to 60 to 100 per cent above normal. Thyroid secretion is con-

trolled primarily by thyroid-stimulating hormone (TSH) secreted by the ante-

rior pituitary gland.

The thyroid gland also secretes calcitonin, an important hormone for calcium

metabolism that is considered in detail in Chapter 79.

The purpose of this chapter is to discuss the formation and secretion of the

thyroid hormones, their metabolic functions, and regulation of their secretion.

Synthesis and Secretion of the Thyroid

Metabolic Hormones

About 93 per cent of the metabolically active hormones secreted by the thyroid

gland is thyroxine, and 7 per cent triiodothyronine. However, almost all the thy-

roxine is eventually converted to triiodothyronine in the tissues, so that both

are functionally important. The functions of these two hormones are qualita-

tively the same, but they differ in rapidity and intensity of action. Triiodothy-

ronine is about four times as potent as thyroxine, but it is present in the blood

in much smaller quantities and persists for a much shorter time than does

thyroxine.

Physiologic Anatomy of the Thyroid Gland. The thyroid gland is composed, as shown

in Figure 76-1, of large numbers of closed follicles (100 to 300 micrometers in

diameter) filled with a secretory substance called colloid and lined with cuboidal

epithelial cells that secrete into the interior of the follicles. The major constituent

of colloid is the large glycoprotein thyroglobulin, which contains the thyroid

hormones within its molecule. Once the secretion has entered the follicles, it

must be absorbed back through the follicular epithelium into the blood before

it can function in the body. The thyroid gland has a blood flow about five times

the weight of the gland each minute, which is a blood supply as great as that of

any other area of the body, with the possible exception of the adrenal cortex.

Iodine Is Required for Formation of Thyroxine

To form normal quantities of thyroxine, about 50 milligrams of ingested iodine

in the form of iodides are required each year, or about 1 mg/week. To prevent

iodine deficiency, common table salt is iodized with about 1 part sodium iodide

to every 100,000 parts sodium chloride.

Fate of Ingested Iodides. Iodides ingested orally are absorbed from the gastro-

intestinal tract into the blood in about the same manner as chlorides. Normally,

931

932

Unit XIV Endocrinology and Reproduction

most of the iodides are rapidly excreted by the

concentration of TSH; TSH stimulates and hypophy-

kidneys, but only after about one fifth are selectively

sectomy greatly diminishes the activity of the iodide

removed from the circulating blood by the cells of the

pump in thyroid cells.

thyroid gland and used for synthesis of the thyroid

hormones.

Thyroglobulin, and Chemistry

of Thyroxine and

Iodide Pump (Iodide Trapping)

Triiodothyronine Formation

The first stage in the formation of thyroid hormones,

Formation and Secretion of Thyroglobulin by the Thyroid Cells.

shown in Figure 76-2, is transport of iodides from the

The thyroid cells are typical protein-secreting glandu-

blood into the thyroid glandular cells and follicles. The

lar cells, as shown in Figure 76-2. The endoplasmic

basal membrane of the thyroid cell has the specific

reticulum and Golgi apparatus synthesize and secrete

ability to pump the iodide actively to the interior of

into the follicles a large glycoprotein molecule called

the cell. This is called iodide trapping. In a normal

thyroglobulin, with a molecular weight of about

gland, the iodide pump concentrates the iodide to

335,000.

about 30 times its concentration in the blood. When

Each molecule of thyroglobulin contains about 70

the thyroid gland becomes maximally active, this con-

tyrosine amino acids, and they are the major substrates

centration ratio can rise to as high as 250 times. The

that combine with iodine to form the thyroid hor-

rate of iodide trapping by the thyroid is influenced

mones. Thus, the thyroid hormones form within the

by several factors, the most important being the

thyroglobulin molecule. That is, the thyroxine and

triiodothyronine hormones formed from the tyrosine

amino acids remain part of the thyroglobulin molecule

during synthesis of the thyroid hormones and even

afterward as stored hormones in the follicular colloid.

Follicle

Oxidation of the Iodide Ion. The first essential step in the

formation of the thyroid hormones is conversion of

Cuboidal epithelial cells

the iodide ions to an oxidized form of iodine, either

nascent iodine (I⁰) or I_{3_}, that is then capable of com-

Red blood cells

bining directly with the amino acid tyrosine. This oxi-

dation of iodine is promoted by the enzyme peroxidase

and its accompanying hydrogen peroxide, which

Colloid

provide a potent system capable of oxidizing iodides.

The peroxidase is either located in the apical mem-

brane of the cell or attached to it, thus providing the

oxidized iodine at exactly the point in the cell where

the thyroglobulin molecule issues forth from the Golgi

apparatus and through the cell membrane into the

stored thyroid gland colloid. When the peroxidase

Figure 76-1

system is blocked or when it is hereditarily absent

Microscopic appearance of the thyroid gland, showing secretion

from the cells, the rate of formation of thyroid hor-

of thyroglobulin into the follicles.

mones falls to zero.

I₂

I^-

H₂O₂

Thyroglobulin

Peroxidase

precursor (T_G)

+ Iodination

T_G

and

Peroxidase

coupling

ER Golgi

MIT, DIT

Figure 76-2

MIT

DIT

T_G

Secretion

T₃

Thyroid cellular mechanisms for iodine transport,

T₄

Pinocytosis

T₄

thyroxine and triiodothyronine formation, and thy-

Proteases

Colloid

roxine and triiodothyronine release into the blood.

droplet

MIT, monoiodotyrosine; DIT, diiodotyrosine; T₃, tri-

iodothyronine; T₄, thyroxine; T_G, thyroglobulin.

Chapter 76

Thyroid Metabolic Hormones

933

Iodination of Tyrosine and Formation of the Thyroid Hormones—

monoiodotyrosine couples with one molecule of

“Organification” of Thyroglobulin. The binding of iodine

diiodotyrosine to form triiodothyronine, which repre-

with the thyroglobulin molecule is called organifica-

sents about one fifteenth of the final hormones.

tion of the thyroglobulin. Oxidized iodine even in the

molecular form will bind directly but very slowly with

Storage of Thyroglobulin. The thyroid gland is unusual

the amino acid tyrosine. In the thyroid cells, however,

among the endocrine glands in its ability to store large

the oxidized iodine is associated with an iodinase

amounts of hormone. After synthesis of the thyroid

enzyme (Figure 76-2) that causes the process to occur

hormones has run its course, each thyroglobulin mol-

within seconds or minutes. Therefore, almost as rapidly

ecule contains up to 30 thyroxine molecules and a few

as the thyroglobulin molecule is released from the

triiodothyronine molecules. In this form, the thyroid

Golgi apparatus or as it is secreted through the apical

hormones are stored in the follicles in an amount suf-

cell membrane into the follicle, iodine binds with

ficient to supply the body with its normal requirements

about one sixth of the tyrosine amino acids within the

of thyroid hormones for 2 to 3 months. Therefore,

thyroglobulin molecule.

when synthesis of thyroid hormone ceases, the physi-

Figure

76-3 shows the successive stages of

ologic effects of deficiency are not observed for several

iodination of tyrosine and final formation of the two

months.

important thyroid hormones, thyroxine and tri-

iodothyronine. Tyrosine is first iodized to monoiodoty-

rosine and then to diiodotyrosine. Then, during the

Release of Thyroxine and

next few minutes, hours, and even days, more and more

of the iodotyrosine residues become coupled with one

Triiodothyronine from the

another.

Thyroid Gland

The major hormonal product of the coupling reac-

tion is the molecule thyroxine that remains part of

Thyroglobulin itself is not released into the circulating

the thyroglobulin molecule. Or one molecule

blood in measurable amounts; instead, thyroxine and

triiodothyronine must first be cleaved from the thy-

roglobulin molecule, and then these free hormones are

released. This process occurs as follows: The apical

surface of the thyroid cells sends out pseudopod exten-

sions that close around small portions of the colloid to

Iodinase

form pinocytic vesicles that enter the apex of the

I₂ + HO

CH₂

CHNH₂

COOH

thyroid cell. Then lysosomes in the cell cytoplasm

immediately fuse with these vesicles to form digestive

Tyrosine

vesicles containing digestive enzymes from the lyso-

somes mixed with the colloid. Multiple proteases

among the enzymes digest the thyroglobulin mole-

CH₂

CHNH₂

COOH +

cules and release thyroxine and triiodothyronine in

free form. These then diffuse through the base of the

Monoiodotyrosine

thyroid cell into the surrounding capillaries. Thus, the

thyroid hormones are released into the blood.

CH₂

CHNH₂

COOH

About three quarters of the iodinated tyrosine in

the thyroglobulin never becomes thyroid hormones

but remains monoiodotyrosine and diiodotyrosine.

Diiodotyrosine

During the digestion of the thyroglobulin molecule to

Monoiodotyrosine + Diiodotyrosine

cause release of thyroxine and triiodothyronine, these

iodinated tyrosines also are freed from the thyroglob-

ulin molecules. However, they are not secreted into the

CH₂

CHNH₂

COOH

blood. Instead, their iodine is cleaved from them by a

deiodinase enzyme that makes virtually all this iodine

available again for recycling within the gland for

3,5,3'-Triiodothyronine

forming additional thyroid hormones. In the congeni-

Diiodotyrosine + Diiodotyrosine

tal absence of this deiodinase enzyme, many persons

become iodine-deficient because of failure of this recy-

cling process.

CH₂

CHNH₂

COOH

Daily Rate of Secretion of Thyroxine and Triiodothyronine.

Thyroxine

About 93 per cent of the thyroid hormone released

from the thyroid gland is normally thyroxine and only

7 per cent is triiodothyronine. However, during the

ensuing few days, about one half of the thyroxine is

Figure 76-3

slowly deiodinated to form additional triiodothyro-

Chemistry of thyroxine and triiodothyronine formation.

nine. Therefore, the hormone finally delivered to and

934

Unit XIV Endocrinology and Reproduction

used by the tissues is mainly triiodothyronine, a total

period as short as 6 to 12 hours and maximal cellular

of about 35 micrograms of triiodothyronine per day.

activity occurring within 2 to 3 days.

Most of the latency and prolonged period of action

of these hormones are probably caused by their

Transport of Thyroxine and

binding with proteins both in the plasma and in the

Triiodothyronine to Tissues

tissue cells, followed by their slow release. However,

we shall see in subsequent discussions that part of the

Thyroxine and Triiodothyronine Are Bound to Plasma Proteins.

latent period also results from the manner in which

On entering the blood, over 99 per cent of the thy-

these hormones perform their functions in the cells

roxine and triiodothyronine combines immediately

themselves.

with several of the plasma proteins, all of which are

synthesized by the liver. They combine mainly with

thyroxine-binding globulin and much less so with

Physiologic Functions of the

thyroxine-binding prealbumin and albumin.

Thyroid Hormones

Thyroxine and Triiodothyronine Are Released Slowly to Tissue

Thyroid Hormones Increase the

Cells. Because of high affinity of the plasma-binding

Transcription of Large Numbers

proteins for the thyroid hormones, these substances—

of Genes

in particular, thyroxine—are released to the tissue

cells slowly. Half the thyroxine in the blood is released

The general effect of thyroid hormone is to activate

to the tissue cells about every 6 days, whereas half the

nuclear transcription of large numbers of genes

triiodothyronine—because of its lower affinity—is

(Figure 76-5). Therefore, in virtually all cells of the

released to the cells in about 1 day.

body, great numbers of protein enzymes, structural

On entering the tissue cells, both thyroxine and tri-

proteins, transport proteins, and other substances are

iodothyronine again bind with intracellular proteins,

synthesized. The net result is generalized increase in

the thyroxine binding more strongly than the tri-

functional activity throughout the body.

iodothyronine. Therefore, they are again stored, but

this time in the target cells themselves, and they are

Most of the Thyroxine Secreted by the Thyroid Is Converted to

used slowly over a period of days or weeks.

Triiodothyronine. Before acting on the genes to increase

genetic transcription, one iodide is removed from

Thyroid Hormones Have Slow Onset and Long Duration of Action.

almost all the thyroxine, thus forming triiodothyro-

After injection of a large quantity of thyroxine into a

nine. Intracellular thyroid hormone receptors have a

human being, essentially no effect on the metabolic

very high affinity for triiodothyronine. Consequently,

rate can be discerned for 2 to 3 days, thereby demon-

more than 90 per cent of the thyroid hormone mole-

strating that there is a long latent period before thy-

cules that bind with the receptors is triiodothyronine.

roxine activity begins. Once activity does begin, it

increases progressively and reaches a maximum in 10

Thyroid Hormones Activate Nuclear Receptors. The thyroid

to 12 days, as shown in Figure 76-4. Thereafter, it

hormone receptors are either attached to the DNA

decreases with a half-life of about 15 days. Some of the

genetic strands or located in proximity to them.

activity persists for as long as 6 weeks to 2 months.

The thyroid hormone receptor usually forms a het-

The actions of triiodothyronine occur about four

erodimer with retinoid X receptor (RXR) at specific

times as rapidly as those of thyroxine, with a latent

thyroid hormone response elements on the DNA. On

binding with thyroid hormone, the receptors become

activated and initiate the transcription process. Then

large numbers of different types of messenger RNA

+10

are formed, followed within another few minutes or

hours by RNA translation on the cytoplasmic ribo-

somes to form hundreds of new intracellular proteins.

However, not all the proteins are increased by similar

percentages—some only slightly, and others at least as

much as sixfold. It is believed that most, if not all, of

the actions of thyroid hormone result from the subse-

Thyroxine injected

quent enzymatic and other functions of these new

proteins.

Days

Thyroid Hormones Increase Cellular

Metabolic Activity

Figure 76-4

Approximate prolonged effect on the basal metabolic rate caused

The thyroid hormones increase the metabolic activi-

by administering a single large dose of thyroxine.

ties of almost all the tissues of the body. The basal

Chapter 76

Thyroid Metabolic Hormones

935

T₄

T₃

Cell membrane

Iodinase

Cytoplasm

T₃

Nuclear

Thyroid

Retinoid X

hormone

membrane

receptor

Gene

Thyroid

hormone

response

Nucleus

Gene

transcription

Figure 76-5

mRNA

Thyroid hormone activation of

target cells. Thyroxine

(T₄) and

triiodothyronine

(T₃)

readily

diffuse through the cell mem-

brane. Much of the T₄ is deiodi-

Synthesis of

nated to form T₃, which interacts

new proteins

with the thyroid hormone re-

ceptor, bound as a heterodimer

with a retinoid X receptor, of

Many other

CNS

the thyroid hormone response

Growth

Cardiovascular

Metabolism

systems

development

element of the gene. This causes

either increases or decreases in

Cardiac output

Mitochondria

transcription of genes that lead

Tissue blood flow

Na⁺-K⁺-ATPase

to formation of proteins, thus

Heart rate

O2 consumption

producing the thyroid hormone

Heart strength

Glucose absorption

response of the cell. The actions

Respiration

Gluconeogenesis

of thyroid hormone on cells

Glycogenolysis

of several different systems

Lipolysis

are shown. mRNA, messenger

Protein synthesis

ribonucleic acid.

BMR

metabolic rate can increase to 60 to 100 per cent above

formation of adenosine triphosphate (ATP) to ener-

normal when large quantities of the hormones are

gize cellular function. However, the increase in the

secreted. The rate of utilization of foods for energy is

number and activity of mitochondria could be the

greatly accelerated. Although the rate of protein syn-

result of increased activity of the cells as well as

thesis is increased, at the same time the rate of protein

the cause of the increase.

catabolism is also increased. The growth rate of young

people is greatly accelerated. The mental processes

Thyroid Hormones Increase Active Transport of Ions Through

are excited, and the activities of most of the other

Cell Membranes. One of the enzymes that increases its

endocrine glands are increased.

activity in response to thyroid hormone is Na⁺-K⁺-

ATPase. This in turn increases the rate of

Thyroid Hormones Increase the Number and Activity of Mito-

transport of both sodium and potassium ions through

chondria. When thyroxine or triiodothyronine is given

the cell membranes of some tissues. Because this

to an animal, the mitochondria in most cells of the

process uses energy and increases the amount of heat

animal’s body increase in size as well as number.

produced in the body, it has been suggested that this

Furthermore, the total membrane surface area of the

might be one of the mechanisms by which thyroid

mitochondria increases almost directly in proportion

hormone increases the body’s metabolic rate. In fact,

to the increased metabolic rate of the whole animal.

thyroid hormone also causes the cell membranes of

Therefore, one of the principal functions of thyroxine

most cells to become leaky to sodium ions, which

might be simply to increase the number and activity

further activates the sodium pump and further

of mitochondria, which in turn increases the rate of

increases heat production.

936

Unit XIV Endocrinology and Reproduction

Effect of Thyroid Hormone on Growth

hypothyroidism is often associated with severe ather-

osclerosis, discussed in Chapter 68.

Thyroid hormone has both general and specific effects

One of the mechanisms by which thyroid hormone

on growth. For instance, it has long been known that

decreases the plasma cholesterol concentration is to

thyroid hormone is essential for the metamorphic

increase significantly the rate of cholesterol secretion

change of the tadpole into the frog.

in the bile and consequent loss in the feces. A possible

In humans, the effect of thyroid hormone on growth

mechanism for the increased cholesterol secretion is

is manifest mainly in growing children. In those who

that thyroid hormone induces increased numbers of

are hypothyroid, the rate of growth is greatly retarded.

low-density lipoprotein receptors on the liver cells,

In those who are hyperthyroid, excessive skeletal

leading to rapid removal of low-density lipoproteins

growth often occurs, causing the child to become con-

from the plasma by the liver and subsequent secretion

siderably taller at an earlier age. However, the bones

of cholesterol in these lipoproteins by the liver cells.

also mature more rapidly and the epiphyses close

at an early age, so that the duration of growth and

Increased Requirement for Vitamins. Because thyroid

the eventual height of the adult may actually be

hormone increases the quantities of many bodily

shortened.

enzymes and because vitamins are essential parts of

An important effect of thyroid hormone is to

some of the enzymes or coenzymes, thyroid hormone

promote growth and development of the brain during

causes increased need for vitamins. Therefore, a rela-

fetal life and for the first few years of postnatal life.

tive vitamin deficiency can occur when excess thyroid

If the fetus does not secrete sufficient quantities of

hormone is secreted, unless at the same time increased

thyroid hormone, growth and maturation of the brain

quantities of vitamins are made available.

both before birth and afterward are greatly retarded,

and the brain remains smaller than normal. Without

Increased Basal Metabolic Rate. Because thyroid

specific thyroid therapy within days or weeks after

hormone increases metabolism in almost all cells of

birth, the child without a thyroid gland will remain

the body, excessive quantities of the hormone can

mentally deficient throughout life. This is discussed

occasionally increase the basal metabolic rate 60 to

more fully later in the chapter.

100 per cent above normal. Conversely, when no

thyroid hormone is produced, the basal metabolic

rate falls almost to one-half normal. Figure 76-6 shows

the approximate relation between the daily supply

Effects of Thyroid Hormone

of thyroid hormones and the basal metabolic rate.

on Specific Bodily Mechanisms

Extreme amounts of the hormones are required to

cause very high basal metabolic rates.

Stimulation of Carbohydrate Metabolism. Thyroid hormone

stimulates almost all aspects of carbohydrate meta-

Decreased Body Weight. Greatly increased thyroid

bolism, including rapid uptake of glucose by the

hormone almost always decreases the body weight,

cells, enhanced glycolysis, enhanced gluconeogenesis,

increased rate of absorption from the gastrointestinal

tract, and even increased insulin secretion with its

resultant secondary effects on carbohydrate metabo-

lism. All these effects probably result from the overall

+30

increase in cellular metabolic enzymes caused by

thyroid hormone.

+20

+10

Stimulation of Fat Metabolism. Essentially all aspects of

fat metabolism are also enhanced under the influence

of thyroid hormone. In particular, lipids are mobilized

rapidly from the fat tissue, which decreases the fat

-10

stores of the body to a greater extent than almost any

other tissue element. This also increases the free fatty

-20

acid concentration in the plasma and greatly acceler-

-30

ates the oxidation of free fatty acids by the cells.

-40

Effect on Plasma and Liver Fats. Increased thyroid

-45

hormone decreases the concentrations of cholesterol,

100

200

300

phospholipids, and triglycerides in the plasma, even

Thyroid hormones (mg/day)

though it increases the free fatty acids. Conversely,

decreased thyroid secretion greatly increases the

plasma concentrations of cholesterol, phospholipids,

Figure 76-6

and triglycerides and almost always causes excessive

deposition of fat in the liver as well. The large increase

Approximate relation of daily rate of thyroid hormone (T₄ and T₃)

in circulating plasma cholesterol in prolonged

secretion to the basal metabolic rate.

Chapter 76

Thyroid Metabolic Hormones

937

and greatly decreased hormone almost always

secretion of the digestive juices and the motility of the

increases the body weight; these effects do not always

gastrointestinal tract. Hyperthyroidism often results in

occur, because thyroid hormone also increases the

diarrhea. Lack of thyroid hormone can cause consti-

appetite, and this may counterbalance the change in

pation.

the metabolic rate.

Excitatory Effects on the Central Nervous System. In general,

Effect of Thyroid Hormones on the Cardiovascular System

thyroid hormone increases the rapidity of cerebration

Increased Blood Flow and Cardiac Output. Increased

but also often dissociates this; conversely, lack of

metabolism in the tissues causes more rapid utilization

thyroid hormone decreases this function. The hyper-

of oxygen than normal and release of greater than

thyroid individual is likely to have extreme nervous-

normal quantities of metabolic end products from the

ness and many psychoneurotic tendencies, such as

tissues. These effects cause vasodilation in most body

anxiety complexes, extreme worry, and paranoia.

tissues, thus increasing blood flow. The rate of blood

flow in the skin especially increases because of the

Effect on the Function of the Muscles. Slight increase in

increased need for heat elimination from the body. As

thyroid hormone usually makes the muscles react with

a consequence of the increased blood flow, cardiac

vigor, but when the quantity of hormone becomes

output also increases, sometimes rising to 60 per cent

excessive, the muscles become weakened because of

or more above normal when excessive thyroid

excess protein catabolism. Conversely, lack of thyroid

hormone is present and falling to only 50 per cent of

hormone causes the muscles to become sluggish, and

normal in very severe hypothyroidism.

they relax slowly after a contraction.

Increased Heart Rate. The heart rate increases con-

Muscle Tremor. One of the most characteristic signs of

siderably more under the influence of thyroid

hyperthyroidism is a fine muscle tremor. This is not the

hormone than would be expected from the increase in

coarse tremor that occurs in Parkinson’s disease or in

cardiac output. Therefore, thyroid hormone seems to

shivering, because it occurs at the rapid frequency of

have a direct effect on the excitability of the heart,

10 to 15 times per second. The tremor can be observed

which in turn increases the heart rate. This effect is of

easily by placing a sheet of paper on the extended

particular importance because the heart rate is one of

fingers and noting the degree of vibration of the paper.

the sensitive physical signs that the clinician uses in

This tremor is believed to be caused by increased reac-

determining whether a patient has excessive or dimin-

tivity of the neuronal synapses in the areas of the

ished thyroid hormone production.

spinal cord that control muscle tone. The tremor is an

important means for assessing the degree of thyroid

Increased Heart Strength. The increased enzymatic

hormone effect on the central nervous system.

activity caused by increased thyroid hormone produc-

tion apparently increases the strength of the heart

Effect on Sleep. Because of the exhausting effect of

when only a slight excess of thyroid hormone is

thyroid hormone on the musculature and on the

secreted. This is analogous to the increase in heart

central nervous system, the hyperthyroid subject often

strength that occurs in mild fevers and during exercise.

has a feeling of constant tiredness, but because of the

However, when thyroid hormone is increased

excitable effects of thyroid hormone on the synapses,

markedly, the heart muscle strength becomes

it is difficult to sleep. Conversely, extreme somnolence

depressed because of long-term excessive protein

is characteristic of hypothyroidism, with sleep some-

catabolism. Indeed, some severely thyrotoxic patients

times lasting 12 to 14 hours a day.

die of cardiac decompensation secondary to myocar-

dial failure and to increased cardiac load imposed by

Effect on Other Endocrine Glands. Increased thyroid

the increase in cardiac output.

hormone increases the rates of secretion of most other

endocrine glands, but it also increases the need of the

Normal Arterial Pressure. The mean arterial pressure

tissues for the hormones. For instance, increased thy-

usually remains about normal after administration of

roxine secretion increases the rate of glucose metabo-

thyroid hormone. Because of increased blood flow

lism everywhere in the body and therefore causes a

through the tissues between heartbeats, the pulse pres-

corresponding need for increased insulin secretion by

sure is often increased, with the systolic pressure ele-

the pancreas. Also, thyroid hormone increases many

vated in hyperthyroidism 10 to 15 mm Hg and the

metabolic activities related to bone formation and, as

diastolic pressure reduced a corresponding amount.

a consequence, increases the need for parathyroid

hormone. Thyroid hormone also increases the rate at

Increased Respiration. The increased rate of metabolism

which adrenal glucocorticoids are inactivated by the

increases the utilization of oxygen and formation of

liver. This leads to feedback increase in adrenocorti-

carbon dioxide; these effects activate all the mecha-

cotropic hormone production by the anterior pituitary

nisms that increase the rate and depth of respiration.

and, therefore, increased rate of glucocorticoid secre-

tion by the adrenal glands.

Increased Gastrointestinal Motility. In addition to

increased appetite and food intake, which has been

Effect of Thyroid Hormone on Sexual Function. For normal

discussed, thyroid hormone increases both the rates of

sexual function, thyroid secretion needs to be

938

Unit XIV Endocrinology and Reproduction

approximately normal. In men, lack of thyroid

The most important early effect after administration

hormone is likely to cause loss of libido; great excesses

of TSH is to initiate proteolysis of the thyroglobulin,

of the hormone, however, sometimes cause impotence.

which causes release of thyroxine and triiodothyro-

In women, lack of thyroid hormone often causes

nine into the blood within 30 minutes. The other

menorrhagia and polymenorrhea— that is, respec-

effects require hours or even days and weeks to

tively, excessive and frequent menstrual bleeding.

develop fully.

Yet, strangely enough, in other women thyroid lack

may cause irregular periods and occasionally even

Cyclic Adenosine Monophosphate Mediates the Stimulatory

amenorrhea.

Effect of TSH. In the past, it was difficult to explain the

A hypothyroid woman, like a man, is likely to have

many and varied effects of TSH on the thyroid cell. It

greatly decreased libido. To make the picture still more

is now clear that most, if not all, of these effects result

confusing, in the hyperthyroid woman, oligomenor-

from activation of the

“second messenger” cyclic

rhea, which means greatly reduced bleeding, is

adenosine monophosphate (cAMP) system of the cell.

common, and occasionally amenorrhea results.

The first event in this activation is binding of TSH

The action of thyroid hormone on the gonads

with specific TSH receptors on the basal membrane

cannot be pinpointed to a specific function but prob-

surfaces of the thyroid cell. This then activates adeny-

ably results from a combination of direct metabolic

lyl cyclase in the membrane, which increases the for-

effects on the gonads as well as excitatory and

mation of cAMP inside the cell. Finally, the cAMP acts

inhibitory feedback effects operating through the

as a second messenger to activate protein kinase, which

anterior pituitary hormones that control the sexual

causes multiple phosphorylations throughout the cell.

functions.

The result is both an immediate increase in secretion

of thyroid hormones and prolonged growth of the

thyroid glandular tissue itself.

Regulation of Thyroid

This method for control of thyroid cell activity is

similar to the function of cAMP as a “second messen-

Hormone Secretion

ger” in many other target tissues of the body, as

discussed in Chapter 74.

To maintain normal levels of metabolic activity in the

body, precisely the right amount of thyroid hormone

must be secreted at all times; to achieve this, specific

feedback mechanisms operate through the hypothala-

Anterior Pituitary Secretion of TSH Is

mus and anterior pituitary gland to control the rate of

Regulated by Thyrotropin-Releasing

thyroid secretion. These mechanisms are as follows.

Hormone from the Hypothalamus

TSH (from the Anterior Pituitary Gland) Increases Thyroid Secre-

Anterior pituitary secretion of TSH is controlled

tion. TSH, also known as thyrotropin, is an anterior

by a hypothalamic hormone, thyrotropin-releasing

pituitary hormone, a glycoprotein with a molecular

hormone (TRH), which is secreted by nerve endings

weight of about 28,000. This hormone, also discussed

in the median eminence of the hypothalamus. From

in Chapter 74, increases the secretion of thyroxine and

the median eminence, the TRH is then transported to

triiodothyronine by the thyroid gland. Its specific

the anterior pituitary by way of the hypothalamic-

effects on the thyroid gland are as follows:

hypophysial portal blood, as explained in Chapter 74.

1. Increased proteolysis of the thyroglobulin that

TRH has been obtained in pure form. It is a simple

has already been stored in the follicles, with

substance, a tripeptide amide—pyroglutamyl-histidyl-

resultant release of the thyroid hormones into

proline-amide. TRH directly affects the anterior pitu-

the circulating blood and diminishment of the

itary gland cells to increase their output of TSH. When

follicular substance itself

the blood portal system from the hypothalamus to the

2. Increased activity of the iodide pump, which

anterior pituitary gland becomes blocked, the rate of

increases the rate of “iodide trapping” in the

secretion of TSH by the anterior pituitary decreases

glandular cells, sometimes increasing the ratio of

greatly but is not reduced to zero.

intracellular to extracellular iodide concentration

The molecular mechanism by which TRH causes

in the glandular substance to as much as eight

the TSH-secreting cells of the anterior pituitary to

times normal

produce TSH is first to bind with TRH receptors in the

3. Increased iodination of tyrosine to form the

pituitary cell membrane. This in turn activates the phos-

thyroid hormones

pholipase second messenger system inside the pituitary

4. Increased size and increased secretory activity of

cells to produce large amounts of phospholipase C, fol-

the thyroid cells

lowed by a cascade of other second messengers,

5. Increased number of thyroid cells plus a change

including calcium ions and diacyl glycerol, which even-

from cuboidal to columnar cells and much

tually leads to TSH release.

infolding of the thyroid epithelium into the

follicles

Effects of Cold and Other Neurogenic Stimuli on TRH and TSH

In summary, TSH increases all the known secretory

Secretion. One of the best-known stimuli for increas-

activities of the thyroid glandular cells.

ing the rate of TRH secretion by the hypothalamus,

Chapter 76

Thyroid Metabolic Hormones

939

and therefore TSH secretion by the anterior pituitary

anterior pituitary gland itself. Regardless of the mech-

gland, is exposure of an animal to cold. This effect

anism of the feedback, its effect is to maintain an

almost certainly results from excitation of the hypo-

almost constant concentration of free thyroid hor-

thalamic centers for body temperature control.

mones in the circulating body fluids.

Exposure of rats for several weeks to severe cold

increases the output of thyroid hormones sometimes

Antithyroid Substances

to more than 100 per cent of normal and can increase

the basal metabolic rate as much as 50 per cent.

Drugs that suppress thyroid secretion are called antithy-

Indeed, persons moving to arctic regions have been

roid substances. The best known of these substances are

known to develop basal metabolic rates 15 to 20 per

thiocyanate, propylthiouracil, and high concentrations

cent above normal.

of inorganic iodides. The mechanism by which each of

Various emotional reactions can also affect the

these blocks thyroid secretion is different from the

output of TRH and TSH and therefore indirectly

others, and they can be explained as follows.

affect the secretion of thyroid hormones. Excitement

Thiocyanate Ions Decrease Iodide Trapping. The same active

and anxiety—conditions that greatly stimulate the

pump that transports iodide ions into the thyroid cells

sympathetic nervous system—cause an acute decrease

can also pump thiocyanate ions, perchlorate ions, and

in secretion of TSH, perhaps because these states

nitrate ions. Therefore, the administration of thio-

increase the metabolic rate and body heat and there-

cyanate (or one of the other ions as well) in high enough

fore exert an inverse effect on the heat control center.

concentration can cause competitive inhibition of

Neither these emotional effects nor the effect of

iodide transport into the cell— that is, inhibition of the

cold is observed after the hypophysial stalk has been

iodide-trapping mechanism.

cut, demonstrating that both of these effects are medi-

The decreased availability of iodide in the glandular

ated by way of the hypothalamus.

cells does not stop the formation of thyroglobulin; it

merely prevents the thyroglobulin that is formed from

becoming iodinated and therefore from forming the

thyroid hormones. This deficiency of the thyroid hor-

Feedback Effect of Thyroid Hormone

mones in turn leads to increased secretion of TSH by

to Decrease Anterior Pituitary

the anterior pituitary gland, which causes overgrowth of

Secretion of TSH

the thyroid gland even though the gland still does not

form adequate quantities of thyroid hormones. There-

Increased thyroid hormone in the body fluids

fore, the use of thiocyanates and some other ions to

block thyroid secretion can lead to development of a

decreases secretion of TSH by the anterior pituitary.

greatly enlarged thyroid gland, which is called a goiter.

When the rate of thyroid hormone secretion rises to

about 1.75 times normal, the rate of TSH secretion

Propylthiouracil Decreases Thyroid Hormone Formation. Propy-

falls essentially to zero. Almost all this feedback

lthiouracil

(and other, similar compounds, such as

depressant effect occurs even when the anterior pitu-

methimazole and carbimazole) prevents formation of

itary has been separated from the hypothalamus.

thyroid hormone from iodides and tyrosine. The mech-

Therefore, as shown in Figure 76-7, it is probable that

anism of this is partly to block the peroxidase enzyme

increased thyroid hormone inhibits anterior pituitary

that is required for iodination of tyrosine and partly to

secretion of TSH mainly by a direct effect on the

block the coupling of two iodinated tyrosines to form

thyroxine or triiodothyronine.

Propylthiouracil, like thiocyanate, does not prevent

formation of thyroglobulin. The absence of thyroxine

and triiodothyronine in the thyroglobulin can lead to

Hypothalamus

tremendous feedback enhancement of TSH secretion

(? increased temperature)

by the anterior pituitary gland, thus promoting growth

(Thyrotropin-releasing hormone)

of the glandular tissue and forming a goiter.

Anterior pituitary

Iodides in High Concentrations Decrease Thyroid Activity and

Thyroid Gland Size. When iodides are present in the blood

Thyroid-

stimulating

in high concentration (100 times the normal plasma

hormone

level), most activities of the thyroid gland are decreased,

Inhibits

but often they remain decreased for only a few weeks.

The effect is to reduce the rate of iodide trapping, so

Cells

that the rate of iodination of tyrosine to form thyroid

hormones is also decreased. Even more important, the

Hypertrophy

normal endocytosis of colloid from the follicles by the

Increased

Thyroxine

thyroid glandular cells is paralyzed by the high iodide

metabolism

secretion

concentrations. Because this is the first step in release

of the thyroid hormones from the storage colloid, there

Thyroid

Iodine

is almost immediate shutdown of thyroid hormone

secretion into the blood.

Because iodides in high concentrations decrease all

Figure 76-7

phases of thyroid activity, they slightly decrease the size

Regulation of thyroid secretion.

of the thyroid gland and especially decrease its blood

940

Unit XIV Endocrinology and Reproduction

supply, in contradistinction to the opposite effects

Symptoms of Hyperthyroidism

caused by most of the other antithyroid agents. For this

reason, iodides are frequently administered to patients

The symptoms of hyperthyroidism are obvious from the

for 2 to 3 weeks before surgical removal of the thyroid

preceding discussion of the physiology of the thyroid

gland to decrease the necessary amount of surgery,

hormones: (1) a high state of excitability, (2) intolerance

especially to decrease the amount of bleeding.

to heat, (3) increased sweating, (4) mild to extreme

weight loss (sometimes as much as 100 pounds), (5)

varying degrees of diarrhea, (6) muscle weakness, (7)

nervousness or other psychic disorders, (8) extreme

Diseases of the Thyroid

fatigue but inability to sleep, and (9) tremor of the

hands.

Hyperthyroidism

Exophthalmos. Most people with hyperthyroidism

Most effects of hyperthyroidism are obvious from the

develop some degree of protrusion of the eyeballs, as

preceding discussion of the various physiologic effects

shown in Figure 76-8. This condition is called exoph-

of thyroid hormone. However, some specific effects

thalmos. A major degree of exophthalmos occurs in

should be mentioned in connection especially with the

about one third of hyperthyroid patients, and the con-

development, diagnosis, and treatment of hyperthy-

dition sometimes becomes so severe that the eyeball

roidism.

protrusion stretches the optic nerve enough to damage

vision. Much more often, the eyes are damaged because

Causes of Hyperthyroidism (Toxic Goiter, Thyrotoxicosis, Graves’

the eyelids do not close completely when the person

Disease). In most patients with hyperthyroidism, the

blinks or is asleep. As a result, the epithelial surfaces of

thyroid gland is increased to two to three times

the eyes become dry and irritated and often infected,

normal size, with tremendous hyperplasia and infolding

resulting in ulceration of the cornea.

of the follicular cell lining into the follicles, so that the

The cause of the protruding eyes is edematous

number of cells is increased greatly. Also, each cell

swelling of the retro-orbital tissues and degenerative

increases its rate of secretion severalfold; radioactive

changes in the extraocular muscles. In most patients,

iodine uptake studies indicate that some of these hyper-

immunoglobulins can be found in the blood that react

plastic glands secrete thyroid hormone at rates 5 to 15

with the eye muscles. Furthermore, the concentration of

times normal.

these immunoglobulins is usually highest in patients

The changes in the thyroid gland in most instances

who have high concentrations of TSIs. Therefore, there

are similar to those caused by excessive TSH. However,

is much reason to believe that exophthalmos, like hyper-

plasma TSH concentrations are less than normal

thyroidism itself, is an autoimmune process. The exoph-

rather than enhanced in almost all patients and often

thalmos usually is greatly ameliorated with treatment of

are essentially zero. However, other substances that

the hyperthyroidism.

have actions similar to those of TSH are found in

the blood of almost all these patients. These substances

are immunoglobulin antibodies that bind with the

same membrane receptors that bind TSH. They induce

continual activation of the cAMP system of the cells,

with resultant development of hyperthyroidism. These

antibodies are called thyroid-stimulating immunoglobu-

lin and are designated TSI. They have a prolonged

stimulating effect on the thyroid gland, lasting for as

long as 12 hours, in contrast to a little over 1 hour for

TSH. The high level of thyroid hormone secretion

caused by TSI in turn suppresses anterior pituitary for-

mation of TSH.

The antibodies that cause hyperthyroidism almost

certainly occur as the result of autoimmunity that has

developed against thyroid tissue. Presumably, at some

time in the history of the person, an excess of thyroid

cell antigens was released from the thyroid cells, and this

has resulted in the formation of antibodies against the

thyroid gland itself.

Thyroid Adenoma. Hyperthyroidism occasionally results

from a localized adenoma (a tumor) that develops in the

thyroid tissue and secretes large quantities of thyroid

hormone. This is different from the more usual type of

hyperthyroidism, in that it usually is not associated with

evidence of any autoimmune disease. An interesting

effect of the adenoma is that as long as it continues to

secrete large quantities of thyroid hormone, secretory

Figure 76-8

function in the remainder of the thyroid gland is almost

totally inhibited because the thyroid hormone from the

Patient with exophthalmic hyperthyroidism. Note protrusion of the

adenoma depresses the production of TSH by the pitu-

eyes and retraction of the superior eyelids. The basal metabolic

itary gland.

rate was +40. (Courtesy Dr. Leonard Posey.)

Chapter 76

Thyroid Metabolic Hormones

941

Diagnostic Tests for Hyperthyroidism. For the usual case of

for the formation of adequate quantities of thyroid

hyperthyroidism, the most accurate diagnostic test is

hormone. In certain areas of the world, notably in the

direct measurement of the concentration of “free” thy-

Swiss Alps, the Andes, and the Great Lakes region of

roxine (and sometimes triiodothyronine) in the plasma,

the United States, insufficient iodine is present in the

using appropriate radioimmunoassay procedures.

soil for the foodstuffs to contain even this minute quan-

Other tests that are sometimes used are as follows:

tity. Therefore, in the days before iodized table salt,

1. The basal metabolic rate is usually increased to +30

many people who lived in these areas developed

to +60 in severe hyperthyroidism.

extremely large thyroid glands, called endemic goiters.

2. The concentration of TSH in the plasma is

The mechanism for development of large endemic

measured by radioimmunoassay. In the usual

goiters is the following: Lack of iodine prevents pro-

type of thyrotoxicosis, anterior pituitary secretion

duction of both thyroxine and triiodothyronine. As a

of TSH is so completely suppressed by the

result, no hormone is available to inhibit production of

large amounts of circulating thyroxine and

TSH by the anterior pituitary; this causes the pituitary

triiodothyronine that there is almost no plasma

to secrete excessively large quantities of TSH. The TSH

TSH.

then stimulates the thyroid cells to secrete tremendous

3. The concentration of TSI is measured by

amounts of thyroglobulin colloid into the follicles, and

radioimmunoassay. This is usually high in

the gland grows larger and larger. But because of lack

thyrotoxicosis but low in thyroid adenoma.

of iodine, thyroxine and triiodothyronine production

does not occur in the thyroglobulin molecule and there-

Physiology of Treatment in Hyperthyroidism. The most direct

fore does not cause the normal suppression of TSH pro-

treatment for hyperthyroidism is surgical removal of

duction by the anterior pituitary. The follicles become

most of the thyroid gland. In general, it is desirable to

tremendous in size, and the thyroid gland may increase

prepare the patient for surgical removal of the gland

to 10 to 20 times normal size.

before the operation. This is done by administering

propylthiouracil, usually for several weeks, until the

Idiopathic Nontoxic Colloid Goiter. Enlarged thyroid glands

basal metabolic rate of the patient has returned to

similar to those of endemic colloid goiter can also occur

normal. Then, administration of high concentrations of

in people who do not have iodine deficiency. These

iodides for 1 to 2 weeks immediately before operation

goitrous glands may secrete normal quantities of

causes the gland itself to recede in size and its blood

thyroid hormones, but more frequently, the secretion of

supply to diminish. By using these preoperative proce-

hormone is depressed, as in endemic colloid goiter.

dures, the operative mortality is less than 1 in 1000 in

The exact cause of the enlarged thyroid gland in

the better hospitals, whereas before development of

patients with idiopathic colloid goiter is not known, but

modern procedures, operative mortality was 1 in 25.

most of these patients show signs of mild thyroiditis;

therefore, it has been suggested that the thyroiditis

causes slight hypothyroidism, which then leads to

Treatment of the Hyperplastic Thyroid Gland with

increased TSH secretion and progressive growth of the

Radioactive Iodine

noninflamed portions of the gland. This could explain

Eighty to 90 per cent of an injected dose of iodide is

why these glands usually are nodular, with some por-

absorbed by the hyperplastic, toxic thyroid gland within

tions of the gland growing while other portions are

1 day after injection. If this injected iodine is radio-

being destroyed by thyroiditis.

active, it can destroy most of the secretory cells of the

In some persons with colloid goiter, the thyroid gland

thyroid gland. Usually 5 millicuries of radioactive iodine

has an abnormality of the enzyme system required for

is given to the patient, whose condition is reassessed

formation of the thyroid hormones. Among the abnor-

several weeks later. If the patient is still hyperthyroid,

malities often encountered are the following:

additional doses are administered until normal thyroid

1. Deficient iodide-trapping mechanism, in which

status is reached.

iodine is not pumped adequately into the thyroid

cells

Hypothyroidism

2. Deficient peroxidase system, in which the iodides

are not oxidized to the iodine state

The effects of hypothyroidism, in general, are opposite

3. Deficient coupling of iodinated tyrosines in the

to those of hyperthyroidism, but there are a few

thyroglobulin molecule, so that the final thyroid

physiologic mechanisms peculiar to hypothyroidism.

hormones cannot be formed

Hypothyroidism, like hyperthyroidism, probably is ini-

4. Deficiency of the deiodinase enzyme, which

tiated by autoimmunity against the thyroid gland, but

prevents recovery of iodine from the iodinated

immunity that destroys the gland rather than stimulates

tyrosines that are not coupled to form the thyroid

it. The thyroid glands of most of these patients first have

hormones (this is about two thirds of the iodine),

autoimmune “thyroiditis,” which means thyroid inflam-

thus leading to iodine deficiency

mation. This causes progressive deterioration and finally

Finally, some foods contain goitrogenic substances

fibrosis of the gland, with resultant diminished or absent

that have a propylthiouracil-type of antithyroid activity,

secretion of thyroid hormone. Several other types of

thus also leading to TSH-stimulated enlargement of the

hypothyroidism also occur, often associated with devel-

thyroid gland. Such goitrogenic substances are found

opment of enlarged thyroid glands, called thyroid goiter,

especially in some varieties of turnips and cabbages.

as follows.

Physiologic Characteristics of Hypothyroidism. Whether

Endemic Colloid Goiter Caused by Dietary Iodide Deficiency. The

hypothyroidism is due to thyroiditis, endemic colloid

term “goiter” means a greatly enlarged thyroid gland.

goiter, idiopathic colloid goiter, destruction of the

As pointed out in the discussion of iodine metabolism,

thyroid gland by irradiation, or surgical removal of the

about 50 milligrams of iodine are required each year

thyroid gland, the physiologic effects are the same. They

942

Unit XIV Endocrinology and Reproduction

include fatigue and extreme somnolence with sleeping

is usually associated with increased atherosclerosis.

up to 12 to 14 hours a day, extreme muscular sluggish-

Therefore, many hypothyroid patients, particularly

ness, slowed heart rate, decreased cardiac output,

those with myxedema, develop atherosclerosis, which

decreased blood volume, sometimes increased body

in turn results in peripheral vascular disease, deafness,

weight, constipation, mental sluggishness, failure of

and coronary artery disease with consequent early

many trophic functions in the body evidenced by

death.

depressed growth of hair and scaliness of the skin,

development of a froglike husky voice, and, in severe

Diagnostic Tests in Hypothyroidism. The tests already

cases, development of an edematous appearance

described for diagnosis of hyperthyroidism give oppo-

throughout the body called myxedema.

site results in hypothyroidism. The free thyroxine in

the blood is low. The basal metabolic rate in myxedema

Myxedema. Myxedema develops in the patient with

ranges between -30 and -50. And the secretion of

almost total lack of thyroid hormone function. Figure

TSH by the anterior pituitary when a test dose of

76-9 shows such a patient, demonstrating bagginess

TRH is administered is usually greatly increased

under the eyes and swelling of the face. In this

(except in those rare instances of hypothyroidism

condition, for reasons not explained, greatly increased

caused by depressed response of the pituitary gland to

quantities of hyaluronic acid and chondroitin sulfate

TRH).

bound with protein form excessive tissue gel in the

interstitial spaces, and this causes the total quantity of

Treatment of Hypothyroidism. Figure 76-4 shows the effect

interstitial fluid to increase. Because of the gel nature of

of thyroxine on the basal metabolic rate, demonstrating

the excess fluid, it is mainly immobile, and the edema is

that the hormone normally has a duration of action of

the nonpitting type.

more than 1 month. Consequently, it is easy to maintain

a steady level of thyroid hormone activity in the body

Atherosclerosis in Hypothyroidism. As pointed out earlier,

by daily oral ingestion of a tablet or more containing

lack of thyroid hormone increases the quantity of blood

thyroxine. Furthermore, proper treatment of the

cholesterol because of altered fat and cholesterol

hypothyroid patient results in such complete normality

metabolism and diminished liver excretion of

that formerly myxedematous patients have lived into

cholesterol in the bile. The increase in blood cholesterol

their 90s after treatment for more than 50 years.

Cretinism

Cretinism is caused by extreme hypothyroidism during

fetal life, infancy, or childhood. This condition is char-

acterized especially by failure of body growth and by

mental retardation. It results from congenital lack of a

thyroid gland (congenital cretinism), from failure of the

thyroid gland to produce thyroid hormone because of a

genetic defect of the gland, or from iodine lack in the

diet (endemic cretinism). The severity of endemic cre-

tinism varies greatly, depending on the amount of iodine

in the diet, and whole populaces of an endemic geo-

graphic iodine-deficient soil area have been known to

have cretinoid tendencies.

A neonate without a thyroid gland may have normal

appearance and function because it was supplied with

some (but usually not enough) thyroid hormone by the

mother while in utero, but a few weeks after birth, the

neonate’s movements become sluggish and both physi-

cal and mental growth begin to be greatly retarded.

Treatment of the neonate with cretinism at any time

with adequate iodine or thyroxine usually causes

normal return of physical growth, but unless the cre-

tinism is treated within a few weeks after birth, mental

growth remains permanently retarded. This results from

retardation of the growth, branching, and myelination

of the neuronal cells of the central nervous system at

this critical time in the normal development of the

mental powers.

Skeletal growth in the child with cretinism is charac-

teristically more inhibited than is soft tissue growth. As

a result of this disproportionate rate of growth, the soft

tissues are likely to enlarge excessively, giving the child

with cretinism an obese, stocky, and short appearance.

Occasionally the tongue becomes so large in relation to

the skeletal growth that it obstructs swallowing and

Figure 76-9

breathing, inducing a characteristic guttural breathing

Patient with myxedema. (Courtesy Dr. Herbert Langford.)

that sometimes chokes the child.

Chapter 76

Thyroid Metabolic Hormones

943

References

Roberts CG, Ladenson PW: Hypothyroidism. Lancet 363:

793, 2004.

Silva JE: The thermogenic effect of thyroid hormone and its

Besser GM, Thorner MO: Comprehensive Clinical

clinical implications. Ann Intern Med 139:205, 2003.

Endocrinology,

3rd ed. Philadelphia: Mosby, Elsevier

Stassi G, De Maria R: Autoimmune thyroid disease: new

Science, 2002.

models of cell death in autoimmunity. Nat Rev Immunol

Burger AG: Environment and thyroid function. J Clin

2:195, 2002.

Endocrinol Metab 89:1526, 2004.

Szkudlinski MW, Fremont V, Ronin C, Weintraub BD:

Cooper DS: Hyperthyroidism. Lancet 362:459, 2003.

Thyroid-stimulating hormone and thyroid-stimulating

De La Vieja A, Dohan O, et al: Molecular analysis of the

hormone receptor structure-function relationships.

sodium/iodide symporter: impact on thyroid and extrathy-

Physiol Rev 82:473, 2002.

roid pathophysiology. Physiol Rev 80:1083, 2000.

Tomer Y, Davies TF: Searching for the autoimmune thyroid

Dayan CM: Interpretation of thyroid function tests. Lancet

disease susceptibility genes: from gene mapping to gene

357:619, 2001.

function. Endocr Rev 24:694, 2003

Dohan O, De La Vieja A, Paroder V, et al: The sodium/iodide

Vaidya B, Kendall-Taylor P, Pearce SH: The genetics of

Symporter

(NIS): characterization, regulation, and

autoimmune thyroid disease. J Clin Endocrinol Metab

medical significance. Endocr Rev 24:48, 2003.

87:5385, 2002.

Larsen PR, Kronenberg HM, Melmed S, Polonsky KS:

Vasudevan N, Ogawa S, Pfaff D: Estrogen and thyroid

Williams Textbook of Endocrinology, 10th ed. Philadel-

hormone receptor interactions: physiological flexibility by

phia: WB Saunders Co, 2003.

molecular specificity. Physiol Rev 82:923, 2002.

Marino M, McCluskey RT: Role of thyroglobulin endocytic

Yen PM: Physiological and molecular basis of thyroid

pathways in the control of thyroid hormone release. Am J

hormone action. Physiol Rev 81:1097, 2001.

Physiol Cell Physiol 279:C1295, 2000

Zhang J, Lazar MA: The mechanism of action of thyroid hor-

O’Reilly DS: Thyroid function tests—time for a reassess-

mones. Annu Rev Physio 62:439, 2000.

ment. BMJ 320:1332, 2000.

Pearce EN, Farwell AP, Braverman LE: Thyroiditis. N Engl

J Med 348:2646, 2003.

C H A P T E R

Adrenocortical Hormones

The two adrenal glands, each of which weighs about

4 grams, lie at the superior poles of the two kidneys.

As shown in Figure 77-1, each gland is composed of

two distinct parts, the adrenal medulla and the

adrenal cortex. The adrenal medulla, the central 20

per cent of the gland, is functionally related to the

sympathetic nervous system; it secretes the hor-

mones epinephrine and norepinephrine in response

to sympathetic stimulation. In turn, these hormones cause almost the same

effects as direct stimulation of the sympathetic nerves in all parts of the body.

These hormones and their effects are discussed in detail in Chapter 60 in rela-

tion to the sympathetic nervous system.

The adrenal cortex secretes an entirely different group of hormones, called

corticosteroids. These hormones are all synthesized from the steroid cholesterol,

and they all have similar chemical formulas. However, slight differences in their

molecular structures give them several different but very important functions.

Corticosteroids Mineralocorticoids, Glucocorticoids, and Androgens. Two major types of

adrenocortical hormones, the mineralocorticoids and the glucocorticoids, are

secreted by the adrenal cortex. In addition to these, small amounts of sex hor-

mones are secreted, especially androgenic hormones, which exhibit about the

same effects in the body as the male sex hormone testosterone. They are nor-

mally of only slight importance, although in certain abnormalities of the adrenal

cortices, extreme quantities can be secreted (which is discussed later in the

chapter) and can result in masculinizing effects.

The mineralocorticoids have gained this name because they especially affect

the electrolytes (the “minerals”) of the extracellular fluids-sodium and potas-

sium, in particular. The glucocorticoids have gained their name because they

exhibit important effects that increase blood glucose concentration. They have

additional effects on both protein and fat metabolism that are equally as impor-

tant to body function as their effects on carbohydrate metabolism.

More than 30 steroids have been isolated from the adrenal cortex, but two

are of exceptional importance to the normal endocrine function of the human

body: aldosterone, which is the principal mineralocorticoid, and cortisol, which

is the principal glucocorticoid.

Synthesis and Secretion of

Adrenocortical Hormones

The Adrenal Cortex Has Three Distinct Layers. Figure 77-1 shows that the adrenal

cortex is composed of three relatively distinct layers:

1. The zona glomerulosa, a thin layer of cells that lies just underneath the

capsule, constitutes about 15 per cent of the adrenal cortex. These cells are

the only ones in the adrenal gland capable of secreting significant amounts

of aldosterone because they contain the enzyme aldosterone synthase,

which is necessary for synthesis of aldosterone. The secretion of these cells

is controlled mainly by the extracellular fluid concentrations of angiotensin

II and potassium, both of which stimulate aldosterone secretion.

2. The zona fasciculata, the middle and widest layer, constitutes about 75 per

cent of the adrenal cortex and secretes the glucocorticoids cortisol and

944

Chapter 77

Adrenocortical Hormones

945

(LDL) in the circulating plasma. The LDLs, which have

high concentrations of cholesterol, diffuse from the

plasma into the interstitial fluid and attach to specific

Zona glomerulosa

receptors contained in structures called coated pits on

aldosterone

the adrenocortical cell membranes. The coated pits are

then internalized by endocytosis, forming vesicles that

Zona fasciculata

eventually fuse with cell lysosomes and release choles-

Cortisol

terol that can be used to synthesize adrenal steroid

and

hormones.

androgens

Transport of cholesterol into the adrenal cells is reg-

Zona reticularis

ulated by feedback mechanisms that can markedly alter

the amount available for steroid synthesis. For example,

Medulla

(catecholamines)

Cortex

ACTH, which stimulates adrenal steroid synthesis,

increases the number of adrenocortical cell receptors

for LDL, as well as the activity of enzymes that liberate

cholesterol from LDL.

Once the cholesterol enters the cell, it is delivered to

the mitochondria, where it is cleaved by the enzyme

cholesterol desmolase to form pregnenolone; this is the

rate-limiting step in the eventual formation of adrenal

steroids (Figure 77-2). In all three zones of the adrenal

Magnified section

cortex, this initial step in steroid synthesis is stimulated

by the different factors that control secretion of the

major hormone products aldosterone and cortisol. For

example, both ACTH, which stimulates cortisol secre-

Figure 77-1

tion, and angiotensin II, which stimulates aldosterone

Secretion of adrenocortical hormones by the different zones of the

secretion, increase the conversion of cholesterol to

adrenal cortex and secretion of catecholamines by the adrenal

pregnenolone.

medulla.

Synthetic Pathways for Adrenal Steroids. Figure 77-2 gives

the principal steps in the formation of the important

steroid products of the adrenal cortex: aldosterone, cor-

corticosterone, as well as small amounts of

tisol, and the androgens. Essentially all these steps occur

adrenal androgens and estrogens. The secretion

in two of the organelles of the cell, the mitochondria and

of these cells is controlled in large part by

the endoplasmic reticulum, some steps occurring in one

the hypothalamic-pituitary axis via

of these organelles and some in the other. Each step is

adrenocorticotropic hormone (ACTH).

catalyzed by a specific enzyme system. A change in even

3. The zona reticularis, the deep layer of the

a single enzyme in the schema can cause vastly differ-

cortex, secretes the adrenal androgens

ent types and relative proportions of hormones to be

dehydroepiandrosterone (DHEA) and

formed. For example, very large quantities of masculin-

izing sex hormones or other steroid compounds not

androstenedione, as well as small amounts of

normally present in the blood can occur with altered

estrogens and some glucocorticoids. ACTH also

activity of only one of the enzymes in this pathway.

regulates secretion of these cells, although other

The chemical formulas of aldosterone and cortisol,

factors such as cortical androgen-stimulating

which are the most important mineralocorticoid and

hormone, released from the pituitary, may also be

glucocorticoid hormones, respectively, are shown in

involved. The mechanisms for controlling adrenal

Figure 77-2. Cortisol has a keto-oxygen on carbon

androgen production, however, are not nearly as

number 3 and is hydroxylated at carbon numbers 11 and

well understood as those for glucocorticoids and

21. The mineralocorticoid aldosterone has an oxygen

mineralocorticoids.

atom bound at the number 18 carbon.

Aldosterone and cortisol secretion are regulated by

In addition to aldosterone and cortisol, other steroids

having glucocorticoid or mineralocorticoid activities, or

independent mechanisms. Factors such as angiotensin

both, are normally secreted in small amounts by the

II that specifically increase the output of aldosterone

adrenal cortex. And several additional potent steroid

and cause hypertrophy of the zona glomerulosa have

hormones not normally formed in the adrenal glands

no effect on the other two zones. Similarly, factors such

have been synthesized and are used in various forms of

as ACTH that increase secretion of cortisol and

therapy. Some of the more important of the corticos-

adrenal androgens and cause hypertrophy of the zona

teroid hormones, including the synthetic ones, are the

fasciculata and zona reticularis have little or no effect

following as summarized in Table 77-1:

on the zona glomerulosa.

Mineralocorticoids

Adrenocortical Hormones Are Steroids Derived from Cholesterol.

• Aldosterone (very potent, accounts for about 90 per

All human steroid hormones, including those produced

cent of all mineralocorticoid activity)

by the adrenal cortex, are synthesized from cholesterol.

• Desoxycorticosterone (1/30 as potent as

Although the cells of the adrenal cortex can synthesize

aldosterone, but very small quantities secreted)

de novo small amounts of cholesterol from acetate,

• Corticosterone (slight mineralocorticoid activity)

approximately 80 per cent of the cholesterol used for

• 9a-Fluorocortisol (synthetic, slightly more potent

steroid synthesis is provided by low-density lipoproteins

than aldosterone)

Chapter 77

Adrenocortical Hormones

947

Table 77-1

Adrenal Steroid Hormones in Adults; Synthetic Steroids and Their Relative Glucocorticoid and Mineralocorticoid Activities

Average Plasma

Concentration

(free and bound,

Average Amount

Glucocorticoid

Mineralocorticoid

Steroids

mg/100 ml)

Secreted (mg/24 hr)

Activity

Adrenal Steroids

Cortisol

Corticosterone

0.4

0.3

15.0

Aldosterone

0.006

0.15

0.3

3000

Deoxycorticosterone

0.006

0.2

100

Dehydroepiandrosterone

175

—

Synthetic Steroids

Cortisone

—

1.0

Prednisolone

—

0.8

Methylprednisone

—

Dexamethasone

—

9a-fluorocortisol

—

125

Glucocorticoid and mineralocorticoid activities of the steroids are relative to cortisol, with cortisol being 1.0.

• Cortisol (very slight mineralocorticoid activity, but

Binding of adrenal steroids to the plasma proteins

large quantity secreted)

may serve as a reservoir to lessen rapid fluctuations

• Cortisone (synthetic, slight mineralocorticoid

in free hormone concentrations, as would occur, for

activity)

example, with cortisol during brief periods of stress and

episodic secretion of ACTH. This reservoir function

Glucocorticoids

may also help to ensure a relatively uniform distribu-

• Cortisol (very potent, accounts for about 95 per

tion of the adrenal hormones to the tissues.

cent of all glucocorticoid activity)

• Corticosterone (provides about 4 per cent of total

Adrenocortical Hormones Are Metabolized in the Liver. The

glucocorticoid activity, but much less potent than

adrenal steroids are degraded mainly in the liver and

cortisol)

conjugated especially to glucuronic acid and, to a lesser

• Cortisone (synthetic, almost as potent as cortisol)

extent, sulfates. These substances are inactive and do

• Prednisone (synthetic, four times as potent as

not have mineralocorticoid or glucocorticoid activity.

cortisol)

About 25 per cent of these conjugates are excreted in

• Methylprednisone (synthetic, five times as potent as

the bile and then in the feces. The remaining conjugates

cortisol)

formed by the liver enter the circulation but are not

• Dexamethasone (synthetic, 30 times as potent as

bound to plasma proteins, are highly soluble in the

cortisol)

plasma, and are therefore filtered readily by the kidneys

It is clear from this list that some of these hormones

and excreted in the urine. Diseases of the liver markedly

have both glucocorticoid and mineralocorticoid activi-

depress the rate of inactivation of adrenocortical hor-

ties. It is especially significant that cortisol has a small

mones, and kidney diseases reduce the excretion of the

amount of mineralocorticoid activity, because some syn-

inactive conjugates.

dromes of excess cortisol secretion can cause significant

The normal concentration of aldosterone in blood

mineralocorticoid effects, along with its much more

is about

6 nanograms (6 billionths of a gram) per

potent glucocorticoid effects.

100 ml, and the average secretory rate is approximately

The intense glucocorticoid activity of the synthetic

150 µg/day (0.15 mg/day).

hormone dexamethasone, which has almost zero min-

The concentration of cortisol in the blood averages

eralocorticoid activity, makes this an especially impor-

12 µg/100 ml, and the secretory rate averages 15 to

tant drug for stimulating specific glucocorticoid activity.

20 mg/day.

Adrenocortical Hormones Are Bound to Plasma Proteins.

Approximately 90 to 95 per cent of the cortisol in the

Functions of the

plasma binds to plasma proteins, especially a globulin

called cortisol-binding globulin or transcortin and, to a

Mineralocorticoids-

lesser extent, to albumin. This high degree of binding to

Aldosterone

plasma proteins slows the elimination of cortisol from

the plasma; therefore, cortisol has a relatively long half-

Mineralocorticoid Deficiency Causes Severe Renal Sodium

life of 60 to 90 minutes. Only about 60 per cent of cir-

Chloride Wasting and Hyperkalemia. Total loss of adreno-

culating aldosterone combines with the plasma proteins,

cortical secretion usually causes death within 3 days to

so that about 40 per cent is in the free form; as a result,

2 weeks unless the person receives extensive salt

aldosterone has a relatively short half-life of about 20

minutes. In both the combined and free forms, the hor-

therapy or injection of mineralocorticoids.

mones are transported throughout the extracellular

Without mineralocorticoids, potassium ion concen-

fluid compartment.

tration of the extracellular fluid rises markedly, sodium

948

Unit XIV Endocrinology and Reproduction

and chloride are rapidly lost from the body, and the

concentration stimulate thirst and increased water

total extracellular fluid volume and blood volume

intake, if water is available. Therefore, the extracellu-

become greatly reduced. The person soon develops

lar fluid volume increases almost as much as the

diminished cardiac output, which progresses to a

retained sodium, but without much change in sodium

shocklike state, followed by death. This entire

concentration.

sequence can be prevented by the administration of

Even though aldosterone is one of the body’s most

aldosterone or some other mineralocorticoid. There-

powerful sodium-retaining hormones, only transient

fore, the mineralocorticoids are said to be the acute

sodium retention occurs when excess amounts are

“lifesaving” portion of the adrenocortical hormones.

secreted. An aldosterone-mediated increase in extra-

The glucocorticoids are equally necessary, however,

cellular fluid volume lasting more than 1 to 2 days

allowing the person to resist the destructive effects of

also leads to an increase in arterial pressure, as

life’s intermittent physical and mental “stresses,” as

explained in Chapter 19. The rise in arterial pressure

discussed later in the chapter.

then increases kidney excretion of both salt and

water, called pressure natriuresis and pressure diuresis,

Aldosterone Is the Major Mineralocorticoid Secreted by the

respectively. Thus, after the extracellular fluid volume

Adrenals. Aldosterone exerts nearly 90 per cent of the

increases 5 to 15 per cent above normal, arterial pres-

mineralocorticoid activity of the adrenocortical secre-

sure also increases 15 to 25 mm Hg, and this elevated

tions, but cortisol, the major glucocorticoid secreted by

blood pressure returns the renal output of salt and

the adrenal cortex, also provides a significant amount

water to normal despite the excess aldosterone (Figure

of mineralocorticoid activity. Aldosterone’s mineralo-

77-3).

corticoid activity is about 3000 times greater than that

This return to normal of salt and water excretion by

of cortisol, but the plasma concentration of cortisol is

the kidneys

a result of pressure natriuresis and

nearly 2000 times that of aldosterone.

Renal and Circulatory Effects

Aldosterone

of Aldosterone

120

Aldosterone Increases Renal Tubular Reabsorption of Sodium

and Secretion of Potassium. It will be recalled from

100

Chapter

27 that aldosterone increases absorption

of sodium and simultaneously increases secretion

of potassium by the renal tubular epithelial cells-

especially in the principal cells of the collecting tubules

and, to a lesser extent, in the distal tubules and col-

120

lecting ducts. Therefore, aldosterone causes sodium to

be conserved in the extracellular fluid while increasing

110

potassium excretion in the urine.

A high concentration of aldosterone in the plasma

100

can transiently decrease the sodium loss into the urine

to as little as a few milliequivalents a day. At the same

time, potassium loss into the urine increases several-

400

fold. Therefore, the net effect of excess aldosterone

in the plasma is to increase the total quantity of

300

sodium in the extracellular fluid while decreasing the

potassium.

200

Conversely, total lack of aldosterone secretion can

cause transient loss of 10 to 20 grams of sodium in the

100

urine a day, an amount equal to one tenth to one fifth

-4

-2

of all the sodium in the body. At the same time, potas-

Time (days)

sium is conserved tenaciously in the extracellular fluid.

Excess Aldosterone Increases Extracellular Fluid Volume and

Arterial Pressure but Has Only a Small Effect on Plasma Sodium

Figure 77-3

Concentration. Although aldosterone has a potent

Effect of aldosterone infusion on arterial pressure, extracellular

effect in decreasing the rate of sodium ion excretion

fluid volume, and sodium excretion in dogs. Although aldosterone

by the kidneys, the concentration of sodium in the

was infused at a rate that raised plasma concentrations to about

extracellular fluid often rises only a few milliequiva-

20 times normal, note the “escape” from sodium retention on the

second day of infusion as arterial pressure increased and urinary

lents. The reason for this is that when sodium is reab-

sodium excretion returned to normal. (Drawn from data in Hall JE,

sorbed by the tubules, there is simultaneous osmotic

Granger JP, Smith MJ Jr, Premen N: Role of hemodynamics and

absorption of almost equivalent amounts of water.

arterial pressure in aldosterone “escape.” Hypertension 6 (suppl

Also, small increases in extracellular fluid sodium

I):I-183-I-192, 1984.)

Chapter 77

Adrenocortical Hormones

949

diuresis is called aldosterone escape. Thereafter, the

tubules. Both these glands form a primary secretion

rate of gain of salt and water by the body is zero, and

that contains large quantities of sodium chloride, but

balance is maintained between salt and water intake

much of the sodium chloride, on passing through the

and output by the kidneys despite continued excess

excretory ducts, is reabsorbed, whereas potassium and

aldosterone. In the meantime, however, the person has

bicarbonate ions are secreted. Aldosterone greatly

developed hypertension, which lasts as long as the

increases the reabsorption of sodium chloride and the

person remains exposed to high levels of aldosterone.

secretion of potassium by the ducts. The effect on the

Conversely, when aldosterone secretion becomes

sweat glands is important to conserve body salt in hot

zero, large amounts of salt are lost in the urine, not

environments, and the effect on the salivary glands is

only diminishing the amount of sodium chloride in the

necessary to conserve salt when excessive quantities of

extracellular fluid but also decreasing the extracellular

saliva are lost.

fluid volume. The result is severe extracellular fluid

Aldosterone also greatly enhances sodium absorp-

dehydration and low blood volume, leading to circula-

tion by the intestines, especially in the colon, which

tory shock. Without therapy, this usually causes death

prevents loss of sodium in the stools. Conversely, in the

within a few days after the adrenal glands suddenly

absence of aldosterone, sodium absorption can be

stop secreting aldosterone.

poor, leading to failure to absorb chloride and other

anions and water as well. The unabsorbed sodium

chloride and water then lead to diarrhea, with further

Excess Aldosterone Causes Hypokalemia and Muscle Weak-

loss of salt from the body.

ness; Too Little Aldosterone Causes Hyperkalemia and Cardiac

Toxicity. Excess aldosterone not only causes loss of

potassium ions from the extracellular fluid into the

urine but also stimulates transport of potassium

Cellular Mechanism of

from the extracellular fluid into most cells of the

Aldosterone Action

body. Therefore, excessive secretion of aldosterone,

as occurs with some types of adrenal tumors, may

Although for many years we have known the overall

cause a serious decrease in the plasma potassium

effects of mineralocorticoids on the body, the basic

concentration, sometimes from the normal value of

action of aldosterone on the tubular cells to increase

4.5 mEq/L to as low as 2 mEq/L. This condition is

transport of sodium is still not fully understood.

called hypokalemia. When the potassium ion concen-

However, the cellular sequence of events that leads

tration falls below about one-half normal, severe

to increased sodium reabsorption seems to be the

muscle weakness often develops. This is caused by

following.

alteration of the electrical excitability of the nerve and

First, because of its lipid solubility in the cellular

muscle fiber membranes (see Chapter 5), which pre-

membranes, aldosterone diffuses readily to the interior

vents transmission of normal action potentials.

of the tubular epithelial cells.

Conversely, when aldosterone is deficient, the extra-

Second, in the cytoplasm of the tubular cells, aldos-

cellular fluid potassium ion concentration can rise far

terone combines with a highly specific cytoplasmic

above normal. When it rises to 60 to 100 per cent above

receptor protein, a protein that has a stereomolecular

normal, serious cardiac toxicity, including weakness of

configuration that allows only aldosterone or very

heart contraction and development of arrhythmia,

similar compounds to combine with it.

becomes evident; progressively higher concentrations

Third, the aldosterone-receptor complex or a

of potassium lead inevitably to heart failure.

product of this complex diffuses into the nucleus,

where it may undergo further alterations, finally induc-

Excess Aldosterone Increases Tubular Hydrogen Ion Secretion,

ing one or more specific portions of the DNA to form

and Causes Mild Alkalosis. Aldosterone not only causes

one or more types of messenger RNA related to the

potassium to be secreted into the tubules in exchange

process of sodium and potassium transport.

for sodium reabsorption in the principal cells of the

Fourth, the messenger RNA diffuses back into the

renal collecting tubules but also causes secretion of

cytoplasm, where, operating in conjunction with the

hydrogen ions in exchange for sodium in the interca-

ribosomes, it causes protein formation. The proteins

lated cells of the cortical collecting tubules. This

formed are a mixture of (1) one or more enzymes

decreases the hydrogen ion concentration in the extra-

and

(2) membrane transport proteins that, all

cellular fluid, causing a mild degree of alkalosis.

acting together, are required for sodium, potassium,

and hydrogen transport through the cell membrane.

One of the enzymes especially increased is sodium-

potassium adenosine triphosphatase, which serves as

Aldosterone Stimulates Sodium and

the principal part of the pump for sodium and potas-

Potassium Transport in Sweat Glands,

sium exchange at the basolateral membranes of the

Salivary Glands, and Intestinal

renal tubular cells. Additional proteins, perhaps

Epithelial Cells

equally important, are epithelial sodium channel pro-

teins inserted into the luminal membrane of the same

Aldosterone has almost the same effects on sweat

tubular cells that allows rapid diffusion of sodium ions

glands and salivary glands as it has on the renal

from the tubular lumen into the cell; then the sodium

950

Unit XIV Endocrinology and Reproduction

is pumped the rest of the way by the sodium-potassium

1. Increased potassium ion concentration in the

pump located in the basolateral membranes of the cell.

extracellular fluid greatly increases aldosterone

Thus, aldosterone does not have an immediate effect

secretion.

on sodium transport; rather, this effect must await the

2. Increased activity of the renin-angiotensin system

sequence of events that leads to the formation of the

(increased levels of angiotensin II) also greatly

specific intracellular substances required for sodium

increases aldosterone secretion.

transport. About 30 minutes is required before new

3. Increased sodium ion concentration in the

RNA appears in the cells, and about 45 minutes is

extracellular fluid very slightly decreases

required before the rate of sodium transport begins to

aldosterone secretion.

increase; the effect reaches maximum only after

4. ACTH from the anterior pituitary gland is

several hours.

necessary for aldosterone secretion but has little

effect in controlling the rate of secretion.

Of these factors, potassium ion concentration

and the renin-angiotensin system are by far the most

Possible Nongenomic Actions

potent in regulating aldosterone secretion. A small

of Aldosterone and Other

percentage increase in potassium concentration can

Steroid Hormones

cause a severalfold increase in aldosterone secretion.

Likewise, activation of the renin-angiotensin system,

Recent studies suggest that many steroids, including

usually in response to diminished blood flow to the

aldosterone, elicit not only slowly developing genomic

kidneys or to sodium loss, can cause a severalfold

effects that have a latency of 60 to 90 minutes and

increase in aldosterone secretion. In turn, the aldos-

require gene transcription and synthesis of new pro-

terone acts on the kidneys (1) to help them excrete the

teins, but also rapid nongenomic effects that take place

excess potassium ions and (2) to increase the blood

in a few seconds or minutes.

volume and arterial pressure, thus returning the renin-

These nongenomic actions are believed to be medi-

angiotensin system toward its normal level of activity.

ated by binding of steroids to cell membrane receptors

These feedback control mechanisms are essential for

that are coupled to second messenger systems, similar

maintaining life, and the reader is referred again to

to those used for peptide hormone signal transduction.

Chapters 27 and 29 for a full understanding of their

For example, aldosterone has been shown to increase

functions.

formation of cAMP in vascular smooth muscle cells

Figure 77-4 shows the effects on plasma aldosterone

and in epithelial cells of the renal collecting tubules in

concentration caused by blocking the formation of

less than two minutes, a time period that is far too

angiotensin II with an angiotensin-converting enzyme

short for gene transcription and synthesis of new pro-

inhibitor after several weeks of a low-sodium diet that

teins. In other cell types, aldosterone has been shown

increases plasma aldosterone concentration several-

to rapidly stimulate the phosphatidylinositol second

fold. Note that blocking angiotensin II formation

messenger system. However, the precise structure of

markedly decreases plasma aldosterone concentration

receptors responsible for the rapid effects of aldos-

without significantly changing cortisol concentration;

terone has not been determined, nor is the physiolog-

this indicates the important role of angiotensin II in

ical significance of these nongenomic actions of

stimulating aldosterone secretion when sodium intake

steroids well understood.

and extracellular fluid volume are reduced.

By contrast, the effects of sodium ion concentration

per se and of ACTH in controlling aldosterone secre-

Regulation of Aldosterone Secretion

tion are usually minor. Nevertheless, a 10 to 20 per cent

decrease in extracellular fluid sodium ion concentra-

The regulation of aldosterone secretion is so deeply

tion, which occurs on rare occasions, can perhaps

intertwined with the regulation of extracellular fluid

double aldosterone secretion. In the case of ACTH, if

electrolyte concentrations, extracellular fluid volume,

there is even a small amount of ACTH secreted by the

blood volume, arterial pressure, and many special

anterior pituitary gland, it is usually enough to permit

aspects of renal function that it is difficult to discuss

the adrenal glands to secrete whatever amount of

the regulation of aldosterone secretion independently

aldosterone is required, but total absence of ACTH

of all these other factors. This subject is presented in

can significantly reduce aldosterone secretion.

detail in Chapters 28 and 29, to which the reader is

referred. However, it is important to list here some of

the more important points of aldosterone secretion

Functions of the

control.

The regulation of aldosterone secretion by the zona

Glucocorticoids

glomerulosa cells is almost entirely independent of the

regulation of cortisol and androgens by the zona fas-

Even though mineralocorticoids can save the life of

ciculata and zona reticularis.

an acutely adrenalectomized animal, the animal still

Four factors are known to play essential roles in the

is far from normal. Instead, its metabolic systems

regulation of aldosterone. In the probable order of

for utilization of proteins, carbohydrates, and fats

their importance, they are as follows:

remain considerably deranged. Furthermore, the

Chapter 77

Adrenocortical Hormones

951

the rate of gluconeogenesis as much as 6- to 10-fold.

This results mainly from two effects of cortisol.

1. Cortisol increases the enzymes required to convert

amino acids into glucose in the liver cells. This

results from the effect of the glucocorticoids to

activate DNA transcription in the liver cell nuclei

in the same way that aldosterone functions in the

renal tubular cells, with formation of messenger

RNAs that in turn lead to the array of enzymes

required for gluconeogenesis.

2. Cortisol causes mobilization of amino acids from

the extrahepatic tissues mainly from muscle. As a

result, more amino acids become available in the

3.0

plasma to enter into the gluconeogenesis process

of the liver and thereby to promote the formation

of glucose.

2.0

One of the effects of increased gluconeogenesis is a

marked increase in glycogen storage in the liver cells.

This effect of cortisol allows other glycolytic hor-

1.0

mones, such as epinephrine and glucagon, to mobilize

glucose in times of need, such as between meals.

0.0

Control

ACE

ACE inhibitor

inhibitor

Decreased Glucose Utilization by Cells. Cortisol also causes

Ang II infusion

a moderate decrease in the rate of glucose utilization

by most cells in the body. Although the cause of this

decrease is unknown, most physiologists believe that

somewhere between the point of entry of glucose

Figure 77-4

into the cells and its final degradation, cortisol directly

delays the rate of glucose utilization. A suggested

Effects of treating

sodium-depleted dogs with an angiotensin-

converting enzyme (ACE) inhibitor for 7 days to block formation

mechanism is based on the observation that glucocor-

of angiotensin II (Ang II) and of infusing exogenous Ang II to

ticoids depress the oxidation of nicotinamide-adenine

restore plasma Ang II levels after ACE inhibition. Note that block-

dinucleotide

(NADH) to form NAD⁺. Because

ing Ang II formation reduced plasma aldosterone concentration

NADH must be oxidized to allow glycolysis, this effect

with little effect on cortisol, demonstrating the important role of

Ang II in stimulating aldosterone secretion during sodium deple-

could account for the diminished utilization of glucose

tion.

(Drawn from data in Hall JE, Guyton AC, Smith MJ Jr,

by the cells.

Coleman TG: Chronic blockade of angiotensin II formation during

sodium deprivation. Am J Physiol 237:F424, 1979.)

Elevated Blood Glucose Concentration and “Adrenal Diabetes.”

Both the increased rate of gluconeogenesis and the

moderate reduction in the rate of glucose utilization

by the cells cause the blood glucose concentrations to

animal cannot resist different types of physical or even

rise. The rise in blood glucose in turn stimulates

mental stress, and minor illnesses such as respiratory

secretion of insulin. The increased plasma levels of

tract infections can lead to death. Therefore, the glu-

insulin, however, are not as effective in maintaining

cocorticoids have functions just as important to the

plasma glucose as they are under normal conditions.

long-continued life of the animal as those of the min-

For reasons that are not entirely clear, high levels

eralocorticoids. They are explained in the following

of glucocorticoid reduce the sensitivity of many

sections.

tissues, especially skeletal muscle and adipose tissue,

At least 95 per cent of the glucocorticoid activity of

to the stimulatory effects of insulin on glucose uptake

the adrenocortical secretions results from the secre-

and utilization. One possible explanation is that high

tion of cortisol, known also as hydrocortisone. In

levels of fatty acids, caused by the effect of glucocor-

addition to this, a small but significant amount of glu-

ticoids to mobilize lipids from fat depots, may impair

cocorticoid activity is provided by corticosterone.

insulin’s actions on the tissues. In this way, excess

secretion of glucocorticoids may produce disturbances

of carbohydrate metabolism very similar to those

Effects of Cortisol on

found in patients with excess levels of growth

Carbohydrate Metabolism

hormone.

The increase in blood glucose concentration is occa-

Stimulation of Gluconeogenesis. By far the best-known

sionally great enough (50 per cent or more above

metabolic effect of cortisol and other glucocorticoids

normal) that the condition is called adrenal diabetes.

on metabolism is their ability to stimulate gluconeo-

Administration of insulin lowers the blood glucose

genesis (formation of carbohydrate from proteins and

concentration only a moderate amount in adrenal

some other substances) by the liver, often increasing

diabetes-not nearly as much as it does in pancreatic

952

Unit XIV Endocrinology and Reproduction

diabetes-because the tissues are resistant to the effects

gluconeogenesis. Thus, it is possible that many of the

of insulin.

effects of cortisol on the metabolic systems of the body

result mainly from this ability of cortisol to mobilize

amino acids from the peripheral tissues while at the

Effects of Cortisol on

same time increasing the liver enzymes required for

Protein Metabolism

the hepatic effects.

Reduction in Cellular Protein. One of the principal effects

of cortisol on the metabolic systems of the body is

Effects of Cortisol on Fat Metabolism

reduction of the protein stores in essentially all body

cells except those of the liver. This is caused by both

Mobilization of Fatty Acids. In much the same manner

decreased protein synthesis and increased catabolism

that cortisol promotes amino acid mobilization from

of protein already in the cells. Both these effects may

muscle, it promotes mobilization of fatty acids from

result from decreased amino acid transport into extra-

adipose tissue. This increases the concentration of free

hepatic tissues, as discussed later; this probably is not

fatty acids in the plasma, which also increases their uti-

the major cause, because cortisol also depresses the

lization for energy. Cortisol also seems to have a direct

formation of RNA and subsequent protein synthesis

effect to enhance the oxidation of fatty acids in the

in many extrahepatic tissues, especially in muscle and

cells.

lymphoid tissue.

The mechanism by which cortisol promotes fatty

In the presence of great excesses of cortisol, the

acid mobilization is not completely understood.

muscles can become so weak that the person cannot

However, part of the effect probably results from

rise from the squatting position. And the immunity

diminished transport of glucose into the fat cells.

functions of the lymphoid tissue can be decreased to a

Recall that a-glycerophosphate, which is derived from

small fraction of normal.

glucose, is required for both deposition and mainte-

nance of triglycerides in these cells, and in its absence

Cortisol Increases Liver and Plasma Proteins. Coinciden-

the fat cells begin to release fatty acids.

tally with the reduced proteins elsewhere in the body,

The increased mobilization of fats by cortisol, com-

the liver proteins become enhanced. Furthermore, the

bined with increased oxidation of fatty acids in the

plasma proteins (which are produced by the liver and

cells, helps shift the metabolic systems of the cells from

then released into the blood) are also increased. These

utilization of glucose for energy to utilization of fatty

increases are exceptions to the protein depletion that

acids in times of starvation or other stresses. This cor-

occurs elsewhere in the body. It is believed that this

tisol mechanism, however, requires several hours to

difference results from a possible effect of cortisol to

become fully developed-not nearly so rapid or so pow-

enhance amino acid transport into liver cells (but

erful an effect as a similar shift elicited by a decrease

not into most other cells) and to enhance the

in insulin, as we discuss in Chapter 78. Nevertheless,

liver enzymes required for protein synthesis.

the increased use of fatty acids for metabolic energy is

an important factor for long-term conservation of

Increased Blood Amino Acids, Diminished Transport of Amino

body glucose and glycogen.

Acids into Extrahepatic Cells, and Enhanced Transport into

Hepatic Cells. Studies in isolated tissues have demon-

strated that cortisol depresses amino acid transport

Obesity Caused by Excess Cortisol. Despite the fact that

into muscle cells and perhaps into other extrahepatic

cortisol can cause a moderate degree of fatty acid

cells.

mobilization from adipose tissue, many people with

The decreased transport of amino acids into extra-

excess cortisol secretion develop a peculiar type of

hepatic cells decreases their intracellular amino acid

obesity, with excess deposition of fat in the chest and

concentrations and consequently decreases the syn-

head regions of the body, giving a buffalo-like torso

thesis of protein. Yet, catabolism of proteins in the cells

and a rounded “moon face.” Although the cause is

continues to release amino acids from the already

unknown, it has been suggested that this obesity

existing proteins, and these diffuse out of the cells to

results from excess stimulation of food intake, with fat

increase the plasma amino acid concentration. There-

being generated in some tissues of the body more

fore, cortisol mobilizes amino acids from the nonhep-

rapidly than it is mobilized and oxidized.

atic tissues and in doing so diminishes the tissue stores

of protein.

The increased plasma concentration of amino acids

and enhanced transport of amino acids into the

Cortisol is Important in Resisting

hepatic cells by cortisol could also account for

Stress and Inflammation

enhanced utilization of amino acids by the liver to

cause such effects as (1) increased rate of deamination

Almost any type of stress, whether physical or neuro-

of amino acids by the liver, (2) increased protein

genic, causes an immediate and marked increase

synthesis in the liver,

(3) increased formation of

in ACTH secretion by the anterior pituitary gland,

plasma proteins by the liver, and (4) increased con-

followed within minutes by greatly increased adreno-

version of amino acids to glucose-that is, enhanced

cortical secretion of cortisol. This is demonstrated

Chapter 77

Adrenocortical Hormones

953

pyrimidines, and creatine phosphate, which are neces-

sary for maintenance of cellular life and reproduction

of new cells.

But all this is mainly supposition. It is supported

only by the fact that cortisol usually does not mobilize

the basic functional proteins of the cells, such as

the muscle contractile proteins and the proteins of

neurons, until almost all other proteins have been

released. This preferential effect of cortisol in

mobilizing labile proteins could make amino acids

available to needy cells to synthesize substances essen-

tial to life.

Anti-inflammatory Effects of High Levels

of Cortisol

When tissues are damaged by trauma, by infection

with bacteria, or in other ways, they almost always

become “inflamed.” In some conditions, such as in

rheumatoid arthritis, the inflammation is more dam-

aging than the trauma or disease itself. The adminis-

-0

45 60

90 2

4 56

8 101215202530

tration of large amounts of cortisol can usually block

Seconds

Minutes

this inflammation or even reverse many of its effects

once it has begun. Before attempting to explain the

way in which cortisol functions to block inflammation,

Figure 77-5

let us review the basic steps in the inflammation

process, discussed in more detail in Chapter 33.

Rapid reaction of the adrenal cortex of a rat to stress caused by

There are five main stages of inflammation: (1)

fracture of the tibia and fibula at time zero. (In the rat, corticos-

release from the damaged tissue cells of chemical

terone is secreted in place of cortisol.) (Courtesy Drs. Guillemin,

substances that activate the inflammation process-

Dear, and Lipscomb.)

chemicals such as histamine, bradykinin, proteolytic

enzymes, prostaglandins, and leukotrienes;

(2) an

increase in blood flow in the inflamed area caused by

dramatically by the experiment shown in Figure 77-5,

some of the released products from the tissues, an

in which corticosteroid formation and secretion

effect called erythema; (3) leakage of large quantities

increased sixfold in a rat within 4 to 20 minutes after

of almost pure plasma out of the capillaries into the

fracture of two leg bones.

damaged areas because of increased capillary perme-

Some of the different types of stress that increase

ability, followed by clotting of the tissue fluid, thus

cortisol release are the following:

causing a nonpitting type of edema; (4) infiltration of

1. Trauma of almost any type

the area by leukocytes; and (5) after days or weeks,

2. Infection

ingrowth of fibrous tissue that often helps in the

3. Intense heat or cold

healing process.

4. Injection of norepinephrine and other

When large amounts of cortisol are secreted or

sympathomimetic drugs

injected into a person, the cortisol has two basic anti-

5. Surgery

inflammatory effects: (1) it can block the early stages

6. Injection of necrotizing substances beneath the

of the inflammation process before inflammation

skin

even begins, or (2) if inflammation has already begun,

7. Restraining an animal so that it cannot move

it causes rapid resolution of the inflammation and

8. Almost any debilitating disease

increased rapidity of healing. These effects are

Even though we know that cortisol secretion often

explained further as follows.

increases greatly in stressful situations, we are not sure

why this is of significant benefit to the animal. One

Cortisol Prevents the Development of Inflammation by Stabiliz-

possibility is that the glucocorticoids cause rapid mobi-

ing Lysosomes and by Other Effects. Cortisol has the fol-

lization of amino acids and fats from their cellular

lowing effects in preventing inflammation:

stores, making them immediately available both for

1. Cortisol stabilizes the lysosomal membranes. This

energy and for synthesis of other compounds, includ-

is one of its most important anti-inflammatory

ing glucose, needed by the different tissues of the body.

effects, because it is much more difficult than

Indeed, it has been shown in a few instances that

normal for the membranes of the intracellular

damaged tissues that are momentarily depleted of pro-

lysosomes to rupture. Therefore, most of the

teins can use the newly available amino acids to form

proteolytic enzymes that are released by damaged

new proteins that are essential to the lives of the cells.

cells to cause inflammation, which are mainly

Also, the amino acids are perhaps used to synthesize

stored in the lysosomes, are released in greatly

other essential intracellular substances such as purines,

decreased quantity.

954

Unit XIV Endocrinology and Reproduction

2. Cortisol decreases the permeability of the

And even though the cortisol does not correct the

capillaries, probably as a secondary effect of the

basic disease condition, merely preventing the damag-

reduced release of proteolytic enzymes. This

ing effects of the inflammatory response, this alone can

prevents loss of plasma into the tissues.

often be a lifesaving measure.

3. Cortisol decreases both migration of white blood

cells into the inflamed area and phagocytosis of the

Other Effects of Cortisol

damaged cells. These effects probably result from

the fact that cortisol diminishes the formation

Cortisol Blocks the Inflammatory Response to Allergic Reactions.

of prostaglandins and leukotrienes that

The basic allergic reaction between antigen and anti-

otherwise would increase vasodilation, capillary

body is not affected by cortisol, and even some of the

permeability, and mobility of white blood cells.

secondary effects of the allergic reaction still occur.

4. Cortisol suppresses the immune system, causing

However, because the inflammatory response is respon-

lymphocyte reproduction to decrease markedly.

sible for many of the serious and sometimes lethal

The T lymphocytes are especially suppressed. In

effects of allergic reactions, administration of cortisol,

followed by its effect in reducing inflammation and the

turn, reduced amounts of T cells and antibodies

release of inflammatory products, can be lifesaving. For

in the inflamed area lessen the tissue reactions

instance, cortisol effectively prevents shock or death in

that would otherwise promote the inflammation

anaphylaxis, which otherwise kills many people, as

process.

explained in Chapter 34.

5. Cortisol attenuates fever mainly because it reduces

the release of interleukin-1 from the white blood

Effect on Blood Cells and on Immunity in Infectious Diseases.

cells, which is one of the principal excitants to the

Cortisol decreases the number of eosinophils and lym-

hypothalamic temperature control system. The

phocytes in the blood; this effect begins within a few

decreased temperature in turn reduces the degree

minutes after the injection of cortisol and becomes

of vasodilation.

marked within a few hours. Indeed, a finding of lym-

phocytopenia or eosinopenia is an important diagnostic

Thus, cortisol has an almost global effect in reduc-

criterion for overproduction of cortisol by the adrenal

ing all aspects of the inflammatory process. How much

gland.

of this results from the simple effect of cortisol in

Likewise, the administration of large doses of cortisol

stabilizing lysosomal and cell membranes versus its

causes significant atrophy of all the lymphoid tissue

effect to reduce the formation of prostaglandins and

throughout the body, which in turn decreases the output

leukotrienes from arachidonic acid in damaged cell

of both T cells and antibodies from the lymphoid tissue.

membranes and other effects of cortisol is unclear.

As a result, the level of immunity for almost all foreign

invaders of the body is decreased. This occasionally can

Cortisol Causes Resolution of Inflammation. Even after

lead to fulminating infection and death from diseases

inflammation has become well established, the admin-

that would otherwise not be lethal, such as fulminating

tuberculosis in a person whose disease had previously

istration of cortisol can often reduce inflammation

been arrested. Conversely, this ability of cortisol and

within hours to a few days. The immediate effect is to

other glucocorticoids to suppress immunity makes them

block most of the factors that are promoting the

useful drugs in preventing immunological rejection of

inflammation. But in addition, the rate of healing is

transplanted hearts, kidneys, and other tissues.

enhanced. This probably results from the same, mainly

Cortisol increases the production of red blood cells

undefined, factors that allow the body to resist many

by mechanisms that are unclear. When excess cortisol is

other types of physical stress when large quantities of

secreted by the adrenal glands, polycythemia often

cortisol are secreted. Perhaps this results from the

results, and conversely, when the adrenal glands secrete

mobilization of amino acids and use of these to repair

no cortisol, anemia often results.

the damaged tissues; perhaps it results from the

increased glucogenesis that makes extra glucose avail-

Cellular Mechanism of

able in critical metabolic systems; perhaps it results

Cortisol Action

from increased amounts of fatty acids available for cel-

lular energy; or perhaps it depends on some effect of

Cortisol, like other steroid hormones, exerts its effects

cortisol for inactivating or removing inflammatory

by first interacting with intracellular receptors in target

products.

cells. Because cortisol is lipid soluble, it can easily

Regardless of the precise mechanisms by which the

diffuse through the cell membrane. Once inside the cell,

anti-inflammatory effect occurs, this effect of cortisol

cortisol binds with its protein receptor in the cytoplasm,

plays a major role in combating certain types of dis-

and the hormone-receptor complex then interacts with

eases, such as rheumatoid arthritis, rheumatic fever,

specific regulatory DNA sequences, called glucocorti-

coid response elements, to induce or repress gene tran-

and acute glomerulonephritis. All these diseases are

scription. Other proteins in the cell, called transcription

characterized by severe local inflammation, and the

factors, are also necessary for the hormone-receptor

harmful effects on the body are caused mainly by

complex to interact appropriately with the glucocorti-

the inflammation itself and not by other aspects of the

coid response elements.

disease.

Glucocorticoids increase or decrease transcription of

When cortisol or other glucocorticoids are adminis-

many genes to alter synthesis of mRNA for the proteins

tered to patients with these diseases, almost invariably

that mediate their multiple physiologic effects. Thus,

the inflammation begins to subside within 24 hours.

most of the metabolic effects of cortisol are not

Chapter 77

Adrenocortical Hormones

955

immediate but require 45 to 60 minutes for proteins to

This is another example of cAMP as a second messen-

be synthesized, and up to several hours or days to fully

ger signal system.

develop. Recent evidence suggests that glucocorticoids,

The most important of all the ACTH-stimulated

especially at high concentrations, may also have some

steps for controlling adrenocortical secretion is acti-

rapid nongenomic effects on cell membrane ion trans-

vation of the enzyme protein kinase A, which causes

port that may contribute to their therapeutic benefits.

initial conversion of cholesterol to pregnenolone. This

initial conversion is the “rate-limiting” step for all the

adrenocortical hormones, which explains why ACTH

Regulation of Cortisol Secretion

normally is necessary for any adrenocortical hormones

by Adrenocorticotropic Hormone

to be formed. Long-term stimulation of the adrenal

from the Pituitary Gland

cortex by ACTH not only increases secretory activity

but also causes hypertrophy and proliferation of the

ACTH Stimulates Cortisol Secretion. Unlike aldosterone

adrenocortical cells, especially in the zona fasciculata

secretion by the zona glomerulosa, which is controlled

and zona reticularis, where cortisol and the androgens

mainly by potassium and angiotensin acting directly

are secreted.

on the adrenocortical cells, almost no stimuli have

direct control effects on the adrenal cells that secrete

Physiologic Stress Increases ACTH and

cortisol. Instead, secretion of cortisol is controlled

Adrenocortical Secretion

almost entirely by ACTH secreted by the anterior

As pointed out earlier in the chapter, almost any type

pituitary gland. This hormone, also called corticotropin

of physical or mental stress can lead within minutes

or adrenocorticotropin, also enhances the production

to greatly enhanced secretion of ACTH and conse-

of adrenal androgens.

quently cortisol as well, often increasing cortisol secre-

tion as much as 20-fold. This effect was demonstrated

by the rapid and strong adrenocortical secretory

Chemistry of ACTH. ACTH has been isolated in pure

responses after trauma shown in Figure 77-5.

form from the anterior pituitary. It is a large polypep-

Pain stimuli caused by physical stress or tissue

tide, having a chain length of 39 amino acids. A smaller

damage are transmitted first upward through the brain

polypeptide, a digested product of ACTH having a

stem and eventually to the median eminence of the

chain length of 24 amino acids, has all the effects of the

hypothalamus, as shown in Figure 77-6. Here CRF is

total molecule.

secreted into the hypophysial portal system. Within

minutes the entire control sequence leads to large

ACTH Secretion Is Controlled by Corticotropin-Releasing Factor

quantities of cortisol in the blood.

from the Hypothalamus. In the same way that other pitu-

Mental stress can cause an equally rapid increase in

itary hormones are controlled by releasing factors

ACTH secretion. This is believed to result from

from the hypothalamus, an important releasing factor

increased activity in the limbic system, especially in the

also controls ACTH secretion. This is called corti-

region of the amygdala and hippocampus, both of

cotropin-releasing factor (CRF). It is secreted into the

which then transmit signals to the posterior medial

primary capillary plexus of the hypophysial portal

hypothalamus.

system in the median eminence of the hypothalamus

and then carried to the anterior pituitary gland, where

Inhibitory Effect of Cortisol on the Hypothalamus and on the

it induces ACTH secretion. CRF is a peptide com-

Anterior Pituitary to Decrease ACTH Secretion. Cortisol has

posed of 41 amino acids. The cell bodies of the neurons

direct negative feedback effects on (1) the hypothala-

that secrete CRF are located mainly in the paraven-

mus to decrease the formation of CRF and (2) the

tricular nucleus of the hypothalamus. This nucleus in

anterior pituitary gland to decrease the formation

turn receives many nervous connections from the

of ACTH. Both of these feedbacks help regulate

limbic system and lower brain stem.

the plasma concentration of cortisol. That is, whenever

The anterior pituitary gland can secrete only minute

the cortisol concentration becomes too great, the

quantities of ACTH in the absence of CRF. Instead,

feedbacks automatically reduce the ACTH toward

most conditions that cause high ACTH secretory rates

a normal control level.

initiate this secretion by signals that begin in the basal

regions of the brain, including the hypothalamus, and

Summary of the Cortisol Control System

are then transmitted by CRF to the anterior pituitary

Figure 77-6 shows the overall system for control of

gland.

cortisol secretion. The key to this control is the exci-

tation of the hypothalamus by different types of stress.

ACTH Activates Adrenocortical Cells to Produce Steroids by

Stress stimuli activate the entire system to cause rapid

Increasing Cyclic Adenosine Monophosphate

(cAMP). The

release of cortisol, and the cortisol in turn initiates a

principal effect of ACTH on the adrenocortical cells is

series of metabolic effects directed toward relieving

to activate adenylyl cyclase in the cell membrane. This

the damaging nature of the stressful state.

then induces the formation of cAMP in the cell cyto-

There is also direct feedback of the cortisol to both

plasm, reaching its maximal effect in about 3 minutes.

the hypothalamus and the anterior pituitary gland to

The cAMP in turn activates the intracellular enzymes

decrease the concentration of cortisol in the plasma

that cause formation of the adrenocortical hormones.

at times when the body is not experiencing stress.

956

Unit XIV Endocrinology and Reproduction

Hypothalamus

Excites

Stress

Portal

Median

eminence

vessel

(CRF)

Relieves

Inhibits

ACTH

12:00

4:00

8:00

12:00

4:00

8:00

12:00

Adrenal

cortex

Cortisol

Noon

1 Gluconeogenesis

Figure 77-7

2 Protein mobilization

3 Fat mobilization

Typical pattern of cortisol concentration during the day. Note the

4 Stabilizes lysosomes

oscillations in secretion as well as a daily secretory surge an hour

or so after awaking in the morning.

Figure 77-6

Mechanism for regulation of glucocorticoid secretion. ACTH,

stimulating hormone (MSH), b-lipotropin, b-endor-

adrenocorticotropic hormone; CRF, corticotropin-releasing factor.

phin, and a few others (Figure 77-8). Under normal

conditions, none of these hormones is secreted in

enough quantity by the pituitary to have a significant

effect on the human body, but when the rate of secre-

However, the stress stimuli are the prepotent ones;

tion of ACTH is high, as may occur in Addison’s

they can always break through this direct inhibitory

disease, formation of some of the other POMC-

feedback of cortisol, causing either periodic exacerba-

derived hormones may also be increased.

tions of cortisol secretion at multiple times during the

The POMC gene is actively transcribed in several

day (Figure 77-7) or prolonged cortisol secretion in

tissues, including the corticotroph cells of the anterior

times of chronic stress.

pituitary, POMC neurons in the arcuate nucleus of

Circadian Rhythm of Glucocorticoid Secretion. The secretory

the hypothalamus, cells of the dermis, and lymphoid

rates of CRF, ACTH, and cortisol are high in the early

tissue. In all of these cell types, POMC is processed to

morning but low in the late evening, as shown in Figure

form a series of smaller peptides. The precise type

77-7; the plasma cortisol level ranges between a high of

of POMC-derived products from a particular tissue

about 20 mg/dl an hour before arising in the morning

depends on the type of processing enzymes present in

and a low of about 5 mg/dl around midnight. This effect

the tissue. Thus, pituitary corticotroph cells express

results from a 24-hour cyclical alteration in the signals

prohormone convertase 1 (PC1), but not PC2, result-

from the hypothalamus that cause cortisol secretion.

ing in the production of N-terminal peptide, joining

When a person changes daily sleeping habits, the cycle

peptide, ACTH, b-endorphin, and b-lipotropin. In the

changes correspondingly. Therefore, measurements of

blood cortisol levels are meaningful only when

hypothalamus, the expression of PC2 leads to the

expressed in terms of the time in the cycle at which the

production of a-, b-, and g-MSH, but not ACTH. As

measurements are made.

discussed in Chapter 71, a-MSH formed by neurons of

the hypothalamus plays a major role in appetite

Synthesis and Secretion of ACTH in

regulation.

Association with Melanocyte-Stimulating

In melanocytes located in abundance between the

Hormone, Lipotropin, and Endorphin

dermis and epidermis of the skin, MSH stimulates

When ACTH is secreted by the anterior pituitary

formation of the black pigment melanin and disperses

gland, several other hormones that have similar chem-

it to the epidermis. Injection of MSH into a person

ical structures are secreted simultaneously. The reason

over 8 to 10 days can greatly increase darkening of the

for this is that the gene that is transcribed to form the

skin. The effect is much greater in people who have

RNA molecule that causes ACTH synthesis initially

genetically dark skins than in light-skinned people.

causes the formation of a considerably larger protein,

In some lower animals, an intermediate “lobe” of

a preprohormone called proopiomelanocortin

the pituitary gland, called the pars intermedia, is highly

(POMC), which is the precursor of ACTH as well

developed, lying between the anterior and posterior

as several other peptides, including melanocyte-

pituitary lobes. This lobe secretes an especially large

Chapter 77

Adrenocortical Hormones

957

COOH

Proopiomelanocortin

Figure 77-8

Proopiomelanocortin

(POMC)

processing by prohormone con-

vertase 1 (PC1, red arrows) and

N-Terminal protein

Joining

ACTH

b-Lipotropin

PC 2 (blue arrows). Tissue spe-

cific expression of these two

protein

enzymes results in different pep-

tides produced in various tissues.

PCI

The anterior pituitary expresses

PC1, resulting in formation of N-

g-MSH

a-MSH

CLIP

g-Lipotropin

b-Endorphin

PC2

terminal peptide, joining peptide,

ACTH, and b-lipotropin. Expres-

sion of PC2 within the hypothala-

mus leads to the production of a-,

b-, and g-melanocyte stimulating

hormone (MSH), but not ACTH.

b-MSH

CLIP, corticotropin-like intermedi-

ate peptide.

amount of MSH. Furthermore, this secretion is inde-

Abnormalities of

pendently controlled by the hypothalamus in response

Adrenocortical Secretion

to the amount of light to which the animal is exposed

or in response to other environmental factors. For

Hypoadrenalism-Addison’s Disease

instance, some arctic animals develop darkened fur in

Addison’s disease results from failure of the adrenal

the summer and yet have entirely white fur in the

cortices to produce adrenocortical hormones, and this

winter.

in turn is most frequently caused by primary atrophy of

ACTH, because it contains an MSH sequence, has

the adrenal cortices. In about 80 per cent of the cases,

about 1/30 as much melanocyte-stimulating effect as

the atrophy is caused by autoimmunity against the cor-

MSH. Furthermore, because the quantities of pure

tices. Adrenal gland hypofunction is also frequently

MSH secreted in the human being are extremely

caused by tuberculous destruction of the adrenal glands

small, whereas those of ACTH are large, it is likely that

or invasion of the adrenal cortices by cancer. The dis-

ACTH normally is more important than MSH in

turbances in Addison’s disease are as follows.

determining the amount of melanin in the skin.

Mineralocorticoid Deficiency. Lack of aldosterone secre-

tion greatly decreases renal tubular sodium reabsorp-

Adrenal Androgens

tion and consequently allows sodium ions, chloride ions,

and water to be lost into urine in great profusion. The

Several moderately active male sex hormones called

net result is a greatly decreased extracellular fluid

adrenal androgens (the most important of which is

volume. Furthermore, hyponatremia, hyperkalemia, and

dehydroepiandrosterone) are continually secreted by

mild acidosis develop because of failure of potassium

the adrenal cortex, especially during fetal life, as dis-

and hydrogen ions to be secreted in exchange for

cussed more fully in Chapter 83. Also, progesterone and

sodium reabsorption.

estrogens, which are female sex hormones, are secreted

As the extracellular fluid becomes depleted, plasma

in minute quantities.

volume falls, red blood cell concentration rises

Normally, the adrenal androgens have only weak

markedly, cardiac output decreases, and the patient dies

effects in humans. It is possible that part of the early

in shock, death usually occurring in the untreated

development of the male sex organs results from child-

patient 4 days to 2 weeks after cessation of mineralo-

hood secretion of adrenal androgens. The adrenal

corticoid secretion.

androgens also exert mild effects in the female, not only

before puberty but also throughout life. Much of the

growth of the pubic and axillary hair in the female

Glucocorticoid Deficiency. Loss of cortisol secretion makes

results from the action of these hormones.

it impossible for a person with Addison’s disease to

In extra-adrenal tissues, some of the adrenal andro-

maintain normal blood glucose concentration between

gens are converted to testosterone, the primary male sex

meals because he or she cannot synthesize significant

hormone, which probably accounts for much of their

quantities of glucose by gluconeogenesis. Furthermore,

androgenic activity. The physiologic effects of andro-

lack of cortisol reduces the mobilization of both

gens are discussed in Chapter 80 in relation to male

proteins and fats from the tissues, thereby depressing

sexual function.

many other metabolic functions of the body. This

958

Unit XIV Endocrinology and Reproduction

sluggishness of energy mobilization when cortisol is not

secretion” of ACTH by a tumor elsewhere in the body,

available is one of the major detrimental effects of glu-

such as an abdominal carcinoma; and (4) adenomas of

cocorticoid lack. Even when excess quantities of glucose

the adrenal cortex. When Cushing’s syndrome is sec-

and other nutrients are available, the person’s muscles

ondary to excess secretion of ACTH by the anterior

are weak, indicating that glucocorticoids are needed to

pituitary, this is referred to as Cushing’s disease.

maintain other metabolic functions of the tissues in

Excess ACTH secretion is the most common cause of

addition to energy metabolism.

Cushing’s syndrome and is characterized by high plasma

Lack of adequate glucocorticoid secretion also makes

levels of ACTH as well as cortisol. Primary overpro-

a person with Addison’s disease highly susceptible to

duction of cortisol by the adrenal glands accounts for

the deteriorating effects of different types of stress, and

about 20 to 25 per cent of clinical cases of Cushing’s syn-

even a mild respiratory infection can cause death.

drome and is usually associated with reduced ACTH

levels due to cortisol feedback inhibition of ACTH

Melanin Pigmentation. Another characteristic of most

secretion by the anterior pituitary gland.

people with Addison’s disease is melanin pigmentation

Administration of large doses of dexamethasone,

of the mucous membranes and skin. This melanin is not

a synthetic glucocorticoid, can be used to distinguish

always deposited evenly but occasionally is deposited in

between ACTH-dependent and ACTH-independent

blotches, and it is deposited especially in the thin skin

Cushing’s syndrome. In patients who have overproduc-

areas, such as the mucous membranes of the lips and the

tion of ACTH due to an ACTH-secreting pituitary

thin skin of the nipples.

adenoma or to hypothalamic-pituitary dysfunction,

The cause of the melanin deposition is believed to be

even large doses of dexamethasone usually do not

the following: When cortisol secretion is depressed, the

suppress ACTH secretion. In contrast, patients with

normal negative feedback to the hypothalamus and

primary adrenal overproduction of cortisol (ACTH-

anterior pituitary gland is also depressed, therefore

independent) usually have low or undetectable levels of

allowing tremendous rates of ACTH secretion as well

ACTH. The dexamethasone test, although widely used,

as simultaneous secretion of increased amounts of

can sometimes give an incorrect diagnosis, because

MSH. Probably the tremendous amounts of ACTH

some ACTH-secreting pituitary tumors respond to

cause most of the pigmenting effect because they can

dexamethasone with suppressed ACTH secretion.

stimulate formation of melanin by the melanocytes in

Therefore, it is usually considered to be a first step in

the same way that MSH does.

the differential diagnosis of Cushing’s syndrome.

Cushing’s syndrome can also occur when large

Treatment of People with Addison’s Disease. An untreated

amounts of glucocorticoids are administered over pro-

person with total adrenal destruction dies within a few

longed periods for therapeutic purposes. For example,

days to a few weeks because of weakness and usually

patients with chronic inflammation associated with dis-

circulatory shock. Yet such a person can live for years if

eases such as rheumatoid arthritis are often treated with

small quantities of mineralocorticoids and glucocorti-

glucocorticoids and may develop some of the clinical

coids are administered daily.

symptoms of Cushing’s syndrome.

A special characteristic of Cushing’s syndrome is

Addisonian Crisis. As noted earlier in the chapter, great

mobilization of fat from the lower part of the body, with

quantities of glucocorticoids are occasionally secreted

concomitant extra deposition of fat in the thoracic and

in response to different types of physical or mental

upper abdominal regions, giving rise to a buffalo torso.

stress. In a person with Addison’s disease, the output of

The excess secretion of steroids also leads to an ede-

glucocorticoids does not increase during stress. Yet

matous appearance of the face, and the androgenic

whenever different types of trauma, disease, or other

potency of some of the hormones sometimes causes

stresses, such as surgical operations, supervene, a person

acne and hirsutism (excess growth of facial hair). The

is likely to have an acute need for excessive amounts of

appearance of the face is frequently described as a

glucocorticoids and often must be given 10 or more

“moon face,” as demonstrated in the untreated patient

times the normal quantities of glucocorticoids to

with Cushing’s syndrome to the left in Figure 77-8.

prevent death.

About 80 per cent of patients have hypertension, pre-

This critical need for extra glucocorticoids and the

sumably because of the slight mineralocorticoid effects

associated severe debility in times of stress is called an

of cortisol.

addisonian crisis.

Effects on Carbohydrate and Protein Metabolism. The abun-

dance of cortisol secreted in Cushing’s syndrome can

Hyperadrenalism-Cushing’s

cause increased blood glucose concentration, some-

Syndrome

times to values as high as 200 mg/dl after meals-as much

as twice normal. This results mainly from enhanced glu-

Hypersecretion by the adrenal cortex causes a complex

coneogenesis and decreased glucose utilization by the

cascade of hormone effects called Cushing’s syndrome.

tissues.

Most of the abnormalities of Cushing’s syndrome are

The effects of glucocorticoids on protein catabolism

ascribable to abnormal amounts of cortisol, but excess

are often profound in Cushing’s syndrome, causing

secretion of androgens may also cause important

greatly decreased tissue proteins almost everywhere in

effects. Hypercortisolism can occur from multiple

the body with the exception of the liver; the plasma pro-

causes, including (1) adenomas of the anterior pituitary

teins also remain unaffected. The loss of protein from

that secrete large amounts of ACTH, which then causes

the muscles in particular causes severe weakness. The

adrenal hyperplasia and excess cortisol secretion; (2)

loss of protein synthesis in the lymphoid tissues leads to

abnormal function of the hypothalamus that causes high

a suppressed immune system, so that many of these

levels of corticotropin-releasing hormone

(CRH),

patients die of infections. Even the protein collagen

which stimulates excess ACTH release; (3) “ectopic

fibers in the subcutaneous tissue are diminished so that

Chapter 77

Adrenocortical Hormones

959

the subcutaneous tissues tear easily, resulting in devel-

paralysis caused by the hypokalemia. The paralysis is

opment of large purplish striae where they have torn

caused by a depressant effect of low extracellular potas-

apart. In addition, severely diminished protein deposi-

sium concentration on action potential transmission by

tion in the bones often causes severe osteoporosis with

the nerve fibers, as explained in Chapter 5.

consequent weakness of the bones.

One of the diagnostic criteria of primary aldostero-

nism is a decreased plasma renin concentration. This

Treatment of Cushing’s Syndrome. Treatment of Cushing’s

results from feedback suppression of renin secretion

syndrome consists of removing an adrenal tumor if this

caused by the excess aldosterone or by the excess extra-

is the cause or decreasing the secretion of ACTH, if

cellular fluid volume and arterial pressure resulting

this is possible. Hypertrophied pituitary glands or even

from the aldosteronism. Treatment of primary aldos-

small tumors in the pituitary that oversecrete ACTH

teronism is usually surgical removal of the tumor or of

can sometimes be surgically removed or destroyed

most of the adrenal tissue when hyperplasia is the cause.

by radiation. Drugs that block steroidogenesis, such as

metyrapone, ketoconazole, and aminoglutethimide, or

that inhibit ACTH secretion, such as serotonin antago-

Adrenogenital Syndrome

nists and GABA-transaminase inhibitors, can also be

used when surgery is not feasible. If ACTH secretion

An occasional adrenocortical tumor secretes excessive

cannot easily be decreased, the only satisfactory treat-

quantities of androgens that cause intense masculiniz-

ment is usually bilateral partial (or even total) adrena-

ing effects throughout the body. If this occurs in a

lectomy, followed by administration of adrenal steroids

female, she develops virile characteristics, including

to make up for any insufficiency that develops.

growth of a beard, a much deeper voice, occasionally

baldness if she also has the genetic trait for baldness,

masculine distribution of hair on the body and the pubis,

Primary Aldosteronism

growth of the clitoris to resemble a penis, and deposi-

(Conn’s Syndrome)

tion of proteins in the skin and especially in the muscles

to give typical masculine characteristics.

Occasionally a small tumor of the zona glomerulosa

In the prepubertal male, a virilizing adrenal tumor

cells occurs and secretes large amounts of aldosterone;

causes the same characteristics as in the female plus

the resulting condition is called “primary aldostero-

rapid development of the male sexual organs, as shown

nism” or “Conn’s syndrome.” Also, in a few instances,

in Figure 77-9, which depicts a 4-year-old boy with

hyperplastic adrenal cortices secrete aldosterone rather

adrenogenital syndrome. In the adult male, the viriliz-

than cortisol. The effects of the excess aldosterone are

ing characteristics of adrenogenital syndrome are

discussed in detail earlier in the chapter. The most

usually obscured by the normal virilizing characteristics

important effects are hypokalemia, slight increase

of the testosterone secreted by the testes. It is often dif-

in extracellular fluid volume and blood volume, very

ficult to make a diagnosis of adrenogenital syndrome in

slight increase in plasma sodium concentration (usually

the adult male. In adrenogenital syndrome, the excre-

not more than a

4 to

6 mEq/L increase), and,

tion of 17-ketosteroids (which are derived from andro-

almost always, hypertension. Especially interesting in

gens) in the urine may be 10 to 15 times normal. This

primary aldosteronism are occasional periods of muscle

finding can be used in diagnosing the disease.

Figure 77-9

A person with Cushing’s syn-

drome before

(left) and after

(right) subtotal adrenalectomy.

(Courtesy Dr. Leonard Posey.)

960

Unit XIV

Endocrinology and Reproduction

syndrome: a consensus statement. J Clin Endocrinol

Metab 88:5593, 2003.

Besser GM, Thorner MO: Comprehensive Clinical

Endocrinology,

3rd ed. Philadelphia: Mosby, Elsevier

Science Limited, 2002.

Boldyreff B, Wehling M: Aldosterone: refreshing a slow

hormone by swift action. News Physiol Sci 19:97, 2004.

Boscaro M, Barzon L, Fallo F, Sonino N: Cushing’s syn-

drome. Lancet 357:783, 2001.

Cooper MS, Stewart PM: Corticosteroid insufficiency in

acutely ill patients. N Engl J Med 348:727, 2003.

De Bosscher K, Vanden Berghe W, Haegeman G: The inter-

play between the glucocorticoid receptor and nuclear

factor-kappa B or activator protein-1: molecular mecha-

nisms for gene repression. Endocr Rev 24:488, 2003.

de Paula RB, da Silva AA, Hall JE: Aldosterone antagonism

attenuates obesity-induced hypertension and glomerular

hyperfiltration. Hypertension 43:41, 2004.

Farman N, Rafestin-Oblin ME: Multiple aspects of miner-

alocorticoid selectivity. Am J Physiol Renal Physiol 280:

F181, 2001.

Hall JE, Granger JP, Smith MJ Jr, Premen AJ: Role of renal

hemodynamics and arterial pressure in aldosterone

“escape.” Hypertension 6 :I183, 1984.

Larsen PR, Kronenberg HM, Melmed S, Polonsky KS:

Williams Textbook of Endocrinology, 10th ed. Philadel-

phia: WB Saunders Co, 2003.

Lösel RM, Falkenstein E, Feuring M, Schultz M, Tillmann

HC, Rossol-Haseroth K, Wehling M: Nongenomic steroid

action: Controversies, questions, and answers. Physiol Rev

83:965, 2003.

New MI: Inborn errors of adrenal steroidogenesis. Mol Cell

Endocrinol 211:75, 2003

Oberleithner H: Unorthodox sites and modes of aldosterone

action. News Physiol Sci 19:51, 2004.

O’Shaughnessy KM, Karet FE: Salt handling and hyperten-

sion. J Clin Invest 113:1075, 2004.

Raff H, Findling JW: A physiologic approach to diagnosis of

the Cushing syndrome. Ann Intern Med 138:980, 2003.

Sheppard KE: Nuclear receptors. II. Intestinal corticosteroid

receptors. Am J Physiol Gastrointest Liver Physiol

282:G742, 2002.

Spat A, Hunyady L: Control of aldosterone secretion: a

model for convergence in cellular signaling pathways

Figure 77-10

Physiol Rev 84:489, 2004.

Adrenogenital

syndrome

4-year-old

boy.

(Courtesy

Dr.

Speiser PW, White PC: Congenital adrenal hyperplasia.

Leonard Posey.)

N Engl J Med 349:776, 2003.

Stewart PM: Adrenal replacement therapy: time for an

inward look to the medulla? J Clin Endocrinol Metab

89:3677, 2004.

References

Stocco DM: StAR protein and the regulation of steroid

hormone biosynthesis. Annu Rev Physiol 63:193, 2001.

Arnaldi G, Angeli A, Atkinson AB, Bertagna X, Cavagnini

Stockand JD: New ideas about aldosterone signaling in

F, Chrousos GP, Fava GA, Findling JW, Gaillard RC,

epithelia. Am J Physiol Renal Physiol 282:F559, 2002.

Grossman AB, Kola B, Lacroix A, Mancini T, Mantero F,

Stowasser M, Gordon RD: Primary aldosteronism: from

Newell-Price J, Nieman LK, Sonino N, Vance ML, Giustina

genesis to genetics. Trends Endocrinol Metab

14:310,

A, Boscaro M: Diagnosis and complications of Cushing’s

2003.

C H A P T E R

Insulin, Glucagon, and

Diabetes Mellitus

The pancreas, in addition to its digestive functions,

secretes two important hormones, insulin and

glucagon, that are crucial for normal regulation of

glucose, lipid, and protein metabolism. Although the

pancreas secretes other hormones, such as amylin,

somatostatin, and pancreatic polypeptide, their func-

tions are not as well established. The main purpose

of this chapter is to discuss the physiologic roles of

insulin and glucagon and the pathophysiology of diseases, especially diabetes

mellitus, caused by abnormal secretion or activity of these hormones.

Physiologic Anatomy of the Pancreas. The pancreas is composed of two major types of

tissues, as shown in Figure 78-1: (1) the acini, which secrete digestive juices into the

duodenum, and (2) the islets of Langerhans, which secrete insulin and glucagon

directly into the blood. The digestive secretions of the pancreas are discussed in

Chapter 64.

The human pancreas has 1 to 2 million islets of Langerhans, each only about 0.3

millimeter in diameter and organized around small capillaries into which its cells

secrete their hormones. The islets contain three major types of cells, alpha, beta, and

delta cells, which are distinguished from one another by their morphological and

staining characteristics.

The beta cells, constituting about 60 per cent of all the cells of the islets, lie mainly

in the middle of each islet and secrete insulin and amylin, a hormone that is often

secreted in parallel with insulin, although its function is unclear. The alpha cells,

about 25 per cent of the total, secrete glucagon. And the delta cells, about 10 per

cent of the total, secrete somatostatin. In addition, at least one other type of cell,

the PP cell, is present in small numbers in the islets and secretes a hormone of uncer-

tain function called pancreatic polypeptide.

The close interrelations among these cell types in the islets of Langerhans allow

cell-to-cell communication and direct control of secretion of some of the hormones

by the other hormones. For instance, insulin inhibits glucagon secretion, amylin

inhibits insulin secretion, and somatostatin inhibits the secretion of both insulin and

glucagon.

Insulin and Its Metabolic Effects

Insulin was first isolated from the pancreas in 1922 by Banting and Best, and

almost overnight the outlook for the severely diabetic patient changed from one

of rapid decline and death to that of a nearly normal person. Historically, insulin

has been associated with “blood sugar,” and true enough, insulin has profound

effects on carbohydrate metabolism. Yet it is abnormalities of fat metabolism,

causing such conditions as acidosis and arteriosclerosis, that are the usual causes

of death in diabetic patients. Also, in patients with prolonged diabetes, dimin-

ished ability to synthesize proteins leads to wasting of the tissues as well as many

cellular functional disorders. Therefore, it is clear that insulin affects fat and

protein metabolism almost as much as it does carbohydrate metabolism.

Insulin Is a Hormone Associated with Energy Abundance

As we discuss insulin in the next few pages, it will become apparent that insulin

secretion is associated with energy abundance. That is, when there is great

961

962

Unit XIV Endocrinology and Reproduction

abundance of energy-giving foods in the diet, espe-

Chapter 3, beginning with translation of the insulin

cially excess amounts of carbohydrates, insulin is

RNA by ribosomes attached to the endoplasmic re-

secreted in great quantity. In turn, the insulin plays an

ticulum to form an insulin preprohormone. This

important role in storing the excess energy. In the case

initial preprohormone has a molecular weight of about

of excess carbohydrates, it causes them to be stored as

11,500, but it is then cleaved in the endoplasmic retic-

glycogen mainly in the liver and muscles. Also, all the

ulum to form a proinsulin with a molecular weight

excess carbohydrates that cannot be stored as glyco-

of about 9000; most of this is further cleaved in the

gen are converted under the stimulus of insulin into

Golgi apparatus to form insulin and peptide fragments

fats and stored in the adipose tissue. In the case of pro-

before being packaged in the secretory granules.

teins, insulin has a direct effect in promoting amino

However, about one sixth of the final secreted product

acid uptake by cells and conversion of these amino

is still in the form of proinsulin. The proinsulin has vir-

acids into protein. In addition, it inhibits the break-

tually no insulin activity.

down of the proteins that are already in the cells.

When insulin is secreted into the blood, it circulates

almost entirely in an unbound form; it has a plasma

Insulin Chemistry and Synthesis

half-life that averages only about 6 minutes, so that it

Insulin is a small protein; human insulin has a molec-

is mainly cleared from the circulation within 10 to 15

ular weight of 5808. It is composed of two amino acid

minutes. Except for that portion of the insulin that

chains, shown in Figure 78-2, connected to each other

combines with receptors in the target cells, the remain-

by disulfide linkages. When the two amino acid chains

der is degraded by the enzyme insulinase mainly in the

are split apart, the functional activity of the insulin

liver, to a lesser extent in the kidneys and muscles, and

molecule is lost.

slightly in most other tissues. This rapid removal from

Insulin is synthesized in the beta cells by the usual

the plasma is important, because, at times, it is as

cell machinery for protein synthesis, as explained in

important to turn off rapidly as to turn on the control

functions of insulin.

Activation of Target Cell Receptors by Insulin

Islet of

Pancreatic

and the Resulting Cellular Effects

Langerhans

acini

To initiate its effects on target cells, insulin first binds

with and activates a membrane receptor protein that

Delta cell

has a molecular weight of about 300,000 (Figure 78-3).

It is the activated receptor, not the insulin, that causes

the subsequent effects.

The insulin receptor is a combination of four sub-

units held together by disulfide linkages: two alpha

subunits that lie entirely outside the cell membrane

and two beta subunits that penetrate through the mem-

brane, protruding into the cell cytoplasm. The insulin

Alpha cell

binds with the alpha subunits on the outside of the cell,

but because of the linkages with the beta subunits, the

Red blood cells

portions of the beta subunits protruding into the cell

Beta cell

become autophosphorylated. Thus, the insulin recep-

tor is an example of an enzyme-linked receptor, dis-

Figure 78-1

cussed in Chapter 74. Autophosphorylation of the beta

subunits of the receptor activates a local tyrosine

Physiologic anatomy of an islet of Langerhans in the pancreas.

NH₂

Gly•Ileu•Val•Glu•Glu•Cy•Cy•Thr•Ser•Ileu•Cy•Ser•Leu•Tyr•Glu•Leu•Glu•Asp•Tyr•Cy•Asp

NH₂

Phe•Val•Asp•Glu•His•Leu•Cy•Gly•Ser•His•Leu•Val•Glu•Ala•Leu•Tyr•Leu•Val•Cy•Gly•Glu•Arg•Gly•Phe•Phe•Tyr•Thr•Pro•Lys•Thr

Figure 78-2

Human insulin molecule.

Chapter 78

Insulin, Glucagon, and Diabetes Mellitus

963

about 3 to 5 minutes and move back to the cell

Insulin

interior to be used again and again as needed.

2. The cell membrane becomes more permeable to

Insulin

many of the amino acids, potassium ions, and

receptor

phosphate ions, causing increased transport of

S S

these substances into the cell.

3. Slower effects occur during the next 10 to 15

minutes to change the activity levels of many

Glucose

more intracellular metabolic enzymes. These

effects result mainly from the changed states of

Cell membrane

phosphorylation of the enzymes.

4. Much slower effects continue to occur for hours

and even several days. They result from changed

Tyrosine

rates of translation of messenger RNAs at the

kinase

ribosomes to form new proteins and still slower

Insulin receptor substrates (IRS)

effects from changed rates of transcription of

Phosphorylation of enzymes

DNA in the cell nucleus. In this way, insulin

remolds much of the cellular enzymatic machinery

Glucose

Fat

Growth

to achieve its metabolic goals.

transport

synthesis

and gene

expression

Protein

Glucose

Effect of Insulin on Carbohydrate

synthesis

Metabolism

Figure 78-3

Immediately after a high-carbohydrate meal, the

Schematic of the insulin receptor. Insulin binds to the a-subunit of

glucose that is absorbed into the blood causes rapid

its receptor, which causes autophosphorylation of the b-subunit

secretion of insulin, which is discussed in detail later

receptor, which in turn induces tyrosine kinase activity. The recep-

in the chapter. The insulin in turn causes rapid uptake,

tor tyrosine kinase activity begins a cascade of cell phosphoryla-

storage, and use of glucose by almost all tissues of the

tion that increases or decreases the activity of enzymes, including

body, but especially by the muscles, adipose tissue, and

insulin receptor substrates, that mediate the effects of glucose on

liver.

glucose, fat, and protein metabolism. For example, glucose trans-

porters are moved to the cell membrane to facilitate glucose entry

into the cell.

Insulin Promotes Muscle Glucose Uptake

and Metabolism

During much of the day, muscle tissue depends not on

kinase, which in turn causes phosphorylation of multi-

glucose for its energy but on fatty acids. The principal

ple other intracellular enzymes including a group

reason for this is that the normal resting muscle mem-

called insulin-receptor substrates

(IRS). Different

brane is only slightly permeable to glucose, except

types of IRS (e.g. IRS-1, IRS-2, IRS-3) are expressed

when the muscle fiber is stimulated by insulin; between

in different tissues. The net effect is to activate some

meals, the amount of insulin that is secreted is too

of these enzymes while inactivating others. In this way,

small to promote significant amounts of glucose entry

insulin directs the intracellular metabolic machinery to

into the muscle cells.

produce the desired effects on carbohydrate, fat, and

However, under two conditions the muscles do use

protein metabolism. The end effects of insulin stimu-

large amounts of glucose. One of these is during mod-

lation are the following:

erate or heavy exercise. This usage of glucose does not

1. Within seconds after insulin binds with its

require large amounts of insulin, because exercising

membrane receptors, the membranes of about

muscle fibers become more permeable to glucose even

80 per cent of the body’s cells markedly increase

in the absence of insulin because of the contraction

their uptake of glucose. This is especially true of

process itself.

muscle cells and adipose cells but is not true of

The second condition for muscle usage of large

most neurons in the brain. The increased glucose

amounts of glucose is during the few hours after a

transported into the cells is immediately

meal. At this time the blood glucose concentration is

phosphorylated and becomes a substrate for all

high and the pancreas is secreting large quantities of

the usual carbohydrate metabolic functions. The

insulin. The extra insulin causes rapid transport of

increased glucose transport is believed to result

glucose into the muscle cells. This causes the muscle

from translocation of multiple intracellular

cell during this period to use glucose preferentially

vesicles to the cell membranes; these vesicles

over fatty acids, as we discuss later.

carry in their own membranes multiple molecules

of glucose transport proteins, which bind with the

Storage of Glycogen in Muscle. If the muscles are not

cell membrane and facilitate glucose uptake into

exercising after a meal and yet glucose is transported

the cells. When insulin is no longer available, these

into the muscle cells in abundance, then most of the

vesicles separate from the cell membrane within

glucose is stored in the form of muscle glycogen

964

Unit XIV Endocrinology and Reproduction

instead of being used for energy, up to a limit of 2 to

The mechanism by which insulin causes glucose

3 per cent concentration. The glycogen can later be

uptake and storage in the liver includes several almost

used for energy by the muscle. It is especially useful

simultaneous steps:

for short periods of extreme energy use by the muscles

1. Insulin inactivates liver phosphorylase, the

and even to provide spurts of anaerobic energy for a

principal enzyme that causes liver glycogen to

few minutes at a time by glycolytic breakdown of the

split into glucose. This prevents breakdown of the

glycogen to lactic acid, which can occur even in the

glycogen that has been stored in the liver cells.

absence of oxygen.

2. Insulin causes enhanced uptake of glucose from

the blood by the liver cells. It does this by

Quantitative Effect of Insulin to Facilitate Glucose Transport

increasing the activity of the enzyme glucokinase,

Through the Muscle Cell Membrane. The quantitative

which is one of the enzymes that causes the initial

effect of insulin to facilitate glucose transport through

phosphorylation of glucose after it diffuses into

the muscle cell membrane is demonstrated by the

the liver cells. Once phosphorylated, the glucose is

experimental results shown in Figure 78-4. The lower

temporarily trapped inside the liver cells because

curve labeled “control” shows the concentration of

phosphorylated glucose cannot diffuse back

free glucose measured inside the cell, demonstrating

through the cell membrane.

that the glucose concentration remained almost zero

3. Insulin also increases the activities of the enzymes

despite increased extracellular glucose concentration

that promote glycogen synthesis, including

up to as high as 750 mg/100 ml. In contrast, the curve

especially glycogen synthase, which is responsible

labeled “insulin” demonstrates that the intracellular

for polymerization of the monosaccharide units to

glucose concentration rose to as high as 400 mg/100 ml

form the glycogen molecules.

when insulin was added. Thus, it is clear that insulin

The net effect of all these actions is to increase the

can increase the rate of transport of glucose into the

amount of glycogen in the liver. The glycogen can

resting muscle cell by at least 15-fold.

increase to a total of about 5 to 6 per cent of the liver

mass, which is equivalent to almost 100 grams of stored

Insulin Promotes Liver Uptake, Storage, and

glycogen in the whole liver.

Use of Glucose

One of the most important of all the effects of insulin

Glucose Is Released from the Liver Between Meals. When the

is to cause most of the glucose absorbed after a meal

blood glucose level begins to fall to a low level

to be stored almost immediately in the liver in the

between meals, several events transpire that cause the

form of glycogen. Then, between meals, when food is

liver to release glucose back into the circulating blood:

not available and the blood glucose concentration

1. The decreasing blood glucose causes the pancreas

begins to fall, insulin secretion decreases rapidly and

to decrease its insulin secretion.

the liver glycogen is split back into glucose, which is

2. The lack of insulin then reverses all the effects

released back into the blood to keep the glucose con-

listed earlier for glycogen storage, essentially

centration from falling too low.

stopping further synthesis of glycogen in the liver

and preventing further uptake of glucose by the

liver from the blood.

3. The lack of insulin (along with increase of

glucagon, which is discussed later) activates the

enzyme phosphorylase, which causes the splitting

400

of glycogen into glucose phosphate.

300

Insulin

4. The enzyme glucose phosphatase, which had been

inhibited by insulin, now becomes activated by the

200

insulin lack and causes the phosphate radical to

split away from the glucose; this allows the free

100

Control

glucose to diffuse back into the blood.

Thus, the liver removes glucose from the blood

when it is present in excess after a meal and returns it

to the blood when the blood glucose concentration

300

600

900

falls between meals. Ordinarily, about 60 per cent of

Extracellular glucose

the glucose in the meal is stored in this way in the liver

(mg/100 ml)

and then returned later.

Insulin Promotes Conversion of Excess Glucose into Fatty Acids

Figure 78-4

and Inhibits Gluconeogenesis in the Liver. When the quan-

tity of glucose entering the liver cells is more than can

Effect of insulin in enhancing the concentration of glucose inside

muscle cells. Note that in the absence of insulin (control), the

be stored as glycogen or can be used for local hepato-

intracellular glucose concentration remains near zero, despite

cyte metabolism, insulin promotes the conversion

high extracellular glucose concentrations. (Data from Eisenstein

AB: The Biochemical Aspects of Hormone Action, Boston, Little,

of all this excess glucose into fatty acids. These fatty

Brown, 1964.)

acids are subsequently packaged as triglycerides in

Chapter 78

Insulin, Glucagon, and Diabetes Mellitus

965

very-low-density lipoproteins and transported in this

automatically decreases the utilization of fat, thus

form by way of the blood to the adipose tissue and

functioning as a fat sparer. However, insulin also

deposited as fat.

promotes fatty acid synthesis. This is especially true

Insulin also inhibits gluconeogenesis. It does this

when more carbohydrates are ingested than can be

mainly by decreasing the quantities and activities of

used for immediate energy, thus providing the sub-

the liver enzymes required for gluconeogenesis.

strate for fat synthesis. Almost all this synthesis occurs

However, part of the effect is caused by an action

in the liver cells, and the fatty acids are then trans-

of insulin that decreases the release of amino acids

ported from the liver by way of the blood lipoproteins

from muscle and other extrahepatic tissues and in

to the adipose cells to be stored. The different factors

turn the availability of these necessary precursors

that lead to increased fatty acid synthesis in the liver

required for gluconeogenesis. This is discussed

include the following:

further in relation to the effect of insulin on protein

Insulin increases the transport of glucose into the

metabolism.

liver cells. After the liver glucogen concentration

reaches 5 to 6 per cent, this in itself inhibits

further glycogen synthesis. Then all the additional

Lack of Effect of Insulin on Glucose Uptake

glucose entering the liver cells becomes available

and Usage by the Brain

to form fat. The glucose is first split to pyruvate

The brain is quite different from most other tissues of

in the glycolytic pathway, and the pyruvate

the body in that insulin has little effect on uptake or

subsequently is converted to acetyl coenzyme A

use of glucose. Instead, the brain cells are permeable to

(acetyl-CoA), the substrate from which fatty acids

glucose and can use glucose without the intermediation

are synthesized.

of insulin.

An excess of citrate and isocitrate ions is formed

The brain cells are also quite different from most

by the citric acid cycle when excess amounts of

other cells of the body in that they normally use only

glucose are being used for energy. These ions then

glucose for energy and can use other energy sub-

have a direct effect in activating acetyl-CoA

strates, such as fats, only with difficulty. Therefore, it is

carboxylase, the enzyme required to carboxylate

essential that the blood glucose level always be main-

acetyl-CoA to form malonyl-CoA, the first stage

tained above a critical level, which is one of the most

of fatty acid synthesis.

important functions of the blood glucose control

Most of the fatty acids are then synthesized within

system. When the blood glucose falls too low, into

the liver itself and used to form triglycerides, the

the range of 20 to 50 mg/100 ml, symptoms of hypo-

usual form of storage fat. They are released from

glycemic shock develop, characterized by progressive

the liver cells to the blood in the lipoproteins.

nervous irritability that leads to fainting, seizures, and

Insulin activates lipoprotein lipase in the capillary

even coma.

walls of the adipose tissue, which splits the

triglycerides again into fatty acids, a requirement

Effect of Insulin on Carbohydrate Metabolism

for them to be absorbed into the adipose cells,

in Other Cells

where they are again converted to triglycerides

Insulin increases glucose transport into and glucose

and stored.

usage by most other cells of the body (with the excep-

tion of the brain cells, as noted) in the same way that

it affects glucose transport and usage in muscle cells.

Role of Insulin in Storage of Fat in the Adipose Cells. Insulin

The transport of glucose into adipose cells mainly pro-

has two other essential effects that are required for fat

vides substrate for the glycerol portion of the fat mol-

storage in adipose cells:

ecule. Therefore, in this indirect way, insulin promotes

1. Insulin inhibits the action of hormone-sensitive

deposition of fat in these cells.

lipase. This is the enzyme that causes hydrolysis of

the triglycerides already stored in the fat cells.

Therefore, the release of fatty acids from the

Effect of Insulin on Fat Metabolism

adipose tissue into the circulating blood is

inhibited.

Although not quite as visible as the acute effects of

2. Insulin promotes glucose transport through the cell

insulin on carbohydrate metabolism, insulin’s effects

membrane into the fat cells in exactly the same

on fat metabolism are, in the long run, equally impor-

ways that it promotes glucose transport into

tant. Especially dramatic is the long-term effect of

muscle cells. Some of this glucose is then used to

insulin lack in causing extreme atherosclerosis, often

synthesize minute amounts of fatty acids, but

leading to heart attacks, cerebral strokes, and other

more important, it also forms large quantities of

vascular accidents. But first, let us discuss the acute

a-glycerol phosphate. This substance supplies the

effects of insulin on fat metabolism.

glycerol that combines with fatty acids to form

the triglycerides that are the storage form of fat

Insulin Promotes Fat Synthesis and Storage

in adipose cells. Therefore, when insulin is not

Insulin has several effects that lead to fat storage in

available, even storage of the large amounts of

adipose tissue. First, insulin increases the utilization

fatty acids transported from the liver in the

of glucose by most of the body’s tissues, which

lipoproteins is almost blocked.

966

Unit XIV Endocrinology and Reproduction

Insulin Deficiency Increases Use of Fat

the liver, are then discharged into the blood in the

for Energy

lipoproteins. Occasionally the plasma lipoproteins

All aspects of fat breakdown and use for providing

increase as much as threefold in the absence of insulin,

energy are greatly enhanced in the absence of insulin.

giving a total concentration of plasma lipids of several

This occurs even normally between meals when secre-

per cent rather than the normal 0.6 per cent. This high

tion of insulin is minimal, but it becomes extreme in

lipid concentration—especially the high concentration

diabetes mellitus when secretion of insulin is almost

of cholesterol—promotes the development of athero-

zero. The resulting effects are as follows.

sclerosis in people with serious diabetes.

Insulin Deficiency Causes Lipolysis of Storage Fat and Release

Excess Usage of Fats During Insulin Lack Causes Ketosis and

of Free Fatty Acids. In the absence of insulin, all the

Acidosis. Insulin lack also causes excessive amounts of

effects of insulin noted earlier that cause storage of

acetoacetic acid to be formed in the liver cells. This

fat are reversed. The most important effect is that

results from the following effect: In the absence of

the enzyme hormone-sensitive lipase in the fat cells

insulin but in the presence of excess fatty acids in the

becomes strongly activated. This causes hydrolysis of

liver cells, the carnitine transport mechanism for trans-

the stored triglycerides, releasing large quantities of

porting fatty acids into the mitochondria becomes

fatty acids and glycerol into the circulating blood.

increasingly activated. In the mitochondria, beta oxi-

Consequently, the plasma concentration of free fatty

dation of the fatty acids then proceeds very rapidly,

acids begins to rise within minutes. This free fatty acid

releasing extreme amounts of acetyl-CoA. A large part

then becomes the main energy substrate used by

of this excess acetyl-CoA is then condensed to form

essentially all tissues of the body besides the brain.

acetoacetic acid, which in turn is released into the cir-

Figure 78-5 shows the effect of insulin lack on the

culating blood. Most of this passes to the peripheral

plasma concentrations of free fatty acids, glucose, and

cells, where it is again converted into acetyl-CoA and

acetoacetic acid. Note that almost immediately after

used for energy in the usual manner.

removal of the pancreas, the free fatty acid concentra-

At the same time, the absence of insulin also

tion in the plasma begins to rise, more rapidly even

depresses the utilization of acetoacetic acid in the

than the concentration of glucose.

peripheral tissues. Thus, so much acetoacetic acid is

released from the liver that it cannot all be metabo-

Insulin Deficiency Increases Plasma Cholesterol and Phospho-

lized by the tissues. Therefore, as shown in Figure 78-5,

lipid Concentrations. The excess of fatty acids in the

its concentration rises during the days after cessation

plasma associated with insulin deficiency also pro-

of insulin secretion, sometimes reaching concentra-

motes liver conversion of some of the fatty acids into

tions of 10 mEq/L or more, which is a severe state of

phospholipids and cholesterol, two of the major prod-

body fluid acidosis.

ucts of fat metabolism. These two substances, along

As explained in Chapter 68, some of the acetoacetic

with excess triglycerides formed at the same time in

acid is also converted into b-hydroxybutyric acid and

acetone. These two substances, along with the ace-

toacetic acid, are called ketone bodies, and their pres-

ence in large quantities in the body fluids is called

ketosis. We see later that in severe diabetes the ace-

Control

Depancreatized

toacetic acid and the b-hydroxybutyric acid can cause

severe acidosis and coma, which often leads to death.

Blood glucose

Effect of Insulin on Protein

Metabolism and on Growth

Free fatty acids

Insulin Promotes Protein Synthesis and Storage. During the

few hours after a meal when excess quantities of nutri-

ents are available in the circulating blood, not only car-

bohydrates and fats but proteins as well are stored in

the tissues; insulin is required for this to occur. The

manner in which insulin causes protein storage is not

Acetoacetic acid

as well understood as the mechanisms for both glucose

and fat storage. Some of the facts follow.

1. Insulin stimulates transport of many of the amino

Days

acids into the cells. Among the amino acids most

strongly transported are valine, leucine, isoleucine,

tyrosine, and phenylalanine. Thus, insulin shares

Figure 78-5

with growth hormone the capability of increasing

the uptake of amino acids into cells. However, the

Effect of removing the pancreas on the approximate concentra-

amino acids affected are not necessarily the same

tions of blood glucose, plasma free fatty acids, and acetoacetic

acid.

ones.

Chapter 78

Insulin, Glucagon, and Diabetes Mellitus

967

Insulin increases the translation of messenger

RNA, thus forming new proteins. In some

Growth hormone

unexplained way, insulin “turns on” the ribosomal

and insulin

machinery. In the absence of insulin, the

250

ribosomes simply stop working, almost as if

Depancreatized and

insulin operates an “on-off” mechanism.

200

hypophysectomized

Over a longer period of time, insulin also

increases the rate of transcription of selected DNA

150

Growth

Insulin

genetic sequences in the cell nuclei, thus forming

hormone

100

increased quantities of RNA and still more

protein synthesis—especially promoting a vast

array of enzymes for storage of carbohydrates,

fats, and proteins.

Insulin inhibits the catabolism of proteins, thus

100

150

200

250

decreasing the rate of amino acid release from the

Days

cells, especially from the muscle cells. Presumably

this results from the ability of insulin to diminish

the normal degradation of proteins by the cellular

Figure 78-6

lysosomes.

In the liver, insulin depresses the rate of

Effect of growth hormone, insulin, and growth hormone plus insulin

gluconeogenesis. It does this by decreasing

on growth in a depancreatized and hypophysectomized rat.

the activity of the enzymes that promote

gluconeogenesis. Because the substrates most used

for synthesis of glucose by gluconeogenesis are

Mechanisms of Insulin Secretion

the plasma amino acids, this suppression of

gluconeogenesis conserves the amino acids in the

Figure 78-7 shows the basic cellular mechanisms for

protein stores of the body.

insulin secretion by the pancreatic beta cells in

In summary, insulin promotes protein formation and

response to increased blood glucose concentration, the

prevents the degradation of proteins.

primary controller of insulin secretion. The beta cells

have a large number of glucose transporters (GLUT-

Insulin Lack Causes Protein Depletion and Increased Plasma

2) that permit a rate of glucose influx that is propor-

Amino Acids. Virtually all protein storage comes to a

tional to the blood concentration in the physiologic

halt when insulin is not available. The catabolism of

range. Once inside the cells, glucose is phosphorylated

proteins increases, protein synthesis stops, and large

to glucose-6-phosphate by glucokinase. This step

quantities of amino acids are dumped into the plasma.

appears to be the rate limiting for glucose metabolism

The plasma amino acid concentration rises consider-

in the beta cell and is considered the major mechanism

ably, and most of the excess amino acids are used

for glucose sensing and adjustment of the amount of

either directly for energy or as substrates for gluco-

secreted insulin to the blood glucose levels.

neogenesis. This degradation of the amino acids also

The glucose-6-phosphate is subsequently oxidized to

leads to enhanced urea excretion in the urine. The

form adenosine triphosphate (ATP), which inhibits the

resulting protein wasting is one of the most serious of

ATP-sensitive potassium channels of the cell. Closure

all the effects of severe diabetes mellitus. It can lead

of the potassium channels depolarizes the cell mem-

to extreme weakness as well as many deranged func-

brane, thereby opening voltage-gated calcium chan-

tions of the organs.

nels, which are sensitive to changes in membrane

voltage. This produces an influx of calcium that stimu-

Insulin and Growth Hormone Interact Synergistically to Promote

lates fusion of the docked insulin-containing vesicles

Growth. Because insulin is required for the synthesis of

with the cell membrane and secretion of insulin into

proteins, it is as essential for growth of an animal as

the extracellular fluid by exocytosis.

growth hormone is. This is demonstrated in Figure

Other nutrients, such as certain amino acids, can also

78-6, which shows that a depancreatized, hypophysec-

be metabolized by the beta cells to increase intracel-

tomized rat without therapy hardly grows at all.

lular ATP levels and stimulate insulin secretion. Some

Furthermore, the administration of either growth

hormones, such as glucagon and gastric inhibitory

hormone or insulin one at a time causes almost no

peptide, as well as acetylcholine increase intracellular

growth. Yet a combination of these hormones causes

calcium levels through other signaling pathways and

dramatic growth. Thus, it appears that the two hor-

enhance the effect of glucose, although they do not

mones function synergistically to promote growth,

have major effects on insulin secretion in the absence

each performing a specific function that is separate

of glucose. Other hormones, including somatostatin

from that of the other. Perhaps a small part of this

and norepinephrine (by activating a-adrenergic recep-

necessity for both hormones results from the fact that

tors), inhibit exocytosis of insulin.

each promotes cellular uptake of a different selection

Sulfonylurea drugs stimulate insulin secretion by

of amino acids, all of which are required if growth is

binding to the ATP-sensitive potassium channels and

to be achieved.

blocking their activity. This results in a depolarizing

968

Unit XIV Endocrinology and Reproduction

Glucose

Insulin

GLUT 2

250

Glucose

Glucokinase

Glucose-6-phosphate

Oxidation

-10

Minutes

ATP

Ca⁺⁺

K⁺

Depolarization

Figure 78-8

Increase in plasma insulin concentration after a sudden increase

in blood glucose to two to three times the normal range. Note an

initial rapid surge in insulin concentration and then a delayed but

ATP + K⁺ channel

Ca⁺⁺ channel

higher and continuing increase in concentration beginning 15 to

(closed)

(open)

20 minutes later.

Figure 78-7

Basic mechanisms of glucose stimulation of insulin secretion by

metabolism, it has become apparent that blood amino

beta cells of the pancreas. GLUT, glucose transporter.

acids and other factors also play important roles in

controlling insulin secretion (see Table 78-1).

Table 78-1

Increased Blood Glucose Stimulates Insulin Secretion. At

the normal fasting level of blood glucose of 80 to

Factors and Conditions That Increase or Decrease

90 mg/100 ml, the rate of insulin secretion is minimal—

Insulin Secretion

on the order of 25 ng/min/kg of body weight, a level

that has only slight physiologic activity. If the blood

Increase Insulin Secretion

Decrease Insulin Secretion

glucose concentration is suddenly increased to a level

two to three times normal and kept at this high level

• Increased blood glucose

• Decreased blood glucose

• Increased blood free fatty acids

• Fasting

thereafter, insulin secretion increases markedly in two

• Increased blood amino acids

• Somatostatin

stages, as shown by the changes in plasma insulin con-

• Gastrointestinal hormones

• a-Adrenergic activity

centration seen in Figure 78-8.

(gastrin, cholecystokinin, secretin,

• Leptin

1. Plasma insulin concentration increases almost

gastric inhibitory peptide)

• Glucagon, growth hormone,

10-fold within 3 to 5 minutes after the acute

cortisol

elevation of the blood glucose; this results from

• Parasympathetic stimulation;

immediate dumping of preformed insulin from the

acetylcholine

beta cells of the islets of Langerhans. However,

• b-Adrenergic stimulation

the initial high rate of secretion is not maintained;

• Insulin resistance; obesity

• Sulfonylurea drugs (glyburide,

instead, the insulin concentration decreases about

tolbutamide)

halfway back toward normal in another 5 to 10

minutes.

2. Beginning at about 15 minutes, insulin secretion

rises a second time and reaches a new plateau in

effect that triggers insulin secretion, making these

2 to 3 hours, this time usually at a rate of

drugs very useful in stimulating insulin secretion in

secretion even greater than that in the initial

patients with type II diabetes, as we will discuss later.

phase. This secretion results both from additional

Table 78-1 summarizes some of the factors that can

release of preformed insulin and from activation

increase or decrease insulin secretion.

of the enzyme system that synthesizes and

releases new insulin from the cells.

Control of Insulin Secretion

Feedback Relation Between Blood Glucose Concentration and

Insulin Secretion Rate. As the concentration of blood

Formerly, it was believed that insulin secretion was

glucose rises above 100 mg/100 ml of blood, the rate

controlled almost entirely by the blood glucose con-

of insulin secretion rises rapidly, reaching a peak some

centration. However, as more has been learned about

10 to 25 times the basal level at blood glucose con-

the metabolic functions of insulin for protein and fat

centrations between 400 and 600 mg/100 ml, as shown

Chapter 78

Insulin, Glucagon, and Diabetes Mellitus

969

cholecystokinin, and gastric inhibitory peptide (which

seems to be the most potent)—causes a moderate

increase in insulin secretion. These hormones are

released in the gastrointestinal tract after a person eats

a meal. They then cause an “anticipatory” increase in

blood insulin in preparation for the glucose and amino

acids to be absorbed from the meal. These gastroin-

testinal hormones generally act the same way as amino

acids to increase the sensitivity of insulin response to

increased blood glucose, almost doubling the rate of

insulin secretion as the blood glucose level rises.

Other Hormones and the Autonomic Nervous System. Other hor-

100

200

300

400

500

600

mones that either directly increase insulin secretion or

Plasma glucose concentration

potentiate the glucose stimulus for insulin secretion

(mg/100 ml)

include glucagon, growth hormone, cortisol, and, to a

lesser extent, progesterone and estrogen. The impor-

tance of the stimulatory effects of these hormones is

that prolonged secretion of any one of them in large

Figure 78-9

quantities can occasionally lead to exhaustion of the

beta cells of the islets of Langerhans and thereby

Approximate insulin secretion at different plasma glucose levels.

increase the risk for developing diabetes mellitus.

Indeed, diabetes often occurs in people who are main-

tained on high pharmacological doses of some of these

in Figure 78-9. Thus, the increase in insulin secretion

hormones. Diabetes is particularly common in giants or

under a glucose stimulus is dramatic both in its rapid-

acromegalic people with growth hormone-secreting

ity and in the tremendous level of secretion achieved.

tumors, or in people whose adrenal glands secrete

excess glucocorticoids.

Furthermore, the turn-off of insulin secretion is almost

Under some conditions, stimulation of the parasym-

equally as rapid, occurring within 3 to 5 minutes after

pathetic nerves to the pancreas can increase insulin

reduction in blood glucose concentration back to the

secretion. However, it is doubtful that this effect is of

fasting level.

physiologic significance for regulating insulin secretion.

This response of insulin secretion to an elevated

blood glucose concentration provides an extremely

important feedback mechanism for regulating blood

glucose concentration. That is, any rise in blood

Role of Insulin (and Other Hormones)

glucose increases insulin secretion, and the insulin in

in “Switching” Between Carbohydrate

turn increases transport of glucose into liver, muscle,

and Lipid Metabolism

and other cells, thereby reducing the blood glucose

concentration back toward the normal value.

From the preceding discussions, it should be clear that

insulin promotes the utilization of carbohydrates for

energy, whereas it depresses the utilization of fats.

Other Factors That Stimulate

Conversely, lack of insulin causes fat utilization mainly

Insulin Secretion

to the exclusion of glucose utilization, except by brain

Amino Acids. In addition to the stimulation of insulin

tissue. Furthermore, the signal that controls this

secretion by excess blood glucose, some of the amino

switching mechanism is principally the blood glucose

acids have a similar effect. The most potent of these are

concentration. When the glucose concentration is low,

arginine and lysine. This effect differs from glucose stim-

insulin secretion is suppressed and fat is used almost

ulation of insulin secretion in the following way: Amino

exclusively for energy everywhere except in the brain.

acids administered in the absence of a rise in blood

When the glucose concentration is high, insulin secre-

glucose cause only a small increase in insulin secretion.

tion is stimulated and carbohydrate is used instead of

However, when administered at the same time that the

fat, and the excess blood glucose is stored in the form

blood glucose concentration is elevated, the glucose-

of liver glycogen, liver fat, and muscle glycogen. There-

induced secretion of insulin may be as much as doubled

in the presence of the excess amino acids. Thus, the

fore, one of the most important functional roles of

amino acids strongly potentiate the glucose stimulus for

insulin in the body is to control which of these two

insulin secretion.

foods from moment to moment will be used by the

The stimulation of insulin secretion by amino acids

cells for energy.

is important, because the insulin in turn promotes

At least four other known hormones also play

transport of amino acids into the tissue cells as well as

important roles in this switching mechanism: growth

intracellular formation of protein. That is, insulin is

hormone from the anterior pituitary gland, cortisol

important for proper utilization of excess amino acids

from the adrenal cortex, epinephrine from the adrenal

in the same way that it is important for the utilization

medulla, and glucagon from the alpha cells of the islets

of carbohydrates.

of Langerhans in the pancreas. Glucagon is discussed

Gastrointestinal Hormones. A mixture of several impor-

in the next section of this chapter. Both growth

tant gastrointestinal hormones—gastrin, secretin,

hormone and cortisol are secreted in response to

970

Unit XIV Endocrinology and Reproduction

hypoglycemia, and both inhibit cellular utilization of

1. Glucagon activates adenylyl cyclase in the hepatic

glucose while promoting fat utilization. However,

cell membrane,

the effects of both of these hormones develop

2. Which causes the formation of cyclic adenosine

slowly, usually requiring many hours for maximal

monophosphate,

expression.

3. Which activates protein kinase regulator protein,

Epinephrine is especially important in increasing

4. Which activates protein kinase,

plasma glucose concentration during periods of stress

5. Which activates phosphorylase b kinase,

when the sympathetic nervous system is excited.

6. Which converts phosphorylase b into

However, epinephrine acts differently from the other

phosphorylase a,

hormones in that it increases the plasma fatty acid

7. Which promotes the degradation of glycogen into

concentration at the same time. The reasons for these

glucose-1-phosphate,

effects are as follows: (1) epinephrine has the potent

8. Which then is dephosphorylated; and the glucose

effect of causing glycogenolysis in the liver, thus

is released from the liver cells.

releasing within minutes large quantities of glucose

This sequence of events is exceedingly important for

into the blood; (2) it also has a direct lipolytic effect

several reasons. First, it is one of the most thoroughly

on the adipose cells because it activates adipose tissue

studied of all the second messenger functions of cyclic

hormone-sensitive lipase, thus greatly enhancing the

adenosine monophosphate. Second, it demonstrates

blood concentration of fatty acids as well. Quantita-

a cascade system in which each succeeding product

tively, the enhancement of fatty acids is far greater

is produced in greater quantity than the preceding

than the enhancement of blood glucose. Therefore,

product. Therefore, it represents a potent amplifying

epinephrine especially enhances the utilization of fat

mechanism; this type of amplifying mechanism is

in such stressful states as exercise, circulatory shock,

widely used throughout the body for controlling many,

and anxiety.

if not most, cellular metabolic systems, often causing

as much as a millionfold amplification in response. This

explains how only a few micrograms of glucagon can

cause the blood glucose level to double or increase even

Glucagon and Its Functions

more within a few minutes.

Infusion of glucagon for about 4 hours can cause such

Glucagon, a hormone secreted by the alpha cells of the

intensive liver glycogenolysis that all the liver stores of

islets of Langerhans when the blood glucose concen-

glycogen become depleted.

tration falls, has several functions that are diametri-

cally opposed to those of insulin. Most important of

Glucagon Increases Gluconeogenesis. Even after all the

these functions is to increase the blood glucose con-

glycogen in the liver has been exhausted under the

centration, an effect that is exactly the opposite that of

influence of glucagon, continued infusion of this

insulin.

hormone still causes continued hyperglycemia. This

Like insulin, glucagon is a large polypeptide. It has

results from the effect of glucagon to increase the rate

a molecular weight of 3485 and is composed of a chain

of amino acid uptake by the liver cells and then the

of 29 amino acids. On injection of purified glucagon

conversion of many of the amino acids to glucose by

into an animal, a profound hyperglycemic effect

gluconeogenesis. This is achieved by activating multi-

occurs. Only 1 mg/kg of glucagon can elevate the blood

ple enzymes that are required for amino acid transport

glucose concentration about 20 mg/100 ml of blood (a

and gluconeogenesis, especially activation of the

25 per cent increase) in about 20 minutes. For this

enzyme system for converting pyruvate to phospho-

reason, glucagon is also called the hyperglycemic

enolpyruvate, a rate-limiting step in gluconeogenesis.

hormone.

Other Effects of Glucagon

Most other effects of glucagon occur only when its

Effects on Glucose Metabolism

concentration rises well above the maximum normally

found in the blood. Perhaps the most important effect

The major effects of glucagon on glucose metabolism

is that glucagon activates adipose cell lipase, making

are (1) breakdown of liver glycogen (glycogenolysis)

increased quantities of fatty acids available to the

and (2) increased gluconeogenesis in the liver. Both of

energy systems of the body. Glucagon also inhibits

these effects greatly enhance the availability of glucose

the storage of triglycerides in the liver, which prevents

to the other organs of the body.

the liver from removing fatty acids from the blood; this

also helps make additional amounts of fatty acids

Glucagon Causes Glycogenolysis and Increased Blood Glucose

available for the other tissues of the body.

Concentration. The most dramatic effect of glucagon is

Glucagon in very high concentrations also

(1)

its ability to cause glycogenolysis in the liver, which in

enhances the strength of the heart; (2) increases blood

turn increases the blood glucose concentration within

flow in some tissues, especially the kidneys;

(3)

minutes.

enhances bile secretion; and (4) inhibits gastric acid

It does this by the following complex cascade of

secretion. All these effects are probably of minimal

events:

importance in the normal function of the body.

Chapter 78

Insulin, Glucagon, and Diabetes Mellitus

971

One of the factors that might increase glucagon

secretion in exercise is increased circulating amino

acids. Other factors, such as b-adrenergic stimulation

of the islets of Langerhans, may also play a role.

Somatostatin Inhibits

Glucagon and Insulin

Secretion

The delta cells of the islets of Langerhans secrete the

hormone somatostatin, a polypeptide containing only 14

amino acids that has an extremely short half-life of only

100

120

3 minutes in the circulating blood. Almost all factors

Blood glucose

related to the ingestion of food stimulate somatostatin

(mg/100 ml)

secretion. They include (1) increased blood glucose, (2)

increased amino acids, (3) increased fatty acids, and (4)

increased concentrations of several of the gastrointesti-

nal hormones released from the upper gastrointestinal

Figure 78-10

tract in response to food intake.

In turn, somatostatin has multiple inhibitory effects

Approximate plasma glucagon concentration at different blood

glucose levels.

as follows:

1. Somatostatin acts locally within the islets of

Langerhans themselves to depress the secretion of

Regulation of Glucagon Secretion

both insulin and glucagon.

2. Somatostatin decreases the motility of the stomach,

duodenum, and gallbladder.

Increased Blood Glucose Inhibits Glucagon Secretion. The

3. Somatostatin decreases both secretion and

blood glucose concentration is by far the most potent

absorption in the gastrointestinal tract.

factor that controls glucagon secretion. Note specifi-

Putting all this information together, it has been sug-

cally, however, that the effect of blood glucose concen-

gested that the principal role of somatostatin is to

tration on glucagon secretion is in exactly the opposite

extend the period of time over which the food nutrients

direction from the effect of glucose on insulin secretion.

are assimilated into the blood. At the same time, the

This is demonstrated in Figure 78-10, showing that

effect of somatostatin to depress insulin and glucagon

a decrease in the blood glucose concentration from its

secretion decreases the utilization of the absorbed

normal fasting level of about 90 mg/100 ml of blood

nutrients by the tissues, thus preventing rapid exhaus-

down to hypoglycemic levels can increase the plasma

tion of the food and therefore making it available over

a longer period of time.

concentration of glucagon severalfold. Conversely,

It should also be recalled that somatostatin is the

increasing the blood glucose to hyperglycemic levels

same chemical substance as growth hormone inhibitory

decreases plasma glucagon. Thus, in hypoglycemia,

hormone, which is secreted in the hypothalamus and

glucagon is secreted in large amounts; it then greatly

suppresses anterior pituitary gland growth hormone

increases the output of glucose from the liver and

secretion.

thereby serves the important function of correcting the

hypoglycemia.

Summary of Blood

Increased Blood Amino Acids Stimulate Glucagon Secretion.

High concentrations of amino acids, as occur in the

Glucose Regulation

blood after a protein meal (especially the amino acids

alanine and arginine), stimulate the secretion of

In a normal person, the blood glucose concentration is

glucagon. This is the same effect that amino acids have

narrowly controlled, usually between 80 and 90 mg/

in stimulating insulin secretion. Thus, in this instance,

100 ml of blood in the fasting person each morning

the glucagon and insulin responses are not opposites.

before breakfast. This concentration increases to 120

The importance of amino acid stimulation of glucagon

to 140 mg/100 ml during the first hour or so after a

secretion is that the glucagon then promotes rapid

meal, but the feedback systems for control of blood

conversion of the amino acids to glucose, thus making

glucose return the glucose concentration rapidly back

even more glucose available to the tissues.

to the control level, usually within 2 hours after the last

absorption of carbohydrates. Conversely, in starvation,

Exercise Stimulates Glucagon Secretion. In exhaustive

the gluconeogenesis function of the liver provides the

exercise, the blood concentration of glucagon often

glucose that is required to maintain the fasting blood

increases fourfold to fivefold. What causes this is not

glucose level.

understood, because the blood glucose concentration

The mechanisms for achieving this high degree of

does not necessarily fall. A beneficial effect of the

control have been presented in this chapter. Let us

glucagon is that it prevents a decrease in blood glucose.

summarize them.

972

Unit XIV Endocrinology and Reproduction

The liver functions as an important blood glucose

not secrete any insulin during this time; otherwise, the

buffer system. That is, when the blood glucose

scant supplies of glucose that are available would all

rises to a high concentration after a meal and the

go into the muscles and other peripheral tissues,

rate of insulin secretion also increases, as much as

leaving the brain without a nutritive source.

two thirds of the glucose absorbed from the gut is

It is also important that the blood glucose concen-

almost immediately stored in the liver in the form

tration not rise too high for four reasons: (1) Glucose

of glycogen. Then, during the succeeding hours,

can exert a large amount of osmotic pressure in the

when both the blood glucose concentration and

extracellular fluid, and if the glucose concentration

the rate of insulin secretion fall, the liver releases

rises to excessive values, this can cause considerable

the glucose back into the blood. In this way, the

cellular dehydration.(2) An excessively high level of

liver decreases the fluctuations in blood glucose

blood glucose concentration causes loss of glucose in

concentration to about one third of what they

the urine. (3) Loss of glucose in the urine also causes

would otherwise be. In fact, in patients with

osmotic diuresis by the kidneys, which can deplete

severe liver disease, it becomes almost impossible

the body of its fluids and electrolytes.(4) Long-term

to maintain a narrow range of blood glucose

increases in blood glucose may cause damage to many

concentration.

tissues, especially to blood vessels. Vascular injury,

Both insulin and glucagon function as important

associated with uncontrolled diabetes mellitus, leads to

feedback control systems for maintaining a normal

increased risk for heart attack, stroke, end-stage renal

blood glucose concentration. When the glucose

disease, and blindness.

concentration rises too high, insulin is secreted;

the insulin in turn causes the blood glucose

concentration to decrease toward normal.

Diabetes Mellitus

Conversely, a decrease in blood glucose stimulates

Diabetes mellitus is a syndrome of impaired carbohy-

glucagon secretion; the glucagon then functions in

drate, fat, and protein metabolism caused by either lack

the opposite direction to increase the glucose

of insulin secretion or decreased sensitivity of the

toward normal. Under most normal conditions,

tissues to insulin. There are two general types of dia-

the insulin feedback mechanism is much more

betes mellitus:

important than the glucagon mechanism, but in

1. Type I diabetes, also called insulin-dependent

instances of starvation or excessive utilization of

diabetes mellitus (IDDM), is caused by lack of

glucose during exercise and other stressful

insulin secretion.

situations, the glucagon mechanism also becomes

2. Type II diabetes, also called non-insulin-dependent

diabetes mellitus (NIDDM), is caused by decreased

valuable.

sensitivity of target tissues to the metabolic effect

Also, in severe hypoglycemia, a direct effect of

of insulin. This reduced sensitivity to insulin is often

low blood glucose on the hypothalamus stimulates

called insulin resistance.

the sympathetic nervous system. In turn, the

In both types of diabetes mellitus, metabolism of all

epinephrine secreted by the adrenal glands causes

the main foodstuffs is altered. The basic effect of insulin

still further release of glucose from the liver. This,

lack or insulin resistance on glucose metabolism is to

too, helps protect against severe hypoglycemia.

prevent the efficient uptake and utilization of glucose

And finally, over a period of hours and days, both

by most cells of the body, except those of the brain. As

growth hormone and cortisol are secreted in

a result, blood glucose concentration increases, cell

response to prolonged hypoglycemia, and they

utilization of glucose falls increasingly lower, and

utilization of fats and proteins increases.

both decrease the rate of glucose utilization by

most cells of the body, converting instead to

greater amounts of fat utilization. This, too, helps

Type I Diabetes—Lack of Insulin

return the blood glucose concentration toward

Production by Beta Cells

normal.

of the Pancreas

Importance of Blood Glucose Regulation. One might ask the

Injury to the beta cells of the pancreas or diseases that

question: Why is it so important to maintain a constant

impair insulin production can lead to type I diabetes.

blood glucose concentration, particularly because

Viral infections or autoimmune disorders may be

most tissues can shift to utilization of fats and proteins

involved in the destruction of beta cells in many patients

for energy in the absence of glucose? The answer is

with type I diabetes, although heredity also plays a

that glucose is the only nutrient that normally can be

major role in determining the susceptibility of the beta

used by the brain, retina, and germinal epithelium

cells to destruction by these insults. In some instances,

there may be a hereditary tendency for beta cell degen-

of the gonads in sufficient quantities to supply them

eration even without viral infections or autoimmune

optimally with their required energy. Therefore, it is

disorders.

important to maintain the blood glucose concentration

The usual onset of type I diabetes occurs at about 14

at a sufficiently high level to provide this necessary

years of age in the United States, and for this reason it

nutrition.

is often called juvenile diabetes mellitus. Type I diabetes

Most of the glucose formed by gluconeogenesis

may develop very abruptly, over a period of a few days

during the interdigestive period is used for metabolism

or weeks, with three principal sequelae: (1) increased

in the brain. Indeed, it is important that the pancreas

blood glucose, (2) increased utilization of fats for energy

Chapter 78

Insulin, Glucagon, and Diabetes Mellitus

973

and for formation of cholesterol by the liver, and (3)

amplify the tissue damage caused by the elevated

depletion of the body’s proteins.

glucose.

Blood Glucose Concentration Rises to Very High Levels in Diabetes

Diabetes Mellitus Causes Increased Utilization of Fats and Meta-

Mellitus. The lack of insulin decreases the efficiency

bolic Acidosis. The shift from carbohydrate to fat metab-

of peripheral glucose utilization and augments

olism in diabetes increases the release of keto acids,

glucose production, raising plasma glucose to 300 to

such as acetoacetic acid and b-hydroxybutyric acid, into

1200 mg/100 ml. The increased plasma glucose then has

the plasma more rapidly than they can be taken up and

multiple effects throughout the body.

oxidized by the tissue cells. As a result, the patient

develops severe metabolic acidosis from the excess keto

Increased Blood Glucose Causes Loss of Glucose in the Urine

acids, which, in association with dehydration due to the

The high blood glucose causes more glucose to filter

excessive urine formation, can cause severe acidosis.

into the renal tubules than can be reabsorbed, and the

This leads rapidly to diabetic coma and death unless the

excess glucose spills into the urine. This normally occurs

condition is treated immediately with large amounts of

when the blood glucose concentration rises above

insulin.

180 mg/100 ml, a level that is called the blood “thresh-

All the usual physiologic compensations that occur

old” for the appearance of glucose in the urine. When

in metabolic acidosis take place in diabetic acidosis.

the blood glucose level rises to 300 to 500 mg/100 ml—

They include rapid and deep breathing, which

common values in people with severe untreated dia-

causes increased expiration of carbon dioxide; this

betes—100 or more grams of glucose can be lost into

buffers the acidosis but also depletes extracellular fluid

the urine each day.

bicarbonate stores. The kidneys compensate by decreas-

ing bicarbonate excretion and generating new bicar-

Increased Blood Glucose Causes Dehydration The very high

bonate that is added back to the extracellular fluid.

levels of blood glucose (sometimes as high as 8 to 10

Although extreme acidosis occurs only in the most

times normal in severe untreated diabetes) can cause

severe instances of uncontrolled diabetes, when the pH

severe cell dehydration throughout the body. This

of the blood falls below about 7.0, acidotic coma and

occurs partly because glucose does not diffuse easily

death can occur within hours. The overall changes in the

through the pores of the cell membrane, and the

electrolytes of the blood as a result of severe diabetic

increased osmotic pressure in the extracellular fluids

acidosis are shown in Figure 78-11.

causes osmotic transfer of water out of the cells.

Excess fat utilization in the liver occurring over a long

In addition to the direct cellular dehydrating effect of

time causes large amounts of cholesterol in the circu-

excessive glucose, the loss of glucose in the urine causes

lating blood and increased deposition of cholesterol in

osmotic diuresis. That is, the osmotic effect of glucose in

the renal tubules greatly decreases tubular reabsorption

of fluid. The overall effect is massive loss of fluid in the

urine, causing dehydration of the extracellular fluid,

which in turn causes compensatory dehydration of the

intracellular fluid, for reasons discussed in Chapter 26.

Thus, polyuria (excessive urine excretion), intracellular

100 mg/dL

and extracellular dehydration, and increased thirst are

Glucose

classic symptoms of diabetes.

400+ mg/dL

Chronic High Glucose Concentration Causes Tissue Injury When

155 mEq

Keto acids

blood glucose is poorly controlled over long periods in

30 mEq

diabetes mellitus, blood vessels in multiple tissues

throughout the body begin to function abnormally and

155 mEq

Total cations

undergo structural changes that result in inadequate

130 mEq

blood supply to the tissues. This in turn leads to

increased risk for heart attack, stroke, end-stage kidney

27 mEq

disease, retinopathy and blindness, and ischemia and

HCO₃

5 mEq

gangrene of the limbs.

Chronic high glucose concentration also causes

103 mEq

damage to many other tissues. For example, peripheral

Cl^-

90 mEq

neuropathy, which is abnormal function of peripheral

nerves, and autonomic nervous system dysfunction are

7.4

frequent complications of chronic, uncontrolled dia-

betes mellitus. These abnormalities can result in

6.9

impaired cardiovascular reflexes, impaired bladder

180 mg/dL

control, decreased sensation in the extremities, and

Cholesterol

other symptoms of peripheral nerve damage.

360 mg/dL

The precise mechanisms that cause tissue injury in

diabetes are not well understood but probably involve

multiple effects of high glucose concentrations and

other metabolic abnormalities on proteins of endothe-

lial and vascular smooth muscle cells, as well as other

Figure 78-11

tissues. In addition, hypertension, secondary to renal

injury, and atherosclerosis, secondary to abnormal lipid

Changes in blood constituents in diabetic coma, showing normal

metabolism, often develop in patients with diabetes and

values (lavender bars) and diabetic coma values (red bars).

974

Unit XIV Endocrinology and Reproduction

the arterial walls. This leads to severe arteriosclerosis

The role of insulin resistance in contributing to some

and other vascular lesions, as discussed earlier.

of the components of the metabolic syndrome is

unclear, although it is clear that insulin resistance is the

primary cause of increased blood glucose concentra-

Diabetes Causes Depletion of the Body’s Proteins. Failure to

tion. The major adverse consequence of the metabolic

use glucose for energy leads to increased utilization and

syndrome is cardiovascular disease, including athero-

decreased storage of proteins as well as fat. Therefore,

sclerosis and injury to various organs throughout the

a person with severe untreated diabetes mellitus suffers

body. Several of the metabolic abnormalities associated

rapid weight loss and asthenia (lack of energy) despite

with the syndrome are risk factors for cardiovascular

eating large amounts of food (polyphagia). Without

disease, and insulin resistance predisposes to the devel-

treatment, these metabolic abnormalities can cause

opment of type II diabetes mellitus, also a major cause

severe wasting of the body tissues and death within a

of cardiovascular disease.

few weeks.

Other Factors That Can Cause Insulin Resistance and Type II Dia-

betes. Although most patients with type II diabetes are

Type II Diabetes—Resistance to the

overweight or have substantial accumulation of visceral

Metabolic Effects of Insulin

fat, severe insulin resistance and type II diabetes can

also occur as a result of other acquired or genetic con-

Type II diabetes is far more common than type I,

ditions that impair insulin signaling in peripheral tissues

accounting for about 90 per cent of all cases of diabetes

(Table 78-2).

mellitus. In most cases, the onset of type II diabetes

Polycystic ovary syndrome (PCOS), for example, is

occurs after age 30, often between the ages of 50 and 60

associated with marked increases in ovarian androgen

years, and the disease develops gradually. Therefore, this

production and insulin resistance and is one of the most

syndrome is often referred to as adult-onset diabetes. In

common endocrine disorders in women, affecting ap-

recent years, however, there has been a steady increase

proximately 6 per cent of all women during their re-

in the number of younger individuals, some less than 20

productive life. Although the pathogenesis of PCOS

years old, with type II diabetes. This trend appears to be

remains uncertain, insulin resistance and hyperinsuline-

related mainly to the increasing prevalence of obesity,

mia are found in approximately 80 per cent of affected

the most important risk factor for type II diabetes in chil-

women. The long-term consequences include increased

dren as well as in adults.

risk for diabetes mellitus, increased blood lipids, and

cardiovascular disease.

Obesity, Insulin Resistance, and “Metabolic Syndrome” Usually

Excess formation of glucocorticoids (Cushing’s syn-

Precede Development of Type II Diabetes. Type II diabetes, in

drome) or growth hormone (acromegaly) also decreases

contrast to type I, is associated with increased plasma

the sensitivity of various tissues to the metabolic effects

insulin concentration (hyperinsulinemia). This occurs as

of insulin and can lead to development of diabetes mel-

a compensatory response by the pancreatic beta cells

litus. Genetic causes of obesity and insulin resistance, if

for diminished sensitivity of target tissues to the meta-

severe enough, also can lead to type II diabetes as well

bolic effects of insulin, a condition referred to as insulin

as many other features of the metabolic syndrome,

resistance. The decrease in insulin sensitivity impairs

including cardiovascular disease.

carbohydrate utilization and storage, raising blood

glucose and stimulating a compensatory increase in

Development of Type II Diabetes During Prolonged Insulin Resis-

insulin secretion.

tance. With prolonged and severe insulin resistance,

Development of insulin resistance and impaired

even the increased levels of insulin are not sufficient to

glucose metabolism is usually a gradual process, begin-

maintain normal glucose regulation. As a result, mod-

ning with excess weight gain and obesity. The mecha-

erate hyperglycemia occurs after ingestion of carbohy-

nisms that link obesity with insulin resistance, however,

drates in the early stages of the disease.

are still uncertain. Some studies suggest that there are

fewer insulin receptors, especially in the skeletal muscle,

liver, and adipose tissue, in obese than in lean subjects.

However, most of the insulin resistance appears to be

Table 78-2

caused by abnormalities of the signaling pathways that

link receptor activation with multiple cellular effects.

Some Causes of Insulin Resistance

Impaired insulin signaling appears to be closely related

to toxic effects of lipid accumulation in tissues such as

• Obesity/overweight (especially excess visceral adiposity)

skeletal muscle and liver secondary to excess weight

• Excess glucocorticoids (Cushing’s syndrome or steroid therapy)

gain.

• Excess growth hormone (acromegaly)

Insulin resistance is part of a cascade of disorders that

• Pregnancy, gestational diabetes

is often called the “metabolic syndrome.” Some of the

• Polycystic ovary disease

features of the metabolic syndrome include: (1) obesity,

• Lipodystrophy (acquired or genetic; associated with lipid

especially accumulation of abdominal fat; (2) insulin

accumulation in liver)

• Autoantibodies to the insulin receptor

resistance; (3) fasting hyperglycemia; (4) lipid abnor-

• Mutations of insulin receptor

malities such as increased blood triglycerides and

• Mutations of the peroxisome proliferators’ activator receptor g

decreased blood high-density lipoprotein-cholesterol;

(PPARg)

and (5) hypertension. All of the features of the meta-

• Mutations that cause genetic obesity (e.g., melanocortin

bolic syndrome are closely related to excess weight gain,

receptor mutations)

especially when it is associated with accumulation of

• Hemochromatosis (a hereditary disease that causes tissue iron

adipose tissue in the abdominal cavity around the vis-

accumulation)

ceral organs.

Chapter 78

Insulin, Glucagon, and Diabetes Mellitus

975

In the later stages of type II diabetes, the pancreatic

large amounts, in proportion to the severity of disease

beta cells become

“exhausted” and are unable to

and the intake of carbohydrates.

produce enough insulin to prevent more severe

hyperglycemia, especially after the person ingests a

Fasting Blood Glucose and Insulin Levels. The fasting blood

carbohydrate-rich meal.

glucose level in the early morning is normally 80 to

Some obese people, although having marked insulin

90 mg/100 ml, and 110 mg/100 ml is considered to be the

resistance and greater than normal increases in blood

upper limit of normal. A fasting blood glucose level

glucose after a meal, never develop clinically significant

above this value often indicates diabetes mellitus or a

diabetes mellitus; apparently, the pancreas in these

least marked insulin resistance.

people produces enough insulin to prevent severe

In type I diabetes, plasma insulin levels are very low

abnormalities of glucose metabolism. In others,

or undetectable during fasting and even after a meal. In

however, the pancreas gradually becomes exhausted

type II diabetes, plasma insulin concentration may be

from secreting large amounts of insulin, and full-blown

severalfold higher than normal and usually increases to

diabetes mellitus occurs. Some studies suggest that

a greater extent after ingestion of a standard glucose

genetic factors play an important role in determining

load during a glucose tolerance test

(see the next

whether an individual’s pancreas can sustain the high

paragraph).

output of insulin over many years that is necessary to

avoid the severe abnormalities of glucose metabolism in

Glucose Tolerance Test. As demonstrated by the bottom

type II diabetes.

curve in Figure

78-12, called a

“glucose tolerance

In many instances, type II diabetes can be effectively

curve,” when a normal, fasting person ingests 1 gram

treated, at least in the early stages, with exercise, caloric

of glucose per kilogram of body weight, the blood

restriction, and weight reduction, and no exogenous

glucose level rises from about 90 mg/100 ml to 120 to

insulin administration is required. Drugs that increase

140 mg/100 ml and falls back to below normal in

insulin sensitivity, such as thiazolidinediones and met-

about 2 hours.

formin, or drugs that cause additional release of insulin

In a person with diabetes, the fasting blood glucose

by the pancreas, such as sulfonylureas, may also be used.

concentration is almost always above 110 mg/100 ml

However, in the later stages of type II diabetes, insulin

and often above 140 mg/100 ml. Also, the glucose toler-

administration is usually required to control plasma

ance test is almost always abnormal. On ingestion of

glucose.

glucose, these people exhibit a much greater than

normal rise in blood glucose level, as demonstrated by

the upper curve in Figure 78-12, and the glucose level

Physiology of Diagnosis

falls back to the control value only after 4 to 6 hours;

of Diabetes Mellitus

furthermore, it fails to fall below the control level. The

slow fall of this curve and its failure to fall below the

Table 78-3 compares some of clinical features of type I

control level demonstrate that either (1) the normal

and type II diabetes mellitus. The usual methods for

increase in insulin secretion after glucose ingestion does

diagnosing diabetes are based on various chemical tests

not occur or (2) there is decreased sensitivity to insulin.

of the urine and the blood.

A diagnosis of diabetes mellitus can usually be estab-

lished on the basis of such a curve, and type I and type

Urinary Glucose. Simple office tests or more complicated

II diabetes can be distinguished from each other by

quantitative laboratory tests may be used to determine

measurements of plasma insulin, with plasma insulin

the quantity of glucose lost in the urine. In general, a

being low or undetectable in type I diabetes and

normal person loses undetectable amounts of glucose,

increased in type II diabetes.

whereas a person with diabetes loses glucose in small to

Table 78-3

Clinical Characteristics of Patients with Type I and Type II

200

Diabetes

Diabetes Mellitus

180

Feature

Type I

Type II

160

Age at onset

Usually <20 years

Usually >30 years

140

Body mass

Low (wasted) to

Obese

120

normal

Normal

Plasma insulin

Low or absent

Normal to high

100

initially

Plasma glucagon

High, can be

High, resistant to

suppressed

suppression

Plasma glucose

Increased

Hours

Insulin sensitivity

Normal

Reduced

Therapy

Insulin

Weight loss,

thiazolidinediones,

metformin,

Figure 78-12

sulfonylureas,

insulin

Glucose tolerance curve in a normal person and in a person with

diabetes.

976

Unit XIV Endocrinology and Reproduction

Acetone Breath. As pointed out in Chapter 68, small

Because the complications of diabetes—such as ath-

quantities of acetoacetic acid in the blood, which

erosclerosis, greatly increased susceptibility to infection,

increase greatly in severe diabetes, are converted to

diabetic retinopathy, cataracts, hypertension, and

acetone. This is volatile and vaporized into the expired

chronic renal disease—are closely associated with the

air. Consequently, one can frequently make a diagnosis

level of blood lipids as well as the level of blood glucose,

of type I diabetes mellitus simply by smelling acetone

most physicians also use lipid-lowering drugs to help

on the breath of a patient. Also, keto acids can be

prevent these disturbances.

detected by chemical means in the urine, and their

quantitation aids in determining the severity of the dia-

betes. In the early stages of type II diabetes, however,

Insulinoma—Hyperinsulinism

keto acids are usually not produced in excess amounts.

Although much rarer than diabetes, excessive insulin

However, when insulin resistance becomes very severe

production occasionally occurs from an adenoma of an

and there is greatly increased utilization of fats for

islet of Langerhans. About 10 to 15 per cent of these

energy, keto acids are then produced in persons with

adenomas are malignant, and occasionally metastases

type II diabetes.

from the islets of Langerhans spread throughout the

body, causing tremendous production of insulin by both

Treatment of Diabetes

the primary and the metastatic cancers. Indeed, more

than 1000 grams of glucose have had to be administered

The theory of treatment of type I diabetes mellitus is to

every 24 hours to prevent hypoglycemia in some of

administer enough insulin so that the patient will have

these patients.

carbohydrate, fat, and protein metabolism that is as

normal as possible. Insulin is available in several forms.

Insulin Shock and Hypoglycemia. As already emphasized,

“Regular” insulin has a duration of action that lasts

the central nervous system normally derives essentially

from 3 to 8 hours, whereas other forms of insulin (pre-

all its energy from glucose metabolism, and insulin is not

cipitated with zinc or with various protein derivatives)

necessary for this use of glucose. However, if high levels

are absorbed slowly from the injection site and there-

of insulin cause blood glucose to fall to low values, the

fore have effects that last as long as 10 to 48 hours. Ordi-

metabolism of the central nervous system becomes

narily, a patient with severe type I diabetes is given a

depressed. Consequently, in patients with insulin-secret-

single dose of one of the longer-acting insulins each day

ing tumors or in patients with diabetes who administer

to increase overall carbohydrate metabolism through-

too much insulin to themselves, the syndrome called

out the day. Then additional quantities of regular insulin

insulin shock may occur as follows.

are given during the day at those times when the blood

As the blood glucose level falls into the range

glucose level tends to rise too high, such as at mealtimes.

50 to

70 mg/100 ml, the central nervous system

Thus, each patient is provided with an individualized

usually becomes quite excitable, because this degree of

pattern of treatment.

hypoglycemia sensitizes neuronal activity. Sometimes

In persons with type II diabetes, dieting and exercise

various forms of hallucinations result, but more often

are usually recommended in an attempt to induce

the patient simply experiences extreme nervousness,

weight loss and to reverse the insulin resistance. If this

trembles all over, and breaks out in a sweat. As the

fails, drugs may be administered to increase insulin sen-

blood glucose level falls to 20 to 50 mg/100 ml, clonic

sitivity or to stimulate increased production of insulin

seizures and loss of consciousness are likely to occur. As

by the pancreas. In many persons, however, exogenous

the glucose level falls still lower, the seizures cease and

insulin must be used to regulate blood glucose.

only a state of coma remains. Indeed, at times it is dif-

In the past, the insulin used for treatment was derived

ficult by simple clinical observation to distinguish

from animal pancreata. However, human insulin pro-

between diabetic coma as a result of insulin-lack acido-

duced by the recombinant DNA process has become

sis and coma due to hypoglycemia caused by excess

more widely used because some patients develop immu-

insulin. The acetone breath and the rapid, deep breath-

nity and sensitization against animal insulin, thus limit-

ing of diabetic coma are not present in hypoglycemic

ing its effectiveness.

coma.

Proper treatment for a patient who has hypoglycemic

Relation of Treatment to Arteriosclerosis. Diabetic patients,

shock or coma is immediate intravenous administration

mainly because of their high levels of circulating cho-

of large quantities of glucose. This usually brings

lesterol and other lipids, develop atherosclerosis, arte-

the patient out of shock within a minute or more. Also,

riosclerosis, severe coronary heart disease, and multiple

the administration of glucagon

(or, less effectively,

microcirculatory lesions far more easily than do normal

epinephrine) can cause glycogenolysis in the liver and

people. Indeed, those who have poorly controlled dia-

thereby increase the blood glucose level extremely

betes throughout childhood are likely to die of heart

rapidly. If treatment is not effected immediately, per-

disease in early adulthood.

manent damage to the neuronal cells of the central

In the early days of treating diabetes, the tendency

nervous system often occurs.

was to severely reduce the carbohydrates in the diet so

that the insulin requirements would be minimized. This

procedure kept the blood glucose from increasing too

high and attenuated loss of glucose in the urine, but it

References

did not prevent many of the abnormalities of fat metab-

olism. Consequently, the current tendency is to allow the

Barrett EJ: Insulin’s effect on glucose production: direct or

patient an almost normal carbohydrate diet and to give

indirect? J Clin Invest 111:434, 2003.

large enough insulin to metabolize the carbohydrates.

Barthel A, Schmoll D: Novel concepts in insulin regulation

This decreases the rate of fat metabolism and depresses

of hepatic gluconeogenesis. Am J Physiol Endocrinol

the high level of blood cholesterol.

Metab 285:E685, 2003.

Chapter 78

Insulin, Glucagon, and Diabetes Mellitus

977

Besser GM, Thorner MO: Comprehensive Clinical Endo-

Hussain MA, Theise ND: Stem-cell therapy for diabetes mel-

crinology, 3rd ed. Philadelphia: Mosby, Elsevier Science

litus. Lancet 364:203, 2004.

Limited, 2002.

Kowluru A: Regulatory roles for small G proteins in the

Bryant NJ, Govers R, James DE: Regulated transport of the

pancreatic beta-cell: lessons from models of impaired

glucose transporter GLUT4. Nat Rev Mol Cell Biol 3:267,

insulin secretion. Am J Physiol Endocrinol Metab

2002.

285:E669, 2003.

Caumo A, Luzi L: First-phase insulin secretion: does it exist

Larsen PR, Kronenberg HM, Melmed S, Polonsky KS:

in real life? Considerations on shape and function. Am J

Williams Textbook of Endocrinology, 10th ed. Philadel-

Physiol Endocrinol Metab 287:E371, 2004.

phia: WB Saunders Co, 2003.

DeWitt DE, Hirsch IB: Outpatient insulin therapy in type 1

List JF, Habener JF: Glucagon-like peptide 1 agonists and

and type 2 diabetes mellitus: scientific review. JAMA

the development and growth of pancreatic beta-cells. Am

289:2254, 2003.

J Physiol Endocrinol Metab 286:E875, 2004.

Dunne MJ, Cosgrove KE, Shepherd RM, et al: Hyperin-

Mann GE, Yudilevich DL, Sobrevia L: Regulation of amino

sulinism in infancy: from basic science to clinical disease.

acid and glucose transporters in endothelial and smooth

Physiol Rev 84:239, 2004.

muscle cells. Physiol Rev 83:183, 2003.

Efrat S: Regulation of insulin secretion: insights from engi-

Perseghin G, Petersen K, Shulman GI: Cellular mechanism

neered beta-cell lines. Ann N Y Acad Sci 1014:88, 2004.

of insulin resistance: potential links with inflammation. Int

Gurnell M, Savage DB, Chatterjee VK, O’Rahilly S: The

J Obes Relat Metab Disord 27(Suppl 3):S6, 2003.

metabolic syndrome: peroxisome proliferator-activated

Pessin JE, Saltiel AR: Signaling pathways in insulin action:

receptor gamma and its therapeutic modulation. J Clin

molecular targets of insulin resistance. J Clin Invest

Endocrinol Metab 88:2412, 2003

106:165, 2000.

Grundy SM, Brewer HB Jr, Cleeman JI, et al: Definition of

Roden M: How free fatty acids inhibit glucose utilization in

metabolic syndrome: Report of the National Heart, Lung,

human skeletal muscle. News Physiol Sci 19:92, 2004.

and Blood Institute/American Heart Association confer-

Saltiel AR: Putting the brakes on insulin signaling. N Engl J

ence on scientific issues related to definition. Circulation

Med 349:2560, 2003.

109:433, 2004.

Shi Y, Taylor SI, Tan SL, Sonenberg N: When translation

Hall JE, Summers RL, Brands MW, et al: Resistance to the

meets metabolism: multiple links to diabetes. Endocr Rev

metabolic actions of insulin and its role in hypertension.

24:91, 2003.

Am J Hypertens 7:772, 1994.

Ten S, Maclaren N: Insulin resistance syndrome in children.

Hattersley AT: Unlocking the secrets of the pancreatic beta

J Clin Endocrinol Metab 89:2526, 2004.

cell: man and mouse provide the key. J Clin Invest 114:314,

Wilson PW, Grundy SM: The metabolic syndrome: practical

2004.

guide to origins and treatment: Part I. Circulation

Holst JJ, Gromada J: Role of incretin hormones in the reg-

108:1422, 2003.

ulation of insulin secretion in diabetic and nondiabetic

humans. Am J Physiol Endocrinol Metab 287:E199, 2004.

C H A P T E R

Parathyroid Hormone, Calcitonin,

Calcium and Phosphate

Metabolism, Vitamin D, Bone,

and Teeth

The physiology of calcium and phosphate metabo-

lism, formation of bone and teeth, and regulation of

vitamin D, parathyroid hormone (PTH), and calci-

tonin are all closely intertwined. Extracellular

calcium ion concentration, for example, is deter-

mined by the interplay of calcium absorption from

the intestine, renal excretion of calcium, and bone

uptake and release of calcium, each of which is reg-

ulated by the hormones just noted. Because phosphate homeostasis and calcium

homeostasis are closely associated, they are discussed together in this chapter.

Overview of Calcium and Phosphate

Regulation in the Extracellular Fluid

and Plasma

Extracellular fluid calcium concentration normally is regulated very precisely,

seldom rising or falling more than a few per cent from the normal value of about

9.4 mg/dl, which is equivalent to 2.4 mmol calcium per liter. This precise control

is essential, because calcium plays a key role in many physiologic processes,

including contraction of skeletal, cardiac, and smooth muscles; blood clotting;

and transmission of nerve impulses, to name just a few. Excitable cells, such as

neurons, are very sensitive to changes in calcium ion concentrations, and

increases in calcium ion concentration above normal (hypercalcemia) cause pro-

gressive depression of the nervous system; conversely, decreases in calcium con-

centration (hypocalcemia) cause the nervous system to become more excited.

An important feature of extracellular calcium regulation is that only about

0.1 per cent of the total body calcium is in the extracellular fluid, about 1 per

cent is in the cells, and the rest is stored in bones. Therefore, the bones can serve

as large reservoirs, releasing calcium when extracellular fluid concentration

decreases and storing excess calcium.

Approximately 85 per cent of the body’s phosphate is stored in bones, 14 to

15 per cent is in the cells, and less than 1 per cent is in the extracellular fluid.

Although extracellular fluid phosphate concentration is not nearly as well reg-

ulated as calcium concentration, phosphate serves several important functions

and is controlled by many of the same factors that regulate calcium.

Calcium in the Plasma and Interstitial Fluid

The calcium in the plasma is present in three forms, as shown in Figure 79-1.

(1) About 41 per cent (1 mmol/L) of the calcium is combined with the plasma

proteins and in this form is nondiffusible through the capillary membrane.

(2) About 9 per cent of the calcium (0.2 mmol/L) is diffusible through the cap-

illary membrane but is combined with anionic substances of the plasma and

interstitial fluids (citrate and phosphate, for instance) in such a manner that it

978

Chapter 79

Parathyroid Hormone, Calcitonin, Calcium and Phosphate Metabolism, Vitamin D, Bone, and Teeth

979

Calcium complexed to

anions 9% (0.2 mmol/L)

Ionized calcium

Protein-bound calcium

50%

41%

(1.2 mmol/L)

(1.0 mmol/L)

Figure 79-2

Figure 79-1

Hypocalcemic tetany in the hand, called carpopedal spasm.

Distribution of ionized calcium (Ca⁺⁺), diffusible but un-ionized

calcium complexed to anions, and nondiffusible protein-bound

calcium in blood plasma.

Non-Bone Physiologic Effects

of Altered Calcium and Phosphate

Concentrations in the Body Fluids

is not ionized. (3) The remaining 50 per cent of the

calcium in the plasma is both diffusible through the

Changing the level of phosphate in the extracellular

capillary membrane and ionized.

fluid from far below normal to two to three times

Thus, the plasma and interstitial fluids have a normal

normal does not cause major immediate effects on the

calcium ion concentration of about 1.2 mmol/L (or

body. In contrast, even slight increases or decreases of

2.4 mEq/L, because it is a divalent ion), a level only

calcium ion in the extracellular fluid can cause extreme

one half the total plasma calcium concentration.

immediate physiologic effects. In addition, chronic

This ionic calcium is the form that is important for

hypocalcemia or hypophosphatemia greatly decreases

most functions of calcium in the body, including the

bone mineralization, as explained later in the chapter.

effect of calcium on the heart, the nervous system, and

bone formation.

Hypocalcemia Causes Nervous System Excitement and Tetany. When

the extracellular fluid concentration of calcium ions

falls below normal, the nervous system becomes

Inorganic Phosphate in the

progressively more excitable, because this causes

Extracellular Fluids

increased neuronal membrane permeability to sodium

ions, allowing easy initiation of action potentials. At

Inorganic phosphate in the plasma is mainly in two

plasma calcium ion concentrations about 50 per cent

forms: HPO4- and H₂PO4-. The concentration of

below normal, the peripheral nerve fibers become so

HPO4- is about 1.05 mmol/L, and the concentration of

excitable that they begin to discharge spontaneously,

H₂PO4- is about 0.26 mmol/L.When the total quantity

initiating trains of nerve impulses that pass to the

of phosphate in the extracellular fluid rises, so does the

peripheral skeletal muscles to elicit tetanic muscle

quantity of each of these two types of phosphate ions.

contraction. Consequently, hypocalcemia causes

Furthermore, when the pH of the extracellular fluid

tetany. It also occasionally causes seizures because of

becomes more acidic, there is a relative increase in

its action of increasing excitability in the brain.

H₂PO_{4_} and a decrease in HPO4-, whereas the oppo-

Figure 79-2 shows tetany in the hand, which usually

site occurs when the extracellular fluid becomes alka-

occurs before tetany develops in most other parts of

line. These relations were presented in the discussion

the body. This is called “carpopedal spasm.”

of acid-base balance in Chapter 30.

Tetany ordinarily occurs when the blood concentra-

Because it is difficult to determine chemically the

tion of calcium falls from its normal level of 9.4 mg/dl

exact quantities of HPO4- and H₂PO4- in the blood,

to about 6 mg/dl, which is only 35 per cent below the

ordinarily the total quantity of phosphate is expressed

normal calcium concentration, and it is usually lethal

in terms of milligrams of phosphorus per deciliter

at about 4 mg/dl.

(100 ml) of blood. The average total quantity of inor-

In laboratory animals, in which calcium can gradu-

ganic phosphorus represented by both phosphate ions

ally be reduced beyond the usual lethal levels, very

is about 4 mg/dl, varying between normal limits of 3 to

extreme hypocalcemia can cause other effects that are

4 mg/dl in adults and 4 to 5 mg/dl in children.

seldom evident in patients, such as marked dilatation

980

Unit XIV Endocrinology and Reproduction

of the heart, changes in cellular enzyme activities,

Calcium

increased membrane permeability in some cells (in

intake

Cells

(350 mg/day)

(13,000 mg)

addition to nerve cells), and impaired blood clotting.

Bone

(1,000,000 mg)

Hypercalcemia Depresses Nervous System and Muscle Activity.

When the level of calcium in the body fluids rises

Absorption

Deposition

(350 mg/day)

(500 mg/day)

above normal, the nervous system becomes depressed

Extracellular

and reflex activities of the central nervous system are

fluid

sluggish. Also, increased calcium ion concentration

(1300 mg)

Secretion

Absorption

decreases the QT interval of the heart and causes

(250 mg/day)

(500 mg/day)

lack of appetite and constipation, probably because of

Filtration

Reabsorption

depressed contractility of the muscle walls of the gas-

(9980 mg/day)

(9880 mg/day)

trointestinal tract.

Feces

(900 mg/day)

Kidneys

These depressive effects begin to appear when the

Urine

blood level of calcium rises above about 12 mg/dl, and

(100 mg/day)

they can become marked as the calcium level rises

above 15 mg/dl. When the level of calcium rises above

about 17 mg/dl in the blood, calcium phosphate crys-

Figure 79-3

tals are likely to precipitate throughout the body; this

Overview of calcium exchange between different tissue compart-

condition is discussed later in connection with

ments in a person ingesting 1000 mg of calcium per day. Note

parathyroid poisoning.

that most of the ingested calcium is normally eliminated in the

feces, although the kidneys have the capacity to excrete large

amounts by reducing tubular reabsorption of calcium.

Absorption and Excretion of Calcium

and Phosphate

selective, depending on the calcium ion concentration

in the blood.

Intestinal Absorption and Fecal Excretion of Calcium and Phos-

When calcium concentration is low, this reabsorp-

phate. The usual rates of intake are about 1000 mg/day

tion is great, so that almost no calcium is lost in the

each for calcium and phosphorus, about the amounts

urine. Conversely, even a minute increase in blood

in 1 liter of milk. Normally, divalent cations such as

calcium ion concentration above normal increases

calcium ions are poorly absorbed from the intestines.

calcium excretion markedly. We shall see later in the

However, as discussed later, vitamin D promotes

chapter that the most important factor controlling this

calcium absorption by the intestines, and about 35 per

reabsorption of calcium in the distal portions of the

cent (350 mg/day) of the ingested calcium is usually

nephron, and therefore controlling the rate of calcium

absorbed; the calcium remaining in the intestine is

excretion, is PTH.

excreted in the feces. An additional 250 mg/day of

Renal phosphate excretion is controlled by an over-

calcium enters the intestines via secreted gastroin-

flow mechanism, as explained in Chapter 29. That is,

testinal juices and sloughed mucosal cells. Thus, about

when phosphate concentration in the plasma is below

90 per cent (900 mg/day) of the daily intake of calcium

the critical value of about 1 mmol/L, all the phosphate

is excreted in the feces (Figure 79-3).

in the glomerular filtrate is reabsorbed and no phos-

Intestinal absorption of phosphate occurs very

phate is lost in the urine. But above this critical con-

easily. Except for the portion of phosphate that is

centration, the rate of phosphate loss is directly

excreted in the feces in combination with nonabsorbed

proportional to the additional increase. Thus, the

calcium, almost all the dietary phosphate is absorbed

kidneys regulate the phosphate concentration in the

into the blood from the gut and later excreted in the

extracellular fluid by altering the rate of phosphate

urine.

excretion in accordance with the plasma phosphate

concentration and the rate of phosphate filtration by

Renal Excretion of Calcium and Phosphate. Approximately

the kidneys.

10 per cent (100 mg/day) of the ingested calcium is

However, as discussed later in the chapter, PTH can

excreted in the urine. About 41 per cent of the plasma

greatly increase phosphate excretion by the kidneys,

calcium is bound to plasma proteins and is therefore

thereby playing an important role in the control of

not filtered by the glomerular capillaries. The rest is

plasma phosphate concentration as well as calcium

combined with anions such as phosphate (9 per cent)

concentration.

or ionized (50 per cent) and is filtered through the

glomeruli into the renal tubules.

Normally, the renal tubules reabsorb 99 per cent of

Bone and Its Relation

the filtered calcium, and about 100 mg/day is excreted

in the urine. Approximately 90 per cent of the calcium

to Extracellular Calcium

in the glomerular filtrate is reabsorbed in the proximal

and Phosphate

tubules, loops of Henle, and early distal tubules.

Then in the late distal tubules and early collecting

Bone is composed of a tough organic matrix that is

ducts, reabsorption of the remaining 10 per cent is very

greatly strengthened by deposits of calcium salts.

Chapter 79

Parathyroid Hormone, Calcitonin, Calcium and Phosphate Metabolism, Vitamin D, Bone, and Teeth

981

Average compact bone contains by weight about 30

properties plus the degree of bondage between the

per cent matrix and 70 per cent salts. Newly formed

collagen fibers and the crystals provide a bony struc-

bone may have a considerably higher percentage of

ture that has both extreme tensile strength and

matrix in relation to salts.

extreme compressional strength.

Organic Matrix of Bone. The organic matrix of bone is 90

Precipitation and Absorption

to 95 per cent collagen fibers, and the remainder is a

homogeneous gelatinous medium called ground sub-

of Calcium and Phosphate

stance. The collagen fibers extend primarily along the

in Bone—Equilibrium with the

lines of tensional force and give bone its powerful

Extracellular Fluids

tensile strength.

The ground substance is composed of extracellular

Hydroxyapatite Does Not Precipitate in Extracellular Fluid

fluid plus proteoglycans, especially chondroitin sulfate

Despite Supersaturation of Calcium and Phosphate Ions. The

and hyaluronic acid. The precise function of each of

concentrations of calcium and phosphate ions in extra-

these is not known, although they do help to control

cellular fluid are considerably greater than those

the deposition of calcium salts.

required to cause precipitation of hydroxyapatite.

However, inhibitors are present in almost all tissues of

Bone Salts. The crystalline salts deposited in the

the body as well as in plasma to prevent such precipi-

organic matrix of bone are composed principally of

tation; one such inhibitor is pyrophosphate. Therefore,

calcium and phosphate. The formula for the major

hydroxyapatite crystals fail to precipitate in normal

crystalline salt, known as hydroxyapatite, is the

tissues except in bone despite the state of supersatu-

following:

ration of the ions.

Ca₁₀(PO₄)₆(OH)₂

Mechanism of Bone Calcification. The initial stage in bone

Each crystal—about 400 angstroms long, 10 to 30

production is the secretion of collagen molecules

angstroms thick, and 100 angstroms wide—is shaped

(called collagen monomers) and ground substance

like a long, flat plate. The relative ratio of calcium to

(mainly proteoglycans) by osteoblasts. The collagen

phosphorus can vary markedly under different nutri-

monomers polymerize rapidly to form collagen fibers;

tional conditions, the Ca/P ratio on a weight basis

the resultant tissue becomes osteoid, a cartilage-like

varying between 1.3 and 2.0.

material differing from cartilage in that calcium salts

Magnesium, sodium, potassium, and carbonate ions

readily precipitate in it. As the osteoid is formed, some

are also present among the bone salts, although x-ray

of the osteoblasts become entrapped in the osteoid

diffraction studies fail to show definite crystals formed

and become quiescent. At this stage they are called

by them. Therefore, they are believed to be conjugated

osteocytes.

to the hydroxyapatite crystals rather than organized

Within a few days after the osteoid is formed,

into distinct crystals of their own. This ability of many

calcium salts begin to precipitate on the surfaces of the

types of ions to conjugate to bone crystals extends to

collagen fibers. The precipitates first appear at inter-

many ions normally foreign to bone, such as strontium,

vals along each collagen fiber, forming minute nidi

uranium, plutonium, the other transuranic elements,

that rapidly multiply and grow over a period of days

lead, gold, other heavy metals, and at least 9 of 14 of

and weeks into the finished product, hydroxyapatite

the major radioactive products released by explosion of

crystals.

the hydrogen bomb. Deposition of radioactive sub-

The initial calcium salts to be deposited are not

stances in the bone can cause prolonged irradiation

hydroxyapatite crystals but amorphous compounds

of the bone tissues, and if a sufficient amount is

(noncrystalline), a mixture of salts such as CaHPO₄ ·

deposited, an osteogenic sarcoma (bone cancer) even-

2H₂O, Ca₃(PO₄)₂ · 3H₂O, and others. Then by a process

tually develops in most cases.

of substitution and addition of atoms, or reabsorption

and reprecipitation, these salts are converted into

Tensile and Compressional Strength of Bone. Each collagen

the hydroxyapatite crystals over a period of weeks or

fiber of compact bone is composed of repeating peri-

months. A few per cent may remain permanently in

odic segments every 640 angstroms along its length;

the amorphous form. This is important because

hydroxyapatite crystals lie adjacent to each segment of

these amorphous salts can be absorbed rapidly when

the fiber, bound tightly to it. This intimate bonding pre-

there is need for extra calcium in the extracellular

vents “shear” in the bone; that is, it prevents the crys-

fluid.

tals and collagen fibers from slipping out of place,

The mechanism that causes calcium salts to be

which is essential in providing strength to the bone. In

deposited in osteoid is not fully understood. One

addition, the segments of adjacent collagen fibers

theory holds that at the time of formation, the colla-

overlap one another, also causing hydroxyapatite crys-

gen fibers are specially constituted in advance for

tals to be overlapped like bricks keyed to one another

causing precipitation of calcium salts. The osteoblasts

in a brick wall.

supposedly also secrete a substance into the osteoid to

The collagen fibers of bone, like those of tendons,

neutralize an inhibitor (believed to be pyrophosphate)

have great tensile strength, whereas the calcium salts

that normally prevents hydroxyapatite crystallization.

have great compressional strength. These combined

Once the pyrophosphate has been neutralized, the

982

Unit XIV Endocrinology and Reproduction

natural affinity of the collagen fibers for calcium salts

Osteoblasts

Fibrous periosteum

causes the precipitation.

Precipitation of Calcium in Nonosseous Tissues Under

Abnormal Conditions. Although calcium salts almost

never precipitate in normal tissues besides bone, under

abnormal conditions, they do precipitate. For instance,

they precipitate in arterial walls in the condition called

arteriosclerosis and cause the arteries to become bone-

like tubes. Likewise, calcium salts frequently deposit in

degenerating tissues or in old blood clots. Presumably,

Osteoclasts

in these instances, the inhibitor factors that normally

Vein

prevent deposition of calcium salts disappear from the

tissues, thereby allowing precipitation.

Bone

Calcium Exchange Between Bone and

Extracellular Fluid

If soluble calcium salts are injected intravenously, the

Figure 79-4

calcium ion concentration may increase immediately

to high levels. However, within 30 minutes to 1 hour

Osteoblastic and osteoclastic activity in the same bone.

or more, the calcium ion concentration returns to

normal. Likewise, if large quantities of calcium ions are

removed from the circulating body fluids, the calcium

monocyte-like cells formed in the bone marrow. The

ion concentration again returns to normal within 30

osteoclasts are normally active on less than 1 per cent

minutes to about 1 hour. These effects result in great

of the bone surfaces of an adult. Later in the chapter we

part from the fact that the bone contains a type of

see that PTH controls the bone absorptive activity of

exchangeable calcium that is always in equilibrium

osteoclasts.

with the calcium ions in the extracellular fluids.

Histologically, bone absorption occurs immediately

A small portion of this exchangeable calcium is also

adjacent to the osteoclasts. The mechanism of this

the calcium found in all tissue cells, especially in highly

absorption is believed to be the following: The osteo-

permeable types of cells such as those of the liver

clasts send out villus-like projections toward the bone,

and the gastrointestinal tract. However, most of the

forming a so-called ruffled border adjacent to the bone.

The villi secrete two types of substances: (1) proteolytic

exchangeable calcium is in the bone. It normally

enzymes, released from the lysosomes of the osteoclasts,

amounts to about 0.4 to 1 per cent of the total bone

and (2) several acids, including citric acid and lactic acid,

calcium. This calcium is deposited in the bones in a

released from the mitochondria and secretory vesicles.

form of readily mobilizable salt such as CaHPO₄ and

The enzymes digest or dissolve the organic matrix of the

other amorphous calcium salts.

bone, and the acids cause solution of the bone salts. The

The importance of exchangeable calcium is that it

osteoclastic cells also imbibe by phagocytosis minute

provides a rapid buffering mechanism to keep the

particles of bone matrix and crystals, eventually also dis-

calcium ion concentration in the extracellular fluids

soluting these and releasing the products into the blood.

from rising to excessive levels or falling to very low

levels under transient conditions of excess or

Bone Deposition and Absorption Are Normally in Equilibrium.

Normally, except in growing bones, the rates of bone

decreased availability of calcium.

deposition and absorption are equal to each other, so

that the total mass of bone remains constant. Osteo-

Deposition and Absorption of

clasts usually exist in small but concentrated masses, and

Bone—Remodeling of Bone

once a mass of osteoclasts begins to develop, it usually

eats away at the bone for about 3 weeks, creating a

Deposition of Bone by the Osteoblasts. Bone is continually

tunnel that ranges in diameter from 0.2 to 1 millimeter

being deposited by osteoblasts, and it is continually

and is several millimeters long. At the end of this time,

being absorbed where osteoclasts are active (Figure

the osteoclasts disappear and the tunnel is invaded by

79-4). Osteoblasts are found on the outer surfaces of

osteoblasts instead; then new bone begins to develop.

the bones and in the bone cavities. A small amount of

Bone deposition then continues for several months, the

osteoblastic activity occurs continually in all living

new bone being laid down in successive layers of con-

bones (on about 4 per cent of all surfaces at any given

centric circles (lamellae) on the inner surfaces of the

time in an adult), so that at least some new bone is being

cavity until the tunnel is filled. Deposition of new bone

formed constantly.

ceases when the bone begins to encroach on the blood

vessels supplying the area. The canal through which

Absorption of Bone—Function of the Osteoclasts. Bone is also

these vessels run, called the haversian canal, is all that

being continually absorbed in the presence of osteo-

remains of the original cavity. Each new area of bone

clasts, which are large phagocytic, multinucleated cells

deposited in this way is called an osteon, as shown in

(as many as 50 nuclei), derivatives of monocytes or

Figure 79-5.

Chapter 79

Parathyroid Hormone, Calcitonin, Calcium and Phosphate Metabolism, Vitamin D, Bone, and Teeth

983

straight, especially in children because of the rapid

remodeling of bone at younger ages.

Epiphyseal line

Repair of a Fracture Activates Osteoblasts. Fracture of a bone

in some way maximally activates all the periosteal and

intraosseous osteoblasts involved in the break. Also,

Magnified

immense numbers of new osteoblasts are formed almost

section

immediately from osteoprogenitor cells, which are bone

Osteon

stem cells in the surface tissue lining bone, called the

“bone membrane.” Therefore, within a short time, a

Haversian

large bulge of osteoblastic tissue and new organic bone

canal

matrix, followed shortly by the deposition of calcium

salts, develops between the two broken ends of the

bone. This is called a callus.

Many bone surgeons use the phenomenon of bone

stress to accelerate the rate of fracture healing. This is

done by use of special mechanical fixation apparatuses

for holding the ends of the broken bone together so that

Canaliculi

the patient can continue to use the bone immediately.

Lacunae

This causes stress on the opposed ends of the broken

bones, which accelerates osteoblastic activity at the

break and often shortens convalescence.

Epiphyseal line

Vitamin D

Figure 79-5

Vitamin D has a potent effect to increase calcium

absorption from the intestinal tract; it also has impor-

Structure of bone.

tant effects on both bone deposition and bone absorp-

tion, as discussed later. However, vitamin D itself is not

the active substance that actually causes these effects.

Value of Continual Bone Remodeling The continual deposi-

tion and absorption of bone have several physiologi-

Instead, vitamin D must first be converted through a

cally important functions. First, bone ordinarily adjusts

succession of reactions in the liver and the kidneys to

its strength in proportion to the degree of bone stress.

the final active product, 1,25-dihydroxycholecalciferol,

Consequently, bones thicken when subjected to heavy

also called 1,25(OH)₂D₃. Figure 79-6 shows the suc-

loads. Second, even the shape of the bone can be

cession of steps that lead to the formation of this sub-

rearranged for proper support of mechanical forces by

stance from vitamin D. Let us discuss these steps.

deposition and absorption of bone in accordance with

stress patterns. Third, because old bone becomes rela-

Cholecalciferol (Vitamin D₃) Is Formed in the Skin. Several

tively brittle and weak, new organic matrix is needed as

compounds derived from sterols belong to the vitamin

the old organic matrix degenerates. In this manner, the

D family, and they all perform more or less the same

normal toughness of bone is maintained. Indeed, the

bones of children, in whom the rates of deposition and

functions. Vitamin D₃ (also called cholecalciferol) is

absorption are rapid, show little brittleness in compari-

the most important of these and is formed in the skin

son with the bones of the elderly, in whom the rates of

as a result of irradiation of 7-dehydrocholesterol, a sub-

deposition and absorption are slow.

stance normally in the skin, by ultraviolet rays from

the sun. Consequently, appropriate exposure to the

Control of the Rate of Bone Deposition by Bone “Stress.” Bone

sun prevents vitamin D deficiency. The additional

is deposited in proportion to the compressional load

vitamin D compounds that we ingest in food are iden-

that the bone must carry. For instance, the bones of

tical to the cholecalciferol formed in the skin, except

athletes become considerably heavier than those of

for the substitution of one or more atoms that do not

nonathletes. Also, if a person has one leg in a cast but

affect their function.

continues to walk on the opposite leg, the bone of the

leg in the cast becomes thin and as much as 30 per cent

decalcified within a few weeks, whereas the opposite

Cholecalciferol Is Converted to 25-Hydroxycholecalciferol in

bone remains thick and normally calcified. Therefore,

the Liver. The first step in the activation of cholecal-

continual physical stress stimulates osteoblastic deposi-

ciferol is to convert it to 25-hydroxycholecalciferol;

tion and calcification of bone.

this occurs in the liver. The process is a limited one,

Bone stress also determines the shape of bones under

because the 25-hydroxycholecalciferol has a feedback

certain circumstances. For instance, if a long bone of the

inhibitory effect on the conversion reactions. This

leg breaks in its center and then heals at an angle, the

feedback effect is extremely important for two

compression stress on the inside of the angle causes

reasons.

increased deposition of bone, and increased absorption

First, the feedback mechanism precisely regulates

occurs on the outer side of the angle where the bone is

not compressed. After many years of increased deposi-

the concentration of 25-hydroxycholecalciferol in the

tion on the inner side of the angulated bone and absorp-

plasma, an effect that is shown in Figure 79-7. Note

tion on the outer side, the bone can become almost

that the intake of vitamin D₃can increase many times,

984

Unit XIV Endocrinology and Reproduction

Skin

Cholecalciferol (vitamin D₃)

Liver

Inhibition

25-Hydroxycholecalciferol

Kidney

Normal

Activation

Parathyroid

hormone

1,25-Dihydroxycholecalciferol

Plasma calcium (mg/100 mL)

Intestinal

epithelium

Figure 79-8

Calcium-

Alkaline

Effect of plasma calcium concentration on the plasma concentra-

binding

stimulated

phosphatase

tion of

1,25-dihydroxycholecalciferol. This figure shows that a

protein

ATPase

slight decrease in calcium concentration below normal causes

increased formation of activated vitamin D, which in turn leads to

Inhibition

greatly increased absorption of calcium from the intestine.

Intestinal absorption of calcium

Plasma calcium ion concentration

and yet the concentration of 25-hydroxycholecalcif-

erol remains nearly normal. This high degree of feed-

back control prevents excessive action of vitamin D

when intake of vitamin D₃ is altered over a wide range.

Figure 79-6

Second, this controlled conversion of vitamin D₃ to

25-hydroxycholecalciferol conserves the vitamin D

Activation of vitamin D₃

to form

1,25-dihydroxycholecalciferol

and the role of vitamin D in controlling the plasma calcium

stored in the liver for future use. Once it is converted,

concentration.

it persists in the body for only a few weeks, whereas in

the vitamin D form, it can be stored in the liver for

many months.

Formation of

1,25-Dihydroxycholecalciferol in the Kidneys

and Its Control by Parathyroid Hormone. Figure

79-6

1.2

Normal range

also shows the conversion in the proximal tubules

1.0

of the kidneys of 25-hydroxycholecalciferol to 1,25-

dihydroxycholecalciferol. This latter substance is by far

0.8

the most active form of vitamin D, because the previ-

ous products in the scheme of Figure 79-6 have less

0.6

than 1/1000 of the vitamin D effect. Therefore, in the

0.4

absence of the kidneys, vitamin D loses almost all its

effectiveness.

0.2

Note also in Figure 79-6 that the conversion of 25-

hydroxycholecalciferol to

1,25-dihydroxycholecalcif-

erol requires PTH. In the absence of PTH, almost

0.5

1.0

1.5

2.0

2.5

none of the 1,25-dihydroxycholecalciferol is formed.

Intake of vitamin D₃ (times normal)

Therefore, PTH exerts a potent influence in determin-

ing the functional effects of vitamin D in the body.

Figure 79-7

Calcium Ion Concentration Controls the Formation of 1,25-

Dihydroxycholecalciferol. Figure 79-8 demonstrates that

intake on the plasma concentration

Effect of increasing vitamin D₃

the plasma concentration of 1,25-dihydroxycholecal-

of 25-hydroxycholecalciferol. This figure shows that tremendous

changes in vitamin D intake have little effect on the final quantity

ciferol is inversely affected by the concentration of

of activated vitamin D that is formed.

calcium in the plasma. There are two reasons for this.

First, the calcium ion itself has a slight effect in pre-

venting the conversion of 25-hydroxycholecalciferol to

1,25-dihydroxycholecalciferol. Second, and even more

Chapter 79

Parathyroid Hormone, Calcitonin, Calcium and Phosphate Metabolism, Vitamin D, Bone, and Teeth

985

important, as we shall see later in the chapter, the rate

thereby tending to decrease excretion of these sub-

of secretion of PTH is greatly suppressed when the

stances in the urine. However, this is a weak effect

plasma calcium ion concentration rises above 9 to

and probably not of major importance in regulating

10 mg/100 ml. Therefore, at calcium concentrations

the extracellular fluid concentration of these

below this level, PTH promotes the conversion of 25-

substances.

hydroxycholecalciferol to

1,25-dihydroxycholecalcif-

erol in the kidneys. At higher calcium concentrations,

Effect of Vitamin D on Bone and Its Relation to Parathyroid

when PTH is suppressed, the 25-hydroxycholecalcif-

Hormone Activity. Vitamin D plays important roles in

erol is converted to a different compound—24,25-

both bone absorption and bone deposition. The

dihydroxycholecalciferol—that has almost no vitamin

administration of extreme quantities of vitamin D

D effect.

causes absorption of bone. In the absence of vitamin

When the plasma calcium concentration is already

D, the effect of PTH in causing bone absorption (dis-

too high, the formation of 1,25-dihydroxycholecalcif-

cussed in the next section) is greatly reduced or even

erol is greatly depressed. Lack of this in turn decreases

prevented. The mechanism of this action of vitamin D

the absorption of calcium from the intestines, the

is not known, but it is believed to result from the effect

bones, and the renal tubules, thus causing the calcium

of 1,25-dihydroxycholecalciferol to increase calcium

ion concentration to fall back toward its normal level.

transport through cellular membranes.

Vitamin D in smaller quantities promotes bone cal-

cification. One of the ways in which it does this is to

Actions of Vitamin D

increase calcium and phosphate absorption from the

intestines. However, even in the absence of such

The active form of vitamin D, 1,25-dihydroxycholecal-

increase, it enhances the mineralization of bone. Here

ciferol, has several effects on the intestines, kidneys,

again, the mechanism of the effect is unknown, but it

and bones that increase absorption of calcium and

probably also results from the ability of 1,25-dihy-

phosphate into the extracellular fluid and contribute

droxycholecalciferol to cause transport of calcium ions

to feedback regulation of these substances.

through cell membranes—but in this instance, perhaps

in the opposite direction through the osteoblastic or

“Hormonal” Effect of Vitamin D to Promote Intestinal Calcium

osteocytic cell membranes.

Absorption.

1,25-Dihydroxycholecalciferol itself func-

tions as a type of “hormone” to promote intestinal

absorption of calcium. It does this principally by

Parathyroid Hormone

increasing, over a period of about 2 days, formation of

a calcium-binding protein in the intestinal epithelial

Parathyroid hormone provides a powerful mechanism

cells. This protein functions in the brush border of

for controlling extracellular calcium and phosphate

these cells to transport calcium into the cell cytoplasm,

concentrations by regulating intestinal reabsorption,

and the calcium then moves through the basolateral

renal excretion, and exchange between the extracellu-

membrane of the cell by facilitated diffusion. The rate

lar fluid and bone of these ions. Excess activity of the

of calcium absorption is directly proportional to the

parathyroid gland causes rapid absorption of calcium

quantity of this calcium-binding protein. Furthermore,

salts from the bones, with resultant hypercalcemia in

this protein remains in the cells for several weeks after

the extracellular fluid; conversely, hypofunction of the

the 1,25-dihydroxycholecalciferol has been removed

parathyroid glands causes hypocalcemia, often with

from the body, thus causing a prolonged effect on

resultant tetany.

calcium absorption.

Other effects of 1,25-dihydroxycholecalciferol that

Physiologic Anatomy of the Parathyroid Glands. Normally

might play a role in promoting calcium absorption are

there are four parathyroid glands in humans; they are

the formation of (1) a calcium-stimulated ATPase in

located immediately behind the thyroid gland—one

the brush border of the epithelial cells and (2) an alka-

behind each of the upper and each of the lower poles

line phosphatase in the epithelial cells. The precise

of the thyroid. Each parathyroid gland is about 6 mil-

details of all these effects are unclear.

limeters long, 3 millimeters wide, and 2 millimeters

thick and has a macroscopic appearance of dark brown

Vitamin D Promotes Phosphate Absorption by the Intestines.

fat. The parathyroid glands are difficult to locate

Although phosphate is usually absorbed easily, phos-

during thyroid operations because they often look like

phate flux through the gastrointestinal epithelium is

just another lobule of the thyroid gland. For this

enhanced by vitamin D. It is believed that this results

reason, before the importance of these glands was gen-

from a direct effect of 1,25-dihydroxycholecalciferol,

erally recognized, total or subtotal thyroidectomy fre-

but it is possible that it results secondarily from this

quently resulted in removal of the parathyroid glands

hormone’s action on calcium absorption, the cal-

as well.

cium in turn acting as a transport mediator for the

Removal of half the parathyroid glands usually

phosphate.

causes no major physiologic abnormalities. However,

Vitamin D Decreases Renal Calcium and Phosphate Excretion.

removal of three of the four normal glands causes

Vitamin D also increases calcium and phosphate

transient hypoparathyroidism. But even a small quan-

absorption by the epithelial cells of the renal tubules,

tity of remaining parathyroid tissue is usually capable

986

Unit XIV Endocrinology and Reproduction

Begin parathyroid hormone

Parathyroid gland

(located on posterior

Calcium

2.40

Thyroid gland

side of the thyroid

2.35

gland)

2.30

1.2

Phosphate

1.0

0.8

Hours

Figure 79-10

Chief cell

Approximate changes in calcium and phosphate concentrations

during the first 5 hours of parathyroid hormone infusion at a mod-

erate rate.

Oxyphil cell

Red blood cell

Effect of Parathyroid Hormone

on Calcium and Phosphate

Concentrations in the

Figure 79-9

Extracellular Fluid

The four parathyroid glands lie immediately behind the thyroid

gland. Almost all of the parathyroid hormone (PTH) is synthesized

Figure 79-10 shows the approximate effects on the

and secreted by the chief cells. The function of the oxyphil cells

blood calcium and phosphate concentrations caused

is uncertain, but they may be modified or depleted chief cells that

by suddenly infusing PTH into an animal and contin-

no longer secrete PTH.

uing this for several hours. Note that at the onset of

infusion the calcium ion concentration begins to rise

and reaches a plateau in about 4 hours. The phosphate

concentration, however, falls more rapidly than the

of hypertrophying satisfactorily to perform the func-

calcium rises and reaches a depressed level within 1 or

tion of all the glands.

2 hours. The rise in calcium concentration is caused

The parathyroid gland of the adult human being,

principally by two effects: (1) an effect of PTH to

shown in Figure 79-9, contains mainly chief cells and

increase calcium and phosphate absorption from the

a small to moderate number of oxyphil cells, but

bone and (2) a rapid effect of PTH to decrease the

oxyphil cells are absent in many animals and in

excretion of calcium by the kidneys. The decline in

young humans. The chief cells are believed to secrete

phosphate concentration is caused by a strong effect

most, if not all, of the PTH. The function of the oxyphil

of PTH to increase renal phosphate excretion, an

cells is not certain, but they are believed to be modi-

effect that is usually great enough to override

fied or depleted chief cells that no longer secrete

increased phosphate absorption from the bone.

hormone.

Parathyroid Hormone Increases Calcium and

Chemistry of Parathyroid Hormone. PTH has been isolated

Phosphate Absorption from the Bone

in a pure form. It is first synthesized on the ribosomes

PTH has two effects on bone in causing absorption of

in the form of a preprohormone, a polypeptide chain

calcium and phosphate. One is a rapid phase that

of 110 amino acids. This is cleaved first to a prohor-

begins in minutes and increases progressively for

mone with 90 amino acids, then to the hormone itself

several hours. This phase results from activation of the

with 84 amino acids by the endoplasmic reticulum and

already existing bone cells (mainly the osteocytes) to

Golgi apparatus, and finally is packaged in secretory

promote calcium and phosphate absorption. The

granules in the cytoplasm of the cells. The final

second phase is a much slower one, requiring several

hormone has a molecular weight of about

9500.

days or even weeks to become fully developed; it

Smaller compounds with as few as 34 amino acids

results from proliferation of the osteoclasts, followed

adjacent to the N terminus of the molecule have also

by greatly increased osteoclastic reabsorption of the

been isolated from the parathyroid glands that exhibit

bone itself, not merely absorption of the calcium phos-

full PTH activity. In fact, because the kidneys rapidly

phate salts from the bone.

remove the whole 84-amino acid hormone within

minutes but fail to remove many of the fragments for

Rapid Phase of Calcium and Phosphate Absorption—Osteoly-

hours, a large share of the hormonal activity is caused

sis. When large quantities of PTH are injected, the

by the fragments.

calcium ion concentration in the blood begins to rise

Chapter 79

Parathyroid Hormone, Calcitonin, Calcium and Phosphate Metabolism, Vitamin D, Bone, and Teeth

987

within minutes, long before any new bone cells can be

Activation of the osteoclastic system occurs in two

developed. Histological and physiologic studies have

stages: (1) immediate activation of the osteoclasts that

shown that PTH causes removal of bone salts from

are already formed and (2) formation of new osteo-

two areas in the bone: (1) from the bone matrix in the

clasts. Several days of excess PTH usually cause the

vicinity of the osteocytes lying within the bone itself

osteoclastic system to become well developed, but it

and (2) in the vicinity of the osteoblasts along the bone

can continue to grow for months under the influence

surface.

of strong PTH stimulation.

One does not usually think of either osteoblasts or

After a few months of excess PTH, osteoclastic

osteocytes functioning to cause bone salt absorption,

resorption of bone can lead to weakened bones and

because both these types of cells are osteoblastic in

secondary stimulation of the osteoblasts that attempt

nature and normally associated with bone deposition

to correct the weakened state. Therefore, the late

and its calcification. However, studies have shown that

effect is actually to enhance both osteoblastic and

the osteoblasts and osteocytes form a system of inter-

osteoclastic activity. Still, even in the late stages, there

connected cells that spreads all through the bone and

is more bone absorption than bone deposition in the

over all the bone surfaces except the small surface

presence of continued excess PTH.

areas adjacent to the osteoclasts. In fact, long, filmy

Bone contains such great amounts of calcium in

processes extend from osteocyte to osteocyte through-

comparison with the total amount in all the extracel-

out the bone structure, and these processes also

lular fluids (about 1000 times as much) that even when

connect with the surface osteocytes and osteoblasts.

PTH causes a great rise in calcium concentration in the

This extensive system is called the osteocytic mem-

fluids, it is impossible to discern any immediate effect

brane system, and it is believed to provide a membrane

on the bones. Prolonged administration or secretion of

that separates the bone itself from the extracellular

PTH—over a period of many months or years—finally

fluid.

results in very evident absorption in all the bones and

Between the osteocytic membrane and the bone is

even development of large cavities filled with large,

a small amount of bone fluid. Experiments suggest that

multinucleated osteoclasts.

the osteocytic membrane pumps calcium ions from the

bone fluid into the extracellular fluid, creating a

Parathyroid Hormone Decreases Calcium

calcium ion concentration in the bone fluid only one

Excretion and Increases Phosphate Excretion

third that in the extracellular fluid. When the osteo-

by the Kidneys

cytic pump becomes excessively activated, the bone

Administration of PTH causes rapid loss of phosphate

fluid calcium concentration falls even lower, and

in the urine owing to the effect of the hormone to

calcium phosphate salts are then absorbed from the

diminish proximal tubular reabsorption of phosphate

bone. This effect is called osteolysis, and it occurs

ions.

without absorption of the bone’s fibrous and gel

PTH also increases renal tubular reabsorption of

matrix. When the pump is inactivated, the bone

calcium at the same time that it diminishes phosphate

fluid calcium concentration rises to a higher level,

reabsorption. Moreover, it increases the rate of reab-

and calcium phosphate salts are redeposited in the

sorption of magnesium ions and hydrogen ions while

matrix.

it decreases the reabsorption of sodium, potassium,

But where does PTH fit into this picture? First,

and amino acid ions in much the same way that it

the cell membranes of both the osteoblasts and the

affects phosphate. The increased calcium absorption

osteocytes have receptor proteins for binding PTH.

occurs mainly in the late distal tubules, the collecting

PTH can activate the calcium pump strongly, thereby

tubules, the early collecting ducts, and possibly the

causing rapid removal of calcium phosphate salts from

ascending loop of Henle to a lesser extent.

those amorphous bone crystals that lie near the cells.

Were it not for the effect of PTH on the kidneys

PTH is believed to stimulate this pump by increasing

to increase calcium reabsorption, continual loss of

the calcium permeability of the bone fluid side of the

calcium into the urine would eventually deplete both

osteocytic membrane, thus allowing calcium ions to

the extracellular fluid and the bones of this mineral.

diffuse into the membrane cells from the bone fluid.

Then the calcium pump on the other side of the cell

Parathyroid Hormone Increases Intestinal

membrane transfers the calcium ions the rest of the

Absorption of Calcium and Phosphate

way into the extracellular fluid.

At this point, we should be reminded again that PTH

greatly enhances both calcium and phosphate absorp-

Slow Phase of Bone Absorption and Calcium Phosphate

tion from the intestines by increasing the formation in

Release—Activation of the Osteoclasts. A much better

the kidneys of

1,25-dihydroxycholecalciferol from

known effect of PTH and one for which the evidence

vitamin D, as discussed earlier in the chapter.

is much clearer is its activation of the osteoclasts. Yet

the osteoclasts do not themselves have membrane

Cyclic Adenosine Monophosphate Mediates the Effects of

receptor proteins for PTH. Instead, it is believed that

Parathyroid Hormone. A large share of the effect of PTH

the activated osteoblasts and osteocytes send a sec-

on its target organs is mediated by the cyclic adeno-

ondary but unknown

“signal” to the osteoclasts,

sine monophosphate

(cAMP) second messenger

causing them to set about their usual task of gobbling

mechanism. Within a few minutes after PTH adminis-

up the bone over a period of weeks or months.

tration, the concentration of cAMP increases in the

988

Unit XIV Endocrinology and Reproduction

osteocytes, osteoclasts, and other target cells. This

PTH concentration. The solid red curve shows the

cAMP in turn is probably responsible for such func-

acute effect when the calcium concentration is

tions as osteoclastic secretion of enzymes and acids to

changed over a period of a few hours. This shows that

cause bone reabsorption and formation of

1,25-

even small decreases in calcium concentration from

dihydroxycholecalciferol in the kidneys. There are

the normal value can double or triple the plasma PTH.

probably other direct effects of PTH that function

The approximate chronic effect that one finds when

independently of the second messenger mechanism.

the calcium ion concentration changes over a period

of many weeks, thus allowing time for the glands to

hypertrophy greatly, is shown by the dashed red line;

Control of Parathyroid Secretion

this demonstrates that a decrease of only a fraction of

by Calcium Ion Concentration

a milligram per deciliter in plasma calcium concentra-

tion can double PTH secretion. This is the basis of the

Even the slightest decrease in calcium ion concentra-

body’s extremely potent feedback system for long-

tion in the extracellular fluid causes the parathyroid

term control of plasma calcium ion concentration.

glands to increase their rate of secretion within

minutes; if the decreased calcium concentration per-

sists, the glands will hypertrophy, sometimes fivefold or

Calcitonin

more. For instance, the parathyroid glands become

greatly enlarged in rickets, in which the level of

Calcitonin, a peptide hormone secreted by the thyroid

calcium is usually depressed only a small amount; also,

gland, tends to decrease plasma calcium concentra-

they become greatly enlarged in pregnancy, even

tion and, in general, has effects opposite to those of

though the decrease in calcium ion concentration in

PTH. However, the quantitative role of calcitonin is

the mother’s extracellular fluid is hardly measurable;

far less than that of PTH in regulating calcium ion

and they are greatly enlarged during lactation because

concentration.

calcium is used for milk formation.

Synthesis and secretion of calcitonin occur in the

Conversely, conditions that increase the calcium ion

parafollicular cells, or C cells, lying in the interstitial

concentration above normal cause decreased activity

fluid between the follicles of the thyroid gland. These

and reduced size of the parathyroid glands. Such con-

cells constitute only about 0.1 per cent of the human

ditions include (1) excess quantities of calcium in the

thyroid gland and are the remnants of the ultimo-

diet, (2) increased vitamin D in the diet, and (3) bone

brachial glands of lower animals such as fish, amphib-

absorption caused by factors other than PTH (for

ians, reptiles, and birds. Calcitonin is a 32-amino acid

example, bone absorption caused by disuse of the

peptide with a molecular weight of about 3400.

bones).

Figure

79-11 shows the approximate relation

Increased Plasma Calcium Concentration Stimulates Calcitonin

between plasma calcium concentration and plasma

Secretion. The primary stimulus for calcitonin secre-

tion is increased plasma calcium ion concentration.

This contrasts with PTH secretion, which is stimulated

by decreased calcium concentration.

In young animals, but much less so in older animals

Parathyroid hormone

and in humans, an increase in plasma calcium concen-

Chronic

Calcitonin

tration of about 10 per cent causes an immediate

Acute

effect

twofold or more increase in the rate of secretion of cal-

effect

1000

citonin, which is shown by the blue line in Figure

79-11. This provides a second hormonal feedback

800

mechanism for controlling the plasma calcium ion

concentration, but one that is relatively weak and

600

works in a way opposite that of the PTH system.

400

Calcitonin Decreases Plasma Calcium Concentration. In

some young animals, calcitonin decreases blood

Normal levels

200

calcium ion concentration rapidly, beginning within

minutes after injection of the calcitonin, in at least two

ways.

Plasma calcium (mg/dL)

1. The immediate effect is to decrease the absorptive

activities of the osteoclasts and possibly the

osteolytic effect of the osteocytic membrane

Figure 79-11

throughout the bone, thus shifting the balance

in favor of deposition of calcium in the

Approximate effect of plasma calcium concentration on the

exchangeable bone calcium salts. This effect is

plasma concentrations of parathyroid hormone and calcitonin.

especially significant in young animals because of

Note especially that long-term, chronic changes in calcium con-

centration of only a few percentage points can cause as much as

the rapid interchange of absorbed and deposited

100 per cent change in parathyroid hormone concentration.

calcium.

Chapter 79

Parathyroid Hormone, Calcitonin, Calcium and Phosphate Metabolism, Vitamin D, Bone, and Teeth

989

2. The second and more prolonged effect of

hypocalcemia. However, there is a first line of defense

calcitonin is to decrease the formation of new

to prevent this from occurring even before the

osteoclasts. Also, because osteoclastic resorption

parathyroid and calcitonin hormonal feedback

of bone leads secondarily to osteoblastic activity,

systems have a chance to act.

decreased numbers of osteoclasts are followed

by decreased numbers of osteoblasts. Therefore,

Buffer Function of the Exchangeable Calcium in Bones—the

over a long period, the net result is reduced

First Line of Defense. The exchangeable calcium salts

osteoclastic and osteoblastic activity and,

in the bones, discussed earlier in this chapter, are

consequently, very little prolonged effect on

amorphous calcium phosphate compounds, probably

plasma calcium ion concentration. That is, the

mainly CaHPO₄ or some similar compound loosely

effect on plasma calcium is mainly a transient one,

bound in the bone and in reversible equilibrium with

lasting for a few hours to a few days at most.

the calcium and phosphate ions in the extracellular

Calcitonin also has minor effects on calcium han-

fluid.

dling in the kidney tubules and the intestines. Again,

The quantity of these salts that is available for

the effects are opposite those of PTH, but they appear

exchange is about 0.5 to 1 per cent of the total calcium

to be of such little import that they are seldom

salts of the bone, a total of 5 to 10 grams of calcium.

considered.

Because of the ease of deposition of these exchange-

able salts and their ease of resolubility, an increase in

the concentrations of extracellular fluid calcium and

Calcitonin Has a Weak Effect on Plasma Calcium Concentration

phosphate ions above normal causes immediate dep-

in the Adult Human. The reason for the weak effect of

osition of exchangeable salt. Conversely, a decrease in

calcitonin on plasma calcium is twofold. First, any

these concentrations causes immediate absorption of

initial reduction of the calcium ion concentration

exchangeable salt. This reaction is rapid because the

caused by calcitonin leads within hours to a powerful

amorphous bone crystals are extremely small and their

stimulation of PTH secretion, which almost overrides

total surface area exposed to the fluids of the bone is

the calcitonin effect. When the thyroid gland is

perhaps 1 acre or more.

removed and calcitonin is no longer secreted, the long-

Also, about 5 per cent of all the blood flows through

term blood calcium ion concentration is not measura-

the bones each minute—that is, about 1 per cent of all

bly altered, which again demonstrates the overriding

the extracellular fluid each minute. Therefore, about

effect of the PTH system of control.

one half of any excess calcium that appears in the

Second, in the adult, the daily rates of absorption

extracellular fluid is removed by this buffer function

and deposition of calcium are small, and even after the

of the bones in about 70 minutes.

rate of absorption is slowed by calcitonin, this still has

In addition to the buffer function of the bones, the

only a small effect on plasma calcium ion concentra-

mitochondria of many of the tissues of the body, espe-

tion. The effect of calcitonin in children is much

cially of the liver and intestine, contain a reasonable

greater because bone remodeling occurs rapidly in

amount of exchangeable calcium (a total of about 10

children, with absorption and deposition of calcium as

grams in the whole body) that provides an additional

great as 5 grams or more per day—equal to 5 to 10

buffer system for helping to maintain constancy of the

times the total calcium in all the extracellular fluid.

extracellular fluid calcium ion concentration.

Also, in certain bone diseases, such as Paget’s disease,

in which osteoclastic activity is greatly accelerated, cal-

Hormonal Control of Calcium Ion Concentration—the Second

citonin has a much more potent effect of reducing the

Line of Defense. At the same time that the exchange-

calcium absorption.

able calcium mechanism in the bones is “buffering” the

calcium in the extracellular fluid, both the parathyroid

and the calcitonin hormonal systems are beginning to

Summary of Control of

act. Within 3 to 5 minutes after an acute increase in the

Calcium Ion Concentration

calcium ion concentration, the rate of PTH secretion

decreases. As already explained, this sets into play

At times, the amount of calcium absorbed into or lost

multiple mechanisms for reducing the calcium ion con-

from the body fluids is as much as 0.3 gram in 1 hour.

centration back toward normal.

For instance, in cases of diarrhea, several grams of

At the same time that PTH decreases, calcitonin

calcium can be secreted in the intestinal juices, passed

increases. In young animals and possibly in young chil-

into the intestinal tract, and lost into the feces each

dren (but probably to a smaller extent in adults), the

day.

calcitonin causes rapid deposition of calcium in the

Conversely, after ingestion of large quantities of

bones, and perhaps in some cells of other tissues.

calcium, particularly when there is also an excess of

Therefore, in very young animals, excess calcitonin can

vitamin D activity, a person may absorb as much as 0.3

cause a high calcium ion concentration to return to

gram in 1 hour. This figure compares with a total quan-

normal perhaps considerably more rapidly than can

tity of calcium in all the extracellular fluid of about

be achieved by the exchangeable calcium-buffering

1 gram. The addition or subtraction of 0.3 gram to

mechanism alone.

or from such a small amount of calcium in the extra-

In prolonged calcium excess or prolonged calcium

cellular fluid would cause serious hypercalcemia or

deficiency, only the PTH mechanism seems to be really

990

Unit XIV Endocrinology and Reproduction

important in maintaining a normal plasma calcium ion

secretion. The cause of primary hyperparathyroidism

concentration. When a person has a continuing defi-

ordinarily is a tumor of one of the parathyroid glands;

ciency of calcium in the diet, PTH often can stimulate

such tumors occur much more frequently in women

than in men or children, mainly because pregnancy and

enough calcium absorption from the bones to main-

lactation stimulate the parathyroid glands and therefore

tain a normal plasma calcium ion concentration for 1

predispose to the development of such a tumor.

year or more, but eventually, even the bones will run

Hyperparathyroidism causes extreme osteoclastic

out of calcium. Thus, in effect, the bones are a large

activity in the bones. This elevates the calcium ion con-

buffer-reservoir of calcium that can be manipulated

centration in the extracellular fluid while usually

by PTH. Yet, when the bone reservoir either runs out

depressing the concentration of phosphate ions because

of calcium or, oppositely, becomes saturated with

of increased renal excretion of phosphate.

calcium, the long-term control of extracellular calcium

ion concentration resides almost entirely in the roles

Bone Disease in Hyperparathyroidism. Although in mild

of PTH and vitamin D in controlling calcium absorp-

hyperparathyroidism new bone can be deposited

rapidly enough to compensate for the increased osteo-

tion from the gut and calcium excretion in the urine.

clastic reabsorption of bone, in severe hyperparathy-

roidism the osteoclastic absorption soon far outstrips

Pathophysiology of

osteoblastic deposition, and the bone may be eaten

away almost entirely. Indeed, the reason a hyper-

Parathyroid Hormone,

parathyroid person seeks medical attention is often a

Vitamin D, and

broken bone. Radiographs of the bone show extensive

Bone Disease

decalcification and, occasionally, large punched-out

cystic areas of the bone that are filled with osteoclasts

Hypoparathyroidism

in the form of so-called giant cell osteoclast “tumors.”

Multiple fractures of the weakened bones can result

When the parathyroid glands do not secrete sufficient

from only slight trauma, especially where cysts develop.

PTH, the osteocytic reabsorption of exchangeable

The cystic bone disease of hyperparathyroidism is called

calcium decreases and the osteoclasts become almost

osteitis fibrosa cystica.

totally inactive. As a result, calcium reabsorption from

Osteoblastic activity in the bones also increases

the bones is so depressed that the level of calcium in the

greatly in a vain attempt to form enough new bone to

body fluids decreases. Yet, because calcium and phos-

make up for the old bone absorbed by the osteoclastic

phates are not being absorbed from the bone, the bone

activity. When the osteoblasts become active, they

usually remains strong.

secrete large quantities of alkaline phosphatase. There-

When the parathyroid glands are suddenly removed,

fore, one of the important diagnostic findings in hyper-

the calcium level in the blood falls from the normal of

parathyroidism is a high level of plasma alkaline

9.4 mg/dl to 6 to 7 mg/dl within 2 to 3 days, and the

phosphatase.

blood phosphate concentration may double. When this

low calcium level is reached, the usual signs of tetany

Effects of Hypercalcemia in Hyperparathyroidism. Hyper-

develop. Among the muscles of the body especially sen-

parathyroidism can at times cause the plasma calcium

sitive to tetanic spasm are the laryngeal muscles. Spasm

level to rise to 12 to 15 mg/dl and, rarely, even higher.

of these muscles obstructs respiration, which is the usual

The effects of such elevated calcium levels, as detailed

cause of death in tetany unless appropriate treatment is

earlier in the chapter, are depression of the central and

applied.

peripheral nervous systems, muscle weakness, constipa-

tion, abdominal pain, peptic ulcer, lack of appetite, and

Treatment of Hypoparathyroidism with PTH and Vitamin D. PTH

depressed relaxation of the heart during diastole.

is occasionally used for treating hypoparathyroidism.

However, because of the expense of this hormone,

Parathyroid Poisoning and Metastatic Calcification When, on

because its effect lasts for a few hours at most, and

rare occasions, extreme quantities of PTH are secreted,

because the tendency of the body to develop anti-

the level of calcium in the body fluids rises rapidly to

bodies against it makes it progressively less and less

high values. Even the extracellular fluid phosphate con-

effective, hypoparathyroidism is usually not treated

centration often rises markedly instead of falling, as is

with PTH administration.

usually the case, probably because the kidneys cannot

In most patients with hypothyroidism, the administra-

excrete rapidly enough all the phosphate being

tion of extremely large quantities of vitamin D, to as high

absorbed from the bone. Therefore, the calcium and

as 100,000 units per day, along with intake of 1 to 2 grams

phosphate in the body fluids become greatly supersatu-

of calcium, keeps the calcium ion concentration in a

rated, so that calcium phosphate (CaHPO₄) crystals

normal range. At times, it might be necessary to admin-

begin to deposit in the alveoli of the lungs, the tubules

ister 1,25-dihydroxycholecalciferol instead of the nonac-

of the kidneys, the thyroid gland, the acid-producing

tivated form of vitamin D because of its much more

area of the stomach mucosa, and the walls of the arter-

potent and much more rapid action. This can also cause

ies throughout the body. This extensive metastatic dep-

unwanted effects, because it is sometimes difficult to

osition of calcium phosphate can develop within a few

prevent overactivity by this activated form of vitamin D.

days.

Ordinarily, the level of calcium in the blood must rise

Primary Hyperparathyroidism

above 17 mg/dl before there is danger of parathyroid

poisoning, but once such elevation develops along with

In primary hyperparathyroidism, an abnormality of the

concurrent elevation of phosphate, death can occur in

parathyroid glands causes inappropriate, excess PTH

only a few days.

Chapter 79

Parathyroid Hormone, Calcitonin, Calcium and Phosphate Metabolism, Vitamin D, Bone, and Teeth

991

Formation of Kidney Stones in Hyperparathyroidism Most

Rickets Weakens the Bones During prolonged rickets, the

patients with mild hyperparathyroidism show few signs

marked compensatory increase in PTH secretion causes

of bone disease and few general abnormalities as a

extreme osteoclastic absorption of the bone; this in turn

result of elevated calcium, but they do have an extreme

causes the bone to become progressively weaker and

tendency to form kidney stones. The reason is that the

imposes marked physical stress on the bone, resulting in

excess calcium and phosphate absorbed from the intes-

rapid osteoblastic activity as well. The osteoblasts lay

tines or mobilized from the bones in hyperparathy-

down large quantities of osteoid, which does not

roidism must eventually be excreted by the kidneys,

become calcified because of insufficient calcium and

causing a proportionate increase in the concentrations

phosphate ions. Consequently, the newly formed, uncal-

of these substances in the urine. As a result, crystals of

cified, and weak osteoid gradually takes the place of the

calcium phosphate tend to precipitate in the kidney,

older bone that is being reabsorbed.

forming calcium phosphate stones. Also, calcium oxalate

stones develop because even normal levels of oxalate

Tetany in Rickets In the early stages of rickets, tetany

cause calcium precipitation at high calcium levels.

almost never occurs because the parathyroid glands

Because the solubility of most renal stones is slight in

continually stimulate osteoclastic absorption of bone

alkaline media, the tendency for formation of renal

and, therefore, maintain an almost normal level of

calculi is considerably greater in alkaline urine than in

calcium in the extracellular fluid. However, when the

acid urine. For this reason, acidotic diets and acidic

bones finally become exhausted of calcium, the level of

drugs are frequently used for treating renal calculi.

calcium may fall rapidly. As the blood level of calcium

falls below 7 mg/dl, the usual signs of tetany develop,

and the child may die of tetanic respiratory spasm

Secondary Hyperparathyroidism

unless intravenous calcium is administered, which

relieves the tetany immediately.

In secondary hyperparathyroidism, high levels of PTH

occur as a compensation for hypocalcemia rather than

Treatment of Rickets. The treatment of rickets depends on

as a primary abnormality of the parathyroid glands. This

supplying adequate calcium and phosphate in the diet

contrasts with primary hyperparathyroidism, which is

and, equally important, on administering large amounts

associated with hypercalcemia.

of vitamin D. If vitamin D is not administered, little

Secondary hyperparathyroidism can be caused by

calcium and phosphate are absorbed from the gut.

vitamin D deficiency or chronic renal disease in which

the damaged kidneys are unable to produce sufficient

Osteomalacia—“Adult Rickets”. Adults seldom have a

amounts of the active form of vitamin D,

1,25-

serious dietary deficiency of vitamin D or calcium

dihydroxycholecalciferol. As discussed in more detail in

because large quantities of calcium are not needed for

the next section, the vitamin D deficiency leads to osteo-

bone growth as in children. However, serious deficien-

malacia (inadequate mineralization of the bones), and

cies of both vitamin D and calcium occasionally

high levels of PTH cause absorption of the bones.

occur as a result of steatorrhea (failure to absorb fat)

because vitamin D is fat-soluble and calcium tends to

form insoluble soaps with fat; consequently, in steator-

Rickets—Vitamin D Deficiency

rhea, both vitamin D and calcium tend to pass into the

feces. Under these conditions, an adult occasionally has

Rickets occurs mainly in children. It results from

such poor calcium and phosphate absorption that adult

calcium or phosphate deficiency in the extracellular

rickets can occur, although this almost never proceeds

fluid, usually caused by lack of vitamin D. If the child is

to the stage of tetany but often is a cause of severe bone

adequately exposed to sunlight, the 7-dehydrocholes-

disability.

terol in the skin becomes activated by the ultraviolet

rays and forms vitamin D₃, which prevents rickets by

Osteomalacia and Rickets Caused by Renal Disease. “Renal

promoting calcium and phosphate absorption from the

rickets” is a type of osteomalacia that results from

intestines, as discussed earlier in the chapter.

prolonged kidney damage. The cause of this

Children who remain indoors through the winter in

condition is mainly failure of the damaged kidneys to

general do not receive adequate quantities of vitamin D

form 1,25-dihydroxycholecalciferol, the active form of

without some supplementation in the diet. Rickets tends

vitamin D. In patients whose kidneys have been

to occur especially in the spring months because vitamin

removed or destroyed and who are being treated by

D formed during the preceding summer is stored in the

hemodialysis, the problem of renal rickets is often a

liver and available for use during the early winter

severe one.

months. Also, calcium and phosphate absorption from

Another type of renal disease that leads to rickets

the bones can prevent clinical signs of rickets for the

and osteomalacia is congenital hypophosphatemia,

first few months of vitamin D deficiency.

resulting from congenitally reduced reabsorption of

phosphates by the renal tubules. This type of rickets

Plasma Concentrations of Calcium and Phosphate Decrease

must be treated with phosphate compounds instead

in Rickets The plasma calcium concentration in rickets

of calcium and vitamin D, and it is called vitamin

is only slightly depressed, but the level of phosphate is

D-resistant rickets.

greatly depressed. This is because the parathyroid

glands prevent the calcium level from falling by pro-

moting bone absorption every time the calcium level

Osteoporosis—Decreased

begins to fall. However, there is no good regulatory

Bone Matrix

system for preventing a falling level of phosphate, and

the increased parathyroid activity actually increases the

Osteoporosis is the most common of all bone diseases

excretion of phosphates in the urine.

in adults, especially in old age. It is different from osteo-

992

Unit XIV Endocrinology and Reproduction

malacia and rickets because it results from diminished

organic bone matrix rather than from poor bone calci-

fication. In osteoporosis the osteoblastic activity in the

Enamel

bone usually is less than normal, and consequently the

Crown

rate of bone osteoid deposition is depressed. But occa-

sionally, as in hyperparathyroidism, the cause of the

diminished bone is excess osteoclastic activity.

Neck

The many common causes of osteoporosis are (1) lack

of physical stress on the bones because of inactivity; (2)

Pulp chamber

malnutrition to the extent that sufficient protein matrix

cannot be formed; (3) lack of vitamin C, which is nec-

essary for the secretion of intercellular substances by all

cells, including formation of osteoid by the osteoblasts;

(4) postmenopausal lack of estrogen secretion because

Dentin

estrogens decrease the number and activity of osteo-

Root

clasts; (5) old age, in which growth hormone and other

growth factors diminish greatly, plus the fact that many

of the protein anabolic functions also deteriorate with

Cementum

age, so that bone matrix cannot be deposited satisfac-

torily; and

(6) Cushing’s syndrome, because massive

quantities of glucocorticoids secreted in this disease

cause decreased deposition of protein throughout the

body and increased catabolism of protein and have the

specific effect of depressing osteoblastic activity. Thus,

many diseases of deficiency of protein metabolism can

Figure 79-12

cause osteoporosis.

Functional parts of a tooth.

Physiology of the Teeth

The crystalline structure of the salts makes the

The teeth cut, grind, and mix the food eaten. To

enamel extremely hard-much harder than the dentin.

perform these functions, the jaws have powerful

Also, the special protein fiber meshwork, although

muscles capable of providing an occlusive force

constituting only about 1 per cent of the enamel mass,

between the front teeth of 50 to 100 pounds and for

makes enamel resistant to acids, enzymes, and other

the jaw teeth, 150 to 200 pounds. Also, the upper and

corrosive agents because this protein is one of the

lower teeth are provided with projections and facets

most insoluble and resistant proteins known.

that interdigitate, so that the upper set of teeth fits with

the lower. This fitting is called occlusion, and it allows

Dentin. The main body of the tooth is composed of

even small particles of food to be caught and ground

dentin, which has a strong, bony structure. Dentin is

between the tooth surfaces.

made up principally of hydroxyapatite crystals similar

to those in bone but much more dense. These crystals

Function of the Different Parts

are imbedded in a strong meshwork of collagen fibers.

of the Teeth

In other words, the principal constituents of dentin are

very much the same as those of bone. The major dif-

Figure

79-12 shows a sagittal section of a tooth,

ference is its histological organization, because dentin

demonstrating its major functional parts: the enamel,

does not contain any osteoblasts, osteocytes, osteo-

dentin, cementum, and pulp. The tooth can also be

clasts, or spaces for blood vessels or nerves. Instead, it

divided into the crown, which is the portion that pro-

is deposited and nourished by a layer of cells called

trudes out from the gum into the mouth, and the root,

odontoblasts, which line its inner surface along the wall

which is the portion within the bony socket of the jaw.

of the pulp cavity.

The collar between the crown and the root where the

The calcium salts in dentin make it extremely resist-

tooth is surrounded by the gum is called the neck.

ant to compressional forces, and the collagen fibers

make it tough and resistant to tensional forces that

Enamel. The outer surface of the tooth is covered by a

might result when the teeth are struck by solid objects.

layer of enamel that is formed before eruption of the

tooth by special epithelial cells called ameloblasts.

Cementum. Cementum is a bony substance secreted

Once the tooth has erupted, no more enamel is

by cells of the periodontal membrane, which lines

formed. Enamel is composed of very large and very

the tooth socket. Many collagen fibers pass directly

dense crystals of hydroxyapatite with adsorbed

from the bone of the jaw, through the periodontal

carbonate, magnesium, sodium, potassium, and other

membrane, and then into the cementum. These colla-

ions imbedded in a fine meshwork of strong and

gen fibers and the cementum hold the tooth in place.

almost insoluble protein fibers that are similar in phys-

When the teeth are exposed to excessive strain, the

ical characteristics (but not chemically identical) to the

layer of cementum becomes thicker and stronger.

keratin of hair.

Also, it increases in thickness and strength with age,

Chapter 79

Parathyroid Hormone, Calcitonin, Calcium and Phosphate Metabolism, Vitamin D, Bone, and Teeth

993

causing the teeth to become more firmly seated in the

jaws by adulthood and later.

Enamel organ

Pulp. The pulp cavity of each tooth is filled with pulp,

Primordium of

of milk tooth

enamel organ of

which is composed of connective tissue with an abun-

permanent tooth

dant supply of nerve fibers, blood vessels, and lym-

phatics. The cells lining the surface of the pulp cavity

are the odontoblasts, which, during the formative years

of the tooth, lay down the dentin but at the same time

encroach more and more on the pulp cavity, making

it smaller. In later life, the dentin stops growing and

Mesenchymal primordium of pulp

the pulp cavity remains essentially constant in size.

However, the odontoblasts are still viable and send

projections into small dentinal tubules that penetrate

Enamel

all the way through the dentin; they are of importance

Dentin

for exchange of calcium, phosphate, and other miner-

Oral epithelium

als with the dentin.

Dentition

Humans and most other mammals develop two sets of

teeth during a lifetime. The first teeth are called the

deciduous teeth, or milk teeth, and they number 20 in

humans. They erupt between the 7th month and the

2nd year of life, and they last until the 6th to the 13th

year. After each deciduous tooth is lost, a permanent

tooth replaces it, and an additional 8 to 12 molars

Alveolar bone

appear posteriorly in the jaws, making the total

number of permanent teeth 28 to 32, depending on

Figure 79-13

whether the four wisdom teeth finally appear, which

A, Primordial tooth organ. B, Developing tooth. C, Erupting tooth.

does not occur in everyone.

Formation of the Teeth. Figure 79-13 shows the forma-

like the deciduous tooth, pushes outward through the

tion and eruption of teeth. Figure

79-13A shows

bone. In so doing, it erodes the root of the deciduous

invagination of the oral epithelium into the dental

tooth and eventually causes it to loosen and fall out.

lamina; this is followed by the development of a tooth-

Soon thereafter, the permanent tooth erupts to take

producing organ. The epithelial cells above form

the place of the original one.

ameloblasts, which form the enamel on the outside of

the tooth. The epithelial cells below invaginate upward

Metabolic Factors Influence Development of the Teeth.

into the middle of the tooth to form the pulp cavity

The rate of development and the speed of eruption of

and the odontoblasts that secrete dentin. Thus, enamel

teeth can be accelerated by both thyroid and growth

is formed on the outside of the tooth, and dentin is

hormones. Also, the deposition of salts in the early-

formed on the inside, giving rise to an early tooth, as

forming teeth is affected considerably by various

shown in Figure 79-13B.

factors of metabolism, such as the availability of

calcium and phosphate in the diet, the amount of

Eruption of Teeth. During early childhood, the teeth

vitamin D present, and the rate of PTH secretion.When

begin to protrude outward from the bone through the

all these factors are normal, the dentin and enamel will

oral epithelium into the mouth. The cause of “erup-

be correspondingly healthy, but when they are defi-

tion” is unknown, although several theories have been

cient, the calcification of the teeth also may be defec-

offered in an attempt to explain this phenomenon. The

tive, so that the teeth will be abnormal throughout life.

most likely theory is that growth of the tooth root as

well as of the bone underneath the tooth progressively

shoves the tooth forward.

Mineral Exchange in Teeth

Development of the Permanent Teeth. During embry-

The salts of teeth, like those of bone, are composed of

onic life, a tooth-forming organ also develops in the

hydroxyapatite with adsorbed carbonates and various

deeper dental lamina for each permanent tooth that

cations bound together in a hard crystalline substance.

will be needed after the deciduous teeth are gone.

Also, new salts are constantly being deposited while

These tooth-producing organs slowly form the perma-

old salts are being reabsorbed from the teeth, as occurs

nent teeth throughout the first 6 to 20 years of life.

in bone. Deposition and reabsorption occur mainly in

When each permanent tooth becomes fully formed, it,

the dentin and cementum and to a very limited extent

994

Unit XIV Endocrinology and Reproduction

in the enamel. In the enamel, these processes occur

parcels throughout the day, such as in the form of

mostly by diffusional exchange of minerals with the

candy, the bacteria are supplied with their preferential

saliva instead of with the fluids of the pulp cavity.

metabolic substrate for many hours of the day, and the

The rate of absorption and deposition of minerals in

development of caries is greatly increased.

the cementum is about equal to that in the surround-

ing bone of the jaw, whereas the rate of deposition and

Role of Fluorine in Preventing Caries. Teeth formed in chil-

absorption of minerals in the dentin is only one third

dren who drink water that contains small amounts of

that of bone. The cementum has characteristics almost

fluorine develop enamel that is more resistant to caries

identical to those of usual bone, including the presence

than the enamel in children who drink water that does

of osteoblasts and osteoclasts, whereas dentin does not

not contain fluorine. Fluorine does not make the

have these characteristics, as explained earlier. This

enamel harder than usual, but fluorine ions replace

difference undoubtedly explains the different rates of

many of the hydroxyl ions in the hydroxyapatite crys-

mineral exchange.

tals, which in turn makes the enamel several times less

In summary, continual mineral exchange occurs in

soluble. Fluorine may also be toxic to the bacteria.

the dentin and cementum of teeth, although the mech-

Finally, when small pits do develop in the enamel, flu-

anism of this exchange in dentin is unclear. However,

orine is believed to promote deposition of calcium

enamel exhibits extremely slow mineral exchange, so

phosphate to “heal” the enamel surface. Regardless of

that it maintains most of its original mineral comple-

the precise means by which fluorine protects the teeth,

ment throughout life.

it is known that small amounts of fluorine deposited in

enamel make teeth about three times as resistant to

caries as teeth without fluorine.

Dental Abnormalities

Malocclusion. Malocclusion is usually caused by a

The two most common dental abnormalities are caries

hereditary abnormality that causes the teeth of one

and malocclusion. Caries refers to erosion of the teeth,

jaw to grow to abnormal positions. In malocclusion,

whereas malocclusion is failure of the projections of

the teeth do not interdigitate properly and therefore

the upper and lower teeth to interdigitate properly.

cannot perform their normal grinding or cutting action

adequately. Malocclusion occasionally also results in

Caries and the Role of Bacteria and Ingested Carbohydrates.

abnormal displacement of the lower jaw in relation to

It is generally agreed that caries result from the action

the upper jaw, causing such undesirable effects as pain

of bacteria on the teeth, the most common of which is

in the mandibular joint and deterioration of the teeth.

Streptococcus mutans. The first event in the develop-

The orthodontist can usually correct malocclusion

ment of caries is the deposit of plaque, a film of pre-

by applying prolonged gentle pressure against the

cipitated products of saliva and food, on the teeth.

teeth with appropriate braces. The gentle pressure

Large numbers of bacteria inhabit this plaque and

causes absorption of alveolar jaw bone on the com-

are readily available to cause caries. These bacteria

pressed side of the tooth and deposition of new bone

depend to a great extent on carbohydrates for their

on the tensional side of the tooth. In this way, the tooth

food. When carbohydrates are available, their meta-

gradually moves to a new position as directed by the

bolic systems are strongly activated and they multiply.

applied pressure.

In addition, they form acids (particularly lactic acid)

and proteolytic enzymes. The acids are the major

culprit in causing caries because the calcium salts of

References

teeth are slowly dissolved in a highly acidic medium.

And once the salts have become absorbed, the remain-

Altkorn D, Vokes T: Treatment of postmenopausal osteo-

ing organic matrix is rapidly digested by the prote-

porosis. JAMA 285:1415, 2001.

olytic enzymes.

Bilezikian JP, Silverberg SJ: Clinical practice. Asymptomatic

The enamel of the tooth is the primary barrier to the

primary hyperparathyroidism. N Engl J Med 350:1746,

development of caries. Enamel is far more resistant to

2004.

demineralization by acids than is dentin, primarily

Chen RA, Goodman WG: Role of the calcium-sensing

because the crystals of enamel are dense, but also

receptor in parathyroid gland physiology. Am J Physiol

because each enamel crystal is about 200 times as large

Renal Physiol 286:F1005, 2004.

in volume as each dentin crystal. Once the carious

Compston JE: Sex steroids and bone. Physiol Rev 81:419,

process has penetrated through the enamel to the

2001.

dentin, it proceeds many times as rapidly because of

Delmas PD: Treatment of postmenopausal osteoporosis.

Lancet 359:2018, 2002.

the high degree of solubility of the dentin salts.

Goodman WG, Juppner H, Salusky IB, Sherrard DJ:

Because of the dependence of the caries bacteria on

Parathyroid hormone (PTH), PTH-derived peptides, and

carbohydrates for their nutrition, it has frequently

new PTH assays in renal osteodystrophy. Kidney Int 63:1,

been taught that eating a diet high in carbohydrate

2003.

content will lead to excessive development of caries.

Gurlek A, Pittelkow MR, Kumar R: Modulation of growth

However, it is not the quantity of carbohydrate

factor/cytokine synthesis and signaling by

1alpha,25-

ingested but the frequency with which it is eaten that

dihydroxyvitamin D(3): implications in cell growth and

is important. If carbohydrates are eaten in many small

differentiation. Endocr Rev 23:763, 2002.

C H A P T E R

Reproductive and Hormonal

Functions of the Male (and

Function of the Pineal Gland)

The reproductive functions of the male can be

divided into three major subdivisions: (1) sper-

matogenesis, which means simply the formation of

sperm; (2) performance of the male sexual act; and

(3) regulation of male reproductive functions

by the various hormones. Associated with these

reproductive functions are the effects of the male

sex hormones on the accessory sexual organs, cellu-

lar metabolism, growth, and other functions of the body.

Physiologic Anatomy of the

Male Sexual Organs

Figure 80-1A shows the various portions of the male reproductive system, and

Figure 80-1B gives a more detailed structure of the testis and epididymis. The testis

is composed of up to 900 coiled seminiferous tubules, each averaging more than one

half meter long, in which the sperm are formed. The sperm then empty into the

epididymis, another coiled tube about 6 meters long. The epididymis leads into the

vas deferens, which enlarges into the ampulla of the vas deferens immediately before

the vas enters the body of the prostate gland.

Two seminal vesicles, one located on each side of the prostate, empty into the pro-

static end of the ampulla, and the contents from both the ampulla and the seminal

vesicles pass into an ejaculatory duct leading through the body of the prostate gland

and then emptying into the internal urethra. Prostatic ducts, too, empty from the

prostate gland into the ejaculatory duct and from there into the prostatic urethra.

Finally, the urethra is the last connecting link from the testis to the exterior. The

urethra is supplied with mucus derived from a large number of minute urethral

glands located along its entire extent and even more so from bilateral bulbourethral

glands (Cowper’s glands) located near the origin of the urethra.

Spermatogenesis

During formation of the embryo, the primordial germ cells migrate into the

testes and become immature germ cells called spermatogonia which lie in two

or three layers of the inner surfaces of the seminiferous tubules (a cross section

of one is shown in Figure 80-2A). The spermatogonia begin to undergo mitotic

division, beginning at puberty, and continually proliferate and differentiate

through definite stages of development to form sperm, as shown in Figure

80-2B.

Steps of Spermatogenesis

Spermatogenesis occurs in the seminiferous tubules during active sexual life as

the result of stimulation by anterior pituitary gonadotropic hormones, begin-

ning at an average age of 13 years and continuing throughout most of the

remainder of life but decreasing markedly in old age.

In the first stage of spermatogenesis, the spermatogonia migrate among

Sertoli cells toward the central lumen of the seminiferous tubule. The Sertoli

996

Chapter 80

Reproductive and Hormonal Functions of the Male (and Function of the Pineal Gland)

997

Urinary

bladder

Ampulla

Seminal

Interstitial cells

vesicle

Prostate

Ejaculatory

Seminiferous

gland

duct

tubules

Bulbourethral

Erectile

gland

tissue

Vas deferens

Epididymis

Prepuce

Seminiferous

Glans

tubules

penis

Spermatids

Testis

Scrotum

Spermatozoa

Head of

epididymis

Secondary

Testicular artery

spermatocyte

Vas deferens

Primary

spermatocyte

Efferent

ductules

Sertoli cell

Body of

epididymis

Seminiferous

tubules

Rete testis

Spermatogonium

Tail of epididymis

Figure 80-2

A, Cross section of a seminiferous tubule. B, Stages in the devel-

Figure 80-1

opment of sperm from spermatogonia.

A, Male reproduction system. (Modified from Bloom V, Fawcett

DW: Textbook of Histology, 10th ed. Philadelphia: WB Saunders

Co, 1975.) B, Internal structure of the testis and relation of the

the father, while the other half are derived from the

testis to the epididymis. (Redrawn from Guyton AC: Anatomy and

oocyte provided by the mother.

Physiology. Philadelphia: Saunders College Publishing, 1985.)

The entire period of spermatogenesis, from sper-

matogonia to spermatozoa, takes about 74 days.

cells are very large, with overflowing cytoplasmic

Sex Chromosomes. In each spermatogonium, one of the

envelopes that surround the developing spermatogo-

23 pairs of chromosomes carries the genetic informa-

nia all the way to the central lumen of the tubule.

tion that determines the sex of each eventual offspring.

This pair is composed of one X chromosome, which is

Meiosis. Spermatogonia that cross the barrier into the

called the female chromosome, and one Y chromo-

Sertoli cell layer become progressively modified and

some, the male chromosome. During meiotic division,

enlarged to form large primary spermatocytes (Figure

the male Y chromosome goes to one spermatid that

80-3). Each of these, in turn, undergoes meiotic

then becomes a male sperm, and the female X chro-

division to form two secondary spermatocytes. After

mosome goes to another spermatid that becomes a

another few days, these too divide to form spermatids

female sperm. The sex of the eventual offspring is

that are eventually modified to become spermatozoa

determined by which of these two types of sperm

(sperm).

fertilizes the ovum. This is discussed further in

During the change from the spermatocyte stage to

Chapter 82.

the spermatid stage, the 46 chromosomes (23 pairs of

chromosomes) of the spermatocyte are divided, so that

Formation of Sperm. When the spermatids are first

23 chromosomes go to one spermatid and the other 23

formed, they still have the usual characteristics of

to the second spermatid. This also divides the chro-

epithelioid cells, but soon they begin to differentiate

mosomal genes so that only one half of the genetic

and elongate into spermatozoa. As shown in Figure

characteristics of the eventual fetus are provided by

80-4, each spermatozoon is composed of a head and a

998

Unit XIV Endocrinology and Reproduction

Acrosome

Birth

Primordial germ cell

Surface membrane

Vacuole

Enters

Anterior head cap

testis

12-14

Posterior head cap

years

Neck

Spermatogonia

Body

Puberty

Mitochondria

Spermatogonia

proliferate by mitotic

cell division inside

Chief piece of tail

testis

25 days

End piece of tail

Primary

spermatocyte

Figure 80-4

9 days

Meiotic division I

Structure of the human spermatozoon.

Secondary

spermatocytes

hyaluronidase

(which can digest proteoglycan

fila-

Meiotic division II

ments of tissues) and powerful proteolytic enzymes

19 days

(which can digest proteins). These enzymes play

important roles in allowing the sperm to enter the

ovum and fertilize it.

Spermatids

The tail of the sperm, called the flagellum, has three

major components: (1) a central skeleton constructed

of 11 microtubules, collectively called the axoneme—

21 days

Differentiation

the structure of this is similar to that of cilia found

Mature

on the surfaces of other types of cells described in

sperm

Chapter 2; (2) a thin cell membrane covering the

axoneme; and (3) a collection of mitochondria sur-

rounding the axoneme in the proximal portion of the

tail (called the body of the tail).

Back-and-forth movement of the tail

(flagellar

movement) provides motility for the sperm. This

Figure 80-3

movement results from a rhythmical longitudinal

sliding motion between the anterior and posterior

Cell divisions

during

spermatogenesis. During embryonic

development the primordial germ cells migrate to the testis where

tubules that make up the axoneme. The energy for this

they become spermatogonia. At puberty (usually 12 to14 years

process is supplied in the form of adenosine triphos-

after birth), the spermatogonia proliferate rapidly by mitosis. Some

phate that is synthesized by the mitochondria in the

begin meiosis to become primary spermatocytes and continue

body of the tail.

through meiotic division I to become secondary spermato-

cytes. After completion of meiotic division II, the secondary

Normal sperm move in a fluid medium at a velocity

spermatocytes produce spermatids, which differentiate to form

of 1 to 4 mm/min. This allows them to move through

spermatozoa.

the female genital tract in quest of the ovum.

Hormonal Factors That Stimulate

tail. The head comprises the condensed nucleus of the

Spermatogenesis

cell with only a thin cytoplasmic and cell membrane

We shall discuss the role of hormones in reproduction

layer around its surface. On the outside of the anterior

later, but at this point, let us note that several hor-

two thirds of the head is a thick cap called the acro-

mones play essential roles in spermatogenesis. Some

some that is formed mainly from the Golgi apparatus.

of these are as follows:

This contains a number of enzymes similar to those

1. Testosterone, secreted by the Leydig cells located

found in lysosomes of the typical cell, including

in the interstitium of the testis, is essential for

Chapter 80

Reproductive and Hormonal Functions of the Male (and Function of the Pineal Gland)

999

growth and division of the testicular germinal

The activity of sperm increases markedly with in-

cells, which is the first stage in forming sperm.

creasing temperature, but so does the rate of metabo-

2. Luteinizing hormone, secreted by the anterior

lism, causing the life of the sperm to be considerably

pituitary gland, stimulates the Leydig cells to

shortened. Although sperm can live for many weeks in

secrete testosterone.

the suppressed state in the genital ducts of the testes,

3. Follicle-stimulating hormone, also secreted by the

life expectancy of ejaculated sperm in the female

anterior pituitary gland, stimulates the Sertoli

genital tract is only 1 to 2 days.

cells; without this stimulation, the conversion

of the spermatids to sperm (the process of

spermiogenesis) will not occur.

Function of the Seminal Vesicles

4. Estrogens, formed from testosterone by the

Sertoli cells when they are stimulated by follicle-

Each seminal vesicle is a tortuous, loculated tube lined

stimulating hormone, are probably also essential

with a secretory epithelium that secretes a mucoid

for spermiogenesis.

material containing an abundance of fructose,

5. Growth hormone (as well as most of the other

citric acid, and other nutrient substances, as well

body hormones) is necessary for controlling

as large quantities of prostaglandins and fibrinogen.

background metabolic functions of the testes.

During the process of emission and ejaculation, each

Growth hormone specifically promotes early

seminal vesicle empties its contents into the ejacula-

division of the spermatogonia themselves; in its

tory duct shortly after the vas deferens empties the

absence, as in pituitary dwarfs, spermatogenesis

sperm. This adds greatly to the bulk of the ejaculated

is severely deficient or absent, thus causing

semen, and the fructose and other substances in the

infertility.

seminal fluid are of considerable nutrient value for

the ejaculated sperm until one of the sperm fertilizes

Maturation of Sperm in the Epididymis

the ovum.

After formation in the seminiferous tubules, the sperm

Prostaglandins are believed to aid fertilization in

require several days to pass through the 6-meter-long

two ways: (1) by reacting with the female cervical

tubule of the epididymis. Sperm removed from the

mucus to make it more receptive to sperm movement

seminiferous tubules and from the early portions of

and (2) by possibly causing backward, reverse peri-

the epididymis are nonmotile, and they cannot fertil-

staltic contractions in the uterus and fallopian tubes to

ize an ovum. However, after the sperm have been

move the ejaculated sperm toward the ovaries (a few

in the epididymis for some 18 to 24 hours, they deve-

sperm reach the upper ends of the fallopian tubes

lop the capability of motility, even though several

within 5 minutes).

inhibitory proteins in the epididymal fluid still prevent

final motility until after ejaculation.

Function of the Prostate Gland

Storage of Sperm. The two testes of the human adult

form up to 120 million sperm each day. A small quan-

The prostate gland secretes a thin, milky fluid that con-

tity of these can be stored in the epididymis, but most

tains calcium, citrate ion, phosphate ion, a clotting

are stored in the vas deferens. They can remain stored,

enzyme, and a profibrinolysin. During emission, the

maintaining their fertility, for at least a month. During

capsule of the prostate gland contracts simultaneously

this time, they are kept in a deeply suppressed inactive

with the contractions of the vas deferens so that the

state by multiple inhibitory substances in the secre-

thin, milky fluid of the prostate gland adds further to

tions of the ducts. Conversely, with a high level of

the bulk of the semen. A slightly alkaline characteris-

sexual activity and ejaculations, storage may be no

tic of the prostatic fluid may be quite important for

longer than a few days.

successful fertilization of the ovum, because the fluid

After ejaculation, the sperm become motile, and

of the vas deferens is relatively acidic owing to the

they also become capable of fertilizing the ovum, a

presence of citric acid and metabolic end products of

process called maturation. The Sertoli cells and the

the sperm and, consequently, helps to inhibit sperm

epithelium of the epididymis secrete a special nutrient

fertility. Also, the vaginal secretions of the female are

fluid that is ejaculated along with the sperm. This fluid

acidic (pH of 3.5 to 4.0). Sperm do not become opti-

contains hormones (including both testosterone and

mally motile until the pH of the surrounding fluids

estrogens), enzymes, and special nutrients that are

rises to about 6.0 to 6.5. Consequently, it is probable

essential for sperm maturation.

that the slightly alkaline prostatic fluid helps to neu-

tralize the acidity of the other seminal fluids during

Physiology of the Mature Sperm. The normal motile, fertile

ejaculation, and thus enhances the motility and fertil-

sperm are capable of flagellated movement though the

ity of the sperm.

fluid medium at velocities of

1 to 4 mm/min. The

activity of sperm is greatly enhanced in a neutral

and slightly alkaline medium, as exists in the ejacu-

Semen

lated semen, but it is greatly depressed in a mildly

acidic medium. A strong acidic medium can cause

Semen, which is ejaculated during the male sexual

rapid death of sperm.

act, is composed of the fluid and sperm from the vas

1000

Unit XIV Endocrinology and Reproduction

deferens (about 10 per cent of the total), fluid from the

the membrane at the head of the sperm (the

seminal vesicles (almost 60 per cent), fluid from the

acrosome) becomes much weaker.

prostate gland (about 30 per cent), and small amounts

3. The membrane of the sperm also becomes much

from the mucous glands, especially the bulbourethral

more permeable to calcium ions, so that calcium

glands. Thus, the bulk of the semen is seminal vesicle

now enters the sperm in abundance and changes

fluid, which is the last to be ejaculated and serves

the activity of the flagellum, giving it a powerful

to wash the sperm through the ejaculatory duct and

whiplash motion in contrast to its previously weak

urethra.

undulating motion. In addition, the calcium ions

The average pH of the combined semen is about 7.5,

cause changes in the cellular membrane that

the alkaline prostatic fluid having more than neutral-

covers the leading edge of the acrosome, making

ized the mild acidity of the other portions of the

it possible for the acrosome to release its enzymes

semen. The prostatic fluid gives the semen a milky

rapidly and easily as the sperm penetrates the

appearance, and fluid from the seminal vesicles and

granulosa cell mass surrounding the ovum, and

mucous glands gives the semen a mucoid consistency.

even more so as it attempts to penetrate the zona

Also, a clotting enzyme from the prostatic fluid causes

pellucida of the ovum itself.

the fibrinogen of the seminal vesicle fluid to form a

Thus, multiple changes occur during the process of

weak fibrin coagulum that holds the semen in the

capacitation. Without these, the sperm cannot make its

deeper regions of the vagina where the uterine cervix

way to the interior of the ovum to cause fertilization.

lies. The coagulum then dissolves during the next 15 to

30 minutes because of lysis by fibrinolysin formed

Acrosome Enzymes, the “Acrosome Reaction,”

from the prostatic profibrinolysin. In the early minutes

and Penetration of the Ovum

after ejaculation, the sperm remain relatively immo-

Stored in the acrosome of the sperm are large quanti-

bile, possibly because of the viscosity of the coagulum.

ties of hyaluronidase and proteolytic enzymes.

As the coagulum dissolves, the sperm simultaneously

Hyaluronidase depolymerizes the hyaluronic acid

become highly motile.

polymers in the intercellular cement that hold the

Although sperm can live for many weeks in the male

ovarian granulosa cells together. The proteolytic

genital ducts, once they are ejaculated in the semen,

enzymes digest proteins in the structural elements of

their maximal life span is only 24 to 48 hours at

tissue cells that still adhere to the ovum.

body temperature. At lowered temperatures, however,

When the ovum is expelled from the ovarian fol-

semen can be stored for several weeks, and when

licle into the fallopian tube, it still carries with it mul-

frozen at temperatures below -100°C, sperm have

tiple layers of granulosa cells. Before a sperm can

been preserved for years.

fertilize the ovum, it must dissolute these granulosa

cell layers, and then it must penetrate though the thick

“Capacitation” of the Spermatozoa—Making It

covering of the ovum itself, the zona pellucida. To

Possible for Them to Penetrate the Ovum

achieve this, the stored enzymes in the acrosome begin

Although spermatozoa are said to be “mature” when

to be released. It is believed that the hyaluronidase

they leave the epididymis, their activity is held in check

among these enzymes is especially important in open-

by multiple inhibitory factors secreted by the genital

ing pathways between the granulosa cells so that the

duct epithelia. Therefore, when they are first expelled

sperm can reach the ovum.

in the semen, they are unable to perform their duties

When the sperm reaches the zona pellucida of the

in fertilizing the ovum. However, on coming in contact

ovum, the anterior membrane of the sperm itself binds

with the fluids of the female genital tract, multiple

specifically with receptor proteins in the zona pellu-

changes occur that activate the sperm for the final

cida. Then, rapidly, the entire acrosome dissolves,

processes of fertilization. These collective changes are

and all the acrosomal enzymes are released. Within

called capacitation of the spermatozoa. This normally

minutes, these enzymes open a penetrating pathway

requires from 1 to 10 hours. Some changes that are

for passage of the sperm head through the zona pel-

believed to occur are the following:

lucida to the inside of the ovum. Within another 30

1. The uterine and fallopian tube fluids wash away

minutes, the cell membranes of the sperm head and of

the various inhibitory factors that suppress sperm

the oocyte fuse with each other to form a single cell.

activity in the male genital ducts.

At the same time, the genetic material of the sperm

2. While the spermatozoa remain in the fluid of the

and the oocyte combine to form a completely new cell

male genital ducts, they are continually exposed

genome, containing equal numbers of chromosomes

to many floating vesicles from the seminiferous

and genes from mother and father. This is the process

tubules containing large amounts of cholesterol.

of fertilization; then the embryo begins to develop, as

This cholesterol is continually added to the

discussed in Chapter 82.

cellular membrane covering the sperm acrosome,

toughening this membrane and preventing release

Why Does Only One Sperm Enter the Oocyte? With as many

of its enzymes. After ejaculation, the sperm

sperm as there are, why does only one enter the

deposited in the vagina swim away from the

oocyte? The reason is not entirely known, but within

cholesterol vesicles upward into the uterine cavity,

a few minutes after the first sperm penetrates the zona

and they gradually lose much of their other excess

pellucida of the ovum, calcium ions diffuse inward

cholesterol over the next few hours. In so doing,

through the oocyte membrane and cause multiple

Chapter 80

Reproductive and Hormonal Functions of the Male (and Function of the Pineal Gland)

1001

cortical granules to be released by exocytosis from

the oocyte into the perivitelline space. These granules

contain substances that permeate all portions of the

zona pellucida and prevent binding of additional

sperm, and they even cause any sperm that have

already begun to bind to fall off. Thus, almost never

does more than one sperm enter the oocyte during

fertilization.

Abnormal Spermatogenesis and

Male Fertility

The seminiferous tubular epithelium can be destroyed

by a number of diseases. For instance, bilateral orchitis

of the testes resulting from mumps causes sterility in

some affected males. Also, some male infants are born

Figure 80-5

with degenerate tubular epithelia as a result of strictures

in the genital ducts or other abnormalities. Finally,

Abnormal infertile sperm, compared with a normal sperm on the

another cause of sterility, usually temporary, is excessive

right.

temperature of the testes.

Effect of Temperature on Spermatogenesis. Increasing the

enough testosterone. The surgical operation for cryp-

temperature of the testes can prevent spermatogenesis

torchidism in these patients is unlikely to be successful.

by causing degeneration of most cells of the semini-

ferous tubules besides the spermatogonia. It has often

Effect of Sperm Count on Fertility. The usual quantity of

been stated that the reason the testes are located in

semen ejaculated during each coitus averages about 3.5

the dangling scrotum is to maintain the temperature

milliliters, and in each milliliter of semen is an average

of these glands below the internal temperature of the

of about 120 million sperm, although even in “normal”

body, although usually only about 2°C below the inter-

males this can vary from 35 million to 200 million. This

nal temperature. On cold days, scrotal reflexes cause

means an average total of 400 million sperm are usually

the musculature of the scrotum to contract, pulling the

present in the several milliliters of each ejaculate. When

testes close to the body to maintain this 2° differential.

the number of sperm in each milliliter falls below about

Thus, the scrotum theoretically acts as a cooling mech-

20 million, the person is likely to be infertile. Thus, even

anism for the testes (but a controlled cooling), without

though only a single sperm is necessary to fertilize the

which spermatogenesis might be deficient during hot

ovum, for reasons not understood, the ejaculate usually

weather.

must contain a tremendous number of sperm for only

one sperm to fertilize the ovum.

Cryptorchidism

Cryptorchidism means failure of a testis to descend

Effect of Sperm Morphology and Motility on Fertility. Occa-

from the abdomen into the scrotum at or near the time

sionally a man has a normal number of sperm but is still

of birth of a fetus. During development of the male

infertile. When this occurs, sometimes as many as one

fetus, the testes are derived from the genital ridges in

half the sperm are found to be abnormal physically,

the abdomen. However, at about 3 weeks to 1 month

having two heads, abnormally shaped heads, or abnor-

before birth of the baby, the testes normally descend

mal tails, as shown in Figure 80-5. At other times, the

through the inguinal canals into the scrotum. Occasion-

sperm appear to be structurally normal, but for reasons

ally this descent does not occur or occurs incompletely,

not understood, they are either entirely nonmotile

so that one or both testes remain in the abdomen, in the

or relatively nonmotile. Whenever the majority of the

inguinal canal, or elsewhere along the route of descent.

sperm are morphologically abnormal or are nonmotile,

A testis that remains throughout life in the abdomi-

the person is likely to be infertile, even though the

nal cavity is incapable of forming sperm. The tubular

remainder of the sperm appear to be normal.

epithelium becomes degenerate, leaving only the

interstitial structures of the testis. It has been claimed

that even the few degrees’ higher temperature in the

Male Sexual Act

abdomen than in the scrotum is sufficient to cause

this degeneration of the tubular epithelium and, conse-

quently, to cause sterility, although this is not certain.

Neuronal Stimulus for Performance

Nevertheless, for this reason, operations to relocate the

of the Male Sexual Act

cryptorchid testes from the abdominal cavity into the

scrotum before the beginning of adult sexual life are

The most important source of sensory nerve signals

frequently performed on boys who have undescended

for initiating the male sexual act is the glans penis.

testes.

The glans contains an especially sensitive sensory end-

Testosterone secretion by the fetal testes themselves

is the normal stimulus that causes the testes to descend

organ system that transmits into the central nervous

into the scrotum from the abdomen. Therefore, many, if

system that special modality of sensation called sexual

not most, instances of cryptorchidism are caused by

sensation. The slippery massaging action of intercourse

abnormally formed testes that are unable to secrete

on the glans stimulates the sensory end-organs, and the

1002

Unit XIV Endocrinology and Reproduction

sexual signals in turn pass through the pudendal nerve,

then through the sacral plexus into the sacral portion

of the spinal cord, and finally up the cord to undefined

Deep penile

areas of the brain.

fascia

Central artery

Impulses may also enter the spinal cord from

Corpus

areas adjacent to the penis to aid in stimulating the

cavernosum

sexual act. For instance, stimulation of the anal epithe-

lium, the scrotum, and perineal structures in general

Corpus

Urethra

spongiosum

can send signals into the cord that add to the sexual

sensation. Sexual sensations can even originate in

internal structures, such as in areas of the urethra,

Figure 80-6

bladder, prostate, seminal vesicles, testes, and vas

Erectile tissue of the penis.

deferens. Indeed, one of the causes of “sexual drive”

is filling of the sexual organs with secretions. Mild

infection and inflammation of these sexual organs

sometimes cause almost continual sexual desire,

This erectile tissue consists of large cavernous sinu-

and some “aphrodisiac” drugs, such as cantharidin,

soids, which are normally relatively empty of blood

increase sexual desire by irritating the bladder and

but become dilated tremendously when arterial

urethral mucosa, inducing inflammation and vascular

blood flows rapidly into them under pressure while the

congestion.

venous outflow is partially occluded. Also, the erectile

bodies, especially the two corpora cavernosa, are

Psychic Element of Male Sexual Stimulation. Appropriate

surrounded by strong fibrous coats; therefore, high

psychic stimuli can greatly enhance the ability of a

pressure within the sinusoids causes ballooning of the

person to perform the sexual act. Simply thinking

erectile tissue to such an extent that the penis becomes

sexual thoughts or even dreaming that the act of inter-

hard and elongated. This is the phenomenon of

course is being performed can initiate the male act,

erection.

culminating in ejaculation. Indeed, nocturnal emissions

during dreams occur in many males during some

Lubrication, a Parasympathetic Function. During sexual

stages of sexual life, especially during the teens.

stimulation, the parasympathetic impulses, in addition

to promoting erection, cause the urethral glands and

Integration of the Male Sexual Act in the Spinal Cord.

the bulbourethral glands to secrete mucus. This mucus

Although psychic factors usually play an important

flows through the urethra during intercourse to aid in

part in the male sexual act and can initiate or inhibit

the lubrication during coitus. However, most of the

it, brain function is probably not necessary for its per-

lubrication of coitus is provided by the female sexual

formance because appropriate genital stimulation can

organs rather than by the male. Without satisfactory

cause ejaculation in some animals and occasionally in

lubrication, the male sexual act is seldom successful

humans after their spinal cords have been cut above

because unlubricated intercourse causes grating,

the lumbar region. The male sexual act results from

painful sensations that inhibit rather than excite sexual

inherent reflex mechanisms integrated in the sacral

sensations.

and lumbar spinal cord, and these mechanisms can be

initiated by either psychic stimulation from the brain

Emission and Ejaculation—Function of the Sympathetic

or actual sexual stimulation from the sex organs, but

Nerves. Emission and ejaculation are the culmination

usually it is a combination of both.

of the male sexual act. When the sexual stimulus

becomes extremely intense, the reflex centers of the

spinal cord begin to emit sympathetic impulses that

Stages of the Male Sexual Act

leave the cord at T-12 to L-2 and pass to the genital

organs through the hypogastric and pelvic sympathetic

Penile Erection—Role of the Parasympathetic Nerves. Penile

nerve plexuses to initiate emission, the forerunner of

erection is the first effect of male sexual stimulation,

ejaculation.

and the degree of erection is proportional to the

Emission begins with contraction of the vas defer-

degree of stimulation, whether psychic or physical.

ens and the ampulla to cause expulsion of sperm into

Erection is caused by parasympathetic impulses that

the internal urethra. Then, contractions of the muscu-

pass from the sacral portion of the spinal cord through

lar coat of the prostate gland followed by contraction

the pelvic nerves to the penis. These parasympathetic

of the seminal vesicles expel prostatic and seminal

nerve fibers, in contrast to most other parasympathetic

fluid also into the urethra, forcing the sperm forward.

fibers, are believed to release nitric oxide and/or

All these fluids mix in the internal urethra with mucus

vasoactive intestinal peptide in addition to acetyl-

already secreted by the bulbourethral glands to form

choline. The nitric oxide especially relaxes the arteries

the semen. The process to this point is emission.

of the penis, as well as relaxes the trabecular mesh-

The filling of the internal urethra with semen

work of smooth muscle fibers in the erectile tissue of

elicits sensory signals that are transmitted through the

the corpora cavernosa and corpus spongiosum in the

pudendal nerves to the sacral regions of the cord,

shaft of the penis, shown in Figure 80-6.

giving the feeling of sudden fullness in the internal

Chapter 80

Reproductive and Hormonal Functions of the Male (and Function of the Pineal Gland)

1003

genital organs. Also, these sensory signals further

excite rhythmical contraction of the internal genital

organs and cause contraction of the ischiocavernosus

Interstitial cells

and bulbocavernosus muscles that compress the bases

of Leydig

of the penile erectile tissue. These effects together

cause rhythmical, wavelike increases in pressure in

Blood vessel

both the erectile tissue of the penis and the genital

ducts and urethra, which “ejaculate” the semen from

the urethra to the exterior. This final process is called

Fibroblasts

ejaculation. At the same time, rhythmical contractions

of the pelvic muscles and even of some of the muscles

of the body trunk cause thrusting movements of the

pelvis and penis, which also help propel the semen into

the deepest recesses of the vagina and perhaps even

Germinal

slightly into the cervix of the uterus.

epithelium

This entire period of emission and ejaculation is

called the male orgasm. At its termination, the male

sexual excitement disappears almost entirely within

1 to 2 minutes and erection ceases, a process called

Figure 80-7

resolution.

Interstitial cells of Leydig, the cells that secrete testosterone,

located in the interstices between the seminiferous tubules.

Testosterone and Other Male

Sex Hormones

than 5 per cent of the total in the adult male) that even

Secretion, Metabolism, and Chemistry

in women they do not cause significant masculine char-

of the Male Sex Hormone

acteristics, except for causing growth of pubic and axil-

lary hair. But when an adrenal tumor of the adrenal

androgen-producing cells occurs, the quantity of

Secretion of Testosterone by the Interstitial Cells of Leydig

androgenic hormones may then become great enough

in the Testes. The testes secrete several male sex

to cause all the usual male secondary sexual charac-

hormones, which are collectively called androgens,

teristics to occur even in the female. These effects

including testosterone, dihydrotestosterone, and

are described in connection with the adrenogenital

androstenedione. Testosterone is so much more abun-

syndrome in Chapter 77.

dant than the others that one can consider it to be the

Rarely, embryonic rest cells in the ovary can deve-

significant testicular hormone, although as we shall

lop into a tumor that produces excessive quantities

see, much, if not most, of the testosterone is eventually

of androgens in women; one such tumor is the

converted into the more active hormone dihy-

arrhenoblastoma. The normal ovary also produces

minute quantities of androgens, but they are not

drotestosterone in the target tissues.

significant.

Testosterone is formed by the interstitial cells of

Leydig, which lie in the interstices between the semi-

Chemistry of the Androgens. All androgens are steroid

niferous tubules and constitute about 20 per cent of

compounds, as shown by the formulas in Figure 80-8 for

the mass of the adult testes, as shown in Figure 80-7.

testosterone and dihydrotestosterone. Both in the testes

Leydig cells are almost nonexistent in the testes during

and in the adrenals, the androgens can be synthesized

childhood when the testes secrete almost no testos-

either from cholesterol or directly from acetyl coen-

terone, but they are numerous in the newborn male

zyme A.

infant for the first few months of life and in the adult

male any time after puberty; at both these times the

Metabolism of Testosterone. After secretion by the testes,

about 97 per cent of the testosterone becomes either

testes secrete large quantities of testosterone. Fur-

loosely bound with plasma albumin or more tightly

thermore, when tumors develop from the interstitial

bound with a beta globulin called sex hormone-binding

cells of Leydig, great quantities of testosterone are

globulin and circulates in the blood in these states

secreted. Finally, when the germinal epithelium of the

for

30 minutes to several hours. By that time, the

testes is destroyed by x-ray treatment or excessive

testosterone either is transferred to the tissues or is

heat, the Leydig cells, which are less easily destroyed,

degraded into inactive products that are subsequently

often continue to produce testosterone.

excreted.

Much of the testosterone that becomes fixed to

Secretion of Androgens Elsewhere in the Body. The term

the tissues is converted within the tissue cells to dihy-

“androgen” means any steroid hormone that has mas-

drotestosterone, especially in certain target organs such

culinizing effects, including testosterone itself; it also

as the prostate gland in the adult and the external gen-

includes male sex hormones produced elsewhere in the

italia of the male fetus. Some actions of testosterone are

body besides the testes. For instance, the adrenal glands

dependent on this conversion, whereas other actions are

secrete at least five androgens, although the total mas-

not. The intracellular functions are discussed later in the

culinizing activity of all these is normally so slight (less

chapter.

1004

Unit XIV Endocrinology and Reproduction

Functions of Testosterone During

Fetal Development

Testosterone begins to be elaborated by the male fetal

CH₃

testes at about the seventh week of embryonic life.

Indeed, one of the major functional differences

CH₃

between the female and the male sex chromosome is

that the male chromosome causes the newly develop-

ing genital ridge to secrete testosterone, whereas the

female chromosome causes this ridge to secrete estro-

gens. Injection of large quantities of male sex hormone

Testosterone

into pregnant animals causes development of male

sexual organs even though the fetus is female. Also,

removal of the testes in the early male fetus causes

Dihydrotestosterone

development of female sexual organs.

Thus, testosterone secreted first by the genital ridges

and later by the fetal testes is responsible for the devel-

opment of the male body characteristics, including

Figure 80-8

the formation of a penis and a scrotum rather than

formation of a clitoris and a vagina. Also, it causes

Testosterone and dihydrotestosterone.

formation of the prostate gland, seminal vesicles, and

male genital ducts, while at the same time suppressing

the formation of female genital organs.

Degradation and Excretion of Testosterone. The testosterone

that does not become fixed to the tissues is rapidly con-

Effect of Testosterone to Cause Descent of the Testes. The

verted, mainly by the liver, into androsterone and dehy-

testes usually descend into the scrotum during the last

droepiandrosterone and simultaneously conjugated as

2 to 3 months of gestation when the testes begin secret-

either glucuronides or sulfates (glucuronides, particu-

ing reasonable quantities of testosterone. If a male

larly). These are excreted either into the gut by way of

child is born with undescended but otherwise normal

the liver bile or into the urine through the kidneys.

testes, the administration of testosterone usually

causes the testes to descend in the usual manner if the

Production of Estrogen in the Male. In addition to testos-

inguinal canals are large enough to allow the testes to

terone, small amounts of estrogens are formed in the

pass.

male (about one fifth the amount in the nonpregnant

Administration of gonadotropic hormones, which

female), and a reasonable quantity of estrogens can be

recovered from a man’s urine. The exact source of estro-

stimulate the Leydig cells of the newborn child’s testes

gens in the male is unclear, but the following are known:

to produce testosterone, can also cause the testes to

(1) the concentration of estrogens in the fluid of the

descend. Thus, the stimulus for descent of the testes is

seminiferous tubules is quite high and probably plays an

testosterone, indicating again that testosterone is an

important role in spermiogenesis. This estrogen is

important hormone for male sexual development

believed to be formed by the Sertoli cells by converting

during fetal life.

testosterone to estradiol.

(2) Much larger amounts

of estrogens are formed from testosterone and

Effect of Testosterone on Development

androstanediol in other tissues of the body, especially

of Adult Primary and Secondary

the liver, probably accounting for as much as 80 per cent

Sexual Characteristics

of the total male estrogen production.

After puberty, the increasing amounts of testosterone

secretion cause the penis, scrotum, and testes to

enlarge about eightfold before the age of 20 years. In

Functions of Testosterone

addition, testosterone causes the secondary sexual

characteristics of the male to develop, beginning at

In general, testosterone is responsible for the distin-

puberty and ending at maturity. These secondary

guishing characteristics of the masculine body. Even

sexual characteristics, in addition to the sexual organs

during fetal life, the testes are stimulated by chorionic

themselves, distinguish the male from the female as

gonadotropin from the placenta to produce moderate

follows.

quantities of testosterone throughout the entire period

of fetal development and for 10 or more weeks after

Effect on the Distribution of Body Hair. Testosterone causes

birth; thereafter, essentially no testosterone is

growth of hair (1) over the pubis, (2) upward along the

produced during childhood until about the ages of 10

linea alba of the abdomen sometimes to the umbilicus

to 13 years. Then testosterone production increases

and above, (3) on the face, (4) usually on the chest, and

rapidly under the stimulus of anterior pituitary

(5) less often on other regions of the body, such as the

gonadotropic hormones at the onset of puberty and

back. It also causes the hair on most other portions of

lasts throughout most of the remainder of life, as

the body to become more prolific.

shown in Figure 80-9, dwindling rapidly beyond age 50

to become 20 to 50 per cent of the peak value by age

Baldness. Testosterone decreases the growth of hair on

80.

the top of the head; a man who does not have func-

Chapter 80

Reproductive and Hormonal Functions of the Male (and Function of the Pineal Gland)

1005

Fetal

Neonatal

Pubertal

Adult

Old age

100

5.0

Figure 80-9

2.5

The different stages of male

sexual function as reflected by

average plasma testosterone

concentrations

(red line) and

sperm production (blue line) at

different ages.

(Modified from

1st

2nd

3rd

Griffin JF, Wilson JD: The testis. In:

Trimester

Year

Bondy PK, Rosenberg LE [eds]:

gestation

Metabolic Control and Disease,

Birth

8th ed. Philadelphia: WB Saun-

ders Co, 1980.)

tional testes does not become bald. However, many

to deposition of proteins in the skin, and the changes

virile men never become bald because baldness is a

in the voice also result partly from this protein ana-

result of two factors: first, a genetic background for the

bolic function of testosterone.

development of baldness and, second, superimposed

Because of the great effect that testosterone and

on this genetic background, large quantities of andro-

other androgens have on the body musculature,

genic hormones. A woman who has the appropriate

synthetic androgens are widely used by athletes to

genetic background and who develops a long-

improve their muscular performance. This practice is to

sustained androgenic tumor becomes bald in the same

be severely deprecated because of prolonged harmful

manner as does a man.

effects of excess androgens, as we discuss in Chapter 84

in relation to sports physiology. Testosterone or syn-

Effect on the Voice. Testosterone secreted by the testes

thetic androgens are also occasionally used in old age

or injected into the body causes hypertrophy of the

as a “youth hormone” to improve muscle strength and

laryngeal mucosa and enlargement of the larynx. The

vigor, but with questionable results.

effects cause at first a relatively discordant, “cracking”

voice, but this gradually changes into the typical adult

Testosterone Increases Bone Matrix and Causes Calcium Reten-

masculine voice.

tion. After the great increase in circulating testos-

terone that occurs at puberty (or after prolonged

Testosterone Increases Thickness of the Skin and Can Con-

injection of testosterone), the bones grow considerably

tribute to Development of Acne. Testosterone increases

thicker and deposit considerable additional calcium

the thickness of the skin over the entire body and

salts. Thus, testosterone increases the total quantity

increases the ruggedness of the subcutaneous tissues.

of bone matrix and causes calcium retention. The

Testosterone also increases the rate of secretion by

increase in bone matrix is believed to result from the

some or perhaps all the body’s sebaceous glands.

general protein anabolic function of testosterone plus

Especially important is excessive secretion by the

deposition of calcium salts in response to the increased

sebaceous glands of the face, because this can result

protein.

in acne. Therefore, acne is one of the most common

Testosterone has a specific effect on the pelvis to (1)

features of male adolescence when the body is first

narrow the pelvic outlet, (2) lengthen it, (3) cause a

becoming introduced to increased testosterone. After

funnel-like shape instead of the broad ovoid shape of

several years of testosterone secretion, the skin nor-

the female pelvis, and (4) greatly increase the strength

mally adapts to the testosterone in a way that allows

of the entire pelvis for load-bearing. In the absence of

it to overcome the acne.

testosterone, the male pelvis develops into a pelvis that

is similar to that of the female.

Testosterone Increases Protein Formation and Muscle Devel-

Because of the ability of testosterone to increase the

opment. One of the most important male characteris-

size and strength of bones, it is often used in older men

tics is development of increasing musculature after

to treat osteoporosis.

puberty, averaging about a 50 per cent increase in

When great quantities of testosterone (or any other

muscle mass over that in the female. This is associated

androgen) are secreted abnormally in the still-growing

with increased protein in the nonmuscle parts of the

child, the rate of bone growth increases markedly,

body as well. Many of the changes in the skin are due

causing a spurt in total body height. However, the

1006

Unit XIV Endocrinology and Reproduction

testosterone also causes the epiphyses of the long

in the prostate gland has also increased and there

bones to unite with the shafts of the bones at an early

has been a simultaneous increase in the number of

age. Therefore, despite the rapidity of growth, this

prostatic cells.

early uniting of the epiphyses prevents the person

Testosterone stimulates production of proteins

from growing as tall as he would have grown had

virtually everywhere in the body, although more

testosterone not been secreted at all. Even in normal

specifically affecting those proteins in “target” organs

men, the final adult height is slightly less than that

or tissues responsible for the development of both

which occurs in males castrated before puberty.

primary and secondary male sexual characteristics.

Recent studies suggest that testosterone, like other

Testosterone Increases Basal Metabolism. Injection of

steroidal hormones, may also exert some rapid, non-

large quantities of testosterone can increase the basal

genomic effects that do not require synthesis of new

metabolic rate by as much as 15 per cent. Also, even

proteins. The physiological role of these nongenomic

the usual quantity of testosterone secreted by the

actions of testosterone, however, has yet to be

testes during adolescence and early adult life increases

determined.

the rate of metabolism some 5 to 10 per cent above

the value that it would be were the testes not active.

This increased rate of metabolism is possibly an

Control of Male Sexual Functions

indirect result of the effect of testosterone on protein

by Hormones from the Hypothalamus

anabolism, the increased quantity of proteins—the

and Anterior Pituitary Gland

enzymes especially—increasing the activities of all

cells.

A major share of the control of sexual functions in

both the male and the female begins with secretion

Effect on Red Blood Cells. When normal quantities of

of gonadotropin-releasing hormone (GnRH) by the

testosterone are injected into a castrated adult, the

hypothalamus (see Figure 80-10). This hormone in

number of red blood cells per cubic millimeter of

turn stimulates the anterior pituitary gland to secrete

blood increases 15 to 20 per cent. Also, the average

two other hormones called gonadotropic hormones:

man has about 700,000 more red blood cells per cubic

(1) luteinizing hormone (LH) and (2) follicle-stimulat-

millimeter than the average woman. This difference

ing hormone (FSH). In turn, LH is the primary stimu-

may be due partly to the increased metabolic rate that

lus for the secretion of testosterone by the testes, and

occurs after testosterone administration rather than

FSH mainly stimulates spermatogenesis.

to a direct effect of testosterone on red blood cell

production.

GnRH and Its Effect in Increasing the

Secretion of LH and FSH

Effect on Electrolyte and Water Balance. As pointed out in

GnRH is a 10-amino acid peptide secreted by neurons

Chapter 77, many steroid hormones can increase the

whose cell bodies are located in the arcuate nuclei of

reabsorption of sodium in the distal tubules of the

the hypothalamus. The endings of these neurons

kidneys. Testosterone also has such an effect, but only

terminate mainly in the median eminence of the

to a minor degree in comparison with the adrenal min-

hypothalamus, where they release GnRH into the

eralocorticoids. Nevertheless, after puberty, the blood

hypothalamic-hypophysial portal vascular system.

and extracellular fluid volumes of the male in relation

Then the GnRH is transported to the anterior

to body weight increase as much as 5 to 10 per cent.

pituitary gland in the hypophysial portal blood and

stimulates the release of the two gonadotropins, LH

and FSH.

Basic Intracellular Mechanism

GnRH is secreted intermittently a few minutes at a

of Action of Testosterone

time once every 1 to 3 hours. The intensity of this

hormone’s stimulus is determined in two ways: (1) by

Most of the effects of testosterone result basically

the frequency of these cycles of secretion and (2) by

from increased rate of protein formation in the target

the quantity of GnRH released with each cycle.

cells. This has been studied extensively in the prostate

The secretion of LH by the anterior pituitary gland

gland, one of the organs that is most affected by testos-

is also cyclical, with LH following fairly faithfully the

terone. In this gland, testosterone enters the prostatic

pulsatile release of GnRH. Conversely, FSH secretion

cells within a few minutes after secretion. Then it

increases and decreases only slightly with each

is most often converted, under the influence of the

fluctuation of GnRH secretion; instead, it changes

intracellular enzyme 5a-reductase, to dihydrotestos-

more slowly over a period of many hours in response

terone, and this in turn binds with a cytoplasmic

to longer-term changes in GnRH. Because of the

“receptor protein.” This combination migrates to the

much closer relation between GnRH secretion and

cell nucleus, where it binds with a nuclear protein and

LH secretion, GnRH is also widely known as LH-

induces DNA-RNA transcription. Within 30 minutes,

releasing hormone.

RNA polymerase has become activated and the con-

centration of RNA begins to increase in the prostatic

Gonadotropic Hormones: LH and FSH

cells; this is followed by progressive increase in cellu-

Both of the gonadotropic hormones, LH and FSH, are

lar protein. After several days, the quantity of DNA

secreted by the same cells, called gonadotropes, in the

Chapter 80

Reproductive and Hormonal Functions of the Male (and Function of the Pineal Gland)

1007

CNS

from the anterior pituitary gland. Furthermore, the

quantity of testosterone secreted increases approxi-

Behavorial

mately in direct proportion to the amount of LH

effects

available.

Mature Leydig cells are normally found in a child’s

testes for a few weeks after birth but then disappear

until after the age of about 10 years. However, either

injection of purified LH into a child at any age or

secretion of LH at puberty causes testicular interstitial

cells that look like fibroblasts to evolve into function-

ing Leydig cells.

Inhibition of Anterior Pituitary Secretion of LH and FSH by

Hypothalamus

Testosterone—Negative Feedback Control of Testosterone

Secretion. The testosterone secreted by the testes in

response to LH has the reciprocal effect of inhibiting

anterior pituitary secretion of LH (see Figure 80-10).

Most of this inhibition probably results from a direct

GnRH

effect of testosterone on the hypothalamus to decrease

the secretion of GnRH. This in turn causes a corre-

sponding decrease in secretion of both LH and FSH

by the anterior pituitary, and the decrease in LH

pituitary

reduces the secretion of testosterone by the testes.

Thus, whenever secretion of testosterone becomes too

great, this automatic negative feedback effect, operat-

ing through the hypothalamus and anterior pituitary

FSH

gland, reduces the testosterone secretion back toward

the desired operating level. Conversely, too little

testosterone allows the hypothalamus to secrete large

amounts of GnRH, with a corresponding increase in

Testis

anterior pituitary LH and FSH secretion and conse-

Inhibin

quent increase in testicular testosterone secretion.

Leydig cell

Sertoli

cell

Regulation of Spermatogenesis by FSH

Testosterone

and Testosterone

FSH binds with specific FSH receptors attached to the

Sertoli cells in the seminiferous tubules. This causes

these cells to grow and secrete various spermatogenic

substances. Simultaneously, testosterone

(and dihy-

Virilizing effects

Spermatogenesis

drotestosterone) diffusing into the seminiferous

tubules from the Leydig cells in the interstitial spaces

also has a strong tropic effect on spermatogenesis.

Figure 80-10

Thus, to initiate spermatogenesis, both FSH and testos-

terone are necessary.

Feedback regulation of the hypothalamic-pituitary-testicular

axis in males. Stimulatory effects are shown by and negative

feedbacks inhibitory effects are shown by

GnRH,

Negative Feedback Control of Seminiferous Tubule Activity—

gonadotropin-releasing hormone; LH, luteinizing hormone; FSH,

Role of the Hormone Inhibin. When the seminiferous

follicle-stimulating hormone.

tubules fail to produce sperm, secretion of FSH by

the anterior pituitary gland increases markedly. Con-

versely, when spermatogenesis proceeds too rapidly,

anterior pituitary gland. In the absence of GnRH

pituitary secretion of FSH diminishes. The cause of this

secretion from the hypothalamus, the gonadotropes in

negative feedback effect on the anterior pituitary is

the pituitary gland secrete almost no LH or FSH.

believed to be secretion by the Sertoli cells of still

LH and FSH are glycoproteins. They exert their

another hormone called inhibin (see Figure 80-10).

effects on their target tissues in the testes mainly by

This hormone has a strong direct effect on the ante-

activating the cyclic adenosine monophosphate second

rior pituitary gland to inhibit the secretion of FSH and

messenger system, which in turn activates specific

possibly a slight effect on the hypothalamus to inhibit

enzyme systems in the respective target cells.

secretion of GnRH.

Inhibin is a glycoprotein, like both LH and FSH,

Testosterone—Regulation of Its Production by LH. Testos-

having a molecular weight between 10,000 and 30,000.

terone is secreted by the interstitial cells of Leydig in

It has been isolated from cultured Sertoli cells. Its

the testes, but only when they are stimulated by LH

potent inhibitory feedback effect on the anterior pitu-

1008

Unit XIV Endocrinology and Reproduction

itary gland provides an important negative feedback

Abnormalities of Male

mechanism for control of spermatogenesis, operating

Sexual Function

simultaneously with and in parallel to the negative

feedback mechanism for control of testosterone

Prostate Gland and

secretion.

Its Abnormalities

The prostate gland remains relatively small throughout

Psychic Factors That Affect Gonadotropin

childhood and begins to grow at puberty under the

Secretion and Sexual Activity

stimulus of testosterone. This gland reaches an almost

Many psychic factors, feeding especially from the

stationary size by the age of 20 years and remains at

limbic system of the brain into the hypothalamus, can

this size up to the age of about 50 years. At that time, in

some men it begins to involute, along with decreased

affect the rate of secretion of GnRH by the hypothal-

production of testosterone by the testes.

amus and therefore can also affect most other aspects

A benign prostatic fibroadenoma frequently develops

of sexual and reproductive functions in both the male

in the prostate in many older men and can cause urinary

and the female. For instance, transporting a prize bull

obstruction. This hypertrophy is caused not by testos-

in a rough truck is said to inhibit the bull’s fertility—

terone but instead by abnormal overgrowth of prostate

and the human male is hardly different.

tissue itself.

Cancer of the prostate gland is a different problem

and is a common cause of death, accounting for about

Human Chorionic Gonadotropin Secreted by

2 to 3 per cent of all male deaths. Once cancer of the

the Placenta During Pregnancy Stimulates

prostate gland does occur, the cancerous cells are

Testosterone Secretion by the Fetal Testes

usually stimulated to more rapid growth by testosterone

During pregnancy, the hormone human chorionic

and are inhibited by removal of both testes so that

gonadotropin (hCG) is secreted by the placenta, and

testosterone cannot be formed. Prostatic cancer usually

it circulates both in the mother and in the fetus. This

can be inhibited by administration of estrogens.

hormone has almost the same effects on the sexual

Even some patients who have prostatic cancer that has

organs as LH.

already metastasized to almost all the bones of the body

can be successfully treated for a few months to years by

During pregnancy, if the fetus is a male, hCG from

removal of the testes, by estrogen therapy, or by both;

the placenta causes the testes of the fetus to secrete

after this therapy the metastases usually diminish in size

testosterone. This testosterone is critical for promoting

and the bones partially heal. This treatment does not

formation of the male sexual organs, as pointed out

stop the cancer but does slow it and sometimes greatly

earlier. We discuss hCG and its functions during preg-

diminishes the severe bone pain.

nancy in greater detail in Chapter 82.

Hypogonadism in the Male

Puberty and Regulation of Its Onset

Initiation of the onset of puberty has long been a

When the testes of a male fetus are nonfunctional

mystery. But it has now been determined that during

during fetal life, none of the male sexual characteristics

childhood the hypothalamus simply does not secrete

develop in the fetus. Instead, female organs are formed.

significant amounts of GnRH. One of the reasons

The reason for this is that the basic genetic characteris-

for this is that, during childhood, the slightest secretion

tic of the fetus, whether male or female, is to form

of any sex steroid hormones exerts a strong inhibitory

female sexual organs if there are no sex hormones. But

in the presence of testosterone, formation of female

effect on hypothalamic secretion of GnRH. Yet, for

sexual organs is suppressed, and instead, male organs

reasons still not understood, at the time of puberty, the

are induced.

secretion of hypothalamic GnRH breaks through the

When a boy loses his testes before puberty, a state of

childhood inhibition, and adult sexual life begins.

eunuchism ensues in which he continues to have infan-

tile sex organs and other infantile sexual characteristics

Male Adult Sexual Life and Male Climacteric. After puberty,

throughout life. The height of an adult eunuch is slightly

gonadotropic hormones are produced by the male pitu-

greater than that of a normal man because the bone

itary gland for the remainder of life, and at least some

epiphyses are slow to unite, although the bones are

spermatogenesis usually continues until death. Most

quite thin and the muscles are considerably weaker

men, however, begin to exhibit slowly decreasing sexual

than those of a normal man. The voice is childlike, there

functions in their late 40s or 50s, and one study showed

is no loss of hair on the head, and the normal adult

that the average age for terminating intersexual rela-

masculine hair distribution on the face and elsewhere

tions was 68, although the variation was great. This

does not occur.

decline in sexual function is related to decrease in

When a man is castrated after puberty, some of his

testosterone secretion, as shown in Figure 80-9. The

male secondary sexual characteristics revert to those of

decrease in male sexual function is called the male cli-

a child and others remain of adult masculine character.

macteric. Occasionally the male climacteric is associated

The sexual organs regress slightly in size but not to a

with symptoms of hot flashes, suffocation, and psychic

childlike state, and the voice regresses from the bass

disorders similar to the menopausal symptoms of the

quality only slightly. Conversely, there is loss of mascu-

female. These symptoms can be abrogated by adminis-

line hair production, loss of the thick masculine bones,

tration of testosterone, synthetic androgens, or even

and loss of the musculature of the virile male.

estrogens that are used for treatment of menopausal

Also in a castrated adult male, sexual desires are

symptoms in the female.

decreased but not lost, provided sexual activities have

Chapter 80

Reproductive and Hormonal Functions of the Male (and Function of the Pineal Gland)

1009

that the eventual adult height actually is considerably

less than that which would have been achieved other-

wise. Such interstitial cell tumors also cause excessive

development of the male sexual organs, all skeletal

muscles, and other male sexual characteristics. In the

adult male, small interstitial cell tumors are difficult

to diagnose because masculine features are already

present.

Much more common than the interstitial Leydig cell

tumors are tumors of the germinal epithelium. Because

germinal cells are capable of differentiating into almost

any type of cell, many of these tumors contain multiple

tissues, such as placental tissue, hair, teeth, bone, skin,

and so forth, all found together in the same tumorous

mass called a teratoma. These tumors often secrete few

hormones, but if a significant quantity of placental tissue

develops in the tumor, it may secrete large quantities

of hCG with functions similar to those of LH. Also,

estrogenic hormones are sometimes secreted by these

tumors and cause the condition called gynecomastia

(overgrowth of the breasts).

Pineal Gland—Its Function

in Controlling Seasonal

Fertility in Some Animals

For as long as the pineal gland has been known to exist,

myriad functions have been ascribed to it, including its

(1) being the seat of the soul, (2) enhancing sex, (3)

staving off infection, (4) promoting sleep, (5) enhancing

mood, and (6) increasing longevity (as much as 10 to 25

per cent). It is known from comparative anatomy that

the pineal gland is a vestigial remnant of what was a

third eye located high in the back of the head in some

lower animals. Many physiologists have been content

Figure 80-11

with the idea that this gland is a nonfunctional remnant,

but others have claimed for many years that it plays

Adiposogenital syndrome in an adolescent male. Note the obesity

important roles in the control of sexual activities

and childlike sexual organs. (Courtesy Dr. Leonard Posey.)

and reproduction, functions that still others said were

nothing more than the fanciful imaginings of physiolo-

gists preoccupied with sexual delusions.

But now, after years of dispute, it looks as though the

been practiced previously. Erection can still occur as

sex advocates have won and that the pineal gland does

before, although with less ease, but it is rare that ejacu-

indeed play a regulatory role in sexual and reproductive

lation can take place, primarily because the semen-

function. In lower animals that bear their young at

forming organs degenerate and there has been a loss of

certain seasons of the year and in which the pineal gland

the testosterone-driven psychic desire.

has been removed or the nervous circuits to the pineal

Some instances of hypogonadism are caused by a

gland have been sectioned, the normal periods of sea-

genetic inability of the hypothalamus to secrete normal

sonal fertility are lost. To these animals, such seasonal

amounts of GnRH. This often is associated with a

fertility is important because it allows birth of the off-

simultaneous abnormality of the feeding center of the

spring at the time of year, usually springtime or early

hypothalamus, causing the person to greatly overeat.

summer, when survival is most likely. The mechanism of

Consequently, obesity occurs along with eunuchism. A

this effect is not entirely clear, but it seems to be the

patient with this condition is shown in Figure 80-11; the

following.

condition is called adiposogenital syndrome, Fröhlich’s

First, the pineal gland is controlled by the amount of

syndrome, or hypothalamic eunuchism.

light or “time pattern” of light seen by the eyes each day.

For instance, in the hamster, greater than 13 hours of

darkness each day activates the pineal gland, whereas

Testicular Tumors and

less than that amount of darkness fails to activate it,

Hypergonadism in the Male

with a critical balance between activation and nonacti-

vation. The nervous pathway involves the passage of

Interstitial Leydig cell tumors develop in rare instances

light signals from the eyes to the suprachiasmal nucleus

in the testes, but when they do develop, they sometimes

of the hypothalamus and then to the pineal gland,

produce as much as 100 times the normal quantities of

activating pineal secretion.

testosterone. When such tumors develop in young chil-

Second, the pineal gland secretes melatonin and

dren, they cause rapid growth of the musculature and

several other, similar substances. Either melatonin or

bones but also cause early uniting of the epiphyses, so

one of the other substances is believed to pass either by

1010

Unit XIV Endocrinology and Reproduction

way of the blood or through the fluid of the third

DeMarzo AM, Nelson WG, Isaacs WB, Epstein JI: Patho-

ventricle to the anterior pituitary gland to decrease

logical and molecular aspects of prostate cancer. Lancet

gonadotropic hormone secretion.

361:955, 2003.

Thus, in the presence of pineal gland secretion,

Foresta C, Moro E, Ferlin A: Y chromosome microdeletions

gonadotropic hormone secretion is suppressed in some

and alterations of spermatogenesis. Endocr Rev 22:226,

species of animals, and the gonads become inhibited and

2001.

even partly involuted. This is what presumably occurs

Heinlein CA, Chang C: Androgen receptor (AR) coregula-

during the early winter months when there is increasing

tors: an overview. Endocr Rev 23:175, 2002.

darkness. But after about 4 months of dysfunction,

Jobling MA, Tyler-Smith C: The human Y chromosome: an

gonadotropic hormone secretion breaks through the

evolutionary marker comes of age. Nat Rev Genet 4:598,

inhibitory effect of the pineal gland and the gonads

2003.

become functional once more, ready for a full spring-

Kandeel FR, Koussa VK, Swerdloff RS: Male sexual func-

time of activity.

tion and its disorders: physiology, pathophysiology, clinical

But does the pineal gland have a similar function for

investigation, and treatment. Endocr Rev 22:342, 2001.

control of reproduction in humans? The answer to this

Lahn BT, Pearson NM, Jegalian K: The human Y chromo-

question is unknown. However, tumors often occur in

some, in the light of evolution. Nat Rev Genet 2:207, 2001.

the region of the pineal gland. Some of these secrete

Lanfranco F, Kamischke A, Zitzmann M, Nieschlag E:

excessive quantities of pineal hormones, whereas others

Klinefelter’s syndrome. Lancet 364:273, 2004.

are tumors of surrounding tissue and press on the pineal

Liu PY, Death AK, Handelsman DJ: Androgens and

gland to destroy it. Both types of tumors are often asso-

cardiovascular disease. Endocr Rev 24:313, 2003.

ciated with hypogonadal or hypergonadal function. So

Nelson WG, De Marzo AM, Isaacs WB: Prostate cancer.

perhaps the pineal gland does play at least some role in

N Engl J Med 349:366, 2003.

controlling sexual drive and reproduction in humans.

Nelson PS, Montgomery B: Unconventional therapy for

prostate cancer: good, bad or questionable? Nat Rev

Cancer 3:845, 2003.

References

O’Donnell L, Robertson KM, Jones ME, Simpson ER:

Estrogen and spermatogenesis. Endocr Rev 22:289, 2001.

Anderson RA, Baird DT: Male contraception. Endocr Rev

Plant TM, Marshall GR: The functional significance of FSH

23:735, 2002.

in spermatogenesis and the control of its secretion in male

Barry MJ, Roehrborn CG: Benign prostatic hyperplasia.

primates. Endocr Rev 22:764, 2001.

BMJ 323:1042, 2001.

Reckelhoff JF: Gender differences in the regulation of blood

Brennan J, Capel B: One tissue, two fates: molecular genetic

pressure. Hypertension 37:1199, 2001.

events that underlie testis versus ovary development. Nat

Rhoden EL, Morgentaler A: Risks of testosterone-

Rev Genet 5:509, 2004.

replacement therapy and recommendations for monitor-

Cajochen C, Krauchi K, Wirz-Justice A: Role of melatonin

ing. N Engl J Med 350:482, 2004.

in the regulation of human circadian rhythms and sleep.

Riggs BL, Khosla S, Melton LJ 3rd: Sex steroids and the con-

J Neuroendocrinol 15:432, 2003.

struction and conservation of the adult skeleton. Endocr

Cheng CY, Mruk DD: Cell junction dynamics in the testis:

Rev 23:279, 2002.

Sertoli-germ cell interactions and male contraceptive

Shabsigh R, Anastasiadis AG: Erectile dysfunction. Annu

development. Physiol Rev 82:825, 2002.

Rev Med 54:153, 2003.

Cooke HJ, Saunders PT: Mouse models of male infertility.

Simonneaux V, Ribelayga C: Generation of the melatonin

Nat Rev Genet 3:790, 2002.

endocrine message in mammals: a review of the complex

de Kretser DM: Is spermatogenic damage associated with

regulation of melatonin synthesis by norepinephrine,

Leydig cell dysfunction? J Clin Endocrinol Metab 89:3158,

peptides, and other pineal transmitters. Pharmacol Rev

2004.

55:325, 2003.

C H A P T E R

Female Physiology Before

Pregnancy and Female Hormones

Female reproductive functions can be divided into

two major phases: (1) preparation of the female

body for conception and pregnancy, and (2) the

period of pregnancy itself. This chapter is concerned

with preparation of the female body for pregnancy,

and Chapter 82 presents the physiology of preg-

nancy and childbirth.

Physiologic Anatomy of the Female

Sexual Organs

Figures 81-1 and 81-2 show the principal organs of the human female reproductive

tract, the most important of which are the ovaries, fallopian tubes, uterus, and vagina.

Reproduction begins with the development of ova in the ovaries. In the middle of

each monthly sexual cycle, a single ovum is expelled from an ovarian follicle into

the abdominal cavity near the open fimbriated ends of the two fallopian tubes. This

ovum then passes through one of the fallopian tubes into the uterus; if it has been

fertilized by a sperm, it implants in the uterus, where it develops into a fetus, a

placenta, and fetal membranes—and eventually into a baby.

During fetal life, the outer surface of the ovary is covered by a germinal epithe-

lium, which embryologically is derived from the epithelium of the germinal ridges.

As the female fetus develops, primordial ova differentiate from this germinal epithe-

lium and migrate into the substance of the ovarian cortex. Each ovum then collects

around it a layer of spindle cells from the ovarian stroma (the supporting tissue of

the ovary) and causes them to take on epithelioid characteristics; they are then

called granulosa cells. The ovum surrounded by a single layer of granulosa cells is

called a primordial follicle. The ovum itself at this stage is still immature, requiring

two more cell divisions before it can be fertilized by a sperm. At this time, the ovum

is called a primary oocyte.

During all the reproductive years of adult life, between about 13 and 46 years of

age, 400 to 500 of the primordial follicles develop enough to expel their ova—one

each month; the remainder degenerate (become atretic). At the end of reproductive

capability (at menopause), only a few primordial follicles remain in the ovaries, and

even these degenerate soon thereafter.

Female Hormonal System

The female hormonal system, like that of the male, consists of three hierarchies

of hormones, as follows:

1. A hypothalamic releasing hormone, gonadotropin-releasing hormone

(GnRH)

2. The anterior pituitary sex hormones, follicle-stimulating hormone (FSH)

and luteinizing hormone (LH), both of which are secreted in response to

the release of GnRH from the hypothalamus

3. The ovarian hormones, estrogen and progesterone, which are secreted by

the ovaries in response to the two female sex hormones from the anterior

pituitary gland

These various hormones are not secreted in constant amounts throughout the

female monthly sexual cycle; they are secreted at drastically differing rates

during different parts of the cycle. Figure

81-3 shows the approximate

1011

1012

Unit XIV Endocrinology and Reproduction

changing concentrations of the anterior pituitary

during the monthly sexual cycle. It is secreted in short

gonadotropic hormones FSH and LH (bottom two

pulses averaging once every 90 minutes, as occurs in

curves) and of the ovarian hormones estradiol (estro-

the male.

gen) and progesterone (top two curves).

The amount of GnRH released from the hypothal-

Monthly Ovarian Cycle;

amus increases and decreases much less drastically

Function of the Gonadotropic

Hormones

Uterine tube

Ovary

The normal reproductive years of the female are char-

acterized by monthly rhythmical changes in the rates

of secretion of the female hormones and correspon-

ding physical changes in the ovaries and other sexual

organs. This rhythmical pattern is called the female

monthly sexual cycle (or, less accurately, the menstrual

Uterus

cycle). The duration of the cycle averages 28 days. It

may be as short as 20 days or as long as 45 days in some

Cervix

women, although abnormal cycle length is frequently

Urinary

associated with decreased fertility.

bladder

There are two significant results of the female sexual

Vagina

cycle. First, only a single ovum is normally released

Urethra

from the ovaries each month, so that normally only a

Clitoris

single fetus will begin to grow at a time. Second, the

Labium

uterine endometrium is prepared in advance for

minora

implantation of the fertilized ovum at the required

Labium

time of the month.

majora

Anus

Rectum

Gonadotropic Hormones and

Uterine tube (sectioned)

Uterine cavity

Uterine tube

Their Effects on the Ovaries

The ovarian changes that occur during the sexual cycle

depend completely on the gonadotropic hormones

FSH and LH, secreted by the anterior pituitary gland.

Ovary

In the absence of these hormones, the ovaries remain

Entrance to

Ovary

Fimbriae

uterine tube

inactive, which is the case throughout childhood,

Uterus

when almost no pituitary gonadotropic hormones are

secreted. At age 9 to 12 years, the pituitary begins to

secrete progressively more FSH and LH, which leads

Cervix

to onset of normal monthly sexual cycles beginning

between the ages of 11 and 15 years. This period of

Vagina

change is called puberty, and the time of the first men-

strual cycle is called menarche. Both FSH and LH are

Figure 81-1

small glycoproteins having molecular weights of about

Female reproductive organs.

30,000.

Ovarian ligament Ovarian stroma

Perimetrium

Isthmus of uterine tube

Ampulla of

uterine tube

Mucosal folds

of uterine tube

Endometrium

Fimbriae

Uterine cavity

Ovarian vessels

Figure 81-2

Myometrium

Corpus albicans

Uterosacral

Internal structures of the uterus,

ligament

Ovarian follicles

ovary, and a uterine tube.

Isthmus of uterus

(Redrawn from Guyton AC:

Cervical canal

Corpus luteum

Physiology of the Human Body,

Vagina

Broad ligament of uterus

Cervix

6th ed. Philadelphia: Saunders

Vaginal rugae

College Publishing, 1984.)

Chapter 81

Female Physiology Before Pregnancy and Female Hormones

1013

Zona pellucida

Antral

Preovulatory

Preantral

Antrum

follicle

Ovum

(mature) follicle

Progesterone

follicle

800

Primordial

600

follicle

400

Theca

200

Granulosa cells

800

Corona radiata

600

400

FSH

200

Degenerating

corpus luteum

8 10 1214 16 18 20 22 24 2628

Ovulation

Days of female sexual cycle

Corpus luteum

Figure 81-3

Ovum

Approximate plasma concentrations of the gonadotropins and

Corona radiata

ovarian hormones during the normal female sexual cycle. FSH,

follicle-stimulating hormone; LH, luteinizing hormone.

Figure 81-4

Stages of follicular growth in the ovary, also showing formation of

the corpus luteum.

During each month of the female sexual cycle, there

is a cyclical increase and decrease of both FSH and

LH, as shown in the bottom of Figure 81-3. These

ovaries, together with some of the follicles within

cyclical variations cause cyclical ovarian changes,

them, begin to grow.

which are explained in the following sections.

The first stage of follicular growth is moderate

Both FSH and LH stimulate their ovarian target

enlargement of the ovum itself, which increases in

cells by combining with highly specific FSH and LH

diameter twofold to threefold. Then follows growth of

receptors in the ovarian target cell membranes. In

additional layers of granulosa cells in some of the fol-

turn, the activated receptors increase the cells’ rates

licles; these follicles are known as primary follicles.

of secretion and usually the growth and proliferation

of the cells as well. Almost all these stimulatory

Development of Antral and Vesicular Follicles. During the

effects result from activation of the cyclic adenosine

first few days of each monthly female sexual cycle,

monophosphate second messenger system in the cell

the concentrations of both FSH and LH secreted by

cytoplasm, which causes the formation of protein

the anterior pituitary gland increase slightly to mod-

kinase and multiple phosphorylations of key enzymes

erately, with the increase in FSH slightly greater than

that stimulate sex hormone synthesis, as explained in

that of LH and preceding it by a few days. These hor-

Chapter 74.

mones, especially FSH, cause accelerated growth of 6

to 12 primary follicles each month. The initial effect is

rapid proliferation of the granulosa cells, giving rise to

Ovarian Follicle Growth—

many more layers of these cells. In addition, spindle

“Follicular” Phase of the

cells derived from the ovary interstitium collect in

Ovarian Cycle

several layers outside the granulosa cells, giving rise to

a second mass of cells called the theca. This is divided

Figure 81-4 shows the progressive stages of follicular

into two layers. In the theca interna, the cells take on

growth in the ovaries. When a female child is born,

epithelioid characteristics similar to those of the gran-

each ovum is surrounded by a single layer of granu-

ulosa cells and develop the ability to secrete additional

losa cells; the ovum, with this granulosa cell sheath, is

steroid sex hormones (estrogen and progesterone).

called a primordial follicle, as shown in the figure.

The outer layer, the theca externa, develops into a

Throughout childhood, the granulosa cells are

highly vascular connective tissue capsule that becomes

believed to provide nourishment for the ovum and to

the capsule of the developing follicle.

secrete an oocyte maturation-inhibiting factor that

After the early proliferative phase of growth, lasting

keeps the ovum suspended in its primordial state in

for a few days, the mass of granulosa cells secretes a

the prophase stage of meiotic division. Then, after

follicular fluid that contains a high concentration of

puberty, when FSH and LH from the anterior pituitary

estrogen, one of the important female sex hormones

gland begin to be secreted in significant quantities, the

(discussed later). Accumulation of this fluid causes an

1014

Unit XIV Endocrinology and Reproduction

antrum to appear within the mass of granulosa cells, as

occupied the central portion of the follicle, to evagi-

shown in Figure 81-4.

nate outward. This viscous fluid carries with it the

The early growth of the primary follicle up to

ovum surrounded by a mass of several thousand small

the antral stage is stimulated mainly by FSH alone.

granulosa cells, called the corona radiata.

Then greatly accelerated growth occurs, leading to still

larger follicles called vesicular follicles. This acceler-

Surge of LH Is Necessary for Ovulation. LH is necessary

ated growth is caused by the following: (1) Estrogen is

for final follicular growth and ovulation. Without this

secreted into the follicle and causes the granulosa cells

hormone, even when large quantities of FSH are

to form increasing numbers of FSH receptors; this

available, the follicle will not progress to the stage

causes a positive feedback effect, because it makes the

of ovulation.

granulosa cells even more sensitive to FSH. (2) The

About 2 days before ovulation (for reasons that are

pituitary FSH and the estrogens combine to promote

not completely understood but are discussed in more

LH receptors on the original granulosa cells, thus

detail later in the chapter), the rate of secretion of LH

allowing LH stimulation to occur in addition to FSH

by the anterior pituitary gland increases markedly,

stimulation and creating an even more rapid increase

rising 6- to 10-fold and peaking about 16 hours before

in follicular secretion. (3) The increasing estrogens

ovulation. FSH also increases about 2-fold to 3-fold at

from the follicle plus the increasing LH from the ante-

the same time, and the FSH and LH act synergistically

rior pituitary gland act together to cause proliferation

to cause rapid swelling of the follicle during the last

of the follicular thecal cells and increase their secre-

few days before ovulation. The LH also has a specific

tion as well.

effect on the granulosa and theca cells, converting

Once the antral follicles begin to grow, their

them mainly to progesterone-secreting cells. There-

growth occurs almost explosively. The ovum itself

fore, the rate of secretion of estrogen begins to

also enlarges in diameter another threefold to four-

fall about 1 day before ovulation, while increasing

fold, giving a total ovum diameter increase up to 10-

amounts of progesterone begin to be secreted.

fold, or a mass increase of 1000-fold. As the follicle

It is in this environment of (1) rapid growth of the

enlarges, the ovum itself remains embedded in a mass

follicle, (2) diminishing estrogen secretion after a pro-

of granulosa cells located at one pole of the follicle.

longed phase of excessive estrogen secretion, and (3)

initiation of secretion of progesterone that ovulation

Only One Follicle Fully Matures Each Month, and the Remain-

occurs. Without the initial preovulatory surge of LH,

der Undergo Atresia. After a week or more of growth—

ovulation will not take place.

but before ovulation occurs—one of the follicles

begins to outgrow all the others; the remaining 5 to 11

Initiation of Ovulation. Figure 81-5 gives a schema for the

developing follicles involute (a process called atresia),

initiation of ovulation, showing the role of the large

and these follicles are said to become atretic.

quantity of LH secreted by the anterior pituitary

The cause of the atresia is unknown, but it has been

gland. This LH causes rapid secretion of follicular

postulated to be the following: The large amounts of

steroid hormones that contain progesterone. Within a

estrogen from the most rapidly growing follicle act on

few hours, two events occur, both of which are neces-

the hypothalamus to depress further enhancement of

sary for ovulation: (1) The theca externa (the capsule

FSH secretion by the anterior pituitary gland, in this

of the follicle) begins to release proteolytic enzymes

way blocking further growth of the less well developed

from lysosomes, and these cause dissolution of the fol-

follicles. Therefore, the largest follicle continues to

licular capsular wall and consequent weakening of the

grow because of its intrinsic positive feedback effects,

wall, resulting in further swelling of the entire follicle

while all the other follicles stop growing and actually

and degeneration of the stigma. (2) Simultaneously,

involute.

there is rapid growth of new blood vessels into the fol-

This process of atresia is important, because it nor-

licle wall, and at the same time, prostaglandins (local

mally allows only one of the follicles to grow large

hormones that cause vasodilation) are secreted into

enough each month to ovulate; this usually prevents

the follicular tissues. These two effects cause plasma

more than one child from developing with each preg-

transudation into the follicle, which contributes to

nancy. The single follicle reaches a diameter of 1 to 1.5

follicle swelling. Finally, the combination of follicle

centimeters at the time of ovulation and is called the

swelling and simultaneous degeneration of the stigma

mature follicle.

causes follicle rupture, with discharge of the ovum.

Ovulation

Ovulation in a woman who has a normal 28-day

Corpus Luteum—“Luteal” Phase

female sexual cycle occurs 14 days after the onset of

of the Ovarian Cycle

menstruation. Shortly before ovulation, the protruding

outer wall of the follicle swells rapidly, and a small area

During the first few hours after expulsion of the ovum

in the center of the follicular capsule, called the stigma,

from the follicle, the remaining granulosa and theca

protrudes like a nipple. In another 30 minutes or

interna cells change rapidly into lutein cells. They

so, fluid begins to ooze from the follicle through the

enlarge in diameter two or more times and become

stigma, and about 2 minutes later, the stigma ruptures

filled with lipid inclusions that give them a yellowish

widely, allowing a more viscous fluid, which has

appearance. This process is called luteinization, and the

Chapter 81

Female Physiology Before Pregnancy and Female Hormones

1015

Secretion by the Corpus Luteum: An Additional Function of LH.

The corpus luteum is a highly secretory organ, secret-

Luteinizing hormone

ing large amounts of both progesterone and estrogen.

Once LH (mainly that secreted during the ovulatory

surge) has acted on the granulosa and theca cells

Follicular steroid hormones

to cause luteinization, the newly formed lutein cells

(progesterone)

seem to be programmed to go through a preordained

sequence of (1) proliferation, (2) enlargement, and (3)

secretion, followed by (4) degeneration. All this occurs

Proteolytic enzymes

Follicular hyperemia

in about 12 days. We shall see in the discussion of

(collagenase)

and

pregnancy in Chapter 82 that another hormone with

prostaglandin secretion

almost exactly the same properties as LH, chorionic

gonadotropin, which is secreted by the placenta, can

Weakened follicle wall

Plasma transudation

act on the corpus luteum to prolong its life—usually

into follicle

maintaining it for at least the first 2 to 4 months of

pregnancy.

Degeneration

Follicle swelling

Involution of the Corpus Luteum and Onset of the Next Ovarian

of stigma

Cycle. Estrogen in particular and progesterone to a

lesser extent, secreted by the corpus luteum during the

luteal phase of the ovarian cycle, have strong feedback

Follicle rupture

effects on the anterior pituitary gland to maintain low

secretory rates of both FSH and LH.

Evagination of ovum

In addition, the lutein cells secrete small amounts of

the hormone inhibin, the same as the inhibin secreted

by the Sertoli cells of the male testes. This hormone

inhibits secretion by the anterior pituitary gland, espe-

Figure 81-5

cially FSH secretion. Low blood concentrations of both

Postulated mechanism of ovulation.

FSH and LH result, and loss of these hormones finally

causes the corpus luteum to degenerate completely, a

process called involution of the corpus luteum.

Final involution normally occurs at the end of

total mass of cells together is called the corpus luteum,

almost exactly 12 days of corpus luteum life, which is

which is shown in Figure 81-4. A well-developed

around the 26th day of the normal female sexual cycle,

vascular supply also grows into the corpus luteum.

2 days before menstruation begins. At this time, the

The granulosa cells in the corpus luteum develop

sudden cessation of secretion of estrogen, proges-

extensive intracellular smooth endoplasmic reticula

terone, and inhibin by the corpus luteum removes the

that form large amounts of the female sex hormones

feedback inhibition of the anterior pituitary gland,

progesterone and estrogen (more progesterone than

allowing it to begin secreting increasing amounts of

estrogen). The theca cells form mainly the androgens

FSH and LH again. FSH and LH initiate the growth

androstenedione and testosterone rather than female

of new follicles, beginning a new ovarian cycle. The

sex hormones. However, most of these hormones are

paucity of secretion of progesterone and estrogen at

also converted by the granulosa cells into the female

this time also leads to menstruation by the uterus, as

hormones.

explained later.

In the normal female, the corpus luteum grows to

about 1.5 centimeters in diameter, reaching this stage

of development 7 to 8 days after ovulation. Then it

Summary

begins to involute and eventually loses its secretory

function as well as its yellowish, lipid characteristic

About every 28 days, gonadotropic hormones from the

about 12 days after ovulation, becoming the corpus

anterior pituitary gland cause about 8 to 12 new folli-

albicans; during the ensuing few weeks, this is replaced

cles to begin to grow in the ovaries. One of these fol-

by connective tissue and over months is absorbed.

licles finally becomes “mature” and ovulates on the

14th day of the cycle. During growth of the follicles,

Luteinizing Function of LH. The change of granulosa and

mainly estrogen is secreted.

theca interna cells into lutein cells is dependent mainly

After ovulation, the secretory cells of the ovulating

on LH secreted by the anterior pituitary gland. In fact,

follicle develop into a corpus luteum that secretes

this function gives LH its name—“luteinizing,” for

large quantities of both the major female hormones,

“yellowing.” Luteinization also depends on extrusion

progesterone and estrogen. After another 2 weeks, the

of the ovum from the follicle. A yet uncharacterized

corpus luteum degenerates, whereupon the ovarian

local hormone in the follicular fluid, called luteiniza-

hormones estrogen and progesterone decrease greatly,

tion-inhibiting factor, seems to hold the luteinization

and menstruation begins. A new ovarian cycle then

process in check until after ovulation.

follows.

1016

Unit XIV Endocrinology and Reproduction

Functions of the Ovarian

peripheral tissues from androgens secreted by the

adrenal cortices and by ovarian thecal cells. Estriol is

Hormones—Estradiol

a weak estrogen; it is an oxidative product derived

and Progesterone

from both estradiol and estrone, with the conversion

occurring mainly in the liver.

The two types of ovarian sex hormones are the estro-

The estrogenic potency of b-estradiol is 12 times

gens and the progestins. By far the most important of

that of estrone and 80 times that of estriol. Consider-

the estrogens is the hormone estradiol, and by far the

ing these relative potencies, one can see that the total

most important progestin is progesterone. The estro-

estrogenic effect of b-estradiol is usually many times

gens mainly promote proliferation and growth of spe-

that of the other two together. For this reason, b-

cific cells in the body that are responsible for the

estradiol is considered the major estrogen, although

development of most secondary sexual characteristics

the estrogenic effects of estrone are not negligible.

of the female. The progestins function mainly to

prepare the uterus for pregnancy and the breasts for

Progestins. By far the most important of the progestins

lactation.

is progesterone. However, small amounts of another

progestin,

17-a-hydroxyprogesterone, are secreted

along with progesterone and have essentially the same

Chemistry of the Sex Hormones

effects. Yet, for practical purposes, it is usually reason-

able to consider progesterone the only important

Estrogens. In the normal nonpregnant female, estro-

progestin.

gens are secreted in significant quantities only by the

In the normal nonpregnant female, progesterone is

ovaries, although minute amounts are also secreted by

secreted in significant amounts only during the latter

the adrenal cortices. During pregnancy, tremendous

half of each ovarian cycle, when it is secreted by the

quantities of estrogens are also secreted by the

corpus luteum.

placenta, as discussed in Chapter 82.

As we shall see in Chapter 82, large amounts of

Only three estrogens are present in significant quan-

progesterone are also secreted by the placenta during

tities in the plasma of the human female: b-estradiol,

pregnancy, especially after the fourth month of

estrone, and estriol, the formulas for which are shown

gestation.

in Figure 81-6. The principal estrogen secreted by

the ovaries is b-estradiol. Small amounts of estrone

Synthesis of the Estrogens and Progestins. Note from the

are also secreted, but most of this is formed in the

chemical formulas of the estrogens and progesterone

in Figure 81-6 that they are all steroids. They are

synthesized in the ovaries mainly from cholesterol

derived from the blood but also to a slight extent from

acetyl coenzyme A, multiple molecules of which can

combine to form the appropriate steroid nucleus.

During synthesis, mainly progesterone and the male

sex hormone testosterone are synthesized first; then,

during the follicular phase of the ovarian cycle, before

these two initial hormones can leave the ovaries,

almost all the testosterone and much of the proges-

terone are converted into estrogens by the granulosa

b-Estradiol

cells. During the luteal phase of the cycle, far too much

Estrone

progesterone is formed for all of it to be converted,

which accounts for the large secretion of progesterone

into the circulating blood at this time. Also, about one

fifteenth as much testosterone is secreted into the

CH₃

plasma of the female by the ovaries as is secreted into

the plasma of the male by the testes.

CH₃

Estrogens and Progesterone Are Transported in the Blood Bound

to Plasma Proteins. Both estrogens and progesterone

CH₃

are transported in the blood bound mainly with

plasma albumin and with specific estrogen- and prog-

esterone-binding globulins. The binding between these

Estriol

hormones and the plasma proteins is loose enough

that they are rapidly released to the tissues over a

Progesterone

period of 30 minutes or so.

Functions of the Liver in Estrogen Degradation. The liver

Figure 81-6

conjugates the estrogens to form glucuronides and sul-

Chemical formulas of the principal female hormones.

fates, and about one fifth of these conjugated products

Chapter 81

Female Physiology Before Pregnancy and Female Hormones

1017

is excreted in the bile; most of the remainder is

the glandular tissues of this lining to proliferate;

excreted in the urine. Also, the liver converts the

especially important, they cause the number of ciliated

potent estrogens estradiol and estrone into the almost

epithelial cells that line the fallopian tubes to increase.

totally impotent estrogen estriol. Therefore, dimin-

Also, activity of the cilia is considerably enhanced.

ished liver function actually increases the

These cilia always beat toward the uterus, which helps

activity of estrogens in the body, sometimes causing

propel the fertilized ovum in that direction.

hyperestrinism.

Effect of Estrogens on the Breasts. The primordial breasts

Fate of Progesterone. Within a few minutes after secre-

of females and males are exactly alike. In fact, under

tion, almost all the progesterone is degraded to other

the influence of appropriate hormones, the masculine

steroids that have no progestational effect. As with the

breast during the first 2 decades of life can develop

estrogens, the liver is especially important for this

sufficiently to produce milk in the same manner as the

metabolic degradation.

female breast.

The major end product of progesterone degradation

Estrogens cause (1) development of the stromal

is pregnanediol. About 10 per cent of the original prog-

tissues of the breasts, (2) growth of an extensive ductile

esterone is excreted in the urine in this form. There-

system, and (3) deposition of fat in the breasts. The

fore, one can estimate the rate of progesterone

lobules and alveoli of the breast develop to a slight

formation in the body from the rate of this excretion.

extent under the influence of estrogens alone, but it

is progesterone and prolactin that cause the ultimate

determinative growth and function of these structures.

In summary, the estrogens initiate growth of the

Functions of the Estrogens—

breasts and of the milk-producing apparatus. They

Their Effects on the Primary and

are also responsible for the characteristic growth

Secondary Female Sex Characteristics

and external appearance of the mature female breast.

However, they do not complete the job of converting

A primary function of the estrogens is to cause cellu-

the breasts into milk-producing organs.

lar proliferation and growth of the tissues of the sex

organs and other tissues related to reproduction.

Effect of Estrogens on the Skeleton. Estrogens inhibit

osteoclastic activity in the bones and therefore stimu-

Effect of Estrogens on the Uterus and External Female Sex

late bone growth. At puberty, when the female enters

Organs. During childhood, estrogens are secreted only

her reproductive years, her growth in height becomes

in minute quantities, but at puberty, the quantity

rapid for several years. However, estrogens have

secreted in the female under the influence of the

another potent effect on skeletal growth: They cause

pituitary gonadotropic hormones increases 20-fold or

uniting of the epiphyses with the shafts of the long

more. At this time, the female sex organs change from

bones. This effect of estrogen in the female is much

those of a child to those of an adult. The ovaries, fal-

stronger than the similar effect of testosterone in the

lopian tubes, uterus, and vagina all increase several

male. As a result, growth of the female usually ceases

times in size. Also, the external genitalia enlarge, with

several years earlier than growth of the male. A female

deposition of fat in the mons pubis and labia majora

eunuch who is devoid of estrogen production usually

and enlargement of the labia minora.

grows several inches taller than a normal mature

In addition, estrogens change the vaginal epithelium

female because her epiphyses do not unite at the

from a cuboidal into a stratified type, which is consid-

normal time.

erably more resistant to trauma and infection than

is the prepubertal cuboidal cell epithelium. Vaginal

Osteoporosis of the Bones Caused by Estrogen

infections in children can often be cured by the admin-

Deficiency in Old Age. After menopause, almost no

istration of estrogens simply because of the resulting

estrogens are secreted by the ovaries. This estrogen

increased resistance of the vaginal epithelium.

deficiency leads to (1) increased osteoclastic activity in

During the first few years after puberty, the size of

the bones,

(2) decreased bone matrix, and

(3)

the uterus increases twofold to threefold, but more

decreased deposition of bone calcium and phosphate.

important than the increase in uterus size are the

In some women, this effect is extremely severe, and the

changes that take place in the uterine endometrium

resulting condition is osteoporosis, described in

under the influence of estrogens. Estrogens cause

Chapter 79. Because this can greatly weaken the bones

marked proliferation of the endometrial stroma

and lead to bone fracture, especially fracture of the

and greatly increased development of the endometrial

vertebrae, a large share of postmenopausal women are

glands, which will later aid in providing nutrition to

treated prophylactically with estrogen replacement to

the implanted ovum. These effects are discussed later

prevent the osteoporotic effects.

in the chapter in connection with the endometrial

cycle.

Effect of Estrogens on Protein Deposition. Estrogens cause

a slight increase in total body protein, which is evi-

Effect of Estrogens on the Fallopian Tubes. The estrogens’

denced by a slight positive nitrogen balance when

effect on the mucosal lining of the fallopian tubes is

estrogens are administered. This mainly results from

similar to that on the uterine endometrium. They cause

the growth-promoting effect of estrogen on the sexual

1018

Unit XIV Endocrinology and Reproduction

organs, the bones, and a few other tissues of the body.

necessary for nutrition of the fertilized, dividing ovum

The enhanced protein deposition caused by testos-

as it traverses the fallopian tube before implantation.

terone is much more general and many times as pow-

erful as that caused by estrogens.

Effect of Progesterone on the Breasts. Progesterone

promotes development of the lobules and alveoli of

Effect of Estrogens on Body Metabolism and Fat Deposition.

the breasts, causing the alveolar cells to proliferate,

Estrogens increase the whole-body metabolic rate

enlarge, and become secretory in nature. However,

slightly, but only about one third as much as the

progesterone does not cause the alveoli to secrete

increase caused by the male sex hormone testosterone.

milk; as discussed in Chapter 82, milk is secreted only

They also cause deposition of increased quantities of

after the prepared breast is further stimulated by pro-

fat in the subcutaneous tissues. As a result, the per-

lactin from the anterior pituitary gland.

centage of body fat in the female body is considerably

Progesterone also causes the breasts to swell. Part

greater than that in the male body, which contains

of this swelling is due to the secretory development in

more protein. In addition to deposition of fat in the

the lobules and alveoli, but part also results from

breasts and subcutaneous tissues, estrogens cause the

increased fluid in the subcutaneous tissue.

deposition of fat in the buttocks and thighs, which is

characteristic of the feminine figure.

Monthly Endometrial Cycle

Effect of Estrogens on Hair Distribution. Estrogens do not

and Menstruation

greatly affect hair distribution. However, hair does

develop in the pubic region and in the axillae after

Associated with the monthly cyclical production

puberty. Androgens formed in increased quantities by

of estrogens and progesterone by the ovaries is an

the female adrenal glands after puberty are mainly

endometrial cycle in the lining of the uterus that oper-

responsible for this.

ates through the following stages: (1) proliferation of

the uterine endometrium; (2) development of secre-

Effect of Estrogens on the Skin. Estrogens cause the skin

tory changes in the endometrium; and (3) desqua-

to develop a texture that is soft and usually smooth,

mation of the endometrium, which is known as

but even so, the skin of a woman is thicker than that

menstruation. The various phases of this endometrial

of a child or a castrated female. Also, estrogens cause

cycle are shown in Figure 81-7.

the skin to become more vascular; this is often associ-

ated with increased warmth of the skin and also pro-

Proliferative Phase (Estrogen Phase) of the Endometrial Cycle,

motes greater bleeding of cut surfaces than is observed

Occurring Before Ovulation. At the beginning of each

in men.

monthly cycle, most of the endometrium has been

desquamated by menstruation. After menstruation,

Effect of Estrogens on Electrolyte Balance. The chemical

only a thin layer of endometrial stroma remains, and

similarity of estrogenic hormones to adrenocortical

the only epithelial cells that are left are those located

hormones has been pointed out. Estrogens, like aldos-

in the remaining deeper portions of the glands and

terone and some other adrenocortical hormones, cause

crypts of the endometrium. Under the influence of

sodium and water retention by the kidney tubules. This

estrogens, secreted in increasing quantities by the

effect of estrogens is normally slight and rarely of sig-

ovary during the first part of the monthly ovarian

nificance, but during pregnancy, the tremendous for-

cycle, the stromal cells and the epithelial cells

mation of estrogens by the placenta may contribute to

body fluid retention, as discussed in Chapter 82.

Functions of Progesterone

Effect of Progesterone on the Uterus. By far the most

important function of progesterone is to promote

secretory changes in the uterine endometrium during

the latter half of the monthly female sexual cycle, thus

preparing the uterus for implantation of the fertilized

ovum. This function is discussed later in connection

with the endometrial cycle of the uterus.

Proliferative

Secretory

Menstrual

In addition to this effect on the endometrium,

phase

progesterone decreases the frequency and intensity

(11 days)

(12 days)

(5 days)

of uterine contractions, thereby helping to prevent

expulsion of the implanted ovum.

Figure 81-7

Effect of Progesterone on the Fallopian Tubes. Progesterone

also promotes increased secretion by the mucosal

Phases of endometrial growth and menstruation during each

lining of the fallopian tubes. These secretions are

monthly female sexual cycle.

Chapter 81

Female Physiology Before Pregnancy and Female Hormones

1019

proliferate rapidly. The endometrial surface is re-

decreased stimulation of the endometrial cells by these

epithelialized within 4 to 7 days after the beginning of

two hormones, followed rapidly by involution of the

menstruation.

endometrium itself to about 65 per cent of its previous

Then, during the next week and a half—that is,

thickness. Then, during the 24 hours preceding the

before ovulation occurs—the endometrium increases

onset of menstruation, the tortuous blood vessels

greatly in thickness, owing to increasing numbers of

leading to the mucosal layers of the endometrium

stromal cells and to progressive growth of the endome-

become vasospastic, presumably because of some

trial glands and new blood vessels into the endo-

effect of involution, such as release of a vasoconstric-

metrium. At the time of ovulation, the endometrium is

tor material—possibly one of the vasoconstrictor types

3 to 5 millimeters thick.

of prostaglandins that are present in abundance at this

The endometrial glands, especially those of the cer-

time.

vical region, secrete a thin, stringy mucus. The mucus

The vasospasm, the decrease in nutrients to the

strings actually align themselves along the length of

endometrium, and the loss of hormonal stimulation

the cervical canal, forming channels that help guide

initiate necrosis in the endometrium, especially of the

sperm in the proper direction from the vagina into the

blood vessels. As a result, blood at first seeps into the

uterus.

vascular layer of the endometrium, and the hemor-

rhagic areas grow rapidly over a period of 24 to 36

Secretory Phase (Progestational Phase) of the Endometrial

hours. Gradually, the necrotic outer layers of the

Cycle, Occurring After Ovulation. During most of the latter

endometrium separate from the uterus at the sites

half of the monthly cycle, after ovulation has occurred,

of the hemorrhages until, about 48 hours after the

progesterone and estrogen together are secreted in

onset of menstruation, all the superficial layers of

large quantities by the corpus luteum. The estrogens

the endometrium have desquamated. The mass of

cause slight additional cellular proliferation in the

desquamated tissue and blood in the uterine cavity,

endometrium during this phase of the cycle, whereas

plus contractile effects of prostaglandins or other

progesterone causes marked swelling and secretory

substances in the decaying desquamate, all acting

development of the endometrium. The glands increase

together, initiate uterine contractions that expel the

in tortuosity; an excess of secretory substances accu-

uterine contents.

mulates in the glandular epithelial cells. Also, the cyto-

During normal menstruation, approximately

plasm of the stromal cells increases; lipid and glycogen

milliliters of blood and an additional 35 milliliters of

deposits increase greatly in the stromal cells; and the

serous fluid are lost. The menstrual fluid is normally

blood supply to the endometrium further increases

nonclotting because a fibrinolysin is released along

in proportion to the developing secretory activity,

with the necrotic endometrial material. If excessive

with the blood vessels becoming highly tortuous. At

bleeding occurs from the uterine surface, the quantity

the peak of the secretory phase, about 1 week after

of fibrinolysin may not be sufficient to prevent clot-

ovulation, the endometrium has a thickness of 5 to

ting. The presence of clots during menstruation is often

6 millimeters.

clinical evidence of uterine pathology.

The whole purpose of all these endometrial changes

Within 4 to 7 days after menstruation starts, the loss

is to produce a highly secretory endometrium that con-

of blood ceases because, by this time, the endometrium

tains large amounts of stored nutrients to provide

has become re-epithelialized.

appropriate conditions for implantation of a fertilized

ovum during the latter half of the monthly cycle. From

Leukorrhea During Menstruation. During menstrua-

the time a fertilized ovum enters the uterine cavity

tion, tremendous numbers of leukocytes are released

from the fallopian tube (which occurs 3 to 4 days

along with the necrotic material and blood. It is prob-

after ovulation) until the time the ovum implants (7

able that some substance liberated by the endometrial

9 days after ovulation), the uterine secretions,

necrosis causes this outflow of leukocytes. As a result

called “uterine milk,” provide nutrition for the early

of these leukocytes and possibly other factors, the

dividing ovum. Then, once the ovum implants in the

uterus is highly resistant to infection during men-

endometrium, the trophoblastic cells on the surface of

struation, even though the endometrial surfaces are

the implanting ovum (in the blastocyst stage) begin to

denuded. This is of extreme protective value.

digest the endometrium and absorb the endometrial

stored substances, thus making great quantities of

nutrients available to the early implanting embryo.

Regulation of the Female

Monthly Rhythm—Interplay

Menstruation. If the ovum is not fertilized, about 2 days

Between the Ovarian and

before the end of the monthly cycle, the corpus luteum

Hypothalamic-Pituitary

in the ovary suddenly involutes, and the ovarian

hormones (estrogens and progesterone) decrease to

Hormones

low levels of secretion, as shown in Figure

81-3.

Menstruation follows.

Now that we have presented the major cyclical

Menstruation is caused by the reduction of estro-

changes that occur during the monthly female sexual

gens and progesterone, especially progesterone, at the

cycle, we can attempt to explain the basic rhythmical

end of the monthly ovarian cycle. The first effect is

mechanism that causes the cyclical variations.

1020

Unit XIV Endocrinology and Reproduction

The Hypothalamus Secretes GnRH, Which

believed that these arcuate nuclei control most

Causes the Anterior Pituitary Gland to Secrete

female sexual activity, although neurons located in the

LH and FSH

preoptic area of the anterior hypothalamus also

As pointed out in Chapter 74, secretion of most of the

secrete GnRH in moderate amounts. Multiple neu-

anterior pituitary hormones is controlled by “releasing

ronal centers in the higher brain’s “limbic” system (the

hormones” formed in the hypothalamus and then

system for psychic control) transmit signals into the

transported to the anterior pituitary gland by way of

arcuate nuclei to modify both the intensity of GnRH

the hypothalamic-hypophysial portal system. In the

release and the frequency of the pulses, thus providing

case of the gonadotropins, one releasing hormone,

a partial explanation of why psychic factors often

GnRH, is important. This hormone has been purified

modify female sexual function.

and has been found to be a decapeptide with the

following formula:

Negative Feedback Effects of Estrogen

and Progesterone in Decreasing Both LH

Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH₂

and FSH Secretion

Estrogen in small amounts has a strong effect to

Intermittent, Pulsatile Secretion of GnRH by the Hypothalamus

inhibit the production of both LH and FSH. Also,

Stimulates Pulsatile Release of LH from the Anterior Pituitary

when progesterone is available, the inhibitory effect of

Gland. Experiments have demonstrated that the hypo-

estrogen is multiplied, even though progesterone by

thalamus does not secrete GnRH continuously but

itself has little effect.

instead secretes it in pulses lasting 5 to 25 minutes that

These feedback effects seem to operate mainly on

occur every 1 to 2 hours. The lower curve in Figure

the anterior pituitary gland directly, but they also

81-8 shows the electrical pulsatile signals in the hypo-

operate to a lesser extent on the hypothalamus to

thalamus that cause the hypothalamic pulsatile output

decrease secretion of GnRH, especially by altering the

of GnRH.

frequency of the GnRH pulses.

It is intriguing that when GnRH is infused continu-

ously so that it is available all the time rather than in

Hormone Inhibin from the Corpus Luteum Inhibits FSH and LH

pulses, its ability to cause the release of LH and FSH

Secretion. In addition to the feedback effects of estro-

by the anterior pituitary gland is lost. Therefore, for

gen and progesterone, other hormones seem to be

reasons unknown, the pulsatile nature of GnRH

involved, especially inhibin, which is secreted along

release is essential to its function.

with the steroid sex hormones by the granulosa cells

The pulsatile release of GnRH also causes intermit-

of the ovarian corpus luteum in the same way that

tent output of LH secretion about every 90 minutes.

Sertoli cells secrete inhibin in the male testes. This

This is shown by the upper curve in Figure 81-8.

hormone has the same effect in the female as in the

male—inhibiting the secretion of FSH and, to a lesser

Hypothalamic Centers for Release of GnRH. The neuronal

extent, LH by the anterior pituitary gland. Therefore,

activity that causes pulsatile release of GnRH occurs

it is believed that inhibin might be especially impor-

primarily in the mediobasal hypothalamus, especially

tant in causing the decrease in secretion of FSH and

in the arcuate nuclei of this area. Therefore, it is

LH at the end of the monthly female sexual cycle.

100

2000

Figure 81-8

Upper curve: Pulsatile change in

luteinizing hormone

(LH) in the

peripheral circulation of a

1000

pentobarbital-anesthetized

ovariectomized rhesus monkey.

Lower curve: Minute-by-minute

recording of multi-unit electrical

MUA

activity (MUA) in the mediobasal

hypothalamus. (Data from Wilson

RC, Kesner JS, Kaufman JM, et

120

240

360

480

al:

Central electrophysiologic

Minutes

correlates of pulsatile luteinizing

hormone secretion. Neuroen-

docrinology 39:256, 1984.)

Chapter 81

Female Physiology Before Pregnancy and Female Hormones

1021

Positive Feedback Effect of Estrogen Before

2. Follicular Growth Phase. Two to 3 days before men-

Ovulation—The Preovulatory LH Surge

struation, the corpus luteum has regressed to almost

For reasons not completely understood, the anterior

total involution, and the secretion of estrogen, proges-

pituitary gland secretes greatly increased amounts of

terone, and inhibin from the corpus luteum decreases

LH for 1 to 2 days beginning 24 to 48 hours before

to a low ebb. This releases the hypothalamus and

ovulation. This effect is demonstrated in Figure 81-3.

anterior pituitary from the negative feedback effect of

The figure shows a much smaller preovulatory surge

these hormones. Therefore, a day or so later, at about

of FSH as well.

the time that menstruation begins, pituitary secretion

Experiments have shown that infusion of estrogen

of FSH begins to increase again, as much as twofold;

into a female above a critical rate for 2 to 3 days during

then, several days after menstruation begins, LH secre-

the latter part of the first half of the ovarian cycle will

tion increases slightly as well. These hormones initiate

cause rapidly accelerating growth of the ovarian folli-

new ovarian follicle growth and a progressive increase

cles, as well as rapidly accelerating secretion of ovarian

in the secretion of estrogen, reaching a peak estrogen

estrogens. During this period, secretions of both FSH

secretion at about 12.5 to 13 days after the onset of the

and LH by the anterior pituitary gland are at first

new female monthly sexual cycle.

slightly suppressed. Then secretion of LH increases

During the first 11 to 12 days of this follicle growth,

abruptly sixfold to eightfold, and secretion of FSH

the rates of pituitary secretion of the gonadotropins

increases about twofold. The greatly increased secre-

FSH and LH decrease slightly because of the negative

tion of LH causes ovulation to occur.

feedback effect, mainly of estrogen, on the anterior

The cause of this abrupt surge in LH secretion is not

pituitary gland. Then there is a sudden, marked

known. However, several possible explanations are as

increase in the secretion of LH and, to a lesser extent,

follows: (1) It has been suggested that estrogen at this

FSH. This is the preovulatory surge of LH and FSH,

point in the cycle has a peculiar positive feedback effect

which is followed by ovulation.

of stimulating pituitary secretion of LH and, to a lesser

extent, FSH; this is in sharp contrast to its normal neg-

3. Preovulatory Surge of LH and FSH Causes Ovulation. At

ative feedback effect that occurs during the remainder

about 11.5 to 12 days after the onset of the monthly

of the female monthly cycle. (2) The granulosa cells of

cycle, the decline in secretion of FSH and LH comes

the follicles begin to secrete small but increasing quan-

to an abrupt halt. It is believed that the high level of

tities of progesterone a day or so before the preovu-

estrogens at this time (or the beginning of proges-

latory LH surge, and it has been suggested that this

terone secretion by the follicles) causes a positive

might be the factor that stimulates the excess LH

feedback stimulatory effect on the anterior pituitary,

secretion.

as explained earlier, which leads to a terrific surge in

Without this normal preovulatory surge of LH,

the secretion of LH and, to a lesser extent, FSH. What-

ovulation will not occur.

ever the cause of this preovulatory LH and FSH surge,

the great excess of LH leads to both ovulation and sub-

sequent development of and secretion by the corpus

luteum. Thus, the hormonal system begins its new

Feedback Oscillation of the

round of secretions until the next ovulation.

Hypothalamic-Pituitary-Ovarian

System

Anovulatory Cycles—Sexual Cycles at Puberty

If the preovulatory surge of LH is not of sufficient

Now, after discussing much of the known information

magnitude, ovulation will not occur, and the cycle is

about the interrelations of the different components

said to be “anovulatory.” The phases of the sexual cycle

of the female hormonal system, we can attempt to

continue, but they are altered in the following ways:

explain the feedback oscillation that controls the

First, lack of ovulation causes failure of development

rhythm of the female sexual cycle. It seems to operate

of the corpus luteum, so there is almost no secretion

in approximately the following sequence of three

of progesterone during the latter portion of the cycle.

events.

Second, the cycle is shortened by several days, but the

rhythm continues. Therefore, it is likely that proges-

1. Postovulatory Secretion of the Ovarian Hormones, and

terone is not required for maintenance of the cycle

Depression of the Pituitary Gonadotropins. The easiest part

itself, although it can alter its rhythm.

of the cycle to explain is the events that occur during

The first few cycles after the onset of puberty are

the postovulatory phase—between ovulation and

usually anovulatory, as are the cycles occurring several

the beginning of menstruation. During this time, the

months to years before menopause, presumably

corpus luteum secretes large quantities of both prog-

because the LH surge is not potent enough at these

esterone and estrogen, as well as the hormone inhibin.

times to cause ovulation.

All these hormones together have a combined nega-

tive feedback effect on the anterior pituitary gland and

hypothalamus, causing the suppression of both FSH

Puberty and Menarche

and LH secretion and decreasing them to their lowest

levels about 3 to 4 days before the onset of menstrua-

Puberty means the onset of adult sexual life, and

tion. These effects are shown in Figure 81-3.

menarche means the beginning of the cycle of

1022

Unit XIV Endocrinology and Reproduction

400

300

Female

300

100

Male

Age (yr)

Figure 81-10

Figure 81-9

Estrogen secretion throughout the sexual life of the female human

being.

Total rates of secretion of gonadotropic hormones throughout the

sexual lives of female and male human beings, showing an espe-

cially abrupt increase in gonadotropic hormones at menopause in

the female.

months to a few years, the cycle ceases altogether, as

shown in Figure 81-10. The period during which the

cycle ceases and the female sex hormones diminish to

almost none is called menopause.

menstruation. The period of puberty is caused by a

The cause of menopause is “burning out” of the

gradual increase in gonadotropic hormone secretion

ovaries. Throughout a woman’s reproductive life,

by the pituitary, beginning in about the eighth year of

about 400 of the primordial follicles grow into mature

life, as shown in Figure 81-9, and usually culminating

follicles and ovulate, and hundreds of thousands of ova

in the onset of puberty and menstruation between ages

degenerate. At about age 45 years, only a few primor-

11 and 16 years in girls (average, 13 years).

dial follicles remain to be stimulated by FSH and LH,

In the female, as in the male, the infantile pituitary

and, as shown in Figure 81-10, the production of

gland and ovaries are capable of full function if appro-

estrogens by the ovaries decreases as the number of

priately stimulated. However, as is also true in the

primordial follicles approaches zero. When estrogen

male, and for reasons not understood, the hypothala-

production falls below a critical value, the estrogens

mus does not secrete significant quantities of GnRH

can no longer inhibit the production of the

during childhood. Experiments have shown that

gonadotropins FSH and LH. Instead, as shown in

the hypothalamus itself is capable of secreting this

Figure 81-9, the gonadotropins FSH and LH (mainly

hormone, but the appropriate signal from some other

FSH) are produced after menopause in large and con-

area of brain to cause the secretion is lacking. There-

tinuous quantities, but as the remaining primordial fol-

fore, it is now believed that the onset of puberty is

licles become atretic, the production of estrogens by

initiated by some maturation process that occurs else-

the ovaries falls virtually to zero.

where in the brain, perhaps somewhere in the limbic

At the time of menopause, a woman must readjust

system.

her life from one that has been physiologically stimu-

Figure 81-10 shows (1) the increasing levels of estro-

lated by estrogen and progesterone production to one

gen secretion at puberty, (2) the cyclical variation

devoid of these hormones. The loss of estrogens often

during the monthly sexual cycle,

(3) the further

causes marked physiological changes in the function

increase in estrogen secretion during the first few years

of the body, including (1) “hot flushes” characterized

of reproductive life, (4) the progressive decrease in

by extreme flushing of the skin, (2) psychic sensations

estrogen secretion toward the end of reproductive life,

of dyspnea, (3) irritability, (4) fatigue, (5) anxiety,

and, finally, (5) almost no estrogen or progesterone

(6) occasionally various psychotic states, and

(7)

secretion beyond menopause.

decreased strength and calcification of bones through-

out the body. These symptoms are of sufficient magni-

tude in about

15 per cent of women to warrant

Menopause

treatment. If counseling fails, daily administration of

estrogen in small quantities usually reverses the symp-

At age 40 to 50 years, the sexual cycle usually becomes

toms, and by gradually decreasing the dose, post-

irregular, and ovulation often fails to occur. After a few

menopausal women can likely avoid severe symptoms.

Chapter 81

Female Physiology Before Pregnancy and Female Hormones

1023

Abnormalities of Secretion

Thinking sexual thoughts can lead to female sexual

desire, and this aids greatly in the performance of the

by the Ovaries

female sexual act. Such desire is based largely on a

Hypogonadism. Less than normal secretion by the ovaries

woman’s background training as well as on her physi-

can result from poorly formed ovaries, lack of ovaries,

ological drive, although sexual desire does increase in

or genetically abnormal ovaries that secrete the wrong

proportion to the level of sex hormones secreted.

hormones because of missing enzymes in the secretory

Desire also changes during the monthly sexual cycle,

cells. When ovaries are absent from birth or when

reaching a peak near the time of ovulation, probably

they become nonfunctional before puberty, female

because of the high levels of estrogen secretion during

eunuchism occurs. In this condition, the usual secondary

sexual characteristics do not appear, and the sexual

the preovulatory period.

organs remain infantile. Especially characteristic of

Local sexual stimulation in women occurs in more

this condition is prolonged growth of the long bones

or less the same manner as in men because massage

because the epiphyses do not unite with the shafts as

and other types of stimulation of the vulva, vagina, and

early as they do in a normal woman. Consequently, the

other perineal regions can create sexual sensations.

female eunuch is essentially as tall as or perhaps even

The glans of the clitoris is especially sensitive for ini-

slightly taller than her male counterpart of similar

tiating sexual sensations.

genetic background.

As in the male, the sexual sensory signals are trans-

When the ovaries of a fully developed woman are

mitted to the sacral segments of the spinal cord

removed, the sexual organs regress to some extent so

through the pudendal nerve and sacral plexus. Once

that the uterus becomes almost infantile in size, the

vagina becomes smaller, and the vaginal epithelium

these signals have entered the spinal cord, they are

becomes thin and easily damaged. The breasts atrophy

transmitted to the cerebrum. Also, local reflexes inte-

and become pendulous, and the pubic hair becomes

grated in the sacral and lumbar spinal cord are at least

thinner. The same changes occur in women after

partly responsible for some of the reactions in the

menopause.

female sexual organs.

Irregularity of Menses, and Amenorrhea Caused by

Female Erection and Lubrication. Located around the

Hypogonadism. As pointed out in the preceding dis-

introitus and extending into the clitoris is erectile

cussion of menopause, the quantity of estrogens pro-

duced by the ovaries must rise above a critical value in

tissue almost identical to the erectile tissue of the

order to cause rhythmical sexual cycles. Consequently,

penis. This erectile tissue, like that of the penis, is

in hypogonadism or when the gonads are secreting

controlled by the parasympathetic nerves that pass

small quantities of estrogens as a result of other factors,

through the nervi erigentes from the sacral plexus to

such as hypothyroidism, the ovarian cycle often does

the external genitalia. In the early phases of sexual

not occur normally. Instead, several months may elapse

stimulation, parasympathetic signals dilate the arteries

between menstrual periods, or menstruation may cease

of the erectile tissue, probably resulting from release

altogether (amenorrhea). Prolonged ovarian cycles are

of acetylcholine, nitric oxide, and vasoactive intestinal

frequently associated with failure of ovulation, presum-

polypeptide (VIP) at the nerve endings. This allows

ably because of insufficient secretion of LH at the time

rapid accumulation of blood in the erectile tissue so

of the preovulatory surge of LH, which is necessary for

ovulation.

that the introitus tightens around the penis; this aids

the male greatly in his attainment of sufficient sexual

Hypersecretion by the Ovaries. Extreme hypersecretion of

stimulation for ejaculation to occur.

ovarian hormones by the ovaries is a rare clinical entity,

Parasympathetic signals also pass to the bilateral

because excessive secretion of estrogens automatically

Bartholin’s glands located beneath the labia minora

decreases the production of gonadotropins by the

and cause them to secrete mucus immediately inside

pituitary, and this limits the production of ovarian

the introitus. This mucus is responsible for much of the

hormones. Consequently, hypersecretion of feminizing

lubrication during sexual intercourse, although much

hormones is usually recognized clinically only when a

is also provided by mucus secreted by the vaginal

feminizing tumor develops.

epithelium and a small amount from the male urethral

A rare granulosa cell tumor can develop in an ovary,

occurring more often after menopause than before.

glands. This lubrication is necessary during intercourse

These tumors secrete large quantities of estrogens,

to establish a satisfactory massaging sensation rather

which exert the usual estrogenic effects, including

than an irritative sensation, which may be provoked

hypertrophy of the uterine endometrium and irregular

by a dry vagina. A massaging sensation constitutes

bleeding from this endometrium. In fact, bleeding is

the optimal stimulus for evoking the appropriate

often the first and only indication that such a tumor

reflexes that culminate in both the male and female

exists.

climaxes.

Female Orgasm. When local sexual stimulation reaches

Female Sexual Act

maximum intensity, and especially when the local

sensations are supported by appropriate psychic

Stimulation of the Female Sexual Act. As is true in the male

conditioning signals from the cerebrum, reflexes are

sexual act, successful performance of the female sexual

initiated that cause the female orgasm, also called

act depends on both psychic stimulation and local

the female climax. The female orgasm is analogous to

sexual stimulation.

emission and ejaculation in the male, and it may help

1024

Unit XIV Endocrinology and Reproduction

promote fertilization of the ovum. Indeed, the human

the 26th day of the cycle. Finally, if the periodicity of the

female is known to be somewhat more fertile when

cycle is 21 days, ovulation usually occurs within 1 day of

inseminated by normal sexual intercourse rather than

the 7th day of the cycle. Therefore, it is usually stated

that avoidance of intercourse for 4 days before the cal-

by artificial methods, thus indicating an important

culated day of ovulation and 3 days afterward prevents

function of the female orgasm. Possible reasons for

conception. But such a method of contraception can be

this are as follows.

used only when the periodicity of the menstrual cycle is

First, during the orgasm, the perineal muscles of the

regular.

female contract rhythmically, which results from spinal

cord reflexes similar to those that cause ejaculation in

Hormonal Suppression of Fertility—“The Pill.” It has long

the male. It is possible that these reflexes increase

been known that administration of either estrogen or

uterine and fallopian tube motility during the orgasm,

progesterone, if given in appropriate quantities during

thus helping to transport the sperm upward through

the first half of the monthly cycle, can inhibit ovulation.

the uterus toward the ovum; information on this

The reason for this is that appropriate administration of

either of these hormones can prevent the preovulatory

subject is scanty, however. Also, the orgasm seems to

surge of LH secretion by the pituitary gland, which is

cause dilation of the cervical canal for up to

essential in causing ovulation.

minutes, thus allowing easy transport of the sperm.

Why the administration of estrogen or progesterone

Second, in many lower animals, copulation causes

prevents the preovulatory surge of LH secretion is not

the posterior pituitary gland to secrete oxytocin; this

fully understood. However, experimental work has sug-

effect is probably mediated through the brain amyg-

gested that immediately before the surge occurs, there

daloid nuclei and then through the hypothalamus to

is probably a sudden depression of estrogen secretion

the pituitary. The oxytocin causes increased rhythmi-

by the ovarian follicles, and this might be the necessary

cal contractions of the uterus, which have been postu-

signal that causes the subsequent feedback effect on the

lated to cause increased transport of the sperm. A few

anterior pituitary that leads to the LH surge. The admin-

istration of sex hormones (estrogens or progesterone)

sperm have been shown to traverse the entire length

could prevent the initial ovarian hormonal depression

of the fallopian tube in the cow in about 5 minutes, a

that might be the initiating signal for ovulation.

rate at least 10 times as fast as that which the swim-

The problem in devising methods for the hormonal

ming motions of the sperm themselves could possibly

suppression of ovulation has been in developing appro-

achieve. Whether this occurs in the human female is

priate combinations of estrogens and progestins that

unknown.

suppress ovulation but do not cause other, unwanted

In addition to the possible effects of the orgasm on

effects. For instance, too much of either hormone can

fertilization, the intense sexual sensations that develop

cause abnormal menstrual bleeding patterns. However,

during the orgasm also pass to the cerebrum and cause

use of certain synthetic progestins in place of proges-

intense muscle tension throughout the body. But after

terone, especially the 19-norsteroids, along with small

amounts of estrogens usually prevents ovulation yet

culmination of the sexual act, this gives way during the

allows an almost normal pattern of menstruation.

succeeding minutes to a sense of satisfaction charac-

Therefore, almost all “pills” used for the control of fer-

terized by relaxed peacefulness, an effect called

tility consist of some combination of synthetic estrogens

resolution.

and synthetic progestins. The main reason for using syn-

thetic estrogens and progestins is that the natural hor-

mones are almost entirely destroyed by the liver within

Female Fertility

a short time after they are absorbed from the gastroin-

testinal tract into the portal circulation. However,

Fertile Period of Each Sexual Cycle. The ovum remains

many of the synthetic hormones can resist this

viable and capable of being fertilized after it is expelled

destructive propensity of the liver, thus allowing oral

from the ovary probably no longer than 24 hours. There-

administration.

fore, sperm must be available soon after ovulation if fer-

Two of the most commonly used synthetic estrogens

tilization is to take place. A few sperm can remain fertile

are ethinyl estradiol and mestranol. Among the most

in the female reproductive tract for up to 5 days. There-

commonly used progestins are norethindrone, norethyn-

fore, for fertilization to take place, intercourse must

odrel, ethynodiol, and norgestrel. The drug is usually

occur sometime between 4 and 5 days before ovulation

begun in the early stages of the monthly cycle and con-

up to a few hours after ovulation. Thus, the period of

tinued beyond the time that ovulation would normally

female fertility during each month is short, about 4 to 5

occur. Then the drug is stopped, allowing menstruation

days.

to occur and a new cycle to begin.

Rhythm Method of Contraception. One of the commonly

Abnormal Conditions That Cause Female Sterility. About 5 to

practiced methods of contraception is to avoid inter-

10 per cent of women are infertile. Occasionally, no

course near the time of ovulation. The difficulty with

abnormality can be discovered in the female genital

this method of contraception is predicting the exact

organs, in which case it must be assumed that the infer-

time of ovulation. Yet the interval from ovulation until

tility is due to either abnormal physiological function of

the next succeeding onset of menstruation is almost

the genital system or abnormal genetic development of

always between 13 and 15 days. Therefore, if the men-

the ova themselves.

strual cycle is regular, with an exact periodicity of 28

Probably by far the most common cause of female

days, ovulation usually occurs within 1 day of the 14th

sterility is failure to ovulate. This can result from

day of the cycle. If, in contrast, the periodicity of the

hyposecretion of gonadotropic hormones, in which

cycle is 40 days, ovulation usually occurs within 1 day of

case the intensity of the hormonal stimuli is simply

Chapter 81

Female Physiology Before Pregnancy and Female Hormones

1025

ovaries. Endometriosis causes fibrosis throughout the

pelvis, and this fibrosis sometimes so enshrouds

99°

the ovaries that an ovum cannot be released into the

Ovulation

abdominal cavity. Often, endometriosis occludes the fal-

lopian tubes, either at the fimbriated ends or elsewhere

along their extent.

98°

Another common cause of female infertility is salp-

ingitis, that is, inflammation of the fallopian tubes; this

causes fibrosis in the tubes, thereby occluding them. In

the past, such inflammation occurred mainly as a result

of gonococcal infection, but with modern therapy,

97°

this is becoming a less prevalent cause of female

infertility.

Still another cause of infertility is secretion of abnor-

mal mucus by the uterine cervix. Ordinarily, at the time

of ovulation, the hormonal environment of estrogen

8 10 12 14 16 18 20 22 24 26 28

Day of cycle

causes the secretion of mucus with special charac-

teristics that allow rapid mobility of sperm into the

uterus and actually guide the sperm up along mucous

“threads.” Abnormalities of the cervix itself, such as

Figure 81-11

low-grade infection or inflammation, or abnormal hor-

monal stimulation of the cervix can lead to a viscous

Elevation in body temperature shortly after ovulation.

mucous plug that prevents fertilization.

References

insufficient to cause ovulation, or it can result from

abnormal ovaries that do not allow ovulation. For

Altkorn D, Vokes T: Treatment of postmenopausal osteo-

instance, thick ovarian capsules occasionally exist on the

porosis. JAMA 285:1415, 2001.

outsides of the ovaries, making ovulation difficult.

Bastian LA, Smith CM, Nanda K: Is this woman peri-

Because of the high incidence of anovulation in

menopausal? JAMA 289:895, 2003.

sterile women, special methods are often used to

Beral V, Banks E, Reeves G: Evidence from randomised

determine whether ovulation occurs. These methods are

trials on the long-term effects of hormone replacement

based mainly on the effects of progesterone on the

therapy. Lancet 360:942, 2002.

body, because the normal increase in progesterone

Compston JE: Sex steroids and bone. Physiol Rev 81:419,

secretion usually does not occur during the latter half

2001.

of anovulatory cycles. In the absence of progestational

Gruber CJ, Tschugguel W, Schneeberger C, Huber JC: Pro-

effects, the cycle can be assumed to be anovulatory.

duction and actions of estrogens. N Engl J Med 346:340,

One of these tests is simply to analyze the urine for a

2002.

surge in pregnanediol, the end product of progesterone

Hamilton-Fairley D, Taylor A: Anovulation. BMJ 327:546,

metabolism, during the latter half of the sexual cycle;

2003.

the lack of this substance indicates failure of ovulation.

Lorenzo J: A new hypothesis for how sex steroid hormones

Another common test is for the woman to chart her

regulate bone mass. J Clin Invest 111:1641, 2003.

body temperature throughout the cycle. Secretion of

Manson JE, Martin KA: Postmenopausal hormone-

progesterone during the latter half of the cycle raises

replacement therapy. N Engl J Med 345:34, 2001.

the body temperature about 0.5°F, with the temperature

Nadal A, Diaz M, Valverde MA: The estrogen trinity:

rise coming abruptly at the time of ovulation. Such a

membrane, cytosolic, and nuclear effects. News Physiol Sci

temperature chart, showing the point of ovulation, is

16:251, 2001.

illustrated in Figure 81-11.

Nelson HD: Commonly used types of postmenopausal estro-

Lack of ovulation caused by hyposecretion of the

gen for treatment of hot flashes: scientific review. JAMA

pituitary gonadotropic hormones can sometimes be

291:1610, 2004.

treated by appropriately timed administration of hu-

Nilsson S, Makela S, Treuter E, et al: Mechanisms of estro-

man chorionic gonadotropin, a hormone (discussed in

gen action. Physiol Rev 81:1535, 2001.

Chapter 82) that is extracted from the human placenta.

Niswender GD, Juengel JL, Silva PJ, et al: Mechanisms con-

This hormone, although secreted by the placenta, has

trolling the function and life span of the corpus luteum.

almost the same effects as LH and is therefore a pow-

Physiol Rev 80:1, 2000.

erful stimulator of ovulation. However, excess use of

Petitti DB: Combination estrogen-progestin oral contracep-

this hormone can cause ovulation from many follicles

tives. N Engl J Med 349:1443, 2003.

simultaneously; this results in multiple births, an effect

Pettersson K, Gustafsson JA: Role of estrogen receptor beta

that has caused as many as eight babies

(mostly

in estrogen action. Annu Rev Physiol 63:165, 2001.

stillborn) to be born to mothers treated for infertility

Riggs BL: The mechanisms of estrogen regulation of bone

with this hormone.

resorption. J Clin Invest 106:1203, 2000.

One of the most common causes of female sterility is

Riggs BL, Hartmann LC: Selective estrogen-receptor mod-

endometriosis, a common condition in which endome-

ulators—mechanisms of action and application to clinical

trial tissue almost identical to that of the normal uterine

practice. N Engl J Med 348:618, 2003.

endometrium grows and even menstruates in the pelvic

Smith S, Pfeifer SM, Collins JA: Diagnosis and management

cavity surrounding the uterus, fallopian tubes, and

of female infertility. JAMA 290:1767, 2003.

C H A P T E R

Pregnancy and Lactation

In Chapters 80 and 81, the sexual functions of the

male and female are described to the point of

fertilization of the ovum. If the ovum becomes

fertilized, a new sequence of events called gestation,

or pregnancy, takes place, and the fertilized ovum

eventually develops into a full-term fetus. The

purpose of this chapter is to discuss the early stages

of ovum development after fertilization and then to

discuss the physiology of pregnancy. In Chapter 83, some special aspects of fetal

and early childhood physiology are discussed.

Maturation and Fertilization of the Ovum

While still in the ovary, the ovum is in the primary oocyte stage. Shortly before

it is released from the ovarian follicle, its nucleus divides by meiosis and a first

polar body is expelled from the nucleus of the oocyte. The primary oocyte then

becomes the secondary oocyte. In this process, each of the 23 pairs of chromo-

somes loses one of its partners, which becomes incorporated in a polar body

that is expelled. This leaves 23 unpaired chromosomes in the secondary oocyte.

It is at this time that the ovum, still in the secondary oocyte stage, is ovulated

into the abdominal cavity. Then, almost immediately, it enters the fimbriated

end of one of the fallopian tubes.

Entry of the Ovum into the Fallopian Tube (Oviduct). When ovulation occurs, the ovum,

along with a hundred or more attached granulosa cells that constitute the

corona radiata, is expelled directly into the peritoneal cavity and must then

enter one of the fallopian tubes to reach the cavity of the uterus. The fimbri-

ated ends of each fallopian tube fall naturally around the ovaries. The inner sur-

faces of the fimbriated tentacles are lined with ciliated epithelium, and the cilia

are activated by estrogen from the ovaries, which causes the cilia to beat toward

the opening, or ostium, of the involved fallopian tube. One can actually see a

slow fluid current flowing toward the ostium. By this means, the ovum enters

one of the fallopian tubes.

It seems likely that many ova might fail to enter the fallopian tubes. However,

on the basis of conception studies, it is probable that as many as 98 per cent

succeed in this task. Indeed, in some recorded cases, women with one ovary

removed and the opposite fallopian tube removed have had several children

with relative ease of conception, thus demonstrating that ova can even enter

the opposite fallopian tube.

Fertilization of the Ovum. After the male ejaculates semen into the vagina during

intercourse, a few sperm are transported within 5 to 10 minutes upward from

the vagina and through the uterus and fallopian tubes to the ampullae of the

fallopian tubes near the ovarian ends of the tubes. This transport of the sperm

is aided by contractions of the uterus and fallopian tubes stimulated by

prostaglandins in the male seminal fluid and also by oxytocin released from the

posterior pituitary gland of the female during her orgasm. Of the almost half a

billion sperm deposited in the vagina, a few thousand succeed in reaching each

ampulla.

Fertilization of the ovum normally takes place in the ampulla of one of the

fallopian tubes soon after both the sperm and the ovum enter the ampulla. But

1027

1028

Unit XIV Endocrinology and Reproduction

Dispersed corona radiata

Fertilization

Corona

Cell division

Blastocyst

(day 1)

radiata

Zygote

Fallopian

tube

Sperm

Blastocyst

reaches

Male

uterus

Sperm

pronucleus

(days 4-5)

Ovary

Blastocyst

Ovulation

Ovum

implants

(days 5-7)

Female

Centrosome

Amniotic

pronucleus

cavity

Uterus

Figure 82-1

Fertilization of the ovum. A, The mature ovum surrounded by the

corona radiata. B, Dispersal of the corona radiata. C, Entry of the

sperm. D, Formation of the male and female pronuclei. E, Reor-

ganization of a full complement of chromosomes and beginning

division of the ovum. (Modified from Arey LB: Developmental

Trophoblastic

Anatomy: A Textbook and Laboratory Manual of Embryology, 7th

cells invading

ed. Philadelphia: WB Saunders, 1974.)

endometrium

Figure 82-2

before a sperm can enter the ovum, it must first pene-

A, Ovulation, fertilization of the ovum in the fallopian tube, and

trate the multiple layers of granulosa cells attached to

implantation of the blastocyst in the uterus. B, Action of tro-

the outside of the ovum (the corona radiata) and then

phoblast cells in implantation of the blastocyst in the uterine

endometrium.

bind to and penetrate the zona pellucida surrounding

the ovum itself. The mechanisms used by the sperm for

these purposes are presented in Chapter 80.

Once a sperm has entered the ovum (which is still

Transport of the Fertilized Ovum

in the secondary oocyte stage of development), the

in the Fallopian Tube

oocyte divides again to form the mature ovum plus

a second polar body that is expelled. The mature

After fertilization has occurred, an additional 3 to 5

ovum still carries in its nucleus (now called the female

days is normally required for transport of the fertilized

pronucleus) 23 chromosomes. One of these chromo-

ovum through the remainder of the fallopian tube into

somes is the female chromosome, known as the X

the cavity of the uterus (Figure 82-2). This transport is

chromosome.

effected mainly by a feeble fluid current in the tube

In the meantime, the fertilizing sperm has also

resulting from epithelial secretion plus action of the

changed. On entering the ovum, its head swells to form

ciliated epithelium that lines the tube; the cilia always

a male pronucleus, shown in Figure 82-1D. Later, the

beat toward the uterus. Weak contractions of the

23 unpaired chromosomes of the male pronucleus and

fallopian tube may also aid the ovum passage.

the 23 unpaired chromosomes of the female pronu-

The fallopian tubes are lined with a rugged, cryptoid

cleus align themselves to re-form a complete comple-

surface that impedes passage of the ovum despite the

ment of 46 chromosomes (23 pairs) in the fertilized

fluid current. Also, the isthmus of the fallopian tube

ovum (see Figure 82-1E).

(the last

2 centimeters before the tube enters the

uterus) remains spastically contracted for about the

What Determines the Sex of the Fetus That Is Created? After

first 3 days after ovulation. After this time, the rapidly

formation of the mature sperm, half of these carry in

increasing progesterone secreted by the ovarian

their genome an X chromosome (the female chromo-

corpus luteum first promotes increasing progesterone

some) and half carry a Y chromosome (the male

receptors on the fallopian tube smooth muscle cells;

chromosome). Therefore, if an X chromosome from

then the progesterone activates the receptors, exerting

a sperm combines with an X chromosome from an

a tubular relaxing effect that allows entry of the ovum

ovum, giving an XX combination, a female child will

into the uterus.

be born, as explained in Chapter 80. But if a Y chro-

This delayed transport of the fertilized ovum

mosome from a sperm is paired with an X chromo-

through the fallopian tube allows several stages of cell

some from an ovum, giving an XY combination, a male

division to occur before the dividing ovum—now

child will be born.

called a blastocyst, with about 100 cells—enters the

Chapter 82

Pregnancy and Lactation

1029

uterus. During this time, the fallopian tube secretory

endometrial stromal cells into large swollen cells con-

cells produce large quantities of secretions used for the

taining extra quantities of glycogen, proteins, lipids,

nutrition of the developing blastocyst.

and even some minerals necessary for development of

the conceptus. Then, when the conceptus implants in

the endometrium, the continued secretion of proges-

Implantation of the Blastocyst

terone causes the endometrial cells to swell further

in the Uterus

and to store even more nutrients. These cells are now

called decidual cells, and the total mass of cells is called

After reaching the uterus, the developing blastocyst

the decidua.

usually remains in the uterine cavity an additional 1 to

As the trophoblast cells invade the decidua, digest-

3 days before it implants in the endometrium; thus,

ing and imbibing it, the stored nutrients in the decidua

implantation ordinarily occurs on about the fifth to

are used by the embryo for growth and development.

seventh day after ovulation. Before implantation,

During the first week after implantation, this is the

the blastocyst obtains its nutrition from the uterine

only means by which the embryo can obtain nutrients;

endometrial secretions, called “uterine milk.”

the embryo continues to obtain at least some of its

Implantation results from the action of trophoblast

nutrition in this way for up to 8 weeks, although the

cells that develop over the surface of the blastocyst.

placenta also begins to provide nutrition after about

These cells secrete proteolytic enzymes that digest and

the 16th day beyond fertilization (a little more than 1

liquefy the adjacent cells of the uterine endometrium.

week after implantation). Figure 82-4 shows this tro-

Some of the fluid and nutrients released are actively

phoblastic period of nutrition, which gradually gives

transported by the same trophoblast cells into the blas-

way to placental nutrition.

tocyst, adding more sustenance for growth. Figure

82-3 shows an early implanted human blastocyst, with

a small embryo. Once implantation has taken place,

Function of the Placenta

the trophoblast cells and other adjacent cells (from the

blastocyst and the uterine endometrium) proliferate

Developmental and Physiologic

rapidly, forming the placenta and the various mem-

Anatomy of the Placenta

branes of pregnancy.

While the trophoblastic cords from the blastocyst are

attaching to the uterus, blood capillaries grow into the

cords from the vascular system of the newly forming

Early Nutrition of the Embryo

embryo. By the 16th day after fertilization, blood also

begins to be pumped by the heart of the embryo itself.

In Chapter 81, we pointed out that the progesterone

Simultaneously, blood sinuses supplied with blood from

secreted by the ovarian corpus luteum during the

the mother develop around the outsides of the tro-

latter half of each monthly sexual cycle has an

phoblastic cords. The trophoblast cells send out more

effect on the uterine endometrium, converting the

and more projections, which become placental villi into

Trophoblasts

Endometrium

100

Placental

diffusion

Ovum

Trophoblastic

nutrition

Duration of pregnancy (weeks)

Figure 82-4

Figure 82-3

Nutrition of the fetus. Most of the early nutrition is due to tro-

Implantation of the early human embryo, showing trophoblastic

phoblastic digestion and absorption of nutrients from the endome-

digestion and invasion of the endometrium. (Courtesy Dr. Arthur

trial decidua, and essentially all the later nutrition results from

Hertig.)

diffusion through the placental membrane.

1030

Unit XIV Endocrinology and Reproduction

PLACENTA

Placental Permeability and Membrane

Placental septum

To the mother

Diffusion Conductance

Stratum spongiosum

From the mother

The major function of the placenta is to provide for

diffusion of foodstuffs and oxygen from the mother’s

Limiting layer

blood into the fetus’s blood and diffusion of excretory

Maternal

products from the fetus back into the mother.

vessels

In the early months of pregnancy, the placental

membrane is still thick because it is not fully devel-

Villus

oped. Therefore, its permeability is low. Further, the

surface area is small because the placenta has not

grown significantly. Therefore, the total diffusion con-

ductance is minuscule at first. Conversely, in later preg-

nancy, the permeability increases because of thinning

of the membrane diffusion layers and because the

Intravillus

surface area expands many times over, thus giving the

space

tremendous increase in placental diffusion shown in

Amnion

Trophoblast

Figure 82-4.

Chorion

Umbilical arteries

Rarely, “breaks” occur in the placental membrane,

Marginal

which allows fetal blood cells to pass into the mother

Umbilical vein

sinus

or, even less commonly, the mother’s cells to pass into

Umbilical cord

the fetus. Fortunately, it is rare for the fetus to bleed

severely into the mother’s circulation because of a rup-

VILLUS

tured placental membrane.

Diffusion of Oxygen Through the Placental Membrane.

Fetal capillaries

Almost the same principles for diffusion of oxygen

through the pulmonary membrane (discussed in detail

Intervillous space

in Chapter 39) are applicable for diffusion of oxy-

gen through the placental membrane. The dissolved

Chorionic epithelium

oxygen in the blood of the large maternal sinuses

passes into the fetal blood by simple diffusion, driven

by an oxygen pressure gradient from the mother’s

blood to the fetus’s blood. Near the end of pregnancy,

Figure 82-5

the mean PO₂ of the mother’s blood in the placental

sinuses is about 50 mm Hg, and the mean PO₂ in the

Above, Organization of the mature placenta. Below, Relation of the

fetal blood in the villus capillaries to the mother’s blood in the inter-

fetal blood after it becomes oxygenated in the placenta

villous spaces. (Modified from Gray H, Goss CM: Anatomy of the

is about 30 mm Hg. Therefore, the mean pressure gra-

Human Body, 25th ed. Philadelphia: Lea & Febiger, 1948; and

from Arey LB: Developmental Anatomy: A Textbook and Labora-

dient for diffusion of oxygen through the placental

tory Manual of Embryology, 7th ed. Philadelphia: WB Saunders,

membrane is about 20 mm Hg.

1974.)

One might wonder how it is possible for a fetus to

obtain sufficient oxygen when the fetal blood leaving

the placenta has a PO₂ of only 30 mm Hg. There are

which fetal capillaries grow. Thus, the villi, carrying fetal

three reasons why even this low PO₂ is capable of

blood, are surrounded by sinuses that contain maternal

allowing the fetal blood to transport almost as much

blood.

oxygen to the fetal tissues as is transported by the

The final structure of the placenta is shown in Figure

mother’s blood to her tissues.

82-5. Note that the fetus’s blood flows through two

First, the hemoglobin of the fetus is mainly fetal

umbilical arteries, then into the capillaries of the villi,

hemoglobin, a type of hemoglobin synthesized in the

and finally back through a single umbilical vein into the

fetus before birth. Figure 82-6 shows the comparative

fetus. At the same time, the mother’s blood flows from

oxygen dissociation curves for maternal hemoglobin

her uterine arteries into large maternal sinuses that sur-

round the villi and then back into the uterine veins of

and fetal hemoglobin, demonstrating that the curve for

the mother. The lower part of Figure 82-5 shows the

fetal hemoglobin is shifted to the left of that for mater-

relation between the fetal blood of each fetal placental

nal hemoglobin. This means that at the low PO₂ levels

villus and the blood of the mother surrounding the out-

in fetal blood, the fetal hemoglobin can carry 20 to 50

sides of the villus in the fully developed placenta.

per cent more oxygen than maternal hemoglobin can.

The total surface area of all the villi of the mature pla-

Second, the hemoglobin concentration of fetal blood

centa is only a few square meters—many times less than

is about 50 per cent greater than that of the mother; this

the area of the pulmonary membrane in the lungs. Nev-

is an even more important factor in enhancing the

ertheless, nutrients and other substances pass through

amount of oxygen transported to the fetal tissues.

this placental membrane mainly by diffusion in much

Third, the Bohr effect, which is explained in relation

the same manner that diffusion occurs through the

alveolar membranes of the lungs and the capillary

to the exchange of carbon dioxide and oxygen in the

membranes elsewhere in the body.

lung in Chapter 40, provides another mechanism to

Chapter 82

Pregnancy and Lactation

1031

mother’s blood. The PCO₂ of the fetal blood is 2 to 3

mm Hg higher than that of the maternal blood. This

100

small pressure gradient for carbon dioxide across the

membrane is more than sufficient to allow adequate

Fetal

diffusion of carbon dioxide, because the extreme sol-

ubility of carbon dioxide in the placental membrane

allows carbon dioxide to diffuse about 20 times as

rapidly as oxygen.

Maternal

Diffusion of Foodstuffs Through the Placental Membrane.

Other metabolic substrates needed by the fetus

diffuse into the fetal blood in the same manner as

oxygen does. For instance, in the late stages of

Human

pregnancy, the fetus often uses as much glucose as

the entire body of the mother uses. To provide this

100

much glucose, the trophoblast cells lining the placen-

PO2

(mm Hg)

tal villi provide for facilitated diffusion of glucose

through the placental membrane. That is, the glucose

is transported by carrier molecules in the trophoblast

cells of the membrane. Even so, the glucose level in

Figure 82-6

fetal blood is 20 to 30 per cent lower than that in

maternal blood.

Oxygen-hemoglobin dissociation curves for maternal and fetal

blood, showing that fetal blood can carry a greater quantity of

Because of the high solubility of fatty acids in cell

oxygen than can maternal blood for a given blood PO₂. (Data from

membranes, these also diffuse from the maternal

Metcalfe J, Moll W, Bartels H: Gas exchange across the placenta.

blood into the fetal blood, but more slowly than

Fed Proc 23:775, 1964.)

glucose, so that glucose is used more easily by the fetus

for nutrition. Also, such substances as ketone bodies

and potassium, sodium, and chloride ions diffuse with

enhance the transport of oxygen by fetal blood. That

relative ease from the maternal blood into the fetal

is, hemoglobin can carry more oxygen at a low PCO₂

blood.

than it can at a high PCO₂. The fetal blood entering the

placenta carries large amounts of carbon dioxide, but

Excretion of Waste Products Through the Placental Membrane.

much of this carbon dioxide diffuses from the fetal

In the same manner that carbon dioxide diffuses

blood into the maternal blood. Loss of the carbon

from the fetal blood into the maternal blood, other

dioxide makes the fetal blood more alkaline, whereas

excretory products formed in the fetus also diffuse

the increased carbon dioxide in the maternal blood

through the placental membrane into the maternal

makes it more acidic.

blood and are then excreted along with the excretory

These changes cause the capacity of fetal blood to

products of the mother. These include especially the

combine with oxygen to increase and that of maternal

nonprotein nitrogens such as urea, uric acid, and crea-

blood to decrease. This forces still more oxygen from

tinine. The level of urea in fetal blood is only slightly

the maternal blood, while enhancing oxygen uptake by

greater than that in maternal blood, because urea dif-

the fetal blood. Thus, the Bohr shift operates in one

fuses through the placental membrane with great ease.

direction in the maternal blood and in the other direc-

However, creatinine, which does not diffuse as easily,

tion in the fetal blood. These two effects make the

has a fetal blood concentration considerably higher

Bohr shift twice as important here as it is for oxygen

than that in the mother’s blood. Therefore, excretion

exchange in the lungs; therefore, it is called the double

from the fetus occurs mainly, if not entirely, as a result

Bohr effect.

of diffusion gradients across the placental membrane,

By these three means, the fetus is capable of receiv-

because there are higher concentrations of the excre-

ing more than adequate oxygen through the placental

tory products in the fetal blood than in the maternal

membrane, despite the fact that the fetal blood leaving

blood.

the placenta has a PO₂ of only 30 mm Hg.

The total diffusing capacity of the entire placenta for

oxygen at term is about 1.2 milliliters of oxygen per

Hormonal Factors

minute per millimeter of mercury oxygen pressure dif-

ference across the membrane. This compares favorably

in Pregnancy

with that of the lungs of the newborn baby.

In pregnancy, the placenta forms especially large

Diffusion of Carbon Dioxide Through the Placental Membrane.

quantities of human chorionic gonadotropin, estrogens,

Carbon dioxide is continually formed in the tissues of

progesterone, and human chorionic somatomam-

the fetus in the same way that it is formed in maternal

motropin, the first three of which, and probably

tissues, and the only means for excreting the carbon

the fourth as well, are all essential to a normal

dioxide from the fetus is through the placenta into the

pregnancy.

1032

Unit XIV Endocrinology and Reproduction

Human Chorionic Gonadotropin

amounts of nutrients rather than being shed in the

menstruum. As a result, the decidua-like cells that

and Its Effect to Cause Persistence

develop in the endometrium during the normal female

of the Corpus Luteum and

sexual cycle become actual decidual cells—greatly

to Prevent Menstruation

swollen and nutritious—at about the time that the

blastocyst implants.

Menstruation normally occurs in a nonpregnant

Under the influence of human chorionic

woman about 14 days after ovulation, at which time

gonadotropin, the corpus luteum in the mother’s ovary

most of the endometrium of the uterus sloughs away

grows to about twice its initial size by a month or so

from the uterine wall and is expelled to the exterior.

after pregnancy begins, and its continued secretion of

If this should happen after an ovum has implanted,

estrogens and progesterone maintains the decidual

the pregnancy would terminate. However, this is

nature of the uterine endometrium, which is necessary

prevented by the secretion of human chorionic

for the early development of the fetus.

gonadotropin by the newly developing embryonic

If the corpus luteum is removed before approxi-

tissues in the following manner.

mately the

7th week of pregnancy, spontaneous

Coincidental with the development of the tro-

abortion almost always occurs, sometimes even up to

phoblast cells from the early fertilized ovum, the

the 12th week. After that time, the placenta secretes

hormone human chorionic gonadotropin is secreted by

sufficient quantities of progesterone and estrogens to

the syncytial trophoblast cells into the fluids of the

maintain pregnancy for the remainder of the gestation

mother, as shown in Figure 82-7. The secretion of this

period. The corpus luteum involutes slowly after the

hormone can first be measured in the blood 8 to 9 days

13th to 17th week of gestation.

after ovulation, shortly after the blastocyst implants in

the endometrium. Then the rate of secretion rises

Effect of Human Chorionic Gonadotropin on the Fetal

rapidly to reach a maximum at about 10 to 12 weeks

Testes. Human chorionic gonadotropin also exerts an

of pregnancy and decreases back to a lower value by

interstitial cell-stimulating effect on the testes of the

16 to 20 weeks. It continues at this level for the remain-

male fetus, resulting in the production of testosterone

der of pregnancy.

in male fetuses until the time of birth. This small secre-

tion of testosterone during gestation is what causes the

Function of Human Chorionic Gonadotropin. Human

fetus to grow male sex organs instead of female

chorionic gonadotropin is a glycoprotein having a

organs. Near the end of pregnancy, the testosterone

molecular weight of about

39,000 and much the

secreted by the fetal testes also causes the testes to

same molecular structure and function as luteinizing

descend into the scrotum.

hormone secreted by the pituitary gland. By far, its

most important function is to prevent involution of the

corpus luteum at the end of the monthly female sexual

cycle. Instead, it causes the corpus luteum to secrete

Secretion of Estrogens

even larger quantities of its sex hormones—proges-

by the Placenta

terone and estrogens—for the next few months. These

sex hormones prevent menstruation and cause the

The placenta, like the corpus luteum, secretes both

endometrium to continue to grow and store large

estrogens and progesterone. Histochemical and

Human chorionic

120

gonadotropin

Progesterone

100

Estrogens

300

200

100

Figure 82-7

Rates of secretion of estrogens

and progesterone, and con-

Duration of pregnancy (weeks)

centration of human chorionic

gonadotropin at different stages

of pregnancy.

Chapter 82

Pregnancy and Lactation

1033

physiological studies show that these two hormones,

2. Progesterone decreases the contractility

like most other placental hormones, are secreted by

of the pregnant uterus, thus preventing uterine

the syncytial trophoblast cells of the placenta.

contractions from causing spontaneous

Figure 82-7 shows that toward the end of pregnancy,

abortion.

the daily production of placental estrogens in-

3. Progesterone contributes to the development of

creases to about 30 times the mother’s normal level

the conceptus even before implantation, because

of production. However, the secretion of estrogens

it specifically increases the secretions of the

by the placenta is quite different from secretion by

mother’s fallopian tubes and uterus to provide

the ovaries. Most important, the estrogens secreted

appropriate nutritive matter for the developing

by the placenta are not synthesized de novo from

morula and blastocyst. There is also reason to

basic substrates in the placenta. Instead, they are

believe that progesterone affects cell cleavage in

formed almost entirely from androgenic steroid

the early developing embryo.

compounds, dehydroepiandrosterone and

16-

4. The progesterone secreted during pregnancy helps

hydroxydehydroepiandrosterone, which are formed

the estrogen prepare the mother’s breasts for

both in the mother’s adrenal glands and in the adrenal

lactation, which is discussed later in this chapter.

glands of the fetus. These weak androgens are trans-

ported by the blood to the placenta and converted by

the trophoblast cells into estradiol, estrone, and estriol.

Human Chorionic

(The cortices of the fetal adrenal glands are extremely

Somatomammotropin

large, and about 80 per cent consists of a so-called

fetal zone, the primary function of which seems to

A more recently discovered placental hormone is

be to secrete dehydroepiandrosterone during

called human chorionic somatomammotropin. It is a

pregnancy.)

protein with a molecular weight of about 38,000, and

it begins to be secreted by the placenta at about the

fifth week of pregnancy. Secretion of this hormone

Function of Estrogen in Pregnancy. In the discussions of

increases progressively throughout the remainder

estrogens in Chapter 81, we pointed out that these hor-

of pregnancy in direct proportion to the weight of

mones exert mainly a proliferative function on most

the placenta. Although the functions of chorionic

reproductive and associated organs of the mother.

somatomammotropin are uncertain, it is secreted in

During pregnancy, the extreme quantities of estrogens

quantities several times greater than all the other preg-

cause (1) enlargement of the mother’s uterus, (2)

nancy hormones combined. It has several possible

enlargement of the mother’s breasts and growth of the

important effects.

breast ductal structure, and (3) enlargement of the

First, when administered to several types of lower

mother’s female external genitalia.

animals, human chorionic somatomammotropin

The estrogens also relax the pelvic ligaments

causes at least partial development of the animal’s

of the mother, so that the sacroiliac joints become

breasts and in some instances causes lactation.

relatively limber and the symphysis pubis becomes

Because this was the first function of the hormone dis-

elastic. These changes allow easier passage of the fetus

covered, it was first named human placental lactogen

through the birth canal. There is much reason to

and was believed to have functions similar to those of

believe that estrogens also affect many general aspects

prolactin. However, attempts to promote lactation in

of fetal development during pregnancy, for example,

humans with its use have not been successful.

by affecting the rate of cell reproduction in the early

Second, this hormone has weak actions similar to

embryo.

those of growth hormone, causing the formation of

protein tissues in the same way that growth hormone

does. It also has a chemical structure similar to that of

Secretion of Progesterone

growth hormone, but

100 times as much human

by the Placenta

chorionic somatomammotropin as growth hormone

is required to promote growth.

Progesterone is also essential for a successful

Third, human chorionic somatomammotropin

pregnancy—in fact, it is just as important as estrogen.

causes decreased insulin sensitivity and decreased uti-

In addition to being secreted in moderate quantities

lization of glucose in the mother, thereby making

by the corpus luteum at the beginning of pregnancy, it

larger quantities of glucose available to the fetus.

is secreted later in tremendous quantities by the

Because glucose is the major substrate used by the

placenta, averaging about a 10-fold increase during the

fetus to energize its growth, the possible importance

course of pregnancy, as shown in Figure 82-7.

of such a hormonal effect is obvious. Further, the

The special effects of progesterone that are essen-

hormone promotes the release of free fatty acids from

tial for the normal progression of pregnancy are as

the fat stores of the mother, thus providing this alter-

follows:

native source of energy for the mother’s metabolism

1. Progesterone causes decidual cells to develop

during pregnancy. Therefore, it appears that human

in the uterine endometrium, and these cells play

chorionic somatomammotropin is a general metabolic

an important role in the nutrition of the early

hormone that has specific nutritional implications for

embryo.

both the mother and the fetus.

1034

Unit XIV Endocrinology and Reproduction

Other Hormonal Factors

probably played mainly by the estrogens, which also

in Pregnancy

cause relaxation of the pelvic ligaments. It has also been

claimed that relaxin softens the cervix of the pregnant

Almost all the nonsexual endocrine glands of the

woman at the time of delivery.

mother also react markedly to pregnancy. This results

mainly from the increased metabolic load on the mother

but also, to some extent, from the effects of placental

Response of the Mother’s

hormones on the pituitary and other glands. Some of the

Body to Pregnancy

most notable effects are the following.

Most apparent among the many reactions of the mother

Pituitary Secretion. The anterior pituitary gland of the

to the fetus and to the excessive hormones of pregnancy

mother enlarges at least 50 per cent during pregnancy

is the increased size of the various sexual organs. For

and increases its production of corticotropin, thy-

instance, the uterus increases from about 50 grams to

rotropin, and prolactin. Conversely, pituitary secretion

1100 grams, and the breasts approximately double in

of follicle-stimulating hormone and luteinizing

size. At the same time, the vagina enlarges and the

hormone is almost totally suppressed as a result of the

introitus opens more widely. Also, the various hormones

inhibitory effects of estrogens and progesterone from

can cause marked changes in a pregnant woman’s

the placenta.

appearance, sometimes resulting in the development of

edema, acne, and masculine or acromegalic features.

Corticosteroid Secretion. The rate of adrenocortical secre-

tion of the glucocorticoids is moderately increased

Weight Gain in the Pregnant Woman

throughout pregnancy. It is possible that these gluco-

The average weight gain during pregnancy is about 24

corticoids help mobilize amino acids from the mother’s

pounds, with most of this gain occurring during the last

tissues so that these can be used for synthesis of tissues

two trimesters. Of this, about 7 pounds is fetus and 4

in the fetus.

pounds is amniotic fluid, placenta, and fetal membranes.

Pregnant women usually have about a twofold

The uterus increases about 2 pounds and the breasts

increase in the secretion of aldosterone, reaching a peak

another

2 pounds, still leaving an average weight

at the end of gestation. This, along with the actions of

increase of 9 pounds. About 6 pounds of this is extra

estrogens, causes a tendency for even a normal pregnant

fluid in the blood and extracellular fluid, and the

woman to reabsorb excess sodium from her renal

remaining 3 pounds is generally fat accumulation. The

tubules and, therefore, to retain fluid, occasionally

extra fluid is excreted in the urine during the first few

leading to pregnancy-induced hypertension.

days after birth, that is, after loss of the fluid-retaining

hormones from the placenta.

Secretion by the Thyroid Gland. The mother’s thyroid gland

During pregnancy, a woman often has a greatly

ordinarily enlarges up to 50 per cent during pregnancy

increased desire for food, partly as a result of removal

and increases its production of thyroxine a correspon-

of food substrates from the mother’s blood by the fetus

ding amount. The increased thyroxine production is

and partly because of hormonal factors. Without appro-

caused at least partly by a thyrotropic effect of human

priate prenatal control of diet, the mother’s weight gain

chorionic gonadotropin secreted by the placenta and

can be as great as 75 pounds instead of the usual 24

by small quantities of a specific thyroid-stimulating

pounds.

hormone, human chorionic thyrotropin, also secreted by

the placenta.

Metabolism During Pregnancy

As a consequence of the increased secretion of many

Secretion by the Parathyroid Glands. The mother’s parathy-

hormones during pregnancy, including thyroxine,

roid glands usually enlarge during pregnancy; this is

adrenocortical hormones, and the sex hormones, the

especially true if the mother is on a calcium-deficient

basal metabolic rate of the pregnant woman increases

diet. Enlargement of these glands causes calcium

about 15 per cent during the latter half of pregnancy. As

absorption from the mother’s bones, thereby maintain-

a result, she frequently has sensations of becoming over-

ing normal calcium ion concentration in the mother’s

heated. Also, owing to the extra load that she is carry-

extracellular fluid even while the fetus removes calcium

ing, greater amounts of energy than normal must be

to ossify its own bones. This secretion of parathyroid

expended for muscle activity.

hormone is even more intensified during lactation after

the baby’s birth, because the growing baby requires

Nutrition During Pregnancy. By far the greatest growth of

many times more calcium than the fetus does.

the fetus occurs during the last trimester of pregnancy;

its weight almost doubles during the last 2 months of

Secretion of “Relaxin” by the Ovaries and Placenta. Another

pregnancy. Ordinarily, the mother does not absorb suf-

substance besides the estrogens and progesterone, a

ficient protein, calcium, phosphates, and iron from her

hormone called relaxin, is secreted by the corpus luteum

diet during the last months of pregnancy to supply these

of the ovary and by placental tissues. Its secretion is

extra needs of the fetus. However, anticipating these

increased by a stimulating effect of human chorionic

extra needs, the mother’s body has already been storing

gonadotropin at the same time that the corpus luteum

these substances—some in the placenta, but most in the

and the placenta secrete large quantities of estrogens

normal storage depots of the mother.

and progesterone.

If appropriate nutritional elements are not present in

Relaxin is a polypeptide having a molecular weight of

a pregnant woman’s diet, a number of maternal defi-

about 9000. This hormone, when injected, causes relax-

ciencies can occur, especially in calcium, phosphates,

ation of the ligaments of the symphysis pubis in the

iron, and the vitamins. For example, about 375 mil-

estrous rat and guinea pig. This effect is weak or possi-

ligrams of iron is needed by the fetus to form its blood,

bly even absent in pregnant women. Instead, this role is

and an additional 600 milligrams is needed by the

Chapter 82

Pregnancy and Lactation

1035

mother to form her own extra blood. The normal store

birth of the baby is about 20 per cent above normal, and

of nonhemoglobin iron in the mother at the outset of

a commensurate amount of carbon dioxide is formed.

pregnancy is often only 100 milligrams and almost never

These effects cause the mother’s minute ventilation to

more than 700 milligrams. Therefore, without sufficient

increase. It is also believed that the high levels of prog-

iron in her food, a pregnant woman usually develops

esterone during pregnancy increase the minute ventila-

hypochromic anemia. Also, it is especially important

tion even more, because progesterone increases the

that she receive vitamin D, because although the total

respiratory center’s sensitivity to carbon dioxide. The

quantity of calcium used by the fetus is small, calcium

net result is an increase in minute ventilation of about

is normally poorly absorbed by the mother’s gastroin-

50 per cent and a decrease in arterial PCO₂ to several

testinal tract without vitamin D. Finally, shortly before

millimeters of mercury below that in a nonpregnant

birth of the baby, vitamin K is often added to the

woman. Simultaneously, the growing uterus presses

mother’s diet so that the baby will have sufficient pro-

upward against the abdominal contents, and these press

thrombin to prevent hemorrhage, particularly brain

upward against the diaphragm, so that the total excur-

hemorrhage, caused by the birth process.

sion of the diaphragm is decreased. Consequently, the

respiratory rate is increased to maintain the extra

ventilation.

Changes in the Maternal Circulatory

System During Pregnancy

Function of the Maternal Urinary System During Pregnancy

The rate of urine formation by a pregnant woman is

Blood Flow Through the Placenta, and Cardiac Output During

usually slightly increased because of increased fluid

Pregnancy. About 625 milliliters of blood flows through

intake and increased load or excretory products. But in

the maternal circulation of the placenta each minute

addition, several special alterations of urinary function

during the last month of pregnancy. This, plus the

occur.

general increase in the mother’s metabolism, increases

First, the renal tubules’ reabsorptive capacity for

the mother’s cardiac output to 30 to 40 per cent above

sodium, chloride, and water is increased as much as

normal by the 27th week of pregnancy; then, for reasons

50 per cent as a consequence of increased production

unexplained, the cardiac output falls to only a little

of steroid hormones by the placenta and adrenal

above normal during the last 8 weeks of pregnancy,

cortex.

despite the high uterine blood flow.

Second, the glomerular filtration rate increases as

much as 50 per cent during pregnancy, which tends to

Blood Volume During Pregnancy. The maternal blood

increase the rate of water and electrolyte excretion in

volume shortly before term is about 30 per cent above

the urine. When all these effects are considered, the

normal. This increase occurs mainly during the latter

normal pregnant woman ordinarily accumulates only

half of pregnancy, as shown by the curve of Figure 82-8.

about 6 pounds of extra water and salt.

The cause of the increased volume is likely due, at least

in part, to aldosterone and estrogens, which are greatly

Amniotic Fluid and Its Formation

increased in pregnancy, and to increased fluid retention

Normally, the volume of amniotic fluid (the fluid inside

by the kidneys. Also, the bone marrow becomes increas-

the uterus in which the fetus floats) is between 500 mil-

ingly active and produces extra red blood cells to go

liliters and 1 liter, but it can be only a few milliliters or

with the excess fluid volume. Therefore, at the time of

as much as several liters. Isotope studies of the rate of

birth of the baby, the mother has about 1 to 2 liters of

formation of amniotic fluid show that, on average, the

extra blood in her circulatory system. Only about one

water in amniotic fluid is replaced once every 3 hours,

fourth of this amount is normally lost through bleeding

and the electrolytes sodium and potassium are replaced

during delivery of the baby, thereby allowing a consid-

an average of once every 15 hours. A large portion of

erable safety factor for the mother.

the fluid is derived from renal excretion by the fetus.

Likewise, a certain amount of absorption occurs by way

Maternal Respiration During Pregnancy

of the gastrointestinal tract and lungs of the fetus.

Because of the increased basal metabolic rate of a preg-

However, even after in utero death of a fetus, some

nant woman and because of her greater size, the total

turnover of the amniotic fluid is still present, which indi-

amount of oxygen used by the mother shortly before

cates that some of the fluid is formed and absorbed

directly through the amniotic membranes.

Preeclampsia and Eclampsia

About 5 per cent of all pregnant women experience a

rapid rise in arterial blood pressure to hypertensive

levels during the last few months of pregnancy. This is

also associated with leakage of large amounts of protein

into the urine. This condition is called preeclampsia or

toxemia of pregnancy. It is often characterized by excess

salt and water retention by the mother’s kidneys and by

weight gain and development of edema and hyperten-

sion in the mother. In addition, there is impaired func-

Duration of pregnancy (weeks)

tion of the vascular endothelium, and arterial spasm

occurs in many parts of the mother’s body, most sig-

nificantly in the kidneys, brain, and liver. Both the renal

blood flow and the glomerular filtration rate are

Figure 82-8

decreased, which is exactly opposite to the changes that

Effect of pregnancy to increase the mother’s blood volume.

occur in the normal pregnant woman. The renal effects

1036

Unit XIV Endocrinology and Reproduction

also include thickened glomerular tufts that contain a

helping to prevent expulsion of the fetus. Conversely,

protein deposit in the basement membranes.

estrogens have a definite tendency to increase the

Various attempts have been made to prove that

degree of uterine contractility, partly because

preeclampsia is caused by excessive secretion of pla-

estrogens increase the number of gap junctions

cental or adrenal hormones, but proof of a hormonal

between the adjacent uterine smooth muscle cells, but

basis is still lacking. Another theory is that preeclamp-

also because of other poorly understood effects. Both

sia results from some type of autoimmunity or allergy

progesterone and estrogen are secreted in progres-

in the mother caused by the presence of the fetus. In

sively greater quantities throughout most of preg-

support of this, the acute symptoms usually disappear

within a few days after birth of the baby. There is also

nancy, but from the seventh month onward, estrogen

evidence that preeclampsia is initiated by insufficient

secretion continues to increase while progesterone

blood supply to the placenta, resulting in the placenta’s

secretion remains constant or perhaps even decreases

release of substances that cause widespread dysfunction

slightly. Therefore, it has been postulated that the

of the maternal vascular endothelium. During normal

estrogen-to-progesterone ratio increases sufficiently

placental development, the trophoblasts invade the

toward the end of pregnancy to be at least partly

arterioles of the uterine endometrium and completely

responsible for the increased contractility of the

remodel the maternal arterioles into large blood vessels

uterus.

with low resistance to blood flow. In patients with

preeclampsia, the maternal arterioles fail to undergo

Effect of Oxytocin on the Uterus. Oxytocin is a hormone

these adaptive changes, for reasons that are still unclear,

and there is insufficient blood supply to the placenta.

secreted by the neurohypophysis that specifically

This, in turn, causes the placenta to release various sub-

causes uterine contraction (see Chapter 75). There are

stances that enter the mother’s circulation and cause

four reasons to believe that oxytocin might be impor-

impaired vascular endothelial function, decreased blood

tant in increasing the contractility of the uterus near

flow to the kidneys, excess salt and water retention, and

term: (1) The uterine muscle increases its oxytocin

increased blood pressure. Although the factors that link

receptors and, therefore, increases its responsiveness

reduced placental blood supply with maternal endothe-

to a given dose of oxytocin during the latter few

lial dysfunction are still uncertain, some experimental

months of pregnancy. (2) The rate of oxytocin secre-

studies suggest a role for increased levels of inflamma-

tion by the neurohypophysis is considerably increased

tory cytokines such as tumor necrosis factor-a and

at the time of labor. (3) Although hypophysectomized

interleukin-6.

Eclampsia is an extreme degree of preeclampsia,

animals can still deliver their young at term, labor is

characterized by vascular spasm throughout the body;

prolonged.

(4) Experiments in animals indicate

clonic seizures in the mother, sometimes followed by

that irritation or stretching of the uterine cervix, as

coma; greatly decreased kidney output; malfunction of

occurs during labor, can cause a neurogenic reflex

the liver; often extreme hypertension; and a generalized

through the paraventricular and supraoptic nuclei of

toxic condition of the body. It usually occurs shortly

the hypothalamus that causes the posterior pituitary

before birth of the baby. Without treatment, a high per-

gland (the neurohypophysis) to increase its secretion

centage of eclamptic mothers die. However, with optimal

of oxytocin.

and immediate use of rapidly acting vasodilating drugs

to reduce the arterial pressure to normal, followed by

Effect of Fetal Hormones on the Uterus. The fetus’s pitu-

immediate termination of pregnancy—by cesarean

section if necessary—the mortality even in eclamptic

itary gland secretes increasing quantities of oxytocin,

mothers has been reduced to 1 per cent or less.

which might play a role in exciting the uterus. Also, the

fetus’s adrenal glands secrete large quantities of corti-

sol, another possible uterine stimulant. In addition, the

Parturition

fetal membranes release prostaglandins in high con-

centration at the time of labor. These, too, can increase

Increased Uterine Excitability

the intensity of uterine contractions.

Near Term

Mechanical Factors That Increase

Parturition means birth of the baby. Toward the end of

Uterine Contractility

pregnancy, the uterus becomes progressively more

Stretch of the Uterine Musculature. Simply stretching

excitable, until finally it develops such strong rhythmi-

smooth muscle organs usually increases their contrac-

cal contractions that the baby is expelled. The exact

tility. Further, intermittent stretch, as occurs repeat-

cause of the increased activity of the uterus is not

edly in the uterus because of fetal movements, can also

known, but at least two major categories of effects lead

elicit smooth muscle contraction. Note especially that

up to the intense contractions responsible for parturi-

twins are born, on average, 19 days earlier than a single

tion:

(1) progressive hormonal changes that cause

child, which emphasizes the importance of mechanical

increased excitability of the uterine musculature, and

stretch in eliciting uterine contractions.

(2) progressive mechanical changes.

Stretch or Irritation of the Cervix. There is reason to

Hormonal Factors That Increase

believe that stretching or irritating the uterine cervix

Uterine Contractility

is particularly important in eliciting uterine contrac-

Increased Ratio of Estrogens to Progesterone. Progesterone

tions. For instance, the obstetrician frequently induces

inhibits uterine contractility during pregnancy, thereby

labor by rupturing the membranes so that the head of

Chapter 82

Pregnancy and Lactation

1037

the baby stretches the cervix more forcefully than

usual or irritates it in other ways.

The mechanism by which cervical irritation excites

the body of the uterus is not known. It has been

suggested that stretching or irritation of nerves in the

cervix initiates reflexes to the body of the uterus, but

the effect could also result simply from myogenic

transmission of signals from the cervix to the body of

the uterus.

Onset of Labor—A Positive Feedback

Mechanism for Its Initiation

During most of the months of pregnancy, the uterus

undergoes periodic episodes of weak and slow rhyth-

mical contractions called Braxton Hicks contractions.

1. Baby's head stretches cervix

These contractions become progressively stronger

2. Cervical stretch excites fundic contraction

3. Fundic contraction pushes baby down and stretches

toward the end of pregnancy; then they change sud-

cervix some more

denly, within hours, to become exceptionally strong

4. Cycle repeats over and over again

contractions that start stretching the cervix and later

force the baby through the birth canal, thereby causing

Figure 82-9

parturition. This process is called labor, and the strong

Theory for the onset of intensely strong contractions during labor.

contractions that result in final parturition are called

labor contractions.

We do not know what suddenly changes the slow,

weak rhythmicity of the uterus into strong labor con-

contractility still more because of positive feedback,

tractions. However, based on experience with other

resulting in a second uterine contraction stronger than

types of physiological control systems, a theory has

the first, a third stronger than the second, and so forth.

been proposed for explaining the onset of labor. The

Once these contractions become strong enough to

positive feedback theory suggests that stretching of

cause this type of feedback, with each succeeding con-

the cervix by the fetus’s head finally becomes great

traction greater than the preceding one, the process

enough to elicit a strong reflex increase in contractil-

proceeds to completion—all because positive feedback

ity of the uterine body. This pushes the baby forward,

initiates a vicious circle when the gain of the feedback

which stretches the cervix more and initiates more

is greater than a critical level.

positive feedback to the uterine body. Thus, the

One might ask about the many instances of false

process repeats until the baby is expelled. This theory

labor, in which the contractions become stronger and

is shown in Figure 82-9, and the observations sup-

stronger and then fade away. Remember that for a

porting it are the following.

vicious circle to continue, each new cycle of the posi-

First, labor contractions obey all the principles of

tive feedback must be stronger than the previous one.

positive feedback. That is, once the strength of uterine

If at any time after labor starts some contractions fail

contraction becomes greater than a critical value, each

to re-excite the uterus sufficiently, the positive feed-

contraction leads to subsequent contractions that

back could go into a retrograde decline, and the labor

become stronger and stronger until maximum effect is

contractions would fade away.

achieved. Referring to the discussion in Chapter 1 of

positive feedback in control systems, one can see that

this is the precise nature of all positive feedback mech-

Abdominal Muscle Contractions

anisms when the feedback gain becomes greater than

During Labor

a critical value.

Second, two known types of positive feedback

Once uterine contractions become strong during

increase uterine contractions during labor: (1) Stretch-

labor, pain signals originate both from the uterus itself

ing of the cervix causes the entire body of the uterus

and from the birth canal. These signals, in addition to

to contract, and this contraction stretches the cervix

causing suffering, elicit neurogenic reflexes in the

even more because of the downward thrust of the

spinal cord to the abdominal muscles, causing intense

baby’s head. (2) Cervical stretching also causes the

contractions of these muscles. The abdominal contrac-

pituitary gland to secrete oxytocin, which is another

tions add greatly to the force that causes expulsion of

means for increasing uterine contractility.

the baby.

To summarize, we can assume that multiple factors

increase the contractility of the uterus toward the

Mechanics of Parturition

end of pregnancy. Eventually a uterine contraction

becomes strong enough to irritate the uterus, espe-

The uterine contractions during labor begin mainly at

cially at the cervix, and this increases uterine

the top of the uterine fundus and spread downward over

1038

Unit XIV Endocrinology and Reproduction

the body of the uterus. Also, the intensity of contraction

Labor Pains

is great in the top and body of the uterus but weak in

the lower segment of the uterus adjacent to the cervix.

With each uterine contraction, the mother experiences

Therefore, each uterine contraction tends to force the

considerable pain. The cramping pain in early labor

baby downward toward the cervix.

is probably caused mainly by hypoxia of the uterine

In the early part of labor, the contractions might

muscle resulting from compression of the blood vessels

occur only once every 30 minutes. As labor progresses,

in the uterus. This pain is not felt when the visceral

the contractions finally appear as often as once every 1

sensory hypogastric nerves, which carry the visceral

to 3 minutes, and the intensity of contraction increases

sensory fibers leading from the uterus, have been

greatly, with only a short period of relaxation between

sectioned.

contractions. The combined contractions of the uterine

However, during the second stage of labor, when the

and abdominal musculature during delivery of the baby

fetus is being expelled through the birth canal, much

cause a downward force on the fetus of about 25 pounds

more severe pain is caused by cervical stretching, per-

during each strong contraction.

ineal stretching, and stretching or tearing of structures

It is fortunate that the contractions of labor occur

in the vaginal canal itself. This pain is conducted to the

intermittently, because strong contractions impede or

mother’s spinal cord and brain by somatic nerves

sometimes even stop blood flow through the placenta

instead of by the visceral sensory nerves.

and would cause death of the fetus if the contractions

were continuous. Indeed, overuse of various uterine

stimulants, such as oxytocin, can cause uterine spasm

Involution of the Uterus

rather than rhythmical contractions and can lead to

After Parturition

death of the fetus.

In about 95 per cent of births, the head is the first part

During the first 4 to 5 weeks after parturition, the uterus

of the baby to be expelled, and in most of the remain-

involutes. Its weight becomes less than half its immedi-

ing instances, the buttocks are presented first. The head

ate postpartum weight within 1 week, and in 4 weeks, if

acts as a wedge to open the structures of the birth canal

the mother lactates, the uterus may become as small as

as the fetus is forced downward.

it was before pregnancy. This effect of lactation results

The first major obstruction to expulsion of the fetus

from the suppression of pituitary gonadotropin and

is the uterine cervix. Toward the end of pregnancy, the

ovarian hormone secretion during the first few months

cervix becomes soft, which allows it to stretch when

of lactation, as discussed later. During early involution

labor contractions begin in the uterus. The so-called first

of the uterus, the placental site on the endometrial

stage of labor is a period of progressive cervical dilation,

surface autolyzes, causing a vaginal discharge known as

lasting until the cervical opening is as large as the head

“lochia,” which is first bloody and then serous in nature,

of the fetus. This stage usually lasts for 8 to 24 hours in

continuing for a total of about 10 days. After this time,

the first pregnancy but often only a few minutes after

the endometrial surface becomes re-epithelialized and

many pregnancies.

ready for normal, nongravid sex life again.

Once the cervix has dilated fully, the fetal membranes

usually rupture and the amniotic fluid is lost suddenly

through the vagina. Then the fetus’s head moves rapidly

Lactation

into the birth canal, and with additional force from

above, it continues to wedge its way through the canal

Development of the Breasts

until delivery is effected. This is called the second stage

of labor, and it may last from as little as 1 minute after

many pregnancies to 30 minutes or more in the first

The breasts, shown in Figure 82-10, begin to develop

pregnancy.

at puberty. This development is stimulated by the

estrogens of the monthly female sexual cycle; estro-

gens stimulate growth of the breasts’ mammary glands

plus the deposition of fat to give the breasts mass. In

Separation and Delivery

addition, far greater growth occurs during the high-

of the Placenta

estrogen state of pregnancy, and only then does the

glandular tissue become completely developed for the

For 10 to 45 minutes after birth of the baby, the

production of milk.

uterus continues to contract to a smaller and smaller

size, which causes a shearing effect between the walls of

the uterus and the placenta, thus separating the placenta

Growth of the Ductal System—Role of the Estrogens. All

from its implantation site. Separation of the placenta

through pregnancy, the large quantities of estrogens

opens the placental sinuses and causes bleeding. The

secreted by the placenta cause the ductal system of the

amount of bleeding is limited to an average of 350 mil-

breasts to grow and branch. Simultaneously, the

liliters by the following mechanism: The smooth muscle

stroma of the breasts increases in quantity, and large

fibers of the uterine musculature are arranged in figures

quantities of fat are laid down in the stroma.

of eight around the blood vessels as the vessels pass

Also important for growth of the ductal system are

through the uterine wall. Therefore, contraction of

at least four other hormones: growth hormone, pro-

the uterus after delivery of the baby constricts the

lactin, the adrenal glucocorticoids, and insulin. Each of

vessels that had previously supplied blood to the pla-

these is known to play at least some role in protein

centa. In addition, it is believed that vasoconstrictor

prostaglandins formed at the placental separation site

metabolism, which presumably explains their function

cause additional blood vessel spasm.

in the development of the breasts.

Chapter 82

Pregnancy and Lactation

1039

Initiation of Lactation—Function

Pectoralis major

of Prolactin

Adipose tissue

Although estrogen and progesterone are essential for

the physical development of the breasts during preg-

Lobules and

nancy, a specific effect of both these hormones is to

alveoli

inhibit the actual secretion of milk. Conversely, the

hormone prolactin has exactly the opposite effect

Lactiferous

on milk secretion—promoting it. This hormone is

sinus (ampulla)

secreted by the mother’s anterior pituitary gland, and

Lactiferous duct

its concentration in her blood rises steadily from the

Nipple

fifth week of pregnancy until birth of the baby, at

which time it has risen to 10 to 20 times the normal

Areola

nonpregnant level. This high level of prolactin at the

end of pregnancy is shown in Figure 82-11.

In addition, the placenta secretes large quantities of

human chorionic somatomammotropin, which proba-

bly has lactogenic properties, thus supporting the pro-

Lobule

lactin from the mother’s pituitary during pregnancy.

Even so, because of the suppressive effects of estrogen

and progesterone, no more than a few milliliters of

Alveoli

fluid are secreted each day until after the baby is born.

The fluid secreted during the last few days before and

the first few days after parturition is called colostrum;

it contains essentially the same concentrations of pro-

teins and lactose as milk, but it has almost no fat, and

Myoepithelial cells

its maximum rate of production is about 1/100 the

subsequent rate of milk production.

Immediately after the baby is born, the sudden loss

of both estrogen and progesterone secretion from the

placenta allows the lactogenic effect of prolactin from

Ductule

the mother’s pituitary gland to assume its natural milk-

Milk

promoting role, and over the next 1 to 7 days, the

breasts begin to secrete copious quantities of milk

instead of colostrum. This secretion of milk requires

Milk

secreting

an adequate background secretion of most of the

epithelial

mother’s other hormones as well, but most important

cells

are growth hormone, cortisol, parathyroid hormone,

and insulin. These hormones are necessary to provide

the amino acids, fatty acids, glucose, and calcium

Figure 82-10

required for milk formation.

After birth of the baby, the basal level of prolactin

The breast and its secretory lobules, alveoli, and lactiferous ducts

secretion returns to the nonpregnant level over the

(milk ducts) that constitute its mammary gland (A). The enlarge-

ments show a lobule (B) and milk-secreting cells of an alveolus

next few weeks, as shown in Figure 82-11. However,

(C).

each time the mother nurses her baby, nervous signals

from the nipples to the hypothalamus cause a 10- to

20-fold surge in prolactin secretion that lasts for about

1 hour, which is also shown in Figure 82-11. This

prolactin acts on the mother’s breasts to keep the

Development of the Lobule-Alveolar System—Role of Proges-

mammary glands secreting milk into the alveoli for the

terone. Final development of the breasts into milk-

subsequent nursing periods. If this prolactin surge is

secreting organs also requires progesterone. Once the

absent or blocked as a result of hypothalamic or pitu-

ductal system has developed, progesterone—acting

itary damage or if nursing does not continue, the

synergistically with estrogen, as well as with the other

breasts lose their ability to produce milk within 1 week

hormones just mentioned—causes additional growth

or so. However, milk production can continue for

of the breast lobules, with budding of alveoli and

several years if the child continues to suckle, although

development of secretory characteristics in the cells of

the rate of milk formation normally decreases consid-

the alveoli. These changes are analogous to the

erably after 7 to 9 months.

secretory effects of progesterone on the endometrium

of the uterus during the latter half of the female

Hypothalamic Control of Prolactin Secretion. The hypothal-

menstrual cycle.

amus plays an essential role in controlling prolactin

1040

Unit XIV Endocrinology and Reproduction

Estrogens

Progesterone

Prolactin

Intermittent secretion

of prolactin during

2.0

300

nursing

200

1.5

Figure 82-11

200

Changes in rates of secretion

1.0

100

of estrogens, progesterone, and

prolactin for 8 weeks before par-

100

turition and 36 weeks thereafter.

0.5

Note especially the decrease of

prolactin secretion back to basal

levels within a few weeks after

parturition, but also the intermit-

-8

-4

tent periods of marked prolactin

Weeks after parturition

secretion (for about 1 hour at a

time) during and after periods of

nursing.

secretion, as it does for almost all the other anterior

Ejection (or “Let-Down”) Process in

pituitary hormones. However, this control is different

Milk Secretion—Function of Oxytocin

in one aspect: The hypothalamus mainly stimulates

production of all the other hormones, but it mainly

Milk is secreted continuously into the alveoli of the

inhibits prolactin production. Consequently, damage

breasts, but milk does not flow easily from the alveoli

to the hypothalamus or blockage of the hypothalamic-

into the ductal system and, therefore, does not contin-

hypophysial portal system often increases prolactin

ually leak from the breast nipples. Instead, the milk

secretion while it depresses secretion of the other

must be ejected from the alveoli into the ducts before

anterior pituitary hormones.

the baby can obtain it. This is caused by a combined

Therefore, it is believed that anterior pituitary secre-

neurogenic and hormonal reflex that involves the

tion of prolactin is controlled either entirely or almost

posterior pituitary hormone oxytocin, as follows.

entirely by an inhibitory factor formed in the hypo-

When the baby suckles, it receives virtually no milk

thalamus and transported through the hypothalamic-

for the first half minute or so. Sensory impulses must

hypophysial portal system to the anterior pituitary

first be transmitted through somatic nerves from the

gland. This factor is called prolactin inhibitory

nipples to the mother’s spinal cord and then to her

hormone. It is almost certainly the same as the cate-

hypothalamus, where they cause nerve signals that

cholamine dopamine, which is known to be secreted

promote oxytocin secretion at the same time that they

by the arcuate nuclei of the hypothalamus and can

cause prolactin secretion. The oxytocin is carried in the

decrease prolactin secretion as much as 10-fold.

blood to the breasts, where it causes myoepithelial cells

(which surround the outer walls of the alveoli) to con-

Suppression of the Female Ovarian Cycles in Nursing Mothers

tract, thereby expressing the milk from the alveoli into

for Many Months After Delivery. In most nursing mothers,

the ducts at a pressure of +10 to 20 mm Hg. Then the

the ovarian cycle (and ovulation) does not resume

baby’s suckling becomes effective in removing the

until a few weeks after cessation of nursing. The reason

milk. Thus, within 30 seconds to 1 minute after a baby

seems to be that the same nervous signals from

begins to suckle, milk begins to flow. This process is

the breasts to the hypothalamus that cause prolactin

called milk ejection or milk let-down.

secretion during suckling—either because of the

Suckling on one breast causes milk flow not only in

nervous signals themselves or because of a subsequent

that breast but also in the opposite breast. It is espe-

effect of increased prolactin—inhibit secretion of

cially interesting that fondling of the baby by the

gonadotropin-releasing hormone by the hypothala-

mother or hearing the baby crying often gives enough

mus. This, in turn, suppresses formation of the pituitary

of an emotional signal to the hypothalamus to cause

gonadotropic hormones—luteinizing hormone and

milk ejection.

follicle-stimulating hormone. However, after several

months of lactation, in some mothers, especially in

those who nurse their babies only some of the time,

Inhibition of Milk Ejection. A particular problem in

the pituitary begins to secrete sufficient gonadotropic

nursing a baby comes from the fact that many psy-

hormones to reinstate the monthly sexual cycle, even

chogenic factors or even generalized sympathetic

though nursing continues.

nervous system stimulation throughout the mother’s

Chapter 82

Pregnancy and Lactation

1041

especially lethal to bacteria that could cause deadly

Table 82-1

infections in newborn babies. Particularly important

Composition of Milk

are antibodies and macrophages that destroy

Escherichia coli bacteria, which often cause lethal diar-

Constituent

Human Milk (%)

Cow’s Milk (%)

rhea in newborns.

When cow’s milk is used to supply nutrition for the

Water

88.5

87.0

Fat

3.3

3.5

baby in place of mother’s milk, the protective agents

Lactose

6.8

4.8

in it are usually of little value because they are

Casein

0.9

2.7

normally destroyed within minutes in the internal

Lactalbumin and other

0.4

0.7

environment of the human being.

proteins

Ash

0.2

0.7

References

Alexander BT, Bennett WA, Khalil RA, Granger JP:

Preeclampsia: linking placental ischemia with cardiovas-

body can inhibit oxytocin secretion and consequently

cular-renal dysfunction. News Physiol Sci 16:282, 2001.

depress milk ejection. For this reason, many mothers

Ben-Jonathan N, Hnasko R: Dopamine as a prolactin (PRL)

must have an undisturbed puerperium if they are to be

inhibitor. Endocr Rev 22:724, 2001.

successful in nursing their babies.

Casey ML, MacDonald PC: The endocrinology of human

parturition. Ann N Y Acad Sci 828:273, 1997.

Challis JR, Lye SJ, Gibb W, et al: Understanding preterm

Milk Composition and the

labor. Ann N Y Acad Sci 943:225, 2001.

Metabolic Drain on the Mother

Cross JC, Simmons DG, Watson ED: Chorioallantoic mor-

phogenesis and formation of the placental villous tree.

Caused by Lactation

Ann N Y Acad Sci 995:84, 2003.

Davison JM, Homuth V, Jeyabalan A, et al: New aspects in

Table 82-1 lists the contents of human milk and cow’s

the pathophysiology of preeclampsia. J Am Soc Nephrol

milk. The concentration of lactose in human milk is

15:2440, 2004.

about 50 per cent greater than in cow’s milk, but the

Dekker G, Sibai B: Primary, secondary, and tertiary preven-

concentration of protein in cow’s milk is ordinarily two

tion of pre-eclampsia. Lancet 357:209, 2001.

or more times greater than in human milk. Finally, only

Freeman ME, Kanyicska B, Lerant A, Nagy G: Prolactin:

one third as much ash, which contains calcium and

structure, function, and regulation of secretion. Physiol

Rev 80:1523, 2000.

other minerals, is found in human milk compared with

Gimpl G, Fahrenholz F: The oxytocin receptor system: struc-

cow’s milk.

ture, function, and regulation. Physiol Rev 81:629, 2001.

At the height of lactation in the human mother, 1.5

Goffin V, Binart N, Touraine P, Kelly PA: Prolactin: the new

liters of milk may be formed each day (and even more

biology of an old hormone. Annu Rev Physiol 64:47, 2002.

if the mother has twins). With this degree of lactation,

Hall JG: Twinning. Lancet 362:735, 2003.

great quantities of metabolic substrates are drained

Kanaka-Gantenbein C, Mastorakos G, Chrousos GP:

from the mother. For instance, about 50 grams of fat

Endocrine-related causes and consequences of intrauter-

enter the milk each day, and about 100 grams of

ine growth retardation. Ann N Y Acad Sci 997:150, 2003.

lactose, which must be derived by conversion from the

Khalaf Y: ABC of subfertility: tubal subfertility. BMJ

mother’s glucose. Also, 2 to 3 grams of calcium phos-

327:610, 2003.

Khalil RA, Granger JP: Vascular mechanisms of increased

phate may be lost each day; unless the mother is drink-

arterial pressure in preeclampsia: lessons from animal

ing large quantities of milk and has an adequate intake

models. Am J Physiol Regul Integr Comp Physiol 283:R29,

of vitamin D, the output of calcium and phosphate by

2002.

the lactating mammae will often be much greater than

Labbok MH, Clark D, Goldman AS: Breastfeeding: main-

the intake of these substances. To supply the needed

taining an irreplaceable immunological resource. Nat Rev

calcium and phosphate, the parathyroid glands enlarge

Immunol 4:565, 2004.

greatly, and the bones become progressively decalci-

MacLaughlin DT, Donahoe PK: Sex determination and

fied. The mother’s bone decalcification is usually not a

differentiation. N Engl J Med 350:367, 2004.

big problem during pregnancy, but it can become more

Mastorakos G, Ilias I: Maternal and fetal hypothalamic-

important during lactation.

pituitary-adrenal axes during pregnancy and postpartum.

Ann N Y Acad Sci 997:136, 2003.

Moffett-King A: Natural killer cells and pregnancy. Nat Rev

Antibodies and Other Anti-infectious Agents in Milk. Not only

Immunol 2:656, 2002.

does milk provide the newborn baby with needed

Roberts JM, Cooper DW: Pathogenesis and genetics of

nutrients, but it also provides important protection

pre-eclampsia. Lancet 357:53, 2001.

against infection. For instance, multiple types of anti-

Roberts JM, Pearson G, Cutler J, Lindheimer M: Summary

bodies and other anti-infectious agents are secreted in

of the NHLBI Working Group on Research on Hyper-

milk along with the nutrients. Also, several different

tension During Pregnancy. Hypertension 41:437, 2003.

types of white blood cells are secreted, including both

Wu G, Bazer FW, Cudd TA, et al: Maternal nutrition and

neutrophils and macrophages, some of which are

fetal development. J Nutr 134:2169, 2004.

C H A P T E R

Fetal and Neonatal Physiology

A complete discussion of fetal development, function-

ing of the child immediately after birth, and growth and

development through the early years of life lies within

the province of formal courses in obstetrics and pedi-

atrics. However, many physiologic principles are pecu-

liar to the infant itself. This chapter discusses the more

important of these.

Growth and Functional Development

of the Fetus

Initial development of the placenta and fetal membranes occurs far more rapidly

than development of the fetus itself. In fact, during the first 2 to 3 weeks after

implantation of the blastocyst, the fetus remains almost microscopic, but thereafter,

as shown in Figure 83-1, the length of the fetus increases almost in proportion to

age. At 12 weeks, the length is about 10 centimeters; at 20 weeks, 25 centimeters;

and at term (40 weeks), 53 centimeters (about 21 inches). Because the weight of the

fetus is approximately proportional to the cube of length, the weight increases

almost in proportion to the cube of the age of the fetus.

Note in Figure 83-1 that the weight remains minuscule during the first 12 weeks

and reaches 1 pound only at 23 weeks (5 ¹/₂ months) of gestation. Then, during the

last trimester of pregnancy, the fetus gains tremendously, so that 2 months before

birth, the weight averages 3 pounds, 1 month before birth 4.5 pounds, and at birth

7 pounds—the final birth weight varying from as low as 4.5 pounds to as high as 11

pounds in normal infants with normal gestational periods.

Development of the Organ Systems

Within 1 month after fertilization of the ovum, the gross characteristics of all the

different organs of the fetus have already begun to develop, and during the next 2

to 3 months, most of the details of the different organs are established. Beyond

month 4, the organs of the fetus are grossly the same as those of the neonate.

However, cellular development in each organ is usually far from complete and

requires the full remaining 5 months of pregnancy for complete development. Even

at birth, certain structures, particularly in the nervous system, the kidneys, and the

liver, lack full development, as discussed in more detail later in the chapter.

Circulatory System. The human heart begins beating during the fourth week after fer-

tilization, contracting at a rate of about 65 beats/min. This increases steadily to about

140 beats/min immediately before birth.

Formation of Blood Cells. Nucleated red blood cells begin to be formed in the yolk sac

and mesothelial layers of the placenta at about the third week of fetal development.

This is followed 1 week later (at 4 to 5 weeks) by formation of non-nucleated red

blood cells by the fetal mesenchyme and also by the endothelium of the fetal blood

vessels. Then, at 6 weeks, the liver begins to form blood cells, and in the third month,

the spleen and other lymphoid tissues of the body begin forming blood cells. Finally,

from the third month on, the bone marrow gradually becomes the principal source

of the red blood cells as well as most of the white blood cells, except for continued

lymphocyte and plasma cell production in lymphoid tissue.

Respiratory System. Respiration cannot occur during fetal life because there is no air

to breathe in the amniotic cavity. However, attempted respiratory movements do

take place beginning at the end of the first trimester of pregnancy. Tactile stimuli

and fetal asphyxia especially cause these attempted respiratory movements.

1042

Chapter 83

Fetal and Neonatal Physiology

1043

Length

Iron

250

Weight

Calcium

Phosphorus

200

150

100

Age of fetus (weeks after last menstruation)

Figure 83-1

Figure 83-2

Growth of the fetus.

Iron, calcium, and phosphorus storage in the fetus at different

stages of gestation.

During the last 3 to 4 months of pregnancy, the res-

piratory movements of the fetus are mainly inhibited,

for reasons unknown, and the lungs remain almost com-

and do not reach full development until a few months

pletely deflated. The inhibition of respiration during the

after birth.

later months of fetal life prevents filling of the lungs

with fluid and debris from the meconium excreted by

Fetal Metabolism. The fetus uses mainly glucose for

the fetus’s gastrointestinal tract into the amniotic fluid.

energy, and it has a high capability to store fat and

Also, small amounts of fluid are secreted into the lungs

protein, much if not most of the fat being synthesized

by the alveolar epithelium up until the moment of birth,

from glucose rather than being absorbed directly from

thus keeping only clean fluid in the lungs.

the mother’s blood. In addition to these generalities,

there are special problems of fetal metabolism in rela-

Nervous System. Most of the reflexes of the fetus that

tion to calcium, phosphate, iron, and some vitamins.

involve the spinal cord and even the brain stem are

present by the third to fourth months of pregnancy.

Metabolism of Calcium and Phosphate. Figure 83-2 shows

However, those nervous system functions that involve

the rates of calcium and phosphate accumulation in the

the cerebral cortex are still only in the early stages of

fetus, demonstrating that about 22.5 grams of calcium

development even at birth. Indeed, myelinization of

and 13.5 grams of phosphorus are accumulated in the

some major tracts of the brain itself becomes complete

average fetus during gestation. About one half of these

only after about 1 year of postnatal life.

accumulate during the last 4 weeks of gestation, which

is coincident with the period of rapid ossification of the

Gastrointestinal. Tract By midpregnancy, the fetus begins

fetal bones and with the period of rapid weight gain of

to ingest and absorb large quantities of amniotic fluid,

the fetus.

and during the last

2 to

3 months, gastrointestinal

During the earlier part of fetal life, the bones are

function approaches that of the normal neonate. By

relatively unossified and have mainly a cartilaginous

that time, small quantities of meconium are continually

matrix. Indeed x-ray films ordinarily do not show any

formed in the gastrointestinal tract and excreted from

ossification until after the fourth month of pregnancy.

the anus into the amniotic fluid. Meconium is composed

Note especially that the total amounts of calcium and

partly of residue from swallowed amniotic fluid and

phosphate needed by the fetus during gestation repre-

partly of mucus and other residues of excretory prod-

sent only about 2 per cent of the quantities of these

ucts from the gastrointestinal mucosa and glands.

substances in the mother’s bones. Therefore, this is a

minimal drain from the mother. Much greater drain

Kidneys. The fetal kidneys begin to excrete urine during

occurs after birth during lactation.

the second trimester pregnancy, and fetal urine accounts

for about 70 to 80 per cent of the amniotic fluid. Abnor-

Accumulation of Iron. Figure 83-2 also shows that iron

mal kidney development or severe impairment of

accumulates in the fetus even more rapidly than calcium

kidney function in the fetus greatly reduce the forma-

and phosphate. Most of the iron is in the form of

tion of amniotic fluid (oligohydramnios) and can lead to

hemoglobin, which begins to be formed as early as the

fetal death.

third week after fertilization of the ovum.

Although the fetal kidneys form urine, the renal

Small amounts of iron are concentrated in the

control systems for regulating fetal extracellular fluid

mother’s uterine progestational endometrium even

volume and electrolyte balances, and especially acid-

before implantation of the ovum; this iron is ingested

base balance, are almost nonexistent until late fetal life

into the embryo by the trophoblastic cells and is used

1044

Unit XIV Endocrinology and Reproduction

to form the very early red blood cells. About one third

progressively more hypoxic and hypercapnic, which

of the iron in a fully developed fetus is normally stored

provides additional stimulus to the respiratory center

in the liver. This iron can then be used for several

and usually causes breathing within an additional

months after birth by the neonate for formation of addi-

minute after birth.

tional hemoglobin.

Delayed or Abnormal Breathing at Birth—Danger of Hypoxia. If

Utilization and Storage of Vitamins. The fetus needs vitamins

the mother has been depressed by a general anesthetic

equally as much as the adult and in some instances to a

during delivery, which at least partially anesthetizes

far greater extent. In general, the vitamins function the

the fetus as well, the onset of respiration is likely to be

same in the fetus as in the adult, as discussed in Chapter

delayed for several minutes, thus demonstrating the

71. Special functions of several vitamins should be

importance of using as little anesthesia as feasible. Also,

mentioned, however.

many infants who have had head trauma during deliv-

The B vitamins, especially vitamin B₁₂ and folic acid,

ery or who undergo prolonged delivery are slow to

are necessary for formation of red blood cells and

breathe or sometimes do not breathe at all. This can

nervous tissue, as well as for overall growth of the fetus.

result from two possible effects: First, in a few infants,

Vitamin C is necessary for appropriate formation of

intracranial hemorrhage or brain contusion causes a

intercellular substances, especially the bone matrix and

concussion syndrome with a greatly depressed respira-

fibers of connective tissue.

tory center. Second, and probably much more impor-

Vitamin D is needed for normal bone growth in the

tant, prolonged fetal hypoxia during delivery can cause

fetus, but even more important, the mother needs it for

serious depression of the respiratory center.

adequate absorption of calcium from her gastrointesti-

Hypoxia frequently occurs during delivery because of

nal tract. If the mother has plenty of this vitamin in her

(1) compression of the umbilical cord; (2) premature

body fluids, large quantities of the vitamin will be stored

separation of the placenta; (3) excessive contraction of

by the fetal liver to be used by the neonate for several

the uterus, which can cut off the mother’s blood flow to

months after birth.

the placenta; or (4) excessive anesthesia of the mother,

Vitamin E, although the mechanisms of its functions

which depresses oxygenation even of her blood.

are not clear, is necessary for normal development of

the early embryo. In its absence in laboratory animals,

Degree of Hypoxia That an Infant Can Tolerate. In an adult,

spontaneous abortion usually occurs at an early stage of

failure to breathe for only 4 minutes often causes death,

pregnancy.

but a neonate often survives as long as 10 minutes of

Vitamin K is used by the fetal liver for formation of

failure to breathe after birth. Permanent and very

Factor VII, prothrombin, and several other blood coag-

serious brain impairment often ensues if breathing is

ulation factors. When vitamin K is insufficient in the

delayed more than 8 to 10 minutes. Indeed, actual

mother, Factor VII and prothrombin become deficient

lesions develop mainly in the thalamus, in the inferior

in the fetus as well as in the mother. Because most

colliculi, and in other brain stem areas, thus permanently

vitamin K is formed by bacterial action in the mother’s

affecting many of the motor functions of the body.

colon, the neonate has no adequate source of vitamin K

for the first week or so of life after birth until normal

Expansion of the Lungs at Birth. At birth, the walls of the

colonic bacterial flora become established in the

alveoli are at first collapsed because of the surface

newborn infant. Therefore, prenatal storage in the fetal

tension of the viscid fluid that fills them. More than

liver of at least small amounts of vitamin K derived from

25 mm Hg of negative inspiratory pressure in the lungs

the mother is helpful in preventing fetal hemorrhage,

is usually required to oppose the effects of this surface

particularly hemorrhage in the brain when the head is

tension and to open the alveoli for the first time. But

traumatized by squeezing through the birth canal.

once the alveoli do open, further respiration can be

effected with relatively weak respiratory movements.

Fortunately, the first inspirations of the normal neonate

Adjustments of the Infant

are extremely powerful, usually capable of creating as

much as 60 mm Hg negative pressure in the intrapleural

to Extrauterine Life

space.

Figure

83-3 shows the tremendous negative

Onset of Breathing

intrapleural pressures required to open the lungs at

The most obvious effect of birth on the baby is loss of

the onset of breathing. At the top is shown the pres-

the placental connection with the mother and, there-

sure-volume curve (“compliance” curve) for the first

fore, loss of this means of metabolic support. One of the

breath after birth. Observe, first, the lower part of

most important immediate adjustments required of the

the curve beginning at the zero pressure point and

infant is to begin breathing.

moving to the right. The curve shows that the volume of

air in the lungs remains almost exactly zero until the

Cause of Breathing at Birth. After normal delivery from a

negative pressure has reached -40 centimeters water

mother who has not been depressed by anesthetics, the

(-30 mm Hg). Then, as the negative pressure increases

child ordinarily begins to breathe within seconds and

to -60 centimeters of water, about 40 milliliters of air

has a normal respiratory rhythm within less than 1

enters the lungs. To deflate the lungs, considerable pos-

minute after birth. The promptness with which the fetus

itive pressure, about

+40 centimeters of water, is

begins to breathe indicates that breathing is initiated by

required because of viscous resistance offered by the

sudden exposure to the exterior world, probably result-

fluid in the bronchioles.

ing from (1) a slightly asphyxiated state incident to the

Note that the second breath is much easier, with far

birth process, but also from (2) sensory impulses that

less negative and positive pressures required. Breathing

originate in the suddenly cooled skin. In an infant who

does not become completely normal until about 40

does not breathe immediately, the body becomes

minutes after birth, as shown by the third compliance

Chapter 83

Fetal and Neonatal Physiology

1045

One of the most characteristic findings in respiratory

distress syndrome is failure of the respiratory epithe-

First Breath

lium to secrete adequate quantities of surfactant, a sub-

stance normally secreted into the alveoli that decreases

the surface tension of the alveolar fluid, therefore allow-

ing the alveoli to open easily during inspiration. The sur-

factant-secreting cells (type II alveolar epithelial cells)

do not begin to secrete surfactant until the last 1 to 3

months of gestation. Therefore, many premature babies

and a few full-term babies are born without the capa-

bility to secrete sufficient surfactant, which causes both

a collapse tendency of the alveoli and development of

+40

+20

-20

-40

-60

pulmonary edema. The role of surfactant in preventing

Pressure

these effects is discussed in Chapter 37.

Second Breath

Circulatory Readjustments at Birth

Equally as essential as the onset of breathing at birth

are immediate circulatory adjustments that allow ade-

quate blood flow through the lungs. Also, circulatory

adjustments during the first few hours of life cause more

and more blood flow through the baby’s liver, which up

to this point has had very little blood flow. To describe

these readjustments, we must first consider the anatom-

+40

+20

-20

-40

-60

Pressure

ical structure of the fetal circulation.

40 Minutes

Specific Anatomical Structure of the Fetal Circulation. Because

the lungs are mainly nonfunctional during fetal life and

because the liver is only partially functional, it is not

necessary for the fetal heart to pump much blood

through either the lungs or the liver. However, the fetal

heart must pump large quantities of blood through the

placenta. Therefore, special anatomical arrangements

cause the fetal circulatory system to operate much

differently from that of the newborn baby.

First, as shown in Figure 83-4, blood returning from

+40

+20

-20

-40

-60

the placenta through the umbilical vein passes through

Pressure

the ductus venosus, mainly bypassing the liver. Then

most of the blood entering the right atrium from the

inferior vena cava is directed in a straight pathway

across the posterior aspect of the right atrium and

Figure 83-3

through the foramen ovale directly into the left atrium.

Thus, the well-oxygenated blood from the placenta

Pressure-volume curves of the lungs (“compliance” curves) of a

enters mainly the left side of the heart, rather than the

neonate immediately after birth, showing the extreme forces

right side, and is pumped by the left ventricle mainly

required for breathing during the first two breaths of life and devel-

opment of a nearly normal compliance curve within 40 minutes

into the arteries of the head and forelimbs.

after birth.

(Redrawn from Smith CA: The first breath. Sci Am

The blood entering the right atrium from the supe-

209:32,

rior vena cava is directed downward through the tri-

reserved.)

cuspid valve into the right ventricle. This blood is mainly

deoxygenated blood from the head region of the fetus,

and it is pumped by the right ventricle into the pul-

curve, the shape of which compares favorably with that

monary artery and then mainly through the ductus arte-

for the normal adult, as shown in Chapter 38.

riosus into the descending aorta, then through the two

umbilical arteries into the placenta, where the deoxy-

Respiratory Distress Syndrome Caused When Surfactant Secretion

genated blood becomes oxygenated.

Is Deficient. A small number of infants, especially pre-

Figure 83-5 gives the relative percentages of the total

mature infants and infants born of diabetic mothers,

blood pumped by the heart that pass through the dif-

develop severe respiratory distress in the early hours to

ferent vascular circuits of the fetus. This figure shows

the first several days after birth, and some die within the

that 55 per cent of all the blood goes through the pla-

next day or so. The alveoli of these infants at death

centa, leaving only 45 per cent to pass through all the

contain large quantities of proteinaceous fluid, almost

tissues of the fetus. Furthermore, during fetal life, only

as if pure plasma had leaked out of the capillaries into

12 per cent of the blood flows through the lungs; imme-

the alveoli. The fluid also contains desquamated alveo-

diately after birth, virtually all the blood flows through

lar epithelial cells. This condition is called hyaline mem-

the lungs.

brane disease because microscopic slides of the lung

show the material filling the alveoli to look like a

Changes in the Fetal Circulation at Birth. The basic changes

hyaline membrane.

in the fetal circulation at birth are discussed in

1046

Unit XIV Endocrinology and Reproduction

Superior

vena cava

Aorta

Ductus arteriosus

Forequarters

Ductus

arteriosus

Lung

Right

atrium

ventricle

Lungs

Foramen ovale

Left

Ductus arteriosus

atrium

ventricle

Liver

Foramen

ovale

Hindquarters

Gut

Umbilical

vein

Placenta

Umbilical

arteries

Figure 83-5

Figure 83-4

Diagram of the fetal circulatory system, showing relative distribu-

tion of blood flow to the different vascular areas. The numerals

Organization of

the

fetal

circulation.

(Modified from Arey LB:

represent the percentage of the total output from both sides of the

Developmental Anatomy: A Textbook and Laboratory Manual of

heart flowing through each particular area.

Embryology. 7th ed. Philadelphia: WB Saunders Co, 1974.)

Chapter 23 in relation to congenital anomalies of the

and systemic resistances at birth cause blood now to

ductus arteriosus and foramen ovale that persist

attempt to flow backward through the foramen ovale;

throughout life in a few persons. Briefly, these changes

that is, from the left atrium into the right atrium, rather

are the following.

than in the other direction, as occurred during fetal life.

Consequently, the small valve that lies over the foramen

Primary Changes in Pulmonary and Systemic Vascular

ovale on the left side of the atrial septum closes over

Resistances at Birth

this opening, thereby preventing further flow through

The primary changes in the circulation at birth are, first,

the foramen ovale.

loss of the tremendous blood flow through the placenta,

In two thirds of all people, the valve becomes adher-

which approximately doubles the systemic vascular

ent over the foramen ovale within a few months to a few

resistance at birth. This increases the aortic pressure as

years and forms a permanent closure. But even if per-

well as the pressures in the left ventricle and left atrium.

manent closure does not occur, the left atrial pressure

Second, the pulmonary vascular resistance greatly

throughout life normally remains 2 to 4 mm Hg greater

decreases as a result of expansion of the lungs. In the

than the right atrial pressure, and the backpressure

unexpanded fetal lungs, the blood vessels are com-

keeps the valve closed.

pressed because of the small volume of the lungs. Imme-

diately on expansion, these vessels are no longer

Closure of the Ductus Arteriosus

compressed and the resistance to blood flow decreases

The ductus arteriosus also closes, but for different

severalfold. Also, in fetal life, the hypoxia of the lungs

reasons. First, the increased systemic resistance elevates

causes considerable tonic vasoconstriction of the lung

the aortic pressure while the decreased pulmonary

blood vessels, but vasodilation takes place when aera-

resistance reduces the pulmonary arterial pressure. As a

tion of the lungs eliminates the hypoxia. All these

consequence, after birth, blood begins to flow backward

changes together reduce the resistance to blood flow

from the aorta into the pulmonary artery through the

through the lungs as much as fivefold, which reduces the

ductus arteriosus, rather than in the other direction as

pulmonary arterial pressure, right ventricular pressure,

in fetal life. However, after only a few hours, the muscle

and right atrial pressure.

wall of the ductus arteriosus constricts markedly, and

Closure of the Foramen Ovale

within 1 to 8 days, the constriction is usually sufficient

The low right atrial pressure and the high left atrial pres-

to stop all blood flow. This is called functional closure

sure that occur secondarily to the changes in pulmonary

of the ductus arteriosus. Then, during the next 1 to

Chapter 83

Fetal and Neonatal Physiology

1047

4 months, the ductus arteriosus ordinarily becomes

systems. This results partly from immature development

anatomically occluded by growth of fibrous tissue into

of the different organs of the body and partly from the

its lumen.

fact that the control systems simply have not become

The cause of ductus arteriosus closure relates to the

adjusted to the new way of life.

increased oxygenation of the blood flowing through the

ductus. In fetal life the PO₂ of the ductus blood is only

15 to 20 mm Hg, but it increases to about 100 mm Hg

Respiratory System

within a few hours after birth. Furthermore, many

The normal rate of respiration in a neonate is about 40

experiments have shown that the degree of contraction

breaths per minute, and tidal air with each breath aver-

of the smooth muscle in the ductus wall is highly related

ages 16 milliliters. This gives a total minute respiratory

to this availability of oxygen.

volume of 640 ml/min, which is about twice as great in

In one of several thousand infants, the ductus fails to

relation to the body weight as that of an adult. The func-

close, resulting in a patent ductus arteriosus, the conse-

tional residual capacity of the infant’s lungs is only one

quences of which are discussed in Chapter 23. The

half that of an adult in relation to body weight. This

failure of closure has been postulated to result from

difference causes excessive cyclical increases and

excessive ductus dilation caused by vasodilating

decreases in the newborn baby’s blood gas concentra-

prostaglandins in the ductus wall. In fact, administration

tions if the respiratory rate becomes slowed because it

of the drug indomethacin, which blocks synthesis of

is the residual air in the lungs that smooths out the

prostaglandins, often leads to closure.

blood gas variations.

Closure of the Ductus Venosus In fetal life, the portal blood

from the fetus’s abdomen joins the blood from the

umbilical vein, and these together pass by way of the

Circulation

ductus venosus directly into the vena cava immediately

Blood Volume. The blood volume of a neonate immedi-

below the heart but above the liver, thus bypassing the

ately after birth averages about 300 milliliters, but if the

liver.

infant is left attached to the placenta for a few minutes

Immediately after birth, blood flow through the

after birth or if the umbilical cord is stripped to force

umbilical vein ceases, but most of the portal blood

blood out of its vessels into the baby, an additional 75

still flows through the ductus venosus, with only a small

milliliters of blood enters the infant, to make a total of

amount passing through the channels of the liver.

375 milliliters. Then, during the ensuing few hours, fluid

However, within 1 to 3 hours the muscle wall of the

is lost into the neonate’s tissue spaces from this blood,

ductus venosus contracts strongly and closes this avenue

which increases the hematocrit but returns the blood

of flow. As a consequence, the portal venous pressure

volume once again to the normal value of about 300 mil-

rises from near 0 to 6 to 10 mm Hg, which is enough to

liliters. Some pediatricians believe that this extra blood

force portal venous blood flow through the liver sinuses.

volume caused by stripping the umbilical cord can lead

Although the ductus venosus rarely fails to close, we

to mild pulmonary edema with some degree of respira-

know almost nothing about what causes the closure.

tory distress, but the extra red blood cells are often very

valuable to the infant.

Nutrition of the Neonate

Cardiac Output. The cardiac output of the neonate

Before birth, the fetus derives almost all its energy from

averages 500 ml/min, which, like respiration and body

glucose obtained from the mother’s blood. After birth,

metabolism, is about twice as much in relation to body

the amount of glucose stored in the infant’s body in the

weight as in the adult. Occasionally a child is born with

form of liver and muscle glycogen is sufficient to supply

an especially low cardiac output caused by hemorrhage

the infant’s needs for only a few hours. The liver of the

of much of its blood volume from the placenta at birth.

neonate is still far from functionally adequate at birth,

which prevents significant gluconeogenesis. Therefore,

Arterial Pressure. The arterial pressure during the first

the infant’s blood glucose concentration frequently falls

day after birth averages about 70 mm Hg systolic and

the first day to as low as 30 to 40 mg/dl of plasma, less

50 mm Hg diastolic; this increases slowly during the

than one half the normal value. Fortunately, however,

next several months to about 90/60. Then there is a

appropriate mechanisms are available for the infant to

much slower rise during the subsequent years until the

use its stored fats and proteins for metabolism until

adult pressure of 115/70 is attained at adolescence.

mother’s milk can be provided 2 to 3 days later.

Special problems are also frequently associated with

Blood Characteristics. The red blood cell count in the

getting an adequate fluid supply to the neonate because

neonate averages about 4 million per cubic millimeter.

the infant’s rate of body fluid turnover averages seven

If blood is stripped from the cord into the infant, the red

times that of an adult, and the mother’s milk supply

blood cell count rises an additional 0.5 to 0.75 million

requires several days to develop. Ordinarily, the infant’s

during the first few hours of life, giving a red blood cell

weight decreases 5 to 10 per cent and sometimes as

count of about 4.75 million per cubic millimeter, as

much as 20 per cent within the first 2 to 3 days of life.

shown in Figure 83-6. Subsequent to this, however, few

Most of this weight loss is loss of fluid rather than of

new red blood cells are formed in the infant during the

body solids.

first few weeks of life, presumably because the hypoxic

stimulus of fetal life is no longer present to stimulate

Special Functional Problems

red cell production. Thus, as shown in Figure 83-6, the

average red blood cell count falls to less than 4 million

in the Neonate

per cubic millimeter by about 6 to 8 weeks of age. From

An important characteristic of the neonate is instability

that time on, increasing activity by the baby provides

of the various hormonal and neurogenic control

the appropriate stimulus for returning the red blood cell

1048

Unit XIV Endocrinology and Reproduction

Fluid Balance, Acid-Base Balance,

and Renal Function

The rate of fluid intake and fluid excretion in the

newborn infant is seven times as great in relation to

Red blood count

weight as in the adult, which means that even a slight

percentage alteration of fluid intake or fluid output can

cause rapidly developing abnormalities.

The rate of metabolism in the infant is also twice as

great in relation to body mass as in the adult, which

means that twice as much acid is normally formed,

which gives a tendency toward acidosis in the infant.

Bilirubin

Functional development of the kidneys is not complete

until the end of about the first month of life. For

instance, the kidneys of the neonate can concentrate

urine to only 1.5 times the osmolality of the plasma

Age in weeks

instead of the adult three to four times. Therefore, con-

sidering the immaturity of the kidneys, together with the

marked fluid turnover in the infant and rapid formation

of acid, one can readily understand that among the most

Figure 83-6

important problems of infancy are acidosis, dehydra-

tion, and, more rarely, overhydration.

Changes in the red blood cell count and in serum bilirubin con-

centration during the first 16 weeks of life, showing physiologic

Liver Function

anemia at 6 to 12 weeks of life and physiologic hyperbilirubine-

mia during the first 2 weeks of life.

During the first few days of life, liver function in the

neonate may be quite deficient, as evidenced by the

following effects:

1. The liver of the neonate conjugates bilirubin with

glucuronic acid poorly and therefore excretes

bilirubin only slightly during the first few days of

life.

count to normal within another 2 to 3 months. Immedi-

2. The liver of the neonate is deficient in forming

ately after birth, the white blood cell count of the

plasma proteins, so that the plasma protein

neonate is about 45,000 per cubic millimeter, which is

concentration falls during the first weeks of life to

about five times as great as that of the normal adult.

15 to 20 per cent less than that for older children.

Occasionally the protein concentration falls so low

Neonatal Jaundice and Erythroblastosis Fetalis. Biliru-

that the infant develops hypoproteinemic edema.

bin formed in the fetus can cross the placenta into

3. The gluconeogenesis function of the liver is

the mother and be excreted through the liver of the

particularly deficient. As a result, the blood glucose

mother, but immediately after birth, the only means

level of the unfed neonate falls to about 30 to 40

for ridding the neonate of bilirubin is through the

mg/dl (about 40 per cent of normal), and the infant

neonate’s own liver, which for the first week or so of life

must depend mainly on its stored fats for energy

functions poorly and is incapable of conjugating signi-

until sufficient feeding can occur.

ficant quantities of bilirubin with glucuronic acid for

4. The liver of the neonate usually also forms too

excretion into the bile. Consequently, the plasma biliru-

little of the blood factors needed for normal blood

bin concentration rises from a normal value of less than

coagulation.

1 mg/dl to an average of 5 mg/dl during the first 3 days

of life and then gradually falls back to normal as the

liver becomes functional. This effect, called physiologic

Digestion, Absorption, and

hyperbilirubinemia, is shown in Figure

83-6, and it

Metabolism of Energy Foods;

is associated with mild jaundice (yellowness) of the

and Nutrition

infant’s skin and especially of the sclerae of its eyes for

a week or two.

In general, the ability of the neonate to digest, absorb,

However, by far the most important abnormal cause

and metabolize foods is no different from that of the

of serious neonatal jaundice is erythroblastosis fetalis,

older child, with the following three exceptions.

which is discussed in detail in Chapter 32 in relation

First, secretion of pancreatic amylase in the neonate

to Rh factor incompatibility between the fetus and

is deficient, so that the neonate uses starches less ade-

mother. Briefly, the erythroblastotic baby inherits Rh-

quately than do older children.

positive red cells from the father, while the mother is

Second, absorption of fats from the gastrointestinal

Rh negative. The mother then becomes immunized

tract is somewhat less than that in the older child. Con-

against the Rh-positive factor (a protein) in the fetus’s

sequently, milk with a high fat content, such as cow’s

blood cells, and her antibodies destroy fetal red cells,

milk, is frequently inadequately absorbed.

releasing extreme quantities of bilirubin into the fetus’s

Third, because the liver functions imperfectly during

plasma and often causing fetal death for lack of ade-

at least the first week of life, the glucose concentration

quate red cells. Before the advent of modern obstetri-

in the blood is unstable and low.

cal therapeutics, this condition occurred either mildly or

The neonate is especially capable of synthesizing and

seriously in 1 of every 50 to 100 neonates.

storing proteins. Indeed, with an adequate diet, as much

Chapter 83

Fetal and Neonatal Physiology

1049

Necessity for Iron in the Diet

If the mother has had adequate amounts of iron in her

diet, the liver of the infant usually has stored enough

Birth

iron to keep forming blood cells for 4 to 6 months after

birth. But if the mother has had insufficient iron in her

diet, severe anemia is likely to occur in the infant after

about 3 months of life. To prevent this possibility, early

feeding of the infant with egg yolk, which contains rea-

sonably large quantities of iron, or the administration of

iron in some other form is desirable by the second or

third month of life.

Vitamin C Deficiency in Infants

Ascorbic acid (vitamin C) is not stored in significant

8 1012 2

8 1012 14 16 18 20

quantities in the fetal tissues; yet it is required for

proper formation of cartilage, bone, and other intercel-

Hours after birth

Days after birth

lular structures of the infant. Furthermore, milk has

poor supplies of ascorbic acid, especially cow’s milk,

which has only one fourth as much as human milk. For

this reason, orange juice or other sources of ascorbic

Figure 83-7

acid are often prescribed by the third week of life.

Fall in body temperature of the neonate immediately after birth,

and instability of body temperature during the first few days of life.

Immunity

The neonate inherits much immunity from the mother

because many protein antibodies diffuse from the

mother’s blood through the placenta into the fetus.

as 90 per cent of the ingested amino acids are used for

However, the neonate does not form antibodies of its

formation of body proteins. This is a much higher per-

own to a significant extent. By the end of the first month,

centage than in adults.

the baby’s gamma globulins, which contain the anti-

bodies, have decreased to less than one half the original

Metabolic Rate and Body Temperature. The normal meta-

level, with a corresponding decrease in immunity. There-

bolic rate of the neonate in relation to body weight is

after, the baby’s own immunity system begins to form

about twice that of the adult, which accounts also for

antibodies, and the gamma globulin concentration

the twice as great cardiac output and twice as great

returns essentially to normal by the age of 12 to 20

minute respiratory volume in relation to body weight in

months.

the infant.

Despite the decrease in gamma globulins soon after

Because the body surface area is large in relation to

birth, the antibodies inherited from the mother protect

body mass, heat is readily lost from the body. As a result,

the infant for about 6 months against most major child-

the body temperature of the neonate, particularly of

hood infectious diseases, including diphtheria, measles,

premature infants, falls easily. Figure 83-7 shows that

and polio. Therefore, immunization against these

the body temperature of even a normal infant often falls

diseases before

6 months is usually unnecessary.

several degrees during the first few hours after birth but

Conversely, the inherited antibodies against whooping

returns to normal in 7 to 10 hours. Still, the body tem-

cough are normally insufficient to protect the neonate;

perature regulatory mechanisms remain poor during

therefore, for full safety, the infant requires immuniza-

the early days of life, allowing marked deviations in

tion against this disease within the first month or so of

temperature, which are also shown in Figure 83-7.

life.

Nutritional Needs During the Early Weeks of Life. At birth, a

Allergy. The newborn infant is seldom subject to allergy.

neonate is usually in complete nutritional balance, pro-

Several months later, however, when the infant’s own

vided the mother has had an adequate diet. Further-

antibodies first begin to form, extreme allergic states

more, function of the gastrointestinal system is usually

can develop, often resulting in serious eczema, gas-

more than adequate to digest and assimilate all the

trointestinal abnormalities, and even anaphylaxis. As

nutritional needs of the infant if appropriate nutrients

the child grows older and still higher degrees of immu-

are provided in the diet. However, three specific prob-

nity develop, these allergic manifestations usually dis-

lems do occur in the early nutrition of the infant.

appear. This relation of immunity to allergy is discussed

in Chapter 34.

Need for Calcium and Vitamin D

The neonate is in a stage of rapid ossification of its

bones at birth, so that a ready supply of calcium

Endocrine Problems

throughout infancy is needed. This is ordinarily supplied

adequately by the usual diet of milk. Yet absorption of

Ordinarily, the endocrine system of the infant is highly

calcium by the gastrointestinal tract is poor in the

developed at birth, and the infant seldom exhibits any

absence of vitamin D. Therefore, the vitamin D-

immediate endocrine abnormalities. However, there are

deficient infant can develop severe rickets in only a few

special instances in which the endocrinology of infancy

weeks. This is particularly true in premature babies

is important:

because their gastrointestinal tracts absorb calcium

1. If a pregnant mother bearing a female child is

even less effectively than those of normal infants.

treated with an androgenic hormone or if an

1050

Unit XIV Endocrinology and Reproduction

androgenic tumor develops during pregnancy,

under the following two headings: (1) immaturity of

the child will be born with a high degree of

certain organ systems and (2) instability of the different

masculinization of her sexual organs, thus resulting

homeostatic control systems. Because of these effects, a

in a type of hermaphroditism.

premature baby seldom lives if it is born more than 3

The sex hormones secreted by the placenta and by

months before term.

the mother’s glands during pregnancy occasionally

cause the neonate’s breasts to form milk

during the first days of life. Sometimes the breasts

Immature Development of the

then become inflamed, or infectious mastitis

Premature Infant

develops.

An infant born of an untreated diabetic mother will

Almost all the organ systems of the body are immature

have considerable hypertrophy and hyperfunction

in the premature infant, but some require particular

of the islets of Langerhans in the pancreas.

attention if the life of the premature baby is to be saved.

As a consequence, the infant’s blood glucose

concentration may fall to lower than 20 mg/dl

Respiration. The respiratory system is especially likely to

shortly after birth. Fortunately, however, in the

be underdeveloped in the premature infant. The vital

neonate, unlike in the adult, insulin shock or coma

capacity and the functional residual capacity of the

from this low level of blood glucose concentration

lungs are especially small in relation to the size of the

only rarely develops.

infant. Also, surfactant secretion is depressed or absent.

Maternal type II diabetes is the most common

As a consequence, respiratory distress syndrome is a

cause of large babies. Type II diabetes in the

common cause of death. Also, the low functional resid-

mother is associated with resistance to the

ual capacity in the premature infant is often associated

metabolic effects of insulin and compensatory

with periodic breathing of the Cheyne-Stokes type.

increases in plasma insulin concentration. The high

levels of insulin are believed to stimulate fetal

Gastrointestinal Function. Another major problem of the

growth factor and contribute to increased birth

premature infant is to ingest and absorb adequate food.

weight. Increased supply of glucose and other

If the infant is more than 2 months premature, the

nutrients to the fetus may also contribute to

digestive and absorptive systems are almost always

increased fetal growth. However, most of the

inadequate. The absorption of fat is so poor that the pre-

increased fetal weight is due to increased body fat;

mature infant must have a low-fat diet. Furthermore,

there is usually little increase in body length

the premature infant has unusual difficulty in absorbing

although the size of some organs may be increased

calcium and, therefore, can develop severe rickets

(organomegaly).

before the difficulty is recognized. For this reason,

In the mother with uncontrolled type I diabetes

special attention must be paid to adequate calcium and

(caused by lack of insulin secretion), fetal growth

vitamin D intake.

may be stunted because of metabolic deficits in the

mother, and growth and tissue maturation of the

Function of Other Organs. Immaturity of other organ

neonate are often impaired. Also, there is a high

systems that frequently causes serious difficulties in the

rate of intrauterine mortality, and among those

premature infant includes (1) immaturity of the liver,

fetuses that do come to term, there is still a high

which results in poor intermediary metabolism and

mortality rate. Two thirds of the infants who die

often a bleeding tendency as a result of poor formation

succumb to respiratory distress syndrome, described

of coagulation factors; (2) immaturity of the kidneys,

earlier in the chapter.

which are particularly deficient in their ability to rid the

Occasionally a child is born with hypofunctional

body of acids, thereby predisposing to acidosis as well

adrenal cortices, often resulting from agenesis of

as to serious fluid balance abnormalities; (3) immaturity

the adrenal glands or exhaustion atrophy, which can

of the blood-forming mechanism of the bone marrow,

occur when the adrenal glands have been vastly

which allows rapid development of anemia; and (4)

overstimulated.

depressed formation of gamma globulin by the lym-

If a pregnant woman has hyperthyroidism or is

phoid system, which often leads to serious infection.

treated with excess thyroid hormone, the infant is

likely to be born with a temporarily hyposecreting

thyroid gland. Conversely, if before pregnancy a

Instability of the Homeostatic

woman had had her thyroid gland removed, her

Control Systems in the

pituitary gland may secrete great quantities of

Premature Infant

thyrotropin during gestation, and the child might be

born with temporary hyperthyroidism.

Immaturity of the different organ systems in the pre-

In a fetus lacking thyroid hormone secretion, the

mature infant creates a high degree of instability in the

bones grow poorly and there is mental retardation.

homeostatic mechanisms of the body. For instance, the

This causes the condition called cretin dwarfism,

acid-base balance can vary tremendously, particularly

discussed in Chapter 76.

when the rate of food intake varies from time to time.

Likewise, the blood protein concentration is usually low

because of immature liver development, often leading

Special Problems

to hypoproteinemic edema. And inability of the infant

to regulate its calcium ion concentration frequently

of Prematurity

brings on hypocalcemic tetany. Also, the blood glucose

All the problems in neonatal life just noted are severely

concentration can vary between the extremely wide

exacerbated in prematurity. They can be categorized

limits of 20 to more than 100 mg/dl, depending princi-

Chapter 83

Fetal and Neonatal Physiology

1051

pally on the regularity of feeding. It is no wonder, then,

with these extreme variations in the internal environ-

ment of the premature infant, that mortality is high.

Instability of Body Temperature. One of the particular prob-

lems of the premature infant is inability to maintain

normal body temperature. Its temperature tends to

approach that of its surroundings. At normal room

temperature, the infant’s temperature may stabilize in

the low 90°s or even in the 80°s F. Statistical studies

show that a body temperature maintained below 96°F

(35.5°C) is associated with a particularly high incidence

of death, which explains the almost mandatory use of

the incubator in treatment of prematurity.

Boys

Girls

Danger of Blindness Caused

by Excess Oxygen Therapy

in the Premature Infant

8 12 16 20 24 4

Because premature infants frequently develop respira-

tory distress, oxygen therapy has often been used in

Age in months

Age in years

treating prematurity. However, it has been discovered

that use of excess oxygen in treating premature infants,

especially in early prematurity, can lead to blindness.

The reason is that too much oxygen stops the growth of

Figure 83-8

new blood vessels in the retina. Then when oxygen

Average height of boys and girls from infancy to 20 years of age.

therapy is stopped, the blood vessels try to make up for

lost time and burst forth with a great mass of vessels

growing all through the vitreous humor, blocking light

from the pupil to the retina. And still later, the vessels

are replaced with a mass of fibrous tissue where the

eye’s clear vitreous humor should be.

This condition, known as retrolental fibroplasia,

causes permanent blindness. For this reason, it is par-

Walks alone

ticularly important to avoid treatment of premature

infants with high concentrations of respiratory oxygen.

Stands alone

Physiologic studies indicate that the premature infant is

usually safe with up to 40 per cent oxygen in the air

Walks with support

breathed, but some child physiologists believe that com-

Pulls up

plete safety can be achieved only at normal oxygen con-

centration in the air that is breathed.

Grasps

Crawls

Growth and Development

Sits briefly

of the Child

Rolls over

The major physiologic problems of the child beyond the

neonatal period are related to special metabolic needs

for growth, which have been fully covered in the sec-

Hand control

tions of this book on metabolism and endocrinology.

Head control

Figure 83-8 shows the changes in heights of boys and

girls from the time of birth until the age of 20 years.

Vocalizes

Note especially that these parallel each other almost

Smiles

exactly until the end of the first decade of life. Between

the ages of 11 and 13 years, the female estrogens begin

Suckles

to be formed and cause rapid growth in height but early

Birth

uniting of the epiphyses of the long bones at about the

14th to 16th year of life, so that growth in height then

ceases. This contrasts with the effect of testosterone in

the male, which causes extra growth at a slightly later

Figure 83-9

age—mainly between ages 13 and 17 years. The male,

Behavioral development of the infant during the first year of life.

however, undergoes much more prolonged growth

because of much delayed uniting of the epiphyses, so

that his final height is considerably greater than that of

the female.

1052

Unit XIV Endocrinology and Reproduction

Behavioral Growth

Hilaire G, Duron B: Maturation of the mammalian respira-

tory system. Physiol Rev 79:325, 1999.

Behavioral growth is principally a problem of maturity

Holemans K, Aerts L, Van Assche FA: Lifetime conse-

of the nervous system. It is extremely difficult to

quences of abnormal fetal pancreatic development. J

dissociate maturity of the anatomical structures of the

Physiol 547:11, 2003.

nervous system from maturity caused by training.

Jensen BL, Stubbe J, Madsen K, et al: The renin-angiotensin

Anatomical studies show that certain major tracts in the

system in kidney development: role of COX-2 and adrenal

central nervous system are not completely myelinated

steroids. Acta Physiol Scand 181:549, 2004.

until the end of the first year of life. For this reason,

Johnson MH: Functional brain development in humans. Nat

it is frequently stated that the nervous system is not

Rev Neurosci 2:475, 2001.

fully functional at birth. The brain cortex and its associ-

Kanwar YS, Wada J, Lin S, Danesh FR, et al: Update of extra-

ated functions, such as vision, seem to require several

cellular matrix, its receptors, and cell adhesion molecules

months after birth for final functional development to

in mammalian nephrogenesis. Am J Physiol Renal Physiol

occur.

286:F202, 2004.

At birth, the infant brain mass is only 26 per cent of

Kovacs CS, Kronenberg HM: Maternal-fetal calcium and

the adult brain mass and 55 per cent at 1 year, but it

bone metabolism during pregnancy, puerperium, and

reaches almost adult proportions by the end of the

lactation. Endocr Rev 18:832, 1997.

second year. This is also associated with closure of the

Labbok MH, Clark D, Goldman AS: Breastfeeding: main-

fontanels and sutures of the skull, which allows only 20

taining an irreplaceable immunological resource. Nat Rev

per cent additional growth of the brain beyond the first

Immunol 4:565, 2004.

2 years of life. Figure 83-9 shows a normal progress

MacLellan WR, Schneider MD: Genetic dissection of

chart for the infant during the first year of life. Com-

cardiac growth control pathways. Annu Rev Physiol

parison of this chart with the baby’s actual development

62:289, 2000.

is used for clinical assessment of mental and behavioral

Matias A, Montenegro N, Areias JC, Leite LP: Haemody-

growth.

namic evaluation of the first trimester fetus with special

emphasis on venous return. Hum Reprod Update 6:177,

2000.

References

McMurtry IF: Pre- and postnatal lung development, matu-

ration, and plasticity. Am J Physiol Lung Cell Mol Physiol

Bissonnette JM: Mechanisms regulating hypoxic respiratory

282:L341, 2002.

depression during fetal and postnatal life. Am J Physiol

Olver RE, Walters DV, M Wilson S: Developmental regula-

Regul Integr Comp Physiol 278:R1391, 2000.

tion of lung liquid transport. Annu Rev Physiol 66:77,

Chen Y, Lasaitiene D, Friberg P: The renin-angiotensin

2004.

system in kidney development. Acta Physiol Scand

Ross MG, Nijland MJ: Development of ingestive behavior.

181:529, 2004.

Am J Physiol 274:R879, 1998.

Challis JRG, Matthews SG, Gibb W, Lye SJ: Endocrine and

Shannon JM, Hyatt BA: Epithelial-mesenchymal interac-

paracrine regulation of birth at term and preterm. Endocr

tions in the developing lung. Annu Rev Physiol 66:625,

Rev 21:514, 2000.

2004.

de Castro F: Chemotropic molecules: guides for axonal

Srivastava D: Genetic assembly of the heart: implications for

pathfinding and cell migration during CNS development.

congenital heart disease. Annu Rev Physiol 63:451, 2001.

News Physiol Sci 18:130, 2003.

Wood CE, Tong H: Central nervous system regulation of

Dunne MJ, Cosgrove KE, Shepherd RM, et al: Hyperin-

reflex responses to hypotension during fetal life. Am J

sulinism in infancy: from basic science to clinical disease.

Physiol 277:R1541, 1999.

Physiol Rev 84:239, 2004.

C H A P T E R

Sports Physiology

There are few stresses to which the body is exposed that

even nearly approach the extreme stresses of heavy

exercise. In fact, if some of the extremes of exercise

were continued for even moderately prolonged periods,

they might be lethal. Therefore, in the main, sports

physiology is a discussion of the ultimate limits to which

several of the bodily mechanisms can be stressed. To

give one simple example: In a person who has

extremely high fever approaching the level of lethality,

the body metabolism increases to about 100 per cent above normal. By compari-

son, the metabolism of the body during a marathon race may increase to 2000 per

cent above normal.

Female and Male Athletes Most of the quantitative data that are given in this chapter

are for the young male athlete, not because it is desirable to know only these values

but because it is only in male athletes that relatively complete measurements have

been made. However, for those measurements that have been made in the female

athlete, almost identical basic physiologic principles apply, except for quantitative

differences caused by differences in body size, body composition, and the presence

or absence of the male sex hormone testosterone.

In general, most quantitative values for women—such as muscle strength, pul-

monary ventilation, and cardiac output, all of which are related mainly to the muscle

mass—vary between two thirds and three quarters of the values recorded in men.

When measured in terms of strength per square centimeter of cross-sectional area,

the female muscle can achieve almost exactly the same maximal force of contrac-

tion as that of the male-between 3 and 4 kg/cm². Therefore, most of the difference

in total muscle performance lies in the extra percentage of the male body that is

muscle, caused by endocrine differences that we discuss later.

The performance capabilities of the female versus the male athlete are illustrated

by the relative running speeds for a marathon race. In a recent comparison, the top

female performer had a running speed that was 11 per cent less than that of the top

male performer. For other events, however, women have at times held records faster

than men—for instance, for the two-way swim across the English Channel, where

the availability of extra fat seems to be an advantage for heat insulation, buoyancy,

and extra long-term energy.

Testosterone secreted by the male testes has a powerful anabolic effect in causing

greatly increased deposition of protein everywhere in the body, but especially in the

muscles. In fact, even a male who participates in very little sports activity but who

nevertheless is well endowed with testosterone will have muscles that grow about

40 per cent larger than those of a comparable female without the testosterone.

The female sex hormone estrogen probably also accounts for some of the differ-

ence between female and male performance, although not nearly so much as testos-

terone. Estrogen is known to increase the deposition of fat in the female, especially

in the breasts, hips, and subcutaneous tissue. At least partly for this reason, the

average nonathletic female has about 27 per cent body fat composition, in contrast

to the nonathletic male, who has about 15 per cent. This is a detriment to the highest

levels of athletic performance in those events in which performance depends on

speed or on ratio of total body muscle strength to body weight.

Muscles in Exercise

Strength, Power, and Endurance of Muscles

The final common determinant of success in athletic events is what the muscles can

do for you—what strength they can give when it is needed, what power they can

achieve in the performance of work, and how long they can continue their activity.

1055

1056

Unit XV Sports Physiology

The strength of a muscle is determined mainly by its

is for the next 30 minutes, because the efficiency for

size, with a maximal contractile force between 3 and

translation of muscle power output into athletic per-

4 kg/cm² of muscle cross-sectional area. Thus, a man who

formance is often much less during rapid activity than

is well supplied with testosterone or who has enlarged

during less rapid but sustained activity. Thus, the veloc-

his muscles through an exercise training program will

ity of the 100-meter dash is only 1.75 times as great as

have correspondingly increased muscle strength.

the velocity of a 30-minute race, despite the fourfold dif-

To give an example of muscle strength, a world-class

ference in short-term versus long-term muscle power

weight lifter might have a quadriceps muscle with a

capability.

cross-sectional area as great as 150 square centimeters.

Another measure of muscle performance is

This would translate into a maximal contractile strength

endurance. This, to a great extent, depends on the nutri-

of 525 kilograms (or 1155 pounds), with all this force

tive support for the muscle—more than anything else

applied to the patellar tendon. Therefore, one can

on the amount of glycogen that has been stored in the

readily understand how it is possible for this tendon at

muscle before the period of exercise. A person on a

times to be ruptured or actually to be avulsed from its

high-carbohydrate diet stores far more glycogen in

insertion into the tibia below the knee. Also, when such

muscles than a person on either a mixed diet or a high-

forces occur in tendons that span a joint, similar forces

fat diet. Therefore, endurance is greatly enhanced by a

are applied to the surfaces of the joint or sometimes to

high-carbohydrate diet. When athletes run at speeds

ligaments spanning the joints, thus accounting for such

typical for the marathon race, their endurance (as meas-

happenings as displaced cartilages, compression frac-

ured by the time that they can sustain the race until

tures about the joint, and torn ligaments.

complete exhaustion) is approximately the following:

The holding strength of muscles is about 40 per cent

greater than the contractile strength. That is, if a muscle

is already contracted and a force then attempts to

Minutes

stretch out the muscle, as occurs when landing after a

High-carbohydrate diet

240

jump, this requires about 40 per cent more force than

Mixed diet

120

can be achieved by a shortening contraction. Therefore,

High-fat diet

the force of 525 kilograms calculated above for the

patellar tendon during muscle contraction becomes 735

kilograms (1617 pounds) during holding contractions.

This further compounds the problems of the tendons,

The corresponding amounts of glycogen stored in the

joints, and ligaments. It can also lead to internal tearing

muscle before the race started explain these differences.

in the muscle itself. In fact, forceful stretching of a max-

The amounts stored are approximately the following:

imally contracted muscle is one of the surest ways to

create the highest degree of muscle soreness.

Mechanical work performed by a muscle is the

g/kg Muscle

amount of force applied by the muscle multiplied by the

High-carbohydrate diet

distance over which the force is applied. The power of

Mixed diet

muscle contraction is different from muscle strength,

High-fat diet

because power is a measure of the total amount of

work that the muscle performs in a unit period of time.

Power is therefore determined not only by the strength

of muscle contraction but also by its distance of

Muscle Metabolic Systems

contraction and the number of times that it contracts

in Exercise

each minute. Muscle power is generally measured in

kilogram meters (kg-m) per minute. That is, a muscle

The same basic metabolic systems are present in muscle

that can lift 1 kilogram weight to a height of 1 meter or

as in other parts of the body; these are discussed in

that can move some object laterally against a force of 1

detail in Chapters

67 through 73. However, special

kilogram for a distance of 1 meter in 1 minute is said to

quantitative measures of the activities of three meta-

have a power of 1 kg-m/min. The maximal power

bolic systems are exceedingly important in understand-

achievable by all the muscles in the body of a highly

ing the limits of physical activity. These systems are (1)

trained athlete with all the muscles working together is

the phosphocreatine-creatine system, (2) the glycogen-

approximately the following:

lactic acid system, and (3) the aerobic system.

Adenosine Triphosphate. The source of energy actually

kg-m/min

used to cause muscle contraction is adenosine triphos-

phate (ATP), which has the following basic formula:

First 8 to 10 seconds

7000

Next 1 minute

4000

Adenosine-PO₃ ~ PO₃ ~ PO₃

Next 30 minutes

1700

The bonds attaching the last two phosphate radicals

to the molecule, designated by the symbol ~, are high-

Thus, it is clear that a person has the capability of

energy phosphate bonds. Each of these bonds stores

extreme power surges for short periods of time, such as

7300 calories of energy per mole of ATP under standard

during a 100-meter dash that is completed entirely

conditions (and even slightly more than this under the

within 10 seconds, whereas for long-term endurance

physical conditions in the body, which is discussed in

events, the power output of the muscles is only one

detail in Chapter 67). Therefore, when one phosphate

fourth as great as during the initial power surge.

radical is removed, more than 7300 calories of energy

This does not mean that one’s athletic performance is

are released to energize the muscle contractile process.

four times as great during the initial power surge as it

Then, when the second phosphate radical is removed,

Chapter 84

Sports Physiology

1057

I. Phosphocreatine

Creatine + PO3-

ATP

Energy

II. Glycogen

Lactic acid

ADP

for muscle

contraction

III. Glucose

AMP

Fatty acids

+ O₂

CO₂ + H₂O

Figure 84-1

Amino acids

Urea

Important metabolic systems

that supply energy for muscle

contraction.

still another 7300 calories become available. Removal

glycolysis, occurs without use of oxygen and, therefore,

of the first phosphate converts the ATP into adenosine

is said to be anaerobic metabolism (see Chapter 67).

diphosphate (ADP), and removal of the second converts

During glycolysis, each glucose molecule is split into two

this ADP into adenosine monophosphate (AMP).

pyruvic acid molecules, and energy is released to form

The amount of ATP present in the muscles, even in a

four ATP molecules for each original glucose molecule,

well-trained athlete, is sufficient to sustain maximal

as explained in Chapter 67. Ordinarily, the pyruvic

muscle power for only about 3 seconds, maybe enough

acid then enters the mitochondria of the muscle cells

for one half of a 50-meter dash. Therefore, except for a

and reacts with oxygen to form still many more

few seconds at a time, it is essential that new ATP be

ATP molecules. However, when there is insufficient

formed continuously, even during the performance of

oxygen for this second stage (the oxidative stage) of

short athletic events. Figure

84-1 shows the overall

glucose metabolism to occur, most of the pyruvic acid

metabolic system, demonstrating the breakdown of

then is converted into lactic acid, which diffuses out of

ATP first to ADP and then to AMP, with the release of

the muscle cells into the interstitial fluid and blood.

energy to the muscles for contraction. The left-hand side

Therefore, much of the muscle glycogen is transformed

of the figure shows the three metabolic systems that

to lactic acid, but in doing so, considerable amounts of

provide a continuous supply of ATP in the muscle fibers.

ATP are formed entirely without the consumption of

oxygen.

Another characteristic of the glycogen-lactic acid

Phosphocreatine-Creatine System

system is that it can form ATP molecules about 2.5

times as rapidly as can the oxidative mechanism of the

Phosphocreatine

(also called creatine phosphate) is

mitochondria. Therefore, when large amounts of ATP

another chemical compound that has a high-energy

are required for short to moderate periods of muscle

phosphate bond, with the following formula:

contraction, this anaerobic glycolysis mechanism can be

Creatine ~ PO₃

used as a rapid source of energy. It is, however, only

about one half as rapid as the phosphagen system.

This can decompose to creatine and phosphate ion, as

Under optimal conditions, the glycogen-lactic acid

shown to the left in Figure 84-1, and in doing so release

system can provide 1.3 to

1.6 minutes of maximal

large amounts of energy. In fact, the high-energy phos-

muscle activity in addition to the 8 to 10 seconds pro-

phate bond of phosphocreatine has more energy than

vided by the phosphagen system, although at somewhat

the bond of ATP, 10,300 calories per mole in compari-

reduced muscle power.

son with 7300. Therefore, phosphocreatine can easily

provide enough energy to reconstitute the high-energy

Aerobic System. The aerobic system is the oxidation of

bond of ATP. Furthermore, most muscle cells have two

foodstuffs in the mitochondria to provide energy. That

to four times as much phosphocreatine as ATP.

is, as shown to the left in Figure 84-1, glucose, fatty acids,

A special characteristic of energy transfer from phos-

and amino acids from the foodstuffs—after some inter-

phocreatine to ATP is that it occurs within a small frac-

mediate processing—combine with oxygen to release

tion of a second. Therefore, all the energy stored in the

tremendous amounts of energy that are used to convert

muscle phosphocreatine is almost instantaneously avail-

AMP and ADP into ATP, as discussed in Chapter 67.

able for muscle contraction, just as is the energy stored

In comparing this aerobic mechanism of energy

in ATP.

supply with the glycogen-lactic acid system and the

The combined amounts of cell ATP and cell phos-

phosphagen system, the relative maximal rates of power

phocreatine are called the phosphagen energy system.

generation in terms of moles of ATP generation per

These together can provide maximal muscle power for

minute are the following:

8 to 10 seconds, almost enough for the 100-meter run.

Thus, the energy from the phosphagen system is used for

Moles of ATP/min

maximal short bursts of muscle power.

Phosphagen system

Glycogen-Lactic Acid System. The stored glycogen in

Glycogen-lactic acid system

2.5

muscle can be split into glucose and the glucose then

Aerobic system

used for energy. The initial stage of this process, called

1058

Unit XV

Sports Physiology

When comparing the same systems for endurance, the

oxidative metabolism of the aerobic system can be used

relative values are the following:

to reconstitute all the other systems-the ATP, the phos-

phocreatine, and the glycogen-lactic acid system.

Reconstitution of the lactic acid system means mainly

Time

the removal of the excess lactic acid that has accumu-

lated in all the fluids of the body. This is especially

Phosphagen system

8 to 10 seconds

Glycogen-lactic acid system

1.3 to 1.6 minutes

important because lactic acid causes extreme fatigue.

Aerobic system

Unlimited time (as long as

When adequate amounts of energy are available from

nutrients last)

oxidative metabolism, removal of lactic acid is achieved

in two ways: (1) A small portion of it is converted back

into pyruvic acid and then metabolized oxidatively by

all the body tissues. (2) The remaining lactic acid is

Thus, one can readily see that the phosphagen system

reconverted into glucose mainly in the liver, and the

is the one used by the muscle for power surges of a few

glucose in turn is used to replenish the glycogen stores

seconds, and the aerobic system is required for pro-

of the muscles.

longed athletic activity. In between is the glycogen-lactic

acid system, which is especially important for giving

Recovery of the Aerobic System After Exercise. Even during

extra power during such intermediate races as the 200-

the early stages of heavy exercise, a portion of one’s

to 800-meter runs.

aerobic energy capability is depleted. This results from

two effects: (1) the so-called oxygen debt and (2) deple-

What Types of Sports Use Which Energy Systems? By consid-

tion of the glycogen stores of the muscles.

ering the vigor of a sports activity and its duration, one

can estimate closely which of the energy systems is used

Oxygen Debt. The body normally contains about 2 liters

for each activity. Various approximations are presented

of stored oxygen that can be used for aerobic metabo-

in Table 84-1.

lism even without breathing any new oxygen. This

stored oxygen consists of the following: (1) 0.5 liter in

Recovery of the Muscle Metabolic Systems After Exercise. In

the air of the lungs, (2) 0.25 liter dissolved in the body

the same way that the energy from phosphocreatine can

fluids, (3) 1 liter combined with the hemoglobin of the

be used to reconstitute ATP, energy from the glycogen-

blood, and (4) 0.3 liter stored in the muscle fibers them-

lactic acid system can be used to reconstitute both phos-

selves, combined mainly with myoglobin, an oxygen-

phocreatine and ATP. And then energy

from

the

binding chemical similar to hemoglobin.

In heavy exercise, almost all this stored oxygen is used

within a minute or so for aerobic metabolism. Then,

Table 84-1

after the exercise is over, this stored oxygen must be

replenished by breathing extra amounts of oxygen over

Energy Systems Used in Various Sports

and above the normal requirements. In addition, about

9 liters more oxygen must be consumed to provide for

reconstituting both the phosphagen system and the

Phosphagen system, almost entirely

100-meter dash

lactic acid system. All this extra oxygen that must be

Jumping

“repaid,” about 11.5 liters, is called the oxygen debt.

Weight lifting

Figure 84-2 shows this principle of oxygen debt.

Diving

During the first 4 minutes of the figure, the person exer-

Football dashes

cises heavily, and the rate of oxygen uptake increases

Phosphagen and glycogen-lactic acid systems

200-meter dash

Basketball

Baseball home run

Ice hockey dashes

Glycogen-lactic acid system, mainly

400-meter dash

100-meter swim

Tennis

Soccer

Alactacid oxygen debt = 3.5 liters

Glycogen-lactic acid and aerobic systems

800-meter dash

200-meter swim

Lactic acid oxygen debt = 8 liters

1500-meter skating

Boxing

2000-meter rowing

1500-meter run

1-mile run

Minutes

400-meter swim

Aerobic system

10,000-meter skating

Figure 84-2

Cross-country skiing

Marathon run (26.2 miles, 42.2 km)

Rate of oxygen uptake by the lungs during maximal exercise for

Jogging

4 minutes and then for about 40 minutes after the exercise is over.

This figure demonstrates the principle of oxygen debt.

Chapter 84

Sports Physiology

1059

2 hours of

exercise

High-carbohydrate diet

No food

Fat and protein diet

Figure 84-3

Effect of diet on the rate of muscle

glycogen replenishment after pro-

longed exercise. (Redrawn from

Hours of recovery

5 days

Fox EL: Sports Physiology.

Philadelphia: Saunders College

Publishing, 1979.)

more than 15-fold. Then, even after the exercise is over,

the oxygen uptake still remains above normal, at first

very high while the body is reconstituting the phospha-

High-carbohydrate diet

gen system and repaying the stored oxygen portion of

Mixed diet

the oxygen debt, and then for another 40 minutes at a

100

High-fat diet

lower level while the lactic acid is removed. The early

portion of the oxygen debt is called the alactacid oxygen

debt and amounts to about 3.5 liters. The latter portion

is called the lactic acid oxygen debt and amounts to

about 8 liters.

Recovery of Muscle Glycogen. Recovery from exhaustive

muscle glycogen depletion is not a simple matter. This

often requires days, rather than the seconds, minutes, or

Exhaustion

hours required for recovery of the phosphagen and

lactic acid metabolic systems. Figure 84-3 shows this

recovery process under three conditions: first, in people

100

on a high-carbohydrate diet; second, in people on a

2 4

high-fat, high-protein diet; and third, in people with no

Seconds

Minutes

Hours

food. Note that on a high-carbohydrate diet, full recov-

Duration of exercise

ery occurs in about 2 days. Conversely, people on a high-

fat, high-protein diet or on no food at all show very little

recovery even after as long as 5 days. The messages of

this comparison are (1) that it is important for an athlete

Figure 84-4

to have a high-carbohydrate diet before a grueling ath-

letic event and (2) not to participate in exhaustive exer-

Effect of duration of exercise as well as type of diet on relative

cise during the 48 hours preceding the event.

percentages of carbohydrate or fat used for energy by muscles.

(Based partly on data in Fox EL: Sports Physiology. Philadelphia:

Saunders College Publishing, 1979.)

Nutrients Used During

Muscle Activity

longer than 4 to 5 hours, the glycogen stores of the

In addition to the large usage of carbohydrates by the

muscle become almost totally depleted and are of little

muscles during exercise, especially during the early

further use for energizing muscle contraction. Instead,

stages of exercise, muscles use large amounts of fat for

the muscle now depends on energy from other sources,

energy in the form of fatty acids and acetoacetic acid (see

mainly from fats.

Chapter 68), and they use to a much less extent proteins

Figure 84-4 shows the approximate relative usage of

in the form of amino acids. In fact, even under the best

carbohydrates and fat for energy during prolonged

conditions, in those endurance athletic events that last

exhaustive exercise under three dietary conditions:

1060

Unit XV

Sports Physiology

high-carbohydrate diet, mixed diet, and high-fat diet.

muscle strength increases about 30 per cent during the

Note that most of the energy is derived from carbohy-

first 6 to 8 weeks but almost plateaus after that time.

drates during the first few seconds or minutes of the

Along with this increase in strength is an approximately

exercise, but at the time of exhaustion, as much as 60 to

equal percentage increase in muscle mass, which is

85 per cent of the energy is being derived from fats,

called muscle hypertrophy.

rather than carbohydrates.

In old age, many people become so sedentary that

Not all the energy from carbohydrates comes from

their muscles atrophy tremendously. In these instances,

the stored muscle glycogen. In fact, almost as much

muscle training often increases muscle strength more

glycogen is stored in the liver as in the muscles, and this

than 100 per cent.

can be released into the blood in the form of glucose

and then taken up by the muscles as an energy source.

Muscle Hypertrophy. The average size of a person’s

In addition, glucose solutions given to an athlete to

muscles is determined to a great extent by heredity plus

drink during the course of an athletic event can provide

the level of testosterone secretion, which, in men, causes

as much as 30 to 40 per cent of the energy required

considerably larger muscles than in women. With train-

during prolonged events such as marathon races.

ing, however, the muscles can become hypertrophied

Therefore, if muscle glycogen and blood glucose are

perhaps an additional 30 to 60 per cent. Most of this

available, they are the energy nutrients of choice for

hypertrophy results from increased diameter of the

intense muscle activity. Even so, for a long-term

muscle fibers rather than increased numbers of fibers,

endurance event, one can expect fat to supply more than

but this probably is not entirely true, because a very few

50 per cent of the required energy after about the first

greatly enlarged muscle fibers are believed to split down

3 to 4 hours.

the middle along their entire length to form entirely

new fibers, thus increasing the number of fibers slightly.

The changes that occur inside the hypertrophied

Effect of Athletic Training on

muscle fibers themselves include (1) increased numbers

Muscles and Muscle Performance

of myofibrils, proportionate to the degree of hypertro-

phy; (2) up to 120 per cent increase in mitochondrial

Importance of Maximal Resistance Training. One of the car-

enzymes; (3) as much as 60 to 80 per cent increase in

dinal principles of muscle development during athletic

the components of the phosphagen metabolic system,

training is the following: Muscles that function under no

including both ATP and phosphocreatine; (4) as much

load, even if they are exercised for hours on end,

as 50 per cent increase in stored glycogen; and (5) as

increase little in strength. At the other extreme, muscles

much as 75 to 100 per cent increase in stored triglyc-

that contract at more than 50 per cent maximal force of

eride (fat). Because of all these changes, the capabilities

contraction will develop strength rapidly even if the

of both the anaerobic and the aerobic metabolic systems

contractions are performed only a few times each day.

are increased, increasing especially the maximum oxi-

Using this principle, experiments on muscle building

dation rate and efficiency of the oxidative metabolic

have shown that six nearly maximal muscle contractions

system as much as 45 per cent.

performed in three sets 3 days a week give approxi-

mately optimal increase in muscle strength, without

Fast-Twitch and Slow-Twitch Muscle Fibers. In the human

producing chronic muscle fatigue.

being, all muscles have varying percentages of fast-

The upper curve in Figure 84-5 shows the approxi-

twitch and slow-twitch muscle fibers. For instance, the

mate percentage increase in strength that can be

gastrocnemius muscle has a higher preponderance of

achieved in a previously untrained young person by this

fast-twitch fibers, which gives it the capability of force-

resistive training program, demonstrating that the

ful and rapid contraction of the type used in jumping.

In contrast, the soleus muscle has a higher preponder-

ance of slow-twitch muscle fibers and therefore is used

to a greater extent for prolonged lower leg muscle

activity.

The basic differences between the fast-twitch and the

Resistive training

slow-twitch fibers are the following:

1. Fast-twitch fibers are about twice as large in

diameter.

2. The enzymes that promote rapid release of energy

from the phosphagen and glycogen-lactic acid

energy systems are two to three times as active in

fast-twitch fibers as in slow-twitch fibers, thus

making the maximal power that can be achieved

for very short periods of time by fast-twitch fibers

No-load

training

about twice as great as that of slow-twitch fibers.

3. Slow-twitch fibers are mainly organized for

endurance, especially for generation of aerobic

energy. They have far more mitochondria than

Weeks of training

the fast-twitch fibers. In addition, they contain

considerably more myoglobin, a hemoglobin-like

protein that combines with oxygen within the

muscle fiber; the extra myoglobin increases the rate

Figure 84-5

of diffusion of oxygen throughout the fiber by

Approximate effect of optimal resistive exercise training on

shuttling oxygen from one molecule of myoglobin

increase in muscle strength over a training period of 10 weeks.

to the next. In addition, the enzymes of the aerobic

Chapter 84

Sports Physiology

1061

metabolic system are considerably more active in

slow-twitch fibers than in fast-twitch fibers.

4. The number of capillaries is greater in the vicinity

120

of slow-twitch fibers than in the vicinity of fast-

110

twitch fibers.

In summary, fast-twitch fibers can deliver extreme

100

amounts of power for a few seconds to a minute or

so. Conversely, slow-twitch fibers provide endurance,

delivering prolonged strength of contraction over many

minutes to hours.

Hereditary Differences Among Athletes for Fast-Twitch Versus

Slow-Twitch Muscle Fibers. Some people have considerably

Moderate

Severe

more fast-twitch than slow-twitch fibers, and others have

exercise

more slow-twitch fibers; this could determine to some

1.0

2.0

3.0

4.0

extent the athletic capabilities of different individuals.

O₂ consumption (L/min)

Athletic training has not been shown to change the rel-

ative proportions of fast-twitch and slow-twitch fibers

however much an athlete might want to develop one

type of athletic prowess over another. Instead, this seems

Figure 84-6

to be determined almost entirely by genetic inheritance,

and this in turn helps determine which area of athletics

Effect of exercise on oxygen consumption and ventilatory rate.

is most suited to each person: some people appear to be

(Redrawn from Gray JS: Pulmonary Ventilation and Its Physiolog-

born to be marathoners; others are born to be sprinters

ical Regulation. Springfield, IL: Charles C Thomas, 1950.)

and jumpers. For example, the following are recorded

percentages of fast-twitch versus slow-twitch fiber in the

quadriceps muscles of different types of athletes:

Limits of Pulmonary Ventilation. How severely do we stress

our respiratory systems during exercise? This can be

answered by the following comparison for a normal

young man:

Fast-Twitch

Slow-Twitch

Marathoners

Swimmers

L/min

Average male

Weight lifters

Pulmonary ventilation at maximal exercise

100 to 110

Sprinters

Maximal breathing capacity

150 to 170

Jumpers

Thus, the maximal breathing capacity is about 50 per

Respiration in Exercise

cent greater than the actual pulmonary ventilation

during maximal exercise. This provides an element of

Although one’s respiratory ability is of relatively little

safety for athletes, giving them extra ventilation that can

concern in the performance of sprint types of athletics,

be called on in such conditions as (1) exercise at high

it is critical for maximal performance in endurance

altitudes, (2) exercise under very hot conditions, and (3)

athletics.

abnormalities in the respiratory system.

The important point is that the respiratory system is

Oxygen Consumption and Pulmonary Ventilation in Exercise.

not normally the most limiting factor in the delivery of

Normal oxygen consumption for a young man at rest is

oxygen to the muscles during maximal muscle aerobic

about 250 ml/min. However, under maximal conditions,

metabolism. We shall see shortly that the ability of the

this can be increased to approximately the following

heart to pump blood to the muscles is usually a greater

average levels:

limiting factor.

Effect of Training on VO2 Max. The abbreviation for the rate

ml/min

VO₂Max. Figure 84.7 shows the progressive effect of

Untrained average male

3600

athletic training on VO₂ Max recorded in a group of sub-

Athletically trained average male

4000

jects beginning at the level of no training and then pur-

Male marathon runner

5100

suing the training program for.7 to 13 weeks. In this

study, it is surprising that the VO₂ Max increased only

about 10 per cent. Furthermore, the frequency of train-

ing, whether two times or f.ve times per week, had little

Figure 84-6 shows the relation between oxygen con-

effect on th

sumption and total pulmonary ventilation at different

earlier, the VO₂ Max of a marathoner is about 45 per

levels of exercise. It is clear from this figure, as would

cent greater

be expected, that there is a linear relation. Both oxygen

this greater VO₂ Max of the marathoner probably is

consumption and total pulmonary ventilation increase

genetically determined; that is, those people who have

about 20-fold between the resting state and maximal

greater chest sizes in relation to body size and stronger

intensity of exercise in the well-trained athlete.

respiratory muscles select themselves to become

1062

Unit XV Sports Physiology

naturally greater diffusing capacities choose these types

of sports, or is it because something about the training

3.8

procedures increases the diffusing capacity? The answer

is not known, but it is very likely that training, particu-

3.6

larly endurance training, does play an important role.

3.4

Blood Gases During Exercise. Because of the great usage of

Training frequency

oxygen by the muscles in exercise, one would expect

3.2

= 5 days/wk

the oxygen pressure of the arterial blood to decrease

= 4 days/wk

markedly during strenuous athletics and the carbon

= 2 days/wk

dioxide pressure of the venous blood to increase far

3.0

above normal. However, this normally is not the case.

Both of these values remain nearly normal, demon-

2.8

strating the extreme ability of the respiratory system to

Weeks of training

provide adequate aeration of the blood even during

heavy exercise.

This demonstrates another important point: The

blood gases do not always have to become abnormal for

Figure 84-7

respiration to be stimulated in exercise. Instead, respira-

tion is stimulated mainly by neurogenic mechanisms

Max over a period of 7 to 13 weeks of athletic

during exercise, as discussed in Chapter 41. Part of this

Increase in VO₂

training. (Redrawn from Fox EL: Sports Physiology. Philadelphia:

stimulation results from direct stimulation of the respi-

Saunders College Publishing, 1979.)

ratory center by the same nervous signals that are trans-

mitted from the brain to the muscles to cause the

exercise. An additional part is believed to result from

marathoners. However, it is also likely tha. many years

sensory signals transmitted into the respiratory center

of training increase the marathoner’s VO₂

Max by

from the contracting muscles and moving joints. All this

values considerably greater than the 10 per cent that has

extra nervous stimulation of respiration is normally suf-

been recorded in short-term experiments such as that in

ficient to provide almost exactly the necessary increase

Figure 84-7.

in pulmonary ventilation required to keep the blood

respiratory gases—the oxygen and the carbon dioxide—

Oxygen Diffusing Capacity of Athletes. The oxygen diffusing

very near to normal.

capacity is a measure of the rate at which oxygen can

diffuse from the pulmonary alveoli into the blood. This

Effect of Smoking on Pulmonary Ventilation in Exercise. It is

is expressed in terms of milliliters of oxygen that will

widely known that smoking can decrease an athlete’s

diffuse each minute for each millimeter of mercury dif-

“wind.” This is true for many reasons. First, one effect

ference between alveolar partial pressure of oxygen and

of nicotine is constriction of the terminal bronchioles of

pulmonary blood oxygen pressure. That is, if the partial

the lungs, which increases the resistance of airflow into

pressure of oxygen in the alveoli is 91 mm Hg and the

and out of the lungs. Second, the irritating effects of the

oxygen pressure in the blood is 90 mm Hg, the amount

smoke itself cause increased fluid secretion into the

of oxygen that diffuses through the respiratory mem-

bronchial tree, as well as some swelling of the epithelial

brane each minute is equal to the diffusing capacity. The

linings. Third, nicotine paralyzes the cilia on the surfaces

following are measured values for different diffusing

of the respiratory epithelial cells that normally beat con-

capacities:

tinuously to remove excess fluids and foreign particles

from the respiratory passageways. As a result, much

debris accumulates in the passageways and adds further

ml/min

to the difficulty of breathing. Putting all these factors

together, even a light smoker often feels respiratory

Nonathlete at rest

strain during maximal exercise, and the level of per-

Nonathlete during maximal exercise

formance may be reduced.

Speed skaters during maximal exercise

Swimmers during maximal exercise

Much more severe are the effects of chronic smoking.

Oarsman during maximal exercise

There are few chronic smokers in whom some degree

of emphysema does not develop. In this disease, the fol-

lowing occur: (1) chronic bronchitis, (2) obstruction of

The most startling fact about these results is the sev-

many of the terminal bronchioles, and (3) destruction

eralfold increase in diffusing capacity between the

of many alveolar walls. In severe emphysema, as much

resting state and the state of maximal exercise. This

as four fifths of the respiratory membrane can be

results mainly from the fact that blood flow through

destroyed; then even the slightest exercise can cause

many of the pulmonary capillaries is sluggish or even

respiratory distress. In fact, many such patients cannot

dormant in the resting state, whereas in maximal exer-

even perform the simple feat of walking across the floor

cise, increased blood flow through the lungs causes

of a single room without gasping for breath.

all the pulmonary capillaries to be perfused at their

maximal rates, thus providing a far greater surface area

through which oxygen can diffuse into the pulmonary

Cardiovascular System

capillary blood.

in Exercise

It is also clear from these values that those athletes

who require greater amounts of oxygen per minute have

Muscle Blood Flow. A key requirement of cardiovascular

higher diffusing capacities. Is this because people with

function in exercise is to deliver the required oxygen

Chapter 84

Sports Physiology

1063

Therefore, a 30 per cent increase in blood pressure can

often more than double the blood flow; this multiplies

the great increase in flow already caused by the meta-

Rhythmic exercise

bolic vasodilation at least another twofold.

Work Output, Oxygen Consumption, and Cardiac Output During

Exercise. Figure 84-9 shows the interrelations among

work output, oxygen consumption, and cardiac output

during exercise. It is not surprising that all these are

directly related to one another, as shown by the linear

functions, because the muscle work output increases

oxygen consumption, and oxygen consumption in turn

dilates the muscle blood vessels, thus increasing venous

return and cardiac output. Typical cardiac outputs at

Calf

several levels of exercise are the following:

flow

Minutes

L/min

Cardiac output in young man at rest

5.5

Maximal cardiac output during exercise in young

untrained man

Figure 84-8

Maximal cardiac output during exercise in

average male marathoner

Effects of muscle exercise on blood flow in the calf of a leg dur-

ing strong rhythmical contraction. The blood flow was much less

during contraction than between contractions. (Redrawn from

Barcroft H, Dornhors AC: Blood flow through human calf during

rhythmic exercise. J Physiol 109:402, 1949.)

Thus, the normal untrained person can increase

cardiac output a little over fourfold, and the well-

trained athlete can increase output about sixfold.

and other nutrients to the exercising muscles. For this

(Individual marathoners have been clocked at cardiac

purpose, the muscle blood flow increases drastically

outputs as great as 35 to 40 L/min, seven to eight times

during exercise. Figure

84-8 shows a recording of

normal resting output.)

muscle blood flow in the calf of a person for a period of

6 minutes during moderately strong intermittent con-

Effect of Training on Heart Hypertrophy and on Cardiac Output.

tractions. Note not only the great increase in flow—

From the foregoing data, it is clear that marathoners can

about 13-fold—but also the flow decrease during each

achieve maximal cardiac outputs about 40 per cent

muscle contraction. Two points can be made from

greater than those achieved by untrained persons. This

this study:

(1) The actual contractile process itself

results mainly from the fact that the heart chambers of

temporarily decreases muscle blood flow because the

marathoners enlarge about 40 per cent; along with this

contracting skeletal muscle compresses the intramuscu-

enlargement of the chambers, the heart mass also

lar blood vessels; therefore, strong tonic muscle con-

increases 40 per cent or more. Therefore, not only do

tractions can cause rapid muscle fatigue because of lack

the skeletal muscles hypertrophy during athletic train-

of delivery of enough oxygen and other nutrients during

ing but the heart does also. However, heart enlargement

the continuous contraction.

(2) The blood flow to

and increased pumping capacity occur almost entirely

muscles during exercise increases markedly. The fol-

in the endurance types, not in the sprint types, of ath-

lowing comparison shows the maximal increase in blood

letic training.

flow that can occur in a well-trained athlete.

Even though the heart of the marathoner is consid-

erably larger than that of the normal person, resting

cardiac output is almost exactly the same as that in the

ml/100 g Muscle/min

normal person. However, this normal cardiac output is

achieved by a large stroke volume at a reduced heart

Resting blood flow

3.6

rate. Table 84-2 compares stroke volume and heart rate

Blood flow during maximal exercise

in the untrained person and the marathoner.

Thus, the heart-pumping effectiveness of each heart-

beat is 40 to 50 per cent greater in the highly trained

Thus, muscle blood flow can increase a maximum of

athlete than in the untrained person, but there is a cor-

about

25-fold during the most strenuous exercise.

responding decrease in heart rate at rest.

Almost one half this increase in flow results from intra-

muscular vasodilation caused by the direct effects of

Role of Stroke Volume and Heart Rate in Increasing the Cardiac

increased muscle metabolism, as explained in Chapter

Output. Figure 84-10 shows the approximate changes in

21. The remaining increase results from multiple factors,

stroke volume and heart rate as the cardiac output

the most important of which is probably the moderate

increases from its resting level of about 5.5 L/min to

increase in arterial blood pressure that occurs in exer-

30 L/min in the marathon runner. The stroke volume

cise, usually about a 30 per cent increase. The increase

increases from 105 to 162 milliliters, an increase of about

in pressure not only forces more blood through the

50 per cent, whereas the heart rate increases from 50 to

blood vessels but also stretches the walls of the arteri-

185 beats/min, an increase of 270 per cent. Therefore,

oles and further reduces the vascular resistance.

the heart rate increase accounts by far for a greater

1064

Unit XV Sports Physiology

Dexter 1951

Douglas 1922

Christensen 1931

Donald 1956

Figure 84-9

Relation between cardiac output

and work output (solid line) and

between oxygen consumption

and work output

(dashed line)

during different levels of exercise.

(Redrawn from Guyton AC, Jones

200

400

600

800

1000 1200 1400

1600

CE, Coleman TB: Circulatory

Work output during exercise (kg-meters/min)

Physiology: Cardiac Output and

Its Regulation. Philadelphia: WB

Saunders Co, 1973.)

Table 84-2

190

Comparison of Cardiac Function Between Marathoner

and Nonathlete

170

Stroke volume

165

150

Stroke Volume (ml)

Heart Rate (beats/min)

Resting

150

130

Nonathlete

Marathoner

105

110

135

Maximum

Nonathlete

110

195

Heart rate

Marathoner

162

185

120

105

proportion of the increase in cardiac output than does

Cardiac output (L/min)

the increase in stroke volume during strenuous exercise.

The stroke volume normally reaches its maximum by

the time the cardiac output has increased only halfway

to its maximum. Any further increase in cardiac output

Figure 84-10

must occur by increasing the heart rate.

Approximate stroke volume output and heart rate at different levels

of cardiac output in a marathon athlete.

Relation of Cardiovascular Performance to VO

Max. During

maximal exercise, both the heart rate and the stroke

volume are increased to about 95 per cent of their

maximal levels. Because the cardiac output is equal

important physiologic benefit of the marathoner’s train-

to stroke volume times heart rate, one finds that the

ing program.

cardiac output is about 90 per cent of the maximum that

the person can achieve. This is in contrast to about 65

Effect of Heart Disease and Old Age on Athletic Performance.

per cent of maximum for pulmonary ventilation. There-

Because of the critical limitation that the cardiovascu-

fore, one can readily see that the ca

lar system places on maximal performance in endurance

is normally much more limiting on VO₂ Max than is the

athletics, one can readily understand that any type of

respiratory system, because oxygen utilization by the

heart disease that reduces maximal cardiac output will

body can never be more than the rate at which the car-

cause an almost corresponding decrease in achievable

diovascular system can transport oxygen to the tissues.

total body muscle power. Therefore, a person with con-

For this reason, it is frequently stated that the level

gestive heart failure frequently has difficulty achieving

of athletic performance that can be achieved by the

even the muscle power required to climb out of bed,

marathoner mainly depends on the performance capa-

much less to walk across the floor.

bility of his or her heart, because this is the most limit-

The maximal cardiac output of older people also

ing link in the delivery of adequate oxygen to the

decreases considerably—there is as much as a 50 per

exercising muscles. Therefore, the 40 per cent greater

cent decrease between age 18 and age 80. Also, there is

cardiac output that the marathoner can achieve over the

even more decrease in maximal breathing capacity. For

average untrained male is probably the single most

these reasons, as well as reduced skeletal muscle mass,

Chapter 84

Sports Physiology

1065

the maximal achievable muscle power is greatly

Body Fluids and Salt

reduced in old age.

in Exercise

As much as a 5- to 10-pound weight loss has been

Body Heat in Exercise

recorded in athletes in a period of

1 hour during

endurance athletic events under hot and humid condi-

Almost all the energy released by the body’s metabo-

tions. Essentially all this weight loss results from loss of

lism of nutrients is eventually converted into body heat.

sweat. Loss of enough sweat to decrease body weight

This applies even to the energy that causes muscle con-

only 3 per cent can significantly diminish a person’s per-

traction for the following reasons: First, the maximal

formance, and a 5 to 10 per cent rapid decrease in

efficiency for conversion of nutrient energy into muscle

weight can often be serious, leading to muscle cramps,

work, even under the best of conditions, is only 20 to 25

nausea, and other effects. Therefore, it is essential to

per cent; the remainder of the nutrient energy is con-

replace fluid as it is lost.

verted into heat during the course of the intracellular

chemical reactions. Second, almost all the energy that

Replacement of Sodium Chloride and Potassium. Sweat con-

does go into creating muscle work still becomes body

tains a large amount of sodium chloride, for which

heat because all but a small portion of this energy is

reason it has long been stated that all athletes should

used for (1) overcoming viscous resistance to the move-

take salt (sodium chloride) tablets when performing

ment of the muscles and joints, (2) overcoming the

exercise on hot and humid days. However, overuse of

friction of the blood flowing through the blood vessels,

salt tablets has often done as much harm as good. Fur-

and (3) other, similar effects—all of which convert

thermore, if an athlete becomes acclimatized to the heat

the muscle contractile energy into heat.

by progressive increase in athletic exposure over a

Now, recognizing that the oxygen consumption by the

period of 1 to 2 weeks rather than performing maximal

body can increase as much as 20-fold in the well-trained

athletic feats on the first day, the sweat glands also

athlete and that the amount of heat liberated in the

become acclimatized, so that the amount of salt lost in

body is almost exactly proportional to the oxygen con-

the sweat becomes only a small fraction of that lost

sumption (as discussed in Chapter 72), one quickly real-

before acclimatization. This sweat gland acclimatization

izes that tremendous amounts of heat are injected into

results mainly from increased aldosterone secretion by

the internal body tissues when performing endurance

the adrenal cortex. The aldosterone in turn has a direct

athletic events. Next, with a vast rate of heat flow into

effect on the sweat glands, increasing reabsorption of

the body, on a very hot and humid day so that the sweat-

sodium chloride from the sweat before the sweat itself

ing mechanism cannot eliminate the heat, an intolera-

issues forth from the sweat gland tubules onto the

ble and even lethal condition called heatstroke can

surface of the skin. Once the athlete is acclimatized,

easily develop in the athlete.

only rarely do salt supplements need to be considered

during athletic events.

Heatstroke. During endurance athletics, even under

Experience by military units exposed to heavy exer-

normal environmental conditions, the body tempera-

cise in the desert has demonstrated still another elec-

ture often rises from its normal level of 98.6° to 102° or

trolyte problem—the loss of potassium. Potassium loss

103°F (37° to 40°C). With very hot and humid condi-

results partly from the increased secretion of aldos-

tions or excess clothing, the body temperature can easily

terone during heat acclimatization, which increases the

rise to 106° to 108°F (41° to 42°C). At this level, the ele-

loss of potassium in the urine as well as in the sweat. As

vated temperature itself becomes destructive to tissue

a consequence of these findings, some of the supple-

cells, especially the brain cells. When this happens, mul-

mental fluids for athletics contain properly propor-

tiple symptoms begin to appear, including extreme

tioned amounts of potassium along with sodium, usually

weakness, exhaustion, headache, dizziness, nausea,

in the form of fruit juices.

profuse sweating, confusion, staggering gait, collapse,

and unconsciousness.

This whole complex is called heatstroke, and failure

Drugs and Athletes

to treat it immediately can lead to death. In fact, even

though the person has stopped exercising, the tempera-

Without belaboring this issue, let us list some of the

ture does not easily decrease by itself. One of the

effects of drugs in athletics.

reasons for this is that at these high temperatures, the

First, caffeine is believed by some to increase athletic

temperature-regulating mechanism itself often fails (see

performance. In one experiment on a marathon runner,

Chapter 73). A second reason is that in heatstroke, the

running time for the marathon was reduced by 7 per

very high body temperature itself approximately

cent by judicious use of caffeine in amounts similar to

doubles the rates of all intracellular chemical reactions,

those found in one to three cups of coffee. Yet experi-

thus liberating still more heat.

ments by others have failed to confirm any advantage,

The treatment of heatstroke is to reduce the body

thus leaving this issue in doubt.

temperature as rapidly as possible. The most practical

Second, use of male sex hormones (androgens) or

way to do this is to remove all clothing, maintain a spray

other anabolic steroids to increase muscle strength

of cool water on all surfaces of the body or continually

undoubtedly can increase athletic performance under

sponge the body, and blow air over the body with a fan.

some conditions, especially in women and even in men.

Experiments have shown that this treatment can reduce

However, anabolic steroids also greatly increase the risk

the temperature either as rapidly or almost as rapidly

of cardiovascular damage because they often cause

as any other procedure, although some physicians

hypertension, decreased high-density blood lipopro-

prefer total immersion of the body in water containing

teins, and increased low-density lipoproteins, all of

a mush of crushed ice if available.

which promote heart attacks and strokes.

1066

Unit XV

Sports Physiology

In men, any type of male sex hormone preparation

Booth FW, Chakravarthy MV, Spangenburg EE: Exercise

also leads to decreased testicular function, including

and gene expression: physiological regulation of the

both decreased formation of sperm and decreased

human genome through physical activity. J Physiol

secretion of the person’s own natural testosterone, with

543:399, 2002.

residual effects sometimes lasting at least for many

Chakravarthy MV, Booth FW: Eating, exercise, and “thrifty”

months and perhaps indefinitely. In a woman, even

genotypes: connecting the dots toward an evolutionary

more dire effects can occur because she is not normally

understanding of modern chronic diseases. J Appl Physiol

adapted to the male sex hormone—hair on the face, a

96:3, 2004.

bass voice, ruddy skin, and cessation of menses.

Clausen T: Effects of age and exercise training on NA⁺K⁺

Other drugs, such as amphetamines and cocaine, have

pumps in skeletal muscle. Am J Physiol Regul Integr

been reputed to increase one’s athletic performance. It

Comp Physiol 285:R720, 2003.

is equally true that overuse of these drugs can lead to

Delp MD, Laughlin MH: Regulation of skeletal muscle per-

deterioration of performance. Furthermore, experi-

fusion during exercise. Acta Physiol Scand 162:411, 1998.

ments have failed to prove the value of these drugs

Evans NA: Current concepts in anabolic-androgenic

except as a psychic stimulant. Some athletes have been

steroids. Am J Sports Med 32:534, 2004.

known to die during athletic events because of interac-

Gandevia SC: Spinal and supraspinal factors in human

tion between such drugs and the norepinephrine and

muscle fatigue. Physiol Rev 81:1725, 2001.

epinephrine released by the sympathetic nervous

Glass JD: Signalling pathways that mediate skeletal muscle

system during exercise. One of the possible causes of

hypertrophy and atropy. Nat Cell Biol 5:87, 2003.

death under these conditions is overexcitability of the

Guyton AC, Jones CE, Coleman TB: Circulatory Physiology:

heart, leading to ventricular fibrillation, which is lethal

Cardiac Output and Its Regulation, 2nd ed. Philadelphia:

within seconds.

WB Saunders Co, 1973.

Hochachka PW, Beatty CL, Burelle Y, et al: The lactate

paradox in human high-altitude physiological perform-

ance. News Physiol Sci 17:122, 2002.

Body Fitness Prolongs Life

Johnson NA, Stannard SR, Thompson MW: Muscle triglyc-

Multiple studies have now shown that people who main-

eride and glycogen in endurance exercise: implications for

tain appropriate body fitness, using judicious regimens

performance. Sports Med 34:51, 2004.

of exercise and weight control, have the additional

Kraemer WJ, Adams K, Cafarelli E, et al: American College

benefit of prolonged life. Especially between the ages of

of Sports Medicine position stand. Progression models in

50 and 70, studies have shown mortality to be three

resistance training for healthy adults. Med Sci Sports

times less in the most fit people than in the least fit.

Exerc 34:364, 2002.

But why does body fitness prolong life? The follow-

Myburgh KH: What makes an endurance athlete world-

ing are the two most evident reasons.

class? Not simply a physiological conundrum. Comp

First, body fitness and weight control greatly reduce

Biochem Physiol A Mol Integr Physiol 136:171, 2003.

cardiovascular disease. This results from (1) mainte-

Noakes TD, Peltonen JE, Rusko HK: Evidence that a central

nance of moderately lower blood pressure and (2)

governor regulates exercise performance during acute

reduced blood cholesterol and low-density lipoprotein

hypoxia and hyperoxia. J Exp Biol 204:3225, 2001.

along with increased high-density lipoprotein. As

Rennie MJ, Wackerhage H, Spangenburg EE, Booth FW:

pointed out earlier, these changes all work together to

Control of the size of the human muscle mass. Annu Rev

reduce the number of heart attacks and brain strokes.

Physiol 66:799, 2004.

Second, and perhaps equally important, the athleti-

Schnermann J: Exercise. Am J Physiol Regul Integr Comp

cally fit person has more bodily reserves to call on when

Physiol 283:R2, 2002.

he or she does become sick. For instance, an 80-year-old

Spangenburg EE, Booth FW: Molecular regulation of indi-

nonfit person may have a respiratory system that limits

vidual skeletal muscle fibre types. Acta Physiol Scand

oxygen delivery to the tissues to no more than 1 L/min;

178:413, 2003.

this means a respiratory reserve of no more than three-

Steele DS, Duke AM: Metabolic factors contributing to

fold to fourfold. However, an athletically fit old person

altered Ca2+ regulation in skeletal muscle fatigue. Acta

may have twice as much reserve. This is especially

Physiol Scand 179:39, 2003.

important in preserving life when the older person

Tanaka H, Seals DR: Dynamic exercise performance in

develops conditions such as pneumonia that can rapidly

Masters athletes: insight into the effects of primary human

require all available respiratory reserve. In addition, the

aging on physiological functional capacity. J Appl Physiol

ability to increase cardiac output in times of need (the

95:2152, 2003.

“cardiac reserve”) is often 50 per cent greater in the ath-

Tschakovsky ME, Hughson RL: Interaction of factors deter-

letically fit old person than in the nonfit person.

mining oxygen uptake at the onset of exercise. J Appl

Physiol 86:1101, 1999.

Watt MJ, Heigenhauser GJ, Spriet LL: Intramuscular tria-

cylglycerol utilization in human skeletal muscle during

References

exercise: is there a controversy? J Appl Physiol 93:1185,

2002.

Blair SN, LaMonte MJ, Nichaman MZ: The evolution of

physical activity recommendations. How much is enough?

Am J Clin Nutr 79:913S, 2004.

N D E X

Note: Page numbers followed by f refer to figures; page numbers followed by t refer to tables.

Acetyl-CoA carboxylase, 846

Acidosis (Continued)

A bands, 72, 73f, 90f

Achalasia, 783, 819

synaptic transmission and, 570

A wave, 107f, 108

Achlorhydria, 797, 820

treatment of, 398

Abdominal cavity

Acid(s). See also Acid-base balance;

Acini, pancreatic, 799

fluid accumulation in, 177, 306, 860

Acidosis; Hydrogen ions.

salivary, 793, 961-962

pressure in, 177

definition of, 383

Acne, testosterone and, 1005

Abdominal compression reflex, 213

ingestion of, 398

Acquired immunodeficiency syndrome

Abdominal muscles

ionization of, 385-386

(AIDS), T-cell destruction in, 447

during parturition, 1037

nonvolatile, 390

Acromegaly, 927, 927f, 974

in defecation, 790

strong, 384

Acrosome reaction, 1000

in respiration, 471, 472f

titratable, 394-395

Actin, 72-74, 73f, 74f

Abdominal veins, reservoir function of, 179

weak, 384

in pinocytosis, 19, 19f

ABO blood group, 451-453, 452f, 452t

Acid-base balance, 383-400

Actin filaments

Absence syndrome, 744

buffer systems in, 385-388, 387f. See also

in ameboid movement, 24

Acceleration

Buffer systems.

of cardiac muscle, 103

angular, 695-696, 695f

disorders of, 396-397, 396t. See also

of skeletal muscle, 72-73, 76-78, 76f

linear, 695

Acidosis; Alkalosis.

of smooth muscle, 93-94, 93f

Acceleratory forces

acid-base nomogram in, 399-400, 400f

Action potential. See also Membrane

centrifugal, 541-542, 542f

anion gap in, 400, 400t

potential.

linear, 542-543, 543f

diagnosis of, 398-400, 399f, 400f, 400t

cardiac muscle, 104-106, 104f, 105f. See

Acclimatization, 519

gastrointestinal tract obstruction and,

also Cardiac muscle, contraction of.

cold, 896

824-825, 824f

at sinus node, 116-118, 117f, 120f

heat, 893-894, 900, 1065

mixed, 399

atrial transmission of, 117f, 118, 118f,

high altitude. See High altitude.

potassium concentration in, 366

120f

natural, 540, 540f

isohydric principle of, 388

duration of, 105

work capacity and, 540

neonatal, 1048

excitation-contraction coupling and, 106

Accommodation

nomogram for, 399-400, 400f

hyperpolarization of, 67-68

ocular, 617-618, 617f, 649-650

normal values for, 399-400, 400f

plateau in, 67-68, 104f, 105

of pacinian corpuscle, 576

renal regulation of, 308, 390-400

refractory period of, 105-106, 105f

Acetate, blood flow and, 203

ammonia buffer system in, 393-394,

relative refractory period of, 105-106,

Acetazolamide, 403t, 404

394f

105f

Acetoacetic acid, 844, 861, 966, 966f

bicarbonate reabsorption in, 390-392,

rhythmicity of, 67-68, 67f, 117-118, 117f

Acetone, 844, 966

390f-392f, 395, 395t

through atrioventricular node, 117f,

Acetone breath, 844, 976

hydrogen ion secretion in, 390-392,

118-119, 118f, 120f

Acetyl coenzyme A, 22f, 23

391f, 392f, 395, 395t

through internodal pathways, 117f, 118,

degradation of, 833-835, 834f

in acidosis, 396, 396t

118f, 120f

fatty acid conversion of, 844-845, 845f

in alkalosis, 396-397, 396t

through Purkinje system, 117f, 119, 120f

fatty acid degradation to, 842-843, 843f

phosphate buffer system in, 392-393,

velocity of, 105

oxidation of, 843, 861

393f

ventricular transmission of, 117f,

pyruvic acid conversion to, 23, 833, 833f

quantification of, 394-395, 395t

119-120, 120f

Acetylcholine, 562-563, 562t, 730f, 731

respiratory regulation of, 388-389, 388f,

gastrointestinal smooth muscle, 772-773,

botulinum toxin effect on, 88, 88f

389f

772f

bronchial effects of, 479

Acid-base nomogram, 399-400, 400f

inspiratory, 514

coronary blood flow and, 251

Acidophils, 919, 919f, 920t

neural, 9, 61-65, 61f-64f, 564-568, 564f,

curare effect on, 88, 88f

Acidosis, 384, 390

566f, 567f. See also

destruction of, 87

ammonium ion excretion in, 394

Neurotransmitters; Synapse(s).

drug effects on, 88-89

hydrogen ion secretion in, 395

absolute refractory period of, 70

in cardiac function, 121, 148

in hemorrhagic shock, 283-284

all-or-nothing principle of, 66

in gallbladder emptying, 803

metabolic, 386, 399f, 400f

anesthetic effect on, 70

in gastrointestinal function, 775

anion gap in, 400, 400t

anions in, 64

in pancreatic secretion, 800-801

calcium reabsorption in, 372

calcium in, 64-65, 86, 86f, 560

molecular biology of, 88

diagnosis of, 398-400, 399f, 400f, 400t

cathode ray recording of, 70-71, 70f

pepsinogen secretion and, 798

hyperchloremic, 400, 400t

conduction of, 68-69, 69f

receptors for, 86-87, 86f, 87f, 96, 752

in chronic renal failure, 411f, 412

depolarization stage of, 61-62, 61f

REM sleep and, 741

in diabetes mellitus type I, 973-974, 973f

electrode excitation of, 69

secretion of, 750-751

potassium concentration in, 366

elicitation of, 69-70, 69f

in bronchiolar function, 479

renal correction of, 396, 396t

energy metabolism and, 66, 66f

in skeletal muscle function, 85-88,

oxygen-hemoglobin dissociation curve in,

frequency of, 575

86f-88f

508, 508f

generation of, 566, 566f

in smooth muscle function, 96

plasma calcium in, 371

hyperpolarization of, 67f, 68

structure of, 751

potassium secretion in, 371

inhibition of, 70

synthesis of, 751

renal tubular, 397, 413

initiation of, 65, 69

Acetylcholine channel, 48, 85-88, 86f-88f

respiratory, 386, 389, 399f, 400f

local, 69, 69f

Acetylcholine pathway, 710, 710f

diagnosis of, 398-400, 399f, 400f

plateau in, 66-67, 67f

Acetylcholinesterase, 87

hydrogen ion secretion in, 395

point of origin of, 566, 566f

drug inactivation of, 89

in diver, 547

positive feedback in, 9

Acetyl-CoA. See Acetyl coenzyme A.

renal correction of, 396, 396t

potassium in, 61-65, 61f-64f, 66

1067

1068

Index

Action potential (Continued)

Adenosine

Adrenal diabetes, 951-952

propagation of, 65-66, 65f

in blood flow, 196-197, 247, 251-252

Adrenal gland, 906f, 944, 945f. See also

receptor potential and, 574, 574f

in irreversible shock, 284

Adrenal cortex; Adrenal medulla.

recording of, 70-71, 70f

Adenosine diphosphate (ADP)

Adrenal medulla, 907t, 944, 945f

refractory period of, 70

formation of, 22, 22f

epinephrine secretion by, 207-208, 755,

repolarization stage of, 61f, 62

in glycolysis regulation, 836

756

resting, 61, 61f, 564-565, 564f

in platelet plug formation, 458

function of, 755

rhythmicity of, 67-68, 67f

oxygen utilization and, 508-509, 509f

norepinephrine secretion by, 207-208, 755,

safety factor for, 66, 70

rate-limiting activity of, 884

756

saltatory conduction of, 68-69, 69f

Adenosine monophosphate (AMP), 830

sympathetic nerve endings in, 749-750,

sodium in, 61-65, 61f-64f, 66, 87,

cyclic (cAMP)

755

87f

in adrenal steroid synthesis, 955

Adrenalin. See Epinephrine.

subthreshold, 69, 69f

second messenger activity of, 912,

Adrenergic receptors, 752, 753t

threshold for, 65, 69-70, 69f

913-914, 913f, 913t

Adrenocorticotropin/adrenocorticotropic

voltage-gated potassium channel in,

thyroid-stimulating hormone function

hormone (ACTH), 907t, 918, 919f,

62-63, 62f, 64, 64f

and, 938

920t

voltage-gated sodium channel in, 62,

Adenosine triphosphatase (ATPase), 23,

aldosterone secretion and, 950

62f, 64, 64f

835-836, 835f

corticotropin-releasing factor regulation

vs. stimulus artifact, 70f, 71

in muscle contraction, 76

of, 955

olfactory, 667-668

in renal potassium secretion, 368, 368f

cortisol secretion and, 955-957, 956f

retinal, 637-638, 637f

in sodium-potassium pump, 53, 53f

excess of, 958-959, 959f

skeletal muscle, 89-91, 90f, 91f. See also

Adenosine triphosphate (ATP), 829-830,

inhibition of, 955

Muscle (skeletal), contraction of.

830f, 881-884

structure of, 955

excitation-contraction coupling in,

cellular utilization of, 23-24, 23f, 829-830,

thyroid hormone effects on, 937

89-91, 91f

830f, 883-884, 883f

Adrenogenital syndrome, 959, 960f

initiation of, 87-88, 88f

formation of, 17, 22-24, 22f, 23f, 829-830,

Afterdischarge, 581-582, 581f

safety factor for, 88

830f, 881

Afterload, 110f, 111

T tubules in, 89, 90f

anaerobic, 836-837

Age

smooth muscle, 96-98, 97f

in citric acid cycle, 834, 834f, 836

cardiac output and, 232, 233f, 237

calcium in, 97

in fatty acid oxidation, 842-844, 843f

growth hormone and, 927

of gastrointestinal tract, 772-773

in glycolysis, 832-837, 833f

pulse pressure and, 173, 173f

plateau of, 96-97, 97f

in mitochondria, 17, 22-24, 22f, 23f,

vision and, 618

spontaneous generation of, 97

835-836, 835f

Agglutination, antigen, 444, 445

stretch excitation of, 97

in oxidative phosphorylation, 835-836,

in transfusion reactions, 452-453

Action tremor, 705, 707

835f

Agglutinins

Activator operator, 35f, 36

summary of, 836

anti-A, 452, 452t, 453, 453t

Active transport, 19, 46, 46f, 52-56

in action potential, 66

anti-B, 452, 452t, 453, 453t

adenosine triphosphate in, 882

in active transport, 882

anti-Rh, 453

co-transport, 54-55, 55f

in cardiac muscle, 251-252

Agglutinogens, 451-452, 452t

renal, 329-330, 330f, 333-334

in glandular secretion, 882

Aggressiveness, 720

sodium-amino acid, 55, 816

in glycolysis regulation, 836

Agouti-related protein, 868-870, 869t

sodium-glucose, 55, 55f, 816, 831

in irreversible shock, 284

Air. See also Nitrogen; Oxygen.

counter-transport, 54-55

in metabolism, 829-830, 830f

alveolar, 493-496

renal, 330, 330f, 333

in muscle contraction, 77, 79-80, 881-882

carbon dioxide concentration in,

in tubular reabsorption, 328-332,

in nerve conduction, 882

495-496, 495f, 496f

328f-331f

phosphocreatine interrelation with, 882

composition of, 493-494, 493t

primary, 53-54, 53f

phosphofructokinase inhibition by, 836

humidification of, 494

renal, 328f, 329

structure of, 22

oxygen concentration in, 494-495, 495f,

secondary, 54-55

Adenosine triphosphate (ATP) synthetase,

496f

renal, 329-330, 330f

renewal rate of, 494, 494f

through cellular sheets, 55-56, 56f

Adenyl cyclase-cAMP second messenger

atmospheric, composition of, 493-494,

Actomyosin filaments, of lymphatic

system, 913-914, 913f, 913t

493t

capillary, 193

ADH. See Antidiuretic hormone (ADH).

dead space, 495-496, 496f

Acupuncture, 603

Adipocytes (fat cells), 842

expired, 495-496, 496f

Adaptation

Adipokines, 905

Air embolism

of olfactory receptors, 668

Adipose cell lipase, 970

brain surgery and, 178

of pacinian corpuscle, 575-576, 575f

Adipose tissue, 842, 906f

submarine escape and, 550

of retinal receptors, 631-632, 632f

brown, 887-888, 896

Air hunger (dyspnea), 527, 531, 532

of sensory receptors, 575-576, 575f

fat storage in, 965

Air travel. See Aviation.

of taste receptors, 666

glucose transport to, 965

Airway obstruction, 526, 526f

of thermal receptors, 608

in athlete, 1055

in asthma, 529

pain receptors and, 599

in feeding regulation, 871

in atelectasis, 528-529, 529f

to cold, 896

lipoprotein lipase of, 841, 842

in emphysema, 526-527, 527f, 528f

to dark, 631-632, 632f

triglycerides of, 12f, 842

Airway resistance, in emphysema,

to heat, 893-894, 900, 1065

Adiposogenital syndrome, 1009, 1009f

527

to high altitude. See High altitude.

ADP. See Adenosine diphosphate (ADP).

Akinesia, 711

to light, 631-632, 632f

Adrenal cortex, 907t, 944, 945f

Alanine, 853f

Adaptive control, 9

disorders of, 957-960, 959f, 960f

glucose formation from, 857

Addisonian crisis, 958

hormones of, 944-960. See also

synthesis of, 856, 856f

Addison’s disease, 342, 957-958

Aldosterone; Androgens, adrenal;

Alarm response, 208, 757, 758

hyperkalemia in, 366, 370

Cortisol.

Albinism, 628

sodium excretion in, 363, 379

layers of, 944-945, 945f

Albino, 628

Adenine, 27, 28f, 29, 29f

tumor of, 959, 960f

Albumin, 855-857, 855f. See also Plasma

Adenohypophysis. See Pituitary gland,

zona fasciculata of, 944-945, 945f

proteins.

anterior.

zona glomerulosa of, 944, 945f

capillary diffusion of, 184, 184t

Adenoma, thyroid, 940

zona reticularis of, 945, 945f

colloid osmotic pressure and, 188

Index

1069

Albumin (Continued)

Alkalosis (Continued)

Amino acids (Continued)

fatty acid binding to, 841

respiratory, 386, 399f, 400f

cortisol effects on, 952

thyroxine binding to, 934

altitude and, 539

co-transport of, 55, 854

urinary, 317

causes of, 397

deamination of, 856, 862

Albuminuria, 317

diagnosis of, 398-400, 399f, 400f

essential, 853f, 855

Albuterol, 759

hydrogen ion secretion in, 395

extracellular, 4, 46f, 854-855

Alcohol ingestion

renal correction of, 396-397, 396t, 539

facilitated diffusion of, 50, 966, 969

headache and, 607

synaptic transmission and, 570

gastrointestinal absorption of, 854

peptic ulcers and, 821

treatment of, 398

glucose formation from, 857

Aldosterone, 907t, 946f, 947t

whole-body, 824

hydrogen bonds of, 854

ACTH effects on, 950

Allergen, 449

insulin secretion and, 969

angiotensin and, 225

Allergy, 449-450

interstitial, 294t

arterial pressure and, 225, 230f, 231,

anaphylaxis in, 285-286, 287, 449-450

intracellular, 22, 22f, 46f, 294t. See also

948-949, 948f

atopic, 449

Adenosine triphosphate (ATP).

cellular effects of, 949-950

basophils in, 436

nonessential, 855-856, 856f, 862

deficiency of, 947-948, 957

cortisol in, 954

oxidation of, 856-857

potassium balance and, 342

delayed-reaction, 449

peptide linkages of, 34-35, 808, 810, 810f,

sodium balance and, 342, 379

eosinophils in, 436

852, 881

excess of, 948-949, 948f, 959

in asthma, 529

plasma concentration of, 854-855

alkalosis and, 398

mast cells in, 436

cortisol effects on, 952

hypertension and, 223

neonatal, 1049

insulin deficiency and, 967

potassium balance and, 342

Allograft, 455

proximal tubular transport of, 330, 330f

sodium balance and, 342, 379

All-or-nothing principle, 66

renal threshold for, 854

extracellular fluid osmolarity and,

Alpha brain waves, 742, 742f, 743, 743f

RNA codons for, 31-32, 32t

362-363, 363f

Alpha receptors, 251, 752, 753t

storage of, 854-855

functions of, 947-950, 948f

Altitude. See High altitude.

transamination of, 856, 856f, 862, 877

hepatic metabolism of, 947

Alveolar macrophages, 433, 481

urinary, 413

hydrogen ion secretion and, 395

Alveolar membrane, 5.

Aminoaciduria, 413

in cardiac failure, 263-264

Alveolar pressure, 472-473, 472f

Aminopolypeptidase, 810, 810f

in extracellular sodium regulation,

Alveolar ventilation, 477-478

Aminotransferases, 856

362-363, 363f

alveolar Pco₂ and, 494-495, 495f

Amitriptyline, 745

in heat acclimatization, 893, 1065

arterial Pco₂ and, 521, 521f

Ammonia, 862. See also Urea.

in pregnancy, 1034

arterial Pco₂ and, 519-520, 519f

Ammonia buffer system, 393-394, 394f

inhibitors of, 403t, 404

dead space and, 477-478, 478f

Ammonium chloride, in alkalosis, 398

intestinal sodium absorption and,

Pco₂ and, 495-496, 495f, 517, 517f

Ammonium citrate, 467

814-815, 814f, 949

pH and, 388-389, 388f, 517, 517f

Ammonium ion, 393-394, 394f

intracellular potassium and, 366, 366t

rate of, 478, 494, 494f

Amnesia

nongenomic actions of, 950

ventilation-perfusion ratio and, 499-501,

anterograde, 737

plasma protein binding of, 947

500f

retrograde, 725, 726

potassium effects on, 950

wasted, 500-501

Amniotic fluid, 1035

potassium secretion and, 366, 369-370,

Alveolus (alveoli), 479, 479f. See also

Amorphosynthesis, 592

369f, 370f, 378, 948

Lungs.

Amphetamines, 759

protein synthesis and, 915, 949-950

air in, 493-496

exercise and, 1066

radioimmunoassay of, 916, 916f

carbon dioxide concentration in,

in obesity, 873

receptor for, 949-950

495-496, 495f, 496f

Ampulla, 693f, 694

regulation of, 950, 951f

composition of, 493-494, 493t

Amygdala, 737-738, 870

renin-angiotensin system effects on, 225,

humidification of, 494

Amylase, pancreatic, 799, 809, 809f

950, 951f

oxygen concentration in, 485, 494-495,

Amylin, 961

salivary gland effects of, 949

495f, 496f

Amyloid plaques, 746

sodium effects on, 950

renewal rate of, 494, 494f

Amyloidosis, 409

sodium reabsorption and, 225, 342, 342t,

carbon dioxide diffusion into, 504-505,

Anaerobic energy, 836-837, 882-883

378-379, 948

505f

Anal sphincters, 789

structure of, 908f

collapse of (atelectasis), 528-529, 529f

Analgesia system, of central nervous

sweat gland effects of, 949

fluid in, 487

system, 602-603, 602f

synthesis of, 945-947, 946f, 947t

gas exchange in. See Gas exchange.

Anaphase, 37f, 39

tumor-related secretion of, 223, 959

interstitial pressure effect on, 488, 488f

Anaphylaxis, 285-286, 287, 449-450

Aldosterone antagonists, 403t, 404

J receptors of, 521

slow-reacting substance of, 450, 480,

Aldosterone escape, 379, 948-949

occlusion of, 474

529

Aldosteronism. See Aldosterone, excess of.

oxygen diffusion from, 502-503, 503f

Anatomic dead space, 478

Alimentary tract, 771, 772f. See also

pressures in, 472-473, 472f, 492

Anchoring filaments, of lymphatic capillary,

Gastrointestinal tract and specific

structure of, 496, 496f, 497f

191, 192f

components.

surface tension of, 473-474

Androgens. See also Testosterone.

Alkali

type II epithelial cells of, 474

adrenal, 944, 957, 1003, 1018

definition of, 383-384

walls of, 496, 497f

tumor-related excess of, 959, 960f

ingestion of, 398

Alzheimer’s disease, 746

chemistry of, 1003, 1004f

Alkaline phosphatase, 990

Amacrine cells, 634, 635, 635f, 636

exercise and, 1065-1066

Alkalosis, 384, 390

Ambenonium, 759

ovarian, 1003

metabolic, 386, 399f, 400f

Ameboid movement, 24, 24f, 431

Androstenedione, 946f

aldosterone excess and, 949

Ameloblasts, 992

Anemia, 422, 426-427

calcium reabsorption in, 372

Amenorrhea, 938, 1023

aplastic, 426

causes of, 397-398

Amiloride, 403t, 404

blood loss, 426

diagnosis of, 398-400, 399f, 400f

Amino acids, 33-35, 34f, 810, 810f, 852-854,

bone marrow response to, 422

hydrogen ion secretion in, 395

853f. See also Protein(s).

cardiac effects of, 236-237, 236f, 427

potassium concentration in, 366

active transport of, 854

exercise and, 427

renal correction of, 396-397, 396t

blood concentration of, 854

hematocrit in, 293

plasma calcium in, 371

glucagon secretion and, 971

hemolytic, 427

1070

Index

Anemia (Continued)

Antibody (antibodies) (Continued)

Aorta

hypochromic, 421f, 425, 426

agglutination by, 444, 445

baroreceptors of, 209-212, 209f

in erythroblastosis fetalis, 454

agglutinin, 452, 452t, 453, 453t

chemoreceptors of, 211-212, 518-519,

in kidney disease, 412, 423

bivalent, 444, 444f

518f

megaloblastic, 421f, 427

classes of, 444

coarctation of, 227, 274

microcytic hypochromic, 421f, 426

complement interaction with, 445-446,

pressure in, 109, 173, 173f

pernicious, 423, 427, 797, 820, 877

445f

Aortic body, 211-212, 518, 518f

sickle cell, 421f, 424, 427

direct action of, 444

mechanism of action of, 518-519

Anencephaly, 697

for passive immunity, 449

Aortic-coronary bypass surgery, 256

Anesthesia

formation of, 442-446, 443f-445f

Aortic pressure curve, 109

cardiac arrest and, 156

in human milk, 1041

Aortic regurgitation

cardiac output and, 242, 242f

lysis by, 444, 445, 445f

circulatory dynamics in, 272-273

local, 70

mechanisms of action of, 444-446,

heart sounds in, 271f, 272

neurogenic shock and, 285

445f

pulse pressure in, 173, 173f, 174

respiratory effects of, 522

neutralization by, 444, 445

Aortic stenosis

synaptic transmission and, 570

precipitation by, 444

circulatory dynamics in, 272-273

Angina pectoris, 145, 255-256. See also

salivary, 794

congenital, 274

Myocardial infarction.

sensitizing, 449

heart sounds in, 271f, 272

Angiogenesis

specificity of, 444, 444f

pulse pressure in, 173, 173f, 174

growth factors in, 41, 200-201

structure of, 443-444, 444f

Aortic valve, 109, 109f

high altitude effects on, 539-540

Anticholinesterase drugs, 759

Aphagia, 868

Angiogenic factors, 41, 200-201

Anticoagulants

Aphasia, 721

Angiogenin, 200

clinical, 466-468

Aplysia, 724, 724f

Angioplasty, coronary, 256

endogenous, 459, 463-464

Apnea, sleep, 522-523

Angiotensin I, 223f, 224

Anticodons, 32-33, 32f

Apocrine glands. See Sweating.

Angiotensin II. See also Renin-angiotensin

Antidepressants, 745

Apoferritin, 425

system.

Antidiuretic hormone (ADH), 907t, 918,

Apolipoprotein E, 746

arteriolar effects of, 201-202

919f

Apoptosis, 40

extracellular fluid osmolarity and,

blood flow and, 202

Apotransferrin, 425, 426

362-363

functions of, 928-929

Appendix, inflammation of, 605, 605f

formation of, 223f, 224

in extracellular fluid sodium regulation,

Appetite, 734, 781, 867, 870. See also

in cardiac failure, 263

358-359, 358f, 362-363, 362f

Feeding; Food, intake of.

glomerular filtration rate and, 322, 322t,

in hemorrhagic shock, 281

brain area of, 795

325

in urine concentration, 337, 350-351, 353,

salt, 363

in arterial pressure regulation, 201-202,

356, 379

Apraxia, motor, 687

224-226, 225f, 226f, 378

in urine dilution, 337, 348-350, 349f

Aquaporins, 928

in extracellular volume control, 377-378

secretion of, 220

Aqueous humor, 623-624, 623f, 624f

in hemorrhagic shock, 281

arterial pressure and, 360, 360t

Arachnoidal villi, 765

in pressure natriuresis, 378, 378f

blood volume and, 360, 360f, 360t

Arcuate arteries, 309, 309f

in renal blood flow, 322, 322t

cardiopulmonary reflexes and, 360

Arcuate veins, 309f, 310

in renal ischemia, 413

drug effects on, 360t, 361

Arginine, 853f

in sodium excretion, 377-378

hypothalamus and, 734

Argyll Robertson pupil, 650

in sodium reabsorption, 342-343, 342t

in cardiac failure, 264

Arm

in tubular reabsorption, 342, 342t

inappropriate, 357, 379

lever system of, 82, 82f

in water reabsorption, 342-343, 342t

nausea and, 360-361

veins of, 178

thirst and, 361, 361t

plasma osmolarity and, 358-360, 358f,

Arrhenoblastoma, 1003

urine output and, 342

360t

Arrhythmias, 147-156. See also at specific

Angiotensin II antagonists, glomerular

regulation of, 358-361, 358f-360f, 360t,

arrhythmias.

filtration rate and, 325

928-929

arrest, 156

Angiotensin-converting enzyme (ACE)

thirst system integration with, 362-363,

atrial fibrillation, 155-156, 155f

inhibitors

362f

atrial flutter, 156, 156f

glomerular filtration rate and, 325

structure of, 928

atrioventricular block, 148-150, 149f

pressure natriuresis effects of, 378, 378f

synthesis of, 359-360, 359f

intraventricular block, 150, 150f

Angiotensinase, 223f, 224

vasoconstrictor effects of, 929

paroxysmal tachycardia, 151-152, 153f

Angiotensinogen, 223f, 224

water reabsorption and, 337, 338, 342t,

premature contraction, 150-151, 150f, 151f

Angular acceleration, 695-696, 695f

343, 348-349, 379, 734

sinoatrial block, 148, 148f

Angular gyrus, 716, 716f, 718

Antigen(s), 440, 441f. See also Antibody

sinus, 148, 148f

Anion gap, 400, 400t

(antibodies).

ventricular fibrillation, 152-155, 153f-155f

Anions

antibody interaction with, 442, 444-446,

Arterial blood pressure, 166-167, 166f

action potential and, 64

445f

abdominal compression reflex and, 213

blood flow and, 203

HLA, 455-456

aldosterone effects on, 225, 948-949, 948f

Annulospiral ending, 675-676

red blood cell, 451-454, 452f, 452t, 453t

angiotensin effect on, 201-202, 224-226,

Anorexia, 874

self-, 448

225f, 226f, 378

Anorexia nervosa, 874

Antigen-presenting cells, 446, 446f

antidiuretic hormone effect on, 360, 379

Anorexigenic substances, 868, 869t

Antihemophilic factor (factor VIII), 459t,

auscultation of, 175, 175f

Anovulation, 1021, 1024-1025

465

baroreceptor response to, 6-7, 209-212,

Anterior commissure, 722

Antimuscarinic drugs, 759

209f-211f, 230, 230f

Anterograde amnesia, 737

Antioncogenes, 41

blood flow and, 164, 164f. See also Blood

Anterolateral sensory pathway, 587,

Antiperistalsis, 824

flow.

595-597, 596f

Antipyrine, for total body water

blood volume and, 172, 172f, 219-220,

Antibiotics

measurement, 296

220f

in peptic ulcers, 821

Antithrombin III, 463-464

body fluid volume and, 219-220, 220f,

renal toxicity of, 406

Antithyroid drugs, 939-940

374-376, 375f

Antibody (antibodies), 432, 441, 441f. See

Anuria

capillary fluid shift and, 230f, 231

also at Immunoglobulin.

in cardiac failure, 259, 263-264

cardiac output and, 114, 114f, 219-220,

affinity constant of, 444

in kidney failure, 405, 406

220f

Index

1071

Arterial blood pressure (Continued)

Artery (arteries) (Continued)

centrifugal acceleratory force effects on,

renal control of, 216-231, 230f, 308, 323,

diameter of, 167-168, 168f

542, 542f

341-342, 374-376, 375f, 376f. See also

distensibility of, 171, 173-176, 173f-176f

cerebral blood flow and, 762-763, 763f

Kidneys; Renal tubules.

function of, 161

chemoreceptor response to, 211-212, 230,

aldosterone escape and, 948-949, 948f

hardening of, 848-851, 849f. See also

230f

angiotensin in, 223-226, 224f-226f

Arteriosclerosis; Atherosclerosis;

control of, 163, 230-231, 230f

atrial reflexes and, 212

Myocardial infarction.

capillary fluid shift mechanism in, 230f,

baroreceptor reflexes and, 211

mean pressure in, 175-176, 176f

231

experimental demonstration of, 217,

nitric oxide synthesis in, 199-200

hypothalamus in, 207, 733, 733f

217f

parallel circuits of, 168-169, 169f

neural. See Arterial blood pressure,

graphical analysis of, 217-218, 218f

pressure in. See Arterial blood

nervous system control of.

peripheral resistance and, 219-220,

pressure.

renal. See Arterial blood pressure, renal

219f, 220f

pressure pulse in, 174-175, 174f

control of.

quantitation of, 217-220, 217f-220f

sympathetic innervation of, 172, 173f, 204,

stress-relaxation mechanisms in,

renal resistance and, 219

205f

230-231, 230f

renin-angiotensin system in, 223-226,

volume-pressure curves of, 172, 172f

diastolic, 162, 163f, 173, 175-176, 175f

224f-226f

Articulation, 721-722, 721f. See also

diuresis and, 216, 217-220, 217f-220f

salt intake/output and, 218-219, 218f,

Language; Speech.

during exercise, 208, 213-214, 235-236,

220, 224-226, 226f

Artificial cooling, 900

248-249, 248f

water intake/output and, 218-219, 218f,

Artificial kidney (dialysis), 414-415, 414f,

equilibrium point of, 217-218

224-226, 226f

415t

frequency distribution of, 210, 211f

renin-angiotensin system effects on,

Artificial respiration, 532, 532f

hemorrhage effect on, 224, 224f

224-226, 224f-226f

Arytenoid cartilage, 481, 481f

high. See Hypertension.

respiratory waves in, 214

Ascites, 177, 306, 381, 860

high-fidelity measurement of, 166-167,

salt sensitivity of, 229, 229f

in thiamine deficiency, 876

167f

sodium excretion and, 374-375, 375f

Ascorbic acid. See Vitamin C (ascorbic

in cardiogenic shock, 262

stress relaxation and, 230-231, 230f

acid).

in cerebral ischemia, 212-213

systemic (greater, peripheral), 162, 163f

Asparagine, 853f

in circulatory shock, 279, 279f

systolic, 162, 163f, 173, 175-176, 175f, 220

Aspartic acid, 853f

in extracellular fluid balance, 374-376,

thirst and, 361, 361t

Aspirin, peptic ulcers and, 821

375f, 376f

thyroid hormone effects on, 937

Astereognosis, 591

in hemorrhage, 224, 224f

units of, 166-167

Asthenia, 974

in hemorrhagic shock, 279-280, 279f, 280f

urine output and, 216, 323, 341-342,

Asthma, 436, 450, 480, 529

in polycythemia, 428

374-376, 375f, 376f

Astigmatism, 620, 620f

in sodium balance, 374-376, 375f

aldosterone escape and, 948-949,

Astronauts. See Space travel.

integrated regulation of, 230-231, 230f

948f

Ataxia, 706

low-pressure receptor response to, 212

quantitation of, 217-220, 217f-220f

Atelectasis, 528-529, 529f

Mayer waves of, 214, 214f

vascular resistance and, 170, 170f, 219,

Atherosclerosis, 842, 848-851, 849f. See also

mean, 175-176, 176f, 220

219f, 220, 220f

Arteriosclerosis.

measurement of, 166-167, 166f, 167f,

vasoconstrictor tone and, 206, 207f

arterial pressure in, 175

175-176, 175f, 178

vasomotor waves of, 214, 214f

blood pressure in, 175

neonatal, 1047

vasopressin effect on, 202

cholesterol in, 850

nervous system control of, 208-213, 230,

Arteriole(s), 181, 182f

coronary, 252, 256. See also Myocardial

230f, 235-236, 235f, 755

angiotensin effect on, 201-202

infarction; Myocardial ischemia.

abdominal compression reflex in, 213

antidiuretic hormone effects on, 929

in Alzheimer’s disease, 746

adrenal medullae in, 207-208

autonomic nervous system control of, 204,

in hypothyroidism, 942

atrial reflex in, 212

205f, 754t

lipoproteins in, 850

Bainbridge reflex in, 212

blood distribution to, 162f

prevention of, 850-851

baroreceptors in, 209-212, 209f-211f,

bradykinin effect on, 202

renal, 408

214, 214f

cross-sectional area of, 162

risk factors for, 850

Cushing reaction in, 213, 213f

diameter of, 168, 181

Athetosis, 709

during exercise, 208, 213-214

during exercise, 247-248

Athlete, 1055. See also Exercise.

ischemic response in, 212-213, 213f,

function of, 161

bradycardia in, 147

214, 214f

hepatic, 859

Atmospheric pressure, under water, 545,

norepinephrine in, 207

hydrogen ion effect on, 202-203

546f

parasympathetic system in, 205-206

intermittent contraction of (vasomotion),

Atony

rapidity of, 208-213, 209f-211f

182-183, 187

bladder, 313-314

reflex mechanisms in, 209-212,

nitric oxide synthesis in, 199-200

colonic, 822

209f-211f, 214, 214f

pressure pulse in, 174-175, 174f

ATP. See Adenosine triphosphate (ATP).

respiratory waves and, 214, 214f

renal, 309, 309f, 311f

Atrial fibrillation, 155-156, 155f, 156f, 273

stress and, 208

resistance of, 168

Atrial flutter, 156, 156f

sympathetic system in, 204-205, 205f,

Arteriosclerosis, 982. See also

Atrial natriuretic peptide, 907t

206-208, 206f

Atherosclerosis.

extracellular fluid volume and, 379-380

vasoconstriction and, 204-205, 205f,

diabetes mellitus and, 976

in cardiac failure, 264

206-208, 206f

pulse pressure in, 173, 173f

tubular reabsorption and, 342t, 343

vasodilation and, 208

Arteriovenous fistula, cardiac output in, 236,

Atrial paroxysmal tachycardia, 152, 152f

vasomotor center in, 206-207, 206f,

236f, 242-243, 243f, 267, 267f

Atrial pressure

212-213, 213f, 214, 214f

Artery (arteries). See also Arteriole(s);

heart rate and, 212

volume reflex in, 212

Capillary (capillaries).

left, 107f, 108, 484, 487

normal, 175, 176f

autonomic nervous system control of,

edema and, 489, 489f

peripheral vascular resistance and, 170,

754-755, 754t

right, 176

170f, 219, 219f, 220, 220f

baroreceptors of. See Baroreceptor(s).

cardiac output and, 240-243, 240f-243f.

pressure diuresis and, 375-376, 375f,

blood flow in. See Blood flow.