Medical
Physiology
Principles for Clinical Medicine
Fourth Edition

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Medical
Physiology
Principles for Clinical Medicine
Fourth Edition

EDI T ED

B Y

Rodney A. Rhoades, Ph.D.
Professor Emeritus
Department of Cellular and Integrative Physiology
Indiana University School of Medicine
Indianapolis, Indiana

David R. Bell, Ph.D.
Associate Professor
Department of Cellular and Integrative Physiology
Indiana University School of Medicine
Fort Wayne, Indiana

p. ; cm.
Includes index.
ISBN 978-1-60913-427-3
1. Human physiology. I. Rhoades, Rodney. II. Bell, David R., 1952[DNLM: 1. Physiological Phenomena. QT 104]
QP34.5.M473 2013
612—dc23
2011023900
DISCLAIMER
Care has been taken to confirm the accuracy of the information present and to describe generally accepted practices. However,
the authors, editors, and publisher are not responsible for errors or omissions or for any consequences from application of the
information in this book and make no warranty, expressed or implied, with respect to the currency, completeness, or accuracy of
the contents of the publication. Application of this information in a particular situation remains the professional responsibility
of the practitioner; the clinical treatments described and recommended may not be considered absolute and universal recommendations.
The authors, editors, and publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are
in accordance with the current recommendations and practice at the time of publication. However, in view of ongoing research,
changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is
urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions.
This is particularly important when the recommended agent is a new or infrequently employed drug.
Some drugs and medical devices presented in this publication have Food and Drug Administration (FDA) clearance for
limited use in restricted research settings. It is the responsibility of the health care provider to ascertain the FDA status of each
drug or device planned for use in their clinical practice.
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9 8 7 6 5 4 3 2 1

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lucid, accurate, and up-to-date as possible, with clearly understandable explanations of processes and mechanisms. The chapters are written by medical school faculty members who have
had many years of experience teaching physiology and who are
experts in their field. They have selected material that is important for medical students to know and have presented this material in a concise, uncomplicated, and understandable fashion.
We have purposefully avoided discussion of research laboratory
methods, and/or historical material. Although such issues are
important in other contexts, most medical students prefer to
focus on the essentials. We have also avoided topics that are as
yet unsettled, while recognizing that new research constantly
provides fresh insights and sometimes challenges old ideas.
●

CONTENT AND
ORGANIZATION

This book begins with a discussion of basic physiologic
concepts, such as homeostasis and cell signaling, in

Chapter 1. Chapter 2 covers the cell membrane, membrane
transport, and the cell membrane potential. Most of the
remaining chapters discuss the different organ systems:
nervous (Chapters 3–7), muscle (Chapter 8), cardiovascular
(Chapters 11–17), respiratory (Chapters 18–21), renal
(Chapters 22–23), gastrointestinal (Chapters 25 and 26),
endocrine (Chapters 30–35), and reproductive physiology (Chapters 36–38). Special chapters on the blood
(Chapter 9), immunology (Chapter 10), and the liver
(Chapter 27) are included. The immunology chapter emphasizes physiologic applications of immunology. Chapters on
acid–base regulation (Chapter 24), temperature regulation (Chapter 28), and exercise (Chapter 29) discuss these
complex, integrated functions. The order of presentation
of topics follows that of most United States medical school
courses in physiology. After the first two chapters, the other

visual consistency with meaning from one figure to the next.
v

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vi

Preface

Artwork was also substantially overhauled to provide
a coherent style and point of view. An effort has also been
made to incorporate more conceptual illustrations alongside
the popular and useful graphs and tables of data. These beautiful new full-color conceptual diagrams guide students to an
understanding of the general underpinnings of physiology.
Figures now work with text to provide meaningful, comprehensible content. Students will be relieved to find concepts
“clicking” like never before.
Text

Another important improvement for the fourth edition is
that most chapters were not only substantially revised and
updated, but they were also edited to achieve unity of voice as
well as to be as concise as possible, both of which approaches
considerably enhance clarity.

All of the abundant chapter review questions (now numbering over 500) are again online and interactive. They have
been updated to United States Medical Licensing Examination (USMLE) format with explanations for right and wrong
answers. These questions are analytical in nature and test

The clinical focus boxes have once again been updated
for the fourth edition. These essays deal with clinical applications of physiology rather than physiology research. In
addition, we are reprising the “From Bench to Bedside”
essays introduced in the third edition. Because these focus
on physiologic applications in medicine that are “just around
the corner” for use in medical practice, readers will eagerly
anticipate these fresh, new essays published with each successive edition.
Students will appreciate the book’s inclusion of such
helpful, useful tools as the glossary of text terms, which has
been expanded by nearly double for the fourth edition and
corresponds to bolded terms within each chapter. Updated
lists of common abbreviations in physiology and of normal
blood values are also provided in this edition.
As done previously, each chapter includes two online
case studies, with questions and answers. In addition, a
third, new style of case study has been added in each chapter,
designed to integrate concepts between organ function and
the various systems. These might require synthesizing material across multiple chapters to prepare students for their
future careers and get them thinking like clinicians.

• Active Learning Objectives. These active statements are
supplied to the student to indicate what they should be
able to do with chapter material once it has been mastered.
• Readability. The text is a pleasure to read, and topics
are developed logically. Difficult concepts are explained
clearly, in a unified voice, and supported with plentiful
illustrations. Minutiae and esoteric topics are avoided.
• Vibrant Design. The fourth edition interior has been
completely revamped. The new design not only makes
navigating the text easier, but also draws the reader in


•

•

•
•

the physiology discussed in the chapter to clinical medicine and help the reader make those connections.
Bulleted Chapter Summaries. These bulleted statements
provide a concise summative description of the chapter,
and provide a good review of the chapter.
Abbreviations and Normal Values. This third edition
includes an appendix of common abbreviations in physiology and a table of normal blood, plasma, or serum values on the inside book covers for convenient access. All
abbreviations are defined when first used in the text, but
the table of abbreviations in the appendix serves as a useful
reminder of abbreviations commonly used in physiology
and medicine. Normal values for blood are also embedded
in the text, but the table on the inside front and back covers
provides a more complete and easily accessible reference.
Index. A comprehensive index allows the student to easily look up material in the text.
Glossary. A glossary of all boldfaced terms in the text is
included for quick access to definition of terms.

Ancillary Package

Still more features round out the colossal ancillary package
online at
. These bonus offerings provide ample
opportunities for self-assessment, additional reading on tangential topics, and animated versions of the artwork to further elucidate the more complex concepts.

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Contributors
DAVID R. BELL, PH.D.
Associate Professor of Cellular and Integrative Physiology
Indiana University School of Medicine
Fort Wayne, Indiana
ROBERT V. CONSIDINE, PH.D.
Associate Professor of Medicine and Physiology
Indiana University School of Medicine
Indianapolis, Indiana
JEFFREY S. ELMENDORF, PH.D.
Associate Professor of Cellular and Integrative Physiology
Physiology
Indiana University School of Medicine
Indianapolis, Indiana

RODNEY A. RHOADES, PH.D.
Professor Emeritus
Department of Cellular and Integrative Physiology
Indiana University School of Medicine
Indianapolis, Indiana
GEORGE A. TANNER, PH.D.
Emeritus Professor of Cellular and Integrative Physiology
Indiana University School of Medicine
Indianapolis, Indiana
GABI NINDL WAITE, PH.D.
Associate Professor of Cellular and Integrative Physiology
Indiana University School of Medicine

Acknowledgments
We would like to express our deepest thanks and appreciation
to all of the contributing authors. Without their expertise
and cooperation, this fourth edition would have not been
possible. We also wish to express our appreciation to all
of our students and colleagues who have provided helpful comments and criticisms during the revision of this
book, particularly, Shloka Anathanarayanan, Robert Banks,
Wei Chen, Steve Echtenkamp, Alexandra Golant, Michael
Hellman, Jennifer Huang, Kristina Medhus, Ankit Patel, and
Yuri Zagvazdin. We would also like to give thanks for a job
well done to our editorial staff for their guidance and assistance in significantly improving each edition of this book.
A very special thanks goes to our Developmental Editor,

Kelly Horvath, who was a delight to work with, and whose
patience and editorial talents were essential to the completion of the fourth edition of this book. We are indebted as
well to our artist, Kim Battista. Finally, we would like to
thank Crystal Taylor, our Acquisitions Editor at Lippincott
Williams and Wilkins, for her support, vision, and commitment to this book. We are indebted to her administrative
talents and her managing of the staff and material resources
for this project.
Lastly, we would like to thank our wives, Pamela Bell
and Judy Rhoades, for their love, patience, support, and
understanding of our need to devote a great deal of personal
time and energy to the development of this book.

ix

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Robert V. Considine, Ph.D.
CHAPTER 2 •

Plasma Membrane Structure 24
Solute Transport Mechanisms 26
Water Movement Across the Plasma Membrane
Resting Membrane Potential 39

PA RT I I •

24

37

NE UROM U SCU LAR PHYSIOLOGY

42

Action Potential, Synaptic Transmission,
and Maintenance of Nerve Function
John C. Kincaid, M.D.
CHAPTER 3 •

42

Neuronal Structure 42
Action Potentials 46
Synaptic Transmission 51
Neurotransmission 54


Spinal Cord in the Control of Movement 96
Supraspinal Influences on Motor Control 98

92

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Contents

xi

Cerebral Cortex Role in Motor Control 100
Basal Ganglia and Motor Control 103
Cerebellum in the Control of Movement 105

Autonomic Nervous System
John C. Kincaid, M.D.

108

CHAPTER 6 •

Overview of the Autonomic Nervous System 108
Sympathetic Nervous System 110
Parasympathetic Nervous System 113
Control of the Autonomic Nervous System 114

Integrative Functions of the Central
Nervous System


CHAPTER 9 •

143

166
166

Blood Functions 166
Whole Blood 167
Soluble Components of Blood and Their Tests 167
Formed Elements of Blood and Their Tests 170
Red Blood Cells 175
White Blood Cells 178
Blood Cell Formation 180
Blood Clotting 182
CHAPTER 10 •

Immunology, Organ Interaction,

and Homeostasis
Gabi Nindl Waite, Ph.D.

188

Immune System Components 188
Immune System Activation 189
Immune System Detection 191
Immune System Defenses 191
Cell-Mediated and Humoral Responses 194

Physics of Blood Containment and Movement 216
Physical Dynamics of Blood Flow 218
Distribution of Pressure, Flow, Velocity, and Blood Volume 224

Electrical Activity of the Heart
David R. Bell, Ph.D.

227

CHAPTER 12 •

Electrophysiology of Cardiac Muscle
Electrocardiogram 236

228

CHAPTER 13 • Cardiac Muscle Mechanics and the Cardiac Pump 248
David R. Bell, Ph.D.
Cardiac Excitation-Contraction Coupling 249
Cardiac Cycle 251
Determinants of Myocardial Performance 253
Cardiac Output 260
Cardiac Output Measurement 262
Imaging Techniques for Measuring Cardiac Structures, Volumes,
Blood Flow, and Cardiac Output 263

Systemic Circulation
David R. Bell, Ph.D.

267

Hepatic Circulation 303
Skeletal Muscle Circulation 304
Cutaneous Circulation 305
Fetal and Placental Circulations 306

Control Mechanisms in Circulatory Function
David R. Bell, Ph.D.
CHAPTER 17 •

311

Autonomic Neural Control of the Circulatory System 311
Hormonal Control of the Cardiovascular System 317
Circulatory Shock 321

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Contents

PA RT V •

RESPI R AT OR Y PHYSIOLOGY

326

Ventilation and the Mechanics of Breathing
Rodney A. Rhoades, Ph.D.

Pulmonary Circulation and Ventilation/Perfusion
Rodney A. Rhoades, Ph.D.

CHAPTER 20 •

369

Functional Organization 369
Hemodynamic Features 370
Fluid Exchange in Pulmonary Capillaries 374
Blood Flow Distribution in the Lungs 376
Shunts and Venous Admixture 378
Bronchial Circulation 380

Control of Ventilation
Rodney A. Rhoades, Ph.D.

382

CHAPTER 21 •

Generation of the Breathing Pattern 382
Lung and Chest Wall Reflexes 386
Feedback Control of Breathing 387
Chemoresponses to Altered Oxygen and Carbon Dioxide
Control of Breathing During Sleep 392
Control of Breathing in Unusual Environments 394

PA RT VI •



399

427

427

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xiv

Contents

Sodium Balance 436
Potassium Balance 442
Calcium Balance 445
Magnesium Balance 446
Phosphate Balance 446
Urinary Tract 447

Acid–Base Homeostasis
George A. Tanner, Ph.D.

451

CHAPTER 24 •

Basic Principles of Acid–Base Chemistry
Acid Production 453

Rodney A. Rhoades, Ph.D.
CHAPTER 26 •

505

Salivary Secretion 505
Gastric Secretion 508
Pancreatic Secretion 511
Biliary Secretion 515
Intestinal Secretion 519
Carbohydrates Digestion and Absorption 520
Lipid Digestion and Absorption 523
Protein Digestion and Absorption 526
Vitamin Absorption 528
Electrolyte and Mineral Absorption 530
Water Absorption 534

Liver Physiology
Rodney A. Rhoades, Ph.D.

536

CHAPTER 27 •

Liver Structure and Function 536
Drug Metabolism in the Liver 539
Energy Metabolism in the Liver 540
Protein and Amino Acid Metabolism in the Liver
Liver as Storage Organ 545
Endocrine Functions of the Liver 548

Heat Acclimatization 565
Responses to Cold 567
Clinical Aspects of Thermoregulation 570
CHAPTER 29 • Exercise Physiology
Frank A. Witzmann, Ph.D.

575

Oxygen Uptake and Exercise 575
Cardiovascular Responses to Exercise 577
Respiratory Responses to Exercise 580
Skeletal Muscle and Bone Responses to Exercise 582
Gastrointestinal, Metabolic, and Endocrine Responses to Exercise
Aging and Immune Responses to Exercise 586

PA RT I X •

E ND O CR INE PHYSIOLOGY

589

Endocrine Control Mechanisms
Jeffrey S. Elmendorf, Ph.D.

589

CHAPTER 30 •

General Concepts of Endocrine Control
Hormone Classes 593


CHAPTER 33 •

Functional Anatomy 633
Metabolism of Adrenal Cortex Hormones
Adrenal Medulla Hormones 647

Rhoades_FM.indd xv

622

635

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xvi

Contents

Endocrine Pancreas
Jeffrey S. Elmendorf, Ph.D.

649

CHAPTER 34 •

Islets of Langerhans 649
Insulin and Glucagon Influence on Metabolic Fuels
Diabetes Mellitus 660

Endocrine Glands of the Male Reproductive System
Testicular Function and Regulation 677
Male Reproductive Organs 679
Spermatogenesis 683
Endocrine Function of the Testis 685
Androgen Action and Male Development 688
Male Reproductive Disorders 690

676

Female Reproductive System
Robert V. Considine, Ph.D.
CHAPTER 37 •

693

Hormonal Regulation of the Female Reproductive System 693
Female Reproductive Organs 695
Folliculogenesis, Steroidogenesis, Atresia, and Meiosis 696
Follicle Selection and Ovulation 701
Menstrual Cycle 703
Estrogen, Progestin, and Androgen Metabolism 708
Infertility 709
CHAPTER 38 • Fertilization, Pregnancy, and Fetal Development
Robert V. Considine, Ph.D.

712

Ovum and Sperm Transport 713
Fertilization and Implantation 714

Upon mastering the material in this chapter you should be
able to:
• Identify important variables essential for life and discuss
how they are altered by external and internal forces.
Explain how homeostasis benefits the survival of an
organism when such forces alter these essential variables.
• Explain the differences between negative and positive
feedback and discuss their relationship to homeostasis.
• Contrast steady and equilibrium states in terms of
whether an organism must expend energy to create
either state.
• Understand how gap junctions and plasma membrane
receptors regulate communications between cells.
• Explain how paracrine, autocrine, and endocrine

Rhoades_Chap01.indd 1

•

•
•
•

signaling are different relative to their roles in the control
of cell function.
Understand how second messengers regulate and
amplify signal transduction.
Explain the interrelationship between the control of
intracellular calcium concentration or the ways in which
calcium is stored in terms of how it is used to transduce

membranes is described in thermodynamic terms, muscle
contraction is analyzed in terms of forces and velocities, and
regulation in the body is described in terms of control systems theory. Because the functions of a living system are carried out by its component structures, an understanding of
its structure from its gross anatomy to the molecular level is
relevant to the understanding of physiology.
The scope of physiology ranges from the activities or
functions of individual molecules and cells to the interaction of our bodies with the external world. In recent years,
we have seen many advances in our understanding of physiologic processes at the molecular and cellular levels. In higher
organisms, changes in cell function occur in the context of the
whole organism, and different tissues and organs can affect

•

OBJ E CTIVE S

BASIS OF PHYSIOLOGIC
REGULATION

Our bodies are made up of incredibly complex and delicate materials, and we are constantly subjected to all kinds
1

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●
2

Part I / Cellular Physiology

of disturbances, yet we keep going for a lifetime. It is clear


Body cells

Skin

●

Figure 1.1 The living cells of our body, surrounded by
an internal environment (extracellular fluid), communicate
with the external world through this medium. Exchanges of
matter and energy between the body and the external environment (indicated by arrows) occur via the gastrointestinal tract,
kidneys, lungs, and skin (including the specialized sensory
organs). 

Rhoades_Chap01.indd 2

to maintain a relatively constant internal environment. A
good example is the ability of warm-blooded animals to
live in different climates. Over a wide range of external
temperatures, core temperature in mammals is maintained
constant by both physiologic and behavioral mechanisms.
This stability offers great flexibility and has an obvious survival value.
Homeostasis is the maintenance of steady
states in the body by coordinated
physiologic mechanisms.

The key to maintaining the stability of the body’s internal
environment is the masterful coordination of important
regulatory mechanisms in the body. The renowned physiologist Walter B. Cannon captured the spirit of the body’s capacity for self-regulation by defining the term homeostasis as
the maintenance of steady states in the body by coordinated


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●
3

Chapter 1 / Homeostasis and Cellular Signaling

The multitude of biochemical reactions characteristic of
a cell must be tightly regulated to provide metabolic energy
and proper rates of synthesis and breakdown of cellular
constituents. Metabolic reactions within cells are catalyzed
by enzymes and are therefore subject to several factors that
regulate or influence enzyme activity:
• First, the final product of the reactions may inhibit the
catalytic activity of enzymes, a process called end-product
inhibition. End-product inhibition is an example of
negative-feedback control (see below).
• Second, intracellular regulatory proteins such as the
calcium-binding protein calmodulin may associate with
enzymes to control their activity.
• Third, enzymes may be controlled by covalent modification, such as phosphorylation or dephosphorylation.
• Fourth, the ionic environment within cells, including
hydrogen ion concentration ([H+]), ionic strength, and
calcium ion concentration, influences the structure and
activity of enzymes.
Hydrogen ion concentration or pH affects the electrical charge of the amino acids that comprise a protein, and
this contributes to their structural configuration and binding properties. A measure of acidity or alkalinity, pH affects
chemical reactions in cells and the organization of structural

Negative feedback promotes stability, and
feedforward control anticipates change.

Engineers have long recognized that stable conditions can
be achieved by negative-feedback control systems (Fig. 1.2).
Feedback is a flow of information along a closed loop. The
components of a simple negative-feedback control system
include a regulated variable, sensor (or detector), controller
(or comparator), and effector. Each component controls the
next component. Various disturbances may arise within or
outside the system and cause undesired changes in the regulated variable. With negative feedback, a regulated variable
is sensed, information is fed back to the controller, and the
effector acts to oppose change (hence, the term negative).
A familiar example of a negative-feedback control system is the thermostatic control of room temperature. Room
temperature (regulated variable) is subjected to disturbances.
For example, on a cold day, room temperature falls. A thermometer (sensor) in the thermostat (controller) detects the
room temperature. The thermostat is set for a certain temperature (set point). The controller compares the actual temperature (feedback signal) with the set point temperature,
and an error signal is generated if the room temperature falls
below the set temperature. The error signal activates the furnace (effector). The resulting change in room temperature is
monitored, and when the temperature rises sufficiently, the
furnace is turned off. Such a negative-feedback system allows
some fluctuation in room temperature, but the components

Feedforward
controller
Command

+

Feedforward path

feedforward control systems. In a negative-feedback control
system, information flows along a closed loop. The regulated
variable is sensed, and information about its level is fed back
to a feedback controller, which compares it with a desired
value (set point). If there is a difference, an error signal is generated, which drives the effector to bring the regulated variable
closer to the desired value. In this example, the negative sign
at the end of the feedback bath signifies that the controller is
signaled to move the regulated variable in the opposite direction of the initial disturbance. A feedforward controller generates commands without directly sensing the regulated variable,
although it may sense a disturbance. Feedforward controllers
often operate through feedback controllers.

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●
4

Part I / Cellular Physiology

act together to maintain the set temperature. Effective communication between the sensor and effector is important in
keeping these oscillations to a minimum.
Similar negative-feedback systems exist to maintain
homeostasis in the body. For example, the maintenance of
water and salts in the body is referred to as osmoregulation
or fluid balance. During exercise, fluid balance can be altered
as a result of water loss from sweating. Loss of water results
in an increased concentration of salts in the blood and tissue
fluids, which is sensed by the cells in the brain as a negative
feedback (see Chapter 23, “Regulation of Fluid and Electrolyte Balance”). The brain responds by telling the kidneys to
reduce secretion of water and also by increasing the sensation of being thirsty. Together the reduction in water loss in

for the good of the body, they are sometimes deficient, inappropriate, or excessive. Many diseases, such as cancer, diabetes, and hypertension, develop because of defects in these
control mechanisms. Alternatively, damaged homeostatic

Rhoades_Chap01.indd 4

mechanisms can also result in autoimmune diseases, in
which the immune system attacks the body’s own tissue.
Formation of a scar is an example of an important homeostatic mechanism for healing wounds, but in many chronic
diseases, such as pulmonary fibrosis, hepatic cirrhosis, and
renal interstitial disease, scar formation goes awry and
becomes excessive.
Positive feedback promotes a change in one
direction.

With positive feedback, a variable is sensed and action is
taken to reinforce a change of the variable. The term positive
refers to the response being in the same direction, leading
to a cumulative or amplified effect. Positive feedback does
not lead to stability or regulation, but to the opposite—a progressive change in one direction. One example of positive
feedback in a physiologic process is the sensation of needing to urinate. As the bladder fills, mechanosensors in the
bladder are stimulated and the smooth muscle in the bladder wall begins to contract (see Chapter 23, “Regulation of
Fluid and Electrolyte Balance”). As the bladder continues to
fill and become more distended, the contractions increase
and the need to urinate becomes more urgent. In this example, responding to the need to urinate results in a sensation
of immediate relief upon emptying the bladder, and this is
positive feedback. Another example of positive feedback
occurs during the follicular phase of the menstrual cycle.
The female sex hormone estrogen stimulates the release of
luteinizing hormone, which in turn causes further estrogen
synthesis by the ovaries. This positive feedback culminates in

●
5

Chapter 1 / Homeostasis and Cellular Signaling

Total body water = ~60% of body weight
Extracellular
compartment:
Intracellular
compartment:

20% of body weight
Interstitial fluid

40% of body weight

Plasma
Transcellular fluid

● Figure 1.3 Fluid compartments in the body. The
body’s fluids, which comprise about 60% of the total body
weight, can be partitioned into two major compartments: the
intracellular compartment and the extracellular compartment.
The intracellular compartment, which is about 40% of the
body’s weight, is primarily a solution of potassium, other ions,
and proteins. The extracellular compartment, which is about
20% of the body weight, comprising the interstitial fluids,
plasma, and other fluids, such as mucus and digestive juices,
is primarily composed of NaCl and NaHCO3.


both suggest stable conditions, but a steady state does not
necessarily indicate an equilibrium condition, and energy
expenditure may be required to maintain a steady state. For
example, in most body cells, there is a steady state for Na+
ions; the amounts of Na+ entering and leaving cells per unit
time are equal. But intracellular and extracellular Na+ ion
concentrations are far from equilibrium. Extracellular [Na+]
is much higher than intracellular [Na+], and Na+ tends to
move into cells down concentration and electrical gradients. The cell continuously uses metabolic energy to pump
Na+ out of the cell to maintain the cell in a steady state with
respect to Na+ ions. In living systems, conditions are often
displaced from equilibrium by the constant expenditure of
metabolic energy.
Figure 1.4 illustrates the distinctions between steady
state and equilibrium. In Figure 1.4A, the fluid level in the
sink is constant (a steady state) because the rates of inflow
and outflow are equal. If we were to increase the rate of
inflow (open the tap), the fluid level would rise, and with
time, a new steady state might be established at a higher level.
In Figure 1.4B, the fluids in compartments X and Y are not in
equilibrium (the fluid levels are different), but the system as
a whole and each compartment are in a steady state, because

B

5 L/min

C

5 L/min

Part I / Cellular Physiology

inputs and outputs are equal. In Figure 1.4C, the system is
in a steady state and compartments X and Y are in equilibrium. Note that the term steady state can apply to a single
or several compartments; the term equilibrium describes the
relation between at least two adjacent compartments that can
exchange matter or energy with each other.
Coordinated body activity requires
integration of many systems.

Body functions can be analyzed in terms of several systems,
such as the nervous, muscular, cardiovascular, respiratory,
renal, gastrointestinal, and endocrine systems. These divisions are rather arbitrary, however, and all systems interact
and depend on each other. For example, walking involves
the activity of many systems besides the muscle and skeletal
systems. The nervous system coordinates the movements of
the limbs and body, stimulates the muscles to contract, and
senses muscle tension and limb position. The cardiovascular
system supplies blood to the muscles, providing for nourishment and the removal of metabolic wastes and heat. The
respiratory system supplies oxygen and removes carbon
dioxide. The renal system maintains an optimal blood composition. The gastrointestinal system supplies energy-yielding metabolites. The endocrine system helps adjust blood
flow and the supply of various metabolic substrates to the
working muscles. Coordinated body activity demands the
integration of many systems.
Recent research demonstrates that many diseases
can be explained on the basis of abnormal function at the
molecular level. These investigations have led to incredible
advances in our knowledge of both normal and abnormal
cellular functions. Diseases occur within the context of
a whole organism, however, and it is important to understand


Paracrine
Receptor

Nervous

Target cell

Neuron

Synapse

Endocrine
Endocrine cell

Target cell
Bloodstream

Neuroendocrine

Target cell
Bloodstream

● Figure 1.5 Modes of intercellular signaling. Cells may
communicate with each other directly via gap junctions or
chemical messengers. With autocrine and paracrine signaling,
a chemical messenger diffuses a short distance through the
extracellular fluid and binds to a receptor on the same cell or
a nearby cell. Nervous signaling involves the rapid transmission of action potentials, often over long distances, and the
release of a neurotransmitter at a synapse. Endocrine signaling


Cytoplasm

Cell membrane

Ions,
nucleotides,
etc.

Connexin
Channel

Paired connexons
● Figure 1.6 The structure of gap junctions. The channel
connects the cytosol of adjacent cells. Six molecules of the
protein connexin form a half channel called a connexon. Ions
and small molecules such as nucleotides can flow through the
pore formed by the joining of connexons from adjacent cells.

junctions are thought to play a role in the control of cell
growth and differentiation by allowing adjacent cells to
share a common intracellular environment. Often when
a cell is injured, gap junctions close, isolating a damaged
cell from its neighbors. This isolation process may result
from a rise in calcium or a fall in pH in the cytosol of the
damaged cell.
Cells communicate locally by paracrine and
autocrine signaling.

Cells may signal to each other via the local release of chemical

contractile machinery in the vascular smooth muscle cell
and produces relaxation or a decrease of tone (see Chapter 8,
“Skeletal and Smooth Muscle,” and Chapter 15, “Microcirculation and Lymphatic System”).
In contrast, during autocrine signaling, the cell releases
a chemical messenger into the extracellular fluid that binds
to a receptor on the surface of the cell that secreted it (see
Fig. 1.5). Eicosanoids (e.g., prostaglandins) are examples of
signaling molecules that can act in an autocrine manner.
These molecules act as local hormones to influence a variety
of physiologic processes such as uterine smooth muscle contraction during pregnancy.
Nervous system provides for rapid and
targeted communication.

The CNS includes the brain and spinal cord, which links the
CNS to the peripheral nervous system (PNS), which is composed of nerves or bundles of neurons. Together the CNS
and the PNS integrate and coordinate a vast number of sensory processes and motor responses. The basic functions of
the nervous system are to acquire sensory input from both
the internal and external environment, integrate the input,
and then activate a response to the stimuli. Sensory input to
the nervous system can occur in many forms, such as taste,
sound, blood pH, hormones, balance or orientation, pressure, or temperature, and these inputs are converted to signals
that are sent to the brain or spinal cord. In the sensory centers of the brain and spinal cord, the input signals are rapidly
integrated, and then a response is generated. The response is
generally a motor output and is a signal that is transmitted to
the organs and tissues, where it is converted into an action
such as a change in heart rate, sensation of thirst, release of
hormones, or a physical movement. The nervous system is
also organized for discrete activities; it has an enormous number of “private lines” for sending messages from one distinct
locus to another. The conduction of information along nerves
occurs via electrical signals, called action potentials, and signal

NO
synthase
(inactive)

NO
synthase
(active)
Arginine

NO + Citrulline

NO

GTP
+

[Ca2 ]

PKG
targets

Endothelial
cell

R

PKG

GMP
PDE

skills and speech. PD is characterized by muscle rigidity, tremors, and slowing of physical movements. These symptoms are
the result of excessive muscle contraction, which is a result
of insufficient dopamine, a neurotransmitter produced by
the dopaminergic neurons of the brain. The symptoms of PD
result from the loss of dopamine-secreting cells in a region of
the brain that regulates movement. Loss of dopamine in this
region of the brain causes other neurons to fire out of control,
resulting in an inability to control or direct movements in a normal manner. There is no cure for PD, but several drugs have
been developed to help patients manage their symptoms,
although they do not halt the disease. The most commonly
used drug is levodopa (L-DOPA), a synthetic precursor of

Rhoades_Chap01.indd 8

Endocrine system provides for slower and
more diffuse communication.

The endocrine system produces hormones in response to
a variety of stimuli, and these hormones are instrumental
in establishing and maintaining homeostasis in the body.
In contrast to the rapid, directed effects resulting from neuronal stimulation, responses to hormones are much slower
(seconds to hours) in onset, and the effects often last longer.
Hormones are secreted from endocrine glands and tissues
and are broadcast to all parts of the body by the bloodstream
(see Fig. 1.5). A particular cell can only respond to a hormone if it possesses the appropriate receptor (“receiver”)
for the hormone. Hormone effects may also be focused. For

Clinical Focus / 1.1
dopamine. L-DOPA is taken up in the brain and changed into
dopamine, allowing the patient to regain some control over his

more will be recognized in years to come. Nerve growth factor
enhances nerve cell development and stimulates the growth of
axons. Epidermal growth factor (EGF) stimulates the growth
of epithelial cells in the skin and other organs. Platelet-derived
growth factor stimulates the proliferation of vascular smooth
muscle and endothelial cells. Insulin-like growth factors
stimulate the proliferation of a wide variety of cells and mediate
many of the effects of growth hormone. Growth factors appear
to be important in the development of multicellular organisms
and in the regeneration and repair of damaged tissues.
Nervous and endocrine control systems
overlap.

The distinction between nervous and endocrine control systems is not always clear. This is because the nervous system
exerts control over endocrine gland function, most if not all
endocrine glands are innervated by the PNS, and these nerves
can directly control the endocrine function of the gland. In
addition, the innervation of endocrine tissues can also regulate blood flow within the gland, which can impact the distribution and thus function of the hormone. On the other hand,
hormones can affect the CNS to alter behavior and mood.
Adding to this highly integrated relationship is the presence
of specialized nerve cells, called neuroendocrine, or neurosecretory cells, which directly convert a neural signal into a
hormonal signal. These cells thus directly convert electrical
energy into chemical energy, and activation of a neurosecretory cell results in hormone secretion. Examples are the hypothalamic neurons, which liberate releasing factors that control
secretion by the anterior pituitary gland, and the hypothalamic
neurons, which secrete arginine vasopressin and oxytocin into
the circulation. In addition, many proven or potential neurotransmitters found in nerve terminals are also well-known
hormones, including arginine vasopressin, cholecystokinin,
enkephalins, norepinephrine, secretin, and vasoactive intestinal peptide. Therefore, it is sometimes difficult to classify a
particular molecule as either a hormone or a neurotransmitter.
●


Hormone
(First messenger)

Extracellular fluid

Receptor

Cell membrane

G protein
(Transducer)
Intracellular fluid

Effector
Adenylyl cyclase
Guanylyl cyclase
Phospholipase C

Phosphorylated precursor

Second messenger

ATP
GTP
Phosphatidylinositol
4,5-bisphosphate

cAMP
cGMP