Integrated Physiology and Pathophysiology

Visit the link below to download the full version of this book:

https://medipdf.com/product/integrated-physiology-and-pathophysiology/

Click Download Now

 INTEGRATED PHYSIOLOGY and

PATHOPHYSIOLOGY
Julian L. Seifter, MD
James G. Haidas Distinguished Chair in Medicine, Brigham
and Women’s Hospital
Master Clinician Educator, Brigham and Women’s Hospital
Associate Professor of Medicine
Harvard Medical School
Boston, MA, USA

Elisa C. Walsh, MD.

Instructor in Anesthesia
Department of Anesthesia, Critical Care and Pain Medicine
Massachusetts General Hospital
Boston, MA, USA

David E. Sloane, MD, EdM

Instructor in Medicine
Division of Allergy and Immunology
Brigham and Women’s Hospital
Dana Farber Cancer Institute
West Roxbury VA Medical Center
Harvard Medical School
Boston, MA, USA

Artist, illustrator, or editorial assistant

(if to appear on the title page):

Elsevier
Philadelphia, PA
Elsevier
1600 John F. Kennedy Blvd.
Ste 1800
Philadelphia, PA 19103-2899

INTEGRATED PHYSIOLOGY AND PATHOPHYSIOLOGY, ISBN: 978-0-323-59732-6

Copyright © 2022 by Elsevier, Inc. All rights reserved.

No part of this publication may be reproduced or transmitted in any form or by any means, electronic or
mechanical, including photocopying, recording, or any information storage and retrieval system, without
permission in writing from the publisher. Details on how to seek permission, further information about the
Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance
Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions.

This book and the individual contributions contained in it are protected under copyright by the Publisher
(other than as may be noted herein).

Notice

Practitioners and researchers must always rely on their own experience and knowledge in evaluating
and using any information, methods, compounds or experiments described herein. Because of rapid
advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages
should be made. To the fullest extent of the law, no responsibility is assumed by Elsevier, authors, editors
or contributors for any injury and/or damage to persons or property as a matter of products liability,
negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas
contained in the material herein.

Library of Congress Control Number: 2021932143

Content Strategist: Elyse O’Grady

Content Development Specialist: Meghan B. Andress
Publishing Services Manager: Deepthi Unni
Project Manager: Radjan Lourde Selvanadin
Design Direction: Bridget Hoette

Printed in India

Last digit is the print number: 9 8 7 6 5 4 3 2 1

 To Betsy, Andrew, Ellie, and Lori,
and in Memory of Charles

Julian Seifter

With love and gratitude to

Marcia
Richard
Susan
Barry and Sandi
Tsila
Nesya, Avi, Moshe, Shalva, and Talya

And in loving memory of

Joe
Irv and Fay

A time for all, and a season for everything under the heavens.
(Ecclesiastes 3:1)

David Sloane
P R E FAC E

You probably suspect that knowing the basic concepts and se- Box, and thereafter a consideration of the treatment of that
lected details of human physiology is critically important. Not disease in a Pharmacology Box. The focus of the text is always
just for understanding the clinical manifestations of diseases, on the science and mechanisms of disease, not pathology or
but for designing and monitoring rational treatment. By asking clinical pharmacology.
the question “What processes are at work to cause this patient’s Clinical Correlation boxes focus on clinically relevant
symptoms and signs?” you are already on the way to asking and applications of physiology, while Fast Fact boxes highlight
answering the subsequent and related questions “What can we the selected facts that are useful to store in long-term memory
do to help this patient?” and “How can we know—what can we so that when you are thinking analytically, you have them at
observe and what can we measure to determine—if treatment the ready.
is working?” Themes: Several principles apply broadly to physiology and
But even more than this, a solid knowledge of physiology thus cross numerous organ systems. These are principles of
may help increase your powers of observation of patients. nature that you must be able to see clearly in different contexts.
When you know physiology, you have a sense of what to look, One of these themes is dynamism: physiology always sug-
listen, feel, and even smell for. Mastering physiology and think- gests motion as critical to life. For anything to happen in the
ing about it actively when you encounter a patient augments body, there must be forces at work. All physiologic phenomena,
your consciousness and sharpens your perception. It makes you from moving blood to moving ions, depend on gradients of
sensitive to important details and helps you distinguish be- pressure or concentration, gravitational force, and electrical
tween what to prioritize in the flow of data. It helps you think force. Part of mastering physiology means looking for a driving
mechanistically and creatively, dynamically, and carefully. force, seeking a reason for things to move. Why and how
This book can help you build that mastery of physiology. It (mechanistically) do things happen in the body? Ohm’s law, for
cannot do everything for you—you will have to work at it and example, is one of many important force-flow relationships. We
on yourself—because it is not an encyclopedia of physiology are talking about energy, and how pressure gradients drive fluid
with every detail. Instead it has expanded bullet points with flow and how voltage gradients drive current.
clear explanations describing medically relevant physiologic A second theme is homeostasis: there are several forms of
processes in health and disease. this, and they work on different levels of resolution from the
Here are a few of the salient features of this text that are the molecular up to the whole human organism. Negative feedback
result of pedagogic considerations. systems maintain physiologic variables like pH, body tempera-
Structure and Function: Most chapters start off reviewing ture, and the extracellular concentration of potassium within a
the basic human body structures (from gross anatomy down to range of utility. Positive feedback mechanisms result in explosive
molecules) germane to the physiology. Structure and function phenomena, such as operate in malignancies. Other systems are
are inextricably intertwined and reinforce each other. You need “feed forward” or anticipatory.
to know the basic composition and arrangement of the systems None of these systems is dichotomous—rather, physiologic
to understand dynamic processes, and learning those processes processes work on a continuum by gradations. We often tell
will help to organize and recall the structures because you know students “Most of the time, you are better off answering a ques-
what they do. tion with a range rather than a number.” There are two such
Case studies: Case studies are narratives that help organize ranges. One is the range of values found in a population of
information in conceptual and realistic ways. They may not be healthy individuals. The second is the range of values that a
studies of large populations in randomized controlled trials, variable can take in a given individual based on perturbations
but they are critical evidence that complement such studies. from a homeostatic set point and physiologic compensatory
Cases can demonstrate the variety of disease phenotype among mechanisms.
individuals. For example, there is no single normal value for the serum
Boxes: Often, the history of the understanding of a disease sodium, but there is a range of, for example, 136 to 143 mEq/L
starts with observation of its character, then moves to treatment in a given laboratory, and within a given person, the variability
(sometimes discovered serendipitously), and only thereafter to is generally tighter, such as less than 5%. Physiologic ranges are
investigating the basic mechanisms, as science fills in the gap determined by measuring the given variable in a large number
between observation and treatment. The smallpox vaccine, for of healthy volunteers, determining the mean and the standard
example, was developed well before the cellular and molecular deviation, and then defining the lower limit of the range as the
mechanisms of immunology that reveal how that vaccine works mean minus two standard deviations and the upper limit of the
were discovered. But for pedagogic purposes, we often present range as the mean plus two standard deviations.
information in an order different from the historical record of Just because something is found to be statistically significant
observation, treatment, and molecular insight. Typically, there does not indicate its physiologic importance. Only experience
is a discussion of the genetic basis of a disease in a Genetics Box, can tell us that. For example, if the thyroid stimulating hor-
then a description of how the disease arises in a Development mone (TSH) is slightly elevated or the platelet count is mildly
vi
 PREFACE vii

low, that does not mean that the patient necessarily has Vasoconstrictors and vasodilators may be at work simultane-
a disease. ously to provide fine control. In addition, a given mediator
But the inverse is true as well—just because a lab value is or substance, such as adenosine or oxygen, can have counter-
within the range does not mean that there is not a significant intuitive effects, such as vasoconstriction or vasodilation,
pathologic process at work. For example, a patient in respira- depending on the location and the context in which it operates.
tory distress from a severe asthma attack may have a partial This can be caused by different receptors for a given mediator
pressure of carbon dioxide within the normal physiologic range or the effects of other influences such as medications. A patient
when measured on an arterial blood gas, but given the context with anaphylaxis who takes a beta adrenergic blocker (which
of the asthma exacerbation, this normal value is actually an works through cyclic adenosine monophosphate [cAMP]) may
ominous sign that the patient is starting to tire and may die. not respond to the adrenergic receptor agonist epinephrine,
Because there are multiple influences on many physiologic vari- but can be treated with glucagon, which generates cAMP via
ables, you have to think about the context in which a given a distinct glucagon receptor. This text does not cover patho-
finding is present to determine its meaning. physiology exhaustively, but emphasizes the mechanisms of
Two key parts of thinking globally about homeostasis are disease states as they are are grounded in the basic physiology.
considering: (1) flows into and out of the body, and (2) multi- We hope that this text will be a helpful contribution to your
ple overlapping regulatory systems. Examples of the former growth in thinking critically about physiology.
include the daily intake and output of sodium and water. An JS
example of the latter is the sometimes additive and sometimes EW
antagonistic activities of various mediators, metabolites, hor- DS
mones, and neurotransmitters in the control of vascular tone.

ACKNOWLEDGEMENTS CONTRIBUTORS
We had critical assistance and invaluable expertise from many The precursor to this text was co-authored and co-edited with
at Elsevier. Austin Ratner, MD, and his positive influence on the organiza-
Elyse O’Grady, content strategist par excellence, oversaw the tion, writing, and thinking behind the present book endures.
project with grace, kindness, and patient persistence. While she An earlier version of the revised manuscript benefited from
maintained a broad view of the project, that did not prevent her important contributions from four students at Harvard Medi-
from working on specific details, especially regarding clear fig- cal School who deserve special thanks. Jasmine Thumb edited
ures. We want to acknowledge the contributions of authors of the neurology material, clarifying and adding new sections.
other textbooks published by Elsevier. Caleb Yeung edited the skeletal muscle chapter. Helen Xu edited
Megan Andress and Kathleen Nahm were content develop- the renal section. Dmitriy Timerman reviewed multiple chap-
ment specialists who did the critical work of gently reminding ters including those in the cardiac and pulmonary sections.
us of deadlines and coordinating with other staff at Elsevier While the text underwent major changes since their contribu-
once drafts were submitted. tions, their hard work catalyzed that transformation, for which
Radjan Lourde Selvanadin was the project manager who fer- we are grateful.
ried drafts to proofs and tirelessly inquired into and corrected
details.
Most importantly, we are indebted to the too numerous to
count medical and dental students who asked questions and
motivated us to think broadly and deeply about physiology,
explain it lucidly, and link it meaningfully to clinically relevant
pathophysiology.
CONTENTS

SECTION I Foundations, 1 8 The Lymphatic System and the Immune System, 118
1 General Principles of Physiology, 2 Introduction, 118
Foundations of Homeostasis, 2 Lymphatic System Structure, 118
Transport Processes in Life, 2 Lymphatic System Function, 119
Cell Membrane Structure and Transport Lymphatic System Pathophysiology, 122
Functions, 2 Introduction, 122
Types of Membrane Transport, 2 Innate Versus Adaptive Immunity, 122
Signal Transduction, 8 Immune System Structure, 123
Cell-Cell Communication, 8 Immune System Function, 131
Homeostasis, 8 Immune System Pathophysiology, 136
An Electromechanical Example of Homeostasis, 8 Case Study 8.1 Blood and Lymph, 140
Pathophysiology, 11 SECTION IV Cardiovascular Physiology, 142
Case Study 1.1 Introduction to Diagnosis, 13
9 The Vasculature, 143
SECTION II Neurophysiology, 15 Introduction, 143
2 An Overview of Nerve Cell Physiology and System Structure, 143
Electrophysiology, 16 System Function, 146
Introduction, 16 Pathophysiology, 152
Nerve Cell Structure and Function, 16 10 The Heart as a Pump, 156
Pathophysiology of Neurons, Glia, and Electrical Introduction, 156
Conduction, 27 System Structure, 156
3 Central Nervous System, 30 System Function, 158
Introduction, 30 Pathophysiology: Heart Failure, 164
Structure and Function: The Brain, 30 11 Cardiac Electrophysiology, 168
Structure and Function: The Spinal Cord, 42 Introduction, 168
Central Nervous System Pathophysiology, 47 System Structure, 168
4 Peripheral Nervous System and Autonomic Nervous System Function, 168
System, 52 Pathophysiology, 177
Introduction, 52 12 Exercise Physiology, 180
Peripheral Nervous System Structure, 52 Introduction, 180
Autonomic Nervous System Structure, 55 System Function, 180
Autonomic Nervous System Function, 59 Pathophysiology, 185
Autonomic Nervous System Pathophysiology, 61 Case Study 12.1 Cardiac Physiology, 187
5 The Neuromuscular Junction and Skeletal Muscle, 64 SECTION V Pulmonary Physiology, 189
Introduction, 64
System Structure, 64 13 The Mechanics of Breathing, 190
System Function, 70 Introduction, 190
Pathophysiology, 77 System Structure: The Thorax, 190
6 Smooth Muscle, 81 System Function: The Bellows, 194
Introduction, 81 Pathophysiology: Disorders of Pulmonary
System Structure, 81 Mechanics, 202
System Function, 83 Aging: Altered Lung Mechanics, 205
Pathophysiology, 92 14 Gas Exchange in the Lung, 207
Case Study 6.1 Musculoskeletal Physiology, 98 Introduction, 207
System Structure: The Distal Respiratory Tree and
Section III Circulatory Physiology, 100 Pulmonary Circulation, 207
7 Blood and the Endothelium, 101 System Function: Oxygenation and the Clearance
Introduction, 101 of Carbon Dioxide, 207
System Structure, 101 Pathophysiology, 217
System Function, 105
Pathophysiology, 112

viii
 CONTENTS ix

15 Gas Transport, 221 23 Micturition, 331

Introduction, 221 Introduction, 331
System Structure: Oxygen Reservoirs and System Structure: Anatomy of the Urinary System, 331
Hemoglobin, 221 System Function: The Transport of Urine and Its
System Function: Oxygen and Carbon Dioxide Neural Control, 333
Transport, 222 Pathophysiology: Urinary Incontinence, 336
Pathophysiology, 226 Case Study 23.1 Renal Physiology, 339
16 The Regulation of Breathing, 229
Core Concepts , 229 Section VII Gastrointestinal Physiology, 342
System Structure and Function, 229 24 Nutrition, Digestion, and Absorption, 343
Pathophysiology: Abnormal Patterns Introduction, 343
of Breathing, 237 System Structure, 343
Case Study 16.1 Pulmonary Physiology, 240 The Oral Cavity, 343
System Function, 347
Section VI Renal Physiology, 242 Pathophysiology, 362
17 Renal Structure and Function, 243 25 Control of Gastrointestinal Motility and Secretion, 366
Introduction, 243 Introduction, 366
System Structure: The Kidney, 243 System Structure, 366
System Function: The Kidney, 246 System Function, 370
Pathophysiology, 256 Pathophysiology, 378
18 Tubular Transport, 259 26 Hepatic Physiology, 382
Introduction, 259 Introduction, 382
System Structure: Functional Anatomy of the Kidney System Structure, 382
Tubule, 259 System Function, 382
System Function: Reabsorption and Secretion, 261 Pathophysiology, 387
Pathophysiology of the Kidney Tubule, 269 27 The Gastrointestinal Immune System, 391
19 The Regulation of Blood Pressure and Extracellular Introduction, 391
Fluid Volume, 273 Enteric Immune System Structure, 391
Introduction, 273 System Function, 394
System Structure: Body Fluid Compartments, 273 System Pathophysiology, 396
System Function: Blood Pressure Homeostasis, 273 Case Study 27.1 Gastrointestinal Physiology, 400
Pathophysiology, 286
20 Osmoregulation, 290 Section VIII Endocrine Physiology, 402
Introduction, 290 28 The Endocrine Pancreas: Fed and Fasted Metabolic
System Structure: Body Fluid Compartments, 290 States, 403
System Function: Homeostasis of Sodium Introduction, 403
Concentration, 290 System Structure: The Islets of Langerhans, 403
Pathophysiology: Disorders of Serum Osmolality System Function: The Regulation of Plasma Glucose
and Their Sequelae, 302 Concentration, 404
21 The Regulation of Potassium Balance, 306 Pathophysiology: Dysregulation of the Plasma
Introduction, 306 Glucose Level, 409
System Structure: The Distribution 29 The Pituitary Gland, 415
of Potassium, 306 Introduction, 415
System Function: Potassium Homeostasis, 306 System Structure, 415
Pathophysiology: Disorders of Plasma [K1] System Function, 417
Regulation, 311 Pathophysiology, 423
Hyperkalemia, 313 30 The Thyroid Gland, 428
Hypokalemia, 314 Introduction, 428
22 Acid-Base Homeostasis, 316 System Structure, 428
Introduction, 316 System Function, 432
System Structure: Components of the pH Regulatory Pathophysiology: Thyroid Hormone Excess and
Apparatus and the Distribution of Body Acid, 316 Deficiency, 436
System Function: The Variation and Control of pH, 317
Pathophysiology: Acidosis and Alkalosis, 325
x CONTENTS

31 The Adrenal Gland, 439 34 The Female Reproductive System, 478

Introduction, 439 Introduction, 478
System Structure: Adrenal Anatomy and System Structure, 478
Embryology, 439 System Function, 483
System Function: The Adrenal Cortex, 439 Pathophysiology, 491
Pathophysiology: Diseases of Cortical Over- and 35 Pregnancy and Parturition, 494
Underproduction, 445 The Organs of Pregnancy, 494
System Function: The Adrenal Medulla, 448 System Function: Pregnancy, 496
Pathophysiology: Medullary Dysfunction, 450 36 The Male Reproductive System, 506
32 Calcium Regulation: Parathyroid Physiology, 453 Introduction, 506
Introduction, 453 System Structure, 506
System Structure: The Parathyroid Glands and the System Function, 508
Distribution of Calcium and Phosphorus, 453 Pathophysiology, 515
System Function: Parathyroid Hormone and Case Study 36.1 Endocrine Physiology, 519
Vitamin D, 455
Pathophysiology, 464 e-only appendices:
33 Calcium Regulation: Bone Physiology, 469 Chapter 1, Appendix 1 5 Cell Membrane Structure
Introduction, 469 and Transport Functions
System Structure, 469 Chapter 1, Appendix 2 5 Cell Membrane Potential
System Function, 472 Chapter 1, Appendix 3 5 Signal Transduction
Pathophysiology, 475 Chapter 1, Appendix 4 5 Cell to Cell Communication
Chapter 1, Appendix 5 5 Endothelium
 SECTION I
Foundations

1
 1
General Principles of Physiology

FOUNDATIONS OF HOMEOSTASIS TRANSPORT PROCESSES IN LIFE

Life functions (e.g., growth and development, reproduction, Dynamic processes govern the movement of fluids and gases
breathing, cognition, movement, self-defense, and responses to within the body do not necessarily occur across cell membranes.
environmental stress) require either the input of energy into the The transport of fluids, such as blood and water like solutes, re-
body or the transformation of energy from one form to a more quires a driving force, such as a pressure gradient. The consequent
useful form by the body. For anything to happen in an organ- movement depends on the nature of any barrier and the magni-
ism, there must be a force, an energy, or work in the form of tude and direction of the pressure gradient.
some gradient—chemical, mechanical, or electrical. The hu- • The heart is a pump that generates a pressure, driving blood
man body is not at equilibrium with the environment, although through the circulation system, where the force is the hydro-
conditions may be fairly constant, in which the body is in or static, (or in a moving fluid hydraulic) pressure gradient and
near a steady state. the flow is blood flow.
The important physiologic force-flow relationships relate • The flow of gases in the respiratory tree follows the same pressure
“intensive” and “extensive” properties of state. These are called gradient rules, but unlike liquids, gases are compressible fluids.
conjugate properties. Fluids (liquids and gases) not only flow through tubes and
• Intensive properties have to do with each part of a system at across cell membranes, but they can leave the circulation by
large and are not additive. Chemical potential, electrical po- crossing capillary basement membranes into the extravascular
tential, temperature, and pressure are intensive properties of space surrounding cells, joining the interstitial fluid.
a system.
• Extensive properties, such as mass, moles, volume, charge, CELL MEMBRANE STRUCTURE AND
and entropy are additive.
For example, all the moles (extensive) of a part of a solution
TRANSPORT FUNCTIONS
add up to the total moles of substance, whereas the concentra- The contents of cells are sealed off from the extracellular environ-
tion (intensive) in each part of a solution is not additive. The ment by a lipid barrier called the plasma membrane that protects
concentration of salt in the harbor is the same at high and low the cell’s interior from the changing conditions of the extracellular
tide, but the volume and the moles of (sodium) Na1 are differ- environment and helps maintain the specific chemical milieu sup-
ent: There is a greater volume of solution and greater mass of porting intracellular metabolic processes. Additional background
Na1 at high tide. But the stable concentration, the ratio of information about the structure and function of the plasma
moles to volume, exemplifies that the quotient of two extensive membrane can be found in the online appendix to this chapter.
properties (solution volume and Na1 mass in this example) is
the conjugate intensive property (concentration).
The difference of an intensive property at two points of a sys-
TYPES OF MEMBRANE TRANSPORT
tem is the “driving force” for the conjugate extensive property: Because the plasma membrane is made up predominantly of
• Electrical gradients (intensive) drive flow of charge (extensive). hydrophobic (lipophilic) molecules, other hydrophobic mole-
• Pressure gradients (intensive) drive flow of volume (extensive). cules are able to enter or exit cells by dissolving into or through
• Chemical gradients (intensive) drive flow of moles (extensive). the membrane. Hydrophilic (lipophobic) molecules, however,
This chapter provides an overview of homeostasis, the ten- must cross the plasma membrane through water-filled channels
dency of the body’s physiologic systems to maintain a relatively or via specific carrier proteins.
stable state and internal milieu despite changing external and
internal environments by keeping physiologic variables within Transport Across the Plasma Membrane
acceptable ranges. Some background information and appendi- Transport across the plasma membrane occurs by several
ces available on the companion website for this text provide mechanisms, including:
detail on general properties of cell membranes, mechanisms by • Diffusion
which solutes and water traverse membranes, membrane trans- • Osmosis
port, mechanisms by which cells receive and respond to signals, • Endocytosis
and how cells in the body communicate with each other, all of • Exocytosis
which are means by which homeostasis occurs. • Protein-mediated transport
2
 CHAPTER 1 General Principles of Physiology 3

Passive transport
Transported (facilitated diffusion) Active transport
molecule

Channel Carrier
protein proteins

Lipid Electrochemical
bilayer gradient

Cytosol
Simple Channel- Carrier- Energy
diffusion mediated mediated
diffusion diffusion

(A) (B) (C) (D) (E)

Fig. 1.1 ​The transport of solutes across the plasma membrane. A. An electrochemical gradient favors the
movement of a solute from the extracellular to the intracellular space. B. If the solute is small and lipid-soluble,
it may pass through the membrane via simple diffusion. C. The solute may require a channel protein to facilitate
passive diffusion across the membrane. D. The facilitated diffusion may require a carrier protein to passively
carry the solute down its gradient. E. In active transport, the carrier protein requires metabolic energy to fulfill
its transport function because transport of the solute against its electrochemical gradient costs energy.

(Fig. 1.1). We would like to post appendices on the website for the membrane and the viscosity of the medium. It has units
this text. micrometers
such as and so resembles a velocity;
seconds
Diffusion and Osmosis • A denotes the surface area for diffusion in units, such as m2;
The diffusion of molecules across the plasma membrane is not and
carrier-mediated and does not require the expenditure of • C1 and C2 represent the respective concentrations of the
chemical energy directly produced by cells, but it depends on molecule across the permeability barrier in typical concen-
electrochemical gradients at adjacent points. Some solutes are tration units of mass per unit volume, such as moles .
permeable through plasma membranes or between cells and m3
may therefore diffuse across the barrier. One such form of dif- Thus small, uncharged molecules diffuse easily across a large
fusion is nonionic diffusion, in which a small electroneutral surface area with a steep concentration gradient (i.e., P, A, and
molecule crosses the cell membrane. (C12C2) are all large), whereas large or highly charged mole-
The magnitude and direction of solute diffusion across cell cules will not diffuse easily and will require protein-mediated
membranes are described quantitatively by Fick’s law of diffusion: transport to cross the membrane. A small surface area (A) or
small concentration gradient (C12C2) will likewise limit the
J  P  A  (C1  C2 )
rate of diffusion. When solutes are charged, the determination
where: of gradients is more complicated because one must account for
• J represents the net rate of diffusion of a solute from com- charge differences, or voltage, across the membrane.
partment 1 into compartment 2. As there may simultane- Osmosis is the diffusion of water across a semipermeable
ously be transport from compartment 2 to compartment 1, membrane from a solution of low solute concentration (which
the meaning of net transport is that the sign of the next thus can be thought of as a solution of high water concentra-
transports is determined by which direction (C1 to C2 or C2 tion) to one of higher solute concentration (and thus lower
to C1) dominates. When they are equal, this is called “steady water concentration). The concentration of “free” water mol-
state.” As it describes the movement of material across a ecules is greater in a solution with a lower solute concentration
moles because less water is occupied in charge interactions with the
membrane per unit time, it has units such as ;
seconds solute. The increased amount of free water molecules on one
• P is the permeability coefficient of the barrier separating the side of a membrane drives the diffusion of water from low
two compartments and is proportional (inversely) to molecu- solute concentration to high. Like diffusion, osmosis does not
lar size and (directly) to mobility of the solute molecule in the require energy expenditure by cells (see Clinical Correlation
medium (diffusivity) and inversely related to the thickness of Box 1.1).
4 SECTION I Foundations

Clinical Correlation Box 1.1 Bacterium

Dialysis
In patients who receive dialysis for kidney failure, two types of transport are
important. The movement of small molecules out of the blood stream occurs Pinocytosis
by diffusion, as the concentrations of waste products are lower in the dialysis
fluid than they are in the blood. Water is removed by filtration (also known as Endocytosis
Phagocytosis
convective or bulk flow). In hemodialysis, the hydraulic or hydrostatic pressure
gradients are produced by pumps in the dialysis machine, while in peritoneal
dialysis, osmotic gradients, usually accomplished with high concentrations of
Vesicle
glucose added to the peritoneal cavity, create osmotic pressure enabling water Phagosome
flow. But in all cases, for net movement to occur, a gradient must be present.
See the renal section for more information.
Early
endosome
Endocytosis and Exocytosis
Endocytosis is a mechanism for transporting substances too large
for diffusion or passage through protein channels from the out-
side of the cell to the cell interior. In this process, extracellular Late
endosome
material is brought into the cell without actually passing through
the lipid bilayer (Fig. 1.2), as the material is surrounded by the Lysosome
plasma membrane and enclosed within a small sphere of bilayer
that pinches off the cell membrane. This envelope derived from
the membrane is called a vesicle. Vesicles can move within the
cytoplasm, and their contents are still extracellular, topologically
speaking. Endocytosis, an energy-dependent process, has other
names depending on the material taken up.
• It is called phagocytosis when particulate matter enters the cell.
Exocytosis
• It is called pinocytosis when soluble small molecules in a
volume of fluid enter.
• It is called receptor-mediated endocytosis when specific ex-
tracellular molecules are bound to integral proteins before Fig. 1.2 ​Endocytosis and exocytosis. A cell can take up material by en-
being endocytosed. closing it in an envelope of lipid bilayer that pinches off of the plasma
Exocytosis is the opposite process, whereby intracellular mate- membrane. When the engulfed material is solid, the process is called
rial in a vesicle is expelled from the cell when the vesicle fuses with phagocytosis. When the enveloped material is mostly liquid, the process
is called pinocytosis. Because the substances remain inside membrane-
the plasma membrane. Like endocytosis, exocytosis requires en-
enclosed spheres called vesicles, they are topologically still “outside”
ergy. Endocytosis and exocytosis also allow the shuttling of recep- the cell. After being metabolized, the cell can extrude waste materials by
tors or transporters from the plasma membrane to an intracellular fusing the vesicle back to the plasma membrane. This process of exocy-
compartment, not for catabolism as in Figure 1.2, but to regulate tosis is the reverse of endocytosis. It is used by the cell to export impor-
the insertion or removal of the receptor, channel, or transporter in tant products made intracellularly into the extracellular environment.
the plasma membrane in the appropriate circumstances.
An example of reversible vesicle movement is the addition and
removal of aquaporins, water channels, to the plasma membrane Sometimes cells need to take up ions or molecules from the
of renal collecting duct cells under the control of antidiuretic extracellular space into the cytoplasm or move intracellular sub-
hormone (ADH, also called vasopressin). When ADH concentra- stances out of the cell against forces that oppose such transport.
tions increase, this hormone stimulates the fusion of collecting This occurs:
duct intracellular vesicles with embedded transmembrane aqua- 1. When a molecule is too large or too hydrophilic to diffuse
porins with the cell membrane, thus adding the water channels freely through the plasma membrane, even if a concentra-
and increasing the resorption of free water from the urine into tion gradient favors the movement; and
the blood. When ADH concentrations decrease, the opposite 2. When the cell needs to transport a substance “up” a chemical,
occurs: The plasma membrane vesicles pinch off and move into electrical, or electrochemical gradient.
the cytoplasm, removing the aquaporins. See the renal section, By “up” a gradient we mean a process that leads to a decrease
Chapter 18, for additional information. in entropy and a corresponding positive change in Gibbs free
energy, while by “down” a gradient we mean a process that leads
Facilitated Diffusion and Active Transport to an increase in entropy and a corresponding negative change
An unequal distribution of a charged substance on the two in Gibbs free energy. The latter reactions may proceed spontane-
sides of the cell membrane will cause a chemical gradient and ously, but the former do not and always require an input of en-
an electrical gradient to coexist as an electrochemical gradient. ergy. When the Gibbs free energy is 0, that state is equilibrium.
 CHAPTER 1 General Principles of Physiology 5

This is the same idea as chemical reactions: those that require • A mechanical-gated channel opens under the influence of
energy to proceed “up” a gradient or against forces are termed hydrostatic or osmotic pressure (see Fig. 1.4).
endergonic, while those that proceed “down” a gradient or with Active transport requires energy and is either primary or
forces are exergonic. Most exergonic reactions in biological sys- secondary, depending on the source of the energy used.
tems are exothermic, such as the cleavage of ATP by ATPases in • Primary active transporters use adenosine triphosphate
muscle mitochondria. Movement against opposing forces occurs (ATP) directly to carry specific ions against an electrochem-
by specific protein transporters (carriers or channels) embedded ical gradient.
in the cell membrane. These proteins are carriers for facilitated • The ubiquitous Na1,K1-ATPase, is a protein pump that
diffusion (situation 1) or active transporters (situation 2), de- transports both Na1 and K1 against their respective elec-
pending on whether they move molecules down or up an elec- trochemical gradients (Fig. 1.5). By simultaneously trans-
trochemical gradient, respectively. porting three Na1 ions out of the cell and two K1 ions in,
Facilitated diffusion is the movement of a substance that the Na1,K1-ATPase (also called “the Na1,K1 pump”)
cannot freely cross the membrane down an electrochemical maintains high extracellular and low intracellular Na1
gradient. Such a process does not require metabolic energy be- concentrations and high intracellular and low extracel-
cause it works “downhill,” much like simple diffusion, except lular K1 concentrations. The activity of this pump is in-
that the net flux of molecules is much greater because of facili- creased by intracellular Na+ and by extracellular K+. Each
tation by the protein carrier or channel (Fig. 1.3): transport cycle of the Na1,K1 pump results in the net loss
• The insulin-dependent glucose transporter allows plasma of a cation from the intracellular compartment. The es-
glucose to enter cells via facilitated diffusion. tablishment and maintenance of such ion gradients are
• Various ion-specific channels for Na1, potassium (K1), chlo- responsible for the resting membrane electrical potential
ride (Cl2), and other species participate in facilitated diffusion discussed in Chapter 2.
because they allow ion entry into cells only in the presence of • Other active transporters are the Ca21-ATPases in the sar-
a favorable “downhill” electrochemical gradient. Many ion coplasmic reticulum, renal tubules, intestine, and cardiac
channels are gated, meaning that they alternate between an muscle. They sequester cytosolic Ca21 within the sarcoplas-
open and a closed conformation, depending on the presence mic reticulum or transport Ca21 against an electrochemical
of an “opening” stimulus (Fig. 1.4). gradient out of the cell.
• Ion channels that open in response to an extracellular • The H1/K1-ATPase, located on the lumenal surface of
hormone are termed ligand-gated ion channels. For ex- gastric parietal cells, pumps hydrogen (H1) against an
ample, the nicotinic acetylcholine receptor, nAChR, is a unfavorable electrochemical gradient into the lumen of
ligand-gated Na1 channel triggered by acetylcholine at the stomach, acidifying gastric contents.
the synaptic cleft. Secondary active transport involves a pump like the Na1,K1-
• Some ion channels open when the resting membrane ATPase and a cotransporter. First, the pump establishes a Na1
electrical potential of the plasma membrane reverses, a gradient. Then, the Na1 diffuses down its concentration gradi-
process known as depolarization. Such channels are called ent across the cotransporter into the cell. The cotransporter
voltage-gated ion channels. couples this movement of Na1 to the movement of another

Fig. 1.3 ​Facilitated diffusion. A. Solute S has an electro-

chemical gradient favoring movement into the cell, but
it is unable to cross the plasma membrane via simple
Extracellular
diffusion either because S is too large or too hydrophilic
to cross the membrane. It enters via facilitated diffusion
Solute
with the help of a carrier protein in an energy-free
manner. B. Solute S enters by facilitated diffusion with
the help of a carrier protein without additional energy
Carrier protein mediating
expenditure. In the model shown, the carrier can exist facilitated diffusion
in two conformational states: state 1, in which solute S
binds to the protein on the outside, and state 2, in
which the solute diffuses into the cell. This arrangement
is known as a “ping-pong” mechanism. The initial rate
of transport rate occurs when the concentration of S
inside the cell is zero and the solute is only present ex- Lipid Electrochemical
tracellularly. In this situation, transports can only occur bilayer gradient
in one direction (into the cell). Once enough solute S
crosses into the intracellular compartment, the electro- 1 2
chemical gradient decreases and the same transporter
may facilitate the movement of S out of the cell. This is
known as bidirectional transport. Depending on which
direction dominates determines the net transport. (A) (B)
When the inward and outward movements of S are
equal the system reaches steady state. Intracellular
6 SECTION I Foundations

Voltage Ligand-gated Ligand-gated Mechanically

gated (extracellular) (intracellular) gated

++ ++

Closed

–– ––

– –

Open

+ +

Fig. 1.4 ​Gated membrane protein channels. A gated channel is one that alternates between a closed state,
which does not allow solutes to go down their electrochemical gradient, and an open state, which does. Such
channels may be opened in response to changes in the membrane electrical potential (voltage-gated), the
presence of an extracellular or intracellular ligand-gated, or the application of a mechanical force such as
stretch or pressure (mechanically-gated).

Extracellular

Na+ Na+
Na+ Na+
Na+
Na+ Na+
K+ and ouabain
Na+ binding site

Sodium Potassium
electrochemical electrochemical
gradient gradient

ATP ADP + Pi
K+
K+ K+ K+
K+ K+
K+ Na+ binding site
K+

Intracellular
Fig. 1.5 ​The Na ,K -ATPase active transporter. Na1 has an electrochemical gradient favoring movement into
1 1

the cell, whereas K1 has a gradient favoring movement out of the cell. The Na1,K1-ATPase creates and main-
tains these gradients by moving Na1 out of the cell and K1 into the cell, against their respective gradients.
Each iteration of the transporters moves three Na1 out and two K1 in and uses one molecule of ATP as the
energy source. Each iteration contributes to the resting membrane potential because more positive charges
move out of the cell than in, so the cell interior is relatively negative compared with the extracellular space.
Such a transporter is electrogenic. Since ATP production is much greater with aerobic respiration in mitochon-
dria, these organelles often accumulate near the plasma membrane and the function of the Na1,K1-ATPase is
sensitive to the need for oxygen. ATPase, Adenosine triphosphatase; K1, potassium; Na1, sodium.
 CHAPTER 1 General Principles of Physiology 7

solute into the cell. ATP is used indirectly, in that transmem- intracellular accumulations of HCO32 by extruding in-
brane gradients created by primary active transporters (e.g., the tracellular HCO32 and taking up Cl2 in exchange.
Na1,K1-ATPase) are used to drive the transport of other solutes A carrier that transports Na1 coupled to a neutral solute,
against unfavorable concentration or electrochemical gradients. such as D-glucose, enables glucose to be transported in a 1:1
• When a secondary active transporter moves two solutes in ratio with Na1. Because cells almost always have a large and
the same direction, it is called a symporter (Fig. 1.6). Ex- inwardly-directed Na1 gradient (i.e., Na1 in extracellular fluid
amples of symporters are: is high and is kept low in the cell by the Na1,K1 pump) there
• The Na1-K1-2Cl2 cotransporter found in the ascending is potential energy in the Na1-gradient that is almost high
limb of the renal tubule. enough to remove the full amount of glucose from the urinary
• Sodium-glucose transport protein (SGLT)-2 is a facilitated or intestinal lumen where these transporters exist (SGLT 2)
diffusion transporter in proximal tubule cells of the neph- because the Na1 concentration in the lumen is much greater
ron that links the resorption of filtered glucose to the re- than the glucose concentration.
sorption of Na1. Inhibitors of this symporter constitute an Some coupled transporters have a stoichiometry different
important class of drugs to treat diabetes mellitus. from 1:1. Consider the cotransport of Na1 and HCO32 out of a
• The Na1-glucose cotransporter in the intestinal mucosa. cell. Because of the action of the electrogenic Na1,K1-ATPase
• The Na1-amino acid cotransporter in the proximal renal that generates a relative negative charge in the interior of the
tubule. cells, for Na1, an electrochemical gradient opposes the move-
• An antiporter transports two solutes in opposite directions ment of this ion out of the cell. For HCO32, the chemical gradi-
across the cell membrane (see Fig. 1.6). ent opposes the movement of this ion out of the cell, but the
• The Ca21/Na1 antiporter found in cardiac muscle uses electrical gradient favors it. The coupling of 1 Na1 to 1 HCO32
the Na1 gradient created by the Na1,K1-ATPase to drive in a Na1/HCO32 cotransporter would thus lack sufficient en-
intracellular Ca21 out of cells against its electrochemical ergy to extrude HCO32. If, however, the transporter had the
gradient. Note that calcium has 21 charges and sodium stoichiometry of coupling 1 Na1:3 HCO32, then it would be
just 11. Unless two Na1 ions were transported, the electrogenic, carrying a net negative charge. Because the inside
transporter would carry a net 11 charge and would be of the cell is negative, there can be an outwardly directed
“electrogenic”. HCO32 gradient only if the magnitude of the electrical gradient
• The electroneutral Cl2/bicarbonate (HCO32) antiporter exceeds the electrochemical gradient for Na1 and the chemical
prevents the cytosol from becoming too basic during gradient for HCO32. Increasing the stoichiometry to 3HCO32:1

Transported molecule Cotransported ion

Uniport Symport Antiport

Coupled transport
Fig. 1.6 ​Plasma membrane transporters. Uniporters carry one solute across the membrane. If this move-
ment is down the electrochemical gradient, it requires no added energy, but if it is against the gradient, en-
ergy must be spent. Cotransporters move more than one solute. Symporters carry two solutes in the same
direction, while antiporters transfer them in opposite directions. If both solutes are moving down their re-
spective gradients, no energy is needed. If one of the solutes is going down its gradient, it may supply
enough energy to move the other against its gradient. If both solutes are transported against their gradients,
energy is required.
8 SECTION I Foundations

Na1 raises the driving force for extrusion of HCO32 to the third is hot, homeostasis purges heat to maintain a constant body
power, providing ample energy for such a transporter to ex- temperature.
trude HCO32 and defend against cell alkalinization. When homeostatic processes are working properly, the body
achieves a steady state, a condition in which the inputs of mat-
ter and energy to a system equal the outputs. Homeostasis
SIGNAL TRANSDUCTION maintains such a state over the long term but not necessarily
To harmonize and coordinate physiologic functions, organ sys- from instant to instant. For example, ingestion of a large
tems, organs, tissues, and cells must communicate with each amount of water will temporarily expand the total body water.
other. These integrated communication systems work on differ- Within minutes to hours, however, homeostatic mechanisms
ent scales or level of resolution. Among those on the smallest will remove excess water through urination, restoring the steady
scale, as the cell membrane is a barrier not only to matter but to state level of body water volume.
information, messages have to traverse it. Various signal trans- Although inputs of matter and energy equal outputs in a
duction networks carry information from outside the cell to steady state, this does not mean the internal system is similar
various receptors embedded in the cell membrane or present in in content to the external environment, in which case there
the cytosol, by means of signaling molecules called ligands, and would be equilibrium. On the contrary, in a steady state the
biochemical alterations in the cell occur in response to contact system maintains its differences from the environment. For
between receptors and their ligands. The complex biochemical example, in a healthy steady state, the dietary intake of potas-
chain reactions culminate in changes in cell function and gene sium must equal the elimination of potassium to maintain a
expression. body fluid potassium concentration within strictly regulated
limits. Similarly, the system is not internally uniform in a
steady state. For example, most of the body’s potassium is
CELL-CELL COMMUNICATION concentrated inside cells, while most of the body’s sodium is
On lager scales of resolution, cell-to-cell communication occurs concentrated outside cells. In a steady state, there are concen-
when one or more cells send a signal to alter the function of a tration gradients and there is flow through the system. Ho-
target cell. meostasis not only controls matter and energy exchange with
• When the target cell is the same as the signaling cell, such the outside environment, but it also preserves the concentra-
communication is called autocrine. tion gradients and other polarities of the internal environ-
• When the target cell is adjacent to the signaling cell, such ment. In contrast to a steady state, equilibrium exists when
communication is called juxtacrine. there is no net flow. When conditions are globally uniform,
• When the target cell is not adjacent but a relatively short there are no concentration or electrochemical gradients at all,
distance away (a few cell radii) from the signaling cell, such and there is no net flow through the entire system; the condi-
communication is called paracrine. tion we colloquially call death.
• When the target cell is a relatively great distance away from Explaining how the body’s homeostatic mechanisms main-
the signaling cell, such communication is called endocrine tain a steady state is the aim of physiology. Pathophysiology is
and the signaling molecules are called hormones. The endo- the study of how and why the body’s homeostatic mechanisms
crine system is the network of hormone secreting tissues fail, and what happens when they do.
commonly referred to as “glands.” See the endocrine section
(see Chs. 28–36). AN ELECTROMECHANICAL EXAMPLE OF
HOMEOSTASIS
HOMEOSTASIS Cruise control in an automobile is a nonbiologic example of a
“A fairly constant or steady state, maintained in many aspects homeostatic system. It maintains a constant speed (the regu-
of the bodily economy even when they are beset by conditions lated variable) despite variations in the road (the environmen-
tending to disturb them, is a most remarkable characteristic of tal influences).
the living organism. Because circumstances are often present,
which, if not controlled, would profoundly modify the con- The Structure of a Homeostatic System
stancy of the state, we must assume that controlling factors are A simple homeostatic system consists of four components
at hand ready to act whenever the constancy is imperiled” (Fig. 1.7):
(Walter B. Cannon, 1926). • Sensor: This is the speedometer, which determines the speed
Walter B. Cannon, the eminent American physiologist, first of the car and relays the information to a computer else-
proposed the term homeostasis for the efforts of the body to where in the car.
maintain the values of physiologic variables within a given • Control center: This is the car’s onboard computer, which
range. The term is an elision of the Greek homeo- meaning compares the input from the sensor (the speedometer) with
“same” and Latin -stasis meaning “standing.” Homeostatic pro- the speed programmed for the cruise control (65 miles per
cesses defend the body against the perturbing forces of the envi- hour [mph], for example). The computer then determines
ronment. If water is scarce, homeostasis conserves water to keep whether the car should speed up, slow down, or continue at
the amount of fluid in our bodies constant. If the environment its present speed.