Uploaded by Rajeev Nepal


Guyton and Hall
Textbook of Medical Physiology
This page intentionally left blank
Twelfth Edition
Guyton and Hall
Textbook of Medical Physiology
John E. Hall, Ph.D.
Arthur C. Guyton Professor and Chair
Department of Physiology and Biophysics
Associate Vice Chancellor for Research
University of Mississippi Medical Center
Jackson, Mississippi
1600 John F. Kennedy Blvd.
Ste 1800
Philadelphia, PA 19103-2899
ISBN: 978-1-4160-4574-8
International Edition: 978-0-8089-2400-5
Copyright © 2011, 2006, 2000, 1996, 1991, 1986, 1981, 1976, 1966,
1961, 1956 by Saunders, an imprint of 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. Permissions may be
sought directly from Elsevier’s Rights Department: phone: (+1) 215 239 3804 (US) or (+44) 1865
843830 (UK); fax: (+44) 1865 853333; e-mail: [email protected] You may also
complete your request on-line via the Elsevier website at http://www.elsevier.com/permissions.
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 his or her 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 assume any liability for any injury and/or damage to persons or property arising out of or
related to any use of the material contained in this book.
The Publisher
Library of Congress Cataloging-in-Publication Data
Hall, John E. (John Edward), 1946Guyton and Hall textbook of medical physiology / John Hall. – 12th ed.
p. ; cm.
Rev. ed. of: Textbook of medical physiology. 11th ed. c2006.
Includes bibliographical references and index.
ISBN 978-1-4160-4574-8 (alk. paper)
1. Human physiology. 2. Physiology, Pathological. I. Guyton, Arthur C. II.
Textbook of medical physiology. III. Title. IV. Title: Textbook of medical physiology.
[DNLM: 1. Physiological Phenomena. QT 104 H1767g 2011]
QP34.5.G9 2011
Publishing Director: William Schmitt
Developmental Editor: Rebecca Gruliow
Editorial Assistant: Laura Stingelin
Publishing Services Manager: Linda Van Pelt
Project Manager: Frank Morales
Design Manager: Steve Stave
Illustrator: Michael Schenk
Marketing Manager: Marla Lieberman
Printed in the United States of America
Last digit is the print number:
My Family
For their abundant support, for their patience and
understanding, and for their love
Arthur C. Guyton
For his imaginative and innovative research
For his dedication to education
For showing us the excitement and joy of physiology
And for serving as an inspirational role model
This page intentionally left blank
The first edition of the Textbook of Medical Physiology
was written by Arthur C. Guyton almost 55 years ago.
Unlike most major medical textbooks, which often have
20 or more authors, the first eight editions of the Textbook
of Medical Physiology were written entirely by Dr. Guyton,
with each new edition arriving on schedule for nearly 40
years. The Textbook of Medical Physiology, first published
in 1956, quickly became the best-selling medical physiology textbook in the world. Dr. Guyton had a gift for
communicating complex ideas in a clear and interesting
manner that made studying physiology fun. He wrote the
book to help students learn physiology, not to impress his
professional colleagues.
I worked closely with Dr. Guyton for almost 30 years
and had the privilege of writing parts of the 9th and 10th
editions. After Dr. Guyton’s tragic death in an automobile
accident in 2003, I assumed responsibility for completing
the 11th edition.
For the 12th edition of the Textbook of Medical
Physiology, I have the same goal as for 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 fun because our
rapidly increasing knowledge of physiology continues to
unravel new mysteries of body functions. Advances in
molecular and cellular physiology have made it possible to explain many physiology principles in the terminology of molecular and physical sciences rather than
in merely a series of separate and unexplained biological
The Textbook of Medical Physiology, however, is not
a reference book that attempts to provide a compendium of the most recent advances in physiology. This is
a book that continues the tradition of being written for
students. It focuses on the basic principles of physiology needed to begin a career in the health care professions, such as medicine, dentistry and nursing, as well
as graduate studies in the biological and health sciences.
It should also be useful to physicians and health care
professionals who wish to review the basic ­principles
needed for understanding the pathophysiology of
human disease.
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 continue to use it during their
­professional careers.
My hope is 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 function,
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? Fortunately, our bodies are endowed with a vast network of feedback controls that achieve the necessary balances without which
we would be unable to live. Physiologists call this high
level of internal bodily control homeostasis. In disease
states, functional balances are often seriously disturbed
and homeostasis is impaired. 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 functions in
Another objective is to be as accurate as possible.
Suggestions and critiques from many students, physiologists, 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 thousands of bits of information, I wish to issue 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 feedback important for
progressive improvement of a textbook of physiology. To
the many persons who have already helped, I express sincere thanks.
A brief explanation is needed about several features of
the 12th edition. Although many of the chapters have been
revised to include new principles of physiology, the text
length has been closely monitored to limit the book size
so that it can be used effectively in physiology courses for
medical students and health care professionals. Many of the
figures have also been redrawn and are in full color. New references have been chosen primarily for their ­presentation
of physiologic principles, for the quality of their own references, and for their easy accessibility. The selected biblio­
graphy at the end of the chapters lists papers mainly from
recently published scientific journals that can be freely
accessed from the PubMed internet site at http://www.
ncbi.nlm.nih.gov/sites/entrez/. Use of these references, as
well as cross-references from them, can give the student
almost complete coverage of the entire field of physiology.
The effort to be as concise as possible has, unfortunately,
necessitated a more simplified and dogmatic presentation
of many physiologic principles than I normally would have
desired. However, the bibliography can be used to learn
more about the controversies and unanswered questions
that remain in understanding the ­complex functions of the
human body in health and disease.
Another feature is that the print is set in two sizes. The
material in large print constitutes the fundamental physiologic information that students will require in virtually
all of their medical activities and studies.
The material in small print is of several different kinds:
first, anatomic, chemical, and other information that is
needed for immediate discussion but that most students
will learn in more detail in other courses; second, physiologic information of special importance to certain fields
of clinical medicine; and, third, information that will be of
value to those students who may wish to study particular
physiologic mechanisms more deeply.
I wish to express sincere thanks to many ­persons who
have helped to prepare this book, including my ­colleagues
in the Department of Physiology and Biophysics at the
University of Mississippi Medical Center who provided
valuable suggestions. The members of our faculty and a
brief description of the research and educational activities of the department can be found at the web site: http://
physiology.umc.edu/. I am also grateful to Stephanie
Lucas and Courtney Horton Graham for their excellent
secretarial services, to Michael Schenk and Walter (Kyle)
Cunningham for their expert artwork, and to William
Schmitt, Rebecca Gruliow, Frank Morales, and the entire
Elsevier Saunders team for continued editorial and
­production excellence.
Finally, I owe an enormous debt to Arthur Guyton
for the great privilege of contributing to the Textbook of
Medical Physiology, for an exciting career in physiology,
for his friendship, and for the inspiration that he provided
to all who knew him.
John E. Hall
Apoptosis—Programmed Cell Death
Introduction to Physiology: The Cell and
General Physiology
Functional Organization of the Human Body
and Control of the “Internal Environment”
Cells as the Living Units of the Body
Extracellular Fluid—The “Internal
“Homeostatic” Mechanisms of the Major
Functional Systems
Control Systems of the Body
Summary—Automaticity of the Body
The Cell and Its Functions
Organization of the Cell
Physical Structure of the Cell
Comparison of the Animal Cell with
Precellular Forms of Life
Functional Systems of the Cell
Locomotion of Cells
Genetic Control of Protein Synthesis, Cell
Function, and Cell Reproduction
Genes in the Cell Nucleus
The DNA Code in the Cell Nucleus Is
Transferred to an RNA Code in the Cell
Cytoplasm—The Process of Transcription
Synthesis of Other Substances in the Cell
Control of Gene Function and Biochemical
Activity in Cells
The DNA-Genetic System Also Controls Cell
Cell Differentiation
Membrane Physiology, Nerve, and Muscle
Transport of Substances Through Cell
The Lipid Barrier of the Cell Membrane,
and Cell Membrane Transport Proteins
“Active Transport” of Substances Through
Membrane Potentials and Action Potentials
Basic Physics of Membrane Potentials
Measuring the Membrane Potential
Resting Membrane Potential of Nerves
Nerve Action Potential
Roles of Other Ions During the Action
Propagation of the Action Potential
Re-establishing Sodium and Potassium
Ionic Gradients After Action Potentials Are
Completed—Importance of Energy
Plateau in Some Action Potentials
Rhythmicity of Some Excitable Tissues—
Repetitive Discharge
Special Characteristics of Signal Transmission
in Nerve Trunks
Excitation—The Process of Eliciting the
Action Potential
Recording Membrane Potentials and
Action Potentials
Contraction of Skeletal Muscle
Physiologic Anatomy of Skeletal Muscle
General Mechanism of Muscle Contraction
Molecular Mechanism of Muscle Contraction
Energetics of Muscle Contraction
Characteristics of Whole Muscle
Excitation of Skeletal Muscle:
Neuromuscular Transmission and
Excitation-Contraction Coupling
Transmission of Impulses from Nerve Endings
to Skeletal Muscle Fibers: The Neuromuscular
Molecular Biology of Acetylcholine Formation
and Release
Drugs That Enhance or Block Transmission
at the Neuromuscular Junction
Myasthenia Gravis Causes Muscle Paralysis
Muscle Action Potential
Excitation-Contraction Coupling
Excitation and Contraction of Smooth Muscle 91
Contraction of Smooth Muscle
Nervous and Hormonal Control of Smooth
Muscle Contraction
The Heart
Cardiac Muscle; The Heart as a Pump and
Function of the Heart Valves
Physiology of Cardiac Muscle
Cardiac Cycle
Relationship of the Heart Sounds to Heart
Work Output of the Heart
Chemical Energy Required for Cardiac Contraction:
Oxygen Utilization by the Heart
Regulation of Heart Pumping
Rhythmical Excitation of the Heart
Specialized Excitatory and Conductive System
of the Heart
Control of Excitation and Conduction in the
The Normal Electrocardiogram
Characteristics of the Normal
Methods for Recording Electrocardiograms
Flow of Current Around the Heart
during the Cardiac Cycle
Electrocardiographic Leads
Electrocardiographic Interpretation of
Cardiac Muscle and Coronary Blood Flow
Abnormalities: Vectorial Analysis
Principles of Vectorial Analysis of
Vectorial Analysis of the Normal
Mean Electrical Axis of the Ventricular
QRS—and Its Significance
Conditions That Cause Abnormal Voltages
of the QRS Complex
Prolonged and Bizarre Patterns of the QRS
Current of Injury
Abnormalities in the T Wave
Cardiac Arrhythmias and Their
Electrocardiographic Interpretation
Abnormal Sinus Rhythms
Abnormal Rhythms That Result from Block
of Heart Signals Within the Intracardiac
Conduction Pathways
Premature Contractions
Paroxysmal Tachycardia
Ventricular Fibrillation
Atrial Fibrillation
Atrial Flutter
Cardiac Arrest
The Circulation
Overview of the Circulation; Biophysics of
Pressure, Flow, and Resistance
Physical Characteristics of the Circulation
Basic Principles of Circulatory Function
Interrelationships of Pressure, Flow, and
Vascular Distensibility and Functions of the
Arterial and Venous Systems
Vascular Distensibility
Arterial Pressure Pulsations
Veins and Their Functions
The Microcirculation and Lymphatic
System: Capillary Fluid Exchange,
Interstitial Fluid, and Lymph Flow
Structure of the Microcirculation
and Capillary System
Flow of Blood in the Capillaries—
Exchange of Water, Nutrients, and Other
Substances Between the Blood and
Interstitial Fluid
Interstitium and Interstitial Fluid
Fluid Filtration Across Capillaries Is
Determined by Hydrostatic and Colloid
Osmotic Pressures, as Well as Capillary
Filtration Coefficient
Lymphatic System
Local and Humoral Control of Tissue
Blood Flow
Local Control of Blood Flow in Response to
Tissue Needs
Mechanisms of Blood Flow Control
Humoral Control of the Circulation
Nervous Regulation of the Circulation,
and Rapid Control of Arterial Pressure
Nervous Regulation of the Circulation
Role of the Nervous System in Rapid
Control of Arterial Pressure
Special Features of Nervous Control
of Arterial Pressure
Role of the Kidneys in Long-Term Control of
Arterial Pressure and in Hypertension: The
Integrated System for Arterial Pressure
Renal–Body Fluid System for Arterial
Pressure Control
The Renin-Angiotensin System: Its Role
in Arterial Pressure Control
Summary of the Integrated, Multifaceted
System for Arterial Pressure Regulation
Cardiac Output, Venous Return,
and Their Regulation
Normal Values for Cardiac Output at Rest
and During Activity
Control of Cardiac Output by Venous
Return—Role of the Frank-Starling Mechanism
of the Heart
Pathologically High or Low Cardiac Outputs
Methods for Measuring Cardiac
Muscle Blood Flow and Cardiac Output
During Exercise; the Coronary Circulation
and Ischemic Heart Disease
Blood Flow Regulation in Skeletal Muscle
at Rest and During Exercise
Coronary Circulation
Cardiac Failure
Circulatory Dynamics in Cardiac Failure
Unilateral Left Heart Failure
Low-Output Cardiac Failure—
Cardiogenic Shock
Edema in Patients with Cardiac Failure
Cardiac Reserve
Heart Valves and Heart Sounds;
Valvular and Congenital Heart
Heart Sounds
Abnormal Circulatory Dynamics in Valvular
Heart Disease
Abnormal Circulatory Dynamics
in Congenital Heart Defects
Use of Extracorporeal Circulation During
Cardiac Surgery
Hypertrophy of the Heart in Valvular
and Congenital Heart Disease
Circulatory Shock and Its Treatment
Physiologic Causes of Shock
Shock Caused by Hypovolemia—
Hemorrhagic Shock
Neurogenic Shock—Increased Vascular
Anaphylactic Shock and Histamine Shock
Septic Shock
Physiology of Treatment in Shock
Circulatory Arrest
The Body Fluids and Kidneys
The Body Fluid Compartments: Extracellular
and Intracellular Fluids; Edema
Fluid Intake and Output Are Balanced
During Steady-State Conditions
Body Fluid Compartments
Extracellular Fluid Compartment
Blood Volume
Constituents of Extracellular and Intracellular
Measurement of Fluid Volumes in the Different
Body Fluid Compartments—the IndicatorDilution Principle
Determination of Volumes of Specific Body
Fluid Compartments
Regulation of Fluid Exchange and Osmotic
Equilibrium Between Intracellular
and Extracellular Fluid
Basic Principles of Osmosis and Osmotic
Osmotic Equilibrium Is Maintained Between
Intracellular and Extracellular Fluids
Volume and Osmolality of Extracellular
and Intracellular Fluids in Abnormal States
Glucose and Other Solutions Administered
for Nutritive Purposes
Clinical Abnormalities of Fluid Volume
Regulation: Hyponatremia and Hypernatremia
Edema: Excess Fluid in the Tissues
Fluids in the “Potential Spaces” of the Body
Urine Formation by the Kidneys:
I. Glomerular Filtration, Renal Blood Flow,
and Their Control
Multiple Functions of the Kidneys
Physiologic Anatomy of the Kidneys
Physiologic Anatomy of the Bladder
Transport of Urine from the Kidney Through
the Ureters and into the Bladder
Filling of the Bladder and Bladder Wall Tone;
the Cystometrogram
Micturition Reflex
Abnormalities of Micturition
Urine Formation Results from Glomerular
Filtration, Tubular Reabsorption, and Tubular
Glomerular Filtration—The First Step in
Urine Formation
Determinants of the GFR
Renal Blood Flow
Physiologic Control of Glomerular Filtration
and Renal Blood Flow
Autoregulation of GFR and Renal Blood Flow
Urine Formation by the Kidneys: II. Tubular
Reabsorption and Secretion
Renal Tubular Reabsorption and Secretion
Tubular Reabsorption Includes Passive
and Active Mechanisms
Reabsorption and Secretion Along Different
Parts of the Nephron
Regulation of Tubular Reabsorption
Use of Clearance Methods to Quantify Kidney
Urine Concentration and Dilution; Regulation
of Extracellular Fluid Osmolarity and Sodium
Kidneys Excrete Excess Water by Forming
Dilute Urine
Kidneys Conserve Water by Excreting
Concentrated Urine
Quantifying Renal Urine Concentration
and Dilution: “Free Water” and Osmolar
Disorders of Urinary Concentrating Ability
Control of Extracellular Fluid Osmolarity and
Sodium Concentration
Osmoreceptor-ADH Feedback System
Importance of Thirst in Controlling
Extracellular Fluid Osmolarity and Sodium
Salt-Appetite Mechanism for Controlling
Extracellular Fluid Sodium Concentration and
Renal Regulation of Potassium, Calcium,
Phosphate, and Magnesium; Integration
of Renal Mechanisms for Control of Blood
Volume and Extracellular Fluid Volume
Regulation of Extracellular Fluid Potassium
Concentration and Potassium Excretion
Control of Renal Calcium Excretion
and Extracellular Calcium Ion Concentration
Control of Renal Magnesium Excretion and
Extracellular Magnesium Ion Concentration
Integration of Renal Mechanisms for Control
of Extracellular Fluid
Importance of Pressure Natriuresis and
Pressure Diuresis in Maintaining Body Sodium
and Fluid Balance
Distribution of Extracellular Fluid
Between the Interstitial Spaces and
Vascular System
Nervous and Hormonal Factors Increase the
Effectiveness of Renal–Body Fluid Feedback
Integrated Responses to Changes in Sodium
Conditions That Cause Large Increases in
Blood Volume and Extracellular Fluid Volume
Conditions That Cause Large Increases in
Extracellular Fluid Volume but with Normal
Blood Volume
Acid-Base Regulation
H+ Concentration Is Precisely Regulated
Acids and Bases—Their Definitions and
Defending Against Changes in H+
Concentration: Buffers, Lungs, and Kidneys
Buffering of H+ in the Body Fluids
Bicarbonate Buffer System
Phosphate Buffer System
Proteins Are Important Intracellular Buffers
Respiratory Regulation of Acid-Base Balance
Renal Control of Acid-Base Balance
Secretion of H+ and Reabsorption of HCO3−
by the Renal Tubules
Combination of Excess H+ with Phosphate
and Ammonia Buffers in the Tubule Generates
“New” HCO3−
Quantifying Renal Acid-Base Excretion
Renal Correction of Acidosis—Increased
Excretion of H+ and Addition of HCO3− to
the Extracellular Fluid
Renal Correction of Alkalosis—Decreased
Tubular Secretion of H+ and Increased
Excretion of HCO3−
Clinical Causes of Acid-Base Disorders
Treatment of Acidosis or Alkalosis
Clinical Measurements and Analysis of
Acid-Base Disorders
Diuretics, Kidney Diseases
Diuretics and Their Mechanisms of Action
Kidney Diseases
Acute Renal Failure
Chronic Renal Failure: An Irreversible Decrease
in the Number of Functional Nephrons
Specific Tubular Disorders
Treatment of Renal Failure by Transplantation
or by Dialysis with an Artificial Kidney
Blood Cells, Immunity, and Blood
Red Blood Cells, Anemia, and Polycythemia
Red Blood Cells (Erythrocytes)
Resistance of the Body to Infection:
I. Leukocytes, Granulocytes, the MonocyteMacrophage System, and Inflammation
Leukocytes (White Blood Cells)
Neutrophils and Macrophages Defend
Against Infections
Monocyte-Macrophage Cell System
(Reticuloendothelial System)
Inflammation: Role of Neutrophils
and Macrophages
Resistance of the Body to Infection:
II. Immunity and Allergy Innate Immunity
Acquired (Adaptive) Immunity
Allergy and Hypersensitivity
Blood Types; Transfusion; Tissue and Organ
Antigenicity Causes Immune Reactions of
O-A-B Blood Types
Rh Blood Types
Transplantation of Tissues and Organs
Hemostasis and Blood Coagulation
Events in Hemostasis
Vascular Constriction
Mechanism of Blood Coagulation
Conditions That Cause Excessive Bleeding in
Thromboembolic Conditions in the
Human Being
Anticoagulants for Clinical Use
Blood Coagulation Tests
Pulmonary Ventilation
Mechanics of Pulmonary Ventilation
Pulmonary Volumes and Capacities
Minute Respiratory Volume Equals Respiratory
Rate Times Tidal Volume
Alveolar Ventilation
Functions of the Respiratory Passageways
Pulmonary Circulation, Pulmonary Edema,
Pleural Fluid
Physiologic Anatomy of the Pulmonary
Circulatory System
Pressures in the Pulmonary System
Blood Volume of the Lungs
Blood Flow Through the Lungs and Its
Effect of Hydrostatic Pressure Gradients in
the Lungs on Regional Pulmonary Blood Flow
Pulmonary Capillary Dynamics
Fluid in the Pleural Cavity
Physical Principles of Gas Exchange;
Diffusion of Oxygen and Carbon Dioxide
Through the Respiratory Membrane
Physics of Gas Diffusion and Gas
Partial Pressures
Compositions of Alveolar Air and Atmospheric
Air Are Different
Diffusion of Gases Through the Respiratory
Effect of the Ventilation-Perfusion Ratio on
Alveolar Gas Concentration
Transport of Oxygen and Carbon Dioxide in
Blood and Tissue Fluids
Transport of Oxygen from the Lungs to the
Body Tissues
Transport of Carbon Dioxide in the Blood
Respiratory Exchange Ratio
Regulation of Respiration
Respiratory Center
Chemical Control of Respiration
Peripheral Chemoreceptor System for Control
of Respiratory Activity—Role of Oxygen in
Respiratory Control
Regulation of Respiration During Exercise
Other Factors That Affect Respiration
Respiratory Insufficiency—Pathophysiology,
Diagnosis, Oxygen Therapy
Useful Methods for Studying Respiratory
Pathophysiology of Specific Pulmonary
Hypoxia and Oxygen Therapy
Hypercapnia—Excess Carbon Dioxide in the
Body Fluids
Artificial Respiration
Aviation, Space, and Deep-Sea Diving
Aviation, High-Altitude, and
Space Physiology
Effects of Low Oxygen Pressure on the Body
Effects of Acceleratory Forces on the Body in
Aviation and Space Physiology
“Artificial Climate” in the Sealed Spacecraft
Weightlessness in Space
Physiology of Deep-Sea Diving and
Other Hyperbaric Conditions
Effect of High Partial Pressures of Individual
Gases on the Body
Scuba (Self-Contained Underwater Breathing
Apparatus) Diving
Special Physiologic Problems in Submarines
Hyperbaric Oxygen Therapy
The Nervous System: A. General Principles
and Sensory Physiology
Organization of the Nervous System, Basic
Functions of Synapses, and
General Design of the Nervous System
Major Levels of Central Nervous System
Comparison of the Nervous System with a
Central Nervous System Synapses
Some Special Characteristics of Synaptic
Sensory Receptors, Neuronal Circuits for
Processing Information
Types of Sensory Receptors and the
Stimuli They Detect
Transduction of Sensory
Stimuli into Nerve Impulses
Nerve Fibers That Transmit Different Types of
Signals and Their Physiologic Classification
Transmission of Signals of Different Intensity
in Nerve Tracts—Spatial and Temporal
Transmission and Processing of Signals in
Neuronal Pools
Instability and Stability of Neuronal Circuits
Somatic Sensations: I. General Organization,
the Tactile and Position Senses
Classification of Somatic Senses
Detection and Transmission of Tactile
Sensory Pathways for Transmitting Somatic
Signals into the Central Nervous System
Transmission in the Dorsal Column–Medial
Lemniscal System
Transmission of Less Critical Sensory Signals
in the Anterolateral Pathway
Some Special Aspects of Somatosensory
Somatic Sensations: II. Pain, Headache, and
Thermal Sensations
Types of Pain and Their Qualities—Fast Pain
and Slow Pain
Pain Receptors and Their Stimulation
Dual Pathways for Transmission of Pain
Signals into the Central Nervous System
Pain Suppression (“Analgesia”) System in the
Brain and Spinal Cord
Referred Pain
Visceral Pain
Some Clinical Abnormalities of Pain
and Other Somatic Sensations
Thermal Sensations
The Nervous System: B. The Special Senses
The Eye: I. Optics of Vision
Physical Principles of Optics
Optics of the Eye
Fluid System of the Eye—Intraocular Fluid
The Eye: II. Receptor and Neural Function
of the Retina
Anatomy and Function of the Structural
Elements of the Retina
Photochemistry of Vision
Color Vision
Neural Function of the Retina
The Eye: III. Central Neurophysiology
of Vision
Visual Pathways
Organization and Function of the Visual
Neuronal Patterns of Stimulation During
Analysis of the Visual Image
Fields of Vision; Perimetry
Eye Movements and Their Control
Autonomic Control of Accommodation
and Pupillary Aperture
The Sense of Hearing
Tympanic Membrane and the Ossicular System
Central Auditory Mechanisms
Hearing Abnormalities
The Chemical Senses—Taste and Smell
Sense of Taste
Sense of Smell
The Nervous System: C. Motor and
Integrative Neurophysiology
Motor Functions of the Spinal Cord; the Cord
Organization of the Spinal Cord for Motor
Muscle Sensory Receptors—Muscle Spindles
and Golgi Tendon Organs—And Their Roles
in Muscle Control
Flexor Reflex and the Withdrawal Reflexes
Crossed Extensor Reflex
Reciprocal Inhibition and Reciprocal Innervation
Reflexes of Posture and Locomotion
Scratch Reflex
Spinal Cord Reflexes That Cause Muscle Spasm
Autonomic Reflexes in the Spinal Cord
Spinal Cord Transection and Spinal Shock
Cortical and Brain Stem Control of Motor
Motor Cortex and Corticospinal Tract
Role of the Brain Stem in Controlling Motor
Vestibular Sensations and Maintenance of
Functions of Brain Stem Nuclei in Controlling
Subconscious, Stereotyped Movements
Contributions of the Cerebellum and Basal
Ganglia to Overall Motor Control
Cerebellum and Its Motor Functions
Basal Ganglia—Their Motor Functions
Integration of the Many Parts of the Total
Motor Control System
Cerebral Cortex, Intellectual Functions of the
Brain, Learning, and Memory
Physiologic Anatomy of the Cerebral Cortex
Functions of Specific Cortical Areas
Function of the Brain in Communication—
Language Input and Language Output
Function of the Corpus Callosum and Anterior
Commissure to Transfer Thoughts, Memories,
Training, and Other Information Between the
Two Cerebral Hemispheres
Thoughts, Consciousness, and Memory
Behavioral and Motivational Mechanisms of the
Brain—The Limbic System and the
Activating-Driving Systems
of the Brain
Limbic System
Functional Anatomy of the Limbic System; Key
Position of the Hypothalamus
Hypothalamus, a Major Control Headquarters
for the Limbic System
Specific Functions of Other Parts of the Limbic
States of Brain Activity—Sleep, Brain Waves,
Epilepsy, Psychoses
Psychotic Behavior and Dementia—Roles
of Specific Neurotransmitter Systems
Schizophrenia—Possible Exaggerated
Function of Part of the Dopamine System
The Autonomic Nervous System and the
Adrenal Medulla
General Organization of the Autonomic
Nervous System
Basic Characteristics of Sympathetic and
Parasympathetic Function
Autonomic Reflexes
Stimulation of Discrete Organs in Some
Instances and Mass Stimulation in Other
Instances by the Sympathetic and
Parasympathetic Systems
Pharmacology of the Autonomic Nervous
Cerebral Blood Flow, Cerebrospinal Fluid,
and Brain Metabolism
Cerebral Blood Flow
Cerebrospinal Fluid System
Brain Metabolism
Disorders of the Stomach
Disorders of the Small Intestine
Disorders of the Large Intestine
General Disorders of the Gastrointestinal
Gastrointestinal Physiology
General Principles of Gastrointestinal
Function—Motility, Nervous Control, and
Blood Circulation
General Principles of Gastrointestinal Motility
Neural Control of Gastrointestinal Function—
Enteric Nervous System
Functional Types of Movements in the
Gastrointestinal Tract
Gastrointestinal Blood Flow—“Splanchnic
Propulsion and Mixing of Food in the
Alimentary Tract
Ingestion of Food
Motor Functions of the Stomach
Movements of the Small Intestine
Movements of the Colon
Other Autonomic Reflexes That Affect Bowel
Secretory Functions of the Alimentary Tract
General Principles of Alimentary Tract
Secretion of Saliva
Esophageal Secretion
Gastric Secretion
Pancreatic Secretion
Secretion of Bile by the Liver; Functions of the
Biliary Tree
Secretions of the Small Intestine
Secretion of Mucus by the Large Intestine
Digestion and Absorption in the
Gastrointestinal Tract
Digestion of the Various Foods by Hydrolysis
Basic Principles of Gastrointestinal Absorption
Absorption in the Small Intestine
Absorption in the Large Intestine: Formation of
Physiology of Gastrointestinal Disorders
Disorders of Swallowing and of the Esophagus
Metabolism and Temperature Regulation
Metabolism of Carbohydrates, and Formation
of Adenosine Triphosphate
Central Role of Glucose in Carbohydrate
Transport of Glucose Through the Cell
Glycogen Is Stored in Liver and Muscle
Release of Energy from Glucose by the
Glycolytic Pathway
Release of Energy from Glucose by the
Pentose Phosphate Pathway
Formation of Carbohydrates from Proteins
and Fats—“Gluconeogenesis”
Blood Glucose
Lipid Metabolism
Transport of Lipids in the Body Fluids
Fat Deposits
Use of Triglycerides for Energy: Formation of
Adenosine Triphosphate
Regulation of Energy Release from
Phospholipids and Cholesterol
Protein Metabolism
Basic Properties
Transport and Storage of Amino Acids
Functional Roles of the Plasma Proteins
Hormonal Regulation of Protein Metabolism
The Liver as an Organ
Physiologic Anatomy of the Liver
Hepatic Vascular and Lymph Systems
Metabolic Functions of the Liver
Measurement of Bilirubin in the Bile as a
Clinical Diagnostic Tool
Dietary Balances; Regulation of Feeding;
Obesity and Starvation; Vitamins and
Energy Intake and Output Are Balanced Under
Steady-State Conditions
Dietary Balances
Regulation of Food Intake and Energy
Inanition, Anorexia, and Cachexia
Mineral Metabolism
Energetics and Metabolic Rate
Adenosine Triphosphate (ATP) Functions as
an “Energy Currency” in Metabolism
Control of Energy Release in the Cell
Metabolic Rate
Energy Metabolism—Factors That Influence
Energy Output
Body Temperature Regulation,
and Fever
Normal Body Temperatures
Body Temperature Is Controlled by
Balancing Heat Production and
Heat Loss
Regulation of Body Temperature—
Role of the Hypothalamus
Abnormalities of Body Temperature
Endocrinology and Reproduction
Introduction to Endocrinology
Coordination of Body Functions by Chemical
Chemical Structure and Synthesis of
Hormone Secretion, Transport, and Clearance
from the Blood
Mechanisms of Action of Hormones
Measurement of Hormone Concentrations
in the Blood
Pituitary Hormones and Their Control by the
Pituitary Gland and Its Relation to the
Hypothalamus Controls Pituitary Secretion
Physiological Functions of Growth Hormone
Posterior Pituitary Gland and Its Relation to
the Hypothalamus
Thyroid Metabolic Hormones
Synthesis and Secretion of the Thyroid
Metabolic Hormones
Physiological Functions of the Thyroid
Regulation of Thyroid Hormone Secretion
Diseases of the Thyroid
Adrenocortical Hormones
Synthesis and Secretion of Adrenocortical
Functions of the Mineralocorticoids—
Functions of the Glucocorticoids
Adrenal Androgens
Abnormalities of Adrenocortical Secretion
Insulin, Glucagon, and Diabetes Mellitus
Insulin and Its Metabolic Effects
Glucagon and Its Functions
Somatostatin Inhibits Glucagon and Insulin
Summary of Blood Glucose Regulation
Diabetes Mellitus
Parathyroid Hormone, Calcitonin, Calcium
and Phosphate Metabolism, Vitamin D, Bone,
and Teeth
Overview of Calcium and
Phosphate Regulation in the Extracellular
Fluid and Plasma
Bone and Its Relation to Extracellular Calcium
and Phosphate
Vitamin D
Parathyroid Hormone
Summary of Control of Calcium Ion
Pathophysiology of Parathyroid Hormone,
Vitamin D, and Bone Disease
Physiology of the Teeth
Reproductive and Hormonal Functions of
the Male (and Function of the Pineal Gland)
Physiologic Anatomy of the Male Sexual
Male Sexual Act
Testosterone and Other Male Sex Hormones
Abnormalities of Male Sexual Function
Erectile Dysfunction in the Male
Pineal Gland—Its Function in Controlling
Seasonal Fertility in Some Animals
Function of the Placenta
Hormonal Factors in Pregnancy
Response of the Mother’s Body to Pregnancy
Fetal and Neonatal Physiology
Growth and Functional Development of the
Development of the Organ Systems
Adjustments of the Infant to Extrauterine Life
Special Functional Problems in the Neonate
Special Problems of Prematurity
Growth and Development of the Child
Female Physiology Before Pregnancy and
Female Hormones
Physiologic Anatomy of the Female Sexual
Female Hormonal System
Monthly Ovarian Cycle; Function of the
Gonadotropic Hormones
Functions of the Ovarian Hormones—
Estradiol and Progesterone
Regulation of the Female Monthly
Rhythm—Interplay Between the Ovarian
and Hypothalamic-Pituitary Hormones
Abnormalities of Secretion by the Ovaries
Female Sexual Act
Female Fertility
Pregnancy and Lactation
Maturation and Fertilization of the Ovum
Early Nutrition of the Embryo
Sports Physiology
Sports Physiology
Muscles in Exercise
Respiration in Exercise
Cardiovascular System in Exercise
Body Heat in Exercise
Body Fluids and Salt in Exercise
Drugs and Athletes
Body Fitness Prolongs Life
This page intentionally left blank
Introduction to Physiology: The Cell
and General Physiology
1. Functional Organization of the Human
Body and Control of the “Internal
2. The Cell and Its Functions
3. Genetic Control of Protein Synthesis, Cell
Function, and Cell Reproduction
This page intentionally left blank
chapter 1
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
physiology 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 characteristics and mechanisms of the human body that make it a living being.
The very fact that we remain alive is the result of complex control systems, 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, in many ways,
like 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 changing 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, the remaining cells of
this type usually generate new cells until the supply is
Extracellular Fluid—The “Internal
About 60 percent 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 is called extracellular fluid. This extracellular fluid is
in constant motion throughout the body. It is transported
rapidly in the circulating blood and then mixed between
the blood and the tissue fluids by diffusion through the
capillary walls.
In the extracellular fluid are the ions and nutrients
needed by the cells to maintain cell life. Thus, all cells live
in essentially the same environment—the extracellular
fluid. For this reason, the extracellular fluid is also called
the internal environment of the body, or the milieu intérieur, a term introduced more than 100 years ago by the
great 19th-century French physiologist Claude Bernard.
Cells are capable of living, growing, and performing
their special functions as long as the proper concentrations of oxygen, glucose, different ions, amino acids, fatty
substances, and other constituents are available in this
internal environment.
Differences Between Extracellular and Intra­
cellular Fluids. The extracellular fluid contains large
amounts of 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
Unit I
Functional Organization of the Human Body
and Control of the “Internal Environment”
Unit I Introduction to Physiology: The Cell and General Physiology
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 the
extracellular fluid; for example, it contains large amounts
of potassium, magnesium, and phosphate ions instead of
the sodium and chloride ions found in the extracellular
fluid. Special mechanisms for transporting ions through
the cell membranes maintain the ion concentration differences between the extracellular and intracellular fluids.
These transport processes are discussed in Chapter 4.
“Homeostatic” Mechanisms of the Major
Functional Systems
The term homeostasis is used by physiologists to mean
maintenance of nearly constant conditions in the internal
environment. Essentially all organs and tissues of the body
perform functions that help maintain these relatively constant conditions. For instance, the lungs provide oxygen
to the extracellular fluid to replenish the oxygen used by
the cells, the kidneys maintain constant ion concentrations, and the gastrointestinal 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 to homeostasis are outlined in this chapter; then we briefly outline the
basic theory of the body’s control systems that allow the
functional systems to operate in support of one another.
Extracellular Fluid Transport and Mixing
System—The Blood Circulatory System
Extracellular fluid is transported through all parts of the
body in two stages. The first stage is movement of blood
through the body in the blood vessels, and the second is
movement of fluid between the blood capillaries and the
intercellular spaces between the tissue cells.
Figure 1-1 shows the overall circulation of blood. All
the blood in the circulation traverses the entire circulatory circuit an average of once each minute when the
body is at rest and as many as six times each minute when
a person is extremely active.
As blood passes through the blood capillaries, continual exchange of extracellular fluid also occurs between
the plasma portion of the blood and the interstitial fluid
that fills the intercellular spaces. This process is shown
in Figure 1-2. The walls of the capillaries are permeable
to most molecules in the plasma of the blood, with the
exception of plasma protein molecules, which are too
large to readily pass through the capillaries. Therefore,
large amounts of fluid and its dissolved constituents
diffuse back and forth between the blood and the tissue
spaces, as shown by the arrows. This process of diffusion is caused by kinetic motion of the molecules in both
Nutrition and excretion
Figure 1-1 General organization of the circulatory system.
Figure 1-2 Diffusion of fluid and dissolved constituents through
the capillary walls and through the interstitial spaces.
the plasma and the interstitial fluid. That is, the fluid and
dissolved molecules are continually moving and bouncing in all directions within the plasma and the fluid in the
intercellular spaces, as well as through the capillary pores.
Chapter 1 Functional Organization of the Human Body and Control of the “Internal Environment”
Origin of Nutrients in the Extracellular Fluid
Respiratory System. Figure 1-1 shows that each time
the blood passes through the body, it also flows through
the lungs. The blood picks up oxygen in the alveoli, thus
acquiring the oxygen needed by the cells. The 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 rapidly diffuses by molecular motion through this membrane into the blood.
Gastrointestinal Tract. A large portion of the blood
pumped by the heart also passes through the walls of 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 Functions. Not all substances absorbed from
the gastrointestinal 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
mucosa, kidneys, and endocrine glands—help modify the
absorbed substances or store them until they are needed.
The liver also eliminates certain waste products produced
in the body and toxic substances that are ingested.
Musculoskeletal System. How does the musculo­
skeletal system contribute to homeostasis? The answer is
obvious and simple: Were it not for the muscles, the 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, without which
the entire body, along with its homeostatic mechanisms,
could be destroyed instantaneously.
Removal of Metabolic End Products
Removal of Carbon Dioxide by the Lungs. At the
same time that blood picks up oxygen in the lungs, carbon
dioxide is released from the blood into the lung alveoli; the
respiratory movement of air into and out of the lungs carries the carbon dioxide to the atmosphere. Carbon dioxide is
the most abundant of all the end products of metabolism.
Kidneys. Passage of the blood through the kidneys
removes from the plasma most of the other substances
besides carbon dioxide that are not needed by the cells.
These substances include different end products of cellular metabolism, such as urea and uric acid; they also
include excesses of ions and water from the food that
might have accumulated in the extracellular fluid.
The kidneys perform their function by first filtering
large quantities of plasma through the glomeruli into the
tubules and then reabsorbing into the blood those substances needed by the body, such as glucose, amino acids,
appropriate amounts of water, and many of the ions. Most
of the other substances that are not needed by the body,
especially the metabolic end products such as urea, are
reabsorbed poorly and pass through the renal tubules into
the urine.
Gastrointestinal Tract. Undigested material that
enters the gastrointestinal tract and some waste products
of metabolism are eliminated in the feces.
Liver. Among the functions of the liver is the detoxification or removal of many drugs and chemicals that are
ingested. The liver secretes many of these wastes into the
bile to be eventually eliminated in the feces.
Regulation of Body Functions
Nervous System. The nervous system is composed
of three major parts: the sensory input portion, the central
nervous system (or integrative portion), and the motor output portion. Sensory receptors detect the state of the body
or the state of the surroundings. For instance, receptors in
the skin apprise one whenever an object touches the skin
at any point. The eyes are sensory organs that give one a
visual image of the surrounding area. The ears are also
sensory organs. The central nervous system is composed
of the brain and spinal cord. The brain can store information, generate thoughts, create ambition, and determine
reactions that the body performs in response to the sensations. Appropriate signals are then transmitted through
the motor output portion of the nervous system to carry
out one’s desires.
An important segment of the nervous system is called
the autonomic system. It operates at a subconscious level
and controls many functions of the internal organs, including the level of pumping activity by the heart, movements
of the gastrointestinal tract, and secretion by many of the
body’s glands.
Hormone Systems. Located in the body are eight
major endocrine glands that secrete chemical substances
called hormones. Hormones are transported in the extracellular fluid to all parts of the body to help regulate cellular function. For instance, thyroid hormone increases
the rates of most chemical reactions in all cells, thus helping to set the tempo of bodily activity. Insulin controls
glucose metabolism; adrenocortical hormones control
sodium ion, potassium ion, and protein metabolism; and
parathyroid hormone controls bone calcium and phosphate. Thus, the hormones provide a system for regulation that complements the nervous system. The nervous
Unit I
Few cells are located more than 50 micrometers from a
capillary, which ensures diffusion of almost any substance
from the capillary to the cell within a few seconds. Thus,
the extracellular fluid everywhere in the body—both that
of the plasma and that of the interstitial fluid—is continually being mixed, thereby maintaining homogeneity of the
extracellular fluid throughout the body.
Unit I Introduction to Physiology: The Cell and General Physiology
system regulates many muscular and secretory activities of the body, whereas the hormonal system regulates
many metabolic functions.
Protection of the Body
Immune System. The immune system consists of the
white blood cells, tissue cells derived from white blood
cells, the thymus, lymph nodes, and lymph vessels that
protect the body from pathogens such as bacteria, viruses,
parasites, and fungi. The immune system provides a mechanism for the body to (1) distinguish its own cells from
foreign cells and substances and (2) destroy the invader
by phagocytosis or by producing sensitized lymphocytes or
specialized proteins (e.g., antibodies) that either destroy
or neutralize the invader.
Integumentary System. The skin and its various
appendages, including the hair, nails, glands, and other
structures, cover, cushion, and protect the deeper tissues
and organs of the body and generally provide a boundary between the body’s internal environment and the outside world. The integumentary system is also important
for temperature regulation and excretion of wastes and
it provides a sensory interface between the body and the
external environment. The skin generally comprises about
12 to 15 percent of body weight.
Sometimes reproduction is not considered a homeostatic function. It does, however, help maintain homeostasis by generating new beings to take the place of those
that are dying. This may sound like a permissive usage of
the term homeostasis, but it illustrates that, in the final
analysis, essentially all body structures are organized
such that they help maintain the automaticity and continuity of life.
Control Systems of the Body
The human body has thousands of control systems. The
most intricate of these are the genetic control systems
that operate in all cells to help control intracellular function and extracellular functions. This subject is discussed
in Chapter 3.
Many other control systems operate within the organs
to control functions of the individual parts of the organs;
others operate throughout the entire body to control the
interrelations between the organs. For instance, the respiratory system, operating in association with the nervous
system, regulates the concentration of carbon dioxide in
the extracellular fluid. The liver and pancreas regulate
the concentration of glucose in the extracellular fluid,
and the kidneys regulate concentrations of hydrogen,
sodium, potassium, phosphate, and other ions in the
extracellular fluid.
Examples of Control Mechanisms
Regulation of Oxygen and Carbon Dioxide
Concentrations in the Extracellular Fluid. Because
oxygen is one of the major substances required for
chemical reactions in the cells, the body has a special control mechanism to maintain an almost exact
and constant oxygen concentration in the extracellular fluid. This mechanism depends principally on the
chemical characteristics of hemoglobin, which is present in all red blood cells. Hemoglobin combines with
oxygen as the blood passes through the lungs. Then, as
the blood passes through the tissue capillaries, hemoglobin, because of its own strong chemical affinity for
oxygen, does not release oxygen into the tissue fluid
if too much oxygen is already there. But if the oxygen
concentration in the tissue fluid is too low, sufficient
oxygen is released to re-establish an adequate concentration. Thus, regulation of oxygen concentration in the
tissues is vested principally in the chemical characteristics of hemoglobin itself. This regulation is called the
oxygen-buffering function of hemoglobin.
Carbon dioxide concentration in the extracellular fluid
is regulated in a much different way. Carbon dioxide is
a major end product of the oxidative reactions in cells.
If all the carbon dioxide formed in the cells continued to
accumulate in the tissue fluids, all energy-giving reactions
of the cells would cease. Fortunately, a higher than normal carbon dioxide concentration in the blood excites the
respiratory center, causing a person to breathe rapidly and
deeply. This increases expiration of carbon dioxide and,
therefore, removes excess carbon dioxide from the blood
and tissue fluids. This process continues until the concentration returns to normal.
Regulation of Arterial Blood Pressure. Several systems contribute to the regulation of arterial blood pressure. One of these, the baroreceptor system, is a simple
and excellent example of a rapidly acting control mechanism. In the walls of the bifurcation region of the carotid
arteries in the neck, and also in the arch of the aorta in
the thorax, are many nerve receptors called baroreceptors, which are stimulated by stretch of the arterial wall.
When the arterial pressure rises too high, the baroreceptors send barrages of nerve impulses to the medulla
of the brain. Here these impulses inhibit the vasomotor
center, which in turn decreases the number of impulses
transmitted from the vasomotor center through the sympathetic nervous system to the heart and blood vessels.
Lack of these impulses causes diminished pumping activity by the heart and also dilation of the peripheral blood
vessels, allowing increased blood flow through the vessels. Both of these effects decrease the arterial pressure
back toward normal.
Conversely, a decrease in arterial pressure below normal relaxes the stretch receptors, allowing the vasomotor
center to become more active than usual, thereby causing vasoconstriction and increased heart pumping. The
decrease in arterial pressure also raises arterial pressure
back toward normal.
Chapter 1 Functional Organization of the Human Body and Control of the “Internal Environment”
Normal Ranges and Physical Characteristics
of Important Extracellular Fluid Constituents
Negative Feedback Nature of Most Control Systems
Characteristics of Control Systems
The aforementioned examples of homeostatic control
mechanisms are only a few of the many thousands in the
body, all of which have certain characteristics in common
as explained in this section.
Most control systems of the body act by negative feedback, which can best be explained by reviewing some of
the homeostatic control systems mentioned previously.
In the regulation of carbon dioxide concentration, a high
concentration of carbon dioxide in the extracellular fluid
increases pulmonary ventilation. This, in turn, decreases
the extracellular fluid carbon dioxide concentration
because the lungs expire greater amounts of carbon dioxide from the body. In other words, the high concentration of carbon dioxide initiates events that decrease the
concentration toward normal, which is negative to the
initiating stimulus. Conversely, if the carbon dioxide concentration falls too low, this causes feedback to increase
the concentration. This response is also negative to the
initiating stimulus.
In the arterial pressure-regulating mechanisms, a
high pressure causes a series of reactions that promote
a lowered pressure, or a low pressure causes a series of
reactions that promote an elevated pressure. In both
instances, these effects are negative with respect to the
initiating stimulus.
Therefore, in general, if some factor becomes excessive or deficient, a control system initiates negative feedback, which consists of a series of changes that return
the factor toward a certain mean value, thus maintaining
“Gain” of a Control System. The degree of effectiveness with which a control system maintains constant 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 functioning, and the arterial pressure rises from the normal level of 100 mm Hg up to
175 mm Hg. Then, let us assume that the same volume of
blood is injected into the same person when the baroreceptor system is functioning, and this time the pressure
increases only 25 mm Hg. Thus, the feedback control system has caused a “correction” of −50 mm Hg—that is, from
Table 1-1 Important Constituents and Physical Characteristics of Extracellular Fluid
Normal Value
Normal Range
Approximate Short-Term
Nonlethal Limit
mm Hg
Carbon dioxide
mm Hg
Sodium ion
Potassium ion
Calcium ion
Chloride ion
Bicarbonate ion
98.4 (37.0)
98-98.8 (37.0)
65-110 (18.3-43.3)
°F (°C)
Body temperature
Unit I
Table 1-1 lists some of the important constituents and
physical characteristics of extracellular fluid, along with
their normal values, normal ranges, and maximum limits
without causing death. Note the narrowness of the normal range for each one. Values outside these ranges are
usually caused by illness.
Most important are the limits beyond which abnormalities can cause death. For example, an increase in the body
temperature of only 11°F (7°C) above normal can lead to a
vicious cycle of increasing cellular metabolism that destroys
the cells. Note also the narrow range for acid-base balance
in the body, with a normal pH value of 7.4 and lethal values
only about 0.5 on either side of normal. Another important factor is the potassium ion concentration because
whenever it decreases to less than one-third normal, a
person is likely to be paralyzed as a result of the nerves’
inability to carry signals. Alternatively, if the potassium ion
concentration increases to two or more times normal, the
heart muscle is likely to be severely depressed. Also, when
the calcium ion concentration falls below about one-half
normal, a person is likely to experience tetanic contraction
of muscles throughout the body because of the spontaneous generation of excess nerve impulses in the peripheral
nerves. When the glucose concentration falls below onehalf normal, a person frequently develops extreme mental
irritability and sometimes even convulsions.
These examples should give one an appreciation for
the extreme value and even the necessity of the vast numbers of control systems that keep the body operating in
health; in the absence of any one of these controls, serious
body malfunction or death can result.
Unit I Introduction to Physiology: The Cell and General Physiology
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 percent effective in preventing change. The gain of the system is then calculated
by the following formula:
Gain =
Thus, in the baroreceptor system example, the correction is −50 mm Hg and the error persisting is +25 mm Hg.
Therefore, the gain of the person’s baroreceptor 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.
The gains of some other physiologic control systems
are much greater than that of the baroreceptor system.
For instance, the gain of the system controlling internal
body temperature when a person is exposed to moderately cold weather is about −33. Therefore, one can see
that the temperature control system is much more effective than the baroreceptor pressure control system.
Positive Feedback Can Sometimes Cause
Vicious Cycles and Death
One might ask the question, Why do most control systems of the body operate by negative feedback rather than
positive feedback? If one considers the nature of positive
feedback, one immediately sees that positive feedback
does not lead to stability but to instability and, in some
cases, can cause death.
Figure 1-3 shows an example in which death can ensue
from positive feedback. This figure depicts the pumping effectiveness of the heart, showing that the heart of
a healthy human being pumps about 5 liters of blood per
minute. If the person is suddenly bled 2 liters, the amount
of blood in the body is decreased to such a low level that
Pumping effectiveness of heart
(Liters pumped per minute)
Return to
Bled 1 liter
Bled 2 liters
Figure 1-3 Recovery of heart pumping caused by negative feedback after 1 liter of blood is removed from the circulation. Death is
caused by positive feedback when 2 liters of blood are removed.
not enough blood is available for the heart to pump effectively. As a result, the arterial pressure falls and the flow
of blood to the heart muscle through the coronary vessels
diminishes. This results in weakening of the heart, further diminished pumping, a further decrease in coronary
blood flow, and still more weakness of the heart; the cycle
repeats itself again and again until death occurs. Note that
each cycle in the feedback results in further weakening of
the heart. In other words, the initiating stimulus causes
more of the same, which is positive feedback.
Positive feedback is better known as a “vicious cycle,”
but a mild degree of positive feedback can be overcome
by the negative feedback control mechanisms of the body
and the vicious cycle fails to develop. For instance, if the
person in the aforementioned example were bled only
1 liter instead of 2 liters, the normal negative feedback
mechanisms for controlling cardiac output and arterial
pressure would overbalance the positive feedback and the
person would recover, as shown by the dashed curve of
Figure 1-3.
Positive Feedback Can Sometimes Be Useful. In
some instances, the body uses positive feedback to its
advantage. Blood clotting is an example of a valuable use
of positive feedback. When a blood vessel is ruptured and
a clot begins to form, multiple enzymes called clotting
factors are activated within the clot itself. Some of these
enzymes act on other unactivated enzymes of the immediately adjacent blood, thus causing more blood clotting. This process continues until the hole in the vessel is
plugged and bleeding no longer occurs. On occasion, this
mechanism can get out of hand and cause the formation
of unwanted clots. In fact, this is what initiates most acute
heart attacks, which are caused by a clot beginning on the
inside surface of an atherosclerotic plaque in a coronary
artery and then growing until the artery is blocked.
Childbirth is another instance in which positive feedback plays a valuable role. When uterine contractions
become strong enough for the baby’s head to begin pushing through the cervix, stretch of the cervix sends signals
through the uterine muscle back to the body of the uterus,
causing even more powerful contractions. Thus, the uterine contractions stretch the cervix and the cervical stretch
causes stronger contractions. When this process becomes
powerful enough, the baby is born. If it is not powerful
enough, the contractions usually die out and a few days
pass before they begin again.
Another important use of positive feedback is for the
generation of nerve signals. That is, when the membrane
of a nerve fiber is stimulated, this causes slight leakage
of sodium ions through sodium channels in the nerve
membrane to the fiber’s interior. The sodium ions entering the fiber then change the membrane potential, which
in turn causes more opening of channels, more change
of potential, still more opening of channels, and so forth.
Thus, a slight leak becomes an explosion of sodium entering the interior of the nerve fiber, which creates the nerve
action potential. This action potential in turn causes electrical current to flow along both the outside and the inside
Chapter 1 Functional Organization of the Human Body and Control of the “Internal Environment”
More Complex Types of Control Systems—Adaptive
Later in this text, when we study the nervous system, we
shall see that this system contains great numbers of interconnected control mechanisms. Some are simple feedback systems similar to those already discussed. Many are
not. For instance, some movements of the body occur so
rapidly that there is not enough time for nerve signals to
travel from the peripheral parts of the body all the way
to the brain and then back to the periphery again to control the movement. Therefore, the brain uses a principle
called feed-forward control to cause required muscle contractions. That is, sensory nerve signals from the moving
parts apprise the brain whether the movement is performed correctly. If not, the brain corrects the feed-forward signals that it sends to the muscles the next time the
movement is required. Then, if still further correction is
necessary, this will be done again for subsequent movements. This is called adaptive control. Adaptive control,
in a sense, is delayed negative feedback.
Thus, one can see how complex the feedback control
systems of the body can be. A person’s life depends on all
of them. Therefore, a major share of this text is devoted to
discussing these life-giving mechanisms.
Summary—Automaticity of the Body
The purpose of this chapter has been to point out, first, the
overall organization of the body and, second, the means
by which the different parts of the body operate in harmony. To summarize, the body is actually a social order
of about 100 trillion cells organized into different functional structures, some of which are called organs. Each
functional structure contributes its share to the maintenance of homeostatic conditions in the extracellular fluid,
which is called the internal environment. As long as normal conditions are maintained in this internal environment, the cells of the body continue to live and function
properly. Each cell benefits from homeostasis, and in turn,
each cell contributes its share toward the maintenance of
homeostasis. This reciprocal interplay provides continuous automaticity of the body until one or more functional
systems lose their ability to contribute their share of function. When this happens, all the cells of the body suffer.
Extreme dysfunction leads to death; moderate dysfunction leads to sickness.
Adolph EF: Physiological adaptations: hypertrophies and superfunctions,
Am Sci 60:608, 1972.
Bernard C: Lectures on the Phenomena of Life Common to Animals and
Plants, Springfield, IL, 1974, Charles C Thomas.
Cannon WB: The Wisdom of the Body, New York, 1932, WW Norton.
Chien S: Mechanotransduction and endothelial cell homeostasis: the
wisdom of the cell, Am J Physiol Heart Circ Physiol 292:H1209, 2007.
Csete ME, Doyle JC: Reverse engineering of biological complexity, Science
295:1664, 2002.
Danzler WH, editor: Handbook of Physiology, Sec 13: Comparative
Physiology, Bethesda, 1997, American Physiological Society.
DiBona GF: Physiology in perspective: the wisdom of the body. Neural
control of the kidney, Am J Physiol Regul Integr Comp Physiol 289:R633,
Dickinson MH, Farley CT, Full RJ, et al: How animals move: an integrative
view, Science 288:100, 2000.
Garland T Jr, Carter PA: Evolutionary physiology, Annu Rev Physiol 56:579,
Gao Q, Horvath TL: Neuronal control of energy homeostasis, FEBS Lett
582:132, 2008.
Guyton AC: Arterial Pressure and Hypertension, Philadelphia, 1980, WB
Guyton AC, Jones CE, Coleman TG: Cardiac Output and Its Regulation,
Philadelphia, 1973, WB Saunders.
Guyton AC, Taylor AE, Granger HJ: Dynamics and Control of the Body Fluids,
Philadelphia, 1975, WB Saunders.
Herman MA, Kahn BB: Glucose transport and sensing in the maintenance
of glucose homeostasis and metabolic harmony, J Clin Invest 116:1767,
Krahe R, Gabbiani F: Burst firing in sensory systems, Nat Rev Neurosci 5:13,
Orgel LE: The origin of life on the earth, Sci Am 271:76, 1994.
Quarles LD: Endocrine functions of bone in mineral metabolism regulation,
J Clin Invest 118:3820, 2008.
Smith HW: From Fish to Philosopher, New York, 1961, Doubleday.
Tjian R: Molecular machines that control genes, Sci Am 272:54, 1995.
Unit I
of the fiber and initiates additional action potentials. This
process continues again and again until the nerve signal
goes all the way to the end 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 clotting,
the positive feedback clotting process is a negative feedback process for maintenance of normal blood volume.
Also, the positive feedback that causes nerve signals
allows the nerves to participate in thousands of negative
feedback nervous control systems.
This page intentionally left blank
chapter 2
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 appropriate
nutrients. To understand
the function of organs and other structures of the body, it
is essential 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 protoplasm. Protoplasm is composed
mainly of five basic substances: water, electrolytes, 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 percent. 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. Important ions in the cell include 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 interrelations 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
electrochemical impulses in nerve and muscle fibers.
Proteins. After water, the most abundant substances
in most cells are proteins, which normally constitute 10 to
20 percent 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 are polymers of many individual
protein molecules. A prominent 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
collagen 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 composed of combinations of a few
molecules in tubular-globular form. These proteins
are mainly the enzymes of the cell and, in contrast to
the fibrillar proteins, are often mobile in the cell fluid.
Also, many of them are adherent to membranous structures inside the cell. The enzymes come into direct contact with other substances in the cell fluid and thereby
catalyze specific intracellular chemical reactions. For
instance, the chemical reactions that split glucose into its
component parts and then combine these with oxygen
to form carbon dioxide and water while simultaneously
providing energy for cellular function are all catalyzed by
a series of protein enzymes.
Figure 2-1 Structure of the cell as seen with the light
Unit I
The Cell and Its Functions
Unit I Introduction to Physiology: The Cell and General Physiology
Lipids. Lipids are several types of substances that are
grouped together because of their common property of
being soluble in fat solvents. Especially important lipids
are phospholipids and cholesterol, which together constitute only about 2 percent of the total cell mass. The significance of phospholipids and cholesterol is that they are
mainly insoluble in water and, therefore, are used to form
the cell membrane and intracellular membrane barriers
that separate the different cell compartments.
In addition to phospholipids and cholesterol, some cells
contain large quantities of triglycerides, also called neutral
fat. In the fat cells, triglycerides often account for as much
as 95 percent of the cell mass. The fat stored in these cells
represents the body’s main storehouse of energy-giving
nutrients that can later be dissoluted and used to provide
energy wherever in the body it is needed.
Carbohydrates. Carbohydrates have little structural
function in the cell except as parts of glycoprotein molecules, but they play a major role in nutrition of the cell.
Most human cells do not maintain large stores of carbohydrates; the amount usually averages about 1 percent
of their total mass but increases to as much as 3 percent
in muscle cells and, occasionally, 6 percent in liver cells.
However, carbohydrate in the form of dissolved glucose
is always present in the surrounding extracellular fluid so
that it is readily available to the cell. Also, a small amount
of carbohydrate is stored in the cells in the form of glycogen, which is an insoluble polymer of glucose that can
be depolymerized and used rapidly to supply the cells’
energy needs.
Physical Structure of the Cell
The cell is not merely a bag of fluid, enzymes, and chemicals; it also contains highly organized physical structures,
called intracellular organelles. The physical nature of each
organelle is as important as the cell’s chemical constituents for cell function. For instance, without one of the
organelles, the mitochondria, more than 95 percent of the
cell’s energy release from nutrients would cease immediately. The most important organelles and other structures
of the cell are shown in Figure 2-2.
Chromosomes and DNA
Figure 2-2 Reconstruction of a typical cell, showing the internal organelles in the cytoplasm and in the nucleus.
Chapter 2 The Cell and Its Functions
Membranous Structures of the Cell
Cell Membrane
The cell membrane (also called the plasma membrane),
which envelops the cell, is a thin, pliable, elastic structure
only 7.5 to 10 nanometers thick. It is composed almost
entirely of proteins and lipids. The approximate composition is proteins, 55 percent; phospholipids, 25 percent;
cholesterol, 13 percent; other lipids, 4 percent; and carbohydrates, 3 percent.
Lipid Barrier of the Cell Membrane Impedes Water
Penetration. Figure 2-3 shows the structure of the cell
membrane. Its basic structure is a lipid bilayer, which is
a thin, double-layered film of lipids—each layer only one
molecule thick—that is continuous over the entire cell
surface. Interspersed in this lipid film are large globular
protein molecules.
The basic lipid bilayer is composed of phospholipid
molecules. One end of each phospholipid molecule is soluble in water; that is, it is hydrophilic. The other end is
soluble only in fats; that is, it is hydrophobic. The phosphate end of the phospholipid is hydrophilic, and the fatty
acid portion is hydrophobic.
Because the hydrophobic portions of the phospholipid
molecules are repelled by water but are mutually attracted
to one another, they have a natural tendency to attach to
one another in the middle of the membrane, as shown in
Figure 2-3. The hydrophilic phosphate portions then constitute the two surfaces of the complete cell membrane, in
contact with intracellular water on the inside of the membrane and extracellular water on the outside surface.
The lipid layer in the middle of the membrane is
impermeable to the usual water-soluble substances, such
as ions, glucose, and urea. Conversely, fat-soluble substances, such as oxygen, carbon dioxide, and alcohol, can
penetrate this portion of the membrane with ease.
Integral protein
Integral protein
Figure 2-3 Structure of the cell membrane, showing that it is composed mainly of a lipid bilayer of phospholipid molecules, but with large
numbers of protein molecules protruding through the layer. Also, carbohydrate moieties are attached to the protein molecules on the outside of the membrane and to additional protein molecules on the inside. (Redrawn from Lodish HF, Rothman JE: The assembly of cell membranes. Sci Am 240:48, 1979. Copyright George V. Kevin.)
Unit I
Most organelles of the cell are covered by membranes
composed primarily of lipids and proteins. These membranes include the cell membrane, nuclear membrane,
membrane of the endoplasmic reticulum, and membranes
of the mitochondria, lysosomes, and Golgi apparatus.
The lipids of the membranes provide a barrier that
impedes the movement of water and water-soluble substances from one cell compartment to another because water
is not soluble in lipids. However, protein molecules in the
membrane often do penetrate all the way through the membrane, thus providing specialized pathways, often organized
into actual pores, for passage of specific substances through
the membrane. Also, many other membrane proteins are
enzymes that catalyze a multitude of different chemical
reactions, discussed here and in subsequent chapters.
Unit I Introduction to Physiology: The Cell and General Physiology
The cholesterol molecules in the membrane are also
lipid in nature because their steroid nucleus is highly fat
soluble. These molecules, in a sense, are dissolved in the
bilayer of the membrane. They mainly help determine the
degree of permeability (or impermeability) of the bilayer
to water-soluble constituents of body fluids. Cholesterol
controls much of the fluidity of the membrane as well.
Integral and Peripheral Cell Membrane Proteins.
Figure 2-3 also shows globular masses floating in the lipid
bilayer. These are membrane proteins, most of which
are glycoproteins. There are two types of cell ­membrane
­proteins: integral proteins that protrude all the way
through the membrane and peripheral proteins that are
attached only to one surface of the membrane and do not
penetrate all the way through.
Many of the integral proteins provide structural channels (or pores) through which water molecules and watersoluble substances, especially ions, can diffuse between
the extracellular and intracellular fluids. These protein
channels also have selective properties that allow preferential diffusion of some substances over others.
Other integral proteins act as carrier proteins for transporting substances that otherwise could not penetrate the
lipid bilayer. Sometimes these even transport substances
in the direction opposite to their electrochemical gradients for diffusion, which is called “active transport.” Still
others act as enzymes.
Integral membrane proteins can also serve as receptors
for water-soluble chemicals, such as peptide hormones,
that do not easily penetrate the cell membrane. Interaction
of cell membrane receptors with specific ligands that bind
to the receptor causes conformational changes in the
receptor protein. This, in turn, enzymatically activates the
intracellular part of the protein or induces interactions
between the receptor and proteins in the cytoplasm that
act as second messengers, thereby relaying the signal from
the extracellular part of the receptor to the interior of the
cell. In this way, integral proteins spanning the cell membrane provide a means of conveying information about
the environment to the cell interior.
Peripheral protein molecules are often attached to
the integral proteins. These peripheral proteins function
almost entirely as enzymes or as controllers of transport
of substances through the cell membrane “pores.”
Membrane Carbohydrates—The Cell “Glycocalyx.”
Membrane carbohydrates occur almost invariably in
combination with proteins or lipids in the form of glycoproteins or glycolipids. In fact, most of the integral proteins
are glycoproteins, and about one tenth of the membrane
lipid molecules are glycolipids. The “glyco” portions of
these molecules almost invariably protrude to the outside of the cell, dangling outward from the cell surface.
Many other carbohydrate compounds, called proteoglycans—which are mainly carbohydrate substances bound
to small protein cores—are loosely attached to the outer
surface of the cell as well. Thus, the entire outside surface
of the cell often has a loose carbohydrate coat called the
The carbohydrate moieties attached to the outer surface of the cell have several important functions: (1) Many
of them have a negative electrical charge, which gives
most cells an overall negative surface charge that repels
other negative objects. (2) The glycocalyx of some cells
attaches to the glycocalyx of other cells, thus attaching
cells to one another. (3) Many of the carbohydrates act as
receptor substances for binding hormones, such as insulin;
when bound, this combination activates attached internal proteins that, in turn, activate a cascade of intracellular enzymes. (4) Some carbohydrate moieties enter into
immune reactions, as discussed in Chapter 34.
Cytoplasm and Its Organelles
The cytoplasm is filled with both minute and large dispersed particles and organelles. The clear fluid portion
of the cytoplasm in which the particles are dispersed is
called cytosol; this contains mainly dissolved proteins,
electrolytes, and glucose.
Dispersed in the cytoplasm are neutral fat globules,
glycogen granules, ribosomes, secretory vesicles, and five
especially important organelles: the endoplasmic reticulum, the Golgi apparatus, mitochondria, lysosomes, and
Endoplasmic Reticulum
Figure 2-2 shows a network of tubular and flat vesicular structures in the cytoplasm; this is the endoplasmic reticulum. The tubules and vesicles interconnect
with one another. Also, their walls are constructed of
lipid bilayer membranes that contain large amounts of
proteins, similar to the cell membrane. The total surface area of this structure in some cells—the liver cells,
for instance—can be as much as 30 to 40 times the cell
membrane area.
The detailed structure of a small portion of endoplasmic reticulum is shown in Figure 2-4. The space inside
the tubules and vesicles is filled with endoplasmic matrix,
a watery medium that is different from the fluid in the
cytosol outside the endoplasmic reticulum. Electron
micrographs show that the space inside the endoplasmic
reticulum is connected with the space between the two
membrane surfaces of the nuclear membrane.
Substances formed in some parts of the cell enter the
space of the endoplasmic reticulum and are then conducted to other parts of the cell. Also, the vast surface
area of this reticulum and the multiple enzyme systems
attached to its membranes provide machinery for a major
share of the metabolic functions of the cell.
Ribosomes and the Granular Endoplasmic Reticulum.
Attached to the outer surfaces of many parts of the endoplasmic reticulum are large numbers of minute granular
particles called ribosomes. Where these are present, the
reticulum is called the granular endoplasmic reticulum.
The ribosomes are composed of a mixture of RNA and
proteins, and they function to synthesize new protein
molecules in the cell, as discussed later in this chapter and
in Chapter 3.
Chapter 2 The Cell and Its Functions
Figure 2-4 Structure of the endoplasmic reticulum. (Modified
from DeRobertis EDP, Saez FA, DeRobertis EMF: Cell Biology, 6th
ed. Philadelphia: WB Saunders, 1975.)
Agranular Endoplasmic Reticulum. Part of the endoplasmic reticulum has no attached ribosomes. This part
is called the agranular, or smooth, endoplasmic reticulum.
The agranular reticulum functions for the synthesis of
lipid substances and for other processes of the cells promoted by intrareticular enzymes.
Golgi Apparatus
The Golgi apparatus, shown in Figure 2-5, is closely
related to the endoplasmic reticulum. It has membranes
similar to those of the agranular endoplasmic reticulum. It
is usually composed of four or more stacked layers of thin,
flat, enclosed vesicles lying near one side of the nucleus.
This apparatus is prominent in secretory cells, where it is
located on the side of the cell from which the secretory
substances are extruded.
Golgi vesicles
ER vesicles
Figure 2-5 A typical Golgi apparatus and its relationship to the
endoplasmic reticulum (ER) and the nucleus.
Lysosomes, shown in Figure 2-2, are vesicular organelles that form by breaking off from the Golgi apparatus and then dispersing throughout the cytoplasm. The
lysosomes provide an intracellular digestive system that
allows the cell to digest (1) damaged cellular 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 cell types, 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 hydrolase (digestive) enzymes. A hydrolytic enzyme
is capable of splitting an organic compound into two or
more parts by combining hydrogen from a water molecule 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 is hydrolyzed to form amino acids, glycogen is hydrolyzed to
form glucose, and lipids are hydrolyzed to form fatty
acids and glycerol.
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 digestive enzymes. These enzymes
then split the organic substances with which they come
in contact into small, highly diffusible substances such as
amino acids and glucose. Some of the specific functions of
lysosomes are discussed later in the chapter.
Peroxisomes are similar physically to lysosomes, but they
are different in two important ways. First, they are believed
to be formed by self-replication (or perhaps by budding
off from the smooth endoplasmic reticulum) rather than
from the Golgi apparatus. Second, they contain oxidases
rather than hydrolases. Several of the oxidases are capable
of combining oxygen with hydrogen ions derived from different intracellular chemicals to form hydrogen peroxide
(H2O2). Hydrogen peroxide is a highly oxidizing substance
and is used in association with catalase, another oxidase
enzyme present in large quantities in peroxisomes, to oxidize many substances that might otherwise be poisonous
Unit I
The Golgi apparatus functions in association with the
endoplasmic reticulum. As shown in Figure 2-5, small
“transport vesicles” (also called endoplasmic reticulum
vesicles, or ER vesicles) continually pinch off from the
endoplasmic reticulum and shortly thereafter fuse with
the Golgi apparatus. In this way, substances entrapped
in the ER vesicles are transported from the endoplasmic
reticulum to the Golgi apparatus. 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.
Unit I Introduction to Physiology: The Cell and General Physiology
to the cell. For instance, about half the alcohol a person
drinks is detoxified by the peroxisomes of the liver cells
in this manner.
Secretory Vesicles
One of the important functions of many cells is secretion
of special chemical substances. Almost all such secretory
substances are formed by the endoplasmic reticulum–
Golgi apparatus system and are then released from the
Golgi apparatus into the cytoplasm in the form of storage vesicles called secretory vesicles or secretory granules.
Figure 2-6 shows typical secretory vesicles inside pancreatic acinar cells; these vesicles store protein proenzymes
(enzymes that are not yet activated). The proenzymes are
secreted later through the outer cell membrane into the
pancreatic duct and thence into the duodenum, where
they become activated and perform digestive functions
on the food in the intestinal tract.
The mitochondria, shown in Figures 2-2 and 2-7, are
called the “powerhouses” of the cell. Without them,
cells would be unable to extract enough energy from the
nutrients, and essentially all cellular functions would
Figure 2-6 Secretory granules (secretory vesicles) in acinar cells
of the pancreas.
Outer membrane
Inner membrane
Outer chamber
Figure 2-7 Structure of a mitochondrion. (Modified from
DeRobertis EDP, Saez FA, DeRobertis EMF: Cell Biology, 6th ed.
Philadelphia: WB Saunders, 1975.)
Mitochondria are present in all areas of each cell’s
cytoplasm, but the total number per cell varies from less
than a hundred up to several thousand, depending on the
amount of energy required by the cell. Further, the mitochondria are concentrated in those portions of the cell that
are responsible for the major share of its energy metabolism. They are also variable in size and shape. Some are
only a few hundred nanometers 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 mitochondrion 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 triphosphate (ATP). ATP is then transported out of
the mitochondrion, and it diffuses throughout the cell to
release its own energy wherever it is needed for performing cellular functions. The chemical details of ATP 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
one mitochondrion can form a second one, a third one,
and so on, whenever there is a need in the cell for increased
amounts of ATP. Indeed, the mitochondria contain DNA
similar to that found in the cell nucleus. In Chapter 3 we
will see that DNA is the basic chemical of the nucleus that
controls replication of the cell. The DNA of the mitochondrion plays a similar role, controlling replication of
the mitochondrion.
Cell Cytoskeleton—Filament and Tubular Structures
The fibrillar proteins of the cell are usually organized into
filaments or tubules. These originate as precursor protein
molecules synthesized by ribosomes in the cytoplasm.
The precursor molecules then polymerize to form filaments. As an example, large numbers of actin filaments
frequently occur in the outer zone of the cytoplasm,
called the ectoplasm, to form an elastic support for the
cell membrane. Also, in muscle cells, actin and myosin filaments are organized into a special contractile machine
that is the basis for muscle contraction, as discussed in
detail in Chapter 6.
A special type of stiff filament composed of poly­
merized tubulin molecules is used in all cells to construct
strong tubular structures, the microtubules. Figure 2-8
shows typical microtubules that were teased from the flagellum of a sperm.
Chapter 2 The Cell and Its Functions
Nuclear envelopeouter and inner
Chromatin material (DNA)
Figure 2-9 Structure of the nucleus.
Figure 2-8 Microtubules teased from the flagellum of a sperm.
(From Wolstenholme GEW, O’Connor M, and the publisher,
JA Churchill, 1967. Figure 4, page 314. Copyright the Novartis
Foundation, formerly the Ciba Foundation.)
Another example of microtubules is the tubular skeletal
structure in the center of each cilium that radiates upward
from the cell cytoplasm to the tip of the cilium. This structure is discussed later in the chapter and is illustrated in
Figure 2-17. Also, both the centrioles and the mitotic spindle of the mitosing cell are composed of stiff microtubules.
Thus, a primary function of microtubules is to act as
a cytoskeleton, providing rigid physical structures for certain parts of cells.
The nucleus is the control center of the cell. Briefly, the
nucleus contains large quantities of DNA, which are the
genes. The genes determine the characteristics of the
cell’s proteins, including the structural proteins, as well
as the intracellular enzymes that control cytoplasmic and
nuclear activities.
The genes also control and promote reproduction of the
cell itself. The genes first reproduce to give two identical
sets of genes; then the cell splits by a special process called
mitosis to form two daughter cells, each of which receives
one of the two sets of DNA genes. All these activities of the
nucleus are considered in detail in the next chapter.
Unfortunately, the appearance of the nucleus under the
microscope does not provide many clues to the mechanisms by which the nucleus performs its control activities.
Figure 2-9 shows the light microscopic appearance of the
interphase nucleus (during the period between mitoses),
revealing darkly staining chromatin material throughout
the nucleoplasm. During mitosis, the chromatin material
organizes in the form of highly structured chromosomes,
which can then be easily identified using the light microscope, as illustrated in the next chapter.
Nuclear Membrane
The nuclear membrane, also called the nuclear envelope,
is actually two separate bilayer membranes, one inside
the other. The outer membrane is continuous with the
endoplasmic reticulum of the cell cytoplasm, and the
space between the two nuclear membranes is also continuous with the space inside the endoplasmic reticulum,
as shown in Figure 2-9.
The nuclear membrane is penetrated by several thousand nuclear pores. Large complexes of protein molecules
are attached at the edges of the pores so that the central
area of each pore is only about 9 nanometers in diameter.
Even this size is large enough to allow molecules up to
44,000 molecular weight to pass through with reasonable
Nucleoli and Formation of Ribosomes
The nuclei of most cells contain one or more highly staining structures called nucleoli. The nucleolus, unlike most
other organelles discussed here, does not have a limiting membrane. Instead, it is simply an accumulation of
large amounts of RNA and proteins of the types found in
ribosomes. The nucleolus becomes considerably enlarged
when the cell is actively synthesizing proteins.
Formation of the nucleoli (and of the ribosomes in
the cytoplasm outside the nucleus) begins in the nucleus.
First, specific DNA genes in the chromosomes cause RNA
to be synthesized. Some of this is stored in the nucleoli,
but most of it is transported outward through the nuclear
pores into cytoplasm. Here, it is used in conjunction with
specific proteins to assemble “mature” ribosomes that
play an essential role in forming cytoplasmic proteins, as
discussed more fully in Chapter 3.
Comparison of the Animal Cell
with Precellular Forms of Life
The cell is a complicated organism that required many
hundreds of millions of years to develop after the earliest
form of life, an organism similar to the present-day virus,
first appeared on earth. Figure 2-10 shows the relative
sizes of (1) the smallest known virus, (2) a large virus, (3)
a rickettsia, (4) a bacterium, and (5) a nucleated cell, demonstrating that the cell has a diameter about 1000 times
that of the smallest virus and, therefore, a volume about
Unit I
Unit I Introduction to Physiology: The Cell and General Physiology
15 nm- Small virus
150 nm- Large virus
350 nm- Rickettsia
1 mm Bacterium
5–10 mm+
Figure 2-10 Comparison of sizes of precellular organisms with
that of the average cell in the human body.
1 billion times that of the smallest virus. Correspondingly,
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 virus is
a nucleic acid embedded in a coat of protein. This nucleic
acid is composed of the same basic nucleic acid constituents
(DNA or RNA) found in mammalian cells, and it is capable
of reproducing itself under appropriate conditions. Thus,
the virus propagates its lineage from generation to generation and is therefore a living structure in the same way that
the cell and the human being are living structures.
As life evolved, other chemicals besides nucleic acid and
simple proteins became integral parts of the organism, and
specialized functions began to develop in different parts
of the virus. A membrane formed around the virus, and
inside the membrane, a fluid matrix appeared. Specialized
chemicals then developed inside the fluid to perform special functions; many protein enzymes appeared that were
capable of catalyzing chemical reactions and, therefore,
determining the organism’s activities.
In still later stages of life, particularly in the rickettsial and bacterial stages, organelles developed inside the
organism, representing physical structures of chemical aggregates that perform functions in a more efficient
manner than can be achieved by dispersed chemicals
throughout the fluid matrix.
Finally, in the nucleated cell, still more complex organelles developed, the most important of which is the
nucleus itself. The nucleus distinguishes this type of cell
from all lower forms of life; the nucleus provides a control
center for all cellular activities, and it provides for exact
reproduction of new cells generation after generation,
each new cell having almost exactly the same structure as
its progenitor.
Ingestion by the Cell—Endocytosis
If a cell is to live and grow and reproduce, it must obtain
nutrients and other substances from the surrounding 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 molecules of the substance; substances move either through
cell membrane pores or, in the case of lipid-soluble substances, through the lipid matrix of the membrane.
Active transport involves the actual carrying of a substance through the membrane by a physical protein structure that penetrates all the way through the membrane.
These active transport mechanisms are so important to cell
function that they are presented in detail in Chapter 4.
Very large particles enter the cell by a specialized function of the cell membrane called endocytosis. The principal forms of endocytosis are pinocytosis and phagocytosis.
Pinocytosis means ingestion of minute particles that form
vesicles of extracellular fluid and particulate constituents
inside the cell cytoplasm. Phagocytosis means ingestion
of large particles, such as bacteria, whole cells, or portions
of degenerating tissue.
Pinocytosis. Pinocytosis occurs continually in the cell
membranes of most cells, but it is especially rapid in some
cells. For instance, it occurs so rapidly in macrophages
that about 3 percent of the total macrophage membrane
is engulfed in the form of vesicles each minute. Even so,
the pinocytotic vesicles are so small—usually only 100 to
200 nanometers in diameter—that most of them can be
seen only with the electron microscope.
Pinocytosis is the only means by which most large macromolecules, such as most protein molecules, can enter
cells. In fact, the rate at which pinocytotic vesicles form
is usually enhanced when such macromolecules attach to
the cell membrane.
Figure 2-11 demonstrates the successive steps of
pinocytosis, showing three molecules of protein attaching to the membrane. These molecules usually attach to
Coated pit
Actin and myosin
Dissolving clathrin
Functional Systems of the Cell
In the remainder of this chapter, we discuss several representative functional systems of the cell that make it a living organism.
Figure 2-11 Mechanism of pinocytosis.
Chapter 2 The Cell and Its Functions
Phagocytosis. Phagocytosis occurs in much the same
way as pinocytosis, except that it involves large particles
rather than molecules. Only certain cells have the capability of phagocytosis, most notably the tissue macrophages
and some of the white blood cells.
Phagocytosis is initiated when a particle such as a bacterium, a dead cell, or tissue debris binds with receptors
on the surface of the phagocyte. In the case of bacteria,
each bacterium is usually already attached to a specific
antibody, and it is the antibody that attaches to the phagocyte receptors, dragging the bacterium along with it. This
intermediation of antibodies is called opsonization, which
is discussed in Chapters 33 and 34.
Phagocytosis occurs in the following steps:
1. The cell membrane receptors attach to the surface
ligands of the particle.
2. The edges of the membrane around the points of
attachment evaginate outward within a fraction of a
second to surround the entire particle; then, progressively more and more membrane receptors attach to
the particle ligands. All this occurs suddenly in a zipper-like manner to form a closed phagocytic vesicle.
3. Actin and other contractile fibrils in the cytoplasm
surround the phagocytic vesicle and contract around
its outer edge, pushing the vesicle to the interior.
4. The contractile proteins then pinch the stem of the
vesicle so completely that the vesicle separates from
the cell membrane, leaving the vesicle in the cell interior in the same way that pinocytotic vesicles are
Digestion of Pinocytotic and Phagocytic Foreign
Substances Inside the Cell—Function of the
Almost immediately after a pinocytotic or phagocytic vesicle appears inside a cell, one or more lysosomes become attached to the vesicle and empty their
acid hydrolases to the inside of the vesicle, as shown in
Figure 2-12. Thus, a digestive vesicle is formed inside
the cell cytoplasm in which the vesicular hydrolases
begin hydrolyzing the proteins, carbohydrates, lipids,
and other substances in the vesicle. The products of
digestion are small molecules of amino acids, glucose,
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, represents indigestible substances. In most instances, this
is finally excreted through the cell membrane by a process called exocytosis, which is essentially the opposite
of endocytosis.
Thus, the pinocytotic and phagocytic vesicles containing lysosomes can be called the digestive organs of the
Regression of Tissues and Autolysis of Cells. Tissues
of the body often regress to a smaller size. For instance,
this occurs in the uterus after pregnancy, in muscles during long periods of inactivity, and in mammary glands at
the end of lactation. Lysosomes are responsible for much
of this regression. The mechanism by which lack of activity in a tissue causes the lysosomes to increase their activity is unknown.
Another special role of the lysosomes is removal of
damaged cells or damaged portions of cells from tissues. Damage to the cell—caused by heat, cold, trauma,
chemicals, or any other factor—induces lysosomes to
rupture. The released hydrolases immediately begin to
digest the surrounding organic substances. If the damage
is slight, only a portion of the cell is removed and the cell
is then repaired. If the damage is severe, the entire cell is
Pinocytotic or
Digestive vesicle
Residual body
Figure 2-12 Digestion of substances in pinocytotic or phagocytic
vesicles by enzymes derived from lysosomes.
Unit I
s­ pecialized protein receptors on the surface of the membrane that are specific for the type of protein that is to
be absorbed. The receptors generally are concentrated
in small pits on the outer surface of the cell membrane,
called coated pits. On the inside of the cell membrane
beneath these pits is a latticework of fibrillar protein
called clathrin, as well as other proteins, perhaps including contractile filaments of actin and myosin. Once the
protein molecules have bound with the receptors, the
surface properties of the local membrane change in such
a way that the entire pit invaginates inward and the fibrillar proteins surrounding the invaginating pit cause its
borders to close over the attached proteins, as well as
over a small amount of extracellular fluid. Immediately
thereafter, the invaginated portion of the membrane
breaks away from the surface of the cell, forming a pinocytotic vesicle inside the cytoplasm of the cell.
What causes the cell membrane to go through the
necessary contortions to form pinocytotic vesicles is still
unclear. This process requires energy from within the cell;
this is supplied by ATP, a high-energy substance discussed
later in the chapter. Also, it requires the presence of calcium ions in the extracellular fluid, which probably react
with contractile protein filaments beneath the coated pits
to provide the force for pinching the vesicles away from
the cell membrane.
Unit I Introduction to Physiology: The Cell and General Physiology
digested, a process called autolysis. In this way, the cell is
completely removed and a new cell of the same type ordinarily is formed by mitotic reproduction of an adjacent
cell to take the place of the old one.
The lysosomes also contain bactericidal agents that
can kill phagocytized bacteria before they can cause cellular damage. These agents include (1) lysozyme, which dissolves the bacterial cell membrane; (2) lysoferrin, which
binds iron and other substances before they can promote
bacterial growth; and (3) acid at a pH of about 5.0, which
activates the hydrolases and inactivates bacterial metabolic systems.
Synthesis and Formation of Cellular Structures by
Endoplasmic Reticulum and Golgi Apparatus
Specific Functions of the Endoplasmic Reticulum
The extensiveness of the endoplasmic reticulum and
the Golgi apparatus in secretory cells has already been
emphasized. These structures are formed primarily of
lipid bilayer membranes similar to the cell membrane,
and their walls are loaded with protein enzymes that
catalyze the synthesis of many substances required by
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
specific portions of the endoplasmic reticulum and the
Golgi apparatus.
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 membrane. As discussed in Chapter 3,
protein molecules are synthesized within the structures of the ribosomes. The ribosomes extrude some
of the synthesized protein molecules directly into
the cytosol, but they also extrude many more through the
wall of the endoplasmic reticulum to the interior of
the endoplasmic vesicles and tubules, into the endoplasmic matrix.
Synthesis of Lipids by the Smooth Endoplasmic
Reticulum. The endoplasmic reticulum also synthesizes
lipids, especially phospholipids and cholesterol. These are
rapidly incorporated into the lipid bilayer of the endoplasmic 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 significant functions of the endoplasmic reticulum,
especially the smooth reticulum, include the following:
1. It provides the enzymes that control glycogen breakdown when glycogen is to be used for energy.
2. It provides a vast number of enzymes that are capable
of detoxifying substances, such as drugs, that might
damage the cell. It achieves detoxification by coagulation, oxidation, hydrolysis, conjugation with glycuronic
acid, and in other ways.
Specific Functions of the Golgi Apparatus
Synthetic Functions of the Golgi Apparatus. Although
the major function of the Golgi apparatus is to provide
additional processing of substances already formed in the
endoplasmic reticulum, it also has the capability of synthesizing certain carbohydrates that cannot be formed
in the endoplasmic reticulum. This is especially true for
the formation of large saccharide polymers bound with
small amounts of protein; important examples include
hyaluronic acid and chondroitin sulfate.
A few of the many functions of hyaluronic acid and
chondroitin sulfate in the body are as follows: (1) they
are the major components of proteoglycans secreted in
mucus and other glandular secretions; (2) they are the
major components of the ground substance outside the
cells in the interstitial spaces, acting as fillers between collagen fibers and cells; (3) they are principal components
of the organic matrix in both cartilage and bone; and (4)
they are important in many cell activities including migration and proliferation.
Processing of Endoplasmic Secretions by the Golgi
Apparatus—Formation of Vesicles. Figure 2-13 summarizes the major functions of the endoplasmic reticulum and Golgi apparatus. As substances are formed in
the endoplasmic reticulum, especially the proteins, they
are transported through the tubules toward portions of
the smooth endoplasmic reticulum that lie nearest the
Ribosomes formation
endoplasmic endoplasmic apparatus
Figure 2-13 Formation of proteins, lipids, and cellular vesicles by
the endoplasmic reticulum and Golgi apparatus.
Chapter 2 The Cell and Its Functions
Extraction of Energy from Nutrients—Function
of the Mitochondria
The principal substances from which cells extract energy
are foodstuffs that react chemically with oxygen—carbohydrates, fats, and proteins. In the human body, essentially all
carbohydrates are converted into glucose by the digestive
tract and liver before they reach the other cells of the body.
Similarly, proteins are converted into amino acids and fats
into fatty acids. Figure 2-14 shows oxygen and the foodstuffs—glucose, fatty acids, and amino acids—all entering
the cell. Inside the cell, the foodstuffs react chemically with
oxygen, under the influence of enzymes that control the
reactions and channel the energy released in the proper
direction. The details of all these digestive and metabolic
functions are given in Chapters 62 through 72.
Briefly, almost all these oxidative reactions occur
inside the mitochondria and the energy that is released is
used to form the high-energy compound ATP. Then, ATP,
not the original foodstuffs, is used throughout the cell to
energize almost all the subsequent intracellular metabolic
Functional Characteristics of ATP
O~ P
Adenosine triphosphate
ATP is a nucleotide composed of (1) the nitrogenous base
adenine, (2) the pentose sugar ribose, and (3) three phosphate radicals. The last two phosphate radicals are connected with the remainder of the molecule by so-called
high-energy phosphate bonds, which are represented in
the formula shown by the symbol ~. Under the physical
and chemical conditions of the body, each of these highenergy 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 high-energy bond. Further, the high-energy phosphate bond is very labile so that it can be split instantly on
demand whenever energy is required to promote other
intracellular reactions.
When ATP releases its energy, a phosphoric acid radical is split away and adenosine diphosphate (ADP) is
formed. This released energy is used to energize virtually many of the cell’s other functions, such as synthesis of
substances and muscular contraction.
Unit I
Golgi apparatus. At this point, small transport vesicles
composed of small envelopes of smooth endoplasmic
reticulum continually break away and diffuse to the deepest layer of the Golgi apparatus. Inside these vesicles are
the synthesized proteins and other products from the
endoplasmic reticulum.
The transport vesicles instantly fuse with the Golgi
apparatus and empty their contained substances into the
vesicular spaces of the Golgi apparatus. Here, additional
carbohydrate moieties are added to the secretions. Also,
an important function of the Golgi apparatus is to compact the endoplasmic reticular secretions into highly
concentrated packets. As the secretions pass toward
the outermost layers of the Golgi apparatus, the compaction and processing proceed. Finally, both small and
large vesicles continually break away from the Golgi
apparatus, carrying with them the compacted secretory
substances, and in turn, the vesicles diffuse throughout
the cell.
To give an idea of the timing of these processes: When
a glandular cell is bathed in radioactive amino acids, newly
formed radioactive protein molecules can be detected in
the granular endoplasmic reticulum within 3 to 5 minutes.
Within 20 minutes, newly formed proteins are already present in the Golgi apparatus, and within 1 to 2 hours, radioactive proteins are secreted from the surface of the cell.
Types of Vesicles Formed by the Golgi Apparatus—
Secretory Vesicles and Lysosomes. In a highly secretory
cell, the vesicles formed by the Golgi apparatus are mainly
secretory vesicles containing protein substances that are
to be secreted through the surface of the cell membrane.
These secretory vesicles first diffuse to the cell membrane,
then fuse with it and empty their substances to the exterior
by the mechanism called exocytosis. Exocytosis, in most
cases, is stimulated by the entry of calcium ions into the
cell; calcium ions interact with the vesicular membrane in
some way that is not understood and cause its fusion with
the cell membrane, followed by exocytosis—that is, opening of the membrane’s outer surface and extrusion of its
contents outside the cell.
Some vesicles, however, are destined for intracellular
Use of Intracellular Vesicles to Replenish Cellular
Membranes. Some of the intracellular vesicles formed
by the Golgi apparatus fuse with the cell membrane or
with the membranes of intracellular structures such as the
mitochondria and even the endoplasmic reticulum. This
increases the expanse of these membranes and thereby
replenishes the membranes as they are used up. For
instance, the cell membrane loses much of its substance
every time it forms a phagocytic or pinocytotic vesicle,
and the vesicular membranes of the Golgi apparatus continually replenish the cell membrane.
In summary, the membranous system of the endoplasmic reticulum and Golgi apparatus represents a highly
metabolic organ capable of forming new intracellular
structures, as well as secretory substances to be extruded
from the cell.
Unit I Introduction to Physiology: The Cell and General Physiology
Fatty acids
Amino acids
36 ADP
Pyruvic acid
CO2 + H2O
36 ATP
Cell membrane
Figure 2-14 Formation of adenosine triphosphate (ATP) in the
cell, showing that most of the ATP is formed in the mitochondria.
ADP, adenosine diphosphate.
To reconstitute the cellular ATP as it is used up, 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 these reasons, ATP has been called the energy currency of the cell
because it can be spent and remade continually, having a
turnover time of only a few minutes.
Chemical Processes in the Formation of ATP—Role
of the Mitochondria. On entry into the cells, glucose is
subjected to enzymes in the cytoplasm that convert it into
pyruvic acid (a process called glycolysis). A small amount
of ADP is changed into ATP by the energy released during
this conversion, but this amount accounts for less than 5
percent of the overall energy metabolism of the cell.
About 95 percent of the cell’s ATP formation occurs
in the mitochondria. The pyruvic acid derived from carbohydrates, fatty acids from lipids, and amino acids from
proteins is eventually converted into the compound
­acetyl-CoA in the matrix of the mitochondrion. This
substance, in turn, is further dissoluted (for the purpose
of extracting its energy) by another series of enzymes in
the mitochondrion matrix, undergoing dissolution in a
sequence of chemical reactions called the citric acid cycle,
or Krebs cycle. These chemical reactions are so important
that they are explained in detail in Chapter 67.
In this citric acid cycle, acetyl-CoA is split into its
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.
The hydrogen atoms, conversely, are highly reactive, and they combine instantly with oxygen that has
also diffused into the mitochondria. This releases a tremendous amount of energy, which is used by the mitochondria to convert large amounts of ADP to ATP. The
processes of these reactions are complex, requiring the
participation of many protein enzymes that are integral
parts of mitochondrial membranous 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 ion. The terminal event
is combination of hydrogen ions with oxygen to form
water plus the release of tremendous amounts of energy
to large globular proteins, called ATP synthetase, that
protrude like knobs from the membranes of the mitochondrial shelves. Finally, the enzyme ATP synthetase
uses the energy from the hydrogen ions to cause the
conversion of ADP to ATP. The newly formed ATP is
transported out of the mitochondria into all parts of
the cell cytoplasm and nucleoplasm, where its energy is
used to energize multiple cell functions.
This overall process for formation of ATP is called the
chemiosmotic mechanism of ATP formation. The chemical and physical details of this mechanism are presented
in Chapter 67, and many of the detailed metabolic functions of ATP in the body are presented in Chapters 67
through 71.
Uses of ATP for Cellular Function. Energy from ATP
is used to promote three major categories of cellular functions: (1) transport of substances through multiple membranes in the cell, (2) synthesis of chemical compounds
throughout the cell, and (3) mechanical work. These uses
of ATP are illustrated by examples in Figure 2-15: (1) to
supply energy for the transport of sodium through the cell
membrane, (2) to promote protein synthesis by the ribosomes, and (3) to supply the energy needed during muscle
In addition to membrane transport of sodium, energy
from ATP is required for membrane transport of potassium ions, calcium ions, magnesium ions, phosphate ions,
Protein synthesis
Muscle contraction
Figure 2-15 Use of adenosine triphosphate (ATP) (formed in the
mitochondrion) to provide energy for three major cellular functions: membrane transport, protein synthesis, and muscle contraction. ADP, adenosine diphosphate.
Chapter 2 The Cell and Its Functions
Locomotion of Cells
By far the most important type of movement that occurs
in the body is that of the muscle cells in skeletal, cardiac,
and smooth muscle, which constitute almost 50 percent of the entire body mass. The specialized functions
of these cells are discussed in Chapters 6 through 9. Two
other types of movement—ameboid locomotion and ciliary movement—occur in other cells.
Ameboid Movement
Ameboid movement is movement of an entire cell in
relation to its surroundings, such as movement of white
blood cells through tissues. It receives its name from the
fact that amebae move in this manner and have provided
an excellent tool for studying the phenomenon.
Typically, ameboid locomotion begins with protrusion of a pseudopodium from one end of the cell. The
pseudopodium projects far out, away from the cell body,
and partially secures itself in a new tissue area. Then the
remainder of the cell is pulled toward the pseudopodium.
Figure 2-16 demonstrates this process, showing an elon-
Movement of cell
Surrounding tissue
Receptor binding
Figure 2-16 Ameboid motion by a cell.
gated cell, the right-hand end of which is a protruding
pseudopodium. The membrane of this end of the cell is
continually moving forward, and the membrane at the
left-hand end of the cell is continually following along as
the cell moves.
Mechanism of Ameboid Locomotion. Figure 2-16
shows the general principle of ameboid motion. Basically,
it results from continual formation of new cell membrane
at the leading edge of the pseudopodium and continual
absorption of the membrane in mid and rear portions of
the cell. Also, two other effects are essential for forward
movement of the cell. The first effect is attachment of the
pseudopodium to surrounding tissues so that it becomes
fixed in its leading position, while the remainder of the
cell body is pulled forward toward the point of attachment. This attachment is effected by receptor proteins that
line the insides of exocytotic vesicles. When the vesicles
become part of the pseudopodial membrane, they open
so that their insides evert to the outside, and the receptors
now protrude to the outside 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 vesicles.
Then, inside the cell, these vesicles stream toward the
pseudopodial end of the cell, where they are used to form
still new membrane for the pseudopodium.
The second essential effect for locomotion is to provide
the energy required to pull the cell body in the direction of
the pseudopodium. Experiments suggest the following as
an explanation: In the cytoplasm of all 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 polymerize to form a filamentous
network, and the network contracts when it binds with an
actin-binding protein such as myosin. The whole process is
energized by the high-energy compound ATP. This is what
happens in the pseudopodium of a moving cell, where such
a network of actin filaments forms anew inside the enlarging pseudopodium. Contraction also occurs in the ectoplasm of the cell body, where a preexisting actin network is
already present beneath the cell membrane.
Unit I
chloride ions, urate ions, hydrogen ions, and many other
ions and various organic substances. Membrane transport
is so important to cell function that some cells—the renal
tubular cells, for instance—use as much as 80 percent of
the ATP that they form for this purpose alone.
In addition to synthesizing proteins, cells make phospholipids, cholesterol, purines, pyrimidines, and a host of
other substances. Synthesis of almost any chemical compound requires energy. For instance, a single protein molecule might be composed of as many as several thousand
amino acids attached to one another by peptide linkages;
the formation of each of these linkages requires energy
derived from the breakdown of four high-energy bonds;
thus, many thousand ATP molecules must release their
energy as each protein molecule is formed. Indeed, some
cells use as much as 75 percent of all the ATP formed in
the cell simply to synthesize new chemical compounds,
especially protein molecules; this is particularly true during the growth phase of cells.
The final major use of ATP is to supply energy for special
cells to perform mechanical work. We see in Chapter 6 that
each contraction of a muscle fiber requires expenditure of
tremendous quantities of ATP energy. Other cells perform
mechanical work in other ways, especially by ciliary and
ameboid motion, described later in this chapter. The source
of energy for all these types of mechanical work is ATP.
In summary, ATP is always available to release its
energy rapidly and almost explosively wherever in the cell
it is needed. To replace the ATP used by the cell, much
slower chemical reactions break down carbohydrates,
fats, and proteins and use the energy derived from these
to form new ATP. More than 95 percent of this ATP is
formed in the mitochondria, which accounts for the mitochondria being called the “powerhouses” of the cell.
Unit I Introduction to Physiology: The Cell and General Physiology
Types of Cells That Exhibit Ameboid Locomotion.
Ciliary stalk
The most common cells to exhibit ameboid locomotion in
the human body are the white blood cells when they move
out of the blood into the tissues to form tissue macrophages.
Other types of cells can also move by ameboid locomotion under certain circumstances. For instance, fibroblasts
move into a damaged area to help repair the damage and
even the germinal cells of the skin, though ordinarily completely sessile cells, move toward a cut area to repair the
opening. Finally, cell locomotion is especially important in
development of the embryo and fetus after fertilization of
an ovum. For instance, embryonic cells often must migrate
long distances from their sites of origin to new areas during development of special structures.
Cross section
Control of Ameboid Locomotion—Chemotaxis.
The most important initiator of ameboid locomotion
is the process called chemotaxis. This results from the
appearance of certain chemical substances in the tissues. Any chemical substance that causes chemotaxis to
occur is called a chemotactic substance. Most cells 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 concentration—which is called positive chemotaxis. Some cells
move away from the source, which is called negative
But how does chemotaxis control the direction of 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.
Cilia and Ciliary Movements
A second type of cellular motion, ciliary movement, is a
whiplike movement of cilia on the surfaces of cells. This
occurs in only two places in the human body: on the surfaces of the respiratory airways and on the inside surfaces
of the uterine tubes (fallopian tubes) of the reproductive
tract. In the nasal cavity and lower respiratory airways,
the whiplike motion of cilia causes a layer of mucus to
move at a rate of about 1 cm/min toward the pharynx, in
this way continually clearing these passageways of mucus
and particles that have become trapped in the mucus. In
the uterine tubes, the cilia cause slow movement of fluid
from the ostium of the uterine tube toward the uterus
cavity; this movement of fluid transports the ovum from
the ovary to the uterus.
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 cilia
often project from a single cell—for instance, as many
as 200 cilia on the surface of each epithelial cell inside
the respiratory passageways. The cilium is covered by an
outcropping of the cell membrane, and it is supported
by 11 microtubules—9 double tubules located around
the periphery of the cilium and 2 single tubules down
Forward stroke
Basal plate
Backward stroke
Basal body
Figure 2-17 Structure and function of the cilium. (Modified from
Satir P: Cilia. Sci Am 204:108, 1961. Copyright Donald Garber:
Executor of the estate of Bunji Tagawa.)
the center, as demonstrated in the cross section shown
in Figure 2-17. Each cilium is an outgrowth of a structure
that lies immediately beneath the cell membrane, called
the basal body of the cilium.
The flagellum of a sperm is similar to a cilium; in fact,
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 sharply where it projects from the surface of the cell.
Then it moves backward slowly to its initial position. The
rapid forward-thrusting, whiplike movement pushes the
fluid lying adjacent to the cell in the direction that the
cilium moves; the slow, dragging movement 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 surfaces and because
all the cilia are oriented in the same direction, this is an
effective means for moving fluids from one part of the
surface to another.
Chapter 2 The Cell and Its Functions
Alberts B, Johnson A, Lewis J, et al: Molecular Biology of the Cell, 6th ed,
New York, 2007, Garland Science.
Bonifacino JS, Glick BS: The mechanisms of vesicle budding and fusion,
Cell 116:153, 2004.
Chacinska A, Koehler CM, Milenkovic D, Lithgow T, Pfanner N: Importing
mitochondrial proteins: machineries and mechanisms, Cell 138:628,
Cohen AW, Hnasko R, Schubert W, Lisanti MP: Role of caveolae and caveolins in health and disease, Physiol Rev 84:1341, 2004.
Danial NN, Korsmeyer SJ: Cell death: critical control points, Cell 116:205,
Dröge W: Free radicals in the physiological control of cell function, Physiol
Rev 82:47, 2002.
Edidin M: Lipids on the frontier: a century of cell-membrane bilayers, Nat
Rev Mol Cell Biol 4:414, 2003.
Ginger ML, Portman N, McKean PG: Swimming with protists: perception,
motility and flagellum assembly, Nat Rev Microbiol 6:838, 2008.
Grant BD, Donaldson JG: Pathways and mechanisms of endocytic recycling,
Nat Rev Mol Cell Biol 10:597, 2009.
Güttinger S, Laurell E, Kutay U: Orchestrating nuclear envelope disassembly
and reassembly during mitosis, Nat Rev Mol Cell Biol 10:178, 2009.
Hamill OP, Martinac B: Molecular basis of mechanotransduction in living
cells, Physiol Rev 81:685, 2001.
Hock MB, Kralli A: Transcriptional control of mitochondrial biogenesis and
function, Annu Rev Physiol 71:177, 2009.
Liesa M, Palacín M, Zorzano A: Mitochondrial dynamics in mammalian
health and disease, Physiol Rev 89:799, 2009.
Mattaj IW: Sorting out the nuclear envelope from the endoplasmic reticulum, Nat Rev Mol Cell Biol 5:65, 2004.
Parton RG, Simons K: The multiple faces of caveolae, Nat Rev Mol Cell Biol
8:185, 2007.
Raiborg C, Stenmark H: The ESCRT machinery in endosomal sorting of
ubiquitylated membrane proteins, Nature 458:445, 2009.
Ridley AJ, Schwartz MA, Burridge K, et al: Cell migration: integrating signals
from front to back, Science 302:1704, 2003.
Saftig P, Klumperman J: Lysosome biogenesis and lysosomal membrane
proteins: trafficking meets function, Nat Rev Mol Cell Biol 10:623,
Scarpulla RC: Transcriptional paradigms in mammalian mitochondrial biogenesis and function, Physiol Rev 88:611, 2008.
Stenmark H: Rab GTPases as coordinators of vesicle traffic, Nat Rev Mol
Cell Biol 10:513, 2009.
Traub LM: Tickets to ride: selecting cargo for clathrin-regulated internalization, Nat Rev Mol Cell Biol 10:583, 2009.
Vereb G, Szollosi J, Matko J, et al: Dynamic, yet structured: the cell membrane three decades after the Singer-Nicolson model, Proc Natl Acad Sci
U S A 100:8053, 2003.
Unit I
Mechanism of Ciliary Movement. Although not all
aspects of ciliary movement are clear, we do know the
following: First, the nine double tubules and the two single tubules are all linked to one another by a complex of
protein cross-linkages; this total complex of tubules and
cross-linkages is called the axoneme. Second, even after
removal of the membrane and destruction of other elements 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
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 cilium, while those on
the back edge remain in place. Fifth, multiple protein arms
composed of the protein dynein, which has ATPase enzymatic activity, project from each double tubule toward an
adjacent double tubule.
Given this basic information, it has been determined
that the release of energy from ATP in contact with the
ATPase dynein arms causes the heads of these arms to
“crawl” rapidly along the surface of the adjacent double
tubule. If the front tubules crawl outward while the back
tubules remain stationary, this will cause bending.
The way in which cilia contraction is controlled is not
understood. The cilia of some genetically abnormal cells
do not have the two central single tubules, and these cilia
fail to beat. Therefore, it is presumed that some signal,
perhaps an electrochemical signal, is transmitted along
these two central tubules to activate the dynein arms.
This page intentionally left blank
chapter 3
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 substances are synthesized within the cell—which structures,
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. The entire process,
from transcription of the genetic code in the nucleus
to translation of the RNA code and formation or proteins in the cell ­c ytoplasm, is often referred to as gene
Because there are approximately 30,000 different genes
in each cell, it is theoretically possible to form a 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 intracellular organelles discussed in Chapter 2. However, the majority of the
proteins 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, glycogen, 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 molecule 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
Gene (DNA)
RNA formation
Translation of
messenger RNA
Protein formation
Cell function
Figure 3-1. General schema by which the genes control cell
Unit I
Genetic Control of Protein Synthesis,
Cell Function, and Cell Reproduction
Unit I Introduction to Physiology: The Cell and General Physiology
Figure 3-2. The helical, double-stranded structure of the gene. The
outside strands are composed of phosphoric acid and the sugar
deoxyribose. The internal molecules connecting the two strands
of the helix are purine and pyrimidine bases; these determine the
“code” of the gene.
H Deoxyribose
Figure 3-4. Deoxyadenylic acid, one of the nucleotides that make
up DNA.
each DNA strand is composed of alternating phosphoric
acid and deoxyribose molecules. In turn, purine and
pyrimidine bases are attached to the sides of the 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:
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 bound together to form two strands of
DNA. The two strands are, in turn, loosely bonded with
each other by weak cross-linkages, illustrated in Figure
3-6 by the central dashed lines. Note that the backbone of
Figure 3-3. The basic building blocks of DNA.
1. Each purine base adenine of one strand always bonds
with a pyrimidine base thymine of the other strand, and
2. Each purine base guanine always bonds with a pyrimidine base cytosine.
Phosphoric acid
Chapter 3 Genetic Control of Protein Synthesis, Cell Function, and Cell Reproduction
twist them into a helix. Ten pairs of nucleotides are present in each full turn of the helix in the DNA molecule, as
shown in Figure 3-2.
Deoxythymidylic acid
Genetic Code
The importance of DNA lies in its ability to control the
formation of proteins in the cell. It does this by means of
a genetic code. That is, when the two strands of a DNA
molecule are split apart, this exposes the purine and
pyrimidine bases projecting to the side of each DNA
strand, as shown by the top strand in Figure 3-7. It is
these p
­ rojecting bases that form the genetic code.
The genetic code consists of successive “triplets”
of bases—that is, each three successive bases is a code
word. The successive triplets eventually control the
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 the
genetic code GGC, AGA, CTT, the triplets being separated from one another by the arrows. As we follow
this genetic code through Figures 3-7 and 3-8, we see
that these three respective triplets are responsible for
successive placement of the three amino acids, proline,
serine, and glutamic acid, in a newly formed molecule
of protein.
Deoxyguanylic acid
Deoxycytidylic acid
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.
Thus, in Figure 3-6, the sequence of complementary
pairs of bases is CG, CG, GC, TA, CG, TA, GC, AT, and
AT. Because of the looseness of the hydrogen bonds, the
two strands can pull apart with ease, and they do so many
times during the course of their function in the cell.
To put the DNA of Figure 3-6 into its proper physical
perspective, one could merely pick up the two ends and
Figure 3-6. Arrangement of deoxyribose nucleotides
in a double strand of DNA.
DNA strand
RNA molecule
Figure 3-7. 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 cytoplasm. The RNA polymerase enzyme
moves along the DNA strand and builds the RNA
RNA polymerase
Figure 3-8. Portion of an RNA molecule, showing three RNA
“codons”—CCG, UCU, and GAA—that control attachment
of the three amino acids, proline, serine, and glutamic acid,
respectively, to the growing RNA chain.
Glutamic acid
Unit I
Deoxyadenylic acid
Unit I Introduction to Physiology: The Cell and General Physiology
The DNA Code in the Cell Nucleus Is
Transferred to an RNA Code in the Cell
Cytoplasm—The Process of Transcription
Because the DNA is located in the nucleus of the cell,
yet most of the functions of the cell are carried out in
the cytoplasm, there must be some means for the DNA
genes of the nucleus to control the chemical reactions
of the cytoplasm. This is achieved through the intermediary of another type of nucleic acid, RNA, the formation of which is controlled by the DNA of the nucleus.
Thus, as shown in Figure 3-7, the code is transferred to
the RNA; this process is called transcription. The RNA,
in turn, diffuses from the nucleus through nuclear pores
into the cytoplasmic compartment, where it controls
protein synthesis.
Synthesis of RNA
During synthesis of RNA, the two strands of the DNA
molecule separate temporarily; one of these strands
is used as a template for synthesis of an RNA molecule. The code triplets in the DNA cause formation
of complementary code triplets (called codons) in the
RNA; these codons, in turn, will control the sequence
of amino acids in a protein to be synthesized in the cell
Basic Building Blocks of RNA. The basic building
blocks of RNA are almost the same as those of DNA,
except for two differences. First, the sugar deoxyribose is
not used in the formation of RNA. In its place is another
sugar of slightly different composition, ribose, containing
an extra hydroxyl ion appended to the ribose ring structure. Second, thymine is replaced by another pyrimidine,
Formation of RNA Nucleotides. The basic building blocks of RNA form RNA nucleotides, exactly as previously described for DNA synthesis. Here again, four
separate nucleotides are used in the formation of RNA.
These nucleotides contain the bases adenine, guanine,
cytosine, and uracil. Note that these are the same bases
as in DNA, except that uracil in RNA replaces thymine
in DNA.
“Activation” of the RNA Nucleotides. The next step
in the synthesis of RNA is “activation” of the RNA nucleotides by an enzyme, RNA polymerase. This occurs by
adding to each nucleotide two extra phosphate radicals to
form triphosphates (shown in Figure 3-7 by the two RNA
nucleotides to the far right during RNA chain formation).
These last two phosphates are combined with the nucleotide by high-energy phosphate bonds derived from ATP
in the cell.
The result of this activation process is that large quantities of ATP energy are made available to each of the nucleotides, and this energy is used to promote the chemical
reactions that add each new RNA nucleotide at the end of
the developing RNA chain.
Assembly of the RNA Chain from Activated
Nucleotides Using the DNA Strand as a
Template—The Process of “Transcription”
Assembly of the RNA molecule is accomplished in 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 for formation of the RNA molecule. They are as follows:
1. In the DNA strand immediately ahead of the initial
gene is a sequence of nucleotides called the promoter.
The RNA polymerase has an appropriate complementary structure that recognizes this promoter and
becomes attached to it. This is the essential step for
initiating formation of the RNA molecule.
2. After the RNA polymerase attaches to the promoter,
the polymerase causes unwinding of about two turns
of the DNA helix and separation of the unwound portions of the two strands.
3. Then the polymerase moves along the DNA strand,
temporarily unwinding and separating the two DNA
strands at each stage of its movement. As it moves
along, it adds at each stage a new activated RNA nucleotide to the end of the newly forming RNA chain by
the following steps:
a. First, it causes a hydrogen bond to form between
the end base of the DNA strand and the base of an
RNA nucleotide in the nucleoplasm.
b. Then, one at a time, the RNA polymerase breaks
two of the three phosphate radicals away from each
of these RNA nucleotides, liberating large amounts
of energy from the broken high-energy phosphate
bonds; this energy is used to cause covalent linkage of the remaining phosphate on the nucleotide
with the ribose on the end of the growing RNA
c. When the RNA polymerase reaches the end of the
DNA gene, it encounters a new sequence of DNA
nucleotides called the chain-terminating sequence;
this causes the polymerase and the newly formed
RNA chain to break away from the DNA strand.
Then the polymerase can be used again and again
to form still more new RNA chains.
d. As the new RNA strand is formed, its weak hydrogen bonds with the DNA template break away,
because the DNA has a high affinity for rebonding
with its own complementary DNA strand. Thus,
the RNA chain is forced away from the DNA and is
released into the nucleoplasm.
Thus, the code that is present in the DNA strand is
eventually transmitted in complementary form to the RNA
chain. The ribose nucleotide bases always combine with
the deoxyribose bases in the following combinations:
Chapter 3 Genetic Control of Protein Synthesis, Cell Function, and Cell Reproduction
4. MicroRNA (miRNA), which are single-stranded RNA
molecules of 21 to 23 nucleotides that can regulate
gene transcription and translation.
RNA Base
cytosine guanine
Messenger RNA—The Codons
thymine adenine
mRNA molecules are long, single RNA strands that are
suspended in the cytoplasm. These molecules are composed of several hundred to several thousand RNA nucleotides in unpaired strands, and they contain codons that
are exactly complementary to the code triplets of the DNA
genes. Figure 3-8 shows a small segment of a molecule of
messenger RNA. Its codons are CCG, UCU, and GAA.
These are the codons for the amino acids proline, serine, and glutamic acid. The transcription of these codons
from the DNA molecule to the RNA molecule is shown
in Figure 3-7.
Four Different Types of RNA. Each type of RNA
plays an independent and entirely different role in protein
1. Messenger RNA (mRNA), which carries the genetic
code to the cytoplasm for controlling the type of protein formed.
2. Transfer RNA (tRNA), which transports activated
amino acids to the ribosomes to be used in assembling
the protein molecule.
3. Ribosomal RNA, which, along with about 75 different
proteins, forms ribosomes, the physical and chemical
structures on which protein molecules are actually
RNA Codons for the Different Amino Acids.
Table 3-1 gives the RNA codons for the 22 common amino
acids found in protein molecules. Note that most of the
amino acids are represented by more than one codon;
Table 3-1. RNA Codons for Amino Acids and for Start and Stop
Amino Acid
RNA Codons
Aspartic acid
Glutamic acid
Start (CI)
Stop (CT)
CI, chain-initiating; CT, chain-terminating.
Unit I
DNA Base
Unit I Introduction to Physiology: The Cell and General Physiology
also, one codon represents the signal “start manufacturing the protein molecule,” and three codons represent
“stop manufacturing the protein molecule.” In Table 3-1,
these two types of codons are designated CI for “chain­initiating” and CT for “chain-terminating.”
­ onding with the codon bases of the mRNA. In this way,
the respective amino acids are lined up one after another
along the mRNA chain, thus establishing the appropriate sequence of amino acids in the newly ­forming protein
Transfer RNA—The Anticodons
Ribosomal RNA
Another type of RNA that plays an essential role in protein synthesis is called tRNA because it transfers amino
acid molecules to protein molecules as the protein is
being synthesized. Each type of tRNA combines specifically with 1 of the 20 amino acids that are to be incorporated into proteins. The tRNA then acts as a carrier to
transport its specific type of amino acid to the ribosomes,
where protein molecules are forming. In the ribosomes,
each specific type of transfer RNA recognizes a particular
codon on the mRNA (described later) and thereby delivers the appropriate amino acid to the appropriate place in
the chain of the newly forming protein molecule.
Transfer RNA, which contains only about 80 nucleotides, is a relatively small molecule in comparison with
mRNA. 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 is always an adenylic acid; it is to this
that the transported amino acid attaches at a hydroxyl
group of the ribose in the adenylic acid.
Because the function of tRNA is to cause attachment
of a specific amino acid to a forming protein chain, it is
essential that each type of tRNA also have specificity for
a particular codon in the mRNA. The specific code in the
tRNA that allows it to recognize a specific codon is again a
triplet of nucleotide bases and is called an anticodon. This
is located approximately in the middle of the tRNA molecule (at the bottom of the cloverleaf configuration shown
in Figure 3-9). During formation of the protein molecule, the anticodon bases combine loosely by ­hydrogen
The third type of RNA in the cell is ribosomal RNA; it
constitutes about 60 percent of the ribosome. The remainder of the ribosome is protein, containing about 75 types
of proteins that are both structural proteins and enzymes
needed in the manufacture of protein molecules.
The ribosome is the physical structure in the cytoplasm
on which protein molecules are actually synthesized.
However, it always functions in association with the other
two types of RNA as well: tRNA transports amino acids to
the ribosome for incorporation into the developing protein molecule, whereas mRNA provides the information
necessary for sequencing the amino acids in proper order
for each specific type of protein to be manufactured.
Thus, the ribosome acts as a manufacturing plant in
which the protein molecules are formed.
Forming protein
Transfer RNA
Formation of Ribosomes in the Nucleolus. The
DNA genes for formation of ribosomal RNA are located
in five pairs of chromosomes in the nucleus, and each of
these chromosomes contains many duplicates of these
particular genes because of the large amounts of ­ribosomal
RNA required for cellular function.
As the ribosomal RNA forms, it collects in the nucleolus, a specialized structure lying adjacent to the chromosomes. When large amounts of ribosomal RNA are being
synthesized, as occurs in cells that manufacture large
amounts of protein, the nucleolus is a large structure,
whereas in cells that synthesize little protein, the nucleolus may not even be seen. Ribosomal RNA is specially
processed in the nucleolus, where it binds with “ribosomal
proteins” to form granular condensation products that
are primordial subunits of ribosomes. These subunits are
then released from the nucleolus and transported through
the large pores of the nuclear envelope to almost all parts
of the cytoplasm. After the subunits enter the cytoplasm,
they are assembled to form mature, functional ribosomes.
Therefore, proteins are formed in the cytoplasm of the
cell, but not in the cell nucleus, because the nucleus does
not contain mature ribosomes.
Start codon
RNA movement
Figure 3-9. A messenger RNA strand is moving through two ribosomes. As each “codon” passes through, an amino acid is added
to the growing protein chain, which is shown in the right-hand
­ribosome. The transfer RNA molecule transports each specific
amino acid to the newly forming protein.
A fourth type of RNA in the cell is miRNA. These are short
(21 to 23 nucleotides) single-stranded RNA fragments
that regulate gene expression (Figure 3-10). The miRNAs
are encoded from the transcribed DNA of genes, but they
are not translated into proteins and are therefore often
called noncoding RNA. The miRNAs are processed by the
cell into molecules that are complementary to mRNA and
act to decrease gene expression. Generation of miRNAs
involves special processing of longer primary precursor
Chapter 3 Genetic Control of Protein Synthesis, Cell Function, and Cell Reproduction
of pri-miRNA
Transport of
pre-miRNA into
Processing of
pre-miRNA into
small RNA
mRNA degradation
Translational repression
Figure 3-10. Regulation of gene expression by microRNA
(miRNA). Primary miRNA (pri-miRNA), the primary transcripts of a
gene processed in the cell nucleus by the microprocessor complex
to pre-miRNAs. These pre-miRNAs are then further processed in
the cytoplasm by dicer, an enzyme that helps assemble an RNAinduced silencing complex (RISC) and generates miRNAs. The miRNAs regulate gene expression by binding to the complementary
region of the RNA and repressing translation or promoting degradation of the mRNA before it can be translated by the ribosome.
RNAs called pri-miRNAs, which are the primary transcripts of the gene. The pri-miRNAs are then processed
in the cell nucleus by the microprocessor complex to premiRNAs, which are 70 nucleotide stem-loop structures.
These pre-miRNAs are then further processed in the
cytoplasm by a specific dicer enzyme that helps assemble
an RNA-induced silencing complex (RISC) and generates
The miRNAs regulate gene expression by binding to
the complementary region of the RNA and promoting
repression of translation or degradation of the mRNA
before it can be translated by the ribosome. miRNAs are
believed to play an important role in the normal regulation of cell function, and alterations in miRNA function
have been associated with diseases such as cancer and
heart disease.
Another type of microRNA is small interfering RNA
(siRNA), also called silencing RNA or short interfering
RNA. The siRNAs are short, double-stranded RNA molecules, 20 to 25 nucleotides in length, that interfere with
the expression of specific genes. siRNAs generally refer
to synthetic miRNAs and can be administered to silence
expression of specific genes. They are designed to avoid
the nuclear processing by the microprocessor complex,
and after the siRNA enters the cytoplasm it activates
the RISC silencing complex, blocking the translation of
mRNA. Because siRNAs can be tailored for any specific
sequence in the gene, they can be used to block translation of any mRNA and therefore expression by any
gene for which the nucleotide sequence is known. Some
researchers have proposed that siRNAs may become useful therapeutic tools to silence genes that contribute to
the pathophysiology of diseases.
Formation of Proteins on the Ribosomes—The
Process of “Translation”
When a molecule of messenger RNA comes in contact
with a ribosome, it travels through the ribosome, beginning at a predetermined end of the RNA molecule specified by an appropriate sequence of RNA bases called the
“chain-initiating” codon. Then, as shown in Figure 3-9,
while the messenger RNA travels through the ribosome,
a protein molecule is formed—a process called translation. Thus, the ribosome reads the codons of the messenger RNA in much the same way that a tape is “read” as it
passes through the playback head of a tape recorder. Then,
when a “stop” (or “chain-terminating”) codon slips past
the ribosome, the end of a protein molecule is signaled
and the protein molecule is freed into the cytoplasm.
Polyribosomes. A single messenger RNA molecule
can form protein molecules in several ribosomes at the
same time because the initial end of the RNA strand
can pass to a successive ribosome as it leaves the first, as
shown at the bottom left in Figure 3-9 and in Figure 3-11.
The protein molecules are in different stages of development in each ribosome. As a result, clusters of ribosomes
frequently occur, 3 to 10 ribosomes being attached to a
single messenger RNA at the same time. These clusters
are called polyribosomes.
It is especially important to note that a messenger
RNA can cause the formation of a protein molecule in any
ribosome; that is, there is no specificity of ribosomes for
given types of protein. The ribosome is simply the physical manufacturing plant in which the chemical reactions
take place.
Many Ribosomes Attach to the Endoplasmic
Reticulum. In Chapter 2, it was noted that many ribo-
somes become attached to the endoplasmic reticulum.
This occurs because the initial ends of many forming protein molecules have amino acid sequences that immediately attach to specific receptor sites on the endoplasmic
reticulum; this causes these molecules to penetrate the
Unit I
of mRNA
Unit I Introduction to Physiology: The Cell and General Physiology
Figure 3-11. Physical structure of
the ribosomes, as well as their functional relation to messenger RNA,
transfer RNA, and the endoplasmic reticulum during the formation
of protein molecules. (Courtesy Dr.
Don W. Fawcett, Montana.)
Transfer RNA
Amino acid
reticulum wall and enter the endoplasmic reticulum
matrix. This gives a granular appearance to those portions of the reticulum where proteins are being formed
and entering the matrix of the reticulum.
Figure 3-11 shows the functional relation of messenger
RNA to the ribosomes and the manner in which the ribosomes attach to the membrane of the endoplasmic reticulum. Note the process of translation occurring in several
ribosomes at the same time in response to the same strand
of messenger RNA. Note also the newly forming polypeptide (protein) chains passing through the endoplasmic
reticulum membrane into the endoplasmic matrix.
Yet it should be noted that except in glandular cells in
which large amounts of protein-containing secretory vesicles are formed, most proteins synthesized by the ribosomes are released directly into the cytosol instead of into
the endoplasmic reticulum. These proteins are enzymes
and internal structural proteins of the cell.
Chemical Steps in Protein Synthesis. Some of the
chemical events that occur in synthesis of a protein molecule are shown in Figure 3-12. This figure shows representative reactions for three separate amino acids, AA1,
Figure 3-12. Chemical events in the formation of a
­protein molecule.
AA2, and AA20. The stages of the reactions are the following: (1) Each amino acid is activated by a chemical ­process
in which ATP combines with the amino acid to form an
adenosine monophosphate complex with the amino acid,
giving up two high-energy phosphate bonds in the process. (2) The activated amino acid, having an excess of
energy, then combines with its specific transfer RNA to
form an amino acid–tRNA complex and, at the same time,
releases the adenosine monophosphate. (3) The transfer
RNA carrying the amino acid complex then comes in
contact with the messenger RNA molecule in the ribosome, where the anticodon of the transfer RNA attaches
temporarily to its specific codon of the messenger RNA,
thus lining up the amino acid in appropriate sequence to
form a protein molecule. Then, under the influence of the
enzyme peptidyl transferase (one of the proteins in the
ribosome), peptide bonds are formed between the successive amino acids, thus adding progressively to the protein
chain. These chemical events require energy from two
additional high-energy phosphate bonds, making a total
of four high-energy bonds used for each amino acid added
to the protein chain. Thus, the synthesis of proteins is one
of the most energy-consuming processes of the cell.
Amino acid
Activated amino acid
Protein chain
Complex between tRNA,
messenger RNA, and
amino acid
RNA-amino acyl complex tRNA1
Messenger RNA
AA2 AA13 AA20
Chapter 3 Genetic Control of Protein Synthesis, Cell Function, and Cell Reproduction
Peptide Linkage. The successive amino acids in the
protein chain combine with one another according to the
typical reaction:
OH + H
In this chemical reaction, a hydroxyl radical (OH−) is
removed from the COOH portion of the first amino acid
and a hydrogen (H+) of the NH2 portion of the other amino
acid is removed. These combine to form water, and the
two reactive sites left on the two successive amino acids
bond with each other, resulting in a single molecule. This
process is called peptide linkage. As each additional amino
acid is added, an additional peptide linkage is formed.
Synthesis of Other Substances in the Cell
Many thousand protein enzymes formed in the manner
just described control essentially all the other chemical
reactions that take place in cells. These enzymes promote
synthesis of lipids, glycogen, purines, pyrimidines, and
hundreds of other substances. We discuss many of these
synthetic processes in relation to carbohydrate, lipid, and
protein metabolism in Chapters 67 through 69. It is by
means of all these substances that the many functions of
the cells are performed.
Control of Gene Function and Biochemical
Activity in Cells
From our discussion thus far, it is clear that the genes control both the physical and chemical functions of the cells.
However, the degree of activation of respective genes must
be controlled as well; otherwise, some parts of the cell
might overgrow or some chemical reactions might overact until they kill the cell. Each cell has powerful internal
feedback control mechanisms that keep the various functional operations of the cell in step with one another. For
each gene (approximately 30,000 genes in all), there is at
least one such feedback mechanism.
There are basically two methods by which the biochemical activities in the cell are controlled: (1) genetic regulation, in which the degree of activation of the genes and
the formation of gene products are themselves controlled
and (2) enzyme regulation, in which the activity levels of
already formed enzymes in the cell are controlled.
Genetic Regulation
Genetic regulation, or regulation of gene expression, covers
the entire process from transcription of the genetic code in
the nucleus to the formation or proteins in the cytoplasm.
The Promoter Controls Gene Expression. Synthesis
of cellular proteins is a complex process that starts with the
transcription of DNA into RNA. The transcription of DNA
is controlled by regulatory elements found in the promoter
of a gene (Figure 3-13). In eukaryotes, which includes all
mammals, the basal promoter consists of a sequence of
seven bases (TATAAAA) called the TATA box, the binding
site for the TATA-binding protein (TBP) and several other
important transcription factors that are collectively referred
to as the transcription factor IID complex. In addition to
the transcription factor IID complex, this region is where
transcription factor IIB binds to both the DNA and RNA
polymerase 2 to facilitate transcription of the DNA into
RNA. This basal promoter is found in all protein-coding
genes and the polymerase must bind with this basal promoter before it can begin traveling along the DNA strand
to synthesize RNA. The upstream promoter is located farther upstream from the transcription start site and contains
several binding sites for positive or negative transcription
factors that can effect transcription through interactions
with proteins bound to the basal promoter. The structure
and transcription factor binding sites in the upstream promoter vary from gene to gene to give rise to the different
expression patterns of genes in different tissues.
RNA polymerase 2
Proximal promoter
Basal promoter
Figure 3-13. Gene transcriptional in eukaryotic cells. A complex
arrangement of multiple clustered enhancer modules interspersed
with insulator elements, which can be located either upstream
or downstream of a basal promoter containing TATA box (TATA),
proximal promoter elements (response elements, RE), and Initiator
sequences (INR).
Unit I
Regulation of gene expression provides all living organisms
the ability to respond to changes in their environment.
In animals that have many different types of cells, tissues,
and organs, differential regulation of gene expression also
permits the many different cell types in the body to each
perform their specialized functions. Although a cardiac
myocyte contains the same genetic code as a renal tubular
epithelia cell, many genes are expressed in cardiac cells that
are not expressed in renal tubular cells. The ultimate measure of gene “expression” is whether (and how much) of the
gene products (proteins) are produced because proteins
carry out cell functions specified by the genes. Regulation
of gene expression can occur at any point in the pathways
of transcription, RNA ­processing, and translation.
Unit I Introduction to Physiology: The Cell and General Physiology
Transcription of genes in eukaryotes is also influenced
by enhancers, which are regions of DNA that can bind
transcription factors. Enhancers can be located a great
distance from the gene they act on or even on a different
chromosome. They can also be located either upstream
or downstream of the gene that they regulate. Although
enhancers may be located a great distance away from their
target gene, they may be relatively close when DNA is
coiled in the nucleus. It is estimated that there are 110,000
gene enhancer sequences in the human genome.
In the organization of the chromosome, it is important to separate active genes that are being transcribed
from genes that are repressed. This can be challenging
because multiple genes may be located close together on
the chromosome. This is achieved by chromosomal insulators. These insulators are gene sequences that provide
a barrier so that a specific gene is isolated against transcriptional influences from surrounding genes. Insulators
can vary greatly in their DNA sequence and the proteins
that bind to them. One way an insulator activity can be
modulated is by DNA methylation. This is the case for
the mammalian insulin-like growth factor 2 (IGF-2) gene.
The mother’s allele has an insulator between the enhancer
and promoter of the gene that allows for the binding of
a transcriptional repressor. However, the paternal DNA
sequence is methylated such that the transcriptional
repressor cannot bind to the insulator and the IGF-2 gene
is expressed from the paternal copy of the gene.
Other Mechanisms for Control of Transcription by
the Promoter. Variations in the basic mechanism for
control of the promoter have been discovered with rapidity in the past 2 decades. Without giving details, let us list
some of them:
1. A promoter is frequently controlled by transcription
factors located elsewhere in the genome. That is, the
regulatory gene causes the formation of a regulatory
protein that in turn acts either as an activator or a
repressor of transcription.
2. Occasionally, many different promoters are controlled
at the same time by the same regulatory protein. In
some instances, the same regulatory protein functions
as an activator for one promoter and as a repressor for
another promoter.
3. Some proteins are controlled not at the starting 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 processing of the
RNA molecules in the nucleus before they are released
into the cytoplasm; rarely, control might occur at the
level of protein formation in the cytoplasm during
RNA translation by the ribosomes.
4. In nucleated cells, the nuclear DNA is packaged in specific structural units, the chromosomes. Within each
chromosome, the DNA is wound around small proteins
called histones, which in turn are held tightly together
in a compacted state by still other proteins. As long as
the DNA is in this compacted state, it cannot function
to form RNA. However, multiple control mechanisms
are beginning to be discovered that can cause selected
areas of chromosomes to become decompacted one
part at a time so that partial RNA transcription can
occur. Even then, specific transcriptor factors control
the actual rate of transcription by the promoter in the
chromosome. Thus, still higher orders of control are
used for establishing proper cell function. In addition,
signals from outside the cell, such as some of the body’s
hormones, can activate specific chromosomal areas
and specific transcription factors, thus controlling the
chemical machinery for function of the cell.
Because there are more than 30,000 different genes
in each human cell, the large number of ways in which
genetic activity can be controlled is not surprising. The
gene control systems are especially important for controlling intracellular concentrations of amino acids, amino
acid derivatives, and intermediate substrates and ­products
of carbohydrate, lipid, and protein metabolism.
Control of Intracellular Function
by Enzyme Regulation
In addition to control of cell function by genetic regulation, some cell activities are controlled by intracellular
inhibitors or activators that act directly on specific intracellular enzymes. Thus, enzyme regulation represents a
second category of mechanisms by which cellular biochemical functions can be controlled.
Enzyme Inhibition. Some chemical substances formed
in the cell have direct feedback effects in inhibiting the specific enzyme systems that synthesize them. Almost always the
synthesized product acts on the first enzyme in a sequence,
rather than on the subsequent enzymes, usually binding
directly with the enzyme and causing an allosteric conformational change that inactivates it. One can readily recognize
the importance of inactivating the first enzyme: this prevents buildup of intermediary products that are not used.
Enzyme inhibition is another example of negative feedback control; it is responsible for controlling intracellular
concentrations of multiple amino acids, purines, pyrimidines, vitamins, and other substances.
Enzyme Activation. Enzymes that are normally inactive often can be activated when needed. An example of
this occurs when most of the ATP has been depleted in a
cell. In this case, a considerable amount of cyclic adenosine
monophosphate (cAMP) begins to be formed as a breakdown product of the ATP; the presence of this cAMP, in
turn, immediately activates the glycogen-splitting enzyme
phosphorylase, liberating glucose molecules that are rapidly metabolized and their energy used for replenishment
of the ATP stores. Thus, cAMP acts as an enzyme activator for the enzyme phosphorylase and thereby helps control intracellular ATP concentration.
Chapter 3 Genetic Control of Protein Synthesis, Cell Function, and Cell Reproduction
Unit I
Another interesting instance of both enzyme inhibition and enzyme activation occurs in the formation of the
purines and pyrimidines. These substances are needed by
the cell in approximately equal quantities for formation of
DNA and RNA. When purines are formed, they inhibit
the enzymes that are required for formation of additional
purines. However, they activate the enzymes for formation of pyrimidines. Conversely, the pyrimidines inhibit
their own enzymes but activate the purine enzymes. In
this way, there is continual 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 mechanism of
enzyme regulation. The genes can be either activated or
inhibited, and likewise, the enzyme systems can be either
activated or inhibited. These regulatory 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.
The DNA-Genetic System Also Controls
Cell Reproduction
Cell reproduction is another example of the ubiquitous
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 also when or whether
these cells will divide to form new cells. In this way, the allimportant genetic system controls each stage in the development of the human being, from the single-cell fertilized
ovum to the whole functioning body. Thus, if there is any
central theme to life, it is the DNA-genetic system.
Life Cycle of the Cell. The life cycle of a cell is the
period from cell reproduction to the next cell reproduction. When mammalian cells are not inhibited and are
reproducing as rapidly as they can, this life cycle may be as
little as 10 to 30 hours. It is terminated by a series of distinct physical events called mitosis that cause division of
the cell into two new daughter cells. The events of mitosis are shown in Figure 3-14 and are described later. The
actual stage of mitosis, however, lasts for only about 30
minutes, so more than 95 percent of the life cycle of even
rapidly reproducing cells is represented by the interval
between mitosis, called interphase.
Except in special conditions of rapid cellular reproduction, inhibitory factors almost always slow or stop the uninhibited life cycle of the cell. Therefore, different cells of the
Figure 3-14. Stages of cell reproduction. A, B, and C, Prophase. D,
Prometaphase. E, Metaphase. F, Anaphase. G and H, Telophase. (From
Margaret C. Gladbach, Estate of Mary E. and Dan Todd, Kansas.)
body actually have life cycle periods that vary from as little
as 10 hours for highly stimulated bone marrow cells to an
entire lifetime of the human body for most nerve cells.
Cell Reproduction Begins with Replication of DNA
As is true of almost all other important events in the cell,
reproduction begins in the nucleus itself. The first step is
replication (duplication) of all DNA in the chromosomes.
Only after this has occurred can mitosis take place.
The DNA begins to be duplicated some 5 to 10 hours
before mitosis, and this is completed in 4 to 8 hours. The
net result is two exact replicas of all DNA. These replicas
become the DNA in the two new daughter cells that will
be formed at mitosis. After replication of the DNA, there
is another period of 1 to 2 hours before mitosis begins
abruptly. Even during this period, preliminary changes that
will lead to the mitotic process are beginning to take place.
Chemical and Physical Events of DNA
Replication. DNA is replicated in much the same way
that RNA is transcribed in response to DNA, except for a
few important differences:
1. Both strands of the DNA in each chromosome are replicated, not simply one of them.
Unit I Introduction to Physiology: The Cell and General Physiology
2. Both entire strands of the DNA helix are replicated
from end to end, rather than small portions of them, as
occurs in the transcription of RNA.
3. The principal enzymes for replicating DNA are a complex of multiple enzymes called DNA polymerase, which
is comparable to RNA polymerase. It attaches to and
moves along the DNA template strand while another
enzyme, DNA ligase, causes bonding of successive
DNA nucleotides to one another, using high-energy
phosphate bonds to energize these attachments.
4. Formation of each new DNA strand occurs simultaneously in hundreds of segments along each of the two
strands of the helix until the entire strand is replicated.
Then the ends of the subunits are joined together by
the DNA ligase enzyme.
5. Each newly formed strand of DNA remains attached
by loose hydrogen bonding to the original DNA strand
that was used as its template. Therefore, two DNA
helixes are coiled together.
6. Because the DNA helixes in each chromosome are approximately 6 centimeters in length and have millions of helix
turns, it would be impossible for the two newly formed
DNA helixes to uncoil from each other were it not for some
special mechanism. This is achieved by enzymes that periodically cut each helix along its entire length, rotate each
segment enough to cause separation, and then resplice the
helix. Thus, the two new helixes become uncoiled.
DNA Repair, DNA “Proofreading,” and “Mutation.”
During the hour or so between DNA replication and the
beginning of mitosis, there is a period of active repair and
“proofreading” of the DNA strands. That is, wherever
inappropriate DNA nucleotides have been matched up
with the nucleotides of the original template strand, special enzymes cut out the defective areas and replace these
with appropriate complementary nucleotides. This is
achieved by the same DNA polymerases and DNA ligases
that are used in replication. This repair process is referred
to as DNA proofreading.
Because of repair and proofreading, the transcription
process rarely makes a mistake. But when a mistake is
made, this is called a mutation. The mutation causes formation of some abnormal protein in the cell rather than
a needed protein, often leading to abnormal cellular function and sometimes even cell death. Yet given that there are
30,000 or more genes in the human genome and that the
period from one human generation to another is about 30
years, one would expect as many as 10 or many more mutations in the passage of the genome from parent to child. As
a further protection, however, each human genome is represented by two separate sets of chromosomes with almost
identical genes. Therefore, one functional gene of each pair
is almost always available to the child despite mutations.
Chromosomes and Their Replication
The DNA helixes of the nucleus are packaged in chromosomes. The human cell contains 46 chromosomes arranged
in 23 pairs. Most of the genes in the two chromosomes of
each pair are identical or almost identical to each other,
so it is usually stated that the different genes also exist in
pairs, although occasionally this is not the case.
In addition to DNA in the chromosome, there is a large
amount of protein in the chromosome, composed mainly
of many small molecules of electropositively charged
histones. The histones are organized into vast numbers of small, bobbin-like cores. Small segments of each
DNA helix are coiled sequentially around one core after
The histone cores play an important role in the regulation of DNA activity because as long as the DNA is packaged tightly, it cannot function as a template for either
the formation of RNA or the replication of new DNA.
Further, some of the regulatory proteins have been shown
to decondense the histone packaging of the DNA and to
allow small segments at a time to form RNA.
Several nonhistone proteins are also major components of chromosomes, functioning both as chromosomal structural proteins and, in connection with the
genetic regulatory machinery, as activators, inhibitors,
and enzymes.
Replication of the chromosomes in their entirety occurs
during the next few minutes after replication of the DNA
helixes has been completed; the new DNA helixes collect
new protein molecules as needed. The two newly formed
chromosomes remain attached to each other (until time
for mitosis) at a point called the centromere located near
their center. These duplicated but still attached chromosomes are called chromatids.
Cell Mitosis
The actual process by which the cell splits into two new
cells is called mitosis. Once each chromosome has been
replicated to form the two chromatids, in many cells,
mitosis follows automatically within 1 or 2 hours.
Mitotic Apparatus: Function of the Centrioles.
One of the first events of mitosis takes place in the cytoplasm, occurring during the latter part of interphase in or
around the small structures called centrioles. As shown in
Figure 3-14, two pairs of centrioles lie close to each other
near one pole of the nucleus. These centrioles, like the
DNA and chromosomes, are also replicated during interphase, usually shortly before replication of the DNA. Each
centriole is a small cylindrical body about 0.4 micrometer long and about 0.15 micrometer in diameter, consisting mainly of nine parallel tubular structures arranged
in the form of a cylinder. The two centrioles of each pair
lie at right angles to each other. Each pair of centrioles,
along with attached pericentriolar material, is called a
Shortly before mitosis is to take place, the two pairs
of centrioles begin to move apart from each other. This
is caused by polymerization of protein microtubules
­growing between the respective centriole pairs and
Chapter 3 Genetic Control of Protein Synthesis, Cell Function, and Cell Reproduction
Prophase. The first stage of mitosis, called prophase,
is shown in Figure 3-14A, B, and C. While the spindle
is forming, the chromosomes of the nucleus (which in
interphase consist of loosely coiled strands) become condensed into well-defined chromosomes.
Prometaphase. During this stage (see Figure 3-14D),
the growing microtubular spines of the aster fragment the
nuclear envelope. At the same time, multiple microtubules
from the aster attach to the chromatids at the centromeres,
where the paired chromatids are still bound to each other;
the tubules then pull one chromatid of each pair toward
one cellular pole and its partner toward the opposite pole.
Metaphase. During metaphase (see Figure 3-14E), the
two asters of the mitotic apparatus are pushed farther apart.
This is believed to occur because the microtubular spines
from the two asters, where they interdigitate with each other
to form the mitotic spindle, actually push each other away.
There is reason to believe that minute contractile protein
molecules called “molecular motors,” perhaps composed
of the muscle protein actin, extend between the respective
spines and, using a stepping action as in muscle, actively
slide the spines in a reverse direction along each other.
Simultaneously, the chromatids are pulled tightly by their
attached microtubules to the very center of the cell, ­lining
up to form the equatorial plate of the mitotic spindle.
Anaphase. During this phase (see Figure 3-14F), the
two chromatids of each chromosome are pulled apart at
the centromere. All 46 pairs of chromatids are separated,
forming two separate sets of 46 daughter chromosomes.
One of these sets is pulled toward one mitotic aster and
the other toward the other aster as the two respective
poles of the dividing cell are pushed still farther apart.
Telophase. In telophase (see Figure 3-14G and H),
the two sets of daughter chromosomes are pushed completely apart. Then the mitotic apparatus dissolutes, and
a new nuclear membrane develops around each set of
chromosomes. This membrane is formed from portions
of the endoplasmic reticulum that are already present
in the cytoplasm. Shortly thereafter, the cell pinches in
two, midway between the two nuclei. This is caused by
­formation of a contractile ring of microfilaments composed of actin and probably myosin (the two contractile
proteins of muscle) at the juncture of the newly developing cells that pinches them off from each other.
Control of Cell Growth and Cell Reproduction
We know that certain cells grow and reproduce all the
time, such as the blood-forming cells of the bone marrow, the germinal layers of the skin, and the epithelium of
the gut. Many other cells, however, such as smooth muscle cells, may not reproduce for many years. A few cells,
such as the neurons and most striated muscle cells, do not
reproduce during the entire life of a person, except during
the original period of fetal life.
In certain tissues, an insufficiency of some types of cells
causes these to grow and reproduce rapidly until appropriate numbers of them are again available. For instance,
in some young animals, seven eighths of the liver can be
removed surgically, and the cells of the remaining one
eighth will grow and divide until the liver mass returns to
almost normal. The same occurs for many glandular cells
and most cells of the bone marrow, subcutaneous tissue,
intestinal epithelium, and almost any other tissue except
highly differentiated cells such as nerve and muscle cells.
We know little about the mechanisms that maintain
proper numbers of the different types of cells in the body.
However, experiments have shown at least three ways in
which growth can be controlled. First, growth often is
controlled by growth factors that come from other parts
of the body. Some of these circulate in the blood, but
­others originate in adjacent tissues. For instance, the epithelial cells of some glands, such as the pancreas, fail to
grow without a growth factor from the sublying connective ­tissue of the gland. Second, most normal cells stop
growing when they have run out of space for growth. This
occurs when cells are grown in tissue culture; the cells grow
until they contact a solid object, and then growth stops.
Third, cells grown in tissue culture often stop growing
when minute amounts of their own secretions are allowed
to collect in the culture medium. This, too, could provide
a means for negative feedback control of growth.
Regulation of Cell Size. Cell size is determined
almost entirely by the amount of functioning DNA in
the nucleus. If replication of the DNA does not occur,
the cell grows to a certain size and thereafter remains at
that size. Conversely, it is possible, by use of the chemical
colchicine, to prevent formation of the mitotic spindle and
therefore to prevent mitosis, even though replication of
the DNA continues. In this event, the nucleus contains far
greater quantities of DNA than it normally does, and the
cell grows proportionately larger. It is assumed that this
results simply from increased production of RNA and cell
proteins, which in turn cause the cell to grow larger.
Cell Differentiation
A special characteristic of cell growth and cell division
is cell differentiation, which refers to changes in physical
and functional properties of cells as they proliferate in the
embryo to form the different bodily structures and organs.
Unit I
a­ ctually ­pushing them apart. At the same time, other
microtubules grow radially away from each of the centriole 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 the two sets of
chromatids during mitosis. The complex of microtubules
extending between the two new centriole pairs is called
the spindle, and the entire set of microtubules plus the two
pairs of centrioles is called the mitotic apparatus.
Unit I Introduction to Physiology: The Cell and General Physiology
The description of an especially interesting ­experiment
that helps explain these processes follows.
When the nucleus from an intestinal mucosal cell of a
frog is surgically implanted into a frog ovum from which
the original ovum nucleus was removed, the result is
often the formation of a normal frog. This demonstrates
that even the intestinal mucosal cell, which is a well­differentiated cell, carries all the necessary genetic information for development of all structures required in the
frog’s body.
Therefore, it has become clear that differentiation
results not from loss of genes but from selective repression of different gene promoters. In fact, electron micrographs suggest that some segments of DNA helixes
wound around histone cores become so condensed that
they no longer uncoil to form RNA molecules. One explanation for this is as follows: It has been supposed that the
cellular genome begins at a certain stage of cell differentiation to produce a regulatory protein that forever after
represses a select group of genes. Therefore, the repressed
genes never function again. Regardless of the mechanism,
mature human cells produce a maximum of about 8000 to
10,000 proteins rather than the potential 30,000 or more
if all genes were active.
Embryological experiments show that certain cells in
an embryo control differentiation of adjacent cells. For
instance, the primordial chorda-mesoderm is called the
primary organizer of the embryo because it forms a focus
around which the rest of the embryo develops. It differentiates into a mesodermal axis that contains segmentally
arranged somites and, as a result of inductions in the surrounding tissues, causes formation of essentially all the
organs of the body.
Another instance of induction occurs when the developing eye vesicles come in contact with the ectoderm
of the head and cause the ectoderm to thicken into a
lens plate that folds inward to form the lens of the eye.
Therefore, a large share of the embryo develops as a result
of such inductions, one part of the body affecting another
part, and this part affecting still other parts.
Thus, although our understanding of cell differentiation is still hazy, we know many control mechanisms by
which differentiation could occur.
Apoptosis—Programmed Cell Death
The 100 trillion cells of the body are members of a 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 death. When cells
are no longer needed or become a threat to the organism, they undergo a suicidal programmed cell death, or
­apoptosis. This process involves a specific proteolytic cascade that causes the cell to shrink and condense, to disassemble its cytoskeleton, and to alter its cell surface so that
a neighboring phagocytic cell, such as a macrophage, can
attach to the cell membrane and digest the cell.
In contrast to programmed death, cells that die as a
result of an acute injury usually swell and burst due to loss
of cell membrane integrity, a process called cell necrosis.
Necrotic cells may spill their contents, causing inflammation and injury to neighboring cells. Apoptosis, however,
is an orderly cell death that results in disassembly and
phagocytosis of the cell before any leakage of its contents
occurs, and neighboring cells usually remain healthy.
Apoptosis is initiated by activation of a family of proteases called caspases. These are enzymes that are synthesized and stored in the cell as inactive procaspases.
The mechanisms of activation of caspases are complex,
but once activated, the enzymes cleave and activate other
procaspases, triggering a cascade that rapidly breaks
down proteins within the cell. The cell thus dismantles
itself, and its remains are rapidly digested by neighboring
phagocytic cells.
A tremendous amount of apoptosis occurs in tissues
that are being remodeled during development. Even in
adult humans, billions of cells die each hour in tissues
such as the intestine and bone marrow and are replaced
by new cells. Programmed cell death, however, is normally
balanced with the formation of new cells in healthy adults.
Otherwise, the body’s tissues would shrink or grow excessively. Recent studies suggest that abnormalities of apoptosis may play a key role in neurodegenerative diseases
such as Alzheimer’s disease, as well as in cancer and autoimmune disorders. Some drugs that have been used successfully for chemotherapy appear to induce apoptosis in
cancer cells.
Cancer is caused in all or almost all instances by mutation
or by some other abnormal activation of cellular genes
that control cell growth and cell mitosis. The abnormal
genes are called oncogenes. As many as 100 different
­oncogenes have been discovered.
Also present in all cells are antioncogenes, which suppress the activation of specific oncogenes. Therefore, loss
or inactivation of antioncogenes can allow activation of
oncogenes that lead to cancer.
Only a minute fraction of the cells that mutate in the
body ever lead to cancer. There are several reasons for
this. First, most mutated cells have less survival capability than normal cells and simply die. Second, only a
few of the mutated cells that do survive become cancerous, because even most mutated cells still have normal
­feedback ­controls that prevent excessive growth.
Third, those cells that are potentially cancerous are
often destroyed by the body’s immune system before
they grow into a cancer. This occurs in the following
way: Most mutated cells form abnormal proteins within
their cell bodies because of their altered genes, and these
proteins activate the body’s immune system, causing it
to form antibodies or sensitized lymphocytes that react
against the cancerous cells, destroying them. In support
Chapter 3 Genetic Control of Protein Synthesis, Cell Function, and Cell Reproduction
1. It is well known that ionizing radiation, such as x-rays,
gamma rays, and particle radiation from ­radioactive substances, and even ultraviolet light can ­predispose individuals to cancer. Ions formed in tissue cells under the
influence of such radiation are highly reactive and can
rupture DNA strands, thus causing many mutations.
2. Chemical substances of certain types also have a high
propensity for causing mutations. It was discovered
long ago that various aniline dye derivatives are likely
to cause cancer, so workers in chemical plants producing such substances, if unprotected, have a special predisposition to cancer. Chemical substances that can
cause mutation are called carcinogens. The carcinogens
that currently cause the greatest number of deaths are
those in cigarette smoke. They cause about one quarter of all cancer deaths.
3. Physical irritants can also lead to cancer, such as continued abrasion of the linings of the intestinal tract by
some types of food. The damage to the tissues leads to
rapid mitotic replacement of the cells. The more rapid
the mitosis, the greater the chance for mutation.
4. In many families, there is a strong hereditary tendency
to cancer. This results from the fact that most cancers require not one mutation but two or more mutations before cancer occurs. In those families that are
particularly predisposed to cancer, it is presumed that
one or more cancerous genes are already mutated in
the inherited genome. Therefore, far fewer additional
mutations must take place in such family members
before a cancer begins to grow.
5. In laboratory animals, certain types of viruses can cause
some kinds of cancer, including leukemia. This usually
results in one of two ways. In the case of DNA viruses,
the DNA strand of the virus can insert itself directly into
one of the chromosomes and thereby cause a mutation
that leads to cancer. In the case of RNA viruses, some
of these carry with them an enzyme called reverse
transcriptase that causes DNA to be transcribed from
the RNA. The transcribed DNA then inserts itself into
the animal cell genome, leading to cancer.
Invasive Characteristic of the Cancer Cell. The
major differences between the cancer cell and the normal cell are the following: (1) The cancer cell does not
respect usual cellular growth limits; the reason for this is
that these cells presumably do not require all the same
growth factors that are necessary to cause growth of normal cells. (2) Cancer cells are often far less adhesive to
one another than are normal cells. Therefore, they tend
to wander through the tissues, enter the blood stream,
and be transported all through the body, where they form
nidi for numerous new cancerous growths. (3) Some cancers also produce angiogenic factors that cause many new
blood vessels to grow into the cancer, thus supplying the
nutrients required for cancer growth.
Why Do Cancer Cells Kill?
The answer to this question is usually simple. Cancer tissue competes with normal tissues for nutrients. Because
cancer cells continue to proliferate indefinitely, their
number multiplying day by day, cancer cells soon demand
essentially all the nutrition available to the body or to
an essential part of the body. As a result, normal tissues
­gradually suffer nutritive death.
Alberts B, Johnson A, Lewis J, et al: Molecular Biology of the Cell, ed 5, New
York, 2008, Garland Science.
Aranda A, Pascal A: Nuclear hormone receptors and gene expression, Physiol
Rev 81:1269, 2001.
Brodersen P, Voinnet O: Revisiting the principles of microRNA target recognition and mode of action, Nat Rev Mol Cell Biol 10:141, 2009.
Cairns BR: The logic of chromatin architecture and remodelling at promoters, Nature 461:193, 2009.
Carthew RW, Sontheimer EJ: Origins and mechanisms of miRNAs and siRNAs, Cell 136:642, 2009.
Castanotto D, Rossi JJ: The promises and pitfalls of RNA-interference-based
therapeutics, Nature 457:426, 2009.
Cedar H, Bergman Y: Linking DNA methylation and histone modification:
patterns and paradigms, Nat Rev Genet 10:295, 2009.
Croce CM: Causes and consequences of microRNA dysregulation in cancer,
Nat Rev Genet 10:704, 2009.
Frazer KA, Murray SS, Schork NJ, et al: Human genetic variation and its contribution to complex traits, Nat Rev Genet 10:241, 2009.
Fuda NJ, Ardehali MB, Lis JT: Defining mechanisms that regulate RNA
­polymerase II transcription in vivo, Nature 461:186, 2009.
Hahn S: Structure and mechanism of the RNA polymerase II transcription
machinery, Nat Struct Mol Biol 11:394, 2004.
Unit I
of this is the fact that in people whose immune systems
have been suppressed, such as in those taking immunosuppressant drugs after kidney or heart transplantation,
the probability of a cancer’s developing is multiplied as
much as fivefold.
Fourth, usually several different activated oncogenes
are required simultaneously to cause a cancer. For instance,
one such gene might promote rapid reproduction of a cell
line, but no cancer occurs because there is not a simultaneous mutant gene to form the needed blood vessels.
But what is it that causes the altered genes? Considering
that many trillions of new cells are formed each year in
humans, a better question might be, why is it that all of us
do not develop millions or billions of mutant cancerous
cells? The answer is the incredible precision with which
DNA chromosomal strands are replicated in each cell
before mitosis can take place, and also the proofreading
process that cuts and repairs any abnormal DNA strand
before the mitotic process is allowed to proceed. Yet
despite all these inherited cellular precautions, probably
one newly formed cell in every few million still has significant mutant characteristics.
Thus, chance alone is all that is required for mutations
to take place, so we can suppose that a large number of
cancers are merely the result of an unlucky occurrence.
However, the probability of mutations can be increased
manyfold when a person is exposed to certain chemical,
physical, or biological factors, including the following:
Unit I Introduction to Physiology: The Cell and General Physiology
Hastings PJ, Lupski JR, Rosenberg SM, et al: Mechanisms of change in gene
copy number, Nat Rev Genet 10:551, 2009.
Hoeijmakers JH: DNA damage, aging, and cancer, N Engl J Med 361:1475,
Hotchkiss RS, Strasser A, McDunn JE, et al: Cell death, N Engl J Med
361:1570, 2009.
Jinek M, Doudna JA: A three-dimensional view of the molecular machinery
of RNA interference, Nature 457:40, 2009.
Jockusch BM, Hüttelmaier S, Illenberger S: From the nucleus toward the cell
periphery: a guided tour for mRNAs, News Physiol Sci 18:7, 2003.
Kim VN, Han J, Siomi MC: Biogenesis of small RNAs in animals, Nat Rev Mol
Cell Biol 10:126, 2009.
Misteli T, Soutoglou E: The emerging role of nuclear architecture in DNA
repair and genome maintenance, Nat Rev Mol Cell Biol 10:243, 2009.
Moazed D: Small RNAs in transcriptional gene silencing and genome
defence, Nature 457:413, 2009.
Siller KH, Doe CQ: Spindle orientation during asymmetric cell division, Nat
Cell Biol 11:365, 2009.
Sims RJ 3rd, Reinberg D: Is there a code embedded in proteins that is based
on post-translational modifications? Nat Rev Mol Cell Biol 9:815, 2008.
Stappenbeck TS, Miyoshi H: The role of stromal stem cells in tissue regeneration and wound repair. Science 324:1666, 2009.
Sutherland H, Bickmore WA: Transcription factories: gene expression in
unions?, Nat Rev Genet 10:457, 2009.
Membrane Physiology,
Nerve, and Muscle
4. Transport of Substances Through Cell
5. Membrane Potentials and Action
6. Contraction of Skeletal Muscle
7. Excitation of Skeletal Muscle:
Neuromuscular Transmission and
Excitation-Contraction Coupling
8. Excitation and Contraction of Smooth
This page intentionally left blank
chapter 4
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 contains very
little. But the concentrations of phosphates and proteins in
the intracellular 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 intracellular fluid. Therefore, it constitutes a barrier against movement of water molecules
and water-soluble substances between the extracellular
and intracellular fluid compartments. However, as demonstrated in Figure 4-2 by the leftmost 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 membrane. Most of these penetrating proteins,
t­ herefore, 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;
conformational 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 for 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.
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
HCO3– ------------ 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 ?
Neutral fat
0.5 g/dl-------------- 2 to 95 g/dl
PO2 --------------- 35 mm Hg --------- 20 mm Hg ?
PCO2 ------------- 46 mm Hg --------- 50 mm Hg ?
pH ----------------- 7.4 ------------------- 7.0
Proteins ---------- 2 g/dl ---------------- 16 g/dl
(5 mEq/L)
(40 mEq/L)
Figure 4-1 Chemical compositions of extracellular and intracellular fluids.
U n i t II
Transport of Substances Through
Cell Membranes
Unit II Membrane Physiology, Nerve, and Muscle
Carrier proteins
Active transport
Figure 4-2 Transport pathways through the cell membrane, and
the basic mechanisms of 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 protein. The energy that causes diffusion is the energy of the normal kinetic motion of matter.
By contrast, active transport means movement of ions
or other substances across the membrane in combination with a carrier protein in such a way that the carrier protein causes the substance to move against an
energy gradient, such as from a low-concentration state
to a high-concentration state. This movement requires
an additional source of energy besides kinetic energy.
Following is a more detailed explanation of the basic
physics and physical chemistry of these two processes.
All molecules and ions in the body fluids, including water
molecules and dissolved substances, are in constant
motion, each particle moving its own separate way. Motion
of these particles is what physicists call “heat”—the greater
the motion, the higher the temperature—and the motion
never ceases under any condition except at absolute zero
temperature. When a moving molecule, A, approaches a
stationary molecule, B, the electrostatic and other nuclear
forces of molecule A repel molecule B, transferring some
of the energy of motion of molecule A to molecule B.
Consequently, 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 another, and so forth,
randomly bouncing thousands of times each second. This
continual movement of molecules among one another in
liquids or in gases is called diffusion.
Ions diffuse in the same manner as whole molecules,
and even suspended colloid particles diffuse in a similar
manner, except that the colloids diffuse far less rapidly
than molecular substances because of their large size.
Diffusion Through the Cell Membrane
Diffusion through the cell membrane is divided into two
subtypes called simple diffusion and facilitated diffusion. Simple diffusion means that kinetic movement of
­molecules or ions occurs through a membrane opening
or through intermolecular spaces without any interaction
with carrier proteins in the membrane. The rate of diffusion is determined by the amount of substance available,
the velocity of kinetic motion, and the number and sizes
of openings in the membrane through which the molecules or ions can move.
Facilitated diffusion requires interaction of a carrier
protein. The carrier protein aids passage of the molecules
or ions through the membrane by binding chemically
with them and shuttling them through the membrane in
this form.
Simple diffusion can occur through the cell ­membrane
by two pathways: (1) through the interstices of the lipid
bilayer if the diffusing substance is lipid soluble and
(2) through watery channels that penetrate all the way
through some of the large transport proteins, as shown to
the left in Figure 4-2.
Diffusion of Lipid-Soluble Substances Through the
Lipid Bilayer. One of the most important factors that deter-
mines how rapidly a substance diffuses through the lipid
bilayer is the lipid solubility of the substance. For instance,
the lipid solubilities of oxygen, nitrogen, carbon dioxide,
and alcohols are high, so all these can dissolve directly in
the lipid bilayer and diffuse through the cell membrane in
the same manner that diffusion of water solutes occurs in a
watery solution. For obvious reasons, the rate of diffusion of
each of these substances through the membrane is directly
proportional to its lipid solubility. Especially large amounts
of oxygen can be transported in this way; therefore, oxygen
can be delivered to the interior of the cell almost as though
the cell membrane did not exist.
Diffusion of Water and Other Lipid-Insoluble
Molecules Through Protein Channels. Even though
Figure 4-3 Diffusion of a fluid molecule during a thousandth of
a second.
water is highly insoluble in the membrane lipids, it readily
passes through channels 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 that diffuses in each direction through the red cell
membrane during each second is about 100 times as great
as the volume of the red cell itself.
Chapter 4 Transport of Substances Through Cell Membranes
Pore loop
Diffusion Through Protein Pores and Channels—
Selective Permeability and “Gating” of Channels
Computerized three-dimensional reconstructions of protein pores and channels have demonstrated tubular pathways all the way from the extracellular to the intracellular
fluid. Therefore, substances can move by simple diffusion
directly along these pores and channels from one side of
the membrane to the other.
Pores are composed of integral cell membrane proteins that form open tubes through the membrane and
are always open. However, the diameter of a pore and its
electrical charges provide selectivity that permits only
certain molecules to pass through. For example, protein
pores, called aquaporins or water channels, permit rapid
passage of water through cell membranes but exclude
other ­molecules. At least 13 different types of aquaporins
have been found in various cells of the human body.
Aquaporins have a narrow pore that permits water molecules to diffuse through the membrane in single file. The
pore is too narrow to permit passage of any hydrated ions.
As discussed in Chapters 29 and 75, the density of some
aquaporins (e.g., aquaporin-2) in cell membranes is not
static but is altered in different physiological conditions.
The protein channels are distinguished by two important characteristics: (1) They are often selectively permeable to certain substances, and (2) many of the channels
can be opened or closed by gates that are regulated by
electrical signals (voltage-gated channels) or chemicals
that bind to the channel proteins (ligand-gated channels).
Selective Permeability of Protein Channels. Many
of the protein channels are highly selective for transport of
one or more specific ions or molecules. This results from
the characteristics of the channel itself, such as its diameter, its shape, and the nature of the electrical charges and
chemical bonds along its inside surfaces.
Potassium channels permit passage of potassium ions
across the cell membrane about 1000 times more readily
than they permit passage of sodium ions. This high degree
of selectivity, however, cannot be explained entirely by
molecular diameters of the ions since potassium ions
are slightly larger than sodium ions. What is the mechanism for this remarkable ion selectivity? This question
was partially answered when the structure of a bacterial
potassium channel was determined by x-ray crystallography. Potassium channels were found to have a tetrameric
U n i t II
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. However, as
they become larger, their penetration falls off rapidly.
For instance, the diameter of the urea molecule is only
20 ­percent 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 the astonishing rate of
water penetration, this amount of urea penetration still
allows rapid transport of urea through the membrane
within minutes.
Pore helix
Figure 4-4 The structure of a potassium channel. The channel is
composed of four subunits (only two are shown), each with two
transmembrane helices. A narrow selectivity filter is formed from
the pore loops and carbonyl oxygens line the walls of the selectivity
filter, forming sites for transiently binding dehydrated potassium
ions. The interaction of the potassium ions with carbonyl oxygens
causes the potassium ions to shed their bound water molecules, permitting the dehydrated potassium ions to pass through the pore.
structure consisting of four identical protein subunits surrounding a central pore (Figure 4-4). At the top of the
channel pore are pore loops that form a ­narrow selectivity filter. Lining the selectivity filter are carbonyl oxygens.
When hydrated potassium ions enter the selectivity filter,
they interact with the carbonyl oxygens and shed most of
their bound water molecules, permitting the dehydrated
potassium ions to pass through the channel. The carbonyl oxygens are too far apart, however, to enable them to
interact closely with the smaller sodium ions, which are
therefore effectively excluded by the selectivity filter from
passing through the pore.
Different selectivity filters for the various ion channels
are believed to determine, in large part, the specificity of
the channel for cations or anions or for particular ions,
such as Na+, K+, and Ca++, that gain access to the channel.
One of the most important of the protein channels, the
sodium channel, is only 0.3 by 0.5 nanometer in diameter, but more important, the inner surfaces of this channel are lined with amino acids that are strongly negatively
charged, as shown by the negative signs inside the channel proteins in the top panel of Figure 4-5. These strong
negative charges can pull small dehydrated sodium ions
into these channels, actually pulling the sodium ions away
from their hydrating water molecules. Once in the channel, the sodium ions diffuse in either direction according
to the usual laws of diffusion. Thus, the sodium channel is
specifically selective for passage of sodium ions.
Unit II Membrane Physiology, Nerve, and Muscle
Gate open
Open-State Versus Closed-State of Gated
Channels. Figure 4-6A shows an especially interest-
closed K+
Gate open
Figure 4-5 Transport of sodium and potassium ions through
­protein channels. Also shown are conformational changes in the
protein molecules to open or close “gates” guarding the channels.
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 4-5
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 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 two
principal ways:
1. 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 4-5, 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 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 4-5, 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.
2. 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 is called chemical gating
or ligand gating. One of the most important instances of
chemical gating is the effect of acetylcholine on the socalled acetylcholine channel. Acetylcholine opens the
gate of this channel, providing a negatively charged pore
about 0.65 nanometer in diameter that allows uncharged
molecules or positive ions smaller than this diameter to
pass through. This gate is exceedingly important for
the transmission of nerve signals from one nerve cell to
another (see Chapter 45) and from nerve cells to muscle
cells to cause muscle contraction (see Chapter 7).
ing characteristic of most voltage-gated channels. This
figure shows two recordings of electrical current flowing through a single sodium channel when there was an
approximate 25-millivolt potential gradient across the
membrane. Note that the channel conducts current either
“all or none.” That is, the gate of the channel snaps open
and then snaps closed, each open state lasting for only a
fraction of a millisecond up to several milliseconds. This
demonstrates the rapidity with 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 or almost all the time, whereas at
another voltage 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, 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 won-
der how it is technically possible to record ion current
flow through single protein channels as shown in Figure
4-6A. This has been achieved by using the “patch-clamp”
method illustrated in Figure 4-6B. Very simply, a micropipette, having a tip diameter of only 1 or 2 micrometers,
is abutted against 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 membrane “patch” at the tip of the pipette
through which electrical current flow can be recorded.
Alternatively, as shown to the right in Figure 4-6B, the
small cell membrane patch at the end of the pipette can be
torn away from the cell. The pipette with 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 as desired. Also, the voltage between the two sides of the membrane can be set at
will—that is, “clamped” to 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.
Chapter 4 Transport of Substances Through Cell Membranes
Open sodium channel
Simple diffusion
Rate of diffusion
U n i t II
Concentration of substance
Figure 4-7 Effect of concentration of a substance on rate of diffusion through a membrane by simple diffusion and facilitated diffusion. This shows that facilitated diffusion approaches a maximum
rate called the Vmax.
To recorder
Figure 4-6 A, Record of current flow through a single voltagegated sodium channel, demonstrating the “all or none” principle for opening and closing of the channel. B, The “patch-clamp”
method for recording current flow through a single protein channel.
To the left, recording is performed from a “patch” of a living cell
membrane. To the right, recording is from a membrane patch that
has been torn away from the cell.
Facilitated Diffusion
Facilitated diffusion is also called carrier-mediated
­diffusion 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.
Facilitated diffusion differs from simple diffusion in
the following important way: Although the rate of simple
diffusion through an open channel increases proportionately with the concentration of the diffusing substance,
in facilitated diffusion the rate of diffusion approaches a
maximum, called Vmax, as the concentration of the ­diffusing
substance increases. This difference between simple
­diffusion and facilitated diffusion is demonstrated in
Figure 4-7. The figure shows that as the concentration
of the diffusing substance increases, the rate of simple
­diffusion continues to increase proportionately, but in the
case of facilitated diffusion, the rate of diffusion cannot
rise greater than the Vmax level.
What is it that limits the rate of facilitated diffusion?
A probable answer is the mechanism illustrated in Figure
4-8. This figure shows a carrier protein with a pore large
enough to transport a specific molecule partway through.
It also shows a binding “receptor” on the inside of the
protein carrier. The molecule to be transported enters the
pore and becomes bound. Then, in a fraction of a second,
a conformational or chemical change occurs in the carrier
protein, so the pore now opens to the opposite side of the
membrane. Because the binding force of the receptor is
weak, the thermal motion of the attached molecule causes
Binding point
Carrier protein
of binding
Figure 4-8 Postulated mechanism for facilitated diffusion.
Unit II
Membrane Physiology, Nerve, and Muscle
it to break away and to be released on the opposite side of
the membrane. The rate at which molecules can be 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 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 most of
the amino acids. In the case of glucose, at least five glucose
transporter molecules have been discovered in various
tissues. Some of these can also transport other monosaccharides that have structures similar to that of glucose,
including galactose and fructose. One of these, glucose
transporter 4 (GLUT4), is activated by insulin, which can
increase the rate of facilitated diffusion of glucose as much
as 10-fold to 20-fold in insulin-sensitive tissues. This is the
principal mechanism by which insulin controls glucose
use in the body, as discussed in Chapter 78.
Net Diffusion Rate Is Proportional to the
Concentration Difference Across a Membrane. Figure
4-9A shows a cell membrane with a substance in high concentration on the outside and low concentration on the
inside. The rate at which the substance diffuses inward
is proportional to the concentration of molecules on
the outside because this concentration determines how
many molecules strike the outside of the membrane each
second. Conversely, the rate at which molecules diffuse
outward is proportional to their concentration inside the
membrane. Therefore, the rate of net diffusion into the
cell is proportional to the concentration on the outside
minus the concentration on the inside, or:
Net diffusion ∝ (Co−Ci)
in which Co is concentration outside and Ci is concentration inside.
Effect of Membrane Electrical Potential on
Diffusion of Ions—The “Nernst Potential.” If an
electrical potential is applied across the membrane, as
shown in Figure 4-9B, the electrical charges of the ions
cause them to move through the membrane even though
no concentration difference exists to cause movement.
Thus, in the left panel of Figure 4-9B, the concentration
of negative ions is the same on both sides of the membrane, but a positive charge has been applied to the right
side of the membrane and a negative charge to the left,
creating an electrical gradient across the membrane.
The positive charge attracts the negative ions, whereas
the negative charge repels them. Therefore, net diffusion
− − –
− −
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
is the net rate of diffusion of a substance in the desired
direction. This net rate is determined by several factors.
− −
− −
− −
− −
− −
− −
− −
Figure 4-9 Effect of concentration difference (A), electrical potential difference affecting negative ions (B), and pressure difference (C) to cause diffusion of molecules and ions through a cell
occurs from left to right. After some time, large quantities of negative ions have moved to the right, creating
the condition shown in the right panel of Figure 4-9B, in
which a concentration difference of the ions has developed in the direction opposite to the electrical potential
difference. The concentration difference now tends to
move the ions to the left, while the electrical difference
tends to move them to the right. When the concentration
difference rises high enough, the two effects balance each
other. At normal body temperature (37°C), the electrical
difference that will balance a given concentration difference of univalent ions—such as sodium (Na+) ions—can
be determined from the following formula, called the
Nernst equation:
EMF (in millivolts ) = ±61 log
in which EMF is the electromotive force (voltage) between
side 1 and side 2 of the membrane, C1 is the concentration on side 1, and C2 is the concentration on side 2. This
equation is extremely important in understanding the
transmission of nerve impulses and is discussed in much
greater detail in Chapter 5.
Effect of a Pressure Difference Across the
Membrane. At times, considerable pressure difference
develops between the two sides of a diffusible membrane.
Chapter 4 Transport of Substances Through Cell Membranes
Osmosis Across Selectively Permeable
Membranes—“Net Diffusion” of Water
By far the most abundant substance that diffuses through
the cell membrane is water. Enough water ordinarily diffuses in each direction through the red cell membrane
per second to equal about 100 times the volume of the cell
itself. Yet normally the amount that diffuses in the two
directions is balanced so precisely that zero net movement of water occurs. Therefore, the volume of the cell
remains constant. However, under certain conditions, a
concentration difference for water can develop across a
membrane, just as concentration differences for other
substances can occur. When this happens, net movement
of water does occur across the cell membrane, causing the
cell either to swell or shrink, depending on the direction
of the water movement. This process of net movement
of water caused by a concentration difference of water is
called osmosis.
To give an example of osmosis, let us assume the conditions shown in Figure 4-10, with pure water on one
side of the cell membrane and a solution of sodium chloride on the other side. Water molecules pass through the
cell membrane with ease, whereas sodium and chloride
ions pass through only with difficulty. Therefore, sodium
chloride solution is actually a mixture of permeant water
molecules and nonpermeant sodium and chloride ions,
and the membrane is said to be selectively permeable to
water but much less so to sodium and chloride ions. Yet
the presence of the sodium and chloride has displaced
some of the water molecules on the side of the membrane
where these ions are present and, therefore, has reduced
the concentration of water molecules to less than that of
pure water. As a result, in the example of Figure 4-10, more
water molecules strike the channels on the left side, where
there is pure water, than on the right side, where the water
concentration has been reduced. Thus, net movement of
water occurs from left to right—that is, osmosis occurs
from the pure water into the sodium chloride solution.
NaCl solution
U n i t II
This occurs, for instance, at the blood capillary membrane
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 lowpressure side. This effect is demonstrated in Figure 4-9C,
which shows a piston developing high pressure on one
side of a “pore,” thereby causing more molecules to strike
the pore on this side and, therefore, more molecules to
“diffuse” to the other side.
Figure 4-10 Osmosis at a cell membrane when a sodium chloride
solution is placed on one side of the membrane and water is placed
on the other side.
Osmotic Pressure
If in Figure 4-10 pressure were applied to the sodium chloride solution, osmosis of water into this solution would
be slowed, stopped, or even reversed. The exact amount
of pressure required to stop osmosis is called the osmotic
pressure of the sodium chloride solution.
The principle of a pressure difference opposing osmosis is demonstrated in Figure 4-11, which shows a selectively permeable membrane separating two columns of
fluid, one containing pure water and the other containing a solution of water and any solute that will not penetrate the membrane. Osmosis of water from chamber B
into chamber A causes the levels of the fluid columns to
become farther and farther apart, until eventually a pressure difference develops between the two sides of the
membrane great enough to oppose the osmotic effect.
cm H2O
Figure 4-11 Demonstration of osmotic pressure caused by osmosis
at a semipermeable membrane.
Unit II
Membrane Physiology, Nerve, and Muscle
The pressure difference across the membrane at this point
is equal to the osmotic pressure of the solution that contains the nondiffusible solute.
Importance of Number of Osmotic Particles (Molar
Concentration) in Determining Osmotic Pressure. The
osmotic pressure exerted by particles in a solution,
whether they are molecules or ions, is determined by
the number of particles per unit volume of fluid, not by
the mass of the particles. The reason for this is that each
particle in a solution, regardless of its mass, exerts, on
average, the same amount of pressure against the membrane. That is, large particles, which have greater mass
(m) than small particles, move at slower velocities (v).
The small particles move at higher velocities in such a
way that their average kinetic energies (k), determined
by the equation
are the same for each small particle as for each large particle. Consequently, the factor that determines the osmotic
pressure of a solution is the concentration of the solution
in terms of number of particles (which is the same as its
molar concentration if it is a nondissociated molecule),
not in terms of mass of the solute.
“Osmolality”—The Osmole. To express the concentration of a solution in terms of numbers of particles, the
unit called the osmole is used in place of grams.
One osmole is 1 gram molecular weight of osmotically active solute. Thus, 180 grams of glucose, which is 1
gram molecular weight of glucose, is equal to 1 osmole of
glucose because glucose does not dissociate into ions. If a
solute dissociates into two ions, 1 gram molecular weight
of the solute will become 2 osmoles because the number
of osmotically active particles is now twice as great as is
the case for the nondissociated solute. Therefore, when
fully dissociated, 1 gram molecular weight of sodium
chloride, 58.5 grams, is equal to 2 osmoles.
Thus, a solution that has 1 osmole of solute dissolved
in each kilogram of water is said to have an osmolality
of 1 osmole per kilogram, and a solution that has 1/1000
osmole dissolved per kilogram has an osmolality of 1
milliosmole per kilogram. The normal 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 concentration is
equivalent to 19.3 mm Hg osmotic pressure. Multiplying
this value by the 300 milliosmolar concentration 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 about 5500 mm Hg. The reason
for this difference is that many of the ions in the body fluids, such as sodium and chloride ions, are highly attracted
to one another; consequently, they cannot move entirely
unrestrained in the fluids and create their full osmotic
pressure potential. Therefore, on average, the actual
osmotic pressure of the body fluids is about 0.93 times
the calculated value.
The Term “Osmolarity.” Osmolarity is the osmolar concentration expressed as osmoles per liter of solution rather
than osmoles per kilogram of water. Although, strictly
speaking, it is osmoles per kilogram of water (osmolality)
that determines osmotic pressure, for dilute solutions such
as those in the body, the quantitative differences between
osmolarity and osmolality are less than 1 percent. Because
it is far more practical to measure osmolarity than osmolality, this is the usual practice in almost all physiological
“Active Transport” of Substances
Through Membranes
At times, a large concentration of a substance is required
in the intracellular fluid even though the extracellular
fluid contains only a small concentration. This is true, for
instance, for potassium ions. Conversely, it is important
to keep the concentrations of other ions very low inside
the cell even though their concentrations in the extracellular fluid are great. This is especially true for sodium
ions. Neither of these two effects could occur by simple diffusion because simple diffusion eventually equilibrates concentrations on the two sides of the membrane.
Instead, some energy source must cause excess movement of potassium ions to the inside of cells and excess
movement of sodium ions to the outside of cells. When a
cell membrane moves molecules or ions “uphill” against a
concentration gradient (or “uphill” against an electrical or
pressure gradient), the process is called active transport.
Different substances that are actively transported
through at least some cell membranes include sodium
ions, potassium ions, calcium ions, iron ions, hydrogen ions, chloride ions, iodide ions, urate ions, several
different sugars, and most of the amino acids.
Primary Active Transport and Secondary Active
Transport. Active transport is divided into two types
according to the source of the energy used to cause the
transport: primary active transport and secondary active
transport. In primary active transport, the energy is
derived directly from breakdown of adenosine triphosphate (ATP) or of some other high-energy phosphate
compound. 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 two sides
of a cell membrane, created originally by primary active
transport. In both instances, transport depends on carrier
proteins that penetrate through the cell membrane, as is
true for facilitated diffusion. However, in active transport,
the carrier protein functions differently from the carrier
in facilitated diffusion because it is capable of imparting
energy to the transported substance to move it against the
Chapter 4 Transport of Substances Through Cell Membranes
electrochemical gradient. Following are some examples
of primary active transport and secondary active transport, with more detailed explanations of their principles
of function.
Among the substances that are transported by primary active transport are sodium, potassium, calcium,
­hydrogen, chloride, and a few other ions.
The active transport mechanism that has been studied in greatest detail is the sodium-potassium (Na+-K+)
pump, a transport process that pumps sodium ions outward through the cell membrane of all cells and at the
same time pumps potassium ions from the outside to
the inside. This pump is responsible for maintaining the
sodium and potassium concentration differences across
the cell membrane, as well as for establishing a negative
electrical voltage inside the cells. Indeed, Chapter 5 shows
that this pump is also the basis of nerve function, transmitting nerve signals throughout the nervous system.
Figure 4-12 shows the basic physical components of
the Na+-K+ pump. The carrier protein is a complex of
two separate globular proteins: a larger one called the α
subunit, with a molecular weight of about 100,000, and a
smaller one called the β subunit, with a molecular weight
of about 55,000. Although the function of the smaller protein is not known (except that it might anchor the protein
complex in the lipid membrane), the larger protein has
three specific features that are important for the functioning of the pump:
1. It has three receptor sites for binding sodium ions on
the portion of the protein that protrudes to the inside
of the cell.
2. It has two receptor sites for potassium ions on the
3. The inside portion of this protein near the sodium
binding sites has ATPase activity.
Figure 4-12 Postulated mechanism of the sodium-potassium
pump. ADP, adenosine diphosphate; ATP, adenosine triphosphate;
Pi, phosphate ion.
Electrogenic Nature of the Na+-K+ Pump. The fact that
the Na+-K+ pump moves three Na+ ions to the exterior for
every two K+ ions to the interior means that a net of one
positive charge is moved from the interior of the cell to the
exterior for each cycle of the pump. This creates positivity
U n i t II
Primary Active Transport
Sodium-Potassium Pump
When two potassium ions bind on the outside of
the carrier protein and three sodium ions bind on the
inside, the ATPase function of the protein becomes activated. This then cleaves one molecule of ATP, splitting it
to ­adenosine diphosphate (ADP) and liberating a highenergy phosphate bond of energy. This liberated energy
is then believed to cause a chemical and conformational
change in the protein carrier molecule, extruding the
three sodium ions to the outside and the two potassium
ions to the inside.
As with other enzymes, the Na+-K+ ATPase pump can
run in reverse. If the electrochemical gradients for Na+ and
K+ are experimentally increased enough so that the energy
stored in their gradients is greater than the chemical energy
of ATP hydrolysis, these ions will move down their concentration gradients and the Na+-K+ pump will synthesize ATP
from ADP and phosphate. The phosphorylated form of the
Na+-K+ pump, therefore, can either donate its phosphate to
ADP to produce ATP or use the energy to change its conformation and pump Na+ out of the cell and K+ into the cell.
The relative concentrations of ATP, ADP, and phosphate, as
well as the electrochemical gradients for Na+ and K+, determine the direction of the enzyme reaction. For some cells,
such as electrically active nerve cells, 60 to 70 percent of the
cells’ energy requirement may be devoted to pumping Na+
out of the cell and K+ into the cell.
The Na+-K+ Pump is Important For Controlling Cell
Volume. One of the most important functions of the
Na+-K+ pump is to control the volume of each cell.
Without function of this pump, most cells of the body
would swell until they burst. The mechanism for controlling the volume is as follows: Inside the cell are large numbers of proteins and other organic molecules that cannot
escape from the cell. Most of these are negatively charged
and therefore attract large numbers of potassium, sodium,
and other positive ions as well. All these molecules and
ions then cause osmosis of water to the interior of the
cell. Unless this is checked, the cell will swell indefinitely
until it bursts. The normal mechanism for preventing this
is the Na+-K+ pump. Note again that this device pumps
three Na+ ions to the outside of the cell for every two K+
ions pumped to the interior. Also, the membrane is far
less permeable to sodium ions than to potassium ions,
so once the sodium ions are on the outside, they have a
strong tendency to stay there. Thus, this represents a net
loss of ions out of the cell, which initiates osmosis of water
out of the cell as well.
If a cell begins to swell for any reason, this automatically activates the Na+-K+ pump, moving still more ions
to the exterior and carrying water with them. Therefore,
the Na+-K+ pump performs a continual surveillance role
in maintaining normal cell volume.
Unit II
Membrane Physiology, Nerve, and Muscle
outside the cell but leaves a deficit of positive ions 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 membrane. As discussed
in Chapter 5, this electrical potential is a basic requirement
in nerve and muscle fibers for transmitting nerve and muscle signals.
Primary Active Transport of Calcium Ions
Another important primary active transport mechanism
is the calcium pump. Calcium ions are normally maintained at extremely low concentration in the intracellular
cytosol of virtually all cells in the body, at a concentration
about 10,000 times less than that in the extracellular fluid.
This is achieved mainly by two primary active transport
calcium pumps. One is in the 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 cell, such as the sarcoplasmic reticulum of muscle cells and the mitochondria in all cells. In
each of these instances, the carrier protein penetrates the
membrane and functions as an enzyme ATPase, having
the same capability to cleave ATP as the ATPase of the
sodium carrier protein. The difference is that this protein
has a highly specific binding site for calcium instead of
for sodium.
Primary Active Transport of Hydrogen Ions
At two places in the body, primary active transport of
hydrogen ions is important: (1) in the gastric glands of the
stomach and (2) in the late distal tubules and cortical collecting ducts of the kidneys.
In the gastric glands, the deep-lying parietal cells have
the most potent primary active mechanism for transporting hydrogen ions of any part of the body. This is
the basis for secreting hydrochloric acid in the stomach
digestive secretions. At the secretory ends of the gastric gland parietal cells, the hydrogen ion concentration
is increased as much as a millionfold and then released
into the stomach along with chloride ions to form hydrochloric acid.
In the renal tubules are special intercalated cells in the
late distal tubules and cortical collecting ducts that also
transport hydrogen ions by primary active transport. In
this case, large amounts of hydrogen ions are secreted
from the blood into the urine for the purpose of eliminating excess hydrogen ions from the body fluids. The
hydrogen ions can be secreted into the urine against a
concentration gradient of about 900-fold.
Energetics of Primary Active Transport
The amount of energy required to transport a substance
actively through a membrane is determined by how
much the substance is concentrated during transport.
Compared with the energy required to concentrate a substance 10-fold, to concentrate it 100-fold requires twice
as much energy, and to concentrate it 1000-fold requires
three times as much energy. In other words, the energy
required is proportional to the logarithm of the degree
that the substance is concentrated, as expressed by the
following formula:
Energy(in calories per osmole)=1400 log
Thus, in terms of calories, the amount of energy
required to concentrate 1 osmole of a substance 10-fold
is about 1400 calories; or to concentrate it 100-fold, 2800
calories. One can see that the energy expenditure for concentrating substances in cells or for removing substances
from cells against a concentration gradient can be tremendous. Some cells, such as those lining the renal tubules
and many glandular cells, expend as much as 90 percent
of their energy for this purpose alone.
Secondary Active Transport—Co-Transport
and Counter-Transport
When sodium ions are transported out of cells by primary active transport, a large concentration gradient of
sodium ions across the cell membrane usually develops—
high concentration outside the cell and low concentration
inside. This gradient represents a storehouse of energy
because the excess sodium outside the cell membrane is
always attempting to diffuse to the interior. Under appropriate conditions, this diffusion energy of sodium can pull
other substances along with the sodium through the cell
membrane. This phenomenon is called co-transport; it is
one form of secondary active transport.
For sodium to pull another substance along with it,
a coupling mechanism is required. This is achieved by
means of still another carrier protein in the cell membrane. The carrier in this instance serves as an attachment
point for both the sodium ion and the substance to be
co-transported. Once they both are attached, the energy
gradient of the sodium ion causes both the sodium ion
and the other substance to be transported together to the
interior of the cell.
In counter-transport, sodium ions again attempt to
diffuse to the interior of the cell because of their large
concentration gradient. However, this time, the substance
to be transported is on the inside of the cell and must be
transported to the outside. Therefore, the sodium ion
binds to the carrier protein where it projects to the exterior surface of the membrane, while the substance to be
counter-transported binds to the interior projection of
the carrier protein. Once both have bound, a conformational change occurs, and energy released by the sodium
ion moving to the interior causes the other substance to
move to the exterior.
Co-Transport of Glucose and Amino Acids
Along with Sodium Ions
Glucose and many amino acids are transported into most
cells against large concentration gradients; the mechanism of this is entirely by co-transport, as shown in Figure
4-13. Note that the transport carrier protein has two
binding sites on its exterior side, one for sodium and one
Chapter 4 Transport of Substances Through Cell Membranes
Na+ Glucose
Figure 4-14 Sodium counter-transport of calcium and hydrogen
Figure 4-13 Postulated mechanism for sodium co-transport of
for glucose. Also, the concentration of sodium ions is high
on the outside and low inside, which provides energy for
the transport. A special property of the transport protein
is that a conformational change to allow sodium movement to the interior will not occur until a glucose molecule also attaches. When they both become attached,
the conformational change takes place automatically, and
the sodium and glucose are transported to the inside of
the cell at the same time. Hence, this is a sodium-glucose
co-transport mechanism. Sodium-glucose co-transporters are especially important mechanisms in transporting
glucose across renal and intestinal epithelial cells, as discussed in Chapters 27 and 65.
Sodium co-transport of the amino acids occurs in the
same manner as for glucose, except that it uses a different set of transport proteins. Five amino acid transport
proteins have been identified, each of which is responsible
for transporting one subset of amino acids with specific
molecular characteristics.
Sodium co-transport of glucose and amino acids
occurs especially through the epithelial cells of the intestinal tract and the renal tubules of the kidneys to promote
absorption of these substances into the blood, as is discussed in later chapters.
Other important co-transport mechanisms in at least
some cells include co-transport of chloride ions, iodine
ions, iron ions, and urate ions.
from the lumen of the tubule to the interior of the tubular cell, while hydrogen ions are counter-transported into
the tubule lumen. As a mechanism for concentrating
hydrogen ions, counter-transport is not nearly as powerful as the primary active transport of hydrogen ions that
occurs in the more distal renal tubules, but it can transport extremely large numbers of hydrogen ions, thus making it a key to hydrogen ion control in the body fluids, as
discussed in detail in Chapter 30.
Active Transport Through Cellular Sheets
At many places in the body, substances must be transported all the way through a cellular sheet instead of simply
through the cell membrane. Transport of this type occurs
through the (1) intestinal epithelium, (2) epithelium of
the renal tubules, (3) epithelium of all exocrine glands, (4)
epithelium of the gallbladder, and (5) membrane of the
choroid plexus of the brain and other membranes.
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 opposite side of the cell.
Figure 4-15 shows a mechanism for transport of
sodium ions through the epithelial sheet of the 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
Sodium Counter-Transport of Calcium
and Hydrogen Ions
Connective tissue
Two especially important counter-transport mechanisms
(transport in a direction opposite to the primary ion) are
sodium-calcium counter-transport and sodium-hydrogen
counter-transport (Figure 4-14).
Sodium-calcium counter-transport occurs through all
or almost all cell membranes, with sodium ions ­moving to
the interior and calcium ions to the exterior, both bound
to the same transport protein in a counter-transport
mode. This is in addition to primary active transport of
calcium that occurs in some cells.
Sodium-hydrogen counter-transport occurs in several
tissues. An especially important example is in the proximal tubules of the kidneys, where sodium ions move
Figure 4-15 Basic mechanism of active transport across a layer
of cells.
U n i t II
Unit II Membrane Physiology, Nerve, and Muscle
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 actively transported into the extracellular fluid of the surrounding
connective tissue and blood vessels. This creates a high
sodium ion concentration gradient across these membranes, which in turn causes osmosis of water as well.
Thus, active transport of sodium ions at the basolateral
sides of the epithelial cells results in transport not only
of sodium ions but also of water.
These are the mechanisms by which almost all the
nutrients, ions, and other substances are absorbed into the
blood from the intestine; they are also the way the same
substances are reabsorbed from the glomerular ­filtrate by
the renal tubules.
Throughout this text are numerous examples of the
different types of transport discussed in this chapter.
Agre P, Kozono D: Aquaporin water channels: molecular mechanisms for
human diseases, FEBS Lett 555:72, 2003.
Ashcroft FM: From molecule to malady, Nature 440:440, 2006.
Benos DJ, Stanton BA: Functional domains within the degenerin/epithelial sodium channel (Deg/ENaC) superfamily of ion channels, J Physiol
520:631, 1999.
Benziane B, Chibalin AV: Frontiers: skeletal muscle sodium pump regulation: a
translocation paradigm, Am J Physiol Endocrinol Metab 295:E553, 2008.
Biel M, Wahl-Schott C, Michalakis S, Zong X: Hyperpolarization-activated
cation channels: from genes to function, Physiol Rev 89:847, 2009.
Blaustein MP, Zhang J, Chen L, et al: The pump, the exchanger, and endogenous ouabain: signaling mechanisms that link salt retention to hypertension, Hypertension 53:291, 2009.
Bröer S: Amino acid transport across mammalian intestinal and renal
­epithelia, Physiol Rev 88:249, 2008.
DeCoursey TE: Voltage-gated proton channels: what’s next? J Physiol
586:5305, 2008.
Decoursey TE: Voltage-gated proton channels and other proton transfer
pathways, Physiol Rev 83:475, 2003.
DiPolo R, Beaugé L: Sodium/calcium exchanger: influence of metabolic regulation on ion carrier interactions, Physiol Rev 86:155, 2006.
Drummond HA, Jernigan NL, Grifoni SC: Sensing tension: epithelial sodium
channel/acid-sensing ion channel proteins in cardiovascular homeostasis, Hypertension 51:1265, 2008.
Gadsby DC: Ion channels versus ion pumps: the principal difference, in principle, Nat Rev Mol Cell Biol 10:344, 2009.
Jentsch TJ, Stein V, Weinreich F, Zdebik AA: Molecular structure and
physiological function of chloride channels, Physiol Rev 82:503,
Kaupp UB, Seifert R: Cyclic nucleotide-gated ion channels, Physiol Rev
82:769, 2002.
King LS, Kozono D, Agre P: From structure to disease: the evolving tale of
aquaporin biology, Nat Rev Mol Cell Biol 5:687, 2004.
Kleyman TR, Carattino MD, Hughey RP: ENaC at the cutting edge: regulation of epithelial sodium channels by proteases, J Biol Chem 284:20447,
Mazzochi C, Benos DJ, Smith PR: Interaction of epithelial ion channels with
the actin-based cytoskeleton, Am J Physiol Renal Physiol 291:F1113,
Peres A, Giovannardi S, Bossi E, Fesce R: Electrophysiological insights into
the mechanism of ion-coupled cotransporters, News Physiol Sci 19:80,
Russell JM: Sodium-potassium-chloride cotransport, Physiol Rev 80:211,
Shin JM, Munson K, Vagin O, Sachs G: The gastric HK-ATPase: structure,
function, and inhibition, Pflugers Arch 457:609, 2009.
Tian J, Xie ZJ: The Na-K-ATPase and calcium-signaling microdomains,
Physiology (Bethesda) 23:205, 2008.
chapter 5
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 generating rapidly changing
electrochemical impulses at their membranes, and these
impulses are used to transmit signals along the nerve or
muscle membranes. In 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 positivity 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 conditions, create a membrane potential. Later in 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.
Relation of the Diffusion Potential to the
Concentration Difference—The Nernst Potential.
The diffusion potential level across a membrane that
exactly opposes the net diffusion of a particular ion
through the membrane is called the Nernst potential
for that ion, a term that was introduced in Chapter 4.
Nerve fiber
(Anions)– Nerve fiber
– +
– +
+ –
– +
– + (Anions) +
– +
+ –
– +
– +
+ –
– +
– +
+ –
Na – +
– +
+ –
– +
– +
+ –
– +
– +
+ –
(–94 mV)
(+61 mV)
– +
– +
– +
+ –
– +
+ –
– +
Figure 5-1 A, Establishment of a “diffusion” potential across a nerve
fiber membrane, caused by diffusion of potassium ions from inside
the cell to outside through a membrane that is selectively permeable only to potassium. B, Establishment of a “diffusion potential”
when the nerve fiber membrane is permeable only to sodium ions.
Note that the internal membrane potential is negative when potassium ions diffuse and positive when sodium ions diffuse because of
opposite concentration gradients of these two ions.
U n i t II
Membrane Potentials and Action Potentials
Unit II Membrane Physiology, Nerve, and Muscle
The magnitude of this Nernst potential is determined by
the ratio of the concentrations of that specific ion on the
two sides of the membrane. The greater this ratio, the
greater the tendency for the ion to diffuse in one direction,
and therefore the greater the Nernst potential required
to prevent additional net diffusion. The following equation, called the Nernst equation, can be used to calculate
the Nernst potential for any univalent ion at normal body
temperature of 98.6°F (37°C):
EMF (millivolts) = ± 61 × log
Concentration inside
Concentration outside
where EMF is electromotive force.
When using this formula, it is usually assumed that
the potential in the extracellular fluid outside the membrane remains at zero potential, and the Nernst potential
is the potential inside the membrane. Also, the sign of the
potential is positive (+) if the ion diffusing from inside to
outside is a negative ion, and it is negative (−) if the ion is
positive. Thus, when the concentration of positive potassium ions on the inside is 10 times that on the outside, the
log of 10 is 1, so the Nernst potential calculates to be −61
millivolts inside the membrane.
Calculation of the Diffusion Potential When the
Membrane Is Permeable to Several Different Ions
When a membrane is permeable to several different ions,
the diffusion potential that develops depends on three factors: (1) the polarity of the electrical charge of each ion, (2)
the permeability of the membrane (P) to each ion, and (3) the
concentrations (C) of the respective ions on the inside (i) and
outside (o) of the membrane. Thus, the following formula,
called the Goldman equation, or the Goldman-HodgkinKatz equation, gives the calculated membrane potential on
the inside of the membrane when two univalent positive
ions, sodium (Na+) and potassium (K+), and one univalent
negative ion, chloride (Cl−), are involved.
EMF (millivolts)
CNa+i PNa+ + CK+i PK+ +CCl-o PCl= -61 × log
CNa+o PNa+ + CK+o PK+ +CCl-i PCl-
Let us study the importance and the meaning of this
equation. First, sodium, potassium, and chloride ions are
the most important ions involved in the development of
membrane potentials in nerve and muscle fibers, as well as
in the neuronal cells in the nervous system. The concentration gradient of each of these ions across the membrane
helps determine the voltage of the membrane potential.
Second, the degree of importance of each of the ions
in determining the voltage is proportional to the membrane permeability for that particular ion. That is, if the
membrane has zero permeability to both potassium and
chloride ions, the membrane potential becomes entirely
dominated by the concentration gradient of sodium ions
alone, and the resulting potential will be equal to the
Nernst potential for sodium. The same holds for each of
the other two ions if the membrane should become selectively permeable for either one of them alone.
Third, a positive ion concentration gradient from inside
the membrane to the outside causes electronegativity
inside the membrane. The reason for this is that excess positive ions diffuse to the outside when their concentration is
higher inside than outside. This carries positive charges to
the outside but leaves the nondiffusible negative anions on
the inside, thus creating electronegativity on the inside. The
opposite effect occurs when there is a gradient for a negative ion. That is, a chloride ion gradient from the outside to
the inside causes negativity inside the cell because excess
negatively charged chloride ions ­diffuse to the inside, while
leaving the nondiffusible positive ions on the outside.
Fourth, as explained later, the permeability of the
sodium and potassium channels undergoes rapid changes
during transmission of a nerve impulse, whereas the permeability of the chloride channels does not change greatly
during this process. Therefore, rapid changes in sodium
and potassium permeability are primarily responsible for
signal transmission in neurons, which is the subject of
most of the remainder of this chapter.
Measuring the Membrane Potential
The method for measuring the membrane potential is
simple in theory but often difficult in practice because
of the small size of most of the fibers. Figure 5-2 shows
a small pipette filled with an electrolyte solution. The
pipette is impaled through the cell membrane to 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 appropriate
voltmeter. This voltmeter is a highly sophisticated electronic apparatus that is capable of measuring small voltages despite extremely high resistance to electrical flow
through the tip of the micropipette, which has a lumen
diameter usually less than 1 micrometer and a resistance
more than a million ohms. For recording rapid changes
in the ­membrane potential during transmission of nerve
impulses, the microelectrode is connected to an oscilloscope, as explained later in the chapter.
The lower part of Figure 5-2 shows the electrical potential that is measured at each point in or near the nerve
fiber membrane, beginning at the left side of the figure and
– – – – – – – – – (–90 – – – – – – –
+ + + + + + + + + mV) + + + + + + + +
Figure 5-2 Measurement of the membrane potential of the nerve
fiber using a microelectrode.
Chapter 5 Membrane Potentials and Action Potentials
Nerve fiber
Electrical potential
Figure 5-3 Distribution of positively and negatively charged ions
in the extracellular fluid surrounding a nerve fiber and in the fluid
inside the fiber; note the alignment of negative charges along the
inside surface of the membrane and positive charges along the
outside surface. The lower panel displays the abrupt changes in
membrane potential that occur at the membranes on the two
sides of the fiber.
passing to the right. As long as the electrode is outside the
nerve membrane, the recorded potential is zero, which is
the potential of the extracellular fluid. Then, as the recording electrode passes through the voltage change area at the
cell membrane (called the electrical dipole layer), the potential decreases abruptly to −90 ­millivolts. Moving across the
center of the fiber, the potential remains at a steady −90-millivolt level but reverses back to zero the instant it passes
through the membrane on the opposite side of the fiber.
To create a negative potential inside the membrane,
only enough positive ions to develop the electrical dipole
layer at the membrane itself must be transported outward. All the remaining ions inside the nerve fiber can be
both positive and negative, as shown in the upper panel
of Figure 5-3. Therefore, an incredibly small number of
ions must be transferred through the membrane to establish the normal “resting potential” of −90 millivolts inside
the nerve fiber; this means that only about 1/3,000,000
to 1/100,000,000 of the total positive charges inside the
fiber must be transferred. Also, an equally small number
of positive ions moving from outside to inside the fiber
can reverse the potential from −90 millivolts to as much
as +35 millivolts within as little as 1/10,000 of a second.
Rapid shifting of ions in this manner causes the nerve signals discussed in subsequent sections of this chapter.
Active Transport of Sodium and Potassium Ions
Through the Membrane—The Sodium-Potassium
(Na+-K+) Pump. First, let us recall from Chapter 4 that
all cell membranes of the body have a powerful Na+-K+
pump that continually transports sodium ions to the outside of the cell and potassium ions to the inside, as illustrated on the left-hand side in Figure 5-4. Further, note
that this is an electrogenic pump because more positive
charges are pumped to the outside than to the inside
(three Na+ ions to the outside for each two K+ ions to the
inside), leaving a net deficit of positive ions on the inside;
this causes a negative potential inside the cell membrane.
The Na+-K+ pump also causes large concentration gradients for sodium and potassium across the resting nerve
membrane. These gradients are the following:
Na+ (outside): 142 mEq/L
Na+ (inside): 14 mEq/L
K+ (outside): 4 mEq/L
K+ (inside): 140 mEq/L
The ratios of these two respective ions from the inside to
the outside are
Na+inside/Na+outside = 0.1
K+inside/K+outside = 35.0
Leakage of Potassium Through the Nerve
Membrane. The right side of Figure 5-4 shows a chan-
nel protein, sometimes called a “tandem pore domain,”
­potassium channel, or potassium (K+) “leak” channel, in the
nerve membrane through which potassium can leak even
in a resting cell. The basic structure of potassium channels was described in Chapter 4 (Figure 4-4). These K+
leak channels may also leak sodium ions slightly but are far
more permeable to potassium than to sodium, normally
about 100 times as permeable. As discussed later, this differential in permeability is a key factor in determining the
level of the normal resting membrane potential.
Resting Membrane Potential of Nerves
The resting membrane potential of large nerve fibers
when not transmitting nerve signals is about −90 millivolts. That is, the potential inside the fiber is 90 millivolts
more negative than the potential in the extracellular fluid
on the outside of the fiber. In the next few paragraphs, the
transport properties of the resting nerve membrane for
sodium and potassium and the factors that determine the
level of this resting potential are explained.
Na -K pump
K+ "leak"
Figure 5-4 Functional characteristics of the Na+-K+ pump and of
the K+ “leak” channels. ADP, adenosine diphosphate; ATP, adenosine triphosphate. The K+ “leak” channels also leak Na+ ions into the
cell slightly, but are much more permeable to K+.
U n i t II
Unit II Membrane Physiology, Nerve, and Muscle
Origin of the Normal Resting Membrane Potential
Figure 5-5 shows the important factors in the establishment of the normal resting membrane potential of −90
millivolts. They are as follows.
Contribution of the Potassium Diffusion Potential.
In Figure 5-5A, we make the assumption that the only
movement of ions through the membrane is diffusion of
potassium ions, as demonstrated by the open channels
between the potassium symbols (K+) inside and outside
the membrane. Because of the high ratio of potassium
ions inside to outside, 35:1, the Nernst potential corresponding to this ratio is −94 millivolts because the logarithm of 35 is 1.54, and this multiplied by −61 millivolts is
−94 millivolts. Therefore, if potassium ions were the only
factor causing the resting potential, the resting potential
4 mEq/L
140 mEq/L
(–94 mV)
(−94 mV)
142 mEq/L
4 mEq/L
14 mEq/L
140 mEq/L
(+61 mV)
(–94 mV)
(–86 mV)
+ + Diffusion
+ 142 mEq/L + + + -
14 mEq/L
+ pump
+ 4 mEq/L + + + + (Anions)- + K+
140 mEq/L
(–90 mV)
Figure 5-5 Establishment of resting membrane potentials in
nerve fibers under three conditions: A, when the membrane
potential is caused entirely by potassium diffusion alone; B, when
the ­membrane 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 ions by the Na+-K+ pump.
Contribution of Sodium Diffusion Through the
Nerve Membrane. Figure 5-5B shows the addition of
slight permeability of the nerve membrane to sodium ions,
caused by the minute diffusion of sodium ions through
the K+-Na+ 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 millivolts. 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. Intuitively, one
can see that if the membrane is highly permeable to potassium but only slightly permeable to sodium, it is logical
that the diffusion of potassium contributes 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 inside the membrane of −86 millivolts, which is
near the potassium potential shown in the figure.
Contribution of the Na+-K+ Pump. In Figure 5-5C,
inside the fiber would be equal to −94 millivolts, as shown
in the figure.
the Na+-K+ pump is shown to provide an additional contribution 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 to the inside causes continual loss of positive charges from inside the membrane;
this creates an additional degree of negativity (about −4
millivolts additional) on the inside beyond that which can
be accounted for by 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
potassium and sodium diffusion would give a membrane
potential of about −86 millivolts, almost all of this being
determined by potassium diffusion. Then, an additional
−4 millivolts is contributed to the membrane potential by
the continuously acting electrogenic Na+-K+ pump, giving
a net membrane potential of −90 millivolts.
Nerve Action Potential
Nerve signals are transmitted by action potentials, which
are rapid changes in the membrane potential that spread
rapidly along the nerve fiber membrane. Each action
potential begins with a sudden change from the normal
resting negative membrane potential to a positive potential
and then ends with an almost equally rapid change back to
the negative potential. To conduct a nerve signal, the action
potential moves along the nerve fiber until it comes to the
fiber’s end.
Chapter 5 Membrane Potentials and Action Potentials
neurons, the potential merely approaches the zero level
and does not overshoot to the positive state.
De p
io n
0.1 0.2 0.3 0.4 0.5 0.6 0.7
Figure 5-6 Typical action potential recorded by the method
shown in the upper panel of the figure.
The upper panel of Figure 5-6 shows the changes that
occur at the membrane during the action potential, with
transfer of positive charges to the interior of the fiber at
its onset and return of positive charges to the exterior at
its end. The lower panel shows graphically the successive changes in membrane potential over a few 10,000ths
of a second, illustrating the explosive onset of the action
potential and the almost equally rapid recovery.
The successive stages of the action potential are as
Resting Stage. This is the resting membrane potential before the action potential begins. The membrane is
said to be “polarized” during this stage because of the −90
millivolts negative membrane potential that is present.
Depolarization Stage. At this time, the membrane
suddenly becomes permeable to sodium ions, allowing
tremendous numbers of positively charged sodium ions
to diffuse to the interior of the axon. The normal “polarized” state of −90 millivolts is immediately neutralized
by the inflowing positively charged sodium ions, with
the potential rising rapidly in the positive direction. This
is called depolarization. In large nerve fibers, the great
excess of positive sodium ions moving to the inside causes
the membrane potential to actually “overshoot” beyond
the zero level and to become somewhat positive. In some
smaller fibers, as well as in many central nervous system
Voltage-Gated Sodium and Potassium Channels
The necessary actor in causing both depolarization and
repolarization of the nerve membrane during the action
potential is the voltage-gated sodium channel. A voltagegated potassium channel also plays an important role in
increasing the rapidity of repolarization of the membrane.
These two voltage-gated channels are in addition to the
Na+-K+ pump and the K+ leak channels.
Voltage-Gated Sodium Channel—Activation
and Inactivation of the Channel
The upper panel of Figure 5-7 shows the voltage-gated
sodium channel in three separate states. This channel
has two gates—one near the outside of the channel called
the activation gate, and another near the inside called the
(−90 mV)
(−90 mV)
(−90 to +35 mV)
(+35 to −90 mV,
Slow activation
(+35 to −90 mV)
Figure 5-7 Characteristics of the voltage-gated sodium (top) and
potassium (bottom) channels, showing successive activation and
inactivation of the sodium channels and delayed activation of the
potassium channels when the membrane potential is changed
from the normal resting negative value to a positive value.
U n i t II
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. Then, rapid
diffusion of potassium ions to the exterior re-establishes
the normal negative resting membrane potential. This is
called repolarization of the membrane.
To explain more fully the factors that cause both depolarization and repolarization, we will describe the special
characteristics of two other types of transport channels
through the nerve membrane: the voltage-gated sodium
and potassium channels.
Unit II Membrane Physiology, Nerve, and Muscle
resting membrane potential within another few 10,000ths
of a second.
Research Method for Measuring the Effect of Voltage on
Opening and Closing of the Voltage-Gated Channels—The
“Voltage Clamp.” The original research that led to quantitative understanding of the sodium and potassium channels
was so ingenious that it led to Nobel Prizes for the scientists
responsible, Hodgkin and Huxley. The essence of these studies is shown in Figures 5-8 and 5-9.
Figure 5-8 shows an experimental apparatus called a voltage clamp, which is used to measure flow of ions through the
different channels. In using this apparatus, two electrodes are
inserted into the nerve fiber. One of these is to measure the
voltage of the membrane potential, and the other is to conduct
electrical current into or out of the nerve fiber. This apparatus
is used in the following way: The investigator decides which
voltage he or she wants to establish inside the nerve fiber.
The electronic portion of the apparatus is then adjusted to
the desired voltage, and this automatically injects either positive or negative electricity through the current electrode at
whatever rate is required to hold the voltage, as measured by
the voltage electrode, at the level set by the operator. When
the membrane potential is suddenly 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
in fluid
Figure 5-8 “Voltage clamp” method for studying flow of ions
through specific channels.
Na+ channel
–90 mV
K+ channel
Voltage-Gated Potassium Channel and Its Activation
The lower panel of Figure 5-7 shows the voltage-gated
potassium channel in two states: during the resting state
(left) and toward the end of the action potential (right).
During the resting state, the gate of the potassium channel
is closed and potassium ions are prevented from passing
through this channel to the exterior. When the membrane potential rises from −90 millivolts toward zero, this
voltage change causes a conformational opening of the
gate and allows increased potassium diffusion outward
through the channel. However, because of the slight delay
in opening of the potassium channels, for the most part,
they open just at the same time that the sodium channels
are beginning to close because of inactivation. Thus, the
decrease in sodium entry to the cell and the simultaneous
increase in potassium exit from the cell combine to speed
the repolarization process, leading to full recovery of the
inactivation gate. The upper left of the figure depicts the
state of these two gates in the normal resting membrane
when the membrane potential is −90 millivolts. In this
state, the activation gate is closed, which prevents any
entry of sodium ions to the interior of the fiber through
these sodium channels.
Activation of the Sodium Channel. When the
­membrane potential becomes less negative than during
the resting state, rising from −90 millivolts toward zero,
it finally reaches a voltage—usually somewhere between
−70 and −50 millivolts—that causes a sudden conformational change in the activation gate, flipping it all the way
to the open position. This is called the activated state;
during this state, sodium ions can pour inward through
the channel, increasing the sodium permeability of the
membrane as much as 500- to 5000-fold.
Inactivation of the Sodium Channel. The upper right
panel of Figure 5-7 shows a third state of the sodium
channel. The same increase in voltage that opens the
activation gate also closes the inactivation gate. The
­inactivation gate, however, closes a few 10,000ths of a
second after the activation gate opens. That is, the conformational change that flips the inactivation gate to the
closed state is a slower process than the conformational
change that opens the activation gate. Therefore, after the
sodium channel has remained open for a few 10,000ths
of a ­second, the inactivation gate closes, and sodium ions
no longer can pour to the inside of the membrane. At this
point, the membrane potential begins to recover back
toward the resting membrane state, which is the repolarization process.
Another important characteristic of the sodium
channel inactivation process is that the inactivation gate
will not reopen until the membrane potential returns to
or near the original resting membrane potential level.
Therefore, it is usually not possible for the sodium
channels to open again without first repolarizing the
nerve fiber.
t io
+10 mV
Membrane potential
Time (milliseconds)
–90 mV
Figure 5-9 Typical changes in conductance of sodium and potassium ion channels when the membrane potential is suddenly
increased from the normal resting value of −90 millivolts to a positive value of +10 millivolts for 2 milliseconds. This figure shows
that the sodium channels open (activate) and then close (inactivate) before the end of the 2 milliseconds, whereas the potassium
channels only open (activate), and the rate of opening is much
slower than that of the sodium channels.
Summary of the Events That Cause
the Action Potential
Figure 5-10 shows in summary form the sequential events
that occur during and shortly after the action potential.
The bottom of the figure shows the changes in membrane
conductance for sodium and potassium ions. During the
resting state, before the action potential begins, the conductance for potassium ions is 50 to 100 times as great
as the conductance for sodium ions. This is caused by
much greater leakage of potassium ions than sodium ions
through the leak channels. However, at the onset of the
action potential, the sodium channels instantaneously
become activated and allow up to a 5000-fold increase in
Action potential
Na+ conductance
K+ conductance
U n i t II
Ratio of conductances
the effect of these ion movements on the desired setting of
the intracellular voltage, electrical current is injected automatically 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 current flow through
the membrane channels. To measure how much current
flow is occurring at each instant, the current electrode is
connected to an oscilloscope 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 invertebrates, especially the giant squid axon, which in some cases is
as large as 1 millimeter in diameter. When 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
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 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, tetraethylammonium 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 the voltage clamp from −90 millivolts to +10 millivolts 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 after the membrane potential is increased to the positive value. However, during the
next millisecond or so, the sodium channels automatically
close (the inactivation stage).
Note the opening (activation) of the potassium channels.
These open slowly and reach their full open state only after
the sodium channels have almost completely closed. Further,
once the potassium channels open, they remain open for
the entire duration of the positive membrane potential and
do not close again until after the membrane potential is
decreased back to a negative value.
Membrane potential (mV)
Chapter 5 Membrane Potentials and Action Potentials
Figure 5-10 Changes in sodium and potassium conductance
during the course of the action potential. Sodium conductance
increases several thousand-fold during the early stages of the
action potential, whereas potassium conductance increases only
about 30-fold during the latter stages of the action potential and
for a short period thereafter. (These curves were constructed from
theory presented in papers by Hodgkin and Huxley but transposed
from squid axon to apply to the membrane potentials of large
mammalian nerve fibers.)
sodium conductance. Then the inactivation process closes
the sodium channels within another fraction of a millisecond. The onset of the action potential also causes voltage
gating of the potassium channels, causing them to begin
opening more slowly a fraction of a millisecond after the
sodium channels open. At the end of the action potential,
the return of the membrane potential to the negative state
causes the potassium channels to close back to their original status, but again, only after an additional millisecond
or more delay.
The middle portion of Figure 5-10 shows the ratio
of sodium conductance to potassium conductance at
each instant during the action potential, and above this
is the action potential itself. During the early portion of
the action potential, the ratio of sodium to potassium
conductance increases more than 1000-fold. Therefore,
far more sodium ions flow to the interior of the fiber
than do potassium ions to the exterior. This is what
causes the membrane potential to become positive at
the action potential onset. Then the sodium channels
begin to close and the potassium channels begin to
open, so the ratio of conductance shifts far in favor of
high potassium conductance but low sodium conductance. This allows very rapid loss of potassium ions to
the exterior but virtually zero flow of sodium ions to
the interior. Consequently, the action potential quickly
returns to its baseline level.
Unit II Membrane Physiology, Nerve, and Muscle
Roles of Other Ions During 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 considered: negative
anions and calcium ions.
Impermeant Negatively Charged Ions (Anions) Inside
the Nerve Axon. Inside the axon are many negatively
charged ions that cannot go through the membrane channels. They include the anions of protein molecules and of
many organic phosphate compounds, sulfate compounds,
and so forth. Because these ions cannot leave the interior of
the axon, any deficit of positive ions inside the membrane
leaves an excess of these impermeant negative anions.
Therefore, these impermeant negative ions are responsible
for the negative charge inside the fiber when there is a net
deficit of positively charged potassium ions and other positive ions.
Calcium Ions. The membranes of almost all cells of the
body have a calcium pump similar to the sodium pump, and
calcium serves along with (or instead of ) sodium in some cells
to cause most of the action potential. Like the sodium pump,
the calcium pump transports calcium ions from the interior
to the exterior of the cell membrane (or into the endoplasmic reticulum of the cell), creating a calcium ion gradient of
about 10,000-fold. This leaves an internal cell concentration
of calcium ions of about 10−7 molar, in contrast to an external
concentration of about 10−3 molar.
In addition, there are voltage-gated calcium channels.
Because calcium ion concentration is more than 10,000
times greater in the extracellular than the intracellular fluid,
there is a tremendous diffusion gradient for passive flow of
calcium ions into the cells. These channels are slightly permeable to sodium ions and calcium ions, but their permeability to calcium is about 1000-fold greater than to sodium
under normal physiological conditions. When they open in
response to a stimulus that depolarizes the cell membrane,
calcium ions flow to the interior of the cell.
A major function of the voltage-gated calcium ion channels is to contribute to the depolarizing phase on the action
potential in some cells. The gating of calcium channels,
however, is slow, requiring 10 to 20 times as long for activation as for the sodium channels. For this reason they are
often called slow channels, in contrast to the sodium channels, which are called fast channels. Therefore, the opening
of calcium channels provides a more sustained depolarization, whereas the sodium channels play a key role in initiating action potentials.
Calcium channels are numerous in both cardiac muscle
and smooth muscle. In fact, in some types of smooth muscle,
the fast sodium channels are hardly present; therefore, the
action potentials are caused almost entirely by activation of
slow calcium channels.
Increased Permeability of the Sodium Channels When
There Is a Deficit of Calcium Ions. The concentration of calcium ions in the extracellular fluid also has a profound effect
on the voltage level at which the sodium channels become
activated. When there is a deficit of calcium ions, the sodium
channels become activated (opened) by a small increase of
the membrane potential from its normal, very negative level.
Therefore, the nerve fiber becomes highly excitable, sometimes discharging repetitively without ­provocation rather
than remaining in the resting state. In fact, the calcium ion
concentration needs to fall only 50 percent below normal
before spontaneous discharge occurs in some peripheral
nerves, often causing muscle “tetany.” This is sometimes lethal
because of tetanic contraction of the respiratory muscles.
The probable way in which calcium ions affect the sodium
channels is as follows: These ions appear to bind to the exterior surfaces of the sodium channel protein molecule. The
positive charges of these calcium ions in turn alter the electrical state of the sodium channel protein itself, in this way
altering the voltage level required to open the sodium gate.
Initiation of the Action Potential
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.
A Positive-Feedback 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 millivolts
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 cycle that, once the feedback is strong enough, continues until all the voltagegated sodium channels have become activated (opened).
Then, within another fraction of a millisecond, the rising
membrane potential causes closure of the sodium channels and opening of potassium channels and the action
potential soon terminates.
Threshold for Initiation of the Action Potential. An
action potential will not occur until the initial rise in
membrane potential is great enough to create the positive feedback 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 the
fiber. A sudden rise in membrane potential of 15 to 30
millivolts is usually required. Therefore, a sudden increase
in the membrane potential in a large nerve fiber from −90
millivolts up to about −65 millivolts usually causes the
explosive development of an action potential. This level of
−65 millivolts is said to be the threshold for stimulation.
Propagation of the Action Potential
In the preceding paragraphs, we discussed the action
potential as it occurs at one spot on the membrane.
However, an action potential elicited at any one point on
an excitable membrane usually excites adjacent portions
of the membrane, resulting in propagation of the action
Chapter 5 Membrane Potentials and Action Potentials
Figure 5-11 Propagation of action potentials in both directions
along a conductive fiber.
potential along the membrane. This mechanism is demonstrated in Figure 5-11. Figure 5-11A shows a normal
resting nerve fiber, and Figure 5-11B shows a nerve fiber
that has been excited in its midportion—that is, the
midportion suddenly develops increased permeability to
sodium. The arrows show a “local circuit” of current flow
from the depolarized areas of the membrane to the adjacent resting membrane areas. That is, positive electrical
charges are carried by the inward-diffusing sodium ions
through the depolarized membrane and then for several millimeters in both directions along the core of the
axon. These positive charges increase the voltage for a
distance of 1 to 3 millimeters inside the large myelinated
fiber to above the threshold voltage value for initiating
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 potential 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 transmission of the depolarization process along a nerve or muscle fiber is called a
nerve or muscle impulse.
Direction of Propagation. As demonstrated in
Figure 5-11, an excitable membrane has no single direction of propagation, but the action potential travels in
all directions away from the stimulus—even along all
branches of a nerve fiber—until the entire membrane has
become depolarized.
Re-establishing Sodium and Potassium
Ionic Gradients After Action Potentials
Are Completed—Importance of Energy
The transmission of each action potential along a nerve
fiber reduces slightly the concentration differences of
sodium and potassium inside and outside the membrane
because sodium ions diffuse to the inside during depolarization and potassium ions diffuse to the outside during repolarization. For a single action potential, this effect
is so minute that it cannot be measured. Indeed, 100,000
to 50 million impulses can be transmitted by large nerve
fibers before the concentration differences reach the point
that action potential conduction ceases. Even so, with
time, it becomes necessary to re-establish the sodium and
potassium membrane concentration differences. This is
achieved by action of the Na+-K+ pump in the same way as
described previously in the chapter for the original establishment of the resting potential. That is, sodium ions
that have diffused to the interior of the cell during the
action potentials and potassium ions that have diffused
to the exterior must be returned to their original state by
the Na+-K+ pump. Because this pump requires energy for
operation, this “recharging” of the nerve fiber is an active
metabolic process, using energy derived from the adeno­
sine triphosphate (ATP) energy system of the cell. Figure
5-12 shows that the nerve fiber produces excess heat during recharging, which is a measure of energy expenditure
when the nerve impulse frequency increases.
A special feature of the Na+-K+ ATPase pump is that
its degree of activity is strongly stimulated when excess
sodium ions accumulate inside the cell membrane. In fact,
the pumping activity increases approximately in proportion to the third power of this intracellular sodium concentration. That is, as the internal sodium concentration rises
from 10 to 20 mEq/L, the activity of the pump does not
merely double but increases about eightfold. Therefore, it
is easy to understand how the “recharging” process of the
nerve fiber can be set rapidly into motion whenever the
concentration differences of sodium and potassium ions
across the membrane begin to “run down.”
U n i t II
All-or-Nothing Principle. Once an action ­potential
has been elicited at any point on the membrane of a
­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 the
all-or-nothing principle, and it applies to all normal excitable tissues. Occasionally, the action potential reaches a
point on the membrane at which it does not generate sufficient voltage to stimulate the next area of the membrane.
When this occurs, the spread of depolarization stops.
Therefore, for continued propagation of an impulse to
occur, the ratio of action potential to threshold for excitation must at all times be greater than 1. This “greater than
1” requirement is called the safety factor for propagation.
Unit II Membrane Physiology, Nerve, and Muscle
Heat production
A second factor that may be partly responsible for the
plateau is that the voltage-gated potassium channels are
slower than usual to open, often not opening much until
the end of the plateau. This delays the return of the membrane potential toward its normal negative value of −80
to −90 millivolts.
At rest
Impulses per second
Figure 5-12 Heat production in a nerve fiber at rest and at
­progressively increasing rates of stimulation.
Plateau in Some Action Potentials
In some instances, the excited membrane does not
repolarize immediately after depolarization; instead,
the potential remains on a plateau near the peak of the
spike potential for many milliseconds, and only then
does repolarization begin. Such a plateau is shown in
Figure 5-13; one can readily see that the plateau greatly
prolongs the period of depolarization. This type of
action potential occurs in heart muscle fibers, where
the plateau lasts for as long as 0.2 to 0.3 second and
causes contraction of heart muscle to last for this same
long period.
The cause of the plateau is a combination of several
factors. First, in heart muscle, two types of channels
enter into the depolarization process: (1) the usual
voltage-activated sodium channels, called fast channels, and (2) voltage-activated calcium-sodium channels, which are slow to open and therefore are called
slow channels. Opening of fast channels causes the
spike portion of the action potential, whereas the prolonged opening of the slow calcium-sodium channels
mainly allows calcium ions to enter the fiber, which is
largely responsible for the plateau portion of the action
potential as well.
Rhythmicity of Some Excitable Tissues—
Repetitive Discharge
Repetitive self-induced discharges occur normally in the
heart, in most smooth muscle, and in many of the neurons of the central nervous system. These rhythmical
discharges cause (1) the rhythmical beat of the heart, (2)
rhythmical peristalsis of the intestines, and (3) such neuronal events as the rhythmical control of breathing.
Also, almost all other excitable tissues can discharge
repetitively if the threshold for stimulation of the ­tissue
cells is reduced low enough. For instance, even large
nerve fibers and skeletal muscle fibers, which normally
are highly stable, discharge repetitively when they are
placed in a solution that contains the drug veratrine or
when the calcium ion concentration falls below a critical
value, both of which increase sodium permeability of the
Re-excitation Process Necessary for Sponta­
neous Rhythmicity. For spontaneous rhythmicity to
occur, the membrane even in its natural state must be permeable enough to sodium ions (or to calcium and sodium
ions through the slow calcium-sodium channels) to allow
automatic membrane depolarization. Thus, Figure 5-14
shows that the “resting” membrane potential in the rhythmical control center of the heart is only −60 to −70 millivolts. This is not enough negative voltage to keep the
sodium and calcium channels totally closed. Therefore,
the following sequence occurs: (1) some sodium and
­calcium ions flow inward; (2) this increases the membrane
voltage in the positive direction, which further increases
membrane permeability; (3) still more ions flow inward;
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9
Figure 5-13 Action potential (in millivolts) from a Purkinje fiber
of the heart, showing a “plateau.”
conductance potentials Threshold
Figure 5-14 Rhythmical action potentials (in millivolts) similar to
those recorded in the rhythmical control center of the heart. Note
their relationship to potassium conductance and to the state of
Chapter 5 Membrane Potentials and Action Potentials
U n i t II
and (4) the permeability increases more, and so on, until
an action potential is generated. Then, at the end of the
action potential, the membrane repolarizes. After another
delay of milliseconds or seconds, spontaneous excitability causes depolarization again and a new action potential occurs spontaneously. This cycle continues over and
over and causes self-induced rhythmical excitation of the
excitable tissue.
Why does the membrane of the heart control center
not depolarize immediately after it has become repolarized, rather than delaying for nearly a second before the
onset of the next action potential? The answer can be
found by observing the curve labeled “potassium conductance” in Figure 5-14. This shows that toward the end of
each action potential, and continuing for a short period
thereafter, the membrane becomes more permeable to
potassium ions. The increased outflow of potassium ions
carries tremendous numbers of positive charges to the
outside of the membrane, leaving inside the fiber considerably more negativity than would otherwise occur. This
continues for nearly a second after the preceding action
potential is over, thus drawing the membrane potential
nearer to the potassium Nernst potential. This is a state
called hyperpolarization, also shown in Figure 5-14. As
long as this state exists, self-re-excitation will not occur.
But the increased potassium conductance (and the state
of hyperpolarization) gradually disappears, as shown after
each action potential is completed in the figure, thereby
allowing the membrane potential again to increase up to
the threshold for excitation. Then, suddenly, a new action
potential results and the process occurs again and again.
Figure 5-15 Cross section of a small nerve trunk containing both
myelinated and unmyelinated fibers.
Schwann cell
Schwann cell
Special Characteristics of Signal Transmission
in Nerve Trunks
Myelinated and Unmyelinated Nerve Fibers. Figure
5-15 shows a cross section of a typical small nerve, revealing
many large nerve fibers that constitute most of the cross-sectional area. However, a more careful look reveals many more
small fibers lying between the large ones. The large fibers are
myelinated, and the small ones are unmyelinated. The average nerve trunk contains about twice as many unmyelinated
fibers as myelinated fibers.
Figure 5-16 shows a typical myelinated fiber. The central
core of the fiber is the axon, and the membrane of the axon
is the membrane that actually conducts the action potential. The axon is filled in its center with axoplasm, which is
a viscid intracellular fluid. Surrounding the axon is a myelin
sheath that is often much thicker than the axon itself. About
once every 1 to 3 millimeters along the length of the myelin
sheath is a node of Ranvier.
The myelin sheath is deposited around the axon by
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, laying down multiple
layers of Schwann cell membrane containing the lipid substance sphingomyelin. This substance is an excellent electrical insulator that decreases ion flow through the membrane
about 5000-fold. At the juncture between each two successive
Node of Ranvier
Unmyelinated axons
Schwann cell nucleus
Schwann cell cytoplasm
Figure 5-16 Function of the Schwann cell to insulate nerve fibers.
A, Wrapping of a Schwann cell membrane around a large axon to
form the myelin sheath of the myelinated nerve fiber. B, Partial
wrapping of the membrane and cytoplasm of a Schwann cell
around multiple unmyelinated nerve fibers (shown in cross section).
(A, Modified from Leeson TS, Leeson R: Histology. Philadelphia: WB
Saunders, 1979.)
Schwann cells along the axon, a small uninsulated area only 2
to 3 micrometers in length remains where ions still can flow
with ease through the axon membrane between the extracellular fluid and the intracellular fluid inside the axon. This area
is called the node of Ranvier.
Unit II Membrane Physiology, Nerve, and Muscle
Node of Ranvier
Figure 5-17 Saltatory conduction along a myelinated axon.
Flow of electrical current from node to node is illustrated by the
“Saltatory” Conduction in Myelinated Fibers from Node
to Node. Even though almost no ions can flow through the
thick myelin sheaths of myelinated nerves, they can flow
with ease through the nodes of Ranvier. Therefore, action
potentials occur only at the nodes. Yet the action potentials
are conducted from node to node, as shown in Figure 5-17;
this is called saltatory conduction. That is, electrical current
flows through the surrounding extracellular fluid outside
the myelin sheath, as well as through the axoplasm inside
the axon from node to node, exciting successive nodes one
after another. Thus, the nerve impulse jumps along the fiber,
which is the origin of the term “saltatory.”
Saltatory conduction is of value for two reasons. First, by
causing the depolarization process to jump long intervals
along the axis of the nerve fiber, this mechanism increases
the velocity of nerve transmission in myelinated fibers as
much as 5- to 50-fold. Second, saltatory conduction conserves energy for the axon because only the nodes depolarize, allowing perhaps 100 times less loss of ions than would
otherwise be necessary, and therefore requiring little metabolism for re-establishing the sodium and potassium concentration differences across the membrane after a series of
nerve impulses.
Still another feature of saltatory conduction in large
myelinated fibers is the following: The excellent insulation
afforded by the myelin membrane and the 50-fold decrease
in membrane capacitance allow repolarization to occur with
little transfer of ions.
Velocity of Conduction in Nerve Fibers. The velocity
of action potential conduction in nerve fibers varies from as
­little as 0.25 m/sec in small unmyelinated fibers to as great as
100 m/sec (the length of a football field in 1 second) in large
myelinated fibers.
Excitation—The Process of Eliciting the Action
Basically, any factor that causes sodium ions to begin to diffuse inward through the membrane in sufficient numbers
can set off automatic regenerative opening of the sodium
channels. This can result from mechanical disturbance
of the membrane, chemical effects on the membrane, or
­passage of electricity through the membrane. All these are
used at different points in the body to elicit nerve or muscle
action potentials: mechanical pressure to excite sensory
nerve ­endings in the skin, chemical neurotransmitters to
transmit signals from one neuron to the next in the brain,
and electrical current to transmit signals between successive muscle cells in the heart and intestine. For the purpose
of understanding the excitation process, let us begin by discussing the principles of electrical stimulation.
Excitation of a Nerve Fiber by a Negatively Charged
Metal Electrode. The usual means for exciting a nerve or
muscle in the experimental laboratory is to apply electricity to the nerve or muscle surface through two small electrodes, one of which is negatively charged and the other
positively charged. When this is done, the excitable membrane becomes stimulated at the negative electrode.
The cause of this effect is the following: Remember that
the action potential is initiated by the opening of voltagegated sodium channels. Further, these channels are opened
by a decrease in the normal resting electrical voltage across
the membrane. That is, negative current from the electrode
decreases the voltage on the outside of the membrane to a
negative value nearer to the voltage of the negative potential inside the fiber. This decreases the electrical voltage
across the membrane and allows the sodium channels to
open, resulting in an action potential. Conversely, at the
positive electrode, the injection of positive charges on
the outside of the nerve membrane heightens the voltage
difference across the membrane rather than lessening it.
This causes a state of hyperpolarization, which actually
decreases the excitability of the fiber rather than causing
an action potential.
Threshold for Excitation, and “Acute Local Potentials.”
A weak negative electrical stimulus may not be able to
excite a fiber. However, when the voltage of the stimulus is
increased, there comes a point at which excitation does take
place. Figure 5-18 shows the effects of successively applied
stimuli of progressing strength. A weak stimulus at point A
causes the membrane potential to change from −90 to −85
millivolts, but this is not a sufficient change for the automatic
regenerative processes of the action potential to develop.
At point B, the stimulus is greater, but again, the intensity
is still not enough. The stimulus does, however, disturb the
membrane potential locally for as long as 1 millisecond or
more after both of these weak stimuli. These local potential
changes are called acute local potentials, and when they fail
to elicit an action potential, they are called acute subthreshold potentials.
Action potentials
Myelin sheath
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 action potential.
Chapter 5 Membrane Potentials and Action Potentials
“Refractory Period” After an Action Potential, During
Which a New Stimulus Cannot Be Elicited
A new action potential cannot occur in an excitable fiber
as long as the membrane is still depolarized from the preceding action potential. The reason for this is that shortly
after the action potential is initiated, the sodium channels
(or ­calcium channels, or both) become inactivated and no
amount of excitatory signal applied to these channels at this
point will open the inactivation gates. The only condition
that will allow them to reopen is for the membrane potential
to return to or near the original resting membrane potential level. Then, within another small fraction of a second,
the inactivation gates of the channels open and a new action
potential can be initiated.
The period during which a second action potential cannot be elicited, even with a strong stimulus, is called the absolute refractory period. This period for large myelinated nerve
fibers is about 1/2500 second. Therefore, one can readily calculate that such a fiber can transmit a maximum of about
2500 impulses per second.
Inhibition of Excitability—“Stabilizers” and Local
In contrast to the factors that increase nerve excitability, still others, called membrane-stabilizing factors, can
decrease excitability. For instance, a high extracellular fluid
calcium ion concentration decreases membrane permeability to sodium ions and simultaneously reduces excitability.
Therefore, calcium ions are said to be a “stabilizer.”
Local Anesthetics. Among the most important stabilizers are the many substances used clinically as local anesthetics, including procaine and tetracaine. Most of these
act directly on the activation gates of the sodium channels, making it much more difficult for these gates to open,
thereby reducing membrane excitability. When excitability
has been reduced so low that the ratio of action potential
strength to excitability threshold (called the “safety factor”)
is reduced below 1.0, nerve impulses fail to pass along the
anesthetized nerves.
Recording Membrane Potentials
and Action Potentials
Cathode Ray Oscilloscope. Earlier in this chapter, we
noted that the membrane potential changes extremely rapidly during the course of an action potential. Indeed, most of
the action potential complex of large nerve fibers takes place
in less than 1/1000 second. In some figures of this chapter,
an electrical meter has been shown recording these potential changes. However, it must be understood that any meter
capable of recording most action potentials must be capable
action potential
Electron gun
sweep circuit
Figure 5-19 Cathode ray oscilloscope for recording transient
action potentials.
of responding extremely rapidly. For practical purposes, the
only common type of meter that is capable of responding
accurately to the rapid membrane potential changes is the
cathode ray oscilloscope.
Figure 5-19 shows the basic components of a cathode
ray oscilloscope. The cathode ray tube itself is composed
basically of an electron gun and a fluorescent screen against
which electrons are fired. Where the electrons hit the screen
­surface, the fluorescent material glows. If the electron beam
is moved across the screen, the spot of glowing light also
moves and draws a fluorescent line on the screen.
In addition to the electron gun and fluorescent surface,
the cathode ray tube is provided with two sets of electrically
charged plates—one set positioned on the two sides of the
electron beam, and the other set positioned above and below.
Appropriate electronic control circuits change the voltage
on these plates so that the electron beam can be bent up or
down in response to electrical signals coming from recording electrodes on nerves. The beam of electrons also is swept
horizontally across the screen at a constant time rate by an
internal electronic circuit of the oscilloscope. This gives the
record shown on the face of the cathode ray tube in the figure, giving a time base horizontally and voltage changes from
the nerve electrodes shown vertically. Note at the left end of
the record a small stimulus artifact caused by the electrical
stimulus used to elicit the nerve action potential. Then further to the right is the recorded action potential itself.
Alberts B, Johnson A, Lewis J, et al: Molecular Biology of the Cell, ed 3, New
York, 2008, Garland Science.
Biel M, Wahl-Schott C, Michalakis S, Zong X: Hyperpolarization-activated
cation channels: from genes to function, Physiol Rev 89:847, 2009.
Blaesse P, Airaksinen MS, Rivera C, Kaila K: Cation-chloride cotransporters
and neuronal function, Neuron 61:820, 2009.
Dai S, Hall DD, Hell JW: Supramolecular assemblies and localized regulation
of voltage-gated ion channels, Physiol Rev 89:411, 2009.
Hodgkin AL, Huxley AF: Quantitative description of membrane current and
its application to conduction and excitation in nerve, J Physiol (Lond)
117:500, 1952.
Kandel ER, Schwartz JH, Jessell TM: Principles of Neural Science, ed 4, New
York, 2000, McGraw-Hill.
U n i t II
At point C in Figure 5-18, the stimulus is even stronger.
Now the local potential has barely reached the level required
to elicit an action potential, called the threshold level, but this
occurs only after a short “latent period.” At point D, the stimulus is still stronger, the acute local potential is also stronger,
and the action potential occurs after less of a latent period.
Thus, this figure shows that even a weak stimulus causes
a local potential change at the membrane, but the intensity
of the local potential must rise to a threshold level before the
action potential is set off.
Unit II Membrane Physiology, Nerve, and Muscle
Kleber AG, Rudy Y: Basic mechanisms of cardiac impulse propagation and
associated arrhythmias, Physiol Rev 84:431, 2004.
Luján R, Maylie J, Adelman JP: New sites of action for GIRK and SK channels,
Nat Rev Neurosci 10:475, 2009.
Mangoni ME, Nargeot J: Genesis and regulation of the heart automaticity,
Physiol Rev 88:919, 2008.
Perez-Reyes E: Molecular physiology of low-voltage-activated T-type
­calcium channels, Physiol Rev 83:117, 2003.
Poliak S, Peles E: The local differentiation of myelinated axons at nodes of
Ranvier, Nat Rev Neurosci 12:968, 2003.
Schafer DP, Rasband MN: Glial regulation of the axonal membrane at
nodes of Ranvier, Curr Opin Neurobiol 16:508, 2006.
Vacher H, Mohapatra DP, Trimmer JS: Localization and targeting of
­voltage-dependent ion channels in mammalian central neurons, Physiol
Rev 88:1407, 2008.
chapter 6
About 40 percent of the
body is skeletal muscle, and
perhaps another 10 percent is smooth and cardiac
muscle. Some of the same
basic principles of contraction apply to all three 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 percent of the
fibers, each fiber is usually innervated by only one nerve
ending, located near the middle of the fiber.
The Sarcolemma Is a Thin Membrane Enclosing a
Skeletal Muscle Fiber. The sarcolemma 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. The tendon fibers in
turn collect into bundles to form the muscle tendons that
then insert into the bones.
Myofibrils Are Composed of 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 filaments, which are large polymerized protein molecules that are responsible for the actual muscle
contraction. These can be seen in longitudinal view in the
electron 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 interdigitate 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 interdigitate with the myosin filaments. The Z disc, which itself
is composed of filamentous proteins different from the
actin and myosin filaments, passes crosswise across the
myofibril and also crosswise from myofibril to myofibril,
attaching the myofibrils to one another all the way across
the muscle fiber. Therefore, the entire muscle fiber has
light and dark bands, as do the individual myofibrils.
These bands give skeletal and cardiac muscle their striated appearance.
The portion of the myofibril (or of the whole muscle
fiber) that lies between two successive Z discs is called
a sarcomere. When the muscle fiber is contracted, as
shown at the bottom of Figure 6-5, the length of the sarcomere is about 2 micrometers. At this length, the actin
filaments completely overlap the myosin filaments,
and the tips of the actin filaments are just beginning to
overlap one another. As discussed later, at this length
the muscle is capable of generating its greatest force of
U n i t II
Contraction of Skeletal Muscle
Unit II Membrane Physiology, Nerve, and Muscle
Muscle fasciculus
Muscle fiber
G-Actin molecules
F-Actin filament
Myosin filament
Myosin molecule
Figure 6-1 Organization of skeletal muscle, from the gross to the molecular level. F, G, H, and I are cross sections at the levels indicated.
Chapter 6 Contraction of Skeletal Muscle
Sarcoplasmic Reticulum Is a Specialized
Endoplasmic Reticulum of Skeletal Muscle. Also in
Figure 6-2 Electron micrograph of muscle myofibrils showing
the detailed organization of actin and myosin filaments. Note the
mitochondria lying between the myofibrils. (From Fawcett DW:
The Cell. Philadelphia: WB Saunders, 1981.)
Titin Filamentous Molecules Keep the Myosin and
Actin Filaments in Place. The side-by-side relation-
ship between the myosin and actin filaments is difficult to
maintain. This is achieved by a large number of filamentous molecules of a protein called titin (Figure 6-3). Each
titin molecule has a molecular weight of about 3 million,
which makes it one of the largest protein molecules in the
body. Also, because it is filamentous, it is very springy.
These springy titin molecules act as a framework that
holds the myosin and actin filaments in place so that the
contractile machinery of the sarcomere will work. One
end of the titin molecule is elastic and is attached to the
Z disk, acting as a spring and changing length as the sarcomere contracts and relaxes. The other part of the titin
molecule tethers it to the myosin thick filament. The titin
molecule itself also appears to act as a template for initial
formation of portions of the contractile filaments of the
sarcomere, especially the myosin filaments.
the sarcoplasm surrounding the myofibrils of each muscle
fiber is an extensive reticulum (Figure 6-4), called the sarcoplasmic reticulum. This reticulum has a special organization that is extremely important in controlling muscle
contraction, as discussed in Chapter 7. The rapidly contracting types of muscle fibers have especially extensive
sarcoplasmic reticula.
General Mechanism of Muscle Contraction
The initiation and execution of muscle contraction occur
in the following sequential steps.
1. An action potential travels along a motor nerve to its
endings on muscle fibers.
2. At each ending, the nerve secretes a small amount of
the neurotransmitter substance acetylcholine.
3. The acetylcholine acts on a local area of the muscle
fiber membrane to open multiple “acetylcholine-gated”
cation channels through protein molecules floating in
the membrane.
4. Opening of the acetylcholine-gated channels allows
large quantities of sodium ions to diffuse to the interior of the muscle fiber membrane. This causes a
local depolarization that in turn leads to opening of
Sarcoplasm Is the Intracellular Fluid Between
Myofibrils. The many myofibrils of each muscle fiber
are suspended side by side in the muscle fiber. The spaces
between the myofibrils are filled with intracellular fluid
Myosin (thick filament)
Actin (thin filament)
M line
Z disc
Figure 6-3 Organization of proteins in a sarcomere. Each titin
molecule extends from the Z disc to the M line. Part of the titin
molecule is closely associated with the myosin thick filament,
whereas the rest of the molecule is springy and changes length as
the sarcomere contracts and relaxes.
Figure 6-4 Sarcoplasmic reticulum in the extracellular spaces
between the myofibrils, showing a longitudinal system paralleling
the myofibrils. Also shown in cross section are T tubules (arrows) that
lead to the exterior of the fiber membrane and are important for
conducting the electrical signal into the center of the muscle fiber.
(From Fawcett DW: The Cell. Philadelphia: WB Saunders, 1981.)
U n i t II
called sarcoplasm, containing large quantities of potassium, magnesium, and phosphate, plus multiple protein
enzymes. Also present are tremendous numbers of mitochondria that lie parallel to the myofibrils. These supply
the contracting myofibrils with large amounts of energy
in the form of adenosine triphosphate (ATP) formed by
the mitochondria.
Unit II Membrane Physiology, Nerve, and Muscle
v­ oltage-gated sodium channels. This initiates an action
potential at the membrane.
The action potential travels along the muscle fiber
membrane in the same way that action potentials travel
along nerve fiber membranes.
The action potential depolarizes the muscle membrane, and much of the action potential electricity
flows through the center of the muscle fiber. Here it
causes the sarcoplasmic reticulum to release large
quantities of calcium ions that have been stored within
this reticulum.
The calcium ions initiate attractive forces between
the actin and myosin filaments, causing them to slide
alongside each other, which is the contractile process.
After a fraction of a second, the calcium ions are
pumped back into the sarcoplasmic reticulum by a
Ca++ membrane pump and remain stored in the reticulum until a new muscle action potential comes along;
this removal of calcium ions from the myofibrils causes
the muscle contraction to cease.
We now describe the molecular machinery of the muscle contractile process.
Molecular Mechanism of Muscle
Sliding Filament Mechanism of Muscle Con­
t­raction. Figure 6-5 demonstrates the basic mecha-
nism of muscle contraction. It shows the relaxed state of
a sarcomere (top) and the contracted state (bottom). In
the relaxed state, the ends of the actin filaments extending from two successive Z discs barely begin to overlap
one another. Conversely, in the contracted state, these
actin filaments have been pulled inward among the myosin filaments, so their ends overlap one another to their
­ aximum extent. Also, the Z discs have been pulled by
the actin filaments up to the ends of the myosin filaments. Thus, muscle contraction occurs by a sliding filament mechanism.
But what causes the actin filaments to slide inward
among the myosin filaments? This is caused by forces
generated by interaction of the cross-bridges from the
myosin filaments with the actin filaments. Under resting
conditions, these forces are inactive. But when an action
potential travels along the muscle fiber, this causes the
sarcoplasmic reticulum to release large quantities of calcium ions that rapidly surround the myofibrils. The calcium ions in turn activate the forces between the myosin
and actin filaments, and contraction begins. But energy
is needed for the contractile process to proceed. This
energy comes from high-energy bonds in the ATP
molecule, which is degraded to adenosine diphosphate
(ADP) to liberate the energy. In the next few sections,
we describe what is known about the details of these
molecular processes of contraction.
Molecular Characteristics of the Contractile
Myosin Filaments Are Composed of Multiple
Myosin Molecules. Each of the myosin molecules, shown
in Figure 6-6A, has a molecular weight of about 480,000.
Figure 6-6B shows the organization of many molecules
to form a myosin filament, as well as interaction of this
­filament on one side with the ends of two actin filaments.
The myosin molecule (see Figure 6-6A) is composed
of six polypeptide chains—two heavy chains, each with a
molecular weight of about 200,000, and four light chains
with molecular weights of about 20,000 each. The two heavy
chains wrap spirally around each other to form a double
Two heavy chains
Light chains
Actin filaments
Figure 6-5 Relaxed and contracted states of a myofibril showing
(top) sliding of the actin filaments (pink) into the spaces between
the myosin filaments (red) and (bottom) pulling of the Z membranes toward each other.
Myosin filament
Figure 6-6 A, Myosin molecule. B, Combination of many myosin
molecules to form a myosin filament. Also shown are thousands
of myosin cross-bridges and interaction between the heads of the
cross-bridges with adjacent actin filaments.
Chapter 6 Contraction of Skeletal Muscle
ATPase Activity of the Myosin Head. Another feature of the myosin head that is essential for muscle contraction is that it functions as an ATPase enzyme. As explained
later, this property allows the head to cleave ATP and use
the energy derived from the ATP’s high-energy phosphate
bond to energize the contraction process.
Actin Filaments Are Composed of Actin,
Tropomyosin, and Troponin. The backbone of the actin
filament is a double-stranded F-actin protein molecule, represented by the two lighter-colored strands in Figure 6-7.
The two strands are wound in a helix in the same manner
as the myosin molecule.
Each strand of the double F-actin helix is composed
of polymerized G-actin molecules, each having a molecular weight of about 42,000. Attached to each one of the
G-actin molecules is one molecule of ADP. It is believed
that these ADP molecules are the active sites on the actin
filaments with which the cross-bridges of the myosin filaments interact to cause muscle contraction. The active
sites on the two F-actin strands of the double helix are
staggered, giving one active site on the overall actin filament about every 2.7 nanometers.
Active sites
Troponin complex
Figure 6-7 Actin filament, composed of two helical strands of
F-actin molecules and two strands of tropomyosin molecules that
fit in the grooves between the actin strands. Attached to one end
of each tropomyosin molecule is a troponin complex that initiates
Each actin filament is about 1 micrometer long. The
bases of the actin filaments are inserted strongly into the
Z discs; the ends of the filaments protrude in both directions to lie in the spaces between the myosin molecules,
as shown in Figure 6-5.
Tropomyosin Molecules. The actin filament also
contains another protein, tropomyosin. Each molecule of
tropomyosin has a molecular weight of 70,000 and a length
of 40 nanometers. These molecules are wrapped spirally
around the sides of the F-actin helix. In the resting state,
the tropomyosin molecules lie on top of the active sites of
the actin strands so that attraction cannot occur between the
actin and myosin filaments to cause contraction.
Troponin and Its Role in Muscle ­Contra­ct­ ion.
Attached intermittently along the sides of the tropomyosin molecules are still other protein molecules called
troponin. These are actually complexes of three loosely
bound protein subunits, each of which plays a specific
role in controlling muscle contraction. One of the subunits (troponin I) has a strong affinity for actin, another
(troponin T) for tropomyosin, and a third (troponin C)
for calcium ions. This complex is believed to attach the
tropomyosin to the actin. The strong affinity of the troponin for calcium ions is believed to initiate the contraction process, as explained in the next section.
Interaction of One Myosin Filament, Two Actin
Filaments, and Calcium Ions to Cause Contraction
Inhibition of the Actin Filament by the TroponinTropomyosin Complex; Activation by Calcium
Ions. A pure actin filament without the presence of the
troponin-tropomyosin complex (but in the presence of
magnesium ions and ATP) binds instantly and strongly
with the heads of the myosin molecules. Then, if the troponin-tropomyosin complex is added to the actin filament, the binding between myosin and actin does not
take place. Therefore, it is believed that the active sites
on the normal actin filament of the relaxed muscle are
inhibited or physically covered by the troponin-tropomyosin complex. Consequently, the sites cannot attach to the
heads of the myosin filaments to cause contraction. Before
contraction can take place, the inhibitory effect of the
­troponin-tropomyosin complex must itself be inhibited.
U n i t II
helix, which is called the tail of the myosin molecule. One
end of each of these chains is folded bilaterally into a globular polypeptide structure called a myosin head. Thus, there
are two free heads at one end of the double-helix myosin
molecule. The four light chains are also part of the myosin
head, two to each head. These light chains help control the
function of the head during muscle contraction.
The myosin filament is made up of 200 or more individual myosin molecules. The central portion of one of these
filaments is shown in Figure 6-6B, displaying the tails of the
myosin molecules bundled together to form the body of the
filament, while many heads of the molecules hang outward
to the sides of the body. Also, part of the body of each myosin molecule hangs to the side along with the head, thus
providing an arm that 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 two points called hinges—one where the arm
leaves the body of the myosin filament, and the other where
the head attaches to the arm. The hinged arms allow the
heads to be either extended far outward from the body
of the myosin filament or brought close to the body. The
hinged heads in turn participate in the actual contraction
process, as discussed in the following sections.
The total length of each myosin filament is uniform,
almost exactly 1.6 micrometers. Note, however, that there
are no cross-bridge heads in the center of the myosin filament for a distance of about 0.2 micrometer because the
hinged arms extend away from the center.
Now, to complete the picture, the myosin filament itself
is twisted so that each successive pair of cross-bridges is
axially displaced from the previous pair by 120 degrees.
This ensures that the cross-bridges extend in all directions around the filament.
Unit II Membrane Physiology, Nerve, and Muscle
This brings us to the role of the calcium ions. In the
presence of large amounts of calcium ions, the inhibitory
effect of the troponin-tropomyosin on the actin filaments
is itself inhibited. The mechanism of this is not known,
but one suggestion is the following: When calcium ions
combine with troponin C, each molecule of which can
bind strongly with up to four calcium ions, the troponin
complex supposedly undergoes a conformational change
that in some way tugs on the tropomyosin molecule and
moves it deeper into the groove between the two actin
strands. This “uncovers” the active sites of the actin, thus
allowing these to attract the myosin cross-bridge heads
and cause contraction 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.
Interaction Between the “Activated” Actin Filament
and the Myosin Cross-Bridges—The “Walk-Along”
Theory of Contraction. As soon as the actin filament
becomes activated by the calcium ions, the heads of
the cross-bridges from the myosin filaments become
attracted to the active sites of the actin filament, and
this, in some way, causes contraction to occur. Although
the precise manner by which this interaction between
the cross-bridges and the actin causes contraction is still
partly theoretical, one hypothesis for which considerable
evidence exists is the “walk-along” theory (or “ratchet”
theory) of contraction.
Figure 6-8 demonstrates this postulated walk-along
mechanism for contraction. The figure shows the heads
of two cross-bridges attaching to and disengaging from
active sites of an actin filament. It is postulated that when
a head attaches to an active site, this attachment simultaneously causes profound changes in the intramolecular
forces between the head and arm of its cross-bridge. The
new alignment of forces causes the head to tilt toward the
arm and to drag the actin filament along with it. This tilt
of the head is called the power stroke. Then, immediately
after tilting, the head automatically breaks away from the
active site. Next, the head returns to its extended direction. In this position, it combines with a new active site
farther down along the actin filament; then the head tilts
again to cause a new power stroke, and the actin filament
moves another step. Thus, the heads of the cross-bridges
bend back and forth and step by step walk along the actin
filament, pulling the ends of two successive actin filaments toward the center of the myosin filament.
Each one of the cross-bridges is believed to operate
independently of all others, each attaching and pulling in
a continuous repeated cycle. Therefore, the greater the
number of cross-bridges in contact with the actin filament
at any given time, the greater the force of contraction.
ATP as the Source of Energy for Contraction—
Chemical Events in the Motion of the Myosin
Heads. When a muscle contracts, work is performed and
energy is required. Large amounts of ATP are cleaved to
form ADP during the contraction process; the greater the
amount of work performed by the muscle, the greater the
amount of ATP that is cleaved, which is called the Fenn
effect. The following sequence of events is believed to be
the means by which this occurs:
1. Before contraction begins, the heads of the crossbridges bind with ATP. The ATPase activity of the
myosin head immediately cleaves the ATP but leaves
the cleavage products, ADP plus phosphate 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 not yet attached to the actin.
2. 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 6-8.
3. The bond between the head of the cross-bridge and
the active site of the actin filament causes a conformational change in the head, prompting the head to tilt
toward the arm of the cross-bridge. This provides the
power stroke for pulling the actin filament. The energy
that activates the power stroke is the energy already
stored, like a “cocked” spring, by the conformational
change that occurred in the head when the ATP molecule was cleaved earlier.
4. Once the head of the cross-bridge tilts, this allows
release of the ADP and phosphate ion that were previously attached to the head. At the site of release of
the ADP, a new molecule of ATP binds. This binding
of new ATP causes detachment of the head from the
5. After the head has detached from the actin, the new
molecule of ATP is cleaved to begin the next cycle,
leading to a new power stroke. That is, the energy
again “cocks” the head back to its perpendicular condition, ready to begin the new power stroke cycle.
6. When the cocked head (with its stored energy derived
from the cleaved ATP) binds with a new active site
on the actin filament, it becomes uncocked and once
again provides a new power stroke.
Thus, the process proceeds again and again until the
actin filaments pull the Z membrane up against the ends
of the myosin filaments or until the load on the muscle
becomes too great for further pulling to occur.
Active sites
Actin filament
Myosin filament
Figure 6-8 “Walk-along” mechanism for contraction of the
Chapter 6 Contraction of Skeletal Muscle
The Amount of Actin and Myosin Filament
Overlap Determines Tension Developed
by the Contracting Muscle
Normal range of contraction
Effect of Muscle Length on Force of Contraction in
the Whole Intact Muscle. The top curve of Figure 6-10
is similar to that in Figure 6-9, but the curve in Figure 6-10
depicts tension of the intact, whole muscle rather than
of a single muscle fiber. The whole muscle has a large
Tension of muscle
before contraction
Figure 6-10 Relation of muscle length to tension in the muscle
both before and during muscle contraction.
amount of connective tissue in it; also, the sarcomeres in
different parts of the muscle do not always contract the
same amount. Therefore, the curve has somewhat different dimensions from those shown for the individual
muscle fiber, but it exhibits the same general form for
the slope in the normal range of contraction, as noted in
Figure 6-10.
Note in Figure 6-10 that when the muscle is at its normal resting length, which is at a sarcomere length of about
2 micrometers, it contracts upon activation with the
approximate maximum force of contraction. However, the
increase in tension that occurs during contraction, called
active tension, decreases as the muscle is stretched beyond
its normal length—that is, to a sarcomere length greater
than about 2.2 micrometers. This is demonstrated by the
decreased length of the arrow in the figure at greater than
normal muscle length.
Relation of Velocity of Contraction to Load
A skeletal muscle contracts rapidly when it contracts
against no load—to a state of full contraction in about 0.1
second for the average muscle. When loads are applied, the
velocity of contraction becomes progressively less as the
load increases, as shown in Figure 6-11. That is, when the
Increase in tension
during contraction
Length of sarcomere (micrometers)
Figure 6-9 Length-tension diagram for a single fully contracted
sarcomere, showing maximum strength of contraction when the
sarcomere is 2.0 to 2.2 micrometers in length. At the upper right
are the relative positions of the actin and myosin filaments at different sarcomere lengths from point A to point D. (Modified from
Gordon AM, Huxley AF, Julian FJ: The length-tension diagram of
single vertebrate striated muscle fibers. J Physiol 171:28P, 1964.)
Velocity of contraction (cm/sec)
Tension developed
Tension during
U n i t II
Figure 6-9 shows the effect of sarcomere length and
amount of myosin-actin filament overlap on the active
tension developed by a contracting muscle fiber. To the
right, shown in black, are different degrees of overlap of the
myosin and actin filaments at different sarcomere lengths.
At point D on the diagram, the actin filament has pulled
all the way out to the end of the myosin filament, with
no actin-myosin overlap. At this point, the tension developed by the activated muscle is zero. Then, as the sarco­
mere shortens and the actin filament begins to overlap the
myosin filament, the tension increases progressively until
the sarcomere length decreases to about 2.2 micrometers.
At this point, the actin filament has already overlapped
all the cross-bridges of the myosin filament but has not
yet reached the center of the myosin filament. With 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 two actin filaments begin to overlap each other in addition to overlapping the myosin filaments. As the sarcomere length falls
from 2 micrometers down to about 1.65 micrometers, at
point A, the strength of contraction decreases rapidly. At
this point, the two Z discs of the sarcomere abut the ends
of the myosin filaments. Then, as contraction proceeds
to still shorter sarcomere lengths, the ends of the myosin
filaments are crumpled and, as shown in the figure, the
strength of contraction approaches zero, but the sarco­
mere has now contracted to its shortest length.
Load-opposing contraction (kg)
Figure 6-11 Relation of load to velocity of contraction in a skeletal muscle with a cross section of 1 square centimeter and a length
of 8 centimeters.
Unit II Membrane Physiology, Nerve, and Muscle
load has been increased to equal the maximum force that
the muscle can exert, the velocity of contraction becomes
zero and no contraction results, despite activation of the
muscle fiber.
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 caused by
muscle contraction. Therefore, the net force that is available to cause velocity of shortening is correspondingly
Energetics of Muscle Contraction
Work Output During Muscle Contraction
When a muscle contracts against a load, it performs work.
This means that energy is transferred from the muscle to
the external load to lift an object to a greater height or to
overcome resistance to movement.
In mathematical terms, work is defined by the following equation:
in which W is the work output, L is the load, and D is
the distance of movement against the load. The energy
required to perform the work is derived from the chemical reactions in the muscle cells during contraction, as
described in the following sections.
Sources of Energy for Muscle Contraction
We have already seen that muscle contraction depends on
energy supplied by ATP. Most of this energy is required
to actuate the walk-along mechanism by which the crossbridges pull the actin filaments, but small amounts are
required for (1) pumping calcium ions from the sarcoplasm into the sarcoplasmic reticulum after the contraction is over and (2) pumping sodium and potassium ions
through the muscle fiber membrane to maintain appropriate ionic environment for propagation of muscle fiber
action potentials.
The concentration of ATP in the muscle fiber, about
4 millimolar, is sufficient to maintain full contraction
for only 1 to 2 seconds at most. The ATP is split to
form ADP, which transfers energy from the ATP molecule to the contracting machinery of the muscle fiber.
Then, as described in Chapter 2, the ADP is rephosphorylated to form new ATP within another fraction of a
second, which allows the muscle to continue its contraction. There are several sources of the energy for this
The first source of energy that is used to reconstitute
the ATP is the substance phosphocreatine, which carries a
high-energy phosphate bond similar to the bonds of ATP.
The high-energy phosphate bond of phosphocreatine has
a slightly higher amount of free energy than that of each
ATP bond, as is discussed more fully in Chapters 67 and
72. Therefore, phosphocreatine 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, is “gly­
colysis” of glycogen previously stored in the muscle cells.
Rapid enzymatic breakdown of the glycogen to pyruvic
acid and lactic acid liberates energy 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.
The importance of this glycolysis mechanism is twofold. First, the glycolytic reactions can occur even in the
absence of oxygen, so muscle contraction 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 formation of ATP by the
glycolytic process is about 2.5 times as rapid as ATP formation in response to cellular foodstuffs reacting with
oxygen. However, so many end products of glycolysis
accumulate in the muscle cells that glycolysis also loses its
capability to sustain maximum muscle contraction after
about 1 minute.
The third and final source of energy is oxidative
metabolism. This means combining oxygen with the
end products of glycolysis and with various other cellular foodstuffs to liberate ATP. More than 95 percent of
all energy used by the muscles for sustained, long-term
contraction is derived from this source. The foodstuffs
that are consumed are carbohydrates, fats, and protein.
For extremely long-term maximal muscle activity—over
a period of many hours—by far the greatest proportion
of energy comes from fats, but for periods of 2 to 4 hours,
as much as one half of the energy can come from stored
The detailed mechanisms of these energetic processes
are discussed in Chapters 67 through 72. In addition, the
importance of the different mechanisms of energy release
during performance of different sports is discussed in
Chapter 84 on sports physiology.
Efficiency of Muscle Contraction. The efficiency of an
engine or a motor is calculated as the percentage of energy
input that is converted into work instead of heat. The
percentage of the input energy to muscle (the chemical
energy in nutrients) that can be converted into work, even
under the best conditions, is less than 25 percent, with the
remainder becoming heat. The reason for this low efficiency is that about one half of the energy in foodstuffs is
lost during the formation of ATP, and even then, only 40 to
45 percent of the energy in the ATP itself can later be converted into work.
Maximum efficiency can be realized only when the muscle contracts at a moderate velocity. If the muscle contracts
slowly or without any movement, small amounts of maintenance heat are released during contraction, even though
little or no work is performed, thereby decreasing the con-
Chapter 6 Contraction of Skeletal Muscle
Many features of muscle contraction can be demonstrated by
eliciting single muscle twitches. This can be accomplished by
instantaneous electrical excitation of the nerve to a muscle
or by passing a short electrical stimulus through the muscle
itself, giving rise to a single, sudden contraction lasting for a
fraction of a second.
Isometric Versus Isotonic Contraction. Muscle contraction is said to be isometric when the muscle does not shorten
during contraction and isotonic when it does shorten but the
tension on the muscle remains constant throughout the contraction. Systems for recording the two types of muscle contraction are shown in Figure 6-12.
In the isometric system, the muscle contracts against
a force transducer without decreasing the muscle length,
as shown on the right in Figure 6-12. In the isotonic system, the muscle shortens against a fixed load; this is illustrated on the left in the figure, showing a muscle lifting a
pan of weights. The characteristics of isotonic contraction
depend on the load against which the muscle contracts, as
well as the inertia of the load. However, the isometric system records strictly changes in force of muscle contraction
itself. Therefore, the isometric system is most often used
when comparing the 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 small stapedius muscle in the
middle ear, measuring only a few millimeters long and a
millimeter or so in diameter, up to the large quadriceps
muscle, a half million times as large as the stapedius.
Further, the fibers may be as small as 10 micrometers in
diameter or as large as 80 micrometers. Finally, the energetics of muscle contraction vary considerably from one
muscle to another. Therefore, it is no wonder that the
mechanical characteristics of muscle contraction differ
among muscles.
Isotonic system
Electronic force
To electronic
Isometric system
Figure 6-12 Isotonic and isometric systems for recording muscle
Force of contraction
Characteristics of Whole Muscle Contraction
Duration of
U n i t II
version efficiency to as little as zero. Conversely, if contraction is too rapid, large proportions of the energy are used to
overcome viscous friction within the muscle itself, and this,
too, reduces the efficiency of contraction. Ordinarily, maximum efficiency is developed when the velocity of contraction is about 30 percent of maximum.
Figure 6-13 Duration of isometric contractions for different types
of mammalian skeletal muscles, showing a latent period between
the action potential (depolarization) and muscle contraction.
Figure 6-13 shows records of isometric contractions of
three types of skeletal muscle: an ocular muscle, which has
a duration of isometric contraction of less than 1/50 second;
the gastrocnemius muscle, which has a duration of contraction of about 1/15 second; and the soleus muscle, which has
a duration of contraction of about 1/5 second. It is interesting
that these durations of contraction are adapted to the functions of the respective muscles. Ocular movements must be
extremely rapid to maintain fixation of the eyes on specific
objects to provide accuracy of vision. The gastrocnemius
muscle must contract moderately rapidly to provide sufficient velocity of limb movement for running and jumping,
and the soleus muscle is concerned principally with slow
contraction for continual, long-term support of the body
against gravity.
Fast Versus Slow Muscle Fibers. As we discuss more fully
in Chapter 84 on sports physiology, every muscle of the body
is composed of a mixture of so-called fast and slow muscle
fibers, with still other fibers gradated between these two
extremes. Muscles that react rapidly, including anterior tibialis, are composed mainly of “fast” fibers with only small numbers of the slow variety. Conversely, muscles such as soleus
that respond slowly but with prolonged contraction are composed mainly of “slow” fibers. The differences between these
two types of fibers are as follows.
Slow Fibers (Type 1, Red Muscle). (1) Smaller fibers. (2)
Also innervated by smaller nerve fibers. (3) More extensive
blood vessel system and capillaries to supply extra amounts
of 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.
Fast Fibers (Type II, White Muscle). (1) Large fibers for
great strength of contraction. (2) Extensive sarcoplasmic
reticulum for rapid release of calcium ions to initiate contraction. (3) Large amounts of glycolytic enzymes for rapid
release of energy by the glycolytic process. (4) Less extensive
blood ­supply because ­oxidative metabolism is of secondary
importance. (5) Fewer mitochondria, also because oxidative
metabolism is secondary. A deficit of red myoglobin in fast
muscle gives it the name white muscle.
Mechanics of Skeletal Muscle Contraction
Motor Unit—All the Muscle Fibers Innervated by a Single
Nerve Fiber. Each motoneuron that leaves the spinal cord
innervates multiple muscle fibers, the number depending
on the type of muscle. All the muscle fibers innervated by
a single nerve fiber are called a motor unit. In general, small
muscles that react rapidly and whose control must be exact
have more nerve fibers for fewer muscle fibers (for instance,
as few as two or three muscle fibers per motor unit in some
of the laryngeal muscles). Conversely, large muscles that do
not require fine control, such as the soleus muscle, may have
several hundred muscle fibers in a motor unit. An average
figure for all the muscles of the body is questionable, but
a good guess would be about 80 to 100 muscle fibers to a
motor unit.
The muscle fibers in each motor unit are not all bunched
together in the muscle but overlap other motor units in
microbundles of 3 to 15 fibers. This interdigitation allows the
separate motor units to contract in support of one another
rather than entirely as individual segments.
Muscle Contractions of Different Force—Force Sum­
mation. Summation means the adding together of individual twitch contractions to increase the intensity of
overall muscle contraction. Summation occurs in two
ways: (1) by increasing the number of motor units contracting simultaneously, which is called multiple fiber
summation, and (2) by increasing the frequency of contraction, which is called frequency summation and can
lead to tetanization.
Multiple Fiber Summation. When the central nervous
system sends a weak signal to contract a muscle, the smaller
motor units of the muscle may be stimulated in preference
to the larger motor units. Then, as the strength of the signal
increases, larger and larger motor units begin to be excited as
well, with the largest motor units often having as much as 50
times the contractile force of the smallest units. This is called
the size principle. It is important because it allows the gradations of muscle force during weak contraction to occur in
small steps, whereas the steps become progressively greater
when large amounts of force are required. The cause of this
size principle is that the smaller motor units are driven by
small motor nerve fibers, and the small motoneurons in the
spinal cord are more excitable than the larger ones, so naturally they are excited first.
Another important feature of multiple fiber summation is
that the different motor units are driven asynchronously by
the spinal cord, so contraction alternates among motor units
one after the other, thus providing smooth contraction even
at low frequencies of nerve signals.
Frequency Summation and Tetanization. Figure 6-14
shows the principles of frequency summation and tetanization. To the left are displayed individual twitch contractions
occurring one after another at low frequency of stimulation.
Then, as the frequency increases, there comes a point where
each new contraction occurs before the preceding one is over.
As a result, the second contraction is added partially to the
first, so the total strength of contraction rises progressively
with increasing frequency. When the frequency reaches a
critical level, the successive contractions eventually become
so rapid that they fuse together and the whole muscle contraction appears to be completely smooth and continuous, as
shown in the figure. This is called tetanization. At a slightly
higher frequency, the strength of contraction reaches its
Strength of muscle contraction
Unit II Membrane Physiology, Nerve, and Muscle
10 15 20 25 30 35 40 45 50 55
Rate of stimulation (times per second)
Figure 6-14 Frequency summation and tetanization.
maximum, so any additional increase in frequency beyond
that point has no further effect in increasing contractile force.
This occurs because enough calcium ions are maintained in
the muscle sarcoplasm, even between action potentials, so
that full contractile state is sustained without allowing any
relaxation between the action potentials.
Maximum Strength of Contraction. The maximum
strength of tetanic contraction of a muscle operating at a
normal muscle length averages between 3 and 4 kilograms
per square centimeter of muscle, or 50 pounds per square
inch. Because a quadriceps muscle can have up to 16 square
inches of muscle belly, as much as 800 pounds of tension
may be applied to the patellar tendon. Thus, one can readily
understand how it is possible for muscles to pull their tendons out of their insertions in bone.
Changes in Muscle Strength at the Onset of Contraction—
The Staircase Effect (Treppe). When a muscle begins to
contract after a long period of rest, its initial strength of
contraction may be as little as one-half its strength 10 to 50
muscle twitches later. That is, the strength of contraction
increases to a plateau, a phenomenon called the staircase
effect, or treppe.
Although all the possible causes of the staircase effect are
not known, it is believed to be caused primarily by increasing calcium ions in the cytosol because of the release of more
and more ions from the sarcoplasmic reticulum with each
successive muscle action potential and failure of the sarcoplasm to recapture the ions immediately.
Skeletal Muscle Tone. Even when muscles are at rest, a
certain amount of tautness usually remains. This is called
muscle tone. Because normal skeletal muscle fibers do not
contract without an action potential to stimulate the fibers,
skeletal muscle tone results entirely from a low rate of nerve
impulses coming from the spinal cord. These, in turn, are
controlled partly by signals transmitted from the brain to the
appropriate spinal cord anterior motoneurons and partly by
signals that originate in muscle spindles located in the muscle itself. Both of these are discussed in relation to muscle
spindle and spinal cord function in Chapter 54.
Muscle Fatigue. Prolonged and strong contraction of
a muscle leads to the well-known state of muscle fatigue.
Studies in athletes have shown that muscle fatigue increases
in almost direct proportion to the rate of depletion of muscle
glycogen. Therefore, fatigue results mainly from inability of
the contractile and metabolic processes of the muscle fibers
to continue supplying the same work output. However, experiments have also shown that transmission of the nerve signal
Chapter 6 Contraction of Skeletal Muscle
Figure 6-15 Lever system activated by the biceps muscle.
is called coactivation of the agonist and antagonist muscles,
and it is controlled by the motor control centers of the brain
and spinal cord.
The position of each separate part of the body, such as
an arm or a leg, is determined by the relative degrees of
contraction of the agonist and antagonist sets of muscles.
For instance, let us assume that an arm or a leg is to be
placed in a midrange position. To achieve this, agonist and
antagonist muscles are excited about equally. Remember
that an elongated muscle contracts with more force than a
shortened muscle, which was demonstrated in Figure 6-10,
showing maximum strength of contraction at full functional muscle length and 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 compensate for different muscle loads when directing this positioning process.
Remodeling of Muscle to Match Function
All the muscles of the body are continually being remodeled
to match the functions that are required of them. Their diameters are altered, their lengths are altered, their strengths are
altered, their vascular supplies are altered, and even the types
of muscle fibers are altered at least slightly. This remodeling process is often quite rapid, within a few weeks. Indeed,
experiments in animals have shown that muscle contractile proteins in some smaller, more active muscles can be
replaced in as little as 2 weeks.
Muscle Hypertrophy and Muscle Atrophy. When the total
mass of a muscle increases, this is called muscle hypertrophy.
When it decreases, the process is called muscle atrophy.
Virtually all muscle hypertrophy results from an
increase in the number of actin and myosin filaments in
each muscle fiber, causing enlargement of the individual muscle fibers; this is called simply fiber hypertrophy.
Hypertrophy occurs to a much greater extent when the
muscle is loaded during the contractile process. Only a few
strong contractions each day are required to cause significant ­hypertrophy within 6 to 10 weeks.
The manner in which forceful contraction leads to hypertrophy is not known. It is known, however, that the rate of
synthesis of muscle contractile proteins is far greater when
hypertrophy is developing, leading also to progressively
greater numbers of both actin and myosin filaments in the
myofibrils, often increasing as much as 50 percent. In turn,
some of the myofibrils themselves have been observed to
split within hypertrophying muscle to form new myofibrils,
but how important this is in usual muscle hypertrophy is still
Along with the increasing size of myofibrils, the
enzyme systems that provide energy also increase. This
is especially true of the enzymes for glycolysis, allowing
rapid supply of energy during short-term forceful muscle
U n i t II
through the neuromuscular junction, which is discussed in
Chapter 7, can diminish at least a small amount after intense
prolonged muscle activity, thus further diminishing muscle
contraction. Interruption of blood flow through a contracting muscle leads to almost complete muscle fatigue within 1
or 2 minutes because of the loss of nutrient supply, especially
loss of oxygen.
Lever Systems of the Body. Muscles operate by applying tension to their points of insertion into bones, and the
bones in turn form various types of lever systems. Figure
6-15 shows the lever system activated by the biceps muscle
to lift the forearm. If we assume that a large biceps muscle
has a cross-sectional area of 6 square inches, the maximum
force of contraction would be about 300 pounds. When the
forearm is at right angles with the upper arm, the tendon
attachment of the biceps is about 2 inches anterior to the fulcrum at the elbow and the total length of the forearm lever
is about 14 inches. Therefore, the amount of lifting power
of the biceps at the hand would be only one seventh of the
300 pounds of muscle force, or about 43 pounds. When the
arm is fully extended, the attachment of the biceps is much
less than 2 inches anterior to the fulcrum and the force with
which the hand can be brought forward is also much less
than 43 pounds.
In short, an analysis of the lever systems of the body
depends on knowledge of (1) the point of muscle insertion, (2) its distance from the fulcrum of the lever, (3) the
length of the lever arm, and (4) the position of the lever.
Many types of movement are required in the body, some of
which need great strength and others of which need large
distances of movement. For this reason, there are many different types of muscle; some are long and contract a long
distance, and some are short but have large cross-sectional
areas and can provide extreme strength of contraction
over short distances. The study of different types of muscles, lever systems, and their movements is called kinesiology and is an important scientific component of human
“Positioning” of a Body Part by Contraction of Agonist
and Antagonist Muscles on Opposite Sides of a Joint—
“Coactivation” of Antagonist Muscles. Virtually all body
movements are caused by simultaneous contraction of agonist and antagonist muscles on opposite sides of joints. This
Unit II Membrane Physiology, Nerve, and Muscle
When a muscle remains unused for many weeks, the rate
of degradation of the contractile proteins is more rapid than
the rate of replacement. Therefore, muscle atrophy occurs.
The pathway that appears to account for much of the protein degradation in a muscle undergoing atrophy is the ATPdependent ubiquitin-proteasome pathway. Proteasomes are
large protein complexes that degrade damaged or unneeded
proteins by proteolysis, a chemical reaction that breaks peptide
bonds. Ubiquitin is a regulatory protein that basically labels
which cells will be targeted for proteasomal degradation.
Adjustment of Muscle Length. Another type of hypertrophy occurs when muscles are stretched to greater than
normal length. This causes new sarcomeres to be added
at the ends of the muscle fibers, where they attach to the
tendons. In fact, new sarcomeres can be added as rapidly
as several per minute in newly developing muscle, illustrating the rapidity of this type of hypertrophy.
Conversely, when a muscle continually remains
shortened 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
Hyperplasia of Muscle Fibers. Under rare conditions
of extreme muscle force generation, the actual number of
muscle fibers has been observed to increase (but only by a
few percentage points), in addition to the fiber hypertrophy process. This increase in fiber number is called fiber
hyperplasia. When it does occur, the mechanism is linear
splitting of previously enlarged fibers.
Effects of Muscle Denervation. When a muscle
loses its nerve supply, it no longer receives the contractile signals that are required to maintain normal muscle size. Therefore, atrophy begins almost immediately.
After about 2 months, degenerative changes also begin to
appear in the muscle fibers themselves. If the nerve supply to the muscle grows back rapidly, full return of function can occur in as little as 3 months, but from that time
onward, the capability of functional return becomes less
and less, with no further return of function after 1 to 2
In the final stage of denervation atrophy, most of the
muscle fibers are destroyed and replaced by fibrous and
fatty tissue. The fibers that do remain are composed of
a long cell membrane with a lineup of muscle cell nuclei
but with few or no contractile properties and little or
no capability of regenerating myofibrils if a nerve does
The fibrous tissue that replaces the muscle fibers during denervation atrophy also has a tendency to continue
shortening for many months, which is called contracture.
Therefore, one of the most important problems in the
practice of physical therapy is to keep atrophying muscles
from developing debilitating and disfiguring contractures.
This is achieved by daily stretching of the muscles or use
of appliances that keep the muscles stretched during the
atrophying process.
Recovery of Muscle Contraction in Poliomyelitis:
Development of Macromotor Units. When some but not
all nerve fibers to a muscle are destroyed, as commonly
occurs in poliomyelitis, the remaining nerve fibers branch off
to form new axons that then innervate many of the paralyzed
muscle fibers. This causes large motor units called macromotor units, which can contain as many as five times the normal
number of muscle fibers for each motoneuron coming from
the spinal cord. This decreases the fineness of control one
has over the muscles but does allow the muscles to regain
varying degrees of strength.
Rigor Mortis
Several hours after death, all the muscles of the body go into
a state of contracture called “rigor mortis”; that is, the muscles contract and become rigid, even without action potentials. This rigidity results from loss of all the ATP, which is
required to cause separation of the cross-bridges from the
actin filaments during the relaxation process. The muscles
remain in rigor until the muscle proteins deteriorate about
15 to 25 hours later, which presumably results from autolysis
caused by enzymes released from lysosomes. All these events
occur more rapidly at higher temperatures.
Allen DG, Lamb GD, Westerblad H: Skeletal muscle fatigue: cellular mechanisms, Physiol Rev 88:287, 2008.
Berchtold MW, Brinkmeier H, Muntener M: Calcium ion in skeletal muscle:
its crucial role for muscle function, plasticity, and disease, Physiol Rev
80:1215, 2000.
Cheng H, Lederer WJ: Calcium sparks, Physiol Rev 88:1491, 2008.
Clanton TL, Levine S: Respiratory muscle fiber remodeling in chronic
hyperinflation: dysfunction or adaptation? J Appl Physiol 107:324,
Clausen T: Na+-K+ pump regulation and skeletal muscle contractility,
Physiol Rev 83:1269, 2003.
Dirksen RT: Checking your SOCCs and feet: the molecular mechanisms of
Ca2+ entry in skeletal muscle, J Physiol 587:3139, 2009.
Fitts RH: The cross-bridge cycle and skeletal muscle fatigue, J Appl Physiol
104:551, 2008.
Glass DJ: Signalling pathways that mediate skeletal muscle hypertrophy
and atrophy, Nat Cell Biol 5:87, 2003.
Gordon AM, Regnier M, Homsher E: Skeletal and cardiac muscle contractile
activation: tropomyosin “rocks and rolls”, News Physiol Sci 16:49, 2001.
Gunning P, O’Neill G, Hardeman E: Tropomyosin-based regulation of the
actin cytoskeleton in time and space, Physiol Rev 88:1, 2008.
Huxley AF, Gordon AM: Striation patterns in active and passive shortening
of muscle, Nature (Lond) 193:280, 1962.
Kjær M: Role of extracellular matrix in adaptation of tendon and skeletal
muscle to mechanical loading, Physiol Rev 84:649, 2004.
Lynch GS, Ryall JG: Role of beta-adrenoceptor signaling in skeletal muscle:
implications for muscle wasting and disease, Physiol Rev 88:729, 2008.
MacIntosh BR: Role of calcium sensitivity modulation in skeletal muscle
performance, News Physiol Sci 18:222, 2003.
Phillips SM, Glover EI, Rennie MJ: Alterations of protein turnover underlying
disuse atrophy in human skeletal muscle, J Appl Physiol 107:645, 2009.
Powers SK, Jackson MJ: Exercise-induced oxidative stress: cellular mechanisms and impact on muscle force production, Physiol Rev 88:1243,
Sandri M: Signaling in muscle atrophy and hypertrophy, Physiology
(Bethesda) 160, 2008.
Sieck GC, Regnier M: Plasticity and energetic demands of contraction in
skeletal and cardiac muscle, J Appl Physiol 90:1158, 2001.
Treves S, Vukcevic M, Maj M, et al: Minor sarcoplasmic reticulum membrane components that modulate excitation-contraction coupling in
striated muscles, J Physiol 587:3071, 2009.
chapter 7
Transmission of
Impulses from Nerve
Endings to Skeletal
Muscle Fibers: The
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 percent 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 membrane 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 numerous 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 triphosphate (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.
On the inside surface of the neural membrane are linear dense bars, shown in cross section in Figure 7-2. To
each side of each dense bar are protein particles that penetrate the neural membrane; these are voltage-gated calcium channels. When an action potential spreads over the
terminal, these channels open and allow calcium ions to
diffuse from the synaptic space to the interior of the nerve
terminal. The calcium ions, in turn, are believed to exert
an attractive influence on the acetylcholine vesicles, drawing them to the neural membrane adjacent to the dense
bars. The vesicles then fuse with the neural membrane
and empty their acetylcholine into the synaptic space by
the process of exocytosis.
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 vesicles is then emptied
through the neural membrane adjacent to the dense bars.
Effect of Acetylcholine on the Postsynaptic Muscle
Fiber Membrane to Open Ion Channels. Figure 7-2
also shows many small acetylcholine receptors in the muscle fiber membrane; these are acetylcholine-gated ion
channels, and they are located almost entirely near the
mouths of the subneural clefts lying immediately below
the dense bar areas, where the acetylcholine is emptied
into the ­synaptic space.
U n i t II
Excitation of Skeletal Muscle:
Neuromuscular Transmission and
Excitation-Contraction Coupling
Unit II Membrane Physiology, Nerve, and Muscle
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, 1986.)
Terminal nerve
Teloglial cell
Synaptic vesicles
sites membrane
Dense bar
Basal lamina
Voltage activated
Na+ channels
Figure 7-2 Release of acetylcholine from synaptic vesicles at the
neural membrane of the neuromuscular junction. Note the proximity of the release sites in the neural membrane to the acetylcholine receptors in the muscle membrane, at the mouths of the
subneural clefts.
Each receptor is a protein complex that has a total
molecular weight of 275,000. The complex is composed
of five subunit proteins, two alpha proteins and one each
of beta, delta, and gamma proteins. These protein molecules penetrate all the way through the membrane, lying
side by side in a circle to form a tubular channel, illus84
Axon terminal in
synaptic trough
Subneural clefts
trated in Figure 7-3. The channel remains constricted, as
shown in section A of the figure, until two acetylcholine
molecules attach respectively to the two alpha subunit
proteins. This causes a conformational change that opens
the channel, as shown in section B of the figure.
The acetylcholine-gated channel has a diameter of
about 0.65 nanometer, which is large enough to allow the
important positive ions—sodium (Na+), potassium (K+),
and calcium (Ca++)—to move easily through the opening.
Conversely, negative ions, such as chloride ions, do not
pass through because of strong negative charges in the
mouth of the channel that repel these negative ions.
In practice, far more sodium ions flow through the
­acetylcholine-gated channels than any other ions, for two
reasons. First, there are only two positive ions in large
concentration: sodium ions in the extracellular fluid and
potassium ions in the intracellular fluid. Second, the negative potential on the inside of the muscle membrane,
−80 to −90 millivolts, pulls the positively charged sodium
ions to the inside of the fiber, while simultaneously preventing efflux of the positively charged potassium ions
when they attempt to pass outward.
As shown in Figure 7-3B, the principal effect of opening
the acetylcholine-gated channels is to allow large numbers
of sodium ions to pour to the inside of the fiber, carrying
with them large numbers of positive charges. This creates a
local positive potential change inside the muscle fiber membrane, called the end plate potential. In turn, this end plate
potential initiates an action potential that spreads along the
muscle membrane and thus causes muscle contraction.
Chapter 7 Excitation of Skeletal Muscle: Neuromuscular Transmission and Excitation-Contraction Coupling
Figure 7-3 Acetylcholine-gated channel. A, Closed state. B, After
acetylcholine (Ach) has become attached and a conformational
change has opened the channel, allowing sodium ions to enter the
muscle fiber and excite contraction. Note the negative charges at
the channel mouth that prevent passage of negative ions such as
chloride ions.
Destruction of the Released Acetylcholine by
Acetylcholinesterase. The acetylcholine, once released
into the synaptic space, continues to activate the acetylcholine 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 membrane. (2) A small amount
of acetylcholine diffuses out of the synaptic space and
is then no longer available to act on the muscle fiber
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 muscle
re-excitation after the muscle fiber has recovered from its
initial action potential.
into the muscle fiber when the acetylcholine-gated 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
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 potentials A and
C are too weak to elicit an action potential, but they do
produce weak local end plate voltage changes, as recorded
in the figure. By contrast, end plate potential B is much
stronger and causes enough sodium channels to open so
that the self-regenerative effect of more and more sodium
ions flowing to the interior of the fiber initiates an action
potential. The weakness of the end plate potential at point
A was caused by poisoning of the muscle fiber with curare,
a drug that blocks the gating action of acetylcholine on the
acetylcholine channels by competing for the acetylcholine
receptor sites. The weakness of the end plate potential at
point C resulted from the effect of botulinum toxin, a bacterial poison that decreases the quantity of acetylcholine
release by the nerve terminals.
Safety Factor for Transmission at the Neuro­
muscular Junction; Fatigue of the Junction. Ordinarily,
each impulse that arrives at the neuromuscular junction
causes about three times as much end plate potential as
that required to stimulate the muscle fiber. Therefore,
the normal neuromuscular junction is said to have a high
safety factor. However, stimulation of the nerve fiber at
rates greater than 100 times per second for several minutes often diminishes the number of acetylcholine vesicles so much that impulses fail to pass into the muscle
Figure 7-4 End plate potentials (in millivolts). A, Weakened end
plate potential recorded in a curarized muscle, too weak to elicit
an action potential. B, Normal end plate potential eliciting a muscle action potential. C, Weakened end plate potential caused by
botulinum toxin that decreases end plate release of acetylcholine,
again too weak to elicit a muscle action potential.
U n i t II
End Plate Potential and Excitation of the Skeletal
Muscle Fiber. The sudden insurgence of sodium ions
Unit II Membrane Physiology, Nerve, and Muscle
fiber. This is called fatigue of the neuromuscular junction, and it is the same effect that causes fatigue of synapses in the central nervous system when the synapses
are overexcited. Under normal functioning conditions,
measurable fatigue of the neuromuscular junction occurs
rarely, and even then only at the most exhausting levels
of muscle activity.
Molecular Biology of Acetylcholine
Formation and Release
Because the neuromuscular junction is large enough to be
studied easily, it is one of the few synapses of the nervous system for which most of the details of chemical transmission
have been worked out. The formation and release of acetylcholine at this junction occur in the following stages:
1. 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 are then transported by
axoplasm that “streams” through the core of the axon from
the central cell body in the spinal cord all the way to the
neuromuscular junction at the tips of the peripheral nerve
fibers. About 300,000 of these small vesicles collect in the
nerve terminals of a single skeletal muscle end plate.
2. Acetylcholine is synthesized in the cytosol of the nerve
fiber terminal but is immediately transported through
the membranes of the vesicles to their interior, where it
is stored in highly concentrated form, about 10,000 molecules of acetylcholine in each vesicle.
3. When an action potential arrives at the nerve terminal,
it opens many calcium channels in the membrane of the
nerve terminal because this terminal has an abundance of
voltage-gated 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 the terminal membrane
about 10,000-fold. This fusion makes many of the vesicles
rupture, allowing exocytosis of acetylcholine into the synaptic space. About 125 vesicles usually rupture with each
action potential. Then, after a few milliseconds, the acetylcholine is split by acetylcholinesterase into acetate ion
and choline and the choline is reabsorbed actively into the
neural terminal to be reused to form new acetylcholine.
This sequence of events occurs within a period of 5 to 10
4. The number of vesicles available in the nerve ending is
sufficient to allow transmission of only a few thousand
nerve-to-muscle impulses. Therefore, for continued function of the neuromuscular junction, new vesicles need
to be re-formed rapidly. Within a few seconds after each
action potential is over, “coated pits” appear in the terminal nerve membrane, caused by contractile proteins in
the nerve ending, especially the protein clathrin, which is
attached to the membrane in the areas of the original vesicles. Within about 20 seconds, the proteins contract and
cause the pits to break away to the interior of the membrane, thus forming new vesicles. Within another few seconds, acetylcholine is transported to the interior of these
vesicles, and they are then ready for a new cycle of acetylcholine release.
Drugs That Enhance or Block Transmission at the
Neuromuscular Junction
Drugs That Stimulate the Muscle Fiber by AcetylcholineLike Action. Many compounds, including methacholine,
carbachol, and nicotine, have the same effect on the muscle
fiber as does acetylcholine. The difference between these
drugs and acetylcholine is that the drugs are not destroyed
by cholinesterase or are destroyed so slowly that their action
often persists for many minutes to several hours. The drugs
work by causing localized areas of depolarization of the muscle fiber membrane at the motor end plate where the acetylcholine receptors are located. Then, every time the muscle
fiber recovers from a previous contraction, these depolarized
areas, by virtue of leaking ions, initiate a new action potential, thereby causing a state of muscle spasm.
Drugs That Stimulate the Neuromuscular Junction
by Inactivating Acetylcholinesterase. Three particularly
well-known drugs, neostigmine, physostigmine, and diisopropyl fluorophosphate, inactivate the acetylcholinesterase
in the synapses so that it no longer hydrolyzes acetylcholine. Therefore, with each successive nerve impulse, additional acetylcholine accumulates and stimulates the muscle
fiber repetitively. This causes muscle spasm when even a
few nerve impulses reach the muscle. Unfortunately, it can
also cause death due to laryngeal spasm, which smothers
the person.
Neostigmine and physostigmine combine with acetylcholinesterase to inactivate the acetylcholinesterase for
up to several hours, after which these drugs are displaced
from the acetylcholinesterase so that the esterase once again
becomes active. Conversely, diisopropyl fluorophosphate,
which is a powerful “nerve” gas poison, inactivates acetylcholinesterase for weeks, which makes this a particularly
lethal poison.
Drugs That Block Transmission at the Neuromuscular
Junction. A group of drugs known as curariform drugs can
prevent passage of impulses from the nerve ending into the
muscle. For instance, D-tubocurarine blocks the action of
acetylcholine on the muscle fiber acetylcholine receptors,
thus preventing sufficient increase in permeability of the
muscle membrane channels to initiate an action potential.
Myasthenia Gravis Causes Muscle Paralysis
Myasthenia gravis, which occurs in about 1 in every 20,000
persons, causes muscle paralysis because of inability of the
neuromuscular junctions to transmit enough signals from
the nerve fibers to the muscle fibers. Pathologically, antibodies that attack the acetylcholine receptors have been demonstrated in the blood of most patients with myasthenia gravis.
Therefore, it is believed that myasthenia gravis is an autoimmune disease in which the patients have developed antibodies that block or destroy their own acetylcholine receptors at
the postsynaptic neuromuscular junction.
Regardless of the cause, the end plate potentials that
occur in the muscle fibers are mostly too weak to initiate
opening of the voltage-gated sodium channels so that muscle
fiber depolarization does not occur. If the disease is intense
enough, the patient dies of paralysis—in particular, paralysis of the respiratory muscles. The disease can usually be
Chapter 7 Excitation of Skeletal Muscle: Neuromuscular Transmission and Excitation-Contraction Coupling
Muscle Action Potential
Almost everything discussed in Chapter 5 regarding initiation and conduction of action potentials in nerve fibers
applies equally to skeletal muscle fibers, except for quantitative differences. Some of the quantitative aspects of
muscle potentials are the following:
1. Resting membrane potential: about −80 to −90 millivolts in skeletal fibers—the same as in large myelinated
nerve fibers.
2. Duration of action potential: 1 to 5 milliseconds in
skeletal muscle—about five times as long as in large
myelinated nerves.
3. Velocity of conduction: 3 to 5 m/sec—about 1/13 the
velocity of conduction in the large myelinated nerve
fibers that excite skeletal muscle.
Spread of the Action Potential to the Interior of
the Muscle Fiber by Way of “Transverse Tubules”
The skeletal muscle fiber is so large that action potentials spreading along its surface membrane cause almost
no current flow deep within the fiber. Yet to cause maximum muscle contraction, current must penetrate deeply
into the muscle fiber to the vicinity of the separate myofibrils. This is achieved by transmission of action potentials along transverse tubules (T tubules) that penetrate
all the way through the muscle fiber from one side of
the fiber to the other, as illustrated in Figure 7-5. The
T tubule action potentials cause release of calcium ions
inside the muscle fiber in the immediate vicinity of the
myofibrils, and these calcium ions then cause contraction. This overall process is called excitation-­contraction
Z line
Triad of the
A band
I band
Figure 7-5 Transverse (T) tubule–sarcoplasmic reticulum system. Note that the T tubules communicate with the outside of the cell membrane, and deep in the muscle fiber, each T tubule lies adjacent to the ends of 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 sarcomere, located at
the Z line. A 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.
U n i t II
­ameliorated for several hours by administering neostigmine
or some other anticholinesterase drug, which allows larger
than normal amounts of acetylcholine to accumulate in the
synaptic space. Within minutes, some of these paralyzed
people can begin to function almost normally, until a new
dose of neostigmine is required a few hours later.
Unit II Membrane Physiology, Nerve, and Muscle
Excitation-Contraction Coupling
Transverse Tubule–Sarcoplasmic
Reticulum System
Figure 7-5 shows myofibrils surrounded by the T tubule–
sarcoplasmic reticulum system. The T tubules are small
and run transverse to the myofibrils. They begin at the cell
membrane and penetrate all the way from one side of the
muscle fiber to the opposite side. Not shown in the figure
is the fact that these tubules branch among themselves
and form entire planes of T tubules interlacing among all
the separate myofibrils. Also, where the T tubules originate from the cell membrane, they are open to the exterior
of the muscle fiber. Therefore, they communicate with the
extracellular fluid surrounding the muscle fiber and they
themselves contain extracellular fluid in their lumens. In
other words, the T tubules are actually internal extensions
of the cell membrane. Therefore, when an action potential
spreads over a muscle fiber membrane, a potential change
also spreads along the T tubules to the deep interior of the
muscle fiber. The electrical currents surrounding these
T tubules then elicit the muscle contraction.
Figure 7-5 also shows a sarcoplasmic reticulum, in yellow. This is composed of two major parts: (1) large chambers called terminal cisternae that abut the T tubules and
(2) long longitudinal tubules that surround all surfaces of
the actual contracting myofibrils.
Release of Calcium Ions by the Sarcoplasmic
One of the special features of the sarcoplasmic reticulum is that within its vesicular tubules is an excess of calcium ions in high concentration, and many of these ions
are released from each vesicle when an action potential
occurs in the adjacent T tubule.
Figure 7-6 Excitation-contraction coupling in skeletal muscle. The
top panel shows an action potential in the T tubule that causes a
conformational change in the voltage-sensing dihydropyridine (DHP)
receptors, opening the Ca++ release channels in the terminal cisternae
of the sarcoplasmic reticulum and permitting Ca++ to rapidly diffuse
into the sarcoplasm and initiate muscle contraction. During repolarization (bottom panel) the conformational change in the DHP receptor closes the Ca++ release channels and Ca++ is transported from the
sarcoplasm into the sarcoplasmic reticulum by an ATP-dependent
calcium pump.
Figures 7-6 and 7-7 show that the action potential of the
T tubule causes current flow into the sarcoplasmic reticular cisternae where they abut the T tubule. As the action
potential reaches the T tubule, the voltage change is sensed
by dihydropyridine receptors that are linked to calcium
release channels, also called ryanodine receptor channels,
in the adjacent sarcoplasmic reticular cisternae (see Figure
7-6). Activation of dihydropyridine receptors triggers the
opening of the calcium release channels in the cisternae, as
well as in their attached longitudinal tubules. These channels remain open for a few milliseconds, releasing calcium
ions into the sarcoplasm surrounding the myofibrils and
causing contraction, as discussed in Chapter 6.
Calcium Pump for Removing Calcium Ions from the
Myofibrillar Fluid After Contraction Occurs. Once the
calcium ions have been released from the sarcoplasmic
tubules and have diffused among the myofibrils, muscle
contraction continues as long as the calcium ions remain in
high concentration. However, a continually active calcium
pump located in the walls of the sarcoplasmic reticulum
pumps calcium ions away from the myofibrils back into
the sarcoplasmic tubules (see Figure 7-6). This pump can
concentrate the calcium ions about 10,000-fold inside the
tubules. In addition, inside the reticulum is a protein called
calsequestrin that can bind up to 40 times more calcium.
Excitatory “Pulse” of Calcium Ions. The normal
resting state concentration (<10−7 molar) of calcium ions
in the cytosol that bathes the myofibrils is too little to
elicit contraction. Therefore, the troponin-tropomyosin
complex keeps the actin filaments inhibited and maintains a relaxed state of the muscle.
Conversely, full excitation of the T tubule and sarcoplasmic reticulum system causes enough release
of calcium ions to increase the concentration in the
Ca++ Release Channel (open)
Terminal Cisterne
Ca++ Release
Channel (closed)
Chapter 7 Excitation of Skeletal Muscle: Neuromuscular Transmission and Excitation-Contraction Coupling
Action potential
U n i t II
Calcium pump
Actin filaments
Myosin filaments
Figure 7-7 Excitation-contraction coupling in the muscle, showing (1) an action potential that causes release of calcium ions from the
­sarcoplasmic reticulum and then (2) re-uptake of the calcium ions by a calcium pump.
myofibrillar fluid to as high as 2 × 10−4 molar concentration, a 500-fold increase, which is about 10 times the
level required to cause maximum muscle contraction.
Immediately thereafter, the calcium pump depletes the
calcium ions again. The total duration of this calcium
“pulse” in the usual skeletal muscle fiber lasts about 1/20 of
a second, although it may last several times as long in some
fibers and several times less in others. (In heart muscle, the
calcium pulse lasts about one third of a second because of
the long duration of the cardiac action potential.)
During this calcium pulse, muscle contraction occurs.
If the contraction is to continue without interruption for
long intervals, a series of calcium pulses must be initiated
by a continuous series of repetitive action potentials, as
discussed in Chapter 6.
Also see references for Chapters 5 and 6.
Brown RH Jr: Dystrophin-associated proteins and the muscular dystrophies, Annu Rev Med 48:457, 1997.
Chaudhuri A, Behan PO: Fatigue in neurological disorders, Lancet 363:978,
Cheng H, Lederer WJ: Calcium sparks, Physiol Rev 88:1491, 2008.
Engel AG, Ohno K, Shen XM, Sine SM: Congenital myasthenic syndromes:
multiple molecular targets at the neuromuscular junction, Ann N Y Acad
Sci 998:138, 2003.
Fagerlund MJ, Eriksson LI: Current concepts in neuromuscular transmission,
Br J Anaesth 103:108, 2009.
Haouzi P, Chenuel B, Huszczuk A: Sensing vascular distension in skeletal muscle by slow conducting afferent fibers: neurophysiological
basis and implication for respiratory control, J Appl Physiol 96:407,
Hirsch NP: Neuromuscular junction in health and disease, Br J Anaesth
99:132, 2007.
Keesey JC: Clinical evaluation and management of myasthenia gravis,
Muscle Nerve 29:484, 2004.
Korkut C, Budnik V: WNTs tune up the neuromuscular junction, Nat Rev
Neurosci 10:627, 2009.
Leite JF, Rodrigues-Pinguet N, Lester HA: Insights into channel function via
channel dysfunction, J Clin Invest 111:436, 2003.
Meriggioli MN, Sanders DB: Autoimmune myasthenia gravis: emerging clinical and biological heterogeneity, Lancet Neurol 8:475,
Rekling JC, Funk GD, Bayliss DA, et al: Synaptic control of motoneuronal
excitability, Physiol Rev 80:767, 2000.
Rosenberg PB: Calcium entry in skeletal muscle, J Physiol 587:3149,
Toyoshima C, Nomura H, Sugita Y: Structural basis of ion pumping
by Ca2+-ATPase of sarcoplasmic reticulum, FEBS Lett 555:106,
Van der Kloot W, Molgo J: Quantal acetylcholine release at the vertebrate
neuromuscular junction, Physiol Rev 74:899, 1994.
Vincent A: Unraveling the pathogenesis of myasthenia gravis, Nat Rev
Immunol 10:797, 2002.
Vincent A, McConville J, Farrugia ME, et al: Antibodies in myasthenia gravis
and related disorders, Ann N Y Acad Sci 998:324, 2003.
This page intentionally left blank
chapter 8
Excitation and Contraction 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 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 piloerector muscles that cause erection of the hairs when stimulated by the sympathetic nervous system.
Unitary Smooth Muscle. This type is also called
syncytial smooth muscle or visceral 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 from one fiber to the
next and cause the muscle fibers to contract together. This
type of smooth muscle is also known as syncytial smooth
muscle because of its syncytial 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 gastrointestinal tract, bile ducts, ureters, uterus, and
many blood vessels.
Small artery
Multi-unit smooth muscle
Unitary smooth muscle
Figure 8-1 Multi-unit (A) and unitary (B) smooth muscle.
U n i t II
Unit II Membrane Physiology, Nerve, and Muscle
Contractile Mechanism in Smooth Muscle
Chemical Basis for Smooth Muscle Contraction
Smooth muscle contains both actin and myosin filaments,
having chemical characteristics similar to those of the
actin and myosin filaments in skeletal muscle. It does not
contain the normal troponin complex that is required in
the control of skeletal muscle contraction, 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
filaments derived from smooth muscle interact with each
other in much the same way that they do in skeletal muscle. Further, the contractile process is activated by calcium
ions, and adenosine triphosphate (ATP) is degraded to
adenosine diphosphate (ADP) to provide the energy for
There are, however, major differences between the
physical organization of smooth muscle and that of skeletal muscle, as well as differences in excitation-contraction
coupling, control of the contractile process by calcium
ions, duration of contraction, and amount of energy
required for contraction.
Dense bodies
Myosin filaments
Physical Basis for Smooth Muscle Contraction
Smooth muscle does not have the same striated arrangement of actin and myosin filaments as is found in skeletal muscle. Instead, electron micrographic techniques
suggest the physical organization exhibited in Figure
8-2. This figure shows large numbers of actin filaments
attached to so-called dense bodies. Some of these bodies
are attached to the cell membrane. Others are dispersed
inside the cell. Some of the membrane-dense bodies of
adjacent cells are bonded together by intercellular protein
bridges. It is mainly through these bonds that the force of
contraction is transmitted from one cell to the next.
Interspersed among the actin filaments in the muscle
fiber are myosin filaments. These have a diameter more
than twice that of the actin filaments. In electron micrographs, one usually finds 5 to 10 times as many actin filaments as myosin filaments.
To the right in Figure 8-2 is a postulated structure of
an individual contractile unit within a smooth muscle cell,
showing large numbers of actin filaments radiating from
two dense bodies; the ends of these filaments overlap a
myosin filament located midway between the dense bodies. This contractile unit is similar to the contractile unit of
skeletal muscle, but without the regularity of the skeletal
muscle structure; in fact, the dense bodies of smooth muscle serve the same role as the Z discs in skeletal muscle.
There is another difference: Most of the myosin filaments have what are called “sidepolar” cross-bridges
arranged so that the bridges on one side hinge in one
direction and those on the other side hinge in the opposite direction. This allows the myosin to pull an actin filament in one direction on one side while simultaneously
pulling another actin filament in the opposite direction
on the other side. The value of this organization is that it
Cell membrane
Figure 8-2 Physical structure of smooth muscle. The upper lefthand fiber shows actin filaments radiating from dense bodies.
The lower left-hand fiber and the right-hand diagram demonstrate
the relation of myosin filaments to actin filaments.
allows smooth muscle cells to contract as much as 80 percent of their length instead of being limited to less than
30 percent, as occurs in skeletal muscle.
Comparison of Smooth Muscle Contraction and
Skeletal Muscle Contraction
Although most skeletal muscles contract and relax rapidly,
most smooth muscle contraction is prolonged tonic contraction, sometimes lasting hours or even days. Therefore,
it is to be expected that both the physical and the chemical characteristics of smooth muscle versus skeletal muscle contraction would differ. Following are some of the
Slow Cycling of the Myosin Cross-Bridges. The rapidity of cycling of the myosin cross-bridges in smooth muscle—that is, their attachment to actin, then release from the
actin, and reattachment for the next cycle—is much slower
Chapter 8 Excitation and Contraction of Smooth Muscle
The importance of the latch mechanism is that it can
maintain prolonged tonic contraction in smooth muscle for
hours with little use of energy. Little continued excitatory
signal is required from nerve fibers or hormonal sources.
Stress-Relaxation of Smooth Muscle. Another important characteristic of smooth muscle, especially the visceral
unitary type of smooth muscle of many hollow organs, is
its ability to return to nearly its original force of contraction seconds or minutes after it has been elongated or
shortened. For example, a sudden increase in fluid volume
in the urinary bladder, thus stretching the smooth muscle
in the bladder wall, causes an immediate large increase in
pressure in the bladder. However, during the next 15 seconds to a minute or so, despite continued stretch of the
bladder wall, the pressure returns almost exactly back to
the original level. Then, when the volume is increased by
another step, the same effect occurs again.
Conversely, when the volume is suddenly decreased,
the pressure falls drastically at first but then rises in
another few seconds or minutes to or near to the original
level. These phenomena are called stress-relaxation and
reverse stress-relaxation. Their importance is that, except
for short periods of time, they allow a hollow organ to
maintain about the same amount of pressure inside its
lumen despite long-term, large changes in volume.
Regulation of Contraction by Calcium Ions
As is true for skeletal muscle, the initiating stimulus for
most smooth muscle contraction is an increase in intracellular calcium ions. This increase can be caused in different
types of smooth muscle by nerve stimulation of the smooth
muscle fiber, hormonal stimulation, stretch of the fiber,
or even change in the chemical environment of the fiber.
Yet smooth muscle does not contain troponin, the regulatory protein that is activated by calcium ions to cause
skeletal muscle contraction. Instead, smooth muscle contraction is activated by an entirely different mechanism,
as follows.
Calcium Ions Combine with Calmodulin to Cause
Activation of Myosin Kinase and Phosphorylation of
the Myosin Head. In place of troponin, smooth muscle
cells contain a large amount of another regulatory protein
called calmodulin (Figure 8-3). Although this protein is
similar to troponin, it is different in the manner in which
it initiates contraction. Calmodulin does this by activating
the myosin cross-bridges. This activation and subsequent
contraction occur in the following sequence:
1. The calcium ions bind with calmodulin.
2. The calmodulin-calcium complex then joins with and
activates myosin light chain kinase, a phosphorylating
3. One of the light chains of each myosin head, called
the regulatory chain, becomes phosphorylated in
response to this myosin kinase. When this chain is not
­phosphorylated, the attachment-detachment cycling of
the ­myosin head with the actin filament does not occur.
U n i t II
than in skeletal muscle; in fact, the frequency is as little as
1/10 to 1/300 that in skeletal muscle. Yet the fraction of
time that the cross-bridges remain attached to the actin filaments, which is a major factor that determines the force
of contraction, is believed to be greatly increased in smooth
muscle. A possible reason for the slow cycling is that the
cross-bridge heads have far less ATPase activity than in
skeletal muscle, so degradation of the ATP that energizes
the movements of the cross-bridge heads is greatly reduced,
with corresponding slowing of the rate of cycling.
Low Energy Requirement to Sustain Smooth Muscle
Contraction. Only 1/10 to 1/300 as much energy is
required to sustain the same tension of contraction in
smooth muscle as in skeletal muscle. This, too, is believed
to result from the slow attachment and detachment cycling
of the cross-bridges and because only one molecule of ATP
is required for each cycle, regardless of its duration.
This sparsity of energy utilization by smooth muscle is
exceedingly important to the overall energy economy of
the body because organs such as the intestines, urinary
bladder, gallbladder, and other viscera often maintain
tonic muscle contraction almost indefinitely.
Slowness of Onset of Contraction and Relaxation of
the Total Smooth Muscle Tissue. A typical smooth muscle tissue begins to contract 50 to 100 milliseconds after it
is excited, reaches full contraction about 0.5 second later,
and then declines in contractile force in another 1 to 2
seconds, giving a total contraction time of 1 to 3 seconds.
This is about 30 times as long as a single contraction of
an average skeletal muscle fiber. But because there are so
many types of smooth muscle, contraction of some types
can be as short as 0.2 second or as long as 30 seconds.
The slow onset of contraction of smooth muscle, as
well as its prolonged contraction, is caused by the slowness of attachment and detachment of the cross-bridges
with the actin filaments. In addition, the initiation of contraction in response to calcium ions is much slower than
in skeletal muscle, as discussed later.
Maximum Force of Contraction Is Often Greater in
Smooth Muscle Than in Skeletal Muscle. Despite the
relatively few myosin filaments in smooth muscle, and
despite the slow cycling time of the cross-bridges, the
maximum force of contraction of smooth muscle is often
greater than that of skeletal muscle—as great as 4 to 6 kg/
cm2 cross-sectional area for smooth muscle, in comparison with 3 to 4 kilograms for skeletal muscle. This great
force of smooth muscle contraction results from the prolonged period of attachment of the myosin cross-bridges
to the actin filaments.
“Latch” Mechanism Facilitates Prolonged Holding of
Contractions of Smooth Muscle. Once smooth muscle
has developed full contraction, the amount of continuing
excitation can usually be reduced to far less than the initial
level yet the muscle maintains its full force of contraction.
Further, the energy consumed to maintain contraction is
often minuscule, sometimes as little as 1/300 the energy
required for comparable sustained skeletal muscle contraction. This is called the “latch” mechanism.
Unit II Membrane Physiology, Nerve, and Muscle
- Calmodulin
been made to explain it. Among the many mechanisms that
have been postulated, one of the simplest is the following.
When the myosin kinase and myosin phosphatase
enzymes are both strongly activated, the cycling frequency
of the myosin heads and the velocity of contraction are
great. Then, as the activation of the enzymes decreases,
the cycling frequency decreases, but at the same time, the
deactivation of these enzymes allows the myosin heads to
remain attached to the actin filament for a longer and longer proportion of the cycling period. Therefore, the number of heads attached to the actin filament at any given
time remains large. Because the number of heads attached
to the actin determines the static force of contraction, tension is maintained, or “latched”; yet little energy is used by
the muscle because ATP is not degraded to ADP except
on the rare occasion when a head detaches.
Figure 8-3 Intracellular calcium ion (Ca++) concentration increases
when Ca++ enters the cell through calcium channels in the cell
membrane or the sarcoplasmic reticulum (SR). The Ca++ binds to
calmodulin to form a Ca++-calmodulin complex, which then activates myosin light chain kinase (MLCK). The MLCK phosphorylates
the myosin light chain (MLC) leading to contraction of the smooth
muscle. When Ca++ concentration decreases, due to pumping of
Ca++ out of the cell, the process is reversed and myosin phosphatase removes the phosphate from MLC, leading to relaxation.
But when the regulatory chain is phosphorylated, the
head has the capability of binding repetitively with the
actin filament and proceeding through the entire cycling
process of intermittent “pulls,” the same as occurs for
skeletal muscle, thus causing muscle contraction.
Myosin Phosphatase Is Important in Cessation of
Contraction. When the calcium ion concentration falls
below a critical level, the aforementioned processes automatically reverse, except for the phosphorylation of the
myosin head. Reversal of this requires another enzyme,
myosin phosphatase (see Figure 8-3), located in the cytosol
of the smooth muscle cell, which splits the phosphate from
the regulatory light chain. Then the cycling stops and contraction ceases. The time required for relaxation of muscle
contraction, therefore, is determined to a great extent by
the amount of active myosin phosphatase in the cell.
Nervous and Hormonal Control
of Smooth Muscle Contraction
Although skeletal muscle fibers are stimulated exclusively
by the nervous system, smooth muscle can be stimulated
to contract by multiple types of signals: by nervous signals, by hormonal stimulation, by stretch of the muscle,
and in several other ways. The principal reason for the
difference is that the smooth muscle membrane contains many types of receptor proteins that can initiate the
contractile process. Still other receptor proteins inhibit
smooth muscle contraction, which is another difference
from skeletal muscle. Therefore, in this section, we discuss nervous control of smooth muscle contraction, followed by hormonal control and other means of control.
Neuromuscular Junctions of Smooth Muscle
Physiologic Anatomy of Smooth Muscle Neu­
romuscular Junctions. Neuromuscular junctions of
the highly structured type found on skeletal muscle
fibers do not occur in smooth muscle. Instead, the autonomic nerve fibers that innervate smooth muscle generally branch diffusely on top of a sheet of muscle fibers,
as shown in Figure 8-4. In most instances, these fibers
Gap junctions
Possible Mechanism for Regulation
of the Latch Phenomenon
Because of the importance of the latch phenomenon in
smooth muscle, and because this phenomenon allows longterm maintenance of tone in many smooth muscle organs
without much expenditure of energy, many attempts have
Figure 8-4 Innervation of smooth muscle.
Chapter 8 Excitation and Contraction of Smooth Muscle
secreted by the 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.
But why are these responses different? 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. Some
of the receptor proteins are excitatory receptors, whereas
others are inhibitory receptors. Thus, the type of receptor determines whether the smooth muscle is inhibited
or excited and also determines which of the two transmitters, acetylcholine or norepinephrine, is effective in
Membrane Potentials and Action Potentials
in Smooth Muscle
Membrane Potentials in Smooth Muscle. The
quantitative voltage of the membrane potential of smooth
muscle depends on the momentary condition of the muscle. In the normal resting state, the intracellular potential
is usually about −50 to −60 millivolts, which is about 30
millivolts less negative than in skeletal muscle.
Action Potentials in Unitary Smooth Muscle. Action
potentials occur in unitary smooth muscle (such as visceral muscle) in the same way that they occur in skeletal
muscle. They do not normally occur in most multi-unit
types of smooth muscle, as discussed in a subsequent
The action potentials of visceral smooth muscle occur
in one of two forms: (1) spike potentials or (2) action
potentials with plateaus.
Spike Potentials. Typical spike action potentials,
such as those seen in skeletal muscle, occur in most types
of unitary smooth muscle. The duration of this type of
action potential is 10 to 50 milliseconds, as shown in
Figure 8-5A. Such action potentials can be elicited in
many ways, for example, by electrical stimulation, by the
Slow waves
Excitatory and Inhibitory Transmitter Substances
Secreted at the Smooth Muscle Neuromuscular
Junction. The most important transmitter substances
causing the excitation or inhibition. These receptors are
discussed in more detail in Chapter 60 in relation to function of the autonomic nervous system.
Figure 8-5 A, Typical smooth muscle action potential (spike
potential) elicited by an external stimulus. B, Repetitive spike
potentials, elicited by slow rhythmical electrical waves that
occur spontaneously in the smooth muscle of the intestinal
wall. C, Action potential with a plateau, recorded from a smooth
muscle fiber of the uterus.
U n i t II
do not make direct contact with the smooth muscle
fiber cell membranes but instead form so-called diffuse
junctions that secrete their transmitter substance into
the matrix coating of the smooth muscle often a few
nanometers to a few micrometers away from the muscle cells; the transmitter substance then diffuses to the
cells. Furthermore, where there are many layers of muscle cells, the nerve fibers often innervate only the outer
layer. Muscle excitation travels from this outer layer to
the inner layers by action potential conduction in the
muscle mass or by additional diffusion of the transmitter substance.
The axons that innervate smooth muscle fibers do not
have typical branching end feet of the type in the motor
end plate on skeletal muscle fibers. Instead, most of the
fine terminal axons have multiple varicosities distributed
along their axes. At these points the Schwann cells that
envelop the axons are interrupted so that transmitter substance can be secreted through the walls of the varicosities. In the varicosities are vesicles similar to those in the
skeletal muscle end plate that contain transmitter substance. But in contrast to the vesicles of skeletal muscle
junctions, which always contain acetylcholine, the vesicles of the autonomic nerve fiber endings contain acetylcholine in some fibers and norepinephrine in others—and
occasionally other substances as well.
In a few instances, particularly in the multi-unit type
of smooth muscle, the varicosities are separated from
the muscle cell membrane by as little as 20 to 30 nanometers—the same width as the synaptic cleft that occurs
in the skeletal muscle junction. These are called contact
junctions, and they function in much the same way as
the skeletal muscle neuromuscular junction; the rapidity
of contraction of these smooth muscle fibers is considerably faster than that of fibers stimulated by the diffuse
Unit II Membrane Physiology, Nerve, and Muscle
action of hormones on the smooth muscle, by the action
of transmitter substances from nerve fibers, by stretch, or
as a result of spontaneous generation in the muscle fiber
itself, as discussed subsequently.
Action Potentials with Plateaus. Figure 8-5C
shows a smooth muscle action potential with a plateau.
The onset of this action potential is similar to that of the
typical spike potential. However, instead of rapid repolarization of the muscle fiber membrane, the repolarization is delayed for several hundred to as much as 1000
milliseconds (1 second). The importance of the plateau
is that it can account for the prolonged contraction that
occurs in some types of smooth muscle, such as the
ureter, the uterus under some conditions, and certain
types of vascular smooth muscle. (Also, this is the type
of action potential seen in cardiac muscle fibers that
have a prolonged period of contraction, as discussed in
Chapters 9 and 10.)
Calcium Channels Are Important in Generating
the Smooth Muscle Action Potential. The smooth
muscle cell membrane has far more voltage-gated calcium
channels than does skeletal muscle but few voltage-gated
sodium channels. Therefore, sodium participates little
in the generation of the action potential in most smooth
muscle. Instead, flow of calcium ions to the interior of
the fiber is mainly responsible for the action potential.
This occurs in the same self-regenerative way as occurs
for the sodium channels in nerve fibers and in skeletal
muscle fibers. However, the calcium channels open many
times more slowly than do sodium channels, and they also
remain open much longer. This accounts in large measure for the prolonged plateau action potentials of some
smooth muscle fibers.
Another important feature of calcium ion entry into
the cells during the action potential is that the calcium
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
Can Lead to Spontaneous Generation of Action
Potentials. Some smooth muscle is self-excitatory. That
is, action potentials arise within the smooth muscle cells
themselves without an extrinsic stimulus. This is often
associated with a basic slow wave rhythm of the membrane potential. A typical slow wave in a visceral smooth
muscle of the gut is shown in Figure 8-5B. The slow wave
itself is not the action potential. That is, it is not a selfregenerative process that spreads progressively over the
membranes of the muscle fibers. Instead, it is a local
property of the smooth muscle fibers that make 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 (presumably
sodium ions) outward through the muscle fiber mem96
brane; that is, the membrane potential becomes more
negative when sodium is pumped rapidly and less negative when the sodium pump becomes less active. Another
suggestion is that the conductances of the ion channels
increase and decrease rhythmically.
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 contraction. However, when the peak of the negative slow wave
potential inside the cell membrane rises in the positive
direction from −60 to about −35 millivolts (the approximate threshold for eliciting action potentials in most visceral smooth muscle), an action potential develops and
spreads over the muscle mass and contraction occurs.
Figure 8-5B demonstrates this effect, showing that at
each peak of the slow wave, one or more action potentials occur. These repetitive sequences of action potentials
elicit rhythmical contraction of the smooth muscle mass.
Therefore, the slow waves are called pacemaker waves. In
Chapter 62, we see that this type of pacemaker activity
controls the rhythmical contractions of the gut.
Excitation of Visceral Smooth Muscle by Muscle
Stretch. When visceral (unitary) smooth muscle is
stretched sufficiently, spontaneous action potentials
are usually generated. They result from a combination
of (1) the normal slow wave potentials and (2) decrease
in overall negativity of the membrane potential caused
by the stretch itself. This response to stretch allows the
gut wall, when excessively stretched, to contract automatically and rhythmically. For instance, when the gut
is overfilled by intestinal contents, local automatic contractions often set up peristaltic waves that move the
contents away from the overfilled intestine, usually in
the direction of the anus.
Depolarization of Multi-Unit Smooth Muscle
Without Action Potentials
The smooth muscle fibers of multi-unit smooth muscle
(such as the muscle of the iris of the eye or the piloerector
muscle of each hair) normally contract mainly in response
to nerve stimuli. The nerve endings secrete acetylcholine in the case of some multi-unit smooth muscles and
norepinephrine in the case of others. In both instances,
the transmitter substances cause depolarization of the
smooth muscle membrane, and this in turn elicits contraction. Action potentials usually do not develop; the
reason is that the fibers are too small to generate an action
potential. (When action potentials are elicited in visceral
unitary smooth muscle, 30 to 40 smooth muscle fibers
must depolarize simultaneously before a self-propagating
action potential ensues.) Yet in small smooth muscle cells,
even without an action potential, the local depolarization (called the junctional potential) caused by the nerve
transmitter substance itself spreads “electrotonically” over
the entire fiber and is all that is necessary to cause muscle
Chapter 8 Excitation and Contraction of Smooth Muscle
Effect of Local Tissue Factors and Hormones
to Cause Smooth Muscle Contraction Without
Action Potentials
Smooth Muscle Contraction in Response to Local
Tissue Chemical Factors. In Chapter 17, we discuss
control of contraction of the arterioles, meta-arterioles,
and precapillary sphincters. The smallest of these vessels
have little or no nervous supply. Yet the smooth muscle is
highly contractile, responding rapidly to changes in local
chemical conditions in the surrounding interstitial fluid.
In the normal resting state, many of these small blood
vessels remain contracted. But when extra blood flow
to the tissue is necessary, multiple factors can relax the
vessel wall, thus allowing for increased flow. In this way,
a powerful local feedback control system controls the
blood flow to the local tissue area. Some of the specific
control factors are as follows:
1. Lack of oxygen in the local tissues causes smooth muscle relaxation and, therefore, vasodilatation.
2. Excess carbon dioxide causes vasodilatation.
3. Increased hydrogen ion concentration causes vaso­
Adenosine, lactic acid, increased potassium ions,
diminished calcium ion concentration, and increased
body temperature can all cause local vasodilatation.
Effects of Hormones on Smooth Muscle
Contraction. Many circulating hormones in the blood
affect smooth muscle contraction to some degree, and
some have profound effects. Among the more important
of these are norepinephrine, epinephrine, acetylcholine,
angiotensin, endothelin, vasopressin, oxytocin, serotonin,
and histamine.
A hormone causes contraction of a smooth muscle when the muscle cell membrane contains hormonegated excitatory receptors for the respective hormone.
Conversely, the hormone causes inhibition if the membrane contains inhibitory receptors for the hormone rather
than excitatory receptors.
Mechanisms of Smooth Muscle Excitation or
Inhibition by Hormones or Local Tissue Factors. Some
hormone receptors in the smooth muscle membrane open
sodium or calcium ion channels and depolarize the membrane, the same as after nerve stimulation. Sometimes
action potentials result, or action potentials that are
already occurring may be enhanced. In other cases, depolarization occurs without action potentials and this depolarization allows calcium ion entry into the cell, which
promotes the contraction.
Source of Calcium Ions That Cause Contraction
Through the Cell Membrane and 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. An important difference is that
the sarcoplasmic reticulum, which provides virtually all
the calcium ions for skeletal muscle contraction, is only
slightly developed in most smooth muscle. Instead, most
of the calcium ions that cause contraction enter the muscle cell from the extracellular 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, in comparison with less than 10−7 molar inside the
smooth muscle cell; this causes rapid diffusion of the calcium ions into the cell from the extracellular fluid when
the calcium channels open. The time required for this
diffusion to occur averages 200 to 300 milliseconds and
U n i t II
Probably half of all smooth muscle contraction is initiated
by stimulatory factors acting directly on the smooth muscle contractile machinery and without action potentials.
Two types of non-nervous and nonaction potential stimulating factors often involved are (1) local tissue chemical
factors and (2) various hormones.
Inhibition, in contrast, occurs when the hormone (or
other tissue factor) closes the sodium and calcium channels to prevent entry of these positive ions; inhibition
also occurs if the normally closed potassium channels are
opened, allowing positive potassium ions to diffuse out of
the cell. Both of these actions increase the degree of negativity inside the muscle cell, a state called hyperpolarization, which strongly inhibits muscle contraction.
Sometimes smooth muscle contraction or inhibition
is initiated by hormones without directly causing any
change in the membrane potential. In these instances, the
hormone may activate a membrane receptor that does
not open any ion channels but instead causes an internal change in the muscle fiber, such as release of calcium
ions from the intracellular sarcoplasmic reticulum; the
calcium then induces contraction. To inhibit contraction,
other receptor mechanisms are known to activate the
enzyme adenylate cyclase or guanylate cyclase in the cell
membrane; the portions of the receptors that protrude
to the interior of the cells are coupled to these enzymes,
causing the formation of cyclic adenosine monophosphate
(cAMP) or cyclic guanosine monophosphate (cGMP), socalled second messengers. The cAMP or cGMP has many
effects, one of which is to change the degree of phosphorylation of several enzymes that indirectly inhibit contraction. The pump that moves calcium ions from the
sarcoplasm into the sarcoplasmic reticulum is activated,
as well as the cell membrane pump that moves calcium
ions out of the cell itself; these effects reduce the calcium
ion concentration in the sarcoplasm, thereby inhibiting
Smooth muscles have considerable diversity in how
they initiate contraction or relaxation in response to
different hormones, neurotransmitters, and other substances. In some instances, the same substance may cause
either relaxation or contraction of smooth muscles in different locations. For example, norepinephrine inhibits
contraction of smooth muscle in the intestine but stimulates contraction of smooth muscle in blood vessels.
Unit II Membrane Physiology, Nerve, and Muscle
is called the latent period before contraction begins.
This latent period is about 50 times as great for smooth
muscle as for skeletal muscle contraction.
Role of the Smooth Muscle Sarcoplasmic Reti­c­
ulum. Figure 8-6 shows a few slightly developed sarco­
plasmic tubules that lie near the cell membrane in some
larger smooth muscle cells. Small invaginations of the
cell membrane, called caveolae, abut the surfaces of these
tubules. The caveolae suggest a rudimentary analog of the
transverse tubule system of skeletal 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 same way that action potentials in skeletal muscle transverse tubules cause release of calcium ions
from the skeletal muscle longitudinal sarcoplasmic tubules.
In general, the more extensive the sarcoplasmic reticulum
in the smooth muscle fiber, the more rapidly it contracts.
Smooth Muscle Contraction Is Dependent on
Extracellular Calcium Ion Concentration. Although
changing the extracellular fluid calcium ion concentration
from normal has little effect on the force of contraction of
skeletal muscle, this is not true for most smooth muscle.
When the extracellular fluid calcium ion concentration
falls to about 1/3 to 1/10 normal, smooth muscle contraction usually ceases. Therefore, the force of contraction of
smooth muscle is usually highly dependent on extracellular fluid calcium ion concentration.
Figure 8-6 Sarcoplasmic tubules in a large smooth muscle fiber
showing their relation to invaginations in the cell membrane called
A Calcium Pump Is Required to Cause Smooth
Muscle Relaxation. To cause relaxation of smooth
muscle after it has contracted, the calcium ions must
be removed from the intracellular fluids. This removal
is achieved by a calcium pump that pumps calcium ions
out of the smooth muscle fiber back into the extracellular fluid, or into a sarcoplasmic reticulum, if it is present.
This pump is slow-acting in comparison with the fastacting sarcoplasmic reticulum pump in skeletal muscle.
Therefore, a single smooth muscle contraction often lasts
for seconds rather than hundredths to tenths of a second,
as occurs for skeletal muscle.
Also see references for Chapters 5 and 6.
Andersson KE, Arner A: Pharmacology of the lower urinary tract: basis for
current and future treatments of urinary incontinence, Physiol Rev
84:935, 2004.
Berridge MJ: Smooth muscle cell calcium activation mechanisms, J Physiol
586:5047, 2008.
Blaustein MP, Lederer WJ: Sodium/calcium exchange: its physiological
implications, Physiol Rev 79:763, 1999.
Cheng H, Lederer WJ: Calcium sparks, Physiol Rev 88:1491, 2008.
Davis MJ, Hill MA: Signaling mechanisms underlying the vascular myogenic
response, Physiol Rev 79:387, 1999.
Drummond HA, Grifoni SC, Jernigan NLA: New trick for an old dogma:
ENaC proteins as mechanotransducers in vascular smooth muscle,
Physiology (Bethesda) 23:23, 2008.
Harnett KM, Biancani P: Calcium-dependent and calcium-independent
contractions in smooth muscles, Am J Med 115(Suppl 3A):24S, 2003.
Hilgers RH, Webb RC: Molecular aspects of arterial smooth muscle contraction: focus on Rho, Exp Biol Med (Maywood) 230:829, 2005.
House SJ, Potier M, Bisaillon J, Singer HA, Trebak M: The non-excitable
smooth muscle: calcium signaling and phenotypic switching during vascular disease, Pflugers Arch 456:769, 2008.
Huizinga JD, Lammers WJ: Gut peristalsis is governed by a multitude of
cooperating mechanisms, Am J Physiol Gastrointest Liver Physiol 296:G1,
Kuriyama H, Kitamura K, Itoh T, Inoue R: Physiological features of visceral
smooth muscle cells, with special reference to receptors and ion channels, Physiol Rev 78:811, 1998.
Morgan KG, Gangopadhyay SS: Cross-bridge regulation by thin filamentassociated proteins, J Appl Physiol 91:953, 2001.
Somlyo AP, Somlyo AV: Ca2+ sensitivity of smooth muscle and nonmuscle
myosin II: modulated by G proteins, kinases, and myosin phosphatase,
Physiol Rev 83:1325, 2003.
Stephens NL: Airway smooth muscle, Lung 179:333, 2001.
Touyz RM: Transient receptor potential melastatin 6 and 7 channels, magnesium transport, and vascular biology: implications in hypertension,
Am J Physiol Heart Circ Physiol 294:H1103, 2008.
Walker JS, Wingard CJ, Murphy RA: Energetics of crossbridge phosphorylation and contraction in vascular smooth muscle, Hypertension 23:1106,
Wamhoff BR, Bowles DK, Owens GK: Excitation-transcription coupling in
arterial smooth muscle, Circ Res 98:868, 2006.
Webb RC: Smooth muscle contraction and relaxation, Adv Physiol Educ
27:201, 2003.
The Heart
9. Cardiac Muscle; The Heart as a Pump
and Function of the Heart Valves
10. Rhythmical Excitation of the Heart
11. The Normal Electrocardiogram
12. Electrocardiographic Interpretation of
Cardiac Muscle and Coronary Blood
Flow Abnormalities: Vectorial Analysis
13. Cardiac Arrhythmias and Their
Electrocardiographic Interpretation
This page intentionally left blank
chapter 9
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 circulation 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 contractions called cardiac rhythmicity, transmitting action potentials throughout the cardiac
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 cardiac muscle itself.
Physiology of Cardiac Muscle
The heart is composed of three major types of cardiac
muscle: atrial muscle, ventricular muscle, and specialized
excitatory and conductive muscle fibers. The atrial and
ventricular types of muscle contract in much the same way
as skeletal muscle, except that the duration of contraction
is much longer. The specialized excitatory and conductive
fibers, however, contract only feebly because they contain
few contractile fibrils; instead, they exhibit either automatic rhythmical 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.
again. One also notes immediately from this figure that
cardiac muscle is striated in the same manner as in skeletal muscle. Further, cardiac muscle has typical myofibrils
that contain actin and myosin filaments almost identical to
those found in skeletal muscle; these filaments 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
At each intercalated disc the cell membranes fuse with
one another in such a way that they form permeable “communicating” junctions (gap junctions) that allow rapid
diffusion of ions. Therefore, from a functional point of
view, ions move with ease in the intracellular fluid along
the longitudinal axes of the cardiac muscle fibers so that
Pulmonary artery
vena cava
Right atrium
Right ventricle
vena cava
Left atrium
Mitral valve
Aortic valve
Physiologic Anatomy of Cardiac Muscle
Figure 9-2 shows the histology of cardiac muscle, demonstrating cardiac muscle fibers arranged in a latticework,
with the fibers dividing, recombining, and then spreading
Figure 9-1 Structure of the heart, and course of blood flow through
the heart chambers and heart valves.
U nit I I I
Cardiac Muscle; The Heart as a Pump
and Function of the Heart Valves
Unit III The Heart
Figure 9-2 “Syncytial,” interconnecting nature of cardiac muscle
action potentials travel easily from one cardiac muscle
cell to the next, past the intercalated discs. Thus, cardiac
muscle is a syncytium of many heart muscle cells in which
the cardiac cells are so interconnected that when one of
these cells becomes excited, the action potential spreads
to all of them, from cell to cell throughout the latticework
The heart actually is composed of two syncytiums: the
atrial syncytium, which constitutes the walls of the two
atria, and the ventricular syncytium, which constitutes the
walls of the two ventricles. The atria are separated from
the ventricles by fibrous tissue that surrounds the atrioventricular (A-V) valvular openings between the atria
and ventricles. Normally, potentials 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 functional syncytiums allows the atria to contract a short time
ahead of ventricular contraction, which is important for
effectiveness of heart pumping.
Action Potentials in Cardiac Muscle
The action potential recorded in a ventricular muscle fiber,
shown in Figure 9-3, averages about 105 millivolts, which
means that the intracellular potential rises from a very negative value, about −85 millivolts, between beats to a slightly
positive value, about +20 millivolts, during each beat. After
the initial spike, the membrane remains depolarized for
about 0.2 second, exhibiting a plateau as shown in the figure,
followed at the end of the plateau by abrupt repolarization.
The presence of this plateau in the action potential causes
ventricular contraction to last as much as 15 times as long in
cardiac muscle as in skeletal muscle.
What Causes the Long Action Potential and the
Plateau? At this point, we address the questions: Why
is the action potential of cardiac muscle so long and
why does it have a plateau, whereas that of skeletal muscle
–100 Purkinje fiber
–100 Ventricular muscle
Figure 9-3 Rhythmical action potentials (in millivolts) from a
Purkinje fiber and from a ventricular muscle fiber, recorded by
means of microelectrodes.
does not? The basic biophysical answers to these questions
were presented in Chapter 5, but they merit ­summarizing
here as well.
At least two major differences between the membrane
properties of cardiac and skeletal muscle account for the
prolonged action potential and the plateau in cardiac muscle. First, the action potential of skeletal muscle is caused
almost entirely by sudden opening of large numbers of socalled fast sodium channels that allow tremendous numbers of sodium ions to enter the skeletal muscle fiber from
the extracellular fluid. These channels are called “fast”
channels because they remain open for only a few thousandths of a second and then abruptly close. At the end of
this closure, repolarization occurs, and the action potential is over within another thousandth of a second or so.
In cardiac muscle, the action potential is caused by
opening of two types of channels: (1) the same fast sodium
channels as those in skeletal muscle and (2) another entirely
different population of slow calcium channels, which are
also called calcium-sodium channels. This second population of channels differs from the fast sodium channels in
that they are slower to open and, even more important,
remain open for several tenths of a second. During this
time, a large quantity of both calcium and sodium ions
flows through these channels to the interior of the cardiac muscle fiber, and this maintains a prolonged period
of depolarization, causing the plateau in the action potential. Further, the calcium ions that enter during this plateau phase activate the muscle contractile process, while
the calcium ions that cause skeletal muscle contraction are
derived from the intracellular ­sarcoplasmic reticulum.
The second major functional difference between cardiac muscle and skeletal muscle that helps account for
both the prolonged action potential and its plateau is this:
Immediately after the onset of the action potential, the permeability of the cardiac muscle membrane for ­potassium
ions decreases about fivefold, an effect that does not occur
Chapter 9 Cardiac Muscle; The Heart as a Pump and Function of the Heart Valves
Refractory period
Force of contraction
Relative refractory
Early premature
Later premature
Figure 9-4 Force of ventricular heart muscle contraction, showing also duration of the refractory period and relative refractory
period, plus the effect of premature contraction. Note that premature contractions do not cause wave summation, as occurs in
skeletal muscle.
Excitation-Contraction Coupling—Function of
Calcium Ions and the Transverse Tubules
The term “excitation-contraction coupling” refers to the
mechanism by which the action potential causes the
myofibrils of muscle to contract. This was discussed for
skeletal muscle in Chapter 7. Once again, there are differences in this mechanism in cardiac muscle that have
important effects on the characteristics of heart muscle
As is true for skeletal muscle, when an action potential passes over the cardiac muscle membrane, the action
potential spreads to the interior of the cardiac muscle fiber
along the membranes of the transverse (T) tubules. The T
tubule action potentials in turn act on the ­membranes of
the longitudinal sarcoplasmic tubules to cause release of
calcium ions into the muscle sarcoplasm from the sarcoplasmic reticulum. In another few thousandths of a second, these calcium ions diffuse into the myofibrils and
catalyze the chemical reactions that promote sliding of
the actin and myosin filaments along one another; this
produces the muscle contraction.
Thus far, this mechanism of excitation-contraction
coupling is the same as that for skeletal muscle, but there
is a second effect that is quite different. In addition to the
calcium ions that are released into the sarcoplasm from
the cisternae of the sarcoplasmic reticulum, calcium ions
also diffuse into the sarcoplasm from the T tubules themselves at the time of the action potential, which opens
voltage-dependent calcium channels in the membrane of
the T tubule (Figure 9-5). Calcium entering the cell then
activates calcium release channels, also called ryanodine
receptor channels, in the sarcoplasmic reticulum membrane, triggering the release of calcium into the sarcoplasm. Calcium ions in the sarcoplasm then interact with
troponin to initiate cross-bridge formation and contraction by the same basic mechanism as described for
­skeletal muscle in Chapter 6.
Without the calcium from the T tubules, the strength
of cardiac muscle contraction would be reduced considerably because the sarcoplasmic reticulum of cardiac muscle is less well developed than that of skeletal muscle and
does not store enough calcium to provide full contraction.
The T tubules of cardiac muscle, however, have a diameter 5 times as great as that of the skeletal muscle tubules,
which means a volume 25 times as great. Also, inside the
T tubules is a large quantity of mucopolysaccharides that
are electronegatively charged and bind an abundant 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.
The strength of contraction of cardiac muscle depends
to a great extent on the concentration of calcium ions in
the extracellular fluids. In fact, a heart placed in a calcium-free solution will quickly stop beating. The reason
for this is that the openings of the T tubules pass directly
through the cardiac muscle cell membrane into the extracellular spaces surrounding the cells, allowing the same
U nit I I I
in skeletal muscle. This decreased potassium ­permeability
may result from the excess ­calcium influx through the
calcium channels just noted. Regardless of the cause,
the decreased potassium permeability greatly decreases
the outflux of positively charged potassium ions during the
action potential plateau and thereby prevents early return
of the action potential voltage to its resting level. When the
slow calcium-sodium channels do close at the end of 0.2
to 0.3 second and the influx of calcium and sodium ions
ceases, the membrane permeability for potassium ions also
increases rapidly; this rapid loss of potassium from the fiber
immediately returns the membrane ­potential to its resting
level, thus ending the action potential.
Velocity of Signal Conduction in Cardiac Muscle. The
velocity of conduction of the excitatory action potential
signal along both atrial and ventricular muscle fibers is
about 0.3 to 0.5 m/sec, or about 1⁄250 the velocity in very
large nerve fibers and about 1⁄10 the velocity in skeletal
muscle fibers. The velocity of conduction in the specialized heart conductive system—in the Purkinje fibers—is as
great as 4 m/sec in most parts of the system, which allows
reasonably rapid conduction of the excitatory signal to the
different parts of the heart, as explained in Chapter 10.
Refractory Period of Cardiac Muscle. Cardiac muscle,
like all excitable tissue, is refractory to restimulation during
the action potential. Therefore, the refractory period of the
heart is the interval of time, as shown to the left in Figure
9-4, during which a normal cardiac impulse cannot reexcite an already excited area of cardiac muscle. The normal refractory period of the ventricle is 0.25 to 0.30 second,
which is about the duration of the prolonged plateau action
potential. There is an additional relative refractory period of
about 0.05 second during which the muscle is more difficult
than normal to excite but nevertheless can be excited by a
very strong excitatory signal, as demonstrated by the early
“premature” contraction in the second example of Figure
9-4. The refractory period of atrial muscle is much shorter
than that for the ­ventricles (about 0.15 second for the atria
compared with 0.25 to 0.30 second for the ventricles).
Unit III The Heart
Ca++ Na+
T Tubule
Figure 9-5 Mechanisms of excitation-contraction coupling and relaxation in cardiac muscle.
e­ xtracellular fluid that is in the cardiac muscle interstitium
to ­percolate through the T tubules as well. Consequently,
the quantity of calcium ions in the T tubule system (i.e.,
the availability of calcium ions to cause cardiac muscle
contraction) depends to a great extent on the ­extracellular
fluid calcium ion concentration.
In contrast, the strength of skeletal muscle contraction is hardly affected by moderate changes in extracellular fluid calcium concentration because skeletal
muscle contraction is caused almost entirely by calcium
ions released from the sarcoplasmic reticulum inside the
­skeletal m
­ uscle fiber.
At the end of the plateau of the cardiac action potential, the influx of calcium ions to the interior of the muscle
fiber is suddenly cut off, and the calcium ions in the sarcoplasm are rapidly pumped back out of the muscle fibers
into both the sarcoplasmic reticulum and the T tubule–
extracellular fluid space. Transport of calcium back into
the sarcoplasmic reticulum is achieved with the help of a
calcium-ATPase pump (see Figure 9-5). Calcium ions are
also removed from the cell by a sodium-calcium exchanger.
The sodium that enters the cell during this exchange is
then transported out of the cell by the sodium-potassium
ATPase pump. As a result, the contraction ceases until
a new action potential comes along.
Duration of Contraction. Cardiac muscle begins to contract a few milliseconds after the action potential begins
and ­continues to contract until a few ­milliseconds
after the action potential ends. Therefore, the ­duration
of ­contraction of cardiac muscle is mainly a function
of the ­duration of the action potential, including the
­plateau—about 0.2 second in atrial muscle and 0.3 second
in ­ventricular muscle.
Cardiac Cycle
The cardiac events that occur from the beginning of
one heartbeat to the beginning of the next are called
the ­cardiac cycle. Each cycle is initiated by spontaneous generation of an action potential in the sinus node,
as explained in Chapter 10. This node is located in the
superior lateral wall of the right atrium near the opening
of the superior vena cava, and the action potential travels
from here rapidly through both atria and then through
the A-V bundle into the ventricles. Because of this special arrangement of the conducting system from the
atria into the ventricles, there is a delay of more than 0.1
second during passage of the cardiac impulse from the
atria into the ventricles. This allows the atria to contract
ahead of ventricular contraction, thereby pumping blood
into the ventricles before the strong ventricular contraction begins. Thus, the atria act as primer pumps for the
ventricles, and the ventricles in turn provide the major
source of power for moving blood through the body’s
vascular system.
Chapter 9 Cardiac Muscle; The Heart as a Pump and Function of the Heart Valves
Diastole and Systole
Relationship of the Electrocardiogram
to the Cardiac Cycle
Volume (ml)
Pressure (mm Hg)
The electrocardiogram in Figure 9-6 shows the P, Q, R, S, and
T waves, which are discussed in Chapters 11, 12, and 13. They
are electrical voltages generated by the heart and recorded by
the electrocardiograph from the surface of the body.
The P wave is caused by spread of depolarization
through the atria, and this is followed by atrial contraction, which causes a slight rise in the atrial pressure curve
immediately after the electrocardiographic P wave.
About 0.16 second after the onset of the P wave, the
QRS waves appear as a result of electrical depolarization
of the ventricles, which initiates contraction of the ventricles and causes the ventricular pressure to begin rising,
as also shown in the figure. Therefore, the QRS complex
begins slightly before the onset of ventricular systole.
Finally, one observes the ventricular T wave in the
­electrocardiogram. This represents the stage of repolarization of the ventricles when the ventricular muscle
fibers begin to relax. Therefore, the T wave occurs slightly
before the end of ventricular contraction.
Function of the Atria as Primer Pumps
Blood normally flows continually from the great veins
into the atria; about 80 percent of the blood flows directly
through the atria into the ventricles even before the atria
contract. Then, atrial contraction usually causes an additional 20 percent filling of the ventricles. Therefore, the atria
simply function as primer pumps that increase the ventricular pumping effectiveness as much as 20 ­percent. However,
the heart can continue to operate under most conditions
Rapid inflow
Atrial systole
Aortic valve
Aortic pressure
A-V valve
A-V valve
Atrial pressure
Ventricular pressure
Ventricular volume
Figure 9-6 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.
U nit I I I
The cardiac cycle consists of a period of relaxation called
diastole, during which the heart fills with blood, followed
by a period of contraction called systole.
The total duration of the cardiac cycle, including systole and diastole, is the reciprocal of the heart rate. For
example, if heart rate is 72 beats/min, the duration of the
cardiac cycle is 1/72 beats/min—about 0.0139 minutes
per beat, or 0.833 second per beat.
Figure 9-6 shows the different events during the cardiac cycle for the left side of the heart. The top three
curves show the pressure changes in the aorta, left ventricle, and left atrium, respectively. The fourth curve depicts
the changes in left ventricular volume, the fifth the electrocardiogram, and the sixth a phonocardiogram, which is
a recording of the sounds produced by the heart—mainly
by the heart valves—as it pumps. It is especially important
that the reader study in detail this figure and understand
the causes of all the events shown.
Effect of Heart Rate on Duration of Cardiac
Cycle. When heart rate increases, the duration of each
cardiac cycle decreases, including the contraction and
relaxation phases. The duration of the action potential
and the period of contraction (systole) also decrease, but
not by as great a percentage as does the relaxation phase
(diastole). At a normal heart rate of 72 beats/min, systole
comprises about 0.4 of the entire cardiac cycle. At three
times the normal heart rate, systole is about 0.65 of the
entire cardiac cycle. This means that the heart beating at
a very fast rate does not remain relaxed long enough to
allow complete filling of the cardiac chambers before the
next contraction.
Unit III The Heart
even without this extra 20 percent ­effectiveness because it
normally has the ­capability of pumping 300 to 400 percent
more blood than is required by the resting body. Therefore,
when the atria fail to function, the difference is unlikely to be
noticed unless a person exercises; then acute signs of heart
failure occasionally develop, especially shortness of breath.
Pressure Changes in the Atria—a, c, and v Waves. In the atrial
pressure curve of Figure 9-6, three minor pressure elevations,
called the a, c, and v atrial pressure waves, are noted.
The a wave is caused by atrial contraction. Ordinarily,
the right atrial pressure increases 4 to 6 mm Hg during atrial
contraction, and the left atrial pressure increases about 7 to
8 mm Hg.
The c wave occurs when the ventricles begin to contract;
it is caused partly by slight backflow of blood into the atria
at the onset of ventricular contraction but mainly by bulging of the A-V valves backward toward the atria because of
increasing pressure in the ventricles.
The v wave occurs toward the end of ventricular contraction; it results from slow flow of blood into the atria from the
veins while the A-V valves are closed during ventricular contraction. Then, when ventricular contraction is over, the A-V
valves open, allowing this stored atrial blood to flow rapidly
into the ventricles and causing the v wave to disappear.
Function of the Ventricles as Pumps
Filling of the Ventricles During Diastole. During ventricular systole, large amounts of blood accumulate in
the right and left atria because of the closed A-V valves.
Therefore, as soon as systole is over and the ventricular
pressures fall again to their low diastolic values, the moderately 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 ventricles, as shown by the rise of the left ventricular ­volume
curve in Figure 9-6. This is called the period of rapid ­filling
of the ventricles.
The period of rapid filling lasts for about the first third
of diastole. During the middle third of diastole, only a
small amount of blood normally flows into the ventricles;
this is blood that continues to empty into the atria from
the veins and passes through the atria directly into the
During the last third of diastole, the atria contract and
give an additional thrust to the inflow of blood into the
ventricles; this accounts for about 20 percent of the filling
of the ventricles during each heart cycle.
no emptying. This is called the period of isovolumic or
­isometric contraction, meaning that tension is increasing in the muscle but little or no shortening of the muscle
fibers is occurring.
Period of Ejection. When the left ventricular pressure rises slightly above 80 mm Hg (and the right ventricular pressure slightly above 8 mm Hg), the ventricular
pressures push the semilunar valves open. Immediately,
blood begins to pour out of the ventricles, with about 70
percent of the blood emptying occurring during the first
third of the period of ejection and the remaining 30 percent emptying during the next two thirds. Therefore, the
first third is called the period of rapid ejection, and the last
two thirds, the period of slow ejection.
Period of Isovolumic (Isometric) Relaxation. At the
end of systole, ventricular relaxation begins suddenly,
allowing both the right and left intraventricular pressures
to decrease rapidly. The elevated pressures in the distended large arteries that have just been filled with blood
from the contracted ventricles immediately push blood
back toward the ventricles, which snaps the aortic and
pulmonary valves closed. For another 0.03 to 0.06 second,
the ventricular muscle continues to relax, even though
the ventricular volume does not change, giving rise to
the period of isovolumic or isometric relaxation. During
this period, the intraventricular pressures decrease rapidly back to their low diastolic levels. Then the A-V valves
open to begin a new cycle of ventricular pumping.
End-Diastolic Volume, End-Systolic Volume, and
Stroke Volume Output. During diastole, normal ­filling
of the ventricles increases the volume of each ventricle
to about 110 to 120 ml. This volume is called the end­diastolic volume. Then, as the ventricles empty during systole, the volume decreases about 70 ml, which is
called the stroke volume output. The remaining volume in
each ventricle, about 40 to 50 ml, is called the end-­systolic
volume. The fraction of the end-diastolic volume that is
ejected is called the ejection fraction—usually equal to
about 60 percent.
When the heart contracts strongly, the end-systolic volume can be decreased to as little as 10 to 20 ml. Conversely,
when large amounts of blood flow into the ventricles during diastole, the ventricular end-diastolic volumes can
become as great as 150 to 180 ml in the healthy heart. By
both increasing the end-diastolic volume and decreasing
the end-systolic volume, the stroke volume output can be
increased to more than double normal.
Emptying of the Ventricles During Systole
Period of Isovolumic (Isometric) Contraction.
Immediately after ventricular contraction begins, the ventricular pressure rises abruptly, as shown in Figure 9-6,
causing the A-V valves to close. Then an additional 0.02
to 0.03 second is required for the ventricle to build up sufficient pressure to push the semilunar (aortic and pulmonary) valves open against the pressures in the aorta
and pulmonary artery. Therefore, during this period,
­contraction is occurring in the ventricles, but there is
Function of the Valves
Atrioventricular Valves. The A-V valves (the t­ ricuspid
and mitral valves) prevent backflow of blood from the
ventricles to the atria during systole, and the ­semilunar
valves (the aortic and pulmonary artery valves) prevent
backflow from the aorta and pulmonary arteries into the
ventricles during diastole. These valves, shown in Figure
9-7 for the left ventricle, close and open p
­ assively. That
is, they close when a backward pressure gradient pushes
Chapter 9 Cardiac Muscle; The Heart as a Pump and Function of the Heart Valves
Aortic Pressure Curve
Chordae tendineae
Papillary muscles
Figure 9-7 Mitral and aortic valves (the left ventricular valves).
blood backward, and they open when a forward pressure
gradient forces blood in the forward direction. For anatomical reasons, the thin, filmy A-V valves require almost
no backflow to cause closure, whereas the much heavier
semilunar valves require rather rapid backflow for a few
Function of the Papillary Muscles. Figure 9-7 also
shows papillary muscles that attach to the vanes of the
A-V valves by the chordae tendineae. The papillary muscles contract when the ventricular walls contract, but
contrary to what might be expected, they do not help the
valves to close. Instead, they pull the vanes of the valves
inward toward the ventricles to prevent their bulging too
far backward toward the atria during ventricular contraction. If a chorda tendinea becomes ruptured or if one of
the papillary muscles becomes paralyzed, the valve bulges
far backward during ventricular contraction, sometimes
so far that it leaks severely and results in severe or even
lethal cardiac incapacity.
Aortic and Pulmonary Artery Valves. The aortic and
pulmonary artery semilunar valves function quite differently from the A-V valves. First, the high pressures in the
arteries at the end of systole cause the semilunar valves to
snap to the closed position, in contrast to the much softer
closure of the A-V valves. Second, because of smaller
openings, the velocity of blood ejection through the aortic and pulmonary valves is far greater than that through
the much larger A-V valves. Also, because of the rapid
closure and rapid ejection, the edges of the aortic and pulmonary valves are subjected to much greater mechanical
abrasion than are the A-V valves. Finally, the A-V valves
are supported by the chordae tendineae, which is not true
for the semilunar valves. It is obvious from the anatomy of
the aortic and pulmonary valves (as shown for the aortic
valve at the bottom of Figure 9-7) that they must be constructed with an especially strong yet very pliable fibrous
tissue base to withstand the extra physical stresses.
Relationship of the Heart Sounds
to Heart Pumping
When listening to the heart with a stethoscope, one does not
hear the opening of the valves because this is a 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 of sudden pressure changes, giving off sound that travels in all directions through the chest.
When the ventricles contract, one first hears a sound
caused by closure of the A-V valves. The vibration is low in
pitch and relatively long-lasting and is known as the first heart
sound. When the aortic and pulmonary valves close at the end
of systole, one hears a rapid snap because these valves close
rapidly, and the surroundings vibrate for a short period. This
sound is called the second heart sound. The precise causes of
the heart sounds are discussed more fully in Chapter 23, in
relation to listening to the sounds with the stethoscope.
Work Output of the Heart
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 work in 1 minute; this
U nit I I I
When the left ventricle contracts, the ventricular pressure
increases rapidly until the aortic valve opens. Then, after
the valve opens, the pressure in the ventricle rises much
less rapidly, as shown in Figure 9-6, because blood immediately flows out of the ventricle into the aorta and then
into the systemic distribution arteries.
The entry of blood into the arteries causes the walls 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.
A so-called incisura occurs in the aortic pressure 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 cessation of the backflow.
After the aortic valve has closed, the pressure in the
aorta decreases slowly throughout diastole because 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 (diastolic pressure),
which is two thirds the maximal pressure of 120 mm Hg
(systolic pressure) that occurs in the aorta during ventricular contraction.
The pressure curves in the right ventricle and pulmonary artery are similar to those in the aorta, except that the
pressures are only about one sixth as great, as ­discussed
in Chapter 14.
Unit III The Heart
is equal to the stroke work output times the heart rate per
Work output of the heart is in two forms. First, by far the
major proportion is used to move the blood from the lowpressure veins to the high-pressure arteries. 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 energy of blood flow component of the
work output.
Right ventricular external work output is normally about
one sixth the work output of the left ventricle because of
the sixfold difference in systolic pressures that the two ventricles pump. The additional work output of each ventricle
required to create kinetic energy of blood flow is proportional to the mass of blood ejected times the square of velocity of ejection.
Ordinarily, the work output of the left ventricle required
to create kinetic energy of blood flow is only about 1 percent of the total work output of the ventricle and therefore
is ignored in the calculation of the total stroke work output.
But in certain abnormal conditions, such as aortic stenosis, in
which blood flows with great velocity through the stenosed
valve, more than 50 percent of the total work output may be
required to create kinetic energy of blood flow.
Left intraventricular pressure (mm Hg)
Graphical Analysis of Ventricular Pumping
Figure 9-8 shows a diagram that is especially useful in explaining the pumping mechanics of the left ventricle. The most
important components of the diagram are the two curves
labeled “diastolic pressure” and “systolic pressure.” These
curves are volume-pressure curves.
The diastolic pressure curve is determined by filling the
heart with progressively greater volumes of blood and then
measuring the diastolic pressure immediately before ventricular contraction occurs, which is the end-diastolic pressure
of the ventricle.
The systolic pressure curve is determined by recording
the systolic pressure achieved during ventricular contraction
at each volume of filling.
Systolic pressure
Period of ejection
Period of filling
Left ventricular volume (ml)
Figure 9-8 Relationship between left ventricular volume and
intraventricular pressure during diastole and systole. Also shown
by the heavy red lines is the “volume-pressure diagram,” demonstrating changes in intraventricular volume and pressure during
the normal cardiac cycle. EW, net external work.
Until the volume of the noncontracting ventricle rises
above about 150 ml, the “diastolic” pressure does not increase
greatly. Therefore, up to this volume, blood can flow easily
into the ventricle from the atrium. Above 150 ml, the ventricular diastolic pressure increases rapidly, partly because of
fibrous tissue in the heart that will stretch no more and partly
because the pericardium that surrounds the heart becomes
filled nearly to its limit.
During ventricular contraction, the “systolic” pressure
increases even at low ventricular volumes and reaches a maximum at a ventricular volume of 150 to 170 ml. Then, as the
volume increases still further, the systolic pressure actually
decreases under some conditions, as demonstrated by the
falling systolic pressure curve in Figure 9-8, because at these
great volumes, the actin and myosin filaments of the cardiac
muscle fibers are pulled apart far enough that the strength of
each cardiac fiber contraction becomes less than optimal.
Note especially in the figure that the maximum systolic
pressure for the normal left ventricle is between 250 and
300 mm Hg, but this varies widely with each person’s heart
strength and degree of heart stimulation by cardiac nerves.
For the normal right ventricle, the maximum systolic pressure is between 60 and 80 mm Hg.
“Volume-Pressure Diagram” During the Cardiac Cycle;
Cardiac Work Output. The red lines in Figure 9-8 form a
loop called the volume-pressure diagram of the cardiac cycle
for normal function of the left ventricle. A more detailed version of this loop is shown in Figure 9-9. It is divided into four
Phase I: Period of filling. This phase in the volume­pressure diagram begins at a ventricular volume of
about 50 ml and a diastolic pressure of 2 to 3 mm Hg.
The amount of blood that remains in the ventricle after
the previous heartbeat, 50 ml, is called the end-systolic
­volume. As venous blood flows into the ventricle from the
left atrium, the ventricular volume normally increases to
about 120 ml, called the end-diastolic volume, an increase
of 70 ml. Therefore, the volume-pressure diagram during phase I extends along the line labeled “I,” from point A
to point B, with the ­volume increasing to 120 ml and the
­diastolic pressure rising to about 5 to 7 mm Hg.
Phase II: Period of isovolumic contraction. During isovolumic contraction, the volume of the ventricle does not change
because all valves are closed. However, the pressure inside
the ventricle increases to equal the pressure in the aorta, at a
pressure value of about 80 mm Hg, as depicted by point C.
Phase III: Period of ejection. During ejection, the systolic
pressure rises even higher because of still more contraction
of the ventricle. At the same time, the volume of the ventricle
decreases because the aortic valve has now opened and blood
flows out of the ventricle into the aorta. Therefore, the curve
labeled “III,” or “period of ejection,” traces the changes in volume and systolic pressure during this period of ejection.
Phase IV: Period of isovolumic relaxation. At the end of
the period of ejection (point D), the aortic valve closes, and
the ventricular pressure falls back to the diastolic pressure
level. The line labeled “IV” traces this decrease in intraventricular pressure without any change in volume. Thus, the
ventricle returns to its starting point, with about 50 ml of
blood left in the ventricle and at an atrial pressure of 2 to
3 mm Hg.
Readers well trained in the basic principles of physics
will recognize that the area subtended by this functional
Chapter 9 Cardiac Muscle; The Heart as a Pump and Function of the Heart Valves
Left intraventricular pressure (mm Hg)
Aortic valve
Aortic valve
Stroke volume
Mitral valve
Period of
Left ventricular volume (ml)
volume-pressure diagram (the tan shaded area, labeled EW)
represents the net external work output of the ventricle during its contraction cycle. In experimental studies of cardiac
contraction, this diagram is used for calculating cardiac work
When the heart pumps large quantities of blood, the area
of the work diagram becomes much larger. That is, it extends
far to the right because the ventricle fills with more blood
during diastole, it rises much higher because the ventricle
contracts with greater pressure, and it usually extends farther to the left because the ventricle contracts to a smaller
volume—especially if the ventricle is stimulated to increased
activity by the sympathetic nervous system.
Concepts of Preload and Afterload. In assessing the
contractile properties of muscle, it is important to specify the degree of tension on the muscle when it begins to
contract, which is called the preload, and to specify the
load against which the muscle exerts its contractile force,
which is called the afterload.
For cardiac contraction, the preload is usually considered to be the end-diastolic pressure when the ventricle
has become filled.
The afterload of the ventricle is the pressure in the
aorta leading from the ventricle. In Figure 9-8, this corresponds to the systolic pressure described by the phase
III curve of the volume-pressure diagram. (Sometimes the
afterload is loosely considered to be the resistance in the
circulation rather than the pressure.)
The importance of the concepts of preload and afterload is that in many abnormal functional states of the heart
or circulation, the pressure during filling of the ventricle
(the preload), the arterial pressure against which the ventricle must contract (the afterload), or both are severely
altered from normal.
Mitral valve
Chemical Energy Required for Cardiac
Contraction: Oxygen Utilization by the Heart
Heart muscle, like skeletal muscle, uses chemical energy to
provide the work of contraction. Approximately 70 to 90 percent of this energy is normally derived from oxidative metabolism of fatty acids with about 10 to 30 percent coming from
other nutrients, especially lactate and glucose. Therefore, the
rate of oxygen consumption by the heart is an excellent measure of the chemical energy liberated while the heart performs its work. The different chemical reactions that liberate
this energy are discussed in Chapters 67 and 68.
Experimental studies have shown that oxygen consumption of the heart and the chemical energy expended during
contraction are directly related to the total shaded area in
Figure 9-8. This shaded portion consists of the external work
(EW) as explained earlier and an additional portion called the
potential energy, labeled PE. The potential energy represents
additional work that could be accomplished by contraction
of the ventricle if the ventricle should empty completely all
the blood in its chamber with each contraction.
Oxygen consumption has also been shown to be nearly
proportional to the tension that occurs in the heart muscle during contraction multiplied by the duration of time
that the contraction persists, called the tension-time index.
Because tension is high when systolic pressure is high, correspondingly more oxygen is used. Also, much more chemical
energy is expended even at normal systolic pressures when
the ventricle is abnormally dilated because the heart muscle
tension during contraction is proportional to pressure times
the diameter of the ventricle. This becomes especially important in heart failure where the heart ventricle is dilated and,
paradoxically, the amount of chemical energy required for a
given amount of work output is greater than normal even
though the heart is already failing.
U nit I I I
Figure 9-9 The “volume-pressure diagram” demonstrating changes in intraventricular volume and
pressure during a single cardiac cycle (red line).
The tan shaded area represents the net external
work (EW) output by the left ventricle during the
cardiac cycle.
Period of ejection
Unit III The Heart
Regulation of Heart Pumping
When a person is at rest, the heart pumps only 4 to 6
liters of blood each minute. During severe exercise, the
heart may be required to pump four to seven times this
amount. The basic means by which the volume pumped
by the heart is regulated are (1) intrinsic cardiac regulation of pumping in response to changes in volume of
blood flowing into the heart and (2) control of heart rate
and strength of heart pumping by the autonomic nervous
Intrinsic Regulation of Heart Pumping—The
Frank-Starling Mechanism
In Chapter 20, we will learn that under most conditions,
the amount of blood pumped by the heart each minute is
normally determined almost entirely by the rate of blood
flow into the heart from the veins, which is called venous
return. That is, each peripheral tissue of the body controls
its own local blood flow, and all the local tissue flows combine and return by way of the veins to the right atrium.
The heart, in turn, automatically pumps this incoming
blood into the arteries so that it can flow around the circuit again.
This intrinsic ability of the heart to adapt to increasing volumes of inflowing blood is called the FrankStarling mechanism of the heart, in honor of Otto Frank
and Ernest Starling, two great physiologists of a century
ago. Basically, the Frank-Starling mechanism means that
the greater the heart muscle is stretched during filling,
the greater is the force of contraction and the greater
the quantity of blood pumped into the aorta. Or, stated
another way: Within physiologic limits, the heart pumps
all the blood that returns to it by the way of the veins.
What Is the Explanation of the Frank-Starling
Mechanism? When an extra amount of blood flows
into the ventricles, the cardiac muscle itself is stretched
to greater length. This in turn causes the muscle to contract with increased force because the actin and myosin
filaments are brought to a more nearly optimal degree
of overlap for force generation. Therefore, the ventricle,
because of its increased pumping, automatically pumps
the extra blood into the arteries.
This ability of stretched muscle, up to an optimal
length, to contract with increased work output is characteristic of all striated muscle, as explained in Chapter 6,
and is not simply a characteristic of cardiac muscle.
In addition to the important effect of lengthening the
heart muscle, still another factor increases heart pumping
when its volume is increased. Stretch of the right atrial
wall directly increases the heart rate by 10 to 20 percent;
this, too, helps increase the amount of blood pumped
each minute, although its contribution is much less than
that of the Frank-Starling mechanism.
Ventricular Function Curves
One of the best ways to express the functional ability of the
ventricles to pump blood is by ventricular function curves,
as shown in Figures 9-10 and 9-11. Figure 9-10 shows a
type of ventricular function curve called the stroke work
output curve. Note that as the atrial pressure for each side
of the heart increases, the stroke work output for that side
increases until it reaches the limit of the ventricle’s pumping ability.
Figure 9-11 shows another type of ventricular function
curve called the ventricular volume output curve. The two
curves of this figure represent function of the two ventricles of the human heart based on data extrapolated
from lower animals. As the right and left atrial pressures
increase, the respective ventricular volume outputs per
minute also increase.
Left ventricular
stroke work
(gram meters)
Right ventricular
stroke work
(gram meters)
Left mean atrial
(mm Hg)
Right mean atrial
(mm Hg)
Figure 9-10 Left and right ventricular function curves recorded
from dogs, depicting ventricular stroke work output as a function
of left and right mean atrial pressures. (Curves reconstructed from
data in Sarnoff SJ: Myocardial contractility as described by ventricular function curves. Physiol Rev 35:107, 1955.)
Ventricular output (L/min)
Efficiency of Cardiac Contraction. During heart muscle contraction, most of the expended chemical energy is
converted into heat and a much smaller portion into work
output. The ratio of work output to total chemical energy
expenditure is called the efficiency of cardiac contraction,
or simply efficiency of the heart. Maximum efficiency of
the normal heart is between 20 and 25 percent. In heart
failure, this can decrease to as low as 5 to 10 percent.
Right ventricle
Left ventricle
Atrial pressure (mm Hg)
Figure 9-11 Approximate normal right and left ventricular volume
output curves for the normal resting human heart as extrapolated
from data obtained in dogs and data from human beings.
Chapter 9 Cardiac Muscle; The Heart as a Pump and Function of the Heart Valves
Control of the Heart by the Sympathetic
and Parasympathetic Nerves
The pumping effectiveness of the heart also is controlled
by the sympathetic and parasympathetic (vagus) nerves,
which abundantly supply the heart, as shown in Figure
9-12. For given levels of atrial pressure, the amount of
blood pumped each minute (cardiac output) often can
be increased more than 100 percent by sympathetic stimulation. By contrast, the output can be decreased to as
low as zero or almost zero by vagal (parasympathetic)
Mechanisms of Excitation of the Heart by the
Sympathetic Nerves. Strong sympathetic stimulation
can increase the heart rate in young adult humans from
the normal rate of 70 beats/min up to 180 to 200 and,
rarely, even 250 beats/min. Also, sympathetic stimulation increases the force of heart contraction to as much
as double normal, thereby increasing the volume of blood
pumped and increasing the ejection pressure. Thus, sympathetic stimulation often can increase the maximum
cardiac output as much as twofold to threefold, in addition to the increased output caused by the 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, the sympathetic nerve fibers to the heart discharge continuously
at a slow rate that maintains pumping at about 30 percent
above that with no sympathetic stimulation. Therefore,
when the activity of the sympathetic nervous system is
depressed below normal, this decreases both heart rate
and strength of ventricular muscle contraction, thereby
decreasing the level of cardiac pumping as much as 30
percent below normal.
Parasympathetic (Vagal) Stimulation of the Heart.
Strong stimulation of the parasympathetic nerve fibers in
the vagus nerves to the heart can stop the heartbeat for
a few seconds, but then the heart usually “escapes” and
beats at a rate of 20 to 40 beats/min as long as the parasympathetic stimulation continues. In addition, strong
vagal stimulation can decrease the strength of heart
­muscle contraction by 20 to 30 percent.
The vagal fibers are distributed mainly to the atria
and not much to the ventricles, where the power contraction of the heart occurs. This explains the effect of
vagal stimulation mainly to decrease heart rate rather
than to decrease greatly the strength of heart contraction.
Nevertheless, the great decrease in heart rate combined
with a slight decrease in heart contraction strength can
decrease ­ventricular pumping 50 percent or more.
Effect of Sympathetic or Parasympathetic Stimula­
tion on the Cardiac Function Curve. Figure 9-13 shows
four cardiac function curves. They are similar to the ventricular function curves of Figure 9-11. However, they
represent function of the entire heart rather than of a single ventricle; they show the relation between right atrial
pressure at the input of the right heart and cardiac output
from the left ventricle into the aorta.
The curves of Figure 9-13 demonstrate that at any given
right atrial pressure, the cardiac output increases during
increased sympathetic stimulation and decreases during
increased parasympathetic stimulation. These changes in
output caused by autonomic nervous system stimulation
result both from changes in heart rate and from changes
in contractile strength of the heart because both change in
response to the nerve stimulation.
Maximum sympathetic
Cardiac output (L/min)
Normal sympathetic
Zero sympathetic
Figure 9-12 Cardiac sympathetic and parasympathetic nerves.
(The vagus nerves to the heart are parasympathetic nerves.)
Right atrial pressure (mm Hg)
Figure 9-13 Effect on the cardiac output curve of different degrees
of sympathetic or parasympathetic stimulation.
U nit I I I
Thus, ventricular function curves are another way of
expressing the Frank-Starling mechanism of the heart.
That is, as the ventricles fill in response to higher atrial
pressures, each ventricular volume and strength of ­cardiac
muscle contraction increase, causing the heart to pump
increased quantities of blood into the arteries.
Unit III The Heart
In the discussion of membrane potentials in Chapter 5, it
was pointed out that potassium ions have a marked effect
on membrane potentials, and in Chapter 6 it was noted
that calcium ions play an especially important role in activating the muscle contractile process. Therefore, it is to
be expected that the concentration of each of these two
ions in the extracellular fluids should also have important
effects on cardiac pumping.
Effect of Potassium Ions. Excess potassium in the
extracellular fluids causes the heart to become dilated
and 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. 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 death occurs.
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. That is, high
extracellular fluid potassium concentration partially depolarizes the cell membrane, causing the membrane potential
to be less negative. As the membrane potential decreases,
the intensity of the action potential also decreases, which
makes contraction of the heart progressively weaker.
Effect of Calcium Ions. An excess of calcium ions
causes effects almost exactly opposite to those of potassium ions, causing the heart to go toward spastic contraction. This is caused by a direct effect of calcium ions
to initiate the cardiac contractile process, as explained
­earlier in the chapter.
Conversely, deficiency of calcium ions causes cardiac flaccidity, similar to the effect of high potassium.
Fortunately, calcium ion levels in the blood normally are
regulated within a very narrow range. Therefore, cardiac
effects of abnormal calcium concentrations are seldom of
clinical concern.
Effect of Temperature on Heart Function
Increased body temperature, as occurs when one has
fever, causes a greatly increased heart rate, sometimes to
double normal. Decreased temperature causes a greatly
decreased heart rate, falling to as low as a few beats per
minute when a person is near death from hypothermia in
the body temperature range of 60° to 70°F. These effects
presumably result from the fact that heat increases the
permeability of the cardiac muscle membrane to ions
that control heart rate, resulting in acceleration of the
­self-excitation process.
Contractile strength of the heart often is enhanced temporarily by a moderate increase in temperature, as occurs
during body exercise, but prolonged elevation of temperature exhausts the metabolic systems of the heart and
eventually causes weakness. Therefore, optimal function
of the heart depends greatly on proper control of body
Normal range
Cardiac output (L/min)
Effect of Potassium and Calcium
Ions on Heart Function
Arterial pressure (mm Hg)
Figure 9-14 Constancy of cardiac output up to a pressure level
of 160 mm Hg. Only when the arterial pressure rises above this
normal limit does the increasing pressure load cause the cardiac
output to fall significantly.
temperature by the temperature control mechanisms
explained in Chapter 73.
Increasing the Arterial Pressure Load (up to a
Limit) Does Not Decrease the Cardiac Output
Note in Figure 9-14 that increasing the arterial pressure
in the aorta does not decrease the cardiac output until
the mean arterial pressure rises above about 160 mm Hg.
In other words, during normal function of the heart at
normal systolic arterial pressures (80 to 140 mm Hg), the
cardiac output is determined almost 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 Chapter 20.
Bers DM: Altered cardiac myocyte Ca regulation in heart failure, Physiology
(Bethesda) 21:380, 2006.
Bers DM: Calcium cycling and signaling in cardiac myocytes, Annu Rev
Physiol 70:23, 2008.
Brette F, Orchard C: T-tubule function in mammalian cardiac myocytes,
Circ Res 92:1182, 2003.
Chantler PD, Lakatta EG, Najjar SS: Arterial-ventricular coupling: mechanistic insights into cardiovascular performance at rest and during exercise,
J Appl Physiol 105:1342, 2008.
Cheng H, Lederer WJ: Calcium sparks, Physiol Rev 88:1491, 2008.
Clancy CE, Kass RS: Defective cardiac ion channels: from mutations to clinical syndromes, J Clin Invest 110:1075, 2002.
Couchonnal LF, Anderson ME: The role of calmodulin kinase II in myocardial
physiology and disease, Physiology (Bethesda) 23:151, 2008.
Fuchs F, Smith SH: Calcium, cross-bridges, and the Frank-Starling relationship, News Physiol Sci 16:5, 2001.
Guyton AC: Determination of cardiac output by equating venous return
curves with cardiac response curves, Physiol Rev 35:123, 1955.
Guyton AC, Jones CE, Coleman TG: Circulatory Physiology: Cardiac Output
and Its Regulation, 2nd ed, Philadelphia, 1973, WB Saunders.
Kang M, Chung KY, Walker JW: G-protein coupled receptor signaling in myocardium: not for the faint of heart, Physiology (Bethesda) 22:174, 2007.
Knaapen P, Germans T, Knuuti J, et al: Myocardial energetic and efficiency:
current status of the noninvasive approach, Circulation 115:918, 2007.
Mangoni ME, Nargeot J: Genesis and regulation of the heart automaticity,
Physiol Rev 88:919, 2008.
Korzick DH: Regulation of cardiac excitation-contraction coupling: a cellular update, Adv Physiol Educ 27:192, 2003.
Olson EN: A decade of discoveries in cardiac biology, Nat Med 10:467,
Chapter 9 Cardiac Muscle; The Heart as a Pump and Function of the Heart Valves
Sarnoff SJ: Myocardial contractility as described by ventricular function
curves, Physiol Rev 35:107, 1955.
Starling EH: The Linacre Lecture on the Law of the Heart, London, 1918,
Longmans Green.
U nit I I I
Rudy Y, Ackerman MJ, Bers DM, et al: Systems approach to understanding
electromechanical activity in the human heart: a National Heart, Lung,
and Blood Institute workshop summary, Circulation 118:1202, 2008.
Saks V, Dzeja P, Schlattner U, et al: Cardiac system bioenergetics: metabolic
basis of the Frank-Starling law, J Physiol 571:253, 2006.
This page intentionally left blank
chapter 10
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 ventricular contraction, which allows filling of the ventricles
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 effect 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 impulses are
generated; the internodal pathways that conduct impulses
from the sinus node to the atrioventricular (A-V) node;
the A-V node, in which impulses from the atria are delayed
before passing into the ventricles; the A-V bundle, which
conducts impulses from the atria into the ventricles; and
the left and right bundle branches of Purkinje fibers, which
conduct the cardiac impulses 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 the fibers of the
heart’s specialized conducting system, including the fibers
of the sinus node. For this reason, the sinus node ordinarily controls the rate of beat of the entire heart, as discussed in detail later in this chapter. First, let us describe
this automatic rhythmicity.
Mechanism of Sinus Nodal Rhythmicity. Figure 10-2
shows action potentials recorded from inside a sinus
nodal 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 are
naturally leaky to sodium and calcium ions, and positive
charges of the entering sodium and calcium ions neutralize some of the intracellular negativity.
Before attempting to explain the rhythmicity of the
sinus nodal fibers, first recall from the discussions of
Chapters 5 and 9 that cardiac muscle has three types of
membrane ion channels that play important roles in causing the voltage changes of the action potential. They are
(1) fast sodium channels, (2) slow sodium-calcium channels, and (3) potassium channels.
Opening of the fast sodium channels for a few
10,000 ths of a second is responsible for the rapid upstroke
spike of the action potential observed in ventricular muscle, because of rapid influx of positive sodium ions to the
U n i t III
Rhythmical Excitation of the Heart
Unit III The Heart
A-V node
A-V bundle
Figure 10-1 Sinus node and the Purkinje system of the heart,
showing also the A-V node, atrial internodal pathways, and ventricular bundle branches.
interior of the fiber. Then the “plateau” of the ventricular
action potential is caused primarily by slower opening of
the slow sodium-calcium channels, which lasts for about
0.3 second. Finally, opening of potassium channels allows
diffusion of large amounts of positive potassium ions in
the outward direction through the fiber membrane and
returns the membrane potential to its resting level.
But there is a difference in the function of these channels in the sinus nodal fiber because the “resting” potential is much less negative—only −55 millivolts in the nodal
fiber instead of the −90 millivolts in the ventricular 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 membrane potential remains less negative than about −55 millivolts for more than a few milliseconds, the inactivation gates on the inside of the cell
membrane that close the fast sodium channels become
closed and remain so. Therefore, only the slow sodiumcalcium channels can open (i.e., can become “activated”)
Threshold for
nodal fiber
muscle fiber
Figure 10-2 Rhythmical discharge of a sinus nodal fiber. Also, the
sinus nodal action potential is compared with that of a ventricular
muscle fiber.
and thereby cause the action potential. As a result, the
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, rather than the
abrupt return that occurs for the ventricular fiber.
Self-Excitation of Sinus Nodal Fibers. Because
of the high sodium ion concentration in the extracellular fluid outside the nodal fiber, as well as a moderate number of already open sodium channels, positive
sodium ions from outside the fibers normally tend
to leak to the inside. Therefore, between heartbeats,
influx of positively charged sodium ions causes a slow
rise in the resting membrane potential in the positive
direction. Thus, as shown in Figure 10-2, the “resting” potential gradually rises and becomes less negative between each two heartbeats. When the potential
reaches a threshold voltage of about −40 millivolts,
the sodium-calcium channels become “activated,”
thus causing the action potential. Therefore, basically,
the inherent leakiness of the sinus nodal fibers to sodium
and calcium ions causes their self-excitation.
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 during the
course of the action potential to prevent this. First, the
sodium-calcium channels become inactivated (i.e., they
close) within about 100 to 150 milliseconds after opening, and second, at about the same time, greatly increased
numbers of potassium channels open. Therefore, influx
of positive calcium and sodium ions through the sodiumcalcium channels ceases, while at the same time large
quantities of positive potassium ions diffuse out of the
fiber. Both of these effects reduce the intracellular potential back to its negative resting level and therefore terminate the action potential. Furthermore, the potassium
channels remain open for another few tenths of a second,
temporarily continuing movement of positive charges
out of the cell, with resultant excess negativity inside the
fiber; this is called hyperpolarization. The hyperpolarization state initially carries the “resting” membrane potential down to about −55 to −60 millivolts at the termination
of the action potential.
Why is this new state of hyperpolarization not maintained forever? The reason is 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 and calcium ions once again
overbalance the outward flux of potassium ions, and
this causes the “resting” potential to drift upward once
more, finally reaching the threshold level for discharge
at a potential of about −40 millivolts. Then the entire
process begins again: self-excitation to cause the action
potential, recovery from the action potential, hyperpolarization after the action potential is over, drift of the
“resting” potential to threshold, and finally re-excitation
to elicit another cycle. This process continues indefinitely
throughout a person’s life.
Chapter 10 Rhythmical Excitation of the Heart
Internodal Pathways and Transmission of
the Cardiac Impulse Through the Atria
Atrioventricular Node and Delay of Impulse
Conduction from the Atria to the Ventricles
The atrial conductive system is organized so that the cardiac impulse does not travel from the atria into the ventricles too rapidly; this delay allows time for the atria to empty
their blood into the ventricles before ventricular contraction
begins. It is primarily the A-V node and its adjacent conductive fibers that delay this transmission into the ventricles.
The A-V node is located in the posterior wall of the right
atrium immediately behind the tricuspid valve, as shown
Transitional fibers
A-V node
fibrous tissue
Penetrating portion
of A-V bundle
Distal portion of
A-V bundle
Left bundle branch
Right bundle branch
Figure 10-3 Organization of the A-V node. The numbers represent the interval of time from the origin of the impulse in the sinus
node. The values have been extrapolated to human beings.
Rapid Transmission in the Ventricular
Purkinje System
Special Purkinje fibers lead from the A-V node through the
A-V bundle into the ventricles. Except for the initial portion of these fibers where they penetrate the A-V fibrous
barrier, they have functional characteristics that are quite
the opposite of those of the A-V nodal fibers. They are
very large fibers, even 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 A-V nodal fibers. This allows almost instantaneous
transmission of the cardiac impulse throughout the entire
remainder of the ventricular muscle.
The rapid transmission of action potentials by Purkinje
fibers is believed to be caused by a very high level of permeability of the gap junctions at the intercalated discs
between the successive cells that make up the Purkinje
fibers. Therefore, ions are transmitted easily from one
cell to the next, thus enhancing the velocity of transmission. The Purkinje fibers also have very few myofibrils,
which means that they contract little or not at all during
the course of impulse transmission.
One-Way Conduction Through the A-V Bundle.
A special characteristic of the A-V bundle is the inability, except in abnormal states, of action potentials to
travel backward from the ventricles to the atria. This
prevents re-entry of cardiac impulses by this route from
U n i t III
The ends of the sinus nodal fibers connect directly
with surrounding atrial muscle fibers. Therefore, action
potentials originating in the sinus node travel outward
into these atrial muscle fibers. In this way, the action
potential spreads through the entire atrial muscle mass
and, eventually, to the A-V node. The velocity of conduction in most atrial muscle is about 0.3 m/sec, but conduction is more rapid, about 1 m/sec, in several small bands
of atrial fibers. One of these, called the anterior interatrial band, passes through the anterior walls of the atria
to the left atrium. In addition, three other small bands
curve through the anterior, lateral, and posterior atrial
walls and terminate in the A-V node; shown in Figures
10-1 and 10-3, these are called, respectively, the anterior,
middle, and posterior internodal pathways. The cause of
more rapid velocity of conduction in these bands is the
presence of specialized conduction fibers. These fibers
are similar to even more rapidly conducting “Purkinje
fibers” of the ventricles, which are discussed as follows.
in Figure 10-1. And Figure 10-3 shows diagrammatically
the different parts of this node, plus its connections with
the entering atrial internodal pathway fibers and the exiting A-V bundle. The figure also shows the approximate
intervals of time in fractions of a second between initial
onset of the cardiac impulse in the sinus node and its subsequent appearance in the A-V nodal system. Note that
the impulse, after traveling through the internodal pathways, reaches the A-V node about 0.03 second after its origin in the sinus node. Then there is a delay of another 0.09
second in the A-V node itself before the impulse enters
the penetrating portion of the A-V bundle, where it passes
into the ventricles. A final delay of another 0.04 second
occurs mainly in this penetrating A-V bundle, which is
composed of multiple small fascicles passing through the
fibrous ­tissue separating the atria from the ventricles.
Thus, the total delay in the A-V nodal and A-V bundle system is about 0.13 second. This, in addition to the
initial conduction delay of 0.03 second from the sinus
node to the A-V node, makes a total delay of 0.16 second
before the excitatory signal finally reaches the contracting
­muscle of the ventricles.
Cause of the Slow Conduction. The slow conduction in the transitional, nodal, and penetrating A-V bundle
fibers is caused mainly by diminished numbers of gap junctions between successive cells in the conducting pathways,
so there is great resistance to conduction of excitatory ions
from one conducting fiber to the next. Therefore, it is easy
to see why each succeeding cell is slow to be excited.
Unit III The Heart
the ventricles to the atria, allowing only forward conduction from the atria to the ventricles.
Furthermore, it should be recalled that everywhere,
except at the A-V bundle, the atrial muscle is separated
from the ventricular muscle by a continuous fibrous barrier, a portion of which is shown in Figure 10-3. This barrier normally acts as an insulator to prevent passage of
the cardiac impulse between atrial and ventricular muscle through any other route besides forward conduction through the A-V bundle itself. (In rare instances, an
abnormal muscle bridge does penetrate the fibrous barrier
elsewhere besides at the A-V bundle. Under such conditions, the cardiac impulse can re-enter the atria from the
ventricles and cause a serious cardiac arrhythmia.)
Distribution of the Purkinje Fibers in the Ventricles—
The Left and Right Bundle Branches. After penetrating
the fibrous tissue between the atrial and ventricular muscle, the distal portion of the A-V bundle passes downward in the ventricular septum for 5 to 15 millimeters
toward the apex of the heart, as shown in Figures 10-1
and 10-3. Then the bundle divides into left and right bundle branches that lie beneath the endocardium on the two
respective sides of the ventricular septum. Each branch
spreads downward toward the apex of the ventricle, 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 one third of the way into
the muscle mass and finally become continuous with the
cardiac muscle fibers.
From the time the cardiac impulse enters the bundle
branches in the ventricular septum until it reaches the ter­
minations of the Purkinje fibers, the total elapsed time averages only 0.03 second. Therefore, once the cardiac impulse
enters the ventricular Purkinje conductive system, it spreads
almost immediately to the entire ventricular muscle mass.
Transmission of the Cardiac Impulse in the
Ventricular Muscle
Once the impulse reaches the ends of the Purkinje fibers,
it is transmitted through the ventricular muscle mass by
the ventricular muscle fibers themselves. The velocity of
transmission is now only 0.3 to 0.5 m/sec, one sixth that
in the Purkinje fibers.
The cardiac muscle wraps around the heart in a double spiral, with fibrous septa between the spiraling layers;
therefore, the cardiac impulse does not necessarily travel
directly outward toward the surface of the heart but instead
angulates toward the surface along the directions of the
spirals. Because of this, transmission from the endocardial
surface to the epicardial surface of the ventricle requires as
much as another 0.03 second, approximately equal to the
time required for transmission through the entire ventricular portion of the Purkinje system. Thus, the total time for
transmission of the cardiac impulse from the initial bundle
branches to the last of the ventricular muscle fibers in the
normal heart is about 0.06 second.
Figure 10-4 Transmission of the cardiac impulse through the
heart, showing the time of appearance (in fractions of a second
after initial appearance at the sinoatrial node) in different parts
of the heart.
Summary of the Spread of the Cardiac Impulse
Through the Heart
Figure 10-4 shows in summary form the transmission
of the cardiac impulse through the human heart. The
numbers on the figure represent the intervals of time,
in fractions of a second, that lapse between the origin
of the cardiac impulse in the sinus node and its appearance at each respective point in the heart. Note that the
impulse spreads at moderate velocity through the atria
but is delayed more than 0.1 second in the A-V nodal
region before appearing in the ventricular septal A-V
bundle. Once it has entered this bundle, it spreads very
rapidly through the Purkinje fibers to the entire endocardial surfaces of the ventricles. Then the impulse once
again spreads slightly less rapidly through the ventricular
­muscle to the epicardial surfaces.
It is important that the student learn in detail the course
of the cardiac impulse through the heart and the precise
times of its appearance in each separate part of the heart,
because a thorough quantitative knowledge of this process
is essential to the understanding of electrocardiography,
which is discussed in Chapters 11 through 13.
Control of Excitation and Conduction
in the Heart
Sinus Node as the Pacemaker of the Heart
In the discussion thus far of the genesis and transmission
of the cardiac impulse through the heart, we have noted
that the impulse normally arises in the sinus node. In some
Chapter 10 Rhythmical Excitation of the Heart
rhythmical impulses until 5 to 20 seconds later because,
before the blockage, the Purkinje fibers had been “overdriven” by the rapid sinus impulses and, consequently, are
in a suppressed state. During these 5 to 20 seconds, the
ventricles fail to pump blood, and the person faints after
the first 4 to 5 seconds because of lack of blood flow to
the brain. This delayed pickup of the heartbeat is called
Stokes-Adams syndrome. If the delay period is too long, it
can lead to death.
Role of the Purkinje System in Causing
Synchronous Contraction of the
Ventricular Muscle
It is clear from our description of the Purkinje system that
normally the cardiac impulse arrives at almost all portions
of the ventricles within a narrow span of time, exciting
the first ventricular muscle fiber only 0.03 to 0.06 second
ahead of excitation of the last ventricular muscle fiber.
This causes all portions of the ventricular muscle in both
ventricles to begin contracting at almost the same time
and then to continue contracting for about another 0.3
Effective pumping by the two ventricular chambers
requires this synchronous type of contraction. If the cardiac impulse should travel through the ventricles slowly,
much of the ventricular mass would contract before
contraction of the remainder, in which case the overall pumping effect would be greatly depressed. Indeed,
in some types of cardiac debilities, several of which are
discussed in Chapters 12 and 13, slow transmission does
occur, and the pumping effectiveness of the ventricles is
decreased as much as 20 to 30 percent.
Control of Heart Rhythmicity and Impulse
Conduction by the Cardiac Nerves: Sympathetic
and Parasympathetic Nerves
The heart is supplied with both sympathetic and parasympathetic nerves, as shown in Figure 9-10 of Chapter 9.
The parasympathetic nerves (the vagi) are distributed
mainly to the S-A and A-V nodes, to a lesser extent to
the muscle of the two atria, and very little directly to the
ventricular muscle. The sympathetic nerves, conversely,
are distributed to all parts of the heart, with strong representation to the ventricular muscle, as well as to all the
other areas.
Parasympathetic (Vagal) Stimulation Can Slow or Even
Block Cardiac Rhythm and Conduction—“Ventricular
Escape.” Stimulation of the parasympathetic nerves to
the heart (the vagi) causes the hormone acetylcholine to
be released at the vagal endings. This hormone has two
major effects on the heart. First, it decreases the rate of
rhythm of the sinus node, and second, it decreases the
excitability of the A-V junctional fibers between the atrial
musculature and the A-V node, thereby slowing transmission of the cardiac impulse into the ventricles.
Weak to moderate vagal stimulation slows the rate
of heart pumping, often to as little as one-half normal.
U n i t III
abnormal conditions, this is not the case. Other parts of
the heart can also exhibit intrinsic rhythmical excitation in the same way that the sinus nodal fibers do; this is
­particularly true of the A-V nodal and Purkinje fibers.
The A-V nodal fibers, when not stimulated from some
outside source, discharge at an intrinsic rhythmical rate
of 40 to 60 times per minute, and the Purkinje fibers discharge at a rate somewhere between 15 and 40 times per
minute. These rates are in contrast to the normal rate of
the sinus node of 70 to 80 times per minute.
Why then does the sinus node rather than the A-V
node or the Purkinje fibers control the heart’s rhythmicity? The answer derives from the fact that the discharge
rate of the sinus node is considerably faster than the natural self-excitatory discharge rate of either the A-V node or
the Purkinje fibers. Each time the sinus node discharges,
its impulse is conducted into both the A-V node and the
Purkinje 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
thresholds 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
because its rate of rhythmical discharge is faster than
that of any other part of the heart. Therefore, the sinus
node is virtually always the pacemaker of the normal
Abnormal Pacemakers—“Ectopic” Pacemaker. Occasio­
n­ally some other part of the heart develops a rhythmical discharge rate that is more rapid than that of the
sinus node. For instance, this sometimes occurs in the
A-V node or in the Purkinje fibers when one of these
becomes abnormal. In either case, the pacemaker of the
heart shifts from the sinus node to the A-V node or to
the excited Purkinje fibers. Under rarer conditions, a place in
the atrial or ventricular muscle develops excessive excitability
and becomes the pacemaker.
A pacemaker elsewhere than the sinus node is called
an “ectopic” pacemaker. An ectopic pacemaker causes an
abnormal sequence of contraction of the different parts
of the heart and can cause significant debility of heart
Another cause of shift of the pacemaker is blockage of
transmission of the cardiac impulse from the sinus node
to the other parts of the heart. The new pacemaker then
occurs most frequently at the A-V node or in the penetrating portion of the A-V bundle on the way to the ventricles.
When A-V block occurs—that is, when the cardiac
impulse fails to pass from the atria into the ventricles
through the A-V nodal and bundle system—the atria continue to beat at the normal rate of rhythm of the sinus
node, while a new pacemaker usually develops in the
Purkinje system of the ventricles and drives the ventricular muscle at a new rate somewhere between 15 and
40 beats per minute. After sudden A-V bundle block,
the Purkinje system does not begin to emit its intrinsic
Unit III The Heart
And strong stimulation of the vagi can stop completely
the rhythmical excitation by the sinus node or block completely transmission of the cardiac impulse from the atria
into the ventricles through the A-V mode. In either case,
rhythmical excitatory signals are no longer transmitted
into the ventricles. The ventricles stop beating for 5 to 20
seconds, but then some small area in the Purkinje fibers,
usually in the ventricular septal portion of the A-V bundle, develops a rhythm of its own and causes ventricular
­contraction at a rate of 15 to 40 beats per minute. This
phenomenon is called ventricular escape.
Mechanism of the Vagal Effects. The acetylcholine
released at the vagal nerve endings greatly increases the
permeability of the fiber membranes to potassium ions,
which allows rapid leakage of potassium out of the conductive fibers. This causes increased negativity inside the
fibers, an effect called hyperpolarization, which makes
this excitable tissue much less excitable, as explained in
Chapter 5.
In the sinus node, the state of hyperpolarization
decreases the “resting” membrane potential of the sinus
nodal fibers to a level considerably more negative than
usual, to −65 to −75 millivolts rather than the normal level
of −55 to −60 millivolts. Therefore, the initial rise of the
sinus nodal membrane potential caused by inward sodium
and calcium leakage requires much longer to reach the
threshold potential for excitation. This greatly slows
the rate of rhythmicity of these nodal fibers. If the vagal
stimulation is strong enough, it is possible to stop entirely
the rhythmical self-excitation of this node.
In the A-V node, a state of hyperpolarization caused
by vagal stimulation makes it difficult for the small atrial
fibers entering the node to generate enough electricity to
excite the nodal fibers. Therefore, the safety factor for trans­
mission of the cardiac impulse through the transitional
fibers into the A-V nodal fibers decreases. A moderate
decrease simply delays conduction of the impulse, but a
large decrease blocks conduction entirely.
Effect of Sympathetic Stimulation on Cardiac Rhythm
and Conduction. Sympathetic stimulation causes essentially the opposite effects on the heart to those caused by
vagal stimulation, as follows: First, it increases the rate
of sinus nodal discharge. Second, it increases the rate of
conduction, as well as the level of excitability in all portions of the heart. Third, it increases greatly the force of
­contraction of all the cardiac musculature, both atrial and
ventricular, as discussed in Chapter 9.
In short, sympathetic stimulation increases the overall activity of the heart. Maximal stimulation can almost
triple the frequency of heartbeat and can increase the
strength of heart contraction as much as twofold.
Mechanism of the Sympathetic Effect. Stimulation of
the sympathetic nerves releases the hormone norepineph-
rine at the sympathetic nerve endings. Norepinephrine in
turn stimulates beta-1 adrenergic receptors, which mediate the effects on heart rate. The precise mechanism by
which beta-1 adrenergic stimulation acts on cardiac
muscle fibers is somewhat unclear, but the belief is that
it increases the permeability of the fiber membrane to
sodium and calcium ions. In the sinus node, an increase
of sodium-calcium permeability causes a more positive
resting potential and also causes increased rate of upward
drift of the diastolic membrane potential toward the
threshold level for self-excitation, thus accelerating selfexcitation and, therefore, increasing the heart rate.
In the A-V node and A-V bundles, increased sodiumcalcium permeability makes it easier for the action potential to excite each succeeding portion of the conducting
fiber bundles, thereby decreasing the conduction time
from the atria to the ventricles.
The increase in permeability to calcium ions is at least
partially responsible for the increase in contractile strength
of the cardiac muscle under the influence of sympathetic
stimulation, because calcium ions play a powerful role in
exciting the contractile process of the myofibrils.
Barbuti A, DiFrancesco D: Control of cardiac rate by “funny” channels in
health and disease, Ann N Y Acad Sci 1123:213, 2008.
Baruscotti M, Robinson RB: Electrophysiology and pacemaker function of the developing sinoatrial node, Am J Physiol Heart Circ Physiol
293:H2613, 2007.
Cheng H, Lederer WJ: Calcium sparks, Physiol Rev 88:1491, 2008.
Chien KR, Domian IJ, Parker KK: Cardiogenesis and the complex biology of
regenerative cardiovascular medicine, Science 322:1494, 2008.
Dobrzynski H, Boyett MR, Anderson RH: New insights into pacemaker
activity: promoting understanding of sick sinus syndrome, Circulation
115:1921, 2007.
James TN: Structure and function of the sinus node, AV node and His bundle of the human heart: part I—structure, Prog Cardiovasc Dis 45:235,
James TN: Structure and function of the sinus node, AV node and His bundle of the human heart: part II—function, Prog Cardiovasc Dis 45:327,
Kléber AG, Rudy Y: Basic mechanisms of cardiac impulse propagation and
associated arrhythmias, Physiol Rev 84:431, 2004.
Lakatta EG, Vinogradova TM, Maltsev VA: The missing link in the mystery
of normal automaticity of cardiac pacemaker cells, Ann N Y Acad Sci
1123:41, 2008.
Leclercq C, Hare JM: Ventricular resynchronization: current state of the art,
Circulation 109:296, 2004.
Mangoni ME, Nargeot J: Genesis and regulation of the heart automaticity,
Physiol Rev 88:919, 2008.
Mazgalev TN, Ho SY, Anderson RH: Anatomic-electrophysiological correlations concerning the pathways for atrioventricular conduction,
Circulation 103:2660, 2001.
Schram G, Pourrier M, Melnyk P, et al: Differential distribution of ­cardiac
ion channel expression as a basis for regional specialization in electrical
function, Circ Res 90:939, 2002.
Yasuma F, Hayano J: Respiratory sinus arrhythmia: why does the heartbeat
synchronize with respiratory rhythm? Chest 125:683, 2004.
chapter 11
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.
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
repolarization wave.
Thus, the electrocardiogram is composed of both
depolarization and repolarization waves. The principles
of depolarization and repolarization are discussed in
Chapter 5. The distinction between depolarization waves
and repolarization waves is so important in electrocardiography that further clarification is necessary.
Depolarization Waves versus
Repolarization Waves
Characteristics of the Normal
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 depolarize before atrial contraction begins.
The QRS complex is caused by potentials 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.
Figure 11-2 shows a single cardiac muscle fiber in four
stages of depolarization and repolarization, the color red
designating depolarization. During depolarization, 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 negativity, 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
RR interval
P-R interval
= 0.16 sec
Q-T interval
Time (sec)
Figure 11-1 Normal electrocardiogram.
U n i t III
The Normal Electrocardiogram
Unit III The Heart
−−−−−−− +++++++++
+++++++ −−−−−−−−−
+++++++ −−−−−−−−−
−−−−−−− +++++++++
Figure 11-3 Above, Monophasic action potential from a ventricular muscle fiber during normal cardiac function, showing rapid
depolarization and then repolarization occurring slowly during the
plateau stage but rapidly toward the end. Below, Electrocardiogram
recorded simultaneously.
0.30 second
Figure 11-2 Recording the depolarization wave (A and B) and the
repolarization wave (C and D) from a cardiac muscle fiber.
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.
In Figure 11-2B, depolarization has extended over the
entire muscle fiber, and the recording to the right has
returned to the zero baseline because both electrodes are
now in areas of equal negativity. The completed wave is
a depolarization wave because it results from spread of
depolarization along the muscle fiber membrane.
Figure 11-2C shows halfway repolarization of the
same muscle fiber, with positivity returning to the outside of the fiber. At this point, the left electrode is in an
area of positivity, and the right electrode is in an area
of negativity. This is opposite to the polarity in Figure
11-2A. Consequently, the recording, as shown 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 negative wave
is a repolarization wave because it results from spread of
repolarization along the muscle fiber membrane.
Relation of the Monophasic Action Potential of
Ventricular Muscle to the QRS and T Waves in the
Standard Electrocardiogram. 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 a monophasic action potential
recorded from a microelectrode inserted to the inside of a
single ventricular muscle fiber. The upsweep of this action
potential is caused by depolarization, and the return of
the potential to the baseline is caused by repolarization.
Note in the lower half of the figure a simultaneous
recording of the electrocardiogram from this same ventricle, which shows the QRS waves appearing at the
beginning of the monophasic action potential and the
T wave appearing at the end. Note especially that no
potential is recorded in the electrocardiogram when the
ventricular muscle is either completely polarized or completely depolarized. Only when the muscle is partly polarized and partly depolarized does current flow from one
part of the ventricles to another part and therefore current also flows to the surface of the body to produce the
Relationship of Atrial and Ventricular Contraction
to the Waves of the Electrocardiogram
Before contraction of muscle can occur, depolarization
must spread through the muscle to initiate the chemical
processes of contraction. Refer again to Figure 11-1; the
P wave occurs at the beginning of contraction of the atria,
and the QRS complex of waves occurs at the beginning
of contraction of the ventricles. The ventricles remain
contracted until after repolarization has occurred, that is,
until after the end of the T wave.
The atria repolarize about 0.15 to 0.20 second after termination of the P wave. This is also approximately when
the QRS complex is being recorded in the electrocardiogram. Therefore, the atrial repolarization wave, known as
the atrial T wave, is usually obscured by the much larger
QRS complex. For this reason, an atrial T wave seldom is
observed in the electrocardiogram.
The ventricular repolarization wave is the T wave of the
normal electrocardiogram. Ordinarily, ventricular muscle begins to repolarize in some fibers about 0.20 second
after the beginning of the depolarization wave (the QRS
complex), but in many other fibers, it takes as long as 0.35
second. Thus, the process of ventricular repolarization
Chapter 11 The Normal Electrocardiogram
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.
As shown in Figure 11-1, the horizontal calibration
lines are arranged so that 10 of the small line divisions
upward or downward in the standard electrocardiogram
represent 1 millivolt, with positivity in the upward direction and negativity in the downward direction.
The vertical lines on the electrocardiogram are time
calibration lines. A typical electrocardiogram is run at a
paper speed of 25 millimeters per second, although faster
speeds are sometimes used. Therefore, each 25 millimeters in the horizontal direction is 1 second, and each
5-millimeter segment, indicated by the dark vertical lines,
represents 0.20 second. The 0.20-second intervals are
then broken into five smaller intervals by thin lines, each
of which represents 0.04 second.
Normal Voltages in the Electrocardiogram. The
recorded voltages of the waves in the normal electrocardiogram depend on the manner in which the electrodes are applied to the surface of the body and how
close the electrodes are to the heart. When one electrode
is placed directly over the ventricles and a second electrode is placed elsewhere on the body remote from the
heart, the voltage of the QRS complex may be as great as
3 to 4 millivolts. Even this voltage is small in comparison
with the monophasic action potential of 110 millivolts
recorded directly at the heart muscle membrane. When
electrocardiograms are recorded from electrodes on the
two arms or on one arm and one leg, the voltage of the
QRS complex usually is 1.0 to 1.5 millivolts from the top
of the R wave to the bottom of the S wave; the voltage of
the P wave is between 0.1 and 0.3 millivolts; and that of the
T wave is between 0.2 and 0.3 millivolts.
P-Q or P-R Interval. The time between the beginning
of the P wave and the beginning of the QRS complex is the
interval between the beginning of electrical excitation of
the atria and the beginning of excitation of the ventricles.
This period is called the P-Q interval. The normal P-Q
interval is about 0.16 second. (Often this interval is called
the P-R interval because the Q wave is likely to be absent.)
Q-T Interval. Contraction of the ventricle lasts almost
from the beginning of the Q wave (or R wave, if the Q wave
is absent) to the end of the T wave. This 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
determined 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 electrical potentials and polarities on the respective sides of the
heart in less than 0.01 second. Therefore, it is essential that
any apparatus for recording electrocardiograms be capable of responding rapidly to these changes in potentials.
Recorders for Electrocardiographs
Many modern clinical electrocardiographs use computer-based systems and electronic display, whereas
others use a direct pen recorder that writes the electrocardiogram with a pen directly on a moving sheet of
paper. Sometimes the pen is a thin tube connected at one
end to an inkwell, and its recording end is connected to
a powerful electromagnet system that is capable of moving the pen back and forth at high speed. As the paper
moves forward, the pen records the electrocardiogram.
The movement of the pen is controlled by appropriate
electronic amplifiers connected to electrocardiographic
electrodes on the patient.
Other pen recording systems use special paper that
does not require ink in the recording stylus. One such
paper turns black when it is exposed to heat; the stylus itself is made very hot by electrical current flowing
through its tip. Another type turns black when electrical
current flows from the tip of the stylus through the paper
to an electrode at its back. This leaves a black line on the
paper where the stylus touches.
Flow of Current Around the Heart during
the Cardiac Cycle
Recording Electrical Potentials from a Partially
Depolarized Mass of Syncytial Cardiac Muscle
Figure 11-4 shows a syncytial mass of cardiac muscle that
has been stimulated at its centralmost point. Before stimulation, all the exteriors of the muscle cells had been positive and the interiors negative. For reasons presented in
Chapter 5 in the discussion of membrane potentials, as
soon as an area of cardiac syncytium becomes depolarized, negative charges leak to the outsides of the depolarized muscle fibers, making this part of the surface
U n i t III
extends over a long period, about 0.15 second. For this reason, the T wave in the normal electrocardiogram 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.
Unit III The Heart
+ + ++++++++
+++++ −+−+−+−+−+ +++++ +
++++++ −−−−−−−−−−−−−−− +−+++++ +
++++++ −− −− −− −− −− −− −− −− −− − +++++ +
+++++ + − − − − − − − − − − +++++ +
+++++ −− −− −− −− −− −− −− −− −− − +++++
+++++ +−−−−−−−−−−−−−−−−− +++++ +
++++++ − − − −− −− −− −− ++++++
+++++ + + + − − + ++++++
+++++++++++ +++
++++++++++ +
Figure 11-4 Instantaneous potentials develop on the surface of a
cardiac muscle mass that has been depolarized in its center.
electronegative, as represented by the negative signs in
Figure 11-4. The remaining surface of the heart, which
is still polarized, is represented by the positive signs.
Therefore, a meter connected with its negative terminal
on the area of depolarization and its positive terminal on
one of the still-polarized areas, as shown to the right in
the figure, records positively.
Two other electrode placements and meter readings
are also demonstrated in Figure 11-4. These should be
studied carefully, and the reader should be able to explain
the causes of the respective meter readings. Because the
depolarization spreads in all directions through the heart,
the potential differences shown in the figure persist for
only a few thousandths of a second, and the actual voltage measurements can be accomplished only with a highspeed recording apparatus.
Flow of Electrical Currents in the Chest Around
the Heart
Figure 11-5 shows the ventricular muscle lying within the
chest. Even the lungs, although mostly filled with air, conduct electricity to a surprising extent, and fluids in other
tissues surrounding the heart conduct electricity even
more easily. Therefore, the heart is actually suspended in
a conductive medium. When one portion of the ventricles
depolarizes and therefore becomes electronegative with
respect to the remainder, electrical current flows from the
depolarized area to the polarized area in large circuitous
routes, as noted in the figure.
It should be recalled from the discussion of the
Purkinje system in Chapter 10 that the cardiac impulse
first arrives in the ventricles in the septum and shortly
thereafter spreads to the inside surfaces of the remainder
of the ventricles, as shown by the red areas and the negative signs in Figure 11-5. This provides electronegativity
on the insides of the ventricles and electropositivity on
the outer walls of the ventricles, with electrical current
flowing through the fluids surrounding the ventricles
along elliptical paths, as demonstrated by the curving
arrows in the figure. If one algebraically averages all the
lines of current flow (the elliptical lines), one finds that the
+ ++
−−−− + ++
−− − + +
++ ++ −− −+ ++
+ ++−+
++ ++
Figure 11-5 Flow of current in the chest around partially depolarized ventricles.
average current flow occurs with negativity toward the
base of the heart and with positivity toward the apex.
During most of the remainder of the depolarization
process, current also continues to flow in this same direction, while depolarization spreads from the endocardial
surface outward through the ventricular muscle mass.
Then, immediately before depolarization has completed
its course through the ventricles, the average direction of
current flow reverses for about 0.01 second, flowing from
the ventricular apex toward the base, because the last part
of the heart to become depolarized is the outer walls of
the ventricles near the base of the heart.
Thus, in normal heart ventricles, current flows
from negative to positive primarily in the direction
from the base of the heart toward the apex during
almost the entire cycle of depolarization, except at the
very end. And if a meter is connected to electrodes
on the surface of the body as shown in Figure 11-5,
the electrode nearer the base will be negative, whereas
the electrode nearer the apex will be positive, and the
recording meter will show positive recording in the
Electrocardiographic Leads
Three Bipolar Limb Leads
Figure 11-6 shows electrical connections between the
patient’s limbs and the electrocardiograph for recording
electrocardiograms from the so-called standard bipolar
Chapter 11 The Normal Electrocardiogram
+ 0 .5 mV
Lead I
+ +
− 0.2 mV
+ 0 .3 mV
+ 0 .7 mV
+ 1.2 mV
Lead II
Lead III
+ 1 .0 mV
Figure 11-6 Conventional arrangement of electrodes for recording the standard electrocardiographic leads. Einthoven’s triangle is
superimposed on the chest.
limb leads. The term “bipolar” means that the electrocardiogram is recorded from two electrodes located on different sides of the heart—in this case, on the limbs. Thus,
a “lead” is not a single wire connecting from the body but
a combination of two wires and their electrodes to make a
complete circuit between the body and the electrocardiograph. The electrocardiograph in each instance is represented by an electrical meter in the diagram, although the
actual electrocardiograph is a high-speed recording meter
with a moving paper.
Lead I. In recording limb lead I, the negative terminal
of the electrocardiograph is connected to the right arm
and the positive terminal to the left arm. Therefore, when
the point where the right arm connects to the chest is
electronegative with respect to the point where the left
arm connects, the electrocardiograph records positively,
that is, above the zero voltage line in the electrocardiogram. When the opposite is true, the electrocardiograph
records below the line.
Lead II. To record limb lead II, the negative terminal
of the electrocardiograph is connected to the right arm
and the positive terminal to the left leg. Therefore, when
the right arm is negative with respect to the left leg, the
­electrocardiograph records positively.
U n i t III
Lead III. To record limb lead III, the negative terminal
of the electrocardiograph is connected to the left arm and
the positive terminal to the left leg. This means that the
electrocardiograph records positively when the left arm is
negative with respect to the left leg.
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. Note, however, 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 millivolts (negative)
with respect to the average potential in the body, the left
arm is +0.3 millivolts (positive), and the left leg is +1.0
millivolts (positive). Observing the meters in the figure,
one can see that lead I records a positive potential of
+0.5 millivolts because this is the difference between
the −0.2 millivolts on the right arm and the +0.3 millivolts on the left arm. Similarly, lead III records a positive potential of +0.7 millivolts, and lead II records a
positive potential of +1.2 millivolts because these are the
instantaneous potential differences between the respective pairs of limbs.
Now, note that the sum of the voltages in leads I and
III equals the voltage in lead II; that is, 0.5 plus 0.7 equals
1.2. Mathematically, this principle, called Einthoven’s law,
holds true at any given instant while the three “standard”
bipolar electrocardiograms are being recorded.
Normal Electrocardiograms Recorded from the Three
Standard Bipolar Limb Leads. Figure 11-7 shows recordings of the electrocardiograms in leads I, II, and III. It is
obvious that the electrocardiograms in these three leads
are similar to one another because they all record positive
P waves and positive T waves, and the major portion of the
QRS complex is also positive in each electrocardiogram.
On analysis of the three electrocardiograms, it can be
shown, with careful measurements and proper observance of polarities, that at any given instant the sum of
the potentials in leads I and III equals the potential in lead
II, thus illustrating the validity of Einthoven’s law.
Because the recordings from all the bipolar limb leads
are similar to one another, it does not matter greatly which
lead is recorded when one wants to diagnose different
cardiac arrhythmias, because diagnosis of arrhythmias
depends mainly on the time relations between the different waves of the cardiac cycle. But when one wants to
diagnose damage in the ventricular or atrial muscle or in
the Purkinje conducting system, it matters greatly which
Unit III The Heart
3 456
Figure 11-7 Normal electrocardiograms recorded from the three
standard electrocardiographic leads.
leads are recorded, because abnormalities of cardiac muscle contraction or cardiac impulse conduction do change
the patterns of the electrocardiograms markedly in some
leads yet may not affect other leads. Electrocardiographic
interpretation of these two types of conditions—cardiac
myopathies and cardiac arrhythmias—is discussed separately in Chapters 12 and 13.
Figure 11-8 Connections of the body with the electrocardiograph
for recording chest leads. LA, left arm; RA, right arm.
Chest Leads (Precordial Leads)
Often electrocardiograms are recorded with one electrode placed on the anterior surface of the chest directly
over the heart at one of the points shown in Figure 11-8.
This electrode is connected to the positive terminal of the
electrocardiograph, and the negative electrode, called the
indifferent electrode, is connected through equal electrical resistances to the right arm, left arm, and left leg all
at the same time, as also shown in the figure. Usually six
standard chest leads are 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 are known as leads V1, V2, V3, V4,
V5, and V6.
Figure 11-9 illustrates the electrocardiograms of the
healthy heart as recorded from these six standard chest
leads. Because the heart surfaces are close to the chest
wall, each chest lead records mainly the electrical potential of the cardiac musculature immediately beneath the
electrode. Therefore, relatively minute abnormalities
in the ventricles, particularly in the anterior ventricular
wall, can cause marked changes in the electrocardiograms
recorded from individual chest leads.
In leads V1 and V2, the QRS recordings of the normal heart are mainly negative because, as shown in Figure
11-8, the chest electrode in these leads is nearer to the
base of the heart than to the apex, and the base of the
heart is the direction of electronegativity during most of
the ventricular depolarization process. Conversely, the
QRS complexes in leads V4, V5, and V6 are mainly positive because the chest electrode in these leads is nearer
the heart apex, which is the direction of electropositivity
during most of depolarization.
Augmented Unipolar Limb Leads
Another system of leads in wide use is the augmented unipolar limb lead. In this type of recording, two of the limbs
are connected through electrical resistances to the negative terminal of the electrocardiograph, and the third limb
is connected to the positive terminal. When the positive
terminal is on the right arm, the lead is known as the aVR
lead; when on the left arm, the aVL lead; and when on the
left leg, the aVF lead.
Figure 11-9 Normal electrocardiograms recorded from the six
standard chest leads.
Chapter 11 The Normal Electrocardiogram
Figure 11-10 Normal electrocardiograms recorded from the
three augmented unipolar limb leads.
See bibliography for Chapter 13.
U n i t III
Normal recordings of the augmented unipolar limb
leads are shown in Figure 11-10. They are all similar to the
standard limb lead recordings, except that the recording
from the aVR lead is inverted. (Why does this inversion
occur? Study the polarity connections to the electrocardiograph to determine this.)
This page intentionally left blank
chapter 12
From the discussion in
Chapter 10 of impulse trans­
mission through the heart,
it is obvious that any change
in the pattern of this trans­
mission can cause abnor­
mal electrical potentials
around the heart and, consequently, alter the shapes of the
waves in the electrocardiogram. For this reason, most seri­
ous abnormalities of the heart muscle can be diagnosed
by analyzing the contours of the 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 abnor­
malities affect the contours 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
generated 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 excitation, electrical current flows between
the depolarized areas inside the heart and the nondepolar­
ized 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, considerably more current
flows downward from the base of the ventricles toward the
apex than in the upward ­direction. Therefore, the summated
vector of the ­generated ­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 12-2. From this
zero reference point, the scale of vectors rotates clock­
wise: when the vector extends from above and straight
downward, it has a direction of +90 degrees; when it
extends from the person’s left to right, it has a direction of
+180 degrees; and when it extends straight upward, it has
a direction of −90 (or +270) degrees.
In a normal heart, the average direction of the vector
during spread of the depolarization wave through the ven­
tricles, called the mean QRS vector, is about +59 degrees,
which is shown by vector A drawn through the center
of Figure 12-2 in the +59-degree direction. This means
that during most of the depolarization wave, the apex of
the heart remains positive with respect to the base of the
heart, as discussed later in the chapter.
+ + ++
− −
− −
+− −
+ + + + +
Figure 12-1 Mean vector through the partially depolarized ventricles.
U n i t III
Electrocardiographic Interpretation
of Cardiac Muscle and Coronary Blood Flow
Abnormalities: Vectorial Analysis
Unit III The Heart
known as the hexagonal reference system. The polarities
of the electrodes are shown by the plus and minus signs
in the figure. The reader must learn these axes and their
polarities, particularly for the bipolar limb leads I, II, and
III, to understand the remainder of this chapter.
Vectorial Analysis of Potentials Recorded
in Different Leads
Figure 12-2 Vectors drawn to represent potentials for several different hearts, and the “axis” of the potential (expressed in degrees)
for each heart.
Axis for Each Standard Bipolar Lead and Each
Unipolar Limb Lead
In Chapter 11, the three standard bipolar and the three
unipolar limb leads are described. Each lead is actually a
pair of electrodes connected to the body on opposite sides
of the heart, and the direction from negative 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 electrodes lie exactly in the hori­
zontal direction, with the positive electrode to the left, the
axis of lead I is 0 degrees.
In recording lead II, electrodes are placed on the 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 direction of this
lead is about +60 degrees.
By similar analysis, it can be seen that lead III has an
axis of about +120 degrees; lead aVR, +210 degrees; aVF,
+90 degrees; and aVL −30 degrees. The directions of the
axes of all these leads are shown in Figure 12-3, which is
aVL +
+ aVR
Figure 12-3 Axes of the three bipolar and three unipolar leads.
Now that we have discussed, first, the conventions for
representing potentials across the heart by means of vec­
tors and, second, the axes of the leads, it is possible to
use these together to determine the instantaneous poten­
tial that will be recorded in the electrocardiogram of each
lead for a given vector in the heart, as follows.
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 mv. In the dia­
gram 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 the
positive end of the lead I axis, which means that the record
momentarily being recorded in the electrocardiogram 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 anal­
ysis. In this example, vector A represents the electrical
potential and its axis at a given instant during ventricu­
lar depolarization in a heart in which the left side of the
heart depolarizes more rapidly than the right. In this
instance, the instantaneous vector has a direction of 100
degrees, and its voltage is again 2 millivolts. To determine
the potential actually recorded in lead I, we draw a per­
pendicular 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
Figure 12-4 Determination of a projected vector B along the axis
of lead I when vector A represents the instantaneous potential in
the ventricles.
Chapter 12 Electrocardiographic Interpretation of Cardiac Muscle and Coronary Blood Flow Abnormalities: Vectorial Analysis
Figure 12-5 Determination of the projected vector B along the
axis of lead I when vector A represents the instantaneous potential in the ventricles.
particular instant, the recording in lead I will be negative
(below the zero line in the electrocardiogram), and the
voltage recorded will be slight, about −0.3 millivolts. This
figure demonstrates that when the vector in the heart is in
a direction almost perpendicular to the axis of the lead,
the voltage recorded in the electrocardiogram of this lead
is very low. Conversely, when the heart vector has almost
exactly the same axis as the lead axis, essentially the entire
voltage of the vector will be recorded.
Vectorial Analysis of Potentials in the Three Standard
Bipolar Limb Leads. In Figure 12-6, vector A depicts the
instantaneous electrical potential of a partially depolarized
heart. To determine the potential recorded at this instant
in the electrocardiogram for each one of the three stan­
dard bipolar limb leads, perpendicular lines (the dashed
lines) are drawn from the tip of vector A to the three lines
representing the axes of the three different standard leads,
as shown in the figure. The projected vector B depicts
the potential recorded at that instant in lead I, pro­jected
­vector C depicts the potential in lead II, and pro­jected vec­
tor D depicts the potential in lead III. In each of these,
the record in the electrocardiogram is positive—that is,
Figure 12-6 Determination of projected vectors in leads I, II, and
III when vector A represents the instantaneous potential in the
Vectorial Analysis of the Normal
Vectors That Occur at Successive Intervals
during Depolarization of the Ventricles—
the QRS Complex
When the cardiac impulse enters the ventricles through
the atrioventricular bundle, the first part of the ventri­
cles to become depolarized is the left endocardial surface
of the septum. Then depolarization spreads rapidly to
involve both endocardial surfaces of the septum, as dem­
onstrated by the darker shaded portion of the ventricle
in Figure 12-7A. Next, depolarization spreads along the
endocardial surfaces of the remainder of the two ventri­
cles, as shown in Figure 12-7B and C. Finally, it spreads
through the ventricular muscle to the outside of the heart,
as shown progressively in Figure 12-7C, D, and E.
At each stage in Figure 12-7, parts A to E, the instan­
taneous mean electrical potential of the ventricles is rep­
resented by a red vector superimposed on the ventricle
in each figure. Each of these vectors is then analyzed by
the method described in the preceding section to deter­
mine the voltages that will be recorded at each instant in
each of the three standard electrocardiographic leads. To
the right in each figure is shown progressive development
of the electrocardiographic QRS complex. Keep in mind
that a positive vector in a lead will cause recording in the
electrocardiogram above the zero line, whereas a negative
­vector will cause recording below the zero line.
Before proceeding with further consideration of vec­
torial analysis, it is essential that this analysis of the suc­
cessive normal vectors presented in Figure 12-7 be
understood. Each of these analyses should be studied in
detail by the procedure given here. A short summary of
this sequence follows.
In Figure 12-7A, the ventricular muscle has just begun
to be depolarized, representing an instant about 0.01 sec­
ond after the onset of depolarization. At this time, the
vector is short because only a small portion of the ven­
tricles—the septum—is depolarized. Therefore, all elec­
trocardiographic voltages are low, as recorded to the right
of the ventricular muscle for each of the leads. The volt­
age in lead II is greater than the voltages in leads I and
III because the heart vector extends mainly in the same
direction as the axis of lead II.
U n i t III
above the zero line—because the projected vectors point
in the positive directions along the axes of all the leads.
The potential in lead I (vector B) is about one-half that of
the actual potential in the heart (vector A); in lead II (vec­
tor C), it is almost equal to that in the heart; and in lead III
(vector D), it is about one-third that in the heart.
An identical analysis can be used to determine poten­
tials recorded in augmented limb leads, except that the
respective axes of the augmented leads (see Figure 12-3)
are used in place of the standard bipolar limb lead axes
used for Figure 12-6.
Unit III The Heart
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).
In Figure 12-7B, which represents about 0.02 second
after onset of depolarization, the heart vector is long
because much of the ventricular muscle mass has become
depolarized. Therefore, the voltages in all electrocardio­
graphic leads have increased.
In Figure 12-7C, about 0.035 second after onset of
depolarization, the heart vector is becoming shorter and
the recorded electrocardiographic voltages are lower
because the outside of the heart apex is now electronega­
tive, neutralizing much of the positivity on the other epi­
cardial surfaces of the heart. Also, the axis of the vector is
beginning to shift toward the left side of the chest because
the left ventricle is slightly slower to depolarize than the
right. Therefore, the ratio of the voltage in lead I to that in
lead III is increasing.
In Figure 12-7D, about 0.05 second after onset of depo­
larization, the heart vector points toward the base of the
left ventricle, and it is short because only a minute portion
of the ventricular muscle is still polarized positive. Because
of the direction of the vector at this time, the voltages
recorded in leads II and III are both negative—that is, below
the line—whereas the voltage of lead I is still positive.
In Figure 12-7E, about 0.06 second after onset of depo­
larization, the entire ventricular muscle mass is depolar­
ized so that no current flows around the heart and no
electrical potential is generated. The vector becomes zero,
and the voltages in all leads become zero.
Thus, the QRS complexes are completed in the three
standard bipolar limb leads.
Sometimes the QRS complex has a slight negative
depression at its beginning in one or more of the leads,
which is not shown in Figure 12-7; this depression is the
Q wave. When it occurs, it is caused by initial depolariza­
tion of the left side of the septum before the right side,
which creates a weak vector from left to right for a fraction
of a second before the usual base-to-apex vector occurs.
The major positive deflection shown in Figure 12-7 is the
R wave, and the final negative deflection is the S wave.
Chapter 12 Electrocardiographic Interpretation of Cardiac Muscle and Coronary Blood Flow Abnormalities: Vectorial Analysis
Electrocardiogram during Repolarization—the
T Wave
Depolarization of the atria begins in the sinus node and
spreads in all directions over the atria. Therefore, the point
of original electronegativity in the atria is about at the point
of entry of the superior vena cava 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 direction throughout the process
of normal atrial depolarization. Because this direction is
generally in the positive directions of the axes of the three
standard bipolar limb leads I, II, and III, the electrocardio­
grams recorded from the atria during depolarization are
also usually positive in all three of these leads, as shown in
Figure 12-9. This record of atrial depolarization is known
as the atrial P wave.
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 depolarization sig­
nal. Therefore, the musculature around the sinus node
becomes depolarized a long time before the muscula­
ture in distal parts of the atria. Because of this, the area
in the atria that also becomes repolarized first is the sinus
nodal region, the area that had originally become depolarized first. Thus, when repolarization begins, the region
around the sinus node becomes positive with respect to
the rest of the atria. Therefore, the atrial ­repolarization
+ + ++
−+ +
− + +
− −
− −
+ SA
+ +
Depolarization of the Atria—the P Wave
Figure 12-8 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.
Figure 12-9 Depolarization of the atria and generation of the
P wave, showing the maximum vector through the atria and
the resultant vectors in the three standard leads. At the right are
the atrial P and T waves. SA, sinoatrial node.
U n i t III
After the ventricular muscle has become depolarized,
about 0.15 second later, repolarization begins and pro­
ceeds until complete at about 0.35 second. This repolar­
ization causes the T wave in the electrocardiogram.
Because the septum and endocardial areas of the ven­
tricular muscle depolarize first, it seems logical that these
areas should repolarize first as well. However, this is not
the usual case because the septum and other endocardial
areas have a longer period of contraction than most of
the external surfaces of the heart. Therefore, the greatest
portion of ventricular muscle mass to repolarize first is the
entire outer surface of the ventricles, especially near
the apex of the heart. The endocardial areas, conversely,
normally repolarize last. This sequence of repolariza­
tion is postulated to be caused by the high blood pressure
inside the ventricles during contraction, which greatly
reduces coronary blood flow to the endocardium, thereby
slowing repolarization in the endocardial areas.
Because the outer apical surfaces of the ventricles repo­
larize before the inner surfaces, the positive end of the
overall ventricular vector during repolarization is toward
the apex of the heart. As a result, the normal T wave in all
three bipolar limb leads is positive, which is also the polarity of most of the normal QRS complex.
In Figure 12-8, five stages of repolarization of the ven­
tricles are denoted by progressive increase of the light tan
areas—the repolarized areas. At each stage, the vector
extends from the base of the heart toward the apex until it
disappears in the last stage. At first, the vector is relatively
small because the area of repolarization is small. Later,
the vector becomes stronger because of greater degrees of
repolarization. Finally, the vector becomes weaker again
because the areas of depolarization still persisting become
so slight that the total quantity of current flow decreases.
These changes also demonstrate that the vector is great­
est when about half the heart is in the polarized state and
about half is depolarized.
The changes in the electrocardiograms of the three
standard limb leads during repolarization are noted under
each of the ventricles, depicting the progressive stages of
repolarization. Thus, over about 0.15 second, the period
of time required for the whole process to take place, the T
wave of the electrocardiogram is generated.
Unit III The Heart
vector is backward to the vector of depolarization. (Note
that this is opposite to the effect that occurs in the
ventricles.) Therefore, as shown to the right in Figure
12-9, the so-called atrial T wave follows about 0.15 second
after the atrial P wave, but this T wave is on the opposite
side of the zero reference line from the P wave; that is, it
is normally negative rather than positive in the three stan­
dard bipolar limb leads.
In the normal electrocardiogram, the atrial T wave
appears at about the same time that the QRS complex
of the ventricles appears. Therefore, it is almost always
totally obscured by the large ventricular QRS complex,
although in some very abnormal states, it does appear in
the recorded electrocardiogram.
It has been noted in the discussion up to this point that
the vector of current flow through the heart changes rap­
idly as the impulse spreads through the myocardium. It
changes in two aspects: First, the vector increases and
decreases in length because of increasing and decreasing
voltage of the vector. Second, the vector changes direction
because of changes in the average direction of the electri­
cal potential from the heart. The so-called vectorcardiogram depicts these changes at different times during the
cardiac cycle, as shown in Figure 12-10.
In the large vectorcardiogram of Figure 12-10, point 5
is the zero reference point, and this point is the negative
end of all the successive vectors. While the heart muscle is
polarized between heartbeats, the positive end of the vec­
tor remains at the zero point because there is no vectorial
electrical potential. However, as soon as current begins to
flow through the ventricles at the beginning of ventricular
depolarization, the positive end of the vector leaves the
zero reference point.
When the septum first becomes depolarized, the vec­
tor extends downward toward the apex of the ventricles,
but it is relatively weak, thus generating the first portion
of the ventricular vectorcardiogram, as shown by the pos­
itive end of vector 1. As more of the ventricular muscle
Figure 12-10 QRS and T vectorcardiograms.
becomes depolarized, the vector becomes stronger and
stronger, usually swinging slightly to one side. Thus, vec­
tor 2 of Figure 12-10 represents the state of depolariza­
tion of the ventricles about 0.02 second after vector 1.
After another 0.02 second, vector 3 represents the poten­
tial, and vector 4 occurs in another 0.01 second. Finally,
the ventricles become totally depolarized, and the vector
becomes zero once again, as shown at point 5.
The elliptical figure generated by the positive ends
of the vectors is called the QRS vectorcardiogram.
Vectorcardiograms can be recorded on an oscilloscope
by connecting body surface electrodes from the neck
and lower abdomen to the vertical plates of the oscillo­
scope and connecting chest surface electrodes from each
side of the heart to the horizontal plates. When the vec­
tor changes, the spot of light on the oscilloscope follows
the course of the positive end of the changing vector,
thus inscribing the vectorcardiogram on the oscilloscopic
Mean Electrical Axis of the Ventricular
QRS—and Its Significance
The vectorcardiogram during ventricular depolarization
(the QRS vectorcardiogram) shown in Figure 12-10 is that
of a normal heart. Note from this vectorcardiogram that
the preponderant direction of the vectors of the ventri­
cles during depolarization is mainly toward the apex of
the heart. That is, during most of the cycle of ventricu­
lar depolarization, the direction of the electrical poten­
tial (negative to positive) is from the base of the ventricles
toward the apex. This preponderant direction of the
potential during depolarization is called the mean electrical axis of the ventricles. The mean electrical axis of
the normal ventricles is 59 degrees. In many pathological
conditions of the heart, this direction changes markedly,
sometimes even to opposite poles of the heart.
Determining the Electrical Axis from Standard
Lead Electrocardiograms
Clinically, the electrical axis of the heart is usually esti­
mated from the standard bipolar limb lead electrocar­
diograms rather than from the vectorcardiogram. Figure
12-11 shows a method for doing this. After recording
the standard leads, one determines the net potential and
polarity of the recordings in leads I and III. In lead I of
Figure 12-11, the recording is positive, and in lead III, the
recording is mainly positive but negative during part of
the cycle. If any part of a recording is negative, this negative potential is subtracted from the positive part of the
potential to determine the net potential for that lead, as
shown by the arrow to the right of the QRS complex for
lead III. Then each net potential for leads I and III is plot­
ted on the axes of the respective leads, with the base of the
potential at the point of intersection of the axes, as shown
in Figure 12-11.
Chapter 12 Electrocardiographic Interpretation of Cardiac Muscle and Coronary Blood Flow Abnormalities: Vectorial Analysis
Figure 12-11 Plotting the mean electrical axis of the ventricles
from two electrocardiographic leads (leads I and III).
If the net potential of lead I is positive, it is plotted
in a positive direction along the line depicting lead I.
Conversely, if this potential is negative, it is plotted in a
negative direction. Also, for lead III, the net potential is
placed with its base at the point of intersection, and, if
positive, it is plotted in the positive direction along the
line depicting lead III. If it is negative, it is plotted in the
negative direction.
To determine the vector of the total QRS ventricular
mean electrical potential, one draws perpendicular lines
(the dashed lines in the figure) from the apices of leads
I and III, respectively. The point of intersection of these
two perpendicular lines represents, by vectorial analysis,
the apex of the mean QRS vector in the ventricles, and the
point of intersection of the lead I and lead III axes rep­
resents the negative end of the mean vector. Therefore,
the mean QRS vector is drawn between these two points.
The approximate average potential generated by the ven­
tricles during depolarization is represented by the length
of this mean QRS vector, and the mean electrical axis is
represented by the direction of the mean vector. Thus,
the orientation of the mean electrical axis of the normal
ventricles, as determined in Figure 12-11, is 59 degrees
­positive (+59 degrees).
Abnormal Ventricular Conditions That Cause
Axis Deviation
Although the mean electrical axis of the ventricles aver­
ages about 59 degrees, this axis can swing even in the nor­
mal heart from about 20 degrees to about 100 degrees.
The causes of the normal variations are mainly anatomi­
cal differences in the Purkinje distribution system or in the
musculature itself of different hearts. However, a number
of abnormal conditions of the heart can cause axis devia­
tion beyond the normal limits, as follows.
Change in the Position of the Heart in the Chest. If
the heart itself is angulated to the left, the mean electri­
cal axis of the heart also shifts to the left. Such shift occurs
(1) at the end of deep expiration, (2) when a ­person
I –
Figure 12-12 Left axis deviation in a hypertensive heart (hypertrophic left ventricle). Note the slightly prolonged QRS complex
as well.
U n i t III
– –60
lies down, because the abdominal contents press upward
against the diaphragm, and (3) quite frequently in obese
people whose diaphragms normally press upward
against the heart all the time due to increased visceral
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, lanky people
whose hearts hang downward.
Hypertrophy of One Ventricle. When one ventricle
greatly hypertrophies, the axis of the heart shifts toward the
hypertrophied ventricle for two reasons. First, a far greater
quantity of muscle exists on the hypertrophied side of the
heart than on the other side, and this allows generation of
greater electrical potential on that side. Second, more time
is required for the depolarization wave to travel through
the hypertrophied ventricle than through the normal
ventricle. Consequently, the normal ventricle becomes
depolarized considerably in advance of the hypertrophied
ventricle, and this causes a strong vector from the normal
side of the heart toward the hypertrophied side, which
remains strongly positively charged. Thus, the axis devi­
ates toward the hypertrophied ventricle.
Vectorial Analysis of Left Axis Deviation Resulting
from Hypertrophy of the Left Ventricle. Figure 12-12
shows the three standard bipolar limb lead electro­
cardiograms. Vectorial analysis demonstrates left axis
deviation with mean electrical axis pointing in the
−15-degree direction. This is a typical electrocardio­
gram caused by increased muscle mass of the left ven­
tricle. In this instance, the axis deviation was caused
by hypertension (high arterial blood pressure), which
caused the left ventricle to hypertrophy so that it could
pump blood against elevated systemic arterial pressure.
A similar picture of left axis deviation occurs when the
Unit III The Heart
left ventricle hypertrophies as a result of aortic valvular
stenosis, aortic valvular regurgitation, or any number
of congenital heart conditions in which the left ventri­
cle enlarges while the right ventricle remains relatively
­normal in size.
Vectorial Analysis of Right Axis Deviation Resulting
from Hypertrophy of the Right Ventricle. The elec­
trocardiogram of Figure 12-13 shows intense right axis
deviation, to an electrical axis of 170 degrees, which is
111 degrees to the right of the normal 59-degree mean
ventricular QRS axis. The right axis deviation demon­
strated in this figure was caused by hypertrophy of the
right ventricle as a result of congenital pulmonary valve
stenosis. Right axis deviation also can occur in other con­
genital heart conditions that cause hypertrophy of the right
­ventricle, such as tetralogy of Fallot and interventricular
septal defect.
Bundle Branch Block Causes Axis Deviation. Ordinarily,
the lateral walls of the two ventricles depolarize at almost
the same instant because both the left and the right bun­
dle branches of the Purkinje system transmit the cardiac
impulse to the two ventricular walls at almost the same
instant. As a result, the potentials generated by the two
ventricles (on the two opposite sides of the heart) almost
neutralize each other. But if only one of the major bundle
branches is blocked, the cardiac impulse spreads through
the normal ventricle long before it spreads through the
other. Therefore, depolarization of the two ventricles does
not occur even nearly simultaneously, and the depolariza­
tion potentials do not neutralize each other. As a result,
axis deviation occurs as follows.
Vectorial Analysis of Left Axis Deviation in Left Bundle
Branch Block. When the left bundle branch is blocked,
cardiac depolarization spreads through the right ventricle
two to three times as rapidly as through the left ventricle.
Consequently, much of the left ventricle remains polarized
for as long as 0.1 second after the right ventricle has become
totally depolarized. Thus, the right ventricle becomes elec­
tronegative, whereas the left ventricle remains electroposi­
tive during most of the depolarization process, and a strong
vector projects from the right ventricle toward the left ven­
tricle. In other words, there is intense left axis deviation of
about −50 degrees because the positive end of the vector
points toward the left ventricle. This is demonstrated in
Figure 12-14, which shows typical left axis deviation result­
ing from left bundle branch block.
Because of slowness of impulse conduction when the
Purkinje system is blocked, in addition to axis deviation,
the duration of the QRS complex is greatly prolonged
because of extreme slowness of depolarization in the
affected side of the heart. One can see this by observing
the excessive widths of the QRS waves in Figure 12-14.
This is discussed in greater detail later in the chapter. This
extremely prolonged QRS complex differentiates bundle
branch block from axis deviation caused by hypertrophy.
Vectorial Analysis of Right Axis Deviation in Right
Bundle Branch Block. When the right bundle branch is
blocked, the left ventricle depolarizes far more rapidly
than the right ventricle, so the left side of the ventricles
becomes electronegative as long as 0.1 second before the
right. Therefore, a strong vector develops, with its neg­
ative end toward the left ventricle and its positive end
toward the right ventricle. In other words, intense right
axis deviation occurs. Right axis deviation caused by right
bundle branch block is demonstrated, and its vector is
I –
I –
Figure 12-13 High-voltage electrocardiogram in congenital pulmonary valve stenosis with right ventricular hypertrophy. Intense
right axis deviation and a slightly prolonged QRS complex also are
Figure 12-14 Left axis deviation caused by left bundle branch
block. Note also the greatly prolonged QRS complex.
Chapter 12 Electrocardiographic Interpretation of Cardiac Muscle and Coronary Blood Flow Abnormalities: Vectorial Analysis
U n i t III
Figure 12-15 Right axis deviation caused by right bundle branch
block. Note also the greatly prolonged QRS complex.
analyzed, in Figure 12-15, which shows an axis of about
105 degrees instead of the normal 59 degrees and a pro­
longed QRS complex because of slow conduction.
Conditions That Cause Abnormal Voltages
of the QRS Complex
Increased Voltage in the Standard Bipolar
Limb Leads
Normally, the voltages in the three standard bipolar limb
leads, as measured from the peak of the R wave to the
bottom of the S wave, vary between 0.5 and 2.0 millivolts,
with lead III usually recording the lowest voltage and lead
II the highest. However, these relations are not invariable,
even for the normal heart. In general, when the sum of the
voltages of all the QRS complexes of the three standard
leads is greater than 4 millivolts, the patient is considered
to have a high-voltage electrocardiogram.
The cause of high-voltage QRS complexes most often
is increased muscle mass of the heart, which ordinar­
ily results from hypertrophy of the muscle in response to
excessive load on one part of the heart or the other. For
example, the right ventricle hypertrophies when it must
pump blood through a stenotic pulmonary valve, and the
left ventricle hypertrophies when a person has high blood
pressure. The increased quantity of muscle causes gen­
eration of increased quantities of electricity around the
heart. As a result, the electrical potentials recorded in the
electrocardiographic leads are considerably greater than
normal, as shown in Figures 12-12 and 12-13.
Decreased Voltage of the Electrocardiogram
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 infarctions
with resultant diminished muscle mass. This also causes
the depolarization wave to move through the ventricles
slowly and prevents major portions of the heart from
becoming massively depolarized all at once. Consequently,
this condition causes some prolongation of the QRS com­
plex along with the decreased voltage. Figure 12-16 shows
Figure 12-16 Low-voltage electrocardiogram following local
damage throughout the ventricles caused by previous myocardial
a typical low-voltage electrocardiogram with prolonga­
tion of the QRS complex, which is common after multiple
small infarctions of the heart have caused local delays of
impulse conduction and reduced voltages due to loss of
muscle mass throughout the ventricles.
Decreased Voltage Caused by Conditions Surround­
ing the Heart. One of the most important causes of
decreased voltage in electrocardiographic leads is fluid
in the pericardium. Because extracellular fluid conducts
electrical currents with great ease, a large portion of the
electricity flowing out of the heart is conducted from one
part of the heart to another through the pericardial fluid.
Thus, this effusion effectively “short-circuits” the electri­
cal potentials generated by the heart, decreasing the elec­
trocardiographic voltages that reach the outside surfaces
of the body. Pleural effusion, to a lesser extent, also can
“short-circuit” the electricity around the heart so that the
voltages at the surface of the body and in the electrocar­
diograms are decreased.
Pulmonary emphysema can decrease the electrocar­
diographic potentials, but for a different reason than
that of pericardial effusion. In pulmonary emphysema,
conduction of electrical current through the lungs is
depressed considerably because of excessive quantity of
air in the lungs. Also, the chest cavity enlarges, and the
lungs tend to envelop the heart to a greater extent than
normally. Therefore, the lungs act as an insulator to pre­
vent spread of electrical voltage from the heart to the
surface of the body, and this results in decreased electro­
cardiographic potentials in the various leads.
Prolonged and Bizarre Patterns of
the QRS Complex
Prolonged QRS Complex as a Result of Cardiac
Hypertrophy or Dilatation
The QRS complex lasts as long as depolarization continues
to spread through the ventricles—that is, as long as part
of the ventricles is depolarized and part is still polarized.
Unit III The Heart
Therefore, prolonged conduction of the impulse through
the ventricles always causes a prolonged QRS complex.
Such prolongation often occurs when one or both ven­
tricles are hypertrophied or dilated, owing to the longer
pathway that the impulse must then travel. The normal
QRS complex lasts 0.06 to 0.08 second, whereas in hyper­
trophy or dilatation of the left or right ventricle, the QRS
complex may be prolonged to 0.09 to 0.12 second.
Prolonged QRS Complex Resulting from Purkinje
System Blocks
When the Purkinje fibers are blocked, the cardiac impulse
must then be conducted by the ventricular muscle instead
of by way of the Purkinje system. This decreases the
velocity of impulse conduction to about one third of nor­
mal. Therefore, if complete block of one of the bundle
branches occurs, the duration of the QRS complex is usu­
ally increased to 0.14 second or greater.
In general, a QRS complex is considered to be abnor­
mally long when it lasts more than 0.09 second; when it
lasts more than 0.12 second, the prolongation is almost
certainly caused by pathological block somewhere in the
ventricular conduction system, as shown by the electro­
cardiograms for bundle branch block in Figures 12-14
and 12-15.
Conditions That Cause Bizarre QRS Complexes
Bizarre patterns of the QRS complex most frequently are
caused by two conditions: (1) destruction of cardiac mus­
cle in various areas throughout the ventricular system,
with replacement of this muscle by scar tissue, and (2)
multiple small local blocks in the conduction of impulses
at many points in the Purkinje system. As a result, car­
diac impulse conduction becomes irregular, causing rapid
shifts in voltages and axis deviations. This often causes
double or even triple peaks in some of the electrocardio­
graphic leads, such as those shown in Figure 12-14.
Current of Injury
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 the patho­
logically depolarized and the normally polarized areas
even between heartbeats. This is called a current of injury.
Note especially that the injured part of the heart is negative, because this is the part that is depolarized and emits
negative charges into the surrounding fluids, whereas the
remainder of the heart is neutral or positive polarity.
Some abnormalities that can cause current of injury
are (1) mechanical trauma, which sometimes makes the
membranes remain so permeable that full repolarization
cannot take place; (2) infectious processes that damage
the muscle membranes; and (3) ischemia of local areas of
heart muscle caused by local coronary occlusions, which is
by far the most common cause of current of injury in the
heart. During ischemia, not enough nutrients from the
coronary blood supply are available to the heart muscle to
maintain normal membrane polarization.
Effect of Current of Injury on the QRS Complex
In Figure 12-17, a small area in the base of the left ventricle
is newly infarcted (loss of coronary blood flow). Therefore,
during the T-P interval—that is, when the normal ventric­
ular muscle is totally polarized—abnormal negative cur­
rent still flows from the infarcted area at the base of the left
ventricle and spreads toward the rest of the ventricles.
The vector of this “current of injury,” as shown in the
first heart in Figure 12-17, is in a direction of about 125
degrees, with the base of the vector, the negative end, toward
the injured muscle. As shown in the lower portions of the
figure, even before the QRS complex begins, this vector
causes an initial record in lead I below the zero potential line, because the projected vector of the current of
injury in lead I points toward the negative end of the lead
I axis. In lead II, the record is above the line because the
projected vector points more toward the positive termi­
nal of the lead. In lead III, the projected vector points in
the same direction as the positive terminal of lead III so
that the record is positive. Furthermore, because the vec­
tor lies almost exactly in the direction of the axis of lead
III, the voltage of the current of injury in lead III is much
greater than in either lead I or lead II.
As the heart then proceeds through its normal process
of depolarization, the septum first becomes depolarized;
then the depolarization spreads down to the apex and
back toward the bases of the ventricles. The last portion
of the ventricles to become totally depolarized is the base
of the right ventricle, because the base of the left ventricle
is already totally and permanently depolarized. By vecto­
rial analysis, the successive stages of electrocardiogram
generation by the depolarization wave traveling through
the ventricles can be constructed graphically, as demon­
strated in the lower part of Figure 12-17.
When the heart becomes totally depolarized, at the end
of the depolarization process (as noted by the next-to-last
stage in Figure 12-17), all the ventricular muscle is in a
negative state. Therefore, at this instant in the electrocar­
diogram, no current flows from the ventricles to the elec­
trocardiographic electrodes because now both the injured
heart muscle and the contracting muscle are depolarized.
Next, as repolarization takes place, all of the heart
finally repolarizes, except the area of permanent depolar­
ization in the injured base of the left ventricle. Thus, repo­
larization causes a return of the current of injury in each
lead, as noted at the far right in Figure 12-17.
The J Point—the Zero Reference Potential for
Analyzing Current of Injury
One might think that the electrocardiograph machines
for recording electrocardiograms could determine when
no current is flowing around the heart. However, many
Chapter 12 Electrocardiographic Interpretation of Cardiac Muscle and Coronary Blood Flow Abnormalities: Vectorial Analysis
Injured area
U n i t III
of injury
of injury
Figure 12-17 Effect of a current of injury on the electrocardiogram.
stray currents exist in the body, such as currents result­
ing from “skin potentials” and from differences in ionic
concentrations in different fluids of the body. Therefore,
when two electrodes are connected between the arms or
between an arm and a leg, these stray currents make it
impossible to predetermine the exact zero reference level
in the electrocardiogram.
For these reasons, the following procedure must be
used to determine the zero potential level: First, one notes
the exact point at which the wave of depolarization just
completes its passage through the heart, which occurs at
the end of the QRS complex. At exactly this point, all
parts of the ventricles have become depolarized, includ­
ing both the damaged parts and the normal parts, so no
current is flowing around the heart. Even the current of
injury disappears at this point. Therefore, the potential
of the electrocardiogram at this instant is at zero voltage.
This point is known as the “J” point in the electrocardio­
gram, as shown in Figure 12-18.
Then, for analysis of the electrical axis of the injury
potential caused by a current of injury, a horizontal
line is drawn in the electrocardiogram for each lead
at the level of the J point. This horizontal line is then
the zero potential level in the electrocardiogram from
which all potentials caused by currents of injury must
be measured.
Use of the J Point in Plotting Axis of Injury Potential.
Figure 12-18 shows electrocardiograms (leads I and III)
from an injured heart. Both records show injury poten­
tials. In other words, the J point of each of these two
electrocardiograms is not on the same line as the T-P
segment. In the figure, a horizontal line has been drawn
through the J point to represent the zero voltage level in
each of the two recordings. The injury potential in each
lead is the difference between the voltage of the electro­
cardiogram immediately before onset of the P wave and
the zero voltage level determined from the J point. In lead
I, the recorded voltage of the injury potential is above the
zero potential level and is, therefore, positive. Conversely,
in lead III, the injury potential is below the zero voltage
level and, therefore, is negative.
At the bottom in Figure 12-18, the respective injury
potentials in leads I and III are plotted on the coordi­
nates of these leads, and the resultant vector of the
injury potential for the whole ventricular muscle mass
“J” point
“J” point
Figure 12-18 J point as the zero reference potential of the electrocardiograms for leads I and III. Also, the method for plotting the
axis of the injury potential is shown by the lowermost panel.
Unit III The Heart
is determined by vectorial analysis as described. In this
instance, the resultant vector extends from the right side
of the ventricles toward the left and slightly upward,
with an axis of about −30 degrees. If one places this vec­
tor for the injury potential directly over the ventricles,
the negative end of the vector points toward the permanently depolarized, “injured” area of the ventricles. In the
example shown in Figure 12-18, the injured area would
be in the lateral wall of the right ventricle.
This analysis is obviously complex. However, it is
essential that the student go over it again and again until
he or she understands it thoroughly. No other aspect of
electrocardiographic analysis is more important.
Coronary Ischemia as a Cause of Injury Potential
Insufficient blood flow to the cardiac muscle depresses
the metabolism of the muscle for three reasons: (1) lack
of oxygen, (2) excess accumulation of carbon dioxide, and
(3) lack of sufficient food nutrients. Consequently, repolar­
ization of the muscle membrane cannot occur in areas of
severe myocardial ischemia. Often the heart muscle does
not die because the blood flow is sufficient to maintain life
of the muscle even though it is not sufficient to cause repo­
larization of the membranes. As long as this state exists,
an injury potential continues to flow during the diastolic
­portion (the T-P portion) of each heart cycle.
Extreme ischemia of the cardiac muscle occurs after
coronary occlusion, and a strong current of injury flows
from the infarcted area of the ventricles during the T-P
interval between heartbeats, as shown in Figures 12-19
and 12-20. Therefore, one of the most important diag­
nostic features of electrocardiograms recorded after acute
coronary thrombosis is the current of injury.
Figure 12-19 Current of injury in acute anterior wall infarction.
Note the intense injury potential in lead V2.
Figure 12-20 Injury potential in acute posterior wall, apical
Acute Anterior Wall Infarction. Figure 12-19 shows
the electrocardiogram in the three standard bipolar limb
leads and in one chest lead (lead V2) recorded from a
patient with acute anterior wall cardiac infarction. The
most important diagnostic feature of this electrocardio­
gram is the intense injury potential in chest lead V2. If one
draws a zero horizontal potential line through the J point
of this electrocardiogram, a strong negative injury poten­
tial during the T-P interval is found, which means that the
chest electrode over the front of the heart is in an area of
strongly negative potential. In other words, the negative
end of the injury potential vector in this heart is against the
anterior chest wall. This means that the current of injury is
emanating from the anterior wall of the ventricles, which
diagnoses this condition as anterior wall infarction.
Analyzing the injury potentials in leads I and III, one
finds a negative potential in lead I and a positive poten­
tial in lead III. This means that the resultant vector of the
injury potential in the heart is about +150 degrees, with
the negative end pointing toward the left ventricle and the
positive end pointing toward the right ventricle. Thus, in
this particular electrocardiogram, the current of injury is
coming mainly from the left ventricle, as well as from the
anterior wall of the heart. Therefore, one would conclude
that this anterior wall infarction almost certainly is caused
by thrombosis of the anterior descending branch of the
left coronary artery.
Posterior Wall Infarction. Figure 12-20 shows the
three standard bipolar limb leads and one chest lead (lead
V2) from a patient with posterior wall infarction. The
major diagnostic feature of this electrocardiogram is also
in the chest lead. If a zero potential reference line is drawn
through the J point of this lead, it is readily apparent that
during the T-P interval, the potential of the current of
injury is positive. This means that the positive end of the
vector is in the direction of the anterior chest wall, and
the negative end (injured end of the vector) points away
Chapter 12 Electrocardiographic Interpretation of Cardiac Muscle and Coronary Blood Flow Abnormalities: Vectorial Analysis
Figure 12-22 Electrocardiograms of anterior and posterior wall
infarctions that occurred about 1 year previously, showing a Q
wave in lead I in anterior wall infarction and a Q wave in lead III in
posterior wall infarction.
dies, but if the muscle does not die, it will continue to
show an injury potential as long as the ischemia exists,
particularly during bouts of exercise when the heart is
Old Recovered Myocardial Infarction. Figure 12-22
shows leads I and III after anterior infarction and leads
I and III after posterior infarction about 1 year after the
acute heart attack. The records show what might be 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 the QRS complex
in lead I in anterior infarction because of loss of muscle
mass in the anterior wall of the left ventricle, but in poste­
rior infarction, a Q wave has developed at the beginning
of the QRS complex in lead III because of loss of muscle
in the posterior apical part of the ventricle.
These configurations are certainly not found in all
cases of old cardiac infarction. Local loss of muscle
and local points of cardiac signal conduction block can
cause very bizarre QRS patterns (especially prominent
Q waves, for instance), decreased voltage, and QRS
Current of Injury in Angina Pectoris. “Angina pec­
toris” means pain from the heart felt in the pectoral
regions of the upper chest. This pain usually also radi­
ates into the left neck area and down the left arm. The
pain is typically caused by moderate ischemia of the
heart. Usually, no pain is felt as long as the person is
quiet, but as soon as he or she overworks the heart, the
pain appears.
An injury potential sometimes appears in the electro­
cardiogram during an attack of severe angina pectoris
because the coronary insufficiency becomes great enough
to prevent adequate repolarization of some areas of the
heart during diastole.
Abnormalities in the T Wave
Same day
1 week
3 weeks
1 year
Figure 12-21 Recovery of the myocardium after moderate posterior wall infarction, demonstrating disappearance of the injury
potential that is present on the first day after the infarction and
still slightly present at 1 week.
Earlier in the chapter, it was pointed out that the T wave is
normally positive in all the standard bipolar limb leads and
that this is caused by repolarization of the apex and outer
surfaces of the ventricles ahead of the intraventricular
surfaces. That is, the T wave becomes ­abnormal when the
normal sequence of repolarization does not occur. Several
factors can change this sequence of repolarization.
U n i t III
from the chest wall. In other words, the current of injury is
coming from the back of the heart opposite to the anterior
chest wall, which is the reason this type of electrocardio­
gram is the basis for diagnosing posterior wall infarction.
If one analyzes the injury potentials from leads II and III
of Figure 12-20, it is readily apparent that the injury poten­
tial is negative in both leads. By vectorial analysis, as shown
in the figure, one finds that the resultant vector of the injury
potential is about −95 degrees, with the negative end point­
ing downward and the positive end pointing upward. Thus,
because the infarct, as indicated by the chest lead, is on the
posterior wall of the heart and, as indicated by the injury
potentials in leads II and III, is in the apical portion of the
heart, one would suspect that this infarct is near the apex
on the posterior wall of the left ventricle.
Infarction in Other Parts of the Heart. By the same
procedures demonstrated in the preceding discussions
of anterior and posterior wall infarctions, it is possible
to determine the locus of any infarcted area emitting a
current of injury, regardless of which part of the heart is
involved. In making such vectorial analyses, it must be
remembered that the positive end of the injury 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 elec­
trocardiogram from the day of the attack to 1 week later,
3 weeks later, and finally 1 year later. From this electro­
cardiogram, one can see that the injury potential is strong
immediately after the acute attack (T-P segment displaced
positively from the S-T segment). However, after about
1 week, the injury potential has diminished considerably,
and after 3 weeks, it is gone. After that, the electrocardio­
gram does not change greatly during the next year. This is
the usual recovery pattern after acute myocardial infarc­
tion of moderate degree, showing that the new collateral coronary blood flow develops enough to re-establish
appropriate nutrition to most of the infarcted area.
Conversely, in some patients with myocardial infarc­
tion, the infarcted area never redevelops adequate
­coronary blood supply. Often, some of the heart muscle
Unit III The Heart
Effect of Slow Conduction of the Depolarization
Wave on the Characteristics of the T Wave
Referring to Figure 12-14, note that the QRS complex is
considerably prolonged. The reason for this prolongation
is delayed conduction in the left ventricle resulting from
left bundle branch block. This causes the left ventricle to
become depolarized about 0.08 second after depolarization
of the right ventricle, which gives a strong mean QRS vec­
tor to the left. However, the refractory periods of the right
and left 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 developing. In other
words, the mean axis of the T wave is now deviated to the
right, which is opposite the mean electrical axis of the QRS
complex in the same electrocardiogram. Thus, when con­
duction of the depolarization impulse through the ven­
tricles is greatly delayed, the T wave is almost always of
opposite polarity to that of the QRS complex.
Shortened Depolarization in Portions of the
Ventricular Muscle as a Cause of T Wave
If the base of the ventricles should exhibit an abnor­
mally short period of depolarization, that is, a shortened
action potential, repolarization of the ventricles would
not begin at the apex as it normally does. Instead, the
base of the ventricles would repolarize ahead of the apex,
and the vector of repolarization would point from the
apex toward the base of the heart, opposite to the stan­
dard vector of repolarization. Consequently, the T wave
in all three standard leads would be negative rather than
the usual positive. Thus, the simple fact that the base of
the ventricles has a shortened period of depolarization is
sufficient to cause marked changes in the T wave, even
to the extent of changing the entire T wave polarity, as
shown in Figure 12-23.
Figure 12-23 Inverted T wave resulting from mild ischemia at the
apex of the ventricles.
Figure 12-24 Biphasic T wave caused by digitalis toxicity.
Mild ischemia is by far the most common cause of
shortening of depolarization of cardiac muscle because
this increases current flow through the potassium chan­
nels. When the ischemia occurs in only one area of the
heart, the depolarization period of this area decreases out
of proportion to that in other portions. As a result, definite
changes in the T wave can take place. The ischemia might
result from chronic, progressive coronary occlusion; acute
coronary occlusion; or relative coronary insufficiency that
occurs during exercise.
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 waves. The changes in the T waves need not be specific
because any change in the T wave in any lead—inver­
sion, for instance, or a biphasic wave—is often evidence
enough that some portion of the ventricular muscle
has a period of depolarization out of proportion to the
rest of the heart, caused by mild to moderate coronary
Effect of Digitalis on the T Wave. As discussed in
Chapter 22, digitalis is a drug that can be used during
coronary insufficiency to increase the strength of car­
diac muscle contraction. But when overdosages of digi­
talis are given, depolarization duration in one part of the
ventricles may be increased out of proportion to that of
other parts. As a result, nonspecific changes, such as T
wave inversion or biphasic T waves, may occur in one or
more of the electrocardiographic leads. A biphasic T wave
caused by excessive administration of digitalis is shown
in Figure 12-24. Therefore, changes in the T wave during
digitalis administration are often the earliest signs of digi­
talis toxicity.
See bibliography for Chapter 13.
chapter 13
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 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 combination of the following abnormalities in the rhythmicity-conduction system of the
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.
The heart rate increases about 10 beats/min for each
degree of Fahrenheit (18 beats per degree Celsius) increase
in body temperature, up to a body temperature 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 tachycardia 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/min.
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.
The term “bradycardia” means a slow heart rate, usually
defined as fewer than 60 beats/min. 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
Abnormal Sinus Rhythms
The term “tachycardia” means fast heart rate, usually
defined in an adult person as faster than 100 beats/min.
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.
Some causes of tachycardia include increased body
temperature, stimulation of the heart by the sympathetic
nerves, or toxic conditions of the heart.
Figure 13-1 Sinus tachycardia (lead I).
Figure 13-2 Sinus bradycardia (lead III).
U n i t III
Cardiac Arrhythmias and Their
Electrocardiographic Interpretation
Unit III The Heart
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.
Vagal Stimulation as a Cause of Bradycardia. Any
circulatory reflex that stimulates the vagus nerves causes
release of acetylcholine at the vagal endings in the heart,
thus giving a parasympathetic effect. Perhaps the most
striking example of this occurs in patients with carotid sinus
syndrome. In these patients, the pressure receptors (baroreceptors) in the carotid sinus region of the carotid artery walls
are excessively sensitive. Therefore, even mild external pressure on the neck elicits a strong baroreceptor reflex, causing
intense vagal-acetylcholine effects on the heart, including
extreme bradycardia. Indeed, sometimes this reflex is so
powerful that it actually stops the heart for 5 to 10 seconds.
Sinus Arrhythmia
Figure 13-3 shows a cardiotachometer recording of the
heart rate, at first during normal and then (in the second
half of the record) during deep respiration. A cardiotachometer is an instrument that records by the height of
successive spikes the duration of the interval between
the successive QRS complexes in the electrocardiogram.
Note from this record that the heart rate increased and
decreased no more than 5 percent during 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 percent.
Sinus arrhythmia can result from any one of many circulatory conditions that alter the strengths of the sympathetic
and parasympathetic nerve signals to the heart sinus node.
In the “respiratory” type of sinus arrhythmia, as shown in
Figure 13-3, this results mainly from “spillover” of signals
from the medullary respiratory center into the adjacent
vasomotor center during inspiratory and expiratory cycles
of respiration. The spillover signals cause alternate increase
and decrease in the number of impulses transmitted through
the sympathetic and vagus nerves to the heart.
Abnormal Rhythms That Result from Block
of Heart Signals Within the Intracardiac
Conduction Pathways
Sinoatrial Block
Heart rate
In rare instances, the impulse from the sinus node is
blocked before it enters the atrial muscle. This phenomenon is demonstrated in Figure 13-4, which shows
Figure 13-3 Sinus arrhythmia as recorded by a cardiotachometer.
To the left is the record when the subject was breathing normally;
to the right, when breathing deeply.
SA block
Figure 13-4 Sinoatrial nodal block, with A-V nodal rhythm during
the block period (lead III).
s­ udden cessation of P waves, with resultant standstill of
the atria. However, the ventricles pick up a new rhythm,
the impulse usually originating spontaneously in the
atrioventricular (A-V) node, so the rate of the ventricular
QRS-T complex is slowed but not otherwise altered.
Atrioventricular Block
The only means by which impulses ordinarily can pass
from the atria into the ventricles is through the A-V bundle, also known as the bundle of His. Conditions that can
either decrease the rate of impulse conduction in this
bundle or block the impulse entirely are as follows:
1. Ischemia of the A-V node or A-V bundle fibers often
delays or blocks conduction from the atria to the ventricles. Coronary insufficiency can cause ischemia of
the A-V node and bundle in the same way that it can
cause ischemia of the myocardium.
2. Compression of the A-V bundle by scar tissue or by calcified portions of the heart can depress or block conduction from the atria to the ventricles.
3. Inflammation of the A-V node or A-V bundle can depress
conductivity from the atria to the ventricles. Inflammation
results frequently from different types of myocarditis,
caused, for example, by diphtheria or rheumatic fever.
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
Prolonged P-R (or P-Q) Interval—First-Degree
Block. The usual lapse of time between beginning of the
P wave and beginning of the QRS complex is about 0.16
second when the heart is beating at a normal rate. This socalled P-R interval usually decreases in length with faster
heartbeat and increases with slower heartbeat. In general,
when the P-R interval increases to greater than 0.20 second, the P-R interval is said to be prolonged and the patient
is said to have first-degree incomplete heart block.
Figure 13-5 shows an electrocardiogram with prolonged P-R interval; the interval in this instance is about
Figure 13-5 Prolonged P-R interval caused by first degree A-V
heart block (lead II).
Chapter 13 Cardiac Arrhythmias and Their Electrocardiographic Interpretation
Complete A-V Block (Third-Degree Block). When
the condition causing poor conduction in the A-V node
or A-V bundle becomes severe, complete block of the
impulse from the atria into the ventricles occurs. In
this instance, the ventricles spontaneously establish
their own signal, usually originating in the A-V node or
A-V bundle. Therefore, the P waves become dissociated
from the QRS-T complexes, as shown in Figure 13-7.
Note that the rate of rhythm of the atria in this electrocardiogram is about 100 beats per minute, whereas
the rate of ventricular beat is less than 40 per minute.
Furthermore, there is no relation between the rhythm of
the P waves and that of the QRS-T complexes because
the ventricles have “escaped” from control by the atria,
and they are beating at their own natural rate, controlled
most often by rhythmical signals generated in the A-V
node or A-V bundle.
Incomplete Intraventricular Block—Electrical
Most of the same factors that can cause A-V block can
also block impulse conduction in the peripheral ventricular Purkinje system. Figure 13-8 shows the condition known as electrical alternans, which results from
partial ­intraventricular block every other heartbeat.
Dropped beat
Stokes-Adams Syndrome—Ventricular Escape. In
some patients with A-V block, the total block comes and
goes; that is, impulses are conducted from the atria into the
ventricles for a period of time and then suddenly impulses
are not conducted. The duration of block may be a few
seconds, a few minutes, a few hours, or even weeks or longer before conduction returns. This condition occurs in
hearts with borderline ischemia of the conductive system.
Each time A-V conduction ceases, the ventricles often
do not start their own beating until after a delay of 5 to 30
seconds. This results from the phenomenon called overdrive suppression. This means that ventricular excitability
is at first in a suppressed state because the ventricles have
been driven by the atria at a rate greater than their natural
rate of rhythm. However, after a few seconds, some part of
the Purkinje system beyond the block, usually in the distal part of the A-V node beyond the blocked point in the
node, or in the A-V bundle, begins discharging rhythmically at a rate of 15 to 40 times per minute and acting as
the pacemaker of the ventricles. This is called ventricular
Because the brain cannot remain active for more than
4 to 7 seconds without blood supply, most patients faint
a few seconds after complete block occurs because the
heart does not pump any blood for 5 to 30 seconds, until
the ventricles “escape.” After escape, however, the slowly
beating ventricles usually pump enough blood to allow
rapid recovery from the faint and then to sustain the
person. These periodic fainting spells are known as the
Stokes-Adams syndrome.
Occasionally the interval of ventricular standstill at
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 with
an artificial pacemaker, a small battery-operated electrical stimulator planted beneath the skin, with electrodes
usually connected to the right ventricle. The pacemaker
provides continued rhythmical impulses that take control
of the ventricles.
Figure 13-6 Second degree A-V block, showing occasional failure
of the ventricles to receive the excitatory signals (lead V3).
Figure 13-7 Complete A-V block (lead II).
Figure 13-8 Partial intraventricular block—“electrical alternans”
(lead III).
U n i t III
0.30 second instead of the normal 0.20 or less. Thus,
­first-degree block is defined as a delay of conduction from
the atria to the ventricles but not actual blockage of conduction. The P-R interval seldom increases above 0.35 to
0.45 second because, by that time, conduction through
the A-V bundle is depressed so much that conduction
stops entirely. One means for determining the severity of
some heart diseases—acute rheumatic heart disease, for
instance—is to measure the P-R interval.
Second-Degree Block. When conduction through
the A-V bundle is slowed enough to increase the P-R interval to 0.25 to 0.45 second, the action potential is sometimes
strong enough to pass through the bundle into the ventricles and sometimes not strong enough. In this instance,
there will be an atrial P wave but no QRS-T wave, and it is
said that there are “dropped beats” of the ventricles. This
condition is called second-degree heart block.
Figure 13-6 shows P-R intervals of 0.30 second, as well
as one dropped ventricular beat as a result of failure of
conduction from the atria to the ventricles.
At times, every other beat of the ventricles is dropped,
so a “2:1 rhythm” develops, with the atria beating twice for
every single beat of the ventricles. At other times, rhythms
of 3:2 or 3:1 also develop.
Unit III The Heart
This ­electrocardiogram also shows tachycardia (rapid
heart rate), which is probably the reason the block has
occurred, because when the rate of the heart is rapid,
it may be impossible for some portions of the Purkinje
system to recover from the previous refractory period
quickly enough to respond during every succeeding
heartbeat. Also, many conditions that depress the heart,
such as ischemia, myocarditis, or digitalis toxicity, can
cause incomplete intraventricular block, resulting in
electrical alternans.
Premature Contractions
A premature contraction is a contraction of the heart
before the time that normal contraction would have been
expected. This condition is also called extrasystole, premature beat, or ectopic beat.
Causes of Premature Contractions. Most pre-
Premature atrial contractions occur frequently in otherwise healthy people. Indeed, they often occur in athletes whose hearts are in very healthy condition. Mild
toxic conditions resulting from such factors as smoking, lack of sleep, ingestion of too much coffee, alcoholism, and use of various drugs can also initiate such
Pulse Deficit. When the heart contracts ahead of
schedule, the ventricles will not have filled with blood
normally, and the stroke volume output during that contraction is depressed or almost absent. Therefore, the
pulse wave passing to the peripheral arteries after a premature contraction may be so weak that it cannot be felt
in the radial artery. Thus, a deficit in the number of radial
pulses occurs when compared with the actual number of
contractions of the heart.
A-V Nodal or A-V Bundle Premature Contractions
mature contractions result from ectopic foci in the heart,
which emit abnormal impulses at odd times during the
cardiac rhythm. Possible causes of ectopic foci are (1)
local areas of ischemia; (2) small calcified plaques at different points in the heart, which press against the adjacent
cardiac muscle so that some of the fibers are irritated;
and (3) toxic irritation of the A-V node, Purkinje system, or myocardium caused by drugs, nicotine, or caffeine. Mechanical initiation of premature contractions is
also frequent during cardiac catheterization; large numbers of premature contractions often occur when the
catheter enters the right ventricle and presses against the
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 of the
premature contraction. Instead, the P wave is superimposed onto the QRS-T complex because the cardiac
impulse traveled backward into the atria at the same
time that it traveled forward into the ventricles; this
P wave slightly distorts the QRS-T complex, 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.
Premature Atrial Contractions
The electrocardiogram of Figure 13-11 shows a series of
premature ventricular contractions (PVCs) alternating
with normal contractions. PVCs cause specific effects in
the electrocardiogram, as follows:
Figure 13-9 shows a single premature atrial contraction. The P wave of this beat occurred too soon in the
heart cycle; the P-R interval is shortened, indicating that
the ectopic origin of the beat is in the atria near the A-V
node. Also, the interval between the premature contraction and the next succeeding contraction is slightly prolonged, which is called a compensatory pause. One of the
reasons for this is that the premature contraction originated in the atrium some distance from the sinus node,
and the impulse had to travel through a considerable
amount of atrial muscle before it discharged the sinus
node. Consequently, the sinus node discharged late in the
premature cycle, and this made the succeeding sinus node
discharge also late in appearing.
Premature Ventricular Contractions
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 other—partially neutralize each other in the ­electrocardiogram. When a PVC
Premature beat
Premature beat
Figure 13-9 Atrial premature beat (lead I).
Figure 13-10 A-V nodal premature contraction (lead III).
Chapter 13 Cardiac Arrhythmias and Their Electrocardiographic Interpretation
Disorders of Cardiac Repolarization—The Long QT
Syndromes. Recall that the Q wave corresponds to ven-
Figure 13-11 Premature ventricular contractions (PVCs) demonstrated by the large abnormal QRS-T complexes (leads II and
III). Axis of the premature contractions is plotted in accordance
with the principles of vectorial analysis explained in Chapter 12;
this shows the origin of the PVC to be near the base of the
occurs, the impulse almost always travels in only one
direction, so 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.
Some PVCs are relatively benign in their effects on
overall pumping by the heart; they can result from such
factors as cigarettes, excessive intake of coffee, lack of
sleep, various mild 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 spontaneous lethal ventricular fibrillation, presumably initiated 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 the ventricles are coming out of refractoriness, as
explained later in the chapter.
Vector Analysis of the Origin of an Ectopic
Premature Ventricular Contraction. In Chapter 12,
the principles of vectorial analysis are explained. Applying
these principles, one can determine from the electrocar-
tricular depolarization while the T wave corresponds to
ventricular repolarization. The Q-T interval is the time
from the Q point to the end of the T wave. Disorders
that delay repolarization of ventricular muscle following
the action potential cause prolonged ventricular action
potentials and therefore excessively long Q-T intervals
on the electrocardiogram, a condition called long QT syndrome (LQTS).
The major reason that the long QT syndrome is of
concern is that delayed repolarization of ventricular muscle increases a person’s susceptibility to develop ventricular arrhythmias called torsades de pointes, which literally
means “twisting of the points.” This type of arrhythmia has
the features shown in Figure 13-12. The shape of the QRS
complex may change over time with the onset of arrhythmia usually following a premature beat, a pause, and then
another beat with a long Q-T interval, which may trigger
arrhythmias, tachycardia, and in some instances ventricular fibrillation.
Disorders of cardiac repolarization that lead to LQTS
may be inherited or acquired. The congenital forms of
LQTS are rare disorders caused by mutations of sodium
or potassium channel genes. At least 10 different mutations of these genes that can cause variable degrees of
Q-T prolongation have been identified.
More common are the acquired forms of LQTS that
are associated with plasma electrolyte disturbances, such
as hypomagnesemia, hypokalemia, or hypocalcemia, or
with administration of excess amounts of antiarrhythmic drugs such as quinidine or some antibiotics such as
fluoroquinolones or erythromycin that prolong the Q-T
Although some people with LQTS show no major
symptoms (other than the prolonged Q-T interval), others
exhibit fainting and ventricular arrhythmias that may be
precipitated by physical exercise, intense emotions such
as fright or anger, or when startled by a noise. The ventricular arrhythmias associated with LQTS can, in some
cases, deteriorate into ventricular fibrillation and sudden
Treatment for LQTS may include magnesium sulfate
for acute LQTS, and for long-term LQTS antiarrhythmia
medications, such as beta-adrenergic blockers, or surgical
implantation of a cardiac defibrillator are used.
U n i t III
diogram in Figure 13-11 the point of origin of the PVC as
follows: Note that the potentials of the premature contractions in leads II and III are both strongly positive.
Plotting these 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 has its negative end (origin) at the base of the
heart and its positive end toward the apex. Thus, the first
portion of the heart to become depolarized during this
premature contraction is near the base of the ventricles,
which therefore is the locus of the ectopic focus.
Unit III The Heart
Premature depolarization
Repetitive premature depolarization
Torsades de pointes
Figure 13-12 Development of arrhythmias in long QT syndrome (LQTS). When the ventricular muscle fiber action potential is prolonged
as a result of delayed repolarization, a premature depolarization (dashed line in top left figure) may occur before complete repolarization.
Repetitive premature depolarizations (right top figure) may lead to multiple depolarizations under certain conditions. In torsades de pointes
(bottom figure), premature ventricular beats lead pauses, postpause prolongation of the Q-T interval, and arrhythmias. (Redrawn from
Murray KT, Roden DM: Disorders of cardiac repolarization: the long QT syndromes. In: Crawford MG, DiMarco JP [eds]: Cardiology. London:
Mosby, 2001.)
Paroxysmal Tachycardia
Some abnormalities in different portions of the heart,
including the atria, the Purkinje system, or the ventricles, can
occasionally cause rapid rhythmical discharge of impulses
that spread in all directions throughout the heart. This is
believed to be caused most frequently by 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.
The term “paroxysmal” means that the heart rate
becomes rapid in paroxysms, with the paroxysm beginning suddenly and lasting for a few seconds, a few minutes, a few hours, or much longer. Then the paroxysm
usually ends as suddenly as it began, with the pacemaker
of the heart instantly shifting back to the sinus node.
Paroxysmal tachycardia often can be stopped by eliciting a
vagal reflex. A type of vagal reflex sometimes elicited for this
purpose is to press on the neck in the regions of the carotid
sinuses, which may cause enough of a vagal reflex to stop
the paroxysm. Various drugs may also be used. Two drugs
frequently used are quinidine and lidocaine, either of which
depresses the normal increase in sodium permeability of the
cardiac muscle membrane during generation of the action
potential, thereby often blocking the rhythmical discharge
of the focal point that is causing the paroxysmal attack.
Figure 13-13 Atrial paroxysmal tachycardia—onset in middle of
record (lead I).
e­ lectro­cardiogram during the rapid heartbeat, an inverted
P wave is seen before each QRS-T complex, and this P wave
is partially superimposed onto the normal T wave of the
preceding beat. This indicates that the origin of this paroxysmal tachycardia is in the atrium, but because the P wave
is abnormal in shape, the origin is not near the sinus node.
A-V Nodal Paroxysmal Tachycardia. Paroxysmal
tachycardia often results from an aberrant rhythm that
involves the A-V node. This usually causes almost normal QRS-T complexes but totally missing or obscured P
Atrial or A-V nodal paroxysmal tachycardia, both of
which are called supraventricular tachycardias, usually
occurs in young, otherwise healthy people, and they generally grow out of the predisposition to tachycardia after
adolescence. In general, supraventricular tachycardia
frightens a person tremendously and may cause weakness
during the paroxysm, but only seldom does permanent
harm come from the attack.
Atrial Paroxysmal Tachycardia
Ventricular Paroxysmal Tachycardia
Figure 13-13 demonstrates in the middle of the record
a sudden increase in the heart rate from about 95
to about 150 beats per minute. On close study of the
Figure 13-14 shows a typical short paroxysm of ventricular tachycardia. The electrocardiogram of ventricular
paroxysmal tachycardia has the appearance of a series of
Chapter 13 Cardiac Arrhythmias and Their Electrocardiographic Interpretation
Phenomenon of Re-entry—“Circus Movements”
as the Basis for Ventricular Fibrillation
ventricular premature beats occurring one after another
without any normal beats interspersed.
Ventricular paroxysmal tachycardia is usually a serious condition for two reasons. First, this type of tachycardia usually does not occur unless considerable ischemic
damage is present in the ventricles. Second, ventricular
tachycardia frequently initiates the lethal condition of
ventricular fibrillation because of rapid repeated stimulation of the ventricular muscle, as we discuss in the next
Sometimes intoxication from the heart treatment drug
digitalis causes irritable foci that lead to ventricular tachycardia. Conversely, quinidine, which increases the refractory period and threshold for excitation of cardiac muscle,
may be used to block irritable foci causing ventricular
Ventricular Fibrillation
The most serious of all cardiac arrhythmias is ventricular fibrillation, which, if not stopped within 1 to 3 minutes, is almost invariably fatal. Ventricular fibrillation
results from cardiac impulses that have gone berserk
within the ventricular muscle mass, stimulating first
one portion of the ventricular muscle, then another
portion, then another, and eventually feeding back onto
itself to re-excite the same ventricular muscle over and
over—never stopping. When this happens, many small
portions of the ventricular muscle will be contracting
at the same time, while equally as many other portions
will be relaxing. Thus, there is never a coordinate contraction of all the ventricular muscle at once, which is
required for a pumping cycle of the heart. Despite massive movement of stimulatory signals throughout the
ventricles, the ventricular chambers neither enlarge
nor contract but remain in an indeterminate stage of
partial contraction, pumping either no blood or negligible amounts. Therefore, after fibrillation begins,
unconsciousness occurs within 4 to 5 seconds for lack
of blood flow to the brain, and irretrievable death of
tissues begins to occur throughout the body within a
few minutes.
Multiple factors can spark the beginning of ventricular fibrillation—a person may have a normal heartbeat
one moment, but 1 second later, the ventricles are in
fibrillation. Especially likely to initiate fibrillation are (1)
sudden electrical shock of the heart or (2) ischemia of
the heart muscle, of its specialized conducting system,
or both.
Figure 13-15 Circus movement, showing annihilation of the
impulse in the short pathway and continued propagation of the
impulse in the long pathway.
U n i t III
Figure 13-14 Ventricular paroxysmal tachycardia (lead III).
When the normal cardiac impulse in the normal heart
has traveled through the extent of the ventricles, it has no
place to go because all the ventricular muscle is refractory
and cannot conduct the impulse farther. Therefore, that
impulse dies, and the heart awaits a new action potential
to begin in the atrial sinus node.
Under some circumstances, however, this normal
sequence of events does not occur. Therefore, let us
explain more fully the background conditions that can
initiate re-entry and lead to “circus movements,” which in
turn cause ventricular fibrillation.
Figure 13-15 shows several small cardiac muscle strips
cut in the form of circles. If such a strip is stimulated at
the 12 o’clock position so that the impulse travels in only
one direction, the impulse spreads progressively around
the circle until it returns to the 12 o’clock position. If the
originally stimulated muscle fibers are still in a refractory
state, the impulse then dies out because refractory muscle
cannot transmit a second impulse. But there are three different conditions that can cause this impulse to continue
to travel around the circle, that is, to cause “re-entry” of
the impulse into muscle that has already been excited.
This is called a “circus movement.”
First, if the pathway around the circle is too long, by
the time the impulse returns to the 12 o’clock position,
the originally stimulated muscle will no longer be refractory and the impulse will continue around the circle again
and again.
Second, if the length of the pathway remains constant
but the velocity of conduction becomes decreased enough,
an increased interval of time will elapse before the impulse
returns to the 12 o’clock position. By this time, the originally stimulated muscle might be out of the refractory
state, and the impulse can continue around the circle
again and again.
Third, the refractory period of the muscle might become
greatly shortened. In this case, the impulse could also continue around and around the circle.
Unit III The Heart
All these conditions occur in different pathological
states of the human heart, as follows: (1) A long pathway typically occurs in dilated hearts. (2) Decreased rate
of conduction frequently results from (a) blockage of the
Purkinje system, (b) ischemia of the muscle, (c) high blood
potassium levels, or (d) many other factors. (3) A shortened refractory period commonly occurs in response to
various drugs, such as epinephrine, or after repetitive electrical stimulation. Thus, in many cardiac disturbances, reentry can cause abnormal patterns of cardiac contraction
or abnormal cardiac rhythms that ignore the pace-setting
effects of the sinus node.
Chain Reaction Mechanism of Fibrillation
In ventricular fibrillation, one sees many separate and
small contractile waves spreading at the same time in different directions over the cardiac muscle. The re-entrant
impulses in fibrillation are not simply a single impulse
moving in a circle, as shown in Figure 13-15. Instead, they
have degenerated into a series of multiple wave fronts that
have the appearance of a “chain reaction.” One of the best
ways to explain this process in fibrillation is to describe
the initiation of fibrillation by electric shock caused by
60-cycle alternating electric current.
Fibrillation Caused by 60-Cycle Alternating
Current. At a central point in the ventricles of heart
A in Figure 13-16, a 60-cycle electrical stimulus is applied
through a stimulating electrode. The first cycle of the electrical 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 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 refractory muscle.
Now, continuing 60-cycle stimuli from the electrode can
cause impulses to travel only in certain directions through
Figure 13-16 A, Initiation of fibrillation in a heart when patches
of refractory musculature are present. B, Continued propagation of
fibrillatory impulses in the fibrillating ventricle.
the heart but not in all directions. Thus, in heart A, certain
impulses travel for short distances, 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 areas. Then, several events transpire in rapid succession, all occurring simultaneously and
eventuating in a state of fibrillation.
First, block of the impulses in some directions but successful transmission in other directions creates one of the
necessary conditions for a re-entrant signal to develop—
that is, transmission of some of the depolarization waves
around the heart in only some directions but not other
Second, the rapid stimulation of the heart causes two
changes in the cardiac muscle itself, both of which predispose to circus movement: (1) The velocity of conduction
through the heart muscle decreases, which allows a longer
time interval for the impulses to travel around the heart.
(2) The refractory period of the muscle is shortened, allowing re-entry of the impulse into previously excited heart
muscle within a much shorter time than normally.
Third, one of the most important features of fibrillation is the division of impulses, as demonstrated in heart
A. When a depolarization wave reaches a refractory area
in the heart, it travels to both sides around the refractory area. Thus, a single impulse becomes two impulses.
Then, when each of these reaches another refractory area,
it, too, divides to form two more impulses. In this way,
many new wave fronts are continually being formed in the
heart by progressive chain reactions until, finally, there are
many small depolarization waves traveling in many directions at the same time. Furthermore, this irregular pattern of impulse travel causes many circuitous routes for
the impulses to 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 refractory areas in the heart.
One can readily see when a vicious circle has been
initiated: More and more impulses are formed; these
cause more and more patches of refractory muscle, and
the refractory patches cause more and more division of
the impulses. Therefore, any time a single area of cardiac
muscle comes out of refractoriness, an impulse is close at
hand to re-enter the area.
Heart B in Figure 13-16 demonstrates the final state that
develops in fibrillation. Here one can see many impulses
traveling in all directions, some dividing and increasing
the number of impulses, whereas others are blocked by
refractory areas. In fact, a single electric shock during this
vulnerable period frequently can lead to an odd pattern of
impulses spreading multidirectionally around refractory
areas of muscle, which will lead to fibrillation.
Electrocardiogram in Ventricular Fibrillation
In ventricular fibrillation, the electrocardiogram is bizarre
(Figure 13-17) and ordinarily shows no tendency toward
a regular rhythm of any type. During the first few seconds
Chapter 13 Cardiac Arrhythmias and Their Electrocardiographic Interpretation
Several thousand volts
for a few milliseconds
of ventricular fibrillation, relatively large masses of muscle
contract simultaneously, and this causes coarse, irregular
waves in the electrocardiogram. After another few seconds, the coarse contractions of the ventricles disappear,
and the electrocardiogram changes into a new pattern
of low-voltage, very irregular waves. Thus, no repetitive
electrocardiographic pattern can be ascribed to ventricular fibrillation. Instead, the ventricular muscle contracts at
as many as 30 to 50 small patches of muscle at a time, and
electrocardiographic potentials change constantly and
spasmodically because the electrical currents in the heart
flow first in one direction and then in another and seldom
repeat any specific cycle.
The voltages of the waves in the electrocardiogram
in ventricular fibrillation are usually about 0.5 millivolt
when ventricular fibrillation first begins, but they decay
rapidly so that after 20 to 30 seconds, they are usually only
0.2 to 0.3 millivolt. Minute voltages of 0.1 millivolt or less
may be recorded for 10 minutes or longer after ventricular fibrillation begins. As already pointed out, because no
pumping of blood occurs during ventricular fibrillation,
this state is lethal unless stopped by some heroic therapy,
such as immediate electroshock through the heart, as
explained in the next section.
Electroshock Defibrillation of the Ventricles
Although a moderate alternating-current voltage applied
directly to the ventricles almost invariably throws the
ventricles into fibrillation, a strong high-voltage alternating electrical current passed through the ventricles for a
fraction of a second can stop fibrillation by throwing all
the ventricular muscle into refractoriness simultaneously.
This is accomplished by passing intense current through
large electrodes placed on two sides of the heart. The current penetrates most of the fibers of the ventricles at the
same time, thus stimulating essentially all parts of the
ventricles simultaneously and causing them all to become
refractory. All action potentials stop, and the heart
remains quiescent for 3 to 5 seconds, after which it begins
to beat again, usually 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 fibrillation often is still present, in which case
fibrillation may begin again immediately.
When electrodes are applied directly to the two sides
of the heart, fibrillation can usually be stopped using
110 volts of 60-cycle alternating current applied for 0.1
second or 1000 volts of direct current applied for a few
thousandths of a second. When applied through two electrodes on the chest wall, as shown in Figure 13-18, the
U n i t III
Figure 13-17 Ventricular fibrillation (lead II).
Handle for
of pressure
Figure 13-18 Application of electrical current to the chest to
stop ventricular fibrillation.
usual procedure is to charge a large electrical capacitor up
to several thousand volts and then to cause the capacitor
to discharge for a few thousandths of a second through
the electrodes and through the heart.
Hand Pumping of the Heart (Cardiopulmonary
Resuscitation) as an Aid to Defibrillation
Unless defibrillated within 1 minute after fibrillation
begins, the heart is usually too weak to be revived by defibrillation because of the lack of nutrition from coronary
blood flow. However, it is still possible to revive the heart
by preliminarily pumping the heart by hand (intermittent
hand squeezing) and then defibrillating the heart later.
In this way, small quantities of blood are delivered into
the aorta and a renewed coronary blood supply develops.
Then, after a few minutes of hand pumping, electrical
defibrillation often becomes possible. Indeed, fibrillating
hearts have been pumped by hand for as long as 90 minutes followed by successful defibrillation.
A technique for pumping the heart without opening
the chest consists of intermittent thrusts of pressure on
the chest wall along with artificial respiration. This, plus
defibrillation, is called cardiopulmonary resuscitation, or
Lack of blood flow to the brain for more than 5 to 8
minutes usually causes permanent mental impairment
or even destruction of brain tissue. Even if the heart is
revived, the person may die from the effects of brain damage or may live with permanent mental impairment.
Atrial Fibrillation
Remember that except for the conducting pathway
through the A-V bundle, the atrial muscle mass is separated from the ventricular muscle mass by fibrous tissue.
Therefore, ventricular fibrillation often occurs without
atrial fibrillation. Likewise, fibrillation often occurs in the
Unit III The Heart
atria without ventricular fibrillation (shown to the right in
Figure 13-20).
The mechanism of atrial fibrillation is identical to that
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 enlargement resulting from heart valve lesions that prevent the
atria from emptying adequately into the ventricles, or
from ventricular failure with excess damming of blood in
the atria. The dilated atrial walls provide ideal conditions
of a long conductive pathway, as well as slow conduction,
both of which predispose to atrial fibrillation.
Pumping Characteristics of the Atria during
Atrial Fibrillation. For the same reasons that the ven-
tricles will not pump blood during ventricular fibrillation, neither do the atria pump blood in atrial fibrillation.
Therefore, the atria become useless as primer pumps for
the ventricles. Even so, blood flows passively through the
atria into the ventricles, and the efficiency of ventricular
pumping is decreased only 20 to 30 percent. Therefore,
in contrast to the lethality of ventricular fibrillation, a
person can live for months or even years with atrial fibrillation, although at reduced efficiency of overall heart
Electrocardiogram in Atrial Fibrillation. Figure
13-19 shows the electrocardiogram during atrial fibrillation. Numerous small depolarization waves spread
in all directions through the atria during atrial fibrillation. Because the waves are weak and many of them
are of opposite polarity at any given time, they usually
almost completely electrically neutralize one another.
Therefore, in the electrocardiogram, one can see
either no P waves from the atria or only a fine, highfrequency, very low voltage wavy record. Conversely,
the QRS-T complexes are normal unless there is some
pathology of the ventricles, but their timing is irregular,
as explained next.
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 irregularly. Because the A-V node will not pass
a second impulse for about 0.35 second after a previous
one, at least 0.35 second must elapse between one ventricular contraction and the next. Then an additional but
variable interval of 0 to 0.6 second occurs before one of
the irregular atrial fibrillatory impulses happens to arrive
at the A-V node. Thus, the interval between successive
ventricular contractions varies from a minimum of about
0.35 second to a maximum of about 0.95 second, causing
a very irregular heartbeat. In fact, this irregularity, demonstrated by the variable spacing of the heartbeats in the
electrocardiogram of Figure 13-19, is one of the clinical
findings used to diagnose the condition. Also, because of
the rapid rate of the fibrillatory impulses in the atria, the
ventricle is driven at a fast heart rate, usually between
125 and 150 beats per minute.
Electroshock Treatment of Atrial Fibrillation.
In the same manner that ventricular fibrillation can be
converted back to a normal rhythm by electroshock,
so too can atrial fibrillation be converted by electroshock. The procedure is essentially the same as for
ventricular fibrillation conversion—passage of a single
strong electric shock through the heart, which throws
the entire heart into refractoriness for a few seconds;
a normal rhythm often follows if the heart is capable
of this.
Atrial Flutter
Atrial flutter is another condition caused by a circus
movement in the atria. It is different from atrial fibrillation, in that the electrical signal travels as a single
large wave always in one direction around and around
the atrial muscle mass, as shown to the left in Figure
13-20. Atrial flutter causes a rapid rate of contraction
of the atria, usually between 200 and 350 beats per minute. However, because one side of the atria is contracting while the other side is relaxing, the amount of blood
pumped by the atria is slight. Furthermore, the signals
reach the A-V node too rapidly for all of them to be
passed into the ventricles, because the refractory periods of the A-V node and A-V bundle are too long to
pass more than a fraction of the atrial signals. Therefore,
there are usually two to three beats of the atria for every
single beat of the ventricles.
Figure 13-21 shows a typical electrocardiogram in
atrial flutter. The P waves are strong because of contraction of semicoordinate masses of muscle. However, note
Atrial flutter
Figure 13-19 Atrial fibrillation (lead I). The waves that can be seen
are ventricular QRS and T waves.
Atrial fibrillation
Figure 13-20 Pathways of impulses in atrial flutter and atrial
Chapter 13 Cardiac Arrhythmias and Their Electrocardiographic Interpretation
in the record that a QRS-T complex follows an atrial
P wave only once for every two to three beats of the atria,
giving a 2:1 or 3:1 rhythm.
Cardiac Arrest
A final serious abnormality of the cardiac rhythmicityconduction system is cardiac arrest. This results from
cessation of all electrical control signals in the heart. That
is, no spontaneous rhythm remains.
Cardiac arrest may occur during deep anesthesia, when
many patients develop severe hypoxia because of inadequate respiration. The hypoxia prevents the muscle fibers
and conductive fibers from maintaining normal electrolyte concentration differentials across their membranes,
and their excitability may be so affected that the automatic rhythmicity disappears.
In most instances of cardiac arrest from anesthesia,
prolonged cardiopulmonary resuscitation (many minutes or even hours) is quite successful in re-establishing
a normal heart rhythm. In some patients, severe myocardial disease can cause permanent or semipermanent cardiac arrest, which can cause death. To treat the condition,
rhythmical electrical impulses from an implanted electronic cardiac pacemaker have been used successfully to
keep patients alive for months to years.
U n i t III
Figure 13-21 Atrial flutter—2:1 and 3:1 atrial to ventricle rhythm
(lead I).
Antzelevitch C: Role of spatial dispersion of repolarization in inherited
and acquired sudden cardiac death syndromes, Am J Physiol Heart Circ
Physiol 293:H2024, 2007.
Awad MM, Calkins H, Judge DP: Mechanisms of disease: molecular genetics
of arrhythmogenic right ventricular dysplasia/cardiomyopathy, Nat Clin
Pract Cardiovasc Med 5:258, 2008.
Barbuti A, DiFrancesco D: Control of cardiac rate by “funny” channels in
health and disease, Ann N Y Acad Sci 1123:213, 2008.
Cheng H, Lederer WJ: Calcium sparks, Physiol Rev 88:1491, 2008.
Dobrzynski H, Boyett MR, Anderson RH: New insights into pacemaker
activity: promoting understanding of sick sinus syndrome, Circulation
115:1921, 2007.
Elizari MV, Acunzo RS, Ferreiro M: Hemiblocks revisited, Circulation
115:1154, 2007.
Jalife J: Ventricular fibrillation: mechanisms of initiation and maintenance,
Annu Rev Physiol 62:25, 2000.
Lubitz SA, Fischer A, Fuster V: Catheter ablation for atrial fibrillation, BMJ
336:819, 2008.
Maron BJ: Sudden death in young athletes, N Engl J Med 349:1064, 2003.
Morita H, Wu J, Zipes DP: The QT syndromes: long and short, Lancet
372:750, 2008.
Murray KT, Roden DM: Disorders of cardiac repolarization: the long QT syndromes. In Crawford MG, DiMarco JP, editors: Cardiology, London, 2001,
Myerburg RJ: Implantable cardioverter-defibrillators after myocardial
infarction, N Engl J Med 359:2245, 2008.
Passman R, Kadish A: Sudden death prevention with implantable devices,
Circulation 116:561, 2007.
Roden DM: Drug-induced prolongation of the QT interval, N Engl J Med
350:1013, 2004.
Sanguinetti MC: Tristani-Firouzi M: hERG potassium channels and cardiac
arrhythmia, Nature 440:463, 2006.
Swynghedauw B, Baillard C, Milliez P: The long QT interval is not only
inherited but is also linked to cardiac hypertrophy, J Mol Med 81:336,
Wang K, Asinger RW, Marriott HJ: ST-segment elevation in conditions other
than acute myocardial infarction, N Engl J Med 349:2128, 2003.
Zimetbaum PJ, Josephson ME: Use of the electrocardiogram in acute myocardial infarction, N Engl J Med 348:933, 2003.
This page intentionally left blank
The Circulation
14. Overview of the Circulation; Biophysics
of Pressure, Flow, and Resistance
15. Vascular Distensibility and Functions of
the Arterial and Venous Systems
16. The Microcirculation and Lymphatic
System: Capillary Fluid Exchange,
Interstitial Fluid, and Lymph Flow
17. Local and Humoral Control of Tissue
Blood Flow
18. Nervous Regulation of the Circulation,
and Rapid Control of Arterial Pressure
19. Role of the Kidneys in Long-Term Control
of Arterial Pressure and in Hypertension;
The Integrated System for Arterial
Pressure Regulation
20. Cardiac Output, Venous Return, and Their
21. Muscle Blood Flow and Cardiac Output
During Exercise; the Coronary Circulation
and Ischemic Heart Disease
22. Cardiac Failure
23. Heart Valves and Heart Sounds; Valvular
and Congenital Heart Defects
24. Circulatory Shock and Its Treatment
This page intentionally left blank
chapter 14
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 transport
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 many tissues is controlled mainly in response to tissue need for nutrients. In
some organs, such as the kidneys, the circulation serves
additional functions. Blood flow to the kidney, for example, is far in excess of its metabolic requirements and is
related to its excretory function, which demands that a
large volume of blood be filtered each minute.
The heart and blood vessels, in turn, are controlled to
provide the necessary cardiac output and arterial pressure to cause the needed tissue blood flow. What are the
mechanisms for controlling 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 function, 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. Arterioles have strong
muscular walls that can close the arterioles completely or
can, by relaxing, dilate the vessels severalfold, thus having
the capability of vastly altering blood flow in each tissue
in response to its needs.
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
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 cir-
culation and lists the percentage of the total blood volume in major segments of the circulation. For instance,
about 84 percent of the entire blood volume of the body is
in the systemic circulation and 16 percent is in the heart
and lungs. Of the 84 percent in the systemic circulation,
64 percent is in the veins, 13 percent in the arteries, and
7 percent in the systemic arterioles and capillaries. The
heart contains 7 percent of the blood, and the pulmonary
vessels, 9 percent.
Most surprising is the low blood volume in the capillaries. It is here, however, that the most important function of the circulation occurs, diffusion of substances back
and forth between the blood and the tissues. This function is discussed in detail in Chapter 16.
Cross-Sectional Areas and Velocities of Blood
Flow. If all the systemic vessels of each type were put side
by side, their approximate total cross-sectional areas for
the average human being would be as follows:
Unit IV
Overview of the Circulation; Biophysics
of Pressure, Flow, and Resistance
Unit IV The Circulation
diffusion of nutrient food substances and electrolytes
that occurs through the capillary walls must do so in
this short time.
Pulmonary circulation–9%
vena cava
vena cava
Veins, venules,
and venous
Figure 14-1 Distribution of blood (in percentage of total blood) in
the different parts of the circulatory system.
Small arteries
Small veins
Venae cavae
Cross-Sectional Area (cm2)
Pressures in the Various Portions of the
Circulation. Because the heart pumps blood continu-
ally into the aorta, the mean pressure in the aorta is high,
averaging about 100 mm Hg. Also, because heart pumping is pulsatile, the arterial pressure alternates between a
systolic pressure level of 120 mm Hg and a diastolic pressure level of 80 mm Hg, as shown on the left side of Figure
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 as
10 mm Hg near the venous ends, but their average “functional” pressure in most vascular beds is about 17 mm
Hg, a pressure low enough that little of the plasma leaks
through the minute pores of the capillary walls, even
though nutrients can diffuse easily through these same
pores to the outlying tissue cells.
Note at the far right side of Figure 14-2 the respective
pressures in the different parts of the pulmonary circulation. In the pulmonary arteries, the pressure is pulsatile,
just as in the aorta, but the pressure is far less: pulmonary artery systolic pressure averages about 25 mm Hg
and diastolic pressure 8 mm Hg, with a mean pulmonary
arterial pressure of only 16 mm Hg. The mean pulmonary
capillary pressure averages only 7 mm Hg. Yet the total
blood flow through the lungs each minute is the same as
through the systemic circulation. The low pressures of
the pulmonary system are in accord with the needs of the
lungs because all that is required is to expose the blood in
the pulmonary capillaries to oxygen and other gases in the
pulmonary alveoli.
Basic Principles of Circulatory Function
Note particularly the much larger cross-sectional areas
of the veins than of the arteries, averaging about four
times those of the corresponding arteries. This explains
the large blood storage capacity of the venous system in
comparison with the arterial system.
Because the same volume of blood flow (F) must pass
through each segment of the circulation each minute, the
velocity of blood flow (v) is inversely proportional to vascular cross-sectional area (A):
v = F/A
Thus, under resting conditions, the velocity averages
about 33 cm/sec in the aorta but only 1/1000 as rapidly
in the capillaries, about 0.3 mm/sec. However, because
the capillaries have a 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
Although the details of circulatory function are complex,
there are three basic principles that underlie all functions
of the system.
1. The rate of blood flow to each tissue of the body
is almost always precisely controlled in relation to
the tissue need. When tissues are active, they need
a greatly increased supply of nutrients and therefore
much more blood flow than when at rest—occasionally as much as 20 to 30 times the resting level. Yet
the heart normally cannot increase its cardiac output
more than four to seven times greater than resting
levels. Therefore, it is not possible simply to increase
blood flow everywhere in the body when a particular
tissue demands increased flow. Instead, the microvessels of each tissue continuously monitor tissue needs,
such as the availability of oxygen and other nutrients
Pulmonary veins
Venae cavae
Large veins
Small veins
Small arteries
Large arteries
Unit IV
Pressure (mm Hg)
Pulmonary arteries
Chapter 14 Overview of the Circulation; Biophysics of Pressure, Flow, and Resistance
Figure 14-2 Normal blood pressures in the different portions of the circulatory system when a person is lying in the horizontal position.
and the accumulation of carbon dioxide and other tissue waste products, and these in turn act directly on
the local blood vessels, dilating or constricting them,
to control local blood flow precisely to that level
required for the tissue activity. Also, nervous control
of the circulation from the central nervous system and
hormones provide additional help in controlling tissue
blood flow.
2. The cardiac output is controlled mainly by the
sum of all the local tissue flows. When blood flows
through a tissue, it immediately returns by way of the
veins to the heart. The heart responds automatically
to this increased inflow of blood by pumping it immediately back into the arteries. Thus, the heart acts as
an automaton, responding to the demands of the tissues. The heart, however, often needs help in the form
of special nerve signals to make it pump the required
amounts of blood flow.
3. Arterial pressure regulation is generally independent of either local blood flow control or cardiac
output control. The circulatory system is provided
with an extensive system for controlling the arterial
blood pressure. For instance, if at any time the pressure falls significantly below the normal level of about
100 mm Hg, within seconds a barrage of nervous
reflexes elicits a series of circulatory changes to raise
the pressure back toward normal. The nervous signals especially (a) increase the force of heart pumping,
(b) cause contraction of the large venous reservoirs to
provide more blood to the heart, and (c) cause generalized constriction of most of the arterioles throughout the body so that more blood accumulates in the
large arteries to increase the arterial pressure. Then,
over more prolonged periods, hours and days, the kidneys play an additional major role in pressure control
both by secreting pressure-controlling hormones and
by regulating the blood volume.
Thus, in summary, the needs of the individual tissues
are served specifically by the circulation. In the remainder
of this chapter, we begin to discuss the basic details of the
management of tissue blood flow and control of cardiac
output and arterial pressure.
Interrelationships of Pressure, Flow,
and Resistance
Blood flow through a blood vessel is determined by two
factors: (1) pressure difference of the blood between the
two ends of the vessel, also sometimes called “pressure
gradient” along the vessel, which is the force that pushes
the blood through the vessel, and (2) the impediment to
blood flow through the vessel, which is called vascular
resistance. Figure 14-3 demonstrates these relationships,
showing a blood vessel segment located anywhere in the
circulatory system.
P1 represents the pressure at the origin of the vessel;
at the other end, the pressure is P2. Resistance occurs as a
result of friction between the flowing blood and the intravascular endothelium all along the inside of the vessel.
The flow through the vessel can be calculated by the following formula, which is called Ohm’s law :
in which F is blood flow, ∆P is the pressure difference
(P1 − P2) between the two ends of the vessel, and R is
the resistance. This formula states that the blood flow
is directly proportional to the pressure difference but
inversely proportional to the resistance.
Pressure gradient
Blood flow
Figure 14-3 Interrelationships of pressure, resistance, and blood
Unit IV The Circulation
Note that it is the difference in pressure between
the two ends of the vessel, not the absolute pressure
in the vessel, that determines rate of flow. For example, if the pressure at both ends of a vessel is 100 mm
Hg and yet no difference exists between the two ends,
there will be no flow despite the presence of 100 mm Hg
Ohm’s law, illustrated in Equation 1, expresses the
most important of all the relations that the reader needs
to understand to comprehend the hemodynamics of the
circulation. Because of the extreme importance of this
formula, the reader should also become familiar with its
other algebraic forms:
DP = F  R
Blood Flow
Blood flow means the quantity of blood that passes a
given point in the circulation in a given period of time.
Ordinarily, blood flow is expressed in milliliters per
minute or liters per minute, but it can be expressed in
milliliters per second or in any other units of flow and
The overall blood flow in the total circulation of an
adult person at rest is about 5000 ml/min. This is called
the cardiac output because it is the amount of blood
pumped into the aorta by the heart each minute.
Methods for Measuring Blood Flow. Many mechanical and mechanoelectrical devices can be inserted in
series with a blood vessel or, in some instances, applied to
the outside of the vessel to measure flow. They are called
Electromagnetic Flowmeter. One of the most important devices for measuring blood flow without opening
the vessel is the electromagnetic flowmeter, the principles of which are illustrated in Figure 14-4. Figure 14-4A
shows the generation of electromotive force (electrical
voltage) in a wire that is moved rapidly in a cross-wise
direction through a magnetic field. This is the well-known
principle for production of electricity by the electric generator. Figure 14-4B shows that the same principle applies
for generation of electromotive force in blood that is moving through a magnetic field. In this case, a blood vessel
is placed between the poles of a strong magnet, and electrodes are placed on the two sides of the vessel perpendicular to the magnetic lines of force. When blood flows
through the vessel, an electrical voltage proportional to
the rate of blood flow is generated between the two electrodes, and this is recorded using an appropriate voltmeter or electronic recording apparatus. Figure 14-4C shows
an actual “probe” that is placed on a large blood vessel to
record its blood flow. The probe contains both the strong
magnet and the electrodes.
A special advantage of the electromagnetic flowmeter
is that it can record changes in flow in less than 1/100 of
a second, allowing accurate recording of pulsatile changes
in flow, as well as steady flow.
Ultrasonic Doppler Flowmeter. Another type of
flowmeter that can be applied to the outside of the vessel
and that has many of the same advantages as the electromagnetic flowmeter is the ultrasonic Doppler flowmeter,
shown in Figure 14-5. A minute piezoelectric crystal is
mounted at one end in the wall of the device. This crystal,
when energized with an appropriate electronic apparatus,
transmits ultrasound at a frequency of several hundred
thousand cycles per second downstream along the flowing
Figure 14-4 Flowmeter of the electromagnetic type, showing generation of an electrical voltage in a wire as it passes through an electromagnetic 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).
Chapter 14 Overview of the Circulation; Biophysics of Pressure, Flow, and Resistance
Unit IV
Figure 14-5 Ultrasonic Doppler flowmeter.
blood. A portion of the sound is reflected by the red
blood cells in the flowing blood. The reflected ultrasound
waves then travel backward from the blood cells toward
the crystal. These reflected waves have a lower frequency
than the transmitted wave because the red 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 while blowing its
whistle. Once the whistle has passed by the person, the
pitch of the sound from the whistle suddenly becomes
much lower than when the train is approaching.)
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 amplified greatly by the electronic apparatus. Another portion of
the electronic apparatus determines the frequency difference
between the transmitted wave and the reflected wave, thus
determining the velocity of blood flow. As long as diameter
of a blood vessel does not change, changes in blood flow in
the vessel are directly related to changes in flow velocity.
Like the electromagnetic flowmeter, the ultrasonic
Doppler flowmeter is capable of recording rapid, pulsatile
changes in flow, as well as steady flow.
Laminar Flow of Blood in Vessels. When blood
flows at a steady rate through a long, smooth blood vessel,
it flows in streamlines, with each layer of blood remaining
the same distance from the vessel wall. Also, the centralmost portion of the blood stays in the center of the vessel.
This type of flow is called laminar flow or streamline flow,
and it is the opposite of turbulent flow, which is blood
flowing in all directions in the vessel and continually mixing within the vessel, as discussed subsequently.
Parabolic Velocity Profile during Laminar Flow. When
laminar flow occurs, the velocity of flow in the center of
the vessel is far greater than that toward the outer edges.
This is demonstrated in Figure 14-6. In Figure 14-6A, a
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
no flow in the vessel. When the fluids are made to flow,
a parabolic interface develops between them, as shown 1
second later in Figure 14-6B; the portion of fluid adjacent
to the vessel wall has hardly moved, the portion slightly
away from the wall has moved a small distance, and the
portion in the center of the vessel has moved a long distance. This effect is called the “parabolic profile for velocity of blood flow.”
Figure 14-6 A, Two fluids (one dyed red, and the other clear)
before flow begins; B, the same fluids 1 second after flow begins;
C, turbulent flow, with elements of the fluid moving in a disorderly
The cause of the parabolic profile is the following: The
fluid molecules touching the wall move slowly because of
adherence to the vessel wall. The next layer of molecules
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 more rapidly than the outer layers.
Turbulent Flow of Blood under Some Conditions.
When the rate of blood flow becomes too great, when
it passes by an obstruction in a vessel, when it makes a
sharp turn, or when it passes over a rough surface, the
flow may then become turbulent, or disorderly, rather
than streamlined (see Figure 14-6C). Turbulent flow
means that the blood flows crosswise in the vessel and
along the vessel, usually forming whorls in the blood,
called eddy currents. These are similar to the whirlpools
that one 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 streamlined, because eddies add tremendously to the overall
friction of flow in the vessel.
The tendency for turbulent flow increases in direct proportion to the velocity of blood flow, the diameter of 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:
Re =
n. d . r
where Re is Reynolds’ number and is the measure of the
tendency for turbulence to occur, ν is the mean velocity of blood flow (in centimeters/second), d is the vessel
diameter (in centimeters), ρ is density, and η is the viscosity (in poise). The viscosity of blood is normally about
⁄30 poise, and the density is only slightly greater than 1.
When Reynolds’ number rises above 200 to 400, turbulent
Unit IV The Circulation
flow will occur at some branches of vessels but will die out
along the smooth portions of the vessels. However, when
Reynolds’ number rises above approximately 2000, turbulence will usually occur even in a straight, smooth vessel.
Reynolds’ number for flow in the vascular system even
normally rises to 200 to 400 in large arteries; as a result
there is almost always some turbulence of flow at the
branches of these vessels. In the proximal portions of the
aorta and pulmonary artery, Reynolds’ number can rise
to several thousand during the rapid phase of ejection by
the ventricles; this causes considerable turbulence in the
proximal aorta and pulmonary artery where many conditions are appropriate for turbulence: (1) high velocity
of blood flow, (2) pulsatile nature of the flow, (3) sudden
change in vessel diameter, and (4) large vessel diameter.
However, in small vessels, Reynolds’ number is almost
never high enough to cause turbulence.
Blood Pressure
Standard Units of Pressure. Blood pressure almost
always is measured in millimeters of mercury (mm Hg)
because the mercury manometer has been used as the
standard reference for measuring pressure since its
invention in 1846 by Poiseuille. Actually, blood pressure 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, this means that the force
exerted is sufficient to push a column of mercury against
gravity up to a level 50 millimeters high. If the pressure
is 100 mm Hg, it will push the column of mercury up to
100 millimeters.
Occasionally, pressure is measured in centimeters of
water (cm H2O). A pressure of 10 cm H2O means a pressure sufficient to raise a column of water against gravity
to a height of 10 centimeters. One millimeter of mercury
pressure equals 1.36 cm water pressure because the specific gravity of mercury is 13.6 times that of water, and 1
centimeter is 10 times as great as 1 millimeter.
High-Fidelity Methods for Measuring Blood Pressure. The
mercury in a manometer has so much inertia that it cannot
rise and fall rapidly. For this reason, the mercury manometer, although excellent for recording steady pressures, cannot
respond to pressure changes that occur more rapidly than
about one cycle every 2 to 3 seconds. Whenever it is desired
to record rapidly changing pressures, some other type of pressure recorder is necessary. Figure 14-7 demonstrates the basic
principles of three electronic pressure transducers commonly
used for converting blood pressure and/or rapid changes in
pressure into electrical signals and then recording the electrical signals on a high-speed electrical recorder. Each of these
transducers uses a very thin, highly stretched metal membrane
that forms one wall of the fluid chamber. The fluid chamber
in turn is connected through a needle or catheter inserted
into the blood vessel in which the pressure is to be measured.
When the pressure is high, the membrane bulges slightly, and
when it is low, it returns toward its resting position.
Figure 14-7 Principles of three types of electronic transducers for
recording rapidly changing blood pressures (explained in the text).
In Figure 14-7A, a simple metal plate is placed a few
hundredths of a centimeter above the membrane. When
the membrane bulges, the membrane comes closer to the
plate, which increases the electrical capacitance between
these two, and this change in capacitance can be recorded
using an appropriate electronic system.
In Figure 14-7B, a small iron slug rests on the membrane, and this can be displaced upward into a center space
inside an electrical wire coil. Movement of the iron into the
coil increases the inductance of the coil, and this, too, can
be recorded electronically.
Finally, in Figure 14-7C, a very thin, stretched resistance wire is connected to the membrane. When this wire
is stretched greatly, its resistance increases; when it is
stretched less, its resistance decreases. These changes, too,
can be recorded by an electronic system.
The electrical signals from the transducer are sent to an
amplifier and then to an appropriate recording device. With
some of these high-fidelity types of recording systems, pressure cycles up to 500 cycles per second have been recorded
accurately. In common use are recorders capable of registering pressure changes that occur as rapidly as 20 to 100
cycles per second, in the manner shown on the recording
paper in Figure 14-7C.
Resistance to Blood Flow
Units of Resistance. Resistance is the impediment to
blood flow in a vessel, but it cannot be measured by
any direct means. Instead, resistance must be calculated from measurements of blood flow and pressure
Chapter 14
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 sec/cm5.
Resistance in these units can be calculated by the following
R in
dyne sec 1333  mm Hg
Total Peripheral Vascular Resistance and Total
Pulmonary Vascular 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 circulation,
called the total peripheral resistance, is about 100/100, or
1 peripheral resistance unit (PRU).
In conditions in which all the blood vessels throughout
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 arterial
pressure averages 16 mm Hg and the mean left atrial pressure averages 2 mm Hg, giving a net pressure difference of
14 mm. Therefore, when the cardiac output is normal at
about 100 ml/sec, the total pulmonary vascular resistance
calculates to be about 0.14 PRU (about one seventh that in
the systemic circulation).
“Conductance” of Blood in a Vessel and Its
Relation to Resistance. Conductance is a measure of
the blood flow through a vessel for a given pressure difference. This is generally expressed in terms of milliliters
per second per millimeter of mercury pressure, but it can
also be expressed in terms of liters per second per millimeter of mercury or in any other units of blood flow and
It is evident that conductance is the exact reciprocal of
resistance in accord with the following equation:
Conductance =
Very Slight Changes in Diameter of a Vessel Can
Change Its Conductance Tremendously! Slight changes in the diameter of a vessel cause tremendous
changes in the vessel’s ability to conduct blood when
the blood flow is streamlined. This is demonstrated
100 mm
1 ml/min
16 ml/min
256 ml/min
Unit iV
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.
Overview of the Circulation; Biophysics of Pressure, Flow, and Resistance
Small vessel
Large vessel
Figure 14-8 A, Demonstration of the effect of vessel diameter on
blood flow. B, Concentric rings of blood flowing at different velocities; the farther away from the vessel wall, the faster the flow.
by the experiment illustrated in Figure 14-8A, which
shows three vessels with relative diameters of 1, 2, and
4 but with the same pressure difference of 100 mm Hg
between the two ends of the vessels. Although the
diameters of these vessels increase only fourfold, the
respective flows are 1, 16, and 256 ml/min, which is a
256-fold increase in flow. Thus, the conductance of
the vessel increases in proportion to the fourth power
of the diameter, in accordance with the following
Conductance µ Diameter4
Poiseuille’s Law. The cause of this great increase in conductance when the diameter increases can be explained by
referring to Figure 14-8B, which shows cross sections of a
large and a small vessel. The concentric rings inside the vessels indicate that the velocity of flow in each ring is different from that in the adjacent rings because of laminar flow,
which was discussed earlier in the chapter. That is, the blood
in the ring touching the wall of the vessel is barely flowing
because of its adherence to the vascular endothelium. The
next ring of blood toward the center of the vessel slips past
the first ring and, therefore, flows more rapidly. The third,
fourth, fifth, and sixth rings likewise flow at progressively
increasing velocities. Thus, the blood that is near the wall of
the vessel flows slowly, whereas that in the middle of the vessel flows much more rapidly.
In the small vessel, essentially all the blood is near the
wall, so the extremely rapidly flowing central stream of blood
simply does not exist. By integrating the velocities of all the
concentric rings of flowing blood and multiplying them by
the areas of the rings, one can derive the following formula,
known as Poiseuille’s law:
pD P
Pr 4
8 h1
in which F is the rate of blood flow, ∆P is the pressure difference
between the ends of the vessel, r is the radius of the vessel, l is
length of the vessel, and η is viscosity of the blood.
Unit IV The Circulation
Note particularly in this equation that the rate of blood
flow is directly proportional to the fourth power of the radius
of the vessel, which demonstrates once again that the diameter of a blood vessel (which is equal to twice the radius) plays
by far the greatest role of all factors in determining the rate
of blood flow through a vessel.
Importance of the Vessel Diameter “Fourth Power
Law” in Determining Arteriolar Resistance. In the
systemic circulation, about two thirds of the total systemic resistance to blood flow is arteriolar resistance in
the small arterioles. The internal diameters of the arterioles 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,
often as much as fourfold. From the fourth power law
discussed earlier 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.
Thus, this fourth power law makes it possible for the
arterioles, responding with only small changes in diameter to nervous signals or local tissue chemical 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 recorded between the
limits of maximum arteriolar constriction and maximum
arteriolar dilatation.
Resistance to Blood Flow in Series and Parallel
Vascular Circuits. Blood pumped by the heart flows
from the high-pressure part of the systemic circulation (i.e., aorta) to the low-pressure side (i.e., vena
cava) through many miles of blood vessels arranged in
series and in parallel. The arteries, arterioles, capillaries, venules, and veins are collectively arranged in series.
When blood vessels are arranged in series, flow through
each blood vessel is the same and the total resistance to
blood flow (Rtotal) is equal to the sum of the resistances of
each vessel:
=R +R +R +R . . .
1 2
The total peripheral vascular resistance is therefore
equal to the sum of resistances of the arteries, arterioles,
capillaries, venules, and veins. In the example shown in
R1 R
R3 R4
Figure 14-9 Vascular resistances: A, in series and B, in parallel.
Figure 14-9A, the total vascular resistance is equal to the
sum of R1 and R2.
Blood vessels branch extensively to form parallel circuits that supply blood to the many organs and tissues of
the body. This parallel arrangement permits each tissue
to regulate its own blood flow, to a great extent, independently of flow to other tissues.
For blood vessels arranged in parallel (Figure 14-9B),
the total resistance to blood flow is expressed as:
1 ...
It is obvious that for a given pressure gradient, far
greater amounts of blood will flow through this 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 14-9B is determined by the pressure gradient and its own resistance, not the resistance of
the other parallel blood vessels. However, increasing the
resistance of any of the blood vessels increases the total
vascular resistance.
It may seem paradoxical that adding more blood vessels to a circuit reduces the total vascular resistance. Many
parallel blood vessels, however, make it easier for blood to
flow through the circuit because each parallel vessel provides another pathway, or conductance, for blood flow.
The total conductance (Ctotal) for blood flow is the sum of
the conductance of each parallel pathway:
Ctotal = C1 + C2 + C3 + C4 . . .
For example, brain, kidney, muscle, gastrointestinal,
skin, and coronary circulations are arranged in parallel,
and each tissue contributes to the overall conductance
of the systemic circulation. Blood flow through each tissue is a fraction of the total blood flow (cardiac output)
and is determined by the resistance (the reciprocal of conductance) for blood flow in the tissue, as well as the pressure gradient. Therefore, amputation of a limb or surgical
removal of a kidney also removes a parallel circuit and
reduces the total vascular conductance and total blood
flow (i.e., cardiac output) while increasing total peripheral
vascular resistance.
Effect of Blood Hematocrit and Blood Viscosity
on Vascular Resistance and Blood Flow
Note especially that another of the important factors in
Poiseuille’s equation is the viscosity of the blood. The
greater the viscosity, the less the flow in a vessel if all
other factors are constant. Furthermore, the viscosity of
normal blood is about three times as great as the viscosity of water.
But what makes the blood so viscous? It is mainly the
large numbers of suspended red cells in the blood, each
of which exerts frictional drag against adjacent cells and
against the wall of the blood vessel.
Chapter 14 Overview of the Circulation; Biophysics of Pressure, Flow, and Resistance
Effects of Pressure on Vascular Resistance
and Tissue Blood Flow
“Autoregulation” Attenuates the Effect of Arterial
Pressure on Tissue Blood Flow. From the discussion
Figure 14-10 Hematocrits in a healthy (normal) person and in
patients with anemia and polycythemia.
Hematocrit. The proportion of the blood that is red
blood cells is called the hematocrit. Thus, if a person
has a hematocrit of 40, this means that 40 percent of the
blood volume is cells and the remainder is plasma. The
hematocrit of adult men averages about 42, while that
of women averages about 38. These values vary tremendously, depending on whether the person has anemia, on
the degree of bodily activity, and on the altitude at which
the person resides. These changes in hematocrit are discussed in relation to the red blood cells and their oxygen
transport function in Chapter 32.
Hematocrit is determined by centrifuging blood in a
calibrated tube, as shown in Figure 14-10. The calibration
allows direct reading of the percentage of cells.
Effect of Hematocrit on Blood Viscosity. The
­viscosity of blood increases drastically as the hematocrit
increases, as shown in Figure 14-11. The ­viscosity of
Viscosity of whole blood
Viscosity (water = 1)
Normal blood
Viscosity of plasma
thus far, one might expect an increase in arterial pressure
to cause a proportionate increase in blood flow through
the various tissues of the body. However, the effect of
arterial pressure on blood flow in many tissues is usually
far less than one would expect, as shown in Figure 14-12.
The reason for this is that an increase in arterial pressure
not only increases the force that pushes blood through the
vessels but it also initiates compensatory increases in vascular resistance within a few seconds through activation
of the local control mechanisms discussed in Chapter 17.
Conversely, with reductions in arterial pressure most vascular resistance is promptly reduced in most tissues and
blood flow is maintained relatively constant. The ability of
each tissue to adjust its vascular resistance and to maintain normal blood flow during changes in arterial pressure between approximately 70 and 175 mm Hg is called
blood flow autoregulation.
Blood flow (x normal)
Viscosity of water
Figure 14-11 Effect of hematocrit on blood viscosity. (Water
­viscosity = 1.)
Mean arterial pressure (mm Hg)
Figure 14-12 Effect of changes in arterial pressure over a period
of several minutes on blood flow in a tissue such as skeletal muscle. Note that between pressure of 70 and 175 mm Hg blood flow
is “autoregulated.” The blue line shows the effect of sympathetic
nerve stimulation or vasoconstriction by hormones such as norepinephrine, angiotensin II, vasopressin, or endothelin on this relationship. Reduced tissue blood flow is rarely maintained for more
than a few hours due to activation of local autoregulatory mechanisms that eventually return blood flow toward normal.
Unit IV
whole blood at normal hematocrit is about 3; this means
that three times as much pressure is required to force
whole blood as to force water through the same blood
vessel. When the hematocrit rises to 60 or 70, which
it often does in polycythemia, the blood viscosity can
become as great as 10 times that of water, and its flow
through blood vessels is greatly retarded.
Other factors that affect blood viscosity are the plasma
protein concentration and types of proteins in the plasma,
but these effects are so much less than the effect of hematocrit that they are not significant considerations in most
hemodynamic studies. The viscosity of blood plasma is
about 1.5 times that of water.
Unit IV The Circulation
Pressure-Flow Relationship in Passive Vascular
Beds. In isolated blood vessels or in tissues that do not
exhibit autoregulation, changes in arterial pressure may
have important effects on blood flow. In fact, the effect
of pressure on blood flow may be greater than predicted by Poiseuille’s equation, as shown by the upward
curving lines in Figure 14-13. The reason for this is that
increased arterial pressure not only increases the force
that pushes blood through the vessels but it also distends
the elastic vessels, actually decreasing vascular resistance.
Conversely, decreased arterial pressure in passive blood
vessels increases resistance as the elastic vessels gradually
collapse due to reduced distending pressure. When pressure falls below a critical level, called the critical closing
pressure, flow ceases as the blood vessels are completely
Sympathetic stimulation and other vasoconstrictors
can alter the passive pressure-flow relationship shown
in Figure 14-13. Thus, inhibition of sympathetic activity
Blood flow (ml/min)
Note in Figure 14-12 that changes in blood flow can
be caused by strong sympathetic stimulation, which
constricts the blood vessels. Likewise, hormonal vasoconstrictors, such as norepinephrine, angiotensin II, vasopressin, or endothelin, can also reduce blood flow, at least
Changes in tissue blood flow rarely last for more than
a few hours even when increases in arterial pressure or
increased levels of vasoconstrictors are sustained. The
reason for the relative constancy of blood flow is that
each tissue’s local autoregulatory mechanisms eventually
override most of the effects of vasoconstrictors in order
to provide a blood flow that is appropriate for the needs
of the tissue.
60 80 100 120 140 160 180 200
Arterial pressure (mm Hg)
Figure 14-13 Effect of arterial pressure on blood flow through a
passive blood vessel at different degrees of vascular tone caused
by increased or decreased sympathetic stimulation of the vessel.
greatly dilates the vessels and can increase the blood flow
twofold or more. Conversely, very strong sympathetic
stimulation can constrict the vessels so much that blood
flow occasionally decreases to as low as zero for a few seconds despite high arterial pressure.
In reality, there are few physiological conditions in
which tissues display the passive pressure-flow relationship shown in Figure 14-13. Even in tissues that do not
effectively autoregulate blood flow during acute changes
in arterial pressure, blood flow is regulated according to
the needs of the tissue when the pressure changes are sustained, as discussed in Chapter 17.
See bibliography for Chapter 15.
chapter 15
A valuable characteristic of
the vascular system is that
all blood vessels are distensible. 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 quantities 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:
Vascular distensibility =
Increase in volume
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
percent 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 veins,
on average, are about eight times more distensible than
the arteries. 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 distensibility 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 mm Hg pressure rise than to know the distensibilities of the individual
vessels. This value is called the compliance or capacitance
of the respective vascular bed; that is,
Vascular compliance =
Increase in volume
Increase in pressure
Compliance and distensibility are quite different. A highly
distensible vessel that has a slight volume may have far
less compliance than a much less distensible vessel that
has a large volume because compliance is equal to distensibility times volume.
The compliance of a systemic vein is about 24 times
that of its corresponding artery because it is about 8 times
as distensible and it has a volume about 3 times as great
(8 × 3 = 24).
Volume-Pressure Curves of the Arterial
and Venous Circulations
A convenient method for expressing the relation of pressure to volume in a vessel or in any portion of the circulation is to use the so-called volume-pressure curve. The
red and blue solid curves in Figure 15-1 represent, respectively, the volume-pressure curves of the normal systemic
arterial system and venous system, showing that when
the arterial system of the average adult person (including all the large arteries, small arteries, and arterioles) is
filled with about 700 milliliters of blood, the mean arterial pressure is 100 mm Hg, but when it is filled with only
400 ­milliliters of blood, the pressure falls to zero.
In the entire systemic venous system, the volume normally ranges from 2000 to 3500 milliliters, and a change of
several hundred millimeters in this volume is required to
change the venous pressure only 3 to 5 mm Hg. This mainly
explains why as much as one half liter of blood can be
Unit IV
Vascular Distensibility and Functions
of the Arterial and Venous Systems
Unit IV The Circulation
Sympathetic inhibition
Normal volume
Arterial system
Venous system
1000 1500 2000 2500 3000 3500
Volume (ml)
Figure 15-1 “Volume-pressure curves” of the systemic arterial
and venous systems, showing the effects of stimulation or inhibition of the sympathetic nerves to the circulatory system.
transfused into a healthy person in only a few minutes
without greatly altering function of the circulation.
Effect of Sympathetic Stimulation or Sympathetic
Inhibition on the Volume-Pressure Relations of the
Arterial and Venous Systems. Also shown in Figure 15-1
are the effects of exciting or inhibiting the vascular sympathetic nerves 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 of the arteries or veins, whereas sympathetic inhibition decreases the pressure at each volume. Control of
the vessels in this manner by the sympathetics is a valuable
means for diminishing the dimensions of one segment of
the circulation, thus transferring blood to other segments.
For instance, an increase in vascular tone throughout the
systemic circulation often causes large volumes of blood to
shift into the heart, which is one of the principal methods
that the body uses to increase heart pumping.
Sympathetic control of vascular capacitance is also
highly important during hemorrhage. Enhancement of
sympathetic tone, especially to the veins, reduces the vessel sizes enough that the circulation continues to operate
almost normally even when as much as 25 percent 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
increase in pressure, but progressive delayed stretching of
smooth muscle in the vessel wall allows the pressure to
return back toward normal over a period of minutes to
hours. This effect is shown in Figure 15-2. In this figure,
the pressure is recorded in a small segment of a 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 removed after it is
injected, the pressure begins to decrease immediately and
approaches about 9 mm Hg after several minutes. In other
words, the volume of blood injected causes immediate
Pressure (mm Hg)
Sympathetic stimulation
Pressure (mm Hg)
co elay
mp ed
Del liance
Figure 15-2 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.
elastic distention of the vein, but then the smooth muscle fibers of the vein begin to “creep” to longer lengths,
and their tensions correspondingly decrease. This effect
is a characteristic of all 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 extra blood when necessary, such as after too large a transfusion. Delayed compliance in the reverse direction is one of the ways in which
the circulation automatically adjusts itself over a period of
minutes or hours to diminished blood volume after serious hemorrhage.
Arterial Pressure Pulsations
With each beat of the heart a new surge of blood fills the
arteries. Were it not for distensibility of the arterial system, all of this new blood would have to flow through the
peripheral blood vessels almost instantaneously, only during cardiac systole, and no flow would occur during diastole. However, the compliance of the arterial tree normally
reduces the pressure pulsations to almost no pulsations by
the time the blood reaches the capillaries; therefore, tissue
blood flow is mainly continuous with very little pulsation.
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 pulse, called the systolic pressure, is about 120 mm Hg. At the lowest point of
each pulse, called the diastolic pressure, it is about 80 mm
Hg. The difference between these two pressures, about
40 mm Hg, is called the pulse pressure.
Two major factors affect the pulse pressure: (1) the stroke
volume output of the heart and (2) the compliance (total distensibility) of the arterial tree. A third, less important factor,
is the character of ejection from the heart during systole.
In general, the greater the stroke volume output, the
greater the amount of blood that must be accommodated
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 pressure. Conversely, the
less the compliance of the arterial system, the greater the
Chapter 15 Vascular Distensibility and Functions of the Arterial and Venous Systems
Slow rise
to peak
Exponential diastolic decline
(may be distorted by
reflected wave)
Pressure (mm Hg)
0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0
Figure 15-3 Pressure pulse contour in the ascending aorta.
rise in pressure for a given stroke volume of blood pumped
into the arteries. For instance, as demonstrated by the
middle top curves in Figure 15-4, the pulse pressure in old
age sometimes rises to as much as twice normal, because
the arteries have become hardened with arteriosclerosis
and therefore are relatively noncompliant.
In effect, pulse pressure is determined approximately
by the ratio of stroke volume output to compliance of the
arterial tree. Any condition of the circulation that affects
either of these two factors also affects the pulse pressure:
Pulse Pressure ª stroke volume/arterial compliance
Abnormal Pressure Pulse Contours
Some conditions of the circulation also cause abnormal
contours of the pressure pulse wave in addition to altering
the pulse pressure. Especially distinctive among these are
aortic stenosis, patent ductus arteriosus, and aortic regurgitation, each of which is shown in Figure 15-4.
In aortic valve stenosis, the diameter of the aortic valve
opening is reduced significantly, and the aortic pressure
pulse is decreased significantly because of diminished
blood flow outward through the stenotic valve.
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 periphery. However,
the rising pressure in the proximal 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 transmission of the pressure pulse in the arteries.
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 explains the slow
transmission in the aorta and the much faster transmission in the much less compliant small distal arteries. In the
aorta, the velocity of transmission of the pressure pulse is
15 or more times the velocity of blood flow because the
Wave fronts
Pressure (mm Hg)
Aortic stenosis
Patent ductus
Figure 15-4 Aortic pressure pulse contours in arteriosclerosis,
aortic stenosis, patent ductus arteriosus, and aortic regurgitation.
Figure 15-5 Progressive stages in transmission of the pressure
pulse along the aorta.
Unit IV
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 heartbeat,
the blood that has just been pumped into the aorta flows
immediately backward into the left ventricle. As a result,
the aortic pressure can fall all the way to zero between
heartbeats. Also, there is no incisura in the aortic pulse
contour because there is no aortic valve to close.
Unit IV The Circulation
pressure pulse is simply a moving wave of pressure that
involves little forward total movement of blood volume.
diastolic pressures by indirect means, usually by the auscultatory method.
Damping of the Pressure Pulses in the Smaller
Arteries, Arterioles, and Capillaries. Figure 15-6 shows
Auscultatory Method. Figure 15-7 shows the auscultatory method for determining systolic and diastolic
arterial pressures. A stethoscope is placed over the antecubital artery and a blood pressure cuff is inflated around
the upper arm. As long as the cuff continues to compress the arm with too little pressure to close the brachial artery, no sounds are heard from the antecubital
artery with the stethoscope. However, when the cuff pressure is great enough to close the artery during part of the
arterial pressure cycle, a sound then is heard with each
pulsation. These sounds are called Korotkoff sounds,
Pressure (mm Hg)
typical changes in the contours of the pressure pulse as
the pulse travels into the peripheral vessels. Note especially in the three lower curves that the intensity of pulsation becomes progressively less in the smaller arteries, the
arterioles, and, especially, the capillaries. In fact, only when
the aortic pulsations are extremely large or the arterioles are
greatly dilated can pulsations be observed in the capillaries.
This progressive diminution of the pulsations in the
periphery is called damping of the pressure pulses. The
cause of this is twofold: (1) resistance to blood movement
in the vessels and (2) compliance of the vessels. The resistance damps the pulsations because a small amount of
blood must flow forward at the pulse wave front to distend
the next segment of the vessel; the greater the resistance,
the more difficult it is for this to occur. The compliance
damps the pulsations because the more compliant a vessel, the greater the quantity of blood required at the pulse
wave front to cause an increase in pressure. Therefore, the
degree of damping is almost directly proportional to the
product of resistance times compliance.
Clinical Methods for Measuring Systolic
and Diastolic Pressures
It is not reasonable to use pressure recorders that require
needle insertion into an artery for making routine arterial pressure measurements in human patients, although
these are used on occasion when special studies are
necessary. Instead, the clinician determines systolic and
Time (sec)
Systole Diastole
Proximal aorta
Femoral artery
Radial artery
Time (seconds)
Figure 15-6 Changes in the pulse pressure contour as the pulse
wave travels toward the smaller vessels.
Figure 15-7 Auscultatory method for measuring systolic and
diastolic arterial pressures.
Chapter 15 Vascular Distensibility and Functions of the Arterial and Venous Systems
Normal Arterial Pressures as Measured by the
Auscultatory Method. Figure 15-8 shows the approxi-
mate normal systolic and diastolic arterial pressures at
different ages. The progressive increase in pressure with
age results from the effects of aging on the blood pressure control mechanisms. We shall see in Chapter 19 that
the kidneys are primarily responsible for this long-term
­regulation of arterial ­pressure; and it is well known that
Pressure (mm Hg)
Unit IV
named after Nikolai Korotkoff, a Russian physician who
described them in 1905.
The Korotkoff sounds are believed to be caused mainly
by blood jetting through the partly occluded vessel and by
vibrations of the vessel wall. The jet causes turbulence in
the vessel beyond the cuff, and this sets up the vibrations
heard through the stethoscope.
In determining blood pressure by the auscultatory
method, the pressure in the cuff is first elevated well above
arterial systolic pressure. As long as this cuff pressure is
higher than systolic pressure, the brachial artery remains
collapsed so that no blood jets into the 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. Just as soon as the pressure in
the cuff falls below systolic pressure (point B, Figure 15-7),
blood begins to slip through the artery beneath the cuff
during the peak of systolic pressure, and one begins to hear
tapping sounds from the antecubital artery in synchrony
with the heartbeat. As soon as these sounds begin to be
heard, the pressure level indicated by the manometer connected to the cuff is about equal to the systolic pressure.
As the pressure in the cuff is lowered still more, the
Korotkoff sounds change in quality, having less of the tapping quality and more of a rhythmical and harsher quality.
Then, finally, when the pressure in the cuff falls near diastolic pressure, the sounds suddenly change to a muffled
quality (point C, Figure 15-7). One notes the manometer
pressure when the Korotkoff sounds change to the muffled quality and this pressure is about equal to the diastolic
pressure, although it slightly overestimates the diastolic
pressure determined by direct intra-arterial catheter. As
the cuff pressure falls a few mm Hg further, the artery no
longer closes during diastole, which means that the basic
factor causing the sounds (the jetting of blood through
a squeezed artery) is no longer present. Therefore, the
sounds disappear entirely. Many clinicians believe that
the pressure at which the Korotkoff sounds completely
disappear should be used as the diastolic pressure, except
in situations in which the disappearance of sounds cannot reliably be determined because sounds are audible
even after complete deflation of the cuff. For example, in
patients with arteriovenous fistulas for hemodialysis or
with aortic insufficiency, Korotkoff sounds may be heard
after complete deflation of the cuff.
The auscultatory method for determining systolic and
diastolic pressures is not entirely accurate, but it usually
gives values within 10 percent of those determined by
direct catheter measurement from inside the arteries.
Age (years)
Figure 15-8 Changes in systolic, diastolic, and mean arterial pressures with age. The shaded areas show the approximate normal
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
decreasing distensibility, or “hardening,” of the arteries,
which is often a result of atherosclerosis. The final effect
is a higher systolic pressure with considerable increase in
pulse pressure, as previously explained.
Mean Arterial Pressure. The mean arterial pressure
is the average of the arterial pressures measured millisecond by millisecond over a period of time. It is not equal
to the average of systolic and diastolic pressure because at
normal heart rates, a greater fraction of the cardiac cycle
is spent in diastole than is systole; thus, the arterial pressure remains nearer to diastolic pressure than to systolic
pressure during the greater part of the cardiac cycle. The
mean arterial pressure is therefore determined about 60
percent by the diastolic pressure and 40 percent by the
systolic pressure. Note in Figure 15-8 that the mean pressure (solid green line) at all ages is nearer to the diastolic
pressure than to the systolic pressure. However, at very
high heart rates diastole comprises a smaller fraction of
the cardiac cycle and the mean arterial pressure is more
closely approximated as the average of systolic and diastolic pressures.
Veins and Their Functions
For years, the veins were considered to be nothing more
than passageways for flow of blood to the heart, but it
is now apparent that they perform other special functions that are necessary for operation of the circulation.
Especially important, they are capable of constricting and
enlarging and thereby storing either small or large quantities of blood and making this blood available when it is
required by the remainder of the circulation. The peripheral veins can also propel blood forward by means of a
so-called venous pump, and they even help to regulate
cardiac output, an exceedingly important function that is
described in detail in Chapter 20.
Unit IV The Circulation
Venous Pressures—Right Atrial Pressure (Central
Venous Pressure) and Peripheral Venous Pressures
To understand the various functions of the veins, it is first
necessary to know something about pressure in the veins
and what determines the pressure.
Blood from all the systemic veins flows into the right
atrium of the heart; therefore, the pressure in the right
atrium is called the central venous pressure.
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) the tendency for blood to
flow from the peripheral veins into the right atrium. If the right
heart is pumping strongly, the right atrial pressure decreases.
Conversely, weakness of the heart elevates the right atrial
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 throughout the body with resultant increased peripheral
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
also contribute to regulation of cardiac output because
the amount of blood pumped by the heart depends on
both the ability of the heart to pump and the tendency
for blood to flow into the heart from the peripheral vessels. Therefore, we will discuss regulation of right atrial
pressure in much more depth in Chapter 20 in connection
with regulation of cardiac output.
The normal right atrial pressure is about 0 mm Hg, which
is equal to the atmospheric pressure around the body. It
can increase to 20 to 30 mm Hg under very abnormal conditions, such as (1) serious heart failure or (2) after massive transfusion of blood, which greatly increases the total
blood volume and causes excessive quantities of blood to
attempt to flow into the heart from the peripheral vessels.
The lower limit to the right atrial pressure is usually
about −3 to −5 mm Hg below atmospheric pressure. This
is also the pressure in the chest cavity that surrounds the
heart. The right atrial pressure approaches these low values when the heart pumps with exceptional vigor or when
blood flow into the heart from the peripheral vessels is
greatly depressed, such as after severe hemorrhage.
Venous Resistance and Peripheral Venous Pressure
Large veins have so little resistance to blood flow when
they are distended that the resistance then is almost zero
and is of almost no importance. However, as shown in
Figure 15-9, most of the large veins that enter the thorax
are compressed at many points by the surrounding tissues so that blood flow is impeded at these points. For
instance, the veins from the arms are compressed by their
sharp angulations over the first rib. Also, the pressure
in the neck veins often falls so low that the atmospheric
pressure on the outside of the neck causes these veins to
collapse in neck
Rib collapse
Axillary collapse
pressure = − 4 mm Hg
Figure 15-9 Compression points that tend to collapse the veins
entering the thorax.
collapse. Finally, veins coursing through the abdomen are
often compressed by different organs and by the intraabdominal pressure, so they usually are at least partially
collapsed to an ovoid or slitlike state. For these reasons,
the large veins do usually offer some resistance to blood
flow, and because of this, the pressure in the more 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 Pressure. 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 atrial pressure
rises above +4 to +6 mm Hg. Then, as the right atrial pressure rises still further, the additional increase causes a corresponding rise in peripheral venous pressure in the limbs and
elsewhere. Because the heart must be weakened to cause a
rise in right atrial pressure as high as +4 to +6 mm Hg, one
often finds that the peripheral venous pressure is not noticeably elevated even in the early stages of heart failure.
Effect of Intra-abdominal Pressure on Venous
Pressures of the Leg. The pressure in the abdominal cavity of a recumbent person normally averages about +6 mm
Hg, but it can rise to +15 to +30 mm Hg as a result of pregnancy, large tumors, abdominal obesity, or excessive fluid
(called “ascites”) in the abdominal cavity. When the intraabdominal pressure does rise, the pressure in the veins of
the legs must rise above the abdominal pressure before
the abdominal veins will open and allow the blood to flow
from the legs to the heart. Thus, if the intra-abdominal
pressure is +20 mm Hg, the lowest possible pressure in
the femoral veins is also about +20 mm Hg.
Effect of Gravitational Pressure on Venous Pressure
In any body of water that is exposed to air, the pressure at
the surface of the water is equal to atmospheric pressure,
but the pressure rises 1 mm Hg for each 13.6 millimeters
Chapter 15 Vascular Distensibility and Functions of the Arterial and Venous Systems
Sagittal sinus
−10 mm
0 mm
0 mm
+6 mm
+8 mm
+22 mm
+35 mm
+40 mm
+90 mm
Figure 15-10 Effect of gravitational pressure on the venous pressures throughout the body in the standing person.
The neck veins of a person standing upright collapse
almost completely all the way to the skull because of 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 zero collapses the veins still more,
which further increases their resistance and again returns
the pressure 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 standing position,
the venous pressure in the sagittal sinus at the top of the
brain is about −10 mm Hg because of 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 immediately into the venous system; the
air may even pass downward to cause air embolism in the
heart, and death can ensue.
Effect of the Gravitational Factor on Arterial and
Other Pressures. The gravitational factor also affects
pressures in the peripheral arteries and capillaries, in
addition to its effects in the veins. For instance, a standing
person who has a mean arterial pressure of 100 mm Hg at
the level of the heart has an arterial pressure in the feet
of about 190 mm Hg. Therefore, when one states that the
arterial pressure is 100 mm Hg, this generally means that
this is the pressure at the gravitational level of the heart
but not necessarily elsewhere in the arterial vessels.
Venous Valves and the “Venous Pump”: Their Effects
on Venous Pressure
Were it not for valves in the veins, the gravitational
pressure effect would cause the venous pressure in the
feet always to be about +90 mm Hg in a standing adult.
However, every time one moves the legs, one tightens
the muscles and compresses the veins in or adjacent to
the muscles, and this squeezes the blood out of the veins.
But the valves in the veins, shown in Figure 15-11, are
arranged so that the direction of venous blood flow can be
only toward the heart. Consequently, every time a person
moves the legs or even tenses the leg muscles, a certain
amount of venous blood is propelled toward the heart.
This pumping system is known as the “venous pump” or
“muscle pump,” and it is efficient enough that under ordinary circumstances, the venous pressure in the feet of a
walking adult remains less than +20 mm Hg.
If a person stands perfectly still, the venous pump
does not work, and the venous pressures in the lower
legs increase to the full gravitational value of 90 mm Hg
in about 30 seconds. The pressures in the capillaries also
increase greatly, causing fluid to leak from the circulatory
system into the tissue spaces. As a result, the legs swell
and the blood volume diminishes. Indeed, 10 to 20 percent of the blood volume can be lost from the circulatory
Unit IV
of distance below the surface. This pressure results from
the weight of the water and therefore is called gravitational pressure or hydrostatic pressure.
Gravitational pressure also occurs in the vascular system of the human being because of weight of the blood
in the vessels, as shown in Figure 15-10. When a person is standing, the pressure in the right atrium remains
about 0 mm Hg because the heart pumps into the arteries any excess blood that attempts to accumulate at this
point. However, in an adult who is standing absolutely
still, the pressure in the veins of the feet is about +90 mm
Hg simply because of the gravitational weight of the blood
in the veins between the heart and the feet. The venous
pressures at other levels of the body are proportionately
between 0 and 90 mm Hg.
In the arm veins, the pressure at the level of the top
rib is usually about +6 mm Hg because of compression
of the subclavian vein as it passes over this rib. The
gravitational pressure down the length of the arm then
is determined by the distance below the level of this rib.
Thus, if the gravitational difference between the level
of the rib and the hand is +29 mm Hg, this gravitational
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 the hand.
Unit IV The Circulation
Deep vein
Figure 15-11 Venous valves of the leg.
system within the 15 to 30 minutes of standing absolutely
still, as often occurs when a soldier is made to stand at
rigid attention.
Venous Valve Incompetence Causes “Varicose”
Veins. The valves of the venous system frequently become
“incompetent” or sometimes even are destroyed. This is
especially true when the veins have been overstretched
by excess venous pressure lasting weeks or months, as
occurs in pregnancy or when one stands most of the
time. Stretching the veins increases their cross-sectional
areas, but the leaflets of the valves do not increase in size.
Therefore, the leaflets of the valves no longer close completely. When this develops, the pressure in the veins of
the legs increases greatly because of failure of the venous
pump; this further increases the sizes of the veins and
finally destroys the function of the valves entirely. Thus,
the person develops “varicose veins,” which are characterized by large, bulbous protrusions of the veins beneath the
skin of the entire leg, particularly the lower leg.
Whenever people with varicose veins stand for more
than a few minutes, the venous and capillary pressures
become very high and leakage of fluid from the capillaries causes constant edema in the legs. The edema in
turn prevents adequate diffusion of nutritional materials
from the capillaries to the muscle and skin cells, so the
muscles become painful and weak and the skin frequently
becomes gangrenous and ulcerates. The best treatment
for such a condition is continual elevation of the legs to a
level at least as high as the heart. Tight binders on the legs
also can be of considerable assistance in preventing the
edema and its sequelae.
Clinical Estimation of Venous Pressure. The venous pressure often can be estimated by simply observing the degree
of distention of the peripheral veins—especially of the neck
veins. For instance, in the sitting position, the neck veins are
never distended in the normal quietly resting person. However,
when the right atrial pressure becomes increased to as much
as +10 mm Hg, the lower veins of the neck begin to protrude;
and at +15 mm Hg atrial pressure essentially all the veins in
the neck become distended.
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 to a
pressure recorder. The only means by which right atrial
pressure can be measured accurately is by inserting a catheter through the peripheral veins and into the right atrium.
Pressures measured through such central venous catheters
are used almost routinely in some types of hospitalized
cardiac patients to provide constant assessment of heart
pumping ability.
Pressure Reference Level for Measuring Venous and
Other Circulatory Pressures
In discussions up to this point, we often have spoken of
right atrial pressure as being 0 mm Hg and arterial pressure
as being 100 mm Hg, but we have not stated the gravitational level in the circulatory system to which this pressure
is referred. There is one point in the circulatory system at
which gravitational pressure factors caused by changes in
body position of a healthy person usually do not affect the
pressure measurement by more than 1 to 2 mm Hg. This
is at or near the level of the tricuspid valve, as shown by
the crossed axes in Figure 15-12. Therefore, all circulatory
pressure measurements discussed in this text are referred
to this level, which is called the reference level for pressure
The reason for lack of gravitational effects at the tricuspid valve is that the heart automatically prevents significant gravitational changes in pressure at this point in the
­following way:
If the pressure at the tricuspid valve rises slightly above
normal, the right ventricle fills to a greater extent than usual,
causing the heart to pump blood more rapidly and therefore to decrease the pressure at the tricuspid valve back
toward the normal mean value. Conversely, if the pressure
falls, the right ventricle fails to fill adequately, its pumping
decreases, and blood dams up in the venous system until
Right ventricle
Right atrium
Natural reference
Figure 15-12 Reference point for circulatory pressure measurement (located near the tricuspid valve).
Chapter 15 Vascular Distensibility and Functions of the Arterial and Venous Systems
Venous sinuses
Blood Reservoir Function of the Veins
As pointed out in Chapter 14, more than 60 percent of all
the blood in the circulatory system is usually in the veins.
For this reason and also because the veins are so compliant, it is said that the venous system serves as a blood reservoir for the circulation.
When blood is lost from the body and the arterial pressure begins to fall, nervous signals are elicited from the
carotid sinuses and other pressure-sensitive areas of the
circulation, as discussed in Chapter 18. These in turn elicit
nerve signals from the brain and spinal cord mainly through
sympathetic nerves to the veins, causing them to constrict.
This takes up much of the slack in the circulatory system
caused by the lost blood. Indeed, even after as much as 20
percent of the total blood volume has been lost, the circulatory system often functions almost normally because of
this variable reservoir function of the veins.
Specific Blood Reservoirs. Certain portions of the
circulatory system are so extensive and/or so compliant that they are called “specific blood reservoirs.” These
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 liver,
the sinuses of which can release several hundred milliliters of blood into the remainder of the circulation; (3) the
large abdominal veins, which can contribute 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, although not parts of the systemic
venous reservoir system, must also be considered blood
reservoirs. The heart, for instance, shrinks during sympathetic stimulation 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.
The Spleen as a Reservoir for Storing Red Blood
Cells. Figure 15-13 shows that the spleen has two sepa-
rate areas for storing blood: the venous sinuses and the
pulp. The sinuses can swell the same as any other part of
the venous system and store whole blood.
In the splenic pulp, the capillaries are so permeable that
whole blood, including the red blood cells, oozes through
the capillary walls into a trabecular mesh, forming the red
pulp. The red cells are trapped by the trabeculae, while
the plasma flows on into the venous sinuses and then into
the general circulation. As a consequence, the red pulp of
Figure 15-13 Functional structures of the spleen. (Courtesy
Dr. Don W. Fawcett, Montana.)
the spleen is a special reservoir that contains large quantities of concentrated red blood cells. These can then be
expelled into the general circulation whenever the sympathetic nervous system becomes excited and causes the
spleen and its vessels to contract. As much as 50 milliliters
of concentrated red blood cells can be released into the
circulation, raising the hematocrit 1 to 2 percent.
In other areas of the splenic pulp are islands of white
blood cells, which collectively are called the white pulp.
Here lymphoid cells are manufactured similar to those
manufactured in the lymph nodes. They are part of the
body’s immune system, described in Chapter 34.
Blood-Cleansing Function of the Spleen—Removal
of Old Cells
Blood cells passing through the splenic pulp before entering the sinuses undergo thorough squeezing. Therefore,
it is to be expected that fragile red blood cells would not
withstand the trauma. For this reason, many of the red
blood cells destroyed in the body have their final demise
in the spleen. After the cells rupture, the released hemoglobin and the cell stroma are digested by the reticuloendothelial cells of the spleen, and the products of digestion
are mainly reused by the body as nutrients, often for
making new blood cells.
Reticuloendothelial Cells of the Spleen
The pulp of the spleen contains many large phagocytic
reticuloendothelial cells, and the venous sinuses are 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 infectious agents,
the reticuloendothelial cells of the spleen rapidly remove
debris, bacteria, parasites, and so forth. Also, in many
chronic infectious processes, the spleen enlarges in the
same manner that lymph nodes enlarge and then performs
its cleansing function even more avidly.
Unit IV
the pressure at the tricuspid level again rises to the normal
value. In other words, the heart acts as a ­feedback regulator
of pressure at the tricuspid valve.
When a person is lying on his or her back, the tricuspid
valve is located at almost exactly 60 percent of the chest
thickness in front of the back. This is the zero pressure
­reference level for a person lying down.
Unit IV The Circulation
Badeer HS: Hemodynamics for medical students, Am J Physiol (Adv Physiol
Educ) 25:44, 2001.
Guyton AC: Arterial pressure and hypertension, Philadelphia, 1980,
WB Saunders.
Guyton AC, Jones CE: Central venous pressure: physiological significance
and clinical implications, Am Heart J 86:431, 1973.
Guyton AC, Jones CE, Coleman TG: Circulatory physiology: cardiac output
and its regulation, Philadelphia, 1973, WB Saunders.
Hall JE: Integration and regulation of cardiovascular function, Am J Physiol
(Adv Physiol Educ) 22:S174, 1999.
Hicks JW, Badeer HS: Gravity and the circulation: “open” vs. “closed” systems,
Am J Physiol 262:R725–R732, 1992.
Jones DW, Appel LJ, Sheps SG, et al: Measuring blood pressure accurately:
New and persistent challenges, JAMA 289:1027, 2003.
Kass DA: Ventricular arterial stiffening: integrating the pathophysiology,
Hypertension 46:185, 2005.
Kurtz TW, Griffin KA, Bidani AK, et al: Recommendations for blood pressure measurement in humans and experimental animals. Part 2: Blood
p­ ressure measurement in experimental animals: a statement for professionals from the Subcommittee of Professional and Public Education
of the American Heart Association Council on High Blood Pressure
Research, Hypertension 45:299, 2005.
O’Rourke MF, Nichols WW: Aortic diameter, aortic stiffness, and wave
reflection increase with age and isolated systolic hypertension,
Hypertension 45:652, 2005.
Laurent S, Boutouyrie P, Lacolley P: Structural and genetic bases of arterial
stiffness, Hypertension 45:1050, 2005.
Pickering TG, Hall JE, Appel LJ, et al: Recommendations for blood pressure measurement in humans and experimental animals: Part 1: blood
pressure measurement in humans: a statement for professionals
from the Subcommittee of Professional and Public Education of the
American Heart Association Council on High Blood Pressure Research,
Hypertension 45:142, 2005.
Wilkinson IB, Franklin SS, Cockcroft JR: Nitric oxide and the regulation of
large artery stiffness: from physiology to pharmacology, Hypertension
44:112, 2004.
chapter 16
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, 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 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 circulating 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 functional 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 the pressure in the venules
is much less than that in the arterioles, so the venules can
still contract considerably despite the weak muscle.
This typical arrangement of the capillary bed is not
found in all parts of the body, although a similar arrangement may serve 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 to control
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 a unicellular layer of endothelial cells
and is surrounded by a thin basement membrane on the
outside of the capillary. The total thickness of the capillary
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 to squeeze through.
“Pores” in the Capillary Membrane. Figure 16-2
shows two small passageways connecting the interior of
the capillary with the exterior. One of these is an intercellular cleft, which is the thin-slit, curving channel that
lies at the bottom of the figure between adjacent endothelial cells. Each cleft is interrupted periodically by short
ridges of protein attachments that hold the endothelial
cells together, but between these ridges fluid can percolate freely through the cleft. The cleft normally has a uniform spacing with a width of about 6 to 7 nanometers (60
to 70 angstroms), slightly smaller than the diameter of an
albumin protein molecule.
Because the intercellular clefts are located only at the
edges of the endothelial cells, they usually represent no
more than 1/1000 of the total surface area of the capillary
wall. Nevertheless, the rate of thermal motion of water
Unit IV
The Microcirculation and Lymphatic
System: Capillary Fluid Exchange, Interstitial
Fluid, and Lymph Flow
Unit IV The Circulation
cell appear to imbibe small packets of plasma or extracellular fluid that contain plasma proteins. These vesicles
can then move slowly through the endothelial cell. Some
of these vesicles may coalesce to form vesicular channels
all the way through the endothelial cell, which is demonstrated in Figure 16-2.
Special Types of “Pores” Occur in the Capillaries
of Certain Organs. The “pores” in the capillaries of
Figure 16-1 Structure of the mesenteric capillary bed. (Redrawn
from Zweifach BW: Factors Regulating Blood Pressure. New York:
Josiah Macy, Jr., Foundation, 1950.)
molecules, as well as most water-soluble ions and small solutes, is so rapid that all of these diffuse with ease between
the interior and exterior of the capillaries through these
“slit-pores,” the intercellular clefts.
Present in the endothelial cells are many minute plasmalemmal vesicles, also called caveolae (small caves).
These form from oligomers of proteins called caveolins
that are associated with molecules of cholesterol and
sphingolipids. Although the precise functions of caveolae are still unclear, they are believed to play a role in
endocytosis (the process by which the cell engulfs material
from outside the cell) and transcytosis of macromolecules
across endothelial cells. The caveolae at the surface of the
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
2. In the liver, the opposite is true. The clefts between the
capillary endothelial cells are wide open so that almost
all dissolved substances of the plasma, including the
plasma proteins, can pass from the blood into the liver
3. The pores of the gastrointestinal capillary membranes
are midway between those of the muscles and those of
the liver.
4. In the glomerular capillaries 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 molecular and ionic
substances (but not the large molecules of the plasma
proteins) can filter through the glomeruli without having to pass through the clefts between the endothelial
Flow of Blood in the
Figure 16-2 Structure of the capillary wall. Note especially the
intercellular cleft at the junction between adjacent endothelial
cells; it is believed that most water-soluble substances diffuse
through the capillary membrane along the clefts. Small membrane invaginations, called caveolae, are believed to play a role in
transporting macromolecules across the cell membrane. Caveolae
contain caveolins, proteins which interact with cholesterol and
polymerize to form the caveolae.
some organs have special characteristics to meet the
peculiar needs of the organs. Some of these characteristics are as follows:
Blood usually does not flow continuously through the
capillaries. Instead, it flows intermittently, turning on and
off every few seconds or minutes. The cause of this intermittency is the phenomenon called vasomotion, which
means intermittent contraction of the metarterioles and
precapillary sphincters (and sometimes even the very
small arterioles as well).
Regulation of Vasomotion. The most important
factor found thus far to affect the degree of opening and
closing of the metarterioles and precapillary sphincters is
the concentration of oxygen in the tissues. When the rate
of oxygen usage by the tissue is great so that 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.
Chapter 16 The Microcirculation and Lymphatic System: Capillary Fluid Exchange, Interstitial Fluid, and Lymph Flow
This effect, along with multiple other factors that control
local tissue blood flow, is discussed in Chapter 17.
Despite the fact that blood flow through each 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 substances between
the blood of the capillaries and the surrounding interstitial
fluid. In the remainder of this chapter, we are concerned
with these averages, although one must remember that the
average functions are, in reality, the functions of literally
billions of individual capillaries, each operating intermittently in response to local conditions in the tissues.
Exchange of Water, Nutrients, and Other
Substances Between the Blood and
Interstitial Fluid
Diffusion Through the Capillary Membrane
By far the most important means by which substances are
transferred between the plasma and the interstitial fluid is
diffusion. Figure 16-3 demonstrates this process, showing
that as the blood flows along the lumen of the capillary,
tremendous numbers of water molecules and dissolved
particles diffuse back and forth through the capillary wall,
providing continual mixing between the interstitial fluid
and the plasma. Diffusion results from thermal motion
of the water molecules and dissolved substances in the
fluid, the different molecules and ions moving first in one
direction and then another, bouncing randomly in every
Arterial end
Blood capillary
Venous end
Figure 16-3 Diffusion of fluid molecules and dissolved substances
between the capillary and interstitial fluid spaces.
fuse directly through the cell membranes of the capillary
without having to go through the pores. Such substances
include oxygen and carbon dioxide. Because these substances can permeate all areas of the capillary membrane,
their rates of transport through the capillary membrane are
many times faster than the rates for lipid-insoluble substances, such as sodium ions and glucose that can go only
through the pores.
Water-Soluble, Non-Lipid-Soluble Substances
Diffuse Through Intercellular “Pores” in the Capillary
Membrane. Many substances needed by the tissues are
soluble in water but cannot pass through the lipid membranes of the endothelial cells; such substances include
water molecules themselves, sodium ions, chloride ions,
and glucose. Despite the fact that not more than 1/1000
of the surface area of the capillaries is represented by
the intercellular clefts between the endothelial cells, the
velocity of thermal molecular motion in the clefts is so
great that even this small area is sufficient to allow tremendous diffusion of water and water-soluble substances
through these cleft-pores. To give one an idea of the rapidity with which these substances diffuse, the rate at which
water molecules diffuse through the capillary membrane is
about 80 times as great as the rate at which plasma itself
flows linearly along the capillary. That is, the water of the
plasma is exchanged with the water of the interstitial fluid
80 times before the plasma can flow the entire distance
through the capillary.
Effect of Molecular Size on Passage Through
the Pores. The width of the capillary intercellular cleft-
pores, 6 to 7 nanometers, is about 20 times the diameter
of the water molecule, which is the smallest molecule that
normally passes through the capillary pores. Conversely,
the diameters of plasma protein molecules are slightly
greater than the width of the pores. Other substances,
such as sodium ions, chloride ions, glucose, and urea,
have intermediate diameters. Therefore, the permeability of the capillary pores for different substances varies
according to their molecular diameters.
Table 16-1 gives the relative permeabilities of the capillary pores in skeletal muscle for substances commonly
encountered, demonstrating, for instance, that 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
A word of caution must be issued at this point. The
capillaries in various tissues have extreme differences
in their permeabilities. For instance, the membranes of
the liver capillary sinusoids are so permeable that even
plasma proteins pass freely through these walls, almost
as easily as water and other substances. Also, the permeability of the renal glomerular membrane for water
Unit IV
Average Function of the Capillary System
Lipid-Soluble Substances Can Diffuse Directly
Through the Cell Membranes of the Capillary
Endothelium. If a substance is lipid soluble, it can dif-
Unit IV The Circulation
Table 16-1 Relative Permeability of Skeletal Muscle Capillary
Pores to Different-Sized Molecules
Molecular Weight
Data from Pappenheimer JR: Passage of molecules through capillary walls.
Physiol Rev 33:387, 1953.
and electrolytes is about 500 times the permeability of
the muscle capillaries, but this is not true for the plasma
proteins; for these, the capillary permeabilities are very
slight, as in other tissues and organs. When we study
these different organs later in this text, it should become
clear why some tissues—the liver, for instance—require
greater degrees of capillary permeability than others to
transfer tremendous amounts of nutrients between the
blood and liver parenchymal cells, and the kidneys to
allow filtration of large quantities of fluid for formation
of urine.
Effect of Concentration Difference on Net Rate
of Diffusion Through the Capillary Membrane. The
“net” rate of diffusion of a substance through any membrane is proportional to the concentration difference of
the substance between the two sides of the membrane.
That is, the greater the difference between the concentrations of any given substance on the two sides of the
capillary membrane, the greater the net movement of
the substance in one direction through the membrane.
For instance, the concentration of oxygen in capillary
blood is normally greater than in the interstitial fluid.
Therefore, large quantities of oxygen normally move
from the blood toward the tissues. Conversely, the concentration of carbon dioxide is greater in the tissues
than in the blood, which causes excess carbon dioxide
to move into the blood and to be carried away from the
The rates of diffusion through the capillary membranes of most nutritionally important substances are
so great that only slight concentration differences suffice to cause more than adequate transport between
the plasma and interstitial fluid. For instance, the concentration of oxygen in the interstitial fluid immediately outside the capillary is no more than a few
percent less than its concentration in the plasma of
the blood, yet this slight difference causes enough
oxygen to move from the blood into the interstitial
spaces to provide all the oxygen required for tissue
metabolism, often as much as several liters of oxygen per
minute during very active states of the body.
Interstitium and Interstitial Fluid
About one sixth of the total volume of the body consists of
spaces between cells, which collectively are called the interstitium. The fluid in these spaces is the interstitial fluid.
The structure of the interstitium is shown in Figure
16-4. It contains two major types of solid structures: (1)
collagen fiber bundles and (2) proteoglycan filaments. The
collagen fiber bundles extend long distances in the interstitium. They are extremely strong and therefore provide
most of the tensional strength of the tissues. The proteoglycan filaments, however, are extremely thin coiled
or twisted molecules composed of about 98 percent
hyaluronic acid and 2 percent protein. These molecules
are so thin that they cannot be seen with a light microscope and are difficult to demonstrate even with the electron microscope. Nevertheless, they form a mat of very
fine reticular filaments aptly described as a “brush pile.”
“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 because
proteins do not easily pass outward through the pores of
the capillaries. The interstitial fluid is entrapped mainly
in the minute spaces among the proteoglycan filaments.
This combination of proteoglycan filaments and fluid
entrapped within them has the characteristics of a gel and
therefore is called tissue gel.
Because of the large number of proteoglycan filaments,
it is difficult for fluid to flow easily through the tissue gel.
Free fluid
of free
Collagen fiber
Figure 16-4 Structure of the interstitium. Proteoglycan filaments
are everywhere in the spaces between the collagen fiber bundles.
Free fluid vesicles and small amounts of free fluid in the form of
rivulets occasionally also occur.
Chapter 16 The Microcirculation and Lymphatic System: Capillary Fluid Exchange, Interstitial Fluid, and Lymph Flow
“Free” Fluid in the Interstitium. Although almost
all the fluid in the interstitium normally is entrapped within
the tissue gel, occasionally small rivulets of “free” fluid and
small free fluid vesicles are also present, which means fluid
that is free of the proteoglycan molecules and therefore
can flow freely. When a dye is injected into the circulating
blood, it often can be seen to flow through the interstitium
in the small rivulets, usually coursing along the surfaces of
collagen fibers or surfaces of cells.
The amount of “free” fluid present in normal tissues is
slight, usually less than 1 percent. Conversely, when the
tissues develop edema, these small pockets and rivulets of
free fluid expand tremendously until one half or more of
the edema fluid becomes freely flowing fluid independent
of the proteoglycan filaments.
Fluid Filtration Across Capillaries Is
Determined by Hydrostatic and Colloid
Osmotic Pressures, as Well as Capillary
Filtration Coefficient
The hydrostatic pressure in the capillaries tends to force
fluid and its dissolved substances through the capillary
pores into the interstitial spaces. Conversely, osmotic pressure caused by the plasma proteins (called colloid osmotic
pressure) tends to cause fluid movement by osmosis from
the interstitial spaces into the blood. This osmotic pressure exerted by the plasma proteins normally prevents
significant loss of fluid volume from the blood into the
interstitial spaces.
Also important is the lymphatic system, which returns
to the circulation the small amounts of excess protein and
fluid that leak from the blood into the interstitial spaces.
In the remainder of this chapter, we discuss the mechanisms that control capillary filtration and lymph flow
function together to regulate the respective volumes of
the plasma and the interstitial fluid.
Hydrostatic and Colloid Osmotic Forces
Determine Fluid Movement Through the Capillary
Membrane. Figure 16-5 shows the four primary forces
that determine whether fluid will move out of the blood
into the interstitial fluid or in the opposite direction. These
forces, called “Starling forces” in honor of the physiologist
who first demonstrated their importance, are:
Plasma colloid
osmotic pressure
fluid pressure
Interstitial fluid
colloid osmotic pressure
Figure 16-5 Fluid pressure and colloid osmotic pressure forces
operate at the capillary membrane, tending to move fluid either
outward or inward through the membrane pores.
1. The capillary pressure (Pc), which tends to force fluid
outward through the capillary membrane.
2. The interstitial fluid pressure (Pif ), which tends to force
fluid inward through the capillary membrane when Pif
is positive but outward when Pif is negative.
3. The capillary plasma colloid osmotic pressure (Πp),
which tends to cause osmosis of fluid inward through
the capillary membrane.
4. The interstitial fluid colloid osmotic pressure (Πif ),
which tends to cause osmosis of fluid outward through
the capillary membrane.
If the sum of these forces—the net filtration pressure—is
positive, there will be a net fluid filtration across the capillaries. If the sum of the Starling forces is negative, there
will be a net fluid absorption from the interstitial spaces
into the capillaries. The net filtration pressure (NFP) is
­calculated as:
NFP = Pc – Pif – Pp + Pif
As discussed later, the NFP is slightly positive under normal conditions, resulting in a net filtration of fluid across
the capillaries into the interstitial space in most organs.
The rate of fluid filtration in a tissue is also determined
by the number and size of the pores in each capillary, as
well as the number of capillaries in which blood is flowing. These factors are usually expressed together as the
capillary filtration coefficient (Kf ). The Kf 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 = Kf × NFP
In the following sections we discuss each of the forces that
determine the rate of capillary fluid filtration.
Capillary Hydrostatic Pressure
Various methods have been used to estimate the capillary
hydrostatic pressure: (1) direct micropipette cannulation
of the capillaries, which has given an average mean capillary pressure of about 25 mm Hg in some tissues such as
Unit IV
Instead, fluid mainly diffuses through the gel; that is, it
moves molecule by molecule from one place to another
by kinetic, thermal motion rather than by large numbers
of molecules moving together.
Diffusion through the gel occurs about 95 to 99 percent as rapidly as it does through free fluid. For the short
distances between the capillaries and the tissue cells, this
diffusion allows rapid transport through the interstitium
not only of water molecules but also of electrolytes, small
molecular weight nutrients, cellular excreta, oxygen, carbon dioxide, and so forth.
Unit IV The Circulation
the skeletal muscle and the gut, and (2) indirect functional
measurement of the capillary pressure, which has given
a capillary pressure averaging about 17 mm Hg in these
Micropipette Method for Measuring Capillary
Pressure. To measure pressure in a capillary by cannu-
Isogravimetric Method for Indirectly Measuring
“Functional” Capillary Pressure. Figure 16-6 demon-
strates an isogravimetric 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
through the blood vessels of the gut wall. When the arterial pressure is decreased, the resulting decrease in capillary pressure allows the osmotic pressure of the plasma
proteins to cause absorption of fluid out of the gut wall
and makes the weight of the gut decrease. This immediately causes displacement of the balance arm. To prevent
this weight decrease, the venous pressure is increased an
amount sufficient to overcome the effect of decreasing
the arterial pressure. In other words, the capillary pressure is kept constant while simultaneously (1) decreasing the arterial pressure and (2) increasing the venous
In the graph in the lower part of the figure, the changes
in arterial and venous pressures that exactly nullify all
weight changes are shown. The arterial and venous lines
meet each other at a value of 17 mm Hg. Therefore, the
capillary pressure must have remained at this same level
of 17 mm Hg throughout these maneuvers; otherwise,
either filtration or absorption of fluid through the capillary walls would have occurred. Thus, in a roundabout
way, the “functional” capillary pressure in this tissue is
measured to be about 17 mm Hg.
It is clear that the isogravimetric method, which determines the capillary pressure that exactly balances all the
forces tending to move fluid into or out of the capillaries,
gives a lower value compared with the capillary pressure
measured directly with a micropipette. A major reason for
this is that capillary fluid filtration is not exactly balanced
Arterial pressure
Venous pressure
lation, a microscopic glass pipette is thrust directly into
the capillary, and the pressure is measured by an appropriate micromanometer system. Using this method, capillary pressures have been measured in capillaries of
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, 10 to 15 mm Hg
in the venous ends, and about 25 mm Hg in the middle.
In some capillaries, such as the glomerular capillaries
of the kidneys, the pressures measured by the micropipette method are much higher, averaging about 60 mm
Hg. The peritubular capillaries of the kidneys, in contrast,
have hydrostatic pressure that average only about 13 mm
Hg. Thus, the capillary hydrostatic pressures in different
tissues are highly variable, depending on the particular
tissue and the physiological condition.
Capillary pressure
= 17 mm Hg
Arterial pressure
– venous pressure
Figure 16-6 Isogravimetric method for measuring capillary
with fluid reabsorption in most tissues. The fluid that is
filtered in excess of what is reabsorbed is carried away by
lymph vessels in most tissues. In the glomerular capillaries
of the kidneys, a very large amount of fluid, approximately
125 ml/min, is continuously filtered.
Interstitial Fluid Hydrostatic Pressure
There are several methods for measuring interstitial fluid
hydrostatic pressure and each of these gives slightly different values, depending on the method used and the tissue
in which the pressure is measured. In loose subcutaneous
tissue, interstitial fluid pressure measured by the different methods is usually a few millimeters of mercury less
than atmospheric pressure; that is, the values are called
negative interstitial fluid pressure. In other tissues that are
surrounded by capsules, such as the kidneys, the interstitial pressure is generally positive (greater than atmospheric pressure). The methods most widely used have
been (1) direct cannulation of the tissues with a micropipette, (2) measurement of the pressure from implanted
perforated capsules, and (3) measurement of the pressure
from a cotton wick inserted into the tissue.
Chapter 16 The Microcirculation and Lymphatic System: Capillary Fluid Exchange, Interstitial Fluid, and Lymph Flow
Interstitial Fluid Pressures in Tightly Encased Tissues
Some tissues of the body are surrounded by tight encasements, such as the cranial vault around the brain, the
strong fibrous capsule around the kidney, the fibrous
sheaths around the muscles, and the sclera around the
eye. In most of these, regardless of the method used for
measurement, the interstitial fluid pressures are positive.
However, these interstitial fluid pressures almost invariably are still less than the pressures exerted on the outsides of the tissues by 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 pressure averages
about +4 to +6 mm Hg. In the kidneys, the capsular pressure surrounding the kidney averages about +13 mm Hg,
whereas the reported renal interstitial fluid pressures
have averaged about +6 mm Hg. Thus, if one remembers that the pressure exerted on the skin is atmospheric
pressure, which is considered to be zero pressure, one
might formulate a general rule that the normal interstitial fluid pressure is usually several millimeters of mercury negative with respect to the pressure that ­surrounds
each tissue.
Is the True Interstitial Fluid Pressure in Loose
Subcutaneous Tissue Subatmospheric?
The concept that the interstitial fluid pressure is subatmospheric in some tissues of the body began with clinical
observations that could not be explained by the previously
held concept that interstitial fluid pressure was always positive. Some of the pertinent observations are the following:
1. When a skin graft is placed on a concave surface of
the body, such as in an eye socket after removal of the
eye, before the skin becomes attached to the sublying
socket, fluid tends to collect underneath the graft. Also,
the skin attempts to shorten, with the result that it tends
to pull it away from the concavity. Nevertheless, some
negative force underneath the skin causes absorption
of the fluid and usually literally pulls the skin back into
the concavity.
2. Less than 1 mm Hg of positive pressure is required to
inject large volumes of fluid into loose subcutaneous
tissues, such as beneath the lower eyelid, in the axillary space, and in the scrotum. Amounts of fluid calculated to be more than 100 times the amount of fluid
normally in the interstitial space, when injected into
these areas, cause no more than about 2 mm Hg of
positive pressure. The importance of these observations is that they show that such tissues do not have
strong fibers that can prevent the accumulation of
fluid. Therefore, some other mechanism, such as a low
compliance system, must be available to prevent such
fluid accumulation.
3. In most natural cavities of the body where there is
free fluid in dynamic equilibrium with the surrounding interstitial fluids, the pressures that have been
measured have been negative. Some of these are the
Intrapleural space: −8 mm Hg
Joint synovial spaces: −4 to −6 mm Hg
Epidural space: −4 to −6 mm Hg
4. The implanted capsule for measuring the interstitial
fluid pressure can be used to record dynamic changes
in this pressure. The changes are approximately those
that one would calculate to occur (1) when the arterial pressure is increased or decreased, (2) when fluid is
injected into the surrounding tissue space, or (3) when
a highly concentrated colloid osmotic agent is injected
into the blood to absorb fluid from the tissue spaces.
It is not likely that these dynamic changes could be
recorded this accurately unless the capsule pressure
closely approximated the true interstitial pressure.
Summary—An Average Value for Negative
Inter­stitial Fluid Pressure in Loose Subcutaneous
Tissue. Although the aforementioned different methods
give slightly different values for interstitial fluid pressure,
there currently is a general belief among most physiologists that the true interstitial fluid pressure in loose subcutaneous tissue is slightly less subatmospheric, averaging
about −3 mm Hg.
Pumping by the Lymphatic System Is the Basic
Cause of the Negative Interstitial Fluid Pressure
The lymphatic system is discussed later in the chapter, but
we need to understand here the basic role that this system
plays in determining interstitial fluid pressure. The lymphatic system is a “scavenger” system that removes excess
fluid, excess protein molecules, debris, and other matter
from the tissue spaces. Normally, when fluid enters the
Unit IV
Measurement of Interstitial Fluid Pressure Using the
Micropipette. The same type of micropipette used for measuring capillary pressure can also be used in some tissues for
measuring interstitial fluid pressure. The tip of the micropipette is about 1 micrometer in diameter, but even this is 20
or more times larger than the sizes of the spaces between
the proteoglycan filaments of the interstitium. Therefore, the
pressure that is measured is probably the pressure in a free
fluid pocket.
The first pressures measured using the micropipette
method ranged from −1 to +2 mm Hg but were usually
slightly positive. With experience and improved equipment
for making such measurements, more recent pressures have
averaged about −2 mm Hg, giving average pressure values in
loose tissues, such as skin, that are slightly less than atmospheric pressure.
Measurement of Interstitial Free Fluid Pressure in
Implanted Perforated Hollow Capsules. Interstitial free fluid
pressure measured by this method when using 2-centimeter
diameter capsules in normal loose subcutaneous tissue averages about −6 mm Hg, but with smaller capsules, the values
are not greatly different from the −2 mm Hg measured by the
Unit IV The Circulation
terminal lymphatic capillaries, the lymph vessel walls
automatically contract for a few seconds and pump the
fluid into the blood circulation. This overall process creates the slight negative pressure that has been measured
for fluid in the interstitial spaces.
Plasma Colloid Osmotic Pressure
Proteins in the Plasma Cause Colloid Osmotic
Pressure. In the basic discussion of osmotic pressure in
Chapter 4, it was pointed out that only those molecules or
ions that fail to pass through the pores of a semipermeable membrane exert osmotic pressure. Because the proteins are the only dissolved constituents in the plasma and
interstitial fluids that do not readily pass through the capillary pores, it is the proteins of the plasma and interstitial
fluids that are responsible for the osmotic pressures on the
two sides of the capillary membrane. To distinguish this
osmotic pressure from that which occurs at the cell membrane, it is called either colloid osmotic pressure or oncotic
pressure. The term “colloid” osmotic pressure is derived
from the fact that a protein solution resembles a colloidal
solution despite the fact that it is actually a true molecular
Normal Values for Plasma Colloid Osmotic
Pressure. The colloid osmotic pressure of normal human
plasma averages about 28 mm Hg; 19 mm of this is caused
by molecular effects of the dissolved protein and 9 mm by
the Donnan effect—that is, extra osmotic pressure caused
by sodium, potassium, and the other cations held in the
plasma by the proteins.
Effect of the Different Plasma Proteins on Colloid
Osmotic Pressure. The plasma proteins are a mixture that
contains albumin, with an average molecular weight of
69,000; globulins, 140,000; and fibrinogen, 400,000. Thus,
1 gram of globulin contains only half as many molecules
as 1 gram of albumin, and 1 gram of fibrinogen contains
only one sixth as many molecules as 1 gram of albumin.
It should be recalled from the discussion of osmotic pressure in Chapter 4 that osmotic pressure is determined by
the number of molecules dissolved in a fluid rather than
by the mass of these molecules. Therefore, when corrected
for number of molecules rather than mass, the following chart gives both the relative mass concentrations (g/
dl) of the different types of proteins in normal plasma and
their respective contributions to the total plasma colloid
osmotic pressure (Πp).
’p (mm Hg)
Thus, about 80 percent of the total colloid osmotic pressure of the plasma results from the albumin fraction, 20 percent from the globulins, and almost none from the fibrinogen.
Therefore, from the point of view of ­capillary and tissue fluid
dynamics, it is mainly albumin that is important.
Interstitial Fluid Colloid Osmotic Pressure
Although the size of the usual capillary pore is smaller
than the molecular sizes of the plasma proteins, this is
not true of all the pores. Therefore, small amounts of
plasma proteins do leak through the pores into the interstitial spaces through pores and by transcytosis in small
The total quantity of protein in the entire 12 liters of
interstitial fluid of the body is slightly greater than the
total quantity of protein in the plasma itself, but because
this volume is four times the volume of plasma, the average protein concentration of the interstitial fluid is usually only 40 percent of that in plasma, or about 3 g/dl.
Quantitatively, one finds that the average interstitial fluid
colloid osmotic pressure for this concentration of proteins is about 8 mm Hg.
Exchange of Fluid Volume Through the Capillary
Now that the different factors affecting fluid movement
through the capillary membrane have been discussed, it
is possible to put all these together to see how the capillary system maintains normal fluid volume distribution
between the plasma and the interstitial fluid.
The average capillary pressure at the arterial ends of
the capillaries is 15 to 25 mmHg greater than at the venous
ends. Because of this difference, fluid “filters” out of the
capillaries at their arterial ends, but at their venous ends
fluid is reabsorbed back into the capillaries. Thus, a small
amount of fluid actually “flows” through the tissues from
the arterial ends of the capillaries to the venous ends. The
dynamics of this flow are as follows.
Analysis of the Forces Causing Filtration at the
Arterial End of the Capillary. The approximate average
forces operative at the arterial end of the capillary that
cause movement through the capillary membrane are
shown as follows:
mm Hg
Forces tending to move fluid outward:
Capillary pressure (arterial end of capillary)
Negative interstitial free fluid pressure
Interstitial fluid colloid osmotic pressure
total outward force
Forces tending to move fluid inward:
Plasma colloid osmotic pressure
total inward force
Summation of forces:
net outward force (at arterial end)
Thus, the summation of forces at the arterial end of the
capillary shows a net filtration pressure of 13 mm Hg, tending to move fluid outward through the capillary pores.
Chapter 16 The Microcirculation and Lymphatic System: Capillary Fluid Exchange, Interstitial Fluid, and Lymph Flow
Analysis of Reabsorption at the Venous End of the
Capillary. The low blood pressure at the venous end
of the capillary changes the balance of forces in favor of
absorption as follows:
mm Hg
Forces tending to move fluid inward:
Plasma colloid osmotic pressure
total inward force
Forces tending to move fluid outward:
Capillary pressure (venous end of capillary)
Negative interstitial free fluid pressure
Interstitial fluid colloid osmotic pressure
total outward force
Summation of forces:
net inward force
Thus, the force that causes fluid to move into the
capillary, 28 mm Hg, is greater than that opposing reabsorption, 21 mm Hg. The difference, 7 mm Hg, is the net
reabsorption pressure at the venous ends of the capillaries.
This reabsorption pressure is considerably less than
the filtration pressure at the capillary arterial ends, but
remember that the venous capillaries are more numerous and more permeable than the arterial capillaries, so
that less reabsorption pressure is required to cause inward
movement of fluid.
The reabsorption pressure causes about nine tenths of
the fluid that has filtered out of the arterial ends of the capillaries to be reabsorbed at the venous ends. The remaining one tenth flows into the lymph vessels and returns to
the circulating blood.
Starling Equilibrium for Capillary Exchange
Ernest H. Starling pointed out more than a century ago
that under normal conditions, a state of near-equilibrium
exists in most capillaries. That is, the amount of fluid filtering outward from the arterial ends of capillaries equals
almost exactly the fluid returned to the circulation by
absorption. The slight disequilibrium that does occur
accounts for the fluid that is eventually returned to the
circulation by way of the lymphatics.
The following chart shows the principles of the Starling
equilibrium. For this chart, the pressures in the arterial
and venous capillaries are averaged to calculate mean
functional capillary pressure for the entire length of the
capillary. This calculates to be 17.3 mm Hg.
mm Hg
Mean forces tending to move
fluid outward:
Mean capillary pressure
Negative interstitial free fluid pressure
Interstitial fluid colloid osmotic pressure
total outward force
Mean force tending to move
fluid inward:
Plasma colloid osmotic pressure
total inward force
Summation of mean forces:
net outward force
Unit IV
This 13 mm Hg filtration pressure causes, on average,
about 1/200 of the plasma in the flowing blood to filter
out of the arterial ends of the capillaries into the interstitial spaces each time the blood passes through the
Thus, for the total capillary circulation, we find a nearequilibrium between the total outward forces, 28.3 mm Hg,
and the total inward force, 28.0 mm Hg. This slight imbalance of forces, 0.3 mm Hg, causes slightly more filtration
of fluid into the interstitial spaces than reabsorption. This
slight excess of filtration is called net filtration, and it is the
fluid that must be returned to the circulation through the
lymphatics. The normal rate of net filtration in the entire
body, not including the kidneys, is only about 2 ml/min.
Filtration Coefficient. In the previous example, an
average net imbalance of forces at the capillary membranes of 0.3 mm Hg causes net fluid filtration in the
entire body of 2 ml/min. Expressing this for each millimeter of mercury imbalance, one finds a net filtration rate of
6.67 ml/min of fluid per mm Hg for the entire body. This
is called the whole body capillary filtration coefficient.
The filtration coefficient can also be expressed for separate parts of the body in terms of rate of filtration per minute per mm Hg 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 tissue. But, because of extreme differences in permeabilities of the capillary systems in different tissues, this coefficient varies more than 100-fold
among the different tissues. It is very small in brain and
muscle, moderately large in subcutaneous tissue, large
in the intestine, and extreme in the liver and glomerulus of the kidney where the pores are either numerous or
wide open. By the same token, the permeation of proteins
through the capillary membranes varies greatly as well.
The concentration of protein in the interstitial fluid of
muscles is about 1.5 g/dl; in subcutaneous tissue, 2 g/dl; in
intestine, 4 g/dl; and in liver, 6 g/dl.
Effect of Abnormal Imbalance of Forces at the
Capillary Membrane
If the mean capillary pressure rises above 17 mm Hg, the
net force tending to cause filtration of fluid into the tissue spaces rises. Thus, a 20 mm Hg rise in mean capillary
pressure causes an increase in net filtration pressure from
0.3 mm Hg to 20.3 mm Hg, which results in 68 times as
Unit IV The Circulation
much net filtration of fluid into the interstitial spaces as
normally occurs. To prevent accumulation 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 lymphatics to carry away. As
a result, fluid will begin to accumulate in the interstitial
spaces and edema will result.
Conversely, if the capillary pressure falls very low, net
reabsorption of fluid into the capillaries will occur instead
of net filtration and the blood volume will increase at the
expense of the interstitial fluid volume. These effects of
imbalance at the capillary membrane in relation to the
development of different kinds of edema are discussed in
Chapter 25.
Lymphatic System
The lymphatic system represents an accessory route
through which fluid can flow from the interstitial spaces
into the blood. Most important, the lymphatics can carry
proteins and large particulate matter away from the tissue spaces, neither of which can be removed by absorption directly into the blood capillaries. This return of
proteins to the blood from the interstitial spaces is an
essential function without which we would die within
about 24 hours.
Lymph Channels of the Body
Almost all tissues of the body have special lymph channels
that drain excess fluid directly from the interstitial spaces.
The exceptions include the superficial portions of the skin,
the central nervous system, the endomysium of muscles,
and the bones. But, even these tissues have minute interstitial channels called prelymphatics through which interstitial fluid can flow; this fluid eventually 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 subclavian vein, as shown
in Figure 16-7.
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 lymph duct
(much smaller than the thoracic duct), which empties into
the blood venous system at the juncture of the right subclavian vein and internal jugular vein.
Masses of lymphocytes
and macrophages
Cervical nodes
Sentinel node
Subclavian vein
R. lymphatic duct
Thoracic duct
Axillary nodes
Cisterna chyli
Abdominal nodes
Inguinal nodes
Peripheral lymphatics
Blood capillary
Tissue cell
Figure 16-7 Lymphatic system.
Chapter 16 The Microcirculation and Lymphatic System: Capillary Fluid Exchange, Interstitial Fluid, and Lymph Flow
Formation of Lymph
Lymph is derived from interstitial fluid that flows into the
lymphatics. Therefore, lymph as it first enters the terminal lymphatics has almost the same composition as the
interstitial fluid.
The protein concentration in the interstitial fluid
of most tissues averages about 2 g/dl, and the protein
Endothelial cells
Rate of Lymph Flow
About 100 milliliters per hour of lymph flows through
the thoracic duct of a resting human, and approximately
another 20 milliliters flows into the circulation each hour
through other channels, making a total estimated lymph
flow of about 120 ml/hr or 2 to 3 liters per day.
Effect of Interstitial Fluid Pressure on Lymph Flow.
Figure 16-9 shows the effect of different levels of interstitial fluid pressure on lymph flow as measured in dog
legs. Note that normal lymph flow is very little at interstitial fluid pressures more negative than the normal value
of −6 mm Hg. Then, as the pressure rises to 0 mm Hg
(atmospheric pressure), flow increases more than 20-fold.
Therefore, any factor that increases interstitial fluid
2 times/
mm Hg
Anchoring filaments
Figure 16-8 Special structure of the lymphatic capillaries that
permits passage of substances of high molecular weight into the
7 times/
mm Hg
PT (mm Hg)
Figure 16-9 Relation between interstitial fluid pressure and
lymph flow in the leg of a dog. Note that lymph flow reaches a
maximum when the interstitial pressure, PT, rises slightly above
atmospheric pressure (0 mm Hg). (Courtesy Drs. Harry Gibson and
Aubrey Taylor.)
Unit IV
ends of blood capillaries flows among the cells and finally
is reabsorbed back into the venous ends of the blood capillaries; but on the average, about one tenth of the fluid
instead enters the lymphatic capillaries and returns to the
blood through the lymphatic system rather than through
the venous capillaries. The total quantity of all this lymph
is normally only 2 to 3 liters each day.
The fluid that returns to the circulation by way of the
lymphatics is extremely important because substances
of high molecular weight, such as proteins, cannot be
absorbed from the tissues in any other way, although
they can enter the lymphatic capillaries almost unimpeded. The reason for this is a special structure of the
lymphatic capillaries, demonstrated in Figure 16-8. This
figure shows the endothelial cells of the lymphatic capillary attached by anchoring filaments to the surrounding
connective tissue. At the junctions of adjacent endothelial
cells, the edge of one endothelial cell overlaps the edge of
the adjacent cell in such a way that the overlapping edge
is free to flap inward, thus forming a minute valve that
opens to the interior of the lymphatic capillary. Interstitial
fluid, along with its suspended particles, can push the
valve open and flow directly into the lymphatic capillary.
But this fluid has difficulty leaving the capillary once it has
entered because any backflow closes the flap valve. Thus,
the lymphatics have valves at the very tips of the terminal
lymphatic capillaries, as well as valves along their larger
vessels up to the point where they empty into the blood
concentration of lymph flowing from these tissues is
near this value. In the liver, lymph formed has a protein
concentration as high as 6 g/dl, and lymph 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 intestines, the thoracic duct
lymph, which is a mixture of lymph from all areas of the
body, usually has a protein concentration of 3 to 5 g/dl.
The lymphatic system is also one of the major routes for
absorption of nutrients from the gastrointestinal tract, especially for absorption of virtually all fats in food, as discussed
in Chapter 65. Indeed, after a fatty meal, thoracic duct lymph
sometimes contains as much as 1 to 2 percent fat.
Finally, even large particles, such as bacteria, can push
their way between the endothelial cells of the lymphatic capillaries and in this way enter the lymph. As the lymph passes
through the lymph nodes, these particles are almost entirely
removed and destroyed, as discussed in Chapter 33.
Relative lymph flow
Terminal Lymphatic Capillaries and Their
Permeability. Most of the fluid filtering from the arterial
Unit IV The Circulation
pressure also increases lymph flow if the lymph vessels are
functioning normally. Such factors include the following:
Elevated capillary hydrostatic pressure
Decreased plasma colloid osmotic pressure
Increased interstitial fluid colloid osmotic pressure
Increased permeability of the capillaries
All of these cause a balance of fluid exchange at the blood
capillary membrane to favor fluid movement into the interstitium, thus increasing interstitial fluid volume, interstitial
fluid pressure, and lymph flow all at the same time.
However, note in Figure 16-9 that when the interstitial fluid pressure becomes 1 or 2 mm Hg greater than
atmospheric pressure (>0 mm Hg), lymph flow fails to
rise any further at still higher pressures. This results
from the fact that the increasing tissue pressure not only
increases entry of fluid into the lymphatic capillaries
but also compresses the outside surfaces of the larger
lymphatics, thus impeding lymph flow. At the higher
pressures, these two factors balance each other almost
exactly, so lymph flow reaches what is called the “maximum lymph flow rate.” This is illustrated by the upper
level plateau in Figure 16-9.
Lymphatic Pump Increases Lymph Flow. Valves
exist in all lymph channels; typical valves are shown in
Figure 16-10 in collecting lymphatics into which the lymphatic capillaries empty.
Motion pictures of exposed lymph vessels in animals
and in human beings show that when a collecting lymphatic or larger lymph vessel becomes stretched with fluid,
the smooth muscle in the wall of the vessel automatically
contracts. Furthermore, each segment of the lymph vessel between successive valves functions as a separate automatic pump. That is, even slight filling of a segment causes
it to contract and the fluid is pumped through the next
valve into the next lymphatic segment. This fills the subsequent segment, and a few seconds later it, too, contracts,
the process continuing all along the lymph vessel until the
fluid is finally emptied into the blood circulation. In a very
large lymph vessel such as the thoracic duct, this lymphatic
pump can generate pressures as great as 50 to 100 mm Hg.
Pumping Caused by External Intermittent Com­
pression of the Lymphatics. In addition to the pumping
caused by intrinsic intermittent contraction of the lymph
vessel walls, any external factor that intermittently compresses the lymph vessel also can cause pumping. In order
of their importance, such factors are as follows:
Contraction of surrounding skeletal muscles
Movement of the parts of the body
Pulsations of arteries adjacent to the lymphatics
Compression of the tissues by objects outside the body
The lymphatic pump becomes very active during
exercise, often increasing lymph flow 10- to 30-fold.
Conversely, during periods of rest, lymph flow is sluggish,
almost zero.
Lymphatic Capillary Pump. The terminal lymphatic
capillary is also capable of pumping lymph, in addition to the
pumping by the larger lymph vessels. As explained earlier
in the chapter, the walls of the lymphatic capillaries are
tightly adherent to the surrounding tissue cells by means
of their anchoring filaments. Therefore, each time excess
fluid enters the tissue and causes the tissue to swell, the
anchoring filaments pull on the wall of the lymphatic capillary and fluid flows into the terminal lymphatic capillary through the junctions between the endothelial cells.
Then, when the tissue is compressed, the pressure inside
the capillary increases and causes the overlapping edges
of the endothelial cells to close like valves. Therefore, the
pressure pushes the lymph forward into the collecting lymphatic instead of backward through the cell junctions.
The lymphatic capillary endothelial cells also contain
a few contractile actomyosin filaments. In some animal
tissues (e.g., the bat’s wing) these filaments have been
observed to cause rhythmical contraction of the lymphatic capillaries in the same way that many of the small
blood and larger lymphatic vessels also contract rhythmically. Therefore, it is probable that at least part of lymph
Figure 16-10 Structure of lymphatic capillaries and a collecting lymphatic, showing also the lymphatic valves.
Chapter 16 The Microcirculation and Lymphatic System: Capillary Fluid Exchange, Interstitial Fluid, and Lymph Flow
pumping results from lymph capillary endothelial cell
contraction in addition to contraction of the larger muscular lymphatics.
two primary factors that determine lymph flow are (1) the
interstitial fluid pressure and (2) the activity of the lymphatic pump. Therefore, one can state that, roughly, the
rate of lymph flow is determined by the product of interstitial fluid pressure times the activity of the lymphatic
Role of the Lymphatic System in Controlling
Interstitial Fluid Protein Concentration,
Interstitial Fluid Volume, and Interstitial Fluid
It is already clear that the lymphatic system functions
as an “overflow mechanism” to return to the circulation
excess proteins and excess fluid volume from the tissue
spaces. Therefore, the lymphatic system also plays a central role in controlling (1) the concentration of proteins in
the interstitial fluids, (2) the volume of interstitial fluid,
and (3) the interstitial fluid pressure. Let us explain how
these factors interact.
First, remember that small amounts of proteins leak
continuously out of the blood capillaries into the interstitium. Only minute amounts, if any, of the leaked proteins
return to the circulation by way of the venous 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 interstitial fluids.
Second, the increasing colloid osmotic pressure in the
interstitial fluid shifts the balance of forces at the blood
capillary membranes in favor of fluid filtration into the
interstitium. Therefore, in effect, fluid is translocated
osmotically outward through the capillary wall by the
proteins and into the interstitium, thus increasing both
interstitial fluid volume and interstitial fluid pressure.
Third, the increasing interstitial fluid pressure greatly
increases the rate of lymph flow, as explained previously.
This in turn carries away the excess interstitial fluid volume and excess protein that has accumulated in the
Thus, once the interstitial fluid protein concentration
reaches a certain level and causes a comparable increase
in interstitial fluid volume and interstitial fluid pressure, the return of protein and fluid by way of the lymphatic system becomes great enough to balance exactly
Significance of Negative Interstitial Fluid Pressure as
a Means for Holding the Body Tissues Together
Traditionally, it has been assumed that the different tissues of the body are held together entirely by connective
tissue fibers. However, at many places in the body, connective tissue fibers are very weak or even absent. This
occurs particularly at points where tissues slide over one
another, such as the skin sliding over the back of the hand
or over the face. Yet even at these places, the tissues are
held together by the negative interstitial fluid pressure,
which is actually a partial vacuum. When the tissues lose
their negative pressure, fluid accumulates in the spaces
and the condition known as edema occurs. This is discussed in Chapter 25.
Dejana E: Endothelial cell-cell junctions: happy together, Nat Rev Mol Cell
Biol 5:261, 2004.
Gashev AA: Physiologic aspects of lymphatic contractile function: current
perspectives, Ann N Y Acad Sci 979:178, 2002.
Gratton JP, Bernatchez P, Sessa WC: Caveolae and caveolins in the cardiovascular system, Circ Res 94:1408, 2004.
Guyton AC: Concept of negative interstitial pressure based on pressures in
implanted perforated capsules, Circ Res 12:399, 1963.
Guyton AC: Interstitial fluid pressure: II. Pressure-volume curves of interstitial space, Circ Res 16:452, 1965.
Guyton AC, Granger HJ, Taylor AE: Interstitial fluid pressure, Physiol Rev
51:527, 1971.
Michel CC, Curry FE: Microvascular permeability, Physiol Rev 79:703, 1999.
Mehta D, Malik AB: Signaling mechanisms regulating endothelial permeability, Physiol Rev 86:279, 2006.
Miyasaka M, Tanaka T: Lymphocyte trafficking across high endothelial
venules: dogmas and enigmas, Nat Rev Immunol 4:360, 2004.
Parker JC: Hydraulic conductance of lung endothelial phenotypes and
Starling safety factors against edema, Am J Physiol Lung Cell Mol Physiol
292:L378, 2007.
Parker JC, Townsley MI: Physiological determinants of the pulmonary filtration coefficient, Am J Physiol Lung Cell Mol Physiol 295:L235, 2008.
Predescu SA, Predescu DN, Malik AB: Molecular determinants of endothelial transcytosis and their role in endothelial permeability, Am J Physiol
Lung Cell Mol Physiol 293:L823, 2007.
Oliver G: Lymphatic vasculature development, Nat Rev Immunol 4:35,
Taylor AE, Granger DN: Exchange of macromolecules across the microcirculation. In Renkin EM, Michel CC, editors: Handbook of Physiology,
Sec 2, vol IV, Bethesda, MD, 1984, American Physiological Society,
pp 467.
Unit IV
Summary of Factors That Determine Lymph
Flow. From the previous discussion, one can see that the
the rate of leakage of these into the interstitium from the
blood capillaries. Therefore, the quantitative values of all
these factors reach a steady state; they will remain balanced at these steady state levels until something changes
the rate of leakage of proteins and fluid from the blood
This page intentionally left blank
chapter 17
Local Control of
Blood Flow in
Response to Tissue
One of the most fundamental principles of circulatory function is the ability of each
tissue to control its own local blood flow in proportion to
its metabolic needs.
What are some of the specific needs of the tissues for
blood flow? The answer to this is manyfold, including the
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 temperature. Also,
delivery of adequate quantities of blood plasma to the kidneys allows the kidneys to excrete the waste products of the
body and to regulate body fluid volumes and electrolytes.
We shall see that these factors exert extreme degrees
of local blood flow control and that different tissues place
different levels of importance on these factors in controlling blood flow.
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 ml/
min per 100 g 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 function 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 percent of the total body mass. In the resting state, the
metabolic 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 question: 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 activity 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 regulated 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. By controlling
local blood flow in such an exact way, the tissues almost
never suffer from oxygen nutritional deficiency and the
workload on the heart is kept at a minimum.
Mechanisms of Blood Flow Control
Local blood flow control can be divided into two phases:
(1) acute control and (2) long-term control.
Acute control is achieved by rapid changes in local
vasodilation or vasoconstriction of the arterioles, metarterioles, and precapillary sphincters, occurring within
seconds to minutes to provide very rapid maintenance of
appropriate local tissue blood flow.
Long-term control, however, means slow, controlled
changes in flow over a period of days, weeks, or even
Unit IV
Local and Humoral Control of
Tissue Blood Flow
Unit IV The Circulation
Table 17-1 Blood Flow to Different Organs and Tissues Under
Basal Conditions
of Cardiac
ml/min/100 g
of Tissue
Muscle (inactive
Skin (cool
Thyroid gland
Adrenal glands
Other tissues
months. In general, these long-term changes provide
even better control of the flow in proportion to the needs
of the tissues. These changes come about as a result of
an increase or decrease in the physical sizes and numbers of actual blood vessels supplying the tissues.
Acute Control of Local Blood Flow
Effect of Tissue Metabolism on Local Blood Flow.
Figure 17-1 shows the approximate acute effect on blood
flow of increasing the rate of metabolism in a local tissue,
such as in a skeletal muscle. Note that an increase in
metabolism up to eight times normal increases the blood
flow acutely about fourfold.
Acute Local Blood Flow Regulation When Oxygen
Availability Changes. One of the most necessary of the
metabolic nutrients is oxygen. Whenever the availability
of oxygen to the tissues decreases, such as (1) at high altitude at the top of a high mountain, (2) in pneumonia, (3)
in carbon monoxide poisoning (which poisons the 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 tissues increases
markedly. Figure 17-2 shows that as the arterial oxygen
saturation decreases to about 25 percent of normal, the
blood flow through an isolated leg increases about threefold; that is, the blood flow increases almost enough, but
not quite enough, to make up for the decreased amount of
oxygen in the blood, thus almost maintaining a relatively
constant supply of oxygen to the tissues.
Total cyanide poisoning of oxygen usage by a local tissue area can cause local blood flow to increase as much
as sevenfold, thus demonstrating the extreme effect of
oxygen deficiency to increase blood flow.
There are two basic theories for the regulation of local
blood flow when either the rate of tissue metabolism
changes or the availability of oxygen changes. They are (1)
the vasodilator theory and (2) the oxygen lack theory.
Vasodilator Theory for Acute Local Blood Flow
Regulation—Possible Special Role of Adenosine.
According to this theory, the greater the rate of metabolism or the less the availability of oxygen or some other
nutrients to a tissue, the greater the rate of formation of
vasodilator substances in the tissue cells. The vasodilator
substances then are believed to diffuse through the tissues to the precapillary sphincters, metarterioles, and
arterioles to cause dilation. Some of the different vasodilator substances that have been suggested are adenosine,
Blood flow (x normal)
Blood flow (x normal)
Normal level
Rate of metabolism (x normal)
Figure 17-1 Effect of increasing rate of metabolism on tissue
blood flow.
Arterial oxygen saturation (percent)
Figure 17-2 Effect of decreasing arterial oxygen saturation on
blood flow through an isolated dog leg.
Chapter 17 Local and Humoral Control of Tissue Blood Flow
Oxygen Lack Theory for Local Blood Flow
Control. Although the vasodilator theory is widely
accepted, several critical facts have made other physiologists favor still another theory, which can be called either
the oxygen lack theory or, more accurately, the nutrient lack theory (because other nutrients besides oxygen are involved). Oxygen (and other nutrients as well)
is required as one of the metabolic nutrients to cause
vascular muscle contraction. Therefore, in the absence
of adequate oxygen, it is reasonable to believe that the
blood vessels simply would relax and therefore naturally
dilate. Also, increased utilization of oxygen in the tissues
as a result of increased metabolism theoretically could
decrease the availability of oxygen to the smooth muscle fibers in the local blood vessels, and this, too, would
cause local vasodilation.
A mechanism by which the oxygen lack theory could
operate is shown in Figure 17-3. This figure shows a tissue
unit, consisting of a metarteriole with a single sidearm capillary and its surrounding tissue. At the origin of the capillary
is a precapillary sphincter, and around the metarteriole are
several other smooth muscle fibers. Observing such a tissue
under a microscope—for example, in a bat’s wing—one sees
that the precapillary sphincters are normally either completely open or completely closed. The number of precapillary sphincters that are open at any given time is roughly
proportional to the requirements of the tissue for nutrition. The precapillary sphincters and metarterioles open
and close cyclically several times per minute, with the duration of the open phases being proportional to the metabolic
needs of the tissues for oxygen. The cyclical opening and
closing is called vasomotion.
Let us explain how oxygen concentration in the local
tissue could regulate blood flow through the area. Because
smooth muscle requires oxygen to remain contracted,
one might assume that the strength of contraction of the
sphincters would increase with an increase in oxygen concentration. Consequently, when the oxygen concentration
in the tissue rises above a certain level, the precapillary
and metarteriole sphincters presumably would close until
the tissue cells consume the excess oxygen. But when the
excess oxygen is gone and the oxygen concentration falls
low enough, the sphincters would open once more to begin
the cycle again.
Thus, on the basis of available data, either a vasodilator
substance theory or an oxygen lack theory could explain
acute local blood flow regulation in response to the metabolic needs of the tissues. Probably the truth lies in a combination of the two mechanisms.
Precapillary sphincter
Sidearm capillary
Figure 17-3 Diagram of a tissue unit area for explanation of acute
local feedback control of blood flow, showing a metarteriole passing through the tissue and a sidearm capillary with its precapillary
sphincter for controlling capillary blood flow.
Unit IV
­carbon dioxide, adenosine phosphate compounds, histamine, potassium ions, and hydrogen ions.
Vasodilator substances may be released from the tissue in response to oxygen deficiency. For instance, experiments have shown that decreased availability of oxygen
can cause both adenosine and lactic acid (containing
hydrogen ions) to be released into the spaces between
the tissue cells; these substances then cause intense
acute vasodilation and therefore are responsible, or partially responsible, for the local blood flow regulation.
Vasodilator substances, such as carbon dioxide, lactic
acid, and potassium ions, tend to increase in the tissues
when blood flow is reduced and cell metabolism continues at the same rate, or when cell metabolism is suddenly
increased. As the concentration of vasodilator metabolites increases, this causes vasodilation of the arterioles,
increasing the tissue blood flow and returning the tissue
concentration of the metabolites toward normal.
Many physiologists believe that adenosine is an important local vasodilator for controlling local blood flow. For
example, minute quantities of adenosine are released from
heart muscle cells when coronary blood flow becomes
too little, and this causes enough local vasodilation in the
heart to return coronary blood flow back to normal. Also,
whenever the heart becomes more active than normal and
the heart’s metabolism increases an extra amount, this,
too, causes increased utilization of oxygen, followed by (1)
decreased oxygen concentration in the heart muscle cells
with (2) consequent degradation of adenosine triphosphate (ATP), which (3) increases the release of adenosine.
It is believed that much of this adenosine leaks out of the
heart muscle cells to cause coronary vasodilation, providing increased coronary blood flow to supply the increased
nutrient demands of the active heart.
Although research evidence is less clear, many physiologists also have suggested that the same adenosine mechanism is an important controller of blood flow in skeletal
muscle and many other tissues, as well as in the heart. It
has been difficult, however, to prove that sufficient quantities of any single vasodilator substance, including adenosine, are indeed formed in the tissues to cause all the
measured increase in blood flow. It is likely that a combination of several different vasodilators released by the tissues contributes to blood flow regulation.
Unit IV The Circulation
has been shown that lack of glucose in the perfusing blood
can cause local tissue vasodilation. Also, it is possible
that this same effect occurs when other nutrients, such
as amino acids or fatty acids, are deficient, although this
has not been studied adequately. In addition, vasodilation
occurs in the vitamin deficiency disease beriberi, in which
the patient has deficiencies of the vitamin B substances
thiamine, niacin, and riboflavin. In this disease, the
peripheral vascular blood flow almost everywhere in
the body often increases twofold to threefold. Because
all these vitamins are necessary for oxygen-induced
phosphorylation, which is required to produce ATP in the
tissue cells, one can well understand how deficiency of
these vitamins might lead to diminished smooth muscle
contractile ability and therefore also local vasodilation.
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 mechanisms”
because all of them function in response to the metabolic
needs of the tissues. Two additional special examples of
metabolic control of local blood flow are reactive hyperemia and active hyperemia.
Reactive Hyperemia. When the blood supply to a tissue is blocked for a few seconds to as long as an hour or
more and then is unblocked, blood flow through the tissue usually increases immediately to four to seven times
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 blood
flow has been stopped for an hour or more. This 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 that
cause vasodilation. After short periods of vascular occlusion, the extra blood flow during the reactive hyperemia
phase lasts long enough to repay almost exactly the tissue oxygen deficit that has accrued during the period of
occlusion. This mechanism emphasizes the close connection between local blood flow regulation and delivery of
oxygen and other nutrients to the tissues.
Active Hyperemia. When any tissue becomes highly
active, such as an exercising muscle, a gastrointestinal gland during a hypersecretory period, or even the
brain during rapid mental activity, the rate of blood flow
through the tissue increases. Here again, by simply applying the basic principles of local blood flow control, one
can easily understand this active hyperemia. The increase
in local metabolism causes the cells to devour tissue
fluid nutrients rapidly and also to release large quantities of vasodilator substances. The result is to dilate the
local blood vessels and, therefore, to increase local blood
flow. In this way, the active tissue receives the additional
nutrients required to sustain its new level of function. As
pointed out earlier, active hyperemia in skeletal muscle
can increase local muscle blood flow as much as 20-fold
during intense exercise.
“Autoregulation” of Blood Flow When the Arterial
Pressure Changes from Normal—“Metabolic” and
“Myogenic” Mechanisms
In any tissue of the body, a rapid increase in arterial pressure causes an immediate rise in blood flow. But, within
less than a minute, the blood flow in most tissues returns
almost to the normal level, even though the arterial pressure is kept elevated. This return of flow toward normal is
called “autoregulation” of blood flow. After autoregulation
has occurred, the local blood flow in most body tissues will
be related to arterial pressure approximately in accord with
the solid “acute” curve in Figure 17-4. Note that between
arterial pressures of about 70 mm Hg and 175 mm Hg the
blood flow increases only 20 to 30 percent even though
the arterial pressure increases 150 percent.
For almost a century, two views have been proposed to
explain this acute autoregulation mechanism. They have
been called (1) the metabolic theory and (2) the myogenic
The metabolic theory can be understood easily by
applying the basic principles of local blood flow regulation discussed in previous sections. Thus, when the arterial pressure becomes too great, the excess flow provides
too much oxygen and too many other nutrients to the tissues and “washes out” the vasodilators released by the tissues. These nutrients (especially oxygen) and decreased
tissue levels of vasodilators then cause the blood vessels to
constrict and the flow to return nearly to normal despite
the increased pressure.
The myogenic theory, however, suggests that still
another mechanism not related to tissue metabolism
explains the phenomenon of autoregulation. This theory
is based on the observation that sudden stretch of small
blood vessels causes the smooth muscle of the vessel wall
Blood flow (x normal)
Possible Role of Other Nutrients Besides Oxygen in
Control of Local Blood Flow. Under special conditions, it
Mean arterial pressure (mm Hg)
Figure 17-4 Effect of different levels of arterial pressure on
blood flow through a muscle. The solid red curve shows the effect
if the arterial pressure is raised over a period of a few minutes.
The dashed green curve shows the effect if the arterial pressure is
raised slowly over a period of many weeks.
Chapter 17 Local and Humoral Control of Tissue Blood Flow
Special Mechanisms for Acute Blood Flow Control
in Specific Tissues
Although the general mechanisms for local blood flow
control discussed thus far are present in almost all tissues
of the body, distinctly different mechanisms operate in a
few special areas. All mechanisms are discussed throughout this text in relation to specific organs, but two notable
ones are as follows:
1. In the kidneys, blood flow control is vested to a
great extent in a mechanism called tubuloglomerular feedback, in which the composition of the fluid
in the early distal tubule is detected by an epithelial
structure of the distal tubule itself called the macula densa. This is located where the distal tubule
lies adjacent to the afferent and efferent arterioles
at the nephron juxtaglomerular apparatus. When
too much fluid filters from the blood through the
glomerulus into the tubular system, feedback signals from the macula densa cause constriction of the
afferent arterioles, in this way reducing both renal
blood flow and glomerular filtration rate back to or
near to normal. The details of this mechanism are
discussed in Chapter 26.
2. In the brain, in addition to control of blood flow by tissue oxygen concentration, the concentrations of carbon dioxide and hydrogen ions play prominent roles.
An increase of either or both of these dilates the cerebral vessels and allows rapid washout of the excess carbon dioxide or hydrogen ions from the brain tissues.
This is important because the level of excitability of the
brain itself is highly dependent on exact control of both
carbon dioxide concentration and hydrogen ion concentration. This special mechanism for cerebral blood
flow control is presented in Chapter 61.
3. In the skin, blood flow control is closely linked to
regulation of body temperature. Cutaneous and subcutaneous flow regulates heat loss from the body by
metering the flow of heat from the core to the surface
of the body, where heat is lost to the environment. Skin
blood flow is controlled largely by the central nervous
system through the sympathetic nerves, as discussed
in Chapter 73. Although skin blood flow is only about
3 ml/min/100 g of tissue in cool weather, large changes
from that value can occur as needed. When humans
are exposed to body heating, skin blood flow may
increase manyfold, to as high as 7 to 8 L/min for the
entire body. When body temperature is reduced, skin
blood flow decreases, falling to barely above zero at
very low temperatures. Even with severe vasoconstriction, skin blood flow is usually great enough to meet
the basic metabolic demands of the skin.
Control of Tissue Blood Flow by Endothelial-Derived
Relaxing or Constricting Factors
The endothelial cells lining the blood vessels synthesize
several substances that, when released, can affect the
degree of relaxation or contraction of the arterial wall. For
many of these endothelial-derived relaxing or constrictor factors, the physiological roles are just beginning to be
understood and clinical applications have, in most cases,
not yet been developed.
Nitric Oxide—A Vasodilator Released from Healthy
Endothelial Cells. The most important of the endothelialderived relaxing factors is nitric oxide (NO), a lipophilic
gas that is released from endothelial cells in response to a
variety of chemical and physical stimuli. Nitric oxide synthase (NOS) enzymes in endothelial cells synthesize NO
from arginine and oxygen and by reduction of inorganic
nitrate. After diffusing out of the endothelial cell, NO
has a half-life in the blood of only about 6 seconds and
acts mainly in the local tissues where it is released. NO
activates soluble guanylate cyclases in vascular smooth
muscle cells (Figure 17-5), resulting in conversion of
cyclic guanosine triphosphate (cGTP) to cyclic guanosine
monophosphate (cGMP) and activation of cGMP-dependent protein kinase (PKG), which has several actions that
cause the blood vessels to relax.
When blood flows through the arteries and arterioles,
this causes shear stress on the endothelial cells because
of viscous drag of the blood against the vascular walls.
Unit IV
to contract. Therefore, it has been proposed that when
high arterial pressure stretches the vessel, this in turn
causes reactive vascular constriction that reduces blood
flow nearly back to normal. Conversely, at low pressures, the degree of stretch of the vessel is less, so that the
smooth muscle relaxes, reducing vascular resistance and
helping to return flow toward normal.
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 arterioles
but can also be observed in arteries, venules, veins, and
even lymphatic vessels. Myogenic contraction is initiated
by stretch-induced vascular depolarization, which then
rapidly increases calcium ion entry from the extracellular fluid into the cells, causing them to contract. Changes
in vascular pressure may also open or close other ion
channels that influence vascular contraction. The precise
mechanisms by which changes in pressure cause opening
or closing of vascular ion channels are still uncertain but
likely involve mechanical effects of pressure on extracellular proteins that are tethered to cytoskeleton elements
of the vascular wall or to the ion channels themselves.
The myogenic mechanism appears to be important in
preventing excessive stretch of blood vessel when blood
pressure is increased. However, the role of the myogenic
mechanism in blood flow regulation is unclear because
this pressure-sensing mechanism cannot directly detect
changes in blood flow in the tissue. Indeed, metabolic factors appear to override the myogenic mechanism in circumstances where the metabolic demands of the tissues
are significantly increased, such as during vigorous muscle exercise, which can cause dramatic increases in skeletal muscle blood flow.
Unit IV The Circulation
Shear stress
O2 + L-Arginine
NO + L-Citrulline
Soluble guanylate
Vascular smooth
Figure 17-5 Nitric oxide synthase (eNOS) enzyme in endothelial cells synthesizes nitric oxide (NO) from arginine and oxygen. NO ­activates
soluble guanylate cyclases in vascular smooth muscle cells, resulting in conversion of cyclic guanosine triphosphate (cGTP) to cyclic guanosine monophosphate (cGMP) which ultimately causes the blood vessels to relax.
This stress contorts the endothelial cells in the direction
of flow and causes significant increase in the release of
NO. The NO then relaxes the blood vessels. This is fortunate because the local metabolic mechanisms for controlling tissue blood flow dilate mainly the very small
arteries and arterioles in each tissue. Yet, when blood
flow through a microvascular portion of the circulation
increases, this secondarily stimulates the release of NO
from larger vessels due to increased flow and shear stress
in these vessels. The released NO increases the diameters of the larger upstream blood vessels whenever microvascular blood flow increases downstream. Without such
a response, the effectiveness of local blood flow control
would be decreased because a significant part of the resistance to blood flow is in the upstream small arteries.
NO synthesis and release from endothelial cells are
also stimulated by some vasoconstrictors, such as angiotensin II, which bind to specific receptors on endothelial
cells. The increased NO release protects against excessive
When endothelial cells are damaged by chronic hypertension or atherosclerosis, impaired NO synthesis may contribute to excessive vasoconstriction and worsening of the
hypertension and endothelial damage, which, if untreated,
may eventually cause vascular injury and damage to vulnerable tissues such as the heart, kidneys, and brain.
Even before NO was discovered, clinicians used nitroglycerin, amyl nitrates, and other nitrate derivatives to
treat patients suffering from angina pectoris, severe chest
pain caused by ischemia of the heart muscle. These drugs,
when broken down chemically, release NO and evoke
dilation of blood vessels throughout the body, including
the coronary blood vessels.
Other important applications of NO physiology and
pharmacology are the development and clinical use of
drugs (e.g., sildenafil) that inhibit cGMP specific phosphodiesterase-5 (PDE-5), an enzyme that degrades cGMP. By
preventing the degradation of cGMP the PDE-5 inhibi196
tors effectively prolong the actions of NO to cause vasodilation. The primary clinical use of the PDE-5 inhibitors
is to treat erectile dysfunction. Penile erection is caused
by parasympathetic nerve impulses through the pelvic
nerves to the penis, where the neurotransmitters acetylcholine and NO are released. By preventing the degradation of NO, the PDE-5 inhibitors enhance the dilation of
the blood vessels in the penis and aid in erection, as discussed in Chapter 80.
Endothelin—A Powerful Vasoconstrictor Released
from Damaged Endothelium. Endothelial cells also
release vasoconstrictor substances. The most important of these is endothelin, a large 21 amino acid peptide
that requires only nanogram quantities to cause powerful vasoconstriction. This substance is present in the
endothelial cells of all or most blood vessels but greatly
increases when the vessels are injured. The usual stimulus for release is damage to the endothelium, such as that
caused by crushing the tissues or injecting a traumatizing
chemical into the blood vessel. After severe blood vessel
damage, release of local endothelin and subsequent vasoconstriction helps to prevent extensive bleeding from
arteries as large as 5 millimeters in diameter that might
have been torn open by crushing injury.
Increased endothelin release is also believed to contribute to vasoconstriction when the endothelium is damaged
by hypertension. Drugs that block endothelin receptors
have been used to treat pulmonary hypertension but have
not generally been used for lowering blood pressure in
patients with systemic arterial hypertension.
Long-Term Blood Flow Regulation
Thus far, most of the mechanisms for local blood flow
regulation that we have discussed act within a few seconds to a few minutes after the local tissue conditions
have changed. Yet, even after full activation of these acute
mechanisms, the blood flow usually is adjusted only
about three quarters of the way to the exact additional
Chapter 17 Local and Humoral Control of Tissue Blood Flow
Mechanism of Long-Term Regulation—Change
in “Tissue Vascularity”
The mechanism of long-term local blood flow regulation is principally to change the amount of vascularity of
the tissues. For instance, if the metabolism in a tissue is
increased for a prolonged period, vascularity increases, a
process generally called angiogenesis; if the metabolism is
decreased, vascularity decreases. Figure 17-6 shows the
large increase in the number of capillaries in a rat anterior tibialis muscle that was stimulated electrically to
contract for short periods of time each day for 30 days,
compared with the unstimulated muscle in the other leg
of the animal.
Thus, there is actual physical reconstruction of the
tissue vasculature to meet the needs of the tissues. This
reconstruction occurs rapidly (within days) in young animals. It also occurs rapidly in new growth tissue, such as in
scar tissue and cancerous tissue; however, it occurs much
slower in old, well-established tissues. Therefore, the time
required for long-term regulation to take place may be
only 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 older, so that in
the neonate, the vascularity will adjust to match almost
exactly the needs of the tissue for blood flow, whereas in
Unit IV
requirements of the tissues. For instance, when the arterial pressure suddenly increases from 100 to 150 mm Hg,
the blood flow increases almost instantaneously about
100 percent. Then, within 30 seconds to 2 minutes, the
flow decreases back to about 10 to 15 percent above the
original control value. This illustrates the rapidity of the
acute mechanisms for local blood flow regulation, but
at the same time, it demonstrates that the regulation is
still incomplete because there remains a 10 to 15 percent
excess blood flow.
However, over a period of hours, days, and weeks, a
long-term type of local blood flow regulation develops
in addition to the acute control. This long-term regulation gives far more complete control of blood flow. For
instance, in the aforementioned example, if the arterial pressure remains at 150 mm Hg indefinitely, within
a few weeks the blood flow through the tissues gradually
approaches almost exactly the normal flow level. Figure
17-4 shows by the dashed green curve the extreme effectiveness of this long-term local blood flow regulation.
Note that once the long-term regulation has had time to
occur, long-term changes in arterial pressure between 50
and 250 mm Hg have little effect on the rate of local blood
Long-term regulation of blood flow is especially
important when the metabolic demands of a tissue
change. Thus, if a tissue becomes chronically overactive
and therefore requires increased quantities of oxygen and
other nutrients, the arterioles and capillary vessels usually
increase both in number and size within a few weeks to
match the needs of the tissue—unless the circulatory system has become pathological or too old to respond.
Figure 17-6 Large increase in the number of capillaries (white
dots) in a rat anterior tibialis muscle that was stimulated electrically to contract for short periods of time each day for 30 days
(B), compared with the unstimulated muscle (A).The 30 days of
intermittent electrical stimulation converted the predominantly
fast twitch, glycolytic anterior tibialis muscle to a predominantly
slow twitch, oxidative muscle with increased numbers of capillaries and decreased fiber diameter as shown. (Photo courtesy
Dr. Thomas Adair.)
older tissues, vascularity frequently lags far behind the
needs of the tissues.
Role of Oxygen in Long-Term Regulation. Oxygen is
important not only for acute control of local blood flow
but also for long-term control. One example of this is
increased vascularity in tissues of animals that live at high
altitudes, where the atmospheric oxygen is low. A second
example is that fetal chicks hatched in low oxygen have
up to twice as much tissue blood vessel conductivity as is
normally true. This same effect is also dramatically demonstrated in premature human babies put into oxygen
tents for therapeutic purposes. The excess oxygen causes
almost immediate cessation of new vascular growth in
the retina of the premature baby’s eyes and even causes
degeneration of some of the small vessels that already
have formed. Then when the infant is taken out of the
oxygen tent, there is explosive overgrowth of new vessels
Unit IV The Circulation
to make up for the sudden decrease in available oxygen;
indeed, there is often so much overgrowth that the retinal vessels grow out from the retina into the eye’s vitreous
humor and eventually cause blindness. (This condition is
called retrolental fibroplasia.)
Importance of Vascular Endothelial Growth Factor
in Formation of New Blood Vessels
A dozen or more factors that increase growth of new
blood vessels have been found, almost all of which are
small peptides. Three of those that have been best characterized are vascular endothelial growth factor (VEGF),
fibroblast growth factor, and angiogenin, each of which
has been isolated from tissues that have inadequate
blood supply. Presumably, it is deficiency of tissue oxygen or other nutrients, or both, that leads to formation
of the vascular growth factors (also called “angiogenic
Essentially all the angiogenic factors promote new vessel growth in the same way. They cause new vessels to
sprout from other small vessels. The first step is dissolution
of the basement membrane of the endothelial cells at the
point of sprouting. This is followed by rapid reproduction
of new endothelial cells that stream outward through the
vessel wall in extended cords directed toward the source
of the angiogenic factor. The cells in each cord continue to
divide and rapidly fold over into a tube. Next, the tube connects with another tube budding from another donor vessel (another arteriole or venule) and forms a capillary loop
through which blood begins to flow. If the flow is great
enough, smooth muscle cells eventually invade the wall, so
some of the new vessels eventually grow to be new arterioles or venules or perhaps even larger vessels. Thus, angiogenesis explains the manner in which metabolic factors in
local tissues can cause growth of new vessels.
Certain other substances, such as some steroid hormones, have exactly the opposite effect on small blood
vessels, occasionally even causing dissolution of vascular
cells and disappearance of vessels. Therefore, blood vessels
can also be made to disappear when not needed. Peptides
produced in the tissues can also block the growth of new
blood vessels. For example, angiostatin, a fragment of the
protein plasminogen, is a naturally occurring inhibitor
of angiogenesis. Endostatin is another antiangiogenic
peptide that is derived from the breakdown of collagen type XVII. Although the precise physiological
functions of these antiangiogenic substances are still
unknown, there is great interest in their potential use
in arresting blood vessel growth in cancerous tumors
and therefore preventing the large increases in blood
flow needed to sustain the nutrient supply of rapidly
growing tumors.
Vascularity Is Determined by Maximum Blood
Flow Need, Not by Average Need. An especially valuable characteristic of long-term vascular control is that
vascularity is determined mainly by the maximum
level of blood flow need rather than by average need.
For instance, 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 required for more than a few minutes each day.
Nevertheless, even this short need can cause enough
VEGF to be formed by the muscles to increase their vascularity as required. Were it not for this capability, every
time that a person attempted heavy exercise, the muscles
would fail to receive the required nutrients, especially
the required oxygen, so that the muscles simply would
fail to contract.
However, after extra vascularity does develop, the
extra blood vessels normally remain mainly vasoconstricted, opening to allow extra flow only when appropriate local stimuli such as oxygen lack, nerve vasodilatory
stimuli, or other stimuli call forth the required extra
Development of Collateral Circulation—
a Phenomenon of Long-Term Local Blood
Flow Regulation
When an artery or a vein is blocked in virtually any tissue of the body, a new vascular channel usually develops
around the blockage and allows at least partial resupply of
blood to the affected tissue. The first stage in this process
is dilation of small vascular loops that already connect the
vessel above the blockage to the vessel below. This dilation
occurs within the first minute or two, indicating that the
dilation is likely mediated by metabolic factors that relax
the muscle fibers of the small vessels involved. After this
initial opening of collateral vessels, the blood flow often is
still less than one quarter that is needed to supply all the
tissue needs. However, further opening occurs within the
ensuing hours, so within 1 day as much as half the tissue
needs may be met, and within a few days the blood flow is
usually sufficient to meet the tissue needs.
The collateral vessels continue to grow for many months
thereafter, almost always forming multiple small collateral
channels rather than one single large vessel. Under resting conditions, the blood flow usually returns very near
to normal, but the new channels seldom become large
enough to supply the blood flow needed during strenuous
tissue activity. Thus, the development of collateral vessels
follows the usual principles of both acute and long-term
local blood flow control, the acute control being rapid
metabolic dilation, followed chronically by growth and
enlargement of new vessels over a period of weeks and
The most important example of the development of
collateral blood vessels occurs after thrombosis of one
of the coronary arteries. Almost all people by the age
of 60 years have had at least one of the smaller branch
coronary vessels closed, or at least partially occluded.
Yet most people do not know that this has happened
because collaterals have developed rapidly enough to
prevent myocardial damage. It is in those other instances
in which coronary insufficiency occurs too rapidly or
too severely for collaterals to develop that serious heart
attacks occur.
Chapter 17 Local and Humoral Control of Tissue Blood Flow
Humoral Control of the Circulation
Vasoconstrictor Agents
Norepinephrine and Epinephrine. Norepinephrine
is an especially powerful vasoconstrictor hormone; epinephrine is less so and in some tissues even causes mild
vasodilation. (A special example of vasodilation caused by
epinephrine occurs to dilate the coronary arteries during
increased heart activity.)
When the sympathetic nervous system is stimulated
in most or all parts of the body during stress or exercise,
the sympathetic nerve endings in the individual tissues
release norepinephrine, which excites the heart and contracts the veins and arterioles. In addition, the sympathetic nerves to the adrenal medullae cause these glands
to secrete both norepinephrine and epinephrine into the
blood. These hormones then circulate to all areas of the
body and cause almost the same effects on the circulation as direct sympathetic stimulation, thus providing a
dual system of control: (1) direct nerve stimulation and
(2) indirect effects of norepinephrine and/or epinephrine
in the circulating blood.
Angiotensin II. Angiotensin II is another powerful
vasoconstrictor substance. As little as one millionth of a
gram can increase the arterial pressure of a human being
50 mm Hg or more.
The effect of angiotensin II is to constrict powerfully
the small arterioles. If this occurs in an isolated tissue
area, the blood flow to that area can be severely depressed.
However, the real importance of angiotensin II is that
it normally acts on many of the arterioles of the body
at the same time to increase the total peripheral resistance, thereby increasing the arterial pressure. Thus, this
hormone plays an integral role in the regulation of arterial
pressure, as is discussed in detail in Chapter 19.
Vasopressin. Vasopressin, also called antidiuretic hor-
mone, is even more powerful than angiotensin II as a vasoconstrictor, thus making it one of the body’s most potent
vascular constrictor substances. It is formed in nerve cells
in the hypothalamus of the brain (see Chapters 28 and 75)
but is then transported downward by nerve axons to the
posterior pituitary gland, where it is finally secreted into
the blood.
It is clear that vasopressin could have enormous effects
on circulatory function. Yet normally, only minute amounts
of vasopressin are secreted, so most physiologists have
Vasodilator Agents
Bradykinin. Several substances called kinins cause
powerful vasodilation when formed in the blood and tissue fluids of some organs.
The kinins are small polypeptides that are split away by
proteolytic enzymes from alpha2-globulins in the plasma
or tissue fluids. A proteolytic enzyme of particular importance for this purpose is kallikrein, which is present in the
blood and tissue fluids in an inactive form. This inactive
kallikrein is activated by maceration of the blood, by tissue inflammation, or by other similar chemical or physical
effects on the blood or tissues. As kallikrein becomes activated, it acts immediately on alpha2-globulin to release
a kinin called kallidin that is then converted by tissue
enzymes into bradykinin. Once formed, bradykinin persists for only a few minutes because it is inactivated by the
enzyme carboxypeptidase or by converting enzyme, the
same enzyme that also plays an essential role in activating angiotensin, as discussed in Chapter 19. The activated
kallikrein enzyme is destroyed by a kallikrein inhibitor
also present in the body fluids.
Bradykinin causes both powerful arteriolar dilation
and increased capillary permeability. For instance, injection of 1 microgram of bradykinin into the brachial artery
of a person increases blood flow through the arm as much
as sixfold, and even smaller amounts injected locally into
tissues can cause marked local edema resulting from
increase in capillary pore size.
There is reason to believe that kinins play special roles
in regulating blood flow and capillary leakage of fluids in
inflamed tissues. It also is believed that bradykinin plays a
normal role to help regulate blood flow in the skin, as well
as in the salivary and gastrointestinal glands.
Histamine. Histamine is released in essentially every
tissue of the body if the tissue becomes damaged or
inflamed or is the subject of an allergic reaction. Most of
the histamine is derived from mast cells in the damaged
tissues and from basophils in the blood.
Histamine has a powerful vasodilator effect on the
arterioles and, like bradykinin, has the ability to increase
greatly capillary porosity, allowing leakage of both fluid and
plasma protein into the tissues. In many pathological conditions, the intense arteriolar dilation and increased capillary
porosity produced by histamine cause tremendous quantities of fluid to leak out of the circulation into the ­tissues,
Unit IV
Humoral control of the circulation means control by
substances secreted or absorbed into the body fluids—
such as hormones and locally produced factors. Some of
these substances are formed by special glands and transported in the blood throughout the entire body. Others
are formed in local tissue areas and cause only local circulatory effects. Among the most important of the humoral
factors that affect circulatory function are the following.
thought that vasopressin plays little role in vascular control.
However, experiments have shown that the concentration
of circulating blood vasopressin after severe hemorrhage
can increase enough to raise the arterial pressure as much
as 60 mm Hg. In many instances, this can, by itself, bring
the arterial pressure almost back up to normal.
Vasopressin has a major function to increase greatly
water reabsorption from the renal tubules back into the
blood (discussed in Chapter 28), and therefore to help
control body fluid volume. That is why this hormone is
also called antidiuretic hormone.
Unit IV The Circulation
i­nducing edema. The local vasodilatory and edema-producing effects of histamine are especially prominent during allergic reactions and are discussed in Chapter 34.
Vascular Control by Ions and Other
Chemical Factors
Many different ions and other chemical factors can either
dilate or constrict local blood vessels. Most of them have
little function in overall regulation of the circulation, but
some specific effects are:
1. An increase in calcium ion concentration causes vasoconstriction. This results from the general effect of
calcium to stimulate smooth muscle contraction, as
discussed in Chapter 8.
2. An increase in potassium ion concentration, within the
physiological range, causes vasodilation. This results
from the ability of potassium ions to inhibit smooth
muscle contraction.
3. An increase in magnesium ion concentration causes
powerful vasodilation because magnesium ions inhibit
smooth muscle contraction.
4. An increase in hydrogen ion concentration (decrease in
pH) causes dilation of the arterioles. Conversely, slight
decrease in hydrogen ion concentration causes arteriolar constriction.
5. Anions that have significant effects on blood vessels are
acetate and citrate, both of which cause mild degrees
of vasodilation.
6. An increase in carbon dioxide concentration causes
moderate vasodilation in most tissues but marked vasodilation in the brain. Also, carbon dioxide in the blood,
acting on the brain vasomotor center, has an extremely
powerful indirect effect, transmitted through the sympathetic nervous vasoconstrictor system, to cause
widespread vasoconstriction throughout the body.
Most Vasodilators or Vasoconstrictors Have Little
Effect on Long-Term Blood Flow Unless They Alter
Metabolic Rate of the Tissues. In most cases, tissue blood
flow and cardiac output (the sum of flow to all of the body’s
tissues) are not substantially altered, except for a day or two,
in experimental studies when one chronically infuses large
amounts of powerful vasoconstrictors such as angiotensin
II or vasodilators such as bradykinin. Why is blood flow not
significantly altered in most tissues even in the presence of
very large amounts of these vasoactive agents?
To answer this question we must return to one of the
fundamental principles of circulatory function that we
previously discussed—the ability of each tissue to autoregulate its own blood flow according to the metabolic
needs and other functions of the tissue. Administration
of a powerful vasoconstrictor, such as angiotensin II,
may cause transient decreases in tissue blood flow and
cardiac output but usually has little long-term effect if
it does not alter metabolic rate of the tissues. Likewise,
most vasodilators cause only short-term changes in tissue blood flow and cardiac output if they do not alter
tissue metabolism. Therefore, blood flow is generally
regulated according to the specific needs of the tissues
as long as the arterial pressure is adequate to perfuse the
Adair TH: Growth regulation of the vascular system: an emerging role for
adenosine, Am J Physiol Regul Integr Comp Physiol 289:R283, 2005.
Campbell WB, Falck JR: Arachidonic acid metabolites as endotheliumderived hyperpolarizing factors, Hypertension 49:590, 2007.
Drummond HA, Grifoni SC, Jernigan NL: A new trick for an old dogma:
ENaC proteins as mechanotransducers in vascular smooth muscle,
Physiology (Bethesda) 23:23, 2008.
Dhaun N, Goddard J, Kohan DE, et al: Role of endothelin-1 in clinical hypertension: 20 years on, Hypertension 52:452, 2008.
Ferrara N, Gerber HP, LeCouter J: The biology of VEGF and its receptors, Nat
Med 9:669, 2003.
Folkman J: Angiogenesis, Annu Rev Med 57:1, 2006.
Folkman J: Angiogenesis: an organizing principle for drug discovery? Nat
Rev Drug Discov 6:273, 2007.
Guyton AC, Coleman TG, Granger HJ: Circulation: overall regulation, Annu
Rev Physiol 34:13, 1972.
Hall JE, Brands MW, Henegar JR: Angiotensin II and long-term arterial
pressure regulation: the overriding dominance of the kidney, J Am Soc
Nephrol 10(Suppl 12):S258, 1999.
Heerkens EH, Izzard AS, Heagerty AM: Integrins, vascular remodeling, and
hypertension, Hypertension 49:1, 2007.
Hester RL, Hammer LW: Venular-arteriolar communication in the regulation
of blood flow, Am J Physiol Regul Integr Comp Physiol 282:R1280, 2002.
Hodnett BL, Hester RL: Regulation of muscle blood flow in obesity,
Microcirculation 14:273, 2007.
Horowitz A, Simons M: Branching morphogenesis, Circ Res 103:784, 2008.
Humphrey JD: Mechanisms of arterial remodeling in hypertension: coupled
roles of wall shear and intramural stress, Hypertension 52:195, 2008.
Jain RK, di Tomaso E, Duda DG, et al: Angiogenesis in brain tumours, Nat
Rev Neurosci 8:610, 2007.
Keeley EC, Mehrad B, Strieter RM: Chemokines as mediators of neovascularization, Arterioscler Thromb Vasc Biol 28:1928, 2008.
Renkin EM: Control of microcirculation and blood-tissue exchange. In
Renkin EM, Michel CC (eds.): Handbook of Physiology, Sec 2, vol IV,
Bethesda, 1984, American Physiological Society, pp 627.
Roman RJ: P-450 metabolites of arachidonic acid in the control of cardiovascular function, Physiol Rev 82:131, 2002.
chapter 18
Nervous Regulation
of the Circulation
As discussed in Chapter 17,
adjustment of blood flow in
the tissues and organs of the
body is mainly the function of local tissue control mechanisms. In this chapter we discuss how nervous control of
the circulation has more global functions, such as redistributing blood flow to different areas of the body, increasing
or decreasing pumping activity by the heart, and providing
very rapid control of systemic arterial pressure.
The nervous system controls the circulation almost
entirely through the autonomic 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 discussion, we will consider additional specific
anatomical and functional characteristics, 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,
however, contributes importantly to regulation of heart
function, as described 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 portions 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 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 are innervated.
Precapillary sphincters and metarterioles are innervated
in some tissues, such as the mesenteric blood vessels,
although their sympathetic innervation is usually not as
dense as in the small arteries, arterioles, and veins.
The innervation of the small arteries and arterioles
allows sympathetic stimulation 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 possible 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 explain later in this and subsequent chapters.
Sympathetic Nerve Fibers to the Heart. Sympathetic
fibers also go directly to the heart, as shown in Figure 18-1
and as 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 and volume of pumping.
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 gastrointestinal actions, it plays only a minor role in
regulation of vascular function in most tissues. Its most
important circulatory effect is to control heart rate by way
of parasympathetic nerve fibers to the heart in the vagus
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. Principally,
parasympathetic stimulation causes a marked decrease
in heart rate and a slight decrease in heart muscle
Sympathetic Vasoconstrictor System and Its
Control by the Central Nervous System
The sympathetic nerves carry tremendous numbers of
vasoconstrictor nerve fibers and only a few vasodilator fibers.
The vasoconstrictor fibers are distributed to ­essentially all
Unit IV
Nervous Regulation of the Circulation,
and Rapid Control of Arterial Pressure
Unit IV The Circulation
Vasomotor center
Sympathetic chain
Figure 18-1 Anatomy of sympathetic nervous control of the circulation. Also shown by the dashed red line, a vagus nerve that carries parasympathetic signals to the heart.
segments of the circulation, but more to some tissues than
others. This sympathetic vasoconstrictor effect is especially
powerful in the kidneys, intestines, spleen, and skin but
much less potent in skeletal muscle and the brain.
Figure 18-2 Sympathetic innervation of the systemic circulation.
Vasomotor Center in the Brain and Its Control
of the Vasoconstrictor System. Located bilaterally
mainly in the reticular substance of the medulla and of
the lower third of the pons is an area called the vasomotor center, shown in Figures 18-1 and 18-3. This
center transmits parasympathetic impulses through
the vagus nerves to the heart and transmits sympathetic impulses through the spinal cord and peripheral
sympathetic nerves to virtually all arteries, arterioles,
and veins of the body.
Although the total organization of the vasomotor
center is still unclear, experiments have made it possible to identify certain important areas in this center, as
1. A vasoconstrictor area located bilaterally in the anterolateral portions of the upper medulla. The neurons
originating in this area distribute their fibers to all levels of the spinal cord, where they excite preganglionic
vasoconstrictor neurons of the sympathetic nervous
Chapter 18 Nervous Regulation of the Circulation, and Rapid Control of Arterial Pressure
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 receive sensory nerve signals from the circulatory system mainly
through the vagus and glossopharyngeal nerves,
and output signals from this sensory area then help
to control activities of both the vasoconstrictor and
vasodilator areas of the vasomotor center, thus providing “reflex” control of many circulatory functions.
An example is the baroreceptor reflex for controlling arterial pressure, which we describe later in this
Continuous Partial Constriction of the Blood Vessels
Is Normally 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 entire body, causing slow firing of these fibers at
a rate of about one half to two impulses per second. This
continual firing is called sympathetic vasoconstrictor
tone. These impulses normally maintain a partial state of
contraction in the blood vessels, called vasomotor tone.
Figure 18-4 demonstrates the significance of vasoconstrictor 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 amount of the hormone norepinephrine was injected into the blood (norepinephrine is the principal vasoconstrictor hormonal substance
secreted at the endings of the sympathetic vasoconstrictor nerve fibers throughout the body). As this injected
hormone was transported in the blood to blood vessels,
the vessels once again became constricted and the arterial pressure rose to a level even greater than normal for 1
to 3 minutes, until the norepinephrine was destroyed.
Control of Heart Activity by the Vasomotor
Center. At the same time that the vasomotor center regulates the amount of vascular constriction, it
also controls heart activity. The lateral portions of
the vasomotor center transmit excitatory impulses
through the sympathetic nerve fibers to the heart
when there is need to increase heart rate and contractility. Conversely, when there is need to decrease heart
pumping, the medial portion of the vasomotor center sends signals to the adjacent dorsal motor nuclei of
the vagus nerves, which then transmit parasympathetic
impulses through the vagus nerves to the heart to
decrease heart rate and heart contractility. Therefore,
the vasomotor center can either increase or decrease
heart activity. Heart rate and strength of heart contraction ordinarily increase when vasoconstriction
occurs and ordinarily decrease when vasoconstriction
is inhibited.
Control of the Vasomotor Center by Higher Nervous
Centers. Large numbers of small neurons located
throughout the reticular substance of the pons, mesencephalon, and diencephalon can either excite or inhibit
the vasomotor center. This reticular substance is shown
in Figure 18-3 by the rose-colored area. In general, the
neurons in the more lateral and superior portions of the
reticular substance cause excitation, whereas the more
medial and inferior portions cause inhibition.
The hypothalamus plays a special role in controlling
the vasoconstrictor system because it can exert either
powerful excitatory or inhibitory effects on the vasomotor center. The posterolateral portions of the hypothalamus cause mainly excitation, whereas the anterior
portion can cause either mild excitation or inhibition,
depending on the precise part of the anterior hypothalamus stimulated.
Many parts of the cerebral cortex can also excite or
inhibit the vasomotor center. Stimulation of the motor
cortex, for instance, excites the vasomotor center because
of impulses transmitted downward into the hypothalamus and then to the vasomotor center. Also, stimulation of the anterior temporal lobe, the orbital areas of the
frontal cortex, the anterior part of the cingulate gyrus, the
amygdala, the septum, and the hippocampus can all either
excite or inhibit the vasomotor center, depending on the
precise portions of these areas that are stimulated and on
the intensity of stimulus. Thus, widespread basal areas
of the brain can have profound effects on cardiovascular
Medulla {
Figure 18-3 Areas of the brain that play important roles in the
nervous regulation of the circulation. The dashed lines represent
inhibitory pathways.
Unit IV
2. A vasodilator area located bilaterally in the anterolateral portions of the lower half of the medulla.
The fibers from these neurons project upward to
the vasoconstrictor area just described; they inhibit
the vasoconstrictor activity of this area, thus causing
Unit IV The Circulation
Arterial pressure (mm Hg)
Total spinal
Injection of norepinephrine
Figure 18-4 Effect of total spinal anesthesia on the arterial pressure, showing marked decrease in pressure resulting from loss of
“vasomotor tone.”
Norepinephrine—The Sympathetic Vasoconstrictor
Transmitter Substance. The substance secreted at the
endings of the vasoconstrictor nerves is almost entirely
norepinephrine, which acts directly on the alpha adrenergic receptors of the vascular smooth muscle to cause vasoconstriction, as discussed in Chapter 60.
Adrenal Medullae and Their Relation to the
Sympathetic Vasoconstrictor System. Sympathetic
impulses are transmitted to the adrenal medullae at
the same time that they are transmitted to the blood
vessels. They cause the medullae to secrete both epinephrine and norepinephrine into the circulating blood.
These two hormones are carried in the blood stream
to all parts of the body, where they act directly on all
blood vessels, usually to cause vasoconstriction. In a
few tissues epinephrine causes vasodilation because it
also has a “beta” adrenergic receptor stimulatory effect,
which dilates rather than constricts certain vessels, as
discussed in Chapter 60.
Sympathetic Vasodilator System and Its Control by the
Central Nervous System. The sympathetic nerves to skeletal
muscles carry sympathetic vasodilator fibers, as well as constrictor fibers. In some animals such as the cat, these dilator
fibers release acetylcholine, not norepinephrine, at their endings, although in primates, the vasodilator effect is believed
to be caused by epinephrine exciting specific beta-adrenergic
receptors in the muscle vasculature.
The pathway for central nervous system control of the
vasodilator system is shown by the dashed lines in Figure
18-3. The principal area of the brain controlling this system
is the anterior hypothalamus.
Possible Unimportance of the Sympathetic Vasodilator
System. It is doubtful that the sympathetic vasodilator
system plays a major role in the control of the circulation
in the human being because complete block of the sympathetic 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 that at the onset
of exercise, the sympathetic vasodilator system might cause
initial vasodilation in skeletal muscles to allow anticipatory increase in blood flow even before the muscles require
increased nutrients.
Emotional Fainting—Vasovagal Syncope. A particularly interesting vasodilatory reaction occurs in people who
experience intense emotional disturbances that cause fainting. In this case, the muscle vasodilator system becomes activated, and at the same time, the vagal cardioinhibitory 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 causes the person to lose consciousness. This overall effect is called vasovagal syncope.
Emotional fainting begins with disturbing thoughts in the
cerebral cortex. The pathway probably then goes to the vasodilatory center of the anterior hypothalamus next to the vagal
centers of the medulla, to the heart through the vagus nerves,
and also through the spinal cord to the sympathetic vasodilator nerves of the muscles.
Role of the Nervous System in Rapid
Control of Arterial Pressure
One of the most important functions of nervous control of the circulation is its capability to cause rapid
increases in arterial pressure. For this purpose, the
entire vasoconstrictor and cardioaccelerator functions of the sympathetic nervous system are stimulated
together. At the same time, there is reciprocal inhibition of parasympathetic vagal inhibitory signals to the
heart. Thus, three major changes occur simultaneously,
each of which helps to increase arterial pressure. They
are as follows:
Chapter 18 Nervous Regulation of the Circulation, and Rapid Control of Arterial Pressure
Rapidity of Nervous Control of Arterial Pressure.
An especially important characteristic of nervous control of arterial pressure is its rapidity of response, beginning within seconds and often increasing the pressure
to two times normal within 5 to 10 seconds. Conversely,
sudden inhibition of nervous cardiovascular stimulation
can decrease the arterial pressure to as little as one-half
normal within 10 to 40 seconds. Therefore, nervous control of arterial pressure is by far the most rapid of all our
mechanisms for pressure control.
Increase in Arterial Pressure During Muscle
Exercise and Other Types of Stress
An important example of the ability of the nervous system
to increase the arterial pressure is the increase in pressure
that occurs during muscle exercise. During heavy exercise,
the muscles require greatly increased blood flow. Part of
this increase results from local vasodilation of the muscle
vasculature caused by increased metabolism of the muscle cells, as explained in Chapter 17. Additional increase
results from simultaneous elevation of arterial pressure
caused by sympathetic stimulation of the overall circulation during exercise. In most heavy exercise, the ­arterial
pressure rises about 30 to 40 percent, which increases
blood flow almost an additional twofold.
The increase in arterial pressure during exercise results
mainly from the following effect: At the same time that the
motor areas of the brain become activated to cause exercise, most of the reticular activating system of the brain
stem is also activated, which includes greatly increased
stimulation of the vasoconstrictor and cardioacceleratory
areas of the vasomotor center. These increase the arterial
pressure instantaneously to keep pace with the increase
in muscle activity.
In many other types of stress besides muscle exercise,
a similar rise in pressure can also occur. For instance, during extreme fright, the arterial pressure sometimes rises
by as much as 75 to 100 mm Hg within a few seconds. This
is called the alarm reaction, and it provides an excess of
arterial pressure that can immediately supply blood to the
muscles of the body that might need to respond instantly
to cause flight from danger.
Reflex Mechanisms for Maintaining Normal
Arterial Pressure
Aside from the exercise and stress functions of the autonomic nervous system to increase arterial pressure, there
are multiple subconscious special nervous control mechanisms that operate all the time to maintain the arterial
pressure at or near normal. Almost all of these are negative feedback reflex mechanisms, which we explain in the
following sections.
Baroreceptor Arterial Pressure Control System—
Baroreceptor Reflexes
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, 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 then sent back through the autonomic nervous system to the circulation to reduce arterial
pressure downward toward the normal level.
Physiologic Anatomy of the Baroreceptors and Their
Innervation. Baroreceptors are spray-type nerve endings that lie in the walls of the arteries; they are stimulated when stretched. A few baroreceptors are located in
the wall of almost every large artery of the thoracic and
neck regions; but, as shown in Figure 18-5, baroreceptors are extremely abundant in (1) the wall of each internal carotid artery slightly above the carotid bifurcation,
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 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.
Response of the Baroreceptors to Arterial
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 progressively more rapidly and reach a
Unit IV
1. Most arterioles of the systemic circulation are constricted. This greatly increases the total peripheral
resistance, thereby increasing the arterial pressure.
2. The veins especially (but the other large vessels of the
circulation as well) are strongly constricted. This displaces blood out of the large peripheral blood vessels toward the heart, thus increasing the volume of
blood in the heart chambers. The stretch of the heart
then causes the heart to beat with far greater force and
therefore to pump increased quantities of blood. This,
too, increases the arterial pressure.
3. Finally, the heart itself is directly stimulated by the
autonomic nervous system, further enhancing cardiac pumping. Much of this is caused by an increase
in the heart rate, the rate sometimes increasing to
as great as three times normal. In addition, sympathetic nervous signals have a significant direct effect
to increase contractile force of the heart muscle, this,
too, increasing the capability of the heart to pump
larger volumes of blood. During strong sympathetic
stimulation, the heart can pump about two times
as much blood as under normal conditions. This
contributes still more to the acute rise in arterial
Unit IV The Circulation
Hering’s nerve
Carotid body
Carotid sinus
Vagus nerve
Aortic baroreceptors
Figure 18-5 The baroreceptor system for controlling arterial
Number of impulses from carotid
sinus nerves per second
maximum at about 180 mm Hg. The responses of the
aortic baroreceptors are similar to those of the carotid
receptors except that they operate, in general, at arterial
pressure levels about 30 mm Hg higher.
Note especially that in the normal operating range of
arterial pressure, around 100 mm Hg, even a slight change
in pressure causes a strong change in the baroreflex signal
to readjust arterial pressure back toward normal. Thus,
the baroreceptor feedback mechanism functions most
effectively in the pressure range where it is most needed.
DI = maximum
Arterial pressure (mm Hg)
Glossopharyngeal nerve
The baroreceptors respond rapidly to changes in arterial pressure; in fact, the rate of impulse firing increases in
the fraction of a second during each systole and decreases
again during diastole. Furthermore, the baroreceptors
respond much more to a rapidly changing pressure than to
a stationary pressure. That is, if the mean arterial pressure
is 150 mm Hg but at that moment is rising rapidly, the
rate of impulse transmission may be as much as twice that
when the pressure is stationary at 150 mm Hg.
Circulatory Reflex Initiated by the Baroreceptors.
After the baroreceptor signals have entered the tractus
solitarius of the medulla, secondary signals inhibit the
vasoconstrictor center of the medulla and excite the vagal
parasympathetic center. The net effects are (1) vasodilation
of the veins and arterioles throughout the peripheral circulatory system and (2) decreased heart rate and strength
of heart contraction. Therefore, excitation of the baroreceptors by high pressure in the arteries reflexly causes the
arterial pressure to decrease because of both a decrease
in peripheral resistance and a decrease in cardiac output.
Conversely, low pressure has opposite effects, reflexly causing the pressure to rise back toward normal.
Figure 18-7 shows a typical reflex change in arterial pressure caused by occluding the two common
carotid arteries. This reduces the carotid sinus pressure;
as a result, signals from the baroreceptors decrease and
cause less inhibitory effect on the vasomotor center. The
vasomotor center then becomes much more active than
usual, causing the aortic arterial pressure to rise and
remain elevated during the 10 minutes that the carotids
are occluded. Removal of the occlusion allows the pressure in the carotid sinuses to rise, and the carotid sinus
reflex now causes the aortic pressure to fall immediately
to slightly below normal as a momentary overcompensation and then return to normal in another minute.
Function of the Baroreceptors During Changes in
Body Posture. The ability of the baroreceptors to maintain relatively constant arterial pressure in the upper body
Arterial blood pressure (mm Hg)
Figure 18-6 Activation of the baroreceptors at different levels of
arterial pressure. ∆I, change in carotid sinus nerve impulses per
second; ∆P, change in arterial blood pressure in mm Hg.
Both common
carotids clamped
Carotids released
Figure 18-7 Typical carotid sinus reflex effect on aortic arterial
pressure caused by clamping both common carotids (after the two
vagus nerves have been cut).
Chapter 18 Nervous Regulation of the Circulation, and Rapid Control of Arterial Pressure
Arterial pressure (mm Hg)
Time (min)
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 had been denervated. (Redrawn from Cowley AW Jr,
Liard JF, 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 Association, Inc.)
Percentage of occurrence
Unit IV
is important when a person stands up after having been
lying down. Immediately on standing, the arterial pressure in the head and upper part of the body tends to fall,
and marked reduction of this pressure could cause loss of
consciousness. However, the falling pressure at the baroreceptors elicits an immediate reflex, resulting in strong sympathetic discharge throughout the body. This minimizes
the decrease in pressure in the head and upper body.
Pressure “Buffer” Function of the Baroreceptor
Control System. Because the baroreceptor system
opposes either increases or decreases in arterial pressure,
it is called a pressure buffer system and the nerves from the
baroreceptors are called buffer nerves.
Figure 18-8 shows the importance of this buffer function of the baroreceptors. The upper record in this figure
shows an arterial pressure recording for 2 hours from a
normal dog, and the lower record shows an arterial pressure recording from a dog whose baroreceptor nerves from
both the carotid sinuses and the aorta had been removed.
Note the extreme variability of pressure in the denervated
dog caused by simple events of the day, such as lying down,
standing, excitement, 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 normally the mean
Mean arterial pressure (mm Hg)
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 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
Association, Inc.)
arterial pressure remained throughout the day within
a narrow range between 85 and 115 mm Hg—indeed,
during most of the day at almost exactly 100 mm Hg.
Conversely, after denervation of the baroreceptors, the
frequency distribution curve became the broad, low curve
of the figure, showing that the pressure range increased
2.5-fold, frequently falling to as low as 50 mm Hg or rising
to over 160 mm Hg. Thus, one can see the extreme variability of pressure in the absence of the arterial baroreceptor system.
In summary, a primary purpose of the arterial baroreceptor system is to reduce the minute-byminute variation in arterial pressure to about one-third
that which would occur if the baroreceptor system was
not present.
Are the Baroreceptors Important in Long-Term
Regulation of Arterial Pressure? Although the arterial
baroreceptors provide powerful moment-to-moment
control of arterial pressure, their importance in long-term
blood pressure regulation has been controversial. One reason that the baroreceptors have been considered by some
physiologists to be relatively unimportant in chronic regulation of arterial pressure chronically is that they tend
to reset in 1 to 2 days to the pressure level to which they
are exposed. That is, if the arterial pressure rises from the
normal value of 100 mm Hg to 160 mm Hg, a very high
rate of baroreceptor impulses are at first transmitted.
During the next few minutes, the rate of firing diminishes
considerably; then it diminishes much more slowly during
the next 1 to 2 days, at the end of which time the rate of
firing will have returned to nearly normal despite the fact
that the mean arterial pressure still remains at 160 mm
Hg. Conversely, when the arterial pressure falls to a very
low level, the baroreceptors at first transmit no impulses,
Unit IV The Circulation
but gradually, over 1 to 2 days, the rate of baroreceptor firing returns toward the control level.
This “resetting” of the baroreceptors may attenuate their
potency as a control system for correcting disturbances
that tend to change arterial pressure for longer than a few
days at a time. Experimental studies, however, have suggested that the baroreceptors do not completely reset and
may therefore contribute to long-term blood pressure regulation, especially by influencing sympathetic nerve activity of the kidneys. For example, with prolonged increases
in arterial pressure, the baroreceptor reflexes may mediate
decreases in renal sympathetic nerve activity that promote
increased excretion of sodium and water by the kidneys.
This, in turn, causes a gradual decrease in blood volume,
which helps to restore arterial pressure toward normal.
Thus, long-term regulation of mean arterial pressure by
the baroreceptors requires interaction with additional systems, principally the renal–body fluid–pressure control
system (along with its associated nervous and hormonal
mechanisms), discussed in Chapters 19 and 29.
Control of Arterial Pressure by the Carotid and Aortic
Chemoreceptors—Effect of Oxygen Lack on Arterial
Pressure. Closely associated with the baroreceptor pressure control system is a chemoreceptor reflex that operates
in much the same way as the baroreceptor reflex except
that chemoreceptors, instead of stretch receptors, initiate
the response.
The chemoreceptors are chemosensitive cells sensitive
to oxygen lack, carbon dioxide excess, and hydrogen ion
excess. They are located in several small chemoreceptor
organs about 2 millimeters in size (two carotid bodies, one
of which lies in the bifurcation of each common carotid
artery, and usually one to three aortic bodies adjacent to
the aorta). The chemoreceptors excite nerve fibers that,
along with the baroreceptor fibers, pass through Hering’s
nerves and the vagus nerves into the vasomotor center of
the brain stem.
Each carotid or aortic body is supplied with an abundant blood flow through a small nutrient artery, so the
chemoreceptors are always in close contact with arterial
blood. Whenever the arterial pressure falls below a critical level, the chemoreceptors become stimulated because
diminished blood flow causes decreased oxygen, as well
as excess buildup of carbon dioxide and hydrogen ions
that are not removed by the slowly flowing blood.
The signals transmitted from the chemoreceptors
excite the vasomotor center, and this elevates the arterial
pressure back toward normal. However, this chemoreceptor reflex is not a powerful arterial pressure controller until
the arterial pressure falls below 80 mm Hg. Therefore, it is
at the lower pressures that this reflex becomes important
to help prevent further decreases in arterial pressure.
The chemoreceptors are discussed in much more
detail in Chapter 41 in relation to respiratory control, in
which they play a far more important role than in blood
pressure control.
Atrial and Pulmonary Artery Reflexes Regulate Arterial Pressure. Both the atria and the pulmonary arteries
have in their walls stretch receptors called low-pressure
receptors. They are similar to the baroreceptor stretch
receptors of the large systemic arteries. These low-pressure receptors play an important role, especially in minimizing arterial pressure changes in response to changes
in blood volume. For example, if 300 milliliters of blood
suddenly are infused into a dog with all receptors intact,
the arterial pressure rises only about 15 mm Hg. With the
arterial baroreceptors denervated, the pressure rises about
40 mm Hg. If the low-pressure receptors also are denervated, the arterial pressure rises about 100 mm Hg.
Thus, one can see that even though the low-pressure
receptors in the pulmonary artery and in the atria cannot detect the systemic arterial pressure, they do detect
simultaneous increases in pressure in the low-pressure
areas of the circulation caused by increase in volume, and
they elicit reflexes parallel to the baroreceptor reflexes to
make the total reflex system more potent for control of
arterial pressure.
Atrial Reflexes That Activate the Kidneys—The
“Volume Reflex.” Stretch of the atria also causes significant reflex dilation of the afferent arterioles in the kidneys. Signals are also transmitted simultaneously from
the atria to the hypothalamus to decrease secretion of
antidiuretic hormone (ADH). The decreased afferent
arteriolar resistance in the kidneys causes the glomerular capillary pressure to rise, with resultant increase in
filtration of fluid into the kidney tubules. The diminution of ADH diminishes the reabsorption of water from
the tubules. Combination of these two effects—increase
in glomerular filtration and decrease in reabsorption of
the fluid—increases fluid loss by the kidneys and reduces
an increased blood volume back toward normal. (We
will also see in Chapter 19 that atrial stretch caused by
increased blood volume also elicits a hormonal effect on
the kidneys—release of atrial natriuretic peptide—that
adds still further to the excretion of fluid in the urine and
return of blood volume toward normal.)
All these mechanisms that tend to return the blood
volume back toward normal after a volume overload act
indirectly as pressure controllers, as well as blood volume controllers, because excess volume drives the heart
to greater cardiac output and leads, therefore, to greater
arterial pressure. This volume reflex mechanism is discussed again in Chapter 29, along with other mechanisms
of blood volume control.
Atrial Reflex Control of Heart Rate (the Bainbridge
Reflex). An increase in atrial pressure also causes
an increase in heart rate, sometimes increasing the
heart rate as much as 75 percent. A small part of this
increase is caused by a direct effect of the increased
atrial volume to stretch the sinus node; it was pointed
out in Chapter 10 that such direct stretch can increase
the heart rate as much as 15 percent. An additional
40 to 60 percent increase in rate is caused by a nervous reflex called the Bainbridge reflex. The stretch
receptors of the atria that elicit the Bainbridge reflex
transmit their afferent signals through the vagus
Chapter 18 Nervous Regulation of the Circulation, and Rapid Control of Arterial Pressure
Central Nervous System Ischemic Response—
Control of Arterial Pressure by the Brain’s
Vasomotor Center in Response to Diminished
Brain Blood Flow
Most nervous control of blood pressure is achieved by
reflexes that originate in the baroreceptors, the chemoreceptors, and the low-pressure receptors, all of which are
located in the peripheral circulation outside the brain.
However, when blood flow to the vasomotor center in
the lower brain stem becomes decreased severely enough
to cause nutritional deficiency—that is, to cause cerebral
ischemia—the vasoconstrictor and cardioaccelerator neurons in the vasomotor center respond directly to the ischemia and become strongly excited. When this occurs, the
systemic arterial pressure often rises to a level as high as
the heart can possibly pump. This effect is believed to be
caused by failure of the slowly flowing blood to carry carbon dioxide away from the brain stem vasomotor center:
At low levels of blood flow to the vasomotor center, the
local concentration of carbon dioxide increases greatly
and has an extremely potent effect in stimulating the sympathetic vasomotor nervous control areas in the brain’s
It is possible that other factors, such as buildup of lactic
acid and other acidic substances in the vasomotor center,
also contribute to the marked stimulation and elevation
in arterial pressure. This arterial pressure elevation in
response to cerebral ischemia is known as the central nervous system (CNS) ischemic response.
The ischemic effect on vasomotor activity can elevate
the mean arterial pressure dramatically, sometimes to as
high as 250 mm Hg for as long as 10 minutes. The degree
of sympathetic vasoconstriction caused by intense cerebral
ischemia is often so great that some of the peripheral vessels become totally or almost totally occluded. The kidneys,
for instance, often entirely cease their production of urine
because of renal arteriolar constriction in response to
the sympathetic discharge. Therefore, the CNS is­chemic
response is one of the most powerful of all the activators of
the sympathetic vasoconstrictor system.
Importance of the CNS Ischemic Response as a
Regulator of Arterial Pressure. Despite the powerful nature of the CNS ischemic response, it does not
become significant until the arterial pressure falls far
below normal, down to 60 mm Hg and below, reaching
its greatest degree of stimulation at a pressure of 15 to
20 mm Hg. Therefore, it is not one of the normal mechanisms for regulating arterial pressure. Instead, it operates principally as an emergency pressure control system
that acts rapidly and very powerfully to prevent further
decrease in arterial pressure whenever blood flow to the
brain decreases dangerously close to the lethal level. It is
sometimes called the “last ditch stand” pressure control
Cushing Reaction to Increased Pressure Around
the Brain. The so-called Cushing reaction is a spe-
cial type of CNS ischemic response that results from
increased pressure of the cerebrospinal fluid around
the brain in the cranial vault. For instance, when the
cerebrospinal fluid pressure rises to equal the arterial
pressure, it compresses the whole brain, as well as the
arteries in the brain, and cuts off the blood supply to
the brain. This initiates a CNS ischemic response that
causes the arterial pressure to rise. When the arterial
pressure has risen to a level higher than the cerebrospinal fluid pressure, blood will flow once again into
the vessels of the brain to relieve the brain ischemia.
Ordinarily, the blood pressure comes to a new equilibrium level slightly higher than the cerebrospinal fluid
pressure, thus allowing blood to begin again to flow
through the brain. The Cushing reaction helps protect
the vital centers of the brain from loss of nutrition if
ever the cerebrospinal fluid pressure rises high enough
to compress the cerebral arteries.
Special Features of Nervous Control
of Arterial Pressure
Role of the Skeletal Nerves and Skeletal Muscles
in Increasing Cardiac Output and Arterial
Although most rapidly acting nervous control of the circulation is effected through the autonomic nervous system, at least two conditions in which the skeletal nerves
and muscles also play major roles in circulatory responses
are the following.
Abdominal Compression Reflex. When a baroreceptor or chemoreceptor reflex is elicited, nerve signals are transmitted simultaneously through skeletal
nerves to skeletal muscles of the body, particularly to the
abdominal muscles. This compresses all the venous reservoirs of the abdomen, helping to translocate blood out
of the abdominal vascular reservoirs toward the heart.
As a result, increased quantities of blood are made available for the heart to pump. This overall response is called
the abdominal compression reflex. The resulting effect
on the circulation is the same as that caused by sympathetic vasoconstrictor impulses when they constrict the
veins: an increase in both cardiac output and arterial
pressure. The abdominal compression reflex is probably
much more important than has been realized in the past
because it is well known that people whose skeletal muscles have been paralyzed are considerably more prone to
hypotensive episodes than are people with normal skeletal muscles.
Unit IV
nerves to the medulla of the brain. Then efferent
signals are transmitted back through vagal and sympathetic nerves to increase heart rate and strength of heart
contraction. Thus, this reflex helps prevent damming of
blood in the veins, atria, and pulmonary circulation.
Increased Cardiac Output and Arterial Pressure
Caused by Skeletal Muscle Contraction During
Exercise. When the skeletal muscles contract during
Pressure (mm Hg)
Unit IV The Circulation
exercise, they compress blood vessels throughout the body.
Even anticipation of exercise tightens the muscles, thereby
compressing the vessels in the muscles and in the abdomen. The resulting effect is to translocate blood from the
peripheral 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 cardiac output that sometimes occurs in heavy exercise. The
increase in cardiac output in turn is an essential 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.
Figure 18-10 A, Vasomotor waves caused by oscillation of the
CNS ischemic response. B, Vasomotor waves caused by baroreceptor reflex oscillation.
Respiratory Waves in the Arterial Pressure
Oscillation of the Baroreceptor and Chemoreceptor
Reflexes. The vasomotor waves of Figure 18-10B are
With each cycle of respiration, the arterial pressure usually rises and falls 4 to 6 mm Hg in a wavelike manner,
causing respiratory waves in the arterial pressure. The
waves result from several different effects, some of which
are reflex in nature, as follows:
1. Many of the “breathing signals” that arise in the 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. This reduces
the quantity of blood returning to the left side of the
heart and thereby momentarily decreases the cardiac
output and arterial pressure.
3. The pressure changes caused in the thoracic vessels
by respiration can excite vascular and atrial stretch
Although it is difficult to analyze the exact relations of
all these factors in causing the respiratory pressure waves,
the net result during normal respiration is usually an
increase in arterial pressure during the early part of expiration and a decrease in pressure during the remainder of
the respiratory cycle. During deep respiration, the blood
pressure can rise and fall as much as 20 mm Hg with each
respiratory cycle.
Arterial Pressure “Vasomotor” Waves—Oscillation
of Pressure Reflex Control Systems
Often while recording arterial pressure from an animal,
in addition to the small pressure waves caused by respiration, some much larger waves are also noted—as great as
10 to 40 mm Hg at times—that rise and fall more slowly
than the respiratory waves. The duration of each cycle
varies from 26 seconds in the anesthetized dog to 7 to 10
seconds in the unanesthetized human. These waves are
called vasomotor waves or “Mayer waves.” Such records
are demonstrated in Figure 18-10, showing the cyclical
rise and fall in arterial pressure.
The cause of vasomotor waves is “reflex oscillation” of
one or more nervous pressure control mechanisms, some
of which are the following.
often seen in experimental pressure recordings, although
usually much less intense than shown in the figure. They
are caused mainly by oscillation of the baroreceptor reflex.
That is, a high pressure excites the baroreceptors; this
then inhibits the sympathetic nervous system and lowers
the pressure a few seconds later. The decreased pressure
in turn reduces the baroreceptor stimulation and allows
the vasomotor center to become active once again, elevating the pressure to a high value. The response is not
instantaneous, and it is delayed until a few seconds later.
This high pressure then initiates another cycle, and the
oscillation continues on and on.
The chemoreceptor reflex can also oscillate to give the
same type of waves. This reflex usually oscillates simultaneously with the baroreceptor reflex. It probably plays
the major role in causing vasomotor waves when the arterial pressure is in the range of 40 to 80 mm Hg because
in this low range, chemoreceptor control of the circulation becomes powerful, whereas baroreceptor control
becomes weaker.
Oscillation of the CNS Ischemic Response. The
record in Figure 18-10A resulted from oscillation of
the CNS ischemic pressure control mechanism. In this
experiment, the cerebrospinal fluid pressure was raised
to 160 mm Hg, which compressed the cerebral vessels
and initiated a CNS ischemic pressure response up to
200 mm Hg. When the arterial pressure rose to such a
high value, the brain ischemia was relieved and the sympathetic nervous system became inactive. As a result, the
arterial pressure fell rapidly back to a much lower value,
causing brain ischemia once again. The ischemia then
initiated another rise in pressure. Again the ischemia
was relieved and again the pressure fell. This repeated
itself cyclically as long as the cerebrospinal fluid pressure
remained elevated.
Thus, any reflex pressure control mechanism can oscillate if the intensity of “feedback” is strong enough and if
there is a delay between excitation of the pressure receptor and the subsequent pressure response. The vasomotor
Chapter 18 Nervous Regulation of the Circulation, and Rapid Control of Arterial Pressure
Cao WH, Fan W, Morrison SF: Medullary pathways mediating specific
sympathetic responses to activation of dorsomedial hypothalamus,
Neuroscience 126:229, 2004.
Cowley AW Jr: Long-term control of arterial blood pressure, Physiol Rev
72:231, 1992.
DiBona GF: Physiology in perspective: the wisdom of the body. Neural control of the kidney, Am J Physiol Regul Integr Comp Physiol 289:R633,
Esler M, Lambert G, Brunner-La Rocca HP, et al: Sympathetic nerve activity
and neurotransmitter release in humans: translation from pathophysiology into clinical practice, Acta Physiol Scand 177:275, 2003.
Freeman R: Clinical practice. Neurogenic orthostatic hypotension, N Engl J
Med 358:615, 2008.
Goldstein DS, Robertson D, Esler M, et al: Dysautonomias: clinical disorders
of the autonomic nervous system, Ann Intern Med 137:753, 2002.
Guyton AC: Arterial pressure and hypertension, Philadelphia, 1980, WB
Guyenet PG: The sympathetic control of blood pressure, Nat Rev Neurosci
7:335, 2006.
Joyner MJ: Baroreceptor function during exercise: resetting the record, Exp
Physiol 91:27, 2006.
Lohmeier TE, Dwyer TM, Irwin ED, et al: Prolonged activation of the baroreflex abolishes obesity-induced hypertension, Hypertension 49:1307,
Lohmeier TE, Hildebrandt DA, Warren S, et al: Recent insights into the interactions between the baroreflex and the kidneys in hypertension, Am J
Physiol Regul Integr Comp Physiol 288:R828, 2005.
Ketch T, Biaggioni I, Robertson R, Robertson D: Four faces of baroreflex failure: hypertensive crisis, volatile hypertension, orthostatic tachycardia,
and malignant vagotonia, Circulation 105:2518, 2002.
Mifflin SW: What does the brain know about blood pressure? News Physiol
Sci 16:266, 2001.
Olshansky B, Sabbah HN, Hauptman PJ, et al: Parasympathetic nervous
system and heart failure: pathophysiology and potential implications
for therapy, Circulation 118:863, 2008.
Schultz HD, Li YL, Ding Y: Arterial chemoreceptors and sympathetic nerve
activity: implications for hypertension and heart failure, Hypertension
50:6, 2007.
Zucker IH: Novel mechanisms of sympathetic regulation in chronic heart
failure, Hypertension 48:1005, 2006.
Unit IV
waves are of considerable theoretical importance because
they show that the nervous reflexes that control arterial
pressure obey the same principles as those applicable to
mechanical and electrical control systems. For instance, if
the feedback “gain” is too great in the guiding mechanism
of an automatic pilot for an airplane and there is also delay
in response time of the guiding mechanism, the plane will
oscillate from side to side instead of following a straight
This page intentionally left blank
chapter 19
Short-term control of arterial pressure by the sympathetic nervous system, as
discussed in Chapter 18,
occurs primarily through
the effects of the nervous
system on total peripheral
vascular resistance and capacitance, as well as on cardiac
pumping ability.
The body, however, also has powerful mechanisms 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 balanced, 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 acts slowly but powerfully as follows: If blood volume increases and vascular capacitance is not altered,
arterial pressure will also increase. The rising pressure in
turn causes the kidneys to excrete the excess volume, 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 and blood 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 less fluid than
is ingested. Therefore, because the hagfish continues to
drink, extracellular fluid volume, blood volume, and pressure all build up again to the higher levels.
Throughout the ages, this primitive mechanism of
pressure control has survived almost as it functions in the
hagfish; in the humans, 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 mm Hg can double renal output of
water, which is called pressure diuresis, as well as double
the output of salt, which is called pressure natriuresis.
In the human being, the renal–body fluid system for
arterial pressure control, just as in the hagfish, is a fundamental mechanism for long-term arterial pressure control. However, through the stages of evolution, multiple
refinements have been added to make this system much
more exact in its control in the human being. An especially important refinement, as discussed later, has been
the addition of the renin-angiotensin mechanism.
Quantitation of Pressure Diuresis as a Basis
for Arterial Pressure Control
Figure 19-1 shows the approximate average effect of different arterial pressure levels on urinary volume output
by an isolated kidney, demonstrating markedly increased
urine volume output as the pressure rises. This increased
urinary output is the phenomenon of pressure diuresis. The
curve in this figure is called a renal urinary output curve or
a renal function curve. In the human being, at an arterial
pressure of 50 mm Hg, the urine output is essentially zero.
At 100 mm Hg it is normal, and at 200 mm Hg it is about six
to eight times normal. Furthermore, not only does increasing the arterial pressure increase urine volume output, but
it causes approximately equal increase in sodium output,
which is the phenomenon of pressure natriuresis.
An Experiment Demonstrating the Renal–Body
Fluid System for Arterial Pressure Control. Figure
19-2 shows the results of an experiment in dogs in which
all the nervous reflex mechanisms for blood pressure
control were first blocked. Then the arterial pressure
was suddenly elevated by infusing about 400 ml of blood
intravenously. Note the rapid increase in cardiac output
Unit IV
Role of the Kidneys in Long-Term Control of
Arterial Pressure and in Hypertension: The
Integrated System for Arterial Pressure Regulation
Intake or output (x normal)
Urinary volume output (x normal)
Unit IV The Circulation
20 40 60 80 100 120 140 160 180 200
Arterial pressure (mm Hg)
Figure 19-1 Typical renal urinary output curve measured in a perfused isolated kidney, showing pressure diuresis when the arterial
pressure rises above normal.
Cardiac output
Renal output of
water and salt
Equilibrium point
Urinary output
Arterial pressure
(mm Hg)
Arterial pressure (mm Hg)
Figure 19-3 Analysis of arterial pressure regulation by equating
the “renal output curve” with the “salt and water intake curve.” The
equilibrium point describes the level to which the arterial pressure
will be regulated. (That small portion of the salt and water intake
that is lost from the body through nonrenal routes is ignored in
this and similar figures in this chapter.)
can be used for analyzing arterial pressure control by the
renal–body fluid system. This analysis is based on two
separate curves that intersect each other: (1) the renal
output curve for water and salt in response to rising
arterial pressure, which is the same renal output curve as
that shown in Figure 19-1, and (2) the line that represents
the net water and salt intake.
Water and
salt intake
Infusion period
0 10 20 30 40 50 60
Time (minutes)
Figure 19-2 Increases in cardiac output, urinary output, and arterial pressure caused by increased blood volume in dogs whose nervous pressure control mechanisms had been blocked. This figure
shows return of arterial pressure to normal after about an hour of
fluid loss into the urine. (Courtesy Dr. William Dobbs.)
to about double normal and increase in mean arterial
pressure to 205 mm Hg, 115 mm Hg above its resting level.
Shown by the middle curve is the effect of this increased
arterial pressure on urine output, which increased 12-fold.
Along with this tremendous loss of fluid in the urine, both
the cardiac output and the arterial pressure returned to
normal during the subsequent hour. Thus, one sees an
extreme capability of the kidneys to eliminate fluid volume
from the body in response to high arterial pressure and in
so doing to return the arterial pressure back to normal.
Arterial Pressure Control by the Renal–Body
Fluid Mechanism—“Near Infinite Feedback Gain”
Feature. Figure 19-3 shows a graphical method that
Over a long period, the water and salt output must
equal the intake. Furthermore, the only place on the graph
in Figure 19-3 at which output equals intake is where the
two curves intersect, which is called the equilibrium
point. Now, let us see what happens if the arterial pressure increases above, or decreases below, the equilibrium
First, assume that the arterial pressure rises to 150 mm Hg.
At this level, the renal output of water and salt is about
three times as great as the intake. Therefore, the body
loses fluid, the blood volume decreases, and the arterial
pressure decreases. Furthermore, this “negative balance”
of fluid will not cease until the pressure falls all the way
back exactly to the equilibrium level. Indeed, even when
the arterial pressure is only 1 mm Hg greater than the
equilibrium level, there still is slightly more loss of water
and salt than intake, so the pressure continues to fall that
last 1 mm Hg until the pressure eventually returns exactly
to the equilibrium point.
If the arterial pressure falls below the equilibrium
point, the intake of water and salt is greater than the output. Therefore, body fluid volume increases, blood volume
increases, and the arterial pressure rises until once again
it returns exactly to the equilibrium point. This return of
the arterial pressure always back to the equilibrium point
is the near infinite feedback gain principle for control of
arterial pressure by the renal–body fluid mechanism.
Two Determinants of the Long-Term Arterial
Pressure Level. In Figure 19-3, one can also see that two
basic long-term factors determine the long-term arterial
pressure level. This can be explained as follows.
Chapter 19 Role of the Kidneys in Long-Term Control of Arterial Pressure and in Hypertension
1. The degree of pressure shift of the renal output curve
for water and salt
2. The level of the water and salt intake
Operation of these two determinants in the control of
arterial pressure is demonstrated in Figure 19-4. In Figure
19-4A, some abnormality of the kidneys has caused the
renal output curve to shift 50 mm Hg in the high-pressure direction (to the right). Note that the equilibrium
point has also shifted to 50 mm Hg higher than normal.
Therefore, one can state that if the renal output curve
shifts to a new pressure level, the arterial pressure will
­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 160 mm Hg,
60 mm Hg above the normal level. Conversely, a decrease
in the intake level would reduce the arterial pressure.
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 arterial pressure—either (1) the level of salt and water 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 thereafter to be regulated
at a new pressure level, the arterial pressure at which the
two new curves intersect.
The Chronic Renal Output Curve Is Much Steeper
than the Acute Curve. An important characteristic of
pressure natriuresis (and pressure diuresis) is that chronic
changes in arterial pressure, lasting for days or months,
have much greater effect on renal output of salt and water
than observed during acute changes in pressure (Figure
19-5). Thus, when the kidneys are functioning normally,
the chronic renal output curve is much steeper than the
acute curve.
The powerful effects of chronic increases in arterial
pressure on urine output are because increased pressure
not only has direct hemodynamic effects on the kidney to
increase excretion, but also indirect effects mediated by
nervous and hormonal changes that occur when blood
pressure is increased. For example, increased arterial
pressure decreases activity of the sympathetic nervous
system and various hormones such as angiotensin II and
aldosterone that tend to reduce salt and water excretion
by the kidneys. Reduced activity of these antinatriuretic
systems therefore amplifies the effectiveness of pressure
natriuresis and diuresis in raising salt and water excretion during chronic increases in arterial ­pressure (see
Chapters 27 and 29 for further discussion).
High intake
Normal intake
Arterial pressure (mm Hg)
Intake or output (x normal)
Intake or output (x normal)
Arterial pressure (mm Hg)
Figure 19-4 Two ways in which the arterial pressure can be
increased: A, by shifting the renal output curve in the right-hand
direction toward a higher pressure level or B, by increasing the
intake level of salt and water.
Figure 19-5 Acute and chronic renal output curves. Under steadystate conditions renal output of salt and water is equal to intake
of salt and water. A and B represent the equilibrium points for
long-term regulation of arterial pressure when salt intake is normal or six times normal, respectively. Because of the steepness of
the chronic renal output curve, increased salt intake causes only
small changes in arterial pressure. In persons with impaired kidney
function, the steepness of the renal output curve may be reduced,
similar to the acute curve, resulting in increased sensitivity of
­arterial pressure to changes in salt intake.
Unit IV
As long as the two curves representing (1) renal output
of salt and water and (2) intake of salt and water remain
exactly as they are shown in Figure 19-3, the mean arterial
pressure level will eventually readjust to 100 mm Hg, which
is the pressure level depicted by the equilibrium point of
this figure. Furthermore, there are only two ways in which
the pressure of this equilibrium point can be changed
from the 100 mm Hg level. One of these is by shifting the
pressure level of the renal output curve for salt and water,
and the other is by changing the level of the water and salt
intake line. Therefore, expressed simply, the two primary
determinants of the long-term arterial pressure level are
as follows:
Unit IV The Circulation
Failure of Increased Total Peripheral 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
she really understands the renal–body fluid mechanism
for arterial pressure control. Recalling the basic equation
for arterial pressure—arterial pressure equals cardiac output times total peripheral resistance—it is clear that an
increase in total peripheral resistance should elevate the
arterial pressure. Indeed, when the total peripheral resistance is acutely increased, the arterial pressure does rise
Arterial pressure
Removal of four limbs
Pulmonary disease
Paget's disease
AV shunts
immediately. Yet if the kidneys continue to function normally, the acute rise in arterial pressure usually is not
maintained. Instead, the arterial pressure returns all the
way to normal within a day or so. Why?
The answer to this is the following: Increasing resistance in the blood vessels everywhere else in the body
besides in the kidneys does not change the equilibrium
point for blood pressure control as dictated by the kidneys (see again Figures 19-3 and 19-4). Instead, the kidneys immediately begin to respond to the high arterial
pressure, causing pressure diuresis and pressure natriuresis. Within hours, large amounts of salt and water are lost
from the body, and this continues until the arterial pressure returns to the pressure level of the equilibrium point.
At this point blood pressure is normalized and extracellular fluid volume and blood volume are decreased to levels
below normal.
As proof of this principle that changes in total peripheral resistance do not affect the long-term level of arterial
pressure if function of the kidneys is still normal, carefully
study Figure 19-6. This figure shows the approximate cardiac outputs and the arterial pressures in different clinical conditions in which the long-term total peripheral
resistance is either much less than or much greater than
normal, but kidney excretion of salt and water is normal.
Note in all these different clinical conditions that the arterial pressure is also exactly normal.
A word of caution is necessary at this point in our discussion. Many times when the total peripheral resistance
increases, this also increases the intrarenal vascular resistance at the same time, which alters the function of the
kidney and can cause hypertension by shifting the renal
Arterial pressure and cardiac output
(percent of normal)
Conversely, when blood pressure is reduced, the sympathetic nervous system is activated and formation of
antinatriuretic hormones is increased, adding to the
direct effects of reduced pressure to decrease renal output of salt and water. This combination of direct effects
of pressure on the kidneys and indirect effects of pressure
on the sympathetic nervous system and various hormone
systems make pressure natriuresis and diuresis extremely
powerful for long-term control of arterial pressure and
body fluid volumes.
The importance of neural and hormonal influences on
pressure natriuresis is especially evident during chronic
changes in sodium intake. If the kidneys and the nervous
and hormonal mechanisms are functioning normally,
chronic increases in intakes of salt and water to as high
as six times normal are usually associated with only small
increases in arterial pressure. Note that the blood pressure equilibrium point B on the curve is nearly the same
as point A, the equilibrium point at normal salt intake.
Conversely, decreases in salt and water intake to as low
as one-sixth normal typically have little effect on arterial
pressure. Thus, many persons are said to be salt insensitive because large variations in salt intake do not change
blood pressure more than a few mm Hg.
Individuals with kidney injury or excessive secretion of
antinatriuretic hormones such as angiotensin II or aldosterone, however, may be salt sensitive with an attenuated
renal output curve similar to the acute curve shown in
Figure 19-5. In these cases, even moderate increases in salt
intake may cause significant increases in arterial pressure.
Some of the factors include loss of functional nephrons
due to kidney injury, or excessive formation of antinatriuretic hormones such as angiotensin II or aldosterone. For
example, surgical reduction of kidney mass or injury to
the kidney due to hypertension, diabetes, and various kidney diseases all cause blood pressure to be more sensitive
to changes in salt intake. In these instances, greater than
normal increases in arterial pressure are required to raise
renal output sufficiently to maintain a balance between
the intake and output of salt and water.
There is some evidence that long-term high salt intake,
lasting for several years, may actually damage the kidneys and eventually make blood pressure more salt sensitive. We will discuss salt sensitivity of blood pressure in
patients with hypertension later in this chapter.
100 120 140
Total peripheral resistance
(percent of normal)
Figure 19-6 Relations of total peripheral resistance to the longterm levels of arterial pressure and cardiac output in different clinical abnormalities. In these conditions, the kidneys were
functioning normally. Note that changing the whole-body total
peripheral resistance caused equal and opposite changes in cardiac
output but in all cases had no effect on arterial pressure. (Redrawn
from Guyton AC: Arterial Pressure and Hypertension. Philadelphia:
WB Saunders, 1980.)
Chapter 19 Role of the Kidneys in Long-Term Control of Arterial Pressure and in Hypertension
Increased Fluid Volume Can Elevate Arterial
Pressure by Increasing Cardiac Output or Total
Peripheral Resistance
The overall mechanism by which increased extracellular
fluid volume may elevate arterial pressure, if vascular capacity is not simultaneously increased, is shown in Figure 19-7.
The sequential events are (1) increased extracellular fluid
volume (2) increases the blood volume, which (3) increases
the mean circulatory filling pressure, which (4) increases
venous return of blood to the heart, which (5) increases
cardiac output, which (6) increases arterial pressure. The
increased arterial pressure, in turn, increases real excretion
of salt and water and may return extracellular fluid volume
to nearly normal if kidney function is normal.
Note especially in this schema the two ways in which
an increase in cardiac output can increase the arterial
pressure. One of these is the direct effect of increased cardiac output to increase the pressure, and the other is an
indirect effect to raise total peripheral vascular resistance
Increased extracellular fluid volume
Increased blood volume
Increased mean circulatory filling pressure
Increased venous return of blood to the heart
Increased cardiac output
Increased total
peripheral resistance
Increased arterial pressure
Increased urine output
Figure 19-7 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 pressure and an indirect effect by first increasing the total
peripheral resistance.
through autoregulation of blood flow. The second effect
can be explained as follows.
Referring to Chapter 17, let us recall that whenever an
excess amount of blood flows through a tissue, the local
tissue vasculature constricts and decreases the blood flow
back toward normal. This phenomenon is called “autoregulation,” which means simply regulation of blood flow by
the tissue itself. When increased blood volume increases
the cardiac output, the blood flow increases in all tissues
of the body, so this autoregulation mechanism constricts
blood vessels all over the body. This in turn increases the
total peripheral resistance.
Finally, because arterial pressure is equal to cardiac
output times total peripheral resistance, the secondary increase in total peripheral resistance that results
from the autoregulation mechanism helps greatly in
increasing the arterial pressure. For instance, only a
5 to 10 percent increase in cardiac output can increase
the ­arterial ­pressure from the normal mean arterial pressure of 100 mm Hg up to 150 mm Hg. In fact, the slight
increase in cardiac output is often not measurable.
Importance of Salt (NaCl) in the Renal–Body Fluid
Schema for Arterial Pressure Regulation
Although the discussions thus far have emphasized the
importance of volume in regulation of arterial pressure,
experimental studies have shown that an increase in salt
intake is far more likely to elevate the arterial 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 is not excreted so easily.
As salt accumulates in the body, it also indirectly increases
the extracellular fluid volume for two basic reasons:
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, making the person
drink extra amounts of water to return the extracellular salt concentration to normal. This increases the
extracellular fluid volume.
2. The increase in osmolality caused by the excess
salt in the extracellular fluid also stimulates the
­hypothalamic-posterior pituitary gland secretory
mechanism to secrete increased quantities of antidiuretic hormone. (This is discussed in Chapter 28.) The
antidiuretic hormone then causes the kidneys to reabsorb greatly increased quantities of water from the renal
tubular fluid, thereby diminishing the excreted volume
of urine but increasing the extracellular fluid volume.
Thus, for these important reasons, the amount of
salt 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 if the vascular
capacity is not simultaneously increased, accumulation of
even a small amount of extra salt in the body can lead to
considerable elevation of arterial pressure.
Unit IV
function curve to a higher pressure level, in the manner
shown in Figure 19-4A. We see an example of this later
in this chapter when we discuss hypertension caused
by vasoconstrictor mechanisms. But it is the increase in
renal resistance that is the culprit, not the increased total
peripheral resistance—an important distinction.
Unit IV The Circulation
As discussed previously, raising salt intake in the
absence of impaired kidney function or excessive formation of antinatriuretic hormones usually does not
increase arterial pressure much because the kidneys rapidly eliminate the excess salt and blood volume is hardly
the brain is involved, a stroke can cause paralysis,
dementia, blindness, or multiple other serious brain
3. High pressure almost always causes injury in the kidneys, producing many areas of renal destruction and,
eventually, kidney failure, uremia, and death.
Chronic Hypertension (High Blood Pressure)
Is Caused by Impaired Renal Fluid Excretion
Lessons learned from the type of hypertension called
“volume-loading hypertension” have been crucial in
understanding the role of the renal–body fluid volume
mechanism for arterial pressure regulation. Volumeloading hypertension means hypertension caused by
excess accumulation of extracellular fluid in the body,
some examples of which follow.
When a person is said to have chronic hypertension (or
“high blood pressure”), it is meant that his or her mean
arterial pressure is greater than the upper range of the
accepted normal measure. A mean arterial pressure
greater than 110 mm Hg (normal is about 90 mm Hg) is
considered to be hypertensive. (This level of mean pressure occurs when the diastolic blood pressure is greater
than about 90 mm Hg and the systolic pressure is greater
than about 135 mm Hg.) In severe hypertension, the mean
arterial pressure can rise to 150 to 170 mm Hg, with diastolic pressure as high as 130 mm Hg and systolic pressure
occasionally as high as 250 mm Hg.
Even moderate elevation of arterial pressure leads to
shortened life expectancy. At severely high pressures—
mean arterial pressures 50 percent or more above normal—a person can expect to live no more than a few more
years unless appropriately treated. The lethal effects of
hypertension are caused mainly in three ways:
Experimental Volume-Loading
Caused by Reduced Renal Mass Along with Simul­
taneous Increase in Salt Intake. Figure 19-8 shows
a typical experiment demonstrating volume-loading
hypertension in a group of dogs with 70 percent 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, the entire opposite kidney
was removed, leaving the animals with only 30 percent of
normal renal mass. Note that removal of this amount of
kidney mass increased the arterial pressure an average of
only 6 mm Hg. Then, the dogs were given salt solution to
drink instead of water. Because salt solution fails to quench
the thirst, the dogs drank two to four times the normal
amounts of volume, and within a few days, their average
arterial pressure rose to about 40 mm Hg above normal.
After 2 weeks, the dogs were given tap water again instead
of salt solution; the pressure returned to normal within
2 days. Finally, at the end of the experiment, the dogs
were given salt solution again, and this time the pressure
1. Excess workload on the heart leads to early heart failure and coronary heart disease, often causing death as
a result of a heart attack.
2. The high pressure frequently damages a major blood
vessel in the brain, followed by death of major portions of the brain; this is a cerebral infarct. Clinically
it is called a “stroke.” Depending on which part of
0.9% NaCl Tap water 0.9% NaCl
Mean arterial pressure
(percent of control)
35–45% of left
kidney removed
Entire right
kidney removed
Figure 19-8 Average effect on arterial pressure of drinking 0.9 percent saline solution instead of water in four dogs with 70 percent of their
renal tissue removed. (Redrawn from Langston JB, Guyton AC, Douglas BH, et al: Effect of changes in salt intake on arterial pressure and renal
function in partially nephrectomized dogs. Circ Res 12:508, 1963. By permission of the American Heart Association, Inc.)
Chapter 19 Role of the Kidneys in Long-Term Control of Arterial Pressure and in Hypertension
fluid volume
Therefore, we can divide volume-loading hypertension into two separate sequential stages: The first stage
results from increased fluid volume causing increased
cardiac output. This increase in cardiac output mediates
the hypertension. The second stage in volume-loading
hypertension is characterized by high blood pressure and
high total peripheral resistance but return of the cardiac
output so near to normal that the usual measuring techniques frequently cannot detect an abnormally elevated
cardiac output.
resistance Cardiac output
(mm Hg/L/min)
changes in circulatory function during progressive
development of volume-loading hypertension. Figure
19-9 shows these sequential changes. A week or so before
the point labeled “0” days, the kidney mass had already
been decreased to only 30 percent of normal. Then, at
this point, the intake of salt and water was increased
to about six times normal and kept at this high intake
thereafter. The acute effect was to increase extracellular
fluid volume, blood volume, and cardiac output to 20 to
40 percent above normal. Simultaneously, the arterial
pressure began to rise but not nearly so much at first as
did the fluid volumes and cardiac output. The reason for
this slower rise in pressure can be discerned by studying
the total peripheral resistance curve, which shows
an initial decrease in total peripheral resistance. This
decrease was caused by the baroreceptor mechanism
discussed in Chapter 18, which tried to prevent the rise
in pressure. However, after 2 to 4 days, the baroreceptors
adapted (reset) and were no longer able to prevent the rise
in pressure. At this time, the arterial pressure had risen
almost to its full height because of the increase in cardiac
output, even though the total peripheral resistance was
still almost at the normal level.
After these early acute changes in the circulatory variables had occurred, more prolonged secondary changes
occurred during the next few weeks. Especially important
was a progressive increase in total peripheral resistance,
while at the same time the cardiac output decreased almost
all the way back to normal, mainly as a result of the longterm blood flow autoregulation mechanism that is discussed in detail in Chapter 17 and earlier in this chapter.
That is, after the cardiac output had risen to a high level
and had initiated the hypertension, the excess blood flow
through the tissues then caused progressive constriction
of the local arterioles, thus returning the local blood flows
in all the body tissues and also the cardiac output almost
all the way back to normal, while simultaneously causing a
secondary increase in total peripheral resistance.
Note, too, that the extracellular fluid volume and blood
volume returned almost all the way back to normal along
with the decrease in cardiac output. This resulted from
1. Hypertension
2. Marked increase in total peripheral resistance
3. Almost complete return of the extracellular fluid volume, blood volume, and cardiac output back to normal
(mm Hg)
Sequential Changes in Circulatory Function
During the Development of Volume-Loading Hyper­
tension. It is especially instructive to study the sequential
two factors: First, the increase in arteriolar resistance
decreased the capillary pressure, which allowed the fluid
in the tissue spaces to be absorbed back into the blood.
Second, the elevated arterial pressure now caused the kidneys to excrete the excess volume of fluid that had initially
accumulated in the body.
Last, let us take stock of the final state of the circulation several weeks after the initial onset of volume loading. We find the following effects:
Figure 19-9 Progressive changes in important circulatory system variables during the first few weeks of volume-loading hypertension. Note especially the initial increase in cardiac output as
the basic cause of the hypertension. Subsequently, the autoregulation mechanism returns the cardiac output almost to normal
while simultaneously causing a secondary increase in total peripheral resistance. (Modified from Guyton AC: Arterial Pressure and
Hypertension. Philadelphia: WB Saunders, 1980.)
Unit IV
rose much more rapidly to an even higher level because
the dogs had already learned to tolerate the salt solution
and therefore drank much more. Thus, this experiment
demonstrates volume-loading hypertension.
If the reader considers again the basic determinants
of long-term arterial pressure regulation, he or she can
immediately understand why hypertension occurred
in the volume-loading experiment of Figure 19-8. First,
reduction of the kidney mass to 30 percent of normal
greatly reduced the ability of the kidneys to excrete salt
and water. Therefore, salt and water accumulated in the
body and in a few days raised the arterial pressure high
enough to excrete the excess salt and water intake.
Unit IV The Circulation
Thus, the increased total peripheral resistance in volume-loading hypertension occurs after the hypertension
has developed and, therefore, is secondary to the hypertension rather than being the cause of the hypertension.
Volume-Loading Hypertension in Patients Who
Have No Kidneys but Are Being Maintained on an
Artificial Kidney
When a patient is maintained on an artificial kidney, it is
especially important to keep the patient’s body fluid volume at a normal level—that is, it is important to remove
an appropriate amount of water and salt each time the
patient is dialyzed. If this is not done and extracellular
fluid volume is allowed to increase, hypertension almost
invariably develops in exactly the same way as shown in
Figure 19-9. 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 the end, the hypertension is a
high peripheral resistance type of hypertension.
Hypertension Caused by Primary Aldosteronism
Another type of volume-loading hypertension is caused
by excess aldosterone in the body or, occasionally, by
excesses of other types of steroids. A small tumor in one
of the adrenal glands occasionally secretes large quantities of aldosterone, which is the condition called “primary aldosteronism.” As discussed in Chapters 27 and 29,
­aldosterone increases the rate of 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 blood volume and extracellular fluid volume.
Consequently, hypertension occurs. And, if salt intake is
increased at the same time, the hypertension becomes
even greater. Furthermore, if the condition persists for
months or years, the excess arterial pressure often causes
pathological changes in the kidneys that make the kidneys
retain even more salt and water in addition to that caused
directly by the aldosterone. Therefore, the hypertension
often finally becomes lethally severe.
Here again, in the early stages of this type of hypertension, the cardiac output is increased, but in later stages,
the cardiac output generally returns almost to normal
while the total peripheral resistance becomes secondarily
elevated, as explained earlier in the chapter for primary
volume-loading hypertension.
The Renin-Angiotensin System: Its Role
in Arterial Pressure Control
Aside from the capability of the kidneys to control arterial
pressure through changes in extracellular fluid volume,
the kidneys also have another powerful mechanism for
controlling pressure. It is the renin-angiotensin system.
Renin is a protein enzyme released by the kidneys
when the arterial pressure falls too low. In turn, it raises
the arterial pressure in several ways, thus helping to correct the initial fall in pressure.
Components of the Renin-Angiotensin System
Figure 19-10 shows the functional steps by which the
renin-angiotensin system helps to regulate arterial
Renin is synthesized and stored in an inactive form
called prorenin in the juxtaglomerular cells (JG cells) of
the kidneys. The JG cells are modified smooth muscle
cells located in the walls of the afferent arterioles immediately proximal to the glomeruli. When the arterial pressure falls, intrinsic reactions in the kidneys themselves
cause many of the prorenin molecules in the JG cells to
split and release renin. Most of 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 local fluids of the kidney and
initiate several intrarenal functions.
Renin itself is an enzyme, not a vasoactive substance.
As shown in the schema of Figure 19-10, renin acts enzymatically on another plasma protein, a globulin called
renin substrate (or angiotensinogen), to release a 10-amino
acid peptide, angiotensin I. 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 more angiotensin I during this entire time.
Within a few seconds to minutes after formation of
angiotensin I, two additional amino acids are split from
arterial pressure
Renin (kidney)
Renin substrate
Angiotensin I
Angiotensin II
Renal retention Vasoconstriction
of salt and water
Increased arterial pressure
Figure 19-10 Renin-angiotensin vasoconstrictor mechanism for
arterial pressure control.
Chapter 19 Role of the Kidneys in Long-Term Control of Arterial Pressure and in Hypertension
Rapidity and Intensity of the Vasoconstrictor
Pressure Response to the Renin-Angiotensin
Arterial pressure (mm Hg)
Figure 19-11 shows a typical experiment demonstrating
the effect of hemorrhage on the arterial pressure under
two separate conditions: (1) with the renin-angiotensin
system functioning and (2) without the system functioning (the system was interrupted by a renin-blocking
antibody). Note that after hemorrhage—enough to cause
renin-angiotensin system
renin-angiotensin system
Figure 19-11 Pressure-compensating effect of the renin-­angiotensin
vasoconstrictor system after severe hemorrhage. (Drawn from
experiments by Dr. Royce Brough.)
acute decrease of the arterial pressure to 50 mm Hg—the
arterial pressure rose back to 83 mm Hg when the reninangiotensin system was functional. Conversely, it rose
to only 60 mm Hg when the renin-angiotensin system
was blocked. This shows that the renin-angiotensin system is powerful enough to return the arterial pressure at
least halfway back to normal within a few minutes after
severe hemorrhage. Therefore, sometimes it can be of
lifesaving service to the body, especially in circulatory
Note also that the renin-angiotensin vasoconstrictor
system requires about 20 minutes to become fully active.
Therefore, it is somewhat slower to act for blood pressure
control than are the nervous reflexes and the sympathetic
norepinephrine-epinephrine system.
Effect of Angiotensin II in the Kidneys to Cause
Renal Retention of Salt and Water—An Important
Means for Long-Term Control of Arterial Pressure
Angiotensin II causes the kidneys to retain both salt and
water in two major ways:
1. Angiotensin II acts directly on the kidneys to cause salt
and water retention.
2. Angiotensin II causes the adrenal glands to secrete
aldosterone, and the aldosterone in turn increases salt
and water reabsorption by the kidney tubules.
Thus, whenever excess amounts of angiotensin II
circulate in the blood, the entire long-term renal–body
fluid mechanism for arterial pressure control automatically becomes set to a higher arterial pressure level than
Mechanisms of the Direct Renal Effects of Angiotensin
II to Cause Renal Retention of Salt and Water.
Angiotensin has several direct renal effects that make the
kidneys retain salt and water. One major effect is to constrict the renal arterioles, thereby diminishing blood flow
through the kidneys. The slow flow of blood reduces the
pressure in the peritubular capillaries, which causes rapid
reabsorption of fluid from the tubules. Angiotensin II also
has important direct actions on the tubular cells themselves to increase tubular reabsorption of sodium and
water. The total result of all these effects is significant,
sometimes decreasing urine output to less than one fifth
of normal.
Stimulation of Aldosterone Secretion by Angiotensin
II, and the Effect of Aldosterone to Increase Salt and
Water Retention by the Kidneys. Angiotensin II is also
one of the most powerful stimulators of aldosterone secretion by the adrenal glands, as we shall discuss in relation
to body 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; and an
important subsequent function of aldosterone is to cause
marked increase in sodium reabsorption by the kidney tubules, thus increasing the total body ­extracellular
Unit IV
the angiotensin I to form the 8-amino acid peptide angiotensin II. This conversion occurs to a great extent in the
lungs while the blood flows through the small vessels of
the lungs, catalyzed by an enzyme called angiotensin converting enzyme that is present in the endothelium of the
lung vessels. Other tissues such as the kidneys and blood
vessels also contain converting enzyme and therefore
form angiotensin II locally.
Angiotensin II is an extremely powerful vasoconstrictor, and it also affects circulatory function in other ways
as well. However, it persists in the blood only for 1 or 2
minutes because it is rapidly inactivated by multiple blood
and tissue enzymes collectively called angiotensinases.
During its persistence in the blood, angiotensin II has
two principal effects that can elevate arterial pressure.
The first of these, vasoconstriction in many areas of the
body, occurs rapidly. Vasoconstriction occurs intensely in
the arterioles and much less so in the veins. Constriction
of the arterioles increases the total peripheral resistance,
thereby raising the arterial pressure, as demonstrated
at the bottom of the schema in Figure 19-10. Also, the
mild constriction of the veins promotes increased venous
return of blood to the heart, thereby helping the heart
pump against the increasing pressure.
The second principal means by which angiotensin II
increases the arterial pressure is to decrease excretion of
both salt and water by the kidneys. This slowly increases
the extracellular fluid volume, which then increases the
arterial pressure during subsequent hours and days. This
long-term effect, acting through the extracellular fluid
volume mechanism, is even more powerful than the acute
vasoconstrictor mechanism in eventually raising the arterial pressure.
Unit IV The Circulation
fluid sodium. This increased sodium then causes water
retention, as already explained, increasing the extracellular fluid volume and leading secondarily to still more
­long-term elevation of the arterial pressure.
Thus both the direct effect of angiotensin on the kidney
and its effect acting through aldosterone are important in
long-term arterial pressure control. However, research in our
laboratory has suggested that the direct effect of angiotensin
on the kidneys is perhaps three or more times as potent as
the indirect effect acting through ­aldosterone—even though
the indirect effect is the one most widely known.
Quantitative Analysis of Arterial Pressure Changes Caused
by Angiotensin II. Figure 19-12 shows a quantitative analysis of the effect of angiotensin in arterial pressure control.
This figure shows two renal output curves, as well as a line
depicting a normal level of sodium intake. The left-hand
renal output curve is that measured in dogs whose reninangiotensin system had been blocked by an angiotensinconverting enzyme inhibitor drug that blocks the conversion
of angiotensin I to angiotensin II. The right-hand curve was
measured in dogs infused continuously with angiotensin II
at a level about 2.5 times the normal rate of angiotensin formation in the blood. Note the shift of the renal output curve
toward higher pressure levels under the influence of angiotensin II. This shift is caused by both the direct effects of
angiotensin II on the kidney and the indirect effect acting
through aldosterone secretion, as explained earlier.
Finally, note the two equilibrium points, one for zero
angiotensin showing an arterial pressure level of 75 mm Hg,
and one for elevated angiotensin showing a pressure level
of 115 mm Hg. Therefore, the effect of angiotensin to cause
renal retention of salt and water can have a powerful effect
in promoting chronic elevation of the arterial pressure.
Sodium intake and output (times normal)
Angiotensin levels in the blood
(times normal)
One of the most important functions of the renin-angiotensin system is to allow a person to eat either very
small or very large amounts of salt without causing great
changes in either extracellular fluid volume or arterial pressure. This function is explained by the schema
in Figure 19-13, which shows that the initial effect of
increased salt intake is to elevate the extracellular fluid
volume, in turn elevating the arterial pressure. Then,
the increased arterial pressure causes increased blood
flow through the kidneys, as well as other effects, which
reduce the rate of secretion of renin to a much lower
level and lead sequentially to decreased renal retention
of salt and water, return of the extracellular fluid volume
almost to normal, and, finally, return of the arterial pressure also almost to normal. Thus, the renin-­angiotensin
system is an automatic feedback mechanism that helps
maintain the arterial pressure at or near the normal level
even when salt intake is increased. Or, when salt intake
is decreased below normal, exactly opposite effects
take place.
To emphasize the efficacy of the renin-angiotensin
system in controlling arterial pressure, when the system
functions normally, the pressure rises no more 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 intake sometimes
causes the pressure to rise 10 times the normal increase,
often as much as 50 to 60 mm Hg.
Increased salt intake
Increased extracellular volume
Increased arterial pressure
Decreased renin and angiotensin
Decreased renal retention of salt and water
Return of extracellular volume almost to normal
Arterial pressure (mm Hg)
Figure 19-12 Effect of two angiotensin II levels in the blood on
the renal output curve, showing regulation of the arterial pressure
at an equilibrium point of 75 mm Hg when the angiotensin II level
is low and at 115 mm Hg when the angiotensin II level is high.
Role of the Renin-Angiotensin System in
Maintaining a Normal Arterial Pressure Despite
Large Variations in Salt Intake
Return of arterial pressure almost to normal
Figure 19-13 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.
Chapter 19 Role of the Kidneys in Long-Term Control of Arterial Pressure and in Hypertension
Types of Hypertension in Which Angiotensin
Is Involved: Hypertension Caused by a ReninSecreting Tumor or by Infusion of Angiotensin II
Renal artery constricted
Constriction released
Systemic arterial
Pressure (mm Hg)
1. By constricting the arterioles throughout the entire
body, thereby increasing the total peripheral resistance
and arterial pressure; this effect occurs within seconds
after one begins to infuse angiotensin.
2. By causing the kidneys to retain salt and water; over a
period of days, this, too, causes hypertension and is the
principal cause of the long-term continuation of the
elevated pressure.
Unit IV
Occasionally a tumor of the renin-secreting juxtaglo­
merular cells (the JG cells) occurs and secretes tremendous quantities of renin; in turn, equally large quantities
of angiotensin II are formed. In all patients in whom this
has occurred, severe hypertension has developed. Also,
when large amounts of angiotensin II are infused continuously for days or weeks into animals, similar severe longterm hypertension develops.
We have already noted that angiotensin II can increase
the arterial pressure in two ways:
Distal renal arterial
“One-Kidney” Goldblatt Hypertension. When one
kidney is removed and a constrictor is placed on the renal
artery of the remaining kidney, as shown in Figure 19-14,
the immediate effect is greatly reduced pressure in the
renal artery beyond the constrictor, as demonstrated by
the dashed curve in the figure. Then, within seconds or
minutes, the systemic arterial pressure begins to rise and
continues to rise for several days. The pressure usually
rises rapidly for the first hour or so, and this is followed
by a slower additional rise during the next several days.
When the systemic arterial pressure reaches its new stable
pressure level, the renal arterial pressure (the dashed
curve in the figure) will have returned almost all the way
back to normal. The hypertension produced in this way
is called “one-kidney” Goldblatt hypertension in honor
of Dr. Harry Goldblatt, who first studied the important
quantitative features of hypertension caused by renal
artery constriction.
The early rise in arterial pressure in Goldblatt hypertension is caused by the renin-angiotensin vasoconstrictor mechanism. That is, because of poor blood flow
through the kidney after acute constriction of the renal
artery, large quantities of renin are secreted by the kidney,
as demonstrated by the lowermost curve in Figure 19-14,
and this increases angiotensin II and aldosterone in the
blood. The angiotensin in turn raises the arterial pressure
acutely. The secretion of renin rises to a peak in an hour
or so but returns nearly to normal in 5 to 7 days because
the renal arterial pressure by that time has also risen back
to normal, so the kidney is no longer ischemic.
The second rise in arterial pressure is caused by retention of salt and water by the constricted kidney (that is
also stimulated by angiotensin II and aldosterone). In 5 to
7 days, the body fluid volume will have increased enough
Times normal
Renin secretion
Figure 19-14 Effect of placing a constricting clamp on the
renal artery of one kidney after the other kidney has been
removed. Note the changes in systemic arterial pressure, renal
artery pressure distal to the clamp, and rate of renin secretion.
The resulting hypertension is called “one-kidney” Goldblatt
to raise the arterial pressure to its new sustained level. The
quantitative value of this sustained pressure level is determined by the degree of constriction of the renal artery.
That is, the aortic pressure must rise high enough so that
renal arterial pressure distal to the constrictor is enough
to cause normal urine output.
A similar scenario occurs in patients with stenosis of
the renal artery of a single remaining kidney, as sometimes occurs after a person receives a kidney transplant.
Also, functional or pathological increases in resistance
of the renal arterioles, due to atherosclerosis or excessive levels of vasoconstrictors, can cause hypertension
through the same mechanisms as constriction of the main
renal artery.
“Two-Kidney” Goldblatt Hypertension. Hyper­
tension also can result when the artery to only one
kidney is constricted while the artery to the other kidney
Unit IV The Circulation
is normal. This hypertension results from the following
mechanism: The constricted kidney secretes renin and
also retains salt and water because of decreased renal
arterial pressure in this kidney. Then the “normal”
opposite kidney retains salt and water because of the
renin produced by the ischemic kidney. This renin
causes formation of angiotension II and aldosterone,
both of which circulate to the opposite kidney and cause
it also to retain salt and water. Thus, both kidneys, but
for different reasons, become salt and water retainers.
Consequently, hypertension develops.
The clinical counterpart of “two-kidney Goldblatt”
hypertension occurs when there is stenosis of a single
renal artery, for example caused by atherosclerosis, in a
person who has two kidneys.
Hypertension Caused by Diseased Kidneys That
Secrete Renin Chronically. Often, patchy areas of
one or both kidneys are diseased and become ischemic
because of local vascular constrictions, whereas other
areas of the kidneys are normal. When this occurs,
almost identical effects occur as in the two-kidney
type of Goldblatt hypertension. That is, the patchy
ischemic kidney tissue secretes renin, and this in turn,
acting through the formation of angiotensin II, causes
the remaining kidney mass also to retain salt and
water. Indeed, one of the most common causes of renal
hypertension, especially in older persons, is such patchy
ischemic kidney disease.
Other Types of Hypertension Caused
by Combinations of Volume Loading
and Vasoconstriction
Hypertension in the Upper Part of the Body Caused by
Coarctation of the Aorta. One out of every few thousand
babies is born with pathological constriction or blockage
of the aorta at a point beyond the aortic arterial branches
to the head and arms but proximal to the renal arteries, a
condition called coarctation of the aorta. When this occurs,
blood flow to the lower body is carried by multiple, small
collateral arteries in the body wall, with much vascular
resistance between the upper aorta and the lower aorta.
As a consequence, the arterial pressure in the upper part
of the body may be 40 to 50 percent higher than that in the
lower body.
The mechanism of this upper-body hypertension is
almost identical to that of one-kidney Goldblatt hypertension. That is, when a constrictor is placed on the aorta
above the renal arteries, the blood pressure in both kidneys at first falls, renin is secreted, angiotensin and aldosterone are formed, and hypertension occurs in the upper
body. The arterial pressure in the lower body at the level of
the kidneys rises approximately to normal, but high pressure persists in the upper body. The kidneys are no longer
ischemic, so secretion of renin and formation of angiotensin
and aldosterone return to normal. Likewise, in coarctation
of the aorta, the arterial pressure in the lower body is usually
almost normal, whereas the pressure in the upper body is far
higher than normal.
Role of Autoregulation in the Hypertension Caused by
Aortic Coarctation. A significant feature of hypertension
caused by aortic coarctation is that blood flow in the arms,
where the pressure may be 40 to 60 percent above normal,
is almost exactly normal. Also, blood flow in the legs, where
the pressure is not elevated, is almost exactly normal. How
could this be, with the pressure in the upper body 40 to 60
percent greater than in the lower body? The answer is not
that there are differences in vasoconstrictor substances in
the blood of the upper and lower body, because the same
blood flows to both areas. Likewise, the nervous system
innervates both areas of the circulation similarly, so there
is no reason to believe that there is a difference in nervous
control of the blood vessels. The only reasonable answer is
that long-term autoregulation develops so nearly completely
that the local blood flow control mechanisms have compensated almost 100 percent for the differences in pressure.
The result is that, in both the high-pressure area and the
low-pressure area, the local blood flow is controlled almost
exactly in accord with the needs of the tissue and not in
accord with the level of the pressure. One of the reasons
these observations are so important is that they demonstrate how nearly complete the long-term autoregulation
process can be.
Hypertension in Preeclampsia (Toxemia of ­Preg­nancy).
Approximately 5 to 10 percent of expectant mothers
develop a syndrome called preeclampsia (also called toxemia of pregnancy). One of the manifestations of preeclampsia is hypertension that usually subsides after delivery of the
baby. Although the precise causes of preeclampsia are not
completely understood, ischemia of the placenta and subsequent release by the placenta of toxic factors are believed
to play a role in causing many of the manifestations of this
disorder, including hypertension in the mother. Substances
released by the ischemic placenta, in turn, cause dysfunction
of vascular endothelial cells throughout the body, including
the blood vessels of the kidneys. This endothelial dysfunction decreases release of nitric oxide and other vasodilator substances, causing vasoconstriction, decreased rate of
fluid filtration from the glomeruli into the renal tubules,
impaired renal-pressure natriuresis, and development of
Another pathological abnormality that may contribute to hypertension in preeclampsia is thickening of the
kidney glomerular membranes (perhaps caused by an
autoimmune process), which also reduces the rate of
glomerular fluid filtration. For obvious reasons, the arterial pressure level required to cause normal formation of
urine becomes elevated, and the long-term level of arterial pressure becomes correspondingly elevated. These
patients are especially prone to extra degrees of hypertension when they have excess salt intake.
Neurogenic Hypertension. Acute neurogenic hyper­tension
can be caused by strong stimulation of the sympathetic nervous
system. For instance, when a person becomes excited for any
reason or at times during states of anxiety, the sympathetic system becomes excessively stimulated, peripheral vasoconstriction occurs everywhere in the body, and acute hypertension
Acute Neurogenic Hypertension Caused by Sectio­ning
the Baroreceptor Nerves. Another type of acute neurogenic hypertension occurs when the nerves leading from
the baroreceptors are cut or when the tractus solitarius
Unit IV The Circulation
hypertension is caused mainly by increased renal tubular
reabsorption of salt and water due to increased sympathetic nerve activity and increased levels of angiotensin II
and aldosterone. However, if hypertension is not effectively
treated, there may also be vascular damage in the kidneys
that can reduce the glomerular filtration rate and increase
the severity of the hypertension. Eventually uncontrolled
hypertension associated with obesity can lead to severe
vascular injury and complete loss of kidney function.
Graphical Analysis of Arterial Pressure Control in
Essential Hypertension. Figure 19-15 is a graphical
analysis of essential hypertension. The curves of this figure
are called sodium-loading renal function curves because
the arterial pressure in each instance is increased very
slowly, over many days or weeks, by gradually increasing
the level of sodium intake. The sodium-loading type
of curve can be determined by increasing the level of
sodium intake to a new level every few days, then waiting
for the renal output of sodium to come into balance with
the intake, and at the same time recording the changes in
arterial pressure.
When this procedure is used in essential hypertensive
patients, two types of curves, shown to the right in Figure
19-15, can be recorded in essential hypertensive patients,
one called (1) salt-insensitive hypertension and the other
(2) salt-sensitive hypertension. Note in both instances that
the curves are shifted to the right, to a higher ­pressure
level than for normal people. Now, let us plot on this same
graph (1) a normal level of salt intake and (2) a high level
of salt intake representing 3.5 times the normal intake.
In the case of the person with salt-insensitive essential hypertension, the arterial pressure does not increase
significantly when changing from normal salt intake to
high salt intake. Conversely, in those patients who have
Salt intake and output
(times normal)
High intake
Normal intake
Treatment of Essential Hypertension. Current
guide­lines for treating hypertension recommend, as a first
step, lifestyle modifications that are aimed at increasing
physical activity and weight loss in most patients.
Unfortunately, many patients are unable to lose weight,
and pharmacological treatment with antihypertensive
drugs must be initiated.
Two general classes of drugs are used to treat hypertension: (1) vasodilator drugs that increase renal blood
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 kidneys. Different
ones act in one of the following ways: (1) by inhibiting
sympathetic nervous signals to the kidneys or by blocking the action of the sympathetic transmitter substance
on the renal vasculature and renal tubules, (2) by directly
relaxing the smooth muscle of the renal vasculature, or
(3) by blocking the action of the renin-angiotensin system
on the renal vasculature or renal tubules.
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 reabsorption
of water, as explained earlier in the chapter. These natriuretic or diuretic drugs are discussed in greater detail in
Chapter 31.
Arterial pressure (mm Hg)
Figure 19-15 Analysis of arterial pressure regulation in (1) nonsalt-sensitive essential hypertension and (2) salt-sensitive essential
hypertension. (Redrawn from Guyton AC, Coleman TG, Young DB, et
al: Salt balance and long-term blood pressure control. Annu Rev Med
31:15, 1980. With permission, from the Annual Review of Medicine,
© 1980, by Annual Reviews http://www.AnnualReviews.org.)
s­ alt-sensitive essential hypertension, the high salt intake
significantly exacerbates the hypertension.
Two additional points should be emphasized: (1) Salt
sensitivity of blood pressure is not an all-or-none characteristic—it is a quantitative characteristic, with some
individuals being more salt sensitive than others. (2) Salt
sensitivity of blood pressure is not a fixed characteristic;
instead, blood pressure usually becomes more salt sensitive as a person ages, especially after 50 or 60 years of age.
The reason for the difference between salt-insensitive
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 hypertension may occur with
different types of chronic renal disease due to gradual loss
of the functional units 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
pressure to become salt sensitive, as discussed previously
in this chapter.
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 by several interrelated systems, each of which performs a specific function. For instance, when a person bleeds severely
Chapter 19 Role of the Kidneys in Long-Term Control of Arterial Pressure and in Hypertension
“Primary (Essential) Hypertension”
About 90 to 95 percent of all people who have hypertension are said to have “primary hypertension,” also widely
known as “essential hypertension” by many clinicians.
These terms mean simply that the hypertension is of
unknown origin, in contrast to those forms of hypertension that are secondary to known causes, such as renal
artery stenosis or monogenic forms of hypertension.
In most patients, excess weight gain and sedentary
lifestyle appear to play a major role in causing hypertension. The majority of patients with hypertension are overweight, and studies of different populations suggest that
excess weight gain and obesity may account for as much as
65 to 75 percent of the risk for developing primary hypertension. Clinical studies have clearly shown the value of
weight loss for reducing blood pressure in most patients
with hypertension. In fact, clinical guidelines for treating
hypertension recommend increased physical activity and
weight loss as a first step in treating most patients with
Some of the characteristics of primary hypertension
caused by excess weight gain and obesity include:
1. Cardiac output is increased due, in part, to the additional blood flow required for the extra adipose tissue.
However, blood flow in the heart, kidneys, gastrointestinal tract, and skeletal muscle also increases with
weight gain due to increased metabolic rate and growth
of the organs and tissues in response to their increased
metabolic demands. As the hypertension is sustained
for many months and years, total peripheral vascular
resistance may be increased.
2. Sympathetic nerve activity, especially in the kidneys,
is increased in overweight patients. The causes of
increased sympathetic activity in obesity are not fully
understood, but recent studies suggest that hormones,
such as leptin, released from fat cells may directly stimulate multiple regions of the hypothalamus, which, in
turn, have an excitatory influence on the vasomotor
centers of the brain medulla.
3. Angiotensin II and aldosterone levels are increased twofold to threefold in many obese patients. This may be
caused partly by increased sympathetic nerve stimulation, which increases renin release by the kidneys and
therefore formation of angiotensin II, which, in turn,
stimulates the adrenal gland to secrete aldosterone.
4. The renal-pressure natriuresis mechanism is impaired,
and the kidneys will not excrete adequate amounts of
salt and water unless the arterial pressure is high or
unless kidney function is somehow improved. In other
words, if the mean arterial pressure in the essential hypertensive person is 150 mm Hg, acute reduction of the mean arterial pressure artificially to the
normal value of 100 mm Hg (but without otherwise
altering renal function except for the decreased pressure) will cause almost total anuria, and the person
will retain salt and water until the pressure rises back
to the elevated value of 150 mm Hg. Chronic reductions in arterial pressure with effective antihypertensive therapies, however, usually do not cause marked
salt and water retention by the kidneys because these
therapies also improve renal-pressure natriuresis, as
discussed later.
Experimental studies in obese animals and obese patients
suggest that impaired renal-pressure natriuresis in obesity
Unit IV
is destroyed in each side of the medulla oblongata (these
are the areas where the nerves from the carotid and ­aortic
baroreceptors connect in the brain stem). The sudden
­cessation of normal nerve signals from the baroreceptors has the same effect on the nervous pressure control
mechanisms as a sudden reduction of the arterial pressure in the aorta and carotid arteries. That is, loss of the
normal inhibitory effect on the vasomotor center caused
by normal baroreceptor nervous signals allows the vasomotor center suddenly to become extremely active and
the mean arterial pressure to increase from 100 mm
Hg to as high as 160 mm Hg. The pressure returns to
nearly normal within about 2 days because the response
of the vasomotor center to the absent baroreceptor signal fades away, which is called central “resetting” of the
baroreceptor pressure control mechanism. Therefore, the
neurogenic hypertension caused by sectioning the baroreceptor nerves is mainly an acute type of hypertension, not
a chronic type.
Genetic Causes of Hypertension. Spontaneous hereditary hypertension has been observed in several strains of
animals, including different strains of rats, rabbits, and at
least one strain of dogs. In the strain of rats that has been
studied to the greatest extent, the Okamoto spontaneously
hypertensive rat strain, there is evidence that in early development of the hypertension, the sympathetic nervous system is considerably more active than in normal rats. In the
later stages of this type of hypertension, structural changes
have been observed in the nephrons of the kidneys: (1)
increased preglomerular renal arterial resistance and (2)
decreased permeability of the glomerular membranes.
These structural changes could also contribute to the longterm continuance of the hypertension. In other strains of
hypertensive rats, impaired renal function also has been
In humans, several different gene mutations have been
identified that can cause hypertension. These forms of
hypertension are called monogenic hypertension because
they are caused by mutation of a single gene. An interesting feature of these genetic disorders is that they all cause
excessive salt and water reabsorption by the renal tubules. In
some cases the increased reabsorption is due to gene mutations that directly increase transport of sodium or chloride in
the renal tubular epithelial cells. In other instances, the gene
mutations cause increased synthesis or activity of hormones
that stimulate renal tubular salt and water reabsorption.
Thus, in all monogenic hypertensive disorders discovered
thus far, the final common pathway to hypertension appears
to be increased salt reabsorption and expansion of extracellular fluid volume. Monogenic hypertension, however, is rare
and all of the known forms together account for less than 1%
of human hypertension.
Chapter 19 Role of the Kidneys in Long-Term Control of Arterial Pressure and in Hypertension
Rapidly Acting Pressure Control Mechanisms,
Acting Within Seconds or Minutes. The rapidly
ss r
lar id ift
Flu sh
volume lood
pr e
controsl sure
¥ !!
Acute change in pressure at this time
Maximum feedback gain at optimal pressure
acting pressure control mechanisms are almost entirely
acute nervous reflexes or other nervous responses. Note
in Figure 19-16 the three mechanisms that show responses
within seconds. They are (1) the baroreceptor feedback
mechanism, (2) the central nervous system ischemic
0 15 30 1 2 4 8 1632 1 2 4 816 1 2 4 8 16 •
Seconds Minutes
Time after sudden change in pressure
Figure 19-16 Approximate potency of various arterial pressure
control mechanisms at different time intervals after onset of a
disturbance to the arterial pressure. Note especially the infinite
gain (•) of the renal body fluid pressure control mechanism that
occurs after a few weeks’ time. (Redrawn from Guyton AC: Arterial
Pressure and Hypertension. Philadelphia: WB Saunders, 1980.)
mechanism, and (3) the chemoreceptor mechanism. Not
only do these mechanisms begin to react within seconds,
but they are also powerful. After any acute fall in pressure,
as might be caused by severe hemorrhage, the nervous
mechanisms combine (1) to cause constriction of the veins
and transfer of blood into the heart, (2) to cause increased
heart rate and contractility of the heart to provide greater
pumping capacity by the heart, and (3) to cause constriction
of most peripheral arterioles to impede flow of blood out
of the arteries; all these effects occur almost instantly to
raise the arterial pressure back into a survival range.
When the pressure suddenly rises too high, as might
occur in response to rapid transfusion of excess blood, the
same control mechanisms operate in the reverse direction, again returning the pressure back toward normal.
Pressure Control Mechanisms That Act After
Many Minutes. Several pressure control mechanisms
exhibit significant responses only after a few minutes
following acute arterial pressure change. Three of these,
shown in Figure 19-16, are (1) the renin-angiotensin
vasoconstrictor mechanism, (2) stress-relaxation of
the vasculature, and (3) shift of fluid through the tissue
capillary walls in and out of the circulation to readjust the
blood volume as needed.
We have already described at length the role of the
renin-angiotensin vasoconstrictor system to provide
a semiacute means for increasing the arterial pressure
when this is necessary. The stress-relaxation mechanism is demonstrated by the following example: When
the pressure in the blood vessels becomes too high, they
become stretched and keep on stretching more and more
for minutes or hours; as a result, the pressure in the vessels falls toward normal. This continuing stretch of the
vessels, called stress-relaxation, can serve as an intermediate-term pressure “buffer.”
The capillary fluid shift mechanism means simply that
any time capillary pressure falls too low, fluid is absorbed
from the tissues through the capillary membranes and
into the circulation, thus building up the blood volume
and increasing the pressure in the circulation. Conversely,
when the capillary pressure rises too high, 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.
These three intermediate mechanisms become mostly
activated within 30 minutes to several hours. During this
time, the nervous mechanisms usually become less and
less effective, which explains the importance of these nonnervous, intermediate time pressure control measures.
Long-Term Mechanisms for Arterial Pressure
Regulation. The goal of this chapter has been to explain
the role of the kidneys in long-term control of arterial
pressure. To the far right in Figure 19-16 is shown the
renal–blood volume pressure control mechanism (which
is the same as the renal–body fluid pressure control
Unit IV
so that the pressure falls suddenly, two 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 the blood volume and arterial
eventually to their normal levels so that the circulatory
system can reestablish full normality, not merely back to
the levels required for survival.
In Chapter 18, we saw that the first line of defense
against acute changes in arterial pressure is the nervous
control system. In this chapter, we have emphasized a
second line of defense achieved mainly by kidney mechanisms for long-term control of arterial pressure. However,
there are other pieces to the puzzle. Figure 19-16 helps to
put these together.
Figure 19-16 shows the approximate immediate (seconds and minutes) and long-term (hours and days) control responses, expressed as feedback gain, of eight arterial
pressure control mechanisms. These mechanisms can be
divided into three groups: (1) those that react rapidly,
within seconds or minutes; (2) those that respond over an
intermediate time period, minutes or hours; and (3) those
that provide long-term arterial pressure regulation, days,
months, and years. Let us see how they fit together as a
total, integrated system for pressure control.
Unit IV The Circulation
mechanism), demonstrating that it takes a few hours
to begin showing significant response. Yet it eventually
develops a feedback gain for control of arterial pressure
nearly equal to infinity. This means that this mechanism
can eventually return the arterial pressure nearly all the
way back, not merely partway back, to that pressure level
that provides normal output of salt and water by the
kidneys. By now, the reader should be familiar with this
concept, which has been the major point of this chapter.
Many factors can affect the pressure-regulating level
of the renal–body fluid mechanism. One of these, shown
in Figure 19-16, is aldosterone. A decrease in arterial
pressure leads within minutes to an increase in aldosterone secretion, and over the next hour or days, this
plays an important role in modifying the pressure control characteristics of the renal–body fluid mechanism.
Especially important is interaction of the reninangiotensin system with the aldosterone and renal fluid
mechanisms. For instance, a person’s salt intake varies tremendously from one day to another. We have seen in this
chapter that the salt intake can decrease to as little as onetenth normal or can increase to 10 to 15 times normal and
yet the regulated level of the mean arterial pressure will
change only a few mm Hg if the renin-angiotensin-aldosterone system is fully operative. But, without a functional
renin-­angiotensin-aldosterone system, blood pressure
becomes very sensitive to changes in salt intake.
Thus, arterial pressure control begins with the lifesaving measures of the nervous pressure controls, then
continues with the sustaining characteristics of the intermediate pressure controls, and, finally, is stabilized at the
long-term pressure level by the renal–body fluid mechanism. This long-term mechanism in turn has multiple
interactions with the renin-angiotensin-­aldosterone system, the nervous ­system, and several other factors that
­ rovide special blood pressure control capabilities for
special purposes.
Chobanian AV, Bakris GL, Black HR, et al: Joint National Committee on
Prevention, Detection, Evaluation, and Treatment of High Blood
Pressure. National High Blood Pressure Education Program Coordinating
Committee. Seventh Report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure,
Hypertension 42:1206, 2003.
Coffman TM, Crowley SD: Kidney in hypertension: Guyton redux,
Hypertension 51:811, 2008.
Cowley AW Jr: Long-term control of arterial blood pressure, Physiol Rev
72:231, 1992.
Guyton AC: Arterial pressure and hypertension, Philadelphia, 1980, WB
Guyton AC: Blood pressure control—special role of the kidneys and body
fluids, Science 252:1813, 1991.
Hall JE: The kidney, hypertension, and obesity, Hypertension 41:625, 2003.
Hall JE, Brands MW, Henegar JR: Angiotensin II and long-term arterial
pressure regulation: the overriding dominance of the kidney, J Am Soc
Nephrol 10(Suppl 12):S258, 1999.
Hall JE, Granger JP, Hall ME, et al: Pathophysiology of hypertension. In
Fuster V, O’Rourke RA, Walsh RA, et al, eds.: Hurst’s The Heart, ed 12,
New York, 2008, McGraw-Hill Medical, pp 1570.
Hall JE, da Silva AA, Brandon E, et al: Pathophysiology of obesity hypertension and target organ injury. In Lip GYP, Hall JE, eds.: Comprehensive
Hypertension, New York, 2007, Elsevier, pp 447.
LaMarca BD, Gilbert J, Granger JP: Recent progress toward the understanding of the pathophysiology of hypertension during preeclampsia,
Hypertension 51:982, 2008.
Lohmeier TE, Hildebrandt DA, Warren S, et al: Recent insights into the interactions between the baroreflex and the kidneys in hypertension, Am J
Physiol Regul Integr Comp Physiol 288:R828, 2005.
Oparil S, Zaman MA, Calhoun DA: Pathogenesis of hypertension, Ann Intern
Med 139:761, 2003.
Reckelhoff JF, Fortepiani LA: Novel mechanisms responsible for postmenopausal hypertension, Hypertension 43:918, 2004.
Rossier BC, Schild L: Epithelial sodium channel: mendelian versus essential
hypertension, Hypertension 52:595, 2008.
chapter 20
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 one of the
most important factors that we have to consider in relation to the circulation because it is the sum of the blood
flows to all of the tissues of the body.
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
Normal Values for Cardiac Output at Rest
and During Activity
Cardiac output varies widely with the level of activity of
the body. The following 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 and mass of some tissues (e.g., skeletal muscle) diminish—the average cardiac
output for the resting adult, in round numbers, is often
stated to be about 5 L/min.
Cardiac Index
Experiments have shown that the cardiac output increases
approximately in proportion 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 s­ urface 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 explain later
in the chapter that the cardiac output is regulated
throughout life almost directly in proportion to the
overall bodily metabolic activity. Therefore, the declining cardiac index is indicative of declining activity or
declining muscle mass 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 normally the primary controller of cardiac output.
Instead, it is the various factors of the peripheral circulation that affect flow of blood into the heart from the veins,
called venous return, that are the primary controllers.
The main reason peripheral factors are usually more
important than the heart itself in controlling cardiac output is that the heart has a built-in mechanism that normally allows it to pump automatically whatever amount
of blood that flows into the right atrium from the veins.
This mechanism, called the Frank-Starling law of the
heart, was discussed in Chapter 9. Basically, this law
states that when increased quantities of blood flow into
the heart, the increased blood stretches the walls of the
heart chambers. As a result of the stretch, the cardiac
muscle contracts with increased force, and this empties
the extra blood that has entered from the systemic circulation. Therefore, the blood that flows into the heart is
automatically pumped without delay into the aorta and
flows again through the circulation.
Another important factor, discussed in Chapter 10,
is that stretching the heart causes the heart to pump
faster—at an increased heart rate. That is, stretch of the
sinus node in the wall of the right atrium has a direct
effect on the rhythmicity of the node itself to increase
heart rate as much as 10 to 15 percent. In addition, the
Unit IV
Cardiac Output, Venous Return,
and Their Regulation
Age in years
Figure 20-1 Cardiac index for the human being (cardiac output per square meter of surface area) at different ages. (Redrawn
from Guyton AC, Jones CE, Coleman TB: Circulatory Physiology:
Cardiac Output and Its Regulation, 2nd ed. Philadelphia: WB
Saunders, 1973.)
stretched right atrium initiates a nervous reflex called
the Bainbridge reflex, passing first to the vasomotor center of the brain and then back to the heart by way of the
sympathetic nerves and vagi, also to increase the heart
Under most normal unstressful conditions, the cardiac
output is controlled almost entirely by peripheral factors
that determine venous return. However, we discuss 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 determines cardiac output.
Cardiac Output Regulation Is the Sum of Blood
Flow Regulation in All the Local Tissues of the
Body—Tissue Metabolism Regulates Most Local
Blood Flow
Work output during exercise (kg-m/min)
Figure 20-2 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.
Philadelphia: WB Saunders, 1973.)
to form the venous return, and the heart automatically
pumps this returning blood back into the arteries to flow
around the system again.
Effect of Total Peripheral Resistance on the
Long-Term Cardiac Output Level. Figure 20-3 is the
same as Figure 19-6. It is repeated here to illustrate an
extremely important principle in cardiac output control:
Under many conditions, the long-term cardiac output
level varies reciprocally with changes in total peripheral
resistance, as long as the arterial pressure is unchanged.
Note in Figure 20-3 that when the total peripheral
resistance is exactly normal (at the 100 percent mark in
the figure), the cardiac output is also normal. Then, when
The venous return to the heart is the sum of all the local
blood flows through all the individual tissue segments of
the peripheral circulation. Therefore, it follows that cardiac output regulation is the sum of all the local blood
flow regulations.
The mechanisms of local blood flow regulation were
discussed in Chapter 17. In most tissues, blood flow
increases mainly in proportion to each tissue’s metabolism. For instance, local blood flow almost always
increases when tissue oxygen consumption increases;
this effect is demonstrated in Figure 20-2 for different
levels of exercise. Note that at each increasing level of
work output during exercise, the oxygen consumption and the cardiac output increase in parallel to each
To summarize, cardiac output is determined by the sum
of all the various factors throughout the body that control local blood flow. All the local blood flows ­summate
AV shunts
Oxygen consumption (L/min)
Cardiac output
and cardiac index
Removal of both arms and legs
Pulmonary disease
Paget’s disease
Cardiac index (L/min/m2)
Arterial pressure or cardiac output
(percentage of normal)
Cardiac index (L/min/m2)
Cardiac output (L/min)
Unit IV The Circulation
Total peripheral resistance
(percentage of normal)
Figure 20-3 Chronic effect of different levels of total peripheral
resistance on cardiac output, showing a reciprocal relationship
between total peripheral resistance and cardiac output. (Redrawn
from Guyton AC: Arterial Pressure and Hypertension. Philadelphia:
WB Saunders, 1980.)
Chapter 20 Cardiac Output, Venous Return, and Their Regulation
Cardiac Output =
Arterial Pressure
Total Peripheral Resistance
The meaning of this formula, and of Figure 20-3, is
simply the following: Any time the long-term level of total
peripheral resistance changes (but no other functions of
the circulation change), the cardiac output changes quantitatively in exactly the opposite direction.
The Heart Has Limits for the Cardiac Output
That It Can Achieve
There are definite limits to the amount of blood that the
heart can pump, which can be expressed quantitatively in
the form of cardiac output curves.
Figure 20-4 demonstrates the normal cardiac output
curve, showing the cardiac output per minute at each
level of right atrial pressure. This is one type of cardiac
function curve, which was discussed in Chapter 9. Note
that the plateau level of this normal cardiac output curve
is about 13 L/min, 2.5 times the normal cardiac output of
about 5 L/min. This means that the normal human heart,
functioning without any special stimulation, can pump an
amount of venous return up to about 2.5 times the normal
venous return before the heart becomes a limiting factor
in the control of cardiac output.
Shown in Figure 20-4 are several other cardiac output
curves for hearts that are not pumping normally. The
uppermost curves are for hypereffective hearts that are
Cardiac output (L/min)
pumping better than normal. The lowermost curves are
for hypoeffective hearts that are pumping at levels below
Factors That Cause a Hypereffective Heart
Two types of factors can make the heart a better pump
than normal: (1) nervous stimulation and (2) hypertrophy
of the heart muscle.
Effect of Nervous Excitation to Increase Heart
Pumping. In Chapter 9, we saw that a combination of (1)
sympathetic stimulation and (2) parasympathetic inhibition does two things to increase the pumping effectiveness of the heart: (1) It greatly increases the heart
rate—sometimes, in young people, from the normal
level of 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