Table Of ContentRESEARCH TOPICS IN PHYSIOLOGY
Charles D. Barnes, Editor
Department of Physiology
Texas Tech University School of Medicine
Lubbock, Texas
1. Donald G. Davies and Charles D. Barnes (Editors). Regulation
of Ventilation and Gas Exchange, 1978
2. Maysie J. Hughes and Charles D. Barnes (Editors). Neural Con
trol of Circulation, 1980
3. John Orem and Charles D. Barnes (Editors). Physiology in Sleep,
1981
4. M. F. Crass, III and C. D. Barnes (Editors). Vascular Smooth
Muscle: Metabolic, Ionic, and Contractile Mechanisms, 1982
Vascular Smooth Muscle:
Metabolic, Ionic,
and Contractile Mechanisms
Edited by
M. F. CRASS, III
C. D. BARNES
Department of Physiology
Texas Tech University Health Sciences Centers
School of Medicine
Lubbock, Texas
1982
ACADEMIC PRESS
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COPYRIGHT © 1982, BY ACADEMIC PRESS, INC.
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Library of Congress Cataloging in Publication Data
Main entry under title:
Vascular smooth muscle: Metabolic, ionic, and
contractile mechanisms.
(Research topics in physiology ; )
Includes bibliographies and index.
1. Vascular smooth muscle. I. Crass, Maurice F.
II. Barnes, Charles Dee. III. Series. [DNLM: 1. Muscle,
Smooth, Vascular. W3 RE488s v. A / WE 500 V331]
QP110.V37V36 612'.13 81-17639
ISBN 0-12-195220-7 AACR2
PRINTED IN THE UNITED STATES OF AMERICA
82 83 84 85 9 8 7 6 5 4 3 2 1
List of Contributors
Numbers in parentheses indicate the pages on which the authors' contributions begin.
Julius C. Allen (99), Department of Medicine, Section of Cardiovascular
Sciences, Baylor College of Medicine, Houston, Texas 77030
Richard D. Bukoski (99), Departments of Physiology and Medicine,
Section of Cardiovascular Sciences, Baylor College of Medicine,
Houston, Texas 77030
*David R. Harder (71), Department of Physiology, East Tennessee State
University College of Medicine, Johnson City, Tennessee 37614
D. J. Hartshorne (135), Muscle Biology Group, Departments of
Biochemistry and Nutrition and Food Science, University of
Arizona, Tucson, Arizona 85721
Per Hellstrand (1), Department of Physiology and Biophysics, Univer
sity of Lund, S-223 62 Lund, Sweden
Richard L. Jackson (163), Division of Lipoprotein Research, Depart
ments of Pharmacology and Cell Biophysics, Biological Chemistry,
and Medicine, University of Cincinnati Medical Center, Cincinnati,
Ohio 45267
Allan W. Jones (37), Department of Physiology, University of Missouri,
Columbia, Missouri 65212
Richard J. Paul (1), Department of Physiology, College of Medicine,
University of Cincinnati, Cincinnati, Ohio 45267
•Present address: Department of Physiology and Biophysics, University of Vermont,
College of Medicine, Burlington, Vermont 05401.
ix
Preface
Because of the widespread incidence of cardiovascular disease,
perhaps no subject of biomedical research is receiving more intensive
investigation than the structure and function of vascular smooth muscle.
This extraordinary effort has spawned several recent comprehensive
and detailed reviews. In accord with the philosophy of the Research
Topics in Physiology series, this fourth volume addresses the subject of
vascular smooth muscle function by focusing on six selected areas de
lineated by chapters authored or coauthored by internationally recog
nized authorities in their specialized areas. In concise fashion, the au
thors have strived to present the historical backgrounds and theoretical
bases of their research areas, placing their work in perspective and iden
tifying directions for future research. Thus, by design, some degree of
comprehensiveness and detail is omitted in favor of giving critical over
views of various key areas in the burgeoning study of vascular smooth
muscle.
It seems appropriate that the first chapter be a discussion of the com
plexities of energy metabolism and how metabolic events can be corre
lated with a simultaneous quantitative assessment of smooth muscle
mechanics and the contractile machinery at the molecular level. Chap
ters 2 and 3 offer the reader a current view of smooth muscle membrane
properties in terms of the distribution, transport, and metabolic control
of electrolytes and specific aspects of ion conductance and electrical
activity. Chapters 4 and 5 are concerned with how smooth muscle cells
regulate their contractile activity through regulation of calcium ion
fluxes and the interaction, at the molecular level, of calcium ions with
regulatory proteins associated with the contractile apparatus.
Each author, in varying extent, makes reference to the relation of
possible anomalies in cellular or subcellular smooth muscle metabolic
xi
Xll Preface
and/or ionic events to the bases of certain types of vascular disease. The
final chapter (Chapter 6) is devoted to the events leading to vascular
pathology in the form of atherogenesis. The author weaves his concise,
expert description of plasma lipoprotein structure, synthesis, and trans
port among the current concepts of altered vascular smooth muscle lipid
metabolism leading to the genesis of atherosclerotic disease.
It is the hope of the Editors that this volume will, in its conciseness and
directed discussion, be a unique guide to researchers and clinicians
presently engaged in the study of smooth muscle and related areas.
M. F. Crass, III
C. D. Barnes
1
Vascular Smooth Muscle:
Relations between Energy
Metabolism and Mechanics
Per Η ells tr and and Richard J. Paul
I. Introduction 1
II. Relations between Metabolism and Contractility in Vascular
Smooth Muscle 2
III. Relations between Metabolism and Contractility—Current
Questions 8
A. Substrate for Oxidative Metabolism 8
B. Anomalous Aerobic Glycolysis 9
IV. Mechanisms and Energetics of Contraction 11
A. Classical Analysis of Muscle Mechanics 12
B. Characteristics of Elastic and Contractile Components 13
C. Efficiency of Chemomechanical Transduction 15
D. Mechanical Transients 18
E. Implications for the Molecular Mechanism of Contraction 22
V. Coordination of Metabolism and Contractility 25
VI. Applied Aspects of Smooth Muscle
Mechanochemistry:Hypertension 27
VII. Summary and Perspectives 30
References 31
I. INTRODUCTION
Vascular smooth muscle (VSM), like all muscle types, can generate
force and shorten when excited. While contraction is a fascinating phe
nomenon in itself, the special adaptations of this muscle type have cap
tured the interest of muscle physiologists. As the primary effector in the
regulation of blood flow, VSM, in maintaining vessel caliber against
1
VASCULAR SMOOTH MUSCLE: METABOLIC, Copyright © 1982 by Academic Press, Inc.
IONIC, AND CONTRACTILE MECHANISMS AH rights of reproduction in any form reserved.
ISBN 0-12-195220-7
2 Per Hellstrand and Richard J. Paul
blood pressure, is called upon to generate large forces for long periods
of time. Under similar conditions, skeletal muscle would rapidly fatigue.
Furthermore, the maintenance of this force by VSM is carried out with
remarkable efficiency. It can be calculated that a vasculature lined with
skeletal muscle would require a metabolic input amounting to about
twice the organ's entire basal metabolic rate (BMR) simply to maintain
vessel caliber—a task which VSM accomplishes utilizing only about 4% of
the BMR (Paul, 1980). This economical maintenance of force is accom
plished utilizing actin and myosin components of the contractile ap
paratus that are similar to those of skeletal muscle. In this chapter we will
focus on the metabolic and mechanical properties of VSM in an attempt
to explore the basis for these specialized characteristics. In recent years,
there have been a number of excellent reviews of VSM; in particular,
"The Handbook of Physiology" (Bohr et al., 1980) and "Biochemistry of
Smooth Muscle" (Stephens, 1977) offer a wide range of comprehensive
information. It is not our intent to duplicate the comprehensive reviews
of this field given in the above-mentioned works, but rather to focus on
recent developments in mechanics and metabolism in an attempt to syn
thesize new perspectives. We will therefore, because of this emphasis
rather than oversight, radically streamline the "review" aspects of this
work. We realize that many significant contributions to the field may not
receive full acknowledgment in this process. However, we hope that the
work will serve as a guide to the literature for those interested in pursu
ing this field in depth.
II. RELATIONS BETWEEN METABOLISM AND
CONTRACTILITY IN VASCULAR SMOOTH
MUSCLE
The phrase "vascular smooth muscle," while often used as if repre
senting a homogeneous class, includes many divergent tissues. Dif
ferences among vascular tissues are often more pronounced than dif
ferences, for example, between cardiac and skeletal muscle. However,
over the last decade a fair amount of data on VSM has accumulated, and
general patterns of mechanical and metabolic behavior can be discerned.
One of the most obvious metabolic differences between smooth and
skeletal muscle is that the phosphagen pool of smooth muscle is 10-20
times lower than in skeletal muscle. The term "phosphagen" is used to
describe the chemical substances serving as the immediate source of free
energy driving contraction and other energy-requiring processes. These
include adenosine triphosphate (ATP) and other so-called high-energy
1. Relations between Energy Metabolism and Mechanics 3
phosphates which can rapidly transfer a terminal inorganic phosphate
group (Pi) to adenosine diphosphate (ADP). For example, phospho-
creatine participates in the Lohman reaction:
Phosphocreatine -I- ADP +± ATP + creatine
The total phosphagen content of VSM is on the order of 2-4 μ,πιοΐ/g
(Paul, 1980) (all weights given are in grams "blotted" or wet tissue
weight), which may be compared to a basal rate of utilization of 1 -3 μ,πιοί
g-1 min-1. Thus, even under basal conditions, the preformed phospha
gen could suffice for only a few minutes in the absence of ATP synthesis
via intermediary metabolism. Under conditions of maximum contractile
activity, energy demand may increase two-to threefold and, for contrac
tion durations typical of vascular tissues, the preformed phosphagen can
provide only a small percentage of the total ATP requirements. In these
terms, intermediary metabolism plays a relatively larger role in the
mechanochemistry of VSM than in skeletal muscle in which brief con
tractions are supported entirely from the phosphagen pools, with resyn-
thesis of the ATP utilized usually not occurring until after the contrac
tion is over. On this basis alone one would anticipate a strong relation
between metabolism and contractility in VSM. Until the past decade,
however, most studies on vascular metabolism ignored contractile condi
tions entirely. Most experiments were performed on vessel slices, strips,
or rings in which the mechanical conditions were unknown or uncon
trolled. While these studies are useful for resolving certain qualitative
questions, for example, to demonstrate the existence of particular
biochemical pathways, the strong dependence of metabolism on contrac
tility tends to obscure quantitative interpretation of such studies.
The development of polarographic electrode techniques for the
measurement of oxygen consumption greatly reduced the complexity
of simultaneous measurement of oxygen consumption and force.
An example of this type of apparatus is shown in Fig. 1. By the
end of the 1970s the relation between steady-state oxygen consumption
rates (/o2) a nd active isometric force (P0) had been measured for various
VSM preparations, including bovine mesenteric vein (Paul et aL, 1973),
rat portal vein (Hellstrand, 1977), porcine carotid (Paul et aL, 1976) and
coronary arteries (Paul et aL, 1979), and rat aorta (Seidel et aL, 1979;
Arner and Hellstrand, 1981). From these studies a linear relation be
tween J and P was consistently observed, in spite of the fact that the
02 0
absolute values of J varied by about fivefold from porcine carotid
0z
artery (0.07 μ,πιοί min-1 g-1) to rat portal vein (0.4 μ,πιοί min-1 g-1). An
example of this dependence is shown in Fig. 2 in which steady-state J is
02
4 Per Hellstrand and Richard J. Paul
Fig. 1. Apparatus for the determination of oxygen consumption of smooth muscle
with simultaneous tension recording. Inset shows muscle holder, a, Magnetic stirrer; b,
measuring chamber (volume 1.3 ml); c, muscle preparation (hidden); d, oxygen electrode;
e, mercury drop sealing mechanical connection; f, Perspex muscle holder; g, inlet tube for
perfusion of chamber; h, outlet tube; i, force transducer; j and k, tubes for circulating
water at 37°C. From Hellstrand (1977).
given as a function of isometric force. Based on the time required to
attain constant rates of oxygen consumption following changes in con
tractility, steady states are achieved quickly (<2 min) and can be main
tained for many hours provided the tissues are adequately supplied with
oxygen and substrate.
Isometric force in smooth muscle can be varied by changing the
agonist level in the bathing solution. A linear relation between J and
02
graded isometric force at fixed length has been generally observed and
appears to be relatively independent of the agonist studied, including
epinephrine, norepinephrine, histamine, and KC1. In an alternative ex
perimental protocol exploiting the force-length characteristic, the
agonist concentration may be held constant and the force varied by
altering the initial tissue length. Here again, an agonist-independent
linear relation has been found; however, this relation, as seen in Fig. 3, is
not in general identical to the relation generated at fixed length by
changing the agonist concentration. The most common interpretation of
these results is dependent on the assumption that a sliding-filament
