Table Of ContentContributors
Burton M. Altura Donald E. McMillan
Francis P. Chinard Antonio Martinez-Hernandez
J. G. Cunha-Vaz K. Messmer
J0rn Ditzel N. A. Mortillaro
Richard M. Effros J. C. Parker
D. N. Granger Johannes A. G. Rhodin
Stanley Greenberg H. Rieger
Carl A. Gruetter G. Rutili
Albert L. Hyman James W. Ryan
Philip J. Kadowitz Una S. Ryan
M. Kessler Holger Schmid-Schönbein
Charles Kilo W. Schoop
David S. Knight L. Sunder-Plassmann
M. Köhler A. E. Taylor
D. W. Lubbers Michael Wiederholt
Joseph . Williamson
Microcirculation
Current Physiologic, Medical,
and Surgical Concepts
Edited by
RICHARD M. EFFROS
Department of Medicine
LAC Harbor-UCLA Medical Center
Torrance, California
HOLGER SCHMID-SCHÖNBEIN
Department of Physiology
Medizin Theoret Institut der RWTH
Aachen, West Germany
J0RN DITZEL
Section of Endocrinology and Metabolism
Aalborg Regional Hospital
Aalborg, Denmark
1981
ACADEMIC PRESS
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COPYRIGHT © 1981, BY ACADEMIC PRESS, INC.
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United Kingdom Edition published by
ACADEMIC PRESS, INC. (LONDON) LTD.
24/28 Oval Road, London NW1 7DX
Library of Congress Cataloging in Publication Data
Main entry under title:
Microcirculation, current concepts.
"Based upon a series of lectures given at the Second
World Congress of Microcirculation, which was held at
the University of California in San Diego in August
1979"—Pref.
Includes bibliographies and index.
1. Microcirculation—Congresses. 2. Diabetic
angiopathies—Congresses. 3. Hemodynamics—Congresses.
I. Effros, Richard M. II. Schmid-Schönbein, H.
III. Ditzel, J0rn, Date. IV. World Congress of
Microcirculation (2nd : 1979: University of California)
[DNLM: 1. Microcirculation—Congresses. WG 104 M626]
QP106.6.M53 612'.135 81-3533
ISBN 0-12-232560-5 AACR2
PRINTED IN THE UNITED STATES OF AMERICA
81 82 83 84 9 8 7 6 5 4 3 2 1
List of Contributors
Numbers in parentheses indicate the pages on which the authors' contributions begin.
Burton M. Altura (51), Department of Physiology, State University of New
York, Downstate Medical Center, Brooklyn, New York 11203
Francis P. Chinard (33), Department of Medicine, CMDNJ-New Jersey Medi-
cal School, Newark, New Jersey 07103
J. G. Cunha-Vaz* (205), Department of Ophthalmology, University of Coimbra,
Coimbra, Portugal
J0rn Ditzel (173), Section of Endocrinology and Metabolism, Aalborg Regional
Hospital, 9000 Aalborg, Denmark
Richard M. Effros (1), Department of Medicine, LAC Harbor-UCLA Medical
Center, Torrance, California 90509
D. N. Granger (19), Department of Physiology, University of South Alabama
College of Medicine, Mobile, Alabama 36688
Stanley Greenberg (107), Departments of Pharmacology and Surgery, Tulane
University School of Medicine, New Orleans, Louisiana 70112
Carl A. Gruetter (107), Departments of Pharmacology and Surgery, Tulane
University School of Medicine, New Orleans, Louisiana 70112
Albert L. Hyman (107), Departments of Pharmacology and Surgery, Tulane
University School of Medicine, New Orleans, Louisiana 70112
Philip J. Kadowitz (107), Department of Pharmacology, Tulane University
School of Medicine, New Orleans, Louisiana 70112
M. Kessler (267), Department of Physiology, University of Emangen-Nünberg,
Emangen, West Germany
Charles Kilo (191), Washington University School of Medicine, St. Louis,
Missouri 63110
David S. Knight (107), Departments of Pharmacology and Surgery, Tulane
University School of Medicine, New Orleans, Louisiana 70112
*Present address: Department of Ophthalmology, University of Illinois Eye and Ear Infirmary,
Chicago, Illinois 60612
xiii
xiv List of Contributors
M. Köhler (281), Department of Physiology, Hospital for Vascular Diseases,
RWTH-Aachen, 5100 Aachen, West Germany
D. W. Lubbers (267), Max-Planck Institut für Systemphysiologie, 4600
Dortmund, West Germany
Donald E. McMillan (229), Sansum Medical Research Foundation, Santa Bar-
bara, California 93105
Antonio Martinez-Hernandez (125), Department of Pathology and Laboratory
Medicine, Hahnemann Medical College, Philadelphia, Pennsylvania 19102
K. Messmer (267, 299), Department of Surgery, University of Munich, 8000
Munich 70, West Germany
N. A. Mortillaro (19), Department of Physiology, University of South
Alabama, College of Medicine, Mobile, Alabama 36688
J. C. Parker (19), Department of Physiology, University of South Alabama,
College of Medicine, Mobile, Alabama 36688
Johannes A. G. Rhodin (11), Department of Anatomy, University of South
Florida, Miami, Florida 33612
H. Rieger (281), Department of Physiology, Hospital for Vascular Diseases,
RWTH-Aachen, 5100 Aachen, West Germany
G. Rutili (19), Department of Clinical Medicine, Washington University
School of Medicine, St. Louis, Missouri 63110
James W. Ryan (147), Department of Medicine, University Miami School of
Medicine, Miami, Florida 33101
Una S. Ryan (147), Department of Medicine, University Miami School of
Medicine, Miami, Florida, 33101
Holger Schmid-Schönbein (249, 281), Medizin Theoret Institut der RWTH,
5100 Aachen, West Germany
W. Schoop (281), Department of Physiology, Hospital for Vascular Diseases,
RWTH-Aachen, 5100 Aachen, West Germany
L. Sunder-Plassmann (267), Department of Surgery, University of Munich,
8000 Munich 70, West Germany
A. E. Taylor (19), Department of Physiology, University of South Alabama
School of Medicine, Mobile, Alabama 36688
Michael Wiederholt (293), Institut fur Klinische Physiologie, Klinikum Steg-
litz, Freie Universität Berlin, 1000 Berlin 45, German Democratic Republic
Joseph R. Williamson (191), Department of Pathology, Washington Univer-
sity School of Medicine, St. Louis, Missouri 63110
Preface
This volume is based on a series of lectures given at the Second World
Congress of Microcirculation, which was held at the University of California in
San Diego in August, 1979. Both the volume and the course from which it was
derived were designed to give students and practitioners of physiology and
medicine an overview of current concepts regarding the structure and properties
of small vessels. Only a handful of volumes have been devoted to this vital area
of cardiovascular function, and information regarding recent advances in micro-
circulatory research tends to be confined to a number of specialty journals.
The first section of this work is devoted to the morphology, physiology, and
pharmacology of microcirculation. The second and third sections are concerned
with the manner in which microvascular phenomena may play a role in various
disease states such as diabetes mellitus and hemoconcentration. Rather than
provide a comprehensive discussion of microcirculation, we have sought to
inform the reader of some of the more interesting aspects of the function and
dysfunction of small blood vessels.
Richard M. Effros
Holger Schmid-Schönbein
J0rn Ditzel
xv
1
Introduction
RICHARD M. EFFROS
During the three centuries that have elapsed since Harvey's discovery of the
circulation of blood, physiologists and clinicians have given considerably more
attention to the heart and great vessels than to the remainder of the circulation. A
casual examination of the shelves of any medical library should convince the
student that this imbalance persists to this very day: The number of books and
articles written about nearly any aspect of the heart and larger vessels greatly
exceeds that available concerning the smaller vessels, i.e., the "microcircula-
tion." The relative ease with which these larger structures can be studied and the
dramatic consequences that may accompany their failure is probably responsible
for this preoccupation with the condition of the heart and large vessels. However,
it is becoming increasingly evident that the status of the cardiovasculature and the
body as a whole is critically dependent upon the function of blood vessels that are
smaller than 0.1 mm in diameter. It is the object of this text to bring to the
attention of students and practitioners of physiology and medicine some insight
into recent advances that have been made in our understanding of the structure
and operation of the microcirculation in health and disease.
Perhaps the best way to begin a text concerning the microcirculation is to ask
whether the existence of a closed network of small vessels is really necessary for
multicellular organisms. An answer to a question of this sort can only be derived
from a study of comparative physiology. Among invertebrates, the circulation is
frequently open. This is illustrated schematically in Fig. 1 (Wigglesworth,
1972), which depicts the circulation of an idealized insect. Fluid is pumped
forward from a contractile vessel along the back of the insect and simply empties
into the tissues of the organism near the head. Since there is no separation
between the blood and lymph in this arrangement, the fluid is referred to as
"hemolymph. " Hemolymph percolates around the cells of the body and returns
to the dorsal vessel by way of a number of small valves that ensure that flow into
the "heart" is unidirectional. Return of hemolymph is encouraged by the de-
velopment of a relatively negative pressure in the heart that is pulled open during
diastole by a series of suspensory muscles.
There are a number of rather attractive features of an open circulation of this
sort. The absence of an endothelial barrier between the circulation and cells
should facilitate exchange, particularly of larger hydrophilic substances. Fur-
thermore, problems associated with shifts of fluid between the vascular and
1
MICROCIRCULATION
Copyright © 1981 by Academic Press, Inc.
All rights of reproduction in any form reserved.
0-12-232560-5
2 Richard M. Effros
Fig. 1. The circulatory system of an insect. Hemolymph is pumped toward the head by
contraction of the tubular "heart." This fluid exits from the vasculature near the head, perco-
lates around the cells of the body and is ultimately returned to the heart by way of ostia in the
wall of the heart. This process is encouraged by aliform muscles that lie along the dorsal
diaphragm (D) and act to dilate the heart during diastole. Note the pulsatile organs (PO) at
the base of the wings that act to pull fluid from the interstitial space through the vessels of the
wings. Septae (S) are present in the legs and antenae. These help maintain a unidirectional
flow of hemolymph in these appendages. Ν designates the nerve cord. From Wigglesworth
(1972) with permission of the author and publisher.
extravascular compartments are avoided. For example, the protein osmotic pres-
sure of the plasma must be kept above that of the interstitial fluid when a closed
circulation is present. Otherwise, the flow of fluid from the vasculature to the
interstitium promoted by the hydrostatic pressure in the vasculature would not be
countered by an opposite osmotic force. Edema formation would be inevitable
with a concomitant contraction of the vascular volume. The edema of nephrotic
syndrome and that of cirrhosis represent two common clinical manifestations of
such a failure to keep plasma protein concentrations sufficiently elevated. Pre-
sumably, insects are not subject to disorders of this kind and there is no need for a
separate lymphatic system in insects to return fluid and protein that have leaked
from the vessels to the interstitium.
It should be emphasized, however, that there are a number of potentially
serious drawbacks associated with open circulations. In the absence of a discrete
vascular compartment, hydrostatic pressures of the hemolymph must be about
the same as those of tissues, and pressure changes induced by alterations in the
posture of the animal may greatly modify the distribution of flow. Typically, the
hydrostatic pressure gradients responsible for hemolymph flow are very small.
Although the resistance to hemolymph flow is also relatively low compared to
resistances found in many vertebrate circulations, the rate of hemolymph flow in
invertebrates is generally more sluggish than in vertebrates. Provided that the
1. Introduction 3
metabolic rate of the organism is relatively modest, slower flow might not
represent a serious problem. However, among invertebrates that have high
metabolic rates, the presence of a slow circulation would limit oxygen and
carbon dioxide exchange with the tissues. Insects have solved this problem by
utilizing a separate "tracheolar" system to deliver 0 and remove C0 from the
2 2
tissues. As indicated in Fig. 2, small openings (referred to as "spiracles") are
located along the body of the insect (Wigglesworth, 1935). These are connected
to an elaborate system of trachea and tracheoles which subdivide to tubes as
small as or smaller than 0.2 /zm in diameter that are located within respiring
cells. In smaller insects, the movement of gases in the tracheal system is primar-
ily accomplished by diffusion, whereas larger insects such as bees are provided
with multiple air sacs that are opened and closed by movements of the body and
serve to ventilate the airways by convection. Complex patterns of gas movement
between spiracles may be established and varied with metabolic needs. This
system is particularly well suited for the conservation of water vapor since the
intervals at which spiracles are opened can be kept to a minimum.
Once respiration and circulation are no longer linked, the requirement for a
rapid circulation is very much diminished. In insects, the hemolymph need only
carry substrates, metabolites, and humoral agents between organs. Because both
pressures and flows are low, the tendency for bleeding is diminished and the need
Abd. i-vii
Fig. 2. The respiratory system of a flea (Xenopsylla). The two thoracic (Th) and eight
abdominal (abd.) spiracles on this side of the insect open into complex and interconnected
system of tracheoles that divide into progressively smaller airways. From Wigglesworth
(1935) with permission of the author and publisher.
4 Richard M. Effros
for a prompt clotting system is less urgent. In many insects, clotting mechanisms
are rudimentary or absent and, indeed, some insects will exude hemolymph to
repel enemies.
Although total flow may be regulated to some extent in animals with open cir-
culations, regional adjustments are difficult to make. Selective adjustments of flow
to extremities and wings are achieved by small auxiliary pumps which withdraw
fluid from the tissues (see Fig. 1). Septate partitions within the extremities act to
keep hemolymph flow unidirectional.
It is unlikely, however, that these structural adaptations would provide the fine
control of regional perfusion permitted by a closed circulation. The remarkable
increase in flow to muscles during exercise and the decrease in flow to extremities
upon diving represent two examples of the manner in which flow can be precisely
regulated by a closed circulation to provide for local needs.
Not only is the ability to regulate local flow less effective in an open circula-
tion but there is less opportunity to regulate exchange between tissues and
hemolymph. In the vertebrates, the capillary walls vary considerably in their
permeability from one organ to another and, as has been appreciated only re-
cently, contribute in an important fashion to the metabolism of a wide variety of
vasoactive substances such as angiotensin I, serotonin, histamine, prostaglan-
dins, and catecholamines (Bakhle and Vane, 1978). In the absence of such an
endothelial membrane, exchange of solutes presumably must be regulated by the
parenchymal cells themselves.
Adequate delivery of oxygen to tissues by the circulation is dependent in large
part upon a variety of respiratory pigments such as hemoglobin in vertebrates and
hemocyanin in invertebrates. Whereas hemocyanin is a large molecule
(molecular weight as high as 6.6 million) that is dissolved in the hemolymph,
hemoglobin is smaller in size (MW 64,000) and is carried within small cells, the
erythrocytes. Restriction of hemoglobin to an intracellular site reduces the loss of
this respiratory pigment in the urine and also permits chemical modification of
hemoglobin function without imposing similar changes in the plasma and intersti-
tial fluid surrounding parenchymal cells. The affinity of hemoglobin for oxygen
is altered by changes in intracellular pH, P , temperature, the concentration of
( ()2
2,3-diphosphoglycerate, and a variety of other factors. These changes generally
tend to adjust oxygen affinity of the molecule to meet tissue needs.
A variety of problems are associated with the flow of red blood cells through a
closed circulation in vertebrates. The diameter of the smallest vessels must be
sufficiently great to permit passage of these cells at reasonable driving pressures.
On the other hand, tissue exchange is optimized when the vessel diameters are
kept as small as possible. Among vertebrates, red cell and capillary diameters
obtain their lowest values in mammals. Mammalian red cells lose their nuclei
during their maturation and because of their remarkable deformability easily pass
through vessels only 3 μτη in diameter, or less than half the erythrocyte diameter.
