Physiol Rev 88: 1009 –1086, 2008;
doi:10.1152/physrev.00045.2006.
Regulation of Coronary Blood Flow During Exercise
DIRK J. DUNCKER AND ROBERT J. BACHE
Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Cardiovascular Research
Institute COEUR, Erasmus University Medical Center, Rotterdam, The Netherlands; and Division
of Cardiology, Department of Medicine, Minnesota Medical School, Minneapolis, Minnesota
I. Introduction
II. Coronary Blood Flow in the Normal Heart During Exercise
A. Myocardial oxygen demand
B. Myocardial oxygen supply
C. Determinants of coronary blood flow
D. Transmural distribution of left ventricular myocardial blood flow
E. Coronary blood flow to the right ventricle and the atria
F. Control of coronary vascular resistance
G. Coronary blood flow in the exercise-trained heart
III. Coronary Blood Flow Distal to a Coronary Artery Obstruction During Exercise
A. Regulation of coronary blood flow distal to a coronary artery stenosis
B. Regulation of coronary blood flow to collateral-dependent myocardium during exercise
C. Exercise training and the coronary collateral circulation
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Duncker DJ, Bache RJ. Regulation of Coronary Blood Flow During Exercise. Physiol Rev 88: 1009 –1086, 2008;
doi:10.1152/physrev.00045.2006.—Exercise is the most important physiological stimulus for increased myocardial oxygen demand. The requirement of exercising muscle for increased blood flow necessitates an increase
in cardiac output that results in increases in the three main determinants of myocardial oxygen demand: heart
rate, myocardial contractility, and ventricular work. The approximately sixfold increase in oxygen demands of
the left ventricle during heavy exercise is met principally by augmenting coronary blood flow (⬃5-fold), as
hemoglobin concentration and oxygen extraction (which is already 70 – 80% at rest) increase only modestly in
most species. In contrast, in the right ventricle, oxygen extraction is lower at rest and increases substantially
during exercise, similar to skeletal muscle, suggesting fundamental differences in blood flow regulation
between these two cardiac chambers. The increase in heart rate also increases the relative time spent in systole,
thereby increasing the net extravascular compressive forces acting on the microvasculature within the wall of
the left ventricle, in particular in its subendocardial layers. Hence, appropriate adjustment of coronary vascular
resistance is critical for the cardiac response to exercise. Coronary resistance vessel tone results from the
culmination of myriad vasodilator and vasoconstrictors influences, including neurohormones and endothelial
and myocardial factors. Unraveling of the integrative mechanisms controlling coronary vasodilation in response
to exercise has been difficult, in part due to the redundancies in coronary vasomotor control and differences
between animal species. Exercise training is associated with adaptations in the coronary microvasculature
including increased arteriolar densities and/or diameters, which provide a morphometric basis for the observed
increase in peak coronary blood flow rates in exercise-trained animals. In larger animals trained by treadmill
exercise, the formation of new capillaries maintains capillary density at a level commensurate with the degree
of exercise-induced physiological myocardial hypertrophy. Nevertheless, training alters the distribution of
coronary vascular resistance so that more capillaries are recruited, resulting in an increase in the permeabilitysurface area product without a change in capillary numerical density. Maintenance of ␣- and ß-adrenergic tone
in the presence of lower circulating catecholamine levels appears to be due to increased receptor responsiveness to adrenergic stimulation. Exercise training also alters local control of coronary resistance vessels. Thus
arterioles exhibit increased myogenic tone, likely due to a calcium-dependent protein kinase C signalingmediated alteration in voltage-gated calcium channel activity in response to stretch. Conversely, training
augments endothelium-dependent vasodilation throughout the coronary microcirculation. This enhanced responsiveness appears to result principally from an increased expression of nitric oxide (NO) synthase. Finally,
physical conditioning decreases extravascular compressive forces at rest and at comparable levels of exercise,
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mainly because of a decrease in heart rate. Impedance to coronary inflow due to an epicardial coronary artery
stenosis results in marked redistribution of myocardial blood flow during exercise away from the subendocardium towards the subepicardium. However, in contrast to the traditional view that myocardial ischemia causes
maximal microvascular dilation, more recent studies have shown that the coronary microvessels retain some
degree of vasodilator reserve during exercise-induced ischemia and remain responsive to vasoconstrictor
stimuli. These observations have required reassessment of the principal sites of resistance to blood flow in the
microcirculation. A significant fraction of resistance is located in small arteries that are outside the metabolic
control of the myocardium but are sensitive to shear and nitrovasodilators. The coronary collateral system
embodies a dynamic network of interarterial vessels that can undergo both long- and short-term adjustments
that can modulate blood flow to the dependent myocardium. Long-term adjustments including recruitment and
growth of collateral vessels in response to arterial occlusion are time dependent and determine the maximum
blood flow rates available to the collateral-dependent vascular bed during exercise. Rapid short-term adjustments result from active vasomotor activity of the collateral vessels. Mature coronary collateral vessels are
responsive to vasodilators such as nitroglycerin and atrial natriuretic peptide, and to vasoconstrictors such as
vasopressin, angiotensin II, and the platelet products serotonin and thromboxane A2. During exercise, ßadrenergic activity and endothelium-derived NO and prostanoids exert vasodilator influences on coronary
collateral vessels. Importantly, alterations in collateral vasomotor tone, e.g., by exogenous vasopressin,
inhibition of endogenous NO or prostanoid production, or increasing local adenosine production can modify
collateral conductance, thereby influencing the blood supply to the dependent myocardium. In addition,
vasomotor activity in the resistance vessels of the collateral perfused vascular bed can influence the volume and
distribution of blood flow within the collateral zone. Finally, there is evidence that vasomotor control of
resistance vessels in the normally perfused regions of collateralized hearts is altered, indicating that the
vascular adaptations in hearts with a flow-limiting coronary obstruction occur at a global as well as a regional
level. Exercise training does not stimulate growth of coronary collateral vessels in the normal heart. However,
if exercise produces ischemia, which would be absent or minimal under resting conditions, there is evidence
that collateral growth can be enhanced. In addition to ischemia, the pressure gradient between vascular beds,
which is a determinant of the flow rate and therefore the shear stress on the collateral vessel endothelium, may
also be important in stimulating growth of collateral vessels.
I. INTRODUCTION
Energy production in the normally functioning
heart is primarily dependent on oxidative phosphorylation, with ⬍5% of ATP production resulting from glycolytic metabolism (436). Because of this dependence
on oxidative energy production, increases of cardiac
activity are dependent on almost instantaneous parallel
increases of oxygen availability. In contrast to skeletal
muscle, which is quiescent with very low metabolic
requirements during resting conditions, the heart continues to pump at a rate of 60 –70 beats/min in humans
even at rest. Consequently, at rest, oxygen consumption
normalized per gram of myocardium is 20-fold higher
than that of skeletal muscle. As an adaptation to the
high oxygen demands, the heart maintains a very high
level of oxygen extraction so that 70 – 80% of the arterially delivered oxygen is extracted, compared with
30 – 40% in skeletal muscle (181, 346). This high level of
oxygen extraction is facilitated by a high capillary density of 3,000 – 4,000/mm2 (353), which is substantially
higher than the 500 –2,000 capillaries/mm2 found in skeletal muscle (226). Because of the high level of oxygen extraction by the myocardium during resting conditions, increases in oxygen demand produced by exercise (increasing
up to 6-fold during maximal exercise) are mediated principally by an increase in coronary blood flow.
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John Hunter stated in 1794 that “blood goes where it
is needed” (485). How the blood “knows” where it is
needed, i.e., the mechanism(s) that enable coronary flow
to respond to the oxygen demands of the myocardium,
most notably during exercise, has been the subject of
cardiovascular research for over a century (485). Significant advances in our understanding of coronary blood
flow regulation have been made over the past 40 years and
are summarized in several previous reviews (53, 138, 181,
346). The aim of this review is to provide a comprehensive
update of the acute and chronic adaptations that regulate
coronary blood flow in response to dynamic exercise under
physiological conditions in the healthy heart (sect. II) and in
the heart with impaired coronary arterial inflow (sect. III).
II. CORONARY BLOOD FLOW IN THE NORMAL
HEART DURING EXERCISE
A. Myocardial Oxygen Demand
Oxygen consumption by the heart is principally required for contraction, with requirements for maintaining
basal metabolism comprising only 10 –20% of total oxygen
consumption (58, 617). The oxygen required for contraction is related to heart rate (62, 302, 582), ventricular wall
tension (217), muscle shortening (78, 217), and contrac-
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tility (43, 162, 217, 417). Precise determination of the
relative contributions of these individual variables in vivo
has been difficult, as pharmacological or electrical
modulation of one of these variables often results in
alterations of one or more of the other variables. An
integrated model of these mechanical determinants of
oxygen consumption has been proposed by Suga and
Sagawa (544, 545). These authors demonstrated that
the oxygen consumption per heart beat is determined
by ventricular work (represented by the ventricular
pressure-volume area which integrates wall tension and
shortening) and contractility (Emax, represented by the
slope of the end-systolic pressure volume relation)
(Fig. 1, top panels).
Exercise is the most important physiological stimulus for increasing myocardial oxygen demands. The
requirement of exercising skeletal muscle for increased
blood flow is met by vasodilation of resistance vessels
in the skeletal muscle, which requires an increase in
cardiac output, and is facilitated by an increase in
arterial pressure. The hemodynamic adjustments that
result in the increased cardiac output and arterial pressure during exercise cause increases in each of the
major determinants of myocardial oxygen demands:
heart rate, contractility, and ventricular work (Fig. 1,
bottom panels, and Fig. 2).
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1. Heart rate
Early studies comparing myocardial oxygen consumption during heavy exercise with similar increases in
heart rate produced by cardiac pacing suggested that
30 – 40% of the increase in coronary blood flow during
exercise can be attributed to the increase in heart rate
(302, 582). However, the contribution of the increase in
heart rate to the increase in myocardial oxygen consumption was likely underestimated, as pacing decreases enddiastolic volume and stroke volume, thereby reducing
ventricular work (72, 531). Indeed, other studies (214, 242,
258, 396, 588) suggest that the increase in heart rate
accounts for 50 –70% of the increase in myocardial oxygen
consumption during exercise (Fig. 2).
2. Contractility
The exercise-induced increase in contractility is due
to ␤-adrenergic activation as well as the direct positive
inotropic effect of heart rate (treppe) (320). Studies in
which the inotropic effect produced by the ␤-adrenergic
nervous system during exercise was blocked with propranolol while heart rate was maintained constant by
atrial pacing were interpreted to suggest that up to 30% of
the increase in myocardial oxygen demands during exercise could be attributed to the adrenergically mediated
FIG. 1. Schematic illustrations of ventricular pressure-volume area [PVA, total
mechanical energy, consisting of external
work (EW) and potential work (PW)] and
maximum elastance (Emax, i.e., contractility)
in a pressure-volume diagram (top left panel;
ESPVR, end-systolic pressure volume relation), and the relation to myocardial oxygen
consumption (top right panel). The PVA-independent MV̇O2 constitutes basal metabolism and the cost of contractility (i.e., electromechanical activation). In the bottom
panels are shown representative alterations
produced by exercise in dogs with an increase in heart rate from ⬃110 to ⬃250
beats/min. An increase in PVA occurs due to
a small increase in end-diastolic volume and
a marked increase in systolic arterial pressure, which together with the increase in
Emax (bottom left panel), cause an estimated
80% increase in MV̇O2 per beat (bottom right
panel). Together with the 120% increase of
heart rate, a quadrupling of MV̇O2 per min
(121, 568) is explained. [Illustrations are
based on Suga (545).]
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DIRK J. DUNCKER AND ROBERT J. BACHE
FIG. 2. Schematic overview of the effect of exercise on myocardial
oxygen balance. Shown are the contributions of various variables to the
exercise-induced increase in myocardial oxygen demand (⌬O2 demand)
and supply (⌬O2 supply). For example, the increase in oxygen demand
is produced exclusively (100%) by an increase in contractile activity,
which in turn is principally (for 60%) the result of an increase in heart
rate. Similarly, the increase in oxygen supply is primarily met (for 80%)
by an increase in blood flow, which is predominantly (for 90%) achieved
by a decrease in coronary vascular resistance (Rcoronary). PPERFUSION,
perfusion pressure; PTISSUE, intramyocardial tissue pressure; [O2]ART,
arterial oxygen content; [O2]CV, coronary venous oxygen content; [Hb],
hemoglobin content; O2 sat, oxygen saturation.
augmentation of contractility (43, 162, 303, 417). The effect of increased contractility on myocardial oxygen consumption in these studies was likely overestimated, as
ß-blockade blunted not only the exercise-induced increase in contractility, but also left ventricular systolic
pressure and stroke volume and consequently left ventricular work per beat (43, 162, 303, 417). Therefore, it is
estimated that contractility contributes 15–25% of the increase in oxygen consumption during exercise (Figs. 1
and 2).
flow (Fig. 2). In some species such as the dog (313, 583),
horse (167, 448), and sheep (415), oxygen delivery is
facilitated by a prominent increase in hemoglobin (by up
to 30 –50%), but in swine (148, 247, 345) and human (484,
486), hemoglobin concentrations increase much less. Although myocardial oxygen extraction also increases during exercise (377, 391, 402, 426, 587, 588), the high level of
basal oxygen extraction (typically 70 – 80% during resting
conditions) limits further increases. In chronically instrumented dogs, von Restorff et al. (587) found that heavy
treadmill exercise caused an increase of myocardial oxygen consumption from 0.09 ⫾ 0.01 at rest to 0.57 ⫾ 0.05
ml䡠min⫺1 䡠g⫺1 during exercise that was provided by a
434% increase of coronary blood flow, an increase of
arterial oxygen content from 20 ⫾ 1 to 23 ⫾ 1 ml/dl, and
an increase of myocardial oxygen extraction from 79 ⫾ 2
to 93 ⫾ 1% (Fig. 3). Thus the principal mechanism for
augmenting myocardial oxygen delivery is by increasing
coronary blood flow and, as a result, coronary flow is
strongly correlated with myocardial oxygen consumption.
The increase in myocardial blood flow results from a
combination of coronary vasodilation, with a decrease of
coronary vascular resistance during heavy exercise to
20 –30% of the resting level, and a 20 – 40% increase in
mean arterial pressure (37, 275, 313, 377, 426, 448, 469,
587, 588).
1. Coronary blood flow
Left ventricular myocardial blood flow during resting
conditions in chronically instrumented large animals in
3. Ventricular work
Left ventricular work increases during exercise in
proportion to the increased systolic arterial pressure and
secondary to a modest increase of left ventricular enddiastolic volume (279, 456, 581). Stroke volume, and
hence external work, is augmented as the increased contractility during exercise causes the ventricle to eject to a
smaller end-systolic volume (279, 456, 581) so that total
ventricular work increases, accounting for an estimated
15–25% of the increase in oxygen consumption (Figs. 1
and 2).
B. Myocardial Oxygen Supply
Increased myocardial oxygen demands during exercise are met principally by augmenting coronary blood
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FIG. 3. Myocardial oxygen balance in awake dogs at rest and during
four incremental levels of treadmill exercise. The increase in myocardial
oxygen consumption was principally accounted for by an increase in
coronary blood flow with only modest contributions of increase in
hematocrit and oxygen extraction. MV̇O2, myocardial oxygen consumption; Hct, hematocrit; ArtSO2, arterial oxygen saturation; CVSO2, coronary venous oxygen saturation. Data are means ⫾ SE. *P ⬍ 0.05 vs rest.
[Data from Restorff et al. (588).]
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the awake state and in normal human subjects is generally
reported in the range of 0.5–1.5 ml䡠min⫺1 䡠g myocardium⫺1
(17, 24 –26, 33, 34, 37, 41, 44, 132, 137, 139 –141, 144, 146,
147, 174, 212, 214, 236, 289, 316, 327, 356, 379, 420, 427,
440, 444, 448, 473, 499, 500, 524, 539, 540, 547, 567–569,
588, 593, 603, 614, 615, 624). The wide range of resting
values of left ventricular blood flow in awake animals
appears to be related to the state of alertness. Animals
conditioned to rest quietly in the laboratory have the
lowest reported values, whereas animals standing on a
treadmill ready to run have higher heart rates and higher
coronary flow rates. Dynamic exercise increases coronary
blood flow in proportion to the heart rate, with peak
values during maximal exercise typically three to five
times the resting level (378, 448, 498 –500, 574, 588, 603).
The strong correlation between coronary flow and heart
rate occurs because heart rate is a common multiplier for
the other determinants of myocardial oxygen demand
(contractility, cardiac work), which are computed per
beat. Regression analysis of published left ventricular
blood flow data against heart rate demonstrates remarkably similar relationships between human, canine, equine,
and porcine data during dynamic exercise (Fig. 4) (17,
24 –26, 33, 34, 37, 41, 44, 76, 77, 132, 137, 139 –141, 144, 146,
147, 162, 174, 212, 214, 236, 250, 258, 275, 289, 302, 303,
316, 327, 345, 356, 378, 379, 420, 426, 427, 430, 431, 440,
444, 448, 469, 473, 499, 500, 524, 539, 540, 547, 567–569,
588, 593, 603, 614, 615, 624). The values reported by
Sanders et al. (498) are for total heart flow and are therefore lower than from other studies in which blood flow
from the left ventricle was reported. In some laboratories
using fluorescent microspheres, absolute blood flow measurements of 7.5– 8.5 ml䡠 min⫺1 䡠g myocardium⫺1 have
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been reported in swine exercising at heart rates of ⬃260
beats/min (106, 327); these values are much higher than
reported by most other groups in which myocardial blood
flow was measured with radioactive microspheres (Fig.
4). These studies have not been included in Figure 4.
A) UNIQUE RESPONSES TO EXERCISE IN RODENTS. An inexpensive small animal model that would reproduce the effects
of exercise seen in larger animals and in humans would be
extremely useful, especially in light of the availability of
genetically modified mouse strains that could be used to
assess the contribution of a gene product to the acute and
chronic coronary blood flow responses to exercise (55).
However, the technical difficulty of measuring coronary
blood flow in small animals is formidable. Consequently,
no studies of coronary or myocardial blood flow responses to exercise in mice are currently available. Flaim
et al. (185) studied myocardial blood flow, measured with
radioactive microspheres injected into the left ventricle of
rats exercised by swimming or running on a treadmill.
The increase in oxygen consumption produced by swimming was due solely to an increased oxygen extraction, so
that compared with resting conditions swimming caused
no increases of heart rate or cardiac output and no increase of myocardial blood flow. Treadmill exercise at 70
ft./min for 5 min or until exhaustion increased heart rates
from ⬃380 to 480 beats/min and increased cardiac output,
while arterial blood pressure was unchanged. Left ventricular myocardial blood flow increased far less during
exercise than in large animals, being 5.9 ml䡠min⫺1 䡠g⫺1 at
rest and 7.8 ml䡠min⫺1 䡠g⫺1 during exercise, an ⬃30% increase. The very high left ventricular myocardial blood
flow rates at rest (⬃5-fold greater than in large animals or
humans) appeared to result from the high basal heart
FIG. 4. Relations between heart rate (HR) and left ventricular myocardial blood flow (LVMBF) at rest and during treadmill exercise in dogs
(24 –26, 33, 34, 37, 41, 44, 132, 137, 140, 141, 144, 174, 212, 214, 289, 356, 427, 440, 444, 473, 524, 567–569, 588, 624), swine (76, 77, 139, 146, 147, 236,
345, 430, 431, 499, 500, 539, 540, 547, 603), and horses (17, 378, 379, 448). Data from humans were obtained principally from young healthy male
subjects performing upright bicycle exercise (162, 258, 275, 302, 303, 316, 420, 426, 469, 593, 614, 615). Data from rats (185) have been added (solid
circles representing rest and exercise data) to illustrate that the high LVMBF values in this species are the result of the high heart rates, so that the
rat data fall right on the regression line for the human data.
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DIRK J. DUNCKER AND ROBERT J. BACHE
rates in rats, and the modest relative increase in myocardial blood flow in response to exercise was proportionate
to the modest further increase in heart rate (Fig. 4). Thus
myocardial blood flow in the rat is much higher than in
larger animals during resting conditions, but the increase
in blood flow during treadmill exercise is much less than
in larger animals. The lack of hemodynamic response to
swimming indicates that this stress is not likely to be
useful for examining coronary responses to exercise (35,
185). Furthermore, the response to treadmill exercise in
rats is so dissimilar to that of larger animals (including
humans) that even treadmill exercise is likely to be of
limited value in understanding regulation of coronary
blood flow responses to exercise in larger animal species
or in humans.
2. Oxygen-carrying capacity of arterial blood
A) HEMOGLOBIN. In the dog, horse, and sheep, oxygen
delivery to the myocardium is facilitated by prominent
increases in hemoglobin concentration during exercise
and the resultant increase in oxygen carrying capacity of
arterial blood. The hemoglobin concentration increases
because exercise elicits splenic contraction that expresses erythrocyte-rich blood into the general circulation. Thus dogs performing near-maximal treadmill exercise have been reported to sustain a 12–21% increase in
hematocrit (313, 588). Vatner et al. (583) reported a 23%
increase in hematocrit during heavy exercise in free running dogs which was abolished by splenectomy. Manohar
(378) reported that in ponies hemoglobin increased from
11.4 g/dl at rest to 16.9 g/dl at maximal exercise, a 48%
increase. This resulted principally from splenic contraction, as in splenectomized ponies hemoglobin content
increased from 12.3 g/dl at rest to 13.9 g/dl at maximal
exercise, an increase of only 13%. Augmentation of the
arterial oxygen content is an important response to exercise, since splenectomized ponies required higher myocardial blood flow rates at similar work loads (378). Furthermore, normal ponies had residual coronary vasodilator reserve in response to adenosine infusion even during
maximal exercise, whereas in splenectomized animals,
vasodilator reserve was exhausted in the subendocardium during heavy exercise (378). In sheep, hemoglobin
concentration increased from 9.1 ⫾ 0.4 g/dl at rest to
13.1 ⫾ 0.8 g/dl during maximal exercise (415). Pretreatment with the nonselective ␣-adrenergic receptor blocker
phenoxybenzamine blunted the increase from 9.0 ⫾ 1.1 to
11.3 ⫾ 0.9 g/dl, indicating that contraction of the spleen is
mediated by ␣-adrenergic receptor activation during exercise. In swine, hemoglobin increases by 10 –20% (16,
148, 247, 345, 395, 539, 540, 547); this increase was abolished by pretreatment with the mixed ␣1/␣2-adrenergic
receptor antagonist phentolamine, supporting a role for
␣-adrenergic-mediated splenic contraction during exer-
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cise (148). The ␣-adrenergic receptor involved in the exercise-induced splenic contraction is likely of the ␣1-subtype, as the exercise-induced increase in hemoglobin can
be mimicked with the ␣1-adrenergic receptor agonist
phenylephrine (502). Blockade of the increase in hemoglobin in both swine or dogs requires a greater increase in
coronary blood flow at each level of myocardial oxygen
consumption (148, 502), indicating that the increase in
hemoglobin is physiologically important in these species,
although less than in horses. The hemoglobin concentration in humans increases by no more than 15% in response
to upright exercise (97); this increase is not the result of
splenic contraction, but rather is due principally to a
decrease in plasma volume resulting from extravasation
of fluid from the capillaries (244, 483, 484).
B) ARTERIAL OXYGEN SATURATION OF HEMOGLOBIN. Arterial
oxygen tension and saturation are generally unchanged
during submaximal and maximal exercise in normal humans (97). However, in endurance athletes with extremely high values of maximum total body oxygen consumption, decreases in arterial oxygen tension have been
reported (127, 296, 551). Arterial oxygen tensions were
not changed during maximal exercise in chronically instrumented dogs (247, 587), whereas a 12- to 20-mmHg
decrease in arterial oxygen tension has been reported in
chronically instrumented ponies during heavy exercise
(301, 377), and a 5- to 10-mmHg decrease in exercising
swine (16, 145, 247, 394), although this is not a uniform
finding in either ponies (378, 448) or swine (149, 345). It is
important to note that small changes in arterial oxygen
tension contribute little to the arterial oxygen content,
since the arterial oxygen-hemoglobin dissociation curve
operates at its upper plateau even during resting conditions. Consequently, even in the studies that reported a
12- to 20-mmHg decrease in oxygen tension, arterial hemoglobin oxygen saturation was maintained (301, 377).
3. Myocardial oxygen extraction
A) RELATION TO MYOCARDIAL OXYGEN CONSUMPTION. In many
species, the increase in oxygen delivery to the heart during exercise does not fully match the increased oxygen
demand, necessitating an increase of myocardial oxygen
extraction, with widening of the arteriovenous oxygen difference and a decrease in coronary venous oxygen content (24,
121, 258, 275, 291, 313, 316, 377, 541, 588). In normal male
human subjects who performed bicycle exercise to
achieve heart rates of 171 beats/min (⬃85% of predicted
maximum heart rate), coronary sinus oxygen content decreased from 8.5 ⫾ 1.6 ml/dl at rest to 6.6 ⫾ 0.7 ml/dl at
peak exercise (22% decrease) (316). Similar findings have
been reported by other investigators in human subjects
during heavy exercise (258, 275), but lesser exercise loads
(⬍70% of maximum heart rate) did not result in increased
myocardial oxygen extraction or decreased coronary ve-
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nous oxygen content compared with resting conditions
(57, 211, 372, 402, 469, 471). It is likely that the relatively
light levels of exercise used in the latter studies can
account for the lesser increases of oxygen extraction. Von
Restorff et al. (588) reported that heavy treadmill exercise
in dogs, which increased heart rate to 284 beats/min,
increased myocardial oxygen extraction from 75 ⫾ 2% at
rest to 93 ⫾ 1% during exercise, with a decrease in coronary venous oxygen saturation from 24 ⫾ 1 to 9 ⫾ 1%.
Bache and Dai (27) observed a decrease in coronary sinus
oxygen tension from 21 ⫾ 2 to 13 ⫾ 1 mmHg over a
similar exercise range. Similarly, Manohar (377) reported
that in horses coronary venous oxygen tension decreased
from 22 ⫾ 1 mmHg at rest to 15 ⫾ 1 mmHg during heavy
exercise. In contrast, in swine, myocardial oxygen extraction and coronary venous oxygen tension remain unaltered during treadmill exercise, even at levels of up to
80 –90% of maximum heart rate (145, 147–149, 393, 395,
396).
Interestingly, Heiss et al. (258) observed in young
healthy male volunteers that the coronary venous oxygen
content decreased by 8% with no change in coronary
venous oxygen tension (Fig. 5). Similarly, in young
healthy male volunteers, Grubbstrom et al. (224) observed a marked decrease in coronary venous oxygen
saturation from 33 ⫾ 2% at rest to 24 ⫾ 2% during heavy
exercise at ⬃90% of maximum heart rate, whereas coro-
FIG. 5. Relation between myocardial oxygen consumption (MV̇O2)
and coronary venous oxygen tension (left panel) and oxygen saturation
(right panel) at rest and during treadmill exercise in swine (148),
humans (258), horses (377, 448), and dogs (24, 588). Note that exercise
does not alter coronary venous oxygen tension in swine, whereas it is
already reduced at low levels of exercise in dogs. Humans and horses
demonstrate an intermediate oxygen tension response. During exercise,
oxygen saturation decreases in horses and humans (similar to dogs),
whereas in swine saturation is not affected, suggesting a rightward shift
of the hemoglobin-oxygen dissociation curve during exercise in humans
and horses. Also note that despite similar resting coronary venous
oxygen tensions, horses and humans have higher hemoglobin oxygen
saturations compared with swine and dogs, consistent with the higher
P50 values reported in the latter species (286, 474). Data are means ⫾ SE.
*P ⬍ 0.05 vs. corresponding rest. See text for further explanation.
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nary venous oxygen tension was minimally affected (21 ⫾
1 mmHg at rest versus 18 ⫾ 2 mmHg during exercise).
These observations suggest that a rightward shift of the
hemoglobin oxygen dissociation curve acts to facilitate
oxygen delivery to the myocardium during heavy exercise
in humans. The decrease in blood pH resulting from lactate production by working skeletal muscle has been
reported to cause a rightward shift of the hemoglobin
oxygen dissociation curve in humans (224, 258) and
horses (377). However, in dogs, the coronary venous
blood pH did not change even during maximal exercise
(247) and therefore cannot contribute to this rightward
shift. This may explain why in dogs coronary venous
oxygen tension is decreased at relatively low levels (⬍70%
of maximum) of exercise, whereas in horses and humans
coronary venous oxygen tensions decrease less despite
similar decrements in oxygen saturation (Fig. 5). The
observation that coronary venous oxygen saturation levels are maintained in exercising swine is consistent with
the unchanged arterial carbon dioxide tension and pH at
submaximal levels of exercise (80 –90% of maximum)
(149). It is possible that during exhaustive exercise lactate
production by skeletal muscle (430, 431) and the associated decrease in blood pH (247) also facilitate a decrease
in coronary venous oxygen saturation in swine.
B) RELATION TO VASOMOTOR CONTROL IN CORONARY RESISTANCE
VESSELS.
Adrenergic vasoconstrictor mechanisms restrain
the increase in coronary blood flow during exercise,
thereby contributing to the increased oxygen extraction.
Thus nonselective ␣-adrenergic blockade with phentolamine or selective ␣1-adrenergic blockade with prazosin
increased myocardial blood flow during exercise, which
was accompanied by decreased myocardial oxygen extraction and increased coronary venous oxygen tension
(27, 31, 122, 214, 266). However, ␣-adrenergic blockade
did not completely eliminate the increase in myocardial
oxygen extraction that occurred during exercise (27, 31),
which could have resulted from incomplete blockade or
from other unidentified factors which restrain coronary
vasodilation during exercise. Alternatively, a decrease in
coronary venous oxygen tension has been proposed to
represent a metabolic error signal, needed for negativefeedback metabolic control of myocardial oxygen delivery and hence coronary blood flow. However, the observation that oxygen tension is minimally affected in exercising swine (148), and during submaximal exercise in
humans (258, 471), indicates that a decrease in oxygen
tension is not obligatory for the exercise-induced increase
in coronary blood flow.
C) RELATION TO VASODILATOR RESERVE, OXIDATIVE METABOLISM,
AND CONTRACTILE FUNCTION. The increased oxygen extraction
indicates that the increase of myocardial blood flow during exercise does not fully compensate for the increased
oxygen demands. Failure of blood flow to fully meet the
increase in myocardial oxygen consumption is not the
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1016
DIRK J. DUNCKER AND ROBERT J. BACHE
result of exhaustion of coronary vasodilator reserve during exercise, since a further increase in coronary blood
flow can be elicited with a pharmacological or ischemic
vasodilator stimulus. For example, during maximal treadmill exercise in dogs and swine, a brief total coronary
occlusion has been shown to result in reactive hyperemia
with a further increase in blood flow (588, 603). Furthermore, intravenous administration of adenosine to swine
resulted in a 15–26% increase in myocardial blood flow
during maximum exercise, despite a significant drop in
arterial pressure (77, 500, 603). When the results were
expressed in terms of coronary resistance, adenosine
caused a 20 ⫾ 1% further decrease in coronary vascular
resistance in swine during maximal exercise (603). Similarly, dipyridamole administered intravenously or into the
left atrium of dogs or swine during near-maximal or maximal treadmill exercise caused a 20 – 46% further increase
in myocardial blood flow (41, 342). An even greater adenosine-recruitable flow reserve was reported in ponies during near-maximal exercise (378, 448), causing an increase
in myocardial blood flow from 5.34 ⫾ 0.31 to 9.34 ⫾ 0.66
ml䡠min⫺1 䡠g⫺1 (448). Taken together, these studies demonstrate that in the normal heart substantial coronary
vasodilator reserve exists even during maximal exercise.
Although the increase in myocardial oxygen extraction indicates that coronary blood flow does not keep
pace with the increased myocardial oxygen demands during exercise, there is no evidence to suggest that this
disparity results in ischemia in the normal heart even
during heavy exercise. Studies examining myocardial lactate metabolism for evidence of anaerobic glycolysis demonstrated continued lactate consumption even during
heavy exercise (258, 275, 291, 402). Nevertheless, Gwirtz
and co-workers (230, 232) found that pharmacologically
induced increases of coronary blood flow during exercise
can enhance contractile function, which is known as the
Gregg effect (see Refs. 181, 599 for in depth reviews).
These investigators observed that intracoronary administration of the selective ␣1-adrenergic blocker prazosin
during treadmill exercise in dogs caused a 21 ⫾ 3% increase in coronary artery blood flow that was associated
with a 21 ⫾ 4% increase in the maximal rate of regional
myocardial segment shortening (total systolic shortening
was unchanged) and a 26% increase in myocardial oxygen
consumption. The increased velocity of shortening was
not mediated by enhanced ␤-adrenergic activation, since
a similar response to prazosin was observed after ␤-adrenergic blockade with propranolol (232). Similarly, intracoronary administration of adenosine during exercise
caused a 25–30% increase in coronary blood flow (230,
291), and this was associated with a 27% increase in the
rate of systolic segment shortening (230) and a 16% increase of myocardial oxygen consumption (291). The effects on contractile function produced by both intracoronary adenosine and prazosin occurred with no change in
Physiol Rev • VOL
heart rate, left ventricular systolic pressure, or myocardial
end-diastolic segment length (230, 232). The observed
increases in the velocity of segment shortening and myocardial oxygen utilization in response to pharmacological
coronary vasodilation during exercise suggest that coronary flow may modulate the increase of myocardial contractility that occurs during exercise.
C. Determinants of Coronary Blood Flow
1. Effective perfusion pressure: extravascular
compressive forces
The effective perfusion pressure of the coronary bed
is determined by the pressure drop across the coronary
vascular bed, with the entrance pressure being aortic
pressure. However, because extravascular forces are exerted on the compressible intramural coronary vasculature by the surrounding myocardium, the effective back
pressure that acts to impede coronary blood flow cannot
simply be equated to right atrial pressure. The interaction
between the intravascular distending pressure and the
extravascular compressive forces can be described by the
“vascular waterfall” and is especially important during
systole (134, 262) but also, albeit to a lesser extent, during
diastole (52, 571, 585, 592). Thus, during systole, the contracting myocardium generates a high level of intramyocardial pressure that compresses the coronary microvasculature, thereby impeding blood flow (Figs. 6 and 7; Refs.
257, 309, 313, 500, 599). Conversely, during diastole, intraventricular pressures transmitted into the left ventricular
wall exert a small compressive force on the intramural
vasculature (20, 154, 163, 274), creating waterfalls at the
level of the arterioles and the venules, and possibly the
epicardial veins (571, 585, 599). For an in depth review of
the interaction of the myocardium and coronary vasculature, the reader is referred to a recent article in this
journal (599).
Isolating the impeding effects of cardiac contraction
on coronary blood flow requires elimination of active
vasomotor influences by producing maximal vasodilation
of the coronary vascular bed. An early study reported that
“minimum” coronary vascular resistance (calculated as
aortic pressure/mean coronary blood flow during intravenous administration of adenosine) was lower during
treadmill exercise than at rest (448). However, computation of vascular resistance from single measurements of
pressure and flow does not fully characterize the effects
of changes in extravascular forces. Comprehensive analysis of mechanical effects of cardiac contraction on blood
flow is provided by the pressure-flow relationship, obtained from multiple measurements of coronary blood
flow over a range of perfusion pressures. During maximum vasodilation, the pressure-flow relationship is determined by the maximum vascular conductance, repre-
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1017
CORONARY BLOOD FLOW
FIG. 6. Hemodynamic responses to
treadmill exercise in dogs. L.CIRC., left
circumflex coronary artery; COR, coronary; SYST, systolic; DIAST, diastolic.
See text for further explanation. [Modified from Khouri et al. (313).]
sented by the slope of the relationship, and the x-intercept
or pressure at which flow ceases (zero-flow pressure; Pzf);
in the maximally dilated circulation, changes in Pzf are
determined principally by changes of the extravascular
compressive forces (15, 318, 503, 621). Duncker et al.
(151) used this technique to study the effect of exercise
on coronary blood flow in dogs. Maximum coronary vasodilation was maintained by intra-arterial infusion of
adenosine (50 ␮g䡠 kg⫺1 䡠min⫺1); this dose was determined
to cause maximum vasodilation, since larger doses
caused no further increase in blood flow. As heart rate
increased from 118 beats/min at rest to 213 beats/min
during treadmill exercise, blood flow in the maximally
vasodilated coronary circulation decreased from 5.66 ⫾
0.41 ml䡠min⫺1 䡠g⫺1 during resting conditions to 4.62 ⫾
0.43 ml䡠min⫺1 䡠g myocardium⫺1 despite a significant increase in coronary perfusion pressure (aortic pressure).
The decrease of coronary blood flow resulted from an
increase of Pzf from 13 ⫾ 1 mmHg at rest to 23 ⫾ 2 mmHg
during exercise, as well as a decrease in the slope of the
pressure-flow relationship from 12.3 ⫾ 0.9 to 10.9 ⫾ 0.9
(ml 䡠min⫺1 䡠g⫺1)/mmHg during exercise (Fig. 8). Several
factors may contribute to this alteration of the coronary
pressure-flow relationship during exercise. First, the increase in heart rate decreases maximum coronary blood
flow rates by increasing the total time spent in systole
(23). Second, the increased contractility increases systolic compression of the intramural coronary vessels (325,
385, 533, 563). However, the increased contractility simulPhysiol Rev • VOL
taneously augments myocardial relaxation which increases the diastolic perfusion time (142, 465, 625). Finally, an increase of left ventricular diastolic filling pressure decreases maximum coronary blood flow (20, 154,
163). Analysis of the individual contributions of each of
these variables to the exercise-induced changes in the
coronary pressure-flow relationship demonstrated that
heart rate and left ventricular diastolic pressure contributed to the increases in the Pzf, whereas the increase in
contractility did not have a significant effect (137, 151),
likely because the impeding effect of the increased force
of contraction was offset by enhanced relaxation which
increased the diastolic perfusion time.
The increase in extravascular compressive forces
during exercise is unlikely to be of physiological significance in the normal coronary circulation, because coronary vasodilator reserve capacity persists even during
maximal exercise (41, 77, 342, 378, 448, 500, 603). However, when the oxygen-carrying capacity of the blood is
reduced by anemia or hypoxia, or when atherosclerotic
coronary artery disease reduces vascular caliber (see
sect. III), then the increased extravascular forces produced
by exercise could produce a functionally significant limitation of coronary blood flow rates during exercise.
2. Coronary vascular resistance
During exercise, the increase in aortic pressure only
slightly exceeds the increase in effective back pressure so
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1018
DIRK J. DUNCKER AND ROBERT J. BACHE
FIG. 7. Hemodynamic responses to treadmill exercise in swine. HR, heart rate; AoBP, aortic blood
pressure; LAP, left atrial pressure; CO, cardiac output; df/dt, cardiac output differentiated over time;
CBF, coronary blood flow; SS, stroke systolic; SD,
stroke diastolic. See text for further explanation.
[Modified from Sanders et al. (500).]
that the effective perfusion pressure increases by no more
than 20 –30% (151, 377). Consequently, the exercise-induced four- to sixfold increase in coronary blood flow is
mediated principally by a decrease in coronary vascular
resistance. Indeed, maximal exercise is associated with
decreases in calculated coronary vascular resistance to
20 –30% of basal resting values in dogs, swine, and horses
(77, 378, 448, 587).
Total coronary resistance is the sum of both passive
(structural) and active (smooth muscle tone) components
(346, 411). In the completely vasodilated bed, flow to the
different regions of the heart is determined by the crosssectional area of the vessels, the length of the vasculature,
and the number of parallel vessels that supply a defined
perfusion territory. Measurements of intravascular presPhysiol Rev • VOL
sure during basal conditions have shown that ⬃90% of
resistance resides in the small arteries and arterioles,
hence the term resistance vessels (101, 105). The total
length of the vessels supplying the subendocardium is
longer than those supplying the subepicardium. In addition, cardiac contraction compresses the intramural vasculature during systole, impeding blood flow especially to
the subendocardium (see sect. IID). To facilitate augmented flow during diastole to compensate for systolic
underperfusion, the subendocardium has a 10% higher
arteriolar and capillary density (53) so that during maximal pharmacological vasodilation under resting conditions, flow to the subendocardium is similar to flow to the
subepicardium (140, 470). In addition, there is evidence
that the subendocardial resistance vessels are more sen-
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CORONARY BLOOD FLOW
FIG. 8. Coronary pressure-flow relation in the dog heart under
conditions of maximal coronary vasodilation with intracoronary adenosine (50 ␮g 䡠 kg⫺1 䡠 min⫺1). Shown are the relations at rest and during
three incremental levels of treadmill exercise. Note the rightward shift
of the pressure-flow relation with an increase in the zero-flow pressure
intercept. See text for further explanation. Data are means ⫾ SE. *P ⬍
0.05 vs. corresponding rest. [Data from Duncker et al. (151).]
sitive to mediators of vasodilation including adenosine
(470) and endothelium-dependent dilators (449). These
structural and functional adaptations aid in maintaining
blood flow to the subendocardial layers.
D. Transmural Distribution of Left Ventricular
Myocardial Blood Flow
1. Systolic compression of intramyocardial vessels
Cardiac contraction impedes myocardial blood flow
during systole so that during basal conditions arterial
inflow occurs predominantly during diastole. Measurements of proximal coronary artery flow in chronically
instrumented dogs (313) and swine (500) demonstrate
that during resting conditions only 15–20% of left ventricular flow occurs during systole (Figs. 6 and 7). However,
the high heart rates associated with exercise result in
progressive encroachment of systole on the diastolic interval, while absolute blood flow rates during systole
increase. As a result, during heavy exercise 40 –50% of
total coronary artery blood flow occurs during systole
(313, 500). The increase in the fraction of coronary flow
during systole has implications for the transmural distribution of left ventricular myocardial blood flow, as the
throttling effect of cardiac contraction on the intramural
coronary vessels is expressed nonuniformly across the
left ventricular wall (Fig. 9). Myocardial compressive
force increases from intrathoracic pressure at the epicardial surface to equal or to exceed intraventricular presPhysiol Rev • VOL
1019
sure at the endocardial surface (15, 71). Interaction of this
gradient of effective tissue pressure with the intravascular
distending pressure acts to create an array of vascular
waterfalls across the wall of the left ventricle that selectively impedes subendocardial blood flow during systole
(134, 140, 262, 305). Furthermore, blood from vessels
within the innermost ventricular layers is squeezed retrograde into more superficial subepicardial arterial vessels
during each systole so that subendocardial vessels have to
be refilled in diastole (analogous to the emptying and
filling of a capacitor; Refs. 274, 305, 599). Consequently,
systolic flow is directed toward the subepicardium, while
antegrade subendocardial blood flow occurs exclusively
during diastole. Moreover, with shortening of diastole
when the heart rate increases, a relatively greater part of
diastole is required to refill the subendocardial vessels,
thereby delaying net forward flow in the subendocardial
microcirculation. The effects of the increased force of
cardiac contraction and increased heart rate during exercise can be studied by maximally vasodilating the coronary circulation with an intracoronary infusion of adenosine (infused regionally to avoid systemic hemodynamic
effects), allowing selective study of the impeding effects of cardiac contraction without the confounding
influence of metabolic vasoregulation of coronary resistance vessel tone. Using this approach, we observed
that exercise caused a redistribution of blood flow
away from the subendocardium toward the subepicardium (Fig. 10). The increase in subepicardial blood flow
during exercise is consistent with the presence of an
intramyocardial pump (274) but was aided, at least in
part, by the exercise-induced increase in coronary perfusion pressure (140).
Despite the mechanical effects of cardiac contraction that act to increase impedance to blood flow to the
deeper myocardial layers during exercise, in the normal
heart with intact coronary tone a modest net transmural gradient of blood flow favoring the subendocardium
exists, reflecting the higher systolic tension development and oxygen requirements of this layer (596). Maintenance of this normal pattern of transmural perfusion
requires augmentation of subendocardial flow during
diastole in proportion to the degree of systolic underperfusion. This diastolic gradient of blood flow favoring
the subendocardium is dependent on a transmural gradient of vasomotor tone, with vascular resistance during diastole being lowest in the subendocardium (23).
2. Subendocardial/subepicardial blood flow ratio
The transmural distribution of myocardial blood
flow during exercise has been measured with radioactive microspheres. In most cases, the left ventricular
wall has been divided into three or four layers, and the
transmural distribution of perfusion was expressed as
ratio of blood flow to the innermost layer (subendocar-
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1020
DIRK J. DUNCKER AND ROBERT J. BACHE
FIG. 9. Graph showing a schematic drawing of the intramyocardial microvasculature (top panel) and the extravascular forces acting on the
coronary microvasculature during diastole (bottom left panel) and systole (bottom right panel). PIM, intramyocardial pressure; PLUMEN, pressure in
left ventricular lumen; PPERI, pressure in pericardial space. See text for further explanation.
dium) divided by blood flow to the outermost layer
(subepicardium) (ENDO/EPI ratio). In chronically instrumented awake dogs and swine, ENDO/EPI blood
flow ratios at rest have been reported between 1.09 and
1.49 (24, 26, 34, 37, 41, 76, 77, 132, 140, 146, 147, 236,
327, 342, 427, 440, 499, 500, 588, 603). ENDO/EPI ratios
are somewhat dependent on the size microsphere used.
In early studies in which 7- to 10-␮m-diameter microspheres were used, ENDO/EPI ratios decreased during
exercise, with values near 1.0 during heavy exercise
(37, 41, 603). In contrast, when 15-␮m-diameter microspheres were used, higher ENDO/EPI ratios have generally been reported with values of 1.10 –1.31 during
heavy exercise (Fig. 11) (24, 26, 327, 430, 431, 440, 499,
500), although several studies in swine reported values
near 1.00 (76, 77, 147, 236, 342). Conversely, Symons
Physiol Rev • VOL
and Stebbins (547) reported higher ENDO/EPI values in
awake swine at rest (1.68) and during moderate exercise (1.53) than any other laboratories; an explanation
for their findings is not readily found. The reason for
the disparity in the transmural distribution of microspheres during exercise based on size is uncertain, but
could be the result of streaming of the larger microspheres into the penetrating arteries that deliver blood
to the subendocardium, or to arteriovenous shunting of
a fraction of the 7- to 10-␮m-diameter microspheres
from the subendocardial microvessels. Size-dependent
characteristics of microsphere measurements in the
myocardium have been previously reviewed (573). Ponies and standard bred horses appear to have a more
prominent decrease in ENDO/EPI ratio during exercise
than either dogs or swine (Fig. 11). Using 15-␮m-diam-
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CORONARY BLOOD FLOW
1021
EPI ratio during heavy exercise in dogs increased from
1.03 during control conditions to 1.15 after the administration of dipyridamole. Intravenous adenosine had no
effect on the ENDO/EPI ratio during maximal exercise in
ponies (378, 448). Furthermore, Breisch et al. (77) reported that during heavy exercise in swine, the ENDO/EPI
ratio was maintained near unity during vasodilation with
adenosine. The reason for this disparity is unclear but
does not appear to be due to adenosine-induced alterations in blood pressure (Table 1). Of greatest importance, however, is the finding that absolute subendocardial blood flow rates increased in response to exogenous
adenosine or dipyridamole during heavy exercise (41, 77,
140, 342, 378, 448, 500, 603), indicating that vasodilator
reserve had not been exhausted (Table 1).
E. Coronary Blood Flow to the Right Ventricle
and the Atria
FIG. 10. Distribution of left ventricular myocardial blood flow in the
dog at rest (open symbols) and during exercise (solid symbols) in the
presence of intact vasomotor tone (circles) and during maximum vasodilation with intracoronary adenosine (squares). Data are means ⫾ SE.
*P ⬍ 0.05 vs corresponding rest. Dot inside symbol denotes significant
(P ⬍ 0.05) increase in flow produced by adenosine. [Data from Duncker
et al. (140).]
1. Right ventricular blood flow
During quiet resting conditions, right ventricular
blood flow in the dog and horse expressed per gram of
eter microspheres, Manohar and associates (378, 448)
reported that ENDO/EPI ratios in ponies decreased
from 1.18 –1.27 at rest to 0.97– 0.99 during heavy treadmill exercise. Similarly, Armstrong et al. (17) reported
a decrease in ENDO/EPI ratio from 1.24 at rest to 1.05
during exercise in standard bred horses. This may be in
part the result of the marked increase in left ventricular
end-diastolic pressure that occurred in horses from 11
⫾ 2 mmHg at rest to 36 ⫾ 4 mmHg during heavy
exercise, which contrasts with increases in left ventricular end-diastolic or left atrial pressure from 2–5 mmHg
at rest to only 5–15 mmHg during heavy exercise in
dogs (7, 24, 26, 37, 153, 279, 440) and swine (147, 500,
603).
3. Influence of vasomotor tone on the transmural
distribution of myocardial blood flow
Several studies suggest that active coronary vasomotor tone is important for maintaining subendocardial
blood flow during exercise. Thus studies in swine and
dogs have demonstrated that coronary vasodilation with
adenosine or dipyridamole during exercise caused the
ENDO/EPI ratio to fall significantly below 1.0 (Fig. 10;
Table 1; Refs. 140, 342, 500, 603). These findings could be
interpreted to suggest that at high heart rates during
exercise, active vasomotion is required to maintain a
gradient of vascular resistance favoring perfusion of the
deeper myocardial layers during diastole. In contrast to
these reports, Barnard et al. (41) reported that the ENDO/
Physiol Rev • VOL
FIG. 11. Relation between heart rate (HR) and left ventricular
subendocardial to subepicardial blood flow ratio (LV endo/epi) at rest
and during treadmill exercise in dogs (24, 26, 34, 132, 140, 427, 440),
swine (76, 77, 147, 236, 327, 342, 430, 431, 499, 500), and horses (17, 378,
448), measured with microspheres 15 ␮m in diameter. No data on
transmural distribution of left ventricular blood flow are available in
humans. Note that exercise results in a modest decrease in endo/epi
ratio, but this typically does not decrease below 1.0 even during heavy
exercise. Also note that endo/epi ratios are lower and decrease more
during exercise in horses (LV E/E ⫽ ⫺1.37HR ⫹ 1.30) than in either
swine (LV E/E ⫽ ⫺1.17HR ⫹ 1.38) or dogs (LV E/E ⫽ ⫺1.06HR ⫹ 1.41).
88 • JULY 2008 •
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1.
Dog
Barnard et al.
(41)
Sanders
et al. (500)
Physiol Rev • VOL
88 • JULY 2008 •
Swine
Swine
Breisch et al.
(77)
Laughlin
et al. (342)
Parks and
Manohar
(448)
Manohar (378)
www.prv.org
Reactive hyperemia
to “brief”
occlusion
Dipyridamole, 0.75
mg/kg ia
Adenosine, 1.5
mg 䡠 kg⫺1 䡠 min⫺1
iv
Adenosine, 0.8
mg 䡠 kg⫺1 䡠 min⫺1
iv
Reactive hyperemia
to 10-s occlusion
Adenosine, 0.8
mg 䡠 kg⫺1 䡠 min⫺1
iv
Dipyridamole, 1-2
mg/kg, iv
Adenosine, 4
␮mol 䡠 kg⫺1 䡠 min⫺1
iv
Adenosine, 3
␮mol 䡠 kg⫺1 䡠 min⫺1
iv
Method of Vasodilation
283 ⫾ 5
?
293 ⫾ 9*
227 ⫾ 6
224 ⫾ 5
281 ⫾ 6
238 ⫾ 15
225 ⫾ 7
224 ⫾ 6
239 ⫾ 3
240 ⫾ 3
283 ⫾ 5
260 ⫾ 9
271 ⫾ 8
282 ⫾ 6
?
284 ⫾ 6
283 ⫾ 5
Exercise ⫹
Vasodilation
Exercise
155 ⫾ 8
160 ⫾ 4
164 ⫾ 10
146 ⫾ 7
138 ⫾ 5
138 ⫾ 5
161 ⫾ 5
?
125 ⫾ 5
Exercise
138 ⫾ 6*
153 ⫾ 9
133 ⫾ 7*
71 ⫾ 3*
136 ⫾ 5
128 ⫾ 6*
155 ⫾ 6
?
?
Exercise ⫹
Vasodilation
Mean Arterial Blood
Pressure, mmHg
5.30 ⫾ 0.32
5.34 ⫾ 0.31
5.26 ⫾ 0.47
4.05 ⫾ 0.20
3.82 ⫾ 0.24
3.82 ⫾ 0.24
2.46 ⫾ 0.24
4.24 ⫾ 0.30
2.56 ⫾ 0.10
Exercise
9.40 ⫾ 0.71*
9.34 ⫾ 0.66*
6.17 ⫾ 0.71*
5.10 ⫾ 0.30*
4.99 ⫾ 0.35*
4.41 ⫾ 0.29*
3.14 ⫾ 0.24*
6.20 ⫾ 0.35*
3.84*
Exercise ⫹
Vasodilation
Mean CBF, ml 䡠 min⫺1 䡠 g⫺1
0.97 ⫾ 0.01
0.99 ⫾ 0.02
1.02 ⫾ 0.05
1.00 ⫾ 0.04
1.04 ⫾ 0.07
1.04 ⫾ 0.07
1.05 ⫾ 0.07
1.03 ⫾ 0.05
?
Exercise
1.02 ⫾ 0.11
1.11 ⫾ 0.15
0.87 ⫾ 0.03*
0.98 ⫾ 0.03
1.41 ⫾ 0.07*
0.89 ⫾ 0.08*
0.87 ⫾ 0.13*
1.15 ⫾ 0.08
?
Exercise ⫹
Vasodilation
Endo/Epi
5.4 ⫾ 0.3
5.1 ⫾ 0.4
5.21 ⫾ 0.44
4.05 ⫾ 0.20
3.89
3.89
2.48 ⫾ 0.19
4.31
?
Exercise
9.5 ⫾ 1.1*
8.7 ⫾ 0.8*
5.62 ⫾ 0.51
5.09 ⫾ 0.32*
5.84a
4.15a
2.82 ⫾ 0.19*
6.64a
?
Exercise ⫹
Vasodilation
Subendocardial Blood Flow,
ml 䡠 min⫺1 䡠 g⫺1
Data
are means ⫾ SE. HR, heart rate; CBF, coronary blood flow; Endo/Epi, subendocardial-to-subepicardial blood flow ratio; “?”, not reported; ia, intra-atrial (infusion into the left
a
atrium). Computed from mean myocardial flow and Endo/Epi ratio. *P ⬍ 0.05, effect of vasodilation during vs. before vasodilation.
Pony
Pony
Swine
White et al.
(603)
Swine
Dog
von Restorff
et al. (588)
Species
HR, beats/min
Coronary vasodilator reserve during severe treadmill exercise
Investigators
TABLE
1022
DIRK J. DUNCKER AND ROBERT J. BACHE
CORONARY BLOOD FLOW
myocardium is typically 50 – 60% of left ventricular blood
flow, while the transmural distribution of perfusion is
uniform or slightly favors the subendocardium (34, 37, 44,
378, 379, 440). In resting swine, right ventricular blood
flow per gram of myocardium is ⬃70 –90% of left ventricular blood flow with an ENDO/EPI ratio of 1.50 (147, 342,
499). The lower resting flows in the right ventricle are the
result of the lower oxygen consumption (245, 626), consistent with the markedly lower right ventricular, compared with left ventricular, systolic pressure. Interestingly, the lower levels of oxygen consumption are associated with significantly lower levels of myocardial
oxygen extraction (46 ⫾ 3%) by the right ventricle (245,
620).
During graded treadmill exercise in dogs, swine, and
horses, right ventricular blood flow increases as a direct
function of heart rate (Fig. 12). Right ventricular blood
flow expressed per gram of myocardium is ⬃75–90% of
flow to the left ventricle during the heaviest levels of
exercise (34, 37, 44, 342, 378, 379), while in one study
of swine exercising at 85–90% of maximum heart rate,
right ventricular blood flow slightly exceeded left ventricular flow (147). The relatively greater exercise-induced
increase in right ventricular blood flow during heavy exercise (3- to 6-fold) compared with left ventricular blood
1023
flow (2.5- to 4-fold), likely reflects the greater increase in
right ventricular myocardial oxygen consumption (245)
secondary to the marked increase in pulmonary artery
pressure during exercise (147, 627). The relative increase
in right ventricular blood flow during heavy exercise appears to be greatest in ponies (8- to 10-fold; Refs. 378, 379)
compared with dogs (5- to 6-fold; Refs. 34, 37), and swine
(3- to 4-fold; Refs. 147, 342). This is likely the result of the
pronounced pulmonary hypertension that occurs during
exercise in horses, with mean pulmonary pressure increasing from 19 –30 mmHg at rest to 66 – 89 mmHg during
maximal exercise (378, 379).
In the left ventricle, the high resting level of oxygen
extraction (70 – 80%) necessitates an increase in coronary
blood flow even at low levels of exercise. Right ventricular oxygen extraction during resting conditions is much
lower, so that ⬃85% of the increment in oxygen consumption produced by mild exercise (60% of maximal heart
rate) was accommodated by an increase in oxygen extraction from 46 ⫾ 3% at rest to 68 ⫾ 2%, with extraction
further increasing to 82 ⫾ 1% during exercise at 80% of
maximal heart rate (Fig. 13) (245). The difference in regulation of oxygen extraction between the right and left
ventricles is incompletely understood, but the blunted
response of right ventricular blood flow to exercise with
FIG. 12. Relation between heart rate
and right ventricular blood flow (top panels)
and left and right atrial blood flow (bottom
panels) in dogs (34, 44), swine (342), and
horses (378, 379) at rest and during treadmill
exercise. Exercise produced significant (P ⬍
0.05) increases in flow to all four cardiac
chambers at each level of exercise studied.
Note that the absolute increases in right ventricular and atrial flows are similar to the
increases in left ventricular flow, but that as
a result of the lower resting right ventricular
and atrial flows, the relative increases are
greater in these cardiac chambers compared
with the left ventricle. Data are means ⫾ SE.
See text for further explanation.
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DIRK J. DUNCKER AND ROBERT J. BACHE
is likely the result of the lower systolic compressive
forces acting on the intramyocardial vasculature in the
right compared with the left ventricle (53).
2. Atrial blood flow
FIG. 13. Relation beween myocardial oxygen consumption and
coronary venous oxygen tension (CVPO2) in the right ventricle (RV) and
the left ventricle (LV) in dogs during treadmill exercise. Note the lower
levels of oxygen consumption and higher coronary venous oxygen tensions in the RV compared with the LV. Data are means ⫾ SE. See text for
further explanation. [Data from Hart et al. (245) for RV flows and from
Gorman et al. (214) for LV flows.]
increased oxygen extraction is not the result of exhaustion of vasodilator reserve. Thus Manohar (378) demonstrated that infusion of adenosine in ponies during maximal treadmill exercise caused right ventricular blood flow
to increase from 4.80 ⫾ 0.31 ml䡠 min⫺1 䡠g⫺1 during maximal exercise to 7.54 ⫾ 0.30 ml䡠min⫺1 䡠g⫺1. Furthermore,
Bauman et al. (45) reported similar vasodilator reserve in
right and left ventricles of dogs at rest and during exercise. Zong et al. (626) demonstrated that the large increase in oxygen extraction during exercise could be in
part explained by an exaggerated ␣-adrenergic vasoconstrictor influence on the right ventricular vasculature.
Nevertheless, following ␣-adrenergic blockade, a significant increase in right ventricular oxygen extraction still
occurred, indicating that other mechanisms must be involved as well.
The transmural distribution of right ventricular blood
flow in dogs and swine does not change from rest to
exercise (34, 37, 342, 440, 499). Furthermore, during maximal exercise in ponies, vasodilator reserve existed in all
transmural layers of the right ventricular wall; the right
ventricular ENDO/EPI ratio during maximal exercise was
1.00 ⫾ 0.02 and actually increased to 1.32 ⫾ 0.10 when
adenosine was infused while exercise continued (378).
The finding that maximal pharmacological coronary vasodilation did not result in a relative redistribution of blood
flow away from the subendocardium in the right ventricle
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During quiet resting conditions, right and left atrial
blood flows expressed per gram of myocardium are typically 20 – 40% of left ventricular blood flow in dogs (44),
swine (342), and horses (379). During treadmill exercise,
atrial flows can increase up to 15-fold reaching 50 – 60% of
left ventricular flow levels during heavy exercise in dogs
and swine, and up to 70% of left ventricular flows in
ponies (Fig. 12). These increases in blood flow do not
require maximal vasodilation of atrial vasculature, as the
degree of vasodilator reserve during exercise was reported to be comparable to those in the ventricular chambers (45). Within the atria, blood flow was reported to be
lowest in the appendage (0.15– 0.30 ml䡠min⫺1 䡠g⫺1) compared with the nonappendage regions (0.33– 0.37
ml䡠min⫺1 䡠g⫺1), whereas the exercise-induced increase in
flow was greater in the appendages (6- to 11-fold in right
and left atria, respectively) compared with the nonappendage regions (4- to 5-fold). These observations suggest
that the appendages perform less work than the body of
the atria under resting conditions, but become increasingly more active as atrial filling is enhanced during exercise (44).
F. Control of Coronary Vascular Resistance
Regulation of coronary vascular resistance is the result of a balance between a myriad of vasodilator and
vasoconstrictor signals exerted by neurohormonal influences, the endothelium, and metabolic signals from the
myocardium (Fig. 14). These vasomotor influences allow
the myocardium to match the coronary blood supply to
the requirement for oxygen and nutrients, while maintaining a consistently high level of oxygen extraction. The
ability of coronary resistance vessels to dilate in response
to increments in myocardial oxygen demand, as illustrated by the tight correlation between myocardial oxygen consumption and coronary blood flow, is critical for
maintaining an adequate supply of oxygen to the myocardium. The matching of coronary vasomotor tone to myocardial metabolism is best studied by examining the relation between coronary venous oxygen tension and myocardial oxygen consumption (27, 143, 266, 267, 565, 566).
For example, an increase in coronary resistance vessel
tone will limit coronary blood flow and hence the oxygen
supply, thereby forcing the myocardium to increase oxygen extraction, with a consequent reduction in coronary
venous oxygen levels. Conversely, a decrease in coronary
tone will increase blood flow and the oxygen supply to the
heart; if oxygen consumption remains constant, oxygen
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1025
FIG. 14. Schematic drawing of a coronary arteriole and the various influences
that determine coronary vasomotor tone
and diameter. PO2, oxygen tension; TxA2,
thromboxane A2 (receptor); 5HT, serotonin
or 5-hydroxytryptamine (receptor); P2X and
P2Y, purinergic receptor subtypes 2X and
2Y that mediate ATP-induced vasoconstriction and vasodilation, respectively; ACh,
acetylcholine; M, muscarinic receptor; H1
and H2, histamine receptors type 1 and 2;
B2, bradykinin receptor subtype 2; ANG I
and ANG II, angiotensin I and II; AT1, angiotensin II receptor subtype 1; ET, endothelin; ETA and ETB, endothelin receptor
subtypes A and B; A2, adenosine receptor
subtype 2; ß2, ß2-adrenergic receptor; ␣1
and ␣2, ␣-adrenergic receptors; NO, nitric
oxide; eNOS, endothelial NO synthase;
PGI2, prostacyclin; IP, prostacyclin receptor;
COX-1, cyclooxygenase-1; EDHF, endotheliumderived hyperpolarizing factor; CYP450, cytochrome P450 2C9; KCa, calcium-sensitive
K⫹ channel; KATP, ATP-sensitive K⫹ channel; KV, voltage-sensitive K⫹ channel; AA,
arachidonic acid; L-Arg, L-arginine; O䡠-2,
superoxide. Receptors, enzymes, and
channels are indicated by an oval or rectangle, respectively. See text for further
explanation.
extraction will decrease and coronary venous oxygen
levels will increase. Thus coronary venous oxygen tension
is an index of tissue oxygenation that reflects the balance
between the oxygen supply and demand of the heart and
is ultimately determined by coronary resistance vessel
tone (565).
1. Autonomic nervous system
Autonomic influences have been studied by examining coronary blood flow at rest and during exercise after
surgical or chemical denervation of the heart or in the
presence of selective autonomic receptor antagonists.
A) CARDIAC NEURAL ABLATION. The coronary vascular bed
is richly innervated by both the sympathetic and parasympathetic divisions of the autonomic nervous system (46,
104, 181, 182, 598). To study their contributions to coronary blood flow regulation during exercise, techniques
have been devised to produce surgical denervation of the
Physiol Rev • VOL
heart confirmed by depletion of myocardial norepinephrine stores and lack of an inotropic response to cardiac
sympathetic nerve stimulation (133, 311). It should be
noted that the results obtained using these preparations
are complicated by supersensitivity to circulating catecholamines which develops after sympathetic neural ablation. This supersensitivity appears to be selective, in that the
response of myocardial contractility to norepinephrine is
augmented (102, 133), whereas ␣-adrenergic responses of
the coronary vasculature do not appear to be enhanced (102,
129, 202).
Cardiac neural ablation does not impair the ability to
maintain steady-state levels of exercise, although the initial hemodynamic adjustment to exercise is delayed. For
example, Gregg et al. (220) observed that in dogs with
surgical cardiac denervation, the onset of heavy treadmill
exercise resulted in a 25% decrease in arterial blood pressure that did not return to control levels until 36 –90 s
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DIRK J. DUNCKER AND ROBERT J. BACHE
after beginning exercise, while in normal dogs arterial
pressure decreased only slightly and recovered within
3– 6 s after beginning exercise. Similarly, the increase in
coronary blood flow was delayed 10 –30 se after the onset
of treadmill exercise in animals with cardiac denervation,
in contrast to a 3- to 6-s delay observed in normal dogs.
Gwirtz et al. (231) observed that cardiac sympathectomy
decreased left ventricular peak systolic pressure and dP/
dtmax during exercise, suggesting that the reduction of
oxygen consumption was due, at least in part, to decreased myocardial contractility. Myocardial oxygen consumption and coronary blood flow were substantially decreased in dogs following surgical denervation at rest and
during treadmill exercise (220, 231). Oxygen extraction at
rest was similar in control and denervated hearts, suggesting that autonomic control of coronary vasomotor
tone is minimal under resting conditions. In contrast, the
exercise-induced increase in myocardial oxygen extraction and decrease in coronary venous oxygen content
were enhanced in denervated compared with innervated
hearts (Fig. 15), indicating that intact innervation contributes in a feed-forward manner to exercise hyperemia.
Further evidence for a role of neural control of coronary blood flow during exercise was provided by
Schwartz and Stone (516) who reported that the increases
of heart rate and contractility during exercise were attenuated by ablation of the right but not the left stellate
ganglion in dogs, while the increase in coronary blood
flow was slightly increased after left stellate ganglionectomy. DiCarlo et al. (130) also found that coronary flow
during submaximal exercise was higher after left stellate
ganglion ablation, and that nonselective ␣-adrenergic
blockade with intracoronary phentolamine (1 mg) had no
further effect, implying that sympathetic neural ablation
FIG. 15. Effect of chronic cardiac neural ablation (left panel; Ref.
220) or selective sympathetic denervation (right panel; Ref. 231) on the
relation between myocardial oxygen consumption (MV̇O2) and coronary
venous oxygen content (CVO2 content) in the left ventricles of dogs
during treadmill exercise. Data are means ⫾ SE. *P ⬍ 0.05 vs. control.
In the study by Gregg et al. (220), statistical analysis was not presented.
See text for further explanation.
Physiol Rev • VOL
abolishes ␣-adrenergic vasoconstriction during exercise.
In contrast, Chilian et al. (102) reported that regional
sympathetic denervation of the posterior left ventricular
wall by epicardial application of phenol caused no difference in mean myocardial blood flow or the transmural
distribution of perfusion either at rest or during treadmill
exercise, thus failing to support neurogenic coronary vasoconstriction during exercise. After ␤-adrenergic blockade with propranolol, nonselective ␣-adrenergic blockade
with phentolamine decreased coronary vascular resistance in both the innervated (28%) and sympathectomized
(23%) regions (likely in part to compensate for an 18%
decrease in mean aortic pressure caused by the systemic
␣-adrenergic blockade). The authors concluded that ␣-adrenergic coronary vasoconstriction does occur during exercise, but is principally mediated by circulating cathecholamines rather than by direct neural connections. Finally, Furuya et al. (202) reported that coronary flow
during exercise was slightly higher in denervated than in
normal hearts at comparable levels of myocardial oxygen
demand (reflected by the heart rate ⫻ mean aortic pressure product), but that ␣-adrenergic receptor blockade
with phentolamine (2 mg/kg iv) caused a slight further
increase in coronary flow. The authors interpreted these
findings to suggest that adrenergic coronary vasoconstriction during exercise is mediated both by circulating catecholamines and by direct neural influences (202). Interpretation of these studies (102, 130, 202, 516) is complicated because myocardial oxygen consumption and
coronary venous oxygen content or tension were not
determined.
In conclusion, cardiac autonomic denervation (220),
or selective sympathetic denervation (130, 231, 516), limits exercise hyperemia in the heart, indicating that sympathetic activity contributes to exercise hyperemia in a
feed-forward manner. Although there is evidence to suggest a role for circulating cathecholamines in the control
of coronary blood flow during exercise as well (102), the
weight of evidence is consistent with the concept that
autonomic influences on the coronary circulation are
principally neurally mediated.
B) ␣-ADRENERGIC CONTROL. Blockade of ␣-adrenergic receptors can influence coronary blood flow through three
separate mechanisms. First, blockade of prejunctional
␣2-adrenoceptors interrupts the negative-feedback control of norepinephrine release (268, 336). The resultant
increase in norepinephrine levels augments cardiac ßadrenergic stimulation and increases coronary blood flow
secondary to the increased myocardial oxygen consumption. Second, ␣-adrenergic blockade can increase coronary flow by interrupting vasoconstriction mediated by
postjunctional ␣1- and ␣2-adrenoceptors located on the
smooth muscle cells of small coronary arteries ⬎100 ␮m
(predominantly ␣1) and arterioles ⬍100 ␮m (both ␣1 and
␣2) (98, 104, 410). Finally, ␣2-adrenergic receptors on
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coronary vascular endothelium stimulate release of nitric
oxide (NO) (109), which can oppose the ␣-adrenergic
vasoconstrictor effect (109, 287).
Under basal resting conditions, cardiac sympathetic
activity is minimal so that ␣-adrenergic blockade has a
neligible effect on coronary flow in awake resting dogs
(100) and humans (263, 272). In contrast, in dogs and
swine, exercise produces a greater increase in coronary
blood flow after systemic ␣-adrenergic blockade than during control conditions (27, 122, 148, 233, 266, 365). Systemic nonselective ␣-adrenergic antagonists exaggerate
the ␤-adrenoceptor-mediated increases of heart rate, left
ventricular systolic pressure, and dP/dtmax during exercise as the result of blockade of prejunctional ␣2-adrenergic receptors which normally inhibit norepinephrine
release (148, 268, 336). In this situation, ␤-adrenergic
blockade inhibits the marked increase in hemodynamic
determinants of myocardial oxygen consumption produced by systemic nonselective ␣-adrenergic blockade.
When nonselective ␣-adrenergic antagonists were administered to dogs by the intracoronary route to minimize
systemic hemodynamic effects, coronary blood flow during exercise was still 10 –30% higher than during control
exercise (123, 130, 232, 235, 282). Furthermore, at comparable levels of myocardial oxygen consumption, ␣-adrenergic blockade increased coronary venous oxygen tension (Fig. 16) and decreased coronary vascular resistance,
indicating competition between ␣-adrenergic vasoconstriction and metabolic coronary vasodilation during exercise (27, 31, 122, 266). However, in swine, nonselective
␣-adrenergic blockade with phentolamine had no effect
on the relation between myocardial oxygen consumption
and coronary venous oxygen tension (Fig. 16), indicating
FIG. 16. Effect of mixed ␣1-/␣2-adrenergic receptor blockade with
phentolamine [2 mg/kg iv (27) or 1 mg/kg iv (148)] or selective ␣1adrenergic receptor blockade with prazosin (0.1 mg/kg iv) on the relation between myocardial oxygen consumption and coronary venous
oxygen tension in the left ventricles of dogs (27; left panel) and swine
(148; right panel) during treadmill exercise. Data are means ⫾ SE. *P ⬍
0.05 prazosin and phentolamine vs. control. See text for further explanation.
Physiol Rev • VOL
1027
negligible ␣-adrenergic control of coronary resistance
vessel tone in this species (148, 514). To date, well-controlled studies of ␣-adrenergic control of coronary resistance vessel tone during exercise in humans are lacking
(263).
Both ␣1- and ␣2-adrenoceptors can mediate coronary
vasoconstriction, but adrenergic coronary vasoconstriction during exercise in the normal dog heart appears to
involve principally ␣1-adrenoceptors. Thus selective ␣1adrenergic blockade with intracoronary prazosin resulted
in higher levels of coronary blood flow and lower coronary vascular resistance during graded treadmill exercise
(123, 542), whereas intracoronary administration of the
selective ␣2-adrenergic blockers yohimbine or idazoxan
did not alter coronary blood flow or coronary resistance
during exercise (123, 542). Since the effect of increased
release of norepinephrine produced by ␣2-adrenoceptor
blockade might be concealed by the ␣1-adrenergic vasoconstriction, which it can produce, studies were repeated
with the addition of ␣1-adrenergic blockade. Combined
intracoronary administration of ␣1- and ␣2-adrenergic
blockers was not more effective in increasing coronary
blood flow or coronary venous oxygen tension during
exercise than was ␣1-adrenergic blockade alone (123).
Although ␣2-adrenergic receptors on coronary vascular
endothelium stimulate release of NO (109, 287), the lack
of effect of blockade of ␣2-adrenoceptors was not due to
simultaneous reduction in NO release, as blockade of
␣2-adrenoceptors failed to increase coronary flow during
exercise in the presence of NO blockade (287). Thus the
␣-adrenergic vasoconstrictor tone that opposes metabolically mediated coronary vasodilation during exercise is
mediated principally by postjunctional ␣1-adrenoceptor
activity.
Feigl and co-workers (183, 282) proposed that adrenergic coronary vasoconstriction can augment subendocardial blood flow during exercise. They observed that the
ENDO/EPI blood flow ratio during exercise was slightly
higher in regions with ␣-adrenoceptors intact than in
regions where ␣-adrenoceptors were blocked with intracoronary phenoxybenzamine, although total blood flow
was higher after adrenergic blockade (282). In contrast,
␣-adrenoceptor blockade caused a transmurally uniform
increase of blood flow in myocardial regions perfused by
a stenotic coronary artery (355), as well as in the pressure-overloaded hypertrophied left ventricular wall of
dogs (155), indicating transmurally uniform ␣-adrenergic
coronary vasoconstriction during exercise. Heusch and
co-workers (46) addressed the issue of the uniformity of
humoral and neuronal ␣-adrenergic vasoconstriction
across the left ventricular wall in anesthetized dogs under
conditions of intact vasomotor tone and during maximal
coronary vasodilation with dipyridamole. During humoral
adrenergic activation, produced by intravenous atropine/
norepinephrine, intracoronary phentolamine increased
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DIRK J. DUNCKER AND ROBERT J. BACHE
blood flow uniformly in all myocardial layers, irrespective
of whether coronary vasomotor tone was intact or abolished. During cardiac sympathetic nerve stimulation,
phentolamine increased flow to all layers when coronary
tone was intact, but during maximal coronary vasodilation, phentolamine increased flow to subepicardium with
a tendency for subendocardial blood flow and the ENDO/
EPI ratio to decrease (both P ⫽ NS).
It is possible that the differing results might be explained in part by the higher heart rates in the study of
Huang and Feigl (⬃240 beats/min) compared with heart
rates of ⬃215 beats/min (155, 355) and ⬍200 beats/min
(46). Thus ␣-adrenergic stiffening of the intramural penetrating arteries that traverse the myocardium to the subendocardium, and the consequent reduction of systolic
retrograde flow, could be of particular importance at high
heart rates (183). To address this question, Morita et al.
(412) mimicked exercise by combining intravenous norepinephrine infusion with cardiac pacing at 150, 200, and
250 beats/min in open-chest dogs with intact coronary
vasomotor tone. At heart rates of 150 and 200 beats/min,
intracoronary phenoxybenzamine produced a transmurally homogeneous increase in myocardial blood flow,
whereas at 250 beats/min phenoxybenzamine produced a
small decrease in blood flow to all myocardial layers.
Interpretation of this transmurally homogeneous flow decrease is difficult because myocardial oxygen consumption was not measured. However, the lack of change in
ENDO/EPI ratio fails to support the concept that the
␣-adrenergic vasoconstriction acts to protect the subendocardium from hypoperfusion during high work loads.
Furthermore, even during maximal exercise, the coronary
bed is not maximally vasodilated and retains residual
vasomotor tone (see sect. IIB3C). These conditions favor a
transmurally homogeneous ␣-adrenergic vasoconstrictor
influence in the normal heart during exercise (46, 412). To
definitively address the issue of whether ␣-adrenergic
vasoconstriction serves to maintain subendocardial blood
flow during heavy exercise, future studies investigating
the effects of intracoronary ␣-blockade on transmural
myocardial blood flow during exercise at maximal heart
rates (⬃300 beats/min in dogs) are needed.
In conclusion, study of ␣-adrenergic influences is
complicated because pharmacological blockers often
cause changes in contractile function that produce myocardial metabolic effects on the coronary circulation
which exceed their direct vascular effects. For example,
postjunctional ␣-adrenergic receptors mediate coronary
vasoconstriction, but blockade of prejunctional ␣2-adrenoceptors interrupts the normal inhibition of norepinephrine release from sympathetic axons so that nonselective
␣-adrenergic blockers increase ␤-adrenergic stimulation
of contractility with a resultant increase of myocardial
oxygen requirements and, therefore, coronary vasodilation. Consequently, although the primary vascular effect
Physiol Rev • VOL
of ␣-adrenergic activation is vasoconstriction, the overall
response to nonselective ␣-adrenergic blockade is dominated by an increase in myocardial oxygen consumption
which causes coronary vasodilation. ␣1-Adrenergic mechanisms act to blunt the increase in coronary flow that
occurs during exercise, and this results in a decrease in
coronary venous oxygen tension in some species as the
dog, and possibly humans, but appears to be absent in
swine. The weight of evidence indicates that ␣-adrenergic
vasoconstriction limits myocardial blood flow in a transmurally homogeneous manner during moderate levels of
exercise. Whether ␣-adrenergic tone acts to maintain subendocardial blood flow during (near) maximal levels of
exercise remains to be established.
C) ␤-ADRENERGIC CONTROL. The direct influence of adrenergic control of coronary vascular resistance via ␤-adrenoceptors [principally ␤2-receptors which are located on
coronary arterioles ⬍100 ␮m (104, 256, 416)], is difficult
to separate from metabolic alterations in coronary vasomotion that result from ␤-adrenergic inotropic and chronotropic effects on the myocardium. In awake resting
dogs (43, 267) and swine (148), nonselective ␤-adrenergic
blockade with propranolol decreased myocardial oxygen
consumption, and this resulted in a parallel reduction of
coronary blood flow; myocardial oxygen extraction was
unchanged, suggesting that ␤-adrenergic control of the
coronary circulation is minimal under resting conditions.
However, during graded treadmill exercise, propranolol
decreased coronary flow more than expected from the
decrease in myocardial oxygen consumption, resulting in
an increase in myocardial oxygen extraction and a decrease in coronary venous oxygen tension in both dogs
and swine (Fig. 17) (43, 148, 214, 215, 266). Similarly, in
normal human subjects or patients with angiographically
normal coronary arteries (608), ␤-adrenergic blockade
with propranolol or sotalol decreased myocardial blood
flow during bicycle exercise out of proportion to the
reduction of myocardial oxygen consumption, necessitating an increase in myocardial oxygen extraction (162,
303). The findings imply that ␤-adrenergic control of the
coronary resistance vessels is minimal under resting conditions, but ␤-adrenergic activation contributes to coronary vasodilation during exercise in a feed-forward manner (408, 409, 566).
Intracoronary administration of the nonselective
␤-adrenergic blocker propranolol to exercising dogs
caused a slightly greater decrease of coronary blood flow
than did the selective ␤1-adrenergic blocker atenolol, indicating that ␤2-adrenergic mechanisms can contribute to
adrenergic coronary vasodilation. In support of this, intracoronary administration of the selective ␤2-adrenoceptor blocker ICI 118,551 during exercise caused no change
in contractile function but produced an 11–14% decrease
in coronary flow during moderate treadmill exercise in
dogs (130, 386). These findings indicate that ␤2-adreno-
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CORONARY BLOOD FLOW
FIG. 17. Top panels show the effect of mixed ß1-/ß2-adrenergic
receptor blockade with propranolol [1 mg/kg iv (214) or 0.5 mg/kg iv
(139)] on the relation between myocardial oxygen consumption and
coronary venous oxygen tension in the left ventricles of dogs (214; left
panel) and swine (139; right panel) during treadmill exercise. Dogs were
studied under ␣-adrenergic blockade with phentolamine (Phento, 1
mg/kg iv) to avoid unopposed ␣-adrenergic vasoconstriction following
ß-blockade. Bottom panels show the effect of combined ␣1/␣2- and
ß1/ß2-adrenergic receptor blockade in swine (139) and dogs (214). Data
are means ⫾ SE. *P ⬍ 0.05 vs. Phento alone or vs. control. See text for
further explanation.
ceptor activation during exercise causes a small but significant degree of coronary resistance vessel dilation independent of the myocardial effects of ␤1-adrenergic
stimulation.
In conclusion, ␤-adrenergic blockade blunts the myocardial response to exercise, with a consequent reduction
of oxygen consumption. However, ␤-adrenergic blockade
causes a greater reduction of coronary flow than of myocardial oxygen consumption, resulting in increased oxygen extraction by the heart and demonstrating a direct
feed-forward ␤-adrenergic vasodilator effect on the coronary vessels. In swine, ␤-adrenergic activation exerts a
feed-forward effect that is unopposed by ␣-adrenergic
vasoconstriction so that coronary venous oxygen tension
does not fall during exercise.
D) PARASYMPATHETIC CONTROL. The coronary resistance
vessels are richly innervated by the parasympathetic diPhysiol Rev • VOL
1029
vision of the autonomic nervous system (181). In dogs,
pretreated with propranolol and paced to maintain a constant heart rate, stimulation of the vagosympathetic trunk
produces coronary vasodilation independent of the cardiac effects of vagal stimulation (79). The coronary vasodilation produced by vagal stimulation was blocked by
atropine and was mimicked by acetylcholine, which involves the release of endothelial NO in the dog (79, 525).
To study the vasodilator influence of vagal activity on
coronary blood flow during exercise, Gwirtz and Stone
(234) administered the muscarinic receptor antagonist
atropine into a coronary artery of dogs during submaximal exercise (heart rates of 190 –210 beats/min). Atropine
had no effect on heart rate or coronary blood flow, indicating that parasympathetic effects on both the myocardium and coronary bed were negligible at this level of
exercise. This is in accord with the finding that vagal tone
to the myocardium is progressively withdrawn during
increasing levels of exercise (434, 584). Importantly, the
high vagal tone in the resting dog exerts a small vasodilator influence on the coronary circulation, the inhibition
of which will limit rather than support the exercise-induced coronary vasodilation.
In swine, the acetylcholine-induced NO-mediated vasodilation (which predominates in dogs) is outweighed by
a direct vasoconstrictor effect on coronary smooth muscle, resulting in a net vasoconstrictor response to acetylcholine (119, 201, 248) or vagal nerve stimulation (201).
Despite ample evidence that stimulation of the parasympathetic system can influence coronary vasomotor tone,
the effects of vagal activity under basal resting conditions
are generally considered to be negligible even during
basal resting conditions when vagal activity is high (119).
However, these studies have been conducted principally
in anesthetized animal models that could have blunted
vagal tone (580). In addition, coronary flow was not related to myocardial oxygen consumption which, in view
of potential myocardial effects of vagal inhibition, makes
interpretation of these studies difficult. Duncker et al.
(148) investigated the effects of muscarinic receptor
blockade with intravenous atropine in chronically instrumented swine at rest and during graded treadmill exercise. Atropine elicited a vasodilator response in the coronary resistance vessels under resting conditions that
waned with increasing levels of exercise intensity. Vasodilation was likely the result of increased ␤-adrenergic
activity, since it was fully blocked when studies were
repeated in the presence of propranolol. Thus the vasoconstrictor influence that was exerted by the parasympathetic nervous system was due to inhibition of ß-adrenergic vasodilator activity. These observations suggest that
withdrawal of vagal tone may contribute to ß-adrenergic
vasodilation at lower levels of exercise. Due to progressive withdrawal of vagal tone with increasing exercise
intensity, parasympathetic influences are unlikely to be
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DIRK J. DUNCKER AND ROBERT J. BACHE
physiologically significant during heavy exercise (139,
140, 234, 584).
In conclusion, parasympathetic activation can exert
weak species-dependent effects on the coronary vessels.
In animals in which acetylcholine causes vasodilation,
parasympathetic activity causes a weak dilator influence
at rest when vagal tone is high, but vagal tone is withdrawn during exercise so that parasympathetic effects are
negligible during exercise. In species in which acetylcholine causes coronary vasoconstriction, as in swine, withdrawal of vagal tone may augment the increase in coronary flow during exercise.
E) SUMMARY AND INTEGRATION. Although coronary blood
flow is strongly responsive to local myocardial metabolic
requirements, the autonomic nervous system provides a
modulating influence that can alter the coupling between coronary flow and myocardial metabolism. During resting conditions, cardiac sympathetic activity is
minimal so that adrenergic blockade has a negligible
effect on coronary flow. During exercise, adrenergic
activation exerts paradoxical effects that both oppose
(alpha) and reinforce (beta) the increase in coronary
flow that occurs in response to the increase in cardiac
work. The net effect of sympathetic stimulation is ßadrenergic feed-forward vasodilation (Fig. 17), which
has been proposed to account for as much as 25% of the
exercise hyperemia (215). However, cardiac denervation or pharmacological inhibition of autonomic control does not result in myocardial ischemia during exercise, implying that other vasodilator mechanisms act
to compensate and mediate exercise hyperemia when
autonomic control is blocked. These findings are consistent with the concept that autonomic control serves
to optimize the matching of coronary blood flow to
myocardial metabolic needs but is not essential for
exercise hyperemia.
2. Angiotensin II
Angiotensin II (ANG II) is a vasoactive octapeptide
produced by cleavage of the decapeptide angiotensin I by
angiotensin converting enzyme. ANG II exerts important
cardiovascular effects, including positive inotropism and
vasoconstriction, as well as causing norepinephrine and
aldosterone release, all of which are mediated via the AT1
receptor (557). Although the AT2 receptor can mediate a
vasodilator response, the (patho)physiological function of
this receptor is less clear, as the vasomotor response to
exogenous ANG II is principally vasoconstriction (557). In
the coronary circulation, exogenous ANG II produces
constriction of epicardial conductance arteries (419), as
well as small arteries (298) and arterioles (623). Furthermore, intravenous as well as intracoronary administration
of ANG II produces coronary vasoconstriction in a variety
of species, including rat (374, 394, 513), dog (435, 624),
Physiol Rev • VOL
and swine (330), indicating that the AT1 receptor is
present in the coronary microvasculature and is capable of influencing coronary vasomotor tone. Furthermore, during treadmill exercise, sympathetic activity,
and hence activity of the renin-angiotensin system, increases. This suggests that the increased levels of ANG II
during exercise could act to increase coronary vasomotor
tone.
Studies in awake swine examining the role of endogenous ANG II in the control of coronary resistance vessel
tone have yielded ambiguous results, with AT1 receptor
blockade having either no effect at rest (539, 547) or
during exercise (106), or causing coronary vasodilation
during exercise (539, 547). None of these studies corrected for alterations in coronary vasomotor tone resulting from changes in myocardial metabolic demands produced by AT1 receptor blockade, making interpretation of
the data difficult. This is particularly important since systemic administration of the AT1 blocker (106, 539, 547)
results in alterations of systemic hemodynamics. However, even when systemic hemodynamic effects are
avoided by intracoronary administration of the AT1 antagonist (457, 475), myocardial oxygen demands can be reduced as a result of a decrease in contractility both directly, through blockade of AT1 receptors on the cardiomyocytes (125), and indirectly, through blockade of AT1
receptors on the sympathetic nerve endings with consequent blunting of norepinephrine release (310, 493, 550).
Hence, the reported failure of coronary blood flow to
increase in response to intracoronary losartan in humans
with endothelial dysfunction (457) may have been due to
a decrease in myocardial oxygen demands produced by
presynaptic and cardiomyocyte AT1 blockade. To isolate
the influence of AT1 receptors on coronary vasomotor
tone, Merkus et al. (394) studied the effect of AT1 blockade on the relation between coronary blood flow and
myocardial oxygen demand (143, 565). They found that
AT1 receptor blockade caused coronary vasodilation at
rest and during exercise of awake swine, indicating that
endogenous ANG II exerts a tonic vasoconstrictor influence on the coronary resistance vessels (Fig. 18). AT1
receptor blockade can decrease norepinephrine levels by
blockade of presynaptic AT1 receptors that act to facilitate norepinephrine release (310, 493, 550). Conversely,
the decrease in blood pressure that often accompanies
AT1 receptor blockade will activate the baroreceptor reflex-mediated release of norepinephrine. The baroreceptor-mediated increase in norepinephrine is likely the predominant effect, as circulating norepinephrine levels increased slightly following AT1 receptor blockade, while
the transmyocardial norepinephrine gradient remained
unchanged, consistent with reports that ANG II-induced
presynaptic modulation of catecholamine release in the
heart is minimal (310, 330). In swine, norepinephrine
exerts its effects on coronary vasomotor tone principally
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3. Autacoids
FIG. 18. Effect of AT1 receptor blockade with telmisartan (0.3
mg/kg iv) or irbesartan (1 mg/kg iv) on the relation between myocardial
oxygen consumption and coronary venous oxygen tension in the left
ventricles of dogs (624; left panel) and swine (394; right panel) during
treadmill exercise. Data are means ⫾ SE. *P ⬍ 0.05 vs. control. See text
for further explanation.
through activation of ␤-adrenoceptors, thereby causing
vasodilation (148) so that the small increase in norepinephrine following AT1 receptor blockade may have contributed to the observed coronary vasodilation. Nevertheless, a vasodilator effect of AT1 receptor blockade remained after ␤-receptor blockade, indicating that the
coronary vasodilation produced by systemic AT1 receptor
blockade was not simply the result of increased coronary
␤-adrenergic stimulation, but also included a direct effect
on the coronary resistance vessels.
In contrast to observations in awake swine, studies in
awake dogs have failed to reveal a significant role for
ANG II in control of coronary resistance vessel tone either
at rest or during exercise. Thus Zhang et al. (624) found
that AT1 receptor blockade with telmisartan had no effect
on the relation between myocardial oxygen consumption
and coronary venous oxygen tension in awake normal
dogs (Fig. 18), suggesting that ANG II does not contribute
to the regulation of coronary resistance vessel tone in the
dog. Similarly, a study in resting humans reported that
intracoronary losartan had no effect on coronary blood
flow or coronary vascular resistance (457). However, a
role of ANG II in the regulation of coronary resistance
vessel tone in exercising healthy humans, determining the
relation between myocardial oxygen consumption and
coronary venous oxygen tension has not been investigated to date.
In summary, in swine, ANG II exerts a weak direct
vasoconstrictor influence on the coronary circulation,
particularly during exercise. In contrast, a role for ANG II
in coronary vasomotor control during exercise in the
canine and human heart has not been convincingly demonstrated.
Physiol Rev • VOL
Histamine and bradykinin are autacoids involved in
inflammatory processes that can exert powerful effects
on vasomotor tone. However, their role in the regulation
of coronary vasomotor tone under normal conditions is
still incompletely understood.
A) HISTAMINE. Histamine, formed from histidine by histidine-decarboxylase and stored in mast cells and basophils, plays an important role in hypersensitivity and
allergic reactions and can modulate vasomotor tone via
stimulation of H1 and H2 receptors in the vascular wall. In
the coronary circulation, H1 receptors located on vascular
smooth muscle cells of large and small arteries mediate
vasoconstriction, while H2 receptors located on vascular
smooth muscle cells of arterioles mediate vasodilation
(312, 403). In addition, H1 receptors located on the endothelium can stimulate NO release to produce coronary
vasodilation (312, 586). To our knowledge, there are no
studies demonstrating a role for endogenous histamine in
regulation of coronary vasomotor tone in awake healthy
animals or humans during physiological conditions either
at rest or during exercise.
B) BRADYKININ. Bradykinin, produced by conversion of
kininogens by tissue and plasma kallikreins, plays an
important role in inflammation, nociception, and possibly
regulation of blood pressure and fluid balance. Bradykinin
synthesized within the vascular wall (85, 438) can exert a
potent vasodilator influence on coronary arterial vessels
of all sizes via stimulation of B2 receptors to produce the
endothelium-derived relaxing factors NO, prostacyclin,
and endothelium-derived hyperpolarizing factor (EDHF)
(578, 579). In addition, some vasodilation also occurs via
B1 receptor stimulation, which appears to be NO-mediated (543), although this is substantially less than that
produced via B2 receptors, likely because induction of B1
receptors principally occurs after tissue damage. Although there is some in vitro evidence for basal bradykinin release, obtained in isolated rat hearts (47), in vivo
observations in awake healthy dogs failed to define a role
for endogenous bradykinin in the regulation of coronary
blood flow (460). Groves et al. (223) reported that infusion
of the selective B2 receptor antagonist HOE 140 into a
coronary artery of patients without significant coronary
stenoses (⬍30% luminal narrowing) caused vasoconstriction with a decrease in epicardial coronary luminal area
and a decrease of coronary blood flow. These observations indicate that both coronary conductance and resistance vessels were subject to a bradykinin-mediated tonic
vasodilator influence. Since this study was performed in
patients with recurrent chest pain, it is uncertain whether
bradykinin contributes to the regulation of coronary vasomotor tone in the normal human heart.
In summary, there is little evidence for a role of
histamine or bradykinin in regulation of coronary blood
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DIRK J. DUNCKER AND ROBERT J. BACHE
flow in the normal heart. It is likely that proinflammatory
conditions, as are likely to occur in isolated heart preparations or in patients with coronary artery disease, will
lead to an increased autacoid-mediated influence on coronary vasomotor.
4. Endothelium-derived vasoactive factors
A) NO. The normal coronary endothelium can cause
vasodilation as constitutive NO synthase acts on L-arginine to produce NO, which causes relaxation of vascular
smooth muscle via an increase in cGMP and consequent
activation of calcium-activated K⫹ channels (KCa) channels and possibly KATP channels (461, 578). Endothelial
production of NO can be triggered by specific receptors
(e.g., muscarinic, bradykinin, and histamine receptors) or
by mechanical deformation resulting from shear forces or
pulsatile strain caused by blood flow (200, 276). NOdependent mechanisms cause vasodilation of both epicardial arteries and coronary resistance vessels in response
to increased blood flow in vitro (328) and contribute to
coronary reactive hyperemia in vivo (7, 445, 618). The
contribution of NO to maintenance of coronary blood
flow has been studied by administering analogs of L-arginine that act as competitive inhibitors of the NO synthesis.
In vivo studies in dogs have generally shown no
change (7, 293, 445, 472, 529, 610, 618) or only a small
decrease (56, 568) of coronary flow in response to inhibitors of NO synthesis during basal conditions. In both
anesthetized (314) and awake swine (147), inhibition of
NO synthesis resulted in a small decrease of coronary
blood flow that was accompanied by increased oxygen
extraction and a decrease in coronary venous oxygen
tension. In the human heart, endogenous NO exerts a
modest vasodilator influence on the coronary vessels under resting conditions (160, 360, 464). In contrast, in isolated non-blood-perfused rodent hearts (rats, guinea pigs,
rabbits), inhibitors of NO synthesis generally cause
marked coronary vasoconstriction (9, 49, 81, 332, 447, 528,
570). The discrepancy between the modest contribution
of NO in in vivo blood-perfused hearts compared with
isolated buffer-perfused rodent hearts is likely due to
differences in experimental conditions. In buffer-perfused
hearts, flow rates are very high (⬃6 ml䡠min⫺1 䡠g⫺1), favoring shear-mediated release of NO. In addition, the absence
of blood (and therefore the NO scavenger hemoglobin)
is likely to increase the biological half-life of NO in the
isolated perfused hearts (42).
Chilian and co-workers (300) reported that inhibition
of NO synthesis with N␻-nitro-L-arginine methyl ester
(L-NAME; 30 ␮g䡠kg⫺1 䡠min⫺, intracoronary) constricted
small coronary arteries (⬎100 ␮m), but this was counterbalanced by vasodilation of arterioles (⬍100 ␮m), indicating that compensatory vasomotor adjustments in dif-
Physiol Rev • VOL
ferent segments of the coronary vasculature occurred to
maintain blood flow. These data imply that under resting
conditions, the effects of NO synthase inhibition can be
blunted by compensatory arteriolar dilation but suggest
that this basal dilation of the coronary arterioles might
limit further exercise-induced increases in coronary
blood flow. There is evidence that during exercise coronary NO production is increased in the dog heart (56,
562), likely due to an increase in endothelial shear secondary to the increased coronary flow rates. Furthermore, NO release from erythrocytes could be stimulated
in the canine heart during exercise in response to the
decrease in intravascular oxygen tension (527, 536). Together these observations suggest that NO might contribute to the increase of coronary blood flow during exercise. However, blockade of NO production with intracoronary NG-nitro-L-arginine (L-NA) did not impair the ability
to increase coronary flow during treadmill exercise in
dogs (7, 56, 288, 568). In fact, coronary flow rates during
exercise were slightly higher after L-NA, in parallel with a
slight increase in myocardial oxygen consumption (7, 56,
288). The relation between myocardial oxygen consumption and coronary venous oxygen tension was not significantly altered by L-NA (Fig. 19), indicating that inhibition
of NO production did not interfere with metabolic regulation of coronary vasomotor tone (7, 288). In swine, the
small decrease in coronary venous oxygen tension that
occurred after NO blockade under resting conditions was
maintained during exercise (Fig. 19), indicating that the
role of NO was not increased compared with resting
conditions, and (similar to observations in the dog) that
NO is not mandatory for the exercise-induced increase in
coronary blood flow in swine (147, 393). It could be
argued that NO released from erythrocytes could have
contributed to exercise hyperemia in the presence of NO
synthase inhibition. However, this mechanism is unlikely
to be of importance in swine, in view of the lack of an
exercise-induced decrease in coronary venous oxygen
tension and saturation in this species.
B) PROSTANOIDS. The coronary endothelium can metabolize arachidonic acid to produce prostacyclin and other
vasodilator prostanoids (121, 331) that act to increase
myocardial blood flow via an increase in cAMP resulting
in opening KATP channels in coronary vascular smooth
muscle (331). Prostanoids have been proposed to contribute to metabolic dilation of coronary resistance vessels in
humans (135, 198), although this is not a consistent finding (159, 439). Inhibition of cyclooxygenase with indomethacin in a dose that caused marked blunting of the
vasodilator response to intracoronary arachidonic acid
caused no change in coronary blood flow during resting
conditions and did not impair the increase in coronary flow
in response to treadmill exercise in dogs (121) so that the
relation between myocardial oxygen consumption and coronary venous oxygen tension remained unaffected (Fig. 19).
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FIG. 19. Top panels show the effect of NO synthase inhibition with
N-nitro-L-arginine (L-NA, 20 mg/kg iv) on the relation between myocardial oxygen consumption and coronary venous oxygen tension in the left
ventricles of dogs (7; left panel) and swine (147; right panel) during
treadmill exercise. Bottom panels show the effect of cyclooxygenase
inhibition with indomethacin [Indo; 5 mg/kg iv (121) or 10 mg/kg iv
(396)] on the relation between myocardial oxygen consumption and
coronary venous oxygen tension in the left ventricles of dogs (121; left
panel) and swine (396; right panel) during treadmill exercise. Data are
means ⫾ SE. *P ⬍ 0.05 vs. control. See text for further explanation.
Interestingly, several studies have suggested that an interaction exists between NO and prostanoids in the canine coronary circulation. Inhibition of cyclooxygenase shortened
the duration of reactive hyperemia in dogs treated with
L-NAME, but not in control dogs (459). These findings indicate an increased contribution of prostanoids when NO
synthase activity is blunted, and could explain why two of
three clinical studies of patients with (minimal) coronary
artery disease reported a role for vasodilator prostanoids
(135, 198), whereas the single study in healthy human volunteers failed to observe a role (159).
Merkus et al. (396) investigated the effects of blocking endogenous prostanoids with indomethacin on coronary resistance vessels, in exercising swine. To study
possible interactions between NO and prostanoids, experiments were repeated after NO synthase blockade with
L-NA. Indomethacin decreased coronary venous oxygen
tension at rest and during exercise (Fig. 19). However,
Physiol Rev • VOL
1033
prostanoids were not mandatory for the exercise-induced
vasodilation, because coronary venous oxygen tension
was not further altered by exercise in the presence of
indomethacin. The contribution of prostanoids to the regulation of coronary vascular tone was not enhanced by
inhibition of NO synthesis in swine (396). These findings
suggest that in the porcine heart, prostanoids and NO do
not act in a compensatory manner when one of these
pathways is blocked.
C) EDHF. Endothelium-derived relaxing factors other
than prostacyclin and NO have been implicated in the
endothelium-dependent vasodilation produced by acetylcholine and bradykinin. These factors have been named
EDHFs, in view of their ability to hyperpolarize the vascular smooth muscle, via opening of KCa channels to
produce vasodilation (463, 579). Several factors appear to
participate in endothelium-derived hyperpolarization, including cytochrome P-450-dependent metabolites of arachidonic acid (463) and hydrogen peroxide (229, 495).
The role of EDHF in coronary vasodilation in healthy
humans or awake dogs at rest or during treadmill exercise
has not been studied to date, although preliminary data in
swine suggest that inhibition of cytochrome P-450 2C9
with sulfaphenazole had no effect on coronary vasomotor
tone in swine (398).
D) ENDOTHELIN. Endothelins are vasoactive peptides
that are produced by coronary vascular endothelium.
Three isoforms have been identified, of which endothelin-1 (ET) is the most abundant and biologically active
isopeptide in the heart (246). ET is produced in endothelial cells by cleavage of its nonvasoactive precursors
preproendothelin and big ET (487) and acts on ET receptors located both on the endothelium and vascular
smooth muscle. Binding of ET to ETB receptors on the
endothelium leads to production of NO and prostacyclin
(190, 560), which induce vasodilation. In contrast, binding
of ET to the ETA and ETB receptors on vascular smooth
muscle leads to vasoconstriction (487). Administration of
exogenous ET causes ETB-mediated vasodilation at low
doses but ETA-mediated constriction at high doses, indicating that the ETB receptor on the endothelium is more
sensitive to ET than the receptors on vascular smooth
muscle (487). Endogenous levels of ET exert a coronary
vasoconstrictor influence in vivo. Thus the mixed ETA/
ETB receptor antagonist tezosentan caused an increase in
coronary venous oxygen tension and saturation both under resting conditions and during treadmill exercise, indicating a small vasoconstrictor influence (Fig. 20). In
swine, the ET-mediated vasoconstrictor influence appears
to be principally ETA mediated, as the ETA receptor antagonist EMD 122946 resulted in a similar response (395).
In contrast, in the coronary circulation of patients with
stable angina pectoris, the nonselective ET receptor antagonist bosentan increased artery diameter, but had no
effect on coronary flow, indicating that endogenous ET
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DIRK J. DUNCKER AND ROBERT J. BACHE
FIG. 20. Effect of mixed ETA/ETB endothelin receptor blockade with tezosentan [1 mg/kg iv (212), 2 mg/kg iv (548), or 3
mg/kg iv (395, 397)] on the relation between myocardial oxygen consumption
and coronary venous oxygen tension and
saturation in the left ventricles of dogs
(212, 548; left panels) and swine (395, 397;
middle panels) during treadmill exercise.
Also shown are the effects of selective ETA
receptor blockade with EMD 122946 (3
mg/kg iv) in swine (395, 397; right panels).
Data are means ⫾ SE. *P ⬍ 0.05 vs. control.
†P ⬍ 0.05 effect of ET receptor antagonist
decreases at higher levels of myocardial oxygen consumption. See text for further explanation.
does not contribute to regulation of coronary resistance
vessel tone in humans (597). However, it should be noted
that bosentan was administered intravenously and caused
a 10% decrease in aortic blood pressure, which likely
caused a decrease in myocardial oxygen demand that may
have masked a direct coronary vasodilator effect. Interestingly, measurements of ET levels in blood yield
concentrations in the picomolar range, while receptor
sensitivities are in the nanomolar range, which is likely
explained by abluminal secretion of ET (196). Consequently, plasma levels do not accurately represent actual
interstitial levels of ET, although they likely reflect directional changes in interstitial levels. The finding that ET
receptor antagonists cause coronary vasodilation in
awake animals (212, 392, 395, 548) implies that receptor
activation does occur despite the subpharmacological
plasma levels.
During exercise, the effect of either ETA or mixed
ETA/ETB blockade on coronary vascular tone in swine
decreased progressively with incremental levels of exercise (392, 395). A similar trend was observed with tezosentan in exercising dogs (212, 548), suggesting that the
vasoconstrictor influence of ET was blunted during exercise (Fig. 20). This seemingly paradoxical finding is in
accord with in vitro findings that the ET-vasoconstrictor
influence on coronary arterioles is modified by the cardiomyocytes according to their metabolic status so that at
Physiol Rev • VOL
higher pacing rates myocytes inhibited the vasoconstrictor influence of ET (392). Merkus et al. (397) investigated
possible mechanisms for the blunted ET influence during
exercise and observed that following inhibition of either
NO synthase or cyclooxygenase, the vasodilator response
to tezosentan that was observed under resting conditions
was now also maintained during exercise. Furthermore,
when both NO synthase and cyclooxygenase were
blocked, the vasodilator effect of tezosentan actually
increased with increasing exercise intensity, implying
that these vasodilator systems acted in concert to limit
the vasoconstrictor influence exerted by endogenous
ET (Fig. 21).
E) SUMMARY AND INTEGRATION. NO and vasodilator prostanoids contribute to the regulation of coronary blood
flow in swine, while in dogs a critical role for these
endothelium-derived vasodilator substances is lacking.
Importantly, in none of these species do NO or vasodilator prostanoids appear mandatory for the exercise-induced increases in coronary blood flow. Conversely, in
swine and in dogs, ET exerts a small coronary vasoconstrictor influence under resting conditions which wanes
with increasing exercise intensities so that it is virtually
absent during heavy exercise. Both NO and prostanoids
act in concert during exercise to blunt the coronary vasoconstrictor influence of ET. Finally, the role of EDHF in
coronary blood flow regulation has not been studied in
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FIG. 21. Effect of combined NO synthase (L-NA, 20 mg/kg iv) and
COX blockade (Indo, 10 mg/kg iv) on the responses to mixed ETA/ETB
endothelin receptor blockade with tezosentan of the relation between
myocardial oxygen consumption and coronary venous oxygen tension in
the left ventricles of swine (397) during treadmill exercise. Data are
means ⫾ SE. *P ⬍ 0.05 vs. control. †P ⬍ 0.05 effect of ET receptor
antagonist decreases (left panels) or increases (right panels) at higher
levels of myocardial oxygen consumption. ‡P ⬍ 0.05 effect of ET receptor antagonist was greater following L-NA and indomethacin. See text for
further explanation.
1035
A) CARBON DIOXIDE AND PH. Case and colleagues (95, 96),
using constant-flow perfused heart preparations to study
the role of carbon dioxide in regulating coronary blood
flow, observed that coronary vascular resistance correlated well with coronary venous carbon dioxide concentrations. Broten et al. (80) proposed that up to 40% of the
increase in coronary blood flow produced by ventricular
pacing could be explained by the synergistic interaction
between myocardial oxygen and carbon dioxide tensions.
The mechanism by which carbon dioxide dilates coronary
arterioles is incompletely understood but could be the
result of an acidosis-induced opening of KATP channels
(292). Despite its attractiveness as a regulator of coronary
resistance vessel tone, carbon dioxide is not a likely
mediator of the exercise-induced coronary vasodilation,
as coronary venous carbon dioxide tension or pH remain
essentially unchanged during exercise (Fig. 22), in either
dogs (568, 569) or swine (149, 393).
B) ADENOSINE. Adenosine predominantly dilates arterioles ⬍100 ␮m in diameter. Vessels of this size correspond to the site at which coronary metabolic regulation
(306) and autoregulation occur (307). Adenosine has characteristics which suggest that it could be a messenger by
which the coronary resistance vessels are regulated in
response to changing myocardial metabolic needs (54,
168, 180). There are two pathways for adenosine production in the heart. Under normal conditions, adenosine is
generated mainly via extracellular pathways: from interstitial AMP, via AMP 5⬘-ectonucleotidase, and from Sadenosylhomocysteine via S-adenosylhomocysteine hy-
exercising animals or humans and awaits further clarification. In humans, a role for vasodilator prostanoids and
particularly for NO is likely under resting conditions, but
interpretation is hampered by the fact that most studies
have been performed in patients with “minimal” coronary
artery disease and hence are likely to have perturbations
in endothelial function. Furthermore, in clinical studies,
coronary blood flow measurements generally have not
been corrected for alterations in myocardial oxygen demand, making interpretation difficult. Future clinical studies
should relate coronary blood flow and coronary venous
oxygen tension to myocardial oxygen consumption.
5. Metabolic messengers
The accumulation of metabolic messengers, including carbon dioxide, H⫹, and adenosine, has been proposed to contribute to coronary vasodilation in response
to an increase in myocardial metabolic activity.
Physiol Rev • VOL
FIG. 22. Arterial and coronary venous carbon dioxide tension and
pH in exercising dogs (568, 569) and swine (149, 393). Data are means ⫾
SE. See text for further explanation.
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DIRK J. DUNCKER AND ROBERT J. BACHE
drolase (54, 168). Under physiological conditions, the
newly formed adenosine is salvaged by the cardiomyocytes for formation of AMP via adenosine kinase; these
extracellular pathways of adenosine metabolism are
largely independent of the metabolic state of the cardiomyocyte. However, if an increase in cardiac work causes
myocardial metabolic requirements to exceed the rate of
oxygen delivery, the intracellular pathway for adenosine
production is activated. Thus, when the rate of ATP hydrolysis by the contractile apparatus exceeds the rate of
resynthesis of ATP through oxidative phosphorylation,
cytosolic free ADP increases. Adenylate kinase can then
act on two molecules of ADP to form one molecule each
of ATP and AMP. The resultant AMP can be catabolized
by AMP 5⬘-nucleotidase to produce adenosine. When cytosolic adenosine concentrations increase from the normal level of 0.8 to ⬃2 ␮M, adenosine is removed from the
cell via degradation by adenosine deaminase or transported out of the cell into the interstitium via nucleoside
transporters where it can act on the coronary arteriolar
smooth muscle to cause vasodilation (54, 168). The pathway for adenosine production and release is responsive to
the metabolic state of the cell and could thus serve as a
metabolic messenger to cause vasodilation of the coronary arterioles. The mechanism of coronary arteriolar
dilation by adenosine is not yet fully elucidated, but may
involve stimulation of A1 receptors directly coupled to
KATP channels and A2 receptor-mediated elevation of
cAMP/protein kinase A (PKA) which produces vasodilation in part via opening of KATP channels (537).
Data obtained in dogs do not support a role for
adenosine in regulation of coronary blood flow during
basal conditions. Thus, in anesthetized open-chest dogs
(207, 241, 326, 494, 515) and in chronically instrumented
awake dogs (28), augmenting adenosine degradation by
intracoronary administration of adenosine deaminase (28,
241, 326, 494), or nonselective blockade of A1/A2 adenosine receptors with either aminophylline (207, 515) or
8-phenyltheophylline (8-PT) (28), did not cause a decrease in basal coronary blood flow or coronary venous
oxygen tension (Fig. 23), although one study reported a
small decrease in coronary venous oxygen tension (569).
In contrast, data obtained in sedated closed-chest swine
(204) and awake resting swine (149, 393) suggest that
adenosine does contribute to maintenance of basal tone
in this species. Thus intravenous administration of aminophylline (204) or 8-phenyltheophylline (149, 393) resulted in small increases in coronary vascular resistance
and oxygen extraction, and a small decrease in coronary
venous oxygen tension, indicating a slight mismatch between oxygen delivery and consumption (Fig. 23). One
study in humans reported no effect of aminophylline on
basal coronary blood flow (479), but other studies reported that intravenous theophylline produced small increases in coronary resistance and oxygen extraction and
Physiol Rev • VOL
FIG. 23. Integrated metabolic control of coronary vasomotor tone in
dogs (left panels) and swine (right panels) at rest and during treadmill
exercise. Shown are the effects of adenosine receptor blockade with
8-phenyltheophylline (8PT, 5 mg/kg iv; top panels), the effects of KATP
channel blockade with glibenclamide [Glib, 50 ␮g/kg/min ic (153) or 3
mg/kg iv (393)] and additional adenosine receptor blockade (middle
panels), and the effects of NO synthase inhibition with N-nitro-L-arginine
[L-NA, 1.5 mg/kg ic (288) or 20 mg/kg iv (393)] and additional adenosine
receptor blockade and KATP channel blockade (bottom panels) on the
relation between myocardial oxygen consumption (MV̇O2) and coronary
venous oxygen tension (CVPO2) in the left ventricles. [Data in dogs are
from Refs. 28, 153, 288. Swine data are from Merkus et al. (393).] Data
are means ⫾ SE. *P ⬍ 0.05 effect of 8PT; †P ⬍ 0.05 effect of glibenclamide; ‡P ⬍ 0.05 effect of L-NA. See text for further explanation.
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CORONARY BLOOD FLOW
decreases in coronary venous oxygen tension (157–159).
In conclusion, although endogenous adenosine causes
tonic vasodilation of the coronary arterioles in normal
swine and possibly humans, this effect is small and does
not represent a principal mechanism for maintaining coronary blood flow during basal conditions. This is also
supported by observations that adenosine receptor blockade does not impair myocardial contractile performance
or cause metabolic evidence of ischemia (28, 149, 616).
Measurement of plasma and tissue levels of adenosine is difficult. Measurements in blood are hampered by
rapid breakdown of adenosine (238, 337), while interstitial measurements with microdialysis techniques require
insertion of permeable fibers into the myocardium,
thereby causing tissue damage and an acute rise in adenosine levels (577). Notwithstanding these difficulties, several studies have reported that adenosine production by
the heart is augmented during increased contractile work
associated with exercise (22, 166, 391, 594), which was
positively correlated with coronary blood flow. Although
these observations appear consistent with an exerciseinduced increase in myocardial adenosine production,
more recent studies have questioned the validity of the
techniques to directly measure pericardial and interstitial
adenosine measurements (see Ref. 180 for a critical in
depth review), and several more recent studies reported
that coronary venous and computed interstitial adenosine
concentrations failed to increase significantly during exercise (568, 569).
Demonstration of an essential role for an exerciseassociated increase in interstitial adenosine concentration in mediating the exercise-induced coronary vasodilation requires that interruption of the adenosine effect
interferes with exercise-induced vasodilation. However,
blockade of adenosine receptors with 8-phenyltheophylline or increasing adenosine catabolism with adenosine
deaminase did not impair exercise-induced increases in
coronary blood flow in dogs (28, 568), swine (149, 393), or
humans (157–159) and did not change the relation between myocardial oxygen consumption and coronary venous oxygen tension (Fig. 23). These findings indicate that
adenosine is not obligatory for the coronary vasodilation
that occurs during exercise and could be interpreted to
suggest that adenosine is either not important for control
of resistance vessel tone under normal inflow conditions
or that other vasodilator systems can compensate when
adenosine is blocked. It has been suggested that blockade
of adenosine receptors would result in increased myocardial interstitial levels of adenosine which might overcome
the effects of the competitive adenosine receptor antagonists (390). However, several investigators have failed to
find increased myocardial interstitial levels of adenosine
following adenosine receptor blockade (569, 616).
In summary, despite the attractiveness of the adenosine hypothesis, there is no evidence to support a role for
Physiol Rev • VOL
1037
adenosine in exercise hyperemia in the normal heart of
dogs, swine, or humans.
C) ATP. ATP is a potent coronary vasodilator (147, 181)
that is progressively released from red blood cells during
decreases in oxygen tension (165) and may thus contribute to the regulation of skeletal muscle blood flow (164).
A role for ATP as an oxygen sensor, and hence a possible
flow regulator, has also been proposed for the coronary
circulation. Thus, during treadmill exercise in dogs, coronary venous oxygen tension decreased from 19 to 13
mmHg, and this was accompanied by an increase in coronary venous plasma ATP level from 13 to 51 nM that was
linearly related to the increase of coronary blood flow
(174). Intravascular ATP produces vasodilation by acting
on endothelial purinergic P2Y-receptors to increase NO
production (164, 165, 387). In addition, ATP can produce
vasodilation after its conversion to adenosine by stimulation of adenosine A2A receptors on vascular smooth muscle cells (421). Studies examining the effects of ATP
receptor antagonists on coronary blood flow regulation
during exercise are lacking. However, NO synthase inhibition either alone or in combination with adenosine
receptor blockade failed to blunt the exercise-induced
vasodilation in dogs (288) and swine (393). These observations do not support a critical role for ATP in exerciseinduced coronary vasodilation.
6. End effectors: K⫹ channels
A) KATP CHANNELS. Vascular smooth muscle cells contain
potassium channels that are sensitive to the intracellular
energy charge (425, 537, 538). Opening of the KATP channels results in an outward flux of potassium that increases
the membrane potential of the sarcolemma. This hyperpolarization closes voltage-dependent calcium channels,
leading to a decreased influx of calcium, thereby causing
vasodilation. Conversely, closing of KATP channels decreases smooth muscle membrane potential, thereby
opening voltage-dependent calcium channels; increased
calcium influx then results in vasoconstriction. The mechanism of regulation of KATP channel activity in the normal
heart is still incompletely understood. Coronary arteriolar
smooth muscle KATP channels are tonically active under
conditions of normal arterial inflow despite the presence
of physiological ATP concentrations (4 –5 mmol), whereas in
in vitro studies KATP channels are inactivated at ATP concentrations well below 1 mmol (461). Other regulators of
vascular KATP channel activity are prostacyclin, adenosine, and ß2-adrenoceptors that increase KATP channel
activity via cAMP/PKA and NO that activates KATP channels via cGMP (461). Several of these vasodilator mechanisms are operative during normal arterial inflow and can
be further activated during myocardial ischemia. In addition, there is substantial evidence for modulation of KATP
channel activity by the metabolic state of the vascular
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DIRK J. DUNCKER AND ROBERT J. BACHE
smooth cell, with an increase in ADP/ATP ratio near the
sarcolemma, acidosis, and hypoxia all being potent activators of KATP channels directly (461). Thus, rather than
the bulk cytosolic ATP concentration, it is likely that the
ADP/ATP ratio in the subsarcolemmal microenvironment
and vasodilator signaling pathways act in concert to regulate KATP channel activity and maintain coronary blood
flow in the normal heart.
The influence of KATP channels on coronary blood
flow has been assessed using selective inhibitors of KATP
channel activity such as glibenclamide. Intracoronary
glibenclamide in doses of 10 –50 ␮g䡠kg⫺1 䡠min⫺1 caused
coronary vasoconstriction with a 20 –55% decrease in
basal coronary blood flow in open-chest dogs (285, 496)
or awake resting dogs (150, 153), resulting in reduced
coronary venous oxygen tension at a given level of myocardial oxygen consumption (153) (Fig. 23). Systemic administration of glibenclamide to dogs in a dose of 1 mg/kg
also resulted in a decrease in coronary venous oxygen
tension (473). Similarly, in awake resting swine, glibenclamide (3 mg/kg iv) produced increases in coronary vascular resistance and decreases in coronary venous oxygen tension (145) (Fig. 23). The decrease in coronary
blood flow produced by KATP channel blockade was associated with a decrease in regional systolic wall thickening (150, 153, 285). When coronary blood flow was
restored to preglibenclamide levels with intracoronary
nitroprusside (which by itself was devoid of any effect on
systolic wall thickening), contractile performance recovered (150, 285), indicating that glibenclamide caused a
primary decrease in coronary flow with a secondary decrease in contractile function. Furthermore, the decrease
in coronary flow produced by intracoronary glibenclamide caused metabolic changes of ischemia, including
a decrease in myocardial phosphocreatine and phosphorylation potential with an increase of inorganic phosphate
and adenosine release (153, 496). This is an important
observation, since it indicates that blockade of the endogenous vasodilator system associated with KATP channel
activity can cause coronary vasoconstriction sufficient to
result in myocardial ischemia.
In humans, a low intracoronary dose of glibenclamide (40 ␮g/min) resulted in a small decrease in resting blood flow (176) and blunted the pacing-induced increase in coronary blood flow by ⬃30% (175), suggesting
that KATP channels contribute to coronary vasodilation
during increased myocardial metabolic activity. KATP
channel blockade also decreases coronary blood flow and
coronary venous oxygen tension in normal dogs (150, 153,
473) and swine (145, 393) during treadmill exercise. However, the exercise-induced increase in coronary flow was
unaffected so that the increase in oxygen extraction and
the decrease in coronary venous oxygen tension were
comparable to the changes under resting conditions (145,
150, 153, 393, 473). These findings could be interpreted
Physiol Rev • VOL
to suggest either that KATP channels are unimportant
for exercise-induced coronary vasodilation, or that
other mechanisms compensate when KATP channels are
blocked.
B) KCa CHANNELS. KCa channels are abundantly expressed in coronary vascular smooth muscle cells (74,
210). Upon activation, these channels hyperpolarize the
cell membrane, thereby closing voltage-sensitive calcium
channels to produce vasodilation. The KCa channel family
consists of small-, intermediate-, and large-conductance
channels (BKCa), all with different structural components
and gating properties (229). The BKCa channel is the most
prominent KCa channel in vascular smooth muscle so that
small changes in open probability have a significant effect
on the sarcolemmal membrane potential and therefore on
vasomotor tone (74, 425, 490, 530). Membrane depolarization and increases in intracellular Ca2⫹ concentration are
thought to be the main activators of KCa channels, thereby
providing an important negative-feedback mechanism to
moderate vasoconstrictor responses (74, 425). In addition, various protein kinases have been shown to modulate the activity of the KCa channels (381, 511). KCa channels are activated by phosphorylation through cGMP-dependent protein kinase (PKG; Refs. 549, 604) and PKA
(406, 517), while protein kinase C (PKC) inhibits KCa
channels (405, 407, 458). Many endogenous vasoactive
substances exert their actions through these protein kinases, thereby modulating KCa channel activity and hence
altering coronary resistance vessel tone. In general, vasodilator substances such as adenosine, EDHF, NO, norepinephrine, and H⫹ act through stimulation of PKA and
PKG (74, 126, 381, 425), resulting in increased opening of
KCa channels, while vasoconstrictor substances, such as
endothelin and angiotensin II, decrease the opening of
KCa channels in part via PKC activation (281, 358, 405).
Hence, it is likely that many vasoactive substances act in
concert to mediate the exercise-induced opening of KCa
channels.
The role of KCa channels has been investigated in
anesthetized dogs. The KCa channel antagonists iberiotoxin (429), charybdotoxin (443), or tetraethylammonium
(477) had no effect on coronary blood flow under basal
conditions, which is in accord with the concept that in
dogs KATP channels are the principal K⫹ channel involved
in metabolic regulation of coronary vasomotor tone. In
swine, tetraethylammonium administered intravenously
in a dose that did not inhibit vasodilation by the KATP
channel opener bimakalim produced a small decrease in
coronary venous oxygen tension that was progressively
amplified with increasing levels of exercise (Fig. 24), suggesting that KCa channels contribute to exercise-induced
coronary vasodilation (399). The upstream vasodilator
pathways that activate the KCa channels in swine remain
to be determined, but are unlikely to involve adenosine,
NO, and prostanoids, as these vasodilator substances ex-
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1039
Voltage-dependent K⫹ channels constitute a diverse family of outwardly rectifying K⫹ channels present in the vascular smooth muscle sarcolemma
(229). These channels are sensitive to membrane potential so that depolarization will induce opening of KV channels and thereby oppose vasoconstriction. In addition,
these channels are sensitive to ␤-adrenoceptor stimulation and other cAMP-mediated vasodilator responses (2,
363). Alterations in the oxidative state of the vasculature
(termed “redox signaling”) most notably superoxide and
H2O2 can also modulate KV channel activity (229). Thus
Rogers et al. (477) recently reported that KV channels play
a role in redox signaling-mediated regulation of coronary
blood flow, as the KV channel antagonist 4-aminopyridine
(4-AP) blocked coronary vasodilation produced by intracoronary H2O2. Furthermore, 4-AP caused a 54 ⫾ 10%
decrease in basal blood flow, suggesting that KV channels
play an important role in maintaining resting coronary
blood flow. A possible role for KV channels in mediating
the coronary vasodilation that occurs in response to exercise has not been studied. However, evidence for a role
of H2O2 and KV channels in metabolic regulation of coronary blood flow was recently reported by Saitoh et al.
(495), who showed in open-chest dogs that the decrease
in coronary venous oxygen tension produced by intracoronary 4-AP increased progressively at higher levels of
myocardial oxygen consumption produced by pacing or
norepinephrine.
C) Kv CHANNELS.
FIG. 24. Effect of KCa channel blockade with tetraethylammonium
(TEA, 20 mg/kg iv) on the relation between myocardial oxygen consumption and coronary venous oxygen tension in the left ventricles of
swine (399) during treadmill exercise. Data are means ⫾ SE. *P ⬍ 0.05
vs. control; †P ⬍ 0.05 effect of TEA increases at higher levels of MV̇O2.
See text for further explanation.
ert a tonic influence on the coronary resistance vessels
that is similar at rest and during exercise. A potential
candidate is ␤-adrenoceptor activation which has been
shown to contribute to exercise-induced vasodilation
(148) and is known to act, at least in part, via KCa channels
(283, 517). Alternatively, the progressive withdrawal of
the vasoconstrictor influence of ET (which is known to
inhibit opening of KCa channels; Refs. 281, 407, 450) could
contribute to activation of these channels during exercise
(392, 395).
Interestingly, in swine the effects of combined KATP
and KCa channel blockade was not greater than the sum of
the effects of KATP and KCa channel blockade alone (399),
suggesting that these channels act in a linear additive,
rather than a nonlinear redundant, fashion (143, 565).
KATP channels are activated directly by increases in intracellular ADP/ATP (425), while vasodilators such as adenosine and prostacyclin are thought to exert their action
principally via cAMP/PKA-mediated opening of KATP
channels (73, 425, 579). In contrast, KCa channels are
activated directly by membrane depolarization and calcium (74, 358), while vasodilators like NO and atrial natriuretic peptide are considered to exert their action predominantly via cGMP/PKG-mediated opening of KCa channels (425, 549, 579). Although some overlap between the
activation pathways appears to exist (74, 425), the separate intracellular signaling pathway involved in the activation of KATP and KCa channels may explain, at least in
part, the observation that KATP and KCa channels act in an
additive manner in the regulation of coronary resistance
vessel tone in swine during exercise.
Physiol Rev • VOL
7. Summary and integration of coronary vasodilator
mechanisms
Enhanced delivery of oxygen and metabolic substrate is essential for the cardiac response to an increased
work load and involves a number of parallel mechanisms
that contribute to coronary vasodilation. In the dog,
blockade of any of these vasodilator mechanisms fails to
blunt the increase in coronary blood flow in response to
exercise, suggesting that adenosine, KATP channel opening, prostanoids, or NO are not mandatory for exerciseinduced coronary vasodilation, or that these redundant
vasodilator mechanisms can compensate when one mechanism is blocked.
A compensatory role for adenosine in the regulation
of coronary blood flow when KATP channels are blocked
was first demonstrated in dogs (153, 496) (Fig. 23). Following KATP channel blockade with intracoronary glibenclamide, which produced a 20% decrease in coronary
blood flow and a 50% decrease in regional wall thickening
(150, 153), adenosine receptor blockade resulted in a
significant further decrease in coronary flow and regional
wall thickening, in particular during exercise (153). In
contrast, Richmond et al. (473) found that administration
of an intravenous dose of 1 mg/kg glibenclamide, which
had no effect on lactate extraction, did not affect coro-
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DIRK J. DUNCKER AND ROBERT J. BACHE
nary venous adenosine concentrations (P ⫽ 0.11), either
at rest or during exercise. In that study, the dose of
glibenclamide may have been too low to fully block vascular KATP channels, as the authors stated that higher
doses resulted in coronary flow oscillations, suggesting
that larger doses did produce vasoconstriction, but this
resulted in generation of an underdamped error signal
that overcompensated for the constriction. The latter was
shown by Samaha et al. (496) to be due to cyclic release
of adenosine resulting from ATP breakdown, i.e., the
presence of myocardial ischemia. In swine, the effect of
simultaneous blockade of KATP channels and adenosine
receptors on oxygen extraction and coronary venous oxygen tension was equal to the sum of the individual effects
of 8-PT and glibenclamide (Fig. 23), indicating that loss of
KATP channel activity was not compensated for by an increased adenosine-mediated vasodilator influence (393).
These findings suggest that adenosine and KATP channels
act in an additive fashion in swine. However, adenosine
mediates its vasodilator effect on porcine coronary resistance vessels via both KATP channels (255) and Kv channels (250). It is therefore possible that following KATP
channel blockade, adenosine levels increased sufficiently
to maintain a vasodilator influence via Kv. Alternatively, it
is possible that following adenosine receptor blockade,
KATP channel activity was maintained via a compensatory
increase of alternate mediators such as NO and prostacyclin (294, 512).
In awake dogs, inhibition of NO synthase alone or in
combination with adenosine receptor blockade did not
affect the relation between oxygen consumption and coronary venous oxygen tension (288) (Fig. 23). However,
combined blockade of adenosine receptors, NO synthase,
and KATP channels markedly (50%) reduced coronary
blood flow at rest and nearly abolished the exerciseinduced coronary vasodilation (288). Those findings suggest that metabolic dilation of canine coronary resistance
vessels is regulated via a myriad of vasodilator systems
that act in concert to match coronary blood flow to myocardial oxygen demand so that when one system fails,
back-up systems ensure an adequate oxygen supply to the
myocardium. The observation that only KATP channel
blockade alone decreased coronary blood flow and
caused myocardial ischemia suggests that this represents
a principal coronary vasodilator pathway in the dog, with
adenosine and NO primarily acting as back-up systems
(153, 288). In contrast, Tune et al. (567) reported that
while simultaneous blockade of adenosine receptors,
KATP channels, and NO synthase caused coronary vasoconstriction in awake resting dogs, the triple blockade
failed to blunt the exercise-induced coronary vasodilation. Consequently, these authors concluded that these
mediators act in a linear additive fashion rather than a
nonlinear redundant manner (565). Interpretation of the
data and comparison with previous studies in dogs (150,
Physiol Rev • VOL
153, 288) are difficult, however, due to differences in
study design. One such difference is the use of a low dose
of glibenclamide (1 mg/kg iv) that was selected to avoid
reductions of coronary blood flow that resulted in myocardial ischemia (473, 567). However, this may have inadvertently resulted in incomplete KATP channel blockade,
allowing coronary blood flow to increase during exercise.
In swine, a high dose of glibenclamide (3 mg/kg iv),
which caused signs of anaerobic myocardial metabolism
and impaired left ventricular function (393), failed to
enhance the vasoconstrictor response to adenosine receptor blockade and NO-synthase inhibition (Fig. 23),
suggesting a vasomotor control design in the porcine
heart in which vasodilator pathways act in a linear additive fashion (393). Simultaneous blockade of adenosine,
KATP channels, and NO caused intense coronary vasoconstriction (forcing oxygen extraction to increase to over
90%) with signs of anaerobic metabolism and impaired
left ventricular function under resting conditions (393).
However, in contrast to the observations by Ishibashi
et al. (288) in the dog heart, the responses of coronary
blood flow and oxygen supply in swine to subsequent
exercise were essentially unperturbed (393). Apparently,
in swine, other vasodilator mechanisms that are not recruited under resting conditions can be recruited during
exercise when NO, adenosine, and KATP channels are
blocked. Such candidate mechanisms include ␤-adrenergic feed-forward vasodilation, prostacyclin, EDHF, and
H⫹. ␤-Adrenergic vasodilation plays an important role in
exercise-induced vasodilation in swine (148) and could
have acted through opening of KCa channels (399).
G. Coronary Blood Flow in the
Exercise-Trained Heart
Chronic endurance exercise leads to myocardial hypertrophy that can produce up to a 30% increase of relative left ventricular mass. Morphometric studies have
shown that this hypertrophy includes proportionate increases of cardiac myocytes and coronary vasculature
with no change in the proportion of extracellular collagen. Coronary vasodilation in response to endotheliumdependent and -independent vasodilators is normal in the
physiologically hypertrophied heart so that vasodilator
reserve is maintained or increased.
Physical conditioning leads to adaptations in the
myocardium that are aimed at increasing maximal cardiac
output and maximal total body oxygen consumption.
These adaptations also affect the major determinants of
myocardial oxygen demand: heart rate, contractility, and
left ventricular work (integrated systolic wall stress and
shortening). Dynamic exercise training lowers heart rates
at rest and at any given level of submaximal exercise, and
this reduction is accompanied by parallel decreases in
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CORONARY BLOOD FLOW
myocardial oxygen consumption (107, 258, 383, 588) and
coronary blood flow (40, 258, 588). Myocardial contractility is difficult to assess in vivo but appears minimally
affected by physical conditioning (87, 432, 492). Left ventricular systolic pressure is not significantly altered by
dynamic exercise training in normal individuals but may
decrease slightly in older or hypertensive subjects (509).
Left ventricular end-diastolic internal diameter and left
ventricular end-diastolic wall thickness increase in parallel so that their ratio is not significantly altered (161, 382,
508, 601). Consequently, left ventricular systolic wall
stress is minimally affected by exercise training. Stroke
volume increases in parallel with the increased enddiastolic volume so that muscle fiber shortening is
maintained. As a result, ventricular work per gram of
myocardium is minimally affected by dynamic exercise
training. These findings indicate that myocardial oxygen demand is decreased at rest or at a given absolute
level of exercise mainly because of the decrease in heart
rate.
In addition to reducing myocardial oxygen demands
at rest and during submaximal exercise, physical conditioning results in coronary vascular adaptations that can
increase the myocardial oxygen supply. Although there is
no evidence to suggest that coronary flow rates limit
oxidative metabolism in the normal heart even during
maximal exercise, an increase in myocardial oxygen supply following exercise training could act to facilitate maximal cardiac performance (see sect. IIB3C). The oxygen
supply can be increased by raising the arterial oxygencarrying capacity, by increasing oxygen extraction, or by
increasing blood flow. The oxygen-carrying capacity of
the blood is generally not significantly altered or may
decrease (⬍10%) following exercise training (97). Myocardial oxygen extraction does increase slightly following
exercise training (541, 588), but this is very modest since
oxygen extraction is already near maximal even in the
1041
untrained state. Therefore, an improvement of oxygen
supply must stem primarily from an increase of coronary
blood flow.
An enhanced ability to increase coronary blood flow
can result from adaptations within the coronary vasculature or from a decrease in the extravascular compressive
forces acting on the intramural coronary microvessels
(Fig. 25). Coronary vascular adaptations in response to
exercise training can be divided into structural (angiogenesis and vascular remodeling) and functional adaptations
(alterations in vasomotor control) (338 –340). Functional
adaptations can include changes in neurohumoral control
mechanisms or changes in local vascular control mechanisms, i.e., metabolic, myogenic, and endothelial control
of vasomotor tone. The following sections will consider
each of these effects of exercise training.
1. Structural adaptations
A) CORONARY ARTERIOLES. The effect of chronic treadmill
exercise training on numerical density (i.e., the number of
vessels per mm2) of coronary arterioles has been studied
in domestic (77) and miniature (600, 601) swine (Table 2).
Numerical density of arterioles, which were defined as
vessels containing at least three layers of smooth muscle
and with diameters between 35 and 75 ␮m, was 40 – 60%
greater in trained swine than in sedentary control animals
(77, 601). White et al. (600) studied in more detail the
adaptations of arterioles of varying sizes to exercise training up to 16 wk. The total cross-sectional area (␮m2
arterioles per mm2 of myocardium) of arterioles in the
range of 20 –120 ␮m increased significantly by 16 wk of
training, with a greater increase in total area in arterioles
of 20 – 40 ␮m (40 – 60%) than in arterioles of 40 –120 ␮m
(15–30%). Interestingly, the mechanism of the cross-sectional area increase also varied depending on the diameter range of the arterioles. Thus, for 20- to 40-␮m arte-
FIG. 25. Graph summarizing the structural and functional coronary microcirculatory adaptations to chronic exercise training. ACh, acetylcholine; M, muscarinic receptor; NE, norepinephrine; ␣1, ␣1-adrenergic receptor; ß2, ß2-adrenergic receptor. See text for further explanation.
Physiol Rev • VOL
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Swine M
Swine M, F
Swine M, F
Y
Y
Y
Y
A
Run
Run
Run
Run
Run
Run
Run
Type
70–85% of max
(⫹ sprints at
80–100% of
max HR), 60
min/day, 5
days/wk, 10
wk
70–80% of max
HR, 70 min/
day, 5 days/
wk, 16 wk
6.4–12.8 km/h,
10%; 60 min/
day, 5 days/
wk, 12 wk
10–20 km/h, 10–
20%; 75 min/
day, 5 days/
wk, 18 wk
70–85% of max
HR (⫹sprints
at 80–100% of
max HR), 70
min/day, 5
days/wk, 12
wk
70–85% of max
HR (⫹ sprints
at 80-90% of
max HR), 60
min/day, 5
days/wk, 10
wk
?
Program
Perfusion fixation LM/EM
Perfusion fixation LM/EM
LVW/BW 24% 1
VO2max 1, HREX 2
Perfusion fixation LM/EM
Perfusion fixation EM
Perfusion fixation EM
EM
Nuclear staining
Histological Technique
LVW 26% 1,
LVW/BW 31% 1
LVW 29% 1,
LVW/BW 15% 1
LVW 13% 1,
LVW/BW 29% 1
LVW, LVW/BW 7
HW 22% 1,
HW/BW ?
LVW 9% 1,
LVW/BW 7% 1
Cardiac Hypertrophy
VO2max 1, SMVO2 1
VO2max 1 SMVO2 1
VO2max 1, HRREST 2
SMVO2 1,
performance1
HRREST 2,
performance 1
HRREST 2
Efficacy
LV free wall
LV free wall full
thickness
Subendocardium
Subepicardium
LV free wall full
thickness
Subendocardium
Subepicardium
LV free wall full
thickness
LV free wall full
thickness
LV free wall full
thickness
LV septum full
thickness
Heart Chamber
1
1
1
1
Arteriolar
Density, mm⫺2
7*
2
2
1
7
7
7
7
1
Capillary
Density, mm⫺2
M, male; F, female; Y, young; A, adult; “?” ⫽ not reported; HRREST, resting heart rate; HREX, heart rate during exercise; SMVO2, skeletal muscle oxidative capactity; VO2max, maximum
total body oxygen consumption; LVW, left ventricular weight; LVW/BW, left ventricular to body weight ratio; HW, heart weight; HW/BW, heart weight-to-body weight ratio; LM, light
microscopy; EM, electron microscopy; 1 ⫽ increase; 2 ⫽ decrease; and 7 ⫽ no change. *An increase was noted after 3 wk of training that had disappeared after 8 and 16 wk.
White et al.
(600)
White et al.
(601)
Swine M, F
Dog M, F
A
Dog M, F
Laughlin
and
Tomanek
(353)
Breisch
et al.
(77)
Y
Dog ?
Thörner
(555)
Wyatt and
Mitchell
(612)
Age
Training
Exercise training and arteriolar and capillary densities in left ventricular myocardium in large animals
Species, Sex
2.
Investigators
TABLE
1042
DIRK J. DUNCKER AND ROBERT J. BACHE
CORONARY BLOOD FLOW
rioles, the increase was principally the result of an increase in numerical density, whereas for arterioles with a
diameter between 40 and 120 ␮m, this was due to an
increase in arteriolar diameter (600).
B) CORONARY CAPILLARIES. Several investigators examined the effects of physical conditioning on the capillaryto-fiber ratio (number of capillaries per myocyte), the
capillary numerical density (number of capillaries per
mm2), or capillary surface density (total capillary surface
area per myocardial tissue volume). Early studies in
which open capillaries were identified by erythrocyte
staining (452, 453) suggested an increase in capillary numerical density and exercise-induced cardiac hypertrophy in young guinea pigs following treadmill-exercise
training. Similar results were obtained with hematoxylineosin staining in treadmill-exercise conditioned dogs
(555). Capillary numerical density was found to be greater
in wild than in domesticated rabbits or rats (589, 590),
suggesting that greater physical activity of wild animals is
associated with higher capillary density. However, it is
not clear to what extent natural selection versus physical
conditioning caused the increased capillary densities in
the wild animals. In contrast, adult guinea pigs subjected
to swimming (193) or young guinea pigs subjected to
running (237) had decreased capillary numerical densities
compared with sedentary controls, as the capillary-tofiber ratio failed to increase in the face of cardiac hypertrophy.
Subsequent studies examined genetically similar rats
trained by either swimming or treadmill exercise. In the
rat, the response of myocardial capillary density is critically dependent on age. In young rats trained by swimming or running, exercise-induced capillary angiogenesis
occurs as indicated by an increase in [3H]thymidine labeling of capillary endothelial cells (94, 572) and an increase
in the capillary-to-fiber ratio (51, 60, 295, 362, 388, 558).
Angiogenesis outweighed myocyte hypertrophy in most
of these studies, resulting in increased capillary numerical
density (13, 60, 295, 553, 558) or relative capillary surface
area (388). In adult rats 3– 4 mo of age, and in old rats
6 –18 mo of age, exercise training was also associated
with enhanced formation of capillaries (60, 295, 361, 371,
558, 572). However, in contrast to the young rats, in adult
(60, 295, 558) and old rats (60, 558) angiogenesis usually
did not outweigh cardiac hypertrophy, leaving capillary
numerical density unchanged. Interestingly, in old rats,
swimming increased the capillary-to-fiber ratio, but this
occurred due to a loss of myocardial fibers (60).
Evidence that supports a positive effect of exercise
training on myocardial capillary density stems mainly
from studies of young male rats trained by swimming (51,
60, 94, 295, 362, 388, 558). In contrast, studies of treadmill
exercise-trained rats have reported both increases (13,
271, 295, 558) as well as no change in capillary density (11,
446, 552). A methodological concern is that several of the
Physiol Rev • VOL
1043
rat studies reported histological data exclusively for the
left ventricle (371, 388, 446, 558), while other studies
reported data averaged for both ventricles (51, 60, 94, 295,
361, 362, 572). Anversa et al. (13) showed that a moderate
treadmill exercise program increased capillary numerical
density in the right but not the left ventricle. Following a
more strenuous exercise program, capillary numerical
density again did not change in the left ventricle (12), but
actually decreased in the right ventricle (11, 14). These
findings raise concern that combined analysis of tissue
from both ventricles might obscure individual differences
in capillarization induced by exercise training in either
the left or the right ventricle.
Most studies in larger animals such as dogs (341, 612,
613) or swine (77) have also failed to observe an increased capillary-to-fiber ratio (77, 341) or capillary numerical density (77, 341, 612, 613) following treadmill
exercise training for at least 10 wk (Table 2). Interestingly, significant DNA labeling via tritium-labeled thymidine incorporation in dividing capillary cells and capillary
sprouting were observed at 1, 3, and 8 wk of training but
were no longer apparent at 16 wk of training (Fig. 26). In
addition, capillary growth outweighed myocyte growth at
the 3-wk time point, but capillary densities had returned
to levels observed in sedentary swine by 8 wk of training
(600). These results suggest that during the training program, capillary growth does occur and may even temporarily outgrow the increase in left ventricular mass that
occurs early during the training program. However, with
prolonged training, capillary growth is not in excess of,
but rather commensurate with, the increase in left ventricular mass.
C) SUMMARY AND INTEGRATION. Exercise training is associated with adaptations in the coronary microvasculature
including increased arteriolar densities and/or diameters,
which provide a morphometric basis for the observed
increase in peak coronary blood flow rates in exercise
trained animals (Fig. 25; see also sect. IIG4A). Most evidence that exercise training increases myocardial capillary density stems from studies of young male rats trained
by swimming. In larger animals trained by treadmill exercise, the formation of new capillaries maintains capillary
density at a level commensurate with the degree of myocardial hypertrophy. This does not imply a lack of effect
of exercise on the formation of new capillaries, since in
pathological forms of hypertrophy caused by hypertension or aortic stenosis capillary rarefaction often occurs
(76, 154).
2. Adaptations of neurohumoral control
Alterations in neurohumoral control of the coronary
vasculature can result from altered central autonomic
activity, changes in the number or affinity of receptors, or
changes in postreceptor events. Several studies reported
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1044
A
D
DIRK J. DUNCKER AND ROBERT J. BACHE
C
B
E
FIG. 26. Effects of exercise training
in swine on DNA labeling in capillaries
(A), sprouting of new capillaries (B), percent labeling of sprouts (C), capillary diameter (D), capillary density (E), and
coronary transport reserve (CTR; F).
Data are means ⫾ SE. *P ⬍ 0.05 vs. 0 wk
time point (sedentary swine). See text
for further explanation. [Data from
White et al. (600).]
F
decreased circulating levels of catecholamines in exercise-trained humans or animals. These differences are
most pronounced between comparable absolute levels of
submaximal exercise before and after training, suggesting
that sympathetic activity is decreased following training
(59, 468, 509). Information concerning adaptations at the
adrenergic receptor level is sparse and equivocal. Current
evidence is controversial with reports indicating that
myocardial ␤-adrenergic receptor density and sensitivity
is unchanged (240, 480, 606), or slightly decreased (38).
Similarly, ␣-adrenergic receptor density has been reported to be either decreased (606) or increased (177) in
rat myocardium following exercise training. An explanation for these discrepant findings is not readily found.
Physical conditioning increases resting parasympathetic
tone to the heart, and this is thought to arise from increased vagal nerve activity rather than changes at the
muscarinic receptor level, since myocardial receptor density and sensitivity appear to be slightly decreased (63,
606) or unchanged (38, 177). It should be noted that all of
these studies pertain to bulk left ventricular myocardium,
containing a mixture of cardiomyocytes, fibroblasts, vascular cells, and nerve endings. Studies of the effects of
exercise training on adrenergic and muscarinic receptor
density and sensitivity in the coronary vasculature are
lacking.
A) ␣-ADRENERGIC CONTROL OF CORONARY RESISTANCE VESSEL
TONE. Stone and co-workers (130, 235, 365) examined
alterations in neurohumoral control in dogs subjected to
daily treadmill exercise for 4 –5 wk. With trained dogs and
untrained dogs exercising at submaximal exercise levels,
Physiol Rev • VOL
the nonselective ␣-adrenergic receptor antagonist phentolamine produced an increase in diastolic coronary
blood flow. The increase in diastolic flow was significantly
less in exercise-trained compared with untrained dogs.
(365), suggesting that ␣-adrenergic vasconstrictor influence was lower in trained animals. In subsequent studies
from the same laboratory, phentolamine produced significantly greater (235) or smaller (130) increases in mean
coronary blood flow in partially trained dogs during submaximal exercise compared with sedentary animals. An
explanation for these divergent results is not readily
found, but in the latter study phentolamine produced
identical increases in mean coronary flow in trained and
sedentary dogs during submaximal exercise in the presence of ␤2-adrenoceptor blockade (130). In open-chest
dogs, ␣1-adrenoceptor blockade caused a slightly greater
increment of mean coronary blood flow in exercisetrained than in sedentary animals (339). Taken together,
the studies suggest that exercise training maintains or
slightly increases ␣-adrenergic tone in coronary resistance vessels during submaximal exercise.
The finding of maintained or increased ␣-adrenergic
tone during exercise despite lower circulating levels of
catecholamines implies increased ␣-adrenergic receptor
responsiveness. There is evidence in both peripheral (357,
376) and coronary vascular beds (129, 235) that resistance
vessels undergo greater constriction in response to ␣1adrenergic stimulation after exercise training. Thus the
decreases in coronary blood flow in awake dogs produced
by intracoronary injections of the ␣1-adrenergic agonist
phenylephrine or the nonselective agonist norepinephrine
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CORONARY BLOOD FLOW
are enhanced following exercise training (129, 235). When
dogs were exercised after left stellate ganglionectomy,
the training-induced increase of ␣-adrenergic responsiveness was abolished, indicating the importance of intact
sympathetic innervation for the coronary vascular adaptations to physical conditioning (129). Maintained or
slightly increased ␣-adrenergic tone in coronary resistance vessels despite lower circulating catecholamines
acts to limit “luxury perfusion” of the myocardium and to
optimize capillary diffusion (see sect. IIG4B). This is supported by the observation that myocardial oxygen extraction is enhanced following exercise training (541, 588).
B) ␤-ADRENERGIC CONTROL OF CORONARY RESISTANCE VESSEL
TONE. Interpretation of studies examining the effects of
exercise training on ␤-adrenergic tone in coronary resistance vessels is complicated by effects of ␤-adrenergic
blockade on the myocardium, which can mask the direct
vascular effect of ␤-adrenergic agents. Several investigators have observed similar coronary flow reductions in
response to nonselective (235, 367), ␤1-selective (235,
367), or ␤2-selective (130) adrenoceptor blockade in exercise-trained dogs during submaximal exercise compared with sedentary dogs. ␤2-Adrenergic receptor responsiveness of coronary resistance vessels has been reported to be enhanced following exercise training (129,
242). Thus it appears that a decrease in sympathetic neuronal input during submaximal exercise is balanced by
increased responsiveness of vascular ␤-adrenergic receptors so that vascular ␤2-adrenergic activity is maintained.
C) PARASYMPATHETIC CONTROL OF CORONARY RESISTANCE VESSEL TONE. Although vagal tone is increased by exercise
training (197, 209), there is no evidence for altered parasympathetic control of coronary resistance vessel tone
after exercise training. Thus the vasoconstrictor responses of isolated porcine arterioles 110 ⫾ 5 ␮m in
diameter to acetylcholine were similar in sedentary and
exercise-trained swine (350). Furthermore, muscarinic receptor blockade had no effect on coronary blood flow in
exercising dogs before or after exercise training (235),
indicating that exercise training did not induce a parasympathetic influence in coronary resistance vessels
during submaximal exercise with heart rates of 190 –
210 beats/min.
D) SUMMARY AND INTEGRATION. The available data indicate
that exercise training maintains or slightly increases ␣-adrenergic coronary tone and does not alter ␤-adrenergic
tone in coronary resistance vessels during submaximal
exercise. Maintenance of adrenergic tone in the presence
of lower circulating catecholamine levels appears to be
due to increased receptor responsiveness to adrenergic
stimulation. Finally, there is no evidence for altered parasympathetic control of coronary resistance vessel tone
after exercise training.
Physiol Rev • VOL
1045
3. Local coronary vascular control of resistance vessels
A) METABOLIC CONTROL. Exercise training has generally
been reported to result in slightly decreased coronary
blood flow rates per gram of myocardium at rest and
during submaximal exercise (258, 588). However, at similar levels of cardiac work, coronary blood flow is not
altered by exercise training (235, 258, 365, 541, 588),
suggesting minimal effect of exercise training on the coupling between myocardial metabolism and coronary
blood flow. Von Restorff et al. (588) and Stone (541)
reported a slight increase in myocardial oxygen extraction in exercise-trained dogs that was not sufficient to
result in a measurable decrease in coronary blood flow at
any submaximal heart rate. The slightly increased myocardial oxygen extraction during treadmill exercise likely
reflects improved capillary blood flow distribution (see
sect. IIG4B), but may be facilitated by increased myogenic
tone (see sect. IIG3B) and/or ␣-adrenergic tone (see sect.
IIG2A) in the coronary resistance vessels.
The mechanisms involved in metabolic regulation of
coronary blood flow likely include metabolic mediators
released by the myocardium that act on K⫹ channels in
the vascular smooth muscle. Although adenosine does not
play an essential role in regulation of coronary blood flow
under conditions of normal arterial inflow (28), exercise
training was reported to increase resistance vessel sensitivity or maximal response to adenosine in dogs in vivo
(129, 339, 353), and miniature swine in vivo (351), but not
in swine resistance vessels in vitro (414). The reason for
this difference is unclear.
Heaps et al. (252) reported that exercise training had
no effect on Kv or KCa channel function in arterioles from
remote normally perfused myocardium in hearts with a
chronic coronary artery occlusion. Conversely, Kv or KCa
channel activity is increased in large-conductance arteries
of exercise-trained swine and may act to facilitate metabolic vasodilation (69). The effects of exercise training on
arteriolar K channel function in the normal heart remain
to be determined.
B) MYOGENIC CONTROL. The myogenic mechanism produces an increase in vasoconstrictor tone in response to
increased stretch of the vascular smooth muscle. This
response has been implicated in autoregulation and reactive hyperemia. Muller et al. (414) studied the effect of
exercise training on the myogenic response of small coronary arteries of swine (75–150 ␮m in diameter) in vitro.
Active changes in vessel diameter measured in response
to 10-mmHg increments of distending pressure were similar in small arteries from exercise-trained and sedentary
swine for intraluminal pressures below 40 mmHg. However, for pressures above 40 mmHg, the myogenic response was significantly greater in vessels from exercisetrained than sedentary swine. The enhanced myogenic
tone was shown to be due to calcium-dependent PKC
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DIRK J. DUNCKER AND ROBERT J. BACHE
signaling in the vascular smooth muscle cells (324), which
enhances voltage-gated calcium currents through L-type
calcium channels in large arterioles (68). This increase in
basal myogenic tone in arterioles from exercise-trained
swine appears to be specific to stretch-mediated contractions. Thus neither the receptor-mediated vasoconstriction by acetylcholine and endothelin, nor the vasoconstriction in response to direct voltage-gated calcium channel activation by K⫹ and the L-type calcium channel
agonist BAY K 8644 were altered by exercise training
(350). The molecular basis for the exercise-induced alterations in intracellular calcium control in coronary arteriolar smooth muscle cells remains to be fully elucidated. On
the basis of observations in epicardial arteries from exercise-trained animals, it could be speculated that the adaptation involves increased activity of voltage-gated and
calcium-activated sarcolemmal K⫹ channels or adaptations at the level of the sarcoplasmic reticulum (70, 251,
340). However, in view of nonuniform effects of exercise
training on coronary vascular smooth muscle throughout
the coronary arterial tree, it is clear that these mechanisms that are involved in epicardial arteries await confirmation by observations in coronary arterioles.
C) ENDOTHELIAL CONTROL. Bove and Dewey (66) observed that 8 wk of exercise training enhanced the increases in myocardial blood flow produced by serotonin
in closed-chest anesthetized dogs. Since coronary resistance vessel dilation by serotonin is mediated through
endothelial 5-HT receptors, the findings suggest that exercise training augmented endothelium-dependent resistance vessel dilation. Similarly, Muller et al. (414) reported that exercise training augmented vasorelaxation in
response to the endothelium-dependent vasodilator bradykinin in isolated coronary arterioles (64 –157 ␮m in
diameter) from swine. Indomethacin decreased the vasodilator responses in both groups but did not alter the
difference between the two groups. In contrast, NG-monomethyl-L-arginine (L-NMMA) inhibited the bradykinin-induced vasodilation to a greater extent in the exercisetrained group and eliminated the difference between the
two groups, suggesting that exercise training enhances
bradykinin-induced vasodilation through increased NO
production (414). The observation that cytosolic copper/
zinc superoxide dismutase (SOD-1) was upregulated suggests that the increased endothelium-dependent vasodilator responses were, at least in part, the result of decreased quenching of NO by superoxide (491). However,
the vasodilator response to sodium nitroprusside was not
different between sedentary and exercise-trained swine,
suggesting that exercise training also caused an increase
in NO production. In support of this, Laughlin et al. (352)
demonstrated increases in endothelial NO synthase content in the coronary arterioles of exercise-trained swine.
D) SUMMARY AND INTEGRATION. The available data indicate
that exercise training alters local control of coronary resisPhysiol Rev • VOL
tance vessels (Fig. 25). Arterioles exhibit increased myogenic tone, which appears specific for stretch-induced contractions, as vasoconstrictor responses to various other agonists are not altered. The molecular basis for the increased
myogenic tone is likely the result of a calcium-dependent
PKC signaling-mediated alteration in voltage-gated calcium
channel activity in response to stretch. It is presently unclear
whether metabolic control mechanisms, including adenosine and K⫹ channel activity, are altered in coronary resistance vessels following exercise training. However, exercise
training augments endothelium-dependent vasodilation
throughout the coronary microcirculation. This enhanced
responsiveness appears to be principally the result of an
increased expression of NO synthase.
4. Integrated coronary vascular adaptations
To document a beneficial effect of exercise training,
it is necessary to show that the structural or functional
adaptations of the different vessel segments have the
potential to improve myocardial oxygen supply. Increases
in maximal blood flow per gram of myocardium or capillary diffusion capacity are the two main determinants of
oxygen supply in the normal heart.
A) MAXIMAL CORONARY BLOOD FLOW. There is controversy
as to whether maximal coronary blood flow is increased
following physical conditioning, with investigators reporting either no change (40, 67, 77, 93, 110, 364, 506, 541, 619)
or an increase (48, 86, 129, 344, 351, 366, 451, 535) in blood
flow capacity. Several factors may contribute to the differing results, including differences in species, sex, and
age of the experimental animals, as well as the type,
intensity, and duration of the exercise-training protocol.
However, the most important factor appears to be the
method used to assess blood flow capacity. Thus studies
in which increments in cardiac work load were used to
increase blood flow have found no change (40, 67, 541) or
increased blood flow capacity (366, 451). Studies in young
rat hearts using hypoxia to dilate the coronary vasculature have also yielded divergent results, with increased
blood flow in isolated buffer-perfused hearts from exercise-trained animals (48), but similar (619) or increased
(535) flow rates in blood-perfused in situ hearts from
exercise-trained rats. Laughlin et al. (344) reported an
increase in peak reactive hyperemia flow following a
10-s coronary artery occlusion in exercise-trained dogs,
whereas Stone (541) found no effect. Vasodilator stimuli
like increased cardiac work, hypoxia, or a 10-s occlusion
may not elicit maximal coronary vasodilation, nor is it
certain that maximal coronary vasodilation was achieved
when adenosine was infused intravenously (77, 93, 364).
In contrast, when maximal vasodilation was achieved
with intracoronary administration of adenosine, maximum coronary blood flow per gram of myocardium was
generally increased following exercise training in swine
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CORONARY BLOOD FLOW
(351, 600), dogs (339, 353), and rats (86) (Table 3). In only
two studies in which maximal coronary vasodilation was
documented and systemic hemodynamic variables were
controlled (110, 506) was maximal blood flow not increased
by exercise training. In the study of Scheel et al. (506), the
size of the perfusion beds was not assessed, and coronary
flow was expressed as milliliters per minute so that interanimal variability might have obscured a difference in flow
between the trained and sedentary dogs. Conversely, DiCarlo (129) reported that maximal coronary flow expressed
as milliliters per minute was enhanced by exercise training
in dogs. The negative results obtained by Cohen (110) could
have been influenced by differences between breeds
(trained greyhounds versus sedentary mongrel dogs). In addition, four of the five studies that reported an increase in
maximal blood flow rates documented a training effect (86,
129, 339, 351, 353), whereas in neither of the two negative
studies was a training effect reported (110, 506) (Table 3). In
summary, the weight of evidence suggests that physical
conditioning increases maximal coronary blood flow per
gram of myocardium when the exercise training program is
of sufficient intensity.
B) CAPILLARY DIFFUSION CAPACITY. Capillary exchange capacity is determined by capillary permeability and total capillary surface area. Although exercise training does not increase the capillary numerical density, an increase in the
permeability-surface area product (PSA) could still result
from optimization of the distribution of blood flow so that all
capillaries are perfused close to their exchange capacity.
This would then increase the effective capillary surface area
without an increase in anatomical surface area. PSA can be
determined using indicator dilution techniques that incorporate a diffusible test substance and an intravascular reference substance. Laughlin and associates have shown an
increase in PSA in exercise-trained dogs (339, 343, 353) and
miniature swine (351). When the PSA and morphometric
measurements of capillarization were examined in the same
hearts, exercise was found to increase PSA with no change
in capillary numerical density (353). This suggests that the
increase in PSA resulted from optimization of the distribution of blood flow, thereby increasing the effective surface
area. In the maximally vasodilated bed, the PSA is a function
of the coronary flow rate, possibly because the latter is
associated with recruitment of more capillaries and hence
microvascular exchange area (353). Although a higher PSA
could be due to the higher maximal flow rates in trained
animals when hearts are perfused at comparable coronary
artery pressures, this is unlikely because a higher PSA was
also observed when exercise-trained and sedentary animals
were compared at similar flow rates by lowering coronary
pressure in the trained animals (349). In summary, exercise
training alters the distribution of coronary vascular resistance
so that more capillaries are recruited, resulting in an increase in
the PSA without a change in capillary numerical density.
Physiol Rev • VOL
1047
5. Extravascular determinants of coronary blood flow
Alterations of systemic hemodynamic variables resulting from exercise training affect not only myocardial
oxygen demands but can also modulate extravascular
compressive forces, which can influence coronary flow.
For example, exercise training results in a lower heart
rate at rest and during submaximal levels of exercise (18,
509). This relative bradycardia not only decreases myocardial oxygen demand (258) but, by reducing the time
spent in systole, decreases the net impedance to blood
flow produced by systolic compression of the intramural
coronary vessels (151). Exercise training slightly improves indices of global left ventricular systolic and diastolic function, mainly because of altered ventricular dimensions and loading conditions (118), as intrinsic myocardial contractility is minimally affected (87, 432).
Improvement of systolic and diastolic function has opposing effects on impedance of coronary blood flow and will
tend to balance each other (151) with a minimal net effect
on impedance to blood flow. Dynamic exercise training
also increases left ventricular end-diastolic internal dimensions and wall thickness so that their ratio is not
significantly altered (382, 601). Since left ventricular diastolic and systolic pressures are minimally affected by
endurance exercise training in normal animals (40, 120,
601), it is likely that left ventricular diastolic and systolic
wall stress are not altered by dynamic exercise training.
The available data indicate that physical conditioning
decreases extravascular compressive forces at rest and at
comparable absolute levels of exercise, mainly because of
a decrease in heart rate.
III. CORONARY BLOOD FLOW DISTAL TO
A CORONARY ARTERY OBSTRUCTION
DURING EXERCISE
A. Regulation of Coronary Blood Flow Distal
to a Coronary Artery Stenosis
1. Effects of a coronary stenosis on myocardial blood
flow during exercise
Autoregulation is defined as the capacity to maintain
constant blood flow in the face of a change in perfusion
pressure (with constant metabolic needs). The vasomotor
mechanisms that underlie autoregulation appear to include those involved in metabolic regulation but likely
also involve the myogenic response. Normally, large epicardial “conductance” coronary arteries contribute little
to total coronary resistance. However, autoregulation becomes clinically important when atherosclerosis causes
narrowing of a large coronary artery that obliterates over
70% of the luminal cross-sectional area (50% diameter
reduction). Such a stenosis results in a significant in-
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3.
Swine M, F
White et al.
(600)
Physiol Rev • VOL
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Dog M, F
Dog M, F
Laughlin and
Tomanek
(353)
DiCarlo et al.
(129)
A
A
A
A
A
A
A
Y
Age
Run
Run
Run
Run
Run
Run
Run
Swim
Type
6.4–12.8
km/h, 0%;
75 min/day,
5 days/wk,
16–22 wk
70–80% of
max HR,
70 min/day,
5 days/wk,
16 wk
5.8 km/h,
25% grade;
45 min/day,
7 days/wk,
6 wk
9.6 km/h,
10–20%;
75 min/day,
5 days/wk,
12–20 wk
Greyhound
dogs
compared
with
mongrel
dogs
9.6 km/h,
10–20%;
75 min/day,
5 days/wk,
12-20 wk
6.4–9.6
km/h, 20%;
5 days/wk,
4–5 wk
150 min/day,
5 days/wk,
8–10 wk
Program
Isolated bloodperfused heart
LVW 7, LVW/BW 7
No*
Awake
Open-chest
extracorporeal
perfusion
HW 7, HW/BW 7
SMVO2 1
?
Awake
LVW 100% 1,
LVW/BW 75% 1
Open-chest
extracorporeal
perfusion
?
SMVO2 1
?
HW 18% 1,
HW/BW 7
Open-chest
extracorporeal
perfusion
LVW/BW 24% 1
VO2max 1, HREX 2
Open-chest
extracorporeal
perfusion
Isolated bufferperfused heart
Experimental
Conditions
SMVO2 1, HREX 2
?
1;
23% 1,
1
35% 1
Cardiac Hypertrophy
Male: HW 7,
HW/BW 10%
Female: HW
HW/BW 24%
HW ?, HW/BW
Efficacy
Ado-ic
Ado-ic
Ado-ic
Ado-ic
Ado-ic
Ado-ic
Ado-ic
Ado-ic
Method of
Vasodilation
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Maximal
Vasodilation
CBF
CBF/g
CBF/g
CBF/g
CBF
CBF/g
CBF/g
CBF/g
Measured
Variable
1
1
7
1
7
1
1
1
Maximum
Blood Flow
HR, heart rate; Ado, adenosine; ic, intracoronary; CBF/g, mean coronary blood flow normalized per gram of myocardium; ? , not reported.*Not reported in that study but based on
previous observations from the same laboratory (Stone, 1980; Liang et al., 1984).
Dog M, F
Dog M, F
Cohen (110)
Laughlin
(339)
Dog M
Swine F
Laughlin et
al. (351)
Scheel et al.
(506)
Rat M, F
Buttrick et al.
(86)
Species, Sex
Training
Exercise training and coronary blood flow capacity
Investigators
TABLE
1048
DIRK J. DUNCKER AND ROBERT J. BACHE
CORONARY BLOOD FLOW
crease in proximal resistance and causes a decrease in
distal coronary perfusion pressure. In this situation, autoregulation can preserve basal coronary blood flow, but
maximum coronary blood flow (as commonly measured
using intracoronary administration of adenosine) is reduced (Fig. 27). Consequently, coronary flow reserve (the
ratio of maximum to basal coronary flow) is attenuated.
When a stenosis becomes sufficiently severe to reduce the
poststenotic pressure below 40 mmHg during resting conditions, endogenous vasodilator reserve becomes exhausted and basal flow decreases, resulting in myocardial
hypoperfusion (29, 92, 138).
Autoregulatory reserve is not homogeneously distributed across the left ventricular wall. Thus Ball and Bache
(36) showed that when dogs were exercised on a treadmill, progressive obstruction of a coronary artery with a
hydraulic occluder resulted in a decrease in flow first in
the subendocardial myocardium while flow to the subepicardial layers was reduced only when more severe levels
of stenosis were applied (Fig. 28). This preferential decrease in subendocardial flow is the result of higher extravascular compressive forces in the subendocardium
(274, 599), causing the lower limb of the autoregulation
curve to be shifted to the right compared with that in the
subepicardial layers (Fig. 27). This also explains the observation that intracoronary infusions of adenosine or
dipyridamole (which have no effect on systemic hemodynamics), in the presence of a critical stenosis that has
exhausted subendocardial flow reserve can result in “coronary epicardial steal” (29, 138). In this situation, adenosine will increase blood flow in subepicardium, but the
resulting increase in coronary arterial inflow will increase
the pressure gradient across the stenosis, thereby decreasing poststenotic perfusion pressure and hence subendocardial blood flow (point c to c⬘ in Fig. 27, top). When
myocardial oxygen consumption increases during exercise, the autoregulatory plateau will be shifted upward,
transposing the break point to the right (Fig. 27, bottom).
During exercise, the increase in heart rate, which results
in an increase in average myocardial tissue pressure (as
relatively more time is spent in systole) shifts the pressure-flow relation to the right, particularly in the subendocardial layers. This explains why a subcritical coronary stenosis (that has no effect on resting coronary
blood flow) can result in selective subendocardial hypoperfusion during exercise (point b to b⬘⬘ in bottom
panel of Fig. 27).
2. Coronary vasomotor tone regulation distal to a
stenosis: importance of functional anatomy of the
coronary microcirculation
Ischemia has generally been assumed to cause maximal vasodilation of the coronary microvasculature and to
render these vessels unresponsive to vasoconstrictor
Physiol Rev • VOL
1049
FIG. 27. Coronary pressure-flow relation in the subepicardial (Epi) and
subendocardial (Endo) layers during autoregulation (auto) or during maximal
coronary vasodilation with adenosine (max), at rest (top panel) and during
exercise (bottom panel). Top panel shows myocardial blood flow under conditions of normal arterial inflow (a and a⬘), modest stenosis (b and b⬘), and
severe stenosis (c and c⬘). Note that with increasing stenosis severity coronary
perfusion distal to the stenosis decreases, thereby reducing the maximal
achievable myocardial blood flow. In the case of the severe stenosis, infusion
of adenosine will result in an increase in subepicardial flow that increases the
pressure drop across the stenosis, thereby further decreasing poststenotic
coronary pressure, thereby causing a decrease in subendocardial blood flow.
Bottom panel shows myocardial blood flow under conditions of normal
arterial inflow (a and a⬙) and modest stenosis (b and b⬙). Note that exercise
causes an upward shift of the autoregulatory plateau. During exercise in the
presence of a stenosis, the rightward shift of particularly the subendocardial pressure-maximal flow relation causes subendocardial flow to decrease
while subepicardial blood flow shows a normal increase. See text for
further explanation.
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1050
DIRK J. DUNCKER AND ROBERT J. BACHE
FIG. 28. Effect of a coronary artery stenosis on the transmural
distribution of myocardial blood flow during treadmill exercise in dogs.
Blood flows are shown at rest and during exercise with normal arterial
inflow and in the presence of a modest (stenosis 1) and severe (stenosis
2) degree of stenosis. Note the progressive hypoperfusion from the
outer- to the innermost layer. Data are means ⫾ SE. *P ⬍ 0.05 vs.
corresponding exercise control. See text for further explanation. [Data
from Ball and Bache (36).]
stimuli. However, even during ischemia, the coronary resistance vessels retain some degree of vasomotor tone
and can respond to vasoconstrictor stimuli. This finding
has required reassessment of the location and function of
the principal sites for resistance to blood flow in the
coronary circulation. The coronary arterial vasculature
has traditionally been divided into two discrete segments:
arteries that offer little resistance to blood flow and do
not participate in regulation of perfusion, and microvessels, which represent the major locus of resistance to
flow. The resistance vessels have generally been treated
as a homogeneous array of vessels, which act principally
in response to local myocardial needs, but can also respond weakly to systemic vasomotor influences. The development of methods to directly visualize the coronary
microvessels has demonstrated that this concept of a
functionally homogeneous coronary microvascular circulation is an oversimplification (Figs. 29 and 30). Direct
measurements of microvascular pressures in beating
hearts have demonstrated that during basal conditions, up
to 40% of total coronary resistance resides in small arteries between 100 and 400 ␮m in diameter, and that during
vasodilation these vessels contribute an even greater fraction of total coronary resistance (105, 380, 556). The
importance of this finding is that although these small
arteries contribute a substantial fraction of total coronary
resistance and are capable of active vasomotion, they do
not appear to be under local metabolic control. The finding that a substantial fraction of resistance resides at the
Physiol Rev • VOL
level of the small arteries may in part explain the finding
that myocardial ischemia does not predictably cause maximal vasodilation of the coronary resistance vessels. Persistence of vasomotor tone in the coronary resistance
vessels during myocardial ischemia can be ascribed (at
least in part) to vasoconstrictor tone in these small arteries, which are not under metabolic control. In addition,
there is evidence that even in coronary arterioles which
are under metabolic control (⬍100 micron in diameter),
vasoconstrictor influences can compete with metabolic
vasodilator activity (103, 380, 556).
A) LARGE EPICARDIAL ARTERIES. In the normal heart, the
large arteries (⬎400 ␮m in diameter) are truly conduit
vessels that contribute ⬍5% of total coronary resistance
(101, 105). When atherosclerosis or vasospasm decreases
coronary artery cross-sectional area by ⬎70%, a substantial fraction of total resistance can reside in these large
vessels, resulting in a pressure drop across the stenotic
segment. In this situation, studies of the regulation of
vasomotor tone of the coronary bed distal to a stenosis
must take into account alterations in stenosis severity and
changes in the pressure drop across the stenosis that
result from changes in flow. For example, pharmacological agents that dilate large arteries can decrease the severity of a compliant stenosis, thereby improving blood
flow. To eliminate effects of changes in stenosis severity,
some investigators have employed experimental models
in which a stenosis maintains a constant limited rate of
arterial inflow. With a constant flow model, vasodilation
of the resistance vessels causes a decrease in coronary
perfusion pressure as the stenosis prevents flow from
increasing in response to distal vasodilation. Since arterial inflow is constant, coronary pressure distal to the
stenosis should reflect changes in vasomotor tone of the
resistance vessels. A problem with the constant flow
model is that at the low perfusion pressures distal to a
coronary stenosis, blood flow is influenced not only by
active vasomotion of the resistance vessels, but also by
interaction between the intravascular distending pressure
and the extravascular forces which act to collapse the
thin-walled microvessels. If distal coronary pressure falls
as the result of microvascular vasodilation while extravascular forces remain constant, then the extravascular forces will exert an increasing influence on blood flow.
The influence of extravascular forces becomes progressively more important as distal coronary pressure decreases and is greater in diseased hearts in which left
ventricular diastolic pressure is elevated or the rate of
relaxation slowed. Because extravascular forces are highest in the subendocardium, a decrease in coronary pressure distal to a stenosis can cause passive redistribution
of blood flow away from the subendocardium. The term
passive redistribution is used since the redistribution of
flow away from the subendocardium with decreasing perfusion pressure can occur independently of active vaso-
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FIG. 29. Schematic overview of the coronary microcirculation and
the relative sensitivities of the various microvascular segments to pressure, flow, and metabolism. [Adapted from Tiefenbacher and Chilian
(556).]
motion. To avoid passive alterations in flow secondary to
changes in the interaction between extravascular forces
and intravascular perfusion pressure (especially at the
low coronary pressures distal to a flow-limiting stenosis),
experimental models have been used in which a stenosis
maintains a constant distal coronary pressure so that only
changes in vasomotor tone of the microvasculature result
in changes in blood flow (25, 33, 92, 137, 140, 141, 144, 287,
289, 354 –356, 529).
B) CORONARY COLLATERAL VESSELS. Collateral vessels that
are sufficiently developed to provide an alternate parallel
blood supply can complicate interpretation of measurements of blood flow in a myocardial region perfused by a
stenotic coronary artery. Thus vasomotion of coronary
collaterals can alter both the inflow of arterial blood and
the poststenotic perfusion pressure in the terminal vascular bed (192, 317). However, if distal coronary pressure
is maintained constant, changes in myocardial tissue
blood flow reflect changes at the level of the intramural
resistance vessels, irrespective of the source of blood
flow (i.e., antegrade or via collateral vessels).
Physiol Rev • VOL
1051
C) SMALL ARTERIES. Active vasomotor tone in arterial
segments that are not under metabolic control but which
contribute substantially to total coronary resistance have
the potential to alter myocardial blood flow. Chilian and
co-workers (101, 105) showed that under normal conditions up to 25% of total coronary resistance can reside in
arterial vessels larger than 170 ␮m in diameter, with as
much as 40% in vessels larger than 100 ␮m. Metabolic
vasodilation and autoregulation occur predominantly in
arterioles smaller than 100 ␮m; under conditions of unimpeded coronary inflow, vasoconstriction of the small
arteries can be compensated for by vasodilation of the
arterioles (104, 299, 300). However, when hypoperfusion
has already caused metabolic vasodilation of the arterioles, the ability to compensate for vasoconstriction of
the small arteries is lost. Furthermore, in the presence of
intense arteriolar vasodilation, an even greater fraction
of total coronary resistance resides in the arteries; in this
situation, vasoconstriction of small arteries can aggravate
hypoperfusion.
D) INTRAMURAL PENETRATING ARTERIES. The penetrating
arteries represent a special group of small arteries that
traverse the left ventricular wall to deliver blood from the
epicardial arteries to the subendocardial microvasculature. The penetrating arteries range from 100 to 500 ␮m in
diameter, with most around 200 ␮m (64, 169). At an aortic
pressure of 100 mmHg, pressure in coronary arterioles
100 ␮m in diameter was 80 mmHg in the subepicardium
but only 60 mmHg in the subendocardium, indicating that
a substantial pressure drop occurs across the penetrating
arteries (99). In the presence of a coronary stenosis,
which has caused the arterioles smaller than 100 ␮m to
undergo metabolic vasodilation, the penetrating arteries
can pose an important additional source of resistance to
subendocardial perfusion. In this situation, variations in
tone in these vessels could directly alter blood flow to the
subendocardium.
E) ARTERIOLES. In the normal heart, a major fraction of
coronary resistance resides in arterial segments ⬍100 ␮m
in diameter (arterioles). These arterioles are responsive
to changing myocardial metabolic needs and are the site
for metabolic vasodilation (306), autoregulation (307),
and ischemic vasodilation (103, 307). Although the arterioles are the site of metabolic vasoregulation, there is
evidence that vasomotor tone can persist in these vessels
even in the presence of myocardial ischemia (103).
3. Mediators of coronary vasodilation distal
to a stenosis
A) ADENOSINE. In contrast to the normal heart where
adenosine does not participate in regulation of coronary
flow under physiological conditions, adenosine does contribute to coronary vasodilation when there is an insufficient supply of oxygen. During ischemia or hypoxia, ATP
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DIRK J. DUNCKER AND ROBERT J. BACHE
FIG. 30. Schematic overview of various vasodilator (yellow text boxes) and vasoconstrictor (blue text boxes) influences in different
(micro)vascular segments (epicardial artery, small intramural arteries class A and B, and arterioles) of the coronary arterial bed of the LV wall. TxA2,
thromboxane A2 (receptor); 5HT, serotonin or 5-hydroxytryptamine (receptor); B2, bradykinin receptor subtype 2; ANG II, angiotensin II; ET,
endothelin; ß1 and ß2, ß1- and ß2-adrenergic receptor; ␣1 and ␣2, ␣1- and ␣2-adrenergic receptors; NO, nitric oxide; PGI2, prostacyclin (receptor);
EDHF, endothelium-derived hyperpolarizing factor; KATP, ATP-sensitive K⫹ channel; KCa, calcium-sensitive K⫹ channel; KV, voltage-sensitive K⫹
channel.
breakdown leads to increased adenosine production and
release from cardiac myocytes and possibly endothelial
cells (39, 180, 510, 534). In this situation, adenosine does
exert a significant vasodilator effect, since the increase in
coronary flow in response to systemic or local myocardial
hypoxia is attenuated following intracoronary administration of adenosine deaminase (205, 359, 400, 401, 595).
Similarly, adenosine plays a role in ischemic coronary
vasodilation. Thus intracoronary adenosine deaminase
(28, 494), or adenosine receptor blockade with intravenous 8-phenyltheophylline (28) or aminophylline (204,
207, 515), caused a decrease in the total volume of excess
flow during reactive hyperemia following a brief total
coronary artery occlusion in open-chest and awake dogs.
Laxson et al. (356) studied the contribution of adenosine to the resistance vessel dilation that occurs when a
coronary artery stenosis results in myocardial hypoperfusion during exercise. During treadmill exercise in dogs, a
hydraulic occluder around the proximal left circumflex
coronary artery was partially inflated to produce a constant distal coronary pressure of 40 – 42 mmHg. Mean
blood flow in the region perfused by the stenotic coronary
artery was decreased to 1.25 ⫾ 0.20 compared with 2.63 ⫾
0.25 ml䡠min⫺1 䡠g myocardium⫺1 in the normally perfused
control region. Hypoperfusion was most severe in the
subendocardium with a subendocardial/subepicardial
(endo/epi) flow ratio of 0.37 ⫾ 0.07 versus 1.21 ⫾ 0.06 in
the control region. To determine whether adenosine contributed to vasodilation of the resistance vessels in the
ischemic region, exercise was repeated during blockade
of adenosine receptors with 8-phenyltheophylline combined with intracoronary adenosine deaminase to augment
Physiol Rev • VOL
adenosine catabolism (390). While the stenosis maintained distal coronary pressure constant at 41 ⫾ 1 mmHg,
adenosine blockade caused a further decrease in mean
blood flow in the region perfused by the stenotic coronary
artery to 0.92 ⫾ 0.13 ml䡠min⫺1 䡠g⫺1 (Fig. 31). Although
there is evidence that adenosine production is positively
correlated with the degree of hypoperfusion (128), the
effect of adenosine was not greater in the subendocardium even though hypoperfusion was most severe in that
region. The decrease in flow produced by adenosine
blockade was associated with further deterioration of
FIG. 31. Effect of adenosine receptor blockade with 8-phenyltheophylline (8PT, 5 mg/kg iv) and increased adenosine catabolism with
adenosine deaminase (ADA; top panel) and effect of NO synthase inhibition with N-nitro-L-arginine (L-NA, 20 mg/kg iv; bottom panel) on blood
flow distal to a coronary artery stenosis. Epi, subepicardium; OM, outer
mid; IM, inner mid; Endo, subendocardium. Data are means ⫾ SE. *P ⬍
0.05 vs. corresponding control. See text for further explanation. [Data
from Laxson et al. (356) and Duncker and Bache (137).]
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CORONARY BLOOD FLOW
systolic segment shortening in the hypoperfused region,
indicating worsening of ischemia (356). These findings
indicate that adenosine does contribute to vasodilation of
the coronary resistance vessels when exercise in the presence of a flow-limiting stenosis results in myocardial
ischemia.
In summary, adenosine does not play a role in metabolic regulation of myocardial blood flow in the normal
heart during physiological conditions. However, adenosine does contribute to coronary vasodilation under conditions of hypoxia or impaired arterial inflow, principally
at the level of the arterioles ⬍100 ␮m in diameter (300,
306).
B) NO. NO production increases during hypoxia, suggesting that NO-dependent vasodilator mechanisms could
have increased importance during ischemia (81, 447, 455).
In accordance with this concept, Smith and Canty (529)
observed that inhibition of NO synthesis with L-NAME had
no effect on coronary flow at normal coronary pressures,
but when coronary artery pressure was reduced below
the autoregulatory range, coronary flow rates were lower
after L-NAME than during control conditions. As a result,
the lower limb of coronary pressure-flow relation during
autoregulation was shifted toward higher coronary pressures after blockade of NO synthesis. We assessed the
contribution of NO to the vasodilation of coronary resistance vessels that occurs during exercise in the presence
of a flow-limiting coronary stenosis (Fig. 31). Dogs underwent moderate treadmill exercise while partial inflation
of a hydraulic occluder created a stenosis that maintained
distal coronary pressure at 55 ⫾ 2 mmHg (137). Inhibition
of NO production with L-NA did not decrease coronary
flow at rest or during exercise in the normally perfused
control region (137). However, in the region perfused by
the stenotic coronary artery, inhibition of NO synthesis
decreased mean myocardial blood flow from 1.09 ⫾ 0.13
to 0.68 ⫾ 0.11 ml䡠min⫺1 䡠g⫺1 (P ⬍ 0.05). This reduction of
blood flow (137, 529) could have resulted from vasoconstriction either in the small coronary arteries that are not
under metabolic control (⬎100 ␮m in diameter) or in
arterioles that are under metabolic control (⬍100 ␮m).
Studies of isolated microvessels have demonstrated that
basal release of NO does occur in canine coronary arterioles
(40 – 80 ␮m) but only in the presence of flow (328, 418). In
the in vivo heart, basal NO release occurs in both arterioles (⬍100 ␮m) and in resistance arteries (⬎100 ␮m)
(298, 299, 323), and vessels of both size dilate in response
to acetylcholine (323). The observation by Jones et al.
(299) that in the normal heart inhibition of NO production
resulted in vasoconstriction of small arteries but (compensatory) vasodilation of the arterioles suggests that
constriction of the small arteries was principally responsible for aggravation of hypoperfusion distal to a coronary
artery stenosis. Thus, in the normal heart, vasoconstriction resulting from inhibition of NO production is comPhysiol Rev • VOL
1053
pensated for by metabolic vasodilator factors acting at the
arteriolar level. However, when a coronary stenosis has
already caused metabolic vasodilation of the arterioles,
the ability to compensate for inhibition of NO production
is lost. In this situation, NO inhibition can aggravate hypoperfusion by causing constriction of the resistance arteries.
It is unclear whether constriction of the resistance
vessels produced by inhibition of NO synthesis in hypoperfused myocardium is the result of unmasking of
normal levels of NO release when other vasodilator mechanisms have been exhausted, or whether it is due to an
actual increase of NO production in response to myocardial hypoperfusion. Impaired tissue oxygenation has been
proposed to result in increased NO release from the endothelium (455) or erythrocytes (527, 536). Oxygen tensions are lower in the walls of arterioles and even small
arteries than in the central aorta (136), suggesting that
conditions exist that could allow the vascular wall to
serve as a tissue oxygen sensor (454). Alternatively, decreases in oxygen tension can stimulate the release of NO
from red blood cells (527, 536). There is evidence that the
vasoconstrictor response to ␣1- and postjunctional ␣2adrenoceptor stimulation is augmented in hypoperfused
myocardium distal to a coronary artery stenosis during
exercise (355, 518). Since endothelial ␣2-adrenoceptors
can stimulate NO production, sympathetic nervous system activation during exercise could potentially augment
NO production distal to a flow-limiting stenosis. In this
situation, inhibition of NO production would aggravate
hypoperfusion by leaving ␣1- and ␣2-adrenergic coronary
vasoconstriction unopposed. This is supported by the
finding that coronary microvessel constriction in response to norepinephrine is enhanced following the administration of L-NA (298) and that after inhibition of NO
synthesis exercise in the presence of a coronary stenosis
unmasked an ␣2-mediated vasoconstrictor response (287).
NO-dependent vasodilator responses are impaired in
patients with atherosclerosis, hyperlipidemia (187), or
hypertension (368, 442). The experimental evidence demonstrating that inhibition of NO production can aggravate
myocardial hypoperfusion distal to a coronary artery stenosis supports the clinical observation that endothelial
dysfunction of the coronary resistance vessels can render
patients more vulnerable to hypoperfusion in myocardial
regions perfused by a stenotic coronary artery (497, 622).
C) PROSTAGLANDINS. In early studies, inhibitors of cyclooxygenase were reported to depress coronary reactive
hyperemia and hypoxic coronary vasodilation (1, 3). However, these results were likely influenced by experimental
preparations in which acute surgical trauma had caused
activation of the prostaglandin system (437), since subsequent studies in intact animals have generally found little
effect of these agents (269, 437). In anesthetized swine in
which an intraluminal hollow plug was used to produce
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DIRK J. DUNCKER AND ROBERT J. BACHE
an 80% reduction in coronary artery cross-sectional area,
cyclooxygenase blockade with indomethacin did not alter
coronary blood flow (489), suggesting that vasodilator
prostaglandins do not contribute to resistance vessel dilation distal to a flow-limiting coronary stenosis. Conversely, in patients with coronary artery disease, inhibition of cyclooxygenase resulted in coronary vasoconstriction (135, 198), suggesting that vasodilator prostaglandins
assume greater importance in regulation of coronary vasomotor control in chronic ischemia. However, in those
studies, it cannot be excluded that vasoconstriction occurred not only in the distal microvasculature but also in
proximal stenotic segments.
D) KATP CHANNELS. Opening of KATP channels contributes to coronary vasodilation during reactive hyperemia
(21, 150, 153) and hypoxia (124). Studies in which coronary microvessels were directly visualized using intravital
microscopy in open-chest dogs demonstrated that KATP
channels become progressively more activated as coronary artery pressure is decreased. Thus Komaru et al.
(322) observed that superfusion of the subepicardial vasculature with the KATP blocker glibenclamide had no effect on arteriolar diameter (⬍100 ␮m) at coronary artery
pressures of 90 –100 mmHg, but abolished the arteriolar
dilation that occurred in response to progressive reductions of coronary pressure. In contrast, small coronary
artery (⬎100 ␮m) diameter decreased as perfusion pressure (distending pressure) was decreased, and this was
not modified by glibenclamide. These findings indicate
that KATP channels in arterioles are important mediators
of the vasodilator response that accounts for coronary
autoregulation. In extracorporeally perfused dog hearts,
intracoronary glibenclamide (10 ␮g䡠kg⫺1 䡠min⫺1) had no
effect on coronary flow when perfusion pressures were
equal to or greater than aortic pressure (⬎100 mmHg),
but caused a decrease in flow when pressures were below
80 mmHg (422). We studied coronary flow responses over
a range of perfusion pressures produced by progressively
inflating a hydraulic occluder in dogs running on a treadmill (heart rates ⬃200 beats/min) (152). KATP channel
blockade with glibenclamide produced similar decreases
in blood flow both at perfusion pressures below the autoregulatory range and at normal pressures, so that the
absolute decrease in flow was similar at all coronary
artery pressures, but the relative flow reduction became
progressively greater as coronary pressure decreased
(152). Furthermore, the selective KATP channel opener
pinacidil increased coronary blood flow at normal perfusion pressures but not at pressures below the autoregulatory range (152), indicating that KATP channels became
progressively activated as coronary pressures decreased,
so that most of the channels were open when perfusion
pressures reached the lower limit of autoregulation. Thus
the available evidence indicates that KATP channels located in coronary arterioles (⬍100 ␮m) contribute imporPhysiol Rev • VOL
tantly to coronary metabolic vasodilation and autoregulation.
E) KCA CHANNELS. A possible role for KCa channel activity in regulation of coronary vasomotor tone distal to a
coronary artery stenosis during exercise has not been
investigated to date. However, in extracorporeally perfused hearts of open-chest dogs, the KCa channel antagonist charybdotoxin had no effect on coronary flow during
normal arterial inflow conditions, but caused a decrease
of coronary flow during myocardial hypoperfusion at a
constant coronary artery perfusion pressure of 42 ⫾ 2
mmHg (429). It cannot be determined from that study
whether the constriction of resistance vessels produced
by KCa channel blockade was the result of unmasking of
normal KCa channel activity because other vasodilator
mechanisms had been exhausted in the hypoperfused
region, or whether it was due to an actual increase in KCa
channel activity in response to myocardial hypoperfusion.
F) SUMMARY AND INTEGRATION. The increased delivery of
oxygen and metabolic substrate which is essential for the
cardiac response to an increased work load involves a
number of parallel mechanisms that produce coronary
vasodilation. In the dog, blockade of any one of these
vasodilator mechanisms fails to blunt the increase in coronary blood flow in response to exercise in the normal
heart, suggesting that adenosine, KATP channel opening,
prostacyclin, or NO either do not contribute to exerciseinduced coronary vasodilation or that redundancy of
these vasodilator mechanisms allows compensation when
one mechanism is blocked. In contrast, when exercise in
the presence of a coronary artery stenosis has caused all
vasodilator mechanisms to become activated, blockade of
any of these vasodilator mechanisms aggravates myocardial hypoperfusion.
4. Is coronary vasodilation maximal in ischemic
myocardium?
Systolic wall stress and hence oxygen demands are
highest in the subendocardial layers of the left ventricular
wall. The need for greater blood flow in the subendocardium requires a transmural gradient of vasomotor tone,
with vascular resistance being lower in the inner than in
the outer left ventricular wall. Since extravascular compressive forces are greatest in the subendocardium, vasodilator reserve is exhausted first in the subendocardium
when perfusion pressure falls (186, 273). As a result,
vasodilator reserve can still exist in the subepicardial
layers of the left ventricle at a time when reduced blood
flow indicates loss of vasodilator reserve in the subendocardium (203, 206). Myocardial ischemia has traditionally
been viewed to produce maximal vasodilation of the coronary resistance vessels and to override any competing
vasoconstrictor influences. However, a number of investigators have demonstrated that subendocardial vasodila-
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tor reserve can exist distal to a coronary artery stenosis
that results in subendocardial hypoperfusion (19, 91, 213,
218, 441). Thus, with coronary artery pressure distal to a
stenosis maintained at a fixed level, intracoronary infusion of adenosine increased subendocardial blood flow by
⬎50%, sometimes with an improvement in myocardial
contractile performance (441). The presence of vasodilator reserve in ischemic myocardial regions may have been
the result of increased sympathetic drive in anesthetized
open-chest animals, since a study in closed-chest sedated
dogs failed to observe recruitable vasodilator reserve in
ischemic myocardium (92). During treadmill exercise
when sympathetic activity is high, intravenous infusion of
the L-type Ca2⫹ channel antagonist nifedipine increased
blood flow and contractile performance of ischemic myocardium perfused by a stenotic coronary artery or by
collateral vessels (265). Laxson et al. (354) exercised dogs
on a treadmill while a stenosis was produced with a
hydraulic occluder. While distal coronary artery pressure
was maintained constant at 43 ⫾ 2 mmHg, an intracoronary infusion of adenosine increased subendocardial
blood flow by 50% (Fig. 32) and improved regional systolic
segment shortening. In contrast to other studies in which
vasodilator reserve was found in only the subepicardium
(186, 203, 206, 273), vasodilator reserve was present in
both the subendocardium and the subepicardium (354). It
is important to note that in this study coronary artery
pressure distal to the coronary stenosis was maintained
constant to prevent passive redistribution of flow due to
changes in poststenotic pressure, whereas distal coronary
perfusion pressure was not controlled in the earlier studies (186, 203, 206, 273). These findings demonstrate that
⫺1
⫺1
FIG. 32. Effect of adenosine (50 ␮g 䡠 kg 䡠 min
ic) (A) and the
nitrovasodilator ITF 296 (2 ␮g 䡠 kg⫺1 䡠 min⫺1 iv) (B) on blood flow distal
to a coronary artery stenosis. Epi, subepicardium; OM, outer mid; IM,
inner mid; Endo, subendocardium. Data are means ⫾ SE. Note that
while adenosine produces similar increases in flow to all myocardial
layers, ITF increases flow selectively to the subendocardial layers. *P ⬍
0.05 vs. corresponding control. See text for further explanation. [Data
from Laxson et al. (354) and Duncker et al. (144).]
Physiol Rev • VOL
1055
vasodilator reserve can exist in coronary resistance vessels within hypoperfused myocardium. In in vivo studies
directly observing subepicardial microvessels in openchest dogs, coronary arterioles (⬍100 ␮m in diameter)
dilated in response to progressive decreases in perfusion
pressure while small arteries ⬎100 ␮m showed either no
change (103) or a decrease (307) in vessel diameter. At a
coronary pressure of 40 mmHg, which produced a significant decrease in blood flow to the subepicardium, local
intra-arterial infusion of adenosine caused dilation of the
arterioles but not of the small arteries (103). These findings support the concept that vasodilator reserve can
persist in coronary arterioles within acutely ischemic
myocardium.
Whereas adenosine is a potent vasodilator of coronary arterioles ⬍100 ␮m in diameter (103, 140, 306), it is
a weak dilator of arterial vessels ⬎100 ␮m in diameter
(103, 306). In contrast, nitrovasodilators are known to
preferentially dilate arteries ⬎100 ␮m in diameter (520,
607). To assess vasodilator reserve at the level of the
small coronary arteries within acutely ischemic myocardium, we investigated the effects of intravenous nitroglycerin, isosorbide dinitrate, and the NO donors ITF 296 and
ITF 1129 on blood flow distal to a coronary artery stenosis
during treadmill exercise in dogs (144, 289). During normal arterial inflow, these agents had no effect on coronary
blood flow either at rest or during exercise, which can be
explained by the small artery dilation being countered by
an autoregulatory increase in arteriolar tone to maintain
blood flow commensurate with the needs of the myocardium (103, 300). In contrast, in the presence of a coronary
artery stenosis that maintained distal perfusion pressure
constant, the nitrovasodilators (Fig. 32) increased blood
flow to the hypoperfused region, an effect that was most
pronounced in the deeper myocardial layers. Improvement in blood flow to hypoperfused regions by nitrovasodilators could involve several mechanisms. First, in patients with an eccentric atherosclerotic narrowing of a
coronary artery, nitrovasodilators can dilate the artery at
the site of the stenosis (199, 466). However, in our experimental model, this effect was prevented by using an
occluder that maintained a constant distal coronary perfusion. Second, nitrates cause venodilation, which can
lower left ventricular diastolic pressure, thereby reducing
extravascular forces that compress the intramyocardial
vasculature. However, even nitrate doses that had no
effect on left ventricular end-diastolic pressure or dimensions enhanced myocardial perfusion distal to the stenosis, indicating that a decrease of extravascular compressive forces could not account for the improved perfusion
(144, 287). In the normal dog heart, intravascular pressure
in coronary arterioles is substantially lower in the subendocardium than in the subepicardium (99), indicating that
a significant pressure drop occurs across the penetrating
arteries (diameter ⬃200 ␮m) which traverse the left ven-
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DIRK J. DUNCKER AND ROBERT J. BACHE
tricular wall to deliver blood to the subendocardium.
Since nitrovasodilators are known to dilate vessels larger
than 100 ␮m in diameter (520, 607), vasodilation of the
penetrating arteries by nitrovasodilators would preferentially enhance flow to the innermost myocardial layers. In
the presence of a flow-limiting stenosis, the arterioles
⬍100 ␮m have already undergone metabolic vasodilation
so that a disproportionate fraction of resistance resides in
the small arteries ⬎100 ␮m, which includes the penetrating arteries. In this situation, dilation of the penetrating
arteries by nitrovasodilators could increase blood flow to
the inner layers of the left ventricle. Although the small
arteries that supply the subepicardial microvasculature
will also be dilated by nitrovasodilators, these arteries
travel a much shorter distance (64, 169). Hence, their
contribution to subepicardial resistance is less than the
contribution of the penetrating arteries to subendocardial
resistance.
In summary, myocardial ischemia that occurs during
exercise in the presence of a flow-limiting coronary artery
stenosis does not cause maximal vasodilation of the coronary resistance vessels so that substantial vasodilator
reserve exists in the terminal vascular bed of the hypoperfused region. This reserve can be recruited with both
small artery dilators (e.g., nitrovasodilators) and arteriolar dilators (e.g., adenosine), indicating persistent vasomotor tone throughout the coronary microcirculation.
5. Mediators of persistent vasomotor tone in ischemic
myocardium
A) ␣-ADRENERGIC CONTROL. ␣-Adrenergic vasoconstriction not only opposes metabolic coronary vasodilation
during exercise in the normal heart, but also limits coronary vasodilation in regions of ischemic myocardium.
Thus, when a coronary artery stenosis resulted in subendocardial underperfusion and impaired regional systolic
segment shortening during treadmill exercise (heart rates
⬃200 beats/min), local blockade of ␣1-adrenoceptors with
intracoronary prazosin significantly increased blood flow
to the hypoperfused region (Fig. 33) and caused improvement of contractile performance with no change in coronary artery pressure distal to the stenosis (355). A similar
increase in flow to the hypoperfused region was observed
when prazosin was administered intravenously (227). Selective blockade of ␣2-adrenoceptors caused variable results with either no change (287, 355) or an increase (228,
518) in blood flow in the ischemic region. The differing
results may be related to the severity of the coronary
artery stenosis; ␣2-adrenoceptor activation appears to be
of greater importance during more severe ischemia. In
open-chest dogs, cardiac nerve stimulation caused resistance vessel constriction in myocardium perfused by a
stenotic coronary artery, which appeared to be mediated
by ␣2-adrenoceptors (264). Postjunctional ␣2-adrenergic
Physiol Rev • VOL
FIG. 33. Effect of ␣1-adrenergic receptor blockade with prazosin
(A) and ␣2-adrenergic receptor blockade with idazoxan (B) on blood
flow distal to a coronary artery stenosis. Epi, subepicardium; OM, outer
mid; IM, inner mid; Endo, subendocardium. Data are means ⫾ SE. *P ⬍
0.05 vs. corresponding control. See text for further explanation. [Data
from Laxson et al. (355).]
vasoconstriction in ischemic myocardial regions is opposed by simultaneous stimulation of endothelial ␣2-receptor-mediated release of NO. Thus, in the presence of a
coronary stenosis which resulted in myocardial hypoperfusion during treadmill exercise, blockade of ␣2-adrenoceptors had no effect on blood flow in the ischemic
region. However, after inhibition of NO production with
L-NA, selective blockade of ␣2-adrenoceptors caused an
increase in coronary flow (287). This indicates that ␣2adrenergic activation during exercise did exert a vasoconstrictor effect on the coronary resistance vessels, but this
effect was opposed by simultaneous release of NO by the
endothelium. When the NO effect was blocked, then the
direct ␣2-adrenergic vasoconstrictor effect was revealed.
These findings suggest that in patients with impaired endothelial function, unopposed ␣2-adrenergic constriction
could contribute to hypoperfusion during exercise in
myocardial regions perfused by a stenotic coronary artery
(622).
Feigl and colleagues (183, 282) proposed that adrenergic coronary vasoconstriction can augment subendocardial blood flow during exercise. However, ␣-adrenoceptor blockade caused a transmurally uniform increase
of blood flow in myocardial regions perfused by a stenotic
coronary artery (355), as well as in the pressure overloaded hypertrophied left ventricles of dogs (155), indicating transmurally uniform ␣-adrenergic coronary vasoconstriction. Furthermore, the relative vasoconstriction
produced by ␣-adrenergic activity was greater during hypoperfusion (355) than during normal arterial inflow (31,
123), suggesting that hypoperfusion amplified the vasoconstrictor response. In agreement with this finding,
Chilian (98) observed that while ␣1- and ␣2-adrenoceptor
stimulation had no effect on vessels smaller than 100 ␮m
during normal arterial inflow, myocardial hypoperfusion
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CORONARY BLOOD FLOW
resulted in unmasking of both ␣1- and ␣2-adrenoceptormediated vasoconstriction in these vessels. The results
suggest that the capacity of the coronary arterioles to
escape from vasoconstrictor influences becomes impaired at the low perfusion pressures that exist distal to a
flow-limiting coronary artery stenosis.
B) ANG II. The role of ANG II in the residual coronary
vasomotor tone that exists distal to a coronary artery
stenosis during exercise has not been investigated. However, in open-chest dogs with extracorporeal perfusion of
the left anterior descending coronary artery, Kitakaze et
al. (315) demonstrated that the AT1 receptor antagonist
CV11974 improved coronary flow and regional segment
systolic shortening in ischemic myocardium while coronary artery perfusion pressure was maintained constant.
These findings suggest that endogenous ANG II can exert
a vasoconstrictor influence on the coronary microcirculation of normal and ischemic myocardium via AT1 receptor activation. It is likely that the vasoconstriction produced by endogenous ANG II is in part due to increased
norepinephrine release from the sympathetic nerve endings (493).
C) ET. A role for ET in the residual coronary vasomotor tone that exists distal to a flow-limiting stenosis during
exercise has not been investigated. Clozel and Sprecher
(108) studied the influence of coronary perfusion pressure on the response of myocardial blood flow and wall
motion to ET in extracorporeally perfused dog hearts. At
a coronary artery pressure of 100 mmHg, intracoronary
bolus injections of ET-1 in doses of 1 and 3 ␮g produced
transmurally homogeneous decreases of blood flow (up
to 60%) and systolic segment shortening (up to 80%). A
reduction of coronary artery pressure to 40 mmHg resulted in a 60% decrease of myocardial blood flow, which
was associated with a 25% decrease of systolic segment
shortening. At this perfusion pressure, ET-1 (1–3 ␮g/kg)
nearly abolished myocardial blood flow (85% flow reduction) and resulted in dyskinesis of the hypoperfused region. In contrast, intracoronary injections of ANG II were
not enhanced by the hypoperfusion, suggesting that the
increased vasoconstrictor response to ET-1 was not simply a dilution effect, i.e., a higher concentration as a result
of a lower flow. The observation that the vasoconstrictor
response to ET-1 was potentiated at lower perfusion pressures supports the concept that hypoperfusion can augment the response of the coronary microvasculature to
vasoconstrictor influences.
D) PLATELET PRODUCTS. Thromboxane A2 is a product of
prostaglandin endoperoxide metabolism, which is liberated during platelet aggregation. Plasma levels of its metabolites, thromboxane B2 and urinary 2,3-dinorthromboxane B2, are increased in patients with unstable angina
and in some patients with postinfarction angina (239,
270). Furthermore, transcardiac serotonin concentrations
can be increased in patients with occlusive coronary arPhysiol Rev • VOL
1057
tery disease, especially those with irregular eccentric atherosclerotic lesions (575). These findings suggest the
presence of intravascular platelet activation, which is in
agreement with angiographic and angioscopic studies
that have documented thrombus formation at the site of a
ruptured atherosclerotic plaque (216, 526). Thromboxane
A2 and serotonin can aggravate myocardial ischemia by
accelerating platelet aggregation, thereby increasing the
degree of local mechanical obstruction and causing platelet microemboli. In addition, these platelet products have
the potential to aggravate ischemia by causing vasoconstriction. Thromboxane A2 constricts both small and large
vessel segments; serotonin constricts epicardial arteries
but dilates coronary resistance vessels (334, 380). These
compounds exert both direct vascular smooth muscle
constrictor and indirect endothelium-dependent dilator
influences so that arterial vasoconstriction is enhanced
when endothelial function is impaired (333, 335, 609).
I) Serotonin. Serotonin (5-hydroxytryptamine, 5-HT)
has the interesting property of causing vasodilation of
coronary arterial vessels smaller than 100 ␮m in diameter
while simultaneously causing constriction of larger coronary artery segments (334). As a result of the microvascular dilation, serotonin causes an increase in coronary
blood flow in the normal heart (65, 284, 334). The increase
in coronary flow is endothelium dependent (605) and is
mediated principally via NO (304, 564). During normal
treadmill exercise, intracoronary infusion of serotonin
into a coronary artery of dogs caused a doubling of coronary blood flow, even when exercise had already resulted in substantial vasodilation of the coronary resistance vessels (33). In contrast to the dilating effect of
serotonin on microvessels, in vivo studies have demonstrated that serotonin caused 25– 45% reductions in crosssectional area of epicardial arteries 2–3 mm in diameter
(284, 335). The arterial constriction produced by serotonin was enhanced by removal of the endothelium (335),
since serotonin causes both direct (109, 117) and flowmediated (335) endothelium-dependent vasodilation,
which opposes its direct vascular smooth muscle constrictor action. Serotonin-induced coronary artery and
arteriolar vasodilation is mediated by endothelial 5-HT receptors (likely the 5-HT2B receptor, although a 5-HT1B/1D receptor may also be involved Ref. 280), while large epicardial
artery constriction involves either 5-HT1B receptors (116,
284) or 5-HT2A receptors (75, 576) located on vascular
smooth muscle cells.
The effect of serotonin on coronary blood flow in the
presence of an arterial stenosis has been studied in anesthetized and in awake animals. In open-chest dogs,
Ichikawa et al. (284) employed a coronary artery stenosis
that caused a 30-mmHg reduction in distal coronary artery
pressure and a 15% decrease in coronary flow. Intracoronary infusion of serotonin, which produced a doubling of
blood flow in the absence of a stenosis, caused a 20%
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DIRK J. DUNCKER AND ROBERT J. BACHE
increase in blood flow in the presence of a stenosis. In
contrast, Woodman (609) reported that an intracoronary
bolus injection of serotonin, which caused a 70% increase
in flow under normal inflow conditions in open-chest
dogs, resulted in a 12% decrease of flow in the presence of
a critical coronary stenosis. Ruocco et al. (488) failed to
observe a significant effect of serotonin on blood flow or
the transmural distribution of perfusion distal to an 80%
coronary artery stenosis in closed-chest sedated swine.
When we exercised dogs on a treadmill (heart rates
⬃190 beats/min), in the presence of a coronary artery
stenosis which maintained a constant distal coronary
pressure of 42 ⫾ 1 mmHg, serotonin tended to increase
flow to the subepicardium but caused a significant decrease in flow to the subendocardium with no change in
total blood flow to the ischemic region (Fig. 34) (33). It
might be argued that the transmurally heterogeneous response to serotonin was the result of ischemia in the inner
but not the outer layer so that autoregulatory reserve
existed in the subepicardial arterioles but not in the subendocardium. However, blood flow in the poststenotic
region was reduced in all myocardial layers, which would
have caused metabolic arteriolar vasodilation. Moreover,
earlier studies using a similar experimental model revealed that intracoronary adenosine produced an increase in blood flow which was essentially uniform in all
transmural layers, suggesting that once endogenous metabolic vasodilator reserve is exhausted, vasodilator reserve in response to exogenous dilators is uniformly distributed across the left ventricular wall. Since both serotonin (334) and adenosine (103, 306) dilate isolated
arterioles with diameters smaller than 100 ␮m, serotonin
might be expected to also increase flow in all transmural
FIG. 34. Effect of serotonin (A) and TxA2 mimetic U46619 (B) on
blood flow distal to a coronary artery stenosis. Epi, subepicardium; OM,
outer mid; IM, inner mid; Endo, subendocardium. Note that while
U46619 decreases flow similarly in all myocardial layers, serotonin
decreases flow selectively in the subendocardial layers. Data are means ⫾
SE. See text for further explanation. [Data from Bache et al. (33) and
Bache and Dai (25).]
Physiol Rev • VOL
layers. Although serotonin caused the expected increase
in flow in the subepicardium, the stenosis unmasked an
unexpected vasoconstrictor action of serotonin in the
subendocardium. The results can be explained by vasoconstriction of the penetrating arteries by serotonin
which would selectively increase resistance to blood flow
to the subendocardium (334). In the normal heart, dilation
of the resistance vessels by serotonin outweighs the effect
of constriction of the penetrating arteries (33). However,
in the presence of a flow-limiting coronary artery stenosis,
which has caused the arterioles to undergo metabolic
vasodilation, vasoconstriction of the penetrating arteries
cannot be counterbalanced by additional arteriolar vasodilation. Although the arteries which supply the subepicardium would also be constricted by serotonin, these
vessels travel a much shorter distance (64, 169), so that
their contribution to subepicardial resistance is less important than the contribution of the penetrating arteries
to subendocardial resistance.
II) Thromboxane A2. Thromboxane A2 (TxA2) receptor activation (using the stable analog U46619) produces
vasoconstriction of epicardial coronary arteries and coronary resistance vessels under conditions of normal coronary artery inflow (83, 380). In vivo studies failed to
demonstrate a decrease in coronary flow in the normal
heart in response to U46619, although a relatively low
dose of the agonist was used (83, 488).
Ruocco et al. (489) examined the interaction between
endogenous prostacyclin and TxA2 in sedated swine in
which an intraluminal hollow plug had been placed into
the anterior descending coronary artery to cause an 80%
decrease in luminal cross-sectional area. The stenosis
resulted in a slight but significant decrease in myocardial
blood flow with a mean distal coronary artery pressure of
78 mmHg. Infusion of U46619 caused a 20% further decrease in blood flow in the region perfused by the stenotic
coronary artery with a change from lactate consumption
to lactate production. Similar results were obtained after
inhibition of cyclooxygenase activity with indomethacin,
indicating that endogenous prostacyclin did not oppose
the vasoconstriction produced by U46619. In the presence
of a coronary artery stenosis that resulted in subendocardial hypoperfusion and ischemic contractile dysfunction
in exercising dogs (heart rates ⬃190 beats/min), U46619
produced vasoconstriction that resulted in a 20 –25% further decrease in myocardial blood flow with aggravation
of the contractile dysfunction (25, 141). Of particular
interest was the observation that the dose of U46619
(0.01 ␮g䡠kg⫺1 䡠min⫺1, intracoronary) decreased blood
flow only in the presence of myocardial ischemia (Fig. 32)
but not during unimpeded coronary arterial inflow (34).
Thus, instead of opposing vasoconstriction, the decreased
blood flow and ischemia produced by the coronary artery
stenosis appeared to facilitate vasoconstriction by U46619.
It is possible that the normal metabolic vasodilator mech-
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anisms are maximally activated in ischemic myocardium
and therefore cannot respond to a further decrease in
blood flow. TxA2 constricts coronary arterial microvessels of all sizes. In the presence of normal arterial inflow,
constriction of the resistance arteries (⬎100 ␮m) can be
compensated for by metabolic vasodilation of the arterioles (104, 299, 300). However, when a coronary artery
stenosis has already caused metabolic arteriolar vasodilation, the ability to compensate for vasoconstriction by
thromboxane in segments larger than 100 ␮m is lost. In
agreement with this hypothesis, we observed that while
endogenous adenosine contributed to coronary vasodilation during myocardial ischemia produced by exercise in
the presence of a coronary artery stenosis, adenosine
failed to attenuate the vasoconstriction produced by
U46619 in hypoperfused myocardium (141). The inability
of endogenous adenosine to attenuate the vasoconstrictor
response in hypoperfused myocardium can be explained
by differing vasoactive profiles of TxA2 and adenosine in
coronary arterial segments of different sizes. Whereas
adenosine predominantly dilates arterioles smaller than
100 ␮m in diameter, thromboxane constricts coronary
arterial vessels of all sizes (308, 380). Thus vasoconstriction by thromboxane of the resistance arteries ⬎100 ␮m,
which are minimally responsive to the vasodilator actions
of adenosine, can aggravate hypoperfusion of ischemic
myocardium. In addition, thromboxane has been shown
to cause constriction in the arteriolar segments that are
dilated by adenosine, so that competition between thromboxane and adenosine can also occur in vessels smaller
than 100 ␮m in diameter. Chilian and Layne (103) reported that even during severe hypoperfusion, exogenous
adenosine caused further vasodilation of the coronary
arterioles. This implies that residual vasomotor tone is
present in ischemic myocardium and lends support to the
hypothesis that vasoconstrictors can directly compete
with endogenous vasodilator substances within a given
vascular segment.
6. Integrated control of resistance vessel tone in
ischemic myocardium
In contrast to the classical concept that myocardial
hypoperfusion would cause the coronary microvasculature distal to the stenosis to become unresponsive to
vasoconstrictor influences, it has become clear that residual vasomotor tone is present in the coronary resistance
vessels within myocardium that becomes ischemic during
exercise in the presence of a coronary artery stenosis.
The residual vasomotor tone can be the result of vasoconstrictor influences of ␣-adrenoceptor activity, the
platelet products TxA2 and serotonin, and the neurohormones ANG II and endothelin. This vasoconstriction can
occur in small arteries (⬎100 ␮m) that account for a
significant fraction of total coronary resistance but are
Physiol Rev • VOL
1059
not under metabolic control (␣1-adrenoceptors, ANG II,
TxA2, serotonin, endothelin), as well in arterioles (⬍100
␮m) which are under metabolic control (␣1- and ␣2-adrenoceptors, ANG II, TxA2, endothelin) (Fig. 35). These
vasoconstrictor influences can compete with endogenous
substances such as adenosine, bradykinin, NO, prostanoids, and EDHF which cause vasodilation through activation of KATP and KCa channels that are recruited during
ischemia (Fig. 35). In support of this concept, clinical
evidence is emerging that demonstrates residual coronary
vasomotor tone in ischemic myocardium distal to a coronary artery stenosis (458, 497, 622).
7. Myocardial responses to chronic ischemia
Ischemia elicits local vasodilator responses that result in decreased vascular resistance and an increase in
the number of open capillaries within the ischemic region,
thereby augmenting blood flow and minimizing the diffusion distance for oxygen and metabolic substrate (138,
277). In addition to these vascular effects, hypoperfusion
(coronary hypotension) can elicit responses within the
cardiac myocytes that act to decrease energy demands,
thereby reducing metabolic markers of ischemia despite
persistently decreased blood flow. Short-term changes of
coronary blood flow (increases or decreases) can result in
directionally similar changes of myocardial oxygen consumption, termed the Gregg effect (219). Sustained limitation of blood flow in myocardial regions perfused by a
stenotic coronary artery or collateral vessels can result in
a state termed “hibernation” in which contractile activity,
and metabolic demands, are decreased to accommodate
the persistently reduced perfusion. Myocardial hibernation has been observed both in patients with occlusive
coronary artery disease (88, 467) and in experimental
animal models (172, 389, 404). Although a comprehensive
discussion of the myocardial responses to reduced blood
flow is beyond the scope of this review, the ability of the
myocardium to reduce contractile activity, and thus energy demands, in response to limited blood flow deserves
brief comment. It should be mentioned that myocardial
hibernation appears to be fundamentally different from
“stunning,” in which a transient period of ischemia results
in hypokinesis with normal myocardial blood flow rates,
although it is likely that repetitive stunning can coexist
with or lead to hibernation over time (89, 90, 554). Regions of hibernating myocardium in which blood flow is
limited either by a proximal coronary stenosis or by collateral vessels have been reported to have resting blood
flow rates 10 –20% less than remote normally perfused
myocardium, with a parallel decrease in contractile function (88, 170, 171, 317, 462, 523, 561). The response to
catecholamine stimulation is blunted in hibernating regions, providing some degree of protection against the
development of demand-induced ischemia (171, 375).
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DIRK J. DUNCKER AND ROBERT J. BACHE
FIG. 35. Schematic overview of various vasodilator (yellow text boxes) and vasoconstrictor (blue text boxes) influences in different
microvascular segments (small intramural arteries class A and B, and arterioles) of the coronary arterial bed of the LV wall, during exercise in the
presence of a proximal coronary artery stenosis. In solid line text boxes are shown the contribution to vasomotor control of endogenous vasoactive
substances, whereas in dashed line text boxes the effects of exogenously administered vasoactive substances have been shown. In regular font are
depicted the mechanisms that have been demonstrated in awake exercising animals; in italics are depicted those mechanisms that have been
demonstrated in open-chest anesthetized animal preparations. TxA2, thromboxane A2; 5HT, serotonin or 5-hydroxytryptamine; AII, angiotensin II; ET,
endothelin; ␣1 and ␣2, ␣1- and ␣2-adrenergic receptors; Ado, adenosine; NO, nitric oxide; KATP, ATP-sensitive K⫹ channel; KCa, calcium-sensitive K⫹
channel.
There are few studies examining coronary responses
to exercise in chronically hypoperfused regions. In a canine model of coronary artery occlusion with moderate
collateral vessel development (blood flow in the collateralized region 15–20% less than in remote normally perfused myocardium), exercise caused an increase in blood
flow to the collateral-dependent region (317, 462, 561).
With the use of measurements of aortic pressure and
pressure in the collateral-dependent artery, it was possible to separately calculate resistance of the collateral
vessels and small vessel resistance in the collateralized
region. Exercise did not cause dilation of the collateral
vessels (transcollateral resistance did not decrease during
exercise). Rather, the increase in blood flow during exercise resulted from vasodilation of the resistance vessels in
the collateral-dependent region (462). Preservation of vasodilator capacity in the collateral zone demonstrates that
the reduced resting blood flow and persistent vasomotor
tone did not result from absence of vasodilator reserve. It
appears rather that energy requirements were decreased,
inasmuch as such relatively hypoperfused collateral-dependent regions do not demonstrate evidence for ischemia during resting conditions (172, 404). It should be
emphasized that although alterations of both the supply
and demand sides of the energy equation can contribute
Physiol Rev • VOL
to maintenance of metabolic equilibrium in the heart,
during physiological conditions the predominant sequence is that changes in hemodynamic demands (as
during exercise) result in changes in contractile work
(and oxygen requirements) that drive parallel changes in
blood flow.
B. Regulation of Coronary Blood Flow
to Collateral-Dependent Myocardium
During Exercise
Coronary artery occlusion can result in development
of an effective intercoronary collateral circulation. If occlusion proceeds gradually, sufficient collateral vessel recruitment and growth may occur to allow progression to
total arterial occlusion with little or no infarction of the
dependent myocardium. In this situation, the collateral
vessels are able to provide adequate arterial inflow to
maintain myocardial integrity during resting conditions,
but the ability to augment blood flow in response to
exercise or other stress may be limited and develop only
gradually. This section will consider studies of the coronary vascular system in the intact heart that contains a
region of collateral-dependent myocardium. Emphasis
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CORONARY BLOOD FLOW
will be placed on studies in which the response of the
coronary collateral system is integrated into the overall
response of the heart to exercise.
1. Coronary collateral blood flow during exercise
Several investigators have examined the ability of
blood flow in collateral-dependent myocardial regions to
increase in response to exercise. These studies have commonly used the ameroid constrictor technique to induce
collateral vessel growth (370). Coronary artery occlusion
is produced by surgically implanting a ring of casein
plastic material (“ameroid”) around a proximal coronary
artery. The hygroscopic ameroid material slowly swells as
it comes in contact with tissue fluid; external expansion is
prevented by a stainless steel backing incorporated into
the ring, so the inward expansion of the material causes
progressive arterial narrowing. The arterial narrowing
and accompanying inflammation generally results in total
arterial occlusion within 3– 4 wk, often in association with
local thrombus formation during the final stages of occlusion. Since occlusion occurs gradually, sufficient growth
of collateral vessels generally occurs to allow progression
to total occlusion with little or no infarct in dogs, although
in swine, a species with negligible innate collateral vessels, some subendocardial necrosis is often present (433).
Fedor et al. (179) measured myocardial blood flow
with radioactive microspheres during moderate treadmill
exercise 11–12 wk after placement of ameroid constrictors on both the right and left circumflex coronary arteries of adult dogs. During resting conditions, myocardial
blood flow was similar in the normally perfused and collateral-dependent regions. During moderate treadmill exercise, blood flow in the collateral region increased normally in 6 of 11 dogs. In the remaining five animals, blood
flow in the subepicardial half of the collateral-dependent
region increased normally during exercise, but the increase in blood flow to the subendocardium was markedly impaired, resulting in a prominent decrease of the
subendocardial-to-subepicardial flow ratio.
Since collateral vessel development is a time-dependent process, the heterogeneous response to exercise
might be related to differences in the rate of collateral
vessel growth between animals. This question has been
examined by measuring the exercise-induced increase in
collateral blood flow relatively early (1 mo) and late (up to
8 mo) after coronary artery occlusion in dogs (32, 329).
One month after ameroid placement, myocardial blood
flow measured with microspheres during resting conditions was similar in the collateral-dependent and normally
perfused regions, but the response of blood flow to exercise in the collateral-dependent region was highly variable
(32). Approximately one-third of the animals had sufficient collateralization to allow a completely normal response of myocardial blood flow during both light and
Physiol Rev • VOL
1061
heavy levels of exercise (group 1). In a second group of
animals (group 2), mean myocardial blood flow was normal at rest and demonstrated a normal increase during
light exercise, but a further increase in exercise intensity
resulted in no further increase in mean blood flow. In the
third group of animals (group 3), blood flow was normal
at rest but failed to increase or underwent a subnormal
increase even during light exercise with no additional
change in response to a further increase of exercise intensity. Animals grouped according to the ability of mean
blood flow in the collateral-dependent region to increase
in response to exercise are shown in Figure 36. The
distribution of blood flow across the left ventricular wall
from epicardium to endocardium is shown for the collateral-dependent region; data from a group of normal animals undergoing similar exercise are shown for comparison. For animals in group 1, not only was the mean blood
flow rate normal in the collateral-dependent region during
both stages of exercise, but the transmural distribution of
perfusion was also normal. For the animals in group 2, the
normal increase in blood flow in response to light exercise was associated with a normal transmural distribution
of perfusion. However, when the exercise level was further increased, mean flow failed to increase and a transmural redistribution of perfusion away from the subendocardium occurred. Finally, for the animals in group 3, any
exercise resulted in a prominent redistribution of perfusion so that subepicardial flow increased, while blood
flow to the inner half of the left ventricular wall did not
change or decreased compared with resting values.
Minipigs studied 4 –16 wk after ameroid placement
on the left circumflex coronary artery had responses to
exercise similar to those of the dogs in group 3 (481, 602).
Exercise which increased heart rates to 245 beats/min
caused a ⬃200% increase in blood flow in the normal
region, while mean blood flow to the collateral-dependent
region increased only ⬃50%. The subnormal increase in
blood flow to the collateral-dependent region during exercise was associated with redistribution of perfusion
away from the subendocardium, with the ratio of subendocardial/subepicardial flow falling to 0.39. The findings
indicate that even in the pig, in which coronary collateralization is notoriously poor, there is some ability to
increase blood flow to the collateral-dependent region
during exercise relatively early after coronary occlusion.
As in the dog, the limited blood flow in the collateraldependent region is delivered primarily to the outer myocardial layers, resulting in preferential underperfusion of
the subendocardium.
The transmural distribution of blood flow away from
the subendocardium that occurs when the collateral vessels are unable to provide a normal increase in blood flow
during exercise is similar to the subendocardial underperfusion that occurs when an arterial stenosis limits myocardial blood flow during exercise (36, 500). The ability to
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DIRK J. DUNCKER AND ROBERT J. BACHE
FIG. 36. Myocardial blood flow to four transmural layers from epicardium to endocardium at rest and during two levels of treadmill exercise.
Data are shown for 7 normal dogs (control) and for collateral-dependent myocardium 1 mo after placement of an ameroid constrictor on the left
circumflex coronary artery of 14 dogs. Animals with coronary occlusion were divided into three groups. Group I represents animals with sufficient
collateralization to allow a completely normal increase of myocardial blood flow during both levels of exercise. In group II, collateralization was
sufficient to allow a normal increase in myocardial blood flow during light exercise, but a further increase in exercise intensity resulted in no further
increase in mean blood flow. In group III, blood flow was normal at rest but underwent a subnormal increase during light exercise with no additional
change during heavy exercise. Note that exercise caused a dramatic redistribution in myocardial blood flow from the inner to the outer layers during
heavy exercise in group II, and during light and heavy exercise in group III. Data are means ⫾ SE. Dot inside symbol denotes significant (P ⬍ 0.05)
differences from corresponding control. See text for further explanation. [Data from Bache and Schwartz (32).]
maintain a normal transmural distribution of perfusion is
likely related to the degree of vasodilation of the resistance
vessels within the collateralized region. When collateral vessels are poorly developed, the resistance vessels in the collateral-dependent region must maintain a substantial degree
of vasodilation even during resting conditions to compensate for the resistance of the collateral vessels. Furthermore,
the poorly developed collateral vessels impose a limit beyond which blood flow cannot increase. When myocardial
demands are below this limit, the resistance vessels are able
to maintain a normal transmural distribution of perfusion
in the collateral-dependent region. However, when myocardial demands exceed the capacity of the collateral
vessels to deliver blood flow, intense vasodilation of the
resistance vessels impairs their ability to maintain a normal transmural distribution of blood flow.
The observed wide variation in the ability of the
collateral vessels to increase blood flow in response to
exercise could be due to intrinsic differences between
animals in the ability to develop collateral vessels, or
differences in the rate of collateral vessel development
between animals. If the latter were true, then allowing
additional time after coronary occlusion would permit all
animals to develop sufficient collateralization to undergo
a uniform increase in blood flow during exercise. To
examine this hypothesis, myocardial blood flow was measured at rest and during two exercise stages 8 mo after
implantation of an ameroid constrictor on the left circumflex coronary artery in dogs (329). Both the increase in
mean myocardial blood flow and the transmural distribuPhysiol Rev • VOL
tion of perfusion were normal at rest and during both
levels of exercise in the collateral-dependent region. Similar findings were reported by Longhurst et al. (373) in
dogs studied 2–3 mo after ameroid occlusion of the left
circumflex coronary artery. These findings demonstrate
that the marked heterogeneity of perfusion in the collateral-dependent region during exercise 1 mo after ameroid
implantation did not result from differences in the intrinsic ability for ultimate collateral vessel development, but
rather from differences in the rate of collateral vessel
growth between animals. When sufficient time was allowed, all animals developed sufficient collateralization to
permit a normal increase in blood flow in response to a
moderate level of treadmill exercise.
In summary, if the coronary collateral vessels can
conduct sufficient arterial inflow to meet the needs of the
dependent myocardium, then the volume and distribution
of blood flow will be determined by the normal autoregulatory responses of the microvasculature in the dependent myocardium. However, if the collateral vessels cannot deliver sufficient arterial inflow to meet the needs of
the dependent myocardium, then the volume of flow will
be determined by the conductance of the collateral system
and the transmural distribution of perfusion will be similar
to that observed when flow is limited by an arterial stenosis.
2. Influence of infarct in the collateral region
A) COLLATERAL FLOW DURING RESTING CONDITIONS. Gradual
application of a coronary occlusion to produce a region of
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collateral-dependent myocardium without infarct allows
study of the collateral circulation uninfluenced by infarcted myocardium. In the clinical setting, however, collateral-dependent regions frequently include areas of infarcted myocardium. In this situation, blood flow to the
collateral-dependent region is influenced not only by the
structure and function of the collateral vessels, but also
by abnormalities resulting from the presence of infarcted
tissue. In both human subjects suffering acute myocardial
infarction and experimental canine models of abrupt coronary occlusion, the area of infarcted myocardium is
smaller than the region of tissue normally perfused by the
coronary artery (“risk region”) (505). Survival of a portion
of myocardium normally perfused by an occluded artery
is dependent on delivery of a limited inflow of arterial
blood by preexisting coronary collateral vessels. The fraction of myocardium surviving acute coronary occlusion is
quantitatively related to the volume of collateral blood
flow available early after coronary occlusion (476).
Several reports have examined blood flow to collateral-dependent myocardium, which included regions of
infarct studied ⬃2 wk after acute coronary artery occlusion (259 –261). Regional myocardial blood flow was measured with radioactive microspheres in multiple myocardial specimens; the percent infarct in each myocardial
specimen was determined using quantitative microscopy.
When blood flow to collateral-dependent myocardial
specimens was plotted against percent infarct during resting conditions, an inverse linear relationship was found,
with myocardial blood flow decreasing in direct proportion to
the fraction of infarct within a myocardial specimen.
B) COLLATERAL FLOW DURING EXERCISE. The above studies
indicate that during resting conditions, blood flow to collateral-dependent regions that include infarct is proportional to the volume of residual viable myocardium. To
examine whether the presence of infarct influences the
response collateral flow during exercise, myocardial
blood flow was measured during three levels of treadmill
exercise (heart rates of 164, 205, and 242 beats/min) in
dogs 2 wk after abrupt total occlusion of the left anterior
descending coronary artery (261). The degree of infarcted
myocardium importantly influenced the response of collateral flow during exercise. In specimens that contained
⬍50% infarct, blood flow during resting conditions was
depressed in direct proportion to the degree of infarct,
but the proportionate increase in blood flow in response
to exercise was not different from a normally perfused
myocardial region. Thus the presence of infarct did not
impair the increase in blood flow in the collateral-dependent noninfarcted myocardium. However, when more
than 50% of a myocardial specimen was occupied by
infarct, not only was resting flow depressed, but the relative increase in flow during exercise was also reduced. It
is likely that impairment of perfusion in regions containing ⬎50% infarct resulted from the high resistance to
Physiol Rev • VOL
1063
blood flow offered by the poorly developed collateral
vessels. Regions with the largest percent infarct were those
with the sparsest native collateral vessels; even 2 wk after
coronary occlusion, collateral vessel development was insufficient to allow a normal increase in flow to the residual
viable myocardium during exercise. In addition, the presence of infarct might directly influence blood flow to the
residual viable myocardium, or metabolic alterations in
the residual myocardium (such as hibernation) might blunt
the increase in oxygen demands during exercise (178).
3. Influence of collateral vessel tone
Studies using isolated vessel segments and in vivo
studies performed in open-chest animals have demonstrated that well-developed collateral vessels are capable
of active vasomotion (243, 249). This suggests that collateral vessels do not behave as fixed conduits with a constant upper limit for conductance of blood to the dependent myocardium, but that vasomotor tone of collateral
vessels can modulate the availability of blood to the dependent myocardium. This hypothesis was tested by infusion of arginine vasopressin in dogs in which a collateral-dependent myocardial region was produced using the
repetitive coronary occlusion technique of Franklin et al.
(195); this technique uses repeated 2-min coronary artery
occlusions to stimulate collateral vessel development. An
intra-arterial microcatheter was implanted distal to the
occluder to allow measurement of the coronary pressure
perfusing the collateralized region and calculation of collateral resistance (192). With the use of this model, distal
occlusion pressures gradually increase as collateralization occurs; when the distal pressure increases to 35– 40
mmHg (⬃3 wk of repetitive 2-min occlusions), permanent
coronary occlusion can be produced without causing infarct. Following permanent occlusion, distal coronary
pressures increase even more rapidly so that within 1 wk
mean distal pressure increases to ⬃75 mmHg. At this
time, myocardial blood flow was measured with microspheres at rest and during treadmill exercise. After completion of control measurements, arginine vasopressin
was infused (0. 01 mg䡠kg⫺1 䡠min⫺1 iv) and blood flow was
again measured at rest and during exercise. Arginine vasopressin was used because it causes constriction of isolated segments of collateral vessels (243) but does not
constrict epicardial coronary arteries, since constriction
of arteries proximal to the origin of the collateral vessels
could also impair collateral blood flow (243, 308). Myocardial blood flow in the normal and collateral-dependent
regions are shown in Figure 37. During resting conditions,
blood flow was slightly but significantly lower in the
collateral zone than in the normal zone. Exercise increased blood flow in both the normal and collateraldependent regions, although the increase was subnormal
in the collateralized region. When exercise was repeated
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DIRK J. DUNCKER AND ROBERT J. BACHE
FIG. 37. Effect of vasopressin on myocardial blood flow to normally
perfused and collateral-dependent left ventricular regions at rest and
during treadmill exercise. During control conditions, exercise resulted
in significant increases in blood flow in both the normal and collateraldependent regions, although the increase in flow was subnormal in the
collateralized region. Infusion of vasopressin did not significantly alter
the response of blood flow during exercise in the normally perfused
region, but essentially abolished the increase in blood flow in response
to exercise in the collateral-dependent region. Data are means ⫾ SE.
*P ⬍ 0.05 vs. corresponding rest. †P ⬍ 0.05 vs. corresponding normal
region. ‡P ⬍ 0.05 vs. corresponding control. See text for further explanation. [Data from Foreman et al. (192).]
during vasopressin infusion, the increase in blood flow in
the normal zone was not significantly different from control. However, vasopressin essentially abolished the increase in collateral zone blood flow in response to exercise. The impaired response of blood flow to exercise
during vasopressin infusion resulted from vasoconstriction of both coronary collateral vessels and the resistance
vessels in the collateral-dependent region. Thus transcollateral resistance (calculated as aortic pressure minus
coronary artery pressure distal to the occlusion divided
by total collateral blood flow) increased 48 ⫾ 14% in
response to vasopressin, while small-vessel resistance
(calculated as coronary artery pressure distal to the occlusion minus left ventricular end-diastolic pressure divided by total collateral blood flow) increased by 40 ⫾ 9%.
In contrast, vasopressin did not increase coronary vascular resistance in the normally perfused region. The finding
that vasopressin caused small-vessel constriction in the
collateral-dependent region but not in the normal zone
indicates that small-vessel responsiveness is altered in
regions of myocardium perfused by collateral vessels.
These results demonstrate that the coronary collateral
vessels do not act as fixed conduits. Rather, active vasoconstriction of both collateral vessels and coronary resistance vessels can worsen hypoperfusion of the collateraldependent myocardium during exercise.
It should be noted that there is no evidence that
vasopressin normally limits collateral blood flow during
exercise, since exercise does not cause a sufficient inPhysiol Rev • VOL
crease in vasopressin levels to have a significant vasomotor effect. Rather, vasopressin was used as a convenient
agent to test the general hypothesis that active constriction of coronary collateral vessels has the potential to
limit perfusion of the dependent myocardium during exercise. Consequently, the dose of vasopressin was calculated to correspond to levels that cause collateral vasoconstriction in vitro without causing substantial systemic
hemodynamic effects (243). As predicted, plasma levels
increased to far above those during physiological conditions, being 2.1 ⫾ 0.64 pg/ml during control conditions
and increasing to 98 ⫾ 34 pg/ml during vasopressin infusion. Individual vasopressin plasma levels were within the
range reported to occur in response to smoking two cigarettes or during hemorrhage of moderate degree (208,
591). Thus, although plasma vasopressin levels are normally far less than would influence collateral flow during
physiological conditions, it is possible that sufficient elevations of vasopressin levels can be achieved during
pathological conditions to cause constriction of coronary
collateral vessels in vivo.
4. Control of coronary blood flow
in collateralized hearts
A) ␣-ADRENERGIC CONTROL. ␣-Adrenergic vasoconstrictor
influences can restrain the increase in coronary blood
flow that occurs in response to the increased myocardial
oxygen demands during exercise in the normal heart (31,
232) and in the presence of a coronary stenosis that
results in myocardial hypoperfusion (82, 227, 297, 354,
518). A study was performed to determine whether ␣-adrenergic vasoconstriction also limits blood flow to collateral-dependent myocardium during exercise (260). Myocardial blood flow was measured at rest and during two
levels of treadmill exercise in dogs 2 wk after acute
coronary occlusion that produced a collateralized region
that included a variable degree of subendocardial infarct.
The increase in subendocardial blood flow in response to
exercise was impaired in the collateral-dependent region,
while subepicardial flow was not different from that in the
remote normally perfused region. During resting conditions, selective ␣1-adrenergic blockade with prazosin
caused no change in either mean blood flow or the transmural distribution of perfusion in either the normal or the
collateral-dependent regions. However, at comparable
levels of exercise, prazosin caused a 27% increase in mean
blood flow in the normally perfused region and a 35%
increase in mean flow in the collateral-dependent region
(P ⬍ 0. 01). Prazosin caused increases in blood flow in all
transmural layers in the collateral-dependent region from
epicardium to endocardium, although the absolute increase in flow was most marked in the subepicardium.
Since previous studies have failed to document ␣-adrenergic vasoconstriction in coronary collateral vessels stud-
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CORONARY BLOOD FLOW
ied either in vitro or in vivo, it is unlikely that the increase
in blood flow to the collateral-dependent region produced
by prazosin was the result of interruption of ␣-adrenergic
vasoconstriction in the collateral vessels (30, 243, 249).
More likely, ␣-adrenergic blockade increased blood flow
by interrupting vasomotor tone of the resistance vessels
in the collateral-dependent myocardium. This is analogous to studies demonstrating that resistance vessels in
regions distal to a flow-limiting coronary stenosis that
results in myocardial ischemia during exercise also retain
vasomotor tone (354). It appears that ␣-adrenergic vasoconstriction of the resistance vessels can also limit myocardial blood flow in region perfused by collateral vessels.
B) ␤-ADRENERGIC CONTROL. ␤-Adrenergic stimulation has
been found to cause relaxation of isolated rings of welldeveloped canine coronary collateral vessels (184). Furthermore, norepinephrine infusion caused a decrease in
collateral resistance in dogs studied 2–3 mo after implantation of an ameroid constrictor on the left circumflex
coronary artery (384). These findings of adrenergic collateral vessel dilation suggest that ␤-adrenergic blockade
might have the potential to decrease collateral flow. However, arterioles isolated from collateral-dependent myocardium are reported to have blunted ß-adrenergic responsiveness (522). The influence of ß-adrenergic activity
on collateral flow was studied in dogs in which acute
coronary occlusion had resulted in a collateral-dependent
myocardial region containing infarct (259). During resting
conditions, selective ß1-adrenergic blockade with timolol
caused no change in blood flow to either the normally
perfused or collateral-dependent myocardium, indicating
minimal adrenergic activity at rest. However, during exercise, timolol decreased blood flow in both collateralized
and remote regions, largely due to the negative chronotropic effect of ß-adrenergic blockade. To correct for
changes resulting from alterations of myocardial oxygen
demands, results were compared at similar rate-pressure
products. At comparable rate-pressure products, timolol
significantly decreased blood flow in both the subepicardium and subendocardium of the normally perfused region. In the collateral region, timolol caused a decrease of
subepicardial blood flow comparable to that in the normally perfused region. However, in the subendocardium
of the collateral region (in which blood flow during exercise was substantially less than normal), ß-adrenergic
blockade did not cause a further reduction of blood flow.
The effect of ß-adrenergic blockade on subepicardial flow
could have resulted from vasoconstriction of either the
collateral vessels or the resistance vessels in the collateral
zone. To further examine this question, Traverse et al.
(559) studied the effect of ß-adrenergic activity on collateral blood flow during treadmill exercise using the nonselective ß-blocker propranolol. Pressure in the coronary
artery distal to the occlusion was measured to separate
the effects of propranolol on collateral resistance and
Physiol Rev • VOL
1065
small-vessel resistance in the collateral zone. Collateral
vessel growth was stimulated with repetitive 2-min coronary occlusions so that myocardial infarction was
avoided. During control exercise, blood flow in the collateral zone was 38 ⫾ 5% less than in the normal zone. At
identical levels of exercise, with heart rate maintained
constant by atrial pacing, propranolol decreased mean
blood flow in the collateralized myocardium by ⬃20%; this
occurred principally in the subepicardium with no significant effect on flow in the subendocardium. The decrease
in collateral zone blood flow in response to propranolol
resulted from a 40% increase in transcollateral resistance
and a ⬃50% increase in small-vessel resistance in the
collateral-dependent region. The decrease in subepicardial flow in the collateral region following ß-adrenergic
blockade was proportionately similar to the decrease in
flow in the normally perfused region. Thus the decrease in
subepicardial blood flow in the collateral region in response to ß-adrenergic blockade resulted from vasoconstriction of the coronary resistance vessels with a smaller
effect on the collateral vessels.
In summary, adrenergic nervous system activity can
influence blood flow to collateral-dependent myocardium
during exercise. The available data suggest that the influence of the adrenergic nervous system on blood flow in
the collateral zone results principally from altered vasomotor activity of the microvasculature within the collateral-dependent region rather than from direct vasomotor
effects on the collateral vessels.
C) NO. In vitro studies using isolated vessel rings have
demonstrated that collateral vessels acquire a functionally competent endothelium and muscular media early in
their development and are responsive to NO-dependent
agonists, such as bradykinin and acetylcholine (5, 10,
188). Furthermore, inhibition of NO synthesis has been
shown to decrease retrograde blood flow from a cannulated collateral-dependent coronary artery in anesthetized
open-chest dogs (188) and to significantly increase collateral vessel vascular resistance in awake dogs (194), demonstrating that tonic production of NO contributes to
maintenance of collateral vasodilation. Conversely, arterioles isolated from collateral-dependent myocardium
demonstrate blunted endothelium-dependent vasodilator
responses to acetylcholine and ADP in dogs (521), and
ADP and bradykinin in swine (222, 519). To determine
whether endogenous NO contributes to maintenance of
blood flow in collateral-dependent myocardium, Traverse
et al. (561) exercised dogs on a treadmill (heart rate 230
beats/min) before and after NO synthase inhibition with
L-NA (20 mg/kg iv). During resting conditions, L-NA tended
to decrease blood flow to the collateral region with no
change in normal zone blood flow. During exercise, L-NA
caused a decrease in mean blood flow to the collateral
region (from 2.24 ⫾ 0.19 to 1.78 ⫾ 0.26 ml䡠min⫺1 䡠g myocardium⫺1 after L-NA, P ⬍ 0.05), which occurred in both
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DIRK J. DUNCKER AND ROBERT J. BACHE
the subendo- and subepicardium (Fig. 38). This decrease
resulted from a near doubling of the collateral vascular
resistance, with a trend toward an increase in small vessel
resistance in the collateral zone. Interestingly, L-NA also
decreased blood flow to the normal myocardial region
during exercise (from 2.99 ⫾ 0.24 to 2.45 ⫾ 0.28
ml䡠min⫺1 䡠g myocardium⫺1) as the result of a 44 ⫾ 13%
increase in coronary vascular resistance. These findings
indicate that, in contrast to the normal heart (7) or normal
regions in hearts with an acute coronary artery stenosis
(137), endogenous NO is important in maintaining flow to
regions of normally perfused myocardium during exercise
in a model of single-vessel coronary artery occlusion.
In view of the observation that endogenous NO contributes to maintenance of perfusion in collateral-dependent myocardium, the question arises as to whether exogenous NO can increase blood flow during exercise in a
collateralized region. Studies in open-chest animals with
well-developed coronary collateral vessels demonstrated
that nitroglycerin increased blood flow and improved contractile function in collateral-dependent myocardium
(113, 173, 249). However, nitroglycerin did not increase
blood flow to collateral-dependent myocardium of exercising dogs with a chronic coronary occlusion (462). The
lack of effect of nitroglycerin on either coronary collateral
resistance or small-vessel resistance in the collateral zone
suggests that the endogenous NO system is already maximally recruited during exercise in the canine model of
single-vessel coronary artery occlusion. This is supported
by the observation that after inhibition of NO synthase
with L-NA, nitroglycerin did increase blood flow to the
collateral zone, and this was associated with an improvement of regional systolic wall thickening (317). This ob-
servation suggests that in patients in whom dyslipidemia
and atherosclerosis have resulted in endothelial dysfunction and impaired NO bioavailability, nitroglycerin would
be able to increase collateral blood flow.
D) PROSTANOIDS. Although coronary vessels are capable
of synthesizing and responding to vasoactive products of
arachidonic acid (423), physiological studies have failed
to demonstrate an important role for the prostaglandin
system in regulation of coronary blood flow in the normal
canine heart. In contrast, in open-chest dogs in which
chronic coronary artery occlusion had resulted in growth
of collateral vessels, cyclooxygenase blockade caused a
decrease in retrograde blood flow from the collateraldependent artery (4, 6), suggesting that basal release of
prostaglandins maintains tonic vasodilation of coronary
collateral vessels. However, interpretation of these findings is complicated by reports that tissue injury during
acute surgical preparation of open-chest animal models
can artificially increase basal prostaglandin synthesis by
the heart. Altman et al. (8) addressed the role of prostaglandins in control of blood flow in collateral-dependent
myocardium in chronically instrumented dogs, free from
the effects of anesthesia and acute surgical trauma. Myocardial blood flow was measured with radioactive microspheres at rest and during treadmill exercise (heart rate
215 ⫾ 7 beats/min). Cyclooxygenase blockade with indomethacin (5 mg/kg iv) caused no change in heart rate or
arterial pressure, and no change in blood flow in the
normal zone or the collateral zone during resting conditions. However, during exercise, indomethacin caused a
42 ⫾ 10% increase in transcollateral resistance that was
associated with a 27 ⫾ 11% decrease in subendocardial
flow in the collateral zone (both P ⬍ 0.05), but no change
FIG. 38. Effect of inhibition of NO synthase inhibition on left ventricular subendocardial and subepicardial blood flows in hearts with a
collateral-dependent region due to chronic coronary artery occlusion and in hearts subjected to an acute coronary artery stenosis during treadmill
exercise. Inhibition of NO synthase decreased blood in the normal as well as in the collateral-dependent regions. In contrast, while NO synthase
inhibition decreased flow distal to a coronary artery stenosis, it had no effect on the normal region. Data are means ⫾ SE. *P ⬍ 0.05 vs.
corresponding control. See text for further explanation. [Data from Traverse et al. (561) and Duncker and Bache (137).]
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CORONARY BLOOD FLOW
in normal zone blood flow. Indomethacin had no effect on
small vessel resistance in the collateral zone so that the
decrease in blood flow was mediated entirely by constriction of the collateral vessels. Thus, in the setting of
chronic coronary occlusion, the cyclooxygenase system
exerts a vasodilator influence on collateral vessels that
becomes apparent during exercise.
E) ADENOSINE. Acadesine (5-AICA riboside) is an adenosine-regulating agent that increases adenosine production. In acutely ischemic myocardium, increased production of adenosine via activation of 5⬘-ectonucleotidase
(278) can exert cardioprotective effects (225). Consequently, a study was performed to determine whether
acadesine would improve blood flow to collateral-dependent myocardium during exercise (290). In dogs with
moderately well-developed coronary collateral vessels
but a subnormal increase in blood flow in the collateral
zone during exercise, acadesine increased blood flow in
the collateral-dependent region during exercise by 24 ⫾
5% with no change in the transmural distribution of perfusion. The increase in collateral zone blood flow produced by acadesine resulted from a 25% decrease
transcollateral resistance and a 20% decrease in smallvessel resistance in the collateral region. Acadesine also
increased normal zone blood flow in the collateralized
dogs but had no effect on coronary flow in normal dogs.
These findings suggest that adenosine metabolism is al-
1067
tered not only in the collateral-dependent region but also
in the remote region of hearts with a chronic coronary
artery occlusion. The importance of endogenous adenosine for the regulation of coronary blood flow in the
collateralized heart during exercise has not been studied
to date.
F) SUMMARY AND INTEGRATION. The coronary collateral
system embodies a dynamic network of interarterial vessels that can undergo both long- and short-term adjustments that are capable of modulating blood flow to the
dependent myocardium. Long-term adjustments including
recruitment and growth of collateral vessels in response
to arterial occlusion are time dependent and determine
the maximum blood flow rates available to the collateraldependent vascular bed during exercise. Rapid short-term
adjustments result from active vasomotor activity of the
collateral vessels. Mature coronary collateral vessels are
responsive to vasodilators such as nitroglycerin (113, 173,
249) and atrial natriuretic peptide (191), to vasoconstrictors such as vasopressin (192) and ANG II (243, 249), and
to the platelet products serotonin and TxA2 (611) (Fig. 39).
During exercise, ß-adrenergic activity and endotheliumderived NO and prostanoids exert vasodilator influences
on coronary collateral vessels. Importantly, alterations
in collateral vasomotor tone, e.g., by exogenous vasopressin, inhibition of endogenous NO or prostanoid
production, or increasing local adenosine production
FIG. 39. Schematic overview of various vasodilator (yellow text boxes) and vasoconstrictor (blue text boxes) influences in collateral arteries
(and epicardial conduit vessels) and distal coronary microcirculation (small intramural arteries class A and B and arterioles) of the coronary arterial
bed of the LV wall, during exercise in the presence of a chronic coronary artery occlusion. In solid line text boxes are shown the contribution to
vasomotor control of endogenous vasoactive substances, whereas in dashed line text boxes the effects of exogenous administration of vasoactive
substances have been shown. ß1 and ß2, ß1- and ß2-adrenergic receptor; NO, nitric oxide; Ado, adenosine (AICA-riboside); NTG, nitroglycerin; PGI2,
prostacyclin; ␣1, ␣1-adrenergic receptor; VP, vasopressin. See text for further explanation.
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DIRK J. DUNCKER AND ROBERT J. BACHE
can modify collateral conductance, thereby influencing
the blood supply to the dependent myocardium. In
addition, vasomotor activity in the resistance vessels of
the collateral perfused vascular bed can influence the
volume and distribution of blood flow within the collateral zone (Fig. 39). Finally, there is evidence that
vasomotor control of resistance vessels in the normally
perfused regions ofcollateralized hearts is altered compared with normal hearts (290, 561), indicating that the
coronary vascular adaptations in hearts with a coronary occlusion involve alterations in resistance vessels
at a global as well as a regional level (532). These
observations caution against using vessels from the
remote “normally perfused” myocardial region as control vessels.
C. Exercise Training and the Coronary
Collateral Circulation
Exercise training has emerged as an intervention for
primary and secondary prevention of coronary artery disease (340, 369). The mechanisms that have been proposed
to contribute to the beneficial effects of exercise include
regression of atherosclerosis, formation of collaterals (arteriogenesis), development of new vessels (angiogenesis/
vasculogenesis), and improvement of endothelial function.
For an overview of the effects of exercise training in
patients with coronary artery disease and potential mechanisms, the reader is referred to a recent article by Linke
et al. (369). Here we focus on the effects of exercise
training on the collateral circulation and the coronary
microcirculation within collateral-dependent myocardium.
1. Coronary collateral blood flow
A) NATIVE COLLATERAL VESSELS IN THE NORMAL HEART. The
effect of exercise training on collateral function in hearts
with a normal coronary circulation has been assessed by
measuring retrograde flow from the cannulated collateraldependent coronary artery opened to atmospheric pressure (84, 114, 506) or by measurement of collateral blood
flow with radioactive microspheres (112, 131, 319, 321,
501, 507) (Table 4). Studies comparing collateral function
in trained and sedentary control groups at the end of a
training period have produced exclusively negative results (84, 114, 131, 321, 501, 506, 507). To compensate for
the substantial interanimal differences in native collaterals present in the dog, Knight and Stone (319) measured
collateral blood flow in chronically instrumented dogs
before and after exercise training; collateral blood flow
was found to increase. Cohen (112) also observed a tendency for collateral flow to increase in chronically instrumented dogs following exercise training, but a similar
increase was also observed in sedentary animals, suggest-
Physiol Rev • VOL
ing that the chronic instrumentation procedure stimulated the growth of coronary collateral vessels independent of exercise training. These findings indicate that
physical conditioning does not enhance native collateral
blood flow in the normal heart.
B) EXERCISE TRAINING WITH A CORONARY STENOSIS OR OCCLUSION. There is considerable interest in whether chronic
exercise is capable of stimulating development of coronary collateral vessels in patients with occlusive coronary
artery disease. Human studies using angiography to assess the collateral vasculature in exercise-trained patients
with coronary artery disease have generally yielded negative results (195, 428). These studies are limited to anatomic assessment of coronary collateral vessels without
measurement of collateral blood flow. In contrast, Belardinelli et al. (50) reported a beneficial effect of 8 wk of
moderate exercise training on collateral-dependent myocardial perfusion, as assessed by thallium uptake in patients with ischemic cardiomyopathy.
Eckstein (156) was the first to report a beneficial
effect of exercise training on collateral formation in dogs
with a coronary artery stenosis (Table 5). The increase in
retrograde blood flow from the cannulated collateral-dependent artery produced by exercise training was most
striking in the presence of a mild stenosis that resulted in
minimal collateral formation in the sedentary animals,
suggesting that exercise produced ischemia which then
acted to stimulate collateral vessel growth. Cohen et al.
(115) reported similar results in chronically instrumented
dogs. Thus, while exercise training under normal inflow
conditions does not stimulate the formation of coronary
collaterals, these studies suggest that chronic exercise
resulting in or aggravating ischemia in a myocardial region distal to a coronary artery stenosis can stimulate
collateral vessel growth.
Studies of the effect of exercise training on collateral
formation in response to a progressive coronary artery
occlusion have yielded equivocal results (Table 5).
Heaton et al. (254) and Neill and Oxendine (424) reported
no differences between sedentary and trained dogs in
collateral blood flow measured 6 – 8 wk after placement of
an ameroid constrictor on a coronary artery, although a
slight improvement in the ENDO/EPI blood flow ratio in
the collateralized region was observed after exercise
training (254). Exercise training may have failed to exert
an effect because the stimulus for collateral formation
was nearly maximal even in the sedentary animals. Thus
blood flow to the collateral-dependent myocardium in
sedentary dogs was not different from flow in the normal
myocardium, so that exercise training may not have induced ischemia in these well-collateralized hearts (254,
424). In contrast, in swine, blood flow in the collateraldependent region was ⬍50% of blood flow in the normal
myocardial segment during exercise, so that exerciseinduced ischemia might have further stimulated collateral
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4.
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Y
Y
Rat M
A
Swine
M, F
Swine
M, F
A
Y
Dog M
Dog M,
F
A
Dog M,
F
A
Y
?
Age
1.6 km/h, 15%; 60
min/day, 5 days/
wk, 12–24 wk
8–16 km/h, 0%; 90
min/day, 5 days/
wk, 4–6 wk
6.4–9.6 km/h, 20%;
75 min/day, 5
days/wk, 12 wk
5.8 km/h, 25%; 45
min/day, 7 days/
wk, 6 wk
6.5–9.6 km/h, 20%;
45 min/day, 5
days/wk, 4 wk
6.4–9.6 km/h, 20%;
75 min/day, 5
days/wk, 12 wk
6.4–9.6 km/h, 20%;
75 min/day, 5
days/wk, 12 wk
6 km/h, 0%; 60
min/day, 5 days/
wk, 10 mo
5.5 km/h, 0%; 40–
60 min/day, 5
days/wk, 8 wk
Program
?
Efficacy
Open chest
Open chest
LVW 20%1,
LVW/BW ?
LVW 7,
LVW/BW 16%1
SMVO2 1
Open chest
Open chest
HREX 2
?
Awake, rest
Awake, rest
Open chest
extracorporeal
perfusion
Isolated bloodperfused heart
Open chest
Experimental
Conditions
HW 7,
HW/BW 7
No
b
Noa
HW 7,
HW/BW 7
LVW 7,
LVW/BW 7
?
Cardiac
Hypertrophy
HRREST 2
HRREST 2
HREX 2
?
?
HREX2,
SMVO2 1
Running Training
Sedentary
Trained
Sedentary
Trained
Sedentary
Trained
Sedentary
Trained
Sedentary
Trained
Trained
Sedentary
Trained
Sedentary
Exercise
Sedentary
Exercise
Study
Groups
7
7
3.2
3.1
5.0
4.1
Retrograde
Flow, ml/min
1.58
1.55
1.48
Before
Training
6.25
4.93
0.95
0.79
0.47
0.43
0.99
1.70
2.06
1.44
1.01
1.08
After
Training
Normal Zone Flow,
ml 䡠 min⫺1 䡠 g⫺1
0.35
0.26
0.71
Before
Training
0.39
0.43
0.21
0.31
0.06
0.05
0.26
0.24
0.61*
0.49*
1.03*
0.33
0.19
After
Training
Collateral Zone
Flow,
ml 䡠 min⫺1 䡠 g⫺1
Collateral zone/Normal zone myocardial blood
flow ratios were measured with radioactive microspheres. a,bNot measured in that study but based on previous observations from the
b
same laboratory (aStone, 1980; aLiang et al., 1984; Cohen, 1978). *P ⬍ 0.05, after training vs. before training. †P ⬍ 0.05, exercise group vs. sedentary group.
Scheffer
and
Verdouw
(507)
Koerner and
Terjung
(321)
Dodd-o and
Gwirtz
(131)
Sanders et
al. (501)
Knight and
Stone
(319)
Cohen (112)
Dog M
Dog M
Dog M,
F
Species,
Sex
Effects of exercise training on native collateral blood flow in animals with normal arterial inflow
Scheel et al.
(506)
Burt and
Jackson
(84)
Cohen et al.
(114)
Investigators
TABLE
CORONARY BLOOD FLOW
1069
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Dog
M, F
Swine
M, F
Swine
M, F
Schaper
et al.
(504)
Bloor et al.
(61)a
Roth etbal.
(482)
Y
A
Y
A
?
A
Y
?
6–8 km/h, 5%;
60 min/day,
5 days/wk, 5 mo
5 km/h, ⱖ5%;
30–50 min/day,
5 days/wk, 5 wk
6 km/h, 22%;
60 min/day,
5 days/wk, 4 wk
5.8 km/h, 25%;
45 min/day,
5 days/wk, 8 wk
8 km/h, 15%;
30 min/day,
5 days/wk, 5 wk
9.6 km/h, 5%;
60 min/day,
5 days/wk, 6 wk
7.5 km/h, 30%;
70 min/day,
5 days/wk,
6–8 wk
6.4–9.6 km/h, 20%;
75 min/day,
5 days/wk,
12 wk
Program
4 wk
postplacement
2 wk
postplacement
2 wk
postplacement
3 mo
postplacement
1 wk
postplacement
2 wk
postplacement
2 wk
postplacement
1 wk
postplacement
Start
Experimental Conditions
Open chest
extracorporeal
perfusion
Rest
Rest
Exercise
Exercise
HW 7,
HW/BW 7
Noc
Fixed Coronary Artery Stenosis
Hypertrophy
Isolated bloodperfused heart;
perfusion pressure
100 mmHg,
maximal
vasodilation
Isolated bloodperfused heart;
perfusion pressure
80 mmHg, maximal
vasodilation
Anesthetized, open
chest
Rest
Rest
Exercise
Exercise
HW 7,
HW/BW 7
LVW 7,
LVW/BW ?
LVW 7,
LVW/BW 7
HREX 2
HRREST 2
HREX 2
Rest
Rest
Exercise
Exercise
Rest
Rest
Pacing, 250 beats/min
Pacing, 250 beats/min
Open chest
LVW 7,
LVW/BW 7
HW 7,
HW/BW 7
?
?
?
HREX 2
Progressive Coronary Artery Occlusion
HREX 2
?
Efficacy
Sedentary
Trained
Sedentary
Trained
Sedentary
Trained
Sedentary
Trained
Sedentary
Trained
Sedentary
Trained
Sedentary
Trained
Sedentary
Trained
Sedentary
Trained
Sedentary
Trained
Sedentary
Trained
Sedentary
Trained
Sedentary
Trained
Study
Groups
17
35†
128
225†
34
50†
Retrograde
Flow,
ml/min
1.33
1.08
1.79
1.79
1.28
1.16
3.30
2.65
Before
Training
0.48
0.48
3.75
3.40
1.53
0.92
1.58
1.76
1.29
1.29
1.11
1.10
1.67
1.29
3.38
4.21
After
Training
Normal Zone
0.92
1.05
0.47
0.53
1.29
1.04
1.50
1.43
0.42
0.41
0.68
0.83
Before
Training
1.01
1.11
0.48
0.72*
0.29
0.35†
1.75
1.65
1.23
0.88
1.54
1.65
1.28
1.22
0.82
0.81
0.58
0.70*
0.95
1.90*
After
Training
Collateral Zone
Normal zone flows and collateral zone flows were measured with radioactive microspheres. aIn the study by Bloor et al. (61), a fixed stenosis was initially implanted; however, at
the time of autopsy the stenosis had progressed into a total occlusion in all animals. bIn the study of Roth et al. (482), absolute flows were not presented; the flow data in the
collateral-dependent zone column represent collateral/normal zone ratios. cNot measured in that study but based on previous observations from the same laboratory (Cohen, 1978).
*P ⬍ 0.05, after training vs. before training. †P ⬍ 0.05, exercise group vs. sedentary group.
Dog M
Scheel
et al.
(506)
Neill and
Dog
Oxendine
M, F
(424)
Dog
M, F
Dog M
Cohen et
al. (115)
Heaton
et al.
(254)
Dog
M, F
Eckstein
(156)
Age
Running-Training
Effects of exercise training on collateral blood flow in animals with impeded coronary arterial inflow
Species,
Sex,
5.
Investigators
TABLE
1070
DIRK J. DUNCKER AND ROBERT J. BACHE
CORONARY BLOOD FLOW
1071
growth (61, 482). Moreover, differences in collateral
blood flow between exercised and sedentary dogs might
not have been detected because maximal resistance vessel dilation was not achieved, i.e., maximal collateral
conductance was not assessed (254, 424). This could explain why retrograde blood flow (which is not affected by
resistance vessel tone) was increased in trained dogs
(424, 506). However, Schaper et al. (504) measured collateral blood flow in isolated dog hearts perfused with
blood at constant pressure during maximal coronary resistance vessel dilation with adenosine and observed no
effect of exercise training on maximum collateral blood
flow. Maximum blood flow in the collateral-dependent
region was 45% of the maximal flow in the normal myocardium of the sedentary animals, which makes it likely
that blood flow to the occluded area was sufficient to
minimize ischemia during exercise training. In none of the
above studies was an attempt made to maximally dilate
the coronary collateral vessels, e.g., with nitroglycerin, so
that differences in collateral vessel tone could have influenced the measured collateral blood flow rates (249).
C) SUMMARY AND INTEGRATION. Exercise does not stimulate growth of coronary collateral vessels in the normal
heart. However, if exercise produces ischemia, which
would be absent or minimal under resting conditions,
there is evidence that collateral growth can be enhanced.
Finally, when there is ischemia even under resting conditions, exercise may have only a modest additional effect.
However, the concept that exercise-induced ischemia can
enhance collateral vessel growth is not supported by two
studies in which ␤-adrenergic blockade with propranolol
was used to minimize the occurrence of myocardial ischemia during gradual coronary occlusion with an ameroid
constrictor. In these studies, propranolol did not impair
the rate of collateral formation either in swine (546) or
dogs (111). These findings suggest that other factors such
as the pressure gradient between vascular beds which
determines the flow rate and therefore the shear stress on
the collateral vessel endothelium may be more important
than ischemia in stimulating growth of collateral vessels.
duced by vascular endothelial growth factor (VEGF165) in
these vessels was enhanced by exercise training, and this
was mediated principally via increased NO bioavailability.
Increased vascular responsiveness to VEGF165 could also
act to promote angiogenesis in the collateral zone. Interestingly, exercise training had no effect on bradykinininduced vasodilation of arterioles isolated from the remote normally perfused region of collateralized hearts
(222), which contrasts with observations in arterioles obtained from exercise-trained normal hearts (414). The
authors proposed that adaptive responses in the nonoccluded arterial beds (which are the source of collateral
flow to the occluded territory) likely modify the response
to exercise training (222). These observations exemplify
the importance of including control vessels from normal
hearts, rather than simply using vessels from the remote
myogenic zone as controls. Exercise training also increases basal myogenic tone in collateral-dependent arterioles, similar to the effect of exercise training on arterioles in normal hearts (413). This increase in basal tone
is associated with augmented vasodilator influences exerted by increased NO production and KV channel activity
(252).
In summary, exercise-induced adaptations of coronary resistance vessels within a collateral-dependent ventricular region consist of simultaneously increased basal
tone and increased vasodilator influences, including increased NO production and K⫹ channel activity. These
microvascular adaptations may provide a greater intrinsic
capacity of local vascular control mechanisms to regulate
blood flow to collateral-dependent myocardium and
thereby contribute to the improved perfusion observed
after exercise training.
2. Vasomotor control of coronary resistance vessels
in collateral-dependent myocardium
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