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MINIREVIEW

Control of Coronary Blood Flow during Exercise

Johnathan D. Tune^*,1, Keith Neu Richmond, Mark W. Gorman and Eric O. Feigl

^* Department of Integrative Physiology, University of North Texas Health Science Center, Fort Worth, Texas 76107;
Division of Cardiovascular Biology, Shen Nippon Biomedical Laboratories, Ltd., USA, Redmond, Washington 98052; and
Department of Physiology and Biophysics, University of Washington School of Medicine, Seattle, Washington 98195

	Abstract

Top Abstract Introduction Adenosine Hypothesis K+ATP Channels Nitric Oxide Compensatory Control and Its... Other Potential Mediators of... Adrenergic Control of Coronary... Pathophysiology Conclusions References

 
Under normal physiological conditions, coronary blood flow is closely matched with the rate of myocardial oxygen consumption. This matching of flow and metabolism is physiologically important due to the limited oxygen extraction reserve of the heart. Thus, when myocardial oxygen consumption is increased, as during exercise, coronary vasodilation and increased oxygen delivery are critical to preventing myocardial underperfusion and ischemia. Exercise coronary vasodilation is thought to be mediated primarily by the production of local metabolic vasodilators released from cardiomyocytes secondary to an increase in myocardial oxygen consumption. However, despite various investigations into this mechanism, the mediator(s) of metabolic coronary vasodilation remain unknown. As will be seen in this review, the adenosine, K⁺_ATP channel and nitric oxide hypotheses have been found to be inadequate, either alone or in combination as multiple redundant compensatory mechanisms. Prostaglandins and potassium are also not important in steady-state coronary flow regulation. Other factors such as ATP and endothelium-derived hyperpolarizing factors have been proposed as potential local metabolic factors, but have not been examined during exercise coronary vasodilation. In contrast, norepinephrine released from sympathetic nerve endings mediates a feed-forward ßadrenoceptor coronary vasodilation that accounts for 25% of coronary vasodilation observed during exercise. There is also a feed-forward -adrenoceptor-mediated vasoconstriction that helps maintain blood flow to the vulnerable subendocardium when heart rate, myocardial contractility, and oxygen consumption are elevated during exercise. Control of coronary blood flow during pathophysiological conditions such as hypertension, diabetes mellitus, and heart failure is also addressed.

Key Words: adenosine • nitric oxide • K⁺_ATP channels • ß-feed-forward vasodilation • -adrenoceptor vasoconstriction

	Introduction

Top Abstract Introduction Adenosine Hypothesis K+ATP Channels Nitric Oxide Compensatory Control and Its... Other Potential Mediators of... Adrenergic Control of Coronary... Pathophysiology Conclusions References

 
The anaerobic capacity of the mammalian heart is very limited and if the oxygen supply is interrupted, the affected myocardium quickly stops beating. During normal resting conditions, the heart extracts 75% of the oxygen delivered by coronary blood flow, therefore the oxygen extraction reserve is quite limited (1–3). Thus, myocardial function is dependent on an adequate coronary blood flow on a moment-to-moment basis.

Despite these seeming constraints at rest, the heart is capable of increasing myocardial oxygen consumption 5-fold or more above resting values when there is tachycardia, augmented contractility, and increased cardiac afterload, as occurs during exercise (1–4). For this reason, exercise is frequently used to test the physiological mechanisms that control coronary blood flow and thus oxygen delivery to the heart.

The dominant determinant of coronary blood flow is the rate of myocardial oxygen consumption, and the central question in coronary physiology is how coronary flow is coupled to myocardial oxygen consumption by a local metabolic mechanism (1–4). As will be seen, the adenosine, K⁺_ATP channel, and nitric oxide hypotheses for the local metabolic control of coronary blood flow during exercise have been found inadequate individually and in combination. Therefore, the mechanism of local metabolic control of coronary blood flow remains unknown, with no strong alternative hypothesis available at this time.

In contrast to the negative results on identifying the local metabolic vasodilator mechanism in the coronary circulation, there have been positive findings on the neural control of coronary blood flow during exercise. A feed-forward ß-adrenoceptor-mediated coronary vasodilation due to norepinephrine released from sympathetic nerve endings has been documented. The feed-forward mechanism operates without an error signal whereby increases in heart rate and myocardial contractility due to activation of the sympathetic nerves to the heart and coronary vasculature also result in a parallel coronary vasodilation. The feed-forward ß-adrenoceptor vasodilation acts primarily on small coronary arterioles and accounts for 25% of the coronary vasodilation observed during exercise. There is also evidence for a feed-forward norepinephrine -adrenoceptor-mediated vasoconstriction in large- and medium-size coronary arteries during exercise. The -adrenoceptor-mediated vasoconstriction upstream from small arterioles has the effect of reducing vessel compliance and thus lessening wasteful systolic-diastolic flow oscillations in the coronary arterial tree. This has the beneficial result of maintaining blood flow to the vulnerable inner layer of the left ventricle when heart rate, myocardial contractility, and myocardial oxygen consumption are all high during exercise.

The experimental details for the interpretations concerning local metabolic and neural control of coronary blood flow during exercise are given below.

	Adenosine Hypothesis

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For many years, adenosine has been thought to be the vasodilatory metabolite that links coronary blood flow to myocardial metabolism (1, 5–7). The adenosine hypothesis predicts that an increase in myocardial oxygen consumption decreases myocardial tissue oxygen tension to stimulate the release of adenosine from cardiomyocytes. The resulting increase in cardiac interstitial adenosine concentration activates adenosine receptors on coronary vascular smooth muscle cells, which increases coronary vascular conductance and augments oxygen delivery. The increase in coronary blood flow and oxygen delivery act to restore myocardial oxygen tension to a normal operating level, thereby decreasing cardiac adenosine production in a negative feedback manner. Thus, the interstitial concentration of adenosine would control coronary blood flow to match myocardial oxygen delivery with myocardial oxygen consumption, and maintain myocardial oxygen tension within the normal physiologic range (8, 9).

Adenosine and Local Metabolic Coronary Vasodilation.
Many investigations have examined the role of adenosine in local metabolic coronary vasodilation during increases in myocardial oxygen consumption (10–28). Results from these studies are inconsistent in that indices of interstitial adenosine concentration were increased during increases myocardial oxygen consumption (10, 11, 13, 15, 16, 18, 20), but blockade of endogenous adenosine receptors did not alter functional coronary hyperemia during increases in myocardial oxygen consumption (12, 17, 24, 26–28). One potential reason for these conflicting findings could be that the adenosine measurements reported in early investigations did not reliably estimate the cardiac interstitial concentration of adenosine (28, 29). An alternative explanation for these discrepant results is that the interstitial adenosine concentration increases sufficiently to overcome the competitive adenosine receptor blockade, as would be predicted if adenosine were part of a high gain negative feedback system (21, 30, 31). In other words, the failure of adenosine receptor blockade to limit coronary vasodilation during increases in myocardial oxygen consumption is due to a sufficient compensatory increase in cardiac adenosine production. Therefore, to adequately test the adenosine hypothesis, it is essential to have an estimate of cardiac interstitial adenosine concentration.

Despite avid uptake of adenosine by coronary vascular endothelial cells, cardiac interstitial adenosine concentration may be estimated (32, 33). The method for estimating the interstitial concentration of adenosine uses measurements of coronary blood flow, hematocrit, and arterial and coronary venous plasma adenosine concentrations in an axially distributed mathematical model. Experiments using this model determined the relationship between interstitial adenosine concentration and coronary blood flow and found that the threshold for adenosine-mediated coronary vasodilation was 117 nM (33).Recently, Tune et al. (28) quantitatively examined the adenosine hypothesis by combining measurements of coronary venous adenosine concentration with adenosine receptor blockade during exercise in chronically instrumented dogs. This is important because if, as postulated, adenosine is part of a high-gain negative feedback system, then adenosine levels will increase to overcome the competitive receptor blockade and little change in coronary blood flow will be observed. Interstitial adenosine concentration was estimated using the mathematical model described above (32, 33). Tune et al. (28) found that adenosine receptor blockade did not alter coronary blood flow at rest or during graded treadmill exercise, which is consistent with earlier studies in dogs (17) and pigs (26). Coronary venous plasma adenosine concentration was little changed when myocardial oxygen consumption was increased over 4-fold during exercise. The slope of the estimated interstitial adenosine concentration versus myocardial oxygen consumption relationship did not differ significantly from zero, and the interstitial adenosine concentration remained well below the threshold concentration necessary for coronary vasodilation (117 nM; Fig. 1). Furthermore, coronary venous and estimated interstitial adenosine concentrations did not increase to overcome the competitive receptor blockade of either 8-phenyltheophylline or 8-p-suflophenyltheophylline. In order for adenosine to have increased sufficiently to overcome the receptor blockade would have required a 12-fold increase in adenosine concentration for 8-phenyltheophylline and a 5-fold increase for 8-p-suflophenyltheophylline (28). This clearly did not occur (Fig. 1). These findings demonstrate that adenosine is not required for local metabolic coronary vasodilation during exercise-induced increases in myocardial oxygen consumption.

View larger version (31K): [in this window] [in a new window]   Figure 1. Relationship between estimated interstitial adenosine concentration and myocardial oxygen consumption during control vehicle and adenosine receptor blockade with 8-phenyltheophylline (8-PT) or 8-sulfophenyltheophylline (8-PST). The slopes of the regression lines do not differ significantly (P = 0.63, R2 = 0.4), and the average slope did not differ significantly from zero (P = 0.23, R2 = 0.4). The estimated interstitial adenosine concentration remained well below the threshold for coronary vasodilation and did not increase to overcome the competitive receptor blockade. This figure was reproduced with the permission of the American Physiological Society from Ref. 28.

In summary, experimental evidence does not support adenosine as the physiologic local metabolic vasodilatory metabolite that links coronary blood flow to myocardial metabolism. This evidence includes: i) Adenosine receptor blockade does not alter the relationship between coronary blood flow and myocardial oxygen consumption (17, 26, 28); ii) Coronary venous plasma adenosine concentration is little changed with exercise-induced increases in myocardial oxygen consumption (28, 39–41); iii) The estimated interstitial adenosine concentration remains well below the threshold value necessary for coronary vasodilation both at rest and during increases in myocardial oxygen consumption (27, 28); and iv) Adenosine receptor blockade does not augment coronary venous or estimated interstitial adenosine concentration to overcome the receptor blockade (27, 28). However, adenosine does act as a coronary vasodilator during pathophysiological conditions when the myocardium is ischemic.

	K+ATP Channels

Top Abstract Introduction Adenosine Hypothesis K+ATP Channels Nitric Oxide Compensatory Control and Its... Other Potential Mediators of... Adrenergic Control of Coronary... Pathophysiology Conclusions References

 
There is a class of potassium channels that can be regulated by intracellular ATP that are present in many tissues, including pancreatic ß cells, skeletal muscle, brain, and smooth muscle (42). These channels are commonly identified by their response to the blocking agent glibenclamide. Glibenclamide is a member of the sulfonylurea class of compounds that have a high selectivity for K⁺_ATP channels, and it has been shown to have a K_i for the channels found in cardiac and smooth muscle in the range of 5–20 µM (48–50). These ATP-sensitive potassium (K⁺_ATP) channels were identified in smooth muscle from mesenteric arteries by Standen et al. in 1989 (44). In 1992, Miyoshi et al. (45) identified K⁺_ATP channels in cultured smooth muscle cells from porcine coronary arteries. Since that time, the role of these channels in the regulation of vessel diameter, particularly in coronary vessels, has been examined by numerous investigators.

K⁺_ATP channels have been found to play a role in hypoxic coronary vasodilation (46, 47). Daut et al. (46) found that hypoxic coronary vasodilation in isolated perfused guinea pig hearts was blunted by glibenclamide. Coronary reactive hyperemia is also reduced during K⁺_ATP channel blockade with glibenclamide (48–50). K⁺_ATP channels are involved in adenosine-induced coronary vasodilation as shown by the ability of glibenclamide to inhibit this response (46, 49, 50, 51, 53–55). However, K⁺_ATP channels are not necessary for coronary autoregulation (relatively constant flow with altered arterial perfusion pressure) as shown by Stepp et al. (55). Because hypoxia and ischemia result in adenosine release from the myocardium, as reviewed above, the blunting of hypoxic or ischemic coronary vasodilation by glibenclamide probably represents an inhibition of adenosine vasodilation.

The evidence for involvement of K⁺_ATP channels in the maintenance of basal coronary blood flow is strong (50, 55–60). When K⁺_ATP channels are inhibited by glibenclamide, coronary blood flow at rest is reduced between 12% and 25%, suggesting that these channels are at least partly responsible for maintaining vessel diameter during steady-state conditions.

However, the regulation of coronary blood flow during exercise or cardiac pacing is not dependent upon K⁺_ATP channels (40, 50, 59, 61, 62). Although flow is reduced at rest when K⁺_ATP channels are blocked by glibenclamide, Richmond et al. (40) found that during exercise, the increase in flow is the same (3.5-fold) with or without K⁺_ATP channel blockade. This is consistent with the results from Duncker et al. (50, 61, 62) who found a decrease in resting coronary blood flow in dogs but not an attenuation of flow during exercise. The combination of these results suggest that another factor must be responsible for the increase in coronary blood flow during exercise.

In summary, there is strong evidence that adenosine causes coronary vasodilation during ischemia or hypoxia and that K⁺_ATP channels mediate the vasodilation. Although K⁺_ATP channels are involved in regulating coronary vessel diameter at rest, they are not required during coronary autoregulation or for the increase in coronary blood flow that occurs during exercise.

	Nitric Oxide

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The coronary vascular endothelium modulates vascular resistance through the production of various vasoactive agents, including the endothelium-derived relaxing factor nitric oxide (63). Nitric oxide is formed from L-arginine by nitric oxide synthase and is continuously released by endothelial cells (64). Nitric oxide release is augmented by agonists such as acetylcholine and bradykinin (64–66) and also by mechanical stimulation such as shear stress (67–73), pulsatile flow (74), and axial strain (75).Endothelial-derived nitric oxide is thought to be one of the factors controlling coronary blood flow both at rest and during exercise. However, inhibition of nitric oxide synthesis with arginine analogues results in either no change (39, 74, 76–85) or a small decrease (86–90) in coronary blood flow at rest and when myocardial oxygen consumption is elevated. Studies also consistently show that blockade of nitric oxide synthesis does not attenuate exercise-induced coronary vasodilation, but does decrease coronary venous oxygen tension at a given level of myocardial oxygen consumption (Fig. 2) (39, 76, 77, 79, 80, 83, 85). These findings are consistent with studies using either systemic (39, 77, 83, 85) or intracoronary infusions of arginine analogs (76, 79, 80) to inhibit nitric oxide synthesis, indicating that nitric oxide is not required for exercise-induced coronary vasodilation. However, these findings do indicate that nitric oxide exerts a tonic coronary vasodilator influence both at rest and during exercise-induced increases in myocardial oxygen consumption.

View larger version (25K): [in this window] [in a new window]   Figure 2. Relationship between coronary venous oxygen tension and myocardial oxygen consumption during control and nitric oxide synthesis inhibition with LNA. The slope of the relationship was unchanged by LNA (P = 0.79), indicating that nitric oxide is not required for local metabolic coronary vasodilator during exercise. The average coronary venous oxygen tension was significantly reduced by LNA (P = 0.004), indicating that nitric oxide exerts a tonic coronary vasodilator influence both at rest and during exercise. This figure was reproduced with the permission of Lippincott, Williams & Wilkins from Ref. 39.

The findings of Bernstein et al. (77) and Traverse et al. (101) indicate that exercise-induced epicardial coronary vasodilation is mediated by an increase in endothelial-mediated nitric oxide production at high levels of myocardial oxygen consumption. The increased nitric oxide produced when myocardial oxygen consumption is significantly elevated is probably due to augmented shear stress that results from the high coronary flow rates (67–73). This hypothesis is supported by the findings of Van Bibber et al. (102) who found that nitric oxide synthesis inhibition attenuated norepinephrine-induced coronary vasodilation when coronary perfusion pressure was held constant, but did not affect coronary vasodilation to norepinephrine when coronary blood flow was held constant.

In summary, nitric oxide does not act as a local metabolic vasodilator in the usual sense because blockade of nitric oxide synthesis does not steepen the relationship between coronary venous oxygen tension and myocardial oxygen consumption (Fig. 2). However, nitric oxide does exert physiological effects within the coronary vascular tree, notably upstream dilation of epicardial coronary arteries, which acts to prevent excessive shear stress on coronary endothelial cells when flow is increased by downstream, arteriolar dilation.

	Compensatory Control and Its Implications

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A recurring theme in recent coronary literature is that there are multiple mechanisms of local metabolic coronary blood flow control, and that when one mechanism is inhibited, another may increase in compensation (50, 62, 80, 103–105). The suggestion is that cardiac adenosine levels increase in compensation when either K⁺_ATP channels or nitric oxide synthesis is inhibited. The reason for postulating multiple compensating mechanisms was the observation that the addition of an adenosine receptor antagonist to a prior K⁺_ATP channel inhibition (50, 62, 80) or nitric oxide synthesis inhibition (103, 105) decreased coronary blood flow and/or depressed the relationship between coronary venous oxygen tension and myocardial oxygen consumption.

The hypothesis that adenosine increases to mediate local metabolic coronary vasodilation when either K⁺_ATP channels (40, 59) or nitric oxide synthesis is inhibited (39) has been examined. Graded treadmill exercise was used to increase myocardial oxygen consumption in chronically instrumented dogs before and during inhibition of K⁺_ATP channels with glibenclamide (40) or nitric oxide synthesis with N-nitro-L-arginine (LNA) (39). Cardiac interstitial adenosine concentration was estimated from arterial and coronary venous measurements using a previously tested mathematical model (32, 33). Inhibition of either K⁺_ATP channels or nitric oxide synthesis at rest and during exercise did not result in a significant increase in coronary venous or estimated interstitial adenosine concentration. Furthermore, the estimated interstitial adenosine concentration remained well below the threshold necessary for coronary vasodilation with or without K⁺_ATP channel (40, 59) or nitric oxide synthesis inhibition (39). These findings indicate that adenosine does not increase to mediate a compensatory local metabolic coronary vasodilation during exercise-induced increases in myocardial oxygen consumption.

An additional study by Tune et al. (106) examined the hypothesis of multiple compensating mechanisms of coronary flow control by combined inhibition of K⁺_ATP channels (glibenclamide), nitric oxide synthesis (LNA), and adenosine receptors (8-phenyltheophylline). This triple blockade did not alter the myocardial oxygen consumption or coronary blood flow response to exercise, but it did significantly lower the coronary venous oxygen tension at a given level of myocardial oxygen consumption (Fig. 3). These results indicate that combined inhibition of K⁺_ATP channels, nitric oxide synthesis, and adenosine receptors lowers the balance between myocardial oxygen delivery and consumption under resting conditions, but they also indicate that these factors are not required for local metabolic coronary vasodilation during exercise. In contrast, Ishibashi et al. (80) found that functional exercise coronary hyperemia and myocardial oxygen consumption were limited during exercise with triple blockade. The major differences between these studies are that glibenclamide and LNA were infused intravenously in the Tune et al. (106) study, and intracoronary infusion was used in the Ishibashi et al. (80) study. Intravenous infusion avoids direct intracoronary injection of the harsh alkaline vehicle that is required to get glibenclamide into solution and provides time for equilibration of the blocking agents in the circulation. A continuous intracoronary infusion is not suitable for steady-state measurements because recirculation of the blocking agents would result in ever increasing coronary concentrations, which might confound the measurement of myocardial oxygen consumption, a critical measurement in coronary studies. Aside from these methodological differences, it is unclear what may account for the differences between these investigations.

View larger version (33K): [in this window] [in a new window]   Figure 3. Relationship between coronary venous oxygen tension and myocardial oxygen consumption with and without triple blockade of K+ATP channels, nitric oxide synthesis, and adenosine receptors. Triple blockade significantly reduced coronary venous oxygen tension at rest and during exercise in a parallel manner (P < 0.001), but did not make the slope more negative. These findings indicate that inhibition of K+ATP channels, nitric oxide synthesis, and adenosine receptors lowers the balance between coronary blood flow and myocardial metabolism at rest, but that these factors are not required for exercise-induced coronary vasodilation. This figure was reproduced with the permission of the American Physiological Society from Ref. 106.

View larger version (23K): [in this window] [in a new window]   Figure 4. Effects of myocardial oxygen consumption (A) and coronary venous oxygen tension (B) on estimated interstitial adenosine concentration with and without triple blockade of K+ATP channels, nitric oxide synthesis, and adenosine receptors. Triple blockade increased the estimated interstitial concentration of adenosine as myocardial oxygen consumption was increased and as coronary venous oxygen tension was reduced. However, the estimated interstitial adenosine concentration remained well below the threshold concentration necessary for coronary vasodilation in the presence of adenosine receptor blockade with 8-phenyltheophylline (8-PT). This figure was reproduced with the permission of the American Physiological Society from Ref. 106.

	Other Potential Mediators of Local Metabolic Vasodilation

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Prostaglandins.
Prostaglandins are metabolites of arachidonic acid that have been implicated as potential mediators of coronary blood flow control. Prostaglandins have been shown to be released into the coronary circulation during episodes of hypoxia (107), anoxia (108), and coronary artery occlusion (109). However, an important role of prostaglandins in local metabolic coronary vasodilation under normal physiological conditions has not been demonstrated. Inhibition of prostaglandin synthesis with indomethacin does not significantly affect resting coronary blood flow or attenuate exercise-induced coronary vasodilation (110). In addition, the relationship between coronary venous oxygen tension and myocardial oxygen consumption is unaltered by indomethacin, demonstrating that prostaglandins do not mediate functional coronary exercise hyperemia.

Other Potential Vasodilators.
Other potential factors that may contribute to local metabolic coronary vasodilation include oxygen, carbon dioxide, potassium, ATP, and endothelium-derived hyperpolarizing factors (EDHFs). However, none of these factors have been examined during exercise-induced increases in myocardial oxygen consumption.

A depletion of oxygen or the accumulation of carbon dioxide are both stimuli for coronary vasodilation (111, 112). Broten et al. (113) developed a model of oxygen and carbon dioxide tension-induced changes in coronary vascular resistance and concluded that 40% of the change in coronary blood flow during modest, pacing-induced increases in myocardial oxygen consumption could be accounted for by changes in coronary venous oxygen and carbon dioxide tensions. However, coronary venous carbon dioxide tension is little changed with exercise (28, 39–41), and the typical 4–6 mm Hg decrease in coronary venous oxygen tension observed during exercise cannot by itself account for the 4-fold increase in coronary blood flow.

Potassium has been shown to be transiently elevated during pacing-induced increases in myocardial oxygen consumption (114) and may account for 33% of the initial coronary vasodilator response to this stimulus. However, this transient elevation of potassium makes it an unlikely mechanism for steady-state increases in coronary blood flow associated with increased myocardial metabolism.

ATP and EDHFs have recently been the focus of several investigations of coronary flow regulation. ATP has been shown to be a potent vasodilator in a number of different experimental models, including isolated arteries and veins (115), coronary arteries (116), hamster cheek pouch (117), and isolated working rat hearts (118). ATP is most likely released locally by cardiomyocytes (119) and by red blood cells (120, 121) during reductions in oxygenation. EDHFs are released by coronary endothelial cells and they mediate vasodilation by hyperpolarizing underlying vascular smooth muscle cells (122, 125). It appears that a component of EDHFs are cytochrome P450-metabolites of arachidonic acid, epoxyeicosatrienoic acids (EETs) and hydroxyeicosatetraenoic acids (HETEs), both of which regulate coronary vascular tone (126–128). Although several studies have shown that ATP and EDHFs mediate coronary vascular relaxation, their role in local metabolic vasodilation during increases in myocardial metabolism has not been defined.

	Adrenergic Control of Coronary Blood Flow

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Activation of the sympathetic nervous system increases heart rate, cardiac contractility, and cardiac afterload. The resulting increase in myocardial oxygen consumption produces metabolic coronary vasodilation, which has been discussed above. This local metabolic vasodilation obscures the direct effects of sympathetic activation on coronary blood vessels. A further complication is that coronary vessels contain both - and ß-adrenoceptors, giving rise to the possibility for both adrenergic vasoconstriction and vasodilation.

-Adrenoceptor-Mediated Coronary Vasoconstriction.
One way to demonstrate direct -adrenoceptor coronary vasoconstriction has been to activate sympathetic nerves while preventing metabolic vasodilation by blocking ß-adrenoceptors. Sympathetic stimulation under these conditions results in a decrease in coronary blood flow (129–132), which can be blocked by -adrenoceptor antagonists (130). Further proof that this is a direct vascular effect rather than a consequence of decreased metabolism is the observation that coronary venous oxygen tension falls under these conditions (133).An alternate approach is to block coronary -adrenoceptors during sympathetic activation. Under these conditions, one sees higher coronary blood flow or lower coronary vascular resistance at a given level of myocardial oxygen consumption compared with control conditions (134, 135). Comparing flow at the same oxygen consumption is essential because this controls for the degree of metabolic vasodilation. The -adrenoceptor blockade experiment has been particularly useful in demonstrating -adrenoceptor coronary vasoconstriction during exercise (136–141).At first glance, -adrenoceptor vasoconstriction during exercise seems to be potentially deleterious because it competes with metabolic coronary vasodilation at a time when myocardial oxygen consumption is greatly increased. The beneficial effect becomes apparent during periods of high coronary blood flow and tachycardia (such as during strenuous exercise). Under these conditions, the highly vasodilated subendocardium (which is only perfused during diastole) is vulnerable to underperfusion due to high myocardial compressive forces and short diastoles. Regional coronary -adrenoceptor blockade during strenuous exercise in dogs increases total transmural coronary blood flow, but reduces subendocardial flow (139). The postulated mechanism is that -adrenoceptor vasoconstriction stiffens the medium-sized intramyocardial coronary vessels, causing a decrease in intramyocardial vascular capacitance. This mechanism is supported by the observation that -adrenoceptor activation by norepinephrine decreases wasteful antegrade-retrograde flow oscillation during the cardiac cycle (142).An interesting aspect of -adrenoceptor coronary vasoconstriction is that it seems to be confined to vessels greater than 100 µm in diameter both in vitro (143, 144) and in vivo (145). Recent studies suggest that vasoconstriction in vessels smaller than this might result not from stimulation of coronary -adrenoceptors, but from -receptor-mediated endothelin release from cardiac myocytes (146, 147). To date, the endothelin mechanism has only been demonstrated in vitro or during intracoronary infusion of high doses of -adrenoceptor agonists. It remains to be determined whether it is active under physiological conditions such as exercise.

ß-Adrenoceptor-Mediated Coronary Vasodilation.
In the case of coronary -adrenoceptors, it is possible to separate their influence from metabolic vasodilation via selective blockade of either - or ß-adrenoceptors. Direct sympathetic vasodilation of coronary vessels is difficult to separate from metabolic vasodilation because ß-adrenoceptors on coronary vessels and cardiac cells are responsible for both actions. In terms of control theory, this means that coronary ß-adrenoceptor vasodilation is a feed-forward mechanism that does not require an error signal. The same stimulus that increases myocardial oxygen consumption (sympathetic activation to increase heart rate and contractility) in this case simultaneously causes vasodilation. The term `feed-forward' is often used when describing this process in order to distinguish it from local metabolic feedback vasodilation secondary to sympathetic activation.

The most direct way to separate feed-forward sympathetic vasodilation from metabolic vasodilation is to use isolated blood vessels. Small coronary arteries in vitro relax in response to catecholamines even without prior -adrenoceptor blockade (143, 144). In the presence of -adrenoceptor blockade, intracoronary norepinephrine injections during long diastoles (to avoid cardiac inotropic and chronotropic effects) produce vasodilation in anesthetized dog hearts (148). These results demonstrate the possibility for feed-forward ß-adrenoceptor-mediated vasodilation, but demonstrating its presence in a beating heart is difficult. Testing for this phenomenon in vivo would be simple if it were possible to selectively block either coronary or myocardial ß-adrenoceptors. However, studies have found both ß₂- and ß₁-adrenoceptors on coronary vessels (148–154), making this approach problematic.

Feed-forward sympathetic coronary vasodilation in vivo was first clearly demonstrated in anesthetized dogs using pacing tachycardia as a stimulus to produce a relatively pure metabolic vasodilation (148). This was compared with an intracoronary infusion of norepinephrine during -adrenoceptor blockade, which produced both metabolic and feed-forward ß-adrenoceptor vasodilation. Because these two interventions produced the same increase in myocardial oxygen consumption, the metabolic components were presumably equal and any differences were due to feed-forward ß-adrenoceptor vasodilation. Norepinephrine plus -adrenoceptor blockade resulted in significantly higher coronary sinus oxygen tension and coronary blood flow than pacing, demonstrating the presence of a feed-forward vasodilation. This approach has subsequently been adapted to demonstrate feed-forward sympathetic coronary vasodilation during exercise (41, 155). In this case, the `metabolic only' vasodilation is produced by exercise during combined - and ß-adrenoceptor blockade. This is compared with exercise with only -adrenoceptor blockade. When coronary venous oxygen tension is plotted versus myocardial oxygen consumption, oxygen tension does not fall significantly during -adrenoceptor blockade, but it does fall steeply during +ß-receptor blockade. The large difference in slopes under these two conditions demonstrates the presence of feed-forward sympathetic coronary vasodilation during exercise (Fig. 5).A drawback to these pharmacologic demonstrations of feed-forward ß-adrenoceptor vasodilation (and -adrenoceptor vasoconstriction) is that blockade of either - or ß-adrenoceptors tends to increase circulating catecholamine concentrations, particularly during exercise. Exercise during -adrenoceptor blockade, for example, leads to higher norepinephrine concentrations that may exaggerate feed-forward ß-adrenoceptor coronary vasodilation (156–158). One way around this problem is to estimate the vascular effects of the cardiac catecholamine concentrations measured during normal exercise without adrenergic blockade. In the case of epinephrine, this approach is relatively straightforward because epinephrine from the adrenal glands reaches the heart via the arterial plasma. When epinephrine is infused into resting dogs to mimic arterial epinephrine concentrations achieved during strenuous exercise, there is little increase (6%) in myocardial oxygen consumption and no change in coronary sinus oxygen tension (158). Therefore, circulating epinephrine has little direct coronary vascular effect during exercise.

View larger version (22K): [in this window] [in a new window]   Figure 5. Mean values of coronary venous oxygen tension at rest and during three levels of exercise plotted as a function of myocardial oxygen consumption with individual regression lines for control, -blockade with phentolamine, and +ß blockade with phentolamine and propranolol (A). Regression lines are repeated with significant differences in slopes indicated (B). The steep slope of combined +ß blockade indicates a modest match by local metabolic factors in the absence of adrenergic mechanisms. The difference in the slopes between +ß blockade and -blockade alone demonstrates feed-forward ß-adrenoceptor-mediated coronary vasodilation. The difference in the slopes between control and -blockade demonstrates the well-established feed-forward -adrenoceptor-mediated coronary vasoconstriction. This figure was reproduced with the permission of the American Physiological Society from Ref. 41.

Integrating -Adrenoceptor Vasoconstriction with ß-Adrenoceptor Vasodilation.
It is apparent that both -vasoconstriction and ß-vasodilation occur simultaneously in the coronary circulation during sympathetic activation. These effects may not be as antagonistic as they at first appear. -Adrenoceptor vasoconstriction is predominantly a large vessel (>100 µm) phenomenon, whereas small vessels only relax in response to norepinephrine (143–145). This may be explained by the distribution of - and ß-adrenoceptors along the coronary arterial tree (160, 161). This reciprocal gradient in adrenoceptors favors sympathetic vasodilation in resistance vessels and vasoconstriction in distribution vessels. Therefore, -adrenoceptor vasoconstriction and ß-adrenoceptor vasodilation appear to be spatially distributed so as to increase coronary blood flow (ß) and at the same time improve transmural flow distribution (). The feed-forward ß-adrenoceptor vasodilation accounts for 25% of the increase in coronary blood flow observed during exercise.

	Pathophysiology

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Studies indicate that control of coronary blood flow is altered at rest and during exercise under pathophysiological conditions such as hypertension, diabetes, and heart failure. However, it is unclear whether these conditions lead to any imbalance between oxygen delivery and myocardial oxygen consumption. In addition, the specific mechanism(s) underlying this impairment remain to be elucidated.

Hypertension.
Hypertension may be accompanied by increased sympathetic nerve activity and/or alterations in adrenergic receptor sensitivity, which may adversely affect coronary flow regulation (162). Increased vascular reactivity to vasoconstrictor substances has been observed in clinical hypertension (163, 164) and in animals models of hypertension (165, 166). Gwirtz (162) determined that enhanced ₁-adrenoceptor-mediated coronary vasoconstriction limits coronary blood flow at rest and during exercise in dogs with renovascular hypertension. However, whether this enhanced adrenergic constriction is sufficient to limit the balance between coronary blood flow and myocardial metabolism is presently unknown. In addition, it is also unclear if vasodilator mechanisms are altered or impaired by chronic hypertension.

Diabetes Mellitus.
Dysfunction of the coronary circulation could, in part, be responsible for the increased incidence of myocardial ischemia, infarction, and sudden cardiac death among patients with diabetes mellitus (167, 168). Coronary flow reserve (169–171) and pacing-induced coronary vasodilation (170) are reduced in diabetic patients with no evidence of coronary artery disease. Pharmacologic and pacing-induced increases in coronary blood flow are also attenuated in experimental diabetes (172–174). However, there has not been an examination of whether coronary blood flow control is impaired sufficiently to decrease the balance between coronary blood flow and myocardial oxygen consumption during exercise-induced increases in myocardial metabolism.

Heart Failure.
The literature on coronary blood flow control in heart failure is discordant. Studies have reported a decrease (175) or no change (176, 177) in resting coronary blood flow from patients with dilated cardiomyopathy and/or congestive heart failure. Investigations in animals with experimental, pacing-induced heart failure have reported both increased (178–180) and decreased (181–184) coronary blood flow. These conflicting results are most likely due to differing levels of myocardial oxygen consumption, the primary determinant of coronary flow. Traverse et al. (184) reported that pacing-induced heart failure in dogs decreased myocardial oxygen consumption and coronary blood flow both at rest and during exercise, but did not appear to result in an imbalance between myocardial oxygen delivery and metabolism. This finding is consistent with an earlier study in patients with congestive heart failure in which myocardial oxygen consumption was increased by dobutamine (185). These studies suggest that mechanisms that regulate coronary control in response to increases in myocardial metabolism appear to be intact during heart failure, and that the diminished coronary blood flow per gram observed during heart failure is secondary to a decreased myocardial oxygen consumption.

	Conclusions

Top Abstract Introduction Adenosine Hypothesis K+ATP Channels Nitric Oxide Compensatory Control and Its... Other Potential Mediators of... Adrenergic Control of Coronary... Pathophysiology Conclusions References

 
The mediator or mediators of local metabolic coronary vasodilation remain unknown. Numerous studies that have examined the role of adenosine, K⁺_ATP channels, and nitric oxide in coronary flow control have produced little evidence that any of these factors contribute to metabolic vasodilation during increases in myocardial oxygen consumption. However, nitric oxide and K⁺_ATP channels do contribute to the regulation of coronary vascular tone under normal, resting conditions. Taken together, these factors do not result in a redundant compensating mechanism of coronary blood flow control during exercise. Prostaglandins and potassium are not important in steady-state coronary flow regulation during exercise. Other factors such as ATP and EDHFs have been implicated as possible local metabolic coronary vasodilators, but have not been examined during exercise hyperemia.

Feed-forward ß-adrenoceptor-mediated coronary vasodilation has been shown to account for 25% of coronary vasodilation observed during exercise. This dilation is a direct effect of norepinephrine's action on small coronary arterioles. Norepinephrine-induced -adrenoceptor-mediated coronary vasoconstriction reduces upstream vessel compliance and lessens wasteful to-and-fro flow in the coronary arterial tree. This paradoxical effect of proximal coronary artery vasoconstriction during exercise helps to maintain blood flow to the vulnerable subendocardium when heart rate, myocardial contractility, and oxygen consumption are elevated.

The fact that ß-adrenoceptor-mediated coronary vasodilation accounts for approximately one-quarter of exercise hyperemia means that local metabolic and/or endothelium-dependent dilation must account for the other three-quarters of exercise-induced vasodilation. This distribution of coronary flow regulation may be altered under pathophysiologic conditions such as in hypertension, diabetes mellitus, or heart failure.

	Footnotes

 
¹ To whom requests for reprint should be addressed at Department of Integrative Physiology, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107-2699. E-mail: jtune{at}hsc.unt.edu

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