This study examined the hypothesis that increases in myocardial blood flow during exercise are mediated by adenosine-induced coronary vasodilation. Active hyperemia associated with graded treadmill exercise and coronary reactive hyperemia were examined in chronically instrumented awake dogs during control conditions, after intracoronary infusion of adenosine deaminase (5 units/kg/min for 10 minutes), and after adenosine receptor blockade with 8-phenyltheophylline. Both adenosine deaminase and 8-phenyltheophylline caused a rightward shift of the dose-response curve to intracoronary adenosine; 8-phenyltheophylline was significantly more potent than adenosine deaminase. Adenosine deaminase caused a 33 +/- 7 to 39 +/- 3% decrease in reactive hyperemia blood flow following coronary occlusions of 5-20 seconds duration, respectively, while 8-phenyltheophylline produced a 40 +/- 6 to 62 +/- 8% decrease in reactive hyperemia. Increasing myocardial oxygen consumption during treadmill exercise was associated with progressive increase of coronary blood flow. Neither adenosine deaminase nor 8-phenyltheophylline attenuated the increase in coronary blood flow or the decrease of coronary vascular resistance during exercise. Neither agent altered the relation between myocardial oxygen consumption and coronary blood flow. Thus, although both adenosine deaminase and 8-phenyltheophylline antagonized coronary vasodilation in response to exogenous adenosine and blunted coronary reactive hyperemia, neither agent impaired coronary vasodilation associated with increased myocardial oxygen requirements produced by exercise. These findings fail to support a substantial role for adenosine in mediating coronary vasodilation during exercise.

SUMMARY. Experimental renovascular hypertension or supravalvular aortic constriction results in left ventricular hypertrophy and impaired minimum coronary vascular resistance. However, these experimental models expose the coronary arteries to increased intra-arterial pressure, so that hypertensive vascular changes might be responsible for the impaired minimum coronary resistance. This study was performed to test the hypothesis that left ventricular hypertrophy in the absence of increased coronary pressure results in abnormalities of myocardial perfusion. Aortic valve stenosis was produced by plication of the noncoronary aortic cusp of 11 dogs at 6-8 weeks of age. Studies were carried out when the animals reached adulthood; mean left ventriculanbody weight ratio was 7.1 ± 0.4 as compared to 4.4 ± 0.3 g/kg in 11 normal dogs (P < 0.01). Under quiet resting conditions, myocardial blood flow measured with microspheres was significantly greater than normal in dogs with aortic stenosis. However, during maximum coronary vasodilation with adenosine, mean left ventricular blood flow in dogs with hypertrophy (3.29 ± 0.39) was substantially less than in normal dogs (6.19 ± 0.54 ml/min per g; P < 0.01), whereas minimum coronary resistance was increased from 14.1 ± 1.7 in normal dogs to 23.7 ± 5.4 mmHgmin-g/ml (P < 0.01). To examine the response of myocardial perfusion to cardiac stress, blood flow was measured during pacing at 200 and 250 beats/min. Compared with normal dogs, animals with hypertrophy had a subnormal increase in myocardial blood flow during tachycardia; this perfusion deficit was most marked in the subendocardium. These data demonstrate that left ventricular hypertrophy alone, without increased coronary artery pressure, is associated with impaired minimum coronary vascular resistance and with abnormalities of myocardial blood flow during pacing stress. (Circ Res 58: 47-57, 1986)

Coronary vascular responses in regions of reversible postischemic myocardial contractile dysfunction (stunned myocardium) were examined in chronically instrumented, awake dogs. Left anterior descending coronary artery blood flow and oxygen extraction, aortic and left ventricular pressures, and regional myocardial segment shortening were determined. Regional myocardial blood flow was measured with microspheres. Coronary reactive hyperemia and vasodilator reserve, and regional myocardial oxygen consumption were determined. Three sequential 10-minute left anterior descending coronary artery occlusions separated by 30-minute reperfusion periods resulted in progressive postischemic dysfunction so that 1 hour after the final coronary artery occlusion, myocardial segment shortening was reduced to 37% of baseline. Despite this decrease in contractile function, left anterior descending artery flow (19.6 +/- 2.6 vs. 18.4 +/- 3.0 ml/min), myocardial blood flow and the transmural distribution of flow measured with microspheres, and regional myocardial oxygen consumption were unchanged. Although the coronary vasodilator reserve in response to adenosine was unaltered (63 +/- 9 vs. 70 +/- 15 ml/min), the reactive hyperemia response to a 10-second coronary occlusion was decreased in intensity (debt repayment ratio = 474 +/- 78% vs. 322 +/- 74%; p less than 0.05) and duration (57 +/- 9.1 vs. 35 +/- 4.5 seconds; p less than 0.05), while the peak flow response was unchanged (57 +/- 6.8 vs. 60 +/- 7.1 ml/min). Thus, in the intact awake animal postischemic myocardial contractile dysfunction was not associated with decreased myocardial oxygen consumption and did not impair the normal relation between coronary blood flow and myocardial oxygen utilization. Although coronary vessels showed a normal ability to vasodilate in response to adenosine, coronary reactive hyperemia was reduced.

To determine whether regional myocardial dysfunction occurring after exercise-induced ischemia might be caused by continued abnormalities of myocardial blood flow in the post-exercise period, nine dogs were instrumented with ultrasonic microcrystals for determination of circumferential segment shortening, circumflex artery electromagnetic flow probes, and hydraulic coronary artery occluders. Dogs performed treadmill exercise during partial inflation of the coronary artery occluder. When the stenosis was maintained after exercise (persistent stenosis), subendocardial hypoperfusion was noted 1 min after exercise (subendocardial flow = 0.79±0.42 ml/min per g vs. 1.39±0.43 ml/ min per g control), and this was associated with continued dysfunction in the ischemic zone (segment shortening 45.4±36.9% of resting control). When the stenosis was released immediately after exercise (temporary stenosis), however, flow was markedly increased 1 min post-exercise (mean transmural flow 4.24±1.22 ml/min per g, subendocardial flow 4.18±1.52 ml/min per g), and this was associated with a transient increase in segment shortening to 104.5±9.3% of resting control. 5 min after exercise, however, moderate reductions in ischemic segment shortening were noted after both temporary stenosis and persistent stenosis runs, and these persisted for 30 min post-exercise. It is concluded that regional left ventricular dysfunction may persist for a significant period of time after exercise-induced ischemia. Furthermore, early after exercise, dysfunction is related to persistent abnormalities of myocardial blood flow, whereas late after exercise it is independent of primary reductions in myocardial blood flow.

This study tested the hypothesis that metabolites of arachidonic acid may contribute to the coronary vascular response to physiological increases of myocardial O2 consumption that occur during exercise. Studies were performed in eight chronically instrumented dogs with electromagnetic flowmeter probes on the left circumflex coronary artery and aortic and coronary sinus catheters. Data were obtained at rest and during graded treadmill exercise during control conditions and after administration of the cyclooxygenase inhibitor indomethacin. During control conditions heart rate, aortic pressure, and coronary blood flow increased progressively during exercise; this was accompanied by a significant increase in myocardial O2 extraction, as evidenced by a decrease in coronary venous O2 tension (Po2) particularly during the first stage of exercise. Indomethacin (5 mg/kg iv) resulted in marked blunting of the coronary vasodilator response to intracoronary arachidonic acid in anesthetized open-chest dogs. After administration of indomethacin to awake dogs, resting heart rate, aortic pressure, and coronary venous Po2 were unaltered, and the response of these variables to exercise was not changed. The increase in coronary blood flow during exercise was also unchanged after indomethacin, so that the relationship between myocardial O2 consumption and coronary blood flow was unaltered by cyclooxygenase inhibition. Thus we were unable to demonstrate a significant effect of the prostaglandin system in mediating the coronary vascular response to exercise.

This study examined the ability of moderately well-developed coronary collateral vasculature to undergo vasoconstriction in response to alpha-adrenergic agonists, vasopressin and angiotensin, and vasodilation in response to nitroglycerin. Studies were performed in 20 dogs 4-16 wk after left anterior descending coronary artery occlusion had been produced by an Ameroid constrictor or hollow intravascular plug. Collateral flow was estimated from retrograde flow from the cannulated left anterior descending artery. Tissue flow was measured with microspheres. Agonists were introduced into the left main coronary artery to reach collaterals arising from the left circumflex and septal arteries. Vasopressin and angiotensin II decreased retrograde flow from 22.7 +/- 5.5 to 15.5 +/- 2.7 and from 19.2 +/- 2.8 to 14.3 +/- 1.9 ml/min, respectively (each P less than 0.05). Both agents also significantly decreased tissue flow to normally perfused and collateral dependent myocardium. Neither the selective alpha 1-adrenergic agonist phenylephrine nor the alpha 2-agonist B-HT 933 decreased retrograde flow. Nitroglycerin increased retrograde flow by 63 +/- 27% (P less than 0.01). Thus, although the moderately well-developed coronary collateral circulation is capable of vasoconstriction in response to vasopressin and angiotensin II, these data fail to support a role for alpha-adrenergic mechanisms in modulating collateral flow.

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This study was carried out to determine the relative importance of alpha 1- and alpha 2-adrenergic vasoconstriction in opposing the increase in coronary blood flow, which occurs during exercise. The response of left circumflex coronary artery blood flow was examined during treadmill exercise in 16 chronically instrumented dogs during control conditions, after selective alpha 1-adrenergic blockade with intracoronary prazosin, and after alpha 2-blockade with intracoronary idazoxan. During control conditions, graded treadmill exercise resulted in progressive increases of coronary blood flow and decreases of coronary vascular resistance. Prazosin produced highly selective alpha 1-adrenergic blockade; coronary blood flow was significantly higher and coronary vascular resistance significantly lower during all but the heaviest exercise stage after prazosin. Idazoxan produced highly effective, but only moderately selective, alpha 2-adrenergic blockade. However, after idazoxan, coronary blood flow and coronary vascular resistance during exercise were not significantly different from control. Combined alpha 1- and alpha 2-adrenergic blockade was not more effective in increasing coronary blood flow during exercise than was alpha 1-adrenergic blockade alone. These data support a role for alpha 1-adrenergic coronary vasoconstriction in limiting the increase in coronary blood flow, which occurs during exercise, but do not support a role for alpha 2-mediated coronary vasoconstriction during exercise.