These data demonstrate that K+ATP channels modulate coronary vasomotor tone under resting conditions and contribute to coronary vasodilation during ischemia. However, the coronary vasculature retains the capacity to dilate in response to increases in oxygen demand produced by exercise when K+ATP channels are blocked.

The mechanism of coronary vasodilation produced by exercise is not understood completely. Recently, we reported that blockade of vascular smooth muscle KAT channels decreased coronary blood flow at rest, but did not attenuate the increments in coronary flow produced by exercise. Adenosine is not mandatory for maintaining basal coronary flow, or the increase in flow produced by exercise during normal arterial inflow, but does contribute to coronary vasodilation in hypoperfused myocardium. Therefore, we investigated whether adenosine opposed the hypoperfusion produced by KA+P channel blockade, thereby contributing to coronary vasodilation during exercise. 11 dogs were studied at rest and during exercise under control conditions, during intracoronary infusion of the KA channel blocker glibenclamide (50 ,ug/kg per min), and during intracoronary glibenclamide in the presence of adenosine receptor blockade. Glibenclamide decreased resting coronary blood flow from 45±5 to 35±4 ml/min (P < 0.05), but did not prevent exerciseinduced increases of coronary flow. Glibenclamide caused an increase in myocardial oxygen extraction at the highest level of exercise with a decrease in coronary venous oxygen tension from 15.5±0.7 to 13.6±0.8 mmHg (P < 0.05). The addition of the adenosine receptor antagonist 8-phenyltheophylline (5 mg/kg intravenous) to KAT channel blockade did not further decrease resting coronary blood flow but did attenuate the increase in coronary flow produced by exercise. This was accompanied by a further decrease of coronary venous oxygen tension to 10.1±0.7 mmHg (P < 0.05), indicating aggravation of the mismatch between oxygen demand and supply. These findings are compatible with the hypothesis that KATP channels modulate coronary vasomotor tone both under resting conditions and during exercise. However, when KA channels are blocked, adenosine released from the hypoperfused myocardium provides an alternate mechanism to mediate coronary vasodilation in response to increases in oxygen demand produced by exercise. (J. Clin. Invest. 1995. 95:285-295.)

Regulation of coronary vasomotor tone during exercise is incompletely understood. We investigated the contributions of K ϩ ATP channels and adenosine to the coronary vasodilation that occurs during exercise in the normal heart and in the presence of a coronary artery stenosis. Dogs that were chronically instrumented with a Doppler flow probe, hydraulic occluder, and indwelling catheter on the left anterior descending coronary artery were exercised on a treadmill to produce heart rates of ‫ف‬ 200 beats/min. By graded inflation of the occluder to produce a wide range of coronary stenosis severities, we determined the coronary pressure-flow relation. K

We examined the impeding effects of exercise on coronary blood flow by analyzing exercise-induced changes in the pressure-flow relationship during maximal coronary vasodilation with adenosine in chronically instrumented dogs and assessed the individual contributions produced by heart rate, contractility, and alpha 1-adrenergic vasoconstriction. Treadmill exercise that increased heart rate from 118 +/- 6 beats/min at rest to 213 +/- 8 beats/min (P < 0.01) decreased maximum coronary blood flows by decreasing the slope of the linear part of the pressure-flow relationship for coronary pressures > or = 30 mmHg (slopeP > or = 30) from 12.3 +/- 0.9 to 10.9 +/- 0.9 ml.min-1 x g-1 x mmHg-1 (P < 0.01) and increasing the measured coronary pressure at zero flow (P zf,measured) from 12.6 +/- 1.2 to 23.3 +/- 2.0 mmHg (P < 0.01). Atrial pacing at 200 beats/min caused an increase of P zf,measured from 15.0 +/- 1.6 to 18.3 +/- 2.1 mmHg (P < 0.05) with no change in slopeP > or = 30. While pacing continued, infusion of dobutamine (20 micrograms.kg-1 x min-1 i.v.) increased contractility to levels similar to those during exercise but caused no significant change in coronary blood flow, as a decrease of the slopeP > or = 30 was compensated for by a slight decrease in P zf,measured. alpha 1-Adrenergic blockade with intracoronary prazosin (10 micrograms/kg) did not prevent the exercise-induced increase of P zf,measured but abolished the decrease of the slopeP > or = 30. When the increases in heart rate, contractility, and alpha 1-adrenergic vasoconstriction were prevented, exercise still increased P zf,measured from 15.8 +/- 2.1 to 21.8 +/- 2.6 mmHg (P < 0.05) but had no effect on the slopeP > or = 30. This residual increase in P zf,measured correlated with the concomitant increase in left ventricular filling pressure. In conclusion, exercise-induced decreases of maximum coronary blood flow were explained by increases in heart rate, alpha 1-adrenergic vasoconstriction, and left ventricular filling pressure, with a minimal contribution of contractility.