Role of K-ATP(+) channels and adenosine in the regulation of coronary blood flow during exercise with normal and restricted coronary blood flow

Regulation of coronary vasomotor tone during exercise is incompletely understood. We investigated the contributions of K-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 similar to 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-ATP(+) channel blockade with intracoronary glibenclamide (10-50 mu g/kg per min) decreased coronary blood flow during exercise at coronary pressures within and below the autoregulatory range, indicating that coronary K-ATP(+) channel activation is critical for producing coronary vasodilation with either normal arterial inflow or when flow is restricted by a coronary artery stenosis. Adenosine receptor blockade with intravenous 8-phenyltheophylline (5 mg/kg) had no effect on coronary flow at pressures within the autoregulatory range but decreased flow at pressures < 55 mmHg. In contrast, in the presence of K-ATP(+) channel blockade, the addition of adenosine receptor blockade further decreased coronary flow even at coronary pressures in the autoregulatory range, indicating increased importance of the vasodilator influence of endogenous adenosine during exercise when K-ATP(+) channels are blocked. Intracoronary adenosine (50 mu g/kg per min) increased coronary now at perfusion pressures both within and below the autoregulatory range. In contrast, selective K-ATP(+) channel activation with intracoronary pinacidil (0.2-5.0 mu g/kg per min) increased flow at normal but not at lower coronary pressures (< 55 mmHg). This finding demonstrates that not all K-ATP(+) channels are activated during exercise at pressures in the autoregulatory range, but that most K-ATP(+) channels are recruited as pressures approach the lower end of the autoregulatory plateau. Thus, K-ATP(+) channels and endogenous adenosine play a synergistic role in maintaining vasodilation during exercise in normal hearts and distal to a coronary artery stenosis that results in myocardial hypoperfusion during exercise.