Influence of dual ETA/ETB-receptor blockade on coronary responses to treadmill exercise in dogs

We hypothesized that endothelin (ET) release during exercise may be triggered by alpha-adrenergic-receptor activation and thereby influence coronary hemodynamics and O-2 metabolism in dogs. Exercise resulted in coronary blood flow increases (to 1.88 +/- 0.26 from 1.10 +/- 0.12 ml.min(-1).g(-1)) and in a fall (P < 0.01) in coronary sinus O-2 saturation (17.4 +/- 1.5 to 9.6 +/- 0.7 vol%), whereas myocardial O-2 consumption (M(V)over dot O-2) increased (109 +/- 13% from 145 +/- 16 mu l O-2.min(-1).g(-1)). Tezosentan, a dual ETA/ETB-receptor blocker, slightly reduced mean arterial pressure (MAP) and increased heart rate throughout exercise. The relationship between coronary sinus O-2 saturation and M(V)over dot O-2 was shifted upward (P < 0.05) after tezosentan administration; i.e., as M(V)over dot O-2 increased during exercise, coronary sinus O-2 saturation was disproportionately higher after ET-receptor blockade. After propranolol, tezosentan resulted in significant decreases (P < 0.05) in left ventricular pressure, the first derivative of left ventricular pressure over time, and MAP during exercise. As M(V)over dot O-2, increased during exercise, coronary sinus O-2 saturation levels after tezosentan became superimposable over those observed before ET-receptor blockade. Thus dual blockade of ETA/ETB receptors alters coronary hemodynamics and O-2 metabolism during exercise, but ET activity failed to increase beyond baseline levels.