In contrast to in vitro studies, experiments in intact animals could not detect a positive inotropic effect of endothelin-1 (ET-1). We presumed that the ET-induced direct positive inotropy is antagonized in vivo by an indirect cardiodepressant effect due to a mainly ETA-mediated and ET-induced coronary constriction, with consequent myocardial ischemia. To confirm this hypothesis we examined in thoracotomized rats the effects of a nonselective activation of ETA and ETB receptors by 1 nmol/kg ET-1 with and without the vasodilator adenosine (2.0 mg/kg/min), and the effects of a selective activation of ETB receptors by the ETB agonist IRL 1620 (2 nmol/kg) on myocardial contractility and energy metabolism (ATP, ADP, AMP). In addition to recordings in the intact circulation, isovolumic measurements (peak LVSP, peak dP/dtmax) were performed for quantification of myocardial contractility. ET-1 had no positive inotropic effect (peak dP/dtmax -2% vs. control, n.s.) due to a marked vasoconstriction with a consequent fall in the myocardial ATP content (-17%; p < 0.01). Adenosine antagonized the ET-induced vasoconstriction in part, normalized myocardial energy metabolism (ATP -7%), and thus unmasked the positive inotropic effect of ET-1 (peak dP/dtmax +20%; p < 0.01). Selective activation of ETB receptors by IRL 1620 had only a small vasoconstrictor effect, which did not produce myocardial ischemia (ATP + 10%; n.s.) and thus caused a positive inotropic effect in vivo (peak dP/dtmax +22%; p < 0.01). The positive inotropic effect of ET-1 is not detectable in vivo as its marked, mainly ETA-mediated, vaso- and coronary constriction causes myocardial ischemia that thus produces an indirect negative inotropic effect.