Endothelin-1 (ET-1) is a potent vasoconstrictor, and ET(A) receptors mainly mediate this effect. Elevated plasma levels of ET-1 are observed in patients with coronary heart disease. The release of this peptide from the damaged endothelium may play a role in the initiation and maintenance of myocardial ischaemia. This study examines the ET(A) receptor-mediated role of endogenous ET-1 in post-ischaemic myocardial function after prolonged hypoperfusion in normal non-failing hearts. In an isolated rat heart model for short-term myocardial hibernation, left ventricular functional recovery after 3 h of hypoperfusion (15% of pre-ischaemic flow) followed by 2 h of reperfusion was determined. Under steady-state conditions, coronary flow, left ventricular pressure (LVP) and dP/dt(max) were measured in the isovolumically beating heart. Additionally, the maximal inotropic response (LVP and dP/dt(max)) to calcium stimulation was determined. To study the role of ET(A) receptors under these pathophysiological conditions, one group was treated with the ET(A) antagonist BQ 610 (0.8 micromol/l) during hypoperfusion, and compared with a control group which received a saline infusion during hypoperfusion. Reperfusion for 2 h after 3 h of hypoperfusion resulted in partial functional recovery in both groups. Post-ischaemic recovery was significantly better in the hearts that were treated with the ET(A) antagonist BQ 610 during hypoperfusion (LVP, +19.5% compared with control; dP/dt(max), +13.7% compared with control). The inotropic response to calcium was nearly normalized after ET(A) blockade. Thus the normal non-failing myocardium profits from ET(A) receptor blockade during a prolonged period of hypoperfusion, resulting in significantly better post-ischaemic recovery of myocardial function.