The effect of three potassium channel openers, nicorandil, aprikalim, and bimakalim, on experimental myocardial ischaemia/reperfusion injury was examined in barbital-anaesthetized dogs. In a model of reversible injury, administration of nicorandil at a hypotensive dose and aprikalim at a non-hypotensive dose resulted in a reduction in contractile dysfunction during reperfusion ('stunning') following brief coronary artery occlusion (15 min) when the drugs were administered before occlusion. Administration of aprikalim only during reperfusion had no beneficial effect. Pre-treatment with the adenosine triphosphate (ATP)-dependent potassium (KATP) channel antagonist, glibenclamide, blocked completely the beneficial effects of nicorandil and aprikalim, although glibenclamide did not block the haemodynamic effects of nicorandil. In a model of irreversible ischaemia/reperfusion injury (120 min of ischaemia and 30 min of reperfusion) pre-treatment with equihypotensive doses of nicorandil and bimakalim produced marked reductions in myocardial infarct size. Similarly, aprikalim at a non-hypotensive dose reduced myocardial infarct size in dogs subjected to 90 min of ischaemia and 5 h of reperfusion, and the protective effects of aprikalim were antagonized completely by glibenclamide. These results indicate that nicorandil, aprikalim, and bimakalim are protective in two experimental models of ischaemia/reperfusion injury. The mechanism of action of these agents is not completely understood, but it appears to be a result of myocardial KATP channel activation.