We endeavored to determine if the enhanced shortening of the myocardial action potential duration (APD) during ischemia can be dissociated from the cardioprotective effects of the adenosine triphosphate (ATP) sensitive potassium channel (KATP) opener cromakalim. To establish if there is a relationship between APD shortening and the cardioprotective effect of cromakalim, we determined the effect of a dose of the delayed rectifier (IKr) blocker dofetilide (which abolishes the APD shortening effect of cromakalim) on the cardioprotective activity of cromakalim. Cromakalim was infused at a previously determined cardioprotective dose (10 [mu] g/kg+ 0.3 [mu] g/kg/min infusion ic), and we determined the effect of 1 mg/kg (followed by a 0.01 mg/kg/min iv infusion) dofetilide alone and in combination with cromakalim on APD shortening and infarct size (90-min coronary occlusion and 5-h reperfusion) in anesthetized dogs. Dofetilide completely abolished the APD shortening effects of cromakalim during ischemia such that APD was similar to preischemic values. Cromakalim only shortened the APD during ischemia, although this effect was attenuated late into ischemia. Cromakalim significantly reduced infarct size (40% reduction from vehicle group value), whereas dofetilide alone had no effect. Dofetilide, at a dose that prevented the cromakalim-induced shortening of APD in ischemic tissue, did not attenuate the cardioprotective effects of cromakalim. No differences in collateral blood flow for any of the groups were observed. Dofetilide did cause a slight bradycardia, but this effect is unlikely to affect the interpretation of the results. These data suggest that APD shortening observed with the KATP opener cromakalim is not correlated with its cardioprotective effects.