CARDIOPROTECTION WITH THE K-ATP OPENER CROMAKALIM IS NOT CORRELATED WITH ISCHEMIC MYOCARDIAL ACTION-POTENTIAL DURATION

We endeavored to determine if the enhanced shortening of the myocardia l action potential duration (APD) during ischemia can be dissociated f rom the cardioprotective effects of the adenosine triphosphate (ATP) s ensitive potassium channel (K-ATP) opener cromakalim. To establish if there is a relationship between APD shortening and the cardioprotectiv e effect of cromakalim, we determined the effect of a dose of the dela yed rectifier (IKr) blocker dofetilide (which abolishes the APD shorte ning effect of cromakalim) on the cardioprotective activity of cromaka lim. Cromakalim was infused at a previously determined cardioprotectiv e dose (10 mu g/kg + 0.3 mu g/kg/min infusion i.c.), and we determined the effect of 1 mg/kg (followed by a 0.01 mg/kg/min i.v. infusion) do fetilide alone and in combination with cromakalim on APD shortening an d infarct size (90-min coronary occlusion and 5-h reperfusion) in anes thetized dogs. Dofetilide completely abolished the APD shortening effe cts of cromakalim during ischemia such that APD was similar to preisch emic values. Cromakalim only shortened the APD during ischemia, althou gh this effect was attenuated late into ischemia. Cromakalim significa ntly reduced infarct size (40% reduction from vehicle group value), wh ereas dofetilide alone had no effect. Dofetilide, at a dose that preve nted the cromakalim-induced shortening of APD in ischemic tissue, did not attenuate the cardioprotective effects of cromakalim. No differenc es in collateral blood flow for any of the groups were observed. Dofet ilide did cause a slight bradycardia, but this effect is unlikely to a ffect the interpretation of the results. These data suggest that APD s hortening observed with the K-ATP opener cromakalim is not correlated with its cardioprotective effects.