Infarct size limitation by nicorandil:: Roles of mitochondrial KATP channels, sarcolemmal KATP channels, and protein kinase C

OBJECTIVES This study aimed to examine: 1) whether nicorandil protects the ischemic myocardium by activating sarcolemmal adenosine triphosphate (ATP)-sensitive K+ (sarcK(ATP)) channels or the mitochondrial K-ATP (mitoK(ATP)) channels, and 2) whether protein kinase C (PKC) activity is necessary for cardioprotection afforded by nicorandil. BACKGROUND Nicorandil is a hybrid of nitrate and a K-ATP channel opener that activates the sarcK(ATP) and mitoK(ATP) channels. Both of these K-ATP channels are regulated by PKC, and this kinase may be activated by nitric oxide and also by oxygen free radicals (OFR) generated after mitoK(ATP) channel opening. METHODS In isolated rabbit hearts, infarction was induced by 30-min global ischemia/2-h reperfusion with monitoring of the activation recovery interval (ARI), an index of action potential duration. Protein kinase C translocation was assessed by Western blotting. RESULTS Nicorandil did not change ARI before ischemia, but it accelerated ARI shortening after the onset of ischemia and reduced infarct size by 90%. A sarcK(ATP) channel selective blocker, HMR1098, abolished acceleration of ischemia-induced ARI-shortening by nicorandil and eliminated 40% of nicorandil-induced infarct size limitation. A mitoK(ATP) channel selective blocker, 5-hydroxydecanoate, abolished the protection afforded by nicorandil without affecting ARI. Cardioprotection by nicorandil was inhibited neither by an OFR scavenger, N-2-mercaptopropionylglycine nor by a PKC inhibitor, calphostin C, at a dose that was capable of inhibiting PKC-epsilon translocation after preconditioning. CONCLUSIONS Both the sarcK(ATP) and mitoK(ATP) channels are involved in anti-infarct tolerance afforded by nicorandil, but PKC activation induced by nitric oxide or OFR generation, if any, does not play a crucial role. (C) 2002 by the American College of Cardiology Foundation.