Selective Pharmacological Agents Implicate Mitochondrial but Not Sarcolemmal K ATP Channels in Ischemic Cardioprotection

Abstract

Background —Pharmacological evidence has implicated ATP-sensitive K + (K ATP ) channels as the effectors of cardioprotection, but the relative roles of mitochondrial (mitoK ATP ) and sarcolemmal (surfaceK ATP ) channels remain controversial. Methods and Results —We examined the effects of the K ATP channel blocker HMR1098 and the K ATP channel opener P-1075 on surfaceK ATP and mitoK ATP channels in rabbit ventricular myocytes. HMR1098 (30 μmol/L) inhibited the surfaceK ATP current activated by metabolic inhibition, whereas the drug did not blunt diazoxide (100 μmol/L)-induced flavoprotein oxidation, an index of mitoK ATP channel activity. P-1075 (30 μmol/L) did not increase flavoprotein oxidation but did elicit a robust surfaceK ATP current that was completely inhibited by HMR1098. These results indicate that HMR1098 selectively inhibits surfaceK ATP channels, whereas P-1075 selectively activates surface K ATP channels. In a cellular model of simulated ischemia, the mitoK ATP channel opener diazoxide (100 μmol/L), but not P-1075, blunted cellular injury. The cardioprotection afforded by diazoxide or by preconditioning was prevented by the mitoK ATP channel blocker 5-hydroxydecanoate (500 μmol/L) but not by the surfaceK ATP channel blocker HMR1098 (30 μmol/L). Conclusions —The cellular effects of mitochondria- or surface-selective agents provide further support for the emerging consensus that mitoK ATP channels rather than surfaceK ATP channels are the likely effectors of cardioprotection.