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

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