Selective pharmacological agents implicate mitochondrial but not sarcolemmal K-ATP channels in ischemic cardioprotection

Background-Pharmacological evidence has implicated ATP-sensitive K+ (K-ATP) channels as the effecters of cardioprotection, but the relative roles of m itochondrial (mitoK(ATP)) and sarcolemmal (surfaceK(ATP)) channels remain c ontroversial. Methods and Results-We examined the effects of the K-ATP channel blocker HM R1098 and the K-ATP channel opener P-1075 on surfaceK(ATP) and mitoK(ATP) c hannels in rabbit ventricular myocytes. HMR1098 (30 mu mol/L) inhibited the surfaceK(ATP) current activated by metabolic inhibition, whereas the drug did not blunt diazoxide (100 mu mol/L)-induced flavoprotein oxidation, an i ndex of mitoK(ATP) channel activity. P-1075 (30 mu mol/L) did not increase flavoprotein oxidation but did elicit a robust surfaceK, current that was c ompletely inhibited by HMR1098. These results indicate that HMR1098 selecti vely inhibits surfaceK(ATP) channels, whereas P-1075 selectively activates surface K-ATP channels. In a cellular model of simulated ischemia, the mito K(ATP) channel opener diazoxide (100 mu mol/L), but not P-1075, blunted cel lular injury, The cardioprotection afforded by diazoxide or by precondition ing was prevented by the mitoK, channel blocker 5-hydroxydecanoate (500 mu mol/L) but not by the surfaceK(ATP) channel blocker HMR1098 (30 mu mol/L). Conclusions-The cellular effects of mitochondria- or surface-selective agen ts provide further support for the emerging consensus that mitoK(ATP) chann els rather than surfaceK(aATP) channels are the likely effectors of cardiop rotection.