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

Article

关键词: SENSITIVE POTASSIUM CHANNELS;    PROTEIN-KINASE-C;    INFARCT SIZE;    SODIUM 5-HYDROXYDECANOATE;    MYOCARDIAL-ISCHEMIA;    DOGS;    ADENOSINE;    BLOCKADE;    RECEPTOR;    OPENER;   

DOI  :  10.1161/01.CIR.101.20.2418

来源: SCIE

【 摘 要 】

Background-Pharmacological evidence has implicated ATP-sensitive K+ (K-ATP) channels as the effecters 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 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 index 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 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 mu mol/L), but not P-1075, blunted cellular injury, The cardioprotection afforded by diazoxide or by preconditioning 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 agents provide further support for the emerging consensus that mitoK(ATP) channels rather than surfaceK(aATP) channels are the likely effectors of cardioprotection.

【 授权许可】

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