Mitochondrial ATP-sensitive K+ channels play a role in cardioprotection by Na+-H+ exchange inhibition against ischemia/reperfusion injury

OBJECTIVES The possible role of the ATP-sensitive potassium (K-ATP) channel in cardioprotection by Na+-H+ exchange (NHE) inhibition was examined. BACKGROUND The K-ATP channel is suggested to be involved not only in ischemic preconditioning but also in some pharmacological cardioprotection. METHODS Infarction was induced by 30-min coronary occlusion in rabbit hearts in situ or by 30-min global ischemia in isolated hearts. Myocardial stunning was induced by five episodes of 5-min ischemia/5-min reperfusion in situ. In these models, the effects of NHE inhibitors (cariporide and ethylisopropyl-amiloride [EIPA]) and the changes caused by K-ATP channel blockers were assessed. In another series of experiments, the effects of EIPA on mitochondrial K-ATP (mito-K-ATP) and sarcolemmal K-ATP (sarc-K-ATP) channels were examined in isolated cardiomyocytes. RESULTS Cariporide (0.6 mg/kg) reduced infarct size in situ by 40%, and this effect was abolished by glibenclamide (0.3 mg/kg), a nonselective K-ATP channel blocker. In vitro, 1 muM cariporide limited infarct size by 90%, and this effect was blocked by 5-hydroxydecanoate (5-HD), a mito-K-ATP channel blocker but not by HMR1098, a sarc-K-ATP channel blocker. Infarct size limitation by 1 muM EIPA was also prevented by 5-HD. Cariporide attenuated regional contractile dysfunction by stunning, and this protection was abolished by glibenclamide and 5-HD. Ethylisopropyl amiloride neither activated the mito-K-ATP channel nor enhanced activation of this channel by diazoxide, a K-ATP channel opener. CONCLUSIONS Opening of the mito-K-ATP channel contributes to cardioprotection by NHE inhibition, though the interaction between NHE and this K-ATP channel remains unclear. (J Am Coil Cardiol 2001;37:957-63) (C) 2001 by the American College of Cardiology.