MITOCHONDRIAL ATP-DEPENDENT POTASSIUM CHANNELS - NOVEL EFFECTORS OF CARDIOPROTECTION

Background-Brief interruptions of coronary blood flow paradoxically pr otect the heart from subsequent prolonged ischemia. The basis of such endogenous cardioprotection, known as ''ischemic preconditioning,'' re mains uncertain. Pharmacological evidence has implicated ATP-dependent potassium (K-ATP) channels in the mechanism of preconditioning; howev er, the effects of sarcolemmal K-ATP channels on excitability cannot a ccount for the protection. Methods and Results-We simultaneously measu red flavoprotein fluorescence, an index of mitochondrial redox state, and sarcolemmal K-ATP currents in intact rabbit ventricular myocytes, Our results show that diazoxide, a K-ATP channel opener, selectively a ctivates mitochondrial K-ATP channels. Diazoxide induced reversible ox idation of flavoproteins with an EC,, of 27 mu mol/L but did not activ ate sarcolemmal K-ATP channels. The subcellular site of diazoxide acti on is further localized to mitochondria by confocal imaging of fluores cence arising from flavoproteins and tetramethylrhodamine ethyl eater, In a cellular model of simulated ischemia, inclusion of diazoxide dec reased the rate of cell death to about half of that in controls. Both the redox changes and protection are inhibited by the K-ATP channel bl ocker 5-hydroxydecanoic acid. Conclusions-Our results demonstrate that diazoxide targets mitochondrial but not sarcolemmal K-ATP channels an d imply that mitochondrial K-ATP channels may mediate the protection f rom K-ATP channel openers.