Mitochondrial ATP dependent potassium channels and ischemic preconditioning

Ischemic preconditioning is a phenomenon in which brief episodes of myocardial ischemia interspersed with reperfusion render the heart remarkably resistant to the injury produced by a subsequent prolonged ischemia and reperfusion. This adaptive response has been demonstrated in various species including humans. Accumulated evidence shows that adenosine receptors, protein kinase C (PKC), and ATP dependent potassium (K(ATP)) channels form the signal transduction pathway for cardioprotection. Recent studies divorced protection from sarcolemmal (surfaceK(ATP)) channels' effect on excitability. K(ATP) channels also exist in mitochondrial inner membrane (mitoK(ATP)). By simultaneously measuring flavoprotein fluorescence, an index of mitochondrial redox state, and surfaceK(ATP) currents in intact rabbit ventricular myocytes, we show that diazoxide selectively opens mitoK(ATP) channels while having no effect on surfaceK(ATP) channels. Diazoxide protects ischemic cardiac myocytes; such protection is blocked by a selective mitoK(ATP) channel blocker suggesting that mitoK(ATP) channels are responsible for cardioprotection. Recognition of this role of mitoK(ATP) channels identifies a promising new target for the development of cardioprotective drugs and implicates the mitochondria in the process of lethal ischemic injury.