Nicorandil, a potent cardioprotective agent, acts by opening mitochondrial ATP-dependent potassium channels

OBJECTIVES To determine the mechanism of cardioprotection afforded by nicorandil, an orally efficacious antianginal drug, we examined its effects on ATP-dependent potassium (K-ATP) channels. BACKGROUND Nicorandil can mimic ischemic preconditioning, while mitochondrial K-ATP (mitoK(ATP)) channels rather than sarcolemmal K-ATP (surfaceK(ATP)) channels have emerged as the likely effecters. METHODS Flavoprotein fluorescence and membrane current in intact rabbit ventricular myocytes were measured simultaneously to assay mitoK(ATP) channel and surface K-ATP channel activities, respectively. In a cell-pelleting model of ischemia, cells permeable to trypan blue were counted as killed by 60 and 120 min of ischemia. RESULTS Nicorandil (100 mu mol/liter) increased flavoprotein oxidation but not membrane current; a 10-fold higher concentration recruits both mitoK(ATP) and surfaceK(ATP) channels. Pooled dose-response data confirm that nicorandil concentrations as low as 10 mu mol/liter turn on mitoK(ATP) channels, while surfaceK(ATP) current requires exposure to millimolar concentrations. Nicorandil blunted the rate of cell death in a pelleting model of ischemia; this cardioprotective effect was prevented by the mitoK(ATP) channel blocker 5-hydroxydecanoate but was unaffected by the surfaceK(ATP) channel blocker HMR1098. CONCLUSIONSNicorandil exerts a direct cardioprotective effect on heart muscle cells, an effect mediated by selective activation of mitoK(ATP) channels. (J Am Coil Cardiol 2000;35:514-8) (C) 2000 by the American College of Cardiology.