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 (KATP) channels. BACKGROUND Nicorandil can mimic ischemic preconditioning, while mitochondrial KATP(mitoKATP) channels rather than sarcolemmal KATP(surfaceKATP) channels have emerged as the likely effectors. METHODS Flavoprotein fluorescence and membrane current in intact rabbit ventricular myocytes were measured simultaneously to assay mitoKATPchannel and surface KATPchannel 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 μmol/liter) increased flavoprotein oxidation but not membrane current; a 10-fold higher concentration recruits both mitoKATPand surfaceKATPchannels. Pooled dose-response data confirm that nicorandil concentrations as low as 10 μmol/liter turn on mitoKATPchannels, while surfaceKATPcurrent 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 mitoKATPchannel blocker 5-hydroxydecanoate but was unaffected by the surfaceKATPchannel blocker HMR1098. CONCLUSIONS Nicorandil exerts a direct cardioprotective effect on heart muscle cells, an effect mediated by selective activation of mitoKATPchannels.