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

OBJECTIVES To determine the mechanism of cardioprotection afforded by nicor andil, an orally efficacious antianginal drug, we examined its effects on A TP-dependent potassium (K-ATP) channels. BACKGROUND Nicorandil can mimic ischemic preconditioning, while mitochondri al 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 ven tricular myocytes were measured simultaneously to assay mitoK(ATP) channel and surface K-ATP channel activities, respectively. In a cell-pelleting mod el 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(AT P) and surfaceK(ATP) channels. Pooled dose-response data confirm that nicor andil 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 ischemi a; this cardioprotective effect was prevented by the mitoK(ATP) channel blo cker 5-hydroxydecanoate but was unaffected by the surfaceK(ATP) channel blo cker HMR1098. CONCLUSIONSNicorandil exerts a direct cardioprotective effect on heart musc le 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 Car diology.