TY - JOUR
T1 - Nicorandil, a potent cardioprotective agent, acts by opening mitochondrial ATP-dependent potassium channels
AU - Sato, Toshiaki
AU - Sasaki, Norihito
AU - O'Rourke, Brian
AU - Marbán, Eduardo
PY - 2000
Y1 - 2000
N2 - 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 effectors. 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 μmol/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 μmol/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. CONCLUSIONS: Nicorandil exerts a direct cardioprotective effect on heart muscle cells, an effect mediated by selective activation of mitoK(ATP) channels. (C) 2000 by the American College of Cardiology.
AB - 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 effectors. 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 μmol/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 μmol/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. CONCLUSIONS: Nicorandil exerts a direct cardioprotective effect on heart muscle cells, an effect mediated by selective activation of mitoK(ATP) channels. (C) 2000 by the American College of Cardiology.
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U2 - 10.1016/S0735-1097(99)00552-5
DO - 10.1016/S0735-1097(99)00552-5
M3 - Article
C2 - 10676702
AN - SCOPUS:0034048933
SN - 0735-1097
VL - 35
SP - 514
EP - 518
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
IS - 2
ER -