Nicorandil, a potent cardioprotective agent, acts by opening mitochondrial ATP-dependent potassium channels.
OBJECTIVE
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 micromol/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 micromol/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.
Sato
T
T
Institute of Molecular Cardiobiology, Johns Hopkins University, Baltimore, Maryland 21205, USA.
Sasaki
N
N
O'Rourke
B
B
Marbán
E
E
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D005420:Flavoproteins; D005453:Fluorescence; D006352:Heart Ventricles / Q000473:pathology; D008929:Mitochondria, Heart / Q000187:drug effects*; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D020108:Nicorandil / Q000494:pharmacology*; D015221:Potassium Channels / Q000378:metabolism*; D011817:Rabbits; D014665:Vasodilator Agents / Q000494:pharmacology*
D005420:Flavoproteins; D015221:Potassium Channels; D014665:Vasodilator Agents; D020108:Nicorandil; D000255:Adenosine Triphosphate