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

Toshiaki Sato, Norihito Sasaki, Brian O'Rourke, Eduardo Marbán

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)514-518
Number of pages5
JournalJournal of the American College of Cardiology
Volume35
Issue number2
DOIs
StatePublished - 2000

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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