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J Am Coll Cardiol, 2000; 35:514-518
© 2000 by the American College of Cardiology Foundation
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CLINICAL STUDIES

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

Toshiaki Sato, MD, PhDa,1, Norihito Sasaki, MD, PhDa, Brian O’Rourke, PhDa and Eduardo Marbán, MD, PhD, FACCa

a Institute of Molecular Cardiobiology, Johns Hopkins University, Baltimore, Maryland, USA

Manuscript received May 24, 1999; revised manuscript received September 10, 1999, accepted October 21, 1999.

Reprint requests and correspondence: Dr. Eduardo Marbán, Institute of Molecular Cardiobiology, Johns Hopkins University, Ross 844/720 Rutland Avenue, Baltimore, Maryland 21205
marban{at}jhmi.edu

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 mitoKATP channel and surface KATP 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 mitoKATP and surfaceKATP channels. Pooled dose-response data confirm that nicorandil concentrations as low as 10 µmol/liter turn on mitoKATP channels, while surfaceKATP 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 mitoKATP channel blocker 5-hydroxydecanoate but was unaffected by the surfaceKATP channel blocker HMR1098.

CONCLUSIONS

Nicorandil exerts a direct cardioprotective effect on heart muscle cells, an effect mediated by selective activation of mitoKATP channels.

Abbreviations and Acronyms
  5HD = 5-hydroxydecanoate
  CONT = control group
  DNP = 2,4-dinitrophenol
  IK,ATP = surfaceKATP current
  IPC = ischemic preconditioning
  KATP = ATP-dependent potassium
  mitoKATP = mitochondrial KATP
  NICO = nicorandil-treated group
  surfaceKATP = sarcolemmal KATP




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