Antiapoptotic effect of nicorandil mediated by mitochondrial ATP-sensitive potassium channels in cultured cardiac myocytes

Masaharu Akao, Yasushi Teshima, Eduardo Marbán

Research output: Contribution to journalArticle

Abstract

OBJECTIVES: We examined whether nicorandil, a clinically useful drug for the treatment of ischemic syndromes, inhibits myocardial apoptosis. BACKGROUND: Nicorandil has been reported to have a cardioprotective action through activation of mitochondrial ATP-sensitive potassium (mitoKATP) channels. Based on our recent observation that mitoKATP channel activation has a remarkable antiapoptotic effect in cultured cardiac cells, we hypothesized that the protective effects of nicorandil may be at least partially due to an antiapoptotic effect. METHODS: Cultured neonatal rat cardiac myocytes were exposed to hydrogen peroxide to induce apoptosis. Effects of nicorandil were evaluated using a number of apoptotic markers. RESULTS: Exposure to 100 μM hydrogen peroxide resulted in apoptotic cell death as shown by TUNEL positivity, cytochrome c translocation, caspase-3 activation and dissipation of mitochondrial inner membrane potential (ΔΨm). Nicorandil (100 μM) suppressed all of these markers of apoptosis. Notably, nicorandil prevented ΔΨm depolarization in a concentration-dependent manner (EC50 ∼ 40 μM, with saturation by 100 μM), as shown by fluorescence-activated cell sorter analysis of cells stained with a fluorescent ΔΨm-indicator, tetramethylrhodamine ethyl ester (TMRE). Time-lapse confocal microscopy of individual cells loaded with TMRE shows that nicorandil suppresses ΔΨm loss. Subcellular calcein localization revealed inhibition of the mitochondrial permeability transition by nicorandil. These protective effects of nicorandil were blocked by the mitoKATP channel antagonist 5-hydroxydecanoate. CONCLUSIONS: Our findings identify nicorandil as an inhibitor of apoptosis induced by oxidative stress in cardiac myocytes, and confirm the critical role of mitoKATP channels in inhibiting apoptosis.

Original languageEnglish (US)
Pages (from-to)803-810
Number of pages8
JournalJournal of the American College of Cardiology
Volume40
Issue number4
DOIs
StatePublished - Aug 21 2002

ASJC Scopus subject areas

  • Nursing(all)

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