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

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      Journal of the American College of Cardiology
      Elsevier BV

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          Abstract

          We examined whether nicorandil, a clinically useful drug for the treatment of ischemic syndromes, inhibits myocardial apoptosis. Nicorandil has been reported to have a cardioprotective action through activation of mitochondrial ATP-sensitive potassium (mitoK(ATP)) channels. Based on our recent observation that mitoK(ATP) 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. Cultured neonatal rat cardiac myocytes were exposed to hydrogen peroxide to induce apoptosis. Effects of nicorandil were evaluated using a number of apoptotic markers. Exposure to 100 microM 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 (Delta(Psi)(m)). Nicorandil (100 microM) suppressed all of these markers of apoptosis. Notably, nicorandil prevented Delta(Psi)(m) depolarization in a concentration-dependent manner (EC(50) approximately 40 microM, with saturation by 100 microM), as shown by fluorescence-activated cell sorter analysis of cells stained with a fluorescent Delta(Psi)(m)-indicator, tetramethylrhodamine ethyl ester (TMRE). Time-lapse confocal microscopy of individual cells loaded with TMRE shows that nicorandil suppresses Delta(Psi)(m) loss. Subcellular calcein localization revealed inhibition of the mitochondrial permeability transition by nicorandil. These protective effects of nicorandil were blocked by the mitoK(ATP) channel antagonist 5-hydroxydecanoate. Our findings identify nicorandil as an inhibitor of apoptosis induced by oxidative stress in cardiac myocytes, and confirm the critical role of mitoK(ATP) channels in inhibiting apoptosis.

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          Author and article information

          Journal
          Journal of the American College of Cardiology
          Journal of the American College of Cardiology
          Elsevier BV
          07351097
          August 2002
          August 2002
          : 40
          : 4
          : 803-810
          Article
          10.1016/S0735-1097(02)02007-7
          12204514
          be816422-31c9-4e23-aa7b-0970fa870f2d
          © 2002

          https://www.elsevier.com/tdm/userlicense/1.0/

          https://www.elsevier.com/open-access/userlicense/1.0/

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