Nicorandil inhibits oxidative stress-induced apoptosis in cardiac myocytes through activation of mitochondrial ATP-sensitive potassium channels and a nitrate-like effect

Kohzo Nagata, Koji Obata, Mari Odashima, Akira Yamada, Fuji Somura, Takao Nishizawa, Sahoko Ichihara, Hideo Izawa, Mitsunori Iwase, Akemi Hayakawa, Toyoaki Murohara, Mitsuhiro Yokota

研究成果: Article査読

48 被引用数 (Scopus)

抄録

The anti-anginal drug nicorandil has been shown to inhibit apoptosis by activating mitochondrial ATP-sensitive potassium (KATP) channels. The possible contribution of the nitrate moiety of this drug to its anti-apoptotic effect has now been investigated in neonatal rat ventricular myocytes subjected to oxidative stress. Exposure of cultured myocytes to 100 μmol/l hydrogen peroxide (H2O2) increased the number of nuclei stained by the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling technique as well as induced internucleosomal DNA fragmentation, loss of mitochondrial membrane potential, cytochrome c release into the cytosol, and activation of caspases-3 and -9, all of which are characteristics of apoptosis. Pretreatment of cells with nicorandil (100 μmol/l) inhibited these effects of H2O2. Both the mitochondrial KATP channel antagonist 5-hydroxydecanoate (5-HD) and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), an inhibitor of soluble guanylyl cyclase, attenuated the anti-apoptotic effect of nicorandil in concentration-dependent manners. Coapplication of ODQ (10 μmol/l) and 5-HD (500 μmol/l) completely abolished nicorandil-induced cytoprotection. The effect of nicorandil was also reduced by an inhibitor of cGMP-dependent protein kinase (KT5823, 1 μmol/l). The nitric oxide donor (±)-S-nitroso-N- acetylpenicillamine (SNAP, 50 μmol/l) mimicked the protective effect of nicorandil in a manner sensitive to ODQ but not to 5-HD. A cell-permeable cGMP analog, 8-bromo-cGMP, also reduced H2O2-induced apoptosis. The inhibition of the H2O2-induced activation of caspase-3, but not that of caspase-9, by nicorandil in the presence of 5-HD or by SNAP was reversed by the addition of dithiothreitol to the enzyme assay. Nicorandil inhibits oxidative stress-induced apoptosis in cardiac myocytes through a nitric oxide/cGMP-dependent mechanism as well as by activating mitochondrial KATP channels.

本文言語English
ページ(範囲)1505-1512
ページ数8
ジャーナルJournal of Molecular and Cellular Cardiology
35
12
DOI
出版ステータスPublished - 12-2003

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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