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

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)1505-1512
Number of pages8
JournalJournal of Molecular and Cellular Cardiology
Volume35
Issue number12
DOIs
Publication statusPublished - 01-01-2003
Externally publishedYes

Fingerprint

Nicorandil
KATP Channels
Cardiac Myocytes
Nitrates
Oxidative Stress
Apoptosis
Caspase 9
Caspase 3
Muscle Cells
S-Nitroso-N-Acetylpenicillamine
Cyclic GMP-Dependent Protein Kinases
Cytoprotection
Nitric Oxide Donors
DNA Nucleotidylexotransferase
Mitochondrial Membrane Potential
Dithiothreitol
Enzyme Assays
DNA Fragmentation
Cytochromes c
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

Nagata, Kohzo ; Obata, Koji ; Odashima, Mari ; Yamada, Akira ; Somura, Fuji ; Nishizawa, Takao ; Ichihara, Sahoko ; Izawa, Hideo ; Iwase, Mitsunori ; Hayakawa, Akemi ; Murohara, Toyoaki ; Yokota, Mitsuhiro. / Nicorandil inhibits oxidative stress-induced apoptosis in cardiac myocytes through activation of mitochondrial ATP-sensitive potassium channels and a nitrate-like effect. In: Journal of Molecular and Cellular Cardiology. 2003 ; Vol. 35, No. 12. pp. 1505-1512.
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Nicorandil inhibits oxidative stress-induced apoptosis in cardiac myocytes through activation of mitochondrial ATP-sensitive potassium channels and a nitrate-like effect. / Nagata, Kohzo; Obata, Koji; Odashima, Mari; Yamada, Akira; Somura, Fuji; Nishizawa, Takao; Ichihara, Sahoko; Izawa, Hideo; Iwase, Mitsunori; Hayakawa, Akemi; Murohara, Toyoaki; Yokota, Mitsuhiro.

In: Journal of Molecular and Cellular Cardiology, Vol. 35, No. 12, 01.01.2003, p. 1505-1512.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Nicorandil inhibits oxidative stress-induced apoptosis in cardiac myocytes through activation of mitochondrial ATP-sensitive potassium channels and a nitrate-like effect

AU - Nagata, Kohzo

AU - Obata, Koji

AU - Odashima, Mari

AU - Yamada, Akira

AU - Somura, Fuji

AU - Nishizawa, Takao

AU - Ichihara, Sahoko

AU - Izawa, Hideo

AU - Iwase, Mitsunori

AU - Hayakawa, Akemi

AU - Murohara, Toyoaki

AU - Yokota, Mitsuhiro

PY - 2003/1/1

Y1 - 2003/1/1

N2 - 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.

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