Nicorandil enhances the effect of endothelial nitric oxide under hypoxia-reoxygenation: role of the KATP channel.
Nicorandil increased the anti-platelet aggregation activity of endothelial cells when endothelial cells were exposed to hypoxia-reoxygenation conditions. However, nicorandil (0.1-10 muM) did not inhibit platelet aggregation directly. The mechanism by which nicorandil increases the anti-aggregation activity of hypoxia-reoxygenation treated endothelial cells was investigated. The effect of nicorandil was observed even in indomethacin-treated endothelial cells, but the effect was eliminated by treating endothelial cells with N(G)-nitro-l-arginine methyl ester (L-NAME). This indicates that nicorandil enhances the anti-aggregation activity of endothelial nitric oxide (NO). Nicorandil did not increase the anti-aggregation activity of endothelial NO when endothelial cells were pre-treated with superoxide dismutase or 4-(2-aminophenyl)-benzenesulfonyl fluoride, an inhibitor of NADPH oxidase. Nicorandil dose-dependently inhibited the reactive oxygen species generation induced by an oxidative stress in endothelial cells. The effect of nicorandil on anti-aggregation activity was abrogated by glibenclamide, an ATP-sensitive potassium (K(ATP)) channel blocker. Pinacidil, a K(ATP) channel opener, also enhanced the anti-aggregation activity of endothelial NO. This effect was similarly abrogated by glibenclamide. These results suggest that nicorandil may inhibit the generation of superoxide (O(2)(-)) from hypoxia-reoxygenation treated endothelial cells through activation of the K(ATP) channel, and that nicorandil may prevent the disappearance of endothelial NO by O(2)(-).
Division of Pharmacology, Department of Diagnostic and Therapeutic Sciences, Meikai University School of Dentistry, Sakado, Saitama 350-0283, Japan. mtajima@dent.meikai.ac.jp
Masamichi
M
Tajima
Nobuhiko
N
Ishizuka
Keiji
K
Saitoh
Hiroshi
H
Sakagami
D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000494:pharmacology*; D015687:Cell Hypoxia; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D020108:Nicorandil / Q000008:administration & dosage / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism*; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors; D013481:Superoxides / Q000378:metabolism; D014471:Umbilical Veins
D000889:Anti-Arrhythmia Agents; D015221:Potassium Channels; D017382:Reactive Oxygen Species; C117780:mitochondrial K(ATP) channel; D013481:Superoxides; D020108:Nicorandil; D009569:Nitric Oxide; D010100:Oxygen