Nicorandil enhances the effect of endothelial nitric oxide under hypoxia-reoxygenation: role of the KATP channel.

Abstract

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)(-).

• Authors: Masamichi Tajima, Nobuhiko Ishizuka, Keiji Saitoh, Hiroshi Sakagami
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 579 Issue 1-3 Pg. 86-92 (Jan 28 2008) ISSN: 0014-2999 [Print] Netherlands
• PMID: 18045588 (Publication Type: Journal Article)

Chemical References

• Anti-Arrhythmia Agents
• Potassium Channels
• Reactive Oxygen Species
• mitochondrial K(ATP) channel
• Superoxides
• Nicorandil
• Nitric Oxide
• Oxygen

Topics

• Anti-Arrhythmia Agents (administration & dosage, pharmacology)
• Cell Hypoxia
• Cells, Cultured
• Dose-Response Relationship, Drug
• Endothelial Cells (drug effects, metabolism)
• Humans
• Nicorandil (administration & dosage, pharmacology)
• Nitric Oxide (metabolism)
• Oxidative Stress
• Oxygen (metabolism)
• Platelet Aggregation (drug effects)
• Potassium Channels (drug effects, metabolism)
• Reactive Oxygen Species (antagonists & inhibitors)
• Superoxides (metabolism)
• Umbilical Veins