Role of oxygen-derived metabolites in the rat gastric mucosal injury induced by nitric oxide donors.
Local intra-arterial infusion of high doses of the nitric oxide (NO) donor, nitroprusside (10-40 micrograms kg-1 min-1 for 15 min) induced dose-dependent haemorrhagic injury to the rat gastric mucosa and reduced systemic arterial blood pressure, whereas intragastric nitroprusside (10-50 mg ml-1), which caused similar falls in blood pressure, failed to induce such injury. The mucosal damage induced by nitroprusside was reduced by local concurrent infusion of superoxide dismutase (500-4000 i.u. kg-1). Local superoxide dismutase also abolished the mucosal injury induced by local infusion of the NO donor, S-nitroso-N-acetyl-penicillamine (40 micrograms kg-1 min-1), but not that induced by local infusion of endothelin-1 (5 pmol kg-1 min-1) indicating specific actions. Intravenous infusion of the iron chelator and peroxyl scavenger, desferrioxamine (0.25-1 mg kg-1 min-1) or the hydroxyl radical scavenger, dimethylthiourea (20 mg kg-1 min-1) also reduced the mucosal damage induced by the local administration of the NO donors, but not that induced by endothelin-1. These findings implicate the involvement of superoxide and possibly other oxygen-derived free radicals in the injurious actions of high levels of nitric oxide generated from NO donors, and may reflect a role of the cytotoxic peroxynitrite moiety.
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002374:Catalase / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D003676:Deferoxamine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D062787:Drug Overdose; D004357:Drug Synergism; D016232:Endothelins / Q000008:administration & dosage / Q000633:toxicity; D016166:Free Radical Scavengers / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D005753:Gastric Mucosa / Q000187:drug effects* / Q000473:pathology; D007261:Infusions, Intra-Arterial; D007262:Infusions, Intravenous; D008297:Male; D009566:Nitrates / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D009599:Nitroprusside / Q000008:administration & dosage / Q000633:toxicity*; D010396:Penicillamine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000009:adverse effects*; D026423:S-Nitroso-N-Acetylpenicillamine; D013276:Stomach Ulcer / Q000139:chemically induced / Q000188:drug therapy; D013482:Superoxide Dismutase / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D013890:Thiourea / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000633:toxicity*
D016232:Endothelins; D016166:Free Radical Scavengers; D009566:Nitrates; D017382:Reactive Oxygen Species; D014665:Vasodilator Agents; D009599:Nitroprusside; C039642:peroxynitric acid; D009569:Nitric Oxide; D026423:S-Nitroso-N-Acetylpenicillamine; C038983:1,3-dimethylthiourea; D002374:Catalase; D013482:Superoxide Dismutase; D010396:Penicillamine; D013890:Thiourea; D003676:Deferoxamine