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 mu g 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 mu g 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.