thiourea and Drug-Overdose

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.

Topics: Animals; Blood Pressure; Catalase; Deferoxamine; Disease Models, Animal; Drug Overdose; Drug Synergism; Endothelins; Free Radical Scavengers; Gastric Mucosa; Infusions, Intra-Arterial; Infusions, Intravenous; Male; Nitrates; Nitric Oxide; Nitroprusside; Penicillamine; Rats; Rats, Wistar; Reactive Oxygen Species; S-Nitroso-N-Acetylpenicillamine; Stomach Ulcer; Superoxide Dismutase; Thiourea; Vasodilator Agents