Abstract
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.
MeSH terms
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Animals
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Blood Pressure / drug effects
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Catalase / administration & dosage
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Catalase / pharmacology
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Catalase / therapeutic use
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Deferoxamine / administration & dosage
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Deferoxamine / pharmacology
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Deferoxamine / therapeutic use
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Disease Models, Animal
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Drug Overdose
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Drug Synergism
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Endothelins / administration & dosage
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Endothelins / toxicity
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Free Radical Scavengers / administration & dosage
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Free Radical Scavengers / pharmacology*
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Free Radical Scavengers / therapeutic use
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Gastric Mucosa / drug effects*
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Gastric Mucosa / pathology
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Infusions, Intra-Arterial
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Infusions, Intravenous
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Male
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Nitrates / metabolism
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Nitric Oxide / metabolism
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Nitroprusside / administration & dosage
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Nitroprusside / toxicity*
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Penicillamine / administration & dosage
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Penicillamine / analogs & derivatives*
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Penicillamine / toxicity
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Rats
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Rats, Wistar
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Reactive Oxygen Species / adverse effects*
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S-Nitroso-N-Acetylpenicillamine
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Stomach Ulcer / chemically induced
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Stomach Ulcer / drug therapy
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Superoxide Dismutase / administration & dosage
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Superoxide Dismutase / pharmacology
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Superoxide Dismutase / therapeutic use
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Thiourea / administration & dosage
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Thiourea / analogs & derivatives
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Thiourea / pharmacology
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Thiourea / therapeutic use
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Vasodilator Agents / administration & dosage
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Vasodilator Agents / toxicity*
Substances
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Endothelins
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Free Radical Scavengers
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Nitrates
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Reactive Oxygen Species
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Vasodilator Agents
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Nitroprusside
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peroxynitric acid
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Nitric Oxide
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S-Nitroso-N-Acetylpenicillamine
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1,3-dimethylthiourea
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Catalase
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Superoxide Dismutase
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Penicillamine
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Thiourea
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Deferoxamine