Involvement of superoxide and xanthine oxidase in neutrophil-independent rat gastric damage induced by NO donors.
1. Nitric oxide (NO) and the superoxide anion can interact to form the cytotoxic moiety, peroxynitrite. The involvement and potential source of superoxide in the gastric mucosal damage induced by local infusion of NO donors, has now been investigated in the pentobarbitone-anaesthetized rat. 2. Local intra-arterial infusion of the NO donor, sodium nitroprusside (40 micrograms kg-1 min-1) for 10 min induced macroscopically apparent gastric mucosal injury. 3. This mucosal damage was dose-dependently reduced by prior administration of a systemically acting form of superoxide dismutase conjugated with polyethylene glycol (500-2000 iu kg-1, i.v.). 4. Likewise, the mucosal damage induced by nitroprusside was dose-dependently reduced by prior administration of the xanthine oxidase inhibitor, allopurinol (20-100 mg kg-1, i.p. or 100 mg kg-1, p.o.). 5. Pretreatment with allopurinol (100 mg kg-1, i.p.) also reduced the mucosal injury induced by local intra-arterial infusion of the nitrosothiol, 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 specificity of action. 6. Prior administration (4h) of rabbit anti-rat neutrophil serum (0.4 ml kg-1, i.p.), which reduced circulating neutrophils by 90%, did not significantly protect against mucosal injury induced by nitroprusside. 7. Intravenous administration of the platelet-activating factor receptor antagonists, WEB 2086 (1 mg kg-1) or BN 52021 (10 mg kg-1), or the thromboxane synthase inhibitor, OKY 15181 (25 mg kg-1), did not modify mucosal damage induced by nitroprusside, showing lack of involvement of these neutrophil-derived mediators. 8. These findings indicate the involvement of superoxide in the injurious actions of the NO donors, implicating a cytotoxic role of peroxynitrite. Xanthine oxidase, but not neutrophils, appears to be a source of the superoxide.
Wellcome Foundation Ltd, Beckenham, Kent.
D
D
Lamarque
B J
BJ
Whittle
D000493:Allopurinol / Q000633:toxicity; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005753:Gastric Mucosa / Q000187:drug effects*; D008297:Male; D009566:Nitrates / Q000633:toxicity; D009569:Nitric Oxide / Q000633:toxicity*; D009599:Nitroprusside / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013482:Superoxide Dismutase / Q000633:toxicity; D013481:Superoxides / Q000494:pharmacology*; D019820:Xanthine; D014970:Xanthines / Q000494:pharmacology*
D009566:Nitrates; D014970:Xanthines; D013481:Superoxides; D009599:Nitroprusside; D019820:Xanthine; C039642:peroxynitric acid; D009569:Nitric Oxide; D000493:Allopurinol; D013482:Superoxide Dismutase