Role of oxygen-derived free radicals in indomethacin-induced gastric injury.
The role of oxygen-derived free radicals in the pathogenesis of acute gastric ulceration induced by indomethacin (Indo) was investigated in rats. Gastric damage was assessed by blood-to-lumen leakage of 51Cr-EDTA, as well as by measuring the extent of macroscopically visible hemorrhagic lesions. The stomach was perfused with isotonic saline for 30 min, followed by Indo (10 mg/ml for 30 min) and HCl (100 mM for 60 min). Rats were given a continuous intravenous infusion of the antioxidant enzymes superoxide dismutase (SOD) or catalase or the iron-chelating agent deferoxamine. Additional rats received an intravenous infusion of the vehicle (control group) or were pretreated with prostaglandin E2 (100 micrograms/kg ip) or allopurinol (50 mg/kg po). Exposure of the stomach to Indo caused a fourfold increase in 51Cr-EDTA leakage compared with that observed in rats receiving only the vehicle for Indo. Subsequent exposure of the stomach to HCl resulted in a further twofold increase in 51Cr-EDTA leakage. Treatment with SOD, catalase, or deferoxamine significantly (P less than 0.05) reduced 51Cr-EDTA leakage during the intragastric perfusion with Indo and during the subsequent exposure to HCl. Pretreatment with PGE2 reduced 51Cr-EDTA leakage during perfusion with HCl only. Pretreatment with allopurinol did not significantly affect 51Cr-EDTA leakage at any time during the experiment. In addition to reducing the leakage of 51Cr-EDTA into the gastric lumen, SOD, catalase, and PGE2 significantly reduced the extent of macroscopically visible mucosal damage (P less than 0.05). These results support the hypothesis that oxygen-derived free radicals, probably derived from neutrophils, contribute to the pathogenesis of Indo-induced ulceration.
Vaananen
P M
PM
Gastrointestinal Research Group, University of Calgary, Alberta, Canada.
Meddings
J B
JB
Wallace
J L
JL
D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D002374:Catalase / Q000494:pharmacology; D002860:Chromium Radioisotopes; D003676:Deferoxamine / Q000494:pharmacology; D016166:Free Radical Scavengers; D005609:Free Radicals; D005753:Gastric Mucosa / Q000187:drug effects / Q000503:physiopathology*; D006851:Hydrochloric Acid / Q000633:toxicity; D007213:Indomethacin / Q000633:toxicity*; D008297:Male; D010100:Oxygen / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D013276:Stomach Ulcer / Q000139:chemically induced / Q000503:physiopathology*; D013482:Superoxide Dismutase / Q000494:pharmacology
D002860:Chromium Radioisotopes; D016166:Free Radical Scavengers; D005609:Free Radicals; D000493:Allopurinol; D002374:Catalase; D013482:Superoxide Dismutase; D003676:Deferoxamine; D006851:Hydrochloric Acid; D010100:Oxygen; D007213:Indomethacin