Role of cytoprotectants and nitric oxide inhibition in nonsteroidal anti-inflammatory drug-induced gastroduodenal injury in the rat.
OBJECTIVE
Nonsteroidal anti-inflammatory drugs (NSAIDs) induce gastroduodenal injury and ulceration. The pathogenesis is uncertain, although reductions in cytoprotective prostaglandins and nitric oxide (NO) have been proposed. The effects of several cytoprotective agents on inhibition of gastroduodenal ulcerogenesis induced by CI-987, a novel NSAID, were evaluated in Wistar rats.


METHODS
Male Wistar rats were given CI-987 orally (p.o.) at a dosage of 300 or 450 mg/kg of body weight or subcutaneously (s.c.) (3 x 50 mg/kg), alone or with misoprostol pretreatment (2 x 1 mg/kg, p.o.). In a second experiment, rats were pre-treated with 2 ml of gelusil p.o., 500 mg of sucralfate/kg, p.o., 100 mg of ranitidine/kg s.c., or 200 mg of N omega-nitro-L-arginine methyl ester (L-NAME)/kg, s.c.. Duodenal injury was induced by administration of 450 mg of CI-987/kg, p.o., 3 x 50 mg of CI-987/kg, s.c., or 300 mg of cysteamine/kg, s.c. Animals were euthanized within 24 to 48 hours, and the gastrointestinal tract was examined for evidence of gross or microscopic change.


RESULTS
The L-NAME significantly reduced the incidence and severity of gastroduodenal injury induced by CI-987 and cysteamine. Prostaglandin ameliorated duodenal lesions induced by CI-987 given s.c., and Gelusil, ranitidine, and sucralfate were without effect on duodenal lesions induced by NSAID.


CONCLUSIONS
Preemptive blockade of NO synthase is important in preventing NSAID-induced duodenal injury in rats. Inhibition of cytoprotective prostaglandins and enhanced acid-induced damage are unlikely to be primary mechanisms underlying NSAID-induced duodenal injury in rats.
Turner
P V
PV
Parke-Davis Research Institute, Mississauga, Ontario, Canada.
Albassam
M A
MA
Percy
D H
DH
Lillie
L E
LE
Macallum
G E
GE
D000284:Administration, Oral; D000527:Alprostadil / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000863:Antacids / Q000008:administration & dosage; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D016861:Cyclooxygenase Inhibitors; D003543:Cysteamine / Q000008:administration & dosage; D019610:Cytoprotection; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D007279:Injections, Subcutaneous; D008297:Male; D016595:Misoprostol / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage; D009569:Nitric Oxide / Q000037:antagonists & inhibitors*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010636:Phenols; D011899:Ranitidine / Q000008:administration & dosage; D051381:Rats; D017208:Rats, Wistar; D013392:Sucralfate / Q000008:administration & dosage; D013844:Thiazoles
D000863:Antacids; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000897:Anti-Ulcer Agents; C410126:CI 987; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D010636:Phenols; D013844:Thiazoles; D016595:Misoprostol; D009569:Nitric Oxide; D013392:Sucralfate; D003543:Cysteamine; D011899:Ranitidine; D019001:Nitric Oxide Synthase; D000527:Alprostadil; D019331:NG-Nitroarginine Methyl Ester