Relationship of gastric mucosal damage induced in pigs by antiinflammatory drugs to their effects on prostaglandin production.
Experiments were performed in pigs to examine the relationship between the effects of various nonsteroid antiinflammatory drugs on gastric (fundic) mucosal content of prostaglandin (PG)E2 and 6-keto-PGF1 alpha, and the development of damage to the fundic mucosa under acute and chronic dosage conditions. Oral administration of a single dose of indomethacin (5 mg/kg) caused an almost immediate reduction in mucosal potential difference, followed at 5-15 min by ultrastructurally observed damage to mucosal capillaries, mucous, and parietal cells; efflux of Na+, K+, and Cl- ions into the gastric lumen with an apparent loss of luminal H+ ions; and a statistically significant reduction (from 10-60 min) in fundic prostaglandin content. Thus, under acute dosage conditions, development of mucosal damage by indomethacin was paralleled by the reduction in prostaglandin production. Repeated oral dosage of aspirin, indomethacin, sulindac, or diclofenac to pigs for 10 days significantly reduced gastric mucosal as well as plasma prostaglandin levels, coincident with the development of severe gastric mucosal damage. The relatively less irritant drugs, flufenamic acid, azapropazone, and fenclofenac, failed to significantly decrease gastric mucosal content of prostaglandins, although these drugs have been reported to inhibit prostaglandin synthesis in vitro and also were found to reduce the prostaglandin plasma levels in animals receiving these drugs. Another drug with low irritancy, meseclazone, markedly decreased both mucosal and plasma levels of prostaglandins. The results show that while ulcerogenic drugs reduce the mucosal and plasma prostaglandins levels in parallel with their ulcerogenicity, this relationship does not always hold for drugs with low ulcerogenic activity.
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D015232:Dinoprostone; D004305:Dose-Response Relationship, Drug; D005260:Female; D005753:Gastric Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D006863:Hydrogen-Ion Concentration; D007213:Indomethacin / Q000494:pharmacology; D011453:Prostaglandins / Q000096:biosynthesis* / Q000097:blood; D011458:Prostaglandins E / Q000096:biosynthesis; D011460:Prostaglandins F / Q000096:biosynthesis; D013552:Swine
D000893:Anti-Inflammatory Agents; D011453:Prostaglandins; D011458:Prostaglandins E; D011460:Prostaglandins F; D015232:Dinoprostone; C100006:prostaglandin F1; D007213:Indomethacin