NSAID-induced gastric damage in rats: Requirement for inhibition of both cyclooxygenase 1 and 2

Background & Aims: Selective cyclooxygenase (COX)-2 inhibitors produce less gastric damage than conventional nonsteroidal anti-inflammatory drugs (NSA IDs), suggesting that NSAIDs cause damage by inhibiting COX-1. We tested th is hypothesis in rats by using a selective COX-1 inhibitor (SC-560). Method s: The effects of SC-560, celecoxib (selective COX-2 inhibitor), or a combi nation of both inhibitors on gastric damage and prostaglandin synthesis wer e determined. Selectivity of the drugs for COX-1 vs. COX-2 was assessed in the carrageenan-airpouch model. A COX-1-preferential inhibitor, ketorolac, was also evaluated. The effects of these inhibitors on leukocyte adherence to vascular endothelium and on gastric blood flow were assessed, Results: S C-560 markedly reduced gastric prostaglandin synthesis and platelet COX-1 a ctivity, but spared COX-2 and did not cause gastric damage. Celecoxib did n ot affect gastric prostaglandin E-2 synthesis and did not cause gastric dam age. However, the combination of SC-560 and celecoxib invariably caused hem orrhagic erosion formation, comparable to that seen with indomethacin, Keto rolac caused damage only at doses that inhibited both COX isoforms, or when given with a COX-2 inhibitor. Celecoxib, but not SC-560, significantly inc reased leukocyte adherence, whereas SC-560, but not celecoxib, reduced gast ric blood flow. Conclusions: Inhibition of both COX-1 and COX-2 is required for NSAID-induced gastric injury in the rat.