Selective cyclo‐oxygenase‐2 inhibitors aggravate ischaemia‐reperfusion injury in the rat stomach

Effects of indomethacin, the selective cyclo‐oxygenase (COX)‐2 inhibitors NS‐398 and DFU, and dexamethasone on gastric damage induced by 30 min ischaemia followed by 60 min reperfusion (I‐R) were investigated in rats. Modulation of gastric levels of COX‐1 and COX‐2 mRNA by I‐R was evaluated using Northern blot and reverse transcription‐polymerase chain reaction. I‐R‐induced gastric damage was dose‐dependently aggravated by administration of indomethacin (1–10 mg kg −1 ), NS‐398 (0.4–4 mg kg −1 ) or DFU (0.02–2 mg kg −1 ) as assessed macroscopically and histologically. Likewise, administration of dexamethasone (1 mg kg −1 ) significantly increased I‐R damage. Low doses of 16,16‐dimethyl‐prostaglandin(PG)E 2 , that did not protect against ethanol‐induced mucosal damage, reversed the effects of the selective COX‐2 inhibitors, indomethacin and dexamethasone. I‐R had no effect on gastric COX‐1 mRNA levels but increased COX‐2 mRNA levels in a time‐dependent manner. Dexamethasone inhibited the I‐R‐induced expression of COX‐2 mRNA. I‐R was not associated with a measurable increase in gastric mucosal formation of 6‐keto‐PGF 1α and PGE 2 . PG formation was substantially inhibited by indomethacin (10 mg kg −1 ) but was not significantly reduced by NS‐398 (4 mg kg −1 ), DFU (2 mg kg −1 ) or dexamethasone (1 mg kg −1 ). The findings indicate that selective COX‐2 inhibitors and dexamethasone markedly enhance gastric damage induced by I‐R. Thus, whereas COX‐2 has no essential role in the maintenance of gastric mucosal integrity under basal conditions, COX‐2 is rapidly induced in a pro‐ulcerogenic setting and contributes to mucosal defence by minimizing injury. This suggests that in certain situations selective COX‐2 inhibitors may have gastrotoxic effects.British Journal of Pharmacology (1999) 128 , 1659–1666; doi: 10.1038/sj.bjp.0702966