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

1 Effects of indomethacin, the selective cyclo-oxygenase (COX)-2 inhibitors NS-398 and DFU, and dexamethasone on gastric damage induced by 30 min isch aemia followed by 60 min reperfusion (I-R) were investigated in rats. Modul ation of gastric levels of COX-1 and COX-2 mRNA by I-R was evaluated using Northern blot and reverse transcription-polymerase chain reaction. 2 I-R-induced gastric damage was dose-dependently aggravated by administrat ion 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. 3 Likewise, administration of dexamethasone (1 mg kg(-1)) significantly inc reased I-R damage. 4 Low doses of 16,16-dimethyl-prostaglandin(PG)E-2, that did not protect ag ainst ethanol-induced mucosal damage, reversed the effects of the selective COX-2 inhibitors, indomethacin and dexamethasone. 5 I-R had no effect on gastric COX-I mRNA levels but increased COX-2 mRNA l evels in a time-dependent manner. Dexamethasone inhibited the I-R-induced e xpression of COX-2 mRNA. 6 I-R was not associated with a measurable increase in gastric mucosal form ation of 6-keto-PGF(1 alpha) and PGE(2). PG formation was substantially inh ibited 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)). 7 The findings indicate that selective COX-2 inhibitors and dexamethasone m arkedly enhance gastric damage induced by I-R. Thus, whereas COX-2 has no e ssential role in the maintenance of gastric mucosal integrity under basal c onditions, COX-2 is rapidly induced in a pro-ulcerogenic setting and contri butes to mucosal defence by minimizing injury. This suggests that in certai n situations selective COX-2 inhibitors may have gastrotoxic effects.