Interaction of cyclooxygenase-2 inhibitors and salicylate in gastric mucosal damage

Abstract

The interactions of sodium salicylate and the selective cyclooxygenase-2 inhibitors N-{2-(cyclohexyloxy)-4-nitrophenyl}-methanesulfonamide (NS-398) and 5.5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl-2(5II)-furanone (DFU), dexamethasone and the nitric oxide (NO) synthase inhibitor N G-nitro- l-arginine methylester ( l-NAME) were examined in ischaemia–reperfusion damage and adaptive protection in the rat stomach. Ischaemia–reperfusion damage was substantially aggravated by pretreatment with NS-398 (4 mg/kg), DFU (2 mg/kg), dexamethasone (1 mg/kg) or l-NAME (3 and 10 mg/kg). Salicylate (0.01–0.05 mg/kg) reversed the aggravating effect of NS-398, DFU and dexamethasone, while the effect of l-NAME was counteracted by l-arginine (twice 400 mg/kg) but not salicylate (0.05 or 10 mg/kg). Instillation of 20% ethanol prevented mucosal damage induced by 70% ethanol. This adaptive gastroprotection was abolished by pretreatment with NS-398 (1 mg/kg), DFU (0.2 mg/kg) or l-NAME (10 mg/kg). Salicylate (0.01–0.05 mg/kg) reversed the inhibition of protection by NS-398 and DFU, while the effect of l-NAME (10 mg/kg) was antagonized by l-arginine (100 mg/kg) but not salicylate (0.05 mg/kg). The precise mechanism of the functional antagonism between extremely low doses of salicylate and selective cyclooxygenase-2 inhibitors remains to be investigated.