Selective cyclo‐oxygenase‐2 inhibitors and their influence on the protective effect of a mild irritant in the rat stomach

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Abstract
The effects of the non‐selective cyclo‐oxygenase (COX) inhibitor indomethacin and the selective COX‐2 inhibitors, N‐[2‐(cyclohexyloxy)‐4‐nitrophenyl] methanesulphonamide (NS‐398), 5‐methanesulphonamido‐6‐(2,4‐difluorothio‐phenyl)‐1‐indanone (L‐745,337) and 5,5‐dimethyl‐3‐(3‐fluorophenyl)‐4‐(4‐methylsulphonyl) phenyl‐2(5H)‐furanone (DFU), on the protection induced by the mild irritant 20% ethanol were investigated in the rat stomach. Instillation of 20% ethanol (1 ml, p.o.) effectively protected against gastric mucosal injury induced by subsequent instillation of 70% or 96% ethanol (1 ml, p.o.). Oral administration of indomethacin (1.25–20 mg kg−1) dose‐dependently counteracted the protective effect of 20% ethanol (ID50: 3.5 mg kg−1). Likewise, NS‐398 (0.1–1 mg kg−1), L‐745,337 (0.2–2 mg kg−1) and DFU (0.02–0.2 mg kg−1) inhibited the protective effect of 20% ethanol in a dose‐dependent manner with ID50 values of 0.3 mg kg−1, 0.4 mg kg−1 and 0.06 mg kg−1, respectively. Inhibition of mild irritant‐induced protection was also found when NS‐398 (1 mg kg−1) was administered s.c. or when 96% ethanol was used to damage the mucosa. Pretreatment with 16,16‐dimethyl‐prostaglandin (PG)E2 at 4 ng kg−1, a dose that did not protect against ethanol (70%)‐induced mucosal damage when given alone, completely reversed the effect of the selective COX‐2 inhibitors on the mild irritant‐induced protection. Pretreatment with dexamethasone (3 mg kg−1, 24 and 2 h before instillation of 20% ethanol) did not affect the protective activity of the mild irritant, indicating that enzyme induction is not involved. Indomethacin (20 mg kg−1, p.o.) did not prevent the protection conferred by sodium salicylate (100 mg kg−1), dimercaprol (30 μg kg−1), iodoacetamide (50 mg kg−1) and lithium (20 mg kg−1). Likewise, the protective effect of these agents was not counteracted by NS‐398 (1 mg kg−1, p.o.). Whereas indomethacin (20 mg kg−1, p.o.) near‐maximally inhibited gastric mucosal formation of PGE2, 6‐keto‐PGF1α and thromboxane (TX) B2 as well as platelet TXB2 release, the selective COX‐2 inhibitors were ineffective. The findings show that selective COX‐2 inhibitors, although lacking in ulcerogenic activity, prevent the protection conferred by a mild irritant. Prostaglandis generated by a constitutive COX‐2 could thus contribute to physiological functions involved in gastric homeostasis, although at present a non‐COX‐2‐related mechanism underlying the effect of the selective COX‐2 inhibitors tested on mild irritant‐induced protection cannot be completely excluded. British Journal of Pharmacology (1998) 123, 927–935; doi:10.1038/sj.bjp.0701673