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

1 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. 2 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.). 3 Oral administration of indomethacin (1.25–20 mg kg −1 ) dose‐dependently counteracted the protective effect of 20% ethanol (ID 50 : 3.5 mg kg −1 ). 4 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 ID 50 values of 0.3 mg kg −1 , 0.4 mg kg −1 and 0.06 mg kg −1 , respectively. 5 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. 6 Pretreatment with 16,16‐dimethyl‐prostaglandin (PG)E 2 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. 7 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. 8 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.). 9 Whereas indomethacin (20 mg kg −1 , p.o.) near‐maximally inhibited gastric mucosal formation of PGE 2 , 6‐keto‐PGF 1α and thromboxane (TX) B 2 as well as platelet TXB2 release, the selective COX‐2 inhibitors were ineffective. 10 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