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 ind omethacin and the selective COX-2 inhibitors, N-[2-(cyclohexyloxy)-4-n itrophenyl] methanesulphonamide (NS-398), ulphonamido-6-(2,4-difluorot hio-phenyl)-1-indanone (L-745,337) and -dimethyl-3-(3-fluorophenyl)-4- (4-methylsulphonyl) phenyl-2(5H)-furanone (DFU), on the protection ind uced by the mild irritant 20% ethanol were investigated in the rat sto mach. 2 Instillation of 20% ethanol (1 mi, p.o.) effectively protected against gastric mucosal injury induced by subsequent instillation of 70% or 96% ethanol (1 mi, p.o.). 3 Oral administration of indomethacin (1.25-20 mg kg(-1)) dose-dependently counteracted the protective effe ct of 20% ethanol (ID50: 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)) inhi bited 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), r espectively. 5 Inhibition of mild irritant-induced protection was also found when NS-398 (1 mg kg(-1)) was administered s.c. or when 96% eth anol 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 aga inst ethanol (70%)-induced mucosal damage when given alone, completely reversed the effect of the selective COX-2 inhibitors on the mild irr itant-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 induc tion is not involved. 8 Indomethacin (20 mg kg(-1), p.o.) did not prev ent the protection conferred by sodium salicylate (100 mg kg(-1)), dim ercaprol (30 mu g kg(-1)), iodoacetamide (50 mg kg(-1)) and lithium (2 0 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 o f PGE(2), 6-keto-PGF(1 alpha) and thromboxane (TX) B-2 as well as plat elet TXB2 release, the selective COX-2 inhibitors were ineffective. 10 The findings show that selective COX-2 inhibitors, although lacking i n ulcerogenic activity, prevent the protection conferred by a mild irr itant. Prostaglandis generated by a constitutive COX-2 could thus cont ribute to physiological functions involved in gastric homeostasis, alt hough at present a non-COX-2-related mechanism underlying the effect o f the selective COX-2 inhibitors tested on mild irritant-induced prote ction cannot be completely excluded.