Effects of specific inhibition of cyclo-oxygenase-1 and cyclo-oxygenase-2 in the rat stomach with normal mucosa and after acid challenge

1 Effects of the cyclo-oxygenase (COX)-1 inhibitor SC-560 and the COX-2 inh ibitors rofecoxib and DFU were investigated in the normal stomach and after acid challenge. 2 In healthy rats, neither SC-560 nor rofecoxib (20 mg kg(-1) each) given a lone damaged the mucosa. Co-treatment with SC-560 and rofecoxib, however, i nduced severe lesions comparable to indomethacin (20 mg kg(-1)) whereas co- administration of SC-560 and DFU (20 mg kg(-1) each) had no comparable ulce rogenic effect 5 h after dosing. 3 SC-560 (20 mg kg(-1)) inhibited gastric 6-keto-prostaglandin (PG) F-1 alp ha by 86 +/- 5% and platelet thromboxane (TX) B-2, formation by 89 +/- 4% c omparable to indomethacin (20 mg kg(-1)). Rofecoxib (20 mg kg-l) did not in hibit gastric and platelet eicosanoids. 4 Intragastric HCl elevated mucosal mRNA levels of COX-2 but not COX-1. Dex amethasone (2 mg kg(-1)) prevented the up-regulation of COX-2. 5 After acid challenge, SC-560 (5 and 20 mg kg(-1)) induced dose-dependent injury. Rofecoxib (20 mg kg(-1)), DFU (5 mg kg(-1)) and dexamethasone (2 mg kg(-1)) given alone were not ulcerogenic but aggravated SC-560-induced dam age. DFU augmented SC-560 damage 1 but not 5 h after administration whereas rofecoxib increased injury after both treatment periods suggesting differe nt time courses. 6 Gastric injurious effects of rofecoxib and DFU correlated with inhibition of inflammatory PGE(2). 7 The findings show that in the normal stomach lesions only develop when bo th COX-1 and COX-2 are inhibited. In contrast, during acid challenge inhibi tion of COX-1 renders the mucosa more vulnerable suggesting an important ro le of COX-1 in mucosal defence in the presence of a potentially noxious age nt. In this function COX-1 is supported by COX-2. In the face of pending in jury, however, COX-2 cannot maintain mucosal integrity when the activity of COX-1 is suppressed.