Interaction of cyclooxygenase-2 inhibitors and salicylate in gastric mucosal damage.
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.
Peskar
Brigitta M
BM
Department of Experimental Clinical Medicine, Medical Faculty, Ruhr-University of Bochum, Floor 1, Building MA, D-44780 Bochum, Germany. dorothea.seier@ruhr-uni-bochum.de
Ehrlich
Karlheinz
K
Peskar
Bernhard A
BA
D000818:Animals; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D019610:Cytoprotection; D004347:Drug Interactions; D000431:Ethanol / Q000633:toxicity; D005663:Furans / Q000494:pharmacology; D005753:Gastric Mucosa / Q000187:drug effects* / Q000473:pathology; D007527:Isoenzymes / Q000187:drug effects*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology; D009578:Nitrobenzenes / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D012980:Sodium Salicylate / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology
C106876:5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl-2(5H)-furanone; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D005663:Furans; D007527:Isoenzymes; D009578:Nitrobenzenes; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D009569:Nitric Oxide; D000431:Ethanol; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D019331:NG-Nitroarginine Methyl Ester; D012980:Sodium Salicylate