Role of nitric oxide-synthase and cyclooxygenase/lipooxygenase systems in development of experimental ulcerative...

Development of ulcerative colitis was accompanied by the activation of iNOS/COX-2/5-LOX and increased contents of nitric oxide (NO), prostaglandin E₂ (PGE₂), and leukotriene B₄ (LTB₄). The following information was assessed: morphological changes, activity of nitric oxide-synthase, content of nitric oxide, and indexes of lipoperoxidation processes in the mucous membrane of the large intestine (MMLI). Colitis was induced in rats by intrarectal administration of 1 ml of 4% acetic acid. Aminoguanidine--selective inducible nitric oxide-synthase (iNOS) blocker, celecoxib--cyclooxygenase-2 (COX-2) inhibitor, indomethacin--non-selective COX inhibitor and AA-861--5-lipooxygenase (5-LOX) blocker were administered in 1 ml volumes per os 1 hour before and 24 hours after the intrarectal application of acetic acid. It was noticed that blockage of iNOS by aminoguanidine caused enhancement of cytoprotective mechanisms, reduction of iNOS activity and oxidative stress, and an increase in blood L-arginine level as compared to their respective indexes in colitis. Combined blockage of iNOS and COX-2 displayed additive character of their effect on the processes of lipoperoxidation and activity of iNOS. Combined blockage of iNOS, COX-2 and 5-LOX had a manifested cytoprotective effect under condition of ulcerative colitis and was accompanied by a sharp decline in NOS activity and oxidative stress. If each of these systems, iNOS/NO, COX-2/PGE₂ and 5-LOX/LTB₄ are simultaneously activated due to inflammation, they contribute to the destructive damage of the MMLI, development of oxidative stress, and affect components of the antioxidant protection system. The obtained results substantiate the relevance of treatment of the inflammatory processes with the use of medication capable of combined blockage of iNOS, COX-2, and 5-LOX.