IMPLICATION OF NITRIC-OXIDE SYNTHASE ACTIVITY IN THE GENESIS OF WATERIMMERSION STRESS-INDUCED GASTRIC-LESIONS IN RATS - THE PROTECTIVE EFFECTS OF FK506

Background: Nitric oxide (NO) is a potent cytoprotective substance of gastric mucosa. FK506, an immunosuppressive drug, shows anti-gastric u lcer effects equivalent to famotidine, an H-2 blocker, in rats. This s tudy was designed to evaluate the cytoprotective mechanism of FK506 on gastric mucosa in relation to the changes in NO synthase activity. Me thods: Gastric lesions were induced in rats by water immersion stress. Changes in NO synthase activity during water immersion stress treatme nt, and effects of FK506 on NO synthase activity were determined enzym atically. Gastric mucosal interleukin (IL)-1 beta and IL-2 were measur ed by immunoradiometric assay, Gastric mucosal blood flow was measured by hydrogen gas clearance technique, Results: FK506 mitigated gastric lesions developed by water immersion stress. Stress-induced lesions w ere exacerbated by N-G-monomethyl-L-arginine (L-NMMA), a specific inhi bitor of NO synthase, while sodium nitroprusside, a NO donor, mitigate d the lesions. Water immersion stress increased NO synthase activity i n the early phase (0.5 h after stress treatment) and decreased it in t he late phase (6 h after). Decrease in NO synthase activity in the lat e phase was significantly mitigated by FK506, though it did not affect changes in NO synthase activity in the early phase. Water immersion s tress increased gastric mucosal IL-1 beta and IL-2 contents 6 h after stress treatment, and these increases were prevented by FK506. FK506 i tself did not affect gastric mucosal blood now. L-NMMA treatment signi ficantly decreased gastric mucosal blood now. In contrast, gastric muc osal blood now was significantly increased by sodium nitroprusside. Co nclusions: Increase in NO synthase activity might contribute to cytopr otection, and a decrease in activity might be a harmful factor for the gastric mucosa. Preservation of NO synthase activity by FK506 might b e involved in FK506's protective effects on the gastric mucosa.