A research to the participation of endotheline-nitric oxide system in pathophysiology of ischemic disorder of a small intestine and a development for its therapeutic usage.

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We investigated the role of nitric oxide in the mucosal injury induced by ischemia-reperfusion in the rat small intestine and evaluated the effect of N^G-nitro-L-arginine methyl pester, a potent inhibitor of nitric oxide synthase to the ischemia-related injury of the small intestine. A transient intestinal ischemia was produced in the catheterized ileal segments of rats by occluding the anterior mesenteric artery for 60 min. Nitric oxide metabolites (NO_2^- and NO_3^-) and lactate dehydrogenase activity in perfusates of the intestinal lumen were measured over 5 h periods after reperfusion. The time-course of histological changes in small intestine was also observed. After ischemia-reperfusion, nitric oxide release in the intestinal lumen increased significantly and the dynamics of nitric oxide release correlated with that of lactate dehydrogenase leakage. The administration of N^G-nitro-L-arginine methyl ester (1.0 - 2.5 mg/kg) inhibited this increase of the nitric oxide release and the lactate dehydrogenase leakage, and afforded protection against the mucosal injury induced by ischemia-reperfusion. These results suggest that the nitric oxide production which was accelerated by ischemia-reperfusion of small intestine may possibly participate in thc breakdown of intestinal mucosa after ischemia-reperfusion insult. Next, we investigated endothelin receptors in the rat small intestine following ischemia-reperfusion, using a quantitative receptor autoradiographic method. In correspondence to the part of mucosal injury in the small intestine following ischemia-reperfusion ^<125>I-cndothelin-1 binding sites were increased in number. These binding sites were characteristically the endothelin ETB receptor. Thus, endothelin system may also participate in the breakdown of intestinal mucosa after ischemia-reperfusion insult. This part of the research is now go on more precisely.