CV-11974, angiotensin II type I receptor antagonist, protects against ischemia–reperfusion injury of the small intestine in rats

Abstract

Background Angiotensin II has been implicated in the pathogenesis of vascular inflammation in various organs. The aim of the present study was to examine the effect of angiotensin II type I receptor antagonist, CV-11974, on reperfusion-induced small intestinal injury in rats. Methods Intestinal damage was induced by clamping both the superior mesenteric artery and the celiac trunk for 30 min followed by reperfusion for 60 min in male Wistar rats. CV-11974 was given to the rats by intravenous injection 1 h before the vascular clamping. The intestinal mucosal injury and inflammation were evaluated by biochemical markers and histological findings. Thiobarbituric acid reactive substances and tissue-associated myeloperoxidase (MPO) activity were measured in the gastric mucosa as indices of lipid peroxidation and neutrophil infiltration. The expressions of pro-inflammatory cytokines (CINC-1) in intestinal mucosa were measured by enzyme-linked immunosorbent assay (ELISA) and reverse transcription-PCR (RT-PCR). In additional experiments with an in vitro flow system, human neutrophils were perfused on human umbilical vein endothelial cells (HUVEC) pretreated with anoxia–reoxygenation with or without CV-11974 and then the adhesive neutrophils were counted. Results Reperfusion after ischemia resulted in an increase in luminal protein concentrations, hemoglobin concentrations, thiobarbituric acid reactive substances, and MPO activity. Pretreatment with CV-11974 significantly inhibited the increases in these parameters. CV-11974 also inhibited increases in intestinal CINC-1 protein and mRNA expression induced by ischemia–reperfusion. Moreover, in an in vitro study, CV-11974 significantly inhibited the adherence of neutrophils to HUVEC exposed to reoxygenation after anoxia. Conclusions These results suggest that the blockade of angiotensin II type I receptor by treatment with CV-11974 remarkably reduced the reperfusion-induced intestinal injury.