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

Eur J Pharmacol. 2006 Mar 27;535(1-3):283-90. doi: 10.1016/j.ejphar.2006.02.005. Epub 2006 Mar 20.

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.

MeSH terms

  • Angiotensin II Type 1 Receptor Blockers / pharmacology*
  • Animals
  • Benzimidazoles / pharmacology*
  • Biphenyl Compounds
  • Cell Adhesion / drug effects
  • Cell Line
  • Chemokine CXCL1
  • Chemokines, CXC / genetics
  • Chemokines, CXC / metabolism
  • Dose-Response Relationship, Drug
  • Endothelial Cells / cytology
  • Endothelial Cells / drug effects
  • Gene Expression / drug effects
  • Hemoglobins / metabolism
  • Humans
  • Intestinal Diseases / etiology
  • Intestinal Diseases / metabolism
  • Intestinal Diseases / prevention & control*
  • Intestinal Mucosa / drug effects
  • Intestinal Mucosa / injuries
  • Intestinal Mucosa / metabolism
  • Intestine, Small / drug effects*
  • Intestine, Small / injuries
  • Intestine, Small / metabolism
  • Male
  • Neutrophils / cytology
  • Neutrophils / drug effects
  • Peroxidase / metabolism
  • Proteins / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Wistar
  • Reperfusion Injury / complications*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tetrazoles / pharmacology*
  • Thiobarbituric Acid Reactive Substances / metabolism

Substances

  • Angiotensin II Type 1 Receptor Blockers
  • Benzimidazoles
  • Biphenyl Compounds
  • Chemokine CXCL1
  • Chemokines, CXC
  • Cxcl1 protein, rat
  • Hemoglobins
  • Proteins
  • RNA, Messenger
  • Tetrazoles
  • Thiobarbituric Acid Reactive Substances
  • Peroxidase
  • candesartan