Endothelin Receptor Antagonism by Tezosentan Attenuates Lung Injury Induced by Aortic Ischemia–Reperfusion

Abstract

Tezosentan is a novel dual endothelin receptor antagonist. The purpose of this study was to examine the effect of tezosentan on lung injury induced by abdominal aortic ischemia-reperfusion (IR) in rats. Thirty-two Wistar-albino rats were randomized into four groups (eight per group) as follows: control group (sham laparotomy), aortic IR group (120 min ischemia and 120 min reperfusion), aortic IR + tezosentan group (a bolus intravenous injection of 10 mg/kg tezosentan before ischemia plus continuous intravenous infusion of 1 mg/kg/hr tezosentan during 120 min ischemia and 120 min reperfusion), and control + tezosentan. Blood and lung tissue samples were obtained for biochemical analysis. Protein concentrations in bronchoalveolar lavage fluid and lung wet/dry weight ratios were measured. A histological evaluation was also done. Aortic IR significantly increased (p < 0.05 vs. control group) and tezosentan significantly decreased (p < 0.05 vs. aortic IR group) the plasma level of tumor necrosis factor-alpha; lung tissue levels of malondialdehyde, catalase, and myleperoxidase; and protein concentration in bronchoalveolar lavage fluid and lung wet/dry weight ratio. Histological evaluation showed that tezosentan attenuated the morphological changes associated with lung injury. The results of this study indicate that tezosentan attenuates lung injury induced by aortic IR in rats. We propose that this protective effect of tezosentan is due to (1) reduced systemic inflammatory response, (2) reduced oxidative stress and lipid peroxidation in lung tissue, (3) reduced pulmonary microvascular leakage, and (4) inhibition of leukocyte infiltration into lung tissue.