Improved survival and reversal of endothelial dysfunction by the 21‐aminosteroid, U‐74389G in splanchnic ischaemia‐reperfusion injury in the rat

Abstract

Anaesthetized rats subjected to total occlusion of the superior mesenteric artery and the coeliac trunk for 45 min developed a severe shock state (splanchnic artery occlusion, SAO shock) resulting in death within 70–90 min after release of the occlusion. Sham‐operated animals were used as controls. Survival rate, survival time, serum tumour necrosis factor (TNF‐α), white blood cell (WBC) count, mean arterial blood pressure (MAP), plasma malonylaldehyde (MAL), myeloperoxidase activity (MPO) and the responsiveness to acetylcholine (ACh 10 nM‐10 μM) of aortic rings were investigated. SAO shocked rats had a decreased survival rate and survival time (74 ± 10 min, while sham‐shocked rats survived more than 4 h), reduced mean arterial blood pressure, increased serum levels of TNF‐α (267 ± 13 u ml−1) and plasma levels of MAL (57 ± 7 nmol ml−1), enhanced MPO activity in the ileum (0.23 ± 0.04 u × 10−3 g−1 tissue) and in the lung (2.2 ± 0.8 u × 10−3 g−1 tissue), leukopenia and reduced responsiveness to ACh of aortic rings. The 21‐aminosteroid U‐74389G (30 mg kg−1, i.v.) increased survival (survival time = 232 ± 15 min), lowered the serum levels of TNF‐α and the plasma levels of MAL, reduced leukopenia and MPO activity both in the ileum (0.021 ± 0.004 u × 10−3 g−1 tissue) and in the lung (0.23 ± 0.03 u × 10−3 g−1 tissue), improved MAP and restored the responsiveness to ACh of aortic rings. Our data suggest that U‐74389G is a potent lipid peroxidation inhibitor and that it has antishock and endothelial protective actions. 1995 British Pharmacological Society