IMPROVED SURVIVAL AND REVERSAL OF ENDOTHELIAL DYSFUNCTION BY THE 21-AMINOSTEROID, U-74389G IN SPLANCHNIC ISCHEMIA-REPERFUSION INJURY IN THE RAT

1 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. 2 Survival rate, survival time, serum tumour necrosis factor (TNF-alpha), 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-mu M) of aortic rings were investigated. 3 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-alpha (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 x 10(-3) g(-1) tissue) and in the lung (2.2 +/- 0.8 u x 10(-3) g(-1) tissue), leukopenia and reduced responsiveness to ACh of aortic rings. 4 The 21-aminosteroid U-74389G (30 mg kg(-1), i.v.) increased survival (survival time = 232 +/- 15 min), lowered the serum levels of TNF-alpha and the plasma levels of MAL, reduced leukopenia and MPO activity both in the ileum (0.021 +/- 0.004 u x 10(-3) g(-1) tissue) and in the lung (0.23 +/- 0.03 u x 10(-3) g(-1) tissue), improved MAP and restored the responsiveness to ACh of aortic rings. 5 Our data suggest that U-74389G is a potent lipid peroxidation inhibitor and that it has antishock and endothelial protective actions.