Abstract

BACKGROUND: Reactive oxygen species contribute to the multiple organ failureendotoxic shock. Here we investigate the effects of a salen-manganese complex, which exhibits both superoxidedismutase and catalase activity (EUK-134), on the circulatory failure and the renal and liver injuryand dysfunction caused by endotoxin in the anaesthetised (thiopentone, 120 mg/kg) rat. MATERIAL/METHODS:Male Wistar rats were anaesthetised with thiopentone sodium (120 mg/kg i.p.) and instrumented for themeasurements of systemic haemodynamics. Animals received lipopolysaccharide (LPS, E. coli, 6 mg/kg i.v.)or saline and were treated with either EUK-134 (0.3 or 1 mg/kg bolus injection followed by an infusionof 0.3 or 1 mg/kg/h) or its vehicle (saline). After 6 h of endotoxaemia, blood was taken to evaluatebiochemical parameters of organ injury and dysfunction. All data are mean I s.e. mean of n observations.Statistical comparisons were made with a ANOVA followed by Dunnet's test for multiple comparisons. RESULTS:Endotoxaemia for 6 h caused hypotension, renal dysfunction, liver injury, skeletal-muscle injury andpancreatic injury. Treatment of rats with EUK-134 attenuated the renal dysfunction as well as the liverand skeletal muscle injury (but not the pancreatic injury) caused by endotoxin. CONCLUSIONS: Thus, anenhanced formation of reactive oxygen species importantly contribute to the organ injury and dysfunctionassociated with endotoxic shock. We propose that small molecules, which have the catalytic activity ofboth superoxide dismutase and catalase, may represent a novel therapeutic approach for the therapy ofendotoxic shock.

Keywords: Endotoxins, Hypotension, Kidney, Liver, Manganese Compounds, Muscle, Skeletal, Organometallic Compounds, Pancreas, Rats, Wistar, Salicylates, Shock, Septic, Time Factors