Superoxide dismutase mimetic with catalase activity, EUK-134, attenuates the multiple organ injury and dysfunction caused by endotoxin in the rat.
BACKGROUND
Reactive oxygen species contribute to the multiple organ failure endotoxic shock. Here we investigate the effects of a salen-manganese complex, which exhibits both superoxide dismutase and catalase activity (EUK-134), on the circulatory failure and the renal and liver injury and dysfunction caused by endotoxin in the anaesthetised (thiopentone, 120 mg/kg) rat.


METHODS
Male Wistar rats were anaesthetised with thiopentone sodium (120 mg/kg i.p.) and instrumented for the measurements 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 infusion of 0.3 or 1 mg/kg/h) or its vehicle (saline). After 6 h of endotoxaemia, blood was taken to evaluate biochemical 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 and pancreatic injury. Treatment of rats with EUK-134 attenuated the renal dysfunction as well as the liver and skeletal muscle injury (but not the pancreatic injury) caused by endotoxin.


CONCLUSIONS
Thus, an enhanced formation of reactive oxygen species importantly contribute to the organ injury and dysfunction associated with endotoxic shock. We propose that small molecules, which have the catalytic activity of both superoxide dismutase and catalase, may represent a novel therapeutic approach for the therapy of endotoxic shock.
Bianca
Roberta d'Emmanuele di Villa
Rd
The William Harvey Research Institute, St. Bartholomew's and The Royal London School of Medicine and Dentistry, London, UK.
Wayman
Nicole S
NS
McDonald
Michelle C
MC
Pinto
Aldo
A
Shape
Martyn A
MA
Chatterjee
Prabal K
PK
Thiemermann
Christoph
C
D000818:Animals; D004731:Endotoxins / Q000494:pharmacology*; D007022:Hypotension; D007668:Kidney / Q000187:drug effects; D008099:Liver / Q000187:drug effects; D008297:Male; D017895:Manganese Compounds / Q000494:pharmacology; D018482:Muscle, Skeletal / Q000187:drug effects; D009942:Organometallic Compounds / Q000494:pharmacology*; D010179:Pancreas / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D012459:Salicylates / Q000494:pharmacology*; D012772:Shock, Septic / Q000628:therapy; D013482:Superoxide Dismutase / Q000737:chemistry* / Q000494:pharmacology*; D013997:Time Factors
C433928:EUK-134; D004731:Endotoxins; D017895:Manganese Compounds; D009942:Organometallic Compounds; D017382:Reactive Oxygen Species; D012459:Salicylates; D013482:Superoxide Dismutase