PROPHYLACTIC AND CURATIVE EFFECTS OF RECOMBINANT HUMAN SUPEROXIDE-DISMUTASE IN LETHAL RAT ENDOTOXEMIA

  • 1 September 1988
    • journal article
    • research article
    • Vol. 38-2  (9) , 1381-1386
Abstract
The continuous infusion of Escherichia coli lipopolysaccharide (100 mg/kg in 4 h) caused a 100%-mortality in pentobarbital-anesthetized rats within 6 h. Recombinant human superoxide dismutase (r-HSOD) infused concomitantly with the E. coli endotoxin dose-dependently (0.1-1.0 mg/kg per min) increased survival rate up to 90%. Significant improvement of survival rate was also obtained when r-HSOD-infusion (0.464 mg/kg per min) was only started up to 3 h after beginning of the endotoxin application. Also, two single bolus injections of r-HSOD (20 mg/kg each) during endotoxemia significantly increased survival rate. Decrease of heart rate was prevented and decline of arterial blood pressure was diminished by r-HSOD (0.464 mg/kg per min) as compared to vehicle-treated endotoxemic rats. Lactic acidosis occurred with no significant statistical difference between r-HSOD-and vehicle-treated groups. Increase of hematocrit in endotoxemic control rats was balanced by fluid uptake. In contrast, in the groups treated with endotoxin plus r-HSOD or saline alone hematocrit decreased identically. Decrease of whole blood leukocytes (to 30.2 .+-. 9.5% of baseline in endotoxemic controls) was less pronounced in the r-HSOD group (fall to 49.2 .+-. 6.5% of baseline), but this difference did not reach statistical significance. Marked thrombocytopenia (to 12.9 .+-. 3.2% of baseline) and consumption of plasma fibrinogen (to 39.5 .+-. 10.3% of baseline) were significantly attenuated in r-HSOD-treated rats, where thrombocytes only decreased to 28.1 .+-. 3.6% and plasma fibrinogen to 76.6 .+-. 5.0% of baseline values at the end of endotoxin infusion. In endotoxemic rats the 4-h infusion of 0.464 mg/kg per min r-HSOD resulted in a plasma level of 136 .+-. 14 .mu.g/ml that declined to 12 .+-. 3 .mu.g/ml 2 h after the cessation of the endotoxin and the r-HSOD infusion. In nonendotoxemic rats the plasma level of r-HSOD after infusion of the same dose and time schedule only reached 93 .+-. 11 .mu.g/ml and decreased to 2 .+-. 1 .mu.g/ml over 2 h. These significantly different kinetics are probably due to endotoxin-induced renal microthrombosis that impedes the elimination of r-HSOD in endotoxemic rats. As mechanisms of the overall protective effect of r-HSOD in lethal rat endotoxemia diminution of cardiovascular depression, inhibition of hemoconcentration and attenuation of consumption coagulopathy could be established.