Effect of a new synthetic complement inhibitor on hepatic glycolytic intermediates in septic rats.
Peritonitis and endotoxemia produce similar derangements in carbohydrate metabolism, indicating a common mechanism of action. Endotoxin activates the complement chain by the alternate pathway with the release of chemical mediators. These mediators may be responsible for the changes occurring in hepatic metabolite pools during endotoxemia. This hypothesis was tested with FUT-175, a complement inhibitor, (2-(6-amidino)naphthyl-4-guanidinobenzoate 2HC1). Peritonitis was induced by cecal incision in fasted male rats. FUT-175 was infused in 5% dextrose at a dose of 0.1 mg/ml/h. Survival time was 12.1 +/- 2.3 h in the FUT-175 group and and 6.6 +/- 1.1 h without FUT-175. Three peritonitis groups received either 5% dextrose alone; FUT-175 2.5 mg/100 g by IP injection, or FUT-175 0.1 mg/ml/h by infusion. Liver was sampled at 5 h by freeze-clamping, and metabolites were assayed by UV spectrophotometry. Peritonitis caused 33% decrease in glucose-6-phosphate (G6P), a 2.5-fold increase in fructose diphosphate (FDP), and 3.5-fold increase in lactate. In FUT-175-injected rats, G6P was decreased by 20%, FDP increased only 50%, and lactate doubled. Phosphoenolpyruvate (PEP) levels were increased 30% above peritonitis values. The drug produced a partial normalization of liver metabolites. The data suggest that the anticomplement action prevented the release of potent mediators which otherwise cause physiological changes leading to the metabolic imbalance of septic shock.
D000818:Animals; D001550:Benzamidines; D003169:Complement Inactivator Proteins / Q000008:administration & dosage; D006019:Glycolysis / Q000187:drug effects*; D006146:Guanidines / Q000008:administration & dosage*; D008099:Liver / Q000378:metabolism*; D008297:Male; D010538:Peritonitis / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality; D010728:Phosphoenolpyruvate / Q000032:analysis; D051381:Rats; D012772:Shock, Septic / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality
D001550:Benzamidines; D003169:Complement Inactivator Proteins; D006146:Guanidines; D010728:Phosphoenolpyruvate; C032855:nafamostat