Modulation of endotoxin lethality in mice by hydrazine sulfate.
Although the precise mechanism of endotoxin lethality has yet to be defined, it is well recognized that the amount of hepatic phosphoenolpyruvate carboxykinase is reproducibly and significantly reduced after challenge with endotoxin. Hydrazine has been shown to be a specific inhibitor of gluconeogenesis, causing a metabolic crossover at the step catalyzed by phosphoenolpyruvate carboxykinase. More recently, it has also been shown that hydrazine sulfate may be of potential therapeutic value against cancer cachexia. The experiments described in this paper demonstrate that treatment of CF1 mice with hydrazine sulfate 5 h prior to challenge with endotoxin from Salmonella enteritidis significantly improved survival. Furthermore, such treatment counteracted the drop in hepatic phosphoenolpyruvate carboxykinase activity in isolated cytosol otherwise evident at 6 h and 12 h after endotoxin challenge. Despite this, there was no corresponding improvement in the plasma glucose, measured at 6, 12, and 24 h following endotoxin challenge. It is suggested that the endogenous response to the metabolic crossover initiated by hydrazine may contribute to the protection. The response to hydrazine sulfate has yet to be fully elaborated but does include the increase in phosphoenolpyruvate carboxykinase activity. In contrast with the protection seen upon hydrazine sulfate pretreatment, injecting a corresponding dose of hydrazine sulfate after the endotoxin resulted in more fatalities.
Silverstein
R
R
Department of Biochemistry, University of Kansas Medical Center, Kansas City 66103.
Christoffersen
C A
CA
Morrison
D C
DC
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D004334:Drug Administration Schedule; D004731:Endotoxins / Q000633:toxicity*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006834:Hydrazines / Q000008:administration & dosage* / Q000627:therapeutic use; D007274:Injections, Intraperitoneal; D007928:Lethal Dose 50; D008070:Lipopolysaccharides / Q000633:toxicity*; D008099:Liver / Q000201:enzymology; D051379:Mice; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000378:metabolism; D011292:Premedication
D001786:Blood Glucose; D004731:Endotoxins; D006834:Hydrazines; D008070:Lipopolysaccharides; C029424:hydrazine; D010729:Phosphoenolpyruvate Carboxykinase (GTP)