Endotoxin lethality is intensified by inhibited gluconeogenesis.
There are two major etiologies regarding the lethal element in the pathophysiology of endotoxemia and severe gram-negative sepsis: 1) metabolic lesions culminating in terminal hypoglycemia and 2) circulatory deficits resulting in early peripheral and late vital organ perfusion failure. Although not mutually exclusive, a direct test of the relative importance of either hypothesis is needed. The impact of inhibited gluconeogenesis on endotoxin lethality in young adult male rats (180-220 g) was investigated. Fasted rats received 20 mg/kg intravenous E. coli endotoxin (LD10) simultaneously with 500 mg/kg intraperitoneal L-tryptophan. This amino acid rapidly forms quinolinic acid, which blocks liver glucose synthesis. Endotoxin together with tryptophan caused hypoglycemic convulsions, killing 22 of 24 rats, 75% within 6 hours. In parallel studies, liver intermediates were assayed in freeze-clamped samples obtained at 5 hours from ether anesthetized rats. The high-energy intermediate phosphoenolpyruvate was 222 +/- 79 nmole/gm +/- 1 S.D. wet liver in the moderately endotoxic rats (N = 8). In the endotoxin-plus tryptophan group (N = 7), the PEP intermediate had fallen to 58 +/- 24 nmole/gm liver (P = 0.005). Liver lactate was increased 2.8-fold over the value in the endotoxin-only group, to 4390 nmole/gm wet tissue, showing the failure to utilize gluconeogenic precursors. Tryptophan given alone was not lethal. It is concluded that inhibited gluconeogenesis greatly intensifies the hepatic metabolic derangement of endotoxemia.
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D004731:Endotoxins / Q000633:toxicity*; D005943:Gluconeogenesis / Q000187:drug effects; D019298:Glucose-6-Phosphate; D005958:Glucosephosphates / Q000378:metabolism; D007773:Lactates / Q000097:blood; D019344:Lactic Acid; D008099:Liver / Q000378:metabolism; D008297:Male; D010728:Phosphoenolpyruvate / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D014115:Toxemia / Q000378:metabolism; D014364:Tryptophan / Q000494:pharmacology
D001786:Blood Glucose; D004731:Endotoxins; D005958:Glucosephosphates; D007773:Lactates; D019344:Lactic Acid; D019298:Glucose-6-Phosphate; D010728:Phosphoenolpyruvate; D014364:Tryptophan