Inhibition of hepatic gluconeogenesis by nitric oxide: a comparison with endotoxic shock.
Isolated hepatocytes incubated in the presence of the NO donors S-nitroso-N-acetylpenicillamine (SNAP) and 3-morpholino-sydnonimine (SIN-1) displayed a time- and dose-dependent inhibition of glucose synthesis from lactate plus pyruvate as the substrate which correlated with NO production, but not nitrite production. Neither the parent compound of SNAP, N-acetyl-DL-penicillamine (NAP), nor nitrite or nitrate had any significant effect on glucose output, indicating that the inhibition was due to the generation of NO within the incubation medium. The concentrations of NO required for this effect (< 800 nM) are within the range reported to occur in intact tissues and in vivo. The magnitude of the inhibitory effect of SNAP (approximately 50%) was comparable with that of endotoxin treatment of the rat with lactate plus pyruvate as the substrate. When the effect of SNAP on glucose synthesis and lactate plus pyruvate synthesis from a number of different substrates was examined, this showed a pattern comparable with that observed after endotoxin treatment of the rat, suggesting that NO may be the inhibitory mediator of the effects of bacterial endotoxin on hepatic gluconeogenesis. The NO donor had no effect on the flux through 6-phosphofructo-1-kinase, supporting the concept that the primary site of inhibition of gluconeogenesis by both NO and endotoxin resides at the level of phosphoenolpyruvate formation.
Horton
R A
RA
School of Biological Sciences, University of Sussex, Brighton, U.K.
Ceppi
E D
ED
Knowles
R G
RG
Titheradge
M A
MA
D000818:Animals; D004098:Dihydroxyacetone / Q000378:metabolism; D004731:Endotoxins / Q000494:pharmacology; D005632:Fructose / Q000378:metabolism; D005943:Gluconeogenesis / Q000187:drug effects; D005990:Glycerol / Q000378:metabolism; D007773:Lactates / Q000096:biosynthesis; D008099:Liver / Q000378:metabolism*; D008297:Male; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis / Q000502:physiology*; D009573:Nitrites / Q000378:metabolism; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D026423:S-Nitroso-N-Acetylpenicillamine; D012772:Shock, Septic / Q000378:metabolism*
D004731:Endotoxins; D007773:Lactates; D009573:Nitrites; D005632:Fructose; D009569:Nitric Oxide; C002385:linsidomine; D026423:S-Nitroso-N-Acetylpenicillamine; D008981:Molsidomine; D010396:Penicillamine; D004098:Dihydroxyacetone; D005990:Glycerol