Effects of NO-generating compounds on synaptosomal energy metabolism.
The effects of nitroprusside and S-nitrosocysteine, compounds that generate nitric oxide (NO), on synaptosomal energy-producing pathways and energy level were investigated. The decrease in respiration was much faster and more pronounced with S-nitrosocysteine than with nitroprusside. S-Nitrosocysteine, at 10 microM, inhibited by 80% respiration with glucose and succinate (plus rotenone) in intact synaptosomes and with ascorbate/cytochrome c in broken preparations. Oxygenated hemoglobin reversed and/or prevented the inhibition, whereas glutathione (GSH) prolonged it. Under aerobic conditions, the synaptosomal energy level (creatine phosphate/creatine and ATP/ADP ratios) was reduced by the presence of S-nitrosocysteine, whereas lactate generation was enhanced. The effects on energy parameters were greater at 5 min than at 15 min of incubation and were more pronounced in the presence of GSH. Under strictly anaerobic conditions, lactate production was reduced by the NO-generating compounds in a concentration-dependent manner. It is concluded that (a) inhibition of oxidative phosphorylation by NO leads to a fall in the synaptosomal energy level, which in turn stimulates glycolysis; (b) glycolysis can be inhibited by higher concentrations of the radical; and (c) inhibitory effects on the energy-generating pathway and ATP level could contribute to NO toxicity under some in vivo situations.
Erecinńska
M
M
Department of Pharmacology, University of Pennsylvania, Philadelphia, USA.
Nelson
D
D
Vanderkooi
J M
JM
D000818:Animals; D003545:Cysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D004734:Energy Metabolism / Q000187:drug effects; D006019:Glycolysis / Q000187:drug effects; D007773:Lactates / Q000096:biosynthesis; D019344:Lactic Acid; D008297:Male; D009569:Nitric Oxide / Q000096:biosynthesis*; D009599:Nitroprusside / Q000494:pharmacology; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D026403:S-Nitrosothiols; D013574:Synaptosomes / Q000378:metabolism*
D007773:Lactates; D026403:S-Nitrosothiols; D009599:Nitroprusside; D009569:Nitric Oxide; D019344:Lactic Acid; C021315:S-nitrosocysteine; D003545:Cysteine