Hyperammonaemia does not impair brain function in the absence of net glutamine synthesis.
1. It has been established that chronic hyperammonaemia, whether caused by portacaval shunting or other means, leads to a variety of metabolic changes, including a depression in the cerebral metabolic rate of glucose (CMRGlc) increased permeability of the blood-brain barrier to neutral amino acids, and an increase in the brain content of aromatic amino acids. The preceding paper [Jessy, DeJoseph & Hawkins (1991) Biochem. J. 277, 693-696] showed that the depression in CMRGlc caused by hyperammonaemia correlated more closely with glutamine, a metabolite of ammonia, than with ammonia itself. This suggested that ammonia (NH3 and NH4+) was without effect. The present experiments address the question whether ammonia, in the absence of net glutamine synthesis, induces any of the metabolic symptoms of cerebral dysfunction associated with hyperammonaemia. 2. Small doses of methionine sulphoximine, an inhibitor of glutamine synthetase, were used to raise the plasma ammonia levels of normal rats without increasing the brain glutamine content. These hyperammonaemic rats, with plasma and brain ammonia levels equivalent to those known to depress brain function, behaved normally over 48 h. There was no depression of cerebral energy metabolism (i.e. the rate of glucose consumption). Contents of key intermediary metabolites and high-energy phosphates were normal. Neutral amino acid transport (tryptophan and leucine) and the brain contents of aromatic amino acids were unchanged. 3. The data suggest that ammonia is without effect at concentrations less than 1 mumol/ml if it is not converted into glutamine. The deleterious effect of chronic hyperammonaemia seems to begin with the synthesis of glutamine.
Hawkins
R A
RA
Department of Physiology and Biophysics, Chicago Medical School, North Chicago, IL 60064.
Jessy
J
J
D000596:Amino Acids / Q000378:metabolism; D000641:Ammonia / Q000097:blood*; D000818:Animals; D001692:Biological Transport; D001921:Brain / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism; D005947:Glucose / Q000378:metabolism; D005973:Glutamine / Q000096:biosynthesis*; D008297:Male; D008717:Methionine Sulfoximine / Q000494:pharmacology; D010710:Phosphates / Q000378:metabolism; D051381:Rats; D013997:Time Factors; D014364:Tryptophan / Q000378:metabolism
D000596:Amino Acids; D010710:Phosphates; D005973:Glutamine; D008717:Methionine Sulfoximine; D000641:Ammonia; D014364:Tryptophan; D005947:Glucose