Effect of reducing brain glutamine synthesis on metabolic symptoms of hepatic encephalopathy.
Liver failure, or shunting of intestinal blood around the liver, results in hyperammonemia and cerebral dysfunction. Recently it was shown that ammonia caused some of the metabolic signs of hepatic encephalopathy only after it was metabolized by glutamine synthetase in the brain. In the present study, small doses of methionine sulfoximine, an inhibitor of cerebral glutamine synthetase, were given to rats either at the time of portacaval shunting or 3-4 weeks later. The effects on several characteristic cerebral metabolic abnormalities produced by portacaval shunting were measured 1-3 days after injection of the inhibitor. All untreated portacaval-shunted rats had elevated plasma and brain ammonia concentrations, increased brain glutamine and tryptophan content, decreased brain glucose consumption, and increased permeability of the blood-brain barrier to tryptophan. All treated rats had high ammonia concentrations, but the brain glutamine content was normal, indicating inhibition of glutamine synthesis. One day after shunting and methionine sulfoximine administration, glucose consumption, tryptophan transport, and tryptophan brain content remained near control values. In the 3-4-week-shunted rats, which were studied 1-3 days after methionine sulfoximine administration, the effect was less pronounced. Brain glucose consumption and tryptophan content were partially normalized, but tryptophan transport was unaffected. The results agree with our earlier conclusion that glutamine synthesis is an essential step in the development of cerebral metabolic abnormalities in hyperammonemic states.
Hawkins
R A
RA
Department of Physiology and Biophysics, University of Health Sciences, Chicago Medical School, North Chicago 60064.
Jessy
J
J
Mans
A M
AM
De Joseph
M R
MR
D000818:Animals; D001921:Brain / Q000378:metabolism*; D005973:Glutamine / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006501:Hepatic Encephalopathy / Q000209:etiology / Q000378:metabolism*; D008297:Male; D008717:Methionine Sulfoximine / Q000494:pharmacology; D011167:Portacaval Shunt, Surgical; D011184:Postoperative Period; D051381:Rats; D011919:Rats, Inbred Strains
D005973:Glutamine; D008717:Methionine Sulfoximine