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Effect of Hyperammonemia and Methionine Sulfoximine on the Kinetic Parameters of Blood‐Brain Transport of Leucine and Phenylalanine
Author(s) -
Jonung Torbjorn,
Rigotti Paolo,
James J. Howard,
Brackett Kim,
Fischer Josef E.
Publication year - 1985
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.1985.tb05508.x
Subject(s) - hyperammonemia , phenylalanine , glutamine , leucine , chemistry , amino acid , methionine , ammonium , ammonia , biochemistry , medicine , metabolism , endocrinology , biology , organic chemistry
Abstract: The activity of the blood‐brain neutral amino acid transport system is increased in rats infused with ammonium salts or rendered hyperammonemic by a portacaval anastomosis. This effect may be due to a direct action of ammonia or to some metabolic consequence of high ammonia levels, such as increased brain glutamine synthesis. To test these possibilities we evaluated the kinetic parameters of blood‐brain transport of leucine and phenylalanine in control rats, in rats after continuous 24 h infusion of ammonium salts (NH 4 + = 2.5 mmol. kg −1 h −1 ), and in rats treated with methionine sulfoximine, an inhibitor of glutamine synthetase, before infusion of ammonium salts. In ammonia‐infused rats without methionine sulfoximine treatment, the K D and V max of phenylalanine transport were increased, respectively, about 170% and 80% compared to controls, whereas the K m and V max of leucine transport were increased, respectively, about 100% and 200%. Electron microscopy demonstrated marked swelling of astrocytic processes around brain capillaries of ammonia‐infused rats; however, capillary permeability to horseradish peroxidase apparently was not increased by ammonia infusion. Administration of methionine sulfoximine before ammonia infusion inhibited glutamine synthesis and prevented the changes in transport of leucine and phenylalanine, but apparently did not reverse the perivascular swelling. These results suggest that the ammonia‐induced increase in the activity of transport of large neutral amino acids across the blood‐brain barrier requires glutamine synthesis in brain, and is not a direct effect of ammonia.