title: Effect of glutamine synthetase inhibition on brain and interorgan ammonia metabolism in bile duct ligated rats.
abstract: Ammonia has a key role in the development of hepatic encephalopathy (HE). In the brain, glutamine synthetase (GS) rapidly converts blood-borne ammonia into glutamine which in high concentrations may cause mitochondrial dysfunction and osmolytic brain edema. In astrocyte-neuron cocultures and brains of healthy rats, inhibition of GS by methionine sulfoximine (MSO) reduced glutamine synthesis and increased alanine synthesis. Here, we investigate effects of MSO on brain and interorgan ammonia metabolism in sham and bile duct ligated (BDL) rats. Concentrations of glutamine, glutamate, alanine, and aspartate and incorporation of (15)NH(4)(+) into these amino acids in brain, liver, muscle, kidney, and plasma were similar in sham and BDL rats treated with saline. Methionine sulfoximine reduced glutamine concentrations in liver, kidney, and plasma but not in brain and muscle; MSO reduced incorporation of (15)NH(4)(+) into glutamine in all tissues. It did not affect alanine concentrations in any of the tissues but plasma alanine concentration increased; incorporation of (15)NH(4)(+) into alanine was increased in brain in sham and BDL rats and in kidney in sham rats. It inhibited GS in all tissues examined but only in brain was an increased incorporation of (15)N-ammonia into alanine observed. Liver and kidney were important for metabolizing blood-borne ammonia.
authors.affiliation: Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Andreas W
authors.initials: AW
authors.lastname: Fries
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Sherry
authors.initials: S
authors.lastname: Dadsetan
authors.affiliation: 1] Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Aarhus, Denmark [2] Department of Hepatology and Gastroenterology V, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Susanne
authors.initials: S
authors.lastname: Keiding
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Lasse K
authors.initials: LK
authors.lastname: Bak
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Arne
authors.initials: A
authors.lastname: Schousboe
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Helle S
authors.initials: HS
authors.lastname: Waagepetersen
authors.affiliation: Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Mette
authors.initials: M
authors.lastname: Simonsen
authors.affiliation: Department of Hepatology and Gastroenterology V, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Ott
authors.affiliation: Department of Hepatology and Gastroenterology V, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Vilstrup
authors.affiliation: 1] Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Aarhus, Denmark [2] Department of Hepatology and Gastroenterology V, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Michael
authors.initials: M
authors.lastname: Sørensen
mesh_terms: D000596:Amino Acids / Q000097:blood / Q000378:metabolism*; D000641:Ammonia / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D005260:Female; D005974:Glutamate-Ammonia Ligase / Q000037:antagonists & inhibitors*; D006501:Hepatic Encephalopathy / Q000201:enzymology / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008717:Methionine Sulfoximine / Q000494:pharmacology*; D009928:Organ Specificity; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000596:Amino Acids; D008717:Methionine Sulfoximine; D000641:Ammonia; D005974:Glutamate-Ammonia Ligase