Astrocyte swelling in liver failure: role of glutamine and benzodiazepines.
We examined the effect of methionine sulfoximine (MSO) and peripheral benzodiazepine (BZD) ligands on ammonia-induced swelling of primary astrocyte cultures. Swelling was completely abolished by co-treatment with MSO, an inhibitor of glutamine synthetase. We also established that many of the effects caused by ammonia, including the reduction in K+ uptake, increase in Cl- uptake and reduction in myo-inositol uptake were diminished by co-treatment with MSO. Agonists of the peripheral-type BZD receptor aggravated ammonia-induced swelling, whereas a peripheral BZD receptor blocker, PK 11195, diminished the extent of swelling. Our findings implicate glutamine and the peripheral-type benzodiazepine receptor in the pathogenesis of the edema associated with fulminant hepatic failure.
Norenberg
M D
MD
Department of Pathology, University of Miami School of Medicine, Florida.
Bender
A S
AS
D000641:Ammonia / Q000633:toxicity; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects / Q000502:physiology; D001929:Brain Edema / Q000503:physiopathology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000503:physiopathology; D002712:Chlorides / Q000378:metabolism; D058787:GABA-A Receptor Antagonists; D005974:Glutamate-Ammonia Ligase / Q000037:antagonists & inhibitors; D005973:Glutamine / Q000037:antagonists & inhibitors / Q000502:physiology*; D006501:Hepatic Encephalopathy / Q000503:physiopathology*; D007294:Inositol / Q000378:metabolism; D007473:Ion Channels / Q000187:drug effects / Q000502:physiology; D007546:Isoquinolines / Q000494:pharmacology; D008717:Methionine Sulfoximine / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism; D051381:Rats; D011963:Receptors, GABA-A / Q000502:physiology*; D014882:Water-Electrolyte Balance / Q000187:drug effects / Q000502:physiology
D002712:Chlorides; D058787:GABA-A Receptor Antagonists; D007473:Ion Channels; D007546:Isoquinolines; D011963:Receptors, GABA-A; D005973:Glutamine; D008717:Methionine Sulfoximine; D007294:Inositol; D000641:Ammonia; D005974:Glutamate-Ammonia Ligase; D011188:Potassium; C037850:PK 11195