Gamma-aminobutyric acid (GABAA) receptor-function in a rat model of hepatic encephalopathy.
The functional activity of the gamma-aminobutyric acid (GABAA) receptor-chloride ionophore complex was studied in rats with hepatic encephalopathy (HE) secondary to thioacetamide-induced fulminant hepatic failure (FHF). Muscimol stimulation and benzodiazepine potentiation of GABA receptor-mediated 36Cl- uptake into cerebral cortical synaptoneurosomes was compared in HE and control rats. [3H]Flumazenil binding assays were conducted to determine whether the levels of endogenous benzodiazepine-like ligands in extracts of cortex were increased with stages of encephalopathy in this animal model of HE. In both control and HE rats maximal uptake of 36Cl- via the GABAA receptor complex occurred at muscimol concentrations of 30 microM. Potentiation of muscimol-stimulated 36Cl- uptake into synaptoneurosomes by diazepam (5 microM) was equivalent in both groups. Aqueous extracts of proteolytically digested homogenates of cerebral cortices prepared from control and HE rats were effective in stimulating 36Cl- uptake into synaptoneurosomes. Alkaline organic extracts of proteolytically digested homogenates of cerebral cortices from HE rats were more effective than corresponding extracts from controls at inhibiting the binding of [3H]flumazenil. Inhibition of [3H] fumazenil binding by organic extracts derived from the cerebral cortices of HE rats did not increase with progression of encephalopathy. The results show that muscimol-stimulated 36Cl- uptake into synaptoneurosomes and, consequently, GABAA receptor-mediated chloride channel function are not significantly altered in the model of HE studied and are consistent with the hypothesis that HE results in an increased availability of one or more endogenous ligands which can augment GABA receptor-gated chloride conductance.
Baker
B L
BL
Liver Diseases Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.
Morrow
A L
AL
Vergalla
J
J
Paul
S M
SM
Jones
E A
EA
D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism; D004195:Disease Models, Animal; D005442:Flumazenil / Q000378:metabolism; D006501:Hepatic Encephalopathy / Q000378:metabolism*; D011869:Radioligand Assay; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000378:metabolism*; D013223:Statistics as Topic; D013574:Synaptosomes / Q000378:metabolism
D002712:Chlorides; D011963:Receptors, GABA-A; D005442:Flumazenil