Gamma-aminobutyric acid and benzodiazepine receptors in an animal model of fulminant hepatic failure.
Hepatic encephalopathy (HE) is a syndrome of generalized neural inhibition, which complicates both acute and chronic liver failure. Since gamma-aminobutyric acid (GABA) is the principal inhibitory neurotransmitter of the brain and HE is associated with increased responsiveness to certain drugs (benzodiazepines and barbiturates) that mediate neural inhibition by binding to the GABA receptor complex on postsynaptic neural membranes, the status of this receptor complex in HE was investigated. Fulminant hepatic failure was induced in rabbits by the intravenous injection of galactosamine hydrochloride. Neural membranes were isolated from the brains of normal rabbits, rabbits in hepatic coma, and rabbits with another type of metabolic encephalopathy, uremic coma. To characterize GABA and benzodiazine receptors, measurements were made of the specific binding to neural membranes of 3H-GABA and 3H-flunitrazepam, respectively. Computer-assisted Scatchard plot analysis of the binding data suggested the presence of two independent receptors for GABA and a single class of receptor for benzodiazepines. Hepatic coma was associated with no changes in the affinities of these receptors but with significant increases in their densities: 0.34 vs. 0.60; 1.1 vs. 2.2; and 4.6 vs. 7.3 pmol/mg of membrane protein for the high-affinity GABA, low-affinity GABA and benzodiazepine receptors, respectively. Uremic coma was associated with no changes in the affinities or densities of GABA receptors. On the basis of these findings, it is suggested that (1) increased numbers of GABA receptors in liver failure may potentiate neural inhibition by increasing the sensitivity of the brain to GABA and (2) increased responsiveness to the sedative-hypnotic effects of benzodiazepines in liver failure may be mediated by increased numbers of receptors for this class of drug, permitting increased drug effect.
D000818:Animals; D003128:Coma / Q000209:etiology / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005445:Flunitrazepam / Q000378:metabolism; D005688:Galactosamine; D006501:Hepatic Encephalopathy / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D011817:Rabbits; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011963:Receptors, GABA-A; D013570:Synaptic Membranes / Q000378:metabolism; D014511:Uremia / Q000150:complications / Q000378:metabolism
D008565:Membrane Proteins; D011956:Receptors, Cell Surface; D011963:Receptors, GABA-A; D005445:Flunitrazepam; D005688:Galactosamine