title: Neurochemical action of the general anaesthetic propofol on the chloride ion channel coupled with GABAA receptors.
abstract: The effect of propofol, a novel short acting anaesthetic, on the function of the GABAA/ionophore receptor complex was studied in vitro in cortical membrane preparations from rat cerebral cortex and was compared with the action of pentobarbital and alphaxalone, two general anaesthetics known to enhance GABAergic transmission. Propofol, mimicking the action of pentobarbital and alphaxalone, increased [3H]GABA binding, reduced [35S]TBPS binding and enhanced muscimol-stimulated 36Cl- uptake in a concentration-dependent manner. While the efficacy of the drugs in affecting these biochemical parameters was similar, they differed markedly in potency being alphaxalone greater than propofol greater than pentobarbital. However, separate sites of action or different mechanisms for these drugs can be suggested by the result that the concomitant addition of propofol either with alphaxalone or pentobarbital or diazepam produced a simple additive inhibition of [35S]TBPS binding as well as an additive enhancement of [3H]GABA binding and muscimol-stimulated 36Cl- uptake. The effect of propofol at the level of the GABA/ionophore receptor complex seems to be strictly dependent on the interaction of GABA with its recognition site. In fact, the specific GABAA receptor antagonist bicuculline antagonized the decrease of [35S]TBPS binding as well as the enhancement of [3H]GABA binding and muscimol-stimulated 36Cl- uptake induced by propofol. On the other hand, propofol was able to enhance [3H]GABA binding in membranes previously incubated with the specific chloride channel blocker picrotoxin. Finally, the finding that propofol fails to affect [3H]flunitrazepam binding together with the failure of Ro 15-1788 and PK 11195 to antagonize its effect on [35S]TBPS binding excludes a direct interaction at the level of benzodiazepine recognition sites.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Experimental Biology, University of Cagliari, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Concas
authors.forename: G
authors.initials: G
authors.lastname: Santoro
authors.forename: M
authors.initials: M
authors.lastname: Serra
authors.forename: E
authors.initials: E
authors.lastname: Sanna
authors.forename: G
authors.initials: G
authors.lastname: Biggio
mesh_terms: D000777:Anesthetics / Q000494:pharmacology; D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018118:Chloride Channels; D002712:Chlorides / Q000378:metabolism; D005445:Flunitrazepam / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000187:drug effects / Q000378:metabolism*; D009118:Muscimol / Q000494:pharmacology; D015742:Propofol / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000777:Anesthetics; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018118:Chloride Channels; D002712:Chlorides; D008565:Membrane Proteins; D011963:Receptors, GABA-A; D009118:Muscimol; D005445:Flunitrazepam; C037476:tert-butylbicyclophosphorothionate; D015742:Propofol