title: I.v. anaesthetic agents inhibit dihydropyridine binding to L-type voltage-sensitive Ca2+ channels in rat cerebrocortical membranes.
abstract: Previous studies have implicated the neuronal L-type voltage-sensitive Ca2+ channel (VSCC) as a target site for i.v. anaesthetic agents. It is unclear if these agents interact with the L-channel alpha-subunit 1,4-dihydropyridine (DHP) binding site. In this study, we have examined the interaction of thiopentone, pentobarbitone, ketamine, etomidate, propofol and alphaxalone, and the non-anaesthetic barbiturate, barbituric acid, with the DHP binding site on rat cerebrocortical membranes. Binding assays were performed in 1-ml volumes of Tris-HCl 50 mmol litre-1, pH 7.4, for 90 min at room temperature containing 200 micrograms of membrane protein with [3H]PN200-110 as a radiolabelled DHP. Non-specific binding was defined in the presence of nifedipine 10(-5) mol litre-1. The interaction of i.v. anaesthetics was determined by displacement of [3H]PN200-110 0.2 nmol litre-1. All i.v. anaesthetics showed some interaction with the DHP binding site. The concentrations of anaesthetic producing 25% inhibition of specific binding (corrected for the competing mass of [3H]PN200-110), K25 were (mumol litre-1): thiopentone 48 (SEM 2), pentobarbitone 95 (7), propofol 40 (2), etomidate 25 (2), alphaxalone 17 (3) and ketamine 198 (16). Barbituric acid was ineffective. With the exception of ketamine, there was a significant correlation between K25 and peak serum concentration during anaesthesia (P = 0.033) and serum concentrations on wakening (P = 0.018), suggesting that the L-channel DHP binding site may be a target for i.v. anaesthetic agents.
authors.affiliation: Department of Anaesthesia, Leicester Royal Infirmary.
authors.forename: K
authors.initials: K
authors.lastname: Hirota
authors.forename: D G
authors.initials: DG
authors.lastname: Lambert
mesh_terms: D018686:Anesthetics, Intravenous / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive; D002121:Calcium Channel Blockers / Q000378:metabolism*; D015220:Calcium Channels / Q000187:drug effects* / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D046508:Culture Techniques; D004095:Dihydropyridines / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D051381:Rats; D017208:Rats, Wistar
chemical_list: D018686:Anesthetics, Intravenous; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004095:Dihydropyridines; C038806:1,4-dihydropyridine