title: Inhibitory effects of intravenous anaesthetic agents on K(+)-evoked glutamate release from rat cerebrocortical slices. Involvement of voltage-sensitive Ca(2+) channels and GABA(A) receptors.
abstract: It is widely accepted that most general anaesthetic agents depress the central nervous system (CNS) by potentiation or activation of the GABA(A) receptor-mediated Cl(-) conductance. These agents also reportedly inhibit voltage-sensitive Ca(2+) channels (VSCCs), thus depressing excitatory transmission in the CNS. However, in this regard there are few functional data at the level of neurotransmitter release. In this study we examined the effects of VSCC antagonists and a range of intravenous anaesthetic agents on K(+)(40 mM)-evoked glutamate release from rat cerebrocortical slices in the absence and presence of the GABA(A) receptor antagonist bicuculline (100 microM). We employed both selective and non-selective VSCC antagonists, the anaesthetic barbiturates thiopental, pentobarbital and phenobarbital, the non-anaesthetic barbiturate barbituric acid, the non-barbiturate anaesthetics alphaxalone, propofol and ketamine and the GABA(A) receptor agonist, muscimol. Glutamate released into the incubation medium was determined by a glutamate dehydrogenase-coupled assay. Omega-agatoxin IV(A) (P-type VSCC), omega-conotoxin MVII(C) (P/Q-type VSCC) and Cd(2+) (non-selective) essentially abolished glutamate release whilst nifedipine (L-type VSCC) and omega-conotoxin GVI(A) (N-type VSCC) reduced release by less than 30%. The concentrations producing 50% of the maximum inhibition (IC(50)) for thiopental, pentobarbital, phenobarbital, alphaxalone, propofol and ketamine were (in microM) 8.3, 22, 112, 6.3, 83 and 120, respectively. Barbituric acid produced a small (about 20%) inhibition. With the exception of ketamine, the IC(50) values for these anaesthetic agents were increased threefold by bicuculline (100 microM). In addition, muscimol significantly inhibited release by 26% with an IC(50) of 1.1 microM. In summary, a range of anaesthetic agents at clinically achievable concentrations inhibit glutamate release and this inhibition of release appears to be due mainly to direct inhibition of P/Q-type VSCCs, although activation of the GABA(A) receptor plays a role in this response.
authors.affiliation: Department of Anesthesiology, University of Hirosaki, School of Medicine, Hirosaki 036-8563, Japan.
authors.forename: Masatou
authors.initials: M
authors.lastname: Kitayama
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Hirota
authors.forename: Mihoko
authors.initials: M
authors.lastname: Kudo
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Kudo
authors.forename: Hironori
authors.initials: H
authors.lastname: Ishihara
authors.forename: Akitomo
authors.initials: A
authors.lastname: Matsuki
mesh_terms: D018686:Anesthetics, Intravenous / Q000494:pharmacology*; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D002104:Cadmium / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism*; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D009118:Muscimol / Q000494:pharmacology; D009543:Nifedipine / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism; D020867:omega-Agatoxin IVA / Q000494:pharmacology; D020866:omega-Conotoxin GVIA / Q000494:pharmacology; D020960:omega-Conotoxins / Q000494:pharmacology
chemical_list: D018686:Anesthetics, Intravenous; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D018755:GABA Agonists; D018756:GABA Antagonists; D011963:Receptors, GABA-A; D020867:omega-Agatoxin IVA; D020960:omega-Conotoxins; D002104:Cadmium; C075851:omega-conotoxin-MVIIC; D009118:Muscimol; D018698:Glutamic Acid; D020866:omega-Conotoxin GVIA; D009543:Nifedipine; D011188:Potassium; D001640:Bicuculline