Inhibitory effects of intravenous anaesthetic agents on K+-evoked glutamate release from rat cerebrocortical slices. Involvement of voltage-sensitive Ca2+ channels and GABAA receptors
It is widely accepted that most general anaesthetic agents depress the central nervous system (CNS) by potentiation or activation of the GABAA receptor-mediated Cl– conductance. These agents also reportedly inhibit voltage-sensitive Ca2+ 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 GABAA receptor antagonist bicuculline (100 µM). 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 GABAA receptor agonist, muscimol. Glutamate released into the incubation medium was determined by a glutamate dehydrogenase-coupled assay. ω-Agatoxin IVA (P-type VSCC), ω-conotoxin MVIIC (P/Q-type VSCC) and Cd2+ (non-selective) essentially abolished glutamate release whilst nifedipine (L-type VSCC) and ω-conotoxin GVIA (N-type VSCC) reduced release by less than 30%. The concentrations producing 50% of the maximum inhibition (IC50) for thiopental, pentobarbital, phenobarbital, alphaxalone, propofol and ketamine were (in µM) 8.3, 22, 112, 6.3, 83 and 120, respectively. Barbituric acid produced a small (about 20%) inhibition. With the exception of ketamine, the IC50 values for these anaesthetic agents were increased threefold by bicuculline (100 µM). In addition, muscimol significantly inhibited release by 26% with an IC50 of 1.1 µM. 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 GABAA receptor plays a role in this response.
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