Stereoselective and non‐stereoselective actions of isoflurane on the GABAA receptor

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Abstract
1 Acutely dissociated cerebellar Purkinje neurones from 8–14 day old rats were studied under voltage clamp in the whole-cell patch-clamp configuration. Cl− currents induced by bath application of γ-aminobutyric acid (GABA) were measured (using symmetrical Cl− solutions) at both low (2 μm) non-desensitizing and high (300 μm) desensitizing concentrations of GABA. 2 At 2 μm GABA, the bicuculline-sensitive Cl− currents were potentiated by racemic isoflurane and both of its optical isomers. Isoflurane had no effect on membrane current in the absence of GABA. The dose-response data for potentiation by racemic isoflurane could be fitted with a Hill equation with an EC50 = 320 ± 20 μm isoflurane and a Hill coefficient of h = 2.7 ± 0.4 (means ± s.e.mean). 3 The potentiations produced by the optical isomers of isoflurane at 2 μm GABA were stereoselective at moderate and high anaesthetic concentrations. The maximum stereoselectivity, about two fold, occurred at the EC50 concentration for general anaesthesia (310 μm isoflurane), with S(+)-isoflurane being more effective than R(−)-isoflurane. At sub-anaesthetic concentrations, the stereoselectivity was less marked and vanished at the lowest concentration used (77 μm isoflurane). 4 The sustained residual current remaining after exposure of neurones to a desensitizing concentration of GABA (300 μm) was inhibited non-stereoselectively, but only at high concentrations of isoflurane. The ratio of inhibitions by S(+)- and R(−)-isoflurane (mean ± s.e.mean) was 1.14 ± 0.21 at 770 μm isoflurane. At the EC50 concentration for general anaesthesia, however, the inhibition was barely significant. 5 The above results are discussed in relation to the possible role of the GABAA receptor channel in general anaesthesia.