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Stereoselective and non‐stereoselective actions of isoflurane on the GABA A receptor

1994; Wiley; Volume: 112; Issue: 3 Linguagem: Inglês

10.1111/j.1476-5381.1994.tb13166.x

1476-5381

Adam C. Hall, W.R. Lieb, Nicholas P. Franks,

Ion channel regulation and function

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 μ m ) non‐desensitizing and high (300 μ m ) desensitizing concentrations of GABA. At 2 μ m 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 EC 50 = 320 ± 20 μ m isoflurane and a Hill coefficient of h = 2.7 ± 0.4 (means ± s.e.mean). The potentiations produced by the optical isomers of isoflurane at 2 μ m GABA were stereoselective at moderate and high anaesthetic concentrations. The maximum stereoselectivity, about two fold, occurred at the EC 50 concentration for general anaesthesia (310 μ m 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 μ m isoflurane). The sustained residual current remaining after exposure of neurones to a desensitizing concentration of GABA (300 μ m ) 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 μ m isoflurane. At the EC 50 concentration for general anaesthesia, however, the inhibition was barely significant. The above results are discussed in relation to the possible role of the GABA A receptor channel in general anaesthesia.