Ac. Hall et al., STEREOSELECTIVE AND NON-STEREOSELECTIVE ACTIONS OF ISOFLURANE ON THE GABA(A) RECEPTOR, British Journal of Pharmacology, 112(3), 1994, pp. 906-910
1 Acutely dissociated cerebellar Purkinje neurones from 8-14 day old r
ats were studied under voltage clamp in the whole-cell patch-clamp con
figuration. Cl- currents induced by bath application of gamma-aminobut
yric acid (GABA) were measured (using symmetrical Cl- solutions) at bo
th low (2 mu M) non-desensitizing and high (300 mu M) desensitizing co
ncentrations of GABA. 2 At 2 mu M GABA, the bicuculline-sensitive Cl-
currents were potentiated by racemic isoflurane and both of its optica
l isomers. Isoflurane had no effect on membrane current in the absence
of GABA. The dose-response data for potentiation by racemic isofluran
e could be fitted with a Hill equation with an EC(50) = 320 +/- 20 mu
M isoflurane and a Hill coefficient of h = 2.7 +/- 0.4 (means +/- s.e.
mean). 3 The potentiations produced by the optical isomers of isoflura
ne at 2 mu M GABA were stereoselective at moderate and high anaestheti
c concentrations. The maximum stereoselectivity, about two fold, occur
red at the EC(50) concentration for general anaesthesia (310 mu M isof
lurane), with S(+)-isoflurane being more effective than R(-)-isofluran
e. At sub-anaesthetic concentrations, the stereoselectivity was less m
arked and vanished at the lowest concentration used (77 mu M isofluran
e). 4 The sustained residual current remaining after exposure of neuro
nes to a desensitizing concentration of GABA (300 mu 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 mu M isoflurane. At the EC(50) concentratio
n for general anaesthesia, however, the inhibition was barely signific
ant. 5 The above results are discussed in relation to the possible rol
e of the GABA(A), receptor channel in general anaesthesia.