Coadministered nitrous oxide enhances the effect of isoflurane on GABAergic transmission by an increase in open-channel block

Clinically relevant concentrations of isoflurane (ISO) and nitrous oxide (N 2O) enhance chloride currents induced by activating gamma -aminobutyric aci d, receptors (GABA(A)R). Channel blocking by ISO overcomes the enhancing ef fect at higher concentrations. In this study, the effect of coadministered ISO and N2O on responses evoked by GABA in transfected human embryonic kidn ey 293 cells carrying alpha (1),beta (2)gamma (2L) GABA(A)R was investigate d. Patch-clamp recordings from these cells were performed in the whole cell mode. A piezo-driven "liquid filament" drug application system was used to apply solutions of GABA, ISO, and N2O. Increasing the concentration of ISO in steps from 0.15 to 1.2 mM resulted in a bell-shaped concentration-respo nse curve for GABA-induced currents. The maximum increase in current (1.51 +/- 0.14-fold) was seen at 0.45 mM ISO (about 1 minimum alveolar concentrat ion, EG(50)). N2O (29.2 mM) increased GABA-evoked currents 1.54 +/- 0.10-fo ld. The enhancing effects of ISO and N2O on the GABAergic response were not additive. However, a transient current, associated with the rapid withdraw al of ISO from the receptor, was markedly increased by N2O. Such rebound cu rrents probably reflect the transition from a "channel-blocked" to a "reope ned" state. An open-channel block at ligand-gated receptors can prolong pos tsynaptic currents. Thus, we conclude that coadministered N2O could increas e the enhancing effect of ISO on the GABAergic transmission by an increase in open-channel block at the GABA(A)R.