title: Coadministered nitrous oxide enhances the effect of isoflurane on GABAergic transmission by an increase in open-channel block.
abstract: Clinically relevant concentrations of isoflurane (ISO) and nitrous oxide (N2O) enhance chloride currents induced by activating gamma-aminobutyric acid(A) receptors (GABA(A)R). Channel blocking by ISO overcomes the enhancing effect at higher concentrations. In this study, the effect of coadministered ISO and N2O on responses evoked by GABA in transfected human embryonic kidney 293 cells carrying alpha1beta2gamma2L GABA(A)R was investigated. 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-response 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 concentration, EC50). N2O (29.2 mM) increased GABA-evoked currents 1.54 +/- 0.10-fold. The enhancing effects of ISO and N2O on the GABAergic response were not additive. However, a transient current, associated with the rapid withdrawal of ISO from the receptor, was markedly increased by N2O. Such rebound currents probably reflect the transition from a "channel-blocked" to a "reopened" state. An open-channel block at ligand-gated receptors can prolong postsynaptic currents. Thus, we conclude that coadministered N2O could increase the enhancing effect of ISO on the GABAergic transmission by an increase in open-channel block at the GABA(A)R.
authors.affiliation: Department of Anaesthesiology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. hapfelmeier@mpipskyl.mpg.de
authors.forename: G
authors.initials: G
authors.lastname: Hapfelmeier
authors.forename: R
authors.initials: R
authors.lastname: Haseneder
authors.forename: E
authors.initials: E
authors.lastname: Kochs
authors.forename: M
authors.initials: M
authors.lastname: Beyerle
authors.forename: W
authors.initials: W
authors.lastname: Zieglgänsberger
mesh_terms: D018685:Anesthetics, Inhalation / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D004338:Drug Combinations; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects* / Q000502:physiology; D007530:Isoflurane / Q000008:administration & dosage / Q000494:pharmacology*; D007668:Kidney / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D009609:Nitrous Oxide / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D018685:Anesthetics, Inhalation; D004338:Drug Combinations; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; D007530:Isoflurane; D009609:Nitrous Oxide