Effects of gaseous anesthetics nitrous oxide and xenon on ligand-gated ion channels: Comparison with isoflurane and ethanol

Background: Ligand-gated ion channels are considered to be potential general anesthetic targets. Although most general anesthetics potentiate the function of gamma-aminobutyric acid receptor type A (GABA(A)), the gaseous anesthetics nitrous oxide and xenon are reported to have little effect on GABA(A) receptors but inhibit N-methyl-D-aspartate (NMDA) receptors. To define the spectrum of effects of nitrous oxide and xenon on receptors thought to be important in anesthesia, the authors tested these anesthetics on a variety of recombinant brain receptors, Methods: The glycine, GABA(A), GABA receptor type C (GABA(C)), NMDA, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), kainate, 5-hydroxytryptamine(3) (5-HT3), and nicotinic acetylcholine (nACh) receptors were expressed in Xenopus oocytes and effects of nitrous oxide and xenon, and as equipotent concentrations of isoflurane and ethanol, were studied using the two-electrode voltage clamp. Results: Nitrous oxide (0.58 atmosphere [atm]) and xenon (0.46 atm) exhibited similar effects on various receptors, Glycine and GABA(A) receptors were potentiated by gaseous anesthetics much less than by isoflurane, whereas nitrous oxide inhibited GABA(C) receptors. Glutamate receptors were inhibited by gaseous anesthetics more markedly than by isoflurane, but less than by ethanol, NMDA receptors were the most sensitive among glutamate receptors and were inhibited by nitrous oxide by 31%, 5-HT3 receptors were slightly inhibited by nitrous oxide, The nACh receptors were inhibited by gaseous and volatile anesthetics, but ethanol potentiated them. The sensitivity was different between alpha 4 beta 2 and alpha 4 beta 4 nACh receptors; alpha 4 beta 2 receptors were inhibited by nitrous oxide by 39%, whereas alpha 4 beta 4 receptors were Inhibited by 7%. The inhibition of NMDA and nACh receptors by nitrous oxide was noncompetitive and was slightly different depending on membrane potentials for NMDA receptors, but not for nACh receptors. Conclusions: Nitrous oxide and xenon displayed a similar spectrum of receptor actions, but this spectrum is distinct from that of Isoflurane or ethanol. These results suggest that NMDA receptors and nACh receptors composed of beta 2 subunits are likely targets for nitrous oxide and xenon.