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

Background: Ligand-gated ion channels are considered to be potential genera l anesthetic targets. Although most general anesthetics potentiate the func tion of gamma-aminobutyric acid receptor type A (GABA(A)), the gaseous anes thetics nitrous oxide and xenon are reported to have little effect on GABA( A) receptors but inhibit N-methyl-D-aspartate (NMDA) receptors. To define t he spectrum of effects of nitrous oxide and xenon on receptors thought to b e important in anesthesia, the authors tested these anesthetics on a variet y 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-hydr oxytryptamine(3) (5-HT3), and nicotinic acetylcholine (nACh) receptors were expressed in Xenopus oocytes and effects of nitrous oxide and xenon, and a s equipotent concentrations of isoflurane and ethanol, were studied using t he two-electrode voltage clamp. Results: Nitrous oxide (0.58 atmosphere [atm]) and xenon (0.46 atm) exhibit ed similar effects on various receptors, Glycine and GABA(A) receptors were potentiated by gaseous anesthetics much less than by isoflurane, whereas n itrous oxide inhibited GABA(C) receptors. Glutamate receptors were inhibite d 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 i nhibited by nitrous oxide, The nACh receptors were inhibited by gaseous and volatile anesthetics, but ethanol potentiated them. The sensitivity was di fferent between alpha 4 beta 2 and alpha 4 beta 4 nACh receptors; alpha 4 b eta 2 receptors were inhibited by nitrous oxide by 39%, whereas alpha 4 bet a 4 receptors were Inhibited by 7%. The inhibition of NMDA and nACh recepto rs 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 recept or actions, but this spectrum is distinct from that of Isoflurane or ethano l. These results suggest that NMDA receptors and nACh receptors composed of beta 2 subunits are likely targets for nitrous oxide and xenon.