Effects of Gaseous Anesthetics Nitrous Oxide and Xenon on Ligand-gated Ion Channels: Comparison with Isoflurane and Ethanol

BackgroundLigand-gated ion channels are considered to be potential general anesthetic targets. Although most general anesthetics potentiate the function of &ggr;-aminobutyric acid receptor type A (GABAA), the gaseous anesthetics nitrous oxide and xenon are reported to have little effect on GABAA 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. MethodsThe glycine, GABAA, GABA receptor type C (GABAC), NMDA, &agr;-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), kainate, 5-hydroxytryptamine3 (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. ResultsNitrous oxide (0.58 atmosphere [atm]) and xenon (0.46 atm) exhibited similar effects on various receptors. Glycine and GABAA receptors were potentiated by gaseous anesthetics much less than by isoflurane, whereas nitrous oxide inhibited GABAC 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 &agr;4&bgr;2 and &agr;4&bgr;4 nACh receptors; &agr;4&bgr;2 receptors were inhibited by nitrous oxide by 39%, whereas &agr;4&bgr;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. ConclusionsNitrous 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 &bgr;2 subunits are likely targets for nitrous oxide and xenon.

[1]  J. Changeux,et al.  Reduced antinociception in mice lacking neuronal nicotinic receptor subunits , 1999, Nature.

[2]  R. Harris,et al.  Anaesthetic concentrations of alcohols potentiate GABAA receptor-mediated currents: lack of subunit specificity. , 1994, European journal of pharmacology.

[3]  D. Lodge,et al.  Effects of optical isomers of ketamine on excitation of cat and rat spinal neurones by amino acids and acetylcholine , 1982, Neuroscience Letters.

[4]  R. Harris,et al.  Inhibition of rho1 receptor GABAergic currents by alcohols and volatile anesthetics. , 1996, The Journal of pharmacology and experimental therapeutics.

[5]  Nicholas P. Franks,et al.  Contrasting Synaptic Actions of the Inhalational General Anesthetics Isoflurane and Xenon , 2000, Anesthesiology.

[6]  C. Gotti,et al.  Human neuronal nicotinic receptors , 1997, Progress in Neurobiology.

[7]  B. van Duijn,et al.  Nitrous Oxide‐induced Enhancement of gamma‐Aminobutyric Acid sub A‐mediated Chloride Currents in Acutely Dissociated Hippocampal Neurons , 1998, Anesthesiology.

[8]  S. Antonarakis,et al.  Cloning of the gamma-aminobutyric acid (GABA) rho 1 cDNA: a GABA receptor subunit highly expressed in the retina. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[9]  W. R. Lieb,et al.  Molecular and cellular mechanisms of general anaesthesia , 1994, Nature.

[10]  S. Heinemann,et al.  Cloning of a cDNA for a glutamate receptor subunit activated by kainate but not AMPA , 1991, Nature.

[11]  E. Eger,et al.  Actions of fluorinated alkanols on GABA(A) receptors: relevance to theories of narcosis. , 1999, Anesthesia and analgesia.

[12]  N. Harrison,et al.  General anaesthetic actions on ligand-gated ion channels , 1999, Cellular and Molecular Life Sciences CMLS.

[13]  J. Trudell,et al.  Sites of Volatile Anesthetic Action on Kainate (Glutamate Receptor 6) Receptors* , 1998, The Journal of Biological Chemistry.

[14]  M. Hudspith.  Glutamate: a role in normal brain function, anaesthesia, analgesia and CNS injury. , 1997, British journal of anaesthesia.

[15]  R. Harris,et al.  Sites of alcohol and volatile anaesthetic action on GABAA and glycine receptors , 1997, Nature.

[16]  J. Olney,et al.  Nitrous oxide (laughing gas) is an NMDA antagonist, neuroprotectant and neurotoxin , 1998, Nature Medicine.

[17]  L. Arendt-Nielsen,et al.  Comparison of the analgesic potency of xenon and nitrous oxide in humans evaluated by experimental pain. , 1998, British journal of anaesthesia.

[18]  Relative potencies of volatile anesthetics in altering the kinetics of ion channels in BC3H1 cells. , 1995, The Journal of pharmacology and experimental therapeutics.

[19]  G. Biggio,et al.  Actions of the general anesthetic propofol on recombinant human GABAA receptors: influence of receptor subunits. , 1995, The Journal of pharmacology and experimental therapeutics.

[20]  S. Daniels,et al.  Post-synaptic inhibitory mechanisms of anaesthesia; glycine receptors. , 1998, Toxicology letters.

[21]  L. Firestone,et al.  Anaesthetic potencies of primary alkanols: implications for the molecular dimensions of the anaesthetic site , 1989, British journal of pharmacology.

[22]  E. Eger,et al.  Anesthetics produce subunit-selective actions on glutamate receptors. , 1996, The Journal of pharmacology and experimental therapeutics.

[23]  R. Dickinson,et al.  How does xenon produce anaesthesia? , 1998, Nature.

[24]  B. Hames,et al.  Transcription and translation : a practical approach , 1984 .

[25]  A. Pohorille,et al.  Minimum alveolar anesthetic concentration of fluorinated alkanols in rats: relevance to theories of narcosis. , 1999, Anesthesia and analgesia.

[26]  C. Luetje,et al.  Neuronal Nicotinic Receptor β2 and β4 Subunits Confer Large Differences in Agonist Binding Affinity , 1998 .

[27]  J. Sikela,et al.  Role of the beta subunit in determining the pharmacology of human gamma-aminobutyric acid type A receptors. , 1993, Molecular pharmacology.

[28]  R. Harris,et al.  Effects of ethanol on recombinant human neuronal nicotinic acetylcholine receptors expressed in Xenopus oocytes. , 1999, The Journal of pharmacology and experimental therapeutics.

[29]  P. Flood,et al.  Alpha4beta2 Neuronal Nicotinic Acetylcholine Receptors in the Central Nervous System Are Inhibited by Isoflurane and Propofol, but alpha7‐type Nicotinic Acetylcholine Receptors Are Unaffected , 1997, Anesthesiology.

[30]  T. Yamakura,et al.  Subunit-dependent Inhibition of Human Neuronal Nicotinic Acetylcholine Receptors and Other Ligand-gated Ion Channels by Dissociative Anesthetics Ketamine and Dizocilpine , 2000, Anesthesiology.

[31]  L. Role,et al.  Nicotinic Receptors in the Development and Modulation of CNS Synapses , 1996, Neuron.

[32]  W. Shen,et al.  Effect of Nitrous Oxide on Excitatory and Inhibitory Synaptic Transmission in Hippocampal Cultures , 1998, The Journal of Neuroscience.

[33]  W. R. Lieb,et al.  Differential Sensitivities of Mammalian Neuronal and Muscle Nicotinic Acetylcholine Receptors to General Anesthetics , 1997, Anesthesiology.

[34]  S. Heinemann,et al.  Molecular cloning and functional expression of glutamate receptor subunit genes. , 1990, Science.

[35]  J. Gaddum,et al.  The Pharmacological Basis of Therapeutics , 1966 .

[36]  T. Mohandas,et al.  Alpha subunit variants of the human glycine receptor: primary structures, functional expression and chromosomal localization of the corresponding genes. , 1990, The EMBO journal.

[37]  R. Myers,et al.  Primary structure and functional expression of the 5HT3 receptor, a serotonin-gated ion channel. , 1991, Science.

[38]  T. Yamakura,et al.  Human neuronal nicotinic acetylcholine receptors expressed in Xenopus oocytes predict efficacy of halogenated compounds that disobey the Meyer-Overton rule. , 1999, Anesthesiology.

[39]  K. Wafford,et al.  Cloning, Functional Coexpression, and Pharmacological Characterisation of Human cDNAs Encoding NMDA Receptor NR1 and NR2A Subunits , 1994, Journal of neurochemistry.

[40]  P. Sargent,et al.  The diversity of neuronal nicotinic acetylcholine receptors. , 1993, Annual review of neuroscience.