title: Nonstereoselective inhibition of neuronal nicotinic acetylcholine receptors by ketamine isomers.
abstract: We have found that racemic ketamine strongly inhibits the current mediated through neuronal nicotinic acetylcholine receptors (nAchRs) in PC12 cells, a rat pheochromocytoma cell line. Ketamine stereoisomers have different potencies for the anesthetic action, with the S-enantiomer being about 3 times as potent as the R-enantiomer. The purpose of this study was to clarify if the inhibitory effects of ketamine on neuronal nAchRs contribute to their anesthetic effect. We compared potencies of ketamine enantiomers for neuronal nAchR inhibition with those for the anesthetic action. S(+) and R(-) ketamine inhibited the nicotine-induced whole-cell current in a dose-dependent manner at the membrane potential of -60 mV. They accelerated the current decay, resulting in the larger effects on the nondesensitized current than on the peak current. There was no significant difference in the concentrations for 50% inhibition between the stereoisomers. The ketamine isomers exerted the same effects on single-channel properties estimated from analysis of the nicotine-induced current noise. These results indicate that the inhibitory action of ketamine isomers on neuronal nAchRs is not stereoselective. Although our findings do not deny possible involvement of these receptors in ketamine anesthesia, they suggest that inhibition of neuronal nAchRs is not primarily responsible for the anesthetic action of this anesthetic.
  
  
  CONCLUSIONS
  We found that inhibition of neuronal nicotinic acetylcholine receptors by ketamine is not stereoselective in PC12 cells. The result suggests that this effect does not directly correlate with the anesthetic action of ketamine.
authors.affiliation: Department of Anesthesiology, Yokohama City University School of Medicine, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Sasaki
authors.forename: T
authors.initials: T
authors.lastname: Andoh
authors.forename: I
authors.initials: I
authors.lastname: Watanabe
authors.forename: Y
authors.initials: Y
authors.lastname: Kamiya
authors.forename: H
authors.initials: H
authors.lastname: Itoh
authors.forename: T
authors.initials: T
authors.lastname: Higashi
authors.forename: T
authors.initials: T
authors.lastname: Matsuura
mesh_terms: D000465:Algorithms; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D007649:Ketamine / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D009538:Nicotine / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D016716:PC12 Cells; D018408:Patch-Clamp Techniques; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects*; D013237:Stereoisomerism; D014101:Torpedo
chemical_list: D018691:Excitatory Amino Acid Antagonists; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D007649:Ketamine; D009538:Nicotine