title: In vitro antagonism of recombinant ligand-gated ion-channel receptors by stereospecific enantiomers of bupivacaine.
abstract: OBJECTIVE
  Bupivacaine is a racemic mixture of S(-)- and R(+)-enantiomers. Both isomers have similar potency as local anesthetics, but the S(-)-enantiomer produces less central nervous system and cardiovascular toxicity. Local anesthetic-induced convulsion is likely to be associated with not only sodium channel but also ligand-gated ion channel. The present study investigates the direct effects of the stereoenantiomers of bupivacaine on 4 recombinant ligand-gated ion-channel receptors.
  
  
  METHODS
  The antagonist activities of the S(-)- and R(+)-enantiomers of bupivacaine were tested at the nicotinic acetylcholine, N-methyl-d-aspartate (NMDA), gamma-aminobutyric acid(A) (GABA(A)), and 5-hydroxytryptamine(3A) (5-HT(3A)) receptors expressed in Xenopus oocytes using a 2-voltage clamp technique.
  
  
  RESULTS
  Racemic bupivacaine and its 2 enantiomers all antagonized the 4 receptors in a concentration-dependent manner. Potencies at nicotinic acetylcholine, NMDA, and 5-HT(3A) receptors were similar. At GABA(A) receptors, the potency of R(+)-bupivacaine was less than racemic bupivacaine or levobupivacaine.
  
  
  CONCLUSIONS
  Comparison of the antagonist potencies with local concentrations obtained in clinical use suggests that bupivacaine and its enantiomers are likely to produce extensive inhibition at the nicotinic acetylcholine, NMDA, and 5-HT(3A) receptors but a much weaker and probably not clinically relevant effect at the GABA(A) receptor. It is possible that direct effects at these receptors may contribute, at least in part, to the spinal and epidural anesthesia induced by these compounds. It is unlikely, however, that the difference of the toxicity in bupivacaine enantiomers is because of the stereoselectivities of bupivacaine at ligand-gated ion-channel receptors studied.
authors.affiliation: Department of Anesthesia, Japan Labour Health and Welfare Organization, Kansai Rosai Hospital, Amagasaki, Hyogo, Japan. kueta@anes.med.osaka-u.ac.jp
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Ueta
authors.forename: Masahiro
authors.initials: M
authors.lastname: Sugimoto
authors.forename: Takahiro
authors.initials: T
authors.lastname: Suzuki
authors.forename: Ichiro
authors.initials: I
authors.lastname: Uchida
authors.forename: Takashi
authors.initials: T
authors.lastname: Mashimo
mesh_terms: D000779:Anesthetics, Local / Q000494:pharmacology*; D000818:Animals; D002045:Bupivacaine / Q000031:analogs & derivatives / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D058787:GABA-A Receptor Antagonists; D007473:Ion Channels / Q000187:drug effects; D000077554:Levobupivacaine; D018733:Nicotinic Antagonists; D009865:Oocytes / Q000187:drug effects; D018408:Patch-Clamp Techniques; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D011978:Receptors, Nicotinic / Q000187:drug effects*; D058831:Serotonin 5-HT3 Receptor Antagonists; D013237:Stereoisomerism; D014981:Xenopus
chemical_list: D000779:Anesthetics, Local; D058787:GABA-A Receptor Antagonists; D007473:Ion Channels; D018733:Nicotinic Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D011978:Receptors, Nicotinic; D058831:Serotonin 5-HT3 Receptor Antagonists; D000077554:Levobupivacaine; D002045:Bupivacaine