In vitro antagonism of recombinant ligand-gated ion-channel receptors by stereospecific enantiomers of bupivacaine

Background and Objectives: Bupivacaine is a racemic mixture of S(-)- and R(+)-enantiomers. Both isomers have similar potency as local anesthetics, but the S(-)-enantiorner produces less central nervous system and cardiovascular toxicity. Local anestbetic-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 bupivacame on 4 recombinant ligand-gated ion-channel receptors. Methods: The antagonist activities of the S(-)- and R(+)-enantiomers of bupivacame were tested at the nicotinic acetylcholine, N-methyl-D-aspartate (NMDA), gamma-aminobutyric acid(A) (GABA(A)), and 5-hydroxytryptamine(3A) (5-HT3A) receptors expressed in Xenopus oocytes using a 2-voltage clamp technique. Results: Racemic bupivacaine and its 2 enantionters all antagonized the 4 receptors in a concentration-dependent manner. Potencies at nicotinic acetylcholine, NMDA, and 5-HT3A 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-HT3A 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.