title: Lidocaine stabilizes the open state of CNS voltage-dependent sodium channels.
abstract: We have previously reported that the lidocaine action is different between CNS and muscle batrachotoxin-modified Na+ channels [Salazar et al., J. Gen. Physiol. 107 (1996) 743-754; Brain Res. 699 (1995) 305-314]. In this study we examined lidocaine action on CNS Na+ currents, to investigate the mechanism of lidocaine action on this channel isoform and to compare it with that proposed for muscle Na+ currents. Na+ currents were measured with the whole cell voltage clamp configuration in stably transfected cells expressing the brain alpha-subunit (type IIA) by itself (alpha-brain) or together with the brain beta(1)-subunit (alphabeta(1)-brain), or the cardiac alpha-subunit (hH1) (alpha-cardiac). Lidocaine (100 microM) produced comparable levels of Na+ current block at positive potentials and of hyperpolarizing shift of the steady-state inactivation curve in alpha-brain and alphabeta(1)-brain Na+ currents. Lidocaine accelerated the rates of activation and inactivation, produced an hyperpolarizing shift in the steady-state activation curve and increased the current magnitude at negative potentials in alpha-brain but not in alphabeta(1)-brain Na+ currents. The lidocaine action in alphabeta(1)-brain resembled that observed in alpha-cardiac Na+ currents. The lidocaine-induced increase in current magnitude at negative potentials and the hyperpolarizing shift in the steady-state activation curve of alpha-brain, are novel effects and suggest that lidocaine treatment does not always lead to current reduction/block when it interacts with Na+ channels. The data are explained by using a modified version of the model proposed by Vedantham and Cannon [J. Gen. Physiol., 113 (1999) 7-16] in which we postulate that the difference in lidocaine action between alpha-brain and alphabeta(1)-brain Na+ currents could be explained by differences in the lidocaine action on the open channel state.
authors.affiliation: Hospital For Special Surgery, Department of Anesthesiology, 535 East 70th Street, New York, NY 10021, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Castañeda-Castellanos
authors.forename: Igor
authors.initials: I
authors.lastname: Nikonorov
authors.forename: Roland G
authors.initials: RG
authors.lastname: Kallen
authors.forename: E
authors.initials: E
authors.lastname: Recio-Pinto
mesh_terms: D000200:Action Potentials / Q000187:drug effects* / Q000502:physiology; D000779:Anesthetics, Local / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D002490:Central Nervous System / Q000187:drug effects* / Q000378:metabolism; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000187:drug effects; D008012:Lidocaine / Q000494:pharmacology*; D008959:Models, Neurological; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D015222:Sodium Channels / Q000187:drug effects* / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology
chemical_list: D000779:Anesthetics, Local; D015222:Sodium Channels; D008012:Lidocaine