title: A comparative study of the action of tolperisone on seven different voltage dependent sodium channel isoforms.
abstract: The specific, acute interaction of tolperisone, an agent used as a muscle relaxant and for the treatment of chronic pain conditions, with the Na(v1.2), Na(v1.3), Na(v1.4), Na(v1.5), Na(v1.6), Na(v1.7), and Na(v1.8) isoforms of voltage dependent sodium channels was investigated and compared to that of lidocaine. Voltage dependent sodium channels were expressed in the Xenopus laevis oocyte expression system and sodium currents were recorded with the two electrode voltage clamp technique. Cumulative dose response relations revealed marked differences in IC(50) values between the two drugs on identical isoforms, as well as between isoforms. A detailed kinetic analysis uncovered that tolperisone as well as lidocaine exhibited their blocking action not only via state dependent association/dissociation with voltage dependent sodium channels, but a considerable fraction of inhibition is tonic, i.e. permanent and basic in nature. Voltage dependent activation was affected to a minor extent only. A shift in steady-state inactivation to more negative potentials could be observed for most drug/isoform combinations. The contribution of this shift to overall block was, however, small at drug concentrations resulting in considerable overall block. Recovery from inactivation was affected notably by both drugs. Lidocaine application led to a pronounced prolongation of the time constant of the fast recovery process for the Na(v1.3), Na(v1.5), and Na(v1.7) isoforms, indicating common structural properties in the local anesthetic receptor site of these three proteins. Interestingly, this characteristic drug action was not observed for tolperisone.
authors.affiliation: Molecular Physiology Laboratory, Institute of Biophysics, Center for Physiological Medicine, Medical University of Graz, Harrachgasse 21/4, A-8010 Graz, Austria.
authors.forename: Doris
authors.initials: D
authors.lastname: Hofer
authors.forename: Birgit
authors.initials: B
authors.lastname: Lohberger
authors.forename: Bibiane
authors.initials: B
authors.lastname: Steinecker
authors.forename: Kurt
authors.initials: K
authors.lastname: Schmidt
authors.forename: Stefan
authors.initials: S
authors.lastname: Quasthoff
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Schreibmayer
mesh_terms: D000595:Amino Acid Sequence; D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D005260:Female; D008012:Lidocaine / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D008969:Molecular Sequence Data; D009125:Muscle Relaxants, Central / Q000494:pharmacology; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology; D017386:Sequence Homology, Amino Acid; D015222:Sodium Channels / Q000235:genetics / Q000502:physiology*; D014049:Tolperisone / Q000494:pharmacology*; D014982:Xenopus laevis
chemical_list: D000779:Anesthetics, Local; D009125:Muscle Relaxants, Central; D020033:Protein Isoforms; D015222:Sodium Channels; D008012:Lidocaine; D014049:Tolperisone