title: Transcainide: biochemical evidence for state-dependent interaction with the class I antiarrhythmic drug receptor.
abstract: The mechanism of action of the lidocaine derivative transcainide was examined using [3H]batrachotoxinin 20 alpha-benzoate, which binds specifically to and stabilizes activated states of the sodium channel. Transcainide (IC50 0.3 microM) inhibited equilibrium [3H]batrachotoxinin binding to sodium channels present on freshly isolated rat cardiac myocytes. Scatchard analysis of [3H]batrachotoxinin binding showed that transcainide both reduced maximal binding and altered the KD for [3H]batrachotoxinin binding, indicating noncompetitive, allosteric inhibition. Inhibition by transcainide of [3H]batrachotoxinin binding was reversible within 60 min. We used state-dependent [3H]batrachotoxinin binding assays to examine whether transcainide preferentially binds to activated or nonactivated sodium channels. Transcainide had little effect on the k-1 of [3H]batrachotoxinin even at concentrations 1000-fold greater than its IC50, indicating low affinity of transcainide for activated channels. However, transcainide decreased the k + 1 of [3H]batrachotoxinin at a concentration very close to its IC50 concentration for inhibiting equilibrium [3H]batrachotoxinin binding. The results are discussed in terms of a model in which transcainide inhibits [3H]batrachotoxinin binding by binding specifically to and stabilizing a nonactivated state of the cardiac sodium channel.
authors.affiliation: Department of Medicine, University of Calgary, Alberta, Canada.
authors.forename: R J
authors.initials: RJ
authors.lastname: Hill
authors.forename: E
authors.initials: E
authors.lastname: Thakore
authors.forename: M
authors.initials: M
authors.lastname: Taouis
authors.forename: H J
authors.initials: HJ
authors.lastname: Duff
authors.forename: R S
authors.initials: RS
authors.lastname: Sheldon
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000378:metabolism / Q000494:pharmacology*; D001496:Batrachotoxins / Q000378:metabolism; D066298:In Vitro Techniques; D008012:Lidocaine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011955:Receptors, Drug / Q000187:drug effects* / Q000378:metabolism; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism
chemical_list: D000889:Anti-Arrhythmia Agents; D001496:Batrachotoxins; D011955:Receptors, Drug; D015222:Sodium Channels; C052070:transcainide; C031775:batrachotoxinin A 20-alpha-benzoate; D008012:Lidocaine