title: Class I antiarrhythmic drugs: allosteric inhibitors of [3H] batrachotoxinin binding to rat cardiac sodium channels.
abstract: This study assessed whether class I antiarrhythmic drugs allosterically inhibit [3H]batrachotoxinin A 20-alpha-benzoate ([3H]BTXB) binding to sodium channels on freshly isolated rat cardiac myocytes. All class I drugs tested inhibited equilibrium [3H]BTXB binding in a concentration-dependent manner. Scatchard analysis showed that disopyramide, flecainide, transcainide, lidocaine and amiodarone reduced [3H]BTXB maximum binding (Bmax) whereas procainamide, mexiletine, quinidine, quinine, tocainide, propafenone, encainide and O-demethylencainide increased [3H]BTXB KD but had little effect on Bmax. Kinetic [3H]BTXB binding assays were used to assess the mechanism by which class I drugs inhibit [3H]BTXB binding. Drugs that increase the unidirectional dissociation rate constant (k-1) of [3H]BTXB probably bind to sodium channels to which [3H]BTXB is already bound. Although all class I drugs increased the k-1 of [3H]BTXB, they did so weakly and at concentrations above the IC50 values of the drugs. Thus, drug binding to [3H]BTXB-bound channels does not appear to be the predominant mechanism underlying their ability to inhibit [3H]BTXB binding. Conversely, drugs which allosterically decrease the unidirectional association rate constant (K+1) of [3H]BTXB probably bind to channels to which [3H]BTXB is not already bound. All class I drugs decreased the k+1 of [3H]BTXB, indicating drug binding to [3H]BTXB-free channels. The estimated affinities of drugs for [3H]BTXB-free channels correlated closely with the IC50 values of these drugs (r = 0.94, P < .001), suggesting that this effect is a common and major determinant in their ability to inhibit [3H]BTXB binding. The results are discussed in light of electrophysiologic theories of class I antiarrhythmic drug action.
authors.affiliation: Department of Medicine, University of Calgary, Alberta, Canada.
authors.forename: R S
authors.initials: RS
authors.lastname: Sheldon
authors.forename: H J
authors.initials: HJ
authors.lastname: Duff
authors.forename: E
authors.initials: E
authors.lastname: Thakore
authors.forename: R J
authors.initials: RJ
authors.lastname: Hill
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000145:classification / Q000494:pharmacology*; D001496:Batrachotoxins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D004594:Electrophysiology; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D026941:Sodium Channel Blockers; D015222:Sodium Channels / Q000378:metabolism; D014316:Tritium
chemical_list: D000889:Anti-Arrhythmia Agents; D001496:Batrachotoxins; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D014316:Tritium; C031775:batrachotoxinin A 20-alpha-benzoate