title: Frequency-independent blockade of cardiac Na+ channels by riluzole: comparison with established anticonvulsants and class I anti-arrhythmics.
abstract: The Na+ channel blocking activity and the antiarrhythmic effects of riluzole, and established anticonvulsants (lamotrigine and lifarizine) and class I antiarrhythmics (lidocaine, flecainide and disopyramide) were studied under in vitro and in vivo conditions. Guinea-pig cardiac Purkinje fibres were superfused with Tyrode solution and electrically driven for recording action potentials with intracellular microelectrodes. In these preparations paced at 1 Hz, all compounds tested produced concentration-dependent (0.3-100 microM) reductions in the maximum rate of depolarization of the action potential (Vmax). For riluzole, phenytoin and carbamazepine this effect was frequency-independent (0.5-6 Hz) but for lamotrigine, lifarizine, lidocaine, flecainide and disopyramide it was frequency-dependent. In anaesthetized rats, riluzole, in contrast to flecainide, did not delay the appearance of aconitine-induced arrhythmias. Riluzole (0.3-3.9 mg/kg, i.v.) also lacked notable cardiac electrophysiological effects in anaesthetized dogs. At an i.v. dose of 3.0 mg/kg riluzole failed to restore a normal sinus rhythm in conscious dogs with polymorphic arrhythmias produced by ligation of the left anterior descending coronary artery 24 h earlier. These results indicate that riluzole, phenytoin and carbamazepine, unlike lamotrigine, lifarizine and flecainide, block cardiac Na+ channels in a frequency-independent manner. This property may account for the lack of antiarrhythmic activity of riluzole, phenytoin and carbamazepine in animal models of arrhythmias that respond to class I antiarrhythmic drugs. It may also account for the clinical observation that riluzole does not seem to cause the unfavourable electrocardiographic changes characteristic of drugs that block cardiac Na+ channels in a frequency-dependent manner.
authors.affiliation: Aventis, CRVA, Vitry-sur-Seine, France. mestremi@cybercable.fr
authors.forename: M
authors.initials: M
authors.lastname: Mestre
authors.forename: Y
authors.initials: Y
authors.lastname: Djellas
authors.forename: T
authors.initials: T
authors.lastname: Carriot
authors.forename: I
authors.initials: I
authors.lastname: Cavero
mesh_terms: D000157:Aconitine / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000758:Anesthesia; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D000927:Anticonvulsants / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000517:prevention & control; D002220:Carbamazepine / Q000494:pharmacology; D003243:Consciousness; D004206:Disopyramide / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004594:Electrophysiology; D005260:Female; D005424:Flecainide / Q000494:pharmacology; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000187:drug effects / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D000077213:Lamotrigine; D008012:Lidocaine / Q000494:pharmacology; D008297:Male; D017202:Myocardial Ischemia / Q000150:complications; D009206:Myocardium / Q000378:metabolism; D010672:Phenytoin / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011690:Purkinje Fibers / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D019782:Riluzole / Q000494:pharmacology*; D026941:Sodium Channel Blockers; D015222:Sodium Channels / Q000378:metabolism; D014227:Triazines / Q000494:pharmacology; D018879:Ventricular Premature Complexes / Q000517:prevention & control
chemical_list: D000889:Anti-Arrhythmia Agents; D000927:Anticonvulsants; D007093:Imidazoles; D010879:Piperazines; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D014227:Triazines; D002220:Carbamazepine; D010672:Phenytoin; D019782:Riluzole; D008012:Lidocaine; C067927:lifarizine; D004206:Disopyramide; D005424:Flecainide; D000077213:Lamotrigine; D000157:Aconitine