Frequency-independent blockade of cardiac Na+ channels by riluzole: comparison with established anticonvulsants and class I anti-arrhythmics

The Na (+) channel blocking activity and the antiarrhythmic effects of rilu zole, and established anticonvulsants (lamotrigine and lifarizine) and clas s I antiarrhythmics (lidocaine, flecainide and disopyramide) were studied u nder in vitro and in vivo conditions. Guinea-pig cardiac Purkinje fibres we re superfused with Tyrode solution and electrically driven for recording ac tion potentials with intracellular microelectrodes. In these preparations p aced at 1 Hz, all compounds tested produced concentration-dependent (0.3-10 0 mu M) reductions in the maximum rate of depolarization of the action pote ntial (V-max). For riluzole, phenytoin and carbamazepine this effect was fr equency-independent (0.5-6 Hz) but for lamotrigine, lifarizine, lidocaine, flecainide and disopyramide it was frequency-dependent. In anaesthetized ra ts, riluzole, in contrast to flecainide, did nor delay the appearance of ac onitine-induced arrhythmias. Riluzole (0.3-3.9 mg/kg, i.v.) also lacked not able 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 cons cious dogs with polymorphic arrhythmias produced by ligation of the left an terior 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. T his property may account for the lack of antiarrhythmic activity of riluzol e, phenytoin and carbamazepine in animal models of arrhythmias that respond to class I antiarrhythmic drugs. It may also account for the clinical obse rvation that riluzole does not seem to cause the unfavourable electrocardio graphic changes characteristic of drugs that block cardiac Na+ channels in a frequency-dependent manner. (C) 2000 Editions scientifiques et medicales Elsevier SAS.