Atrial-selective sodium channel block as a strategy for suppression of atrial fibrillation.
Antiarrhythmic drug therapy remains the principal approach for suppression of atrial fibrillation (AF) and flutter (AFl) and prevention of their recurrence. Among the current strategies for suppression of AF/AFl is the development of antiarrhythmic agents that preferentially affect atrial, rather than ventricular electrical parameters. Inhibition of the ultrarapid delayed rectifier potassium current (IKur), present in the atria, but not in the ventricles, is an example of an atrial-selective approach. Our recent study examined the hypothesis that sodium channel characteristics differ between atrial and ventricular cells and that atrial-selective sodium channel block is another effective strategy for the management of AF. We have demonstrated very significant differences in the inactivation characteristics of atrial versus ventricular sodium channels and a striking atrial selectivity for the action of ranolazine, an inactivated-state sodium channel blocker, to produce use-dependent block of the sodium channels, leading to depression of excitability, development of post-repolarization refractoriness (PRR), and suppression of AF. Lidocaine and chronic amiodarone, both predominantly inactivated-state sodium channel blockers, also produced a preferential depression of sodium channel-dependent parameters (VMax conduction velocity, diastolic threshold of excitation, and PRR) in the atria. Propafenone, a predominantly open-state sodium channel blocker, produced similar changes of electrophysiological parameters, which were was not atrial-selective. The ability of ranolazine, chronic amiodarone, and propafenone to prolong the atrial action potential potentiated their ability to suppress AF in coronary-perfused canine atrial preparations.


CONCLUSIONS
Our data demonstrate important differences in the inactivation characteristics of atrial versus ventricular sodium channels and a striking atrial selectivity for the action of agents like ranolazine to produce use-dependent block of sodium channels leading to suppression of AF. Our findings suggest that atrial-selective sodium channel block may be a valuable strategy to combat AF.
Burashnikov
Alexander
A
Masonic Medical Research Laboratory, 2150 Bleecker Street, Utica, NY 13501, USA.
Di Diego
José M
JM
Zygmunt
Andrew C
AC
Belardinelli
Luiz
L
Antzelevitch
Charles
C
D000083:Acetanilides / Q000627:therapeutic use; D000638:Amiodarone / Q000627:therapeutic use; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D001281:Atrial Fibrillation / Q000503:physiopathology / Q000517:prevention & control*; D004285:Dogs; D004594:Electrophysiology; D006325:Heart Atria / Q000503:physiopathology*; D006801:Humans; D008012:Lidocaine / Q000627:therapeutic use; D010879:Piperazines / Q000627:therapeutic use; D011405:Propafenone / Q000627:therapeutic use; D000069458:Ranolazine; D026941:Sodium Channel Blockers / Q000627:therapeutic use*; D016276:Ventricular Function
D000083:Acetanilides; D000889:Anti-Arrhythmia Agents; D010879:Piperazines; D026941:Sodium Channel Blockers; D011405:Propafenone; D008012:Lidocaine; D000069458:Ranolazine; D000638:Amiodarone