Comparison of electrophysiological and antiarrhythmic effects of vernakalant, ranolazine, and sotalol in canine pulmonary vein sleeve preparations.
BACKGROUND
Vernakalant (VER) is a relatively atrial-selective antiarrhythmic drug capable of blocking potassium and sodium currents in a frequency- and voltage-dependent manner. Ranolazine (RAN) is a sodium-channel blocker shown to exert antiarrhythmic effects in pulmonary vein (PV) sleeves. dl-Sotalol (SOT) is a β-blocker commonly used in the rhythm-control treatment of atrial fibrillation. This study evaluated the electrophysiological and antiarrhythmic effects of VER, RAN, and SOT in canine PV sleeve preparations in a blinded fashion.


METHODS
Transmembrane action potentials were recorded from canine superfused PV sleeve preparations exposed to VER (n = 6), RAN (n = 6), and SOT (n = 6). Delayed afterdepolarizations were induced in the presence of isoproterenol and high-calcium concentrations by periods of rapid pacing.


RESULTS
In PV sleeves, VER, RAN, and SOT (3-30 μM) produced small (10-15 ms) increases in action potential duration. The effective refractory period, diastolic threshold of excitation, and the shortest S(1)-S(1) cycle length permitting 1:1 activation were significantly increased by VER and RAN in a rate- and concentration-dependent manner. VER and RAN significantly reduced V(max) in a concentration- and rate-dependent manner. SOT did not significantly affect the effective refractory period, V(max), diastolic threshold of excitation, or the shortest S(1)-S(1) cycle length permitting 1:1 activation. All 3 agents (3-30 μM) suppressed delayed afterdepolarization-mediated triggered activity induced by isoproterenol and high calcium.


CONCLUSIONS
In canine PV sleeves, the effects of VER and RAN were similar and largely characterized by concentration- and rate-dependent depression of sodium-channel-mediated parameters, which were largely unaffected by SOT. All 3 agents demonstrated an ability to effectively suppress delayed afterdepolarization-induced triggers of atrial arrhythmia.
Masonic Medical Research Laboratory, Utica, New York 13501, USA. sicouris@mmrl.edu
Serge
S
Sicouri
Marc
M
Pourrier
John K
JK
Gibson
Joseph J
JJ
Lynch
Charles
C
Antzelevitch
D000083:Acetanilides / Q000493:pharmacokinetics; D000200:Action Potentials / Q000187:drug effects; D000318:Adrenergic beta-Agonists / Q000493:pharmacokinetics; D000818:Animals; D000840:Anisoles / Q000493:pharmacokinetics; D000889:Anti-Arrhythmia Agents / Q000493:pharmacokinetics; D001281:Atrial Fibrillation / Q000188:drug therapy* / Q000378:metabolism; D001682:Biological Availability; D054849:Cardiac Electrophysiology / Q000379:methods; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004285:Dogs; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007545:Isoproterenol / Q000493:pharmacokinetics; D008564:Membrane Potentials / Q000187:drug effects; D010879:Piperazines / Q000493:pharmacokinetics; D011667:Pulmonary Veins / Q000378:metabolism / Q000473:pathology; D011759:Pyrrolidines / Q000493:pharmacokinetics; D000069458:Ranolazine; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism; D013015:Sotalol / Q000493:pharmacokinetics
D000083:Acetanilides; D000318:Adrenergic beta-Agonists; D000840:Anisoles; D000889:Anti-Arrhythmia Agents; D010879:Piperazines; D011759:Pyrrolidines; D015222:Sodium Channels; C524581:vernakalant; D013015:Sotalol; D000069458:Ranolazine; D007545:Isoproterenol