Synergistic electrophysiologic and antiarrhythmic effects of the combination of ranolazine and chronic amiodarone in canine atria.
BACKGROUND
Amiodarone and ranolazine have been characterized as inactivated- and activated-state blockers of cardiac sodium channel current (I(Na)), respectively, and shown to cause atrial-selective depression of I(Na)-related parameters. This study tests the hypothesis that their combined actions synergistically depress I(Na)-dependent parameters in atria but not ventricles.


RESULTS
The effects of acute ranolazine (5 to 10 micromol/L) were studied in coronary-perfused right atrial and left ventricular wedge preparations and superfused left atrial pulmonary vein sleeves isolated from chronic amiodarone-treated (40 mg/kg daily for 6 weeks) and untreated dogs. Floating and standard microelectrode techniques were used to record transmembrane action potentials. When studied separately, acute ranolazine and chronic amiodarone caused atrial-predominant depression of I(Na)-dependent parameters. Ranolazine produced a much greater reduction in V(max) and much greater increase in diastolic threshold of excitation and effective refractory period in atrial preparations isolated from amiodarone-treated versus untreated dogs, leading to a marked increase in postrepolarization refractoriness. The drug combination effectively suppressed triggered activity in pulmonary vein sleeves but produced relatively small changes in I(Na)-dependent parameters in the ventricle. Acetylcholine (0.5 micromol/L) and burst pacing induced atrial fibrillation in 100% of control atria, 75% of ranolazine-treated (5 micromol/L) atria, 16% of atria from amiodarone-treated dogs, and in 0% of atria from amiodarone-treated dogs exposed to 5 micromol/L ranolazine.


CONCLUSIONS
The combination of chronic amiodarone and acute ranolazine produces a synergistic use-dependent depression of I(Na)-dependent parameters in isolated canine atria, leading to a potent effect of the drug combination to prevent the induction of atrial fibrillation.
Sicouri
Serge
S
Masonic Medical Research Laboratory, Utica, NY.
Burashnikov
Alexander
A
Belardinelli
Luiz
L
Antzelevitch
Charles
C
D000083:Acetanilides / Q000494:pharmacology*; D000638:Amiodarone / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001281:Atrial Fibrillation / Q000517:prevention & control*; D004285:Dogs; D004357:Drug Synergism; D022062:Electrophysiologic Techniques, Cardiac; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D000069458:Ranolazine; D012032:Refractory Period, Electrophysiological / Q000187:drug effects; D026941:Sodium Channel Blockers / Q000494:pharmacology*
D000083:Acetanilides; D000889:Anti-Arrhythmia Agents; D004791:Enzyme Inhibitors; D010879:Piperazines; D026941:Sodium Channel Blockers; D000069458:Ranolazine; D000638:Amiodarone