Synergistic electrophysiologic and antiarrhythmic effects of the combination of ranolazine and chronic amiodarone in canine atria.

Abstract

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.

METHODS AND 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.

• Authors: Serge Sicouri, Alexander Burashnikov, Luiz Belardinelli, Charles Antzelevitch
• Journal: Circulation. Arrhythmia and electrophysiology (Circ Arrhythm Electrophysiol) Vol. 3 Issue 1 Pg. 88-95 (Feb 2010) ISSN: 1941-3084 [Electronic] United States
• PMID: 19952329 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Acetanilides
• Anti-Arrhythmia Agents
• Enzyme Inhibitors
• Piperazines
• Sodium Channel Blockers
• Ranolazine
• Amiodarone

Topics

• Acetanilides (pharmacology)
• Amiodarone (pharmacology)
• Animals
• Anti-Arrhythmia Agents (pharmacology)
• Atrial Fibrillation (prevention & control)
• Dogs
• Drug Synergism
• Electrophysiologic Techniques, Cardiac
• Enzyme Inhibitors (pharmacology)
• In Vitro Techniques
• Membrane Potentials (drug effects)
• Piperazines (pharmacology)
• Ranolazine
• Refractory Period, Electrophysiological (drug effects)
• Sodium Channel Blockers (pharmacology)