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Research ArticleCardiovascular

Atrial-Selective Sodium Channel Block Strategy to Suppress Atrial Fibrillation: Ranolazine versus Propafenone

Alexander Burashnikov, Luiz Belardinelli and Charles Antzelevitch
Journal of Pharmacology and Experimental Therapeutics January 2012, 340 (1) 161-168; DOI: https://doi.org/10.1124/jpet.111.186395
Alexander Burashnikov
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Luiz Belardinelli
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Charles Antzelevitch
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Abstract

Ranolazine has been shown to produce atrial-selective depression of sodium channel-dependent parameters and suppress atrial fibrillation (AF) in a variety of experimental models. The present study contrasts the effects of ranolazine and those of a clinically used anti-AF class IC agent, propafenone. Electrophysiological and anti-AF effects of propafenone and ranolazine were compared at clinically relevant concentrations (i.e., 0.3–1.5 and 1–10 μM, respectively) in canine isolated coronary-perfused atrial and ventricular preparations. Transmembrane action potential and pseudo-ECG were recorded. Both ranolazine and propafenone produced atrial-selective prolongation of action potential duration. Propafenone depressed sodium channel-mediated parameters [maximum rate of rise of the action potential upstroke (Vmax), conduction time, and diastolic threshold of excitation] and induced postrepolarization refractoriness to a greater degree than ranolazine, and these effects, unlike those induced by ranolazine, were not or only mildly atrial-selective at normal rates (cycle length 500 ms). At fast pacing rates, however, the effects of propafenone on Vmax and conduction time became atrial-selective, because of the elimination of diastolic interval in atria, but not in ventricles. Propafenone (1.5 μM) and ranolazine (10.0 μM) were effective in preventing the initiation of persistent acetylcholine-mediated AF (6/7 and 9/11 atria, respectively), its termination (8/10 and 8/12 atria, respectively), and subsequent reinduction (8/8 and 7/8 atria, respectively). Thus, propafenone and ranolazine both suppress AF, but ranolazine, unlike propafenone, does it with minimal effects on ventricular myocardium, suggesting a reduced potential for promoting ventricular arrhythmias.

Footnotes

  • This study was supported by Gilead Sciences, Inc. (C.A.); the National Institutes of Health National Heart, Lung, and Blood Institute [Grant HL-47687] (to C.A.); and the New York State and Florida Free and Accepted Masons.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    http://dx.doi.org/10.1124/jpet.111.186395.

  • ABBREVIATIONS:

    AF
    atrial fibrillation
    ACh
    acetylcholine
    AP
    action potential
    APD
    AP duration
    CL
    cycle length
    DTE
    diastolic threshold of excitation
    ERP
    effective refractory period
    PM
    pectinate muscle
    PRR
    postrepolarization refractoriness
    Vmax
    maximum rate of rise of the AP upstroke
    AZD1305
    tert-butyl (2-{7-[2-(4-cyano-2-fluorophenoxy)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non3-yl}ethyl)carbamate
    E-4031
    N-[4-[1-[2-(6-methylpyridin-2-yl)ethyl]piperidine-4-carbonyl]phenyl]
    GE-68
    1-[3-(phenylethyl)-2-benzofuryl]-2-(propylamino)-ethanol hydrochloride.

  • Received July 26, 2011.
  • Accepted October 14, 2011.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 340 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 340, Issue 1
1 Jan 2012
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Research ArticleCardiovascular

Atrial-Selective Sodium Channel Block

Alexander Burashnikov, Luiz Belardinelli and Charles Antzelevitch
Journal of Pharmacology and Experimental Therapeutics January 1, 2012, 340 (1) 161-168; DOI: https://doi.org/10.1124/jpet.111.186395

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Research ArticleCardiovascular

Atrial-Selective Sodium Channel Block

Alexander Burashnikov, Luiz Belardinelli and Charles Antzelevitch
Journal of Pharmacology and Experimental Therapeutics January 1, 2012, 340 (1) 161-168; DOI: https://doi.org/10.1124/jpet.111.186395
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