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.
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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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