NDLI: Rate-dependent effects of vernakalant in the isolated non-remodeled canine left atria are primarily due to block of the sodium channel: comparison with ranolazine and dl-sotalol.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Burashnikov, Alexander Pourrier, Marc Gibson, John K. Lynch, Joseph J. Antzelevitch, Charles
Description	Country affiliation: United States Author Affiliation: Burashnikov A ( Masonic Medical Research Laboratory, Utica, NY 13501, USA.)
Abstract	BACKGROUND: Several clinical trials have shown that vernakalant is effective in terminating recent onset atrial fibrillation (AF). The electrophysiological actions of vernakalant are not fully understood. METHODS AND RESULTS: Here we report the results of a blinded study comparing the in vitro canine atrial electrophysiological effects of vernakalant, ranolazine, and dl-sotalol. Action potential durations (APD(50,75,90)), effective refractory period (ERP), post repolarization refractoriness (PRR), maximum rate of rise of the action potential (AP) upstroke (V(max)), diastolic threshold of excitation (DTE), conduction time (CT), and the shortest S(1)-S(1) permitting 1:1 activation (S(1)-S(1)) were measured using standard stimulation and microelectrode recording techniques in isolated normal, non-remodeled canine arterially perfused left atrial preparations. Vernakalant caused variable but slight prolongation of APD(90) (P=not significant), but significant prolongation of APD(50) at 30 µmol/L and rapid rates. In contrast, ranolazine and dl-sotalol produced consistent concentration- and reverse rate-dependent prolongation of APD(90). Vernakalant and ranolazine caused rate-dependent, whereas dl-sotalol caused reverse rate-dependent, prolongation of ERP. Significant rate-dependent PRR developed with vernakalant and ranolazine, but not with dl-sotalol. Other sodium channel-mediated parameters (ie, V(max), CT, DTE, and S(1)-S(1)) also were depressed significantly by vernakalant and ranolazine, but not by dl-sotalol. Only vernakalant elevated AP plateau voltage, consistent with blockade of ultrarapid delayed rectified potassium current and transient outward potassium current. CONCLUSIONS: In isolated canine left atria, the effects of vernakalant and ranolazine were characterized by use-dependent inhibition of sodium channel-mediated parameters, and those of dl-sotalol by reverse rate-dependent prolongation of APD(90) and ERP. This suggests that during the rapid activation rates of AF, the I(Na) blocking action of the mixed ion channel blocker vernakalant takes prominence. This mechanism may explain vernakalant's anti-AF efficacy.
File Format	HTM / HTML
ISSN	19413149
e-ISSN	19413084
DOI	10.1161/CIRCEP.111.968305
Journal	Circulation: Arrhythmia and Electrophysiology
Issue Number	2
Volume Number	5
Language	English
Publisher	Lippincott Williams & Wilkins
Publisher Date	2012-04-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Discipline Cardiology Discipline Vascular Diseases Acetanilides Pharmacology Anisoles Heart Atria Drug Effects Piperazines Pyrrolidines Sodium Channels Sotalol Action Potentials Physiology Animals Anti-arrhythmia Agents In Vitro Techniques Models, Animal Ranolazine Refractory Period, Electrophysiological Sodium Channel Blockers Time Factors Comparative Study Research Support, N.i.h., Extramural Research Support, Non-u.s. Gov't
Content Type	Text
Resource Type	Article
Subject	Physiology (medical) Cardiology and Cardiovascular Medicine

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Rate-Dependent Effects of Vernakalant in the Isolated Non-Remodeled Canine Left Atria Are Primarily Due to Block of the Sodium Channel Comparison with Ranolazine and dl-Sotalol

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