Robust anti-arrhythmic efficacy of verapamil and flunarizine against dofetilide-induced TdP arrhythmias is based upon a shared and a different mode of action |
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Authors: | A Oros MJ Houtman P Neco AM Gomez S Rajamani P Oosterhoff NJ Attevelt JD Beekman MAG van der Heyden L Ver Donck L Belardinelli S Richard G Antoons MA Vos for the CONTICA investigators |
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Affiliation: | 1Department of Medical Physiology, Division Heart & Lungs, UMC Utrecht, the Netherlands;2Inserm U-637, Physiopathologie Cardiovasculaire, Montpellier, France;3Department of Biology, Gilead Sciences Inc, Palo Alto, CA, USA;4Janssen Research, J&J, Beerse, Belgium |
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Abstract: | BACKGROUND AND PURPOSEThe high predisposition to Torsade de Pointes (TdP) in dogs with chronic AV-block (CAVB) is well documented. The anti-arrhythmic efficacy and mode of action of Ca2+ channel antagonists, flunarizine and verapamil against TdP were investigated.EXPERIMENTAL APPROACHMongrel dogs with CAVB were selected based on the inducibility of TdP with dofetilide. The effects of flunarizine and verapamil were assessed after TdP and in different experiments to prevent dofetilide-induced TdP. Electrocardiogram and ventricular monophasic action potentials were recorded. Electrophysiological parameters and short-term variability of repolarization (STV) were determined. In vitro, flunarizine and verapamil were added to determine their effect on (i) dofetilide-induced early after depolarizations (EADs) in canine ventricular myocytes (VM); (ii) diastolic Ca2+ sparks in RyR2R4496+/+ mouse myocytes; and (iii) peak and late INa in SCN5A-HEK 293 cells.KEY RESULTSDofetilide increased STV prior to TdP and in VM prior to EADs. Both flunarizine and verapamil completely suppressed TdP and reversed STV to baseline values. Complete prevention of TdP was achieved with both drugs, accompanied by the prevention of an increase in STV. Suppression of EADs was confirmed after flunarizine. Only flunarizine blocked late INa. Ca2+ sparks were reduced with verapamil.CONCLUSIONS AND IMPLICATIONSRobust anti-arrhythmic efficacy was seen with both Ca2+ channel antagonists. Their divergent electrophysiological actions may be related to different additional effects of the two drugs. |
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Keywords: | ventricular repolarization drug-induced TdP arrhythmias safety pharmacology flunarizine verapamil CAVB dog |
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