Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Oros, A; Houtman, MJ; Neco, P; Gomez, AM; Rajamani, S; Oosterhoff, P; Attevelt, NJ; Beekman, JD; van der Heyden, MA; Ver Donck, L; Belardinelli, L; Richard, S; Antoons, G; Vos, MA; CONTICA investigators.
Robust anti-arrhythmic efficacy of verapamil and flunarizine against dofetilide-induced TdP arrhythmias is based upon a shared and a different mode of action.
Br J Pharmacol. 2010; 161(1):162-175
Doi: 10.1111/j.1476-5381.2010.00883.x
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- Co-Autor*innen der Med Uni Graz
- Antoons Gudrun
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- Abstract:
- BACKGROUND AND PURPOSE The 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 APPROACH Mongrel 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 I(Na) in SCN5A-HEK 293 cells. KEY RESULTS Dofetilide 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 I(Na). Ca2+ sparks were reduced with verapamil. CONCLUSIONS AND IMPLICATIONS Robust 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.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals -
- Anti-Arrhythmia Agents - therapeutic use
- Calcium Signaling - drug effects
- Cell Line -
- Dogs -
- Flunarizine - therapeutic use
- Humans -
- Lidocaine - administration and dosage Lidocaine - therapeutic use
- Mice -
- Myocytes, Cardiac - drug effects Myocytes, Cardiac - physiology
- Phenethylamines - toxicity
- Sulfonamides - toxicity
- Torsades de Pointes - chemically induced Torsades de Pointes - drug therapy
- Verapamil - administration and dosage Verapamil - therapeutic use
- Find related publications in this database (Keywords)
- ventricular repolarization
- drug-induced TdP arrhythmias
- safety pharmacology
- flunarizine
- verapamil
- CAVB dog