Robust anti-arrhythmic efficacy of verapamil and flunarizine against dofetilide-induced TdP arrhythmias is based upon a shared and a different mode of action.
OBJECTIVE
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 Ca(2+) channel antagonists, flunarizine and verapamil against TdP were investigated.


METHODS
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 Ca(2+) sparks in RyR2(R4496+/+) mouse myocytes; and (iii) peak and late I(Na) in SCN5A-HEK 293 cells.


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). Ca(2+) sparks were reduced with verapamil.


CONCLUSIONS
Robust anti-arrhythmic efficacy was seen with both Ca(2+) channel antagonists. Their divergent electrophysiological actions may be related to different additional effects of the two drugs.
Oros
A
A
Department of Medical Physiology, Division Heart & Lungs, UMC Utrecht, the Netherlands.
Houtman
M J
MJ
Neco
P
P
Gomez
A M
AM
Rajamani
S
S
Oosterhoff
P
P
Attevelt
N J
NJ
Beekman
J D
JD
van der Heyden
M A G
MA
Ver Donck
L
L
Belardinelli
L
L
Richard
S
S
Antoons
G
G
Vos
M A
MA
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D020013:Calcium Signaling / Q000187:drug effects; D002460:Cell Line; D004285:Dogs; D005444:Flunarizine / Q000627:therapeutic use*; D006801:Humans; D008012:Lidocaine / Q000008:administration & dosage / Q000627:therapeutic use; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D010627:Phenethylamines / Q000633:toxicity*; D013449:Sulfonamides / Q000633:toxicity*; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000188:drug therapy*; D014700:Verapamil / Q000008:administration & dosage / Q000627:therapeutic use*
D000889:Anti-Arrhythmia Agents; D010627:Phenethylamines; D013449:Sulfonamides; D008012:Lidocaine; D014700:Verapamil; C063533:dofetilide; D005444:Flunarizine