The effect of flunarizine and ryanodine on acquired torsades de pointes arrhythmias in the intact canine heart.
BACKGROUND
Ryanodine, a specific blocker of the Ca2+ release channel of the sarcoplasmic reticulum, and flunarizine, a [Ca2+]i overload blocker, possess antiarrhythmic effects against delayed afterdepolarizations (DADs) and DAD-dependent arrhythmias. In vitro controversy exists about their effect on early after-depolarizations (EADs): no effect was reported on cesium-induced EADs, while ryanodine did prevent EADs induced by isoproterenol. To study the possible role of intracellular Ca2+ overload in acquired EAD-dependent torsades de pointes (TdP) arrhythmias, we tested the effects of flunarizine and ryanodine in our animal model of TdP.


RESULTS
Anaesthetized dogs with chronic AV block received d-sotalol or almokalant followed by pacing. A subset of dogs with reproducible TdP (> or = 3 times) were selected to receive flunarizine (2 mg/kg per 2 min) or ryanodine (10 micrograms/kg per 10 min). After d-sotalol, TdP was induced at a mean cycle length of the idioventricular rhythm (CL-IVR) of 2070 +/- 635 msec and a QT(U) interval of 535 +/- 65 msec. Induction of TdP was prevented by flunarizine in all experiments (8/8): electrophysiologically this was associated with a decrease in CL-IVR, QT(U), and QTc interval (390 +/- 100 to 320 +/- 45, P < 0.05). Ryanodine prevented TdP induction in 4 of 5 experiments and decreased the CL-IVR, QT(U), and the QTc interval from 385 +/- 75 to 320 +/- 20 msec (P < 0.05). Both drugs also suppressed the almokalant-induced EADs and related ectopic activity. This antiarrhythmic action corresponded with the inability to reinduce TdP by pacing.


CONCLUSIONS
Blockade of the Ca2+ release channel of the sarcoplasmic reticulum by ryanodine or the reduction of [Ca2+]i overload by flunarizine prevents induction of EAD-dependent acquired TdP arrhythmias, suggesting a role for [Ca2+]i overload in acquired TdP.
Verduyn
S C
SC
Department of Cardiology, Cardiovascular Research Institute Maastricht, University of Limburg, The Netherlands.
Vos
M A
MA
Gorgels
A P
AP
van der Zande
J
J
Leunissen
J D
JD
Wellens
H J
HJ
D000200:Action Potentials / Q000502:physiology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D005444:Flunarizine / Q000494:pharmacology* / Q000627:therapeutic use; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D007545:Isoproterenol / Q000009:adverse effects / Q000494:pharmacology; D008297:Male; D011412:Propanolamines / Q000494:pharmacology; D012433:Ryanodine / Q000494:pharmacology* / Q000627:therapeutic use; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000502:physiology; D013015:Sotalol / Q000494:pharmacology; D013997:Time Factors; D016171:Torsades de Pointes / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology*
D000889:Anti-Arrhythmia Agents; D015220:Calcium Channels; D011412:Propanolamines; D012433:Ryanodine; D013015:Sotalol; C074334:almokalant; D007545:Isoproterenol; D005444:Flunarizine