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  • Title: The effect of flunarizine and ryanodine on acquired torsades de pointes arrhythmias in the intact canine heart.
    Author: Verduyn SC, Vos MA, Gorgels AP, van der Zande J, Leunissen JD, Wellens HJ.
    Journal: J Cardiovasc Electrophysiol; 1995 Mar; 6(3):189-200. PubMed ID: 7620644.
    Abstract:
    INTRODUCTION: 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. METHODS AND 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.
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