Abstract 16336: “Use-Dependent” Block of Ryanodine Receptor Calcium Channels by Flecainide and R-Propafenone Determines Their Potency for Calcium Wave Annihilation in Catecholaminergic Polymorphic Ventricular Tachycardia
Background- Myocytes lacking calsequestrin (casq2-/-) exhibit frequent spontaneous RyR2 channel openings and Ca2+ waves that can trigger delayed afterdepolarizations and ventricular arrhythmias. We recently showed that flecainide (FLEC) and R-propafenone (RPROP) inhibit RyR2 channels in the open state, suppress Ca2+ waves and prevent catecholaminergic-polymorphic ventricular tachycardia (CPVT) in mice and humans. We hypothesized that the open-state RyR2 block by FLEC and RPROP significantly contributes to their antiarrhythmic potency in CPVT.
Methods and Results- We studied the effects of FLEC and RPROP on Ca2+ waves in permeabilized myocytes isolated from casq2-/- and wild-type (WT) littermates. Drug effects were compared with tetracaine (TET), a non-state dependent RyR2 channel blocker. Myocytes were imaged in the line-scan mode using confocal microscopy. Drug effects on wave incidence, amplitude, frequency, and propagation speed were analyzed. Concentration-response curves were constructed for each drug to obtain the IC50 (potency) and the maximum % inhibition (efficacy). Both FLEC and RPROP reduced all four-wave parameters with significantly higher potency (lower IC50) and efficacy in casq2-/- compared to WT myocytes (n=15-20 cells per group, p<0.01, Fig. A). Exposure of WT cells to caffeine (150 μM) increases RyR2 channel activity and partially restores the response to FLEC and RPROP, thereby increasing the apparent potency of wave inhibition by these drugs (Fig. Panel A). In contrast, TET, a state-independent blocker, had similar potency in casq2-/- and WT myocytes (Fig. Panel B).
Conclusions- RyR2 channel activity determines the potency of open-state RyR2 blockers such as FLEC and RPROP for suppressing arrhythmogenic Ca2+ waves, a mechanism likely relevant to antiarrhythmic drug efficacy in CPVT.
- Excitation-contraction coupling (ECC)
- Arrhythmias, treatment of
- Ventricular arrhythmia
- © 2011 by American Heart Association, Inc.