Abstract 13707: Sodium Channel Blockers Prevent Triggered Activity but Not Abnormal Ca2+ Release in a Knock-in Mouse Model With Ryanodine Receptor Mutation R4496C
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited disease characterized by adrenergically mediated polymorphic VT leading to syncope and sudden cardiac death. The present therapies are inadequate. Recently it has been reported that flecainide prevents CPVT in mice and humans. Here we assess the effects of flecainide and mexiletine on the arrhythmogenesis of RyR2R4496C+/− myocytes. We performed patch clamp and Ca2+ imaging studies in fluo-4 loaded RyR2R4496C+/− myocytes assessing cells after administration of Isoproterenol (Iso, 1 µM). Iso elicited spontaneous Ca2+ release (SCR) in 87% of RyR2R4496C+/− myocytes (n=30); pretreatment with flecainide (Fle, 6 µM) or mexiletine (Mex, 10 µM) did not influence Iso-induced enhancement of Ca2+ transient amplitude and decay, SR Ca2+ content and release fraction. Both drugs were unable to prevent Iso-induced SCR (77% SCR in Fle-treated cells, n=35; 83% SCR in Mex-treated cells, n=30). However they significantly prevented Iso induced- triggered activity (TA) from 60% in untreated cells to 14% in Fle-treated cells, p<0.001; 30% TA in Mex-treated cells, p<0.05. Patch clamp studies confirmed this observation showing that DADs were not abolished by Fle or Mex while the drugs completely abolished Iso-induced TA. Interestingly washout of drugs resulted in the reappearance of the TA. We hypothesized that sodium channel blockers do not affect release of calcium from RyR2 but they rather reduce excitability by blocking the sodium current. We tested the threshold for current induced action potential in RyR2R4496C+/− myocytes, Fle and Mex significantly increase the threshold for action potential induction by 80% and 69% respectively (p<0.01, vs control cells). We conclude that sodium channel blockers, Fle and Mex, do not prevent SCR induced by Iso in RyR2R4496C+/− myocytes but are able to abolish SCR-induced TA by reducing availability of sodium channels and increasing the threshold for TA.
- © 2010 by American Heart Association, Inc.