P555Flecainide reduces calcium transient amplitude in rat cardiomyocytes with an absence of a significant reduction in l-type calcium current

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Flecainide is a class 1c antiarrhythmic drug that has been shown to reduce spark amplitude and mass in a Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) mouse model and has shown translational potential in its successful treatment of two human subjects with the condition. Given the effects on arrhythmogenesis through its actions on the ryanodine receptor (RyR), we hypothesised that there may also be an effect on the release of calcium (Ca) producing the normal Ca transient. We studied the effects of flecainide on the Ca transient of field-stimulated intact rat cardiomyocytes superfused with normal tyrode (NT) + /- isoprenaline (ISO) + /- 5µM flecainide (FLEC). Confocal microscopy was used to measure cytosolic Ca of cells loaded with the fluorescent Ca indicator fluo-4. We subsequently assessed whether the effects seen were related to reduced Ca flux through the RyR or the L-type Ca current (LTCC) by measuring LTCC in voltage clamped isolated guinea-pig cardiomyocytes. Mean transient amplitude was significantly reduced in cells superfused with NT + FLEC (F/F0 3.5 ± 0.2) compared to the NT group (5.3 ± 0.3, 34% mean reduction), p=0.0041 (n=36 cells). There was also a smaller but still significant reduction of mean transient amplitude in cells superfused with NT + ISO + FLEC (F/F0 9.8 ± 0.4) compared with cells treated with NT + ISO alone (11.2 ± 0.5, 13% mean reduction), p=0.0356 (n=52 cells). Peak LTCC induced by a voltage step from -40 to 0mV showed no significant change in flecainide treated cells (p=0.08). The larger effect on transient amplitude compared with LTCC suggests that RyR stabilization has a more important role on reduction of transient amplitude. The partial abrogation of the effect on transient amplitude in the presence of isoprenaline may relate to phosphorylation of key Ca cycling proteins such as L-type calcium channel, phospholamban and RyR.

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