Flecainide reduces Ca2+ spark and wave frequency via inhibition of the sarcolemmal sodium current

Abstract

Ca²⁺ waves are thought to be important in the aetiology of ventricular tachyarrhythmias. There have been conflicting results regarding whether flecainide reduces Ca²⁺ waves in isolated cardiomyocytes. We sought to confirm whether flecainide inhibits waves in the intact cardiomyocyte and to elucidate the mechanism. We imaged spontaneous sarcoplasmic reticulum (SR) Ca²⁺ release events in healthy adult rat cardiomyocytes. Variation in stimulation frequency was used to produce Ca²⁺ sparks or waves. Spark frequency, wave frequency, and wave velocity were reduced by flecainide in the absence of a reduction of SR Ca²⁺ content. Inhibition of I_Na via alternative pharmacological agents (tetrodotoxin, propafenone, or lidocaine) produced similar changes. To assess the contribution of I_Na to spark and wave production, voltage clamping was used to activate contraction from holding potentials of −80 or −40 mV. This confirmed that reducing Na⁺ influx during myocyte stimulation is sufficient to reduce waves and that flecainide only causes Ca²⁺ wave reduction when I_Na is active. It was found that Na⁺/Ca²⁺-exchanger (NCX)-mediated Ca²⁺ efflux was significantly enhanced by flecainide and that the effects of flecainide on wave frequency could be reversed by reducing [Na⁺]_o, suggesting an important downstream role for NCX function. Flecainide reduces spark and wave frequency in the intact rat cardiomyocyte at therapeutically relevant concentrations but the mechanism involves I_Na reduction rather than direct ryanodine receptor (RyR2) inhibition. Reduced I_Na results in increased Ca²⁺ efflux via NCX across the sarcolemma, reducing Ca²⁺ concentration in the vicinity of the RyR2.