AIMS: Ca(2+) waves are thought to be important in the aetiology of ventricular 
tachyarrhythmias. There have been conflicting results regarding whether 
flecainide reduces Ca(2+) waves in isolated cardiomyocytes. We sought to confirm 
whether flecainide inhibits waves in the intact cardiomyocyte and to elucidate 
the mechanism.
METHODS AND RESULTS: We imaged spontaneous sarcoplasmic reticulum (SR) Ca(2+) 
release events in healthy adult rat cardiomyocytes. Variation in stimulation 
frequency was used to produce Ca(2+) sparks or waves. Spark frequency, wave 
frequency, and wave velocity were reduced by flecainide in the absence of a 
reduction of SR Ca(2+) 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 Ca(2+) wave reduction when I(Na) is active. It was found that 
Na(+)/Ca(2+)-exchanger (NCX)-mediated Ca(2+) 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.
CONCLUSION: 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 Ca(2+) efflux via NCX across the 
sarcolemma, reducing Ca(2+) concentration in the vicinity of the RyR2.