201. Flecainide reduces Ca2+ spark and wave frequency via inhibition of the sarcolemmal sodium current
- Author
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Thomas P. Collins, Sian E. Harding, Mit Shah, Alexander R. Lyon, Markus B. Sikkel, Christina Rowlands, Kenneth T. MacLeod, Peter O'Gara, and Alan J. Williams
- Subjects
Male ,Physiology ,Voltage clamp ,Propafenone ,Tetrodotoxin ,030204 cardiovascular system & hematology ,Pharmacology ,Ryanodine receptor 2 ,Sodium-Calcium Exchanger ,Rats, Sprague-Dawley ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Sarcolemma ,Physiology (medical) ,medicine ,Animals ,Calcium Signaling ,Flecainide ,030304 developmental biology ,Na+ current ,Voltage-Gated Sodium Channel Blockers ,0303 health sciences ,Sodium-calcium exchanger ,Ca2+ waves ,Ryanodine receptor ,Ca2+ sparks ,Rats ,Original Articles: Spotlight on T-Tubules and Ryanodine Receptor Microdomain Signalling in Cardiac Hypertrophy and Failure ,Sarcoplasmic Reticulum ,chemistry ,Cardiology and Cardiovascular Medicine ,Calcium-Calmodulin-Dependent Protein Kinase Type 2 ,medicine.drug - Abstract
Aims 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. Methods and results 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. 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 Ca2+ efflux via NCX across the sarcolemma, reducing Ca2+ concentration in the vicinity of the RyR2.
- Published
- 2013