title: Flecainide reduces Ca(2+) spark and wave frequency via inhibition of the sarcolemmal sodium current.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors: Myocardial Function Section, National Heart and Lung Institute, Fourth Floor, Imperial Centre for Translational and Experimental Medicine, Imperial College, Hammersmith Campus, Du Cane Road, London W12 0NN, UK. m.sikkel@imperial.ac.uk
authors: Markus B
authors: MB
authors: Sikkel
authors: Thomas P
authors: TP
authors: Collins
authors: Christina
authors: C
authors: Rowlands
authors: Mit
authors: M
authors: Shah
authors: Peter
authors: P
authors: O'Gara
authors: Alan J
authors: AJ
authors: Williams
authors: Sian E
authors: SE
authors: Harding
authors: Alexander R
authors: AR
authors: Lyon
authors: Kenneth T
authors: KT
authors: MacLeod
mesh_terms: D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000502:physiology; D005424:Flecainide / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012508:Sarcolemma / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000502:physiology; D013779:Tetrodotoxin / Q000494:pharmacology; D061567:Voltage-Gated Sodium Channel Blockers / Q000494:pharmacology*
chemical_list: D019831:Sodium-Calcium Exchanger; D061567:Voltage-Gated Sodium Channel Blockers; D013779:Tetrodotoxin; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D005424:Flecainide