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

Sikkel, M., Collins, T., Rowlands, C., Shah, M., O'Gara, P., Williams, Alan John, Harding, S., Lyon, A. and MacLeod, K. 2013. Flecainide reduces Ca2+ spark and wave frequency via inhibition of the sarcolemmal sodium current. Cardiovascular Research 98 (2) , pp. 286-296. 10.1093/cvr/cvt012

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Abstract

AimsCa2+ 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 resultsWe imaged spontaneous sarcoplasmic reticulum (SR) Ca2+ 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 INa via alternative pharmacological agents (tetrodotoxin, propafenone, or lidocaine) produced similar changes. To assess the contribution of INa 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 INa is active. It was found that Na+/Ca2+-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.ConclusionFlecainide reduces spark and wave frequency in the intact rat cardiomyocyte at therapeutically relevant concentrations but the mechanism involves INa reduction rather than direct ryanodine receptor (RyR2) inhibition. Reduced INa results in increased Ca2+ efflux via NCX across the sarcolemma, reducing Ca2+ concentration in the vicinity of the RyR2.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	R Medicine > R Medicine (General) R Medicine > RC Internal medicine R Medicine > RZ Other systems of medicine
Uncontrolled Keywords:	Animals; Calcium Signaling; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Flecainide; Male; Rats; Rats, Sprague-Dawley; Sarcolemma; Sarcoplasmic Reticulum; Sodium-Calcium Exchanger; Tetrodotoxin; Voltage-Gated Sodium Channel Blockers
Publisher:	Elsevier
ISSN:	0008-6363
Last Modified:	12 Jun 2019 02:30
URI:	https://orca.cardiff.ac.uk/id/eprint/76241

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