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Cardiovascular Research Advance Access [Accepted Manuscript] published online on October 1, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn274
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org.

Intracellular calcium modulation of voltage-gated sodium channels in ventricular myocytes

Simona Casini, PhD1, Arie O. Verkerk, PhD1, Marcel M.G.J. van Borren, PhD1, Antoni C.G. van Ginneken, PhD1, Marieke W. Veldkamp, PhD1, Jacques M.T. de Bakker, PhD1 and Hanno L. Tan,, PhD1,2

1 Heart Failure Research Center and University of Amsterdam, Amsterdam, The Netherlands
2 Department of Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

Correspondence to: Hanno L. Tan, MD, PhD Department of Clinical and Experimental Cardiology Heart Failure Research Center Academic Medical Center Meibergdreef 9 1105 AZ Amsterdam The Netherlands E-mail: h.l.tan{at}amc.nl Phone: +31-20-5663264 Fax: +31-20-6975458

Aims: Cardiac voltage-gated sodium channels control action potential (AP) upstroke and cell excitability. Intracellular calcium (Cai2+) regulates AP properties by modulating various ion channels. Whether Cai2+ modulates sodium channels in ventricular myocytes, is unresolved. We studied whether Cai2+ modulates sodium channels in ventricular myocytes at Cai2+ concentrations ([Cai2+]) present during the cardiac AP (0-500 nM), and how this modulation affects sodium channel properties in heart failure (HF), a condition in which Cai2+ homeostasis is disturbed.

Methods: Sodium current (INa) and maximal AP upstroke velocity (dV/dtmax), a measure of INa, were studied at 20ºC and 37ºC, respectively, in freshly isolated left ventricular myocytes of control and HF rabbits, using whole-cell patch-clamp methodology. [Cai2+] was varied using different pipette solutions, the Cai2+ buffer BAPTA, and caffeine administration.

Results: Elevated [Cai2+] reduced INa density and dV/dtmax, but caused no INa gating changes. Reductions in INa density occurred simultaneously with increases in [Cai2+], suggesting that these effects were due to permeation block. Accordingly, unitary sodium current amplitudes were reduced at higher [Cai2+]. While INa density and gating at fixed [Cai2+] were not different between HF and control, reductions in dV/dtmax upon increases in stimulation rate were larger in HF than in control; these differences were abolished by BAPTA.

Conclusion: Cai2+ exerts acute modulation of INa density in ventricular myocytes, but does not modify INa gating. These effects, occurring rapidly and in the [Cai2+] range observed physiologically, may contribute to beat-to-beat regulation of cardiac excitability in health and disease.

KEYWORDS ion channels; Na-channel; arrhythmia

Time for primary review: 32 days


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