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Cardiovascular Research Advance Access first published online on October 1, 2008
This version [Corrected Proof] published online on October 23, 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 Casini1, Arie O. Verkerk1, Marcel M.G.J. van Borren1, Antoni C.G. van Ginneken1, Marieke W. Veldkamp1, Jacques M.T. de Bakker1 and Hanno L. Tan1,2,*

1 Department of Clinical and Experimental Cardiology, Heart Failure Research Center, Academic Medical Center, University of Amsterdam, Meibergdreef 9, AZ 1105 Amsterdam, The Netherlands
2 Department of Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

* Corresponding author. Tel: +31 20 5663264; fax: +31 20 6975458. E-mail address: h.l.tan{at}amc.nl

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 and results: Sodium current (INa) and maximal AP upstroke velocity (dV/dtmax), a measure of INa, were studied at 20 and 37°C, 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. Elevated [Cai2+] reduced INa density and dV/dtmax, but caused no INa gating changes. Reductions in INa density occurred simultaneously with increase 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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