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

• Published in: Cardiovascular research Vol. 81; no. 1; pp. 72 - 81
• Main Authors: Casini, Simona, Verkerk, Arie O., van Borren, Marcel M.G.J., van Ginneken, Antoni C.G., Veldkamp, Marieke W., de Bakker, Jacques M.T., Tan, Hanno L.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01-01-2009
• Subjects: Action Potentials - drug effects; Action Potentials - physiology; Animals; Arrhythmia; Biological and medical sciences; Buffers; Caffeine - pharmacology; Calcium - metabolism; Calcium - pharmacology; Cardiac dysrhythmias; Cardiology. Vascular system; Cell Line; Cells, Cultured; Disease Models, Animal; Egtazic Acid - analogs & derivatives; Egtazic Acid - pharmacology; Heart; Heart Failure - metabolism; Heart Failure - pathology; Heart Failure - physiopathology; Heart Rate - drug effects; Heart Rate - physiology; Heart Ventricles - cytology; Heart Ventricles - metabolism; Homeostasis; Humans; Ion channels; Medical sciences; Muscle Proteins - genetics; Muscle Proteins - metabolism; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Na-channel; NAV1.5 Voltage-Gated Sodium Channel; Patch-Clamp Techniques; Phosphodiesterase Inhibitors - pharmacology; Rabbits; Sodium Channels - genetics; Sodium Channels - metabolism; Transfection; Arrhythmia; Ion channels; Na-channel; Calcium; Cardiovascular disease; Ionic channel; Phlebology; Myocyte; Sodium; Heart disease; Modulation; Voltage; Circulatory system; Intracellular; Cardiology
• ISSN: 0008-6363; 1755-3245
• DOI: 10.1093/cvr/cvn274

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.