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

Cardiac voltage-gated sodium channels control action potential (AP) upstroke and cell excitability. Intracellular calcium (Ca-i(2+)) regulates AP properties by modulating various ion channels. Whether Ca-i(2+) modulates sodium channels in ventricular myocytes is unresolved. We studied whether Ca-i(2+) modulates sodium channels in ventricular myocytes at Ca-i(2+) concentrations ([Ca-i(2+)]) present during the cardiac AP (0-500 nM), and how this modulation affects sodium channel properties in heart failure (HF), a condition in which Ca-i(2+) homeostasis is disturbed. Sodium current (I-Na) and maximal AP upstroke velocity (dV/dt(max)), a measure of I-Na, were studied at 20 and 37 degrees C, respectively, in freshly isolated left ventricular myocytes of control and HF rabbits, using whole-cell patch-clamp methodology. [Ca-i(2+)] was varied using different pipette solutions, the Ca-i(2+) buffer BAPTA, and caffeine administration. Elevated [Ca-i(2+)] reduced I-Na density and dV/dt(max), but caused no I-Na gating changes. Reductions in I-Na density occurred simultaneously with increase in [Ca-i(2+)], suggesting that these effects were due to permeation block. Accordingly, unitary sodium current amplitudes were reduced at higher [Ca-i(2+)]. While I-Na density and gating at fixed [Ca-i(2+)] were not different between HF and control, reductions in dV/dt(max) upon increases in stimulation rate were larger in HF than in control; these differences were abolished by BAPTA. Ca-i(2+) exerts acute modulation of I-Na density in ventricular myocytes, but does not modify I-Na gating. These effects, occurring rapidly and in the [Ca-i(2+)] range observed physiologically, may contribute to beat-to-beat regulation of cardiac excitability in health and disease.