Aims: 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.
Methods and results: 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.
Conclusion: 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.