Acute Modulation of Sodium Channel Biophysical Properties using High-Frequency Stimulation

Abstract

Voltage-gated ion channels are typically characterized by families of voltage-dependent curves, in particular, steady-state activation/inactivation (SSA/SSI) and peak current-voltage (IV) curves, which are often shifted or altered during disease. Previous studies have demonstrated that high-frequency stimulation (HFS) can be used to block electrical conduction in nerve axons, and more recently, in cardiac tissue. However, the use of HFS to acutely modulate ion channels has not been explored. We demonstrate that HFS can acutely and reversibly modulate sodium channel biophysical properties using a combined theoretical, computational, and experimental approach. Using the sodium channel kinetic description from the LR1 myocyte model and a multi-scale method based on a separation of time scales, HFS is predicted to shift and reduce the steepness of the SSA and SSI curves, and shift and reduce the peak IV curve. Myocyte simulations demonstrate HFS depolarizes the resting membrane potential, such that the steady-state inactivation is increased. In agreement with theoretical and computational predictions, whole-cell patch clamp of isolated guinea pig ventricular myocytes show that 25-kHz HFS significantly reduces peak sodium current and suggest a shift in the peak to more depolarized potentials. Importantly, upon HFS cessation, peak current returns to control levels, demonstrating that HFS is acutely reversible. Further, in whole-heart optical mapping experiments, 25-kHz HFS reversibly decreased lateral and transverse conduction velocities in a graded manner, consistent with increased sodium channel inactivation. We demonstrate a novel method for the acute modulation of sodium channel biophysics using HFS. Further, our theoretical work predicts that HFS may be a general approach to modulate all voltage-dependent ion channels, suggesting a multitude of potential applications.