Figure 10.

In silico investigation on neuronal and cardiac I_NaL components in HF dog ventricular cell

A, predicted current–voltage relationships. The upper panels show families of predicted current traces at different membrane voltages for the cardiac and neuronal Na_v components. The lower panels show plotted amplitude values of these predictions. Left lower sub-panel shows the peak I_NaL (at zero time after the depolarization onset) and right lower sub-panel shows the current amplitudes 200 ms after depolarization onset. Holding potential was V_h = −120 mV, test pulses were applied from –70 mV to +70 mV. B, predicted profile of I_NaL generated by cardiac and neuronal Na_vs in numerical model simulations of AP. C and D, predicted differential contribution of I_NaL by the neuronal and cardiac Na_vs to shape and duration of AP and intracellular Ca²⁺ dynamics, respectively, at the pacing rate of 1 Hz. Complete I_NaL elimination from simulations (I_NaL = 0) reduces AP duration and eliminates diastolic Ca²⁺ accumulation. Introduction of only the cardiac or neuronal component of I_NaL increases AP duration and leads to diastolic Ca²⁺ accumulation, whereas incorporation of both I_NaL components, which reflects the situation in situ, affects these physiological responses dramatically. All numerical simulations were performed at a physiological temperature of 37 °C using our modification of the Winslow E–C coupling model of canine failing VCMs (Winslow et al. 1999) with formulations for I_NaL which were previously developed based on our experimental voltage-clamp data (Undrovinas et al. 2010; Mishra et al. 2011). In the present study I_NaL formulations included two separate I_NaL components for cardiac and neuronal isoforms, respectively. Each component has its own activation and inactivation gating variables evaluated from patch-clamp data obtained in the present study (see section ‘Patch-clamp data’).