Figure 1. I_Na Markov model schematic.

When no drug is applied, I_Na is modeled with a 13-state Markov scheme [15, 16] accounting for both canonical and burst gating modes (see drug-free layer in figure). O and LO are respectively the conducting open states for normal and burst mode, and C₁-C₃ and LC₁-LC₃ are the corresponding closed states. IF is the fast inactivation state, IM₁-IM₂ represent intermediate inactivation, and IC₂-IC₃ are the deeply inactivated states. To model ranolazine interaction with the Na⁺ channel, we used the extended scheme shown here, assuming that the channel can reside in any state in drug-free or drug-bound conditions (as done in [18, 19]). Transitions between layers are E_m- and dose-dependent, and can occur between analogous states only. Ranolazine binding is facilitated when the channel resides in the open states. The drug unbinds rapidly from the closed states, but stays trapped in the inactivated states. O and LO in the drug-bound layer are not conducting states.