(A) To change the resting membrane potential, the potassium equilibrium potential was varied between –120 and –50 mV. In the default model, the experimentally observed resting membrane potential (indicated by the horizontal black dashed line and the gray bar; mean ± SEM) was obtained with a potassium equilibrium potential of –98 mV (vertical black dashed line). (B) Upon depolarization, the inactivation of voltage-dependent sodium (NaV) channels increased. For the control model, the NaV inactivation was 12%. For the model reproducing the experiments with ZD7288 and 1 mM intracellular cAMP, the NaV inactivation was 6% and 17%, respectively. Because the steady-state NaV availability depends mostly on the resting membrane potential, the relation between resting membrane potential and NaV availability was identical for all three models (data not shown). (C) Upon depolarization, the conduction velocity increased up to a potassium equilibrium potential of about –65 mV (vertical gray dashed arrow), corresponding to an NaV availability of about 50% (horizontal gray dashed arrow in panel (B)) and a resting membrane potential of about –60 mV (horizontal gray dashed arrow in panel (A)). Thus, despite increasing NaV inactivation, the conduction velocity increased in this range (as illustrated by the green bar). With stronger depolarization, the conduction velocity declined, indicating that the NaV availability becomes limiting for conduction velocity (purple bar).