Simulation of Na/K pump function in an intact cell with and without inactivation that generates a pump reserve three times larger than the active pump pool with 7 mM cytoplasmic Na. (A) Simulated cytoplasmic Na changes with and without inactivation. As indicated, a background Na current of 47 pA was doubled to 94 pA in the simulation for 5 min and then decreased again to 47 pA. Na-dependent recovery from inactivation blunts the increase of Na by 50% and doubles the apparent speed with which Na homeostasis occurs. Na homeostasis occurs nearly exponentially with a time constant that is substantially smaller than the average dwell time of Na ions in the cell. (B) Predicted physiological implications of regulated Na/K pump inactivation for cardiac myocytes. As the inactivation rate increases from negligible values to 1.8 s ⁻¹, 65% of Na/K pumps inactivate, consistent with pump currents described in Fig. 5 (top graph). This degree of inactivation causes a doubling of cytoplasmic Na from 4 to 8 mM (second graph), which would in turn cause a nearly fourfold increase of the cardiac Ca transient (third graph). Assuming a C–force relationship with a Hill slope of 2.7, these Ca changes translate to contraction changes over the full range of cardiac contractility (bottom graph). More details for cardiac ECC are outlined in a separate article (Hilgemann, 2019).