Figure 6. Simulated effects of pentamidine and dofetilide on K_v11.1 gating and trafficking.

A, Time course of I_Kr (top panel) and K_v11.1 membrane levels (middle panel) during 24 hours at baseline (solid lines) or with 5 μmol/L pentamidine (dashed lines), followed by 24 hours with simulated dofetilide application (1 μmol/L) and 24 hours at baseline, revealing acute inhibition and long-term rescue of K_v11.1 membrane levels only during the presence of pentamidine. The dashed vertical lines (grey) indicate the start and end time of dofetilide application. The bottom panel shows the action-potential morphology at various points in the time course shown in the other panels for the simulations with 1 μmol/L dofetilide with pentamidine (solid lines) and without pentamidine (dashed lines), showing acute prolongation of repolarization duration for both conditions, but only a slight shortening of repolarization after cessation of simulated dofetilide application due to the complete rescue and minor increase in K_v11.1 membrane levels. B, Similar to panel A, for 3.4 nmol/L dofetilide. The bottom panel shows action potential prolongation when pentamidine is present due to a reduction of the number of membrane channels. The subsequent simulated dofetilide administration (3.4 nmol/L) had minimal effects on K_v11.1 trafficking.