Fig 9.

Effect of E-4031 on the action potential. The left column shows action potentials from the Fink modified³⁵ ten Tusscher action potential model³⁶ in which hERG 1a/1b (blue) and hERG 1a (red) were substituted for the native I_Kr. As [E-4031] increases (0, 5, and 10 nM for panels A, B, and C respectively), APD₉₀ increases, and I_hERG decreases for both hERG 1a/1b and 1a. ΔAPD₉₀ (the difference in APD₉₀ between hERG 1a/1b and hERG 1a) also increases with [E-4031] ([E-4031] = 0 nM, ΔAPD₉₀ = 38 ms; [E-4031] = 5 nM, ΔAPD₉₀ = 168 ms; [E-4031] = 10 nM, ΔAPD₉₀ = 728 ms). In all cases, APD₉₀ is longer and peak I_hERG is smaller for hERG 1a. For control and for [E-4031] = 5 nM, peak I_hERG occurs later for hERG 1a. For hERG 1a at [E-4031] = 10 nM (bottom row, red), repolarization fails to occur within the 1 sec cycle length on odd numbered beats. To mark the takeoff potential of the odd beat for hERG 1a, we place a red arrow. The alternating pattern for hERG 1a is a consequence of sustained depolarization curtailing deactivation at the end of even beats.