Fig. 2.

Doxepin inhibition of I_HERG during action potential (AP) voltage clamp and of native I_Kr tails. (A) The upper traces show (leak corrected) representative currents of heterologously expressed I_HERG in the absence and presence of 10 μM doxepin elicited by an AP clamp protocol (lower trace; voltage command applied at 4 s intervals). (B) Schematic representation of protocol used to assess blockade of native I_Kr tails by doxepin. (C) Representative tail currents from a rabbit ventricular myocyte upon repolarization from +20 to −40 mV in the absence (left panel) and in the presence of 100 μM doxepin (right panel). Upper traces show current records and lower traces show corresponding portion of the voltage protocol. The horizontal dashed line is drawn at the level of the current at −40 mV at the end of the initial (100 ms) step to −40 mV, against which peak I_Kr amplitude on repolarization from +20 to +40 mV was measured. (D) Mean fractional tail current block produced by three different concentrations of doxepin fitted with Eq. (2), which yielded an IC₅₀ value of 4.4 (± 0.6 μM) with a Hill coefficient of 0.7 (± 0.1). Each drug concentration was applied to a minimum of twelve cells.