Inhibition of the current of heterologously expressed HERG potassium channels by imipramine and amitriptyline

1 Tricyclic antidepressants (TCAs) are associated with cardiovascular side effects including prolongation of the QT interval of the EGG. In this repor t we studied the effects of two TCAs (imipramine and amitriptyline) on ioni c current mediated by cloned HERG potassium channels. 2 Voltage clamp measurements of HERG currents were made from CHO cells tran siently transfected with HERG cDNA. HERG-encoded potassium channels were in hibited in a reversible manner by both imipramine and amitriptyline. HERG t ail currents (I-HERG) following test pulses to +20 mV were inhibited by imi pramine with an IC50 of 3.4+/-0.4 mu M (mean+/-s.e.mean) and a Hill coeffic ient of 1.17+/-0.03 (n=5). 3 mu M amitriptyline inhibited IHERG by 34+/-6% (n=3). The inhibition showed only weak voltage dependence. 3 Using an 'envelope of tails' comprised of pulses to +20 mV of varying dur ations, the tau of activation was found to be 155+/-30 ms for control and 1 32+/-26 ms for 3 mu M imipramine (n=5). Once maximal channel activation was achieved after 320 ms (as demonstrated by maximal tail currents), further prolongation of depolarization did not increase imipramine-mediated HERG ch annel inhibition. 4 Taking current measurements every second during a 10 s depolarizing pulse from -80 mV to 0 mV, block was observed during the first pulse in the pres ence of imipramine and the level of IHERG block was similar throughout the pulse (n=5). 5 A three pulse protocol (two depolarizing pulses to +20 mV separated by 20 ms at -80 mV) revealed that imipramine did not significantly alter the kin etics of IHERG inactivation. The tau of inactivation was 8+/-2 ms and 5.6+/ -0.4 ms (n=5) in the absence and presence of 3 mu M imipramine, respectivel y, and currents inactivated to a similar extent. 6 Our data are consistent with TCAs causing components of block of the HERG channel in both the closed and open states. Any component of open channel block occurs rapidly upon depolarization. Inhibition of I-HERG by the proto type TCAs imipramine and amitriptyline may suggest a mechanism for QT prolo ngation associated with risks of arrhythmia and sudden death that accompany high concentrations of TCAs following overdose.