NEPHRIDIA IN THE LARVAE OF HEMICHORDATES AND ECHINODERMS

Volume: 171Start Page: 188End Page: 19

Identification of Asteroid Genera With Species Capable of Larval Cloning

Volume: 204Start Page: 246End Page: 25

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 ECG. In this report we studied the effects of two TCAs (imipramine and amitriptyline) on ionic current mediated by cloned HERG potassium channels. 2. Voltage clamp measurements of HERG currents were made from CHO cells transiently transfected with HERG cDNA. HERG-encoded potassium channels were inhibited in a reversible manner by both imipramine and amitriptyline. HERG tail currents (I(HERG)) following test pulses to +20 mV were inhibited by imipramine with an IC(50) of 3.4±0.4 μM (mean±s.e.mean) and a Hill coefficient of 1.17±0.03 (n=5). 3 μM amitriptyline inhibited I(HERG) 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 durations, the τ of activation was found to be 155±30 ms for control and 132±26 ms for 3 μM 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 channel 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 presence of imipramine and the level of I(HERG) 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 kinetics of I(HERG) inactivation. The τ of inactivation was 8±2 ms and 5.6±0.4 ms (n=5) in the absence and presence of 3 μM imipramine, respectively, 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 prototype TCAs imipramine and amitriptyline may suggest a mechanism for QT prolongation associated with risks of arrhythmia and sudden death that accompany high concentrations of TCAs following overdose