Atypical tetracyclic antidepressant maprotiline is an antagonist at cardiac hERG potassium channels.
Maprotiline is an antidepressant compound with an atypical tetracyclic structure that is widely used in elderly patients due to its favourable side-effect profile. However, there have been reports of proarrhythmia associated with maprotiline and in vitro studies of its electrophysiological properties have been lacking. Therefore, we characterised the effects of maprotiline on cardiac hERG channels. hERG channels were expressed in HEK cells and in the Xenopus oocyte expression system. Currents were measured using a whole-cell patch clamp and a two-microelectrode voltage-clamp. Maprotiline inhibited hERG currents with an IC(50) of 8.2 micromol/l in HEK cells and 29.2 micromol/l in Xenopus oocytes. Onset of the effect was rather slow and took several minutes. No wash-out of effect was observed. Maprotiline blocked hERG channels in the open and inactivated states, but not in the closed states. In mutant hERG channels Y652A and F656A, the effect was markedly attenuated (hERG-F656A) or completely abolished (hERG-Y652A). Voltage dependence of hERG current activation and inactivation was not affected by maprotiline. hERG inactivation was accelerated at positive potentials. The effect of maprotiline on hERG currents was voltage-dependent with a marked reduction at a more positive potential. hERG blockade by maprotiline was not frequency-dependent. Maprotiline is an antagonist of cardiac hERG potassium channels that preferably accesses the putative pore binding site Y652/F656. Although the affinity of maprotiline to hERG channels is low, its use in patients with risk factors for acquired long QT syndrome should be monitored appropriately.
Kiesecker
Claudia
C
Department of Cardiology, Medical University Hospital Heidelberg, Im Neuenheimer Feld 350, 69120, Heidelberg, Germany. ckiesecker@gmx.de
Alter
Markus
M
Kathöfer
Sven
S
Zitron
Edgar
E
Scholz
Eberhard P
EP
Thomas
Dierk
D
Kreuzer
Jörg
J
Katus
Hugo A
HA
Bauer
Alexander
A
Karle
Christoph A
CA
D000818:Animals; D000928:Antidepressive Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D004594:Electrophysiology; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008376:Maprotiline / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D009154:Mutation / Q000235:genetics; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010649:Phenylalanine / Q000235:genetics / Q000378:metabolism; D011083:Polycyclic Compounds / Q000737:chemistry / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism; D014982:Xenopus laevis
D000928:Antidepressive Agents; D051638:Ether-A-Go-Go Potassium Channels; D011083:Polycyclic Compounds; D026902:Potassium Channel Blockers; D008376:Maprotiline; D014443:Tyrosine; D010649:Phenylalanine