title: Atypical tetracyclic antidepressant maprotiline is an antagonist at cardiac hERG potassium channels.
abstract: 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.
authors.affiliation: Department of Cardiology, Medical University Hospital Heidelberg, Im Neuenheimer Feld 350, 69120, Heidelberg, Germany. ckiesecker@gmx.de
authors.forename: Claudia
authors.initials: C
authors.lastname: Kiesecker
authors.forename: Markus
authors.initials: M
authors.lastname: Alter
authors.forename: Sven
authors.initials: S
authors.lastname: Kathöfer
authors.forename: Edgar
authors.initials: E
authors.lastname: Zitron
authors.forename: Eberhard P
authors.initials: EP
authors.lastname: Scholz
authors.forename: Dierk
authors.initials: D
authors.lastname: Thomas
authors.forename: Jörg
authors.initials: J
authors.lastname: Kreuzer
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.forename: Alexander
authors.initials: A
authors.lastname: Bauer
authors.forename: Christoph A
authors.initials: CA
authors.lastname: Karle
mesh_terms: 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
chemical_list: D000928:Antidepressive Agents; D051638:Ether-A-Go-Go Potassium Channels; D011083:Polycyclic Compounds; D026902:Potassium Channel Blockers; D008376:Maprotiline; D014443:Tyrosine; D010649:Phenylalanine