Inhibition of cardiac hERG potassium channels by tetracyclic antidepressant mianserin.
The antidepressant mianserin exhibits a tetracyclic structure that is different from typical tricyclic antidepressants (TCA) and that of selective serotonin reuptake inhibitors. In comparison to the older TCA, mianserin has been shown to have a superior risk profile regarding proarrhythmic effects, both in vitro and in vivo. However, the underlying molecular electrophysiological basis has not been elucidated to date. Therefore, we studied the effects of mianserin on cardiac hERG potassium channels, the predominant target of drug-induced proarrhythmia. HERG channels were expressed in the Xenopus oocyte expression system and in human embryonic kidney (HEK) cells and currents were measured with two-microelectrode voltage-clamp and whole-cell patch-clamp, respectively. Mianserin inhibited hERG currents in a dose-dependent manner with an IC(50) of 3.2 micromol/l in HEK cells. Onset of blockade was slow and the inhibitory effect was not reversible upon wash-out of the drug. In hERG channel mutants, Y652A and F656A, lacking aromatic residues in the S6 domain, the effect of mianserin was significantly reduced in comparison to the wild type. Mianserin inhibited hERG currents in the open and inactivated state, but not in the closed states. HERG inactivation kinetics were significantly altered by mianserin without marked effects on channel activation kinetics. The inhibitory effect was not frequency dependent. In conclusion, mianserin is a low-affinity hERG-blocking agent. However, taken together with the lack of APD-prolongation shown in other studies, mianserin seems to have a good safety profile. Lack of consistent QT prolonging effects of mianserin in previous studies may therefore be linked to additional effects such as inhibition of other cardiac ion channels. However, as demonstrated by clinical case reports, mianserin can induce proarrhythmic effects in susceptible patients. Therefore, in patients with complex co-medication (i.e., additional hERG-blocking agents) and in patients with risk factors for acquired long QT syndrome as well as in cases of overdose, adequate monitoring should be recommended.
Scherer
Daniel
D
Department of Internal Medicine III-Cardiology, University Hospital Heidelberg, Im Neuenheimer Feld 410, D-69120, Heidelberg, Germany.
von Löwenstern
Katharina
K
Zitron
Edgar
E
Scholz
Eberhard P
EP
Bloehs
Ramona
R
Kathöfer
Sven
S
Thomas
Dierk
D
Bauer
Alexander
A
Katus
Hugo A
HA
Karle
Christoph A
CA
Kiesecker
Claudia
C
D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000008:administration & dosage / Q000633:toxicity*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D007668:Kidney / Q000166:cytology; D008803:Mianserin / Q000008:administration & dosage / Q000633:toxicity*; D009865:Oocytes / Q000187:drug effects; D018408:Patch-Clamp Techniques / Q000379:methods; D018675:Toxicity Tests; D014981:Xenopus
D018687:Antidepressive Agents, Second-Generation; D051638:Ether-A-Go-Go Potassium Channels; D008803:Mianserin