Inhibition of cardiac HERG potassium channels by the atypical antidepressant trazodone.
Trazodone is an atypical antidepressant that is commonly used in the treatment of affective disorders. There have repeatedly been reports of cardiac arrhythmia associated with this drug and concerns have been raised regarding the cardiac safety of trazodone. However, interaction with HERG channels as a main factor of cardiac side effects has not been studied to date. Therefore, we investigated the effect of trazodone on HERG potassium channels expressed in human embryonic kidney (HEK) cells and in Xenopus oocytes. Trazodone inhibited HERG currents in a dose-dependent manner with an IC50 of 2.9 microM in HEK cells and 13.2 microM in Xenopus oocytes. The electrophysiological properties of HERG blockade were analysed in detail. In HERG channel mutants Y652A and F656A lacking aromatic residues in the S6 domain, the affinity of trazodone was reduced profoundly. Trazodone accelerated inactivation of HERG currents without markedly affecting activation. Blockade was voltage dependent with a small reduction of block at positive membrane potentials. Frequency dependence of block was not observed. Trazodone block of HERG channels was state dependent. Channels were affected in the activated and inactivated states, but not in the closed states. In summary, the atypical antidepressant trazodone blocks cardiac HERG channels at concentrations that are probably relevant in vivo, particularly in overdosage.
Zitron
Edgar
E
Department of Internal Medicine III (Cardiology), Medical University Hospital Heidelberg, Bergheimerstrasse 58, 69115, Heidelberg, Germany.
Kiesecker
Claudia
C
Scholz
Eberhard
E
Lück
Sonja
S
Bloehs
Ramona
R
Kathöfer
Sven
S
Thomas
Dierk
D
Kiehn
Johann
J
Kreye
Volker A W
VA
Katus
Hugo A
HA
Schoels
Wolfgang
W
Karle
Christoph A
CA
D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006801:Humans; D015640:Ion Channel Gating; D008564:Membrane Potentials / Q000187:drug effects; D009154:Mutation; D009206:Myocardium; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D024642:Potassium Channels, Voltage-Gated / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D013997:Time Factors; D014196:Trazodone / Q000494:pharmacology*; D014982:Xenopus laevis
D018687:Antidepressive Agents, Second-Generation; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; D014196:Trazodone