Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Naunyn Schmiedebergs Arch Pharmacol
2004 Aug 01;3702:146-56. doi: 10.1007/s00210-004-0952-3.
Show Gene links
Show Anatomy links
Inhibition of cardiac HERG potassium channels by the atypical antidepressant trazodone.
Zitron E
,
Kiesecker C
,
Scholz E
,
Lück S
,
Bloehs R
,
Kathöfer S
,
Thomas D
,
Kiehn J
,
Kreye VA
,
Katus HA
,
Schoels W
,
Karle CA
.
???displayArticle.abstract???
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.
Abbott,
MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia.
1999, Pubmed,
Xenbase
Abbott,
MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia.
1999,
Pubmed
,
Xenbase
Alvarez,
Safety of antidepressant drugs in the patient with cardiac disease: a review of the literature.
2003,
Pubmed
Casis,
Mechanism of block of cardiac transient outward K+ current (I(to)) by antidepressant drugs.
1998,
Pubmed
Chen,
Position of aromatic residues in the S6 domain, not inactivation, dictates cisapride sensitivity of HERG and eag potassium channels.
2002,
Pubmed
,
Xenbase
de Meester,
Fatal overdose with trazodone: case report and literature review.
2001,
Pubmed
DeVane,
Differential pharmacology of newer antidepressants.
1998,
Pubmed
Feighner,
Mechanism of action of antidepressant medications.
1999,
Pubmed
Goodnick,
Psychotropic drugs and the ECG: focus on the QTc interval.
2002,
Pubmed
Haria,
Trazodone. A review of its pharmacology, therapeutic use in depression and therapeutic potential in other disorders.
1994,
Pubmed
Jo,
Blockade of the HERG human cardiac K(+) channel by the antidepressant drug amitriptyline.
2000,
Pubmed
,
Xenbase
Kiehn,
Pathways of HERG inactivation.
1999,
Pubmed
,
Xenbase
Kiehn,
Inhibitory effects of the class III antiarrhythmic drug amiodarone on cloned HERG potassium channels.
1999,
Pubmed
,
Xenbase
Levenson,
Prolonged QT interval after trazodone overdose.
1999,
Pubmed
Madeja,
Follicular tissues reduce drug effects on ion channels in oocytes of Xenopus laevis.
1997,
Pubmed
,
Xenbase
Milnes,
Blockade of HERG potassium currents by fluvoxamine: incomplete attenuation by S6 mutations at F656 or Y652.
2003,
Pubmed
Mitcheson,
A structural basis for drug-induced long QT syndrome.
2000,
Pubmed
,
Xenbase
Mitcheson,
Trapping of a methanesulfonanilide by closure of the HERG potassium channel activation gate.
2000,
Pubmed
,
Xenbase
Mitcheson,
Drug binding to HERG channels: evidence for a 'non-aromatic' binding site for fluvoxamine.
2003,
Pubmed
Redfern,
Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development.
2003,
Pubmed
Roden,
Cardiac ion channels.
2002,
Pubmed
Sánchez-Chapula,
Molecular determinants of voltage-dependent human ether-a-go-go related gene (HERG) K+ channel block.
2002,
Pubmed
,
Xenbase
Sănchez-Chapula,
Voltage-dependent profile of human ether-a-go-go-related gene channel block is influenced by a single residue in the S6 transmembrane domain.
2003,
Pubmed
,
Xenbase
Sanguinetti,
A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel.
1995,
Pubmed
,
Xenbase
Scholz,
Drug binding to aromatic residues in the HERG channel pore cavity as possible explanation for acquired Long QT syndrome by antiparkinsonian drug budipine.
2003,
Pubmed
,
Xenbase
Smith,
The inward rectification mechanism of the HERG cardiac potassium channel.
1996,
Pubmed
Spector,
Class III antiarrhythmic drugs block HERG, a human cardiac delayed rectifier K+ channel. Open-channel block by methanesulfonanilides.
1996,
Pubmed
,
Xenbase
Teschemacher,
Inhibition of the current of heterologously expressed HERG potassium channels by imipramine and amitriptyline.
1999,
Pubmed
Thomas,
High-affinity blockade of human ether-a-go-go-related gene human cardiac potassium channels by the novel antiarrhythmic drug BRL-32872.
2001,
Pubmed
,
Xenbase
Thomas,
The antidepressant drug fluoxetine is an inhibitor of human ether-a-go-go-related gene (HERG) potassium channels.
2002,
Pubmed
,
Xenbase
Vitezic,
Erectile dysfunction: oral pharmacotherapy options.
2002,
Pubmed
Witchel,
Inhibitory actions of the selective serotonin re-uptake inhibitor citalopram on HERG and ventricular L-type calcium currents.
2002,
Pubmed
Witchel,
Troubleshooting problems with in vitro screening of drugs for QT interval prolongation using HERG K+ channels expressed in mammalian cell lines and Xenopus oocytes.
2002,
Pubmed
,
Xenbase
Witchel,
Psychotropic drugs, cardiac arrhythmia, and sudden death.
2003,
Pubmed
Zitron,
Bertosamil blocks HERG potassium channels in their open and inactivated states.
2002,
Pubmed
,
Xenbase
