Skip to main content
SpringerLink
Log in

Inhibition of cardiac HERG potassium channels by the atypical antidepressant trazodone

  • Original Article
  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

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 μM in HEK cells and 13.2 μM 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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2A–D
Fig. 3A, B
Fig. 4A–C
Fig. 5
Fig. 6A–C
Fig. 7A–F
Fig. 8A–C
Fig. 9
Fig. 10A–D

Similar content being viewed by others

Abbreviations

aLQTS:

Acquired long QT syndrome

HERG:

Human ether-a-go-go-related gene

IC50:

Half-maximal inhibitory drug concentration

I Kr :

The rapid component of the delayed-rectifier potassium current

SSRI:

Selective serotonin reuptake inhibitor

TCA:

Tricyclic antidepressant

TdP:

Torsade-de-Pointes tachycardia

wt:

Wild type

References

  • Abbott GW, Sesti F, Splawski I, Buck ME, Lehmann MH, Timothy KW, Keating MT, Goldstein SA (1999) MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia. Cell 97:175–187

    Article  CAS  PubMed  Google Scholar 

  • Alvarez W, Pickworth K (2003) Safety of antidepressant drugs in the patient with cardiac disease: a review of the literature. Pharmacotherapy 23:754–771

    Article  CAS  PubMed  Google Scholar 

  • Casis O, Sanchez-Capula JA (1998) Mechanism of block of cardiac transient outward K+ current Ito by antidepressant drugs. J Cardiovasc Pharmacol 32:527–534

    Article  CAS  PubMed  Google Scholar 

  • Chen J, Seebohm G, Sanguinetti MC (2002) Position of aromatic residues in the S6 domain, not inactivation, dictates cisapride sensitivity of HERG and eag potassium channels. Proc Natl Acad Sci 99:12461–12466

    Article  CAS  PubMed  Google Scholar 

  • De Meester A, Carbutti G, Gabriel L, Jacques JM (2001) Fatal overdose with trazodone: case report and literature review. Acta Clin Belg 56:258–261

    PubMed  Google Scholar 

  • Devane CL (1998) Differential pharmacology of newer antidepressants. J Clin Psychiatry 59:85–93

    CAS  Google Scholar 

  • Feighner JP (1999) Mechanism of action of antidepressant medications. J Clin Psychiatry 60:4–11

    CAS  Google Scholar 

  • Goodnick PJ, Jerry J, Parra F (2002) Psychotropic drugs and the ECG: focus on the QT interval. Expert Opin Pharmacother 3:479–498

    CAS  PubMed  Google Scholar 

  • Haria M, Fitton A, McTavish D (1994) Trazodone: a review of its pharmacology, therapeutic use in depression and therapeutic potential in other disorders. Drugs Aging 4:331–355

    CAS  PubMed  Google Scholar 

  • Jo SH, Youm JB, Lee CO, Earm YE, Ho WK (2000) Blockade of the HERG human cardiac K+ channel by the antidepressant drug amitriptyline. Br J Pharmacol 129:1474–1480

    CAS  PubMed  Google Scholar 

  • Kiehn J, Lacerda AE, Brown AM (1999a) Pathways of HERG inactivation. Am J Physiol 277:H199–H210

    CAS  PubMed  Google Scholar 

  • Kiehn J, Thomas D, Karle CA, Schoels W, Kubler W (1999b) Inhibitory effects of the class III antiarrhythmic drug amiodarone on cloned HERG potassium channels. Naunyn-Schmiedebergs Arch Pharmacol 359:212–219

    CAS  PubMed  Google Scholar 

  • Levenson JL (1999) Prolonged QT interval after trazodone overdose. Am J Psychiatry 156:969–970

    CAS  Google Scholar 

  • Madeja M, Musshoff U, Speckmann EJ (1997) Follicular tissues reduce drug effects on ion channels in oocytes of Xenopus laevis. Eur J Neurosci 9:599–604

    CAS  PubMed  Google Scholar 

  • Milnes JT, Crociani O, Arcangeli A, Hancox JC, Witchel HJ (2003) Blockade of HERG potassium currents by fluvoxamine: incomplete attenuation by S6 mutations at F656 or Y652. Br J Pharmacol 139:887–898

    Article  CAS  PubMed  Google Scholar 

  • Mitcheson JS (2003) Drug binding to HERG channels: evidence for a ‘non-aromatic binding site’ for fluvoxamine. Br J Pharmacol 139:883–884

    Article  CAS  PubMed  Google Scholar 

  • Mitcheson JS, Chen J, Sanguinetti MC (2000a) Trapping of a methanesulfonanilide by closure of the HERG potassium channel activation gate. J Gen Physiol 115:229–239

    Article  CAS  PubMed  Google Scholar 

  • Mitcheson JS, Chen J, Culberson C, Sanguinetti MC (2000b) A structural basis for drug-induced long QT syndrome. Proc Natl Acad Sci 97:12329–12333

    Article  CAS  PubMed  Google Scholar 

  • Redfern WS, Carlsson L, Davis AS, Lynch WG, MacKenzie I, Palethorpe S, Siegl PK, Strang I, Sullivan AT, Wallis R, Camm AJ, Hammond TG (2003) 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. Cardiovasc Res 58:32–45

    Article  CAS  PubMed  Google Scholar 

  • Roden DM, Balser JR, George AL, Anderson ME (2002) Cardiac ion channels. Annu Rev Physiol 64:431–475

    Article  CAS  PubMed  Google Scholar 

  • Sanchez-Chapula J, Navarro-Polanco RA, Culberson C, Chen J, Sanguinetti MC (2002) Molecular determinants of voltage-dependent profile of human ether-a-gogo-related gene (HERG) K(+) channel block. J Biol Chem 277:23587–23595

    Article  CAS  PubMed  Google Scholar 

  • Sanchez-Chapula J, Ferrer T, Navarro-Polanco RA, Sanguinetti MC (2003) Voltage-dependent profile of human ether-a-gogo-related gene channel block is influenced by a single residue in the S6 transmembrane domain. Mol Pharmacol 63:1051–1058

    Article  CAS  PubMed  Google Scholar 

  • Sanguinetti MC, Changan J, Curran ME, Keating M (1995) A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel. Cell 81:1–20

    PubMed  Google Scholar 

  • Scholz EP, Zitron E, Kiesecker C, Lueck S, Kathofer S, Thomas D, Weretka S, Peth S, Kreye VA, Schoels W, Katus HA, Kiehn J, Karle CA (2003) Drug binding to aromatic residues in the HERG channel pore cavity as possible explanation for acquired long QT syndrome by antiparkinsonian drug budipine. Naunyn-Schmiedebergs Arch Pharmacol 368:404–414

    Article  CAS  PubMed  Google Scholar 

  • Smith PL, Baukrowitz T, Yellen G (1996) The inward rectification mechanism of the HERG cardiac potassium channel. Nature 379:833–836

    Article  CAS  PubMed  Google Scholar 

  • Spector PS, Curran ME, Keating M, Sanguinetti MC (1996) Class III antiarrhythmic drugs block HERG, a human cardiac delayed rectifier K+ channel open-channel block by methanesulfonanilides. Circ Res 78:499–503

    CAS  PubMed  Google Scholar 

  • Teschemacher A, Seward EP, Hancox JP, Witchel HJ (1999) Inhibition of the current of heterologously expressed HERG potassium channels by imipramine and amitryptiline. Br J Pharmacol 128:479–485

    CAS  PubMed  Google Scholar 

  • Thomas D, Wendt-Nordahl G, Rockl K, Ficker E, Brown AM, Kiehn J (2001) High-affinity blockade of human ether-a-gogo-related gene human cardiac potassium channels by the novel antiarrhythmic drug BRL-32872. J Pharmacol Exp Ther 297:753–761

    CAS  PubMed  Google Scholar 

  • Thomas D, Gut B, Wendt-Nordahl G, Kiehn J (2002) The antidepressant drug fluoxetine is an inhibitor of human ether-a-go-go-related gene (HERG) potassium channels. J Pharmacol Exp Ther 300:543–548

    Article  CAS  PubMed  Google Scholar 

  • Vitecic D, Pelcic JM (2002) Erectile dysfunction: oral pharmacotherapy options. Int J Clin Pharmacol Ther 40:393–403

    PubMed  Google Scholar 

  • Witchel HJ, Pabbathi VK, Hofmann G, Paul AA, Hancox JC (2002a) Inhibitory actions of the selective serotonin re-uptake inhibitor citalopram on HERG and L-type calcium currents. FEBS Lett 512:59–66

    Article  CAS  PubMed  Google Scholar 

  • Witchel HJ, Milnes JT, Mitcheson JS, Hancox JC (2002b) Troubleshooting problems with in vitro screening of drugs for QT interval prolongation using HERG K+ channels expressed in mammalian cell lines and Xenopus oocytes. J Pharmacol Toxicol Methods 48:65–80

    Article  CAS  PubMed  Google Scholar 

  • Witchel HJ, Hancox JC, Nutt DJ (2003) Psychotropic drugs, cardiac arrhythmia, and sudden death. J Clin Psychopharmacol 23:58–77

    Article  CAS  PubMed  Google Scholar 

  • Zitron E, Karle CA, Wendt-Nordahl G, Kathofer S, Zhang W, Thomas D, Weretka S, Kiehn J (2002) Bertosamil blocks HERG potassium channels in their open and inactivated states. Br J Pharmacol 137:221–228

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The excellent technical assistance of Klara Gueth is gratefully acknowledged. This work was supported by a grant of the Deutsche Forschungsgemeinschaft KA 1714/1-1 to Dr Karle E. Zitron was supported by the German National Academic Foundation and E.M. König. Dr Thomas was supported by grants from the University of Heidelberg (AiP+F), the Novartis Foundation and the Foundation Cardiology 2000 (Forssmann-Scholarship)

Author information

Authors and Affiliations

  1. Department of Internal Medicine III (Cardiology), Medical University Hospital Heidelberg, Bergheimerstrasse 58, 69115, Heidelberg, Germany

    Edgar Zitron, Claudia Kiesecker, Eberhard Scholz, Sonja Lück, Ramona Bloehs, Sven Kathöfer, Dierk Thomas, Johann Kiehn, Hugo A. Katus, Wolfgang Schoels & Christoph A. Karle

  2. Department of Physiology and Pathophysiology, University of Heidelberg, Heidelberg, Germany

    Volker A. W. Kreye

Authors
  1. Edgar Zitron
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Claudia Kiesecker
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eberhard Scholz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sonja Lück
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ramona Bloehs
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sven Kathöfer
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Dierk Thomas
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Johann Kiehn
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Volker A. W. Kreye
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hugo A. Katus
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Wolfgang Schoels
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Christoph A. Karle
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Christoph A. Karle.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zitron, E., Kiesecker, C., Scholz, E. et al. Inhibition of cardiac HERG potassium channels by the atypical antidepressant trazodone. Naunyn-Schmiedeberg's Arch Pharmacol 370, 146–156 (2004). https://doi.org/10.1007/s00210-004-0952-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00210-004-0952-3

Keywords

Search

Navigation