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hERG K+ channel-associated cardiac effects of the antidepressant drug desipramine

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Abstract

Cardiac side effects of antidepressant drugs are well recognized. Adverse effects precipitated by the tricyclic drug desipramine include prolonged QT intervals, torsade de pointes tachycardia, heart failure, and sudden cardiac death. QT prolongation has been primarily attributed to acute blockade of hERG/I Kr currents. This study was designed to provide a more complete picture of cellular effects associated with desipramine. hERG channels were expressed in Xenopus laevis oocytes and human embryonic kidney (HEK 293) cells, and potassium currents were recorded using patch clamp and two-electrode voltage clamp electrophysiology. Ventricular action potentials were recorded from guinea pig cardiomyocytes. Protein trafficking and cell viability were evaluated in HEK 293 cells and in HL-1 mouse cardiomyocytes by immunocytochemistry, Western blot analysis, or colorimetric MTT assay, respectively. We found that desipramine reduced hERG currents by binding to a receptor site inside the channel pore. hERG protein surface expression was reduced after short-term treatment, revealing a previously unrecognized mechanism. When long-term effects were studied, forward trafficking was impaired and hERG currents were decreased. Action potential duration was prolonged upon acute and chronic desipramine exposure. Finally, desipramine triggered apoptosis in cells expressing hERG channels. Desipramine exerts at least four different cellular effects: (1) direct hERG channel block, (2) acute reduction of hERG surface expression, (3) chronic disruption of hERG trafficking, and (4) induction of apoptosis. These data highlight the complexity of hERG-associated drug effects.

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Acknowledgments

We thank William C. Claycomb (New Orleans) for providing HL-1 cells, R. Bloehs for excellent technical support, and H. Erdal for assistance with cell viability assays. This work was supported in part by grants from the University of Heidelberg and the German Research Foundation (FRONTIERS program to D.T.), the ADUMED-Foundation (to D.T.), the German Heart Foundation/German Foundation of Heart Research (to D.T.), the Max-Planck-Society (TANDEM program to P.A.S.), and the National Institutes of Health (HL71789 to E.F.). W.W. and F.T. acknowledge support from the Landesstiftung Baden-Württemberg and the German Research Foundation Center for Functional Nanostructures.

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Authors and Affiliations

  1. Department of Cardiology, Medical University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany

    Ingo Staudacher, Sabrina Obers, Kathrin Staudacher, Jana Kisselbach, Patrick A. Schweizer, Hugo A. Katus & Dierk Thomas

  2. Rammelkamp Center, Case Western Reserve University, MetroHealth Campus, Cleveland, OH, 44109, USA

    Lu Wang, Xiaoping Wan & Eckhard Ficker

  3. Institute of Nanotechnology, Karlsruhe Institute of Technology, 76021, Karlsruhe, Germany

    Wolfgang Wenzel & Frank Tristram

  4. Department of Gastroenterology, Medical University Hospital Heidelberg, 69120, Heidelberg, Germany

    Ronald Koschny

  5. Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, 76021, Karlsruhe, Germany

    Patrick Koelsch

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  1. Ingo Staudacher
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Staudacher, I., Wang, L., Wan, X. et al. hERG K+ channel-associated cardiac effects of the antidepressant drug desipramine. Naunyn-Schmied Arch Pharmacol 383, 119–139 (2011). https://doi.org/10.1007/s00210-010-0583-9

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