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Inhibition of human ether-a-go-go-related gene potassium channels by α1-adrenoceptor antagonists prazosin, doxazosin, and terazosin

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Abstract

Human ether-a-go-go-related gene (HERG) potassium channels are expressed in multiple tissues including the heart and adenocarcinomas. In cardiomyocytes, HERG encodes the α-subunit underlying the rapid component of the delayed rectifier potassium current, IKr, and pharmacological reduction of HERG currents may cause acquired long QT syndrome. In addition, HERG currents have been shown to be involved in the regulation of cell proliferation and apoptosis. Selective α1-adrenoceptor antagonists are commonly used in the treatment of hypertension and benign prostatic hyperplasia. Recently, doxazosin has been associated with an increased risk of heart failure. Moreover, quinazoline-derived α1-inhibitors induce apoptosis in cardiomyocytes and prostate tumor cells independently of α1-adrenoceptor blockade. To assess the action of the effects of prazosin, doxazosin, and terazosin on HERG currents, we investigated their acute electrophysiological effects on cloned HERG potassium channels heterologously expressed in Xenopus oocytes and HEK 293 cells.

Prazosin, doxazosin, and terazosin blocked HERG currents in Xenopus oocytes with IC50 values of 10.1, 18.2, and 113.2 μM respectively, whereas the IC50 values for HERG channel inhibition in human HEK 293 cells were 1.57 µM, 585.1 nM, and 17.7 µM. Detailed biophysical studies revealed that inhibition by the prototype α1-blocker prazosin occurred in closed, open, and inactivated channels. Analysis of the voltage-dependence of block displayed a reduction of inhibition at positive membrane potentials. Frequency-dependence was not observed. Prazosin caused a negative shift in the voltage-dependence of both activation (−3.8 mV) and inactivation (−9.4 mV). The S6 mutations Y652A and F656A partially attenuated (Y652A) or abolished (F656A) HERG current blockade, indicating that prazosin binds to a common drug receptor within the pore-S6 region.

In conclusion, this study demonstrates that HERG potassium channels are blocked by prazosin, doxazosin, and terazosin. These data may provide a hypothetical molecular explanation for the apoptotic effect of quinazoline-derived α1-adrenoceptor antagonists.

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Acknowledgements

The excellent technical assistance of S. Lück and R. Bloehs is gratefully acknowledged. We thank Dr. M.T. Keating for generously donating the HERG clone and Dr. S.A. Goldstein for providing the hMiRP1 clone. This work was supported in part by grants from the Deutsche Forschungsgemeinschaft (project KI 663/1–1 to J.K.; project KA 1714/1–1 to C.A.K.), from the University of Heidelberg (Young Investigator Award and Hans Dengler Research Scholarship to D.T.), from the Novartis-Foundation (to D.T.), and from the Foundation Cardiology 2000 (Forssmann-Scholarship to D.T.).

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  1. Department of Cardiology, Medical University Hospital Heidelberg, Bergheimerstrasse 58, 69115, Heidelberg, Germany

    Dierk Thomas, Anna-Britt Wimmer, Kezhong Wu, Bettina C. Hammerling, Johann Kiehn, Hugo A. Katus, Wolfgang Schoels & Christoph A. Karle

  2. Rammelkamp Center, MetroHealth Campus, Case Western Reserve University, 2500 MetroHealth Drive, Cleveland, OH 44109, USA

    Eckhard K. Ficker & Yuri A. Kuryshev

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  1. Dierk Thomas
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Thomas, D., Wimmer, AB., Wu, K. et al. Inhibition of human ether-a-go-go-related gene potassium channels by α1-adrenoceptor antagonists prazosin, doxazosin, and terazosin. Naunyn-Schmiedeberg's Arch Pharmacol 369, 462–472 (2004). https://doi.org/10.1007/s00210-004-0931-8

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