Titre du document / Document title

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

Auteur(s) / Author(s)

THOMAS Dierk ; WIMMER Anna-Britt ; KEZHONG WU ; HAMMERLING Bettina C. ; FICKER Eckhard K. ; KURYSHEV Yuri A. ; KIEHN Johann ; KATUS Hugo A. ; SCHOELS Wolfgang ; KARLE Christoph A. ;

Résumé / 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, I^Kr, 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 al-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 al-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 al-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 a 1-adrenoceptor antagonists.

Revue / Journal Title

Naunyn-Schmiedeberg's archives of pharmacology   ISSN 0028-1298   CODEN NSAPCC 

Source / Source

2004, vol. 369, n^o5, pp. 462-472 [11 page(s) (article)]

Langue / Language

Anglais

Editeur / Publisher

Springer, Berlin, ALLEMAGNE  (1972) (Revue)

Localisation / Location

INIST-CNRS, Cote INIST : 4750, 35400011001733.0020