title: Inhibition of human ether-a-go-go-related gene potassium channels by alpha 1-adrenoceptor antagonists prazosin, doxazosin, and terazosin.
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 alpha-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 alpha 1-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 alpha 1-inhibitors induce apoptosis in cardiomyocytes and prostate tumor cells independently of alpha1-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 IC(50) values of 10.1, 18.2, and 113.2 microM respectively, whereas the IC(50) values for HERG channel inhibition in human HEK 293 cells were 1.57 microM, 585.1 nM, and 17.7 microM. Detailed biophysical studies revealed that inhibition by the prototype alpha 1-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 alpha1-adrenoceptor antagonists.
authors.affiliation: Department of Cardiology, Medical University Hospital Heidelberg, Bergheimerstrasse 58, 69115, Heidelberg, Germany. Dierk_Thomas@med.uni-heidelberg.de
authors.forename: Dierk
authors.initials: D
authors.lastname: Thomas
authors.forename: Anna-Britt
authors.initials: AB
authors.lastname: Wimmer
authors.forename: Kezhong
authors.initials: K
authors.lastname: Wu
authors.forename: Bettina C
authors.initials: BC
authors.lastname: Hammerling
authors.forename: Eckhard K
authors.initials: EK
authors.lastname: Ficker
authors.forename: Yuri A
authors.initials: YA
authors.lastname: Kuryshev
authors.forename: Johann
authors.initials: J
authors.lastname: Kiehn
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Schoels
authors.forename: Christoph A
authors.initials: CA
authors.lastname: Karle
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D017292:Doxazosin / Q000494:pharmacology; D000072237:ERG1 Potassium Channel; D004558:Electric Stimulation; D051638:Ether-A-Go-Go Potassium Channels; D006801:Humans; D018408:Patch-Clamp Techniques; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors*; D011224:Prazosin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014981:Xenopus
chemical_list: D000317:Adrenergic alpha-Antagonists; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D024642:Potassium Channels, Voltage-Gated; C041226:Terazosin; D017292:Doxazosin; D011224:Prazosin