Inhibition of human ether-a-go-go-related gene potassium channels by a1-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.

Doxazosin induces activation of GADD153 and cleavage of focal adhesion kinase in cardiomyocytes en route to apoptosis

“…Proteins that have previously been described as possibly being actively or passively involved in mediating the apoptotic effects of doxazosin, include transforming growth factor h (TGF-h) [6], caspase 3 and focal adhesion kinase (FAK) [7], tumor necrosis factor a and reactive oxygen species [8], ether-a-go-go-gene-related potassium channels [9], and vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF-2) [10].…”

Mechanisms of zolpidem‐induced long QT syndrome: acute inhibition of recombinant hERG K+ channels and action potential prolongation in human cardiomyocytes derived from induced pluripotent stem cells

“…Aromatic residues Y652 and F656, located in the S6 domain of hERG, are critical determinants of drug binding to hERG channels (Mitcheson et al, 2000;Thomas et al, 2004b;El Harchi et al, 2012). We investigated the effects of zolpidem on mutant hERG Y652A and hERG F656A channels to assess the significance of these amino acid residues in channel blockade ( Figure 1D).…”

Benign prostat hiperplazisi (BPH) ve apopitozis Benign prostatic hyperplasia (BPH) and apoptosis

“…2004'de Thomas ve arkadaşla-rı çalışmalarında HERG potasyum kanallarının prazosin, doksazosin ve terazosin tarafından bloke edildiğini ve bu bulgunun quinazoline deriveleri olan α-1 AR antogonistlerinin apopitotik etkilerini açıklayan moleküler mekanizma olabileceğini bildirmişlerdir (35).…”