Inhibition of human ether-a-go-go-related gene potassium channels by a1-adrenoceptor antagonists prazosin, doxazosin, and terazosin
文摘
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 -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 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 1-inhibitors induce apoptosis in cardiomyocytes and prostate tumor cells independently of 1-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 M 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 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.
