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Naunyn Schmiedebergs Arch Pharmacol
2004 May 01;3695:462-72. doi: 10.1007/s00210-004-0931-8.
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Inhibition of human ether-a-go-go-related gene potassium channels by alpha 1-adrenoceptor antagonists prazosin, doxazosin, and terazosin.
Thomas D
,
Wimmer AB
,
Wu K
,
Hammerling BC
,
Ficker EK
,
Kuryshev YA
,
Kiehn J
,
Katus HA
,
Schoels W
,
Karle CA
.
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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.
Abbott,
MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia.
1999, Pubmed,
Xenbase
Abbott,
MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia.
1999,
Pubmed
,
Xenbase
Akduman,
Terazosin, doxazosin, and prazosin: current clinical experience.
2001,
Pubmed
Benning,
Quinazoline-derived alpha1-adrenoceptor antagonists induce prostate cancer cell apoptosis via an alpha1-adrenoceptor-independent action.
2002,
Pubmed
Bian,
HERG K(+) channel activity is regulated by changes in phosphatidyl inositol 4,5-bisphosphate.
2001,
Pubmed
Bianchi,
herg encodes a K+ current highly conserved in tumors of different histogenesis: a selective advantage for cancer cells?
1998,
Pubmed
,
Xenbase
Bril,
Combined potassium and calcium channel blocking activities as a basis for antiarrhythmic efficacy with low proarrhythmic risk: experimental profile of BRL-32872.
1996,
Pubmed
Chaignon,
Clinical pharmacology of prazosin in hypertensive patients with chronic renal failure.
1981,
Pubmed
Cherubini,
HERG potassium channels are more frequently expressed in human endometrial cancer as compared to non-cancerous endometrium.
2000,
Pubmed
Chouabe,
HERG and KvLQT1/IsK, the cardiac K+ channels involved in long QT syndromes, are targets for calcium channel blockers.
1998,
Pubmed
Crociani,
Cell cycle-dependent expression of HERG1 and HERG1B isoforms in tumor cells.
2003,
Pubmed
Elliott,
Pharmacokinetic overview of doxazosin.
1987,
Pubmed
Fawzy,
Clinical correlation of maximal urinary flow rate and plasma doxazosin concentrations in the treatment of benign prostatic hyperplasia. Multicenter Study Group.
1999,
Pubmed
González-Juanatey,
Doxazosin induces apoptosis in cardiomyocytes cultured in vitro by a mechanism that is independent of alpha1-adrenergic blockade.
2003,
Pubmed
Jaillon,
Clinical pharmacokinetics of prazosin.
1980,
Pubmed
Jiang,
Use-dependent 'agonist' effect of azimilide on the HERG channel.
1999,
Pubmed
,
Xenbase
Karle,
Antiarrhythmic drug carvedilol inhibits HERG potassium channels.
2001,
Pubmed
,
Xenbase
Kiehn,
Inhibitory effects of the class III antiarrhythmic drug amiodarone on cloned HERG potassium channels.
1999,
Pubmed
,
Xenbase
Kyprianou,
Suppression of human prostate cancer cell growth by alpha1-adrenoceptor antagonists doxazosin and terazosin via induction of apoptosis.
2000,
Pubmed
Kyprianou,
Doxazosin and terazosin suppress prostate growth by inducing apoptosis: clinical significance.
2003,
Pubmed
Mitcheson,
A structural basis for drug-induced long QT syndrome.
2000,
Pubmed
,
Xenbase
Mitcheson,
Drug binding to HERG channels: evidence for a 'non-aromatic' binding site for fluvoxamine.
2003,
Pubmed
Mitcheson,
Trapping of a methanesulfonanilide by closure of the HERG potassium channel activation gate.
2000,
Pubmed
,
Xenbase
NULL,
Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). ALLHAT Collaborative Research Group.
2000,
Pubmed
Napolitano,
Torsade de pointes. Mechanisms and management.
1994,
Pubmed
Patterson,
Terazosin kinetics after oral and intravenous doses.
1985,
Pubmed
Pitterman,
Alpha adrenoceptor blockade with oral prazosin.
1981,
Pubmed
Pool,
Doxazosin: a new approach to hypertension and benign prostatic hyperplasia.
1996,
Pubmed
Sanguinetti,
A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel.
1995,
Pubmed
,
Xenbase
Scholz,
Drug binding to aromatic residues in the HERG channel pore cavity as possible explanation for acquired Long QT syndrome by antiparkinsonian drug budipine.
2003,
Pubmed
,
Xenbase
Shionoiri,
Antihypertensive effects and pharmacokinetics of single and consecutive administration of doxazosin in patients with mild to moderate essential hypertension.
1987,
Pubmed
Smith,
Functional up-regulation of HERG K+ channels in neoplastic hematopoietic cells.
2002,
Pubmed
Sonders,
Pharmacokinetics of terazosin.
1986,
Pubmed
Taguchi,
Radioreceptor assay analysis of tamsulosin and terazosin pharmacokinetics.
1998,
Pubmed
Thomas,
The antidepressant drug fluoxetine is an inhibitor of human ether-a-go-go-related gene (HERG) potassium channels.
2002,
Pubmed
,
Xenbase
Thomas,
Regulation of HERG potassium channel activation by protein kinase C independent of direct phosphorylation of the channel protein.
2003,
Pubmed
,
Xenbase
Thomas,
High-affinity blockade of human ether-a-go-go-related gene human cardiac potassium channels by the novel antiarrhythmic drug BRL-32872.
2001,
Pubmed
,
Xenbase
Thomas,
Inhibition of cloned HERG potassium channels by the antiestrogen tamoxifen.
2003,
Pubmed
,
Xenbase
Thomas,
Deletion of protein kinase A phosphorylation sites in the HERG potassium channel inhibits activation shift by protein kinase A.
1999,
Pubmed
,
Xenbase
Thomas,
The antipsychotic drug chlorpromazine inhibits HERG potassium channels.
2003,
Pubmed
,
Xenbase
Viskin,
Long QT syndromes and torsade de pointes.
1999,
Pubmed
Wang,
HERG K+ channel, a regulator of tumor cell apoptosis and proliferation.
2002,
Pubmed
Warmke,
A family of potassium channel genes related to eag in Drosophila and mammals.
1994,
Pubmed
Weerapura,
A comparison of currents carried by HERG, with and without coexpression of MiRP1, and the native rapid delayed rectifier current. Is MiRP1 the missing link?
2002,
Pubmed
,
Xenbase
Wonderlin,
Potassium channels, proliferation and G1 progression.
1996,
Pubmed
Zhang,
Mechanism of block and identification of the verapamil binding domain to HERG potassium channels.
1999,
Pubmed
