Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Br J Pharmacol
2007 Aug 01;1518:1368-76. doi: 10.1038/sj.bjp.0707356.
Show Gene links
Show Anatomy links
State dependent dissociation of HERG channel inhibitors.
Stork D
,
Timin EN
,
Berjukow S
,
Huber C
,
Hohaus A
,
Auer M
,
Hering S
.
???displayArticle.abstract???
Inhibition of HERG channels prolongs the ventricular action potential and the QT interval with the risk of torsade de pointes arrhythmias and sudden cardiac death. Many drugs induce greater inhibition of HERG channels when the cell membrane is depolarized frequently. The dependence of inhibition on the pulsing rate may yield different IC(50) values at different frequencies and thus affect the quantification of HERG channel block. We systematically compared the kinetics of HERG channel inhibition and recovery from block by 8 blockers at different frequencies.HERG channels were expressed heterologously in Xenopus oocytes and currents were measured with the two-electrode voltage clamp technique.Frequency-dependent block was observed for amiodarone, cisapride, droperidol and haloperidol (group 1) whereas bepridil, domperidone, E-4031 and terfenadine (group 2) induced similar pulse-dependent block at all frequencies. With the group 1 compounds, HERG channels recovered from block in the presence of drug (recovery being voltage-dependent). No substantial recovery from block was observed with the second group of compounds. Washing out of bepridil, domperidone, E-4031 and terfenadine was substantially augmented by frequent pulsing. Mutation D540K in the HERG channel (which exhibits reopening at negative voltages) facilitated recovery from block by these compounds at -140 mV.Drug molecules dissociate at different rates from open and closed HERG channels ('use-dependent' dissociation). Our data suggest that apparently 'trapped' drugs (group 2) dissociated from the open channel state whereas group 1 compounds dissociated from open and resting states.
Armstrong,
Interaction of tetraethylammonium ion derivatives with the potassium channels of giant axons.
1971, Pubmed
Armstrong,
Interaction of tetraethylammonium ion derivatives with the potassium channels of giant axons.
1971,
Pubmed
Baburin,
Automated fast perfusion of Xenopus oocytes for drug screening.
2006,
Pubmed
,
Xenbase
Carmeliet,
Voltage- and time-dependent block of the delayed K+ current in cardiac myocytes by dofetilide.
1992,
Pubmed
Choi,
Inhibition of human ether-a-go-go-related gene K+ channel and IKr of guinea pig cardiomyocytes by antipsychotic drug trifluoperazine.
2005,
Pubmed
,
Xenbase
Curran,
A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome.
1995,
Pubmed
De Bruin,
Anti-HERG activity and the risk of drug-induced arrhythmias and sudden death.
2005,
Pubmed
Fermini,
The impact of drug-induced QT interval prolongation on drug discovery and development.
2003,
Pubmed
Grabner,
Transfer of 1,4-dihydropyridine sensitivity from L-type to class A (BI) calcium channels.
1996,
Pubmed
Ishii,
Dissociation of E-4031 from the HERG channel caused by mutations of an amino acid results in greater block at high stimulation frequency.
2003,
Pubmed
,
Xenbase
Jo,
Blockade of the HERG human cardiac K(+) channel by the antidepressant drug amitriptyline.
2000,
Pubmed
,
Xenbase
Kamiya,
Molecular determinants of HERG channel block.
2006,
Pubmed
,
Xenbase
Keating,
Molecular and cellular mechanisms of cardiac arrhythmias.
2001,
Pubmed
Kiehn,
Inhibitory effects of the class III antiarrhythmic drug amiodarone on cloned HERG potassium channels.
1999,
Pubmed
,
Xenbase
Kikuchi,
Blockade of HERG cardiac K+ current by antifungal drug miconazole.
2005,
Pubmed
Kirsch,
Variability in the measurement of hERG potassium channel inhibition: effects of temperature and stimulus pattern.
2004,
Pubmed
Kushida,
Inhibitory effect of the class III antiarrhythmic drug nifekalant on HERG channels: mode of action.
2002,
Pubmed
,
Xenbase
Mitcheson,
A structural basis for drug-induced long QT syndrome.
2000,
Pubmed
,
Xenbase
Pearlstein,
Understanding the structure-activity relationship of the human ether-a-go-go-related gene cardiac K+ channel. A model for bad behavior.
2003,
Pubmed
Recanatini,
QT prolongation through hERG K(+) channel blockade: current knowledge and strategies for the early prediction during drug development.
2005,
Pubmed
Redfern,
Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development.
2003,
Pubmed
Sanguinetti,
A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel.
1995,
Pubmed
,
Xenbase
Sanguinetti,
Predicting drug-hERG channel interactions that cause acquired long QT syndrome.
2005,
Pubmed
Suessbrich,
Blockade of HERG channels expressed in Xenopus oocytes by the histamine receptor antagonists terfenadine and astemizole.
1996,
Pubmed
,
Xenbase
Suessbrich,
The inhibitory effect of the antipsychotic drug haloperidol on HERG potassium channels expressed in Xenopus oocytes.
1997,
Pubmed
,
Xenbase
Trudeau,
HERG, a human inward rectifier in the voltage-gated potassium channel family.
1995,
Pubmed
Tseng,
I(Kr): the hERG channel.
2001,
Pubmed
Tsujimae,
Comparison of kinetic properties of quinidine and dofetilide block of HERG channels.
2004,
Pubmed
,
Xenbase
Vandenberg,
HERG K+ channels: friend and foe.
2001,
Pubmed
Waldegger,
Effect of verapamil enantiomers and metabolites on cardiac K+ channels expressed in Xenopus oocytes.
1999,
Pubmed
,
Xenbase
Walker,
Inhibition of the human ether-a-go-go-related gene (HERG) potassium channel by cisapride: affinity for open and inactivated states.
1999,
Pubmed
Witchel,
The low-potency, voltage-dependent HERG blocker propafenone--molecular determinants and drug trapping.
2004,
Pubmed
,
Xenbase
Zhang,
Mechanism of block and identification of the verapamil binding domain to HERG potassium channels.
1999,
Pubmed
