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Titolo:
High-affinity blockade of human ether-a-go-go-related gene human cardiac potassium channels by the novel antiarrhythmic drug BRL-32872
Autore:
Thomas, D; Wendt-Nordahl, G; Rockl, K; Ficker, E; Brown, AM; Kiehn, J;
Indirizzi:
Med Univ Hosp Heidelberg, Dept Cardiol, D-69115 Heidelberg, Germany Med Univ Hosp Heidelberg Heidelberg Germany D-69115 Heidelberg, Germany Case Western Reserve Univ, Metrohlth Med Ctr, Rammelkamp Ctr Educ& Res, Cleveland, OH USA Case Western Reserve Univ Cleveland OH USA Educ& Res, Cleveland, OH USA
Titolo Testata:
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
fascicolo: 2, volume: 297, anno: 2001,
pagine: 753 - 761
SICI:
0022-3565(200105)297:2<753:HBOHEG>2.0.ZU;2-H
Fonte:
ISI
Lingua:
ENG
Soggetto:
TORSADE-DE-POINTES; LONG QT SYNDROME; K+ CHANNELS; D-SOTALOL; HERG; INACTIVATION; REPOLARIZATION; ARRHYTHMIA; AMIODARONE; RECTIFICATION;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
40
Recensione:
Indirizzi per estratti:
Indirizzo: Kiehn, J Med Univ Hosp Heidelberg, Dept Cardiol, Bergheimerstr 58, D-69115Heidelberg, Germany Med Univ Hosp Heidelberg Bergheimerstr 58 Heidelberg Germany D-69115
Citazione:
D. Thomas et al., "High-affinity blockade of human ether-a-go-go-related gene human cardiac potassium channels by the novel antiarrhythmic drug BRL-32872", J PHARM EXP, 297(2), 2001, pp. 753-761

Abstract

Human ether-a-go-go-related gene (HERG) potassium channels are one primarytarget for the pharmacological treatment of cardiac arrhythmias by class III antiarrhythmic drugs. These drugs are characterized by high antiarrhythmic efficacy, but they can also initiate life-threatening "torsade de pointes" tachyarrhythmias. Recently, it has been suggested that combining potassium and calcium channel blocking mechanisms reduces the proarrhythmic potential of selective class III antiarrhythmic agents. BRL-32872 is a novel antiarrhythmic drug that inhibits potassium and calcium currents in isolated cardiomyocytes. In our study, we investigated the effects of BRL-32872 on cloned HERG channels heterologously expressed in Xenopus oocytes. Using the two-microelectrode voltage clamp technique, we found that BRL-32872 caused a high-affinity, state-dependent block of open HERG channels (IC50 = 241 nM) in a frequency-dependent manner with slow unbinding kinetics. Inactivated channels mainly had to open to be blocked by BRL-32872. The HERG S620T mutant channel, which has a strongly reduced degree of inactivation, was 51-foldless sensitive to BRL-32872 block, indicating that BRL-32872 binding was enhanced by the inactivation process. In an additional approach, we studied HERG channels expressed in a human cell line (HEK 293) using the whole-cellpatch-clamp technique. BRL-32872 inhibited HERG currents in HEK 293 cells in a dose-dependent manner, with an IC50 value of 19.8 nM. We conclude thatBRL-32872 is a potent blocker of HERG potassium channels, which accounts for the class III antiarrhythmic action of BRL-32872.

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Documento generato il 26/09/20 alle ore 10:35:58