Probucol-induced QT prolongation and syncope.

Tamura, Masazumi; Ueki, Yuji; Ohtsuka, Eiji; Oribe, Motohiro; Seita, Masashi; Oribe, Kazuhiro; Ito, Mrio

doi:10.1253/jcj.58.374

Cited by 16 publications

(7 citation statements)

References 5 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, probucol prolongs the QT interval of the electrocardiogram. Such a change in QT interval is associated with malignant arrhythmias . Strikingly, in this study, we not only found anti‐oxidant activities of probucol, but also its destruction of endothelial cell–cell connections on the early‐stage AS model (Figure C).…”

Section: Discussionsupporting

confidence: 58%

An Early‐Stage Atherosclerosis Research Model Based on Microfluidics

Zheng

Huang

Jiang

et al. 2016

Small

View full text Add to dashboard Cite

The arterial microenvironment plays a vital role in the pathology of atherosclerosis (AS). However, the interplay between the arterial microenvironment and atherogenesis remains unclear, partially due to the gap between cell culture and animal experiments. Addressing this problem, the present study reports a microfluidic AS model reconstituting early-stage AS. Physiological or AS-prone hemodynamic conditions are recapitulated on the model. The on-chip model recaptures the atherogenic responses of endothelial cells (ECs) in ways that the Petri dish could not. Significant cytotoxicity of a clinical anti-atherosclerotic drug probucol is discovered on the model, which does not appear on Petri dish but is supported by previous clinical evidence. Moreover, the anti-AS efficiency of platinum-nanoparticles (Pt-NPs) on the model shows excellent consistency with animal experiments. The early-stage AS model shows an excellent connection between Petri dish and animal experiments and highlights its promising role in bridging fundamental AS research, drug screening, and clinical trials.

show abstract

Section: Discussionsupporting

confidence: 58%

An Early‐Stage Atherosclerosis Research Model Based on Microfluidics

Zheng

Huang

Jiang

et al. 2016

Small

View full text Add to dashboard Cite

show abstract

“…Probucol has been used as a cholesterol-lowering reagent for the treatment of hyperlipidemia, but clinical reports have indicated that it can cause QT prolongation and ventricular arrhythmias, including TdP. 10,24 In our previous article, we postulated that a reduction in I Ks channels on the plasma membrane might be responsible for the prolongation of the QT interval. 13 One possible mechanism involves the cholesterol-lowering effect of probucol, since cholesterol in the plasma membrane has an important role in the formation of lipid rafts and the distribution of ion channels to these lipid rafts.…”

Section: Discussionmentioning

confidence: 99%

Probucol and the cholesterol synthesis inhibitors simvastatin and triparanol regulate I_ks channel function differently

et al. 2013

View full text Add to dashboard Cite

Channels responsible for slowly activating delayed-rectifier potassium current (I(Ks)) are composed of KCNQ1 and KCNE1 subunits, and these channels play a role in the repolarization of cardiac action potentials. Recently, we showed that the antihyperlipidemic drug probucol, which induces QT prolongation, decreases the I(Ks) after 24-h treatment. In the present study, we investigated the effects of three cholesterol-lowering agents (probucol, an enhancer of cholesterol efflux; simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor; and triparanol, a 3β-hydroxysterol-▵24-reductase inhibitor) on cholesterol synthesis, the KCNQ1 current (I KCNQ1), and the I(Ks) to clarify the differences in the modes of action of these agents on the I(Ks). Probucol did not inhibit cholesterol synthesis and had no effect on I KCNQ1, while I(Ks) decreased after 24-h treatment. Simvastatin inhibited cholesterol synthesis and decreased I KCNQ1 and I(Ks). Additionally, the activation kinetics of I(Ks) became faster, compared with that of control I(Ks). Triparanol inhibited cholesterol synthesis but did not reduce I KCNQ1 and I(Ks). However, the activation kinetics of I(Ks) became faster. Our data indicated that the mechanism by which probucol inhibits I(Ks) was not mediated by the inhibition of cholesterol synthesis but depended on an interaction with the KCNQ1/KCNE1 complex. Meanwhile, the reduction in cholesterol induced by simvastatin and triparanol is one of the mechanisms that affects the kinetics of I(ks).

show abstract

“…Probucol is a cholesterol-lowering drug that has been found to cause long QT syndrome and torsades de pointes arrhythmia in patients and sudden cardiac death in experimental animals (Elharrar et al, 1979;McCaughan, 1982;Browne et al, 1984;Dujovne et al, 1984;Matsuhashi et al, 1989;Tamura et al, 1994;Reinoehl et al, 1996;Hayashi et al, 2004). Our data indicate that chronic probucol exposure reduces the hERG current with an IC 50 of 10.6 M and reduces native I Kr with an IC 50 of 20.6 M. We chose 48-h treatment of cells with probucol because the turnover of the hERG channel occurs at a rather slow rate (approximately 11 h) (Ficker et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Identification of I_Kr and Its Trafficking Disruption Induced by Probucol in Cultured Neonatal Rat Cardiomyocytes

Guo

Massaeli

et al. 2007

J Pharmacol Exp Ther

103

116

View full text Add to dashboard Cite

The human ether-a-go-go-related gene (hERG) encodes a channel that conducts the rapidly activating delayed rectifier K ϩ current (I Kr ), which is important for cardiac repolarization. Mutations in hERG reduce I Kr and cause congenital long QT syndrome (LQTS). More frequently, common medications can reduce I Kr and cause LQTS as a side effect. Protein trafficking abnormalities are responsible for most hERG mutation-related LQTS and are recently recognized as a mechanism for druginduced LQTS. Whereas hERG trafficking has been studied in recombinant expression systems, there has been no reported study on cardiac I Kr trafficking at the protein level. In the present study, we identified that I Kr is present in cultured neonatal rat ventricular myocytes and can be robustly recorded using Cs ϩ as the charge carrier. We further discovered that 4,4Ј-(isopropylidenedithio)-bis-(2,6-di-t-butylphenol) (probucol), a cholesterol-lowering drug that induces LQTS, disrupted I Kr trafficking and prolonged the cardiac action potential duration. Probucol did not directly block I Kr . Probucol also disrupted hERG trafficking and did not block hERG channels expressed in human embryonic kidney 293 cells. We conclude that probucol induces LQTS by disrupting ether-a-go-go-related gene trafficking, and that primary culture of neonatal rat cardiomyocytes represents a useful system for studying native I Kr trafficking.

show abstract

Probucol-induced QT prolongation and syncope.

Cited by 16 publications

References 5 publications

An Early‐Stage Atherosclerosis Research Model Based on Microfluidics

An Early‐Stage Atherosclerosis Research Model Based on Microfluidics

Probucol and the cholesterol synthesis inhibitors simvastatin and triparanol regulate I_ks channel function differently

Identification of I_Kr and Its Trafficking Disruption Induced by Probucol in Cultured Neonatal Rat Cardiomyocytes

Contact Info

Product

Resources

About

Probucol-induced QT prolongation and syncope.

Cited by 16 publications

References 5 publications

An Early‐Stage Atherosclerosis Research Model Based on Microfluidics

An Early‐Stage Atherosclerosis Research Model Based on Microfluidics

Probucol and the cholesterol synthesis inhibitors simvastatin and triparanol regulate Iks channel function differently

Identification of IKr and Its Trafficking Disruption Induced by Probucol in Cultured Neonatal Rat Cardiomyocytes

Contact Info

Product

Resources

About

Probucol and the cholesterol synthesis inhibitors simvastatin and triparanol regulate I_ks channel function differently

Identification of I_Kr and Its Trafficking Disruption Induced by Probucol in Cultured Neonatal Rat Cardiomyocytes