scholarly journals The Grapefruit Flavonoid Naringenin Inhibits Multiple Cardiac Ion Channels

2022 ◽  
Author(s):  
Camille Sanson ◽  
Rachid Boukaiba ◽  
Sylvie Houtmann ◽  
Magali-Anne Maizières ◽  
Sophie Fouconnier ◽  
...  
Keyword(s):  
Ion Channels ◽  
Grapefruit Juice ◽  
Rank Order ◽  
Cardiac Ion Channels ◽  
Mammalian Cell Lines ◽  
Significant Prolongation ◽  
Citrus Juices ◽  
Automated Patch Clamp ◽  
Electrocardiogram Ecg

Abstract Drinking fresh grapefruit juice is associated with a significant prolongation of the QT segment on the electrocardiogram (ECG) in healthy volunteers. Among the prominent flavonoids contained in citrus fruits, the flavanone naringenin is known to be a blocker of the human ether-a-go-go related gene (hERG) potassium channel. We hypothesized that naringenin could interfere with other major ion channels shaping the cardiac ventricular action potential (AP). To this end, we examined the effects of naringenin on the seven currents comprising the Comprehensive in vitro Pro-Arrhythmia (CiPA) panel for early arrhythmogenic risk assessment in drug discovery and development. We used automated patch-clamp of human ion channels heterologously expressed in mammalian cell lines to evaluate half-maximal inhibitory concentrations (IC50). Naringenin blocked all CiPA currents tested with IC50 values in the 30 µM – 100 µM concentration-range. The rank-order of channel sensitivity was the following: hERG > Kir2.1 > NaV1.5 late > NaV1.5 peak > KV7.1 > KV4.3 > CaV1.2. This multichannel inhibitory profile of naringenin suggests exercising caution when large amounts of grapefruit juice or other citrus juices enriched in this flavanone are drunk in conjunction with QT prolonging drugs or by carriers of congenital long QT syndromes.

Cyamemazine metabolites: effects on human cardiac ion channels in-vitro and on the QTc interval in guinea pigs

2008 ◽  
Vol 60 (11) ◽  
pp. 1507-1513 ◽  
Author(s):  
William Crumb ◽  
Amine Benyamina ◽  
Christophe Arbus ◽  
George P. Thomas ◽  
Ricardo P. Garay ◽  
...  
Keyword(s):  
Ion Channels ◽  
Guinea Pigs ◽  
Qtc Interval ◽  
Cardiac Ion Channels

Abstract 62: The Coxsackie Virus B3 modulates Cardiac Ion Channels

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Guiscard Seebohm ◽  
Katja Steinke ◽  
Ulrike Henrion ◽  
Nicole Ettischer ◽  
Frank Sachse ◽  
...  
Keyword(s):  
Ion Channels ◽  
Cardiac Cells ◽  
Coxsackie Virus ◽  
Cardiac Ion Channels ◽  
Increased Risk ◽  
Chronic Myocarditis ◽  
Life Threatening ◽  
The Common ◽  
In Silico Analyses

Infections with coxsackieviruses of type B (CVB) induce severe forms of acute and chronic myocarditis that are often accompanied by ventricular arrhythmias. The mechanisms underlying the development of virus-induced, life-threatening arrhythmia, remain largely elusive. Here, we show time-dependent CVB3-induced modulation of the cardiac ion channels Kv7.1, hERG1 and CaV1.2 in vitro. Channel protein localizations within cells and plasma membrane abundance are altered in infected mouse cardiac cells. In silico analyses of infected human myocytes suggest increased risk of arrhythmogenesis. These modifications are attenuated by the common Asian polymorphism KCNQ1-P448R, a genetic determinant preventing coxsackievirus-induced effects in vitro. This study provides a previously unknown explanation for the development of arrhythmias in enteroviral myocarditis, which will help to develop therapeutic strategies for arrhythmia treatment.

scholarly journals Automated Patch Clamp on mESC-Derived Cardiomyocytes for Cardiotoxicity Prediction

2011 ◽  
Vol 16 (8) ◽  
pp. 910-916 ◽  
Author(s):  
Sonja Stoelzle ◽  
Alison Haythornthwaite ◽  
Ralf Kettenhofen ◽  
Eugen Kolossov ◽  
Heribert Bohlen ◽  
...  
Keyword(s):  
Stem Cell ◽  
Ion Channels ◽  
Patch Clamp ◽  
Cell Model ◽  
Single Type ◽  
Ion Currents ◽  
Drug Induced ◽  
Cardiovascular Side Effects ◽  
Automated Patch Clamp

Cardiovascular side effects are critical in drug development and have frequently led to late-stage project terminations or even drug withdrawal from the market. Physiologically relevant and predictive assays for cardiotoxicity are hence strongly demanded by the pharmaceutical industry. To identify a potential impact of test compounds on ventricular repolarization, typically a variety of ion channels in diverse heterologously expressing cells have to be investigated. Similar to primary cells, in vitro–generated stem cell–derived cardiomyocytes simultaneously express cardiac ion channels. Thus, they more accurately represent the native situation compared with cell lines overexpressing only a single type of ion channel. The aim of this study was to determine if stem cell–derived cardiomyocytes are suited for use in an automated patch clamp system. The authors show recordings of cardiac ion currents as well as action potential recordings in readily available stem cell–derived cardiomyocytes. Besides monitoring inhibitory effects of reference compounds on typical cardiac ion currents, the authors revealed for the first time drug-induced modulation of cardiac action potentials in an automated patch clamp system. The combination of an in vitro cardiac cell model with higher throughput patch clamp screening technology allows for a cost-effective cardiotoxicity prediction in a physiologically relevant cell system.

scholarly journals Tox-Database.net: a curated resource for data describing chemical triggered in vitro cardiac ion channels inhibition

2012 ◽  
Vol 13 (1) ◽  
Author(s):  
Sebastian Polak ◽  
Barbara Wiśniowska ◽  
Anna Glinka ◽  
Miłosz Polak
Keyword(s):  
Ion Channels ◽  
Cardiac Ion Channels

Cyamemazine metabolites: effects on human cardiac ion channels in-vitro and on the QTc interval in guinea pigs

2008 ◽  
Vol 60 (11) ◽  
pp. 1507-1513
Author(s):  
William Crumb ◽  
Amine Benyamina ◽  
Christophe Arbus ◽  
George P. Thomas ◽  
Ricardo P. Garay ◽  
...  
Keyword(s):  
Ion Channels ◽  
Guinea Pigs ◽  
Qtc Interval ◽  
Cardiac Ion Channels

scholarly journals Screening system for drug-induced arrhythmogenic risk combining a patch clamp and heart simulator

2015 ◽  
Vol 1 (4) ◽  
pp. e1400142 ◽  
Author(s):  
Jun-ichi Okada ◽  
Takashi Yoshinaga ◽  
Junko Kurokawa ◽  
Takumi Washio ◽  
Tetsushi Furukawa ◽  
...  
Keyword(s):  
Patch Clamp ◽  
Ventricular Arrhythmia ◽  
Paradigm Shift ◽  
Screening System ◽  
Drug Induced ◽  
Characteristic Type ◽  
Drug Concentrations ◽  
Automated Patch Clamp ◽  
Electrocardiogram Ecg

To save time and cost for drug discovery, a paradigm shift in cardiotoxicity testing is required. We introduce a novel screening system for drug-induced arrhythmogenic risk that combines in vitro pharmacological assays and a multiscale heart simulator. For 12 drugs reported to have varying cardiotoxicity risks, dose-inhibition curves were determined for six ion channels using automated patch clamp systems. By manipulating the channel models implemented in a heart simulator consisting of more than 20 million myocyte models, we simulated a standard electrocardiogram (ECG) under various doses of drugs. When the drug concentrations were increased from therapeutic levels, each drug induced a concentration-dependent characteristic type of ventricular arrhythmia, whereas no arrhythmias were observed at any dose with drugs known to be safe. We have shown that our system combining in vitro and in silico technologies can predict drug-induced arrhythmogenic risk reliably and efficiently.

scholarly journals Validation of an Automated Patch-Clamp Screening Assay on Human Kir2.1 Cardiac Ion Channels

2018 ◽  
Vol 114 (3) ◽  
pp. 311a
Author(s):  
Georg Andrees Bohme ◽  
Camille Sanson ◽  
Brigitte Schombert ◽  
Michel Partiseti
Keyword(s):  
Ion Channels ◽  
Patch Clamp ◽  
Screening Assay ◽  
Cardiac Ion Channels ◽  
Automated Patch Clamp

Cannabidiol inhibits multiple cardiac ion channels and shortens ventricular action potential duration in vitro

2020 ◽  
Vol 886 ◽  
pp. 173542
Author(s):  
Marguerite Le Marois ◽  
Véronique Ballet ◽  
Camille Sanson ◽  
Magali-Anne Maizières ◽  
Thierry Carriot ◽  
...  
Keyword(s):  
Ion Channels ◽  
Action Potential ◽  
Action Potential Duration ◽  
Cardiac Ion Channels ◽  
Ventricular Action Potential

Effects of Two Different Doses of Hirudin on APTT, Determined with Eight Different Reagents

1995 ◽  
Vol 73 (02) ◽  
pp. 219-222 ◽  
Author(s):  
Manuel Monreal ◽  
Luis Monreal ◽  
Rafael Ruiz de Gopegui ◽  
Yvonne Espada ◽  
Ana Maria Angles ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Anticoagulant Activity ◽  
Subcutaneous Administration ◽  
In Vitro Study ◽  
Ex Vivo Model ◽  
Suitable Candidate ◽  
Significant Prolongation ◽  
High Doses ◽  
Different Doses

SummaryThe APTT has been considered the most suitable candidate to monitor the anticoagulant activity of hirudin. However, its use is hampered by problems of standardization, which make the results heavily dependent on the responsiveness of the reagent used. Our aim was to investigate if this different responsiveness of different reagents when added in vitro is to be confirmed in an ex vivo study.Two different doses of r-hirudin (CGP 39393), 0.3 mg/kg and 1 mg/kg, were administered subcutaneously to 20 New Zealand male rabbits, and the differences in prolongation of APTT 2 and 12 h later were compared, using 8 widely used commercial reagents. All groups exhibited a significant prolongation of APTT 2 h after sc administration of hirudin, both at low and high doses. But this prolongation persisted 12 h later only when the PTTa reagent (Boehringer Mannheim) was used. In general, hirudin prolonged the APTT most with the silica- based reagents.In a further study, we compared the same APTT reagents in an in vitro study in which normal pooled plasma was mixed with increasing amount of hirudin. We failed to confirm a higher sensitivity for silica- containing reagents. Thus, we conclude that subcutaneous administration of hirudin prolongs the APTT most with the silica-based reagents, but this effect is exclusive for the ex vivo model.

scholarly journals Emerging Roles for Ion Channels in Ovarian Cancer: Pathomechanisms and Pharmacological Treatment

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 668
Author(s):  
Concetta Altamura ◽  
Maria Raffaella Greco ◽  
Maria Rosaria Carratù ◽  
Rosa Angela Cardone ◽  
Jean-François Desaphy
Keyword(s):  
Ovarian Cancer ◽  
Ion Channels ◽  
Transient Receptor Potential ◽  
Critical Role ◽  
Gynecologic Cancer ◽  
Receptor Potential ◽  
Transient Receptor Potential Channels ◽  
Platinum Resistance

Ovarian cancer (OC) is the deadliest gynecologic cancer, due to late diagnosis, development of platinum resistance, and inadequate alternative therapy. It has been demonstrated that membrane ion channels play important roles in cancer processes, including cell proliferation, apoptosis, motility, and invasion. Here, we review the contribution of ion channels in the development and progression of OC, evaluating their potential in clinical management. Increased expression of voltage-gated and epithelial sodium channels has been detected in OC cells and tissues and shown to be involved in cancer proliferation and invasion. Potassium and calcium channels have been found to play a critical role in the control of cell cycle and in the resistance to apoptosis, promoting tumor growth and recurrence. Overexpression of chloride and transient receptor potential channels was found both in vitro and in vivo, supporting their contribution to OC. Furthermore, ion channels have been shown to influence the sensitivity of OC cells to neoplastic drugs, suggesting a critical role in chemotherapy resistance. The study of ion channels expression and function in OC can improve our understanding of pathophysiology and pave the way for identifying ion channels as potential targets for tumor diagnosis and treatment.

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