Electrocardiographic Method for Identifying Drug-induced Repolarization Abnormalities Associated with a Reduction of the Rapidly Activating Delayed Rectifier Potassium Current

2006 ◽  
Author(s):  
JP Couderc ◽  
M. Vaglio ◽  
X. Xia ◽  
S. McNitt ◽  
O. Hyrien
Keyword(s):  
Potassium Current ◽  
Delayed Rectifier ◽  
Drug Induced ◽  
Delayed Rectifier Potassium Current ◽  
Repolarization Abnormalities

scholarly journals Slow Delayed Rectifier Potassium Current Blockade Contributes Importantly to Drug-Induced Long QT Syndrome

2013 ◽  
Vol 6 (5) ◽  
pp. 1002-1009 ◽  
Author(s):  
Christiaan C. Veerman ◽  
Arie O. Verkerk ◽  
Marieke T. Blom ◽  
Christine A. Klemens ◽  
Pim N.J. Langendijk ◽  
...  
Keyword(s):  
Long Qt Syndrome ◽  
Potassium Current ◽  
Delayed Rectifier ◽  
Long Qt ◽  
Drug Induced ◽  
Delayed Rectifier Potassium Current ◽  
Qt Syndrome

scholarly journals High-Throughput Drug Screening System Based on Human Induced Pluripotent Stem Cell-Derived Atrial Myocytes ∼ A Novel Platform to Detect Cardiac Toxicity for Atrial Arrhythmias

2021 ◽  
Vol 12 ◽  
Author(s):  
Yayoi Honda ◽  
Jun Li ◽  
Aya Hino ◽  
Shinji Tsujimoto ◽  
Jong-Kook Lee
Keyword(s):  
Ventricular Arrhythmia ◽  
High Throughput ◽  
Potassium Current ◽  
Delayed Rectifier ◽  
Atrial Arrhythmias ◽  
Drug Induced ◽  
Ips Cell ◽  
Evaluation Systems ◽  
Delayed Rectifier Potassium Current ◽  
Induced Pluripotent

Evaluation of proarrhythmic properties is critical for drug discovery. In particular, QT prolongation in electrocardiograms has been utilized as a surrogate marker in many evaluation systems to assess the risk of torsade de pointes and lethal ventricular arrhythmia. Recently, new evaluation systems based on human iPS cell-derived cardiomyocytes have been established. On the other hand, in clinical situations, it has been reported that the incidence of atrial arrhythmias such as atrial fibrillation has been increasing every year, with the prediction of a persistent increase in the near future. As to the increased incidence of atrial arrhythmias, in addition to the increased population of geriatric patients, a wide variety of drug treatments may be related, as an experimental method to detect drug-induced atrial arrhythmia has not been established so far. In the present study, we characterized the atrial-like cardiomyocytes derived from human induced pluripotent stem cells and examined their potential for the evaluation of drug-induced atrial arrhythmia. Atrial-like cardiomyocytes were induced by adding retinoic acid (RA) during the process of myocardial differentiation, and their characteristics were compared to those of RA-free cardiomyocytes. Using gene expression and membrane potential analysis, it was confirmed that the cells with or without RA treatment have atrial or ventricular like cardiomyocytes, respectively. Using the ultra-rapid activating delayed rectifier potassium current (IKur) channel inhibitor, which is specific to atrial cardiomyocytes, Pulse width duration (PWD) 30cF prolongation was confirmed only in atrial-like cardiomyocytes. In addition, ventricular like cardiomyocytes exhibited an early after depolarization by treatment with rapidly activating delayed rectifier potassium current (IKr) channel inhibitor, which induces ventricular arrhythmia in clinical situations. Here, we have established a high-throughput drug evaluation system using human iPS cell-derived atrial-like cardiomyocytes. Based on the obtained data, the system might be a valuable platform to detect potential risks for drug-induced atrial arrhythmias.

Ionic mechanisms of electrophysiological properties and repolarization abnormalities in rabbit Purkinje fibers

2011 ◽  
Vol 300 (5) ◽  
pp. H1806-H1813 ◽  
Author(s):  
Alberto Corrias ◽  
Wayne Giles ◽  
Blanca Rodriguez
Keyword(s):  
Purkinje Cells ◽  
Mechanisms Of Action ◽  
Delayed Rectifier ◽  
Pharmacological Interventions ◽  
Drug Induced ◽  
Current Increase ◽  
Detailed Model ◽  
Purkinje Fibers ◽  
Electrophysiological Properties ◽  
Repolarization Abnormalities

Purkinje cells play an important role in drug-induced arrhythmogenesis and are widely used in preclinical drug safety assessments. Repolarization abnormalities such as action potential (AP) prolongation and early afterdeploarizations (EAD) are often observed in vitro upon pharmacological interventions. However, because drugs do not act on only one defined target, it is often difficult to fully explain the mechanisms of action and their potential arrhythmogenicity. Computational models, when appropriately detailed and validated, can be used to gain mechanistic insights into the mechanisms of action of certain drugs. Nevertheless, no model of Purkinje electrophysiology that is able to reproduce characteristic Purkinje responses to drug-induced changes in ionic current conductances such as AP prolongation and EAD generation currently exists. In this study, a novel biophysically detailed model of rabbit Purkinje electrophysiology was developed by integration of data from voltage-clamp and AP experimental recordings. Upon validation, we demonstrate that the model reproduces many key electrophysiological properties of rabbit Purkinje cells. These include: AP morphology and duration, both input resistance and rate dependence properties as well as response to hyperkalemia. Pharmacological interventions such as inward rectifier K+ current and rapid delayed rectifier K+ current block as well as late Na+ current increase result in significant AP changes. However, enhanced L-type Ca2+ current ( iCaL) dominates in EAD genesis in Purkinje fibers. In addition, iCaL inactivation dynamics and intercellular coupling in tissue strongly modulate EAD formation. We conclude that EAD generation in Purkinje cells is mediated by an increase in iCaL and modulated by its inactivation kinetics.

scholarly journals Excavatolide-B Enhances Contextual Memory Retrieval via Repressing the Delayed Rectifier Potassium Current in the Hippocampus

Marine Drugs ◽  
2018 ◽  
Vol 16 (11) ◽  
pp. 405 ◽  
Author(s):  
Irene Huang ◽  
Yu-Luan Hsu ◽  
Chien-Chang Chen ◽  
Mei-Fang Chen ◽  
Zhi-Hong Wen ◽  
...  
Keyword(s):  
Memory Retrieval ◽  
Potassium Current ◽  
Memory Function ◽  
Long Term Potentiation ◽  
Autism Spectrum ◽  
Absence Epilepsy ◽  
Delayed Rectifier ◽  
Contextual Memory ◽  
Term Potentiation ◽  
Delayed Rectifier Potassium Current

Memory retrieval dysfunction is a symptom of schizophrenia, autism spectrum disorder (ASD), and absence epilepsy (AE), as well as an early sign of Alzheimer’s disease. To date, few drugs have been reported to enhance memory retrieval. Here, we found that a coral-derived natural product, excavatolide-B (Exc-B), enhances contextual memory retrieval in both wild-type and Cav3.2−/− mice via repressing the delayed rectifier potassium current, thus lowering the threshold for action potential initiation and enhancing induction of long-term potentiation (LTP). The human CACNA1H gene encodes a T-type calcium channel (Cav3.2), and its mutation is associated with schizophrenia, ASD, and AE, which are all characterized by abnormal memory function. Our previous publication demonstrated that Cav3.2−/− mice exhibit impaired contextual-associated memory retrieval, whilst their retrieval of spatial memory and auditory cued memory remain intact. The effect of Exc-B on enhancing the retrieval of context-associated memory provides a hope for novel drug development.

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