Arrhythmia Models for Drug Research: Classification of Antiarrhythmic Drugs

Hashimoto, Keitaro

doi:10.1254/jphs.crj06013x

Cited by 16 publications

(10 citation statements)

References 91 publications

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“…It is now apparent that TdP, a life-threatening ventricular tachyarrhythmia can be induced by common medications which prolong duration of the cardiac action potential (Drici et al , 1998; Hashimoto, 2007; Hreiche et al , 2008; James et al , 2007; Lehmann et al , 1996; Makkar et al , 1993; Tamargo, 2000). Acquired long QT syndrome (LQTS) can be associated with drug-induced prolonged QT C intervals and arrhythmia, and results from delay of cardiac repolarization caused mostly by inhibition of the human ether-a-go-go-related gene (hERG) channel, which conducts the rapid component of the delayed rectifier K + current (I Kr ).…”

Section: Gender Differences In Drug-induced Long Qt Syndromementioning

confidence: 99%

Sex hormonal regulation of cardiac ion channels in drug-induced QT syndromes

Kurokawa

Kodama

Clancy

et al. 2016

Pharmacology & Therapeutics

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Female sex is an independent risk factor for development of torsade de pointes (TdP) arrhythmias not only in congenital long QT syndromes but also in acquired long QT syndromes. Clinical and experimental evidences suggest that the gender differences may be due to, at least in part, gender differences in regulation of rate-corrected QT (QTC) interval between men and women. In adult women, both QTC interval and arrhythmic risks in TdP alter cyclically during menstrual cycle, suggesting a critical role of female sex hormones in cardiac repolarization process. These gender differences in fundamental cardiac electrophysiology result from variable ion channel expression and diverse sex hormonal regulation via long term genomic and acute non-genomic actions, and sex differences in drug responses and metabolisms. In particular, non-genomic actions of testosterone and progesterone on cardiac ion channels are likely to contribute to the gender differences in cardiac repolarization processes. This review summarizes current knowledge on sex hormonal regulation of cardiac ion channels which contribute to cardiac repolarization processes and its implication for gender differences in drug-induced long QT syndromes.

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Section: Gender Differences In Drug-induced Long Qt Syndromementioning

confidence: 99%

Sex hormonal regulation of cardiac ion channels in drug-induced QT syndromes

Kurokawa

Kodama

Clancy

et al. 2016

Pharmacology & Therapeutics

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“…[17][18][19][20][21][22][23] drug-induced arrhythmia, an acquired long QT syndrome (LQTS), is associated with prolonged QT c intervals, resulting from delay of cardiac repolarization caused mostly by inhibition of the human ether-a-go-go-related gene (hERG) channel, which conducts the rapid component of the delayed rectifier K + current (I Kr ). Thus, regulatory agencies including Food and drug Administration (FdA) and Pharmaceuticals and Medical devices Agency (PMdA) require hERG inhibition data for any drug candidate referred as hERG pre-clinical test.…”

Section: Gender Differences In Drug-induced Long Qt Syndromementioning

confidence: 99%

Non-genomic Action of Sex Steroid Hormones and Cardiac Repolarization

Kurokawa

Furukawa

2013

Biological & Pharmaceutical Bulletin

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Gender differences play a major role in the manifestation of cardiovascular disease including cardiac arrhythmias. In particular, female sex is an independent risk factor for development of torsade de pointes (TdP) arrhythmias not only in congenital long QT syndromes but also in acquired long QT syndromes which occur as adverse effects of existing drugs. Recent clinical and experimental studies suggest that the gender differences may stem, at least in part, from gender differences in cardiac repolarization process, that is longer rate-corrected QT (QT(C)) interval in women than in men. In women, QT(C) interval and arrhythmic risks in TdP alter cyclically during menstrual cycle, suggesting a critical role of female sex hormones in cardiac repolarization process. These gender differences in fundamental cardiac electrophysiology result from variable ion channel expression and diverse sex hormonal regulation via long term genomic and acute non-genomic pathways, and sex differences in drug responses and metabolisms. In particular, non-genomic actions of testosterone and progesterone on cardiac ion channels likely to contribute to the gender differences in cardiac repolarization processes.

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“…Presently, there are several methods or technologies for screening candidates of antiarrhythmic drugs, including the conventional patch-clamp technique, chemical models induced by acute infusion of various chemicals, e.g. aconitine, digitalis, barium [1,2], electrical-stimulation models [3], neural stimulation models [4], ischemic arrhythmias models [1]. In general, different methods or technologies should be combined to evaluate the efficacy of anti-arrhythmic candidate drugs.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of 2-Aminoethoxydiphenyl Borate-induced Rat Atrial Ectopic Activity by Anti-arrhythmic Drugs

Hu¹,

Li²,

Lu³

et al. 2010

Cell Physiol Biochem

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Background/Aims: 2-aminoethoxydiphenyl borate (2-APB) provokes spontaneous mechanical activity in isolated rat left atria. The present study is to characterize 2-APB-induced ectopic activity in rat atria and to investigate the inhibition of 2-APB-induced ectopic activity by anti-arrhythmic drugs. Methods: 2-APB-induced ectopic activity was measured through an isometric force transducer connected to a multichannel acquisition and analysis system. Intracellular [Ca²⁺]_i was measured with fluorescence laser scanning confocal microscopy. Voltage-dependent L- type Ca²⁺ currents were recorded by using patch-clamp technique. Results: 2-APB dose-dependently increased the ectopic activity of left atria at 1, 5, 10, 20, 50 µM. Anti-arrhythmic drugs, quinidine (10µM), lidocaine (10µM), verapamil (5µM), and amiodarone (50µM,100µM) inhibited 2-APB-induced ectopic activity. 2-APB-induced ectopic activity was inhibited by Ca²⁺-free bath, Na⁺/Ca²⁺ exchanger blockers, 3′,4′-dichlorobenzamil hydrochloride (DHC) and Ni²⁺, not by non-selective cation channel blocker Gd³⁺. 2-APB also induced ectopic contractions in ventricular tissue straps and the ectopic contractions were inhibited by quinidine, verapamil and DHC. Lidocaine, verapamil and DHC inhibited 2-APB-induced increase of intracellular Ca²⁺ concentration in cardiomyocytes. Low molecular weight heparin inhibited phenylephrine (PE)-induced but not 2-APB -induced atria ectopic activity, and the pattern of 2-APB-induced ectopic activity was continuous, distinct from the discontinuous activity induced by PE. Conclusion: 2-APB-induced atria ectopic activity was inhibited by classic anti-arrhythmic drugs quinidine, lidocaine, verapamil, amiodarone, and Na⁺/Ca²⁺ exchanger blockers. It can be used for testing agents able to affect any of Na⁺, Ca²⁺ channel, Na⁺/Ca²⁺ exchanger without selectivity.

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Arrhythmia Models for Drug Research: Classification of Antiarrhythmic Drugs

Cited by 16 publications

References 91 publications

Sex hormonal regulation of cardiac ion channels in drug-induced QT syndromes

Sex hormonal regulation of cardiac ion channels in drug-induced QT syndromes

Non-genomic Action of Sex Steroid Hormones and Cardiac Repolarization

Inhibition of 2-Aminoethoxydiphenyl Borate-induced Rat Atrial Ectopic Activity by Anti-arrhythmic Drugs

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