QT PRODACT: Evaluation of the Potential of Compounds to Cause QT Interval Prolongation by Action Potential Assays Using Guinea-Pig Papillary Muscles

Kii, Yoshihide; Hayashi, Seiji; Tabo, Mitsuyasu; Shimosato, Takashi; Fukuda, Hitoshi; Itoh, Tetsuji; Amano, Hideaki; Saitō, Mamoru; Morimoto, Hajime; Yamada, Kiyoshi; Kanda, Atsuhiro; Ishitsuka, Toshimasa; Yamazaki, Takanobu; Kiuchi, Yoichi; Taniguchi, Shinya; Mori, T.; Shimizu, Shigekazu; Tsurubuchi, Yuji; Yasuda, Shun-ichi; Kitani, Shin-ichi; Shimada, Chiaki; Kobayashi, Kazuo; Komeno, Masaharu; Kasai, Chieko; Hombo, Toshiyasu; Yamamoto, Keiji

doi:10.1254/jphs.qt-c8

Cited by 20 publications

(13 citation statements)

References 25 publications

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“…Cardiac AP is formed via a balanced activity of each ion channel and is necessary for the electrical conduction system of the heart. Because the duration of AP reflects a delicate balance between outward and inward currents related to various ion channels (11,12), investigating the effects of pharmacological modulators on APD is essential to clarify the characteristics of AP waveforms in hiPS-CMs. Application of 1 μM diltiazem induced significant shortening of APD 30 and APD 90 , whereas 0.1 μM E-4031 and 10 μM chromanol 293B induced significant prolongation of APD 30 , APD 90 , and APD in this study.…”

Section: Discussionmentioning

confidence: 99%

“…In the voltage-clamp mode, we recorded four ion currents (I Na , I Ca , I Kr , and I Ks ) and the pharmacological response to each ion-channel blocker because these currents are essential for AP generation (11,12 After achieving a conventional whole-cell configuration, the amplifier was switched to current-clamp mode. Spontaneous beating activity of the single hiPS-CMs stopped then, so we could not record AP waveform of spontaneous activity.…”

Section: Patch-clampmentioning

confidence: 99%

“…Thus, hiPS cells have a capacity to differentiate functional cardiomyocytes, but to our knowledge, there are no reports on the electrophysiological/pharmacological properties of major cardiac ion currents in hiPS-CMs. Because cardiac ion currents essentially determine the electrical activity of the heart (11,12), we should clarify the characteristics of major ion currents in hiPS-CMs for their use as a drug discovery tool. The balance of functional ion currents in cardiomyocytes is also important for evaluating the effects of drugs on cardiac APs because AP waveforms are the result of the balanced activity of several ion channels (11,12).…”

Section: Introductionmentioning

confidence: 99%

“…Because cardiac ion currents essentially determine the electrical activity of the heart (11,12), we should clarify the characteristics of major ion currents in hiPS-CMs for their use as a drug discovery tool. The balance of functional ion currents in cardiomyocytes is also important for evaluating the effects of drugs on cardiac APs because AP waveforms are the result of the balanced activity of several ion channels (11,12). Hence, the investigation of pharmacological responsiveness of AP waveforms is necessary to elucidate the ion current components that contribute to the generation of AP in hiPS-CMs.…”

Section: Introductionmentioning

confidence: 99%

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Electrophysiological Characterization of Cardiomyocytes Derived From Human Induced Pluripotent Stem Cells

Honda¹,

Kiyokawa²,

Tabo³

et al. 2011

J Pharmacol Sci

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Abstract. Cardiomyocytes derived from human induced pluripotent stem cells (hiPS-CMs) hold great promise for development of in vitro research tools to assess cardiotoxicity, including QT prolongation. In the present study, we aimed to clarify the electrophysiological/pharmacological characteristics of hiPS-CMs using the patch-clamp technique. The hiPS cells were differentiated into beating cardiomyocytes by the embryoid body method. The expression of genes related to cardiac ion channels and differentiation markers in cardiomyocytes were detected by RT-PCR. Whole-cell patch-clamp recordings were performed using single hiPS-CMs dispersed from beating colonies. We confirmed voltage-dependence of major cardiac ion currents (I Na , I Ca , I Kr , and I Ks ) and pharmacological responses to ion-channel blockers. Action potential duration (APD) was prolonged by both I Kr /hERG and I Ks blockers, whereas it was shortened by an I Ca blocker, indicating that these ion current components contribute to action potential generation in hiPS-CMs. As for multiple ion channel blockers, terfenadine prolonged APD, but verapamil did not, results which were identical to clinically relevant pharmacological responses. These data suggest that patchclamp assay using hiPS-CMs could be an accurate method of predicting the human cardiac responses to drug candidates. This study would be helpful in establishing an electrophysiological assay to assess the risk of drug-induced arrhythmia using hiPS-CMs.

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Section: Discussionmentioning

confidence: 99%

Section: Patch-clampmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Electrophysiological Characterization of Cardiomyocytes Derived From Human Induced Pluripotent Stem Cells

Honda¹,

Kiyokawa²,

Tabo³

et al. 2011

J Pharmacol Sci

Self Cite

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“…The triangulation parameter (APD 30-90 ) was defined as the difference between APD 90 and APD 30 (11,12). Preparations that satisfied the following criteria when given a stimulus at 1 Hz were used in this study: RMP < −80 mV, APA >100 mV, V max >120 V/ s, and APD 90 >160 ms.…”

Section: Methodsmentioning

confidence: 99%

QT PRODACT: Inter- and Intra-facility Variability of the Action Potential Assay Using Isolated Guinea-Pig Papillary Muscles

et al. 2005

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Abstract. Sixteen pharmaceutical companies and 6 contract research organizations in QT PRODACT acquired data on the action potentials in isolated guinea-pig papillary muscles using a standard protocol established by the QT PRODACT. Inter-and intra-facility variability for each of the parameters in the pre-application values and ∆% change after vehicle (0.1% DMSO) or dl-sotalol (30 µmol / L) treatment were examined using a nested model. Inter-facility variability of each of the parameters in the pre-application values were V max > APDs = APD 30-90 > APA = RMP (descending order). The inter-facility variability of all of the parameters was almost the same or was less as compared with the intra-facility variability. Inter-facility variability for the ∆% change for each parameter after dl-sotalol treatment showed a tendency similar to the results for the pre-application values. Comparing the inter-and the intra-facility variability, the interfacility variation did not exceed the intra-facility variation. All facilities found that dl-sotalol prolonged APD. Therefore, it is suggested that the test system using this standard protocol is useful as a non-clinical evaluation system for QT prolongation. Moreover, the results are considered to be directly comparable between multiple facilities. Supplementary material (Appendix): available only at http://dx.doi.org / 10.1254 / jphs.QT-B5.

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Predicting Drug‐Induced QT Prolongation and Torsades de Pointes: A Review of Preclinical Endpoint Measures

Townsend

Brown

2013

CP Pharmacology

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Compound-induced prolongation of the cardiac QT interval is a major concern in drug development and this unit discusses approaches that can predict QT effects prior to undertaking clinical trials. The majority of compounds that prolong the QT interval block the cardiac rapid delayed rectifier potassium current, IKr (hERG). Described in this overview are different ways to measure hERG, from recent advances in automated electrophysiology to the quantification of channel protein trafficking and binding. The contribution of other cardiac ion channels to hERG data interpretation is also discussed. In addition, endpoint measures of the integrated activity of cardiac ion channels at the single-cell, tissue, and whole-animal level, including for example the well-established action potential to the more recent beat-to-beat variability, transmural dispersion of repolarization, and field potential duration, are described in the context of their ability to predict QT prolongation and torsadogenicity in humans.

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QT PRODACT: Evaluation of the Potential of Compounds to Cause QT Interval Prolongation by Action Potential Assays Using Guinea-Pig Papillary Muscles

Cited by 20 publications

References 25 publications

Electrophysiological Characterization of Cardiomyocytes Derived From Human Induced Pluripotent Stem Cells

Electrophysiological Characterization of Cardiomyocytes Derived From Human Induced Pluripotent Stem Cells

QT PRODACT: Inter- and Intra-facility Variability of the Action Potential Assay Using Isolated Guinea-Pig Papillary Muscles

Predicting Drug‐Induced QT Prolongation and Torsades de Pointes: A Review of Preclinical Endpoint Measures

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