Safety pharmacology studies using EFP and impedance

Obergrussberger, Alison; Juhász, Krisztina; Thomas, Ulrike; Stölzle‐Feix, Sonja; Becker, Norbert; Dörr, Leo; Beckler, Matthias; Bot, Corina; George, Michael; Fertig, Niels

doi:10.1016/j.vascn.2016.04.006

Cited by 30 publications

(24 citation statements)

References 47 publications

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“…100 nM E-4031 has been shown to induce EADs in stem-cell derived cardiomyocytes (Peng et al, 2010 ). We, similarly to Obergrussberger et al ( 2016 ) detected significant APD90 prolongation already at 30 nM under both spontaneous and paced beat rates in optogenetic measurements as well as under spontaneous beating measured by patch clamp. In both methods, the prolongation of APD under spontaneous beat rate was followed by EADs at 30–100 nM concentration of E-4031.…”

Section: Discussionsupporting

confidence: 90%

“…Contractile and structural cardiotoxicity, seen with e.g., some kinase-targeted cancer drugs, represent another safety concern (Cheng and Force, 2010 ). Cellular electric impedance assays have been implemented with multielectrode assays for contractility measurements (Obergrussberger et al, 2016 ), but do not provide the spatial resolution to detect movements within the cell in detail, in contrast to the minimum quadratic difference method based on video motion tracking used here (Ahola et al, 2014 , 2017 ). We aimed to evaluate whether optogenetic measurements of cardiomyocyte electrophysiology can be combined with an assay measuring the end point of the cardiomyocyte electrical activity, i.e., contraction and relaxation.…”

Section: Discussionmentioning

confidence: 99%

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Evaluation of Optogenetic Electrophysiology Tools in Human Stem Cell-Derived Cardiomyocytes

et al. 2017

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Current cardiac drug safety assessments focus on hERG channel block and QT prolongation for evaluating arrhythmic risks, whereas the optogenetic approach focuses on the action potential (AP) waveform generated by a monolayer of human cardiomyocytes beating synchronously, thus assessing the contribution of several ion channels on the overall drug effect. This novel tool provides arrhythmogenic sensitizing by light-induced pacing in combination with non-invasive, all-optical measurements of cardiomyocyte APs and will improve assessment of drug-induced electrophysiological aberrancies. With the help of patch clamp electrophysiology measurements, we aimed to investigate whether the optogenetic modifications alter human cardiomyocytes' electrophysiology and how well the optogenetic analyses perform against this gold standard. Patch clamp electrophysiology measurements of non-transduced stem cell-derived cardiomyocytes compared to cells expressing the commercially available optogenetic constructs Optopatch and CaViar revealed no significant changes in action potential duration (APD) parameters. Thus, inserting the optogenetic constructs into cardiomyocytes does not significantly affect the cardiomyocyte's electrophysiological properties. When comparing the two methods against each other (patch clamp vs. optogenetic imaging) we found no significant differences in APD parameters for the Optopatch transduced cells, whereas the CaViar transduced cells exhibited modest increases in APD-values measured with optogenetic imaging. Thus, to broaden the screen, we combined optogenetic measurements of membrane potential and calcium transients with contractile motion measured by video motion tracking. Furthermore, to assess how optogenetic measurements can predict changes in membrane potential, or early afterdepolarizations (EADs), cells were exposed to cumulating doses of E-4031, a hERG potassium channel blocker, and drug effects were measured at both spontaneous and paced beating rates (1, 2 Hz). Cumulating doses of E-4031 produced prolonged APDs, followed by EADs and drug-induced quiescence. These observations were corroborated by patch clamp and contractility measurements. Similar responses, although more modest were seen with the IKs potassium channel blocker JNJ-303. In conclusion, optogenetic measurements of AP waveforms combined with optical pacing compare well with the patch clamp gold standard. Combined with video motion contractile measurements, optogenetic imaging provides an appealing alternative for electrophysiological screening of human cardiomyocyte responses in pharmacological efficacy and safety testings.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Evaluation of Optogenetic Electrophysiology Tools in Human Stem Cell-Derived Cardiomyocytes

et al. 2017

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“…In addition, many drugs that were originally on the market have been withdrawn due to clinical cases of cardiotoxicity. The HERG channel in Chinese hamster ovary or human embryonic kidney cells has been found to be closely related to QT prolongation and torsade de pointes (TdP) and has become an important component of early drug screening and safety pharmacology experiments [2, 3]. However, the assessment of cardiotoxicity cannot be completely dependent on these simple model cell lines, as they do not reproduce the integrated cardiomyocyte system and had species differences [4].…”

Section: Introductionmentioning

confidence: 99%

“…For example, there were cases in which compounds that interacted with hERG may not have caused TdP, e.g., verapamil [3]. Besides, cardiac safety was evaluated by some complementary assays such as multi-electrode arrays (MEA) and impedance, which the current needs were still not meet [2]. Therefore, there is an urgent need for a method to comprehensively evaluate cardiotoxicity in both pre-drug development stage and post-evaluation stage of listed drugs.…”

Section: Introductionmentioning

confidence: 99%

An integrated characterization of contractile, electrophysiological, and structural cardiotoxicity of Sophora tonkinensis Gapnep. in human pluripotent stem cell-derived cardiomyocytes

Wang

et al. 2019

Stem Cell Res Ther

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BackgroundCardiotoxicity remains an important concern in drug discovery and clinical medication. Meanwhile, Sophora tonkinensis Gapnep. (S. tonkinensis) held great value in the clinical application of traditional Chinese medicine, but cardiotoxic effects were reported, with matrine, oxymatrine, cytisine, and sophocarpine being the primary toxic components.MethodsIn this study, impedance and extracellular field potential (EFP) of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were recorded using the cardio non-labeled cell function analysis and culture system (Cardio-NLCS). The effects of matrine, oxymatrine, cytisine, and sophocarpine (2, 10, 50 μM) on cell viability; level of lactate dehydrogenase (LDH), creatine kinase MB isoenzyme (CK-MB), and cardiac troponin I (CTn-I); antioxidant activities; production of reactive oxygen species (ROS) and malondialdehyde (MDA); and disruption of intracellular calcium homeostasis were also added into the integrated assessment.ResultsThe results showed that matrine and sophocarpine dose-dependently affected both impedance and EFP, while oxymatrine and cytisine altered impedance significantly. Our study also indicated that cardiotoxicity of matrine, oxymatrine, cytisine, and sophocarpine was related to the disruption of calcium homeostasis and oxidative stress. Four alkaloids of S. tonkinensis showed significant cardiotoxicity with dose dependence and structural cardiotoxicity synchronized with functional changes of cardiomyocytes.ConclusionsThis finding may provide guidance for clinical meditation management. Furthermore, this study introduced an efficient and reliable approach, which offers alternative options for evaluating the cardiotoxicity of the listed drugs and novel drug candidates.Electronic supplementary materialThe online version of this article (10.1186/s13287-018-1126-4) contains supplementary material, which is available to authorized users.

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“…The experiment was set up as described in Obergrussberger et al . () making sure to insert the correct information into the compound plates and reference solutions. Oxycodone was prepared at 10× concentration in culture media.…”

Section: Methodsmentioning

confidence: 99%

The opioid oxycodone use‐dependently inhibits the cardiac sodium channel Na_V1.5

Meents

Juhász

Stölzle‐Feix

et al. 2018

British J Pharmacology

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Oxycodone leads to an accumulation of Na 1.5 channels in inactivated states, with a slow time course. Although the concentrations needed to elicit cardiac arrhythmias in vitro are relatively high, some patients under long-term treatment with oxycodone as well as drug abusers and addicts might suffer from severe cardiac side effects induced by the slowly developing effects of oxycodone on Na 1.5 channels.

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Safety pharmacology studies using EFP and impedance

Cited by 30 publications

References 47 publications

Evaluation of Optogenetic Electrophysiology Tools in Human Stem Cell-Derived Cardiomyocytes

Evaluation of Optogenetic Electrophysiology Tools in Human Stem Cell-Derived Cardiomyocytes

An integrated characterization of contractile, electrophysiological, and structural cardiotoxicity of Sophora tonkinensis Gapnep. in human pluripotent stem cell-derived cardiomyocytes

The opioid oxycodone use‐dependently inhibits the cardiac sodium channel Na_V1.5

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Safety pharmacology studies using EFP and impedance

Cited by 30 publications

References 47 publications

Evaluation of Optogenetic Electrophysiology Tools in Human Stem Cell-Derived Cardiomyocytes

Evaluation of Optogenetic Electrophysiology Tools in Human Stem Cell-Derived Cardiomyocytes

An integrated characterization of contractile, electrophysiological, and structural cardiotoxicity of Sophora tonkinensis Gapnep. in human pluripotent stem cell-derived cardiomyocytes

The opioid oxycodone use‐dependently inhibits the cardiac sodium channel NaV1.5

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The opioid oxycodone use‐dependently inhibits the cardiac sodium channel Na_V1.5