2019
DOI: 10.1152/ajpregu.00190.2019
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Investigating the utility of adult zebrafish ex vivo whole hearts to pharmacologically screen hERG channel activator compounds

Abstract: There is significant interest in the potential utility of small-molecule activator compounds to mitigate cardiac arrhythmia caused by loss of function of hERG1a voltage-gated potassium channels. Zebrafish ( Danio rerio) have been proposed as a cost-effective, high-throughput drug-screening model to identify compounds that cause hERG1a dysfunction. However, there are no reports on the effects of hERG1a activator compounds in zebrafish and consequently on the utility of the model to screen for potential gain-of-… Show more

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Cited by 8 publications
(18 citation statements)
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“…Rescue of the gain-of-function reggae zERG mutant cardiac phenotype by terfenadine block ( Hassel et al, 2008 ) further demonstrated the targeted action of hERG-specific drugs in zebrafish. Indeed isolated zERG ( zkcnh6a ) channels have subsequently been shown to present similar pharmacological sensitivity to blocker compounds, such as terfenadine, as observed in hERG ( hKCNH2 ) channels ( Hull et al, 2019 ). Further developments to incorporate high-throughput zebrafish larvae screens revealed that bradycardia and susceptibility to 2:1 block provided accurate detection of QT prolonging compounds with high sensitivity and specificity ( Burns et al, 2005 ; Mittelstadt et al, 2008 ; Peal et al, 2011 ; Letamendia et al, 2012 ) as shown in Table 1 .…”
Section: Zebrafish As a Model Of Acquired Long-qt Syndromementioning
confidence: 99%
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“…Rescue of the gain-of-function reggae zERG mutant cardiac phenotype by terfenadine block ( Hassel et al, 2008 ) further demonstrated the targeted action of hERG-specific drugs in zebrafish. Indeed isolated zERG ( zkcnh6a ) channels have subsequently been shown to present similar pharmacological sensitivity to blocker compounds, such as terfenadine, as observed in hERG ( hKCNH2 ) channels ( Hull et al, 2019 ). Further developments to incorporate high-throughput zebrafish larvae screens revealed that bradycardia and susceptibility to 2:1 block provided accurate detection of QT prolonging compounds with high sensitivity and specificity ( Burns et al, 2005 ; Mittelstadt et al, 2008 ; Peal et al, 2011 ; Letamendia et al, 2012 ) as shown in Table 1 .…”
Section: Zebrafish As a Model Of Acquired Long-qt Syndromementioning
confidence: 99%
“…Direct comparison of action potentials recorded from adult zebrafish ventricular cells with those from human papillary muscle and murine ventricular strips revealed the closely associated morphology of zebrafish and human ventricular action potential ( Nemtsas et al, 2010 ). As a result, measurements of APD in adult and larval (e.g., 3 dpf) zebrafish hearts report values of ∼140–230 ms (see Table 1 ), which are remarkably dependent on temperature ( Rayani et al, 2018 ), but reflect the duration of the human ventricular action potential reasonably well ( Alday, 2014 ; Vornanen and Hassinen, 2016 ; Hull et al, 2019 ; Shi et al, 2020 ; Zhao et al, 2020 ). The QT interval measured from ECG recordings in zebrafish demonstrates comparable resting heart rate and conduction intervals with humans and the QT interval has a near linear relationship with the RR interval ( Milan et al, 2006b ), features that are imperative for a model examining LQTS that involves delayed ventricular repolarization and prolongation of the APD and QTc interval.…”
Section: Zebrafish As a Cardiac Modelmentioning
confidence: 99%
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