ArticlePloS one2014
Pronounced effects of HERG-blockers E-4031 and erythromycin on APD, spatial APD dispersion and triangulation in transgenic long-QT type 1 rabbits.
Article in PloS one, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 18 citations in OpenAlex.
- Beneficial action potential duration-shortening effects, but deleterious negative inotropism of IKs-activator docosahexaenoyl glycine in long QT syndrome type 2.Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology · 2025Article
- In vitro to in vivo extrapolation from 3D hiPSC-derived cardiac microtissues and physiologically based pharmacokinetic modeling to inform next-generation arrhythmia risk assessment.Toxicological sciences : an official journal of the Society of Toxicology · 2024Article
- Oxytocin exerts harmful cardiac repolarization prolonging effects in drug-induced LQTS.International journal of cardiology. Heart & vasculature · 2022Article
- Transgenic LQT2, LQT5, and LQT2-5 rabbit models with decreased repolarisation reserve for prediction of drug-induced ventricular arrhythmias.British journal of pharmacology · 2020Article
- Transgenic Rabbit Models in Proarrhythmia Research.Frontiers in pharmacology · 2020Review
- Machine Learning of Human Pluripotent Stem Cell-Derived Engineered Cardiac Tissue Contractility for Automated Drug Classification.Stem cell reports · 2017Article
- Potassium currents in the heart: functional roles in repolarization, arrhythmia and therapeutics.The Journal of physiology · 2017Review
- Dominant negative consequences of a hERG 1b-specific mutation associated with intrauterine fetal death.Progress in biophysics and molecular biology · 2016Article
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Authors and funding
10 authors at 2 institutions in 2 countries.
Funding
Abstract
backgroundProlongation of action potential duration (APD), increased spatial APD dispersion, and triangulation are major factors promoting drug-induced ventricular arrhythmia. Preclinical identification of HERG/IKr-blocking drugs and their pro-arrhythmic potential, however, remains a challenge. We hypothesize that transgenic long-QT type 1 (LQT1) rabbits lacking repolarizing IKs current may help to sensitively detect HERG/IKr-blocking properties of drugs.
methodsHearts of adult female transgenic LQT1 and wild type littermate control (LMC) rabbits were Langendorff-perfused with increasing concentrations of HERG/IKr-blockers E-4031 (0.001-0.1 µM, n=9/7) or erythromycin (1-300 µM, n=9/7) and APD, APD dispersion, and triangulation were analyzed.
resultsAt baseline, APD was longer in LQT1 than in LMC rabbits in LV apex and RV mid. Erythromycin and E-4031 prolonged APD in LQT1 and LMC rabbits in all positions. However, erythromycin-induced percentaged APD prolongation related to baseline (%APD) was more pronounced in LQT1 at LV base-lateral and RV mid positions (100 µM, LQT1, +40.6 ± 9.7% vs. LMC, +24.1 ± 10.0%, p<0.05) and E-4031-induced %APD prolongation was more pronounced in LQT1 at LV base-lateral (0.01 µM, LQT1, +29.6 ± 10.6% vs. LMC, +19.1 ± 3.8%, p<0.05) and LV base-septal positions. Moreover, erythromycin significantly increased spatial APD dispersion only in LQT1 and increased triangulation only in LQT1 in LV base-septal and RV mid positions. Similarly, E-4031 increased triangulation only in LQT1 in LV apex and base-septal positions.
conclusionsE-4031 and erythromycin prolonged APD and increased triangulation more pronouncedly in LQT1 than in LMC rabbits. Moreover, erythromycin increased APD dispersion only in LQT1, indicating that transgenic LQT1 rabbits could serve as sensitive model to detect HERG/IKr-blocking properties of drugs.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.