ArticleThe Journal of physiology2013
Ionic mechanisms limiting cardiac repolarization reserve in humans compared to dogs.
Article in The Journal of physiology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 86 papers.
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Who cites it
86 citing papers in PubMed, 153 citations in OpenAlex.
- Predicting QRS and PR interval prolongations in humans using nonclinical data.British journal of pharmacology · 2017Trial
- Sex differences in human atrial electrophysiology: the dark side of the moon? Will engineered heart tissue help to bring light into the darkness?Naunyn-Schmiedeberg's archives of pharmacology · 2026Review
- The slow delayed rectifier KScientific reports · 2025Article
- Saline-based modified del Nido cardioplegia versus multidose St. Thomas cardioplegia in canine mitral valve repair: A randomized controlled trial.Veterinary surgery : VS · 2025Article
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- Beta-Adrenergic Activation of the Inward Rectifier KInternational journal of molecular sciences · 2024Article
- Effects of SZV-2649, a new multiple ion channel inhibitor mexiletine analogue.Scientific reports · 2024Article
- A Comparative Study of the Rapid (IPharmaceuticals (Basel, Switzerland) · 2024Article
- Genetics and Pharmacogenetics of Atrial Fibrillation: A Mechanistic Perspective.JACC. Basic to translational science · 2024Review
- Human induced pluripotent stem cell-derived atrial cardiomyocytes recapitulate contribution of the slowly activating delayed rectifier currents IKs to repolarization in the human atrium.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 · 2024Article
- Relationship between ion currents and membrane capacitance in canine ventricular myocytes.Scientific reports · 2024Article
- Cellular electrophysiological effects of the citrus flavonoid hesperetin in dog and rabbit cardiac ventricular preparations.Scientific reports · 2024Article
- Selective Inhibition of Cardiac Late NaBiomedicines · 2023Article
- In Vitro Models for Improved Therapeutic Interventions in Atrial Fibrillation.Journal of personalized medicine · 2023Review
- Ionic current changes underlying action potential repolarization responses to physiological pacing and adrenergic stimulation in adult rat ventricular myocytes.Physiological reports · 2023Article
- IBiomedicines · 2023Article
- Electrophysiological and calcium-handling development during long-term culture of human-induced pluripotent stem cell-derived cardiomyocytes.Basic research in cardiology · 2023Article
- Choice of experimental model determines translational impact: The link between bisphenol A and cardiotoxicity.Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association · 2023Article
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- Injection of IFrontiers in physiology · 2023Article
26 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
21 authors at 7 institutions in 4 countries.
Funding
Abstract
The species-specific determinants of repolarization are poorly understood. This study compared the contribution of various currents to cardiac repolarization in canine and human ventricle. Conventional microelectrode, whole-cell patch-clamp, molecular biological and mathematical modelling techniques were used. Selective IKr block (50-100 nmol l(-1) dofetilide) lengthened AP duration at 90% of repolarization (APD90) >3-fold more in human than dog, suggesting smaller repolarization reserve in humans. Selective IK1 block (10 μmol l(-1) BaCl2) and IKs block (1 μmol l(-1) HMR-1556) increased APD90 more in canine than human right ventricular papillary muscle. Ion current measurements in isolated cardiomyocytes showed that IK1 and IKs densities were 3- and 4.5-fold larger in dogs than humans, respectively. IKr density and kinetics were similar in human versus dog. ICa and Ito were respectively ~30% larger and ~29% smaller in human, and Na(+)-Ca(2+) exchange current was comparable. Cardiac mRNA levels for the main IK1 ion channel subunit Kir2.1 and the IKs accessory subunit minK were significantly lower, but mRNA expression of ERG and KvLQT1 (IKr and IKs α-subunits) were not significantly different, in human versus dog. Immunostaining suggested lower Kir2.1 and minK, and higher KvLQT1 protein expression in human versus canine cardiomyocytes. IK1 and IKs inhibition increased the APD-prolonging effect of IKr block more in dog (by 56% and 49%, respectively) than human (34 and 16%), indicating that both currents contribute to increased repolarization reserve in the dog. A mathematical model incorporating observed human-canine ion current differences confirmed the role of IK1 and IKs in repolarization reserve differences. Thus, humans show greater repolarization-delaying effects of IKr block than dogs, because of lower repolarization reserve contributions from IK1 and IKs, emphasizing species-specific determinants of repolarization and the limitations of animal models for human disease.
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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.