ArticlePloS one2014
Inhibiting Na+/K+ ATPase can impair mitochondrial energetics and induce abnormal Ca2+ cycling and automaticity in guinea pig cardiomyocytes.
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 28 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
28 citing papers in PubMed, 54 citations in OpenAlex.
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- Involvement of Oxidative Stress in Mitochondrial Abnormalities During the Development of Heart Disease.Biomedicines · 2025Review
- Article
- Role of NaInternational journal of molecular sciences · 2024Review
- Impact of stress on cardiac phenotypes in mice harboring an ankyrin-B disease variant.The Journal of biological chemistry · 2023Article
- Endothelial cell TRPA1 activity exacerbates cerebral hemorrhage during severe hypertension.Frontiers in molecular biosciences · 2023Article
- Integrating cell morphology with gene expression and chemical structure to aid mitochondrial toxicity detection.Communications biology · 2022Article
- Digitoxin Affects Metabolism, ROS Production and Proliferation in Pancreatic Cancer Cells Differently Depending on the Cell Phenotype.International journal of molecular sciences · 2022Article
- Involvement of Oxidative Stress in the Development of Subcellular Defects and Heart Disease.Biomedicines · 2022Review
- Mitochondria as a target and central hub of energy division during cold stress in insects.Frontiers in zoology · 2022Review
- Resibufogenin Targets the ATP1A1 Signaling Cascade to Induce G2/M Phase Arrest and Inhibit Invasion in Glioma.Frontiers in pharmacology · 2022Article
- Secondary Brain Injury by Oxidative Stress After Cerebral Hemorrhage: Recent Advances.Frontiers in cellular neuroscience · 2022Review
- Astrocyte deletion of α2-Na/K ATPase triggers episodic motor paralysis in mice via a metabolic pathway.Nature communications · 2020Article
- NaInternational journal of molecular sciences · 2020Article
- Role of Oxidation-Dependent CaMKII Activation in the Genesis of Abnormal Action Potentials in Atrial Cardiomyocytes: A Simulation Study.BioMed research international · 2020Article
- Fluoride Exposure Induces Inhibition of Sodium-and Potassium-Activated Adenosine Triphosphatase (NaInternational journal of environmental research and public health · 2019Review
- The Contribution of Fluoride to the Pathogenesis of Eye Diseases: Molecular Mechanisms and Implications for Public Health.International journal of environmental research and public health · 2019Review
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Cardiac glycosides have been used for the treatment of heart failure because of their capabilities of inhibiting Na+/K+ ATPase (NKA), which raises [Na+]i and attenuates Ca2+ extrusion via the Na+/Ca2+ exchanger (NCX), causing [Ca2+]i elevation. The resulting [Ca2+]i accumulation further enhances Ca2+-induced Ca2+ release, generating the positive inotropic effect. However, cardiac glycosides have some toxic and side effects such as arrhythmogenesis, confining their extensive clinical applications. The mechanisms underlying the proarrhythmic effect of glycosides are not fully understood. Here we investigated the mechanisms by which glycosides could cause cardiac arrhythmias via impairing mitochondrial energetics using an integrative computational cardiomyocyte model. In the simulations, the effect of glycosides was mimicked by blocking NKA activity. Results showed that inhibiting NKA not only impaired mitochondrial Ca2+ retention (thus suppressed reactive oxygen species (ROS) scavenging) but also enhanced oxidative phosphorylation (thus increased ROS production) during the transition of increasing workload, causing oxidative stress. Moreover, concurrent blocking of mitochondrial Na+/Ca2+ exchanger, but not enhancing of Ca2+ uniporter, alleviated the adverse effects of NKA inhibition. Intriguingly, NKA inhibition elicited Ca2+ transient and action potential alternans under more stressed conditions such as severe ATP depletion, augmenting its proarrhythmic effect. This computational study provides new insights into the mechanisms underlying cardiac glycoside-induced arrhythmogenesis. The findings suggest that targeting both ion handling and mitochondria could be a very promising strategy to develop new glycoside-based therapies in the treatment of heart failure.
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Registered trials
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.