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Progesterone Regulates Cardiac Repolarization Through a Nongenomic Pathway: An In Vitro Patch-Clamp and Computational Modeling Study
Abstract
Background— Female sex is an independent risk factor for torsade de pointes in long-QT syndrome. In women, QT interval and torsade de pointes risk fluctuate dynamically during the menstrual cycle and pregnancy. Accumulating clinical evidence suggests a role for progesterone; however, the effect of progesterone on cardiac repolarization remains undetermined. Methods and Results— We investigated the effects of progesterone on action potential duration and membrane currents in isolated guinea pig ventricular myocytes. Progesterone rapidly shortened action potential duration, which was attributable mainly to enhancement of the slow delayed rectifier K + current (I Ks ) under basal conditions and inhibition of L-type Ca 2+ currents (I Ca,L ) under cAMP-stimulated conditions. The effects of progesterone were mediated by nitric oxide released via nongenomic activation of endothelial nitric oxide synthase; this signal transduction likely takes place in the caveolae because sucrose density gradient fractionation experiments showed colocalization of the progesterone receptor c-Src, phosphoinositide 3-kinase, Akt, and endothelial nitric oxide synthase with KCNQ1, KCNE1, and Ca V 1.2 in the caveolae fraction. We used computational single-cell and coupled-tissue action potential models incorporating the effects of progesterone on I Ks and I Ca,L ; the model reproduces the fluctuations of cardiac repolarization during the menstrual cycle observed in women and predicts the protective effects of progesterone against rhythm disturbances in congenital and drug-induced long-QT syndrome. Conclusions— Our data show that progesterone modulates cardiac repolarization by nitric oxide produced via a nongenomic pathway. A combination of experimental and computational analyses of progesterone effects provides a framework to understand complex fluctuations of QT interval and torsade de pointes risks in various hormonal states in women.
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“All three studies identified through our search suggested that sex is not a significant modifier of dementia in individuals with AF.88–90”
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Metadata
- Authors
- Nakamura, H., Kurokawa, J., Bai, C.-X., Asada, K., Xu, J., Oren, R. V., Zhu, Z. I., Clancy, C. E., Isobe, M., & Furukawa, T.
- Affiliations
- Cornell University (US)
- ORCID
- Venue
- Circulation
- Published
- 2007-12-18
- Volume
- 116
- Issue
- 25
- Pages
- 2913-2922
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- OpenAlex
- W2128601322
- Cited by
- 190
- References
- 26
- Citations by year
- 2026: 8 · 2025: 9 · 2024: 5 · 2023: 4 · 2022: 4 · 2021: 9 · 2020: 15 · 2019: 8 · 2018: 5 · 2017: 14 · 2016: 15 · 2015: 11 · 2014: 15 · 2013: 9 · 2012: 14
- FWCI
- 7.49
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL085592)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Arrhythmias and Treatments
- Keywords
- progesterone, cardiac repolarization, long QT syndrome, torsades de pointes, non-genomic signaling, nitric oxide, endothelial nitric oxide synthase, slow delayed rectifier potassium current, L-type calcium current, action potential duration, ventricular myocytes, caveolae, menstrual cycle, pregnancy, KCNQ1, KCNE1
- MeSH terms
- Action Potentials, Cyclic AMP, Animals, Female, Guinea Pigs, Long QT Syndrome, Models, Cardiovascular, Myocardial Contraction, Nitric Oxide, Progesterone, Sex Factors, Potassium Channels, Signal Transduction, Torsades de Pointes, Patch-Clamp Techniques, Computational Biology, Myocytes, Cardiac, In Vitro Techniques
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