The DOI matches its Crossref record; 26 of the 26 references it cites were found in a registry or an index.
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“All three studies identified through our search suggested that sex is not a significant modifier of dementia in individuals with AF.88–90”
From Atrial fibrillation in women: epidemiology, pathophysiology, presentation, and prognosis (2016) · cites this paper as [90]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Calcium channel modulation by neurotransmitters, enzymes and drugs
REUTER, H. (1983) · Nature · doi:10.1038/301569a0 · Cited by 1,266
Female Gender as a Risk Factor for Torsades de Pointes Associated With Cardiovascular Drugs
Makkar, R. (1993) · JAMA · doi:10.1001/jama.270.21.2590 · Cited by 972
Mutations in the hminK gene cause long QT syndrome and suppress lKs function
Splawski, I., Tristani‐Firouzi, M., Lehmann, M. H., Sanguinetti, M. C., & Keating, M. T. (1997) · Nature Genetics · doi:10.1038/ng1197-338 · Cited by 767
Marx, S. O., Kurokawa, J., Reiken, S. R., Motoike, H. K., D'Armiento, J. M., Marks, A. R., & Kass, R. S. (2002) · Science · doi:10.1126/science.1066843 · Cited by 719
Self-citationSchwartz, P. J., Priori, S. G., Cerrone, M., Spazzolini, C., Odero, A., Napolitano, C., Bloise, R., Ferrari, G. M. D., Klersy, C., Moss, A. J., et al. (2004) · Circulation · doi:10.1161/01.cir.0000125523.14403.1e · Cited by 686
Locati, E. H., Zaręba, W., Moss, A. J., Schwartz, P. J., Vincent, G. M., Lehmann, M. H., Towbin, J. A., Priori, S. G., Napolitano, C., Robinson, J. L., et al. (1998) · Circulation · doi:10.1161/01.cir.97.22.2237 · Cited by 490
Action Potential and Contractility Changes in [Na+]i Overloaded Cardiac Myocytes: A Simulation Study
Faber, G. M., & Rudy, Y. (2000) · Biophysical Journal · doi:10.1016/s0006-3495(00)76783-x · Cited by 439
Long QT Syndrome and Pregnancy
Seth, R., Moss, A. J., McNitt, S. A., Zaręba, W., Andrews, M. L., Qi, M., Robinson, J. L., Goldenberg, I., Ackerman, M. J., Benhorin, J., et al. (2007) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2006.09.054 · Cited by 350
Regulation of a Heart Potassium Channel by Protein Kinase A and C
Walsh, K. B., & Kass, R. S. (1988) · Science · doi:10.1126/science.2845575 · Cited by 321
Long QT syndrome: reduced repolarization reserve and the genetic link
Roden, D. M. (2005) · Journal of Internal Medicine · doi:10.1111/j.1365-2796.2005.01589.x · Cited by 318
Drug-Induced QT Prolongation in Women During the Menstrual Cycle
Rodríguez, I. (2001) · JAMA · doi:10.1001/jama.285.10.1322 · Cited by 315
Predicting drug–hERG channel interactions that cause acquired long QT syndrome
Sanguinetti, M. C., & Mitcheson, J. S. (2005) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2005.01.003 · Cited by 300
Nontranscriptional Regulation of Cardiac Repolarization Currents by Testosterone
Bai, C., Kurokawa, J., Tamagawa, M., Nakaya, H., & Furukawa, T. (2005) · Circulation · doi:10.1161/circulationaha.104.523217 · Cited by 254
Self-citationThe influence of menstrual cycle phase on skeletal muscle contractile characteristics in humans
de Jonge, X. J., Boot, C. R. L., Thom, J. M., Ruell, P. A., & Thompson, M. W. (2001) · The Journal of Physiology · doi:10.1111/j.1469-7793.2001.0161m.x · Cited by 246
Bayaa, M., Booth, R. A., Sheng, Y., & Liu, X. J. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.220302597 · Cited by 215
Influence of Menstrual Cycle on QT Interval Dynamics
Nakagawa, M., Ooie, T., Takahashi, N., Taniguchi, Y., Anan, F., Yonemochi, H., & Saikawa, T. (2006) · Pacing and Clinical Electrophysiology · doi:10.1111/j.1540-8159.2006.00407.x · Cited by 174
Autonomic Control of Cardiac Action Potentials
Terrenoire, C., Clancy, C. E., Cormier, J. W., Sampson, K. J., & Kass, R. S. (2005) · Circulation Research · doi:10.1161/01.res.0000160555.58046.9a · Cited by 165
Self-citationEhring, G. R., Kerschbaum, H. H., Eder, C., Neben, A. L., Fanger, C. M., Khoury, R. M., Negulescu, P. A., & Cahalan, M. D. (1998) · The Journal of Experimental Medicine · doi:10.1084/jem.188.9.1593 · Cited by 163
Requirement of subunit expression for cAMP-mediated regulation of a heart potassium channel
Kurokawa, J., Chen, L., & Kass, R. S. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0434935100 · Cited by 131
Self-citationSpecies- and tissue-dependent effects of NO and cyclic GMP on cardiac ion channels
Fischmeister, R., Castro, L. R., Abi‐Gerges, A., Rochais, F., & Vandecasteele, G. (2005) · Comparative Biochemistry and Physiology Part A Molecular & Integrative Physiology · doi:10.1016/j.cbpb.2005.04.012 · Cited by 125
Bai, C., Takahashi, K., Masumiya, H., Sawanobori, T., & Furukawa, T. (2004) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0705814 · Cited by 105
Self-citationEstrogen and Progestin Use and the QT Interval in Postmenopausal Women
Kadish, A. H., Greenland, P., Limacher, M. C., Frishman, W. H., Daugherty, S. A., & Schwartz, J. B. (2004) · Annals of Noninvasive Electrocardiology · doi:10.1111/j.1542-474x.2004.94580.x · Cited by 105
Furukawa, T., Bai, C., Kaihara, A., Ozaki, E., Kawano, T., Nakaya, Y., Awais, M., Sato, M., Umezawa, Y., & Kurokawa, J. (2006) · Molecular Pharmacology · doi:10.1124/mol.106.028134 · Cited by 101
Self-citationK+ Channel Structure-Activity Relationships and Mechanisms of Drug-Induced QT Prolongation
Clancy, C. E., Kurokawa, J., Tateyama, M., Wehrens, X. H. T., & Kass, R. S. (2003) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.43.100901.140245 · Cited by 78
Self-citationLilley, K. G., Epping, R., & Hafner, L. M. (1997) · PubMed · Cited by 33
Mendiberri, J., Rauschemberger, M. B., Sellés, J., & Massheimer, V. (2005) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2005.09.012 · Cited by 19
Cited by
Sorted by citations
hERG K + Channels: Structure, Function, and Clinical Significance
Vandenberg, J. I., Perry, M., Perrin, M. J., Mann, S. A., Ke, Y., & Hill, A. P. (2012) · Physiological Reviews · doi:10.1152/physrev.00036.2011 · Cited by 720
Andrade, J. G., Aguilar, M., Atzema, C. L., Bell, A., Cairns, J. A., Cheung, C. C., Cox, J. L., Dorian, P., Gladstone, D. J., Healey, J. S., et al. (2020) · Canadian Journal of Cardiology · doi:10.1016/j.cjca.2020.09.001 · Cited by 593
Atrial fibrillation in women: epidemiology, pathophysiology, presentation, and prognosis
Ko, D., Rahman, F., Schnabel, R. B., Yin, X., Benjamin, E. J., & Christophersen, I. E. (2016) · Nature Reviews Cardiology · doi:10.1038/nrcardio.2016.45 · Cited by 353
Varró, A., Tomek, J., Nagy, N., Virág, L., Passini, E., Rodríguez, B., & Baczkó, I. (2020) · Physiological Reviews · doi:10.1152/physrev.00024.2019 · Cited by 272
Molecular Pathophysiology of Congenital Long QT Syndrome
Bohnen, M. S., Peng, G., Robey, S., Terrenoire, C., Iyer, V. R., Sampson, K. J., & Kass, R. S. (2016) · Physiological Reviews · doi:10.1152/physrev.00008.2016 · Cited by 174
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
