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Ursodeoxycholic acid prevents ventricular conduction slowing and arrhythmia by restoring T-type calcium current in fetuses during cholestasis

BACKGROUND: Increased maternal serum bile acid concentrations in intrahepatic cholestasis of pregnancy (ICP) are associated with fetal cardiac arrhythmias. Ursodeoxycholic acid (UDCA) has been shown to demonstrate anti-arrhythmic properties via preventing ICP-associated cardiac conduction slowing an...

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Autores principales: Adeyemi, Oladipupo, Alvarez-Laviada, Anita, Schultz, Francisca, Ibrahim, Effendi, Trauner, Michael, Williamson, Catherine, Glukhov, Alexey V., Gorelik, Julia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5608194/
https://www.ncbi.nlm.nih.gov/pubmed/28934223
http://dx.doi.org/10.1371/journal.pone.0183167
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author Adeyemi, Oladipupo
Alvarez-Laviada, Anita
Schultz, Francisca
Ibrahim, Effendi
Trauner, Michael
Williamson, Catherine
Glukhov, Alexey V.
Gorelik, Julia
author_facet Adeyemi, Oladipupo
Alvarez-Laviada, Anita
Schultz, Francisca
Ibrahim, Effendi
Trauner, Michael
Williamson, Catherine
Glukhov, Alexey V.
Gorelik, Julia
author_sort Adeyemi, Oladipupo
collection PubMed
description BACKGROUND: Increased maternal serum bile acid concentrations in intrahepatic cholestasis of pregnancy (ICP) are associated with fetal cardiac arrhythmias. Ursodeoxycholic acid (UDCA) has been shown to demonstrate anti-arrhythmic properties via preventing ICP-associated cardiac conduction slowing and development of reentrant arrhythmias, although the cellular mechanism is still being elucidated. METHODS: High-resolution fluorescent optical mapping of electrical activity and electrocardiogram measurements were used to characterize effects of UDCA on one-day-old neonatal and adult female Langendorff-perfused rat hearts. ICP was modelled by perfusion of taurocholic acid (TC, 400μM). Whole-cell calcium currents were recorded from neonatal rat and human fetal cardiomyocytes. RESULTS: TC significantly prolonged the PR interval by 11.0±3.5% (P<0.05) and slowed ventricular conduction velocity (CV) by 38.9±5.1% (P<0.05) exclusively in neonatal and not in maternal hearts. A similar CV decline was observed with the selective T-type calcium current (I(Ca,T)) blocker mibefradil 1μM (23.0±6.2%, P<0.05), but not with the L-type calcium current (I(Ca,L)) blocker nifedipine 1μM (6.9±6.6%, NS). The sodium channel blocker lidocaine (30μM) reduced CV by 60.4±4.5% (P<0.05). UDCA co-treatment was protective against CV slowing induced by TC and mibefradil, but not against lidocaine. UDCA prevented the TC-induced reduction in the I(Ca,T) density in both isolated human fetal (−10.2±1.5 versus −5.5±0.9 pA/pF, P<0.05) and neonatal rat ventricular myocytes (−22.3±1.1 versus −9.6±0.8 pA/pF, P<0.0001), whereas UDCA had limited efficacy on the I(Ca,L). CONCLUSION: Our findings demonstrate that I(Ca,T) plays a significant role in ICP-associated fetal cardiac conduction slowing and arrhythmogenesis, and is an important component of the fetus-specific anti-arrhythmic activity of UDCA.
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spelling pubmed-56081942017-10-09 Ursodeoxycholic acid prevents ventricular conduction slowing and arrhythmia by restoring T-type calcium current in fetuses during cholestasis Adeyemi, Oladipupo Alvarez-Laviada, Anita Schultz, Francisca Ibrahim, Effendi Trauner, Michael Williamson, Catherine Glukhov, Alexey V. Gorelik, Julia PLoS One Research Article BACKGROUND: Increased maternal serum bile acid concentrations in intrahepatic cholestasis of pregnancy (ICP) are associated with fetal cardiac arrhythmias. Ursodeoxycholic acid (UDCA) has been shown to demonstrate anti-arrhythmic properties via preventing ICP-associated cardiac conduction slowing and development of reentrant arrhythmias, although the cellular mechanism is still being elucidated. METHODS: High-resolution fluorescent optical mapping of electrical activity and electrocardiogram measurements were used to characterize effects of UDCA on one-day-old neonatal and adult female Langendorff-perfused rat hearts. ICP was modelled by perfusion of taurocholic acid (TC, 400μM). Whole-cell calcium currents were recorded from neonatal rat and human fetal cardiomyocytes. RESULTS: TC significantly prolonged the PR interval by 11.0±3.5% (P<0.05) and slowed ventricular conduction velocity (CV) by 38.9±5.1% (P<0.05) exclusively in neonatal and not in maternal hearts. A similar CV decline was observed with the selective T-type calcium current (I(Ca,T)) blocker mibefradil 1μM (23.0±6.2%, P<0.05), but not with the L-type calcium current (I(Ca,L)) blocker nifedipine 1μM (6.9±6.6%, NS). The sodium channel blocker lidocaine (30μM) reduced CV by 60.4±4.5% (P<0.05). UDCA co-treatment was protective against CV slowing induced by TC and mibefradil, but not against lidocaine. UDCA prevented the TC-induced reduction in the I(Ca,T) density in both isolated human fetal (−10.2±1.5 versus −5.5±0.9 pA/pF, P<0.05) and neonatal rat ventricular myocytes (−22.3±1.1 versus −9.6±0.8 pA/pF, P<0.0001), whereas UDCA had limited efficacy on the I(Ca,L). CONCLUSION: Our findings demonstrate that I(Ca,T) plays a significant role in ICP-associated fetal cardiac conduction slowing and arrhythmogenesis, and is an important component of the fetus-specific anti-arrhythmic activity of UDCA. Public Library of Science 2017-09-21 /pmc/articles/PMC5608194/ /pubmed/28934223 http://dx.doi.org/10.1371/journal.pone.0183167 Text en https://creativecommons.org/publicdomain/zero/1.0/ This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 (https://creativecommons.org/publicdomain/zero/1.0/) public domain dedication.
spellingShingle Research Article
Adeyemi, Oladipupo
Alvarez-Laviada, Anita
Schultz, Francisca
Ibrahim, Effendi
Trauner, Michael
Williamson, Catherine
Glukhov, Alexey V.
Gorelik, Julia
Ursodeoxycholic acid prevents ventricular conduction slowing and arrhythmia by restoring T-type calcium current in fetuses during cholestasis
title Ursodeoxycholic acid prevents ventricular conduction slowing and arrhythmia by restoring T-type calcium current in fetuses during cholestasis
title_full Ursodeoxycholic acid prevents ventricular conduction slowing and arrhythmia by restoring T-type calcium current in fetuses during cholestasis
title_fullStr Ursodeoxycholic acid prevents ventricular conduction slowing and arrhythmia by restoring T-type calcium current in fetuses during cholestasis
title_full_unstemmed Ursodeoxycholic acid prevents ventricular conduction slowing and arrhythmia by restoring T-type calcium current in fetuses during cholestasis
title_short Ursodeoxycholic acid prevents ventricular conduction slowing and arrhythmia by restoring T-type calcium current in fetuses during cholestasis
title_sort ursodeoxycholic acid prevents ventricular conduction slowing and arrhythmia by restoring t-type calcium current in fetuses during cholestasis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5608194/
https://www.ncbi.nlm.nih.gov/pubmed/28934223
http://dx.doi.org/10.1371/journal.pone.0183167
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