Cargando…

Labetalol and soluble endoglin aggravate bile acid retention in mice with ethinylestradiol-induced cholestasis

Labetalol is used for the therapy of hypertension in preeclampsia. Preeclampsia is characterized by high soluble endoglin (sEng) concentration in plasma and coincides with intrahepatic cholestasis during pregnancy (ICP), which threatens the fetus with the toxicity of cumulating bile acids (BA). Ther...

Descripción completa

Detalles Bibliográficos
Autores principales: Cristina Igreja Sá, Ivone, Tripska, Katarina, Alaei Faradonbeh, Fatemeh, Hroch, Milos, Lastuvkova, Hana, Schreiberova, Jolana, Kacerovsky, Marian, Pericacho, Miguel, Nachtigal, Petr, Micuda, Stanislav
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9909014/
https://www.ncbi.nlm.nih.gov/pubmed/36778021
http://dx.doi.org/10.3389/fphar.2023.1116422
_version_ 1784884477307125760
author Cristina Igreja Sá, Ivone
Tripska, Katarina
Alaei Faradonbeh, Fatemeh
Hroch, Milos
Lastuvkova, Hana
Schreiberova, Jolana
Kacerovsky, Marian
Pericacho, Miguel
Nachtigal, Petr
Micuda, Stanislav
author_facet Cristina Igreja Sá, Ivone
Tripska, Katarina
Alaei Faradonbeh, Fatemeh
Hroch, Milos
Lastuvkova, Hana
Schreiberova, Jolana
Kacerovsky, Marian
Pericacho, Miguel
Nachtigal, Petr
Micuda, Stanislav
author_sort Cristina Igreja Sá, Ivone
collection PubMed
description Labetalol is used for the therapy of hypertension in preeclampsia. Preeclampsia is characterized by high soluble endoglin (sEng) concentration in plasma and coincides with intrahepatic cholestasis during pregnancy (ICP), which threatens the fetus with the toxicity of cumulating bile acids (BA). Therefore, we hypothesized that both labetalol and increased sEng levels worsen BA cumulation in estrogen-induced cholestasis. C57BL/6J, transgenic mice overexpressing human sEng, and their wild-type littermates were administrated with ethinylestradiol (EE, 10 mg/kg s.c., the mice model of ICP) and labetalol (10 mg/kg s.c.) for 5 days with sample collection and analysis. Plasma was also taken from healthy pregnant women and patients with ICP. Administration of labetalol to mice with EE cholestasis aggravated the increase in BA plasma concentrations by induction of hepatic Mrp4 efflux transporter. Labetalol potentiated the increment of sEng plasma levels induced by estrogen. Increased plasma levels of sEng were also observed in patients with ICP. Moreover, increased plasma levels of human sEng in transgenic mice aggravated estrogen-induced cholestasis in labetalol-treated mice and increased BA concentration in plasma via enhanced reabsorption of BAs in the ileum due to the upregulation of the Asbt transporter. In conclusion, we demonstrated that labetalol increases plasma concentrations of BAs in estrogen-induced cholestasis, and sEng aggravates this retention. Importantly, increased sEng levels in experimental and clinical forms of ICPs might present a novel mechanism explaining the coincidence of ICP with preeclampsia. Our data encourage BA monitoring in the plasma of pregnant women with preeclampsia and labetalol therapy.
format Online
Article
Text
id pubmed-9909014
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-99090142023-02-10 Labetalol and soluble endoglin aggravate bile acid retention in mice with ethinylestradiol-induced cholestasis Cristina Igreja Sá, Ivone Tripska, Katarina Alaei Faradonbeh, Fatemeh Hroch, Milos Lastuvkova, Hana Schreiberova, Jolana Kacerovsky, Marian Pericacho, Miguel Nachtigal, Petr Micuda, Stanislav Front Pharmacol Pharmacology Labetalol is used for the therapy of hypertension in preeclampsia. Preeclampsia is characterized by high soluble endoglin (sEng) concentration in plasma and coincides with intrahepatic cholestasis during pregnancy (ICP), which threatens the fetus with the toxicity of cumulating bile acids (BA). Therefore, we hypothesized that both labetalol and increased sEng levels worsen BA cumulation in estrogen-induced cholestasis. C57BL/6J, transgenic mice overexpressing human sEng, and their wild-type littermates were administrated with ethinylestradiol (EE, 10 mg/kg s.c., the mice model of ICP) and labetalol (10 mg/kg s.c.) for 5 days with sample collection and analysis. Plasma was also taken from healthy pregnant women and patients with ICP. Administration of labetalol to mice with EE cholestasis aggravated the increase in BA plasma concentrations by induction of hepatic Mrp4 efflux transporter. Labetalol potentiated the increment of sEng plasma levels induced by estrogen. Increased plasma levels of sEng were also observed in patients with ICP. Moreover, increased plasma levels of human sEng in transgenic mice aggravated estrogen-induced cholestasis in labetalol-treated mice and increased BA concentration in plasma via enhanced reabsorption of BAs in the ileum due to the upregulation of the Asbt transporter. In conclusion, we demonstrated that labetalol increases plasma concentrations of BAs in estrogen-induced cholestasis, and sEng aggravates this retention. Importantly, increased sEng levels in experimental and clinical forms of ICPs might present a novel mechanism explaining the coincidence of ICP with preeclampsia. Our data encourage BA monitoring in the plasma of pregnant women with preeclampsia and labetalol therapy. Frontiers Media S.A. 2023-01-26 /pmc/articles/PMC9909014/ /pubmed/36778021 http://dx.doi.org/10.3389/fphar.2023.1116422 Text en Copyright © 2023 Cristina Igreja Sá, Tripska, Alaei Faradonbeh, Hroch, Lastuvkova, Schreiberova, Kacerovsky, Pericacho, Nachtigal and Micuda. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Cristina Igreja Sá, Ivone
Tripska, Katarina
Alaei Faradonbeh, Fatemeh
Hroch, Milos
Lastuvkova, Hana
Schreiberova, Jolana
Kacerovsky, Marian
Pericacho, Miguel
Nachtigal, Petr
Micuda, Stanislav
Labetalol and soluble endoglin aggravate bile acid retention in mice with ethinylestradiol-induced cholestasis
title Labetalol and soluble endoglin aggravate bile acid retention in mice with ethinylestradiol-induced cholestasis
title_full Labetalol and soluble endoglin aggravate bile acid retention in mice with ethinylestradiol-induced cholestasis
title_fullStr Labetalol and soluble endoglin aggravate bile acid retention in mice with ethinylestradiol-induced cholestasis
title_full_unstemmed Labetalol and soluble endoglin aggravate bile acid retention in mice with ethinylestradiol-induced cholestasis
title_short Labetalol and soluble endoglin aggravate bile acid retention in mice with ethinylestradiol-induced cholestasis
title_sort labetalol and soluble endoglin aggravate bile acid retention in mice with ethinylestradiol-induced cholestasis
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9909014/
https://www.ncbi.nlm.nih.gov/pubmed/36778021
http://dx.doi.org/10.3389/fphar.2023.1116422
work_keys_str_mv AT cristinaigrejasaivone labetalolandsolubleendoglinaggravatebileacidretentioninmicewithethinylestradiolinducedcholestasis
AT tripskakatarina labetalolandsolubleendoglinaggravatebileacidretentioninmicewithethinylestradiolinducedcholestasis
AT alaeifaradonbehfatemeh labetalolandsolubleendoglinaggravatebileacidretentioninmicewithethinylestradiolinducedcholestasis
AT hrochmilos labetalolandsolubleendoglinaggravatebileacidretentioninmicewithethinylestradiolinducedcholestasis
AT lastuvkovahana labetalolandsolubleendoglinaggravatebileacidretentioninmicewithethinylestradiolinducedcholestasis
AT schreiberovajolana labetalolandsolubleendoglinaggravatebileacidretentioninmicewithethinylestradiolinducedcholestasis
AT kacerovskymarian labetalolandsolubleendoglinaggravatebileacidretentioninmicewithethinylestradiolinducedcholestasis
AT pericachomiguel labetalolandsolubleendoglinaggravatebileacidretentioninmicewithethinylestradiolinducedcholestasis
AT nachtigalpetr labetalolandsolubleendoglinaggravatebileacidretentioninmicewithethinylestradiolinducedcholestasis
AT micudastanislav labetalolandsolubleendoglinaggravatebileacidretentioninmicewithethinylestradiolinducedcholestasis