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Tezosentan reduces the microvascular filtration coefficient in isolated lungs from rats subjected to cecum ligation and puncture

INTRODUCTION: We recently demonstrated that the non-selective endothelin-1 (ET-1) receptor blocker tezosentan antagonizes ovine acute lung injury (ALI) following infusion of endotoxin or ET-1 by reducing the enhanced lung microvascular pressure, although we could not exclude the possibility of a sim...

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Autores principales: Kuklin, Vladimir, Sovershaev, Mikhail, Andreasen, Thomas, Skogen, Vegard, Ytrehus, Kirsti, Bjertnaes, Lars
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2005
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1413997/
https://www.ncbi.nlm.nih.gov/pubmed/16280068
http://dx.doi.org/10.1186/cc3882
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author Kuklin, Vladimir
Sovershaev, Mikhail
Andreasen, Thomas
Skogen, Vegard
Ytrehus, Kirsti
Bjertnaes, Lars
author_facet Kuklin, Vladimir
Sovershaev, Mikhail
Andreasen, Thomas
Skogen, Vegard
Ytrehus, Kirsti
Bjertnaes, Lars
author_sort Kuklin, Vladimir
collection PubMed
description INTRODUCTION: We recently demonstrated that the non-selective endothelin-1 (ET-1) receptor blocker tezosentan antagonizes ovine acute lung injury (ALI) following infusion of endotoxin or ET-1 by reducing the enhanced lung microvascular pressure, although we could not exclude the possibility of a simultaneous decline in microvascular permeability. In the present study, our aim was to find out if tezosentan reverses the rise in microvascular filtration coefficient (Kfc) in rat lungs that have been isolated and perfused 12 h after cecum ligation and puncture (CLP) or infusion of ET-1. METHODS: Wistar rats (n = 42) were subjected to CLP. Postoperatively, rats were randomized to a CLP group (n = 7) and a CLP + tezosentan group (n = 7); the latter received tezosentan 30 mg/kg. A sham-operated group (n = 5) underwent laparotomy without CLP. Twelve hours postoperatively, the lungs were isolated and perfused with blood from similarly treated rats that also were used to assess plasma concentration of ET-1 and protein kinase Cα (PKCα) in lung tissue. Additionally, isolated blood perfused lungs from healthy rats were randomized to a control group (n = 8), an ET-1 group (n = 7) subjected to pulmonary arterial injection of ET-1 10 nM, and an ET-1 + tezosentan group (n = 7) that received tezosentan 30 mg/kg. All lung preparations received papaverine 0.1 μg/kg added to the perfusate for vasoplegia. Pulmonary hemodynamic variables, Kfc and lung compliance (C(L)) were assessed. RESULTS: After CLP, the plasma concentration of ET-1 increased. Papaverine abolished the vasoconstrictor response to ET-1 and the pulmonary vascular pressures remained close to baseline throughout the experiments. Both CLP and injection of ET-1 caused significant changes in Kfc and C(L )that were prevented in tezosentan-treated rats. Compared to sham-operated animals, CLP increased the content of PKCα by 50% and 70% in the cytosolic and the membrane fractions of lung tissue homogenates, respectively. Tezosentan prevented the upregulation of PKCα in the membrane fraction. CONCLUSION: In rat lungs isolated and perfused after CLP, tezosentan precludes both the increase in Kfc and the upregulation of PKCα in the membrane fraction of lung tissue.
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spelling pubmed-14139972006-03-28 Tezosentan reduces the microvascular filtration coefficient in isolated lungs from rats subjected to cecum ligation and puncture Kuklin, Vladimir Sovershaev, Mikhail Andreasen, Thomas Skogen, Vegard Ytrehus, Kirsti Bjertnaes, Lars Crit Care Research INTRODUCTION: We recently demonstrated that the non-selective endothelin-1 (ET-1) receptor blocker tezosentan antagonizes ovine acute lung injury (ALI) following infusion of endotoxin or ET-1 by reducing the enhanced lung microvascular pressure, although we could not exclude the possibility of a simultaneous decline in microvascular permeability. In the present study, our aim was to find out if tezosentan reverses the rise in microvascular filtration coefficient (Kfc) in rat lungs that have been isolated and perfused 12 h after cecum ligation and puncture (CLP) or infusion of ET-1. METHODS: Wistar rats (n = 42) were subjected to CLP. Postoperatively, rats were randomized to a CLP group (n = 7) and a CLP + tezosentan group (n = 7); the latter received tezosentan 30 mg/kg. A sham-operated group (n = 5) underwent laparotomy without CLP. Twelve hours postoperatively, the lungs were isolated and perfused with blood from similarly treated rats that also were used to assess plasma concentration of ET-1 and protein kinase Cα (PKCα) in lung tissue. Additionally, isolated blood perfused lungs from healthy rats were randomized to a control group (n = 8), an ET-1 group (n = 7) subjected to pulmonary arterial injection of ET-1 10 nM, and an ET-1 + tezosentan group (n = 7) that received tezosentan 30 mg/kg. All lung preparations received papaverine 0.1 μg/kg added to the perfusate for vasoplegia. Pulmonary hemodynamic variables, Kfc and lung compliance (C(L)) were assessed. RESULTS: After CLP, the plasma concentration of ET-1 increased. Papaverine abolished the vasoconstrictor response to ET-1 and the pulmonary vascular pressures remained close to baseline throughout the experiments. Both CLP and injection of ET-1 caused significant changes in Kfc and C(L )that were prevented in tezosentan-treated rats. Compared to sham-operated animals, CLP increased the content of PKCα by 50% and 70% in the cytosolic and the membrane fractions of lung tissue homogenates, respectively. Tezosentan prevented the upregulation of PKCα in the membrane fraction. CONCLUSION: In rat lungs isolated and perfused after CLP, tezosentan precludes both the increase in Kfc and the upregulation of PKCα in the membrane fraction of lung tissue. BioMed Central 2005 2005-10-18 /pmc/articles/PMC1413997/ /pubmed/16280068 http://dx.doi.org/10.1186/cc3882 Text en Copyright © 2005 Kuklin et al.; licensee BioMed Central Ltd.
spellingShingle Research
Kuklin, Vladimir
Sovershaev, Mikhail
Andreasen, Thomas
Skogen, Vegard
Ytrehus, Kirsti
Bjertnaes, Lars
Tezosentan reduces the microvascular filtration coefficient in isolated lungs from rats subjected to cecum ligation and puncture
title Tezosentan reduces the microvascular filtration coefficient in isolated lungs from rats subjected to cecum ligation and puncture
title_full Tezosentan reduces the microvascular filtration coefficient in isolated lungs from rats subjected to cecum ligation and puncture
title_fullStr Tezosentan reduces the microvascular filtration coefficient in isolated lungs from rats subjected to cecum ligation and puncture
title_full_unstemmed Tezosentan reduces the microvascular filtration coefficient in isolated lungs from rats subjected to cecum ligation and puncture
title_short Tezosentan reduces the microvascular filtration coefficient in isolated lungs from rats subjected to cecum ligation and puncture
title_sort tezosentan reduces the microvascular filtration coefficient in isolated lungs from rats subjected to cecum ligation and puncture
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1413997/
https://www.ncbi.nlm.nih.gov/pubmed/16280068
http://dx.doi.org/10.1186/cc3882
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