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Modulation of hepatic perfusion did not improve recovery from hepatic outflow obstruction

BACKGROUND: Focal hepatic venous outflow obstruction frequently occurs after extended liver resection and leads to a portal hypertension, arterial hypoperfusion and parenchymal necrosis. In this study, we investigated the pharmacological modulation of liver perfusion and hepatic damage in a surgical...

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Autores principales: Arlt, J., Wei, W., Xie, C., Homeyer, A., Settmacher, U., Dahmen, U., Dirsch, O.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5485608/
https://www.ncbi.nlm.nih.gov/pubmed/28651622
http://dx.doi.org/10.1186/s40360-017-0155-4
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author Arlt, J.
Wei, W.
Xie, C.
Homeyer, A.
Settmacher, U.
Dahmen, U.
Dirsch, O.
author_facet Arlt, J.
Wei, W.
Xie, C.
Homeyer, A.
Settmacher, U.
Dahmen, U.
Dirsch, O.
author_sort Arlt, J.
collection PubMed
description BACKGROUND: Focal hepatic venous outflow obstruction frequently occurs after extended liver resection and leads to a portal hypertension, arterial hypoperfusion and parenchymal necrosis. In this study, we investigated the pharmacological modulation of liver perfusion and hepatic damage in a surgical model of hepatic outflow obstruction after extended liver resection by administration of 5 different drugs in comparison to an operative intervention, splenectomy. METHODS: Male inbred Lewis rats (Lew/Crl) were subjected to right median hepatic vein ligation + 70% partial hepatectomy. Treatment consisted of a splenectomy or the application of saline, carvedilol or isosorbide-5-mononitrate (ISMN) (5 mg · kg(−1) respectively 7,2 mg · kg(−1) per gavage 12 h(−1)). The splenectomy was performed during operation. The effect of the treatments on hepatic hemodynamics were measured in non-operated animals, immediately after operation (n = 4/group) and 24 h after operation (n = 5/group). Assessment of hepatic damage (liver enzymes, histology) and liver cell proliferation (BrdU-immunohistochemistry) was performed 24 h after operation. Furthermore sildenafil (10 μg · kg(−1) i.p. 12h(−1)), terlipressin (0.05 mg · kg(−1) i.v. 12 h(−1)) and octreotide (10 μg · kg(−1) s.c. 12 h(−1)) were investigated regarding their effect on hepatic hemodynamics and hepatic damage 24 h after operation (n = 4/group). RESULTS: Carvedilol and ISMN significantly decreased the portal pressure in normal non-operated rats from 11,1 ± 1,1 mmHg (normal rats) to 8,4 ± 0,3 mmHg (carvedilol) respectively 7,4 ± 1,8 mmHg (ISMN). ISMN substantially reduced surgery-induced portal hypertension from 15,4 ± 4,4 mmHg to 9,6 ± 2,3 mmHg. Only splenectomy reduced the portal flow immediately after operation by approximately 25%. No treatment had an immediate effect on the hepatic arterial perfusion. In all treatment groups, portal flow increased by approximately 3-fold within 24 h after operation, whereas hepatic arterial flow decreased substantially. Neither treatment reduced hepatic damage as assessed 24 h after operation. The distribution of proliferating cells appeared very similar in all drug treated groups and the splenectomy group. CONCLUSION: Transient relative reduction of portal pressure did not result in a reduction of hepatic damage. This might be explained by the development of portal hyperperfusion which was accompanied by arterial hypoperfusion. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40360-017-0155-4) contains supplementary material, which is available to authorized users.
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spelling pubmed-54856082017-06-30 Modulation of hepatic perfusion did not improve recovery from hepatic outflow obstruction Arlt, J. Wei, W. Xie, C. Homeyer, A. Settmacher, U. Dahmen, U. Dirsch, O. BMC Pharmacol Toxicol Research Article BACKGROUND: Focal hepatic venous outflow obstruction frequently occurs after extended liver resection and leads to a portal hypertension, arterial hypoperfusion and parenchymal necrosis. In this study, we investigated the pharmacological modulation of liver perfusion and hepatic damage in a surgical model of hepatic outflow obstruction after extended liver resection by administration of 5 different drugs in comparison to an operative intervention, splenectomy. METHODS: Male inbred Lewis rats (Lew/Crl) were subjected to right median hepatic vein ligation + 70% partial hepatectomy. Treatment consisted of a splenectomy or the application of saline, carvedilol or isosorbide-5-mononitrate (ISMN) (5 mg · kg(−1) respectively 7,2 mg · kg(−1) per gavage 12 h(−1)). The splenectomy was performed during operation. The effect of the treatments on hepatic hemodynamics were measured in non-operated animals, immediately after operation (n = 4/group) and 24 h after operation (n = 5/group). Assessment of hepatic damage (liver enzymes, histology) and liver cell proliferation (BrdU-immunohistochemistry) was performed 24 h after operation. Furthermore sildenafil (10 μg · kg(−1) i.p. 12h(−1)), terlipressin (0.05 mg · kg(−1) i.v. 12 h(−1)) and octreotide (10 μg · kg(−1) s.c. 12 h(−1)) were investigated regarding their effect on hepatic hemodynamics and hepatic damage 24 h after operation (n = 4/group). RESULTS: Carvedilol and ISMN significantly decreased the portal pressure in normal non-operated rats from 11,1 ± 1,1 mmHg (normal rats) to 8,4 ± 0,3 mmHg (carvedilol) respectively 7,4 ± 1,8 mmHg (ISMN). ISMN substantially reduced surgery-induced portal hypertension from 15,4 ± 4,4 mmHg to 9,6 ± 2,3 mmHg. Only splenectomy reduced the portal flow immediately after operation by approximately 25%. No treatment had an immediate effect on the hepatic arterial perfusion. In all treatment groups, portal flow increased by approximately 3-fold within 24 h after operation, whereas hepatic arterial flow decreased substantially. Neither treatment reduced hepatic damage as assessed 24 h after operation. The distribution of proliferating cells appeared very similar in all drug treated groups and the splenectomy group. CONCLUSION: Transient relative reduction of portal pressure did not result in a reduction of hepatic damage. This might be explained by the development of portal hyperperfusion which was accompanied by arterial hypoperfusion. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40360-017-0155-4) contains supplementary material, which is available to authorized users. BioMed Central 2017-06-26 /pmc/articles/PMC5485608/ /pubmed/28651622 http://dx.doi.org/10.1186/s40360-017-0155-4 Text en © The Author(s). 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Arlt, J.
Wei, W.
Xie, C.
Homeyer, A.
Settmacher, U.
Dahmen, U.
Dirsch, O.
Modulation of hepatic perfusion did not improve recovery from hepatic outflow obstruction
title Modulation of hepatic perfusion did not improve recovery from hepatic outflow obstruction
title_full Modulation of hepatic perfusion did not improve recovery from hepatic outflow obstruction
title_fullStr Modulation of hepatic perfusion did not improve recovery from hepatic outflow obstruction
title_full_unstemmed Modulation of hepatic perfusion did not improve recovery from hepatic outflow obstruction
title_short Modulation of hepatic perfusion did not improve recovery from hepatic outflow obstruction
title_sort modulation of hepatic perfusion did not improve recovery from hepatic outflow obstruction
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5485608/
https://www.ncbi.nlm.nih.gov/pubmed/28651622
http://dx.doi.org/10.1186/s40360-017-0155-4
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