| Treatment with the leukotriene inhibitor montelukast for 10 days attenuates portal hypertension in rat liver cirrhosis. | |
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MedLine Citation:
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PMID: 20512996 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The mechanisms underlying intrahepatic vasoconstriction are not fully elucidated. Here we investigated the Kupffer cell (KC)-dependent increase in portal pressure by way of actions of vasoconstrictive cysteinyl leukotrienes (Cys-LTs). Liver cirrhosis was induced in rats by bile duct ligation (BDL for 4 weeks; controls: sham-operation) and thioacetamide application (18 weeks). Infusion of leukotriene (LT) C(4) or LTD(4) in isolated perfused livers (20 nM, BDL and sham) demonstrated that LTC(4) is a more relevant vasoconstrictor. In BDL animals the Cys-LT(1) receptor inhibitor montelukast (1 microM) reduced the maximal portal perfusion pressure following LTC(4) or LTD(4) infusion. The infusion of LTC(4) or D(4) in vivo (15 microg/kg b.w.) confirmed LTC(4) as the more relevant vasoconstrictor. Activation of KCs with zymosan (150 microg/mL) in isolated perfused BDL livers increased the portal perfusion pressure markedly, which was attenuated by LT receptor blockade (Ly171883, 20 microM). Cys-LTs in the effluent perfusate increased with KC activation but less with additional blockade of KCs with gadolinium chloride (10 mg/kg body weight, 48 and 24 hours pretreatment). KCs were isolated from normal rat livers and activated with zymosan or lipopolysaccharide at different timepoints. This resulted in an increase in Cys-LT production that was not influenced by preincubation with montelukast (1 microM). Infusion of LTC(4) (20 nM) and the thromboxane analog U46619 (0.1 microM) further enhanced portal pressure, indicating additive effects. Treatment with montelukast for 10 days resulted in an impressive reduction in the basal portal pressure and an attenuation of the KC-dependent increase in portal pressure. CONCLUSION: Activation of isolated KCs produced Cys-LTs. Infusion of Cys-LTs increased portal pressure and, vice versa, treatment with montelukast reduced portal pressure in rat liver cirrhosis. Therefore, montelukast may be of therapeutic benefit for patients with portal hypertension. |
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Authors:
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Christian J Steib; Manfred Bilzer; Mark op den Winkel; Susanne Pfeiler; Anna C Hartmann; Martin Hennenberg; Burkhard G?ke; Alexander L Gerbes |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Hepatology (Baltimore, Md.) Volume: 51 ISSN: 1527-3350 ISO Abbreviation: Hepatology Publication Date: 2010 Jun |
Date Detail:
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Created Date: 2010-05-31 Completed Date: 2010-06-17 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8302946 Medline TA: Hepatology Country: United States |
Other Details:
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Languages: eng Pagination: 2086-96 Citation Subset: IM |
Affiliation:
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Department of Medicine II (Gastroenterology and Hepatology), Liver Center Munich, University of Munich, Grosshadern, Munich, Germany. christian.steib@med.uni-muenchen.de |
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| MeSH Terms | |
Descriptor/Qualifier:
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Acetates
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therapeutic use* Animals Hypertension, Portal / drug therapy*, etiology, metabolism Kupffer Cells / metabolism Leukotriene Antagonists / therapeutic use* Leukotrienes / metabolism* Ligation Liver / pathology Liver Cirrhosis / complications*, pathology Male Quinolines / therapeutic use* Rats Rats, Sprague-Dawley Thioacetamide Thromboxane A2 / metabolism rho-Associated Kinases / metabolism |
| Chemical | |
Reg. No./Substance:
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0/Acetates; 0/Leukotriene Antagonists; 0/Leukotrienes; 0/Quinolines; 158966-92-8/montelukast; 57576-52-0/Thromboxane A2; 62-55-5/Thioacetamide; EC 2.7.11.1/rho-Associated Kinases |
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