Document Detail


Telmisartan plus propranolol improves liver fibrosis and bile duct proliferation in the PSC-like Abcb4-/- mouse model.
MedLine Citation:
PMID:  23247798     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease leading to cirrhosis and cholangiocellular carcinoma. Inhibitors of the renin-angiotensin system or the sympathetic nervous system delay liver fibrogenesis in animal models.
AIMS: We investigated the antifibrotic potential of telmisartan, an angiotensin II type 1 receptor antagonist, and the β-adrenoceptor blocker propranolol in the PSC-like Abcb4 knockout mouse model.
METHODS: Sixty-five Abcb4 (-/-) mice were treated with telmisartan for 3 or 5 months (T) and with telmisartan plus propranolol for 3, 5, or 8 months (TP), or for 2 or 5 months starting with a delay of 3 months (TP delayed). Liver hydroxyproline content, inflammation, fibrosis, and bile duct proliferation were assessed; fibrosis-related molecules were analyzed by real-time polymerase chain reaction and Western blotting.
RESULTS: Compared to controls, telmisartan monotherapy had no significant influence on hydroxyproline; however, telmisartan plus propranolol reduced hydroxyproline (TP 3 months, p = 0.008), fibrosis score (TP 3 months and TP 8 months, p = 0.043 and p = 0.008, respectively; TP delayed 8 months, p < 0.0005), bile duct proliferation (TP 8 months and TP delayed 8 months, p = 0.006 and p < 0.0005, respectively), and procollagen α1(I), endothelin-1, TIMP-1 and MMP3 mRNA as well as α-SMA, CK-19, and TIMP-1 protein.
CONCLUSIONS: Telmisartan plus propranolol reduces liver fibrosis and bile duct proliferation in the PSC-like Abcb4 (-/-) mouse model, even when started at late stages of fibrosis, and may thus represent a novel therapeutic option for cholestatic liver diseases such as PSC.
Authors:
Susanne Mende; Sigrid Schulte; Ingo Strack; Heike Hunt; Margarete Odenthal; Galyna Pryymachuck; Maria Quasdorff; Münevver Demir; Dirk Nierhoff; Hans-Peter Dienes; Tobias Goeser; Hans-Michael Steffen; Ulrich Töx
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-12-18
Journal Detail:
Title:  Digestive diseases and sciences     Volume:  58     ISSN:  1573-2568     ISO Abbreviation:  Dig. Dis. Sci.     Publication Date:  2013 May 
Date Detail:
Created Date:  2013-05-22     Completed Date:  2013-07-22     Revised Date:  2014-01-09    
Medline Journal Info:
Nlm Unique ID:  7902782     Medline TA:  Dig Dis Sci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1271-81     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
Adrenergic beta-Antagonists / pharmacology,  therapeutic use*
Animals
Benzimidazoles / pharmacology,  therapeutic use*
Benzoates / pharmacology,  therapeutic use*
Bile Ducts / drug effects,  pathology
Cholangitis, Sclerosing / drug therapy*,  metabolism
Collagen Type I / metabolism
Cytokines / metabolism
Disease Models, Animal
Drug Evaluation, Preclinical
Drug Therapy, Combination
Liver / drug effects,  pathology
Mice
Mice, Inbred BALB C
Mice, Knockout
Myofibroblasts / metabolism
P-Glycoproteins / genetics
Propranolol / pharmacology,  therapeutic use*
RNA, Messenger / metabolism
Receptor, Angiotensin, Type 1 / therapeutic use*
Chemical
Reg. No./Substance:
0/Adrenergic beta-Antagonists; 0/Benzimidazoles; 0/Benzoates; 0/Collagen Type I; 0/Cytokines; 0/P-Glycoproteins; 0/P-glycoprotein 2; 0/RNA, Messenger; 0/Receptor, Angiotensin, Type 1; 0/collagen type I, alpha 1 chain; 9Y8NXQ24VQ/Propranolol; U5SYW473RQ/telmisartan

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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