| A role for asymmetric dimethylarginine in the pathophysiology of portal hypertension in rats with biliary cirrhosis. | |
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MedLine Citation:
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PMID: 16317694 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Reduced intrahepatic endothelial nitric oxide synthase (eNOS) activity contributes to the pathogenesis of portal hypertension (PHT) associated with cirrhosis. We evaluated whether asymmetric dimethylarginine (ADMA), a putative endogenous NOS inhibitor, may be involved in PHT associated with cirrhosis. Two rat models of cirrhosis (thioacetamide [TAA]-induced and bile duct excision [BDE]-induced, n = 10 each), one rat model of PHT without cirrhosis (partial portal vein-ligated [PPVL], n = 10), and sham-operated control rats (n = 10) were studied. We assessed hepatic NOS activity, eNOS protein expression, plasma ADMA levels, and intrahepatic endothelial function. To evaluate intrahepatic endothelial function, concentration-effect curves of acetylcholine were determined in situ in perfused normal rat livers and livers of rats with TAA- or BDE-induced cirrhosis (n = 10) that had been preincubated with either vehicle or ADMA; in addition, measurements of nitrite/nitrate (NOx) and ADMA were made in perfusates. Both models of cirrhosis exhibited decreased hepatic NOS activity. In rats with TAA-induced cirrhosis, this decrease was associated with reduced hepatic eNOS protein levels and immunoreactivity. Rats with BDE-induced cirrhosis had eNOS protein levels comparable to those in control rats but exhibited significantly higher plasma ADMA levels than those in all other groups. In normal perfused liver, ADMA induced impaired endothelium-dependent vasorelaxation and reduced NOx perfusate levels, phenomena that were mimicked by N(G)-nitro-L-arginine-methyl ester. In contrast to perfused livers with cirrhosis induced by TAA, impaired endothelial cell-mediated relaxation in perfused livers with cirrhosis induced by BDE was exacerbated by ADMA and was associated with a decreased rate of removal of ADMA (34.3% +/- 6.0% vs. 70.9% +/- 3.2%). In conclusion, in rats with TAA-induced cirrhosis, decreased eNOS enzyme levels seem to be responsible for impaired NOS activity; in rats with biliary cirrhosis, an endogenous NOS inhibitor, ADMA, may mediate decreased NOS activity. |
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Authors:
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Wim Laleman; Anita Omasta; Marc Van de Casteele; Marcel Zeegers; Ingrid Vander Elst; Lien Van Landeghem; Tamara Severi; Jos van Pelt; Tania Roskams; Johan Fevery; Frederik Nevens |
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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: 42 ISSN: 0270-9139 ISO Abbreviation: Hepatology Publication Date: 2005 Dec |
Date Detail:
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Created Date: 2005-12-05 Completed Date: 2005-12-22 Revised Date: 2006-11-15 |
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: 1382-90 Citation Subset: IM |
Affiliation:
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Laboratories of Hepatology, University Hospital Gasthuisberg, Leuven, Belgium. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Acetylcholine
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pharmacology Animals Arginine / analogs & derivatives*, blood, physiology Hypertension, Portal / etiology*, physiopathology Liver / drug effects, enzymology Liver Cirrhosis, Biliary / complications*, etiology Male NG-Nitroarginine Methyl Ester / pharmacology Nitric Oxide / physiology* Nitric Oxide Synthase Type III / analysis, genetics Rats Rats, Wistar Thioacetamide / toxicity Vasodilation |
| Chemical | |
Reg. No./Substance:
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10102-43-9/Nitric Oxide; 30315-93-6/N,N-dimethylarginine; 50903-99-6/NG-Nitroarginine Methyl Ester; 51-84-3/Acetylcholine; 62-55-5/Thioacetamide; 74-79-3/Arginine; EC 1.14.13.39/Nitric Oxide Synthase Type III |
| Comments/Corrections | |
Comment In:
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Hepatology. 2005 Dec;42(6):1255-7
[PMID:
16317700
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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