Please use this identifier to cite or link to this item: http://ahro.austin.org.au/austinjspui/handle/1/10807
Title: Portal pressure responses and angiotensin peptide production in rat liver are determined by relative activity of ACE and ACE2.
Authors: Herath, Chandana B;Lubel, John S;Jia, Zhiyuan;Velkoska, Elena;Casley, David J;Brown, Lindsay;Tikellis, Christos;Burrell, Louise M;Angus, Peter W
Affiliation: Department of Medicine, The University of Melbourne, Austin Repatriation Hospital, Heidelberg Heights, Victoria, Australia. cherath@unimelb.edu.au
Issue Date: 23-Apr-2009
Citation: American Journal of Physiology. Gastrointestinal and Liver Physiology 2009; 297(1): G98-G106
Abstract: Angiotensin converting enzyme (ACE) 2 activity and angiotensin-(1-7) [Ang-(1-7)] levels are increased in experimental cirrhosis; however, the pathways of hepatic Ang-(1-7) production have not been studied. This study investigated the role of ACE2, ACE, and neutral endopeptidase (NEP) in the hepatic formation of Ang-(1-7) from angiotensin I (Ang I) and Ang II and their effects on portal resistance. Ang I or Ang II were administered to rat bile duct ligated (BDL) and control livers alone and in combination with the ACE inhibitor lisinopril, the ACE and NEP inhibitor omapatrilat, or the ACE2 inhibitor MLN4760 (n = 5 per group). BDL markedly upregulated ACE, ACE2, and NEP. Ang-(1-7) was produced from Ang II in healthy and in BDL livers and was increased following ACE inhibition and decreased by ACE2 inhibition. In contrast, Ang-(1-7) production from Ang I was minimal and not affected by ACE or NEP inhibition. Surprisingly, ACE2 inhibition in BDLs dramatically increased Ang-(1-7) production from Ang I, an effect abolished by ACE2/NEP inhibition. Ang II and Ang I induced greater portal pressure increases in BDL livers than controls. The effects of Ang I were closely correlated with Ang II production and were strongly attenuated by both ACE and ACE/NEP inhibition. These findings show that the major substrate for hepatic production of Ang-(1-7) is Ang II and this is catalyzed by ACE2. Ang I is largely converted to Ang II by ACE, and net conversion of Ang I to Ang-(1-7) is small. NEP has the ability to generate large amounts of Ang-(1-7) in the BDL liver from Ang I only when ACE2 activity is greatly decreased or inhibited.
Internal ID Number: 19389807
URI: http://ahro.austin.org.au/austinjspui/handle/1/10807
DOI: 10.1152/ajpgi.00045.2009
URL: http://www.ncbi.nlm.nih.gov/pubmed/19389807
Type: Journal Article
Subjects: Angiotensin I.metabolism
Angiotensin II.metabolism
Angiotensin-Converting Enzyme Inhibitors.pharmacology
Angiotensins.administration & dosage.metabolism
Animals
Common Bile Duct.surgery
Gene Expression Regulation, Enzymologic
Imidazoles.pharmacology
Leucine.analogs & derivatives.pharmacology
Ligation
Lisinopril.pharmacology
Liver.blood supply.drug effects.enzymology.pathology
Liver Cirrhosis, Experimental.drug therapy.enzymology.etiology.physiopathology
Male
Neprilysin.antagonists & inhibitors.metabolism
Peptide Fragments.metabolism
Peptidyl-Dipeptidase A.genetics.metabolism
Portal Pressure.drug effects
Pyridines.pharmacology
Rats
Rats, Sprague-Dawley
Renin-Angiotensin System.genetics
Severity of Illness Index
Thiazepines.pharmacology
Time Factors
Vascular Resistance
Appears in Collections:Journal articles

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