Document Detail

Amiloride reduces portal hypertension in rat liver cirrhosis.
MedLine Citation:
PMID:  20551467     Owner:  NLM     Status:  MEDLINE    
OBJECTIVE: This study aimed to investigate the effect of amiloride on portal hypertension. Amiloride is known to inhibit Na(+)/H(+) exchangers on activated hepatic stellate cells. METHODS: Liver cirrhosis in rats was induced by bile duct ligation (BDL) or thioacetamide (TAA) administration. The effects of zymosan for Kupffer cell (KC) activation or a thromboxane (TX) analogue (U46619) were tested in isolated perfused livers of cirrhotic rats and in vivo. Downstream mechanisms were investigated using Rho kinase inhibitor (Y-27632) or amiloride. Acute and chronic effects of amiloride and canrenoate on portal pressure were compared in perfused livers and in vivo. TXB(2) efflux was measured by ELISA. The phosphorylation state of moesin (p-moesin) as an indicator of Rho kinase activity and expression of the thromboxane synthase were assessed by western blot analyses. The activity of hepatic stellate cells was analysed by western blot and staining for alpha-smooth muscle actin (alpha-SMA). RESULTS: In BDL rats, KC activation via zymosan increased portal pressure. This was attenuated by the Rho kinase inhibitor Y-27632. Increased thromboxane efflux following zymosan infusion remained unaltered by Y-27632. The infusion of amiloride attenuated zymosan- and U46619-induced increases in portal perfusion pressure. In vivo, direct administration of amiloride, but not of canrenoate, lowered portal pressure. In TAA and BDL rats, treatment with amiloride for 3 days reduced basal portal pressure and KC-induced increases in portal pressure whereas canrenoate had no effect. In livers of amiloride-treated animals, the phosphorylation state of moesin and the number of alpha-SMA positive cells were reduced. CONCLUSIONS: Amiloride lowers portal pressure in rat liver cirrhosis by inhibition of intrahepatic vasocontraction. Therefore, patients with cirrhosis and portal hypertension may benefit from amiloride therapy.
Christian J Steib; Martin Hennenberg; Frigga Beitinger; Anna C Hartmann; Markus Bystron; Enrico N De Toni; Alexander L Gerbes
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Gut     Volume:  59     ISSN:  1468-3288     ISO Abbreviation:  Gut     Publication Date:  2010 Jun 
Date Detail:
Created Date:  2010-06-16     Completed Date:  2010-07-12     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  2985108R     Medline TA:  Gut     Country:  England    
Other Details:
Languages:  eng     Pagination:  827-36     Citation Subset:  AIM; IM    
Department of Medicine II (Gastroenterology and Hepatology), Liver Center Munich, University of Munich e Grosshadern, Munich 81377, Germany.
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MeSH Terms
Amiloride / administration & dosage,  therapeutic use*
Antihypertensive Agents / administration & dosage,  therapeutic use*
Canrenoate Potassium / administration & dosage,  therapeutic use
Dose-Response Relationship, Drug
Drug Evaluation, Preclinical / methods
Hypertension, Portal / drug therapy*,  etiology,  physiopathology
Kupffer Cells / physiology
Liver Cirrhosis, Experimental / complications*,  physiopathology
Portal Pressure / drug effects,  physiology
Rats, Sprague-Dawley
Sodium Channel Blockers / administration & dosage,  therapeutic use
Thromboxane A2 / physiology
rho-Associated Kinases / physiology
Reg. No./Substance:
0/Antihypertensive Agents; 0/Sodium Channel Blockers; 2181-04-6/Canrenoate Potassium; 2609-46-3/Amiloride; 57576-52-0/Thromboxane A2; EC Kinases

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