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Treatment with the leukotriene inhibitor montelukast for 10 days attenuates portal hypertension in rat liver cirrhosis
Author(s) -
Steib Christian J.,
Bilzer Manfred,
op den Winkel Mark,
Pfeiler Susanne,
Hartmann Anna C.,
Hennenberg Martin,
Göke Burkhard,
Gerbes Alexander L.
Publication year - 2010
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.23596
Subject(s) - portal venous pressure , leukotriene c4 , endocrinology , medicine , leukotriene , portal hypertension , montelukast , chemistry , cirrhosis , asthma
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 μM) reduced the maximal portal perfusion pressure following LTC 4 or LTD 4 infusion. The infusion of LTC 4 or D 4 in vivo (15 μg/kg b.w.) confirmed LTC 4 as the more relevant vasoconstrictor. Activation of KCs with zymosan (150 μg/mL) in isolated perfused BDL livers increased the portal perfusion pressure markedly, which was attenuated by LT receptor blockade (Ly171883, 20 μM). 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 μM). Infusion of LTC 4 (20 nM) and the thromboxane analog U46619 (0.1 μM) 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. (H EPATOLOGY 2010)