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Hemodynamic effects of urotensin II and its specific receptor antagonist palosuran in cirrhotic rats
Author(s) -
Trebicka Jonel,
Leifeld Ludger,
Hennenberg Martin,
Biecker Erwin,
Eckhardt Andreas,
Fischer Nicolas,
Pröbsting Andrea Schulze,
Clemens Christoph,
Lammert Frank,
Sauerbruch Tilman,
Heller Jörg
Publication year - 2008
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.22170
Subject(s) - endocrinology , medicine , portal hypertension , splanchnic , hyperdynamic circulation , portal venous pressure , mean arterial pressure , vasodilation , rhoa , vascular resistance , hemodynamics , cirrhosis , chemistry , blood pressure , signal transduction , heart rate , biochemistry
Abstract In cirrhosis, splanchnic vasodilation contributes to portal hypertension, subsequent renal sodium retention, and formation of ascites. Urotensin II(U‐II) is a constrictor of large conductive vessels. Conversely, it relaxes mesenteric vessels, decreases glomerular filtration, and increases renal sodium retention. In patients with cirrhosis, U‐II plasma levels are increased. Thus, we investigated hemodynamic and renal effects of U‐II and its receptor antagonist, palosuran, in cirrhotic bile duct–ligated rats (BDL). In BDL and sham‐operated rats, we studied acute effects of U‐II (3 nmol/kg; intravenously) and palosuran (10 mg/kg; intravenously) and effects of oral administration of palosuran (30 mg/kg/day; 3 days) on hemodynamics and renal function. We localized U‐II and U‐II‐receptor (UTR) in livers and portal veins by immunostaining. We determined U‐II‐plasma levels by enzyme‐linked immunosorbent assay (ELISA), and mesenteric nitrite/nitrate‐levels by Griess‐reaction. RhoA/Rho‐kinase and endothelial nitric oxide synthase (eNOS) pathways were determined by western blot analysis and reverse transcription polymerase chain reaction (RT‐PCR) in mesenteric arteries. U‐II plasma levels, as well as U‐II and UTR‐receptor expression in livers and portal veins of cirrhotic rats were significantly increased. U‐II administration further augmented the increased portal pressure (PP) and decreased mean arterial pressure (MAP), whereas palosuran decreased PP without affecting MAP. The decrease in PP was associated with an increase in splanchnic vascular resistance. In mesenteric vessels, palosuran treatment up‐regulated expression of RhoA and Rho‐kinase, increased Rho‐kinase‐activity, and diminished nitric oxide (NO)/cyclic guanosine 3′,5′‐monophosphate (cGMP) signaling. Moreover, palosuran increased renal blood flow, sodium, and water excretion in BDL rats. Conclusion: In BDL rats, U‐II is a mediator of splanchnic vasodilation, portal hypertension and renal sodium retention. The U‐II‐receptor antagonist palosuran might represent a new therapeutic option in liver cirrhosis with portal hypertension. (H EPATOLOGY 2008.)