Hemodynamic effects of urotensin II and its specific receptor antagonist palosuran in cirrhotic rats.
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.


CONCLUSIONS
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.
Trebicka
Jonel
J
Department of Internal Medicine I, University of Bonn, Bonn, Germany. jonel.trebicka@ukb.uni-bonn.de
Leifeld
Ludger
L
Hennenberg
Martin
M
Biecker
Erwin
E
Eckhardt
Andreas
A
Fischer
Nicolas
N
Pröbsting
Andrea Schulze
AS
Clemens
Christoph
C
Lammert
Frank
F
Sauerbruch
Tilman
T
Heller
Jörg
J
D000284:Administration, Oral; D000818:Animals; D006152:Cyclic GMP / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects*; D007668:Kidney / Q000187:drug effects*; D007677:Kidney Function Tests; D008099:Liver / Q000378:metabolism; D008105:Liver Cirrhosis, Biliary / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008638:Mesenteric Arteries / Q000378:metabolism; D009566:Nitrates / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D011169:Portal Vein / Q000378:metabolism; D011804:Quinolines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D014508:Urea / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D014579:Urotensins / Q000097:blood / Q000378:metabolism / Q000627:therapeutic use*; D054460:rho-Associated Kinases / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D009566:Nitrates; D009573:Nitrites; D011804:Quinolines; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D014579:Urotensins; C473142:Uts2r protein, rat; D009569:Nitric Oxide; D014508:Urea; C029677:urotensin II; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D054460:rho-Associated Kinases; D017869:Cyclic GMP-Dependent Protein Kinases; D020742:rhoA GTP-Binding Protein; D006152:Cyclic GMP; C493249:1-(2-(4-benzyl-4-hydroxypiperidin-1-yl)ethyl)-3-(2-methylquinolin-4-yl)urea