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-IIreceptor (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 Griessreaction. RhoA/Rho-kinase and endothelial nitric oxide synthase ( P ortal hypertension in liver cirrhosis is mediated by an increased portal tributary blood flow 1 and an increase in intrahepatic resistance to portal flow. 2 The increased portal tributary blood flow is attributable to decreased splanchnic vascular resistance and consecutive splanchnic vasodilation. Consequences of this vasodilation are activation of the renin angiotensin aldosterone system, renal sodium retention, and formation of ascites. 3 This splanchnic vasodilation is mediated by an overproduction of the vasodilator nitric oxide (NO) 4,5 and by concomitant defects in contractile signaling. Thus, we have recently shown that a decrease in RhoA/Rho-kinase signaling contributes to vasodilation in cirrhosis. 6,7 Urotensin II (U-II) is a cyclic oligopeptide with vasoactive potential. [8][9][10][11] By activation of the urotensin II receptor (UTR), U-II might influence different pathways, depending on the cells and vascular compartment where Abbreviations: ⌬C T , the difference in the number of PCR

I ncreased intrahepatic resistance to portal flow 1 and decreased splanchnic vascular resistance 2 cause portal hypertension in liver cirrhosis. Dysregulation of intracellular vasoconstrictive Rho-kinase-mediated pathways may contribute to both processes. According to our findings, it is overactivated in the liver and dysfunctional in splanchnic vessels. [2][3][4][5][6][7] Reduction of extrahepatic vascular resistance leads to hyperdynamic circulation characterized by increased cardiac output and decreased systemic vascular resistance and mean arterial pressure. In an attempt to maintain effective circulating volume, endogenous vasoconstrictor systems are recruited, including catecholamines. 8,9 The effects of catecholamines are characteristically mediated by the ␤ 1 -and

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