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

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-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

Novel rat model of repetitive portal venous embolization mimicking human non-cirrhotic idiopathic portal hypertension

“…Splanchnic vascular resistance was significantly decreased in weekly embolized rats compared to rats with only a single embolization (Fig 3e). This is in line with hemodynamic findings in portal hypertension [16,25]. There were no significant differences in the MAP (weekly embolization: 87.0 ± 13.2; single embolization: 96.2 ± 12.2; control: 91.0 ± 6.9) and in the cardiac output (weekly embolization: 19.0 ± 1.6; single embolization: 29.8 ± 5.3; control: 16.7 ± 4.1), respectively.…”

“…Hemodynamic studies were performed under ketamine/xylazine anesthesia (78mg/kg / 12.5mg/kg i.p.) as previously described [14][15][16][17]. Rats were fasted overnight but allowed free access to water.…”

“…Hemodynamics were investigated using the coloured microsphere technique as previously described [14][15][16][17]. The colored microsphere technique was validated by the more frequently used radioactive microsphere method [18].…”

“…It has the advantage of being non-radioactive and using different colors at the same organism. This technique has been shown very accurate in the measurement of hemodynamics in many studies of our group and others [14][15][16][18][19][20][21][22][23]. A reference sample was obtained for 1 min at a rate of 0.65mL/min, using a continuous withdrawal pump (Hugo-Sachs-Elektronik,March-Hugstetten,Germany).…”

Increased expression of urotensin II and GPR14 in patients with cirrhosis and portal hypertension

“…Co-localization experiments with UT (C4, arrow) and CD68 (C5, arrow) show that these cells were Kupffer cells (C6, arrow). Tribeka et al in a rat model of cirrhosis (20,21). In apparent variance with our data, Leifeld et al have shown by immunohistochemistry that there was no significant difference in UII/UT between cirrhotic and control liver.…”