e., boceprevir and telaprevir) is still conditioned by IFN responsiveness. “
“Study purpose: The farnesoid-X-receptor (FXR) is a nuclear bile acid receptor involved in bile acid homeostasis, Talazoparib mouse hepatic and intestinal inflammation, liver fibrosis and cardiovascular disease. We studied the effect of short-term treatment with obeticholic acid (INT-747), a potent selective FXR agonist, on intrahepatic hemodynamic dysfunction and signaling pathways in different rat models of cirrhotic portal hypertension. Methods: Thioacetamide (TAA)-intoxicated and bile duct ligated (BDL) rats were used as models. After gavage of 2 doses of 30mg/kg INT-747 or vehicle within 24 hours,

in vivo hemodynamics were assessed. Additionally, we evaluated the direct effect of INT-747 on total intrahepatic www.selleckchem.com/products/MK-1775.html vascular resistance (IHVR) and intrahepatic vascular tone (endothelial dysfunction and hyperresponsiveness to methoxamine) by means of an in-situ liver perfusion system and on hepatic stellate cell contraction in vitro. FXR-expression and involved intrahepatic vasoactive pathways (e. g. endothelial nitric oxide synthase: eNOS, Rho-kinase, dimethylarginine dimethylaminohydrolase: DDAH) were analyzed by immunohistochemistry, RT-PCR or Western Blot. Results: In both cirrhotic models, FXR expression was heavily decreased. Immunohistochemically,

this coincided with a disappearance of the typical FXR hepatocytic medchemexpress nuclear staining pattern seen in healthy livers. Treatment with INT-747 in TAA and BDL reactivated the FXR downstream signaling pathway and decreased portal pressure without deleterious systemic hypotension (portal pressure decreased from 13.8 ± 0, 6 mm Hg to 11.6 ± 0, 8 mm Hg in TAA, P=0.045, n=14 and from 12.3 ± 0, 8 mm Hg to 10.1 ± 0, 6 mm Hg in BDL, P=0.037, n=15). This was related to a decrease in total intrahepatic vascular resistance during liver perfusion (relative decrease in IHVR after INT747 treatment in TAA: −8.06 ± 0.69%, P<0.001,

n=10 and in BDL: −21.8 ± 2.50%, P<0.001, n=10). In the perfused TAA and BDL cirrhotic liver, INT-747 improved endothelial vasorelaxation capacity but not hyperresponsiveness. In both groups, this was associated with an increased eNOS-activity which in TAA related to down-regulation of the Rho-kinase pathway and in BDL to up-regulation of DDAH-2.Furthermore, INT-747 induced a dose-dependent relaxation of cultured rat primary hepatic stellate cells in vitro. Conclusion: FXR-agonist INT-747 improves portal hypertension in 2 different rat models of cirrhosis by decreasing the IHVR. This hemodynamic effect relates to restoration of endothelial dysfunction by increased intrahep-atic eNOS-activity. The mechanisms of eNOS activity increase differ depending on the etiology of cirrhosis. Disclosures: Frederik Nevens – Grant/Research Support: Ipsen, Roche, MSD, Astellas, CAF The following people have nothing to disclose: Len D.