4-(2-phenyl-5-7-bis(trifluoromethyl)pyrazolo(1-5-a)pyrimidin-3-yl)phenol and Hypertension--Portal

To investigate the role of diarylpropionitrile (DPN), a selective agonist of estrogen receptor β (ERβ), in liver cirrhosis with portal hypertension (PHT) and isolated hepatic stellate cells (HSCs).. Female Sprague-Dawley rats were ovariectomized (OVX), and liver cirrhosis with PHT was induced by CCl4 injection. DPN and PHTPP, the selective ERβ agonist and antagonist, were used as drug interventions. Liver fibrosis was assessed by hematoxylin and eosin (HE) and Masson's trichrome staining and by analyzing smooth muscle actin expression. Hemodynamic parameters were determined in vivo using colored microspheres technique. Protein expression and phosphorylation were determined by immunohistochemical staining and Western blot analysis. Messenger RNA levels were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). Collagen gel contraction assay was performed using gel lattices containing HSCs treated with DPN, PHTPP, or Y-27632 prior to ET-1 addition.. Treatment with DPN in vivo greatly lowered portal pressure and improved hemodynamic parameters without affecting mean arterial pressure, which was associated with the attenuation of liver fibrosis and intrahepatic vascular resistance (IHVR). In CCl4-treated rat livers, DPN significantly decreased the expression of RhoA and ROCK II, and even suppressed ROCK II activity. Moreover, DPN remarkedly increased the levels of endothelial nitric oxide synthase (eNOS) and phosphorylated eNOS, and promoted the activities of protein kinase G (PKG), which is an NO effector in the liver. Furthermore, DPN reduced the contractility of activated HSCs in the 3-dimensional stress-relaxed collagen lattices, and decreased the ROCK II activity in activated HSCs. Finally, in vivo/in vitro experiments demonstrated that MLC activity was inhibited by DPN.. For OVX rats with liver cirrhosis, DPN suppressed liver RhoA/ROCK signal, facilitated NO/PKG pathways, and decreased IHVR, giving rise to reduced portal pressure. Therefore, DPN represents a relevant treatment choice against PHT in cirrhotic patients, especially postmenopausal women.

Topics: Actins; Animals; Carbon Tetrachloride; Cells, Cultured; Chemical and Drug Induced Liver Injury; Cyclic GMP-Dependent Protein Kinases; Estrogen Receptor beta; Estrogens; Female; Hepatic Stellate Cells; Hypertension, Portal; Liver Cirrhosis, Experimental; Male; Myosin Light Chains; Nitric Oxide; Nitric Oxide Synthase Type III; Nitriles; Ovariectomy; Phosphorylation; Portal Pressure; Propionates; Pyrazoles; Pyrimidines; Rats, Sprague-Dawley; rho-Associated Kinases; rhoA GTP-Binding Protein; Selective Estrogen Receptor Modulators; Signal Transduction; Vascular Resistance