Effects Of ET-1 On Portal Hypertension In Hepatic Cirrhosis And The Mechanism Of CNP,Radix Salviae Miltiorrhizae On ET-1-Mediated Contraction Of HSCs

Portal hypertension(PHT) of hepatic cirrhosis is the pathologic basis of severe complications, such as ascites, upper gastrointestinal hemorrhage, hepatorenal syndrome, PHT is the result of augmented intrahepatic vascular resistance and increased portal blood flow. The pathophysiology of PHT is increased hepatic vascular resistance to portal flow. It caused primarily by structural changes such as fibrotic scar tissue and regenerative nodules compressing portal and central venules. Furthermore, it has been shown that swelling of hepatocytes and capillarisation of hepatic sinusoids are part of the increased vascular resistance. Increased blood flow in the portal vein occurs in a more advanced stage of PHT and contributes to its maintenance and aggravation. Increase in portal inflow results from hyperdynamic circulation in the splanchnic and systemic blood vessels, which is characterized by increased cardiac output, reduced mean arterial pressure(MAP), systemic vascular resistance, and expanded plasma volume. Although structural changes are most important in intrahepatic vascular resistance, it has become clear in the past years that not only fixed, but also variable, factors contribute significantly to the increased hepatic vascular resistance. In patients and rats with hepatic cirrhosis, plasma concentrations of endothelin-1(ET-1) and nitrite/nitrate were significantly higher than normal controls, which served as a marker reflecting the severity of PHT. Therefore, disorders of vasoactive substances such as ET-1 and nitric oxide(NO) may play an important role in PHT. Due to lacking of combined study of ET-1 in isolated liver and isolated vascular rings, with the technique of external hepatic perfusion and isolated vascular rings, we inquire into the role of ET-1,NO in pathogenesis and development of PHT.For many years it has been accepted that hepatic stellate cells(HSCs) play a key role in hepatic fibrosis. Accumulating evidence from in vitro and in vivo studies suggests that stellate cells are also involved in the regulation of the liver microcirculation and portal hypertension. Activated hepatic stellate cells have the necessary machinery to contract or relax in response to a number of vasoactive substances, such as ET-1,thrombin,angiotensin â…¡(Angâ…¡),arginine vasopressin,NO,atrial natriuretic peptide(ANP), et al. ET-1 is the most potent vasoconstrictor known, while NO can elicit relaxation. Recent studies have demonstrated that intracellular Ca2+ may play an important role in contraction of HSCs. Because HSCs play a role in both fibrosis and portal hypertension, they are currently regarded as therapeutic targets to prevent and treat the diseases of chronic liver disease. Therefore, elucidating the machinery of intracellular signalling pathways further would provide the basis theory of antagon inhibiting contraction of HSCs. The study was designed to determine the effects of ET-1 on intracellular free calcium([Ca2+]i) using laser scanning confocal microscopy(LSCM).C-type natriuretic peptide(CNP) belongs to natriuretic peptide family. CNP has been shown to inhibit the proliferation and promote relaxation of several cell types, including vascular smooth muscle cells,kidney mesangial cells,chondrocytes, et al, but the effects of CNP on chronic hepatic diseases remain largely unknown. Vollmar et al proved that there exists three natriuretic peptides and natriuretic peptide receptor subtypes in human liver. Gulberg et al indicated that plasma CNP was lower in cirrhotic patients. Pharmacological doses of CNP reduced portal pressure and systemic vascular resistance and increased cardiac output of cirrhotic rats. So CNP may play a role in treatment of chronic hepatic diseases, but it is unknown that whether CNP can have effects of relaxation and proliferation inhibition on HSCs directly. The study has elucidated the role of CNP on the second messenger cAMP and cGMP, mitogen-activated protein kinase(MAPK),DNA and ET-1-induced changes of [Ca2+]i in orderto provide the possible mechanism...