Endothelin-1 modulates intrahepatic resistance in a rat model of noncirrhotic portal hypertension

Abstract

Factors that increase resistance to blood flow through the hepatic sinusoids when portal hypertension occurs in the absence of significant hepatic fibrosis are not completely understood. Experiments were designed to test the hypothesis that endothelin-1 (ET-1) is one of the humoral factors that increases sinusoidal vascular resistance in a bile ductligated noncirrhotic portal hypertensive (BDL) rat. The effect of ET-1 and nitric oxide (NO) on contractility of rings of portal vein taken from BDL rats was tested. The effect of ET-1 and NO on intrahepatic resistance in an isolated perfused liver was studied, and localization of ET-1 in the liver was identified by immunohistochemistry. Portal vein rings in BDL rats showed increased maximal tension in response to ET-1, as well as a shift of the dose-response curve to the left as compared with sham-operated animals. Removal of the endothelium further increased contractility. In isolated perfused liver studies, ET-1 increased portal resistance in both sham operated and BDL rats. Portal hypertension is a circulatory consequence of increased portal blood flow and increased resistance to hepatic sinusoidal blood flow 1 . Nitric oxide (NO) is believed to be a significant factor contributing to increased portal blood flow, 2 but the factors responsible for increasing vascular resistance within the liver are not clearly established, especially in noncirrhotic portal hypertension. A major factor that may increase sinusoidal resistance in cirrhosis is fibrosis with nodule formation, which distorts hepatic sinusoidal architecture, thus increasing resistance to blood flow. Fibrosis, however, is a late feature of liver disease. Thus, early in the onset of portal hypertension, before fibrosis becomes sufficiently established to distort sinusoidal structure, there may be humoral factors that initiate an increase in portal resistance. The role of humoral factors is suggested by recent studies that indicate that portal resistance is decreased by vasodilators such as papavarine and sodium nitroprusside. 3 Endothelin-1 (ET-1) is a member of a family of 21 amino acid peptides, which are potent constrictors of vascular smooth muscle. ET-1 is elevated in the peripheral blood of patients with chronic liver disease with or without ascites [4][5][6] and in the hepatorenal syndrome. 7 ET-1 has been identified in endothelial cells of the hepatic sinusoids, portal vein, and hepatic central vein 8 and has been shown to cause contraction of hepatic sinusoids as well as preterminal portal venules. 9-11 Studies of cirrhotic liver tissue in humans have shown enhanced ET-1 expression, activated hepatic stellate cells (HSC) being the major site of synthesis. 12-13 Endothelin receptors expression is increased in portal hypertensive rats 14 and bosentan, a mixed ET A and ET B receptor antagonist, lowers portal pressure in cirrhotic rats, as well as portal vein stenosed animals. 15 Thus, indirect evidence suggests that ET-1 can act as a paracrine or autocrine factor contributing to increased resistance t...

Hepatic Localization of Endothelin-1 in Patients With Idiopathic Portal Hypertension and Cirrhosis of the Liver

“…16 ET-1-induced constriction of preterminal portal venules causes significant increases in portal pressure in rats, 17 whereas bosentan, a non-receptor-selective antagonist, and BQ123, an ET-1 type A-receptor antagonist, can decrease portal pressure. 9,18 In experimental animals, ET-1 caused increased intrahepatic vascular resistance in the absence of significant fibrosis. 9 Thus, considerable indirect evidence points to ET-1 as a potential mediator of the increased hepatic sinusoidal resistance that results in portal hypertension.…”

“…9,18 In experimental animals, ET-1 caused increased intrahepatic vascular resistance in the absence of significant fibrosis. 9 Thus, considerable indirect evidence points to ET-1 as a potential mediator of the increased hepatic sinusoidal resistance that results in portal hypertension. The localization of ET-1 in patients with IPH in the present study is consistent with ET-1 affecting hepatic resistance in the absence of hepatic fibrosis.…”

“…In rats with portal hypertension, hepatic sinusoidal resistance increases even before the onset of fibrosis, an action mediated by ET-1. 9 Because endothelin levels are increased in idiopathic pulmonary hypertension (IPH), 10 we postulate that ET-1 level similarly may increase in humans early in the onset of portal hypertension before diffuse fibrosis and nodule formation (cirrhosis) develop. In contrast, in late stages of liver cirrhosis, the fixed component related to fibrosis and nodule formation may be more important than the reversible component related to ET-1.…”

Analysis of In Vivo Nuclear Factor-κB Activation during Liver Inflammation in Mice: Prevention by Catalase Delivery

“…It has been reported that hydrogen peroxide is able to directly activate NF-B, and a variety of antioxidants and antioxidant enzymes, such as catalase, down-regulate TNF-␣-mediated NF-B activation (Schreck et al, 1991;Anderson et al, 1994). TA is a thiono-sulfur-containing compound that is commonly used for inducing fulminant hepatic failure (Bruck et al, 2002) and liver cirrhosis (Kamath et al, 1999) in animal models. During the biotransformation of TA, both flavin-containing monooxygenase (Chieli and Malvaldi, 1984) and cytochrome P450 reduce dioxygen to superoxide anion, which is then catalyzed to produce hydrogen peroxide.…”

In vivo validation of 4D flow MRI for assessing the hemodynamics of portal hypertension

“…Indeed, in patients with advanced cirrhosis, flow is the primary determinant of portal pressure. This is largely due to the high levels of circulating endogenous vasodilators that lead to an elevated cardiac output that increases portal blood flow (Q), paradoxically exacerbating portal hypertension (17). It is for this reason that most pharmacological and interventional therapies, such as transjugular intrahepatic portosystemic shunt (TIPS), aim to reduce portal pressure by reducing or redirecting flow to the systemic venous circulation (10,(18)(19)(20)(21)(22)(23).…”