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Endothelin‐1 modulates intrahepatic resistance in a rat model of noncirrhotic portal hypertension
Author(s) -
Kamath Patrick S.,
Tyce Gertrude M.,
Miller Virginia M.,
Edwards Brooks S.,
Rorie Duane K.
Publication year - 1999
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.510300235
Subject(s) - portal hypertension , medicine , portal venous pressure , endocrinology , contractility , endothelin 1 , endothelin receptor , vascular resistance , nitric oxide , fibrosis , nitroarginine , hemodynamics , receptor , cirrhosis , nitric oxide synthase
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 duct– ligated 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. The endothelin Type A receptor antagonist BQ 123 lowered the high portal resistance in BDL rats to levels comparable with sham operated animals. Infusion of l ‐arginine lowered resistance to a much smaller extent. In livers from Bdl Rats, Et‐1 was localized in periportal and pericentral hepatocytes and hepatic sinusoidal cells. We conclude that in a BDL model of portal hypertension where distortion of hepatic architecture by fibrosis is minimal, increased resistance to portal blood flow may be mediated by ET‐1.