Ps. Kamath et al., Endothelin-1 modulates intrahepatic resistance in a rat model of noncirrhotic portal hypertension, HEPATOLOGY, 30(2), 1999, pp. 401-407
Factors that increase resistance to blood flow through the hepatic sinusoid
s when portal hypertension occurs in the absence of significant hepatic fib
rosis are not completely understood. Experiments were designed to test the
hypothesis that endothelin-1 (ET-1) is one of the humoral factors that incr
eases sinusoidal vascular resistance in a bile duct-ligated noncirrhotic po
rtal hypertensive (BDL) rat. The effect of ET-1 and nitric oxide (NO) on co
ntractility of rings of portal vein taken from BDL rats was tested. The eff
ect 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 immun
ohistochemistry. Portal vein rings in BDL rats showed increased maximal ten
sion 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 endothe
lin Type A receptor antagonist BQ 123 lowered the high portal resistance in
BDL rats to levels comparable with sham operated animals. Infusion of L-ar
ginine 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 wh
ere distortion of hepatic architecture by fibrosis is minimal, increased re
sistance to portal blood flow may be mediated by ET-1.