Endothelin-1 (ET-1), the most powerful agent to cause constriction of
the hepatic vasculature, is synthesized in the liver by sinusoidal end
othelial cells. Circulating ET-1 levels have been shown to increase in
liver cirrhosis. As liver could be a major source of increased plasma
ET-1 as well as a target for its pathologic actions, this study was d
esigned to determine hepatic ET-1 and ET receptor(s) in experimental l
iver cirrhosis. Cirrhosis was induced in rats by intraperitoneal admin
istration of carbon tetrachloride for 8 weeks. Hepatic ET-1 was measur
ed by radioimmunoassay and ET receptors were determined by radioligand
competition binding procedure. A four fold increase in ET-1 concentra
tion accompanied by a 65% increase in ET-receptor density was observed
in the cirrhotic liver. There was no change in the ET receptor affini
ty. The capacity of the liver to metabolize ET-1 was reduced significa
ntly in cirrhosis. Interestingly, transforming growth factor-p, hepati
c levels of which increase in cirrhosis, stimulated ET-1 synthesis in
cultured Ito cells. It has been shown that ET-1 is a potent constricto
r of Ito cells that proliferate and transform into highly contractile
myofibroblasts in liver cirrhosis. Thus, interactions between ET-1 and
Ito cells may have significant