Increased hepatic endothelin-1 levels and endothelin receptor density in cirrhotic rats.
Endothelin-1 (ET-1), the most powerful agent to cause constriction of the hepatic vasculature, is synthesized in the liver by sinusoidal endothelial 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 designed to determine hepatic ET-1 and ET receptor(s) in experimental liver cirrhosis. Cirrhosis was induced in rats by intraperitoneal administration of carbon tetrachloride for 8 weeks. Hepatic ET-1 was measured by radioimmunoassay and ET receptors were determined by radioligand competition binding procedure. A four fold increase in ET-1 concentration accompanied by a 65% increase in ET-receptor density was observed in the cirrhotic liver. There was no change in the ET receptor affinity. The capacity of the liver to metabolize ET-1 was reduced significantly in cirrhosis. Interestingly, transforming growth factor-beta, hepatic levels of which increase in cirrhosis, stimulated ET-1 synthesis in cultured Ito cells. It has been shown that ET-1 is a potent constrictor 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 implications in the pathogenesis and complications of liver cirrhosis.
Gandhi
C R
CR
Department of Anesthesiology/Critical Care Medicine, University of Pittsburgh, Pennsylvania, USA.
Sproat
L A
LA
Subbotin
V M
VM
D000818:Animals; D001667:Binding, Competitive; D002251:Carbon Tetrachloride / Q000633:toxicity; D016232:Endothelins / Q000378:metabolism*; D008099:Liver / Q000201:enzymology / Q000378:metabolism* / Q000648:ultrastructure*; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017466:Receptors, Endothelin / Q000378:metabolism*
D016232:Endothelins; D017466:Receptors, Endothelin; D002251:Carbon Tetrachloride