Endothelins 1 and 3: potent cholestatic agents secreted and excreted by the liver that interact with cyclosporine.
Autoradiographic studies have shown that the liver accumulates endothelin. High-affinity binding sites for endothelin have been identified on rat liver plasma membranes. We investigated the role of endothelin isopeptides as mediators of cholestasis with isolated rat liver perfused by a recirculating solution of buffer and blood. These studies demonstrated that endothelin-1, as measured by means of radioimmunoassay, was cleared from the perfusate by the liver and that the liver concentrated both endothelin-1 and endothelin-3 in bile. Addition of endothelin-1 to the liver perfusate solution increased the concentration of endothelin-3 measured in the perfusate, suggesting that endothelin-1 caused release or secretion of endothelin-3. Both endothelin-1 and endothelin-3 at 5 nmol/L caused almost complete cessation of bile flow, but this effect was more prolonged after endothelin-1 than after endothelin-3 administration. Because it has been reported that cyclosporine increases endothelin levels, we studied the interaction of these two compounds. Cyclosporine (100 mumol/L) also produced cholestasis. Endothelin-3 secretion in bile, however, was decreased in livers perfused with cyclosporine compared with secretion in controls. Simultaneous addition of endothelin-1 and cyclosporine that on their own were not significantly cholestatic produced cholestasis. In conclusion, endothelin is a potent cholestatic agent secreted and excreted by the liver. It may potentiate the cholestatic action of cyclosporine.
Bluhm
R E
RE
Department of Medicine, Vanderbilt University, School of Medicine, Nashville, Tennessee 37207.
Frazer
M G
MG
Vore
M
M
Pinson
C W
CW
Badr
K F
KF
D000818:Animals; D002779:Cholestasis / Q000209:etiology* / Q000378:metabolism; D016572:Cyclosporine / Q000009:adverse effects*; D004357:Drug Synergism; D016232:Endothelins / Q000378:metabolism / Q000502:physiology*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
D016232:Endothelins; D016572:Cyclosporine