Endothelin-1 induces cholestasis which is mediated by an increase in portal pressure.
Endothelin-1 (ET-1) is a potent vasoactive peptide which generally exerts its effect on target cells by increasing [Ca++]i. Both vasoconstriction (resulting in an increase in perfusion pressure) and increased [Ca++]i are actions of ET-1 that may result in cholestasis. Single-pass isolated perfused rat liver (IPRL) were used, and [Ca++]i was measured in both populations of hepatocytes and single cells. ET-1 (0.1-100 nM) induced a dose-dependent increase in perfusion pressure and decrease in bile flow. Perfusion pressure increased by 112% (p < 0.001) and bile flow decreased by 17% (p < 0.008) in response to 2 nM ET-1. At this concentration of ET-1, but not at higher concentrations, the cholestasis was abolished (p > 0.18 vs basal) and the rise in perfusion pressure was decreased (by 62%; p < 0.002) by the vasodilator papaverine. This ET-1 concentration also had no measurable effect on [Ca++]i in isolated hepatocytes. Taken together these findings indicate that ET-1 inhibits bile flow in IPRL and suggests that this effect is mediated by vasoconstriction and not by changes in hepatocyte cytosolic Ca++.
Isales
C M
CM
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT.
Nathanson
M H
MH
Bruck
R
R
D000818:Animals; D001646:Bile / Q000378:metabolism*; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002779:Cholestasis / Q000139:chemically induced*; D016232:Endothelins / Q000494:pharmacology*; D008297:Male; D010208:Papaverine / Q000494:pharmacology; D011168:Portal System / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D014661:Vasoconstriction / Q000187:drug effects
D016232:Endothelins; D010208:Papaverine; D002118:Calcium