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⁺⁺.