by two major endothelin receptors, endothelin A (ET A ) and Hepatic stellate cells are similar to tissue pericytes endothelin B (ET B ). 2-3 ET A receptors are abundant on vascuand have been shown to be contractile. In this study, we lar smooth muscle cells, have a high affinity for endothelinexamined the effects of known mediators of stellate cell 1, produce sustained contraction of vascular smooth muscle contraction on portal pressure in rat livers after carbon cells, and mediate vasoconstriction. 3 In contrast, ET B receptetrachloride induced injury (including cirrhosis) and tors bind both endothelin-1 and endothelin-3 with equal affininvestigated the contractility of stellate cells as a funcity. The ET B receptor appears to mediate either vasoconstriction of liver injury. Sarafotoxin S6C, an endothelin B tion or vasorelaxation depending on tissue type. 4 As such, (ET B ) receptor agonist, had minor effects on portal presthe endothelins are implicated in normal physiological as sure when perfused into normal livers at concentrations well as pathological responses. known to elicit stellate cell contraction (2 nmol/L). In Early work in liver has shown that endothelin-1 and endocontrast, both endothelin-1 (2 nmol/L) and angiotensin thelin-3 perfused into the portal system results in elevation II (8.6 nmol/L) caused a rapid and pronounced rise in of portal pressure and an increase in glycogenolysis. [5][6][7] Addiportal pressure. The effects of sarafotoxin S6C (a potent tionally, endothelin-1 may mediate sinusoidal vasoconstricstellate cell contractile agonist) on portal pressure were tion induced by ethanol. 8 While the precise mechanism by greater in cirrhotic than normal liver, whereas those of which endothelin-1 and endothelin-3 cause vasoconstriction angiotensin II were unchanged after liver injury. Endoin liver is unknown, it has been proposed that they act on thelin-1 and sarafotoxin S6C The tent with its inhibitory effect on stellate cell contraction.most compelling evidence that endothelin may mediate sinuWe conclude that stellate cell contractility increases soidal vasoconstriction via its effects on stellate cells stems with progressive liver injury and is proportional to the from work directly showing their contraction in response to degree of stellate cell activation, becoming most promiendothelin-1 and endothelin-3. 13-15 nent in the cirrhotic liver. Endothelin-stimulated conDuring liver injury, stellate cells undergo a process charactraction of stellate cells in cirrhotic liver may contribute terized by loss of retinoid droplets, enhanced collagen producto increased intrahepatic resistance and portal prestion, and expression of smooth muscle a actin, which has sure. (HEPATOLOGY 1996;24:233-240.) been termed ''activation''. 16 It occurs spontaneously in cultured stellate cells, and in vivo during liver injury. 17 Further The three known endothelins comprise a family of homolo-studies have indirectly suggested that myofibroblasts (i.e., gous 21 amino acid peptides. 1,2 While they have diverse ef-acti...