Endothelin induced contractility of stellate cells from normal and cirrhotic rat liver: implications for regulation of portal pressure and resistance

Abstract

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...

Gene Expression of Endothelin-1 and ET_A and ET_B Receptors in Human Cirrhosis: Relationship with Hepatic Hemodynamics

“…However, unlike ET-1, upregulation of ET A and ET B receptor gene expression was closely related with HVPG. These findings are in keeping with previous investigations demonstrating that nonselective endothelin receptor antagonists [27, 29], but not selective antagonists for the ET A receptor [13], moderately albeit significantly reduce portal pressure in cirrhotic rats.…”

“…These cell types express both ET A and ET B receptor, but until very recently it was thought that cell constriction induced by ET-1 was solely mediated by the ET A receptor [3]. However, the availability of selective ET B receptor agonists has evidenced that ET B receptor can also mediate contraction in the liver [27] and isolated stellate cells of rats [28]. The ET B -mediated vasoconstrictor response has also been observed in human nonhepatic vascular beds [7].…”

Hemodynamics and pharmacokinetics of tezosentan, a dual endothelin receptor antagonist, in patients with cirrhosis

“…Elevated endothelin-1 plasma and hepatic tissue concentrations correlate with the severity of cirrhosis and the hepatic venous pressure gradient (HVPG) [6,8]. Several experimental studies have shown that oral administration of bosentan, a dual ET A and ET B receptor antagonist, significantly reduced the degree of portal hypertension in cirrhotic rats [10][11][12]. The effects of this class of drugs have, however, never been evaluated on the splanchnic circulation in patients with cirrhosis and portal hypertension.…”

Increased sinusoidal resistance is responsible for the basal state and endothelin-induced venoconstriction in perfused cirrhotic rat liver

“…In normal livers, ET-1 is reported to contract not only portal venules but also hepatic sinusoids [56,57]. The contractility of hepatic sinusoids by ET-1 is ascribed to that of hepatic stellate cells [40,43]. However, no investigators measured the sinusoidal resistance of the liver administered of ET-1 or determined which hepatic vascular segments of the portal veins, the sinusoids, and the hepatic veins most extensively contract in response to ET-1.…”

“…On the other hand, in cirrhotic patients and animals, abnormal splanchnic and systemic vasodilation [24,44] and the hyporeactivity of these vessels to vasoactive substances [13,55] are well known, which are presumably caused by increased NO production. However, the hepatic vascular responsiveness to vasoconstrictors such as ET-1 is varied in animals with liver cirrhosis; it is increased [10,40] or decreased [21,22]. Furthermore, it is possible that the vasoreactivity may be variable depending on the hepatic vascular segments.…”