Beneficial hemodynamic effects of bosentan, a mixed ETA and ETB receptor antagonist, in portal hypertensive rats

Abstract

In patients with cirrhosis, the plasma level of endothelin, a potent vasoconstrictor peptide, is elevated, and endothelin plays a role in increased intrahepatic vascular resistance. Thus, the aim of this study was to evaluate the hemodynamic effects of bosentan, a mixed ET A and ET B endothelin receptor antagonist in three models of portal hypertension. In all groups of rats, endothelin (2 g/kg intravenously) administration significantly increased intrahepatic vascular resistance. In rats with secondary biliary cirrhosis, bosentan (30 mg/kg) significantly reduced portal pressure from 14.6 ؎ 1.2 to 12.1 ؎ 0.6 mm Hg, while portal blood flow and cardiac output increased by 45% and 57%, respectively. Thus, hepatocollateral vascular resistance decreased significantly from 177 ؎ 19 to 101 ؎ 9 dyn · s · cm ؊5 ؋ 10 ؊3 . Similar results were observed in rats with CCl 4 -induced cirrhosis. In isolated perfused cirrhotic rat livers, bosentan (1 to 100 mol/L) had no significant effect on hepatic vascular resistance. In portal vein-stenosed rats, bosentan administration significantly decreased portal pressure from 13.1 ؎ 0.6 to 11.4 ؎ 0.5 mm Hg by reducing portosystemic vascular resistance, because bosentan had no effect on vascular resistance of normal rat liver. In conclusion, bosentan administration decreased portal pressure in vivo by reducing hepatocollateral vascular resistance in rats with cirrhosis. Thus, mixed endothelin receptor antagonists might be a new approach in the pharmacological treatment of portal hypertension. (HEPATOLOGY 1998;28:655-659.)Numerous studies have found that plasma concentrations of endothelin-1 (ET-1) and endothelin-3 (ET-3) are increased in patients with cirrhosis and are related to the severity of the liver disease. 1-8 Despite this, these patients have low arterial pressure and systemic vascular resistance. This discrepant finding may be caused, at least in part, by a vascular hyporesponsiveness to endothelins that has been identified in cirrhotic rats. 9,10 Moreover, it has been shown that endothelins induce sinusoidal vasoconstriction through both ET A and ET B receptors and increase intrahepatic vascular resistance in the normal and perfused cirrhotic liver. [11][12][13][14][15] These results suggest that endothelins play a role in the mechanism of intrahepatic portal hypertension. Thus, administration of the mixed ET A and ET B receptor antagonist, 16,17 bosentan, may decrease intrahepatic vascular resistance and decrease portal hypertension. The aim of this study was to evaluate the acute hemodynamic effect of both bosentan and endothelin in two animal models of cirrhosis and in one model with extrahepatic portal hypertension. MATERIALS AND METHODSAnimals. Sixty-four male Sprague-Dawley rats (Charles River Laboratories, Saint-Aubin-lès-Elbeuf, France) were divided into four groups. The first group contained 16 normal rats. The second group contained 16 rats with portal hypertension induced by the partial ligation of the portal vein, as previously described. 18 The hemodynamic study w...

Endothelin–1 Induces Vasoconstriction on Portal–Systemic Collaterals of Portal Hypertensive Rats

“…[4][5][6]15,23,24 However, the vasoactivity of ET-1 on the collateral circulation has never been done before. This study shows that ET-1 has a direct vasoconstrictive effect on the collateral vessels of portal hypertensive rats and may consequently increase the collateral vascular resistance and participate in the development and maintenance of portal hypertension.…”

“…5 Recently, it has been shown that bosentan, a nonselective endothelin receptor antagonist, significantly reduced the portal pressure of portal hypertensive rats. 15 However, it is not clear if ET-1 could modulate portal pressure by a direct constrictive effect on the collateral vessels of portal hypertensive rats.The aims of this study were to investigate the vascular activity and the receptor-mediated effects of ET-1 on the portalsystemic collaterals of portal hypertensive rats. The regulation of nitric oxide (NO) and prostaglandin on the effects of ET-1 was also evaluated.…”

“…5 Recently, it has been shown that bosentan, a nonselective endothelin receptor antagonist, significantly reduced the portal pressure of portal hypertensive rats. 15 However, it is not clear if ET-1 could modulate portal pressure by a direct constrictive effect on the collateral vessels of portal hypertensive rats.…”

Endothelin-1 modulates intrahepatic resistance in a rat model of noncirrhotic portal hypertension

“…12-13 Endothelin receptors expression is increased in portal hypertensive rats 14 and bosentan, a mixed ET A and ET B receptor antagonist, lowers portal pressure in cirrhotic rats, as well as portal vein stenosed animals. 15 Thus, indirect evidence suggests that ET-1 can act as a paracrine or autocrine factor contributing to increased resistance to portal flow in the liver.Endothelins act on 2 types of receptors, the A receptor, the B receptor, 16 and probably a C receptor; ET-1 has a greater affinity for A receptors, which mediate vasoconstriction. Endothelin B receptors expressed on endothelial cells mediate transient vasodilatation, probably through the stimulation of NO and prostaglandin I 2 (PGI 2 ) production; B receptors on smooth muscle may also mediate vasoconstriction.…”

“…[12][13] Endothelin receptors expression is increased in portal hypertensive rats 14 and bosentan, a mixed ET A and ET B receptor antagonist, lowers portal pressure in cirrhotic rats, as well as portal vein stenosed animals. 15 Thus, indirect evidence suggests that ET-1 can act as a paracrine or autocrine factor contributing to increased resistance to portal flow in the liver.…”