BACKGROUND/AIMS: To characterize the effects of endothelin-1 and of Bosentan, a mixed endothelin antagonist, on hepatic hemodynamics in cirrhotic animals in vivo and on hepatic microvascular exchange in the perfused rat liver. METHODS: Biliary cirrhosis was induced by bile duct ligation, and micronodular cirrhosis by chronic exposure to phenobarbital/CCl4 in male rats. Hepatic hemodynamics were studied under basal conditions and after administration of Bosentan (3-30 mg/kg) by the microsphere technique. Microvascular exchange was assessed in the in situ perfused rat liver by the multiple indicator dilution technique. RESULTS: Bosentan lowered portal pressure in a dose-dependent fashion; at the highest dose tested, this decrease averaged -29+/-11 and -26+/-8% in biliary and micronodular cirrhosis, respectively (p<0.01). This was achieved mainly via a marked decrease in hepatic arterial flow. In the perfused liver, endothelin-1 induced a dose-dependent vasoconstriction; up to 10(-9) mol/l; this was not associated with any effect on viability. At this dose, endothelin-1 markedly decreased extravascular albumin space in both controls and micronodular cirrhosis; this could be antagonized by Bosentan 10(-5) mol/l. CONCLUSIONS: Endothelin-1 affects hepatic microvascular exchange, presumably by a direct effect on hepatic sinusoidal endothelial cells. A mixed endothelin antagonist lowers portal pressure in vivo, presumably by acting on hepatic stellate cells, and counteracts the microvascular effects of endothelin-1 in vitro. These properties could prove useful in treatment of portal hypertension.
BACKGROUND/AIMS: To characterize the effects of endothelin-1 and of Bosentan, a mixed endothelin antagonist, on hepatic hemodynamics in cirrhotic animals in vivo and on hepatic microvascular exchange in the perfused rat liver. METHODS:Biliary cirrhosis was induced by bile duct ligation, and micronodular cirrhosis by chronic exposure to phenobarbital/CCl4 in male rats. Hepatic hemodynamics were studied under basal conditions and after administration of Bosentan (3-30 mg/kg) by the microsphere technique. Microvascular exchange was assessed in the in situ perfused rat liver by the multiple indicator dilution technique. RESULTS:Bosentan lowered portal pressure in a dose-dependent fashion; at the highest dose tested, this decrease averaged -29+/-11 and -26+/-8% in biliary and micronodular cirrhosis, respectively (p<0.01). This was achieved mainly via a marked decrease in hepatic arterial flow. In the perfused liver, endothelin-1 induced a dose-dependent vasoconstriction; up to 10(-9) mol/l; this was not associated with any effect on viability. At this dose, endothelin-1 markedly decreased extravascular albumin space in both controls and micronodular cirrhosis; this could be antagonized by Bosentan 10(-5) mol/l. CONCLUSIONS:Endothelin-1 affects hepatic microvascular exchange, presumably by a direct effect on hepatic sinusoidal endothelial cells. A mixed endothelin antagonist lowers portal pressure in vivo, presumably by acting on hepatic stellate cells, and counteracts the microvascular effects of endothelin-1 in vitro. These properties could prove useful in treatment of portal hypertension.
Authors: Didier Lebrec; Jaime Bosch; Rajiv Jalan; Francis J Dudley; Rada Jessic; Richard Moreau; Juan Carlos Garcia-Pagan; Rajeshwar P Mookerjee; Eleonora Chiossi; Paul L M Van Giersbergen; Andjela Kusic-Pajic; Jasper Dingemanse Journal: Eur J Clin Pharmacol Date: 2011-11-20 Impact factor: 2.953
Authors: V Chongsrisawat; P Chatchatee; R Samransamruajkit; P Vanapongtipagorn; P Chottivittayatarakorn; Y Poovorawan Journal: Pediatr Surg Int Date: 2003-05-13 Impact factor: 1.827