The effect of endothelin and its antagonist Bosentan on hemodynamics and microvascular exchange in cirrhotic rat liver

J Hepatol. 1998 Jun;28(6):1020-30. doi: 10.1016/s0168-8278(98)80352-8.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bile Acids and Salts / blood
  • Bile Ducts / physiology
  • Bilirubin / blood
  • Blood Pressure / drug effects
  • Body Weight / drug effects
  • Bosentan
  • Carbon Tetrachloride Poisoning
  • Cardiac Output / drug effects
  • Endothelin-1 / pharmacokinetics
  • Endothelin-1 / pharmacology*
  • Endothelin-1 / physiology
  • Hemodynamics / drug effects*
  • Hemodynamics / physiology
  • Hepatic Artery / drug effects
  • Hepatic Artery / physiology
  • Hepatic Artery / physiopathology
  • Liver / blood supply
  • Liver Circulation / drug effects
  • Liver Circulation / physiology*
  • Liver Cirrhosis, Biliary / blood
  • Liver Cirrhosis, Biliary / chemically induced
  • Liver Cirrhosis, Biliary / physiopathology*
  • Male
  • Metabolic Clearance Rate
  • Microcirculation / drug effects
  • Microcirculation / physiology*
  • Organ Size / drug effects
  • Phenobarbital
  • Portal System / drug effects
  • Rats
  • Rats, Sprague-Dawley
  • Sulfonamides / pharmacology*

Substances

  • Bile Acids and Salts
  • Endothelin-1
  • Sulfonamides
  • Bosentan
  • Bilirubin
  • Phenobarbital