The effect of endothelin and its antagonist Bosentan on hemodynamics and microvascular exchange in cirrhotic rat liver.
OBJECTIVE
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.
Department of Clinical Pharmacology, University of Berne, Switzerland. reichen@ikp.unibe.ch
J
J
Reichen
A L
AL
Gerbes
M J
MJ
Steiner
H
H
Sägesser
M
M
Clozel
D000818:Animals; D001647:Bile Acids and Salts / Q000097:blood; D001652:Bile Ducts / Q000502:physiology; D001663:Bilirubin / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D000077300:Bosentan; D002252:Carbon Tetrachloride Poisoning; D002302:Cardiac Output / Q000187:drug effects; D019332:Endothelin-1 / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000502:physiology; D006439:Hemodynamics / Q000187:drug effects* / Q000502:physiology; D006499:Hepatic Artery / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology; D008099:Liver / Q000098:blood supply; D008102:Liver Circulation / Q000187:drug effects / Q000502:physiology*; D008105:Liver Cirrhosis, Biliary / Q000097:blood / Q000139:chemically induced / Q000503:physiopathology*; D008297:Male; D008657:Metabolic Clearance Rate; D008833:Microcirculation / Q000187:drug effects / Q000502:physiology*; D009929:Organ Size / Q000187:drug effects; D010634:Phenobarbital; D011168:Portal System / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology*
D001647:Bile Acids and Salts; D019332:Endothelin-1; D013449:Sulfonamides; D000077300:Bosentan; D001663:Bilirubin; D010634:Phenobarbital