Beneficial hemodynamic effects of bosentan, a mixed ET(A) and ET(B) receptor antagonist, in portal hypertensive rats.
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 microg/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 x s x cm(-5) x 10(-3). Similar results were observed in rats with CCl4-induced cirrhosis. In isolated perfused cirrhotic rat livers, bosentan (1 to 100 micromol/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.
Sogni
P
P
Laboratoire d'Hémodynamique Splanchnique et de Biologie Vasculaire, INSERM, Hôpital Beaujon, Clichy, France.
Moreau
R
R
Gomola
A
A
Gadano
A
A
Cailmail
S
S
Calmus
Y
Y
Clozel
M
M
Lebrec
D
D
D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D000077300:Bosentan; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects*; D006975:Hypertension, Portal / Q000188:drug therapy* / Q000503:physiopathology; D008106:Liver Cirrhosis, Experimental / Q000188:drug therapy; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*
D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D013449:Sulfonamides; D000077300:Bosentan