Treatment of bile duct-ligated rats with the nitric oxide synthase transcription enhancer AVE 9488 ameliorates portal hypertension.
OBJECTIVE
Nitric oxide levels are decreased in the cirrhotic liver and increased in the systemic vasculature. We investigated whether the nitric oxide synthase (NOS) transcription enhancer AVE 9488 ameliorates portal hypertension in cirrhotic rats.


METHODS
Rats with secondary biliary cirrhosis [bile duct ligation (BDL)] were treated with AVE 9488. BDL animals without treatment served as controls. Blood flow was determined with the microsphere technique. Intrahepatic resistance was measured by in situ perfusion. NOS-3 mRNA and protein levels in the liver, aorta and superior mesenteric artery (SMA) were measured.


RESULTS
Arterial pressure did not differ between treated and non-treated animals. Portal pressure, hepatic portal-vascular resistance and perfusion pressure of the in situ perfused liver were lower in the AVE 9488-treated animals. Arterial splanchnic resistance, portal venous inflow and shunt volume were increased by AVE 9488. N (G)-nitro-l-arginine methyl ester abolished the effect of AVE 9488. AVE 9488-treated rats had higher liver NOS-3 mRNA and protein levels, whereas NOS-3 mRNA and protein in the aorta and the SMA did not vary between groups. Phosphorylation of liver vasodilator-stimulated phosphoprotein (VASP) and NOS-3 as well as hepatic nitrite/nitrate was increased by AVE 9488.


CONCLUSIONS
Treatment of BDL rats with the NOS transcription enhancer AVE 9488 induces an increase in NOS-3 mRNA and protein in the liver. This is associated with an amelioration of portal hypertension.
Biecker
Erwin
E
Department of Internal Medicine I, University Hospital of Bonn, University of Bonn, Bonn, Germany. erwin.biecker@helios-kliniken.de
Trebicka
Jonel
J
Kang
Alice
A
Hennenberg
Martin
M
Sauerbruch
Tilman
T
Heller
Jörg
J
D000818:Animals; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D001651:Cholestasis, Extrahepatic; D006975:Hypertension, Portal / Q000188:drug therapy* / Q000209:etiology*; D008099:Liver / Q000098:blood supply / Q000378:metabolism*; D008105:Liver Cirrhosis, Biliary / Q000150:complications* / Q000188:drug therapy; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000627:therapeutic use*
C528454:4-fluoro-N-indan-2-yl-benzamide; D001549:Benzamides; D014157:Transcription Factors; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat