Hemodynamic and antifibrotic effects of a selective liver nitric oxide donor V-PYRRO/NO in bile duct ligated rats.
OBJECTIVE
To assess whether a liver specific nitric oxide (NO) donor (V-PYRRO/NO) would prevent the development of portal hypertension and liver fibrosis in rats with bile duct ligation (BDL).


METHODS
Treatment (placebo or V-PYRRO/NO 0.53 micromol/kg per hour) was administered i.v. to rats 2 d before BDL (D-2) and maintained until the day of hemodynamic measurement (D26). Intra-hepatic NO level was estimated by measuring liver cGMP level. Effects of V-PYRRO/NO on liver fibrosis and lipid peroxidation were also assessed.


RESULTS
Compared to placebo treatment, V-PYRRO/NO improved splanchnic hemodynamics in BDL rats: portal pressure was significantly reduced by 27% (P<0.0001) and collateral circulation development was almost completely blocked (splenorenal shunt blood flow by 74%, P=0.007). Moreover, V-PYRRO/NO significantly prevented liver fibrosis development in BDL rats (by 30% in hepatic hydroxyproline content and 31% in the area of fibrosis, P<0.0001 respectively), this effect being probably due to a decrease in lipid peroxidation by 44% in the hepatic malondialdehyde level (P=0.007). Interestingly, we observed a significant and expected increase in liver cGMP, without any systemic hemodynamic effects (mean arterial pressure, vascular systemic resistance and cardiac output) in both sham-operated and BDL rats treated with V-PYRRO/NO. This result is in accordance with studies on V-PYRRO/NO metabolism showing a specific release of NO in the liver.


CONCLUSIONS
Continuous administrations of V-PYRRO/NO in BDL rats improved liver fibrosis and splanchnic hemodynamics without any noxious systemic hemo-dynamic effects.
Moal
Frédéric
F
Laboratoire HIFIH, UPRES 3859, Université, Angers, and INSERM U481, Hôpital Beaujon, Clichy, France.
Veal
Nary
N
Vuillemin
Eric
E
Barrière
Eric
E
Wang
Jianhua
J
Fizanne
Lionel
L
Oberti
Frédéric
F
Douay
Olivier
O
Gallois
Yves
Y
Bonnefont-Rousselot
Dominique
D
Rousselet
Marie Christine
MC
Calès
Paul
P
D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001652:Bile Ducts / Q000503:physiopathology*; D001663:Bilirubin / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D006339:Heart Rate / Q000187:drug effects; D006975:Hypertension, Portal / Q000209:etiology / Q000517:prevention & control*; D008026:Ligation; D015227:Lipid Peroxidation / Q000187:drug effects; D008102:Liver Circulation / Q000187:drug effects; D008103:Liver Cirrhosis / Q000209:etiology / Q000517:prevention & control*; D008297:Male; D009569:Nitric Oxide / Q000097:blood; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014655:Vascular Resistance / Q000187:drug effects
D020030:Nitric Oxide Donors; C107010:O(2)-vinyl-1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate; D011759:Pyrrolidines; D009569:Nitric Oxide; D001219:Aspartate Aminotransferases; D000469:Alkaline Phosphatase; D001663:Bilirubin