Three-day tetrahydrobiopterin therapy increases in vivo hepatic NOS activity and reduces portal pressure in CCl4 cirrhotic rats.
OBJECTIVE
Tetrahydrobiopterin is an essential cofactor for NOS enzymes to synthesize NO. It has been suggested that reduced intrahepatic tetrahydrobiopterin decreases intrahepatic NO and contributes to increase hepatic vascular resistance and portal pressure in cirrhosis. The main aim of the study was to evaluate the effect of tetrahydrobiopterin supplementation in portal pressure in CCl4 cirrhotic rats.


METHODS
Cirrhotic rats received vehicle or tetrahydrobiopterin (10mg/kg/day i.p.) for 3 days. Hepatic and systemic hemodynamics and hepatic tetrahydrobiopterin, NOS activity and cGMP levels were measured. In addition, hepatic and systemic hemodynamics were evaluated in normal rats in which tetrahydrobiopterin deficiency was induced by administrating 2,4-diamino-6-hydroxy-pyrimidine (DAHP) for 8h.


RESULTS
In cirrhotic rats, tetrahydrobiopterin administration increased liver NOS activity and cGMP levels and markedly and significantly reduced portal pressure. Amelioration of portal hypertension was associated with a normalization of arterial pressure. In normal rats DAHP decreased hepatic tetrahydrobiopterin and NOS activity and increased hepatic vascular tone. These effects of DAHP administration were corrected by tetrahydrobiopterin supplementation.


CONCLUSIONS
The present study shows that tetrahydrobiopterin markedly reduces portal hypertension and improves systemic hemodynamics in cirrhotic rats. These data support the concept that tetrahydrobiopterin supplementation may represent a new therapeutic strategy for portal hypertension.
Hepatic Hemodynamic Laboratory, Liver Unit, Institut de Malalties Digestives i Metabòliques, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Villarroel 170, 08036 Barcelona, Spain.
Vasilica
V
Matei
Aina
A
Rodríguez-Vilarrupla
Ramon
R
Deulofeu
Héctor
H
García-Calderó
Mercedes
M
Fernández
Jaime
J
Bosch
Joan-Carles
JC
Garcia-Pagán
D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives* / Q000172:deficiency / Q000494:pharmacology; D002251:Carbon Tetrachloride / Q000633:toxicity; D006152:Cyclic GMP / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006975:Hypertension, Portal / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D007042:Hypoxanthines / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013152:Splanchnic Circulation / Q000187:drug effects
D004791:Enzyme Inhibitors; D007042:Hypoxanthines; D001708:Biopterins; D002251:Carbon Tetrachloride; D019001:Nitric Oxide Synthase; C017202:2,4-diaminohypoxanthine; C003402:sapropterin; D006152:Cyclic GMP