Aims: 

Asymmetric N^G,N^G-dimethyl-L-arginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), decreases intrahepatic endothelial nitric oxide synthesis and contributes to the pathogenesis of portal hypertension associated with cirrhosis. We evaluated whether the expression and/or activity of dimethylarginine dimethylaminohydrolase (DDAH), enzyme that catabolises ADMA, is responsible for increased levels of ADMA in cirrhotic livers.

Methods: 

Cirrhosis was induced in rats by common bile duct ligation (CBDL), and they were compared with sham rats. Experiments were conducted 4 weeks after either the sham or CBDL surgery. The expression of DDAH-I in the liver was estimated by immunoblotting and TaqMan QRT-PCR analysis. The ratio between the mRNA levels of DDAH-I and the mRNA level of GAPDH, a constitutively expressed protein, was used for comparison. DDAH enzyme activity was measured by ADMA conversion to L-citrulline.

Results: 

DDAH-I is highly expressed in liver. In liver from CBDL rats, the mRNA levels of DDAH-I were downregulated (446%, p<0.05 versus sham-operated rats, n=6). Immunoblots showed a significant decrease (758%, p<0.05, n=6) of DDAH-I protein expression in liver from CBDL rats. DDAH activity from homogenized livers was lower (557%, p<0.05, n=6) in CBDL than in sham-operated rats.

Conclusions: 

In livers from CBDL rats DDAH activity and DDAH-I expression are decreased. These results suggest that impaired DDAH expression and activity in cirrhotic livers may cause accumulation of ADMA, an endogenous inhibitor of endothelial NOS, thereby contributing to portal hypertension in rats with biliary cirrhosis.

This work was supported by Conselleria de Sanidad (AP-052/08), Generalitat Valenciana.