Aim: 

ADMA plays a regulatory role in the arginine-NO pathway by inhibiting the nitric oxide synthase (NOS). ADMA mainly catabolized by DDAH is increased in various phatologic conditions. DDAH and NOS participate in the regulation of intrahepatic vascular tone by increasing the synthesis of NO in endothelial sinusoidal cells and thus inducing local vasorelaxation. Because obesity is a major risk factor for the development of endothelial dysfunction and plays an important role in hepatic damage, the aim of the present study was to determine the alterations in DDAH-ADMA-NO pathway in patients with morbid obesity.

Methods: 

Patients were classified according to body mass index (BMI) in morbid obesity group (BMI >= 45, n=16) and control group (BMI <= 24, n=7). Plasma NO_x levels (nitrates plus nitrites) were measured by using Griess reaction. Plasma concentration of ADMA was assessed by high-performance-chromatography (HPLC). The expression of genes encoding DDAH (types I and II) and endothelial NOS were estimated by quantitative RT-PCR Taqman analysis in liver biopsies obtained during gastric bypass procedures. Control liver tissues and plasma samples were obtained from hepatic surgery in nonobese patients.

Results: 

ADMA plasma levels were increased in morbid obesity group (1.31 0.39 mmol/l) compared with controls (0.53 0.05 mmol/l, P<0.05). NO_x plasma levels were significally decresed in morbid obesity group (27.26 2.51 mmol/l) compared with control group (40.41 3.64 mmol/l, P<0.05). An increment of mRNA expression of eNOS was observed in morbid obesity samples (21828%, P<0.05). Genic expression of DDAH-1 was four times higher in morbid obesity than in controls (4.48 0.37 vs 1 0.18 mmol/l, P<0.05) but mRNA levels of DDAH-2 were similar in both goups (1.03 0.19 vs 1.06 0.18 mmol/l P>0.05)

Conclusion: 

Obesity is associated with a decrease of NO plasma levels which could be due to an increment of ADMA plasma levels. Obesity is also accompanied by a greater increment in both the hepatic expression of eNOS and DDAH-I but not DDAH-II. This effect could augment the ADMA degradation and decrease the inhibitory effects on NO synthesis.

Supported by Conselleria de Educación, Generalitat Valenciana.