Plasma concentrations of asymmetric (ADMA) and symmetric (SDMA) dimethylarginine are increased in end-stage renal disease (ESRD), contributing to endothelial dysfunction through direct (ADMA) and indirect (SDMA) inhibition of nitric oxide (NO) synthesis. Little is known on the direct relationship between NO and methylated arginines in ESRD, however. We addressed this issue in ESRD patients undergoing haemodialysis.Methods
Plasma concentrations of nitrite:nitrate (NOx, a marker of NO synthesis), L-arginine, ADMA, SDMA, and markers of inflammation (C-reactive protein, CRP) and oxidative stress (malondialdehyde, MDA) were measured in 47 ESRD patients (age 64.4 ± 13.4 years) on haemodialysis for 21 (3-126) months.Results
There was a positive correlation between ADMA and NOx (r=0.404, P=0.005) and between SDMA and NOx (r=0.587, P < 0.001) in the whole population. ADMA correlated positively with MDA (r=0.426, P=0.007), SDMA (r=0.538, P < 0.001), and L-Arginine (r=0.434, P=0.002). L-Arginine, in turn, also correlated with MDA (r=0.367, P=0.022). When dividing patients based on median MDA (1.06 μmol/L) the ADMA-NOx and SDMA-NOx correlations were significant only in the higher MDA group (Table 1). When patients were divided based on median CRP (6.0 mg/L), the SDMA-NOx correlation was significant both in the low CRP and in the high CRP groups. The ADMA-NOx correlation was significant in the higher CRP group but not in the lower CRP group (Table 1).Conclusions
We found positive correlations between plasma NOx, ADMA, and SDMA in ESRD, particularly in patients with higher CRP and MDA concentrations. These surprising findings, given the inhibitory effects of methylated arginines on NO synthesis, suggest that 1) higher NOx concentrations are secondary to excessive NO synthesis due to a pro-inflammatory state; and 2) the relationship between methylated arginines and NO depends on the existing inflammatory and oxidation status.