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l-Arginine (Arg) and l-homoarginine (hArg) are precursors of nitric oxide (NO), a signalling molecule with multiple important roles in human organism. In the circulation of adults, high concentrations of asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) and low concentrations of hArg emerged as cardiovascular risk factors. Yet, the importance of the Arg/hArg/NO pathway, especially of hArg and ADMA, in preterm neonates is little understood. We comprehensively investigated the Arg/hArg/NO pathway in 106 healthy preterm infants (51 boys, 55 girls) aged between 23 + 6 and 36 + 1 gestational weeks. Babies were divided into two groups: group I consisted of 31 babies with a gestational age of 23 + 6 - 29 + 6 weeks; group II comprised 75 children with a gestational age of 30 + 0 - 36 + 1 weeks. Plasma and urine concentrations of ADMA, SDMA, hArg, Arg, dimethylamine (DMA) which is the major urinary ADMA metabolite, as well as of nitrite and nitrate, the major NO metabolites, were determined by GC-MS and GC-MS/MS methods. ADMA and hArg plasma levels, but not the hArg/ADMA molar ratio, were significantly higher in group II than in group I: 895 ± 166 nM vs. 774 ± 164 nM ( P = 0.001) for ADMA and 0.56 ± 0.04 µM vs. 0.48 ± 0.08 µM ( P = 0.010) for hArg. There was no statistical difference between the groups with regard to urinary ADMA (12.2 ± 4.6 vs 12.8 ± 3.6 µmol/mmol creatinine; P = 0.61) and urinary SDMA. Urinary hArg, ADMA, SDMA correlated tightly with each other. Urinary excretion of DMA was slightly higher in group I compared to group II: 282 ± 44 vs. 247 ± 35 µmol/mmol creatinine ( P = 0.004). The DMA/ADMA molar ratio in urine was tendentiously higher in neonates of group I compared to group II: 27 ± 13 vs. 20 ± 5 ( P = 0.065). There were no differences between the groups with respect to Arg in plasma and to nitrite and nitrate in plasma and urine. In preterm neonates, ADMA and hArg biosynthesis increases with gestational age without remarkable changes in the hArg/ADMA ratio or NO biosynthesis. Our study suggests that ADMA and hArg are involved in foetal growth. [ABSTRACT FROM AUTHOR]

Asymmetric dimethylarginine (ADMA) systemic concentrations are elevated in hypercholesterolemic adults and contribute to nitric oxide (NO) dependent endothelial dysfunction. Decreased activity of the key ADMA-hydrolyzing enzyme dimethylarginine dimethylaminohydrolase (DDAH) may be involved. Yet, the ADMA/DDAH/NO pathway has not been investigated in childhood hypercholesterolemia. We studied 64 children with hypercholesterolemia type II (HCh-II) and 54 normocholesterolemic (NCh) children (mean ± SD; age, years: 11.1 ± 3.5 vs. 11.9 ± 4.6). Plasma and urine ADMA was measured by GC-MS/MS. Dimethylamine (DMA), the ADMA metabolite, creatinine, nitrite and nitrate in urine were measured by GC-MS. The DMA/ADMA molar ratio in urine was calculated to estimate whole body DDAH activity. ADMA plasma concentration (mean ± SD; nM: 571 ± 85 vs. 542 ± 110, P = 0.17) and ADMA urinary excretion rate (mean ± SD: 7.1 ± 2 versus 7.2 ± 3 μmol/mmol creatinine, P = 0.6) were similar in HCh-II and NCh children. Both DMA excretion rate [median (25th-75th percentile): 56.3 (46.4-109.1) vs. 45.2 (22.2-65.5) μmol/mmol creatinine, P = 0.0004] and DMA/ADMA molar ratio [median (25th-75th percentile): 9.2 (6.0-16.3) vs. 5.4 (3.8-9.4), P = 0.0004] were slightly but statistically significantly increased in HCh-II children compared to NCh children. Plasma and urinary nitrite and nitrate were similar in both groups. In HCh-II whole body DDAH activity is elevated as compared to NCh. HCh-II children treated with drugs for hypercholesterolemia had lower plasma ADMA levels than untreated HCh-II or NCh children, presumably via increased DDAH activity. Differences between treated and untreated HCh-II children were not due to differences in age. In conclusion, HCh-II children do not have elevated ADMA plasma levels, largely due to an apparent increase in DDAH activity. While this would tend to limit development of endothelial dysfunction, it is not clear whether this might be medication-induced or represent a primary change in HCh-II children. [ABSTRACT FROM AUTHOR]

Plasma concentration of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide (NO) synthesis from l-arginine and a cardiovascular risk factor, was found to be elevated in plasma of homocysteinemic adults. Enhanced cardiovascular risk due to homocystinuria and impaired renal function has been found in patients with phenylketonuria (PKU) on protein-restricted diet. However, it is still unknown whether ADMA synthesis is also elevated in children with homocystinuria due to cystathionine beta-synthase deficiency (classical homocystinuria), and whether ADMA may play a role in phenylketonuria in childhood. In the present study, we investigated the status of the l-arginine/NO pathway in six young patients with homocystinuria, in 52 young phenylketonuria patients on natural protein-restricted diet, and in age- and gender-matched healthy children serving as controls. ADMA in plasma and urine was determined by GC-MS/MS. The NO metabolites nitrate and nitrite in plasma and urine, and urinary dimethylamine (DMA), the dimethylarginine dimethylaminohydrolase (DDAH) metabolite of ADMA, were measured by GC-MS. Unlike urine ADMA excretion, plasma ADMA concentration in patients with homocystinuria was significantly higher than in controls (660 ± 158 vs. 475 ± 77 nM, P = 0.035). DMA excretion rate was considerably higher in children with homocystinuria as compared to controls (62.2 ± 24.5 vs. 6.5 ± 2.9 μmol/mmol creatinine, P = 0.068), indicating enhanced DDAH activity in this disease. In contrast and unexpectedly, phenylketonuria patients had significantly lower ADMA plasma concentrations compared to controls (512 ± 136 vs. 585 ± 125 nM, P = 0.009). Phenylketonuria patients and controls had similar l-arginine/ADMA molar ratios in plasma. Urinary nitrite excretion was significantly higher in phenylketonuria as compared to healthy controls (1.7 ± 1.7 vs. 0.7 ± 1.2 μmol/mmol creatinine, P = 0.003). Our study shows that the l-arginine/NO pathway is differently altered in children with phenylketonuria and homocystinuria. Analogous to hyperhomocysteinemic adults, elevated ADMA plasma concentrations could be a cardiovascular risk factor in children with homocystinuria. In phenylketonuria, the l-arginine/NO pathway seems not be altered. Delineation of the role of ADMA in childhood phenylketonuria and homocystinuria demands further investigation. [ABSTRACT FROM AUTHOR]