Unchanged plasma levels of dimethylarginines and nitric oxide in chronic hepatitis C

Objective. Previous studies have shown that asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA) and nitric oxide (NO) play a prominent role in liver dysfunction. The objective of this study was to determine whether plasma levels of ADMA, SDMA and NO are altered in patients with chronic hepatitis C. Material and methods. Plasma levels of ADMA, SDMA and NO (nitrite plus nitrate) were measured in 22 patients with chronic hepatitis C and 24 patients with sustained virologic response after treatment with peginterferon plus ribavirin. Seven healthy volunteers served as controls. Results. Plasma levels of ADMA, SDMA and NO were not significantly different between groups: chronic hepatitis C, ADMA 0.55±0.06, SDMA 0.22±0.03, NO 36.3±5.9 µmol/l; treated patients, ADMA 0.60±0.15, SDMA 0.31±0.05, NO 36.1±5.5 µmol/l; controls, ADMA 0.65±0.08, SDMA 0.28±0.05, NO 40.7±8.9 µmol/l). Conclusions. Our results show that plasma NO, ADMA and SDMA concentrations are not changed in patients with chronic hepatitis C without superimposed signs of acute inflammatory activity. Furthermore, no significant differences in plasma values of NO and dimethylarginines were observed between the group of untreated patients and the group of patients treated with interferon plus ribavirin     

ADMA: a novel risk factor that explains excess cardiovascular event rate in patients with end-stage renal disease

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide (NO) synthase. By competitively displacing L-arginine from the substrate binding site of NO synthase, ADMA interferes with many of the physiological functions of NO, like endothelium-dependent vasodilation and leukocyte adhesion. ADMA, like its biologically inactive regioisomer, symmetric dimethylarginine (SDMA), can be found in human plasma and urine in low concentrations. The concentrations of both dimethylarginines are increased in patients with end-stage renal disease, which may explain at least in part endothelial dysfunction and cardiovascular complications in this patient population. In addition, the metabolism of ADMA, but not SDMA, occurs via hydrolytic degradation to citrulline and dimethylamine by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). Data from experimental studies suggest that ADMA inhibits vascular NO elaboration at concentrations that can be measured in plasma of patients with renal disease. Interestingly, ADMA and SDMA are poorly eliminated during hemodialysis. This is probably due to a high level of binding of both molecules to plasma proteins. High ADMA concentrations in patients with end-stage renal disease may contribute to their excess cardiovascular event rate, as in clinical studies a relationship between ADMA and carotid artery intimal thickening was found. Moreover, in a prospective study we demonstrated recently that determination of ADMA plasma concentration is useful to predict future cardiovascular event rate and total mortality in this patient population. As other researchers reported observations that are in line with our findings, there is evidence that ADMA may be a novel cardiovascular risk factor.     

Increasing dimethylarginine levels are associated with adverse clinical outcome in severe alcoholic hepatitis

Previous studies suggest reduced hepatic endothelial nitric oxide synthase activity contributes to increased intrahepatic resistance. Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, undergoes hepatic metabolism via dimethylarginine-dimethylamino-hydrolase, and is derived by the action of protein-arginine-methyltransferases. Our study assessed whether ADMA, and its stereo-isomer symmetric dimethylarginine (SDMA), are increased in alcoholic hepatitis patients, and determined any relationship with severity of portal hypertension (hepatic venous pressure gradient measurement) and outcome. Fifty-two patients with decompensated alcoholic cirrhosis were studied, 27 with acute alcoholic hepatitis and cirrhosis, in whom hepatic venous pressure gradient was higher (P = 0.001) than cirrhosis alone, and correlated with ADMA measurement. Plasma ADMA and SDMA were significantly higher in alcoholic hepatitis patients and in nonsurvivors. Dimethylarginine-dimethylamino-hydrolase protein expression was reduced and protein-arginine-methyltransferase-1 increased in alcoholic hepatitis livers. ADMA, SDMA and their combined sum, which we termed a dimethylarginine score, were better predictors of outcome compared with Pugh score, MELD and Maddrey's discriminant-function. CONCLUSION: Alcoholic hepatitis patients have higher portal pressures associated with increased ADMA, which may result from both decreased breakdown (decreased hepatic dimethylarginine-dimethylamino-hydrolase) and/or increased production. Elevated dimethylarginines may serve as important biological markers of deleterious outcome in alcoholic hepatitis.     

The role of asymmetric and symmetric dimethylarginines in renal disease

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthases. By inhibiting nitric oxide formation, ADMA causes endothelial dysfunction, vasoconstriction, elevation of blood pressure, and aggravation of experimental atherosclerosis. Levels of ADMA and its isomer symmetric dimethylarginine (SDMA), which does not inhibit nitric oxide synthesis, are both elevated in patients with kidney disease. Currently available data from prospective clinical trials in patients with chronic kidney disease suggest that ADMA is an independent marker of progression of renal dysfunction, vascular complications and death. High SDMA levels also negatively affect survival in populations at increased cardiovascular risk, but the mechanisms underlying this effect are currently only partly understood. Beyond glomerular filtration, other factors influence the plasma concentrations of ADMA and SDMA. Elevated plasma concentrations of these dimethylarginines might also indirectly influence the activity of nitric oxide synthases by inhibiting the uptake of cellular L-arginine. Other mechanisms may exist by which SDMA exerts its biological activity. The biochemical pathways that regulate ADMA and SDMA, and the pathways that transduce their biological function, could be targeted to treat renal disease in the future.     

Transjugular intrahepatic portosystemic shunt-placement increases arginine/asymmetric dimethylarginine ratio in cirrhotic patients

AIM：To analyze the change of dimethylarginine plasma levels in cirrhotic patients receiving transjugular intrahepatic portosystemic shunt（TIPS）.METHODS：To determine arginine,asymmetric dimethylarginine（ADMA）,symmetric dimethylarginine（SDMA）,and nitric oxide（NO） plasma levels,blood samples were collected from the superior cava,hepatic,and portal vein just before,directly after,and 3 mo after TIPS-placement.RESULTS：A significant increase in the arginine/ADMA ratio after TIPS placement was shown.Moreover,TIPS placement enhanced renal function and thereby decreased systemic SDMA levels.In patients with renal dysfunction before TIPS placement,both the arginine/ADMA ratio and creatinine clearance rate increased significantly,while this was not the case in patients with normal renal function before TIPS placement.Hepatic function did not change significantly after TIPS placement and no significant decline in ADMA plasma levels was measured.CONCLUSION：The increase of the arginine/ADMA ratio after TIPS placement suggests an increase in intracellular NO bioavailability.In addition,this study suggests that TIPS placement does not alter dimethylarginine dimethylaminohydrolase（DDAH） activity and confirms the major role of the liver as an ADMA clearing organ.     

The emerging role of asymmetric dimethylarginine as a novel cardiovascular risk factor

There is abundant evidence that the endothelium plays a crucial role in the maintenance of vascular tone and structure. One of the major endothelium-derived vasoactive mediators is nitric oxide (NO). Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthase. ADMA inhibits vascular NO production at concentrations found in pathophysiological conditions (i.e., 3-15 micromol/l); ADMA also causes local vasoconstriction when it is infused intraarterially. The biochemical and physiological pathways related to ADMA are now well understood: dimethylarginines are the result of the degradation of methylated proteins; the methyl group is derived from S-adenosylmethionine. Both ADMA and its regioisomer, SDMA, are eliminated from the body by renal excretion, whereas only ADMA, but not SDMA, is metabolized via hydrolytic degradation to citrulline and dimethylamine by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). DDAH activity and/or expression may therefore contribute to the pathogenesis of endothelial dysfunction in various diseases. ADMA is increased in the plasma of humans with hypercholesterolemia, atherosclerosis, hypertension, chronic renal failure, and chronic heart failure. Increased ADMA levels are associated with reduced NO synthesis as assessed by impaired endothelium-dependent vasodilation. In several prospective and cross-sectional studies, ADMA evolved as a marker of cardiovascular risk. With our increasing knowledge of the role of ADMA in the pathogenesis of cardiovascular disease, ADMA is becoming a goal for pharmacotherapeutic intervention. Among other treatments, the administration of L-arginine has been shown to improve endothelium-dependent vascular function in subjects with high ADMA levels.     

Asymmetric dimethylarginine levels in thyroid diseases

Thyroid diseases may lead to endothelial dysfunction; however, the mechanism underlying the endothelial dysfunction in thyroid disease is not clear yet. Asymmetric dimethylarginine (ADMA), a novel inhibitor of endothelial nitric oxide synthase (eNOS), blocks nitric oxide (NO) synthesis from L-arginine. Symmetric dimethylarginine (SDMA) is the structural isomer of the eNOS inhibitor ADMA. SDMA does not directly inhibit eNOS but is a competitive inhibitor of arginine transport. Increased plasma ADMA, SDMA concentrations, and low L-arginine/ADMA ratio were considered as possible contributing factors for endothelial dysfunction in hyperthyroid patients. On the other hand, plasma ADMA, SDMA levels and L-arginine/ADMA ratio in the hypothyroid group were unexpectedly found to be similar to those of the control subjects. The aim of this study is to evaluate and compare the plasma ADMA levels in hyperthyroid, hypothyroid and healthy subjects. Plasma ADMA, SDMA, and L-arginine levels were measured by high performance liquid chromatography. Plasma ADMA levels were significantly higher in both patients with hyperthyroidism and hypothyroidism than in the control group. SDMA concentrations were significantly increased in hypothyroid patients compared to control subjects. Patients with hyperthyroidism and hypothyroidism had significantly higher plasma L-arginine levels compared with healthy controls. L-arginine/ADMA ratio, which shows NO bioavailability, was significantly lower in hyperthyroid patients than in both hypothyroid and control subjects. In hyperthyroidism, plasma ADMA levels were related to age, L-arginine, and SDMA levels. SDMA was associated with age and L-arginine. L-arginine/ADMA ratio was negatively associated with freeT4 levels. There was a relationship between ADMA and L-arginine in hypothyroid patients. SDMA was significantly related to L-arginine, total cholesterol, and LDL. In conclusion, not only hyperthyroidism but also hypothyroidism was associated with alterations of ADMA and SDMA metabolism.     

Asymmetric dimethylarginine, derangements of the endothelial nitric oxide synthase pathway, and cardiovascular diseases

Analogues of L-arginine that are chemically modified at the terminal guanidino nitrogen group, such as Nomega-monomethy-L-arginine (L-NMMA), have been used for nitric oxide synthase inhibition. However, L-NMMA and other methylated L-arginine analogues are also endogenously formed. Among these, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) have been shown to be the most abundant. Like L-NMMA, ADMA is an inhibitor of NO synthase, whereas SDMA is inactive. ADMA is synthesized by N-methyltransferases, a family of enzymes that methylate L-arginine residues within specific proteins. Free ADMA is released during proteolytic cleavage of methylated proteins; it can be detected in plasma and urine, but its intracellular concentrations appear to be much higher. ADMA is metabolized by the enzyme dimethylarginine dimethylaminohydrolase (DDAH), and inhibition of DDAH activity has been shown to lead to increased ADMA levels and endothelial dysfunction. Plasma levels of ADMA are elevated in endstage renal failure, in atherosclerosis and hypercholesterolemia, in hypertension, and in heart failure. Although the molecular cause for elevation of ADMA concentration in these diseases has not been fully elucidated, evidence is accumulating that ADMA is one cause of endothelial dysfunction in these diseases. Moreover, it may be a marker or even a risk factor for cardiovascular disease. Therefore, pharmacological modulation of ADMA concentration may be a novel therapeutic target in cardiovascular diseases.     

Relationships between dimethylarginine and the presence of vertebral fractures in type 2 diabetes mellitus

Objective Although previous studies suggested that nitric oxide (NO) could affect bone metabolism, little is known about whether asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase, is associated with the risk of osteoporotic fractures. Methods A cross‐sectional study was carried out to examine the associations of serum dimethylarginines with bone mineral density (BMD), bone turnover markers, and the presence of vertebral fractures in 226 men and 152 postmenopausal women with type 2 diabetes. Results In subjects with vertebral fractures, there was significantly higher serum ADMA in men (0·61 ± 0·20 [mean ± SD] vs 0·55 ± 0·19 μm , P = 0·030) and symmetric dimethylarginine (SDMA) in postmenopausal women (0·72 ± 0·37 vs 0·56 ± 0·16 μm , P < 0·001) than in those without fractures. In men with vertebral fractures, serum ADMA was negatively correlated with Z‐score at one‐third radius (multiple regression β = ?0·28, p = 0·016), and SDMA was positively correlated with serum osteocalcin (β = 0·38, P = 0·044) and urinary N‐terminal cross‐linked telopeptide of type‐I collagen (β = 0·40, P = 0·027). In addition, serum ADMA in men and SDMA in postmenopausal women were positively associated with the presence of vertebral fractures after adjusting for age, duration of diabetes, and lumbar BMD (multiple logistic regression odds ratio [OR] = 1·36, P = 0·044 and OR = 1·78, P = 0 .006, respectively). Conclusions We report, for the first time, that serum dimethylarginines may be independent risk factors for prevalent vertebral fractures in patients with type 2 diabetes.     

The L-Arginine–Asymmetric Dimethylarginine Ratio is an Independent Predictor of Mortality in Dilated Cardiomyopathy

BackgroundAsymmetric dimethylarginine (ADMA) is associated with increased mortality in patients with chronic heart failure but it remains unclear if the etiology of heart failure influences the prognostic value of dimethylarginines.Methods and ResultsL-Arginine, ADMA, and symmetric dimethylarginine (SDMA) were measured by liquid chromatography–tandem mass spectrometry in 341 patients with chronic heart failure due to dilated cardiomyopathy (DCM; n = 226) or ischemic cardiomyopathy (ICM; n = 115). Median (interquartile range [IQR]) ADMA and SDMA plasma levels were higher, L-arginine and the L-arginine–ADMA ratio were lower in patients with severe forms of heart failure (New York Heart Association (NYHA) functional class III or IV) compared with milder forms (NYHA functional class I or II) (ADMA 0.57 (0.14) μmol/L vs 0.54 (0.12) μmol/L [P < .001]; SDMA 0.47 (0.27) μmol/L vs 0.37 (0.13) μmol/L [P < .001]; L-arginine 81.8 (39.1) μmol/L vs 92.6 (39.3) μmol/L [P < .01]), but no significant differences were observed between the different etiologies. The L-arginine–ADMA ratio was associated with outcome only in patients with DCM. In multivariate analysis, the mortality risk of DCM patients was significantly lower for those in the highest quartile compared with the lowest quartile during a median observation time of 3.3 years (hazard ratio 0.31, 95% CI 0.11–0.88; P = .028, adjusted for other risk factors).ConclusionsDCM patients with unfavourable L-arginine–ADMA ratio are at increased risk for death.     

Relations between plasma asymmetric dimethylarginine (ADMA) and risk factors for coronary disease

BACKGROUND: Elevated plasma levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide production, are reported to be associated with coronary artery disease (CAD). METHODS: We measured plasma levels of ADMA and related compounds, nitrate+nitrite (NO(x)), total homocysteine (tHCY) and assessed renal function and lipid profiles in 145 patients--75 with triple vessel coronary disease and 70 with no detectable coronary disease. RESULTS: Levels of ADMA, l-arginine, l-arginine/ADMA and plasma NO(x) were not different in the two groups but smokers with triple vessel disease had higher ADMA and lower NO(x) levels than the non-smokers, relationships also present for all smokers and non-smokers in the two groups combined. In all 145 patients ADMA, symmetric dimethylarginine (SDMA) and tHCY levels were significantly higher in patients with glomerular filtration rate (GFR) <81 mL/min/1.73 m(2) than in patients with GFR> or =81 mL/min/1.73 m(2). There was a modest positive correlation between tHCY and ADMA and both were strongly correlated with SDMA which is excreted by the kidney. ADMA, SDMA and tHCY were negatively correlated with GFR. CONCLUSIONS: We suggest that the reported ADMA increases in CAD patients are due to an associated reduction in renal function and to smoking habit.     

Dimethylarginines at the crossroad of insulin resistance and atherosclerosis

We tested if asymmetric dimethylarginine (ADMA) contributes to the simultaneous evolution of atherosclerosis and insulin resistance. We investigated the significant predictors of insulin resistance in the context of atherosclerosis, focusing on the role ADMA, symmetric dimethylarginine (SDMA), and l-arginine play in a cohort of young atherosclerotic patients and their age-matched controls. In a case-control study, 60 patients younger than 55 years having at least 30% stenosis of the internal carotid artery and 30 age- and sex-matched controls were recruited at a community-based neurosonologic laboratory. We found a strong positive association between the homeostasis model assessment of beta-cell function and insulin resistance and the ADMA/SDMA ratio that remained statistically significant even after adjusting for all significant and a priori identified determinants (beta = 6.76; 95% confidence interval [CI], 2.13-11.39; P = .005). Interestingly, this relationship was even more pronounced in the atherosclerotic stratum (beta = 8.29; 95% CI, 1.43-15.15; P = .019), whereas, on multiple linear regression, lack of association was seen in subjects free of carotid atherosclerosis (beta = 1.39; 95% CI, -5.46 to 8.26; P = .671). We conclude that ADMA/SDMA ratio is a significant determinant of insulin resistance and may be a better parameter to monitor than ADMA alone. By accounting for the competition at the y+ transporters, ADMA/SDMA ratio could be an indicator of intracellular ADMA level.     

L-Arginine Pathway in COPD Patients with Acute Exacerbation: A New Potential Biomarker

Background: Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) remains a major cause of mortality. Clinical criteria of AECOPD are subjective. Biomarkers for AECOPD may aid in the initiation of early treatment. Increased production of asymmetric and symmetric dimethylarginine (ADMA, SDMA) is related to hypoxia. In COPD, a rise in ADMA results in a shift of L-arginine breakdown, contributing to airway obstruction. We aimed to compare serum levels of ADMA, SDMA and L-arginine in patients with and without AECOPD.

Methods: L-arginine metabolites quantified by high-performance liquid chromatography in venous blood samples and partial capillary oxygen pressure were prospectively investigated in 32 patients with COPD, 12 with AECOPD and 30 healthy subjects.

Results: Both ADMA and SDMA were significantly higher in AECOPD compared to stable COPD (p = 0.004 and p < 0.001, respectively). Oxygen content in capillaries correlated with serum ADMA concentration. However, the concentration of L-arginine was not different between AECOPD and stable COPD. Both ADMA and SDMA separated AECOPD with high sensitivity and specificity (AUC: 0.81, p = 0.001; AUC: 0.91, p < 0.001, respectively). A cut-off value ≥0.57 for SDMA was an independent variable to confirm AECOPD in a regression model (OR: 1.632, p = 0.001). All markers were significantly higher in the sera of both patient groups compared to the controls (p < 0.05, respectively).

Conclusions: COPD is associated with elevated L-arginine, ADMA and SDMA serum levels. In patients with AECOPD, production of ADMA and SDMA are more pronounced presumably due to more severe hypoxic insult. Methylated arginine derivatives in the sera may help early recognition of AECOPD.     

Asymmetric dimethylarginine as a mediator of vascular dysfunction in cirrhosis

Cirrhosis is associated with marked abnormalities in the circulatory function that involve a reduction in systemic vascular resistance. An important cause of this vasodilatation is the increased production or activity of nitric oxide (NO) in the splanchnic circulation. During portal hypertension and cirrhosis an increased endothelial NO synthase (eNOS) activity is demonstrated in splanchnic vessels. In contrast, the activity of eNOS in the cirrhotic liver is decreased, which suggests a different regulation of eNOS in the liver and in the splanchnic vessels. Asymmetric dimethylarginine (ADMA) is an endogenous NO inhibitor and higher plasma levels of ADMA are related to increased cardiovascular risk in both the general population and among patients with cirrhosis. It has been demonstrated that the liver is a key player in the metabolism of ADMA. This observation was further supported by investigations in human patients, showing a close correlation between ADMA plasma levels and the degree of hepatic dysfunction. ADMA is degraded to citrulline and dimethylamine by dimethylarginine dimethylaminohydrolases (DDAHs). DDAHs are expressed as type 1 and 2 isoforms and are widely distributed in various organs and tissues, including the liver. In this review, we discuss experimental and clinical data that document the effects of dimethylarginines on vascular function in cirrhosis. Our increasing understanding of the routes of synthesis and metabolism of methylarginines is beginning to provide insights into novel mechanisms of liver disease and allowing us to identify potential therapeutic opportunities.     

Plasma concentrations of nitric oxide and asymmetric dimethylarginine in human alcoholic cirrhosis

BACKGROUND/AIMS: The liver plays a prominent role in the metabolism of asymmetric dimethyl-l-arginine (ADMA), an endogenous inhibitor of nitric oxide (NO) synthase. This study was designed to determine whether plasma levels of ADMA and NO production are altered in patients with compensated and decompensated alcoholic cirrhosis. METHODS: Plasma levels of l-arginine, ADMA, symmetric dimethylarginine (SDMA) and NO (nitrite plus nitrate, NOx) were measured in nine patients with compensated alcoholic cirrhosis (Child-Pugh A) and 11 patients with advanced cirrhosis (Child-Pugh B-C). Seven healthy volunteers served as controls. RESULTS: ADMA and NOx concentrations in decompensated cirrhosis were higher than in the compensated group and control group (ADMA: 1.12+/-0.08 vs. 0.58+/-0.05 and 0.58+/-0.07micromol/l, respectively; P<0.05; NOx 97.90+/-10.27 vs. 37.42+/-3.91 and 40.43+/-5.30micromol/l, respectively; P<0.05). There was a positive correlation between the clinical score of the patients and concentrations of ADMA (r(2)=0.547, P<0.01) and NOx (r(2)=0.689, P<0.01). SDMA and l-arginine levels were not significantly different between the three groups. CONCLUSIONS: The results suggest that hepatocellular damage is a main determinant of elevated ADMA concentration in advanced alcoholic cirrhosis. By inhibiting NO release from vascular endothelium, ADMA might oppose the peripheral vasodilation caused by excessive NO production in severe cirrhosis.     

Dimethylarginines in patients with type 2 diabetes mellitus: relation with the glycaemic control

We tested the relationship between plasma levels of dimethylarginines (ADMA and SDMA) and glycaemic control in 43 type 2 diabetic patients. Type 2 diabetics with poor glycaemic control (HbA1c > 6.5) had significantly lower SDMA and higher ADMA concentrations than those with well-controlled glycaemia (HbA1c < 6.5).     

内源性一氧化氮合成酶抑制物在冠心病中的表达及意义研究

目的:探讨冠心病患者血中内源性一氧化氮合成酶(NOS)抑制物非对称性二甲基精氨酸(ADMA)与冠心病的关系及其临床意义。方法:随机选择37例冠心病患者和18例正常人,分别作为冠心病组和正常对照组,均经选择性冠脉造影确定冠状动脉有无病变及病变程度,测定血清中ADMA、对称性二甲基精氨酸(SDMA)和L-精氨酸水平及血脂水平。结果:冠心病组血清中NOS抑制物ADMA水平较正常对照组明显增高(P<0.01);冠心病组血清中的内源性ADMA水平随着冠状动脉病变的加重略有增高的趋势(P>0.05);冠心病组与正常对照组之间的SDMA和L-精氨酸的水平无明显差异(P>0.05);ADMA水平与冠状动脉病变程度有正相关关系(r=0.28,P<0.05)。结论:内源性NOS抑制物ADMA的异常增高与冠心病发病有关,ADMA水平增高可能是冠心病的一项值得关注的危险因素。     

Elevated concentrations of asymmetric dimethylarginine are associated with deterioration of glucose tolerance in women with previous gestational diabetes mellitus

OBJECTIVE: Women with previous gestational diabetes mellitus (GDM) have a high risk for development of type 2 diabetes mellitus. The endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) could be related to disorders of the glucose metabolism. To evaluate if ADMA predicts deterioration of glucose tolerance in women with previous GDM and to assess concentration changes we analysed ADMA in women with previous GDM after delivery and after a median follow-up of 2.75 years (interquartile range: 1.47-4.60). DESIGN: Prospective cohort study. Subjects and methods. ADMA, symmetric dimethylarginine (SDMA) and L-arginine were determined in 77 women with previous GDM who underwent a 75-g oral glucose tolerance test 4 months after delivery and at follow-up. RESULTS: Deterioration in glucose tolerance was observed in 36% of the women with ADMA above and 11% of those with ADMA below the median (0.56 micromol L(-1); P = 0.008, log-rank test). ADMA correlated significantly with mean arterial blood pressure and nonsignificantly with body mass index (P = 0.050) but not with insulin resistance, fasting glucose, lipids or glomerular filtration rate. The fully adjusted hazard ratio for a decline of glucose tolerance during follow-up was 3.94 (95% CI: 1.16-13.37; P = 0.028) for subjects with ADMA above the median. SDMA and L-arginine were not associated with changes in the glucose tolerance status. ADMA and L-arginine decreased significantly during follow-up. CONCLUSIONS: High serum ADMA after delivery is associated with deterioration in glucose tolerance in women with previous GDM and declines in the following years.     

Effects of combined supplementation with B vitamins and antioxidants on plasma levels of asymmetric dimethylarginine (ADMA) in subjects with elevated risk for cardiovascular disease

Elevated plasma asymmetric dimethylarginine (ADMA) concentrations have been suggested as a potential risk factor for cardiovascular disease (CVD). Studies indicate a linkage between hyperhomocysteinemia, oxidative stress and ADMA metabolism. We tested the hypothesis that combined supplementation of B vitamins and antioxidants reduces ADMA concentrations in subjects with at least two CVD risk factors. A total of 123 men and women (58+/-8.1 years) were randomly assigned to take either a preparation including B vitamins and antioxidants (verum) or placebo for 6 months in a double-blind design. Blood concentrations of ADMA, symmetric dimethylarginine (SDMA), L-arginine, B vitamins, total homocysteine (tHcy), alpha-tocopherol, antioxidant capacity (TEAC), and oxLDL were measured pre- and post-intervention. Treatment with verum significantly decreased tHcy (-2.14 micromol/L; P<0.001) and significantly increased TEAC values (+39.3 microM; P<0.022), but no effect on ADMA was observed. OxLDL was significantly reduced in verum (-7.3 U/L; P=0.001) and placebo (-9.2U/L; P<0.001). At baseline, significant correlations were found only between ADMA and SDMA (r=0.281; P=0.002), L-arginine/ADMA and SDMA (r=-0.294; P<0.001), L-arginine/ADMA and oxLDL (r=-0.281; P=0.016), and L-arginine/ADMA and age (r=-0.231; P=0.010). Our results indicate that combined supplementation of B vitamins and antioxidants is not an adequate strategy to reduce ADMA plasma levels in subjects with elevated CVD risk.