Dietary composition as a determinant of plasma asymmetric dimethylarginine in subjects with mild hypercholesterolemia

Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide synthase inhibitor that participates in the regulation of vasodilatory function and is also linked to hypertension, whereas its stereoisomere, symmetric dimethylarginine (SDMA), is biologically inactive. Dietary components influence vascular functions and a high-fat meal seems to increase postprandial plasma ADMA levels. However, it has not been published whether diet influences plasma ADMA levels. In this study, we investigated the impact of diet on plasma ADMA and SDMA levels. Thirty-four mildly hypercholesterolemic, otherwise healthy women (n = 14) and men (n = 20) with a mean age of 46.2 years (range, 35 to 62 years) participated in the study. The subjects were examined twice at intervals of 2 months. Seven-day food records were used to analyze diet and alcohol intake. ADMA was measured by using high-performance liquid chromatography (HPLC)-tandem mass spectrometry. In a multivariate analysis (R2 = 0.20, P < .002), low amount of energy received from carbohydrates (r = -0.31, P = .009) and high plasma triglycerides (r = 0.30, P = .01) were predictors of high ADMA plasma levels. Alcohol drinkers had higher plasma ADMA concentrations than abstainers (0.50 +/- 0.13 v 0.42 +/- 0.11 micromol/L, P = .04). Plasma ADMA correlated with systolic (r = 0.60, P = .005) and diastolic blood pressure (r = 0.53, P = .02) in abstainers but not in alcohol drinkers. Plasma SDMA was not associated with any dietary components or with blood pressure. In conclusion, a high amount of dietary carbohydrates is strongly associated with low levels of plasma ADMA. Concentration of ADMA in plasma seems to be higher in alcohol drinkers than in abstainers.     

Asymmetric dimethylarginine and hemodynamic regulation in middle-aged men

The goal of this study was to evaluate the role of asymmetric dimethylarginine (ADMA) in the regulation of hemodynamic functions in hypertensive men. It has been suggested that ADMA, as an endogenous nitric oxide synthase inhibitor, is linked to hypertension and vascular reactivity. Sixty-seven men aged 51.1 years (range, 45-55 years) were studied. Plasma ADMA and symmetric dimethylarginine were determined by high-performance liquid chromatography-tandem mass spectrometry. Blood pressure (BP) was measured by 24-hour ambulatory recordings and casual measurements. Hemodynamic regulation was assessed by noninvasive methods. The nitric oxide production was estimated based on plasma nitrate (NO₃⁻) determination. Results showed that plasma arginine derivatives or l-arginine/ADMA ratio was not associated with BP values observed during 24-hour monitoring or in casual measurements. Systemic vascular resistance, pulse wave velocity, or cardiac output was not associated with plasma ADMA or plasma NO₃⁻ levels. No association was found between plasma ADMA and NO₃⁻ either. Interestingly, subjects on antihypertensive treatment had lower plasma ADMA concentrations than nontreated subjects (0.30 ± 0.08 and 0.36 ± 0.11 μmol/L, respectively, P = .04) despite higher BP values. In conclusion, these results suggest that plasma ADMA does not have a determinative role in the regulation of hemodynamic functions in Finnish middle-aged men.     

High tea and vegetable consumption is associated with low ADMA generation in older healthy subjects

Asymmetric dimethylarginine (ADMA) has been recognized as a marker of cardiovascular risk. We sought to investigate whether consumption of tea, coffee, fruit or vegetables is associated with ADMA. In 148 consecutive apparently healthy subjects (104 men and 44 women aged 40 to 70), daily tea, coffee, fruit and vegetable consumption was ascertained by questionnaire. Plasma ADMA, symmetric dimethylarginine (SDMA), and l-arginine levels were measured by high-performance liquid chromatography. Median tea and coffee consumption was 2 cups/d, while vegetable and fruit intake was 152 (120-179)g/d and 120 (108-134)g/d, respectively. Median plasma ADMA, SDMA and arginine were 0.47 (0.43-0.53)μmol/L, 0.59 (0.54-0.66)μmol/L and 86 (68-101)μmol/L, respectively. ADMA correlated inversely with tea (r = -0.70, P < .0001) and vegetable consumption (r = -0.50, P < .0001) even after adjustment for age, sex, body mass index, smoking status, and potential dietary and biochemical parameters. No association between ADMA and fruit consumption was found. ADMA correlated positively with coffee intake (r = 0.37, P < .0001), although these associations were less potent after adjustment for dietary factors. Higher tea and vegetable intake is associated with lower plasma ADMA levels in healthy middle-aged subjects.     

Plasma concentrations of asymmetric-dimethyl-arginine in type 2 diabetes associate with glycemic control and glomerular filtration rate but not with risk factors of vasculopathy

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase (NOS). Increased plasma levels of ADMA may indicate endothelial dysfunction and increased risk of angiopathy. The relation of ADMA to diabetes, glycemic control, and renal function, especially early diabetic hyperfiltration, remains unknown. We tried to evaluate whether there is an association between ADMA and glycosylated hemoglobin (GHbA(1c)) on the one hand and glomerular filtration rate (GFR) on the other hand in diabetic subjects with normal or slightly increased GFR. We also studied whether plasma ADMA is associated with some risk factors of vasculopathy (hypercholesterolemia and hypertension). The study subjects consisted of 86 patients with type 2 diabetes and 65 control subjects. Plasma ADMA levels were measured by high-pressure liquid chromatography as o-pthalaldehyde (OPA) derivatives and GFR was determined by the plasma clearance of chromium 51-EDTA. The diabetic patients had lower plasma ADMA levels than the nondiabetic control subjects (0.29 +/- 0.15 v 0.34 +/- 0.16 micromol/L, P <.03). In the diabetic subjects, plasma ADMA concentrations were inversely correlated with GHbA(1c) (R = -0.28, P =.01). In a multivariate linear model, significant predictors of ADMA were GFR (R = -0.32, P =.008) in diabetic subjects and GHbA(1c) (R = -0.19, P =.03) and GFR (R = -0.19, P =.02) in all subjects. Plasma ADMA was not associated with risk factors of vasculopathy. We conclude that diabetic patients with a normal or slightly increased GFR have lower circulating ADMA concentrations than nondiabetic control subjects. In type 2 diabetic patients high GFR and poor glycemic control were related to low plasma ADMA concentrations.     

Uncomplicated type 1 diabetes is associated with increased asymmetric dimethylarginine concentrations

CONTEXT: Asymmetric dimethylarginine (ADMA) has recently emerged as an independent risk marker for cardiovascular disease, but studies investigating the ADMA levels in type 1 diabetes mellitus (DM) are scarce. OBJECTIVE: We aimed to evaluate plasma ADMA, L-arginine concentrations, and L-arginine to ADMA ratio in uncomplicated type 1 diabetic patients and controls. DESIGN AND SUBJECTS: Forty patients with type 1 DM who did not have clinical evidence of vascular complications and 35 healthy controls were included in the study. RESULTS: Plasma ADMA concentrations were higher (2.6 +/- 1.9 vs. 1.7 +/- 0.7 micromol/liter, P < 0.01), and L-arginine levels were lower (79.3 +/- 22.6 vs. 89.6 +/- 19.4 micromol/liter, P < 0.05) in the diabetic group, compared with controls. The L-arginine to ADMA ratio was also lower in the diabetic group (38.7 +/- 17.1 vs. 62.0 +/- 27.9, P < 0.0001). In diabetic patients, logADMA correlated positively with body mass index (BMI) (P = 0.01), fasting blood glucose (P = 0.006), and low-density lipoprotein cholesterol (LDL-c) (P = 0.01) and negatively with high-density lipoprotein cholesterol (P = 0.03). L-arginine to ADMA ratio correlated negatively with BMI (P = 0.004), fasting blood glucose (P = 0.02), and LDL-c (P = 0.01) and positively with high-density lipoprotein cholesterol (P = 0.04). In controls, logADMA and L-arginine to ADMA ratio correlated with BMI and LDL-c (P < 0.05). In regression analysis, BMI predicted 15% variance of ADMA levels (P = 0.02). CONCLUSIONS: We demonstrated that ADMA increases and L-arginine to ADMA ratio decreases, even before the development of vascular complications in type 1 DM.     

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.     

Plasma asymmetric dimethylarginine and hyperemic myocardial blood flow in young subjects with borderline hypertension or familial hypercholesterolemia

OBJECTIVE: The goal of this study was to examine the relationship between plasma asymmetric dimethylarginine (ADMA) level and hyperemic myocardial blood flow (MBF) in subjects with borderline hypertension (BHT) and familial hypercholesterolemia (FH). METHODS: Asymmetric dimethylarginine is an endogenous competitive inhibitor of nitric oxide synthase that may modulate vascular function.We measured plasma ADMA levels and myocardial flow in 77 young men (mean age 35 +/- 5 years), including 47 healthy controls, 16 men with BHT, and 14 men with FH. Basal and dipyridamole-induced myocardial flow was measured using positron emission tomography. Plasma ADMA levels were measured using high-pressure liquid chromatography. RESULTS: Asymmetric dimethylarginine levels were significantly elevated in the BHT group compared with controls (0.59 +/- 0.13 micromol/l vs. 0.43 +/- 0.12 micromol/l, p < 0.001), and they had significantly lower dipyridamole flow (2.85 +/- 1.20 ml/min/g vs. 3.69 +/- 1.68 ml/min/g, p < 0.05). In a multivariate regression model adjusted for the study group, dipyridamole flow was inversely associated with ADMA (p < 0.05), age (p < 0.05), and apolipoprotein B concentration (p < 0.05). CONCLUSIONS: We conclude that plasma ADMA concentration is related to dipyridamole-induced vasodilatory function in young men, independently of blood pressure elevation and hypercholesterolemia. Subjects with BHT have significantly increased plasma ADMA levels, which may partly explain the impaired hyperemic MBF in this condition.     

Plasma asymmetric dimethylarginine modifies the effect of pravastatin on myocardial blood flow in young adults

Elevated plasma levels of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) are related to decreased myocardial vasodilatory capacity and increased risk of acute coronary events. As statin treatment is known to increase nitric oxide bioavailability and enhance myocardial function, we tested whether ADMA concentration modifies the effect of pravastatin on myocardial blood flow in young adults with mild hypercholesterolemia. Fifty-one men (35 +/- 4 years) were randomly assigned to receive either pravastatin (40 mg/day) or placebo for 6 months. Myocardial blood flow was measured at rest and during adenosine-induced hyperemia using positron emission tomography and oxygen-15-labeled water at baseline and after treatment. Plasma ADMA levels were assessed with high performance liquid chromatography. Low baseline plasma ADMA concentration (< median) predicted a significant improvement of adenosine-induced blood flow after statin intervention (baseline to follow-up change +35%, p = 0.004), whereas high baseline ADMA (> or = median) was associated with no increase in adenosine-induced flow.     

Homocyst(e)ine-lowering therapy does not affect plasma asymmetrical dimethylarginine concentrations in patients with peripheral artery disease

BACKGROUND: Elevated plasma asymmetrical dimethylarginine (ADMA) is suggested to contribute to hyperhomocyst(e)ine-related vascular dysfunction in patients with peripheral artery disease (PAD). The present trial investigated whether homocyst(e)ine (Hcy)-lowering therapy with vitamin-B (vit-B) and folic acid affects plasma concentrations of ADMA in patients with PAD and hyperhomocyst(e)inemia. SUBJECTS AND METHODS: Forty-nine subjects (15 women, 34 men) with PAD and fasting plasma total Hcy concentrations greater than 15 micromol/liter were randomized to receive either oral vit-B and folic acid therapy (n = 27) or placebo (n = 22) for 6 wk. Fasting venous blood samples were monitored for plasma total Hcy, vit-B12 and folate, ADMA, symmetric dimethylarginine, L-arginine, and high-sensitivity C-reactive protein. RESULTS: After 6 wk, plasma Hcy concentrations were decreased, and concentrations of vit-B12 and folate were elevated in patients with vitamin supplementation (all P < 0.05 vs. baseline) and unchanged in the placebo group. Dimethylarginine plasma concentrations were not affected by treatment. High-sensitivity C-reactive protein correlated with ADMA plasma concentrations (r = 0.29; P < 0.01). CONCLUSION: The lack of vit-B and folic acid therapy on plasma concentrations of ADMA renders a role of extracellular methylarginines unlikely to be involved in the pathophysiology of hyperhomocyst(e)inemia and its complications.     

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.     

Asymmetrical dimethylarginine level in atrial fibrillation

OBJECTIVE: Atrial fibrillation (AF) is known to be related with increased risk of thromboembolic events. Asymmetrical dimethylarginine (ADMA), which is an endogenous inhibitor of nitric oxide synthase (NOS), can cause endothelial dysfunction by decreasing nitric oxide (NO) and lead to increased risk of thrombosis. In the present study our aim was to compare plasma levels of ADMA in patients with acute onset (< 24 hours) and chronic AF (> 1 year) to determine the risk of thrombosis. METHOD: 17 patients with the first detected attack of AF within the first 24 hours of presentation (group 1), 25 patients who had permanent chronic AF lasting at least 1 year or more (group II) and 18 healthy persons as the control group (group III) were included in the study. For each patient the plasma ADMA, L-arginine, symmetrical dimethylarginine (SDMA) concentrations were measured by high-performance liquid chromatography in venous blood samples collected before cardioversion. We compared the plasma ADMA, L-arginine and SDMA concentrations between the groups. RESULTS: Plasma L-arginine (78.18 +/- 28.29 vs. 73.14 +/- 14.11 vs. 71.03 +/- 21.31, P = 0.549) and plasma SDMA concentrations (0.38 +/-0.18 vs. 0.42 +/- 0.21 vs. 0.32 +/- 0.24, P = 0.224) were similar in all groups. There was a significant difference between plasma ADMA concentrations (0.76 +/- 0.27 vs. 0.50 +/- 0.26 vs. 0.36 +/- 0.20, P < 0.001) among the groups. When we compared plasma ADMA levels between the subgroups, we also found a significant difference (P = 0.002 when comparing group I and group II, P < 0.001 when comparing of group I and group III, P = 0.042 when compareng of group II and group III). CONCLUSION: ADMA levels in patients with acute onset AF were significantly increased when compared with patients with chronic AF and the healthy control group indicating the presence of endothelial dysfunction and a prothrombotic state even in a very early phase of AF.     

Asymmetric dimethylarginine level in hyperglycemic gestation

We aimed to evaluate plasma asymmetric dimethylarginine (ADMA) concentrations and its relation with insulin sensitivity/resistance indices in pregnant women with different degrees of carbohydrate intolerance. This study included a two step approach; 50 g glucose challenge test (GCT) followed by 100 g oral glucose tolerance test (OGTT) was used for diagnosis of carbohydrate intolerance within 24-28th weeks of gestation. Pregnant women with positive GCT but negative OGTT (AGCT group, n=30) and gestational diabetics (GDM group, n=58) were compared to healthy pregnant controls (n=50). Plasma ADMA concentration and its relationship with glucose and insulin levels and insulin sensitivity/resistance indices (HOMA-IR, QUICKI, ISIOGTT) were evaluated. Both AGCT and GDM groups were found to have similarly higher plasma ADMA levels than control subjects (3.60±1.21; 4.00±1.70; 2.65±0.82 μmol/l, respectively, P=0.001). ADMA was significantly but slightly correlated with insulin sensitivity/resistance indices and moderately correlated with 2-h insulin level. The 2-h insulin value of the OGTT was the independent influencing constant for ADMA (R=0.57, P=0.0001). In conclusion, plasma asymmetric dimethylarginine level was higher in cases with abnormal glucose challenge test but normal OGTT as well as in gestational diabetics, compared to pregnant women with normal glucose tolerance. The elevated ADMA level in pregnant women with carbohydrate intolerance may possibly be due to elevated insulin level.     

Weight loss reduces circulating asymmetrical dimethylarginine concentrations in morbidly obese women

The endogenous nitric oxide-synthase inhibitor asymmetrical dimethyl-L-arginine (ADMA) is elevated in patients with increased risk for arteriosclerosis. Obesity is a risk factor for cardiovascular disease. We measured plasma ADMA concentrations in morbidly obese women before and after weight loss following gastroplastic surgery. ADMA and symmetrical dimethyl-L-arginine concentrations were analyzed by HPLC from 34 female patients (age 41 +/- 7 yr) with a body mass index (BMI) of 49 +/- 1 kg/m2 before and 14 months after vertical ring gastroplasty. Age-matched healthy women (BMI < 25 kg/m2; n = 24) were studied as controls. After gastroplastic surgery, BMI decreased to 34 +/- 1 kg/m2 in obese women (P < 0.00001), and ADMA concentrations were reduced from 1.06 +/- 0.06 micromol/liter at baseline to 0.81 +/- 0.04 micromol/liter after weight loss (P < 0.00001). Symmetrical dimethyl-L-arginine plasma levels were not affected. ADMA correlated with high-sensitivity C-reactive protein at baseline (r = 0.42; P < 0.05) and after weight loss (r = 0.56; P < 0.005). No association with blood pressure or plasma lipids could be observed. ADMA concentrations were lower in controls (0.68 +/- 0.04 micromol/liter; P < 0.05) compared with obese patients before or after weight reduction. The decrease of highly elevated ADMA concentrations in morbidly obese patients is paralleled by improvement of parameters associated with the metabolic syndrome after weight loss.     

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.     

Increased circulating concentrations of asymmetric dimethylarginine (ADMA) in white coat hypertension

Elevated plasma levels of the endogenous nitric oxide (NO) synthase inhibitor asymmetric dimethylarginine (ADMA) contribute to endothelial dysfunction and seem to be a predictor for cardiovascular mortality. Elevated ADMA plasma concentrations have been demonstrated in patients with hypertension. However, the plasma concentrations of ADMA in white coat hypertension (WCH) has not been previously studied. The aim of this study was to evaluate ADMA in WCH and compare with normotensive (NT) and hypertensive (HT) patients. We also evaluated the relation between ADMA and NO in these three groups. For this purpose, 34 NT, 34 white coat hypertensive (clinical hypertension and ambulatory daytime blood pressure <135/85 mmHg) and 34 HT patients were recruited in this study. The subjects were matched for age, gender, body mass index (BMI) and the patients with smoking habit, dyslipidaemia and diabetes mellitus were excluded. The ADMA levels were determined by high performance liquid chromatography. Plasma ADMA levels were significantly higher in WCH group than in the NT group (3.21+/-0.49 micromol/l vs 2.84+/-0.58 micromol/l, P=0.046). It was significantly higher in the HT group than in the NTs (4.24+/-0.38 micromol/l, P<0.001). There was also a significant difference between the HT and WCH groups (P<0.001). The WCH subjects had significantly higher levels of NO than the HTs (41.68+/-2.23 vs 32.18+/-2.68 micromol/l; P<0.001) and significantly lower values than the NTs (48.24+/-4.29 micromol/l; P<0.001). In WCH and HT group, there was a negative correlation between ADMA and NO (r=-0.515, P=0.003 and r=-0.389, P=0.034, respectively). In NT subjects, there was no correlation between these two parameters (r=-0.287, P=0.124). The correlation between ADMA and NO was stronger in WCH group than in HT group. Although NO levels in HT patients were lower than WCHs and ADMA levels were higher in HT patients than WCHs, the negative correlation of these two parameters were more pronounced in WCH group. Decreased NO and increased ADMA levels in WCH may indicate endothelial dysfunction. Our data indicate also that WCH represent an intermediate group between NT and HT when endothelial dysfunction is concerned.     

Putative role of asymmetric dimethylarginine in microvascular disease of kidney and heart in hypertensive patients

BACKGROUND: Despite the frequent simultaneous presentation of cardiac and renal dysfunction, the relationship between these pathophysiological processes remains unclear. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide (NO) synthase, which has been linked to endothelial dysfunction and atherosclerosis. This study elucidates the relationship between ADMA and intrarenal and coronary microvascular diseases. METHODS: In this study, we included 66 consecutive hypertensive patients with normal renal function or mild renal insufficiency (creatinine or=90 ml/min; renal insufficiency group, eGFR <90 ml/min). Coronary flow velocity reserve (CFVR) was measured using adenosine-triphosphate stress transthoracic Doppler echocardiography. In addition, a plasma ADMA assay, echocardiography, carotid ultrasound, and brachial-ankle pulse wave velocity measurement were performed. RESULTS: The plasma ADMA level was the highest in patients with both renal insufficiency and reduced CFVR. ADMA was significantly associated with eGFR (r = -0.342, P = 0.006) and CFVR (r = -0.459, P < 0.001), and eGFR and CFVR were significantly associated with each other (r = 0.337, P = 0.006). Multiple regression analysis revealed that ADMA was an independent clinical parameter associated with both eGFR and CFVR. CONCLUSIONS: Plasma ADMA is suggested to be an incipient biochemical marker of microvascular disease in both kidney and heart in hypertensive patients. ADMA might play an important role in the pathogenesis of organ damage in the kidney and heart in essential hypertension.     

Relationship between S-adenosylmethionine, S-adenosylhomocysteine, asymmetric dimethylarginine, and endothelial function in healthy human subjects during experimental hyper- and hypohomocysteinemia

Experimental hyperhomocysteinemia after an oral methionine or homocysteine load is associated with impaired nitric oxide-dependent vasodilatation in healthy human beings. However, it remains unproven that this effect is mediated by elevations in plasma homocysteine. There is evidence that an increase in plasma homocysteine may increase the formation of asymmetric dimethylarginine (ADMA), an inhibitor of nitric oxide synthase. The methyl groups within ADMA are derived from the conversion of S -adenosylmethionine to S -adenosylhomocysteine intermediates in the methionine/homocysteine pathway. No previous study has assessed the role of methylation status, its impact on ADMA formation, and their association with endothelial function in healthy human beings. In a randomized, placebo-controlled, crossover study, 10 healthy subjects (mean age, 29.1 +/- 3.9 years) were administered an oral dose of methionine (0.1 g/kg), l -homocysteine (0.01 g/kg), N-acetylcysteine (NAC) (0.1 g/kg), or placebo. Endothelial function as assessed by flow-mediated dilatation (FMD) of the brachial artery was impaired after both the methionine and homocysteine load compared with placebo at 4 hours (36 +/- 15, 67 +/- 23 vs 219 +/- 26 microm, respectively, P < .001). N-Acetylcysteine had no effect on flow-mediated dilatation. Plasma total homocysteine was significantly elevated at 4 hours after methionine (23.1 +/- 6.2) and homocysteine (41.5 +/- 8.9) loading, but significantly reduced after NAC 2.4 +/- 0.6 vs 7.1 +/- 2.1 micromol/L in the placebo (P < .001). Plasma S-adenosylmethionine/S-adenosylhomocysteine ratio was significantly (P < .001) increased at 4 hours after methionine (10.9 +/- 0.7) compared with homocysteine (5.4 +/- 0.4), NAC (5.0 +/- 0.3), and placebo (6.0 +/- 0.5). Plasma ADMA concentrations were not altered by any intervention. Our results suggest that endothelial dysfunction due to methionine or homocysteine loading is not associated with an increase in plasma ADMA or a disruption in methylation status.     

Relationship between obesity, smoking, and the endogenous nitric oxide synthase inhibitor, asymmetric dimethylarginine

We investigated the levels of asymmetric dimethylarginine (ADMA), an important endogenous inhibitor of nitric oxide (NO), as related to metabolic risk factors known to contribute to atherosclerotic disease. Dimethylarginines were analysed in a cross-sectional study of 563 elderly high-risk men (70 +/- 6 years). ADMA and the l-arginine/ADMA (l-arg/ADMA) ratio were highly significantly correlated with several metabolic risk factors. However, only the association with body mass index (BMI) remained significant after adjustment for inter-related variables. When analyzing the results according to being overweight or not, ADMA levels were independently significantly higher (P = .05) and the L-arg/ADMA ratios were significantly lower (P < .008) in individuals with high BMI (> or =26 kg/m(2), median value) as compared with subjects with low BMI. ADMA levels were furthermore significantly lower (P = .037) and L-arginine and the l-arg/ADMA ratios were significantly higher (P = .004 and P = .001, respectively) in smokers compared with nonsmokers, the latter being independent of other risk factors. The strong relationship found between BMI and plasma levels of ADMA and the l-arg/ADMA ratio indicate a link to endothelial dysfunction in overweight subjects. The beneficial dimethylarginine profile observed in smokers in this elderly population is not easily explainable and should be further investigated.     

Asymmetric dimethyl-arginine and coronary artery calcification in young adults entering middle age: the CARDIA Study.

BACKGROUND: Normal endothelial function depends on nitric oxide (NO) release by endothelial cells. Asymmetric dimethylarginine (ADMA), by competing with L-arginine, inhibits NO production and may lead to endothelial dysfunction and atherosclerotic development. Our aim was to ascertain the association between ADMA and coronary artery calcification (CAC), a marker of atherosclerotic coronary disease burden. DESIGN: A nested case-control study within the Coronary Artery Risk Development in Young Adults (CARDIA) cohort, an observational study among young adults residing in four US cities. METHODS: Participants were 263 white and black male and female cases with the presence of CAC and 263 sex and race-matched controls without evidence of CAC by computed tomography, 33-47 years old in 2000-2001. RESULTS: The median level (range) of ADMA was significantly higher in cases (0.55; 0.20-2.22 micromol/l) than in controls (0.53; 0.32-1.30 micromol/l; P=0.03). In conditional logistic regression adjusting for age, field center, educational attainment, smoking status, alcohol consumption, body mass index, waist circumference, hypertension, diabetes, low-density lipoprotein and high-density lipoprotein-cholesterol, triglycerides, renal function and C-reactive protein, the highest tertile of ADMA, compared with the lowest tertile, was associated with 1.80 (95% confidence interval 1.03-3.15) increased odds of the presence of any CAC. By linear regression, a significant independent relationship was also found between ADMA and the degree of CAC. CONCLUSION: These results support a role for ADMA as a biochemical marker of CAC.