Serum Asymmetric Dimethylarginine Concentrations Research Articles

Levels of asymmetric dimethylarginine throughout normal pregnancy and in pregnancies complicated with preeclampsia or had a small for gestational age baby

Objective: The aim of this study was to investigate maternal asymmetric dimethylarginine (ADMA) concentrations at the three trimesters of pregnancy in uncomplicated pregnancies and in women who developed preeclampsia or had small for gestational age infants (SGA) without preeclampsia. Methods: ADMA concentrations were retrospectively determined in the first, second and third trimester of pregnancy in 41 uncomplicated pregnancies, 10 pregnancies complicated with preeclampsia and 14 pregnancies that delivered a SGA baby. ADMA was measured with an ELISA kit. Results: Mean (±SD) concentrations of ADMA (µmol/L) in uncomplicated l pregnancies were: 0.51 ± 0.14; 0.52 ± 0.13; 0.58 ± 0.16 in the three trimesters, respectively. ADMA concentrations in SGA pregnancies were significantly lower in each trimester compared to uncomplicated pregnancies: (0.40 ± 0.10, p = 0.005 1st trim; 0.42 ± 0.10, p = 0.007 2nd trim; 0.45 ± 0.10, p = 0.007 3rd trim). Although pregnancies that developed preeclampsia had higher ADMA concentration in all trimesters compared to uncomplicated pregnancies (0.58 ± 0.10; 0.63 ± 0.14; 0.68 ± 0.11), the difference was statistically significant only in the 2nd trimester (p = 0.02). Conclusions: Maternal serum ADMA concentration tends to increase during normal pregnancy. Pregnancies with SGA infants had significantly lower ADMA levels in all trimesters of pregnancy. ADMA concentrations in the 2nd trimester was significantly elevated in pregnancies that later developed preeclampsia.

Vascular endothelial function assessed by a noninvasive ultrasound method and serum asymmetric dimethylarginine concentrations in mild-to-moderate plaque-type psoriatic patients

ObjectivesOur aim was to evaluate vascular endothelial function assessed by serum asymmetric dimethylarginine (ADMA) concentrations and noninvasive ultrasonographic parameters such as flow-mediated dilatation (FMD) and nitroglycerin-induced dilatation (NID) in mild-to-moderate plaque-type psoriatic patients, as rated by the Psoriasis Area and Severity Index. Design and methodsPlaque-type psoriatic patients (n=29) diagnosed with clinical and/or histopathological findings and control subjects (n=25) without skin and systemic metabolic diseases were included in the study. ResultsThere was no statistically significant difference between patients and control subjects in respect to FMD (p=0.441), NID (p=0.557), or serum ADMA concentrations (p=0.225). Also, among the acute-phase reactants, serum C-reactive protein and plasma fibrinogen levels were moderately higher in patients when compared to control subjects (p=0.008 and p=0.011, respectively). ConclusionsMild-to-moderate plaque-type psoriatic patients with low-to-medium grade systemic inflammation did not have evidence of vascular endothelial function.

Asymmetric dimethylarginine concentration and recurrence of atrial tachyarrythmias after catheter ablation in patients with persistent atrial fibrillation

It has been reported that elevation of asymmetric dimethylarginine (ADMA) concentration is involved in atrial fibrillation (AF) process. The purpose of this study was to determine whether ADMA concentration is related to recurrences of AF after catheter ablation. A total of one hundred and thirty-eight patients with persistent AF (49.91 ± 7.23 years), but without known heart disease, who underwent successful mapping and catheter ablation were included. Serum ADMA levels were measured 1 day before the catheter ablation. After a mean follow-up period of 285 days (range, 98-651 days), 80 (58%) patients underwent the AF recurrence. Comparing with no AF recurrence group, the serum ADMA concentration, left atrial diameter, and persistent duration of AF in patients with AF recurrence group were significantly increased. Left atrial diameter, persistent duration of AF, and the number of non-pulmonary vein ectopy ablation were increased when serum ADMA concentration was elevated. In addition, AF recurrences were significantly increased when serum ADMA concentration was elevated. A multivariable Cox regression analysis demonstrated that the elevated ADMA concentration [hazard ration (95% CI), 4.59 (1.81-11.62); P = 0.001], the left atrial diameter [1.35 (1.18-1.55), P < 0.001], and the number of non-pulmonary vein ectopy ablation [1.94 (1.18-3.18), P = 0.009] were independent factors associated with the AF recurrence after catheter ablation. This study demonstrated that (1) serum ADMA concentrations were associated with non-PV ectopies and (2) increased serum ADMA concentrations were associated with higher rate of AF recurrence after catheter ablation in patients with persistent AF, supporting our hypothesis that ADMA might participate in the process of atrial remodeling.

Relationships between serum levels of thyroid hormones and serum concentrations of asymmetric dimethylarginine (ADMA) and N-terminal-pro-B-type natriuretic peptide (NT-proBNP) in patients with Graves’ disease

Endothelial dysfunction as well as abnormal thyroid hormone levels may be responsible for increased cardiovascular risk in Graves' disease (GD). Asymmetric dimethylarginine (ADMA) and N-terminal-pro-B-type natriuretic peptide (NT-proBNP) are new markers of endothelial and myocardial dysfunction, respectively. The purpose of this study was to investigate the relationship among the serum levels of ADMA, NT-proBNP, and thyroid hormones in GD patients. This was a cross-sectional investigation conducted in a university teaching hospital. Two hundred and thirty-nine GD (Female: 182, Male: 57) patients and 81 normal controls were enrolled in this study. Serum levels of ADMA were positively related with FT3 (r = 0.584, P < 0.001), FT4 (r = 0.551, P < 0.001), and TRAb levels (r = 0.502, P < 0.001). Serum NT-proBNP levels were positively associated with FT3 (r = 0.243, P < 0.001) and FT4 levels (r = 0.274, P < 0.001), as well as heart rate (r = 0.271, P < 0.03). The elevation of serum ADMA and NT-proBNP levels were also observed in patients with controlled hyperthyroidism. It is thus concluded that serum ADMA and NT-proBNP levels were increased in GD patients. Future studies may determine the usefulness of these two biomarkers to detect early signs of endothelial dysfunction, vascular stiffness, and fluid volume in GD patients.

Asymmetric dimethylarginine and vascular indices of atherosclerosis in patients after coarctation of aorta repair

ObjectiveCardiovascular events are the main cause of premature death after successful repair of aortic coarctation (CoA). The aim of this study was to assess the selected biochemical markers of atherosclerosis in normotensive CoA repaired patients and to establish its relation to ultrasound indexes of vascular pathology. Methods62 patients after CoA repair (37 males, age: 34.1±1.4yrs) and 20 control individuals (10 males, age: 34.8±2.2yrs) were enrolled in the study. The serum markers: asymmetric dimethylarginine (ADMA), nitrites/nitrates (NOx), high-sensitivity C-reactive protein (hsCRP), and following vascular parameters: flow-mediated dilatation (FMD), intima-media thickness (IMT) and pulse wave velocity (PWV) were analyzed. Results33 CoA repaired patients were normotensive, and compared to controls, they presented higher serum ADMA concentrations (0.59±0.04umol/l vs. 0.46±0.03umol/l, p=0.035). An analysis of the vascular parameters revealed decreased FMD (4.75±0.5%), NMD (11.86±0.8%) and increased PWV (6.90±0.2m/s) values in the normotensive patients as compared with the control group (FMD: 8.6±0.9%, p<0.001, NMD: 20.94±1.7%, p<0.001; PWV: 5.49±0.2, p=0.023). There were no differences in the serum levels of NOx, hsCRP as well as IMT values between normotensive patients and the control group. A multivariate regression analysis revealed that serum ADMA level was a factor independently associated with the FMD value (r=−0.334; p=0.031) in normotensive CoA repaired group. ConclusionsEarly biochemical and vascular indices of atherosclerosis such as increased serum ADMA concentration as well as impaired vasodilatation and increased arterial stiffness are observed in patients after CoA repair. Serum ADMA is a strong predictor of endothelial dysfunction in patients with CoA repair.

Statin Treatment Decreased Serum Asymmetric Dimethylarginine (ADMA) Levels in Ischemic Stroke Patients

It remains unclear whether the decrease in the ADMA level associated with statin treatment results from the LDL-C-lowering effect or the pleiotropic effects of statins. A prospective, controlled study was conducted to examine whether statin treatment affects serum ADMA concentrations in ischemic stroke patients. Consecutive outpatients with non-cardiogenic ischemic stroke who had never been treated with statins and whose LDL-cholesterol level was higher than 140 mg/dL were enrolled and compared with control patients whose LDL-cholesterol level was lower than 140 mg/dL. Overall, 114 patients were enrolled in the study (56 and 58 in statin-treated and non-statin-treated groups, respectively). Patients in the statin group were treated with pravastatin 10 mg/day (n=15), fluvastatin 20 mg/day (n=14), pitavastatin 1 mg/day (n=14), or atorvastatin 10 mg/day (n=13). The serum ADMA concentration and LDL-C level were significantly decreased by statin treatment (p=0.003 and p< 0.001, respectively), and the ADMA concentration in subjects treated with statins was significantly lower than that of the control (p=0.028). Multiple linear regression analysis showed that age (β=0.26, p< 0.05) and statin use (β=-0.20, p< 0.05) were independently associated with the ADMA level. A significant relation between statin treatment and decreased levels of ADMA was demonstrated in ischemic stroke patients with an adequately controlled lipid profile, suggesting the statin treatment might prevent atherosclerotic disease in ischemic stroke patients through suppression of ADMA concentration.

N-3 polyunsaturated fatty acids early supplementation improves ultrasound indices of endothelial function, but not through NO inhibitors in patients with acute myocardial infarction: N-3 PUFA supplementation in acute myocardial infarction.

Our aim was to evaluate early initiated one month n-3 polyunsaturated fatty acids (PUFA) supplementation effects on ultrasound indices of endothelial function and serum asymmetric dimethylarginine (ADMA) levels in patients with acute myocardial infarction (AMI). Forty patients with AMI and successful percutaneous coronary intervention (PCI) were recruited into the study and randomized to the study group (group P; n = 20; standard therapy + n-3 PUFA 1 g daily) or the control group (group C; n = 20; standard therapy). Ultrasound indices of endothelial function: flow-mediated dilatation (FMD), nitroglycerin-mediated dilatation (NMD) and serum ADMA concentrations (ELISA) were obtained before and after one month (30 ± 1 days) therapy (presented as means ± standard deviations). There was a significant difference between both groups in mean delta (baseline/after one month) FMD (P: 8.1 ± 12.6% vs C: -2.2 ± 11.8%; p = 0.02) with no difference in mean delta NMD (P: 3.3 ± 11.9% vs 0.66 ± 14.3%; p = 0.53). We found also a significant increase in mean FMD (7.4 ± 6.4 to 15.5 ± 10.5%; p = 0.02) with a nonsignificant change in mean NMD values (26.9 ± 12.1 to 30.2 ± 14.0%; p = 0.24) after 1-month therapy with n-3 PUFA. FMD and NMD mean values did not change in control patients (FMD: 11.6 ± 6.1% to 9.4 ± 8.0%; p = 0.5 NMD: 25.1 ± 11.4% to 25.8 ± 14.0%; p = 0.84). The comparison of mean delta ADMA values for both groups revealed no differences (P: 6.2 ± 9.7 μmol/l vs C: 3.6 ± 9.5 μmol/l; p = 0.43). Mean serum ADMA concentrations were significantly increased after 1-month therapy in the group P (P: 2.1 ± 1.8 to 8.3 ± 9.7 μmol/l; p = 0.001; C: 4.5 ± 7.1 to 8.1 ± 9.5 μmol/l; p = 0.09). However, there was a nonsignificant difference in mean baseline serum ADMA levels between both groups (P: 2.1 ± 1.8 μmol/l vs C: 4.5 ± 7.1 μmol/l; p = 0.32). There were no significant correlations between FMD, NMD, ADMA levels and demographic, clinical or biochemical parameters. Early and short-term n-3 PUFA supplementation improved ultrasound indices of endothelial function without affecting serum ADMA levels in patients with AMI and successful primary PCI.

Increased proinflammatory cytokine production in adipose tissue of obese patients with chronic kidney disease

Obesity is a known high-risk factor for the development of vascular diseases and chronic kidney disease (CKD). In this study we aimed to elucidate the impact of adipose tissue on the inflammatory state in CDK patients with obesity. A cohort of 40 patients with CKD (stages 3-4) with mild proteinuria (2.3-3.5 g/day) were analyzed in a prospective cross-sectional study: single blood samples and visceral and subcutaneous samples of adipose tissue were taken from 20 patients with obesity and 20 without obesity (control group) during elective abdominal surgery (laparoscopic cholecystectomy). Serum concentrations of asymmetric dimethylarginine (ADMA), adiponectin, C-reactive protein, interleukin-6, tumor necrosis factor-alpha, pentosidine and monocyte chemoattractant protein-1 were measured. Messenger RNA expression of tumor necrosis factor-alpha, monocyte chemoattractant protein-1, adiponectin receptors 1 and 2, and immunocompetent cell marker CD68 was measured in subcutaneous and visceral fat samples using real-time PCR. Adipose tissue was examined immunohistochemically for CD68-positive cells. Other biochemical parameters (insulin, glycated hemoglobin, cholesterol, LDL cholesterol, and triglycerides) were assessed in the two groups of patients at the same time. Serum concentrations of ADMA, C-reactive protein, pentosidine, interleukin-6, tumor necrosis factor-alpha and monocyte chemoattractant protein-1 were significantly higher in obese CKD patients than in the control group; adiponectin was lower in the obese group. Subcutaneous and visceral mRNA expressions of tumor necrosis factor-alpha, CD68, adiponectin receptor-1, and monocyte chemoattractant protein-1 were significantly increased in the obese patients, whereas expression of adiponectin, interleukin-6, and adiponectin receptor-2 did not significantly differ between the patient groups. In general, mRNA expressions were higher in visceral than in subcutaneous samples (P < 0.01 vs. P < 0.05). Increased infiltration of subcutaneous and visceral adipose tissue by CD68-positive immunocompetent cells was found in the obese CKD group. With respect to lipid metabolism parameters, a small but significant increase in levels was found in the obese patients (P < 0.02). Changes in triglycerides were more marked in this group (P < 0.01) and a similar increase was noted in insulin and HbA1c levels (P < 0.02). Increased expression of proinflammatory cytokines and increased infiltration by immunocompetent cells were found in adipose tissue of obese patients with CKD stages 3-4. This upregulated inflammation may contribute to the induction of a systemic proinflammatory state in patients with CKD and could accelerate the progression of renal dysfunction.

Randomized Controlled Trial of the Effect of Short-term Coadministration of Methylcobalamin and Folate on Serum ADMA Concentration in Patients Receiving Long-term Hemodialysis

Serum asymmetric dimethylarginine (ADMA) levels are increased in maintenance hemodialysis patients, and this abnormality may increase cardiovascular risk. We investigated whether combined administration of oral folate and intravenous methylcobalamin in such patients is more beneficial than oral folate alone at decreasing circulating ADMA levels. Randomized controlled trial. Patients undergoing hemodialysis. 40 patients were randomly assigned to 1 of 2 groups. For 3 weeks, they received supplementation with either folate alone (15 mg/d; n = 20; folate group) or coadministered folate (15 mg/d) and methylcobalamin (500 mug after each hemodialysis treatment 3 times weekly; n = 20; methylcobalamin group). normalization of plasma homocysteine levels (<15 mumol/L), decrease in serum ADMA levels. change in augmentation index in the carotid artery and ratios of S-adenosylmethionine to S-adenosylhomocysteine (as a transmethylation indicator) and dimethylamine to ADMA (as an indicator of ADMA hydrolysis). Blood samples were collected under fasting conditions during the prehemodialysis procedure. The proportion showing normalization of plasma homocysteine levels was much greater in the methylcobalamin group (18 of 20 patients; 90%) than in the folate group (6 of 20; 30%; P < 0.001). The percentage of decrease in ADMA levels was greater in the methylcobalamin than folate group (25.4% +/- 10.2% vs 13.2% +/- 11.2%; P < 0.001). The increase in ratio of S-adenosylmethionine to S-adenosylhomocysteine was not different between the 2 groups; however, the ratio of dimethylamine to ADMA was increased in only the methylcobalamin group (P = 0.04). Augmentation index was decreased in only the methylcobalamin group (P = 0.03). This study had an open-label nature and did not examine long-term effects of homocysteine-normalizing therapy (no clinical end points). Coadministration of intravenous methylcobalamin and oral folate in hemodialysis patients normalized hyperhomocysteinemia and decreased ADMA levels and arterial stiffness. We suggest that this regimen may have greater potential than folate alone to decrease cardiovascular risk in such patients.

Sequence Variation in DDAH1 and DDAH2 Genes Is Strongly and Additively Associated with Serum ADMA Concentrations in Individuals with Type 2 Diabetes

BackgroundAsymmetric dimethylarginine (ADMA), present in human serum, is an endogenous inhibitor of nitric oxide synthase and contributes to vascular disease. Dimethylarginine dimethylaminohydrolase (DDAH) is an ADMA degrading enzyme that has two isoforms: DDAHI and DDAHII. We sought to determine whether serum ADMA levels in type 2 diabetes are influenced by common polymorphisms in the DDAH1 and DDAH2 genes.Methodology/Principal FindingsRelevant clinical parameters were measured and peripheral whole blood obtained for serum and genetic analysis on 343 participants with type 2 diabetes. Serum ADMA concentrations were determined by mass spectroscopy. Twenty six tag SNPs in the DDAH1 and 10 in the DDAH2 gene were genotyped in all subjects and tested for association with serum ADMA levels. Several SNPs and haplotypes in the DDAH genes were strongly associated with ADMA levels. Most significantly in the DDAH1 gene, rs669173 (p = 2.96×10−7), rs7521189 (p = 6.40×10−7), rs2474123 (p = 0.00082) and rs13373844 (p = 0.00027), and in the DDAH2 gene, rs3131383 (p = 0.0029) and the TGCCCAGGAG haplotype (p = 0.0012) were significantly associated with ADMA levels. Sub-analysis by diabetic retinopathy (DR) status revealed these variants were associated with ADMA levels predominantly in participants without DR. Combined analysis of the most strongly associated SNPs in DDAH1 (rs669173) and DDAH2 (rs3131383) revealed an additive effect (p = 1.37×10−8) on ADMA levels.Conclusions/SignificanceGenetic variation in the DDAH1 and 2 genes is significantly associated with serum ADMA levels. Further studies are required to determine the pathophysiological significance of elevated serum ADMA in type 2 diabetes and to better understand how DDAH gene variation influences ADMA levels.

Asymmetric dimethylarginine (ADMA) as a possible risk marker for ischemic stroke

Background Asymmetric dimethylarginine (ADMA) affects vascular function by blocking nitric oxide synthesis. We examined the relationship of ADMA concentration to vascular risk factors in subjects who have undergone annual medical check-up. Methods ADMA concentration, lipid profile and vascular risk factors were assessed during an annual medical examination in 116 subjects (mean age 58.7 years). Univariate and multivariate analyses were carried out to assess factors associated with ADMA concentration. ADMA concentration was also assessed in 50 age-matched patients with ischemic stroke. Results Mean serum ADMA concentration was significantly higher in the ischemic stroke patients than the medical check-up subjects (0.461 ± 0.076 versus 0.433 ± 0.056 μmol/l; P = 0.022). Univariate analysis showed that ADMA concentration in the medical check-up subjects was significantly associated with age, hypertension, dyslipidemia, fasting blood glucose, total and LDL cholesterol concentrations. Multiple stepwise linear regression analysis showed that hypertension (β = 0.25, P = 0.008) and dyslipidemia (β = 0.19, P = 0.048) were significant independent determinants of ADMA concentration. ADMA concentration increased progressively with number of vascular risk factors, with a significant ( P = 0.001) difference between subjects with no risk factors and subjects with ≥ 2 risk factors. Conclusions Serum ADMA concentration was significantly associated with vascular risk factors in subjects undergoing routine medical check-up. ADMA concentration warrants further examination as a possible marker of future development of ischemic stroke.

Serum ADMA concentration – an independent factor determining FMD impairment in cardiac syndrome X

Mechanisms of decreased endogenous vascular reactivity in individuals with cardiac syndrome X (CSX) are not fully understood.Aim. To evaluate the following serum markers: total nitric oxide (NO), asymmetric dimethylarginine (ADMA), platelet-derived growth factor (PDGF), and to establish their relation to ultrasound indexes of endothelial function and structural remodeling in CSX patients.Method. The study group consisted of 43 CSX patients (mean age: 56.3 ± 9 years), while the control group included 21 healthy subjects (mean age: 54.86 ± 6.9 years). The high-resolution ultrasound was performed to measure: flow-mediated vasodilatation (FMD), nitroglycerine-mediated vasodilatation (NMD) and intima-media thickness (IMT) of carotid arteries.Results. In CSX patients, significantly lower FMD (9.06 ± 3.2%) and significantly higher IMT (0.667 ± 0.14 mm) values were observed compared to healthy individuals (17.42 ± 8.4%, 0.571 ± 0.2 mm; P < 0.05). Mean total NO serum concentration was significantly higher in the CSX group (48.2 ± 18.2 μmol/L) as compared to controls (32.1 ± 1.4 μmol/L; P < 0.0001). There were no differences in serum ADMA and PDGF levels. In CSX patients, FMD values correlated with NO (r = 0.323; P = 0.039) and ADMA (r = -0.387; P = 0.012) serum levels; however, there were no significant correlations between NO and ADMA concentrations.Conclusion. Serum ADMA concentration is the only independent factor determining FMD impairment.

Acute effects of 5-methyltetrahydrofolate on endothelial function and asymmetric dimethylarginine in patients with chronic heart failure

Folic acid enhances endothelial function in vascular disease states but its effects in chronic heart failure (CHF) are largely unknown. We studied the acute effects of i.v. methyltetrahydrofolate (5MTHF), the active metabolite of folic acid, on endothelial function and asymmetric dimethylarginine (ADMA) in CHF patients. Twenty two CHF patients and 22 controls received one of the following three-step infusions (1h per each step) in a randomized, parallel group, placebo-control study: (1) active treatment (saline, 5MTHF, and 5MTHF+the endothelial nitric oxide inhibitor N(G)-monomethyl l-arginine, LNMMA); or (2) placebo (salinex3). Endothelium-dependent vasodilatation was assessed by pulse-wave analysis (salbutamol-mediated changes in augmentation index, AIx). 5MTHF did not exert any significant effects on endothelium-dependent vasodilatation both in controls [DeltaAIx post-salbutamol baseline -7.6% (-24.8/-4.1) vs. 5MTHF -5.5% (-16.7/-3.6), medians and interquartile range, and CHF patients [-1.8% (-17.3/+1.3) vs. -2.4% (-3.8/-1.2)]. However, a significant reduction in ADMA concentrations was observed in both groups [controls baseline 0.68micromol/L (0.64/0.77) vs. 5MTHF 0.65 (0.57/0.74); CHF baseline 0.76 (0.63/0.82) vs. 5MTHF 0.69 (0.66/0.71), P=0.05 for both vs. baseline and placebo. These effects persisted during co-infusion with LNMMA. 5MTHF did not affect endothelial function but significantly reduced serum ADMA concentrations both in CHF patients and controls. This suggests a direct effect of 5MTHF on ADMA metabolism.

Renal Resistance Index in Renal Allograft Recipients: A Role for ADMA

Renal resistance index, a predictor of kidney allograft function and patient survival, seems to depend on renal and peripheral vascular compliance and resistance. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase and therefore influences vascular resistance. We investigated the relationship between renal resistance index, ADMA, and risk factors for cardiovascular diseases and kidney function in a cross-sectional study. 200 stable renal allograft recipients (133 men and 67 women with a mean age of 52.8 years). Serum ADMA concentration, pulse pressure, estimated glomerular filtration rate and recipient age. Renal resistance index. Renal resistance index measured by color-coded duplex ultrasound, serum ADMA concentration measured by liquid chromatography-tandem mass spectrometry, estimated glomerular filtration rate (Nankivell equation), arterial stiffness measured by digital volume pulse, Framingham and other cardiovascular risk factors, and evaluation of concomitant antihypertensive and immunosuppressive medication. Mean serum ADMA concentration was 0.72 +/- 0.21 (+/-SD) micromol/L and mean renal resistance index was 0.71 +/- 0.07. Multiple stepwise regression analysis showed that recipient age (P < 0.001), pulse pressure (P < 0.001), diabetes (P < 0.01) and ADMA concentration (P < 0.01) were independently associated with resistance index. ADMA concentrations were correlated with estimated glomerular filtration rate (P < 0.01). The cross-sectional nature of this study precludes cause-effect conclusions. In addition to established cardiovascular risk factors, ADMA appears to be a relevant determinant of renal resistance index and allograft function and deserves consideration in prospective outcome trials in renal transplantation.

Increased Circulating Asymmetric Dimethylarginine (ADMA) Levels in the Active Stage of Behçet’s Syndrome

There is little evidence in the literature about circulating asymmetric dimethylarginine (ADMA) levels in Behcet’s syndrome (BS). The aim of the present study was 1. to measure the levels of ADMA in male patients with BS, 2. to compare ADMA levels with healthy volunteers, and 3. to evaluate whether there is any difference between patients both with/without thrombosis and in active/inactive stage. In patients with BS, CRP levels were higher than controls. The mean ADMA and C-reactive protein (CRP) levels were significantly higher in active stage patients and patients with thrombosis than in patients during the inactive stage and without thrombosis. In conclusion, we did not find any significant difference in ADMA levels between patients with BS and healthy controls. Serum ADMA concentrations, however, were higher in active patients and patients with thrombosis than in patients during the inactive stage and patients without thrombosis.

Increased Levels of Asymmetric Dimethylarginine (ADMA) in Patients with Ankylosing Spondylitis

Endothelial dysfunction is present in ankylosing spondylitis (AS). However, the etiology of events is still unclear. The aim of the present study was to investigate whether there are abnormalities in nitric oxide (NO) metabolism and endothelin-1 (ET-1) in AS patients. Subjects without any classical cardiovascular (CV) risk factors were studied. Fasting glucose, serum lipids, high sensitive CRP (hsCRP), ESR, asymmetric dimethylarginine (ADMA) and ET-1 were studied. Patients were also evaluated with the Bath Ankylosing Spondylitis Metrology Index, Bath Ankylosing Spondylitis Functional Index, and the Bath Ankylosing Spondylitis Disease Activity Index. A total of 48 AS patients (38.6+/-10.6 years; 36M/12F) and 38 controls (36.4+/-11.1 years; 27M/11F) were studied. Acute phase reactants including hsCRP, and ESR were significantly increased in the patients group (p<0.05). Serum ADMA concentrations were also significantly higher in AS than in controls. Plasma levels of ET-1 did not differ between the groups (p>0.05). Comparison of three groups (conventional and anti-TNF treatment groups and controls) revealed that ADMA was significantly higher in the conventional treated AS than in controls. The levels of ADMA were not different between anti-TNF group and healthy subjects. Plasma ET-1 concentrations were similar between groups (p>0.05). Correlation analysis yielded significant correlations between ADMA, hsCRP, LDL cholesterol, HDL cholesterol and triglycerides (p<0.05). The increased ADMA levels obtained in a group of relatively young AS patients who did not have classical CV risk factors suggest that NO metabolism is impaired in AS. On the other hand, anti-TNF treatments may have a beneficial effect on vascular function in AS.

Decrease in the synthesis and release of calcitonin gene-related peptide in dorsal root ganglia of spontaneously hypertensive rat: Role of nitric oxide synthase inhibitors

Calcitonin gene-related peptide (CGRP), the major transmitter in capsaicin-sensitive sensory nerves, and asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, participate in the regulation of blood pressure. In the present study, we tested the relationship between CGRP and ADMA in spontaneously hypertensive rats (SHRs). For the in vivo study, SHRs were treated with or without l-arginine for 2 weeks, and Wistar Kyoto (WKY) rats were used as controls. Systolic arterial pressure was measured, and the levels of CGRP, ADMA, and NO were analyzed. For the in vitro study, neural cells from dorsal root ganglia were treated with NO inhibitor or donor. Synthesis and release of CGRP were measured. Compared with WKY rats, serum concentration of ADMA in SHRs increased while CGRP and NO level decreased. Treatment with l-arginine significantly decreased blood pressure, concomitantly with an increase in the level of NO and the synthesis and release of CGRP in SHRs, but it did not affect ADMA levels. In cultured neural cells, ADMA reduced the level of NO and inhibited the synthesis and release of CGRP in a concentration-dependent manner. The effects of ADMA were reversed by l-arginine. Treatment with NOC-18, a donor of NO, increased the release and synthesis of CGRP in neural cells in a concentration-dependent manner. Decreased synthesis and release of CGRP is related to a reduction in NO levels, and corresponds to the increased concentrations of ADMA in spontaneously hypertensive rats.

SHORT TERM FLUVASTATIN TREATMENT LOWERS SERUM ASYMMETRIC DIMETHYLARGININE LEVELS IN PATIENTS WITH METABOLIC SYNDROME

Elevated concentrations of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, are associated with endothelial dysfunction. Metabolic syndrome (MetS) is also a condition associated with impaired endothelial function. To test the hypothesis that lipid lowering treatment with a statin lowers ADMA levels, we investigated the effect of fluvastatin treatment on serum ADMA levels in patients with MetS. A total of 85 hypercholesterolemic MetS patients (53 females, 32 males; mean age, 55.8 ± 9.1 years) were included in this prospective, randomized, controlled study. Patients were randomly assigned to either the treatment (n = 42) or control group (n = 43). Recommendations for lifestyle modification were provided to both groups. In addition, the patients in the treatment group received fluvastatin, extended release tablets, 80 mg/day, orally for 6 weeks. Serum levels of ADMA and lipids were assessed at baseline and at the completion of treatment. High performance liquid chromatography was used to measure serum ADMA concentrations. In the fluvastatin group, there was a significant reduction in serum ADMA levels compared to baseline (from 1.57 ± 1.07 μmol/L to 1.17 ± 1.41 μmol/L, P 0.05). There was a statistically significant difference between the groups in terms of mean percent change from baseline (P = 0.047). Fluvastatin treatment for hypercholesterolemia in patients with MetS is associated with a decrease in serum ADMA levels at 6 weeks. This finding is consistent with known beneficial effects of statin treatment on endothelial function in hypercholesterolemic patients.

Human recombinant erythropoietin augments serum asymmetric dimethylarginine concentrations but does not compromise nitric oxide generation in mice

Patients with advanced chronic renal disease (CRD) suffer from excessive morbidity and mortality due to complications of accelerated atherosclerosis. Recombinant human erythropoietin (EPO), which is routinely used to treat the anaemia present in approximately 90% of dialysis-dependent patients with end-stage renal disease, may induce vascular dysfunction by reducing nitric oxide (NO) availability. Pathophysiologic concentrations of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), are found in patients with CRD and correlate with vascular disease and cardiovascular mortality. The aim of the current study was to investigate the effect of EPO on ADMA concentrations and NO generation in vitro and in vivo. Furthermore, we wanted to study the effect of EPO on the expression of the enzymes that regulate ADMA metabolism and NO generation. Human umbilical vein endothelial cells (HUVECs) were exposed to therapeutic concentrations of EPO. The expression and metabolic activity of dimethylarginine dimethylaminohydrolase II (DDAH II), the enzyme that degrades ADMA, was evaluated. Following subcutaneous administration of EPO to Balb/c mice for 10 weeks, serum ADMA concentrations were determined. Systolic blood pressure was measured noninvasively. Urinary nitrite and nitrate (NOx) concentrations were assessed by Griess assay. Protein expression of DDAH and NOS in livers and kidneys was measured by western blotting. EPO suppressed ADMA elaboration by HUVECs. Systolic blood pressure and serum concentrations of ADMA were significantly elevated in EPO-treated mice. The protein expression of DDAH I in the kidney and liver was upregulated while hepatic expression of DDAH II was decreased and renal DDAH II expression remained unchanged by EPO administration. However, EPO augmented urinary NOx concentrations as well as the expression of NOS 1 and NOS 2 in the kidney. In spite of elevating serum ADMA concentrations, EPO does not appear to compromise overall NO generation in Balb/c mice.

Effect of angiotensin-converting enzyme inhibitor on serum asymmetric dimethylarginine and coronary circulation in patients with type 2 diabetes mellitus

Measurements of serum asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, and coronary flow velocity reserve (CFVR) using transthoracic Doppler echocardiography were performed at baseline and after 4 weeks of temocapril therapy (2 mg/day) in 18 patients with type 2 diabetes. Although blood pressure, fasting blood sugar and lipid profiles remained unchanged, serum ADMA concentrations decreased significantly (0.51 ± 0.08 to 0.46 ± 0.07 μmol/l, p < 0.01) and CFVR increased significantly (2.78 ± 0.36 to 3.35 ± 0.46, p < 0.001) after the treatment. Moreover, a strong correlation was observed between the difference of ADMA and that of CFVR ( r = − 0.80, p < 0.001). Temocapril reduced serum ADMA concentrations, improved CFVR beyond its blood pressure lowering effect. Our results suggest that decrease in ADMA by temocapril treatment is related to improvement of coronary circulation as determined by CFVR in patients with type 2 diabetes.