Changes In Asymmetric Dimethylarginine Levels Research Articles

Effect of Antihypertensive Drugs Therapy Concognitive Functions and Asymmetric Dimethylarginine (Adma) Levels In Hypertensive Patients

The purpose of this study is to evaluate cognitive functions and its association with Asymmetric Dimethylarginine(ADMA) levels in hypertensive patients treated with antihypertensive drugs.Methods: At least 100 subjects of hypertension were proposed for this study keeping in mind the time constraint andlimitation of resources.Results: Treatment with antihypertensive medications caused change in HMSE score from 24. 51 ± 2.27 at day 1 to 25.64 ±2.31at four weeks Treatment with antihypertensive medications caused change in ADMA levels from 15519.65 ± 7311.63ng/L at day 1 to 12314.47 ± 10696.09 ng/L at four weeks.Conclusion: Treatment with antihypertensive medications caused change in HMSE score from 24. 51 ± 2.27 at day 1 to25.64 ± 2.31at four weeks

Relationship between plasma asymmetric dimethylarginine and nitric oxide levels affects aerobic exercise training-induced reduction of arterial stiffness in middle-aged and older adults.

[Purpose]Aerobic exercise training (AT) reverses aging-induced deterioration of arterial stiffness via increased arterial nitric oxide (NO) production. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase, was decreased by AT. However, whether AT-induced changes in ADMA levels are related to changes in nitrite/nitrate (NOx) levels remains unclear. Accordingly, we aimed to clarify whether the relationship between plasma ADMA and NOx levels affected the AT-induced reduction of arterial stiffness in middle-aged and older adults.[Methods]Thirty-one healthy middle-aged and older male and female subjects (66.4 ± 1.3 years) were randomly divided into two groups: exercise intervention and sedentary controls. Subjects in the training group completed an 8-week AT (60%–70% peak oxygen uptake [] for 45 min, 3 days/week).[Results]AT significantly increased (p < 0.05) and decreased carotid β-stiffness (p < 0.01). Moreover, plasma ADMA levels were significantly decreased while plasma NOx levels and NOx/ADMA ratio were significantly increased by AT (p < 0.01). Additionally, no sex differences in AT-induced changes of circulating ADMA and NOx levels, NOx/ADMA ratio, and carotid β-stiffness were observed. Furthermore, the AT-induced increase in circulating ADMA levels was negatively correlated with an increase in circulating NOx levels (r = -0.414, p < 0.05), and the AT-induced increase in NOx/ADMA ratio was negatively correlated with a decrease in carotid β-stiffness (r = -0.514, p < 0.01).[Conclusion]These results suggest that the increase in circulating NOx with reduction of ADMA elicited by AT is associated with a decrease in arterial stiffness regardless of sex in middle-aged and older adults.

The effect of α-lipoic acid treatment on plasma asymmetric dimethylarginine, a biomarker of endothelial dysfunction in diabetic neuropathy

IntroductionDiabetic neuropathy may develop on a background of hyperglycaemia and is associated with increased oxidative stress. Elevated asymmetric dimethylarginine (ADMA) levels are linked to oxidative stress reducing the synthesis of nitric oxide (NO) by uncoupling NO synthase. Oxidative stress induces considerable changes in nerve conduction velocity in diabetic patients. There is strong evidence that α-lipoic acid (ALA) as an antioxidant may improve nerve conduction and relieve neuropathic symptoms. We aimed to investigate the relationship between endothelial dysfunction and NO synthesis in type 2 diabetic patients with peripheral neuropathy after ALA treatment.Material and methodsFifty-four type 2 diabetic patients with neuropathy were included in the study. Serum ADMA concentration, ICAM-1, VCAM-1, oxidised low-density lipoprotein (oxLDL), and TNF-α levels were determined with Enzyme-Linked Immunosorbent Assay (ELISA). Nitric oxide concentration was measured by Griess reaction. Peripheral sensory nerve function was assessed by current perception threshold (CPT) testing. Autonomic function was assessed by Ewing’s five standard cardiovascular reflex tests composite autonomic score (CAS).ResultsAsymmetric dimethylarginine levels were significantly decreased (0.62 ±0.11 vs. 0.53 ±0.11 µmol/l, p &lt; 0.001), as well as TNF-α concentrations (1.21 ±0.42 pg/ml vs. 1.05 ±0.5 pg/ml, p &lt; 0.05), while NO levels were significantly increased (16.78 ±11.1 vs. 21.58 ±8.84 µmol/l, p &lt; 0.05) after six-months of 600 mg/day ALA treatment. VCAM-1, ICAM-1, and oxLDL levels did not change significantly. The CPT and CAS significantly improved after ALA treatment. The improvement of CPT values was correlated positively with the change of ADMA levels (r = 0.58, p &lt; 0.001). The change in ADMA level was more pronounced in responder patients based on both CPT and CAS.ConclusionsOur results suggest that ALA supplementation improves endothelial function characterised by serum levels of ADMA and TNF-α in patients with diabetic neuropathy. Changes in serum ADMA levels may predict the clinical response to ALA treatment.

Effect of febuxostat on oxidative stress in hemodialysis patients with endothelial dysfunction: a randomized, placebo-controlled, double-blinded study.

Oxidative stress, which is most likely a key mediator in the development of cardiovascular disease, is implicated in the progression and deterioration of chronic kidney disease. Patients on hemodialysis exhibit the excessive generation of oxidative stressors, which may also be responsible for the endothelial dysfunction prevalent in these patients. Febuxostat, an inhibitor of xanthine oxidase enzyme, is emerging as a novel drug in the amelioration of oxidative stress status. However, studies regarding its effect among hemodialysis patients are still lacking. This prospective, block-randomized, double-blinded, placebo-controlled study was carried out to assess the effect of oral 40mg febuxostat on oxidative stress in hemodialysis patients. In total, fifty-seven eligible patients were randomly assigned to either a drug group or a placebo group for the 2-month study period. Serum malondialdehyde (MDA) and serum superoxide dismutase (SOD) were assessed at baseline and at the end of the study. A correlation analysis between previously reported serum asymmetric dimethylarginine (ADMA), serum MDA and serum SOD was performed. Febuxostat significantly decreased the serum MDA and significantly increased the serum SOD, while no significant results were observed in the placebo group. A highly positive correlation between the MDA levels and ADMA levels at baseline was noticed in both groups, while there was a highly negative correlation between the SOD levels and ADMA levels at baseline in both groups. A positive correlation between the change in ADMA levels and MDA levels from baseline was observed only in the drug group. Febuxostat appears to have a direct ameliorating effect on oxidative stress in hemodialysis patients with endothelial dysfunction.

Demographic, clinical and lifestyle predictors for severity of erectile dysfunction and biomarkers level in Malaysian patients

The incidence of erectile dysfunction (ED) is rising worldwide and its prevalence is one of the main health concerns that affect overall men well-being in Malaysia. The cluster of demographic, clinical and lifestyle factors may have contributed to the severity of ED and changes in biomarkers level; nevertheless these have not been studied extensively. This cross sectional study involved a total of 276 patients with 138 was diagnosed with ED. The demographic, clinical, lifestyle factors and severity of ED were assessed using a set of questionnaire and the International Index of Erectile Function (IIEF-5). Meanwhile, Total Testosterone (TT) and Asymmetric dimethylarginine (ADMA) levels were determined using the enzyme-linked immunosorbant assay (ELISA). Binary logistic regression test was used to demonstrate the predictors of severity of ED, TT and ADMA levels. Significant predictors for worsening of severity of ED are self-employed [10.55 (0.43 - 257.06), p=0.004], pensioner [8.07 (0.19 - 352.45), p=0.026], non-government employee [1.16 (0.05 - 26.26), p=0.04] and TT [0.41 (0.25 - 0.69), p=0.001]. Nevertheless, pensioner [0.08 (0.01 - 0.87), p=0.038] and unemployed [0.04 (0.01 - 0.42), p=0.007], were the predictors that may influence the changes of TT levels. On the other hand, academic qualification (secondary) [4.51 (0.48 - 42.83), p=0.014] and intensity of physical activities (< 1 hour/day) [2.61 (0.65 - 10.48), p=0.008] were the predictors which were more likely to influence the changes of ADMA levels in ED patients. TT and ADMA levels were influenced by demographic and lifestyle factors whilst severity of ED was predicted by demographic and clinical factors in Malaysian ED population. These predictors may provide new knowledge on risk factors of severity of ED and help in management of ED. Thus, the predictive models could serve as a primary guidance to physicians to ensure ED being managed and treated more effectively.

Relationship between asymmetric dimethylarginine, nitrite and genetic polymorphisms: Impact on erectile dysfunction therapy

Sildenafil is the most used treatment of erectile dysfunction, however a large part of patients do not respond to therapy. This drug enhances nitric oxide (NO) signaling, and therefore factors that alter NO production may impact this drug responsiveness. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of all NO synthases, and is metabolized by Dimethylarginine Dimethilaminohydrolase (DDAH) 1 and 2. Here we aimed to assess the relationship between plasma levels of ADMA and nitrite (marker of nitric oxide production) with Sildenafil responsiveness. We also studied genetic polymorphisms in DDAH1 and DDAH2 genes and their relation with biochemical and clinical data. Were included here 140 patients, divided in Clinical Erectile Dysfunction (CED) or Post-Prostatectomy Erectile Dysfunction (PPED) groups. Erectile function was evaluated before and after Sildenafil on-demand treatment using the International Index for Erectile Function Questionnaire. We have found that nitrite was associated with worse response to Sildenafil (r = − 0.25, P = 0.040). rs1554597 and rs18582 DDAH1 polymorphisms were associated with changes in ADMA levels in CED (B = − 0.23, P = 0.002; B = − 0.15, P = 0.017 for both variant genotypes, respectively). Finally, DDAH2 polymorphisms were associated with altered responsiveness to Sildenafil in PPED (B = +0.19, P = 0.027).

Physical activity - related changes in ADMA and vWF levels in patients with type 2 diabetes: A preliminary study.

The activity and the role of methylarginine in diabetic patients are subject to continuous research. The mechanism through which diabetes or insulin resistance increases asymmetric dimethylarginine (ADMA) serum levels is not fully understood. Studies indicate increased ADMA serum levels in patients with hypertension, hypercholesterolemia and hyperhomocysteinemia. The aim of the study was to assess the changes in ADMA levels and its derivatives related to the current disease process, as well as the levels of selected prothrombotic factors and their changes induced by physical activity. The study included 44 patients: group A (22 patients) - patients with diabetes with no vascular complications with mean age of 55.83 ± 7.37 years; and group B (22 patients) - healthy volunteers with the mean age of 51.16 ± 6.39 years. The authors' questionnaire was used to collect sociodemographic data in the study group. Physical exercise (Nordic walking) was practiced once per day for 30 min, 5 times a week. The assessment of peripheral blood parameters was performed using the ABX MICROS OT 16-parameter hematology analyzer. Additionally, chromatographic assay of serum levels of L-arginine, ADMA and symmetric dimethylarginine (SDMA) was performed. There were statistically significant differences in ADMA levels in the respondents with type 2 diabetes vs healthy volunteers after training (0.763 ± 0.043 vs 0.532 ± 0.046; p = 0.001). ADMA and SDMA levels in diabetic patients significantly exceeded standard values.

MCD diet-induced steatohepatitis is associated with alterations in asymmetric dimethylarginine (ADMA) and its transporters.

Using an experimental model of NASH induced by a methionine-choline-deficient (MCD) diet, we investigated whether changes occur in serum and tissue levels of asymmetric dimethylarginine (ADMA). Male Wistar rats underwent NASH induced by 8-week feeding with an MCD diet. Serum and hepatic biopsies at 2, 4 and 8weeks were taken, and serum enzymes, ADMA and nitrate/nitrite (NOx), were evaluated. Hepatic biopsies were used for mRNA and protein expression analysis of dimethylarginine dimethylaminohydrolase-1 (DDAH-1) and protein methyltransferases (PRMT-1), enzymes involved in ADMA metabolism and synthesis, respectively, and ADMA transporters (CAT-1, CAT-2A and CAT-2B). Lipid peroxides (TBARS), glutathione, ATP/ADP and DDAH activity were quantified. An increase in serum AST and ALT was detected in MCD animals. A time-dependent decrease in serum and tissue ADMA and increase in mRNA expression of DDAH-1 and PRMT-1 as well as higher rates of mRNA expression of CAT-1 and lower rates of CAT-2A and CAT-2B were found after 8-week MCD diet. An increase in serum NOx and no changes in protein expression in DDAH-1 and CAT-1 and higher content in CAT-2 and PRMT-1 were found at 8weeks. Hepatic DDAH activity decreased with a concomitant increase in oxidative stress, as demonstrated by high TBARS levels and low glutathione content. In conclusion, a decrease in serum and tissue ADMA levels in the MCD rats was found associated with a reduction in DDAH activity due to the marked oxidative stress observed. Changes in ADMA levels and its transporters are innovative factors in the onset and progression of hepatic alterations correlated with MCD diet-induced NASH.

Abstract 19253: Chronic Hypobaric Hypoxia and Chronic Intermittent Hypobaric Hypoxia in Rats Leads to a Mismatch in the ADMA-NO Pathway

Introduction: Chronic Hypoxia (CH) as well as chronic intermittent hypoxia (CIH) are associated with pathophysiological conditions like acute/chronic mountain sickness and pulmonary hypertension. In the manifestation of these diseases the endothelium and the L-arginine/NO pathway plays a crucial role. Asymmetric dimethylarginine (ADMA) is an endogenous formed NO synthase (NOS) inhibitor and well known as a risk factor for respiratory diseases associated with an endothelial dysfunction in the pulmonary circulation. ADMA is metabolized by dimethylarginine dimethylaminohydrolases (DDAH). In order to have a broader view of the involvement and behavior of ADMA and DDAH under CH as well as CIH our study was aimed to assess the changes in ADMA levels and the underlying molecular mechanisms. Methods: Wistar rats were maintained under conditions of CIH (2 days of hypobaric hypoxia followed by 2 days of normoxia (NX) for 30 days (428 torr), CH (30 days, 428 torr) and a control group maintained under NX (n=8 within each group). Systemic blood pressure (SBP) was measured by tail cuff plethysmography. ADMA concentration and DDAH activity were measured in lung tissue by a LC-MS/MS assay. Vascular oxidative stress response was determined by expression of Nox4 and the formation of malondialdehyde. Results: Hemodynamic measurements showed an increase in SBP in CH compared to NX (171.9±1.2 mmHg vs 176.7±4.6 mmHg; p=0.037). CH and CIH led to the development of a moderate right ventricular hypertrophy. ADMA concentrations in the lung were increased under hypoxia (P(NX vs CIH)=0.01 (85.3±66.3 nM vs 140.3±46.7 nM); P(NX vs CH)=0.007 (85.3±66.3 nM vs 197.1±56.0 nM) although it was more pronounced in CH (P=0.04). Hypoxia increased oxidative stress in the lung in combination with a reduced DDAH activity, more pronounced in CH. Expression of the endothelial NOS was increased but NO bioavailability was reduced in CH and CIH. Conclusion: The increase of ADMA might be one reason for impaired NO bioavailability in CH and CIH, resulting in an endothelial dysfunction. Likewise, oxidative stress seems to be another main cause of the mismatch in the ADMA-NO pathway.

AB0439 Clinical remission following treatment with tumour necrosis factor-alpha antagonists is not accompanied by changes in asymmetric dimethylarginine in patients with rheumatoid arthritis

BackgroundRheumatoid arthritis is characterised by impaired endothelial function which contributes to increased cardiovascular morbidity and mortality. Modern therapies such as tumour necrosis factor alpha antagonists appear to reduce cardiovascular risk...

Decrease of Asymmetric Dimethylarginine Predicts Acute Mountain Sickness

Each year, 40 million tourists worldwide are at risk of getting acute mountain sickness (AMS), because they travel to altitudes of over 2500 m. As asymmetric dimethylarginine (ADMA) is a nitric oxide synthase (NOS) inhibitor, it should increase pulmonary artery pressure (PAP) and raise the risk of acute mountain sickness and high-altitude pulmonary edema (HAPE). With this in mind, we investigated whether changes in ADMA levels (Δ-ADMA) at an altitude of 4000 m can predict an individual's susceptibility to AMS or HAPE. Twelve subjects spent two nights in a hypobaric chamber, the first night without exposure to altitude conditions and the second night at a simulated altitude of 4000 m. At identical time points during both nights (after 2, 5, and 11 hours), we determined ADMA serum levels, PAP by Doppler echocardiography and estimated hypoxia related symptoms by Lake Louise Score (LLS). Contrary to our initial hypothesis, subjects with a marked increase in ADMA at 4000 m showed PAP levels below the critical threshold for HAPE and were not affected by AMS. By contrast, subjects with a decrease in ADMA suffered from AMS and had PAP levels above 40 mmHg. After 2 hours of hypoxia we found a significant relationship between Δ-PAP t(2) (Spearmans ρ = 0.30, p ≤ 0.05) respectively Δ-ADMA t(2) (ρ = -0.92, p ≤ 0.05) and LLS. After 2 hours of hypoxia, the Δ-ADMA (positive or negative) can predict an LLS of >5 with a sensitivity of 80% and a specificity of 100% and can help assess the risk of an increase in PAP to more than 40 mmHg and thus the risk of HAPE (ϕ coefficient: 0.69; p ≤ 0.05).

Acute Endotoxemia Inhibits Microvascular Nitric Oxide-Dependent Vasodilation in Humans

Nitric oxide (NO) is crucial for the microvascular homeostasis, but its role played in the microvascular alterations during sepsis remains controversial. We investigated NO-dependent vasodilation in the skin microcirculation and plasma levels of asymmetric dimethylarginine (ADMA), a potent endogenous inhibitor of the NO synthases, in a human model of sepsis. In this double-blind, randomized, crossover study, microvascular NO-dependent (local thermal hyperemia) and NO-independent vasodilation (post-occlusive reactive hyperemia) assessed by laser Doppler imaging, plasma levels of ADMA, and l-arginine were measured in seven healthy obese volunteers, immediately before and 4 h after either a i.v. bolus injection of Escherichia coli endotoxin (LPS; 2 ng/kg) or normal saline (placebo) on two different visits at least 2 weeks apart. LPS caused the expected systemic effects, including increases in heart rate (+43%, P < 0.001), cardiac output (+16%, P < 0.01), and rectal temperature (+1.4°C, P < 0.001), without change in arterial blood pressure. LPS affected neither baseline skin blood flow nor post-occlusive reactive hyperemia but decreased the NO-dependent local thermal hyperemia response, l-arginine, and, to a lesser extent, ADMA plasma levels. The changes in NO-dependent vasodilation were not correlated with the corresponding changes in the plasma levels of ADMA, l-arginine, or the l-arginine/ADMA ratio. Our results show for the first time that experimental endotoxemia in humans causes a specific decrease in endothelial NO-dependent vasodilation in the microcirculation, which cannot be explained by a change in ADMA levels. Microvascular NO deficiency might be responsible for the heterogeneity of tissue perfusion observed in sepsis and could be a therapeutic target.

The Impact of Fiber Supplementation on ADMA Levels

Asymmetric dimethylarginine (ADMA) is an emerging biomarker that has been associated with oxidative metabolism and increased cardiovascular risk. Little information is available regarding the effect of diet on ADMA. The authors studied 86 overweight/obese adults as part of a clinical trial of psyllium supplementation to determine whether 3 months of such supplementation would affect ADMA levels. Forty-one people in the intervention group received 14 g/day of psyllium in addition to their usual diet compared with 45 controls who followed their usual diet alone. The 2 groups were comparable at baseline in demographic characteristics and body mass index. Baseline ADMA levels were elevated in this overweight/obese population compared with published reference values in healthy individuals (0.75 vs 0.50 micromol/L). The change in ADMA levels over 3 months was not different in the psyllium group compared with the control group (-.03 vs -.01 micromol/L, P=.73). These findings do not support a significant effect of psyllium fiber supplementation on ADMA.

Randomized Placebo-Controlled Trial Assessing a Treatment Strategy Consisting of Pravastatin, Vitamin E, and Homocysteine Lowering on Plasma Asymmetric Dimethylarginine Concentration in Mild to Moderate CKD

Chronic kidney disease (CKD) is associated with an increased incidence of cardiovascular disease (CVD). The Anti-oxidant Therapy In Chronic Renal Insufficiency (ATIC) Study showed that a multistep treatment strategy improved carotid intima-media thickness, endothelial function, and microalbuminuria in patients with stages 2 to 4 CKD. Increased plasma concentrations of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, have been linked to greater CVD risk in patients with CKD. The aim of this study is to assess effects of the multistep intervention on plasma ADMA concentrations in the ATIC Study. Secondary analysis of a randomized double-blind placebo-controlled trial. 93 patients with creatinine clearance of 15 to 70 mL/min/1.73 m(2) (according to the Cockcroft-Gault equation) from 7 outpatient clinics in Amsterdam, The Netherlands. The treatment group received sequential treatment consisting of pravastatin, 40 mg/d. After 6 months, vitamin E, 300 mg/d, was added, and after another 6 months, homocysteine-lowering therapy (folic acid, 5 mg/d; pyridoxine, 100 mg/d; and vitamin B(12), 1 mg/d, all in 1 tablet) were added and continued for another year. The control group received matching placebos. Plasma ADMA levels. 36 participants (77%) in the treatment group and 38 (83%) in the placebo group completed the study. Mean ADMA and symmetric dimethylarginine concentrations in the total study population were 0.53 +/- 0.07 (SD) and 1.14 +/- 0.46 mumol/L, respectively. After 24 months, there was no overall effect of the treatment strategy on ADMA concentrations (beta = -0.006; P = 0.27). Analysis of separate treatment effects suggested that vitamin E significantly decreased ADMA levels by 4% in the treatment group compared with the placebo group (multiple adjusted P = 0.02). The study was a secondary analysis, power calculation was based on the primary end point of carotid intima-media thickness, mean plasma ADMA levels were relatively low. Overall, a multistep treatment strategy consisting of pravastatin, vitamin E, and B vitamins had no effect on plasma ADMA levels in a stage 2 to 4 CKD population. This suggests that the beneficial effects of the intervention were not mediated by changes in ADMA levels. Possible ADMA-lowering effects of vitamin E deserve further attention.

Nebivolol Treatment Reduces Serum Levels of Asymmetric Dimethylarginine and Improves Endothelial Dysfunction in Essential Hypertensive Patients

This study was conducted to evaluate (i) the effect of nebivolol, a selective beta1-adrenergic receptor antagonist, on plasma concentration of asymmetric dimethylarginine (ADMA) and on flow-mediated dilation (FMD) in essential hypertensive patients; (ii) the effect of serum derived from the treated hypertensive patients on ADMA and on dimethylarginine dimethylaminohydrolase 2 (DDAH2), the enzyme that selectively degrades ADMA, in human umbilical vein endothelial cells (HUVECs). Forty healthy subjects and 40 matched essential hypertensive patients treated with atenolol and nebivolol according to a double-blind, randomized design participated in the study. Evaluation of brachial artery (BA) reactivity was performed by a longitudinal B-mode scan of the right BA. ADMA and L-arginine were measured by high-performance liquid chromatography. DDAH2 expression and endothelial nitric oxide synthase activity (eNOS) were also evaluated in HUVECs. ADMA levels were significantly decreased and FMD increased only in patients receiving nebivolol (P < 0.01). Furthermore, in nebivolol group, we found a significant correlation between changes in ADMA levels and changes in FMD (P < 0.01). Sera derived from patients treated with nebivolol but not with atenolol decreased ADMA and increased DDAH2 expression and eNOS activity (P < 0.001) in HUVECs. The results of this study demonstrate that the improvement of endothelial dysfunction induced by nebivolol in hypertensive patients may be related to its effect on circulating ADMA levels. Although the mechanism by which nebivolol reduces circulating ADMA in hypertensive patients remains unclear, our ex vivo results suggest that the upregulation of DDAH2 expression may have a role.

Methylated arginines in stable and acute patients with coronary artery disease before and after percutaneous revascularization

BackgroundImpairment of the nitric oxide synthase (NOS) pathway independently predicts cardiovascular events. We investigated whether plasma levels of the NOS inhibitor asymmetric dimethylarginine (ADMA), of symmetric dimethylarginine (SDMA) and of the nitrogen oxide substrate l-arginine can serve as additional staging biomarkers in stable coronary artery disease, non-ST-segment myocardial infarction (NSTEMI) and ST-segment myocardial infarction (STEMI). Materials and methodsConsecutive patients referred for percutaneous coronary intervention (PCI) were studied. Peripheral blood samples were drawn immediately before, immediately after and 24 h following PCI and analyzed by means of high-performance liquid chromatography. ResultsSeventy-four patients were studied: 27 patients with stable angina pectoris (7 women, 61.4±1.9 years), 23 NSTEMI patients (9 women, 61.8±2.3 years) and 24 STEMI patients (7 women, 61.3±2.8 years). Plasma concentrations of ADMA and SDMA were elevated following PCI compared to before PCI but there were no differences in concentrations between STEMI, NSTEMI and stable angina patients. Plasma concentrations of l-arginine rose after PCI but remained lower in patients with STEMI than in those with NSTEMI or in stable angina patients. Medication might influence l-arginine concentrations and the use of HMG CoA reductase inhibitors and β-adrenoceptor antagonists at study inclusion was significantly less common in STEMI patients compared to NSTEMI and stable angina patients. Conclusionl-arginine levels were lower in patients with STEMI and we found changes in ADMA levels over shorter time periods than previously considered possible. We speculate that these variations may be related to the natural history of myocardial infarction or to peri-procedural stress related to PCI.

Decreased plasma soluble RAGE in patients with hypercholesterolemia: Effects of statins

The receptor for advanced glycation endproducts (RAGE) is overexpressed at sites of vascular pathology. A soluble RAGE isoform (sRAGE) neutralizes the ligand-mediated damage by acting as a decoy. We hypothesized that in hypercholesterolemia up-regulation of the ligand–RAGE axis may bridge impairment of nitric oxide biosynthesis with oxidative stress. We measured in 60 hypercholesterolemic patients and 20 controls plasma total sRAGE levels, urinary 8-iso-prostaglandin (PG) F 2α excretion, and plasma levels of asymmetric dimethylarginine (ADMA). The effects of two structurally different statins (pravastatin and atorvastatin) on these parameters were analyzed in 20 hypercholesterolemic subjects free of vascular disease. Plasma sRAGE was significantly lower, ADMA and urinary 8-iso-PGF 2α were higher, in hypercholesterolemic versus normocholesterolemic patients. Patients on statin treatment with previous myocardial infarction had lower 8-iso-PGF 2α, higher sRAGE, and unchanged ADMA levels compared to subjects free of vascular disease. On multivariate regression analysis only 8-iso-PGF 2α and ADMA predicted sRAGE levels. An 8-week treatment with either statin was associated with a significant reduction in urinary 8-iso-PGF 2α, whereas only atorvastatin raised sRAGE levels near to normal values, with no change in ADMA levels. sRAGE might serve as an endogenous protecting factor for accelerated atherosclerosis mediated by oxidative stress and endothelial dysfunction in hypercholesterolemia.

Improvement in Central Arterial Pressure Waveform during Hemodialysis Is Related to a Reduction in Asymmetric Dimethylarginine (ADMA) Levels

Background: Cardiovascular mortality is high in hemodialysis (HD) patients. Early arterial pressure wave reflections, reflecting arterial stiffness and the endogenous nitric oxide synthesis inhibitor asymmetric dimethylarginine (ADMA) levels predict mortality in HD patients. Therefore, we aimed to study changes in ADMA levels and central arterial pressure waveform during HD. Methods: Thirty-two chronic HD patients were studied before and after a HD session. In a subset of 22 patients without arrhythmias, pulse wave analysis was performed on radial artery (SphygmoCor). Augmentation index (AIx), defined as difference between the second and first systolic peak divided by central pulse pressure, was used as a measure of arterial stiffness. ADMA was measured in plasma with the ELISA technique. Homocysteine was measured in plasma using the EIA technique. Results: HD reduced both AIx (19%; p = 0.003) and ADMA levels (17%; p < 0.001). The magnitudes of changes in AIx and ADMA during HD were correlated (r = 0.44; p = 0.045). Mean arterial pressure change was not significant. HD reduced homocysteine levels, but homocysteine was not related to ADMA or AIx. Conclusion: The reduction in ADMA level seen after HD was associated with improvement in the central arterial pressure waveform, suggesting involvement of nitric oxide in the regulation of arterial stiffness in HD patients.

ADMA regulates angiogenesis: genetic and metabolic evidence

Endothelium-derived nitric oxide (NO) plays an important role in transducing the effects of angiogenic factors. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthase (NOS). We used a murine model of hindlimb ischemia to investigate whether genetic or metabolic changes in ADMA levels could impair angiogenic response in vivo. Hindlimb ischemia was surgically induced in C57BL/6J mice, apo E-deficient mice, or transgenic mice overexpressing dimethylarginine dimethylaminohydrolase (DDAH). Some animals were also treated with the NOS antagonist L-nitro-arginine, or the NO precursor L-arginine. Angiogenesis was quantified in the hindlimb skeletal muscle by capillary/myocyte ratio. Plasma or tissue ADMA levels were measured by HPLC. In normal mice, hindlimb ischemia increased tissue ADMA twofold, and reduced DDAH and NOS expression. This was associated with a reduced NOS activity (by over 80%) three days following surgery. On day seven, a threefold increase in DDAH expression and a fall in tissue ADMA levels were associated with a sevenfold increase in NOS activity, whereas NOS expression did not increase above baseline. In DDAH transgenic mice, the elevation of ADMA and decrement in NOS activity was blunted during hindlimb ischemia. Plasma ADMA levels were increased in apo E-mice (1.79 +/- 0.45 versus 1.07 +/- 0.08 pmol/l; p = 0.008). Capillary index was significantly reduced in apo E-mice up to seven weeks after surgery (0.25 +/- 0.05 versus 0.62 +/- 0.08; p < 0.001). The effect of hypercholesterolemia on capillary index was reversed by L-arginine, and (in wild-type mice) mimicked by administration of the NOS antagonist L-nitro-arginine. In conclusion, metabolic or genetic changes in plasma and tissue ADMA levels affect tissue NO production and angiogenic response to ischemia.

Dimethylarginine dimethylaminohydrolase activity modulates ADMA levels, VEGF expression, and cell phenotype

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase and is metabolised by dimethylarginine dimethylaminohydrolase (DDAH). Elevated levels of circulating ADMA correlate with various cardiovascular pathologies less is known about the cellular effects of altered DDAH activity. We modified DDAH activity in cells and measured the changes in ADMA levels, morphological phenotypes on Matrigel, and expression of vascular endothelial growth factor (VEGF). DDAH over-expressing ECV304 cells secreted less ADMA and when grown on Matrigel had enhanced tube formation compared to untransfected cells. VEGF mRNA levels were 2.1-fold higher in both ECV304 and murine endothelial cells (sEnd.1) over-expressing DDAH. In addition the DDAH inhibitor, S-2-amino-4(3-methylguanidino)butanoic acid (4124W 1 mM), markedly reduced human umbilical vein endothelial cell tube formation in vitro. We have found that upregulating DDAH activity lowers ADMA levels, increases the levels of VEGF mRNA in endothelial cells, and enhances tube formation in an in vitro model, whilst blockade of DDAH reduces tube formation.