Plasma Asymmetric Dimethylarginine Concentrations Research Articles

Increased ADMA levels are associated with poor pulmonary outcome in preterm neonates

Background: Nitric oxide (NO), synthesized from the amino acid L-arginine by the action of NO synthases (NOS), is a pulmonary vasodilator. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NOS. Preterm infants have higher plasma ADMA concentrations than term infants which could cause inhibition of NO synthesis and deterioration in pulmonary functions. We aimed to investigate the relationship between serum ADMA and L-arginine levels of preterm infants and respiratory distress syndrome (RDS), requirement of surfactant treatment, duration of mechanical ventilation, oxygen treatment, and development of bronchopulmonary dysplasia (BPD).Methods: A prospective cohort study was conducted including 80 preterm infants born with gestational age (GA) ≤ 32 weeks and birth weight (BW) ≤ 1500 g. Blood samples were obtained from all infants immediately after birth, and at postnatal 28th day of age. The relationship of first-day serum ADMA and L-arginine levels and surfactant requirement, duration of mechanical ventilation, oxygen treatment was investigated. Serum ADMA and L-arginine levels at 1st and 28th days were compared at patients with and without BPD. The role of serum ADMA levels at postnatal 28th day of age to predict the requirement of oxygen at postmenstrual 36 weeks of age was also investigated.Results: Eighty preterm infants (42 male, 38 female) were enrolled in the study. Mean BW and GA for the total cohort was 1144.81 ± 220.44 g and 28.3 ± 1.8 weeks, respectively. Sixty-one infants were diagnosed as RDS and 44 infants treated with surfactant. The first-day ADMA levels were significantly higher in infants with surfactant requirement (1.14 ± 0.23 versus 0.86 ± 0.37, p < 0.01). First-day L-arginine levels were lower in infants with surfactant requirement compared to infants without surfactant requirement (22.32 ± 2.33 versus 23.75 ± 2.42, p > 0.05) but not significantly. Serum ADMA and L-arginine concentrations at first day were not different among infants with and without BPD (p > 0.05). ADMA concentrations at 28th day was significantly higher in infants with BPD (1.00 ± 0.25 versus 0.81 ± 0.25, p < 0.05). The cutoff level of 0.875 μmol/L for ADMA at 28th day offered the best predictive value for oxygen requirement at postnatal 36 weeks of age with a sensitivity of 88% and a specificity of 54%.Conclusıon: Serum ADMA and L-arginine levels are related to pulmonary morbidities in newborn. The results of this study show that increased ADMA levels are associated with poor pulmonary outcomes in preterm infants.

Early regression of coronary artery remodeling with esmolol and DDAH/ADMA pathway in hypertensive rats.

Our preclinical study demonstrated that esmolol produces early regression of left ventricular hypertrophy in arterial hypertension. The aim of this study was to assess the effects of short-term esmolol therapy on the regression of left anterior descending artery remodeling in spontaneously hypertensive rats (SHRs), and to determine whether the asymmetric dimethylarginine (ADMA)/dimethylarginine dimethylaminohydrolase (DDAH) pathway, a regulator of nitric oxide (NO) bioavailability, accounted for this regression. Fourteen-month-old male SHRs were treated intravenously with vehicle (SHR, n=15) or esmolol (SHR-E, n=20) (300 μg kg-1 min-1). Age-matched, vehicle-treated male Wistar-Kyoto rats (WKY, n=15) served as controls. SHRs were also treated with nitroglycerin (SHR-N, n=5). After 48 h, the left anterior descending artery structure and morphology were assessed, and dose-response curves for 5-hydroxytryptamine (5-HT, 10-9-3 × 10-5 mol l-1) were constructed. ADMA concentrations in plasma and left ventricle and DDAH activity in tissue were analyzed. Wall thickness and cross-sectional area were significantly lower after treatment with esmolol in SHR-E than in SHR. Media thickness and smooth muscle cell count were lower in SHR-E than in SHR. Esmolol induced a significant reduction in adventitial cell count in SHR-E. The area under the concentration-response curves was significantly higher in SHR than in SHR-E, as were the esmolol normalized coronary artery contracting responses to 5-HT. We found significantly lower ADMA levels and significantly higher DDAH activity in the ventricle in SHR-E than in SHR. The protective effect of esmolol on the regression of left anterior descending artery remodeling may be related to the reduction in ADMA levels.

NO synthesis from arginine is favored by α-linolenic acid in mice fed a high-fat diet.

Alterations in NO availability and signaling play a pivotal role at early stages of the metabolic syndrome (MetSynd). We hypothesized that dietary α-linolenic acid (ALA, 18:3 n-3) favors NO availability by modulating amino acid metabolism, with a specific impact on the arginine-NO pathway. Mice were fed a hyperlipidic diet (285g lipid/kg, 51.1% energy), rich in either saturated fatty acids (SFA, provided by palm oil, PALM group) or ALA (provided by linseed oil, LIN group). We measured whole-body NO synthesis and systemic arginine hydrolysis with a tracer-based method, plasma concentration of related metabolites, and hepatic mRNA level of related enzymes, and the study was completed by a transcriptomic analysis in the liver. As expected with this model, hyperlipidic diets resulted in increased adiposity and glycemia after 5weeks. As compared to PALM mice, LIN mice had a higher plasma nitrite and nitrate concentration, a higher whole-body conversion of arginine into NO vs urea, and a similar plasma concentration of asymmetric dimethylarginine (ADMA), despite a higher expression of the liver dimethylargininase-1. In LIN mice, there was a higher expression of genes involved in PPARα signaling, but a little impact on gene expression related to amino acids and arginine metabolism. This effect cannot be directly ascribed to changes in arginase activity in the liver or ADMA metabolism, nor to direct regulation of the related target genes. In conclusion, dietary ALA favors NO synthesis, which could contribute to rescue NO availability when jeopardized by the nutritional conditions in relation with the initiation of the MetSynd.

Single Low-Density Lipoprotein Apheresis Does Not Improve Vascular Endothelial Function in Chronically Treated Hypercholesterolemic Patients.

Objective. To investigate vascular endothelial function (VEF) responses to a single low-density lipoprotein (LDL) apheresis session in hypercholesterolemic patients undergoing chronic treatment. Methods. We measured brachial artery flow-mediated dilation (FMD), plasma lipids, vitamin E (α- and γ-tocopherol), markers of oxidative/nitrative stress (malondialdehyde (MDA) and nitro-γ-tocopherol (NGT)), and regulators of NO metabolism (arginine (ARG) and asymmetric dimethylarginine (ADMA)) prior to (Pre) and immediately following (Post) LDL apheresis and at 1, 3, 7, and 14 d Post in 5 hypercholesterolemic patients (52 ± 11 y). Results. Relative to Pre, total cholesterol (7.8 ± 1.5 mmol/L) and LDL-cholesterol (6.2 ± 1.2 mmol/L) were 61% and 70% lower (P < 0.01), respectively, at Post and returned to Pre levels at 14 d. Brachial FMD responses (6.9 ± 3.6%) and plasma MDA, ARG, and ADMA concentrations were unaffected by LDL apheresis. Plasma α-tocopherol, γ-tocopherol, and NGT concentrations were 52–69% lower at Post (P < 0.01), and α-tocopherol remained 36% lower at 1 d whereas NGT remained 41% lower at d 3. Conclusions. Acute cholesterol reduction by LDL apheresis does not alter VEF, oxidative stress, or NO homeostasis in patients treated chronically for hypercholesterolemia.

S.04.04 Clinical and brain structural correlates of NCAM and polysialic acid serum levels in schizophrenia

Cognitive deficits are a core feature of schizophrenia. Previous studies have shown that plasma asymmetric dimethylarginine (ADMA), an endogenous inhibitor of the nitric oxide synthase, was increased in patients with schizophrenia. This study aimed to investigate the association of ADMA with cognitive deficits in schizophrenia. Forty-seven patients with schizophrenia and 45 healthy control subjects were recruited in present study. Cognitive function was assessed with a neuropsychological battery including 7 neurocognitive tests. Schizophrenic symptoms were assessed using the Positive and Negative Syndrome Scale and plasma ADMA concentration was measured by HPLC. We found that patients with schizophrenia exhibited poorer performances in nearly all of the cognitive tests except for the visual memory index compared with healthy controls. Plasma ADMA levels were significantly increased in patients with schizophrenia when compared to normal controls, and the mean ADMA concentration in patients with multiple episode schizophrenia was much higher than that of patients with first episode schizophrenia. For the patients, ADMA was negatively associated with attention, working memory and executive function in schizophrenia. These results suggest that ADMA may be involved in the pathophysiology of schizophrenia-associated cognitive impairments, and plasma ADMA could be a peripheral biomarker for evaluation of cognitive function in schizophrenia.

Elevated Levels of Asymmetric Dimethylarginine (ADMA) in the Pericardial Fluid of Cardiac Patients Correlate with Cardiac Hypertrophy.

BackgroundPericardial fluid (PF) contains several biologically active substances, which may provide information regarding the cardiac conditions. Nitric oxide (NO) has been implicated in cardiac remodeling. We hypothesized that L-arginine (L-Arg) precursor of NO-synthase (NOS) and asymmetric dimethylarginine (ADMA), an inhibitor of NOS, are present in PF of cardiac patients and their altered levels may contribute to altered cardiac morphology.MethodsL-Arg and ADMA concentrations in plasma and PF, and echocardiographic parameters of patients undergoing coronary artery bypass graft (CABG, n = 28) or valve replacement (VR, n = 25) were determined.ResultsWe have found LV hypertrophy in 35.7% of CABG, and 80% of VR patients. In all groups, plasma and PF L-Arg levels were higher than that of ADMA. Plasma L-Arg level was higher in CABG than VR (75.7±4.6 μmol/L vs. 58.1±4.9 μmol/L, p = 0.011), whereas PF ADMA level was higher in VR than CABG (0.9±0.0 μmol/L vs. 0.7±0.0 μmol/L, p = 0.009). L-Arg/ADMA ratio was lower in the VR than CABG (VRplasma: 76.1±6.6 vs. CABGplasma: 125.4±10.7, p = 0.004; VRPF: 81.7±4.8 vs. CABGPF: 110.4±7.2, p = 0.009). There was a positive correlation between plasma L-Arg and ADMA in CABG (r = 0.539, p = 0.015); and plasma and PF L-Arg in CABG (r = 0.357, p = 0.031); and plasma and PF ADMA in VR (r = 0.529, p = 0.003); and PF L-Arg and ADMA in both CABG and VR (CABG: r = 0.468, p = 0.006; VR: r = 0.371, p = 0.034). The following echocardiographic parameters were higher in VR compared to CABG: interventricular septum (14.7±0.5 mm vs. 11.9±0.4 mm, p = 0.000); posterior wall thickness (12.6±0.3 mm vs. 11.5±0.2 mm, p = 0.000); left ventricular (LV) mass (318.6±23.5 g vs. 234.6±12.3 g, p = 0.007); right ventricular (RV) (33.9±0.9 cm2 vs. 29.7±0.7 cm2, p = 0.004); right atrial (18.6±1.0 cm2 vs. 15.4±0.6 cm2, p = 0.020); left atrial (19.8±1.0 cm2 vs. 16.9±0.6 cm2, p = 0.033) areas. There was a positive correlation between plasma ADMA and RV area (r = 0.453, p = 0.011); PF ADMA and end-diastolic (r = 0.434, p = 0.015) and systolic diameter of LV (r = 0.487, p = 0.007); and negative correlation between PF ADMA and LV ejection fraction (r = -0.445, p = 0.013) in VR.ConclusionWe suggest that elevated levels of ADMA in the PF of patients indicate upregulated RAS and reduced bioavailability of NO, which can contribute to the development of cardiac hypertrophy and remodeling.

A systematic review and meta-analysis on the effect of statins on plasma asymmetric dimethylarginine concentrations

A systematic review and meta-analysis on the effect of statins on plasma asymmetric dimethylarginine concentrations

Biosynthesis of homoarginine (hArg) and asymmetric dimethylarginine (ADMA) from acutely and chronically administered free L-arginine in humans.

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide (NO) synthesis, whereas L-arginine (Arg) and L-homoarginine (hArg) serve as substrates for NO synthesis. ADMA and other methylated arginines are generally believed to exclusively derive from guanidine (N (G))-methylated arginine residues in proteins by protein arginine methyltransferases (PRMTs) that use S-adenosylmethionine (SAM) as the methyl donor. L-Lysine is known for decades as a precursor for hArg, but only recent studies indicate that arginine:glycine amidinotransferase (AGAT) is responsible for the synthesis of hArg. AGAT catalyzes the formation of guanidinoacetate (GAA) that is methylated to creatine by guanidinoacetate methyltransferase (GAMT) which also uses SAM. The aim of the present study was to learn more about the mechanisms of ADMA and hArg formation in humans. Especially, we hypothesized that ADMA is produced by N (G)-methylation of free Arg in addition to the known PRMTs-involving mechanism. In knockout mouse models of AGAT- and GAMT-deficiency, we investigated the contribution of these enzymes to hArg synthesis. Arg infusion (0.5 g/kg, 30 min) in children (n = 11) and ingestion of high-fat protein meals by overweight men (n = 10) were used to study acute effects on ADMA and hArg synthesis. Daily Arg ingestion (10 g) or placebo for 3 or 6 months by patients suffering from peripheral arterial occlusive disease (PAOD, n = 20) or coronary artery disease (CAD, n = 30) was used to study chronic effects of Arg on ADMA synthesis. Mass spectrometric methods were used to measure all biochemical parameters in plasma and urine samples. In mice, AGAT but not GAMT was found to contribute to plasma hArg, while ADMA synthesis was independent of AGAT and GAMT. Arg infusion acutely increased plasma Arg, hArg and ADMA concentrations, but decreased the plasma hArg/ADMA ratio. High-fat protein meals acutely increased plasma Arg, hArg, ADMA concentrations, as well as the plasma hArg/ADMA ratio. In the PAOD and CAD studies, plasma Arg concentration increased in the verum compared to the placebo groups. Plasma ADMA concentration increased only in the PAOD patients who received Arg. Our study suggests that in humans a minor fraction of free Arg is rapidly metabolized to ADMA and hArg. In mice, GAMT and N (G)-methyltransferases contribute to ADMA and hArg synthesis from Arg, whereas AGAT is involved in the synthesis of hArg but not of ADMA. The underlying biochemical mechanisms remain still elusive.

A systematic review and meta-analysis of the effect of statins on plasma asymmetric dimethylarginine concentrations.

The impact of statin therapy on plasma asymmetric dimethylarginine (ADMA) levels has not been conclusively studied. Therefore the aim of the meta-analysis was to assess the effect of statins on circulating ADMA levels. We searched selected databases (up to August 2014) to identify randomized controlled trials (RCTs) that investigate the effect of statins on plasma ADMA concentrations. A weighted meta-regression (WMD) using unrestricted maximum likelihood model was performed to assess the impact of statin dose, duration of statin therapy and baseline ADMA concentrations as potential variables on the WMD between statin and placebo group. In total, 1134 participants in 9 selected RCTs were randomized; 568 were allocated to statin treatment and 566 were controls. There was a significant reduction in plasma ADMA concentrations following statin therapy compared with placebo (WMD: − 0.104 μM, 95% confidence interval: − 0.131 to − 0.077, Z = − 7.577, p < 0.0001). Subgroups analysis has shown a significant impact of hydrophilic statins (WMD: − 0.207 μM, 95%CI: − 0.427 to + 0.013, Z = − 7.250, p < .0001) and a non-significant effect of hydrophobic statins (WMD: − 0.101 μM, 95%CI: − 0.128 to − 0.074, Z = − 1.845, p = 0.065). In conclusion, this meta-analysis of available RCTs showed a significant reduction in plasma ADMA concentrations following therapy with hydrophilic statins.

Endothelial Dimethylarginine Dimethylaminohydrolase 1 Is an Important Regulator of Angiogenesis but Does Not Regulate Vascular Reactivity or Hemodynamic Homeostasis.

Asymmetrical dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthesis and a risk factor for cardiovascular disease. Dimethylarginine dimethylaminohydrolase (DDAH) enzymes are responsible for ADMA breakdown. It has been reported that endothelial DDAH1 accounts for the majority of ADMA metabolism. However, we and others have shown strong DDAH1 expression in a range of nonendothelial cell types, suggesting that the endothelium is not the only site of metabolism. We have developed a new endothelium-specific DDAH1 knockout mouse (DDAH1(En-/-)) to investigate the significance of endothelial ADMA in cardiovascular homeostasis. DDAH1 deletion in the DDAH1(En-/-) mouse was mediated by Tie-2 driven Cre expression. DDAH1 deletion was confirmed through immunocytochemistry, whereas Western blotting showed that DDAH1 remained in the kidney and liver, confirming expression in nonendothelial cells. Plasma ADMA was unchanged in DDAH1(En-/-) mice, and cultured aortas released amounts of ADMA to similar to controls. Consistent with these observations, vasoreactivity ex vivo and hemodynamics in vivo were unaltered in DDAH1(En-/-) mice. In contrast, we observed significantly impaired angiogenic responses both ex vivo and in vivo. We demonstrate that endothelial DDAH1 is not a critical determinant of plasma ADMA, vascular reactivity, or hemodynamic homeostasis. DDAH1 is widely expressed in a range of vascular and nonvascular cell types; therefore, the additive effect of DDAH1 expression in multiple organ systems determines plasma ADMA concentrations. Endothelial deletion of DDAH1 profoundly impairs the angiogenic capacity of endothelial cells, indicating that intracellular ADMA is a critical determinant of endothelial cell response.

Reduced Renal Methylarginine Metabolism Protects against Progressive Kidney Damage.

Nitric oxide (NO) production is diminished in many patients with cardiovascular and renal disease. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthesis, and elevated plasma levels of ADMA are associated with poor outcomes. Dimethylarginine dimethylaminohydrolase-1 (DDAH1) is a methylarginine-metabolizing enzyme that reduces ADMA levels. We reported previously that a DDAH1 gene variant associated with increased renal DDAH1 mRNA transcription and lower plasma ADMA levels, but counterintuitively, a steeper rate of renal function decline. Here, we test the hypothesis that reduced renal-specific ADMA metabolism protects against progressive renal damage. Renal DDAH1 is expressed predominately within the proximal tubule. A novel proximal tubule-specific Ddah1 knockout (Ddah1(PT-/-)) mouse demonstrated tubular cell accumulation of ADMA and lower NO concentrations, but unaltered plasma ADMA concentrations. Ddah1(PT-/-) mice were protected from reduced kidney tissue mass, collagen deposition, and profibrotic cytokine expression in two independent renal injury models: folate nephropathy and unilateral ureteric obstruction. Furthermore, a study of two independent kidney transplant cohorts revealed higher levels of human renal allograft methylarginine-metabolizing enzyme gene expression associated with steeper function decline. We also report an association among DDAH1 expression, NO activity, and uromodulin expression supported by data from both animal and human studies, raising the possibility that kidney DDAH1 expression exacerbates renal injury through uromodulin-related mechanisms. Together, these data demonstrate that reduced renal tubular ADMA metabolism protects against progressive kidney function decline. Thus, circulating ADMA may be an imprecise marker of renal methylarginine metabolism, and therapeutic ADMA reduction may even be deleterious to kidney function.

Asymmetric dimethylarginine in somatically healthy schizophrenia patients treated with atypical antipsychotics: a case-control study.

BackgroundSchizophrenia is associated with increased cardiovascular morbidity and mortality. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of the nitric oxide synthase, and the L-arginine:ADMA ratio are markers of endothelial dysfunction that predict mortality and adverse outcome in a range of cardiovascular disorders. Increased ADMA levels may also lead to increased oxidative stress. We hypothesized that ADMA and the L-arginine:ADMA ratio are increased in somatically healthy schizophrenia patients treated with atypical antipsychotics (AAP), and that the ADMA and the L-arginine: ADMA ratio are positively correlated to measures of oxidative stress.MethodsWe included 40 schizophrenia patients treated with AAP, but without somatic disease or drug abuse, and 40 healthy controls. Plasma concentrations of ADMA and L-arginine were determined by high-performance liquid chromatography. Data were related to markers of systemic oxidative stress on DNA, RNA and lipids, as well as measures of medication load, duration of disease and current symptomatology.ResultsPlasma ADMA and the L-arginine:ADMA ratio did not differ between schizophrenia patients and controls. Furthermore, ADMA and the L-arginine:ADMA ratio showed no correlations with oxidative stress markers, medication load, or Positive and Negative Syndrome Scale scores.ConclusionsSchizophrenia and treatment with AAP was not associated with increased levels of plasma ADMA or the L-arginine:ADMA ratio. Furthermore, plasma levels of ADMA were not associated with levels of systemic oxidative stress in vivo.

Single LDL‐Cholesterol Apheresis Treatment Does Not Improve Vascular Endothelial Function in Hypercholesterolemic Patients

Low‐density lipoprotein cholesterol (LDL‐C) apheresis is an effective therapy to reduce CVD risk in hypercholesterolemic patients who are refractory or intolerant to lipid‐lowering therapy. We hypothesized that a single treatment of LDL‐C apheresis would increase vascular endothelial function by decreasing oxidative stress responses that limit nitric oxide (NO) bioavailability. Patients (n=5; 52±11 y) were actively receiving bi‐weekly LDL‐C apheresis treatments (duration=54±41 mo). Brachial artery flow‐mediated dilation (FMD), plasma lipids, vitamin E (α‐ and γ‐tocopherol), markers of oxidative stress (nitro‐γ‐tocopherol, malondialdehyde (MDA)), and regulators of NO metabolism (arginine (ARG), asymmetric dimethylarginine (ADMA)) were assessed prior to (Pre) and immediately following LDL‐C apheresis (Post) and at 1, 3, 7, and 14 d Post. Relative to Pre, total C (300±58 mg/dL) and LDL‐C (239±46 mg/dL) at Post were 61% and 70% lower (P&lt;0.01), respectively, and remained 46‐56%, 27‐34%, and 14‐16% lower at 1, 3, and 7 d, respectively. Plasma α‐, γ‐, and nitro‐γ‐tocopherol concentrations were 52‐69% lower at Post (P&lt;0.01), and α‐tocopherol remained 36% lower at 1 d while nitro‐γ‐tocopherol remained 41% lower at d 3. Brachial FMD responses (6.9±3.6%) and plasma MDA, ARG, and ADMA concentrations were unaffected following LDL‐C apheresis. A single LDL‐C apheresis session did not alter FMD in patients treated chronically for hypercholesterolemia, a finding potentially attributed to the effect of chronic treatment or the decline in plasma antioxidants induced by cholesterol lowering. Funded by Kaneka Pharma, LLC

Arginine, dimethylated arginine and homoarginine in relation to cardiovascular risk in patients with moderate chronic kidney disease

ObjectivesArginine, asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), arginine/ADMA ratio and homoarginine could potentially affect nitric oxide production and have been studied in relation to cardiovascular risk (CVR) in various clinical populations. Prospective studies on the CVR associated with arginine/ADMA ratio and homoarginine in patients with moderate chronic kidney disease (CKD) are still scarce. We have studied how arginine, homoarginine and dimethylated arginine can predict cardiovascular events in such a population. Design and methodsWe measured plasma concentrations of arginine (P-arginine), ADMA (P-ADMA), SDMA (P-SDMA), homoarginine (P-homoarginine) and other covariates in 160 patients with predialytic CKD (mean age 57years and mean eGFR 43mL/min/1.73m2) and followed them for 58months in median. The risks of fatal and non-fatal cardiovascular events associated with the predictors were evaluated with multivariable Cox proportional hazard analysis. ResultsThere were 31 cardiovascular events during the observation period. In a multivariable model adjusted for age, sex, previous cardiovascular disease, P-cystatin C and P-homoarginine, the hazard ratio (HR) associated with an increase in arginine/ADMA ratio by 10 was 0.83 (P=0.03). The HR of a 1μmol/L increase in P-homoarginine in the same model was 1.78 (P=0.01). A statistically significant interaction between P-homoarginine and P-cystatin C was found in an extended multivariable model. P-SDMA was not associated with increased CVR after adjustment for basic covariates. ConclusionThis study demonstrates a negative association between arginine/ADMA ratio and CVR in CKD patients and a positive association between P-homoarginine and CVR. The latter is in contrast to what has been demonstrated by others.

Arginine metabolic endotypes in pulmonary arterial hypertension.

Decreased synthesis of nitric oxide (NO) by NO synthases (NOS) is believed to play an important role in the pathogenesis of pulmonary arterial hypertension (PAH). Multiple factors may contribute to decreased NO bioavailability, including increased activity of arginase, the enzyme that converts arginine to ornithine and urea, which may compete with NOS for arginine; inadequate de novo arginine production from citrulline; and increased concentration of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NOS. We hypothesized that PAH patients with the lowest arginine availability secondary to increased arginase activity and/or inadequate de novo arginine synthesis might have a slower rate of NO synthesis and greater pulmonary vascular resistance. Nine patients with group 1 PAH and 10 healthy controls were given primed, constant intravenous infusions of (15)N2-arginine, (13)C,(2)H4-citrulline, (15)N2-ornithine, and (13)C-urea in the postabsorptive state. The results showed that, compared with healthy controls, PAH patients had a tendency toward increased arginine clearance and ornithine flux but no difference in arginine and citrulline flux, de novo arginine synthesis, or NO synthesis. Arginine-to-ADMA ratio was increased in PAH patients. Two endotypes of patients with low and high arginase activity were identified; compared with the low-arginase group, the patients with high arginase had increased arginine flux, slower NO synthesis, and lower plasma concentrations of ADMA. These results demonstrate that increased breakdown of arginine by arginase occurs in PAH and affects NO synthesis. Furthermore, there is no compensatory increase in de novo arginine synthesis to overcome this increased utilization of arginine by arginase.

Left ventricular diastolic dysfunction and plasma asymmetric dimethylarginine concentration in persons with essential hypertension.

IntroductionThe study aimed to evaluate the relationship between plasma asymmetric dimethylarginine (ADMA) concentration and development of left ventricular diastolic dysfunction (LVDD) in patients with essential hypertension (EH). Moreover, an attempt was made to define independent risk factors of LVDD in patients with EH.Material and methodsA group of 106 individuals with EH was obtained (mean age: 47.18 ±11.76 years). Two groups of patients were distinguished: group I – individuals with EH with LVDD (n = 57); group II – persons with EH without LVDD (n = 49). Echocardiographic examination was conducted by the transthoracic technique. High-performance liquid chromatography was used to measure dimethylarginine concentrations.ResultsIn the group suffering from EH with LVDD, mean ADMA concentration was significantly higher and the ratio of arginine to ADMA was significantly lower than in patients with EH without LVDD. No significant differences were detected between mean concentrations of plasma symmetric dimethylarginine concentration (SDMA) and arginine or in arginine/SDMA ratios in the studied groups. Independent factors of LVDD risk in the study group included higher plasma ADMA concentration, higher serum low-density lipoprotein (LDL) concentration, higher values of body mass index (BMI), higher values of left ventricular mass index (LVMI) and higher values of mean blood pressure (mBP) (ORADMA = 1.731; ORLDL = 1.188; ORBMI = 1.056; ORLVMI = 1.062; ORmBP = 1.014; p < 0.05).ConclusionsThe results of this study showed that ADMA concentration may be of prognostic value in relation to manifestation of LVDD in patients with EH.

Physical exercise reduces synthesis of ADMA, SDMA, and L-Arg.

Increased levels of asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA) and low plasma level of L-arginine (L-ARG) are all conditions likely to decrease nitric oxide (NO) production. Aim of this study is to evaluate ADMA, SDMA, and L-ARG plasmatic levels before and after physical exercise in patients with coronary artery disease (CAD). We studied 30 patient with mean age 52 + 4.5 years. After inclusion in the study, before the execution of physical exercise, heparinized blood sample was drawn from an indwelling arterial line for determination of ADMA, L-ARG and SDMA (baseline values). Subsequently a blood sample was drawn after the physical exercise. The mean plasma concentrations of ADMA (0.68 + 0.06 vs 0.48 + 0.05 µmol/L) and SDMA (0.45 + 0.03 vs 0.30 + 0.03 µmol/L) were significantly lower after physical exercise in comparison to baseline value, while L-ARG mean levels were increased (44.20 + 10.5 vs 74.13 + 11.2 µmol/L). Physical exercise has a beneficial effect by reducing plasmatic ADMA and SDMA levels, and increasing L-ARG substrate for endothelial NO.

Physical exercise reduces synthesis of ADMA SDMA and L-Arg

Increased levels of asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA) and low plasma level of L-arginine (L-ARG) are all conditions likely to decrease nitric oxide (NO) production. Aim of this study is to evaluate ADMA, SDMA, and L-ARG plasmatic levels before and after physical exercise in patients with coronary artery disease (CAD). We studied 30 patient with mean age 52 ± 4.5 years. After inclusion in the study, before the execution of physical exercise, heparinized blood sample was drawn from an indwelling arterial line for determination of ADMA, L-ARG and SDMA (baseline values). Subsequently a blood sample was drawn after the physical exercise. The mean plasma concentrations of ADMA (0.68 ± 0.06 vs 0.48 ± 0.05 µmol/L) and SDMA (0.45 ± 0.03 vs 0.30 ± 0.03 µmol/L) were significantly lower after physical exercise in comparison to baseline value, while L-ARG mean levels were increased (44.20 ± 10.5 vs 74.13 ± 11.2 µmol/L). Physical exercise has a beneficial effect by reducing plasmatic ADMA and SDMA levels, and increasing L-ARG substrate for endothelial NO.

New Insights into Possible Role of NOS-NO-ADMA Pathway Dysfunction in the Development of Cognitive Decline and Dementia: Exploring the Vascular Features of Alzheimer’s Disease

In recent years significant overlap between cardio-metabolic risk factors and cognitive decline has been reported. Cardio-metabolic and vascular factors shown to be associated with Alzheimer’s disease (AD) and other forms of dementia include midlife diabetes and hypertension, cerebrovascular lesions, diminished vascular function, dyslipidemia, obesity, and cigarette smoking. Accordingly, it has been recently proposed that amyloid is not the cause of AD but merely a marker and a later consequence of upstream changes that lead to neuronal and synaptic losses. However, although the idea that features of vascular dysfunction and injury are present in cognitive decline and AD patients was suggested over 25 years ago, the role of cardio-metabolic and cerebrovascular mechanisms in the pathogenesis of AD is far from being fully elucidated. Based on newly proposed vascular hypothesis, there is an impaired structure and function of cerebral blood vessels and cells in patients with cognitive decline and AD which is mediated by vascular oxidative stress. Consistent with these observations, the importance of endothelial dysfunction in the development of AD has been highlighted. One of the most prominent features of endothelial dysfunction is decreased production and bioavailability of Nitric Oxide (NO). Based on versatile properties in physiological as well as in pathophysiological conditions NO is regarded as a key molecule for longevity and cardiovascular health. NO is produced by three different isoforms of the enzyme NO synthase (NOS), namely: endothelial (eNOS), neuronal (nNOS), and inducible (iNOS). Reduced NO bioavailability and altered vascular expression and activity of NOS enzymes are implicated as major molecular players in the process of vascular aging. In the process of aging, the mechanisms by which NOS enzymes promote vascular dysfunction are specific for each NOS isoform. Normal activity of eNOS is required for the balanced production/bioavailability of NO, which is the main prerequisite for optimal vascular function. Conversely, excessive amount of NO produced by iNOS contributes to vascular dysfunction. Furthermore, although the possible role of nNOS-derived NO in aging-associated vascular dysfunction is far from being fully elucidated, experimental findings indicate that impaired perivascular NO release from nNOS increases vasoconstriction in aged arterioles. Oxidative stress and inhibitors of NO synthase are regarded as most potent initiators of disturbed production and bioavailability of NO. Important endogenous inhibitor of all three isoforms of NOS is asymmetrical dimethylarginine (ADMA). It has been recently proposed that ADMA may be a possible link between vascular disease and dementia. Based on this assumption ADMA might represent a unifying pathophysiological pathway linking the presence of vascular risk factors with the onset and progression of cognitive decline and dementia. These observations were made based on good evidence from literature that higher plasma ADMA concentrations favor atherosclerosis and independently predict adverse cardiovascular and cerebrovascular outcomes in several patient groups. However, possible role of ADMA in pathophysiology of cognitive decline and AD is still not fully understood. Prospective studies are warranted aiming at further clarification of ADMA involvement in development and progression of dementia. Moreover, use of ADMA in CSF and /or plasma as prospective biomarker of AD should be explored. According to newly introduced hypothesis disturbed NOS-NO-ADMA pathway is one of the most important attributes of cerebrovascular dysfunction that plays a pathogenic role in the development of cognitive decline and dementia. Experimental data from cell cultures and animal models have demonstrated that dysfunction of the NO-NOS- ADMA pathway results in cell death, blood-brain barrier (BBB) disruption, and brain edema via different pathological mechanisms. However, exact underlining mechanisms through which disturbed NOS-NO-ADMA pathway contributes to cognitive decline and dementia remain to be elucidated. Clarification of these mechanisms may be helpful in the identification of new therapeutic targets for aging and neurodegenerative diseases. Future research should also explain whether endothelial dysfunction precede or follow neurological changes which characterize cognitive decline and dementia. Moreover, clinical and epidemiological studies have shown that healthy nutrition and physical exercise are important non-pharmacological, lifestyle-related interventions that could help in maintaining appropriate vascular tone, adequate cerebral blood flow and normal cognition during aging. It is reasonable to suggest that prevention of cardio-metabolic diseases via endorsement of healthy aging determinants such as control of blood pressure, lipids and glucose levels as well as maintenance of optimal body weight achieved by regular physical activity and nutrition with high anti-oxidant capacity might be effective strategy in the preservation of cognitive function.

Working Memory and Aphasia

In recent years significant overlap between cardio-metabolic risk factors and cognitive decline has been reported. Cardio-metabolic and vascular factors shown to be associated with Alzheimer’s disease (AD) and other forms of dementia include midlife diabetes and hypertension, cerebrovascular lesions, diminished vascular function, dyslipidemia, obesity, and cigarette smoking. Accordingly, it has been recently proposed that amyloid is not the cause of AD but merely a marker and a later consequence of upstream changes that lead to neuronal and synaptic losses. However, although the idea that features of vascular dysfunction and injury are present in cognitive decline and AD patients was suggested over 25 years ago, the role of cardio-metabolic and cerebrovascular mechanisms in the pathogenesis of AD is far from being fully elucidated. Based on newly proposed vascular hypothesis, there is an impaired structure and function of cerebral blood vessels and cells in patients with cognitive decline and AD which is mediated by vascular oxidative stress. Consistent with these observations, the importance of endothelial dysfunction in the development of AD has been highlighted. One of the most prominent features of endothelial dysfunction is decreased production and bioavailability of Nitric Oxide (NO). Based on versatile properties in physiological as well as in pathophysiological conditions NO is regarded as a key molecule for longevity and cardiovascular health. NO is produced by three different isoforms of the enzyme NO synthase (NOS), namely: endothelial (eNOS), neuronal (nNOS), and inducible (iNOS). Reduced NO bioavailability and altered vascular expression and activity of NOS enzymes are implicated as major molecular players in the process of vascular aging. In the process of aging, the mechanisms by which NOS enzymes promote vascular dysfunction are specific for each NOS isoform. Normal activity of eNOS is required for the balanced production/bioavailability of NO, which is the main prerequisite for optimal vascular function. Conversely, excessive amount of NO produced by iNOS contributes to vascular dysfunction. Furthermore, although the possible role of nNOS-derived NO in aging-associated vascular dysfunction is far from being fully elucidated, experimental findings indicate that impaired perivascular NO release from nNOS increases vasoconstriction in aged arterioles. Oxidative stress and inhibitors of NO synthase are regarded as most potent initiators of disturbed production and bioavailability of NO. Important endogenous inhibitor of all three isoforms of NOS is asymmetrical dimethylarginine (ADMA). It has been recently proposed that ADMA may be a possible link between vascular disease and dementia. Based on this assumption ADMA might represent a unifying pathophysiological pathway linking the presence of vascular risk factors with the onset and progression of cognitive decline and dementia. These observations were made based on good evidence from literature that higher plasma ADMA concentrations favor atherosclerosis and independently predict adverse cardiovascular and cerebrovascular outcomes in several patient groups. However, possible role of ADMA in pathophysiology of cognitive decline and AD is still not fully understood. Prospective studies are warranted aiming at further clarification of ADMA involvement in development and progression of dementia. Moreover, use of ADMA in CSF and /or plasma as prospective biomarker of AD should be explored. According to newly introduced hypothesis disturbed NOS-NO-ADMA pathway is one of the most important attributes of cerebrovascular dysfunction that plays a pathogenic role in the development of cognitive decline and dementia. Experimental data from cell cultures and animal models have demonstrated that dysfunction of the NO-NOS- ADMA pathway results in cell death, blood-brain barrier (BBB) disruption, and brain edema via different pathological mechanisms. However, exact underlining mechanisms through which disturbed NOS-NO-ADMA pathway contributes to cognitive decline and dementia remain to be elucidated. Clarification of these mechanisms may be helpful in the identification of new therapeutic targets for aging and neurodegenerative diseases. Future research should also explain whether endothelial dysfunction precede or follow neurological changes which characterize cognitive decline and dementia. Moreover, clinical and epidemiological studies have shown that healthy nutrition and physical exercise are important non-pharmacological, lifestyle-related interventions that could help in maintaining appropriate vascular tone, adequate cerebral blood flow and normal cognition during aging. It is reasonable to suggest that prevention of cardio-metabolic diseases via endorsement of healthy aging determinants such as control of blood pressure, lipids and glucose levels as well as maintenance of optimal body weight achieved by regular physical activity and nutrition with high anti-oxidant capacity might be effective strategy in the preservation of cognitive function.