Changes In Asymmetric Dimethylarginine Research Articles

Asymmetric Dimethylarginine and NT-proBNP Levels Provide SynergisticInformation in PulmonaryArterial Hypertension.

Plasma asymmetric dimethylarginine (ADMA) is elevated in pulmonary arterial hypertension (PAH) and is associated with unfavorable outcomes. The aim of this study was to assess changes in ADMA plasma levels for monitoring disease progression and outcomes during PAH-specific therapy. ADMA was measured at baseline and after at least 6months of follow-up using enzyme-linked immunosorbent assay and high-performance liquid chromatography. Changes in ADMA were analyzed in relation to changes in established PAH markers, including hemodynamic status, N-terminal pro-brain natriuretic peptide (NT-proBNP) and risk assessment scores. Impact on survival was assessed using Kaplan-Meier curves and Cox proportional hazards models. Between 2008 and 2019, ADMA samples were collected prospectively from 215 patients with PAH. Change in ADMA plasma level was a predictor of disease progression and survival. ΔADMA (median-0.03μmol/L; 95%CI:-0.145 to 0.0135) was correlated with change in mean pulmonary arterial pressure (P< 0.005; rS=0.287) but was not significantly correlated with ΔNT-proBNP (P=0.056; rS=0.135). Patients with decreased ADMA plasma levels at follow-up had better 3-year and 5-year survival rates (88% and 80%, respectively, vs 72% and 53% in those without decreases in ADMA) (P< 0.005; pulmonary hypertension-related mortality or lung transplantation). Patients with decreases in both ADMA and NT-proBNP had better survival rates compared with patients in whom only 1 parameter improved (P< 0.005). ΔADMA was a significant predictor of survival in Cox regression analysis and also when corrected for ΔNT-proBNP (HRs: 1.27 and 1.35, respectively; P< 0.005). ADMA and NT-proBNP provide synergistic prognostic information for patients with PAH. ADMA could be used as an objective and distinct biomarker for monitoring treatment response in PAH.

Characterization of the skeletal muscle arginine methylome in health and disease reveals remodeling in amyotrophic lateral sclerosis.

Arginine methylation is a protein posttranslational modification important for the development of skeletal muscle mass and function. Despite this, our understanding of the regulation of arginine methylation under settings of health and disease remains largely undefined. Here, we investigated the regulation of arginine methylation in skeletal muscles in response to exercise and hypertrophic growth, and in diseases involving metabolic dysfunction and atrophy. We report a limited regulation of arginine methylation under physiological settings that promote muscle health, such as during growth and acute exercise, nor in disease models of insulin resistance. In contrast, we saw a significant remodeling of asymmetric dimethylation in models of atrophy characterized by the loss of innervation, including in muscle biopsies from patients with myotrophic lateral sclerosis (ALS). Mass spectrometry-based quantification of the proteome and asymmetric arginine dimethylome of skeletal muscle from individuals with ALS revealed the largest compendium of protein changes with the identification of 793 regulated proteins, and novel site-specific changes in asymmetric dimethyl arginine (aDMA) of key sarcomeric and cytoskeletal proteins. Finally, we show that invivo overexpression of PRMT1 and aDMA resulted in increased fatigue resistance and functional recovery in mice. Our study provides evidence for asymmetric dimethylation as a regulator of muscle pathophysiology and presents a valuable proteomics resource and rationale for numerous methylated and nonmethylated proteins, including PRMT1, to be pursued for therapeutic development in ALS.

L-arginine and Its Derivatives Correlate with Exercise Capacity in Patients with Advanced Heart Failure

Methylated arginine metabolites interrupt nitric oxide synthesis, which can result in endothelium dysfunction and inadequate vasodilation. Since little is known about the dynamics of arginine derivatives in patients with heart failure (HF) during physical exercise, we aimed to determine this as well as its impact on the patient outcomes. Fifty-one patients with HF (left ventricle ejection fraction-LVEF ≤ 35%, mean 21.7 ± 5.4%) underwent the cardiopulmonary exercise test (CPET). Plasma concentrations of L-arginine, citrulline, ornithine, asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA) were measured before and directly after CPET. All patients were followed for a mean of 23.5 ± 12.6 months. The combined endpoint was: any death, urgent heart transplantation, or urgent LVAD implantation. L-arginine concentrations increased significantly after CPET (p = 0.02), when ADMA (p = 0.01) and SDMA (p = 0.0005) decreased. The parameters of better exercise capacity were positively correlated with post-CPET concentration of L-arginine and inversely with post-CPET changes in ADMA, SDMA, and baseline and post-CPET SDMA concentrations. Baseline and post-CPET SDMA concentrations increased the risk of endpoint occurrence (HR 1.02, 95% CI 1.009-1.03, p = 0.04 and HR 1.02, 95% CI 1.01-1.03, p = 0.02, respectively). In conclusion, in patients with HF, extensive exercise is accompanied by changes in arginine derivatives that can reflect endothelium function. These observations may contribute to the explanation of the pathophysiology of exercise intolerance in HF.

Corticosteroid Withdrawal-Induced Loss of Control in Mild to Moderate Asthma Is Independent of Classic Granulocyte Activation

Loss of asthma control and asthma exacerbations are associated with increased sputum eosinophil counts. However, whether eosinophils, or the also present neutrophils, actively contribute to the accompanying inflammation has not been extensively investigated. Twenty-three patients with mild to moderate asthma were included in a standardized prospective inhaled corticosteroid (ICS) withdrawal study; 22 of the patients experienced loss of asthma control. The study assessed various immune, inflammatory, and oxidative stress parameters, as well as markers of eosinophil and neutrophil activity, in exhaled breath condensate, plasma, and sputum collected at three phases (baseline, during loss of control, and following recovery). Loss of asthma control was characterized by increased sputum eosinophils, whereas no differences were detected between the three phases for most inflammatory and oxidative stress responses. There were also no differences detected for markers of activated eosinophils (eosinophil cationic protein and bromotyrosine) and neutrophils (myeloperoxidase and chlorotyrosine). However, free eosinophilic granules and citrullinated histone H3, suggestive of eosinophil cytolysis and potentially eosinophil extracellular trap formation, were enhanced. Baseline blood eosinophils and changes in asymmetric dimethylarginine (an inhibitor of nitric oxide synthase) in plasma were found to correlate with the decrease in FEV1 percent predicted upon ICS withdrawal (both, rs= 0.46; P= .03). The clinical effect in mild to moderate asthma upon interruption of ICS therapy is not related to the classic inflammatory activation of eosinophils and neutrophils. It may, however, reflect another pathway underlying the onset of loss of disease control and asthma exacerbations. The Netherlands Trial Register; No.: NTR3316; URL: trialregister.nl/trial/3172.

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.

Exhaled nitric oxide dynamics in asthmatic reactions induced by diisocyanates.

Isocyanate-induced asthmatic reactions are associated with delayed increase in fractional exhaled nitric oxide measured at expiratory flow of 50mL/s (FeNO50), a biomarker of airway inflammation. The time course of FeNO increase is compatible with the activation of NO synthase, but the origin of NO production in the lung is undetermined. The aim of this study was to define the dynamics of airway and alveolar NO during specific inhalation challenge (SIC) with isocyanates and the role of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase. Spirometry, exhaled NO parameters (FeNO50, bronchial wall NO concentration, NO airway diffusing capacity, NO flux to luminal space, alveolar NO) and ADMA levels in exhaled breath condensate were measured before and at intervals up to 24h after exposure to isocyanates. The results were compared between 17 SIC-positive and eight SIC-negative subjects. A significant FeNO50 increase in SIC-positive subjects was detected 24h after exposure and was associated with the augmented NO flux from airway wall to the lumen, whereas airway NO diffusion and alveolar NO were not affected. The changes in NO dynamics were specific for the subjects who developed an asthmatic reaction, but were independent from the pattern and magnitude of bronchoconstriction. There was no evidence that exhaled NO is modulated by the changes in ADMA concentration. Because isocyanate-induced increase in FeNO50 was almost exclusively determined by the increase in NO flux, the use of FeNO50 appears adequate to monitor the exhaled NO dynamics during SIC. FeNO50 measurement may provide additional information to spirometry, because bronchoconstriction and airway inflammatory responses are dissociated.

Changes in plasma levels of asymmetric dimethylarginine, symmetric dimethylarginine, and arginine after a single dose of vardenafil in patients with pulmonary hypertension

ObjectiveWe investigated whether vardenafil, a phosphodiesterase-5 inhibitor, alters plasma levels of asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and arginine. Patients and methodsADMA, SDMA, and arginine were measured (0–540min) in 12 patients with pulmonary hypertension after a single oral dose of vardenafil. Invasive hemodynamic data were collected at baseline and after 60min. ResultsA reduction in ADMA was observed at 30 and 45min with a median change of −11.1% (P=0.021) and −12.5% (P=0.002). SDMA decreased with a median −5.3% change (P=0.032) at 45min. An increase in arginine, median 40.3% (P=0.002), 45.0% (P=0.010), and 77.1% (P=0.008) was observed at 120, 300, and 540min respectively. An increase in the arginine/ADMA ratio, median 11.7% (P=0.012), 32.5% (P=0.003), 26.5% (P=0.021), 33% (P=0.007), 48.5% (P=0.007), and 63.1% (P=0.008) was observed at 15, 45, 60, 120, 300, and 540min respectively. There was a positive correlation between vardenafil exposure and the percent change in the arginine/ADMA ratio from baseline to 540min (r=0.80; P=0.01). A correlation between baseline mean right atrial pressure (mRAP) and baseline ADMA (r=0.65; P=0.023), and baseline SDMA (r=0.61; P=0.035) was observed. A correlation between the baseline arginine/ADMA ratio and baseline cardiac output (CO) (r=0.59; P=0.045) and baseline cardiac index (CI) (r=0.61; P=0.036) was observed. Baseline arginine/ADMA ratio correlated with baseline mRAP (r=−0.79; P=0.002). A correlation between change (0–60min) in CI and change in arginine (r=0.77; P=0.003) as well as change in the arginine/ADMA ratio (r=0.61; P=0.037) was observed. ConclusionsVardenafil induced changes in ADMA, SDMA, arginine, and the arginine/ADMA ratio in patients with PH. An increase in arginine and the arginine/ADMA ratio was associated with improvement in CI.

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...

Improved blood pressure, nitric oxide and asymmetric dimethylarginine are independent after bariatric surgery

Obesity is associated with hypertension, but the exact mechanism is not fully understood. Bariatric surgery significantly decreases weight and blood pressure (BP). Low plasma nitric oxide (NO) and raised asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO, concentrations are associated with both obesity and hypertension. Correlations between the changes in these parameters were studied after bariatric surgery. Weight, BP, plasma ADMA and NO were measured in 29 obese patients (24 female, 5 male) before and six weeks after bariatric surgery. Patients were 39.2 ± 1.2 (mean ± SEM) years old and weighed 126 ± 3 kg. Six weeks after the surgery, patients had lost 10 ± 0.7 kg (P < 0.0001) and mean arterial pressure (MAP) decreased by 11 ± 1.0 mmHg (P < 0.0001). The plasma ADMA concentration decreased by 24 ± 2% from 5 ± 0.4 to 4.0 ± 0.3 μmol/L (P < 0.0001). The plasma total nitrite concentration increased by 15 ± 1% from 51.4 ± 2.6 to 60 ± 3 μmol/L (P < 0.0001). The correlation between the decrease of ADMA and increase of NO subsequent to weight loss was significant (P < 0.0001). However, MAP was not correlated to the changes in ADMA or NO. After bariatric surgery, beneficial changes in BP, NO and ADMA occur, but our findings suggest that these BP changes are independent of changes in the NO-ADMA axis. Other causes for the changes in BP should therefore be considered.

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

ObjectivesRheumatoid arthritis (RA) is characterised by impaired endothelial function which contributes to increased cardiovascular morbidity and mortality. Asymmetric dimethylarginine (ADMA) is an endogenous competitive inhibitor of nitric oxide synthase and contributes to endothelial dysfunction. The aim of the present longitudinal study was to investigate the effects of tumour necrosis factor alpha (TNFα) antagonists on serum concentrations of ADMA in RA patients. Design and methodsThirty-five patients (age (mean±SD) 55±15years, 21 women) who qualified for anti-TNFα therapy were included in the study. ADMA was measured by ELISA in all patients prior to starting anti-tumour necrosis factor alpha treatment, and 2weeks and 3months after initiation of treatment. Generalised estimating equations were used to analyse the change in a range of factors after the treatment commenced, and to test the relationship between ADMA and various inflammatory parameters. ResultsAnti-tumour necrosis factor alpha therapy significantly reduced ESR, CRP, fibrinogen and disease activity score 28 (all p<0.001). ADMA levels did not change significantly following 2weeks or 3months treatment using three different tumour necrosis factor alpha inhibitors, despite the fact that CRP (p=0.016), and DAS28 (p=0.025) were found to be significantly associated with ADMA levels after treatment with TNFα antagonists. ConclusionADMA levels do not change significantly during anti-TNF therapy, despite the fact that they associate with CRP and DAS28, which are significantly reduced during such treatment in patients with rheumatoid arthritis. Levels of inflammation after treatment with TNFα antagonists are significantly associated with ADMA levels in patients with rheumatoid arthritis.

Changes in ADMA and TAFI levels after stenting in coronary artery disease patients

The aim of this study was to examine the contribution of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS) and a novel marker of vascular endothelial dysfunction, and thrombin-activatable fibrinolysis inhibitor (TAFI), a risk factor for venous thrombosis, to the predisposition of coronary restenosis following stent implantation in coronary artery disease (CAD) patients. Thirty-seven patients with CAD were recruited from the Kobry El Obba Military Hospital, Cairo, Egypt. The patients were hospitalized for coronary angiography and coronary stenting (CS). Overnight fasting blood samples were collected from patients prior to CS and four months later for the determination of plasma ADMA and TAFI levels. The patients underwent follow-up coronary angiography to reveal in-stent restenosis. The results showed that plasma ADMA levels in CAD patients were significantly higher than those reported for healthy subjects. ADMA levels were significantly increased by 30% in CAD patients four months following CS. CAD patients who developed in-stent restenosis had a 35% increase in ADMA levels following CS. TAFI levels were not significantly changed after CS in CAD patients or in any of the subgroups. In conclusion, ADMA, but not TAFI, is linked to the predisposition of in-stent restenosis following CS.

HIV Replication, Inflammation, and the Effect of Starting Antiretroviral Therapy on Plasma Asymmetric Dimethylarginine, a Novel Marker of Endothelial Dysfunction

HIV infection is associated with premature development of cardiovascular disease. Understanding the effects of HIV replication on endothelial dysfunction and platelet activation may identify treatment targets to reduce cardiovascular disease risk. A subgroup of HIV-infected participants in the Strategies for Management of Antiretroviral Therapy study off antiretroviral therapy (ART) at entry enabled a randomized comparison of immediate versus deferred ART initiation of changes in asymmetric dimethylarginine (ADMA), soluble CD40 ligand (sCD40L), and P-selectin levels. At study entry, median (interquartile range) levels of ADMA, sCD40L, and P-selectin were 0.57 (0.49-0.66) μg/mL, 251 (135-696) μmol/L, and 34 (28-44) pg/mL. Compared to those randomized to deferral of ART (n = 114), participants randomized to immediate ART (n = 134) had 10.3% lower ADMA levels (P = 0.003) at 12 months; treatment differences in sCD40L (95% confidence interval: -17% to 44%; P = 0.53) and P-selectin (95% confidence interval: -10% to 10%; P = 0.95) were not significant. The difference in ADMA for those assigned immediate ART compared with those assigned ART deferral was greater among younger patients and those with higher levels of high-sensitivity C-reactive protein and D-dimer (P ≤ 0.05 for interaction for both) but not HIV RNA level at baseline (P = 0.51). ART initiation leads to declines in ADMA levels, a marker of nitric oxide-mediated endothelial dysfunction. Improvement in ADMA levels was related to the degree of inflammation and coagulation, suggesting that upregulation of these pathways contributes to premature vascular disease among individuals with HIV infection. Whether declines in ADMA levels impact risk of disease requires further research.

Changes in the arginine methylation of organ proteins during the development of diabetes mellitus

Aim In this study, we examined changes in asymmetric dimethylarginine (ADMA), dimethylarginine dimethylaminohydrolase (DDAH), nitric oxide synthesis (NOS), and the arginine methylation of organ proteins during the development of diabetes in mice. Methods Db/db mice developed significant obesity and fasting hyperglycemia during diabetogenesis. During diabetogenesis, the expression of ADMA and nNOS was increased, while that of DDAH1 and protein-arginine methyltransferase 1 (PRMT1) was decreased. Additionally, arginine methylation in the liver and adipose tissue was altered during diabetogenesis. Results Changes were evident at 75, 60, and 52 kDa in liver tissue and at 38 and 25 kDa in adipose tissue. Collectively, DDAH and ADMA are closely associated with the development of obesity and diabetes, and the arginine methylation levels of certain proteins were changed during diabetes development. Conclusion Protein arginine methylation plays a role in the pathogenesis of diabetes.

Contribution of Endogenous Inhibitor of Nitric Oxide Synthase to Hepatic Mitochondrial Dysfunction in Streptozotocin-induced Diabetic Rats

Aims: Mitochondrial dysfunction plays important roles in the development of diabetes. Elevated nitric oxide (NO) synthase inhibitor asymmetric dimethylarginine (ADMA) has been shown to be closely related to diabetes. But the relationship between them in diabetes has not been determined. This study was to explore the role of ADMA in hepatic mitochondrial dysfunction and its potential mechanisms in diabetic rats and hepatocytes. Methods: Respiratory enzymes activities, mitochondrial transmembrane potential and ATP content were measured to evaluate mitochondrial function. The copy number ratio of mitochondrial gene to nuclear gene was used to represent mitochondrial biogenesis. The activity of superoxide dismutase and malondialdehyde content were detected to reflect oxidative stress. Furthermore, changes in ADMA and NO contents, uncoupling protein 2 (UCP2) and peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) transcriptions were determined. Results: Elevated ADMA levels in serum of diabetic rats were found to be associated with hepatic mitochondrial dysfunction reflected by reductions of respiratory enzyme activities, mitochondrial membrane potential and ATP contents. Similar mitochondrial dysfunction also occurred in ADMA-treated hepatocytes. The mitochondrial dysfunction observed in diabetic rats or hepatocytes was accompanied with suppressions of mitochondrial biogenesis, PGC-1α transcription and NO synthesis as well as enhances of UCP 2 transcription and oxidative stress. These effects of ADMA could be attenuated by treatments with antioxidant or NO donor. Conclusions: These results indicate that elevated endogenous ADMA contributes to hepatic mitochondrial dysfunction in diabetic rats, and underlying mechanisms may be related to the suppression of mitochondrial biogenesis and mitochondrial uncoupling via inhibiting NO synthesis and enhancing oxidative stress.

Subtle changes in ADMA andl‐arginine concentrations in normal pregnancies are unlikely to account for pregnancy‐related increased flow‐mediated dilatation

Our objective was to investigate whether serum concentrations of asymmetric dimethylarginine (ADMA) or l-arginine correlate to hyperlipidemia or endothelial function in normal pregnancy compared with the non-pregnant subjects. As a part of population-based, prospective cohort Cardiovascular Risk in Young Finns study conducted in Finland we examined 57 pregnant Finnish women throughout gestation and 62 control women matched for age and smoking. Serum glucose, triglycerides (TG), total cholesterol (TC), low-density cholesterol (LDL-C), high-density cholesterol (HDL-C) and ADMA, symmetric dimethylarginine (SDMA) and l-arginine were determined concomitantly with endothelium-dependent brachial artery flow-mediated dilation (FMD), measured by ultrasound. All serum lipid concentrations were significantly higher in pregnant women than in non-pregnant women (P < 0.001 for each). The mean serum ADMA concentration in pregnant women was significantly lower compared with the non-pregnant controls (0.513 micromol l(-1) +/- 0.0593 versus 0.577 micromol l(-1) +/- 0.0710, P < 0.001). Lowered ADMA concentrations did not correlate statistically to FMD in these healthy pregnant women but FMD was enhanced towards the end of pregnancy. ADMA and l-arginine concentrations fall in normal pregnancy despite marked hypercholesterolemia. Endothelium-dependent vasodilation is enhanced in normal pregnancy but is not statistically correlated to maternal serum ADMA or l-arginine concentrations.

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.

Relation of Improvement in Endothelium-Dependent Flow-Mediated Vasodilation After Rosiglitazone to Changes in Asymmetric Dimethylarginine, Endothelin-1, and C-Reactive Protein in Nondiabetic Patients With the Metabolic Syndrome

The mechanisms by which thiazolidinediones exert beneficial effects on the endothelium are still not clear. We examined the effects of rosiglitazone on the plasma markers of metabolic control (glucose, insulin, adiponectin, resistin, and lipid profiles), markers of inflammation (high-sensitivity C-reactive protein [CRP], interleukin-6, soluble CD40 ligand, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1), and markers of vasoreactivity (asymmetric dimethylarginine [ADMA] and endothelin-1) and analyzed the relations between changes in endothelium-dependent flow-mediated dilation of the brachial artery and changes in these markers to elucidate their roles in mediating the vascular protective effects of rosiglitazone. Of 70 nondiabetic patients who met a modified National Cholesterol Education Program definition of the metabolic syndrome, 35 were randomized to receive rosiglitazone (4 mg/day) and 35 to receive placebo for 8 weeks. At study end, treatment with rosiglitazone had significantly reduced plasma insulin (-25%, p = 0.004) and resistin (-16%, p <0.001), increased adiponectin (164%, p <0.001), low-density lipoprotein cholesterol (16%, p = 0.005), and apolipoprotein-B (14%, p = 0.003), and decreased CRP (-30%, p = 0.005), soluble CD40 ligand (-20%, p = 0.014), ADMA (-16%, p <0.001), and endothelin-1 (-11%, p <0.001) concentrations and systolic and diastolic blood pressures. Rosiglitazone treatment significantly improved flow-mediated dilation (p <0.001) and nitroglycerin-induced vasodilation (p = 0.001) of the right brachial artery. On multivariate analysis, changes in ADMA, endothelin-1, and CRP were independent predictors of improved endothelial reactivity with rosiglitazone. In conclusion, we have, for the first time, demonstrated the independent associations between the improvement in flow-mediated dilation and reductions in ADMA, endothelin-1, and CRP after 8 weeks of treatment with rosiglitazone in nondiabetic patients with the metabolic syndrome. These findings suggest that decreases in ADMA, endothelin-1, and CRP may serve as possible mechanisms for the improvement in endothelial function conferred by rosiglitazone treatment.

Nitric oxide inhibition as a mechanism for blood pressure increase during salt loading in normotensive postmenopausal women.

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide (NO), which plays an important role in natriuresis. We determined whether changes in endothelium-dependent vasodilation (EDD) and plasma ADMA predict changes in blood pressure (BP) after salt loading in normotensive postmenopausal women (PMW). In 15 normotensive PMW (age 50-60 years), not receiving estrogen, ambulatory 24-h BP, plasma lipids, and ADMA were measured after 4 days of a low-salt diet (70 mEq/day) and following 7 days of high-salt intake (260 mEq/day). Brachial artery diameter at rest, during reactive hyperemia, i.e. EDD, and after sublingual nitroglycerin, i.e. non-EDD, were measured by ultrasound. The 24-h urinary NO metabolite (NOx) was measured by Griess reaction. Plasma ADMA was measured by high-pressure liquid chromatography. During low-salt, 24-h BP levels averaged 121 +/- 11 and 69 +/- 7 mmHg for systolic BP (SBP) and diastolic BP (DBP), respectively. After salt loading, average 24-h BP increases were: 7.6 mmHg for SBP, 2.2 mmHg for DBP, and 5.5 mmHg for pulse pressure (PP). Increases of 24-h SBP and 24-h PP after salt loading correlated directly with changes in ADMA (partial R2 = 0.16 for 24-h SBP and 0.17 for 24-h PP, P < 0.05 for both) and inversely with changes in EDD (partial R2 = 0.13, P = 0.09 for 24 h SBP and partial R2 = 0.15, P = 0.07 for 24-h PP), after adjustment for age and cholesterol. Inhibition of NO bioavailability by ADMA and a subsequent reduction in EDD contribute to the increase in BP during high-salt intake in normotensive PMW not receiving estrogen.

1410 高血圧肥大心と Vascular Remodeling

Time sequential impairement in endothelium-dependent and-independent vasodilation of subendocardial arterioles (Endo-A) were evaluated in hypertensive (HT) canine hearts (2-clip and 2-kidney model). Then, changes in asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide (NO) and dimethylarginine dimethylaminohydrolase (DDAH), which degrades ADMA were studied in spontaneously hypertensive rats (SHR) and diabetes mellitus rats (DM) in early stage. In an early stage of HT (4week), the endothelium-dependent response of Endo-A was impaired, and in the later stage (12week), both the endothelium-dependent and independent responses of Endo-A were impaired. These sequential changes may be related with the degree of decreased coronary flow reserve in progression of LVH. ADMA was elevated and DDAH activity was decreased significantly in SHR, but not DM. This may indicate that hypertension increased ADMA by reducing DDAH activity, whereas increased DDAH in early stage of DM may compensate for endothelial dysfunction with increased ADMA.