Lower Asymmetric Dimethylarginine Levels Research Articles

Jia-Wei-Si-Miao-Yong-An decoction modulates intestinal flora and metabolites in acute coronary syndrome model.

We assessed the efficacy of the traditional Chinese medicine formulation Jia-Wei-Si-Miao-Yong-An decoction (HJ11) in the treatment of acute coronary syndrome and evaluated its impact on the intestinal microbiota and their metabolites. An acute coronary syndrome model was established in rats, which were randomly assigned to the model, HJ11 treatment, and atorvastatin treatment groups. Rats were then administered saline solution (model and sham operation control groups) or drugs by oral gavage for 28 d. Echocardiography was performed and serum creatine kinase-MB and cardiac troponin I levels were monitored to examine the cardiac function. Inflammation was evaluated using hematoxylin and eosin staining of heart tissue, and serum interleukin-2, interleukin-6, tumor necrosis factor alpha, and high-sensitivity C-reactive protein measurements. Gut microbiota composition was analyzed via 16S rRNA gene sequencing. Metabolomics was used to determine fecal metabolites and elucidate the modes of action of HJ11 in acute coronary syndrome treatment. HJ11 improved cardiac function and attenuated inflammation in rats with acute coronary syndrome. Relative to the untreated model group, the HJ11-treated group presented normalized Firmicutes/Bacteroidetes ratio and reduced abundances of the bacterial genera norank_f__Ruminococcaceae, Desulfovibrio, Clostridium_sensu_stricto_1, Adlercreutzia, Staphylococcus, Bacteroides, Prevotella, Rikenellaceae_RC9_gut_group, unclassified_o__Bacteroidales, and Ruminococcus_gauvreauii_group. We found 23 differentially expressed intestinal metabolites, and the enriched metabolic pathways were mainly related to amino acid metabolism. We also discovered that asymmetric dimethylarginine levels were strongly associated with cardiovascular disease. Correlation analyses revealed strong associations among intestinal microflora, their metabolites, proinflammatory factors, and cardiac function. Hence, the therapeutic effects of HJ11 on acute coronary syndrome are related to specific alterations in gut microbiota and their metabolites. This work demonstrated that HJ11 effectively treats acute coronary syndrome. HJ11 seems to increase the abundance of beneficial bacterial taxa (Bacteroides and Rikenellaceae_RC9_gut_group), mitigate the risk factors associated with cardiovascular disease, alter bacterial metabolites, lower asymmetric dimethylarginine levels, and effectively treat acute coronary syndrome.

The effect of nitric oxide, endothelial nitric oxide synthetase, and asymmetric dimethylarginine in hemorrhoidal disease.

The aim of this study was to examine the roles of nitric oxide (NOx), endothelial nitric oxide synthetase (eNOS), and asymmetric dimethylarginine (ADMA), which is the major endogenous inhibitor of nitric oxide synthases (NOS), in the pathophysiology of hemorrhoidal disease. This study included 54 patients with grades 3 and 4 internal hemorrhoidal disease and 54 patients without the disease who attended the General Surgery Clinic. NOx, eNOS, and ADMA levels were measured with the Enzyme-Linked ImmunoSorbent Assay (ELISA) method. The patients had higher NO and eNOS levels and lower ADMA levels than the control subjects (p<0.001). A significant highly positive correlation was found between NO and eNOS (p<0.001). Nevertheless, there was a highly negative correlation between ADMA and NO-eNOS(p<0.001, p<0.001). This preliminary study reveals that higher NOx and eNOS activities and lower ADMA levels in the rectal mucosa are observed in patients with hemorrhoidal disease than in those with normal rectal tissue. The imbalance between endothelium-derived relaxing factors, such as NO and endogenous competitive inhibitor of NOS, ADMA, may cause hemorrhoidal disease. Our study proposes that hemorrhoids display apparent vascular dilatation and present with bleeding or swelling. ADMA is an effective NOS inhibitor and may be a promising therapeutic option for hemorrhoidal disease.

Influence of phenylketonuria's diet on dimethylated arginines and methylation cycle.

Phenylketonuria's (PKU) treatment based on low natural protein diet may affect homocysteine (Hcys) metabolic pathway. Hcys alteration may be related to the methylation of arginine to asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA), which both modify nitric oxide production. The aim of this work is to evaluate the status of Hcys formation methylation cycle and ADMA and SDMA levels in patients with PKU in order to establish a potential relationship.Forty-two early diagnosed PKU patients under dietary treatment and good adherence to their diets were enrolled in this cross-sectional study. Their nutritional and biochemical profile, as well as Hcys synthesis status, ADMA and SDMA levels were analyzed and compared with a control group of 40 healthy volunteers. ADMA and SDMA were determined by high-performance liquid chromatography system coupled to triple quadrupole mass spectrometer.In this study, 23 classic PKU, 16 moderate PKU, and 3 mild HPA were enrolled. The median age was 10 years old. Median ADMA, SDMA, and Hcys concentration levels (5.1 μM [2.3–25.7], 0.35 μM [0.18–0.57], 0.43 μM [0.26–0.61], respectively) were lower in patients with PKU (P < .001 for ADMA and SDMA) whereas vitamin B12 and folate levels (616 pg/mL [218–1943] and 21 ng/mL [5–51], respectively) were higher comparing with controls. Statistically significant correlations were found between ADMA, and Phe (r = −0.504, P = .001) and Hcys (r = −0.458, P = .037) levels. Several nutrition biomarkers, such as prealbumin, 25-hydroxy vitamin D, selenium, and zinc, were below the normal range.Our study suggests that patients with PKU suffer from poor methylation capacity. Restriction of natural proteins in addition to high intake of vitamin B12 and folic acid supplementation in the dietary products, produce an impairment of methylation cycle that leads to low Hcys and ADMA levels. As a result, methylated compounds compete for methyl groups, and there is an impairment of methylation cycle due to low Hcys levels, which is related to the lack of protein quality, despite of elevated concentrations of cofactors.

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.

Are increased oxidative stress and asymmetric dimethylarginine levels associated with masked hypertension?

ABSTRACTObjective: In this study, our aim was to determine total oxidative stress and asymmetric dimethylarginine (ADMA) levels in patients with masked hypertension (MHT) and to examine their association with blood pressure. Methods: Fifty patients diagnosed with MHT and 48 healthy volunteers without any known chronic diseases have been included in this study. Results: When compared to the control group, patients with MHT had higher levels of mean ADMA (p < 0.001), total oxidant status (TOS) (p < 0.001), and oxidative stress index (OSI) (p < 0.001), and a lower mean total antioxidant status (TAS) (p < 0.001) level. While a positive correlation was determined between the systolic blood pressure (SBP) and diastolic blood pressure (DBP) levels with ADMA, TOS, and OSI levels, a negative correlation was determined with the TAS level. During the stepwise multivariable logistic regression analysis, age (OR = 1.221; p = 0.003), body mass index (OR = 1.512; p = 0.005), low density lipoprotein (OR = 0.925; p = 0.016), ADMA (OR = 1.200; p = 0.002), and OSI (OR = 3.750; p = 0.002) levels were determined to be the predictors of MHT. During the linear regression analysis, it was determined that the independent risk factors of SBP and DBP are ADMA and OSI, and the independent risk factor of TOS, OSI, and ADMA is SBP. Our study found out that oxidative stress and ADMA levels of patients with MHT are higher than those of the control group. ADMA and OSI were determined to be predictors of MHT. Conclusion: Based on these results, it could be said that oxidative stress, and therefore the ADMA level, could have an effect on the etiopathogenesis of MHT.

Abstract 373: Transgenic Overexpression of Alanine-glyoxylate Aminotransferase 2 Lowers Tissue Levels of Asymmetric Dimethylarginine and Improves Endothelial Function in Mouse Aortas

Introduction: Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase, which has been proposed to play a direct role in the pathogenesis of cardiovascular disease. There are two enzymatic pathways for degradation of ADMA: hydrolysis to citrulline by dimethylarginine dimethylaminohydrolase (DDAH) and transamination by alanine-glyoxylate aminotransferase 2 (AGXT2) with formation of asymmetric dimethylguanidino valeric acid (ADGV). The first pathway is well characterized, whereas the physiological role of AGXT2 is still poorly understood. The goal of our study was to test the hypothesis that transgenic overexpression of AGXT2 would lead to lowering of systemic levels of ADMA and improved vasomotor function. Methods and results: We generated transgenic mice (TG) with ubiquitous overexpression of AGXT2 under control of the chicken beta actin (CAG) promoter. Ubiquitous overexpression of the transgene was confirmed by qPCR and Western Blot. TG animals had normal weight and no observed developmental abnormalities. Biochemical data were generated using HPLC-MS/MS. ADMA plasma levels in AGXT2 TG animals were decreased by 15% (p&lt;0.05), whereas ADGV levels were 6 times higher in TG animals in comparison with wild-types (p&lt;0.001). Lung and heart of TG animals exhibited 2 times lower tissue ADMA content in comparison with controls (p&lt;0.05). Isolated aortic rings were used to estimate endothelium-dependent and -independent relaxation in response to acetylcholine (Ach) and sodium nitroprusside (SNP), respectively. Aortas from AGXT2 TG mice demonstrated an increase in maximal response to ACh (p&lt;0.05). There was a similar relaxation in response to SNP in both groups. Conclusions: Our findings show that upregulation of AGXT2 results in lower ADMA levels and improved endothelial-dependent relaxation in vivo. AGXT2 thereby may be a therapeutic target for long-term reduction of systemic ADMA levels and improvement of vascular function in vivo. This is especially important, because all the efforts to develop ADMA-lowering interventions by means of upregulation of DDAH have not been successful so far. Our data suggest that AGXT2 might be a promising drug target for cardiovascular pathologies associated with elevated ADMA levels.

Abstract T P161: Asymmetric Dimethylarginine, C-reactive Protein, and the Risk of Developing Metabolic Syndrome in Middle-Aged Men

BACKGROUND: The metabolic syndrome has known as an independent risk factor of stroke. We have recently shown that the measurement of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, may be useful for identifying individuals with a high risk of stroke among Japanese population. We aimed to examine whether serum levels of ADMA and a high-sensitivity C-reactive protein (hs-CRP) are associated with the risk of developing metabolic syndrome in middle-aged men. METHODS: In this longitudinal study, serum ADMA and hs-CRP levels were measured in Japanese men without metabolic syndrome, which was diagnosed according to the currently accepted unified criteria. The subjects were followed-up for a maximum of four years to determine new-onset metabolic syndrome. A Cox proportional hazards model with adjusting for potential confounders was applied to determine the hazard ratio (HR) for developing metabolic syndrome according to serum levels of ADMA and hs-CRP, considered either alone or in combination. RESULTS: Of the 848 subjects (mean age, 43 ± 6 years), 100 subjects developed metabolic syndrome. High ADMA levels (≥ 0.45μmol/L) alone did not show a significant HR for developing metabolic syndrome, while high hs-CRP levels (≥ 0.3 mg/L) did (HR 1.82, 95% CI 1.17-2.83). The combination of high levels of both hs-CRP and ADMA had a high HR (2.32, 95% CI 1.30-4.14) as compared to low levels of both markers. In contrast, the HR was not significant in the combination of high hs-CRP and low ADMA levels, as well as low hs-CRP and high ADMA levels. CONCLUSIONS: Serum hs-CRP, but not ADMA, levels were associated with the risk of metabolic syndrome. Furthermore, the combination of high ADMA and high CRP levels increased the risk of metabolic syndrome. Hence, further studies are needed, but measuring the new combination of two markers may potentiate the predictive value for developing cardiovascular diseases including stroke.

Predictive value of asymmetric dimethylarginine and C-reactive protein for the risk of developing metabolic syndrome in middle-aged men

BackgroundWe aimed to examine whether serum levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, and C-reactive protein (CRP) are associated with the risk of developing metabolic syndrome in middle-aged men. MethodsIn this longitudinal study, serum ADMA and CRP levels were measured in Japanese men without metabolic syndrome, which was diagnosed according to the currently accepted unified criteria. The subjects were followed-up for a maximum of four years to determine new-onset metabolic syndrome. A Cox proportional hazards model with adjusting for potential confounders was applied to determine the hazard ratio (HR) for developing metabolic syndrome according to serum levels of ADMA and CRP, considered either alone or in combination. ResultsOf the 848 subjects (mean age, 43 ± 6 years), 100 subjects developed metabolic syndrome. High ADMA levels (≥ 0.45 μmol/L) alone did not show a significant HR for developing metabolic syndrome, while high CRP levels (≥ 0.3 mg/L) did (HR 1.75, 95% CI 1.12–2.74). The combination of high levels of both CRP and ADMA had a high HR (2.09, 95% CI 1.12–3.76) as compared to low levels of both markers. In contrast, the HR was not significant in the combination of high CRP and low ADMA levels, as well as low CRP and high ADMA levels. ConclusionsSerum CRP, but not ADMA, levels were associated with the risk of metabolic syndrome. Nevertheless, the risk of metabolic syndrome could be predicted more reliably by considering these two markers together rather than CRP alone.

Asymmetric dimethylarginine, race, and mortality in hemodialysis patients.

Levels of asymmetric dimethylarginine, an inhibitor of nitric oxide synthase, are elevated in kidney disease and associated with mortality in white European hemodialysis populations. Nitric oxide production and degradation are partially genetically determined and differ by racial background. No studies have measured asymmetric dimethylarginine in African Americans on dialysis and assessed whether differences exist in its association with mortality by race. Asymmetric dimethylarginine was measured in 259 patients on maintenance hemodialysis assembled from 2004 to 2012 in Boston area outpatient centers. Cox proportional hazards models were used to determine the association between asymmetric dimethylarginine and all-cause mortality, and an interaction with race was tested. Mean (SD) age was 63 (17) years, 46% were women, and 22% were African American. Mean asymmetric dimethylarginine in non-African Americans was 0.79 µmol/L (0.16) versus 0.70 µmol/L (0.11) in African Americans (P<0.001); 130 patients died over a median follow-up of 2.3 years. African Americans had lower mortality risk than non-African Americans (hazard ratio, 0.27; 95% confidence interval, 0.15 to 0.50) that was robust to adjustment for age, comorbidity, and asymmetric dimethylarginine (hazard ratio, 0.35; 95% confidence interval, 0.17 to 0.69). An interaction was noted between race and asymmetric dimethylarginine (P=0.03), such that asymmetric dimethylarginine was associated with higher mortality in non-African Americans (adjusted hazard ratio, 1.29; 95% confidence interval, 1.06 to 1.57 per 1 SD higher asymmetric dimethylarginine) but not in African Americans (adjusted hazard ratio, 0.57; 95% confidence interval, 0.28 to 1.18). Additional adjustment for fibroblast growth factor 23 partially attenuated the association for non-African Americans (adjusted hazard ratio, 1.22; 95% confidence interval, 0.98 to 1.50). African Americans have lower asymmetric dimethylarginine levels and lower hazard for mortality compared with non-African Americans. Levels of asymmetric dimethylarginine did not explain lower hazard for mortality in non-African American patients. High asymmetric dimethylarginine was a risk factor for mortality exclusively in non-African Americans. Mechanisms explaining these relationships need to be evaluated.

Effect of Lowering Asymmetric Dimethylarginine (ADMA) on Vascular Pathology in Atherosclerotic ApoE-Deficient Mice with Reduced Renal Mass

The purpose of the work was to study the impact of the endogenous nitric oxide synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA) and its degrading enzyme, dimethylarginine dimethylaminohydrolase (DDAH1), on atherosclerosis in subtotally nephrectomized (SNX) ApoE-deficient mice. Male DDAH1 transgenic mice (TG, n = 39) and C57Bl/6J wild-type littermates (WT, n = 27) with or without the deletion of the ApoE gene underwent SNX at the age of eight weeks. Animals were sacrificed at 12 months of age, and blood chemistry, as well as the extent of atherosclerosis within the entire aorta were analyzed. Sham treated (no renal mass reduction) ApoE-competent DDAH1 transgenic and wild-type littermates (n = 11) served as a control group. Overexpression of DDAH1 was associated with significantly lower ADMA levels in all treatment groups. Surprisingly, SNX mice did not exhibit higher ADMA levels compared to sham treated control mice. Furthermore, the degree of atherosclerosis in ApoE-deficient mice with SNX was similar in mice with or without overexpression of DDAH1. Overexpression of the ADMA degrading enzyme, DDAH1, did not ameliorate atherosclerosis in ApoE-deficient SNX mice. Furthermore, SNX in mice had no impact on ADMA levels, suggesting a minor role of this molecule in chronic kidney disease (CKD) in this mouse model.

Predictors of asymmetric dimethylarginine levels in patients with rheumatoid arthritis: the role of insulin resistance

Objective: To determine whether demographic, inflammatory, and metabolic factors predict elevated asymmetric dimethylarginine (ADMA) levels in rheumatoid arthritis (RA).Method: A total of 67 RA patients [mean age 56 ± 12 years, median disease duration 8 (3–15) years] were assessed. Routine biochemistry tests, lipid profile, glycaemic profile [glucose, insulin, homeostasis model assessment (HOMA), quantitative insulin sensitivity check index (QUICKI)], and inflammatory markers were measured in all patients. ADMA levels were measured by enzyme-linked immunosorbent assay (ELISA). Regression analyses were performed to identify predictors of ADMA in RA.Results: Regression analysis revealed that HOMA (β = 0.149, p = 0.003) was an independent predictor of ADMA in RA. From the drug factors, anti-hypertensive medication use was associated with lower ADMA levels (β = −0.081, p = 0.004). ADMA was not associated with RA disease-related parameters or any of the other cardiovascular risk factors that were assessed.Conclusions: HOMA, a strong indicator of insulin resistance, seems to be the main predictor of elevated ADMA levels in RA patients; ADMA may reflect an important pathway linking abnormal insulin metabolism with endothelial dysfunction in RA.

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.

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

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

In patients with aortic stenosis increased flow-mediated dilation is independently associated with higher peak jet velocity and lower asymmetric dimethylarginine levels

Recently, it has been shown that endothelial dysfunction and aortic stenosis (AS) share several risk factors. Endothelial function represents a crucial factor for the regulation of vascular tonus and its malfunction influences the formation of thrombosis and inflammation. However, the role of endothelial dysfunction in AS remains unclear. Echocardiographic, clinical, and laboratory data of 34 patients (age 74.5 ± 7.9 years, 20 men) with at least moderate AS (peak jet velocity 3.8 ± 0.8 m/s) were collected. In all patients, endothelial function was determined by brachial artery flow-mediated dilation (FMD). Patients with rheumatic or endocarditic valve disease, bicuspid valves, a left ventricular ejection fraction of ≤40%, and coronary artery disease were excluded. Sixteen volunteers (age 69.3 ± 9.4 years, 10 men) without valve disease served as controls. Patients with AS had a trend toward a lower FMD than controls with a comparable risk profile (5.4% ± 3.6% vs 7.4% ± 4.1%, P = .1). Univariate correlates of FMD in patients with AS were peak jet velocity, medication with angiotensin-converting enzyme inhibitor, diabetes, diastolic blood pressure, and asymmetric dimethylarginine. Backward elimination identified peak jet velocity (β = 0.51, P = .001), and asymmetric dimethylarginine (β = -0.45, P = .003) as independent predictors of FMD in multivariate analysis. In patients with AS, we found a strong positive relation between the peak jet velocity and a higher FMD. This effect might be mediated by nitric oxide release due to turbulent poststenotic blood flow or the rising transvalvular gradient, and the increasing pulse pressure may be counteracted by a parallel increase in FMD.

Asymmetric Dimethylarginine Levels in Buerger’s Disease

Endothelial dysfunction may play a major role in both peripheral arterial disease (PAD) and Buerger's disease (BD). Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of endothelial nitric oxide synthase and increased ADMA levels impairvascular homeostasis. We aimed to determine the plasma levels of ADMA and evaluate the relationship of ADMA levels with smoking and clinical severity of the disease in patients with BD and to compare these results with those of patients with PAD and healthy individuals. In our center, 45 patients undergoing peripheral arterial surgery, 28 patients being followed up for BD, and 24 healthy individuals without vascular or cardiac disease, were enrolled in the study. Intra- and intergroup analysis was performed to evaluate the relationship of ADMA levels with smoking behaviors and clinical disease severity according to Fontaine classification. ADMA levels were 1.26 ± 0.76 mmol/L, 0.87 ± 0.27 mmol/L, and 1.07 ± 0.88 mmol/L in patients with PAD, in patients with BD, and in the control group, respectively. ADMA levels were significantly higher in patients with PAD than those in control patients (p = 0.003) and the levels observed in patients with BD were significantly lower than those in control patients (p = 0.001). Smokers with PAD had higher ADMA levels than smokers with BD (p = 0.03). ADMA levels were higher in patients with Fontaine stage III and IV disease than those with Fontaine stage II diseases, for patients with PAD as well as those with BD. The lower ADMA levels observed in patients with BD might be related to the degradation of ADMA by dimethylarginine dimethylaminohydrolase in response to ischemia and could act as a defensive mechanism during the acute or quiescent phases. In patients with BD experiencing severe clinical conditions or with a longer time course for the disease, higher ADMA levels may suggest a poor prognosis.

Regional Differences in Hypertensive Cardiovascular Remodeling Between Fishing and Farming Communities in Japan

Effects of dietary n-3 polyunsaturated fatty acids (n-3 PUFA) intake on the cardiovascular system have been reported, and thus we hypothesized that the prevalence of hypertensive cardiovascular remodeling would be lower in a fishing than a farming community. We recruited 263 essential hypertensives from a fishing and 333 from a farming village; all subjects were ≥40 years (mean 73 years; 42% men). They were cross-sectionally examined for serum eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), asymmetric dimethylarginine (ADMA) levels, left ventricular mass index (LVMI), and common-carotid artery (CCA) and internal-carotid artery (ICA) intima-media thickness (IMT). Compared to the patients in the farming village, those in the fishing village had higher serum EPA and DHA levels (63.3 vs.70.9 µg/ml, 137.2 vs.157.8 µg/ml) and lower ADMA levels (0.49 vs.0.47 nmol/ml; all P < 0.05). LVMI and both CCA-IMT and ICA-IMT levels were lower in the fishing than the farming village (113.2 vs.121.6 g/m(2), 0.88 vs.0.94 mm, 1.10 vs.1.17 mm: all P < 0.01) even after adjustment for age, sex, body mass index (BMI), duration of hypertensive medication, number of antihypertensive medications, and 24-h systolic blood pressure (SBP) level. The differences in LVMI and IMT levels between these communities also remained unchanged (all P < 0.01) after additional adjustment for the regional differences in EPA, DHA, and ADMA levels. A multivariable linear regression analysis showed that the difference in place of residence was independently associated with LVMI as well as with both CCA-IMT and ICA-IMT levels (all P < 0.01). The prevalence of cardiovascular remodeling was significantly lower in patients in the fishing community than in those in the farming community. Further investigations are required to explain the mechanisms underlying this association.

Low arginine/asymmetric dimethylarginine ratio deteriorates systemic hemodynamics and organ blood flow in a rat model

Both arginine and asymmetric dimethylarginine (ADMA) play a crucial role in the arginine-nitric oxide pathway. Low arginine and high ADMA levels can be found in critically ill patients after major surgery. The aim of this study was to evaluate the effects of low arginine plasma concentrations in combination with high ADMA plasma concentrations on hemodynamics and organ blood flow. Randomized, placebo-controlled animal laboratory investigation. Male Wistar rats (n = 21), anesthetized. Rats were randomly assigned to three groups: a control group, an ADMA group, or an arginase (ASE)/ADMA group. In the control group, rats received (at t = 0) an intravenous (IV) infusion of 1.5 mL 0.9% NaCl during a 20-minute period. After 60 minutes (t = 60), rats received an IV bolus of 1.0 mL 0.9% NaCl. In the ADMA group, rats received an IV infusion of 1.5 mL 0.9% NaCl during a 20-minute period and at t = 60 an IV bolus of 1.0 mL ADMA (20 mg/kg). In the ASE/ADMA group, rats received an IV infusion of 1.5 mL ASE (3200 IU) solution during a 20-minute period and at t = 60 an IV bolus of 1.0 mL ADMA (20 mg/kg). Infusion of ADMA (20 mg/kg) and ASE (3200 IU) resulted in increased plasma ADMA levels and decreased arginine levels. During the whole experiment, systemic hemodynamics (heart rate, mean arterial pressure [MAP], and cardiac output) were measured. In addition, organ blood flow was measured at t = 90 and t = 180 minutes, using fluorescent microspheres. Compared with the control group, MAP and systemic vascular resistance were increased after infusion of ADMA. Infusion of ASE in combination with ADMA significantly deteriorated systemic hemodynamics (MAP, cardiac output, stroke volume, and systemic vascular resistance) and organ blood flow through the kidney and spleen. In addition, an initial decrease in arterial flow, followed by a later major increase, and panlobular apoptosis and necrosis of the liver was observed. The current study shows that low arginine plasma levels in combination with high ADMA plasma levels deteriorates systemic hemodynamics and reduces blood flow through the kidney and spleen and liver. These data suggest that a diminished nitric oxide production may be involved in the onset of organ failure.

Asymmetric dimethylarginine is closely associated with the development and progression of nephropathy in patients with type 2 diabetes

Nitric oxide (NO) is thought to play an important role in the pathogenesis of diabetic nephropathy. We conducted a prospective, observational cohort study to explore the relationship between plasma levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase, and the development and progression of nephropathy in patients with type 2 diabetes. This was a hospital-based observational cohort study in Japanese type 2 diabetic patients with normoalbuminuria [urinary albumin-to-creatinine ratio (ACR) <30 mg/g creatinine] or microalbuminuria (30 < or = ACR <300 mg/g creatinine). The primary endpoint was the development or progression of diabetic nephropathy, based on transition from any given stage to a more advanced stage of albuminuria. We studied 225 diabetic patients, 81 women and 144 men, with a mean (+/-SD) age of 64 +/- 10 years. The majority (183) of patients were normoalbuminuric, with the remainder microalbuminuric (42). During the median follow-up period of 5.2 years, 27 normoalbuminuric and 10 microalbuminuric patients reached the primary endpoint. When patients were separated according to the median ADMA level (0.46 mumol/l), patients with higher ADMA levels had a greater incidence of reaching the endpoint (P = 0.014 by the log-rank test). In the multivariate Cox proportional hazard model, the hazard ratio for reaching the endpoint for patients with higher versus lower ADMA levels was 2.72 (95% confidence interval 1.25-5.95; P = 0.012). Higher plasma levels of ADMA may be a novel and potent predictor of the progression of nephropathy in adult Japanese type 2 diabetic patients.

Differential effects of arginine methylation on diastolic dysfunction and disease progression in patients with chronic systolic heart failure.

To investigate the association of arginine methylation with myocardial function and prognosis in chronic systolic heart failure patients. Asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA), as well as N-mono-methylarginine (MMA) and methyl-lysine, were simultaneously measured by tandem mass spectrometry in 132 patients with chronic systolic heart failure with echocardiographic evaluation and follow-up. Increasing ADMA and SDMA levels were associated with elevated natriuretic peptide levels (both P < 0.001), and increasing SDMA levels were associated with worsening renal function (P < 0.001). Higher plasma levels of methylated arginine metabolites (but not methyl-lysine) were associated with the presence of left ventricular (LV) diastolic dysfunction (E/septal E', Spearman's r = 0.31-0.36, P < 0.001). Patients taking beta-blockers had lower ADMA levels than those not taking beta-blockers [0.42 (0.33, 0.50) vs. 0.51 (0.40, 0.58), P < 0.001]. Only increasing ADMA levels were associated with advanced right ventricular (RV) systolic dysfunction. Elevated ADMA levels remained a consistent independent predictor of adverse clinical events (hazard ratio = 1.64, 95% CI: 1.20-2.22, P = 0.002). In chronic systolic heart failure, accumulation of methylated arginine metabolites is associated with the presence of LV diastolic dysfunction. Among the methylated derivatives of arginine, ADMA provides the strongest independent prediction of disease progression and adverse long-term outcomes.

Modulation of regional nitric oxide metabolism: Blood glucose control or insulin?

Tight glycaemic control by intensive insulin therapy (IIT) reduces morbidity and mortality in critically ill patients. As potential mechanisms contributing to the clinical benefits we hypothesized that glycaemic control affects regional nitric oxide (NO) bioavailability by changing NO synthases (NOS) activity, NOS transcription, NOS substrate availability or the endogenous NOS inhibitor asymmetric dimethylarginine (ADMA) levels. Prospective, randomized experimental study. University medical laboratory. In a rabbit model of prolonged critical illness we assessed the relative impact of maintaining normal insulin/normoglycaemia (n = 8), high insulin/normoglycaemia (n = 8), normal insulin/hyperglycaemia (n = 9) and high insulin/hyperglycaemia (n = 8) plasma levels over 7 days on activity and gene expression of endothelial and inducible NOS isoforms in muscle, liver and aorta biopsies, and on plasma levels of NO, arginine and ADMA. Compared with normoglycaemic groups, both hyperglycaemic groups revealed 53% higher day-3 NO plasma levels (p < 0.05), 40% lower NOS activity in muscle (p < 0.01) and 35% lower endothelium-mediated relaxation of aortic rings (p < 0.01), 515% higher gene expression of iNOS in muscle (p < 0.01) and 99% higher eNOS gene expression in aorta (p < 0.01). Only the hyperglycaemic/hyperinsulinaemic group showed lower arginine plasma levels (53% lower, p < 0.0001). Compared with healthy controls, normoglycaemic animals revealed 33% lower ADMA levels (p < 0.05). In this animal model of prolonged critical illness, maintaining normoglycaemia, and not glycaemia-independent actions of insulin, prevented excessive systemic NO release on day 3 and appeared to preserve local endothelial function. Factors contributing to this finding may comprise direct endothelial cell damage, direct effects on the enzyme activity, decreased substrate availability or less NO-induced inhibition.