Endogenous Nitric Oxide Synthase Inhibitor

Miyazaki, Hiroshi; Matsuoka, Hidehiro; Cooke, John P.; Usui, Michiaki; Ueda, Seinosuke; Okuda, Seiya; Imaizumi, Tsutomu

doi:10.1161/01.cir.99.9.1141

Cited by 698 publications

(499 citation statements)

References 82 publications

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“…We found no sex-related difference in SDMA or NMMA in any of our groups (Fig. 1), nor any effect of age (consistent with [39]) for SDMA and NMMA. It should be borne in mind that the number of subjects in our study precludes these sex-related and age differences being definitive findings, and requires confirmation in larger cohorts.…”

Section: Discussionsupporting

confidence: 49%

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Elevations of plasma methylarginines in obesity and ageing are related to insulin sensitivity and rates of protein turnover

et al. 2005

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Elevations of plasma methylarginines in obesity and ageing are related to insulin sensitivity and rates of protein turnover Abstract Aims/hypothesis: Increased circulating methylarginines (MA) have been linked to the metabolic syndrome to explain endothelial dysfunction and cardiovascular disease risk. Proteins that contain MA are regulatory and release them during catabolism. We hypothesised that increased protein turnover in insulin-resistant states contributes to an increase in circulating MA. Materials and methods: We performed hyperinsulinaemic, euglycaemic, and isoaminoacidaemic experiments on 49 lean, obese and elderly subjects, with measurements of the kinetics of glucose and protein metabolism. Plasma MA, i.e. asymmetrical dimethylarginine (ADMA), symmetrical dimethylarginine (SDMA), and N G -monomethyl-L-arginine (NMMA), lipids and body composition were measured. Results: Insulin resistance of glucose and protein metabolism occurred in obese and elderly subjects. ADMA concentrations were 29 to 120% higher in obese and 34% higher in elderly than in lean subjects. SDMA were 34 and 20% higher in obese than in lean and than in elderly subjects, respectively. NMMA were 32% higher in obese than in lean subjects. ADMA differed by sex, being higher in men, namely by 1.75× in obese men and by 1.27× in elderly men. Postabsorptive ADMA (r=0.71), SDMA (r=0.46), and NMMA (r=0.31) correlated (all p<0.05) with rates of protein flux. All three MA correlated negatively with clamp glucose infusion rates and uptake (p<0.001). ADMA and SDMA correlated negatively with net protein synthesis and clamp amino acid infusion rates (p<0.05). All MA also correlated with adiposity indices and fasting insulin and triglycerides (p<0.05). Conclusions/ interpretation: Obesity, sex and ageing affect MA. Elevations of the three MA in obese, and of ADMA in elderly men, are related to increased protein turnover and to lesser insulin sensitivity of protein metabolism. These interrelationships might amplify insulin resistance and endothelial dysfunction.

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Section: Discussionsupporting

confidence: 49%

“…The elderly men showed elevations compared with lean subjects, albeit smaller than those of obese men. Without controlling for sex, an increase with age has been reported in humans [39]. The elevated plasma levels of ADMA in subjects with a mean age of 70 years and without hypertension were even higher with hypertension [40].…”

Section: Discussionmentioning

confidence: 97%

Elevations of plasma methylarginines in obesity and ageing are related to insulin sensitivity and rates of protein turnover

et al. 2005

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“…The lack of a correlation with cholesterol has also been reported [18] and there was also no correlation with blood pressure in another study [28]. Associations with systemic blood pressure have been described in other studies [19,29], but this could be more difficult to detect since increases in total peripheral resistance can be compensated for by changes in cardiac output and larger cohorts could be required to establish a clear relation. However, as these cardiovascular risk factors were in the normal range in most subjects under study, this finding cannot rule out an association of these parameters with ADMA in different patient groups.…”

Section: Discussionmentioning

confidence: 72%

Circulating concentrations of asymmetrical dimethyl- L -arginine are increased in women with previous gestational diabetes

Mittermayer

Meyer

et al. 2002

Diabetologia

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Aims/hypothesis. The concentration of asymmetrical dimethyl-L-arginine (ADMA), an endogenous inhibitor of the nitric oxide synthase, is increased in patients at risk or with cardiovascular disease. We have investigated ADMA concentrations in women with a history of gestational diabetes (GDM), who could develop endothelial dysfunction and Type II (non-insulin-dependent) diabetes mellitus after delivery, and in healthy control subjects. Methods. Previous GDM patients were grouped according to their BMI as obese (≥25 kg/m 2 , n=46) or non-adipose (<25 kg/m 2 , n=31). Serum samples were taken 14 to 16 weeks after delivery and after 1 year. The control group comprised 17 healthy women (BMI<25 kg/m 2 ). ADMA concentrations were analysed by high performance liquid chromatography. Results. ADMA concentrations were comparable between obese and non-adipose GDM patients (0.58±0.02 and 0.57±0.02 µmol/l, respectively), and higher than in the control group (0.47±0.03 µmol/l; p<0.006). Insulin resistance as estimated by the insulin sensitivity index was more frequent among the obese than the non-adipose GDM women (p<0.05) and control subjects (p<0.05, both). No change in ADMA concentrations was found after 1 year in women with GDM. There was only a slight correlation between ADMA and BMI (r=0.26, p<0.02), triglycerides (r=0.29, p<0.004), or fasting plasma glucose (r=0.21, p<0.05), and not with the insulin sensitivity index or other parameters. In a multiple regression analysis ADMA serum concentrations were only associated with triglycerides. Conclusion/interpretation. Circulating ADMA concentrations are increased in normoglycaemic women with previous GDM. This increase is independent from other risk factors or surrogate markers for diabetes or cardiovascular events. [Diabetologia (2002[Diabetologia ( ) 45:1372[Diabetologia ( -1378 Keywords Gestational diabetes, asymmetrical dimetylarginine, nitric oxide, insulin resistance, cholesterol. . L-arginine can also be methylated by intracellular methyltransferases [3], but the exact regulation of this pathway is not known. The methylated L-arginine metabolite, asymmetrical dimethyl-L-arginine (ADMA), inhibits the cellular L-arginine uptake and nitric oxide synthase activity in endothelial cells competitively [4]. The allosteric symmetrical dimethyl-L-arginine (SDMA) is produced in equivalent amounts, but is not a structural antagonist in nitric oxide synthesis [5].It has been speculated that accumulation of endogenous L-arginine metabolites and low availability of LNitric oxide is synthesized from the amino acid L-arginine by constitutive and inducible nitric oxide synthases [1] and plays an important role in the regulation

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“…Recently, asymmetrical dimethylarginine (ADMA) has been implicated as an important contributing factor. [13][14][15] Asymmetrical dimethylarginine is characterized as a circulating endogenous inhibitor of NO synthase. 16,17 It may compete with L-arginine as the substrate for NO synthase, increase oxidative stress by uncoupling of electron transport between NO synthase and L-arginine, and hence decrease both the production and availability of endothelium-derived NO.…”

Section: Introductionmentioning

confidence: 99%

Asymmetrical dimethylarginine: A novel risk factor for coronary artery disease

Ding

Charng

et al. 2003

Clinical Cardiology

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SummaryBackground: Asymmetrical dimethylarginine (ADMA) is an endogenous competitive inhibitor of nitric oxide synthase and has been associated with systemic atherosclerosis; however, the role of ADMA in patients with coronary artery disease (CAD) has not been investigated.Hypothesis: The present study was designed to determine whether the plasma ADMA level predicts the presence of CAD independently, and whether the plasma ADMA level correlates with the extent and severity of coronary atherosclerosis.Methods: In all, 97 consecutive patients with angina and positive exercise stress test were enrolled prospectively for coronary angiography. According to the result of angiography, the subjects were divided into two groups: Group 1 (n = 46): patients with normal coronary artery or mild CAD (< 50% stenosis of major coronary arteries); Group 2 (n = 51): patients with significant CAD (≥ 50% stenosis of major coronary arteries). Plasma levels of ADMA and L-arginine were determined by high-performance liquid chromatography. In addition, we used coronary atherosclerotic score to assess the extent and severity of CAD.Results: The plasma levels of ADMA in Group 2 patients were significantly higher than those in Group 1 patients (0.66

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Endogenous Nitric Oxide Synthase Inhibitor

Cited by 698 publications

References 82 publications

Elevations of plasma methylarginines in obesity and ageing are related to insulin sensitivity and rates of protein turnover

Elevations of plasma methylarginines in obesity and ageing are related to insulin sensitivity and rates of protein turnover

Circulating concentrations of asymmetrical dimethyl- L -arginine are increased in women with previous gestational diabetes

Asymmetrical dimethylarginine: A novel risk factor for coronary artery disease

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