Asymmetric Dimethylarginine (ADMA): A Novel Risk Factor for Endothelial Dysfunction

Böger, Rainer H.; Bode‐Böger, Stefanie M.; Szuba, Andrzej; Tsao, Philip S.; Chan, Jason R.; Tangphao, Oranee; Blaschke, Terrence F.; Cooke, John P.

doi:10.1161/01.cir.98.18.1842

Cited by 1,077 publications

(820 citation statements)

References 57 publications

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“…This study is consistent with reports on increased circulating concentrations of ADMA in patients at risk or with vascular dysfunction or arteriosclerosis [7,10,13,25]. Serum concentrations of ADMA were approximately 20% higher in women with a history of GDM than in healthy women.…”

Section: Discussionsupporting

confidence: 92%

“…So far, no threshold data for ADMA leading to a reduction in endothelial function have been established. In hypercholesterolaemia, an increment of ADMA from 1 µmol/l to 1.5 µmol/l reduced flow-mediated dilatation of the brachial artery from 9% to 6% [7]. In patients with Type II diabetes, a high-fat meal resulted in a nearly 2.5-fold increased mean plasma ADMA concentration and a further deterioration of already impaired endothelial function as estimated by measurement of flow-mediated dilatation of the brachial artery [18].…”

Section: Discussionmentioning

confidence: 94%

“…A decreased plasma L-arginine to ADMA ratio or increased ADMA concentrations has been described in hypercholesterolemia [6,7], hypertension [8,9], arterial occlusive disease [10], chronic renal failure [11], and preeclampsia [12]. It has been suggested that alteration of the L-arginine to ADMA ratio could affect the clinical course of arteriosclerosis, which has not been seen in patients with stable angina [13].…”

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confidence: 99%

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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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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 94%

mentioning

confidence: 99%

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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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“…42,43 Circulating levels of nitrite/nitrate, cyclic guanosine 3 0 ,5 0 -monophosphate, vascular cell adhesion molecule-1, intracellular adhesion molecule-1, monocyte chemoattractant protein-1, plasminogen activator inhibitor-1, von Willebrand factor, asymmetrical dimethylarginine, endothelial microparticles and progenitor cells are also measured as indices of endothelial function. 21,[44][45][46][47] However, these measurements do not directly reflect the production of NO from endothelial cells and are not 'function' . Measurement of circulating levels of NO metabolites, inflammatory markers and adhesion molecules should be used as an adjuvant to the measurement of forearm blood flow responses to vasoactive agents or FMD.…”

Section: Endothelial Functionmentioning

confidence: 99%

Endothelial dysfunction and hypertension in aging

2012

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Hypertension is one of the common diseases in the elderly. The prevalence of hypertension markedly increases with advancing age. Both aging and hypertension have a critical role in cardiovascular and cerebrovascular complications. Although aging and hypertension, either independently or collectively, impair endothelial function, aging and hypertension may have similar cascades for the pathogenesis and development of endothelial dysfunction. Nitric oxide (NO) has an important role in regulation of vascular tone. Decrease in NO bioavailability by endothelial dysfunction would lead to elevation of blood pressure. An imbalance of reduced production of NO or increased production of reactive oxygen species, mainly superoxide, may promote endothelial dysfunction. One possible mechanism by which the prevalence of hypertension is increased in relation to aging may be advancing endothelial dysfunction associated with aging through an increase in oxidative stress. In addition, endothelial cell senescence is also involved in aging-related endothelial dysfunction. In this review, we focus on recent findings and interactions between endothelial function, oxidative stress and hypertension in aging.

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“…It is possible that an increase in superoxide anion production may reduce nitric oxide availability by direct inactivation of nitric oxide (to form peroxynitrite) or by oxidation of tetrahydrobiopterin leading to an uncoupling of NOS (Landmesser et al, 2003;Landmesser et al, 2006). In addition, it is possible that superoxide anion may inhibit dimethylarginine dimethylaminodydrolase (DDAH), the enzyme that hydrolyzes the endogenous NOS inhibitor asymmetric dimethlarginine (ADMA) (Boger et al, 1998). …”

Section: Consideration Of Methodsmentioning

confidence: 99%

nNOS-dependent reactivity of cerebral arterioles in Type 1 diabetes

et al. 2007

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Our goals were to determine whether Type 1 diabetes (T1D) alters neuronal nitric oxide synthase (nNOS) dependent reactivity of cerebral arterioles and to identify a potential role for oxidative stress in T1D-induced impairment in nNOS-dependent responses of cerebral arterioles. Rats were injected with vehicle (sodium citrate buffer) or streptozotocin (50 mg/kg IP) to induce T1D. Two to three months later, we measured functional responses of cerebral arterioles to nNOS-dependent (NMDA and kainate) and -independent (nitroglycerin) agonists in nondiabetic and diabetic rats before and during inhibition of oxidative stress using tempol (100 μM). In addition, we measured superoxide anion production under basal conditions, during stimulation with NMDA and kainate, and during treatment with tempol. We found that nNOS-dependent, but not -independent, vasodilatation was impaired in diabetic compared to nondiabetic rats. In addition, treatment of the cerebral microcirculation with tempol restored impaired nNOS-dependent vasodilatation in diabetic rats towards that observed in nondiabetic rats. Further, the production of superoxide anion (lucigenin chemiluminescence) was increased in parietal cortical tissue of diabetic rats under basal conditions. Application of NMDA and kainate did not increase superoxide anion production in nondiabetic or diabetic rats. However, tempol decreased basal production of superoxide anion in diabetic rats. Our findings suggest that T1D impairs nNOS dependent dilatation of cerebral arterioles by a mechanism that appears to be related to the formation of superoxide anion.

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Asymmetric Dimethylarginine (ADMA): A Novel Risk Factor for Endothelial Dysfunction

Cited by 1,077 publications

References 57 publications

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

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

Endothelial dysfunction and hypertension in aging

nNOS-dependent reactivity of cerebral arterioles in Type 1 diabetes

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