http://www.positivedesigns.com/cardio/Arginine%20&%20Kidney%20Disease.pdf

Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: A prospective study

Introduction Patients affected by end-stage renal disease (ESRD) experience an excess of morbidity and mortality due to cardiovascular disease (CVD), which cannot be fully explained by the classical CVD risk factors Among emerging CVD risk factors, oxidative stress is currently being given emphasis Methods We achieved a consensus on key points relating to oxidative stress in ESRD patients Results ESRD patients are subjected to enhanced oxidative stress, as a result of reduced anti-oxidant systems (vitamin C and selenium deficiency, reduced intracellular levels of vitamin E, reduced activity of the glutathione system) and increased pro-oxidant activity (advanced age, high frequency of diabetes, chronic inflammatory state, uraemic syndrome, bioincompatibility of dialysis membranes and solutions) Oxidative stress and inflammation are deeply interrelated, as different oxidant free radicals are generated by phagocytic cells in response to inflammatory stimuli: both are related to endothelial dysfunction, as the endothelium is a source and a target of oxidants and participates in the inflammatory response There is growing evidence, from experimental and clinical studies, that oxidative stress may be implicated in the pathogenesis of atherosclerosis and other complications of ESRD, namely dialysis-related amyloidosis, malnutrition and anaemia Given that free radicals have very short half-lives (seconds), the clinical assessment of oxidative stress is based on the measurement of different stable oxidized compounds (such as lipid peroxidation products, advanced glycation and oxidation lipid and protein products, nucleic acid oxidation derivatives) or antibodies directed against oxidized epitopes (such as anti-oxidized low-density lipoprotein antibodies) At the same time, both enzymatic anti-oxidants (superoxide dismutase, catalase, glutathione peroxidase) and non-enzymatic antioxidants (glutathione, vitamin C, vitamin E, negative inflammatory proteins) can be evaluated However, many laboratory methods assessing various oxidative stress components still have to be standardized Moreover, it is still uncertain whether it is better measuring plasma anduor intracellular concentrations or activities of these components The possibility of improving patient outcome by therapeutic interventions aimed at reducing oxidative stress, eg by vitamin C or vitamin E supplementation, currently is to the fore, but results so far have remained inconclusive Conclusions It is important to consider oxidative stress as a potentially important source of patient morbidity and mortality, although this knowledge is not yet immediately applicable in the clinical arena Further well-designed, randomized controlled clinical trials with anti-oxidants (eg vitamin E, vitamin C, N-acetyl cysteine, L-arginine) are required to establish evidence-based recommendations for clinical practice

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Oxidative stress in end‐stage renal disease: an emerging threat to patient outcome

Background— An endogenous inhibitor of nitric oxide synthase, asymmetric dimethylarginine (ADMA), is elevated in patients with type 2 diabetes mellitus (DM). This study explored the mechanisms by which ADMA becomes elevated in DM. Methods and Results— Male Sprague-Dawley rats were fed normal chow or high-fat diet (n=5 in each) with moderate streptozotocin injection to induce type 2 DM. Plasma ADMA was elevated in diabetic rats (1.33±0.31 versus 0.48±0.08 μmol/L; P<0.05). The activity, but not the expression, of dimethylarginine dimethylaminohydrolase (DDAH) was reduced in diabetic rats and negatively correlated with their plasma ADMA levels (P<0.05). DDAH activity was significantly reduced in vascular smooth muscle cells and human endothelial cells (HMEC-1) exposed to high glucose (25.5 mmol/L). The impairment of DDAH activity in vascular cells was associated with an accumulation of ADMA and a reduction in generation of cGMP. In human endothelial cells, coincubation with the antioxidant polyethylene glyco...

Impaired nitric oxide synthase pathway in diabetes mellitus: role of asymmetric dimethylarginine and dimethylarginine dimethylaminohydrolase.

Background—Hyperhomocysteinemia is a putative risk factor for cardiovascular disease, which also impairs endothelium-dependent vasodilatation. A number of other risk factors for cardiovascular disease may exert their adverse vascular effects in part by elevating plasma levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase. Accordingly, we determined if homocysteine could increase ADMA levels. Methods and Results—When endothelial or nonvascular cells were exposed to DL-homocysteine or to its precursor L-methionine, ADMA concentration in the cell culture medium increased in a dose- and time-dependent fashion. This effect was associated with the reduced activity of dimethylarginine dimethylaminohydrolase (DDAH), the enzyme that degrades ADMA. Furthermore, homocysteine-induced accumulation of ADMA was associated with reduced nitric oxide synthesis by endothelial cells and segments of pig aorta. The antioxidant pyrrollidine dithiocarbamate preserved DDAH activity and reduced ADMA accumulation. Moreover, homocysteine dose-dependently reduced the activity of recombinant human DDAH in a cell free system, an effect that was due to a direct interaction between homocysteine and DDAH. Conclusion—Homocysteine post-translationally inhibits DDAH enzyme activity, causing ADMA to accumulate and inhibit nitric oxide synthesis. This may explain the known effect of homocysteine to impair endothelium-mediated nitric oxide– dependent vasodilatation. (Circulation. 2001;104:2569-2575.)

Homocysteine Impairs the Nitric Oxide Synthase Pathway Role of Asymmetric Dimethylarginine

ContextIncreased levels of asymmetric dimethylarginine (ADMA) are associated
with endothelial dysfunction and increased risk of cardiovascular disease.
Several cardiovascular risk factors are associated with reduced sensitivity
to insulin, but elevated ADMA concentrations have not been fully linked to
the metabolic syndrome.ObjectiveTo evaluate the relationship between insulin sensitivity and plasma
ADMA concentrations, and to determine whether a pharmacological treatment
that increases insulin sensitivity would also modulate ADMA concentrations.Design, Setting, and SubjectsCross-sectional study, containing a nonrandomized controlled trial component,
of 64 healthy volunteers without diabetes (42 women, 22 men; 48 with normal
blood pressure and 16 with hypertension), which was conducted at a university
medical center between October 2000 and July 2001.InterventionRosiglitazone (4 mg/d for 4 weeks and then 4 mg twice daily for 8 weeks),
an insulin-sensitizing agent, was given to 7 insulin-resistant subjects with
hypertension. These subjects were studied before and after 12-week treatment.Main Outcome MeasuresInsulin sensitivity measured by the insulin suppression test, and fasting
plasma levels of low-density lipoprotein cholesterol, triglycerides, high-density
lipoprotein cholesterol, glucose, insulin, and ADMA concentrations.ResultsPlasma ADMA concentrations were positively correlated with impairment
of insulin-mediated glucose disposal in nondiabetic, normotensive subjects
(r = 0.73; P<.001). Consistent
with the metabolic syndrome, ADMA levels were also positively correlated with
fasting triglyceride levels (r = 0.52; P<.001) but not with low-density lipoprotein cholesterol levels
(r = 0.19; P = .20). Plasma
ADMA concentrations increased in insulin-resistant subjects independent of
hypertension. Pharmacological treatment improved insulin sensitivity and reduced
mean (SD) plasma ADMA concentrations from 1.50 (0.30) to 1.05 (0.33) µmol/L
(P = .001).ConclusionA significant relationship exists between insulin resistance and plasma
concentrations of ADMA. Pharmacological intervention with rosiglitazone enhanced
insulin sensitivity and reduced ADMA levels. Increases in plasma ADMA concentrations
may contribute to the endothelial dysfunction observed in insulin-resistant
patients.

https://jamanetwork.com/journals/jama/articlepdf/194735/JCI10069.pdf

Relationship between insulin resistance and an endogenous nitric oxide synthase inhibitor.

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of endothelial nitric oxide (NO) synthase. Its concentration is elevated in patients with end-stage renal disease (ESRD), in part because it is excreted via the kidneys. In this study, the plasma concentrations of ADMA, symmetric dimethylarginine, and L-arginine were determined in relation to plasma nitrate levels (as an index of NO formation) for a group of 80 patients with ESRD. The effects of two treatment methods, i.e., hemodialysis (HD) and peritoneal dialysis (PD), and the role of the presence of atherosclerotic disease were evaluated. Forty-three patients receiving HD and 37 patients receiving PD were compared with healthy control subjects. Plasma L-arginine and dimethylarginine levels were determined by HPLC, using precolumn derivatization with o-phthaldialdehyde. Plasma nitrate levels were determined by gas chromatography-mass spectrometry. Predialysis ADMA concentrations in HD-treated patients were approximately sixfold higher than those in the control group (6.0+/-0.5 versus 1.0+/-0.1 micromol/L; P < 0.05). Plasma nitrate concentrations were significantly lower in HD-treated patients, which suggests that ADMA may inhibit NO synthase. In contrast, plasma ADMA levels and nitrate concentrations in PD-treated patients were similar to those in control subjects. Plasma L-arginine concentrations were not significantly decreased in patients with ESRD. ADMA concentrations were significantly decreased 5 h after HD, compared with baseline values. ADMA levels were significantly higher in HD-treated patients with manifest atherosclerotic disease than in HD-treated patients without atherosclerotic disease (7.31+/-0.70 versus 3.95+/-0.52 micromol/L; P < 0.05). This study confirms that ADMA is accumulated in ESRD. PD-treated patients exhibit significantly lower ADMA levels than do HD-treated patients. Accumulation of ADMA may be a risk factor for the development of endothelial dysfunction and cardiovascular disease in patients with ESRD.

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Asymmetric dimethylarginine plasma concentrations differ in patients with end-stage renal disease: relationship to treatment method and atherosclerotic disease.

Stefanine M. Bode-Böger

Papers

Asymmetric dimethylarginine plasma concentrations differ in patients with end-stage renal disease: relationship to treatment method and atherosclerotic disease.