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

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 and competitive inhibitor of nitric oxide synthase. Plasma levels of this inhibitor are elevated in patients with atherosclerosis and in those with risk factors for atherosclerosis. In these patients, plasma ADMA levels are correlated with the severity of endothelial dysfunction and atherosclerosis. By inhibiting the production of nitric oxide, ADMA may impair blood flow, accelerate atherogenesis, and interfere with angiogenesis. ADMA may be a novel risk factor for vascular disease.

Does ADMA cause endothelial dysfunction

Asymmetrical dimethylarginine (ADMA) is an endogenous nitric oxide synthase inhibitor. It is formed by protein arginine N-methyltransferases (PRMTs), which utilize S-adenosylmethionine as methyl group donor. ADMA plasma concentration is elevated in hypercholesterolemia, leading to endothelial dysfunction and producing proathero- genic changes of endothelial cell function. Four different isoforms of human PRMTs have been identified. Because the release of ADMA from human endothelial cells is increased in the presence of native or oxidized LDL cholesterol, we investigated the potential involvement of PRMT activity and gene expression in this effect. We found that the production of ADMA by human endothelial cells is upregulated in the presence of methionine or homocysteine and inhibited by either of the methyltransferase inhibitors S-adenosylhomocysteine, adenosine dialdehyde, or cycloleucine. This effect is specific for ADMA but not symmetrical dimethylarginine. The upregulation of ADMA release by native and oxidized LDL is abolished by S-adenosylhomocysteine and by the antioxidant pyrrollidine dithiocarbamate. Furthermore, a methyl- 14 C label is transferred from S-adenosylmethionine to ADMA but not symmetrical dimethylarginine, in human endothelial cells. The expression of PRMTs is upregulated in the presence of native or oxidized LDL. Our data suggest that the production of ADMA by human endothelial cells is regulated by S-adenosylmethionine- dependent methyl- transferases. This activity is upregulated by LDL cholesterol, which may be due in part to the enhanced gene expression of PRMTs. In concentrations reached by stimulation of methyltransferases (5 to 50 mmol/L), ADMA significantly inhibited the formation of 15 N-nitrite from L-(guanidino- 15 N2)arginine. These findings suggest a novel mechanism by which ADMA concentration is elevated in hypercholesterolemia, leading to endothelial dysfunction and atherosclerosis. (Circ Res. 2000;87:99-105.)

/pdf/ldl-cholesterol-upregulates-synthesis-of-asymmetrical-11mhkr4i6y.pdf

LDL cholesterol upregulates synthesis of asymmetrical dimethylarginine in human endothelial cells: involvement of S-adenosylmethionine-dependent methyltransferases.

Determination of Arginine, Asymmetric Dimethylarginine, and Symmetric Dimethylarginine in Human Plasma and Other Biological Samples by High-Performance Liquid Chromatography

Summary:Our aim was to investigate systemic nitric oxide (NO) production and its potential determinants such as insulin resistance, dyslipidemia, and circulating methylated analogs of L-arginine in uncomplicated essential hypertension (EH). Nineteen newly diagnosed, untreated male subjects with mild

Reduced urinary excretion of nitric oxide metabolites and increased plasma levels of asymmetric dimethylarginine in men with essential hypertension.

Insulin stimulates the production of endothelin-1 (ET-1) and nitric oxide (NO) by isolated endothelial cells. Additionally, insulin-dependent glucose transport and insulin-mediated NO production partially share common elements in signal transduction. There are discordant data on plasma ET-1 levels during acute euglycemic systemic hyperinsulinemia in normotensive men and men with essential hypertension (EH) (known to be insulin-resistant), as well as on the relations between insulin sensitivity and vascular function. Our aim was to assess the response of approximate measures of whole-body generation of NO and ET-1 to acute euglycemic hyperinsulinemia in EH patients and controls. We studied 17 newly diagnosed untreated men with uncomplicated EH and 10 normotensive controls. Plasma ET-1 and urinary excretion of nitrite plus nitrate, stable NO metabolites (Uno x ), were measured before and during a 3-hour hyperinsulinemic-euglycemic clamp. Both in hypertensives and normotensives, plasma ET-1 levels were reduced after 2 hours of the clamp (EH: baseline, 3.1 ± 1.9 pg/mL; 2 hours, 1.9 ± 1.2 pg/mL, P = .04 v baseline; controls: baseline, 4.2 ± 2.6 pg/mL; 2 hours, 2.8 ± 1.4 pg/mL, P = .04 v baseline). No significant changes in Uno x during the clamp were observed. Changes in Uno x during the clamp (ΔUno x ) and differences in plasma ET-1 measured before the end and before the beginning of the clamp (ΔET-1) were correlated in the controls ( r = .75, P = .01) but not in EH ( r = −.01, P = .97). No parameter of glucose metabolism correlated with basal Uno x , basal plasma ET-1, ΔUno x , and ΔET-1, whether absolute or percent values, in either group. Thus, acute euglycemic hyperinsulinemia produces a decrease in plasma ET-1 in both EH patients and controls. The lack of correlation between ΔUno x and ΔET-1 under these conditions in EH may suggest an impairment of systems governing interactions between the NO-dependent pathway and ET-1. In addition, insulin actions on glucose metabolism and on the endothelial mediators appear dissociated.

Effects of acute euglycemic hyperinsulinemia on urinary nitrite/nitrate excretion and plasma endothelin-1 levels in men with essential hypertension and normotensive controls.

Joerg Sandmann

Papers

Reduced urinary excretion of nitric oxide metabolites and increased plasma levels of asymmetric dimethylarginine in men with essential hypertension.

Effects of acute euglycemic hyperinsulinemia on urinary nitrite/nitrate excretion and plasma endothelin-1 levels in men with essential hypertension and normotensive controls.