Reduced renal plasma clearance does not explain increased plasma asymmetric dimethylarginine in hypertensive subjects with mild to moderate renal insufficiency

2012 ◽  
Vol 303 (1) ◽  
pp. F149-F156 ◽  
Author(s):  
Rianne A. Ronden ◽  
Alfons J. H. M. Houben ◽  
Tom Teerlink ◽  
Jaap A. Bakker ◽  
Jörgen Bierau ◽  
...  
Keyword(s):  
Renal Insufficiency ◽  
Confidence Intervals ◽  
Plasma Clearance ◽  
Asymmetric Dimethylarginine ◽  
Plasma Concentrations ◽  
Minor Importance ◽  
Nitric Oxide Synthase Inhibitor ◽  
Hypertensive Patients ◽  
Plasma Adma ◽  
Moderate Renal Insufficiency

Plasma concentrations of the nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) increase already in the early stages of renal insufficiency. There is no agreement as to whether reduced renal plasma clearance (RPCL) contributes to this increase. Therefore, we investigated the relationship between estimated glomerular filtration rate (eGFR), RPCL, and plasma ADMA and SDMA in essential hypertensive patients with mild to moderate renal insufficiency. In 171 patients who underwent renal angiography, we drew blood samples from the aorta and both renal veins and measured mean renal blood flow (MRBF) using the 133Xe washout technique. RPCL was calculated using arteriovenous concentration differences and MRBF. After correction for potential confounders, reduced eGFR was associated with higher plasma ADMA and SDMA [standardized regression coefficient (β) = −0.22 (95% confidence intervals: −0.41, −0.04) and β = −0.66 (95% confidence intervals: −0.83, −0.49), respectively]. However, eGFR was not independently associated with RPCL of ADMA. Moreover, reduced RPCL of ADMA was not associated with higher plasma ADMA. Contrary to ADMA, reduced eGFR was indeed associated with lower RPCL of SDMA [β = 0.21 (95% confidence intervals: 0.02, 0.40)] . In conclusion, our findings indicate that RPCL of ADMA is independent of renal function in hypertensive patients with mild to moderate renal insufficiency. Unlike the case for SDMA, reduced RPCL of ADMA is of minor importance for the increase in plasma ADMA in these patients, which indicates that increased plasma ADMA in this population is not a direct consequence of the kidneys failing as a plasma ADMA-regulating organ.

Effect of acute variations of insulin and glucose on plasma concentrations of asymmetric dimethylarginine in young people with Type 1 diabetes

2008 ◽  
Vol 115 (12) ◽  
pp. 361-369 ◽  
Author(s):  
M. Loredana Marcovecchio ◽  
Barry Widmer ◽  
David B. Dunger ◽  
R. Neil Dalton
Keyword(s):  
Type 1 Diabetes ◽  
Risk Factor ◽  
Young People ◽  
Asymmetric Dimethylarginine ◽  
Plasma Concentrations ◽  
Young Patients ◽  
Glucose Levels ◽  
Significant Fall ◽  
Plasma Adma

ADMA (asymmetric dimethylarginine), an endogenous inhibitor of nitric oxide synthase, is considered a major risk factor for cardiovascular disease and progression of renal disease. In the present study we aim to investigate the effect of acute variations in plasma glucose and insulin on plasma ADMA levels in young people with T1D (Type 1 diabetes). Fifteen young patients (ten males) with T1D, median age 18.3 (13.2–24.4) years, HbA1c (glycated haemoglobin) 9% (6.4–13.6%), underwent an overnight (18:00–08:00 hours) variable insulin infusion for euglycaemia, followed by a hyperinsulinaemic–euglycaemic clamp (08:00–12:00 hours). Blood samples were collected every 15 min for determination of ADMA, SDMA (symmetric dimethylarginine), valine, phenylalanine, arginine, creatinine and glucose. Insulin levels were assessed every 30 min. During the overnight period, glucose levels increased following the evening meal. In response to the protein intake there was a significant increase in ADMA, arginine, valine, phenylalanine and creatinine. For the remaining part of the night, glucose levels progressively decreased reaching 5 mmol/l by 04:00 hours. ADMA and SDMA did not change significantly. During the hyperinsulinaemic clamp, a significant fall in ADMA was observed, from 0.468±0.056 to 0.364±0.050 μmol/l (P<0.001). A significant fall was also found in SDMA, valine, phenylalanine, arginine and the ADMA/SDMA ratio (all P<0.001), but not in creatinine levels. No correlation was found between insulin sensitivity and ADMA. We conclude that acute changes in glycaemia do not significantly affect plasma ADMA levels whereas infusion of insulin significantly reduces ADMA, suggesting an important role for insulin in the regulation of this cardiovascular risk factor.

scholarly journals Pharmacotherapies and their influence on asymmetric dimethylargine (ADMA)

2005 ◽  
Vol 10 (1_suppl) ◽  
pp. S49-S57 ◽  
Author(s):  
Renke Maas
Keyword(s):  
Cardiovascular Disease ◽  
Hormone Replacement ◽  
Plasma Concentrations ◽  
Critical Discussion ◽  
Therapeutic Interventions ◽  
Hypoglycemic Agents ◽  
Vitamin Supplementation ◽  
Nitric Oxide Synthase Inhibitor ◽  
Plasma Adma ◽  
Arginine Residues

Elevated plasma concentrations of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) are found in various clinical settings, including renal failure, coronary heart disease, hypertension, diabetes and pre eclampsia. In healthy people acute infusion of ADMA promotes vascular dysfunc tion, and in mice chronic infusion of ADMA promotes progression of atherosclerosis. Thus, ADMA may not only be a marker but also an active player in cardiovascular disease, which makes it a potential target for therapeutic interventions. This review provides a summary and critical discussion of the presently available data concern ing the effects on plasma ADMA levels of cardiovascular drugs, hypoglycemic agents, hormone replacement therapy, antioxidants, and vitamin supplementation. We assess the evidence that the beneficial effects of drug therapies on vascular func tion can be attributed to modification of ADMA levels. To develop more specific ADMA-lowering therapies, mechanisms leading to elevation of plasma ADMA con centrations in cardiovascular disease need to be better understood. ADMA is formed endogenously by degradation of proteins containing arginine residues that have been methylated by S-adenosylmethionine-dependent methyltransferases (PRMTs). There are two major routes of elimination: renal excretion and enzymatic degrada tion by the dimethylarginine dimethylaminohydrolases (DDAH-1 and -2). Oxidative stress causing upregulation of PRMT expression and/or attenuation of DDAH activity has been suggested as a mechanism and possible drug target in clinical conditions associated with elevation of ADMA. As impairment of DDAH activity or capacity is associated with substantial increases in plasma ADMA concentrations, DDAH is likely to emerge as a prime target for specific therapeutic interventions.

Acceptability of rilmenidine and long-term surveillance of plasma concentrations in hypertensive patients with renal insufficiency

1989 ◽  
Vol 87 (3) ◽  
pp. S41-S45 ◽  
Author(s):  
Robert L. Lins ◽  
Ronald Daelemans ◽  
Max Dratwa ◽  
Dirk Verbeelen ◽  
Jacques Sennesael ◽  
...  
Keyword(s):  
Renal Insufficiency ◽  
Plasma Concentrations ◽  
Hypertensive Patients

Role of the human erythrocyte in generation and storage of asymmetric dimethylarginine

2012 ◽  
Vol 302 (8) ◽  
pp. H1762-H1770 ◽  
Author(s):  
Mariska Davids ◽  
Albert J. van Hell ◽  
Marlieke Visser ◽  
Robert J. Nijveldt ◽  
Paul A. M. van Leeuwen ◽  
...  
Keyword(s):  
Human Erythrocyte ◽  
Asymmetric Dimethylarginine ◽  
Nitric Oxide Synthase Inhibitor ◽  
Plasma Adma ◽  
Erythrocyte Lysis ◽  
Endogenous Nitric Oxide ◽  
Complete Lysis ◽  
Synthase Inhibitor ◽  
Oxide Synthase

Proteolytic activity in whole blood may lead to release of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA). We investigated the role of the human erythrocyte in storage and generation of ADMA in healthy controls ( n = 36) and critically ill patients ( n = 38). Both free and total (sum of free and protein-incorporated) ADMA were measured. Upon incubation of intact erythrocytes with extracellular ADMA (0 to 40 μmol/l), equilibrium between intra- and extracellular ADMA was reached within 3 h. Compared with controls, patients had significantly higher basal concentrations of ADMA in plasma (0.88 ± 0.75 vs. 0.41 ± 0.07 μmol/l) and erythrocytes (1.28 ± 0.55 vs. 0.57 ± 0.14 μmol/l). Intracellular and plasma ADMA were significantly correlated in the patient group only ( r = 0.834). Upon lysis, followed by incubation at 37°C for 2 h, free ADMA increased sevenfold (to 8.60 ± 3.61 μmol/l in patients and 3.90 ± 0.78 μmol/l in controls). In lysates of controls, free ADMA increased further to 9.85 ± 1.35 μmol/l after 18 h. Total ADMA was 15.43 ± 2.44 μmol/l and did not change during incubation. The increase of free ADMA during incubation corresponded to substantial release of ADMA from the erythrocytic protein-incorporated pool (21.9 ± 4.6% at 2 h and 60.8 ± 7.6% at 18 h). ADMA was released from proteins other than hemoglobin, which only occurred after complete lysis and was blocked by combined inhibition of proteasomal and protease activity. Neither intact nor lysed erythrocytes mediated degradation of free ADMA. We conclude that intact erythrocytes play an important role in storage of ADMA, whereas upon erythrocyte lysis large amounts of free ADMA are generated by proteolysis of methylated proteins, which may affect plasma levels in hemolysis-associated diseases.

Plasma Concentrations of Asymmetric Dimethylarginine, an Endogenous Nitric Oxide Synthetase Inhibitor, Are Elevated in Sickle Cell Patients but Do Not Increase during Painful Crises.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3795-3795
Author(s):  
Pearl Landburg ◽  
Tom Teerlink ◽  
Sigrid de Jong ◽  
Frits A. Muskiet ◽  
Ashley J. Duits ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Sickle Cell ◽  
Asymmetric Dimethylarginine ◽  
Plasma Concentrations ◽  
Endothelial Activation ◽  
Healthy Controls ◽  
Asymptomatic Patients ◽  
Plasma Adma ◽  
One Way Anova ◽  
Painful Crisis

Abstract Plasma concentrations of asymmetric dimethylarginine (ADMA), an endogenously produced inhibitor of nitric oxide (NO) synthase, are elevated and related to endothelial activation in clinically asymptomatic patients with sickle cell disease (SCD). However, ADMA concentrations have not been defined during acute vaso-occlusive complications. We determined plasma ADMA and arginine concentrations in 96 samples (40 collected in the clinically asymptomatic state and 56 collected at presentation with a painful crisis) of 44 HbSS patients (mean age 32±13 years, m:f=23:21) and in 39 samples (22 collected in the clinically asymptomatic state and 17 collected at presentation with a painful crisis) of 22 HbSC patients (mean age 30±14 years, m:f=10:12). Thirty-five race, sex and age matched HbAA blood donors served as healthy controls. Plasma ADMA concentrations were elevated in asymptomatic sickle cell patients as compared to healthy controls (HbSS: mean 0.7±0.1 umol/L, HbSC mean 0.5±0.1 umol/L, HbAA mean 0.4±0.1 umol/L; p<0.001 one way ANOVA). Plasma arginine concentrations were lower in asymptomatic HbSS patients as compared to asymptomatic HbSC patients and healthy controls (HbSS: mean 59.6±25.8 umol/L, HbSC mean 75.5±25.8 umol/L, HbAA mean 74.0±27.1 umol/L; p=0.03 one way ANOVA). Ratio’s of ADMA to arginine (ADMA/Arginine × 1000) were highest in HbSS patients (HbSS: mean 16.2±11.6, HbSC mean 7.8±2.9, HbAA mean 6.3±3.2; p=0.001 one way ANOVA). In both HbSS and HbSC patients, neither ADMA (p=0.17/p=0.57), arginine (p=0.13/p=0.18) nor the ADMA/arginine ratio (p=0.88/p=0.08) differed between the asymptomatic phase and at presentation with a painful crisis. In conclusion, even though ADMA is elevated in SCD and therefore may well be involved in the development of chronic organ complications by limiting NO availability, ADMA concentrations are not affected during acute painful sickle cell crises.

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