(Circulation. 1998;98:1842-1847.)
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports |
Asymmetric Dimethylarginine (ADMA): A Novel Risk Factor for Endothelial Dysfunction
Its Role in Hypercholesterolemia
From the Divisions of Cardiovascular Medicine (R.H.B., S.M.B.-B., P.S.T., J.R.C., J.P.C.) and Clinical Pharmacology (O.T., T.F.B.), Stanford University School of Medicine, Stanford, Calif, and Department of Angiology (A.S.), Jaegellonian University, Wroclaw, Poland.
Correspondence to John P. Cooke, MD, PhD, Division of Cardiovascular Medicine, Stanford University School of Medicine, 300 Pasteur Dr, Stanford, CA 94305-5246.
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Background—Asymmetric dimethylarginine (ADMA) is an endogenous competitive inhibitor of nitric oxide (NO) synthase. Because endothelial NO elaboration is impaired in hypercholesterolemia, we investigated whether plasma concentrations of ADMA are elevated in young, clinically asymptomatic hypercholesterolemic adults. We further studied whether such elevation of ADMA levels was correlated with impaired endothelium-dependent, NO-mediated vasodilation and urinary nitrate excretion. In a randomized, double-blind, placebo-controlled study, we investigated whether these changes could be reversed with exogenous L-arginine.
Methods and Results—We measured plasma levels of L-arginine, ADMA, and symmetrical dimethylarginine (SDMA) by high-performance liquid chromatography in 49 hypercholesterolemic (HC) and 31 normocholesterolemic (NC) humans. In 8 HC subjects, endothelium-dependent forearm vasodilation was assessed before and after an intravenous infusion of L-arginine or placebo and compared with 8 NC control subjects. ADMA levels were significantly elevated by >100% (2.17±0.15 versus 1.03±0.09 µmol/L; P<0.05) in HC subjects compared with NC adults. L-Arginine levels were similar, resulting in a significantly decreased L-arginine/ADMA ratio in HC subjects (27.7±2.4 versus 55.7±5.4; P<0.05). In 8 HC subjects, intravenous infusion of L-arginine significantly increased the L-arginine/ADMA ratio and normalized endothelium-dependent vasodilation and urinary nitrate excretion. ADMA levels were inversely correlated with endothelium-mediated vasodilation (R=0.762, P<0.01) and urinary nitrate excretion rates (R=0.534, P<0.01).
Conclusions—We find that ADMA is elevated in young HC individuals. Elevation of ADMA is associated with impaired endothelium-dependent vasodilation and reduced urinary nitrate excretion. This abnormality is reversed by administration of L-arginine. ADMA may be a novel risk factor for endothelial dysfunction in humans.
Key Words: asymmetric dimethylarginine • atherosclerosis • nitric oxide • endothelium-derived factors • vasodilation
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Endothelium-derived nitric oxide (NO) is a potent endogenous vasodilator.1 2 In addition to regulating vascular tone, endothelium-derived NO suppresses vascular smooth muscle proliferation,3 4 inhibits platelet adhesion and aggregation,5 6 and interferes with leukocyte-endothelial cell interaction.7 8 Vascular NO activity is decreased in hypercholesterolemia, leading to impaired endothelium-dependent vasodilation,9 increased platelet aggregability,10 and monocyte adhesiveness for the endothelium.11 This impairment of the NO synthase pathway may contribute to the development and progression of atherosclerosis. Indeed, in animal models of hypercholesterolemia, pharmacological inhibition of NO synthase accelerates atherosclerosis, whereas enhancement of vascular NO activity slows progression of disease and may even induce regression.12 13 14 15 16 17 The mechanism by which hypercholesterolemia leads to an impairment of the L-arginine/NO pathway has remained unclear; however, this defect is reversed by exogenous L-arginine in hypercholesterolemia or atherosclerosis.18 19 20 21 22
Recently, asymmetric dimethylarginine (ADMA) has been characterized as an endogenous, competitive inhibitor of NO synthase.23 Plasma levels of ADMA and its biologically inactive, symmetrical stereoisomer (SDMA) have been shown to be elevated in hypercholesterolemic rabbits.24 25 The elevation in ADMA is associated with reduced activity of NO synthase in this animal model.25 It is unknown if ADMA levels are elevated in hypercholesterolemic (HC) humans before the clinical onset of vascular disease. If so, this might explain in part the endothelial dysfunction in this disorder, which can be detected as reduced endothelium-dependent vasodilation or decreased urinary nitrate excretion.
In the present study, we determined whether ADMA plasma concentrations were elevated in asymptomatic HC human subjects compared with normocholesterolemic (NC) control subjects. We also determined the functional significance of elevated ADMA levels in terms of indexes of endothelial function. Finally, we performed a randomized, double-blind, placebo-controlled study to determine if L-arginine could reverse the perturbation of the NO synthase pathway in these patients.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Subjects
HC subjects (n=49) with no symptoms or signs of atherosclerotic vascular disease (by a complete cardiovascular history and examination, including an ankle-brachial index and an ECG) were recruited from the Stanford University preventive medicine and vascular medicine clinics. Hypercholesterolemia was defined as the presence of fasting total cholesterol levels >220 mg/dL or LDL concentrations >160 mg/dL. HC subjects were compared with a group of age-matched NC control subjects (n=31). None of the subjects were taking lipid-lowering medication. Subjects with a previous history of liver or renal disease or with diabetes mellitus were excluded; all subjects were nonsmokers. Their characteristics and fasting plasma lipid levels are given in the Table
. The study protocol was
approved by the Stanford University Review Board for Human Studies, and
each subject gave written informed consent.
|
Determination of L-Arginine and
Dimethylarginines
Plasma concentrations of L-arginine,
NG,NG'-dimethylarginine
(ADMA), and
NG,NG-dimethylarginine
(SDMA) were measured by high-performance liquid
chromatography (HPLC) and precolumn derivatization with
o-phthaldialdehyde (OPA) by a modification of a previously
published method.15 L-Homoarginine
(10 µmol/L) was added to 0.5 mL of plasma as an internal
standard. Plasma samples and standards were extracted on solid-phase
extraction cartridges (CBA Bond Elut, Varian). Recovery rates
were 82.9±3.8%. Eluates were dried over nitrogen and resuspended in
double-distilled water for HPLC analysis. HPLC was performed on
a computer-controlled Varian Star chromatography system
consisting of a ternary gradient HPLC pump (Varian 9010), an automatic
injector with automated sample-reagent mixing capabilities (Varian
9050), and a fluorescence detector (Varian Fluorichrom III).
Samples and standards were incubated for exactly 1 minute with OPA
reagent (5.4 mg/mL OPA in borate buffer, pH 8.4, containing 0.4%
2-mercaptoethanol) before automatic injection into the HPLC. The OPA
derivatives of L-arginine, ADMA, and SDMA were separated on
a 250x4.5-mm-ID 7-µm Nucleosil phenyl column (Supelco) with the
fluorescence detector set at 
ex=340 nm
and em=450 nm. Samples were eluted from the
column with 0.96% citric acid/methanol (70:30), pH 6.8, at a flow rate
of 1 mL/min. Variability of the method was < 7%, and the
detection limit of the assay was 0.15 µmol/L.
Biochemical Analyses
Urinary nitrate excretion was determined by use of a
commercially available chemiluminescence apparatus (Dasibi
Corp) as previously described.13 Fasting lipid
levels and creatinine concentrations were determined in
plasma samples drawn into sodium EDTA by the Stanford University
Hospital Laboratory using standard laboratory methods.
Creatinine clearance was calculated either from plasma and
urinary creatinine concentrations or according to the
method of Cockroft and Gault26 when urine samples
were not available. Total cholesterol, HDL, and
triglyceride concentrations were measured with an Abbott
Spectrum II autoanalyzer. LDL concentrations were calculated
according to the Friedewald formula.27
L-Arginine Infusion and Forearm Blood Flow
Measurement
In 8 HC subjects (4 men, 4 women), the effects of acute
intravenous infusion of L-arginine or vehicle
on the plasma L-arginine/ADMA ratio, urinary nitrate
excretion, and endothelium-dependent, NO-mediated
vasodilation were studied in a double-blind, randomized,
placebo-controlled crossover study. The subjects received, in a
randomized sequence on 2 experimental days separated by 1 week, a
single intravenous infusion of 14 g of
L-arginine (
10 mg/kg of body weight) or the
corresponding placebo (0.9% saline) over 20 minutes. Flow-induced
vasodilation was assessed as the increase in brachial artery diameter
in response to augmented flow elicited by 3 minutes of vascular
occlusion.21 It has been previously
shown28 that flow-induced vasodilation in the
human brachial artery is largely due to the endothelial
elaboration of NO. Brachial artery blood flow and diameter were
measured by duplex ultrasonography (Hewlett-Packard 2500, 7.5-MHz
transducer with 5.5-MHz pulsed Doppler) before and immediately
after infusion. Venous plasma samples were drawn before and 2 minutes
after the infusion for measurement of L-arginine and
dimethylarginine concentrations. Urine samples were collected in the
period 1 hour before and the period 1 hour after the start of the
infusion to assess urinary nitrate excretion as an index of systemic NO
production. Urinary dimethylarginine clearances were calculated
from plasma and urinary concentrations of ADMA and SDMA. Basal
measurements of flow-dependent brachial artery vasodilation and urinary
nitrate excretion were also made in a group of 8 NC control subjects (4
men, 4 women).
Calculations and Statistical Analyses
All data are given as mean±SEM. Differences between HC and NC
subjects as well as the effects of L-arginine versus
vehicle administration were tested for statistical significance by
ANOVA followed by Fisher's protected least significant difference
test. Linear regression curves and correlation coefficients were
calculated according to the least squares method. Statistical
significance was assumed for P<0.05.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Baseline Plasma L-Arginine and Dimethylarginine Concentrations
Plasma L-arginine concentrations were 52.4±5.4 µmol/L in HC subjects and 49.8±4.2 µmol/L in NC control subjects (P=NS). HC subjects had significantly higher ADMA plasma levels than NC control subjects (2.17±0.15 and 1.03±0.09 µmol/L, respectively; P<0.05). More than half of the HC subjects studied had ADMA levels >2 SDs above the mean value in the NC control group (Figure 1A
). SDMA plasma concentrations were not
different in HC than in NC subjects (0.73±0.10 and 0.60±0.09
µmol/L, respectively; P=NS). Elevation of ADMA plasma
concentrations resulted in a lower mean L-arginine/ADMA
ratio in HC subjects than in NC subjects (27.7±2.4 versus 55.7±5.4;
P<0.05; Figure 1B).
|
Lipid profiles and creatinine clearances for both groups
are given in the Table
. There was a positive correlation between plasma
LDL cholesterol and ADMA concentrations
(R=0.421, P<0.01; Figure 2) and between plasma total
cholesterol and ADMA concentrations (R=0.372,
P<0.01) but not between creatinine clearances
and ADMA concentrations (R=0.113, P=0.402).
|
Perturbation of the NO Synthase Pathway in
Hypercholesterolemia
Baseline flow-induced brachial artery vasodilation was 2.7±1.8%
in 8 HC subjects compared with 9.8±1.0% in NC control subjects
(P<0.01). Plasma ADMA levels were significantly higher in
these HC subjects than in NC control subjects (2.2±0.2 and
0.9±0.1 µmol/L, respectively; P<0.05), whereas
L-arginine concentrations did not differ significantly
(36.8±3.0 and 34.8±3.6 µmol/L, respectively; P=NS).
Urinary nitrate excretion was lower in HC than in NC subjects at
baseline (124.0±14.1 versus 205.8±12.1 µmol/mmol
creatinine; P<0.05).
In multiple regression analysis, baseline flow-induced
vasodilation was inversely correlated with plasma ADMA levels
(R=0.762, P<0.01; Figure 3A), whereas total
cholesterol, LDL cholesterol, HDL
cholesterol, triglycerides, age, and blood
pressure were not independent predictors of
endothelium-dependent, NO-mediated vasodilation.
Urinary nitrate excretion was also inversely correlated with plasma
ADMA levels (R=0.534, P<0.01; Figure 3B).
|
Significant amounts of ADMA and SDMA were found in urine. In HC subjects, renal ADMA and SDMA clearances were 14.6±2.7 and 48.0±6.5 mL/min, respectively, compared with 18.4±2.9 and 51.7±7.7 mL/min, respectively, in NC control subjects (P=NS).
Effects of Intravenous L-Arginine Infusion
in HC Subjects
L-Arginine infusion increased plasma
L-arginine concentrations to 4843.9±233.5 µmol/L
without significantly changing ADMA levels (2.2±0.2 µmol/L).
This resulted in improved flow-induced vasodilation in each of the 8
subjects (mean, 8.6±2.2%; Figure 4A).
In contrast, placebo infusion did not affect plasma
L-arginine or ADMA concentrations (36.3±3.1 and
2.1±0.1 µmol/L, respectively; each P=NS versus
baseline), nor did it improve flow-induced vasodilation (mean,
3.5±2.5%; P=NS versus baseline; Figure 4B). Urinary
nitrate excretion increased after L-arginine infusion but
not after placebo infusion (P<0.05; Figure 5). Infusion of L-arginine or
placebo did not affect renal clearances of ADMA
(L-arginine, 17.2±3.4 mL/min; placebo, 15.8±7.3 mL/min)
or SDMA (L-arginine, 57.5±8.8 mL/min; placebo, 49.9±8.5
mL/min), nor did the infusions influence creatinine
clearance.
|
|
P<0.05 vs
control. |
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Our study shows for the first time that plasma concentrations of ADMA, an endogenous competitive inhibitor of NO synthesis, are elevated in asymptomatic HC humans compared with NC control subjects. This is associated with impaired endothelium-dependent, NO-mediated vasodilation in the brachial artery and reduced urinary nitrate excretion. Intravenous infusion of L-arginine reverses the endothelial dysfunction. The improvement in endothelial vasodilator function is likely due to the metabolism of L-arginine to NO, as reflected by an increase in urinary nitrate excretion.
Previous studies have shown that endothelial vasodilator function is impaired in HC humans, even in the absence of overt atherosclerotic vascular disease. The maximal increase in forearm blood flow in response to intra-arterial acetylcholine is reduced in young HC humans,9 as is flow-induced vasodilation during the hyperemic response after transient arterial occlusion.29 Joannides and coworkers28 have previously shown that flow-induced vasodilation in the human brachial artery is blocked by intra-arterial infusion of NG-monomethyl-L-arginine (L-NMMA), indicating that flow-induced vasodilation is NO dependent. The degree of impairment of endothelium-dependent vasodilator function is related to the number of cardiovascular risk factors present,30 among which the plasma LDL cholesterol level may be one of the most important.31 The mechanism(s) leading to this defect may include an increased degradation and/or reduced synthesis of NO.32 33
We found that plasma ADMA levels are doubled in HC humans in association with evidence of reduced NO synthesis. ADMA has been shown to be an endogenous inhibitor of NO synthesis.23 Studies of isolated vessels and cultured endothelial cells suggest that ADMA concentrations between 1 and 10 µmol/L inhibit endothelium-dependent vasodilation and vascular NO synthase activity.34 35 36 This is further corroborated by the present study, which shows an inverse correlation between the L-arginine/ADMA ratio and NO-dependent vasodilation as well as between this ratio and urinary nitrate excretion. The doubling of ADMA plasma concentrations in HC subjects may reflect an even greater level of this endogenous NO synthase inhibitor within endothelial cells. In experimental models of vascular injury, there is attenuated endothelium-dependent vasodilation even after the intimal lining has been fully regenerated.37 Recently, it has been shown that in regenerated endothelial cells, levels of ADMA (as well as another NO synthase inhibitor, L-monomethyl-arginine) are elevated 3-fold compared with normal cells.38
The origin of ADMA in hypercholesterolemia is currently unclear. Data from metabolism studies in animals suggest that dimethylarginines derive from the degradation of methylated proteins.39 Increased endogenous formation, impaired metabolic degradation, or reduced clearance of ADMA may cause its increased plasma levels. Dimethylarginines have been shown to be excreted via the kidneys and to accumulate in chronic renal failure.40 In the present study, however, there was no evidence of impaired renal function in our subjects. Moreover, direct measurement of renal ADMA and SDMA clearances revealed no significant difference compared with NC control subjects. ADMA is metabolized to citrulline by the enzyme dimethylarginine dimethylaminohydrolase (DDAH).41 Inhibition of DDAH causes a gradual vasoconstriction of vascular segments, which is reversed by L-arginine.42 This latter finding suggests that ADMA may be an endogenous modulator of NO synthase activity. Whether hypercholesterolemia affects this metabolic pathway or whether another pathway is involved in the hypercholesterolemia-induced accumulation of ADMA remains undetermined.
Administration of L-arginine has been shown to reverse endothelial dysfunction in HC rabbits.12 15 In HC humans, intravenous or oral administration of L-arginine improves endothelium-dependent, acetylcholine-induced vasodilation.20 21 22 A vasodilator effect of intravenous L-arginine has also been observed in patients with severe peripheral arterial occlusive disease.43 Taken together with these previous studies, our observations indicate that exogenous L-arginine may compete with the endogenous NO synthase inhibitor ADMA to restore NO synthesis. This interaction between L-arginine and ADMA is likely a direct competition for the NO synthase enzyme, because L-arginine infusion did not affect renal ADMA clearance.
We speculate that ADMA may represent a novel risk factor for atherosclerosis. In HC rabbits, long-term oral administration of L-arginine restores endothelial elaboration of NO, reduces endothelial adhesiveness for monocytes, inhibits platelet aggregation, retards atherogenesis, and even induces regression of preexisting lesions.12 13 15 16 17 18 19 20 21 22 44 By contrast, long-term antagonism of NO synthase accelerates atherogenesis in animal models.13 14 16 45 Recently, it has been observed that ADMA levels are correlated with the severity of disease in patients with peripheral arterial disease.46
In conclusion, the present study shows that the plasma concentration of ADMA, an endogenous competitive inhibitor of NO synthesis, is elevated in HC humans. Elevated ADMA concentrations are associated with impaired endothelium-dependent, NO-mediated vasodilation and reduced urinary nitrate excretion. These effects of ADMA are counteracted by administration of the NO precursor, L-arginine. ADMA may be a determinant of endothelial vasodilator dysfunction and a novel risk factor for atherosclerosis.
|
Acknowledgments |
|---|
This work was supported in part by a grant from the National Heart, Lung, and Blood Institute (1R01-HL-58638). Dr Böger is the recipient of a postdoctoral grant from the Boehringer Ingelheim foundation. Dr Bode-Böger received a postdoctoral grant from the Deutsche Forschungsgemeinschaft. Dr Tsao is the recipient of a National Service Research Award (1F32-HL-08779). Dr Cooke is an Established Investigator of the American Heart Association. The authors thank Michelle Rhodes and Barb Anderson for their excellent technical assistance.
Received April 22, 1998; accepted July 2, 1998.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980;288:373–376.[Medline] [Order article via Infotrieve]
2. Palmer RMJ, Ferrige AG, Moncada S. Nitric oxide accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987;327:524–526.[Medline] [Order article via Infotrieve]
3. Garg UC, Hassid A. Nitric oxide-generating vasodilators and 8-bromo-cyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J Clin Invest. 1989;83:1774–1777.
4.
von der Leyen HE, Gibbons GH, Morishita R, Lewis NP,
Zhang L, Nakajima M, Kaneda Y, Cooke JP, Dzau VJ. Gene therapy
inhibiting neointimal vascular lesion: in vivo transfer of
endothelial cell nitric oxide synthase gene. Proc
Natl Acad Sci U S A. 1995;92:1137–1141.
5.
Stamler JS, Mendelsohn ME, Amarante P, Smick D, Andon
N, Davies PF, Cooke JP, Loscalzo J. N-Acetylcysteine
potentiates platelet inhibition by
endothelium-derived relaxing factor. Circ
Res. 1989;65:789–795.
6. Radomski MW, Palmer RMJ, Moncada S. Endogenous nitric oxide inhibits human platelet adhesion to vascular endothelium. Lancet. 1987;2:1057–1058.[Medline] [Order article via Infotrieve]
7.
Bath PMW, Hassal DG, Gladwin AM, Palmer RM, Martin JF.
Nitric oxide and prostacyclin: divergence of inhibitory
effects on monocyte chemotaxis and adhesion to
endothelium in vitro. Arterioscler Thromb. 1991;11:254–260.
8. Kubes P, Suzuki M, Granger DN. Nitric oxide: an endogenous modulator of leukocyte adhesion. Proc Natl Acad Sci U S A. 1991;8:4651–4655.
9. Creager MA, Cooke JP, Mendelsohn ME, Gallagher SJ, Coleman SM, Loscalzo J, Dzau VJ. Impaired vasodilation of forearm resistance vessels in hypercholesterolemic humans. J Clin Invest. 1990;86:228–234.
10. Wolf A, Zalpour C, Theilmeier G, Wang BY, Ma A, Anderson B, Tsao PS, Cooke JP. Dietary L-arginine supplementation normalizes platelet aggregation in hypercholesterolemic humans. J Am Coll Cardiol. 1997;29:479–485.[Abstract]
11.
Theilmeier G, Chan JR, Zalpour C, Anderson B, Wang BY,
Wolf A, McEvoy LM, Butcher EC, Tsao PS, Cooke JP. Adhesiveness of
mononuclear cells in hypercholesterolemic humans is
normalized by dietary L-arginine. Arterioscler Thromb
Vasc Biol. 1997;17:3557–3564.
12. Cooke JP, Singer AH, Tsao P, Zera P, Rowan RA, Billingham ME. Antiatherosclerotic effects of L-arginine in the hypercholesterolemic rabbit. J Clin Invest. 1992;90:1168–1172.
13.
Tsao PS, McEvoy LM, Drexler H, Butcher EC, Cooke JP.
Enhanced endothelial adhesiveness in
hypercholesterolemia is attenuated by
L-arginine. Circulation. 1994;89:2176–2182.
14.
Cayatte AJ, Palacino JJ, Horten K, Cohen RA. Chronic
inhibition of nitric oxide production accelerates
neointima formation and impairs endothelial
function in hypercholesterolemic rabbits.
Arterioscler Thromb. 1994;14:753–759.
15. Böger RH, Bode-Böger SM, Mügge A, Kienke S, Brandes R, Dwenger A, Frölich JC. Supplementation of hypercholesterolaemic rabbits with L-arginine reduces the vascular release of superoxide anions and restores NO production. Atherosclerosis. 1995;117:273–284.[Medline] [Order article via Infotrieve]
16.
Aji W, Ravalli S, Szabolcs M, Jiang YC, Sciacca RR,
Michler RE, Cannon PJ. L-Arginine prevents xanthoma
development and inhibits atherosclerosis in LDL
receptor knockout mice. Circulation. 1997;95:430–437.
17.
Candipan RC, Wang BY, Buitrago R, Tsao PS, Cooke JP.
Regression or progression: dependency on vascular nitric oxide.
Arterioscler Thromb Vasc Biol. 1996;16:44–50.
18.
Cooke JP, Andon NA, Girerd XJ, Hirsch AT, Creager MA.
Arginine restores cholinergic relaxation of
hypercholesterolemic rabbit thoracic aorta.
Circulation. 1991;83:1057–1062.
19. Drexler H, Zeiher AM, Meinzer K, Just H. Correction of endothelial dysfunction in coronary microcirculation of hypercholesterolaemic patients by L-arginine. Lancet. 1991;338:1546–1550.[Medline] [Order article via Infotrieve]
20. Creager MA, Gallagher SJ, Girerd XJ, Coleman SM, Dzau VJ, Cooke JP. L-Arginine improves endothelium-dependent vasodilation in hypercholesterolemic humans. J Clin Invest. 1992;90:1248–1253.
21. Clarkson P, Adams MR, Powe AJ, Donald AE, McCredie R, Robinson J, McCarthy SN, Keech A, Celermajer DS, Deanfield JE. Oral L-arginine improves endothelium-dependent dilation in hypercholesterolemic young adults. J Clin Invest. 1996;97:1989–1994.[Medline] [Order article via Infotrieve]
22.
Drexler H, Fischell TA, Pinto FJ, Chenzbraun A, Botas
J, Cooke JP, Alderman EL. Effect of L-arginine on
coronary endothelial function in cardiac
transplant recipients: relation to vessel wall morphology.
Circulation. 1994;89:1615–1623.
23. Vallance P, Leone A, Calver A, Collier J, Moncada S. Endogenous dimethylarginine as an inhibitor of nitric oxide synthesis. J Cardiovasc Pharmacol. 1992;20(suppl 12):S60–S62.
24. Yu X, Li Y, Xiong Y. Increase of an endogenous inhibitor of nitric oxide synthesis in serum of high cholesterol fed rabbits. Life Sci. 1994;54:753–758.[Medline] [Order article via Infotrieve]
25. Bode-Böger SM, Böger RH, Kienke S, Junker W, Frölich JC. Elevated L-arginine/dimethylarginine ratio contributes to enhanced systemic NO production by dietary L-arginine in hypercholesterolemic rabbits. Biochem Biophys Res Commun. 1996;219:598–603.[Medline] [Order article via Infotrieve]
26. Cockroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31–41.[Medline] [Order article via Infotrieve]
27. Friedewald WT, Levi RI, Fredrickson DS. Estimation of the concentration of low density lipoprotein cholesterol in the plasma without the use of the preparative ultracentrifuge. Clin Chem. 1958;18:499–502.[Abstract]
28.
Joannides R, Haefeli WE, Linder L, Richard V, Bakkali
EH, Thuillez C, Lüscher TF. Nitric oxide is responsible for
flow-dependent dilatation of human peripheral conduit
arteries in vivo. Circulation. 1995;91:1314–1319.
29. Celermajer DS, Sorensen KE, Gooch VM, Spiegelhalter DJ, Miller OI, Sullivan ID, Lloyd JK, Deanfield JE. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet. 1992;340:1111–1115.[Medline] [Order article via Infotrieve]
30. Celermajer DS, Sorensen KE, Bull C, Robinson J, Deanfield JE. Endothelium-dependent dilation in the systemic arteries of asymptomatic subjects related to coronary risk factors and their interaction. J Am Coll Cardiol. 1994;24:1468–1474.[Abstract]
31. Arcaro G, Zenere BM, Travia D, Zenti MG, Covi G, Lechi A, Muggeo M. Noninvasive detection of early endothelial dysfunction in hypercholesterolemic subjects. Atherosclerosis. 1995;114:247–254.[Medline] [Order article via Infotrieve]
32. Minor RL, Myers PR, Guerra R Jr, Bates JN, Harrison DG. Diet-induced atherosclerosis increases the release of nitrogen oxides from rabbit aorta. J Clin Invest. 1990;86:2109–2116.
33. Cooke JP, Dzau VJ. Nitric oxide synthase: role in the genesis of vascular disease. Annu Rev Med. 1997;48:489–509.[Medline] [Order article via Infotrieve]
34.
Kurose I, Wolf R, Grisham MB, Granger DN. Effects of an
endogenous inhibitor of nitric oxide synthesis
on postcapillary venules. Am J Physiol. 1995;268:H2224–H2231.
35.
Faraci FM, Brian JE, Heistad DD. Response of cerebral
blood vessels to an endogenous inhibitor of
nitric oxide synthase. Am J Physiol. 1995;269:H1522–H1527.
36. Fickling SA, Leone AM, Nussey SS, Vallance P, Moncada S. Synthesis of NG,NG-dimethylarginine by human endothelial cells. Endothelium. 1993;1:137–140.
37.
Weidinger FF, McLenachan JM, Cybulsky MI, Gordon JB,
Rennke HG, Hollenberg NK, Fallon JT, Ganz P, Cooke JP. Persistent
dysfunction of regenerated endothelium after balloon
angioplasty of rabbit iliac artery. Circulation. 1990;81:1667–1679.
38. Azumi H, Sato J, Hamasaki H, Sugimoto A, Isotani E, Obayashi S. Accumulation of endogenous inhibitors for nitric oxide synthesis and decreased content of L-arginine in regenerated endothelial cells. Br J Pharmacol. 1995;115:1001–1004.[Medline] [Order article via Infotrieve]
39. McDermott JR. Studies on the catabolism of NG-methylarginine, NG,N'G-dimethylarginine and NG,NG-dimethylarginine in the rabbit. Biochem J. 1976;154:179–184.[Medline] [Order article via Infotrieve]
40. Vallance P, Leone A, Calver A, Collier J, Moncada S. Accumulation of an endogenous inhibitor of NO synthesis in chronic renal failure. Lancet. 1992;339:572–575.[Medline] [Order article via Infotrieve]
41. MacAllister RJ, Fickling SA, Whitley GSJ, Vallance P. Metabolism of methylarginines by human vasculature: implications for the regulation of nitric oxide synthesis. Br J Pharmacol. 1994;112:43–48.[Medline] [Order article via Infotrieve]
42. MacAllister RJ, Parry H, Kimoto M, Ogawa T, Russell RJ, Hodson H, Whitley GSJ, Vallance P. Regulation of nitric oxide synthesis by dimethylarginine dimethylaminohydrolase. Br J Pharmacol. 1996;119:1533–1540.[Medline] [Order article via Infotrieve]
43.
Bode-Böger SM, Böger RH, Alfke H, Heinzel
D, Tsikas D, Creutzig A, Alexander K, Frölich JC.
L-Arginine induces nitric oxide–dependent vasodilation in
patients with critical limb ischemia: a randomized, controlled
study. Circulation. 1996;93:85–90.
44.
Tsao PS, Theilmeier G, Singer AH, Leung LLK, Cooke JP.
L-Arginine attenuates platelet reactivity in
hypercholesterolemic rabbits. Arterioscler
Thromb. 1994;14:1529–1533.
45.
Naruse K, Shimizu K, Muramatsu M, Toki Y, Miyazaki Y,
Okumura K, Hashimoto H, Ito T. Long-term inhibition of NO synthesis
promotes atherosclerosis in the
hypercholesterolemic rabbit thoracic aorta.
Arterioscler Thromb. 1994;14:746–752.
46.
Böger RH, Bode-Böger SM, Thiele W, Junker
W, Alexander K, Frölich JC. Biochemical evidence for impaired
nitric oxide synthesis in patients with peripheral
arterial occlusive disease. Circulation. 1997;95:2068–2074.
This article has been cited by other articles:
 |
|
 |
|
  Z. Wang, W. H. W. Tang, L. Cho, D. M. Brennan, and S. L. Hazen Targeted Metabolomic Evaluation of Arginine Methylation and Cardiovascular Risks: Potential Mechanisms Beyond Nitric Oxide Synthase Inhibition Arterioscler Thromb Vasc Biol, September 1, 2009; 29(9): 1383 - 1391. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Pikula, R. H. Boger, A. S. Beiser, R. Maas, C. DeCarli, E. Schwedhelm, J. J. Himali, F. Schulze, R. Au, M. Kelly-Hayes, et al. Association of Plasma ADMA Levels With MRI Markers of Vascular Brain Injury: Framingham Offspring Study Stroke, September 1, 2009; 40(9): 2959 - 2964. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. J Maxwell, J. Niebauer, P. S Lin, P. S Tsao, D. Bernstein, and J. P Cooke Hypercholesterolemia impairs exercise capacity in mice Vascular Medicine, August 1, 2009; 14(3): 249 - 257. [Abstract] [PDF]
|
|
|
|
 |
|
 J. G Ayer, J. A Harmer, W. Xuan, B. Toelle, K. Webb, C. Almqvist, G. B Marks, and D. S Celermajer Dietary supplementation with n-3 polyunsaturated fatty acids in early childhood: effects on blood pressure and arterial structure and function at age 8 y Am. J. Clinical Nutrition, August 1, 2009; 90(2): 438 - 446. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Schwedhelm, V. Xanthakis, R. Maas, L. M. Sullivan, F. Schulze, U. Riederer, R. A. Benndorf, R. H. Boger, and R. S. Vasan Asymmetric Dimethylarginine Reference Intervals Determined with Liquid Chromatography-Tandem Mass Spectrometry: Results from the Framingham Offspring Cohort Clin. Chem., August 1, 2009; 55(8): 1539 - 1545. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Maas, V. Xanthakis, J. F. Polak, E. Schwedhelm, L. M. Sullivan, R. Benndorf, F. Schulze, R. S. Vasan, P. A. Wolf, R. H. Boger, et al. Association of the Endogenous Nitric Oxide Synthase Inhibitor ADMA With Carotid Artery Intimal Media Thickness in the Framingham Heart Study Offspring Cohort Stroke, August 1, 2009; 40(8): 2715 - 2719. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Turiel, F. Atzeni, L. Tomasoni, S. de Portu, L. Delfino, B. D. Bodini, M. Longhi, S. Sitia, M. Bianchi, P. Ferrario, et al. Non-invasive assessment of coronary flow reserve and ADMA levels: a case-control study of early rheumatoid arthritis patients Rheumatology, July 1, 2009; 48(7): 834 - 839. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W.H. W. Tang, Z. Wang, L. Cho, D. M. Brennan, and S. L. Hazen Diminished global arginine bioavailability and increased arginine catabolism as metabolic profile of increased cardiovascular risk. J. Am. Coll. Cardiol., June 2, 2009; 53(22): 2061 - 2067. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Hanai, T. Babazono, I. Nyumura, K. Toya, N. Tanaka, M. Tanaka, A. Ishii, and Y. Iwamoto Asymmetric dimethylarginine is closely associated with the development and progression of nephropathy in patients with type 2 diabetes Nephrol. Dial. Transplant., June 1, 2009; 24(6): 1884 - 1888. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. G. Ayer, J. A. Harmer, S. Nakhla, W. Xuan, M. K.C. Ng, O. T. Raitakari, G. B. Marks, and D. S. Celermajer HDL-Cholesterol, Blood Pressure, and Asymmetric Dimethylarginine Are Significantly Associated With Arterial Wall Thickness in Children Arterioscler Thromb Vasc Biol, June 1, 2009; 29(6): 943 - 949. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Young, N. Terrin, X. Wang, T. Greene, G. J. Beck, J. W. Kusek, A. J. Collins, M. J. Sarnak, and V. Menon Asymmetric Dimethylarginine and Mortality in Stages 3 to 4 Chronic Kidney Disease Clin. J. Am. Soc. Nephrol., June 1, 2009; 4(6): 1115 - 1120. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. H. Boger, L. M. Sullivan, E. Schwedhelm, T. J. Wang, R. Maas, E. J. Benjamin, F. Schulze, V. Xanthakis, R. A. Benndorf, and R. S. Vasan Plasma Asymmetric Dimethylarginine and Incidence of Cardiovascular Disease and Death in the Community Circulation, March 31, 2009; 119(12): 1592 - 1600. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Unal, M. Sipahioglu, F. Oguz, M. Kaya, H. Kucuk, B. Tokgoz, H. Buyukoglan, O. Oymak, and C. Utas PULMONARY HYPERTENSION IN PERITONEAL DIALYSIS PATIENTS: PREVALENCE AND RISK FACTORS Perit. Dial. Int., March 1, 2009; 29(2): 191 - 198. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. R. Andersen, U. Simonsen, N. Uldbjerg, C. Aalkjaer, and S. Stender Smoking Cessation Early in Pregnancy and Birth Weight, Length, Head Circumference, and Endothelial Nitric Oxide Synthase Activity in Umbilical and Chorionic Vessels: An Observational Study of Healthy Singleton Pregnancies Circulation, February 17, 2009; 119(6): 857 - 864. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N.-z. Lei, X.-y. Zhang, H.-z. Chen, Y. Wang, Y.-y. Zhan, Z.-h. Zheng, Y.-m. Shen, and Q. Wu A feedback regulatory loop between methyltransferase PRMT1 and orphan receptor TR3 Nucleic Acids Res., February 1, 2009; 37(3): 832 - 848. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Wang, S. Strandgaard, J. Iversen, and C. S. Wilcox Asymmetric dimethylarginine, oxidative stress, and vascular nitric oxide synthase in essential hypertension Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2009; 296(2): R195 - R200. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.-C. Wu, S.-C. Wen, C.-W. Yang, S.-Y. Pu, K.-C. Tsai, and J.-W. Chen Plasma ADMA Predicts Restenosis of Arteriovenous Fistula J. Am. Soc. Nephrol., January 1, 2009; 20(1): 213 - 222. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Siekmeier, T. Grammer, and W. Marz Roles of Oxidants, Nitric Oxide, and Asymmetric Dimethylarginine in Endothelial Function Journal of Cardiovascular Pharmacology and Therapeutics, December 1, 2008; 13(4): 279 - 297. [Abstract] [PDF]
|
|
|
|
 |
|
 M. C. Richir, R. H. Bouwman, T. Teerlink, M. P.C. Siroen, T. P.G.M. de Vries, and P. A.M. van Leeuwen The Prominent Role of the Liver in the Elimination of Asymmetric Dimethylarginine (ADMA) and the Consequences of Impaired Hepatic Function JPEN J Parenter Enteral Nutr, November 1, 2008; 32(6): 613 - 621. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Galle, E. Schwedhelm, S. Pinnetti, R. H. Boger, C. Wanner, and on behalf of the VIVALDI investigators Antiproteinuric effects of angiotensin receptor blockers: telmisartan versus valsartan in hypertensive patients with type 2 diabetes mellitus and overt nephropathy Nephrol. Dial. Transplant., October 1, 2008; 23(10): 3174 - 3183. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Kobayashi, M. Oka, K. Maesato, R. Ikee, T. Mano, M. Hidekazu, and T. Ohtake Coronary Artery Calcification, ADMA, and Insulin Resistance in CKD Patients Clin. J. Am. Soc. Nephrol., September 1, 2008; 3(5): 1289 - 1295. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Dayal, R. N. Rodionov, E. Arning, T. Bottiglieri, M. Kimoto, D. J. Murry, J. P. Cooke, F. M. Faraci, and S. R. Lentz Tissue-specific downregulation of dimethylarginine dimethylaminohydrolase in hyperhomocysteinemia Am J Physiol Heart Circ Physiol, August 1, 2008; 295(2): H816 - H825. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Ellger, M. C. Richir, P. A. M. van Leeuwen, Y. Debaveye, L. Langouche, I. Vanhorebeek, T. Teerlink, and G. Van den Berghe Glycemic Control Modulates Arginine and Asymmetrical-Dimethylarginine Levels during Critical Illness by Preserving Dimethylarginine-Dimethylaminohydrolase Activity Endocrinology, June 1, 2008; 149(6): 3148 - 3157. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. R. Archer, J. K. Stiles, G. W. Newman, A. Quarshie, L. L. Hsu, P. Sayavongsa, J. Perry, E. M. Jackson, and J. M. Hibbert C-Reactive Protein and Interleukin-6 Are Decreased in Transgenic Sickle Cell Mice Fed a High Protein Diet J. Nutr., June 1, 2008; 138(6): 1148 - 1152. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Leong, D. Zylberstein, I. Graham, L. Lissner, D. Ward, J. Fogarty, C. Bengtsson, C. Bjorkelund, D. Thelle, and for The Swedish-Irish-Norwegian (SIN) Collaboratio Asymmetric Dimethylarginine Independently Predicts Fatal and Nonfatal Myocardial Infarction and Stroke in Women: 24-Year Follow-Up of the Population Study of Women in Gothenburg Arterioscler Thromb Vasc Biol, May 1, 2008; 28(5): 961 - 967. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Heutling, H. Schulz, I. Nickel, J. Kleinstein, P. Kaltwasser, S. Westphal, F. Mittermayer, M. Wolzt, K. Krzyzanowska, H. Randeva, et al. Asymmetrical Dimethylarginine, Inflammatory and Metabolic Parameters in Women with Polycystic Ovary Syndrome before and after Metformin Treatment J. Clin. Endocrinol. Metab., January 1, 2008; 93(1): 82 - 90. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. L. Onozato, A. Tojo, J. Leiper, T. Fujita, F. Palm, and C. S. Wilcox Expression of NG,NG-Dimethylarginine Dimethylaminohydrolase and Protein Arginine N-Methyltransferase Isoforms in Diabetic Rat Kidney: Effects of Angiotensin II Receptor Blockers Diabetes, January 1, 2008; 57(1): 172 - 180. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Baylis Nitric oxide deficiency in chronic kidney disease Am J Physiol Renal Physiol, January 1, 2008; 294(1): F1 - F9. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Palm, M. L. Onozato, Z. Luo, and C. S. Wilcox Dimethylarginine dimethylaminohydrolase (DDAH): expression, regulation, and function in the cardiovascular and renal systems Am J Physiol Heart Circ Physiol, December 1, 2007; 293(6): H3227 - H3245. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. J. Nicholls, Z. Wang, R. Koeth, B. Levison, B. DelFraino, V. Dzavik, O. W. Griffith, D. Hathaway, J. A. Panza, S. E. Nissen, et al. Metabolic Profiling of Arginine and Nitric Oxide Pathways Predicts Hemodynamic Abnormalities and Mortality in Patients With Cardiogenic Shock After Acute Myocardial Infarction Circulation, November 13, 2007; 116(20): 2315 - 2324. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Gozal, L. Kheirandish-Gozal, L. D. Serpero, O. Sans Capdevila, and E. Dayyat Obstructive Sleep Apnea and Endothelial Function in School-Aged Nonobese Children: Effect of Adenotonsillectomy Circulation, November 13, 2007; 116(20): 2307 - 2314. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Thum, F. Fleissner, I. Klink, D. Tsikas, M. Jakob, J. Bauersachs, and D. O. Stichtenoth Growth Hormone Treatment Improves Markers of Systemic Nitric Oxide Bioavailability via Insulin-Like Growth Factor-I J. Clin. Endocrinol. Metab., November 1, 2007; 92(11): 4172 - 4179. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Imamura, Y. Waseda, G. V. Marinova, T. Ishibashi, S. Obayashi, A. Sasaki, A. Nagai, and H. Azuma Alterations of NOS, arginase, and DDAH protein expression in rabbit cavernous tissue after administration of cigarette smoke extract Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2007; 293(5): R2081 - R2089. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Santhanam, H. K. Lim, H. K. Lim, V. Miriel, T. Brown, M. Patel, S. Balanson, S. Ryoo, M. Anderson, K. Irani, et al. Inducible NO Synthase Dependent S-Nitrosylation and Activation of Arginase1 Contribute to Age-Related Endothelial Dysfunction Circ. Res., September 28, 2007; 101(7): 692 - 702. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Schnabel and S. Blankenberg Oxidative Stress in Cardiovascular Disease: Successful Translation From Bench to Bedside? Circulation, September 18, 2007; 116(12): 1338 - 1340. [Full Text] [PDF]
|
|
|
|
|
|
M. Juonala, J. S.A. Viikari, G. Alfthan, J. Marniemi, M. Kahonen, L. Taittonen, T. Laitinen, and O. T. Raitakari Brachial Artery Flow-Mediated Dilation and Asymmetrical Dimethylarginine in the Cardiovascular Risk in Young Finns Study Circulation, September 18, 2007; 116(12): 1367 - 1373. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. K Rudolph, K. Ruempler, E. Schwedhelm, J. Tan-Andresen, U. Riederer, R. H Boger, and R. Maas Acute effects of various fast-food meals on vascular function and cardiovascular disease risk markers: the Hamburg Burger Trial Am. J. Clinical Nutrition, August 1, 2007; 86(2): 334 - 340. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Hasegawa, S. Wakino, S. Tatematsu, K. Yoshioka, K. Homma, N. Sugano, M. Kimoto, K. Hayashi, and H. Itoh Role of Asymmetric Dimethylarginine in Vascular Injury in Transgenic Mice Overexpressing Dimethylarginie Dimethylaminohydrolase 2 Circ. Res., July 20, 2007; 101(2): e2 - e10. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. I. Boger, T. K. Rudolph, R. Maas, E. Schwedhelm, E. Dumbadze, A. Bierend, R. A. Benndorf, and R. H. Boger Asymmetric Dimethylarginine Determines the Improvement of Endothelium-Dependent Vasodilation by Simvastatin: Effect of Combination With Oral L-Arginine J. Am. Coll. Cardiol., June 12, 2007; 49(23): 2274 - 2282. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Sasaki, S. Doi, S. Mizutani, and H. Azuma Roles of accumulated endogenous nitric oxide synthase inhibitors, enhanced arginase activity, and attenuated nitric oxide synthase activity in endothelial cells for pulmonary hypertension in rats Am J Physiol Lung Cell Mol Physiol, June 1, 2007; 292(6): L1480 - L1487. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. E. Altinova, M. Arslan, A. Sepici-Dincel, M. Akturk, N. Altan, and F. B. Toruner Uncomplicated Type 1 Diabetes Is Associated with Increased Asymmetric Dimethylarginine Concentrations J. Clin. Endocrinol. Metab., May 1, 2007; 92(5): 1881 - 1885. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. M. Wells and A. Holian Asymmetric Dimethylarginine Induces Oxidative and Nitrosative Stress in Murine Lung Epithelial Cells Am. J. Respir. Cell Mol. Biol., May 1, 2007; 36(5): 520 - 528. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Konishi, K. Sydow, and J. P. Cooke Dimethylarginine Dimethylaminohydrolase Promotes Endothelial Repair After Vascular Injury J. Am. Coll. Cardiol., March 13, 2007; 49(10): 1099 - 1105. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Toth, A. Racz, P. M. Kaminski, M. S. Wolin, Z. Bagi, and A. Koller Asymmetrical Dimethylarginine Inhibits Shear Stress-Induced Nitric Oxide Release and Dilation and Elicits Superoxide-Mediated Increase in Arteriolar Tone Hypertension, March 1, 2007; 49(3): 563 - 568. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Mittermayer, K. Krzyzanowska, M. Exner, W. Mlekusch, J. Amighi, S. Sabeti, E. Minar, M. Muller, M. Wolzt, and M. Schillinger Asymmetric Dimethylarginine Predicts Major Adverse Cardiovascular Events in Patients With Advanced Peripheral Artery Disease Arterioscler Thromb Vasc Biol, November 1, 2006; 26(11): 2536 - 2540. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. O. Yildirim, P. Bulau, D. Zakrzewicz, K. E. Kitowska, N. Weissmann, F. Grimminger, R. E. Morty, and O. Eickelberg Increased Protein Arginine Methylation in Chronic Hypoxia: Role of Protein Arginine Methyltransferases Am. J. Respir. Cell Mol. Biol., October 1, 2006; 35(4): 436 - 443. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. S. Billecke, L. A. Kitzmiller, J. J. Northrup, S. E. Whitesall, M. Kimoto, A. V. Hinz, and L. G. D'Alecy Contribution of whole blood to the control of plasma asymmetrical dimethylarginine Am J Physiol Heart Circ Physiol, October 1, 2006; 291(4): H1788 - H1796. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Hallund, I. Tetens, S. Bugel, T. Tholstrup, M. Ferrari, T. Teerlink, A. Kjaer, and N. Wiinberg Daily Consumption for Six Weeks of a Lignan Complex Isolated from Flaxseed Does Not Affect Endothelial Function in Healthy Postmenopausal Women J. Nutr., September 1, 2006; 136(9): 2314 - 2318. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Matsuguma, S. Ueda, S.-i. Yamagishi, Y. Matsumoto, U. Kaneyuki, R. Shibata, T. Fujimura, H. Matsuoka, M. Kimoto, S. Kato, et al. Molecular Mechanism for Elevation of Asymmetric Dimethylarginine and Its Role for Hypertension in Chronic Kidney Disease J. Am. Soc. Nephrol., August 1, 2006; 17(8): 2176 - 2183. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Leiper and P. Vallance New tricks from an old dog: nitric oxide-independent effects of dimethylarginine dimethylaminohydrolase. Arterioscler Thromb Vasc Biol, July 1, 2006; 26(7): 1419 - 1420. [Full Text] [PDF]
|
|
|
|
 |
|
 J. Menne, J.-K. Park, R. Agrawal, C. Lindschau, J. T. Kielstein, T. Kirsch, A. Marx, D. Muller, F. H. Bahlmann, M. Meier, et al. Cellular and molecular mechanisms of tissue protection by lipophilic calcium channel blockers FASEB J, May 1, 2006; 20(7): 994 - 996. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. Bode-Boger, F. Scalera, J. T. Kielstein, J. Martens-Lobenhoffer, G. Breithardt, M. Fobker, and H. Reinecke Symmetrical Dimethylarginine: A New Combined Parameter for Renal Function and Extent of Coronary Artery Disease J. Am. Soc. Nephrol., April 1, 2006; 17(4): 1128 - 1134. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Martens-Lobenhoffer and S. M. Bode-Boger Fast and Efficient Determination of Arginine, Symmetric Dimethylarginine, and Asymmetric Dimethylarginine in Biological Fluids by Hydrophilic-Interaction Liquid Chromatography-Electrospray Tandem Mass Spectrometry Clin. Chem., March 1, 2006; 52(3): 488 - 493. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Daghini, A. R. Chade, J. D. Krier, D. Versari, A. Lerman, and L. O. Lerman Acute inhibition of the endogenous xanthine oxidase improves renal hemodynamics in hypercholesterolemic pigs Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2006; 290(3): R609 - R615. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Cevik, O. Unay, F. Durmusoglu, T. Yurdun, and A S. Bilsel Plasma markers of NO synthase activity in women after ovarian hyperstimulation: influence of estradiol on ADMA Vascular Medicine, February 1, 2006; 11(1): 7 - 12. [Abstract] [PDF]
|
|
|
|
 |
|
 M. L. Diez-Marques, M. P. Ruiz-Torres, M. Griera, S. Lopez-Ongil, M. Saura, D. Rodriguez-Puyol, and M. Rodriguez-Puyol Arg-Gly-Asp (RGD)-containing peptides increase soluble guanylate cyclase in contractile cells Cardiovasc Res, February 1, 2006; 69(2): 359 - 369. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. P. Schulman, L. C. Becker, D. A. Kass, H. C. Champion, M. L. Terrin, S. Forman, K. V. Ernst, M. D. Kelemen, S. N. Townsend, A. Capriotti, et al. L-Arginine Therapy in Acute Myocardial Infarction: The Vascular Interaction With Age in Myocardial Infarction (VINTAGE MI) Randomized Clinical Trial JAMA, January 4, 2006; 295(1): 58 - 64. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Reimann, J. Dierkes, A. Carlsohn, D. Talbot, M. Ferrari, J. Hallund, W. L. Hall, K. Vafeiadou, U. Huebner, F. Branca, et al. Consumption of Soy Isoflavones Does Not Affect Plasma Total Homocysteine or Asymmetric Dimethylarginine Concentrations in Healthy Postmenopausal Women J. Nutr., January 1, 2006; 136(1): 100 - 105. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. A. Carello, S. E. Whitesall, M. C. Lloyd, S. S. Billecke, and L. G. D'Alecy Asymmetrical dimethylarginine plasma clearance persists after acute total nephrectomy in rats Am J Physiol Heart Circ Physiol, January 1, 2006; 290(1): H209 - H216. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. T. Chan, P. J. Harvey, R. Boger, A. Pierratos, and J. S. Floras Letter to the Editor: Dissociation Between the Short-Term Effects of Nocturnal Hemodialysis on Endothelium Dependent Vasodilation and Plasma ADMA Arterioscler Thromb Vasc Biol, December 1, 2005; 25(12): 2685 - 2686. [Full Text] [PDF]
|
|
|
|
|
|
X. Jiang, F. Yang, H. Tan, D. Liao, R. M. Bryan Jr, J. K. Randhawa, R. E. Rumbaut, W. Durante, A. I. Schafer, X. Yang, et al. Hyperhomocystinemia Impairs Endothelial Function and eNOS Activity via PKC Activation Arterioscler Thromb Vasc Biol, December 1, 2005; 25(12): 2515 - 2521. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Ruano, J. Lopez-Miranda, F. Fuentes, J. A. Moreno, C. Bellido, P. Perez-Martinez, A. Lozano, P. Gomez, Y. Jimenez, and F. Perez Jimenez Phenolic Content of Virgin Olive Oil Improves Ischemic Reactive Hyperemia in Hypercholesterolemic Patients J. Am. Coll. Cardiol., November 15, 2005; 46(10): 1864 - 1868. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. K Oka, A. Szuba, J. C Giacomini, and J. P Cooke A pilot study of l-arginine supplementation on functional capacity in peripheral arterial disease Vascular Medicine, November 1, 2005; 10(4): 265 - 274. [Abstract] [PDF]
|
|
|
|
|
|
J. Martens-Lobenhoffer, S. Westphal, F. Awiszus, S. M. Bode-Boger, and C. Luley Determination of Asymmetric Dimethylarginine: Liquid Chromatography-Mass Spectrometry or ELISA? Clin. Chem., November 1, 2005; 51(11): 2188 - 2189. [Full Text] [PDF]
|
|
|
|
 |
|
 T. Hayashi, P. A. R. Juliet, H. Matsui-Hirai, A. Miyazaki, A. Fukatsu, J. Funami, A. Iguchi, and L. J. Ignarro L-citrulline and L-arginine supplementation retards the progression of high-cholesterol-diet-induced atherosclerosis in rabbits PNAS, September 20, 2005; 102(38): 13681 - 13686. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Tanaka, K. Sydow, F. Gunawan, J. Jacobi, P. S. Tsao, R. C. Robbins, and J. P. Cooke Dimethylarginine Dimethylaminohydrolase Overexpression Suppresses Graft Coronary Artery Disease Circulation, September 13, 2005; 112(11): 1549 - 1556. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. K. Krempl, R. Maas, K. Sydow, T. Meinertz, R. H. Boger, and J. Kahler Elevation of asymmetric dimethylarginine in patients with unstable angina and recurrent cardiovascular events Eur. Heart J., September 2, 2005; 26(18): 1846 - 1851. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I E M Bultink, T Teerlink, J A Heijst, B A C Dijkmans, and A E Voskuyl Raised plasma levels of asymmetric dimethylarginine are associated with cardiovascular events, disease activity, and organ damage in patients with systemic lupus erythematosus Ann Rheum Dis, September 1, 2005; 64(9): 1362 - 1365. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Voisine, J. Li, C. Bianchi, T. A. Khan, M. Ruel, S.-H. Xu, J. Feng, A. Rosinberg, T. Malik, Y. Nakai, et al. Effects of L-Arginine on Fibroblast Growth Factor 2-Induced Angiogenesis in a Model of Endothelial Dysfunction Circulation, August 30, 2005; 112(9_suppl): I-202 - I-207. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Vallance and J. Leiper Asymmetric Dimethylarginine and Kidney Disease--Marker or Mediator? J. Am. Soc. Nephrol., August 1, 2005; 16(8): 2254 - 2256. [Full Text] [PDF]
|
|
|
|
|
|
E. Schwedhelm, J. Tan-Andresen, R. Maas, U. Riederer, F. Schulze, and R. H. Boger Liquid Chromatography-Tandem Mass Spectrometry Method for the Analysis of Asymmetric Dimethylarginine in Human Plasma Clin. Chem., July 1, 2005; 51(7): 1268 - 1271. [Full Text] [PDF]
|
|
|
|
|
|
S. Anthony, J. Leiper, and P. Vallance Endogenous production of nitric oxide synthase inhibitors Vascular Medicine, July 1, 2005; 10(1_suppl): S3 - S9. [Abstract] [PDF]
|
|
|
|
|
|
J. P Cooke ADMA: its role in vascular disease Vascular Medicine, July 1, 2005; 10(1_suppl): S11 - S17. [Abstract] [PDF]
|
|
|
|
|
|
R. H Boger Asymmetric dimethylarginine (ADMA) and cardiovascular disease: insights from prospective clinical trials Vascular Medicine, July 1, 2005; 10(1_suppl): S19 - S25. [Abstract] [PDF]
|
|
|
|
|
|
S. Dayal and S. R Lentz ADMA and hyperhomocysteinemia Vascular Medicine, July 1, 2005; 10(1_suppl): S27 - S33. [Abstract] [PDF]
|
|
|
|
|
|
R. Maas Pharmacotherapies and their influence on asymmetric dimethylargine (ADMA) Vascular Medicine, July 1, 2005; 10(1_suppl): S49 - S57. [Abstract] [PDF]
|
|
|
|
|
|
E. Schwedhelm Quantification of ADMA: analytical approaches Vascular Medicine, July 1, 2005; 10(1_suppl): S89 - S95. [Abstract] [PDF]
|
|
|
|
|
|
R. H Boger, E. Schwedhelm, R. Maas, S. Quispe-Bravo, and C. Skamira ADMA and oxidative stress may relate to the progression of renal disease: rationale and design of the VIVALDI study Vascular Medicine, July 1, 2005; 10(1_suppl): S97 - S102. [Abstract] [PDF]
|
|
|
|
|
|
J. T. Kielstein, S. M. Bode-Boger, G. Hesse, J. Martens-Lobenhoffer, A. Takacs, D. Fliser, and M. M. Hoeper Asymmetrical Dimethylarginine in Idiopathic Pulmonary Arterial Hypertension Arterioscler Thromb Vasc Biol, July 1, 2005; 25(7): 1414 - 1418. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Voisine, C. Bianchi, T. A. Khan, M. Ruel, S.-H. Xu, J. Feng, J. Li, T. Malik, A. Rosinberg, and F. W. Sellke Normalization of coronary microvascular reactivity and improvement in myocardial perfusion by surgical vascular endothelial growth factor therapy combined with oral supplementation of L-arginine in a porcine model of endothelial dysfunction J. Thorac. Cardiovasc. Surg., June 1, 2005; 129(6): 1414 - 1420. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Anthony, J. Leiper, and P. Vallance Endogenous production of nitric oxide synthase inhibitors Vascular Medicine, May 1, 2005; 10(2_suppl): S3 - S9. [Abstract] [PDF]
|
|
|
|
|
|
J. P Cooke ADMA: its role in vascular disease Vascular Medicine, May 1, 2005; 10(2_suppl): S11 - S17. [Abstract] [PDF]
|
|
|
|
|
|
R. H Boger Asymmetric dimethylarginine (ADMA) and cardiovascular disease: insights from prospective clinical trials Vascular Medicine, May 1, 2005; 10(2_suppl): S19 - S25. [Abstract] [PDF]
|
|
|
|
|
|
S. Dayal and S. R Lentz ADMA and hyperhomocysteinemia Vascular Medicine, May 1, 2005; 10(2_suppl): S27 - S33. [Abstract] [PDF]
|
|
|
|
|
|
R. Maas Pharmacotherapies and their influence on asymmetric dimethylargine (ADMA) Vascular Medicine, May 1, 2005; 10(2_suppl): S49 - S57. [Abstract] [PDF]
|
|
|
|
|
|
E. Schwedhelm Quantification of ADMA: analytical approaches Vascular Medicine, May 1, 2005; 10(2_suppl): S89 - S95. [Abstract] [PDF]
|
|
|
|
|
|
R. H Boger, E. Schwedhelm, R. Maas, S. Quispe-Bravo, and C. Skamira ADMA and oxidative stress may relate to the progression of renal disease: rationale and design of the VIVALDI study Vascular Medicine, May 1, 2005; 10(2_suppl): S97 - S102. [Abstract] [PDF]
|
|
|
|
 |
|
 J. Niebauer, A. L. Clark, K. M. Webb-Peploe, R. Boger, and A. J.S. Coats Home-based exercise training modulates pro-oxidant substrates in patients with chronic heart failure Eur J Heart Fail, March 2, 2005; 7(2): 183 - 188. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V Achan, H. Ho, C Heeschen, M Stuehlinger, J. Jang, M Kimoto, P Vallance, and J. Cooke ADMA regulates angiogenesis: genetic and metabolic evidence Vascular Medicine, February 1, 2005; 10(1): 7 - 14. [Abstract] [PDF]
|
|
|
|
|
|
K. Krzyzanowska, F. Mittermayer, H.-P. Kopp, M. Wolzt, and G. Schernthaner Weight Loss Reduces Circulating Asymmetrical Dimethylarginine Concentrations in Morbidly Obese Women J. Clin. Endocrinol. Metab., December 1, 2004; 89(12): 6277 - 6281. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. J. Nijveldt, T. Teerlink, M. P. C. Siroen, B. van der Hoven, H. A. Prins, M. J. Wiezer, C. Meijer, J. R. M. van der Sijp, M. A. Cuesta, S. Meijer, et al. Elevation of Asymmetric Dimethylarginine (ADMA) in Patients Developing Hepatic Failure After Major Hepatectomy JPEN J Parenter Enteral Nutr, November 1, 2004; 28(6): 382 - 387. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Scalera, J. Borlak, B. Beckmann, J. Martens-Lobenhoffer, T. Thum, M. Tager, and S. M. Bode-Boger Endogenous Nitric Oxide Synthesis Inhibitor Asymmetric Dimethyl L-Arginine Accelerates Endothelial Cell Senescence Arterioscler Thromb Vasc Biol, October 1, 2004; 24(10): 1816 - 1822. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Gokce L-Arginine and Hypertension J. Nutr., October 1, 2004; 134(10): 2807S - 2811S. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. H. Boger Asymmetric Dimethylarginine, an Endogenous Inhibitor of Nitric Oxide Synthase, Explains the "L-Arginine Paradox" and Acts as a Novel Cardiovascular Risk Factor J. Nutr., October 1, 2004; 134(10): 2842S - 2847S. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||