© 2000 American Heart Association, Inc.
Brief Review |
Does ADMA Cause Endothelial Dysfunction?
From the Division of Cardiovascular Medicine, Falk Cardiovascular Research Center, Stanford University School of Medicine, Stanford, Calif.
Correspondence to John P. Cooke, MD, PhD, Associate Professor and Director, Section of Vascular Medicine, Division of Cardiovascular Medicine, CVRC, Falk Cardiovascular Research Center, Stanford University School of Medicine, 300 Pasteur Dr, Stanford, CA 94305-5406. E-mail john.cooke{at}stanford.edu
 |
Abstract |
|---|
 Top Abstract NO and Vascular HomeostasisEndothelial Dysfunction Is...ADMA Is an Endogenous...Dysregulation of DDAH: A...Does ADMA Explain the...Is ADMA a Risk...Future DirectionsReferences |
|---|
Abstract—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.
Key Words: arginine • nitric oxide • atherosclerosis • vasodilation
|
NO and Vascular Homeostasis |
|---|
|
TopAbstractNO and Vascular HomeostasisEndothelial Dysfunction Is...ADMA Is an Endogenous...Dysregulation of DDAH: A...Does ADMA Explain the...Is ADMA a Risk...Future DirectionsReferences |
|---|
Endothelium-derived nitric oxide (NO) is the most potent endogenous vasodilator known, exerting its effect via stimulation of soluble guanylate cyclase to produce cyclic GMP.1 2 3 NO is a critical modulator of blood flow and blood pressure.4 5 6 7 It is released by the endothelium in response to shear stress and plays an important role in flow-mediated vasodilation.4 5 Endothelial release of NO opposes the vasoconstrictor effects of norepinephrine, endothelin, angiotensin II, and serotonin.8 Pharmacological inhibition or a genetic deficiency of endothelial NO synthase (NOS) impairs endothelium-dependent vasodilation and increases vascular resistance.6 7 8 9 In patients with coronary artery disease, an impairment of NO activity may contribute to ischemic syndromes.10 11
Vascular NO also influences vascular structure. NO suppresses the proliferation of vascular smooth muscle.12 A chronic deficiency or loss of NO activity may contribute to medial thickening and/or myointimal hyperplasia.13 14 Conversely, treatment with NO donors or gene therapy with NOS reduces lesion formation after vascular injury in animal models.15 16 Furthermore, NO inhibits the interaction of circulating blood elements with the vessel wall. Platelet aggregation and leukocyte adherence are unlikely when the endothelium is healthy.17 18 19 The loss of NO activity accelerates the development of vascular lesions.20 21 A loss of NO activity occurs early in the course of human vascular disease22 23 and is a contributing factor to abnormal vasomotion and ischemic symptoms.10 11 In addition, there is accumulating evidence that the deficit of NO participates in the initiation and progression of atherosclerosis. Intriguingly, very recent data indicate that defective endothelial vasodilator function is predictive of vascular events.24 Accordingly, there is a compelling clinical rationale to understand the mechanisms of endothelial dysfunction.
|
Endothelial Dysfunction Is Multifactorial |
|---|
|
TopAbstractNO and Vascular HomeostasisEndothelial Dysfunction Is...ADMA Is an Endogenous...Dysregulation of DDAH: A...Does ADMA Explain the...Is ADMA a Risk...Future DirectionsReferences |
|---|
The mechanisms of endothelial vasodilator dysfunction are multifactorial and dependent on the nature of the vascular disorder. Because of the multifactorial nature of endothelial dysfunction, therapy targeted at restoring endothelial function must be informed by an understanding of the pathophysiology. Endothelial vasodilator dysfunction may be due to increased vasoconstrictor and/or reduced vasodilator influence. Of the causes of reduced vasodilator influence, derangements of the NOS pathway have been most studied. Derangements of the NOS pathway may be categorized as reductions in (1) NO half-life, (2) sensitivity to NO, (3) NOS expression, or (4) NOS activity. Experimental evidence exists for each of these mechanisms.
Increased vascular elaboration of superoxide anion is an abnormality commonly associated with atherosclerosis and its risk factors.25 The half-life of NO is reduced under conditions of oxidative stress.26 The attendant formation of peroxynitrite anion produces lipid peroxidation and nitrosation of tyrosine moieties, thereby disrupting cell membranes, cell signaling, and cell survival.27 Conversely, antioxidant strategies lengthen NO half-life, increase NOS expression, and restore endothelial vasodilator function.28 29 30 The oxidative enzymes responsible for increased oxidative stress in the vessel wall include NAD(P)H oxidase, xanthine oxidase, and NOS itself. Under conditions of reduced availability of L-arginine (the NO precursor) or tetrahydrobiopterin (an NOS cofactor), the preferred substrate of the monomer is oxygen, producing superoxide anion.31 32 33 34 35 Antioxidants may enhance the activity of NOS by preserving tetrahydrobiopterin.36
In the later stages of atherosclerosis, reduced sensitivity to endogenous and exogenous NO is observed, possibly due to oxidative inactivation of NO and/or soluble guanylate cyclase. In addition, in advanced atherosclerosis, reduced expression of the endothelial isoform of the NOS enzyme is observed, possibly due to cytokine- or lipid-induced instability and/or reduced transcription of NOS mRNA.37 38 Additionally, certain polymorphisms of the NOS gene may be associated with functional alterations in the enzyme and vascular disease.39 Finally, a growing body of data indicates that endogenous inhibitors of NOS may be responsible for endothelial vasodilator dysfunction in many individuals with coronary and peripheral arterial diseases and in those with their risk factors, particularly hypercholesterolemia, hyperhomocysteinemia, tobacco use, and aging. The endogenous inhibitors are asymmetric dimethylarginine (ADMA) and N-monomethylarginine (NMA). Because the former is the predominant species (plasma levels of ADMA are 10-fold greater than those of NMA), further discussion will focus on ADMA.
|
ADMA Is an Endogenous Inhibitor of NOS |
|---|
|
TopAbstractNO and Vascular HomeostasisEndothelial Dysfunction Is...ADMA Is an Endogenous...Dysregulation of DDAH: A...Does ADMA Explain the...Is ADMA a Risk...Future DirectionsReferences |
|---|
It has long been known to biochemists that methylated arginines are excreted in the urine.40 However, Vallance et al41 recognized the physiological significance of this observation and were the first to demonstrate that endogenous ADMA antagonized endothelium-dependent vasodilation. They observed a 9-fold elevation of plasma ADMA in patients with renal failure. Intriguingly, plasma from patients with renal failure induced vasoconstriction of vascular rings in vitro, an effect that was reversed by the addition of L-arginine to the medium. The marked elevation in plasma ADMA may explain the severe endothelial impairment of patients with renal failure. In these patients, dialysis normalizes ADMA levels, an effect that is temporally related to an improvement in endothelium-dependent vasodilation.42 43 Administration of L-arginine to patients with renal failure also restores endothelial function.43
Subsequently, plasma ADMA has been found to be elevated in patients with vascular disease, as well as in the setting of risk factors for vascular disease.44 45 46 47 48 49 Hypercholesterolemic animals and humans manifest an impairment of endothelium-dependent vasodilation.49 50 51 In these individuals, plasma ADMA levels are better correlated with endothelial dysfunction than are LDL cholesterol levels.49 Furthermore, the endothelial vasodilator dysfunction associated with an elevated plasma ADMA level is reversible by administration of L-arginine, consistent with the notion that ADMA is a competitive inhibitor.49
Intriguingly, plasma levels of ADMA appear to be dynamically regulated and can be correlated with measures of NO synthesis. In the Dahl salt-sensitive rat, a high-salt diet is associated with an increase in urinary ADMA excretion and an increase in blood pressure.52 In humans with salt-sensitive hypertension, administration of a high-salt diet increases plasma ADMA levels and blood pressure and reduces urinary NOx; a low-salt diet reverses these abnormalities.46 Preliminary studies indicate that plasma ADMA also increases with administration of a high-fat diet, which is associated with a temporally related impairment in endothelial vasodilator dysfunction.53 The mechanisms by which ADMA becomes elevated under these conditions require an understanding of its origin and metabolic fate.
Origin and Fate of ADMA
ADMA is not derived from the methylation of free
L-arginine. Rather, ADMA is derived from the catabolism of
proteins containing methylated arginine residues (Figure 1
). These proteins are largely
found in the nucleus and appear to be involved in RNA processing and
transcriptional control.55 There are 2 types of enzymes
that methylate arginine residues. These are protein arginine
methyltransferase types I and II (PRMT I and PRMT
II).56 57 PRMT type I forms ADMA and NMA, whereas PRMT
type II forms symmetric dimethylarginine (SDMA) and NMA. SDMA does not
inhibit NOS. There are a number of type I PRMTs, with specificity for
different proteins.55 By contrast, the only known
substrate for type II PRMT is myelin basic protein.
|
When these proteins undergo hydrolysis, their methylated arginine residues are released. Methylated arginines are excreted in the urine.40 This explains the increase in plasma ADMA levels in patients with renal insufficiency. Methylated arginines may also be metabolized. A minor source of metabolism occurs via dimethylarginine pyruvate transferase in the kidney and possibly, via acetylation in the liver. However, the major metabolic pathway for NMA and ADMA is the enzyme dimethylarginine dimethylaminohydrolase (DDAH).58 Two isoforms of DDAH are known, I and II. Either or both isoforms have been found in every cell type examined. DDAH I is typically found in tissues expressing neuronal NOS, whereas DDAH II predominates in tissues containing the endothelial isoform of NOS.59
|
Dysregulation of DDAH: A Novel Mechanism of Endothelial Dysfunction |
|---|
|
TopAbstractNO and Vascular HomeostasisEndothelial Dysfunction Is...ADMA Is an Endogenous...Dysregulation of DDAH: A...Does ADMA Explain the...Is ADMA a Risk...Future DirectionsReferences |
|---|
DDAH plays an important role in regulating ADMA levels. When SDMA is injected intravenously, 60% is recovered in the urine; by contrast, after intravenous administration, only 5% of ADMA is recovered in the urine.60 Furthermore, in renal failure, there is a significantly greater increase in plasma SDMA than in ADMA.61 These observations are explained by the fact that ADMA, but not SDMA, is a substrate for DDAH.58 ADMA undergoes extensive metabolism in vivo compared with SDMA.
Additional evidence that DDAH is a critical regulator of ADMA levels comes from observations of the effects of the DDAH inhibitor 4124W. Addition of 4124W to an isolated vascular segment induces gradual vasoconstriction, which is reversed by addition of L-arginine to the medium.62 This finding is most consistent with the view that ADMA is constantly being produced in the course of normal protein turnover. The production of ADMA is balanced by its metabolism by DDAH. Accordingly, inhibition of DDAH activity will cause a gradual accumulation of ADMA, sufficient to induce vasoconstriction.
Recent data from our laboratory indicate that hypercholesterolemia may cause a decline in DDAH activity. The accumulation of ADMA that ensues may contribute to lipid-induced endothelial vasodilator dysfunction. We found that when cultured endothelial cells were exposed to oxidized LDL cholesterol, ADMA accumulated in the medium at a faster rate than when cells were treated with vehicle or native LDL cholesterol.63 The accelerated accumulation of ADMA was associated with a temporally related decline in DDAH activity. Similarly, the activity of DDAH is reduced in both vascular and nonvascular tissues of hypercholesterolemic rabbits (in which the animals’ plasma ADMA levels are known to be elevated).63 More recently, we have made similar observations in vitro and in vivo regarding the adverse effect of hyperglycemia to reduce DDAH activity and to increase ADMA accumulation (J.P.C. et al, unpublished observations, 2000). Furthermore, the decline in DDAH activity appears to be related to oxidative stress and can be prevented by the use of antioxidants.
|
Does ADMA Explain the Arginine Paradox? |
|---|
|
TopAbstractNO and Vascular HomeostasisEndothelial Dysfunction Is...ADMA Is an Endogenous...Dysregulation of DDAH: A...Does ADMA Explain the...Is ADMA a Risk...Future DirectionsReferences |
|---|
The "arginine paradox" refers to the discordance between observations made in vitro and those made in vivo regarding the sensitivity of NO synthesis to arginine availability. Studies of a partially purified preparation of NOS in a cell-free system indicated that the Km of NOS for L-arginine was in the micromolar range.64 Accordingly, L-arginine should not be rate-limiting for NO synthesis because it is in the 50 micromolar range in plasma and in the millimolar range within the endothelial cell. Indeed, in normal animals and humans, most investigators report no effect of L-arginine on endothelial vasodilator function. Yet under certain circumstances, L-arginine does seem to be rate-limiting. This is most apparent in animal models or in patients with hypercholesterolemia and/or atherosclerosis, wherein endothelium-dependent vasodilation is impaired. There is a high degree of concordance among investigators that under these conditions, administration of L-arginine improves endothelium-dependent vasodilation and increases NO synthesis.49 65 66 67 68 69 70 71 Moreover, L-arginine relieves symptoms and improves exercise tolerance in patients with coronary and peripheral arterial disease. Indeed, the weight of the evidence indicates that there is a nutritional requirement for supplemental L-arginine in these individuals.
The elevation of plasma ADMA provides a possible explanation for the
benefits of supplemental L-arginine in these patients. The
plasma level of ADMA is normally 
1 µmol/L, is typically
increased 2-fold in subjects with risk factors for vascular disease,
and is increased even further (up to 10-fold) in patients with clinical
atherosclerosis. But with circulating
L-arginine levels at 50 µmol/L, is this elevation
in ADMA sufficient to have an effect on NOS? Perhaps the sensitivity to
ADMA could be explained by the fact that it also competes with
L-arginine for uptake by the y+ transporter. Furthermore,
the y+ transporter and endothelial NOS are physically
associated in the caveolae of endothelial
cells.72 The arginine interventions discussed above
certainly support the view that NO synthesis is sensitive to changes in
extracellular arginine availability. Furthermore, Faraci and
colleagues73 have shown that the
Km of NOS isolated from the cerebellum
(largely neuronal NOS) is 2.8 µmol/L. Also, concentrations of 1
to 10 µmol/L ADMA were sufficient to cause modest contractions
of cerebral vessels in situ.
Intravenous infusion of ADMA sufficient to increase plasma
concentrations 9-fold increased systolic blood pressure by 15%
in anesthetized guinea pigs.41
Intra-arterial infusion of ADMA (8 µmol/min) reduced
forearm blood flow by 30% in healthy volunteers.41
Finally, we have observed intriguing changes in
endothelial behavior when cultured cells are
chronically exposed to concentrations of ADMA and
L-arginine similar to those found in the plasma of
hypercholesterolemic individuals. ADMA-exposed cells
increase the adhesiveness of monocytes in coculture.74
Furthermore, monocytes and T lymphocytes derived from
hypercholesterolemic individuals are hyperadhesive, an
abnormality that is reversed by several weeks of oral administration of
L-arginine.74 This finding is
consistent with previous observations in
hypercholesterolemic animal models and humans that
administration of the NO precursor inhibits
endothelial-monocyte interaction.18 75 76
These observations raise the following question.
|
Is ADMA a Risk Factor for Vascular Disease? |
|---|
|
TopAbstractNO and Vascular HomeostasisEndothelial Dysfunction Is...ADMA Is an Endogenous...Dysregulation of DDAH: A...Does ADMA Explain the...Is ADMA a Risk...Future DirectionsReferences |
|---|
Preclinical studies suggest that NO is a potent, endogenous, antiatherogenic molecule, suppressing key processes in atherosclerosis. This view is supported by the fact that pharmacological inhibition or a genetic deficiency of endothelial NOS accelerates atherogenesis in animal models.20 21 77 Does endogenous ADMA accelerate atherosclerosis? Our earlier observations that chronic administration of L-arginine can slow and even reverse the progression of vascular lesions are consistent with this hypothesis.78 79 80 81 82 83 84 85 86 The hypothesis is further supported by the observation that supplemental dietary arginine enhances NO synthesis in the rabbit aorta, as measured directly by chemiluminescence.18
Intriguingly, in animal models and in humans, endogenous ADMA levels may be predictive of vascular lesion formation. After balloon injury, the regenerating endothelial cells manifest higher intracellular levels of ADMA and impaired endothelium-dependent vasodilation.87 88 89 The severity of the endothelial dysfunction and the intracellular levels of ADMA are directly related to the intimal thickness of the injured vessel.87 89 There are similar data for humans. In 120 Japanese individuals with varying levels of risk, intimal-medial thickness of the carotid artery was measured by ultrasound and was correlated with blood pressure, lipid profile, smoking history, blood sugar, age, and ADMA. A multivariate analysis revealed that ADMA and age were the only independent predictors in these patients.90
Finally, 3 groups have independently offered evidence that endothelial vasodilator dysfunction is an independent predictor of vascular events.24 91 92 Impaired coronary blood flow response to acetylcholine or reduced brachial artery response to flow was predictive of vascular morbidity and mortality. To the extent that ADMA is responsible for the impairment of endothelial vasodilator dysfunction in these patients, it may be a predictor for vascular events.
|
Future Directions |
|---|
|
TopAbstractNO and Vascular HomeostasisEndothelial Dysfunction Is...ADMA Is an Endogenous...Dysregulation of DDAH: A...Does ADMA Explain the...Is ADMA a Risk...Future DirectionsReferences |
|---|
Work in this area would be facilitated by an improved assay. Currently, detection of ADMA is labor-intensive and requires its derivatization to a fluorescent probe, followed by high-pressure liquid chromatography combined with a fluorescent detector. High-throughput and reproducible assays are needed and may arise as immunoassays or enzymatic assays. These assays will facilitate determination of the clinical significance of ADMA as a contributor to pathophysiology and symptoms and as a risk factor for vascular events.
The regulation of DDAH is just beginning to be understood, and modulators of its expression are being defined. Structure-function studies and novel drug discovery will be enhanced by obtaining its crystal structure. Genetically engineered animals that overexpress or are deficient in DDAH are being created and will provide new insights into the developmental and physiological actions of DDAH. Other enzymes along the metabolic pathway of ADMA deserve further scrutiny; for example, can increased methylation of specific proteins or increased catabolism of these proteins be involved in elevation of plasma ADMA?
Other interesting biological questions remain to be answered. Does ADMA play an important regulatory role in inflammation or infection (ie, as a "brake" on the action of inducible NOS)? Does ADMA have a role in the central or peripheral nervous system? Are other processes that are modulated by NO (eg, angiogenesis) affected by endogenous ADMA? There are many unanswered questions, but it seems certain that endogenous NOS inhibitors represent an important new class of biological mediators. An understanding of their physiological and pathological roles and their regulation may lead to new therapeutic avenues.
|
Acknowledgments |
|---|
This work was supported in part by a grant from the National Heart, Lung, and Blood Institute (RO1 HL58638) and funding from the Tobacco Related Diseases Research Program. Dr Cooke is an Established Investigator of the American Heart Association.
Received May 5, 2000; accepted June 1, 2000.
|
References |
|---|
|
TopAbstractNO and Vascular HomeostasisEndothelial Dysfunction Is...ADMA Is an Endogenous...Dysregulation of DDAH: A...Does ADMA Explain the...Is ADMA a Risk...Future DirectionsReferences |
|---|
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.
Ignarro LJ, Burke TM, Wood KS, Wolin MS, Kadowitz PJ.
Association between cyclic GMP accumulation and acetylcholine-elicited
relaxation of bovine intrapulmonary artery. J
Pharmacol Exp Ther. 1984;228:682–690.
3.
Murad F. The 1996 Albert Lasker Medical Research
Awards: signal transduction using nitric oxide and cyclic guanosine
monophosphate. JAMA. 1996;276:1189–1192.
4.
Pohl U, Holtz J, Busse R, Bassenge E. Crucial role of
endothelium in the vasodilator response to increased
flow in vivo. Hypertension. 1986;8:37–44.
5. Cooke JP, Rossitch E Jr, Andon NA, Loscalzo J, Dzau VJ. Flow activates an endothelial potassium channel to release an endogenous nitrovasodilator. J Clin Invest. 1991;88:1663–1671.
6.
Rees DD, Palmer RMJ, Moncada S. Role of
endothelium-derived nitric oxide in the regulation of
blood pressure. Proc Natl Acad Sci U S A. 1989;86:3375–3378.
7. Vallance P, Collier J, Moncada S. Effects of endothelium-derived nitric oxide on peripheral arteriolar tone in man. Lancet. 1989;2:997–1000.[Medline] [Order article via Infotrieve]
8. 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]
9. Huang PL, Hyang Z, Mashimo H, Block KD, Moskowitz MA, Bevan JA, Fishman MC. Hypertension in mice lacking the gene for endothelial nitric oxide synthase. Nature. 1995;377:239–242.[Medline] [Order article via Infotrieve]
10. Ludmer PL, Selwyn AP, Shook TL, Wayne RR, Mudge GH, Alexander RW, Ganz P. Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries. N Engl J Med. 1986;315:1046–1051.[Abstract]
11. Nabel EG, Selwyn AP, Ganz P. Large coronary arteries in humans are responsive to changing blood flow: an endothelium-dependent mechanism that fails in patients with atherosclerosis. J Am Coll Cardiol.. 1990;16:349–356.[Abstract]
12. Garg UC, Hassid A. Nitric oxide-generating vasodilators and 8-bromocyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J Clin Invest. 1989;83:1774–1777.
13. Numaguchi K, Egashira K, Takemoto M, Kadokami T, Shimokawa H, Sueishi K, Takeshita A. Chronic inhibition of nitric oxide synthesis causes coronary microvascular remodeling in rats. Hypertension. 1995;26(pt 1):957–962.
14.
Weidinger FF, McLenachan JM, Cybulsky M, Gordon JM,
Rennke HA, Hollenberg NK, Ganz P, Cooke JP. Persistent dysfunction of
regenerated endothelium following balloon angioplasty
of rabbit iliac artery. Circulation. 1990;81:1667–1679.
15.
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.
16.
Le Tourneau T, Van Belle E, Corseaux D, Vallet B,
Lebuffe G, Dupuis B, Lablanche JM, McFadden E, Bauters C, Bertrand ME.
Role of nitric oxide in restenosis after experimental balloon
angioplasty in the hypercholesterolemic rabbit: effects
on neointimal hyperplasia and vascular remodeling.
J Am Coll Cardiol. 1999;33:876–882.
17.
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.
18.
Tsao P, McEvoy LM, Drexler H, Butcher EC, Cooke JP.
Enhanced endothelial adhesiveness in
hypercholesterolemia is attenuated by
L-arginine. Circulation. 1994;89:2176–2182.
19.
Tsao P, Theilmeier G, Singer AH, Leung LL, Cooke JP.
L-Arginine attenuates platelet reactivity in
hypercholesterolemic rabbits. Arterioscler
Thromb. 1994;14:1529–1533.
20.
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.
21.
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:
PGH2 does not contribute to impaired
endothelium-dependent relaxation. Arterioscler
Thromb. 1994;14:746–752.
22. Creager MA, Cooke JP, Mendelsohn ME, Gallagher SJ, Coleman SM, Loscalzo J, Dzau VJ. Impaired vasodilatation of forearm resistance vessels in hypercholesterolemic humans. J Clin Invest. 1990;86:228–234.
23. 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]
24.
Suwaidi JA, Hamasaki S, Higano ST, Nishimura RA, Holmes
DR Jr, Lerman A. Long-term follow-up of patients with mild
coronary artery disease and endothelial
dysfunction. Circulation.. 2000;101:948–954.
25. Ohara Y, Petersen TE, Harrison DG. Hypercholesterolemia increases endothelial superoxide anion production. J Clin Invest.. 1993;91:2546–2551.
26. Rubanyi GM, Vanhoutte PM. Superoxide anions and hyperoxia inactivate endothelium-derived relaxing factor. Am J Physiol. 1986;250(pt 2):H822–H87.
27.
Beckman JS, Koppenol WH. Nitric oxide, superoxide, and
peroxynitrite: the good, the bad, and the ugly. Am J
Physiol.. 1996;271:C1424–C1437.
28.
Mügge A, Elwell JH, Peterson TE, Hofmeyer TG,
Heistad DD, Harrison DG. Chronic treatment with polyethylene-glycolated
superoxide dismutase partially restores
endothelium-dependent vascular relaxations in
cholesterol-fed rabbits. Circ Res. 1991;69:1293–1300.
29.
Gokce N, Keaney JF Jr, Frei B, Holbrook M, Olesiak M,
Zachariah BJ, Leeuwenburgh C, Heinecke JW, Vita JA. Long-term ascorbic
acid administration reverses endothelial vasomotor
dysfunction in patients with coronary artery disease.
Circulation. 1999;99:3234–3240.
30.
Ramasamy S, Drummond GR, Ahn J, Storek M, Pohl J,
Parthasarathy S, Harrison DG. Modulation of expression of
endothelial nitric oxide synthase by
nordihydroguaiaretic acid, a phenolic antioxidant in cultured
endothelial cells. Mol Pharmacol. 1999;56:116–123.
31.
Pou S, Pou WS, Bredt DS, Snyder SH, Rosen GM.
Generation of superoxide by purified brain nitric oxide synthase.
J Biol Chem. 1992;267:24173–24176.
32. Stroes E, Kastelein J, Cosentino F, Erkelens W, Wever R, Koomans H, Lüscher T, Rabelink T. Tetrahydrobiopterin restores endothelial function in hypercholesterolemia. J Clin Invest.. 1997;99:41–46.
33.
Xia Y, Tsai AL, Berka V, Zweier JL. Superoxide
generation from endothelial nitric-oxide synthase: a
Ca2+/calmodulin-dependent and
tetrahydrobiopterin regulatory process. J Biol Chem. 1998;273:25804–25808.
34.
Pritchard KA Jr, Groszek L, Smalley DM, Sessa WC, Wu M,
Villalon P, Wolin MS, Stemerman MB. Native low-density lipoprotein
increases endothelial cell nitric oxide synthase
generation of superoxide anion. Circ Res. 1995;77:510–518.
35.
Vasquez-Vivar J, Kalyanaraman B, Martasek P, Hogg N,
Masters BS, Karoui H, Tordo P, Pritchard KA Jr. Superoxide generation
by endothelial nitric oxide synthase: the influence of
cofactors. Proc Natl Acad Sci U S A. 1998;95:9220–9225.
36.
Huang A, Vita JA, Venema RC, Keaney J. Ascorbic acid
enhances endothelial nitric oxide synthase activity by
increasing intracellular tetrahydrobiopterin. J Biol
Chem. 2000;275:17399–17406.
37.
Oemar BS, Tschudi MR, Godoy N, Brovkovich V, Malinski
T, Luscher TF. Reduced endothelial nitric oxide
synthase expression and production in human
atherosclerosis. Circulation. 1998;97:2494–2498.
38.
Liao JK, Shin WS, Lee WY, Clark SL. Oxidized
low-density lipoprotein decreases the expression of
endothelial nitric oxide synthase. J Biol
Chem. 1995;270:319–324.
39.
Hingorani AD, Liang CF, Fatibene J, Lyon A, Monteith S,
Parsons A, Haydock S, Hopper RV, Stephens NG, O’Shaughnessy KM, Brown
MJ. A common variant of the endothelial nitric oxide
synthase (Glu298
Asp) is a major risk factor for
coronary artery disease in the UK. Circulation. 1999;100:1515–1520.
40.
Kakimoto Y, Akazawa S. Isolation and identification of
NG,
NG-, and
NG,
N'G-dimethyl-arginine,
N-mono-, di-, and trimethyllysine, and glucosylgalactosyl-,
and galactosyl-
-hydroxylysine from human urine. J Biol
Chem. 1970;245:5751–5758.
41. Vallance P, Leone A, Calver A, Collier J, Moncada S. Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet.. 1992;339:572–575.[Medline] [Order article via Infotrieve]
42.
Kielstein J, Böger R, Bode-Böger S,
Schäffer J, Barbey M, Koch K, Frölich J. Asymmetric
dimethylarginine plasma concentrations differ in patients with
end-stage renal disease: relationship to treatment method and
atherosclerotic disease. J Am Soc Nephrol. 1999;10:594–600.
43. Hand MF, Haynes WG, Webb DJ. Hemodialysis and L-arginine, but not D-arginine, correct renal failure-associated endothelial dysfunction. Kidney Int. 1998;53:1068–1077.[Medline] [Order article via Infotrieve]
44.
Boger RH, Bode-Boger SM, Thiele W, Junker W, Alexander
K, Frolich JC. Biochemical evidence for impaired nitric oxide synthesis
in patients with peripheral arterial occlusive
disease. Circulation. 1997;95:2068–2074.
45. Usui M, Matsuoka H, Miyazaki H, Ueda S, Okuda S, Imaizumi T. Increased endogenous nitric oxide synthase inhibitor in patients with congestive heart failure. Life Sci. 1998;62:2425–2430.[Medline] [Order article via Infotrieve]
46.
Fujiwara N, Osanai T, Kamada T, Katoh T, Takahashi K,
Okumura K. Study on the relationship between plasma nitrite and nitrate
level and salt sensitivity in human hypertension: modulation of nitric
oxide synthesis by salt intake. Circulation. 2000;101:856–861.
47. Holden D, Fickling S, Whitley G, Nussey S. Plasma concentrations of asymmetric dimethylarginine, a natural inhibitor of nitric oxide synthase, in normal pregnancy and preeclampsia. Am J Obstet Gynecol. 1998;178:551–556.[Medline] [Order article via Infotrieve]
48. Surdacki S, Nowicki M, Sandmann J, Tsikas D, Boeger R, Bode-Boeger S, Kruszelnicka-Kwiatkowska O, Kokot F, Dubiel J, Froelich J. Reduced urinary excretion of nitric oxide metabolites and increased plasma levels of asymmetric dimethylarginine in men with essential hypertension. J Cardiovasc Pharmacol. 1999;33:652–658.[Medline] [Order article via Infotrieve]
49.
Boger RH, Bode-Boger SM, Szuba A, Tsao PS, Chan JR,
Tangphao O, Blaschke TF, Cooke JP. Asymmetric dimethylarginine (ADMA):
a novel risk factor for endothelial dysfunction: its
role in hypercholesterolemia.
Circulation. 1998;98:1842–1847.
50. Yu XJ, Li YJ, 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]
51. Bode-Boger SM, Boger RH, Kienke S, Junker W, Frolich 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]
52. Matsuoka H, Itoh S, Kimoto M, Kohno K, Tamai O, Wada Y, Yasukawa H, Iwami G, Okuda S, Imaizumi T. Asymmetrical dimethylarginine, an endogenous nitric oxide synthase inhibitor, in experimental hypertension. Hypertension. 1997;29(pt 2):242–247.
53. Fard A, Tuck C, Donis J, Sciacca R, DiTullio M, Wu H, Bryant T, Chen N, Torres-Tamayo M, Ramasamy R, Berglund L, Ginsberg H, Homma S, Cannon P. Acute elevations of plasma asymmetric dimethylarginine and impaired endothelial function in response to a high-fat meal in patients with type 2 diabetes. Arterioscler Thromb Vasc Biol. In press.
54.
Ogawa T, Kimoto M, Sasaoka K. Dimethylarginine:pyruvate
aminotransferase in rats: purification, properties, and identity with
alanine:glyoxylate aminotransferase. J Biol Chem. 1990;265:20938–20945.
55.
Najbauer J, Johnson BA, Young AL, Aswad DW. Peptides
with sequences similar to glycine, arginine-rich motifs in proteins
interacting with RNA are efficiently recognized by methyltransferase(s)
modifying arginine in numerous proteins. J Biol Chem. 1993;268:10501–10509.
56.
Ghosh SK, Paik WK, Kim S. Purification and molecular
identification of two protein methylases I from calf brain: myelin
basic protein- and histone-specific enzyme. J Biol
Chem. 1988;263:19024–19033.
57.
Tang J, Frankel A, Cook RJ, Kim S, Paik WK, Williams
KR, Clarke S, Herschman HR. PRMT1 is the predominant type I protein
arginine methyltransferase in mammalian cells. J Biol
Chem. 2000;275:7723–7730.
58. Ogawa T, Kimoto M, Sasaoka K. Occurrence of a new enzyme catalyzing the direct conversion of NG,NG-dimethyl-L-arginine to L-citrulline in rats. Biochem Biophys Res Commun. 1987;148:671–677.[Medline] [Order article via Infotrieve]
59. Leiper JM, Santa Maria J, Chubb A, MacAllister RJ, Charles IG, Whitley GS, Vallance P. Identification of two human dimethylarginine dimethylaminohydrolases with distinct tissue distributions and homology with microbial arginine deiminases. Biochem J. 1999;343(pt 1):209–214.
60. McDermott. 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]
61.
MacAllister RJ, Rambausek MH, Vallance P, Williams D,
Hoffman KH, Ritz E. Concentration of dimethyl-L-arginine in
the plasma of patients with end-stage renal failure. Nephrol Dial
Transplant. 1996;11:2449–2452.
62. MacAllister RJ, Parry H, Kimoto M, Ogawa T, Russell RJ, Hodson H, Whitley GS, Vallance P. Regulation of nitric oxide synthesis by dimethylarginine dimethylaminohydrolase. Br J Pharmacol. 1996;119:1533–1540.[Medline] [Order article via Infotrieve]
63.
Ito A, Tsao PS, Adimoolam S, Kimoto M, Ogawa T, Cooke
JP. Novel mechanism for endothelial dysfunction:
dysregulation of dimethylarginine dimethylaminohydrolase.
Circulation. 1999;99:3092–3095.
64.
Pollock JS, Forstermann U, Mitchell JA, Warner TD,
Schmidt HH, Nakane M, Murad F. Purification and characterization of
particulate endothelium-derived relaxing factor
synthase from cultured and native bovine aortic
endothelial cells. Proc Natl Acad Sci
U S A. 1991;88:10480–10484.
65.
Cooke JP, Andon NA, Girerd XJ, Hirsch
AT, Creager MA. Arginine restores cholinergic relaxation of
hypercholesterolemic rabbit thoracic aorta.
Circulation. 1991;83:1057–1062.
66. 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]
67. 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]
68. Ceremuzynski L, Chamiec T, Herbaczynska-Cedro K. Effect of supplemental oral L-arginine on exercise capacity in patients with stable angina pectoris. Am J Cardiol. 1997;80:331–333.[Medline] [Order article via Infotrieve]
69.
Boger RH, Bode-Boger SM, Thiele W, Creutzig A,
Alexander K, Frolich JC. Restoring vascular nitric oxide formation by
L-arginine improves the symptoms of intermittent
claudication in patients with peripheral
arterial occlusive disease. J Am Coll
Cardiol. 1998;32:1336–1344.
70.
Lerman A, Burnett JC Jr, Higano ST, McKinley LJ, Holmes
DR Jr. Long-term L-arginine supplementation improves
small-vessel coronary endothelial function in
humans. Circulation. 1998;97:2123–2128.
71.
Maxwell A, Anderson B, Cooke JP. Nutritional therapy
for peripheral arterial disease: a double
blind, placebo-controlled randomized trial of HeartBar. Vasc
Med.. 2000;5:11–19.
72.
McDonald KK, Zharikov S, Block ER, Kilberg MS. A
caveolar complex between the cationic amino acid transporter 1 and
endothelial nitric-oxide synthase may explain the
‘arginine paradox.’ J Biol Chem. 1997;272:31213–31216.
73. Faraci FM, Brian JE Jr, Heistad DD. Response of cerebral blood vessels to an endogenous inhibitor of nitric oxide synthase. Am J Physiol. 1995;269(pt 2):H1522–H1527.
74.
Chan J, Böger R, Bode-Böger S, Tangphao O,
Tsao P, Blaschke T, Cooke J. Asymmetric dimethylarginine increases
mononuclear cell adhesiveness in hypercholesterolemic
humans. Arterioscler Thromb Vasc Biol. 2000;20:1040–1046.
75.
Theilmeier G, Chan J, Zalpour C, Ma A, Anderson B, Wang
B-Y, Wolf A, McEvoy L, Butcher E, Tsao PS, Cooke JP. Adhesiveness of
mononuclear cells in hypercholesterolemic humans is
normalized by dietary arginine. Arterioscler Thromb Vasc
Biol.. 1997;17:3557–3564.
76. Adams MR, McCredie R, Jessup W, Robinson J, Sullivan D, Celermajer DS. Oral L-arginine improves endothelium-dependent dilatation and reduces monocyte adhesion to endothelial cells in young men with coronary artery disease. Atherosclerosis. 1997;129:261–269.[Medline] [Order article via Infotrieve]
77. Huang PL. Disruption of the endothelial nitric oxide synthase gene: effect on vascular response to injury. Am J Cardiol. 1998;82(10A):57S–59S.
78. Cooke JP, Singer AH, Tsao PS, Zera P, Rowan RA, Billingham ME. Anti-atherogenic effects of L-arginine in the hypercholesterolemic rabbit. J Clin Invest. 1992;90:1168–1172.
79. McNamara DB, Bedi B, Aurora H, Tena L, Ignarro LJ, Kadowitz PJ, Akers DL. L-Arginine inhibits balloon catheter-induced intimal hyperplasia. Biochem Biophys Res Commun.. 1993;193:291–296.[Medline] [Order article via Infotrieve]
80.
Tarry WC, Makhoul RG. L-Arginine improves
endothelium-dependent vasorelaxation and reduces
intimal hyperplasia after balloon angioplasty. Arterioscler
Thromb. 1994;14:938–943.
81.
Hamon M, Vallet B, Bauters C, Wernert N, McFadden EP,
Lablanche JM, Dupuis B, Bertrand ME. Long-term oral administration of
L-arginine reduces intimal thickening and enhances
neoendothelium-dependent acetylcholine-induced
relaxation after arterial injury. Circulation. 1994;90:1357–1362.
82. Wang BY, Candipan RC, Arjomandi M, Hsiun PT, Tsao PS, Cooke JP. Arginine restores nitric oxide activity and inhibits monocyte accumulation after vascular injury in hypercholesterolemic rabbits. J Am Coll Cardiol. 1996;28:1573–1579.[Abstract]
83.
Candipan RC, Wang B, Buitrago R, Tsao PS, Cooke JP.
Regression or progression: dependency on vascular nitric oxide.
Arterioscler Thromb Vasc Biol. 1996;16:44–50.
84.
Aji W, Ravalli S, Szabolcs M, Jiang XC, Sciacca RR,
Michler RE, Cannon PJ. L-Arginine prevents xanthoma
development and inhibits atherosclerosis in LDL
receptor knockout mice. Circulation. 1997;95:430–437.
85.
Boger RH, Bode-Boger SM, Brandes RP, Phivthong-ngam L,
Bohme M, Nafe R, Mugge A, Frolich JC. Dietary L-arginine
reduces the progression of atherosclerosis in
cholesterol-fed rabbits: comparison with
lovastatin. Circulation. 1997;96:1282–1290.
86.
Schwarzacher SP, Lim TT, Wang B, Kernoff RS, Niebauer
J, Cooke JP, Yeung AC. Local intramural delivery of
L-arginine enhances nitric oxide generation and inhibits
lesion formation after balloon angioplasty. Circulation. 1997;95:1863–1869.
87. Weidinger FF, McLenachan JM, Cybulsky M, Gordon JM, Rennke HA, Hollenberg NK, Ganz P, Cooke JP. Persistent dysfunction of regenerated endothelium following balloon angioplasty of rabbit iliac artery. Circulation. 1990;81:1667–1679.
88. Azuma 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]
89. Masuda H, Goto M, Tamaoki S, Azuma H. Accelerated intimal hyperplasia and increased endogenous inhibitors for NO synthesis in rabbits with alloxan-induced hyperglycaemia. Br J Pharmacol. 1999;126:211–218.[Medline] [Order article via Infotrieve]
90.
Miyazaki H, Matsuoka H, Cooke JP, Usui M, Ueda S, Okuda
S, Imaizumi T. Endogenous nitric oxide synthase
inhibitor: a novel marker of
atherosclerosis. Circulation. 1999;99:1141–1146.
91. Murakami T, Mizuno S, Kaku B. Clinical morbidities in subjects with Doppler-evaluated endothelial dysfunction of coronary artery. J Am Coll Cardiol. 1998;31(suppl A):419A. Abstract.
92.
Schächinger V, Britten MB, Zeiher AM. Prognostic
impact of coronary vasodilator dysfunction on adverse long-term
outcome of coronary heart disease. Circulation.. 2000;101:1899–1906.
This article has been cited by other articles:
 |
|
 |
|
  R. M. Wilson, D. S. De Silva, K. Sato, Y. Izumiya, and F. Sam Effects of Fixed-Dose Isosorbide Dinitrate/Hydralazine on Diastolic Function and Exercise Capacity in Hypertension-Induced Diastolic Heart Failure Hypertension, September 1, 2009; 54(3): 583 - 590. [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. Sakurada, M. Shichiri, M. Imamura, H. Azuma, and Y. Hirata Nitric Oxide Upregulates Dimethylarginine Dimethylaminohydrolase-2 via Cyclic GMP Induction in Endothelial Cells Hypertension, November 1, 2008; 52(5): 903 - 909. [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]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
F. Scalera, J. Martens-Lobenhoffer, A. Bukowska, U. Lendeckel, M. Tager, and S. M. Bode-Boger Effect of Telmisartan on Nitric Oxide-Asymmetrical Dimethylarginine System: Role of Angiotensin II Type 1 Receptor and Peroxisome Proliferator Activated Receptor {gamma} Signaling During Endothelial Aging Hypertension, March 1, 2008; 51(3): 696 - 703. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. I. Yilmaz, A. Sonmez, M. Saglam, A. R. Qureshi, J. J. Carrero, K. Caglar, T. Eyileten, E. Cakir, Y. Oguz, A. Vural, et al. ADMA Levels Correlate with Proteinuria, Secondary Amyloidosis, and Endothelial Dysfunction J. Am. Soc. Nephrol., February 1, 2008; 19(2): 388 - 395. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. W.T. Liu and P. L. Huang Cardiovascular roles of nitric oxide: A review of insights from nitric oxide synthase gene disrupted mice Cardiovasc Res, January 1, 2008; 77(1): 19 - 29. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. J. Pope, L. Druhan, J. E. Guzman, S. P. Forbes, V. Murugesan, D. Lu, Y. Xia, L. G. Chicoine, N. L. Parinandi, and A. J. Cardounel Role of DDAH-1 in lipid peroxidation product-mediated inhibition of endothelial NO generation Am J Physiol Cell Physiol, November 1, 2007; 293(5): C1679 - C1686. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. P. Coggins and K. D. Bloch Nitric Oxide in the Pulmonary Vasculature Arterioscler Thromb Vasc Biol, September 1, 2007; 27(9): 1877 - 1885. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. C. Stuhlinger, E. Conci, B. J. Haubner, E.-M. Stocker, J. Schwaighofer, J. P. Cooke, P. S. Tsao, O. Pachinger, and B. Metzler Asymmetric Dimethyl L-Arginine (ADMA) is a critical regulator of myocardial reperfusion injury Cardiovasc Res, July 15, 2007; 75(2): 417 - 425. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Matsumoto, S. Ueda, S.-i. Yamagishi, K. Matsuguma, R. Shibata, K. Fukami, H. Matsuoka, T. Imaizumi, and S. Okuda Dimethylarginine Dimethylaminohydrolase Prevents Progression of Renal Dysfunction by Inhibiting Loss of Peritubular Capillaries and Tubulointerstitial Fibrosis in a Rat Model of Chronic Kidney Disease J. Am. Soc. Nephrol., May 1, 2007; 18(5): 1525 - 1533. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Zoccali, R. Maas, S. Cutrupi, P. Pizzini, P. Finocchiaro, F. Cambareri, V. Panuccio, C. Martorano, F. Schulze, G. Enia, et al. Asymmetric dimethyl-arginine (ADMA) response to inflammation in acute infections Nephrol. Dial. Transplant., March 1, 2007; 22(3): 801 - 806. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. E. Gates, M. L. Boucher, A. E. Silver, K. D. Monahan, and D. R. Seals Impaired flow-mediated dilation with age is not explained by L-arginine bioavailability or endothelial asymmetric dimethylarginine protein expression J Appl Physiol, January 1, 2007; 102(1): 63 - 71. [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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
W.-Z. Zhang, K. Venardos, J. Chin-Dusting, and D. M. Kaye Adverse Effects of Cigarette Smoke on NO Bioavailability: Role of Arginine Metabolism and Oxidative Stress Hypertension, August 1, 2006; 48(2): 278 - 285. [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]
|
|
|
|
|
|
K. Hasegawa, S. Wakino, T. Tanaka, M. Kimoto, S. Tatematsu, T. Kanda, K. Yoshioka, K. Homma, N. Sugano, M. Kurabayashi, et al. Dimethylarginine Dimethylaminohydrolase 2 Increases Vascular Endothelial Growth Factor Expression Through Sp1 Transcription Factor in Endothelial Cells Arterioscler Thromb Vasc Biol, July 1, 2006; 26(7): 1488 - 1494. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Yasuda, S. Miyazaki, M. Kanda, Y. Goto, M. Suzuki, Y. Harano, and H. Nonogi Intensive treatment of risk factors in patients with type-2 diabetes mellitus is associated with improvement of endothelial function coupled with a reduction in the levels of plasma asymmetric dimethylarginine and endogenous inhibitor of nitric oxide synthase Eur. Heart J., May 2, 2006; 27(10): 1159 - 1165. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. A. Elesber, H. Solomon, R. J. Lennon, V. Mathew, A. Prasad, G. Pumper, R. E. Nelson, J. P. McConnell, L. O. Lerman, and A. Lerman Coronary endothelial dysfunction is associated with erectile dysfunction and elevated asymmetric dimethylarginine in patients with early atherosclerosis Eur. Heart J., April 1, 2006; 27(7): 824 - 831. [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]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 T Kawata, M Daimon, R Hasegawa, K Teramoto, T Toyoda, T Sekine, K Yamamoto, D Uchida, T Himi, K Yoshida, et al. Serum asymmetric dimethylarginine as a marker of coronary microcirculation in patients with non-insulin dependent diabetes mellitus: correlation with coronary flow reserve Heart, December 1, 2005; 91(12): 1607 - 1608. [Full Text] [PDF]
|
|
|
|
|
|
N. Tyagi, K. C. Sedoris, M. Steed, A. V. Ovechkin, K. S. Moshal, and S. C. Tyagi Mechanisms of homocysteine-induced oxidative stress Am J Physiol Heart Circ Physiol, December 1, 2005; 289(6): H2649 - H2656. [Abstract] [Full Text] [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]
|
|
|
|
 |
|
 R. Schnabel, S. Blankenberg, E. Lubos, K. J. Lackner, H. J. Rupprecht, C. Espinola-Klein, N. Jachmann, F. Post, D. Peetz, C. Bickel, et al. Asymmetric Dimethylarginine and the Risk of Cardiovascular Events and Death in Patients With Coronary Artery Disease: Results from the AtheroGene Study Circ. Res., September 2, 2005; 97(5): e53 - e59. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Ravani, G. Tripepi, F. Malberti, S. Testa, F. Mallamaci, and C. Zoccali Asymmetrical Dimethylarginine Predicts Progression to Dialysis and Death in Patients with Chronic Kidney Disease: A Competing Risks Modeling Approach J. Am. Soc. Nephrol., August 1, 2005; 16(8): 2449 - 2455. [Abstract] [Full Text] [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. L. Huang Unraveling the Links Between Diabetes, Obesity, and Cardiovascular Disease Circ. Res., June 10, 2005; 96(11): 1129 - 1131. [Full Text] [PDF]
|
|
|
|
 |
|
 A. J. Cardounel, Y. Xia, and J. L. Zweier Endogenous Methylarginines Modulate Superoxide as Well as Nitric Oxide Generation from Neuronal Nitric-oxide Synthase: DIFFERENCES IN THE EFFECTS OF MONOMETHYL- AND DIMETHYLARGININES IN THE PRESENCE AND ABSENCE OF TETRAHYDROBIOPTERIN J. Biol. Chem., March 4, 2005; 280(9): 7540 - 7549. [Abstract] [Full Text] [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]
|
|
|
|
 |
|
 N. Gokce L-Arginine and Hypertension J. Nutr., October 1, 2004; 134(10): 2807S - 2811S. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. L. Gornik and M. A. Creager Arginine and Endothelial and Vascular Health J. Nutr., October 1, 2004; 134(10): 2880S - 2887S. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Suda, M. Tsutsui, T. Morishita, H. Tasaki, S. Ueno, S. Nakata, T. Tsujimoto, Y. Toyohira, Y. Hayashida, Y. Sasaguri, et al. Asymmetric Dimethylarginine Produces Vascular Lesions in Endothelial Nitric Oxide Synthase-Deficient Mice: Involvement of Renin-Angiotensin System and Oxidative Stress Arterioscler Thromb Vasc Biol, September 1, 2004; 24(9): 1682 - 1688. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. V. Smirnova, M. Kajstura, T. Sawamura, and M. S. Goligorsky Asymmetric dimethylarginine upregulates LOX-1 in activated macrophages: role in foam cell formation Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H782 - H790. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. El-Magadmi, H. Bodill, Y. Ahmad, P. N. Durrington, M. Mackness, M. Walker, R. M. Bernstein, and I. N. Bruce Systemic Lupus Erythematosus: An Independent Risk Factor for Endothelial Dysfunction in Women Circulation, July 27, 2004; 110(4): 399 - 404. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Davignon and P. Ganz Role of Endothelial Dysfunction in Atherosclerosis Circulation, June 15, 2004; 109(23_suppl_1): III-27 - III-32. [Abstract] [Full Text]
|
|
|
|
|
|
S. Kawashima and M. Yokoyama Dysfunction of Endothelial Nitric Oxide Synthase and Atherosclerosis Arterioscler Thromb Vasc Biol, June 1, 2004; 24(6): 998 - 1005. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Vallance and J. Leiper Cardiovascular Biology of the Asymmetric Dimethylarginine:Dimethylarginine Dimethylaminohydrolase Pathway Arterioscler Thromb Vasc Biol, June 1, 2004; 24(6): 1023 - 1030. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. Landmesser, B. Hornig, and H. Drexler Endothelial Function: A Critical Determinant in Atherosclerosis? Circulation, June 1, 2004; 109(21_suppl_1): II-27 - II-33. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. J. Quinones, M. Hernandez-Pampaloni, H. Schelbert, I. Bulnes-Enriquez, X. Jimenez, G. Hernandez, R. De La Rosa, Y. Chon, H. Yang, S. B. Nicholas, et al. Coronary Vasomotor Abnormalities in Insulin-Resistant Individuals Ann Intern Med, May 4, 2004; 140(9): 700 - 708. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Sydow, B. Hornig, N. Arakawa, S. M Bode-Boger, D. Tsikas, T. Munuzel, and R. H Boger Endothelial dysfunction in patients with peripheral arterial disease and chronic hyperhomocysteinemia: potential role of ADMA Vascular Medicine, May 1, 2004; 9(2): 93 - 101. [Abstract] [PDF]
|
|
|
|
|
|
K. Tsuda, I. Nishio, J. P. Cooke, and M. Stuhlinger Asymmetric Dimethylarginine and Circulatory Disorders in Postmenopausal Women * Response Circulation, February 10, 2004; 109 (5): e35 - e35. [Full Text] [PDF]
|
|
|
|
|
|
M. Weis, T. N. Kledal, K. Y. Lin, S. N. Panchal, S. Z. Gao, H. A. Valantine, E. S. Mocarski, and J. P. Cooke Cytomegalovirus Infection Impairs the Nitric Oxide Synthase Pathway: Role of Asymmetric Dimethylarginine in Transplant Arteriosclerosis Circulation, February 3, 2004; 109(4): 500 - 505. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Fonseca, C. Desouza, S. Asnani, and I. Jialal Nontraditional Risk Factors for Cardiovascular Disease in Diabetes Endocr. Rev., February 1, 2004; 25(1): 153 - 175. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Mallamaci, G. Tripepi, R. Maas, L. Malatino, R. Boger, and C. Zoccali Analysis of the Relationship between Norepinephrine and Asymmetric Dimethyl Arginine Levels among Patients with End-Stage Renal Disease J. Am. Soc. Nephrol., February 1, 2004; 15(2): 435 - 441. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. T. Kielstein, B. Impraim, S. Simmel, S. M. Bode-Boger, D. Tsikas, J. C. Frolich, M. M. Hoeper, H. Haller, and D. Fliser Cardiovascular Effects of Systemic Nitric Oxide Synthase Inhibition With Asymmetrical Dimethylarginine in Humans Circulation, January 20, 2004; 109(2): 172 - 177. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Zoccali, F. Mallamaci, and G. Tripepi Novel Cardiovascular Risk Factors in End-Stage Renal Disease J. Am. Soc. Nephrol., January 1, 2004; 15(90010): S77 - 80. [Abstract] [Full Text]
|
|
|
|
|
|
R. J. Nijveldt, T. Teerlink, C. van Guldener, H. A. Prins, A. A. van Lambalgen, C. D. A. Stehouwer, J. A. Rauwerda, and P. A. M. van Leeuwen Handling of asymmetrical dimethylarginine and symmetrical dimethylarginine by the rat kidney under basal conditions and during endotoxaemia Nephrol. Dial. Transplant., December 1, 2003; 18(12): 2542 - 2550. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Saran, J. E. Novak, A. Desai, E. Abdulhayoglu, J. S. Warren, R. Bustami, G. J. Handelman, D. Barbato, W. Weitzel, L. G. D'Alecy, et al. Impact of vitamin E on plasma asymmetric dimethylarginine (ADMA) in chronic kidney disease (CKD): a pilot study Nephrol. Dial. Transplant., November 1, 2003; 18(11): 2415 - 2420. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Simon, L. Plies, A. Habermeier, U. Martine, M. Reining, and E. I. Closs Role of Neutral Amino Acid Transport and Protein Breakdown for Substrate Supply of Nitric Oxide Synthase in Human Endothelial Cells Circ. Res., October 31, 2003; 93(9): 813 - 820. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. P. Cooke A Novel Mechanism for Pulmonary Arterial Hypertension? Circulation, September 23, 2003; 108(12): 1420 - 1421. [Full Text] [PDF]
|
|
|
|
|
|
M. C. Stuhlinger, R. K. Oka, E. E. Graf, I. Schmolzer, B. M. Upson, O. Kapoor, A. Szuba, M. R. Malinow, T. C. Wascher, O. Pachinger, et al. Endothelial Dysfunction Induced by Hyperhomocyst(e)inemia: Role of Asymmetric Dimethylarginine Circulation, August 26, 2003; 108(8): 933 - 938. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. T. Kielstein, S. M. Bode-Boger, H. Haller, and D. Fliser Functional changes in the ageing kidney: is there a role for asymmetric dimethylarginine? Nephrol. Dial. Transplant., July 1, 2003; 18(7): 1245 - 1248. [Full Text] [PDF]
|
|
|
|
|
|
J. P. Cooke, K. Sydow, J. Chen, and P. Huang A Peculiar Result and a Fanciful Hypothesis Regarding L-Arginine * Arterioscler Thromb Vasc Biol, June 1, 2003; 23(6): 1128 - 1128. [Full Text] [PDF]
|
|
|
|
|
|
J. T. Kielstein, S. M. Bode-Boger, J. C. Frolich, E. Ritz, H. Haller, and D. Fliser Asymmetric Dimethylarginine, Blood Pressure, and Renal Perfusion in Elderly Subjects Circulation, April 15, 2003; 107(14): 1891 - 1895. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Weis and J. P. Cooke Cardiac Allograft Vasculopathy and Dysregulation of the NO Synthase Pathway Arterioscler Thromb Vasc Biol, April 1, 2003; 23(4): 567 - 575. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Ueda, S. Kato, H. Matsuoka, M. Kimoto, S. Okuda, M. Morimatsu, and T. Imaizumi Regulation of Cytokine-Induced Nitric Oxide Synthesis by Asymmetric Dimethylarginine: Role of Dimethylarginine Dimethylaminohydrolase Circ. Res., February 7, 2003; 92(2): 226 - 233. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. P. Cooke Flow, NO, and atherogenesis PNAS, February 4, 2003; 100(3): 768 - 770. [Full Text] [PDF]
|
|
|
|
|
|
P. Piatti, G. Fragasso, L. D. Monti, E. Setola, P. Lucotti, I. Fermo, R. Paroni, E. Galluccio, G. Pozza, S. Chierchia, et al. Acute Intravenous l-Arginine Infusion Decreases Endothelin-1 Levels and Improves Endothelial Function in Patients With Angina Pectoris and Normal Coronary Arteriograms: Correlation With Asymmetric Dimethylarginine Levels Circulation, January 28, 2003; 107(3): 429 - 436. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Knipp, O. Braun, P. M. Gehrig, R. Sack, and M. Vasak Zn(II)-free Dimethylargininase-1 (DDAH-1) Is Inhibited upon Specific Cys-S-Nitrosylation J. Biol. Chem., January 24, 2003; 278(5): 3410 - 3416. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Maeda, T. Yoshimura, and H. Okamura Asymmetric Dimethylarginine, an Endogenous Inhibitor of Nitric Oxide Synthase, in Maternal and Fetal Circulation Reproductive Sciences, January 1, 2003; 10(1): 2 - 4. [Abstract] [PDF]
|
|
|
|
 |
|
 G. E. Mann, D. L. Yudilevich, and L. Sobrevia Regulation of Amino Acid and Glucose Transporters in Endothelial and Smooth Muscle Cells Physiol Rev, January 1, 2003; 83(1): 183 - 252. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Schachinger and A. M. Zeiher Atherogenesis--recent insights into basic mechanisms and their clinical impact Nephrol. Dial. Transplant., December 1, 2002; 17(12): 2055 - 2064. [Full Text] [PDF]
|
|
|
|
|
|
A. J. Cardounel and J. L. Zweier Endogenous Methylarginines Regulate Neuronal Nitric-oxide Synthase and Prevent Excitotoxic Injury J. Biol. Chem., September 6, 2002; 277(37): 33995 - 34002. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Tousoulis, C. Antoniades, C. Tentolouris, G. Goumas, C. Stefanadis, and P. Toutouzas L-Arginine in cardiovascular disease: dream or reality? Vascular Medicine, August 1, 2002; 7(3): 203 - 211. [Abstract] [PDF]
|
|
|
|
|
|
T.-H. Hung, J. N. Skepper, D. S. Charnock-Jones, and G. J. Burton Hypoxia-Reoxygenation: A Potent Inducer of Apoptotic Changes in the Human Placenta and Possible Etiological Factor in Preeclampsia Circ. Res., June 28, 2002; 90(12): 1274 - 1281. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. P. Cooke and D. W. Losordo Nitric Oxide and Angiogenesis Circulation, May 7, 2002; 105(18): 2133 - 2135. [Full Text] [PDF]
|
|
|
|
 |
|
 D. T. Nash Insulin Resistance, ADMA Levels, and Cardiovascular Disease JAMA, March 20, 2002; 287(11): 1451 - 1452. [Full Text] [PDF]
|
|
|
|
|
|
J. T. Kielstein, R. H. Boger, S. M. Bode-Boger, J. C. Frolich, H. Haller, E. Ritz, and D. Fliser Marked Increase of Asymmetric Dimethylarginine in Patients with Incipient Primary Chronic Renal Disease J. Am. Soc. Nephrol., January 1, 2002; 13(1): 170 - 176. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. R. Edelman On Causes: Hippocrates, Aristotle, Robert Koch, and the Dread Pirate Roberts Circulation, November 20, 2001; 104(21): 2509 - 2512. [Full Text] [PDF]
|
|
|
|
|
|
M. C. Stuhlinger, P. S. Tsao, J.-H. Her, M. Kimoto, R. F. Balint, and J. P. Cooke Homocysteine Impairs the Nitric Oxide Synthase Pathway: Role of Asymmetric Dimethylarginine Circulation, November 20, 2001; 104(21): 2569 - 2575. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Vermeersch, Z. Nong, E. Stabile, O. Varenne, H. Gillijns, M. Pellens, N. Van Pelt, M. Hoylaerts, I. De Scheerder, D. Collen, et al. L-Arginine Administration Reduces Neointima Formation After Stent Injury in Rats by a Nitric Oxide-Mediated Mechanism Arterioscler Thromb Vasc Biol, October 1, 2001; 21(10): 1604 - 1609. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. T. Kielstein, J. C. Frolich, H. Haller, and D. Fliser ADMA (asymmetric dimethylarginine): an atherosclerotic disease mediating agent in patients with renal disease? Nephrol. Dial. Transplant., September 1, 2001; 16(9): 1742 - 1745. [Full Text] [PDF]
|
|
|
|
 |
|
 P. Lundman, M. J. Eriksson, M. Stuhlinger, J. P. Cooke, A. Hamsten, and P. Tornvall Mild-to-moderate hypertriglyceridemia in young men is associated with endothelial dysfunction and increased plasma concentrations of asymmetric dimethylarginine J. Am. Coll. Cardiol., July 1, 2001; 38(1): 111 - 116. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Knipp, J. M. Charnock, C. D. Garner, and M. Vasak Structural and Functional Characterization of the Zn(II) Site in Dimethylargininase-1 (DDAH-1) from Bovine Brain. Zn(II) RELEASE ACTIVATES DDAH-1 J. Biol. Chem., October 26, 2001; 276(44): 40449 - 40456. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||