This Article Extract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cooke, J. P. Search for Related Content PubMed PubMed Citation Articles by Cooke, J. P. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB (L)-ARGININE Related Collections Pathophysiology Risk Factors Endothelium/vascular type/nitric oxide

(Circulation. 2004;109:1813-1818.)
© 2004 American Heart Association, Inc.

Special Review

Asymmetrical Dimethylarginine

The Über Marker?

John P. Cooke, MD, PhD

From the Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, Calif.

Correspondence to John P. Cooke, MD, PhD, Division of Cardiovascular Medicine, Stanford University School of Medicine, 300 Pasteur Dr, Stanford, CA 94305. E-mail john.cooke{at}stanford.edu

Key Words: arginine • nitric oxide synthase • endothelium • risk factors • amidohydrolases

	Introduction

Top Introduction ADMA: A Major Cause... ADMA Regulates Vascular... ADMA and Vascular Structure Mechanisms by Which ADMA... Central Role of DDAH ADMA and the "l-Arginine... Therapeutic Modulation of Plasma... Conclusion References

 
The traditional risk factors of hypercholesterolemia, hypertension, diabetes mellitus, and tobacco exposure identify a subset of patients at greater cardiovascular risk. A variety of clinical phenotypes, biochemical markers, and genetic polymorphisms have been proposed to explain the variance in risk not explained by the traditional factors. Notably, all of the traditional risk factors, as well as the great majority of new risk markers, are associated with endothelial vasodilator dysfunction.

Because the end points (endothelial dysfunction leading to plaque formation, progression, and rupture) are the same, it follows that diverse risk factors ultimately share common pathways(s) of pathobiology. We and others have provided evidence for a ubiquitous mechanism of endothelial pathobiology shared by all risk factors and markers examined to date. This mechanism of endothelial derangement is mediated by an endogenous inhibitor of nitric oxide synthase (NOS), a molecule known as asymmetrical dimethylarginine (ADMA). Risk factors impair endothelial vasodilator function by causing the accumulation of ADMA. Furthermore, by blocking NO generation, ADMA initiates and promotes processes involved in atherogenesis, plaque progression. and plaque rupture. This review examines the burgeoning body of literature that supports ADMA as an "Über marker," a biochemical factor mediating the adverse vascular effects of many other risk factors and markers.

	ADMA: A Major Cause of Endothelial Dysfunction

Top Introduction ADMA: A Major Cause... ADMA Regulates Vascular... ADMA and Vascular Structure Mechanisms by Which ADMA... Central Role of DDAH ADMA and the "l-Arginine... Therapeutic Modulation of Plasma... Conclusion References

 
Endothelial NOS converts the amino acid L-arginine into L-citrulline and NO. The importance of NO in vascular homeostasis has been discussed elsewhere.¹ In addition to its vasodilator activity, NO inhibits key processes involved in vascular disease, including leukocyte adhesion, platelet aggregation, and vascular smooth muscle cell proliferation. In animal models, alterations in vascular NO synthesis profoundly influence the progression of atherosclerosis and restenosis.^2–6 These experimental observations have gained greater significance with recent reports that impairment of the NOS pathway independently predicts cardiovascular events.^7–11

Major causes of impairment of the NOS pathway are the endogenous NOS inhibitors ADMA and N-monomethylarginine (MMA). Plasma levels of ADMA are 10-fold greater than those of MMA.¹² Because it is the predominant species in plasma, most studies to date have focused on ADMA. The importance of ADMA as an endogenous inhibitor of NOS was first recognized by Vallance and colleagues¹² in patients with end-stage renal disease. In these patients, ADMA accumulates as a result of reduced renal clearance. Dialysis reduces plasma ADMA levels and normalizes endothelial function. Associations between increased levels of ADMA and many cardiovascular risk factors such as age, hypertension, diabetes, insulin resistance, hypercholesterolemia, hypertriglyceridemia, and hyperhomocystinemia have been documented.^13–20 Furthermore, evidence for a causal relationship between increased ADMA levels and endothelial vasodilator dysfunction has been demonstrated in many of these conditions. In hypercholesterolemic adults (but not children), elevated ADMA levels are inversely correlated with endothelium-dependent vasodilation in the forearm.^18,21 Consistent with the notion that ADMA is a competitive inhibitor, in hypercholesterolemic adults an intravenous infusion of L-arginine restores endothelial function and increases urinary nitrate excretion (a surrogate parameter of NO production).

Plasma ADMA levels can change quite rapidly in humans, temporally associated with alterations in endothelial vasodilator function. A single high-fat meal doubled ADMA levels in diabetic patients and was temporally associated with a significant impairment of flow-mediated endothelium-dependent vasodilation in the forearm.²² A single oral dose of methionine increases plasma homocysteine levels, paralleled by an increase in plasma ADMA and a decline in endothelium-dependent vasodilation.²⁰ In humans with salt-sensitive hypertension, administration of a high-salt diet increases plasma ADMA and blood pressure and reduces urinary nitrogen oxides.¹⁵ A low-salt diet reverses these abnormalities.

	ADMA Regulates Vascular Resistance

Top Introduction ADMA: A Major Cause... ADMA Regulates Vascular... ADMA and Vascular Structure Mechanisms by Which ADMA... Central Role of DDAH ADMA and the "l-Arginine... Therapeutic Modulation of Plasma... Conclusion References

 
There is substantial evidence that ADMA regulates vascular resistance in humans. Intra-arterial infusion of ADMA reduces endothelium-dependent vasodilation in the human forearm.¹² Moreover, intravenous infusion of ADMA (to increase plasma ADMA levels approximately 3-fold) increases systemic vascular resistance by approximately 24% in healthy human subjects.²³ Elevated plasma levels of ADMA are predictive of the increased renovascular resistance observed with aging, hypertension, and heart failure.^24,25 In patients with renal failure, plasma ADMA levels correlate directly with left ventricular thickness and inversely with ejection fraction,²⁶ which is consistent with the effect of ADMA to increase systemic resistance.

In normal pregnancy, there is an initial fall in blood pressure and subsequent return toward baseline values in the third trimester. These changes in blood pressure are mirrored by similar changes in plasma ADMA values. In women who develop preeclampsia, plasma ADMA values are elevated.²⁷ Intriguingly, the impairment of maternal endothelial function and the elevation of plasma ADMA occur before clinical evidence of preeclampsia.²⁸

These clinical studies are supported by experimental studies with cell culture or isolated vessels demonstrating that ADMA inhibits endothelium-dependent vasodilation and/or NO synthesis.^1,29 In mice genetically engineered to express low plasma ADMA levels, NO synthesis is increased, and vascular resistance is reduced.³⁰

	ADMA and Vascular Structure

Top Introduction ADMA: A Major Cause... ADMA Regulates Vascular... ADMA and Vascular Structure Mechanisms by Which ADMA... Central Role of DDAH ADMA and the "l-Arginine... Therapeutic Modulation of Plasma... Conclusion References

 
By reducing the activity of endothelial NOS, ADMA may affect vascular structure as well as vascular reactivity. Endothelial cells resurfacing an injured vessel manifest higher intracellular levels of ADMA and impaired endothelium-dependent vasodilation.^5,31 The severity of the endothelial dysfunction and the intracellular levels of ADMA are directly related to intimal thickness of the injured vessel.^5,31 A recent clinical trial is consistent with a role of ADMA in restenosis. Patients undergoing coronary angioplasty and stent placement received a single intramural delivery of L-arginine or vehicle. Intravascular ultrasound at 6 months revealed a 36% reduction of neointimal volume in those patients receiving L-arginine.³²

Exposure of endothelial cells in culture to pathophysiologically relevant concentrations of ADMA reduces NO synthesis, increases superoxide generation, and increases the adhesiveness of endothelial cells for monocytes.²⁹ Evidence also exists in humans that ADMA enhances endothelial-monocyte interaction. Mononuclear cells of hypercholesterolemic individuals are hyperadhesive, an abnormality that is positively correlated to plasma ADMA levels and that is reversed by oral L-arginine supplementation.³³ Similarly, platelets from hypercholesterolemic animals or humans are hyperreactive. This abnormality is reversed by L-arginine administration, an effect that is associated with increases in platelet cGMP.^34,35 These findings are consistent with previous observations in hypercholesterolemic animals or humans that administration of L-arginine restores NO synthesis and reduces endothelial-monocyte interaction.^33,36,37

Thus, elevations in ADMA are associated with critical processes in atherogenesis. Clinical studies support this linkage. In Japanese individuals with varying levels of risk, multivariate analysis revealed that ADMA and age were the only independent predictors of carotid intimal-medial thickness.¹³ In patients with end-stage renal disease, ADMA levels correlated with carotid intima-media thickness and were predictive for progression of disease.³⁸ Intimal thickening in uterine arteries after hysterectomy is correlated to plasma ADMA levels.³⁹

As expected of a factor that may adversely affect vascular structure, plasma ADMA levels are associated with cardiovascular complications such as stroke, congestive heart failure, or peripheral arterial disease.^40–42 In peripheral arterial disease, plasma ADMA levels are related to the severity of disease.⁴² Notably, an intravenous infusion of L-arginine significantly improves limb blood flow and pain-free walking distance in patients with peripheral arterial disease.⁴³ Cerebrovascular disease is the second most common cause of dementia after Alzheimer disease, which also may have a vascular component. In this context, plasma ADMA levels are reportedly elevated in patients with dementia, associated with a reduction in plasma nitrogen oxides.⁴⁴

Plasma ADMA levels may be predictive of cardiovascular events and/or mortality. In critically ill patients on a surgical intensive care unit, elevated plasma ADMA values were associated with an adverse outcome.⁴⁵ In nonsmoking men with a history of coronary heart disease, those in the upper quartile of ADMA levels had a 4-fold increased risk of an acute coronary event.¹¹ In patients with end-stage renal disease, ADMA levels emerged as the second strongest predictor of all-cause mortality after age, outweighing established risk factors such as hypertension, diabetes, hypercholesterolemia, or smoking.⁴⁶ These small studies suggest that plasma ADMA may be an independent risk factor for vascular disease. However, its value as a prognostic indicator needs to be validated in large, prospective clinical trials that are now under way.⁴⁷

	Mechanisms by Which ADMA Becomes Elevated

Top Introduction ADMA: A Major Cause... ADMA Regulates Vascular... ADMA and Vascular Structure Mechanisms by Which ADMA... Central Role of DDAH ADMA and the "l-Arginine... Therapeutic Modulation of Plasma... Conclusion References

 
Generation of ADMA
ADMA is not derived from the methylation of free L-arginine. Rather, ADMA is generated from posttranslational modification of arginine residues within a variety of specific proteins that are predominantly found in the cell nucleus (for review, see Tran et al⁴⁸). Methylation of arginine residues is catalyzed by a group of enzymes termed protein arginine N-methyltransferases (PRMTs) (Figure). When the proteins undergo proteolysis, free methylarginines are released.

View larger version (21K): [in this window] [in a new window]   Biochemical pathway for generation, elimination, and degradation of ADMA. ADMA derives from methylation of arginine residues in proteins. The reaction is catalyzed by PRMTs that transfer a methyl group from S-adenosyl-L-methionine (SAM) to each guanidino nitrogen of an arginine residue. This reaction results in a methylated arginine derivative (protein containing ADMA) and S-adenosyl-L-homocysteine (SAH). Hydrolysis of the methylated proteins releases ADMA. ADMA is a competitive inhibitor of endothelial NOS. All methylarginines are excreted into the urine and are in part metabolized to -keto acids by the enzyme activity of dimethylarginine pyruvate aminotransferase (DPT). The major metabolism of ADMA occurs via degradation through the enzyme DDAH. The enzyme DDAH hydrolyzes ADMA to form dimethylamine and L-citrulline. DM indicates diabetes mellitus; HTN, hypertension, LDL-C, LDL cholesterol; HCY, hyperhomocystinemia; and CMV, cytomegalovirus.

Two distinct PRMT activities (PRMT types I and II) have been classified. Both subtypes can monomethylate arginine to form MMA but differ in that type I asymmetrically dimethylates arginine to form ADMA, whereas type II catalyzes a symmetrical dimethylation of arginine to form SDMA.⁴⁸ Whereas ADMA and MMA each inhibit NOS, SDMA is not capable of doing so.

To date, there is scant evidence that elevated plasma levels of ADMA are due to increased methylation of arginine residues. The methylation of arginine residues on proteins is a highly regulated process, and methylated proteins have a wide range of functions. Although PRMT activity is influenced by oxidized lipoprotein in vitro,⁴⁹ it is unlikely that primary regulation of ADMA occurs so proximal in the pathway that it would secondarily alter an array of diverse nuclear proteins.

Elimination of ADMA
Humans generate approximately 300 µmol/d (approximately 60 mg) of ADMA.²³ Of this amount, approximately 50 µmol/d is excreted in the urine.¹² Thus, ADMA accumulates in patients with renal failure.¹² Kidney transplantation normalizes SDMA levels, whereas ADMA levels remain elevated.⁵⁰ This may be due to persistent impairment in the degradation of ADMA. Degradation of ADMA (but not SDMA) is mediated largely by dimethylarginine dimethylaminohydrolase (DDAH).^51,52 Two isoforms exist: DDAH I predominates in tissues containing neuronal NOS, whereas DDAH II is more prevalent in tissues expressing endothelial NOS.⁵³ We have proposed that the elevation in plasma ADMA that occurs with vascular disease and risk factors is largely due to impaired activity of DDAH.⁵⁴

	Central Role of DDAH

Top Introduction ADMA: A Major Cause... ADMA Regulates Vascular... ADMA and Vascular Structure Mechanisms by Which ADMA... Central Role of DDAH ADMA and the "l-Arginine... Therapeutic Modulation of Plasma... Conclusion References

 
The first evidence that DDAH is a critical regulator of the NOS pathway came from observations regarding the DDAH inhibitor, 4124W. Addition of 4124W to an isolated vascular segment induces a gradual vasoconstriction, which is reversed by addition of L-arginine to the medium.⁵⁵ 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, pharmacological inhibition of DDAH activity causes ADMA to accumulate, to disrupt NO synthesis, and to thereby induce vasoconstriction.

We have shown that impaired DDAH activity is a central mechanism by which cardiovascular risk factors disrupt the NOS pathway. The activity of DDAH is impaired by oxidative stress, permitting ADMA to accumulate. A wide range of pathological stimuli induces endothelial oxidative stress such as oxidized LDL cholesterol, inflammatory cytokines, hyperhomocystinemia, hyperglycemia, and infectious agents. Each of these insults attenuates DDAH activity in vitro and in vivo.^54,56–58 The attenuation of DDAH allows ADMA to accumulate and to block NO synthesis (Figure). The adverse effect of these stimuli can be reversed in vitro by antioxidants, which preserve the activity of DDAH.

The sensitivity of DDAH to oxidative stress is conferred by a critical sulfhydryl in the active site of the enzyme that is required for the metabolism of ADMA. This sulfhydryl can also be reversibly inhibited by NO in an elegant form of negative feedback.⁵⁹ We have shown that homocysteine mounts an oxidative attack on DDAH to form a mixed disulfide, inactivating the enzyme.⁵⁶ By oxidizing a sulfhydryl moiety critical for DDAH activity, homocysteine and other risk factors cause ADMA to accumulate and to suppress NOS activity.

In apolipoprotein E–deficient mice, hypercholesterolemia is associated with increased levels of plasma ADMA and attenuated angiogenesis.⁶⁰ The effect of ADMA on angiogenesis can be reversed by administration of supplemental L-arginine. These data are consistent with previous observations disclosing a critical role of endothelium-derived NO in angiogenesis.⁶¹ The role of ADMA in modulating angiogenesis was strengthened by the finding that C6 glioma cells genetically engineered to constitutively overexpress the enzyme DDAH resulted in tumors that were more vascular and grew faster than wild type.⁶² Expression of DDAH can also be increased by exposing endothelial cells to retinoic acid. This effect is associated with reduced accumulation of ADMA and increased endothelial cGMP levels.⁶³

In experimental models of pulmonary hypertension, a reduction in pulmonary DDAH activity or expression is associated with an increase in plasma ADMA levels and reduced pulmonary NO synthesis.^64,65 A reduction in DDAH activity could explain elevated plasma ADMA levels and L-arginine responsiveness in patients with pulmonary hypertension.^66–68

The critical role of DDAH activity in regulating NO synthesis in vivo was convincingly demonstrated by our group with the use of a transgenic DDAH mouse.³⁰ In this animal, the activity of DDAH is increased, and plasma ADMA levels are reduced by 50%. The reduction in plasma ADMA is associated with a significant increase in NOS activity, as plasma and urinary nitrate levels are increased 2-fold. The increase in NOS activity translates into a 15-mm Hg reduction in systolic blood pressure in the transgenic mouse. This study provides compelling evidence for the importance of DDAH activity and plasma ADMA levels in the regulation of NO synthesis.

	ADMA and the "L-Arginine Paradox"

Top Introduction ADMA: A Major Cause... ADMA Regulates Vascular... ADMA and Vascular Structure Mechanisms by Which ADMA... Central Role of DDAH ADMA and the "l-Arginine... Therapeutic Modulation of Plasma... Conclusion References

 
The L-arginine paradox relates to observations first made by our group that the administration of L-arginine can reverse endothelial vasodilator dysfunction under some conditions.¹² Later, biochemists who had purified NOS enzyme found that its K_m for L-arginine was in the range of approximately 5 µmol/L. Because L-arginine plasma levels are in the range of 50 µmol/L, it was paradoxical that L-arginine could be rate limiting. Possible explanations for this phenomenon include nonenzymatic generation of NO from L-arginine, release of growth hormone or insulin, or effects at the level of the y⁺-transporter responsible for cellular uptake of L-arginine. However, reversal of the effect of ADMA represents a more likely mechanism.

Endothelial cells exposed for 24 hours to concentrations of ADMA that exist in the plasma of hypercholesterolemic individuals generate less NO and more superoxide anion and are more adhesive for monocytes.²⁹ Similarly, a reduction of plasma ADMA levels from 1.6 µmol/L (in normal mice) to 0.7 µmol/L in our transgenic DDAH mice is associated with a 2-fold increase in plasma and urinary nitrogen oxides.⁵⁰ The striking effect of modest changes in plasma ADMA is surprising given the high intracellular concentrations of L-arginine, which are almost 3 orders of magnitude greater. However, intracellular L-arginine may not have access to NOS (intracellular compartmentalization). Indeed, eNOS colocalizes with plasma membrane regions referred to as caveolae.⁶⁹ Finally, there is evidence that ADMA may also "uncouple" endothelial NOS, such that molecular oxygen becomes the substrate for electron transfer rather than arginine.⁷⁰ Under these conditions, endothelial NOS generates superoxide anion to increase oxidative stress, attenuate NO bioactivity, and induce additional endothelial dysfunctions.

However, an elevation of plasma ADMA does not necessarily predict a beneficial response to L-arginine supplementation. In a small study of men with stable angina and elevated plasma ADMA levels, oral L-arginine supplementation did not improve forearm endothelial vasodilator function, treadmill walking time, or time to ST segment depression.⁷¹ The lack of benefit of L-arginine in this study likely reflects the multifactorial mechanisms of endothelial vasodilator dysfunction. For example, NOS may become a major source of superoxide anion and endothelial dysfunction when L-arginine availability becomes rate limiting. However, deficiencies or reduced activity of tetrahydrobiopterin, heat shock protein 90, or specific tyrosine kinases would probably not be addressed by supplementation with L-arginine.^72–74 L-Arginine may not be useful in later stages of atherosclerosis, in which cytokine- or lipid-induced instability and/or reduced transcription of NOS may decrease its expression.⁷⁵ Endothelial dysfunction secondary to certain NOS gene polymorphisms¹⁰ might be unresponsive to supplemental L-arginine.

	Therapeutic Modulation of Plasma ADMA

Top Introduction ADMA: A Major Cause... ADMA Regulates Vascular... ADMA and Vascular Structure Mechanisms by Which ADMA... Central Role of DDAH ADMA and the "l-Arginine... Therapeutic Modulation of Plasma... Conclusion References

 
Notably, plasma ADMA can be reduced by pharmacotherapy. When glycemic control is improved by administration of metformin, plasma ADMA levels are reduced in diabetics.⁷⁶ In patients with insulin resistance, rosiglitazone improved insulin resistance and lowered plasma ADMA levels.⁷⁷ Treatment of hypertensive patients with a converting-enzyme inhibitor or angiotensin receptor antagonist reduces plasma ADMA levels.^78,79 Estrogen therapy, alone or with progestogens, modestly reduces plasma ADMA (but not SDMA) levels, an effect that may be due to estrogen-induced increases in DDAH activity.^80,81 However, hormonal replacement may also reduce plasma L-arginine levels, so that the L-arginine/ADMA ratio is not favorably affected.⁸² Strategies to reduce oxidative stress would likely enhance DDAH activity and thereby reduce plasma ADMA levels, but the results of 2 small studies of antioxidant vitamins have been negative or inconclusive.^21,83 In the future, a likely target for pharmacotherapy is the enzyme DDAH.

	Conclusion

Top Introduction ADMA: A Major Cause... ADMA Regulates Vascular... ADMA and Vascular Structure Mechanisms by Which ADMA... Central Role of DDAH ADMA and the "l-Arginine... Therapeutic Modulation of Plasma... Conclusion References

 
To summarize, there is compelling evidence that ADMA plays an important role in the regulation of vascular tone by acting as an endogenous inhibitor of NO synthesis. By inhibiting NO synthesis, plasma ADMA may reduce vascular compliance, increase vascular resistance, and limit blood flow. Furthermore, plasma ADMA may promote atherogenesis as it opposes the vasoprotective effects of NO. Thus, elevations in plasma ADMA may accelerate the progression of atherosclerosis and increase the risk of cardiovascular events. ADMA may mediate the effect of many risk factors and risk markers on the NOS pathway. Plasma ADMA level may be an "Über marker," reflecting the summative effect of various risk factors on endothelial health.

	Acknowledgments

 
This study was supported by the National Heart, Lung, and Blood Institute (R01 HL-HL63685, R01 HL00204, and P01 AG18784) and the Tobacco-Related Disease Research Program (7RT-0128).

	References

Top Introduction ADMA: A Major Cause... ADMA Regulates Vascular... ADMA and Vascular Structure Mechanisms by Which ADMA... Central Role of DDAH ADMA and the "l-Arginine... Therapeutic Modulation of Plasma... Conclusion References

 
1. Cooke JP, Dzau VJ. Nitric oxide synthase: role in the genesis of vascular disease. Annu Rev Med. 1997; 48: 489–509.[CrossRef][Medline] [Order article via Infotrieve]

2. von der Leyen HE, Gibbons GH, Morishita R, et al. 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.[Abstract/Free Full Text]

3. Cooke JP, Singer AH, Tsao P, et al. Anti-atherogenic effects of L-arginine in the hypercholesterolemic rabbit. J Clin Invest. 1992; 90: 1168–1172.[Medline] [Order article via Infotrieve]

4. Candipan RC, Wang B, Buitrago R, et al. Regression or progression: dependency upon vascular nitric oxide. Arterioscler Thromb Vasc Biol. 1996; 16: 44–50.[Abstract/Free Full Text]

5. Weidinger FF, McLenachan JM, Cybulsky M, et al. Persistent dysfunction of regenerated endothelium following balloon angioplasty of rabbit iliac artery. Circulation. 1990; 81: 1667–1679.[Abstract/Free Full Text]

6. Kuhlencordt PJ, Gyurko R, Han F, et al. Accelerated atherosclerosis, aortic aneurysm formation, and ischemic heart disease in apolipoprotein E/endothelial nitric oxide synthase double-knockout mice. Circulation. 2001; 104: 448–454.[Abstract/Free Full Text]

7. Schachinger 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.[Abstract/Free Full Text]

8. Suwaidi JA, Hamasaki S, Higano ST, et al. Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction. Circulation. 2000; 101: 948–954.[Abstract/Free Full Text]

9. Gokce N, Keaney JF Jr, Hunter LM, et al. Predictive value of noninvasively determined endothelial dysfunction for long-term cardiovascular events in patients with peripheral vascular disease. J Am Coll Cardiol. 2003; 41: 1769–1775.[Abstract/Free Full Text]

10. Shimasaki Y, Yasue H, Yoshimura M, et al. Association of the missense Glu298Asp variant of the endothelial nitric oxide synthase gene with myocardial infarction. J Am Coll Cardiol. 1998; 31: 1506–1510.[Abstract/Free Full Text]

11. Valkonen VP, Paiva H, Salonen JT, et al. Risk of acute coronary events and serum concentration of asymmetrical dimethylarginine. Lancet. 2001; 358: 2127–2128.[CrossRef][Medline] [Order article via Infotrieve]

12. Vallance P, Leone A, Calver A, et al. Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet. 1992; 339: 572–575.[CrossRef][Medline] [Order article via Infotrieve]

13. Miyazaki H, Matsuoka H, Cooke JP, et al. Endogenous nitric oxide synthase inhibitor: a novel marker of atherosclerosis. Circulation. 1999; 99: 1141–1146.[Abstract/Free Full Text]

14. Surdacki A, Nowicki M, Sandmann J, et al. 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.[CrossRef][Medline] [Order article via Infotrieve]

15. Fujiwara N, Osanai T, Kamada T, et al. 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.[Abstract/Free Full Text]

16. Abbasi F, Asagmi T, Cooke JP, et al. Plasma concentrations of asymmetric dimethylarginine are increased in patients with type 2 diabetes mellitus. Am J Cardiol. 2001; 88: 1201–1203.[CrossRef][Medline] [Order article via Infotrieve]

17. Stuhlinger MC, Abbasi F, Chu JW, et al. Relationship between insulin resistance and an endogenous nitric oxide synthase inhibitor. JAMA. 2002; 287: 1420–1426.[Abstract/Free Full Text]

18. Boger RH, Bode-Boger SM, Szuba A, et al. Asymmetric dimethylarginine (ADMA): a novel risk factor for endothelial dysfunction: its role in hypercholesterolemia. Circulation. 1998; 98: 1842–1847.[Abstract/Free Full Text]

19. Lundman P, Eriksson MJ, Stuhlinger M, et al. Mild-to-moderate hypertriglyceridemia in young men is associated with endothelial dysfunction and increased plasma concentrations of asymmetric dimethylarginine. J Am Coll Cardiol. 2001; 38: 111–116.[Abstract/Free Full Text]

20. Stuhlinger MC, Oka RK, Graf EE, et al: Endothelial dysfunction induced by hyperhomocysteinemia: role of ADMA. Circulation. 2003; 108: 933–938.[Abstract/Free Full Text]

21. Engler MM, Engler MB, Malloy MJ, et al. Antioxidant vitamins C and E improve endothelial function in children and adolescents with hyperlipidemia: Endothelial Assessment of Risk From Lipids in Youth (EARLY) trial. Circulation. 2003; 108: 1059–1063.[Abstract/Free Full Text]

22. Fard A, Tuck CH, Donis JA, et al. 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. 2000; 20: 2039–2044.[Abstract/Free Full Text]

23. Achan V, Broadhead M, Malaki M, et al. Asymmetric dimethylarginine causes hypertension and cardiac dysfunction in humans and is actively metabolized by dimethylarginine dimethylaminohydrolase. Arterioscler Thromb Vasc Biol. 2003; 23: 1455–1459.[Abstract/Free Full Text]

24. Kielstein JT, Bode-Böger SM, Frölich JC, et al. Asymmetric dimethylarginine, blood pressure, and renal perfusion in elderly subjects. Circulation. 2003; 107: 1891–1895.[Abstract/Free Full Text]

25. Kielstein JT, Bode-Böger SM, Klein G, et al. Endogenous nitric oxide synthase inhibitors and renal perfusion in patients with heart failure. Eur J Clin Invest. 2003; 33: 370–375.[CrossRef][Medline] [Order article via Infotrieve]

26. Zoccali C, Mallamaci F, Maas R, et al. Left ventricular hypertrophy, cardiac remodelling and asymmetric dimethylarginine (ADMA) in hemodialysis patients. Kidney Int. 2002; 62: 339–345.[CrossRef][Medline] [Order article via Infotrieve]

27. Holden DP, Fickling SA, Whitley GS, et al. 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.[CrossRef][Medline] [Order article via Infotrieve]

28. Savvidou MD, Hingorani AD, Tsikas D, et al. Endothelial dysfunction and raised plasma concentrations of asymmetric dimethylarginine in pregnant women who subsequently develop pre-eclampsia. Lancet. 2003; 361: 1511–1517.[CrossRef][Medline] [Order article via Infotrieve]

29. Boger RH, Bode-Boger SM, Tsao PS, et al. An endogenous inhibitor of nitric oxide synthase regulates endothelial adhesiveness for monocytes. J Am Coll Cardiol. 2000; 36: 2287–2295.[Abstract/Free Full Text]

30. Dayoub H, Achan V, Adimoolam S, et al. DDAH regulates NO synthesis: genetic and physiological evidence. Circulation. 2003; 108: 1043–1048.

31. Masuda H, Goto M, Tamaoki S, et al. Accelerated intimal hyperplasia and increased endogenous inhibitors for NO synthesis in rabbits with alloxan-induced hyperglycaemia. Br J Pharmacol. 1999; 126: 211–218.[CrossRef][Medline] [Order article via Infotrieve]

32. Suzuki T, Hayase M, Hibi K, et al. Effect of local delivery of L-arginine on in-stent restenosis in humans. Am J Cardiol. 2002; 89: 363–367.[CrossRef][Medline] [Order article via Infotrieve]

33. Chan J, Böger R, Bode-Böger S, et al. Asymmetric dimethylarginine increases mononuclear cell adhesiveness in hypercholesterolemic humans. Arterioscler Thromb Vasc Biol. 2000; 20: 1040.[Abstract/Free Full Text]

34. Tsao PS, Theilmeier G, Singer AH, et al. L-Arginine attenuates platelet reactivity in hypercholesterolemic rabbits. Arterioscler Thromb. 1994; 14: 1529–1533.[Abstract/Free Full Text]

35. Wolf A, Zalpour C, Theilmeier G, et al. Dietary L-arginine supplementation normalizes platelet aggregation in hypercholesterolemic humans. J Am Coll Cardiol. 1997; 29: 479–485.[Abstract]

36. Tsao P, McEvoy LM, Drexler H, et al. Enhanced endothelial adhesiveness in hypercholesterolemia is attenuated by L-arginine. Circulation. 1994; 89: 2176–2182.[Abstract/Free Full Text]

37. Adams MR, McCredie R, Jessup W, et al. 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.[CrossRef][Medline] [Order article via Infotrieve]

38. Zoccali C, Benedetto FA, Maas R, et al. Asymmetric dimethylarginine, C-reactive protein, and carotid intima-media thickness in end-stage renal disease. J Am Soc Nephrol. 2002; 13: 490–496.[Abstract/Free Full Text]

39. Beppu M, Obayashi S, Aso T, et al. Endogenous nitric oxide synthase inhibitors in endothelial cells, endothelin-1 within the vessel wall, and intimal hyperplasia in perimenopausal human uterine arteries. J Cardiovasc Pharmacol. 2002; 39: 192–200.[CrossRef][Medline] [Order article via Infotrieve]

40. Yoo JH, Lee SC. Elevated levels of plasma homocyst(e)ine and asymmetric dimethylarginine in elderly patients with stroke. Atherosclerosis. 2001; 158: 425–430.[CrossRef][Medline] [Order article via Infotrieve]

41. Usui M, Matsuoka H, Miyazaki H, et al. Increased endogenous nitric oxide synthase inhibitor in patients with congestive heart failure. Life Sci. 1998; 62: 2425–2430.[CrossRef][Medline] [Order article via Infotrieve]

42. Boger RH, Bode-Boger SM, Thiele W, et al. Biochemical evidence for impaired nitric oxide synthesis in patients with peripheral arterial occlusive disease. Circulation. 1997; 95: 2068–2074.[Abstract/Free Full Text]

43. Boger RH, Bode-Boger SM, Thiele W, et al. 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.[Abstract/Free Full Text]

44. Selley ML. Increased concentrations of homocysteine and asymmetric dimethylarginine and decreased concentrations of nitric oxide in the plasma of patients with Alzheimer’s disease. Neurobiol Aging. 2003; 24: 903–907.[CrossRef][Medline] [Order article via Infotrieve]

45. Nijveldt RJ, Teerlink T, van der Hoven B, et al. Asymmetrical dimethylarginine (ADMA) in critically ill patients: high plasma ADMA concentration is an independent risk factor of ICU mortality. Clin Nutr. 2003; 22: 23–30.[Medline] [Order article via Infotrieve]

46. Zoccali C, Bode-Boger S, Mallamaci F, et al. Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: a prospective study. Lancet. 2001; 358: 2113–2117.[CrossRef][Medline] [Order article via Infotrieve]

47. Mügge A, Hanefeld C, Böger RH, et al. Plasma concentration of asymmetric dimethylarginine and the risk of coronary heart disease: rationale and design of the multicenter CARDIAC study. Atheroscler Suppl. 2003; 4: 29–32.[Medline] [Order article via Infotrieve]

48. Tran CT, Leiper JM, Vallance P. The DDAH/ADMA/NOS pathway. Atheroscler Suppl. 2003; 4: 33–40.[Medline] [Order article via Infotrieve]

49. Boger RH, Sydow K, Borlak J, et al. LDL cholesterol upregulates synthesis of asymmetrical dimethylarginine in human endothelial cells: involvement of S-adenosylmethionine–dependent methyltransferases. Circ Res. 2000; 87: 99–105.[Abstract/Free Full Text]

50. Fleck C, Janz A, Schweitzer F, et al. Serum concentrations of asymmetric (ADMA) and symmetric (SDMA) dimethylarginine in renal failure patients. Kidney Int Suppl. 2001; 78: S14–S18.[Medline] [Order article via Infotrieve]

51. McDermott JR. Studies on the catabolism of NG-methylarginine, NG,N'G-dimethylarginine and NG,NG-dimethylarginine. Biochem J. 1976; 154: 179–184.[Medline] [Order article via Infotrieve]

52. Murray-Rust J, Leiper J, McAlister M, et al. Structural insights into the hydrolysis of cellular nitric oxide synthase inhibitors by dimethylarginine dimethylaminohydrolase. Nat Struct Biol. 2001; 8: 679–683.[CrossRef][Medline] [Order article via Infotrieve]

53. Leiper JM, Santa Maria J, Chubb A, et al. Identification of two human dimethylarginine dimethylaminohydrolases with distinct tissue distributions and homology with microbial arginine deiminases. Biochem J. 1999; 343: 209–214.[CrossRef][Medline] [Order article via Infotrieve]

54. Ito A, Tsao PS, Adimoolam S, et al. Novel mechanism for endothelial dysfunction: dysregulation of dimethylarginine dimethylaminohydrolase. Circulation. 1999; 99: 3092–3095.[Abstract/Free Full Text]

55. MacAllister RJ, Parry H, Kimoto M, et al. Regulation of nitric oxide synthesis by dimethylarginine dimethylaminohydrolase. Br J Pharmacol. 1996; 119: 1533–1540.[Medline] [Order article via Infotrieve]

56. Stuhlinger MC, Tsao PS, Her JH, et al. Homocysteine impairs the nitric oxide synthase pathway: role of asymmetric dimethylarginine. Circulation. 2001; 104: 2569–2575.[Abstract/Free Full Text]

57. Lin KY, Ito A, Asagami T, et al. Impaired nitric oxide synthase pathway in diabetes mellitus: role of asymmetric dimethylarginine and dimethylarginine dimethylaminohydrolase. Circulation. 2002; 106: 987–992.[Abstract/Free Full Text]

58. Weis M, Kledal TN, Lin KY, et al. Cytomegalovirus infection impairs the NOS pathway: role of ADMA in transplant arteriosclerosis. Circulation. 2004; 109: 500–505.[Abstract/Free Full Text]

59. Leiper J, Murray-Rust J, McDonald N, et al. S-Nitrosylation of dimethylarginine dimethylaminohydrolase regulates enzyme activity: further interactions between nitric oxide synthase and dimethylarginine dimethylaminohydrolase. Proc Natl Acad Sci U S A. 2002; 99: 13527–13532.[Abstract/Free Full Text]

60. Jang J, Ho H-K, Kwan HH, et al. Angiogenesis is impaired by hypercholesterolemia: role of asymmetric dimethylarginine. Circulation. 2000; 102: 1414–1419.[Abstract/Free Full Text]

61. Cooke JP. NO and angiogenesis. Atheroscler Suppl. 2003; 4: 53–60.[Medline] [Order article via Infotrieve]

62. Kostourou V, Robinson SP, Cartwright JE, et al. Dimethylarginine dimethylaminohydrolase I promotes tumour growth and angiogenesis. Br J Cancer. 2002; 87: 673–680.[CrossRef][Medline] [Order article via Infotrieve]

63. Achan V, Tran CT, Arrigoni F, et al. All-trans-retinoic acid increases nitric oxide synthesis by endothelial cells: a role for the induction of dimethylarginine dimethylaminohydrolase. Circ Res. 2002; 90: 764–769.[Abstract/Free Full Text]

64. Millat LJ, Whitley GSJ, Li D, et al. Evidence for dysregulation of dimethylarginine dimethylaminohydrolase I in chronic hypoxia–induced pulmonary hypertension. Circulation. 2003; 108: 1493–1498.[Abstract/Free Full Text]

65. Arrigoni FI, Vallance P, Haworth SG, et al. Metabolism of asymmetric dimethylarginines is regulated in the lung developmentally and with pulmonary hypertension induced by hypobaric hypoxia. Circulation. 2003; 107: 1195–1201.[Abstract/Free Full Text]

66. Mehta S, Stewart DJ, Langleben D, et al. Short-term pulmonary vasodilation with L-arginine in pulmonary hypertension. Circulation. 1995; 92: 1539–1545.[Abstract/Free Full Text]

67. Nagaya N, Uematsu M, Oya H, et al. Short-term oral administration of L-arginine improves hemodynamics and exercise capacity in patients with precapillary pulmonary hypertension. Am J Respir Crit Care Med. 2001; 163: 887–891.[Abstract/Free Full Text]

68. Gorenflo M, Zheng C, Werle E, et al. Plasma levels of asymmetrical dimethyl-L-arginine in patients with congenital heart disease and pulmonary hypertension. J Cardiovasc Pharmacol. 2001; 37: 489–492.[CrossRef][Medline] [Order article via Infotrieve]

69. McDonald KK, Zharikov S, Block ER, et al. 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.[Abstract/Free Full Text]

70. Sydow K, Münzel T. ADMA and oxidative stress. Atheroscler Suppl. 2003; 4: 41–51.[Medline] [Order article via Infotrieve]

71. Walker HA, McGing E, Fisher I, et al. Endothelium-dependent vasodilation is independent of the plasma L-arginine/ADMA ratio in men with stable angina: lack of effect of oral L-arginine on endothelial function, oxidative stress and exercise performance. J Am Coll Cardiol. 2001; 38: 499–505.[Abstract/Free Full Text]

72. Xia Y, Tsai AL, Berka V, et al. Superoxide generation from endothelial nitric-oxide synthase: a Ca2+/calmodulin-dependent and tetrahydrobiopterin regulatory process. J Biol Chem. 1998; 273: 25804–25808.[Abstract/Free Full Text]

73. Vasquez-Vivar J, Kalyanaraman B, Martasek P, et al. Superoxide generation by endothelial nitric oxide synthase: the influence of cofactors. Proc Natl Acad Sci U S A. 1998; 95: 9220–9225.[Abstract/Free Full Text]

74. Ou J, Fontana JT, Ou Z, et al. Heat shock protein 90 and tyrosine kinase regulate eNOS NO* generation but not NO* bioactivity. Am J Physiol. 2004; 286: H561–H569.

75. Liao JK, Shin WS, Lee WY, et al. Oxidized low-density lipoprotein decreases the expression of endothelial nitric oxide synthase. J Biol Chem. 1995; 270: 319–324.[Abstract/Free Full Text]

76. Asagmi T, Abbasi F, Stuehlinger M, et al. Metformin treatment lowers asymmetric dimethylarginine concentrations in patients with type 2 diabetes. Metabolism. 2002; 51: 843–846.[CrossRef][Medline] [Order article via Infotrieve]

77. Stuhlinger MC, Abbasi F, Chu JW, et al. Relationship between insulin resistance and an endogenous nitric oxide synthase inhibitor. JAMA. 2002; 287: 1420–1426.[Abstract/Free Full Text]

78. Ito A, Egashira K, Narishige T, et al. Renin-angiotensin system is involved in the mechanism of increased serum asymmetric dimethylarginine in essential hypertension. Jpn Circ J. 2001; 65: 775–778.[CrossRef][Medline] [Order article via Infotrieve]

79. Delles C, Schneider MP, John S, et al. Angiotensin converting enzyme inhibition and angiotensin II AT1-receptor blockade reduce the levels of asymmetrical N(G), N(G)-dimethylarginine in human essential hypertension. Am J Hypertens. 2002; 15(pt 1): 590–593.

80. Teerlink T, Neele SJM, de Jong S, et al. Estrogen replacement therapy lowers plasma levels of asymmetrical dimethylarginine in healthy postmenopausal women. Clin Sci (Lond). 2003; 105: 67–71.[Medline] [Order article via Infotrieve]

81. Holden DP, Cartwright JE, Nussey SS, et al. Estrogen stimulates dimethylarginine dimethylaminohydrolase activity and the metabolism of asymmetric dimethylarginine. Circulation. 2003; 108: 1575–1580.[Abstract/Free Full Text]

82. Post MS, Verhoeven MO, Van der Mooren MJ, et al. Effect of hormone replacement therapy on plasma levels of the cardiovascular risk factor asymmetric dimethylarginine: a randomized, placebo-controlled 12-week study in healthy early postmenopausal women. J Clin Endocrinol Metab. 2003; 88: 4221–4226.[Abstract/Free Full Text]

83. Saran R, Novak JE, Desai A, et al. Impact of vitamin E on plasma asymmetric dimethylarginine (ADMA) in chronic kidney disease (CKD): a pilot study. Nephrol Dial Transplant. 2003; 18: 2415–2420.[Abstract/Free Full Text]

This article has been cited by other articles:

				A. Surdacki, E. Marewicz, E. Wieczorek-Surdacka, T. Rakowski, G. Szastak, J. Pryjma, D. Dudek, and J. S. Dubiel Synergistic effects of asymmetrical dimethyl-L-arginine accumulation and endothelial progenitor cell deficiency on renal function decline during a 2-year follow-up in stable angina Nephrol. Dial. Transplant., September 3, 2009; (2009) gfp439v1. [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]

				E. Schepers, G. Glorieux, A. Dhondt, L. Leybaert, and R. Vanholder Role of symmetric dimethylarginine in vascular damage by increasing ROS via store-operated calcium influx in monocytes Nephrol. Dial. Transplant., May 1, 2009; 24(5): 1429 - 1435. [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]

				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]

				M. C. Stuehlinger, B. Metzler, and J. P. Cooke Letter by Stuehlinger et al Regarding Article, "Metabolic Profiling of Arginine and Nitric Oxide Pathways Predicts Hemodynamic Abnormalities and Mortality in Patients With Cardiogenic Shock After Acute Myocardial Infarction" Circulation, September 2, 2008; 118(10): e149 - e149. [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]

				K. Sydow, C. E. Mondon, J. Schrader, H. Konishi, and J. P. Cooke Dimethylarginine Dimethylaminohydrolase Overexpression Enhances Insulin Sensitivity Arterioscler Thromb Vasc Biol, April 1, 2008; 28(4): 692 - 697. [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]

				A. M. Wilson, R. K. Harada, N. Nair, N. Balasubramanian, and J. P. Cooke Response to Letter Regarding Article, "L-Arginine Supplementation in Peripheral Arterial Disease: No Benefit and Possible Harm" Circulation, February 12, 2008; 117(6): e158 - e158. [Full Text] [PDF]

				H. Dayoub, R. N. Rodionov, C. Lynch, J. P. Cooke, E. Arning, T. Bottiglieri, S. R. Lentz, and F. M. Faraci Overexpression of Dimethylarginine Dimethylaminohydrolase Inhibits Asymmetric Dimethylarginine-Induced Endothelial Dysfunction in the Cerebral Circulation Stroke, January 1, 2008; 39(1): 180 - 184. [Abstract] [Full Text] [PDF]

				L. Hong and W. Fast Inhibition of Human Dimethylarginine Dimethylaminohydrolase-1 by S-Nitroso-L-homocysteine and Hydrogen Peroxide: ANALYSIS, QUANTIFICATION, AND IMPLICATIONS FOR HYPERHOMOCYSTEINEMIA J. Biol. Chem., November 30, 2007; 282(48): 34684 - 34692. [Abstract] [Full Text] [PDF]

				J. B. Meigs, M. G. Larson, C. S. Fox, J. F. Keaney Jr., R. S. Vasan, and E. J. Benjamin Association of Oxidative Stress, Insulin Resistance, and Diabetes Risk Phenotypes: The Framingham Offspring Study Diabetes Care, October 1, 2007; 30(10): 2529 - 2535. [Abstract] [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]

				A. M. Wilson, R. Harada, N. Nair, N. Balasubramanian, and J. P. Cooke L-Arginine Supplementation in Peripheral Arterial Disease: No Benefit and Possible Harm Circulation, July 10, 2007; 116(2): 188 - 195. [Abstract] [Full Text] [PDF]

				E. L. Schiffrin, M. L. Lipman, and J. F.E. Mann Chronic Kidney Disease: Effects on the Cardiovascular System Circulation, July 3, 2007; 116(1): 85 - 97. [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]

				F. Mariotti, J. F. Huneau, I. Szezepanski, K. J. Petzke, Y. Aggoun, D. Tome, and D. Bonnet Meal Amino Acids with Varied Levels of Arginine do Not Affect Postprandial Vascular Endothelial Function in Healthy Young Men J. Nutr., June 1, 2007; 137(6): 1383 - 1389. [Abstract] [Full Text] [PDF]

				N. Melikian, S. B. Wheatcroft, O. S. Ogah, C. Murphy, P. J. Chowienczyk, A. S. Wierzbicki, T. A.B. Sanders, B. Jiang, E. R. Duncan, A. M. Shah, et al. Asymmetric Dimethylarginine and Reduced Nitric Oxide Bioavailability in Young Black African Men Hypertension, April 1, 2007; 49(4): 873 - 877. [Abstract] [Full Text] [PDF]

				B. Cortes, I. Nunez, M. Cofan, R. Gilabert, A. Perez-Heras, E. Casals, R. Deulofeu, and E. Ros Acute Effects of High-Fat Meals Enriched With Walnuts or Olive Oil on Postprandial Endothelial Function J. Am. Coll. Cardiol., October 17, 2006; 48(8): 1666 - 1671. [Abstract] [Full Text] [PDF]

				C. Antoniades, D. Tousoulis, K. Marinou, C. Vasiliadou, C. Tentolouris, G. Bouras, C. Pitsavos, and C. Stefanadis Asymmetrical dimethylarginine regulates endothelial function in methionine-induced but not in chronic homocystinemia in humans: effect of oxidative stress and proinflammatory cytokines. Am. J. Clinical Nutrition, October 1, 2006; 84(4): 781 - 788. [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]

				W.-Z. Zhang, K. Venardos, J. Chin-Dusting, and D. M. Kaye Response to Cigarettes and ADMA: The Smoke Hasn't Cleared Yet Hypertension, October 1, 2006; 48(4): E21 - E21. [Full Text] [PDF]

				J. T. Kielstein, C. Peter, and M. C. Adams Cigarettes and ADMA: The Smoke Hasn't Cleared Yet Hypertension, October 1, 2006; 48(4): E20 - E20. [Full Text] [PDF]

				J. T. Kielstein, S. R. Salpeter, S. M. Bode-Boeger, J. P. Cooke, and D. Fliser Symmetric dimethylarginine (SDMA) as endogenous marker of renal function--a meta-analysis Nephrol. Dial. Transplant., September 1, 2006; 21(9): 2446 - 2451. [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]

				C. B. Taylor, A. Conrad, F. H. Wilhelm, E. Neri, A. DeLorenzo, M. A. Kramer, J. Giese-Davis, W. T. Roth, R. Oka, J. P. Cooke, et al. Psychophysiological and Cortisol Responses to Psychological Stress in Depressed and Nondepressed Older Men and Women With Elevated Cardiovascular Disease Risk Psychosom Med, July 1, 2006; 68(4): 538 - 546. [Abstract] [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]

				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]

				R. Yamamoto and Y. Aso Synergistic Association of Metabolic Syndrome and Overt Nephropathy With Elevated Asymmetric Dimethylarginine in Serum and Impaired Cutaneous Microvasodilation in Patients With Type 2 Diabetes Diabetes Care, April 1, 2006; 29(4): 928 - 930. [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]

				G. S. Getz and C. A. Reardon Arginine/Arginase NO NO NO Arterioscler Thromb Vasc Biol, February 1, 2006; 26(2): 237 - 239. [Full Text] [PDF]

				M. Gritters, M. P. C. Grooteman, M. Schoorl, M. Schoorl, P. C. M. Bartels, P. G. Scheffer, T. Teerlink, C. G. Schalkwijk, M. Spreeuwenberg, and M. J. Nube Citrate anticoagulation abolishes degranulation of polymorphonuclear cells and platelets and reduces oxidative stress during haemodialysis Nephrol. Dial. Transplant., January 1, 2006; 21(1): 153 - 159. [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]

				J. T. Kielstein and J. P. Cooke Arginine Metabolism, Pulmonary Hypertension, and Sickle Cell Disease JAMA, November 16, 2005; 294(19): 2433 - 2433. [Full Text] [PDF]

				C. R. Morris, E. P. Vichinsky, G. J. Kato, M. T. Gladwin, S. Hazen, and S. M. Morris Jr Arginine Metabolism, Pulmonary Hypertension, and Sickle Cell Disease--Reply JAMA, November 16, 2005; 294(19): 2433 - 2434. [Full Text] [PDF]

				N. Nair, R. K Oka, L. D Waring, E. M Umoh, C B. Taylor, and J. P Cooke Vascular compliance versus flow-mediated vasodilation: correlation with cardiovascular risk factors Vascular Medicine, November 1, 2005; 10(4): 275 - 283. [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]

				C. Antoniades, D. Tousoulis, and C. Stefanadis Letter Regarding Article by Becker et al, "Hyperhomocysteinemia, a Cardiac Metabolic Disease: Role of Nitric Oxide and the p22phox Subunit of NADPH Oxidase" Circulation, October 11, 2005; 112(15): e266 - e266. [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]

				F. Perticone, A. Sciacqua, R. Maio, M. Perticone, R. Maas, R. H. Boger, G. Tripepi, G. Sesti, and C. Zoccali Asymmetric Dimethylarginine, L-Arginine, and Endothelial Dysfunction in Essential Hypertension J. Am. Coll. Cardiol., August 2, 2005; 46(3): 518 - 523. [Abstract] [Full Text] [PDF]

				R. E. Girgis, H. C. Champion, G. B. Diette, R. A. Johns, S. Permutt, and J. T. Sylvester Decreased Exhaled Nitric Oxide in Pulmonary Arterial Hypertension: Response to Bosentan Therapy Am. J. Respir. Crit. Care Med., August 1, 2005; 172(3): 352 - 357. [Abstract] [Full Text] [PDF]

				D. Fliser, F. Kronenberg, J. T. Kielstein, C. Morath, S. M. Bode-Boger, H. Haller, and E. Ritz Asymmetric Dimethylarginine and Progression of Chronic Kidney Disease: The Mild to Moderate Kidney Disease Study J. Am. Soc. Nephrol., August 1, 2005; 16(8): 2456 - 2461. [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]

				R. H Boger, J. P Cooke, and P. Vallance ADMA: an emerging cardiovascular risk factor Vascular Medicine, July 1, 2005; 10(1_suppl): S1 - S2. [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]

				K. Sydow, C. E Mondon, and J. P Cooke Insulin resistance: potential role of the endogenous nitric oxide synthase inhibitor ADMA Vascular Medicine, July 1, 2005; 10(1_suppl): S35 - S43. [Abstract] [PDF]

				R. Maas Pharmacotherapies and their influence on asymmetric dimethylargine (ADMA) Vascular Medicine, July 1, 2005; 10(1_suppl): S49 - S57. [Abstract] [PDF]

				T. Teerlink ADMA metabolism and clearance Vascular Medicine, July 1, 2005; 10(1_suppl): S73 - S81. [Abstract] [PDF]

				R. H Boger, J. P Cooke, and P. Vallance ADMA: an emerging cardiovascular risk factor Vascular Medicine, May 1, 2005; 10(2_suppl): S1 - S2. [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]

				K. Sydow, C. E Mondon, and J. P Cooke Insulin resistance: potential role of the endogenous nitric oxide synthase inhibitor ADMA Vascular Medicine, May 1, 2005; 10(2_suppl): S35 - S43. [Abstract] [PDF]

				R. Maas Pharmacotherapies and their influence on asymmetric dimethylargine (ADMA) Vascular Medicine, May 1, 2005; 10(2_suppl): S49 - S57. [Abstract] [PDF]

				T. Teerlink ADMA metabolism and clearance Vascular Medicine, May 1, 2005; 10(2_suppl): S73 - S81. [Abstract] [PDF]

				F. Scalera, J. T. Kielstein, J. Martens-Lobenhoffer, S. C. Postel, M. Tager, and S. M. Bode-Boger Erythropoietin Increases Asymmetric Dimethylarginine in Endothelial Cells: Role of Dimethylarginine Dimethylaminohydrolase J. Am. Soc. Nephrol., April 1, 2005; 16(4): 892 - 898. [Abstract] [Full Text] [PDF]

				J. Jacobi, K. Sydow, G. von Degenfeld, Y. Zhang, H. Dayoub, B. Wang, A. J. Patterson, M. Kimoto, H. M. Blau, and J. P. Cooke Overexpression of Dimethylarginine Dimethylaminohydrolase Reduces Tissue Asymmetric Dimethylarginine Levels and Enhances Angiogenesis Circulation, March 22, 2005; 111(11): 1431 - 1438. [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]

				A. T. Hirsch and A. R. Folsom The Continuum of Risk: Vascular Pathophysiology, Function, and Structure Circulation, November 2, 2004; 110(18): 2774 - 2777. [Full Text] [PDF]

This Article Extract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cooke, J. P. Search for Related Content PubMed PubMed Citation Articles by Cooke, J. P. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB (L)-ARGININE Related Collections Pathophysiology Risk Factors Endothelium/vascular type/nitric oxide