• Asymmetric dimethylarginine;
  • atherosclerosis;
  • cardiovascular risk;
  • dimethylarginine dimethylaminohydrolase;
  • nitric oxide;
  • renal dysfunction


  1. Top of page
  2. Abstract
  3. The ADMA–NO connection
  4. Conclusion
  5. References

Endothelial dysfunction as a result of reduced bioavailability of nitric oxide (NO) plays a central role in the process of atherosclerotic vascular disease. In endothelial cells NO is synthesized from the amino acid l-arginine by the action of the NO synthase (NOS), which can be blocked by endogenous inhibitors such as asymmetric dimethylarginine (ADMA). Acute systemic administration of ADMA to healthy subjects significantly reduces NO generation, and causes an increase in systemic vascular resistance and blood pressure. Increased plasma ADMA levels as a result of reduced renal excretion have been associated with atherosclerotic complications in patients with terminal renal failure. However, a significant relationship between ADMA and traditional cardiovascular risk factors such as advanced age, high blood pressure and serum LDL-cholesterol, has been documented even in individuals without manifest renal dysfunction. As a consequence, the metabolism of ADMA by the enzyme dimethylarginine dimethylaminohydrolase (DDAH) has come into the focus of cardiovascular research. It has been proposed that dysregulation of DDAH with consecutive increase in plasma ADMA concentration and chronic NOS inhibition is a common pathophysiological pathway in numerous clinical conditions. Thus, ADMA has emerged as a potential mediator of atherosclerotic complications in patients with coronary heart disease, peripheral vascular disease, stroke, etc., being the culprit and not only an innocent biochemical marker of the atherosclerotic disease process.

The ADMA–NO connection

  1. Top of page
  2. Abstract
  3. The ADMA–NO connection
  4. Conclusion
  5. References

It is now widely accepted that endothelial dysfunction as a result of reduced bioavailability of nitric oxide (NO) plays a central role in the process of atherosclerotic vascular disease [1]. NO is a very active but short-living molecule that is released in the circulation from endothelial cells. It is a potent vasodilator that regulates vascular tone and tissue blood flow, and inhibits platelet aggregation and leukocyte adhesion on the endothelial surface. It is synthesized by stereospecific oxidation of the terminal guanidino nitrogen of the amino acid l-arginine by the action of a family of NO synthases (NOS) [2]. In endothelial cells, NO is synthesized by the endothelial NOS (eNOS), which converts the amino acid l-arginine into l-citrulline and NO. In clinical studies, impairment of the l-arginine/NO pathway independently predicted cardiovascular complications related to atherosclerosis [3–5]. Consequently, guanidino-substituted analogues of l-arginine which competitively block the NOS active site, i.e. endogenous NOS inhibitors such as asymmetric dimethylarginine (ADMA) and N-monomethylarginine (MMA), have gained much interest in cardiovascular medicine over the past decade [6,7]. Experimental and clinical research has focused on ADMA, however, because it is the predominant NOS inhibitor in humans with plasma levels 10-fold greater than those of MMA [8]. ADMA is released in endothelial cells (and other cell lines) after post-translational methylation from proteins involved in RNA processing and transcriptional control [9,10] (Fig. 1). The enzyme protein arginine methyltransferase type I (PRMT I) produces ADMA, whereas PRMT II produces symmetric dimethylarginine (SDMA), i.e. the stereoisomer of ADMA which has no proven direct inhibitory effect on NOS [11]. Meanwhile several PRMTs that produce methylarginines have been described [12].


Figure 1. Biochemical pathways for generation and degradation of asymmetric dimethylarginine (ADMA). PRMT I = protein arginine methyltransferase type I; NOS = nitric oxide synthase; DDAH = dimethylarginine dimethylaminohydrolase; DPT = dimethylarginine pyruvate aminotransferase. For detailed explanation please see text.

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Data from experimental studies document that biologically relevant ADMA blood levels significantly inhibit NOS and reduce NO generation in cultured endothelial cells and in isolated human blood vessels [13–15]. Further, administration of ADMA to laboratory animals caused an increase in renal, mesenteric and hindquarters vascular resistance and an increase in blood pressure [16,17]. In humans, indirect evidence for a biologically relevant action of ADMA comes from a study in renal patients, in whom plasma ADMA concentrations were markedly increased as compared with healthy controls [18]. Their blood significantly inhibited NO production in cultured endothelial cells ex vivo. In addition, Chan et al. have found that mononuclear cell adhesiveness ex vivo significantly correlates with plasma ADMA levels [19]. The authors could also enhance leukocyte adhesiveness by coculturing them with ADMA-stimulated endothelial cells. Moreover, local infusion of ADMA into the brachial artery significantly attenuated endothelial-dependent vasodilatation in healthy volunteers [8,20]. Finally, we and others have demonstrated that systemic administration of ADMA to healthy subjects causes a dose-dependent and sustained reduction of NO production and cardiac output, and an increase in peripheral vascular resistance accompanied by a rise in mean arterial blood pressure (Fig. 2) [21,22]. In addition, infusion of ADMA significantly reduced renal perfusion and increased sodium reabsorption. These renal effects can be induced even with low dose ADMA administration, i.e. a dose which does not cause an (acute) increase in blood pressure [23]. Importantly, these adverse cardiovascular effects were documented at plasma ADMA concentrations that are encountered in patients with different cardiovascular diseases [7,21]. Taken together, in vitro and in vivo findings confirm that ADMA is a potent and long-lasting (endogenous) NOS inhibitor.


Figure 2. Effect of systemic intravenous administration of asymmetric dimethylarginine (ADMA) to healthy subjects on cardiac output (a) and systemic vascular resistance (b) measured invasively using a right heart catheter. The infusion of ADMA caused an immediate significant increase in systemic vascular resistance and a decrease in cardiac output. The cardiovascular effects of ADMA persisted for at least 2 h after discontinuation of the infusion (with permission from reference [21]).

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The role of renal dysfunction in the metabolism of ADMA

In their seminal paper, Vallance et al. reported increased plasma concentrations of methylarginines (i.e. ADMA and SDMA) in a small group of patients on maintenance haemodialysis [8]. They hypothesized that the high incidence of hypertension and atherosclerosis encountered in patients with terminal renal failure might be caused, at least in part, by dysfunction of the l-arginine/NO pathway secondary to accumulation of ADMA because of declining renal excretion. Indeed, in several subsequent studies, markedly increased plasma ADMA levels have been documented in patients with terminal renal failure [24–28]. As pointed out previously, plasma ADMA concentrations in these patients are certainly high enough to significantly reduce NO production. Indirect evidence for a pathophysiological role of ADMA comes from the observation that in patients on maintenance haemodialysis with vascular complications, plasma ADMA levels are significantly higher than in patients without manifest atherosclerotic disease [26]. Moreover, in a prospective study in 225 patients with terminal renal failure, increased plasma ADMA concentrations were not only significantly related to the severity of carotid atherosclerosis and left ventricular dysfunction but, in addition, were the second strongest predictor (after age) of all-cause and cardiovascular mortality (Fig. 3) among several traditional and nontraditional risk factors assessed [27,29,30]. A subsequent analysis of the same study population revealed that ADMA also significantly correlates with plasma noradrenaline levels in these patients [31]. Because of the compelling data obtained in patients with renal failure, ADMA has been regarded by many rather as a uraemic toxin than a substance with more general significance in cardiovascular medicine.


Figure 3. ADMA and cardiovascular morbidity and mortality in 225 patients with terminal renal failure. In the Cox's regression model plasma ADMA concentration ranked as the second factor (after age) predicting cardiovascular outcome. The overall risk of fatal and nonfatal cardiovascular events (adjusted for age and sex) was progressively higher from the 50th percentile of plasma ADMA levels onwards (Adapted from data in reference [27]).

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DDAH and ADMA – a less nephrocentric view of the problem?

The assumption that renal excretion of ADMA is the main route of elimination has been recently questioned. Particularly our observation of significantly increased plasma ADMA concentrations in patients with incipient renal disease, i.e. in patients with normal glomerular filtration rate as documented by invasive clearance measurements, support the notion that other degradation pathways must also be involved [32]. It is now well established that the key elimination route for ADMA is enzyme degradation by dimethylarginine dimethylaminohydrolase (DDAH), which hydrolyses ADMA to dimethylamine and l-citrulline (Fig. 1) [33,34]. So far, two isoforms of DDAH have been characterized; DDAH2 is the predominant form in tissues expressing eNOS. It has been estimated that in humans, approximately 300 µmol of ADMA is generated per day, of which approximately 250 µmol is metabolized by DDAHs, whereas only a minor amount is excreted by the kidneys [18]. Moreover, the finding that DDAH and NOS are colocalized in cells supports the hypothesis that intracellular ADMA concentration is actively regulated in NO-generating cells [35]. Because NO has tremendous biological activity, its tissue and/or blood concentration must be kept within narrow limits in order to prevent harmful effects on cell activity. This could be accomplished by cell-specific competitive NOS inhibitors such as ADMA. Indeed, recent experimental results even point to the possibility that DDAH activity is directly regulated by S-nitrosylation of its active site by NO, thereby creating a regulatory feedback loop between NO, DDAH, ADMA and NOS (Fig. 1) [36]. The implication of this finding is that under conditions of increased NO production, such as in inflammation where the inducible NOS (iNOS) generates abundant NO, S-nitrosylation diminishes DDAH activity and this in turn would lead to accumulation of ADMA and to NOS inhibition. This putative feedback loop would also help explain, at least in part, the link between infectious diseases, inflammation and atherosclerosis [37,38].

The finding that DDAH is present in abundance in endothelial cells within the glomerulus and renal vessels, and particularly in renal tubular cells supports the concept that impaired ADMA degradation by renal DDAH rather than by reduced renal filtration is the major cause of increased plasma ADMA concentrations in patients with renal disease [7,32]. DDAH in renal cells regulates (intra)cellular methylarginine levels thereby governing cell-specific l-arginine uptake and NO generation [35]. Indirect proof for the assumption that destruction of DDAH-rich renal tissue could impair ADMA degradation comes from metabolic balance studies in laboratory animals and in healthy subjects with normal renal function, which have revealed that the kidney is a major extraction site for ADMA from the circulation [39,40]. Collectively, these data may explain why plasma ADMA concentrations can increase in patients with even minor renal dysfunction, potentially contributing to their significantly increased cardiovascular morbidity and mortality [41,42]. Another important aspect of NOS inhibition by increased ADMA levels in patients with renal dysfunction is the progression of renal disease. Experimental studies have revealed that reduced NO bioavailability plays a critical role in progression, and increased ADMA blood levels may contribute to this process [43]. In this respect, it is of interest that plasma ADMA levels significantly correlate with the age-related decrease in renal perfusion in elderly subjects [44]. Prospective clinical studies are warranted to clarify the role of ADMA in the progression of renal disease.

NOS inhibition by ADMA – a common pathway of endothelial dysfunction and atherosclerosis

A growing number of published studies in individuals without manifested renal disease documented a strong relationship between several traditional cardiovascular risk factors and increased plasma ADMA levels (Table 1). For example, results from a cross-sectional study in 116 otherwise healthy Japanese subjects revealed that plasma ADMA concentrations were positively correlated with age, mean arterial blood pressure and glucose intolerance [45]. Most strikingly, plasma ADMA levels were also significantly correlated with the intima-media thickness of the carotid arteries, an established surrogate parameter of atherosclerosis. Moreover, in a large cohort of Finish men with normal renal function in whom several (traditional) cardiovascular risk factors were present, increased plasma ADMA levels were predictive for future coronary events [69].

Table 1.  Clinical conditions, diseases and experimental settings in which increased plasma asymmetric dimethylarginine (ADMA) concentrations have been reported. ADMA may serve as a cardiovascular risk marker in many of these conditions, whereas in some it is thought to play a definite pathophysiological role
Condition/diseaseClinical evidence [reference]Experimental evidence [reference]
Salt intake/high blood pressure[44,45,47,48][49]
Insulin resistance/hyperglycaemia[45,60][61]
Hypertension (essential)[45,47,51,62–64][65]
Hypertension (pulmonary)[66,67][68]
Coronary heart disease[27,69–72] 
Vascular disease/stroke[26,73–76][77]
Heart failure[78,79][80]

The key mechanism for an increase of plasma ADMA concentrations in populations without renal dysfunction is thought to be dysregulation of DDAH, i.e. inhibition of DDAH activity by hypercholesterolemia (LDL-cholesterol), hyperglycemia, inflammation, etc. This concept is also supported by data obtained in various experimental settings (Table 1). It is therefore conceivable that an increase in plasma ADMA concentrations as a result of DDAH inhibition may be a common pathway through which traditional as well as nontraditional cardiovascular risk factors may cause chronic endothelial dysfunction leading to atherosclerotic vascular disease (Fig. 1) [6]. Further evidence for this idea comes from a recent experiment with transgenic mice harbouring the human DDAH gene [88]. In these animals, additional DDAH activity lowers plasma ADMA concentration and increases NO bioavailability. As a result, vascular resistance and blood pressure are significantly lower than in wild type animals.

Based on the clinical and experimental data reviewed in this article, the hypothesis has been put forward that chronically elevated plasma ADMA concentrations may be of definite relevance in human cardiovascular biology, i.e. ADMA being the culprit and not only an innocent biochemical bystander of the atherosclerotic disease process [6,7,89]. Several recently published experimental studies revealing direct adverse effects of ADMA at the cellular and tissue level have provided further evidence in favour of this hypothesis [90–92]. In this respect, the discovery of a DDAH2 promoter polymorphism in human tissue is of particular interest, as it may be responsible for individual differences in the ability to metabolize ADMA [93]. This could theoretically contribute to the individual susceptibility for atherosclerosis and related vascular disorders.

Therapeutic perspectives

Because ADMA is thought to be a competitive NOS inhibitor, the logical therapeutic intervention would be administration of l-arginine in order to overcome NOS inhibition. To date, a large body of evidence has accumulated on the beneficial role of l-arginine administration on several aspects of endothelial (dys)function, but surprisingly few studies have specifically addressed the potential role of ADMA [6]. Böger et al. showed that administration of l-arginine to laboratory animals and to patients with peripheral vascular disease increased the l-arginine/ADMA ratio and thereby NO production and, in addition, also ameliorated clinical symptoms in patients [94,95]. Moreover, several pharmaceutical interventions have been tested in clinical trials, e.g. oral oestrogen, lipid-lowering drugs and ACE inhibitors (Table 2). There is evidence that hormone replacement therapy in postmenopausal women can reduce plasma ADMA concentrations via stimulation of DDAH activity [98–100]. In contrast, most studies examining the effect of HMG-CoA-reductase inhibitors (statins) on plasma ADMA levels were disappointing in this respect (Table 2). Results from two smaller studies in patients with essential hypertension and type 2 diabetes mellitus have suggested that pharmacological treatment with ACE inhibitors and/or AT1-receptor antagonists may reduce plasma ADMA concentrations [108,109], but we were not able to confirm this finding in a recent double-blind placebo-controlled trial with olmesartan [110]. Finally, improvement of insulin sensitivity was accompanied by a decrease in plasma ADMA concentrations in nondiabetic as well as in diabetic subjects [60,111].

Table 2.  The effect of various therapeutic interventions on plasma asymmetric dimethylarginine (ADMA) concentrations. Studies that have reported reduction of plasma ADMA levels are indicated as positive evidence, whereas reports in which no significant effect on ADMA has been observed are listed as negative evidence
Therapeutic interventionPositive evidence [reference]Negative evidence [reference]
Intravenous l-arginine[94–96][97]
Oral estrogen[98–100] 
Lipid lowering agents (statins/fibrates)[101,102][103–107]
ACE inhibitors/AT1-receptor antagonists[108,109][110]
Glucose lowering agents[60,111] 

Despite the theoretical possibility of therapeutic DDAH modulation and hence, plasma ADMA concentration, it has yet to be proven in controlled clinical studies that lowering ADMA also improves cardiovascular outcome in populations at risk. A major obstacle for the conduction of large-scale intervention trials as well as of epidemiological surveys is the measurement of ADMA, however. The available analytical methods of choice – high performance liquid chromatography (HPLC) and tandem liquid chromatography-mass spectrometry (LC-MS) – are rather sophisticated, impractical for routine use and quite expensive. In addition, most laboratories using these methods report different values for the normal range. In face of the growing importance of ADMA in cardiovascular medicine [6,89], the introduction of a sensitive and reliable standardized measurement into routine diagnostic should be soon accomplished.


  1. Top of page
  2. Abstract
  3. The ADMA–NO connection
  4. Conclusion
  5. References

ADMA is a potent and long-lasting endogenous NOS inhibitor that is thought to be a key player in the process of chronic vascular disease. Future research must therefore elucidate in detail the relationship between ADMA, DDAH, NOS and NO in human disease. In addition, large controlled trials on therapeutic interventions that reduce plasma ADMA levels should assess outcome in populations at risk.


  1. Top of page
  2. Abstract
  3. The ADMA–NO connection
  4. Conclusion
  5. References
  • 1
    Landmesser U, Hornig B, Drexler H. Endothelial function: a critical determinant in atherosclerosis? Circulation 2004;109 (Suppl. 1):II27II33.
  • 2
    Moncada S, Higgs A. The 1-arginine-nitric oxide pathway. N Engl J Med 1993;329: 200212.
  • 3
    Schachinger V, Britten MB, Zeiher AM. Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation 2000;101: 1899906.
  • 4
    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: 94854.
  • 5
    Gokce N, Keaney JF Jr, Hunter LM, Watkins MT, Nedeljkovic ZS, Menzoian JO 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: 176975.
  • 6
    Cooke JP. Asymmetrical dimethylarginine – the über marker? Circulation 2004;109: 18138.
  • 7
    Fliser D, Kielstein JT, Bode-Böger SM, Haller H. Asymmetric dimethylarginine (ADMA): a cardiovascular risk factor in patients with renal disease? Kidney Int 2003;63 (Suppl. 84):S37S40.
  • 8
    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: 5725.
  • 9
    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: 105019.
  • 10
    Tang J, Kao PN, Herschman HR. Protein-arginine methyltransferase I, the predominant protein-arginine methyltransferase in cells, interacts with and is regulated by interleukin enhancer-binding factor 3. J Biol Chem 2000;275: 1986676.
  • 11
    MacAllister RJ, Fickling SA, Whitley GS, Vallance P. Metabolism of methylarginines by human vasculature; implications for the regulation of nitric oxide synthesis. Br J Pharmacol 1994;112: 438.
  • 12
    Lee JH, Cook JR, Yang ZH, Mirochnitchenko O, Gunderson S, Felix AM et al. PRMT7: A new protein arginine methyltransferase that synthesizes symmetric dimethylarginine. J Biol Chem 2004 October 19 [Epub ahead of print].
  • 13
    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: H15227.
  • 14
    Segarra G, Medina P, Ballester RM, Lluch P, Aldasoro M, Vila JM et al. Effects of some guanidino compounds on human cerebral arteries. Stroke 1999;30: 220610.
  • 15
    Segarra G, Medina P, Vila JM, Chuan P, Domenech C, Torondel B et al. Inhibition of nitric oxide activity by arginine analogs in human renal arteries. Am J Hypertens 2001;14: 11428.
  • 16
    Gardiner SM, Kemp PA, Bennett T, Palmer RM, Moncada S. Regional and cardiac haemodynamic effects of NG, NG,dimethyl-L-arginine and their reversibility by vasodilators in conscious rats. Br J Pharmacol 1993;110: 145764.
  • 17
    Jin JS, D’Alecy LG. Central and peripheral effects of asymmetric dimethylarginine, an endogenous nitric oxide synthetase inhibitor. J Cardiovasc Pharmacol 1996;28: 43946.
  • 18
    Xiao S, Wagner L, Schmidt RJ, Baylis C. Circulating endothelial nitric oxide synthase inhibitory factor in some patients with chronic renal disease. Kidney Int 2001;59: 146672.
  • 19
    Chan JR, Boger RH, Bode-Boger SM, Tangphao O, Tsao PS, Blaschke TF et al. Asymmetric dimethylarginine increases mononuclear cell adhesiveness in hypercholesterolemic humans. Arterioscler Thromb Vasc Biol 2000;20: 10406.
  • 20
    Calver A, Collier J, Leone A, Moncada S, Vallance P. Effect of local intra-arterial asymmetric dimethylarginine (ADMA) on the forearm arteriolar bed of healthy volunteers. J Hum Hypertens 1993;7: 1934.
  • 21
    Kielstein JT, Impraim B, Simmel S, Bode-Boger SM, Tsikas D, Frolich JC et al. Cardiovascular effects of systemic NO synthase inhibition with asymmetric dimethylarginine in humans. Circulation 2004;109: 1727.
  • 22
    Achan V, Broadhead M, Malaki M, Whitley G, Leiper J, MacAllister R et al. Asymmetric dimethylarginine causes hypertension and cardiac dysfunction in humans and is actively metabolized by dimethylarginine dimethylaminohydrolase. Arterioscler Thromb Vasc Biol 2003;23: 14559.
  • 23
    Kielstein JT, Simmel S, Bode-Boger SM, Roth HJ, Schmidt-Gayk H, Haller H et al. Subpressor dose asymmetric dimethylarginine modulates renal function in humans through nitric oxide synthase inhibition. Kidney Blood Press Res 2004, 27, 143–7.
  • 24
    MacAllister RJ, Rambausek MH, Vallance P, Williams D, Hoffmann KH, Ritz E. Concentration of dimethyl-L-arginine in the plasma of patients with end-stage renal failure. Nephrol Dial Transplant 1996;11: 244952.
  • 25
    Anderstam B, Katzarski K, Bergstrom J. Serum levels of NG, NG-dimethyl-L-arginine, a potential endogenous nitric oxide inhibitor in dialysis patients. J Am Soc Nephrol 1997;8: 143742.
  • 26
    Kielstein JT, Boger RH, Bode-Boger SM, Schaffer J, Barbey M, Koch KM et al. 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: 594600.
  • 27
    Zoccali C, Bode-Boger S, Mallamaci F, Benedetto F, Tripepi G, Malatino L et al. Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: a prospective study. Lancet 2001;358: 21137.
  • 28
    Kielstein JT, Boger RH, Bode-Boger SM, Martens-Lobenhoffer J, Lonnemann G, Frolich JC et al. Low dialysance of asymmetric dimethylarginine (ADMA) –in vivo and in vitro evidence of significant protein binding. Clin Nephrol 2004;62: 295300.
  • 29
    Zoccali C, Benedetto FA, Maas R, Mallamaci F, Tripepi G, Malatino LS et al. Asymmetric dimethylarginine, C-reactive protein, and carotid intima-media thickness in end-stage renal disease. J Am Soc Nephrol 2002;13: 4906.
  • 30
    Zoccali C, Mallamaci F, Maas R, Benedetto FA, Tripepi G, Malatino LS et al. Left ventricular hypertrophy, cardiac remodeling and asymmetric dimethylarginine (ADMA) in hemodialysis patients. Kidney Int 2002;62: 33945.
  • 31
    Mallamaci F, Tripepi G, Maas R, Malatino L, Boger R, Zoccali C. Analysis of the relationship between norepinephrine and asymmetric dimethyl arginine levels among patients with end-stage renal disease. J Am Soc Nephrol 2004;15: 43541.
  • 32
    Kielstein JT, Boger RH, Bode-Boger SM, Frolich JC, Haller H, Ritz E et al. Marked increase of asymmetric dimethylarginine in patients with incipient primary chronic renal disease. J Am Soc Nephrol 2002;13: 1706.
  • 33
    Leiper JM, Santa Maria J, Chubb A, MacAllister RJ, Charles IG, Whitley GS et al. Identification of two human dimethylarginine dimethylaminohydrolases with distinct tissue distributions and homology with microbial arginine deaminases. Biochem J 1999;343: 20914.
  • 34
    Murray-Rust J, Leiper J, McAlister M, Phelan J, Tilley S, Santa Maria J et al. Structural insights into the hydrolysis of cellular nitric oxide synthase inhibitors by dimethylarginine dimethylaminohydrolase. Nat Struct Biol 2001;8: 67983.
  • 35
    Tojo A, Welch WJ, Bremer V, Kimoto M, Kimura K, Omata M et al. Colocalization of demethylating enzymes and NOS and functional effects of methylarginines in rat kidney. Kidney Int 1997;52: 1593601.
  • 36
    Leiper J, Murray-Rust J, McDonald N, Vallance P. S-nitrosylation of dimethylarginine dimethylaminohydrolase regulates enzyme activity: further interactions between nitric oxide synthase and dimethylarginine dimethylaminohydrolase. Proc Natl Acad Sci USA 2002;99: 1352732.
  • 37
    Kiechl S, Egger G, Mayr M, Wiedermann CJ, Bonora E, Oberhollenzer F et al. Chronic infections and the risk of carotid atherosclerosis: prospective results from a large population study. Circulation 2001;103: 106470.
  • 38
    Espinola-Klein C, Rupprecht HJ, Blankenberg S, Bickel C, Kopp H, Rippin G et al. Impact of infectious burden on extent and long-term prognosis of atherosclerosis. Circulation 2002;105: 1521.
  • 39
    Nijveldt RJ, Van Leeuwen PA, Van Guldener C, Stehouwer CD, Rauwerda JA, Teerlink T. Net renal extraction of asymmetrical (ADMA) and symmetrical (SDMA) dimethylarginine in fasting humans. Nephrol Dial Transplant 2002;17: 19992002.
  • 40
    Nijveldt RJ, Teerlink T, Van Guldener C, Prins HA, Van Lambalgen AA, Stehouwer CD et al. Handling of asymmetrical dimethylarginine and symmetrical dimethylarginine by the rat kidney under basal conditions and during endotoxaemia. Nephrol Dial Transplant 2003;18: 254250.
  • 41
    Kielstein JT, Frolich JC, Haller H, Fliser D. ADMA (asymmetric dimethylarginine): an atherosclerotic disease mediating agent in patients with renal disease? Nephrol Dial Transplant 2001;16: 17425.
  • 42
    Pinkau T, Hilgers KF, Veelken R, Mann JF. How does minor renal dysfunction influence cardiovascular risk and the management of cardiovascular disease? J Am Soc Nephrol 2004;15: 51723.
  • 43
    Wagner L, Riggleman A, Erdely A, Couser W, Baylis C. Reduced nitric oxide synthase activity in rats with chronic renal disease due to glomerulonephritis. Kidney Int 2002;62: 5326.
  • 44
    Kielstein JT, Bode-Boger SM, Frolich JC, Ritz E, Haller H, Fliser D. Asymmetric dimethylarginine, blood pressure, and renal perfusion in elderly subjects. Circulation 2003;107: 18915.
  • 45
    Miyazaki H, Matsuoka H, Cooke JP, Usui M, Ueda S, Okuda S et al. Endogenous nitric oxide synthase inhibitor: a novel marker of atherosclerosis. Circulation 1999;99: 11416.
  • 46
    Xiong Y, Yuan LW, Deng HW, Li YJ, Chen BM. Elevated serum endogenous inhibitor of nitric oxide synthase and endothelial dysfunction in aged rats. Clin Exp Pharmacol Physiol 2001;28: 8427.
  • 47
    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: 85661.
  • 48
    Scuteri A, Stuehlinger MC, Cooke JP, Wright JG, Lakatta EG, Anderson DE et al. Nitric oxide inhibition as a mechanism for blood pressure increase during salt loading in normotensive postmenopausal women. J Hypertens 2003;21: 133946.
  • 49
    Osanai T, Saitoh M, Sasaki S, Tomita H, Matsunaga T, Okumura K. Effect of shear stress on asymmetric dimethylarginine release from vascular endothelial cells. Hypertension 2003;42: 98590.
  • 50
    Boger RH, Bode-Boger SM, Szuba A, Tsao PS, Chan JR, Tangphao O et al. Asymmetric dimethylarginine (ADMA): a novel risk factor for endothelial dysfunction: its role in hypercholesterolemia. Circulation 1998;98: 18427.
  • 51
    Paiva H, Laakso J, Laine H, Laaksonen R, Knuuti J, Raitakari OT. Plasma asymmetric dimethylarginine and hyperemic myocardial blood flow in young subjects with borderline hypertension or familial hypercholesterolemia. J Am Coll Cardiol 2002;40: 12417.
  • 52
    Ito A, Tsao PS, Adimoolam S, Kimoto M, Ogawa T, Cooke JP. Novel mechanism for endothelial dysfunction: dysregulation of dimethylarginine dimethylaminohydrolase. Circulation 1999;99: 30925.
  • 53
    Boger RH, Bode-Boger SM, Sydow K, Heistad DD, Lentz SR. Plasma concentration of asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, is elevated in monkeys with hyperhomocyst(e)inemia or hypercholesterolemia. Arterioscler Thromb Vasc Biol 2000;20: 155764.
  • 54
    Boger RH, Sydow K, Borlak J, Thum T, Lenzen H, Schubert B et al. LDL cholesterol up-regulates synthesis of asymmetrical dimethylarginine in human endothelial cells: involvement of S-adenosylmethionine-dependent methyltransferases. Circ Res 2000;87: 99105.
  • 55
    Fard A, Tuck CH, Donis JA, Sciacca R, Di Tullio MR, Wu HD 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: 203944.
  • 56
    Lundman P, Eriksson MJ, Stuhlinger M, Cooke JP, Hamsten A, Tornvall P. 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: 1116.
  • 57
    Stuhlinger MC, Oka RK, Graf EE, Schmolzer I, Upson BM, Kapoor O et al. Endothelial dysfunction induced by hyperhomocyst (e) inemia: role of asymmetric dimethylarginine. Circulation 2003;108: 9338.
  • 58
    Sydow K, Hornig B, Arakawa N, Bode-Boger SM, Tsikas D, Munzel T et al. Endothelial dysfunction in patients with peripheral arterial disease and chronic hyperhomocysteinemia: potential role of ADMA. Vasc Med 2004;9: 93101.
  • 59
    Stuhlinger MC, Tsao PS, Her JH, Kimoto M, Balint RF, Cooke JP. Homocysteine impairs the nitric oxide synthase pathway: role of asymmetric dimethylarginine. Circulation 2001;104: 256975.
  • 60
    Stuhlinger MC, Abbasi F, Chu JW, Lamendola C, McLaughlin TL, Cooke JP et al. Relationship between insulin resistance and an endogenous nitric oxide synthase inhibitor. JAMA 2002;287: 14206.
  • 61
    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: 2118.
  • 62
    Goonasekera CD, Rees DD, Woolard P, Frend A, Shah V, Dillon MJ. Nitric oxide synthase inhibitors and hypertension in children and adolescents. J Hypertens 1997;15: 9019.
  • 63
    Surdacki A, Nowicki M, Sandmann J, Tsikas D, Boeger RH, Bode-Boeger SM 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: 6528.
  • 64
    Takiuchi S, Fujii H, Kamide K, Horio T, Nakatani S, Hiuge A et al. Plasma asymmetric dimethylarginine and coronary and peripheral endothelial dysfunction in hypertensive patients. Am J Hypertens 2004;17: 8028.
  • 65
    Matsuoka H, Itoh S, Kimoto M, Kohno K, Tamai O, Wada Y et al. Asymmetrical dimethylarginine, an endogenous nitric oxide synthase inhibitor, in experimental hypertension. Hypertension 1997;29: 2427.
  • 66
    Gorenflo M, Zheng C, Werle E, Fiehn W, Ulmer HE. Plasma levels of asymmetrical dimethyl-L-arginine in patients with congenital heart disease and pulmonary hypertension. J Cardiovasc Pharmacol 2001;37: 48992.
  • 67
    Kielstein JT, Bode-Böger SM, Martens-Lobenhoffer J, Hesse G, Gatzke R, Tacacs A et al. Asymmetric dimethylarginine (ADMA), pulmonary hemodynamic indices, and survival in patients with primary pulmonary hypertension. (Submitted).
  • 68
    Arrigoni FI, Vallance P, Haworth SG, Leiper JM. Metabolism of asymmetric dimethylarginines is regulated in the lung developmentally and with pulmonary hypertension induced by hypobaric hypoxia. Circulation 2003;107: 1195201.
  • 69
    Valkonen VP, Paiva H, Salonen JT, Lakka TA, Lehtimaki T, Laakso J et al. Risk of acute coronary events and serum concentration of asymmetrical dimethylarginine. Lancet 2001;358: 21278.
  • 70
    Lu TM, Ding YA, Lin SJ, Lee WS, Tai HC. Plasma levels of asymmetrical dimethylarginine and adverse cardiovascular events after percutaneous coronary intervention. Eur Heart J 2003;24: 19129.
  • 71
    Lu TM, Ding YA, Charng MJ, Lin SJ. Asymmetrical dimethylarginine: a novel risk factor for coronary artery disease. Clin Cardiol 2003;26: 45864.
  • 72
    Tarnow L, Hovind P, Teerlink T, Stehouwer CD, Parving HH. Elevated plasma asymmetric dimethylarginine as a marker of cardiovascular morbidity in early diabetic nephropathy in type 1 diabetes. Diabetes Care 2004;27: 7659.
  • 73
    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: 206874.
  • 74
    Yoo JH, Lee SC. Elevated levels of plasma homocyst (e) ine and asymmetric dimethylarginine in elderly patients with stroke. Atherosclerosis 2001;158: 42530.
  • 75
    Rajagopalan S, Pfenninger D, Kehrer C, Chakrabarti A, Somers E, Pavlic R et al. Increased asymmetric dimethylarginine and endothelin 1 levels in secondary Raynaud's phenomenon: implications for vascular dysfunction and progression of disease. Arthritis Rheum 2003;48: 19922000.
  • 76
    Hori T, Matsubara T, Ishibashi T, Ozaki K, Tsuchida K, Mezaki T et al. Significance of asymmetric dimethylarginine (ADMA) concentrations during coronary circulation in patients with vasospastic angina. Circ J 2003;67: 30511.
  • 77
    Jang JJ, Ho HK, Kwan HH, Fajardo LF, Cooke JP. Angiogenesis is impaired by hypercholesterolemia: role of asymmetric dimethylarginine. Circulation 2000;102: 14149.
  • 78
    Kielstein JT, Bode-Boger SM, Klein G, Graf S, Haller H, Fliser D. Endogenous nitric oxide synthase inhibitors and renal perfusion in patients with heart failure. Eur J Clin Invest 2003;33: 3705.
  • 79
    Saitoh M, Osanai T, Kamada T, Matsunaga T, Ishizaka H, Hanada H et al. High plasma level of asymmetric dimethylarginine in patients with acutely exacerbated congestive heart failure: role in reduction of plasma nitric oxide level. Heart Vessels 2003;18: 17782.
  • 80
    Feng Q, Lu X, Fortin AJ, Pettersson A, Hedner T, Kline RL et al. Elevation of an endogenous inhibitor of nitric oxide synthesis in experimental congestive heart failure. Cardiovasc Res 1998;37: 66775.
  • 81
    Savvidou MD, Hingorani AD, Tsikas D, Frolich JC, Vallance P, Nicolaides KH. Endothelial dysfunction and raised plasma concentrations of asymmetric dimethylarginine in pregnant women who subsequently develop pre-eclampsia. Lancet 2003;361: 15117.
  • 82
    Mittermayer F, Mayer BX, Meyer A, Winzer C, Pacini G, Wagner OF et al. Circulating concentrations of asymmetrical dimethyl-L-arginine are increased in women with previous gestational diabetes. Diabetologia 2002;45: 13728.
  • 83
    Lin KY, Ito A, Asagami T, Tsao PS, Adimoolam S, Kimoto M et al. Impaired nitric oxide synthase pathway in diabetes mellitus: role of asymmetric dimethylarginine and dimethylarginine dimethylaminohydrolase. Circulation 2002;106: 98792.
  • 84
    Xiong Y, Fu YF, Fu SH, Zhou HH. Elevated levels of the serum endogenous inhibitor of nitric oxide synthase and metabolic control in rats with streptozotocin-induced diabetes. J Cardiovasc Pharmacol 2003;42: 1916.
  • 85
    Hermenegildo C, Medina P, Peiro M, Segarra G, Vila JM, Ortega J et al. Plasma concentration of asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, is elevated in hyperthyroid patients. J Clin Endocrinol Metab 2002;87: 563640.
  • 86
    Weis M, Kledal TN, Lin KY, Panchal SN, Gao SZ, Valantine HA et al. Cytomegalovirus infection impairs the nitric oxide synthase pathway: role of asymmetric dimethylarginine in transplant arteriosclerosis. Circulation 2004;109: 5005.
  • 87
    Ueda S, Kato S, Matsuoka H, Kimoto M, Okuda S, Morimatsu M et al. Regulation of cytokine-induced nitric oxide synthesis by asymmetric dimethylarginine: role of dimethylarginine dimethylaminohydrolase. Circ Res 2003;92: 22633.
  • 88
    Dayoub H, Achan V, Adimoolam S, Jacobi J, Stuehlinger MC, Wang BY et al. Dimethylarginine dimethylaminohydrolase regulates nitric oxide synthesis: genetic and physiological evidence. Circulation 2003;108: 30427.
  • 89
    Vallance P, Leiper J. Cardiovascular biology of the asymmetric dimethylarginine: dimethylarginine dimethylaminohydrolase pathway. Arterioscler Thromb Vasc Biol 2004;24: 102330.
  • 90
    Smirnova IV, Kajstura M, Sawamura T, Goligorsky MS. Asymmetric dimethylarginine upregulates LOX-1 in activated macrophages: role in foam cell formation. Am J Physiol Heart Circ Physiol 2004;287: H78290.
  • 91
    Scalera F, Borlak J, Beckmann B, Martens-Lobenhoffer J, Thum T, Tager M et al. Endogenous nitric oxide synthesis inhibitor asymmetric dimethyl 1-arginine accelerates endothelial cell senescence. Arterioscler Thromb Vasc Biol 2004;24: 181622.
  • 92
    Suda O, Tsutsui M, Morishita T, Tasaki H, Ueno S, Nakata S 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 2004;24: 16828.
  • 93
    Jones LC, Tran CT, Leiper JM, Hingorani AD, Vallance P. Common genetic variation in a basal promoter element alters DDAH2 expression in endothelial cells. Biochem Biophys Res Commun 2003;310: 83643.
  • 94
    Boger RH, Bode-Boger SM, Brandes RP, Phivthong-ngam L, Bohme M, Nafe R et al. Dietary 1-arginine reduces the progression of atherosclerosis in cholesterol-fed rabbits: comparison with lovastatin. Circulation 1997;96: 128290.
  • 95
    Boger RH, Bode-Boger SM, Thiele W, Creutzig A, Alexander K, Frolich JC. Restoring vascular nitric oxide formation by 1-arginine improves the symptoms of intermittent claudication in patients with peripheral arterial occlusive disease. J Am Coll Cardiol 1998;32: 133644.
  • 96
    Piatti P, Fragasso G, Monti LD, Setola E, Lucotti P, Fermo I et al. Acute intravenous 1-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 2003;107: 42936.
  • 97
    Walker HA, McGing E, Fisher I, Boger RH, Bode-Boger SM, Jackson G et al. Endothelium-dependent vasodilation is independent of the plasma 1-arginine/ADMA ratio in men with stable angina: lack of effect of oral 1-arginine on endothelial function, oxidative stress and exercise performance. J Am Coll Cardiol 2001;38: 499505.
  • 98
    Teerlink T, Neele SJ, De Jong S, Netelenbos JC, Stehouwer CD. Oestrogen replacement therapy lowers plasma levels of asymmetrical dimethylarginine in healthy postmenopausal women. Clin Sci (Lond) 2003;105: 6771.
  • 99
    Holden DP, Cartwright JE, Nussey SS, Whitley GS. Estrogen stimulates dimethylarginine dimethylaminohydrolase activity and the metabolism of asymmetric dimethylarginine. Circulation 2003;108: 157580.
  • 100
    Post MS, Verhoeven MO, Van Der Mooren MJ, Kenemans P, Stehouwer CD, Teerlink T. 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: 42216.
  • 101
    Jiang JL, Li Ns NS, Li YJ, Deng HW. Probucol preserves endothelial function by reduction of the endogenous nitric oxide synthase inhibitor level. Br J Pharmacol 2002;135: 117582.
  • 102
    Lu TM, Ding YA, Leu HB, Yin WH, Sheu WH, Chu KM. Effect of rosuvastatin on plasma levels of asymmetric dimethylarginine in patients with hypercholesterolemia. Am J Cardiol 2004;94: 15761.
  • 103
    Jiang JL, Jiang DJ, Tang YH, Li NS, Deng HW, Li YJ. Effect of simvastatin on endothelium-dependent vaso-relaxation and endogenous nitric oxide synthase inhibitor. Acta Pharmacol Sin 2004;25: 893901.
  • 104
    Pereira EC, Bertolami MC, Faludi AA, Salem M, Bersch D, Abdalla DS. Effects of simvastatin and 1-arginine on vasodilation, nitric oxide metabolites and endogenous NOS inhibitors in hypercholesterolemic subjects. Free Radic Res 2003;37: 52936.
  • 105
    Paiva H, Laakso J, Lehtimaki T, Isomustajarvi M, Ruokonen I, Laaksonen R. Effect of high-dose statin treatment on plasma concentrations of endogenous nitric oxide synthase inhibitors. J Cardiovasc Pharmacol 2003;41: 21922.
  • 106
    Eid HM, Eritsland J, Larsen J, Arnesen H, Seljeflot I. Increased levels of asymmetric dimethylarginine in populations at risk for atherosclerotic disease. Effects Pravastatin Atherosclerosis 2003;166: 27984.
  • 107
    Dierkes J, Westphal S, Martens-Lobenhoffer J, Luley C, Bode-Boger SM. Fenofibrate increases the 1-arginine. ADMA ratio by increase of 1-arginine concentration but has no effect on ADMA concentration. Atherosclerosis 2004;173: 23944.
  • 108
    Chen JW, Hsu NW, Wu TC, Lin SJ, Chang MS. Long-term angiotensin-converting enzyme inhibition reduces plasma asymmetric dimethylarginine and improves endothelial nitric oxide bioavailability and coronary microvascular function in patients with syndrome X. Am J Cardiol 2002;90: 97482.
  • 109
    Delles C, Schneider MP, John S, Gekle M, Schmieder RE. 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: 5903.
  • 110
    Fliser D, Wagner KK, Loos A, Tsikas D, Haller H. Chronic angiotensin II receptor blockade reduces (intra) renal vascular resistance in patients with type 2 diabetes mellitus (in revision).
  • 111
    Asagami T, Abbasi F, Stuelinger M, Lamendola C, McLaughlin T, Cooke JP et al. Metformin treatment lowers asymmetric dimethylarginine concentrations in patients with type 2 diabetes. Metabolism 2002;51: 8436.