Donate Help Contact The AHA Sign In Home
American Heart Association
Circulation
Search: search_blue_button Advanced Search
Circulation. 2003;107:1891-1895
Published online before print April 7, 2003, doi: 10.1161/01.CIR.0000060496.23144.A7
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
107/14/1891    most recent
01.CIR.0000060496.23144.A7v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Kielstein, J. T.
Right arrow Articles by Fliser, D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kielstein, J. T.
Right arrow Articles by Fliser, D.
Related Collections
Right arrow Clinical Studies

(Circulation. 2003;107:1891.)
© 2003 American Heart Association, Inc.


Clinical Investigation and Reports

Asymmetric Dimethylarginine, Blood Pressure, and Renal Perfusion in Elderly Subjects

Jan T. Kielstein, MD; Stefanie M. Bode-Böger, MD, MPH; Jürgen C. Frölich, MD; Eberhard Ritz, MD; Hermann Haller, MD; Danilo Fliser, MD

From the Department of Internal Medicine, Medical School Hannover, Germany (J.T.K., H.H., D.F.); the Institute of Clinical Pharmacology, Otto-von-Guericke University Magdeburg, Germany (S.M.B.-B.); the Institute of Clinical Pharmacology, Medical School Hannover, Germany (J.C.F.); and the Department of Internal Medicine, Ruperto-Carola University Heidelberg, Germany (E.R.).

Correspondence to D. Fliser, MD, Associate Professor of Internal Medicine, Division of Nephrology, Department of Internal Medicine, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany. E-mail fliser.danilo{at}mh-hannover.de


*    Abstract
up arrowTop
*Abstract
down arrowIntroduction
down arrowMethods
down arrowResults
down arrowDiscussion
down arrowReferences
 
Background— Reduced availability of nitric oxide (NO) is thought to contribute to the age-associated increase of renovascular tone and blood pressure. We assessed blood concentrations of the endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA) as well as renal hemodynamics, comparing young (n=24, 13 men, 25±1 years) and elderly (n=24, 13 men, 69±2 years) healthy subjects and elderly subjects with essential hypertension (n=24, 13 men, 70±2 years).

Methods and Results— Plasma ADMA concentration and renovascular resistance (RVR) were significantly higher (P<0.05) and effective renal plasma flow (ERPF) significantly lower (P<0.05) in elderly (2.77±0.20 µmol/L, 125±10 mm Hg/mL per minute, 487±26 mL/min per 1.73 m2) than in young healthy subjects (1.30±0.11, 77±3, 654±18). Both ADMA levels and RVR were higher and ERPF lower in the hypertensive elderly subjects (3.53±0.23, 163±11, 427±19; P<0.05 versus both groups). In contrast, plasma concentrations of the biologically inactive stereoisomer symmetric dimethylarginine, L-arginine, and homocysteine were similar in the 3 groups studied. In the logistic regression analysis only ADMA was an independent determinant of both ERPF (P<0.001; r2=0.80) and RVR (P<0.002; r2=0.86). In addition, ADMA (P<0.002) and serum glucose (P<0.036) were independently related (r2=0.67) to the level of blood pressure.

Conclusions— These results are compatible with the notion that accumulation of the endogenous NO synthase inhibitor ADMA in senescent individuals is involved in the decrease of renal perfusion and increase of blood pressure.


Key Words: aging • nitric oxide synthase • kidney • hypertension


*    Introduction
up arrowTop
up arrowAbstract
*Introduction
down arrowMethods
down arrowResults
down arrowDiscussion
down arrowReferences
 
Reduced nitric oxide (NO)-dependent vasodilation as an early indicator of atherosclerotic disease has been documented in elderly subjects, particularly if cardiovascular risk factors such as smoking or hypertension were present.1–3 NO synthase (NOS) synthesizes NO from the amino acid L-arginine. Guanidino-substituted analogues of L-arginine such as asymmetric dimethylarginine (ADMA) can selectively inhibit NOS by competitive blockade of its active site.4 Several clinical studies examined different populations and found that increased plasma ADMA levels are not only correlated with the severity of atherosclerotic disease but also predict increased cardiovascular mortality rates.5–11 Thus, ADMA is thought to be not only a biochemical marker of atherosclerosis but potentially a pathogenic mediator.4,9,12

Past and more recent studies have documented that aging is accompanied by changes in renal hemodynamics, particularly by an increase in renovascular tone with reduced ability of postglomerular vessels to dilate in response to stimuli such as acetylcholine or amino acids.13–16 Furthermore, in senescent individuals, reduced availability of NO is thought to be linked to the increase in blood pressure and in renovascular resistance, possibly a reflection of arteriosclerosis.17,18 So far, no specific information on plasma ADMA concentration and its potential relation to abnormal renal hemodynamics in the elderly is available. To address this issue, we measured renal hemodynamics and blood concentrations of dimethylarginines in young and elderly healthy normotensive subjects and in elderly patients with mild to moderate essential hypertension. True glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were assessed by using the inulin- and PAH-clearance techniques, respectively.


*    Methods
up arrowTop
up arrowAbstract
up arrowIntroduction
*Methods
down arrowResults
down arrowDiscussion
down arrowReferences
 
Participants and Protocol
The local ethics committee approved the study protocol; all participants gave written informed consent. Twenty-four young and 24 elderly healthy normotensive subjects and, in addition, 24 elderly patients with mild to moderate essential hypertension were examined. Hypertension was defined according to World Health Organization criteria as blood pressure >140/90 mm Hg or antihypertensive medication. To exclude individuals with primary renal disease, sonography, urine analysis, and serum chemistry were performed in all participants and only subjects with normal plasma creatinine concentration were enrolled. In elderly subjects, manifest atherosclerotic vascular disease and/or heart failure were excluded by clinical examination and echocardiography. Thus, with the exception of essential hypertension, none of the elderly participants had relevant medical problems. All participants were nonsmoking whites. The three groups were matched with regard to gender and body weight.

All participants were studied under outpatient conditions. Dietary counseling was given to all participants who were advised to ingest a standardized diet with regard to sodium chloride (100 mmol/d) and calorie content (30 kcal/kg body weight) 1 week before and during the examination. Cardiovascular drugs with the potential to confound the measurement of renal hemodynamics were discontinued in elderly hypertensive patients at least 1 week before the examination, in accordance with their respective pharmacodynamic half-life. GFR and ERPF were measured after 12 hours of fasting in a quiet room, in supine position, using the inulin (Cin) and para-aminohippurate (CPAH) infusion clearance techniques as described before.13 In brief, a priming dose of 1500 mg inulin/m2 (Inutest, Laevosan Co) and of 500 mg para-aminohippurate/m2 (Nephrotest, BGA) was followed by continuous infusion of inulin (10 mg/m2 per minute) and para-aminohippurate (8 mg/m2 per minute) with ultraprecise pumps (Perfusor FT, Braun Melsungen). After an equilibration period of 100 minutes, blood samples for determination of Cin and CPAH were taken at regular intervals. To calculate renovascular resistance, mean arterial blood pressure (MAP) was measured at the same time points during the clearance studies by using a noninvasive oscillometric technique (Dinamap, Criticon Inc). Blood samples for measurements of dimethylarginines, L-arginine, homocysteine, glucose, total, HDL, and LDL cholesterol, and triglyceride concentrations were taken without venous compression at the start of the clearance measurement after at least 100 minutes of supine position. In addition, ambulatory 24-hour blood pressure was assessed on a separate day with the use of an automatic device (model 90207, SpaceLabs Inc).

Measurements and Calculations
Inulin was measured enzymatically with inulinase19 and PAH was measured photometrically. The clearances of inulin and PAH were calculated from the delivered dose: C=(IrxIc)/Sc; where C is the clearance, Ir is the infusion rate, Ic is the concentration of the analyte in the infusion fluid, and Sc is the plasma concentration of the analyte. Filtration fraction (FF) was calculated as the ratio Cin/CPAH and renovascular resistance (RVR) by using the equation RVR=[(MAP-12)x723/ERPF]. Plasma levels of L-arginine, ADMA, and the biologically inactive stereoisomer symmetric dimethylarginine (SDMA) were measured with high-performance liquid chromatography (HPLC), using precolumn derivatization with o-phthalaldehyde (OPA). Plasma samples and internal standards were extracted on CBA solid-phase extraction cartridges (MDUL Varian) and thereafter were incubated for 30 seconds with the OPA reagent (5.4 mg/mL OPA in borate buffer, pH 8.5 containing 0.4% mercaptoethanol) before automatic injection into the HPLC. The OPA derivatives of L-arginine, ADMA, and SDMA were separated on a C6H5 column (Macherey and Nagel) with the fluorescence monitor set at an excitation wavelength of 340 nm and an emission wavelength of 455 nm. The coefficients of variation of this method are 5.2% within assay and 5.5% between assays; the detection limit of the assay is 0.1 µmol/L. Plasma total homocysteine (Hcy) concentrations were measured with a fluorescence-polarization immunoassay. All other measurements were done with routine laboratory tests by certified assay methods.

Statistics
The SPSS package was used for statistical analysis. Comparison between groups was done by using ANOVA after normality of data distribution was confirmed with the Shapiro-Wilk test. A 2-tailed t test for comparison of random data between groups was used when ANOVA gave significant differences, and the Bonferroni correction was applied to account for multiple comparisons. The zero hypothesis was rejected at a probability level of 0.05. All data are presented as mean±SEM. In addition, a multinomial logistic regression analysis was performed with the three groups defined as part of the analysis to detect significant characteristics of individuals studied apart from the predetermined group variables of age and blood pressure. The regression model included body weight, ADMA, SDMA, L-arginine, Hcy, triglycerides, glucose, and LDL and HDL cholesterol. Furthermore, independent predictors of ERPF, RVR, and the level of blood pressure were evaluated with the use of logistic regression analysis. Data of the dependent variables ERPF, RVR, and MAP were categorized, and forward stepwise inclusion (likelihood quotient) was applied to reveal significant independent determinants for each dependent variable. The Nagel Kerkes coefficient (r2) indicates the percentage of variability of the dependent variable explained by the significant independent determinant(s).


*    Results
up arrowTop
up arrowAbstract
up arrowIntroduction
up arrowMethods
*Results
down arrowDiscussion
down arrowReferences
 
The clinical characteristics of the three groups of subjects studied are presented in the Table. GFR was significantly lower in both groups of elderly individuals than in young healthy subjects, and ERPF was significantly lower in both groups of elderly individuals, being significantly higher in healthy elderly subjects than in elderly subjects with hypertension. Conversely, RVR and FF were higher in both groups of elderly subjects as compared with young individuals, particularly in the elderly patients with high blood pressure. In addition, the elderly hypertensive patients not taking drugs had a significantly higher MAP and total and LDL cholesterol serum concentrations than young and elderly healthy subjects. Furthermore, both in healthy elderly and in hypertensive elderly, HDL cholesterol was significantly lower than in young healthy subjects. In contrast, serum glucose concentrations were not significantly different in all three groups studied. Plasma ADMA concentrations were significantly higher in healthy elderly than in healthy young subjects and were even higher in hypertensive elderly. Plasma SDMA, L-arginine, and Hcy levels were not significantly different in young and healthy elderly and in hypertensive elderly subjects (Table). Individual data on plasma ADMA concentrations and RVR are shown in Figure 1 and Figure 2.


View this table:
[in this window]
[in a new window]
 
Characteristics of the Study Populations



View larger version (11K):
[in this window]
[in a new window]
 
Figure 1. Individual values of plasma ADMA in young healthy subjects (n=24, 25±1 years of age), elderly healthy subjects (n=24, 69±2 years of age), and elderly patients with essential hypertension (n=24, 70±2 years of age). {bullet}indicates men; {circ}, women; black bar, mean value.



View larger version (14K):
[in this window]
[in a new window]
 
Figure 2. Individual values of ERPF in young healthy subjects (n=24, 25±1 years of age), elderly healthy subjects (n=24, 69±2 years of age), and elderly patients with essential hypertension (n=24, 70±2 years of age). {bullet}indicates men; {circ}, women; black bar, mean value.

The multinomial logistic regression analysis revealed that ADMA (P<0.001) and LDL cholesterol (P<0.004) blood levels were important independent characteristics of individuals studied. The logistic regression analysis further revealed that ADMA blood levels were the only significant independent determinant of ERPF (P<0.001, r2=0.80) after adjustment for potential confounding by age (P=0.196), body weight (P=0.736), MAP (P=0.289) and blood SDMA (P=0.899), L-arginine (P=0.596), Hcy (P=0.116), LDL cholesterol (P=0.887), HDL cholesterol (P=0.514), triglyceride (P=0.500), and glucose (P=0.152) levels. In addition, after elimination of age in the second step of the analysis, only ADMA blood concentrations remained a significant determinant of RVR (P<0.002) in the final regression equation, explaining most of its variability (r2=0.86). All other potential cofounders were not significantly related to RVR: age (P=0.356), body weight (P=0.514), MAP (P=0.491) and blood SDMA (P=0.838), L-arginine (P=0.251), Hcy (P=0.053), LDL cholesterol (P=0.669), HDL cholesterol (P=0.280), triglyceride (P=0.061), and glucose (P=0.226) levels. Furthermore, plasma ADMA (P<0.002) and serum glucose (P<0.036) concentrations were independent predictors of the blood pressure level after adjustment for age (P=0.672), body weight (P=0.841) and blood SDMA (P=0.608), L-arginine (P=0.889), Hcy (P=0.101), LDL cholesterol (P=0.189), HDL cholesterol (P=0.683), and triglyceride (P=0.665) levels. ADMA and glucose plasma concentrations together explained a large part of blood pressure variability (r2=0.67) in the individuals that we studied.


*    Discussion
up arrowTop
up arrowAbstract
up arrowIntroduction
up arrowMethods
up arrowResults
*Discussion
down arrowReferences
 
The results of the present study document that markedly increased plasma concentrations of the endogenous NOS inhibitor ADMA are present even in nonsmoking healthy normotensive elderly subjects. This finding is in agreement with a recent observation of a significant positive correlation between age and ADMA in a random population sample.7 Moreover, in the logistic regression analysis, plasma ADMA levels were a significant predictor of reduced effective renal plasma flow and increased calculated renovascular resistance. In contrast, this was not the case with L-arginine, the substrate for NOS, nor SDMA, that is, the stereoisomer of ADMA that has no inhibitory effect on NOS. Thus, despite the limitations of the cross-sectional study design, our results indicate that the increase of blood ADMA levels with senescence is linked to the reduction of renal perfusion. In addition, a significant relation between plasma ADMA levels and blood pressure was documented as well, and this observation is also in line with recently published results.7

Our findings are of interest with regard to the pathophysiology of the aging of the kidney. It is well known that even normal aging is associated with some loss of renal tissue accompanied by changes in renal hemodynamics.15 The observed decrease in ERPF and increase in FF and RVR is particularly pronounced in elderly persons with cardiovascular comorbidity such as hypertension and/or heart failure,14,20,21 that is, conditions in which the availability of NO is reduced.1 In this context, it has not been resolved whether age-related changes in renal hemodynamics are caused by structural abnormalities or whether there exists a functional abnormality as well, for example, reduced capacity of renal vessels to dilate as a consequence of reduced availability of (or responsiveness to) vasodilator substances. Experimental studies and studies in humans support the latter concept.13,15–18,22 In this context, it must be pointed out that the postglomerular renal (micro) vasculature is particularly sensitive to NOS inhibition.23–25 This has been recently demonstrated by using ADMA in animal experiments and in studies with isolated organs.26,27 Increased blood levels of ADMA in the elderly may therefore reduce the availability of NO and thus contribute to endothelial dysfunction and arteriosclerosis and finally may lead to increased renovascular resistance and hypertension.28,29 This hypothesis is supported by the fact that the highest plasma ADMA levels have been found in elderly subjects with the highest FF and/or with the highest RVR, respectively. Furthermore, in line with this assumption are indirect observations related to biological effects of ADMA: In patients with kidney disease, high plasma ADMA concentrations correlate significantly with the ex vivo capability of the patient’s blood to inhibit NO production in cultured endothelial cells.30 Furthermore, intrabrachial ADMA infusion abolished endothelium-dependent vasodilation in healthy subjects.31 Further indirect support for the assumption that increased plasma ADMA levels reduce renal perfusion and increase blood pressure with senescence comes from our recent experiments in which systemic ADMA administration significantly decreased ERPF and increased RVR and MAP in healthy subjects [Kielstein JT et al, unpublished data, 2002]. Long-term intervention studies with substances that increase NO production and overcome NOS inhibition by ADMA within the renal vascular bed such as L-arginine are needed to clarify this issue. It is currently uncertain whether the moderate increase of plasma ADMA levels in the hypertensive elderly as compared with normotensive elderly subjects, as found in this study, has pathophysiological relevance. We emphasize, however, that according to several studies in different populations, in the long run even small differences in mean plasma ADMA levels (ie, {approx}1 µmol/L) are associated with deterioration of endothelial function and a significant increase in the rate of cardiovascular events.10,32–34

What could be the explanation for the increase in ADMA blood levels with age? ADMA is released from proteins that have been posttranslationally methylated and hydrolyzed.4,9,12 These proteins are found in the nucleolus and appear to be involved in RNA processing and transcriptional control. Two types of enzymes methylate arginine residues—protein arginine methyltransferase type I (PRMT I) forms ADMA, whereas PRMT II forms SDMA. Increased activity of PRMT I could theoretically lead to increased appearance of ADMA with aging, although this is an unlikely explanation. On the other hand, decreased ADMA breakdown may be of importance. ADMA is excreted by the kidneys to some extent, but the predominant metabolic pathway is degradation by the enzyme dimethylarginine dimethylaminohydrolase (DDAH), which hydrolyzes ADMA (but not SDMA) to dimethylamine and L-citrulline.4,9,12 Colocalization of DDAH and NOS in various cell types including renal tubular cells supports the hypothesis that the intracellular concentration of ADMA is actively and cell-specifically regulated in NO-generating cells.35 To date, DDAH activity is difficult to assess, however, and no data are available on DDAH activity in persons of advanced age. Furthermore, the clearance of ADMA may be reduced, secondary to a decrease in GFR and/or reduced numbers of tubular cells containing DDAH as a consequence of renal tissue involution with age. The former explanation is less likely, however, because we and others have shown that plasma ADMA concentrations depend less on GFR than do plasma SDMA levels.36,37 Thus, SDMA accumulates proportionally more when GFR is reduced. This was not the case in our population of elderly individuals.

Another explanation for increased plasma ADMA levels with age might be increased generation of ADMA from the metabolism of Hcy, because the metabolic pathways generating Hcy and ADMA are closely linked.38 In addition, high Hcy levels have been shown to inhibit DDAH activity in vitro.39 Plasma Hcy levels were in the normal range, however, in our elderly and young subjects. In contrast, mean total and LDL cholesterol concentrations were significantly higher in the elderly patients with essential hypertension. Hypercholesteremia was shown to be associated with increased plasma ADMA concentrations in vivo,32 and an inhibitory effect of LDL cholesterol on DDAH activity was documented in vitro.40 Thus, increased cholesterol concentration could contribute to the increase of plasma ADMA levels, at least in hypertensive elderly subjects. In this regard, a recent observation of a significant relation between plasma ADMA levels and insulin resistance suggests that increased plasma ADMA levels may characterize patients with the metabolic syndrome.41

In conclusion, our finding of a significant relation between high blood ADMA levels with reduced renal perfusion and high blood pressure values is consistent with a causal role of ADMA in the pathophysiology of the age-related endothelial dysfunction, resulting in increased renovascular tone and blood pressure.


*    Acknowledgments
 
We thank Dr Hecker and Dr Hoy from the Department of Statistics of the Medical School Hannover for their advice.

Received December 19, 2002; accepted January 21, 2003.


*    References
up arrowTop
up arrowAbstract
up arrowIntroduction
up arrowMethods
up arrowResults
up arrowDiscussion
*References
 

  1. Celermajer DS. Endothelial dysfunction: does it matter? Is it reversible? J Am Coll Cardiol. 1997; 30: 325–333.[Abstract]
  2. Chauhan A, More RS, Mullins PA, et al. Aging-associated endothelial dysfunction in humans is reversed by L-arginine. J Am Coll Cardiol. 1996; 28: 1796–1804.[Abstract]
  3. 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]
  4. Cooke JP. Does ADMA cause endothelial dysfunction? Arterioscler Thromb Vasc Biol. 2000; 20: 2032–2037.[Abstract/Free Full Text]
  5. 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]
  6. Kielstein JT, Boger RH, Bode-Boger SM, 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: 594–600.[Abstract/Free Full Text]
  7. 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]
  8. 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]
  9. Vallance P. Importance of asymmetrical dimethylarginine in cardiovascular risk. Lancet. 2001; 358: 2096–2097.[CrossRef][Medline] [Order article via Infotrieve]
  10. 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]
  11. 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]
  12. Kielstein JT, Frolich JC, Haller H, et al. ADMA (asymmetric dimethylarginine): an atherosclerotic disease mediating agent in patients with renal disease? Nephrol Dial Transplant. 2001; 16: 1742–1745.[Free Full Text]
  13. Fliser D, Zeier M, Nowack R, et al. Renal functional reserve in healthy elderly subjects. J Am Soc Nephrol. 1993; 3: 1371–1377.[Abstract]
  14. Fliser D, Franek E, Joest M, et al. Renal function in the elderly: impact of hypertension and cardiac function. Kidney Int. 1997; 51: 1196–1204.[Medline] [Order article via Infotrieve]
  15. Hollenberg NK, Adams DF, Solomon HS, et al. Senescence and the renal vasculature in normal man. Circ Res. 1974; 34: 309–316.[Abstract/Free Full Text]
  16. Fuiano G, Sund S, Mazza G, et al. Renal hemodynamic response to maximal vasodilating stimulus in healthy older subjects. Kidney Int. 2001; 59: 1052–1058.[CrossRef][Medline] [Order article via Infotrieve]
  17. Campo C, Lahera V, Garcia-Robles R, et al. Aging abolishes the renal response to L-arginine infusion in essential hypertension. Kidney Int Suppl. 1996; 55: S126–S128.[Medline] [Order article via Infotrieve]
  18. Higashi Y, Oshima T, Ozono R, et al. Aging and severity of hypertension attenuate endothelium-dependent renal vascular relaxation in humans. Hypertension. 1997; 30: 252–258.[Abstract/Free Full Text]
  19. Kuehnle HF, von DK, Schmidt FH. Fully enzymatic inulin determination in small volume samples without deproteinization. Nephron. 1992; 62: 104–107.[Medline] [Order article via Infotrieve]
  20. Cody RJ, Torre S, Clark M, et al. Age-related hemodynamic, renal, and hormonal differences among patients with congestive heart failure. Arch Intern Med. 1989; 149: 1023–1028.[Abstract]
  21. Schmieder RE, Schachinger H, Messerli FH. Accelerated decline in renal perfusion with aging in essential hypertension. Hypertension. 1994; 23: 351–357.[Abstract/Free Full Text]
  22. Sabbatini M, Sansone G, Uccello F, et al. Functional versus structural changes in the pathophysiology of acute ischemic renal failure in aging rats. Kidney Int. 1994; 45: 1355–1361.[Medline] [Order article via Infotrieve]
  23. Bech JN, Nielsen CB, Pedersen EB. Effects of systemic NO synthesis inhibition on RPF, GFR, UNa, and vasoactive hormones in healthy humans. Am J Physiol. 1996; 270: F845–F851.[Medline] [Order article via Infotrieve]
  24. Broere A, Van Den Meiracker AH, Boomsma F, et al. Human renal and systemic hemodynamic, natriuretic, and neurohumoral responses to different doses of L-NAME. Am J Physiol. 1998; 275: F870–F877.[Medline] [Order article via Infotrieve]
  25. Lahera V, Salom MG, Miranda-Guardiola F, et al. Effects of NG-nitro-L-arginine methyl ester on renal function and blood pressure. Am J Physiol. 1991; 261: F1033–F1037.[Medline] [Order article via Infotrieve]
  26. Gardiner SM, Kemp PA, Bennett T, et al. Regional and cardiac haemodynamic effects of NG, NG,dimethyl-L-arginine and their reversibility by vasodilators in conscious rats. Br J Pharmacol. 1993; 110: 1457–1464.[Medline] [Order article via Infotrieve]
  27. Segarra G, Medina P, Vila JM, et al. Inhibition of nitric oxide activity by arginine analogs in human renal arteries. Am J Hypertens. 2001; 14: 1142–1148.[CrossRef][Medline] [Order article via Infotrieve]
  28. Sander M, Chavoshan B, Victor RG. A large blood pressure-raising effect of nitric oxide synthase inhibition in humans. Hypertension. 1999; 33: 937–942.[Abstract/Free Full Text]
  29. Xiong Y, Yuan LW, Deng HW, et al. Elevated serum endogenous inhibitor of nitric oxide synthase and endothelial dysfunction in aged rats. Clin Exp Pharmacol Physiol. 2001; 28: 842–847.[CrossRef][Medline] [Order article via Infotrieve]
  30. Xiao S, Wagner L, Schmidt RJ, et al. Circulating endothelial nitric oxide synthase inhibitory factor in some patients with chronic renal disease. Kidney Int. 2001; 59: 1466–1472.[CrossRef][Medline] [Order article via Infotrieve]
  31. 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]
  32. 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]
  33. 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]
  34. 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]
  35. Tojo A, Welch WJ, Bremer V, et al. Colocalization of demethylating enzymes and NOS and functional effects of methylarginines in rat kidney. Kidney Int. 1997; 52: 1593–1601.[Medline] [Order article via Infotrieve]
  36. Kielstein JT, Boger RH, Bode-Boger SM, et al. Marked increase of asymmetric dimethylarginine in patients with incipient primary chronic renal disease. J Am Soc Nephrol. 2002; 13: 170–176.[Abstract/Free Full Text]
  37. Xiao ZS, Quarles LD, Chen QQ, et al. Effect of asymmetric dimethylarginine on osteoblastic differentiation. Kidney Int. 2001; 60: 1699–1704.[CrossRef][Medline] [Order article via Infotrieve]
  38. Boger RH, Lentz SR, Bode-Boger SM, et al. Elevation of asymmetrical dimethylarginine may mediate endothelial dysfunction during experimental hyperhomocyst(e)inaemia in humans. Clin Sci (Lond). 2001; 100: 161–167.[Medline] [Order article via Infotrieve]
  39. 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]
  40. 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]
  41. 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]



This article has been cited by other articles:


Home page
PhysiologyHome page
C. Baylis
Sexual Dimorphism of the Aging Kidney: Role of Nitric Oxide Deficiency
Physiology, June 1, 2008; 23(3): 142 - 150.
[Abstract] [Full Text] [PDF]


Home page
Arterioscler. Thromb. Vasc. Bio.Home page
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]


Home page
Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
M. Imamura, Y. Waseda, G. V. Marinova, T. Ishibashi, S. Obayashi, A. Sasaki, A. Nagai, and H. Azuma
Alterations of NOS, arginase, and DDAH protein expression in rabbit cavernous tissue after administration of cigarette smoke extract
Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2007; 293(5): R2081 - R2089.
[Abstract] [Full Text] [PDF]


Home page
CirculationHome page
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]


Home page
CJASNHome page
S. B. Ahmed, N. D.L. Fisher, and N. K. Hollenberg
Gender and the Renal Nitric Oxide Synthase System in Healthy Humans
Clin. J. Am. Soc. Nephrol., September 1, 2007; 2(5): 926 - 931.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
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]


Home page
J. Physiol.Home page
L. A. Holowatz, C. S. Thompson, and W. L. Kenney
L-Arginine supplementation or arginase inhibition augments reflex cutaneous vasodilatation in aged human skin
J. Physiol., July 15, 2006; 574(2): 573 - 581.
[Abstract] [Full Text] [PDF]


Home page
J. Am. Soc. Nephrol.Home page
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]


Home page
J. Am. Soc. Nephrol.Home page
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]


Home page
Arterioscler. Thromb. Vasc. Bio.Home page
J. T. Kielstein, S. M. Bode-Boger, G. Hesse, J. Martens-Lobenhoffer, A. Takacs, D. Fliser, and M. M. Hoeper
Asymmetrical Dimethylarginine in Idiopathic Pulmonary Arterial Hypertension
Arterioscler. Thromb. Vasc. Biol., July 1, 2005; 25(7): 1414 - 1418.
[Abstract] [Full Text] [PDF]


Home page
Vasc MedHome page
S. M Bode-Boger, F. Scalera, and J. Martens-Lobenhoffer
Asymmetric dimethylarginine (ADMA) accelerates cell senescence
Vascular Medicine, May 1, 2005; 10(2_suppl): S65 - S71.
[Abstract] [PDF]


Home page
J. Am. Soc. Nephrol.Home page
D. Fliser, K.-K. Wagner, A. Loos, D. Tsikas, and H. Haller
Chronic Angiotensin II Receptor Blockade Reduces (Intra)Renal Vascular Resistance in Patients with Type 2 Diabetes
J. Am. Soc. Nephrol., April 1, 2005; 16(4): 1135 - 1140.
[Abstract] [Full Text] [PDF]


Home page
HypertensionHome page
J. C. Verhave, P. Fesler, G. du Cailar, J. Ribstein, M. E. Safar, and A. Mimran
Elevated Pulse Pressure Is Associated With Low Renal Function in Elderly Patients With Isolated Systolic Hypertension
Hypertension, April 1, 2005; 45(4): 586 - 591.
[Abstract] [Full Text] [PDF]


Home page
Nephrol Dial TransplantHome page
D. Fliser
Ren sanus in corpore sano: the myth of the inexorable decline of renal function with senescence
Nephrol. Dial. Transplant., March 1, 2005; 20(3): 482 - 485.
[Full Text] [PDF]


Home page
Arterioscler. Thromb. Vasc. Bio.Home page
F. Scalera, J. Borlak, B. Beckmann, J. Martens-Lobenhoffer, T. Thum, M. Tager, and S. M. Bode-Boger
Endogenous Nitric Oxide Synthesis Inhibitor Asymmetric Dimethyl L-Arginine Accelerates Endothelial Cell Senescence
Arterioscler. Thromb. Vasc. Biol., October 1, 2004; 24(10): 1816 - 1822.
[Abstract] [Full Text] [PDF]


Home page
J. Am. Soc. Nephrol.Home page
D. H. Endemann and E. L. Schiffrin
Endothelial Dysfunction
J. Am. Soc. Nephrol., August 1, 2004; 15(8): 1983 - 1992.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
I. V. Smirnova, M. Kajstura, T. Sawamura, and M. S. Goligorsky
Asymmetric dimethylarginine upregulates LOX-1 in activated macrophages: role in foam cell formation
Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H782 - H790.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Renal Physiol.Home page
I. V. Smirnova, T. Sawamura, and M. S. Goligorsky
Upregulation of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) in endothelial cells by nitric oxide deficiency
Am J Physiol Renal Physiol, July 1, 2004; 287(1): F25 - F32.
[Abstract] [Full Text] [PDF]


Home page
CirculationHome page
V. Achan, J. T. Kielstein, B. Impraim, S. Simmel, M. M. Hoeper, H. Haller, D. Fliser, D. Tsikas, J. C. Frolich, and S. M. Bode-Boger
Cardiovascular Effects of Asymmetric Dimethylarginine * Response
Circulation, June 29, 2004; 109(25): e327 - e327.
[Full Text] [PDF]


Home page
Nephrol Dial TransplantHome page
C. Delles, A. U. Klingbeil, M. P. Schneider, R. Handrock, T. Schaufele, and R. E. Schmieder
The role of nitric oxide in the regulation of glomerular haemodynamics in humans
Nephrol. Dial. Transplant., June 1, 2004; 19(6): 1392 - 1397.
[Abstract] [Full Text] [PDF]


Home page
CirculationHome page
J. P. Cooke
Asymmetrical Dimethylarginine: The Uber Marker?
Circulation, April 20, 2004; 109(15): 1813 - 1818.
[Full Text] [PDF]


Home page
Diabetes CareHome page
L. Tarnow, P. Hovind, T. Teerlink, C. D.A. Stehouwer, and H.-H. Parving
Elevated Plasma Asymmetric Dimethylarginine as a Marker of Cardiovascular Morbidity in Early Diabetic Nephropathy in Type 1 Diabetes
Diabetes Care, March 1, 2004; 27(3): 765 - 769.
[Abstract] [Full Text] [PDF]


Home page
J. Am. Soc. Nephrol.Home page
F. Mallamaci, G. Tripepi, R. Maas, L. Malatino, R. Boger, and C. Zoccali
Analysis of the Relationship between Norepinephrine and Asymmetric Dimethyl Arginine Levels among Patients with End-Stage Renal Disease
J. Am. Soc. Nephrol., February 1, 2004; 15(2): 435 - 441.
[Abstract] [Full Text] [PDF]


Home page
J. Am. Soc. Nephrol.Home page
Z. A. Massy, C. Fumeron, D. Borderie, P. Tuppin, T. Nguyen-Khoa, M.-O. Benoit, C. Jacquot, C. Buisson, T. B. Drueke, O. G. Ekindjian, et al.
Increased Plasma S-Nitrosothiol Concentrations Predict Cardiovascular Outcomes among Patients with End-Stage Renal Disease: A Prospective Study
J. Am. Soc. Nephrol., February 1, 2004; 15(2): 470 - 476.
[Abstract] [Full Text] [PDF]


Home page
CirculationHome page
J. T. Kielstein, B. Impraim, S. Simmel, S. M. Bode-Boger, D. Tsikas, J. C. Frolich, M. M. Hoeper, H. Haller, and D. Fliser
Cardiovascular Effects of Systemic Nitric Oxide Synthase Inhibition With Asymmetrical Dimethylarginine in Humans
Circulation, January 20, 2004; 109(2): 172 - 177.
[Abstract] [Full Text] [PDF]