Published online before print December 8, 2003, doi: 10.1161/01.CIR.0000105764.22626.B1
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2004;109:172-177.)
© 2004 American Heart Association, Inc.
Clinical Investigation and Reports |
Cardiovascular Effects of Systemic Nitric Oxide Synthase Inhibition With Asymmetrical Dimethylarginine in Humans
From the Department of Internal Medicine (J.T.K., B.I., S.S., M.M.H., H.H., D.F.) and the Institute of Clinical Pharmacology (D.T., J.C.F.), Medical School Hannover; and the Institute of Clinical Pharmacology, Otto-von-Guericke-University Magdeburg (S.M.B.-B.), Germany.
Correspondence to J.T. Kielstein, MD, Department of Internal Medicine, Medical School Hannover, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany. E-mail kielstein{at}yahoo.com
Received August 8, 2003; revision received September 23, 2003; accepted September 25, 2003.
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Background— Increased blood concentrations of the endogenous nitric oxide synthase (NOS) inhibitor asymmetrical dimethylarginine (ADMA) have been linked to excess cardiovascular morbidity and mortality and to progression of renal disease. We evaluated systemic cardiovascular effects of ADMA infusion in healthy subjects using invasive techniques, ie, right heart catheter and inulin/para-aminohippurate clearance.
Methods and Results— Plasma ADMA concentrations encountered in patients with cardiovascular diseases, ie, between 2 and 10 µmol/L, caused a significant (P<0.05) decrease in concentrations of plasma cGMP, the main second messenger of NO. In addition, cardiac output was significantly lower (5.3±0.4 versus 5.8±0.6 L/min; P<0.05 versus baseline), and systemic vascular resistance was significantly higher (1403±123 versus 1221±100 dyn · s · cm-5; P<0.05 versus baseline). The infusion of 0.25 mg ADMA · kg-1 · min-1 or 3 µg NG-nitro-L-arginine methyl ester · kg-1 · min-1, a potent synthetic NOS inhibitor with long action, resulted in a comparable decrease in effective renal plasma flow (from 670±40 to 596±29 mL · min-1; P<0.05) and an increase in renovascular resistance (from 79±5 to 90±7 mm Hg · mL-1 · min-1; P<0.05). Moreover, administration of ADMA caused significant sodium retention and blood pressure increase (both P<0.05). The observed effects of ADMA in the systemic circulation were sustained corresponding to a mean plasma half-life of 23.5±6.8 minutes, calculated from plasma ADMA decay curves in healthy subjects.
Conclusions— Systemic ADMA infusion is responsible for a short-term, modest decrease in cardiac output with comparable decrease in effective renal plasma flow while increasing systemic vascular resistance and blood pressure in a dose-related manner.
Key Words: nitric oxide synthase • vasculature • asymmetrical dimethylarginine
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Endothelium-derived nitric oxide (NO) plays a critical role in the regulation of endothelial cell function. It exerts its cardiovascular effects primarily via stimulation of soluble guanylate cyclase to produce cGMP.1,2 There are abundant experimental data that endothelial dysfunction caused by reduced availability of NO is an early step in the course of atherosclerotic vascular disease. Evidence has accumulated that inhibition of NO synthesis by endogenous inhibitors of the NO synthase (NOS) may be causally involved in this process.3 In 1992, Vallance et al4 first reported markedly elevated plasma levels of the NOS inhibitor asymmetrical dimethylarginine (ADMA) in patients with end-stage renal disease. In the following decade, a number of studies in renal and in nonrenal patients have been published in which a strong correlation between ADMA blood levels and increased cardiovascular morbidity and mortality was documented.5–10 Hence, ADMA not only is a biochemical marker of atherosclerosis but also is thought to play a causal role in its genesis.3,11 Moreover, recent experimental studies have revealed that reduced bioavailability of NO plays a critical role in the progression of renal disease,12,13 and increased plasma ADMA levels may contribute to this process.14
Evidence for a biological action of ADMA is limited primarily to in vitro studies and studies in animals.14–20 Controlled trials examining the effects of ADMA on different vascular beds in humans have not yet been reported. We infused ADMA intravenously in escalating doses to healthy subjects and assessed corresponding plasma concentrations and dose-response effects on NO production and renal hemodynamics. We have chosen this experimental setting because the human (postglomerular) renal circulation is very sensitive to NOS inhibition and can be easily assessed with accurate invasive clearance techniques.21,22 In a second study, we compared the renal effects of ADMA with those of NG-nitro-L-arginine methyl ester (L-NAME), a potent synthetic NOS inhibitor for clinical use with long-lasting action.22–24 Finally, we assessed the effect of ADMA on systemic cardiovascular parameters, eg, cardiac output and systemic vascular resistance, by placing a right heart catheter in healthy volunteers.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Subjects and Protocols
All study protocols were approved by the Ethics Committee of the Hannover Medical School. Written informed consent was given by all participants, who were healthy nonsmoking male volunteers. During the studies, all participants adhered to an isocaloric standardized diet.
In a first series of experiments, we assessed safety, plasma ADMA concentrations achieved, and the dose-response effects on NO production and renal hemodynamics of a systemic ADMA infusion (NG,NG-ADMA, Sigma Chemicals) in 6 healthy subjects. In each volunteer, the following doses were administered intravenously on 7 separate study days: 0 (placebo infusion), 0.0125, 0.025, 0.0375, 0.075, 0.15, and 0.25 mg ADMA · kg-1 · min-1. ADMA was prepared by sterile filtration and dissolved in 50 mL of a 0.9% NaCl solution. The lowest ADMA dose was chosen on the basis of results of animal studies.16 The infusion of 0.25 mg · kg-1 · min-1 was the highest dose approved by the Ethics Committee. Participants were admitted to our metabolic ward at 8 PM on the day before the experiments to minimize environmental stress. The next morning, glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were examined with the subjects in the supine position by use of steady-state inulin and para-aminohippurate (PAH) infusion techniques as described in detail elsewhere.25 After an appropriate equilibration period, blood samples for measurements of baseline GFR and ERPF were taken at regular intervals during a steady-state period of 50 minutes. Thereafter, ADMA was infused for 40 minutes, and renal hemodynamics were assessed in this period and after discontinuation of the infusion for another 50 minutes. Mean arterial blood pressure (MAP) was monitored noninvasively at regular intervals throughout with Dinamap (Critikon Co). Blood samples for measurements of plasma ADMA and cGMP concentrations were taken at the start (minute 50) and the end (minute 90) of the infusion period and immediately centrifuged at 1.500g at 4°C for 10 minutes, and the supernatants stored in aliquots at -80°C until further use.
In addition to the above protocol, blood samples for measurement of plasma ADMA levels were taken at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, and 60 minutes after discontinuation of infusion of 0.025 mg ADMA · kg-1 · min-1 (n=6). We calculated the disappearance plasma half-life of ADMA from the plasma concentration decay profile in each subject individually. We fitted the plasma ADMA concentration time series to a decay model that takes into consideration the admixture of a persistent simultaneous low level of endogenous ADMA production, given by the equation C(t)=C0xe-k/t+b, where k is ln2/half-life and b is the postdecay baseline ADMA concentration.
Using a double-blind placebo-controlled crossover study design, we allocated 11 healthy men in random order to infusion of either placebo, 0.25 mg ADMA · kg-1 · min-1, or 3 µg L-NAME · kg-1 · min-1. These infusions were administered on separate days, and GFR, ERPF, and MAP were assessed as described above. The synthetic NOS inhibitor L-NAME was chosen because of its long duration of action. For this reason, hemodynamic parameters were assessed for a total of 120 minutes after discontinuation of the infusions. The infusion rate of L-NAME was adopted from studies in healthy volunteers21 to achieve an effect on ERPF comparable to that observed with 0.25 mg ADMA · kg-1 · min-1 (Table 1). Blood samples for measurements of plasma ADMA and cGMP concentrations were drawn before (minute 50) and immediately after the infusion period (minute 90) and at the end of the postinfusion period (minute 210). In addition, we obtained urine samples from all subjects after the postinfusion period for assessment of urinary sodium excretion.
|
Finally, in a third series of experiments, we infused 0.10 mg ADMA · kg-1 · min-1 to 7 volunteers and invasively assessed cardiac output, systemic vascular resistance, and heart rate (ECG monitoring). For this purpose, a right heart catheter was placed under local anesthesia, and measurements were performed as described previously.26 After an appropriate equilibration period to minimize stress after the catheter placement, systemic hemodynamics were assessed at regular time points during a placebo infusion period (50 minutes), followed by the ADMA infusion (40 minutes), and for another 120 minutes after discontinuation of the ADMA infusion. The mean of 4 measurements at each time point was taken into analysis. Blood samples for measurement of ADMA levels were taken before (minute 50) and after (minute 90) the infusion period and at the end of the postinfusion period (minute 210). The infusion rate was chosen on the basis of the results from the dose-response study.
Measurements and Calculations
Inulin plasma concentration was measured enzymatically with inulinase and that of PAH photometrically, and inulin and PAH clearances were calculated as described previously.25 Filtration fraction was calculated as the ratio between inulin and PAH clearance, and renovascular resistance (RVR) was calculated by the equation RVR=[(MAP-12)x723/ERPF]. Plasma ADMA levels were determined by high-performance liquid chromatography with precolumn derivatization with o-phthalaldehyde as described previously.27 The coefficients of variation of this method is 5.2% within assay and 5.5% between assay; the detection limit of the assay is 0.1 µmol/L. Plasma cGMP was measured by ELISA (R&D Systems). All routine laboratory measurements in plasma and urine were performed by certified assay methods.
Statistical Analysis
The primary efficacy parameters in the dose-finding experiments were plasma cGMP concentration and ERPF. We compared preinfusion (baseline) and postinfusion values using a Student paired t test (SPSS statistical package). All other data were analyzed descriptively. In the comparative trial with placebo, ADMA, and L-NAME infusion, we compared preinfusion (baseline) and postinfusion (minute 210) data of the 3 groups by ANOVA. If this procedure revealed significant differences, we used a paired t test to compare means between different infusion protocols; Bonferroni correction was applied. In addition, we compared intraindividual preinfusion (baseline) and postinfusion (minute 210) values using a paired t test. The latter test was also used to compare data on systemic cardiovascular parameters obtained during the right heart catheter experiments. The significance level was set at P<0.05. Data in text and in tables are presented as mean±SD, whereas data in figures are presented as mean±SEM.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The effect of increasing systemic ADMA blood levels on NO production, GFR, ERPF, and blood pressure are summarized in Table 1. Acute increase of plasma ADMA levels within the pathophysiologically relevant range, ie, between 2 and 10 µmol/L, were achieved with infusion rates of 0.0125 and 0.025 mg ADMA · kg-1 · min-1. With these ADMA doses, we observed a significant decrease in plasma cGMP concentrations. A significant effect on ERPF was documented with infusion rates of 0.075 mg ADMA · kg-1 · min-1 and above, whereas GFR remained unaffected (Table 1). Mean plasma ADMA half-life calculated from plasma concentration decay profiles of 6 healthy subjects was 23.5±6.8 minutes, and the individual half-lives were 22.8, 25.4, 20.4, 35.9, 19.9, and 16.4 minutes.
Infusion of 3.0 µg L-NAME · kg-1 · min-1 and 0.25 mg ADMA · kg-1 · min-1 caused a significant decrease in ERPF and a significant increase in filtration fraction and RVR (Figure 1). The effect of ADMA on ERPF and RVR was observed immediately after the start of the infusion, whereas the effect of L-NAME with some delay. The effect on renal perfusion was sustained with administration of both L-NAME and ADMA, lasting for at least 2 hours after the end of infusions (Figure 1). Moreover, infusion of both L-NAME and ADMA caused a small but significant increase in MAP (Figure 2). Plasma ADMA and cGMP levels are shown in Table 2. Two hours after discontinuation of the infusion, mean ADMA blood concentration was <10 µmol/L. In contrast, plasma cGMP concentration decreased significantly with administration of both NOS inhibitors and was still 30% below baseline values 2 hours after the infusions stopped. The changes in NO production and renal hemodynamics with ADMA and L-NAME infusion were accompanied by a significant decrease in renal sodium excretion. Urinary sodium excretion was lower with infusion of ADMA (127±26 µmol/min) and L-NAME (123±28 µmol/min) than with placebo infusion (153±23 µmol/min; P<0.05 versus both NOS inhibitors).
|
) on renal hemodynamics in 11 healthy volunteers. A, GFR; B, ERPF; C, filtration fraction (FF); D, RVR. *P<0.05, preinfusion (baseline) vs postinfusion (minute 210) data; #P<0.05, ADMA vs placebo infusion; 
P<0.05, L-NAME vs placebo infusion.
|
|
Infusion of ADMA to 7 healthy subjects caused a significant and sustained decrease in cardiac output (Figure 3A) and a significant increase in systemic vascular resistance (Figure 3B). Like the response of the renal circulation, we observed an immediate effect of ADMA on systemic cardiovascular parameters, and the action of ADMA lasted until the end of the postinfusion period (minute 210). In addition, we observed a significant (P<0.05) decrease in heart rate during ADMA infusion from 58±7 to 54±6 bpm; at the end of the postinfusion period, mean heart rate was 56±8 bpm. Mean plasma ADMA concentration increased from 0.95±0.27 (baseline) to 22.95±4.91 µmol/L at the end of the infusion period (minute 90). It was 5.31±1.43 µmol/L at the end of the postinfusion period (minute 210), ie, within a pathophysiologically relevant range.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Our results, obtained in a series of controlled clinical experiments with invasive assessment of cardiovascular parameters, document for the first time that systemic administration of the (endogenous) NOS inhibitor ADMA has definite effects on cardiovascular and renal function in healthy subjects. We observed these effects after infusion of doses that acutely yielded plasma ADMA levels above those encountered in patients with renal and/or cardiovascular disease,4–7,9,28,29 but administration of even smaller doses caused a significant decrease in plasma cGMP concentrations, ie, the main second messenger of NO in the cardiovascular system. Moreover, after discontinuation of the infusion, plasma ADMA levels returned to the pathophysiologically relevant range, ie, to <10 µmol/L. At this concentration, the systemic and renal hemodynamic effects of ADMA in healthy subjects were still clearly measurable, however. It is therefore conceivable that ADMA causes sustained changes in vascular function through an intracellular action in endothelial cells at blood concentrations found in patients with cardiovascular pathological conditions.
Indirect evidence for the above assumption comes from a recent study in renal patients, in whom plasma ADMA levels were increased 
4 times compared with healthy control levels. Ex vivo, their blood markedly inhibited NO production in cultured endothelial cells.30 With the lowest infusion rate chosen, plasma ADMA levels increased acutely 4-fold in healthy subjects and caused a significant reduction in NO production. Our results are therefore in line with evidence accumulated from experimental studies that indicate that ADMA is a potent endogenous NOS inhibitor.3,12–14 As a consequence, chronically elevated plasma ADMA levels may be of definite relevance in human vascular pathology. A rapidly growing number of published clinical studies documenting a strong correlation between increased ADMA levels and cardiovascular morbidity and mortality in different populations support this hypothesis.5–8,10,29,31
We have chosen L-NAME for direct comparison with ADMA with respect to NOS inhibition because of its long-lasting action. The response of ERPF and RVR in our healthy subjects to administration of 3 µg L-NAME · kg-1 · min-1 was similar to that found in previous studies.22,22,24 With infusion of either L-NAME or ADMA, we observed a sustained decrease in ERPF and an increase in RVR and MAP. It is therefore conceivable that higher ADMA doses cause a larger increase in blood pressure, similar to that shown for L-NAME.21,23,24 In addition, our finding of significant renal vasoconstriction with ADMA infusion yielding acute plasma levels in the supraphysiological range is reminiscent of the action of angiotensin II. The latter exerts renal vasoconstrictor effects at blood levels that are above those found in patients with hypertension and/or cardiovascular disease.32 Nevertheless, angiotensin II has a number of effects promoting atherogenesis, possibly because of high (local) tissue concentrations. The latter may be true for ADMA as well, and chronically elevated ADMA blood and/or tissue levels may cause vascular injury at the endothelial cell level.
Of particular interest in this respect is the time course of the action of ADMA. Like L-NAME, ADMA has a long duration of action, contrasting with the short-lived action of NO. This is in accordance with the relatively long ADMA plasma half-life of >20 minutes calculated from plasma decay curves in healthy subjects. The plasma half-life could theoretically be even longer in conditions in which the main pathway of ADMA degradation by the enzyme dimethylarginine dimethylaminohydrolase is dysregulated, such as in hypercholesterolemia and diabetes mellitus.33,34 In addition to its long-lasting action, the effect of ADMA was already seen within the infusion period, pointing to immediate NOS inhibition. In this respect, ADMA differs from L-NAME, which is a prodrug and has first to be metabolized to its active form, ie, NG-nitro-L-arginine.35
In conclusion, systemic ADMA infusion is responsible for a short-term, modest decrease in cardiac output with a comparable decrease in ERPF while increasing systemic vascular resistance and blood pressure in a dose-related manner.
|
Acknowledgments |
|---|
The study was supported by a research grant from the Medical School Hannover (HiLF). We thank S. Graf, T. Suchi, and B. Beckmann for the excellent laboratory work.
|
Footnotes |
|---|
Presented in part as a poster at the 56th Annual Fall Conference and Scientific Sessions of the Council for High Blood Pressure Research, September 25–28, 2002.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Moncada S, Higgs A. The L-arginine-nitric oxide pathway. N Engl J Med. 1993; 329: 2002–2012.
2. Murad F, Rapoport RM, Fiscus R. Role of cyclic-GMP in relaxations of vascular smooth muscle. J Cardiovasc Pharmacol. 1985; 7 (suppl 3): S111–S118.[Medline] [Order article via Infotrieve]
3. Cooke JP. Does ADMA cause endothelial dysfunction? Arterioscler Thromb Vasc Biol. 2000; 20: 2032–2037.
4. 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]
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.
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.
7. Miyazaki H, Matsuoka H, Cooke JP, et al. Endogenous nitric oxide synthase inhibitor: a novel marker of atherosclerosis. Circulation. 1999; 99: 1141–1146.
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. 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]
10. 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]
11. Vallance P. Importance of asymmetrical dimethylarginine in cardiovascular risk. Lancet. 2001; 358: 2096–2097.[CrossRef][Medline] [Order article via Infotrieve]
12. Baylis C, Mitruka B, Deng A. Chronic blockade of nitric oxide synthesis in the rat produces systemic hypertension and glomerular damage. J Clin Invest. 1992; 90: 278–281.[Medline] [Order article via Infotrieve]
13. Benigni A, Zoja C, Noris M, et al. Renoprotection by nitric oxide donor and lisinopril in the remnant kidney model. Am J Kidney Dis. 1999; 33: 746–753.[Medline] [Order article via Infotrieve]
14. Wagner L, Riggleman A, Erdely A, et al. Reduced nitric oxide synthase activity in rats with chronic renal disease due to glomerulonephritis. Kidney Int. 2002; 62: 532–536.[CrossRef][Medline] [Order article via Infotrieve]
15. 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 (5 pt 2): H1522–H1527.[Medline] [Order article via Infotrieve]
16. 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]
17. Jin JS, D’Alecy LG. Central and peripheral effects of asymmetric dimethylarginine, an endogenous nitric oxide synthetase inhibitor. J Cardiovasc Pharmacol. 1996; 28: 439–446.[CrossRef][Medline] [Order article via Infotrieve]
18. 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 (11 pt 1): 1142–1148.[CrossRef][Medline] [Order article via Infotrieve]
19. 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]
20. 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]
21. 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 (5 pt 2): F845–F851.[Medline] [Order article via Infotrieve]
22. 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 (6 pt 2): F1033–F1037.[Medline] [Order article via Infotrieve]
23. Sander M, Chavoshan B, Victor RG. A large blood pressure-raising effect of nitric oxide synthase inhibition in humans. Hypertension. 1999; 33: 937–942.
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 (6 pt 2): F870–F877.[Medline] [Order article via Infotrieve]
25. Fliser D, Zeier M, Nowack R, et al. Renal functional reserve in healthy elderly subjects. J Am Soc Nephrol. 1993; 3: 1371–1377.[Abstract]
26. Hoeper MM, Maier R, Tongers J, et al. Determination of cardiac output by the Fick method, thermodilution, and acetylene rebreathing in pulmonary hypertension. Am J Respir Crit Care Med. 1999; 160: 535–541.
27. Bode-Boger SM, Boger RH, Kienke S, et al. Elevated L-arginine/dimethylarginine ratio contributes to enhanced systemic NO production by dietary L-arginine in hypercholesterolemic rabbits. Biochem Biophys Res Commun. 1996; 219: 598–603.[CrossRef][Medline] [Order article via Infotrieve]
28. 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.
29. 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.
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. Kielstein JT, Bode-Boger SM, Frolich JC, et al. Asymmetric dimethylarginine, blood pressure, and renal perfusion in elderly subjects. Circulation. 2003; 107: 1891–1895.
32. Unger T. The role of the renin-angiotensin system in the development of cardiovascular disease. Am J Cardiol. 2002; 89: 3A–9A.[Medline] [Order article via Infotrieve]
33. Ito A, Tsao PS, Adimoolam S, et al. Novel mechanism for endothelial dysfunction: dysregulation of dimethylarginine dimethylaminohydrolase. Circulation. 1999; 99: 3092–3095.
34. Stuhlinger MC, Abbasi F, Chu JW, et al. Relationship between insulin resistance and an endogenous nitric oxide synthase inhibitor. JAMA. 2002; 287: 1420–1426.
35. Avontuur JA, Buijk SL, Bruining HA. Distribution and metabolism of NG-nitro-L-arginine methyl ester in patients with septic shock. Eur J Clin Pharmacol. 1998; 54: 627–631.[CrossRef][Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  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]
|
|
|
|
 |
|
 W.H. W. Tang, Z. Wang, L. Cho, D. M. Brennan, and S. L. Hazen Diminished global arginine bioavailability and increased arginine catabolism as metabolic profile of increased cardiovascular risk. J. Am. Coll. Cardiol., June 2, 2009; 53(22): 2061 - 2067. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Sharma, Z. Zhou, H. Miura, A. Papapetropoulos, E. T. McCarthy, R. Sharma, V. J. Savin, and E. A. Lianos ADMA injures the glomerular filtration barrier: role of nitric oxide and superoxide Am J Physiol Renal Physiol, June 1, 2009; 296(6): F1386 - F1395. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. H. Boger, L. M. Sullivan, E. Schwedhelm, T. J. Wang, R. Maas, E. J. Benjamin, F. Schulze, V. Xanthakis, R. A. Benndorf, and R. S. Vasan Plasma Asymmetric Dimethylarginine and Incidence of Cardiovascular Disease and Death in the Community Circulation, March 31, 2009; 119(12): 1592 - 1600. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.-C. Wu, S.-C. Wen, C.-W. Yang, S.-Y. Pu, K.-C. Tsai, and J.-W. Chen Plasma ADMA Predicts Restenosis of Arteriovenous Fistula J. Am. Soc. Nephrol., January 1, 2009; 20(1): 213 - 222. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Siekmeier, T. Grammer, and W. Marz Roles of Oxidants, Nitric Oxide, and Asymmetric Dimethylarginine in Endothelial Function Journal of Cardiovascular Pharmacology and Therapeutics, December 1, 2008; 13(4): 279 - 297. [Abstract] [PDF]
|
|
|
|
 |
|
 J. A. Chirinos, R. David, J. A. Bralley, H. Zea-Diaz, E. Munoz-Atahualpa, F. Corrales-Medina, C. Cuba-Bustinza, J. Chirinos-Pacheco, and J. Medina-Lezama Endogenous Nitric Oxide Synthase Inhibitors, Arterial Hemodynamics, and Subclinical Vascular Disease: The PREVENCION Study Hypertension, December 1, 2008; 52(6): 1051 - 1059. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Kobayashi, M. Oka, K. Maesato, R. Ikee, T. Mano, M. Hidekazu, and T. Ohtake Coronary Artery Calcification, ADMA, and Insulin Resistance in CKD Patients Clin. J. Am. Soc. Nephrol., September 1, 2008; 3(5): 1289 - 1295. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Lajer, L. Tarnow, A. Jorsal, T. Teerlink, H.-H. Parving, and P. Rossing Plasma Concentration of Asymmetric Dimethylarginine (ADMA) Predicts Cardiovascular Morbidity and Mortality in Type 1 Diabetic Patients With Diabetic Nephropathy Diabetes Care, April 1, 2008; 31(4): 747 - 752. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Lucke, N. Kanzelmeyer, K. Chobanyan, D. Tsikas, D. Franke, M. J. Kemper, J. H.H. Ehrich, and A. M. Das Elevated asymmetric dimethylarginine (ADMA) and inverse correlation between circulating ADMA and glomerular filtration rate in children with sporadic focal segmental glomerulosclerosis (FSGS) Nephrol. Dial. Transplant., February 1, 2008; 23(2): 734 - 740. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Vanholder, S. V. Laecke, F. Verbeke, G. Glorieux, and W. V. Biesen Uraemic toxins and cardiovascular disease: in vitro research versus clinical outcome studies NDT Plus, February 1, 2008; 1(1): 2 - 10. [Full Text] [PDF]
|
|
|
|
|
|
C. Baylis Nitric oxide deficiency in chronic kidney disease Am J Physiol Renal Physiol, January 1, 2008; 294(1): F1 - F9. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Kjolby and P. Bie Chronic activation of plasma renin is log-linearly related to dietary sodium and eliminates natriuresis in response to a pulse change in total body sodium Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2008; 294(1): R17 - R25. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Skoro-Sajer, F. Mittermayer, A. Panzenboeck, D. Bonderman, R. Sadushi, R. Hitsch, J. Jakowitsch, W. Klepetko, M. P. Kneussl, M. Wolzt, et al. Asymmetric Dimethylarginine Is Increased in Chronic Thromboembolic Pulmonary Hypertension Am. J. Respir. Crit. Care Med., December 1, 2007; 176(11): 1154 - 1160. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Vanholder, N. Meert, E. Schepers, G. Glorieux, A. Argiles, P. Brunet, G. Cohen, T. Drueke, H. Mischak, G. Spasovski, et al. Review on uraemic solutes II Variability in reported concentrations: causes and consequences Nephrol. Dial. Transplant., November 1, 2007; 22(11): 3115 - 3121. [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]
|
|
|
|
 |
|
 D. Wang, P. S. Gill, T. Chabrashvili, M. L. Onozato, J. Raggio, M. Mendonca, K. Dennehy, M. Li, P. Modlinger, J. Leiper, et al. Isoform-Specific Regulation by NG,NG-Dimethylarginine Dimethylaminohydrolase of Rat Serum Asymmetric Dimethylarginine and Vascular Endothelium-Derived Relaxing Factor/NO Circ. Res., September 14, 2007; 101(6): 627 - 635. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. T. Kielstein, K. Sydow, and T. Thum Tilarginine in Patients With Acute Myocardial Infarction and Cardiogenic Shock JAMA, September 5, 2007; 298(9): 971 - 971. [Full Text] [PDF]
|
|
|
|
|
|
T. Teerlink Tilarginine in Patients With Acute Myocardial Infarction and Cardiogenic Shock JAMA, September 5, 2007; 298(9): 971 - 972. [Full Text] [PDF]
|
|
|
|
 |
|
 C. Duckelmann, F. Mittermayer, D. G. Haider, J. Altenberger, J. Eichinger, and M. Wolzt Asymmetric Dimethylarginine Enhances Cardiovascular Risk Prediction in Patients With Chronic Heart Failure Arterioscler Thromb Vasc Biol, September 1, 2007; 27(9): 2037 - 2042. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q. Zhao, Z. Liu, Z. Wang, C. Yang, J. Liu, and J. Lu Effect of Prepro-Calcitonin Gene-Related Peptide Expressing Endothelial Progenitor Cells on Pulmonary Hypertension Ann. Thorac. Surg., August 1, 2007; 84(2): 544 - 552. [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]
|
|
|
|
|
|
K. Tsuda Asymmetric Dimethylarginine and Hypertension in Cerebral Small Vessel Disease Stroke, July 1, 2007; 38(7): e48 - e48. [Full Text] [PDF]
|
|
|
|
 |
|
 P. J. Blankestijn SYMPATHETIC HYPERACTIVITY--A HIDDEN ENEMY IN CHRONIC KIDNEY DISEASE PATIENTS Perit. Dial. Int., June 1, 2007; 27(Supplement_2): S293 - S297. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. T. Kielstein and C. Zoccali A New Perspective for the Treatment of Renal Diseases? J. Am. Soc. Nephrol., May 1, 2007; 18(5): 1365 - 1367. [Full Text] [PDF]
|
|
|
|
 |
|
 R. Maas, F. Schulze, J. Baumert, H. Lowel, K. Hamraz, E. Schwedhelm, W. Koenig, and R. H. Boger Asymmetric Dimethylarginine, Smoking, and Risk of Coronary Heart Disease in Apparently Healthy Men: Prospective Analysis from the Population-Based Monitoring of Trends and Determinants in Cardiovascular Disease/Kooperative Gesundheitsforschung in der Region Augsburg Study and Experimental Data Clin. Chem., April 1, 2007; 53(4): 693 - 701. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Tsuda Asymmetric Dimethylarginine and Cerebrovascular Disorders in Humans Stroke, December 1, 2006; 37(12): 2870 - 2870. [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, J. P. Cooke, and C. Zoccali Letter by Kielstein et al Regarding Article, "Renal Function as a Predictor of Outcome in a Broad Spectrum of Patients With Heart Failure" Circulation, August 8, 2006; 114(6): e242 - e242. [Full Text] [PDF]
|
|
|
|
|
|
K. Matsuguma, S. Ueda, S.-i. Yamagishi, Y. Matsumoto, U. Kaneyuki, R. Shibata, T. Fujimura, H. Matsuoka, M. Kimoto, S. Kato, et al. Molecular Mechanism for Elevation of Asymmetric Dimethylarginine and Its Role for Hypertension in Chronic Kidney Disease J. Am. Soc. Nephrol., August 1, 2006; 17(8): 2176 - 2183. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. T. Kielstein, F. Donnerstag, S. Gasper, J. Menne, A. Kielstein, J. Martens-Lobenhoffer, F. Scalera, J. P. Cooke, D. Fliser, and S. M. Bode-Boger ADMA Increases Arterial Stiffness and Decreases Cerebral Blood Flow in Humans Stroke, August 1, 2006; 37(8): 2024 - 2029. [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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
P. Vallance and J. Leiper Asymmetric Dimethylarginine and Kidney Disease--Marker or Mediator? J. Am. Soc. Nephrol., August 1, 2005; 16(8): 2254 - 2256. [Full Text] [PDF]
|
|
|
|
|
|
E. Schwedhelm, J. Tan-Andresen, R. Maas, U. Riederer, F. Schulze, and R. H. Boger Liquid Chromatography-Tandem Mass Spectrometry Method for the Analysis of Asymmetric Dimethylarginine in Human Plasma Clin. Chem., July 1, 2005; 51(7): 1268 - 1271. [Full Text] [PDF]
|
|
|
|
 |
|
 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. Thum and J. Bauersachs Spotlight on endothelial progenitor cell inhibitors: short review Vascular Medicine, July 1, 2005; 10(1_suppl): S59 - S64. [Abstract] [PDF]
|
|
|
|
|
|
J. T. Kielstein, S. M. Bode-Boger, G. Hesse, J. Martens-Lobenhoffer, A. Takacs, D. Fliser, and M. M. Hoeper Asymmetrical Dimethylarginine in Idiopathic Pulmonary Arterial Hypertension Arterioscler Thromb Vasc Biol, July 1, 2005; 25(7): 1414 - 1418. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Mittermayer, G. Schaller, J. Pleiner, A. Vychytil, G. Sunder-Plassmann, W. H. Horl, and M. Wolzt Asymmetrical Dimethylarginine Plasma Concentrations Are Related to Basal Nitric Oxide Release but Not Endothelium-Dependent Vasodilation of Resistance Arteries in Peritoneal Dialysis Patients J. Am. Soc. Nephrol., June 1, 2005; 16(6): 1832 - 1838. [Abstract] [Full Text] [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. Thum and J. Bauersachs Spotlight on endothelial progenitor cell inhibitors: short review Vascular Medicine, May 1, 2005; 10(2_suppl): S59 - S64. [Abstract] [PDF]
|
|
|
|
 |
|
 J. J. Puder, S. Nilavar, K. D. Post, and P. U. Freda Relationship between Disease-Related Morbidity and Biochemical Markers of Activity in Patients with Acromegaly J. Clin. Endocrinol. Metab., April 1, 2005; 90(4): 1972 - 1978. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Ziegler, F. Mittermayer, C. Plank, E. Minar, M. Wolzt, and G.-H. Schernthaner Homocyst(e)ine-Lowering Therapy Does Not Affect Plasma Asymmetrical Dimethylarginine Concentrations in Patients with Peripheral Artery Disease J. Clin. Endocrinol. Metab., April 1, 2005; 90(4): 2175 - 2178. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
M.-A. Devynck, A. Simon, M.-G. Pernollet, G. Chironi, J. Gariepy, F. Rendu, and J. Levenson Plasma cGMP and Large Artery Remodeling in Asymptomatic Men Hypertension, December 1, 2004; 44(6): 919 - 923. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Bourraindeloup, C. Adamy, G. Candiani, M. Cailleret, M.-C. Bourin, T. Badoual, J. B. Su, S. Adubeiro, F. Roudot-Thoraval, J.-L. Dubois-Rande, et al. N-Acetylcysteine Treatment Normalizes Serum Tumor Necrosis Factor-{alpha} Level and Hinders the Progression of Cardiac Injury in Hypertensive Rats Circulation, October 5, 2004; 110(14): 2003 - 2009. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Gokce L-Arginine and Hypertension J. Nutr., October 1, 2004; 134(10): 2807S - 2811S. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. H. Boger Asymmetric Dimethylarginine, an Endogenous Inhibitor of Nitric Oxide Synthase, Explains the "L-Arginine Paradox" and Acts as a Novel Cardiovascular Risk Factor J. Nutr., October 1, 2004; 134(10): 2842S - 2847S. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
P. J. Blankestijn Sympathetic hyperactivity in chronic kidney disease Nephrol. Dial. Transplant., June 1, 2004; 19(6): 1354 - 1357. [Full Text] [PDF]
|
|
|
|
|
|
P. Vallance and J. Leiper Cardiovascular Biology of the Asymmetric Dimethylarginine:Dimethylarginine Dimethylaminohydrolase Pathway Arterioscler Thromb Vasc Biol, June 1, 2004; 24(6): 1023 - 1030. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||