- Email: [email protected]
Elevated dimethylarginine dimethylaminohydrolase (DDAH) activity in rheumatoid arthritis and spondyloarthritis
Nitric Oxide 25 (2011) 436–438
Contents lists available at SciVerse ScienceDirect
Nitric Oxide journal homepage: www.elsevier.com/locate/yniox
Letter to the Editor Elevated dimethylarginine dimethylaminohydrolase activity in rheumatoid arthritis and spondyloarthritis
(DDAH)
To the Editor, Asymmetric dimethylarginine (ADMA) is hydrolyzed by dimethylarginine dimethylaminohydrolase (DDAH) to dimethylamine (DMA) and L-citrulline. We have proposed the molar ratio of DMA to ADMA in urine, the DMA/ADMA ratio, as an estimate of the whole body dimethylarginine dimethylaminohydrolase (DDAH) activity and as an indicator of the balance between ADMA formation, on the one hand, and ADMA renal excretion and ADMA elimination via hepatic and renal DDAH activity, on the other hand, in humans [1,2]. In support of this proposal we found a lower DMA/ADMA ratio in end-stage liver disease (about 9:1) but a higher DMA/ADMA ratio in coronary artery disease (about 17:1) compared to healthy humans (about 11:1) [1]. Elevated plasma ADMA concentration is commonly attributed to impaired DDAH activity because of its putative susceptibility to oxidative stress [3]. Yet, there is no convincing evidence of the supposed sensitivity of DDAH towards oxidative and nitrosative stress [4]. In the present work, we provide additional data from a human study that support the utility of the DMA/ADMA ratio as a measure of the ADMA/DDAH pathway and that argue against a DDAH susceptibility to oxidative/nitrosative stress. In a recent study we found that oxidative stress, measured as the urinary excretion of the F2-isoprostane 15(S)-8-iso-prostaglandin F2a (15(S)-8-iso-PGF2a), did not differ between patients with chronic inflammatory rheumatic diseases and healthy volunteers [5]. However, we found that nitrite and 3-nitrotyrosine urinary excretion rates were elevated in the patients compared to healthy controls, possibly due to elevated myeloperoxidase activity in the inflamed joints [5]. Recently, Surdacki and colleagues reported on elevated plasma concentrations of ADMA but not of symmetric dimethylarginine (SDMA) in plasma of rheumatoid arthritis patients who were free of cardiovascular disease or risk factors [6]. The study by Surdacki suggests that ADMA may promote atherogenesis in rheumatoid arthritis by a mechanism involving ADMA-induced depletion of endothelial progenitor cells. In consideration of the elevated plasma ADMA concentration found in rheumatoid arthritis [6], we determined the whole body DDAH activity by assessing DMA and ADMA concentrations in urine samples of patients previously collected and analyzed for nitrosative stress [5]. The cohort consisted of 10 patients with rheumatoid arthritis fulfilling the American College of Rheumatology criteria, 10 patients with undifferentiated arthritis, five patients with spondyloarthropathy, and three patients with vasculitis. Ten age-matched healthy subjects served as the control group. DMA and ADMA were measured in urine samples that had been stored aliquoted at 80 °C. DMA and ADMA concentrations were measured in 100-lL and 10-lL aliquots of thawed urine sam1089-8603/$ - see front matter Ó 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.niox.2011.08.003
ples by fully validated gas chromatography–mass spectrometry (GC–MS) [1] and gas chromatography tandem mass spectrometry (GC–MS/MS) [7] methods, respectively. Data are reported as mean ± SEM. The DMA/ADMA ratio of the control group was compared with the DMA/ADMA ratio of the individual groups by using the Mann Whitney test. The creatinine-corrected urinary excretion of DMA (Fig. 1A) and ADMA (Fig. 1B), as well as the DMA/ADMA ratio (Fig. 1C) were higher in the patients compared to the healthy controls. In the rheumatoid arthritis (RA) and spondyloarthropathy (SPA) patients the DMA/ADMA ratio was by a factor of 2.5 statistically significantly higher than in healthy controls who were free of any chronic inflammatory rheumatic disease. In three patients with vasculitis and 10 patients with undifferentiated arthritis, the DMA/ADMA ratio was comparable to that in healthy controls. There was no worth mentioning correlation between the DMA/ADMA ratio and oxidative stress in terms of the urinary excretion rate of 15(S)-8-isoPGF2a or nitrative stress measured as urinary 3-nitrotyrosine excretion considering the whole cohort (Fig. 2) or in the individual groups (data not shown). In rheumatoid arthritis there seems to be even a negative correlation between ADMA excretion and nitrosative stress and a positive correlation between DMA excretion and nitrosative stress [8]. The present study and the study by Surdacki and colleagues [6] have limitations. The number of the patients investigated (n = 28 and n = 30, respectively) is relatively small. The correlations observed by Surdacki and colleagues [6] are weak. Also, we observed relatively great variations both for DMA excretion rates (RSD, 16% to 104%) and for the DMA/ADMA ratio (RSD, 17% to 102%). These limitations do not allow drawing far-reaching conclusions about the status of the ADMA/DDAH pathway in chronic rheumatic disease. Studies on larger cohorts of patients and healthy subjects are warranted. Another uncertainty is that DMA may originate from additional exogenous sources such as food, especially canned fish, and from endogenous still unknown sources. As an example, we have found that even 12 h after fish consumption by a healthy volunteer the DMA/ADMA ratio was about 32 compared to the value of 10 before ingestion [1]. Therefore, analogous to nitrite and nitrate, avoidance of DMA-rich food is mandatory in studies on ADMA metabolism and elimination via the DDAH pathway. Yet, the results of the study by Surdacki et al. and of the present work suggest that rheumatoid arthritis patients (and spondyloarthropathy patients in our study) are likely to have elevated ADMA synthesis. The urinary DMA/ADMA ratios we measured in patients and healthy controls suggest that DDAH activity is elevated rather than diminished in rheumatoid arthritis and spondyloarthropathy (Fig. 3). By contrast, in undifferentiated arthritis and vasculitis patients, the balance between ADMA synthesis and ADMA metabolism/elimination seems to be more or less equal to that in health. Differences seen in plasma ADMA concentrations in healthy subjects and humans with various diseases are rather very low
Letter to the Editor / Nitric Oxide 25 (2011) 436–438
A
437
A
B B
C Fig. 2. Relationship between the urinary DMA/ADMA molar ratio and (A) urinary 15(S)-8-iso-PGF2a, a biomarker of oxidative stress, or (B) urinary 3-nitrotyrosine, a biomarker of nitrative stress, in the whole patients cohort.
Fig. 1. Creatinine-corrected excretion of DMA (A) and ADMA (B) and urinary DMA/ ADMA molar ratio (C) in healthy subjects and in patients suffering from various chronic inflammatory rheumatic diseases. Data are shown as mean ± SEM. The means of the DMA/ADMA ratio in patients with rheumatoid arthritis and spondyloanthropathy were statistically significantly different (Mann Whitney test). Control (n = 10); RA, rheumatoid arthritis (n = 10); SPA, spondyloarthropathy (n = 5); UndiffArthritis, undifferentiated arthritis (n = 10); Vasculitis (n = 3). Parts of the data on rheumatoid arthritis have been reported elsewhere [8].
[6,9–13]. Thus, inter-individual variation is of the order of 15%. Also, the decreases seen in plasma ADMA concentrations upon pharmacological treatment are fairly small (about 10%), but clinically highly relevant [12,13]. The precise mechanisms by which ADMA may powerfully contribute to cardiovascular diseases, such as chronic heart disease and coronary artery disease, and to chronic inflammatory rheumatic diseases, such as rheumatoid arthritis and spondyloarthropathy, are incompletely understood. Given the relatively low inhibitory potency of ADMA towards endothelial NO synthase (IC50 12 lM; see Ref. [14]), it is possible that ADMA depresses endothelial progenitor cells [6] not only by
Fig. 3. Simplified schematic of the L-arginine/NO/ADMA/DDAH pathway in health, rheumatoid arthritis (RA) and spondyloarthritis (SPA). The width of the arrow below the small box containing ‘‘ADMA’’ indicates roughly the contribution of the urinary excretion of unchanged ADMA and of the elimination of ADMA by hepatic and renal DDAH metabolism to DMA and its renal excretion. PRMT, protein arginine methyl transferase; PL, plasma; U, urine.
inhibiting endothelial NO synthase activity (Fig. 3). Improvement of DDAH activity and/or DDAH expression could be a promising therapeutic means in the treatment of particular chronic
438
Letter to the Editor / Nitric Oxide 25 (2011) 436–438
inflammatory rheumatic diseases such as rheumatoid arthritis and spondyloarthropathy [8,15]. In summary, assessment of the DMA/ADMA ratio in the urine should be useful to follow the disease progression of rheumatoid arthritis and spondyloarthropathy, as well to monitor the effect of pharmacological treatment on these chronic inflammatory rheumatic diseases. The significance of the DMA/ADMA ratio as a reliable measure of ADMA homeostasis in health and disease remains to be demonstrated in larger studies. References [1] D. Tsikas, T. Thum, T. Becker, V.V. Pham, K. Chobanyan, A. Mitschke, B. Beckmann, F.M. Gutzki, J. Bauersachs, D.O. Stichtenoth, Accurate quantification of dimethylamine (DMA) in human urine by gas chromatography- mass spectrometry as pentafluorobenzamide derivative: evaluation of the relationship between DMA and its precursor asymmetric dimethylarginine (ADMA) in health and disease, J. Chromatogr. B 851 (2007) 229–239. [2] T. Becker, I. Mevius, D.K. de Vries, A.F.M. Schaaherder, A. Meyer zu Vilsendorf, J. Klempnauer, J.C. Frölich, D. Tsikas, The L-arginine/NO pathway in end-stage liver disease and during orthotopic liver and kidney transplantation: biological and analytical ramifications, Nitric Oxide 20 (2009) 61–67. [3] J.M. Leiper, P. Vallance, The synthesis and metabolism of asymmetric dimethylarginine (ADMA), Eur. J. Clin. Pharmacol. 62 (2006) 33–38. [4] D. Tsikas, K. Chobanyan, Pitfalls in the measurement of tissue DDAH activity: is DDAH sensitive to nitrosative and oxidative stress?, Kidney Int 74 (2008) 969. Authors reply: 969–970. [5] V.V. Pham, D.O. Stichtenoth, D. Tsikas, Nitrite correlates with 3-nitrotyrosine but not with the F2-isoprostane 15(S)-8-iso-PGF2a in urine of rheumatic patients, Nitric Oxide 21 (2009) 210–215. [6] A. Surdacki, J. Martens-Lobenhoffer, A. Wloch, E. Marewicz, T. Rakowski, E. Wieczorek-Surdacka, J.S. Dubiel, J. Pryjma, S.M. Bode-Böger, Elevated plasma asymmetric dimethyl-L-arginine levels are linked to endothelial progenitor cell depletion, carotid atherosclerosis in rheumatoid arthritis, Arthritis Rheum. 56 (2007) 809–819. [7] D. Tsikas, B. Schubert, F.M. Gutzki, J. Sandmann, J.C. Frölich, Quantitative determination of circulating, urinary asymmetric dimethylarginine (ADMA) in humans by GC-tandem MS as methyl ester tri(N-pentafluoropropionyl) derivative, J. Chromatogr. B 798 (2003) 87–99. [8] K. Chobanyan-Jürgens, V.V. Pham, D.O. Stichtenoth, D. Tsikas, Asymmetrical dimethylarginine, oxidative stress, and atherosclerosis, Hypertension, doi:10.1161/HYPERTENSIONAHA.111.180984.
[9] J.D. Horowitz, T. Heresztyn, An overview of plasma concentrations of asymmetric dimethylarginine (ADMA) in health and disease and in clinical studies, J. Chromatogr. B 851 (2007) 42–50. [10] D. Tsikas, Determination of asymmetric dimethylarginine (ADMA) in biological fluids: A paradigm for a successful analytical story, Curr. Opin. Clin. Nutr. Metab. Care 11 (2008) 592–600. [11] T. Thum, D. Tsikas, S. Stein, M. Schultheiss, M. Eigenthaler, S.D. Anker, P.A. Poole-Wilson, G. Ertl, J. Bauersachs, Suppression of endothelial progenitor cells in human coronary artery disease by the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine, J. Am. Coll. Cardiol. 46 (2005) 1693– 1701. [12] T.M. Lu, Y.A. Ding, H.B. Leu, W.H. Yin, W.H. Sheu, K.M. Chu, Effect of rosuvastatin on plasma levels of asymmetric dimethylarginine in patients with hypercholesterolemia, Am. J. Cardiol. 94 (2004) 1571–1161. [13] E. Leifke, M. Kinzel, D. Tsikas, L. Gooren, J.C. Frölich, G. Brabant, Effects of normalization of plasma testosterone levels in hypogonadal men on plasma levels, urinary excretion of asymmetric dimethylarginine ADMA, Exp. Clin. Endocrinol. Diabetes 40 (2008) 56–59. [14] A. Kielstein, D. Tsikas, G.P. Galloway, J.E. Mendelson, Asymmetric dimethylarginine (ADMA) – A modulator of nociception in opiate tolerance and addiction?, Nitric Oxide 17 (2007) 55–59. [15] C. Antoniades, M. Demosthenous, D. Tousoulis, A.S. Antonopoulos, C. Vlachopoulos, M. Toutouza, K. Marinou, C. Bakogiannis, K. Mavragani, G. Lazaros, N. Koumallos, C. Triantafyllou, D. Lymperiadis, M. Koutsilieris, C. Stafanadis, Role of asymmetrical dimethylarginine in inflammation-induced endothelial dysfunction in human atherosclerosis, Hypertension 58 (2011) 93–98.
Kristine Chobanyan-Jürgens 1 Vu Vi Pham 1 Dirk O. Stichtenoth Dimitrios Tsikas Institute of Clinical Pharmacology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany Fax: +49 511 532 2750. E-mail address: [email protected] (D. Tsikas) Available online 3 September 2011
1
These authors contributed equally to the work.
Contents lists available at SciVerse ScienceDirect
Nitric Oxide journal homepage: www.elsevier.com/locate/yniox
Letter to the Editor Elevated dimethylarginine dimethylaminohydrolase activity in rheumatoid arthritis and spondyloarthritis
(DDAH)
To the Editor, Asymmetric dimethylarginine (ADMA) is hydrolyzed by dimethylarginine dimethylaminohydrolase (DDAH) to dimethylamine (DMA) and L-citrulline. We have proposed the molar ratio of DMA to ADMA in urine, the DMA/ADMA ratio, as an estimate of the whole body dimethylarginine dimethylaminohydrolase (DDAH) activity and as an indicator of the balance between ADMA formation, on the one hand, and ADMA renal excretion and ADMA elimination via hepatic and renal DDAH activity, on the other hand, in humans [1,2]. In support of this proposal we found a lower DMA/ADMA ratio in end-stage liver disease (about 9:1) but a higher DMA/ADMA ratio in coronary artery disease (about 17:1) compared to healthy humans (about 11:1) [1]. Elevated plasma ADMA concentration is commonly attributed to impaired DDAH activity because of its putative susceptibility to oxidative stress [3]. Yet, there is no convincing evidence of the supposed sensitivity of DDAH towards oxidative and nitrosative stress [4]. In the present work, we provide additional data from a human study that support the utility of the DMA/ADMA ratio as a measure of the ADMA/DDAH pathway and that argue against a DDAH susceptibility to oxidative/nitrosative stress. In a recent study we found that oxidative stress, measured as the urinary excretion of the F2-isoprostane 15(S)-8-iso-prostaglandin F2a (15(S)-8-iso-PGF2a), did not differ between patients with chronic inflammatory rheumatic diseases and healthy volunteers [5]. However, we found that nitrite and 3-nitrotyrosine urinary excretion rates were elevated in the patients compared to healthy controls, possibly due to elevated myeloperoxidase activity in the inflamed joints [5]. Recently, Surdacki and colleagues reported on elevated plasma concentrations of ADMA but not of symmetric dimethylarginine (SDMA) in plasma of rheumatoid arthritis patients who were free of cardiovascular disease or risk factors [6]. The study by Surdacki suggests that ADMA may promote atherogenesis in rheumatoid arthritis by a mechanism involving ADMA-induced depletion of endothelial progenitor cells. In consideration of the elevated plasma ADMA concentration found in rheumatoid arthritis [6], we determined the whole body DDAH activity by assessing DMA and ADMA concentrations in urine samples of patients previously collected and analyzed for nitrosative stress [5]. The cohort consisted of 10 patients with rheumatoid arthritis fulfilling the American College of Rheumatology criteria, 10 patients with undifferentiated arthritis, five patients with spondyloarthropathy, and three patients with vasculitis. Ten age-matched healthy subjects served as the control group. DMA and ADMA were measured in urine samples that had been stored aliquoted at 80 °C. DMA and ADMA concentrations were measured in 100-lL and 10-lL aliquots of thawed urine sam1089-8603/$ - see front matter Ó 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.niox.2011.08.003
ples by fully validated gas chromatography–mass spectrometry (GC–MS) [1] and gas chromatography tandem mass spectrometry (GC–MS/MS) [7] methods, respectively. Data are reported as mean ± SEM. The DMA/ADMA ratio of the control group was compared with the DMA/ADMA ratio of the individual groups by using the Mann Whitney test. The creatinine-corrected urinary excretion of DMA (Fig. 1A) and ADMA (Fig. 1B), as well as the DMA/ADMA ratio (Fig. 1C) were higher in the patients compared to the healthy controls. In the rheumatoid arthritis (RA) and spondyloarthropathy (SPA) patients the DMA/ADMA ratio was by a factor of 2.5 statistically significantly higher than in healthy controls who were free of any chronic inflammatory rheumatic disease. In three patients with vasculitis and 10 patients with undifferentiated arthritis, the DMA/ADMA ratio was comparable to that in healthy controls. There was no worth mentioning correlation between the DMA/ADMA ratio and oxidative stress in terms of the urinary excretion rate of 15(S)-8-isoPGF2a or nitrative stress measured as urinary 3-nitrotyrosine excretion considering the whole cohort (Fig. 2) or in the individual groups (data not shown). In rheumatoid arthritis there seems to be even a negative correlation between ADMA excretion and nitrosative stress and a positive correlation between DMA excretion and nitrosative stress [8]. The present study and the study by Surdacki and colleagues [6] have limitations. The number of the patients investigated (n = 28 and n = 30, respectively) is relatively small. The correlations observed by Surdacki and colleagues [6] are weak. Also, we observed relatively great variations both for DMA excretion rates (RSD, 16% to 104%) and for the DMA/ADMA ratio (RSD, 17% to 102%). These limitations do not allow drawing far-reaching conclusions about the status of the ADMA/DDAH pathway in chronic rheumatic disease. Studies on larger cohorts of patients and healthy subjects are warranted. Another uncertainty is that DMA may originate from additional exogenous sources such as food, especially canned fish, and from endogenous still unknown sources. As an example, we have found that even 12 h after fish consumption by a healthy volunteer the DMA/ADMA ratio was about 32 compared to the value of 10 before ingestion [1]. Therefore, analogous to nitrite and nitrate, avoidance of DMA-rich food is mandatory in studies on ADMA metabolism and elimination via the DDAH pathway. Yet, the results of the study by Surdacki et al. and of the present work suggest that rheumatoid arthritis patients (and spondyloarthropathy patients in our study) are likely to have elevated ADMA synthesis. The urinary DMA/ADMA ratios we measured in patients and healthy controls suggest that DDAH activity is elevated rather than diminished in rheumatoid arthritis and spondyloarthropathy (Fig. 3). By contrast, in undifferentiated arthritis and vasculitis patients, the balance between ADMA synthesis and ADMA metabolism/elimination seems to be more or less equal to that in health. Differences seen in plasma ADMA concentrations in healthy subjects and humans with various diseases are rather very low
Letter to the Editor / Nitric Oxide 25 (2011) 436–438
A
437
A
B B
C Fig. 2. Relationship between the urinary DMA/ADMA molar ratio and (A) urinary 15(S)-8-iso-PGF2a, a biomarker of oxidative stress, or (B) urinary 3-nitrotyrosine, a biomarker of nitrative stress, in the whole patients cohort.
Fig. 1. Creatinine-corrected excretion of DMA (A) and ADMA (B) and urinary DMA/ ADMA molar ratio (C) in healthy subjects and in patients suffering from various chronic inflammatory rheumatic diseases. Data are shown as mean ± SEM. The means of the DMA/ADMA ratio in patients with rheumatoid arthritis and spondyloanthropathy were statistically significantly different (Mann Whitney test). Control (n = 10); RA, rheumatoid arthritis (n = 10); SPA, spondyloarthropathy (n = 5); UndiffArthritis, undifferentiated arthritis (n = 10); Vasculitis (n = 3). Parts of the data on rheumatoid arthritis have been reported elsewhere [8].
[6,9–13]. Thus, inter-individual variation is of the order of 15%. Also, the decreases seen in plasma ADMA concentrations upon pharmacological treatment are fairly small (about 10%), but clinically highly relevant [12,13]. The precise mechanisms by which ADMA may powerfully contribute to cardiovascular diseases, such as chronic heart disease and coronary artery disease, and to chronic inflammatory rheumatic diseases, such as rheumatoid arthritis and spondyloarthropathy, are incompletely understood. Given the relatively low inhibitory potency of ADMA towards endothelial NO synthase (IC50 12 lM; see Ref. [14]), it is possible that ADMA depresses endothelial progenitor cells [6] not only by
Fig. 3. Simplified schematic of the L-arginine/NO/ADMA/DDAH pathway in health, rheumatoid arthritis (RA) and spondyloarthritis (SPA). The width of the arrow below the small box containing ‘‘ADMA’’ indicates roughly the contribution of the urinary excretion of unchanged ADMA and of the elimination of ADMA by hepatic and renal DDAH metabolism to DMA and its renal excretion. PRMT, protein arginine methyl transferase; PL, plasma; U, urine.
inhibiting endothelial NO synthase activity (Fig. 3). Improvement of DDAH activity and/or DDAH expression could be a promising therapeutic means in the treatment of particular chronic
438
Letter to the Editor / Nitric Oxide 25 (2011) 436–438
inflammatory rheumatic diseases such as rheumatoid arthritis and spondyloarthropathy [8,15]. In summary, assessment of the DMA/ADMA ratio in the urine should be useful to follow the disease progression of rheumatoid arthritis and spondyloarthropathy, as well to monitor the effect of pharmacological treatment on these chronic inflammatory rheumatic diseases. The significance of the DMA/ADMA ratio as a reliable measure of ADMA homeostasis in health and disease remains to be demonstrated in larger studies. References [1] D. Tsikas, T. Thum, T. Becker, V.V. Pham, K. Chobanyan, A. Mitschke, B. Beckmann, F.M. Gutzki, J. Bauersachs, D.O. Stichtenoth, Accurate quantification of dimethylamine (DMA) in human urine by gas chromatography- mass spectrometry as pentafluorobenzamide derivative: evaluation of the relationship between DMA and its precursor asymmetric dimethylarginine (ADMA) in health and disease, J. Chromatogr. B 851 (2007) 229–239. [2] T. Becker, I. Mevius, D.K. de Vries, A.F.M. Schaaherder, A. Meyer zu Vilsendorf, J. Klempnauer, J.C. Frölich, D. Tsikas, The L-arginine/NO pathway in end-stage liver disease and during orthotopic liver and kidney transplantation: biological and analytical ramifications, Nitric Oxide 20 (2009) 61–67. [3] J.M. Leiper, P. Vallance, The synthesis and metabolism of asymmetric dimethylarginine (ADMA), Eur. J. Clin. Pharmacol. 62 (2006) 33–38. [4] D. Tsikas, K. Chobanyan, Pitfalls in the measurement of tissue DDAH activity: is DDAH sensitive to nitrosative and oxidative stress?, Kidney Int 74 (2008) 969. Authors reply: 969–970. [5] V.V. Pham, D.O. Stichtenoth, D. Tsikas, Nitrite correlates with 3-nitrotyrosine but not with the F2-isoprostane 15(S)-8-iso-PGF2a in urine of rheumatic patients, Nitric Oxide 21 (2009) 210–215. [6] A. Surdacki, J. Martens-Lobenhoffer, A. Wloch, E. Marewicz, T. Rakowski, E. Wieczorek-Surdacka, J.S. Dubiel, J. Pryjma, S.M. Bode-Böger, Elevated plasma asymmetric dimethyl-L-arginine levels are linked to endothelial progenitor cell depletion, carotid atherosclerosis in rheumatoid arthritis, Arthritis Rheum. 56 (2007) 809–819. [7] D. Tsikas, B. Schubert, F.M. Gutzki, J. Sandmann, J.C. Frölich, Quantitative determination of circulating, urinary asymmetric dimethylarginine (ADMA) in humans by GC-tandem MS as methyl ester tri(N-pentafluoropropionyl) derivative, J. Chromatogr. B 798 (2003) 87–99. [8] K. Chobanyan-Jürgens, V.V. Pham, D.O. Stichtenoth, D. Tsikas, Asymmetrical dimethylarginine, oxidative stress, and atherosclerosis, Hypertension, doi:10.1161/HYPERTENSIONAHA.111.180984.
[9] J.D. Horowitz, T. Heresztyn, An overview of plasma concentrations of asymmetric dimethylarginine (ADMA) in health and disease and in clinical studies, J. Chromatogr. B 851 (2007) 42–50. [10] D. Tsikas, Determination of asymmetric dimethylarginine (ADMA) in biological fluids: A paradigm for a successful analytical story, Curr. Opin. Clin. Nutr. Metab. Care 11 (2008) 592–600. [11] T. Thum, D. Tsikas, S. Stein, M. Schultheiss, M. Eigenthaler, S.D. Anker, P.A. Poole-Wilson, G. Ertl, J. Bauersachs, Suppression of endothelial progenitor cells in human coronary artery disease by the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine, J. Am. Coll. Cardiol. 46 (2005) 1693– 1701. [12] T.M. Lu, Y.A. Ding, H.B. Leu, W.H. Yin, W.H. Sheu, K.M. Chu, Effect of rosuvastatin on plasma levels of asymmetric dimethylarginine in patients with hypercholesterolemia, Am. J. Cardiol. 94 (2004) 1571–1161. [13] E. Leifke, M. Kinzel, D. Tsikas, L. Gooren, J.C. Frölich, G. Brabant, Effects of normalization of plasma testosterone levels in hypogonadal men on plasma levels, urinary excretion of asymmetric dimethylarginine ADMA, Exp. Clin. Endocrinol. Diabetes 40 (2008) 56–59. [14] A. Kielstein, D. Tsikas, G.P. Galloway, J.E. Mendelson, Asymmetric dimethylarginine (ADMA) – A modulator of nociception in opiate tolerance and addiction?, Nitric Oxide 17 (2007) 55–59. [15] C. Antoniades, M. Demosthenous, D. Tousoulis, A.S. Antonopoulos, C. Vlachopoulos, M. Toutouza, K. Marinou, C. Bakogiannis, K. Mavragani, G. Lazaros, N. Koumallos, C. Triantafyllou, D. Lymperiadis, M. Koutsilieris, C. Stafanadis, Role of asymmetrical dimethylarginine in inflammation-induced endothelial dysfunction in human atherosclerosis, Hypertension 58 (2011) 93–98.
Kristine Chobanyan-Jürgens 1 Vu Vi Pham 1 Dirk O. Stichtenoth Dimitrios Tsikas Institute of Clinical Pharmacology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany Fax: +49 511 532 2750. E-mail address: [email protected] (D. Tsikas) Available online 3 September 2011
1
These authors contributed equally to the work.