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Asymmetric dimethylarginine in children with homocystinuria or phenylketonuria

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Abstract

Plasma concentration of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide (NO) synthesis from l-arginine and a cardiovascular risk factor, was found to be elevated in plasma of homocysteinemic adults. Enhanced cardiovascular risk due to homocystinuria and impaired renal function has been found in patients with phenylketonuria (PKU) on protein-restricted diet. However, it is still unknown whether ADMA synthesis is also elevated in children with homocystinuria due to cystathionine beta-synthase deficiency (classical homocystinuria), and whether ADMA may play a role in phenylketonuria in childhood. In the present study, we investigated the status of the l-arginine/NO pathway in six young patients with homocystinuria, in 52 young phenylketonuria patients on natural protein-restricted diet, and in age- and gender-matched healthy children serving as controls. ADMA in plasma and urine was determined by GC–MS/MS. The NO metabolites nitrate and nitrite in plasma and urine, and urinary dimethylamine (DMA), the dimethylarginine dimethylaminohydrolase (DDAH) metabolite of ADMA, were measured by GC–MS. Unlike urine ADMA excretion, plasma ADMA concentration in patients with homocystinuria was significantly higher than in controls (660 ± 158 vs. 475 ± 77 nM, P = 0.035). DMA excretion rate was considerably higher in children with homocystinuria as compared to controls (62.2 ± 24.5 vs. 6.5 ± 2.9 μmol/mmol creatinine, P = 0.068), indicating enhanced DDAH activity in this disease. In contrast and unexpectedly, phenylketonuria patients had significantly lower ADMA plasma concentrations compared to controls (512 ± 136 vs. 585 ± 125 nM, P = 0.009). Phenylketonuria patients and controls had similar l-arginine/ADMA molar ratios in plasma. Urinary nitrite excretion was significantly higher in phenylketonuria as compared to healthy controls (1.7 ± 1.7 vs. 0.7 ± 1.2 μmol/mmol creatinine, P = 0.003). Our study shows that the l-arginine/NO pathway is differently altered in children with phenylketonuria and homocystinuria. Analogous to hyperhomocysteinemic adults, elevated ADMA plasma concentrations could be a cardiovascular risk factor in children with homocystinuria. In phenylketonuria, the l-arginine/NO pathway seems not be altered. Delineation of the role of ADMA in childhood phenylketonuria and homocystinuria demands further investigation.

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References

  • Achan V, Broadhead M, Malaki M, Whitley G, Leiper J, MacAlister R, Vallance P (2003) Asymmetric dimethylarginine causes hypertension and cardiac dysfunction in humans and is actively metabolized by dimethylarginine dimethylaminohydrolase. Arterioscler Thromb Vasc Biol 23:1455–1459

    Article  PubMed  CAS  Google Scholar 

  • Austin RC, Lentz SR, Werstuck GH (2004) Role of hyperhomocystinuria in endothelial dysfunction and atherothrombotic disease. Cell Death Differ 11:56–64

    Article  Google Scholar 

  • Böger RH, Zoccali C (2003) ADMA: a novel risk factor that explains excess cardiovascular event rate in patients with end-stage renal disease. Atheroscler Suppl 4:23–28

    Article  PubMed  Google Scholar 

  • Böger RH, Bode-Böger SM, Thiele W, Junker W, Alexander K, Frölich JC (1997) Biochemical evidence for impaired nitric oxide synthesis in patients with peripheral arterial occlusive disease. Circulation 95:2068–2074

    PubMed  Google Scholar 

  • Cines DB, Pollak ES, Buck CA, Loscalzo J, Zimmerman GA, McEver RP, Pober JS, Wick TM, Konkle BA, Schwarzt BS, Barnathan ES, McCrae KR, Hug BA, Schmidt AM, Stern DM (1998) Endothelial cells in physiology and in the pathophysiology of vascular disorders. Blood 91:3527–3561

    PubMed  CAS  Google Scholar 

  • Cooke JP, Dzau VJ (1997) Nitric oxide synthase: role in the genesis of vascular disease. Annu Rev Med 48:489–509

    Article  PubMed  CAS  Google Scholar 

  • Dayal S, Lentz SR (2005) ADMA and hyperhomocystinuria. Vasc Med 10(Suppl 1):27–33

    Article  Google Scholar 

  • Dayal S, Rodionov RN, Arning E, Bottiglieri T, Kimoto M, Murry DJ, Cooke JP, Faraci FM, Lentz SR (2008) Tissue-specific downregulation of dimethylarginine dimethylaminohydrolase in hyperhomocystinuria. Am J Physiol Heart Circ Physiol 295:H816–H825

    Article  PubMed  CAS  Google Scholar 

  • Hennermann JB, Roloff S, Gellermann J, Vollmer I, Mönch E (2005) Renal function in adolescent and adult patients with phenylketonuria. J Inherit Metab Dis 28(Supp 1):18

    Google Scholar 

  • Kielstein JT, Tsikas D, Fliser D (2006) Effects of asymmetric dimethylarginine (ADMA) infusion in humans. Eur J Clin Pharmacol 62:39–44

    Article  CAS  Google Scholar 

  • Kielstein A, Tsikas D, Galloway GP, Mendelson JE (2007) Asymmetric dimethylarginine (ADMA): A modulator of nociception in opiate tolerance and addiction? Nitric Oxide 17:55–59

    Article  PubMed  CAS  Google Scholar 

  • Korandji C, Zeller M, Guilland JC, Vergely C, Sicard P, Duvillard L, Gambert P, Moreau D, Cottin Y, Rochette L (2007) Asymmetric dimethylarginine (ADMA) and hyperhomocystinuria in patients with acute myocardial infarction. Clin Biochem 60:66–72

    Article  Google Scholar 

  • Lücke T, Tsikas D, Kanzelmeyer N, Vaske B, Das AM (2006) Elevated plasma concentrations of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) in citrullinemia. Metabolism 55:1599–1603

    Article  PubMed  Google Scholar 

  • Lücke T, Kanzelmeyer N, Kemper MJ, Tsikas D, Das AM (2007) Developmental changes in the l-arginine/nitric oxide pathway from infancy to adulthood: plasma asymmetric dimethylarginine levels decrease with age. Clin Chem Lab Med 45:1525–1530

    Article  PubMed  Google Scholar 

  • Lücke T, Kanzelmeyer N, Chobanyan K, Tsikas D, Franke D, Kemper MJ, Ehrich JH, Das A (2008) Elevated asymmetric dimethylarginine (ADMA) and inverse correlation between circulating ADMA and glomerular filtration rate in children with sporadic focal segmental glomerulosclerosis (FSGS). Nephrol Dial Transpl 23:734–740

    Article  Google Scholar 

  • Mansoor MA, Kristensen O, Hervig T, Stakkestad JA, Berge T, Drablos PA, Rolfsen S, Wentzel-Larsen T (2005) Relationship between serum folate and plasma nitrate concentrations: possible clinical implications. Clin Chem 51:1266–1268

    Article  PubMed  CAS  Google Scholar 

  • Moens AL, Kass DA (2006) Tetrahydrobiopterin and cardiovascular disease. Arterioscler Thromb Vasc Biol 26:2439–2444

    Article  PubMed  CAS  Google Scholar 

  • Mudd SH, Skovby F, Levy HL, Pettigrew KD, Wilcken B, Pyeritz RE, Andria G, Boers GHJ, Bromberg IL, Cerone R, Fowler B, Gröbe H, Schmidt H, Schweitzer L (1985) The natural history of homocystinuria due to cystathionine beta-synthase deficiency. Am J Hum Genet 37:1–31

    PubMed  CAS  Google Scholar 

  • Ozkor MA, Quyyumi AA (2008) Tetrahydrobiopterin. Curr Hypertens Rep 10:58–64

    Article  PubMed  CAS  Google Scholar 

  • Pham VV, Stichtenoth DO, Tsikas D (2009) Nitrite correlates with 3-nitrotyrosine but not with the F2-isoprostane 15(S)-8-iso-PGF2α in urine of rheumatic patients. Nitric Oxide 21:210–215

    Article  PubMed  CAS  Google Scholar 

  • Schmidt TS, Alp NJ (2007) Mechanisms for the role of tetrahydrobiopterin in endothelial function and vascular disease. Clin Sci 113:47–63

    PubMed  CAS  Google Scholar 

  • Schroecksnadel K, Weiss G, Stanger O, Teerlink T, Fuchs D (2007) Increased asymmetric dimethylarginine concentrations in stimulated peripheral blood mononuclear cells. Scand J Immunol 65:525–529

    Article  PubMed  CAS  Google Scholar 

  • Schulpis KH, Karikas GA, Papakonstantinou E (2002) Homocysteine and other vascular risk factors in patients with phenylketonuria on a diet. Acta Paediatr 91:905–909

    Article  PubMed  CAS  Google Scholar 

  • Sitta A, Barschak AG, Deon M, Terroso T, Pires R, Giugliani R, Dutra-Filho CS, Wajner M, Vargas CR (2006) Investigation of oxidative stress parameters in treated phenylketonuric patients. Metab Brain Dis 21:287–296

    Article  PubMed  CAS  Google Scholar 

  • Spoelstra-de Man AM, Teerlink T, Brouwer CB, Rauwerda JA, Stehouwer CD, Smuöders YM (2006) No effect of B vitamins an ADMA levels in patients at increased cardiovascular risk. Clin Endocrinol 65:495–501

    Article  Google Scholar 

  • Tsikas D (2000) Simultaneous derivatization and quantification of the nitric oxide metabolites nitrite and nitrate in biological fluids by gas chromatography–mass spectrometry. Anal Chem 72:4064–4072

    Article  PubMed  CAS  Google Scholar 

  • Tsikas D (2003) Incorrect and inconsistent use of homocysteine’s nomenclature: a potential source of misunderstandings. Eur J Clin Invest 33:1095–1096

    Article  PubMed  CAS  Google Scholar 

  • Tsikas D (2008) A critical review and discussion of analytical methods in the l-arginine/nitric oxide area of basic and clinical research. Anal Biochem 379:139–163

    Article  PubMed  CAS  Google Scholar 

  • Tsikas D, Böger RH, Sandmann J, Bode-Böger SM, Frölich JC (2000) Endogenous nitric oxide synthase inhibitors are responsible for the l-arginine paradox. FEBS Lett 478:1–3

    Article  PubMed  CAS  Google Scholar 

  • Tsikas D, Schubert B, Gutzki FM, Sandmann J, Frölich JC (2003) Quantitative determination of circulating and urinary asymmetric dimethylarginine (ADMA) in humans by gas chromatography–tandem mass spectrometry as methyl ester tri(N-pentafluoropropionyl) derivative. J Chromatogr B 798:87–99

    Article  CAS  Google Scholar 

  • Tsikas D, Wolf A, Frölich JC (2004) Simplified HPLC method for urinary and circulating creatinine. Clin Chem 50:201–203

    Article  PubMed  CAS  Google Scholar 

  • Tsikas D, Gutzki FM, Stichtenoth DO (2006) Circulating and excretory nitrite and nitrate as indicators of nitric oxide synthesis in humans: methods of analysis. Eur J Clin Pharmacol 62:51–59

    Article  CAS  Google Scholar 

  • Tsikas D, Thum T, Becker T, Pham VV, Chobanyan K, Mitschke A, Beckmann B, Gutzki FM, Bauersachs J, Stichtenoth DO (2007) 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. J Chromatogr B 851:229–239

    Article  CAS  Google Scholar 

  • Tsikas D, Schwarz A, Stichtenoth DO (2010) Simultaneous measurement of [15N]nitrate and [15N]nitrite enrichment and concentration in urine by gas chromatography mass spectrometry as pentafluorobenzyl derivatives. Anal Chem 82:2585–2587

    Article  PubMed  CAS  Google Scholar 

  • Verduyn I, Bosdet T, Selvage C, Sirrs S, O’Riley M (2005) Reduced HDL levels in adult patients with phenylketonuria (PKU). J Inherit Metab Dis 28(Suppl 1):56–64

    Google Scholar 

  • Welch GN, Loscalzo J (1998) Homocysteine and atherothrombosis. N Engl J Med 338:1042–1050

    Article  PubMed  CAS  Google Scholar 

  • Williams RA, Mamotte CDS, Burnett JR (2008) Phenylketonuria: an inborn error of phenylalanine metabolism. Clin Biochem Rev 29:31–41

    PubMed  Google Scholar 

  • Wolf C, Lorenzen JM, Stein S, Tsikas D, Störk S, Weidemann F, Ertl G, Anker SD, Bauersachs J, Thum T (2010) Urinary asymmetric dimethylarginine (ADMA) is a predictor of mortality risk in patients with coronary artery disease. Intern J Cardiol. doi:10.1016/j.ijcard.2010.11.003

  • Wu G (2009) Amino acids: metabolism, functions, and nutrition. Amino Acids 37:1–17

    Article  PubMed  Google Scholar 

  • Wu G, Bazer FW, Davis TA, Kim SW, Li P, Rhoads JM, Satterfield MC, Smith SB, Spencer TE, Yin Y (2009) Arginine metabolism and nutrition in growth, health and disease. Amino Acids 37:153–168

    Google Scholar 

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Acknowledgments

The authors would like to thank A. Mitschke for the excellent laboratory assistance and F.-M. Gutzki for performing GC–MS and GC–MS/MS analyses.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Pediatrics, Medical School Hannover, Carl-Neuberg Str. 1, 30625, Hannover, Germany

    Nele Kanzelmeyer, Kristine Chobanyan-Jürgens, Sabine Illsinger & Anibh M. Das

  2. Institute of Clinical Pharmacology, Medical School Hannover, Carl-Neuberg Str. 1, 30625, Hannover, Germany

    Dimitrios Tsikas, Kristine Chobanyan-Jürgens & Bibiana Beckmann

  3. Institute of Biometry, Medical School Hannover, Hannover, Germany

    Bernhard Vaske

  4. Department of Neuropediatrics, University Children’s Hospital, Ruhr University Bochum, Bochum, Germany

    Thomas Lücke

Authors
  1. Nele Kanzelmeyer
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  2. Dimitrios Tsikas
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  3. Kristine Chobanyan-Jürgens
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  4. Bibiana Beckmann
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  5. Bernhard Vaske
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  6. Sabine Illsinger
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  7. Anibh M. Das
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  8. Thomas Lücke
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Corresponding authors

Correspondence to Nele Kanzelmeyer or Dimitrios Tsikas.

Additional information

N. Kanzelmeyer and D. Tsikas contributed equally to this work and are both corresponding authors.

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Kanzelmeyer, N., Tsikas, D., Chobanyan-Jürgens, K. et al. Asymmetric dimethylarginine in children with homocystinuria or phenylketonuria. Amino Acids 42, 1765–1772 (2012). https://doi.org/10.1007/s00726-011-0892-4

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  • DOI: https://doi.org/10.1007/s00726-011-0892-4

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