Amino Acids

, Volume 47, Issue 9, pp 1847–1852 | Cite as

Plasma and tissue homoarginine concentrations in healthy and obese humans

  • Marcus MayEmail author
  • Arslan Arinc Kayacelebi
  • Sandor Batkai
  • Jens Jordan
  • Dimitrios Tsikas
  • Stefan Engeli
Original Article
Part of the following topical collections:
  1. Homoarginine, Arginine and Relatives


Increased cardiovascular risk associated with obesity cannot be fully explained by traditional risk markers. We therefore assessed plasma and interstitial concentrations of the novel cardiovascular risk biomarker homoarginine (hArg) in 18 individuals without signs of cardiovascular disease, including 4 morbidly obese subjects before and after bariatric surgery and subsequent weight reduction of 36 ± 7 kg. hArg concentrations were greater in skeletal muscle compared with adipose tissue. Plasma and tissue hArg concentrations did not correlate with BMI. Adipose tissue interstitial hArg concentrations were not affected by obesity, an oral glucose load, or dramatic weight loss. In conclusion, obesity seems not to have a major effect on hArg homeostasis, and hArg may not explain the added cardiovascular risk associated with obesity. Yet, given the small sample size of the study, the significance of hArg in obesity should be investigated in a larger population.


Adipose tissue Skeletal muscle Biomarker Insulin resistance L-Homoarginine Microdialysis Obesity 



N G,N G-Dimethyl-l-arginine


Body mass index




Homeostasis model assessment-insulin resistance (index)




Nitric oxide


Nitric oxide synthase


Selected-reaction monitoring



The laboratory assistance of Bibiana Beckmann, Anja Mitschke and Maria-Theresia Suchy is gratefully acknowledged. We thank Frank-Mathias Gutzki for performing GC–MS/MS analyses of homoarginine and ADMA in plasma and microdialysate samples.

Conflict of interest

The authors declare that they have no conflict of interest.


  1. Atzler D, Gore MO, Ayers CR, Choe CU, Böger RH, de Lemos JA, McGuire DK, Schwedhelm E (2014a) Homoarginine and cardiovascular outcome in the population-based Dallas Heart Study. Arterioscler Thromb Vasc Biol 34:2501–2507CrossRefPubMedGoogle Scholar
  2. Atzler D, Schwedhelm E, Nauck M, Ittermann T, Böger RH, Friedrich N (2014b) Serum reference intervals of homoarginine, ADMA, and SDMA in the Study of Health in Pomerania. Clin Chem Lab Med 52:1835–1842CrossRefPubMedGoogle Scholar
  3. Bretscher LE, Li H, Poulos TL, Griffith OW (2003) Structural characterization and kinetics of nitric-oxide synthase inhibition by novel N5-(iminoalkyl)- and N5- (iminoalkenyl)-ornithines. J Biol Chem 278:46789–46797CrossRefPubMedGoogle Scholar
  4. Choe CU, Atzler D, Wild PS, Carter AM, Böger RH, Ojeda F, Simova O, Stockebrand M, Lackner K, Nabuurs C, Marescau B, Streichert T, Muller C, Luneburg N, De Deyn PP, Benndorf RA, Baldus S, Gerloff C, Blankenberg S, Heerschap A, Grant PJ, Magnus T, Zeller T, Isbrandt D, Schwedhelm E (2013a) Homoarginine levels are regulated by l-arginine:glycine amidinotransferase and affect stroke outcome: results from human and murine studies. Circulation 128:1451–1461CrossRefPubMedGoogle Scholar
  5. Choe CU, Nabuurs C, Stockebrand MC, Neu A, Nunes P, Morellini F, Sauter K, Schillemeit S, Hermans-Borgmeyer I, Marescau B, Heerschap A, Isbrandt D (2013b) l-arginine:glycine amidinotransferase deficiency protects from metabolic syndrome. Hum Mol Genet 22:110–123CrossRefPubMedGoogle Scholar
  6. Collaboration Prospective Studies, Whitlock G, Lewington S, Sherliker P, Clarke R, Emberson J, Halsey J, Qizilbash N, Collins R, Peto R (2009) Body-mass index and cause-specific mortality in 900000 adults: collaborative analyses of 57 prospective studies. Lancet 373:1083–1096CrossRefGoogle Scholar
  7. Davids M, Teerlink T (2013) Plasma concentrations of arginine and asymmetric dimethylarginine do not reflect their intracellular concentrations in peripheral blood mononuclear cells. Metab Clin Exp 62:1455–1461CrossRefPubMedGoogle Scholar
  8. Davids M, Ndika JD, Salomons GS, Blom HJ, Teerlink T (2012) Promiscuous activity of arginine:glycine amidinotransferase is responsible for the synthesis of the novel cardiovascular risk factor homoarginine. FEBS Lett 586:3653–3657CrossRefPubMedGoogle Scholar
  9. Drechsler C, Kollerits B, Meinitzer A, März W, Ritz E, König P, Neyer U, Pilz S, Wanner C, Kronenberg F (2013) Homoarginine and progression of chronic kidney disease: results from the mild to moderate kidney disease study. PLoS One 8:e63560PubMedCentralCrossRefPubMedGoogle Scholar
  10. Engeli S, Tsikas D, Lehmann AC, Böhnke J, Haas V, Strauß A, Janke J, Gorzelniak K, Luft FC, Jordan J (2012) Influence of dietary fat ingestion on asymmetrical dimethylarginine in lean and obese human subjects. Nutr Metab Cardiovasc Dis 22:720–726CrossRefPubMedGoogle Scholar
  11. Fellander G, Linde B, Bolinder J (1996) Evaluation of the microdialysis ethanol technique for monitoring of subcutaneous adipose tissue blood flow in humans. Int J Obes Relat Metab Disord 20:220–226PubMedGoogle Scholar
  12. Henningsson R, Lundquist I (1998) Arginine-induced insulin release is decreased and glucagon increased in parallel with islet NO production. Am J Physiol 275:E500–E506PubMedGoogle Scholar
  13. Kayacelebi AA, Beckmann B, Gutzki FM, Jordan J, Tsikas D (2014a) GC-MS and GC-MS/MS measurement of the cardiovascular risk factor homoarginine in biological samples. Amino Acids 46:2205–2217CrossRefPubMedGoogle Scholar
  14. Kayacelebi AA, Nguyen TH, Neil C, Horowitz JD, Jordan J, Tsikas D (2014b) Homoarginine and 3-nitrotyrosine in patients with takotsubo cardiomyopathy. Int J Cardiol 173:546–547CrossRefPubMedGoogle Scholar
  15. Khalil AA, Tsikas D, Akolekar R, Jordan J, Nicolaides KH (2013) Asymmetric dimethylarginine, arginine and homoarginine at 11-13 weeks’ gestation and preeclampsia: a case-control study. J Hum Hypertens 27:38–43CrossRefPubMedGoogle Scholar
  16. Kleber ME, Seppälä I, Pilz S, Hoffmann MM, Tomaschitz A, Oksala N, Raitoharju E, Lyytikäinen LP, Mäkelä KM, Laaksonen R, Kähönen M, Raitakari OT, Huang J, Kienreich K, Fahrleitner-Pammer A, Drechsler C, Krane V, Boehm BO, Koenig W, Wanner C, Lehtimäki T, März W, Meinitzer A (2003) Circ Cardiovasc Genet 6:505–513CrossRefGoogle Scholar
  17. März W, Meinitzer A, Drechsler C, Pilz S, Krane V, Kleber ME, Fischer J, Winkelmann BR, Böhm BO, Ritz E, Wanner C (2010) Homoarginine, cardiovascular risk, and mortality. Circulation 122:967–975CrossRefPubMedGoogle Scholar
  18. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28:412–419CrossRefPubMedGoogle Scholar
  19. May M, Batkai S, Zoerner AA, Tsikas D, Jordan J, Engeli S (2013) Enhanced human tissue microdialysis using hydroxypropyl-ss-cyclodextrin as molecular carrier. PLoS One 8:e60628PubMedCentralCrossRefPubMedGoogle Scholar
  20. May M, Ahrens J, Menne J, Haller H, Beige J, Eckert S, Jordan J, Engeli S (2014) Limited acute influences of electrical baroreceptor activation on insulin sensitivity and glucose delivery: a randomized, double-blind, cross-over clinical study. Diabetes 63:2833–2837CrossRefPubMedGoogle Scholar
  21. Moali C, Boucher JL, Sari MA, Stuehr DJ, Mansuy D (1998) Substrate specificity of NO synthases: detailed comparison of l-arginine, homo-L-arginine, their N omega-hydroxy derivatives, and N omega-hydroxynor-L-arginine. Biochemistry 37:10453–10460CrossRefPubMedGoogle Scholar
  22. Moali C, Brollo M, Custot J, Sari MA, Boucher JL, Stuehr DJ, Mansuy D (2000) Recognition of alpha-amino acids bearing various C = NOH functions by nitric oxide synthase and arginase involves very different structural determinants. Biochemistry 39:8208–8218CrossRefPubMedGoogle Scholar
  23. Patle R, Dubb S, Alaghband-Zadeh J, Sherwood RA, Tam F, Frankel A, Moniz C, Bueter M, Vincent RP, le Roux CW (2012) Improved blood pressure, nitric oxide and asymmetric dimethylarginine are independent after bariatric surgery. Ann Clin Biochem 49:589–594CrossRefPubMedGoogle Scholar
  24. Pilz S, Tomaschitz A, Meinitzer A, Drechsler C, Ritz E, Krane V, Wanner C, Bohm BO, März W (2011) Low serum homoarginine is a novel risk factor for fatal strokes in patients undergoing coronary angiography. Stroke 42:1132–1134CrossRefPubMedGoogle Scholar
  25. Pilz S, Teerlink T, Scheffer PG, Meinitzer A, Rutters F, Tomaschitz A, Drechsler C, Kienreich K, Nijpels G, Stehouwer CD, März W, Dekker JM (2014) Homoarginine and mortality in an older population: the Hoorn study. Eur J Clin Invest 44:200–208CrossRefPubMedGoogle Scholar
  26. Plock N, Kloft C (2005) Microdialysis–theoretical background and recent implementation in applied life-sciences. Eur J Pharm Sci 25:1–24CrossRefPubMedGoogle Scholar
  27. Ryan WL, Wells IC (1964) Homocitrulline and homoarginine synthesis from lysine. Science 144:1122–1127CrossRefPubMedGoogle Scholar
  28. Sobczak A, Prokopowicz A, Radek M, Szula M, Zaciera M, Kurek J, Goniewicz ML (2014a) Tobacco smoking decreases plasma concentration of the emerging cardiovascular risk marker, L-homoarginine. Circ J 78:1254–1258CrossRefPubMedGoogle Scholar
  29. Sobczak A, Prokopowicz A, Radek M, Szula M, Zaciera M, Kurek J, Goniewicz ML (2014b) Do homoarginine and asymmetric dimethylarginine act antagonistically in the cardiovascular system? Circ J 78:2096CrossRefPubMedGoogle Scholar
  30. Tomaschitz A, Meinitzer A, Pilz S, Rus-Machan J, Genser B, Drechsler C, Grammer T, Krane V, Ritz E, Kleber ME, Pieske B, Kraigher-Krainer E, Fahrleitner-Pammer A, Wanner C, Boehm BO, März W (2014) Homoarginine, kidney function and cardiovascular mortality risk. Nephrol Dial Transplant 29:663–671CrossRefPubMedGoogle Scholar
  31. Tsikas D, Kayacelebi AA (2014) Do homoarginine and asymmetric dimethylarginine act antagonistically in the cardiovascular system? Circ J 78:2094–2095CrossRefPubMedGoogle Scholar
  32. 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 798:87–99CrossRefGoogle Scholar
  33. Valtonen P, Laitinen T, Lyyra-Laitinen T, Raitakari OT, Juonala M, Viikari JS, Heiskanen N, Vanninen E, Punnonen K, Heinonen S (2008) Serum L-homoarginine concentration is elevated during normal pregnancy and is related to flow-mediated vasodilatation. Circ J 72:1879–1884CrossRefPubMedGoogle Scholar
  34. WHO (2000) Obesity: preventing and managing the global epidemic, Report of a WHO consultation. World Health Organ Tech Rep Ser 894(i–xii):1–253Google Scholar
  35. Wu G, Bazer FW, Davis TA, Kim SW, Li P, Marc Rhoads J, Carey Satterfield M, Smith SB, Spencer TE, Yin Y (2009) Arginine metabolism and nutrition in growth, health and disease. Amino Acids 37:153–168PubMedCentralCrossRefPubMedGoogle Scholar
  36. Wyss M, Kaddurah-Daouk R (2000) Creatine and creatinine metabolism. Physiol Rev 80:1107–1213PubMedGoogle Scholar

Copyright information

© Springer-Verlag Wien 2015

Authors and Affiliations

  • Marcus May
    • 1
    Email author
  • Arslan Arinc Kayacelebi
    • 2
  • Sandor Batkai
    • 3
  • Jens Jordan
    • 1
  • Dimitrios Tsikas
    • 2
  • Stefan Engeli
    • 1
  1. 1.Institute of Clinical PharmacologyHannover Medical SchoolHannoverGermany
  2. 2.Centre of Pharmacology and ToxicologyHannover Medical SchoolHannoverGermany
  3. 3.Institute of Molecular and Translational Therapeutic StrategiesHannover Medical SchoolHannoverGermany

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