Skip to main content

Effect of chronic elevated asymmetric dimethylarginine (ADMA) levels on granulopoiesis

Annals of Hematology volume 92, pages 505–508 (2013)Cite this article

Abstract

The endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) is elevated in both animal models of chronic inflammatory disorders as well as in patients with chronic inflammatory disease. In vivo data suggest that ADMA can increase the number of circulating monocytes and possibly affect their adhesion potential in vitro. The aim of our study was to evaluate possible effects of chronically elevated levels of ADMA on white blood cell count (WBC), leukocyte subsets, and WBC distribution pattern using a model of chronic exogenous ADMA infusion. Male Sprague–Dawley rats (n = 20, 10 weeks of age) were randomized to receive either (1) isotonic saline or (2) ADMA applied by osmotic mini pumps. After 28 days of infusion, all animals were sacrificed for blood and tissue sampling. WBC count, flow cytometry for subtype assessment, and histological assessment were performed. Over a time period of 28 days, continuous ADMA infusion significantly increased mean plasma levels (1.26 ± 0.07 μmol/l) as compared to saline infusion (0.57 ± 0.02 μmol/l). Clinical side effects were not observed. Despite a physiologically relevant rise in ADMA plasma levels, measured by decrease of the l-arginine/AMDA ratio—a surrogate parameter of NO production capacity—there was no effect on WBC count or pattern of leukocyte subsets. Numbers and morphology of peripheral blood cells as well as number of NK-cells leveling liver and spleen were not affected by chronic ADMA infusion. Chronically elevated ADMA levels in otherwise healthy rats did not affect WBC counts or leukocyte subsets. Furthermore, anemia frequently found in patients with progressive renal failure and elevated ADMA levels, was not observed. In a chronic inflammatory state, elevated ADMA levels themselves are rather the result than the cause of the underlying inflammatory process.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1

References

  1. Zoccali C, Benedetto FA, Maas R, Mallamaci F, Tripepi G, Malatino LS, Boger R (2002) Asymmetric dimethylarginine, C-reactive protein, and carotid intima-media thickness in end-stage renal disease. J Am Soc Nephrol 13:490–496

    PubMed  Article  CAS  Google Scholar 

  2. Miyazaki H, Matsuoka H, Cooke JP, Usui M, Ueda S, Okuda S, Imaizumi T (1999) Endogenous nitric oxide synthase inhibitor: a novel marker of atherosclerosis. Circulation 99:1141–1146

    PubMed  Article  CAS  Google Scholar 

  3. 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

    PubMed  Article  CAS  Google Scholar 

  4. Chen M, Li Y, Yang T, Wang Y, Bai Y, Xie X (2008) ADMA induces monocyte adhesion via activation of chemokine receptors in cultured THP-1 cells. Cytokine 43:149–159

    PubMed  Article  CAS  Google Scholar 

  5. Greenberg SS, Ouyang J, Zhao X, Giles TD (1998) Human and rat neutrophils constitutively express neural nitric oxide synthase mRNA. Nitric Oxide 2:203–212

    PubMed  Article  CAS  Google Scholar 

  6. Roman A, Legallo R, McGahren ED (2004) Blocking of endogenous nitric oxide increases white blood cell accumulation in rat lung. J Pediatr Surg 39:48–52

    PubMed  Article  Google Scholar 

  7. Michurina T, Krasnov P, Balazs A, Nakaya N, Vasilieva T, Kuzin B, Khrushchov N, Mulligan RC, Enikolopov G (2004) Nitric oxide is a regulator of hematopoietic stem cell activity. Mol Ther 10:241–248

    PubMed  Article  CAS  Google Scholar 

  8. Kurz K, Teerlink T, Sarcletti M, Weiss G, Zangerle R, Fuchs D (2009) Plasma concentrations of the cardiovascular risk factor asymmetric dimethylarginine (ADMA) are increased in patients with HIV-1 infection and correlate with immune activation markers. Pharmacol Res 60:508–514

    PubMed  Article  CAS  Google Scholar 

  9. Molnar M, Suto T, Toth T, Hertelendy F (1994) Prolonged blockade of nitric oxide synthesis in gravid rats produces sustained hypertension, proteinuria, thrombocytopenia, and intrauterine growth retardation. Am J Obstet Gynecol 170:1458–1466

    PubMed  CAS  Google Scholar 

  10. Kielstein JT, Boger RH, Bode-Boger SM, Schaffer J, Barbey M, Koch KM, Frolich JC (1999) Asymmetric dimethylarginine plasma concentrations differ in patients with end-stage renal disease: relationship to treatment method and atherosclerotic disease. J Am Soc Nephrol 10:594–600

    PubMed  CAS  Google Scholar 

  11. Chen LY, Mehta JL (1996) Variable effects of l-arginine analogs on l-arginine-nitric oxide pathway in human neutrophils and platelets may relate to different nitric oxide synthase isoforms. J Pharmacol Exp Ther 276:253–257

    PubMed  CAS  Google Scholar 

  12. Bedoui S, Kuhlmann S, Nave H, Drube J, Pabst R, von Horsten S (2001) Differential effects of neuropeptide Y (NPY) on leukocyte subsets in the blood: mobilization of B-1-like B-lymphocytes and activated monocytes. J Neuroimmunol 117:125–132

    PubMed  Article  CAS  Google Scholar 

Download references

Acknowledgment

This study is supported by a grant of the Werner Jackstädt Stiftung to JTK and HK.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Affiliations

  1. Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany

    Gernot Beutel

  2. Department of Anatomy and Cell Biology, Faculty of Medicine, Martin Luther University Halle-Wittenberg, Halle, Germany

    Ronny Perthel & Heike Kielstein

  3. Institute of Clinical Pharmacology, Hospital of the Otto-von-Guericke-University of Magdeburg, Magdeburg, Germany

    Stefanie M. Bode-Böger & Jens Martens-Lobenhoffer

  4. Department of Nephrology and Hypertension, Medical School Hannover, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany

    Mayuren Suntharalingam & Jan T. Kielstein

Authors
  1. Gernot Beutel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ronny Perthel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mayuren Suntharalingam
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Stefanie M. Bode-Böger
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jens Martens-Lobenhoffer
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jan T. Kielstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Heike Kielstein
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jan T. Kielstein.

Additional information

GB and RP contributed equally to the manuscript and are both considered first authors.

JTK and HK contributed equally to the manuscript and are both considered senior authors.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Beutel, G., Perthel, R., Suntharalingam, M. et al. Effect of chronic elevated asymmetric dimethylarginine (ADMA) levels on granulopoiesis. Ann Hematol 92, 505–508 (2013). https://doi.org/10.1007/s00277-012-1636-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00277-012-1636-6

Keywords

  • Asymmetric dimethylarginine
  • ADMA
  • Peripheral blood count
  • Granulopoiesis
  • Lymphocytes subsets