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Arzneimittelforschung 2011; 61(6): 340-346
DOI: 10.1055/s-0031-1296208
Cardiac Drugs · Cardiac Stimulants · Coronary Drugs
Editio Cantor Verlag Aulendorf (Germany)

Simultaneous determination of L-arginine, asymmetric dimethylarginine, and symmetric dimethylarginine in the plasma of rodents with LC-MS/MS

Jung-woo Chae
1   College of Pharmacy, Chungnam National University, Daejeon, Korea
,
In-hwan Baek
1   College of Pharmacy, Chungnam National University, Daejeon, Korea
,
Wonku Kang
2   College of Pharmacy, Yeongnam University of Daegu, Kyungbuk, Korea
,
Kwang-il Kwon
1   College of Pharmacy, Chungnam National University, Daejeon, Korea
› Author Affiliations
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Publication History

Publication Date:
27 November 2011 (online)

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Abstract

Nitric oxide (NO) is synthesized from L-arginine (Arg) by NO synthase (NOS), and asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) are endogenous inhibitors of NO formation. Normal distribution values of Arg, ADMA, and SDMA are required to evaluate the effects of cardiovascular drugs on blood vessels, but insufficient normal reference values from rat and mouse plasma exist for new drug development and screening. To determine the means and variations in the basal endogenous materials concentration, Arg, ADMA, and SDMA in blank rat (n = 24) and mouse (n = 37) plasma samples were

quantified using LC-MS/MS equipped with an electrospray ionization interface to generate positive mode ions. Accuracy and precision were within 90.42-1 10.91 %, and 0.88-13.84%, respectively, for analyses of Arg, ADMA, and SDMA. The average plasma concentrations of Arg, ADMA, and SDMA were 175.38 ± 13.87 μM, 0.79 ± 0.20 μM, and 0.84 ± 0.20 μM, respectively, in rats and 70.81 ± 19.38 μM, 0.66 ± 0.21 μM, and 0.42 ± 0.10 μM, respectively, in mice. These results will provide a basis on which to evaluate cardiovascular drug effects on ARG, ADMA, and SDMA levels in new drug development.

Key words

L-Arginine - Asymmetric dimethylarginine - Cardiovascular drug - Symmetric dimethylarginine
 

  • References

  • 1 Gryglewski RJ, Botting RM, Vane JR. Mediators produced by the endothelial cell. Hypertension 1988; Dec; 12 (6) 530-48
    CrossrefPubMedGoogle Scholar
  • 2 Moncada S, Higgs A. The L-arginine-nitric oxide pathway. N Engl J Med. 1993; Dec 30 329 (27) 2002-12
    CrossrefPubMedGoogle Scholar
  • 3 Palmer RM, Rees DD, Ashton DS, Moncada S. L-arginine is the physiological precursor for the formation of nitric oxide in endothelium-dependent relaxation. Biochem Bio-phys Res Commun. 1988; Jun 30 153 (3) 1251-6
    CrossrefPubMedGoogle Scholar
  • 4 Vallance P, Leone A, Calver A, Collier J, Moncada S. Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet 1992; Mar 7 339 (8793) 572-5
    CrossrefPubMedGoogle Scholar
  • 5 Aisaka K, Gross SS, Griffith OW, Levi R. NG-methylarginine, an inhibitor of endothelium-derived nitric oxide synthesis, is a potent pressor agent in the guinea pig: does nitric oxide regulate blood pressure in vivo?. Biochem Biophys Res Commun. 1989; Apr 28 160 (2) 881-6
    CrossrefPubMedGoogle Scholar
  • 6 Vallance P, Leiper J. Blocking NO synthesis: how, where and why?. Nat Rev Drug Discov. 2002; Dec 1 (12) 939-50
    CrossrefPubMedGoogle Scholar
  • 7 Gehrig PM, Hunziker PE, Zahariev S, Pongor S. Fragmentation pathways of N(G)-methylated and unmodified argi-nine residues in peptides studied by ESI-MS/MS and MAL-DI-MS. J Am Soc Mass Spectrom. 2004; Feb 15 (2) 142-9
    CrossrefPubMedGoogle Scholar
  • 8 Fleck C, Janz A, Schweitzer F, Karge E, Schwertfeger M, Stein G. Serum concentrations of asymmetric (ADMA) and symmetric (SDMA) dimethylarginine in renal failure patients. Kidney Int Suppl. 2001; Feb 78: S14-8
    PubMedGoogle Scholar
  • 9 Miyazaki H, Matsuoka H, Cooke JP, Usui M, Ueda S, Okuda S et al. Endogenous nitric oxide synthase inhibitor: a novel marker of atherosclerosis. Circulation 1999; Mar 9 99 (9) 1141-6
    CrossrefPubMedGoogle Scholar
  • 10 Cooke JP. Does ADMA cause endothelial dysfunction?. Ar-terioscler Thromb Vasc Biol. 2000; Sep 20 (9) 2032-7
    CrossrefPubMedGoogle Scholar
  • 11 Böger RH, Bode-Böger SM, Thiele W, Junker W, Alexander K, Frölich JC. Biochemical evidence for impaired nitric oxide synthesis in patients with peripheral arterial occlusive disease. Circulation 1997; Apr 15 95 (8) 2068-74
    CrossrefPubMedGoogle Scholar
  • 12 Böger RH, Bode-Böger SM, Szuba A, Tsao PS, Chan JR, Tangphao O et al. Asymmetric dimethylarginine (ADMA): a novel risk factor for endothelial dysfunction: its role in hypercholesterolemia. Circulation 1998; Nov 3 98 (18) 1842-7
    CrossrefPubMedGoogle Scholar
  • 13 Kielstein JT, Böger RH, Bode-Böger SM, Schäffer J, Barbey M, Koch KM et al. Asymmetrie dimethylarginine plasma concentrations differ in patients with end-stage renal disease: relationship to treatment method and atherosclerotic disease. J Am Soc Nephrol. 1999; Mar 10 (3) 594-600
    PubMedGoogle Scholar
  • 14 Marescau B, Nagels G, Possemiers I, De Broe ME, Becaus I, Billiouw JM et al. Guanidino compounds in serum and urine of nondialyzed patients with chronic renal insufficiency. Metabolism 1997; Sep 46 (9) 1024-31
    CrossrefPubMedGoogle Scholar
  • 15 MacAllister RJ, Rambausek MH, Vallance P, Williams D, Hoffmann KH, Ritz E. Concentration of dimethyl-L-argi-nine in the plasma of patients with end-stage renal failure. Nephrol Dial Transplant. 1996; Dec 11 (12) 2449-52
    CrossrefPubMedGoogle Scholar
  • 16 Schmidt RJ, Domico J, Samsell LS, Yokota S, Tracy TS, Sorkin MI et al. Indices of activity of the nitric oxide system in hemodialysis patients. Am J Kidney Dis. 1999; Aug 34 (2) 228-34
    CrossrefPubMedGoogle Scholar
  • 17 Al Banchaabouchi M, Marescau B, Possemiers I, D’Hooge R, Levillain O, De Deyn PP. NG, NG-dimethylarginine and NG, NG-dimethylarginine in renal insufficiency. Pflugers Arch. 2000; Mar 439 (5) 524-31
    CrossrefPubMedGoogle Scholar
  • 18 Schmidt RJ, Baylis C. Total nitric oxide production is low in patients with chronic renal disease. Kidney Int. 2000; Sep 58 (3) 1261-6
    CrossrefPubMedGoogle Scholar
  • 19 Goonasekera CD, Shah V, Rees DD, Dillon MJ. Vascular endothelial cell activation associated with increased plasma asymmetric dimethyl arginine in children and young adults with hypertension: a basis for atheroma?. Blood Press 2000; 9 (1) 16-21
    CrossrefPubMedGoogle Scholar
  • 20 Surdacki A, Nowicki M, Sandmann J, Tsikas D, Boeger RH, Bode-Boeger SM et al. Reduced urinary excretion of nitric oxide metabolites and increased plasma levels of asymmetric dimethylarginine in men with essential hypertension. J Cardiovasc Pharmacol. 1999; Apr 33 (4) 652-8
    CrossrefPubMedGoogle Scholar
  • 21 Tsao PS, Cooke JP.. Endothelial alterations in hypercholesterolemia: more than simply vasodilator dysfunction. J Cardiovasc Pharmacol. 1998; 32 (03) S48-53 Review
    PubMedGoogle Scholar
  • 22 Böger RH, Bode-Böger SM, Sydow K, Heistad DD, Lentz SR. Plasma concentration of asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, is elevated in monkeys with hyperhomocyst(e)inemia or hypercholesterolemia. Arterioscler Thromb Vasc Biol. 2000; Jun 20 (6) 1557-64
    CrossrefPubMedGoogle Scholar
  • 23 Valkonen VP, Päivä H, Salonen JT, Lakka TA, Lehtimäki T, Laakso J et al. Risk of acute coronary events and serum concentration of asymmetrical dimethylarginine. Lancet 2001; Dec 22-29 358 (9299) 2127-8
    CrossrefPubMedGoogle Scholar
  • 24 Post MS, Verhoeven MO, van der Mooren MJ, Kenemans P, Stehouwer CD, Teerlink T. Effect of hormone replacement therapy on plasma levels of the cardiovascular risk factor asymmetric dimethylarginine: a randomized, placebo-controlled 12-week study in healthy early postmenopausal women. J Clin Endocrinol Metab. 2003; Sep 88 (9) 4221-6
    CrossrefPubMedGoogle Scholar
  • 25 Stühlinger MC, Abbasi F, Chu JW, Lamendola C, McLaughlin TL, Cooke JP et al. Relationship between insulin resistance and an endogenous nitric oxide synthase inhibitor. JAMA 2002; Mar 20 287 (11) 1420-6
    CrossrefPubMedGoogle Scholar
  • 26 Nestorov I, Graham G, Duffull S, Aarons L, Fuseau E, Coates P. Modeling and stimulation for clinical trial design involving a categorical response: a phase II case study with naratriptan. Pharm Res. 2001; Aug 18 (8) 1210-9
    CrossrefPubMedGoogle Scholar
  • 27 Nijveldt RJ, Teerlink T, van Guidener C, Prins HA, van Lam-balgen AA, Stehouwer CD et al. Handling of asymmetrical dimethylarginine and symmetrical dimethylarginine by the rat kidney under basal conditions and during endotox-aemia. Nephrol Dial Transplant. 2003; Dec 18 (12) 2542-50
    CrossrefPubMedGoogle Scholar
  • 28 Dobashi Y, Santa T, Nakagomi K, Imai K. An automated analyzer for methylated arginines in rat plasma by high-performance liquid chromatography with post-column fluorescence reaction. Analyst. 2002; Jan 127 (1) 54-9
    CrossrefPubMedGoogle Scholar
  • 29 Palm F, Buerk DG, Carlsson PO, Hanseil P, Liss P. Reduced nitric oxide concentration in the renal cortex of streptozo-tocin-induced diabetic rats: effects on renal oxygenation and microcirculation. Diabetes 2005; Nov 54 (11) 3282-7
    CrossrefPubMedGoogle Scholar
  • 30 Lin KY, Ito A, Asagami T, Tsao PS, Adimoolam S, Kimoto M et al. Impaired nitric oxide synthase pathway in diabetes mellitus: role of asymmetric dimethylarginine and dimethylarginine dimethylaminohydrolase. Circulation 2002; Aug 20 106 (8) 987-92
    CrossrefPubMedGoogle Scholar
  • 31 Schwedhelm E, Maas R, Tan-Andresen J, Schulze F, Riederer U, Böger RH. High-throughput liquid chromato-graphic-tandem mass spectrometric determination of arginine and dimethylated arginine derivatives in human and mouse plasma. J Chromatogr B Analyt Technol Biomed Life Sci. 2007; May 15 851 (1-2) 211-9 Epub 2006 Dec 27
    PubMedGoogle Scholar
  • 32 Schulze F, Wesemann R, Schwedhelm E, Sydow K, Albsmeier J, Cooke JP et al. Determination of asymmetric dimethylarginine (ADMA) using a novel ELISA assay. Clin Chem Lab Med. 2004; 42 (12) 1377-83
    CrossrefPubMedGoogle Scholar