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Synthesis of homoagmatine and GC–MS analysis of tissue homoagmatine and agmatine: evidence that homoagmatine but not agmatine is a metabolite of pharmacological L-homoarginine in the anesthetized rat

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Abstract

Low L-homoarginine (hArg) concentrations in human blood and urine are associated with renal and cardiovascular morbidity and mortality, yet the underlying mechanisms and the biological activities of hArg are elusive. In humans and rats, hArg is metabolized to l-lysine. The aim of the present work was to study hArg metabolism to agmatine (Agm) and homoagmatine (hAgm) in the anesthetized rat. Using a newly developed and validated GC–MS method and a newly synthesized and structurally characterized hAgm we investigated the metabolism of i.p. administered hArg (0, 20, 220, 440 mg/kg) to hAgm and Agm in lung, kidney, liver and heart in anesthetized rats. Our study provides unequivocal evidence that hArg is metabolized to hAgm but not to Agm. Whether hAgm derived from hArg’s metabolism may contribute to the pathophysiological significance of endogenous hArg and for the favoured effects of pharmacological hArg remains to be demonstrated. The biology of hArg warrants further investigations.

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Abbreviations

ADC:

l-Arginine decarboxylase

AGAT:

l-Arginine:glycine amidinotransferase

Agm:

Agmatine

AGMA:

Agmatinase

GC–MS:

Gas chromatography–mass spectrometry

hAgm:

Homoagmatine

hArg:

L-Homoarginine

i.p:

Intraperitoneal

LLOQ:

Lower limit of quantitation (LLOQ)

m/z :

Mass-to-charge ratio

NO:

Nitric oxide synthase

NOS:

Nitric oxide

ODC:

l-Ornithine decarboxylase

PAR:

Peak area ratio

PFP:

Pentafluoropropionyl

PFPA:

Pentafluoropropionic anhydride

PUT:

Putrescine

SIM:

Selected-ion monitoring

SPD:

Spermidine

References

  • Agostinelli E, Marques MP, Calheiros R, Gil FP, Tempera G, Viceconte N, Battaglia V, Grancara S, Toninello A (2010) Polyamines: fundamental characters in chemistry and biology. Amino Acids 38:393–403

    Article  CAS  Google Scholar 

  • Akasaka N, Fujiwara S (2019) The therapeutic and nutraceutical potential of agmatine, and its enhanced production using Aspergillus oryzae. Amino Acids. https://doi.org/10.1007/s00726-019-02720-7

    Article  PubMed  Google Scholar 

  • Alesutan I, Feger M, Tuffaha R, Castor T, Musculus K, Buehling SS, Heine CL, Kuro-O M, Pieske B, Schmidt K, Tomaschitz A, Maerz W, Pilz S, Meinitzer A, Voelkl J, Lang F (2016) Augmentation of phosphate-induced osteo-/chondrogenic transformation of vascular smooth muscle cells by homoarginine. Cardiovasc Res 110:408–418

    Article  CAS  Google Scholar 

  • Atzler D, Schwedhelm E, Choe CU (2015) L-homoarginine and cardiovascular disease. Curr Opin Clin Nutr Metab Care 18:83–88

    Article  CAS  Google Scholar 

  • Atzler D, Schönhoff M, Cordts K, Ortland I, Hoppe J, Hummel FC, Gerloff C, Jaehde U, Jagodzinski A, Böger RH, Choe CU, Schwedhelm E (2016) Oral supplementation with L-homoarginine in young volunteers. Br J Clin Pharmacol 82:1477–1485

    Article  CAS  Google Scholar 

  • Benítez J, García D, Romero N, González A, Martínez-Oyanedel J, Figueroa M, Salas M, López V, García-Robles M, Dodd PR, Schenk G, Carvajal N, Uribe E (2018) Metabolic strategies for the degradation of the neuromodulator agmatine in mammals. Metabolism 81:35–44

    Article  Google Scholar 

  • Berkels R, Taubert D, Gründemann D, Schömig E (2004) Agmatine signaling: odds and threads. Cardiovasc Drug Rev 22:7–16

    Article  CAS  Google Scholar 

  • Blantz RC, Satriano J, Gabbai F, Kelly C (2000) Biological effects of arginine metabolites. Acta Physiol Scand 168:21–25

    Article  CAS  Google Scholar 

  • Bollenbach A, Cordts K, Hanff E, Atzler D, Choe CU, Schwedhelm E, Tsikas D (2019) Evidence by GC–MS that lysine is an arginase-catalyzed metabolite of homoarginine in vitro and in vivo in humans. Anal Biochem 577:59–66

    Article  CAS  Google Scholar 

  • Frenay ARS, Kayacelebi AA, Beckmann B, Soedamah-Muhtu SS, de Borst MH, van den Berg E, van Goor H, Bakker SJL, Tsikas D (2015) High urinary homoarginine excretion is associated with low rates of all-cause mortality and graft failure in renal transplant recipients. Amino Acids 47(9):1827–1836

    Article  CAS  Google Scholar 

  • Galea E, Regunathan S, Eliopoulos V, Feinstein DL, Reis DJ (1996) Inhibition of mammalian nitric oxide synthases by agmatine, an endogenous polyamine formed by decarboxylation of arginine. Biochem J 316(Pt 1):247–249

    Article  CAS  Google Scholar 

  • Gao Y, Gumusel B, Koves G, Prasad A, Hao Q, Hyman A, Lippton H (1995) Agmatine: a novel endogenous vasodilator substance. Life Sci 57:PL83–PL86

    Article  CAS  Google Scholar 

  • Grancara S, Ohkubo S, Artico M, Ciccariello M, Manente S, Bragadin M, Toninello A, Agostinelli E (2016) Milestones and recent discoveries on cell death mediated by mitochondria and their interactions with biologically active amines. Amino Acids 48:2313–2326

    Article  CAS  Google Scholar 

  • Günes DN, Kayacelebi AA, Hanff E, Lundgren J, Redfors B, Tsikas D (2017) Metabolism and distribution of pharmacological homoarginine in plasma and main organs of the anesthetized rat. Amino Acids 49:2033–2044

    Article  Google Scholar 

  • Halaris A, Zhu H, Feng Y, Piletz JE (1999) Plasma agmatine and platelet imidazoline receptors in depression. Ann N Y Acad Sci 881:445–451

    Article  CAS  Google Scholar 

  • Hanff E, Bollenbach A, Beckmann B, Brunner G, Tsikas D (2019a) GC-MS measurement of spermidine and putrescine in serum of elderly subjects: intriguing association between spermidine and homoarginine. Amino Acids. https://doi.org/10.1007/s00726-019-02786-3

    Article  PubMed  Google Scholar 

  • Hanff E, Ruben S, Kreuzer M, Bollenbach A, Kayacelebi AA, Das AM, von Versen-Höynck F, von Kaisenberg C, Haffner D, Ückert S, Tsikas D (2019b) Development and validation of GC-MS methods for the comprehensive analysis of amino acids in plasma and urine and applications to the HELLP syndrome and pediatric kidney transplantation: evidence of altered methylation, transamidination, and arginase activity. Amino Acids 51:529–547

    Article  CAS  Google Scholar 

  • Hegstrand LR (1985) A direct, sensitive microassay for mammalian histidine decarboxylase. Biochem Pharmacol 34:3711–3716

    Article  CAS  Google Scholar 

  • Hesterberg RS, Cleveland JL, Epling-Burnette PK (2018) Role of polyamines in immune cell functions. Med Sci 6(1):E22. https://doi.org/10.3390/medsci6010022

    Article  CAS  Google Scholar 

  • Hussain T, Tan B, Ren W, Rahu N, Kalhoro DH, Yin Y (2017) Exploring polyamines: functions in embryo/fetal development. Anim Nutr. 3:7–10

    Article  Google Scholar 

  • Karetnikova ES, Jarzebska N, Markov AG, Weiss N, Lentz SR, Rodionov RN (2019) Is homoarginine a protective cardiovascular risk factor? Arterioscler Thromb Vasc Biol 39:869–875

    Article  CAS  Google Scholar 

  • Kayacelebi AA, Langen J, Weigt-Usinger K, Chobanyan-Jürgens K, Mariotti F, Schneider JY, Rothmann S, Frölich JC, Atzler D, Choe C, Schwedhelm E, Huneau JF, Lücke T, Tsikas D (2015) Biosynthesis of homoarginine (hArg) and asymmetric dimethylarginine (ADMA) from acutely and chronically administered free l-arginine in humans. Amino Acids 47(9):1893–1908

    Article  CAS  Google Scholar 

  • Kayacelebi AA, Minović I, Hanff E, Frenay ARS, de Borst MH, Feelisch M, van Goor H, Bakker SJL, Tsikas D (2017) Low plasma homoarginine concentration is associated with high rates of all-cause mortality in renal transplant recipients. Amino Acids 49(7):1193–1202

    Article  CAS  Google Scholar 

  • Laube G, Bernstein HG (2017) Agmatine: multifunctional arginine metabolite and magic bullet in clinical neuroscience? Biochem J 474:2619–2640

    Article  CAS  Google Scholar 

  • Maltsev AV, Evdokimovskii EV, Kokoz YM (2019) Synergism of myocardial β-adrenoceptor blockade and I1-imidazoline receptor-driven signaling: kinase-phosphatase switching. Biochem Biophys Res Commun 511:363–368

    Article  CAS  Google Scholar 

  • Nguyen HO, Goracke-Postle CJ, Kaminski LL, Overland AC, Morgan AD, Fairbanks CA (2003) Neuropharmacokinetic and dynamic studies of agmatine (decarboxylated arginine). Ann N Y Acad Sci 1009:82–105

    Article  CAS  Google Scholar 

  • Pilz S, Meinitzer A, Gaksch M, Grübler M, Verheyen N, Drechsler C, Hartaigh BÓ, Lang F, Alesutan I, Voelkl J, März W, Tomaschitz A (2015) Homoarginine in the renal and cardiovascular systems. Amino Acids 47:1703–1713

    Article  CAS  Google Scholar 

  • Popolo A, Adesso S, Pinto A, Autore G, Marzocco S (2014) l-Arginine and its metabolites in kidney and cardiovascular disease. Amino Acids 46:2271–2286

    Article  CAS  Google Scholar 

  • Raghavan SA, Dikshit M (2004) Vascular regulation by the l-arginine metabolites, nitric oxide and agmatine. Pharmacol Res 49:397–414

    Article  CAS  Google Scholar 

  • Ramakrishna S, Adiga PR (1973) Homoagmatine from Lathyrus sativus seedlings. Phytochemistry 12:2691–2695

    Article  CAS  Google Scholar 

  • Ramani D, De Bandt JP, Cynober L (2014) Aliphatic polyamines in physiology and diseases. Clin Nutr 33:14–22

    Article  CAS  Google Scholar 

  • Ramos-Molina B, Queipo-Ortuño MI, Lambertos A, Tinahones FJ, Peñafiel R (2019) Dietary and gut microbiota polyamines in obesity- and age-related diseases. Front Nutr 6:24. https://doi.org/10.3389/fnut.2019.00024.eCollection

    Article  PubMed  PubMed Central  Google Scholar 

  • Redfors B, Oras J, Shao Y, Seemann-Lodding H, Ricksten SE, Omerovic E (2014) Cardioprotective effects of isoflurane in a rat model of stress-induced cardiomyopathy (takotsubo). Int J Cardiol 176:815–821

    Article  Google Scholar 

  • Srivenugopal KS, Adiga PR (1980) Partial purification and properties of a transamidinase from Lathyrus sativus seedlings. Involvement in homoarginine metabolism and amine interconversions. Biochem J. 189:553–560

    Article  CAS  Google Scholar 

  • Su RB, Li J, Qin BY (2003) A biphasic opioid function modulator: agmatine. Acta Pharmacol Sin 24:631–636

    CAS  PubMed  Google Scholar 

  • Tommasi S, Elliot DJ, Da Boit M, Gray SR, Lewis BC, Mangoni AA (2018) Homoarginine and inhibition of human arginase activity: kinetic characterization and biological relevance. Sci Rep 8:3697

    Article  CAS  Google Scholar 

  • Velásquez RD, Brunner G, Varrentrapp M, Tsikas D, Frölich JC (1996) Helicobacter pylori produces histamine and spermidine. Z Gastroenterol 34:116–122

    PubMed  Google Scholar 

  • Wang X, Ying W, Dunlap KA, Lin G, Satterfield MC, Burghardt RC, Wu G, Bazer FW (2014) Arginine decarboxylase and agmatinase: an alternative pathway for de novo biosynthesis of polyamines for development of mammalian conceptuses. Biol Reprod 90:84

    PubMed  Google Scholar 

  • Wu N, Su RB, Li J (2008) Agmatine and imidazoline receptors: their role in opioid analgesia, tolerance and dependence. Cell Mol Neurobiol 28:629–641

    Article  CAS  Google Scholar 

  • 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 37:153–168

    Article  CAS  Google Scholar 

  • Zinellu A, Paliogiannis P, Carru C, Mangoni AA (2018) Homoarginine and all-cause mortality: a systematic review and meta-analysis. Eur J Clin Invest 48:e12960

    Article  Google Scholar 

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Author notes

    Authors and Affiliations

    1. Institute of Toxicology, Core Unit Proteomics, Core Unit Proteomics, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany

      Dimitrios Tsikas, Alexander Bollenbach & Erik Hanff

    2. Institute of Occupational Medicine, Hannover Medical School, Hannover, Germany

      Bibiana Beckmann

    3. Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden

      Björn Redfors

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    1. Dimitrios Tsikas
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    2. Alexander Bollenbach
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    3. Erik Hanff
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    4. Bibiana Beckmann
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    Correspondence to Dimitrios Tsikas.

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    Rats received humane care and the study protocol complied with the institutional guidelines of the Sahlgrenska University Hospital.

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    Tsikas, D., Bollenbach, A., Hanff, E. et al. Synthesis of homoagmatine and GC–MS analysis of tissue homoagmatine and agmatine: evidence that homoagmatine but not agmatine is a metabolite of pharmacological L-homoarginine in the anesthetized rat. Amino Acids 52, 235–245 (2020). https://doi.org/10.1007/s00726-019-02808-0

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