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Asymmetric dimethylarginine (ADMA, NG, NG-dimethyl-L-arginine) is endogenously produced by asymmetric dimethylation of the guanidine group of L-arginine residues. ADMA is generally considered a powerful cardiovascular risk factor, an Übermarker, due to its inhibitory action on the activity of nitric oxide synthase (NOS) isoforms. In the endothelium, the constitutively expressed and Ca2+/calmodulin-dependent NOS (eNOS) catalyzes the conversion of L-arginine to nitric oxide (NO). NO is one of the most potent endogenous activators of soluble guanylyl cyclase which produces the second messenger cyclic guanosine monophosphate (cGMP). There is experimental evidence from in vitro and in vivo experiments that challenges the extraordinary importance of ADMA as the culprit of NO-related cardiovascular diseases in the human circulation. Most notably, we present data showing that ADMA is a weak competitive inhibitor of recombinant endothelial NOS (eNOS) activity (Ki 3.9 μM, IC50 12 μM). Thus, at its relatively low concentrations of 0.4 to 0.5 μM in the human blood, ADMA is unlikely to inhibit NO synthesis in the endothelium to an extent sufficient enough to cause endothelium dysfunction. Furthermore, ADMA does not “uncouple” eNOS and does not diminish the bioavailability of NO through its reaction with superoxide radical anions produced by “uncoupled” eNOS. Consequently, the particular importance assigned to ADMA in the human circulation is likely to be due to other not yet recognized biological actions beyond inhibition of eNOS activity. This “ADMA paradox” remains to be solved.
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2. Moncada S, Higgs EA. Molecular mechanisms and therapeutic strategies. FASEB J. 1995;9:1319–30.
3. Tsikas D, Böger RH, Sandmann J, Bode-Böger SM, Frölich JC. Endogenous nitric oxide synthase inhibitors are responsible for the L-arginine paradox. FEBS Lett. 2000;478:1–3. http://dx.doi.org/10.1016/S0014-5793(00)01686-0
4. Marletta MA. Nitric oxide synthase structure and mechanism. J Biol Chem. 1993;268:12231–4.
5. Andrew PJ, Mayer B. Enzymatic function of nitric oxide synthases. Cardiovasc Res. 1999;43:521–31. http://dx.doi.org/10.1016/S0008-6363(99)00115-7
6. Hibbs JB, Taintor RR, Vavrin Z. Macrophage cytotoxicity: Role for L-arginine deiminase and imino nitrogen oxidation to nitrite. Science. 1987;235:473–6. http://dx.doi.org/10.1126/science.2432665
7. Rees DD, Palmer RMJ, Hodson HF, Moncada S. A specific inhibitor of nitric oxide formation from L-arginine attenuates endothelium-dependent relaxation. Br J Pharmacol. 1989;96:418–24. http://dx.doi.org/10.1111/j.1476-5381.1989.tb11833.x
8. Vallance P, Leone A, Calver A, Collierr J, Moncada S. Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet 1992;339:572–5. http://dx.doi.org/10.1016/0140-6736(92)90865-Z
9. Kotani K, Ueno SI, Kakimoto Y. Isolation and identification of methylarginines from bovine brain. J Neurochem. 1992;58:1127–9. http://dx.doi.org/10.1111/j.1471-4159.1992.tb09371.x
10. Bredt DS, Snyder SS. Isolation of nitric oxide synthetase, a calmodulin-requiring enzyme. Proc Natl Acad Sci U S A. 1990;87:682–5. http://dx.doi.org/10.1073/pnas.87.2.682
11. Klatt P, Schmidt K, Uray G, Mayer B. Multiple catalytic functions of brain nitric oxide synthase. J Biol Chem. 1993;268:14781–7.
12. Furfine ES, Harmon MF, Paith JE, Garvey EP. Selective inhibition of constitutive nitric oxide synthase by L-NG-nitroarginine. Biochemistry. 1993;32:8512–17. http://dx.doi.org/10.1021/bi00084a017
13. Klatt P, Schmidt K, Brunner F, Mayer B. Inhibitors of brain nitric oxide synthase: Binding kinetics, metabolism, and enzyme inactivation. J Biol Chem. 1994;269:1674–80.
14. Furfine ES, Carbine K, Bunker S, Tanoury G, Harmon M, Laubach V, Sherman P. Potent inhibition of human neuronal nitric oxide synthase by NG-nitro-L-arginine methyl ester results from contaminating NG-nitro-L-arginine. Life Sci. 1997;60:1803–9. http://dx.doi.org/10.1016/S0024-3205(97)00140-9
15. Kielstein A, Tsikas D, Galloway GP, Mendelson JE. The inhibitory action of ADMA and its importance in the cardiovascular. Nitric Oxide. 2007;17:55–9.
16. Olken NM, Rusche KM, Richards MK, Marletta MA. Inactivation of macrophage nitric oxide synthase by NG-methyl-L-arginine. Biochem Biophys Res Commun. 1991;177:828–33. http://dx.doi.org/10.1016/0006-291X(91)91864-9
17. Pufahl RA, Nanjappan PG, Woodard RW, Marletta MA. Mechanistic probes of N-hydroxylation of L-arginine by the inducible nitric oxide synthase from murine macrophages. Biochemistry. 1992;31:6822–8. http://dx.doi.org/10.1021/bi00144a024
18. Feldmann PL, Griffith OW, Hong H, Stuehr DJ. Irreversible inactivation of macrophage and brain nitric oxide synthase by L-NG-methylarginine requires NADPH-dependent hydroxylation. J Med Chem. 1993;36:491–6. http://dx.doi.org/10.1021/jm00056a009
19. Tsikas D, Sandmann J, Savva A, Lueßen P, Böger RH, Gutzki FM, et al. Assessment of nitric oxide synthase activity in vitro and in vivo by gas chromatography-mass spectrometry. J Chromatogr B. 2000;742:143–53. http://dx.doi.org/10.1016/S0378-4347(00)00142-0
20. Böger RH, Bode-Böger SM, Szuda A, Tsao PS, Chan JR, Tangphao O, et al. Asymmetric dimethylarginine: A novel risk factor for endothelial dysfunction: Its role in hypercholesterolemia. Circulation. 1998;98:1842–7. http://dx.doi.org/10.1161/01.CIR.98.18.1842
21. Leiper J, Vallance P. Biological significance of endogenous methylarginines that inhibit nitric oxide synthases. Cardiovasc Res. 1999;43:542–8. http://dx.doi.org/10.1016/S0008-6363(99)00162-5
22. Faraci FM, Brain JE Jr, Heistad DD. Response of cerebral blood vessels to an endogenous inhibitor of nitric oxide synthase. Am J Physiol. 1995;269:H1522–7.
23. Sandmann J. PhD thesis, Untersuchungen zur Bedeutung der S-Transnitrosylierungs-Reaktion für die Bildung, den Metabolismus und die Vermittlung der biologischen Aktivitäten von NO und S-Nitroso-Substanzen. University of Hannover, Hannover, Germany, 2002.
24. Albsmeier J. PhD thesis, Bedeutung endogener Inhibitoren der NO-Synthase für kardiovaskuläre Erkrankungen und ihre pharmakologische Therapie. University of Hamburg, Hamburg, Germany, 2004.
25. Cardounel AJ, Zweier JL. Endogenous methylarginines regulate neuronal nitric-oxide synthase and prevent excitotoxic injury. J Biol Chem. 2002;277:33995–4002. http://dx.doi.org/10.1074/jbc.M108983200
26. Kielstein JT, Impraim B, Simmel S, Bode-Böger SM, Tsikas D, Frölich JC, et al. Cardiovascular effects of systemic NO synthase inhibition with asymmetric dimethylarginine in humans. Circulation. 2004;109(2):172–7. http://dx.doi.org/10.1161/01.CIR.0000105764.22626.B1
27. Kielstein JT, Tsikas D, Fliser D. Effects of asymmetric dimethylarginine (ADMA) infusion in humans. Eur J Clin Pharmacol. 2006;62(Suppl 2):39–44. http://dx.doi.org/10.1007/s00228-005-0010-1
28. Tsikas D, Junker W, Frölich JC. Determination of dimethylated arginines in human plasma by high-performance liquid chromatography. J Chromatogr B. 1998;705:174–6.
29. Lücke T, Kanzelmeyer N, Kemper MJ, Tsikas D, Das AM. Developmental changes in the L-arginine/nitric oxide pathway from infancy to adulthood: Plasma asymmetric dimethylarginine levels decrease with age. Clin Chem Lab Med. 2007;45(11):1525–30. http://dx.doi.org/10.1515/CCLM.2007.300