Asymmetric dimethylarginine 4533264 215553237 2008-05-28T18:36:55Z DOI bot 6652755 Citation maintenance. You can [[WP:DOI|use this bot]] yourself! Please [[User:DOI_bot/bugs|report any bugs]]. {{NatOrganicBox | image= [[Image:ADMA.svg]] | name=2-amino-5-[(amino-dimethylamino- methylidene)amino] pentanoic acid | PubChem = 123831 | C=8 | H=18 | N=4 | O=2 | mass=202.25 | SMILES = CN(C)C(=NCCCC(C(=O)O)N)N }} '''Asymmetric dimethylarginine''' (ADMA) is a naturally occurring chemical found in [[blood plasma]]. It is a [[metabolism|metabolic]] [[by-product]] of continual [[protein]] modification processes in the [[cytoplasm]] of all human cells. It is closely related to L-[[arginine]], a conditionally-essential [[amino acid]]. ADMA interferes with L-arginine in the production of [[nitric oxide]], a key chemical to [[endothelium|endothelial]] and hence [[circulatory system|cardiovascular]] health. ==Discovery== Patrick Vallance and his [[London]] co-workers first noted the interference role for asymmetric dimethylarginine.<!-- --><ref>{{cite journal | author= Vallance P., Leone A., Calver A., Collier J., Moncada S. | year=1992 | title=Endogenous dimethyl-arginine as an inhibitor of nitric oxide synthesis | journal=J. Cardiovasc. Pharmacol | volume=20 |issue=Suppli. 12 | pages=S60–S62}}</ref> Today biochemical and clinical research continues into the role of ADMA in [[cardiovascular disease]], [[diabetes mellitus]], [[erectile dysfunction]] and certain forms of [[kidney]] disease. ==Synthesis and regulation in the body== [[Image:Heart-and-lungs.jpg|thumb|right|210px|[[Cardiovascular]] effects have been linked to ADMA]] Asymmetric dimethylarginine is created in protein [[methylation]], a common mechanism of post-translational protein modification. This reaction is catalyzed by an [[enzyme]] set called S-adenosylmethionine protein N-methyltransferases (protein methylases I and II).<!-- --><ref>{{cite journal | author=Rawal N, Rajpurohit R, Lischwe MA, Williams KR, Paik WK, Kim S | title=Structural specificity of substrate for S-adenosylmethionine:protein arginine N-methyltransferases | journal=Biochim Biophys Acta | year=1995 | pages=11–8 | volume=1248 | issue=1 | pmid=7536038}} </ref> The methyl groups transferred to create ADMA are derived from the [[methyl]] group donor S-adenosylmethionine, an intermediate in the metabolism of [[homocysteine]]. (Homocysteine is an important blood chemical, because it is also a [[genetic marker|marker]] of cardiovascular disease). After [[synthesis]], ADMA migrates into the [[extracellular]] space and thence into blood plasma. Asymmetric dimethylarginine is measured using [[high performance liquid chromatography]]. ADMA concentrations are substantially elevated by native or oxidized [[LDL]] [[cholesterol]].<!-- --><ref>{{cite journal | author=Boger RH, Sydow K, Borlak J, Thum T, Lenzen H, Schubert B, Tsikas D, Bode-Boger SM | title=LDL cholesterol upregulates synthesis of asymmetrical dimethylarginine in human endothelial cells: involvement of S-adenosylmethionine-dependent methyltransferases | journal=Circ Res | year=2000 | pages=99–105 | volume=87 | issue=2 | pmid=10903992 | url=http://circres.ahajournals.org/cgi/content/full/87/2/99}}</ref> Thus a spiralling effect occurs with high endothelial LDL levels causing greater ADMA values, which in turn inhibit NO production needed to promote [[vasodilation]]. The elimination of ADMA occurs through urine excretion and metabolism by the enzyme [[dimethylarginine dimethylaminohydrolase]] (DDAH). The role of homocysteine as a risk factor for cardiovascular disease is suggested to be mediated by homocysteine down-regulating production of DDAH in the body. [[Polyphenol antioxidant]]s also play a role in down-regulating homocysteine. ==ADMA and suggested lines of therapeutic research== [[Image:Kidney_section.jpg|thumb|right|160px|ADMA may play a role in certain forms of [[kidney]] disease]] With raised levels of ADMA seemingly to be associated with adverse human health consequences for cardiovascular disease, metabolic diseases and also a wide range of diseases of the elderly, the possible lowering of ADMA levels may have important therapeutic effects. However it has yet to be established whether ADMA levels can be manipulated and, more importantly, if this results in useful clinical benefits. The association of ADMA with abnormalities of lipid regulation suggested that supplements of [[fatty acid|free fatty acids]] might manipulate ADMA levels. However research has failed to show that these have an effect.<!-- --><ref name=NutrMetab2006-Eid>{{cite journal | author=Eid HM, Arnesen H, Hjerkinn EM, Lyberg T, Ellingsen I, Seljeflot I | title=Effect of diet and omega-3 fatty acid intervention on asymmetric dimethylarginine | journal=Nutr Metab (Lond) | year=2006 | pages=4 | volume=3 | pmid=16396682 | url =http://www.nutritionandmetabolism.com/content/3/1/4 | doi=10.1186/1743-7075-3-4}}</ref><!-- --><ref name=HormMetabRes2005-Namiranian>{{cite journal | author=Namiranian K, Mittermayer F, Artwohl M, Pleiner J, Schaller G, Mayer BX, Bayerle-Eder M, Roden M, Baumgartner-Parzer S, Wolzt M | title=Free fatty acids do not acutely increase asymmetrical dimethylarginine concentrations | journal=Horm Metab Res | year=2005 | pages=768–72 | volume=37 | issue=12 | pmid=16372232 | doi=10.1055/s-2005-921100}}</ref> ADMA role has been linked with elevated levels of [[homocysteine]].<!-- --><ref name=Atherosclerosis2006-Krzyzanowska>{{cite journal | author=Krzyzanowska K, Mittermayer F, Krugluger W, Schnack C, Hofer M, Wolzt M, Schernthaner G | title=Asymmetric dimethylarginine is associated with macrovascular disease and total homocysteine in patients with type 2 diabetes | journal=Atherosclerosis | year=2006 | pages= | volume= | pmid=16414052 | doi=10.1016/j.atherosclerosis.2005.12.007}}</ref><!-- --><ref name=VascMed2006-Dayal>{{cite journal | author=Dayal S, Lentz SR | title=ADMA and hyperhomocysteinemia | journal=Vasc Med | year=2005 | pages=S27–33 | volume=10 Suppl 1 | pmid=16444866 | doi=10.1191/1358863x05vm599oa}}</ref><!-- --><ref name=CurrDrugMetab2005-Stuhlinger>{{cite journal | author=Stuhlinger MC, Stanger O | title=Asymmetric dimethyl-L-arginine (ADMA): a possible link between homocyst(e)ine and endothelial dysfunction | journal=Curr Drug Metab | year=2005 | pages=3–14 | volume=6 | issue=1 | pmid=15720202 | doi=10.2174/1389200052997393}}</ref> Whilst approaches at modifying the later with oral supplements of [[folic acid]] were strongly suggested, studies have shown this fails to give any clinical benefit and suggested that B vitamins might instead increase some cardiovascular risks.<!-- --><ref name="JAmCollCardiol2006-Zoungas">{{cite journal | author=Zoungas S, McGrath BP, Branley P, Kerr PG, Muske C, Wolfe R, Atkins RC, Nicholls K, Fraenkel M, Hutchison BG, Walker R, McNeil JJ | title=Cardiovascular morbidity and mortality in the Atherosclerosis and Folic Acid Supplementation Trial (ASFAST) in chronic renal failure: a multicenter, randomized, controlled trial | journal=J Am Coll Cardiol | year=2006 | pages=1108–16 | volume=47 | issue=6 | pmid=16545638 | doi=10.1016/j.jacc.2005.10.064}}</ref><!-- --><ref name="NEJM2006a">{{cite journal | author= | title=Homocysteine Lowering with Folic Acid and B Vitamins in Vascular Disease | journal=N Engl J Med | year=2006 | pages= | volume= | pmid=16531613 | url=http://content.nejm.org/cgi/reprint/NEJMoa060900v1.pdf}}</ref><!-- --><ref anme="NEJM2006-Bonna>{{cite journal | author=Bonaa KH, Njolstad I, Ueland PM, Schirmer H, Tverdal A, Steigen T, Wang H, Nordrehaug JE, Arnesen E, Rasmussen K | title=Homocysteine Lowering and Cardiovascular Events after Acute Myocardial Infarction | journal=N Engl J Med | year=2006 | pages= | volume= | pmid=16531614 | url=http://content.nejm.org/cgi/reprint/NEJMoa055227v1.pdf | doi=10.1056/NEJMoa055227}}</ref> Direct alteration of ADMA levels with supplements of L-arginine have been suggested.<!-- --><ref name="VascMed2003-Bode-Boger">{{cite journal | author=Bode-Boger SM, Muke J, Surdacki A, Brabant G, Boger RH, Frolich JC | title=Oral L-arginine improves endothelial function in healthy individuals older than 70 years | journal=Vasc Med | year=2003 | pages=77–81 | volume=8 | issue=2 | pmid=14518608 | doi=10.1191/1358863x03vm474oa}}</ref><!-- --><ref>{{cite book | author=John P. Cooke | title=The Cardiovascular Cure | publisher=Random House | year=2002 | id=ISBN 0-7679-0881-3}}</ref> The hope is that such intervention might not only improve endothelial function but also reduce clinical symptoms of overt cardiovascular disease.<!-- --><ref>{{cite journal | author=Rector TS, Bank AJ, Mullen KA, Tschumperlin LK, Sih R, Pillai K, Kubo SH | title=Randomized, double-blind, placebo-controlled study of supplemental oral L-arginine in patients with heart failure | journal=Circulation | year=1996 | pages=2135–41 | volume=93 | issue=12 | pmid=8925582 | url=http://circ.ahajournals.org/cgi/content/full/93/12/2135}}</ref><!-- --><ref>{{cite journal | author=Ceremuzynski L, Chamiec T, Herbaczynska-Cedro K | title=Effect of supplemental oral L-arginine on exercise capacity in patients with stable angina pectoris | journal=Am J Cardiol | year=1997 | pages=331–3 | volume=80 | issue=3 | pmid=9264427 | doi=10.1016/S0002-9149(97)00354-8}}</ref> However studies show inconsistency in results in a clinical context,<!-- --><ref name="JNutr2004-Loscalzo">{{cite journal | author=Loscalzo J | title=L-arginine and atherothrombosis | journal=J Nutr | year=2004 | pages=2798S–2800S; discussion 2818S–2819S | volume=134 | issue=10 Suppl | pmid=15465788 }}</ref> and the recent results with manipulating homocysteine levels warrant extreme care with what clinical outcomes might arise from this approach. [[Statin]]s, as well as affecting circulating cholesterol levels, also increase nitric oxide levels and so have a direct effect on blood supply to the heart. Elevated levels of ADMA seems to modify this effect and so may have consequences for patients' responsiveness to taking statins.<!-- --><ref name="VascMed2003-Janatuinen">{{cite journal | author=Janatuinen T, Laakso J, Laaksonen R, Vesalainen R, Nuutila P, Lehtimaki T, Raitakari OT, Knuuti J | title=Plasma asymmetric dimethylarginine modifies the effect of pravastatin on myocardial blood flow in young adults | journal=Vasc Med | year=2003 | pages=185–9 | volume=8 | issue=3 | pmid=14989559 | doi=10.1191/1358863x03vm490oa}}</ref> ==See also== * [[Arginine]] * [[Cardiovascular disease]] * [[Hypertension]] * [[Nitric oxide]] * [[Statin]]s * [[Vasoconstriction]] In the "See Also" section please add "Dimethylarginine Dimethylaminohydrolase" ==External links== *[http://www.medicalnewstoday.com/medicalnews.php?newsid=31545 ADMA article, Medical News Today, March 27, 2006] *[http://www.allaboutadma.com/ Summary of ADMA research literature] *[http://www.adma.com www.adma.com] [[Category:Cardiovascular system]] [[de:ADMA]] [[zh:非對稱性二甲基精氨酸]]