title: Cellular ADMA: regulation and action.
abstract: Asymmetric (N(G),N(G)) dimethylarginine (ADMA) is present in plasma and cells. It can inhibit nitric oxide synthase (NOS) that generates nitric oxide (NO) and cationic amino acid transporters (CATs) that supply intracellular NOS with its substrate, l-arginine, from the plasma. Therefore, ADMA and its transport mechanisms are strategically placed to regulate endothelial function. This could have considerable clinical impact since endothelial dysfunction has been detected at the origin of hypertension and chronic kidney disease (CKD) in human subjects and may be a harbinger of large vessel disease and cardiovascular disease (CVD). Indeed, plasma levels of ADMA are increased in many studies of patients at risk for, or with overt CKD or CVD. However, the levels of ADMA measured in plasma of about 0.5micromol.l(-1) may be below those required to inhibit NOS whose substrate, l-arginine, is present in concentrations many fold above the Km for NOS. However, NOS activity may be partially inhibited by cellular ADMA. Therefore, the cellular production of ADMA by protein arginine methyltransferase (PRMT) and protein hydrolysis, its degradation by N(G),N(G)-dimethylarginine dimethylaminohydrolase (DDAH) and its transmembrane transport by CAT that determines intracellular levels of ADMA may also determine the state of activation of NOS. This is the focus of the review. It is concluded that cellular levels of ADMA can be 5- to 20-fold above those in plasma and in a range that could tonically inhibit NOS. The relative importance of PRMT, DDAH and CAT for determining the intracellular NOS substrate:inhibitor ratio (l-arginine:ADMA) may vary according to the pathophysiologic circumstance. An understanding of this important balance requires knowledge of these three processes that regulate the intracellular levels of ADMA and arginine.
authors.affiliation: Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Tom
authors.initials: T
authors.lastname: Teerlink
authors.forename: Zaiming
authors.initials: Z
authors.lastname: Luo
authors.forename: Fredrik
authors.initials: F
authors.lastname: Palm
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Wilcox
mesh_terms: D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000502:physiology; D002318:Cardiovascular Diseases / Q000175:diagnosis / Q000201:enzymology / Q000378:metabolism; D042783:Endothelial Cells / Q000201:enzymology / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000502:physiology
chemical_list: C018524:N,N-dimethylarginine; D001120:Arginine; D019001:Nitric Oxide Synthase
references.citation: Clin Nutr. 2003 Feb;22(1):99-104
references.pmid: 12553957
references.citation: Am J Cardiol. 2001 Nov 15;88(10):1201-3
references.pmid: 11703973
references.citation: Am J Physiol Cell Physiol. 2001 Oct;281(4):C1077-93
references.pmid: 11546643
references.citation: Kidney Int. 2001 Apr;59(4):1466-72
references.pmid: 11260409
references.citation: Arterioscler Thromb Vasc Biol. 2003 Aug 1;23(8):1455-9
references.pmid: 12805079
references.citation: Curr Opin Nephrol Hypertens. 2002 Jan;11(1):99-107
references.pmid: 11753094
references.citation: J Biol Chem. 1989 Jun 15;264(17):10205-9
references.pmid: 2722865
references.citation: FEBS Lett. 2000 Jul 28;478(1-2):1-3
references.pmid: 10922458
references.citation: Pharmacol Ther. 2007 Dec;116(3):428-36
references.pmid: 17915331
references.citation: J Clin Invest. 1997 Nov 1;100(9):2235-42
references.pmid: 9410901
references.citation: Am J Kidney Dis. 2008 Feb;51(2):184-91
references.pmid: 18215696
references.citation: J Physiol. 1997 Feb 15;499 ( Pt 1):135-40
references.pmid: 9061645
references.citation: Cardiovasc Res. 2007 Jan 15;73(2):359-67
references.pmid: 17078937
references.citation: J Biol Chem. 1993 Apr 5;268(10):7538-44
references.pmid: 8385111
references.citation: Am J Physiol Regul Integr Comp Physiol. 2001 Apr;280(4):R1069-75
references.pmid: 11247829
references.citation: JPEN J Parenter Enteral Nutr. 2008 Nov-Dec;32(6):613-21
references.pmid: 18974239
references.citation: Diabetes Care. 2004 Mar;27(3):765-9
references.pmid: 14988299
references.citation: J Am Soc Nephrol. 1997 Sep;8(9):1437-42
references.pmid: 9294836
references.citation: Circulation. 2003 Dec 16;108(24):3042-7
references.pmid: 14638548
references.citation: Cell. 1989 May 19;57(4):659-66
references.pmid: 2541919
references.citation: Diabetes. 2005 Nov;54(11):3282-7
references.pmid: 16249456
references.citation: Circulation. 1999 Mar 9;99(9):1141-6
references.pmid: 10069780
references.citation: Am J Physiol Renal Physiol. 2009 Jul;297(1):F163-8
references.pmid: 19386725
references.citation: Circulation. 2004 Dec 14;110(24):3680-6
references.pmid: 15569830
references.citation: Physiol Rev. 2003 Jan;83(1):183-252
references.pmid: 12506130
references.citation: Circulation. 2007 Mar 13;115(10):1269-74
references.pmid: 17325243
references.citation: Pharmacol Res. 2009 Dec;60(6):481-7
references.pmid: 19596069
references.citation: Annu Rev Nutr. 2004;24:377-99
references.pmid: 15459982
references.citation: J Biol Chem. 1996 May 17;271(20):11694-702
references.pmid: 8662674
references.citation: Circulation. 2004 Jan 20;109(2):172-7
references.pmid: 14662708
references.citation: Biochem J. 1998 Nov 15;336 ( Pt 1):1-17
references.pmid: 9806879
references.citation: Clin Sci (Lond). 2004 Jun;106(6):577-81
references.pmid: 14741043
references.citation: J Biol Chem. 2001 Apr 13;276(15):12285-91
references.pmid: 11114306
references.citation: J Biol Chem. 2002 Sep 13;277(37):33995-4002
references.pmid: 12091378
references.citation: Amino Acids. 1998;15(4):321-37
references.pmid: 9891757
references.citation: Kidney Int. 2006 Dec;70(12):2109-15
references.pmid: 17063175
references.citation: Hypertension. 2002 Feb;39(2):287-92
references.pmid: 11847199
references.citation: Am J Physiol Heart Circ Physiol. 2007 Dec;293(6):H3227-45
references.pmid: 17933965
references.citation: J Biol Chem. 1997 Dec 12;272(50):31213-6
references.pmid: 9395443
references.citation: Am J Physiol. 1999 Jun;276(6):H2020-8
references.pmid: 10362683
references.citation: Biochemistry. 2008 Jul 8;47(27):7256-63
references.pmid: 18553936
references.citation: J Biol Chem. 2005 Mar 4;280(9):7540-9
references.pmid: 15574418
references.citation: Clin Sci (Lond). 2003 Jul;105(1):67-71
references.pmid: 12625833
references.citation: Diabetologia. 2002 Dec;45(12):1609-16
references.pmid: 12488950
references.citation: Atheroscler Suppl. 2003 Dec;4(4):1-3
references.pmid: 14664896
references.citation: Metabolism. 2003 Mar;52(3):303-7
references.pmid: 12647267
references.citation: Br J Pharmacol. 1999 Jan;126(1):211-8
references.pmid: 10051138
references.citation: J Nutr. 2004 Oct;134(10 Suppl):2842S-2847S; discussion 2853S
references.pmid: 15465797
references.citation: J Clin Endocrinol Metab. 2007 May;92(5):1881-5
references.pmid: 17311854
references.citation: J Clin Invest. 1980 May;65(5):1162-73
references.pmid: 7364943
references.citation: Physiol Rev. 1998 Apr;78(2):487-545
references.pmid: 9562037
references.citation: Nutrition. 2002 Sep;18(9):761-6
references.pmid: 12297216
references.citation: Eur J Clin Invest. 2003 May;33(5):361-2
references.pmid: 12713447
references.citation: Circulation. 2000 Nov 28;102(22):2707-12
references.pmid: 11094036
references.citation: Anal Biochem. 2002 Apr 15;303(2):131-7
references.pmid: 11950212
references.citation: J Cardiovasc Pharmacol. 2003 Aug;42(2):191-6
references.pmid: 12883321
references.citation: Am J Physiol Renal Physiol. 2008 Jan;294(1):F1-9
references.pmid: 17928410
references.citation: Nat Clin Pract Nephrol. 2006 Apr;2(4):209-20
references.pmid: 16932427
references.citation: Mol Genet Metab. 2007 Aug;91(4):309-17; discussion 308
references.pmid: 17560156
references.citation: Res Vet Sci. 2006 Jun;80(3):336-42
references.pmid: 16182327
references.citation: Atherosclerosis. 2009 Sep;206(1):245-50
references.pmid: 19324362
references.citation: J Physiol. 1996 Jan 1;490 ( Pt 1):229-41
references.pmid: 8745290
references.citation: Pflugers Arch. 2004 Jul;448(4):383-94
references.pmid: 15064952
references.citation: Am J Physiol Heart Circ Physiol. 2006 Jan;290(1):H209-16
references.pmid: 16113067
references.citation: Am J Hypertens. 2002 Jul;15(7 Pt 1):590-3
references.pmid: 12118904
references.citation: Hum Mutat. 2009 Mar;30(3):328-33
references.pmid: 19067360
references.citation: Diabetologia. 2002 Oct;45(10):1372-8
references.pmid: 12378377
references.citation: J Hypertens. 1997 Aug;15(8):901-9
references.pmid: 9280214
references.citation: Biochem J. 1976 Jan 15;154(1):179-84
references.pmid: 1275907
references.citation: Diabetes Care. 2008 Apr;31(4):747-52
references.pmid: 18162497
references.citation: J Biol Chem. 1997 Mar 28;272(13):8717-22
references.pmid: 9079705
references.citation: J Biol Chem. 1996 Nov 22;271(47):29799-806
references.pmid: 8939918
references.citation: Am J Kidney Dis. 1999 Aug;34(2):228-34
references.pmid: 10430967
references.citation: Cardiovasc Res. 2001 Mar;49(4):697-712
references.pmid: 11230969
references.citation: Cell. 2006 Jun 16;125(6):1111-24
references.pmid: 16777601
references.citation: JAMA. 2002 Mar 20;287(11):1420-6
references.pmid: 11903029
references.citation: J Membr Biol. 2006;213(2):67-77
references.pmid: 17417706
references.citation: Metabolism. 2007 Apr;56(4):464-9
references.pmid: 17379002
references.citation: Metabolism. 2002 Jul;51(7):843-6
references.pmid: 12077728
references.citation: J Am Soc Nephrol. 2005 Aug;16(8):2449-55
references.pmid: 15944335
references.citation: Clin Sci (Lond). 2002 Aug;103 Suppl 48:241S-244S
references.pmid: 12193095
references.citation: J Chromatogr B Analyt Technol Biomed Life Sci. 2007 May 15;851(1-2):42-50
references.pmid: 17045556
references.citation: Annu Rev Nutr. 2006;26:203-28
references.pmid: 16848705
references.citation: Crit Care Med. 2005 Mar;33(3):504-10
references.pmid: 15753739
references.citation: RNA Biol. 2004 Jul;1(2):106-13
references.pmid: 17179747
references.citation: Kidney Int. 2006 Jan;69(2):298-303
references.pmid: 16408119
references.citation: Am J Physiol Regul Integr Comp Physiol. 2005 Oct;289(4):R913-35
references.pmid: 16183628
references.citation: J Chromatogr B Analyt Technol Biomed Life Sci. 2007 May 15;851(1-2):21-9
references.pmid: 16931194
references.citation: Circ Res. 2003 Jan 10;92(1):64-72
references.pmid: 12522122
references.citation: Am J Physiol Regul Integr Comp Physiol. 2009 Feb;296(2):R195-200
references.pmid: 18685064
references.citation: Crit Care Med. 2000 Jun;28(6):1991-7
references.pmid: 10890653
references.citation: Biochem Biophys Res Commun. 1987 Oct 29;148(2):671-7
references.pmid: 3689365
references.citation: Circulation. 2002 Aug 20;106(8):987-92
references.pmid: 12186805
references.citation: Circulation. 2009 Mar 31;119(12):1592-600
references.pmid: 19289633
references.citation: J Virol. 1994 Mar;68(3):1615-23
references.pmid: 8107222
references.citation: Cardiovasc Res. 2003 Jan;57(1):244-52
references.pmid: 12504835
references.citation: Am J Physiol Heart Circ Physiol. 2008 Feb;294(2):H1058-66
references.pmid: 18156199
references.citation: Hypertension. 2006 Aug;48(2):278-85
references.pmid: 16801489
references.citation: Kidney Int. 1997 Dec;52(6):1593-601
references.pmid: 9407505
references.citation: Hypertension. 1995 Aug;26(2):256-62
references.pmid: 7635532
references.citation: J Vet Intern Med. 2005 Sep-Oct;19(5):712-9
references.pmid: 16231716
references.citation: J Clin Invest. 1995 Jun;95(6):2565-72
references.pmid: 7539455
references.citation: Nephrol Dial Transplant. 2003 Dec;18(12):2542-50
references.pmid: 14605276
references.citation: Clin Sci (Lond). 1997 Apr;92(4):367-74
references.pmid: 9176035
references.citation: Cell Mol Life Sci. 2006 Dec;63(23):2838-46
references.pmid: 17075694
references.citation: Nephrol Dial Transplant. 2002 Nov;17(11):1999-2002
references.pmid: 12401860
references.citation: J Clin Endocrinol Metab. 2003 Sep;88(9):4221-6
references.pmid: 12970290
references.citation: Eur J Endocrinol. 2008 May;158(5):631-41
references.pmid: 18426821
references.citation: Nitric Oxide. 1997 Feb;1(1):65-73
references.pmid: 9701046
references.citation: Nephrol Dial Transplant. 2006 Dec;21(12):3409-14
references.pmid: 16998217
references.citation: Diabetes. 2008 Jan;57(1):172-80
references.pmid: 17909098
references.citation: J Biol Chem. 2007 Jan 12;282(2):879-87
references.pmid: 17082183
references.citation: Nephrol Dial Transplant. 2009 Jun;24(6):1884-8
references.pmid: 19131352
references.citation: J Cardiovasc Pharmacol. 1999 Apr;33(4):652-8
references.pmid: 10218738
references.citation: Endocrinology. 2008 Jun;149(6):3148-57
references.pmid: 18292189
references.citation: Am J Physiol Renal Physiol. 2009 Jan;296(1):F78-86
references.pmid: 18945823
references.citation: Nephrol Dial Transplant. 1996 Dec;11(12):2449-52
references.pmid: 9017621
references.citation: Biochim Biophys Acta. 1985 Dec 9;822(3-4):355-74
references.pmid: 2933076
references.citation: Clin Sci (Lond). 2008 Dec;115(12):361-9
references.pmid: 18498242
references.citation: Life Sci. 2005 May 27;77(2):149-59
references.pmid: 15862600
references.citation: J Biol Chem. 2002 Apr 5;277(14):11780-7
references.pmid: 11781318
references.citation: Hypertension. 2008 Nov;52(5):903-9
references.pmid: 18824664
references.citation: Vasc Med. 2005 Jul;10 Suppl 1:S73-81
references.pmid: 16444872
references.citation: Amino Acids. 2006 May;30(3):225-32
references.pmid: 16680555
references.citation: Vasc Med. 2005 Jul;10 Suppl 1:S35-43
references.pmid: 16444867
references.citation: Ren Fail. 2007;29(8):1031-8
references.pmid: 18067052
references.citation: J Biol Chem. 2003 Dec 12;278(50):50000-9
references.pmid: 14523001
references.citation: Circulation. 2003 Sep 30;108(13):1575-80
references.pmid: 12963642
references.citation: Circ Res. 2003 Feb 7;92(2):226-33
references.pmid: 12574151
references.citation: Am J Nephrol. 2009;30(3):209-17
references.pmid: 19420905
references.citation: J Cardiovasc Pharmacol. 1992;20 Suppl 12:S60-2
references.pmid: 1282988
references.citation: Am J Physiol Renal Physiol. 2001 Jun;280(6):F989-95
references.pmid: 11352838
references.citation: Am J Physiol Renal Physiol. 2008 Jan;294(1):F30-7
references.pmid: 17942569
references.citation: Clin Nutr. 2003 Feb;22(1):23-30
references.pmid: 12553946
references.citation: Hypertens Res. 2005 Feb;28(2):181-9
references.pmid: 16025746
references.citation: J Am Soc Nephrol. 2005 Aug;16(8):2254-6
references.pmid: 15987745
references.citation: Proc Natl Acad Sci U S A. 1990 Nov;87(21):8607-11
references.pmid: 1978327
references.citation: Kidney Int. 2006 Jul;70(1):26-33
references.pmid: 16723985
references.citation: Clin Sci (Lond). 1997 Dec;93(6):519-25
references.pmid: 9497788
references.citation: Circulation. 2003 Apr 15;107(14):1891-5
references.pmid: 12681993
references.citation: Lancet. 2001 Dec 22-29;358(9299):2113-7
references.pmid: 11784625
references.citation: Free Radic Biol Med. 2002 Jan 15;32(2):122-31
references.pmid: 11796200
references.citation: Biochim Biophys Acta. 1984 Sep 3;779(3):255-69
references.pmid: 6383473
references.citation: Int J Biochem Cell Biol. 2008;40(5):920-8
references.pmid: 18069040
references.citation: Pflugers Arch. 2000 Mar;439(5):524-31
references.pmid: 10764210
references.citation: Kidney Int. 2002 Nov;62(5):1700-6
references.pmid: 12371970
references.citation: Lancet. 1992 Mar 7;339(8793):572-5
references.pmid: 1347093
references.citation: J Nutr. 2004 Oct;134(10 Suppl):2880S-2887S; discussion 2895S
references.pmid: 15465805
references.citation: J Physiol Pharmacol. 2007 Jun;58(2):191-206
references.pmid: 17622691
references.citation: J Virol. 1992 Jul;66(7):4377-81
references.pmid: 1318407
references.citation: J Hepatol. 1998 Dec;29(6):923-32
references.pmid: 9875639
references.citation: J Nutr. 2004 Oct;134(10 Suppl):2791S-2795S; discussion 2796S-2797S
references.pmid: 15465786
references.citation: Kidney Int. 2003 Oct;64(4):1381-8
references.pmid: 12969157
references.citation: Science. 2005 Sep 2;309(5740):1573-6
references.pmid: 16081698
references.citation: J Biol Chem. 1996 May 17;271(20):11838-43
references.pmid: 8662668
references.citation: Cardiovasc Res. 1999 Aug 15;43(3):542-8
references.pmid: 10690326
references.citation: J Vasc Res. 2007;44(5):391-402
references.pmid: 17551258
references.citation: Circulation. 2001 Feb 27;103(8):1121-7
references.pmid: 11222476