(Circulation. 1999;99:1141-1146.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Endogenous Nitric Oxide Synthase Inhibitor
A Novel Marker of Atherosclerosis
From the Department of Internal Medicine III and the Cardiovascular Research Institute, Kurume University School of Medicine (H. Miyazaki, H. Matsuoka, M.U., S.U., S.O., T.I.), Kurume, Japan, and the Section of Vascular Medicine, Falk Cardiovascular Research Center, Stanford University School of Medicine (J.P.C.), Stanford, Calif.
Correspondence to Hidehiro Matsuoka, MD, PhD, The Cardiovascular Research Institute, Department of Internal Medicine III, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011 Japan. E-mail matsuoka{at}med.kurume-u.ac.jp
Background—Exposure to risk factors such as hypertension or hypercholesterolemia decreases the bioavailability of endothelium-derived nitric oxide (NO) and impairs endothelium-dependent vasodilation. Recently, a circulating endogenous NO synthase inhibitor, asymmetric dimethylarginine (ADMA), has been detected in human plasma. The purpose of this study was to examine the relationship between plasma ADMA and atherosclerosis in humans.
Methods and Results—Subjects (n=116; age, 52±1 years;
male:female ratio, 100:16) underwent a complete history and physical
examination, determination of serum chemistries and ADMA levels, and
duplex scanning of the carotid arteries. These individuals had no
symptoms of coronary or peripheral artery disease
and were taking no medications. Univariate and
multivariate analyses revealed that plasma
levels of ADMA were positively correlated with age
(P<0.0001), mean arterial pressure
(P<0.0001), and 
glucose (an index of glucose
tolerance) (P=0.0006). Most intriguingly, stepwise
regression analysis revealed that plasma ADMA levels were
significantly correlated to the intima-media thickness of the carotid
artery (as measured by high-resolution ultrasonography).
Conclusions—This study reveals that plasma ADMA levels are positively correlated with risk factors for atherosclerosis. Furthermore, plasma ADMA level is significantly correlated with carotid intima-media thickness. Our results suggest that this endogenous antagonist of NO synthase may be a marker of atherosclerosis.
Key Words: aging • risk factors • diabetes mellitus • dimethylarginine • hypertension • smoking
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Z. A. Massy, C. Fumeron, D. Borderie, P. Tuppin, T. Nguyen-Khoa, M.-O. Benoit, C. Jacquot, C. Buisson, T. B. Drueke, O. G. Ekindjian, et al. Increased Plasma S-Nitrosothiol Concentrations Predict Cardiovascular Outcomes among Patients with End-Stage Renal Disease: A Prospective Study J. Am. Soc. Nephrol., February 1, 2004; 15(2): 470 - 476. [Abstract] [Full Text] [PDF]
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J. T. Kielstein, B. Impraim, S. Simmel, S. M. Bode-Boger, D. Tsikas, J. C. Frolich, M. M. Hoeper, H. Haller, and D. Fliser Cardiovascular Effects of Systemic Nitric Oxide Synthase Inhibition With Asymmetrical Dimethylarginine in Humans Circulation, January 20, 2004; 109(2): 172 - 177. [Abstract] [Full Text] [PDF]
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H. Dayoub, V. Achan, S. Adimoolam, J. Jacobi, M. C. Stuehlinger, B.-y. Wang, P. S. Tsao, M. Kimoto, P. Vallance, A. J. Patterson, et al. Dimethylarginine Dimethylaminohydrolase Regulates Nitric Oxide Synthesis: Genetic and Physiological Evidence Circulation, December 16, 2003; 108(24): 3042 - 3047. [Abstract] [Full Text] [PDF]
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R. J. Nijveldt, T. Teerlink, C. van Guldener, H. A. Prins, A. A. van Lambalgen, C. D. A. Stehouwer, J. A. Rauwerda, and P. A. M. van Leeuwen Handling of asymmetrical dimethylarginine and symmetrical dimethylarginine by the rat kidney under basal conditions and during endotoxaemia Nephrol. Dial. Transplant., December 1, 2003; 18(12): 2542 - 2550. [Abstract] [Full Text] [PDF]
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T.-M. Lu, Y.-A. Ding, S.-J. Lin, W.-S. Lee, and H.-C. Tai Plasma levels of asymmetrical dimethylarginine and adverse cardiovascular events after percutaneous coronary intervention Eur. Heart J., November 1, 2003; 24(21): 1912 - 1919. [Abstract] [Full Text] [PDF]
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D. P. Holden, J. E. Cartwright, S. S. Nussey, and G. S. J. Whitley Estrogen Stimulates Dimethylarginine Dimethylaminohydrolase Activity and the Metabolism of Asymmetric Dimethylarginine Circulation, September 30, 2003; 108(13): 1575 - 1580. [Abstract] [Full Text] [PDF]
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M. C. Stuhlinger, R. K. Oka, E. E. Graf, I. Schmolzer, B. M. Upson, O. Kapoor, A. Szuba, M. R. Malinow, T. C. Wascher, O. Pachinger, et al. Endothelial Dysfunction Induced by Hyperhomocyst(e)inemia: Role of Asymmetric Dimethylarginine Circulation, August 26, 2003; 108(8): 933 - 938. [Abstract] [Full Text] [PDF]
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R. H Boger Asymmetric dimethylarginine (ADMA) modulates endothelial function - therapeutic implications Vascular Medicine, August 1, 2003; 8(3): 149 - 151. [PDF]
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T. Janatuinen, J. Laakso, R. Laaksonen, R. Vesalainen, P. Nuutila, T. Lehtimaki, O. T Raitakari, and J. Knuuti Plasma asymmetric dimethylarginine modifies the effect of pravastatin on myocardial blood flow in young adults Vascular Medicine, August 1, 2003; 8(3): 185 - 189. [Abstract] [PDF]
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V. Achan, M. Broadhead, M. Malaki, G. Whitley, J. Leiper, R. MacAllister, and P. Vallance Asymmetric Dimethylarginine Causes Hypertension and Cardiac Dysfunction in Humans and Is Actively Metabolized by Dimethylarginine Dimethylaminohydrolase Arterioscler Thromb Vasc Biol, August 1, 2003; 23(8): 1455 - 1459. [Abstract] [Full Text] [PDF]
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J. T. Kielstein, S. M. Bode-Boger, H. Haller, and D. Fliser Functional changes in the ageing kidney: is there a role for asymmetric dimethylarginine? Nephrol. Dial. Transplant., July 1, 2003; 18(7): 1245 - 1248. [Full Text] [PDF]
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S. M Bode-Boger, J. Muke, A. Surdacki, G. Brabant, R. H Boger, and J. C Frolich Oral L-arginine improves endothelial function in healthy individuals older than 70 years Vascular Medicine, May 1, 2003; 8(2): 77 - 81. [Abstract] [PDF]
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D Tousoulis, G J Davies, C Tentolouris, T Crake, G Goumas, C Stefanadis, and P Toutouzas Effects of L-arginine on flow mediated dilatation induced by atrial pacing in diseased epicardial coronary arteries Heart, May 1, 2003; 89(5): 531 - 534. [Abstract] [Full Text] [PDF]
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J. T. Kielstein, S. M. Bode-Boger, J. C. Frolich, E. Ritz, H. Haller, and D. Fliser Asymmetric Dimethylarginine, Blood Pressure, and Renal Perfusion in Elderly Subjects Circulation, April 15, 2003; 107(14): 1891 - 1895. [Abstract] [Full Text] [PDF]
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D.C Felmeden, A.D Blann, and G.Y.H Lip Angiogenesis: basic pathophysiology and implications for disease Eur. Heart J., April 1, 2003; 24(7): 586 - 603. [Full Text] [PDF]
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M. Weis and J. P. Cooke Cardiac Allograft Vasculopathy and Dysregulation of the NO Synthase Pathway Arterioscler Thromb Vasc Biol, April 1, 2003; 23(4): 567 - 575. [Abstract] [Full Text] [PDF]
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S. Ueda, S. Kato, H. Matsuoka, M. Kimoto, S. Okuda, M. Morimatsu, and T. Imaizumi Regulation of Cytokine-Induced Nitric Oxide Synthesis by Asymmetric Dimethylarginine: Role of Dimethylarginine Dimethylaminohydrolase Circ. Res., February 7, 2003; 92(2): 226 - 233. [Abstract] [Full Text] [PDF]
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C. Hermenegildo, P. Medina, M. Peiro, G. Segarra, J. M. Vila, J. Ortega, and S. Lluch Plasma Concentration of Asymmetric Dimethylarginine, an Endogenous Inhibitor of Nitric Oxide Synthase, Is Elevated in Hyperthyroid Patients J. Clin. Endocrinol. Metab., December 1, 2002; 87(12): 5636 - 5640. [Abstract] [Full Text] [PDF]
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H. Paiva, J. Laakso, H. Laine, R. Laaksonen, J. Knuuti, and O. T. Raitakari Plasma asymmetric dimethylarginine and hyperemic myocardial blood flow in young subjects with borderline hypertension or familial hypercholesterolemia J. Am. Coll. Cardiol., October 2, 2002; 40(7): 1241 - 1247. [Abstract] [Full Text] [PDF]
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