Association of plasma asymmetrical dimethylarginine (ADMA) with elevated vascular superoxide production and endothelial nitric oxide synthase uncoupling: implications for endothelial function in human atherosclerosis

Eur Heart J. 2009 May;30(9):1142-50. doi: 10.1093/eurheartj/ehp061. Epub 2009 Mar 18.


Background: Asymmetrical dimethylarginine (ADMA), an endogenous inhibitor of endothelial nitric oxide synthase (eNOS), is considered to be a risk factor for atherosclerosis. However, the mechanisms relating ADMA with vascular function have been evaluated in vitro and in animal models, but its effect in human vasculature is unclear.

Aims: We examined the impact of serum ADMA on endothelial nitric oxide (NO) bioavailability and vascular superoxide radical (O2-) production in patients with advanced atherosclerosis.

Methods and results: Paired samples of saphenous veins (SVs) and internal mammary arteries (IMAs) were collected from 201 patients undergoing coronary bypass surgery, and serum ADMA was measured pre-operatively. The vasomotor responses of SV segments to acetylcholine (ACh) and bradykinin (Bk) were evaluated ex vivo. Vascular O2- was measured in paired SV and IMA by lucigenin-enhanced chemiluminescence. The l-NAME-inhibitable as well as the NADPH-stimulated vascular O2- generation was also determined by chemiluminescence. High serum ADMA levels were associated with decreased vasorelaxation of SV to ACh (P < 0.05) and Bk (P < 0.05). Similarly, high serum ADMA was associated with higher total O2- production in both SVs and IMAs (P < 0.05) and greater L-NAME-inhibitable vascular O2- (P < 0.05). However, serum ADMA was not associated with NADPH-stimulated vascular O2-. In multivariable linear regression, serum ADMA was independently associated with vascular O2- in both SVs [beta (SE): 0.987 (0.412), P = 0.019] and IMAs [beta (SE): 1.905 (0.541), P = 0.001]. Asymmetrical dimethylarginine was also independently associated with maximum vasorelaxation in response to both ACh [beta (SE): 14.252 (3.976), P = 0.001] and Bk [beta (SE): 9.564 (3.762), P = 0.013].

Conclusion: This is the first study that demonstrates an association between ADMA and important measures of vascular function, such as vascular O2- production and NO bioavailability directly in human vessels. Although serum ADMA has no effect on NADPH-stimulated superoxide in intact vessels, it is associated with greater eNOS uncoupling in the human vascular endothelium of patients with coronary artery disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Arginine / analogs & derivatives*
  • Arginine / blood
  • Atherosclerosis / metabolism*
  • Atherosclerosis / physiopathology
  • Coronary Artery Bypass
  • Coronary Artery Disease / metabolism*
  • Coronary Artery Disease / physiopathology
  • Endothelium, Vascular / metabolism
  • Endothelium, Vascular / physiology
  • Female
  • Humans
  • Male
  • Nitric Oxide Synthase Type III / metabolism*
  • Oxidative Stress
  • Saphenous Vein / physiology
  • Superoxides / analysis
  • Superoxides / metabolism*
  • Vasodilation / drug effects
  • Vasodilation / physiology


  • Superoxides
  • N,N-dimethylarginine
  • Arginine
  • Nitric Oxide Synthase Type III