title: Association of plasma asymmetrical dimethylarginine (ADMA) with elevated vascular superoxide production and endothelial nitric oxide synthase uncoupling: implications for endothelial function in human atherosclerosis.
abstract: 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.
  
  
  OBJECTIVE
  We examined the impact of serum ADMA on endothelial nitric oxide (NO) bioavailability and vascular superoxide radical (O2-) production in patients with advanced atherosclerosis.
  
  
  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].
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, UK.
authors.forename: Charalambos
authors.initials: C
authors.lastname: Antoniades
authors.forename: Cheerag
authors.initials: C
authors.lastname: Shirodaria
authors.forename: Paul
authors.initials: P
authors.lastname: Leeson
authors.forename: Alexios
authors.initials: A
authors.lastname: Antonopoulos
authors.forename: Nicholas
authors.initials: N
authors.lastname: Warrick
authors.forename: Tim
authors.initials: T
authors.lastname: Van-Assche
authors.forename: Colin
authors.initials: C
authors.lastname: Cunnington
authors.forename: Dimitris
authors.initials: D
authors.lastname: Tousoulis
authors.forename: Ravi
authors.initials: R
authors.lastname: Pillai
authors.forename: Chandi
authors.initials: C
authors.lastname: Ratnatunga
authors.forename: Christodoulos
authors.initials: C
authors.lastname: Stefanadis
authors.forename: Keith M
authors.initials: KM
authors.lastname: Channon
mesh_terms: D000368:Aged; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood; D050197:Atherosclerosis / Q000378:metabolism* / Q000503:physiopathology; D001026:Coronary Artery Bypass; D003324:Coronary Artery Disease / Q000378:metabolism* / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000378:metabolism / Q000502:physiology; D005260:Female; D006801:Humans; D008297:Male; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D018384:Oxidative Stress; D012501:Saphenous Vein / Q000502:physiology; D013481:Superoxides / Q000032:analysis / Q000378:metabolism*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
chemical_list: D013481:Superoxides; C018524:N,N-dimethylarginine; D001120:Arginine; D052250:Nitric Oxide Synthase Type III