title: Endothelial dysfunction induced by hyperhomocyst(e)inemia: role of asymmetric dimethylarginine.
abstract: BACKGROUND
  Endothelial function is impaired by hyperhomocyst(e)inemia. We have previously shown that homocyst(e)ine (Hcy) inhibits NO production by cultured endothelial cells by causing the accumulation of asymmetric dimethylarginine (ADMA). The present study was designed to determine if the same mechanism is operative in humans.
  
  
  RESULTS
  We studied 9 patients with documented peripheral arterial disease (6 men; 3 women; age, 64+/-3 years), 9 age-matched individuals at risk for atherosclerosis (older adults; 9 men; age, 65+/-1 years), and 5 young control subjects (younger adults; 5 men; age, 31+/-1 years) without evidence of or risk factors for atherosclerosis. Endothelial function was measured by flow-mediated vasodilatation of the brachial artery before and 4 hours after a methionine-loading test (100 mg/kg body weight, administered orally). In addition, blood was drawn at both time points for measurements of Hcy and ADMA concentrations. Plasma Hcy increased after the methionine-loading test in each group (all, P<0.001). Plasma ADMA levels rose in all subjects, from 0.9+/-0.2 to 1.6+/-0.2 micromol/L in younger adults, from 1.5+/-0.2 to 3.0+/-0.4 micromol/L in older adults, and from 1.8+/-0.1 to 3.9+/-0.3 micromol/L in peripheral arterial disease patients (all, P<0.001). Flow-mediated vasodilatation was reduced from 13+/-2% to 10+/-1% in younger adults, from 6+/-1% to 5+/-1% in older adults, and from 7+/-1% to 3+/-1% in peripheral arterial disease patients (all, P<0.001). Furthermore, we found positive correlations between plasma Hcy and ADMA concentrations (P=0.03, r=0.450), as well as ADMA and flow-mediated vasodilatation (P=0.002, r=0.623).
  
  
  CONCLUSIONS
  Our results suggest that experimental hyperhomocyst(e)inemia leads to accumulation of the endogenous NO synthase inhibitor ADMA, accompanied by varying degrees of endothelial dysfunction according to the preexisting state of cardiovascular health.
authors.affiliation: University Clinic of Innsbruck, Austria.
authors.forename: Markus C
authors.initials: MC
authors.lastname: Stühlinger
authors.forename: Roberta K
authors.initials: RK
authors.lastname: Oka
authors.forename: Eric E
authors.initials: EE
authors.lastname: Graf
authors.forename: Isabella
authors.initials: I
authors.lastname: Schmölzer
authors.forename: Barbara M
authors.initials: BM
authors.lastname: Upson
authors.forename: Om
authors.initials: O
authors.lastname: Kapoor
authors.forename: Andrzej
authors.initials: A
authors.lastname: Szuba
authors.forename: M Rene
authors.initials: MR
authors.lastname: Malinow
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Wascher
authors.forename: Otmar
authors.initials: O
authors.lastname: Pachinger
authors.forename: John P
authors.initials: JP
authors.lastname: Cooke
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism*; D001161:Arteriosclerosis / Q000503:physiopathology; D001916:Brachial Artery / Q000187:drug effects / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D005260:Female; D006710:Homocysteine / Q000097:blood; D006711:Homocystine / Q000097:blood; D006801:Humans; D020138:Hyperhomocysteinemia / Q000097:blood / Q000503:physiopathology*; D008297:Male; D008715:Methionine / Q000494:pharmacology; D008875:Middle Aged; D016491:Peripheral Vascular Diseases / Q000503:physiopathology; D012039:Regional Blood Flow / Q000187:drug effects; D012044:Regression Analysis; D014664:Vasodilation / Q000187:drug effects
chemical_list: D006710:Homocysteine; D006711:Homocystine; C018524:N,N-dimethylarginine; D001120:Arginine; D008715:Methionine