title: Role of oxidant stress in endothelial dysfunction produced by experimental hyperhomocyst(e)inemia in humans.
abstract: BACKGROUND
  Moderate elevations in plasma homocyst(e)ine concentrations are associated with atherosclerosis and hypertension. We tested the hypothesis that experimental perturbation of homocysteine levels produces resistance and conduit vessel endothelial dysfunction and that this occurs through increased oxidant stress.
  
  
  RESULTS
  Oral administration of L-methionine (100 mg/kg) was used to induce moderate hyperhomocyst(e)inemia ( approximately 25 micromol/L) in healthy human subjects. Endothelial function of forearm resistance vessels was assessed by use of forearm vasodilatation to brachial artery administration of the endothelium-dependent dilator acetylcholine. Conduit vessel endothelial function was assessed with flow-mediated dilatation of the brachial artery. Forearm resistance vessel dilatation to acetylcholine was significantly impaired 7 hours after methionine (methionine, 477+/-82%; placebo, 673+/-110%; P=0.016). Methionine did not alter vasodilatation to nitroprusside and verapamil. Flow-mediated dilatation was significantly impaired 8 hours after methionine loading (0.3+/-2.7%) compared with placebo (8. 2+/-1.6%, P=0.01). Oral administration of the antioxidant ascorbic acid (2 g) prevented methionine-induced endothelial dysfunction in both conduit and resistance vessels (P=0.03).
  
  
  CONCLUSIONS
  Experimentally increasing plasma homocyst(e)ine concentrations by methionine loading rapidly impairs both conduit and resistance vessel endothelial function in healthy humans. Endothelial dysfunction in conduit and resistance vessels may underlie the reported associations between homocysteine and atherosclerosis and hypertension. Increased oxidant stress appears to play a pathophysiological role in the deleterious endothelial effects of homocysteine.
authors.affiliation: Departments of Pediatrics, University of Iowa College of Medicine, Iowa City, Iowa 52242, USA.
authors.forename: P M
authors.initials: PM
authors.lastname: Kanani
authors.forename: C A
authors.initials: CA
authors.lastname: Sinkey
authors.forename: R L
authors.initials: RL
authors.lastname: Browning
authors.forename: M
authors.initials: M
authors.lastname: Allaman
authors.forename: H R
authors.initials: HR
authors.lastname: Knapp
authors.forename: W G
authors.initials: WG
authors.lastname: Haynes
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000328:Adult; D000975:Antioxidants / Q000494:pharmacology; D001205:Ascorbic Acid / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000503:physiopathology*; D005260:Female; D006710:Homocysteine / Q000097:blood; D006801:Humans; D020138:Hyperhomocysteinemia / Q000139:chemically induced / Q000503:physiopathology*; D008297:Male; D008715:Methionine / Q000008:administration & dosage; D009599:Nitroprusside / Q000494:pharmacology; D018384:Oxidative Stress / Q000502:physiology*; D014664:Vasodilation / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D014665:Vasodilator Agents; D006710:Homocysteine; D009599:Nitroprusside; D008715:Methionine; D014700:Verapamil; D000109:Acetylcholine; D001205:Ascorbic Acid