title: The effect of elevated homocysteine levels on adrenergic vasoconstriction of human resistance arteries: the role of the endothelium and reactive oxygen species.
abstract: OBJECTIVE
  This study investigated the effect of elevated homocysteine levels on adrenergic contraction of human resistance arteries and tested the hypothesis that homocysteine-induced generation of reactive oxygen species contributes to vascular reactivity changes.
  
  
  METHODS
  Small (<200 microm) subcutaneous arteries were cannulated and pressurized in an arteriograph chamber that allowed the measurement of lumen diameter. Two arteries from the same patient were obtained; one was perfused and superfused (intraluminal pressure = 50 mm Hg) with physiologic saline solution (control, n = 6), and the other was perfused and superfused with physiologic saline solution plus 200 micromol/L homocysteine (HC, n = 6); the reactivity to adrenergic stimulation was assessed. Another group of arteries was incubated in 200 micromol/L homocysteine plus 1200 U/mL superoxide dismutase and 120 U/mL catalase (HC + SC, n = 6), and the reactivity to norepinephrine was determined. The vasoreactivity of homocysteine was further assessed in intact (n = 6) and denuded (n = 6) arteries that were precontracted with an intermediate concentration of norepinephrine and homocysteine (20-200 micromol/L) added to the bath while the lumen diameter was continuously recorded.
  
  
  RESULTS
  Sensitivity to norepinephrine was diminished in HC arteries, which increased the median effective concentration (EC(50)) from 0.24 +/- 0.06 micromol/L in control arteries to 0.65 +/- 0.10 micromol/L in HC arteries (P <.01). Homocysteine also caused concentration-dependent vasodilation of arteries contracted with an intermediate concentration of norepinephrine that was greater in intact than denuded arteries, with the half-maximum responses occurring at 61 +/- 6 micromol/L (intact) and 90 +/- 11 micromol/L (denuded; P <.05). There was no significant difference in sodium nitroprusside sensitivity between control and homocysteine arteries (EC(50) = 61 +/- 3 nmol/L vs 50 +/- 19 nmol/L; P >.05) or in sensitivity to acetylcholine (EC(50) = 19 +/- 7 nmol/L vs 12 +/- 3 nmol/L; P >.05). Arteries in the presence of superoxide dismutase and catalase had similarly impaired reactivity to norepinephrine as did homocysteine arteries (EC(50), 0.58 +/- 0.15 micromol/L; P >.05 vs HC, P <.01 vs control).
  
  
  CONCLUSIONS
  An elevated homocysteine level in vitro diminishes adrenergic contraction, with a differential endothelial versus smooth muscle influence that appears unrelated to the generation of reactive oxygen species.
authors.affiliation: Departments of Obstetrics/Gynecology, Pharmacology, and Neurology University of Vermont College of Medicine, Burlington, VT 05405, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Cipolla
authors.forename: W K
authors.initials: WK
authors.lastname: Williamson
authors.forename: M L
authors.initials: ML
authors.lastname: Nehler
authors.forename: L M
authors.initials: LM
authors.lastname: Taylor
authors.forename: J M
authors.initials: JM
authors.lastname: Porter
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000368:Aged; D001158:Arteries / Q000187:drug effects*; D002374:Catalase / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology; D006710:Homocysteine / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009599:Nitroprusside / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D011312:Pressure; D017382:Reactive Oxygen Species / Q000502:physiology*; D012867:Skin / Q000098:blood supply; D012965:Sodium Chloride; D013482:Superoxide Dismutase / Q000494:pharmacology; D014655:Vascular Resistance / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000316:Adrenergic alpha-Agonists; D016166:Free Radical Scavengers; D017382:Reactive Oxygen Species; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D006710:Homocysteine; D009599:Nitroprusside; D012965:Sodium Chloride; D002374:Catalase; D013482:Superoxide Dismutase; D000109:Acetylcholine; D009638:Norepinephrine