title: Increased alpha2-adrenergic constriction of isolated arterioles in diffuse scleroderma.
abstract: OBJECTIVE
  Vasospasm and ischemic organ injury are important in the pathogenesis of systemic sclerosis (SSc; scleroderma). The present study was performed to determine whether SSc arterioles have an intrinsic disturbance in vasoconstrictor activity.
  
  
  METHODS
  Skin biopsy samples were obtained from the upper arm of 11 patients with diffuse SSc (clinically uninvolved skin) and 8 age- and sex-matched control subjects. Dermal arterioles were dissected from the biopsy sample and mounted in a myograph for continuous monitoring of arteriolar diameter. The resting internal diameter of control and SSc arterioles was similar (mean +/- SEM 164+/-15 micro and 166+/-18micro, respectively).
  
  
  RESULTS
  Dermal arterioles displayed no spontaneous constrictor activity in the absence of stimulation. Vasoconstriction in response to KCI, a receptor-independent activator of smooth muscle, or to phenylephrine, a selective alpha1-adrenergic receptor (alpha1-AR) agonist, was similar in control and SSc arterioles. However, constrictor responses to UK 14,304, a selective alpha2-AR agonist, were increased in SSc compared with control arterioles (maximal constriction responses of 25+/-5% and 67+/-4% [mean +/- SEM] in control and SSc arterioles, respectively; P = 0.000014). Mechanical denudation of the endothelium did not alter reactivity to alpha2-AR activation, indicating that the enhanced constriction in SSc was not mediated by changes in endothelial dilator activity. Indeed, in arterioles constricted with phenylephrine, the endothelial stimuli acetylcholine or bradykinin evoked endothelium-dependent relaxation that was similar in control and SSc arterioles.
  
  
  CONCLUSIONS
  Vascular smooth muscle in SSc arterioles displayed a selective increase in alpha2-AR reactivity. The endothelial dilator function appeared normal. Altered activity of smooth muscle alpha2-ARs may contribute to the vasospastic activity that is a prominent feature of the SSc disease process.
authors.affiliation: Heart and Lung Institute, Ohio State University, Medical Research Facility, Columbus, OH 43210, USA.
authors.forename: N A
authors.initials: NA
authors.lastname: Flavahan
authors.forename: S
authors.initials: S
authors.lastname: Flavahan
authors.forename: Q
authors.initials: Q
authors.lastname: Liu
authors.forename: S
authors.initials: S
authors.lastname: Wu
authors.forename: W
authors.initials: W
authors.lastname: Tidmore
authors.forename: C M
authors.initials: CM
authors.lastname: Wiener
authors.forename: R J
authors.initials: RJ
authors.lastname: Spence
authors.forename: F M
authors.initials: FM
authors.lastname: Wigley
mesh_terms: D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000328:Adult; D001160:Arterioles / Q000502:physiology*; D000068438:Brimonidine Tartrate; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010656:Phenylephrine / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology*; D012595:Scleroderma, Systemic / Q000503:physiopathology*; D014661:Vasoconstriction / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists; D011810:Quinoxalines; D014665:Vasodilator Agents; D010656:Phenylephrine; D000068438:Brimonidine Tartrate