title: Improvement of vascular endothelial function using the oral endothelin receptor antagonist bosentan in patients with systemic sclerosis.
abstract: OBJECTIVE
  Increased endothelin activity may play a role in the pathogenesis of vascular injury, a primary feature of systemic sclerosis (SSc; scleroderma). Our goal was to test the hypothesis that treatment with the oral endothelin receptor antagonist bosentan might improve vascular endothelial function in SSc patients.
  
  
  METHODS
  A 4-week, prospective, parallel-group study compared 12 SSc patients who did not receive bosentan treatment with 12 patients who did receive treatment (125 mg/day) for pulmonary hypertension and/or digital ulcers. There were no differences in demographic and clinical characteristics or medications between the 2 groups. Baseline endothelial dysfunction was documented by decreased brachial artery ultrasound-derived flow-mediated dilation (FMD%; <5.5). Pulse wave analysis, venous occlusion plethysmography, and measurement of serum vascular markers were performed in parallel.
  
  
  RESULTS
  FMD%, the main end point, increased significantly from a mean +/- SD of 3.1 +/- 1.3% to 8.4 +/- 2.6% after 4 weeks of bosentan treatment (P < 0.001, compared with a change from 2.4 +/- 1.6% to 2.4 +/- 2.2% in control patients). Arterial blood pressure, endothelium-independent vascular function, augmentation index, peripheral flow reserve, as well as circulating intercellular adhesion molecule 1, E-selectin, vascular endothelial growth factor, and endothelin 1 were not significantly affected by bosentan treatment. In patients continuously treated for 4 months, during which the dosage of bosentan remained at 125 mg/day (n = 5) or increased to 250 mg/day (n = 5), the 4-week results remained unchanged.
  
  
  CONCLUSIONS
  Small doses of bosentan improve endothelial function without affecting hemodynamic parameters or endothelial activation-related processes, thus supporting a direct, reversible effect of endothelin in SSc-associated vascular injury. A long-term, controlled trial to examine the potentially global clinical benefit of endothelin receptor blockade in patients with early SSc may be warranted.
authors.affiliation: First Department of Propedeutic and Internal Medicine, Laikon Hospital, Athens University Medical School, Athens, Greece. psfikakis@med.uoa.gr
authors.forename: P P
authors.initials: PP
authors.lastname: Sfikakis
authors.forename: C
authors.initials: C
authors.lastname: Papamichael
authors.forename: K S
authors.initials: KS
authors.lastname: Stamatelopoulos
authors.forename: D
authors.initials: D
authors.lastname: Tousoulis
authors.forename: K G
authors.initials: KG
authors.lastname: Fragiadaki
authors.forename: P
authors.initials: P
authors.lastname: Katsichti
authors.forename: C
authors.initials: C
authors.lastname: Stefanadis
authors.forename: M
authors.initials: M
authors.lastname: Mavrikakis
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000077300:Bosentan; D001916:Brachial Artery / Q000000981:diagnostic imaging / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D019040:E-Selectin / Q000097:blood; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology*; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000503:physiopathology; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012039:Regional Blood Flow / Q000502:physiology; D012595:Scleroderma, Systemic / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology*; D013449:Sulfonamides / Q000008:administration & dosage / Q000627:therapeutic use*; D014463:Ultrasonography; D042461:Vascular Endothelial Growth Factor A / Q000097:blood; D014664:Vasodilation / Q000502:physiology
chemical_list: D019040:E-Selectin; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D013449:Sulfonamides; D042461:Vascular Endothelial Growth Factor A; D018799:Intercellular Adhesion Molecule-1; D000077300:Bosentan