title: Selective endothelin A receptor antagonism with sitaxentan reduces neointimal lesion size in a mouse model of intraluminal injury.
abstract: OBJECTIVE
  Endothelin (ET) receptor antagonism reduces neointimal lesion formation in animal models. This investigation addressed the hypothesis that the selective ETA receptor antagonist sitaxentan would be more effective than mixed ETA / B receptor antagonism at inhibiting neointimal proliferation in a mouse model of intraluminal injury.
  
  
  METHODS
  Antagonism of ETA receptors by sitaxentan (1-100 nM) was assessed in femoral arteries isolated from adult, male C57Bl6 mice using isometric wire myography. Neointimal lesion development was induced by intraluminal injury in mice receiving sitaxentan (ETA antagonist; 15 mg·kg(-1) ·day(-1) ), A192621 (ETB antagonist; 30 mg·kg(-1) ·day(-1) ), the combination of both antagonists or vehicle. Treatment began 1 week before, and continued for 28 days after, surgery. Femoral arteries were then harvested for analysis of lesion size and composition.
  
  
  RESULTS
  Sitaxentan produced a selective, concentration-dependent parallel rightward shift of ET-1-mediated contraction in isolated femoral arteries. Sitaxentan reduced neointimal lesion size, whereas ETB and combined ETA / B receptor antagonism did not. Macrophage and α-smooth muscle actin content were unaltered by ET receptor antagonism but sitaxentan reduced the amount of collagen in lesions.
  
  
  CONCLUSIONS
  These results suggest that ETA receptor antagonism would be more effective than combined ETA /ETB receptor antagonism at reducing neointimal lesion formation.
authors.affiliation: Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.
authors.forename: Karolina M
authors.initials: KM
authors.lastname: Duthie
authors.affiliation: Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.
authors.forename: Patrick W F
authors.initials: PW
authors.lastname: Hadoke
authors.affiliation: Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Kirkby
authors.affiliation: Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.
authors.forename: Eileen
authors.initials: E
authors.lastname: Miller
authors.affiliation: Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.
authors.forename: Jessica R
authors.initials: JR
authors.lastname: Ivy
authors.affiliation: Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.
authors.forename: John F
authors.initials: JF
authors.lastname: McShane
authors.affiliation: Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.
authors.forename: Win Gel
authors.initials: WG
authors.lastname: Lim
authors.affiliation: Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Webb
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D065130:Endothelin A Receptor Antagonists / Q000494:pharmacology*; D065131:Endothelin B Receptor Antagonists / Q000494:pharmacology*; D005263:Femoral Artery / Q000187:drug effects* / Q000293:injuries / Q000473:pathology; D007555:Isoxazoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009119:Muscle Contraction / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009213:Myography; D058426:Neointima / Q000473:pathology*; D011759:Pyrrolidines / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*
chemical_list: C120508:A 192621; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D007555:Isoxazoles; D011759:Pyrrolidines; D013876:Thiophenes; C106276:sitaxsentan