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Selective endothelin A receptor antagonism with sitaxentan reduces neointimal lesion size in a mouse model of intraluminal injury
Author(s) -
Duthie Karolina M,
Hadoke Patrick W F,
Kirkby Nicholas S,
Miller Eileen,
Ivy Jessica R,
McShane John F,
Lim Win Gel,
Webb David J
Publication year - 2015
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13086
Subject(s) - antagonism , lesion , antagonist , endothelin receptor , medicine , receptor , receptor antagonist , endothelin receptor antagonist , endocrinology , pharmacology , pathology
Background and Purpose Endothelin ( ET ) receptor antagonism reduces neointimal lesion formation in animal models. This investigation addressed the hypothesis that the selective ET A receptor antagonist sitaxentan would be more effective than mixed ET A / B receptor antagonism at inhibiting neointimal proliferation in a mouse model of intraluminal injury. Experimental Approach Antagonism of ET A receptors by sitaxentan (1–100 nM) was assessed in femoral arteries isolated from adult, male C 57Bl6 mice using isometric wire myography. Neointimal lesion development was induced by intraluminal injury in mice receiving sitaxentan ( ET A antagonist; 15 mg·kg −1 ·day −1 ), A 192621 ( ET B 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. Key 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 ET B and combined ET A / 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 and Implications These results suggest that ET A receptor antagonism would be more effective than combined ET A / ET B receptor antagonism at reducing neointimal lesion formation.