title: Selective endothelin ET(B) receptor antagonist improves left ventricular function but exaggerates degeneration of cardiomyocytes in J2N-k hamsters.
abstract: BACKGROUND
  Endothelin-1 (ET-1) receptor antagonist is expected to improve the prognosis of patients with heart failure, but the role of the ET(B) receptor in cardiac function and structure is complicated. In the present study the NADPH diaphorase activity and ET-1 content in the failing heart treated with ET(A) or ET(B) receptor antagonist were evaluated in a model of dilated cardiomyopathy.
  
  
  RESULTS
  Selective ET(A) receptor antagonist, ABT-627 (10 mg/kg per day), or selective ET(B) antagonist, A-192621 (30 mg/kg per day), was given to 22-week-old J2N-k cardiomyopathic hamsters for 8 weeks. The effects of ABT-627 and A-192621 on cardiac function, left ventricular (LV) histology, ET-1 content and NADPH diaphorase activity in the LV were evaluated. Treatment with ABT-627, but not A-192621, significantly decreased ET-1 content and NADPH diaphorase activity. Although the improvement of LV function was modest, ABT-627 prevented tissue damage in J2N-k hamsters. In contrast, A-192621 worsened the degeneration of cardiomyocytes despite improving hemodynamic parameters.
  
  
  CONCLUSIONS
  Selective ET(A) antagonist, but not ET(B) antagonist, reduced the ET-1 content as well as the NADPH diaphorase activity, and preserved the fine structure of LV myocardium in cardiomyopathic hamsters. Long-term blockade of ET(B) receptor might worsen the degeneration of cardiomyocytes through the ET-1/ET(A) system even if LV function could be improved.
authors.affiliation: Department of Pharmacology, Osaka University of Pharmaceutical Sciences, Osaka, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nishida
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Hayashi
authors.forename: Miyuki
authors.initials: M
authors.lastname: Ieshima
authors.forename: Keiko
authors.initials: K
authors.lastname: Eshiro
authors.forename: Kenji
authors.initials: K
authors.lastname: Akiyoshi
authors.forename: Masanori
authors.initials: M
authors.lastname: Takaoka
authors.forename: Minoru
authors.initials: M
authors.lastname: Yoshiyama
authors.forename: Junichi
authors.initials: J
authors.lastname: Yoshikawa
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Mori
authors.forename: Yoshikatsu
authors.initials: Y
authors.lastname: Okada
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kitaura
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Matsumura
mesh_terms: D000818:Animals; D000077868:Atrasentan; D002311:Cardiomyopathy, Dilated / Q000188:drug therapy* / Q000473:pathology; D006224:Cricetinae; D004195:Disease Models, Animal; D065131:Endothelin B Receptor Antagonists; D006321:Heart / Q000187:drug effects; D006334:Heart Function Tests; D008297:Male; D032342:Muscle Cells / Q000187:drug effects / Q000473:pathology*; D009206:Myocardium / Q000473:pathology*; D011759:Pyrrolidines / Q000627:therapeutic use*; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology*
chemical_list: C120508:A 192621; D065131:Endothelin B Receptor Antagonists; D011759:Pyrrolidines; D000077868:Atrasentan