Selective endothelin ET(B) receptor antagonist improves left ventricular function but exaggerates degeneration of cardiomyocytes in J2N-k hamsters.
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.
Nishida
Masahiro
M
Department of Pharmacology, Osaka University of Pharmaceutical Sciences, Osaka, Japan.
Hayashi
Tetsuya
T
Ieshima
Miyuki
M
Eshiro
Keiko
K
Akiyoshi
Kenji
K
Takaoka
Masanori
M
Yoshiyama
Minoru
M
Yoshikawa
Junichi
J
Mori
Tatsuhiko
T
Okada
Yoshikatsu
Y
Kitaura
Yasushi
Y
Matsumura
Yasuo
Y
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*
C120508:A 192621; D065131:Endothelin B Receptor Antagonists; D011759:Pyrrolidines; D000077868:Atrasentan