Selective endothelin ETB 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 ETB 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 ETA or ETB receptor antagonist were evaluated in a model of dilated cardiomyopathy. Methods and Results: Selective ETA receptor antagonist, ABT-627 (10 mg/kg per day), or selective ETB 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 ETA antagonist, but not ETB 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 ETB receptor might worsen the degeneration of cardiomyocytes through the ET-1/ETA system even if LV function could be improved.