Selective Endothelin ET_B Receptor Antagonist Improves Left Ventricular Function but Exaggerates Degeneration of Cardiomyocytes in J2N-k Hamsters

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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. Methods and 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. (Circ J 2005; 69: 107 - 113)