INHIBITION OF ANGIOTENSIN-CONVERTING ENZYME AND ATTENUATION OF MYOCARDIAL FIBROSIS BY LISINOPRIL IN RATS RECEIVING ANGIOTENSIN-II

High-density angiotensin-converting enzyme (ACE) binding is present in heart valve leaflets and the fibrous tissue that appears in the rat m yocardium after either chronic administration of angiotensin II (AngII ) or after myocardial infarction. This suggests that connective tissue ACE is independent of circulating AngII and that ACE may be an integr al component of normal and pathologic tissue repair. To address this p ossibility the present study was undertaken. We sought to determine wh ether the ACE inhibitor lisinopril would attenuate fibrous tissue ACE binding and fibrous tissue formation in the myocardium of rats receivi ng AngII. Three experimental groups were examined: untreated, age-matc hed controls; rats receiving subcutaneous AngII (150 ng/min) by minipu mp for 2 weeks; and rats receiving AngII plus oral lisinopril (20 mg/ kg/day) for 2 weeks. Cardiac ACE binding density was localized and qua ntified by in vitro autoradiography with [I-125]-labeled 351A, a tyros yl derivative of lisinopril, while fibrosis was identified by light mi croscopy in serial sections stained with picrosirius red. Hematoxylin and eosin and anti-fibronectin antibody were used to identify cardiac myocyte necrosis. Immunohistochemical labeling with alpha-smooth muscl e actin was used to identify myofibroblasts. We found that (1) ACE bin ding was low in the myocardium and high in intramyocardial coronary ar teries of the normal heart; (2) myocardial fibrosis, including perivas cular fibrosis of intramural vessels and microscopic scars, which appe ared in both ventricles, was evident offer 2 weeks of AngII; (3) high- density ACE binding was anatomically coincident with sites of fibrosis ; (4) ACE binding throughout the myocardium and at fibrous tissue site s was attenuated by lisinopril; (5) perivascular fibrosis and scarring were markedly attenuated by lisinopril despite evidence of cardiac my ocyte necrosis; and (6) endothelial cells, macrophages, and myofibrobl asts are responsible for ACE production at sites of fibrosis. Thus inh ibition of connective tissue ACE by lisinopril attenuates fibrous tiss ue formation associated with AngII administration.