CARDIOMYOCYTE APOPTOSIS AND CARDIAC ANGIOTENSIN-CONVERTING ENZYME IN SPONTANEOUSLY HYPERTENSIVE RATS

Increased apoptosis has been reported in the heart of rats with sponta neous hypertension and cardiac hypertrophy. This study was designed to investigate the relationship between apoptosis and hypertrophy in car diomyocytes from the left ventricle of spontaneously hypertensive rats (SHR). In addition, we evaluated whether the development of cardiomyo cyte apoptosis is related to blood pressure or to the activity of the local angiotensin-converting enzyme (ACE) in SHR. The study was perfor med in 16-week-old SHR, 30-week-old untreated SHR, and 30-week-old SHR treated with quinapril (10 mg . kg(-1) . d(-1)) during 14 weeks befor e they were killed. Cardiomyocyte apoptosis was assessed by direct imm unoperoxidase detection of digoxigenin-labeled 3'-hydroxyl ends of DNA . Nuclear polyploidization measured by DNA flow cytometry was used to assess cardiomyocyte hypertrophy. Compared with 16-week-old normotensi ve Wistar-Kyoto rats, 16-week-old SHR exhibited increased blood pressu re (P<.001), increased rate of tetraploidy (P<.05), and similar levels of ACE activity and apoptosis. Compared with 30-week-old Wistar-Kyoto rats, 30-week-old SHR showed increased blood pressure (P<.001), incre ased ACE activity (P<.05), increased rate of tetraploidy (P<.01), and increased apoptosis (P<.01). Untreated 30-week-old SHR exhibited simil ar values of blood pressure and tetraploidy and higher ACE activity (P <.05) and apoptosis (P<.001) than 16-week-old SHR. A direct correlatio n (P<.01) was found between ACE activity and the apoptotic index in un treated 30-week-old SHR. The long-term administration of quinapril was associated with the normalization of ACE activity and apoptosis in tr eated SHR. These results suggest that the timing and mechanisms respon sible for apoptosis and hypertrophy of cardiomyocytes are different in SHR. Whereas hypertrophy seems to be an earlier alteration that devel ops in parallel with hypertension, apoptosis develops later in associa tion with overactivity of the local ACE. Our data suggest that cell de ath dysregulation may be a novel target for antihypertensive agents th at interfere with the renin-angiotensin system in hypertension.