UP-REGULATION OF CARDIAC ANGIOTENSIN-II AT(1) RECEPTORS IN CONGENITAL CARDIOMYOPATHIC HAMSTERS

Angiotensin II (Ang II) is a growth factor that stimulates protein synthesis and induces cellular hypertrophy in cardiac myocytes. To gain insight into the role of Ang II in cardiac hypertrophy, we examined the expression and subtype distribution of Ang II receptors in the ventricles of embryonic and of 25- to 350-day-old inbred control and cardiomyopathic (CHF 146) hamsters. Studies were also performed with heterozygous (cardiomyopathic X control) animals. Compared with the control hamsters, cardiomyopathic hamsters presented decreased body weights and increased ratios of ventricular weight to body weight in every adult group studied. Typical histological lesions appeared in the left ventricle of cardiomyopathic animals around 70 to 75 days, and their severity increased with time. Radioligand binding studies with cardiac ventricular membranes indicated that iodinated [Sar(1),Ile(8)]Ang II (sarile) binds to a homogeneous population of sites in membranes derived from adult normal and cardiomyopathic animals. Competition curves using specific receptor subtype antagonists revealed that I-125-sarile binding sites were exclusively of the AT(1) subtype in both groups of animals. Importantly, the density of AT(1) receptors was found to be significantly increased (90% augmentation at 70 to 75 days) in the ventricles of cardiomyopathic hamsters. This augmented expression was observed in all adult groups and was already present at 25 days, when no histological lesions were visible. The affinity of the receptor for losartan did not vary significantly between adult normal and cardiomyopathic animals (mean K-d, 19.6 and 16.7 nmol/L, respectively). No significant differences were observed in the total expression of Ang II receptors and in the proportion of AT(1) and AT(2) subtypes between the two groups of embryonic hearts. Heterozygous animals expressed an intermediate level of AT(1) receptor binding activity in their ventricles. Together, these results suggest that Ang II acting through the AT(1) receptor may play a critical role in the development and/or maintenance of cardiac hypertrophy.