INDUCTION OF ANGIOTENSIN-CONVERTING ENZYME AND ANGIOTENSIN-II RECEPTORS IN THE ATHEROSCLEROTIC AORTA OF HIGH-CHOLESTEROL FED CYNOMOLGUS MONKEYS

Antiatherogenic effects of imidapril and involvement of renin angioten sin system were examined in experimental atherosclerosis induced by fe eding a high-cholesterol diet to Cynomolgus monkeys. Eighteen male mon keys were divided into three groups and placed under (1) normal diet ( normal group), (2) high-cholesterol diet (control group), (3) high-cho lesterol diet with imidapril (20 mg/kg body wt/day, orally) treatment (imidapril group). At the end of the experiment, the normal group show ed no apparent atherosclerosis in their aorta evaluated by oil red-O s taining, while the control group exhibited marked atherosclerotic invo lvement of the intimal surface of the aorta (58.4+/-9.3%, P<0.01). Imi dapril reduced systolic blood pressure and atherosclerotic involvement (24.1+/-5.5%, P<0.05). Total cholesterol content of the descending th oracic aorta was also significantly reduced in the imidapril group. In the atherosclerotic vessels, angiotensin converting enzyme (ACE) acti vity evaluated by quantitative in vitro autoradiography was significan tly increased in the intimal lesion. Further evaluation revealed angio tensin II (Ang II) type I (AT(1)) receptor density was significantly i ncreased in the medial lesion and type II (AT(2)) receptor density in the adventitia. When the progression of atherosclerosis was impeded by imidapril treatment, the ACE activity level as well as the AT(1) and AT(2) receptor density remained at normal. Expression of mRNA for fibr onectin, TGF-beta 1, types I and III collagen was studied by Northern blot analysis. No significant differences in types I and III collagen mRNA levels were found between the control and imidapril group. On the other hand, mRNA expression for fibronectin and TGF-beta 1 were much lower in the imidapril group than in the control group. These results suggest that increased production of Ang II and activated receptors ma y be involved in atherosclerotic process in this model and also antiat herogenic effect of imidapril may be derived from reduction of local A ng II production as well as its hypotensive action. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.