PERINDOPRIL INHIBITS BOTH THE DEVELOPMENT OF ATHEROSCLEROSIS IN THE CHOLESTEROL-FED RABBIT AND LIPOPROTEIN BINDING TO SMOOTH-MUSCLE CELLS IN CULTURE

The aim of the study was to examine the effect of low doses of perindopril, approximating those used therapeutically and sub-therapeutically in human hypertensives, on the development of atherosclerosis in the cholesterol-fed rabbit. The right carotid artery of 12 week old rabbits was balloon de-endothelialized to induce the formation of a myointimal thickening. After 14 weeks rabbits were placed into 6 groups, 6 rabbits per group. Groups I, II and III were fed a 1% cholesterol diet for the following 6 week experimental period, while Groups IV, V and VI received a normolipemic diet. In addition, Groups II and V rabbits received in their drinking water 0.3 mg/kg per day perindopril, and Groups III and VI 0.01 mg/kg per day. At the end of 6 weeks' treatment, the mean arterial pressure (MAP) in Groups II and V decreased by about 12%, while that in Groups III and VI decreased by 13%. Plasma cholesterol levels of rabbits on a normolipemic diet (Groups IV, V, VI) averaged 1.3 mmol/l while those on a cholesterol-enriched diet (Groups I, II, III) averaged 10.5 mmol/l. Plasma perindoprilat concentrations and percentage of plasma angiotensin converting enzyme (ACE) inhibition in Groups II and V averaged 14 ng/ml and 92.1% respectively, while in Groups III and VI they were 5.7 ng/ml and 80.5%, respectively. The percentage luminal surface area of the thoracic aorta covered by lipid-filled plaques (as observed by en face staining with Oil-Red-O) averaged 26.3% in Group I, 4.7% in Group II and 20.0% in Group III. No lesions developed in Groups IV, V and VI. Microscopic examination of the right (manipulated) carotid arteries of Group I rabbits revealed lesions of large, lipid-filled cells radially oriented, overlying the pre-formed myointimal thickening. Both doses of perindopril in the cholesterol-fed rabbits (Groups II and III) decreased the amount of lipid-filled cells which were oriented circumferentially. More extracellular matrix was present in the lesions of Groups II and III than of Group I. No lesions were observed in the right carotid arteries of Groups IV, V and VI (normal diet) or in the unmanipulated left carotid arteries of all 6 groups. The sizes of the neointima plus lesion in Groups I, II and III were, however, not significantly different, being 42.4%, 48.5% and 46.9% of the cross-sectional area of the artery wall. Culture studies revealed that perindoprilat decreased specific binding of I-125-labelled beta-very low density lipoprotein to passaged smooth muscle cells (SMC) from the rabbit aorta in a dose-dependent manner. Perindoprilat had no effect on SMC proliferation, but did increase collagen synthesis. These results indicate that perindopril at low doses has a beneficial effect in decreasing the severity of atherosclerosis in the cholesterol-fed rabbit. The effect is not related to MAP, or to any effect on plasma cholesterol level. Instead, perindopril appears to have a direct effect on the biology of the cells of the artery wall, in particular increasing collagen synthesis by the SMC and decreasing their binding and uptake of atherogenic lipoprotein.