INHIBITORS OF ANGIOTENSIN-CONVERTING ENZYME DECREASE EARLY ATHEROSCLEROSIS IN HYPERLIPIDEMIC HAMSTERS - FOSINOPRIL REDUCES PLASMA-CHOLESTEROL AND CAPTOPRIL INHIBITS MACROPHAGE FOAM CELL ACCUMULATION INDEPENDENTLY OF BLOOD-PRESSURE AND PLASMA-LIPIDS

The effect of two angiotensin converting enzyme (ACE) inhibitors on the development of atherosclerosis was determined in hyperlipidemic hamsters. Preliminary studies indicated that only fosinopril (50 mg/kg) temporarily decreased mean arterial pressure, while after chronic dosing fosinopril and captopril (50 mg/kg) were ineffective. The same dose of fosinopril and captopril inhibited the angiotensin I presser response, indicating these agents suppressed ACE activity in vivo. In the 3 week atherosclerosis experiment, all hamsters were fed chow supplemented with 0.05% cholesterol and 10% coconut oil. Control hamsters were compared with those receiving either 50 mg/kg per day of fosinopril or 50 mg/kg per day of captopril. After 3 weeks, fosinopril reduced plasma total cholesterol, low density lipoprotein (LDL) plus very low density lipoprotein cholesterol and total triglycerides by 17%, 27% and 45%, respec tively. Captopril only reduced high density lipoprotein cholesterol by 20%. Neither fosinopril or captopril altered blood pressure at 3 weeks. Atherosclerosis was quantified from en face preparations of the lesion-prone aortic arch that were stained with oil red O (for cholesteryl ester and triglycerides). In control hamsters, oil red O labeled numerous subendothelial macrophage-foam cells located along the inner curvature of the aortic arch. Compared with controls, fosinopril reduced the number of intimal macrophage-foam cells/mm(2), foam cell size and the fatty streak area by 85%, 38% and 90%, respectively. Captopril decreased these parameters by 44%, 16% and 53%. Thus captopril decreased early atherosclerosis without affecting plasma LDL cholesterol or blood pressure, which suggested that inhibiting ACE (or kininase II) directly impeded the accumulation and formation of macrophage-foam cells. Fosinopril probably further suppressed early atherosclerosis by lowering plasma LDL cholesterol.