EFFECT OF THE ACYL-COA-CHOLESTEROL ACYLTRANSFERASE INHIBITOR, E5324, ON EXPERIMENTAL ATHEROSCLEROSIS IN RABBITS

E5324, nyl-1H-imidazol-1-yl)propoxy]-6-methylphenyl]urea, a novel and orally absorbable acyl-CoA:cholesterol acyltransferase (ACAT) inhibito r, was evaluated for its antiatherosclerotic and antihyperlipidemic ef fects in cholesterol-fed hypercholesterolemic rabbits. When administer ed concurrently with a high-cholesterol (0.5% cholesterol) diet for 12 weeks, E5324 (0.0025%, 0.005% and 0.01% in diet) lowered plasma total cholesterol levels dose-dependently (by about 55%-87% at the end of t he experiment compared with the control) and also reduced atherosclero tic plaque formation (about 90% reduction at the highest dose; P < 0.0 1). In pre-established hypercholesterolemic rabbits, which had been pr e-fed a high-cholesterol diet for 8 weeks, E5324 administered in the s ame diet at a dose of 0.005%, 0.01% or 0.02% for 4 weeks significantly reduced plasma cholesterol levels dose-dependently. Cholesterol conte nt and ACAT activity in the aortic arch were also decreased (by about 72% and 58% at the highest dose, respectively) compared with the contr ol. Another ACAT inhibitor, Cl-976, had a similar action, but cholesty ramine and probucol (2% and 1% in diet, respectively) lacked anti-athe rosclerotic activity in this model. Furthermore, when pre-established hypercholesterolemic rabbits were fed normal rabbit chow diet with or without 0.02% E5324 for 4 weeks, changes in plasma cholesterol levels were similar in both E5324-treated and control groups. On the other ha nd, E5324 significantly reduced cholesterol content and ACAT activity in the aortic arch (by about 52% and 50%, respectively) compared with the control group. These results indicate that E5324 not only has hypo cholesterolemic activity, but also may have a direct effect on the art erial wall in experimental atherosclerosis.