ANTIATHEROSCLEROTIC EFFECT OF E5324, AN INHIBITOR OF ACYL-COA-CHOLESTEROL ACYLTRANSFERASE, IN WATANABE HERITABLE HYPERLIPIDEMIC RABBITS

E5324, 4-phenyl-1H-imidazol-1-yl)propoxy]-6-methylphenyl] a novel and potent inhibitor of acyl-CoA:cholesterol acyltransferase (ACAT), was e valuated for its anti-atherosclerotic and lipid-lowering effects in Wa tanabe heritable hyperlipidemic (WHHL) rabbits. At 3 months of age, 40 male WHHL rabbits were divided into 4 groups. The rabbits were fed a standard rabbit chow (control group), or standard rabbit chow containi ng E5324 (0.1% or 0.02%) or 1% probucol for 16 weeks. Even the high do se of E5324 did not lower the plasma total cholesterol levels througho ut the experiment. Probucol slightly reduced the plasma cholesterol le vels, and showed anti-atherosclerotic activity, i.e., reductions of at herosclerotic plaque formation and cholesterol content in the aorta. A lthough E5324 did not lower plasma cholesterol, atherosclerotic plaque formation in the aortic arch and thoracic aorta was reduced (by about 34% and 41%, respectively, at the high dose; P < 0.05). Cholesterol c ontent in the aortic arch and thoracic aorta was also reduced (by abou t 59% and 62% at the high dose, respectively) compared with the contro l. These results suggest that E5324 acts directly on the arterial wall through ACAT inhibition, and prevents the progression of atherosclero sis in WHHL rabbits.