INHIBITORY EFFECT OF MONATEPIL MALEATE ON ACYL-COA-CHOLESTEROL ACYLTRANSFERASE ACTIVITY IN THE LIVER OF CHOLESTEROL-FED JAPANESE MONKEYS

e have previously demonstrated that monatepil maleate, AJ-2615, a new calcium antagonist endowed with alpha-adrenoceptor blocking property, has antiatherosclerotic and plasma Iipid-lowering effects in Japanese monkeys fed on a cholesterolrich diet. To clarify the mechanisms on pl asma lipid-lowering action, we investigated the effect of monatepil ma leate in these monkeys on hepatic acyl-CoA:cholesterol acyltransferase (ACAT) activity. Both ACAT activity and esterified cholesterol conten t in the livers of monkeys fed on a cholesterol-rich diet for 6 months significantly increased about 7- and 16-fold, respectively, as compar ed with those in monkeys fed on a standard diet. Monatepil maleate (30 mg/kg/day for 6 months, orally inhibited the increases of ACAT activi ty and esterified cholesterol content by 51% and 71%, respectively. In in vitro experiments, monatepiI maleate inhibited ACAT activity in a concentration-dependent manner, whereas it did not affect 3-hydroxy-3- methylglutaryl-CoA (HMG-CoA) reductase activity. A kinetic analysis re vealed that monatepil maleate was a noncompetitive type inhibitor of A CAT. Hepatic ACAT activity was significantly correlated to hepatic est erified cholesterol content (r = 0.775, P < .0001), to plasma very low density lipoprotein (VLDL) content (r = 0.765, P < .0001) and to plas ma total cholesterol content (r = 0.573, P < .005) in the monkeys. The se results suggest that ACAT-inhibiting effect of monatepil maleate pl ays an important role in the reduction of hyperlipidemia. (C) 1997 Ame rican Journal of Hypertension, Ltd.