Inhibitory effect of monatepil maleate on acyl-CoA:cholesterol acyltransferase activity in the liver of cholesterol-fed Japanese monkeys.
We have previously demonstrated that monatepil maleate, AJ-2615, a new calcium antagonist endowed with alpha1-adrenoceptor blocking property, has antiatherosclerotic and plasma lipid-lowering effects in Japanese monkeys fed on a cholesterol-rich diet. To clarify the mechanisms on plasma lipid-lowering action, we investigated the effect of monatepil maleate in these monkeys on hepatic acyl-CoA:cholesterol acyltransferase (ACAT) activity. Both ACAT activity and esterified cholesterol content in the livers of monkeys fed on a cholesterol-rich diet for 6 months significantly increased about 7- and 16-fold, respectively, as compared with those in monkeys fed on a standard diet. Monatepil maleate (30 mg/kg/day for 6 months, orally) inhibited the increases of ACAT activity and esterified cholesterol content by 51% and 71%, respectively. In in vitro experiments, monatepil 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 revealed that monatepil maleate was a noncompetitive type inhibitor of ACAT. Hepatic ACAT activity was significantly correlated to hepatic esterified cholesterol content (r = 0.775, P < .0001), to plasma very low density lipoprotein (VLDL) content (r = 0.765, P < .0001) and to plasma total cholesterol content (r = 0.573, P < .005) in the monkeys. These results suggest that ACAT-inhibiting effect of monatepil maleate plays an important role in the reduction of hyperlipidemia.
Sumiya
T
T
Department of Pharmacology I, Dainippon Pharmaceutical Co., Ltd., Suita, Osaka, Japan.
Ikeno
A
A
Kato
H
H
Fujitani
B
B
Masuda
Y
Y
Hosoki
K
K
Miyazaki
M
M
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002784:Cholesterol / Q000097:blood; D002791:Cholesterol, Dietary / Q000494:pharmacology*; D003988:Dibenzothiepins / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008251:Macaca; D008297:Male; D010879:Piperazines / Q000494:pharmacology; D011506:Proteins / Q000378:metabolism; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*
D002121:Calcium Channel Blockers; D002791:Cholesterol, Dietary; D003988:Dibenzothiepins; D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010879:Piperazines; D011506:Proteins; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D002785:Sterol O-Acyltransferase; C067818:monatepil