Akihisa Ikeno (1), Toshiki Sumiya (1), Hisao Minato (1), Buichi Fujitani
(1), Yoshinobu Masuda (1), Kanoo Hosoki (1), Masuo Kurono (2) and Masashi
Yasuba (3)
(1) Department of Pharmacology I, Discovery Research Laboratories, (2)
Department of Physicochemical Analysis, Discovery Research Laboratories,
(3) Department of Toxicology and Teratology, Developmental Research Laboratories,
Dainippon Pharmaceutical Co., Ltd., 33-94 Enoki, Suita, Osaka 564-0053,
Japan
Abstract: The mechanism of the prophylactic effect against hyperlipidemia
by monatepil maleate was investigated in animal models. Monatepil maleate
is an antihypertensive agent with Ca2+-channel antagonistic,
alpha1-adrenergic receptor-blocking, and lipid peroxidation inhibitory
activity. In high cholesterol diet-fed rabbits, monatepil maleate (30 mg/kg,
p.o., once daily for 9 weeks) showed a prophylactic effect against increases
in total cholesterol and beta-lipoprotein. Monatepil maleate significantly
accelerated the clearance of radioactivity from the blood after intravenous
injection of low-density lipoprotein (LDL) labeled with [1alpha,2alpha (n)-3H]cholesterol,
increasing biliary excretion of [3H]-bile acids without modifying
bile acid composition. Furthermore, monatepil maleate tended to inhibit
the absorption of orally administered [1alpha,2alpha (n)-3H]cholesterol
from the gastrointestinal tract in these rabbits. In Watanabe heritable
hyperlipidemic (WHHL) rabbits, an animal model of hepatic LDL receptor deficiency,
monatepil maleate (30 mg/kg, p.o., once daily for 6 months) did not suppress
the increase in plasma lipids. These results suggest that the plasma lipid
lowering effect of monatepil maleate requires the presence of hepatic LDL
receptors. It is also suggested that monatepil maleate improves plasma lipid
metabolism through two mechanisms: enhancement of clearance of plasma LDL,
which may be mediated by up-regulation of hepatic LDL receptors, and acceleration
of conversion of free cholesterol to bile acids in the liver.
Keywords: Monatepil maleate, Cholesterol absorption, Cholesterol catabolism,
Acylcoenzyme A:cholesterol acyltransferase (ACAT)