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.