Effects of monatepil maleate, a new Ca2+ channel antagonist with alpha(1)-adrenoceptor antagonistic activity, on cholesterol absorption and catabolism in high cholesterol diet-fed rabbits

The mechanism of the prophylactic effect against hyperlipidemia by monatepi l maleate was investigated in animal models. Monatepil maleate is an antihy pertensive agent with Ca2+-channel antagonistic, alpha(1)-adrenergic recept or-blocking, and lipid peroxidation inhibitory activity. In high cholestero l diet-fed rabbits, monatepil maleate (30 mg/kg, p.o., once daily for 9 wee ks) showed a prophylactic effect against increases in total cholesterol and beta-lipoprotein. Monatepil maleate significantly accelerated the clearanc e of radioactivity from the blood after intravenous injection of low-densit y lipoprotein (LDL) labeled with [1 alpha,2 alpha (n)-H-3]cholesterol, incr easing biliary excretion of [H-3]-bile acids without modifying bile acid co mposition. Furthermore, monatepil maleate tended to inhibit the absorption of orally administered [1 alpha,2 alpha (n)-H-3]cholesterol from the gastro intestinal tract in these rabbits. In Watanabe heritable hyperlipidemic (WH HL) 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 incr ease 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 metabol ism through two mechanisms: enhancement of clearance of plasma LDL, which m ay be mediated by up-regulation of hepatic LDL receptors, and acceleration of conversion of free cholesterol to bile acids in the liver.