Jpn. J. Pharmacol. 78 (3), 303-312 (1998)

Effects of Monatepil Maleate, a New Ca2+ Channel Antagonist With alpha1-Adrenoceptor Antagonistic Activity, on Cholesterol Absorption and Catabolism in High Cholesterol Diet-Fed Rabbits

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)

Copyrightę The Japanese Pharmacological Society 1998

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