Vol. 282, Issue 2, 882-890, 1997

Possible Mechanism of Action of AE0047, a Calcium Antagonist, on Triglyceride Metabolism

Kazutaka Hayashi, Maki Gohda, Sumio Matzno, Yoshiji Kubo, Hideaki Kido, Takeshi Yamauchi and Norifumi Nakamura

Pharmacology Laboratories, Central Research Laboratories, The Green Cross Corporation, 2-25-1, Shodai-Ohtani, Hirakata, Osaka 573, Japan

We evaluated the effect of AE0047, a dihydropyridine-type calcium antagonist, on the plasma lipid levels of obese Zucker rats. In rats treated orally with 3 to 10 mg/kg/day AE0047 for 7 days, plasma triglyceride (TG) and TG-rich lipoprotein levels dose-dependently decreased, whereas those of high-density lipoprotein cholesterol increased. Total cholesterol and low-density lipoprotein levels did not change. To elucidate the mechanism by which AE0047 decreases plasma TG levels, we examined the effect of AE0047 on the synthesis and secretion of TG-rich lipoproteins in human intestinal cell line Caco-2, as well as on the association and degradation of very low density lipoprotein (VLDL) in human hepatoblastoma cells HepG2. When Caco-2 cells were grown on a membrane filter and ¹⁴C-oleic acid was added to the apical side, 10⁵ and 10⁶ M AE0047 inhibited basolateral secretion of ¹⁴C-TG. AE0047 also suppressed the basolateral secretion of apolipoprotein B. In HepG2 cells, AE0047 increased the cellular uptake of ¹²⁵I-VLDL. These results suggested that AE0047 decreased plasma TG level by the inhibition of intestinal chylomicron secretion and the enhancement of hepatic uptake of VLDL. AE0047 may be beneficial for the treatment of hypertensive patients with hypertriglyceridemia to reduce the risk factors of coronary heart disease.