Cholesterol lowering action of HOE 402 in the normolipidemic and hypercholesterolemic Golden Syrian hamster

Abstract

The potent hypolipidemic activity of HOE 402 (4-amino-2-(4,4-dimethyl-2-oxo- l-imidazolidinyl)pyrimidine-5- N-(trifluoromethylphenyl)carboxamide monohydrochloride), which was previously demonstrated in rat and rabbit, was investigated in noncholesterol and cholesterol fed male hamsters. In normolipidemic hamsters fed a low cholesterol chow diet containing 0.10% or 0.15% HOE 402 for 3 weeks, the plasma total cholesterol level fell by 13% and 20% respectively, but no effect on hepatic total cholesterol content was detected. Hepatic sterol synthesis was increased 3-fold in hamsters fed 0.15% HOE 402. In hamsters fed a chow diet containing 0.25% cholesterol for 3 weeks, the plasma cholesterol level increased to 226 mg/dl (compared to 123 mg/dl in their chow fed controls) and the liver cholesterol content was 26.2 mg/g compared to 2.3 mg/g in the control group. However, 0.15% HOE 402 led to a 48% reduction and 0.20% HOE 402 to a 80% reduction, in total hepatic cholesterol concentration. There was a 43% fall in plasma cholesterol level being observed with the higher HOE 402 dose. Using the dual isotope plasma ratio method, no inhibition of intestinal cholesterol absorption by HOE 402 was found, either in the noncholesterol fed or in the cholesterol fed hamsters. Cholesterol feeding diminished the whole LDL animal clearance to 393 ± 17 μl/h per 100 g animal (control 666 ± 81 μl/h per 100 g). When treated with 0.20% HOE 402, the whole animal LDL clearance rate was enhanced 2.3-fold to 824 ± 66 μl/h per 100 g. In the hamsters fed 0.25% cholesterol alone whole liver LDL receptor activity was suppressed to 63 ± 5%, compared to that in the untreated controls (100%). The addition of 0.20% HOE 402 to the cholesterol enriched diet not only reversed this suppression, but resulted in a marked stimulation of liver receptor activity to 165 ± 15% (whole body LDL receptor activity 141 ± 10%). These results indicate that HOE 402 exerts its lipid lowering effect by a more direct activation on hepatic LDL receptor activity rather than by an indirect intestinal effect on cholesterol absorption.