Effect of FR145237, a novel ACAT inhibitor, on atherogenesis in cholesterol-fed and WHHL rabbits. Evidence for a direct effect on the arterial wall.
The hypocholesterolemic and antiatherosclerotic activities of FR145237, a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, were evaluated in cholesterol-fed and Watanabe heritable hyperlipidemic (WHHL) rabbits. In the first experiment, rabbits were fed a high cholesterol (1% cholesterol) diet for 2 weeks and further fed a high cholesterol diet containing FR145237 for 8 weeks. FR145237 (0.1, 0.32 and 1.0 mg/kg) dose-dependently lowered the plasma total cholestrol levels by 80%, 96% and 97%, respectively. and reduced aortic atherosclerosis by 44%, 90% and 90%, respectively. To clarify a direct effect of FR145237 at the aortic wall, a second experiment was performed. Rabbits were fed a high-cholesterol diet for 8 weeks to establish aortic atherosclerosis and then fed a normal diet with or without FR145237 for 8 weeks. Cholesterol content in the aorta and the liver was significantly reduced in the FR145237 group (10 mg/kg) by 50% and 43%, respectively, though plasma total cholesterol level did not differ from that in the control group. In the WHHL rabbits, FR145237 (10 mg/kg) did not affect plasma cholesterol level but significantly reduced the atherosclerotic lesion in the coronary arteries by 61%. These results suggest that FR145237 potently lowers the plasma cholesterol level in hypercholesterolemia induced by dietary cholesterol but not that by LDL receptor deficiency, and that FR145237 has a direct antiatherosclerotic activity on the arterial wall independent of its hypocholesterolemic activity.
Department of Pharmacology, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
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Matsuo
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Ito
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Konto
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Aketa
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Tomoi
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Shimomura
D000818:Animals; D001011:Aorta / Q000737:chemistry / Q000187:drug effects*; D001161:Arteriosclerosis / Q000188:drug therapy* / Q000378:metabolism; D001572:Benzofurans / Q000494:pharmacology*; D002352:Carrier Proteins; D002784:Cholesterol / Q000032:analysis* / Q000097:blood; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D004036:Diet, Atherogenic; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006937:Hypercholesterolemia / Q000188:drug therapy / Q000378:metabolism; D006949:Hyperlipidemias / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL / Q000378:metabolism; D008099:Liver / Q000737:chemistry / Q000187:drug effects; D008297:Male; D015394:Molecular Structure; D010671:Phenylurea Compounds / Q000494:pharmacology*; D016601:RNA-Binding Proteins; D011817:Rabbits; D018110:Receptors, Lipoprotein / Q000172:deficiency; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*
D001572:Benzofurans; D002352:Carrier Proteins; D002791:Cholesterol, Dietary; D004791:Enzyme Inhibitors; C097564:FR 145237; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D010671:Phenylurea Compounds; D016601:RNA-Binding Proteins; D018110:Receptors, Lipoprotein; C031616:high density lipoprotein receptors; C075197:high density lipoprotein binding protein; D002784:Cholesterol; D002785:Sterol O-Acyltransferase