title: CGP 43371 paradoxically inhibits development of rabbit atherosclerotic lesions while inducing extra-arterial foam cell formation.
abstract: Ansamycins are hypolipidemic compounds which, when administered to various animal species, dramatically lower high density lipoprotein (HDL) cholesterol levels, in addition to reducing the levels of other lipoprotein classes. The current study tested one of these ansamycins (CGP 43371) for its hypolipidemic and anti-atherosclerotic activity in cholesterol-fed rabbits. Rabbits were fed a 0.25% cholesterol-enriched diet with or without admixed CGP 43371, equivalent to 30 mg/kg per day for 16 weeks. Compared with control rabbits, CGP 43371 treatment lowered total cholesterol levels (46%, P<0.05) and lipoprotein cholesterol levels (HDL, 58%; VLDL, 49% [both P<0.05]; LDL, 28% [not significant]). Despite the dramatic lowering of HDL cholesterol levels, aortic atherosclerosis, assessed by grossly visible sudanophilia, was significantly inhibited versus controls (total aorta=38%; aortic arch=32%; thoracic aorta=60%). Of particular note in CGP 43371-treated rabbits was a striking splenomegaly, which correlated with the presence of massive accumulations of macrophage foam cells in the splenic red pulp. We speculate that CGP 43371 inhibits the development of atheroselerotic lesions in rabbits by both a hypolipidemic mechanism, and by a mechanism(s) in which macrophage foam cells accumulate in the spleen.
authors.affiliation: Novartis Institute for Biomedical Research, LSB 2195, Novartis Pharmaceuticals Corp., 556 Morris Ave., Summit, NJ 07901, USA. david.feldman@pharma.novartis.com
authors.forename: D L
authors.initials: DL
authors.lastname: Feldman
authors.forename: W K
authors.initials: WK
authors.lastname: Sawyer
authors.forename: M R
authors.initials: MR
authors.lastname: Jeune
authors.forename: T C
authors.initials: TC
authors.lastname: Mogelesky
authors.forename: J
authors.initials: J
authors.lastname: Von Linden-Reed
authors.forename: M
authors.initials: M
authors.lastname: Forney Prescott
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000187:drug effects / Q000473:pathology; D001161:Arteriosclerosis / Q000097:blood / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D002455:Cell Division / Q000187:drug effects; D002784:Cholesterol / Q000097:blood; D002791:Cholesterol, Dietary / Q000633:toxicity; D005487:Foam Cells / Q000187:drug effects / Q000473:pathology*; D008074:Lipoproteins / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000473:pathology*; D008297:Male; D010537:Peritoneum / Q000187:drug effects / Q000473:pathology*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D012293:Rifampin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D013154:Spleen / Q000187:drug effects / Q000473:pathology*
chemical_list: D000924:Anticholesteremic Agents; D002791:Cholesterol, Dietary; D008074:Lipoproteins; C080602:CGP 43371; D002784:Cholesterol; D012293:Rifampin