CGP 43371 paradoxically inhibits development of rabbit atherosclerotic lesions while inducing extra-arterial foam cell formation

Ansamycins are hypolipidemic compounds which, when administered to various animal species, dramatically lower high density lipoprotein (HDL) cholester ol levels, in addition to reducing the levels of other lipoprotein classes. The current study tested one of these ansamycins (CGP 43371) for its hypol ipidemic and anti-atherosclerotic activity in cholesterol-fed rabbits. Rabb its were fed a 0.25% cholesterol-enriched diet with or without admired CGP 43371, equivalent to 30 mg/kg per day for 16 weeks. Compared with control r abbits, 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 cholester ol levels, aortic atherosclerosis, assessed by grossly visible sudanophilia . was significantly inhibited versus controls (total aorta = 38%; aortic ar ch = 32%; thoracic aorta = 60%). Of particular note in CGP 43371-treated ra bbits was a striking splenomegaly, which correlated with the presence of ma ssive accumulations of macrophage foam cells in the splenic red pulp. We sp eculate that CGP 43371 inhibits the development of atheroselerotic lesions in rabbits by both a hypolipidemic mechanism, and by a mechanism(s) in whic h macrophage foam cells accumulate in the spleen. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.