Antiatherosclerotic activity of inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase in cholesterol-fed rabbits: a biochemical and morphological evaluation.
Atherosclerotic lesion development was assessed in the thoracic aorta and chronically denuded iliac-femoral artery of hypercholesterolemic New Zealand White rabbits using inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase which have previously been shown to possess varying degrees of hepatoselectivity in rats. Atorvastatin, previously known as CI-981 (2.5 mg/kg), PD135022 (1.0 mg/kg), simvastatin (2.5 mg/kg), lovastatin (2.5 mg/kg), PD134965 (1.0 mg/kg), pravastatin (2.5 mg/kg) and BMY22089 (2.5 mg/kg) were added to a 0.5% cholesterol, 3% peanut, 3% coconut oil diet and fed for 8 weeks. Although reductions in plasma total cholesterol of 27% to 60%, VLDL-cholesterol of 31% to 71% and plasma total cholesterol exposure of 37% to 43% were obtained, no correlation between these parameters and vascular lipid content, lesion size or monocyte-macrophage content was noted. Iliac-femoral lipid content was unchanged; however, atorvastatin and simvastatin significantly reduced the cholesterol content of the thoracic aorta by 45%-62%. Atorvastatin and PD135022 reduced the size of the iliac-femoral lesion by 67% and monocyte-macrophage content by 72%. Simvastatin, lovastatin and PD134965 decreased the monocyte-macrophage content; however, lesion size was unchanged. Pravastatin and BMY22089 had no effect on lesion size or content. No compound significantly reduced the extent of thoracic aortic lesions. We concluded that changes in plasma lipids and lipoproteins noted with the various HMG-CoA reductase inhibitors did not account for the beneficial effect on atherosclerotic lesion development. The antiatherosclerotic potential of the HMG-CoA reductase inhibitors was compound-specific and clearly not a class effect.
Bocan
T M
TM
Department of Atherosclerosis Therapeutics, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, MI 48105.
Mazur
M J
MJ
Mueller
S B
SB
Brown
E Q
EQ
Sliskovic
D R
DR
O'Brien
P M
PM
Creswell
M W
MW
Lee
H
H
Uhlendorf
P D
PD
Roth
B D
BD
D000818:Animals; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D001161:Arteriosclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001808:Blood Vessels / Q000378:metabolism / Q000473:pathology; D002784:Cholesterol / Q000097:blood; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D015243:Cholesterol, VLDL / Q000097:blood; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D008264:Macrophages / Q000473:pathology; D008297:Male; D009000:Monocytes / Q000473:pathology; D011817:Rabbits
D000924:Anticholesteremic Agents; D002791:Cholesterol, Dietary; D015243:Cholesterol, VLDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D002784:Cholesterol