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 N ew Zealand White rabbits using inhibitors bf 3-hydroxy-3-methylglutary l coenzyme A (HMG-CoA) reductase which have previously been shown to p ossess varying degrees of hepatoselectivity in rats. Atorvastatin, pre viously 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), pravastati n (2.5 mg/kg) and BMY22089 (2.5 mg/kg) were added to a 0.5% cholestero l, 3% peanut, 3% coconut oil diet and fed for 8 weeks. Although reduct ions in plasma total cholesterol of 27% to 60%, VLDL-cholesterol of 31 % to 71% and plasma total cholesterol exposure of 37% to 43% were obta ined, no correlation between these parameters and vascular lipid conte nt, lesion size or monocyte-macrophage content was noted. Iliac-femora l lipid content was unchanged; however, atorvastatin and simvastatin s ignificantly reduced the cholesterol content of the thoracic aorta by 45%-62%. Atorvastatin and PD135022 reduced the size of the iliac-femor al lesion by 67% and monocyte-macrophage content by 72%. Simvastatin, lovastatin and PD134965 decreased the monocyte-macrophage content; how ever, lesion size was unchanged. Pravastatin and BMY22089 had no effec t on lesion size or content. No compound significantly reduced the ext ent of thoracic aortic lesions. We concluded that changes in plasma li pids and lipoproteins noted with the various HMG-CoA reductase inhibit ors did not account for the beneficial effect on atherosclerotic lesio n development. The antiatherosclerotic potential of the HMG-CoA reduct ase inhibitors was compound-specific and clearly not a class effect.