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. Louis MO 63110; {Departments of Artherosclerosis Therapeutics, }Biochemistry and }Chemistry Parke-Davis, Ann Arbor MI 48105 and #Department of Pharmacology, Columbia University, New York, NY 10032, U.S.A.1 15-Lipoxygenase (15-LO) has been implicated in the pathogenesis of atherosclerosis because of its localization in lesions and the many biological activities exhibited by its products. To provide further evidence for a role of 15-LO, the e ects of PD 146176 on the development of atherosclerosis in cholesterol-fed rabbits were assessed. This novel drug is a speci®c inhibitor of the enzyme in vitro and lacks signi®cant non speci®c antioxidant properties. 2 PD 146176 inhibited rabbit reticulocyte 15-LO through a mixed noncompetitive mode with a K i of 197 nM. The drug had minimal e ects on either copper or 2,2'-azobis(2-amidinopropane)hydrochloride (ABAP) induced oxidation of LDL except at concentrations 2 orders higher than the K i . 3 Control New Zealand rabbits were fed a high-fat diet containing 0.25% wt./wt. cholesterol; treated animals received inhibitor in this diet (175 mg kg 71 , b.i.d.). Plasma concentrations of inhibitor were similar to the estimated K i (197 nM). During the 12 week study, there were no signi®cant di erences in weight gain, haematocrit, plasma total cholesterol concentrations, or distribution of lipoprotein cholesterol. 4 The drug plasma concentrations achieved in vivo did not inhibit low-density lipoprotein (LDL) oxidation in vitro. Furthermore, LDL isolated from PD 146176-treated animals was as susceptible as that from controls to oxidation ex vivo by either copper or ABAP. 5 PD 146176 was very e ective in suppressing atherogenesis, especially in the aortic arch where lesion coverage diminished from 15+4 to 0% (P50.02); esteri®ed cholesterol content was reduced from 2.1+0.7 to 0 mg mg 71 (P50.02) in this region. Immunostainable lipid-laden macrophages present in aortic intima of control animals were totally absent in the drug-treated group. 6 Results of these studies are consistent with a role for 15-LO in atherogenesis.

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Human platelets contain a mitogen, the platelet-derived growth actor (PDGF), that stimulates the proliferation of a variety of cell types in culture and that may play a role in atherogenesis. Studies were conducted to explore the effects of PDGF on low density lipoprotein (LDL) receptor activity of cultured human fibroblasts. The PDGF utilized in these studies was partially purified from human platelet-rich plasma by ion exchange chromatography and gel filtration. LDL rece tor activity was assessed by both specific binding of