SUPPRESSION OF NEOINTIMAL THICKENING BY A NEWLY DEVELOPED HMG-COA REDUCTASE INHIBITOR, BAYW6228 AND ITS INHIBITORY EFFECT ON VASCULAR SMOOTH-MUSCLE CELL-GROWTH

1 The aim of this study was to determine whether BAYw6228 (BAYw), a ne wly developed 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhib itor, could suppress an atherogenic process such as intimal thickening by a mechanism other than lowering the level of serum cholesterol. 2 First, we evaluated the in vitro effect of BAYw on the proliferation o f vascular smooth muscle cells (SMC) from various species: Sprague-Daw ley (SD rats, New Zealand (NZ white rabbits, intimal cells from Watana be hereditary hyperlipidemic (WHHL) rabbit and SMC from the new-born h uman aorta. The increasing rate of total protein content of these cell s was inhibited by the addition of BAYw in a dose-dependent fashion. I n the presence of 2% foetal calf serum (FCS), the value of IC50 was 1. 0 mu M in SD rats. 2.1 mu M in NZ white rabbits, and 0.3 mu M in WHHL rabbits. With human SMC, the value was 0.02 mu M in the presence of 10 % FCS and 0.2 mu M with a mixture of growth factors. 3 Based on these above in vitro findings, we next examined the in vivo effect of the ag ent to determine whether it could suppress rabbit intimal thickening i nduced by balloon catheterization. A balloon catheter was inserted fro m a peripheral branch of the left external carotid artery to the aorta to denude the endothelium of the left common carotid artery in Japane se a white rabbits. After 12 days they were divided into control and B AYw groups. The former were subcutaneously injected with saline and th e latter with BAYw 1 mg kg(-1) day(-1). Two days after the beginning o f treatment, a second balloon injury was performed to the previously i njured left common carotid artery in both groups. After another two we eks, the left common carotid artery was removed and variously stained. Although the total serum cholesterol in the BAYw group was significan tly lower than in the control (P<0.05), the difference was not enough to affect intimal thickening. In addition, the BAYw group had a smalle r intima-media ratio than the control group, decreasing to 45% of cont rol (P<0.05). By anti-alpha smooth muscle actin antibody staining, the se intimal thickening areas were entirely occupied by SMCs. and their amount was attenuated by BAYw. By anti-rabbit macrophage antibody (RAM 11) staining, the number of positive cells in the intimal thickening was markedly decreased in the BAYw group compared to control (P<0.01). 4 These results indicate that BAYw has an inhibitory effect on intima l thickening by attenuating intimal SMC proliferation and infiltration of macrophages, suggesting that BAYw could be effective in the preven tion of the progression of atherosclerotic plaque-like restenosis afte r angioplasty.