Dual effects of the antioxidant agents probucol and carvedilol on proliferative and fatty lesions in    hypercholesterolemic rabbits

    在两种不同类型动脉粥样硬化损伤（增生和损伤）的胆固醇饮食（1%）饲养的相同家兔模型中评价抗氧化剂普罗布考(200 mg/kg/天)的体内直接抗动脉粥样硬化作用和β受体阻断剂卡维地洛(10和20 mg/kg/天)的抗氧化性质。标准饮食中添加药物饲养8周中，各组动物体重和血脂未表现出差异。普罗布考和卡维地洛均能显著减轻和降低降低胆固醇饮食导致的大动脉脂纹及其在大动脉内皮的面积(28.2+/-9.6%, P <0.05, 19.9+/-6.2%, P <0.01 分别为低剂量和高剂量卡维地洛治疗组；22.3+/-7.6%, P <0.01 为普罗布考治疗组 probucol, 41.6+/-10.7%为对照组家兔模型)。饮食饲养6周后，药物治疗前在动物颈动脉中放置中空硅胶环制备增生损伤动物模型（每组n=5）。内膜的形成通过测定内膜（I）与中膜（M）横断层面厚度的比值判断。后颈动脉产生显著的内膜细胞聚集而中膜厚度则无变化。I/M比值降低50%的在普罗布考治疗组为0.51+/-0.1，高剂量与低剂量卡维地洛治疗组分别为：0.66+/-0.21 和0.52+/-0.1。普罗布考治疗组和高剂量卡地维洛治疗组总血浆TBARS均降低50%以上。结果表明抗氧化剂预处理能直接抑制早期动脉粥样硬化进程，显示其在预防动脉粥样硬化中具有潜在的应用价值。

    The in vivo direct antiatherogenic activity of the antioxidant probucol (200 mg/kg per day) or the beta-blocker with antioxidant properties carvedilol (10 and 20 mg/kg per day) was tested in the same animal in two different types of      atherosclerotic lesion (proliferative and fatty lesions) induced in cholesterol-fed rabbits (1%). Drugs were given daily mixed with standard diet for 8 weeks; body weight and plasma lipid profile were not different among groups throughout the study. Aortic fatty lesions were induced by cholesterol feeding (n = 25 in each group) and their extent expressed as % of aorta inner surface covered by plaques was significantly reduced by both drugs (28.2+/-9.6%,P <0.05, 19.9+/-6.2%, P <0.01 for low- and high-dose carvedilol, respectively; 22.3+/-7.6%, P <0.01 for probucol, versus 41.6+/-10.7% in control       rabbits).

    Proliferative lesions were obtained by positioning a hollow silastic collar around one carotid artery 6 weeks after  dietary and drug treatments started (n = 5 in each group). The neointimal formation, mostly composed by myocytes, was    determined by measuring cross-sectional thickness ratio of intimal (I) and medial (M) tissue of fixed arteries. In       untreated animals, collared arteries resulted in a significant neointimal cell accumulation compared to the sham (1.10+/-0.14 versus 0.02+/-0.01) without change in medial thickness. I/M ratio was reduced by about 50% in animals treated with  probucol (0.51+/-0.1) and carvedilol (0.66+/-0.21 and 0.52+/-0.1 in the low- and high-dose group, respectively). Total   plasma TBARS were more than 50% lower in both probucol- and high-dose carvedilol-treated rabbits. Results show that      pharmacological pretreatment with antioxidants directly inhibits early atherogenic processes, representing a potentially useful approach in the prevention of atherosclerosis.