Pauletto P, Scannapieco G, Borrione A C, Zanellato A M, Tonello M, Giuriato L, Pessina A C, Palù C D, Sartore S
Institute of Clinical Medicine, University of Padova, Italy.
Arterioscler Thromb. 1991 Jul-Aug;11(4):928-39. doi: 10.1161/01.atv.11.4.928.
We evaluated the ability of the Ca2+ channel blocker nifedipine to influence the severity of atherosclerotic lesions and the pattern of aortic smooth muscle cell (SMC) differentiation in cholesterol-fed New Zealand White rabbits. The animals were fed a 1% cholesterol-enriched diet for 12 weeks. After 4 weeks of the diet, some rabbits were given nifedipine (20 mg b.i.d.) for another 8 weeks without discontinuation of the cholesterol-enriched diet (experiment 1). Another group of rabbits was treated with nifedipine from the beginning of the cholesterol-enriched diet for the entire 12 weeks (experiment 2). The severity of ahterosclerotic lesions was determined by computerized planimetry, and qualitative effects of nifedipine on SMCs were studied by monoclonal antibodies specific for smooth muscle and nonmuscle myosins. In the aortic media of normal rabbits, these antibodies can identify an SMC population with an "immature" type of myosin pattern; a marked increase in the number of these cells is observed during atherogenesis. In experiment 1, we observed a marked decrease of medial SMCs with the immature type of myosin pattern, without any significant reduction in atherosclerosis severity. In experiment 2, disappearance of the previously mentioned medial SMC population was accompanied by a dramatic slowing of intimal lesion development. These results indicate that nifedipine treatment is effective in reducing atherosclerotic lesions only when given from the beginning of a cholesterol-enriched diet. Delay of nifedipine administration until the fourth week of the cholesterol-enriched diet fails to halt progression of the disease. The observed antiatherosclerotic activity can be attributable to a direct effect of the drug on the medial SMC population, which increases during the course of experimental atherogenesis.
我们评估了钙离子通道阻滞剂硝苯地平对高胆固醇喂养的新西兰白兔动脉粥样硬化病变严重程度以及主动脉平滑肌细胞（SMC）分化模式的影响。给这些动物喂食富含1%胆固醇的饮食，持续12周。在饮食4周后，一些兔子在不停止富含胆固醇饮食的情况下，再给予硝苯地平（20毫克，每日两次），持续8周（实验1）。另一组兔子从开始富含胆固醇饮食起就用硝苯地平治疗，持续整个12周（实验2）。通过计算机辅助平面测量法确定动脉粥样硬化病变的严重程度，并用针对平滑肌和非肌肉肌球蛋白的单克隆抗体研究硝苯地平对SMC的定性作用。在正常兔子的主动脉中膜，这些抗体可识别出具有“未成熟”型肌球蛋白模式的SMC群体；在动脉粥样硬化形成过程中，观察到这些细胞数量显著增加。在实验1中，我们观察到具有未成熟型肌球蛋白模式的中膜SMC数量显著减少，但动脉粥样硬化严重程度没有任何显著降低。在实验2中，上述中膜SMC群体消失，同时内膜病变发展显著减缓。这些结果表明，只有在开始富含胆固醇饮食时就给予硝苯地平治疗，才对减少动脉粥样硬化病变有效。将硝苯地平给药推迟到富含胆固醇饮食的第4周，无法阻止疾病进展。观察到的抗动脉粥样硬化活性可归因于该药物对中膜SMC群体的直接作用，而在实验性动脉粥样硬化形成过程中，中膜SMC群体数量会增加。
