Corsini A, Accomazzo M R, Canavesi M, Sartani A, Testa R, Catapano A L, Fumagalli R, Paoletti R, Bernini F
Institute of Pharmacological Sciences, University of Milan, Italy.
Blood Press Suppl. 1998;2:18-22. doi: 10.1080/080370598438997.
Atherosclerosis results from multiple factors and involves several mechanisms, including endothelial monocyte and smooth muscle cell (SMC) changes, cholesterol accumulation, plaque rupture and thromboembolism. Calcium ions play a role in the initial and chronic development of atherosclerotic lesions. Several studies in experimental animal models have demonstrated the potential direct antiatherosclerotic effects of calcium antagonists. In this study the antiatherogenic activity of lercanidipine, a new lipophilic, second-generation calcium antagonist, was investigated. Lercanidipine and its enantiomers inhibited the replication and migration of arterial myocytes in concentrations ranging from 10 to 50 microM. The antiproliferative effect of lercanidipine was dose dependent, with a potency similar to that of lacidipine and nifedipine, and was unrelated to the stereoselectivity of enantiomers to bind L-type calcium channels. Lercanidipine and its enantiomers (25 microM) decreased the serum-induced elevation of [Ca2+]i in SMC, with the (S)-enantiomer (69% inhibition) being 2.4-fold more active than the (R)-counterpart (29% inhibition). The studies performed with enantiomers of lercanidipine suggest that the observed effects are not related to the blockade of voltage-dependent Ca2+ channels and confirm, at least in vitro, the pharmacological potential of the compound to influence negatively the process of atherogenesis.
动脉粥样硬化由多种因素引起，涉及多种机制，包括内皮单核细胞和平滑肌细胞（SMC）变化、胆固醇积聚、斑块破裂和血栓栓塞。钙离子在动脉粥样硬化病变的初始和慢性发展中起作用。多项针对实验动物模型的研究已证明钙拮抗剂具有潜在的直接抗动脉粥样硬化作用。在本研究中，对新型亲脂性第二代钙拮抗剂乐卡地平的抗动脉粥样硬化活性进行了研究。乐卡地平及其对映体在10至50微摩尔的浓度范围内抑制动脉肌细胞的复制和迁移。乐卡地平的抗增殖作用呈剂量依赖性，效力与拉西地平和硝苯地平相似，且与对映体结合L型钙通道的立体选择性无关。乐卡地平及其对映体（25微摩尔）降低了血清诱导的SMC中[Ca2+]i升高，其中（S）-对映体（抑制率69%）的活性比（R）-对映体（抑制率29%）高2.4倍。对乐卡地平对映体进行的研究表明，观察到的效应与电压依赖性Ca2+通道的阻断无关，并至少在体外证实了该化合物对动脉粥样硬化形成过程产生负面影响的药理潜力。
