Corsini A, Bonfatti M, Quarato P, Accomazzo M R, Raiteri M, Sartani A, Testa R, Nicosia S, Paoletti R, Fumagalli R
Institute of Pharmacological Sciences, University of Milan, Italy.
J Cardiovasc Pharmacol. 1996 Nov;28(5):687-94. doi: 10.1097/00005344-199611000-00012.
The in vitro effects were investigated of the new dihydropyridine calcium antagonist (CA) lercanidipine and its enantiomers on arterial myocyte (smooth muscle cell; SMC) migration and proliferation as related to L-type calcium channel inhibition. Lercanidipine and its enantiomers inhibited the replication and migration of arterial myocytes in concentration ranging from 10 to 50 microM. The antiproliferative effect of lercanidipine, evaluated as cell number, 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. The cell doubling time increased with drug concentration < or = 122 versus 38 h for controls. The cell growth inhibition induced by lercanidipine and its enantiomers was reversible. Lercanidipine dose dependently decreased [3H]thymidine incorporation into DNA; the (R)-enantiomer, displaying the lowest CA activity, was the most potent in this respect. The tested compounds were able to inhibit fibrinogen-induced myocyte migration in a dose-dependent manner, with the (R)-enantiomer showing the more pronounced effect. To directly rule out the role of calcium channels in the antiatherosclerotic properties of lercanidipine, we examined the effect of the compounds on serum-stimulated calcium influx in SMC. Fluorimetry of Fluo 3 was used to measure changes in free cytosolic Ca2+ concentration ([Ca2+]i) in SMC after long-term preincubation (24 h) with the tested CA. Lercanidipine and its enantiomers (25 microM) decreased the serum-induced elevation of [Ca2+]i in SMC with the (S)-enantiomer (69% inhibition) 2.4-fold more active than the counterpart and the racemate (29% inhibition). In conclusion, our in vitro results suggest that lercanidipine may directly interfere with events involved in atherogenesis. 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 a pharmacologic potential of the compound to negatively influence the process of atherogenesis.
研究了新型二氢吡啶类钙拮抗剂（CA）乐卡地平及其对映体对动脉肌细胞（平滑肌细胞；SMC）迁移和增殖的体外作用，这些作用与L型钙通道抑制有关。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。以细胞数量评估，乐卡地平的抗增殖作用呈剂量依赖性，其效力与拉西地平及硝苯地平相似，且与对映体结合L型钙通道的立体选择性无关。药物浓度≤122微摩尔时细胞倍增时间增加，而对照组为38小时。乐卡地平及其对映体诱导的细胞生长抑制是可逆的。乐卡地平剂量依赖性地降低[3H]胸腺嘧啶核苷掺入DNA的量；（R）-对映体的CA活性最低，但在这方面最为有效。所测试的化合物能够以剂量依赖性方式抑制纤维蛋白原诱导的肌细胞迁移，（R）-对映体的作用更为明显。为了直接排除钙通道在乐卡地平抗动脉粥样硬化特性中的作用，我们研究了这些化合物对血清刺激的SMC钙内流的影响。使用Fluo 3荧光测定法测量经测试的CA长期预孵育（24小时）后SMC中游离胞质Ca2+浓度（[Ca2+]i）的变化。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69%）的活性比对映体和外消旋体（抑制29%）高2.4倍。总之，我们的体外研究结果表明，乐卡地平可能直接干扰动脉粥样硬化发生过程中的相关事件。对乐卡地平对映体的研究表明，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发生过程产生负面影响的药理学潜力。
