Angelico P, Guarneri L, Leonardi A, Testa R
Pharmaceutical R & D Division, Recordati S.p.A., Milano, Italy.
J Pharm Pharmacol. 1999 Jun;51(6):709-14. doi: 10.1211/0022357991772844.
The aim of this study was to characterize the in-vitro vasoselectivity of lercanidipine (in comparison with lacidipine, amlodipine, nitrendipine and felodipine) by evaluating its functional calcium antagonistic activity on rabbit vascular (aorta) and cardiac tissues (heart ventricle). Although incubation with all the compounds tested elicited a concentration-dependent relaxant effect on vascular tissue precontracted with KCl (80 mM), 50% relaxation was reached at different times for each concentration and drug tested. At 10 nM concentration 50% relaxation was reached after 210 min with lercanidipine, 278 min with amlodipine, 135 min with lacidipine, 75 min with nitrendipine and 70 min with felodipine. The onset of the effect was, therefore, similar for lercanidipine, amlodipine and lacidipine, but faster for nitrendipine and felodipine. Similarly, all the compounds tested concentration-dependently reduced the force of cardiac contraction (negative inotropic activity). In this model, the time needed to reach 50% reduction in contractile force was also concentration-dependent, and the ranking order of the speed of onset of the effect (evaluated as the ratio of the IC50 values (the concentrations inhibiting contraction by 50%) calculated after 1 and 4 h incubation) was lacidipine (3.8) > amlodipine (9.6) > felodipine (39) > lercanidipine (68) = nitrendipine (89). The vasoselectivity, expressed as the ratio of the IC50 values obtained on cardiac and vascular tissue, were (for 4 h incubation) 730, 193, 95, 6 and 3 for lercanidipine, lacidipine, amlodipine, felodipine and nitrendipine, respectively, showing that lercanidipine is the most vasoselective of the calcium-antagonists tested. The results show that lercanidipine reduces the inotropic force of the rabbit heart to a lesser extent than do other calcium antagonists, and that this drug had the best heart/vessel selectivity index among the compounds tested at all the times tested.
本研究的目的是通过评估乐卡地平（与拉西地平、氨氯地平、尼群地平和非洛地平相比）对兔血管（主动脉）和心脏组织（心室）的功能性钙拮抗活性，来表征其体外血管选择性。尽管与所有测试化合物孵育均能引起对用氯化钾（80 mM）预收缩的血管组织产生浓度依赖性的舒张作用，但对于每种浓度和测试药物，在不同时间达到50%舒张。在10 nM浓度下，乐卡地平在210分钟后达到50%舒张，氨氯地平在278分钟后达到，拉西地平在135分钟后达到，尼群地平在75分钟后达到，非洛地平在70分钟后达到。因此，乐卡地平、氨氯地平和拉西地平的起效时间相似，但尼群地平和非洛地平更快。同样，所有测试化合物均浓度依赖性地降低心脏收缩力（负性肌力活性）。在该模型中，达到收缩力降低50%所需的时间也呈浓度依赖性，起效速度的排序（以孵育1小时和4小时后计算的IC50值（抑制收缩50%的浓度）之比评估）为拉西地平（3.8）>氨氯地平（9.6）>非洛地平（39）>乐卡地平（68）=尼群地平（89）。以心脏和血管组织上获得的IC50值之比表示的血管选择性（对于4小时孵育），乐卡地平、拉西地平、氨氯地平、非洛地平和尼群地平分别为730、193、95、6和3，表明乐卡地平是所测试钙拮抗剂中血管选择性最高的。结果表明，乐卡地平比其他钙拮抗剂对兔心脏肌力的降低程度更小，并且在所有测试时间内，该药物在所测试化合物中具有最佳的心脏/血管选择性指数。
