Effect of the new calcium antagonist lercanidipine and its enantiomers on the migration and proliferation of arterial myocytes

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 concentrations ranging from 10 to 50 mu M. 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 less than or equal to 122 versus 38 h for controls. The cell growth inhibition induced by lercanidipine and its enantiomers was reversible. Lercanidipine dose dependently decreased [H-3]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 Flue 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 mu M) 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). Zn 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.