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 calc ium antagonist (CA) lercanidipine and its enantiomers on arterial myoc yte (smooth muscle cell; SMC) migration and proliferation as related t o L-type calcium channel inhibition. Lercanidipine and its enantiomers inhibited the replication and migration of arterial myocytes in conce ntrations ranging from 10 to 50 mu M. The antiproliferative effect of lercanidipine, evaluated as cell number, was dose dependent, with a po tency similar to that of lacidipine and nifedipine, and was unrelated to the stereoselectivity of enantiomers to bind L-type calcium channel s. The cell doubling time increased with drug concentration less than or equal to 122 versus 38 h for controls. The cell growth inhibition i nduced by lercanidipine and its enantiomers was reversible. Lercanidip ine dose dependently decreased [H-3]thymidine incorporation into DNA; the (R)-enantiomer, displaying the lowest CA activity, was the most po tent in this respect. The tested compounds were able to inhibit fibrin ogen-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-stimul ated 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 i ts enantiomers (25 mu M) decreased the serum-induced elevation of [Ca2 +](i) in SMC with the (S)-enantiomer (69% inhibition) 2.4-fold more ac tive than the counterpart and the racemate (29% inhibition). Zn conclu sion, our in vitro results suggest that lercanidipine may directly int erfere with events involved in atherogenesis. The studies performed wi th enantiomers of lercanidipine suggest that the observed effects are not related to the blockade of voltage-dependent Ca2+ channels and con firm at least in vitro a pharmacologic potential of the compound to ne gatively influence the process of atherogenesis.