In Vitro Calcium Antagonist Activity of Lercanidipine and Its Enantiomers

Abstract

This study was undertaken to examine the in vitro calcium antagonist properties of lercanidipine and its enantiomers compared with nifedipine, nitrendipine, nicardipine, niguldipine, and amlodipine. Lercanidipine exhibited high affinity for the dihydropyridine (DHP) subunit of the L-type calcium channel, where it was much more potent than nifedipine and amlodipine. The (R)-enantiomer of lercanidipine was about 100-200-fold less potent than the (S)-one, indicating (S)-lercanidipine as the eutomer. Functional in vitro studies performed in isolated rat aorta preparations contracted by K+ demonstrated that lercanidipine and its enantiomers have a slower onset and cessation of calcium antagonist activity compared with other calcium antagonists. Inhibition of K+-induced contraction is due to the capacity of lercanidipine to interfere with Ca2+ homeostasis, as confirmed by parallel effects elicited by this compound on both muscle tone and [Ca2+]i elevation in guinea pig ileal longitudinal muscle. The slow onset and cessation of calcium antagonist activity of the compound, compared with nicardipine, was confirmed ex vivo studies in isolated rat aorta preparations taken fr?? rats orally treated with lercanidipine. In rat aortic str?? maintained at different degrees of depolarization during cubation with lercanidipine, functional calcium antagon activity was markedly increased by raising the tissue dep?? larization, and a potency ratio of 138 was found between t?? IC50 values evaluated at 5 and 100 mM K+. (S)-Lercani?? pine provided very similar results, whereas the (R)-enan?? omer activity did not appear to be affected by raising t?? tissue depolarization. The data reported here indicate th?? lercanidipine interferes with the L-type calcium chann?? where it reduces the inward calcium current, in a time- a?? voltage-dependent manner. This calcium antagonist effe?? has a gradual onset, is long-lasting, and can be mainly ?? lated to the (S)-enantiomer.