PHARMACOLOGICAL IN-VITRO STUDIES OF THE NEW 1,4-DIHYDROPYRIDINE CALCIUM-ANTAGONIST LERCANIDIPINE

The present studies were undertaken to examine the in vitro calcium an tagonistic properties of lercanidipine (GAS 132866-11-6, Rec 15/2375) in vascular and non-vascular tissues, as well as its binding profile a nd in particular its affinity to the calcium channel binding sites. Le rcanidipine proved to be endowed with high affinity for the dihydropyr idine subunit of the L-type calcium channel, where it was much more po tent than on the other receptors tested. The nature of the interaction of lercanidipine with the calcium channel appears competitive, as evi denced by a progressive increase in the apparent K-d Of the ligand wit h no change in B-max. The performed functional in vitro studies in iso lated vascular and cardiac tissues demonstrated that lercanidipine has a slower onset and offset of calcium antagonistic activity compared w ith other calcium antagonists. The time-course of inhibition of vascul ar smooth muscle contraction showed substantial differences after addi tion of lercanidipine with regard to the other calcium antagonists tes ted (nitrendipine and amlodipine). On repeated washing of rat aorta to remove the drugs from the preparation, the effects of nitrendipine di sappeared rapidly. After amlodipine incubation, contractility of the t issue was still impaired after 6 h washout with the highest concentrat ions tested, but completely recovered in 1-3 h after washout of the lo west concentration. On the contrary the preparations incubated with le rcanidipine showed a decrease in contractility that reached the maximu m 1 to 3 h after the removal of the compound from the bath at all the active concentrations tested. The functional calcium antagonistic acti vity of lercanidipine was also evaluated as relaxing potency against t he tonic contractions induced by preincubation of rat aorta, bladder a nd colon with 80 mmol/l K+. In rat aorta, lercanidipine proved more po tent than nitrendipine. Comparing the IC50 values evaluated after 3 h of contact time. lercanidipine resulted more active on the vascular ti ssue with potency ratios of 177 and 8.5 for aorta vs bladder and aorta vs colon, respectively. In contrast, nitrendipine showed about the sa me activity in the three tested tissues, and potency ratios of 2.0 and 0.8 for aorta vs bladder and aorta vs colon were calculated. In rat a ortic strips maintained during the incubation with lercanidipine at di fferent degrees of depolarization, the functional calcium antagonistic activity markedly increased by raising the tissue depolarization and the potency ratio between the IC50 values evaluated at 5 and 100 mmol/ l K+ resulted 138. Nitrendipine provided very similar results, whereas nifedipine activity did not seem to be affected by raising the tissue depolarization. The negative inotropic effects of lercanidipine on no rmally and partially depolarized rabbit ventricular strips, as well as in guinea-pig atria, were negligible in comparison to its effects on vasculature. On the whole these characteristics suggest a slow onset o f action and long duration of effects also after in vivo administratio n. In addition, the unique vascular selectivity of lercanidipine impli es that the therapeutically desirable vasodilator activity is not or s carcely associated with a decrease in cardiac contractile force.