title: Pharmacological in vitro studies of the new 1,4-dihydropyridine calcium antagonist lercanidipine.
abstract: The present studies were undertaken to examine the in vitro calcium antagonistic properties of lercanidipine (CAS 132866-11-6, Rec 15/2375) in vascular and non-vascular tissues, as well as its binding profile and in particular its affinity to the calcium channel binding sites. Lercanidipine proved to be endowed with high affinity for the dihydropyridine subunit of the L-type calcium channel, where it was much more potent than on the other receptors tested. The nature of the interaction of lercanidipine with the calcium channel appears competitive, as evidenced by a progressive increase in the apparent Kd of the ligand with no change in Bmax. The performed functional in vitro studies in isolated vascular and cardiac tissues demonstrated that lercanidipine has a slower onset and offset of calcium antagonistic activity compared with other calcium antagonists. The time-course of inhibition of vascular smooth muscle contraction showed substantial differences after addition of lercanidipine with regard to the other calcium antagonists tested (nitrendipine and amlodipine). On repeated washing of rat aorta to remove the drugs from the preparation, the effects of nitrendipine disappeared rapidly. After amlodipine incubation, contractility of the tissue was still impaired after 6 h washout with the highest concentrations tested, but completely recovered in 1-3 h after washout of the lowest concentration. On the contrary, the preparations incubated with lercanidipine showed a decrease in contractility that reached the maximum 1 to 3 h after the removal of the compound from the bath at all the active concentrations tested. The functional calcium antagonistic activity of lercanidipine was also evaluated as relaxing potency against the tonic contractions induced by preincubation of rat aorta, bladder and colon with 80 mmol/l K+. In rat aorta, lercanidipine proved more potent than nitrendipine. Comparing the IC50 values evaluated after 3 h of contact time, lercanidipine resulted more active on the vascular tissue with potency ratios of 177 and 8.5 for aorta vs bladder and aorta vs colon, respectively. In contrast, nitrendipine showed about the same 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 aortic strips maintained during the incubation with lercanidipine at different 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 normally 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 of action and long duration of effects also after in vivo administration. In addition, the unique vascular selectivity of lercanidipine implies that the therapeutically desirable vasodilator activity is not or scarcely associated with a decrease in cardiac contractile force.
authors.affiliation: Pharmaceutical R&D Division, Recordati S.p.A., Milan, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Guarneri
authors.forename: P
authors.initials: P
authors.lastname: Angelico
authors.forename: M
authors.initials: M
authors.lastname: Ibba
authors.forename: E
authors.initials: E
authors.lastname: Poggesi
authors.forename: C
authors.initials: C
authors.lastname: Taddei
authors.forename: A
authors.initials: A
authors.lastname: Leonardi
authors.forename: R
authors.initials: R
authors.lastname: Testa
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D002118:Calcium / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects; D020746:Calcium Channels, L-Type; D004095:Dihydropyridines / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000316:Adrenergic alpha-Agonists; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D004095:Dihydropyridines; D011188:Potassium; D002118:Calcium; C060343:lercanidipine; D009638:Norepinephrine