title: Contribution of aranidipine metabolites with slow binding kinetics to the vasodilating activity of aranidipine.
abstract: Aranidipine, a novel dihydropyridine derivative, gives rise to two active metabolites, M-1(alpha) and M-1(beta), which exhibit hypotensive activity comparable to that of nifedipine. The aim of this study was to examine the recovery phase of the vasodilating effect of M-1(alpha) and of M-1(beta), to determine their binding characteristics and to compare the results with those for aranidipine and other dihydropyridine derivatives. During intra-arterial infusion into the femoral vascular beds of anesthetized dogs, M-1(alpha), M-1(beta), and nifedipine, produced increases in femoral blood flow at doses three times higher than the dose of aranidipine required to produce a comparable effect. The onset and recovery of the effects of the metabolites on femoral blood flow were significantly slower than the onset and recovery of the effect of nifedipine. The inhibitory activities of M-1(alpha) and M-1(beta) towards stimulated 45Ca uptake in isolated guinea pig aorta were less than that of aranidipine. In binding studies, using porcine heart membrane preparations, [3H]M-1(alpha) and [3H]M-1(beta) had larger Kd values than [3H]aranidipine and [3H]nitrendipine, but the maximal binding number for each of them was almost the same. The association and dissociation rate constants for [3H]M-1(alpha) and [3H]M-1(beta) binding, as well as those for [3H]aranidipine binding, were significantly smaller than those for [3H]nitrendipine, corresponding to the recovery of the in vivo vasodilating effects of the metabolites. The dissociation rate constants of these radiolabeled ligands were highly positively correlated with the elimination rate constants of their in vivo vasodilating effects. From these results, we conclude that M-1(alpha) and M-1(beta), although their binding affinities and Ca2+ antagonistic actions are less potent, possess slower kinetic binding properties than many other dihydropyridines and that the slow kinetic interaction of these metabolites with the dihydropyridine receptor may contribute to the long-lasting in vivo vasodilating effect of aranidipine.
authors.affiliation: Pharmacology Research Laboratory, Taiho Pharmaceutical Co., Ltd., Tokushima, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Miyoshi
authors.forename: H
authors.initials: H
authors.lastname: Miyake
authors.forename: K
authors.initials: K
authors.lastname: Ichihara
authors.forename: H
authors.initials: H
authors.lastname: Kamei
authors.forename: M
authors.initials: M
authors.lastname: Nagasaka
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000378:metabolism / Q000494:pharmacology*; D015220:Calcium Channels / Q000378:metabolism; D020746:Calcium Channels, L-Type; D004095:Dihydropyridines / Q000378:metabolism / Q000494:pharmacology*; D004285:Dogs; D005260:Female; D006168:Guinea Pigs; D007700:Kinetics; D008297:Male; D009543:Nifedipine / Q000494:pharmacology; D012039:Regional Blood Flow / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: C105972:2-hydroxypropylmethyl-1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylate; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D004095:Dihydropyridines; D014665:Vasodilator Agents; C059427:aranidipine; D009543:Nifedipine; D002118:Calcium