title: NZ-105, a new 1,4-dihydropyridine derivative: correlation between dihydropyridine receptor binding and inhibition of calcium uptake in rabbit aorta.
abstract: The correlation between the binding of NZ-105, a newly synthesized 1,4-dihydropyridine (DHP) derivative, on DHP receptors and its inhibitory activity on transmembrane 45Ca2+ uptake was investigated. 3H-NZ-105 bound rabbit aortic microsomes more slowly than did 3H-nitrendipine (3H-NTD): the association and dissociation rate constants of 3H-NZ-105 were about 70 times and 10 times less than those of 3H-NTD, respectively. The dissociation constant (Kd) of 3H-NZ-105 (4.48 nM) was about 6 times larger than that of 3H-NTD (0.79 nM), and the maximum number of binding sites (Bmax) for 3H-NZ-105 (112.5 fmoles/mg protein) was about the same as that for 3H-NTD (106.2 fmoles/mg protein). Unlabelled NZ-105 and nicardipine fully, and in a concentration-dependent manner, displaced 3H-NZ-105 specific binding. Pre-incubation with NZ-105 also concentration-dependently (more than 0.1 microM) inhibited the transmembrane 45Ca2+ uptake increment induced by a high-K+ (50 mM) solution. The inhibitory efficacy of NZ-105 became larger as the incubation period with this compound increased (from 1 hr incubation to 3 hr incubation), and recovery was difficult even after washout for 3 hr. Based on these results, we conclude that NZ-105 causes blockade of voltage-dependent calcium channels (VDCs) by binding to DHP receptors. Moreover, the very slow onset and recovery from NZ-105-induced vasodilation may be attributable to the slow and long-lasting inhibition of transmembrane calcium uptake, which accompanies its very slow binding to and dissociation from DHP receptors.
authors.affiliation: Shiraoka Research Station of Biological Science, Nissan Chemical Industries, Ltd., Japan.
authors.forename: T
authors.initials: T
authors.lastname: Yamashita
authors.forename: Y
authors.initials: Y
authors.lastname: Masuda
authors.forename: T
authors.initials: T
authors.lastname: Sakai
authors.forename: S
authors.initials: S
authors.lastname: Tanaka
authors.forename: Y
authors.initials: Y
authors.lastname: Kasuya
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000378:metabolism* / Q000494:pharmacology; D001011:Aorta / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D001667:Binding, Competitive; D002118:Calcium / Q000493:pharmacokinetics*; D002121:Calcium Channel Blockers / Q000378:metabolism / Q000494:pharmacology; D015220:Calcium Channels; D002132:Calcium Radioisotopes; D004095:Dihydropyridines / Q000378:metabolism* / Q000494:pharmacology; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008566:Membranes / Q000378:metabolism; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D009568:Nitrendipine / Q000378:metabolism; D009596:Nitrophenols; D009943:Organophosphorus Compounds / Q000378:metabolism* / Q000494:pharmacology; D011817:Rabbits; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013997:Time Factors; D014316:Tritium
chemical_list: D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D002132:Calcium Radioisotopes; D004095:Dihydropyridines; D009596:Nitrophenols; D009943:Organophosphorus Compounds; D011978:Receptors, Nicotinic; D014316:Tritium; C066425:efonidipine; D009568:Nitrendipine; D002118:Calcium