In vitro assessment for vascular selectivity of a new dihydropyridine derivative, NB-818.
The vascular selectivity of NB-818 (isopropyl methyl 2-carbamoyloxymethyl-6-methyl-4-(2,3-dichlorophenyl)-1,4-dihydropyridine -3, 5-dicarboxylate), a newly synthesized dihydropyridine derivative, was evaluated in in vitro experiments. NB-818 and nifedipine concentration dependently caused a relaxant effect in rabbit femoral arteries precontracted with 60 mM K+, a negative inotropic effect in guinea-pig papillary muscles, and a negative chronotropic effect in guinea-pig right atria. The onset of these inhibitory effects of NB-818 was much slower than that of nifedipine when compared at concentrations producing the same inhibition. The relaxant effect of NB-818 was about 10 times more potent than that of nifedipine, while the negative inotropic effect of NB-818 was about 100 times less potent than that of nifedipine. As a result, NB-818 showed about 300 times higher vascular selectivity than nifedipine. The two drugs exhibited a similar potency for the negative chronotropic effect. In a whole-cell configuration with voltage clamp, the blocking effect of NB-818 on L-type Ca2+ current (ICa) in guinea-pig ventricular cells appeared much more slowly than that of nifedipine and was hardly washed out. The potency of NB-818 to block ICa was markedly enhanced under depolarized conditions (i.e. at a holding potential of -30 mV) compared to that under polarized conditions (i.e. at a holding potential of -70 mV). Such a voltage-dependent blocking action on ICa was less pronounced for nifedipine. These results indicate that NB-818 is a slow-acting Ca2+ channel antagonist with much high vascular selectivity. Its vascular selectivity may be at least in part related to the marked voltage-dependent inhibition of ICa.
Hattori
Y
Y
Department of Pharmacology, Hokkaido University School of Medicine, Sapporo, Japan.
Fukao
M
M
Houzen
H
H
Qi
F
F
Yamada
Y
Y
Kanno
M
M
D000818:Animals; D001808:Blood Vessels / Q000187:drug effects*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D004095:Dihydropyridines / Q000494:pharmacology*; D004594:Electrophysiology; D005260:Female; D005263:Femoral Artery / Q000187:drug effects; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009200:Myocardial Contraction / Q000187:drug effects; D009543:Nifedipine / Q000494:pharmacology; D010210:Papillary Muscles / Q000187:drug effects; D018408:Patch-Clamp Techniques; D011817:Rabbits
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004095:Dihydropyridines; C048962:NPK 1886; D009543:Nifedipine