Hattori Y, Fukao M, Houzen H, Qi F, Yamada Y, Kanno M
Department of Pharmacology, Hokkaido University School of Medicine, Sapporo, Japan.
Eur J Pharmacol. 1996 Apr 22;301(1-3):99-106. doi: 10.1016/0014-2999(96)00007-6.
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.
在体外实验中评估了新合成的二氢吡啶衍生物NB - 818（异丙基甲基2 - 氨甲酰氧基甲基 - 6 - 甲基 - 4 - (2,3 - 二氯苯基) - 1,4 - 二氢吡啶 - 3,5 - 二羧酸酯）的血管选择性。NB - 818和硝苯地平在浓度依赖性方面对用60 mM K⁺预收缩的兔股动脉产生舒张作用，对豚鼠乳头肌产生负性肌力作用，对豚鼠右心房产生负性变时作用。当在产生相同抑制作用的浓度下比较时，NB - 818这些抑制作用的起效比硝苯地平慢得多。NB - 818的舒张作用比硝苯地平强约10倍，而NB - 818的负性肌力作用比硝苯地平弱约100倍。结果，NB - 818的血管选择性比硝苯地平高约300倍。两种药物对负性变时作用的效力相似。在电压钳的全细胞模式下，NB - 818对豚鼠心室细胞L型Ca²⁺电流（ICa）的阻断作用比硝苯地平出现得慢得多，且几乎不被洗脱。与极化条件下（即保持电位为 - 70 mV）相比，在去极化条件下（即保持电位为 - 30 mV），NB - 818阻断ICa的效力明显增强。硝苯地平对ICa的这种电压依赖性阻断作用不太明显。这些结果表明，NB - 818是一种起效缓慢的Ca²⁺通道拮抗剂，具有很高的血管选择性。其血管选择性可能至少部分与对ICa明显的电压依赖性抑制有关。
