新型二氢吡啶衍生物NZ-105在离体兔主动脉中的血管舒张及受体结合特性

Vasorelaxing and receptor binding properties of NZ-105, a novel dihydropyridine derivative, in isolated rabbit aorta.

作者信息

Masuda Y, Iwama T, Yamashita T, Sakai T, Hibi M, Tanaka S, Shigenobu K, Kasuya Y

机构信息

Shiraoka Research Station of Biological Science, Nissan Chemical Industries, Ltd., Saitama, Japan.

出版信息

Arch Int Pharmacodyn Ther. 1991 Jul-Aug;312:86-103.

PMID:1663336

Abstract

The vasorelaxing and dihydropyridine receptor binding properties of NZ-105, a new dihydropyridine derivative, were studied using isolated rabbit aorta, and compared with those of nicardipine, nifedipine and diltiazem. NZ-105 (3 x 10(-10)-3 x 10(-9) M), nicardipine (3 x 10(-10), 10(-9) M), and diltiazem (3 x 10(-7), 10(-6) M) selectively relaxed aortic strips precontracted with high-K+ solution (50 mM) with little effect on strips precontracted with phenylephrine (10(-5) M) or clonidine (10(-6) M). The relaxation produced by NZ-105 was of very slow onset, and no recovery was observed after a 2 hr washout with high-K+ or normal bathing solution. NZ-105 (3 x 10(-10)-3 x 10(-9) M) caused a non-parallel depression of the concentration-response curve for the CaCl2-induced contraction in high-K(+)-depolarized rabbit aorta, whereas nicardipine (10(-10), 3 x 10(-10) M), nifedipine (10(-9), 3 x 10(-9) M) and diltiazem (10(-7), 3 x 10(-7) M) all produced a concentration-related rightward displacement of the curve. The depression induced by NZ-105, but not by nicardipine, became greater as the period of preincubation with the drug was prolonged. NZ-105, nicardipine and diltiazem, at the very high concentration of 10(-6) M, caused a slight and noncompetitive inhibition of the concentration-response curves for norepinephrine, prostaglandin F2 alpha, angiotensin II and 5-hydroxytryptamine. NZ-105 displaced 3H-nitrendipine binding to rabbit aortic membranes in a manner similar to that of nicardipine and nifedipine, and this was also incubation time-dependent. These results indicate that NZ-105 possesses selective calcium antagonist properties, with respect to the rabbit isolated vascular smooth muscle, which are of very slow onset and long-lasting. The slow onset of the vasorelaxation may be due to a slow association rate to dihydropyridine receptors. These pharmacological properties of NZ-105 may, at least in part, be responsible for the slow onset and long duration of its antihypertensive action in vivo.

摘要

使用离体兔主动脉研究了新型二氢吡啶衍生物NZ-105的血管舒张和二氢吡啶受体结合特性，并与尼卡地平、硝苯地平和地尔硫䓬进行了比较。NZ-105（3×10⁻¹⁰ - 3×10⁻⁹ M）、尼卡地平（3×10⁻¹⁰、10⁻⁹ M）和地尔硫䓬（3×10⁻⁷、10⁻⁶ M）可选择性舒张用高钾溶液（50 mM）预收缩的主动脉条，而对用去氧肾上腺素（10⁻⁵ M）或可乐定（10⁻⁶ M）预收缩的条带影响很小。NZ-105产生的舒张起效非常缓慢，用高钾或正常浴液冲洗2小时后未观察到恢复。NZ-105（3×10⁻¹⁰ - 3×10⁻⁹ M）使高钾去极化兔主动脉中氯化钙诱导收缩的浓度-反应曲线呈非平行下降，而尼卡地平（10⁻¹⁰、3×10⁻¹⁰ M）、硝苯地平（10⁻⁹、3×10⁻⁹ M）和地尔硫䓬（10⁻⁷、3×10⁻⁷ M）均使曲线产生浓度相关的右移。NZ-105诱导的下降而非尼卡地平诱导的下降随着药物预孵育时间的延长而增大。NZ-105、尼卡地平和地尔硫䓬在10⁻⁶ M的极高浓度下对去甲肾上腺素、前列腺素F2α、血管紧张素II和5-羟色胺的浓度-反应曲线产生轻微的非竞争性抑制。NZ-105以与尼卡地平和硝苯地平相似的方式取代3H-尼群地平与兔主动脉膜的结合，且这也呈孵育时间依赖性。这些结果表明，就兔离体血管平滑肌而言，NZ-105具有选择性钙拮抗剂特性，起效非常缓慢且作用持久。血管舒张起效缓慢可能是由于与二氢吡啶受体的结合速率缓慢。NZ-105的这些药理特性可能至少部分地解释了其在体内降压作用起效缓慢和持续时间长的原因。