Relationship between the stereoselective negative inotropic effects of verapamil enantiomers and their binding to putative calcium channels in human heart
Relationship between the stereoselective negative inotropic effects of verapamil enantiomers and their binding to putative calcium channels in human heart
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维拉帕米对映体的立体选择性负性肌力作用与其与人心脏中假定的钙通道的结合之间的关系
DOI：
10.1111/j.1476-5381.1985.tb17375.x
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发表时间：
1985
影响因子：
7.3
通讯作者：
A. Kaumann
中科院分区：
文献类型：
--
作者：
D. Ferry;H. Glossmann;A. Kaumann
对二尖瓣疾病和肥厚性梗阻性心肌病（HOCM）患者的心室制剂进行等距收缩。还制备了心室膜颗粒，并用[3H]‐尼莫地平标记了假定的钙通道。2在6 - 60 μm（-）‐肾上腺素或（-）‐去甲肾上腺素存在下，通过改变离体条带的刺激速率从6 min−1到120 min−1诱导阳性阶梯。（-）‐维拉帕米3-5 μm或（+）‐维拉帕米20-30 μm在二尖瓣疾病或HOCM患者的制剂中逆转了力-频率关系（即引起负阶梯）。在5例心率为60 min−1的HOCM患者的心内膜下室间隔条中，（-）‐维拉帕米和（+）‐维拉帕米均可引起心脏抑制。0.4 μm（-）‐维拉帕米组和3 μm（+）‐维拉帕米组可观察到半最大心脏抑制。4 [3H]‐尼莫地平以饱和可逆的方式与心室膜颗粒结合到一个高亲和力位点，平衡解离常数为0.23 nm。这些位点的膜蛋白密度为95 fmol mg−1。1,4‐二氢吡啶对映体和硝苯地平立体选择性地抑制了氚化的1,4‐二氢吡啶的结合。5（-）‐维拉帕米和（+）‐维拉帕米抑制高亲和力[3H]‐尼莫地平以负异异性变构方式结合，（-）‐维拉帕米的IC50效比（+）‐维拉帕米高5倍。在给定的[3H]‐尼莫地平浓度下，（+）‐维拉帕米抑制了更大比例的特异性[3H]‐尼莫地平结合。动力学研究证实了（+）‐维拉帕米抑制[3H]‐尼莫地平结合的变构模式。（-）‐维拉帕米以明显的竞争方式将（+）‐维拉帕米结合抑制曲线向右平移。两种维拉帕米对映体引起的阶梯倒置表明它们引起了依赖于使用的通道阻塞。结合和抑制心脏的相似效价比表明，这两种维拉帕米对映体在钙通道内具有共同的作用位点。
1 Ventricular preparations from patients with mitral disease and hypertrophic obstructive cardiomyopathy (HOCM) were set up to contract isometrically. Ventricular membrane particles were also prepared and putative calcium channels were labelled with [3H]‐nimodipine. 2 Positive staircase was induced by varying the rate of stimulation of isolated strips from 6 min−1 to 120 min−1 in the presence of 6–60 μm (—)‐adrenaline or (—)‐noradrenaline. (—)‐Verapamil 3–5 μm or (+)‐verapamil 20–30 μm reversed the force‐frequency relationship (i.e. caused negative staircase) in preparations from patients with mitral disease or HOCM. 3 In subendocardial strips of ventricular septum from 5 patients with HOCM paced at 60 min−1, both (—)‐verapamil and (+)‐verapamil caused cardiodepression. Half‐maximal cardiodepression was observed with 0.4 μm (—)‐verapamil and with 3 μm (+)‐verapamil. 4 [3H]‐nimodipine bound to ventricular membrane particles in a saturable, reversible fashion to a high affinity site with an equilibrium dissociation constant of 0.23 nm. The density of these sites was 95 fmol mg−1 of membrane protein. Binding of the tritiated 1,4‐dihydropyridine was stereoselectively inhibited by 1,4‐dihydropyridine enantiomers and nifedipine. 5 (—)‐Verapamil and (+)‐verapamil inhibited high affinity [3H]‐nimodipine binding in a negative heterotropic allosteric manner with (—)‐verapamil being 5 times more potent than (+)‐verapamil on an IC50 basis. At a given [3H]‐nimodipine concentration, (+)‐verapamil inhibited a greater fraction of specific [3H]‐nimodipine binding. 6 The allosteric mode of (+)‐verapamil inhibition of [3H]‐nimodipine binding was confirmed by kinetic studies. (—)‐Verapamil shifted (+)‐verapamil‐binding inhibition curves to the right in an apparently competitive fashion. 7 The inversion of staircase caused by both verapamil enantiomers suggests that they cause a use‐dependent channel blockade. The similar potency ratios for binding and for cardiodepression are indicative of a common locus of action for both verapamil enantiomers within the calcium channel.
[3H]尼莫地平与心肌细胞和亚细胞部分特异性结合。
DOI：
10.1016/0006-291x(83)90449-7
发表时间：
1983
影响因子：
3.1
作者：
DePover,A;Lee,SW;Matlib,MA;Whitmer,K;Davis,BA;Powell,T;Schwartz,A
通讯作者：
Schwartz,A
Ca 通道拮抗剂 [3H]尼群地平与豚鼠回肠平滑肌结合的表征。
DOI：
--
发表时间：
1983
期刊：
The Journal of pharmacology and experimental therapeutics
影响因子：
--
作者：
Bolger,GT;Gengo,P;Klockowski,R;Luchowski,E;Siegel,H;Janis,RA;Triggle,AM;Triggle,DJ
通讯作者：
Triggle,DJ
地尔硫卓增强尼莫地平在心脏中的负性肌力作用。
DOI：
10.1016/0006-291x(83)90648-4
发表时间：
1983
影响因子：
3.1
作者：
DePover,A;Grupp,IL;Grupp,G;Schwartz,A
通讯作者：
Schwartz,A