Identification of two calcium channel receptor sites for [3H]nitrendipine in mammalian cardiac and smooth muscle membrane.
Identification of two calcium channel receptor sites for [3H]nitrendipine in mammalian cardiac and smooth muscle membrane.
复制标题
哺乳动物心脏和平滑肌膜中[3H]尼群地平的两个钙通道受体位点的鉴定。
DOI：
10.1073/pnas.83.19.7452
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发表时间：
1986
影响因子：
11.1
通讯作者：
Dzau,VJ
中科院分区：
文献类型：
--
作者：
Rogart,RB;deBruynKops,A;Dzau,VJ
各种钙通道阻滞剂的心血管作用不同，尽管在钙通道的共同作用。许多研究者报道，只有一个单一的高亲和力受体结合[3 H]尼群地平，二氢吡啶钙通道阻滞剂。它的平衡解离常数（Kd）不匹配的尼群地平对哺乳动物心脏钙通道的生理效应所需的浓度。这些研究的目的是澄清尼群地平受体的药理学性质和二氢吡啶阻滞剂的生理作用之间的现有差异。在这方面特别重要的是提供一个药理学相关的电生理学研究，证明了多种电压依赖性构象状态的钙通道，这表明不同的亲和力的二氢吡啶钙通道阻滞剂。通过使用一种改进的配体结合试验，我们的研究表明，“高亲和力”和“低亲和力”[3 H]尼群地平受体的Kd值对应以及观察到的生理有效尼群地平浓度。我们检测到两个不同的尼群地平受体在大鼠心脏和牛主动脉膜。发现0.2-0.3 nM的高亲和力Kd值，这似乎对应于平滑肌中Ca通道的生理功能状态，因为Kd值与尼群地平抑制收缩的浓度相似。然而，与许多其他研究相反，我们观察到[3 H]尼群地平结合的主要成分（95-99%）具有低亲和力Kd值（235 nM）。这种假定的低亲和力[3 H]尼群地平受体可能对应于心肌中Ca通道的生理功能状态。
Various Ca-channel blockers differ in cardiovascular action despite common effects at the Ca channel. Many investigators have reported only a single high-affinity receptor for binding of [3H]nitrendipine, a dihydropyridine Ca-channel blocker. Its equilibrium dissociation constant (Kd) does not match the concentration of nitrendipine needed for a physiological effect on the mammalian cardiac Ca channel. The purpose of these studies was to clarify the existing discrepancy between pharmacological properties of nitrendipine receptors and the physiological effects of the dihydropyridine blockers. Of particular importance in this regard was to provide a pharmacological correlate for electrophysiological studies demonstrating multiple voltage-dependent conformational states of the Ca channel, which show differing affinities for the dihydropyridine Ca-channel blockers. By use of an improved ligand binding assay, our studies demonstrate both "high-affinity" and "low-affinity" [3H]nitrendipine receptors with Kd values corresponding well with observed physiologically effective nitrendipine concentrations. We detected two distinct populations of nitrendipine receptors in rat heart and bovine aortic membrane. A high-affinity Kd value of 0.2-0.3 nM was found, which seems to correspond to the physiologically functional state of the Ca channel in smooth muscle, since the Kd value is similar to the concentration at which nitrendipine inhibits contraction. However, in contrast to numerous other studies, we observed that the predominant component of [3H]nitrendipine binding (95-99%) had a low-affinity Kd value (235 nM). This putative low-affinity [3H]nitrendipine receptor may correspond to the physiologically functional state of the Ca channel in cardiac muscle.