Papaioannou S, Panzer-Knodle S, Yang P C
J Pharmacol Exp Ther. 1987 Apr;241(1):91-6.
Ten known calcium channel blockers were studied for inhibition of K+-induced 45Ca++ uptake into rabbit aortic smooth muscle cells in culture, and for displacement of [3H]nitrendipine [2,6-dimethyl-3-carbomethoxy-5-carbomethoxy-4-(3-nitro)phenyl-1, 4-dihydroxypyridine] binding to rat ventricular membrane preparations, in order to relate their effects on receptor binding with their inhibitory activities on 45Ca++ uptake and on contractile responses of vascular smooth muscle. Steady-state 45Ca++ uptake increased with K+ concentration in a dose-dependent manner. With 25 to 50 mM K+, Ca++ uptake was 0.6 nmol of Ca++ per one million cells. All calcium channel blockers inhibited K+-induced 45Ca++ uptake and [3H]nitrendipine binding in a dose-dependent fashion. The enatiomeric dihydropyridines 202-791 [isopropyl-4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-2, 6-dimethyl-5-nitro-3-pyridinecarboxylate] exhibited marked stereoselectivity in both studies, the agonist (+)-202-791 significantly enhancing 45Ca++ uptake at 15 to 50 mM K+. The similarity between the order of potency in inhibiting 45Ca++ uptake and displacing [3H]nitrendipine resulted in a highly significant linear (1:1) correlation. An equally significant correlation was also established for the 10 blockers between their inhibitory potencies on 45Ca++ uptake and the contractile response of rabbit aortic strips as cited in the literature. These findings support the hypothesis that calcium channel blockers block contraction of vascular muscle by inhibiting cellular calcium uptake through voltage-dependent calcium channels as a result of binding to receptors associated with these channels. The aortic cells possess channels that are functionally similar to those found in intact vascular tissue.
研究了10种已知的钙通道阻滞剂对培养的兔主动脉平滑肌细胞中钾离子诱导的45Ca++摄取的抑制作用，以及对[3H]尼群地平[2,6 - 二甲基 - 3 - 甲氧羰基 - 5 - 甲氧羰基 - 4 - (3 - 硝基)苯基 - 1,4 - 二氢吡啶]与大鼠心室膜制剂结合的置换作用，以将它们对受体结合的影响与其对45Ca++摄取和血管平滑肌收缩反应的抑制活性联系起来。稳态45Ca++摄取随钾离子浓度以剂量依赖的方式增加。在25至50 mM钾离子浓度下，每百万个细胞的钙离子摄取量为0.6 nmol Ca++。所有钙通道阻滞剂均以剂量依赖的方式抑制钾离子诱导的45Ca++摄取和[3H]尼群地平结合。对映体二氢吡啶202 - 791[异丙基 - 4 - (2,1,3 - 苯并恶二唑 - 4 - 基) - 1,4 - 二氢 - 2,6 - 二甲基 - 5 - 硝基 - 3 - 吡啶羧酸酯]在两项研究中均表现出明显的立体选择性，激动剂(+) - 202 - 791在15至50 mM钾离子浓度下显著增强45Ca++摄取。抑制45Ca++摄取的效力顺序与置换[3H]尼群地平的效力顺序之间的相似性导致了高度显著的线性(1:1)相关性。对于这10种阻滞剂，它们对45Ca++摄取的抑制效力与文献中引用的兔主动脉条的收缩反应之间也建立了同样显著的相关性。这些发现支持了这样的假设，即钙通道阻滞剂通过与这些通道相关的受体结合，抑制通过电压依赖性钙通道的细胞钙摄取，从而阻断血管肌肉的收缩。主动脉细胞具有与完整血管组织中发现的功能相似的通道。
