Kim H C, Raess B U
Department of Pharmacology, Indiana University School of Medicine, Evansville 47732.
Biochem Pharmacol. 1988 Mar 1;37(5):917-20. doi: 10.1016/0006-2952(88)90181-5.
The functional interactions of the three prototype Ca2+ antagonists, verapamil, diltiazem and nifedipine, were examined in relation to the calmodulin regulated plasma membrane Ca2+ pump ATPase. For this we used low ionic strength derived, calmodulin depleted, human red cell ghost membranes. Exogenously added calmodulin activated basal (Ca2+ + Mg2+)-ATPase in a concentration-dependent manner. Half-maximal activation by 6 nM calmodulin was antagonized by 10(-3) M verapamil and 10(-3) M diltiazem 25.1 and 12.1% respectively. The inhibition appeared to be specific for calmodulin activation since basal activity was not affected by these agents. Nifedipine had no effects on basal or calmodulin stimulated (Ca2+ + Mg2+)-ATPase activity. Unlike dihydropyridine modulation of verapamil and diltiazem binding at high affinity channel sites, nifedipine in this system did not alter the inhibitory responses of verapamil and diltiazem. The calmodulin directed antagonism of the two drugs was shown to be strictly additive over a full range of calmodulin concentrations and appeared to change predominantly the Vmax and, to a lesser degree, the affinity of calmodulin for the (Ca2+ + Mg2+)-ATPase. It is concluded that this model system provides evidence for additional functional discrepancies among the various classes of Ca2+ antagonists.
研究了三种原型钙拮抗剂维拉帕米、地尔硫䓬和硝苯地平与钙调蛋白调节的质膜钙泵ATP酶的功能相互作用。为此，我们使用了低离子强度、去除钙调蛋白的人红细胞血影膜。外源添加的钙调蛋白以浓度依赖的方式激活基础（Ca2+ + Mg2+）-ATP酶。6 nM钙调蛋白引起的半数最大激活分别被10(-3) M维拉帕米和10(-3) M地尔硫䓬拮抗25.1%和12.1%。这种抑制似乎对钙调蛋白激活具有特异性，因为基础活性不受这些药物影响。硝苯地平对基础或钙调蛋白刺激的（Ca2+ + Mg2+）-ATP酶活性没有影响。与维拉帕米和地尔硫䓬在高亲和力通道位点的二氢吡啶调节结合不同，该系统中的硝苯地平不会改变维拉帕米和地尔硫䓬的抑制反应。在整个钙调蛋白浓度范围内，这两种药物的钙调蛋白介导的拮抗作用显示出严格的加和性，并且似乎主要改变Vmax，在较小程度上改变钙调蛋白对（Ca2+ + Mg2+）-ATP酶的亲和力。结论是，该模型系统为各类钙拮抗剂之间的其他功能差异提供了证据。
