BEPRIDIL AND CETIEDIL - VASODILATORS WHICH INHIBIT CA-2+-DEPENDENT CALMODULIN INTERACTIONS WITH ERYTHROCYTE-MEMBRANES
BEPRIDIL AND CETIEDIL - VASODILATORS WHICH INHIBIT CA-2+-DEPENDENT CALMODULIN INTERACTIONS WITH ERYTHROCYTE-MEMBRANES
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DOI：
10.1172/jci111497
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发表时间：
1984-01-01
影响因子：
15.9
通讯作者：
BENNETT, V
中科院分区：
文献类型：
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作者：
AGRE, P;VIRSHUP, D;BENNETT, V
两种新的血管平滑肌松弛剂，bepridil 和 cetiedil，被发现具有与三氟拉嗪相似的特定 CaM[钙调蛋白]抑制特性。三氟拉嗪、苄普地尔和西替地尔抑制Ca2+依赖性125I-CaM与红细胞膜的结合和膜Ca2+-ATP酶的CaM活化，IC50[产生50%抑制的浓度]值分别为.apprx.12、.apprx.17和.apprx.40.mu.M。这似乎不是非特异性疏水相互作用的结果，因为用微摩尔浓度的许多其他疏水剂没有观察到抑制作用。对结合和 Ca2+-ATPase 激活的主要抑制作用与 CaM 具有竞争性。苄普地尔和西替地尔直接与 CaM 结合，因为这些药物从 CaM 上的位点取代了 [3H]三氟拉嗪。 Ca2+-ATP酶和药物结合的抑制不是由于干扰该酶的催化活性，因为：这些试剂既不抑制不依赖于CaM的基础Ca2+-ATP酶活性，也不抑制蛋白水解激活的Ca2+-ATP酶活性，并且当膜与这些试剂一起预孵育但在添加125I-CaM之前洗涤时，没有检测到药物诱导的CaM结合抑制。 Bepridil 和 cetiedil 竞争性抑制 Ca2+ 依赖性 CaM 与红细胞膜的相互作用，很可能是通过这些药物与 CaM 之间的直接相互作用。这些药物的主要临床作用可以解释为它们与 CaM 或 CaM 相关蛋白的相互作用，导致某些其他组织中 Ca2+ 调节酶的激活减少，例如血管平滑肌中的肌球蛋白 L 链激酶。
Two new vascular smooth muscle relaxants, bepridil and cetiedil, were found to possess specific CaM[calmodulin]-inhibitory properties which resembled those of trifluoperazine. Trifluoperazine, bepridil and cetiedil inhibited Ca2+-dependent 125I-CaM binding to erythrocyte membranes and CaM activation of membrane Ca2+-ATPase with IC50 [concentration producing 50% inhibition] values of .apprx.12, .apprx.17, and .apprx.40 .mu.M, respectively. This does not appear to be the result of a nonspecific hydrophobic interaction since inhibition was not observed with micromolar concentrations of many other hydrophobic agents. The predominant inhibition of binding and Ca2+-ATPase activation was competitive with respect to CaM. Bepridil and cetiedil bind directly to CaM since these drugs displaced [3H]trifluoperazine from sites on CaM. Inhibition of Ca2+-ATPase and binding by the drugs was not due to interference with the catalytic activity of this enzyme since: neither inhibition of CaM-independent basal Ca2+-ATPase activity nor inhibition of proteolytically-activated Ca2+-ATPase activities were produced by these agents, and no drug-induced inhibition of CaM binding was detected when membranes were preincubated with these agents but washed prior to addition of 125I-CaM. Bepridil and cetiedil competitively inhibit Ca2+-dependent interactions of CaM with erythrocyte membranes, most likely by a direct interaction between these drugs and CaM. The principal clinical actions of these drugs may be explained by their interactions with CaM or CaM-related proteins leading to reduced activation of Ca2+-regulated enzymes in certain other tissues, such as myosin L chain kinase in vascular smooth muscle.