Bayer R, Schwarzmaier J, Pernice R
Institute for Clinical Physiology, University of Düsseldorf, Federal Republic of Germany.
Curr Med Res Opin. 1988;11(4):254-72. doi: 10.1185/03007998809114244.
The calcium antagonists prenylamine and fendiline both bind with rather low affinity to the dihydropyridine (nifedipine) binding site. As calmodulin (CaM) antagonists, they both inhibit CaM-dependent enzymes and relax smooth muscle preparation in nearly the same concentration range. If compared with other calcium antagonists, their action on smooth muscle develops rather slowly and cannot be inhibited by the calcium agonist Bay k 8644. In contrast, basic pharmacology reveals major differences of the actions of prenylamine and fendiline in heart muscle, indicating that, after all, the change in structure close to the asymmetric carbon strongly influences the molecular action of the compounds and their respective isomers. The negative inotropic effect of racemic prenylamine is rather independent of stimulation rate, whereas fendiline preferably depresses contraction at high rate stimulation. The negative inotropic potencies are determined by the (-)-isomers, but only in the case of prenylamine the isomeric ratio of 6 reveals a considerable stereoselectivity of action. In low concentrations and preferably at low rate stimulation, (+)-prenylamine exerts a strong positive inotropic effect. At low rate stimulation, total duration of transmembrane action potential is prolonged by (+/-)- and (+)-prenylamine, but discretely shortened by (+/-)- and (+)-fendiline. At high rate stimulation, it is shortened by (+/-)- and (-)-prenylamine, but prolonged (only) at the very final repolarization level by (+/-)- and (-)-fendiline. The positive inotropic action of prenylamine and the prolongation of action potential at low stimulation rate can be interpreted as a calcium agonistic side-effect due to the action of the (+)-isomer. It seems possible that, under the condition of low heart rate, prenylamine (as reported for the calcium agonist Bay k 8644) increases the potential-dependent transmembrane calcium current. In addition, it is argued that during the long-lasting action potential, a reactivation of the calcium current induces early after-depolarizations. These effects are postulated to represent the main mechanisms triggering torsade de pointes during therapy with prenylamine. Though fendiline, from a chemical point of view, rather resembles prenylamine, its pharmacological profile is different. In particular, in regard to electrophysiology, torsade de pointes are not expected to be induced by fendiline.
钙拮抗剂普尼拉明和芬地林与二氢吡啶（硝苯地平）结合位点的亲和力都相当低。作为钙调蛋白（CaM）拮抗剂，它们在几乎相同的浓度范围内均能抑制CaM依赖性酶并使平滑肌制剂松弛。与其他钙拮抗剂相比，它们对平滑肌的作用起效相当缓慢，且不能被钙激动剂Bay k 8644抑制。相比之下，基础药理学揭示了普尼拉明和芬地林在心肌作用方面的主要差异，这表明毕竟靠近不对称碳原子的结构变化强烈影响化合物及其各自异构体的分子作用。消旋普尼拉明的负性肌力作用相当独立于刺激频率，而芬地林在高频率刺激时更倾向于抑制收缩。负性肌力作用强度由（-）-异构体决定，但仅在普尼拉明的情况下，6的异构体比例显示出相当大的作用立体选择性。在低浓度且优选低频率刺激时，（+）-普尼拉明发挥强烈的正性肌力作用。在低频率刺激时，（±）-和（+）-普尼拉明可延长跨膜动作电位的总持续时间，但（±）-和（+）-芬地林会使其略微缩短。在高频率刺激时，（±）-和（-）-普尼拉明会使其缩短，但（±）-和（-）-芬地林仅在极终复极化水平使其延长。普尼拉明的正性肌力作用以及低刺激频率下动作电位的延长可解释为（+）-异构体作用导致的钙激动剂副作用。在心率较低的情况下，普尼拉明（如钙激动剂Bay k 8644的报道）似乎有可能增加电压依赖性跨膜钙电流。此外，有人认为在持久的动作电位期间，钙电流的重新激活会诱发早期后去极化。这些效应被假定为普尼拉明治疗期间引发尖端扭转型室速的主要机制。尽管从化学角度来看，芬地林与普尼拉明颇为相似，但其药理学特征却有所不同。特别是在电生理学方面，预计芬地林不会诱发尖端扭转型室速。
