Spedding M, Cavero I
Life Sci. 1984 Aug 6;35(6):575-87. doi: 10.1016/0024-3205(84)90252-2.
This minireview discusses some simple pharmacological tests useful in detecting biological activity (screening), characterizing mechanisms of action and predicting possible therapeutic applications for calcium antagonists in general and calcium slow channel blockers in particular. In smooth muscle preparations these agents inhibit mechanical effects evoked by K+-depolarization which selectively opens voltage-operated calcium channels (VOC) to allow extracellular Ca++ into the cytosol. In contrast, any inhibition of receptor-mediated responses by calcium antagonists appears to depend on the transduction system and the specific cellular mechanism (e.g. VOC opening consequent to partial depolarization) activated by the receptor and, evidently, on ancillary pharmacological properties of the studied compound. For instance, whereas calcium slow channel blockers antagonize contractions produced by norepinephrine and K+-depolarization in the rat isolated portal vein, they inhibit effectively only the latter response in the rabbit aorta. This apparent discrepancy may be accounted for by the different pool of Ca++ mobilized in the two tissues by norepinephrine. Agents (e.g. diphenylalkylamines, calmodulin blockers) that impair the interaction of Ca++ with intracellular proteins produce effects which are less specific than those of slow channel blockers. Currently, the pharmacological profile of calcium antagonists can be appropriately defined by studying their effects on radioligand (dihydropyridine) binding, radioactive calcium movements through biological membranes, electrophysiological parameters in cardiac and vascular smooth muscle and on various in vivo cardiovascular preparations. Together, these approaches allow a functional classification of new calcium antagonists in relation to already known compounds and some hypotheses on their potential clinical applications. Finally, desirable pharmacokinetics and pharmacological properties for novel calcium antagonists are mentioned. This point will be further explored in the forthcoming minireview which will deal with the clinical applications of calcium antagonists.
本综述讨论了一些简单的药理学试验，这些试验可用于检测生物活性（筛选）、表征作用机制以及预测钙拮抗剂（尤其是钙慢通道阻滞剂）的潜在治疗应用。在平滑肌制剂中，这些药物可抑制由钾离子去极化诱发的机械效应，钾离子去极化会选择性地打开电压门控钙通道（VOC），使细胞外钙离子进入细胞质。相比之下，钙拮抗剂对受体介导反应的任何抑制作用似乎都取决于转导系统以及受体激活的特定细胞机制（例如部分去极化后导致的VOC开放），显然还取决于所研究化合物的辅助药理学特性。例如，虽然钙慢通道阻滞剂可拮抗去甲肾上腺素和钾离子去极化在大鼠离体门静脉中产生的收缩，但它们仅能有效抑制兔主动脉中的后一种反应。这种明显的差异可能是由于去甲肾上腺素在两种组织中动员的不同钙离子池所致。损害钙离子与细胞内蛋白质相互作用的药物（如二苯烷基胺、钙调蛋白阻滞剂）产生的效应不如慢通道阻滞剂那样具有特异性。目前，通过研究钙拮抗剂对放射性配体（二氢吡啶）结合、放射性钙通过生物膜的移动、心脏和血管平滑肌的电生理参数以及各种体内心血管制剂的影响，可以适当地定义其药理学特征。这些方法共同作用，可根据已知化合物对新的钙拮抗剂进行功能分类，并对其潜在临床应用提出一些假设。最后，提到了新型钙拮抗剂理想的药代动力学和药理学特性。这一点将在即将发表的综述中进一步探讨，该综述将讨论钙拮抗剂的临床应用。
