Silver P J
J Cardiovasc Pharmacol. 1986;8 Suppl 9:S34-46.
The Ca2+-dependent regulation of contractile protein interactions in cardiac and vascular smooth muscle involves structurally related but distinct Ca2+ binding proteins. In vascular smooth muscle, Ca2+ binds to calmodulin, and Ca2+-calmodulin activates myosin light chain (MLC) kinase with ultimate stimulation of MLC phosphorylation and actin-myosin interactions. The largest class of inhibitors of vascular contractile protein interactions are the calmodulin antagonists which include certain Ca2+ entry blockers. Pharmacologically, some of these agents can be distinguished from pure Ca2+ entry blockers by being more effective vs. vasoconstrictor agents in vitro, less cardiac depressant, and more effective as platelet aggregation inhibitors. An even greater distinction from Ca2+ entry blockers is evident with another series of agents, isoquinolinesulfonamides, which directly inhibit protein kinase activity. Cardiac muscle myofibrillar regulation involves Ca2+ binding to troponin C (TnC). Some cardiotonics, such as Vardax and APP 201-533, increase the Ca2+ sensitivity of cardiac myofibrillar ATPase activity with a concomitant increase in Ca2+ binding to TnC. Several calmodulin antagonists, Ca2+ blockers, and structurally related agents differentially affect cardiac myofibrillar ATPase activity. Potency and efficacy of some of these stimulating agents is markedly greater than Vardax or APP 201-533. Mechanistically, all agents do not affect cardiac MLC phosphorylation, but directly enhance the Ca2+ sensitivity of ATPase activity. However, differential effects on basal and maximum ATPase activity by some agents suggest more complex or additional effects which are related to the type of agent as well as the species (dog vs. hamster). A major subcellular defect in congestive heart failure in various small animal models is a depressed maximum ATPase activity. Thus, a desired goal would be a pharmacological modulator which increases maximum ATPase activity, not necessarily Ca2+ sensitivity. In sum, it is possible to identify agents, Ca2+ binding protein modulators, which directly inhibit vascular smooth muscle and stimulate cardiac muscle contractile protein interactions. The potential advantages/disadvantages of this approach for vasodilator/cardiotonic drug development will have to await future development of novel compounds targeted specifically for these cellular regulatory processes.
心肌和血管平滑肌中收缩蛋白相互作用的钙依赖性调节涉及结构相关但不同的钙结合蛋白。在血管平滑肌中，钙与钙调蛋白结合，钙 - 钙调蛋白激活肌球蛋白轻链（MLC）激酶，最终刺激MLC磷酸化和肌动蛋白 - 肌球蛋白相互作用。血管收缩蛋白相互作用的最大一类抑制剂是钙调蛋白拮抗剂，其中包括某些钙通道阻滞剂。从药理学角度来看，这些药物中的一些与纯钙通道阻滞剂的区别在于，它们在体外对血管收缩剂更有效，对心脏的抑制作用更小，并且作为血小板聚集抑制剂更有效。与钙通道阻滞剂更明显的区别在于另一系列药物，异喹啉磺酰胺，它们直接抑制蛋白激酶活性。心肌肌原纤维调节涉及钙与肌钙蛋白C（TnC）结合。一些强心剂，如Vardax和APP 201 - 533，增加心肌肌原纤维ATP酶活性的钙敏感性，同时增加钙与TnC的结合。几种钙调蛋白拮抗剂、钙通道阻滞剂和结构相关药物对心肌肌原纤维ATP酶活性有不同影响。其中一些刺激剂的效力和功效明显大于Vardax或APP 201 - 533。从机制上讲，所有药物都不影响心肌MLC磷酸化，但直接增强ATP酶活性的钙敏感性。然而，一些药物对基础和最大ATP酶活性的不同影响表明存在更复杂或额外的影响，这与药物类型以及物种（狗与仓鼠）有关。各种小动物模型中充血性心力衰竭的一个主要亚细胞缺陷是最大ATP酶活性降低。因此，一个理想的目标将是一种药理学调节剂，它能增加最大ATP酶活性，而不一定是钙敏感性。总之，有可能鉴定出直接抑制血管平滑肌并刺激心肌收缩蛋白相互作用的药物，即钙结合蛋白调节剂。这种方法在血管扩张剂/强心药物开发中的潜在优点/缺点将不得不等待专门针对这些细胞调节过程的新型化合物的未来发展。
