Development of Novel Therapeutic Agents for Treatment of Congestive Heart Failure by Means of Model Animals

强心剂对心肌收缩能力的调节是通过增加细胞内钙动员(上游机制)、提高钙与肌钙蛋白C的结合亲和力(中央机制)以及促进钙与肌钙蛋白C结合后的过程(下游机制)来实现的。CAMP通过上游机制介导钙激动剂如肾上腺素能受体激动剂和选择性PDE III抑制剂的调节作用。这些药物在与cAMP介导的TNL磷酸化相关的降低TNC钙敏感性的中枢机制中起着同样的作用。除了cAMP的这种众所周知的作用外，我们还揭示了钙增敏剂，如左西孟丹、OR-1896和UD-CG 212Cl，需要cAMP介导的信号来诱导钙增敏效应。这些药物使[Ca^&lt；2+&gt；]_i-force关系左移，但它们的正性变力作用(PIE)被氨基甲胆碱抑制。这些发现表明，cAMP可能对钙敏感性具有双重作用，依赖于浓度的不同，即在较高浓度时，它降低钙敏感性，但在较低浓度时，它可能通过与个别强心剂对收缩蛋白作用的串扰而增加钙敏感性。目前还没有可用的药物主要通过钙敏感性发挥作用，但匹莫本丹和左西孟丹的馅饼部分是通过增加钙敏感性而起作用的。越来越多的证据表明，具有钙增敏作用的强心剂在临床上比单纯通过上游机制起作用的强心剂更有效。需要进一步的临床试验来确定钙增敏剂在充血性心力衰竭患者的长期治疗中的有效性。

Regulation of myocardial contractility by cardiotonic agents is achieved by an increase in intracellular Ca^<2+> mobilization (upstream mechanism), an increase in Ca^<2+> binding affinity to troponin C (TnC; central mechanism) and facilitation of the process subsequent to the Ca^<2+> binding to TnC (downstream mechanism). cAMP mediates the regulation induced by Ca^<2+> mobilizers such as _-adrenoceptor agonists and selective PDE III inhibitors acting through the upstream mechanism. These agents act likewise on the central mechanism to decrease Ca^<2+> sensitivity of TnC in association with the cAMP-mediated phosphorylation of Tnl. In addition to such a well-known action of cAMP, we revealed that Ca^<2+> sensitizers, such as levosimendan, OR-1896 and UD-CG 212 Cl, require cAMP-mediated signaling to induce the Ca^<2+> sensitizing effect. These agents shift the [Ca^<2+>]_i-force relationship to the left, but their positive inotropic effect (PIE) is inhibited by carbachol. These findings imply that cAMP may have a dual action on the Ca^<2+> sensitivity depending on the concentration, i.e., at higher concentrations it decreases the Ca^<2+> sensitivity, but at lower concentrations it may increase the Ca^<2+> sensitivity by cross talk with the action of individual cardiotonic agents on contractile proteins. No currently available agents act primarily via Ca^<2+> sensitization, but the PIE of pimobendan and levosimendan is partly mediated by an increase in Ca^<2+> sensitivity. Pieces of evidence are accumulating that cardiotonic agents with Ca^<2+> sensitizing effects are clinically more effective than the agents that act purely via the upstream mechanism. Further clinical trials are required to establish the effectiveness of Ca^<2+> sensitizers in long-term therapy of congestive heart failure patients.