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

通过模型动物开发治疗充血性心力衰竭的新型治疗剂

• 批准号: 11557203
• 负责人: ENDOH Masao
• 金额: $ 8.64万
• 依托单位: Yamagata University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11557203/
• 关键词: Ca^<2+> sensitizers; Pimobendan; Levosimendan; OR-1896; UD-CG 212 Cl; Upstream mechanism; Central mechanis; Downstream mechanism; cAMP; 容量負荷モデル; レボシメンダン; OR1896; UD-CG212Cl; PDE III阻害作用; 容量負荷心; 心不全; 心肥大; ベータ受容体; 心筋収縮性; 収縮タンパク

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.

强心剂对心肌收缩力的调节是通过细胞内Ca^<2+>动员的增加（上游机制）、Ca^<2+>与肌钙蛋白C （TnC）结合亲和力的增加（中枢机制）以及Ca^<2+>与TnC结合后的过程的促进（下游机制）来实现的。cAMP介导Ca^<2+>动员剂（如-肾上腺素能受体激动剂和选择性PDE III抑制剂）通过上游机制诱导的调节。这些药物同样作用于降低与camp介导的Tnl磷酸化相关的TnC的Ca^<2+>敏感性的中心机制。除了这种众所周知的cAMP作用外，我们还发现Ca^<2+>增敏剂，如左西门丹、OR-1896和UD-CG 212 Cl，需要cAMP介导的信号传导才能诱导Ca^<2+>增敏作用。这些药物将[Ca^<2+>]_i-force关系向左移动，但它们的正性肌力效应（PIE）被苯酚抑制。这些发现表明cAMP可能对Ca^<2+>的敏感性具有双重作用，即在浓度较高时，它会降低Ca^<2+>的敏感性，但在浓度较低时，它可能通过与个别强心剂对收缩蛋白的作用的交叉作用来增加Ca^<2+>的敏感性。目前还没有可用的药物主要通过Ca^<2+>致敏作用，但匹莫苯丹和左西孟丹的PIE部分是由Ca^<2+>敏感性的增加介导的。越来越多的证据表明，具有Ca^<2+>致敏作用的强心剂在临床上比纯粹通过上游机制起作用的药物更有效。需要进一步的临床试验来确定Ca^<2+>增敏剂在长期治疗充血性心力衰竭患者中的有效性。

项目成果

日野正孝: "Investigation on SCH00013,a novel cardiotonic agent with Ca^<++> sensitizing action, 1st Communication : Phosphodiesterase III inhibitory effect and class III antiarmythmic effect in guorea-pig heast."Arzneimittel-Forschung Drug Research. 49. 3-11

Masataka Hino：“对 SCH00013 的研究，一种具有 Ca^<++> 敏化作用的新型强心剂，第一次通讯：猪肝脏中的磷酸二酯酶 III 抑制作用和 III 类抗心律失常作用。”Arzneimittel-Forschung 药物研究 49. 3。 -11

吉村朗: "Investigation on SCH00013,a novel cardiotonic agent with Ca^<++> sensitizing action. 4th Communication : Influence on experimentally induced ventricular anythemia in dogs"Arzneimittel-Forschung Drug Research. 49. 25-31 (1999)

Akira Yoshimura：“对 SCH00013 的研究，一种具有 Ca^<++> 敏化作用的新型强心剂。第 4 次通讯：对狗实验诱导的心室贫血的影响”Arzneimittel-Forschung Drug Research 49. 25-31 (1999)。

Endoh,M: "Cardiac action of Angiotensin II"Heart Physiology and Pathophysiology . Fourth Edition. 609-631 (2001)

Endoh，M：“血管紧张素 II 的心脏作用”心脏生理学和病理生理学。

Chu, L.: "Biphasic inotropic response to endothalin-1 in the presence of various concentrations of norepinephrine in dog ventricular myocardium"J. Cardiovasc. Pharmacol.. 36. S9-S14 (2000)

Chu, L.：“狗心室肌中存在不同浓度的去甲肾上腺素时对内皮素-1 的双相正性肌力反应”J。

Wang, H.: "Pharmacological analysis by HOE642 and KB-R9032 of the role of Na^+/H^+ exchange in the endothetin-1-induced Ca^<2+> sigalling in rabbit ventricular myocytes"Br. J. Pharmacol.. 131. 638-644 (2000)

Wang, H.：“通过 HOE642 和 KB-R9032 对 Na^/H^ 交换在内皮素-1 诱导的兔心室肌细胞 Ca^2 信号传导中的作用进行药理学分析”Br。