Development of novel cardiotonic agents

新型强心剂的开发

• 批准号: 04557009
• 负责人: ENDOH Masao
• 金额: $ 7.42万
• 依托单位: Yamagata University School of Medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Developmental Scientific Research (B)
• 财政年份: 1992
• 资助国家: 日本
• 起止时间: 1992 至 1994
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-04557009/
• 关键词: OPC-18790; OPC-8212; positive inotropic effect; cyclic AMP; Ca^<2+> sensitizers; intracelluar Ca^<2+>; Org 9731; mechanism of action of cardiotonics; Org30029; Org9731; 新しい強心薬; Denopamine; Caセンシタイザー; CAMP; PDE-III阻害薬; Y-20487; カルバコール

The purpose of the study was to elucidate the mechanism of action of novel cardiotonic agents to provide basic information about useful for clinical application of these agents. Among new compounds investigated, Org 30029 [N-hydroxy-5,6-dimethoxybenzo [b] thiophene-2-carboximide hydrochloride] was the agent with most efficacious positive inotropic effect (PIE), which was mainly due to an increase in Ca^<2+> sensitivity of myofibrils. Because agents belonging to this class (Ca^<2+> sensitizer) neither require activation energy nor cause Ca^<2+> overload, they may provide beneficial clinical procedures to cure the patients with heart failure. Org 3731 with a slight modification of chemical structure of Org 30029 had much less Ca^<2+> sensitizing action and acted mainly by PDE inhibition, indicating that the site of these actions may possess a closely related characteristic. Another result obtained are concerned with the mechanism of action of PDE III inhibitors in intact cardiac muscle. … More These are summarized as follows : 1) PDE isozymes involved in cAMP hydrolysis in mammalian cardiac muscle show a wide range of species dependent variation ; 2) PDE inhibitors have a dual action, i.e., a direct PIE and the action to potentiate the PIE of adrenoceptor activation. The former action requires much higher concentration than the latter, which has a crucial meaning in clinical application of these agents ; 3) some novel compounds such as vesnarinone and pimobendan possess ancillary actions in addition to PDE inhibition. Since both agents have beneficial effects on the prognosis (survival rate) of the patients with severe heart failure, it is important to differentiate which mechanisms contribute most significantly to the clinical usefulness ; 4) while cAMP decreases the Ca^<2+> sensitivity of myofibrils in association with phosphorylation of troponin I,PDE III inhibitors did not produce such an action in contrast to beta- agonists, implying the intracellular compartmentation of cAMP in myocardial cells. Pathophysiological relevance of this difference under clinical setting is unknown for the time being and requires further study. Several novel agents have been developed, but there are no agents so far to replace digitalis in the treatment of heart failure. Further intensive effort will be required including evaluation of the clinical usefulness of these agents by careful investigation and synthesis of new agents with novel mechanism. Less

本研究旨在阐明新型强心剂的作用机制，为该类药物的临床应用提供基础资料。在研究的新化合物中，Org 30029 [n -羟基-5,6-二甲氧基苯并[b]噻吩-2-盐酸碳酰亚胺]是最有效的正性肌力作用（PIE）剂，主要是由于增加了肌原纤维对Ca^<2+>的敏感性。由于这类药物（Ca^<2+>敏化剂）既不需要活化能，也不引起Ca^<2+>过载，因此它们可能为治疗心力衰竭患者提供有益的临床方法。Org 3731与Org 30029的化学结构发生了轻微的变化，其对Ca^<2+>的增敏作用明显减弱，主要通过PDE抑制作用，表明这些作用位点可能具有密切相关的特征。获得的另一个结果与PDE III抑制剂在完整心肌中的作用机制有关。主要研究结果如下：1)哺乳动物心肌中参与cAMP水解的PDE同工酶具有广泛的物种依赖性；2) PDE抑制剂具有双重作用，即直接的PIE作用和增强肾上腺素能受体激活的PIE作用。前者的作用浓度远高于后者，这对这些药物的临床应用具有至关重要的意义；3)一些新的化合物如蛇皮苷酮和匹莫苯丹除了抑制PDE外还具有辅助作用。由于这两种药物对严重心力衰竭患者的预后（生存率）都有有益的影响，因此区分哪种机制对临床有用性贡献最大是很重要的；4)虽然cAMP降低肌原纤维的Ca^<2+>敏感性与肌钙蛋白I的磷酸化有关，但与β -激动剂相比，PDE III抑制剂没有产生这种作用，这表明cAMP在心肌细胞中存在细胞内区隔。这种差异在临床环境下的病理生理相关性尚不清楚，需要进一步研究。一些新的药物已经开发出来，但目前还没有药物可以取代洋地黄治疗心力衰竭。需要进一步的努力，包括通过仔细研究和合成具有新机制的新药来评估这些药物的临床有效性。少

项目成果

遠藤 政夫: "The effects of theophylline on aequorin lighe transients and force in the isolated dog right ventricular myocardium." J.Mol.Cell.Cardiol.26. 87-98 (1994)

Masao Endo：“茶碱对离体狗右心室心肌中水母发光蛋白瞬变和力的影响。”J.Mol.Cell.Cardiol.26（1994）。

遠藤 政夫: "心筋細胞機能調節機構と細胞内カルシウム:新しい心不全治療薬の作用機序解明" 臨床薬理の進歩'92別刷. 13. 3-22 (1992)

Masao Endo：“心肌细胞功能调节机制和细胞内钙：新型心力衰竭治疗药物的作用机制的阐明”临床药理学进展92转载。

遠藤政夫: "The effects of theophylline on aequorin light transients and force in the isolated dog right ventricular myocardium." J. Mol. Cell. Cardiol. 26. 87-98 (1994)

Masao Endo：“茶碱对离体狗右心室心肌中水母发光蛋白瞬变和力的影响。”J. Mol Cell。

Katano, Y., Ishihata, A., Morinobu, S., Endoh, M.: "Modulation by aging of the coronary vascular response to endothelin-1 in the rat isolated perfused heart." Naunyn-Schmiedeberg's Arch. Pharmacol.348. 82-27 (1993)

Katano, Y.、Ishihata, A.、Morinobu, S.、Endoh, M.：“大鼠离体灌注心脏中冠状血管对内皮素-1 反应的老化调节。”

片野 由美: "Cyclic AMP metabolism in intact rat ventricular cardiac myocytes:Interaction of carbachol with isoproterenol and 3-isobutyl-1-methylxanthine." Mol.Cel.Biochem.119. 195-201 (1993)

Yumi Katano：“完整大鼠心室心肌细胞中的环 AMP 代谢：卡巴胆碱与异丙肾上腺素和 3-异丁基-1-甲基黄嘌呤的相互作用。Mol.Cel.Biochem.119（1993）”