Basic and applied studies on cardiotonic

强心剂的基础与应用研究

• 批准号: 05557103
• 负责人: OHIZUMI Yasushi
• 金额: $ 4.48万
• 依托单位: TOHOKU UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Developmental Scientific Research (B)
• 财政年份: 1993
• 资助国家: 日本
• 起止时间: 1993 至 1995
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-05557103/
• 关键词: Gingerol; Xestquinone; Myosin; Ca; Ca pump; Evodiamine; 強心薬; チャンネル; Ca^<2+>ATPアーゼ

During recent years there have been numerous effeors to find and develop novel cardiotonic agensts that are more effeorive and more selective than the cardiac glycosides or catecholamines. [8]-Gingerol produced a concentration-dependent positive inotropic effect on guinea pig isolated left atria. The inotropic effect of gingerol was abolished by ryanodine. Furthermore, our pharmacological studies suggest that the enhancement of the Ca^<2+>-pumping activity of sarcoplasmic reticulum (SR) plays an important role in the cardiotonic action of gingerol. We synthesized gingerol related compounds (AP-004, AP-005 and AP-015) and investigated the effects of these compounds on the Ca^<2+>-ATPase activity of SR.The Ca^<2+>-ATPase activity and the Ca^<2+>-pumping activity increased by these compounds in a concentration-dependent manner. It is probable that both o-methoxy phenol and hydeocarbon chain in the molecule of gingerol analogues are a request for activation of the Ca^<2+>-pumping ATPase.In … More the course of our survey of cardiotonic substances from natural sources having unique mechanism of action, xestoquinone (XQN) was isolated and purified as a powerfully cardiotonic principle of an Okinawa sea sponge Xestospongia sapra. Our pharmacological data suggest that an enhancement of intracellular cyclic AMP content and Ca^<2+> influx across the cell membrane contribute to the late phase of XQN-caused cardiotonic responses, wheres the early phase may largely be elicited through direct activation of contractile elements. XQN may provide an novel leading compound for valuable cardiotonic agents. Unlike N-ethylmaleimide, modification of 2 mol of SH groups per myosin by xestoxinone caused a marked increase in the actomyosin ATPase activity. XQN modifies the specific SH groups in myosin distinct from SH_1 and SH_2, resulting in activation of actocyosin ATPase.The crude acetone extract of the fruits of Evodia retaecarpa Bentham (Rutaceae) exhibited a positive inotropic effect with a novel mechanism on the guinea pig isolated left atria. Less

近年来，人们一直在努力寻找和开发比强心苷或儿茶酚胺更有效、更有选择性的新型强心药物。[8]-姜酚对豚鼠离体左心房产生浓度依赖性正性肌力作用。姜辣素的正性肌力作用可被ryanodine阻断。此外，我们的药理学研究表明，增强肌浆网（SR）的Ca^<2+>泵活性在姜酚的强心作用中起着重要作用。我们合成了姜辣素相关化合物AP-004、AP-005和AP-015，并研究了这些化合物对SR的Ca^<2+>-ATP酶活性的影响，发现这些化合物以浓度依赖的方式增加SR的Ca^<2+>-ATP酶活性和Ca^<2+>泵活性。姜酚类似物分子中的邻甲氧基苯酚和碳氢链可能是激活Ca^2+泵ATP酶的必要条件。 ...更多信息 在我们对来自天然来源的具有独特作用机制的强心物质的研究过程中，分离并纯化了作为冲绳海绵Xestospongiasapra的强心成分的Xestoquinone（XQN）。我们的药理学数据表明，细胞内cAMP含量的增加和Ca^2+穿过细胞膜的内流有助于XQN引起的强心反应的晚期，而早期主要是通过直接激活收缩元件引起的。XQN可能为有价值的强心药物提供新的先导化合物。不像N-乙基马来酰亚胺，修改2摩尔的SH基团每个肌球蛋白的xestoxinone引起的肌动球蛋白ATP酶活性显着增加。XQN修饰了肌球蛋白中不同于SH_1和SH_2的SH基团，激活了肌动球蛋白ATP酶。吴茱萸果实丙酮粗提物对豚鼠离体左心房有正性肌力作用，其作用机制新颖。少

项目成果

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Imaizumi, Y.: "Effects of 9-methyl-7-bromoeudistomin D (MBED), a powerful Ca^<2+> releaser, on smooth muscles of the guinea pig" The Annals of the New York Academy of Science, 565 (1993)

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