MORECULAR PHARMACOLOGICAL STUDY OF SIGNAL TRANSDUCTION

信号转导的更常规药理学研究

• 批准号: 11470021
• 负责人: ENDOH Masao
• 金额: $ 9.66万
• 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 Scientific Research (B)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11470021/
• 关键词: Na^+-Ca^<2+> exchange; Na^+-H^+ exchange; Intracellular alkalinization; Ca^<2+> transients; Increased Ca^<2+> sensitivity; Rabbit ventricular myocytes; Protein kinase C; Positive inotropic effect; エンドセリン; アンジオテンシンII; Na; H交換機構; Ca交換機構; Ethyli

Signal transduction processes triggered by activation of endothelin (ET) and angiotensin II (Ang II) play a crucial role in a number of cardiovascular diseases, namely in congestive heart failure, for the pathophysiological regulation of myocardial cell function and progression of the disease at the level of gene expression. Activation of α-adrenoceptors shares signal transduction triggered by these receptors. They may regulate the process of cardiac hypertrophy and remodeling. Therefore the study on the signal transduction subsequent to activation of these classes of receptor is of extreme importance for understanding of pathophysiology of cardiac diseases and for constitution of therapeutic strategies. Although activation of protein kinase C (PKC) induced by diacylglycerol (DAG), the product of stimulation of PI hydrolysis resulting from receptor activation, may be primarily involved in the regulation, phorbol esters that activate PKC and PKC inhibitors, such as calphostin C and chel … More erythrine, do not mimic the regulatory effect of receptor stimulation in intact myocardial cells.The study was carried out to elucidate the role of signal transduction, namely PI hydrolysis, in regulation of myocardial contractility in intact myocardium and myocytes. ET-1 and Ang II elicit an increase in intracellular Ca^<2+> mobilization and an increase in myofilament Ca^<2+> sensitivity. It has been postulated that the activation of PKC and subsequent activation of Na^+/H^+ exchanger that leads to intracellular alkalinization and secondary increase in intracellular Ca^<2+> ions may play a crucial role, but compelling pieces of evidence have not yet been obtained because of lack of pharmacological tools, ion exchange inhibitors, with sufficiently high selectivity, in intact myocardium.In the present study, it was clarified that selective inhibitors of Na^+/H^+ exchanger HOE642 and KB-R9032 inhibited the positive inotropic effect (the increase in shortening) of ET-1 without affecting the effect of isoproterenol in rabbit single myocytes loaded with indo-1. On the other hand, the increase in Ca^<2+> transients induced by ET-1 was inhibited by the Na^+/Ca^<2+> inhibitor KB-R7943. It became evident that ET-1 did not cause a prominent effect on L-type Ca^<2+> current by means of whole cell patch clamp in rabbit myocytes. Similar results have been obtained also with Ang II. These results indicate that stimulation of ion exchangers mediated by receptor activation with ET-1 and Ang II plays a crucial role in regulation of Ca^<2+> signaling in intact myocardial cells. Less

通过激活内皮素（ET）和血管紧张素II（ANG II）激活触发的信号转导过程在许多心血管疾病中起着至关重要的作用，即在充血性心力衰竭中，对于心脏生理学调节，对心肌细胞功能的病理生理调节和基因表达水平的疾病水平的进展。 α-肾上腺素受体的激活共享这些受体触发的信号转导。它们可能调节心脏肥大和重塑的过程。因此，对这些受体激活后的信号转导的研究对于理解心脏病的病理生理学和治疗策略的构成至关重要。 Although activation of protein kinase C (PKC) induced by diacylglycerol (DAG), the product of stimulation of PI hydrolysis resulting from receptor activation, may be primarily involved in the regulation, phorbol esters that activate PKC and PKC inhibitors, such as Calchostin C and chel … More erythrine, do not mimic the regulatory effect of receptor stimulation in intact myocardial细胞。该研究的目的是阐明信号转导的作用，即PI水解在完整心肌和心肌细胞中心肌收缩性调节中的作用。 ET-1和ANG II引起细胞内Ca^<2+>动员的增加和肌丝Ca^<2+>敏感性的增加。据推测，PKC的激活以及随后的Na^+/H^+交换器的激活，导致细胞内碱化和细胞内Ca^<2+离子的次要增加可能起着至关重要的作用，但由于缺乏足够的供应工具，因此尚未获得造成的证据，但尚未获得造成的证据。研究，澄清说，Na^+/H^+交换器HOE642和KB-R9032的选择性抑制剂抑制了ET-1的阳性肌瘤效应（增加），而不会影响异位醇在用Indo-1负载的兔单一肌细胞中的异位醇的作用。另一方面，Na^+/Ca^<2+>抑制剂KB-R7943抑制了ET-1诱导的Ca^<2+>瞬变的增加。证据表明，ET-1不会通过兔心肌细胞中的全细胞贴片夹对L型Ca^<2+>电流产生显着影响。 ANG II也获得了类似的结果。这些结果表明，用ET-1和ANG II受体激活介导的离子交换的刺激在调节完整心肌细胞中的Ca^<2+>信号传导中起着至关重要的作用。较少的

项目成果

Chu,L.: "Biphasic inotropic response to endothelin-I 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-I 的双相正性肌力反应。”J.Cardiovasc.Pharmacol.. 36. S9-S14 (2000)

Wang H. Sakurai K, Endoh M.: "Pharmacological analysis by HOE642 and KB-R9032 of the role or Na^+/H^+ exchange in the endothelin-1-induced Ca^<2+> signalling in rabbit ventricular myocytes"Br J Pharmacol. Oct; 131(3). 638-44 (2000)

Wang H. Sakurai K、Endoh M.：“HOE642 和 KB-R9032 对兔心室肌细胞内皮素-1 诱导的 Ca^2 信号传导中 Na^/H^ 作用或 Na^/H^ 交换的药理学分析”Br J Pharmacol

Chu L, Endoh M.: "Biphasic inotropic response to endothelin-1 in the presence of various concentrations of norepinephrine in dog ventricular myocardium"J Cartliovasc Pharmacol. 36 Suppl 2. 9-14 (2000)

Chu L, Endoh M.：“狗心室心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 Cartliovasc Pharmacol。

渡辺知緒: "Characterization of the endothelin-1-induced regulation of L-type Ca^<2+> current in rabbit ventricular myocytes."Naunyn-Schmiedeberg's Arch.Pharmacol.. 360. 654-664 (1999)

Tomoo Watanabe：“兔心室肌细胞中内皮素-1 诱导的 L 型 Ca^2+ 电流调节的特征。”Naunyn-Schmiedebergs Arch.Pharmacol.. 360. 654-664 (1999)

Qiao,X.: "Pharmacological characteristics of inhibitory action of the selective α_1-antagonist JTH-601 on the positive inotropic effect mediated by α_1-adrenoceptors in isolated rabbit papillary muscle."Jpn.J.Pharmacol.. 84. 301-309 (2000)

乔X.：“选择性α_1-拮抗剂JTH-601对离体兔乳头肌中α_1-肾上腺素受体介导的正性肌力作用的抑制作用的药理学特征。”Jpn.J.Pharmacol.. 84. 301-309（ 2000)