Studies on the role of Ttype calcium channels in the cardiovascular system using a specific inhibitor

使用特定抑制剂研究 T 型钙通道在心血管系统中的作用

• 批准号: 18590243
• 负责人: TANAKA Hikaru
• 金额: $ 2.57万
• 依托单位: Toho University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590243/
• 关键词: T-type calcium channel; dihvelrnnvricline; heart rate; action notential; sinoatrial node; エホニジピン; 心収縮力; 幼若期; 心臓; 自動能

The T-type calcium channel has different properties and distribution for those of the L-type. It is considered to be involved in various physiological and pathophysiological phenomena such as cardiac automaticity, secretion of various active substances, and is therefore anticipated to be a novel therapeutic target. In the this project, I studied the physiological role of the T-type calcium channel using R (-) -efonidipine, the specific inhibitor I found in my previous studies. Contractile force experiments with isolated murine ventricular tissue revealed that the T-type calcium channel contributes to myocardial contraction in the fetal period but not at adulthood. Activation of the T-type calcium channel was involved in the endothelin- 1-induced positive inotropy. Microelectrode recordings in isolated sinoatrial-node preparations revealed that the T-type calcium channel is involved in the pacemaker depolarization of the mouse and guinea-pig but not in the rabbit, which agreed with earliler data on current density. This indicated that the different contribution of the T-type calcium current to pacemaking underlies species difference in heart rate. As it was shown that the factors which determines heart rate is different among species and the condition of the heart, extension of the present study to hearts from various pathological models may lead to the development of novel pharmacological therapy through regulation of heart rate.

T型钙通道与L型钙通道具有不同的特性和分布。它被认为参与各种生理和病理生理现象，例如心脏自动性、各种活性物质的分泌，因此有望成为新的治疗靶点。在这个项目中，我使用R(-)-依福地平（我在之前的研究中发现的特异性抑制剂）研究了T型钙通道的生理作用。对离体小鼠心室组织进行的收缩力实验表明，T 型钙通道有助于胎儿期的心肌收缩，但在成年期则无作用。 T型钙通道的激活参与了内皮素-1诱导的正性肌力。孤立窦房结制剂中的微电极记录显示，T 型钙通道参与小鼠和豚鼠的起搏器去极化，但不参与兔子的起搏器去极化，这与早期的电流密度数据一致。这表明T型钙电流对起搏的不同贡献是心率物种差异的基础。由于研究表明，决定心率的因素因物种和心脏状况而异，因此将本研究扩展到各种病理模型的心脏可能会导致通过调节心率开发新的药物疗法。

项目成果

SERCA活性化薬によるSTZ誘発性糖尿病マウス摘出心室筋のCa2+排出と弛緩機能の改善

SERCA激活剂改善STZ诱导的糖尿病小鼠离体心室肌的Ca2+排泄和舒张功能

• 发表时间: 2008
• 作者: 松田智行;伊藤美恵;石丸小夜子;鶴岡範子;齋藤智亮;橋本哲郎;田中光;重信弘毅;杉本貴彦;田中光;小川亨;行方衣由紀;野内秀明;宇野洋司;大原皆人
• 通讯作者: 大原皆人

Tanaka H., Shigenobu K. : Quantitative fluorescence measurement of cardiac Na^+/Ca^<2+> exchanger inhibition by kinetic analysis in stably transfected HEK293 cells.

Tanaka H.，Shigenobu K.：通过稳定转染的HEK293细胞中的动力学分析定量荧光测量心脏Na 2 /Ca 2 交换体抑制。

• 发表时间: 2006
• 期刊: J. Pharmacol. Sci. 101
• 作者: 行方衣由紀;川西徹;飯田田中直子;田中光;重信弘毅
• 通讯作者: 重信弘毅

Involvement of the Na^+/Ca^+ exchanger in ouabaininduced inotropy and arrhythmogenesis in guinea-pig myocardium as revealed by SEAO400

SEAO400 揭示了 Na^/Ca^ 交换剂参与哇巴因诱导的豚鼠心肌正性肌力和心律失常发生

• 发表时间: 2007
• 期刊: J. Pharmacol. Sci 103
• 作者: Tanaka;H.;Shimada;H.;Namekata;I.;Kawanishi;T.;lida-Tanaka;N.;Shigenobu;K
• 通讯作者: K

Blockade by NIP-142 of carbachol-induced action potential shortening and GIRK 1/4 channel.

NIP-142 阻断卡巴胆碱诱导的动作电位缩短和 GIRK 1/4 通道。

• 发表时间: 2006
• 期刊: J. Pharmacol. Sci. 101
• 作者: 松田智行;伊藤美恵;石丸小夜子;鶴岡範子;齋藤智亮;橋本哲郎;田中光;重信弘毅
• 通讯作者: 重信弘毅

Effect of R(-)-efonidipine,a selective T-type Ca^<2+> channel blocker,on myocardial automaticity

选择性T型Ca^2通道阻滞剂R(-)-依福地平对心肌自律性的影响

• 发表时间: 2006
• 作者: Chisa KOMIKADO;Hikaru TANAKA;et. al.
• 通讯作者: et. al.