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

T型钙通道与L型钙通道具有不同的性质和分布。它被认为与心脏自律性、各种活性物质的分泌等多种生理和病理生理现象有关，因此有望成为一种新的治疗靶点。在这个项目中，我使用R(-)-非那地平来研究T型钙通道的生理作用，这是我在以前的研究中发现的一种特定的抑制剂。对分离的小鼠心室组织进行的收缩力实验表明，T型钙通道在胎儿期对心肌收缩起作用，但在成年时不起作用。T型钙通道的激活参与了内皮素-1诱导的正性变力作用。在分离的窦房结标本上的微电极记录表明，T型钙通道参与了小鼠和豚鼠起搏器的去极化，而对兔则无此作用，这与早期关于电流密度的数据一致。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。由于决定心率的因素因物种和心脏状况的不同而不同，因此，将本研究从不同的病理模型扩展到心脏，可能会通过调节心率来开发新的药物疗法。

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.