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Studies on the developmental and species difference of cardiac function : physiological specificity of mouse and generalization of species difference

心脏功能的发育和物种差异的研究：小鼠的生理特异性和物种差异的普遍化

基本信息

批准号：
15590235
负责人：
SHIGENOBU Koki
金额：
$ 2.18万
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：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

项目摘要

1)Negative inotropic response to α-receptor stimulation was examined with various selective antagonists. As a result, it was suggested that this response is mediated by tyrosine kinase, D-phosphatide phosphohydrolase pathway, and the activation of protein kinase C. Finally, as confirmed in the previous study, it is considered that the negative inotropy is produced by the augmentation of reverse mode of Na^+, Ca2+-exchange reaction.2)In contrast to ventricular muscle, ET-1, AII, and PGF2α produces positive inotropic effect., the mechanism of which was examined. Since the positive inotropy produced by the above agents was inhibited by an inhibitor of Rho-associated kinase (ROCK), Y-27632, it was suggested that Rho/ROCK pathway is involved in this response.3)As a mechanism underlying the specific nature of mouse myocardium including negative inotropy by α1-receptor stimulation of ET-1, etc., the involvement of Na+, Ca2+-exchange reaction (NCX) was suggested. This was able to be clarified with using a selective NCX inhibitor, SEA0400, which was developed by ourselves.1.NCX is involved in the Ca extrusion during the late repolarization phase of mouse ventricular action potential.2.Negative staircase phenomenon observed specifically in mouse ventricle can be explained by the augmented Ca extrusion via NCX at high frequency of contraction leading to the diminution of the amount of Ca which can be controlled by SR function.3.Negative inotropy produced by α-stimulation, ATII and ET-1 is basically the same in their mechanism, i.e., activation of NCX.4.Developmental change from positive to negative of the inotropic response to α-stimulation is explained by the decrease in the contribution of Na+,H+-exchange reaction to contractile function and the increase in the contribution of NCX.

1)用多种选择性拮抗剂检测α-受体刺激的负性肌力反应。因此，我们认为这种反应是由酪氨酸激酶、d -磷脂磷酸水解酶途径和蛋白激酶c的激活介导的。最后，正如之前的研究证实的那样，我们认为负性肌力是通过Na^+、Ca2+交换反应的反向模式增强而产生的。2)与心室肌相反，ET-1、AII和PGF2α具有正性肌力作用。，对其机理进行了研究。由于上述药物产生的正性肌力被Rho相关激酶（ROCK）抑制剂Y-27632所抑制，这表明Rho/ROCK途径参与了这种反应。3) α -1受体刺激ET-1等引起小鼠心肌负性肌力变化的机制可能与Na+， Ca2+-交换反应（NCX）有关。这可以通过使用我们开发的选择性NCX抑制剂SEA0400来澄清。NCX参与了小鼠心室动作电位复极化后期Ca的挤压。在小鼠心室中观察到的负阶梯现象可以解释为在高收缩频率下NCX增强钙挤压导致钙量减少，而钙的减少可由SR功能控制。α-刺激、ATII和ET-1产生负性肌力的机制基本相同，都是激活ncx。α-刺激下肌力反应由正向负的发育变化可以解释为Na+、H+交换反应对收缩功能的贡献减少而NCX的贡献增加。