Development of the modulator drug specifically targeting biomechanical reaction in the circulatory system and the application for experimental therapeutics.

目的心血管对血流动力学/生物力学刺激的反应，包括压力和流量，是心脏和血管中的一种物理接受和随后的细胞内/细胞间信号传递。异常生物力学刺激也可引起血管痉挛、高血压、心肌肥大等病理生理状态。为了阐明机械转导的机制并开发一种新的心血管系统生物力学反应的调节剂，我们进行了以下实验：1)分离的脑动脉和肺的动脉组织和细胞对压力和拉伸反应的细胞内/细胞间信号机制，特别是对蛋白质酪氨酸磷酸化、细胞内钙离子浓度和机械活性的反应。2)寻找对血流动力学刺激反应的新调节剂。3)野百合碱诱导的大鼠肺动脉高压的实验治疗。结果和讨论A…S进一步探讨了机械信号转导的机制，提出如下过程：通过机械门控通道的蛋白酪氨酸磷酸化激活膜去极化和激活L类钙通道，触发机械活性。Morcover、血小板衍生生长因子受体b链、酪氨酸激酶的一种受体类型，以及细胞内信使，如Rho，一种低分子GTP结合蛋白，都特异性地参与了机械信号转导的信号转导。未来展望心血管对血流动力学刺激的反应触及最新问题的核心，包括血压和流量的调节、肌张力、机械门控离子通道、切应力和内皮功能，以及高和低切应力和血流动力学过载的病理生理学意义。我们目前的研究必将为开发具有新作用机制的新型心血管药物开辟道路，我们的一般原则将提高人们对心血管系统在健康和疾病方面的认识。较少

Purpose The cardiovascular response to hemodynamic/biomechanical stimuli, including pressure and flow, is a type of physical reception and a subsequent intra/inter cellular signaling in the heart and blood vessels. Pathophysiological conditions, such as vasospasm, hypertension, and myocardial hypertrophy, are also caused by the abnormal biomechanical stimuli. In order to elucidate the mechanism for mechano-transduction and to develop a new modulator of biomechanical reaction in the cardiovascular system, the following experiments were undertaken : 1) intra/intercellular signaling mechanism of arterial tissues and cells isolated from brain artery and lung in response to pressure and stretch with the special regard to protein tyrosyl phosphorylation, intracellular Ca2+ concentration, and mechanical activity. 2) Search for a new modulator of the response to hemodynamic stimuli. 3) Experimental therapeutics in the monocrotaline-induced pulmonary hypertensive rats. Results and discussions A … More s to the mechanism for mechano-transduction, the following process could be suggested : The membrane depolarization and activation of L-type Ca2+ channels through protein tyrosyl phosphorylation of the mechano-gated channel triggers the mechanical activity. Morcover, platelet-derived growth factor receptor- b chain, a receptor type of tyrosine kinase, and an intracellular messenger, such as Rho, a low molecular GTP-binding protein, are specifically involved in the signaling of mechano-transduction. Future prospect The cardiovascular response to hemodynamic stimuli touch the core of up to-date problems, including regulation of blood pressure and flow, myogenic tone, mechano-gated ion channels, shear stress and endothelial function, and pathophysiological implications of high and low shear stress and hemodynamic overload. Our present studies will surely open the way to an era for the development of new cardiovascular drugs with a novel mechanism of action, and our general principle will improve the knowledge about the cardiovascular system in health and disease. Less