【作者】 张乐宁；

【导师】 张立藩；

【作者基本信息】 第四军医大学 ， 航空航天医学， 2001， 博士

【摘要】 航天飞行后心血管失调的发生机理及其对抗措施研究对实现新世纪载人航天目标及阐明微重力心血管影响基本规律具有重要的理论与实际意义。近年航天观察已提示，脑血管的适应性变化在飞行后立位耐力不良发生中可能起重要作用。本实验室前期工作已发现，模拟失重可引起大鼠后身动脉血管发生萎缩性改变和收缩反应性降低，以及脑部血管肥厚的分化性适应变化。但脑动脉血管反应性变化究如何？还未见报道。本工作第一部分即为对4周模拟失重大鼠脑基底动脉血管反应性变化及其内皮机制的实验研究。此外，根据现代血管生物学研究进展，我们认为血管组织局部的肾素-血管紧张素系统（局部RAS）可能在调控动脉血管分化性适应变化中发挥重要作用。故本工作第二部分即为用分子生物学与药理学方法对4周模拟失重大鼠不同动脉血管（特别是脑血管）血管紧张素Ⅱ（AngⅡ）受体变化的观察。再者，为实现21世纪“探险级航天任务”，是否需采用人工重力作为对抗措施？已是亟待解决的重要科学问题。本工作第三部分即以间断性头高位倾斜、站立或离心机旋转模拟不同方向间断性人工重力，研究其对抗模拟失重下脑动脉血管功能与结构变化的对抗效果。 本实验的主要发现如下： 1.4周模拟失重后，大鼠脑基底动脉对氯化钾、精氨酸加压素或5-羟色胺（5-HT）的收缩反应性较对照大鼠均显著增强；而对乙酰胆碱、 承回旱邑失吵浴土 大 一 凝血酶、腺昔或硝普钠的舒张反应性较对照大鼠则无明显改变。对照大 鼠基底动脉内皮对5．＊T引起的收缩反应起抑制性调制作用：而在模拟 失重大鼠，这种抑制性调制作用已经减弱或消失，其基底动脉对5羽T 收缩反应性的增强可能即与此有关。结果还表明，对照大鼠基底动脉血 管内皮对5．HT收缩反应的抑制性调制作用可能是通过释放内皮超极化 因子样物质而实现的。 2．RT－PCR分析结果表明：大鼠颈总动脉，腹主动脉及股动脉组织 均有 Aug 11的 AT；，AT；。及 AT受体 InRN的表达；而基底动脉组织则 只有 AT；：和 AT；。InRNA的表达。其主理意义尚待阐明。模拟失重一周大 鼠颈总动脉、腹主动脉、股动脉及基底动脉组织 Aug 11的 AT；．、AT；。和 AT；受体InRNA的表达，较对照大鼠均无显著变化。药理学实验表明， Aug 11可引起基底动脉血管环发生收缩反应，选择性受体阻断实验又进 一步证明此收缩反应是通过 AT；受体介导的。但 Aug 11不引起基底动脉 发生舒张反应。模拟失重 4周大鼠基底动脉血管环对 Aug 11的收缩反应 性较对照大鼠无显著变化。 3．每日不同持续时间的头高位倾斜（4或 2 h／d）、站立（4、二或 fo／d） 或离心机旋转门 h，1．5或2．6 G）均具有防止3周模拟失重大鼠基底动 脉收缩反应性增强的对抗效果。形态学实验还证明，3周模拟失重已可 引起大鼠基底动脉血管发生平滑肌细胞由4层增为6层的增生性肥厚变 化，而每日4h的头高位倾斜己可充分防止此种变化的发生。 本工作有关模拟失重下脑基底动脉血管功能和结构适应性改变的发－。现，是对本实验室提出的“航天飞行后心血管失调外周效应器机制”假 说的一项有力支持，也为航天飞行后立位耐力不良的“脑血管晕厥始动 机制”假说提供了动物实验依据。而有关间断性重力对抗脑血管不良影 响效果的研究则提示，每日l～4h的间断性人工重力暴露已有可能在微 重力环境使脑血管在功能和结构上保持地面IG条件下的生理稳态。以 上为进一步发展以人工重力为基础的对抗措施提供了重要实验依据。至 于血管组织局部RAS系统在动脉血管分化性适应过程中是否发挥关键性 互巨互 ） 写回旱邑失＠憎由＠芭倍大 一 调控作用问题，则尚有待进一步阐明。更多还原

【Abstract】 Abstract: The mechanism of postflight cardiovascular deconditioning has been considered as an important problem in the field of gravitational physiology that merits paying great attention to. The recent observations during spaceflight have suggested that adaptive alterations in the arterial vasculature may play a pivotal role in the occurrence of postflight cardiovascular deconditioning. Previous findings from our laboratory have demonstrated that simulated microgravity may result in atrophic change and depressed vasoconstrictor responsiveness in hindquarter vessels, and hypertrophic change in cerebral arteries. However, the vasoreactivity of cerebral arteries is still not known. In the first part of the present work the changes of the vasoreactivity of cerebral arteries were investigated. According to recent advances in the biomedicine of vessels, we have postulated that the tissue renin-angiotensin system (RAS) of the vessels may play an important role in the occurrence of the differentiated vascular adaptation during microgravity. Therefore, in the second part of the present work the alterations of angiotensin receptors were investigated for understanding the mechanism ofvascular adaptational alterations. Whether gravity-based countermeasures should be adopted in the future exploration-class spaceflights in this new century is an urgent science problem that needs further clarification. Hence, in the third part of the present work, the head-up tilt (HUT), standing (STD) and centrifugation were used to simulate the intermittent artificial gravity (IAG), and the preventing effects of them on the structural and functional alterations in cerebral arteries caused by simulated microgravity were investigated.The major findings of the present work are as follows:1. After four weeks of simulated microgravity, the maximal isometric contractile responsiveness of basilar arterial rings evoked by vasoconstrictors, like KC1, AVP or 5-HT was enhanced, whereas, vasodilatory responsiveness to vasodilators (Ach, thrombin, adenosine, and SNP) showed no significant changes as compared with that in control rats. It has also been found that the endothelium has an inhibitory modulatory influence on the vasoconstrictor responsiveness to 5-HT in basilar arteries, and the hyperreactivity to 5-HT in basilar arteries from simulated-microgravity rats may also be due to an impairment in this endothelial modulatory function. The results further suggest that substances like endothelium-derived hyperpolarizing factors (EDHF) are responsible for this endothelium-dependent attenuating modulatory mechanism in contractile responsiveness of rat basilar arteries to 5-HT.2. Results from RT-PCR demonstrated that mRNAs of angiotensin II receptors, AT,a, AT,b and AT, were expressed in carotid arteries, abdominal aorta and femoral arteries, whereas only mRNAs of AT,a and AT,b were expressed in bailar arteries. There were no significant differences between the simulated-microgravtiy and control rats in the expression of mRNAs of ATU, ATlb and AT2 in these arteries. Angiotensin II can evoke only contractile rather than vasodalitory responsiveness in basilar arterial rings which are mediated by AT, receptors. There were no significant differences in contractileresponsiveness induced by Angiotensin II between the simulated-microgravtiy and control rats.3. Daily exposure with different durations to head-up tilt (4 or 2 h), standing (4, 2, or 1 h) or centrifugation (1.5 or 2.6 G for 1 h/d) showed a counteracting effect in preventing the enhancement of contractile responsiveness in basilar arterial rings from simulated-microgravity rats. It has also been demonstrated that the hypertrophy of vascular wall with smooth muscle cell hyperplasia in rat basilar arteries resulted from 3-wk simulated microgravity can be prevented by daily 4-h exposure to head-up tilt.These findings about the structural and functional changes in cerebral arteries from simulated-microgravity rats have provided a strong evidence for the "peripheral e更多还原