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Cardiorespiratory Regulation in Endothelin- 1 Gene Knockedout Mice

内皮素-1基因敲除小鼠的心肺调节

基本信息

批准号：
06670047
负责人：
KUWAKI Tomoyuki
金额：
$ 1.54万
依托单位：
THE UNIVERSITY OF TOKYO
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1994
资助国家：
日本
起止时间：
1994 至 1995
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-06670047/
关键词：
Endothelin-1 Knockedout Mice Hypertension Respiratory Reflex Cardiorespiratory Center Power Spectral Analysis New Born Mice 延髄循環呼吸中枢

项目摘要

We successfully developed endothelin (ET)-1 gene knckout mice and used them in the following experiment. 1) We were able to obtain stable recordings of the mice's blood pressure and heart rate, without any restriction nor anesthesia, for more than 2 hours. Obtained large quantity of data was handled with an aid of a computer. 2) By body plethysmography, we measured ventilation movement and its reflex change to hypoxia or hypercapnia in mature and new born conscious mice. 3) We recorded phrenic nerve discharges in urethane-anesthetized adult mice and measured their reflex change in response to hypoxia or hypercapnia. 4) Finally, we tested whether power spectral analysis of blood pressure fluctuations could be used in the mice as an evaluation method of autonomic nerve function.As a result, homozygotes that completely lost ET-1 gene died soon after birth by abnormal formation of craniofacial tissues. On the other hand, heterozygotes of which plasma concentration of ET-1 was about half of … More the normal mice showed significantly higher blood pressure than in the controls. In ET-1 deficient heterozygous mice, arterial pO_2 was significantly lower, pCO_2 tended to be higher and pH tended to be lower than in wild-type littermates. When these conscious mice breathed room air, respiratory minute volume and rate were not different between the two groups, although reflex increase to hypoxia or hypercapnia was significantly attenuated in ET-1^<+/-> heterozygotes. Since impaired reflex responses were also evident by recording phrenic nerve discharges, the cause of ventilatory impairment lay, at least in part, in the nervous system. Furthermore, in homozygotes that were delivered by cesarian sections and tracheotomized, reflex increase in ventilation was severely attenuated. Thus ET-1 plays a pivotal role in reflex control of respiration. Abnormality of breathing regulation in ET-1 deficient mice may account for the elevated blood pressure. In fact, similar cardiorespiratory abnormality was suggested by power spectrum analysis of blood pressure fluctuations.In summary, ET-1 participates in development and cardiorespiratory regulation in mice. This is an important and new finding and widens the suggested notion that ET-1 is not a mere vasoconstrictor but a playr of a variety of physiological roles. Moreover, it becomes clear that many of the techniques to study autonomic nervous function in the whole animal can be used in such a small animal as mouse with some modifications. Less

我们成功地建立了内皮素(ET)-1基因敲除小鼠，并将其用于后续实验。1)在没有任何限制和麻醉的情况下，我们能够获得超过2小时的稳定的小鼠血压和心率的记录。获得的大量数据是用计算机处理的。2)通过体体积描记技术，观察成年和新生清醒小鼠的呼吸运动及其对低氧、高碳酸血症的反射变化。3)我们记录了乌拉坦麻醉的成年小鼠的膈神经放电，并测定了它们对低氧或高二氧化碳反应的反射变化。4)最后，我们测试了血压波动的功率谱分析是否可以作为评估自主神经功能的方法，结果是，完全缺失ET-1基因的纯合子出生后不久就因头面部组织的异常形成而死亡。另一方面，血浆ET-1浓度约为…一半的杂合子更多的正常小鼠表现出明显高于对照组的血压。ET-1基因缺陷杂合子小鼠的动脉血氧分压显著低于野生型，PCO_2有升高的趋势，pH值有降低的趋势。当这些清醒小鼠呼吸室内空气时，两组小鼠的呼吸分钟容量和呼吸频率没有差异，尽管ET-1；+/-&gt；杂合子对低氧或高碳酸血症的反射增加明显减弱。由于通过记录膈神经放电，反射反应受损也是明显的，因此呼吸机能受损的原因至少部分在神经系统。此外，在通过剖腹产和气管切开术生下的纯合子中，呼吸反射增加严重减弱。因此，ET-1在呼吸反射控制中起着关键作用。ET-1缺陷小鼠呼吸调节异常可能是导致血压升高的原因之一。事实上，血压波动的功率谱分析也提示了类似的心肺异常。综上所述，ET-1参与了小鼠的发育和心肺调节。这是一项重要的新发现，扩大了ET-1不仅仅是一种血管收缩因子，而是一种具有多种生理作用的Playr的观点。此外，很明显，许多研究整个动物自主神经功能的技术只要进行一些修改，就可以用于像老鼠这样的小动物。较少