尾加压素Ⅱ在SHR大鼠中枢心血管效应的机制研究：活性氧的作用
发布时间：2018-07-25 12:19
【摘要】：尾加压素Ⅱ(UⅡ)的外周心血管效应可因动物种属及解剖部位的差异而表现明显不同,然而UⅡ的中枢心血管效应却相当一致而稳定。已知UⅡ可能通过激活交感神经系统影响心血管功能,但至今对于UⅡ的中枢机制尚知之甚少。由于近年研究显示中枢活性氧可引起交感兴奋,因此本课题提出活性氧(ROS)可能中介中枢UⅡ的心血管效应的假设,具体的设想为UⅡ可能通过激活NADPH氧化酶的途径引起中枢活性氧水平增高,继而引起交感兴奋和相应的心血管效应；如果阻断活性氧对UⅡ的介导作用,就可阻断中枢UⅡ的心血管效应。本课题通过形态结合功能、整体结合分子生物学等实验手段研究中枢活性氧在介导UⅡ心血管效应中的可能作用,并进而探讨活性氧介导UⅡ中枢作用的信号转导途径,期望从整体和分子水平两方面对中枢活性氧中介UⅡ心血管效应的机制作较深入的研究。本课题的研究结果对于探索治疗高血压的新途径可能具有潜在的应用价值。 本工作首先采用免疫组织化学方法观察自发性高血压大鼠(SHR)和正常血压大鼠(WKY)延髓UⅡ受体(UT)的表达,以明确心血管相关核团UT的表达特征。结果显示,在大鼠延髓头端腹外侧部(RVLM)和孤束核(NTS)均有UT免疫阳性细胞表达。光密度分析的结果显示,SHR大鼠的RVLM和NTS的UT阳性细胞的平均表达水平显著高于WKY大鼠(P0.05)。为进一步验证SHR和WKY大鼠中枢UT的表达差异,用免疫印迹实验(Western blot)定量分析UT在延髓腹外侧和下丘脑的表达,结果显示：UT在WKY和SHR大鼠中枢延髓腹外侧和下丘脑均有表达,且SHR大鼠延髓腹外侧UT表达的水平高于WKY大鼠(P0.05)。上述结果提示,UT在SHR和WKY延髓腹外侧部表达的差异可能与自发性高血压的发生相关。为研究UⅡ在中枢的分布,用放射免疫法测定了WKY和SHR大鼠延髓腹外侧、中脑和下丘脑中UⅡ的含量,结果表明,在延髓腹外侧和中脑,两组UⅡ含量无明显差别(p0.05)；但在下丘脑,SHR大鼠的UⅡ含量明显高于WKY大鼠(P0.05)。为明确UT在中枢神经细胞分布的定位,采用免疫荧光双标结合激光共聚焦显微镜,观察了UT在RVLM神经元和胶质细胞的表达。结果显示：WKY大鼠和SHR的RVLM区大多数神经元上都有UT受体的表达；同时观察了UT在RVLM胶质细胞的表达,结果显示,RVLM区胶质细胞上无UT受体的表达。上述结果表明,在RVLM区UT主要分布在神经元上。 采用侧脑室和微量注射UⅡ的方法观察UⅡ的心血管效应,结果显示：在SHR和WKY大鼠,侧脑室微量注射UⅡ,都可引起血压升高,在SHR升压效应更明显(p0.05)。给SHR大鼠预先注射UⅡ受体的拮抗剂Urantide可阻断UⅡ的心血管效应。单独注射Urantide血压在注射后5分钟(时间点0和5min)有明显下降(p0.05),结合上述形态学实验结果,提示中枢UⅡ在SHR和WKY大鼠的效应的差异可能与两种动物延髓中UT密度的不同相关,UⅡ受体可能参与自发性高血压的病理过程。为明确UⅡ所作用的心血管相关核团,本实验观察RVLM微量注射UⅡ的效应,结果显示：SHR大鼠RVLM微量注射UⅡ可引起血压明显升高,；预先给予UⅡ受体的拮抗剂Urantide可阻断UⅡ的心血管效应。结合上述形态学观察结果,提示RVLM是UⅡ产生中枢心血管效应的重要核团,其他脑区微量注射UⅡ产生的效应可能在RVLM进行整合。 为了观察U的心血管效应是否由活性氧介导,在SHR大鼠侧脑室注射U前先给予SOD类似物Tempol或U受体拮抗剂Urantide,然后观察U引起的血压变化。结果显示：侧脑室单独注射人工脑脊液(aCSF)组,大鼠的血压平稳,无明显变化；单独注射Urantide血压在注射后5分钟(时间点0和5min)有明显下降(p0.05),提示在SHR大鼠UⅡ有内源性紧张性作用；侧脑室单独注射Tempol,血压略有下降趋势,但与aCSF组相比,差异无统计学显著意义。侧脑室注射UⅡ可引起血压显著升高(p0.05),与aCSF组相比,在注射后10、15、20、25、30min时间点有显著意义(p0.05)。预先给予Urantide或Tempol均可阻断UⅡ的心血管效应。为确定活性氧介导中枢UⅡ心血管效应的相关核团,我们进一步在SHR大鼠预先给予Tempol或NADPH酶抑制剂Apocynin,结果均可阻断RVLM区注射UⅡ的心血管效应。这一结果提示,UⅡ在RVLM的升血压效应可能是由活性氧介导的。 采用DHE荧光测定法结合激光共聚焦显微镜观察SHR和WKY大鼠RVLM区ROS的水平。结果显示：WKY组红色荧光阳性细胞较散在,而SHR组红色荧光阳性细胞较多；SHR+UⅡ组红色荧光阳性细胞较密集。这一结果通过酶标法定量测定超氧阴离子的方法得到了验证,这一结果提示,中枢UⅡ可引起SHR的RVLM区ROS水平增高。为进一步观察UⅡ的效应是否与NADPH氧化酶的激活相关,用酶标法测定SHR和WKY大鼠RVLM区NADPH氧化酶的活性,结果显示：SHR的RVLM区NADPH氧化酶的活性比WKY大鼠的高(p0.05)；侧脑室注射UⅡ可引起NADPH氧化酶的活性增高(p0.05),NADPH氧化酶抑制剂Apocynin可阻断UⅡ的效应(p0.05)。上述结果也支持上面的假设,即活性氧介导了中枢UⅡ的心血管效应。 为进一步研究中枢UⅡ的心血管效应是否通过激活NADPH氧化酶产生的ROS信号途径介导,本实验采用免疫荧光结合激光共聚焦的方法观察了胞膜亚单位gp91phox或胞浆亚单位p47phox与UT在RVLM的神经元的共表达。结果显示：胞膜亚单位gp91phox或胞浆亚单位p47phox与UT在RVLM的神经元上均有共表达。这一结果为UⅡ和NADPH氧化酶的功能联系提供了结构上的基础,提示UⅡ可能通过作用于RVLM的UT,激活NADPH氧化酶而起效应。进一步采用Real-Time PCR和Western blot方法分别检测了SHR大鼠延髓腹外侧区NADPH氧化酶的亚单位gp91phox P47phoxmRNA和P47phox蛋白磷酸化的水平。结果观察到,侧脑室注射UⅡ可增加SHR大鼠延髓腹外侧区NADPH氧化酶亚单位gp91phox、P47phoxmRNA的水平。在SHR大鼠侧脑室内注射UⅡ后5分钟,延髓腹外侧区p47phox磷酸化蛋白相对总蛋白的比值升高。上述结果提示,中枢UⅡ可能作用于RVLM的UT,然后促使胞浆亚单位p47phox磷酸化,与膜亚单位gp91等形成有活性的氧化酶,催化超氧阴离子的生成.。 综上所述,本工作提示UⅡ在SHR大鼠的中枢心血管效应通过以下途径介导：UⅡ作用于RVLM的UⅡ受体UT,激活NADPH氧化酶,引起超氧阴离子等活性氧水平增加,继而介导交感兴奋的心血管效应。SttR大鼠UⅡ受体可能参与自发性高血压的病理过程。
[Abstract]:The peripheral cardiovascular effects of the U II (U II) can be significantly different due to the differences in the species and the anatomical sites of the animals. However, the central cardiovascular effect of U II is quite consistent and stable. It is known that the cardiovascular function may be influenced by the activation of the sympathetic nervous system, but so far little is known about the central mechanism of the U II. Studies have shown that central active oxygen can cause sympathetic excitement, so this topic proposes the hypothesis that reactive oxygen species (ROS) may mediate the cardiovascular effect of central U II. The specific assumption is that U II may increase the level of central active oxygen by activating NADPH oxidase, and then cause sympathetic excitement and corresponding cardiovascular effects; if it is blocked, it is blocked. The mediating effect of active oxygen on U II can block the cardiovascular effect of central U II. This subject studies the possible role of central active oxygen in the mediating the cardiovascular effect of U II by means of morphological binding and integrated molecular biology, and further explores the signal transduction pathway of active oxygen mediated U II central role. The mechanism of the cardiovascular effect of central reactive oxygen mediator U II is studied in two aspects of body and molecular level. The results of this study may be of potential application value for exploring new ways to treat hypertension.
In this work, the expression of U II receptor (UT) in the medulla oblongata of spontaneously hypertensive rats (SHR) and normal blood pressure rats (WKY) was observed by immunohistochemistry. The expression of UT in the cardiovascular related nucleus was clearly defined. The results showed that the expression of UT immunoreactive cells in the ventral lateral part of the medulla oblongata (RVLM) and the nucleus of the solitary tract (NTS) in the rat medulla oblongata (NTS). The results showed that the average expression level of RVLM and NTS UT positive cells in SHR rats was significantly higher than that in WKY rats (P0.05). To further verify the difference in the expression of UT in the central nervous system of SHR and WKY rats, the expression of UT in the ventrolateral medulla and the hypothalamus was quantitatively analyzed by immunoblotting (Western blot). The expression of the ventrolateral and hypothalamus in the medulla was higher than that of the WKY rat (P0.05) in SHR rats. The results suggested that the difference in the expression of UT in the ventrolateral medulla of SHR and WKY may be related to the occurrence of spontaneous hypertension. The distribution of U II in the central part of the medulla and the ventral medulla oblongata in WKY and SHR rats was measured by radioimmunoassay. The content of U II in the lateral, mesencephalon and hypothalamus showed that there was no significant difference between the two groups of U II in the ventrolateral medulla and the midbrain (P0.05), but in the hypothalamus, the content of U II in the SHR rats was significantly higher than that of the WKY rats (P0.05). The location of UT in the distribution of central nerve cells was clearly defined by double immunofluorescence combined with laser confocal microscopy. The expression of UT in RVLM neurons and glial cells showed that the expression of UT receptor in most of the neurons in the RVLM region of WKY rats and SHR was expressed, and the expression of UT in RVLM glial cells was observed. The results showed that there was no UT receptor on the RVLM region glial cells. The results showed that UT was mainly distributed on the neurons in RVLM region.
The cardiovascular effects of U II were observed by using the lateral ventricle and microinjection of U II. The results showed that in the SHR and WKY rats, the microinjection of U II in the lateral ventricle could cause the increase of blood pressure and the increase in the SHR pressure effect (P0.05). The pre injection of U II receptor antagonist Urantide for SHR rats could block the cardiovascular effect of U II. The blood pressure was significantly decreased (P0.05) 5 minutes after the injection (time point 0 and 5min). Combined with the results of these morphological experiments, the difference in the effect of central U II in SHR and WKY rats may be related to the difference in the density of UT in the medulla of two animals. The U II receptor may participate in the pathological process of spontaneous high blood pressure. The effect of RVLM microinjection of U II was observed in this experiment. The results showed that the microinjection of U II to RVLM in SHR rats could cause a significant increase in blood pressure, and Urantide, an antagonist given to U II receptor, could block the cardiovascular effect of U II. The results of the morphological observation suggested that RVLM is an important nucleus of the cardiovascular effect of U II. The effect of microinjection of U II in other brain regions may be integrated in RVLM.
In order to observe whether the cardiovascular effect of U was mediated by reactive oxygen species, the SOD analogue Tempol or U receptor antagonist Urantide was given before U in the lateral ventricle of SHR rats, and then the blood pressure changes caused by U were observed. The results showed that the lateral ventricle was injected with artificial cerebrospinal fluid (aCSF) alone, the blood pressure of the rat was stable and no obvious change; Urantide alone was injected into Urantide. Urantide was injected alone. The blood pressure was significantly decreased (P0.05) 5 minutes after injection (time point 0 and 5min), suggesting that U II had endogenous tension in SHR rats; the blood pressure decreased slightly in the lateral ventricles of Tempol alone, but compared with the aCSF group, the difference was not statistically significant. The lateral ventricle injection of U II could cause a significant increase in blood pressure (P0.05), compared with the aCSF group. The 10,15,20,25,30min time point after injection was significant (P0.05). Prior to Urantide or Tempol could block the cardiovascular effect of U II. In order to determine the related nucleus of the central U II cardiovascular effect of the active oxygen mediated central U II, we were further given Tempol or NADPH enzyme inhibitor Apocynin in the SHR rats, the results of which could block the RVLM zone injection of U II. This result suggests that the blood pressure effect of U II in RVLM may be mediated by reactive oxygen species.
The level of ROS in the RVLM region of SHR and WKY rats was observed by DHE fluorimetry and confocal laser scanning microscope. The results showed that the red fluorescent positive cells in the WKY group were scattered, while the red fluorescent positive cells in the SHR group were more, and the red fluorescent positive cells in the group SHR+U II were denser. This result was a result of the quantitative determination of the superoxide anion in the group SHR+U II. The results showed that the central U II could cause the increase in the level of ROS in the RVLM region of SHR. The activity of NADPH oxidase in SHR and WKY rats was determined by the effect of U II on the activation of NADPH oxidase, and the activity of NADPH oxidase in RVLM region of SHR and WKY rats was measured by enzyme labeling. The injection of U II in the lateral ventricle can cause an increase in the activity of NADPH oxidase (P0.05), and the NADPH oxidase inhibitor Apocynin can block the effect of U II (P0.05). The above results also support the above hypothesis that active oxygen mediates the cardiovascular effect of central U II.
In order to further investigate whether the cardiovascular effect of central U II is mediated by the activation of the ROS signal pathway produced by NADPH oxidase, the co expression of the cell membrane subunit gp91phox or the cytoplasmic subunit p47phox and UT in RVLM neurons is observed by the method of immunofluorescence combined with laser confocal. The results show that the subunit gp91phox of the cell membrane is gp91phox. Or the cytoplasmic subunit p47phox and UT are co expressed on the neurons of RVLM. This result provides a structural basis for the functional association of U II and NADPH oxidase, suggesting that U II may activate the NADPH oxidase by acting on the UT of the RVLM. Further, Real-Time PCR and Western methods are used to detect the rat extension. The level of phosphorylation of NADPH oxidase subunit gp91phox P47phoxmRNA and P47phox protein in the lateral medullary ventral region. Results showed that the lateral ventricle injection of U II could increase the level of NADPH oxidase subunit gp91phox and P47phoxmRNA in the ventrolateral medulla of SHR rats. 5 minutes after U II was injected into the lateral brain of SHR rats, p47phox phosphorylation of the ventrolateral medulla oblongata was 5 minutes later. The above results suggest that the central U II may act on the UT of RVLM, then promote the phosphorylation of the cytoplasmic subunit p47phox, and form active oxidase with the membrane subunit gp91 to catalyze the formation of superoxide anion.
To sum up, this work suggests that the central cardiovascular effect of U II in SHR rats is mediated by the following pathways: U II acts on the U II receptor UT of RVLM, activates NADPH oxidase, causes an increase in the level of superoxide anion and other reactive oxygen species, and then mediates the cardiovascular effect of sympathetic excitation, and the U II receptor in.SttR rats may be involved in the pathology of spontaneous hypertension. Process.
【学位授予单位】：复旦大学
【学位级别】：博士
【学位授予年份】：2009
【分类号】：R331
本文编号：2143800
[Abstract]:The peripheral cardiovascular effects of the U II (U II) can be significantly different due to the differences in the species and the anatomical sites of the animals. However, the central cardiovascular effect of U II is quite consistent and stable. It is known that the cardiovascular function may be influenced by the activation of the sympathetic nervous system, but so far little is known about the central mechanism of the U II. Studies have shown that central active oxygen can cause sympathetic excitement, so this topic proposes the hypothesis that reactive oxygen species (ROS) may mediate the cardiovascular effect of central U II. The specific assumption is that U II may increase the level of central active oxygen by activating NADPH oxidase, and then cause sympathetic excitement and corresponding cardiovascular effects; if it is blocked, it is blocked. The mediating effect of active oxygen on U II can block the cardiovascular effect of central U II. This subject studies the possible role of central active oxygen in the mediating the cardiovascular effect of U II by means of morphological binding and integrated molecular biology, and further explores the signal transduction pathway of active oxygen mediated U II central role. The mechanism of the cardiovascular effect of central reactive oxygen mediator U II is studied in two aspects of body and molecular level. The results of this study may be of potential application value for exploring new ways to treat hypertension.
In this work, the expression of U II receptor (UT) in the medulla oblongata of spontaneously hypertensive rats (SHR) and normal blood pressure rats (WKY) was observed by immunohistochemistry. The expression of UT in the cardiovascular related nucleus was clearly defined. The results showed that the expression of UT immunoreactive cells in the ventral lateral part of the medulla oblongata (RVLM) and the nucleus of the solitary tract (NTS) in the rat medulla oblongata (NTS). The results showed that the average expression level of RVLM and NTS UT positive cells in SHR rats was significantly higher than that in WKY rats (P0.05). To further verify the difference in the expression of UT in the central nervous system of SHR and WKY rats, the expression of UT in the ventrolateral medulla and the hypothalamus was quantitatively analyzed by immunoblotting (Western blot). The expression of the ventrolateral and hypothalamus in the medulla was higher than that of the WKY rat (P0.05) in SHR rats. The results suggested that the difference in the expression of UT in the ventrolateral medulla of SHR and WKY may be related to the occurrence of spontaneous hypertension. The distribution of U II in the central part of the medulla and the ventral medulla oblongata in WKY and SHR rats was measured by radioimmunoassay. The content of U II in the lateral, mesencephalon and hypothalamus showed that there was no significant difference between the two groups of U II in the ventrolateral medulla and the midbrain (P0.05), but in the hypothalamus, the content of U II in the SHR rats was significantly higher than that of the WKY rats (P0.05). The location of UT in the distribution of central nerve cells was clearly defined by double immunofluorescence combined with laser confocal microscopy. The expression of UT in RVLM neurons and glial cells showed that the expression of UT receptor in most of the neurons in the RVLM region of WKY rats and SHR was expressed, and the expression of UT in RVLM glial cells was observed. The results showed that there was no UT receptor on the RVLM region glial cells. The results showed that UT was mainly distributed on the neurons in RVLM region.
The cardiovascular effects of U II were observed by using the lateral ventricle and microinjection of U II. The results showed that in the SHR and WKY rats, the microinjection of U II in the lateral ventricle could cause the increase of blood pressure and the increase in the SHR pressure effect (P0.05). The pre injection of U II receptor antagonist Urantide for SHR rats could block the cardiovascular effect of U II. The blood pressure was significantly decreased (P0.05) 5 minutes after the injection (time point 0 and 5min). Combined with the results of these morphological experiments, the difference in the effect of central U II in SHR and WKY rats may be related to the difference in the density of UT in the medulla of two animals. The U II receptor may participate in the pathological process of spontaneous high blood pressure. The effect of RVLM microinjection of U II was observed in this experiment. The results showed that the microinjection of U II to RVLM in SHR rats could cause a significant increase in blood pressure, and Urantide, an antagonist given to U II receptor, could block the cardiovascular effect of U II. The results of the morphological observation suggested that RVLM is an important nucleus of the cardiovascular effect of U II. The effect of microinjection of U II in other brain regions may be integrated in RVLM.
In order to observe whether the cardiovascular effect of U was mediated by reactive oxygen species, the SOD analogue Tempol or U receptor antagonist Urantide was given before U in the lateral ventricle of SHR rats, and then the blood pressure changes caused by U were observed. The results showed that the lateral ventricle was injected with artificial cerebrospinal fluid (aCSF) alone, the blood pressure of the rat was stable and no obvious change; Urantide alone was injected into Urantide. Urantide was injected alone. The blood pressure was significantly decreased (P0.05) 5 minutes after injection (time point 0 and 5min), suggesting that U II had endogenous tension in SHR rats; the blood pressure decreased slightly in the lateral ventricles of Tempol alone, but compared with the aCSF group, the difference was not statistically significant. The lateral ventricle injection of U II could cause a significant increase in blood pressure (P0.05), compared with the aCSF group. The 10,15,20,25,30min time point after injection was significant (P0.05). Prior to Urantide or Tempol could block the cardiovascular effect of U II. In order to determine the related nucleus of the central U II cardiovascular effect of the active oxygen mediated central U II, we were further given Tempol or NADPH enzyme inhibitor Apocynin in the SHR rats, the results of which could block the RVLM zone injection of U II. This result suggests that the blood pressure effect of U II in RVLM may be mediated by reactive oxygen species.
The level of ROS in the RVLM region of SHR and WKY rats was observed by DHE fluorimetry and confocal laser scanning microscope. The results showed that the red fluorescent positive cells in the WKY group were scattered, while the red fluorescent positive cells in the SHR group were more, and the red fluorescent positive cells in the group SHR+U II were denser. This result was a result of the quantitative determination of the superoxide anion in the group SHR+U II. The results showed that the central U II could cause the increase in the level of ROS in the RVLM region of SHR. The activity of NADPH oxidase in SHR and WKY rats was determined by the effect of U II on the activation of NADPH oxidase, and the activity of NADPH oxidase in RVLM region of SHR and WKY rats was measured by enzyme labeling. The injection of U II in the lateral ventricle can cause an increase in the activity of NADPH oxidase (P0.05), and the NADPH oxidase inhibitor Apocynin can block the effect of U II (P0.05). The above results also support the above hypothesis that active oxygen mediates the cardiovascular effect of central U II.
In order to further investigate whether the cardiovascular effect of central U II is mediated by the activation of the ROS signal pathway produced by NADPH oxidase, the co expression of the cell membrane subunit gp91phox or the cytoplasmic subunit p47phox and UT in RVLM neurons is observed by the method of immunofluorescence combined with laser confocal. The results show that the subunit gp91phox of the cell membrane is gp91phox. Or the cytoplasmic subunit p47phox and UT are co expressed on the neurons of RVLM. This result provides a structural basis for the functional association of U II and NADPH oxidase, suggesting that U II may activate the NADPH oxidase by acting on the UT of the RVLM. Further, Real-Time PCR and Western methods are used to detect the rat extension. The level of phosphorylation of NADPH oxidase subunit gp91phox P47phoxmRNA and P47phox protein in the lateral medullary ventral region. Results showed that the lateral ventricle injection of U II could increase the level of NADPH oxidase subunit gp91phox and P47phoxmRNA in the ventrolateral medulla of SHR rats. 5 minutes after U II was injected into the lateral brain of SHR rats, p47phox phosphorylation of the ventrolateral medulla oblongata was 5 minutes later. The above results suggest that the central U II may act on the UT of RVLM, then promote the phosphorylation of the cytoplasmic subunit p47phox, and form active oxidase with the membrane subunit gp91 to catalyze the formation of superoxide anion.
To sum up, this work suggests that the central cardiovascular effect of U II in SHR rats is mediated by the following pathways: U II acts on the U II receptor UT of RVLM, activates NADPH oxidase, causes an increase in the level of superoxide anion and other reactive oxygen species, and then mediates the cardiovascular effect of sympathetic excitation, and the U II receptor in.SttR rats may be involved in the pathology of spontaneous hypertension. Process.
【学位授予单位】：复旦大学
【学位级别】：博士
【学位授予年份】：2009
【分类号】：R331
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