【摘要】：尾加壓素Ⅱ(UⅡ)的外周心血管效應(yīng)可因動物種屬及解剖部位的差異而表現(xiàn)明顯不同,然而UⅡ的中樞心血管效應(yīng)卻相當(dāng)一致而穩(wěn)定。已知UⅡ可能通過激活交感神經(jīng)系統(tǒng)影響心血管功能,但至今對于UⅡ的中樞機(jī)制尚知之甚少。由于近年研究顯示中樞活性氧可引起交感興奮,因此本課題提出活性氧(ROS)可能中介中樞UⅡ的心血管效應(yīng)的假設(shè),具體的設(shè)想為UⅡ可能通過激活NADPH氧化酶的途徑引起中樞活性氧水平增高,繼而引起交感興奮和相應(yīng)的心血管效應(yīng)；如果阻斷活性氧對UⅡ的介導(dǎo)作用,就可阻斷中樞UⅡ的心血管效應(yīng)。本課題通過形態(tài)結(jié)合功能、整體結(jié)合分子生物學(xué)等實驗手段研究中樞活性氧在介導(dǎo)UⅡ心血管效應(yīng)中的可能作用,并進(jìn)而探討活性氧介導(dǎo)UⅡ中樞作用的信號轉(zhuǎn)導(dǎo)途徑,期望從整體和分子水平兩方面對中樞活性氧中介UⅡ心血管效應(yīng)的機(jī)制作較深入的研究。本課題的研究結(jié)果對于探索治療高血壓的新途徑可能具有潛在的應(yīng)用價值。 本工作首先采用免疫組織化學(xué)方法觀察自發(fā)性高血壓大鼠(SHR)和正常血壓大鼠(WKY)延髓UⅡ受體(UT)的表達(dá),以明確心血管相關(guān)核團(tuán)UT的表達(dá)特征。結(jié)果顯示,在大鼠延髓頭端腹外側(cè)部(RVLM)和孤束核(NTS)均有UT免疫陽性細(xì)胞表達(dá)。光密度分析的結(jié)果顯示,SHR大鼠的RVLM和NTS的UT陽性細(xì)胞的平均表達(dá)水平顯著高于WKY大鼠(P0.05)。為進(jìn)一步驗證SHR和WKY大鼠中樞UT的表達(dá)差異,用免疫印跡實驗(Western blot)定量分析UT在延髓腹外側(cè)和下丘腦的表達(dá),結(jié)果顯示：UT在WKY和SHR大鼠中樞延髓腹外側(cè)和下丘腦均有表達(dá),且SHR大鼠延髓腹外側(cè)UT表達(dá)的水平高于WKY大鼠(P0.05)。上述結(jié)果提示,UT在SHR和WKY延髓腹外側(cè)部表達(dá)的差異可能與自發(fā)性高血壓的發(fā)生相關(guān)。為研究UⅡ在中樞的分布,用放射免疫法測定了WKY和SHR大鼠延髓腹外側(cè)、中腦和下丘腦中UⅡ的含量,結(jié)果表明,在延髓腹外側(cè)和中腦,兩組UⅡ含量無明顯差別(p0.05)；但在下丘腦,SHR大鼠的UⅡ含量明顯高于WKY大鼠(P0.05)。為明確UT在中樞神經(jīng)細(xì)胞分布的定位,采用免疫熒光雙標(biāo)結(jié)合激光共聚焦顯微鏡,觀察了UT在RVLM神經(jīng)元和膠質(zhì)細(xì)胞的表達(dá)。結(jié)果顯示：WKY大鼠和SHR的RVLM區(qū)大多數(shù)神經(jīng)元上都有UT受體的表達(dá)；同時觀察了UT在RVLM膠質(zhì)細(xì)胞的表達(dá),結(jié)果顯示,RVLM區(qū)膠質(zhì)細(xì)胞上無UT受體的表達(dá)。上述結(jié)果表明,在RVLM區(qū)UT主要分布在神經(jīng)元上。 采用側(cè)腦室和微量注射UⅡ的方法觀察UⅡ的心血管效應(yīng),結(jié)果顯示：在SHR和WKY大鼠,側(cè)腦室微量注射UⅡ,都可引起血壓升高,在SHR升壓效應(yīng)更明顯(p0.05)。給SHR大鼠預(yù)先注射UⅡ受體的拮抗劑Urantide可阻斷UⅡ的心血管效應(yīng)。單獨注射Urantide血壓在注射后5分鐘(時間點0和5min)有明顯下降(p0.05),結(jié)合上述形態(tài)學(xué)實驗結(jié)果,提示中樞UⅡ在SHR和WKY大鼠的效應(yīng)的差異可能與兩種動物延髓中UT密度的不同相關(guān),UⅡ受體可能參與自發(fā)性高血壓的病理過程。為明確UⅡ所作用的心血管相關(guān)核團(tuán),本實驗觀察RVLM微量注射UⅡ的效應(yīng),結(jié)果顯示：SHR大鼠RVLM微量注射UⅡ可引起血壓明顯升高,；預(yù)先給予UⅡ受體的拮抗劑Urantide可阻斷UⅡ的心血管效應(yīng)。結(jié)合上述形態(tài)學(xué)觀察結(jié)果,提示RVLM是UⅡ產(chǎn)生中樞心血管效應(yīng)的重要核團(tuán),其他腦區(qū)微量注射UⅡ產(chǎn)生的效應(yīng)可能在RVLM進(jìn)行整合。 為了觀察U的心血管效應(yīng)是否由活性氧介導(dǎo),在SHR大鼠側(cè)腦室注射U前先給予SOD類似物Tempol或U受體拮抗劑Urantide,然后觀察U引起的血壓變化。結(jié)果顯示：側(cè)腦室單獨注射人工腦脊液(aCSF)組,大鼠的血壓平穩(wěn),無明顯變化；單獨注射Urantide血壓在注射后5分鐘(時間點0和5min)有明顯下降(p0.05),提示在SHR大鼠UⅡ有內(nèi)源性緊張性作用；側(cè)腦室單獨注射Tempol,血壓略有下降趨勢,但與aCSF組相比,差異無統(tǒng)計學(xué)顯著意義。側(cè)腦室注射UⅡ可引起血壓顯著升高(p0.05),與aCSF組相比,在注射后10、15、20、25、30min時間點有顯著意義(p0.05)。預(yù)先給予Urantide或Tempol均可阻斷UⅡ的心血管效應(yīng)。為確定活性氧介導(dǎo)中樞UⅡ心血管效應(yīng)的相關(guān)核團(tuán),我們進(jìn)一步在SHR大鼠預(yù)先給予Tempol或NADPH酶抑制劑Apocynin,結(jié)果均可阻斷RVLM區(qū)注射UⅡ的心血管效應(yīng)。這一結(jié)果提示,UⅡ在RVLM的升血壓效應(yīng)可能是由活性氧介導(dǎo)的。 采用DHE熒光測定法結(jié)合激光共聚焦顯微鏡觀察SHR和WKY大鼠RVLM區(qū)ROS的水平。結(jié)果顯示：WKY組紅色熒光陽性細(xì)胞較散在,而SHR組紅色熒光陽性細(xì)胞較多；SHR+UⅡ組紅色熒光陽性細(xì)胞較密集。這一結(jié)果通過酶標(biāo)法定量測定超氧陰離子的方法得到了驗證,這一結(jié)果提示,中樞UⅡ可引起SHR的RVLM區(qū)ROS水平增高。為進(jìn)一步觀察UⅡ的效應(yīng)是否與NADPH氧化酶的激活相關(guān),用酶標(biāo)法測定SHR和WKY大鼠RVLM區(qū)NADPH氧化酶的活性,結(jié)果顯示：SHR的RVLM區(qū)NADPH氧化酶的活性比WKY大鼠的高(p0.05)；側(cè)腦室注射UⅡ可引起NADPH氧化酶的活性增高(p0.05),NADPH氧化酶抑制劑Apocynin可阻斷UⅡ的效應(yīng)(p0.05)。上述結(jié)果也支持上面的假設(shè),即活性氧介導(dǎo)了中樞UⅡ的心血管效應(yīng)。 為進(jìn)一步研究中樞UⅡ的心血管效應(yīng)是否通過激活NADPH氧化酶產(chǎn)生的ROS信號途徑介導(dǎo),本實驗采用免疫熒光結(jié)合激光共聚焦的方法觀察了胞膜亞單位gp91phox或胞漿亞單位p47phox與UT在RVLM的神經(jīng)元的共表達(dá)。結(jié)果顯示：胞膜亞單位gp91phox或胞漿亞單位p47phox與UT在RVLM的神經(jīng)元上均有共表達(dá)。這一結(jié)果為UⅡ和NADPH氧化酶的功能聯(lián)系提供了結(jié)構(gòu)上的基礎(chǔ),提示UⅡ可能通過作用于RVLM的UT,激活NADPH氧化酶而起效應(yīng)。進(jìn)一步采用Real-Time PCR和Western blot方法分別檢測了SHR大鼠延髓腹外側(cè)區(qū)NADPH氧化酶的亞單位gp91phox P47phoxmRNA和P47phox蛋白磷酸化的水平。結(jié)果觀察到,側(cè)腦室注射UⅡ可增加SHR大鼠延髓腹外側(cè)區(qū)NADPH氧化酶亞單位gp91phox、P47phoxmRNA的水平。在SHR大鼠側(cè)腦室內(nèi)注射UⅡ后5分鐘,延髓腹外側(cè)區(qū)p47phox磷酸化蛋白相對總蛋白的比值升高。上述結(jié)果提示,中樞UⅡ可能作用于RVLM的UT,然后促使胞漿亞單位p47phox磷酸化,與膜亞單位gp91等形成有活性的氧化酶,催化超氧陰離子的生成.。 綜上所述,本工作提示UⅡ在SHR大鼠的中樞心血管效應(yīng)通過以下途徑介導(dǎo)：UⅡ作用于RVLM的UⅡ受體UT,激活NADPH氧化酶,引起超氧陰離子等活性氧水平增加,繼而介導(dǎo)交感興奮的心血管效應(yīng)。SttR大鼠UⅡ受體可能參與自發(fā)性高血壓的病理過程。
[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.
【學(xué)位授予單位】：復(fù)旦大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2009
【分類號】：R331

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