孤束核内γ-氨基丁酸B受体对大鼠血压的调控作用
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摘要
孤束核是压力感受器和外周心血管受体的初级传入纤维的一个终止位点，同时也是血压敏感神经元。因此，孤束核介导的压力感受器对交感神经放电起抑制作用。NTS的中间亚核是由各种脑细胞发出的丰富的神经纤维支配的，在心血管调节中有重要作用，同时延髓最后区和丘脑下部核也对心血管调节起到作用。因此，我们认为，孤束核对血压调控起着非常重要的作用。另有研究证明，自发性高血压大鼠（SHR）的孤束核联合部与血压正常大鼠相比（WKY）发生了改变。另外，一些神经递质和调节因子对心血管调节起到重要作用，例如，γ-氨基丁酸（GABA）。
GABA是一个著名的神经递质，包括药理学定义的离子型GABAA受体（GAR），生理学定义的代谢型GABAB受体（GBR），通过其受体介导能在大脑中起到抑制作用。离子型GAR有一个内在的氯离子的通道，能够快速诱导抑制性突触后电位。代谢型GBR是一个G-蛋白偶联受体，通过激活钾离子通道调节神经元的活性，反过来又可以导致神经元膜的超极化，慢性抑制神经细胞的活动。孤束核内以发现高密度的GAR、GBR和高密度的GABA的神经末梢。GBR是由GBR1、GBR2蛋白组成的异源二聚体。GBR1对于激活的异源二聚体配体是至关重要的，而GBR2仅仅是用来转换GBR1细胞膜的表面上的穿梭蛋白。大量研究已经证实GAR和GBR在压力感受器的传入和反射功能的整合中发挥重要作用。显微注射进入孤束核的GAR激动剂（蝇蕈醇），或GBR激动剂（巴氯芬）通过抑制压力感受器反射，使交感神经张力升高产，抗利尿激素的释放增多，产生了显着的升压反应。相反，GBR拮抗剂显微注射能够拮抗GABA能神经元，抑制孤束核神经元，结果是使动脉压下降。更有趣的是，显微注射GBR激动剂（巴氯芬）进入孤束核后，升压作用更明显，这一结果在一些高血压的动物模型中也可以看到，例如DOCA-盐型高血压大鼠，血管紧张素Ⅱ灌注诱导的高血压大鼠，肾外包扎性高血压模型大鼠。这些研究表明，在这些动物中观察到的高血压可能与增强的GBR功能有关。然而，NTS内的GBR的表达是否在高血压时增强，或者GBR在NTS表达增强是否会导致血压升高，仍然没有答案。
在本研究中，我们检测了GBR、GAR在SHR大鼠和WKY大鼠的孤束核中的表达。并且发现含GBR基因的病毒载体显微注射入孤束核后，GBR表达增强并引起血压升高。
方法：
1.采用Real-time PCR和Western Blots的方法分别检测GABAB受体在WKY大鼠和SHR大鼠的NTS中的表达情况。
2.采用立体定位仪进行双侧NTS定位，基因转移的方法，通过显微注射AAV2-GBR1病毒载体进入WKY大鼠的NTS后，利用免疫荧光染色和免疫印迹的方法检测GABAB受体的表达情况。
3.采用无线电遥测系统记录AAV2病毒载体介导GBR1基因转移至WKY大鼠NTS中，WKY大鼠MAP、HR和血浆中去甲肾上腺素水平变化情况。利用血压传感器和桥式放大器记录GBR和GAR的激动剂和拮抗剂对SHR大鼠和WKY大鼠的BP、HR及RSNA的影响。
结果：
1.与血压正常大鼠相比，GBR1在自发性高血压大鼠的孤束核中表达增加。
2. AAV2病毒载体介导GBR1基因转移至WKY大鼠NTS中可诱导GBR1表达显著增加;并且WKY大鼠MAP、HR增加及血浆中去甲肾上腺素水平增高。
3. GBR激动剂和拮抗剂对SHR大鼠的BP、HR及RSNA变化的影响较WKY大鼠更为显著。
结论：
与血压正常大鼠相比，GABAB受体（GBR）在自发性高血压大鼠的孤束核中的表达增加；GBR1在孤束核中过度表达，可诱发血压正常大鼠导致慢性高血压和心率增加；在急性升压反应的研究中，把巴氯芬显微注射到孤束核中，与血压正常大鼠相比自发性高血压大鼠的升压反应增强。
The nucleus tractus solitarius (NTS) is a termination site forprimary afferent fibers from baroreceptors,and other peripheralcardiovascular receptors,that contain blood pressure (BP)-sensitiveneurons.As such,it mediates the inhibitory actions of baroreceptors onsympathetic discharge.The intermediate portion of the NTS is richlyinnervated by fibers from various brain nuclei that are known to have animportant role in cardiovascular control,including the area postrema andhypothalamic nuclei.Thus,it is believed that the NTS plays an importantrole in BP regulation,as well as contributing to the development andmaintenance of hypertension.Several studies have demonstrated that thecommissural NTS may be altered in the spontaneous hypertensive rat(SHR). These cardiovascular regulatory actions are carriedout by several neuronal transmitters and modulators [eg, such as γ-aminobutyric acid (GABA)].
GABA is a well-known neurotransmitter that exerts inhibitoryactions in the brain,mediated through its receptors,which include theionotropic GABA A receptor (GAR) and metabotropic GABA B receptor (GBR), that are defined on the basis of pharmacological andphysiological studies.The ionotropic GAR has an intrinsic Cl-channel,which is responsible for inducing fast inhibitory postsynapticpotentials.The GBR is a G-protein-coupled receptor,and regulatesneuronal activity via activation of K+channels, which in turn induceshyperpolarization of the neuronal membrane and chronic inhibition ofneuronal activity. A high density of both GAR and GBR and a highdensity of GABA-containing nerve terminals have been found within theNTS. The GBR is a heterodimer comprised of GBR1and GBR2proteins. GBR1is critical for ligand activation of the heterodimer,whereas GBR2is merely a shuttle protein to transfer GBR1ontothe surface of the cell membrane. A large number of studies havedemonstrated that both GAR and GBR play an important role in theintegration of baroreceptor afferent inputs and baroreflexfunction.Microinjection of the GAR agonist,muscimol,or the GBRagonist, baclofen,into the NTS produces a marked pressor response viainhibition of baroreflexes, elevation of sympathetic tone,and vasopressinrelease.Conversely, microinjection of GBR antagonists removes tonicGABAergic inhibition of NTS neurons and results in a fall in arterialpressure. More interestingly, the pressor response to microinjection ofbaclofen into the NTS is enhanced in several hypertensive animalmodels, such as DOCA-salt hypertensive rats, rats with AngII-infusion induced hypertension,and1-kidney renal wrap hypertensive rats.Thosestudies demonstrated that enhanced GBR function could be associatedwith the high BP observed in those animals.However,whether GBRexpression is enhanced in the NTS during hypertension,and whether theenhanced expression of GBR in the NTS would lead to elevatedBP,remains unanswered.
In the present study, we examined the GBR and GAR expression inthe NTS of SHR and WKY rats.We also investigated the functionalconsequences of enhanced GBR expression in the NTS duringhypertension by microinjection of a viral vector containing the GBRgene into the NTS.
Methods:
1.Real-time PCR and Western Blots were used to detect changes in theexpression of GBR in the NTS of SHR rats and WKY rats.
2.Rats whose microinjection sites were within the boundaries of the NTSwere used for data analysis,and took advantage of the ways of genetransfer into the NTS. By bilateral microinjection of the AAV2-GBR1viral vector into the NTS of WKY rats.Immunofluorescence staining andwestern blots detect changes in the expression of GBR in the NTS ofWKY rats.
3.A radiotelemetry system records Eeffect of GBR1gene transfer onarterial pressure,HR,and norepinephrine plasma levels. Taking use of a pressure transducer which was connectedto a Bridge Amplifier recordseffect of agonists and antagonists of GBR and GAR on BP, HR, andRSNA in SHR and WKY rats.
Results:
1.GBR1expression is enhanced in the NTS of SHR vs. WKY rats
2.GBR was overexpressed in the NTS by bilateral microinjection of theAAV2-GBR1viral vector into the NTS of WKY rats.Effect of GBR1gene transfer on arterial pressure, HR, and norepinephrine plasma levelswere increased steadily.
3.Effect of agonists and antagonists of GBR on BP, HR, and RSNA inSHR was significantly enhanced compared with WKY rats.
Conclusions:
GBR1expression is enhanced in the NTS of SHR vs. WKY ratsand overexpression of this gene in the NTS results in chronic elevationof blood pressure and heart rate in normotensive rats. In an acutestudy,the pressor response to baclofen microinjected into the NTS wasenhanced in SHR as compared with WKY rats.
GABA是一个著名的神经递质，包括药理学定义的离子型GABAA受体（GAR），生理学定义的代谢型GABAB受体（GBR），通过其受体介导能在大脑中起到抑制作用。离子型GAR有一个内在的氯离子的通道，能够快速诱导抑制性突触后电位。代谢型GBR是一个G-蛋白偶联受体，通过激活钾离子通道调节神经元的活性，反过来又可以导致神经元膜的超极化，慢性抑制神经细胞的活动。孤束核内以发现高密度的GAR、GBR和高密度的GABA的神经末梢。GBR是由GBR1、GBR2蛋白组成的异源二聚体。GBR1对于激活的异源二聚体配体是至关重要的，而GBR2仅仅是用来转换GBR1细胞膜的表面上的穿梭蛋白。大量研究已经证实GAR和GBR在压力感受器的传入和反射功能的整合中发挥重要作用。显微注射进入孤束核的GAR激动剂（蝇蕈醇），或GBR激动剂（巴氯芬）通过抑制压力感受器反射，使交感神经张力升高产，抗利尿激素的释放增多，产生了显着的升压反应。相反，GBR拮抗剂显微注射能够拮抗GABA能神经元，抑制孤束核神经元，结果是使动脉压下降。更有趣的是，显微注射GBR激动剂（巴氯芬）进入孤束核后，升压作用更明显，这一结果在一些高血压的动物模型中也可以看到，例如DOCA-盐型高血压大鼠，血管紧张素Ⅱ灌注诱导的高血压大鼠，肾外包扎性高血压模型大鼠。这些研究表明，在这些动物中观察到的高血压可能与增强的GBR功能有关。然而，NTS内的GBR的表达是否在高血压时增强，或者GBR在NTS表达增强是否会导致血压升高，仍然没有答案。
在本研究中，我们检测了GBR、GAR在SHR大鼠和WKY大鼠的孤束核中的表达。并且发现含GBR基因的病毒载体显微注射入孤束核后，GBR表达增强并引起血压升高。
方法：
1.采用Real-time PCR和Western Blots的方法分别检测GABAB受体在WKY大鼠和SHR大鼠的NTS中的表达情况。
2.采用立体定位仪进行双侧NTS定位，基因转移的方法，通过显微注射AAV2-GBR1病毒载体进入WKY大鼠的NTS后，利用免疫荧光染色和免疫印迹的方法检测GABAB受体的表达情况。
3.采用无线电遥测系统记录AAV2病毒载体介导GBR1基因转移至WKY大鼠NTS中，WKY大鼠MAP、HR和血浆中去甲肾上腺素水平变化情况。利用血压传感器和桥式放大器记录GBR和GAR的激动剂和拮抗剂对SHR大鼠和WKY大鼠的BP、HR及RSNA的影响。
结果：
1.与血压正常大鼠相比，GBR1在自发性高血压大鼠的孤束核中表达增加。
2. AAV2病毒载体介导GBR1基因转移至WKY大鼠NTS中可诱导GBR1表达显著增加;并且WKY大鼠MAP、HR增加及血浆中去甲肾上腺素水平增高。
3. GBR激动剂和拮抗剂对SHR大鼠的BP、HR及RSNA变化的影响较WKY大鼠更为显著。
结论：
与血压正常大鼠相比，GABAB受体（GBR）在自发性高血压大鼠的孤束核中的表达增加；GBR1在孤束核中过度表达，可诱发血压正常大鼠导致慢性高血压和心率增加；在急性升压反应的研究中，把巴氯芬显微注射到孤束核中，与血压正常大鼠相比自发性高血压大鼠的升压反应增强。
The nucleus tractus solitarius (NTS) is a termination site forprimary afferent fibers from baroreceptors,and other peripheralcardiovascular receptors,that contain blood pressure (BP)-sensitiveneurons.As such,it mediates the inhibitory actions of baroreceptors onsympathetic discharge.The intermediate portion of the NTS is richlyinnervated by fibers from various brain nuclei that are known to have animportant role in cardiovascular control,including the area postrema andhypothalamic nuclei.Thus,it is believed that the NTS plays an importantrole in BP regulation,as well as contributing to the development andmaintenance of hypertension.Several studies have demonstrated that thecommissural NTS may be altered in the spontaneous hypertensive rat(SHR). These cardiovascular regulatory actions are carriedout by several neuronal transmitters and modulators [eg, such as γ-aminobutyric acid (GABA)].
GABA is a well-known neurotransmitter that exerts inhibitoryactions in the brain,mediated through its receptors,which include theionotropic GABA A receptor (GAR) and metabotropic GABA B receptor (GBR), that are defined on the basis of pharmacological andphysiological studies.The ionotropic GAR has an intrinsic Cl-channel,which is responsible for inducing fast inhibitory postsynapticpotentials.The GBR is a G-protein-coupled receptor,and regulatesneuronal activity via activation of K+channels, which in turn induceshyperpolarization of the neuronal membrane and chronic inhibition ofneuronal activity. A high density of both GAR and GBR and a highdensity of GABA-containing nerve terminals have been found within theNTS. The GBR is a heterodimer comprised of GBR1and GBR2proteins. GBR1is critical for ligand activation of the heterodimer,whereas GBR2is merely a shuttle protein to transfer GBR1ontothe surface of the cell membrane. A large number of studies havedemonstrated that both GAR and GBR play an important role in theintegration of baroreceptor afferent inputs and baroreflexfunction.Microinjection of the GAR agonist,muscimol,or the GBRagonist, baclofen,into the NTS produces a marked pressor response viainhibition of baroreflexes, elevation of sympathetic tone,and vasopressinrelease.Conversely, microinjection of GBR antagonists removes tonicGABAergic inhibition of NTS neurons and results in a fall in arterialpressure. More interestingly, the pressor response to microinjection ofbaclofen into the NTS is enhanced in several hypertensive animalmodels, such as DOCA-salt hypertensive rats, rats with AngII-infusion induced hypertension,and1-kidney renal wrap hypertensive rats.Thosestudies demonstrated that enhanced GBR function could be associatedwith the high BP observed in those animals.However,whether GBRexpression is enhanced in the NTS during hypertension,and whether theenhanced expression of GBR in the NTS would lead to elevatedBP,remains unanswered.
In the present study, we examined the GBR and GAR expression inthe NTS of SHR and WKY rats.We also investigated the functionalconsequences of enhanced GBR expression in the NTS duringhypertension by microinjection of a viral vector containing the GBRgene into the NTS.
Methods:
1.Real-time PCR and Western Blots were used to detect changes in theexpression of GBR in the NTS of SHR rats and WKY rats.
2.Rats whose microinjection sites were within the boundaries of the NTSwere used for data analysis,and took advantage of the ways of genetransfer into the NTS. By bilateral microinjection of the AAV2-GBR1viral vector into the NTS of WKY rats.Immunofluorescence staining andwestern blots detect changes in the expression of GBR in the NTS ofWKY rats.
3.A radiotelemetry system records Eeffect of GBR1gene transfer onarterial pressure,HR,and norepinephrine plasma levels. Taking use of a pressure transducer which was connectedto a Bridge Amplifier recordseffect of agonists and antagonists of GBR and GAR on BP, HR, andRSNA in SHR and WKY rats.
Results:
1.GBR1expression is enhanced in the NTS of SHR vs. WKY rats
2.GBR was overexpressed in the NTS by bilateral microinjection of theAAV2-GBR1viral vector into the NTS of WKY rats.Effect of GBR1gene transfer on arterial pressure, HR, and norepinephrine plasma levelswere increased steadily.
3.Effect of agonists and antagonists of GBR on BP, HR, and RSNA inSHR was significantly enhanced compared with WKY rats.
Conclusions:
GBR1expression is enhanced in the NTS of SHR vs. WKY ratsand overexpression of this gene in the NTS results in chronic elevationof blood pressure and heart rate in normotensive rats. In an acutestudy,the pressor response to baclofen microinjected into the NTS wasenhanced in SHR as compared with WKY rats.
引文
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