Central Endocannabinoid System Dysfunction and Hypertension

中枢内源性大麻素系统功能障碍和高血压

• 批准号: 8394625
• 负责人: JEANNE L SEAGARD
• 金额: --
• 依托单位: CLEMENT J. ZABLOCKI VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8394625
• 关键词: 2-arachidonylglycerol; Acetates; Acute; Address; Afferent Neurons; Age; Agonist; American; Animals; Antihypertensive Agents; Anxiety; Attenuated; Baroreflex; Binding; Binding Sites; Blood Pressure; Brain; Brain Stem; Butyric Acids; Cardiac; Cardiovascular Diseases; Central Nervous System Diseases; Characteristics; Chronic; Conscious; Data; Deoxycorticosterone; Development; Diabetes Mellitus; Diffusion; Disinhibition; Distal; Dorsal; Endocannabinoids; Enzymes; Excitatory Synapse; Fiber; Functional disorder; Funding; Glutamates; Goals; Human; Hypertension; Hypertensive Crisis; Implant; Inbred SHR Rats; Inbred WKY Rats; Interneurons; Kidney; Knock-out; Lead; Lentivirus Vector; Maintenance; Malignant - descriptor; Measures; Mental Depression; Metabolism; Methods; Microinjections; Modeling; Monoacylglycerol Lipases; Nerve; Neuraxis; Neurons; Neurotransmitters; Nucleus solitarius; Orthostatic Hypotension; Output; Parkinson Disease; Pathway interactions; Pattern; Physiological; Play; Polymerase Chain Reaction; Pressoreceptors; Pressure Transducers; Process; RNA; RNA Interference; Rattus; Recombinants; Reflex action; Refractory; Reporting; Reverse Transcription; Role; SR141716; Series; Signal Transduction; Signaling Molecule; Sodium Chloride; Stroke; Synapses; System; Techniques; Therapeutic; Time; anandamide; blood pressure regulation; cannabinoid receptor; conditioning; density; fatty acid amide hydrolase; insight; meetings; normotensive; novel; presynaptic; relating to nervous system; response; small hairpin RNA; transmission process; uptake

DESCRIPTION (provided by applicant): The arterial baroreceptors provide a powerful beat-to-beat regulation of blood pressure (BP) via a well- defined CNS reflex. The physiological importance of the baroreflex is underscored by the consequences of impaired baroreflex function - volatile BP, orthostatic hypotension, and occasionally malignant vagotonia. The primary baroreceptor afferent fibers make their first excitatory synapse onto second-order neurons in the nucleus tractus solitarius (NTS). This is a pivotal regulatory moment because the signal conditioning at these gateway synapses determines the magnitude, pattern and duration of the baroreceptor signals transmitted to the central network to coordinate baroreflex output. In prior studies, evidence was obtained that suggested that endocannabinoids (ECBs), endogenous agonists of neural cannabinoid receptors (CB1Rs), provide a presynaptic mechanism that modulates central integration of baroreceptor inputs in the NTS and thus provide a regulatory mechanism for baroreflex function. ECB agonists and ECBs produced in the NTS were found to activate CB1Rs and modulated inhibitory (GABA) transmission, resulting in enhanced baroreflex sympathoin- hibition in normotensive rats. However, the effects of ECBs in the NTS of spontaneously hypertensive rats (SHRs), which have enhanced GABAergic function in the NTS, were greatly attenuated. In addition, density of CB1Rs in the NTS of SHRs was significantly reduced as compared to normotensive rats. It was not clear if the changes in the ECB system in the SHR were a cause or an effect to development of hypertension. Thus, the goal of the proposed studies is to determine the extent of alteration of the ECB system during devel- opment of hypertension and determine if the changes in function of the ECB system are the consequences of, or contributors to, the development or maintenance of hypertension. As a more global goal, data from this study will also help to determine if the ECB system provides a mechanism for modulation of synaptic processing in the brainstem that has not been described previously. It is possible that modulation of the endogenous ECB system could provide therapeutic benefits in the treatment of conditions in which alteration of autonomic control is compromised. Specific Aim 1 - Determine the correlation of timing between the development of hypertension versus the effects of ECBs in the NTS by examining the effects of ECBs on baroreflex-evoked sympathoinhibition and either 1) changes in CB1R binding density in the dorsal medulla, including the NTS, or 2) CB1R message using quantitative reverse transcription-polymerase chain reaction (RT-PCR) specifically in the NTS in spontaneously hypertensive animals. Specific Aim 2 - Determine the effects of ECBs on baroreflex-evoked sympathoinhibition and either 1) CB1R density in the dorsal medulla, including the NTS or 2) CB1R message using RT-PCR specifically in the NTS during the development of hypertension in models other than SHR which are also distinguished by decreases in baroreflex control and increases in sympathetic nerve activity and NTS GABAergic function. Specific Aim 3 - Examine the consequences of the prolonged loss of CB1R activity in normotensive rats, using pharmacologic or recombinant techniques to recapitulate the changes seen in CB1R density in the SHR model. If attenuated function of the ECB system is found to correlate with the development or maintenance of hypertension, it is possible that increasing levels of ECBs or CB1Rs within the NTS could help to correct hypertension through enhancing activity of an endogenous regulatory system. Characterizing this mechanism and precisely how and when it acts will help to understand central baroreflex control in general and may also lead to new insights into baroreflex dysfunction - a feature not only of cardiovascular diseases but also of diabetes and CNS disorders, including Parkinson's, depression, and anxiety.

描述（由申请人提供）： 动脉压力感受器通过定义明确的CNS反射提供了对血压（BP）的强大Beat-to-Beat调节。压力反射的生理重要性受到降压功能受损的后果 - 挥发性BP，体位性低血压以及有时是恶性的Vagotonia。主要的压力感受器传入纤维使其首次兴奋性突触到soltractus solitarius（NTS）中的二阶神经元上。这是一个关键的调节时刻，因为这些网关突触处的信号调节决定了传输到中心网络的压力感受器信号的大小，模式和持续时间以协调BaroreFlex输出。在先前的研究中，获得了证据表明，内源性大麻素（ECB），神经大麻素受体的内源性激动剂（CB1R）提供了突触前机制，可调节NTS中的baroreceptor输入的中心整合，从而为Baroreflex功能提供调节机制。发现在NTS中产生的ECB激动剂和ECB可激活CB1RS并调节抑制性（GABA）的传播，从而在正常的大鼠中增强了压力反射交感神素。但是，ECB在自发性高血压大鼠（SHR）的NT中的影响大大减弱了NTS的GABA能功能。另外，与正常的大鼠相比，SHR NTS中CB1RS的密度显着降低。目前尚不清楚SHR中欧洲央行系统的变化是否是高血压发展的原因或影响。因此，拟议的研究的目的是确定高血压开发过程中欧洲央行系统改变的程度，并确定欧洲央行系统功能的变化是否是高血压发展或维持的后果或贡献者的后果。作为一个更全球的目标，这项研究的数据还将有助于确定欧洲央行系统是否提供了调节脑干中突触处理的机制，但前面尚未描述。内源性欧洲央行系统的调节可能会在治疗自主控制改变的条件下提供治疗益处。具体目的1-通过检查ECB对压力反射诱发的交感神经抑制的影响与ECB对NTS中ECB的影响与ECB在NTS中的影响之间的时间相关性的相关性。自发性高血压动物中的NT。 Specific Aim 2 - Determine the effects of ECBs on baroreflex-evoked sympathoinhibition and either 1) CB1R density in the dorsal medulla, including the NTS or 2) CB1R message using RT-PCR specifically in the NTS during the development of hypertension in models other than SHR which are also distinguished by decreases in baroreflex control and increases in sympathetic nerve activity and NTS GABAergic function.具体目标3-使用药理或重组技术来概括SHR模型中CB1R密度的变化，检查正常大鼠CB1R活性长期丧失的后果。 如果发现欧洲央行系统的减弱功能与高血压的发展或维持相关，则NTS内ECB或CB1R水平的增加可能会通过增强内源性调节系统的活动来帮助纠正高血压。表征这种机制，并精确地表征其行为的方式以及何时有助于理解总体上的BaroreFlex控制，并且还可能导致对BaroreFlex功能障碍的新见解 - 不仅是心血管疾病的功能，而且是糖尿病和CNS疾病的特征，包括帕金森氏症，抑郁症和焦虑症。