CENTRAL NEURONAL-GLIAL MECHANISMS AND NEUROHUMORAL ACTIVATION IN HYPERTENSION

摘要 而交感神经和神经内分泌系统的协调活动对于 维持心血管(CV)动态平衡，持续交感神经体液高度激活 有害的，导致包括高血压在内的心血管疾病。因此，阐明机制 调节交感体液激活对于预防和更有效地治疗 高血压。下丘脑室旁核在下丘脑室旁核的形成中起关键作用。 交感-体液反应。这个核团内的神经元活动受以下两种平衡控制 内在属性和外在突触输入。在最近的研究中，我们发现A型K+ 电流(IA)抑制下丘脑室旁核(PVN)的放电活动，而IA功能减弱有助于神经元的增强 高血压时的活动性。高血压的另一个主要致病因素是谷氨酸NMDA的增加 受体功能。然而，这两种不同的机制是否在功能上和因果上是 再加上，目前还不得而知。采用体外和体内相结合的多学科方法 研究中，我们获得了令人兴奋的初步数据，支持突触外NMDAR之间的因果联系 IA在介导高血压时神经元活动增强和交感神经道德激活中起重要作用。 此外，我们发现星形胶质细胞是影响eNMDAR-IA偶联疗效的关键角色。 在这项提案中，我们将检验eNMDAR过度激活及其负面影响这一中心假设 与IA的偶联是导致神经元活动增加的主要因素 交感神经体液激活在高血压中的作用此应用程序的主要目标是将 ENMDAR-IA偶联的信号机制。此外，我们的目标是澄清 (A)胶质功能改变和(B)内在神经元机制对过度激活的相对贡献 抑制eNMDAR-IA偶联，并增加神经元活性和交感体液激活 高血压大鼠。利用肾血管性高血压动物模型，我们提出了以下特定的 目标1--描述eNMDAR和IA之间的功能偶联；目标2--确定 胶质功能改变有助于高血压大鼠eNMDAR-IA偶联增强；Aim 3-to 确定神经元机制改变是否有助于高血压患者eNMDAR-IA偶联增强 老鼠。我们希望这项工作将扩大我们对基本神经生物学原理的了解，这些原理涉及 产生动态平衡的神经体液反应。更重要的是，我们希望确定关键 神经体液异常反应的病理生理学脑机制 高血压。我们希望我们的工作将有助于开发新的和更有效的治疗方法 高血压病的治疗策略。

Abstract While coordinated activities of the sympathetic and neuroendocrine systems are essential for proper maintenance of cardiovascular (CV) homeostasis, sustained sympathohumoral activation is highly detrimental, contributing to CV disorders including hypertension. Thus, elucidating mechanisms regulating sympathohumoral activation is critical for the prevention and more efficient treatment of hypertension. The hypothalamic paraventricular (PVN) nucleus plays pivotal roles in the generation of sympathohumoral responses. Neuronal activity within this nucleus is controlled by a balance between intrinsic properties and extrinsic synaptic inputs. In recent studies, we showed that the A-type K+ current (IA) inhibits PVN firing activity, and that blunted IA function contributes to enhanced neuronal activity in hypertension. Another major pathogenic factor in hypertension is increased glutamate NMDA receptor function. However, whether these two distinct mechanisms are functionally and causally coupled, is at present unknown. Using a multidisciplinary approach combining in vitro and in vivo studies, we obtained exciting preliminary data supporting a causal link between extrasynaptic NMDARs and IA in mediating increased neuronal activity and sympathoumoral activation in hypertension. Moreover we found astrocytes to be pivotal players influencing the efficacy of the eNMDAR-IA coupling. In this proposal, we will test the central hypothesis that over-activation of eNMDARs and its negative coupling to IA is a major contributing factor underlying increased neuronal activity and sympathohumoral activation in hypertension. The main objective of this application is to characterize the signaling mechanisms underlying the eNMDAR-IA coupling. Moreover, we aim to elucidate the relative contribution of (a) altered glial function and (b) intrinsic neuronal mechanisms to overactivation of the eNMDAR-IA coupling, and increased neuronal activity and sympathohumoral activation in hypertensive rats. Using a renovascular hypertensive animal model, we propose the following Specific Aims: Aim 1- To characterize the functional coupling between eNMDARs and IA; Aim 2- To determine if altered glial function contributes to enhanced eNMDAR-IA coupling in hypertensive rats; and Aim 3- To determine if altered neuronal mechanisms contribute to enhanced eNMDAR-IA coupling in hypertensive rats. We expect this work to expand our knowledge on basic neurobiological principles implicated in the generation of homeostatic neurohumoral responses. More importantly, we expect to identify key pathophysiological brain mechanisms contributing to maldaptive neurohumoral responses in hypertension. We hope our work will help in the development of novel and more efficient therapeutic strategies for the treatment of hypertensive conditions.