NEUROHORMONAL MECHANISMS IN HYPERTENSION

本计划项目的多学科研究工作 继续专注于阐明细胞，生物化学， 以及肾素-血管紧张素- 醛固酮系统参与心血管疾病的调控 功能和动脉高血压的发病机制。 广大 所提出的研究的目的是探索生物化学， 中枢神经系统的神经解剖学和生理学基础 血管紧张素II（Ang II）及其同源肽的作用， 醛固酮对延髓神经元回路的影响， 下丘脑参与紧张和反射调节 心血管功能，以及神经和体液 维持细胞外液体积和组成的因子。 具体而言，我们寻求确定 血管紧张素肽（Angs）影响神经元通路， 髓质参与心血管调节，通过建立：1） Angs改变电生理的能力 背内侧核离体切片神经元的特性 （2）Angs改变髓质（DMM）释放的能力。 DMM切片中的P物质、去甲肾上腺素和血清素， 结状神经节外植体; 3）运输机制和 DMM中Ang结合位点的功能意义， 颈部迷走神经;和4）解剖，电生理，和 血管紧张素II升压作用的神经激素机制 在延髓腹外侧 此外，我们将调查 血管紧张素II的不同中枢作用是否可以解释为： 1)血管紧张素受体在血脑内外的位置 或脑脊液（CSF）-脑屏障，2）存在 作用于共同受体的Angs分子变体，或 亚群，或3）两种可能性的组合。 这些 将通过确定以下内容来研究替代方案：1） 血管紧张素II及其片段的表达和调控，以及那些 加工酶可能有助于产生 多种生物活性Angs; 2）结构-活性 血管紧张素Ⅱ与其七肽片段（Ang- (1-7)，Ang-（2-8），其决定受体结合并赋予 在神经元或神经分泌事件中的不同作用：和3） Ang II、Ang-（1-7）和Ang-（2-8）的生理机制 参与神经垂体加压素的作用 和动脉压反射控制的调节 DMM。 最后，我们将检查血流动力学和神经体液 以降压量给予CSF的醛固酮的作用 为了确定这种类固醇在中枢心血管疾病中的作用， 调控 拟议的研究将利用 我们团队的多学科专业知识， 关于调节体内平衡的神经激素机制， 会导致高血压。

The multidisciplinary research efforts of this Program Project continue to focus on the elucidation of the cellular, biochemical, and functional mechanisms by which the renin-angiotensin- aldosterone system participates in the control of cardiovascular function and the pathogenesis of arterial hypertension. The broad objective of the proposed studies is to explore the biochemical, neuroanatomical, and physiological substrate for the central actions of angiotensin II (Ang II), its congener peptides, and aldosterone on the neuronal circuits of the medulla oblongata and hypothalamus involved in tonic and reflex regulation of cardiovascular function, and integration of neural and humoral factors that maintain extracellular fluid volume and composition. Specifically, we seek to determine the mechanism(s) by which angiotensin peptides (Angs) influence neuronal pathways in the medulla involved in cardiovascular regulation by establishing: 1) the capacity of Angs to alter the electrophysiological characteristics of neurons in an in vitro slice of the dorsomedial medulla (DMM); 2) the ability of Angs to alter the release of substance P, norepinephrine, and serotonin from DMM slices and nodose ganglion explants; 3) the transport mechanisms and functional significance of Ang binding sites in the DMM and cervical vagus; and 4) the anatomical, electrophysiological, and neurohormonal mechanisms involved in the pressor actions of Ang II in the ventrolateral medulla. In addition, we will investigate whether the differing central actions of Ang II are explained by: 1) the location of Ang receptors within vs. outside the blood-brain or cerebrospinal fluid (CSF)-brain barriers, 2) the presence of molecular variants of Angs that act on a common receptor or subpopulations, or 3) a combination of both possibilities. These alternatives will be investigated by determining: 1) the expression and regulation of Ang II and its fragments, and those processing enzymes that may contribute to the generation of multiple biologically active Angs; 2) structure-activity relationships between Ang II and its heptapeptide fragments (Ang- (1-7), Ang-(2-8) that determine receptor binding and impart different roles in neuronal or neurosecretory events: and 3) the physiological mechanisms by which Ang II, Ang-(1-7), and Ang-(2-8) participate in the relate of vasopressin from the neurohypophysis and modulation of the reflex control of arterial pressure by the DMM. Finally, we will examine the hemodynamic and neurohumoral effects of aldosterone given into the CSF in sub-pressor amounts to establish the role of this steroid in central cardiovascular regulation. The proposed studies will take advantage of the multidisciplinary expertise of our group to uncover new information about the neurohormonal mechanisms that regulate homeostasis and can produce hypertension.