Circumventricular Organs and Cardiovascular Regulation

描述（由申请人提供）：尚未完全了解中枢神经系统对长期血压（BP）调节的控制。 许多研究者研究了穹窿下器（subfornicalorgan，SFO）和最后区（areapostrema，AP）在血管紧张素II（angiotensinII，AngII）中枢效应中的作用。 AngII被认为调节这些室周器官（CVO）的交感神经系统（SNS）活动并调节血压（BP）。 这个提议表明Angll通过这些CVO的操作存在冗余。 这是第一项同时检查内源性和外源性AngII在这2个CVO处的作用的研究。 首先，我们提出内源性AngII行为通过这些CVO。 目的1：SFO和AP在内源性AngII的长期作用中的联合作用是什么？ 将在用AT1拮抗剂Iosartan处理10天的SFOx、APx和XX大鼠中测量BP和心输出量（CO）。 此外，我们提出改变内源性AngII的水平通过这些CVO来调节BP。 目的2：在饮食盐摄入量改变时，SFO和AP在维持血压中的联合作用是什么？ 将在SFOx、APx和XX大鼠中测量BP和CO，这些大鼠经历2周的增加和减少饮食盐的时期。 最后，我们提出慢性AngII高血压是通过这些CVO的作用介导的。 目的3：SFO和AP联合应用在预防AngII诱导的高血压中的作用是什么？ 在10天AngII输注期间，将在APx、SFOx和XX大鼠中进行BP和CO测量。 我们预测XX大鼠将具有减弱的对伊奥沙坦的过度反应、在饮食盐的变化期间的BP失调以及减弱的AngII介导的高血压。 此外，AIM 3a：SFO和AP在Angll诱导RVLM中Fos表达中的联合作用是什么？ 将在经历AngII输注的APx、SFOx和XX大鼠的RVLM中测量Fos表达。 我们预测SFO和AP对于Angll诱导RVLM中Fos表达是必要的。 我们的假设是基于这样的想法，即在上述操作过程中，损伤的动物将不能以与假手术大鼠相同的方式适当地改变SNS活动，这将导致血压反应的改变。 为了解决这一潜在的假设，并将SNS与观察到的血压变化联系起来，我们将在对照和治疗期间测量所有大鼠对神经节阻滞剂六甲铵的急性降压反应以及血浆去甲肾上腺素水平。 这些多种方法将使我们能够确定在观察到的血压变化期间交感神经对血管紧张度的贡献。 这些研究的结果将极大地增强我们对Angll在两个特定大脑区域的中枢作用的理解，以及这些相互作用如何在动脉压的长期控制中发挥作用。

DESCRIPTION (provided by applicant): Central nervous system control over long-term blood pressure (BP) regulation is not completely understood. Many investigators have studied the individual roles of the subfornical organ (SFO) and area postrema (AP) in the central effects of Angiotensin II (Angll). Angll is thought to modulate sympathetic nervous system (SNS) activityat these circumventricular organs (CVOs) and regulate blood pressure (BP). This proposal suggests there is redundancy in the actions of Angll via these CVOs. This is the first study to simultaneously examine effects of both endogenous and exogenous Angll at these 2 CVOs. First, we propose endogenous Angll acts via these CVOs. AIM 1: What are the combined roles of the SFO and AP in the long-term effects of endogenous Angll? BP and cardiac output (CO) will be measured in SFOx, APx and XX rats treated with the AT1 antagonist, Iosartan, for 10 days. Furthermore, we propose changing levels of endogenous Angll act via these CVOs to regulate BP. AIM 2: What are the combined roles of the SFO and AP in the maintenance of BP during changes in dietary salt intake? BP and CO will be measured in SFOx, APx and XX rats subjected to 2 week periods of increased and decreased dietary salt. Lastly, we propose chronic Angll hypertension is mediated through effectsat these CVOs. AIM 3: What are the combined roles of the SFO and AP in the prevention of Angll induced hypertension? BP and CO measurements will be made in APx, SFOx, and XX rats during a 10 day infusionof Angll. We predict that XX rats will have an attenuated hypotensive response to Iosartan, dysregulation of BP during changes in dietary salt, and an attenuated Angll mediated hypertension. Furthermore, AIM3a: What are the combined roles of the SFO and AP in Angll induced Fos expression in the RVLM? Fos expression will be measured in the RVLM in APx, SFOx and XX rats subjected to Angll infusion. We predicteither or both the SFO and AP are necessary for Angll induced Fos expression in the RVLM. Our hypothesis is based on the idea that lesioned animals will not be able to alter SNS activity appropriatelyin the same manner as sham rats during the above manipulations, and this will lead to the altered blood pressure responses. In order to address this underlying hypothesis, and link the SNS to the observed changes in blood pressure, we will measure acute depressor responses to the ganglionic blockingagent, hexamethonium, as well as plasma norepinephrine levels in all rats during control and treatment periods. These multiple methods will allow us to determine the sympathetic contribution to vasomotor tone during the observed changes in blood pressure. The results of these studies will greatly enhance our understanding of the central effects of Angll at two specific brain regions, and how these interactions play a role in the long-term control of arterial pressure.