Circumventricular Organs and Cardiovascular Regulation

描述(由申请人提供)：中枢神经系统对长期血压(BP)调节的控制尚不完全清楚。许多研究人员研究了穹隆下器(SFO)和最后区(AP)在血管紧张素II(Ang11)中枢作用中的单独作用。血管紧张素转换酶被认为可以调节交感神经系统(SNS)的活动，并调节血压(BP)。这一提议表明，Angll通过这些CVO的行动存在冗余。这是第一次同时检测内源性和外源性Ang11对这两个CVO的影响的研究。首先，我们提出了通过这些CVO的内生Angll作用。目的1：在内源性血管紧张素转换酶的长期效应中，SFO和AP的联合作用是什么？用AT1拮抗剂Iosartan治疗SFOx、APx和XX大鼠10天，测量血压和心输出量(CO)。此外，我们建议改变内源性血管紧张素转换酶水平，通过这些血管紧张素转换酶调节血压。目的2：在饮食盐摄入量改变期间，SFO和AP在维持血压方面的联合作用是什么？测定SFOx、APx和XX大鼠在饮食盐增加和减少2周后的BP和CO。最后，我们提出慢性血管紧张素Ⅱ高血压是通过这些CVO的作用来调节的。目的3：SFO和AP在预防血管紧张素转换酶诱导的高血压中的联合作用是什么？在给APx、SFOx和XX大鼠输注Ang11的10天期间，测量血压和CO。我们预测，XX大鼠对氯沙坦的降压反应减弱，饮食盐改变时血压调节失调，血管紧张素转换酶介导的高血压减弱。此外，AIM3a：SFO和AP在Ang11诱导的RVLM中Fos表达中的联合作用是什么？观察注射Ang11后APx、SFOx和XX大鼠RVLM中FOS表达的变化。我们推测，在Ang11诱导的RVLM中，Fos的表达可能是SFO或AP所必需的，或者两者都是必需的。 我们的假设是基于这样的想法，即在上述操作中，受损动物将不能以与假手术大鼠相同的方式适当地改变SNS的活性，这将导致血压反应的改变。为了解决这一基本假设，并将SNS与观察到的血压变化联系起来，我们将测量所有大鼠在对照和治疗期间对神经节阻滞剂六甲溴铵的急性降压反应，以及血浆去甲肾上腺素水平。这些多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舒缩张力的贡献。 这些研究的结果将极大地增强我们对Ang11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长期控制动脉压方面发挥作用。

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.