Neural Mechanisms of Lone-Term Cardiovascular Control

描述（由申请人提供）：我们假设存在一个中枢神经系统（CNS）的“设定点”来长期控制平均动脉压（MAP），许多形式的高血压是由于钠保留激素（如醛固酮）对“CNS-MAP设定点”的初步重置。我们认为这种重置是对心室周围器官（CVOs）的激素激活的反应，CVOs通过激活阿米洛利敏感的钠通道刺激下游交感神经通路。为了验证这一假设，我们将使用连续24小时/天的MAP和心输出量或肾血流记录来分别表征doca盐高血压大鼠的全身和肾脏血流动力学的时间特征。在特异性目标1中，我们将比较CVOs、后脑区（AP）和皮质下器官（SFO）病变的影响，以及矿皮质激素受体（MR）拮抗剂和阿米洛利敏感钠通道拮抗剂（苯甲胺）的慢性脑室内给药对这些血流动力学特征和关键中枢调节部位Fos免疫反应性的影响。在Specific Aim 2中，我们将通过外科和药理学方法建立外周交感通路中断对全身和肾脏血流动力学的影响，以确定肾脏和“非肾脏”交感靶点对MAP的长期调节和doca -盐性高血压的发展的贡献。在Specific Aim 3中，我们将结合频域（即功率谱和相干性分析）和传递函数分析在Specific Aims 1和2中收集的数据，定量确定多巴胺盐高血压中神经源性和自我调节性血管张力控制的动态相对贡献。综上所述，这种综合生理学方法将促进我们对长期控制动脉压和神经源性高血压发病机制的神经机制的理解。

DESCRIPTION (provided by applicant): We hypothesize that a central nervous system (CNS) "set point" exists for the long-term control of mean arterial pressure (MAP), and many forms of hypertension are due to primary resetting of the "CNS-MAP set point" by sodium retaining hormones such as aldosterone. We propose that this resetting occurs in response to hormonal activation of circumventricular organs (CVOs), which stimulate downstream sympathetic pathways by activation of amiloride-sensitive sodium channels. To test this hypothesis, we will use continuous 24hr/day recordings of MAP and either cardiac output or renal blood flow to characterize the temporal profile of systemic and renal hemodynamics, respectively in the DOCA-salt hypertensive rats. In Specific Aim 1, we will compare the effects of lesions of the CVOs, the area postrema (AP) and subfornical organ (SFO), and the chronic intracerebroventricular administration of a mineralocorticoid receptor (MR) antagonist and an antagonist of amiloride-sensitive sodium channels (benzamil) on these hemodynamic profiles and Fos immunoreactivity of key central regulatory sites. In Specific Aim 2, we will establish the effect of interruption of peripheral sympathetic pathways on the systemic and renal hemodynamic profiles using surgical and pharmacological methods, to determine the contribution of renal and "non-renal" sympathetic targets to the long-term regulation of MAP and the development of DOCA-salt hypertension. In Specific Aim 3, we will use a combination of frequency domain (i.e., power spectra and coherence analyses) and transfer function analyses on data collected in Specific Aims 1 and 2 to quantitatively determine the dynamic relative contributions of neurogenic and autoregulatory control of vascular tone in DOCA-salt hypertension. Taken together, this integrative physiological approach will advance our understanding of the neural mechanisms for long-term control of arterial pressure and pathogenesis of neurogenic hypertension.