权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Blood pressure control by caudal ventrolateral medulla

通过尾部腹外侧延髓控制血压

基本信息

批准号：
8520376
负责人：
ANN M SCHREIHOFER
金额：
$ 34.16万
依托单位：
UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-05-03 至 2016-05-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Essential hypertension is a leading form of cardiovascular disease that greatly increases the risks of morbidity and mortality. Many forms of essential hypertension are associated with augmented sympathetic nerve activity (SNA), although the basis of the sympatho-activation is not well understood. Respiratory regulatory neurons in the brain provide a significant influence on SNA, and altered respiratory-related modulation of SNA is present in several models of hypertension. Links between central respiratory neurons and those that regulate the SNA that maintains arterial pressure (AP) are completely unknown. This project will elucidate connections from central respiratory neurons to cardiovascular regulatory neurons and determine whether the influences of these respiratory-related inputs are changed in a hypertensive model associated with altered respiratory-related modulation of SNA, namely exposure to chronic intermittent hypoxia (CIH). The long range goals of this research are to elucidate central neural circuits that regulate the SNA that maintains AP and pinpoint alterations that may lead to elevated SNA and hypertension. This SNA is driven by neurons in the rostral ventrolateral medulla (RVLM), and the RVLM is powerfully restrained by GABAergic neurons in the caudal ventrolateral medulla (CVLM). The role of GABAergic CVLM neurons in the baroreflex control of SNA is well established, but baro-activated GABAergic CVLM neurons also tonically inhibit the RVLM independent of baroreceptor inputs. In the previous period of this project we showed that individual baro-activated GABAergic CVLM neurons in anesthetized rats display distinct patterns of respiratory-related activity, though sources of these inputs are unknown. We also showed the CVLM is essential to evoke respiratory-related sympathetic responses to acute hypoxia. These observations suggest the CVLM is an important site for cardio-respiratory integration and respiratory-related regulation of SNA. Previous studies have identified 2 respiratory-related regions that appear to send glutamatergic projections to the CVLM, namely the Kolliker-Fuse nucleus and the pre-Botzinger nucleus. In Aims 1 and 2 of this renewal we will perform electrophysiological experiments in anesthetized rats to determine whether the Kolliker-Fuse and pre- Botzinger nuclei influence the activity of baro-activated GABAergic CVLM neurons, and whether these inputs are selective for particular baro-activated CVLM neurons or phases of the respiratory cycle. We will also determine whether these inputs impact acute hypoxia-induced changes in CVLM neuronal activity and SNA. In Aims 3 and 4 we will determine whether regulation of the CVLM is altered in rats exposed to chronic intermittent hypoxia, a hypertensive model for obstructive sleep apnea in humans. These studies will produce novel information regarding a powerful baroreceptor-independent influence upon the CVLM neurons that are likely to influence the RVLM, SNA, and AP. In addition, these studies will further our understanding of the impact of cardio-respiratory integration upon the regulation of AP in health and hypertension.

描述（由申请人提供）：原发性高血压是一种主要的心血管疾病，大大增加了发病率和死亡率的风险。许多形式的原发性高血压与交感神经活动增强（SNA）有关，尽管交感神经激活的基础尚不清楚。大脑中的呼吸调节神经元对SNA有重要影响，并且在几种高血压模型中存在呼吸相关的SNA调节改变。中枢呼吸神经元和那些调节维持动脉压（AP）的SNA的神经元之间的联系是完全未知的。该项目将阐明中枢呼吸神经元与心血管调节神经元之间的联系，并确定这些呼吸相关输入的影响是否在高血压模型中与呼吸相关的SNA调节改变有关，即暴露于慢性间歇性缺氧（CIH）。本研究的长期目标是阐明调节维持AP的SNA的中枢神经回路，并查明可能导致SNA升高和高血压的改变。这种SNA由吻侧腹外侧髓质（RVLM）神经元驱动，RVLM受到尾侧腹外侧髓质（CVLM） gaba能神经元的强烈抑制。GABAergic CVLM神经元在SNA的压力反射控制中的作用已得到证实，但高压激活的GABAergic CVLM神经元也会在不依赖压力感受器输入的情况下抑制性地抑制RVLM。在这个项目的前一阶段，我们发现麻醉大鼠的单个高压激活的gaba能CVLM神经元显示出不同的呼吸相关活动模式，尽管这些输入的来源未知。我们还发现，CVLM对于引起急性缺氧时呼吸相关的交感神经反应至关重要。这些观察结果表明，CVLM是心肺一体化和呼吸相关的SNA调节的重要部位。先前的研究已经确定了两个与呼吸相关的区域，即Kolliker-Fuse核和pre-Botzinger核，它们似乎向CVLM发送谷氨酸能投射。在本次更新的目的1和2中，我们将在麻醉大鼠中进行电生理实验，以确定Kolliker-Fuse和pre- Botzinger核是否影响高压激活的GABAergic CVLM神经元的活动，以及这些输入是否对特定的高压激活的CVLM神经元或呼吸周期的阶段具有选择性。我们还将确定这些输入是否影响急性缺氧诱导的CVLM神经元活动和SNA的变化。在目的3和4中，我们将确定暴露于慢性间歇性缺氧（人类阻塞性睡眠呼吸暂停的高血压模型）的大鼠的CVLM调节是否改变。这些研究将提供关于CVLM神经元强大的不依赖于压力感受器的影响的新信息，这些影响可能会影响RVLM、SNA和AP。此外，这些研究将进一步加深我们对心肺一体化对健康和高血压中AP调节的影响的理解。