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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(申请人提供)：原发性高血压是心血管疾病的主要形式，极大地增加了发病率和死亡率的风险。许多形式的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有显著的影响，在几种高血压模型中，SNA的呼吸相关调制发生了变化。中枢呼吸神经元和调节维持动脉压(AP)的SNA之间的联系完全未知。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，并确定在与SNA呼吸相关调制改变相关的高血压模型中，这些呼吸相关输入的影响是否发生变化，即暴露于慢性间歇性低氧(CIH)。这项研究的长期目标是阐明调节维持AP的SNA的中枢神经回路，并精确定位可能导致SNA升高和高血压的改变。这种SNA是由延髓头端腹外侧区(RVLM)的神经元驱动的，尾侧延髓腹外侧区(CVLM)的GABA能神经元强烈抑制RVLM。GABA能CVLM神经元在SNA的压力感受性反射控制中的作用已被证实，但气压激活的GABA能CVLM神经元也不依赖于压力感受器的输入而强直地抑制RVLM。在本项目的前一阶段，我们展示了麻醉大鼠单个气压激活的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尚不清楚。我们还表明，CVLM在急性缺氧时唤起与呼吸相关的交感反应是必不可少的。这些观察结果表明，CVLM是SNA的心肺整合和呼吸相关调节的重要部位。以前的研究已经确定了两个似乎向CVLM发送谷氨酸能投射的呼吸相关区域，即Kolliker-Fuse核和Botzinger前核。在更新的目标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核是否影响气压激活的GABA能CVLM神经元的活动，以及这些输入是否对特定的气压激活的CVLM神经元或呼吸周期的各个阶段具有选择性。我们还将确定这些输入是否会影响急性缺氧诱导的CVLM神经元活动和SNA的变化。在目标3和4中，我们将确定暴露于慢性间歇性低氧的大鼠的CVLM调节是否发生改变，慢性间歇性低氧是人类阻塞性睡眠呼吸暂停的一种高血压模型。这些研究将产生新的信息，关于可能影响RVLM、SNA和AP的CVLM神经元上强大的压力感受器非依赖性影响。此外，这些研究将进一步加深我们对心肺整合对健康和高血压中AP调节的影响的理解。