Blood pressure control by caudal ventrolateral medulla

原发性高血压是心血管疾病的一种主要形式，它极大地增加了 发病率和死亡率。许多形式的原发性高血压与交感神经增强有关。 神经活动(SNA)，尽管交感神经激活的基础还不是很清楚。阻塞性睡眠 30%-50%的高血压患者存在呼吸暂停，大多数梗阻性高血压患者存在呼吸暂停。 睡眠呼吸暂停导致SNA和动脉压(AP)升高。睡眠呼吸暂停，特征是慢性 间歇性低氧也会改变中枢呼吸驱动和SNA的呼吸相关调节。有氧运动- 呼吸整合似乎是睡眠呼吸暂停的缺陷的核心，因为 SNA和AP的睡眠呼吸暂停可以通过改变夜间呼吸来部分缓解。不幸的是，有一个 缺乏关于中枢呼吸驱动和发生的SNA升高之间的联系的信息 伴有慢性间歇性低氧。这项研究的长期目标是阐明中枢神经回路 它调节维持AP的SNA，并精确定位可能导致SNA和AP升高的变化。这 SNA是由延髓头端腹外侧区(RVLM)的神经元驱动的，RVLM受到强有力的抑制 尾侧延髓腹外侧区(CVLM)内的GABA能神经元。GABA能CVLM神经元在脑内的作用 SNA对压力感受性反射的控制已经确立，但压力激活的GABA能CVLM神经元也受到张力抑制 RVLm不依赖压力感受器输入。在本项目的前一阶段，我们展示了中央 呼吸神经元为大鼠气压激活的GABA能CVLM神经元提供多个输入，尽管 消息来源不明。我们还表明，CVLM对于唤起呼吸相关的交感神经是必不可少的 对缺氧引起的外周化学感受器急性激活的反应。这些观察结果表明， CVLM是心肺整合的重要部位。监管AP的SNA受以下因素影响 中枢呼吸神经元，但中枢神经系统心肺整合的机制不是 明白了。在更新的目标1和2中，我们将在麻醉状态下进行电生理实验 以确定是否有两个中枢呼吸核团投射到CVLm，Kolliker-Fuse和Pre-Pre. Botzinger核影响压力激活的CVLM神经元的活动，以及这些输入是否是选择性的 对于特定的CVLM神经元或呼吸周期的不同阶段。此外，我们将确定这些是否 输入影响低氧诱导的CVLM神经元活动和SNA的变化。在目标3和4中，我们将 确定慢性间歇性低氧是否改变了CVLM的调节，以此作为梗阻的模型 睡眠呼吸暂停。这些研究将提供关于强大的非压力感受器的新信息 对可能影响RVLM、SNA和AP的CVLM神经元的影响。此外，这些 研究将进一步加深我们对心肺整合对心脏功能调节的影响 健康中的血压和高血压。

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. Obstructive sleep apnea is present in 30-50% of patients with essential hypertension, and the majority of patients with obstructive sleep apnea develop elevated SNA and arterial pressure (AP). Sleep apnea, characterized by chronic intermittent hypoxia, also alters central respiratory drive and the respiratory-related regulation of SNA. Cardio- respiratory integration appears to be at the heart of deficits observed with sleep apnea, because the elevated SNA and AP with sleep apnea are partially alleviated by altering nighttime breathing. Unfortunately, there is a paucity of information regarding the link between central respiratory drive and the elevated SNA that occurs with chronic intermittent hypoxia. 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 AP. 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 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 central respiratory neurons provide multiple inputs to baro-activated GABAergic CVLM neurons in rats, although the sources are unknown. We also showed the CVLM is essential for evoking respiratory-related sympathetic responses to acute activation of peripheral chemoreceptors by hypoxia. These observations suggest that the CVLM is an important site for cardio-respiratory integration. The SNA that regulates AP is influenced by central respiratory neurons, but mechanisms underlying cardio-respiratory integration in the CNS are not understood. In Aims 1 and 2 of this renewal we will perform electrophysiological experiments in anesthetized rats to determine whether two central respiratory nuclei that project to the CVLM, the Kolliker-Fuse and pre- Botzinger nuclei, influence the activity of baro-activated CVLM neurons, and whether these inputs are selective for particular CVLM neurons or phases of the respiratory cycle. In addition, we will determine whether these inputs impact hypoxia-induced changes in CVLM neuronal activity and SNA. In Aims 3 and 4 we will determine whether regulation of the CVLM is altered by chronic intermittent hypoxia, as a model for obstructive sleep apnea. These studies will provide 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 blood pressure in health and hypertension.