Cardiorespiratory Afferent Control in Heart Failure

描述（由申请人提供）：心力衰竭（HF）是死亡的主要原因，与呼吸模式起起落落以及对血气的敏感性增强而对血压的敏感性降低有关。持续气道正压治疗的患者不仅通气改善，而且心肌功能出乎意料地改善。我们的长期目标是了解心血管和呼吸功能的协调控制（心肺耦合）。对于心衰，失去对肺、气压和化学感觉反馈的脑桥调节可能是交感呼吸合并症的基础。我们的具体目标是：1)确定激活肺牵张、气压和化学受体对交感和呼吸运动模式和耦合的影响，并确定这些影响在心衰中是如何改变的；2)确定这些感觉输入在形成髓腹外侧和桥脑背外侧神经元呼吸和脉搏相关活动的幅度和一致性方面的相互作用；3)确定脑桥gaba能受体和NMDA受体在正常和心衰动物这些传入事件对心肺偶联的影响中的作用。为了实现这些目标，我们提出了一种提供新能力和协同作用的合作方法。该项目将在正常和啮齿动物心衰模型中研究交感-呼吸耦合的神经机制。HF啮齿动物群体将由Hoit博士维持，他也将评估HF大鼠的心功能（目的1和3）。Siegel博士将描述脑桥GABAA和NMDA受体亚基mRNA的表达、亚型形成和定位（Aim 3）。与USF的Morris博士一起，PI将分析脑干神经元及其在迷走神经切开术前后对化学和气压传入刺激的反应（目的2）。这些研究将证明脑桥调节传入输入在确定肺、气压和化学感觉信息对健康和心衰患者交感呼吸节律的影响中的作用。

DESCRIPTION (provided by applicant): Heart failure (HF) is a leading cause of mortality and is associated with a waxing and waning breathing pattern as well as enhanced sensitivity to blood gases but decreased sensitivity to blood pressure. Patients treated with continuous positive airway pressure not only have improved ventilation but also, unexpectedly, myocardial function. Our long-term goal is to understand the coordinated control of cardiovascular and respiratory function (cardiorespiratory coupling). With HF, the loss of pontine conditioning of pulmonary, baro- and chemo-sensory feedback may underlie the sympatho-respiratory co-morbidities. Our Specific Aims are: 1) To determine the influence of activating pulmonary stretch-, baro-and chemo-receptors, on sympathetic and respiratory motor patterns and coupling, and to determine how these influences are altered in HF, 2) To determine the interaction between these sensory inputs in shaping the magnitude and consistency of respiratory-and pulse-correlated activities of ventrolateral medullary and dorsolateral pontine neurons, and 3) To determine the role of pontine GABAergic and NMDA receptors in mediating the effect of these afferents on cardiorespiratory coupling in normal and HF animals. To address these Aims, we propose a collaborative approach that offers novel capabilities and synergisms. The PI will study neural mechanisms of sympatho-respiratory coupling in normal and a rodent model of HF. The HF rodent colony will be maintained by Dr. Hoit, who will also assess cardiac function in HF rats (Aims 1 & 3). Dr. Siegel will characterize pontine GABAA and NMDA receptor subunit mRNA expression, subtype formation and localization (Aim 3). With Dr. Morris at USF, the PI will analyze brainstem neurons and their responses to chemo- and baro-afferent stimulation before and after vagotomy (Aim 2). These studies will demonstrate the role of pontine conditioning of afferent input in determining the effect pulmonary, baro-and chemo-sensory information on sympatho-respiratory rhythm in health and in HF.