Cardiorespiratory Afferent Control in Heart Failure

描述(申请人提供)：心力衰竭(HF)是导致死亡的主要原因，与呼吸模式大起大落有关，对血气的敏感性增强，但对血压的敏感性降低。持续气道正压治疗的患者不仅改善了呼吸，而且出人意料地改善了心肌功能。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HF，桥脑对肺、气压和化学感觉反馈的条件反射的丧失可能是交感-呼吸共病的基础。我们的具体目标是：1)确定激活肺拉伸、压力和化学感受器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力衰竭中是如何改变的；2)确定这些感觉输入之间的相互作用对延髓腹外侧区和脑桥背外侧区呼吸和脉搏相关活动的幅度和一致性的影响；以及3)确定桥脑GABA能和NMDA受体在介导这些传入对正常和心力衰竭动物心肺耦合的影响中的作用。为了实现这些目标，我们提出了一种协作方法，提供了新的能力和协同效应。PI将研究正常和心力衰竭啮齿动物模型中交感-呼吸耦合的神经机制。HF啮齿动物群体将由Hoit博士维护，他还将评估HF大鼠的心脏功能(目标1和3)。Siegel博士将研究脑桥GABAA和NMDA受体亚单位mRNA的表达、亚型形成和定位(目标3)。在USF的莫里斯博士的帮助下，PI将分析脑干神经元及其在迷走神经切断术前后对化学和压力传入刺激的反应(目标2)。这些研究将展示桥脑对传入输入的条件作用，以确定肺、气压和化学感觉信息对健康和心力衰竭患者交感呼吸节律的影响。

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.