Sympathetic Nervous System and Heart Failure-Role of Primary Afferent Neurons

在美国，充血性心力衰竭（HF）是一种常见且致命的疾病，每年有50万患者被诊断出来，约有30万人死亡。交感神经兴奋在疾病进展中起重要作用。已知交感神经兴奋与疾病预后呈负相关。在正常受试者中，交感神经活动（SNA）随着运动而增加，在HF患者休息时和运动后，交感神经活动（SNA）增加。这些夸大的SNA反应与心衰患者的发病率和死亡率密切相关。PI的长期目标是更好地了解心衰患者运动时自主神经系统的调节机制。机械和代谢敏感的肌肉传入神经有助于心衰患者SNA的调节。刺激这些肌肉传入事件的受体尚未被精确地识别和表征。在过去的几年里，我们的研究工作主要集中在嘌呤能P2X受体、辣椒素受体（TRPV1）和酸感离子通道在引起心衰患者肌肉收缩异常SNA反应中的作用。这些数据表明，初级传入神经元中这些受体的异常可能引发HF中肌肉反射的过度发展。虽然我们的实验室和其他人已经收集了大量证据，表明在这种疾病中肌肉传入介导的反应发生了变化，但对初级传入神经元的潜在受体机制知之甚少。前列腺素和腺苷是活跃肌肉的重要副产物，参与心衰的异常反射反应。本提案的具体目的1是研究前列腺素对心衰患者肌肉反射过度的作用。我们假设前列腺素促进了HF大鼠背根神经节（DRG）神经元中P2X受体的反应。本提案的具体目的2是确定腺苷对心衰患者肌肉代谢反射钝化的贡献。我们假设，与对照组相比，腺苷在HF中更大程度地抑制DRG神经元的TRPV1反应。拟议的实验基于我们实验室最近发表的工作，以及已经收集的试点数据，并将使用全细胞膜片钳方法对解离的DRG细胞进行实验。这些研究的完成将在细胞水平上对心衰患者肌肉传入介导的循环反应进行评估。这些研究将为未来的实验奠定基础，以研究治疗这种疾病的运动不耐受的新疗法。

In the US, congestive heart failure (HF) is a common and lethal disease with 500,000 patients being diagnosed, and with ~300,000 deaths each year. Sympathoexcitation plays a prominent role in disease progression. It is known that sympathoexcitation is inversely related to disease prognosis. Sympathetic nervous activity (SNA) is increased with exercise in normal subjects and is increased in HF patients at rest and in response to exercise. These exaggerated SNA responses are well correlated with morbidity and mortality in HF patients. The long-term goals of the PI are to better understand the mechanisms that regulate the autonomic nervous system during exercise in HF. The mechano- and metabo-sensitive muscle afferents contribute to regulation of SNA in HF. The receptors that stimulate those muscle afferents have yet to be precisely identified and characterized. Over the last several years our research efforts have focused on the roles played by purinergic P2X receptors, capsaicin receptors (TRPV1) and acid sensing ion channels in evoking abnormal SNA responses to muscle contraction in HF. The data indicate that abnormalities in those receptors in primary afferent neurons may initiate the development of an exaggerated muscle reflex in HF. While our laboratory and others have collected substantial evidence showing alternations in muscle afferent-mediated response in this disease, little is known regarding the underlying receptor mechanisms of primary afferent neurons. Prostaglandins and adenosine are important by-products in active muscles and engaged in the abnormal reflex response in HF. Specific Aim #1 of this proposal is to examine contributions of prostaglandin to exaggerated muscle reflex in HF. We hypothesize that prostaglandins facilitate responses of P2X receptors in the dorsal root ganglion (DRG) neurons of HF rats. Specific Aim #2 of this proposal is to determine contributions of adenosine to blunted muscle metaboreflex in HF. We hypothesize that adenosine inhibits TRPV1 responses of DRG neurons to a greater degree in HF as compared with controls. The proposed experiments are based on recently published work from our laboratory as well as pilot data that have been gathered and will be performed on dissociated DRG cells using whole cell patch-clamp methods. Completion of these studies will provide an evaluation of muscle afferent-mediated circulatory responses in HF patients at the cellular level. These studies will lay the groundwork for future experiments to examine novel therapeutics to treat exercise intolerance in this disease.