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

交感神经系统和心力衰竭-初级传入神经元的作用

• 批准号: 7650500
• 负责人: JIANHUA LI
• 金额: $ 38.78万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7650500
• 关键词: ASIC channel; Adenosine; Afferent Neurons; Animals; Attenuated; Autonomic nervous system; Capsaicin; Cells; Cessation of life; Characteristics; Congestive Heart Failure; Coronary; Data; Development; Diagnosis; Dinoprostone; Disease; Disease Progression; Evaluation; Exercise; Extracellular Fluid; Fluorescence; Future; Goals; Grant; Heart failure; Hindlimb; Laboratories; Lead; Ligation; Literature; Little' s Disease; Mechanoreceptors; Mediating; Methods; Modeling; Morbidity - disease rate; Muscle; Muscle Contraction; Myocardial Infarction; Nerve; Nerve Endings; Neurons; P2X-receptor; Patients; Peripheral; Play; Preparation; Prostaglandin Receptor; Prostaglandins; Publishing; Rattus; Reflex action; Regulation; Reporting; Research; Rest; Role; Sensory; Small Interfering RNA; Spinal Ganglia; Sympathetic Nervous System; Testing; Tracer; Vanilloid; Work; abnormal reflex; base; capsaicin receptor; femoral artery; ganglion cell; mortality; neuronal cell body; novel therapeutics; outcome forecast; patch clamp; receptor; research study; response; study characteristics

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.

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50万例患者被诊断，约30万例死亡。交感神经兴奋在疾病进展中起着重要作用。已知交感神经兴奋与疾病预后呈负相关。交感神经活动（SNA）在正常受试者中随着运动而增加，在HF患者中在休息时和对运动的反应中增加。这些夸大的SNA反应与HF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HF运动期间调节自主神经系统的机制。机械和代谢敏感的肌肉传入有助于调节SNA在HF。刺激这些肌肉传入的受体尚未被精确识别和表征。在过去的几年里，我们的研究工作集中在嘌呤能P2X受体，辣椒素受体（TRPV1）和酸敏感离子通道在引起异常SNA反应的HF肌肉收缩中发挥的作用。这些数据表明，这些受体在初级传入神经元的异常可能会启动一个夸张的肌肉反射在HF的发展。虽然我们的实验室和其他人已经收集了大量的证据表明，在这种疾病的肌肉传入介导的反应的变化，鲜为人知的是初级传入神经元的潜在受体机制。前列腺素和腺苷是活动肌肉的重要副产物，参与HF的异常反射反应。本提案的具体目标#1是检查前列腺素对HF中过度肌肉反射的贡献。我们推测，胡枝子素促进HF大鼠背根神经节（DRG）神经元的P2X受体的反应。该建议的具体目标#2是确定腺苷对HF中钝化的肌肉代谢反射的贡献。我们推测，腺苷抑制TRPV1反应的DRG神经元在HF的程度更大，与对照组相比。所提出的实验是基于我们实验室最近发表的工作以及已经收集的试验数据，并将使用全细胞膜片钳方法对解离的DRG细胞进行。这些研究的完成将在细胞水平上对HF患者的肌肉传入介导的循环反应进行评价。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。