Role of Nonclassical Transmitters in Cardiac Ganglia

非经典递质在心脏神经节中的作用

• 批准号: 6382501
• 负责人: DONALD B HOOVER
• 金额: $ 20.81万
• 依托单位: EAST TENNESSEE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-09 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6382501
• 关键词: acetylcholine; afferent nerve; autonomic ganglion; calcitonin gene related peptide; guinea pigs; heart conduction system; heart electrical activity; heart innervation; immunocytochemistry; myocardium; neuromuscular transmission; neuropeptides; neuroregulation; paracrine; substance P

Abnormal neural regulation of the heart plays a prominent role in the pathophysiology of cardiac arrhythmias, congestive heart failure and sudden cardiac death. Mechanism of neural dysfunction at the end organ level are poorly understood. The central hypothesis of this renewal application is the intrinsic cardiac ganglia are major targets where sensory neuropeptides and paracrine mediators act to disrupt neural regulation of the heart. Specific Aims 1 3 focus on the neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) and their role as mediators in intracardiac reflexes. In Aim 1 we use neuroanatomical techniques to map collateral nerve projection that link the ventricular myocardium with the intrinsic cardiac ganglia. Experiments to evaluate the presence of AP and CGRP in these collaterals are an important element of this Aim. Aim 2 focuses on identifying stimuli that trigger intracardiac reflexes mediated by SP and CGRP and defining mechanisms underlying cardiac responses. The following questions are addressed in studies using the isolated heart preparation and anesthetized guinea pigs: Are SP/CGRP-containing afferents activated by mechanical stimuli as well as chemical stimuli? In Aim 3 a cellular approach is used to evaluate the impact of SP on cholinergic neurotransmission in the intrinsic cardiac ganglia and determine whether SP and CGRP interact in affecting intracardiac neurons. Intracellular recording methods will be used to quantify responses of intracardiac neurons to applied peptides, acetylcholine and vagal stimulation? Do SP and CGRP interact in stimulating intracardiac neurons? If so, does the mechanism of interaction require activation of CGRP receptors? Aim 4 is conceptually similar to the preceding work but focuses on the hypothesis that proadrenomedullin N-terminal 20 peptide (PAMP) and adrenomedullin (ADM) function as paracrine mediators in the intrinsic cardiac ganglia. Intracellular recording techniques and in vivo physiological measurements will be used to address two basic questions. Do PAMP and ADM affect intracardiac neurons of their response to acetylcholine? Do PAMP and ADM inhibit release of SP and CGRP and cardiac afferents? Results from these studies will improve our understanding of neural mechanisms that operate within the heart and their importance in cardiac pathophysiology.

心脏的神经调节异常在心律失常、充血性心力衰竭和心源性猝死的病理生理学中起着重要作用。 终末器官水平的神经功能障碍机制知之甚少。 该更新申请的中心假设是心内神经节是感觉神经肽和旁分泌介质作用以破坏心脏的神经调节的主要靶点。具体目标1 第三部分着重于神经肽P物质（SP）和降钙素基因相关肽（CGRP）在心内反射中的介导作用。 在目标1中，我们使用神经解剖学技术来映射连接心室肌与心内神经节的侧支神经投射。 评估这些侧支中AP和CGRP存在的实验是这一目的的重要组成部分。 目的2着重于识别由SP和CGRP介导的触发心内反射的刺激，并定义心脏反应的潜在机制。 在使用离体心脏制备物和麻醉豚鼠的研究中解决了以下问题：机械刺激和化学刺激是否激活含SP/CGRP的传入神经？ 在目的3中，使用细胞方法来评估SP对心内神经节中胆碱能神经传递的影响，并确定SP和CGRP是否在影响心内神经元中相互作用。 细胞内记录方法将被用来量化的反应，心内神经元应用肽，乙酰胆碱和迷走神经刺激？ SP和CGRP在刺激心内神经元中是否相互作用？ 如果是这样，相互作用的机制是否需要激活CGRP受体？ 目的4在概念上类似于前面的工作，但侧重于假设，即肾上腺髓质素前体N-末端20肽（PAMP）和肾上腺髓质素（ADM）的功能作为旁分泌介质的内在心脏神经节。 细胞内记录技术和体内生理测量将用于解决两个基本问题。 PAMP和ADM是否影响心内神经元对乙酰胆碱的反应？ PAMP和ADM是否抑制SP和CGRP以及心脏传入神经的释放？ 这些研究的结果将提高我们对心脏内运作的神经机制及其在心脏病理生理学中的重要性的理解。