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: 6537205
• 负责人: DONALD B HOOVER
• 金额: $ 21.85万
• 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/6537205
• 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不齐，充血性心力衰竭和猝死的病理生理学中起着重要作用。 末端器官水平的神经功能障碍的机制知之甚少。 这种更新应用的中心假设是内在心脏神经节是感觉神经肽和旁分泌介质作用以破坏心脏神经调节的主要目标。具体目的1 3专注于神经肽物质P（SP）和降钙素基因相关肽（CGRP）及其在心脏内反射中的作用。 在AIM 1中，我们使用神经解剖技术来绘制核心心肌与内在心脏神经节联系起来的副神经投影。 在这些侧支中评估AP和CGRP的存在的实验是该目标的重要组成部分。 AIM 2专注于识别刺激触发由SP和CGRP介导的心脏内反射以及心脏反应基础机制的定义机制。 在研究中使用孤立的心脏制剂和麻醉豚鼠来解决以下问题：是否通过机械刺激和化学刺激激活了含SP/CGRP的传入？ 在AIM 3中，使用一种细胞方法来评估SP对内在心脏神经节中胆碱能神经传递的影响，并确定SP和CGRP是否在影响心脏内神经元的影响方面是否相互作用。 细胞内记录方法将用于量化心脏内神经元对应用肽，乙酰胆碱和迷走神经刺激的反应？ SP和CGRP在刺激心脏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？ AIM 4在概念上与前面的工作相似，但重点是假设原内肾上腺素甲肾上腺素N-末端20肽（PAMP）和肾上腺肾上腺素（ADM）在内在心脏神经节中起旁分泌介质的功能。 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是否会影响其对乙酰胆碱反应的心脏内神经元？ PAMP和ADM是否抑制SP和CGRP和心脏传入的释放？ 这些研究的结果将提高我们对心脏内部起作用的神经机制及其在心脏病理生理学中的重要性的理解。