Role of Nonclassical Transmitters in Cardiac Ganglia

心脏异常的神经调节在心律失常、充血性心力衰竭和心源性猝死的病理生理中起着突出的作用。神经功能障碍在终末器官水平的机制尚不清楚。这一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破坏心脏神经调节的主要靶点。特异性目的13关注神经肽P物质（SP）和降钙素基因相关肽（CGRP）及其在心内反射中的介导作用。在目的1中，我们使用神经解剖学技术来绘制连接心室心肌和内在心脏神经节的侧支神经投影。评估这些抵押品中AP和CGRP存在的实验是本目的重要组成部分。目的2侧重于识别触发由SP和CGRP介导的心内反射的刺激，并确定心脏反应的机制。在使用离体心脏制剂和麻醉豚鼠的研究中，解决了以下问题：含有SP/ cgrp的传入事件是否被机械刺激和化学刺激激活？在Aim 3中，采用细胞方法评估SP对心内神经节胆碱能神经传递的影响，并确定SP和CGRP是否相互作用影响心内神经元。细胞内记录方法将用于量化心内神经元对应用肽、乙酰胆碱和迷走神经刺激的反应。SP和CGRP是否相互作用刺激心内神经元？如果是这样，相互作用的机制是否需要激活CGRP受体？Aim 4在概念上与之前的工作相似，但重点放在肾上腺髓质素前n端20肽（PAMP）和肾上腺髓质素（ADM）作为内在心神经节的旁分泌介质的假设上。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的释放和心脏事件？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。

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.