Role of Nonclassical Transmitters in Cardiac Ganglia

心脏神经调节异常在心律失常、充血性心力衰竭和心脏性猝死的病理生理学中起着重要作用。神经功能障碍在终末器官水平的机制尚不清楚。这种更新应用的中心假设是，心脏内源性神经节是感觉神经肽和旁分泌介质作用于心脏神经调节的主要靶点。具体目标1、3重点介绍神经肽P物质(SP)和降钙素基因相关肽(CGRP)及其在心内反射中的中介作用。在目标1中，我们使用神经解剖学技术绘制连接心室肌和心内神经节的侧支神经投射图。评估AP和CGRP在这些络脉中的存在的实验是这一目标的重要组成部分。目的2着重于识别由P物质和降钙素基因相关肽介导的心内反射的刺激，并确定心脏反应的潜在机制。在使用离体心准备和麻醉豚鼠的研究中，提出了以下问题：含有SP/CGRP的传入是否被机械刺激和化学刺激所激活？在目的3中，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是否在影响心内神经元方面相互作用。细胞内记录方法将用于量化心内神经元对施加的多肽、乙酰胆碱和迷走神经刺激的反应。P物质和降钙素基因相关肽在刺激心内神经细胞过程中是否相互作用？如果是，这种相互作用的机制是否需要CGRP受体的激活？目的4在概念上与前面的工作类似，但侧重于假设肾上腺髓质素前体N末端20肽(PAMP)和肾上腺髓质素(ADM)在心脏内神经节中作为旁分泌介质发挥作用。细胞内记录技术和体内生理测量将被用来解决两个基本问题。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P物质和降钙素基因相关肽的释放及心脏传入？这些研究的结果将提高我们对心脏内工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.