NONCLASSICAL TRANSMITTERS AND CARDIAC GANGLIA

描述（改编自申请人的摘要）：神经机制具有 与心律失常的产生有关， 可能引发冠状动脉痉挛。 心脏含有一个 包括交感神经、心脏固有神经、 神经节和感觉神经。 这项提议是基于最近的发现 感觉神经元可以通过速激肽介导传出功能 (TKs)和降钙素基因相关肽（CGRP）， 他们的外围进程。 PI将评估TK 直接影响冠状动脉血流，影响心脏功能 通过刺激胆碱能神经元上的连接后TK受体来刺激神经节。 该问题将在细胞、离体器官和整个动物上解决 水平使用豚鼠。 PI还将检验以下假设： TK和/或CGRP的局部作用有助于心脏和冠状动脉的 由缺血和再灌注引起的反应。 六个具体目标 定义为解决假设。 目标1. 用孤立的心脏来识别 由特定类型的TK受体介导的反应和放射自显影 定位和定量这些受体的方法。 目标2. 确定 TK受体类型、一氧化氮、胆碱能神经元和 对SP和NKA诱发的反应的非胆碱能机制 心中 目标3. 确定和描述对内源性TK的反应， 离体心脏模型 目标4。 确定外源性和 内源性TKs对心内神经元的作用及神经节内传递 体外使用微电极记录技术。 目标5。 确定影响 外源性和内源性TKs对心脏神经节胆碱能神经元的作用 vivo. 目标6。 使用选择性TK和CGRP拮抗剂来鉴定心脏和 离体心脏内源性感觉神经肽的冠状动脉效应 在缺血和再灌注期间麻醉豚鼠。 这行 研究最终确定了感觉神经元肽受体， 治疗特定心律失常和冠状动脉血管痉挛的靶点。

DESCRIPTION (Adapted from Applicant's Abstract): Neural mechanisms have been implicated in the generation of cardiac arrhythmias and also have the potential for triggering coronary vasospasm. The heart contains an elaborate neural network that includes sympathetic nerves, intrinsic cardiac ganglia and sensory nerves. This proposal is based on the recent discovery that sensory neurons can have efferent functions mediated by tachykinins (TKs) and calcitonin gene-related peptide (CGRP) that are released from their peripheral processes. The PI will evaluate the hypothesis that TKs have direct effects on coronary flow and affect the function of cardiac ganglia by stimulating postjunctional TK receptors on cholinergic neurons. The problem will be addressed at cellular, isolated organ and whole animal levels using the guinea pig. The PI will also test the hypothesis that local effects of the TKs and/or CGRP contribute to cardiac and coronary responses evoked by ischemia and reperfusion. Six specific aims have been defined to address the hypotheses. Aim 1. Use isolated hearts to identify the responses mediated by specific types of TK receptor and autoradiographic methods to localize and quantify these receptors. Aim 2. Determine the importance of TK receptor types, nitric oxide, cholinergic neurons and noncholinergic mechanisms to responses evoked by SP and NKA in isolated hearts. Aim 3. Identify and characterize responses to endogenous TKs in the isolated heart model. Aim 4. Determine effects of exogenous and endogenous TKs on intracardiac neurons and intraganglionic transmission in vitro using microelectrode recording techniques. Aim 5. Determine effects of exogenous and endogenous TKs on cholinergic neurons in cardiac ganglia in vivo. Aim 6. Use selective TK and CGRP antagonists to identify cardiac and coronary effects of endogenous sensory neuropeptides in isolated hearts and anesthetized guinea pigs during ischemia and reperfusion. This line of investigation could ultimately establish sensory neuron peptide receptors as targets for therapy of specific cardiac arrhythmias and coronary vasospasm.