NONCLASSICAL TRANSMITTERS AND CARDIAC GANGLIA

描述(改编自申请者摘要)：神经机制有 与心律失常的产生有牵连，还有 有可能引发冠状动脉血管痉挛。心脏包含一个 复杂的神经网络，包括交感神经、心脏内脏 神经节和感觉神经。这项建议是基于最近的发现 感觉神经元可能具有由速激肽介导的传出功能 (TKS)和降钙素基因相关肽(CGRP) 它们的外周突起。PI将评估TKS的假设 直接影响冠脉流量，影响心脏功能 通过刺激胆碱能神经元上的突触后TK受体。 这个问题将在细胞、隔离器官和整个动物上得到解决。 以豚鼠为实验对象。PI还将检验以下假设 TKS和/或CGRP对心脏和冠状动脉的局部作用 缺血和再灌流引起的反应。有六个具体目标 其定义是为了解决假设。目标1.使用分离的心脏来识别 特异性TK受体介导的反应与放射自显影 方法对这些受体进行定位和定量。目标2.确定 TK受体类型、一氧化氮、胆碱能神经元和 SP和NKA诱发的非胆碱能机制 红心。目的3.确定和表征对内源性TKS的反应 隔离心脏模型。目的4.确定外源和 内源性TKS对大鼠心内神经元和神经节内传递的影响 体外使用微电极记录技术。目标5.确定效果 外源性和内源性TKS对大鼠心脏神经节胆碱能神经元的影响 活着。目的6.使用选择性的TK和CGRP拮抗剂来识别心脏和 内源性感觉神经肽对心脏和心脏的冠脉效应 麻醉豚鼠缺血再灌流过程中的变化。这一行 研究可能最终确定感觉神经元肽受体为 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.