Remodeling of the guinea pig intrinsic cardiac plexus with chronic heart disease

慢性心脏病豚鼠内在心丛的重塑

基本信息

批准号：
8207240
负责人：
JEAN C HARDWICK
金额：
$ 11.65万
依托单位：
ITHACA COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-01-01 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8207240
关键词：
AGTR2 gene Acetylcholine Action Potentials Acute Address Adrenergic Agents Adrenergic Agonists Affect Angiotensin II Angiotensin-Converting Enzyme Inhibitors Animal Model Animals Arrhythmia Attention Autonomic ganglion Autonomic nervous system Calcium Channel Blockers Cardiac Cardiovascular Physiology Cavia Cells Characteristics Cholinergic Agonists Chronic Chronic Disease Coupled Data Disease Disease model Electric Stimulation Elements Fiber Frequencies Functional disorder Ganglia Generations Goals Heart Heart Diseases Histamine In Vitro Individual Measurement Measures Mediating Modeling Molecular Monitor Muscle Cells Myocardial Infarction Nerve Nervous System Physiology Nervous system structure Neurokinin B Neuromodulator Neurons Neurotransmitters Nitric Oxide Nitric Oxide Donors Nitric Oxide Synthase Norepinephrine Organ Output Pathway interactions Pattern Peripheral Physiological Population Population Heterogeneity Preparation Process Production Receptor Inhibition Reflex control Renin-Angiotensin System Risk Role Stress Sudden Death Synapses Therapeutic Time Tissues Up-Regulation adrenergic base beta-adrenergic receptor cholinergic improved indexing information processing inhibitor/antagonist meetings nerve supply neuronal excitability neuroregulation pituitary adenylate cyclase activating polypeptide pressure public health relevance receptor relating to nervous system research study response voltage

项目摘要

DESCRIPTION (provided by applicant): Previous studies have shown that an imbalance in autonomic efferent neuronal tone, with reduced parasympathetic activity coupled with increased and heterogeneous sympathetic outflow, increases the risk of cardiac arrhythmias and sudden death. While the progression of cardiac disease affects multiple aspects of cardiac control, it is those changes in peripheral autonomic neuronal processing and their projections that ultimately determine the neuronal coordination of the heart. The intrinsic cardiac nervous system (ICN), the final common pathway for such neural control, integrates information from multiple inputs and mediates short- loop reflex control of regional cardiac indices. Although multiple studies have focused on cardiac stress- induced changes in post-ganglionic innervation patterns to the heart, little attention has been paid to the critical role of information processing within autonomic ganglia and how they remodel/adapt to imposed stress. It is our hypothesis that cardiac stress-induced adaptations within the ICN facilitate coordination of efferent parasympathetic output and that these changes are reflected in functional and phenotypic alterations in select intrinsic cardiac neuronal populations. These cardioprotective adaptations within the ICN could counteract, in part, the maladaptive effects of excessive sympatho-excitation associated cardiac stress. Numerous studies have identified molecular mechanisms associated with cardiac remodeling, including increased activity of the renin-angiotensin system, changes in nitric oxide (NO) production, and alterations in end-organ sensitivity to neurotransmitters. For each of these factors, while their direct effects on myocyte function are well established, recent data indicates that many of their cardiac effects are mediated via alterations in function within the cardiac nervous system. To specifically address these points this proposal will evaluate how the elements of the ICN adapt to chronic disease using two different animal models of heart disease: myocardial infarction (MI) and chronic pressure overload (PO). The proposed experiments will focus on two specific adaptations of the ICN: (1) changes in neuronal responses to neuromodulators and (2) changes in ICN network efficiency. We will also evaluate the efficacy of targeted pharmacologic therapy to mitigate adverse remodeling of the ICN. Using a whole mount preparation of the guinea pig cardiac plexus, we will evaluate the physiological responses of individual intrinsic cardiac neurons to autonomic neurotransmitters with and without potential neuromodulators, such as angiotensin II and NO in tissues from control, MI and PO animals to characterize stress-induced changes in neuronal responses. In addition, we will evaluate the output of individual neurons to stimulation of vagal and intraganglionic fiber inputs to evaluate integrated network function. Changes in neuronal activity will then be compared between untreated disease models and disease models treated with standard therapeutics such as 2-receptor blockage, AT receptor inhibition, or inhibition of NO generation, to determine if these therapies modulate the ICN function. PUBLIC HEALTH RELEVANCE: This proposal will examine how the autonomic nervous system adapts to chronic heart disease, with the goal of developing better therapeutics for the treatment of chronic disease. The project will use animal models of chronic heart disease to examine the changes that occur within the cardiac autonomic nervous system with disease as well as evaluating how standard therapies for cardiac disease affect these processes.

描述（由申请人提供）：先前的研究表明，自主传出神经元张力失衡，副交感神经活动减少，加上交感神经流出增加和异质性，会增加心律失常和猝死的风险。虽然心脏病的进展影响心脏控制的多个方面，但正是外周自主神经元处理及其预测的变化最终决定了心脏的神经元协调。内在心脏神经系统（ICN）是这种神经控制的最终共同途径，它整合来自多个输入的信息并介导区域心脏指数的短环反射控制。尽管多项研究都集中在心脏应激引起的心脏节后神经支配模式的变化，但很少有人关注自主神经节内信息处理的关键作用以及它们如何重塑/适应施加的压力。我们的假设是，心脏应激引起的 ICN 内的适应促进了传出副交感神经输出的协调，并且这些变化反映在选定的内在心脏神经元群体的功能和表型改变中。 ICN 内的这些心脏保护性适应可以部分抵消与心脏应激相关的过度交感神经兴奋的适应不良效应。许多研究已经确定了与心脏重塑相关的分子机制，包括肾素-血管紧张素系统活性增加、一氧化氮（NO）产生的变化以及终末器官对神经递质敏感性的改变。对于这些因素中的每一个，虽然它们对心肌细胞功能的直接影响已得到充分证实，但最近的数据表明，它们的许多心脏影响是通过心脏神经系统内功能的改变来介导的。为了具体解决这些问题，该提案将使用两种不同的心脏病动物模型：心肌梗塞（MI）和慢性压力超负荷（PO）来评估ICN的要素如何适应慢性疾病。拟议的实验将重点关注 ICN 的两个具体适应：（1）神经元对神经调节剂反应的变化和（2）ICN 网络效率的变化。我们还将评估靶向药物治疗减轻 ICN 不良重塑的功效。使用豚鼠心丛的整体制备，我们将评估单个内在心脏神经元对有或没有潜在神经调节剂的自主神经递质的生理反应，例如来自对照、MI和PO动物的组织中的血管紧张素II和NO，以表征应激-引起神经元反应的变化。此外，我们将评估单个神经元对迷走神经和神经节内纤维输入的刺激的输出，以评估综合网络功能。然后将未治疗的疾病模型和用标准疗法（例如 2-受体阻断、AT 受体抑制或 NO 生成抑制）治疗的疾病模型之间的神经元活性变化进行比较，以确定这些疗法是否调节 ICN 功能。公共健康相关性：该提案将研究自主神经系统如何适应慢性心脏病，目标是开发更好的治疗慢性疾病的疗法。该项目将使用慢性心脏病的动物模型来检查心脏自主神经系统内发生疾病的变化，并评估心脏病的标准疗法如何影响这些过程。