Mechanisms of Cardiac Afferents and CNS Reflex Processing

心脏传入和中枢神经系统反射处理的机制

基本信息

批准号：
8501628
负责人：
Liang-Wu Fu
金额：
$ 36.05万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8501628
关键词：
Abbreviations Acetylcholine Acids Adenosine Adenosine Triphosphate Agonist Angina Pectoris Animals Anterior Descending Coronary Artery Applications Grants Area Arrhythmia Blood Pressure Boxing Bradykinin Brain Butyric Acids CNS processing CTOP Cardiac Cardiac Myocytes Cardiovascular Physiology Cardiovascular system Cataloging Catalogs Cations Cell Nucleus Chemicals Chest Pain Complex Coronary artery Data Diphosphates Dorsal Endorphins Endothelin Enkephalin, Ala(2)-MePhe(4)-Gly(5)-Enkephalins Event FOS gene Funding Glutamates Grant Heart Heart Ventricle High Pressure Liquid Chromatography Histamine Hypertension Individual Infarction Investigation Ischemia Kidney Knowledge Kynurenic Acid Lactic acid Lateral Lead Left Left atrial structure Left ventricular structure Leukocytes Life Measurement Medial Mediating Mediator of activation protein Metabolic Microdialysis Morbidity - disease rate Muscle Cells Myocardial Ischemia Myocardial Reperfusion N-Methylaspartate Nerve Nerve Endings Neuraxis Neurons Neurotransmitters Nitric Oxide Oncogenes Opioid Opioid Peptide Opioid Receptor P2X-receptor Peripheral Play Pontine structure Process Production Propionic Acids Prostaglandin-Endoperoxide Synthase Protocols documentation Protons Quinoxalines Radioimmunoassay Reactive Oxygen Species Reflex action Reperfusion Therapy Role Rupture Sensory Nerve Endings Serotonin Side Signal Transduction Spinal Spinal Ganglia Spinal nerve structure Stimulus Symptoms System TRPV1 gene Testing Thromboxane A2 Thromboxanes Time Ventricular Work afferent nerve artery occlusion azastene design extracellular gamma-Aminobutyric Acid hemodynamics member mortality parabrachial nucleus pressure public health relevance pyridoxal phosphate-6-azophenyl-2&apos ,4&apos -disulfonic acid receptor relating to nervous system response tripolyphosphate vesicular glutamate transporter 1

项目摘要

DESCRIPTION (provided by applicant): Both inhibitory (vagal afferent) and excitatory (sympathetic or spinal afferent) reflexes are manifested during myocardial ischemia and reperfusion. Cardiac sympathetic afferent stimulation leads to symptoms of angina pectoris and potentially life threatening hemodynamic adjustments, including hypertension and arrhythmias that can exacerbate ischemia and infarction. During the last four cycles of this grant we have identified a number of chemical mediators released during ischemia that play an important role in activating ischemically sensitive cardiac spinal nerve endings to evoke reflex hypertension. These include bradykinin (BK), reactive oxygen species, protons, cyclooxygenase metabolites, serotonin (5HT), histamine, and most recently thromboxane A2 and endothelin. In the last funding cycle we observed that thromboxane and endothelin activate cardiac afferents during myocardial ischemia and reflexly elevates blood pressure. However, it is clear that other mediators signal these nerve endings since inhibition of the action or synthesis of a metabolite does not fully eliminate afferent activation during ischemia. In addition, we have identified roles for glutamate and nitric oxide in the rostral ventral lateral medulla (rVLM), which processes cardiac spinal afferent information, and, in turn, regulate sympathetic outflow. The current proposal further examines interactions between previously identified and new chemical mediators, including adenosine 5'- triphosphate (ATP) and opioids during myocardial ischemia, which act independently and interactively with other mediators to stimulate ventricular nerve endings. Thus, we have begun to investigate mechanisms of inhibitory chemical mediators in the heart that appear to modulate cardiac sympathetic afferent excitability during ischemia. With respect to central neural processing we are capitalizing on our previous observation that the external lateral parabrachial nucleus (elPBN) is activated by cardiac sympathetic afferent stimulation, to evaluate its role in processing input from the heart. This grant proposal thus proposes five sets of hypotheses designed to extend our past and preliminary studies of mechanisms of activation of cardiac afferents by 1) ATP, 2) opioid system, 3) interactions between excitatory and inhibitory peripheral chemical signals; and CNS processing of the cardiac afferents involving 4) excitation by glutamate and modulation by GABA through GABAB and GABAA receptors in elPBN neurons and 5) their projections to the rVLM. We will use combined whole animal reflex, cellular electrophysiological, microdialysis/HPLC measurement and pharmacological approaches in the proposed investigations. Additional knowledge derived from these studies will allow a better understanding of the mechanisms underlying the genesis of angina pectoris and reflex activation of the cardiovascular system during myocardial ischemia and reperfusion.

描述（由申请人提供）：在心肌缺血和再灌注期间，都表现出抑制性（迷走传入）和兴奋性（交感或脊柱传入）反射。心脏交感神经传入刺激会导致心绞痛的症状，并潜在地危及生命的血液动力学调整，包括高血压和心律不齐，会加剧缺血和梗塞。在这笔赠款的最后四个周期中，我们确定了在缺血期间释放的许多化学介质在激活局部敏感的心脏脊髓神经末端起着重要作用以引起反射性高血压。其中包括心动激肽（BK），活性氧，质子，环氧合酶代谢产物，5-羟色胺（5HT），组胺以及最近的Thromboxane A2和内皮素。在最后一个资金周期中，我们观察到血栓烷和内皮素在心肌缺血期间激活心脏传入，反射升高血压。但是，很明显，由于抑制了代谢产物的作用或合成，其他介体对这些神经终结表示信号，并不能完全消除缺血期间传入激活。此外，我们已经确定了谷氨酸和一氧化氮在腹侧腹侧髓质（RVLM）中的作用，该髓质（RVLM）处理心脏的脊柱传入信息，然后调节交感神经流出。当前的提案进一步研究了先前确定的和新的化学介质之间的相互作用，包括5'-三磷酸腺苷（ATP）和心肌缺血期间阿片类药物，它们与其他介体进行独立和互动以刺激心室神经端。因此，我们已经开始研究心脏中抑制性化学介质的机制，这些机制似乎调节了缺血期间心脏交感神经传入的兴奋性。关于中央神经加工，我们正在利用我们先前的观察结果，即外侧侧旁核（ELPBN）被心脏交感神经传入刺激激活，以评估其在心脏加工输入中的作用。因此，该赠款提议提出了五组假设，旨在扩展我们的过去和初步研究心脏传入的机制，通过1）ATP，2）阿片类药物系统，3）兴奋性和抑制性周围化学信号之间的相互作用；以及涉及4）谷氨酸激发的心脏传入的中枢神经系统处理以及GABA通过ELPBN神经元中的GABAB和GABAA受体进行调节，以及5）它们对RVLM的预测。在拟议的研究中，我们将使用整个动物反射，细胞电生理学，微透析/HPLC测量和药理方法。从这些研究中得出的其他知识将可以更好地理解心绞痛的起源和心血管系统期间心血管系统的反射激活的机制。