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）：抑制性（迷走神经传入）和兴奋性（交感神经或脊髓传入）反射均在心肌缺血和再灌注过程中表现出来。心脏交感传入刺激会导致心绞痛症状和可能危及生命的血流动力学调整，包括可能加剧缺血和梗塞的高血压和心律失常。在这项资助的最后四个周期中，我们已经确定了缺血期间释放的许多化学介质，这些介质在激活缺血敏感的心脏脊髓神经末梢以引起反射性高血压方面发挥着重要作用。这些包括缓激肽 (BK)、活性氧、质子、环氧合酶代谢物、血清素 (5HT)、组胺以及最近的血栓素 A2 和内皮素。在上一个资助周期中，我们观察到血栓素和内皮素在心肌缺血期间激活心脏传入并反射性升高血压。然而，很明显，其他介质向这些神经末梢发出信号，因为抑制代谢物的作用或合成并不能完全消除缺血期间的传入激活。此外，我们还确定了谷氨酸和一氧化氮在延髓头端腹侧外侧（rVLM）中的作用，rVLM 处理心脏脊髓传入信息，进而调节交感神经流出。目前的提案进一步研究了先前确定的化学介质和新的化学介质之间的相互作用，包括心肌缺血期间的腺苷 5'-三磷酸 (ATP) 和阿片类药物，它们独立地发挥作用，并与其他介质相互作用，刺激心室神经末梢。因此，我们已经开始研究心脏中抑制性化学介质的机制，这些介质似乎在缺血期间调节心脏交感神经传入兴奋性。关于中枢神经处理，我们利用之前的观察结果，即外侧臂旁核（elPBN）被心脏交感神经传入刺激激活，以评估其在处理心脏输入中的作用。因此，本拨款提案提出了五组假设，旨在扩展我们过去和初步对心脏传入激活机制的研究，包括 1) ATP、2) 阿片类药物系统、3) 兴奋性和抑制性外周化学信号之间的相互作用；心脏传入的 CNS 处理涉及 4) 谷氨酸的激发和 GABA 通过 elPBN 神经元中的 GABAB 和 GABAA 受体的调节，以及 5) 它们对 rVLM 的投射。我们将在拟议的研究中结合使用整体动物反射、细胞电生理学、微透析/高效液相色谱测量和药理学方法。从这些研究中获得的更多知识将有助于更好地理解心绞痛发生的机制以及心肌缺血和再灌注期间心血管系统的反射激活。