MECHANISMS OF REGULATION OF CARDIAC AFFERENTS

描述（由申请人提供）：来自心脏的反射， 在心血管系统调节中的重要作用， 缺血和再灌注。反应可以包括深刻的改变， 血流动力学功能表现为反射性心血管抑制 在刺激迷走神经传入末梢或兴奋时， 交感神经（脊髓）传入神经。刺激心脏的感觉神经， 可引起低血压、缓慢心律失常、恶心和呕吐（迷走神经传入） 或心绞痛、高血压和心律失常（交感神经传入）。有限 关于交感心脏神经激活机制的信息是可用的， 虽然我们最近的数据显示， 在猫中的研究表明，与腺苷相反，活性氧（ROS）， 特别是羟基自由基（'OH'）、激肽、质子（H+）和胰高血糖素， 重要的刺激。因为抑制这些刺激及其受体 相互作用并不能完全消除这些感觉传入的反应， 我们怀疑其他代谢或机械刺激也起作用， 在它们的激活中起作用，刺激之间存在相互作用。 我们提出了一系列的研究来验证血小板是一种 5-羟色胺（5-HT）和组胺的来源。活化血小板释放血清素 组胺通过5 HT 3和H1受体，可能还有H2受体， 分别在缺血期间刺激心脏交感神经传入， 再灌注这两种假定的和其他已知的化学品之间的相互作用 调解人将进行调查。此外，甘油二酯/蛋白质的作用 激酶C（PKC）和环磷酸腺苷（cAMP）/蛋白激酶A（PKA） 组胺对缺血敏感性心脏作用的信号系统 将定义交感传入神经。我们将采用液相色谱法， 测量血液和组织中介质的产生。单单位传入 电活动将被记录和选择性药理学受体 阻断或酶途径抑制将用于评价 每一种潜在的化学介质。化学敏感、机械敏感和双峰 无髓和有髓纤维的末端将通过 一系列化学和机械挑战，后者由 血流动力学测量和局部心肌变形。拟议 因此，研究将确定心脏交感神经末梢 在缺血和再灌注期间被激活。这些信息将提供 对心绞痛和潜在危险有更好了解的医生 交感神经兴奋性心脏反射，并可能建议治疗方法 旨在限制这些影响患者发病率和死亡率的事件 在心肌缺血期间。

DESCRIPTION (provided by the applicant): Reflexes from the heart play an important role in regulation of the cardiovascular system during myocardial ischemia and reperfusion. Responses can include profound alterations in hemodynamic function manifested as either reflex cardiovascular depression during stimulation of vagal afferent endings or excitation with activation of sympathetic (spinal) afferents. Stimulation of sensory nerves in the heart thus can cause hypotension, bradyarrhythmias, nausea and vomiting (vagal afferents) or angina, hypertension and tachyarrhythmias (sympathetic afferents). Limited information is available on mechanisms of activation of sympathetic cardiac afferents that also function as cardiac nociceptors, although our recent data in cats indicate that, in contrast to adenosine, reactive oxygen species (ROS), especially hydroxyl radicals ('OH), kinins, protons (H+) and prostaglandins are important stimuli. Because inhibition of these stimuli and their receptor interactions does not fully eliminate the response of these sensory afferent endings to ischemia, we suspect that other metabolic or mechanical stimuli play a role in their activation and that interactions between stimuli are present. We propose a series of studies to test the hypotheses that platelets are a source of serotonin (5HT) and histamine. Activated platelets release serotonin and histamine that, through 5HT3 and H1 and possibly H2 receptors, respectively, stimulate cardiac sympathetic afferents during ischemia and reperfusion. Interactions between these two putative and other known chemical mediators will be explored. In addition, the role of diacylglycerol/protein kinase C (PKC) and cyclic adenosine monophosphate (cAMP)/protein kinaseA (PKA) signaling systems in histamine's action on ischemically sensitive cardiac sympathetic afferents will be defined. We will employ liquid chromatography to measure the production of mediators in blood and tissue. Single unit afferent electrical activity will be recorded and selective pharmacological receptor blockade or enzymatic pathway inhibition will be used to evaluate the role of each potential chemical mediator. Chemosensitive, mechanosensitive and bimodal endings of unmyelinated and myelinated fibers will be identified through a series of chemical and mechanical challenges, the latter assessed by hemodynamic measurement and regional myocardial deformation. The proposed studies therefore will define mechanisms by which cardiac sympathetic endings are activated during ischemia and reperfusion. Such information will provide physicians with a better understanding of angina and potentially dangerous sympathoexcitatory cardiac reflexes and may suggest therapeutic approaches designed to limit these events that impact patient morbidity and mortality during myocardial ischemia.