Histamine Receptor/Norepinephrine in Cardiac Dysfunction

描述(逐字摘自申请者摘要)：在心肌缺血中，由于过量释放去甲肾上腺素(NE)而导致的心律失常是 高发病率和高死亡率。因此，心脏的去甲肾上腺素释放减少 交感神经末梢(SNE)是一个关键的目标。我们会研究 内源性调节剂调节心脏交感神经的机制 正常和缺血条件下的神经传递。在具体目标1中，我们 将研究组胺H3受体的转导机制 (H3R)减弱钙依赖的NE胞吐和载体介导的NE释放， 与短期和长时间的缺血/再灌注(I/R)相关， 分别进行了分析。我们将研究H3R在细胞系中的心脏保护作用 用克隆的H3R基因转染豚鼠和人的SNE 表达H3R的心脏。对于NE胞吐和短期I/R，我们将评估 N型钙通道抑制作用及细胞内钙通道活性降低 磷脂酰肌醇和cAMP途径。载体介导的去甲肾上腺素释放和 延长的I/R，我们将研究H3R激活与Na+/H+的偶联 交换抑制，并确定涉及的转导机制。在……里面 具体目标2，我们将扩展我们的最新发现，即ATP，共同发布 来自心脏SNE的NE促进NE的释放，并且SNE被赋予 胞外核糖核酸酶活性。因此，我们将考察 胞外核酸酶控制三磷酸腺苷的作用。我们还将调查 SNE去极化是否增强胞外核苷酸酶活性，它是如何增强的 影响ATP诱导的去甲肾上腺素释放的调节，以及是否在 缺血，导致NE释放增强。在具体目标3中，我们将 探讨加压素(AVP)和催产素(OT)对去甲肾上腺素(NE)释放的控制作用。 我们最近在心脏SNE中发现的多肽将被释放 在离体豚鼠心脏L‘R期间，并在加入时引起NE释放 到心脏的SNE。我们将研究AVP和OT受体亚型并 AVP和OT增强NE的转导机制 在正常和缺血条件下释放。这些研究将阐明 内源性调控去甲肾上腺素释放的机制。此外，由于东北方向的减少 释放对心肌缺血、识别和保护有保护作用 对去甲肾上腺素释放的控制因素的表征将提供基础 用于开发心血管疾病的新治疗策略。

DESCRIPTION (Verbatim from the Applicant's Abstract): In myocardial ischemia, arrhythmias due to excessive norepinephrine (NE) release are responsible for high morbidity and mortality. Hence, reduction of NE release from cardiac sympathetic nerve endings (SNE) is a critical goal. We will study the mechanisms by which endogenous modulators regulate cardiac sympathetic neurotransmission under normal and ischemic conditions. In Specific Aim 1, we will investigate the transductional mechanisms by which histamine H3-receptors (H3R) attenuate Ca2+-dependent NE exocytosis and carrier-mediated NE release, associated with short-term and protracted ischemia/reperfusion (I/R), respectively. We will examine the cardioprotective effects of H3R in cell lines transfected with cloned H3R, and in SNE isolated from guinea-pig and human hearts which express H3R. For NE exocytosis and short-term I/R we will assess the role of N-type Ca2+-channel inhibition, and decreased activities of phosphoinositide and cAMP pathways. For carrier-mediated NE release and protracted I/R, we will investigate the coupling of H3R activation to Na+/H+ exchanger inhibition and identify the transductional mechanisms involved. In Specific Aim 2, we will expand on our recent findings that ATP, co-released with NE from cardiac SNE, enhances NE release, and that SNE are endowed with ectonucleotidase activity. Thus, we will examine the ability of ecto-nucleotidases to control the effects of ATP. We will also investigate whether ecto-nucleotidase activity is enhanced by SNE depolarization, how it affects ATP-induced modulation of NE release, and whether it decreases during ischemia, leading to enhanced NE release. In Specific Aim 3, we will investigate the control of NE release by vasopressin (AVP) and oxytocin (OT), peptides we have recently found to be present in cardiac SNE, to be released during L'R in isolated guinea-pig hearts, and to elicit NE release when added to cardiac SNE. We will investigate the AVP and OT receptor subtypes and transductional mechanisms involved in AVP- and OT-induced enhancement of NE release under normal and ischemic conditions. These studies will elucidate the mechanisms for endogenous control of NE release. Further, since reduction of NE release is protective in myocardial ischemia, identification and characterization of the factors controlling NE release will provide the basis for the development of novel therapeutic strategies in cardiovascular diseases.