Histamine Receptor/Norepinephrine in Cardiac Dysfunction

描述（逐字引用申请人摘要）：在心肌缺血中， 由于过量的去甲肾上腺素（NE）释放引起的心律失常是导致 发病率和死亡率高。因此，心脏NE释放减少， 交感神经末梢（SNE）是关键目标。我们会研究 内源性调节剂调节心脏交感神经的机制 在正常和缺血条件下的神经传递。在具体目标1中， 将研究组胺H3受体的转导机制， (H3R)减弱Ca 2+依赖性NE胞吐和载体介导的NE释放， 与短期和长期缺血/再灌注（I/R）相关， 分别我们将研究H3 R在细胞系中的心脏保护作用。 用克隆的H3 R转染，并在从豚鼠和人分离的SNE中 表达H3 R的心脏。对于NE胞吐和短期I/R，我们将评估 N型钙通道抑制的作用，并降低活动的 磷酸肌醇和cAMP途径。对于载体介导的NE释放， 延长I/R，我们将研究H3 R活化与Na+/H+的偶联 交换抑制，并确定所涉及的转导机制。在 具体目标2，我们将扩大我们最近的发现，ATP，共同发布 与来自心脏SNE的NE，增强NE释放，并且SNE被赋予 外核苷酸酶活性因此，我们将检查 外核苷酸酶来控制ATP的作用。我们亦会研究 SNE去极化是否增强了外核苷酸酶活性， 影响NE释放的ATP诱导的调制，以及它是否在 缺血，导致NE释放增强。在具体目标3中，我们 探讨加压素（AVP）和催产素（OT）对NE释放的调节作用， 我们最近发现的肽存在于心脏SNE中， 在离体豚鼠心脏的L 'R过程中， 心脏SNE。我们将研究AVP和OT受体亚型， AVP和OT诱导NE增强的转导机制 在正常和缺血条件下释放。这些研究将阐明 NE释放的内源性控制机制。此外，由于NE的减少， 释放在心肌缺血中是保护性的，鉴定和 控制NE释放的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.