Histamine Receptor/Norepinephrine in Cardiac Dysfunction

描述(申请人提供)：在心肌缺血中，由于过量释放去甲肾上腺素(NE)而导致的心律失常会导致高发病率和死亡率。因此，减少心肌缺血时交感神经末梢(SNE)的去甲肾上腺素(NE)释放是一个重要目标。我们将研究内源性调节剂如何在正常和缺血条件下调节心脏交感神经传递。在目标1中，我们将分别研究组胺H3受体(H3R)抑制短期和长时间缺血/再灌注(I/R)相关的钙依赖的NE胞吐和载体介导的NE释放的转导机制。这将在H3R转基因细胞和表达天然H3R的豚鼠心脏的SNE中进行研究。对于NE胞吐和短期I/R，我们将评估H3R激活如何限制通过N型钙通道的钙内流，以及PKC和PlaA在实现这一过程中的作用。对于载体介导的NE释放和延长的I/R，我们将研究H3R激活和Na+/H+交换(NHE)抑制的偶联，并将在NHE水平上评估SNE中H3R和血管紧张素ATI受体之间的相互作用。缺乏H3R的小鼠心脏将被研究。在肥大细胞缺陷小鼠的缺血心脏中，内源性组胺对H3R激活的心脏保护作用的贡献将被确定。在H3R介导的NHE活性降低和载体介导的NE释放的转导信号中，PKC和钙调蛋白将被研究。在目标2中，我们将确定组织型纤溶酶原激活剂促进正常和缺血心脏去甲肾上腺素释放的机制。具有纤溶级联反应各种成分的基因缺失的小鼠将被使用。这些研究将阐明内源性控制去甲肾上腺素释放的机制。由于NE释放的减少在心肌缺血中具有保护作用，识别和表征控制NE释放的因素将有助于开发心血管疾病的新治疗策略。

DESCRIPTION (provided by applicant): In myocardial ischemia, arrhythmias due to excessive norepinephrine (NE) release cause high morbidity and mortality. Thus, reduction of NE release from cardiac sympathetic nerve endings (SNE) in myocardial ischemia is a critical goal. We will study how endogenous modulators regulate cardiac sympathetic neurotransmission in normal and ischemic conditions. In 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. This will be studied in H3R-transfected cells and in SNE from guinea-pig hearts expressing native H3R. For NE exocytosis and short-term I/R we will assess how H3R activation limits Ca2+ entry through N-type Ca2+-channels, and the roles of PKC and PLAa in implementing this. For carrier-mediated NE release and protracted I/R, we will investigate the coupling of H3R activation to Na+/H+ exchanger (NHE) inhibition, and will assess the interaction between H3R and angiotensin ATI receptors at the NHE level in SNE. Mouse hearts lacking H3R will be studied. The contribution of endogenous histamine to the cardioprotective effects of H3R activation will be determined in ischemic hearts from mast-cell-deficient mice. Among the transductional signals involved in the H3R-mediated reduction of NHE activity and carrier- mediated NE release, PKC and calmodulin will be investigated. In Aim 2, we will determine by which mechanisms tissue plasminogen activator promotes NE release in normal and ischemic hearts. Mice with genetic deletions of various components of the fibrinolytic cascade will be used. These studies will elucidate the mechanisms for endogenous control of NE release. Since reduction of NE release is protective in myocardial ischemia, identification and characterization of the factors controlling NE release will help in the development of novel therapeutic strategies in cardiovascular diseases.