Histamine Receptor Norepinephrine in Cardiac Dysfunction

描述(由申请人提供)： 我们的初步研究已经确定了组胺H3受体激活的两种原始的心脏保护作用。它们是：1)模拟缺血预适应的新范例，防止局部肥大细胞依赖的肾素-血管紧张素系统(RAS)的激活及其功能障碍的后果；以及，2)抑制先前未被怀疑的心钠素多肽的肾上腺素能原作用。深入探索这些新的H3受体介导的心脏保护作用是这一应用的主要目标。目的确定：a)缺血预适应如何阻止依赖肥大细胞的RAS的激活，从而减轻去甲肾上腺素和血管紧张素诱导的心律失常；以及b)H3受体的激活如何模仿预适应的心脏保护抗RAS效应。用siRNA技术研究腺苷A2B/A3受体、蛋白激酶C5(PKC5)和乙醛脱氢酶2型(ALDH2)在缺血/再灌注豚鼠和PKC5-/-小鼠心脏以及野生型和缺失的肥大细胞中对预适应介导的抗RAS效应的作用。H3受体抑制分离心脏肥大细胞脱颗粒神经肽释放的能力。PKC2I、7和8在抑制肥大细胞脱颗粒中的作用将在肥大细胞培养中进行研究。目的II试图确定利钠肽发挥肾上腺素能原作用的机制，以及这种作用如何被H3受体激活所抑制。我们将评估利钠肽的儿茶酚胺释放效应是否源于cGMP/PKG介导的阻止PDE3的cAMP水解，以及H3受体的激活是否通过抑制PKG和/或刺激PDE3来限制这些肾上腺素能原作用。将使用分离的心脏、交感神经末梢和PC12细胞，包括野生型和被siRNA耗尽的PKG和PDE3。总的来说，这些研究将阐明控制心脏中肾素和去甲肾上腺素释放的新机制。随着对有效心脏保护药物的探索有增无减，我们拟议的研究将促进设计新的药物(例如，选择性H3受体激动剂)来模拟预适应的有益效果，并使安全有效地使用利钠肽治疗充血性心力衰竭。和ATP感觉/交感神经将被评估 公共卫生相关性： 心肌缺血和心力衰竭的一个关键目标是减少肾素和去甲肾上腺素在心脏中的直接释放，以降低与这些疾病相关的高发病率和死亡率。这项研究的总体目标是阐明新的心脏保护机制，旨在减少局部肾素和去甲肾上腺素的释放，减轻心功能障碍。

DESCRIPTION (provided by applicant): Our preliminary studies have identified two original cardioprotective effects of histamine H3-receptor activation. These are: 1) The mimicking of a new paradigm of ischemic preconditioning, which prevents the activation of a local mast cell-dependent renin- angiotensin system (RAS) and its dysfunctional consequences; and, 2) The inhibition of a previously unsuspected pro-adrenergic effect of cardiac natriuretic peptides. An in- depth exploration of these novel H3-receptor-mediated cardioprotective effects is the main goal of this application. Aim I seeks to define: a) how ischemic preconditioning prevents the activation of the mast cell-dependent RAS, thus alleviating norepinephrine- and angiotensin-induced arrhythmias; and, b) how H3-receptor activation mimics the cardioprotective anti-RAS effects of preconditioning. The contribution of adenosine A2b/A3-receptors, protein kinase C5 (PKC5) and aldehyde dehydrogenase type-2 (ALDH2) to preconditioning-mediated anti-RAS effects will be studied in isolated guinea- pig and PKC5-/- mouse hearts subjected to ischemia/reperfusion, and in cultured mast cell, both wild-type and depleted of PKC5 and ALDH2 by siRNA technology. The capacity of H3-receptors to inhibit the release of mast cell-degranulating neuropeptides from in isolated hearts. Roles of PKC2I, 7 and 8 in inhibiting mast cell degranulation will be studied in mast cell cultures. Aim II seeks to determine by which mechanisms natriuretic peptides exert a pro- adrenergic effect and how this is inhibited by H3-receptor activation. We will assess whether the catecholamine-releasing effects of natriuretic peptides derive from a cGMP/PKG-mediated prevention of cAMP hydrolysis by PDE3 and whether H3-receptor activation limits these proadrenergic effects by inhibiting PKG and/or stimulating PDE3. Isolated hearts, sympathetic nerve endings and PC12 cells, both wild-type and PKG- and PDE3-depleted by siRNA, will be used. Collectively, these studies will elucidate new mechanisms for the control of renin and norepinephrine release in the heart. As the search for effective cardioprotective drugs continues unabated, our proposed studies will foster the design of new agents (e.g., selective H3-receptor agonists) mimicking the beneficial effects of preconditioning and enabling a safe and effective treatment of congestive heart failure with natriuretic peptides. and ATP sensory/sympathetic nerves will be assessed PUBLIC HEALTH RELEVANCE: A critical goal in myocardial ischemia and heart failure is to reduce renin and norepinephrine release directly in the heart, in order to decrease the high morbidity and mortality associated with these conditions. The general objective of this investigation is to elucidate novel mechanisms of cardioprotection designed to attenuate the local release of renin and norepinephrine and alleviate cardiac dysfunction.