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受体激活的两个原始的心脏保护作用。这些措施是：1）模拟缺血预处理的新范例，其防止局部肥大细胞依赖性肾素-血管紧张素系统（RAS）的激活及其功能障碍后果;和2）抑制先前未被怀疑的心脏利钠肽的肾上腺素能前体作用。本申请的主要目的是深入探索这些新的H3受体介导的心脏保护作用。目标一力求界定：a）缺血预处理如何防止肥大细胞依赖性RAS的活化，从而减轻去甲肾上腺素和血管紧张素诱导的心律失常;和，B）H3受体活化如何模拟预处理的心脏保护性抗RAS作用。将在接受缺血/再灌注的离体豚鼠和PKC 5-/-小鼠心脏以及培养的肥大细胞（野生型和通过siRNA技术耗尽PKC 5和ALDH 2）中研究腺苷A2 b/A3受体、蛋白激酶C5（PKC 5）和2型醛脱氢酶（ALDH 2）对预处理介导的抗RAS作用的贡献。H3受体抑制离体心脏肥大细胞脱颗粒神经肽释放的能力。将在肥大细胞培养物中研究PKC 2 I、7和8在抑制肥大细胞脱粒中的作用。目的II旨在确定利钠肽通过何种机制发挥肾上腺素能作用，以及这种作用如何被H3受体激活抑制。我们将评估利钠肽释放儿茶酚胺的作用是否来源于cGMP/PKG介导的PDE 3对cAMP水解的预防，以及H3受体激活是否通过抑制PKG和/或刺激PDE 3来限制这些肾上腺素原能作用。将使用分离的心脏、交感神经末梢和PC 12细胞，野生型和PKG-和PDE 3-均被siRNA耗尽。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研究持续不断，我们提出的研究将促进新药物的设计（例如，选择性H3-受体激动剂）模拟预处理的有益作用，并能够用利钠肽安全有效地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关键目标是减少心脏中直接释放的肾素和去甲肾上腺素，以降低与这些病症相关的高发病率和死亡率。本研究的总体目标是阐明新的心脏保护机制，旨在减弱局部释放的肾素和去甲肾上腺素，减轻心功能不全。

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.