Histamine Receptor Norepinephrine in Cardiac Dysfunction

组胺受体去甲肾上腺素在心脏功能障碍中的作用

基本信息

批准号：
7888932
负责人：
ROBERTO LEVI
金额：
$ 50.29万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-01 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7888932
关键词：
Adenosine Adrenergic Agents Agonist Aldehydes Angiotensins Arrhythmia Atrial Natriuretic Factor Attenuated Binding Brain natriuretic peptide Cardiac Catecholamines Cattle Cavia Cell Culture Techniques Cell Degranulation Cell membrane Cell model Cells Cessation of life Congestive Heart Failure Coupled Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cyclic GMP Denervation Dopamine Exocytosis Fostering Functional disorder Goals Heart Heart failure Histamine H3 Agonist Histamine H3 Receptors Histamine Receptor Hydrolysis Investigation Ischemia Ischemic Preconditioning Isoenzymes Link Magnetism Measures Mediating Mitochondria Morbidity - disease rate Mus Muscle Cells Myocardial Ischemia Natriuretic Peptides Nerve Nerve Endings Neurons Neuropeptides Neurotransmitters New Agents Norepinephrine Organ PC12 Cells Patients Pharmaceutical Preparations Pheochromocytoma Prevention Protein Kinase Reactive Oxygen Species Receptor Activation Recombinants Renin Renin-Angiotensin System Reperfusion Therapy Research Risk Role Sensory Small Interfering RNA Source Synaptosomes Technology Translating adrenergic aldehyde dehydrogenases design effective therapy inhibitor/antagonist mast cell mortality myocardial infarct sizing neurotensin mimic 1 novel preconditioning prevent public health relevance receptor research study response

项目摘要

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.

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心脏保护作用。这些是：1）模仿缺血性预处理的新范式，从而阻止了局部肥大细胞依赖性的肾上腺素 - 血管紧张素系统（RAS）及其功能障碍后果的激活； 2）抑制心脏纳地那二肽肽先前未经引起的肾上腺素能作用。对这些新型H3受体介导的心脏保护作用的深入探索是该应用的主要目标。目的我试图定义：a）缺血性预处理如何阻止肥大细胞依赖性Ras的激活，从而减轻了去甲肾上腺素和血管紧张素诱导的心律不齐； b）H3受体激活如何模仿预处理的心脏保护抗RAS效应。 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由siRNA技术耗尽了PKC5和ALDH2。 H3受体的能力抑制从分离的心脏中释放肥大细胞降解神经肽的能力。 PKC2I，7和8在抑制肥大细胞脱粒中的作用将在肥大细胞培养物中研究。 AIM II旨在确定哪种机制发挥促肽产生肾上腺素能作用，以及H3受体激活如何抑制这种效果。我们将评估源自CGMP/PKG介导的PDE3 cAMP水解的预防以及H3受体激活是否通过抑制PKG和/或刺激PDE3来限制这些肾上腺素能效应的持续预防CGMP/PKG介导的cAMP水解的预防是否限制了这些pDE3的cAMP水解。将使用孤立的心脏，交感神经末端和PC12细胞，包括由siRNA耗尽的野生型和PKG-和PDE3。总的来说，这些研究将阐明心脏中肾素和去甲肾上腺素释放的新机制。随着寻找有效的心脏保护药物的持续不断，我们提出的研究将促进新的药物的设计（例如，选择性的H3受体激动剂），模仿了预处理的有益效果，并有效地治疗了对娜托尿素肽的美味心力衰竭的安全和有效治疗。将评估ATP的感觉/交感神经公共卫生相关性：心肌缺血和心力衰竭的关键目标是直接减少肾素和去甲肾上腺素的释放，以降低与这些疾病相关的高发病率和死亡率。这项研究的一般目标是阐明旨在减轻肾素和去甲肾上腺素的局部释放并减轻心脏功能障碍的新型心脏保护机制。