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Attenuation of cardiac parasympathetic nerve acetylcholine release in obesity by

肥胖症中心脏副交感神经乙酰胆碱释放的减弱

基本信息

批准号：
8325098
负责人：
Wohaib Hasan
金额：
$ 19.25万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8325098
关键词：
Acetylcholine Adrenergic Agents Arrhythmia Attenuated Biological Assay Cardiac Cardiovascular Physiology Cardiovascular system Catecholamines Congestive Heart Failure Development Diet Electric Stimulation Functional disorder Galanin Ganglia Genes Heart Heart Atrium Heart Rate High Pressure Liquid Chromatography Hypertension In Vitro Label Lead Left Ventricular Hypertrophy Measurement Measures Methods Myocardial dysfunction Nerve Neurons Neuropeptide Receptor Neuropeptides Neurotransmitters Obesity Pacemakers Peripheral Peripheral Nervous System Plasma Proteins Rattus Receptor Gene Regulation Reverse Transcriptase Polymerase Chain Reaction Role Site Stimulus Sympathetic Ganglia System Testing Therapeutic Toxic effect Workload adrenergic attenuation autonomic nerve base cholinergic chronotropic heart rate variability in vivo knock-down laser capture microdissection liquid chromatography mass spectrometry neurochemistry neuropeptide Y neurotransmitter release novel novel strategies

项目摘要

DESCRIPTION (provided by applicant): Obesity can lead to several cardiovascular problems including hypertension and left ventricular hypertrophy. In addition, increased heart rate and plasma catecholamines, and reduced heart rate variability in obesity are due to altered cardiac autonomic control including increased sympathetic and reduced parasympathetic, activity. Abnormal autonomic drive is a causal factor in hypertension and congestive heart failure, and may similarly promote cardiovascular disturbances in obesity. Neuropeptides such as neuropeptide Y (NPY) and galanin, released from sympathetic terminals in the heart, can inhibit acetylcholine release from adjacent parasympathetic nerves. Increased sympathetic drive in obesity may therefore augment neuropeptide release from atrial nerves, thereby promoting the inhibition of acetylcholine release from parasympathetic terminals. This study examines the role of sympathetic neuropeptides in inhibiting both short-term release, and long-term synthesis, of the parasympathetic neurotransmitter acetylcholine in the diet-induced obesity-prone rat heart. An atrial explant system will be utilized to stimulate release of neurotransmitters and neuropeptides from atrial terminals and these proteins will be measured with a sensitive HPLC-MS method. The development of a non-radioactivity based, sensitive assay for simultaneous measurements of absolute levels of neurotransmitters and neuropeptides, is an important novel approach that will be established through this study. We will also co-stimulate autonomic peripheral outflow in vivo to examine functional consequences of parasympathetic disturbances in obesity. Laser capture microdissection of parasympathetic cardiac ganglion neurons followed by qRT-PCR will allow examination of cholinergic marker genes in obesity. Cultured cardiac ganglion neurons will have neuropeptide receptor genes knocked down to examine neuropeptide regulation of acetylcholine synthesis and transport. Attenuated parasympathetic function can result in dysregulated heart rate control, potential for arrhythmias and indirectly contribute to myocardial dysfunction from catecholamine toxicity and increased workload. These studies should identify novel neuropeptide targets for reversing abnormal parasympathetic activity in obese subjects. In addition, a sensitive HPLC-MS method for simultaneous determination of neurochemicals will be developed.

描述（由申请人提供）：肥胖可导致多种心血管问题，包括高血压和左心室肥厚。此外，肥胖者心率和血浆儿茶酚胺的增加以及心率变异性的降低是由于心脏自主控制的改变，包括交感神经活动的增加和副交感神经活动的减少。自主神经驱动异常是高血压和充血性心力衰竭的致病因素，并且可能同样促进肥胖引起的心血管紊乱。心脏交感神经末梢释放的神经肽，如神经肽 Y (NPY) 和甘丙肽，可以抑制邻近副交感神经释放乙酰胆碱。因此，肥胖症中交感神经驱动力的增加可能会增加心房神经释放的神经肽，从而促进副交感神经末梢释放乙酰胆碱的抑制。本研究探讨了交感神经肽在抑制饮食诱导的肥胖大鼠心脏中副交感神经递质乙酰胆碱的短期释放和长期合成中的作用。心房外植体系统将用于刺激心房末梢释放神经递质和神经肽，并通过灵敏的 HPLC-MS 方法测量这些蛋白质。开发一种基于非放射性的灵敏测定法，用于同时测量神经递质和神经肽的绝对水平，是通过本研究建立的一种重要的新方法。我们还将在体内共同刺激自主外周流出，以检查肥胖中副交感神经紊乱的功能后果。副交感心脏神经节神经元的激光捕获显微切割随后进行 qRT-PCR 将允许检查肥胖中的胆碱能标记基因。培养的心脏神经节神经元将敲除神经肽受体基因，以检查神经肽对乙酰胆碱合成和运输的调节。副交感神经功能减弱可导致心率控制失调、心律失常的可能性，并因儿茶酚胺毒性和工作负荷增加而间接导致心肌功能障碍。这些研究应该确定新的神经肽靶标，用于逆转肥胖受试者的异常副交感神经活动。此外，还将开发一种用于同时测定神经化学物质的灵敏 HPLC-MS 方法。