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

• 批准号: 8225095
• 负责人: Wohaib Hasan
• 金额: $ 23.1万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 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/8225095
• 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

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. PUBLIC HEALTH RELEVANCE: Some cardiovascular complications of obesity may be caused by an imbalance between the autonomic nerves that project to the heart and control heart rate. This study aims to develop sensitive assays for measurement of proteins released by nerves in the heart. Therapeutic sites in the peripheral nervous system may be identified as a result of these studies for reversing detrimental cardiovascular function in obesity.

描述（由申请人提供）：肥胖可导致几种心血管问题，包括高血压和左心室肥大。此外，肥胖者心率和血浆儿茶酚胺增加以及心率变异性降低是由于心脏自主控制改变，包括交感神经活动增加和副交感神经活动减少。异常的自主神经驱动是高血压和充血性心力衰竭的一个致病因素，并可能同样促进肥胖者的心血管紊乱。从心脏中的交感神经末梢释放的神经肽如神经肽Y（NPY）和甘丙肽可以抑制从邻近的副交感神经释放乙酰胆碱。因此，肥胖症中交感神经驱动的增加可能会增加心房神经释放神经肽，从而促进对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倾向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。将使用心房外植系统刺激心房末梢释放神经递质和神经肽，并使用灵敏的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，是一种重要的新方法，将通过本研究建立。我们还将共同刺激自主神经外周流出体内检查副交感神经紊乱的功能后果肥胖。激光捕获显微切割副交感神经节神经元，然后进行qRT-PCR，将允许检查肥胖症中的胆碱能标记基因。培养的心神经节神经元将具有敲低的神经肽受体基因以检查乙酰胆碱合成和转运的神经肽调节。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，并间接导致儿茶酚胺毒性和工作负荷增加导致的心肌功能障碍。这些研究应该确定新的神经肽靶点，用于逆转肥胖受试者的异常副交感神经活动。此外，一个敏感的HPLC-MS方法，同时测定神经化学物质将被开发。 公共卫生关系：肥胖的一些心血管并发症可能是由投射到心脏和控制心率的自主神经之间的不平衡引起的。本研究旨在开发用于测量心脏神经释放的蛋白质的灵敏测定法。外周神经系统中的治疗位点可以被确定为这些研究的结果，用于逆转肥胖症中有害的心血管功能。