BRAIN MECHANISMS IN SUDDEN CARDIAC DEATH

提案的主题重点是大脑的描绘 介导特定环境事件影响的机制（即， 心理社会压力）对缺血性心脏的脆弱性， 胚胎发生 先前的研究表明去甲肾上腺素能 大脑皮层中的一个过程是该机制的关键部分。 项目1将研究大脑和药理学的影响 对与压力相关的心脏脆弱性增加的干预措施， 在已建立的清醒猪模型中发生心脏性猝死。 项目2将探讨什么样的压力相关的生化反应， 心脏，然后，一旦确定，研究他们的逆转，由特定的 大脑和药物干预。 项目3是一个互联 这项研究将涉及在整个大脑中研究的药理学， 有意识的动物在项目4中的模型大脑系统中进行了研究， 5. 在项目3中，分类将由 相关神经和心脏组织中的毒蕈碱受体，和 在项目1和2中研究的配体的表征也将 执行。 项目3和项目4将一起研究监管机构的作用， 蛋白质和β-和毒蕈碱受体的相互作用， 突触功效的长时程增强的细胞机制。 项目 4将研究β-肾上腺素能和毒蕈碱相互作用对 海马切片制备中突触功效的改变， 大脑皮层的简单模型。 项目5将描述 去甲肾上腺素能机制的药理学在另一个简单的模型， 大脑皮层嗅球 项目6将研究联合 药物干预对脑事件相关性慢波的影响 潜在的和心脏异位;慢电位已被以前 在动物研究中被确定为环境的大脑表征 压力源 项目7将研究各种环境事件及其 随后的大脑和心脏反应，以确定这些范式最 有效识别心脏性猝死风险患者。 这最后一个项目也将试图解释为什么吸烟行为是 与心源性猝死风险增加有关。 两者 管理核心和动物手术和器械核心将 支持六大项目。

The theme of the proposal focuses on the delineation of the cerebral mechanisms that mediate the effects of specific environmental events (i.e., psychosocial stressors) on the vulnerability of the ischemic heart to arrhythmogenesis. Previous investigations have implicated a noradrenergic process in the cerebral cortex to be a crucial part of the mechanism. Project 1 will investigate the effects of both cerebral and pharmacologic interventions on the stress-related increase in cardiac vulnerability that occurs in an established conscious-pig model for sudden cardiac death. Project 2 will explore what the stress-related biochemical responses of the heart are and then, once identified, study their reverals by specific cerebral and pharmacologic interventions. Project 3 is an interconnecting study that will relate the pharmacology studied in the whole brain of the conscious animal to that studied in model brain-systems in Projects 4 and 5. In Project 3 the classification will be made of subtypes of the muscarinic receptors in relevant neural and cardiac tissues, and characterization of ligands studied in Projects 1 and 2 will also be performed. Projects 3 and 4 together will study the role of the regulatory proteins and the interactions of the beta- and muscarinic-receptors in the cellular mechanism of long-term potentiation of synaptic efficacy. Project 4 will study the effects of beta-adrenergic and muscarinic interactions on the alterations of synaptic efficacy in the hippocampal slice preparation, a simple model of the cerebral cortex. Project 5 will characerize the pharmacology of noradrenergic mechanisms in another simple model of the cerebral cortex, the olfactory bulb. Project 6 will study the joint effects of pharmacologic interventions on the cerebral event-related slow potential and cardiac ectopy; the slow potential has been previously identified in animal studies as a cerebral representation of environmental stressors. Project 7 will study various environmental events and their consequent cerebral and cardiac responses to determine those paradigms most effective in identifying the patient-at-risk for sudden cardiac death. This last project will also attempt to explain why smoking behavior is associated with increased risk for sudden cardiac death. Both an Administrative Core and an Animal Surgery and Instrumentation Core will support the six projects.