Neural Mechanisms in Congestive Heart Failure

充血性心力衰竭的神经机制

• 批准号: 6917855
• 负责人: GLENN M TONEY
• 金额: $ 29.2万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6917855
• 关键词: GABA receptor; angiotensin II; angiotensin receptor; congestive heart failure; free radical oxygen; gamma aminobutyrate; hormone regulation /control mechanism; laboratory rat; membrane potentials; neural plasticity; neurophysiology; neuroregulation; nontherapeutic iontophoresis; paraventricular nucleus; sympathetic nervous system; tissue /cell culture; voltage /patch clamp

DESCRIPTION (provided by applicant): Exaggerated sympathetic nervous system activity is a major contributor to the pathogenesis of congestive heart failure (CHF). Two factors appear critical in producing the sympathoexcitatory state. First, an elevated level of plasma angiotensin II (ANG II) in CHF acts within the brain to increase sympathetic nerve activity (SNA). Second, chronic extracellular fluid accumulation reduces cardiopulmonary reflex function and thus inhibitory restraint of SNA. These findings are key to the present proposal because neurons in the hypothalamic paraventricular nucleus (PVN) are required for both the sympathoexcitatory actions of elevated ANG II as well as the sympathoinhibitory effects of volume expansion. Experiments will be performed in rats with CHF induced by ligating the left anterior descending coronary artery and in sham-operated control rats. We will test the hypothesis that sympathetic hyperactivity in CHF results from increased ANG II-mediated synaptic input to the PVN and that this has an enhanced excitatory effect due to a concurrent reduction in GABA-mediated cardiopulmonary reflex inhibition. In Aim 1, effects of acute GABA-A and ANG II AT1 receptor blockade in the PVN on the level of ongoing renal and lumbar SNA will be determined. Effects will be compared among rats with graded levels of CHF. Studies will also determine how SNA responses to physiological activation of ANG II and GABA inputs to the PVN are altered in CHF. In Aim 2, we will record the response of individual RVLM-, IML- and NTS-projecting PVN neurons to activation of volume-/mechanosensitive cardiopulmonary inputs and ANG II-sensitive inputs in vivo. We anticipate that PVN unit responses to cardiopulmonary input will be significantly attenuated in CHF. This, in turn, is postulated to leave sympathoexcitatory effects of central ANG II relatively unopposed. Therefore, we expect ANG II effects on SNA and PVN unit discharge to be enhanced. In Aim 3, brain slices will be prepared and whole cell patch-clamp recordings will be performed in vitro from PVN neurons retrogradely labelled from the RVLM, IML and NTS. We will determine how the amplitude and frequency of synaptic activity are altered in each cell group in CHF. We will determine interactions between ANG II and GABA inputs in regulating PVN neuronal excitability and how these are altered in CHF. Finally, we will also determine how postsynpatic depolarization, discharge and inward current responses to ANG II are altered in CHF. The proposed studies are the first to examine mechanisms of synaptic plasticity in CHF among identified sympathetic-regulatory neurons. This information will yeild new and potentially important insight into the processes that lead to sympathetic activation and progression of disease severity in CHF.

描述（由申请人提供）：交感神经系统活动增强是充血性心力衰竭（CHF）发病机制的主要因素。 在产生交感神经兴奋状态中，有两个因素显得至关重要。 首先，CHF中血浆血管紧张素II（ANG II）水平升高在脑内起作用以增加交感神经活动（SNA）。 第二，慢性细胞外液积聚降低心肺反射功能，从而抑制SNA的抑制性抑制。 这些发现是本提案的关键，因为下丘脑室旁核（PVN）中的神经元是升高的ANG II的交感神经兴奋作用以及体积扩张的交感神经抑制作用所必需的。 实验将在通过结扎冠状动脉左前降支诱导的CHF大鼠和假手术对照大鼠中进行。 我们将测试的假设，CHF的交感神经功能亢进的结果增加血管紧张素II介导的突触输入PVN，这有一个增强的兴奋作用，由于同时减少GABA介导的心肺反射抑制。 在目的1中，将确定PVN中急性GABA-A和ANG II AT 1受体阻断对持续性肾脏和腰椎SNA水平的影响。 将在分级CHF水平的大鼠中比较效果。 研究还将确定SNA对ANG II和GABA输入PVN的生理激活的反应在CHF中如何改变。 在目标2中，我们将记录个体RVLM-、IML-和NTS-投射PVN神经元对体内体积/机械敏感性心肺输入和ANG II敏感性输入激活的反应。 我们预计，室旁核单位的反应，心肺输入将显着衰减在CHF。 反过来，这被假定为离开中央ANG II的交感神经兴奋作用相对不受反对。 因此，我们预计ANG II对SNA和PVN单位放电的影响将增强。 在目标3中，将制备脑切片，并对RVLM、IML和NTS逆行标记的PVN神经元进行体外全细胞膜片钳记录。 我们将确定CHF中每个细胞群中突触活动的幅度和频率是如何改变的。 我们将确定血管紧张素II和GABA输入之间的相互作用，在调节PVN神经元的兴奋性，以及如何改变这些在CHF。 最后，我们也将确定如何synthesizeddepolarization，放电和内向电流反应ANG II在CHF中改变。 这些拟议的研究是第一次在已确定的交感调节神经元中研究CHF中突触可塑性的机制。 这一信息将产生新的和潜在的重要见解的过程中，导致交感神经激活和疾病的严重程度在CHF的进展。