Neural Mechanisms in Congestive Heart Failure

充血性心力衰竭的神经机制

• 批准号: 7076185
• 负责人: GLENN M TONEY
• 金额: $ 35.64万
• 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/7076185
• 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）：过度的交感神经系统活动是充血性心力衰竭（CHF）发病机制的主要原因。 有两个因素对于产生交感神经兴奋状态至关重要。 首先，CHF 患者血浆血管紧张素 II (ANG II) 水平升高，在大脑内发挥作用，增加交感神经活动 (SNA)。 其次，慢性细胞外液积聚会降低心肺反射功能，从而抑制 SNA。 这些发现是本提议的关键，因为下丘脑室旁核 (PVN) 中的神经元对于 ANG II 升高的交感兴奋作用以及容量扩张的交感抑制作用都是必需的。 实验将在通过结扎左冠状动脉前降支诱发CHF的大鼠和假手术对照大鼠中进行。 我们将检验以下假设：CHF 中的交感神经过度活跃是由于 ANG II 介导的 PVN 突触输入增加所致，并且由于 GABA 介导的心肺反射抑制同时减少，因此具有增强的兴奋作用。 在目标 1 中，将确定 PVN 中的急性 GABA-A 和 ANG II AT1 受体阻断对正在进行的肾脏和腰椎 SNA 水平的影响。 将在具有分级 CHF 水平的大鼠之间比较效果。 研究还将确定 CHF 中 SNA 对 ANG II 和 GABA 输入到 PVN 的生理激活的反应如何改变。 在目标 2 中，我们将记录单个 RVLM、IML 和 NTS 投射 PVN 神经元对体内容量/机械敏感心肺输入和 ANG II 敏感输入激活的反应。 我们预计，CHF 时 PVN 单位对心肺输入的反应将显着减弱。 反过来，这被认为使得中枢 ANG II 的交感兴奋作用相对不受对抗。 因此，我们预计 ANG II 对 SNA 和 PVN 单位放电的影响将会增强。 在目标 3 中，将制备脑切片，并在体外对从 RVLM、IML 和 NTS 逆行标记的 PVN 神经元进行全细胞膜片钳记录。 我们将确定 CHF 中每个细胞组突触活动的幅度和频率如何改变。 我们将确定 ANG II 和 GABA 输入在调节 PVN 神经元兴奋性方面的相互作用，以及这些在 CHF 中如何改变。 最后，我们还将确定 CHF 中突触后去极化、放电和对 ANG II 的内向电流反应如何改变。 拟议的研究首次检查了已确定的交感调节神经元中 CHF 突触可塑性的机制。 这些信息将为了解导致 CHF 交感神经激活和疾病严重程度进展的过程提供新的、潜在的重要见解。