NEUROCIRCULATORY FUNCTION IN CHRONIC HEART FAILURE

慢性心力衰竭(CHF)状态的标志性外周调节之一是激活各种神经体液系统，包括交感神经系统、肾素-血管紧张素系统和加压素系统。最初，这些改变对机体有益，有助于维持灌流压，以提供足够的冠状动脉和脑血流。然而，长期而言，这些调整会适得其反，并导致以严重充血性心力衰竭为特征的心血管恶化螺旋式下降。了解神经体液激活发生的机制对于制定合理的治疗CHF患者的策略是至关重要的。我们提出了一个新的项目来研究CHF环境下心血管反射功能改变的机制。我们已经组建了一个经验丰富的研究小组，他们的专业知识围绕着循环的反射控制展开。在项目I中，Zucker博士和Patel博士将研究中枢血管紧张素II(Ang II)和一氧化氮(NO)在实验性CHF兔交感神经流出调节中的作用。重复练习对反射异常的改善效果也将被检验。在项目II中，Patel博士和Pucker博士将研究NO和室旁核GABA能系统在CHF大鼠交感神经流出调节中的作用。项目III将由舒尔茨、罗赞斯基和王博士领导。本课题主要研究CHF兔的外周化学反射及其对增强交感神经张力的作用。化学感受器NO变化对化学感受性反射传入成分的影响将被研究。增强的化学反射敏感性可能参与了CHF的交感神经兴奋。在项目IV中，王博士、Pucker博士和Schultz博士将在CHF犬模型中研究心脏“交感传入”反射在交感神经流出调节中的作用。这种兴奋性反射在CHF时表现出更高的敏感性，可能是通过中枢AII和NO的改变来调节的。最后，在项目V中，Sinoway博士和Leunberger博士将研究CHF患者的肌肉代谢反射。他们将确定运动肌肉的传入信号，该信号负责增强这种反射，以及运动对这种信号的作用。微透析将用于CHF患者，以确定各种物质的间质浓度，这些物质可能负责激活III型和IV型传入细胞。因此，项目I、II和IV将关注CHF的中枢异常。项目三、四和五将涉及传入异常。所有独特的项目都与CHF的神经循环控制这一中心主题相关。

One of the hallmark peripheral adjustments in the state of chronic heart failure (CHF) is activation of a variety of neuro-humoral systems, including the sympathetic nervous system, the renin-angiotensin system and the vasopressin system. Initially, these alterations are of benefit to the organism, helping to maintain perfusion pressure to provide adequate coronary and cerebral blood flow. However, chronically these adjustments become counter productive and contribute to the downward spiral of cardiovascular deterioration characteristic of severe CHF. Understanding the mechanisms by which neuro-humoral activation occurs is crucial to the development of rational strategies for the treatment of patients with CHF. We propose a new program project to investigate the mechanisms by which cardiovascular reflex function is altered in the setting of CHF. We have assembled a experienced group of investigators whose expertise revolved around the reflex control of the circulation. In project I, Drs. Zucker and Patel will investigate the role of central angiotensin II (Ang II) and nitric oxide (NO) in modulating sympathetic outflow in rabbits with experimental CHF. The ameliorating effects of repetitive exercises on reflex abnormalities will also be examined. In project II, Drs. Patel and Pucker will examine the role of NO and the GABAnergic system in the paraventricular nucleus on the modulation of sympathetic outflow in rats with CHF. Project III will be led by Drs. Schultz, Rozanski and Wang. This project is focused on the peripheral chemoreflex and its contribution to augmented sympathetic tone in rabbits with CHF. The involvement of alterations in chemoreceptor NO on the afferent component of the chemoreflex will be investigated. Enhanced chemoreflex sensitivity may contribute to sympatho-excitation in CHF. In project IV, Drs. Wang, Pucker and Schultz will investigate the role of the cardiac "sympathetic afferent" reflex in the modulation of sympathetic outflow in a canine model of CHF. This excitatory reflex exhibits enhanced sensitivity in CHF and may be mediated by alterations in central AII and NO. Finally, in Project V, Drs. Sinoway and Leunberger will examine the muscle metaboreflex in humans with CHF. They will determine the afferent signal from exercising muscle which is responsible for augmentation of this reflex and the role of exercise on this signal. Microdialysis will be used in patients with CHF to determine the interstitial concentrations of various substances which may be responsible for activating Type III and Type IV afferents. Thus projects, I, II and IV will be concerned with central abnormalities in CHF. Projects III, IV and V will be concerned with afferent abnormalities. All projects unique interrelate to the central theme of neuro-circulatory control in CHF.