ANGIOTENSIN AND CENTRAL NEUROHUMORAL ACTIVATION IN CHF

在充血性心力衰竭(CHF)中，交感神经动力增加和肾脏灌注量减少激活了外周肾素-血管紧张素-醛固酮系统(RAAS)。由此产生的外周血管收缩和肾脏的钠和水滞留，通过增加已经衰竭的脑室的压力，加速了临床进一步恶化。RAAS激活的这些外周效应已经成为心力衰竭成功的治疗干预(后负荷减少和容量控制)的靶点。然而，心力衰竭的临床过程是渐进的，长期预后仍然令人沮丧，对创新治疗方法的探索仍在继续。血管紧张素II(AngII)对中枢神经系统(CNS)具有显著的液体平衡和交感神经驱动作用，这些作用已在高血压方面得到了很好的研究，但在心力衰竭方面基本上被忽视了。这些研究的假设是，高循环血管紧张素Ⅱ的中枢神经系统效应对交感神经驱动增强和液体积聚有很大贡献，这是已建立的心力衰竭晚期的特征。第二个假设是，血管紧张素转换酶的这些中枢神经系统作用被高水平的醛固酮加剧，并被衰竭的心脏分泌的高水平的心钠素(ANP)所对抗。要研究的模型是大鼠冠状动脉近端闭塞引起的左心功能障碍，模拟了人类心力衰竭的最常见原因。左心功能不全的程度将由超声心动图确定，并经解剖学证实。其具体目的是确定在CHF大鼠中：1)高水平的循环神经肽激活的前脑机制是否有助于增强神经体液驱动；2)作用于前脑室周器官的血源性神经肽改变了下丘脑室旁核兴奋性和抑制性神经递质系统的平衡，从而有利于神经体液兴奋。这项工作将提供有关中枢神经系统在CHF病理生理学中的作用的新信息，并将引起人们对中枢神经系统导向药物治疗心力衰竭的可能性的关注。

In congestive heart failure (CHF), increased sympathetic drive and reduced renal perfusion activate the peripheral renin-angiotensin-aldosterone-system (RAAS). The resulting peripheral vasoconstriction and sodium and water retention by the kidneys precipitate further clinical deterioration by increasing the stress on the already failing ventricle. These peripheral effects of RAAS activation have been the targets of successful therapeutic interventions (afterload reduction and volume control) in heart failure. Nevertheless, the clinical course of heart failure is progressive, the long-term prognosis remains dismal, and the search for innovative approaches to therapy continues. Angiotensin II (ANGII) has prominent central nervous system (CNS) effects on fluid balance and sympathetic drive that have been well studied in the context of hypertension, but have been largely overlooked in heart failure. The hypothesis of the proposed studies is that the CNS effects of high circulating ANGII contribute substantially to the augmented sympathetic drive and fluid accumulation that characterize the late stage of established heart failure. Secondary hypotheses are that these CNS effects of ANGII are exacerbated by high aldosterone levels, and opposed by high levels of atrial natriuretic peptide (ANP), secreted by the failing heart. The model to be studied is left ventricular dysfunction caused by proximal occlusion of a coronary artery in the rat, simulating the most common cause of heart failure in humans. Extent of left ventricular dysfunction will be determined by echocardiography and confirmed anatomically. The specific aims are to determine whether, in rats with CHF: 1) forebrain mechanisms activated by high levels of circulating neuropeptides contribute to augmented neurohumoral drive, 2) blood-borne neuropeptides acting on forebrain circumventricular organs alter the balance of excitatory and inhibitory neurotransmitter systems in the paraventricular nucleus of the hypothalamus to favor neurohumoral excitation. This work will provide new information concerning the role of the central nervous system in the pathophysiology of CHF and will draw attention to the possibility of CNS directed drug therapy for heart failure.