ANGIOTENSIN AND CENTRAL NEUROHUMORAL ACTIVATION IN CHF

在充血性心力衰竭（CHF）中，交感驱动增加和肾灌注减少激活外周肾素-血管紧张素-醛固酮系统（RAAS）。由此产生的周围血管收缩和肾脏的钠和水潴留，通过增加对已经衰竭的心室的压力，促使进一步的临床恶化。RAAS激活的这些外周效应已经成为心力衰竭成功治疗干预（后负荷减少和容量控制）的目标。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）的体液平衡和交感神经驱动有显著的影响，这在高血压的研究中得到了很好的研究，但在心力衰竭中却被忽视了。提出的研究假设是，高循环ANGII对中枢神经系统的影响在很大程度上促进了交感神经驱动和液体积聚的增强，这是晚期心力衰竭的特征。第二种假说认为，ANGII对中枢神经系统的影响会因高醛固酮水平而加剧，而由衰竭心脏分泌的高水平心房利钠肽（ANP）则与之相反。所研究的模型是大鼠由冠状动脉近端闭塞引起的左心室功能障碍，模拟人类心力衰竭最常见的原因。左心室功能障碍的程度将由超声心动图确定并经解剖证实。具体目的是确定，在CHF大鼠中：1)高水平循环神经肽激活的前脑机制有助于增强神经体液驱动；2)作用于前脑心室周围器官的血源性神经肽改变下丘脑室旁核兴奋性和抑制性神经递质系统的平衡，以促进神经体液兴奋。这项工作将提供关于中枢神经系统在CHF病理生理中的作用的新信息，并将引起人们对中枢神经系统指导心力衰竭药物治疗的可能性的关注。

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.