ANGIOTENSIN AND CENTRAL NEUROHUMORAL ACTIVATION IN CHF

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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.