This application continues our effort to develop a quantitative systems analysis of the long-term role of various intrarenal and extrarenal hormonal systems in controlling renal hemodynamics, tubular reabsorption, electrolyte excretion and arterial pressure. Most of the proposed studies are designed to investigate the long- term importance of neurohumoral systems in intact conscious animals since our current knowledge is based mainly on short- term studies in anesthetized animals. The effectiveness of neurohumoral systems in regulating renal function after various perturbations, such as changes in sodium intake or in pathophysiological conditions such as heart failure and hypertension, will be quantitated in intact animals and in animals in which one or more of the feedbacks have been interrupted (open-loop feedback conditions) by surgical or pharmacological methods. Our studies are also designed to quantitate long-term interactions between different hormonal systems and the sympathetic nervous system in regulating renal function and arterial pressure. Two new areas that our studies will focus on include (1) the intrarenal and hormonal mechanisms that initiate and sustain the vicious cycles associated with development of renal failure and malignant hypertension, and (2) the role of atrial natriuretic factor (ANF) in long-term control of renal function and arterial pressure in normotensive and hypertensive animals. Changes in renal hemodynamics and tubular function after various perturbations, and the role of neurohumoral mechanisms in mediating these changes, will be quantitated with techniques developed in our laboratory that allow us to accurately measure these variables over long periods of time in conscious animals. Also, techniques have been developed for continuous recording of arterial pressure and cardiac output 24 hours a day, continuous i.v. and intrarenal infusions, and for measurements of various indices of renal and endocrine function. These methods will allow us to examine the intrarenal mechanisms by which the different hormonal systems regulate renal hemodynamics and electrolyte excretion chronically and the pivotal role of these actions in overall control of circulatory dynamics. Each of these studies is also designed to provide the quantitative information necessary to develop a systems analysis of the various hormonal systems and their role in controlling renal and circulatory function.
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