The renin-angiotensin system exerts a major regulatory influence on body fluid volume, electrolyte balance and arterial pressure. However, the mechanisms whereby these actions occur have not been fully elucidated. The applicant's studies suggest that angiotensin II generated intrarenally functions as a paracrine substance, locally modulating renal hemodynamic and excretory function. Dopamine, formed within the kidney, also has been demonstrated to modulate renal function. The applicant's studies indicate that, within the kidney, dopamine is counteractive in the regulation of fluid and electrolyte balance. Thus, angiotensin II may serve to modulate renal responses to the renal dopaminergic system. The applicant has developed a unique experimental model which functionally isolates the kidney and incorporates a novel method of study of the renal interstitial fluid compartment in vivo in the conscious animal. Using this model, the applicant proposes to demonstrate that the intrarenal renin-angiotensin and dopaminergic systems act specifically through alterations in the renal interstitial concentrations of angiotensin II and dopamine, respectively. The effects of changes in sodium balance on the response to blockade of the intrarenal dopaminergic system will be demonstrated. The relationship of renal dopaminergic """"""""tone"""""""" to renal dopamine production will be clarified. The compartmentalization of these paracrine systems within the kidney will be determined by isolating, measuring and manipulating renin, the angiotensins and dopamine within renal interstitial fluid. Renal production of angiotensinogen will be determined. The role of renal interstitial fluid cyclic AMP as a physiologic mediator of the actions of dopamine and angiotensin II will be investigated and the physiological role of eicosanoids as modulators of intrarenal AII action will be determined. The interactions of the intrarenal renin-angiotensin and dopaminergic systems will be demonstrated. The proposed physiologic studies in unanesthetized animals will provide essential demonstration of the biologic significance and mechanisms of parallel cell and molecular studies of the renin-angiotensin and dopaminergic systems in the kidney. The proposed studies are related to the long-term goal of increased understanding of the pathophysiology of hypertension and edema-forming states.
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