The renin-angiotensin system exerts a major regulatory influence on body fluid volume, electrolyte balance and arterial blood pressure. However, the mechanisms by which 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. Atrial natriuretic peptides, released from cardiac myocytes, have been demonstrated to modulate renal function. The applicant's studies indicate that, within the kidney, atrial natriuretic peptides are counteractive in the regulation of fluid and electrolyte balance. Thus, angiotensin II may serve to modulate renal responses to other endocrine and/or paracrine substances. The applicant has developed a new and unique experimental model with functionally isolates the kidney in vivo in the conscious animal; this model employes state-of-the-art techniques appropriate for both acute and chronic studies. Using this model, the applicant proposes to demonstrate that intrarenal angiotensin II is important physiologically in the control of renal function. Specifically, the applicant proposes to demonstrate that the renal effects of intrarenal renin-angiotensin blockade, with a series of antagonists and inhibitors with different mechanisms of action, can be neutralized with intrarenal angiotensin. The role of eicosanoids and atrial natriuretic peptides in renal escape from the sodium retaining action of intrarenal angiotensin II will be clarified. The interactions of angiotensin II with atrial natriuretic factor and dopamine within the kidney will be studied. The intrarenal sites of action of angiotensin II which are important to its paracrine functions will be localized with novel angiotensin analogs with selective tubular actions. The cellular nature of the intrarenal renin-angiotensin system will be explored with use of new renin inhibitors. The relative roles of the intrarenal and extrarenal renin-angiotensin system on renal function and on feedback suppression of renin release will be elucidated. 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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