Studies have shown that the renal kallikrein-kinin system is involved in the regulation of body sodium and water excretion and arterial blood pressure. However, the mechanisms by which these actions occur have not been fully elucidated. Data obtained in preliminary studies suggest that the renal kallikrein-kinin system functions as a paracrine system, locally modulating renal function. The renal kallikrein-kinin system can stimulate production of both endothelium-derived relaxing factor (EDRF) and eicosanoids. The sites and regions where the renal kallikrein-kinin, EDRF and prostaglandin systems interact are not definitively established. Bradykinin can stimulate the release of both EDRF and prostacyclin from endothelial cells and prostaglandin E2 from renal tubular epithelial cells. Within the kidney, EDRF and eicosanoids may function in a cell-to-cell manner to regulate renal hemodynamic and excretory function. Furthermore, defects in these systems could lead to pathophysiologic states such as hypertension. The applicant has been involved in studies using an experimental model which functionally isolates the kidney in vivo in the conscious animal and can be employed for acute and chronic studies. Using this model, the applicant proposes to determine if the intrarenal kallikrein-kinin system is important physiologically in the control of renal function through modulation of EDRF and/or eicosanoid release. Specifically, the applicant proposes to localize the cellular targets of intrarenal kallikrein-kinin system by monitoring the levels of second messengers for EDRF (cyclic GMP) and eicosanoids (cyclic AMP) following receptor stimulation. The intrarenal paracrine effects of the kallikrein-kinin system will be explored with the use of a novel method developed by the applicant for interstitial fluid sampling in vivo in conscious animals. The proposed studies are related to the long term goal of increased understanding of the pathophysiology of fluid/electrolyte disorders and hypertension.
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