Data obtained in preliminary studies suggest that the renal kallikrein-kinin system (KKS) functions as a paracrine system, locally modulating renal function. The mechanisms by which these actions occur have not been fully elucidated. This proposal intends to examine the hypothesis that the renal actions of the KKS are mediated by endothelium-derived relaxing factor (EDRF), and eicosanoids. There are two specific aims that will be addressed in this proposal: (l) to examine the contribution of EDRF to the renal modulatory effects the renal KKS and (2) to examine whether kinin- induced changes in hemodynamics and excretory function are dependent on eicosanoid mechanisms. 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. 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. Recently, the applicant developed a novel microdialysis method to sample renal interstitial fluid in the conscious dog and applied it to studies of the role of various hormones, including kinins in kidney function. The development of this microdialysis technique is essential to the examination of the hypothesis expressed in both Aims 1 and 2 which studies are to be conducted in conscious, chronically instrumented dogs. 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). 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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