Previous studies suggest that the renal kallikrein-kinin system (KKS) functions as a renal paracrine system, locally modulating fluid and electrolyte homeostasis and blood pressure regulation. Recently the applicant has developed novel methods to sample renal interstitial fluid (RIF) and monitor changes in renal regional blood flow. The development of the conscious animal model is essential to the investigation of the physiological role of the renal kallikrein-kinin system. Our preliminary studies utilizing the renal interstitial microdialysis technique demonstrated our ability to measure both renal cortical and medullary interstitial bradykinin, prostaglandin E/2, cyclic GMP, cyclic AMP and angiotensin II. RIF bradykinin increases during chronic low sodium intake and in response to acute salt loading. The increase in bradykinin may be essential in protection against the harmful effects of high salt intake (e.g., hypertension). However it is not clear why bradykinin, a natriuretic substance, increases during chronic salt depletion. It is possible that bradykinin counteracts the vasoconstrictor action of hormones (e.g., angiotensin II) induced by sodium depletion. This proposal examines the hypothesis that the renal actions of the KKS are mediated by endothelium-derived relaxing factor (EDRF) and eicosanoids, and investigates the relationship between the KKS and the renin-angiotensin system in the kidney.
Three specific aims will be addressed: (1) to determine the paracrine action and renal compartmentalization of the KKS and its mediators in the kidney, (2) to ascertain the interaction between the intrarenal KKS and renin-angiotensin system and (3) to determine the role of intrarenal KKS and its mediators in the regulation of blood pressure. The proposed studies are related to the long-term goal of increasing our understanding of the pathophysiology of fluid/electrolyte disorders and hypertension.
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