Pressure-natriuresis is the major regulatory mechanism in mammalian physiology whereby an acute elevation in blood pressure (BP) induces a rapid increase in renal sodium excretion. An understanding of the mechanisms that mediate pressure-natriuresis is critical, because all forms of hypertension in experimental animals and man are accompanied by a defective natriuretic response to increased BP. The underlying mechanism of pressure-natriuresis is unknown. The overall goals of this project are to understand the role of extracellular renal interstitial (Rl) guanosine cyclic 3', 5'-monophosphate (cGMP), as opposed to intracellular cGMP, and renal proximal tubule (RPT) cell protein kinase G (PKG) in mediating pressure-natriuresis, to determine whether the nitric oxide (NO)-soluble guanylyl cyclase (sGC)-extracellular Rl cGMP-cellular PKG pathway mediates the natriuretic response to an acute increase in renal perfusion pressure (RPP), to determine the specific PKG isoform involved and to identify the point(s) along this pathway which is (are) deficient in salt-sensitive hypertension and spontaneous hypertension in the rat. The central hypothesis is that extracellular Rl cGMP plays a major critical role in pressure natriuresis via PKG and that defects in this pathway lead to salt-sensitivity and hypertension.
The specific aims are (1) to test the hypothesis that pressure-natriuresis is mediated by extracellular Rl cGMP and cellular PKG (type I) in RPT cells and (2) to test the hypothesis that the dampening of pressure-natriuresis in salt-sensitive hypertension is due to a defect in extracellular Rl cGMP production and in spontaneous hypertension is due to a defect in Rl cGMP action. Proof of the specific aims will identify and characterize a novel role of extracellular Rl cGMP and provide a potential therapeutic target for hypertension and other disease states associated with sodium retention.
