RENAL HUMORAL FACTORS IN RENAL FUNCTION AND HYPERTENSION

Project: Research project

Description

The hypothesis underlying the studies of this proposal is that the regulation of sodium balance involves a number of natriuretic mechanisms, however, the most essential components are changes in the synthesis of prostaglandins (PG), nitric oxide (NO), and angiotensin II (Ang II) which may be directly coupled to the intrarenal distribution of blood flow. The regulation of sodium balance may occur on two levels. First, elevations in sodium intake and-the accompanying increases in blood volume induce increases in urinary sodium excretion predominately through a NO-mediated mechanism. Under these conditions, inhibition of NO synthesis impairs the natriuresis, whereas, inhibition of PG synthesis has no effect The impairment of sodium excretion during volume expansion leads to sodium retention and an elevation of the blood pressure. The developing hypertension results in a pressure-induced natriuresis (the second level of sodium regulation), which is even capable of overcoming the effects of NO synthesis inhibition. The pressure-induced natriuresis is PG- dependent because PG synthesis inhibition significantly blunts the response. This proposal intends to elucidate the manner in which PG, Ang II, and/or NO act upon the renal cortical and medullary circulations to couple hemodynarnic changes to alterations in sodium excretion. This is achieved by: a) specifically blocking the production of Ang II, PG, or NO during pressure-induced natriuresis or volume expansion and restoring their effects by administration of exogenous Ang II, PG, or NO donors, and b) using selective renal cortical or medullary vasodilators to explore the significance of cortical and medullary vasodilatation on sodium excretion. Furthermore, the specific manner in which the withdrawal of PG and/or NO blunts sodium excretion and fosters salt- sensitive hypertension will he explored using three dimensional computerized tomography (cine CT) which allows the precise determination of the hemodynamic and tubular events occurring in these situations. Cine CT will also be used to evaluate hemodynamic-to-tubular coupling during chronic renal hyper-and hypo-perfusion induced by Goldblatt hypertension and to evaluate the regulatory roles of Ang II, PG, and NO on this coupling. Finally, novel studies are proposed to use cine CT to assess transit times through the loop of Henle and distal tubules. We believe that these studies will considerably advance our knowledge about fundamental mechanisms of hypertension. Most of the proposed studies are based on our observations that uncoupling changes in cardiovascular volume or arterial pressure and sodium excretion produces salt sensitive hypertension. Consequently, elucidation of the pathophysiology of this phenomenon has important clinical and therapeutical implications.
StatusFinished
Effective start/end date6/1/797/31/09

Funding

  • National Institutes of Health: $390,059.00

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Renovascular Hypertension
Renal Hypertension
Kidney
Endothelins
Angiotensin II
Oxidative Stress
Swine
Hypertension
Technology
Hydrodynamics
Angioplasty
Renin
Ischemia
Hemodynamics
Maintenance
Magnetic Resonance Imaging
Pharmacology

ASJC

  • Medicine(all)