• Mattson, David L (PI)
  • Lombard, Julian (PI)
  • Cowley, Allen (PI)
  • Cowley, Allen (PI)
  • Roman, Richard (PI)
  • Greene, Andrew (PI)

Project: Research project

Project Details


Project 1 examines the role of nitric oxide (NO) in the regulation of
blood flow to the renal medulla. Although the medulla receives only about
5-10% of total renal blood flow, we have shown that perfusion of this
region plays an important role in the regulation of sodium excretion and
in the long-term control of arterial pressure. The mechanisms which
regulate medullary blood flow remain poorly understood, but NO appears to
be importantly involved. We have shown that nitric oxide synthase (NOS)
activity is substantially greater in the medulla than in the cortex.
Furthermore, chronic inhibition of medullary NOS activity greatly reduces
medullary blood flow and results in sodium retention and hypertension. The
goal of this project is to determine in medullary [NO] plays an important
role in the normal homeostatic regulation of medullary flow by moderating
the effects of vasoconstrictor hormones. such as angiotensin II (ANGII)
and norepinephrine (NE), which may be trapped and concentrated by the
counter-current vasa recta circulation. We hypothesize that these
compounds stimulate the release of NO which in turn buffers reductions of
medullary flow, tissue P0/2, and prevents hypertension. The application of
techniques ranging from the molecular to the whole animal will enable
examination of this hypothesis. We have developed a method for the direct
tissue measurement of NO concentrations within the renal medulla in both
anesthetized and conscious instrumented rats (microdialysis oxyHb-NO
trapping). Implanted optical fibers and laser-Doppler flowmetry will also
be used to measure regional blood flow changes in the renal medulla and
cortex in unanesthetized rats. Techniques have also been developed to
quantify regional changes of NOS gene expression, protein expression,
enzyme activity and L-arginine concentrations in whole tissue and in
isolated medullary microvessels and tubules of the renal medulla.

Studies will determine if circulating angiotensin II (ANGII) and
norepinephrine (NE) stimulate medullary NO production which buffers
against acute reductions of regional blood flow. We will determine whether
medullary NO serves to protect flow to the renal medulla and prevention
hypertension in the face of chronic elevations of ANGII or NE. Towards
this end, we will compare the influence of ANGII and NE on medullary blood
flow in rats in which medullary NOS production is blunted
pharmacologically with L-NAME and in the Dahl S rat, a non-pharmacological
model which we find has a reduced capacity to release NO. Localization
and quantification of acute and chronic effects of ANGII and NE on
medullary microvascular and tubular NOS mRNA (nNOS, iNOS, eNOS), NOS
enzyme activity and protein expression will be determined in Sprague
Dawley rats. The proposed project builds upon the unique interdisciplinary
and collaborative strengths of this PPG and will provide important new
insights regarding the role of NO in the regulation of renal medullary
blood flow and the long-term control to arterial pressure.
StatusNot started