Previous data from our laboratory demonstrated the importance of renal medullary. NOS in the short- and long-term control of renal function and arterial pressure. The role of the individual NOS isoforms in the control of renal function and arterial pressure is not clear. Recent work from our laboratory indicates that inducible NOS (INOS) is present in high levels in the renal medulla of normal rats and chronic systemic iNOS inhibition leads to an elevation of arterial pressure. This proposal will address the hypothesis that renal medullary iNOS is differentially expressed in different cell types in the renal medulla of normal rates and influences sodium and water excretion by direct effects at the level of the colocynth duct. Experiments will be performed in the first half of this proposal to determine the acute and chronic fluid and electrolyte balance and blood pressure effects of selective inhibition of renal medullary iNOS. These experiments will be performed using techniques unique to our laboratory (implanted optical fibers for laser- Doppler flometery and selective infusion directly into the renal medullary interstitial space) as renal medullar iNOS is inhibited with selective enzyme inhibitors. Confirmation of inhibition will be determined by in vitro measures of NOS enzyme activity in tissues obtained from the treated animals. These experiments will demonstrate the importance of iNOS in the regulation of sodium and water balance and blood pressure. The experiments in the second half of the proposal will focus on the distribution and functional importance of iNOS in renal tubular and vascular segments as sodium intake is changed. comparison of mRNA levels, immunoreactive protein levels, and calcium- dependent and -independent NOS enzymatic activity will initially be performed on whole tissue obtained from rats maintained on a low, normal, or high sodium intake. Quantitative RT-PCR measurements of mRNA for iNOS will then be used to determine the location and relative quantity of iNOS message in microdissected renal medullary tubular and/or vascular segments. Finally, the relationship between sodium intake and blood pressure in rats chronically administered with the selective iNOS inhibitors will be determined to in order to draw a functional correlate with the observed changes in iNOS in renal medullary structures.
- National Institute of Diabetes and Digestive and Kidney Diseases
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