Project 1 hypothesizes that Dahl salt-sensitive (SS) rats when fed a high salt diet will reabsorb greaterthan normal amounts of NaCI in the renal medullary thick ascending limb (mTAL) that in turn will stimulateexcess production of reactive oxygen species (ROS) and thereby reduce medullary blood flow (MBF). ThemTAL of SS rats express greater amounts of Na/K/2CI co-transporter than salt-insensitive control SS.13 ratsand it will be determined if they also express greater amounts of isoforms of the Na/H exchanger (NHE) thatcould account for excess superoxide (O*2~) production. We propose that increased luminal delivery of NaCItogether with increases of outer medullary interstitial NaCI concentration may stimulate NAD(P)H oxidase andenhance production of O*2' and H2O2. It will be determined if greater diffusion of O'2~ and/or H2O2 occurs frommTAL to vasa recta pericytes in the presence of reduced NO bioavailability and whether this leads to areduction of MBF. These events will be studied using time resolved fluorescence videomicroscopy ofmedullary tissue strips. Physiological relevance of these observations will be assessed by studies in consciousinstrumented rats. Sequential measurements of medullary interstitial O'2~, H202, NO and medullary interstitial[NaCI] will be obtained using implanted microdialysis fibers. Changes of medullary blood flow and arterialpressure will be measured daily in these conscious rats using implanted optical fibers and laser-Dopplertechniques together with indwelling arterial catheters before and following an increase in salt (NaCI) intake andthe development of hypertension. The project is defined by three specific aims: 1) To determine if exposure ofmTAL to increased NaCI by either tubular microperfusion and/or bath superfusion results in greater mTALproduction of O*2' or H2O2 and subsequent constriction of surrounding vasa recta vessels in SS compared tothe control SS.13BN rats; 2) To explore the cellular mechanisms whereby increased luminal delivery of NaCI tomTAL and increases of interstitial NaCI concentrations enhance 0*2' production in SS rats; 3) To characterizethe temporal responses of renal medullary production of O*2', H2O2, and NO in conscious SS rats to determineif increases in ROS initiate reductions of medullary blood flow following increased NaCI intake.
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