this project will examine the role of endogenous cP450 metabolites of arachidonic acid (AA) in the regulation of renal tubular and vascular function in vivo, and the contribution of this system to the resetting of the pressure-natriuretic relationship and the development of hypertension in SHR. The role of endogenous cP450 products of AA on renal tubular and vascular function in vivo will be determined using cP450 inhibitors infused directly into the renal interstitium or microperfused into individual nephron segments. Tubular function will be accessed using micropuncture and tubular perfusion techniques. the cellular mechanisms by which cP450 metabolites of AA influence tubular transport will be studied by measuring oxygen consumption and intracellular pH, Ca++, and Na+ in isolated tubules using fluorescent probes. The effects of cP450 system on the autoregulation of RBF and GFR and tubuloglomerular feedback will be studied in vivo to determine the role of this system in the control of renal vascular tone. The effects of cP450 metabolites of AA on the renal microcirculation will also be studied in vitro using the isolated perfused rat juxtamedullary nephron microvascular preparation. The cellular mechanisms by which cP450 metabolites of AA influence vascular tone will be evaluated by measuring changes in intracellular calcium in vascular smooth cells isolated from the renal microcirculation of rats. In addition, we will determine whether the antihypertensive effects of chronic intrarenal infusions of compounds that reduce renal cP450 activity in SHR is associated with resetting of the pressure-natriuretic relationship to lower pressures, elevations in papillary blood flow and renal interstitial pressure and a reduction in preglomerular vascular tone in deep nephrons.
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