The renal cytochrome P450 system as it relates to arachidonic acid (AA) metabolism and blood pressure control has become the centerpiece and has provided thematic unity for the PPG renewal. The first five years gave convincing testimony to the overriding importance of cytochrome P450-dependent-AA (P450-AA) metabolites to the future directions of the PPG. We developed the means to modify the renal production of AA metabo- lites by perturbing the P450 system, and identified novel P450-AA metabolites capable of affecting blood pressure by influencing vasomotion and ion movement. 1)Transport function of the medullary thick ascending limb of Henle's loop (mTALH), and regulation of vascular tone. 2)Glucocorticoid-induced changes in their intrarenal activity. 3)Renal vasodilator mechanisms. 4)Mitogenesis and signal transduction. 5)Development of hypertension in the young SHR. The above Projects make use of a variety of techniques and methods from diverse disciplines to arrive at an integrated and comprehensive approach to the Overall Hypothesis: Renal cytochrome P450-dependent-AA metabolites participate in renal vascular and transport mechanisms relevant to the regulation of blood pressure and to the pathophysiology of hypertension. These Projects are heavily dependent upon a GC-MS Core Facility for structural analysis of P450-AA metabolites generated by tissues and cells within the kidney. In addition, a Cell Culture Core is required to meet the needs of all Projects in order to address the cell biology of P450-AA metabolites, including effects on second messengers, tubular transport mechanisms and transcellular metabolism of P450-AA metabolites.
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