The application combines both in vitro and clinical studies to evaluate two important factors regulating vascular tone and blood pressure to man. We will focus on the role of arachidonic acid (AA) products of the lipoxygenase (LO) pathway in the regulation of aldosterone synthesis and renal prostacyclin PGI2 formation. Much evidence suggests that the cyclooxgenase (CO) pathway of AA does not play a role in aldosterone synthesis in the adrenal glomerulosa cell. However, our recent studies indicate that LO inhibition blocks angiotensin II (All) induced aldosterone synthesis in isolated rat alomerulosa cells and that a 12-LO product 12- hydroxyeicosatetraenoic acid (12-HETE) completely restores All action. We will extend these observations by determining whether the LO pathway is specific for All action or is involved in ACTH or K+ mediated aldosterone release. In addition, the effect and mechanism of All, ACTH and K+ on HETE formation will be evaluated using HPLC, RIA and GOMS techniques to assay the LO products. Finally, the potential mechanisms of HETE action will be evaluated with the use of various inhibitors of the calcium messenger system and calcium measurements. These studies will be performed in both static incubations and perfusions of isolated rat and human glomerulosa cells. Preliminary results are exciting and suggest that both rat and human glomerulosa cells derived from adenomatous and normal adrenal glands synthesize 12 and 15-HETE. In addition, All increases HETE formation and LO inhibitors reduce both aldosterone and HETE levels, suggesting that the LO pathway may be a key regulator of All action in the adrenal. In the second area, the role of HETEs in the regulation of renal PGI2 formation in man will be studied using normal controls, patients with mild renal insufficiency, and those with disorders including hyporeninemic hypoaldosteronism (HH) and systemic lupus erythematosus (SLE). The renal disease in HH and SLE has been shown to related to low renal PGI2 formation. Recent evidence from our group suggests that 12 and 15-HETE are potent inhibitors of renin release in vitro. In addition, studies by others indicate that the HETEs in vitro can reduce vascular PGI2 formation. Our hypothesis is that increased HETE production in HH and SLE reduces renal PGI2 formation which produces alterations in renin release and renal vascular tone. We will measure 12 and 15-HETE in urine using GOMS validated RIA techniques after HPLC purification in the normals, renal insufficiency controls and patients with HH and SLE. The added effect on CO inhibition and calcium infusion on HETE levels will be evaluated and correlated with renin release, PGI2 formation and renal blood flow. Preliminary evidence suggests that HETE levels are increased in patients with HH and SLE. These studies in man should provide new information that will lead to important evidence for the role of HETEs in the regulation of renal PGI2 formation in disease states including diabetes and other glomerular disorders that are characterized by glomerular disease and altered vasomotor tone.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK039721-01
Application #
3239623
Study Section
General Medicine B Study Section (GMB)
Project Start
1988-03-01
Project End
1991-02-28
Budget Start
1988-03-01
Budget End
1989-02-28
Support Year
1
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Southern California
Department
Type
Schools of Medicine
DUNS #
041544081
City
Los Angeles
State
CA
Country
United States
Zip Code
90033
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