While hypertension is an important health problem in America affecting over 58 million people, in 90% of cases the cause is unknown. Adrenal steroids are believed to cause hypertension in a small percentage of these. We are proposing two hypothesis: the first addresses an unusual form of primary aldosteronism called Glucocorticoid-Suppressible Aldosteronism (GSA). In these patients """"""""The abnormal secretion of adrenal steroids is due to a persistence of the Transitional zone of the adrenal which replaces the normal Zona Fasciculata"""""""". The transitional zone of the adrenal retains the Cytochrome P-450 methyl oxidase (s) normally present only in the glomerulosa and acquires the 17a-hydroxylase of the fasciculata, resulting in the excessive secretion of the hybrid steroids 18-hydroxycortisol and 18-oxocortisol. We propose to study the regulation of these two steroids using recently developed RIAs to measure their plasma and urine concentrations. We will also measure their secretory and metabolic clearance rates and study the in vivo metabolism of these steroids to determine their main metabolites. We are also postulating that the defect in these patients is due to the absence of an intracellular inhibitor of the late pathway of aldosterone secretion which leads to the persistence of the enzyme in areas of the adrenal where it is not supposed to be active. We have detected such an inhibitor and are proposing to study its regulation, intracellular location and characterization using bovine adrenal zona glomerulosa and fasciculata in culture. The second hypothesis expressed that """"""""The adrenal defect in some cases of essential hypertension is analogous to the adrenal defect which occurs in the Dahl S, or salt sensitive, rat model of hypertension, considering that the human adrenal produces mainly 17a-hydroxylated steroids"""""""". In the human the steroids produced would be 18-hydroxy-11-deoxycortisol (which we have identified) and 19-hydroxy-11-deoxycortisol. We have design methods for their measurement and are proposing to study their plasma and urine concentrations and regulation. It is also postulated that these steroids, rather than producing the hypertension themselves, are markers of more biologically active steroids which we propose to try to identify.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL027255-09
Application #
3339023
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Project Start
1980-09-01
Project End
1993-08-31
Budget Start
1989-09-30
Budget End
1990-08-31
Support Year
9
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of South Florida
Department
Type
Schools of Medicine
DUNS #
City
Tampa
State
FL
Country
United States
Zip Code
33612
Seccia, Teresa M; Caroccia, Brasilina; Gomez-Sanchez, Elise P et al. (2018) The Biology of Normal Zona Glomerulosa and Aldosterone-Producing Adenoma: Pathological Implications. Endocr Rev 39:1029-1056
Meyer, Lucie S; Wang, Xiao; Sušnik, Eva et al. (2018) Immunohistopathology and Steroid Profiles Associated With Biochemical Outcomes After Adrenalectomy for Unilateral Primary Aldosteronism. Hypertension 72:650-657
Kobuke, Kazuhiro; Oki, Kenji; Gomez-Sanchez, Celso E et al. (2018) Calneuron 1 Increased Ca2+ in the Endoplasmic Reticulum and Aldosterone Production in Aldosterone-Producing Adenoma. Hypertension 71:125-133
Gomez-Sanchez, Celso E; Williams, Tracy A (2018) Visualizing Adrenal Steroids in Primary Aldosteronism. Hypertension 72:1269-1271
Lenders, Jacques W M; Williams, Tracy Ann; Reincke, Martin et al. (2018) DIAGNOSIS OF ENDOCRINE DISEASE: 18-Oxocortisol and 18-hydroxycortisol: is there clinical utility of these steroids? Eur J Endocrinol 178:R1-R9
Gomez-Sanchez, Celso E; Qi, Xin; Gomez-Sanchez, Elise P et al. (2017) Disordered zonal and cellular CYP11B2 enzyme expression in familial hyperaldosteronism type 3. Mol Cell Endocrinol 439:74-80
Gomez-Sanchez, Celso E; Kuppusamy, Maniselvan; Gomez-Sanchez, Elise P (2017) Of Mice and Man and the Regulation of Aldosterone Secretion. Hypertension 70:240-242
Yamazaki, Yuto; Nakamura, Yasuhiro; Omata, Kei et al. (2017) Histopathological Classification of Cross-Sectional Image-Negative Hyperaldosteronism. J Clin Endocrinol Metab 102:1182-1192
Williams, Tracy A; Lenders, Jacques W M; Mulatero, Paolo et al. (2017) Outcomes after adrenalectomy for unilateral primary aldosteronism: an international consensus on outcome measures and analysis of remission rates in an international cohort. Lancet Diabetes Endocrinol 5:689-699
Nishimoto, Koshiro; Koga, Minae; Seki, Tsugio et al. (2017) Immunohistochemistry of aldosterone synthase leads the way to the pathogenesis of primary aldosteronism. Mol Cell Endocrinol 441:124-133

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