A major focus of this proposal is to extend our knowledge of the regulation of aldosterone in hyperaldosteronism, in particular, patients who have primary adrenocortical hyperplasia (PAH), but biochemically and physiologically behave like adenoma. In patients with PAH, elevated 18-hydroxycortisol levels seen usually in adenoma patients would likely result in a surgically curable disease. In these patients, the failure to crease aldosterone by spironolactone, as is characteristic of adenoma, will be further examined. Deoxycorticosterone (DOC), a zona fasciculata (ZF) steroid, can show increases independent of cortisol, the other major ZF steroid and is observed in pure DOC tumors, producing evidence that steroids in the DOC pathway can suppress DOC in contralateral adrenal but not cortisol. A non-adrenocorticotrophic hormone (ACTH) regulator of DOC is suspected. The DOC pathway is also poorly stimulated by ACTH in patients with Acquired Immunodeficiency Syndrome (AIDS) and is a harbinger of progressive adrenal deterioration. This pathway is now being examined in patients with AIDS related complexes (ARC) and positive antibody titers. Adrenal deficiency may be secondary to the DOC regulator defect since patients with adrenal insufficiency and AIDS rarely increase ACTH levels. To test for a possible central nervous system (CNS) or pituitary defect the pituitary will be stimulated by ovine corticotropin releasing hormone (oCRH) for ACTH cortisol and DOC responses. Discordant responses of ACTH and cortisol from DOC could indicate a pituitary trophic defect of DOC. If normal, an insulin tolerance test will be used to detect possible CNS impairment of hypothalmic CRH. Adrenal impairment of DOC to ACTH stimulation may be an early lesion in AIDS and ARC. A likely source for other regulators of the adrenal cortex would be the N-terminal fragment (NTF) of proopiomelanocortin (POMC). When processed on high performance liquid chromatography (HPLC), the NTF has revealed five new peptide fragments, sharing the amino acid (AA) sequence of 31-49 (mid portion of NTF), which are not adrenocorticotrophic hormone (ACTH) or melanocyte stimulating hormone (MSH). The AA 31- 49 can stimulate aldosterone and possibly other corticosteroids in vitro. The presence, absence, or elevation of these fragments in disorders of hypermineralocorticoidism, hypertension, and AIDS, could identify a pituitary influence on mineralocorticoid hormone secretion. We will study the interaction of ANH with other volume regulating factors such as aldosterone, angiotensin II (AII) catechols, contrived and disease states with expanded extracellular fluid (ECF).

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK006415-29
Application #
3224484
Study Section
Cardiovascular and Renal Study Section (CVB)
Project Start
1977-09-01
Project End
1992-08-31
Budget Start
1990-09-01
Budget End
1991-08-31
Support Year
29
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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Biglieri, E G; Kater, C E (1991) Steroid characteristics of mineralocorticoid adrenocortical hypertension. Clin Chem 37:1843-8
Farese Jr, R V; Biglieri, E G; Shackleton, C H et al. (1991) Licorice-induced hypermineralocorticoidism. N Engl J Med 325:1223-7
Biglieri, E G; Kater, C E (1991) 17 alpha-hydroxylation deficiency. Endocrinol Metab Clin North Am 20:257-68
Kater, C E; Irony, I; Biglieri, E G et al. (1990) Continuous adrenocorticotropin administration in hypopituitarism produces asynchronous increases of deoxycorticosterone and 11-deoxycortisol relative to other reduced zona fasciculata steroids. J Clin Endocrinol Metab 71:305-10
Irony, I; Kater, C E; Biglieri, E G et al. (1990) Correctable subsets of primary aldosteronism. Primary adrenal hyperplasia and renin responsive adenoma. Am J Hypertens 3:576-82
Biglieri, E G; Arteaga, E; Kater, C E (1987) Effect of ACTH on aldosterone and other mineralocorticoid hormones. Ann N Y Acad Sci 512:426-37
Schambelan, M; Sebastian, A; Katuna, B A et al. (1987) Adrenocortical hormone secretory response to chronic NH4Cl-induced metabolic acidosis. Am J Physiol 252:E454-60