The principal objective of this proposal is the characterization of the production and metabolism of the 19-oxygenated and 19-nor- corticosteroids in rats and man. It has been demonstrated in this laboratory that the 19-nor-corticosteroids are produced in excess in some forms of genetic and experimental hypertension in the rat and is certain adrenocortical and salt-sensitive hypertensive disorders in man. We demonstrated that the principal secretagogue for activation of the 19-nor-corticosteroid pathway is corticotropin with a minor role for the renin-angiotensin system. It is proposed that the 19-nor-corticosteroids and their precursors be isolated, identified and quantified in biological fluids from rats and man. Rigorous identification of these steroids will be accomplished by HPLC separation, gas liquid chromatography mass spectrometry and nuclear magnetic resonance. Quantification can be accomplished chemically or by radioimmunoassay. Because this laboratory possesses a large library of adrenal venous effluent specimens from human subjects the content of the various 19-oxygenated corticosteroid and 19- nor-corticosteroid will be estimated. The concentration of precursors of the 19-nor-corticosteroids before and after ACTH stimulation will be related to their peripheral concentrations and the appearance of the respective 19-nor-corticosteroids in the peripheral circulation. Utilizing labelled precursors of the 19- nor-steroids, it is proposed that the production and overall metabolic clearance rates of these steroids be determined in man. Mitochondria of human adrenal tumors and rat adrenal cortices will be characterized for 19-hydroxylating activity. Parallel studies on the development of a specific inhibitor of the 19- hydroxylating system will be undertaken and the mitochondrial preparation used to test the degree of inhibition of 19- hydroxylation of these compounds. The role of obligatory 19- hydroxylation by the adrenal in the formation of 19-nor- corticosteroid will be studied using these specific inhibitors in vivo in the rat. Inhibition of 19-hydroxylation and the production of precursors of the 19-nor-corticosteroids might be expected to reverse the phenomenon associated with 19-nor-corticosteroids excess.
|Rao, A; Melby, J C; Wilson, T E (1995) Prohormones in adrenal venous effluent in patients with primary hyperaldosteronism. J Clin Endocrinol Metab 80:1677-80|
|Delaney, M L; Melby, J C (1995) 19-Acetylenic-deoxycorticosterone inhibits 19-hydroxylase and 11 beta-hydroxylase activities in dispersed bovine zona fasciculata cells. Steroids 60:265-7|
|Griffing, G T; Melby, J C; Holbrook, M et al. (1991) Antihypertensive effects of an aromatase inhibitor in inbred salt-sensitive rats. Hypertension 17:771-5|
|Melby, J C (1989) Clinical review 1: Endocrine hypertension. J Clin Endocrinol Metab 69:697-703|