title: Investigating the function of an aldosterone response pathway in primary human adrenocortical cells obtained from Conn's and phaeochromocytoma patients.
abstract: The components of the classical renal aldosterone response pathway are expressed in human adrenocortical cells; however, studies in H295R cells have shown that pharmacological manipulation of this pathway has no effect on aldosterone production. We have characterised aldosterone and cortisol production by primary human adrenocortical cells and tested the hypothesis that a mineralocorticoid response pathway modulates aldosterone secretion. Aldosterone production by cells obtained from normal adrenal cortex was stimulated by angiotensin II, extracellular K(+) and a reduction in extracellular Na(+). Conn's adenoma cells, in comparison, produced higher aldosterone/cortisol ratios and were less responsive to angiotensin II and extracellular Na(+). Close coupling of aldosterone and cortisol secretion was observed in all adrenocortical cells. The mineralocorticoid receptor antagonists, eplerenone and potassium canrenoate, had no significant effect on aldosterone or cortisol production. In contrast, the glucocorticoid receptor antagonist, mifepristone, and the Na(+) uptake inhibitor, amiloride, had significant inhibitory effects on steroid production. Our current experiments do not support the hypothesis that an adrenal aldosterone-response pathway mediates the negative feedback of aldosterone on its own release, but do raise interest in the glucocorticoid receptor and downstream targets of the mineralocorticoid receptor as mediators of corticosteroid production.
authors.affiliation: Clinical Pharmacology, University of Cambridge, Addenbrooke's Hospital, Box 110, Hills Road, Cambridge, CB2 0QQ, UK. tjb23@cam.ac.uk
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Burton
authors.forename: Elena A B
authors.initials: EA
authors.lastname: Azizan
authors.forename: Morris J
authors.initials: MJ
authors.lastname: Brown
mesh_terms: D000302:Adrenal Cortex / Q000378:metabolism* / Q000473:pathology*; D000315:Adrenalectomy; D018246:Adrenocortical Adenoma / Q000378:metabolism* / Q000473:pathology* / Q000601:surgery; D000450:Aldosterone / Q000096:biosynthesis / Q000378:metabolism*; D000804:Angiotensin II / Q000494:pharmacology; D002478:Cells, Cultured; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006854:Hydrocortisone / Q000096:biosynthesis; D008901:Mineralocorticoids / Q000378:metabolism; D018358:Neuroendocrine Tumors / Q000378:metabolism* / Q000473:pathology* / Q000601:surgery; D011188:Potassium / Q000378:metabolism; D012964:Sodium / Q000378:metabolism
chemical_list: D008901:Mineralocorticoids; D000804:Angiotensin II; D000450:Aldosterone; D012964:Sodium; D011188:Potassium; D006854:Hydrocortisone