title: Stress-induced Aldosterone Hyper-Secretion in a Substantial Subset of Patients With Essential Hypertension.
abstract: BACKGROUND
  Aldosterone (ALD) secretion is regulated mainly by angiotensin II, K(+), and adrenocorticotropic hormone (ACTH). Mineralocorticoid receptor antagonists (MRAs) have effectively been used for the treatment of patients with hypertension who do not have primary aldosteronism (PA).
  
  
  OBJECTIVE
  We tested whether chronic stress-related ACTH-mediated ALD hypersecretion and/or zona glomerulosa hypersensitivity could be implicated in the pathogenesis of essential hypertension (ESHT).
  
  
  METHODS
  One hundred thirteen hypertensives without PA and 61 normotensive controls underwent an ultralow-dose (0.03-μg) ACTH stimulation and a treadmill test. Patients with ALD hyper-response according to the cutoffs obtained from controls received treatment with MRAs and underwent genomic DNA testing for the presence of the CYP11B1/CYP11B2 chimeric gene and KCNJ5 gene mutations. A control group of 22 patients with simple ESHT received treatment with MRAs.
  
  
  RESULTS
  Based on the cutoffs of ALD and aldosterone-to-renin ratio (ARR) post-ACTH stimulation obtained from controls, 30 patients (27%) exhibited an ALD but not cortisol (F) hyper-response (HYPER group). This group had no difference in basal ACTH/renin (REN) concentrations compared with controls and the 83 patients with hypertension (73%) without an ALD hyper-response to ACTH stimulation. Patients in the HYPER group demonstrated significantly higher ALD concentrations, ARR, and ALD/ACTH ratio (AAR) in the treadmill test. Treatment with MRAs alone produced normalization of blood pressure in these patients whereas patients with hypertension with neither PA nor ALD hyper-response to ACTH stimulation who served as a control group failed to lower blood pressure. Also, two novel germline heterozygous KCNJ5 mutations were detected in the HYPER group.
  
  
  CONCLUSIONS
  A number of patients with hypertension without PA show ACTH-dependent ALD hyper-secretion and benefit from treatment with MRAs. This could be related to chronic stress via ACTH hyper secretion and/or gene-mutations increasing the zona glomerulosa responsiveness to excitatory stimuli.
authors.affiliation: Department of Endocrinology and Diabetes Center (A.M., I.I.A., C.M. T.P., A.G., L.P., S.F., D.R., G.P.P.), G. Gennimatas General Hospital, Athens 11527, Greece; Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics (A.S., E.C., G.P.C.), University of Athens Medical School, Aghia Sophia Children's Hospital, Athens 11527, Greece; Department of Pathophysiology (G.K.), University of Athens Medical School, Laikon Hospital, Athens 11527, Greece; and Department of Cardiology (A.Z., A.K.), G. Gennimatas General Hospital, Athens 11527, Greece.
authors.forename: Athina
authors.initials: A
authors.lastname: Markou
authors.affiliation: Department of Endocrinology and Diabetes Center (A.M., I.I.A., C.M. T.P., A.G., L.P., S.F., D.R., G.P.P.), G. Gennimatas General Hospital, Athens 11527, Greece; Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics (A.S., E.C., G.P.C.), University of Athens Medical School, Aghia Sophia Children's Hospital, Athens 11527, Greece; Department of Pathophysiology (G.K.), University of Athens Medical School, Laikon Hospital, Athens 11527, Greece; and Department of Cardiology (A.Z., A.K.), G. Gennimatas General Hospital, Athens 11527, Greece.
authors.forename: Amalia
authors.initials: A
authors.lastname: Sertedaki
authors.affiliation: Department of Endocrinology and Diabetes Center (A.M., I.I.A., C.M. T.P., A.G., L.P., S.F., D.R., G.P.P.), G. Gennimatas General Hospital, Athens 11527, Greece; Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics (A.S., E.C., G.P.C.), University of Athens Medical School, Aghia Sophia Children's Hospital, Athens 11527, Greece; Department of Pathophysiology (G.K.), University of Athens Medical School, Laikon Hospital, Athens 11527, Greece; and Department of Cardiology (A.Z., A.K.), G. Gennimatas General Hospital, Athens 11527, Greece.
authors.forename: Gregory
authors.initials: G
authors.lastname: Kaltsas
authors.affiliation: Department of Endocrinology and Diabetes Center (A.M., I.I.A., C.M. T.P., A.G., L.P., S.F., D.R., G.P.P.), G. Gennimatas General Hospital, Athens 11527, Greece; Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics (A.S., E.C., G.P.C.), University of Athens Medical School, Aghia Sophia Children's Hospital, Athens 11527, Greece; Department of Pathophysiology (G.K.), University of Athens Medical School, Laikon Hospital, Athens 11527, Greece; and Department of Cardiology (A.Z., A.K.), G. Gennimatas General Hospital, Athens 11527, Greece.
authors.forename: Ioannis I
authors.initials: II
authors.lastname: Androulakis
authors.affiliation: Department of Endocrinology and Diabetes Center (A.M., I.I.A., C.M. T.P., A.G., L.P., S.F., D.R., G.P.P.), G. Gennimatas General Hospital, Athens 11527, Greece; Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics (A.S., E.C., G.P.C.), University of Athens Medical School, Aghia Sophia Children's Hospital, Athens 11527, Greece; Department of Pathophysiology (G.K.), University of Athens Medical School, Laikon Hospital, Athens 11527, Greece; and Department of Cardiology (A.Z., A.K.), G. Gennimatas General Hospital, Athens 11527, Greece.
authors.forename: Chrisanthi
authors.initials: C
authors.lastname: Marakaki
authors.affiliation: Department of Endocrinology and Diabetes Center (A.M., I.I.A., C.M. T.P., A.G., L.P., S.F., D.R., G.P.P.), G. Gennimatas General Hospital, Athens 11527, Greece; Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics (A.S., E.C., G.P.C.), University of Athens Medical School, Aghia Sophia Children's Hospital, Athens 11527, Greece; Department of Pathophysiology (G.K.), University of Athens Medical School, Laikon Hospital, Athens 11527, Greece; and Department of Cardiology (A.Z., A.K.), G. Gennimatas General Hospital, Athens 11527, Greece.
authors.forename: Theodora
authors.initials: T
authors.lastname: Pappa
authors.affiliation: Department of Endocrinology and Diabetes Center (A.M., I.I.A., C.M. T.P., A.G., L.P., S.F., D.R., G.P.P.), G. Gennimatas General Hospital, Athens 11527, Greece; Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics (A.S., E.C., G.P.C.), University of Athens Medical School, Aghia Sophia Children's Hospital, Athens 11527, Greece; Department of Pathophysiology (G.K.), University of Athens Medical School, Laikon Hospital, Athens 11527, Greece; and Department of Cardiology (A.Z., A.K.), G. Gennimatas General Hospital, Athens 11527, Greece.
authors.forename: Aggeliki
authors.initials: A
authors.lastname: Gouli
authors.affiliation: Department of Endocrinology and Diabetes Center (A.M., I.I.A., C.M. T.P., A.G., L.P., S.F., D.R., G.P.P.), G. Gennimatas General Hospital, Athens 11527, Greece; Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics (A.S., E.C., G.P.C.), University of Athens Medical School, Aghia Sophia Children's Hospital, Athens 11527, Greece; Department of Pathophysiology (G.K.), University of Athens Medical School, Laikon Hospital, Athens 11527, Greece; and Department of Cardiology (A.Z., A.K.), G. Gennimatas General Hospital, Athens 11527, Greece.
authors.forename: Labrini
authors.initials: L
authors.lastname: Papanastasiou
authors.affiliation: Department of Endocrinology and Diabetes Center (A.M., I.I.A., C.M. T.P., A.G., L.P., S.F., D.R., G.P.P.), G. Gennimatas General Hospital, Athens 11527, Greece; Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics (A.S., E.C., G.P.C.), University of Athens Medical School, Aghia Sophia Children's Hospital, Athens 11527, Greece; Department of Pathophysiology (G.K.), University of Athens Medical School, Laikon Hospital, Athens 11527, Greece; and Department of Cardiology (A.Z., A.K.), G. Gennimatas General Hospital, Athens 11527, Greece.
authors.forename: Stelios
authors.initials: S
authors.lastname: Fountoulakis
authors.affiliation: Department of Endocrinology and Diabetes Center (A.M., I.I.A., C.M. T.P., A.G., L.P., S.F., D.R., G.P.P.), G. Gennimatas General Hospital, Athens 11527, Greece; Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics (A.S., E.C., G.P.C.), University of Athens Medical School, Aghia Sophia Children's Hospital, Athens 11527, Greece; Department of Pathophysiology (G.K.), University of Athens Medical School, Laikon Hospital, Athens 11527, Greece; and Department of Cardiology (A.Z., A.K.), G. Gennimatas General Hospital, Athens 11527, Greece.
authors.forename: Achilles
authors.initials: A
authors.lastname: Zacharoulis
authors.affiliation: Department of Endocrinology and Diabetes Center (A.M., I.I.A., C.M. T.P., A.G., L.P., S.F., D.R., G.P.P.), G. Gennimatas General Hospital, Athens 11527, Greece; Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics (A.S., E.C., G.P.C.), University of Athens Medical School, Aghia Sophia Children's Hospital, Athens 11527, Greece; Department of Pathophysiology (G.K.), University of Athens Medical School, Laikon Hospital, Athens 11527, Greece; and Department of Cardiology (A.Z., A.K.), G. Gennimatas General Hospital, Athens 11527, Greece.
authors.forename: Apostolos
authors.initials: A
authors.lastname: Karavidas
authors.affiliation: Department of Endocrinology and Diabetes Center (A.M., I.I.A., C.M. T.P., A.G., L.P., S.F., D.R., G.P.P.), G. Gennimatas General Hospital, Athens 11527, Greece; Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics (A.S., E.C., G.P.C.), University of Athens Medical School, Aghia Sophia Children's Hospital, Athens 11527, Greece; Department of Pathophysiology (G.K.), University of Athens Medical School, Laikon Hospital, Athens 11527, Greece; and Department of Cardiology (A.Z., A.K.), G. Gennimatas General Hospital, Athens 11527, Greece.
authors.forename: Despoina
authors.initials: D
authors.lastname: Ragkou
authors.affiliation: Department of Endocrinology and Diabetes Center (A.M., I.I.A., C.M. T.P., A.G., L.P., S.F., D.R., G.P.P.), G. Gennimatas General Hospital, Athens 11527, Greece; Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics (A.S., E.C., G.P.C.), University of Athens Medical School, Aghia Sophia Children's Hospital, Athens 11527, Greece; Department of Pathophysiology (G.K.), University of Athens Medical School, Laikon Hospital, Athens 11527, Greece; and Department of Cardiology (A.Z., A.K.), G. Gennimatas General Hospital, Athens 11527, Greece.
authors.forename: Evangelia
authors.initials: E
authors.lastname: Charmandari
authors.affiliation: Department of Endocrinology and Diabetes Center (A.M., I.I.A., C.M. T.P., A.G., L.P., S.F., D.R., G.P.P.), G. Gennimatas General Hospital, Athens 11527, Greece; Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics (A.S., E.C., G.P.C.), University of Athens Medical School, Aghia Sophia Children's Hospital, Athens 11527, Greece; Department of Pathophysiology (G.K.), University of Athens Medical School, Laikon Hospital, Athens 11527, Greece; and Department of Cardiology (A.Z., A.K.), G. Gennimatas General Hospital, Athens 11527, Greece.
authors.forename: George P
authors.initials: GP
authors.lastname: Chrousos
authors.affiliation: Department of Endocrinology and Diabetes Center (A.M., I.I.A., C.M. T.P., A.G., L.P., S.F., D.R., G.P.P.), G. Gennimatas General Hospital, Athens 11527, Greece; Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics (A.S., E.C., G.P.C.), University of Athens Medical School, Aghia Sophia Children's Hospital, Athens 11527, Greece; Department of Pathophysiology (G.K.), University of Athens Medical School, Laikon Hospital, Athens 11527, Greece; and Department of Cardiology (A.Z., A.K.), G. Gennimatas General Hospital, Athens 11527, Greece.
authors.forename: George P
authors.initials: GP
authors.lastname: Piaditis
mesh_terms: D000236:Adenoma / Q000150:complications / Q000235:genetics / Q000378:metabolism; D000310:Adrenal Gland Neoplasms / Q000150:complications / Q000235:genetics / Q000378:metabolism; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000450:Aldosterone / Q000097:blood / Q000378:metabolism*; D016022:Case-Control Studies; D019405:Cytochrome P-450 CYP11B2 / Q000235:genetics; D000075222:Essential Hypertension; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000235:genetics; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D006929:Hyperaldosteronism / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D006973:Hypertension / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D050506:Mutant Chimeric Proteins / Q000235:genetics; D012083:Renin / Q000097:blood; D013252:Steroid 11-beta-Hydroxylase / Q000235:genetics; D013315:Stress, Psychological / Q000235:genetics / Q000378:metabolism*
chemical_list: D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C484274:KCNJ5 protein, human; D050506:Mutant Chimeric Proteins; D000450:Aldosterone; D000324:Adrenocorticotropic Hormone; D019405:Cytochrome P-450 CYP11B2; D013252:Steroid 11-beta-Hydroxylase; D012083:Renin; D006854:Hydrocortisone