Stress-induced Aldosterone Hyper-Secretion in a Substantial Subset of Patients With Essential Hypertension.

Abstract

CONTEXT:

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).

PATIENTS AND 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: Athina Markou, Amalia Sertedaki, Gregory Kaltsas, Ioannis I Androulakis, Chrisanthi Marakaki, Theodora Pappa, Aggeliki Gouli, Labrini Papanastasiou, Stelios Fountoulakis, Achilles Zacharoulis, Apostolos Karavidas, Despoina Ragkou, Evangelia Charmandari, George P Chrousos, George P Piaditis
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 100 Issue 8 Pg. 2857-64 (Aug 2015) ISSN: 1945-7197 [Electronic] United States
• PMID: 25974737 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• G Protein-Coupled Inwardly-Rectifying Potassium Channels
• KCNJ5 protein, human
• Mutant Chimeric Proteins
• Aldosterone
• Adrenocorticotropic Hormone
• Cytochrome P-450 CYP11B2
• Steroid 11-beta-Hydroxylase
• Renin
• Hydrocortisone

Topics

• Adenoma (complications, genetics, metabolism)
• Adrenal Gland Neoplasms (complications, genetics, metabolism)
• Adrenocorticotropic Hormone (blood)
• Aldosterone (blood, metabolism)
• Case-Control Studies
• Cytochrome P-450 CYP11B2 (genetics)
• Essential Hypertension
• G Protein-Coupled Inwardly-Rectifying Potassium Channels (genetics)
• Humans
• Hydrocortisone (blood)
• Hyperaldosteronism (complications, genetics, metabolism)
• Hypertension (complications, genetics, metabolism)
• Middle Aged
• Mutant Chimeric Proteins (genetics)
• Renin (blood)
• Steroid 11-beta-Hydroxylase (genetics)
• Stress, Psychological (genetics, metabolism)