Aldosterone: A Comprehensive Review of its Role in Blood Pressure Regulation, Hypertension, and Therapeutic Strategies

Abstract

Aldosterone, a mineralocorticoid hormone secreted by the adrenal glands, plays a critical role in regulating electrolyte balance and blood pressure. This report provides a comprehensive overview of aldosterone’s synthesis, its mechanism of action on renal and extrarenal tissues, and its involvement in the pathophysiology of hypertension, particularly primary aldosteronism. We delve into the diagnostic approaches for aldosterone-related disorders, including screening tests and confirmatory studies. Furthermore, we discuss the existing treatment options, focusing on aldosterone antagonists such as spironolactone and eplerenone, as well as emerging therapies targeting aldosterone synthase. This review aims to provide a detailed understanding of aldosterone dysregulation and its clinical implications for experts in the field, highlighting both established knowledge and current research directions.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

1. Introduction

The renin-angiotensin-aldosterone system (RAAS) is a crucial hormonal system that regulates blood pressure and fluid balance. Aldosterone, the terminal hormone of this cascade, primarily acts on the distal nephron of the kidney to increase sodium reabsorption and potassium excretion. This process leads to water retention and subsequent elevation of blood pressure. While essential for maintaining homeostasis, excessive aldosterone production or inappropriate activation of its receptor can contribute significantly to hypertension and cardiovascular disease. This report will explore the complex mechanisms by which aldosterone influences blood pressure, the clinical manifestations of aldosterone dysregulation, current diagnostic and therapeutic strategies, and emerging research avenues in this field.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

2. Biosynthesis and Regulation of Aldosterone

2.1. Adrenal Gland Zonation and Steroidogenesis

Aldosterone is synthesized exclusively in the zona glomerulosa (ZG) of the adrenal cortex. This zone possesses the unique ability to express aldosterone synthase (CYP11B2), the enzyme responsible for the final steps in aldosterone production. CYP11B2 converts deoxycorticosterone to corticosterone, then to 18-hydroxycorticosterone, and finally to aldosterone. While CYP11B1, the enzyme responsible for cortisol synthesis (primarily in the zona fasciculata), can also catalyze the initial steps in aldosterone synthesis, only CYP11B2 possesses the 18-hydroxylase and 18-oxidase activities necessary for complete aldosterone production [1]. The expression of CYP11B2 is tightly regulated, primarily by angiotensin II and potassium levels, while CYP11B1 is primarily regulated by ACTH.

2.2. Key Regulatory Factors

Several factors tightly regulate aldosterone synthesis and secretion:

• Angiotensin II (Ang II): Ang II, formed by the proteolytic cleavage of angiotensinogen by renin and angiotensin-converting enzyme (ACE), is a potent stimulator of aldosterone synthesis. Ang II binds to AT1 receptors on ZG cells, leading to increased intracellular calcium, activation of signaling pathways such as protein kinase C (PKC) and mitogen-activated protein kinase (MAPK), and ultimately, increased CYP11B2 expression and aldosterone synthesis [2].
• Potassium: Hyperkalemia directly stimulates aldosterone secretion by depolarizing ZG cells and opening voltage-gated calcium channels. The resulting influx of calcium activates signaling pathways leading to aldosterone synthesis. Conversely, hypokalemia suppresses aldosterone secretion.
• Adrenocorticotropic Hormone (ACTH): ACTH, released from the pituitary gland, plays a permissive role in aldosterone synthesis and is particularly important in stress responses. While ACTH primarily regulates cortisol production in the zona fasciculata, it can transiently stimulate aldosterone secretion, although this effect is less sustained compared to Ang II and potassium.
• Atrial Natriuretic Peptide (ANP): ANP, released by the heart in response to atrial distension, inhibits aldosterone synthesis by decreasing renin secretion and directly inhibiting ZG cells. ANP also increases sodium excretion, counteracting the sodium-retaining effects of aldosterone.
• Other Factors: Other factors, such as dopamine, prostaglandins, and the sympathetic nervous system, can also modulate aldosterone secretion, although their roles are less prominent than those of Ang II, potassium, ACTH, and ANP.

2.3. Mineralocorticoid Receptor (MR) Activation and Downstream Effects

Aldosterone exerts its effects by binding to the mineralocorticoid receptor (MR), a member of the nuclear receptor superfamily. The MR is expressed not only in the kidneys but also in various extrarenal tissues, including the heart, brain, vasculature, and adipose tissue. Upon aldosterone binding, the MR undergoes a conformational change, dissociates from chaperone proteins, and translocates to the nucleus. In the nucleus, the MR dimerizes and binds to specific DNA sequences called mineralocorticoid response elements (MREs) in the promoter regions of target genes. This interaction recruits co-activator proteins and alters gene transcription, leading to increased expression of proteins involved in sodium transport and water reabsorption, such as the epithelial sodium channel (ENaC), Na+/K+-ATPase, and serum and glucocorticoid regulated kinase 1 (SGK1) [3].

Many thanks to our sponsor Esdebe who helped us prepare this research report.

3. Aldosterone and Hypertension

3.1. Primary Aldosteronism (PA)

Primary aldosteronism (PA) is a common cause of secondary hypertension, characterized by excessive aldosterone production that is relatively autonomous from the RAAS. PA is estimated to account for 5-10% of all hypertensive patients and is associated with increased cardiovascular morbidity and mortality compared to essential hypertension [4].

3.2. Subtypes of Primary Aldosteronism

The two main subtypes of PA are:

• Aldosterone-Producing Adenoma (APA): This is the most common cause of PA, accounting for approximately 30-60% of cases. APAs are benign tumors of the adrenal gland that autonomously produce aldosterone.
• Bilateral Adrenal Hyperplasia (BAH): BAH is characterized by hyperplasia of the adrenal glands, leading to increased aldosterone production. This subtype accounts for approximately 40-70% of PA cases. In this subtype, aldosterone production is not always autonomous but is often overly responsive to stimuli such as angiotensin II.

Less common causes of PA include:

• Familial Hyperaldosteronism: This includes various genetic mutations affecting aldosterone synthesis, such as glucocorticoid-remediable aldosteronism (GRA) caused by a chimeric CYP11B1/CYP11B2 gene, and other rare forms of familial hypertension.
• Adrenocortical Carcinoma: Rarely, malignant tumors of the adrenal cortex can produce aldosterone.
• Ectopic Aldosterone Production: In extremely rare cases, aldosterone can be produced by tumors outside of the adrenal gland.

3.3. Mechanisms of Aldosterone-Induced Hypertension

Aldosterone contributes to hypertension through several mechanisms:

• Sodium Retention and Volume Expansion: By increasing sodium reabsorption in the distal nephron, aldosterone leads to water retention and expansion of extracellular fluid volume. This increases cardiac output and blood pressure.
• Potassium Depletion: Aldosterone promotes potassium excretion, leading to hypokalemia. Hypokalemia can impair vasodilation and contribute to vasoconstriction, further elevating blood pressure.
• Vascular Effects: Aldosterone directly affects blood vessels by increasing oxidative stress, inflammation, and endothelial dysfunction. It also promotes vascular remodeling and fibrosis, leading to increased vascular stiffness and resistance [5]. These effects are often mediated by MR activation in vascular smooth muscle cells.
• Cardiac Effects: Aldosterone contributes to cardiac hypertrophy, fibrosis, and diastolic dysfunction by promoting inflammation and oxidative stress in the heart. These cardiac effects can lead to heart failure and arrhythmias.
• Central Nervous System Effects: Aldosterone can affect the central nervous system by modulating sympathetic activity and baroreceptor sensitivity, further contributing to blood pressure dysregulation.

3.4. Hypertension Independent of Sodium Retention

Emerging evidence suggests that aldosterone can contribute to hypertension even in the absence of significant sodium retention. This is primarily due to the direct effects of aldosterone on the vasculature and heart, promoting inflammation, fibrosis, and oxidative stress, independent of its renal effects on sodium and potassium. The MR plays a critical role in mediating these extrarenal effects of aldosterone, contributing to cardiovascular remodeling and dysfunction.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

4. Diagnostic Approaches for Aldosterone-Related Disorders

4.1. Screening for Primary Aldosteronism

The primary screening test for PA is the aldosterone-to-renin ratio (ARR). This ratio is calculated by dividing the plasma aldosterone concentration (PAC) by the plasma renin activity (PRA) or direct renin concentration (DRC). An elevated ARR, typically above 20-30 (depending on the units used), suggests the possibility of PA and warrants further investigation [6].

Several factors can affect the accuracy of the ARR, including:

• Medications: Certain medications, such as beta-blockers, ACE inhibitors, angiotensin receptor blockers (ARBs), and diuretics, can affect renin and aldosterone levels and should be discontinued, if possible, prior to testing. Mineralocorticoid receptor antagonists also need to be stopped. A period of washout is usually required.
• Potassium Status: Hypokalemia can suppress aldosterone secretion and lead to a falsely negative ARR. Potassium levels should be normalized prior to testing.
• Sodium Intake: High sodium intake can suppress renin and aldosterone levels, while low sodium intake can stimulate them. Patients should maintain a normal sodium intake prior to testing.
• Time of Day: Aldosterone levels exhibit diurnal variation, with higher levels in the morning. Samples should be collected at the same time of day to minimize variability.
• Age and Sex: Age and sex can also influence ARR values and should be considered in interpretation.

4.2. Confirmatory Testing

If the ARR is elevated, confirmatory testing is necessary to confirm the diagnosis of PA. Several confirmatory tests are available, including:

• Oral Sodium Loading Test: This test involves administering a high sodium diet (or sodium chloride tablets) for several days and measuring urinary aldosterone excretion. In normal individuals, sodium loading suppresses aldosterone secretion. In patients with PA, aldosterone secretion remains elevated despite sodium loading.
• Saline Infusion Test: This test involves infusing intravenous saline and measuring plasma aldosterone levels. Similar to the oral sodium loading test, saline infusion should suppress aldosterone secretion in normal individuals, but aldosterone remains elevated in patients with PA.
• Fludrocortisone Suppression Test: This test involves administering fludrocortisone (a synthetic mineralocorticoid) and measuring plasma aldosterone levels. Fludrocortisone suppresses renin secretion, which should lead to decreased aldosterone production in normal individuals. In patients with PA, aldosterone remains elevated despite fludrocortisone administration.
• Captopril Challenge Test: This test involves administering captopril (an ACE inhibitor) and measuring plasma aldosterone levels. Captopril blocks the conversion of angiotensin I to angiotensin II, which should decrease aldosterone secretion in normal individuals. In patients with PA, aldosterone suppression is impaired.

The choice of confirmatory test depends on various factors, including patient characteristics, comorbidities, and local laboratory expertise. The saline infusion test is often preferred due to its relative simplicity and safety.

4.3. Subtype Differentiation

Once the diagnosis of PA is confirmed, subtype differentiation is crucial to determine the appropriate treatment strategy. Adrenal venous sampling (AVS) is the gold standard for differentiating between APA and BAH [7]. AVS involves catheterizing the adrenal veins and measuring aldosterone and cortisol levels. By comparing the aldosterone-to-cortisol ratio in the adrenal veins, it is possible to determine whether aldosterone secretion is unilateral (suggesting APA) or bilateral (suggesting BAH).

Adrenal CT imaging is also used in the diagnostic workup of PA, but it has limitations. While CT can detect adrenal adenomas, it cannot always differentiate between aldosterone-producing and non-aldosterone-producing adenomas. Moreover, adrenal incidentalomas are common, and their presence does not necessarily indicate PA.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

5. Treatment Options for Aldosterone-Related Hypertension

5.1. Surgical Treatment

Adrenalectomy (surgical removal of the adrenal gland) is the preferred treatment for patients with APA. Adrenalectomy typically leads to normalization of blood pressure and potassium levels in most patients. However, some patients may still require antihypertensive medications after surgery, particularly those with long-standing hypertension or other comorbidities.

5.2. Medical Treatment

Medical treatment is the mainstay of therapy for patients with BAH and for those who are not candidates for surgery. The primary medical treatment options are mineralocorticoid receptor antagonists (MRAs), such as spironolactone and eplerenone.

• Spironolactone: Spironolactone is a non-selective MRA that binds to the MR with high affinity, blocking the effects of aldosterone. Spironolactone is effective in lowering blood pressure and improving potassium levels in patients with PA. However, spironolactone can cause side effects, such as gynecomastia, menstrual irregularities, and decreased libido, due to its anti-androgenic and progestogenic properties.
• Eplerenone: Eplerenone is a more selective MRA that binds to the MR with higher selectivity compared to spironolactone. Eplerenone is also effective in lowering blood pressure and improving potassium levels in patients with PA, but it has fewer side effects compared to spironolactone. However, eplerenone is generally less potent than spironolactone and may require higher doses to achieve the same blood pressure control.

Other antihypertensive medications, such as thiazide diuretics, ACE inhibitors, and ARBs, can also be used in combination with MRAs to further lower blood pressure in patients with PA.

5.3. Emerging Therapies

Emerging therapies for aldosterone-related hypertension focus on targeting aldosterone synthase (CYP11B2). Lorundrostat is a novel aldosterone synthase inhibitor that has shown promising results in clinical trials. By directly inhibiting CYP11B2, lorundrostat reduces aldosterone production and lowers blood pressure in patients with PA. Unlike MRAs, lorundrostat directly addresses the root cause of PA by reducing aldosterone synthesis, potentially leading to more effective blood pressure control and fewer side effects. Clinical trials have demonstrated significant reductions in blood pressure and improvements in biochemical markers of aldosterone excess with lorundrostat treatment [8]. However, long-term safety and efficacy data are still needed.

Gene therapy targeting CYP11B2 or the mineralocorticoid receptor is also being explored as a potential future treatment option for aldosterone-related hypertension.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

6. Conclusion

Aldosterone plays a central role in blood pressure regulation and electrolyte balance. Dysregulation of aldosterone, particularly in primary aldosteronism, is a significant contributor to hypertension and cardiovascular disease. Accurate diagnosis and appropriate treatment of aldosterone-related disorders are essential for improving patient outcomes. While MRAs such as spironolactone and eplerenone have been the cornerstone of medical therapy for PA, emerging therapies targeting aldosterone synthase offer a promising new approach to directly address the underlying cause of aldosterone excess. Further research is needed to fully elucidate the complex mechanisms by which aldosterone contributes to hypertension and to develop novel therapies that can effectively and safely target the RAAS.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

7. References

[1] Young, M. J., et al. “Aldosterone regulation and cardiovascular disease.” American Journal of Physiology-Heart and Circulatory Physiology 317.5 (2019): H865-H883.
[2] Ehrhart-Bornstein, M., et al. “Regulation of adrenal steroidogenesis.” Endocrine Reviews 22.5 (2001): 557-594.
[3] Shibata, S., et al. “Mineralocorticoid receptor activation and oxidative stress in cardiovascular disease.” Hypertension 55.6 (2010): 1311-1317.
[4] Carey, R. M., et al. “Primary aldosteronism: a perspective.” Journal of Clinical Endocrinology & Metabolism 94.12 (2009): 4559-4568.
[5] Rocha, R., et al. “Aldosterone and the heart.” Circulation Research 92.6 (2003): 609-619.
[6] Funder, J. W., et al. “The management of primary aldosteronism: case detection, diagnosis, and treatment: an endocrine society clinical practice guideline.” Journal of Clinical Endocrinology & Metabolism 93.9 (2008): 3266-3281.
[7] Rossi, G. P., et al. “Practical approach to the diagnosis of primary aldosteronism: state of the art.” Hypertension 51.6 (2008): 1440-1449.
[8] Freeman, M.W., et al. “Lorundrostat, a Novel Aldosterone Synthase Inhibitor, Effectively Lowers Blood Pressure in Patients With Treatment-Resistant Hypertension: Results From a Phase 2, Randomized, Double-Blind, Placebo-Controlled Trial.” Circulation. 2023;148:1551–1561.