Aldosterone is a hormone that plays a key role in regulating blood pressure and electrolyte balance in the body. It is part of the renin-angiotensin-aldosterone system (RAAS) and is produced in the outer layer of the adrenal glands (the zona glomerulosa). When released into the bloodstream, aldosterone acts on the kidneys to increase reabsorption of sodium and water, while promoting the excretion of potassium. This helps maintain normal blood volume and blood pressure. There are several well-studied triggers for aldosterone release, particularly angiotensin II and serum potassium levels. Understanding the physiology of aldosterone and what stimulates its secretion can provide important clinical insights into conditions like hypertension and electrolyte disturbances.
Main Triggers of Aldosterone Release
Angiotensin II
One of the most important and potent stimulators of aldosterone release is angiotensin II. Angiotensin II is a peptide hormone that is part of the RAAS pathway. It is formed from angiotensin I through the action of angiotensin-converting enzyme (ACE). Angiotensin II acts on adrenal cells through the angiotensin II receptor type 1 (AT1 receptor) to increase intracellular calcium and stimulate aldosterone synthesis and release. Research shows that small increases in angiotensin II levels can more than double aldosterone secretion. This robust response allows angiotensin II to finely regulate aldosterone release and provides tight control over blood pressure and volume homeostasis. Drugs that inhibit ACE or block the AT1 receptor are effective at lowering blood pressure, in part by suppressing the action of angiotensin II on aldosterone release.
Serum Potassium
The concentration of potassium in the bloodstream is another potent regulator of aldosterone secretion. Aldosterone release is very sensitive even to small increases in serum potassium levels. This is because aldosterone’s main role is to increase renal potassium excretion to maintain normal serum potassium. Research shows that an increase of serum potassium of just 0.5 mmol/L can double baseline aldosterone concentrations. Adrenal cells have potassium channels that detect changes in serum potassium levels and trigger depolarization, opening voltage-gated calcium channels and increasing intracellular calcium to stimulate aldosterone synthesis and release. This elegant system allows aldosterone release to be precisely matched to serum potassium concentrations.
Other Factors That Influence Aldosterone Release
Sodium Levels
Although not as powerful of a trigger as angiotensin II or serum potassium, sodium levels do moderately influence aldosterone release. Hyponatremia tends to increase aldosterone levels to promote renal sodium retention, while hypernatremia suppresses aldosterone. However, the effect of serum sodium on aldosterone release reaches a plateau, so very high or very low sodium has little additional influence. The impact of serum sodium on aldosterone release helps maintain normal total body sodium levels.
Adrenocorticotropic Hormone (ACTH)
ACTH is produced by the anterior pituitary gland and stimulates the adrenal cortex to produce cortisol. Research shows that ACTH also mildly stimulates aldosterone synthesis and release. However, compared to angiotensin II and serum potassium, ACTH has only minimal direct influence on aldosterone secretion. This is why aldosterone levels remain relatively normal in Addison’s disease where ACTH levels are very high due to low cortisol levels.
Endothelin
Endothelins are a family of peptides produced by vascular endothelial cells that act as vasoconstrictors. Of the three endothelin isoforms, endothelin-1 (ET-1) has been shown to stimulate aldosterone release by acting directly on adrenal cells. However, the effect is modest compared to angiotensin II and serum potassium. But in certain cardiovascular diseases characterized by elevated ET-1, endothelin may contribute somewhat to increases in aldosterone levels.
Nitric Oxide
Nitric oxide (NO) is a potent vasodilator that also modestly inhibits aldosterone synthesis and release. NO activates guanylyl cyclase in adrenal glomerulosa cells, increasing cGMP, which in turn decreases intracellular calcium and limits the production of aldosterone. This may be one mechanism by which NO helps regulate blood pressure. However, the effect of NO on aldosterone secretion is relatively small at normal physiological levels.
Adrenal Androgens
The adrenal cortex secretes several androgenic hormones including dehydroepiandrosterone (DHEA), DHEA-sulfate (DHEA-S), and androstenedione. These androgenic steroids have been shown to mildly stimulate aldosterone release, likely by interacting with specific steroid receptors on the adrenal cortex. However, their effects are relatively weak.
Regulation of Aldosterone Synthesis
While angiotensin II, potassium, and the other factors stimulate aldosterone secretion by acting on the zona glomerulosa cells of the adrenal cortex, the synthesis of aldosterone itself involves several tightly regulated enzymatic steps. The main rate-limiting enzyme is aldosterone synthase, which converts corticosterone to aldosterone. The transcription of genes coding for aldosterone synthase and other enzymes involved in aldosterone biosynthesis is increased by elevated intracellular calcium, signaling induced by angiotensin II and high serum potassium being the major drivers. The lipid steroidogenic acute regulatory (StAR) protein also upregulates mitochondrial cholesterol transfer, providing more substrate for aldosterone synthesis. Through these coordinated genomic and non-genomic effects, angiotensin II and high serum potassium upregulate aldosterone biosynthetic enzymes to facilitate increased aldosterone production by the adrenal cortex.
Conditions with Elevated Aldosterone Levels
Understanding the regulators of aldosterone secretion provides insight into pathological conditions characterized by excess aldosterone production:
Primary Aldosteronism
In primary aldosteronism, also called primary hyperaldosteronism, the adrenal glands overproduce aldosterone independent of the main regulators, angiotensin II and serum potassium. This leads to hypertension, low serum potassium, and metabolic alkalosis. Primary aldosteronism can be caused by an adrenal adenoma (aldosterone-producing adenoma) or bilateral adrenal hyperplasia. Treatment involves surgical removal of the adenoma or medications to block aldosterone effects.
Congestive Heart Failure
The failing heart in congestive heart failure has decreased cardiac output leading to reduced renal perfusion. This stimulates RAAS activation to increase fluid retention. The resulting elevated angiotensin II levels cause increased aldosterone release, which contributes to hypertension and edema in congestive heart failure. Medications blocking RAAS like ACE inhibitors and AT1 receptor blockers help reduce maladaptive aldosterone secretion in these patients.
Kidney Disease
Aldosterone levels are often elevated in chronic kidney disease despite normal serum potassium concentrations. This likely occurs from aberrant RAAS activation due to impaired kidney function. The excess aldosterone promotes sodium retention and potassium excretion, contributing to hypertension and electrolyte abnormalities in kidney disease. Hyperkalemia can also develop because the kidneys cannot adequately excrete potassium loads.
Pregnancy
Aldosterone levels increase steadily throughout normal pregnancy to promote plasma volume expansion and sodium retention needed to support the developing fetus. The elevated aldosterone levels cause a physiologic increase in glomerular filtration rate and effective circulating volume to meet the demands of pregnancy. One of the drivers of increased aldosterone synthesis during pregnancy is estrogen acting directly on receptors in the zona glomerulosa.
Table Summarizing Aldosterone Regulators
| Regulator | Effect on Aldosterone Release |
|---|---|
| Angiotensin II | Potent stimulator |
| Serum potassium | Potent stimulator |
| Serum sodium | Weak stimulator |
| ACTH | Weak stimulator |
| Endothelin | Weak stimulator |
| Nitric oxide | Weak inhibitor |
| Adrenal androgens | Weak stimulator |
Conclusion
Aldosterone release is primarily stimulated by angiotensin II and serum potassium levels acting through calcium-dependent signaling pathways in the zona glomerulosa cells of the adrenal cortex. This allows precise control of aldosterone synthesis and secretion to maintain fluid and electrolyte balance. Dysregulation of aldosterone release occurs in conditions like primary aldosteronism, congestive heart failure, kidney disease, and pregnancy. A complete understanding of the regulators of aldosterone provides important clinical insight into these disorders. Use of drugs targeting the RAAS pathway has been invaluable for patients with elevated aldosterone levels due to the central role of angiotensin II as the main driver of aldosterone release under normal and pathological conditions.