MOA of AldosteroneMOA of Aldosterone

Mechanism of Action of Aldosterone

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Introduction

Aldosterone is a mineralocorticoid hormone synthesized in the zona glomerulosa of the adrenal cortex. It plays a vital role in maintaining electrolyte balance, blood volume, and blood pressure through regulation of sodium and potassium homeostasis. Mechanism of Action of Aldosterone involves binding to intracellular mineralocorticoid receptors (MR) in epithelial cells of the distal nephron, leading to increased sodium reabsorption and potassium secretion. Its effects are critical in the renin–angiotensin–aldosterone system (RAAS) and are essential for fluid balance and cardiovascular stability.

Mechanism of action of Aldosterone
Aldosterone pharmacology
Aldosterone pharmacology
Hormonal regulation of sodium and potassium by Aldosterone

Mechanism of Action (Step-wise)

  1. Hormone Release and Circulation
    • Aldosterone secretion is stimulated by angiotensin II, elevated plasma potassium, and adrenocorticotropic hormone (ACTH).
    • It travels through the bloodstream bound to plasma proteins such as albumin and corticosteroid-binding globulin.
  2. Receptor Binding
    • In the distal convoluted tubule and collecting duct of the nephron, aldosterone diffuses through the cell membrane and binds to intracellular mineralocorticoid receptors (MR) in the cytoplasm.
  3. Gene Transcription Activation
    • The aldosterone–receptor complex translocates to the nucleus, where it binds to specific DNA response elements.
    • This triggers transcription of genes encoding epithelial sodium channels (ENaC) and Na⁺/K⁺-ATPase pumps.
  4. Protein Synthesis and Cellular Changes
    • Newly synthesized ENaC channels are inserted into the luminal membrane.
    • Na⁺/K⁺-ATPase pumps are upregulated on the basolateral side of tubular cells.
  5. Physiological Effects
    • Increased sodium reabsorption from tubular fluid into the bloodstream.
    • Increased potassium excretion into the urine.
    • Water retention secondary to sodium reabsorption, leading to increased extracellular fluid volume and blood pressure.
  6. Overall Effect
    • Conserves sodium and water.
    • Promotes potassium excretion.
    • Maintains intravascular volume and arterial pressure.
Stepwise mechanism of action of Aldosterone FlowchART
Aldosterone MOA Flowchart

Pharmacokinetics

  • Source: Endogenously secreted steroid hormone.
  • Half-life: Approximately 15–20 minutes in plasma.
  • Metabolism: Rapid hepatic metabolism to tetrahydroaldosterone and conjugates.
  • Excretion: Metabolites eliminated via urine.
  • Receptor type: Nuclear/cytosolic receptor (acts via gene transcription).

Clinical Importance

  • Physiological role: Electrolyte and fluid balance via the RAAS pathway.
  • Deficiency: Seen in Addison’s disease (adrenal insufficiency) — results in hyponatremia, hyperkalemia, and hypotension.
  • Excess: Seen in primary hyperaldosteronism (Conn’s syndrome) — causes hypertension, hypokalemia, and metabolic alkalosis.
  • Therapeutic modulation:
    • Agonists: Fludrocortisone (synthetic mineralocorticoid).
    • Antagonists: Spironolactone, Eplerenone — used in heart failure, hypertension, and hyperaldosteronism.

Adverse Effects of Excess Aldosterone

  • Hypertension due to sodium and water retention.
  • Hypokalemia → muscle weakness, arrhythmias.
  • Metabolic alkalosis.
  • Cardiac remodeling and fibrosis in chronic cases.

Comparative Analysis

FeatureAldosteroneCortisolSpironolactone (Antagonist)
SourceZona glomerulosa (adrenal cortex)Zona fasciculataSynthetic drug
Primary receptorMineralocorticoid receptor (MR)Glucocorticoid receptor (GR)Mineralocorticoid receptor antagonist
Main actionNa⁺ retention, K⁺ excretionGlucose metabolism, stress responseK⁺ retention, Na⁺ loss
Effect on BPIncreasesMild increaseDecreases
Clinical correlationRAAS control, BP regulationStress and metabolismTreatment of hyperaldosteronism

MCQs

1. Aldosterone is secreted from which part of the adrenal gland?
a) Zona fasciculata
b) Zona glomerulosa
c) Zona reticularis
d) Medulla

Answer: b) Zona glomerulosa

2. Aldosterone acts on which part of the nephron?
a) Proximal tubule
b) Loop of Henle
c) Distal convoluted tubule and collecting duct
d) Glomerulus

Answer: c) Distal convoluted tubule and collecting duct

3. The main effect of aldosterone is:
a) Sodium excretion and potassium retention
b) Sodium retention and potassium excretion
c) Both sodium and potassium retention
d) Sodium excretion only

Answer: b) Sodium retention and potassium excretion

4. The receptor for aldosterone is located in the:
a) Cell membrane
b) Cytoplasm/nucleus
c) Synaptic cleft
d) Extracellular matrix

Answer: b) Cytoplasm/nucleus

5. Aldosterone increases expression of which transport protein?
a) Na⁺/K⁺-ATPase
b) Ca²⁺ channels
c) H⁺/K⁺-ATPase
d) Glucose transporter

Answer: a) Na⁺/K⁺-ATPase

6. Which of the following stimulates aldosterone secretion?
a) Low potassium
b) High sodium
c) Angiotensin II
d) Low ACTH

Answer: c) Angiotensin II

7. The main mechanism of hypertension in hyperaldosteronism is:
a) Increased cardiac output
b) Increased sodium and water reabsorption
c) Decreased peripheral resistance
d) Increased renin release

Answer: b) Increased sodium and water reabsorption

8. Which drug blocks aldosterone receptors?
a) Spironolactone
b) Furosemide
c) Hydrochlorothiazide
d) Metoprolol

Answer: a) Spironolactone

9. The half-life of aldosterone is approximately:
a) 5 minutes
b) 15–20 minutes
c) 1 hour
d) 12 hours

Answer: b) 15–20 minutes

10. Which condition is associated with aldosterone deficiency?
a) Addison’s disease
b) Cushing’s syndrome
c) Diabetes insipidus
d) Pheochromocytoma

Answer: a) Addison’s disease

FAQs

Q1. How does aldosterone increase blood pressure?
It promotes sodium and water reabsorption, increasing blood volume and consequently blood pressure.

Q2. What stimulates aldosterone secretion?
Mainly angiotensin II, elevated plasma potassium, and to a lesser extent, ACTH.

Q3. How does aldosterone differ from cortisol?
Aldosterone primarily regulates electrolytes, while cortisol regulates metabolism and stress responses.

Q4. What happens in hyperaldosteronism?
Excess aldosterone leads to hypertension, hypokalemia, and metabolic alkalosis.

Q5. What drugs inhibit aldosterone action?
Spironolactone and eplerenone — both are mineralocorticoid receptor antagonists.

Q6. Can aldosterone deficiency cause dehydration?
Yes, due to excessive sodium and water loss in urine.

References

  • Goodman & Gilman’s The Pharmacological Basis of Therapeutics
  • Katzung’s Basic and Clinical Pharmacology
  • Harrison’s Principles of Internal Medicine
  • Guyton & Hall Textbook of Medical Physiology

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