Regulation of Water-Salt Balance: ADH, Aldosterone, RAAS, and ANP

General principles of water and electrolyte metabolism regulation

The body's water and electrolyte balance is maintained by the combined action of several hormones and a regulatory system: antidiuretic hormone (ADH), aldosterone, renin-angiotensin-aldosterone system (RAAS), and atrial natriuretic peptide (ANP). The main target organs are the kidneys, specifically the distal tubules and collecting ducts, where facultative reabsorption of water and ions takes place.

Antidiuretic hormone (ADH, vasopressin)

ADH is a 9-amino-acid peptide with a single disulfide bond. It is synthesized in the anterior hypothalamus, transported by the carrier protein neurophysin to the posterior pituitary, and secreted from there into the blood. The stimulus for secretion is an increase in the osmolarity of extracellular fluid, primarily a rise in sodium ion concentration.

The hormone has two types of receptors:

• V1 receptors — located in vascular smooth muscle; upon activation, they cause vasoconstriction (hence the secondary name, vasopressin);
• V2 receptors — mediate water and electrolyte function in the kidneys.

The signal through V2 receptors is transmitted via the adenylate cyclase system: cAMP levels rise, activating protein kinase A, which phosphorylates proteins that induce the transcription of aquaporin-2. Aquaporin-2 is integrated into the membrane of distal tubule and collecting duct cells, ensuring water reabsorption. In the absence of ADH, water reabsorption does not occur.

Aldosterone

Aldosterone is a mineralocorticoid synthesized from cholesterol in the zona glomerulosa of the adrenal cortex. A structural feature is the absence of the 17-OH group; 17-ketosteroids are not formed during its catabolism, which serves as a differential diagnostic sign.

Stimuli for aldosterone synthesis:

• low sodium concentration in extracellular fluid;
• high potassium ion concentration;
• activation of the renin-angiotensin system.

Aldosterone interacts with intracellular receptors and, by regulating DNA transcription, stimulates the synthesis of three groups of proteins:

• components of apical sodium channels — increasing Na⁺ influx into the cell;
• enzymes of the tricarboxylic acid (TCA) cycle — increasing ATP production;
• enzymes of Na⁺/K⁺-ATPase — enhancing Na⁺ extrusion into the blood and K⁺ influx into the cell.

The net effect is the retention of sodium and chlorides in the body, and the excretion of potassium.

Renin-angiotensin-aldosterone system (RAAS)

The RAAS is activated by a decrease in renal perfusion pressure: in hemorrhage, dehydration, renal artery stenosis, or nephrosclerosis. When pressure drops in the glomerular afferent arteriole, juxtaglomerular cells secrete renin, a proteolytic enzyme.

Cascade of transformations:

1. Renin cleaves angiotensinogen (synthesized in the liver) into angiotensin I (10 amino acids).
2. ACE (angiotensin-converting enzyme, carboxycathepsin) cleaves two amino acids from the C-terminus, forming angiotensin II (8 amino acids).

Effects of angiotensin II:

• potent vasoconstriction via the inositol phosphate system and increased intracellular Ca²⁺;
• stimulation of aldosterone secretion and, consequently, Na⁺ reabsorption;
• indirect activation of ADH secretion via hypothalamic osmoreceptors — enhancing water reabsorption;
• induction of the sensation of thirst;
• increase in circulating blood volume and blood pressure.

Clinical situations activating the RAAS: profuse vomiting, diarrhea, marked sweating, hemorrhage — conditions requiring the restoration of circulating blood volume.

Atrial natriuretic peptide (ANP)

ANP is a hormonal antagonist of the RAAS, produced by atrial cells in response to elevated pressure and stretching of the atrial wall. Its main effects aim to lower blood pressure:

• inhibition of renin secretion and blockade of the entire RAAS cascade;
• suppression of aldosterone secretion in the adrenal cortex — reducing sodium reabsorption;
• inhibition of ADH release — decreasing water reabsorption;
• direct spasmolytic action on vascular smooth muscle — vasodilation.

The cumulative result is a decrease in circulating blood volume and blood pressure.

Key points

• The primary site of action for water and electrolyte-regulating hormones is the distal tubules and collecting ducts of the kidneys.
• ADH ensures water reabsorption via V2 receptors and aquaporin-2; it causes vasoconstriction via V1 receptors.
• Aldosterone stimulates the synthesis of Na⁺ channels, TCA cycle enzymes, and Na⁺/K⁺-ATPase, retaining Na⁺ and Cl⁻ while excreting K⁺.
• The RAAS is triggered by a drop in renal perfusion pressure; the key effector is angiotensin II.
• Angiotensin II causes vasoconstriction, enhances aldosterone and ADH secretion, and triggers thirst.
• ACE is the sole enzyme that cleaves two amino acids from the C-terminus of the protein.
• ANP is secreted by the atria during elevated pressure and acts as a functional antagonist of the RAAS.
• The absence of 17-ketosteroids in aldosterone catabolism has diagnostic significance.