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Maintenance of the tonicity of extracellular fluids within a very narrow range is crucial for proper cellular function. Normal blood tonicity is maintained over a 10-fold variation in water intake by a coordinated interaction among vasopressin, thirst, and the renal system. Intravascular volume, on the other hand, is controlled mainly by the renin–angiotensin–aldosterone system and the natriuretic peptide family.

To maintain water balance, vasopressin secretion stimulates water reabsorption by the kidney, thereby reducing future water losses; and thirst stimulates water ingestion, which restores past water losses. The 2 systems work in parallel to efficiently regulate the tonicity of the extracellular fluid (Fig. 518-1). However, when both vasopressin secretion and thirst are compromised, life-threatening abnormalities in plasma osmolality can occur.

Figure 518-1

Regulation of vasopressin secretion and serum osmolality. Hyperosmolality, hypovolemia, or hypotension is sensed by osmosensors, volume sensors, or barosensors, respectively. These stimulate both vasopressin secretion and thirst. Vasopressin, acting on the kidney, causes increased reabsorption of water (antidiuresis). Thirst causes increased water ingestion. The results of these dual negative feedback loops cause a reduction in hyperosmolality or hypotension/hypovolemia.


Vasopressin (also termed antidiuretic hormone [ADH]) is a 9-amino acid peptide synthesized in hypothalamic paraventricular and supraoptic magnocellular neurons and stored in the posterior pituitary, or neurohypophysis, from where it is released into the systemic circulation (Fig. 518-2) to regulate plasma osmolality.

Figure 518-2

Vasopressin (VP) action in the kidney. [1] VP binds to the V2 receptor (V2R), causing [2] dissociation of the trimeric G protein (α, β, γ) Gs, allowing Gsα to [3] activate adenylate cyclase (AC), resulting in an increase in cyclic adenosine monophosphate (cAMP) and [4] activation of protein kinase A (PKA). The catalytic subunit of PKA phosphorylates the aquaporin-2 (AQP2) water channel, causing it to [5] aggregate as a homotetramer in the collecting duct luminal membrane, resulting in [6 and 7] an increase in water flow down its osmotic gradient from the urine into the hypertonic renal medullary interstitium containing NaCl and urea. Demeclocycline, lithium, high calcium, and low potassium interfere with these processes.

Normal blood osmolality ranges between 280 and 290 mOsm/kg H2O. An osmosensor located outside the blood-brain barrier near the anterior hypothalamus can detect as little as a 1% to 2% change in blood osmolality. When osmolality increases above a threshold of 283 mOsm/kg, vasopressin is released from the posterior pituitary at a concentration proportional to plasma osmolality, up to a maximum of 20 pg/mL when blood osmolality reaches 320 mOsm/kg.

Vasopressin is also secreted in response to a substantial decrease of at least 8% in intravascular volume or pressure. By ...

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