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Thursday, February 4, 2021



Vasopressin, also known as antidiuretic hormone (ADH), is the key hormone involved in the regulation of water homeostasis and osmolality of body fluids. The secretion and action of vasopressin are regulated by osmotic and pressure/volume factors. Osmoreceptors continuously monitor plasma osmolality. The osmoreceptors are outside the blood–brain barrier, are located in the organum vasculosum of the lamina terminalis (adjacent to the anterior hypothalamus near the anterior wall of the third ventricle), and are perfused by fenestrated capillaries. The normal extracellular fluid osmolality determined to a major degree by serum sodium concentration varies from 282 to 287 mOsm/ kg in healthy individuals. The keys to maintaining this narrow normal range are (1) the very sensitive osmore-ceptor-regulated response of vasopressin secretion to changes in plasma osmolality, (2) the prompt response of urine osmolality to changes in plasma vasopressin, and (3) the short plasma half-life of vasopressin (~15 minutes). Thus, small increases in plasma osmolality result in a prompt increase in urine concentration, and small decreases in osmolality result in prompt water diuresis.

Plate 1-26

Over 24 hours, glomerular filtration presents 180 L of isoosmotic fluid to the proximal convoluted renal tubules. Ninety percent of the filtered water is reabsorbed in the proximal tubule without the help of vasopressin. This passive transfer of water is determined by the active reabsorption of solutes (e.g., sodium and chloride) taking along water by osmotic forces. Thus, proximal tubular urine remains isoosmotic with plasma. Distal collecting duct reabsorption of water is control- led by vasopressin. The loop of Henle and the collecting duct in the kidney are critical to water conservation. The countercurrent multiplier system in the loop of Henle generates a high osmolality in the renal medulla. The ascending, or distal, limb of Henle loop actively transports sodium without water from the tubular urine to the interstitial fluid of the renal medulla, making it very hypertonic. The water impermeability of this limb of Henle loop renders the urine entering the distal tubule hypotonic with respect to plasma. In the absence of vasopressin, the distal tubule and collecting ducts remain largely impermeable to water, and very dilute urine leaves the kidney. With maximum vasopressin secretion, urine osmolality plateaus at approximately 1000 to 1200 mOsm/kg, limited by the maximal osmolality of the inner renal medulla. When vasopressin is absent, 14 to 16 L of urine is excreted per day.

The site of action of vasopressin is the V2 receptor on the epithelial principal cells of the collecting ducts. Activation of the collecting duct V2 receptor increases water permeability to allow for osmotic equilibration between the urine and the hypertonic medullary interstitium. Thus, water is extracted from the urine into the medullary interstitial blood vessels, causing an increased urine concentration and decreased urine volume. Aquaporins are intracellular organelles, or water channels, that mediate rapid water transport across collecting duct cell membranes. V2-receptor activation by vasopressin increases intracellular cyclic adenosine monophosphate (cAMP) levels by activating adenylate cyclase. cAMP activates protein kinase A, which phosphorylates aquaporin-2 and induces a fusion of aquaporin-2–containing intracytoplasmic vesicles with the apical plasma membranes of the principal cells, thus increasing apical water permeability by markedly increasing the number of water-conducting pores in the apical plasma membrane. The aquaporin-containing vesicles are shuttled into and out of the membrane in response to changes in intracellular cAMP levels, resulting in a minute-to-minute regulation of renal water excretion in response to changes in circulating vasopressin.

Water intake is also a key factor in maintaining water homeostasis. Increases in plasma osmolality of the extracellular fluid or decreases in intravascular volume stimulate thirst. Thirst is regulated by osmoreceptors in the anterior hypothalamus and baroreceptors in the chest. The sensation of thirst is typically triggered by a 2% increase in plasma osmolality. Because of unregulated fluid ingestion (e.g., coffee, tea, soft drinks, and water from metabolized food), thirst does not represent a major regulatory mechanism and, in a typical healthy person, excess water is excreted daily by the osmoregulated secretion of vasopressin.

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