Regulation of Body Fluid Osmolality: Regulation of Water Balance

As described in Chapter 1 , water constitutes approximately 60% of the healthy adult human body. Body water is divided into two compartments (i.e., intracellular fluid [ICF] and extracellular fluid [ECF]), which are in osmotic equilibrium. Water intake into the body generally occurs orally, and the water ingested is absorbed into the ECF by the gastrointestinal tract. However, in clinical situations, intravenous infusion is an important route of water entry. Regardless of the route of entry (oral versus intravenous), water first enters the ECF and then equilibrates with the ICF. The kidneys are responsible for regulating water balance and under most conditions are the major route for elimination of water from the body ( Table 5.1 ). Other routes of water loss from the body include evaporation from the cells of the skin and respiratory passages. Collectively, water loss by these routes is termed insensible water loss , because people are unaware of its occurrence. The production of sweat accounts for the loss of additional water. Water loss by this mechanism can increase dramatically in a hot environment, with exercise, or in the presence of fever ( Table 5.2 ). Finally, water can be lost from the gastrointestinal tract. Fecal water loss is normally small (∼100 mL/day) but can increase dramatically with diarrhea (e.g., 20 L/day in persons with cholera). Vomiting also can cause gastrointestinal water loss.

Although water loss from sweating, defecation, and evaporation from the lungs and skin can vary depending on the environmental conditions or during pathologic conditions, the loss of water by these routes cannot be regulated. In contrast, the renal excretion of water is tightly regulated to maintain whole-body water balance. The maintenance of water balance requires that water intake and loss from the body are precisely matched. If intake exceeds losses, positive water balance exists. Conversely, when intake is less than losses, negative water balance exists.

When water intake is low or water losses increase, the kidneys conserve water by producing a small volume of urine that is hyperosmotic with respect to plasma. When water intake is high, a large volume of hypoosmotic urine is produced. In a healthy person the urine osmolality (U _osm ) can vary from approximately 50 to 1200 mOsm/kg H ₂ O, and the corresponding urine volume can vary from approximately 18 to 0.5 L/day.

It is important to recognize that disorders of water balance are manifested by alterations in the body fluid osmolality, which can be assessed by measuring plasma osmolality (P _osm ). Because the major determinant of plasma osmolality is Na ⁺ (with its anions Cl ⁻ and HCO ₃ ^– ), these disorders also result in alterations in the plasma [Na ⁺ ] ( Fig. 5.1 ). When an abnormal plasma [Na ⁺ ] is observed in an individual, it is tempting to suspect a problem in Na ⁺ balance. However, the problem usually is related to water balance, not Na ⁺ balance. As described in Chapter 6 , changes in Na ⁺ balance usually result in alterations in the volume of the ECF, not its osmolality.

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Response to changes in water balance. Illustrated are the effects of adding or removing 1 L of water from the ECF of a person weighing 70 kg. Positive water balance: (1) Addition of 1 L of water increases the ECF volume and reduces its osmolality. [Na ⁺ ] also is decreased (hyponatremia). (2) The normal renal response is to excrete 1 L of water as hypoosmotic urine. (3) As a result of the renal excretion of water, the ECF volume, osmolality, and [Na ⁺ ] are returned to normal. Negative water balance: (4) The loss of 1 L of water from the ECF decreases its volume and increases its osmolality. The [Na ⁺ ] also is increased (hypernatremia). (5) The renal response is to conserve water by excreting a small volume of hyperosmotic urine. (6) With ingestion of water, stimulated by thirst, and the conservation of water by the kidneys, the ECF volume, osmolality, and [Na ⁺ ] are returned to normal. The size of the boxes indicates the relative volume of ECF.

Under steady-state conditions, the kidneys control water excretion more or less independently of their ability to control the excretion of various other physiologically important substances ( Fig. 5.2 ). This ability allows water balance to be achieved without upsetting the other homeostatic functions of the kidneys.

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Relationships between plasma arginine vasopressin (AVP) levels and urine osmolality, urine flow rate, and total solute excretion. Max, Maximum; Min, minimum.

This chapter discusses the mechanisms by which the kidneys maintain water balance by excreting either hypoosmotic (dilute) or hyperosmotic (concentrated) urine (see Fig. 5.2 ). The control of arginine vasopressin (AVP) secretion and its important role in regulating the excretion of water by the kidneys also are explained.

Arginine Vasopressin

AVP, also known as antidiuretic hormone (ADH) , acts on the kidneys to regulate the volume and osmolality of the urine. When plasma AVP levels are low, a large volume of urine is excreted ( diuresis ) and the urine is dilute. ^a

a Diuresis is simply a large urine output. When the urine contains primarily water, it is referred to as a water diuresis, which is in contrast to the diuresis seen with the administration of diuretic agents (see Chapter 10 ). In the latter case, urine output is large, but the urine contains solute plus water, which sometimes is termed a solute diuresis

When plasma AVP levels are high, a small volume of urine is excreted ( antidiuresis ) and the urine is concentrated. Fig. 5.2 illustrates the effect of AVP on the urine flow rate and osmolality.

AVP is a small peptide that is nine amino acids long. It is synthesized in neuroendocrine cells located within the supraoptic and paraventricular nuclei of the hypothalamus. ^b

b Neurons within the supraoptic and paraventricular nuclei synthesize either AVP or the related peptide oxytocin. AVP-secreting neurons predominate in the supraoptic nucleus, and the oxytocin-secreting neurons are found primarily in the paraventricular nucleus

The synthesized hormone is packaged in granules that are transported down the axon of the neuron and stored in the nerve terminals located in the neurohypophysis (posterior pituitary). The anatomy of the hypothalamus and pituitary gland is shown in Fig. 5.3 .

The secretion of AVP by the posterior pituitary can be influenced by several factors. The two primary physiologic regulators of AVP secretion are the osmolality of the body fluids (osmotic) and volume and pressure of the vascular system (hemodynamic). Other factors that can alter AVP secretion include nausea (stimulates), atrial natriuretic peptide (inhibits), and angiotensin II (stimulates). Several drugs, prescription and nonprescription, also affect AVP secretion. For example, nicotine stimulates secretion, whereas ethanol inhibits secretion.

At the Cellular Level

The gene for arginine vasopressin (AVP) is found on chromosome 20. It contains approximately 2000 base pairs with three exons and two introns. The gene codes for a 145-amino-acid prohormone that consists of a signal peptide, the AVP molecule, neurophysin, and a glycopeptide (copeptin). As the cell processes the prohormone, the signal peptide is cleaved off in the rough endoplasmic reticulum. Once packaged in neurosecretory granules, the preprohormone is further cleaved into AVP, neurophysin, and copeptin molecules. The neurosecretory granules are then transported down the axon to the posterior pituitary and stored in the nerve endings until released. When the neurons are stimulated to secrete AVP, the action potential opens Ca ⁺⁺ channels in the nerve terminal, which raises the intracellular [Ca ⁺⁺ ] and causes exocytosis of the neurosecretory granules. All three peptides are secreted in this process. Neurophysin and copeptin do not have an identified physiologic function.

Osmotic Control of Arginine Vasopressin Secretion

Changes in the osmolality of body fluids play the most important role in regulating AVP secretion; changes as minor as 1% are sufficient to alter it significantly. Although the neurons in the supraoptic and paraventricular nuclei respond to changes in body fluid osmolality by altering their secretion of AVP, cells in the anterior hypothalamus also sense changes in body fluid osmolality and regulate the activity of the AVP-secreting neurons. These cells, termed osmoreceptors , sense changes in body fluid osmolality by either shrinking or swelling. ^c

c Osmoreceptors have been identified in the anterior hypothalamus; one of these sites is the organum vasculosum of the lamina terminalis, which is located outside the blood-brain barrier. In addition, the subfornical organ, which is also located in the anterior hypothalamus outside the blood-brain barrier, responds to circulating levels of angiotensin II, which stimulates AVP secretion.

The osmoreceptors respond only to solutes in plasma that are effective osmoles (see Chapter 1 ). For example, urea is an ineffective osmole when the function of osmoreceptors is considered. Thus elevation of the plasma urea concentration alone has little or no effect on AVP secretion.

When the effective osmolality of the plasma increases, the osmoreceptors send signals to the AVP-synthesizing/secreting cells located in the supraoptic and paraventricular nuclei of the hypothalamus, and AVP synthesis and secretion are stimulated. Conversely, when the effective osmolality of the plasma is reduced, secretion is inhibited. Because AVP is rapidly degraded in the plasma, circulating levels can be reduced to zero within minutes after secretion is inhibited. As a result, the AVP system can respond rapidly to fluctuations in body fluid osmolality.

Fig. 5.4A illustrates the effect of changes in plasma osmolality on circulating AVP levels. The set point of the system is the plasma osmolality value at which AVP secretion begins to increase. Below this set point, virtually no AVP is released. Above this set point, the slope of the relationship is quite steep and accounts for the sensitivity of this system. The set point varies among individuals and is genetically determined. In healthy adults it varies from 275 to 290 mOsm/kg H ₂ O (average ∼280 to 285 mOsm/kg H ₂ O). As described later in this chapter, the set point shifts in response to changes in blood volume and pressure. It also shifts during pregnancy, with the osmolality of the mother’s body fluids decreasing during the third trimester. The reasons for the shift of the set point during pregnancy are not completely known but likely involve hormones (e.g., relaxin and chorionic gonadotropin) whose circulating levels are elevated during pregnancy.

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