Introduction

Osmolality (or concentration of the solutes in the body fluids) is critical to organ function and must be closely regulated.

  • Disturbances in the osmolality of the body fluids arise from the gain or loss of water, or from the gain or loss of osmoles (glucose, urea, salts).

  • Accordingly, normal plasma osmolality is restored by:

    • Excretion of extra water

    • Replenishment of lost water

    • Restoration of normal amounts of solutes in the body

System structure: Body fluid compartments

Osmoregulation is coupled to the regulation of perfusion pressure, both of which are affected by shifts between the body’s fluid compartments. Instead of modulating the volume of the extracellular fluid (ECF) through variations in Na + reabsorption, however, the osmoregulatory apparatus modulates the Na + i the ECF by varying the amount of water within the total body water space. For the purposes of osmoregulation, the total body water is the compartment of interest, because water can freely move between cells and the ECF (see Fast Fact Box 20.1 ).

Fast Fact Box 20.1

Recall that in the adult, approximately 50% to 60% of body weight is water and that two-thirds of the water is within cells (the intracellular water), whereas one-third is in the extracellular fluid (ECF). The plasma volume is 1/4 of the ECF and is the most important determinant of blood pressure.

The anatomic elements that constitute the homeostatic feedback loop are fewer than those in the loop that controls ECF volume and blood pressure. The organs involved in osmoregulation are the brain and the kidney, and to a lesser extent, the intestines and the circulatory system, which act as conduits.

System function: Homeostasis of sodium concentration

Before detailing the governance of Na + concentration, it is first necessary to establish the physiologic importance of a stable Na + concentration and the challenges to the stability of plasma [Na + ]. To do that, we should review the concept of osmolality and reexamine the constitution of the body fluid compartments.

Osmolality, osmosis, and fluid shifts between body fluid compartments

Recall that molarity and molality both describe the concentration of solute in a solution, but in different units of measurement.

  • Molarity: the units of molarity are mol solute/L solution. Because volume changes with temperature, molarity is temperature-dependent.

  • Molality: the units of molality are mol solute/kg solvent. Molality is independent of temperature because it is relative to mass of solvent (see Fast Fact 20.2 ).

Fast Fact Box 20.2

Osmolarity and osmolality reflect the number of moles of solute particles in a solution, as opposed to moles of compound in a solution. So, if a solution contained 140 mmol NaCl per 1 kg water, its molality would be 140 mmol/kg. Its os molality would be 280 mOsm/kg because we would count the free-floating ions Na + and Cl separately.

Also recall that osmosis is the diffusion of water (as solvent) across a membrane from an area of low-solute concentration to an area of high-solute concentration (i.e., along a concentration gradient).

  • It is a passive process that occurs only in liquids, not gases, and obeys the second law of thermodynamics, the law of entropy.

  • The random molecular motion of the water molecules causes them to traverse the membrane in both directions. Molecules starting on the high-solute concentration side of the membrane and moving toward the membrane for crossover are obstructed in their progress by their “sticky” interactions with the excess solute.

  • Fewer water molecules make it across from the high-solute concentration side than do molecules from the low-solute concentration side. A net influx of water molecules onto the high-solute concentration side occurs.

  • The influx of water from the high-solute concentration side stops when the solute concentrations on each side are equal—that is, when the amount of solute obstructing water efflux is equal on both sides. The rate of efflux is the same on both sides, and osmotic equilibrium is reached.

Osmotic pressure

The osmolarity or osmolality of the compartments on either side of a membrane is what determines the compartments’ osmotic pressure, which is a reflection of how much water that compartment will draw into it through osmosis.

  • With 1 mmol/kg of glucose on one side of a membrane and 1 mmol/kg NaCl on the other, water will diffuse into the NaCl side because that side’s osmolality is twice as high.

  • Osmosis is sensitive to the number of free dissolved particles and does not distinguish between different molecular species like Na + and Cl .

Effective osmoles

Note that in the situations considered in the preceding paragraph, the osmoles of solute may or may not be able to cross the membrane. If the osmoles of solute could cross the membrane freely, as water does, the solute would distribute evenly, and there would no longer be a concentration gradient to drive osmosis. Such solutes (e.g., ethanol and urea) are not effective osmoles because they do not create osmotic pressure.

Effective osmoles cannot freely diffuse across membranes; their movement is determined by the presence of pumps and the distribution of channels.

  • Examples of effective osmoles are the solutes Na + , K + , and Cl .

  • The pumps and channels keep Na + mostly outside of cells and K + mostly inside of cells as effective osmoles (see Fig. 1.5 ) (see Clinical Correlation Box 20.1 ).

    Fig. 20.1, The hypothalamus and pituitary. Osmoreceptors in the hypothalamus project their axons into the posterior pituitary, also known as the neurohypophysis. The termini of these axons secrete antidiuretic hormone. Circumventricular organs, such as the subfornical organ, also participate in osmoreception and thirst generation.

Clinical Correlation Box 20.1

In a diabetic patient, when glucose cannot freely enter cells because of low insulin levels, glucose becomes an effective osmole, attracting water from cells to the extracellular fluid (ECF).

Aquaporins

It is also important to note that just as the body limits the diffusion of solutes, in some cases, it can limit the diffusion of its primary solvent; although water freely crosses most cell membranes in the body, this is not the case universally.

  • The default state of the cell membrane is relatively low permeability to water.

    • Recall that the interior of the cell membrane phospholipid bilayer is nonpolar and hydrophobic.

  • Consequently, ions can cross membranes only via channels, and a polar molecule like H 2 O only crosses the membrane to a limited extent without a channel.

    • The permeability of cells to water is greatly increased by water channels called aquaporins in the membrane.

    • Permeability to water increases in proportion to the number of these channels.

    • Different tissues have various densities and types of aquaporins, so their cells may be more or less water permeable than others.

      • The proximal tubule, descending limb of Henle, has high water permeability at all times associated with aquaporin-1.

      • Cells in the tip of Henle’s loop, transitioning from descending to ascending limb, abruptly lose aquaporin-1 in the lumenal membranes.

      • Some tissues are practically impermeable to water, like the ascending limb of Henle’s loop, and some have a low permeability, greatly augmented by vasopressin through the type 2 vasopressin receptor which regulates the insertion and removal of aquaporin-2 into the lumenal membrane of distal nephron cells after the distal convoluted tubule.

Fluid shifts

What are the implications of the fact that the body fluid compartments (ECF and intracellular fluid [ICF]; see Fig. 8.1 ) are in general freely permeable to water and contain effective osmoles Na + in the ECF and K + in the ICF?

  • First, the free movement of water means that the ECF and ICF always come to osmotic equilibrium and achieve equal osmolality, because when the osmolality changes on one side of the membrane, water shifts until the solute concentrations are equal.

  • Second, the presence of effective osmoles means that osmotic pressure can be created on one side of the membrane.

An increase or decrease in [Na + ] in the ECF will cause fluid shifts between ECF and ICF.

  • Ingesting a salty meal adds salt to the ECF, raising the ECF osmolality. Fluid moves from the ICF into the ECF, shrinking the ICF volume and expanding the ECF volume.

  • Adding isotonic saline to the ECF (i.e., adding NaCl in solution with the same osmolality as the ECF) will increase the size of the ECF but no fluid shift will occur, so ICF volume will stay the same.

  • Drinking water adds pure water to the ECF, dropping the ECF osmolality, so some fluid will shift from the ECF to the ICF. ECF and ICF volume both expand slightly (in proportion to the relative volume of ICF and ECF). Because only changes in the level of effective osmoles in the ECF can produce such fluid shifts, fluid shifts do not necessarily correlate with the total osmolality of the ECF, but only with the osmolality of the effective osmoles, most importantly Na + .

Tonicity refers to the effect that a particular solute concentration has on cell volume.

  • Hypertonic ECF will lead to cell shrinkage, an isotonic ECF no change at all in ICF.

  • Hypotonic ECF will expand cell volume.

The physiologic importance of maintaining constant plasma osmolality

The body encounters daily changes in ECF osmolality relative to ICF as a consequence of variations in water elimination and intake.

  • If the body had no means of regulating the plasma osmolality, fluid shifts would occur unopposed between the ECF and ICF.

  • The body would not be able to tolerate those fluid shifts, which create swelling or shrinkage of the ICF volume and hence, of the cells. This can be catastrophic, particularly in the brain.

Thus when the body’s sensors detect that a fluid shift has begun to occur, which indicates a change in ECF osmolality, effector mechanisms restore normal ECF osmolality. This reverses the fluid shift and protects the ICF from expansion or contraction.

Physiologic challenges to osmolality homeostasis

In the normal state, fluids lost from or added to the ECF are usually hypotonic.

  • When hypotonic fluid is lost, water is lost in excess of solute and the plasma solute concentration increases.

  • When hypotonic fluid is added to the plasma, its solute concentration decreases.

The osmoregulatory apparatus of the kidney and brain modulates water elimination and intake to maintain constant osmolality.

A variety of physiologic processes involve exchanges of hypotonic fluid with the external environment ( Table 20.1 ). Water may be lost in:

  • Excess of solute in the stool.

  • Evaporation from the respiratory tract (in this case, the loss is all water and no solute).

  • Hypotonic fluid of sweat, which is produced in connection with the hypothalamic regulation of body temperature

  • Excretion of nitrogenous wastes requires a minimal level of urinary water loss that concentrates the plasma.

TABLE 20.1
Physiologic Challenges to Osmolality Homeostasis a
Adopted from Rose BD, Post TW. Clinical Physiology of Acid-Base and Elecirolyte Disorders . 5th Edition. New York: McGraw-Hill; 2001. Table 9-1. The figure 7000 mL/day comes from Smith H., p. 161.
Source of Unregulated Water Loss From ECF Volume
Stool 200 mL/day
Respiratory tract 400 mL/day
Urine 500 mL/day is the minimum loss of water to urine for excretion of nitrogenous wastes.
Skin Evaporation 500 mL/day evaporates from skin and mucous membranes under any circumstances.
Sweat under circumstances of elevated body temperature, up to 7000 mL water/day or more can be lost to sweat.
Source of Unregulated Water Addition to ECF Volume (mL/day)
Dietary Habitual drinking 1000 b
Eating (preformed water) 850
Metabolic (oxidative phosphorylation) 350
Rose and Post estimate total average water consumption at 400 to 1400 mL/day.

a The table does not include urinary losses of hypotonic fluid that occur as a part of osmoregulation, as those losses respond to the unregulated additions of water to the ECF. The table also does not include ADH-mediated additions to the ECF, or water ingested due to thirst, because these additions respond to, and should be differentiated from, the unregulated losses from the ECF.

b Obviously, habitual and social water ingestion is highly variable from person to person. It is also difficult to distinguish habitual drinking fron osmoregulatory (thirst-stimulated) drinking quantitatively.

Unregulated additions of water to the ECF occur through drinking and the ingestion of food, which has a water content that can approach 1 L/day.

  • The water inside dietary food is sometimes called preformed water.

  • Unregulated additions of water to the ECF also occur metabolically. Recall from biochemistry that oxidative phosphorylation is the means by which the reduced cofactors of the citric acid cycle are aerobically transduced to adenosine triphosphate (ATP). This process consumes oxygen and yields H 2 O on an ongoing basis in every aerobic cell. Water produced from oxidative phosphorylation is sometimes called metabolic water (see Fast Fact 20.3 ).

Fast Fact Box 20.3

Approximately 20 mol of water (and CO 2 ) may be produced per day normally in an adult. Because water is 55 mol/L, water production is approximately 20/55 of a liter, or close to 400 mL/day.

Obligatory water loss in the excretion of nitrogenous wastes

It may not seem immediately obvious why urinary excretion of nitrogenous wastes causes an obligatory concentration of the plasma. If the urine is even more concentrated than the blood (plasma osmolality is around 280 mOsm/kg, whereas maximum urine concentration is around 1200 mOsm/kg), how can hypotonic fluid be lost in the urine?

To understand this better, we must first understand the obligation to excrete nitrogenous wastes.

  • The digestion of dietary proteins yields amino acids.

  • Some of these amino acids are used in protein synthesis, whereas others are metabolized to nitrogen-free compounds (such as pyruvate) that may yield energy through the citric acid cycle.

  • Hence metabolism of amino acids requires their deamination and yields the toxic substance, ammonia (NH 3 ).

  • The liver combines NH 3 with CO 2 to make the less-toxic substance, urea (NH 2 -CO-NH 2 ), but urea must also be eliminated, lest it have toxic effects, particularly on the brain.

  • One of the kidney’s important functions is to excrete urea.

If urea is to be excreted from the body in solution, it must be transported in a certain amount of water donated from the plasma.

  • The plasma must donate a hypotonic volume of water for this purpose so that this volume of water can be loaded with osmoles of urea.

  • If the plasma donated an isotonic volume of water, the body would waste excess salt in urea excretion and compromise extracellular fluid volume.

  • The maximal osmolality of human urine is about 1200 mOsm/kg; 600 mOsm can be excreted in a half liter of water. About half of this amount of normal osmole excretion is urea.

  • Thus the plasma must donate a minimum level of hypotonic fluid to urine to excrete urea in solution. Around 10 mL of water is required for every gram of metabolized protein, meaning that a minimum of approximately 500 mL water/day must be lost to the urine.

Low-protein diets can help reduce this obligatory urinary water loss. Even on a protein-free diet, however, the kidney has excretory duties that require water to transport wastes from the body. The absolute lower limit of obligatory water loss on a protein-free diet is about 300 mL water/day.

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