Water transport is driven by osmotic and hydrostatic pressure differences across membranes
Transport of water across biological membranes is always passive. No H2O pumps have ever been described. N5-21 To a certain extent, single H2O molecules can dissolve in lipid bilayers and thus move across cell membranes at a low but finite rate by simple diffusion. The ease with which H2O diffuses through the lipid bilayer depends on the lipid composition of the bilayer. Membranes with low fluidity (see p. 10)—that is, those whose phospholipids have long saturated fatty-acid chains with few double bonds (i.e., few kinks)—exhibit lower H2O permeability. The addition of other lipids that decrease fluidity (e.g., cholesterol) may further reduce H2O permeability. Therefore, it is not surprising that the plasma membranes of many types of cells have specialized H2O channels—the AQPs—that serve as passive conduits for H2O transport. The presence of AQPs greatly increases membrane H2O permeability. In some cells, such as erythrocytes or the renal proximal tubule, AQP1 is always present in the membrane. The collecting-duct cells of the kidney regulate the H2O permeability of their apical membranes by inserting AQP2 H2O channels into their apical membranes under the control of arginine vasopressin.
The Water-Pump Controversy
Contributed by Emile Boulpaep, Walter Boron
Loo and colleagues have proposed that the Na/glucose cotransporter SGLT1 in the human small intestine cotransports not only Na+ and glucose, but water as well. In other words, with each cycle, SGLT1 would move 2 Na+ ions, 1 glucose molecule, and >200 water molecules. The authors envisage that the Na+ ions and glucose molecule—along with the water molecules—would diffuse from the extracellular fluid into a pore within the cotransporter protein. The cotransporter would then undergo a conformational change that would close an outer gate and thereby occlude these ions and molecules from the extracellular fluid. By opening an inner gate, the cotransporter would deocclude these particles and allow the 2 Na+ ions, the glucose molecule, and the 200+ water molecules to enter the cytoplasm of the intestinal cell (i.e., enterocyte). There is no controversy that this general model—minus the water—explains how SGLT1 works. The question is whether each cycle of the cotransporter also moves a fixed number of water molecules through the membrane protein along with the Na+ and glucose. Loo and colleagues suggest that the water pumped by SGLT1 would account for about half of the water taken up by the small intestine.
On the other hand, Lapointe and colleagues have challenged the conclusion of Loo and colleagues, suggesting that the data of Loo and colleagues can more easily be explained by the classical model. That is, as SGLT1 cotransport Na+ and glucose from the extracellular to the intracellular fluid, water would follow osmotically.
Lapointe J-Y, Gagnon M, Poirier S, Bissonnette P. The presence of local osmotic gradients can account for the water flux driven by the Na+–glucose cotransporter. J Physiol. 2002;542:61–62.
Loo DDF, Wright EM, Zeuthen T. Water pumps. J Physiol. 2002;542:53–60.
Loo DDF, Zeuthen T, Chandy G, Wright EM. Cotransport of water by the Na+/glucose cotransporter. Proc Natl Acad Sci U S A. 1996;93:13367–13370.
Water transport across a membrane is always a linear, nonsaturable function of its net driving force. The direction of net passive transport of an uncharged solute is always down its chemical potential energy difference. For H2O, we must consider two passive driving forces. The first is the familiar chemical potential energy difference (), which depends on the difference in water concentration on the two sides of the membrane. The second is the energy difference, per mole of H2O, that results from the difference in hydrostatic pressure () across the membrane. Thus, the relevant energy difference across the membrane is the sum of the chemical and pressure potential energy differences:
P is the hydrostatic pressure and is the partial molar volume of H2O (i.e., volume occupied by 1 mole of H2O). Because the product of pressure and volume is work, the second term in Equation 5-23 is work per mole. Dealing with H2O concentrations is cumbersome and imprecise because [H2O] is very high (i.e., ~56 M) and does not change substantially in the dilute solutions that physiologists are interested in. Therefore, it is more practical to work with the inverse of [H2O], namely, the concentration of osmotically active solutes, or osmolality. N5-21 The units of osmolality are osmoles per kilogram of H2O, or Osm. In dilute solutions, the H2O gradient across the cell membrane is roughly proportional to the difference in osmolalities across the membrane:
where Osm is the total concentration of all osmotically active solutes in the indicated compartment (e.g., Na+ + Cl− + K+ + …). Substituting Equation 5-24 into Equation 5-23 yields a more useful expression for the total energy difference across the membrane:
In this equation, the terms inside the brackets have the units of pressure (force per area) and thus describe the driving force for H2O movement from the inside to the outside of the cell. This driving force determines the flux of H2O across the membrane:
JV is positive when H2O flows out of the cell and has the units of L/(cm2 ⋅ s). The proportionality constant Lp is the hydraulic conductivity.
Water is in equilibrium across the membrane when the net driving force for H2O transport is nil. If we set to zero in Equation 5-25:
The term on the left is referred to as the osmotic pressure difference (Δπ). Thus, at equilibrium the osmotic pressure difference is equal to the hydrostatic pressure difference (ΔP). An osmotic pressure difference of 1 milliosmole/kg H2O (or 1 mOsm) is equivalent to a hydrostatic pressure difference of 19.3 mm Hg at normal body temperature.
The plasma membranes of animal cells are not rigid (unlike the walls of plant cells) and cannot tolerate any significant hydrostatic pressure difference without deforming. Therefore, the hydrostatic pressure difference across a cell membrane is virtually always near zero and is therefore not a significant driving force for H2O transport.
Movement of H2O in and out of cells is driven by osmotic gradients only, that is, by differences in osmolality across the membrane. For example, if the osmolality is greater outside the cell than inside, H2O will flow out of the cell and the cell will shrink. Such a movement of H2O driven by osmotic gradients is called osmosis. H2O is at equilibrium across cell membranes only when the osmolality inside and outside the cell is the same.
Hydrostatic pressure differences are an important force for driving fluid out across the walls of capillaries (see p. 468). Small solutes permeate freely across most capillaries. Thus, any difference in osmotic pressure as a result of these small solutes does not exert a driving force for H2O flow across that capillary. The situation is quite different for plasma proteins, which are too large to penetrate the capillary wall freely. As a result, the presence of a greater concentration of plasma proteins in the intravascular compartment than in interstitial fluid sets up a difference in osmotic pressure that tends to pull fluid back into the capillary. This difference is called the colloid osmotic pressure or oncotic pressure. H2O is at equilibrium across the wall of a capillary when the colloid osmotic and hydrostatic pressure differences are equal. When the hydrostatic pressure difference exceeds the colloid osmotic pressure difference, the result is movement of H2O out of the capillary, called ultrafiltration.
Because of the presence of impermeant, negatively charged proteins within the cell, Donnan forces will lead to cell swelling
NaCl, the most abundant salt in ECF, is largely excluded from the intracellular compartment by the direct and indirect actions of the Na-K pump. This relative exclusion of NaCl from the intracellular space is vital for maintaining normal cell H2O content (i.e., cell volume). In the absence of Na-K pumps, cells tend to swell even when both the intracellular and extracellular osmolalities are normal and identical. This statement may appear to contradict the principle that there can be no H2O flux without a difference in osmolality across the cell membrane (see Equation 5-26). To understand this apparent paradox, consider a simplified model that illustrates the key role played by negatively charged, impermeant macromolecules (i.e., proteins) inside the cell (Fig. 5-15).
FIGURE 5-15 Gibbs-Donnan equilibrium. A semipermeable membrane separates two compartments that have rigid walls and equal volumes. The membrane is permeable to Na+, Cl−, and water, but not to the macromolecule Y, which carries 150 negative charges. The calculations of ψi and P assume a temperature of 37°C.
Imagine that a semipermeable membrane separates a left compartment (analogous to the extracellular space) and a right compartment (analogous to the intracellular space). The two compartments are rigid and have equal volumes throughout the experiment. The right compartment is fitted with a pressure gauge. The membrane is nondeformable and permeable to Na+, Cl−, and H2O, but it is not permeable to a negatively charged macromolecule (Y). For the sake of simplicity, assume that each Y carries 150 negative charges and is restricted to the intracellular solution. Figure 5-15A illustrates the ionic conditions at the beginning of the experiment. At this initial condition, the system is far out of equilibrium; although [Na+] is the same on both sides of the membrane, [Cl−] and [Y−150] have opposing concentration gradients of 150 mM.
What will happen now? The system will tend toward equilibrium. Cl− will move down its concentration gradient into the cell. This entry of negatively charged particles will generate an inside-negative membrane voltage, which in turn will attract Na+ and cause Na+ to move into the cell. In the final equilibrium condition, both Na+ and Cl− will be distributed so that the concentration of each is balanced against the same Vm, which is given by the Nernst equation (Equation 5-8):
Because Vm must be the same in the two cases, we combine the two equations, obtaining
where r is the Donnan ratio because this equilibrium state is a Gibbs-Donnan equilibrium (often shortened to Donnan equilibrium). All the values for ionic concentrations in Equation 5-30 are new values. As Na+ entered the cell, not only did [Na+]i rise but [Na+]o also fell, by identical amounts. The same is true for Cl−. How much did the Na+ and Cl− concentrations have to change before the system achieved equilibrium? An important constraint on the system as it approaches equilibrium is that in each compartment, the total number of positive charges must balance the total number of negative charges (bulk electroneutrality) at all times. Imagine an intermediate state, between the initial condition and the final equilibrium state, in which 10 mM of Na+ and 10 mM of Cl− have moved into the cell (see Fig. 5-15B). This condition is still far from equilibrium because the Na+ ratio in Equation 5-30 is 0.875, whereas the Cl− ratio is only 0.071; thus, these ratios are not equal. Therefore, Na+ and Cl− continue to move into the cell until the Na+ ratio and the Cl− ratio are both 0.5, the Donnan r ratio (see Fig. 5-15C). This final ratio corresponds to Nernst potentials of −18.4 mV for both Na+ and Cl−.
However, although the ions are in equilibrium, far more osmotically active particles are now on the inside than on the outside. Ignoring the osmotic effect of Y−150, the sum of [Na+] and [Cl−] on the inside is 250 mM, whereas it is only 200 mM on the outside. Because of this 50-mOsm gradient (ΔOsm) across the membrane, H2O cannot be at equilibrium and will therefore move into the cell. In our example, the right (inside) compartment is surrounded by a rigid wall so that only a minuscule amount of H2O needs to enter the cell to generate a hydrostatic pressure of 967 mm Hg to oppose the additional net entry of H2O. This equilibrium hydrostatic pressure difference (ΔP) opposes the osmotic pressure difference (Δπ):
Thus, in the rigid “cell” of our example, achieving Gibbs-Donnan equilibrium would require developing within the model cell a hydrostatic pressure that is 1.3 atm greater than the pressure in the left compartment (outside).
The Na-K pump maintains cell volume by doing osmotic work that counteracts the passive Donnan forces
Unlike in the preceding example, the plasma membranes of animal cells are not rigid but deformable, so that transmembrane hydrostatic pressure gradients cannot exist. Thus, in animal cells, the distribution of ions toward the Donnan equilibrium condition would, it appears, inevitably lead to progressive water entry, cell swelling, and, ultimately, bursting. Although the Donnan equilibrium model is artificial (e.g., it ignores all ions other than Na+, Cl−, and Y−150), it nevertheless illustrates a point that is important for real cells: the negative charge on impermeant intracellular solutes (e.g., proteins and organic phosphates) will lead to bursting unless the cell does “osmotic work” to counteract the passive Donnan-like swelling. The net effect of this osmotic work is to largely exclude NaCl from the cell and thereby make the cell functionally impermeable to NaCl. In a sense, NaCl acts as a functionally impermeant solute in the extracellular space that offsets the osmotic effects of intracellular negative charges. This state of affairs is not an equilibrium but a steady state maintained by active transport.
As an illustration of the role of active transport, consider a somewhat more realistic model of a cell (Fig. 5-16). Under “normal” conditions, [Na+]i, [K+]i, and [Cl−]i are constant because (1) the active extrusion of three Na+ ions in exchange for two K+ ions is balanced by the passive influx of three Na+ ions and the passive efflux of two K+ ions, and (2) the net flux of Cl− is zero (i.e., we assume that Cl− is in equilibrium). When the Na-K pump is inhibited, the passive entry of three Na+ ions exceeds the net passive efflux of two K+ ions and thereby results in a gain of one intracellular cation and an immediate small depolarization (i.e., the cell becomes less negative inside). In addition, as intracellular [K+] slowly declines after inhibition of the Na-K pump, the cell depolarizes even further because the outward K+ gradient is the predominant determinant of the membrane voltage. The inside-negative Vm is the driving force that is largely responsible for excluding Cl− from the cell, and depolarization of the cell causes Cl− to enter through anion channels. Cl− influx results in the gain of one intracellular anion. The net gain of one intracellular cation and one anion increases the number of osmotically active particles and in so doing creates the inward osmotic gradient that leads to cell swelling. Thus, in the normal environment in which cells are bathed, the action of the Na-K pump is required to prevent the cell swelling that would otherwise occur.
FIGURE 5-16 Role of the Na-K pump in maintaining cell volume.
A real cell, of course, is far more complex than the idealized cell in Figure 5-16, having myriad interrelated channels and transporters (see Fig. 5-14). These other pathways, together with the Na-K pump, have the net effect of excluding NaCl and other solutes from the cell. Because the solute gradients that drive transport through these other pathways ultimately depend on the Na-K pump, inhibiting the Na-K pump will de-energize these other pathways and lead to cell swelling.
Cell volume changes trigger rapid changes in ion channels or transporters, returning volume toward normal
The joint efforts of the Na-K pump and other transport pathways are necessary for maintaining normal cell volume. What happens if cell volume is acutely challenged? A subset of “other pathways” respond to the cell volume change by transferring solutes across the membrane, thereby returning the volume toward normal.
Response to Cell Shrinkage
If we increase extracellular osmolality by adding an impermeant solute such as mannitol (Fig. 5-17A), the extracellular solution becomes hyperosmolal and exerts an osmotic force that draws H2O out of the cell. The cell continues to shrink until the osmolality inside and out becomes the same. Many types of cells respond to this shrinkage by activating solute uptake processes to increase cell solute and H2O content. This response is known as a regulatory volume increase (RVI). Depending on the cell type, cell shrinkage activates different types of solute uptake mechanisms. In many types of cells, shrinkage activates the ubiquitous NHE1 isoform of the Na-H exchanger. In addition to mediating increased uptake of Na+, extrusion of H+ alkalinizes the cell and consequently activates Cl-HCO3 exchange. The initial net effect is the entry of Na+ and Cl−. However, the Na-K pump then extrudes the Na+ in exchange for K+, so that the final net effect is the gain of intracellular KCl. The resulting increase in intracellular osmoles then draws H2O into the cell to restore cell volume toward normal. Alternatively, the RVI response may be mediated by activation of the NKCC1 isoform of the Na/K/Cl cotransporter.
FIGURE 5-17 Short-term regulation of cell volume.
Response to Cell Swelling
If extracellular osmolality is decreased by the addition of H2O (see Fig. 5-17B), the extracellular solution becomes hypo-osmolal and exerts a lesser osmotic force so that H2O moves into the cell. The cell continues to swell until the osmolality inside and out becomes the same. Many cell types respond to this swelling by activating solute efflux pathways to decrease cell solute and H2O content and thereby return cell volume toward normal. This response is known as a regulatory volume decrease (RVD). Depending on the cell type, swelling activates different types of solute efflux mechanisms. In many types of cells, swelling activates Cl− or K+ channels (or both). Because the electrochemical gradients for these two ions are generally directed outward across the plasma membrane, activating these channels causes a net efflux of K+ and Cl−, which lowers the intracellular solute content and causes H2O to flow out of the cell. The result is restoration of cell volume toward normal. Alternatively, the RVD response may be initiated by activating the K/Cl cotransporter.
In the normal steady state, the transport mechanisms that are responsible for RVI and RVD are usually not fully quiescent. Not only does cell shrinkage activate the transport pathways involved in RVI (i.e., solute loaders), it also appears to inhibit at least some of the transport pathways involved in RVD (i.e., solute extruders). The opposite is true of cell swelling. In all cases, the Na-K pump ultimately generates the ion gradients driving the movements of NaCl and KCl that regulate cell volume in response to changes in extracellular osmolality (Box 5-1).
Disorders of Extracellular Osmolality
Regulatory adjustments in cell volume can be extremely important clinically. In major disorders of extracellular osmolality, the principal signs and symptoms arise from abnormal brain function, which can be fatal. For example, it is all too common for the elderly or infirm, unable to maintain proper fluid intake because of excessive heat or disability, to be brought to the emergency department in a state of severe dehydration. The hyperosmolality that results from dehydration can lead to brain shrinkage, which in extreme cases can cause intracerebral hemorrhage from tearing of blood vessels. If the brain cells compensate for this hyperosmolality by the long-term mechanisms discussed (e.g., manufacturing of idiogenic osmoles), cell shrinkage may be minimized. However, consider the consequence if an unsuspecting physician, unaware of the nuances of cell volume regulation, rapidly corrects the elevated extracellular hyperosmolality back down to normal. Rapid H2O entry into the brain cells will cause cerebral edema (i.e., brain swelling) and may result in death from herniation of the brainstem through the tentorium. For this reason, severe disturbances in ECF osmolality must usually be corrected slowly.
Cells respond to long-term hyperosmolality by accumulating new intracellular organic solutes
Whereas the acute response (seconds to minutes) to hyperosmolality (i.e., RVI) involves the uptake of salts, long-term adaptation (hours to days) to hyperosmolality involves accumulation of organic solutes (osmolytes) within the cell. Examples of such intracellularly accumulated osmolytes include two relatively impermeant alcohol derivatives of common sugars (i.e., sorbitol and inositol) as well as two amines (betaine and taurine). Generation of organic solutes (idiogenic osmoles) within the cell plays a major role in raising intracellular osmolality and restoring cell volume during long-term adaptation to hyperosmolality—a response that is particularly true in brain cells. Sorbitol is produced from glucose by a reaction that is catalyzed by the enzyme aldose reductase. Cell shrinkage is a powerful stimulus for the synthesis of aldose reductase.
In addition to synthesizing organic solutes, cells can also transport them into the cytosol from the outside. For example, cells use distinct Na+-coupled cotransport systems to accumulate inositol, betaine, and taurine. In some types of cells, shrinkage induces greatly enhanced expression of these transporters, thereby leading to the accumulation of these intracellular solutes.
The gradient in tonicity—or effective osmolality—determines the osmotic flow of water across a cell membrane
Total-body water (TBW) is distributed among blood plasma and the interstitial, intracellular, and transcellular fluids. The mechanisms by which H2O exchanges between interstitial fluid and ICF, and between interstitial fluid and plasma, rely on the principles that we have just discussed.
Water Exchange Across Cell Membranes
Because cell membranes are not rigid, hydrostatic pressure differences never arise between cell H2O and interstitial fluid. Increasing the hydrostatic pressure in the interstitial space will cause the cell to compress so that the intracellular hydrostatic pressure increases to a similar extent. Thus, H2O does not enter the cell under these conditions. However, increasing the interstitial osmotic pressure, and thus generating a Δπ, is quite a different matter. If we suddenly increase ECF osmolality by adding an impermeant solute such as mannitol, the resulting osmotic gradient across the cell membrane causes H2O to move out of the cell. If the cell does not have an RVI mechanism or if the RVI mechanism is blocked, cell volume will remain reduced indefinitely.
On the other hand, consider what would happen if we suddenly increase ECF osmolality by adding a permeant solute such as urea. Urea can rapidly penetrate cell membranes by facilitated diffusion through members of the UT family of transporters; however, cells have no mechanism for extruding urea. Because urea penetrates the membrane more slowly than H2O does, the initial effect of applying urea is to shrink the cell (Fig. 5-18). However, as urea gradually equilibrates across the cell membrane and abolishes the initially imposed osmotic gradient, the cell reswells to its initial volume. Thus, sustained changes in cell volume do not occur with a change in the extracellular concentration of a permeant solute.
FIGURE 5-18 Effect of urea on the volume of a single cell bathed in an infinite volume of ECF. We assume that the cell membrane is permeable only to water during the initial moments in steps 2 and 3. Later, during steps 4 and 5, we assume that the membrane is permeable to both water and urea.
The difference between the effects of mannitol and urea on the final cell volume illustrates the need to distinguish between total osmolality and effective osmolality (also known as tonicity). In terms of clinically measured solutes, total and effective osmolality of the ECF can be approximated as
BUN stands for blood urea nitrogen, that is, the concentration of the nitrogen that is contained in the plasma as urea. The clinical laboratory reports the value of [Na+] in Equation 5-32 in milliequivalents per liter. Because laboratories in the United States report the glucose and BUN concentrations in terms of milligrams per deciliter, we divide glucose by one tenth of the molecular weight of glucose and BUN by one tenth of the summed atomic weights of the two nitrogen atoms in urea. The computed tonicity does not include BUN because—as we saw above—urea easily equilibrates across most cell membranes. On the other hand, the computed tonicity includes both Na+ and glucose. It includes Na+ because Na+ is functionally impermeant owing to its extrusion by the Na-K pump. Tonicity includes glucose because this solute does not appreciably accumulate in most cells as a result of metabolism. In some clinical situations, the infusion of impermeant solutes, such as radiographic contrast agents or mannitol, can also contribute to tonicity of the ECF.
Osmolality describes the number of osmotically active solutes in a single solution. If we regard a plasma osmolality of 290 mOsm as being normal, solutions having an osmolality of 290 mOsm are isosmolal, solutions with osmolalities >290 mOsm are hyperosmolal, and those with osmolalities <290 mOsm are hypo-osmolal. On the other hand, when we use the terms isotonic, hypertonic, and hypotonic, we are comparing one solution with another solution (e.g., ICF) across a well-defined membrane (e.g., a cell membrane). A solution is isotonic when its effective osmolality is the same as that of the reference solution, which for our purposes is the ICF. A hypertonic solution is one that has a higher effective osmolality than the reference solution, and a hypotonic solution has a lower effective osmolality.
Shifts of H2O between the intracellular and interstitial compartments result from alterations in effective ECF osmolality, or tonicity. Clinically, such changes in tonicity are usually caused by decreases in [Na+] in the plasma and ECF (hyponatremia), increases in [Na+] (hypernatremia), or increases in glucose concentration (hyperglycemia). Changes in the concentration of a highly permeant solute such as urea, which accumulates in patients with kidney failure, have no effect on tonicity.
Water Exchange Across the Capillary Wall
The barrier separating the blood plasma and interstitial compartments—the capillary wall—is, to a first approximation, freely permeable to solutes that are smaller than plasma proteins. Thus, the only net osmotic force that acts across the capillary wall is that caused by the asymmetric distribution of proteins in plasma versus interstitial fluid. Several terms may be used for the osmotic force that is generated by these impermeant plasma proteins, such as protein osmotic pressure, colloid osmotic pressure, and oncotic pressure. These terms are synonymous and can be represented by the symbol πoncotic. The oncotic pressure difference (Δπoncotic), which tends to pull H2O from the interstitium to the plasma, is opposed by the hydrostatic pressure difference across the capillary wall (ΔP), which drives fluid from plasma into the interstitium. All net movements of H2O across the capillary wall are accompanied by the small solutes dissolved in this H2O, at their ECF concentrations; that is, the pathways taken by the H2O across the capillary wall are so large that small solutes are not sieved out.
To summarize, fluid shifts between plasma and the interstitium respond only to changes in the balance between ΔP and Δπoncotic. Small solutes such as Na+, which freely cross the capillary wall, do not contribute significantly to osmotic driving forces across this barrier and move along with the H2O in which they are dissolved. We will return to this subject when we discuss capillary exchange of H2O, beginning on p. 467.
Adding isotonic saline, pure water, or pure NaCl to the ECF will increase ECF volume but will have divergent effects on ICF volume and ECF osmolality
Adding various combinations of NaCl and solute-free water to the ECF will alter the volume and composition of the body fluid compartments. Three examples illustrate the effects seen with intravenous therapy. In Figure 5-19A, we start with a TBW of 42 L (60% of a 70-kg person), subdivided into an ICF volume of 25 L (60% of TBW) and an ECF volume of 17 L (40% of TBW). These numerical values are the same as those in Figure 5-1 and Table 5-1.
FIGURE 5-19 Effect on body fluid compartments of infusing different solutions.
Infusion of Isotonic Saline
Consider the case in which we infuse or ingest 1.5 L of isotonic saline, which is a 0.9% solution of NaCl in H2O (see Fig. 5-19B). This solution has an effective osmolality of 290 mOsm in the ECF. This 1.5 L is initially distributed throughout the ECF and raises ECF volume by 1.5 L. Because the effective osmolality of the ECF is unaltered, no change occurs in the effective osmotic gradient across the cell membranes, and the added H2O moves neither into nor out of the ICF. This outcome is, of course, in accord with the definition of an isotonic solution. Thus, we see that adding isotonic saline to the body is an efficient way to expand the ECF without affecting the ICF. Similarly, if it were possible to remove isotonic saline from the body, we would see that this measure would efficiently contract the ECF and again have no effect on the ICF.
Infusion of “Solute-Free” Water
Now consider a case in which we either ingest 1.5 L of pure H2O or infuse 1.5 L of an isotonic (5%) glucose solution (see Fig. 5-19C). Infusing the glucose solution intravenously is equivalent, in the long run, to infusing pure H2O because the glucose is metabolized to CO2 and H2O, with no solutes left behind in the ECF. Infusing pure H2O would be unwise inasmuch as it would cause the cells near the point of infusion to burst.
How do the effects of adding 1.5 L of pure H2O compare with those in the previous example? At first, the 1.5 L of pure H2O will be rapidly distributed throughout the ECF and increase its volume from 17 to 18.5 L (see Fig. 5-19C, left side [Early]). This added H2O will also dilute the pre-existing solutes in the ECF, thereby lowering ECF osmolality to 290 mOsm × 17/18.5 = 266 mOsm. Because intracellular osmolality remains at 290 mOsm at this imaginary, intermediate stage, a large osmotic gradient is created that favors the entry of H2O from the ECF into the ICF. Water will move into the ICF and consequently lower the osmolality of the ICF and simultaneously raise the osmolality of the ECF until osmotic equilibrium is restored (see Fig. 5-19C, right side [Final]). Because the added H2O is distributed between the ICF and ECF according to the initial ICF/ECF ratio of 60%/40%, the final ECF volume is 17.6 L (i.e., 17 L expanded by 40% of 1.5 L). Thus, infusion of solute-free H2O is a relatively ineffective means of expanding the ECF. More of the added H2O has ended up intracellularly (60% of 1.5 L = 0.9 L of expansion). The major effect of the H2O has been to dilute the osmolality of body fluids. The initial total-body solute content was 290 mOsm × 42 L = 12,180 milliosmoles. This same solute has now been diluted in 42 + 1.5 or 43.5 L, so the final osmolality is 12,180/43.5 = 280 mOsm.
Ingestion of Pure NaCl Salt
The preceding two “experiments” illustrate two extremely important principles that govern fluid and electrolyte homeostasis; namely, that adding or removing Na+ will mainly affect ECF volume (see Fig. 5-19B), whereas adding or removing solute-free H2O will mainly affect the osmolality of body fluids (see Fig. 5-19C). The first point can be further appreciated by considering a third case, one in which we add the same amount of NaCl that is contained in 1.5 L of isotonic (i.e., 0.9%) saline: 1.5 L × 290 mOsm = 435 milliosmoles. However, we will not add any H2O. At first, these 435 milliosmoles of NaCl will rapidly distribute throughout the 17 L of ECF and increase the osmolality of the ECF (see Fig. 5-19D, left side [Early]). The initial total osmolal content of the ECF was 290 mOsm × 17 L = 4930 milliosmoles. Because we added 435 milliosmoles, we now have 5365 milliosmoles in the ECF. Thus, the ECF osmolality is 5365/17 = 316 mOsm. The resulting hyperosmolality draws H2O out of the ICF into the ECF until osmotic equilibrium is re-established. What is the final osmolality? The total number of milliosmoles dissolved in TBW is the original 12,180 milliosmoles plus the added 435 milliosmoles, for a total of 12,615 milliosmoles. Because these milliosmoles are dissolved in 42 L of TBW, the final osmolality of the ICF and ECF is 12,615/42 = 300 mOsm. In the new equilibrium state, the ECF volume has increased by 0.9 L even though no H2O at all was added to the body. Because the added ECF volume has come from the ICF, the ICF shrinks by 0.9 L. This example further illustrates the principle that the total-body content of Na+ is the major determinant of ECF volume.
Whole-body Na+ content determines ECF volume, whereas whole-body water content determines osmolality
Changes in ECF volume are important because they are accompanied by proportional changes in the volume of blood plasma, which in turn affects the adequacy with which the circulatory system can perfuse vital organs with blood (see pp. 554-555). The blood volume that is necessary to achieve adequate perfusion of key organs is sometimes referred to as the effective circulating volume. Because the body generally stabilizes osmolality, an increase in extracellular Na+ content will increase ECF volume:
Because cells contain very little Na+, extracellular Na+ content is nearly the same as total-body Na+ content.
We will see in Chapter 40 how the body regulates effective circulating volume. Increases in effective circulating volume, which reflect increases in ECF volume or total-body Na+ content, stimulate the renal excretion of Na+. In contrast, the plasma Na+ concentration does not regulate renal excretion of Na+. It makes sense that regulation of Na+ excretion is not sensitive to the plasma Na+ concentration because the concentration is not an indicator of ECF volume.
As discussed, when we hold osmolality constant, Na+ content determines ECF volume. What would happen if we held constant the Na+ content, which is a major part of total-body osmoles? An increase in TBW would decrease osmolality. N5-2
Thus, a net gain or loss of solute-free H2O has a major impact on the osmolality and [Na+] of the ECF. Moreover, because a large part (~60%) of the added solute-free water distributes into the ICF, a gain or loss of solute-free H2O affects ICF more than ECF. We will see beginning on p. 844 how the body regulates osmolality: a small decrease in osmolality triggers osmoreceptors to diminish thirst (which results in diminished intake of solute-free H2O) and increase renal H2O excretion. In emergency states of very low ECF and effective circulating volume, some crosstalk occurs between the control systems for volume and osmolality. As a result, the body not only will try to conserve Na+ but will also seek H2O (by triggering thirst) and conserve H2O (by concentrating the urine). Although water (in comparison to saline) is not a very good expander of plasma and ECF volume, it is better than nothing.