Cellular physiology - Clinical Tree

Understanding the functions of the organ systems requires profound knowledge of basic cellular mechanisms. Although each organ system differs in its overall function, all are undergirded by a common set of physiologic principles.

The following basic principles of physiology are introduced in this chapter: body fluids, with particular emphasis on the differences in composition of intracellular fluid and extracellular fluid (ECF); creation of these concentration differences by transport processes in cell membranes; the origin of the electrical potential difference across cell membranes, particularly in excitable cells such as nerve and muscle; generation of action potentials and their propagation in excitable cells; transmission of information between cells across synapses and the role of neurotransmitters; and the mechanisms that couple the action potentials to contraction in muscle cells.

These principles of cellular physiology constitute a set of recurring and interlocking themes. Once these principles are understood, they can be applied and integrated into the function of each organ system.

Volume and composition of body fluids

Distribution of water in the body fluid compartments

In the human body, water constitutes a high proportion of body weight. The total amount of fluid or water is called total body water, which accounts for 50% to 70% of body weight. For example, a 70-kilogram (kg) man whose total body water is 65% of his body weight has 45.5 kg or 45.5 liters (L) of water (1 kg water ≈ 1 L water). In general, total body water correlates inversely with body fat. Thus total body water is a higher percentage of body weight when body fat is low and a lower percentage when body fat is high. Because females have a higher percentage of adipose tissue than males, they tend to have less body water. The distribution of water among body fluid compartments is described briefly in this chapter and in greater detail in Chapter 6 .

Total body water is distributed between two major body fluid compartments: intracellular fluid (ICF) and extracellular fluid (ECF) ( Fig. 1.1 ). The ICF is contained within the cells and is two-thirds of total body water; the ECF is outside the cells and is one-third of total body water. ICF and ECF are separated by the cell membranes.

ECF is further divided into two compartments: plasma and interstitial fluid. Plasma is the fluid circulating in the blood vessels and is the smaller of the two ECF subcompartments. Interstitial fluid is the fluid that actually bathes the cells and is the larger of the two subcompartments. Plasma and interstitial fluid are separated by the capillary wall. Interstitial fluid is an ultrafiltrate of plasma formed by filtration processes across the capillary wall. Because the capillary wall is virtually impermeable to large molecules such as plasma proteins, interstitial fluid contains little, if any, protein.

The method for estimating the volume of the body fluid compartments is presented in Chapter 6 .

Composition of body fluid compartments

The composition of the body fluids is not uniform. ICF and ECF have vastly different concentrations of various solutes. There are also certain predictable differences in solute concentrations between plasma and interstitial fluid that occur as a result of the exclusion of protein from interstitial fluid.

Units for measuring solute concentrations

Typically, amounts of solute are expressed in moles, equivalents, or osmoles. Likewise, concentrations of solutes are expressed in moles per liter (mol/L), equivalents per liter (Eq/L), or osmoles per liter (Osm/L). In biologic solutions, concentrations of solutes are usually quite low and are expressed in milli moles per liter (mmol/L), milli equivalents per liter (mEq/L), or milli osmoles per liter (mOsm/L).

One mole is 6 × 10 ²³ molecules of a substance. One millimole is 1/1000 or 10 ⁻³ moles. A glucose concentration of 1 mmol/L has 1 × 10 ⁻³ moles of glucose in 1 L of solution.

An equivalent is used to describe the amount of charged (ionized) solute and is the number of moles of the solute multiplied by its valence. For example, one mole of potassium chloride (KCl) in solution dissociates into one equivalent of potassium (K ⁺ ) and one equivalent of chloride (Cl ⁻ ). Likewise, one mole of calcium chloride (CaCl ₂ ) in solution dissociates into two equivalents of calcium (Ca ²⁺ ) and two equivalents of chloride (Cl ⁻ ); accordingly, a Ca ²⁺ concentration of 1 mmol/L corresponds to 2 mEq/L.

One osmole is the number of particles into which a solute dissociates in solution. Osmolarity is the concentration of particles in solution expressed as osmoles per liter. If a solute does not dissociate in solution (e.g., glucose), then its osmolarity is equal to its molarity. If a solute dissociates into more than one particle in solution (e.g., NaCl), then its osmolarity equals the molarity multiplied by the number of particles in solution. For example, a solution containing 1 mmol/L NaCl is 2 mOsm/L because NaCl dissociates into two particles.

pH is a logarithmic term that is used to express hydrogen (H ⁺ ) concentration. Because the H ⁺ concentration of body fluids is very low (e.g., 40 × 10 ⁻⁹ Eq/L in arterial blood), it is more conveniently expressed as a logarithmic term, pH. The negative sign means that pH decreases as the concentration of H ⁺ increases, and pH increases as the concentration of H ⁺ decreases. Thus

pH =- {log}_{10} [H^{+}]

$pH =- {log}_{10} [H^{+}]$

Sample problem.

Two men, Subject A and Subject B, have disorders that cause excessive acid production in the body. The laboratory reports the acidity of Subject A’s blood in terms of [H ⁺ ] and the acidity of Subject B’s blood in terms of pH. Subject A has an arterial [H ⁺ ] of 65 × 10 ⁻⁹ Eq/L, and Subject B has an arterial pH of 7.3. Which subject has the higher concentration of H ⁺ in his blood?

Solution.

To compare the acidity of the blood of each subject, convert the [H ⁺ ] for Subject A to pH as follows:

\begin{matrix} pH =- lo g_{10} [H^{+}] \\ =- lo g_{10} (65 × 10^{− 9} Eq / L) \\ =- lo g_{10} (6.5 × 10^{− 8} Eq / L) \\ lo g_{10} 6.5 = 0.81 \\ lo g_{10} 10^{− 8} =- 8.0 \\ lo g_{10} 6.5 × 10^{− 8} = 0.81 + (− 8.0) =- 7.19 \\ pH =- (− 7.19) = 7.19 \end{matrix}

$\begin{matrix} pH =- lo g_{10} [H^{+}] \\ =- lo g_{10} (65 × 10^{− 9} Eq / L) \\ =- lo g_{10} (6.5 × 10^{− 8} Eq / L) \\ lo g_{10} 6.5 = 0.81 \\ lo g_{10} 10^{− 8} =- 8.0 \\ lo g_{10} 6.5 × 10^{− 8} = 0.81 + (− 8.0) =- 7.19 \\ pH =- (− 7.19) = 7.19 \end{matrix}$

Thus Subject A has a blood pH of 7.19 computed from the [H ⁺ ], and Subject B has a reported blood pH of 7.3. Subject A has a lower blood pH, reflecting a higher [H ⁺ ] and a more acidic condition.

Electroneutrality of body fluid compartments

Each body fluid compartment must obey the principle of macroscopic electroneutrality; that is, each compartment must have the same concentration, in mEq/L, of positive charges (cations) as of negative charges (anions) . There can be no more cations than anions, or vice versa. Even when there is a potential difference across the cell membrane, charge balance still is maintained in the bulk (macroscopic) solutions. (Because potential differences are created by the separation of just a few charges adjacent to the membrane, this small separation of charges is not enough to measurably change bulk concentrations.)

Sample problem.

A biologic fluid sample is found to have the following concentrations of ions, reported in mEq/L.

Cations	Anions
Na ⁺ , 140 mEq/L	Cl ⁻ , 110 mEq/L
K ⁺ , 4 mEq/L	HPO ₄ ⁻² , 6 mEq/L
Ca ²⁺ , 2 mEq/L	Protein, 0 mEq/L

The lab was unable to measure the HCO ₃ ⁻ concentration. What must the HCO ₃ ⁻ concentration of the solution be, in milliequivalents per liter?

Solution.

Because all biologic solutions must obey the principle of electroneutrality, this fluid must have equal concentrations of anions and cations (i.e., equal concentrations of plus and minus charges). Concentrations reported in milliequivalents per liter express the concentration of charge . Because the total concentration of cations is 146 mEq/L and the total concentration of anions is 116 mEq/L, the HCO ₃ ⁻ concentration must be 30 mEq/L.

Composition of intracellular fluid and extracellular fluid

The compositions of ICF and ECF are strikingly different, as shown in Table 1.1 . The major cation in ECF is sodium (Na ⁺ ), and the balancing anions are chloride (Cl ⁻ ) and bicarbonate (HCO ₃ ⁻ ). The major cations in ICF are potassium (K ⁺ ) and magnesium (Mg ²⁺ ), and the balancing anions are proteins and organic phosphates. Other notable differences in composition involve Ca ²⁺ and pH. Typically, ICF has a very low concentration of ionized Ca ²⁺ (≈10 ⁻⁷ mol/L), whereas the Ca ²⁺ concentration in ECF is higher by approximately four orders of magnitude. ICF is more acidic (has a lower pH) than ECF. Thus substances found in high concentration in ECF are found in low concentration in ICF, and vice versa.

TABLE 1.1

Approximate Compositions of Extracellular and Intracellular Fluids

Substance and Units	Extracellular Fluid	Intracellular Fluid ^a
Na ⁺ (mEq/L)	140	14
K ⁺ (mEq/L)	4	120
Ca ²⁺ , ionized (mEq/L)	2.5 ^b	1 × 10 ⁻⁴
Cl ⁻ (mEq/L)	105	10
HCO ₃ ⁻ (mEq/L)	24	10
pH ^c	7.4	7.1
Osmolarity (mOsm/L)	290	290

a The major anions of intracellular fluid are proteins and organic phosphates.

b The corresponding total [Ca ²⁺ ] in extracellular fluid is 5 mEq/L or 10 mg/dL.

c pH is −log ₁₀ of the [H ⁺ ]; pH 7.4 corresponds to [H ⁺ ] of 40 × 10 ⁻⁹ Eq/L.

Remarkably, given all of the concentration differences for individual solutes, the total solute concentration (osmolarity) is the same in ICF and ECF. This equality is achieved because water flows freely across cell membranes. Any transient differences in osmolarity that occur between ICF and ECF are quickly dissipated by water movement into or out of cells to reestablish the equality.

Creation of concentration differences across cell membranes

The differences in solute concentration across cell membranes are created and maintained by energy-consuming transport mechanisms in the cell membranes.

The best known of these transport mechanisms is the Na ⁺ -K ⁺ ATPase (Na ⁺ -K ⁺ pump), which transports Na ⁺ from ICF to ECF and simultaneously transports K ⁺ from ECF to ICF. Both Na ⁺ and K ⁺ are transported against their respective electrochemical gradients; therefore an energy source, adenosine triphosphate (ATP), is required. The Na ⁺ -K ⁺ ATPase is responsible for creating the large concentration gradients for Na ⁺ and K ⁺ that exist across cell membranes (i.e., the low intracellular Na ⁺ concentration and the high intracellular K ⁺ concentration).

Similarly, the intracellular Ca ²⁺ concentration is maintained at a level much lower than the extracellular Ca ²⁺ concentration. This concentration difference is established, in part, by a cell membrane Ca ²⁺ ATPase that pumps Ca ²⁺ against its electrochemical gradient. Like the Na ⁺ -K ⁺ ATPase, the Ca ²⁺ ATPase uses ATP as a direct energy source.

In addition to the transporters that use ATP directly, other transporters establish concentration differences across the cell membrane by utilizing the transmembrane Na ⁺ concentration gradient (established by the Na ⁺ -K ⁺ ATPase) as an energy source. These transporters create concentration gradients for glucose, amino acids, Ca ²⁺ , and H ⁺ without the direct utilization of ATP.

Clearly, cell membranes have the machinery to establish large concentration gradients. However, if cell membranes were freely permeable to all solutes, these gradients would quickly dissipate. Thus it is critically important that cell membranes are not freely permeable to all substances but, rather, have selective permeabilities that maintain the concentration gradients established by energy-consuming transport processes.

Directly or indirectly, the differences in composition between ICF and ECF underlie every important physiologic function, as the following examples illustrate: (1) The resting membrane potential of nerve and muscle critically depends on the difference in concentration of K ⁺ across the cell membrane; (2) The upstroke of the action potential of these same excitable cells depends on the differences in Na ⁺ concentration across the cell membrane; (3) Excitation-contraction coupling in muscle cells depends on the differences in Ca ²⁺ concentration across the cell membrane and the membrane of the sarcoplasmic reticulum (SR); and (4) Absorption of essential nutrients depends on the transmembrane Na ⁺ concentration gradient (e.g., glucose absorption in the small intestine or glucose reabsorption in the renal proximal tubule).

Concentration differences between plasma and interstitial fluids

As previously discussed, ECF consists of two subcompartments: interstitial fluid and plasma. The most significant difference in composition between these two compartments is the presence of proteins (e.g., albumin) in the plasma compartment. Plasma proteins do not readily cross capillary walls because of their large molecular size and therefore are excluded from interstitial fluid.

The exclusion of proteins from interstitial fluid has secondary consequences. The plasma proteins are negatively charged, and this negative charge causes a redistribution of small, permeant cations and anions across the capillary wall, called a Gibbs-Donnan equilibrium. The redistribution can be explained as follows: The plasma compartment contains the impermeant, negatively charged proteins. Because of the requirement for electroneutrality, the plasma compartment must have a slightly lower concentration of small anions (e.g., Cl ⁻ ) and a slightly higher concentration of small cations (e.g., Na ⁺ and K ⁺ ) than that of interstitial fluid. The small concentration difference for permeant ions is expressed in the Gibbs-Donnan ratio, which gives the plasma concentration relative to the interstitial fluid concentration for anions and interstitial fluid relative to plasma for cations. For example, the Cl ⁻ concentration in plasma is slightly less than the Cl ⁻ concentration in interstitial fluid (due to the effect of the impermeant plasma proteins); the Gibbs-Donnan ratio for Cl ⁻ is 0.95, meaning that [Cl ⁻ ] _plasma /[Cl ⁻ ] _{interstitial fluid} equals 0.95. For Na ⁺ , the Gibbs-Donnan ratio is also 0.95, but Na ⁺ , being positively charged, is oriented the opposite way, and [Na ⁺ ] _{interstitial fluid} /[Na ⁺ ] _plasma equals 0.95. Generally, these minor differences in concentration for small cations and anions between plasma and interstitial fluid are ignored.

Characteristics of cell membranes

Cell membranes are composed primarily of lipids and proteins. The lipid component consists of phospholipids, cholesterol, and glycolipids and is responsible for the high permeability of cell membranes to lipid-soluble substances such as carbon dioxide, oxygen, fatty acids, and steroid hormones. The lipid component of cell membranes is also responsible for the low permeability of cell membranes to water-soluble substances such as ions, glucose, and amino acids. The protein component of the membrane consists of transporters, enzymes, hormone receptors, cell-surface antigens, and ion and water channels.

Phospholipid component of cell membranes

Phospholipids consist of a phosphorylated glycerol backbone (“head”) and two fatty acid “tails” ( Fig. 1.2 ). The glycerol backbone is hydrophilic (water soluble), and the fatty acid tails are hydrophobic (water insoluble). Thus phospholipid molecules have both hydrophilic and hydrophobic properties and are called amphipathic. At an oil-water interface (see Fig. 1.2 A), molecules of phospholipids form a monolayer and orient themselves so that the glycerol backbone dissolves in the water phase and the fatty acid tails dissolve in the oil phase. In cell membranes (see Fig. 1.2 B), phospholipids orient so that the lipid-soluble fatty acid tails face each other and the water-soluble glycerol heads point away from each other, dissolving in the aqueous solutions of the ICF or ECF. This orientation creates a lipid bilayer.

Fig. 1.2, Orientation of phospholipid molecules at oil and water interfaces.

Protein component of cell membranes

Proteins in cell membranes may be either integral or peripheral. The distribution of proteins in a phospholipid bilayer is illustrated in the fluid mosaic model shown in Figure 1.3 .

♦
Integral membrane proteins are embedded in, and anchored to, the cell membrane by hydrophobic interactions. Integral membrane proteins include: receptors, adhesion molecules, proteins involved in transmembrane movement of solutes and water, enzymes, and proteins involved in cell signaling. To remove an integral protein from the cell membrane, its attachments to the lipid bilayer must be disrupted (e.g., by detergents). Some integral proteins are transmembrane proteins, meaning they span the lipid bilayer one or more times; thus transmembrane proteins are in contact with both ECF and ICF. Examples of transmembrane integral proteins are ligand-binding receptors (e.g., for hormones or neurotransmitters); transport proteins (e.g., Na ⁺ -K ⁺ ATPase); pores and ion channels that permit passage of water and ions, respectively; cell adhesion molecules; and guanosine triphosphate (GTP)–binding proteins (G proteins). A second category of integral proteins is embedded in the lipid bilayer of the membrane but does not span it. A third category of integral proteins is not embedded in the lipid bilayer but is covalently linked to a lipid component of the membrane.
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Peripheral membrane proteins are not embedded in the membrane and are not covalently bound to cell membrane components. They are loosely attached to either the intracellular or extracellular side of the cell membrane by ionic interactions (e.g., with phospholipid head groups) or by attachment to the extracellular or intracellular side of integral membrane proteins. Peripheral membrane proteins can be removed with mild treatments that disrupt ionic or hydrogen bonds. One example of a peripheral membrane protein is ankyrin, which “anchors” the cytoskeleton of red blood cells to an integral membrane transport protein, the Cl ⁻ -HCO ₃ ⁻ exchanger (also called band 3 protein); in this example, ankyrin, a peripheral membrane protein, anchors a spectrin-actin network to an integral membrane protein of the red blood cell membrane.

Fig. 1.3, Fluid mosaic model for cell membranes.

Transport across cell membranes

Several types of mechanisms are responsible for transport of substances across cell membranes ( Table 1.2 ).

TABLE 1.2

Summary of Membrane Transport

Type of Transport	Active or Passive	Carrier-Mediated	Uses Metabolic Energy	Dependent on Na ⁺ Gradient
Simple diffusion	Passive; downhill	No	No	No
Facilitated diffusion	Passive; downhill	Yes	No	No
Primary active transport	Active; uphill	Yes	Yes; direct	No
Cotransport	Secondary active ^a	Yes	Yes; indirect	Yes (solutes move in same direction as Na ⁺ across cell membrane)
Countertransport	Secondary active ^a	Yes	Yes; indirect	Yes (solutes move in opposite direction as Na ⁺ across cell membrane)

a Na ⁺ is transported downhill, and one or more solutes are transported uphill.

Substances may be transported down an electrochemical gradient (downhill) or against an electrochemical gradient (uphill). Downhill transport occurs by diffusion, either simple or facilitated, and requires no input of metabolic energy. Uphill transport occurs by active transport, which may be primary or secondary. Primary and secondary active transport processes are distinguished by their energy source. Primary active transport requires a direct input of metabolic energy; secondary active transport utilizes an indirect input of metabolic energy.

Further distinctions among transport mechanisms are based on whether the process involves a protein carrier. Simple diffusion is the only form of transport that is not carrier mediated. Facilitated diffusion, primary active transport, and secondary active transport all involve integral membrane proteins and are called carrier-mediated transport. All forms of carrier-mediated transport share the following three features: saturation, stereospecificity, and competition.

♦
Saturation. Saturability is based on the concept that carrier proteins have a limited number of binding sites for the solute. Figure 1.4 shows the relationship between the rate of carrier-mediated transport and solute concentration. At low solute concentrations, many binding sites are available and the rate of transport increases steeply as the concentration increases. However, at high solute concentrations, the available binding sites become scarce and the rate of transport levels off. Finally, when all of the binding sites are occupied, saturation is achieved at a point called the transport maximum, or T _m . The kinetics of carrier-mediated transport are similar to Michaelis-Menten enzyme kinetics—both involve proteins with a limited number of binding sites. (The T _m is analogous to the V _max of enzyme kinetics.) T _m -limited glucose transport in the proximal tubule of the kidney is an example of saturable transport.
♦
Stereospecificity. The binding sites for solute on the transport proteins are stereospecific. For example, the transporter for glucose in the renal proximal tubule recognizes and transports the natural isomer d -glucose, but it does not recognize or transport the unnatural isomer l -glucose. In contrast, simple diffusion does not distinguish between the two glucose isomers because no protein carrier is involved.
♦
Competition. Although the binding sites for transported solutes are quite specific, they may recognize, bind, and even transport chemically related solutes. For example, the transporter for glucose is specific for d -glucose, but it also recognizes and transports a closely related sugar, d -galactose. Therefore the presence of d -galactose inhibits the transport of d -glucose by occupying some of the binding sites and making them unavailable for glucose.

Simple diffusion

Diffusion of nonelectrolytes

Simple diffusion occurs as a result of the random thermal motion of molecules, as shown in Figure 1.5 . Two solutions, A and B, are separated by a membrane that is permeable to the solute. The solute concentration in A is initially twice that of B. The solute molecules are in constant motion, with equal probability that a given molecule will cross the membrane to the other solution. However, because there are twice as many solute molecules in Solution A as in Solution B, there will be greater movement of molecules from A to B than from B to A. In other words, there will be net diffusion of the solute from A to B, which will continue until the solute concentrations of the two solutions become equal (although the random movement of molecules will go on forever).

Net diffusion of the solute is called flux, or flow (J), and depends on the following variables: size of the concentration gradient, partition coefficient, diffusion coefficient, thickness of the membrane, and surface area available for diffusion.

Concentration gradient (C _A − C _B )

The concentration gradient across the membrane is the driving force for net diffusion. The larger the difference in solute concentration between Solution A and Solution B, the greater the driving force and the greater the net diffusion. It also follows that, if the concentrations in the two solutions are equal, there is no driving force and no net diffusion.

Partition coefficient (K)

The partition coefficient, by definition, describes the solubility of a solute in oil relative to its solubility in water. The greater the relative solubility in oil, the higher the partition coefficient and the more easily the solute can dissolve in the cell membrane’s lipid bilayer. Nonpolar solutes tend to be soluble in oil and have high values for partition coefficient, whereas polar solutes tend to be insoluble in oil and have low values for partition coefficient. The partition coefficient can be measured by adding the solute to a mixture of olive oil and water and then measuring its concentration in the oil phase relative to its concentration in the water phase. Thus

K = \frac{Concentration in olive oil}{Concentration in water}

$K = \frac{Concentration in olive oil}{Concentration in water}$

Diffusion coefficient (D)

The diffusion coefficient depends on such characteristics as size of the solute molecule and the viscosity of the medium. It is defined by the Stokes-Einstein equation (see later). The diffusion coefficient correlates inversely with the molecular radius of the solute and the viscosity of the medium. Thus small solutes in nonviscous solutions have the largest diffusion coefficients and diffuse most readily; large solutes in viscous solutions have the smallest diffusion coefficients and diffuse least readily. Thus

D = \frac{KT}{6 π r η}

$D = \frac{KT}{6 π r η}$

where

\begin{matrix} D = Diffusion coefficient \\ K = Boltzmann constant \\ T = Absolute temperature (K) \\ r = Molecular radius \\ η = Viscosity of the medium \end{matrix}

$\begin{matrix} D = Diffusion coefficient \\ K = Boltzmann constant \\ T = Absolute temperature (K) \\ r = Molecular radius \\ η = Viscosity of the medium \end{matrix}$

Thickness of the membrane (ΔX)

The thicker the cell membrane, the greater the distance the solute must diffuse and the lower the rate of diffusion.

Surface area (A)

The greater the surface area of membrane available, the higher the rate of diffusion. For example, lipid-soluble gases such as oxygen and carbon dioxide have particularly high rates of diffusion across cell membranes. These high rates can be attributed to the large surface area for diffusion provided by the lipid component of the membrane.

To simplify the description of diffusion, several of the previously cited characteristics can be combined into a single term called permeability (P). Permeability includes the partition coefficient, the diffusion coefficient, and the membrane thickness. Thus

P = \frac{KD}{Δ x}

$P = \frac{KD}{Δ x}$

By combining several variables into permeability, the rate of net diffusion is simplified to the following expression:

J = PA (C_{A} − C_{B})

$J = PA (C_{A} − C_{B})$

where

\begin{matrix} J = Net rate of diffusion (mmol/s) \\ P = Permeability (cm/s) \\ A = Surface area for diffusion ({cm}^{2}) \\ C_{A} = Concentration in Solution A (mmol/L) \\ C_{B} = Concentration in Solution B (mmol/L) \end{matrix}

$\begin{matrix} J = Net rate of diffusion (mmol/s) \\ P = Permeability (cm/s) \\ A = Surface area for diffusion ({cm}^{2}) \\ C_{A} = Concentration in Solution A (mmol/L) \\ C_{B} = Concentration in Solution B (mmol/L) \end{matrix}$

Sample problem.

Solution A and Solution B are separated by a membrane whose permeability to urea is 2 × 10 ⁻⁵ cm/s and whose surface area is 1 cm ² . The concentration of urea in A is 10 mg/mL, and the concentration of urea in B is 1 mg/mL. The partition coefficient for urea is 10 ⁻³ , as measured in an oil-water mixture. What are the initial rate and direction of net diffusion of urea?

Solution.

Note that the partition coefficient is extraneous information because the value for permeability, which already includes the partition coefficient, is given. Net flux can be calculated by substituting the following values in the equation for net diffusion: Assume that 1 mL of water = 1 cm ³ . Thus

J = PA (C_{A} − C_{B})

$J = PA (C_{A} − C_{B})$

where

\begin{matrix} J = 2 × 10^{− 5} cm / s × 1 c m^{2} × (10 mg / mL − 1 mg / mL) \\ J = 2 × 10^{− 5} cm / s × 1 c m^{2} × (10 {mg / cm}^{3} − 1 {mg / cm}^{3}) \\ = 1.8 × 10^{− 4} mg / s \end{matrix}

$\begin{matrix} J = 2 × 10^{− 5} cm / s × 1 c m^{2} × (10 mg / mL − 1 mg / mL) \\ J = 2 × 10^{− 5} cm / s × 1 c m^{2} × (10 {mg / cm}^{3} − 1 {mg / cm}^{3}) \\ = 1.8 × 10^{− 4} mg / s \end{matrix}$

The magnitude of net flux has been calculated as 1.8 × 10 ⁻⁴ mg/s. The direction of net flux can be determined intuitively because net flux will occur from the area of high concentration (Solution A) to the area of low concentration (Solution B). Net diffusion will continue until the urea concentrations of the two solutions become equal, at which point the driving force will be zero.

Diffusion of electrolytes

Thus far, the discussion concerning diffusion has assumed that the solute is a nonelectrolyte (i.e., it is uncharged). However, if the diffusing solute is an ion or an electrolyte, there are two additional consequences of the presence of charge on the solute.

First, if there is a potential difference across the membrane, that potential difference will alter the net rate of diffusion of a charged solute. (A potential difference does not alter the rate of diffusion of a nonelectrolyte.) For example, the diffusion of K ⁺ ions will be slowed if K ⁺ is diffusing into an area of positive charge, and it will be accelerated if K ⁺ is diffusing into an area of negative charge. This effect of potential difference can either add to or negate the effects of differences in concentrations, depending on the orientation of the potential difference and the charge on the diffusing ion. If the concentration gradient and the charge effect are oriented in the same direction across the membrane, they will combine; if they are oriented in opposite directions, they may cancel each other out.

Second, when a charged solute diffuses down a concentration gradient, that diffusion can itself generate a potential difference across a membrane called a diffusion potential. The concept of diffusion potential will be discussed more fully in a following section.

Facilitated diffusion

Like simple diffusion, facilitated diffusion occurs down an electrochemical potential gradient; thus it requires no input of metabolic energy. Unlike simple diffusion, however, facilitated diffusion uses a membrane carrier and exhibits all the characteristics of carrier-mediated transport: saturation, stereospecificity, and competition. At low solute concentration, facilitated diffusion typically proceeds faster than simple diffusion (i.e., is facilitated) because of the function of the carrier. However, at higher concentrations, the carriers will become saturated and facilitated diffusion will level off. (In contrast, simple diffusion will proceed as long as there is a concentration gradient for the solute.)

An excellent example of facilitated diffusion is the transport of d -glucose into skeletal muscle and adipose cells by the GLUT4 transporter, a member of the family of GLUT glucose transporters. Glucose transport can proceed as long as the blood concentration of glucose is higher than the intracellular concentration of glucose; the rate of glucose transport can increase until the carriers are saturated, at which point glucose transport rate is maximal. Other monosaccharides such as d -galactose, 3- O -methyl glucose, and phlorizin competitively inhibit the transport of glucose because they bind to transport sites on the carrier. The competitive solute may itself be transported (e.g., d -galactose), or it may simply occupy the binding sites and prevent the attachment of glucose (e.g., phlorizin). As noted previously, the nonphysiologic stereoisomer, l -glucose, is not recognized by the carrier for facilitated diffusion and therefore is not bound or transported.

Other examples of facilitated diffusion include urea transporters (UTs) and organic cation transporters.

Primary active transport

In active transport, one or more solutes are moved against an electrochemical potential gradient (uphill). In other words, solute is moved from an area of low concentration (or low electrochemical potential) to an area of high concentration (or high electrochemical potential). Because movement of a solute uphill is work, metabolic energy in the form of ATP must be provided. In the process, ATP is hydrolyzed to adenosine diphosphate (ADP) and inorganic phosphate (P _i ), releasing energy from the terminal high-energy phosphate bond of ATP. When the terminal phosphate is released, it is transferred to the transport protein, initiating a cycle of phosphorylation and dephosphorylation. When the ATP energy source is directly coupled to the transport process, it is called primary active transport. Three examples of primary active transport in physiologic systems are the Na ⁺ -K ⁺ ATPase present in all cell membranes, the Ca ²⁺ ATPase present in SR and endoplasmic reticulum, and the H ⁺ -K ⁺ ATPase present in gastric parietal cells and renal α-intercalated cells.

Na ⁺ -K ⁺ ATPase (Na ⁺ -K ⁺ pump)

Na ⁺ -K ⁺ ATPase is present in the membranes of all cells. It pumps Na ⁺ from ICF to ECF and K ⁺ from ECF to ICF ( Fig. 1.6 ). Each ion moves against its respective electrochemical gradient. The stoichiometry can vary but, typically, for every three Na ⁺ ions pumped out of the cell, two K ⁺ ions are pumped into the cell. This stoichiometry of three Na ⁺ ions per two K ⁺ ions means that, for each cycle of the Na ⁺ -K ⁺ ATPase, more positive charge is pumped out of the cell than is pumped into the cell. Thus the transport process is termed electrogenic because it creates a charge separation and a potential difference. The Na ⁺ -K ⁺ ATPase is responsible for maintaining concentration gradients for both Na ⁺ and K ⁺ across cell membranes, keeping the intracellular Na ⁺ concentration low and the intracellular K ⁺ concentration high.

Fig. 1.6, Na + -K + pump of cell membranes.

The Na ⁺ -K ⁺ ATPase consists of α and β subunits. The α subunit contains the ATPase activity, as well as the binding sites for the transported ions, Na ⁺ and K ⁺ . The Na ⁺ -K ⁺ ATPase switches between two major conformational states, E ₁ and E ₂ . In the E ₁ state, the binding sites for Na ⁺ and K ⁺ face the ICF and the enzyme has a high affinity for Na ⁺ . In the E ₂ state, the binding sites for Na ⁺ and K ⁺ face the ECF and the enzyme has a high affinity for K ⁺ . The enzyme’s ion-transporting function (i.e., pumping Na ⁺ out of the cell and K ⁺ into the cell) is based on cycling between the E ₁ and E ₂ states and is powered by ATP hydrolysis.

The transport cycle is illustrated in Figure 1.6 . The cycle begins with the enzyme in the E ₁ state, bound to ATP. In the E ₁ state, the ion-binding sites face the ICF, and the enzyme has a high affinity for Na ⁺ ; three Na ⁺ ions bind, ATP is hydrolyzed, and the terminal phosphate of ATP is transferred to the enzyme, producing a high-energy state, E ₁ ∼ P. Now, a major conformational change occurs, and the enzyme switches from E ₁ ∼ P to E ₂ ∼ P. In the E ₂ state, the ion-binding sites face the ECF, the affinity for Na ⁺ is low, and the affinity for K ⁺ is high. The three Na ⁺ ions are released from the enzyme to ECF, two K ⁺ ions are bound, and inorganic phosphate is released from E ₂ . The enzyme now binds intracellular ATP, and another major conformational change occurs that returns the enzyme to the E ₁ state; the two K ⁺ ions are released to ICF, and the enzyme is ready for another cycle.

Cardiac glycosides (e.g., ouabain and digitalis ) are a class of drugs that inhibit Na ⁺ -K ⁺ ATPase. Treatment with this class of drugs causes certain predictable changes in intracellular ionic concentration: The intracellular Na ⁺ concentration will increase, and the intracellular K ⁺ concentration will decrease. Cardiac glycosides inhibit the Na ⁺ -K ⁺ ATPase by binding to the E ₂ ∼ P form near the K ⁺ -binding site on the extracellular side, thereby preventing the conversion of E ₂ ∼ P back to E ₁ . By disrupting the cycle of phosphorylation-dephosphorylation, these drugs disrupt the entire enzyme cycle and its transport functions.

Ca ²⁺ ATPase (Ca ²⁺ pump)

Most cell (plasma) membranes contain a Ca ²⁺ ATPase, or plasma-membrane Ca ²⁺ ATPase (PMCA), whose function is to extrude Ca ²⁺ from the cell against an electrochemical gradient; one Ca ²⁺ ion is extruded for each ATP hydrolyzed. PMCA is responsible, in part, for maintaining the very low intracellular Ca ²⁺ concentration. In addition, the sarcoplasmic reticulum (SR) of muscle cells and the endoplasmic reticulum of other cells contain variants of Ca ²⁺ ATPase that pump two Ca ²⁺ ions (for each ATP hydrolyzed) from ICF into the interior of the SR or endoplasmic reticulum (i.e., Ca ²⁺ sequestration). These variants are called SR and endoplasmic reticulum Ca ²⁺ ATPase (SERCA). Ca ²⁺ ATPase functions similarly to Na ⁺ -K ⁺ ATPase, with E ₁ and E ₂ states that have, respectively, high and low affinities for Ca ²⁺ . For PMCA, the E ₁ state binds Ca ²⁺ on the intracellular side, a conformational change to the E ₂ state occurs, and the E ₂ state releases Ca ²⁺ to ECF. For SERCA, the E ₁ state binds Ca ²⁺ on the intracellular side and the E ₂ state releases Ca ²⁺ to the lumen of the SR or endoplasmic reticulum.

H ⁺ -K ⁺ ATPase (H ⁺ -K ⁺ pump)

H ⁺ -K ⁺ ATPase is found in the parietal cells of the gastric mucosa and in the α-intercalated cells of the renal collecting duct. In the stomach, it pumps H ⁺ from the ICF of the parietal cells into the lumen of the stomach, where it acidifies the gastric contents. Omeprazole, an inhibitor of gastric H ⁺ -K ⁺ ATPase, can be used therapeutically to reduce the secretion of H ⁺ in the treatment of some types of peptic ulcer disease.

Secondary active transport

Secondary active transport processes are those in which the transport of two or more solutes is coupled. One of the solutes, usually Na ⁺ , moves down its electrochemical gradient (downhill), and the other solute moves against its electrochemical gradient (uphill). The downhill movement of Na ⁺ provides energy for the uphill movement of the other solute. Thus metabolic energy, as ATP, is not used directly, but it is supplied indirectly in the Na ⁺ concentration gradient across the cell membrane. (The Na ⁺ -K ⁺ ATPase, utilizing ATP, creates and maintains this Na ⁺ gradient.) The name secondary active transport therefore refers to the indirect utilization of ATP as an energy source.

Inhibition of the Na ⁺ -K ⁺ ATPase (e.g., by treatment with ouabain) diminishes the transport of Na ⁺ from ICF to ECF, causing the intracellular Na ⁺ concentration to increase and thereby decreasing the size of the transmembrane Na ⁺ gradient. Thus indirectly, all secondary active transport processes are diminished by inhibitors of the Na ⁺ -K ⁺ ATPase because their energy source, the Na ⁺ gradient, is diminished.

There are two types of secondary active transport distinguishable by the direction of movement of the uphill solute. If the uphill solute moves in the same direction as Na ⁺ , it is called cotransport, or symport. If the uphill solute moves in the opposite direction of Na ⁺ , it is called countertransport, antiport, or exchange.

Cotransport

Cotransport (symport) is a form of secondary active transport in which all solutes are transported in the same direction across the cell membrane. Na ⁺ moves into the cell on the carrier down its electrochemical gradient; the solutes, cotransported with Na ⁺ , also move into the cell. Cotransport is involved in several critical physiologic processes, particularly in the absorbing epithelia of the small intestine and the renal tubule. For example, Na ⁺ -glucose cotransport (SGLT) and Na ⁺ -amino acid cotransport are present in the luminal membranes of the epithelial cells of both small intestine and renal proximal tubule. Another example of cotransport involving the renal tubule is Na ⁺ -K ⁺ -2Cl ⁻ cotransport, which is present in the luminal membrane of epithelial cells of the thick ascending limb. In each example, the Na ⁺ gradient established by the Na ⁺ -K ⁺ ATPase is used to transport solutes such as glucose, amino acids, K ⁺ , or Cl ⁻ against electrochemical gradients.

Figure 1.7 illustrates the principles of cotransport using the example of Na ⁺ -glucose cotransport (SGLT1, or Na ⁺ -glucose transport protein 1) in intestinal epithelial cells. The cotransporter is present in the luminal membrane of these cells and can be visualized as having two specific recognition sites, one for Na ⁺ ions and the other for glucose. When both Na ⁺ and glucose are present in the lumen of the small intestine, they bind to the transporter. In this configuration, the cotransport protein rotates and releases both Na ⁺ and glucose to the interior of the cell. (Subsequently, both solutes are transported out of the cell across the basolateral membrane—Na ⁺ by the Na ⁺ -K ⁺ ATPase and glucose by facilitated diffusion.) If either Na ⁺ or glucose is missing from the intestinal lumen, the cotransporter cannot rotate. Thus both solutes are required, and neither can be transported in the absence of the other ( Box 1.1 ).

Fig. 1.7, Na + -glucose cotransport in an intestinal epithelial cell.

BOX 1.1

Clinical Physiology: Glucosuria Due to Diabetes Mellitus

Description of case.

At his annual physical examination, a 14-year-old boy reports symptoms of frequent urination and severe thirst. A dipstick test of his urine shows elevated levels of glucose. The physician orders a glucose tolerance test, which indicates that the boy has type I diabetes mellitus. He is treated with insulin by injection, and his dipstick test is subsequently normal.

Explanation of case.

Although type I diabetes mellitus is a complex disease, this discussion is limited to the symptom of frequent urination and the finding of glucosuria (glucose in the urine). Glucose is normally handled by the kidney in the following manner: Glucose in the blood is filtered across the glomerular capillaries. The epithelial cells, which line the renal proximal tubule, then reabsorb all of the filtered glucose so that no glucose is excreted in the urine. Thus a normal dipstick test would show no glucose in the urine. If the epithelial cells in the proximal tubule do not reabsorb all of the filtered glucose back into the blood, the glucose that escapes reabsorption is excreted. The cellular mechanism for this glucose reabsorption is the Na ⁺ -glucose cotransporter in the luminal membrane of the proximal tubule cells. Because this is a carrier-mediated transporter, there is a finite number of binding sites for glucose. Once these binding sites are fully occupied, saturation of transport occurs (transport maximum).

In this patient with type I diabetes mellitus, the hormone insulin is not produced in sufficient amounts by the pancreatic β cells. Insulin is required for normal uptake of glucose into liver, muscle, and other cells. Without insulin, the blood glucose concentration increases because glucose is not taken up by the cells. When the blood glucose concentration increases to high levels, more glucose is filtered by the renal glomeruli and the amount of glucose filtered exceeds the capacity of the Na ⁺ -glucose cotransporter. The glucose that cannot be reabsorbed because of saturation of this transporter is then “spilled” in the urine.

Treatment.

Treatment of the patient with type I diabetes mellitus consists of administering exogenous insulin by injection. Whether secreted normally from the pancreatic β cells or administered by injection, insulin lowers the blood glucose concentration by promoting glucose uptake into cells. When this patient received insulin, his blood glucose concentration was reduced; thus the amount of glucose filtered was reduced, and the Na ⁺ -glucose cotransporters were no longer saturated. All of the filtered glucose could be reabsorbed, and therefore no glucose was excreted, or “spilled,” in the urine.

Finally, the role of the intestinal Na ⁺ -glucose cotransport process can be understood in the context of overall intestinal absorption of carbohydrates. Dietary carbohydrates are digested by gastrointestinal enzymes to an absorbable form, the monosaccharides. One of these monosaccharides is glucose, which is absorbed across the intestinal epithelial cells by a combination of Na ⁺ -glucose cotransport in the luminal membrane and facilitated diffusion of glucose in the basolateral membrane. Na ⁺ -glucose cotransport is the active step, allowing glucose to be absorbed into the blood against an electrochemical gradient.

Countertransport

Countertransport (antiport or exchange) is a form of secondary active transport in which solutes move in opposite directions across the cell membrane. Na ⁺ moves into the cell on the carrier down its electrochemical gradient; the solutes that are countertransported or exchanged for Na ⁺ move out of the cell. Countertransport is illustrated by Ca ²⁺ -Na ⁺ exchange ( Fig. 1.8 ) and by Na ⁺ -H ⁺ exchange. As with cotransport, each process uses the Na ⁺ gradient established by the Na ⁺ -K ⁺ ATPase as an energy source; Na ⁺ moves downhill and Ca ²⁺ or H ⁺ moves uphill.

Ca ²⁺ -Na ⁺ exchange is one of the transport mechanisms, along with the Ca ²⁺ ATPase, that helps maintain the intracellular Ca ²⁺ concentration at very low levels (≈10 ⁻⁷ molar). To accomplish Ca ²⁺ -Na ⁺ exchange, active transport must be involved because Ca ²⁺ moves out of the cell against its electrochemical gradient. Figure 1.8 illustrates the concept of Ca ²⁺ -Na ⁺ exchange in a muscle cell membrane. The exchange protein has recognition sites for both Ca ²⁺ and Na ⁺ . The protein must bind Ca ²⁺ on the intracellular side of the membrane and, simultaneously, bind Na ⁺ on the extracellular side. In this configuration, the exchange protein rotates and delivers Ca ²⁺ to the exterior of the cell and Na ⁺ to the interior of the cell.

The stoichiometry of Ca ²⁺ -Na ⁺ exchange varies between different cell types and may even vary for a single cell type under different conditions. Usually, however, three Na ⁺ ions enter the cell for each Ca ²⁺ ion extruded from the cell. With this stoichiometry of three Na ⁺ ions per one Ca ²⁺ ion, three positive charges move into the cell in exchange for two positive charges leaving the cell, making the Ca ²⁺ -Na ⁺ exchanger electrogenic.

Osmosis

Osmosis is the flow of water across a semipermeable membrane because of differences in solute concentration. Concentration differences of impermeant solutes establish osmotic pressure differences, and this osmotic pressure difference causes water to flow by osmosis. Osmosis of water is not diffusion of water: Osmosis occurs because of a pressure difference, whereas diffusion occurs because of a concentration (or activity) difference of water.

Osmolarity

The osmolarity of a solution is its concentration of osmotically active particles, expressed as osmoles per liter or milliosmoles per liter. To calculate osmolarity, it is necessary to know the concentration of solute and whether the solute dissociates in solution. For example, glucose does not dissociate in solution; theoretically, NaCl dissociates into two particles and CaCl ₂ dissociates into three particles. The symbol “g” gives the number of particles in solution and also takes into account whether there is complete or only partial dissociation. Thus if NaCl is completely dissociated into two particles, g equals 2.0; if NaCl dissociates only partially, then g falls between 1.0 and 2.0. Osmolarity is calculated as follows:

Osmolarity = g C

$Osmolarity = g C$

where

\begin{matrix} Osmolarity = Concentration of particles (mOsm/L) \\ g = Number of particles per mole in \\ solution (Osm/mol) \\ C = Concentration (mmol/L) \end{matrix}

$\begin{matrix} Osmolarity = Concentration of particles (mOsm/L) \\ g = Number of particles per mole in \\ solution (Osm/mol) \\ C = Concentration (mmol/L) \end{matrix}$

If two solutions have the same calculated osmolarity, they are called isosmotic . If two solutions have different calculated osmolarities, the solution with the higher osmolarity is called hyperosmotic and the solution with the lower osmolarity is called hyposmotic.

Osmolality

Osmolality is similar to osmolarity, except that it is the concentration of osmotically active particles, expressed as osmoles (or milliosmoles) per kilogram of water. Because 1 kg of water is approximately equivalent to 1 L of water, osmola r ity and osmola l ity will have essentially the same numerical value.

Sample problem.

Solution A is 2 mmol/L urea, and Solution B is 1 mmol/L NaCl. Assume that g _NaCl = 1.85. Are the two solutions isosmotic?

Solution.

Calculate the osmolarities of both solutions to compare them. Solution A contains urea, which does not dissociate in solution. Solution B contains NaCl, which dissociates partially in solution but not completely (i.e., g < 2.0). Thus

\begin{matrix} Osmolarit y_{A} = 1 Osm / mol × 2 mmol / L \\ = 2 m Osm / L \\ Osmolarit y_{B} = 1.85 Osm / mol × 1 mmol / L \\ = 1.85 m Osm / L \end{matrix}

$\begin{matrix} Osmolarit y_{A} = 1 Osm / mol × 2 mmol / L \\ = 2 m Osm / L \\ Osmolarit y_{B} = 1.85 Osm / mol × 1 mmol / L \\ = 1.85 m Osm / L \end{matrix}$

The two solutions do not have the same calculated osmolarity; therefore they are not isosmotic. Solution A has a higher osmolarity than Solution B and is hyperosmotic; Solution B is hyposmotic.

Osmotic pressure

Osmosis is the flow of water across a semipermeable membrane due to a difference in solute concentration. The difference in solute concentration creates an osmotic pressure difference across the membrane, and that pressure difference is the driving force for osmotic water flow.

Figure 1.9 illustrates the concept of osmosis. Two aqueous solutions, open to the atmosphere, are shown in Figure 1.9 A. The membrane separating the solutions is permeable to water but is impermeable to the solute. Initially, solute is present only in Solution 1. The solute in Solution 1 produces an osmotic pressure and causes, by the interaction of solute with pores in the membrane, a reduction in hydrostatic pressure of Solution 1. The resulting hydrostatic pressure difference across the membrane then causes water to flow from Solution 2 into Solution 1. With time, water flow causes the volume of Solution 1 to increase and the volume of Solution 2 to decrease.

Fig. 1.9, Osmosis across a semipermeable membrane.

Figure 1.9 B shows a similar pair of solutions; however, the preparation has been modified so that water flow into Solution 1 is prevented by applying pressure to a piston. The pressure required to stop the flow of water is the osmotic pressure of Solution 1.

The osmotic pressure (π) of Solution 1 depends on two factors: the concentration of osmotically active particles and whether the solute remains in Solution 1 (i.e., whether the solute can cross the membrane or not). Osmotic pressure is calculated by the van’t Hoff equation (as follows), which converts the concentration of particles to a pressure, taking into account whether the solute is retained in the original solution.

Thus

π = g C σ R T

$π = g C σ R T$

where

\begin{matrix} π = Osmotic pressure (atm or mm Hg) \\ g = Number of particles per mole in solution \\ (Osm/mol) \\ C = Concentration (mmol/L) \\ σ = Reflection coefficient (varies from 0 to 1) \\ R = Gas constant (0 .082 L − atm/mol − K) \\ T = Absolute temperature (K) \end{matrix}

$\begin{matrix} π = Osmotic pressure (atm or mm Hg) \\ g = Number of particles per mole in solution \\ (Osm/mol) \\ C = Concentration (mmol/L) \\ σ = Reflection coefficient (varies from 0 to 1) \\ R = Gas constant (0 .082 L − atm/mol − K) \\ T = Absolute temperature (K) \end{matrix}$

The reflection coefficient (σ) is a dimensionless number ranging between 0 and 1 that describes the ease with which a solute crosses a membrane. Reflection coefficients can be described for the following three conditions ( Fig. 1.10 ):

♦
σ = 1.0 (see Fig. 1.10 A). If the membrane is impermeable to the solute, σ is 1.0 and the solute will be retained in the original solution and exert its full osmotic effect. In this case, the effective osmotic pressure will be maximal and will cause maximal water flow. For example, serum albumin and intracellular proteins are solutes where σ = 1.
♦
σ = 0 (see Fig. 1.10 C). If the membrane is freely permeable to the solute, σ is 0 and the solute will diffuse across the membrane down its concentration gradient until the solute concentrations of the two solutions are equal. In other words, the solute behaves as if it were water. In this case, there will be no effective osmotic pressure difference across the membrane and therefore no driving force for osmotic water flow. Refer again to the van’t Hoff equation and notice that, when σ = 0, the calculated effective osmotic pressure becomes zero. Urea is an example of a solute where σ = 0 (or nearly 0).
♦
σ = a value between 0 and 1 (see Fig. 1.10 B). Most solutes are neither impermeant (σ = 1) nor freely permeant (σ = 0) across membranes, but the reflection coefficient falls somewhere between 0 and 1. In such cases, the effective osmotic pressure lies between its maximal possible value (when the solute is completely impermeable) and zero (when the solute is freely permeable). Refer once again to the van’t Hoff equation and notice that, when σ is between 0 and 1, the calculated effective osmotic pressure will be less than its maximal possible value but greater than zero.

Fig. 1.10, Reflection coefficient ( σ ).

When two solutions separated by a semipermeable membrane have the same effective osmotic pressure, they are isotonic; that is, no water will flow between them because there is no effective osmotic pressure difference across the membrane. When two solutions have different effective osmotic pressures, the solution with the lower effective osmotic pressure is hypotonic and the solution with the higher effective osmotic pressure is hypertonic. Water will flow from the hypotonic solution into the hypertonic solution ( Box 1.2 ).

BOX 1.2

Clinical Physiology: Hyposmolarity With Brain Swelling

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Volume and composition of body fluids

Distribution of water in the body fluid compartments

Composition of body fluid compartments

Units for measuring solute concentrations

Sample problem.

Solution.

Electroneutrality of body fluid compartments

Sample problem.

Solution.

Composition of intracellular fluid and extracellular fluid

Creation of concentration differences across cell membranes

Concentration differences between plasma and interstitial fluids

Characteristics of cell membranes

Phospholipid component of cell membranes

Protein component of cell membranes

Transport across cell membranes

Simple diffusion

Diffusion of nonelectrolytes

Concentration gradient (C A − C B )

Partition coefficient (K)

Diffusion coefficient (D)

Thickness of the membrane (ΔX)

Surface area (A)

Sample problem.

Solution.

Diffusion of electrolytes

Facilitated diffusion

Primary active transport

Na + -K + ATPase (Na + -K + pump)

Ca 2+ ATPase (Ca 2+ pump)

H + -K + ATPase (H + -K + pump)

Secondary active transport

Cotransport

Description of case.

Explanation of case.

Treatment.

Countertransport

Osmosis

Osmolarity

Osmolality

Sample problem.

Solution.

Osmotic pressure

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Common abbreviations and symbols

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Na ⁺ -K ⁺ ATPase (Na ⁺ -K ⁺ pump)

Ca ²⁺ ATPase (Ca ²⁺ pump)

H ⁺ -K ⁺ ATPase (H ⁺ -K ⁺ pump)