Distribution in the Body

A 70-kg adult has about 100 g of sodium, 95 g of chloride, and 140 g of potassium in the body (Forbes, 1987). Distribution of these electrolytes within the various fluid compartments and body tissues is highly variable in terms of concentration and content. Sodium and chloride are the major electrolytes found predominantly in extracellular fluid, whereas potassium is retained inside the cells (Figure 34-1). The concentration of sodium ions (Na⁺) in the extracellular fluid, and thus in the plasma, is maintained within narrow limits at approximately 145 mmol/L. Its concentration in the intracellular fluid is low, about 12 mmol/L. Distribution of chloride ions (Cl^–) generally follows that of Na⁺, with an extracellular concentration of about 110 mmol/L and an intracellular concentration of about 2 mmol/L. About one third of the body’s sodium is sequestered as part of the integral structure of skeleton and therefore is not available for exchange with the fluid compartments. The concentration of potassium ions (K⁺) is 150 mmol/L inside the cells and 4 to 5 mmol/L in the extracellular fluid. The largest fraction of body potassium, about 60% to 70% of the total, is located in the skeletal muscles, which make up about 40% of body weight.

Properties of Plasma Membranes

Plasma membranes surrounding cells separate the body fluid compartment into an extracellular and an intracellular component. Movement of ions across cell membranes can occur by passive diffusion along a concentration or electrical gradient through ion channels or by an energy-yielding process of active transport of ions against these gradients. The selective permeability of the cell membranes prevents the movement of proteins and phosphates out of the cells. High concentrations of these intracellular organic anions require neutralization of the excess negative charges by cations, of which K⁺ is the most important (see Figure 34-1). The intracellular accumulation of K⁺ in exchange for Na⁺, against their concentration gradients, is achieved by the Na⁺,K⁺-pump of the plasma membrane.

Sodium–Potassium Pump

This magnesium ion–dependent, Na⁺– and K⁺-activated ATPase (Na⁺,K⁺-ATPase) is the molecular basis of the Na⁺,K⁺-pump. The Na⁺,K⁺-ATPase belongs to the P-type ATPases, which are characterized by the transient phosphorylation of the ATPase protein during the transport cycle. Structurally, the functional unit of this enzyme is a heterodimer of two subunit proteins, the α-subunit and a smaller β-subunit. Other smaller membrane peptides, such as the γ-subunit, have been found to be closely associated with Na⁺,K⁺-ATPase, but their presence does not seem to affect the expression of the functional enzyme (Horisberger and Doucet, 2007). Several isoforms of both the α- and β-subunits have been identified in a variety of tissues; the relative proportion of each subunit isoform varies among tissues, and the isoforms are tissue-specific. At present, four different genes of α-subunits and three of β-subunits have been identified in mammalian Na⁺,K⁺-ATPases. Aside from their kinetic characteristics and tissue distribution, little is known regarding their differential physiological importance.

The larger α-subunit (∼120 kDa) spans the membrane and has two large cytoplasmic domains. It binds ATP and both Na⁺ and K⁺ and contains the phosphorylation site. It is responsible for transport of Na⁺ and K⁺. The smaller β-subunit (∼50 kDa), with a large extracellular domain, is a glycoprotein that also spans the membrane. It is an essential component of the functional Na⁺,K⁺-ATPase. Affinity of the α-subunit for Na⁺ and K⁺ appears to be influenced by the particular β-subunit. As illustrated in Figure 34-2, the α-subunit binds ATP and three Na⁺ from the cytoplasm. ATP activates the catalytic site of the transporter, which then cleaves the ATP and phosphorylates the aspartate residue on the α-subunit. A conformational change in the transport protein exposes the three Na⁺ to the outside. The three Na⁺ dissociate from the enzyme and are released into the extracellular fluid. The transporter is now available for binding two extracellular K⁺. Binding of K⁺ results in dephosphorylation of the α-subunit. The transport protein returns to its original conformation, and two K⁺ are released into the cytosol in the process. The transport protein is ready for another cycle of transport.

The overall stoichiometry of the Na⁺,K⁺-ATPase reaction is that, with the hydrolysis of one molecule of ATP, three Na⁺ and two K⁺ are translocated in opposite directions across the cell membrane to maintain or restore the normally high K⁺ and low Na⁺ concentrations inside the cells. Because its activity results in a net movement of cations out of the cell and a negative charge is created in the cell relative to the outside, the Na⁺,K⁺-pump is an electrogenic pump.

Importance of the Sodium–Potassium Pump

The establishment of a differential electrical and chemical gradient for Na⁺ and K⁺ across cell membranes by the Na⁺,K⁺-pump generates and maintains a negative resting membrane potential of all cells, and this is the basis for excitability in nerve and muscle cells. Transport of three Na⁺ in exchange for two K⁺ also helps to maintain ionic homeostasis of the cells and to regulate cell volume. Furthermore, active transport of Na⁺ out of the cells provides a driving force for the transport of other solutes, such as ions, sugars, amino acids, and neurotransmitters, across cell membranes through various Na⁺-coupled cotransport systems.

The concentrations of the three major ions in body fluids are controlled within narrow limits in order for the body to function properly. The volume of the extracellular fluid compartment (interstitial fluid and plasma) is determined primarily by the total amount of osmotic particles present. Because of its high concentration, Na⁺, together with its accompanying anions Cl^– and HCO₃^–, is the major determinant of osmolarity of plasma and extracellular fluid. The osmolarity of plasma and body fluids, at 290 mmol/L, can be estimated by doubling its Na⁺ concentration of 145 mmol/L. Any change in plasma Na⁺ concentration will alter plasma osmolarity, or tonicity, and trigger physiological regulatory mechanisms to adjust water intake and water excretion to restore the osmolarity toward normal. Because the volume of extracellular fluid depends on the amount of Na⁺ present in the extracellular space, regulation of plasma volume and extracellular fluid volume involves the regulation of ingestion and excretion of sodium (Hall, 2011d). Therefore, in the control of body fluid balance, sodium and water are the two primary variables, and balance can be achieved by adjustments of their ingestion and excretion.

Role of the Electrochemical Sodium Gradient in Nutrient Transport Processes

Absorption of dietary sodium in the small intestine and reabsorption of filtered sodium from the glomerular filtrate in the kidneys back into the circulation is important in many nutrient transport processes, for example, the absorption of chloride, amino acids, glucose, galactose, and water. Transepithelial transport of Na⁺ involves movement across two membranes: the apical membrane facing the lumen of the intestine or the renal tubules, and the basolateral membrane, which faces the interstitial space. These two membranes have different transport properties. The apical membrane contains very few if any Na⁺,K⁺-ATPase transporters, whereas the basolateral membrane contains a large amount of Na⁺,K⁺-ATPase. Active extrusion of Na⁺ across the basolateral membrane by the Na⁺,K⁺-ATPase reduces the concentration of intracellular Na⁺ and provides an electrochemical potential gradient for the movement of Na⁺ from the lumen into the cytosol to replace the Na⁺ that is extruded. This transepithelial transport of Na⁺ creates an electrochemical potential difference for Na⁺ across the epithelial cells so that the epithelial cells are polarized, with the lumen slightly electronegative with respect to the interstitial fluid on the basal side of the epithelial cells (Hall, 2011e).

Entry of Na⁺ down an electrical gradient across the apical membrane is either through the voltage-dependent Na⁺ channels or by carrier-mediated transport (facilitated diffusion) in which other solutes are cotransported in the same direction or countertransported in the opposite direction. Absorption of Na⁺ causes either the entry of an equimolar amount of Cl^– in the same direction as Na⁺ movement or the secretion of an equimolar amount of K⁺ or H⁺ in the opposite direction in exchange for Na⁺ (Figure 34-3). The absorption of Cl^– is either through the paracellular spaces (junctions between the apical borders of adjacent epithelial cells) or across the epithelial cells via the apical and basal membranes. Uptake of Na⁺ and Cl^– across epithelial cells increases the intracellular concentrations of these two ions and provides an osmotic gradient for the absorption of water. A large proportion of water uptake occurs by the paracellular route, and only a small proportion of water flux is through the epithelial cells.

Some of the carrier proteins in the apical membrane, such as the sodium/glucose cotransporter 1 (SGLT1) and a number of the amino acid transport systems, have receptor sites for binding both Na⁺ and a monosaccharide, or both Na⁺ and an amino acid (see Figure 34-3). Because Na⁺ is coupled to either a monosaccharide or an amino acid on the carrier protein, entry of Na⁺ across the apical membrane also brings in a monosaccharide or an amino acid. This process of cotransport of these organic solutes is frequently referred to as secondary active transport because the energy used to establish the Na⁺ gradient allows cotransport of these solutes to occur against their concentration gradients. The increase in concentrations of these organic solutes inside the epithelial cells then allows the diffusion, usually facilitated by another carrier, of these nutrients across the basolateral membrane into the interstitial fluid.

Importance of Potassium

The high concentration gradient of K⁺ between the intracellular and extracellular fluid is important for maintaining the normal resting membrane potential across cell membranes and for excitability of nerves and muscles. It plays a crucial role in the triggering of action potentials that initiate nerve impulse transmission and muscle contraction. Changes in the concentration of K⁺ in the plasma alter this gradient and will adversely affect the aforementioned functions (Rodriguez-Soriano, 1995). For instance, in hyperkalemia, when the concentration of K⁺ in the plasma exceeds 5.5 mmol/L, the membrane depolarizes, causing muscle weakness, flaccid paralysis, and cardiac dysrhythmias. Cardiac dysrhythmias associated with hyperkalemia range from sinus bradycardia to ventricular tachycardia, ventricular fibrillation, and ultimately cardiac arrest (asystole) when a plasma concentration of 8 mmol/L is reached. Because of the adverse effects of hyperkalemia on the heart, hyperkalemia constitutes a medical emergency. In contrast, in hypokalemia, when the concentration of K⁺ in the plasma is less than 3.5 mmol/L, the membrane hyperpolarizes, and this can interfere with the normal functioning of nerves and muscles, resulting in muscle weakness and decreased smooth muscle contractility. Hypokalemia is also a risk factor for atrial and ventricular dysrhythmias (He and MacGregor, 2008). Severe hypokalemia can lead to paralysis, metabolic alkalosis, and death. Therefore physiological regulatory mechanisms are present to regulate the concentration of K⁺ in the plasma within narrow limits.

Many macromolecules present in the extracellular and intracellular compartments contain multiple ionizing groups on their surfaces and are classified as macroions. Their behavior in solution depends on their surface charges, which either repel each other so that they remain separated in solution or attract each other so that they associate. Examples of macroions are proteins, nucleic acids, and a group of polysaccharides called the glycosaminoglycans. Proteins are polyampholytes that carry both acidic and basic groups on their surfaces. Depending on the pH of the solution, proteins may carry substantial net positive or net negative charges. At a plasma pH of 7.4, most plasma and intracellular proteins have net negative charges, but a few have net positive charges. The glycosaminoglycans carry carboxylate and sulfate groups and are of major structural importance. Chondroitin sulfates and keratan sulfates of connective tissue and dermatan sulfates of skin form matrices to hold together the protein components of connective tissue and skin. A very highly sulfated glycosaminoglycan is heparin, a natural anticoagulant produced by the mast cells that line the arterial walls. Heparan sulfate, which is less highly sulfated than heparin, is linked to many cell surface proteins and matrix proteoglycans.

Macroion surfaces are modified by a counterion atmosphere enriched in oppositely charged small ions, mainly Na⁺, K⁺, and Cl^–. The counterion atmosphere is greatly affected by the ionic strength of the solution. At low ionic strength, the counterion atmosphere is diffuse and there is minimal interference to interactions of macroions. At high ionic strength, the counterion atmosphere is concentrated about the macroions and effectively reduces their interactions. This explains the observation that increasing salt concentration of a solution containing protein increases the solubility of the protein.

Loss of Sodium, Chloride, and Potassium

Obligatory loss of fluids through skin, feces, and urine inevitably causes loss of sodium and chloride (see Chapter 35). Minimum obligatory loss of sodium in the absence of profuse sweating and gastrointestinal and renal diseases has been estimated to be approximately 0.04 to 0.185 g/day, which consists of 0.005 to 0.035 g/day in urine, 0.01 to 0.125 g/day in feces, and dermal losses of 0.025 g/day (Dahl, 1958). Studies over a 12-day period have shown that sweat and fecal excretion accounted for only 2% to 5% of total sodium excretion in adults who consume an average intake of salt; the remainder of the salt consumed was excreted in the urine (Sanchez-Castillo et al., 1987b). However, loss of sodium can increase greatly under certain circumstances, such as diarrhea, diabetes, and profuse sweating during strenuous physical activity in hot weather. Under most but not all circumstances, loss of sodium is accompanied by a similar molar loss of chloride.

As with sodium and chloride, obligatory loss of fluid also causes loss of potassium. In a healthy adult, potassium loss via these routes is less than 0.8 g/day, with less than 0.4 g via fecal loss, 0.2 to 0.4 g via urinary loss, and negligible amounts from sweat (National Research Council, 1989).

Dietary sodium is consumed mainly as sodium chloride, with small amounts as sodium bicarbonate, sodium glutamate, and sodium citrate. These sodium salts are low in fresh vegetables and fresh fruits but high in cured meat products, processed foods, and canned vegetables. Studies in a British population found that only 10% of sodium intake came from natural foods, 15% from table salt added during cooking and at the table, and 75% from salts added during manufacturing and processing (Sanchez-Castillo et al., 1987a). The amount of chloride consumed parallels the amount of sodium, as dietary chloride is consumed almost exclusively as a salt of sodium.

Daily salt consumption has been estimated by assessing salt intake or measuring urinary sodium excretion. Usually consumption far exceeds the needs of an individual, although it varies widely between individuals and cultures.

Americans consume between 1.8 and 5 g/day of sodium or between 4.8 and 13 g/day of sodium chloride (National Research Council, 1989). This wide range of reported intakes is due to the different methods of assessment and to the large variability of discretionary salt intake. Individuals consuming a diet high in processed foods have high salt intakes. In Japan, where consumption of salt-preserved fish and the use of salt for seasoning are customary, salt intake is high, ranging from 14 to 20 g/day (Kono et al., 1983). Conversely, salt consumption estimated from urinary sodium excretion of the Yanomami Indians in Brazil is very low, 0.053 g/day of sodium chloride (Mancilha-Carvalho and Souza e Silva, 2003). Vegetarians typically consume an average of 0.8 g/day of sodium chloride. Individuals with low or very low sodium intakes do not normally exhibit chronic deficiencies because of the efficiency of the body’s mechanism of salt conservation.

Potassium is widely distributed in foods, especially in vegetables and fruits. Intakes of potassium vary widely, depending on dietary habits. Based on the NHANES III data, the median intake of potassium in the United States is about 3.3 g/day for men and 2.2 g/day for women (IOM, 2004). These values do not include the use of salt substitutes or reduced-sodium salts. Salt substitutes contain from 0.4 to

2.8 g potassium per teaspoon as potassium chloride. Because of the growing evidence of the beneficial effects of potassium in protecting against cardiovascular diseases and reducing cardiovascular disease mortality, concern of possible underconsumption of potassium has led to recommendations for increased intake of dietary fruits and vegetables (He and MacGregor, 2008).

Renal Excretion of Sodium, Chloride, and Potassium

These electrolytes are filtered freely from the glomerular capillaries across the glomerular membrane into the Bowman’s space of the nephrons (functional units of the kidneys) so that their concentrations in the glomerular filtrate are similar to those in the plasma. As the filtrate flows along the renal tubules, reabsorption of Na⁺, Cl^–, and K⁺ and secretion of K⁺ by renal tubular cells alter the concentrations of these electrolytes in the urine. Figure 34-4 illustrates the basic renal processing of Na⁺, Cl^–, and K⁺. Normally 95% to 98% of the filtered load of these ions and water are reabsorbed by the proximal tubules, the thick ascending limbs of the loop of Henle, and the distal convoluted tubules, irrespective of intakes. Reabsorption of the remaining 2% to 5% of the filtered Na⁺, Cl^–, and water, and the secretion of K⁺ in the cortical collecting tubules are variable and depend greatly on the needs of the individual.

When intake of sodium is high, reabsorption of Na⁺ from the cortical collecting tubule is low so that the excess Na⁺ is excreted in the urine. However, when there is a sodium deficit due to low intake or excessive loss via the skin or the gastrointestinal tract, much of the Na⁺ in the filtrate is reabsorbed, resulting in very low Na⁺ concentration in the urine. In contrast to Na⁺, K⁺ is secreted by the tubular cells of the cortical collecting tubules (Rodriguez-Soriano, 1995). In the absence of disease, changes in K⁺ excretion are not due to changes in reabsorption of K⁺ in the proximal tubules but to changes in K⁺ secretion by the cortical collecting tubules. During potassium depletion, most of the filtered K⁺ is reabsorbed, and virtually no K⁺ is excreted. The small amount of K⁺ excreted comes from the filtered K⁺ that escaped reabsorption. However, when potassium intake is high, secretion of K⁺ is increased, thereby eliminating the excess potassium. A normal Western diet contains about 2 to 3 g/day of potassium and requires secretion of K⁺ in order to maintain potassium balance.

Control of Renal Excretion of Sodium and Chloride

No important receptors capable of detecting the amount of sodium in the body have been identified. However, because Na⁺ is the main determinant of extracellular fluid volume, physiological mechanisms that control the volume of extracellular fluid effectively maintain a balance for sodium and chloride (Hall, 2011c). Changes in extracellular fluid volume lead to corresponding changes in the effective circulating volume and affect the “fullness” or “pressure” in the circulation. This changes cardiac filling pressure, cardiac output, and arterial pressure. Volume or pressure sensors (baroreceptors) that detect these changes are located throughout the vascular system. These baroreceptors send either excitatory or inhibitory signals to the central nervous system and the endocrine glands to effect appropriate responses by the kidneys to match the amount of sodium ingested. Three major mechanisms participate in the regulation of sodium balance: (1) vascular pressure receptors and their efferent renal sympathetic and arginine vasopressin (AVP) pathways, (2) the renin–angiotensin–aldosterone system, and (3) natriuretic peptides. Two of these mechanisms, vascular pressure receptors and their corresponding efferent pathways, and the renin–angiotensin–aldosterone system, respond effectively to hypovolemia by conservation of body sodium and water, whereas the natriuretic peptides are effective in hypervolemia when excess sodium and water are excreted in the urine (Hall, 2011b, 2011c, 2011d).

Vascular Pressure Receptors, Renal Sympathetic and Arginine Vasopressin Pathways

This reflex mechanism involves vascular pressure receptors (baroreceptors) that sense changes in circulating volume, afferent nerve fibers from these baroreceptors to the central nervous system, and the central efferent pathways to the kidneys. Secretion of a hormone, AVP (also called antidiuretic hormone), and changes in the renal sympathetic nerve activity modify renal excretion of sodium and water, thus minimizing the changes in circulating volume.

Baroreceptors and Afferent Pathways

Baroreceptors present in several sites within the vascular bed sense changes in a physical parameter, such as stretch or tension. There are essentially two kinds of vascular baroreceptors, low-pressure receptors and high-pressure receptors. The low-pressure receptors located in the central venous portion of the circulation respond primarily to changes in blood volume, which distends the walls of the cardiac atria and the pulmonary vein. The high-pressure receptors located in the arterial side of the vascular tree respond primarily to changes in blood pressure in the walls of the aortic arch and the carotid sinus. These baroreceptors send impulses to the hypothalamic and medullary regions of the central nervous system by way of the vagus and the glossopharyngeal nerves.

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