Medical Physiology, 3rd Edition

Cellular Mechanisms of Na+ Absorption

Both the small intestine and the large intestine absorb large amounts of Na+ and Cl daily, but different mechanisms are responsible for this extremely important physiological process in different segments of the intestine. The villous epithelial cells in the small intestine and the surface epithelial cells in the colon are responsible for absorbing most of the Na+. Absorption of Na+ is the result of a complex interplay of both apical and basolateral membrane transport processes. Figure 44-3 summarizes the four fundamental mechanisms by which Na+ may enter the cell across the apical membrane. In each case, the Na-K pump is responsible, at least in part, for the movement of Na+ from cell to blood. Also in each case, the driving force for apical Na+ entry is provided by the large, inwardly directed electrochemical gradient for Na+, which in turn is provided by the Na-K pump.

image

FIGURE 44-3 Modes of active Na+ absorption by the intestine. A, Nutrient-coupled Na+ absorption occurs in the villous cells of the jejunum and ileum and is the primary mechanism for postprandial Na+ absorption. B, Electroneutral Na-H exchange at the apical membrane, in the absence of Cl-HCO3 exchange, is stimulated by the high pH of the image-rich luminal contents. C, Na-H and Cl-HCO3 exchange may be coupled by an intracellular pH, resulting in electroneutral NaCl absorption, the primary mechanism for interdigestive Na+ absorption. D, In electrogenic Na+ absorption, the apical step of Na+ movement occurs via ENaC channels. The thickness of the arrows in the insets indicates the relative magnitudes of Na+ absorptive fluxes in different segments. CA, carbonic anhydrase.

The following four sections describe these four apical membrane transport processes.

Na/glucose and Na/amino-acid cotransport in the small intestine is a major mechanism for postprandial Na+ absorption

“Nutrient-coupled” Na+ absorption (see Fig. 44-3A) occurs throughout the small intestine. Although glucose- and amino acid–coupled Na+ absorption also takes place in the colon of the newborn, it disappears during the neonatal period. Glucose- and amino acid–coupled Na+ absorption occurs only in villous epithelial cells and not in crypt epithelial cells (see Fig. 44-1A). This process is the primary mechanism for Na+absorption after a meal, but it makes little contribution during the interdigestive period, when only limited amounts of glucose and amino acids are present in the intestinal lumen.

Glucose- and amino acid–coupled Na+ absorption is mediated by specific apical membrane transport proteins. The Na/glucose cotransporter SGLT1 (see pp. 121–122) is responsible for glucose uptake across the apical membrane, as discussed in Chapter 45. Several distinct Na/amino-acid cotransporters, each specific for a different class of amino acids (see Table 36-1), are responsible for the Na+-coupled uptake of amino acids across the apical membrane. Because these transporters couple the energetically downhill movement of Na+ to the uphill movement of glucose or an amino acid, the transporter processes are examples of secondary active transport (see p. 115). The glucose and amino acid–coupled uptake of Na+ entry across the apical membrane increases [Na+]i, which in turn increases Na+ extrusion across the basolateral membrane through the Na-K pump. Because the apical Na/glucose and Na/amino-acid cotransporters are electrogenic, as is the Na-K pump, the overall transport of Na+ carries net charge and makes Vte more lumen negative. Thus, glucose- and amino acid–stimulated Na+ absorption is an electrogenic process. As discussed below, the increase in the lumen-negative Vte provides the driving force for the parallel absorption of Cl.

Nutrient-coupled Na+ transporters, unlike other Na+ absorptive mechanisms in the small intestine, are not inhibited by either cAMP or [Ca2+]i. Thus, agonists that increase [cAMP]i (i.e., Escherichia coli or cholera enterotoxins) or [Ca2+]i (i.e., serotonin) do not inhibit glucose- or amino acid–stimulated Na+ absorption.

Electroneutral Na-H exchange in the duodenum and jejunum is responsible for Na+ absorption that is stimulated by luminal alkalinity

Luminal image—the result of pancreatic, biliary, and duodenal secretion—increases Na+ absorption in the proximal portion of the small intestine by stimulating apical membrane Na-H exchange (see Fig. 44-3B). The Na-H exchanger couples Na+ uptake across the apical membrane to proton extrusion into the intestinal lumen, a process that is enhanced by both decreases in intracellular pH (pHi) and increases in luminal pH. The energy for Na-H exchange comes from the Na+ gradient, a consequence of the ability of the Na-K pump to extrude Na+, thereby lowering [Na+]i. This process is characteristically inhibited by millimolar concentrations of the diuretic amiloride (Box 44-1).

Box 44-1

Oral Rehydration Solution

The therapeutic use of oral rehydration solution (ORS) provides an excellent demonstration of applied physiology. Many diarrheal illnesses (see Box 44-3) are caused by bacterial exotoxins that induce fluid and electrolyte secretion by the intestine. Hence such a toxin is referred to as an enterotoxin. Despite the massive toxin-induced fluid secretion, both intestinal morphology and nutrient-coupled Na+absorption are normal. Because nutrient-coupled (e.g., glucose- or amino acid–coupled) fluid absorption is intact, therapeutically increasing the concentration of glucose or amino acids in the intestinal lumen can enhance absorption. ORS contains varying concentrations of glucose, Na+, Cl, and image and is extremely effective in enhancing fluid and electrolyte absorption in secretory diarrhea when the intestine secretes massive amounts of fluid. Administration of ORS can reverse the dehydration and metabolic acidosis that may occur in severe diarrhea and that are often the primary cause of morbidity and mortality, especially in children younger than 5 years. ORS is the major advance of the past half century in the treatment of diarrheal disease, especially in developing countries. The development of ORS was a direct consequence of research on the physiology of glucose- and amino acid–stimulated Na+ absorption.

Several isoforms of the Na-H exchanger exist (see p. 124), and different isoforms are present on the apical and basolateral membranes. Intestinal epithelial cells also have Na-H exchangers on their basolateral membranes. However, this NHE1 isoform, like its counterpart in nonepithelial cells, regulates pHi (a “housekeeping” function) and does not contribute to the transepithelial movement of Na+. In contrast, both the NHE2 and NHE3 exchanger isoforms present on the apical membrane are responsible for transepithelial Na+ movement and pHi regulation. Although Na-H exchangers are present on the apical membrane of villous epithelial cells throughout the entire intestine, only in the duodenum and jejunum (i.e., the proximal part of the small intestine) is Na-H exchange present without the parallel presence of Cl-HCO3exchangers (see next section). Thus, in the proximal portion of the small intestine, the Na-H exchanger solely mediates the Na+ absorption that is stimulated by the alkalinity of the image-rich intraluminal contents.

Parallel Na-H and Cl-HCO3 exchange in the ileum and proximal part of the colon is the primary mechanism of Na+ absorption during the interdigestive period

Electroneutral NaCl absorption occurs in portions of both the small and large intestine (see Fig. 44-3C). Electroneutral NaCl absorption is the result not of an Na/Cl cotransporter but rather of parallel apical membrane Na-H and Cl-HCO3 exchangers that are closely linked by small changes in pHi. In the human colon, DRA (downregulated-in-adenoma, SLC26A3; see Table 5-4) mediates this Cl-HCO3 exchange. This mechanism of NaCl absorption is the primary method of Na+ absorption between meals (i.e., the interdigestive period), but it does not contribute greatly to postprandial Na+ absorption, which is mediated primarily by the nutrient-coupled transporters described previously. Electroneutral NaCl absorption occurs in the ileum and throughout the large intestine, with the exception of the most distal segment. It is not affected by either luminal glucose or luminal image.

The overall electroneutral NaCl absorptive process is under the control of both cAMP and cGMP, as well as intracellular Ca2+. Increases in each of these three intracellular messengers reduce NaCl absorption. Conversely, decreases in [Ca2+]i and increases in aldosterone both increase electroneutral NaCl absorption.

Decreased NaCl absorption is important in the pathogenesis of most diarrheal disorders. For example, one of the common causes of traveler's diarrhea (see Box 44-3) is the heat-labile enterotoxin produced by the bacterium E. coli. This toxin activates adenylyl cyclase and increases [cAMP]i, which in turn decreases NaCl absorption and stimulates active Cl secretion, as discussed below (see pp. 905–908). This toxin does not affect glucose-stimulated Na+ absorption (see pp. 903–904).

Epithelial Na+ channels are the primary mechanism of “electrogenic” Na+ absorption in the distal part of the colon

In electrogenic Na+ absorption (see Fig. 44-3D), Na+ entry across the apical membrane occurs through epithelial Na+ channels (ENaCs) that are highly specific for Na+ (see pp. 137–138). Like the Na-H exchanger, these ENaCs are blocked by the diuretic amiloride, but at micromolar rather than millimolar concentrations. Na+ absorption in the distal part of the colon is highly efficient. Because this segment of the colon is capable of absorbing Na+ against large concentration gradients, it plays an important role in Na+ conservation. Na+ movement via electrogenic Na+ absorption is not affected by luminal glucose or by image, nor is it regulated by cyclic nucleotides. However, it is markedly enhanced by mineralocorticoids (e.g., aldosterone).

Mineralocorticoids increase Na+ absorption in the colon—as in other aldosterone-responsive epithelia, notably the renal collecting duct (see pp. 765–766)—via multiple mechanisms. Aldosterone increases electrogenic Na+ absorption by increasing Na+ entry through the apical Na+ channel and by stimulating activity of the Na-K pump. The increase in apical Na+ uptake can occur (1) rapidly (i.e., within seconds) as a consequence of an increase in the opening of apical Na+ channels, (2) more gradually (within minutes) because of the insertion of preformed Na+ channels from subapical epithelial vesicle pools into the apical membrane, or (3) very slowly (within hours) as a result of an increase in the synthesis of both new apical Na+ channels and Na-K pumps.

 

SMALL INTESTINE

LARGE INTESTINE

Length (m)

6

2.4

Area of apical plasma membrane (m2)

~200

~25

Folds

Yes

Yes

Villi

Yes

No

Crypts or glands

Yes

Yes

Microvilli

Yes

Yes

Nutrient absorption

Yes

No

Active Na+ absorption

Yes

Yes

Active K+ secretion

No

Yes