5.1 Passive Permeability to Ions and Water

The epithelium of the small intestine exhibits a high passive permeability to salt and water that is a consequence of the leakiness of the junctions between epithelial cells. Osmotic equilibration between plasma and lumen is fairly rapid; therefore, large differences in ion concentration do not develop. These intercellular junctions are more permeable to cations than anions, so that lumen-to-blood concentration differences for Na⁺ and K⁺ are generally smaller than those for Cl^- and HCO₃. The colonic epithelium displays lower passive permeability to salt and water. This ionic permeability diminishes from cecum to rectum. It also decreases from duodenum to ileum. One consequence of this lower passive ionic permeability (higher electrical resistance) is that electric potential differences across the colonic epithelium are an order of magnitude greater than those in the small intestine (remember Ohm's law, E = IR, where E is electrical potential, I is electrical current, and R is electrical resistance). Active Na⁺ absorption, which is the main transport activity of the distal colon, generates a serosa-positive charge or potential difference (PD). Under the influence of aldosterone (i.e., salt depletion), this PD can be 60 mV or even higher. A 60 mV PD will thus sustain a 10-fold concentration difference for a monovalent ion such as K⁺. Most of the high K⁺ concentration in the rectum is accounted for, therefore, by the PD. Despite the high fecal K⁺ level, little K⁺ is lost in the stool, since stool volume (about 200-300 mL per day) is normally so low. In contrast, during high-volume (several liters per day) diarrhea of small bowel origin, the stool K⁺ concentration is considerably lower (10-30 mmol) but stool K⁺ loss is nonetheless great because of the large volumes involved. In such states, the stool K⁺ concentration is low (and the Na⁺ concentration relatively high) because diarrheal fluid passes through the colon too rapidly to equilibrate across the colonic epithelium.

The intestine, especially the small intestine, has the largest capacity for secreting water and electrolytes of any organ system in the body. In both the small bowel and the colon, secretion appears to arise predominantly, if not exclusively, in crypts; the more superficial villous tip epithelium is absorptive. Disease processes that result in damage to the villus or to superficial portions of the intestinal epithelium (e.g., viral enteritis) inevitably shift the overall balance between absorption and secretion toward secretion. This is especially important in patients with celiac disease, where there is villous atrophy as well as hypertrophy of the crypts of LieberkŸhn.

In the small intestine, active electrolyte and fluid absorption can be conceived of as either nutrient-dependent or nutrient-independent.

The absorptive processes for the nutrients glucose and neutral amino acids are Na⁺-dependent - i.e., one Na⁺ molecule is translocated across the brush border with each glucose or amino acid molecule (Figure 4). The sodium pump (Na⁺/K⁺-ATPase), which is located exclusively in the basolateral membrane of the enterocyte, extrudes Na⁺ that has entered the cell from the lumen, thereby maintaining a low intracellular Na⁺, a high intracellular K+ and a negative intracellular electric potential. This Na⁺/K⁺ pump provides the potential energy for uphill sugar and amino acid absorption. Glucose is cotransported with sodium. Patients in intestinal secretory states such as cholera can absorb glucose normally. Na⁺ (and thus water) are also absorbed, accompanying the transport of glucose. As a consequence, the fluid losses incurred by these patients can be replaced by oral glucose-electrolyte solutions¹ and do not require intravenous fluids unless the patient is comatose or too nauseated to drink the necessary large volumes of fluid to correct the dehydration. Application of this knowledge has had a major impact on world health, and especially on that of children, since the parts of the world where cholera-like diarrheas are prevalent generally have very limited hospital facilities and insufficient supplies of sterile electrolyte solutions.

Note 1: The WHO oral rehydration solution contains in mmol/L: glucose, 111; Na⁺, 90; K⁺, 20; Cl ^-, 80; HCO₃^-, 30.

5.2.2 NUTRIENT-INDEPENDENT TRANSPORT

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Nutrient-independent active absorption of electrolytes and water by intestinal epithelial cells occurs through several specific mechanisms, located at different levels of the mammalian intestinal tract (Figure 5 and Figure 6). All of these mechanisms have in common the Na⁺/K⁺-ATPase pump, located on the basolateral membrane, and also a requirement for luminal Na⁺.

In the distal colon (Figure 5), the luminal membrane contains Na⁺ channels, which can be blocked by low concentrations of the pyrazine diuretic amiloride. The Na⁺ entering through these channels in the luminal membrane is then extruded across the basolateral membrane by the Na⁺/K⁺-ATPase pump. Aldosterone increases the number of these channels and also, more slowly, increases the number of Na⁺/K⁺-ATPase pumps. Aldosterone therefore enhances active Na⁺ absorption in the distal colon. To a more limited extent, aldosterone also causes the appearance of Na⁺ channels more proximally in the colon and even in the distal ileum. Cl^- is absorbed along with Na⁺ and traverses the epithelium by both cellular and paracellular routes. Its transcellular route involves a Cl^-/HCO₃^- exchanger in the luminal membrane and Cl^- channels in the basolateral membrane. Intracellular mediators such as cyclic AMP (cAMP) do not appear to affect these Na⁺ channels. Thus, patients with secretory diarrheas, especially those who are salt-depleted and therefore have elevated blood levels of aldosterone, are able to reabsorb some of the secreted fluid in their distal colon. Spironolactone, which inhibits the action of aldosterone, can increase the severity of diarrhea in such patients.

In the more proximal colon and in the ileum, the luminal membrane contains Na⁺/H⁺ exchangers that permit net Na⁺ entry (Figure 6). The colon and the ileum (but not the jejunum) also have Cl^-/HCO₃^- exchangers in their luminal borders. Cell pH adjusts the relative rates of these two exchangers. Thus, H⁺ extrusion by Na⁺/H⁺ exchange can cause cell alkalinization, which then stimulates Cl^- entry and HCO₃^- extrusion by this Cl^-/HCO₃^- exchange. The latter exchanger increases cell H⁺, thereby sustaining Na⁺/H⁺ exchange. Increases in cell concentrations of cAMP and free Ca²⁺ inhibit the Na⁺/H⁺ exchange. Cyclic AMP and its agonists thereby cause cell acidification - which, in turn, inhibits Cl^-/HCO₃^- exchange. Therefore, electrolyte absorption in small and large intestinal segments (except the distal colon) can be down-regulated by hormones, neurotransmitters and certain luminal substances (bacterial enterotoxins, bile salts, hydroxylated fatty acids) that increase cell concentrations of cAMP or free Ca²⁺. For this reason, body fluid secreted in response to these stimuli cannot be effectively reabsorbed in the absence of amino acids and sugars, except in the distal colon. In the jejunum, where Cl^-/HCO₃^- exchange does not appear to be present, Na⁺/H⁺ exchange can be well sustained by anaerobic glycolysis, which generates H⁺ as well as some ATP.

There is also some evidence for a direct cotransport of Na⁺ and Cl^-, although this is difficult to separate experimentally from dual exchangers. This entry mechanism may exist in the ileum and proximal colon.

In the secretory cell, the entry of Cl^- from the contraluminal bathing medium (blood or serosal side of the enterocyte) is coupled to that of Na⁺ and probably also K⁺ by a triple cotransporter with a stoichiometry of 1 Na⁺, 1 K⁺ and 2 Cl^-. Na⁺ entering in this fashion is then recycled to the contraluminal solution by the Na⁺/K⁺ exchange pump (Figure 7). K⁺, entering via the pump and also the triple cotransporter, diffuses back to the contraluminal side through K⁺ channels. Owing to the Na⁺ gradient, Cl^- accumulates above electrochemical equilibrium and can either (1) recycle back to the contraluminal solution through the Na⁺/K⁺/2 Cl^- cotransporter or through basolateral membrane Cl^- channels, or (2) be secreted into the lumen through luminal membrane Cl^- channels. When Cl^- is secreted into the lumen it generates a serosa-positive electric potential difference, which provides the driving force for Na+ secretion through the paracellular pathway between cells. In the resting secretory cell, the luminal Cl^- channels are closed. When secretion is stimulated by a hormone or neurotransmitter, these channels open. Secretion is initiated, therefore, by opening the Cl^- "gate" in the luminal membrane of the secretory cell.

The known intracellular mediators of secretion are cAMP, cGMP and Ca²⁺ (Table 2).

Predictably, since there are hormones and neurotransmitters that stimulate active electrolyte secretion in the gut, there are also agonists that inhibit secretion and/or stimulate absorption. These include adrenocorticosteroids, norepinephrine, somatostatin, enkephalins and dopamine. Glucocorticoids enhance electrolyte absorption throughout the intestinal tract, but the mechanisms involved are less well understood than for aldosterone. They may act in part by inhibiting phospholipase A₂ and therefore the arachidonic acid cascade. The adrenergic receptors on enterocytes are almost exclusively a₂ in type. The sympathetic nervous system in the intestinal mucosa releases norepinephrine (an a₂ antagonist) and so inhibits electrolyte secretion and stimulates absorption. Sympathectomy, whether chemical or surgical, leads to diarrhea, at least transiently. Chronic diabetics with autonomic neuropathy sometimes develop persistent diarrhea that is associated with degeneration of adrenergic nerve fibers to the gut. Somatostatin and endogenous enkephalins are also antisecretory.