Stimulation of active and passive sodium absorption by sugars in the human jejunum.

The effects of glucose and fructose on water and sodium absorption in the human jejunum were compared to assess the relative contribution of active and passive sugar stimulation of sodium transport. The effect of fructose is assumed to be entirely passive, and the difference between the effects of fructose and glucose is assumed to be a measure of sugar-stimulated, active sodium absorption. Water and sodium movement with mannitol was the base line. Three sets of test solutions with differing sugar concentrations were studied. Fructose stimulated 66-100 per cent as much net sodium and water absorption as glucose. Fructose stimulated potassium absorption, whereas glucose stimulated potassium secretion. Urea absorption was stimulated by both sugars. Glucose and fructose stimulated sodium absorption when chloride was the major anion, but they had relatively little effect on net sodium movement when chloride was replaced by bicarbonate or sulfate. It is concluded that glucose stimulates passive and active sodium transport in the human jejunum. Stimulated active sodium absorption generates an electrical potential across the mucosa that causes sodium (and potassium) secretion and partly or completely nullifies the effect of active sodium transport on net sodium movement. Net sodium absorption sitmulated by glucose is mainly (66-100 per cent) the passive consequence of solvent flow. The accompanying anion determines the degree to which sugars stimulate sodium absorption (C1 greater than SO-4 greater than HCO3). The effects of bicarbonate and sugars on jejunal sodium absorption are not additive.

PIP: The carrier interaction and solvent drag components of sugar-stimulated sodium absorption were evaluated by comparing the effects of mannitol, fructose, and glucose on jejunal absorption of water, sodium, potassium, and urea. Using water and sodium movement with mannitol as the baseline, 3 sets of test solutions with differing sugar concentrations were studied. Fructose stimulated 66-100% as much net sodium and water absorption as glucose; in addition, fructose stimulated potassium absorption, whereas glucose stimulated potassium secretion. Both sugars stimulated urea absorption. When chloride was the major anion in the solution, glucose and fructose stimulated sodium absorption, however, the sugars had little effect on net sodium movement when chloride was replaced by bicarbonate or sulfate. From these observations it was concluded that glucose stimulates both passive and active sodium transport in human jejunum. Active sodium absorption generates an electrical potential causing secretion. Net sodium absorption stimulated by glucose was mainly the passive consequence of solvent flow. The effects of bicarbonate and sugars on jejunal sodium absorption were not additive.

Gastric acid secretion rate and buffer content of the stomach after eating. Results in normal subjects and in patients with duodenal ulcer.

New methods are described by which the buffer content and the rate and pattern of net gastric acid secretion in human subjects fed normal meals can be measured by use of sodium bicarbonate infusion to control intragastric pH. With these techniques, it was shown that the rate of acid secretion in response to a steak meal in seven duodenal ulcer patients was twice the rate achieved in six control subjects and that the amount of acid secreted after eating exceeded the peak histamine response in the ulcer patients but not in the controls. Meal-stimulated acid secretion, expressed as a function of the peak histamine response, was roughly correlated with the serum gastrin concentration (r = 0.45), but it was concluded that other factors must also contribute to the higher than normal secretory responses to a meal found in duodenal ulcer patients. Measurement of buffer content of the stomach revealed that the duodenal ulcer patients emptied the meal buffer at a much more rapid rate than the normal subjects. By 2 h after eating, the ulcer subjects had less than half as much buffer in their stomachs as the controls. The combination of acid hypersecretion and rapid buffer emptying leads to abnormally high gastric acidity after a meal in duodenal ulcer patients. These results suggest that, in addition to a large parietal cell mass, parietal cell responsiveness to a meal and the rate of buffer emptying may be important in the pathogenesis of duodenal ulcer.

Effect of dietary calcium and age on jejunal calcium absorption in humans studied by intestinal perfusion.

Jejunal calcium absorption was measured from test solutions containing 1.0, 2.5, 5, and 10 mM calcium (as calcium gluconate). Absorption rates increased progressively as luminal calcium concentration was increased, although there was a tendency toward saturation of the absorptive process at the higher concentrations. Calcium absorption was higher in normal young adults than in normal subjects over age 60. In both groups a 300 mg calcium diet for 4-8 wk enhanced calcium absorption relative to absorption rates after 4-8 wk on a 2,000 mg calcium diet. This adaptation was more definite and dramatic in the young than in the old subjects. Indirect estimates suggest that adaptation to a low calcium diet and the higher absorption in young than old normal subjects are mediated by an increased V(max) rather than a decreased K(m).

The role of intraluminal sodium in glucose absorption in vivo.

Active glucose absorption is thought to depend on a gradient of sodium ion concentration across the brush border membrane of intestinal epithelial cells. This concept is generally accepted, although its validity has never been adequately evaluated in the human small intestine in vivo. According to this hypothesis, the rate of glucose absorption should decrease markedly if the luminal sodium concentration is markedly reduced, and glucose absorption against a concentration gradient should cease entirely if luminal sodium is lower than intracellular sodium concentration. In the present series of experiments we were not able to show an important role of intraluminal sodium concentration in the active absorption of glucose from the human, rat, and dog ileum in vivo. Specifically, glucose absorption was minimally reduced or not reduced at all when intraluminal sodium concentration was reduced from 140 to as low as 2.5 mEq/liter. The discrepancy between our results and those of previous workers whose data suggest that removal of intraluminal sodium should markedly inhibit active glucose absorption is not entirely clear, but there are a number of differences in experimental design between most previous studies and our own. Although our data show that active glucose absorption proceeds at a near normal rate even when lumen sodium concentration is reduced below 3 mEq/liter, our results do not disprove the sodium gradient theory because of the theoretic possibility that the microclimate adjacent to the brush border has a high concentration of sodium even when luminal sodium concentration is markedly reduced. The validity of the sodium gradient hypothesis would appear to be critically dependent on such a microclimate.

Thyrocalcitonin and the jejunal absorption of calcium, water, and electrolytes in normal subjects.

Jejunal absorption of calcium, water, and electrolytes was measured in 10 normal subjects by the triple-lumen perfusion method. During the control period, water and electrolyte movements were minimal when a bicarbonate-free test solution was infused. By contrast, bicarbonate-containing solutions were readily absorbed in the control period. Intravenous infusion of synthetic salmon calcitonin (SCT) (1 Medical Research Council U/kg wt/h) over 110-120 min resulted in a marked jejunal secretion of water, sodium, potassium, and chloride in 8 of the 10 subjects. This jejunal secretion occurred with both the bicarbonate-free and the bicarbonate-containing test solutions. Calcium absorption was not affected by SCT, and the serum calcium concentration did not fall during SCT infusion. These results suggest that diarrhea in patients with medullary carcinoma of the thyroid may be due to intestinal secretion secondary to high blood concentrations of thyrocalcitonin.

pH dependence of acid secretion and gastrin release in normal and ulcer subjects.

By use of a recently described method, which estimates the rate of gastric acid secretion by measuring the rate of sodium bicarbonate infusion needed to keep intragastric pH constant, gastric acid secretion rates and changes in serum gastrin were measured in five normal subjects while gastric pH was kept at 5.5, 4.0, 3.0, or 2.5. Preliminary experiments revealed that the method did not accurately measure acid secretion at a pH lower than 2.5. Stimulation of acid secretion was produced by gastric instillation of a solution of amino acids and cornstarch. The secretion rate with the amino acid meal was highest at pH 5.5 and was 60% of that produced by a steak meal at the same pH. As the pH of the amino acid meal was decreased, there was a stepwise reduction in acid secretion so that at pH 2.5 the rate was only half as great as at pH 5.5. The amino acid meal produced increases in serum gastrin that were also less marked than those produced by a steak meal. With amino acid stimulation, serum gastrin responses were similar at pH 5.5, 4.0, and 3.0, but no increase in gastrin could be measured when the meal was maintained at pH 2.5. A group of six patients with duodenal ulcers was compared with seven normal subjects at pH 5.5 and 2.5. Ulcer patients released more gastrin and secreted more acid at each time period at both pH values. More important, the degree of inhibition at pH 2.5 was significantly less in ulcer patients. For example, during the 2nd h after stimulation acid secretion was inhibited by only 30% in ulcer patients compared with 70% in normal subjects. These findings suggest a defect in autoregulation of gastrin release and gastric acid secretion at low pH in ulcer patients which may play a role in pathogenesis of this disease.

Pathogenesis of congenital alkalosis with diarrhea. Implications for the physiology of normal ileal electrolyte absorption and secretion.

Using a triple-lumen constant perfusion system, we have studied ileal electrolyte transport in a patient with congenital alkalosis with diarrhea and made the following observations. First, chloride cannot be transported against electrochemical gradients, but can be readily absorbed or secreted down electrochemical gradients. Second, chloride secretion down an electrochemical gradient can be increased by raising lumen bicarbonate concentration. Third, sodium absorption does occur against electrochemical gradients and is associated with hydrogen ion secretion. Fourth, electrical potential difference (PD) between lumen and blood is near zero when lumen sodium concentration is 140 mEq/liter. Fifth, a normal sodium diffusion potential is present. Sixth, potassium is transported passively in response to electrochemical gradients. The ileal electrolyte transport disorder of congenital alkalosis with diarrhea can be simulated exactly in normal subjects perfused with a solution in which chloride is replaced with poorly absorbable sulfate and phosphate. These results can be explained by postulating a single defect in the double ion exchange model (sodium-hydrogen, chloride-bicarbonate) previously proposed for normal ileal transport: i.e., normal sodium-hydrogen exchange, but a chloride-bicarbonate exchange that is incapable of transporting chloride against an electrochemical gradient, yet continues to transport anions passively. In contrast, the results appear incompatible with the concept of ileal electrogenic sodium transport.

The mechanisms of sodium absorption in the human small intestine.

The present studies were designed to characterize sodium transport in the jejunum and ileum of humans with respect to the effects of water flow, sodium concentration, addition of glucose and galactose, and variations in aniomic composition of luminal fluid. In the ileum, sodium absorption occurred against very steep electrochemical gradients (110 mEq/liter, 5-15 mv), was unaffected by the rate or direction of water flow, and was not stimulated by addition of glucose, galactose, or bicarbonate. These findings led to the conclusion that there is an efficiently active sodium transport across a membrane that is relatively impermeable to sodium. In contrast, jejunal sodium (chloride) absorption can take place against only the modest concentration gradient of 13 mEq/liter, was dramatically influenced by water movement, and was stimulated by addition of glucose, galactose, and bicarbonate. The stimulatory effect of glucose and galactose was evident even when net water movement was inhibited to zero by mannitol. These observations led to the conclusion that a small fraction of jejunal sodium absorption was mediated by active transport coupled either to active absorption of bicarbonate or active secretion of hydrogen ions. The major part of sodium absorption, i.e. sodium chloride absorption, appeared to be mediated by a process of bulk flow of solution along osmotic pressure gradients. The stimulatory effect of glucose and galactose, even at zero water flow, was explained by a model in which the active transport of monosaccharide generates a local osmotic force for the absorption of solution (NaCl and water) from the jejunal lumen, which, in the presence of mannitol, is counterbalanced by a reverse flow of pure solvent (H(2)O) through a parallel set of channels which are impermeable to sodium. Support for the model was obtained by the demonstration that glucose and bicarbonate stimulated the absorption of the nonactively transported solute urea even when net water flow was maintained at zero by addition of mannitol to luminal contents.

Studies on the mechanisms of food-stimulated gastric acid secretion in normal human subjects.

Liquid test meals were infused into the stomach and acid secretion was measured by intragastric titration at pH 5.0 Acid secretion after 500 or 750-ml sodium chloride meals was two to three times higher than basal secretion rates and was equivalent to 25-30% of the peak acid output in response to histamine. Since these meals did not cause a rise in serum gastrin concentration, it is assumed that they stimulate acid secretion by causing distention of the body and fundus of the stomach. Compared with this distention stimulus, glucose meals had no effect on acid secretion and fat-inhibited acid secretion; however, both glucose and fat caused an increase in serum gastrin concentration. Amino acids caused a much greater increase in serum gastrin concentration and enhanced acid secretion above that noted with distention alone. In contrast, albumin did not enhance the serum gastrin concentration or stimulate acid secretion to a statistically significant extent. There was a close correlation between the rise in serum gastrin concentration and rate of acid secretion after different test meals when average results for each test meal were plotted. However, there was a poor correlation between acid secretion and serum gastrin concentration when the responses of the individual subjects with a given test meal were compared. Our interpretations are: (a) Distention is an important stimulant of the acid-secretory response to a meal, and this is not mediated by gastrin release. (b) Gastrin is one but probably not the only mediator of the chemical phase of acid secretion, i.e., acid secretion noted with amino acids that cannot be explained by distention. (c) Glucose and fat also release gastrin; however, with glucose the rise in serum gastrin is too small and too transient to enhance acid secretion, and fat probably releases unmeasured inhibitors that overwhelm the effect of gastrin on acid secretion. (d) Albumin is not a stimulant of acid secretion.

Intestinal secretion induced by vasoactive intestinal polypeptide. A comparison with cholera toxin in the canine jejunum in vivo.

The effect of vasoactive intestinal polypeptide (VIP) on intestinal water and electrolyte transport and transmucosal potential difference was investigated in the dog jejunum in vivo and compared to secretion induced by cholera toxin. Isolated jejunal loops were perfused with a plasma-like electrolyte solution. VIP (0.08 mug/kg per min) was administered directly into the superior mesenteric artery by continuous infusion over 1 h. From a dye dilution method, it was estimated that a mean plasma VIP concentration of 12,460 pg/ml reached the loops. VIP caused secretion of water and electrolytes; for example, chloride: control, 8 mueq/cm per h absorption; VIP, 92 mueq/cm per h secretion. A marked increase in transmucosal potential difference (control, -1.0 mV; VIP, -5.9 mV, lumen negative) occurred within 1 min after starting VIP infusion. Analysis of unidirectional fluxes showed increased plasma-to-lumen flux of sodium and chloride and decreased lumen-to-plasma flux of sodium. Chloride and bicarbonate were actively secreted against an electrochemical gradient. Although sodium secretion occurred down an electrochemical gradient, flux ratio analysis suggested a component of active sodium secretion. VIP caused a slight increase in protein output into the loops; light microscopy revealed capillary dilatation and closed intercellular spaces. The effect of VIP was readily reversible. Except for the delayed onset of secretion, the effect of cholera toxin was qualitatively similar to VIP; however, capillary dilatation and increased protein output were not noted with cholera toxin.

An evaluation of the significance of microscopic colitis in patients with chronic diarrhea.

Some patients with chronic idiopathic diarrhea have an apparent nonspecific inflammation of colonic mucosa, even though their colons appear normal by barium enema and colonoscopy. This has been referred to as microscopic colitis. However, the significance of this finding is unclear, because the ability of pathologists to accurately distinguish mild degrees of abnormality has not been established. Furthermore, even if the mucosa of these patients is nonspecifically inflamed, it is not known whether this is associated with deranged colonic function that could contribute to the development of chronic diarrhea. To assess these questions, we first examined colonic biopsy specimens in a blinded fashion, comparing biopsy results from patients with microscopic colitis with biopsy specimens from subjects in two control groups. This analysis revealed that colonic mucosa from six patients with microscopic colitis was in fact abnormal. For example, their mucosa contained an excess of both neutrophiles and round cells in the lamina propria, cryptitis, and reactive changes. These and other differences were statistically significant. Second, colonic absorption, measured by the steady state nonabsorbable marker perfusion method, was severely depressed in the patients. For example, mean water absorption rate was 159 ml/h in normal subjects and was reduced to only 26 ml/h in six patients with microscopic colitis. Results of net and unidirectional electrolyte fluxes and of electrical potential difference suggested that colonic fluid absorption was abnormal because of reduced active and passive sodium and chloride absorption and because of reduced Cl/HCO3 exchange. Small intestinal fluid and electrolyte absorption was abnormally reduced in two of the six patients, suggesting the possibility of coexistent small intestinal involvement in some of these patients. We conclude that nonspecific inflammation of colonic mucosa is associated with a severe reduction of colonic fluid absorption, and that the latter probably contributes to the development of chronic diarrhea.

Studies of osmotic diarrhea induced in normal subjects by ingestion of polyethylene glycol and lactulose.

The purpose of these studies was to gain insight into the pathophysiology of pure osmotic diarrhea and the osmotic diarrhea caused by carbohydrate malabsorption. Diarrhea was induced in normal volunteers by ingestion of polyethylene glycol (PEG), which is nonabsorbable, not metabolized by colonic bacteria, and carries no electrical charge. In PEG-induced diarrhea, (a) stool weight was directly correlated with the total mass of PEG ingested; (b) PEG contributed 40-60% of the osmolality of the fecal fluid, the remainder being contributed by other solutes either of dietary, endogenous, or bacterial origin; and (c) fecal sodium, potassium, and chloride were avidly conserved by the intestine, in spite of stool water losses exceeding 1,200 g/d. Diarrhea was also induced in normal subjects by ingestion of lactulose, a disaccharide that is not absorbed by the small intestine but is metabolized by colonic bacteria. In lactulose-induced diarrhea, (a) a maximum of approximate 80 g/d of lactulose was metabolized by colonic bacteria to noncarbohydrate moieties such as organic acids; (b) the organic acids were partially absorbed in the colon; (c) unabsorbed organic acids obligated the accumulation of inorganic cations (Na greater than Ca greater than K greater than Mg) in the diarrheal fluid; (d) diarrhea associated with low doses of lactulose was mainly due to unabsorbed organic acids and associated cations, whereas with larger doses of lactulose unmetabolized carbohydrates also played a major role; and (e) the net effect of bacterial metabolism of lactulose and partial absorption of organic acids on stool water output was done dependent. With low or moderate doses of lactulose, stool water losses were reduced by as much as 600 g/d (compared with equimolar osmotic loads of PEG); with large dose, the increment in osmotically active solutes within the lumen exceeded the increment of the ingested osmotic load, and the severity of diarrhea was augmented.

Intestinal absorption of magnesium from food and supplements.

The purpose of this study was to measure magnesium absorption over the wide range of intakes to which the intestine may be exposed from food and/or magnesium-containing medications. Net magnesium absorption was measured in normal subjects after they ingested a standard meal supplemented with 0, 10, 20, 40, and 80 mEq of magnesium acetate. Although absorption increased with each increment in intake, fractional magnesium absorption fell progressively (from 65% at the lowest to 11% at the highest intake) so that absorption as a function of intake was curvilinear. This absorption-intake relationship was almost perfectly represented by an equation containing a hyperbolic function plus a linear function. Our results are statistically compatible with a magnesium absorption process that simultaneously uses a mechanism that reaches an absorptive maximum, plus a mechanism that endlessly absorbs a defined fraction (7%) of ingested magnesium. Compared to previous studies of calcium absorption, much less magnesium that calcium was absorbed at intakes above 8 mEq/meal, apparently due to greater restriction of intestinal permeability to magnesium. We also found that magnesium from a high magnesium-containing food source, almonds, was just as bioavailable as from soluble magnesium acetate. In contrast, magnesium absorption from commercially available enteric-coated magnesium chloride was much less than from magnesium acetate, suggesting that enteric coating can impair magnesium bioavailability.

Water and solute movement in the small intestine of patients with sprue.

Water and electrolyte movement in the jejunum of normal subjects and patients with sprue was measured during perfusion with isotonic electrolyte solutions. Normal subjects absorbed water, sodium, and potassium. By contrast, in patients with sprue (seven with adult celiac sprue and one with tropical sprue) who had diarrhea and steatorrhea, these substances were secreted into the intestinal lumen. This indicates that the jejunal mucosa of these patients was in a secretory state with respect to water and electrolytes.A method is presented for detecting abnormalities in the effective pore size in disease states. The method is based on the principle of restrictive diffusion and involves measuring the simultaneous diffusion rates of solutes of different molecular size. Since the method does not depend on measurement of water flow in response to osmotic pressure gradients, it can be used in disease states in which absorption and secretory processes involving water may be abnormal.The ratio of urea to tritiated water diffusion in the jejunum of normal subjects averaged 0.8, compared to 0.2 in patients with sprue. This indicates a marked decrease in the effective pore size of the jejunal mucosa in sprue. This conclusion was strengthened by the finding that erythritol and L-xylose, which are somewhat larger solutes than urea, are essentially non-absorbable in small bowel involved with sprue.

The effect of an H2-receptor antagonist on food-stimulated acid secretion, serum gastrin, and gastric emptying in patients with duodenal ulcers. Comparison with an anticholinergic drug.

The purpose of the present series of experiments was to measure and compare the effects of an anticholinergic drug (isopropamide) and an antagonist of the histamine H2 receptor (metiamide) on food-stimulated acid secretion. Patients with duodenal ulcers were stimulated by a steak meal, and acid secretion was measured by in vivo intragastric titration. The largest dose of isopropamide that can be taken clinically without producing intolerable side effects (maximum tolerated dose) suppressed food-stimulated acid secretion by 35%. By contrast, metiamide in a 400-mg dose produced no side effects and almost completely abolished food-stimulated acid secretion. A dose-response curve revealed that a 50-mg dose of metiamide was required to suppress food-stimulated acid secretion by 50%. Further studies showed that metiamide and isopropamide are additive in suppressing food-stimulated acid secretion, and that metiamide has no effect on serum gastrin concentration or on gastric emptying.

Effect of continuous infusion of pentagastrin on lower esophageal sphincter pressure and gastric acid secretion in normal subjects.

Bolus injections of gastrin or pentagastrin (PG) cause a marked elevation in lower esophageal sphincter pressure (LESP), and it has been suggested that serum gastrin concentration is the main physiological and pathophysiological regulator of LESP. We evaluated this hypothesis by measuring LESP and gastric acid secretion simultaneously in normal subjects during continuous infusion of PG (0.004-12 mjg/kg per h), since continuous infusion of a hormone probably simulates physiological hormone release better than bolus injection. In groups of 8-13 subjects there was no statistically significant increase in average LESP with any of seven PG infusion rates. However, a bolus of PG superimposed on the continuous infusion of PG resulted in a 20-mm Hg increase in LESP. Examination of results in individual subjects suggested that PG by infusion might be stimulating LESP in some subjects and inhibiting it in others. Therefore, individual dose-response studies were performed in two normal subjects. These revealed that 0.9 mug/kg per h PG by infusion elevated LESP by 10-12 mm Hg. This dose of PG also elicited maximal rates of gastric acid secretion. In one of the subjects an infusion of PG calculated to give one-half maximal acid secretion (D50) elevated LESP by 8 mm Hg; in the other the PG-D50 for acid secretion had no effect on sphincter pressure. Infusion of smaller amounts of PG had no effect on LESP, even though gastric acid secretion was stimulated submaximally. Thus, the parietal cells are more sensitive than the lower esophageal sphincter to the effect of PG by infusion. We conclude that PG by continuous infusion elevates LESP to only a modest degree (compared with the contraction that occurs after bolus injections of PG) and that the contraction occurs only within a narrow dose range between the D50 and D100 for acid secretion. Higher doses cause transient relaxation of LESP. Additional studies showed that basal LESP varied between 16 and 71 mm Hg in two subjects studied on 29 separate occasions, but there was no correlation with basal acid secretion. This suggests that the wide day-to-day fluctuations in basal LESP are not due to changing concentrations of gastrin in serum. The results of these experiments cast doubt on the hypothesis that serum gastrin concentration is the major determinant of LESP.

Interrelationships of chloride, bicarbonate, sodium, and hydrogen transport in the human ileum.

Using a triple-lumen constant perfusion system, the following observations were made in normal subjects. First, chloride, bicarbonate, and sodium were found to exhibit net movement across ileal mucosa against electrochemical gradients. Second, during perfusion with a balanced electrolyte solution simulating plasma, the ileum generally absorbed, but sometimes secreted fluid. A reciprocal net movement of chloride and bicarbonate was noted when sodium movement was zero. Increasing rates of sodium absorption were associated with decreasing bicarbonate secretion rates and finally bicarbonate absorption. Even when bicarbonate was absorbed ileal contents were alkalinized (by contraction of luminal volume). Third, net chloride movement was found to be sensitive to bicarbonate concentration in ileal fluid. For instance, chloride was absorbed from solutions containing 14 or 44 mEq/liter of bicarbonate, but was secreted when ileal fluid contained 87 mEq/liter of bicarbonate. Fourth, when chloridefree (sulfate) solutions were infused, the ileum absorbed sodium bicarbonate and the ileal contents were acidified. Fifth, when plasma-like solutions were infused, the potential difference (PD) between skin and ileal lumen was near zero and did not change when chloride was replaced by sulfate in the perfusion solution. These results suggest that ileal electrolyte transport occurs via a simultaneous double exchange, Cl/HCO2 and Na/H. In this model neither the anion nor the cation exchange causes net ion movement; net movement results from the chemical reaction between hydrogen and bicarbonate. No other unitary model explains all of the following observations: (a) human ileal transport in vivo is essentially nonelectrogenic even though Na, Cl, and HCO3 are transported against electrochemical gradients, (b) the ileum can secrete as well as absorb, (c) ileal contents are alkalinized during absorption of or during secretion into a plasma-like solution, and (d) the ileum acidifies its contents when sulfate replaces chloride. Data obtained with a carbonic anhydrase inhibitor support the proposed model.

PIP: Studies using a triple-lumen perfusion system in normal subjects were conducted to elucidate mechanisms of ileal electrolyte absorption. 4 primary observations were made in this study of interrelationships of chloride, bicarbonate, sodium, and hydrogen transport in human ileum: 1) chloride, sodium, and bicarbonate all exhibited net movement across ileal mucosa against electrochemical gradients; 2) when perfusion was performed in conjunction with administration of a balanced electrolyte solution stimulating plasma, the ileum generally absorbed, but sometimes secreted fluid; 3) net chloride movement was sensitive to bicarbonate concentration in ileal fluids; and 4) infusion of chloride-free (sulfate) solutions showed that the ileum absorbed sodium bicarbonate and that the ileal contents were acidified. A model to explain these findings suggests that ileal electrolyte transport occurs via a simultaneous double exchange, Cl/HCO3 and Na/H. In this model, net movement results from the chemical reaction between hydrogen and bicarbonate, not because of anion or cationic exchange.

Mechanism of bicarbonate absorption and its relationship to sodium transport in the human jejunum.

Using a constant perfusion technique, sodium and bicarbonate absorption was studied in human subjects. The following observations were made on sodium absorption from saline solution: (a) the rate of sodium absorption is markedly influenced by bulk water flow, (b) when net water flow is zero, sodium absorption is zero if there are no concentration gradients between plasma and lumen that favor net NaCl diffusion; and (c) the PD between abraded skin and jejunal lumen is near zero when saline is perfused and does not change with partial substitution of sulfate or bicarbonate for chloride. Based on these observations, we conclude that sodium absorption from saline is entirely passive in the human jejunum. On the other hand, in the presence of bicarbonate sodium is absorbed actively against electrochemical gradients. The mechanism of the link between bicarbonate and sodium absorption was studied in normal subjects and in 11 patients with pernicious anemia; the latter were chosen because they do not secrete gastric acid which can react with bicarbonate in the jejunal lumen. We observed that bicarbonate absorption (a) occurs against steep electrochemical gradients, (b) does not generate a potential difference between abraded skin and jejunal lumen, (c) is inhibited by acetazolamide, and (d) generates a high CO2 tension in jejunal fluid. These observations suggest that bicarbonate absorption is mediated by active hydrogen secretion, rather than by bicarbonate ion transport per se, and that the link between sodium and bicarbonate transport is best explained by a sodium-hydrogen exchange process.

PIP: In this study of bicarbonate and sodium absorption in the intestine, absorption in a 30-cm segment of intestine was studied by the Ingelfinger triple-lumen perfusion system, which involves perfusion of test solutions into the intestine and sampling of gut contents 10 and 40 cm beyond the infusion marker. Human subjects were used. Observations made from these experiments on the mechanism of bicarbonate absorption and its relationship to sodium transport in the jejunum from saline solutions include: 1) the rate of sodium absorption is influenced greatly by bulk water flow; 2) when net water flow is zero, sodium absorption is zero in the absence of concentration gradients betwee plasma and lumen; and 3) the potential difference between abraded skin and jejunal lumen is near zero when saline is perfused and does not change when sulfate or bicarbonate is partially substituted for the chloride. It is concluded that sodium absorption from saline is entirely passive in the human jejunum; in the presence of bicarbonate, sodium is actively absorbed against electrochemical gradients. This study also looked at the mechanism of the link between bicarbonate and sodium absorption. Normal subjects and 11 patients with pernicious anemia were studied. Bicarbonate absorption was found to 1) occur against steep electrochemical gradients; 2) not generate a potential difference between abraded skin and jejunal lumen; 3) be inhibited by acetazolamide; and 4) generate a high carbon dioxide tension in jejunal. These observations led to the conclusion that bicarbonate absorption is mediated by active hydrogen secretion rather than by bicarbonate ion transport per se, making the best explanation for the link between sodium and bicarbonate transport a sodium-hydrogen exchange process.

Bile salt and micellar fat concentration in proximal small bowel contents of ileectomy patients.

Studies were carried out to test the hypothesis that abnormal bile salt metabolism (interruption of the enterohepatic circulation) is responsible for steatorrhea in patients with ileal disease and (or) ileectomy.Duodenal bile salt concentration after a single, standard meal eaten at 8 a.m. was measured in 8 patients with ileectomy steatorrhea and compared with 11 normal control subjects and 7 hospitalized patients without gastrointestinal disease. Mean bile salt concentration was approximately half normal in the ileectomy group, but some of the patients fell well within the normal range, even on repeat studies. However, it was shown that the second and third meals eaten during a single day were associated with a marked depression of duodenal bile salt concentration in ileectomy patients, which suggested that the first meals in these patients flush out a large fraction of the bile salt pool. Simultaneously measured turnover studies with taurocholate-(14)C showed at t((1/2)) of 3.1 hr in these patients compared with 29.5 and 32 hr in two control subjects, proving that the enterohepatic circulation had indeed been interrupted by ileectomy. Hepatic synthesis can apparently partially reconstitute the bile salt pool during the overnight period. Additional studies were carried out to determine the relation between bile salt and micellar fat concentration in proximal small bowel contents after ingestion of the same standard meal. Below a bile salt concentration of 1.7 mg/ml, less than 0.8 mg/ml of lipid existed in the micellar phase of intestinal contents, whereas when bile salt concentration exceeded this level the amount of fat in the micellar phase rose progressively. Only 1 of 11 samples from three ileectomy patients had a micellar fat concentration > 0.8 mg/ml, whereas 33 of 42 samples from control subjects had micellar fat concentration > 0.8 mg/ml.Thus, abnormally low duodenal bile salt concentration during at least a portion of the day, with the associated depression of micellar fat, appears to be a major cause of decreased fat absorption in patients with ileectomy steatorrhea.

Evaluation of chloride/bicarbonate. Exchange in the human colon in vivo.

During perfusion of a plasma-like solution, colonic absorption rate of chloride was much higher than the secretion rate of bicarbonate (34 vs. 3.5 meq/h, respectively). This might suggest that anion exchange (Cl/HCO3) accounts for only a small fraction of total chloride absorption. However, if the colon absorbs as well as secretes bicarbonate, this reasoning would underestimate the magnitude of the anion exchange. To see if the colon absorbs bicarbonate, we perfused a chloride-free solution (which would eliminate bicarbonate secretion via (Cl/HCO3 exchange) and found that the colon absorbed bicarbonate at a rate of 5.1 meq/h. Calculation of electrochemical gradients and measurement of luminal fluid PCO2 indicated that this bicarbonate absorption was mediated passively in response to electrical gradients, rather than via reversed Cl/HCO3 exchange or acid secretion. The combined results of the plasma-like and chloride-free perfusion experiments suggest Cl/HCO3 exchange at a rate of 8.6 meq/h (the sum of bicarbonate movements, 3.5 and 5.1 meq/h, observed in the two experiments). To obtain a second estimate under different experimental conditions, a choline chloride-choline bicarbonate (sodium-free) solution was perfused; with this solution, chloride and bicarbonate absorption dependent on active sodium transport should be eliminated or markedly reduced, and the magnitude of Cl/HCO3 exchange should be revealed. This experiment suggested a Cl/HCO3 exchange rate of 9.3 meq/h, similar to the first estimate. As chloride was absorbed at a rate of 34 meq/h during perfusion of the plasma-like solution, the Cl/HCO3 exchange provides for approximately one-fourth of total chloride absorption.