The effects of theophylline and choleragen on sodium and chloride ion movements within isolated rabbit ileum.

1. Theophylline (10 mM) and choleragen change the direction of net Cl- movements across rabbit ileum, in the short-circuit current condition, from absorption to secretion. The specific activity ratio R of Cl- tracers within the tissue coming from mucosal and serosal solutions respectively is increased, which is consistent with an increase in Cl- exchange flux across the mucosal border. 2. Net Na+ movement is also changed from net absorption to secretion by theophylline and choleragen; the specific activity ratio R of Na+ tracers is raised by theophylline. Because of the large paracellular component to transepithelial Na+ movements, an increase in Na+ exchange flux across the mucosal border is not detected. 3. 2,4,6-Triaminopyrimidine (20 mM) which has been previously shown to block paracellular Na+ movements, blocks both the theophylline and choleragen-dependent reversal of net Na+ movement by preventing the decrease in m-s Na flux. The theophylline-dependent increase in the ratio R of Na+ is still present, and is consistent with an increase in Na+ exchange flux across the mucosal border--unmasked by removal of the paracellular flux components. 4. Ouabain (0.1 mM) abolishes net absorption of Na+ and Cl- in control and net secretion of Na+ and Cl- in theophylline-treated tissue. Ouabain does not affect the theophylline-dependent increase in Cl- exchange across the mucosal border. 5. Replacement of Ringer Cl- with SO24- or Na+ by choline prevents the effects of theophylline and choleragen on Na+ and Cl- fluxes respectively. 6. Ethacrynate (0.1 mM) prevents the theophylline-dependent effects on net Na+ movement. Raising ethacrynate to 0.2 mM abolishes the effects of theophylline on Cl- exchange. An interpretation of these results is that theophylline and choleragen raise the Cl- permeability of the brush border. This increases NaCl leakage from the hypertonic lateral intercellular space into the mucosal solution thereby causing secretion. The selective action of triaminopyrimidine and ethacrynate (0.1 mM) on Na+ flux indicates that Na+ and Cl- move via separate transport pathways across the mucosal border.     

Effects of methylprednisolone on electrolyte transport by in vitro rat ileum

Administration of the glucocorticoid methylprednisolone (MP) (30 mg/kg body wt for 3 days) to rats increased intestinal mucosal guanylate cyclase and Na-K-ATPase activities, short-circuit current (Isc), electrical potential difference (PD), net Na absorption, and net Cl secretion and reversed HCO3 transport from secretion to absorption. In the MP-treated animals, removal of HCO3 from both the mucosal and serosal bathing solutions increased Cl secretion but did not alter the Isc, PD, and net Na flux. Removal of Cl abolished the MP-induced increase in Isc but did not affect the MP-induced changes in net Na and HCO3 fluxes. At 6 h, after a single dose of MP, stimulation of guanylate cyclase activity was already maximal, whereas Na-K-ATPase activity was not detectably altered. The changes in intestinal transport properties present 6 h after MP treatment and associated with the increased guanylate cyclase activity were an increase in Isc and PD and a reversal of net Cl absorption to net secretion. These results suggest that an initial response to MP administration is a persistent increase in intestinal guanylate cyclase activity that mediates an electrogenic Cl secretory process, then is followed by a superimposed effect of increased Na-K-ATPase activity that mediates an increase in net Na absorption.     

Anion effects on fluid absorption from rat jejunum perfused in vivo

Perfusion of rat jejunal segments in vivo with an isotonic, HCO3-free SO4-Ringer solution resulted in low rates of net sodium (JNanet) and water absorption. When the perfusion fluid was changed to one containing 25 mM Na2SO3, JNanet increased from 4.7 +/- 1.2 to 11.6 +/- 1.5 (SE) mumol X cm-1 X h-1 (P less than 0.001). This increased absorption was accompanied by comparable increases in chloride and water absorption, occurred without a detectable change in potential difference across the perfused segment, and was readily reversed on reinstitution of perfusion with SO4-Ringer. Perfusion with SO3-Ringer had no effect on electrolyte absorption from terminal segments of rat ileum. Addition of L-phenylalanine stimulated absorption from SO4-Ringer perfusate but not from SO3-Ringer perfusate. Addition of 25 mM NaHCO3 to SO4-Ringer perfusate caused parallel increases in JNanet and JHCO3net; when 25 mM NaHCO3 was added to SO4-Ringer perfusate that also contained 25 mM NaSCN, the same increase in JHCO3net occurred but was not associated with any increase in JNanet. These results indicate a potent effect of SO2-3 and HCO-3 to stimulate JNanet from rat jejunum but not from ileum. These anion effects on intestinal transport in vivo resemble their effects on ATPase activity of brush-border fractions from small intestine in vitro and raise the possibility that these effects on ion transport could be mediated through the changes in brush-border ATPase activity, which are brought about by exposure to these anions, although other explanations are also possible.     

Fluid movements across rabbit ileum coupled to passive paracellular ion movements.

1. Theophylline (10 mM) and choleragen (1 x 10(-6) g ml.-1) abolish net fluid absorption by everted sacs of rabbit ileum. Triaminopyrimidine (20 mM) and ethacrynate (0.1 mM) prevent this inhibition of net fluid movement. Replacing Ringer Cl- with isethionate prevents the theophylline-dependent decrease in fluid absorption also. 2. Ouabain (0.1 mM) abolishes net fluid movements in both control and theophylline-treated tissue. 3. With ouabain present, hypertonic NaCl (200 mM) in the mucosal solution causes net fluid secretion (serosal-mucosal flux). With theophylline added to both the mucosal and serosal solution, net fluid absorption (mucosal-serosal flux) is observed (P less than 0.001). Triaminopyrimidine (20 mM), or ethacrynate (0.1 mM), or replacement of Ringer Na+ with choline, or Ringer Cl- with isethionate all prevent the theophylline-induced reversal of osmotic flow. 4. Theophylline increases passive net flux of Na+ and Cl- from mucosal solution containing hypertonic (200 mM) NaCl+ ouabain (0.1 mM) across sheets of ileum into serosal solution containing mannitol Ringer + ouabain. The increased passive Na+ flux is blocked by triaminopyrimidine and the increased Na+ and Cl- fluxes are blocked by ethacrynate (0.1 mM). 5. The suggested route of increased NaCl leakage is via the paracellular pathway as it is inhibited by triaminopyrimidine. The increase, itself, is a consequence of the increased passive permeability of the mucosal border to Cl-, induced by theophylline or choleragen. Water is apparently electro-osmotically coupled to the paracellular Na+ leakage (100 mole water mole-1 Na+), hence increased passive leakage reverses osmotic flow. In active tissue the lateral intercellular space contains hypertonic NaCl, and hence increased leakage of NaCl across the tight-junction in theophylline or choleragen-treated tissue gives rise to net fluid secretion.     

Response of Amphiuma small intestine to theophylline: effect on bicarbonate transport.

The electrolyte transport properties of isolated proximal segments of Amphiuma small intestine and their response to theophylline were observed under various conditions. In the absence of theophylline the intestine generates a transepithelial potential (psi ms) serosa negative to mucosa when Cl- and HCO3- are present in the bath. Replacement of Cl- or HCO3- reduced the magnitude and usually reversed the sign of psi ms. Acetazolamide (10(-4) M) nearly abolished the serosa negative psi ms. Theophylline (10 mM) drove psi ms serosa positive, the magnitude depending on the bath Na+ and HCO3- concentrations. Simultaneously it increased the short-circuit current (Isc) and tissue resistance (Rt). The increase in Isc was not due to increase net Na+ transport in Cl-free buffer and was attributed to a residual ion flux. Acetazolamide reduced the Isc, Rt, and the net residual flux observed in theophylline-treated intestine. The magnitude of the acetazolamine effect on Isc was proportional to the Na+ and HCO3- concentrations of the bath. The results suggest that in the absence of theophylline, HCO3-, and Cl- transport are related. Furthermore, acetazolamide inhibits the movement of an ion, possibly HCO3-, secreted in response to theophylline.     

Transport of Na, Cl, and water by the rabbit corneal epithelium at resting potential.

Theophylline (1 mM) produced a net transport of Na and Cl from aqueous humor to tears (.02-.04 mumol/cm2 h) in the isolated rabbit cornea denuded of endothlium and in the presence of normal resting potential (25-35 mV). The active transport of Na (tears to aqueous) and of Cl (aqueous to tears), estimated with the Goldman constant-field equations, was confirmed. A 10 degrees C rise in temperature produced changes close to those predicted for passive processes in both unidirectional fluxes of Na and in the tears-to-aqueous flux of Cl, but not for the aqueous-to-tears flux of Cl. Theophylline treatment doubled Cl permeability but did not significantly affect Na or urea permeability, suggestingspecificity of affect. In separate experiments it was shown that stromal thinning occurred in previously swollen corneas when the endothelium was blocked by silicone oil and the epithelium was treated with theophylline. These findings provide further support for the argument that the mammalian epithelium could have an active role in the regulation of corneal thickness in situ.     

Evidence for Na+ independent active secretion of K+ and HCO 3 − by rat salivary duct epithelium

In order to elucidate whether or not active secretion of potassium and bicarbonate by the rat submaxillary duct epithelium operates independently of sodium reabsorption, Na+ transport was blocked by amiloride, which is known to inhibit Na+ entry from lumen into cell. With 10(-4) M amiloride in HCO - 3 -Ringer at the luminal side, the transepithelial electrical potential difference approached zero, the Na+ conductance of the luminal cell membrane was drastically reduced, and the K+ conductance was significantly reduced. Net K+ secretion was reduced by 80%, whereas net HCO - 3 secretion was significantly increased. The remaining 20% of net K+ secretion proceeded at zero net Na+ transport and in the absence of significant chemical and electrical potential differences between lumen and interstitium of the duct. This active component of net K+ secretion was accompanied by an equal rate of active HCO - 3 secretion. These findings confirm the independence of this active secretion of K+ and HCO - 3 from Na+ transport. They indicate an electrically neutral secretion of K+ and HCO - 3, probably by the postulated luminal K+ -H+ -exchange mechanism. The 80% of net K+ secretion, which were abolished by amiloride together with Na+ reabsorption, seem to be functionally coupled with Na+ transport. The linkage of K+ -to- Na+ is probably mediated by a luminal carrier exchanging Na+ for K+ and H+.     

Effects of theophylline on Na and alanine transport across isolated rabbit ileum.

Addition of theophylline to isolated rabbit ileal mucosa resulted in a persistent increase in short-circuit current (SCC) and a persistent decrease in DC conductance. Under short-circuit condition, net Na flux (JNanet) was reversed by theophylline from absorption to secretion (-0.6 mueq/h cm2) and was due to a decrease in unidirectional mucosal- (M) toserosal (S) flux (JNams). Addition of L-alanine to theophylline-treated m-ucosa increased SCC, JNanet, and JNams. Theophylline reduced JAlanet by 25%. Na flux ratios, determined in the presence of theophylline at +26 and -11 mV (mucosal reference), differed from flux ratios expected for a diffusional process by less than 8%. In contrast, Na flux ratios, determined in the absence of theophylline and presence of glucose at +26 and O mV, differed from diffusional ratios by 35%. The results are consistent with the hypothesis that theophylline inhibits active Na absorption, but the data do not conclusively demonstrate the diffusional nature of unidirectional Na fluxes in the presence of theophylline.     

Chloroquine stimulates absorption and inhibits secretion of ileal water and electrolytes

The effects of chloroquine diphosphate, a drug with "'membrane-stabilizing" properties, were studied on basal ileal absorption and on ileal secretion induced by increased intracellular cAMP levels and calcium (serotonin). The studies were performed on rat (in vivo) and rabbit ileum (in vitro). Intraluminal chloroquine (10(-4) M) reversed cholera toxin- and theophylline-induced secretion in rat ileum but did not alter the cholera toxin- and theophylline-induced increases in cAMP content. Addition of chloroquine (10(-4) M) to the mucosal surface of rabbit ileum did not alter basal active electrolyte transport or the serotonin-induced decreased Na and Cl absorption but inhibited the theophylline-induced C1 secretion. Addition of chloroquine (10(-4)) M) to the serosal surface stimulated net Na and Cl absorption. This effect may involve intracellular calcium. Chloroquine increased the rabbit ileal calcium content and decreased 45Ca2+ influx from the serosal surface. Both the mucosal and serosal effects of chloroquine described led to a net increase in absorptive function of the intestine and should prove useful in developing treatment of diarrheal diseases.     

Ileal mucosal cyclic AMP and Cl secretion: serosal vs. mucosal addition of cholera toxin.

Changes in ion transport and cyclic AMP (cAMP) concentration produced by addition of cholera toxin to the serosal side of isolated rabbit ileal mucosa (CTs) were compared to the changes produced by addition to the mucosal side (CTm). CTs increased short-circuit current (SCC) as did CTm but it did so more slowly. CTs, unlike CTm, did not significantly decrease electrical conductance. Inhibition of the SCC response to theophylline, a measure of preexisting secretion, was almost complete 180 min after CTm but was not yet significant 180 min after CTs. Longer (280 min) after CTs, the SCC response to theophylline was reduced by 59%, a significant reduction but less than that caused by CTm. A statistically significant change in net Cl flux could not be demonstrated after CTs, although at 280 min the measured flux was halfway between the fluxes for control and CTm tissues. Cyclic AMP concentrations were determined at 190 min, 10 min after addition of theophylline. CTs, despite little or no effect on ion transport, increased cAMP to the same level as did CTm, and the effect on cAMP of adding toxin to both sides was additive. We conclude that 1) active secretion is probably stimulated by cholera toxin added on the serosal side, although more slowly than after addition to the mucosal side and 2) much of the toxin-stimulated cAMP content of the mucosa is not coupled to secretion.     

pH stat studies on bicarbonate secretion in the isolated mouse ileum

Bicarbonate secretion occurs in almost all segments of the gastrointestinal tract. This study examined HCO(3)(-) secretion in the ileum, since it is less understood than HCO(3)(-) secretion in other intestinal segments. Mouse ileal mucosa was mounted in vitro in Ussing chambers, and the mucosal alkalinization rate (J(OH)) was determined by pH stat titration, while the mucosal side was bathed with a buffer-free solution (100% O(2)) and the serosal side with a HCO(3)(-)/CO(2)-buffered solution. The transmural potential difference (PD) was recorded. The mucosal alkalinization rate (J(OH)) was higher in the presence of mucosal Cl(-) than in its absence. Forskolin, an activator of adenylate cyclase, enhanced J(OH) and PD in both the presence and absence of mucosal Cl(-). Mucosal SO(4)(2-) also caused an increase in J(OH), although the magnitude was smaller than that induced by Cl(-). Mucosal Cl(-)-dependent J(OH) was partially inhibited by acetazolamide, 5-nitro-2-(3-phenylpropylamino)-benzoic acid (NPPB), tenidap and probably also by niflumic acid, but not by glibenclamide, DIDS or bumetanide. The forskolin-induced J(OH) value and PD were both inhibited by NPPB and probably also by tenidap. It is concluded that HCO(3)(-)- secretion in the ileum follows a mucosal Cl(-)-dependent pathway and a cAMP-activated pathway, each being distinct from each other. The Cl(-)-dependent pathway is probably mediated by the slc26a6 anion exchanger, and possibly also by the slc26a3 anion exchanger. The cAMP-activated HCO(3)(-) secretion is probably mediated by the cystic fibrosis transmembrane conductance regulator.     

Ion transport by rabbit jejunum in vivo.

Net ion and H2O transport by jejunum adjacent to the ligament of Treitz (proximal jejunum) and midjejunum were measured in vivo by continuous perfusion with HCO3-Ringer solution containing a volume marker. Proximal jejunum secreted Na and H2O, whereas midjejunum absorbed Na and H2O. Both segments secreted CO2 and absorbed K and Cl. D-glucose stimulated absorption of Na and H2O and the transmural electrical potential difference (PD) in both segments, but these changes were not accompanied by alterations in Cl, CO2, or K fluxes. However, the increse in Na absorption caused by 3-O-methylglucose was matched by an increase in Cl absorption. This, in addition to increased tissue lactate concentration after addition of D-glucose, suggests that organic anion maintains electroneutrality for Na transport enhanced by D-glucose. Cholera toxin had no effect on ion transport or PD in proximal jejunum, but cholera toxin stimulated secretion and increased the PD in more distal jejunum. Although proximal jejunum shows spontaneous secretory activity, its capacity for secretion is not as great as more distal small intestine.     

Comparison of transport mechanisms in isolated ascending and descending rat colon.

The mechanisms of water and ion transport in ascending and descending rat colon were compared using an everted open mucosal sac preparation. Net water flux, measured gravimetrically, was similar in both segments (15.3 plus or minus 1.2 and 13.7 plus or minus 1.3mul h(-1) mg(-1), NS). Net catonic flux J(Na+K),net anionic flux J(Cl-HCO3), and net solute flux Josm were also similar; but the constituents of these flux , namely JNA, JK, and JHCO3, were significantly different. The descending colon absorbed significantly less Na and secreted significantly more HCO3. Only the descending colon absorbed K, whereas net JK across the ascending colon was zero. The PD across either segment ranged from 3 to 7 mV, mucosal side negative. Consideration of net flux and electrochemical gradient indicated that in both segments Na was absorbed actively. The nature of Cl transport could not be ascertained. Assuming transmural movement, HCO3 was secreted (or H ion absorbed) actively. Only the descending colon absorbed K actively. Across the ascending colon K was distributed close to electrochemical equilibrium.The compostion of the absorbates was calculated from Ji/Jv after correction of Jv for filtered water. Both absorbates were equally hypertonic (448.5 plus orminus 9.3 and 421.7 plus or minus 13.2; NS.)The ascending colon absorbate contained a significantly higher Na concentration and no K. The descending colon absorbate contained 15 mM K, about 3 times the K concentration in the bathing solution. It was concluded that the ascending colon and descending colon displayed quantitative differences in Na absorption and HCO3 secretion and a qualitative difference in K transport.     

Transport of H plus and other electrolytes across isolated gastric mucosa of the rabbit.

The relationship of transmural and cellular phenomena to the rate of spontaneous luminal HH+ secretion by short-circuited gastric mucosa bathed in HCO3- and CO2-free Ringer solution was studied by the pH-stat technique. The bulk of luminal acidification can be accounted for by the appearance of H+ and not by organic acids. Acid secretion requires the presence of O2 and exogenous substrate but is not limited by endogenous CO2 production. The rate of H+ secretion is matched by the serosal appearance of alkali. The greater appearance of CO2 on the serosal side of the mucosa is consistent with hydroxylation of CO2 and greater permeability of the serosal border to HCO3-. Luminal changes in H+ concentrations affect H+ secretion but serosal changes do not, suggesting that the gradient produced by H+ secretion is at the luminal border. Steady-state isotopic Na+ and Cl- fluxes indicate net secretion of both ions, but net K+ transport is negligible.     

Ion transport across the excised bullfrog lung.

Fluxes of ions and water across the short-circuited, excised bullfrog lung were determined by radioisotope techniques. The unidirectional flows of Na+, K+, Ca++, TcO4 minus, HCO3 minus, gluconate, rho-aminohippurate, dinitrophenolate, SO4 equal to, and water were symmetrical. Both HCO3 minus fluxes were reduced by acetazolamide. In contrast, Cl minus, Br minus I minus, and SCN minus movement from serosa to mucosa exceeded the flux in the opposite direction. Net Cl minus transport followed the kinetics of a saturable process and was inhibited by dinitrophenol and hypoxia. These results indicate an active secretion of halide anions and SCN minus into the lumen. Attempts to demonstrate Br minus anatagonism of Cl minus transport were equivocal. Cl minus transport accounted for 50 percent minus of the early short-circuit current but after 90 min the two measurements were equal. Incubation of the lung in bicarbonate-free Ringer revealed unequal decreases in the H+ concentration of the bathing solutions. Net "base" addition to the serosal solution was reduced by prior removal of the blood from the pulmonary vasculature. Therefore, "base" release could not be localized to the epithelia. The Na+, K+, Ca++ and Cl minus composition of the lung tissue was unchanged over 3 h. Since tissue and, hence cell Cl minus is lower than the concentration in the bathing solution the Cl pump is probably located in the luminal border of the alveolar epithelial cell.     

Antisecretory effects of berberine in rat ileum

The in vitro antisecretory effects of the alkaloid berberine (1.0 mM) on intestinal ion secretion and mucosal adenylate cyclase and Na-K-ATPase activities were studied in the rat ileum. Mucosal berberine did not alter the individual basal net ion fluxes and basal adenylate cyclase activity but decreased short-circuit current (Isc) and increased the net absorption of chloride plus bicarbonate. In the cholera toxin-treated tissue, mucosal berberine stimulated absorption of Na and Cl and inhibited the increased adenylate cyclase activity but did not change the specific Na-K-ATPase activity, whereas serosal berberine stimulated Na secretion and decreased Isc. Mucosal berberine also decreased Isc, increased Cl permeability, and reversed the ion secretion induced by dibutyryl cyclic AMP, the heat-stable enterotoxin of Escherichia coli, and methylprednisolone administration. The antisecretory effects of mucosal berberine may be explained by stimulation of a Na-Cl-coupled absorptive transport process. The mechanism of action of serosal berberine remains to be elucidated. However, it is clear that mucosal berberine affects intestinal ion transport by mechanisms different from stimulation of the Na pump and probably at a step distal to the production or degradation of cyclic AMP or cyclic GMP.     

Effect of acetazolamide on sodium and chloride transport by in vitro rabbit ileum.

Acetazolamide (8 mM) aboishes active Cl absorption and inhibits but does not abolish active Na absorption by stripped, short-circuited rabbit ileum. These effects are not accompanied by significant changes in the transmural electrical potential difference or short-circuit current. Studies of the undirectional influxes of Na andCl indicate that acetazolamide inhibits the neutral, coupled NaCl influx process at the mucosal membranes. This action appears to explain the observed effect of acetazolamide on active, transepithelial Na and Cl transport. Acetazolamide did not significantly inhibit either spontaneous or theophylline-induced Cl secretion by this preparation, suggesting that the theophylline-induced secretion may not simply be due tothe unmasking of a preexisting efflux process when the neutral influx mechanism is inhibited by theophylline. Finally, inhibition of the neutral NaCl influx process by acetazolamide does not appear to be attributable to an inhibition of endogenous HCO3production or an elevation in intracellular cyclic-AMP levels. Instead, it appearstheat the effect of acetazolamide is due to a direct interaction with a membrane component involved in the coupled influx process.     

Coupled sodium-chloride transport by rabbit ileal brush-border membrane vesicles

Uptake of Na and Cl into brush-border membrane vesicles isolated from rabbit ileal epithelial cells was investigated with a rapid filtration technique using 22Na and 36Cl as tracers. The rank order of anion dependence for Na uptake in the absence of anion gradients was SCN greater than NO3 greater than gluconate. The sequence of cation specificity for Cl uptake was Na congruent to Li greater than K greater than choline. The transport of Na and Cl were both inhibited by harmaline, furosemide, 4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonic acid, and 4,4'-diisothiocyano-2,2'-stilbene disulfonic acid. Carrier mediation of Cl-stimulated Na transport was suggested by the competition for 22Na uptake with increasing concentrations of unlabeled Na in the presence of Cl but not when gluconate was the counterion. Chloride-dependent Na uptake had an apparent Km of 4.5 mM and a Vmax of 20 nmol . mg prot-1 . 15 s-1. Na-H exchange and Cl-OH (or HCO3) exchange were also demonstrated in these vesicles. These findings confirm the presence of an electrically neutral carrier-mediated, Na-Cl-coupled transport process in the apical cell membrane of rabbit ileal epithelial cells. The nature of the coupling of Na to Cl transport, i.e., NaCl symport or a process that combines Na-H antiport with Cl-OH (or HCO3) antiport, remains to be determined.     

Ion transport by amphibian antrum in vitro. I. General characteristics.

Both Necturus and bullfrog antrum show stable PD, resistance, and short-circuit current (Isc) when mounted in an Ussing chamber. Measurements of Na+ and Cl minus flux showed that both ions are actively transported across Necturus antrum, Na+ from secretory to nutrient, Cl minus from nutrient to secretory (both net fluxes being similar to 0.30 mueq cm minus 2 h minus 1). Only the Na+ transport contributed to the Isc and PD as evidenced by a) Na+ removal, b) the effects of amiloride on the secretory surface, c) the effects of ouabain on the nutrient side. Microelectrode experiments confirm the Na+ conductance of the secretory cell membrance, a HCO3 minus conductance of both cell membranes, and a KCl conductance across the nutrient cell membrane. In addition, antrum apparently secretes alkali (similar to 0.35 mueq cm minus 2 h minus 1), which secretion is sensitive to metabolic inhibitors and Diamox. Nutrientside HCO3 minus increased the rate of alkaline secretion and a transmucosal HCO3 minus gradient could contribute to ISC and PD. A model is proposed to account for the electrical properties of the tissue.     

Chloride and bicarbonate have similar affinities to the intestinal anion exchanger DRA (down regulated in adenoma)

DRA (down regulated in adenoma, SLC26A3) is an anion exchanger that mediates electroneutral NaCl absorption in the ileum and proximal colon together with NHE3 (Na/H exchanger isoform 3), and that is involved in duodenal and possibly pancreatic bicarbonate secretion. Thus, its chloride and bicarbonate affinities are important for both processes. [Cl]i and pHi transients were measured using MQAE and BCECF. HEK293 cells stably expressing DRA were exposed to 0 mM Cl at various [HCO3] (9 to 51 mM, at 5% CO2 or 15 to 57 mM, at pH 7.5) to determine the HCO3 affinity. After intracellular Cl depletion, 10, 30, and 90 mM Cl were readded at various [HCO3]s to determine the relative Cl and HCO3 affinities. The k0.5 for extracellular HCO3 is between 18.5 and 32.8 mM. Cl and HCO3 compete with similar affinities for transport by DRA. DRA activity is independent of pHo between 7.0 and 7.75. DRA is activated by alkaline pHi. Competition of Cl and HCO3 does not significantly impair NaCl absorption, because in the ileum and colon, luminal Cl is comparably high. Activation at alkaline pHi supports functional coupling of DRA and NHE3 by the subapical pHi. In the distal pancreatic ductal system, luminal HCO3 is high compared to luminal Cl. Under these conditions, competition of Cl and HCO3 is difficult to reconcile with a role of DRA in Cl reabsorption in exchange for HCO3. Our data, thus, provide indirect evidence against a role of DRA in pancreatic HCO3 secretion.