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Background & Aims: The duodenum is a cystic fibrosis transmembrane conductance regulator (CFTR)-expressing epithelium with high bicarbonate secretory capacity. We aimed to define the role of CFTR in human duodenal epithelial bicarbonate secretion in normal (NL) subjects and patients with cystic fibrosis (CF)., Methods: Endoscopic biopsy specimens of the duodenal bulb were obtained from 9 CF patients and 16 volunteers. Tissues were mounted in modified Ussing chambers. Bicarbonate secretion and short-circuit current (Isc) were quantitated under basal conditions and in response to dibutyryl adenosine 3',5'-cyclic monophosphate (db-cAMP), carbachol, and the heat-stable toxin of Escherichia coli (STa). Duodenocytes were also isolated and loaded with the pH-sensitive fluoroprobe BCECF/AM, and intracellular pH (pH(i)) was measured at rest and after intracellular acidification and alkalinization., Results: Basal HCO(3)(-) secretion and Isc were significantly lower in the CF vs. NL duodenal mucosa. In contrast to NL, db-cAMP failed to alter either HCO(3)(-) or Isc in CF tissues. However, in CF, carbachol resulted in an electroneutral HCO(3)(-) secretion, whereas STa induced electrogenic HCO(3)(-) secretion that was similar to NL. In CF and NL duodenocytes, basal pH(i) and recovery from an acid load were comparable, but pH(i) recovery after an alkaline load in CF duodenocytes was Cl(-) dependent, whereas in NL duodenocytes it was Cl(-) independent., Conclusions: These findings implicate CFTR in NL duodenal alkaline transport and its absence in CF. Although duodenal bicarbonate secretion is impaired in CF tissues, alternate pathway(s) likely exist that can be activated by carbachol and STa.

Background & Aims: Duodenal bicarbonate secretion is an important factor in epithelial protection. The role of the cystic fibrosis transmembrane conductance regulator (CFTR) in acid-induced bicarbonate secretion is unknown. The aim of this study was to determine whether CFTR mediates acid-stimulated duodenal epithelial bicarbonate secretion., Methods: Basal and stimulated bicarbonate secretion was examined in the cystic fibrosis murine model cftrm1UNC, which displays defective CFTR in various organs including chloride transport abnormalities in epithelia. After anesthesia, the proximal duodenum was cannulated and perfused with isotonic saline, and [HCO3-] was determined., Results: Basal bicarbonate secretion was diminished in cystic fibrosis vs. normal mice, 2.8 +/- 0.7 vs. 4.7 +/- 1.7 mumol.cm-1.h-1, respectively (P < 0.001). Luminal acidification failed to elicit a bicarbonate secretory response in cystic fibrosis compared with normal littermates (peak response, 2.3 +/- 0.2 vs. 9.9 +/- 1.5 mumol.cm-1.h-1, respectively; P < 0.01). Prostaglandin E2- and vasoactive intestinal peptide-stimulated bicarbonate secretion were also significantly impaired in cystic fibrosis. Defective bicarbonate secretion in cystic fibrosis genotypes was due to decreased net fluid secretion and [HCO3-]., Conclusions: Basal and stimulated proximal duodenal bicarbonate secretion may involve a CFTR-mediated transport pathway. It is likely that CFTR, directly or indirectly, has a major functional role in mediating bicarbonate transport in the proximal duodenum.

Background & Aims: Eradication of Helicobacter pylori expedites duodenal ulcer healing and prevents recurrences. Most patients with duodenal ulcers have impaired proximal duodenal mucosal bicarbonate secretion (DMBS). In patients with inactive, healed duodenal ulcers and normal subjects, the effect of H. pylori infection on DMBS and proximal duodenal secretory function and structure were examined., Methods: DMBS was quantitated before and after eradication of H. pylori. Mucosal structure (duodenal bulb histopathology) and function (DMBS at rest and stimulated, effect of active vs. healed ulcer and of age) were determined in patients with duodenal ulcers and normal subjects., Results: In patients with duodenal ulcers, H. pylori eradication normalized proximal DMBS. Histological examination of duodenal biopsy samples was comparable in patients with duodenal ulcers and normal subjects without apparent relationship between inflammation and DMBS. Significantly impaired DMBS occurred in response to all agonists tested (luminal acid, prostaglandin E2, and cephalic-vagal stimulation) in patients with duodenal ulcers, suggesting a generalized secretory defect. Neither the presence of active (vs.inactive) ulcer nor age significantly affected bicarbonate secretion., Conclusions: In patients with duodenal ulcers, eradication of H. pylori normalized proximal DMBS and may thereby reduce ulcer recurrences. Altered DMBS in patients with duodenal ulcers was unrelated to histopathologic abnormalities. Impaired bicarbonate secretion in patients with duodenal ulcers could be caused by a cellular and/or physiological regulatory transport defect possibly related to H. pylori.

Background & Aims: Duodenal bicarbonate secretion is impaired in patients with duodenal ulcer. Before characterization of any cellular transport defect is possible, the origin of duodenal bicarbonate (epithelial cells and/or Brunner's glands) must be determined. The aim of this study was to determine the role of Brunner's glands in duodenal bicarbonate secretion., Methods: Rats, which have Brunner's glands only in the proximal duodenum, and rabbits, which have Brunner's glands throughout the duodenum, were anesthetized. Basal and stimulated (with HCl, prostaglandin E2, and vasoactive intestinal polypeptide [VIP]) bicarbonate secretion was measured in three isolated intestinal segments: proximal duodenum, distal duodenum, and proximal jejunum. Mucosal surface area and Brunner's gland thickness was quantitated in each segment., Results: Secretion rates in proximal and distal duodenum and proximal jejunum were significantly different. Normalized proximal-to-distal duodenal gradients in bicarbonate secretion were similar in the two species despite significantly different gradients of Brunner's gland thickness. In rabbits, gradients of bicarbonate secretion and Brunner's gland thickness were not correlated. In both species, HCl, prostaglandin E2, and VIP stimulated secretion in all three segments. If the agonists specifically stimulated Brunner's gland bicarbonate secretion, relationships between gradients of bicarbonate secretion and Brunner's gland thickness would have been anticipated. This was not observed., Conclusions: The higher rates of bicarbonate secretion in the proximal duodenum than in the distal duodenum and proximal jejunum are independent of Brunner's glands.

Background/aims: The gastroduodenal epithelium is protected from acid peptic damage by an adherent mucus-bicarbonate layer. Bicarbonate is secreted by the surface epithelial cells into this mucus layer. Patients with duodenal ulcer disease have impaired proximal duodenal bicarbonate secretion. Mast cells, present in large numbers in the duodenal mucosa, release a number of inflammatory mediators, including histamine. Release of such mast cell mediators has been implicated in ulcer disease. In this study, the ability of histamine to regulate bicarbonate secretion was examined., Methods: Bicarbonate secretion by rabbit proximal duodenal mucosa was examined in vitro, and the effects of histamine, its agonists, and its antagonists were studied., Results: Histamine essentially eliminated prostaglandin E2-stimulated duodenal mucosal bicarbonate secretion, an effect reversed both by the neurotoxin, tetrodotoxin, and the histamine H2-receptor antagonist, cimetidine, as well as reproduced by the H2-receptor agonist, dimaprit., Conclusions: In addition to the stimulatory action of histamine on gastric acid secretion, histamine expresses an additional antidefensive action by inhibiting prostaglandin E2-stimulated duodenal epithelial bicarbonate secretion. This effect of histamine is likely mediated via H2 receptors located on enteric nerves.

Background/aims: Carbonic anhydrase activity plays a role in electrolyte transport in many tissues. This study examined the effect of the carbonic anhydrase inhibitor acetazolamide on human basal and prostaglandin E2- and acid-stimulated duodenal mucosal bicarbonate secretion and transmucosal electrical potential difference., Methods: Seven healthy volunteers participated in four separate experiments. The variables included oral acetazolamide vs. control test and, as agonists of bicarbonate secretion, either luminal acidification or luminal prostaglandin E2. The proximal 4 cm of the duodenum (i.e., the duodenal bulb) was isolated between balloons as previously described and perfused with an HCO(3-)-containing (24 mmol/L) balanced electrolyte glucose-containing (10 mmol/L) solution., Results: Acetazolamide treatment significantly decreased mean basal HCO3- secretion and basal transmucosal potential difference. After luminal acidification, duodenal mucosal bicarbonate increased significantly after both acetazolamide treatment (mean, 626; 95% CI, 91-1160 mumol.cm-1.h-1) and in the control tests (mean, 868; 95% CI, 652-1084 mumol.cm-1.h-1). However, acetazolamide treatment significantly decreased prostaglandin E2-stimulated HCO3- secretion from 461 (95% CI, 307-615) to 222 (95% CI, 121-324) mumol.cm-1.h-1., Conclusions: Duodenal mucosal carbonic anhydrase activity has an important function in the regulation of basal and prostaglandin E2-stimulated human duodenal mucosal bicarbonate transport.

Background: Interaction of the enteric nerves in regulating mammalian duodenal mucosal bicarbonate secretion is not well understood. The purpose of the present experiments was to evaluate the role of the enteric nervous system on bicarbonate secretion from rabbit duodenal mucosa in vitro., Methods: Proximal duodenum from male New Zealand White rabbits was stripped of seromuscular layers, mounted in Ussing chambers, and studied under short-circuited conditions. Effects of electrical field stimulation, vasoactive intestinal polypeptide (VIP), carbachol, prostaglandin E2 (PGE2), dibutyryl-cyclic adenosine monophosphate (db-cAMP), and the neurotoxin tetrodotoxin (TTX) and muscarinic blockade by atropine were studied., Results: Electrical field stimulation significantly (P < 0.01) stimulated bicarbonate secretion, short-circuit current (Isc), and electrical potential difference (PD) that was sensitive to both TTX and atropine. VIP-stimulated bicarbonate secretion was significantly inhibited by TTX (-73%), yet Isc and PD remained unchanged. Atropine decreased VIP-induced bicarbonate secretion (-69%) and Isc (-43%). Carbachol-stimulated bicarbonate secretion, Isc, and PD were abolished by atropine, whereas TTX was without affect. Neither TTX nor atropine had a significant effect on PGE2 or db-cAMP-stimulated bicarbonate secretion., Conclusions: These results suggest that (1) enteric nerve stimulation activates an acetylcholine receptor that in turn stimulates duodenal epithelial bicarbonate secretion; (2) VIP stimulates bicarbonate secretion, in large part, via the enteric nervous system; and (3) PGE2 and cAMP stimulate bicarbonate secretion independent of the enteric nervous system.

Background: Duodenal surface cells secrete bicarbonate that provides a barrier against injury. The current experiments were performed to identify duodenal bicarbonate regulatory and transport pathways., Methods: Rabbit proximal duodenal mucosa were mounted in chambers under short-circuited conditions. Bicarbonate transport, short-circuit current (Isc), and potential difference (PD) were quantitated in response to prostaglandin E2 (PGE2), vasoactive intestinal polypeptide (VIP), and dibutyryl cyclic adenosine monophosphate (db-cAMP). Anoxia (N2), 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) and Cl(-)-free solutions, ouabain, and Na-free solutions were also studied, as was the effect of VIP and PGE2 on duodenocyte cAMP., Results: PGE2, VIP, db-cAMP, and theophylline significantly increased bicarbonate secretion, Isc, and PD. Ouabain, Na(+)-free bathing solutions, and anoxia (N2) inhibited the responses. DIDS and Cl(-)-free solutions abolished the PGE2-induced response, reduced the response to VIP by about 50%, and had no effect on the response to db-cAMP. After PGE2 and VIP, cAMP concentration increased, yet was likely independent of bicarbonate secretion., Conclusions: Mammalian duodenal HCO3- transport requires Na+, Na+/K(+)-adenosine triphosphatase and O2-dependent metabolic pathways and is stimulated by PGE2, VIP, and cAMP, acting by distinct pathways.

Cyclic adenosine monophosphate (cAMP) has been implicated as an intracellular "second" messenger in duodenal mucosal bicarbonate secretion in animals. The purpose of this study was to determine whether cAMP may mediate duodenal mucosal bicarbonate secretion in humans. In healthy volunteers, a 4-cm segment of proximal duodenum was isolated from gastric and pancreaticobiliary secretions. Either the phosphodiesterase inhibitor theophylline, prostaglandin (PG) E2, or a combination thereof was administered topically to the isolated duodenal mucosa. Theophylline (10(-2) mol/L) and PGE2 (10(-5)-10(-4) mol/L) each significantly increased bicarbonate secretion and transmucosal potential difference. Moreover, when theophylline and PGE2 were administered in combination, the duodenal bicarbonate output was additive compared to either agent alone. When theophylline was infused with increasing doses of PGE2, the dose-response curve was shifted to the left. Furthermore, increases in bicarbonate secretion and transmucosal potential difference were correlated significantly. These results suggest that cAMP may act as an intracellular mediator of human duodenal mucosal bicarbonate secretion.

Gastric acid enters the proximal duodenum both as free and buffered H+. The procedures in this study were threefold: (a) to determine the pH threshold for duodenal mucosal bicarbonate secretion, iso-osmolar citric acid (pH 2.5-4.0; H+, 1.1 mmol) was infused; (b) to examine the effect of varying acid loads (H+, 0.4-5.1 mmol), citric acid (pH 3.0) was perfused; and (c) to quantitate duodenal diffusion of CO2, citric acid (pH 5.0) gassed with CO2 (PCO2, 0-210 mm Hg) was tested. Basal bicarbonate secretion was similar on each test day, 230 mumol/cm.h. Citric acid at pH 2.5 and 3.0 increased bicarbonate output equally to about 560 mumol/cm.h (similar to 2 mmol of 100 mmol/L HCl); citric acid at pH 3.5 and 4.0 had no effect. Varying the acid load increased bicarbonate output similarly. Duodenal loss of CO2 was minimal (4%) with infusion of 50 mm Hg PCO2 and increased to approximately 25% (15 mm Hg/min) at higher PCO2 values. It is concluded that (a) the pH threshold for human duodenal mucosal bicarbonate secretion is 3.0; (b) a pH-sensitive, rather than an acid load-sensitive, regulatory process exists; and (c) CO2 loss plateaus at 15 mm Hg/min at a PCO2 of 200 mm Hg.

Proximal duodenal mucosal bicarbonate production is impaired in patients with duodenal ulcer disease. Because prostaglandins of the E class increase human proximal duodenal bicarbonate secretion, this study tested the hypothesis that endogenous prostaglandin E2 production is defective in patients with duodenal ulcer. Ten patients, five with active and five with inactive duodenal ulcer disease, were studied along with 10 normal volunteers. The proximal 4 cm of duodenum, the bulb, was isolated and continuously perfused with 154 mmol/L NaCl. Basal bicarbonate secretion was measured for 30 minutes. The test segment was then acidified with a physiological amount of HCl (2 mmol over 5 minutes), and acid-stimulated bicarbonate secretion was measured by pH/PCO2 and back-titration for 55 more minutes. Prostaglandin E2 was measured in the effluents by a radioimmunologic assay validated by gas chromatography-mass spectrometry. Compared with the normal subjects after luminal acidification, the duodenal ulcer patients had significantly greater PGE2 release and decreased total 1-hour bicarbonate output. The peak 5-minute acid-stimulated bicarbonate responses were not significantly different between the duodenal ulcer patients and normal subjects. After luminal acidification, PGE2 output remained elevated in the duodenal ulcer patients but returned promptly to basal in the normal subjects. Furthermore, the ratio of bicarbonate secreted to the amount of PGE2 released was significantly less in the ulcer patients. These findings suggest that patients with duodenal ulcer disease have an impaired mucosal bicarbonate response to endogenous PGE2. The increased acid-stimulated PGE2 response in duodenal ulcer patients suggests a compensatory phenomenon in response to the diminished mucosal bicarbonate production.

When the proximal duodenum of animals or humans is perfused with isoosmolar NaCl, bicarbonate enters the luminal effluent. In addition, duodenal bicarbonate output is stimulated by luminal acidification and prostaglandins of the E class. The hypothesis that in vivo human duodenal bicarbonate transport persists in the absence of a plasma-to-lumen bicarbonate gradient and therefore is probably an active transport process was tested. In healthy subjects, a 4-cm segment of the proximal duodenum was isolated from gastric and pancreaticobillary secretions. Net duodenal bicarbonate secretion remained similar to basal levels during luminal perfusion with either 24 or 32 mM bicarbonate (each isoosmolar with plasma by the addition of NaCl). In addition, peak increases in acid-induced bicarbonate outputs with luminal perfusion of 154 mM NaCl and 32 mM NaHCO3 (+122 mM NaCl) were similar. Moreover, prostaglandin E2-stimulated bicarbonate secretion with perfusion of 154 mM NaCl and 32 mM NaHCO3 (+122 mM NaCl) was similar. It was concluded that in humans, proximal duodenal mucosal bicarbonate transport remains unaltered in the absence of a plasma-to-lumen bicarbonate gradient at rest and after stimulation with HCl or prostaglandin E2. These observations suggest that human proximal duodenal bicarbonate secretion involves active transport.

This study was conducted to determine whether taurocholate alters human gastric function and structure at a neutral pH, when ionized, and to contrast this with its effect at an acid intraluminal pH, when pronated. Five fasted healthy subjects were studied on 4 days in random order. Net ion fluxes, mucosal damage (as quantitated endoscopically), and potential difference were measured. The control solution instilled into the stomach in the first, third, and fourth 15-min periods contained 200 ml of 100 mM HCl, 54 mM mannitol, and [14C]polyethylene glycol. Taurocholate (10 mM) was added to the control solution (pH 1.1) or citrate buffer (pH 7.0) during the second 15-min period. The effect of citrate buffer alone or control solution alone was also tested. Because hydrogen and sodium fluxes could not be quantitated at pH 7 in the presence of citrate buffer, the net ion fluxes during the 15 min immediately after exposure to the test agent were measured. At both pH 1.1 and 7.0 taurocholate produced similar and significant increases in net hydrogen ion flux (-1.7 +/- 0.4 and -1.8 +/- 0.3 mmol/15 min, respectively), net sodium ion flux (1.8 +/- 0.4 and 1.7 +/- 0.2 mmol/15 min, respectively), decreases in potential difference, and mucosal erosions. The net hydrogen ion fluxes were significantly greater than occurred after citrate buffer alone or the HCl control. The net sodium fluxes after taurocholate in citrate were significantly greater than the pH 1.1 acid control, but not citrate buffer alone. These findings indicate that pronated (pH 1.1) or ionized (pH 7.0) taurocholate significantly damaged the in vivo human gastric mucosa. Taurocholate at pH 7 could in part be responsible for the gastric mucosal injury that occurs in patients with bile reflux gastritis.

A new, sensitive, and reproducible method for measuring hydrogen and sodium ion fluxes across the human gastric mucosa was developed and validated. By the use of a double-balloon tube that obstructed the pylorus, the stomach was converted into an in vivo Pavlov-type pouch. Duodenogastric reflux was prevented, and emptying of gastric contents into the duodenum was, on the average, 6%, thereby eliminating two important sources of error in quantitative gastric ion fluxes in humans. Transmucosal potential difference and endoscopic appearance of the gastric mucosa were also evaluated during each experiment. The mean percentage variation between duplicate tests for hydrogen ion was 3.2%, for sodium 17.5%, and the potential difference was 2.5%. Instillation of acetylsalicylic acid (36 mM, 1300 mg) in 200 ml of 100 mM hydrochloric acid for just 15 min resulted in a mean net hydrogen ion loss of 3.4 mmol/15 min, a net sodium ion gain of 1.9 mmol/15 min, a decrease in the potential difference of 23 mV, and marked gastric mucosal changes. Furthermore, exposure for 15 min to 20% ethanol (vol/vol, in 200 ml of 100 mM hydrochloric acid) and two separate hyperosmolar solutions (3600 mosmol/kg and 1800 mosmol/kg, both in 200 ml of 100 mM hydrochloric acid) also resulted in marked changes of net hydrogen ion loss (3.1, 4.8, 5.2 mmol/15 min, respectively), net sodium ion gain (2.4, 3.3, 2.4 mmol/15 min, respectively), decrease in potential difference (32, 30, 36 mV, respectively), and gross damage to the gastric mucosa. Each parameter was significantly different from the control test. Acetaminophen (86 mM, 2600 mg) or 10% ethanol (vol/vol) in 200 ml of 100 mM hydrochloric acid did not significantly alter ion fluxes or potential difference. Acetaminophen also did not significantly alter the endoscopic appearance of the gastric mucosa, whereas 10% ethanol had only a modest effect. In the control, aspirin, and acetaminophen experiments, maximal changes in the four parameters (i.e., hydrogen and sodium ion fluxes, potential difference, and endoscopic score) were significantly correlated with one another.

To examine the effect of proximal small intestinal stimulants of gastric acid secretion in cirrhotic patients with portacaval shunt, unshunted cirrhotics, and normal subjects, a mixture of L-amino acids was administered intraduodenally, into the proximal jejunum, or intravenously to 8 cirrhotic patients with portacaval shunt and to 8 unshunted subjects (4 cirrhotic and 4 healthy volunteers). In addition, the effect of intrajejunally administered hyperosmolar mannitol (850 mosmol/kg) and intrajejunal balloon distention (40 mmHg) was determined. In the shunted and unshunted groups gastric acid secretion significantly increased equally in response to intravenous and intraduodenal amino acid infusion, whereas amino acids administered intrajejunally did not significantly alter acid secretion. Perfusion of the jejunum with hyperosmolar mannitol resulted in significant stimulation of acid secretion in the shunted subjects, whereas in the unshunted subjects it caused significant inhibition. In addition, jejunal balloon distention significantly stimulated secretion in the shunted subjects, but not in the unshunted group. Serum gastrin did not change significantly during any of the experiments and plasma amino acids were not different after jejunal compared with duodenal perfusion. These studies indicate the following: Enteral and parenteral amino acids increase gastric acid secretion similarly in subjects with and without portacaval shunt. The intestinal phase of gastric acid secretion is initiated by intraduodenal, but not intrajejunal, amino acids. As plasma amino acid concentrations were similar regardless of the route used, this suggests that the intestinal phase of acid secretion cannot be fully explained by the postabsorptive stimulation by amino acids. Intrajejunal distention with a balloon or infusion of hyperosmolar mannitol into the proximal jejunum stimulates acid secretion only in subjects with portacaval shunt.

Aspirin and ethanol damage the gastric mucosa in humans, whereas acetaminophen does not. Acetaminophen increases prostacyclin activity in animals and thus may increase endogenous prostaglandin synthesis. The effect of acetaminophen was examined in five healthy subjects after intragastric aspirin or ethanol. Hydrogen and sodium ion fluxes were measured in the pylorus-occluded stomach that prevents duodenogastric reflux and gastric fluid losses. Studies were in random order and on 8 separate days. Potential difference was measured throughout and mucosal erosions were endoscopically quantitated (endoscopist masked, no premedication). The isoosmolar test solution (200 ml, 100 mM HC1, 54 mM mannitol, [14C]polyethylene glycol) was instilled into the stomach and removed 15 min later for four 15-min periods. Either aspirin (1300 mg) or ethanol (20% vol/vol) was added to the test solution only during the second 15 min. Acetaminophen (2600 mg) was given orally 1 h before aspirin or ethanol administration. To determine if the effect of acetaminophen was related to prostaglandin synthesis, prostaglandin production was inhibited with indomethacin (50 mg orally 12 h and 1 h before acetaminophen). Aspirin and ethanol alone each produced significant changes in net hydrogen and sodium fluxes, potential difference, and endoscopic changes. Acetaminophen significantly inhibited hydrogen ion flux, change in potential difference, and endoscopic damage; however, it did not totally abolish these changes. The protective effect of acetaminophen was abolished by pretreatment with indomethacin, suggesting that the effect of acetaminophen is likely to be prostaglandin-mediated. Indomethacin alone was without effect. These results demonstrate that oral acetaminophen protects the human gastric mucosa against the damaging effects of aspirin and ethanol.

The factors responsible for prevention of duodenal mucosal injury are not known. This series of experiments was performed to determine whether the human duodenum secretes bicarbonate that could prevent mucosal damage. To isolate a 4-cm segment of proximal (i.e., the duodenal bulb) or distal duodenum free of contamination from either gastric or pancreaticobiliary secretion, or both, methods were developed using occlusive balloons. The test segment was perfused with NaCl (2 ml/min, 37 degrees C) containing [14C]PEG as a nonabsorbable marker, and bicarbonate output was quantitated. Mean (+/- SE) basal proximal duodenal bicarbonate output was 143 +/- 17 mumol/cm X h. A 5-min infusion of 25, 50, and 100 mM HCl directly into the isolated proximal duodenal test segment increased bicarbonate output to 167 +/- 29, 199 +/- 19, and 278 +/- 49 mumol/cm X h, respectively, during the hour after acidification. Distal duodenal acidification (25, 50, and 100 mM) also increased bicarbonate output from the isolated proximal duodenal test segment. A synthetic prostaglandin E1 analogue, misoprostol (1.67-13.3 micrograms/min), infused directly into proximal or distal test segments significantly stimulated bicarbonate outbreak; peak responses were 644 +/- 35 mumol/cm X h and 171 +/- 20 mumol/cm X h (p less than 0.001), respectively. Thus, in humans, the proximal and distal duodenal mucosa secretes bicarbonate at rest; direct acidification of the proximal duodenum stimulates bicarbonate output; acidification of the distal duodenum beyond the isolated test segment also increased proximal duodenal bicarbonate output; and a synthetic prostaglandin E1 analogue stimulated both proximal and distal bicarbonate output; however, distal duodenal bicarbonate output was significantly less, indicating a proximal-to-distal gradient in bicarbonate secretion.