Comparison of the effects of immediate-release omeprazole oral suspension, delayed-release lansoprazole capsules and delayed-release esomeprazole capsules on nocturnal gastric acidity after bedtime dosing in patients with night-time GERD symptoms.

BACKGROUND: Gastro-oesophageal reflux disease (GERD) patients on proton pump inhibitors before breakfast or dinner have acid recovery at night. Bedtime immediate-release omeprazole (IR-OME) demonstrated better control of nocturnal pH than pantoprazole before dinner. AIM: To compare repeated once daily bedtime dosing of IR-OME, lansoprazole and esomeprazole on nocturnal gastric acidity. METHODS: Open-label, randomized, crossover study enrolling 54 patients with nocturnal GERD symptoms comparing IR-OME, lansoprazole and esomeprazole at steady state for nocturnal acid breakthrough (NAB), percentage of time with gastric pH > 4 and median gastric pH. RESULTS: Onset of nocturnal acid control with IR-OME was rapid. During the first half of the night, percentage of time with gastric pH > 4 and median gastric pH were significantly higher after IR-OME compared to esomeprazole or lansoprazole (P < 0.001, both comparisons). Over the 8-h night-time period, acid control with IR-OME was significantly better than lansoprazole (P < 0.001), and comparable to esomeprazole. IR-OME reduced NAB compared with esomeprazole and lansoprazole (61% vs. 92% and 92%; P < 0.001, both comparisons). CONCLUSIONS: Bedtime IR-OME provided more rapid control of night-time gastric pH and decreased NAB compared with esomeprazole and lansoprazole. Nocturnal acid control with IR-OME was superior to lansoprazole and comparable to esomeprazole. Bedtime dosing with IR-OME may be effective for patients with night-time heartburn.

A role for guanylate cyclase C in acid-stimulated duodenal mucosal bicarbonate secretion.

Luminal acidification provides the strongest physiological stimulus for duodenal HCO3- secretion. Various neurohumoral mechanisms are believed to play a role in acid-stimulated HCO3- secretion. Previous studies in the rat and human duodenum have shown that guanylin and Escherichia coli heat-stable toxin, both ligands of the transmembrane guanylyl cyclase receptor [guanylate cyclase C (GC-C)], are potent stimulators for duodenal HCO3- secretion. We postulated that the GC-C receptor plays an important role in acid-stimulated HCO3- secretion. In vivo perfusion studies performed in wild-type (WT) and GC-C knockout (KO) mice indicated that acid-stimulated duodenal HCO3- secretion was significantly decreased in the GC-C KO animals compared with the WT counterparts. Pretreatment with PD-98059, an MEK inhibitor, resulted in attenuation of duodenal HCO3- secretion in response to acid stimulation in the WT mice with no further effect in the KO mice. In vitro cGMP generation studies demonstrated a significant and comparable increase in cGMP levels on acid exposure in the duodenum of both WT and KO mice. In addition, a rapid, time-dependent phosphorylation of ERK was observed with acid exposure in the duodenum of WT mice, whereas a marked attenuation in ERK phosphorylation was observed in the KO animals despite equivalent levels of ERK in both groups of animals. On the basis of these studies, we conclude that transmembrane GC-C is a key mediator of acid-stimulated duodenal HCO3- secretion. Furthermore, ERK phosphorylation may be an important intracellular mediator of duodenal HCO3- secretion.

Human duodenal mucosal brush border Na(+)/H(+) exchangers NHE2 and NHE3 alter net bicarbonate movement.

The proximal duodenal mucosa secretes HCO that serves to protect the epithelium from injury. In isolated human duodenal enterocytes in vitro, multiple luminal membrane proteins are involved in acid/base transport. We postulated that one or more isoforms of the Na(+)/H(+) exchanger (NHE) family is located on the apical surface of human duodenal mucosal epithelial cells and thereby contributes to duodenal mucosal HCO transport. Duodenal biopsies were obtained from human volunteers, and the presence of NHE2 and NHE3 was determined by using previously characterized polyclonal antibodies (Ab 597 for NHE2 and Ab 1381 for NHE3). In addition, proximal duodenal mucosal HCO(3)(-) transport was measured in humans in vivo in response to luminal perfusion of graded doses of amiloride; 10(-5)--10(-4) M amiloride was used to inhibit NHE2 and 10(-3) M amiloride to inhibit NHE3. Both NHE2 and NHE3 were localized principally to the brush border of duodenal villus cells. Sequential doses of amiloride resulted in significant, step-wise increases in net duodenal HCO(3)(-) output. Inhibition of NHE2 with 10(-5) M and 10(-4) M amiloride significantly increased net HCO(3)(-) output. Moreover, there was an additional, equivalent increase (P < 0.05) in duodenal HCO(3)(-) output with 10(-3) M amiloride, which inhibited NHE3. We conclude that 1) NHE2 and NHE3 are localized principally to the brush border of human duodenal villus epithelial cells; 2) sequential inhibition of NHE2 and NHE3 isoforms resulted in step-wise increases in net HCO(3)(-) output; 3) NHE2 and NHE3 participate in human duodenal villus cell HCO(3)(-) transport; and 4) the contribution of NHE-related transport events should be considered when studying duodenal HCO(3)(-) transport processes.

Identification of transport abnormalities in duodenal mucosa and duodenal enterocytes from patients with cystic fibrosis.

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.

Utility of endoscopic biopsy samples to quantitate human duodenal ion transport.

Duodenal mucosal bicarbonate secretion (DMBS) prevents acid-peptic damage and facilitates nutrient absorption. DMBS is diminished in patients with duodenal ulcers and is normalized after Helicobacter pylori eradication. The measurement of DMBS in human patients in vivo requires intubation with a multi-lumen balloon tube and permits limited testing with putative agonists and antagonists. Our purpose was to develop a means to investigate transport events in human duodenal biopsy samples in vitro. After validation studies in a modified mini-Ussing chamber were performed, duodenal transport events were examined in proximal endoscopic biopsy samples from normal volunteers (n = 17). Tissues were mounted in modified mini-Ussing chambers (volume 2.5 ml, surface area 3.8 mm2). Short circuit current (Isc), potential difference (PD), and bicarbonate secretion were determined under basal conditions and after stimulation with graded doses of prostaglandin E2 (PGE2)(10(-8) to 10(-4) mol/L) and dibutyryl cAMP (db-cAMP)(10(-4) to 10(-2) mol/L). Duodenal tissues remained viable for at least 2 hours and exhibited stable basal HCO3(-) secretion and electrical parameters. Stimulation with PGE2 and db-cAMP resulted in dose-related increases in both Isc and HCO3(-) secretion (P < .05) that were abolished by ouabain and anoxia. It is concluded (1) that human duodenal bulb biopsy samples maintain their inherent transport function in mini-Ussing chambers and (2) that by using this novel method it will be possible to define the transport events that modulate human duodenal secretion, in particular bicarbonate secretion, in both health and disease.

Acid/base transporters in human duodenal enterocytes.

BACKGROUND: Duodenal mucosal bicarbonate secretion serves as a key defensive factor against mucosal injury. The purpose of the present study was to isolate human proximal duodenal enterocytes and identify their inherent acid/base transporters that participate in duodenal alkaline secretion. METHODS: Biopsy specimens were obtained from the duodenal bulb in 18 healthy volunteers. Individual duodenal epithelial cells were isolated by means of a combination of calcium chelation and collagenase. Intracellular pH (pHi) was measured by the pH-sensitive dye BCECF and dynamic fluorescence ratio imaging. RESULTS: Cytologic and histologic examination confirmed that isolated cells were of epithelial origin. In HCO3--free media, pHi recovery after acidification with NH4Cl was amiloride-sensitive and Na+-dependent, indicating the presence of an Na+/H+ exchanger. pHi recovery after acidification was significantly enhanced by the presence of HCO3-, showing the presence of an HCO3--dependent recovery mechanism (that is, a base loader/acid extruder). HCO3--dependent recovery required external Na+ yet was Cl-- and amiloride-insensitive, characteristic of an NaHCO3 cotransporter. In the presence of HCO3-, a Cl--dependent anion exchanger serving as a base extruder was shown, indicative of a Cl-/HCO3- exchanger. CONCLUSIONS: Human duodenal enterocytes contain at least three acid/base transporters: an Na+/H+ exchanger that serves as to extrude acid, an NaHCO3 cotransporter that functions as base loader, and a Cl-/HCO3- exchanger that operates as a base extruder.

Human proximal duodenal alkaline secretion is mediated by Cl-/HCO3- exchange and HCO3- conductance.

The proximal duodenal epithelium secretes bicarbonate into an adherent mucus layer, thereby protecting the mucosa from injury by gastric acid and pepsin. While bicarbonate secretion is stimulated and inhibited by a number of agonists and antagonists, the apical anion transport pathways have not been addressed fully. The objective was to assess if apical Cl-/HCO3- exchange and Cl-:HCO3- conductance are involved in duodenal mucosal bicarbonate secretion (DMBS). In healthy volunteers, the proximal 4 cm of duodenum was isolated, perfused with either saline or 4,4'-diisothiocyano-2,2'-disulfonic acid (DIDS), and bicarbonate secretion and transepithelial potential difference (PD) were stimulated by either PGE2 or the phosphodiesterase inhibitor theophylline to increase cyclic AMP. Luminal DIDS abolished PGE2-stimulated DMBS, yet had no effect on the increase in PD and failed to significantly alter theophylline-induced DMBS and PD. Therefore, in human proximal duodenum, it appears that PGE2 and cAMP activate distinct HCO3- transport pathways likely involving a DIDS-sensitive Cl-/HCO3- exchanger and DIDS-insensitive HCO3- conductance.

Modulation of bicarbonate secretion in rabbit duodenum: the role of calcium.

Surface epithelial bicarbonate secretion protects the proximal duodenum from acid peptic injury. Cyclic adenosine monophosphate and calcium serve as intracellular mediators of intestinal transport. Experiments were performed to examine whether calcium participates in duodenal bicarbonate transport. Stripped duodenal mucosa from rabbits was studied in Ussing chambers. HCO3- transport was stimulated by the calcium ionophore A23187, carbachol, vasoactive intestinal peptide, prostaglandin E2, dibutyryl-cyclic adenosine monophosphate, and electrical field stimulation. A23187 stimulated HCO3- secretion and Isc; tetrodotoxin failed to inhibit this effect. The calcium-channel blocker verapamil abolished HCO3- secretion stimulated by carbachol, vasoactive intestinal peptide, and electrical field stimulation, but failed to alter basal, prostaglandin E2- or dibutyryl-cyclic adenosine monophosphate-stimulated HCO3- secretion. Therefore, calcium is likely required during stimulation of duodenal epithelial HCO3- transport by carbachol, vasoactive intestinal peptide, and electrical field stimulation. Prostaglandin E2 and dibutyryl-cyclic adenosine monophosphate appear to activate duodenal HCO3- secretion by a calcium-independent pathway(s).

Acid-stimulated duodenal bicarbonate secretion involves a CFTR-mediated transport pathway in mice.

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.

CFTR mediates cAMP- and Ca2+-activated duodenal epithelial HCO3- secretion.

The role of the cystic fibrosis transmembrane conductance regulator (CFTR) in duodenal alkaline secretion has not been directly examined. The aims of this series of experiments were to determine if CFTR mediates basal and stimulated duodenal epithelial HCO3- secretion. Utilizing the cystic fibrosis murine model (cftr(m1UNC)), we compared normal [CFTR(+/+)] littermates (34-46 days old) with CFTR(-/-) animals (34-39 days old). Anesthesia was induced and maintained with intraperitoneal Hypnorm-midazolam. The proximal duodenum (4-7 mm) was cannulated and perfused with 154 mM NaCl. Either forskolin (10(-6)-10(-4) M) or carbachol (10(-6)-10(-3) M) was perfused intraluminally to activate adenosine 3',5'-cyclic monophosphate (cAMP)- and Ca2+-mediated HCO3- secretion, respectively. Effluent volumes were weighed and HCO3- quantitated by back titration. Basal HCO3- secretion was diminished significantly (P < 0.01) in CFTR(-/-)vs. normal CFTR(+/+) mice (2.8 +/- 0.5 vs. 5.3 +/- 0.4 micromol x cm(-1) x h(-1)). Moreover, in CFTR(-/-) mice, both forskolin- and carbachol-stimulated peak HCO3- secretions were fourfold less compared with those in CFTR(+/+) littermates (3.7 +/- 0.2 vs. 15.6 +/- 2.1 and 4.7 +/- 0.3 vs. 14.2 +/- 2.5 micromol x cm(-1) x h(-1), respectively; P < 0.01). In conclusion, CFTR plays a significant role in mediating basal, cAMP-, and Ca2+-activated duodenal epithelial HCO3- secretion.

Acid-base transport in isolated rabbit duodenal villus and crypt cells.

BACKGROUND: Duodenal mucosal bicarbonate secretion is an important first line of defense against gastric acid. Studies in the ileum indicate that the secretion originates from the crypt cells, whereas villus cells are mainly absorptive. Data on acid/base transporters along the crypt-villus axis in duodenal epithelia are not available. It was our purpose to identify and compare acid/base transporters in isolated mammalian duodenal villus and crypt cells. METHODS: The proximal duodenum of rabbits was excised, and duodenal epithelial cells were isolated in five fractions by a modified calcium chelation technique. Intracellular pH (pHi) was measured with a pH-sensitive dye and dynamic fluorescence ratio imaging. RESULTS: In both villus and crypt cells incubated in Hepes buffer, removal of Na+ or addition of amiloride decreased basal pHi and pHi recovery after intracellular acidification, indicating an Na+/H+ exchanger in both cell types. In both cell types acid extrusion rates in bicarbonate-buffered Ringer's solution were significantly higher than in Hepes buffer. The bicarbonate-dependent acid extruder was unaffected by removal of Cl- or addition of amiloride but was blocked by removal of Na+, indicating the presence of a NaHCO3 cotransporter in both villus and crypt cells. Removal of external Cl induced a reversible increase in pHi (inhibited by H2DIDS) in both villus and crypt cells, indicating a Cl-/HCO3- exchanger in both. CONCLUSIONS: Mammalian duodenal villus and crypt cells have identical acid-base transporters. These findings tend to negate the theory of a functional difference in acid-base transporters between duodenal villus and crypt cells and instead imply alkaline secretion by both cell fractions. However, as these experiments were performed in unpolarized, single cells, additional studies with either membrane vesicles or polarized cells are needed.

Duodenal bicarbonate secretion: eradication of Helicobacter pylori and duodenal structure and function in humans.

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.

Cyclic adenosine-3',5'-monophosphate production is greater in rabbit duodenal crypt than in villus cells.

BACKGROUND: Duodenal surface epithelial cells secrete bicarbonate. Agonists of duodenal alkaline secretion (such as vasoactive intestinal polypeptide (VIP), prostaglandin E2 (PGE(2)), and forskolin) increase intracellular cyclic adenosine-3', 5-monophosphate (cAMP), and cAMP stimulates Cl-HCO(3)- exchange in duodenal brush border membrane vesicles. As intestinal villus and crypt cells differ in function, our aims were to contrast cAMP generation in duodenal villus versus crypt cells in response to VIP, PGE(2), and forskolin. METHODS: Villus and crypt rabbit duodenal enterocytes were isolated by calcium chelation. To prevent the degradation of cAMP in vitro, phosphodiesterase activity was inhibited. cAMP production was quantitated in response to VIP (10(-10)-10(-5)M), PGE(2) (10(-10)-10(-4)M), and forskolin (10(-8)-10(-3)M). RESULTS: In crypt cells cAMP generation was approximately 10-fold greater (P < 0.001) in response to VIP, PGE(2), and forskolin than to villus cells. The relative orders of potency (that is, D(50), VIP > PGE(2) > forskolin) and efficacy (that is, V max, forskolin > VIP and PGE(2)) were similar in villus and crypt cells. CONCLUSION: cAMP production is greater in duodenal crypt than in villus enterocytes at rest and in response to forskolin, VIP, and PGE(2), suggesting that alkaline secretion may differ along the villus-to-crypt axis.

Higher proximal duodenal mucosal bicarbonate secretion is independent of Brunner's glands in rats and rabbits.

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.

Histamine inhibits prostaglandin E2-stimulated rabbit duodenal bicarbonate secretion via H2 receptors and enteric nerves.

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.

Human proximal duodenal ion and water transport. Role of enteric nervous system and carbonic anhydrase.

Intestinal ion transport is mediated by the interaction of enterocyte function, the enteric nervous system, humoral agents, and mucosal production of carbonic anhydrase. Our purpose was to examine the effect of the carbonic anhydrase inhibitor acetazolamide and inhibition of the enteric nervous system with the topical anesthetic lidocaine on basal and prostaglandin E2-stimulated ion and water transport and transmucosal electrical potential difference. At rest, mean basal (95% confidence intervals) net ion secretion into the human proximal duodenum was: Cl- 670 (288-1052), Na+ 818 (410-1225), K+ 32 (14-51) mumol/cm/hr. Basal net water transport was 30 (14.6-45.3) ml/hr, and the potential difference (PD) was 7.0 (3.6-10.9) mV, lumen negative. Intraluminal prostaglandin E2 increased the secretion of all ions, water, and the PD. After pretreatment with acetazolamide and luminal administration of lidocaine, basal ion transport was unchanged, but the response to luminal PGE2 was inhibited. It is concluded that: (1) at rest there is a net secretion of Na+, K+, Cl-, and water by the human proximal duodenum; and (2) PGE2-stimulated water electrolyte secretion is dependent in part upon mucosal carbonic anhydrase activity and the enteric nervous system.

Acetazolamide inhibits basal and stimulated HCO3- secretion in the human proximal duodenum.

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.

Review article: gastroduodenal bicarbonate secretion.

The gastroduodenal epithelium is covered by an adherent mucus layer into which bicarbonate is secreted by surface epithelial cells. This mucus-bicarbonate barrier is an important first line of defence against damage by gastric acid and pepsin, and has been demonstrated in all species including human. Similar to gastric acid secretion, regulation of gastric and duodenal bicarbonate secretion can be divided into three phases: cephalic, gastric and duodenal. In humans, sham-feeding increases bicarbonate secretion in both the stomach and duodenum which is mediated by cholinergic vagal fibres in the stomach, but seems to be noncholinergic in the duodenum. Gastric distention and luminal acidification increases gastric bicarbonate production. Whereas there are no data relating to the gastric phase of human duodenal bicarbonate secretion, in animals, food and acid in the stomach independently stimulate duodenal bicarbonate output. To date, the duodenal phase of human gastric bicarbonate secretion has not been studied, but data from animals reveal that duodenal acidification augments bicarbonate secretion in the stomach. In all species tested, direct acidification of the duodenum is a potent stimulant of local bicarbonate production. In humans, the pH threshold for bicarbonate secretion is pH 3.0. Mediation of gastroduodenal bicarbonate secretion is provided by a variety of agonists and antagonists, tested mainly in animals, but some have been evaluated in humans. Prostaglandins of the E class and VIP are major factors that control bicarbonate secretion. Bicarbonate secretion, and the mucus-bicarbonate layer in general, is adversely effected by ulcerogenic factors such as aspirin, NSAIDs, bile salts, and cigarette smoking. Furthermore, duodenal ulcer patients have an impairment in bicarbonate production within the duodenal bulb, at rest and in response to stimulation. These findings indicate that the mucus-bicarbonate barrier is an important first line of defence in the pathogenesis of peptic ulcer disease.

Age-related differences in the pharmacokinetics and pharmacodynamics of lansoprazole.

1. The pharmacokinetics and pharmacodynamics of lansoprazole, an antisecretory and antiulcer agent, were evaluated in 12 older (> 60 years) and 12 younger (< 60 years) healthy men. 2. Doses of lansoprazole (15 or 30 mg) or placebo were each given once daily for 7 consecutive days in this randomized, double-blind, three-way crossover study. Plasma concentrations and urinary excretion of lansoprazole and its metabolites, and gastric acid secretion were monitored after dosing on days 1 and 7 of each treatment period. 3. Within each age group, lansoprazole pharmacokinetics were linear. The mean clearance and elimination half-life of lansoprazole were about 40% lower and higher, respectively, in the older subjects (CL0: 12-14 vs 20-24 1 h(-1); t1/2,z: 1.90-2.19 vs 1.26-1.44 h). 4. At each dose level, acid secretion was more inhibited in the older group. However, the AUC associated with a 50% decrease in acid secretion was similar (849 vs 892 ng ml(-1) h) for both age groups. Multiple dosing decreased the maximum possible inhibition more in the older group than in the younger group. 5. Since the decrease in acid output associated with equivalent AUCs on day 1 was similar for the two age groups, the greater difference between day 1 and day 7 secretion in the older group indicates that recovery of secretory activity may decline with increasing age.

Cigarette smoking inhibits acid-stimulated duodenal mucosal bicarbonate secretion.

OBJECTIVE: To determine the effect of cigarette smoking on proximal duodenal mucosal bicarbonate secretion, an important defense mechanism against acid and peptic damage. DESIGN: Prospective study. SETTING: Clinical research laboratory in a university hospital. PATIENTS: Thirteen healthy adults (7 smokers and 6 nonsmokers) who had no history of peptic ulcer disease. INTERVENTIONS: Participants smoked (1 cigarette/15 min during a period of 1 hour, smokers only) or sham smoked (puffing on an unlit cigarette) during duodenal perfusion with either saline, hydrochloric acid, or prostaglandin E2 (PGE2). MEASUREMENTS: Collection of proximal duodenal secretions using a modified duodenal tube with occluding balloons and quantitation of duodenal mucosal bicarbonate secretion. RESULTS: During sham smoking both smokers and nonsmokers had comparable basal as well as H(+)-stimulated and PGE2-stimulated duodenal mucosal bicarbonate secretion. Compared with sham smoking, smoking did not significantly alter basal bicarbonate secretion (201 mumol/cm per hour [95% CI, 152 to 250 mumol/cm per hour] compared with 178 mumol/cm per hour [CI, 134 to 222 mumol/cm per hour], respectively). However, compared with sham smoking, smoking markedly reduced (P < 0.01) the increase in duodenal bicarbonate secretion in response to luminal acidification by approximately 80% (from 242 mumol/cm per hour [CI, 41 to 443 mumol/cm per hour] to 53 mumol/cm per hour [CI, -107 to 197 mumol/cm per hour]); a decrease was observed in each participant. In contrast, smoking had no significant effect on the response to luminal PGE2. CONCLUSIONS: Cigarette smoking markedly inhibited acid-stimulated human duodenal mucosal bicarbonate secretion. This adverse effect of smoking may, at least in part, explain the role of cigarette smoking in the pathogenesis and natural history of duodenal ulcer disease.