Search

Background & Aims: 5-hydroxytryptamine (5-HT) is an important neurotransmitter and intercellular messenger that modulates many gastrointestinal functions. Because little is known about the role of 5-HT in the regulation of duodenal bicarbonate secretion, we examined the role of 5-HT on duodenal bicarbonate secretion and define neural pathways involved in the actions of 5-HT. Methods: Duodenal mucosa from National Institutes of Health Swiss mice was stripped of seromuscular layers and mounted in Ussing chambers. The effect of 5-HT on duodenal bicarbonate secretion was determined by the pH stat technique. Acetylcholine (ACh) release from duodenal mucosa was assessed by preincubating the tissue with [^3H] choline and measuring 5-HT-evoked release of tritium. Results: 5-HT added to the serosal bath markedly stimulated duodenal bicarbonate secretion and short circuit current (Isc) in a dose-dependent manner (10^-^7 mol/L to 10^-^3 mol/L; P < 0.0001), whereas mucosally added 5-HT was without effect. 5-HT-stimulated bicarbonate secretion was independent of luminal Cl^-. Pretreatment with tetrodotoxin (TTX) (10^-^6 mol/L) or atropine (10^-^5 mol/L) markedly reduced 5-HT-stimulated duodenal bicarbonate secretion (by 60% and 65%, respectively; P < 0.001) and Isc (by 45% and 27%, respectively; P < 0.001 and P < 0.05). Pretreatment with N@w-nitro-l-arginine methyl ester (l-NAME) (10^-^3 mol/L), propranolol (10^-^5 mol/L), or phentolamine (10^-^5 mol/L) did not significantly alter 5-HT-stimulated duodenal mucosal bicarbonate secretion or Isc. 5-HT concentration-dependently evoked ACh release from duodenal mucosal preparations (P < 0.0001). TTX markedly inhibited 5-HT-evoked ACh release (P < 0.001). Conclusions: 5-HT is a potent activator of duodenal mucosal bicarbonate secretion in mice. Duodenal bicarbonate secretion induced by 5-HT in vitro occurs principally via a cholinergic neural pathway.

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. GASTROENTEROLOGY 2000;118:1051-1060

Background & Aims: The gastroduodenal epithelium is protected from acid-peptic damage, in part, by its ability to secrete bicarbonate. Patients with duodenal ulcer disease have impaired proximal duodenal mucosal bicarbonate secretion. We have shown in vitro that histamine inhibits prostaglandin-stimulated bicarbonate secretion in rabbit duodenal mucosa via histamine H"2 receptors and enteric nerves. In this study we examined whether the proulcerogenic compounds aspirin or ethanol regulate duodenal bicarbonate secretion and the involvement of histamine. Methods: Bicarbonate secretion by rabbit proximal duodenal mucosa was examined in vitro in Ussing chambers. Results: Aspirin and ethanol decreased basal and prostaglandin-stimulated bicarbonate secretion; the latter effect was specific for prostaglandin. The inhibitory effects of the two ulcerogenic compounds were at least additive. Ranitidine and tetrodotoxin abolished the inhibitory effects on stimulated, but not basal, secretion. Aspirin and ethanol also induced release of duodenal histamine. Conclusions: Aspirin and ethanol act by two distinct pathways to impair duodenal bicarbonate secretion. Both agents inhibit basal secretion via a histamine-independent and neurally independent pathway while they inhibit prostaglandin E"2-stimulated secretion via histamine release, likely from mast cells, and actions on enteric nerves. Our findings may be of relevance to the understanding and potential treatment of nonsteroidal anti-inflammatory drug-associated mucosal injury. GASTROENTEROLOGY 1998;114:527-535