Luminal Acid Research Articles

Mucus and alkali secretion in the rat duodenum: Effects of indomethacin, Nω-Nitro- l-arginine, and luminal acid

Background & Aims Duodenal mucus and bicarbonate secretion appear to play an essential role in the protection of the duodenum. The aim of this study was to examine duodenal bicarbonate and mucus secretion and the effects of cyclooxygenase inhibition, nitric oxide synthase inhibition, and luminal acid. Methods Duodenal mucus gel thickness was measured using microelectrodes during intravital microscopy in anesthetized rats. Bicarbonate secretion was measured using back-titration. Results A continuous layer of mucus with a mean thickness of 284 ± 11 μm (n = 35) and a mean alkaline secretion of 0.18 ± 0.01 μmol · cm −2 · min −1 were found in untreated animals. Indomethacin decreased both mucus and bicarbonate secretion by about 35%. NO synthase inhibition with N ω-nitro- l-arginine reduced mucus secretion by about 21% but increased bicarbonate secretion by 39%. Exposure of the mucosal surface to 10 mmol/L HCl increased mucus secretion by 44% and bicarbonate secretion by 22%. Conclusions The duodenal mucus layer is continuous. It can be easily removed, and new secretion can be followed. Duodenal mucus secretion is strongly stimulated by luminal acid and endogenous prostanoids and less markedly by NO, whereas bicarbonate secretion is stimulated by acid and endogenous prostanoids and inhibited by endogenous NO

Gastroduodenal mucosal defense

The observation that a significant proportion of patients who are infected with Helicobacter pylori or who consume nonsteroidal anti-inflammatory drugs on a regular basis do not develop gastric or duodenal ulcers suggests that differences in host responses to these agents play an important role in the pathogenesis of the gastroduodenal injury. In the past year, significant progress has been made in understanding the contribution of various components of the “mucosal defense network” to resistance to injury. For example, advances have been made in understanding the mechanisms through which epithelial cells maintain their intracellular pH near neutrality in the face of significant luminal acid loads. The importance of nitric oxide and prostaglandins in the regulation of mucosal blood flow and other components of mucosal defense is becoming more clearly understood. Advances have been made in understanding the contribution of the mucosal immune system and the mediators and cytokines it produces in the responses of the mucosa to bacterial infection or ingestion of noxious substances. The role of the sensory afferent neurons in modulating mucosal defense has been the subject of a number of studies, as has been the mechanisms underlying restitution of the gastroduodenal epithelium, factors influencing healing of ulcers, and factors contributing to the adaptation of the stomach to repeated administration of nonsteroidal anti-inflammatory drugs.

Bicarbonate diffusion through mucus.

The mucus layer overlying duodenal epithelium maintains a pH gradient against high luminal acid concentrations. Despite these adverse conditions, epithelial surface pH remains close to neutrality. The exact nature of the gradient-forming barrier remains unknown. The barrier consists of mucus into which HCO3- is secreted. Quantification of the ability of HCO3- to establish and maintain the gradient depends on accurate measurement of this ion's diffusion coefficient through mucus. We describe new experimental and mathematical methods for diffusion measurement and report diffusion coefficients for HCO3- diffusion through saline, 5% mucin solutions, and rat duodenal mucus. The diffusion coefficients were 20.2 +/- 0.10, 3.02 +/- 0.31, and 1.81 +/- 0.12 x 10(-6) cm2/s, respectively. Modeling of the mucobicarbonate layer with this latter value suggests that for conditions of high luminal acid strength the neutralization of acid by HCO3- occurs just above the epithelial surface. Under these conditions the model predicts that fluid convection toward the lumen could be important in maintaining the pH gradient. In support of this hypothesis we were able to demonstrate a net luminal fluid flux of 5 microliters.min-1.cm-2 after perfusion of 0.15 N HCl in the rat duodenum.

Calcitonin gene-related peptide modulates acid-mediated regulation of somatostatin and gastrin release from rat antrum

Background & Aims : Acid has been shown to stimulate calcitonin gene-related peptide (CGRP) release from peripheral sensory afferent nerve endings in the stomach. The aim of this study was to determine whether endogenous CGRP was involved, by a neurocrine mechanism, in acid-mediated stimulation of somatostatin and inhibition of gastrin release. Methods : A two-compartment sleeve of antral mucosal/submucosal tissue was perfused to determine sensory nerve and endocrine cell responses to luminal acid. CGRP receptor antagonist, CGRP 8–37, was used to inhibit the actions of endogenously released CGRP. Results : Perfusion of the antral sleeve lumen with media of increasing hydrogen ion concentration caused pH-dependent increases in CGRP and somatostatin release and decrease in gastrin release. CGRP 8–37 inhibited significantly basal somatostatin (−36%) and stimulated basal gastrin (+65%) release ( P < 0.02). Furthermore, CGRP 8–37 administration prevented luminal acid-mediated inhibition of gastrin release and stimulation of somatostatin release. These results indicate that CGRP 8–37 prevented acid-mediated feedback inhibition of gastrin release and acid-induced feedforward somatostatin release. Conclusions : These results suggest that CGRP plays an important role in the response of antral D and G cells to luminal acid and that local effector action of endogenous CGRP participates in regulation of antral regulatory peptide secretion.

Release of somatostatin, neurotensin and vasoactive intestinal peptide upon inhibition of gastric acid secretion by duodenal acid and hyperosmolal solutions in the conscious rat.

The inhibitory effect of duodenal exposure to acid and hyperosmolal solutions on pentagastrin-stimulated gastric acid secretion was studied in conscious rats equipped with chronic gastric fistula and duodenal Thiry-Vella loop. The loop was challenged with saline, HCl or hyperosmolal polyethylene glycol. Gastric acid secretion was measured in samples from the gastric fistula. Gut peptide concentrations were measured in duodenal perfusates collected each 30 min, and in plasma samples collected both during stimulated acid secretion alone, and at the end of experiments in combination with luminal challenges of the loops. During pentagastrin-stimulated gastric acid secretion, luminal perfusion of the duodenal loop with acid caused inhibition of acid secretion (P < 0.001) and a prominent release of somatostatin both to the lumen (P < 0.001) and to the circulation (P < 0.05). Also, neurotensin (P < 0.01) and vasoactive intestinal peptide (P < 0.01) were released to the lumen, but not to the circulation. Upon perfusion of the duodenal loop with hyperosmolal polyethylene glycol, acid secretion was inhibited (P < 0.05) and somatostatin alone was released to the luminal side (P < 0.01). In conclusion, duodenal exposure to acid inhibits pentagastrin-stimulated gastric acid secretion and releases SOM to the circulation that may directly inhibit acid secretion. Concomitantly, somatostatin (SOM), neurotensin and vasoactive intestinal peptide are released to the lumen. Duodenal exposure to hyperosmolal polyethylene glycol inhibits acid secretion with a luminal release of SOM only. Thus, luminal acid and hyperosmolal solutions inhibit gastric acid secretion by separate mechanisms. After acid or hyperosmolal challenge, the release of SOM to the circulation indicates gastric acid inhibition in an endocrine manner, while a luminal release of gut peptides indicates a local peptide overflow that might be of importance via paracrine regulatory mechanisms in the intact animal.

Role of nitric oxide in restitution of injured guinea pig gastric mucosa in vitro

The role of nitric oxide (NO) in restitution was examined in intact sheets of in vitro guinea pig gastric mucosae after mucosal injury induced by exposure of the luminal surface to 1.25 M NaCl for 10 min. The recovery of transmucosal electrical resistance and [3H]mannitol flux after the injury were significantly greater at luminal pH (pH1) 7.0 than 3.0. The recovery was abolished by pretreatment with 1 mM NG-nitro-L-arginine methyl ester (L-NAME), only at pHL 3.0, an effect reversed by 1 mM L-arginine. Enhancement of the recovery by L-arginine at pHL 3.0 was abolished by 50 microM methylene blue (MB), an effect restored by 1 mM N6,2'-O-dibutyryl guanosine 3',5'-cyclic monophosphate (DBcGMP). In L-arginine- but not L-NAME-treated tissues, recovery was enhanced further by an increase in serosal [HCO3-] and was inhibited by 5% N-acetyl-L-cysteine in the luminal solution or by the removal of serosal HCO3-. Morphological examination showed the formation of a thick "mucoid cap" in L-arginine-but not L-NAME-treated tissues. These results suggest that, in the presence of luminal acid, endogenous NO contributes to restitution in injured gastric mucosa at least in part by facilitating the formation of the mucoid cap.

Role of pepsin in the development of indomethacin-induced antral ulceration in the rat.

To examine the effects of a pepsin inhibitor, pepstatin-A, a long acting H2-receptor blocker, loxtidine, exogenous pepsin and exogenous acid against indomethacin-induced antral ulceration in the rat. Indomethacin (60 mg/kg s.c.) caused antral ulceration in fasted/re-fed rats over a period of 4 h. Ulceration was prevented in a dose-dependent manner by treatment with pepstatin-A (0.1-1 mg.kg hourly) or loxtidine (3 mg/kg) given orally. Acidified methylcellulose (1 mL hourly per os) enhanced damage and also prevented protection by loxtidine (3 mg/kg per os). The protection by pepstatin-A was not altered by treatment with acidified methylcellulose but was reversed by treatment with a 10-fold excess of pepsin. These studies suggest that mucosal degradation by pepsin, rather than direct damage by luminal acid, was the major factor in the development of indomethacin-induced antral ulceration in the rat.

Duodenal mucus and alkaline secretion in vivo; effects of cyclo-oxygenase inhibitor, nitric oxide synthase inhibitor and luminal acid

Duodenal mucus and alkaline secretion in vivo; effects of cyclo-oxygenase inhibitor, nitric oxide synthase inhibitor and luminal acid

High systemic HCO3 and topical 16,16-dimethyl PGE2 protect the gastric mucosa against luminal acid by enhancing its pre-epithelial buffer capacity

High systemic HCO3 and topical 16,16-dimethyl PGE2 protect the gastric mucosa against luminal acid by enhancing its pre-epithelial buffer capacity

N-Butyrate Mediation of Ganglioside Expression of Human and Murine Cancer Cells Demonstrates Relative Cell Specificity

1. n-Butyrate, a short chain fatty acid produced by colonic fermentation, induces differentiation in human neoplastic cell lines, and reduces expression in vitro of a sialyltransferase that glycosylates N-linked glycoproteins in hepatoblastoma cells. Gangliosides are amphipathic, sialylated glycosphingolipids that undergo profound changes in many transformed cells and may protect neoplastic cells from host immune surveillance. Colonic mucosal cells are exposed to luminal short-chain fatty acid concentrations of up to 80 mmol/l, and there is some evidence that short-chain fatty acids may alter ganglioside expression in colon cancer cells. 2. Because of the importance of gangliosides in cancer pathogenesis, we investigated the effects of n-butyrate on ganglioside expression of colonic (human and murine) and non-colonic cancer cells. 3. Three separate colon cancer cell lines (LS174T, T84 and MCA-38), when butyrate treated, demonstrated striking amplification of specific individual gangliosides. However, the total lipid-bound sialic acid content of gangliosides of butyrate-treated LS174T cells diminished. In contrast to earlier reports, n-butyrate did not mediate expression of all gangliosides and specifically did not mediate expression of GM3. This effect persisted even after removal of butyrate. 4. In contrast, exposure of extracolonic cells to butyrate, including cervical cancer (HeLa) and laryngeal cancer (HEp-2) cell lines in this study and hepatoblastoma cells (Hep G2) in our previous work, caused no detectable changes in ganglioside expression. 5. In conclusion, our results indicate a relative tissue specificity of butyrate-mediated alterations in ganglioside expression that is not universal but is limited to specific gangliosides.

Increased esophageal blood flow (EBF) during luminal acid exposure is insensitive to tetrodotoxin (TTX): [formula omitted], G.P. Morris, P.K. Dinda, and W.G. Paterson, GI Diseases Research Unit, Queen's University, Kingston, Ontario, Canada

Increased esophageal blood flow (EBF) during luminal acid exposure is insensitive to tetrodotoxin (TTX): [formula omitted], G.P. Morris, P.K. Dinda, and W.G. Paterson, GI Diseases Research Unit, Queen's University, Kingston, Ontario, Canada

Regulation of intracellular pH in isolated Necturus gastric mucosa during short-term exposure to luminal acid

Background/Aims: Continuous exposure to gastric acid implies efficient control mechanisms of intracellular pH (pH i) in the gastric epithelium. This study assessed the roles of Na +, H +, and HCO 3 − transport mechanisms in controlling pH i during short-term exposure of the gastric epithelium to luminal acid. Methods: pH i and Na + activity (a i Na) were measured with liquid sensor microelectrodes in isolated Necturus antral mucosa, modulating ion transport mechanisms by ion removal and pharmacological inhibition. Results: Shortterm exposure to luminal acid (pH 2.3) acidified pH i by 0.3 pH units, whereafter pH i stabilized. This was associated with transient increase in a i Na. Blocking of Na +/H + exchange (in the presence of HCO 3 −/CO 2) by removal of Na + or addition of amiloride eliminated the increase in a Na i and resulted in uncontrolled acidification of pH i. Similarly, blocking of HCO 3 − transport (in the presence of Na +) by removal of HCO 3 − /CO 2 or addition of 4-acetamido-4-isothiocyanatostilbene-2,2-disulfonic acid resulted in uncontrolled acidification of pH i despite increase in a Na i. Blocking of Na +/K + exchange with ouabain eliminated the recovery of a Na i and also resulted in uncontrolled acidification of pH i. Conclusions: The data indicate that during short-term exposure of the gastric mucosa to luminal acid, both Na +/H + antiport and HCO 3 − transport are needed to control pH i and maintain it within physiological ranges.

Effect of HCl on transmembrane potentials and intracellular pH in rabbit esophageal epithelium

Background/Aims : Acidification of the basolateral membrane by adding HCl to the serosal solution of esophageal epithelium leads to more necrosis than acidification of the apical membrane by adding HCl to the luminal solution. The aim of this study was to examine the mechanism for this difference. Methods : The effect of low extracellular pH (pH o) (HCl) on intracellular pH (pH i) and transmembrane potentials was examined in rabbit esophageal cells by impalement with intracellular microelectrodes. Results : Lowering luminal pH to 3.0 had no effect on membrane voltage and/or pH i in either luminally or serosally impaled cells, although a decline in both parameters occurred at pH 1.5 in luminally impaled cells. In contrast, lowering serosal pH from 7.4 to 3.0 progressively reduced membrane voltage and/or pH i. Membrane depolarization at low pH o was inhibited by a high-potassium solution or barium and mimicked by lowering pH i (gassing with CO 2) at neutral pH o. Conclusions : Basolateral, but not apical, membranes of esophageal epithelial cells are highly permeable to H +, accounting for the greater susceptibility to damage from exposure to serosal than luminal acid. Membrane depolarization at low pH o is mediated by low pH i through inhibition of basolateral membrane K + conductance.

Role of vagal and splanchnic capsaicin-sensitive afferents in enterogastric inhibition of acid secretion in rats.

The role of capsaicin-sensitive afferent innervation and neural pathways involved in the enterogastric inhibition of gastric acid secretion by luminal acid was investigated in urethan-anesthetized rats. Intestinal perfusion with graded concentrations of HCl (50, 75, and 100 mM) for 1 h dose dependently inhibited both thyrotropin-releasing hormone (TRH) analogue- and pentagastrin-stimulated acid output (P < 0.01). The inhibitory effect of intestinal perfusion with HCl (100 mM) on pentagastrin-stimulated acid secretion was blocked by bilateral vagotomy, whereas celiac ganglionectomy had no effect. Systemic capsaicin pretreatment (125 mg/kg sc) reduced the antisecretory effects of luminal acid on both TRH analogue- and pentagastrin-stimulated acid secretion. Neither selective perivagal nor selective periceliac capsaicin treatments (1% solution) modified the antisecretory effect of intestinal perfusion with HCl (75 mM) on TRH analogue-stimulated acid secretion. However, combined selective perivagal plus periceliac capsaicin treatment reduced it to the same extent as systemic capsaicin treatment. We conclude that enterogastric inhibition of acid secretion by luminal acid in urethan-anesthetized rats is mediated by extrinsic reflexes involving both vagal and splanchnic capsaicin-sensitive afferent fibers.

4-Maleimidohippuric acid — a tailor-made, direct, site-specific nephrotoxin: effects on renal function and ultrastructure in pentobarbital-anesthetized dogs

A model has been proposed to explain at least one of the possible pathways through which a xenobiotic might produce proximal tubule necrosis. The model is formulated on the idea that a compound must possess two structural fea tures: (i) a carboxyl or amino acid moiety that would allow for selective uptake into proximal tubule cells via the strategically located antilurninal membrane-bound organic anion transport system or the luminal membrane-bound amino acid transport system(s), respectively, and (ii) a highly reactive moiety that can directly alkylate proximal tubular components, or a moiety that can be biotransformed within proximal tubular cells to such a substance. In an attempt to validate the proposed structural features as prerequisites for xenobiotic induction of proximal tubular necrosis, a novel compound, 4-maleimidohippuric acid (4-MHA), was synthesized which possesses an anionic group and a reactive moiety. Following the administration of 4-MHA directly into the renal artery of pentobarbital-anesthetized dogs, specific unilateral ultrastructural damage was noted only in the S 1 and S 2 cell types of the proximal tubule; the most notable renal function changes included proteinuria and glucosuria. Anionic, but non-alkylating, relatives of 4-MHA failed to alter renal function or ultrastructure. The specific proximal tubular toxicity of 4-MHA validates the proposed structural requirements for induction of proximal tubular necrosis.

Purification and characterization of two forms of β-d-galactosidase from rat epididymal luminal fluid: evidence for their role in the modification of sperm plasma membrane glycoprotein(s)

Previous studies from this laboratory have identified rat epididymal luminal fluid acid beta-D-galactosidase activity which also optimally hydrolyses a glycoprotein substrate at neutral pH [Skudlarek, Tulsiani and Orgebin-Crist (1992) Biochem. J. 286, 907-914]. We have now separated the luminal fluid beta-D-galactosidase into two molecular forms by ion-exchange chromatography on a column of DE-52. The separated enzyme activities were purified to an apparent homogeneity by molecular-sieve chromatography followed by affinity chromatography on a column of immobilized p-nitrophenyl beta-D-thiogalactopyranoside. The purified forms, when resolved by SDS/PAGE under reducing conditions, showed apparent molecular masses of 84 and 97 kDa. Kinetic studies, including a pH-dependent substrate preference and pH-dependent association/dissociation, disclosed no differences between these two forms. The two forms had identical N-terminal amino acid sequences. However, the 97 kDa form contained much more total carbohydrate and sialic acid than the 84 kDa form. The carbohydrate moieties in the two forms were assessed by comparing their size on SDS/PAGE before and after treatment with endo-enzymes. The removal of N-linked glycans by treatment with N-glycanase or endoglycosidase F generated de-N-glycosylated polypeptides of an apparent molecular mass of 70 kDa, and indicated that the two forms contained varying amounts of asparagine (N)-linked high mannose/hybrid-type and biantennary complex-type oligosaccharides. This result and the fact that the two molecular forms had identical N-terminal amino acid sequences indicated that the two forms probably have identical or very similar polypeptides. The potential role of the enzyme in modification of sperm plasma membrane (PM) glycoproteins was examined by resolving caput sperm PM proteins (before and after treatment in vitro of the membranes with the purified beta-D-galactosidase) on SDS/PAGE, followed by staining with peanut agglutinin (PNA), a lectin which preferentially binds to Gal beta 1,3GalNAc-linkages found in O-linked glycoproteins. The evidence presented in this report has indicated that a PNA-positive glycoprotein of an apparent molecular mass of 135-150 kDa present on the caput (but not cauda) sperm PM is degalactosylated by the digestion in vitro of the membranes with purified luminal fluid beta-D-galactosidase. This result suggests a possible role for the epididymal luminal fluid beta-D-galactosidases.

Loss of circadian rhythm in luminal acidity of canine stomach by implantation of a gastric fistula.

One to four months after implantation of a gastric fistula, a circadian rhythm in gastric acidity could be demonstrated by use of the intragastric 24-hour pH-metry in dogs with the gastric fistula protruding on the left side of the upper abdomen. This circadian rhythm was found to be fully developed within 3 years, and it remained unchanged up to 5 years after implantation. It is characterized by a daytime intragastric median pH of about 2 and a nocturnal intragastric median pH of about 7. In contrast, a circadian rhythm did not develop within 5 months after instrumentation of the dogs with a gastric fistula protruding on the right side of the upper abdomen. Only 2 years after implantation of the fistula, an intragastric daytime median pH of about 2 and a nocturnal median pH of about 4 appeared. Four years after implantation, the circadian rhythm had evolved. The results show a delayed postoperative restoration of circadian rhythm in canine gastric acidity if a gastropexy occurs at an untolerated position. This may lead to unphysiological distensions in the gastric wall with subsequent continuous stimulation of acid secretion.

Prostaglandin E2 enhances gastric defense mechanisms against acid injury in uremic rats

Background/Aims: Uremia increases gastric mucosal H+ permeability and acid back-diffusion-related injury in rats. The aim of this study was to examine the effect of the synthetic gastroprotective compound 16,16-di-methyl prostaglandin E2 (16,16-dm PGE2) on the gastric barrier to acid injury in uremic rats. Methods: Chronic renal failure was induced by subtotal nephrectomy. Acid back-diffusion injury was induced by superfusion with 15% ethanol in 0.15N HCl and was assessed by image analysis. Intracellular pH, initial surface cell acidification rate, and thickness of mucous gel layer were measured with in vivo microscopy. Gastric mucosal blood flow was measured in separate experiments by laser-Doppler flowmetry. Results: Pretreatment with 16,16-dm PGE2 attenuated H+ back-diffusion and prevented the production of gross lesions. 16,16-dm PGE2 increased gastric mucous gel thickness, decreased initial acidification rate, and maintained intracellular pH homeostasis during exposure to luminal acid. Gastric mucosal blood flow was not changed during superfusion with a neutral buffer but increased during acid exposure in rats treated with 16,16-dm PGE2. Conclusions: 16,16-dm PGE2 attenuated H+ back-diffusion injury in uremic rats. This effect was associated with blunting of the initial decrease of intracellular pH and enhanced surface cell intracellular pH homeostasis during acid exposure. These effects were associated with an increased mucous gel layer thickness and an acid-related increase in blood flow.

Role of bradykinin in the hyperaemia following acid challenge of the rat gastric mucosa.

1. This study examined whether the hyperaemia following acid challenge of the rat gastric mucosa involves bradykinin, a peptide formed in response to tissue injury. 2. Gastric mucosal blood flow in urethane-anaesthetized rats was assessed by the hydrogen gas clearance method. Infusion of a bradykinin solution (10 microM) into the gastric wall augmented gastric mucosal blood flow by a factor of 2.3, an effect that was prevented by the bradykinin B2 antagonist Hoe-140 (icatibant; 100 mumol kg-1, i.v.). 3. I.V. injection of bradykinin (20-60 nmol kg-1) caused a 2.3-3.5 fold increase in blood flow through the left gastric artery as measured by the ultrasonic transit time shift technique. The hyperaemic effect of bradykinin in this gastric artery was also prevented by Hoe-140 (100 mumol kg-1, i.v.). 4. Gastric acid back diffusion was evoked by perfusing the stomach with 15% ethanol, to break the gastric mucosal barrier, in the presence of luminal acid. Depending on the concentration of acid (0.05 and 0.15 M HCl), this procedure increased gastric mucosal blood flow by a factor of 1.6-2.8 and caused formation of gross damage in 1.5-3% of the glandular mucosa. Hoe-140 (100 mumol kg-1, i.v.) failed to alter the moderate vasodilatation seen in the presence of 0.05 M HCl but significantly (P < 0.05) attenuated the marked hyperaemia and enhanced the gross mucosal damage observed in the presence of 0.15 M HCl. 5. These data show that bradykinin is able to enhance gastric mucosal blood flow via activation of B2 receptors. It appears as if this kinin is formed during severe acid challenge of the rat gastric mucosa and participates in the hyperaemic reaction to gastric acid back diffusion.

Role of dopamine and other stimuli of mucosal bicarbonate secretion in duodenal protection

Duodenal mucosal secretion of bicarbonate is one main mechanism in the protection of this epithelium against luminal acid. The duodenal secretagogue vasoactive intestinal polypeptide, at doses not affecting mucosal blood flow, protects against acid-induced morphological changes. Some sigma receptor ligands, which increase the duodenal alkaline secretion, prevent duodenal but not gastric mucosal ulceration. Dopamine D-1 receptor agonists and the peripherally acting catechol-O-methyl-transferase (COMT) inhibitor nitecapone stimulate the bicarbonate secretion in the rat and a similar increase in secretion has been observed in human volunteers. COMT inhibitors decrease tissue degradation of catecholamines, including dopamine. The D-2 agonist bromocriptine, in contrast, decreases the secretion. These results, indicating that the bicarbonate secretion is stimulated via peripheral dopamine D-1 receptors, are supported by the finding that dopamine D-1 (but not D-2) agonists increase the production of cyclic AMP in isolated duodenal enterocytes. The increase in mucosal alkaline secretion may contribute to the previously observed ulceroprotective actions of dopaminergic compounds.