Secretion of bicarbonate into the adherent layer of mucus gel creates a pH gradient with a near-neutral pH at the epithelial surfaces in stomach and duodenum, providing the first line of mucosal protection against luminal acid. The continuous adherent mucus layer is also a barrier to luminal pepsin, thereby protecting the underlying mucosa from proteolytic digestion. In this article we review the present state of the gastroduodenal mucus bicarbonate barrier two decades after the first supporting experimental evidence appeared. The primary function of the adherent mucus gel layer is a structural one to create a stable, unstirred layer to support surface neutralization of acid and act as a protective physical barrier against luminal pepsin. Therefore, the emphasis on mucus in this review is on the form and role of the adherent mucus gel layer. The primary function of the mucosal bicarbonate secretion is to neutralize acid diffusing into the mucus gel layer and to be quantitatively sufficient to maintain a near-neutral pH at the mucus-mucosal surface interface. The emphasis on mucosal bicarbonate in this review is on the mechanisms and control of its secretion and the establishment of a surface pH gradient. Evidence suggests that under normal physiological conditions, the mucus bicarbonate barrier is sufficient for protection of the gastric mucosa against acid and pepsin and is even more so for the duodenum.

The barrier that protects the undamaged gastroduodenal mucosa from autodigestion by gastric juice is a dynamic multicomponent system. The major elements of this barrier are the adherent mucus gel layer, which is percolated by the HCO3- secretion from the underlying epithelial cells; the epithelial layer itself, which provides a permeability barrier and can rapidly repair superficial damage by a process of cell migration referred to as reepithelization or restitution; and a specially adapted vasculature, which provides a supply of HCO3- for transcellular transport and/or diffusion into the mucus layer. Passive diffusion of intestinal HCO3- into the lumen is particularly important when there is superficial damage resulting in increased leakiness of the mucosal epithelium. The process of reepithelization occurs by the migration of performed cells from gastric pits or duodenal crypts. This process is quite distinct from the wound healing and associated inflammatory response that accompany more severe injury or chronic damage. The adherent mucus gel acts as a physical barrier against luminal pepsin and provides a stable unstirred layer that supports surface neutralization of acid by mucosal HCO3-. Surface neutralization by mucosal HCO3- provides a major mechanism of protection against acid in the proximal duodenum. In the stomach, where luminal acidity can fall to around pH 1, other mechanisms of protection must exist, since the surface pH gradient is reported to collapse when luminal H+ exceeds approximately 10 mM. This collapse of the surface pH gradients may reflect, at least in part, that such studies have been mostly performed on non-acid-secreting mucosa where the supply of HCO3- to the interstitium from the parietal cells will be reduced. However, because the gastric mucosa can withstand prolonged exposure to acid without apparent damage, this implies an intrinsic resistance of the epithelial apical surface. This is amply illustrated within the gastric glands that do not secrete mucus and HCO3- yet are exposed to undiluted pepsin and an isotonic solution of HCl. Bicarbonate and mucus secretions together with mucosal blood flow are under paracrine, endocrine, and neural control. The rate of reepithelialization will depend on local chemotactic factors, adhesion mechanisms, and the creation of an acid/pepsin/irritant-free environment under a protective gelatinous or mucoid cap. If optimal conditions are met, then the rate of reepithelialization appears to depend primarily on the intrinsic properties of the migrating cells themselves rather than control by exogenous mediators.(ABSTRACT TRUNCATED AT 400 WORDS)

The gastroduodenal mucosa is a dynamic barrier restricting entry of gastric acid and other potentially hostile luminal contents. Mucosal HCO3(-) is a key element in preventing epithelial damage, and knowledge about HCO3(-) transport processes, including the role of the cystic fibrosis transmembrane conductance regulator channel, and their neurohumoral control are in rapid progress.

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Gastric HCO3(-) transport (basal) studied in isolated amphibian mucosa and mammalian stomach in vivo amounts to 2-10% of maximal H+ secretion. Duodenal mucosa, devoid of Brunner's glands, transports HCO3(-) at a greater rate (per unit surface area) than either stomach or jejunum in vitro and in vivo. Gastric (but not duodenal) HCO3(-) transport is stimulated by dibutyryl cGMP, carbachol, and cholecystokinin and duodenal (but not gastric) transport by dibutyryl cAMP and gastric inhibitory peptide. Glucagon and E- and F-type prostaglandins stimulate, whereas histamine, gastrin, and secretin are without effect in both stomach and duodenum. Gastric transport very probably occurs by Cl--HCO3(-) exchange at the luminal membranes of the surface epithelial cells. In addition to this mechanism, the duodenum also transports HCO3(-) electrogenically. Lowering the luminal pH increases transport in both the stomach and duodenum. This response, probably mediated via both local production of prostaglandins and tissue-specific humoral agents, may be important in mucosal protection against acid. Metabolism-dependent transport of HCO3(-), stimulated by acid, seems quantitatively sufficient to account for all of the duodenal and most of the gastric mucosa's ability to remove luminal acid.

The duodenum, in contrast to the jejunum, actively secretes HCO3- at a high rate, a process that protects the mucosa from acid/peptic injury. Our purpose was to define the mechanisms involved in HCO3- transport by studying the acid-base transport processes in isolated duodenal enterocytes. Individual rat duodenocytes, isolated by a combination of Ca2+ chelation and collagenase, attached to a collagen matrix were loaded with the pH-sensitive fluoroprobe 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein acetoxymethyl ester (BCECF-AM), and intracellular pH was monitored by microfluorospectrophotometry. To identify Na(+)-H+ transport, cells in N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid 1) were pulsed with NH4Cl (40 mM) in the absence and presence of amiloride and 2) were removed of Na+. To examine Cl(-)-HCO3- exchange, Cl- was removed from Ringer-HCO3- superfusate in the presence and absence of dihydro-4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (H2DIDS). The NaHCO3 cotransporter was studied by addition and subtraction of Na+ to amiloride-treated and Cl(-)-depleted enterocytes perfused with Na(+)- and Cl(-)-free Ringer-HCO3- buffer with and without H2DIDS. Mammalian duodenocytes contain at least three acid-base transporters: an amiloride-sensitive Na(+)-H+ exchanger that extrudes acid, a DIDS-sensitive Cl(-)-HCO3- exchanger that extrudes base, and a NaHCO3 cotransporter, also DIDS sensitive, that functions as a base loader. These acid-base transporters likely play a key role in duodenal mucosal HCO3- secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Duodenal surface epithelial transport of HCO3(-) was measured by direct titration in anesthetized animals. Alkalinization of the lumen occurred in all species, although basal rates varied considerably: rats (approximately 10), cats (approximately 15), pigs (approximately 25), dogs (approximately 25), guinea pigs (approximately 40), and rabbits (approximately 170 mueq.cm-1.h-1). In cats duodenum transported HCO3(-) at a greater basal rate than jejunum (approximately 5 mueq.cm-2.h-1) and developed a higher transmucosal electrical potential difference (PD, lumen negative). Luminal application of 10 mM HCl for 5 min produced a sustained increase in the rate of duodenal HCO3(-) transport that was accompanied by a rise in appearance of E-like prostaglandin immunoreactivity in the lumen and a decrease in DNA release. In cats pretreated with indomethacin (10 mg/kg iv), acid caused only a transient increase in HCO3(-) transport. Exogenous prostaglandin E2 (1-12 microM, luminal) increased basal HCO3(-) transport in cats, rats, and dogs but had no effect on this transport in guinea pigs and rabbits. However, prostaglandin E2 increased HCO3(-) transport and PD in guinea pigs pretreated with inhibitors of tissue cyclooxygenase activity (indomethacin or aspirin) or gastric H+ secretion (cimetidine). Thus the continuous exposure of the duodenum of herbivores to HCl discharged from the stomach may itself stimulate HCO3(-) transport via an increase in endogenous prostaglandin levels and render exogenous prostaglandins ineffective. Secretin (1-15 CU/kg iv) was without effect in both cats and guinea pigs. In guinea pigs, intravenous glucagon (120-360 micrograms.kg-1.h-1) or gastric inhibitory peptide (5 micrograms/kg) both increased HCO3(-) transport but not PD. Hence, prostaglandin-stimulated and hormone-stimulated mechanisms of HCO3(-) transport probably occur in mammalian duodenum as found previously in the isolated amphibian duodenum. The results suggest that epithelial HCO3(-) transport is a major mechanism of acid disposal, and thus mucosal protection, in mammalian duodenum under the control of hormones and endogenous prostaglandins.

Melatonin, originating from intestinal enterochromaffin cells, mediates vagal and sympathetic neural stimulation of the HCO secretion by the duodenal mucosa. This alkaline secretion is considered the first line of mucosal defense against hydrochloric acid discharged from the stomach. We have studied whether luminally applied melatonin stimulates the protective secretion and whether a melatonin pathway is involved in acid‐induced stimulation of the secretion. Rats were anaesthetized (Inactin®) and a 12‐mm segment of proximal duodenum with an intact blood supply was cannulated in situ. Mucosal HCO secretion (pH‐stat) and the mean arterial blood pressure were continuously recorded. Luminal melatonin at a concentration of 1.0 μm increased (P < 0.05) the secretion from 7.20 ± 1.35 to 13.20 ± 1.51 μEq/cm/hr. The MT2 selective antagonist luzindole (600 nmol/kg, i.v.) had no effect on basal HCO secretion, but inhibited (P < 0.05) secretion stimulated by luminal melatonin. Hexamethonium (10 mg/kg i.v. followed by continuous i.v. infusion at a rate of 10 mg/kg/hr), abolishes neurally mediated rises in secretion and also inhibited (P < 0.05) the stimulation by luminal melatonin. Exposure of the lumen to acid containing perfusate (pH 2.0) for 5 min increased (P < 0.05) the HCO secretion from 5.85 ± 0.82 to 12.35 ± 1.51 μEq/cm/hr, and luzindole significantly inhibited (P < 0.05) this rise in secretion. The study thus demonstrates that luminal melatonin is a potent stimulant of duodenal HCO secretion and, furthermore, strongly suggests melatonin as an important mediator of acid‐induced secretion.