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Duodenal alkaline secretion: its mechanisms and role in mucosal protection against gastric acid
Digestive and Liver Disease 36 (2004) 505–512
Clinical Review
Duodenal alkaline secretion: its mechanisms and role in mucosal protection against gastric acid P.C. Konturek a , S.J. Konturek b,∗ , E.G. Hahn a b
a First Department of Medicine, University Erlangen–Nuernberg, Erlangen, Germany Department of Physiology, Jagiellonian University Medical College, 16, Grzegorzecka Street, 31-531 Cracow, Poland
Received 2 October 2003; accepted 3 March 2004 Available online 25 May 2004
Abstract Duodenal mucosa, especially its proximal portion, is exposed to intermittent pulses of gastric acid (H+ ). This review summarises the mechanisms of duodenal bicarbonate (HCO3 − ) secretion and their role in protecting duodenal epithelium against gastric H+ . Duodenal epithelium is a leaky barrier against gastric H+ , which diffuses into duodenocytes, but fails to damage them due to: (a) an enhanced expression of cyclooxygenase, producing protective prostaglandins and expression of nitric oxide synthase, releasing nitric oxide, both stimulating duodenal HCO3 − secretion and (b) the release of several neurotransmitters also stimulating HCO3 − secretion such as vasoactive intestinal peptide, pituitary adenylate cyclase-activating polypeptide, acetylcholine and melatonin. At the apical duodenocyte membrane, several HCO3 − /Cl− anion exchangers operate in response to luminal H+ to extrude HCO3 − into duodenal lumen. In baso-lateral duodenocyte membrane, both non-electrogenic and electrogenic Na+ –HCO3 − cotransporters are activated after exposure of duodenum to gastric H+ , causing inward movement of HCO3 − from extracellular fluid to duodenocytes. There are also at least three Na+ /H+ exchangers, eliminating H+ which diffused into these cells. The Helicobacter pylori infection with gastric metaplasia in the duodenum and bacterium inoculation results in the inhibition of HCO3 − secretion by its endogenous inhibitor dimethyl arginine, resulting in ulcerogenesis. © 2004 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. Keywords: Duodenal HCO3 − ; Duodenal ulcerogenesis; Nitric oxide; Prostaglandins
1. Introduction The duodenal cluster unit consists of a group of organs, including duodenum itself, stomach, pancreas, liver and biliary tree. These organs originate embryologically from the closely related structures, whose functions are regulated, at least in part, by the duodenal mechanisms. The lining of the duodenum is equipped with a variety of receptors sensitive to chemical (pH, osmolarity and nutrients) and physical factors (pressure and contractile activity) that activate neuro-hormonal mechanisms maintaining the integrity of the duodenal mucosa and also regulating gastric, pancreatic and hepato-biliary functions. This article is designed to overview the duodenal HCO3 − secretion and its role in mucoso-protective and anti-ulcer mechanisms of the duodenum, which is intermittently
exposed to various irritants emptied by the stomach, especially the aggressive factors such as gastric acid (H+ ) and pepsin as well as other irritants present in the ingested meal, including bacteria and their toxins. Since the identification of HCl in the stomach by Prout in 1823 [1], its secretory mechanisms have been the subject of extensive investigations during last century leading to discovery of important role of vagal nerves by Pavlov in 1886 [2], gastrin by Edkins in 1906 [3] and histamine by Popielski in 1920 [4]. With the synthesis of antagonists of H2 -receptors, discovered by Black et al. [5], and proton pump inhibitors, discovered by Sachs et al. [6], that were found to inhibit all forms of gastric secretion including those induced by meal, a major breakthrough occurred in the physiology of gastric secretion. 2. Gastric H+ (and pepsin) as aggressive factor
∗ Corresponding author. Tel.: +48-12-4211-006; fax: +48-12-4211-578. E-mail address: [email protected] (S.J. Konturek).
Gastric H+ (and pepsin) is considered as predominant aggressive factor against the gastro-duodenal mucosa as
1590-8658/$30 © 2004 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.dld.2004.03.008
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Fig. 1. Two dictums of Schwarz [7] related to pathogenesis of gastro-duodenal ulcerations.
outlined in 1910 by German surgeon, K. Schwarz [7], who formulated famous dictum ‘No acid–no ulcer’, implying that the presence of acid is the ‘condition sine qua non’ of ulcer formation (Fig. 1). It is of interest that in the same publication, Schwarz indicated that another factor, namely ‘the mucosal resistance’, determines the possible formation of peptic ulceration. Schwarz’s dictum related to pathogenesis of peptic ulcer formation were not challenged until Allen and Garner [8] and then Flemstrom and Garner [9] provided direct evidence for the ability of duodenal mucosa to respond to the action of gastric acid with an immediate and abundant secretion of HCO3 − . Apparently, the secretion of HCO3 − was soon found to be an active, metabolism-dependent process occurring along the entire gastrointestinal tract. 3. Duodenal HCO3 − secretion Using animals with pouches prepared from the oxyntic and antral portions of the stomach and loops fashioned from the proximal and distal duodenum, a direct evidence was provided that, indeed, upper GI mucosa possesses the ability to secrete HCO3 − , the most effective in this respect being proximal part of the duodenum, namely duodenal bulb, though some less impressive alkaline secretion was also noticed in distal duodenum and in the gastric antrum and corpus [10]. Another study with the in situ perfused proximal duodenum including duodenal bulb, kept between two balloons, showed higher HCO3 − secretion than that detected in the isolated (and externally denervated) proximal duodenal loop of similar length, suggesting an important role of autonomic innervation in maintaining this secretion [11]. Interestingly, such denervation of the proximal duodenum also resulted in the elimination of acid-induced duodeno-gastric inhibitory reflexes controlling gastric H+ secretion [12].
As predicted by Boldyreff [13], who first recognised in 19th century the cyclic periodicity of motor and secretory gastrointestinal functions, the duodenal alkaline secretion also shows periodicity in phase with migrating motor complex (MMC), reaching peaks at phases II and III and nadir at phase I of this MMC [10]. Feeding interrupts this periodicity and induces enhanced, but more uniform, alkaline secretion. The rise in HCO3 − at the phase II/III has been attributed to the stimulation of duodenal HCO3 − secretion by increments in plasma motilin and activation by cholinergic nerves of enteric nervous system (ENS) as this increase of alkaline secretion can be suppressed by atropine [11]. Since, at phase II/III, there is also an increase in gastric acid secretion and enhanced gastric emptying with progressing motor activity, it is possible that gastric H+ discharged into the duodenum acts on duodenal HCO3 − to release CO2 and raise partial pressure, pCO2 , additionally stimulating HCO3 − secretion. Vagal excitation with sham-feeding was found to result in a dramatic stimulation of proximal duodenal alkaline secretion that could be partly attenuated using atropine [11], suggesting that vagal-cholinergic innervation plays a crucial role in the regulation of sham-feeding-induced duodenal HCO3 − . Unlike vagally-induced duodenal HCO3 − secretion, which was little affected by the suppression of prostaglandin (PG) biosynthesis with indomethacin, basal and HCl- or arachidonic acid-induced duodenal alkaline secretion was found to be PG dependent [11,12]. These acidic stimulants applied on the duodenal mucosa caused concentration-dependent increase in the HCO3 − as well as in mucus glycoprotein secretion [14]. The increase in duodenal HCO3 − brought about by arachidonic acid was prevented by the pre-treatment with indomethacin in a manner similar to the one for the increase induced by HCl. As mucus layer covering the epithelial surface of the duodenum is the first line of mucosal defence against chemical, predominantly acidic
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Fig. 2. Duodenal HCO3 secretion under basal conditions and in response to acid load in proximal and distal duodenum in H. pylori-negative normal subjects and H. pylori-positive DU patients.
irritants, as well as the mechanical, bacterial or enzymatic insults, the components responsible for these protective functions appear to be highly glycosylated mucus glycoproteins. Following arachidonate application, mucus glycoproteins were significantly enriched in phospholipids and this certainly enhanced the protective qualities of the mucus gel [14]. Using a technique similar to our duodenal perfusion technique, Isenberg et al. [15] confirmed that in normal subjects, the proximal duodenal HCO3 − secretion reaches higher values than those in distal duodenum, and that it is greatly enhanced by mucosal acidification or administration of exogenous PGE2 . It is of interest that duodenal ulcer (DU) patients showed reduced HCO3 − response to luminal acid, despite of higher endogenous PGE2 release in these patients, and this deficiency of alkaline secretion has been attributed to mucosal infection with Hp, inflammation, gastric metaplasia and scarring (Fig. 2) [16]. The eradication of Hp was found to increase duodenal alkaline secretion [17] and this has been attributed to the recovery of duodenal mucosa from the inflammation induced by Hp infection and the regression of gastric metaplasia [18,19]. These and other studies seem to confirm that both in humans and animals, PGE2 is a potent stimulant of duodenal HCO3 − secretion and appears to be involved in basal and H+ -induced alkaline secretion [12,15–17,20].
as anti-ulcer and mucoso-protective agents significantly increased duodenal HCO3 − secretion [21] and this has been attributed to PG-dependent stimulation, but this effect could also be explained by the eradication or, at least, bismuth suppression of Hp infection in these subjects, though testing for Hp was not available at that time. Since administration of l-nitro-arginine derivatives, such as l-NNA, was reported to inhibit gastric and duodenal alkaline secretion and these effects were reversed by the addition of l-arginine to l-NNA, endogenous nitric oxide (NO) has also been implicated in the regulation of duodenal HCO3 − secretion [22,23]. This is in keeping with the observation that exogenous donors of NO, such as glycerin trinitrate, or stimulants of sensory nerves releasing CGRP, such as capsacin, were also effective stimulants of gastro-duodenal alkaline secretion [22]. Takeuchi et al. [24] documented that NO, like PG, is involved in acid-induced duodenal HCO3 − secretion and this could be attributed to the enhanced activity of constitutive NO synthase (cNOS). Yao et al. [25] identified in in vitro preparation of rabbit duodenal mucosa the HCO3 − secretory pathway related to vasoactive intestinal peptide (VIP) and cyclic AMP. Glad et al. [26] confirmed in anaesthetised pigs that VIP and its chemical analogue,
4. Neuro-hormonal mechanisms of alkaline secretion In addition to PG, numerous other substances, both naturally occurring or used therapeutically in peptic ulcer, have been reported to contribute to the stimulation of duodenal HCO3 − secretion. We reported that sucralfate and colloidal bismuth subcitrate (DeNol) administered in humans
Fig. 3. Mechanisms of duodenal HCO3 in response to gastric H+ involves a variety of neurotransmitters, pCO2 , COX-1–PG and cNOS–NO systems.
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Fig. 4. Involvement of capsaicin sensitive nerves, CGRP, NO, PG and increase in pCO2 in the stimulation of mucus–HCO3 − secretion by duodenal mucosa in response to its acidification.
pituitary adenylate cyclase-activating polypeptide (PACAP), stimulate duodenal as well as hepato-biliary HCO3 − secretion. Sjoblom and Flemstrom [27] reported recently that melatonin, a neurotransmitter released by neuro-endocrine cells of the gut, is also an effective stimulant of duodenal alkaline secretion in anaesthetised rats and suggested that this indole is involved in H+ -induced alkaline secretion acting via MT2 receptors (Fig. 3). Furthermore, sensory nerves in the duodenal mucosa, activated by acid or capsaicin, have been proposed to be involved in the stimulation of alkaline secretion by axon-reflex stimulation of the release of sensory neuropeptides such as CGRP that in turn activate the release and action of NO [22,23]. The overall mechanisms
operating in the duodenum in response to topical application of H+ and involving COX–PG, NOS–NO and sensory nerves–CGRP–NO systems are depicted in Fig. 4. It is of interest that gastric H+ entering the duodenum not only stimulates COX–PG system but also hydrolyses HCO3 − present in duodenal lumen to increase partial pressure of CO2 , and this was shown to stimulate duodenal HCO3 − secretion (Fig. 5) [28]. Quantitatively, the amounts of HCO3 − secreted by proximal duodenum are only a small portion of the amounts of maximally stimulated gastric H+ secreted in the stomach [11]. Jarbur et al. [28], who quantified gastric H+ and duodenal HCO3 − secretion in fasting humans, found that the
Fig. 5. Acidification of the duodenal mucosa results in the stimulation of COX–PG system due to increased luminal pCO2 resulting from the interaction of gastric acid with duodenal luminal HCO3 − .
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Fig. 6. In the stomach luminal gastric H+ does not reach the mucosal cells because of its neutralization by HCO3 − secreted continuously by surface epithelial cells. Pepsin molecules infuse only into the upper portion of the mucus layer, causing its degradation but do not reach the surface of gastric epithelium.
amounts of HCO3 − produced in the duodenum under basal conditions were similar to duodenal loads of gastric H+ and this stimulation may be mediated, at least in part, by increased pCO2 generated in the duodenal lumen by gastric H+ during phase III of MMC (Fig. 5). Mucus–alkaline secretion and formation of protective mucosal barrier in the stomach differ from those in the duodenum. In the stomach, gastric mucosa is covered by tight epithelial cells with continuous surface mucus layer to which HCO3 − is secreted by goblet cells, creating the pH gradient across mucus layer that neutralises any H+ diffusing from the gastric lumen towards the surface epithelial
cells and thus preventing their acidification and damage (Fig. 6). The total amount of HCO3 − secreted by the gastric mucosa is relatively small when compared to maximal gastric H+ secretion, but due to the fact that HCO3 − is secreted into the thin layer of adherent mucus gel, it is highly effective in neutralising the penetrating luminal H+ . The duodenum is covered, however, by a leaky epithelium (Fig. 7) that, despite of the thick mucus gel layer and secreted HCO3 − , is easily penetrated by gastric H+ discharged to the duodenum. Although, the duodenum is supplied with large amounts of pancreatic and biliary HCO3 − secreted in response to duodenal acidification due to release
Fig. 7. In the duodenum an active HCO3 − secretion in exchange for Cl− occurs at the apical cell membrane and these bicarbonate are neutralized by gastric acid entering the proximal duodenum.
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of secretin, the major ‘chemical battlefield’ with gastric H+ entering the duodenum is the duodenal bulb. The bulb is located just distal to gastric antrum and proximal to the duodenal entry of pancreatico-biliary ducts and uniquely exposed to a highly variable pH environment due to peristaltically conveyed pulses of concentrated gastric H+ discharged by the stomach to duodenum. Since the duodenal mucosa does not have the inherent acid-protective structural properties of gastric mucosa (with intercellular tight junctions), it evolved very efficient means of defence against gastric H+ [30]. The proximal duodenum could be compared to the titration unit with gastric H+ neutralised mostly in the duodenal bulb by HCO3 − originating from bulbar mucosa and secreted due to local action on duodenocytes of numerous mediators including already-mentioned pCO2 , PG, NO, Ach, melatonin, VIP, PACAP and others (see Fig. 3).
5. Duodenocyte membrane transport systems It should be emphasised that duodenal HCO3 − secretion increases after acid perfusion of duodenal bulb when H+ ions actually diffuse into duodenocytes and reduce their intracellular pH (pHi ) (see Fig. 8). To understand the sequence of events following duodenal acid challenge, it is necessary to identify the apical and baso-lateral transport mechanisms in duodenocytes (Fig. 9). It has been proposed [28,29] that the apical duodenocyte membrane is equipped with active exchangers HCO3 − /Cl− , extruding HCO3 − to duodenal lumen in exchange for Cl− (AE—anion exchanger) and several types of AE exchangers function in apical duodenocyte membrane such as AE2 and AE4 [30,31]. Wang et al. [31] identified PAT1 to function in apical duodenocyte membrane as active HCO3 − /Cl− exchanger. In addition, several Na+ /H+ exchangers (NHE1–3) operate in this membrane to eliminate the H+ ions from the duodenocytes
Fig. 8. Duodenum is covered by leaky epithelium and gastric acid entering duodenocytes activate various mechanisms leading to increased secretion of HCO3 in duodenal mucosa.
Fig. 9. Numerous transporters of HCO3 − , Cl− , and Na+ in apical and basolateral; membrane of duodenocytes without and with blocking of Cl− /HCO3 − exchange (CFTR) with SLC266Ax basolateral Na+ /K+ exchange and Na+ –HCO3 − cotransport in Fig. 8. Inactivation of specific Na+ /H+ exchange by amiloride increases bicarbonate secretion.
back to duodenal lumen [32]. The AE exchangers have been related to cystic fibrosis transmembrane conductance regulator (CFTR) and found to be expressed predominantly in duodenal crypts [33]. At the baso-lateral duodenocyte membrane, both electroneutral Na+ –HCO3 − cotransport (NBC1 ) and electrogenic cotransport NBC (NBCn1 ) as well as N+ /H+ exchanger (NHE) are present [34]. Kaunitz and Akiba [35], summarising the protective duodenal response to gastric acid challenge in humans, pointed out that luminal H+ , diffusing into the duodenocytes, lowers pHi and initially decreases the buffer power of these cells but subsequently decreases HCO3 − secretion due to the decrease of CFTR conductance. Lowering pHi immediately increases, however, the activity of baso-lateral NBC1 and promotes an inward movement of HCO3 − from extracellular fluid to increase the cellular content of HCO3 − and its secretion into duodenal lumen through CFTR-related HCO3 − /Cl− exchanger [33]. Furthermore, acidic intracellular pHi increases the activity of baso-lateral NHE and enhances an extrusion of H+ into the submucosal space with increase of cellular alkali load. Luminal H+ in the duodenum also increases the mucus secretion from goblet cells, resulting in the increase of the thickness of mucus gel. This increase in mucus secretion is accompanied by an enhancement of mucosal blood flow mediated by the H+ stimulation of the sensory nerves, releasing CGRP and NO causing vasodilation in the mucosa [35]. DU patients may not exhibit only excessive gastric H+ secretion and accelerated gastric H+ emptying but also produce a potent endogenous NOS inhibitor, asymetric dimethylated arginine derivative (ADMA), that reduces duodenal HCO3 − response to gastric H+ and thus favours the damage of duodenal mucosa and ulcer formation in these patients [36].
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6. Concluding remarks This overview provides an insight into how duodenal mucosa defends itself against the damage by pulses of concentrated gastric H+ entering the duodenum. Unlike the stomach, where mucosal barrier with tight epithelial cells and covering mucus layer actually prevents luminal H+ from entering and damaging the surface epithelium, in the duodenum the epithelium is leaky permitting luminal H+ to diffuse into the duodenocytes and acidify their interior with subsequent fall in intracellular pH (pHi ) and activation of the baso-lateral Na+ –HCO3 − cotransporter. This leads to the movement of extracellular alkali into these cells with subsequent excessive HCO3 − secretion due to activation of apical membrane HCO3 − /Cl− exchangers (AE). Acidic pHi of duodenocytes also activates baso-lateral Na+ /H+ exchangers (NBC), causing extrusion of H+ from duodenocytes and acidification of submucosal tissue with stimulation of capsaicin receptors on afferent nerves leading to increased mucosal blood flow and increased thickness of mucus gel layer enhancing duodenal protective activity. In certain conditions such as Hp infection, the inflammatory changes in the mucosa result in decrease in mucus–alkaline secretion, partly due to ADMA effect and reduced mucosal resistance to acid injury leading to the formation of peptic ulcerations. Eradication of Hp leading to ulcer healing restores the ability of duodenal mucosa to produce HCO3 − due to reduction in ADMA formation, regression of duodenal inflammation, increased ability to secrete HCO3 − and the restoration of the integrity of duodenal mucosa. Conflict of interest statement None declared.
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Clinical Review
Duodenal alkaline secretion: its mechanisms and role in mucosal protection against gastric acid P.C. Konturek a , S.J. Konturek b,∗ , E.G. Hahn a b
a First Department of Medicine, University Erlangen–Nuernberg, Erlangen, Germany Department of Physiology, Jagiellonian University Medical College, 16, Grzegorzecka Street, 31-531 Cracow, Poland
Received 2 October 2003; accepted 3 March 2004 Available online 25 May 2004
Abstract Duodenal mucosa, especially its proximal portion, is exposed to intermittent pulses of gastric acid (H+ ). This review summarises the mechanisms of duodenal bicarbonate (HCO3 − ) secretion and their role in protecting duodenal epithelium against gastric H+ . Duodenal epithelium is a leaky barrier against gastric H+ , which diffuses into duodenocytes, but fails to damage them due to: (a) an enhanced expression of cyclooxygenase, producing protective prostaglandins and expression of nitric oxide synthase, releasing nitric oxide, both stimulating duodenal HCO3 − secretion and (b) the release of several neurotransmitters also stimulating HCO3 − secretion such as vasoactive intestinal peptide, pituitary adenylate cyclase-activating polypeptide, acetylcholine and melatonin. At the apical duodenocyte membrane, several HCO3 − /Cl− anion exchangers operate in response to luminal H+ to extrude HCO3 − into duodenal lumen. In baso-lateral duodenocyte membrane, both non-electrogenic and electrogenic Na+ –HCO3 − cotransporters are activated after exposure of duodenum to gastric H+ , causing inward movement of HCO3 − from extracellular fluid to duodenocytes. There are also at least three Na+ /H+ exchangers, eliminating H+ which diffused into these cells. The Helicobacter pylori infection with gastric metaplasia in the duodenum and bacterium inoculation results in the inhibition of HCO3 − secretion by its endogenous inhibitor dimethyl arginine, resulting in ulcerogenesis. © 2004 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. Keywords: Duodenal HCO3 − ; Duodenal ulcerogenesis; Nitric oxide; Prostaglandins
1. Introduction The duodenal cluster unit consists of a group of organs, including duodenum itself, stomach, pancreas, liver and biliary tree. These organs originate embryologically from the closely related structures, whose functions are regulated, at least in part, by the duodenal mechanisms. The lining of the duodenum is equipped with a variety of receptors sensitive to chemical (pH, osmolarity and nutrients) and physical factors (pressure and contractile activity) that activate neuro-hormonal mechanisms maintaining the integrity of the duodenal mucosa and also regulating gastric, pancreatic and hepato-biliary functions. This article is designed to overview the duodenal HCO3 − secretion and its role in mucoso-protective and anti-ulcer mechanisms of the duodenum, which is intermittently
exposed to various irritants emptied by the stomach, especially the aggressive factors such as gastric acid (H+ ) and pepsin as well as other irritants present in the ingested meal, including bacteria and their toxins. Since the identification of HCl in the stomach by Prout in 1823 [1], its secretory mechanisms have been the subject of extensive investigations during last century leading to discovery of important role of vagal nerves by Pavlov in 1886 [2], gastrin by Edkins in 1906 [3] and histamine by Popielski in 1920 [4]. With the synthesis of antagonists of H2 -receptors, discovered by Black et al. [5], and proton pump inhibitors, discovered by Sachs et al. [6], that were found to inhibit all forms of gastric secretion including those induced by meal, a major breakthrough occurred in the physiology of gastric secretion. 2. Gastric H+ (and pepsin) as aggressive factor
∗ Corresponding author. Tel.: +48-12-4211-006; fax: +48-12-4211-578. E-mail address: [email protected] (S.J. Konturek).
Gastric H+ (and pepsin) is considered as predominant aggressive factor against the gastro-duodenal mucosa as
1590-8658/$30 © 2004 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.dld.2004.03.008
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Fig. 1. Two dictums of Schwarz [7] related to pathogenesis of gastro-duodenal ulcerations.
outlined in 1910 by German surgeon, K. Schwarz [7], who formulated famous dictum ‘No acid–no ulcer’, implying that the presence of acid is the ‘condition sine qua non’ of ulcer formation (Fig. 1). It is of interest that in the same publication, Schwarz indicated that another factor, namely ‘the mucosal resistance’, determines the possible formation of peptic ulceration. Schwarz’s dictum related to pathogenesis of peptic ulcer formation were not challenged until Allen and Garner [8] and then Flemstrom and Garner [9] provided direct evidence for the ability of duodenal mucosa to respond to the action of gastric acid with an immediate and abundant secretion of HCO3 − . Apparently, the secretion of HCO3 − was soon found to be an active, metabolism-dependent process occurring along the entire gastrointestinal tract. 3. Duodenal HCO3 − secretion Using animals with pouches prepared from the oxyntic and antral portions of the stomach and loops fashioned from the proximal and distal duodenum, a direct evidence was provided that, indeed, upper GI mucosa possesses the ability to secrete HCO3 − , the most effective in this respect being proximal part of the duodenum, namely duodenal bulb, though some less impressive alkaline secretion was also noticed in distal duodenum and in the gastric antrum and corpus [10]. Another study with the in situ perfused proximal duodenum including duodenal bulb, kept between two balloons, showed higher HCO3 − secretion than that detected in the isolated (and externally denervated) proximal duodenal loop of similar length, suggesting an important role of autonomic innervation in maintaining this secretion [11]. Interestingly, such denervation of the proximal duodenum also resulted in the elimination of acid-induced duodeno-gastric inhibitory reflexes controlling gastric H+ secretion [12].
As predicted by Boldyreff [13], who first recognised in 19th century the cyclic periodicity of motor and secretory gastrointestinal functions, the duodenal alkaline secretion also shows periodicity in phase with migrating motor complex (MMC), reaching peaks at phases II and III and nadir at phase I of this MMC [10]. Feeding interrupts this periodicity and induces enhanced, but more uniform, alkaline secretion. The rise in HCO3 − at the phase II/III has been attributed to the stimulation of duodenal HCO3 − secretion by increments in plasma motilin and activation by cholinergic nerves of enteric nervous system (ENS) as this increase of alkaline secretion can be suppressed by atropine [11]. Since, at phase II/III, there is also an increase in gastric acid secretion and enhanced gastric emptying with progressing motor activity, it is possible that gastric H+ discharged into the duodenum acts on duodenal HCO3 − to release CO2 and raise partial pressure, pCO2 , additionally stimulating HCO3 − secretion. Vagal excitation with sham-feeding was found to result in a dramatic stimulation of proximal duodenal alkaline secretion that could be partly attenuated using atropine [11], suggesting that vagal-cholinergic innervation plays a crucial role in the regulation of sham-feeding-induced duodenal HCO3 − . Unlike vagally-induced duodenal HCO3 − secretion, which was little affected by the suppression of prostaglandin (PG) biosynthesis with indomethacin, basal and HCl- or arachidonic acid-induced duodenal alkaline secretion was found to be PG dependent [11,12]. These acidic stimulants applied on the duodenal mucosa caused concentration-dependent increase in the HCO3 − as well as in mucus glycoprotein secretion [14]. The increase in duodenal HCO3 − brought about by arachidonic acid was prevented by the pre-treatment with indomethacin in a manner similar to the one for the increase induced by HCl. As mucus layer covering the epithelial surface of the duodenum is the first line of mucosal defence against chemical, predominantly acidic
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Fig. 2. Duodenal HCO3 secretion under basal conditions and in response to acid load in proximal and distal duodenum in H. pylori-negative normal subjects and H. pylori-positive DU patients.
irritants, as well as the mechanical, bacterial or enzymatic insults, the components responsible for these protective functions appear to be highly glycosylated mucus glycoproteins. Following arachidonate application, mucus glycoproteins were significantly enriched in phospholipids and this certainly enhanced the protective qualities of the mucus gel [14]. Using a technique similar to our duodenal perfusion technique, Isenberg et al. [15] confirmed that in normal subjects, the proximal duodenal HCO3 − secretion reaches higher values than those in distal duodenum, and that it is greatly enhanced by mucosal acidification or administration of exogenous PGE2 . It is of interest that duodenal ulcer (DU) patients showed reduced HCO3 − response to luminal acid, despite of higher endogenous PGE2 release in these patients, and this deficiency of alkaline secretion has been attributed to mucosal infection with Hp, inflammation, gastric metaplasia and scarring (Fig. 2) [16]. The eradication of Hp was found to increase duodenal alkaline secretion [17] and this has been attributed to the recovery of duodenal mucosa from the inflammation induced by Hp infection and the regression of gastric metaplasia [18,19]. These and other studies seem to confirm that both in humans and animals, PGE2 is a potent stimulant of duodenal HCO3 − secretion and appears to be involved in basal and H+ -induced alkaline secretion [12,15–17,20].
as anti-ulcer and mucoso-protective agents significantly increased duodenal HCO3 − secretion [21] and this has been attributed to PG-dependent stimulation, but this effect could also be explained by the eradication or, at least, bismuth suppression of Hp infection in these subjects, though testing for Hp was not available at that time. Since administration of l-nitro-arginine derivatives, such as l-NNA, was reported to inhibit gastric and duodenal alkaline secretion and these effects were reversed by the addition of l-arginine to l-NNA, endogenous nitric oxide (NO) has also been implicated in the regulation of duodenal HCO3 − secretion [22,23]. This is in keeping with the observation that exogenous donors of NO, such as glycerin trinitrate, or stimulants of sensory nerves releasing CGRP, such as capsacin, were also effective stimulants of gastro-duodenal alkaline secretion [22]. Takeuchi et al. [24] documented that NO, like PG, is involved in acid-induced duodenal HCO3 − secretion and this could be attributed to the enhanced activity of constitutive NO synthase (cNOS). Yao et al. [25] identified in in vitro preparation of rabbit duodenal mucosa the HCO3 − secretory pathway related to vasoactive intestinal peptide (VIP) and cyclic AMP. Glad et al. [26] confirmed in anaesthetised pigs that VIP and its chemical analogue,
4. Neuro-hormonal mechanisms of alkaline secretion In addition to PG, numerous other substances, both naturally occurring or used therapeutically in peptic ulcer, have been reported to contribute to the stimulation of duodenal HCO3 − secretion. We reported that sucralfate and colloidal bismuth subcitrate (DeNol) administered in humans
Fig. 3. Mechanisms of duodenal HCO3 in response to gastric H+ involves a variety of neurotransmitters, pCO2 , COX-1–PG and cNOS–NO systems.
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Fig. 4. Involvement of capsaicin sensitive nerves, CGRP, NO, PG and increase in pCO2 in the stimulation of mucus–HCO3 − secretion by duodenal mucosa in response to its acidification.
pituitary adenylate cyclase-activating polypeptide (PACAP), stimulate duodenal as well as hepato-biliary HCO3 − secretion. Sjoblom and Flemstrom [27] reported recently that melatonin, a neurotransmitter released by neuro-endocrine cells of the gut, is also an effective stimulant of duodenal alkaline secretion in anaesthetised rats and suggested that this indole is involved in H+ -induced alkaline secretion acting via MT2 receptors (Fig. 3). Furthermore, sensory nerves in the duodenal mucosa, activated by acid or capsaicin, have been proposed to be involved in the stimulation of alkaline secretion by axon-reflex stimulation of the release of sensory neuropeptides such as CGRP that in turn activate the release and action of NO [22,23]. The overall mechanisms
operating in the duodenum in response to topical application of H+ and involving COX–PG, NOS–NO and sensory nerves–CGRP–NO systems are depicted in Fig. 4. It is of interest that gastric H+ entering the duodenum not only stimulates COX–PG system but also hydrolyses HCO3 − present in duodenal lumen to increase partial pressure of CO2 , and this was shown to stimulate duodenal HCO3 − secretion (Fig. 5) [28]. Quantitatively, the amounts of HCO3 − secreted by proximal duodenum are only a small portion of the amounts of maximally stimulated gastric H+ secreted in the stomach [11]. Jarbur et al. [28], who quantified gastric H+ and duodenal HCO3 − secretion in fasting humans, found that the
Fig. 5. Acidification of the duodenal mucosa results in the stimulation of COX–PG system due to increased luminal pCO2 resulting from the interaction of gastric acid with duodenal luminal HCO3 − .
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Fig. 6. In the stomach luminal gastric H+ does not reach the mucosal cells because of its neutralization by HCO3 − secreted continuously by surface epithelial cells. Pepsin molecules infuse only into the upper portion of the mucus layer, causing its degradation but do not reach the surface of gastric epithelium.
amounts of HCO3 − produced in the duodenum under basal conditions were similar to duodenal loads of gastric H+ and this stimulation may be mediated, at least in part, by increased pCO2 generated in the duodenal lumen by gastric H+ during phase III of MMC (Fig. 5). Mucus–alkaline secretion and formation of protective mucosal barrier in the stomach differ from those in the duodenum. In the stomach, gastric mucosa is covered by tight epithelial cells with continuous surface mucus layer to which HCO3 − is secreted by goblet cells, creating the pH gradient across mucus layer that neutralises any H+ diffusing from the gastric lumen towards the surface epithelial
cells and thus preventing their acidification and damage (Fig. 6). The total amount of HCO3 − secreted by the gastric mucosa is relatively small when compared to maximal gastric H+ secretion, but due to the fact that HCO3 − is secreted into the thin layer of adherent mucus gel, it is highly effective in neutralising the penetrating luminal H+ . The duodenum is covered, however, by a leaky epithelium (Fig. 7) that, despite of the thick mucus gel layer and secreted HCO3 − , is easily penetrated by gastric H+ discharged to the duodenum. Although, the duodenum is supplied with large amounts of pancreatic and biliary HCO3 − secreted in response to duodenal acidification due to release
Fig. 7. In the duodenum an active HCO3 − secretion in exchange for Cl− occurs at the apical cell membrane and these bicarbonate are neutralized by gastric acid entering the proximal duodenum.
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of secretin, the major ‘chemical battlefield’ with gastric H+ entering the duodenum is the duodenal bulb. The bulb is located just distal to gastric antrum and proximal to the duodenal entry of pancreatico-biliary ducts and uniquely exposed to a highly variable pH environment due to peristaltically conveyed pulses of concentrated gastric H+ discharged by the stomach to duodenum. Since the duodenal mucosa does not have the inherent acid-protective structural properties of gastric mucosa (with intercellular tight junctions), it evolved very efficient means of defence against gastric H+ [30]. The proximal duodenum could be compared to the titration unit with gastric H+ neutralised mostly in the duodenal bulb by HCO3 − originating from bulbar mucosa and secreted due to local action on duodenocytes of numerous mediators including already-mentioned pCO2 , PG, NO, Ach, melatonin, VIP, PACAP and others (see Fig. 3).
5. Duodenocyte membrane transport systems It should be emphasised that duodenal HCO3 − secretion increases after acid perfusion of duodenal bulb when H+ ions actually diffuse into duodenocytes and reduce their intracellular pH (pHi ) (see Fig. 8). To understand the sequence of events following duodenal acid challenge, it is necessary to identify the apical and baso-lateral transport mechanisms in duodenocytes (Fig. 9). It has been proposed [28,29] that the apical duodenocyte membrane is equipped with active exchangers HCO3 − /Cl− , extruding HCO3 − to duodenal lumen in exchange for Cl− (AE—anion exchanger) and several types of AE exchangers function in apical duodenocyte membrane such as AE2 and AE4 [30,31]. Wang et al. [31] identified PAT1 to function in apical duodenocyte membrane as active HCO3 − /Cl− exchanger. In addition, several Na+ /H+ exchangers (NHE1–3) operate in this membrane to eliminate the H+ ions from the duodenocytes
Fig. 8. Duodenum is covered by leaky epithelium and gastric acid entering duodenocytes activate various mechanisms leading to increased secretion of HCO3 in duodenal mucosa.
Fig. 9. Numerous transporters of HCO3 − , Cl− , and Na+ in apical and basolateral; membrane of duodenocytes without and with blocking of Cl− /HCO3 − exchange (CFTR) with SLC266Ax basolateral Na+ /K+ exchange and Na+ –HCO3 − cotransport in Fig. 8. Inactivation of specific Na+ /H+ exchange by amiloride increases bicarbonate secretion.
back to duodenal lumen [32]. The AE exchangers have been related to cystic fibrosis transmembrane conductance regulator (CFTR) and found to be expressed predominantly in duodenal crypts [33]. At the baso-lateral duodenocyte membrane, both electroneutral Na+ –HCO3 − cotransport (NBC1 ) and electrogenic cotransport NBC (NBCn1 ) as well as N+ /H+ exchanger (NHE) are present [34]. Kaunitz and Akiba [35], summarising the protective duodenal response to gastric acid challenge in humans, pointed out that luminal H+ , diffusing into the duodenocytes, lowers pHi and initially decreases the buffer power of these cells but subsequently decreases HCO3 − secretion due to the decrease of CFTR conductance. Lowering pHi immediately increases, however, the activity of baso-lateral NBC1 and promotes an inward movement of HCO3 − from extracellular fluid to increase the cellular content of HCO3 − and its secretion into duodenal lumen through CFTR-related HCO3 − /Cl− exchanger [33]. Furthermore, acidic intracellular pHi increases the activity of baso-lateral NHE and enhances an extrusion of H+ into the submucosal space with increase of cellular alkali load. Luminal H+ in the duodenum also increases the mucus secretion from goblet cells, resulting in the increase of the thickness of mucus gel. This increase in mucus secretion is accompanied by an enhancement of mucosal blood flow mediated by the H+ stimulation of the sensory nerves, releasing CGRP and NO causing vasodilation in the mucosa [35]. DU patients may not exhibit only excessive gastric H+ secretion and accelerated gastric H+ emptying but also produce a potent endogenous NOS inhibitor, asymetric dimethylated arginine derivative (ADMA), that reduces duodenal HCO3 − response to gastric H+ and thus favours the damage of duodenal mucosa and ulcer formation in these patients [36].
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6. Concluding remarks This overview provides an insight into how duodenal mucosa defends itself against the damage by pulses of concentrated gastric H+ entering the duodenum. Unlike the stomach, where mucosal barrier with tight epithelial cells and covering mucus layer actually prevents luminal H+ from entering and damaging the surface epithelium, in the duodenum the epithelium is leaky permitting luminal H+ to diffuse into the duodenocytes and acidify their interior with subsequent fall in intracellular pH (pHi ) and activation of the baso-lateral Na+ –HCO3 − cotransporter. This leads to the movement of extracellular alkali into these cells with subsequent excessive HCO3 − secretion due to activation of apical membrane HCO3 − /Cl− exchangers (AE). Acidic pHi of duodenocytes also activates baso-lateral Na+ /H+ exchangers (NBC), causing extrusion of H+ from duodenocytes and acidification of submucosal tissue with stimulation of capsaicin receptors on afferent nerves leading to increased mucosal blood flow and increased thickness of mucus gel layer enhancing duodenal protective activity. In certain conditions such as Hp infection, the inflammatory changes in the mucosa result in decrease in mucus–alkaline secretion, partly due to ADMA effect and reduced mucosal resistance to acid injury leading to the formation of peptic ulcerations. Eradication of Hp leading to ulcer healing restores the ability of duodenal mucosa to produce HCO3 − due to reduction in ADMA formation, regression of duodenal inflammation, increased ability to secrete HCO3 − and the restoration of the integrity of duodenal mucosa. Conflict of interest statement None declared.
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