Back-diffusion--fact or fiction?

Recent Advances Digestion IS: 53-72 (1977)

Back-Diffusion —Fact or Fiction? B. Thjodleifsson and K.G. Wormsley1 Department of Therapeutics, University of Dundee, Dundee

Key Words. Bicarbonates ■Chloride ■Diffusion • Electrolytes • Gastric acidity determi nation • Gastric juice - Gastric mucosa • Hydrogen ion concentration • Pepsin ■Peptic ulcer • Sodium Abstract. Alterations in the concentration of acid in gastric juice secreted at different flow rates and disappearance of acid from the gastric lumen, when the gastric mucosa is exposed to acid luminal contents, have been interpreted as indicating ‘back-diffusion’ of acid into the gastric mucosa from the luminal contents. The loss of acid from the gastric contents increases when the mucosa is exposed to certain drugs or is diseased, giving rise to the suggestion that the increased degree of ‘back-diffusion’ of acid indicates mucosal damage, reflecting a breakdown of the gastric mucosal ‘barrier’ to back-diffusion of acid from the gastric lumen. The change in the ‘barrier’ properties of the gastric mucosa has been found to be associated with change in the electrical properties of the mucosa, so that alterations of the transmucosal potential difference has been considered to denote gastric mucosal damage. The case for every one of these hypotheses and for their underlying assumptions is discussed and found wanting for lack of direct evidence.

The body of knowledge that is gastroenterology contains many concepts which apparently explain diverse phenomena in a satisfactory manner but which, on analysis, turn out to be based on incomplete inferences from inconclusive experimentation. ‘Back-diffusion of acid’ is one such concept.

Received: March 17, 1976.

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1 The valuable criticism of Prof. J.N. Hunt is gratefully acknowledged. K.G.W. is in receipt of a research grant from the Scottish Hospital Endowments Trust.

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The composition of secreted gastric juice is not constant. For example, at low rates of secretion the concentration of hydrogen ions is low (63, 73, 75, 115, 145) and the concentration of sodium is high, while at high rates of secre tion healthy gastric mucosa produces juice with high concentration of acid and low concentration of sodium. Similarly, if the fundic mucosa is exposed to certain chemicals, the juice secreted in response to stimulants contains a lower than normal concentration of acid, so that the output of acid is less than from untreated gastric mucosa (10, 12, 19,97, 109). The variability of the concentra tion of secreted gastric juice contrasts with, and raises theoretical problems for, the hypothesis proposed by Heidenhain (69) at the end of the last century that the composition of the secretion of normal, healthy, gastric parietal cells is constant(43, 73, 74, 99, 113, 144, 145) and isosmotic with extracellular fluid, with a high concentration of hydrogen ions, low concentration of potassium, no sodium and a concentration of chloride equivalent to that of the two cations. Clearly, if the composition of ‘primary’ gastric juice is constant, then something happens to the gastric juice during or after secretion. To account for the low concentrations of acid found under some circumstances in gastric juice, there must be either intraluminal dissipation of acid or, alternatively, diffusion of acid down the proton activity gradient into the mucosa or a combination of these processes. Intraluminal dissipation of acid could result from buffering by protonacceptor ions or molecules such as bicarbonate or anionic proteins. The best known variant of the hypothesis of intraluminal buffering of acid, proposed by Hollander about 40 years ago, suggested that a 'second component’ or gastric juice, containing sodium bicarbonate, was secreted by cells in the gastric mucosa different from the parietal cells (55, 73, 75, 78, 103, 107). Other secreted buffers, such as glycoproteins, play a theoretically less important role in dis sipating gastric intraluminal acid (28, 74, 82,96, 102, 115). The alternative hypothesis to explain how acid disappears from the gastric lumen proposes that acid diffuses from the lumen into the gastric mucosa. The hypothesis of ‘back-diffusion of acid’ was systematically tested by Teorell (142, 143, 145, 146), also about 40 years ago. Teorell considered that protons under went ‘exchange-diffusion’ with sodium ions, the latter appearing in the gastric lumen in place of the hydrogen ions. In order to study ‘back-diffusion’ experi mentally, Teorell and subsequently many other investigators (4, 5, 10, 15. 17, 18, 29, 51, 53, 80, 82, 84, 85, 88, 89, 100, 109,117, 129, 134, 137, 138, 147, 153, 156, 160) exposed gastric mucosa to bulk solutions containing known amounts of acid, withdrew the residue after intervals of time and measured the recovery of the instilled acid. To simplify the experimental situation, the acid was instilled into separated pouches of fundic or antral mucosa or applied to


Background

Back-Diffusion

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open sheets of gastric mucosa, since contamination with extragastric se cretions such as saliva, oesophageal secretions and duodenal contents could be avoided. Most of the investigators found that acid disappeared, relative to non absorbable marker substances, when acid solutions were instilled into gastric pouches. The disappearance of the hydrogen ions was considered to prove the process of ‘back-diffusion’ of acid from the gastric luminal contents and it was assumed, without further proof, that ‘back-diffusion’ explained not only the disappearance of acid from instilled solutions of exogenous acid, but also from acid produced during the process of secretion. Although the action of topical chemical agents on the gastric mucosal reten tion of acid had been studied previously (19), the concept o f ‘back-diffusion’ of acid was given an enormous boost by the studies of Davenport (37,40, 42-45) during tire past 12 years. Davenport showed that when certain chemical and physical agents were applied to the luminal surface of the gastric mucosa, exog enous acid disappeared at a greatly increased rate. That is to say, there was more ‘back-diffusion’ of acid because the normal ‘barrier’ to ‘back-diffusion’ of acid had been ‘broken’ and the mucosa had, therefore, been rendered more ‘leaky’. The process of ‘back diffusion’ underlying tire increased disappearance of acid from instilled acid solutions was considered, by extrapolation, to explain the abnormally low acid concentration of the juice secreted by chemically treated, or injured, gastric mucosa. The hypothesis of ‘back-diffusion’ has been further extended (82) to explain the observation that patients with gastric ulcer or with gastritis secrete gastric juice which contains abnormally little acid and abnormal ly high concentrations of sodium (11, 106). As a result of re-emphasis by Daven port (39), increased ‘leakiness’ of the gastric mucosa with excessive ‘back-dif fusion’ o f acid into the mucosa was sought, and found, in human gastric mucosal diseases (2 4,2 5 ,4 8 , 85, 88, 117) and considered responsible for the ‘apparently’ impaired secretion of acid by patients with gastric ulcer - ‘apparently’ impaired, because it was proposed that the stomach actually secreted acid normally in response to stimulants but lost acid so rapidly as a result o f ‘back-diffusion’ that only abnormally small amounts of acid could be recovered from the gastric lumen.

We are, therefore, dealing with several problems, the interrelationships of which have been assumed or proposed: (a) the cause of the variability of tire composition of gastric juice which has been secreted into the gastric lumen; (b) the cause of the decreased concentration and output of acid from chemically


Nature o f the Problem

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treated gastric mucosa; (c) the cause of the disappearance of acid instilled into gastric pouches (and intact stomach), and (d) the cause of the hyposecretion of acid in patients with gastric ulcer and gastritis. In considering proglem (a), it is necessary to be sure that there actually is a problem and that we are not dealing with a pseudoproblem. That is to say, it is necessary to be sure that the secretion of the parietal cells is of constant, fixed composition and undergoes modification only after secretion, since if the com position of the juice secreted by the parietal cells does change with the degree and duration of stimulation, or circumstances physiological and pathological which modify the function of the parietal cells, then the problem changes from ‘What happens to gastric juice in the gastric lumen?’ to ‘Why do parietal cells secrete juice of variable composition and what are the factors which de termine the composition under defined experimental or physiological circum stances?’. No published information available at present permits us to select between the hypotheses of constant, as opposed to varying, composition of parietal cell secretion and the matter will, therefore, not be discussed further in the present paper. Problems (b) and (d) involve two potentially separate aspects of gastric secretory pathophysiology, summarised respectively by ‘What is the cause of the hyposecretion?’ and ‘What is the cause of the abnormal composition of the gastric juice from chemically treated gastric mucosa and from patients with gastric mucosal disease?’. Alternatively phrased, these questions become: ‘Do the parietal cells secrete normal amounts of gastric juice of normal composition and does something abnormal happen to the gastric juice after secretion into the gastric lumen?’ or ‘Do the parietal cells secrete too little gastric juice? If so, is that gastric juice of normal or abnormal composition?’. The secretion of acid in response to secretory stimuli decreases markedly when the mucosa has been exposed to ‘barrier-breaking’ chemicals (10, 12, 19, 37, 68, 93, 97, 110). Unfortunately, it has not been possible to resolve the problem of whether the decreased output of acid reflects inhibition of acid secretion or, alternatively, indicates either the ‘back-diffusion’ or buffering of acid which has been secreted (10, 12, 19, 68, 93. 97, 110, 132, 133, 158). The current controversy probably reflects a multiplicity of processes since, for ex ample, parenteral administration of a drug or chemical can decrease tire secreto ry capacity of the gastric mucosa without changing its permeability to ions (114). Similar controversy surrounds the mechanisms underlying the hyposecretion characteristic of gastric mucosal disease. The abnormal gastric mucosa of pa tients with gastric ulcer or gastritis contains abnormally few parietal cells (35, 128) so that the hyposecretion of patients with gastric mucosal disease is pre sumably principally attributable to the decreased mass of the secreting cells. In addition, most patients with gastric ulcer suffer from severe and abnormal duo-


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deno-gastric reflux (22, 49, 56, 125, 163) so that these patients also ‘lose’ acid by intraluminal buffering with bicarbonate in the regurgitated duodenal con tents. It is not yet possible to be certain, on the basis of published information, whether there is also ‘back-diffusion’ of acid into the gastric mucosa during secretion. Even if it is considered that ‘back-diffusion’ accounts for the greater than normal disappearance of acid instilled into the stomachs of patients with gastric mucosal disease (89), no convincing evidence is available that permits the further inference that the ‘back-diffusion’ is in any way related to, or responsible for, the hyposecretion of these patients.

The principal evidence adduced for ‘back-diffusion’ o f acid is derived from correlations based on studies which have shown that acid disappears when in stilled into the stomach or gastric pouches (or applied to sheets of gastric muco sa) while sodium ions appear in the gastric lumen (10, 15, 18-20, 24, 29, 37, 4 2 - 4 4 ,5 1 ,8 3 - 8 5 ,8 9 , 100, 109,114,117,127,137, 138, 143, 153, 156,160) and the osmolality (9, 15, 24, 5 1 ,8 4 -8 6 , 89, 100, 127) or the concentration (10,57, 143, 145) of the gastric contents decreases. In pouches of healthy canine (10, 15, 17, 29, 37, 43, 51, 109, 114, 153, 156) or feline (19, 57, 68, 142, 143) fundic mucosa, the net disappearance of hydrogen ions from instilled acid solutions is small. Hence the postulate of the ‘gastric mucosal barrier’ (37, 43, 46, 76, 83), to diffusion of hydrogen ions out of the gastric lumen. In studies involving the human stomach, interpretation of the apparent disappearance of acid is difficult, if not impossible, because the rate of disappearance is small and it has not proved possible to satisfactorily de termine the degree of contamination with bicarbonate-containing fluids such as saliva or regurgitated duodenal contents. A further difficulty, which has not yet been resolved, results from the fact that instillation of acid solutions into the human stomach (9,80, 83, 86, 88, 89, 100, 129, 134) or gastric pouches of experimental animals (42, 68, 123, 126) stimulates gastric secretion of acid and it is not yet possible to quantitate this secretory response. Since the instillation of other solutions into the stomach stimulates the secretion of acid (79, 81) it seems probable that distension is responsible for this type of stimulation of gastric secretion (14, 152). Alterna tively it has been suggested by Davenport that the stimulant effect of acid instillates is a manifestation of ‘back-diffusion’, the back-diffused acid having caused gastric intramural release of histamine, which in turn has stimulated secretion of acid (40, 43, 151). Similarly, the ‘back-diffusion’ of acid into the mucosa is considered to be responsible for the secretion of pepsin (38, 90, 92)


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and for the stimulation of gastric motor activity (41). There is, as yet, no evidence for the proposed direct stimulant effect of acid within the gastric mucosa. In any case, whatever the mechanism of stimulation of acid secretion, the tendency to secrete acid in response to an instilled acid load makes interpre tation of the rates of disappearance o f acid from pouches and whole stomach non-quantitative and potentially invalid. Indeed, the situation is so complex and speculative that when sodium appears in the gastric contents (with chloride) in response to, but without any loss of, instilled exogenous acid (118, 156), the ‘failure' of acid to disappear has been interpreted as showing that ‘secretion of acid exactly balances “back-diffusion” ’ (43, 45). Attempts have been made to inhibit the secretion of endogenous acid with drugs such as atropine (83, 84, 87, 89) and metiamide (148) in order to 'unmask' the presumed ‘normal’ disap pearance of acid within the stomach, but atropine has been shown to change the gastric mucosal permeability to ions directly (127) so that ‘unmasking’ may not be a simple process. ‘Back-diffusion’ of instilled acid has been studied under three sets of condi tions - in the normal stomach or gastric pouches (9, 53,82, 84, 100, 117, 118, 142, 143, 148, 160); in stomach or pouches which have been treated with ‘barrier-breaking’ chemicals (10, 18-20, 29, 32, 37, 38, 42, 44, 57, 83, 85, 86, 89, 108, 110, 114, 126, 138, 153, 158), and in stomachs which are diseased (24, 88, 117, 137). It has been assumed that the fate of intraluminal acid is identical under these different circumstances and that the mechanisms of the dissipation of acid are the same. There is no experimental evidence for these assumptions. Such morphological studies as have been carried out are compatible with the contrary view that there are different mechanisms. Thus, chemical or physical agents which markedly alter the disposal of instilled acid may be associated with severe mucosal destruction (52, 76, 109, 126, 143) but may, alternatively, fail to alter nomial mucosal appearances (126). Conversely, even quite severe gastric mucosal damage produced experimentally (26) or caused by disease (129) — may be associated with quite normal ‘retention’ of hydrogen ions in the gastric lumen. Moreover, the morphological appearance of chemically injured mucosa differs markedly from the gastric mucosal changes associated with gastritis or gastric ulcer. It has, therefore, not been possible to decide whether the con siderable increase in the rate of disappearance of instilled acid which results from topical application of ‘barrier-breaking’ chemicals to the gastric mucosa both in man (32, 83, 8 5 -8 7 , 89, 118, 135, 138) and in fundic pouches (17- 20, 29, 38, 4 2 -4 4 , 57, 110, 126, 153, 156, 158) represents an exaggerated ‘normal’ mecha nism or indicates some qualitatively abnormal mechanism of dissipation of acid. Similarly, it is not known to what extent, if any, the reported increase in disappearance of acid from the stomach of some patients with gastric mucosal disease (24, 108, 117) is an augmented ‘normal’ clearance of intraluminal acid or represents involvement of a pathological mechanism.



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Ionic Changes in Gastric Contents Accompanying Disappearance o f Acid The disappearance of acid within pouches is calculated from the ratio of the concentration of residual acid to that of residual ‘non-absorbed’ marker sub stance. If more acid than marker disappears, then acid has been dissipated within or diffused out of the stomach. Measurement of the concentration of marker in the gastric luminal contents often shows that secretion of water has occurred during the period of the test, since the concentration of the marker is less than in the original instillate (15, 100). The actual volume of gastric contents may also be greater than the original volume of instillate, so that the inference from the dilution of marker is confirmed directly (109, 127, 143).

The disappearance of hydrogen ions from within the stomach is associated with the appearance of sodium ions in the gastric luminal contents (10, 15, 18-20, 24, 29, 37, 4 2 -4 4 , 51, 68, 83, 86, 89, 108, 110, 126, 143, 153). In gastric pouches, the sodium must have originated from the gastric mucosa and a similar origin has been assumed in the anatomically intact stomach. The two principal mechanisms which have been proposed to account for the appearance of sodium ions in the gastric contents involve, on the one hand, the ‘exchangediffusion’ of sodium ions into the gastric lumen while hydrogen ions diffuse into the mucosa or, alternatively, represent the secretion of sodium ions as ‘counter ion’ accompanying secreted bicarbonate. Unfortunately, these two mechanisms — ‘exchange-diffusion’ of sodium for hydrogen ions (142, 143, 153, 160) or secretion of sodium bicarbonate (55, 74, 75, 78, 103, 107) — cannot yet be distinguished experimentally or by mathematical analysis of the available experi mental data (103, 142). The actual processes underlying the concept o f ‘exchange-diffusion’ and the reason for these processes becoming more obvious under the influence of ‘bar rier-breaking’ chemicals have not been specified. If the hypothesis o f ‘exchangediffusion’ were correct and if there were no other mechanism for the disap pearance of hydrogen ions or for tire secretion or absorption of sodium ions, then one would expect a ratio of one excess sodium ion in the gastric contents to every one hydrogen ion which has disappeared. The available experimental data have resulted in disagreement as to whether the amount of secreted sodium is equimolar with the amount of acid which has disappeared from the gastric lumen (19, 37, 109, 110, 143, 153, 160) or bears no direct quantitative relation ship to the amounts of acid which have disappeared (4, 17, 18, 68, 86, 127). These contradictory results highlight the point that, in any case, a 1:1 ratio of excess sodium to vanished hydrogen ions does not prove ‘exchange-diffusion’


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since that ratio would be expected if bicarbonate were secreted with sodium as counter-ion. Conversely, absence of a 1:1 ratio between disappearance of hydro gen ions and appearance of sodium ions does not help to discriminate between the possible mechanisms of disappearance of acid, since it is probable that the total amount of sodium appearing in the gastric lumen is the resultant of a whole series of ‘diffusional’ processes, involving both ‘active’ and ‘passive’ secretion and absorption. In this connection, it has been shown that sodium may be secreted from the gastric mucosa as counter-ion to secreted chloride (60, 109, 143, 156) - although it has also been suggested that the chloride enters the gastric lumen as hydrochloric acid, the hydrogen ions then exchanging for sodium ions (161), while exposure of the gastric mucosa to ‘barrier-breaking’ chemicals may greatly increase the permeability of the gastric mucosa to sodium ions (37) so that absorption (efflux of sodium ions) from the gastric lumen increases, as well as secretion. The secretion of sodium bicarbonate by the gastric mucosa has been re peatedly demonstrated (2, 8, 61,82, 136), although the conditions under which bicarbonate is secreted, and its rate of secretion, have not been defined and there is no experimental evidence for the uniform rates of secretion or uniform com position of bicarbonate-containing fluid from the gastric mucosa which have been assumed for the purpose of mathematical analysis (55, 103). If sodium bicarbonate is secreted in response to gastric intraluminal acid as sodium bicar bonate is secreted by the small intestinal mucosa in response to intraluminal acid (149, 159, 162), then an increase in the volume of pouch, or gastric, secretion or contents would be expected and has, indeed, often been observed (17, 24, 38, 40, 51, 104, 108, 109, 123, 127, 157, 158). However, the net increase in intraluminal volume is usually small when related to the increase in the quantity of intraluminal sodium ions or rate of disappearance of acids, so that the calcu lated net concentration of sodium or bicarbonate in the secreted water is very high and only explicable by assuming secretion of (sometimes very) hyperosmo lar solutions of sodium bicarbonate (1, 109) - unless, that is, the apparent change of the intraluminal volume is misleading because absorption of water from the gastric lumen has occurred.

When acid is instilled into a pouch o f fundic mucosa or into the whole stomach, the osmolality of the luminal contents decreases as acid disappears, giving rise to an apparent gradient for absorption of water from the luminal contents. Although Teorell (143) dismissed the process of absorption of water from instilled acid solutions as ‘improbable’, it has been shown that absorption of water occurs from the stomach if the intraluminal solution is hyposmolar


A bsorption o f Water


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(relative to extracellular fluid) (3, 31, 77, 123, 130). It has also been demon strated that water, labelled with deuterium or tritium, readily diffuses out of gastric luminal contents (3 1 ,3 3 , 1 16, 124, 131) although the free mobility of protons in water makes it impossible to be certain that the flux of deuterium or tritium necessarily reflects flux of water molecules, particularly when there is a large activity gradient for hydrogen ions from lumen into the mucosa. However, no one has specifically measured the rate of absorption of water from acid intraluminal solutions in order to determine whether the osmolality of the con tents represents an equilibrium situation which has resulted from the absorption of water from even more hypotonic solutions. If there has been net transfer of water out of the gastric lumen and if the lowered osmolality of the aspirated pouch contents after an experimental study with instilled acid is the resultant of the reactions underlying the disappearance of acid as well as net movement of water out of the lumen, then the mechanism of dissipation of acid is more likely to be buffering of acid by bicarbonate than ‘exchange-diffusion’ of hydrogen for sodium ions.

There has been speculation about the causes of hyposmolality in general (47, 64, 65, 155) and about the cause of the hyposmolality of gastric luminal contents in particular (6, 37, 120, 139, 146). ‘Hyposmolality’ in the context of ‘exchange-diffusion’ has been explained by assuming that during ‘exchange’ of hydrogen for sodium ions across the gastric mucosa, some degree of hyposmo lality of the luminal contents may result from the greater rate of diffusion of hydrogen ions out of the lumen than sodium ions into the lumen (120, 146). It has also been suggested that the structural organisation of the gastric mucosa, particularly of the gastric pits, contributes to the hyposmolality resulting from different mobilities of the two cations (120). Hyposmolar gastric contents would also result from the interaction of hydrogen and bicarbonate ions, because two ions are removed during the reac tion while an additional molecule of water is created. That is, the equivalent of three molecules of water appear for every hydrogen ion which disappears. The key criterion for distinguishing between ‘exchange-diffusion’ and buffering of acid is, therefore, clearly not the occurrence of hyposmolality of the gastric contents, but the fact that the reaction of bicarbonate with acid also results in the formation of carbon dioxide. It is, therefore, unfortunate that the investiga tion of the tensions of carbon dioxide in, and diffusion from, gastric contents has been almost completely neglected (98, 101) while study during the dissipa tion of acid from pouch contents has only been reported by Teorell (142) in cats. No increase in pC 02 was detected and Teorell, therefore, inferred that the


Mechanisms o f Hyposmolality


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disappearance of acid from the pouch contents was attributable to ‘back-dif fusion’. However, the absence of carbon dioxide from gastric luminal contents cannot be interpreted in terms o f failure of formation from bicarbonate and acid, unless the rate of disappearance of carbon dioxide from the luminal con tents is simultaneously measured. Tire rate of diffusion of carbon dioxide in water (150) and across some tissues (27, 141) is rapid and if the carbon dioxide is produced near the mucosa, as seems probable, then the diffusion may become more rapid still, since proteins (66) and particularly carbonic anhydrase (54, 67, 141) increase the rate o f diffusion of carbon dioxide. In summary, it is clear that neither the appearance of sodium ions nor the decrease in the osmolality of the gastric contents can provide evidence to distin guish between the mechanisms of dissipation of acid. Clearly the rate of transmucosal transport of carbon dioxide from the gastric lumen must be measured, since evidence for or against the production of carbon dioxide will indicate which is the correct mechanism underlying the disappearance of hydrogen ions from the gastric contents.

When Davenport described the increased ionic flux across the gastric mucosa treated with eugenol, he also noted that the appearance of sodium ions in the gastric luminal contents correlated with the alterations in the gastric trans mucosal potential difference (PD). Subsequently, it has been suggested that the increased permeability of the ‘gastric mucosal barrier’, reflecting ‘gastric mucosal damage’, may be detected by monitoring the potential difference across the gastric mucosa (7, 17, 18, 20, 23,29, 30,62, 112, 156). The normal human fundic mucosal potential is about 40 mV negative com pared with blood (30, 62, 112). The cause of the negative mucosal charge is not known in man, but seems to differ between species and under different experi mental circumstances, such as feeding (50,95). The isolated frog gastric mucosa achieves a luminal-negative potential because the transport of chloride ions into the gastric lumen is greater than the transport of hydrogen ions, so that there is a greater transfer of negative than of positive ions into the lumen (50, 58, 70, 71). The situation in the mammalian stomach is not clear, but the negative mucosal PD appears to be partly, or largely, attributable to the transfer of positivelycharged sodium ions from the gastric lumen into the mucosa (36, 50, 59, 95, 105) - that is, represents a sodium diffusion potential at the luminal surface of the mucosa. However, it has not been shown how data derived from the shortcircuited mucosa of experimental animals relates functionally to the normal or abnormal human gastric mucosa. Moreover, the role of sodium transport from the gastric lumen is particularly difficult to interpret in the context of the in


Gastric Transmucosal Potential Difference

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vivo gastric mucosa since the gastric mucosa is (slightly) permeable to sodium ions from the lumen when the luminal contents are neutral (19, 31,34, 37, 124) under which conditions the role of sodium in producing the gastric mucosal PD appears to be least important (95), while the gastric mucosa becomes virtually or totally impermeable to sodium when there is acid in the gastric lumen (5, 31,34, 95) although under these circumstances transport of sodium into the mucosa from the lumen is said to contribute maximally to PD (95). In response to chemical injury or disease, the gastric transmucosal PD be comes less negative or disappears (17, 18, 20, 23, 29, 30, 37, 62, 91, 112, 122, 126, 138, 153, 156). It is not known whether the decreased negativity of the PD under these circumstances merely reflects quantitative changes in the mechanism of production of the PD or denotes a qualitative change, in part because it has not even been experimentally established whether the site of production of the PD within the mucosa (91, 119, 154) remains the same as normal or changes after injury or in disease. The problem is obviously very complex, since it has shown that under some circumstances, ‘back-diffusion’ of acid and transport of sodium into the healthy canine gastric pouch in response to instilled acid may not be accompanied by alteration in the transmucosal PD (29, 135) or may even result in increased negativity of the PD (116). Generally, it seems that the ‘back-diffusion’ of acid coincides with significant decrease in the negativity of the PD only when the pouch mucosa has been exposed to fairly high concentra tions of ‘barrier-breaking’ chemicals (29). ‘Back-diffusion’ of acid and luminal gain of sodium ions is not associated with changes in PD when caused by low concentrations of these chemicals, although the rate of flux of ions is consider ably greater than normal under these circumstances (18, 153). The absence of a direct relationship between ‘back-diffusion’ of acid and PD is also shown by the finding that mucosal injury by alcohol or anoxia may decrease the negativity of the PD (16, 62, 97, 133) without any significant difference from normal in ‘back-diffusion’ of acid (16,97, 129, 133, 156). There is some degree of correlation between the morphological appearances of the gastric mucosa and PD, but morphological evidence of experimental injury may persist, while the levels of PD return to preinjury levels. Many of the problems associated with the interpretation of changes in gas tric transmucosal PD under experimental conditions reflect the (probably mis taken) assumption that change in PD always indicates change in the ‘barrier’ properties of the gastric mucosa. In this connection, it has been shown, for example, that the occurrence, or alteration, of solely physico-chemical effects such as the development of liquid junction potentials (13, 111, 140) resulting from chemical treatment of the mucosa may affect transmucosal PD (21, 72, 121). It seems certain, therefore, that the origin of gastric transmucosal PD, and the causes of change in the PD, are much more complex (146) than appears from the present interpretation of changes in PD in terms of change only in produc




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tion of current, the latter in turn resulting from change in the flux of ions across the gastric mucosa. If the change in PD does at least partly reflect change in the transmucosal passage of ions, the cause of the altered ionic flux is presumably change in permselectivity or change in shunt pathways, which is usually referred to as change in ‘barrier integrity’ (62, 112). However, the actual mechanisms whereby reduced negativity of the transmucosal PD reflects increased flux of hydrogen ions into the mucosa and/or sodium ions from the mucosa into the gastric lumen has not been specified. Indeed it is necessary to remember that both the net flux of sodium into the gastric lumen and tire decreased negativity of the PD (7,62, 72, 94, 122) are associated with the flow of hydrogen ions into the lumen (during secretion) as well as during disappearance of hydrogen ions from the lumen. Summarising, the present increasing practice of equating change in trans mucosal PD with change in transmucosal ionic flux is not based on a satisfactory experimental basis. The current tendency to summarise changes in gastric trans mucosal PD in terms o f ‘barrier integrity’ is, therefore, unjustifiable.

Conclusion At present there is no direct evidence that the disappearance of hydrogen ions from the gastric lumen is caused by ‘back-diffusion’. There is no evidence that the mechanisms underlying the disappearance of acid from the gastric lu men in the healthy stomach, the chemically treated stomach and the diseased stomach are identical or that the disappearance of hydrogen ions is specifically attributable to ‘back-diffusion’ under any of these circumstances. Even if there is ‘back-diffusion’ across all three types of gastric mucosa, there is no evidence that the mechanisms of the ‘back-diffusion’ are necessarily identical. There is no evidence that, whatever the fate of exogenous instilled hydrogen ions, the mechanisms of disposal of exogenous acid is related to changes in the secretion of acid by the normal gastric mucosa under different experimental conditions or in gastric mucosal disease.

1 2 3

Adair, R.K. and Wlodek, G.K.: Ionic changes in Pavlov pouches after insulin hypo glycemia, gastrin, and pentagastrin. Archs Surg., Chicago, 97: 423-435 (1968). Altamirano, M.: Alkaline secretion produced by intra-arterial acetylcholine. J. Physiol., Lond. 168: 787-803 (1963). Altamirano, M.: Action of solutions of reduced osmotic concentration on the dog gastric mucosa. Am. J. Physiol. 216: 25-32 (1969).


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115 Öbriitk, KJ.: Studies on the kinetics of the parietal secretion of the stomach. Acta physiol, scand. 15: suppl. 51, pp. 1-106 (1948). 116 Öbrink, K.J. and Waller, M.: The transmucosal migration of water and hydrogen ions in the stomach. Acta physiol, scand. 63: 175-185 (1965). 117 Overholt, B.F. and Pollard, H.M.: Acid diffusion into the human gastric mucosa. Gastroenterology 54: 182-189 (1968). 118 Overholt, B.E. and Pollard, H.M.: Acetylsalicylic acid and ionic fluxes across the gastric mucosa of man. Gastroenterology 54: 528-542 (1968). 119 Rehm, It'.S.: Evidence that the major portion of the gastric potential originates be tween the submucosa and mucosa. Am. J. Physiol. 147: 69-77 (1946). 120 Rehm, W.S.; Butler, C.F.; Spangler, S.G., and Sanders, S.S.: A model to explain uphill water transport in the mammalian stomach. J. theor. Biol. 27: 433-453 (1970). 121 Rehm, It'S, and Enelow, A.J.: A study of the alleged effect of milk on the human gastric potential and a description of a new method for measuring the potential. Gastroenterology 3: 306-313 (1944). 122 Rehm, It'S. and Hokin, L.E.: The effect of pilocarpine, mccholyl, atropine and alcohol on the gastric potential and the secretion of hydrochloric acid. Am. J. Physiol. 149: 162-176(1947). 123 Rehm, W.S.: Schlesinger, //., and Dennis, W.H.: Effect of osmotic gradients on water transport, hydrogen ion and chloride ion production in the resting and secreting stomach. Am. J. Physiol. 175: 4 73 -486 (1953). 124 Reitemeier, R.J.; Code, C.F., and Orvis, A.L.: Barrier offered by gastric mucosa of healthy persons to absorption of sodium. J. appl. Physiol. 10: 261-266 (1957). 125 Rhodes. J.: Barnardo, D.E.: Phillips, S.F.; Rovestad, R.A., and Hofmann. A.F.: In creased reflux of bile into the stomach of patients with gastric ulcer. Gastroenterology 57: 241-252(1969). 126 Ritchie, W.P.: Acute gastric mucosal damage induced by bile salts, acid, and ischemia. Gastroenterology 68: 699-707 (1975). 127 Rudick, J.: Werlher, J.L.; Chapman, M.L., and Janowitz, H.D.: Ionic flux across the gastric mucosa: effects of atropine on the permeability of fundus and antrum. Proe. Soc. exp. Biol. Med. 135: 605-608 (1970). 128 Schmidt, H.A.: Haake, U. und Riecken, E.O.: Untersuchungen zur Beziehung zwischen Säuresekretion und Belegzellzahl im Biopsiematerial. Klin. Wschr. 50: 744-750 (1972). 129 Schneider, R.P. and Bernstein, R.B.: A comparison of gastric acid back-diffusion in control and alcoholic patients. Am. J. dig. Dis. 18: 567-572 (1973). 130 Scholer, J.F. and Code, C.F.: Rate of absorption of water from stomach and small bowel in human beings. Gastroenterology 27: 565-577 (1954). 131 Schütz, H.B. and Kenedi, T: Water exchange through the stomach wall. Scand. J. clin. Lab. Invest. 15: 445 -449 (1963). 132 Sernka, T.J.; Gilleland, C.W., and Shanbour, L.L.: Effects of ethanol on active trans port in the dog stomach. Am. J. Physiol. 226: 397-400 (1974). 133 Shanbour. 1..L: Miller. J., and Chowdhury, T.K.: Effects of alcohol on active transport in the rat stomach. Am. J. dig. Dis. 18: 311-316 (1973). 134 Shay. H.: Gershon-Cohen, J., and Fels, S.S.: The absorption of hydrochloric acid by the human stomach. Am. J. dig. Dis. 6: 361-363 (1939). 135 Silen. W.: Studies of the gastric mucosal barrier - its relevance to clinical gastric disease. Guy’s Hosp. Rep. 121: 247 -257 (1972). 136 Silvis, S.E. and Doscherholmen, A.: Production of bicarbonate by the human stomach. Am. J. Gastroent., N.Y. 58: 138-144 (1972).



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137 Skillman, J.J.; Gould, S.A.; Chung, K.S.K., and Silen, It'.: The gastric mucosal barrier: clinical and experimental studies in critically ill and normal man and in the rabbit. Ann. Surg. 172: 564 - 5 8 2 (1970). 138 Smith, B.M.; Skillman. J.J.: Edwards, B.G., and Silen, W.: Permeability of the human gastric mucosa. Alteration by acetylsalicylic acid and ethanol. New Engl. J. Med. 285: 716-721 (1971). 139 Spangler, S.G.: Sanders, S.S.; Butler, C.F., and Rehm, W.S.: Can the osmotic theory still he used to explain net uphill water transport occurring in the resting stomach bathed with isotonic HCl? Biophys. J. 9: A 264 (1969). 140 Spiegler, K.S. and Wyllie, Electrical potential differences; in Edsall and Wyman Biophysical chemistry, vol. I, pp. 301-392 (Academic Press, New York 1958). 141 Suchdeo, S.R. and Schultz, J.S.: Mass transfer of CO, across membranes: facilitation in the presence of bicarbonate ion and the enzyme carbonic anhydrase. Biochim. biophys. Acta 352: 412-440(1974). 142 Teorell, T.: Untersuchungen über die Magensaftsekretion. Skand. Arch. Physiol. 66: 225-317 (1933). 143 Teorell, T.: On the permeability of the stomach mucosa for acids and some other substances. J. gen. Physiol. 23: 263-274 (1939). 144 Teorell, T.: On the primary acidity of the gastric juice. J. Physiol.. Lond. 97: 308-315 (1940). 145 Teorell, T: Electrolyte diffusion in relation to the acidity regulation of the gastric juice. Gastroenterology 9: 425-443 (1947). 146 Teorell, T: Transport processes and electrical phenomena in ionic membranes. Prog. Biophys. biophys. Chem. 3: 305-369 (1953). 147 Terner, C: The reduction of gastric acidity by back-diffusion of hydrogen ions through the mucosa. Biochem. J. 45: 150-158 (1949). 148 Thjodleifsson, B. and Wormsley, K.G.: Effects of metiamide on the human stomach. Clin. Sei. mol. Med. 49: 445-458 (1975). 149 Thjodleifsson, B. and Wormsley, J.G.: Response to jejunal acidification in man. 1. Changes in the composition of perfusate. Scand. J. Gastroent. II: 273-281 (1976). 150 Thomas, W.J. and Adams, M.J.: Measurement of the diffusion coefficients of carbon dioxide and nitrous oxide in water and aqueous solutions of glycerol. Trans. Faraday Soc. 61: 668-673 (1965). 151 Thompson. M.R.: Studies on the acid secretion that occurs during the back diffusion of acid into the mucosa. Gastroenterology 68: 1063 (1975). 152 Vagne, M. and Grossman, M.I.: Gastric and pancreatic secretion in response to gastric distension in dogs. Gastroenterology 57: 300-310 (1969). 153 Ventura, U.L.; Schlegel, J.F.: Force, R.C., La, and Code, C.F.: Acceleration of ex change of Na* for H+ across gastric mucosa by short-chain fatty acids. Am. J. Physiol. 225: 33-37 (1973). 154 Villegas, L.: Cellular location of the electrical potential difference in frog gastric mucosa. Biochim. biophys. Acta 64: 359-367 (1962). 155 Weinstein, J.N. and Caplan, S.R.: Charge-mosaic membranes: enhanced permeability and negative osmosis with a symmetrical salt. Science, N.Y. 161: 70-72 (1968). 156 Weisbrodt, N.W.: Kienzle, M., and Cooke, A.R.: Comparative effects of aliphatic alco hols on the gastric mucosa. Proc. Soc. exp. Biol. Med. 142: 450-454 (1973). 157 Werther, J.L.: The gastric mucosal barrier: physiological and clinical considerations. J. Mt Sinai Hosp. 34: 482-491 (1970). 158 Werther, J.L.; Hollander, F., and Altamirano, M.: Effect of acetazolamide on gastric mucosa in canine vivo-vitro preparations. Am. J. Physiol. 209: 127-133 (1965).



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159 Winship, DM. and Robinson, J.E.: Acid loss in the human duodenum. Volume change, osmolal loss and CO, production in response to acid loads. Gastroenterology 66: 181-188(1974). 160 Wlodek, G.K.; Greenberg, L , and Lajzerowicz, R.: Exchange diffusion in acid-filled gastric pouches. J. surg. Res. 9: 611-618 (1969). 161 Wlodek. G.K. and Leach, R.K.: Effects of histamine, feeding, and insulin hypoglycemia on net ionic fluxes in gastric pouches. Archs Surg. Chicago 93: 175—181 (1966). 162 Wormsley, K.G.: Response to duodenal acidification in man. 1. Electrolyte changes in duodenal aspirate. Scand. J. Gastroent. 4: 717-726 (1969). 163 Wormsley, K.G.: Aspects of duodeno-gastric reflux in man. Gut 13: 243-250 (1972).


Dr. K.G. Wormsley, Ninewells Hospital,Dundee, DD2 IUB (Scotland)

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