EFFECTS OF ALCOHOL ON ION TRANSPORT BY ISOLATED GASTRIC AND ESOPHAGEAL MUCOSA

Transcription

1 GASTROENTEROLOGY 70: , 1976 Copyright 1976 by The Williams & Wilkins Co. Vol. 70, No.2 Printed in U.S.A. EFFECTS OF ALCOHOL ON ION TRANSPORT BY ISOLATED GASTRIC AND ESOPHAGEAL MUCOSA DAVID FROMM, M.D., AND RUSSELL ROBERTSON, B.A. Department of Surgery, Harvard Medical School, and Beth Israel Hospital, Boston, Massachusetts The effects of ethyl alcohol, 20%, were measured on steady state rates of ion transport by isolated mucosa. Luminal, but not serosal, addition of alcohol altered ion transport. Alcohol caused a sustained reduction in apparent basal acid secretion by fundic mucosa. These tissues were resistant to ordinarily effective stimulants of acid secretion (histamine, theophyline, dibutyryl cyclic AMP, and gastrin) by rabbit mucosa. Across antral mucosa, net Na transport was inhibited, and net Cl transport was reduced in the presence of alcohol. The unidirectional fluxes of both ions were increased as was permeability to erythritol. These effects of alcohol did not require the presence of acid in the lumen. The rate of luminal acid loss by antrum was increased by alcohol. Addition of ouabain alone, which inhibits net Na and Cl transport, did not alter the rate of luminal acid loss by antrum. Alcohol, however, still increased the rate of luminal acid loss by antral mucosa treated with ouabain. Alcohol reduced the electrical resistance of fundic and antral mucosa but had no effect on the rate of luminal acid loss or electrical resistance of esophageal mucosa. Luminal application of alcohol inhibits active ion transport in addition to increasing cation and anion permeability. However, inhibition of active transport per se is not necessarily associated with an increase in mucosal permeability. It is generally agreed that ethyl alcohol increases permeability of the gastric mucosa.i- 6 Whereas several of the alterations of ion transport reported to occur in vivo are suggestive of altered permeability, these changes also could be due in part or totally to inhibition of active ion transport. Inhibition of active ion transport as the initial effect of alcohol has been suggested by Shanbour 7 and Sernka 8 and co-workers. Data from their in vivo studies of electrical resistance imply that this inhibitory effect of alcohol lasts for at least 30 min in the rat 7 and perhaps for a more prolonged period in the dog. 8 Various effects of luminal application or intravenous administration of alcohol on the rate of acid secretion in vivo have been reported, and in many instances it is unclear whether or not these effects are a result of a direct action on the parietal cells or indirect ones related to humoral or neurogenic factors.3, 6, 9-18 Although it is generally agreed that lower concentrations of alcohol (8% or less) stimulate acid secretion and do not alter mucosal permeability, I, 8, in the presence of altered mucosal permeability induced by higher concentrations of alcohol, it Received June 27, Accepted, September 10, Address requests for reprints to: David Fromm, M.D., Department of Surgery, Beth Israel Hospital, 330 Brookline Avenue, Boston, Massachusetts This investigation was supported by Research Grant AM from the National Institutes of Health, United States Public Health Service. Dr. Fromm is the recipient of Research Career Development Award AM from the National Institutes of Health. 220 is difficult to distinguish between active and passive ion transport processes in vivo. In part, this is due to the presence of ion concentration gradients across the mucosa as well as to the difficulty l9 in interpreting electrophysiological parameters 7,8 in vivo as they relate to ion transport. In vitro data indicate that alcohol inhibits acid secretion and imply that if alcohol has any effect on active Na or Cl transport by the stomach, this effect is transient. However, the lack of assurance of steady state conditions allow other interpretations. This study examines some of the effects of ethyl alcohol on acid secretion by fundic mucosa, Na and Cl transport, and luminal acid loss by antral mucosa and the premeability of esophageal mucosa to acid under steady state conditions in vitro. The emphasis of the data is for antral mucosa, since less is known of the effects of alcohol on the distal stomach. Methods New Zealand white male rabbits, previously allowed access to a standard diet and water, were sacrificed by an intravenous injection of pentobarbital. A portion of fundic mucosa adjacent to the medial tip of the spleen or the antrum or the esophagus was excised. The tissue was mounted on a Lucite half-chamber in which the mucosa was bubbled and oxygenated with Ringer's solution while the serosa and muscularis propria were stipped away. The remaining mucosa with its thin muscularis mucosa was clamped between identical half-chambers, each being perfused with its own gas-lift circulating reservoir maintained at 37.5 C. The luminal and serosal surfaces were

2 February 1976 ALCOHOL AND ION TRANSPORT 221 initially bathed with identical Ringer's solution bubbled with 100% O 2 and containing the following in millimoles per liter: Na, 136.0; K, 5.0; Ca, 3.5; Mg, 1.2; Cl, 150.4; and glucose, 10. When a given volume of absolute ethyl alcohol was added either to the luminal or serosal bathing solution, an equal volume of bathing solution was removed. In order to avoid dilution of the salt and sugar contents of the bathing solution, Na, K, Ca, and Mg as their chloride salts and glucose were added in amounts so that the final concentrations of these substances in the bathing solution containing alcohol were equal to that of the bathing solution on the opposite side of the mucosa. During measurement of isotopic fluxes, alcohol was present on both sides of the mucosa. Short circuit current (Isc) and transmural electrical potential difference (PD) of the tissues were measured, and electrical resistance was determined as described previously for small intestine.'o Steady state rates of acid secretion, measured at ph 7, using NaOH, 0.01 N, as the titrant, and luminal acid loss measured at ph 4, using HCl 0.01 N, were determined by the ph stat method. 21 During measurement of the rate of acid secretion, the ph of the serosal bathing solution was kept as close to ph 7 as possible by the manual addition of HCl. 21 The PD and Isc were allowed to stabilize, and when this occurred steady rates of acid secretion or luminal acid loss occurred. 21 For measurement of acid fluxes, each tissue served as its own control so that following an initial 30-min flux measurement at a given ph, another 40- to 60-min steady state flux measurement was made after the addition of ethyl alcohol at the same ph. Steady state unidirectional luminal to serosal and serosal to luminal fluxes of Na were either measured simultaneously across antral mucosa by labeling the reservoir on one side of the tissue with 22Na and the other side with 24Na, or measured across adjacent mucosal segments by labeling opposite sides of the tissues with 22Na. Unidirectional fluxes of Cl were measured simultaneously by labeling opposite sides of adjacent mucosal segments with ' Cl. 22Na was also added to alternate sides of these paired tissues so that 22Na and ' Cl were present on the same side of the tissue. Analysis of preliminary experiments (N = 6) to determine the duration of steady-state rates of isotopic transfer in the presence of alcohol made the measurement of two 30- to 40-min flux intervals impractical so that each tissue could not serve as its own control. Steady state rates of 22Na and ' Cl transfer were reached no later than 10 min after the addition of ethyl alcohol and were maintained for at least 50 min thereafter (fig. 1). Either duplicate 1-ml sample was removed from both the luminal and serosal reservoirs 10 and approximately 60 min after the addition of isotope, or 1-ml samples were removed every 10 min beginning 10 min after the addition of isotope. The isotopes were added once the PD and Isc stabilized. 24Na and 22Na were assayed in a 'Y-well spectrometer. 22Na was assayed 2 weeks after the assay of 24Na. The sum of the 22Na and ' Cl activities were assayed in a liquid scintillation spectrometer. The activity of.bcl was obtained by subtracting the activity of 22Na, which was determined by 'Y counting and corrected for efficiency between the spectrometers. When bidirectional fluxes of Na were measured on single tissues, the unidirectional fluxes were averaged in order to give a single value for the tissue pair. There was no significant difference (P > 0.4, N = 12) between either the simultaneous or paired tissue method for determination of net Na flux. The net flux is the arithmetic difference between the unidirectional luminal to serosal and serosal to luminal fluxes. In a separate series of experiments, unidirectional luminal to serosal fluxes of "c erythritol were measured in the presenc'e of 5 mm erythritol in the luminal bathing solution. HC was assayed in a liquid scintillation spectrometer. Results Concentration of ethyl alcohol. The concentration of alcohol required to give consistent changes in acid secretion by fundic mucosa (N = 10) and luminal acid loss by antral mucosa (N = 5) was found to be 20% v/v. Concentrations of 1 to 5% alcohol in the luminal bathing solution did not have a significant effect (P > 0.4) on the rate of acid secretion by fundic mucosa (N = 5). For some, but not all, tissues, exposure to 10 or 15% alcohol resulted in changes similar to those observed with 20% alcohol. Twenty percent alcohol was used throughout the rest of this study unless stated to the contrary. Acid secretion by fundic mucosa. The mean rate of acid secretion by segments of fundic mucosa did not change significantly (P > 0.5) in the absence of alcohol over a 9O-min interval (fig. 2A) once the initial rate of acid secretion stabilized. The electrical resistance of these tissues also did not change significantly (P > 0.5) during this 90-min interval. After the addition of alcohol to the luminal side of the mucosa, the rate of acid secretion decreased (fig. 2B). The mean rate of acid secretion before the addition of alcohol, 2.6 ± 0.5 JLEq per hr/cm 2 (mean ± 1 SEM), decreased by 1.8 ± 0.3 JLEq per hr/cm 2 (P < 0.001). This change was associated with a significant decrease in mean PD (P < 0.001), from 3.3 ± 0.6 mv to 0.4 ± mv, and mean electrical re r N=6 I=2 SEM o Minutes CI S - L FIG. 1. Rates of transfer of 22Na (dashed lines) and a CI (solid lines) from luminal to serosal reservoir ( L solid S, circles) and serosal to luminal ( S open L, circles) as functions of time. Each point is the mean of values for 6 rabbits, from which antral mucosa was obtained and treated with ethyl alcohol, 20%, in both bathing solutions. Lines were drawn by the method of least squares excluding the first 10-min values.

3 2 2 FROMM AND ROBERTSON Vol. 70, No Ng A Fundus N=IO I= 2SEM O rate - -of- luminal acid - loss was measured for antral mucosa.;:r 8 3. z 4 N=IO I=2 SEM Q f- w 0::2 2 t Serosal EtOH 0 L L MINUTES FIG. 2. Fundus. A, basal rate of acid secretion by mucosa unexposed to alcohol. B, effect of luminal addition of ethyl alcohol, 20%, (EtOH) on the rate of acid secretion. C, effect of serosal addition of EtOH on rate of acid secretion. N number of rabbits. sistance (P < 0.001), from 109 ± 5.0 ohms/cm 2 to 54.5 ± 4.8 ohms/cm 2. In contrast to the effects of luminal exposure to alcohol, the serosal addition of this agent did not have a significant effect on the rate of acid secretion (P > 0.5) (fig. 2C) or electrical resistance (P > 0.5). Addition of alcohol to both sides of the mucosa gave results similar to those observed for luminal addition only. After the addition of alcohol to the luminal side of seven tissues, the luminal bathing solution was removed 30 to 60 min later and replaced with alcohol-free solution. Removal of alcohol had no effect on the rate of acid secretion or electrical parameters for three tissues, but in another three tissues the rate of acid secretion and electrical parameters returned to their base line levels. In one tissue there was a partial return of the measured parameters toward baseline values. Before or after the addi tion of alcohol to these seven tissues, there were no distinguishing features among the parameters measured which allowed prediction of recovery to base line values after removal of alcohol. The rate of acid secretion in the presence of alcohol in the lumen was resistant to stimulation by the serosal addition of histamine, 0.09 mm (N = 5, P > 0.4); theophylline, 10 mm (N = 5, P > 0.5), or dibutyryl cyclic AMP, 2 mm (N = 5, P > 0.4). Each of these agents has been previously shown to be an effective stimulant of basal acid secretion by isolated fundic mucosa of the rabbit. 22 In the absence of alcohol, serosal addition of porcine gastrin, J..Lg per ml, causes a 68% increase in rate of acid secretion (N = 7, P < 0.025). However, gastrin also is an ineffective stimulant for mucosa treated with alcohol (N = 8, P > 0.4). When the luminal concentration of alcohol is 5%, which has no significant effect on the rate of acid secretion or electrical resistance, addition of histamine or theophylline more than trippled and porcine gastrin more than doubled the rate of basal acid secretion (N = 3 for each agent). Because alcohol inhibits acid secretion, the rate of luminal acid loss was not measured for fundic mucosa. Under these conditions, it would be difficult to determine the actual rate of luminal acid loss. Therefore, the which does not actively secrete acid. 24 Luminal Acid Loss by Antral Mucosa. In the absence of alcohol, the mean rate of luminal acid loss by segments of antral mucosa did not change significantly t " O a... l over an 80-min interval (P > 0.5) (fig. 3A). The mean O electrical - - -resistance of these tissues also did not change C N=12 4 f-+-1-t-h =2SEM significantly (P > 0.5) during this interval. However, the addition of alcohol to the luminal side of the mucosa was followed by an increase in the rate of luminal acid loss (fig. 3B). The mean rate of luminal acid loss before the addition of alcohol, 0.7 ± 0.1 J..LEq per hr/cm 2 increased by 0.7 ± 0.1 J..LEq per hr/cm 2 (P < 0.001). This change was associated with a significant decrease in PD (p < 0.001), from 11.7 ± 0.5 mv to 1.3 ± 0.5 mv, and electrical resistance (P < 0.001), from ± 8.8 ohms/cm 2 to 50.4 ± 10.4 ohms/cm 2. In contrast to the luminal addition of alcohol, serosal addition of this agent did not significantly alter the mean rate of luminal acid loss (P > 0.5) (fig. 2C) or the electrical resistance (P> 0.5). Addition of alcohol to both sides of the mucosa gave results qualitatively similar to those observed for luminal addition only. Porcine gastrin, 0.5 J..Lg per ml, had no effect on luminal acid loss or electrical resistance in the absence (N = 8) or presence (N = 5) of alcohol (P> 0.5 for each). Na, Cl, and erythritol fluxes across antral mucosa. In the absence of alcohol, there is net secretion of N a and Cl (table 1). However, in the presence of alcohol, the net Na 2 A Antrum N=IO I=2SEM t t t t i! "E O " B.;:r 3. 2 if) if) o 1 01 '3 J++-H <C <i L u m i a l o E t O H :C> -' 21 c N= 10 I=2SEM 1=2 SEM I I I ' t I - L : 5erotol I o ElOH _L,, MINUTES FIG. 3. Antrum. A, rate of luminal acid loss by mucosa not exposed to alcohol. B, effect of luminal addition of ethyl alcohol, 20%, (EtOH) on the rate of luminal acid loss. C, effect of serosal addition of EtOH on rate of luminal acid loss. N number of rabbits.

4 February 1976 ALCOHOL AND ION TRANSPORT ",ii: O Z&1 '"- ";;; 00'" ""0 "... ci '" M"""'; " 1 1 1::: f'<l "" on '" :::1..0, NO ::i "' '" '" g: " '5 '" '" ".0; --:; >.. { ",-0 + flux is not significantly different from zero (P > 0.5), and a 63% reduction (P < 0.001) in net Cl secretion occurs (table 1). These changes were associated with significant increases (P < for each) in the unidirectional luminal to serosal and serosal to luminal fluxes of Na and Cl and a significant decrease (P < 0.001) in electrical resistance. In the absence and presence of alcohol, the sum of the net Na and Cl fluxes does not differ significantly from the short circuit current suggesting that there is a negligible unmeasured net flux. All fluxes shown in table 1 were measured in bathing solutions with a ph of 7. Na and Cl fluxes were also measured in the presence of alcohol with the luminal bathing solution kept at ph 4. In eight experiments, the alterations caused by alcohol appeared to be similar to those observed at ph 7, and the data suggested that the increases in both undirectional fluxes of Na and Cl were greater than those observed at neutral ph. However, steady state rates of isotopic transfer were observed in only two of these experiments. The addition of alcohol to the lumen at ph 7 was also associated with a significant (P < 0.005) increase in the unidirectional luminal to serosal flux of erythritol (table 1). Effects of ouabain on acid loss by antral mucosa. In the absence of alcohol, ouabain, mm, added to the serosal bathing solution inhibits active Na and Cl transport by isolated antral mucosa of the rabbit. In 10 experiments, each tissue served as its own control. Prior to adding ouabain in the net Na flux was -1.1 ± 0.2 E q per hr/cm 2, and the net Cl flux was -3.9 ± 0.2 E q per hr/cm 2; but after adding ouabain the net fluxes of Na, 0.1 ± 0.1 Eper q hr/cm 2, and Cl, -0.3 ± 0.2 E q per hr/cm 2, were not significantly different from zero. In the absence of alcohol, ouabain does not significantly alter (P > 0.1) the rate of luminal acid loss (fig. 4A) or mean electrical resistance (P> 0.5). However, alcohol is still effective in increasing the rate of luminal acid loss by antral mucosa pretreated with ouabain (fig. 4B). The rate of luminal acid loss in the presence of ouabain, 0.8 ± 0.1 E q per hr per cm 2, increased by 1.0 ± 0.2 Eper q hr A -t Antrum N;6 I SEM 2. OuobOln B N"5 I"2SEM I I I 1 1 Ouabain Luminal EtOH o MINUTES FIG. 4. Antrum. A, effect of ouabain, mm, on the rate of luminal acid loss. B, effect of luminal addition of ethyl alcohol, 20%, (EtOH) on the rate of luminal acid loss by mucosa pretreated with ouabain, mm. N number of rabbits.

5 224 FROMM AND ROBERTSON Vol. 70, No.2 per cm 2 (P < 0.001) following the addition of alcohol. The electrical resistance prior to the addition alcohol, ± 12. ohms/cm 2, decreased to 45.1 ± 10.3 ohms/ cm 2 (P < 0.001) in the presence of alcohol. Following removal of ouabain and alcohol by replacing the bathing solutions, there was a partial return to base line values for rate of luminal acid loss and electrical parameters in three of the five tissues. Luminal acid loss by esophageal mucosa. In the absence of alcohol, approximately 90 min were required before steady rates of luminal acid loss were observed for esophageal mucosa. This is approximately 30 min greater than that required for antral mucosa at the same luminal ph. The mean rate of luminal acid loss for esophagus is at least 50% less than that observed for antrum and remains steady over an 80-min interval. During the latter, the mean electrical resistance of esophagus, 1786 ± 168 ohms/cm 2 (N = 15), is at least 13 times greater than observed for antral mucosa. No difference in the rate of luminal acid loss (P > 0.5) or electrical resistance (P > 0.5) was observed between tissue pairs of proximal and distal esophagus (N = 7 pairs). In contrast to antral mucosa, addition of alcohol to the lumen did not significantly alter the rate of luminal acid loss (P > 0.05). The mean rate of luminal acid loss before alcohol, 0.28 ± 0.09 Eper q hr/cm2, changed only by 0.10 ± 0.04 Eper q hr/cm 2 (N = 10, P > 0.05), in the presence of alcohol. In a separate series of experiments the ph of the luminal bathing solution was decreased from 4 to 2, and the addition of alcohol to the lumen did not significantly alter the rate of luminal acid loss (N = 5, P > 0.5). Alcohol did not significantly affect the PD or electrical resistance at either ph (P > 0.5 for both). Serosal addition of alcohol (N = 10) also did not significantly alter (P > 0.4) the rate of luminal acid loss or the electrical resistance (P > 0.5). Discussion The addition of ethyl alcohol to the lumen of isolated fundic mucosa of the rabbit causes a sustained reduction in apparent basal acid secretion. Although the decrease in electrical resistance after the application of alcohol indicates that there is also an increase in permeability,25 it is doubtful that a major portion of acid secreted into the luminal bathing solution diffused back into the tissue, for the rate of acid secretion was measured at ph 7. It is also unlikely that a significant amount of HCO a, released from the serosal side of the tissue,21 entered the luminal bathing solution, for the serosal solution was maintained at the ph of the luminal solution. However, the data do not exclude an effect of alcohol on parietal cell permeability which could result in a decrease in luminal appearance of acid. Thus, it is not clear if alcohol prevents hydrogen ions from reaching the pump by protons diffusing out of the parietal cells or affects the acid secretory pump or the production of protons. The diminished rate of basal acid secretion occurring after the luminal addition of alcohol appears to be resistant to stimulation by histamine, theophylline, and dibutyryl cyclic AMP, which have been shown to be effective stimulants of acid secretion by isolated fundic mucosa of the rabbit. 22 Although it has been reported that alcohol decreases adenyl ate cyclase and phosphodiesterase activities stimulated by NaF without altering the concentration of cyclic AMP in rat gastric mucosa,26 these findings are difficult to interpret, particularly in view of the exfoliation of mucosal cells caused by alcohol. 2,27 The observation that dibutyryl cyclic AMP has no stimulatory effect on acid secretion by rabbit mucosa suggests that the inhibitory effect of alcohol involves more than adenyl ate cyclase and phosphodiesterase. This notion is consistent with an effect of alcohol on multiple enzyme systems. 28 Alcohol also causes release of antral gastrin,29 but acid secretion by isolated fundic mucosa exposed to 20% alcohol is resistant to stimulation by gastrin. However, gastrin, histamine, and theophylline stimulate acid secretion when the mucosa is exposed to a lower concentration of alcohol 5%, which does not significantly alter permeability. Alcohol, in addition to causing a generalized increase in antral mucosal permeability, also inhibits active ion transport. However, these effects of alcohol do not imply that an increase in permeability is associated with, or results from, inhibition of active transport. Inhibition of active ion transport across antral mucosa by ouabain is not associated with a significant increase in permeability to acid or an alteration in electrical resistance. Exposure of the antrum to ouabain also does not appear to inhibit the mechanism whereby ethyl alcohol increases permeability. These lines of indirect evidence suggest that the permeability alterations induced by alcohol are independent of its inhibitory effects on active transport. The effects of alcohol on ion transport by antral mucosa cannot be attributed to diffusion of acid from the lumen into the mucosa, because the alterations induced by alcohol occur at a neutral ph. By implication, the effects of alcohol on fundic mucosal permeability are not necessarily caused by acid diffusing from the parietal cells and altering the permeability pathway(s). In contrast to gastric mucosa, the rate of luminal acid loss and the electrical resistance of isolated esophageal mucosa are unaffected by alcohol. This lack of response does not appear to be related to the presence of acid in the luminal bathing solution. REFERENCES 1. Davenport HW: Ethanol damage to canine oxyntic glandular mucosa. 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