Protection by histamine receptor antagonists and prostaglandin against gastric mucosal barrier disruption in the rat

GASTROENTEROLOGY

77:303-308,1979

Protection by Histamine Receptor Antagonists and Prostaglandin Against Gastric Mucosal Barrier Disruption in the Rat G. BOMMELAER

and

P. H. GUTH

Medical and Research Services, VA Wadsworth Medicine, Los Angeles, California

This study was undertaken to determine if the cytoprotective effect of prostaglandin and the H, histamine receptor antagonist cimetidine involves protection against disruption of the gastric mucosal barrier. Croups of anesthetized, vagotomized rats received one of the following parenterally: saline (control), mepyramine-on H, histamine receptor antagonist, cimetidine, cimetidine and mepyramine, or 16,26 dimethyl prostaglandin E,. Parameters of barrier disruption were then determined before and after exposure of the gastric mucosa to 40mM acetylsalicylic acid. At the end of the study, gastric lesions were scored according to size and number. Lesion score and fall in potential difference were significantly lower in rats receiving cimetidine, cimetidine and mepyramine, and prostaglandin. Other parameters of barrier disruption-H+ back diffusion, Na’ and K’ influx, and protein outpouring-exhibited the same pattern and correlated with change in potential difference. We conclude that both prostaglandin and cimetidine, but not mepyramine, protect against barrier disruption by topical aspirin, and this may be a factor in the mechanism of their cytoprotective action.

Received December 11.1978. Accepted February 25,1979. Address reprint requests to: Paul H. Guth, M.D., VA Wadsworth Medical Center, Gastroenterology Section (691/111C), Wilshire and Sawtelle Boulevards, Los Angeles, California 90673. Dr. Bommelaer’s present address is Inserm u 151, C.H.U. de Rangueil, 31052 Toulouse, Cedex, France. This work was supported by Grant 17326 from the National Institute of Arthritis, Metabolism and Digestive Diseases to CURE (Center far Ulcer Research and Education), and Veterans Administration Medical Research Funds. The authors are indebted to Dr. Janet Elashoff for help with the statistical analysis. The authors are grateful for the secretarial assistance of Alan L. Gutcheon. 0 1979 by the American Gastroenterological Association 0016-5085/79/080303-06$02.06

Medical Center, and the UCLA School of

Prostaglandins, in non-antisecretory doses or in the presence of exogenous acid, protect the gastric mucosa against lesions produced by a variety of agents.‘-5 Robert’ proposed calling this property of prostaglandins cytoprotection. It has recently been shown that cimetidine also has a cytoprotective effect in the rat on gastric mucosal lesions induced by either topical’ or parenteral aspirin.’ Disruption of the gastric mucosal barrier is involved in gastric mucosal damage induced by topical aspirin.’ Although prostaglandins have been shown to protect against mucosal barrier disruption,“,‘” the effect of histamine antagonists remains controversial.“-‘4 Whereas several studies reported no effect of H, antagonists on increased canine gastric mucosal permeability induced by bile salt,“-‘4 Rees et al. observed that H, + H, antagonists protected against gastric mucosal barrier disruption.‘” This study was undertaken to determine whether or not prevention of barrier disruption was involved in the protective effect of prostaglandin and histamine H, receptor antagonists against aspirin plus HCl-induced lesions in the rat. In view of the finding of Rees et al., the effect of a histamine H, receptor antagonist on the gastric mucosal barrier was also studied.

Material and Methods fasted

Sprague-Dawley

rats

for 36 hr but were

allowed

anesthesia

with pentobarbital,

weighing water

45 mg/kg

15O-ZoO

g were

ad libitum.

After

intraperitoneally,

the trachea was cannulated, the abdomen opened, and bilateral subdiaphragmatic vagotomy performed. The esophagus was then ligated at the gastroesophageal junction, and a catheter was introduced into the stomach via the pylorus through an opening in the duodenum. For potential difference (PD) measurement, a polyethylene catheter filled with 3% agar in saturated KC1 was also in-

Table

GASTROENTEROLOGY Vol. 77, No. 2

BOMMELAER AND GUTH

304

1.

Parameters

of Barrier Disruption

Before, During, and After Gastric Instillation

of Acetylsalicylic

Acid

Treatment NaCl Number of rats

7

PD (mV)

I

II III H+ (@q/30

I

min)

II III I II III I II

Na+ (pEq/JO min)

K+ (pEq/30

min)

III Protein (mg/30 min)

I II III I II III

Volume (ml/30 min)

Abbreviations

6

CIM+MEP

6

DMPGE,

6

-42.1 -22.6 -27.1 -8.1

f + + f

0.7 1.2 2.2 2.0

-41.5 -21.3 -25.5 -8.7

f f f f

1.3 3.1 3.2 2.6

-45.5 -30.0 -37.3 -13.9

-51.3 17.0 69.2 62.3 1.7 4.9 3.7 3.1 17.8 12.3 0.22 0.28 0.25

+ + + + + f f k f + f f f

10.9 3.3 17.1 10.4 0.3 0.9 0.9 0.4 0.5 1.7 .04 .09 .05

-49.0 15.8 46.2 48.7 1.6 3.9 2.6 3.2 16.4 11.9 0.12 0.13 0.15

f f f + f f + f f + f * f

3.7 3.0 6.8 6.1 0.3 0.4 0.3 0.6 0.8 3.3 .04 .04 .05

-36.3 f 5.3 17.5 f 4.7 30.0 f 6.7 21.5 f 3.8 1.3 f 0.3 2.1 f 0.4 1.0 f 0.2 2.2 + 0.2 13.9 It 0.7 4.8 + 0.4 0.15 + .05 0.12 f .06 0.01 f .Ol

used in column headings are as follows:

16,16 dimethyl prostaglandin

CIM

MEP

f f * f

0.9 1.3 1.7 3.2

-45.5 -29.7 -39.6 -15.5

7 f f + +

1.2 1.4 1.3 5.0

-29.2 + 7.3 13.3 f 1.8 26.5 + 5.7 26.2 rt 4.9 2.4 f 0.3 2.4 + 0.4 1.1 + 0.2 2.3 f 0.3 13.5 -c 1.3 4.0 f 0.5 0.07 f .04 0.09 f .06 0.01 f .02

NaCl = sodium chloride, MEP = mepyramine,

-42.7 -27.1 -36.3 -14.8

f f f f

-37.4 18.7 40.7 45.1 2.1 2.9 2.2 2.8 15.5 7.1 0.14 0.15 0.18

-+ 9.5 + 3.1 -t 6.2 +- 9.9 + 0.5 f 0.3 + 0.8 + 0.5 -+ 1.1 + 1.3 f .05 + .04 -+ .05

CIM = cimetidine,

DMPGE, =

E,.

I, II, and III = SO-min study period before (control), during, and after, respectively, the gastric instillation of 40 mM acetylsalicylic Results are expresed

1.2 1.9 2.7 4.8

as mean + standard

acid.

error.

traduced into the stomach through the pylorus, which was then ligated. A reference KCl+agar-filled catheter was placed in the peritoneal cavity. Each electrode led to a separate beaker filled with saturated KC1 in which a balanced calomel half-cell electrode was placed, which in turn led to a recorder. The recorder was calibrated at the start of each day with a device supplying known voltages of 25 and 50 mV. Groups of six or seven rats received one of the following combinations: NaCl i.p. + NaCl s.c., 7.5 mg/kg mepyramine (MEP) S.C. + NaCl i.p., 50 mg/kg cimetidine (CIM) i.p. + NaCl s.c., MEP + CIM, or 20 pg/kg 16,16 dimethyl prostaglandin E, (DMPGE,) S.C. + NaCl i.p. The experimentor did not know which solutions were injected. One-half hour after the injection, the study, divided into three periods of 30 min each, was begun. In periods I and III, the stomach was filled with the following solution: 1OOmM HCl, 15 mM NaCl, 76 mM mannitol, and ‘%rCl,, 100 &i/liter as a dilution indicator. In period II, the same solution but containing 40 mM acetylsalicylic acid was instilled. In each period, exactly 4 ml of test solution were instilled into the stomach and 2 ml immediately removed and saved for analysis. Thirty minutes later, the gastric content was gently aspirated as completely as possible and saved at 4’C for analysis. The two aspirates were analyzed for ion and Yr concentration. The H+ concentration was determined by titration to pH 7.0 using an automatic titrator (Radiometer, Copenhagen). The Na+ and K+ concentrations were measured on a flame photometer with automatic dilutor (Instrumentation Laboratories, Boston) and YrCl, radioactivity in a scintillation spectrometer (Nuclear Chicago, Searle). Protein content of the

second aspirate was determined by the method of Lowry.15 The corrected volume of the initial instillate and the final recovered aspirate were determined from the dilution of the Yr. Multiplying the ion concentration by this corrected volume gave the ion content of the instilled and recovered aspirate. Net flux of each ion was calculated by subtracting the amount of ion instilled from the amount recovered. At the end of period III, the animal was killed and the stomach was removed and opened along the greater curvature. Lesions were scored according to size and number: Petachiae were given a score of 1,erosions less than 1 mm a score of 2, l-2 mm a score of 3,2-4 mm a score of 4, and 4 mm a score of 5. Lastly, the mucosa was stripped off, weighed, and placed in 1 ml of perchloric acid and frozen for salicylate content determination. Salicylate assays were all performed on the same day by the Saltzman method,” using an Aminco-Bowman spectroflurometer set at 310 nm for excitation and 400 nm for emission.

Statistical Student

Analysis

Data were analyzed t-test, and correlation

using analysis analysis.

of variance,

Results The results of tests for disruption of the gastric mucosal barrier to acid back diffusion are pre-

August 1979

PROTECTION

AGAINST

sented in Table 1. There were no major differences among the five treatment groups in values in period I, the control period before the instillation of acetylsalicylic acid. No values are given for H’ ion flux during period II, because the presence of acetylsalicylic acid in the instillate during that period makes such determinations difficult (as gastric content H’ titrations then reflect both unabsorbed acetylsalicylic acid and hydrochloric acid). Therefore, comparisons for evidence of barrier disruption were made between periods I and III. In Table 2, lesion scores, changes in parameters of barrier disruption (expressed as period III results minus period I results), and salicylate content of the mucosa are presented.

Lesions occurred primarily in the corpus of the stomach. Occasionally, lesions were also present in the antrum but not in the forestomach. The lesion scores were lower in the CIM (13 f 3), CIM+MEP (11 f 3) and DMPGE, (22 f 10) groups than in the NaCl(59 f 7) or MEP (47 f 2) groups. An analysis of variance revealed that the five groups differed significantly (P < O.Ol), and individual t-tests between each treatment group and the NaCl groups showed that the CIM, CIM+MEP, and DMPGE, but not the MEP groups were significantly different from the NaCl group (all Ps < 0.01). Potential

305

H’ and Na’ Flux As can be seen in Table 2, H’ back diffusion was within the same range in the NaCl and MEP groups but was less in the CIM, CIM+MEP, and DMPGE, groups. Na’ flux exhibited the same pattern showing less sodium influx in the groups treated with cimetidine or prostaglandin. One animal in the DMPGE, group had a high lesion score associated with marked evidence of barrier disruption (H’ = -55 pEq/30 min and Na = 77 pEq/30 min), explaining the higher mean and SE for the DMPGE, group. Without that animal, ion fluxes would have

Differences

To avoid multiple t-tests in analyzing for evidence of barrier disruption, PD was selected as a basic parameter of barrier disruption. In each group,

Table 2. Lesion score, Changes in Parameters

BARRIER DISRUPTION

the individual basal PD at the end of period I ranged between -38 and -48 mV and the group means between -41.5 and -45.5 mV (Table 1). Instillation of aspirin led to an immediate fall in PD (period II value in Table l), which then returned toward but did not reach the basal value (period II, Table 1). The difference in PD between the end of periods III and I was less in the CIM (8 f l), CIM+MEP (8 f l), and DMPGE, (6 + 3) groups than in NaCl (15 f 2) and MEP (16 f 3) groups. The analysis of variance showed a significant difference among all groups (P < 0.01) and individual t-tests showed that CIM, CIM+MEP and DMPGE, but not MEP treated animals differed significantly from the NaCl group (all Ps < 0.01). To confirm the conclusions reached by analysis of PD changes, mean changes of the other parameters were examined and correlation analyses of PD with the other parameters were performed. Because cimetidine and prostaglandin significantly protected against the PD fall, the other parameters should be correlated with PD if these agents truly inhibited barrier disruption.

Lesion Score

Transmucosal

GASTRIC MUCOSAL

of Barrier Disruption,

and Salicylate

Content of the Mucosa

in

the Differ-

ent Groups. Treatment Parameters Lesion score Parameters, of barrier disruption PD (mv) H+ (pEq/‘30 min) Na+ @Eq/30 min) K+ (/.dZq/36 min) Protein (mg/30 min) Volume (:m1/30 min) Salicylate (Icg/mg)

NaCl

MEP

CIM

59 + 7

47 + 2

13 + 3b

15 + 2 -43 f 11 45 + 9 2 f 0.6 9fl 0.09 f 0.09 55 +6

16 + -40+5 33 + 1* 9f3 0.03 f 51+

3 6 0.4

8 + 1” -22f4 4f6 -0.3 f 0.3

0.07 4

3 f 0.5 -0.16 f 0.08 48 + 6

CIM+MEP 11 f 3b 6 f lh -12It9 13 -+ 6 -1.3 + 0.2 2fl -0.09 + 0.04 46 f 4

DMPGE, 22 f lob 6f -20.3 f 26 f 0.12 + 4&l 0.04 -t 51*

3b 7 10 0.8 0.08 3

Abbreviations used in column headings are as follows: NACl = sodium chloride, MEP = mepyramine, CIM = cimetidine, DMPGE,=16,16 dimethyl prostaglandin E,. All data except lesion scores and aspirin content of mucosa are expressed as period III results minus period I results. Results are expressed as mean f SE. Student t-tests were performed for lesion score and PD only and significance is indicated as follows: O different from NaCl group at P < 0.05; b different from NaCl group at P < 0.01.

306

BOMMELAER

AND

GUTH

GASTROENTEROLOGY

H’ tyEq130min) -80.

r -0.71 p’ 0.01

Vol. 77. No. 2

tein in all groups. However, this decreased markedly in period III in the CIM, CIM+MEP, and DMPGE, groups.

- 60

SaJicyJate

4+

80

12

16

20

24

28

. 32

PDtmV)

of H+ back diffusion (pEq/SO min) to PD (mv) in the different groups; each point represents value of period III-period I data for each animal. In this figure and all subsequent figures, symbols are used as follows: closed circles, sodium chloride: open circles, mepyramine; triangles, cimetidine; star in closed circles, mepyramine + cimetidine; star, 16.16 dimethyl prostaglandin E,. The good correlation between change in H+ flux and PD, with clustering of cimetidine, cimetidine + mepyramine, and dimethyl prostaglandin E, data at the lower end of the line indicate that these agents inhibited barrier disruption (statistical analysis had shown significant protection against PD fall by these agents).

Comparison Groups

1. Relationship

been -17 + 6 for H’ and 18 + 5 for Na’. The correlations between H’ and PD (Figure 1) and Na’ and PD (Figure 2) were H’ vs. PD, r = 0.71, P < 0.01; and Na’ vs. PD, r = 0.68, P < 0.01.

K’ Flux K’ flux reflects cell damage as well as barrier disruption.” The mean difference between periods III and I gave positive value in the NaCl and MEP groups, whereas negligible or negative values were found in the CIM, CIM+MEP, and DMPGE, groups (Table 1). This suggests continuing cell damage and/ or barrier disruption in period III in the NaCl and MEP groups, but not in the latter groups. As shown in Figure 3, K’ fluxes also exhibited a significant correlation with PD fall (r = 0.69, P < 0.01).

Protein

of the Mucosa

There was no significant difference in salicylate content of the mucosa at the end of the study among the 5 groups (Table 2).

ad o Figure

Content

Between

CiM and CIM+MEP

When comparisons were made between CIM and CIM+MEP groups (Student t-test), no differences were found for lesion score, PD fall, H’, Na’, protein fluxes and salicylate content of the mucosa.

Discussion Both cimetidine and prostaglandin significantly reduced lesions produced by topical aspirin plus HCl. The H, histamine receptor antagonist mepyramine did not have any protective effect, nor did it add to the protective effect of the H, antagonist cimetidine. In the present study, antisecretory doses of cimetidine or prostaglandin were used. However, the protective effect against aspirin plus HCl was unlikely to be due to their antisecretory property, since exogenous acid was added to the gastric content. Thus, this study confirms previous reports of the cytoprotective effect of cimetidine”,’ and prostaglandin’.’ and the absence of a cytoprotective effect of the H, antagonist mepyramine.” Carmichael et al.

Output

Protein outpouring was greater in control and MEP groups than in groups treated with cimetidine or prostaglandin (Table 1) and correlation with PD fall (r = 0.67) was significant P < 0.01 (Figure 4). It is of interest that while the pattern of greater fall in PD and increase in Na’ and K’ efflux in period III in the NaCl and MEP groups was also true of period II changes (Table l), this did not hold for protein loss. In period II there was a marked outpouring of pro-

Figure

2. Relationship of Na+ flux (pEq/30 min) to PD (mv) in the different groups; each point represents value of period III-period I data for one animal. The good correlation between Na+ flux change and PD change supports the concept of significant barrier protection by cimetidine, alone or with mepyramine, and the prostaglandin. (See Figure 1 for explanation of symbols.)

August 1979

PROTECTION

AGAINST

GASTRIC

MUCOSAL

BARRIER

DISRUPTION

307

study supports the concept that prostaglandins could act through modification of gastric mucosal permeability. The available information on the effect of histamine and its antagonists during gastric mucosal damage remains controversial.“’ When the gastric mucosa is damaged, histamine is liberated into the interstitial space.” Topical application of histamine /80 fi “13 20 24 28 PD (mV) leads to further damage with increase in ion fluxes.22~23O’Brien and Carter” observed no effect of metiamide on the increase in mucosal permeability Figure 3. R.elationship of K+ flux (pEq/30 min) to PD (mV) in the to H’ and Na’ produced by bile salt in the canine different groups; each point represents value of period Heidenhain pouch. Gurll et al.‘* reported similar III-period I data for one animal. The good correlation findings, except metiamide did decrease protein outsupports the concept of significant barrier protection by cimetidine, alone or with mepyramine and the prospouring. Rees et a1.13observed that the combination taglandin. (See Figure 1 for explanation of symbols.) of H, and H, antagonists (cimetidine plus mepyramine), but neither alone, protected against canine gastric mucosal barrier disruption by taurocholate. reported” that whereas prostaglandin protected However, Cheung and Porterfield” recently reported against lesions produced by aspirin plus exogenous that this combination of antagonists neither diminHCl, cimetidine did not. However, their cimetidineished H’ back diffusion in the taurocholate damaged treated groups had a lower lesion score than the concanine stomach nor exhibited any cytoprotective eftrol group (19.7 + 3.2vs.27.4f 2.4), and this differfect. Our study indicates that cimetidine, but not meence approached statistical significance (P = 0.06, pyramine, is cytoprotective and diminishes the aspiStudent t-test applied to their data), suggesting that rin-induced increase in permeability to H’, Na’, K’, cimetidine also protected. and protein in the rat. Whether the discrepancy beIn the present study, we have shown that cimetitween the present study and these studies could be dine and prostaglandin significantly protected due to differences in the species studied or in the against aspirin plus HCl induced gastric mucosal damaging agent is not known. damage and fall in potential difference, an indicator In this study, the salicylate content of the mucosa of barrier disruption. All other parameters of barrier measured 1 hr after instillation of aspirin did not difdisruption, except volume, exhibited the same patfer among the groups, suggesting that changes in abtern as potential difference change and correlated sorption of aspirin are not involved in cytowith potential difference. Disruption of the gastric protection. However, we have no data on possible mucosal barrier is associated with gastric mucosal damage induced by topical aspirin.” Our data inPROTEIN (mg130 mid dicate that protection of the gastric mucosal barrier is associated with the cytoprotective effect of cimeti0 r- 0.07 dine and prostaglandin against lesions induced by PN 0.01 topical aspirin in the rat. Whether this protection of the barrier is the cause or consequence of the cytoprotective effect of these drugs cannot be determined from our data. The mechanism of cytoprotection is unknown. Cohen’ showed that the 15 methyl PGE, analog prevents the increase in mucosal permeability caused by aspirin and indomethacin. Whittle’” suggested that prostaglandin could act through a decrease in PDbllVb 4 8 12 16 20 24 28 32 38 mucosal permeability and/or an increase in mucosal blood flow. Chaudhury and Jacobson” showed that Figure 4. Relationship of protein output (mg/30 min) to PD (mv) in the different groups; each point represents value of prostaglandin could prevent the inhibition of active period III-period I data for one animal. The good correNa’ transport by aspirin and indomethacin. Prostalation supports the concept of significant barrier proglandin also has been shown to stimulate mucus setection by cimetidine, alone or with mepyramine, and cretion.” These studies suggest that several mechathe prostaglandin. (See Figure 1 for explanation of nisms might be involved in cytoprotection. Our symbols.) K+ (pEql3Omin)

r 0.69 p
308

BOMMELAER

GASTROENTEROLOGY

AND GUTH

differences that might have occurred time following instillation.

at an earlier

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4.

5.

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Robert A: Antisecretory, antiulcer, cytoprotective and diarrheogenic properties of prostaglandins. In Advances in Prostaglandin and Thromboxane Research, Vol. 2. Edited by B Samuelsson, R Paoletti. New York. Raven Press, 1976. p 507-521. Robert A, Nezamis JE, Lancaster C, et al: The cytoprotective property of prostaglandins. Gastroenterology 72:1121,1977 Whittle BJR: Relationship between the prevention of rat gastric erosions and the inhibition of acid secretion by prostaglandins. Eur J Pharmacol40:233-239,1976 Carmichael HA, Nelson L, Russel RI, et al: The effect of the synthetic prostaglandin analog 15 (R) 15 methyl-PGEp methylester on gastric mucosal hemmorhage induced in rats by taurocholic acid and hydrochloric acid. Am J Dig Dis 22:411-414.1977 Carmichael HA, Nelson LM, Russell RI: Cimetidine and prostaglandins: evidence for different modes of action on the gastric mucosa. Gastroenterology 76:1229-1232,1978 Guth PH, Aures D, Paulsen G: Topical aspirin plus HCl lesions in the rat: cytoprotective effect of prostaglandin, cimetidine and probanthine. Gastroenterology 7688-93.1979 Kauffman GL Jr., Grossman MI: Prostaglandin and cimetidine inhibit the formation of ulcers produced by parenteral salicylates. Gastroenterology 75:1899-1102,1978 Davenport HW: Gastric mucosal injury by fatty and acetylsalicylic acids. Gastroenterology 46:245-253.1984 Cohen MM: 15-Methyl prostaglandin E, protects gastric mucosal barrier. In Advances in Prostaglandin and Thromboxane Research. Edited by B. Samuelsson, R. Paoletti. New York, Raven Press, 1975, p 937-938 Whittle BJR: Mechanisms underlying gastric mucosal damage

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induced by indomethacin and bile salts, and the action of prostaglandin. Br J Pharmacol60:455-4681977 11. O’Brien PE, Carter DC: Effect of gastric secretory inhibitors on the gastric mucosal barrier. Gut 16:437-442,1975 12. Gurll NJ, Zimmer MJ, Callahan W: Effect of histamine H, antagonism by metiamide on the response of the canine gastric mucosa to acid and bile salt. Gastroenterology 73:255-259, 1977 13. Rees WDW, Rhodes J, Wheeler MH, et al: The role of histamine receptors in the pathophysiology of gastric mucosal damage. Gastroenterology 72:67-71,1977 14. Cheung LY, Porterfield G: Is histamine a mediator in bile-induced gastric mucosal injury? J Surg Res 24:272-276.1978 15. Lowry OH, Rosebrough NJ, Farr AL, et al: Protein measurement with the Folin phenol reagent. J Biol Chem 193:265-275, 1951 16. Saltzman A: Flurometric methods for the estimation of salicylate in blood. J Biol Chem 174:399-404,1968 17. Davenport HW: Potassium fluxes across the resting and stimulated gastric mucosa: injury by salicylic and acetic acids. Gastroenterology 49:238-245.1965 18. Chaudhury TK, Jacobson ED: Prostaglandin cytoprotection of gastric mucosa. Gastroenterology 74:59-63, 1978 19. Bolton JP, Palmer D, Cohen MM: Stimulation of mucus and non-parietal cell secretion by the Ez prostaglandin. Am J Dig Dis 23:359-364,1978 20. Guth PH. Code CF: Histamine release and gastric mucosal damage. Gastoenterology 74:622-623.1978 21. Johnson LR: Histamine liberation by gastric mucosa of pylorus ligated rat damaged by acetic or salicylic acids. Proc Sot Exp Biol Med 121:384-388,1966 22. Davenport HW: Fluid produced by the gastric mucosa during damage by acetic and salicylic acids. Gastroenterology 50:487-499,1966 23. Moody FG, Davis WL: Hydrogen and sodium formation of canine gastric mucosa during histamine and sodium thiocyanate administration. Gastroenterology 59:350-357,197O