- Email: [email protected]
Prevention of Aspirin-Induced Gastric Ulceration by Bile Duct or Pylorus Ligation in the Rat
Vol. 65, No.4
65: 630- 633, 1973 Copyright© 1973 by The Williams & Wilkins Co. GASTROENTEHOLOGY
Printed in U.S.A.
PREVENTION OF ASPIRIN-INDUCED GASTRIC ULCERATION BY BILE DUCT OR PYLORUS LIGATION IN THE RAT BIJAN DJAHANGUIRI, M .D., FOROUGH
s. ABTAHI,
M . D. , AND MASOUD HEMMATI, M .D .
Department of Experimental Medicine and Pharmacology, School of M edicine , Uni versity of Tehran , Tehran , Iran
The oral administration of aspirin, 200 mg per kg, produced gastric ulceration in 100% of rats. Aspirin-induced ulcerations are prevented by bile duct or pylorus ligation. In bile duct- or pylorus-ligated rats the concomitant administration of bile + aspirin produced ulcerations in a number of animals similar to that of aspirin treatment alone. The mechanisms by which aspirin and bile damage the gastric mucosa are discussed. It has been assumed that impaired mucosal resistance caused by the reflux of bile into the stomach is an important etiological factor in gastric ulcers. 1 Slight ref1ux of bile into the stomach is a normal finding. du Plessis 2 reported the presence of an excessive amount of bile acid conjugates in the fasting gastric aspirates of patients with gastric ulcer. Capper et al. 3 have injected barium into the duodenum and have studied duodenal reflux radiologically. Nineteen out of 29 patients with gastric ulcer had duodenal reflux compared with none of the 15 control subjects. Rhodes and associates 4 demonstrated that patients with ulceration of the proximal lesser curvature had significantly higher concentrations of bile acids in the stomach after eating. Recently DenBesten and Hamza 5 demonstrated the presence of bile reflux in hemorrhagic shock-induced gastric ulceration in the dog. Aspirin is known to produce gastric mucosal damage both in man and animals. The observations of du Plessis 2 and Rhodes and associates 4 prompted us to study the possible part played by bile in aspirininduced gastric mucosal ulceration in aniReceived February 6, 1973. Accepted May 4, 1973. Address requests for reprints to: Dr. Bijan Djahanguiri, Department of Experimental Medicine and Pharmacology , University of Tehran School of Medicine, Tehran, Iran .
mals. To delineate the part played by bile, we have studied the ulcerogenic action of aspirin in intact, bile duct-ligated, and pylorus-ligated rats. The effects of separate and concomitant administration of bile and aspirin on unoperated, sham-operated, bile duct-ligated, and pylorus-ligated rats are also studied.
Materials and Methods Sprague-Dawley rats of both sexes weighing 140 to 165 g were used . They were fasted 24 hr before experiment but had free access to water. Bile duct and py lorus ligation. Animals were anesthetized with ether . The abdomen was opened and the common bile duct was exposed to its root at the liver. The bile duct was tied low enough to prevent bile drainage from any lobe of the liver, but high enough so that pancreatic juice flow was not impaired. At autopsy animals were inspected for bile duct dilation which was considered as evidence of complete bile duct ligation . Only data from rats with this condition were used. For pylorus ligation the pyloric end of the stomach was tied off. This was checked at autopsy by observing the dilation of the stomach . Sham-operated animals underwent similar surgical procedures except that the bile duct and pylorus were not ligated. A spirin administration. Aspirin was suspended in 1% methylcellulose suspension and administered orally at the dose of200 mg per kg, 30 min after animals recovered from anesthesia. Bile administration. Bile was collected from the gallbladders of 2 healthy male dogs of 14 and 19 kg, anesthetized with Na pentobarbital.
630
October 1973
631
BILE AND ASPIRIN UL CERATION
It was diluted volume for volume with 0.15 M NaCI. After dilution, the bile salt concentration was 70 mEq per liter . The pH of diluted bile was 6.9. It was administered orally at the dose of 0.5 ml per 100 g of body weight, 5 min before aspirin treatment. Animals were divided into 12 groups of 10 rats each. Ten animals received aspirin and 10 other animals received bile alone without operation at all. Twenty animals were sham-operated a nd treated as the above groups . Forty animals were subjected to bile duct ligation. Ten rats from this group received aspirin and 10 other rats rece ived bile alone. Ten other rats received aspirin + bile and the remaining animals received 1 ml per rat of 0.85% NaCl solution . Forty other animals received the sa me treatment as the bile duct-ligated groups, but instead of bile duct the pylorus was ligated. Four hours after aspirin administration the animals were killed by a blow on the head. The abdomen was opened and the stomach was removed . It was opened along the lesser curvature and examined for the presence of ulceration by an observer who was not aware what treatment the animals received. The blood was gently wiped off from the surface of the stomach. Necrohemorrhagic spots larger than 2 mm in di ameter were considered as evidence of erosion formation . The frequency of these spots, found in t he glandular part of the stomach, ran ged from 2 to 6. Microscopic examination of erosion-containing stomachs, chosen at random , confirmed the presence of ulcerations in the mucosal layer, rarely reaching the muscularis mucosa, and always accompanied by edema, hemorrhage, and infiltration of inflammatory cells. The macroscopic and microscopic findings in positive cases were the same. Student's t-test was performed for the statistical analysis of the data. 6
Results The results are summarized in table 1. The table shows that the oral administration of aspirin, at the dose of 200 mg per kg and after 4 hr, produced gastric mucosal ulceration in 100% of rats. This confirmed the results obtained by Brodie and Chase. 7 The table also shows that aspirin-induced ulcerations are prevented significantly (P < 0.001) by bile duct or pylorus ligation . The concomitant administration of aspirin + bile, in bile duct- or pylorus-ligated rats, resulted in ulceration in a number of rats similar to aspirin administration alone.
TABLE
1. Effects of bile duct and pylorus ligation on
aspirin-induced gastric lesions in rats
Operation Groups performed• 1 2 3 4
5 6 7
so so BDL BDL BDL
10 11
BDL PL PL PL
12
PL
8 9
Drugs and dosages
Aspirin 200 mg/kg Bile 0.5 ml/100 g Aspirin 200 mg/kg Bile 0.5 ml/ 100 g Aspirin 200 m g/kg Bile 0.5 ml/ 100 g Aspirin 200 mg/kg + bile 0.5 ml/100 g 0.85% NaC11 ml/rat Aspirin 200 m g/kg Bile 0.5 ml/100 g Aspirin 200 mg/kg + bile 0.5 ml/100 g 0.85% NaC11 ml/rat
No. of rats
Percent· age of rats with ulceration
10 10 10 10 10 10 10
100 0 100 0 20" 0
10 10 10 10
0 30" 10
10
10
soc
7(]'
• SO, sham operation; BDL, bile duct ligation; PL, pylorus ligation . • Significantly diffe rent (P < 0.001) when compared with groups 1 an d 3. c No significant difference was observed when compared with groups 1 and 3.
Bile administration failed to produce gastric mucosal lesions in unoperated, shamoperated, bile duct-ligated, or pylorusligated rats . None of the bile duct-ligated animals showed ulceration, and only 1 out of 10 rats subjected to pylorus ligation showed gastric ulceration.
Discussion Several mechanisms have been proposed to explain the ulcerogenic action of aspirin. According to Davenport 8 aspirin damages the gastric mucosal barrier which allows back-diffusion of H +. When the mucosa is damaged by salicylates, histamine is released within it and capillary permeability is increased which is followed by bleeding. Hingson and lto 9 have studied the fine structure of mouse gastric mucosa after aspirin treatment. They have observed that pathological changes were first noted within the cell without being preceded by detectable damage to the cell membrance glycocalyx or junctional complex. Menguy 10 reported that parenteral ad-
632
DJAHANGUIRI ET AL.
ministration of aspirin to rats, or the oral administration of aspirin to dogs with antral pouches or Heidenhain pouches, reduced gastric secretion of mucus and increased the rate of cell loss from the gastric mucosal surface, loss which was not accompanied by an increased rate of cell turnover. What the bile does in the stomach is not well understood. Its ulcerogenic action is demonstrated in dogs and rats.'' The failure of bile to produce gastric mucosal lesion, in this experiment, may be due to the dose of bile used, or to its neutral pH, or both. However, it has been known that bile causes cytolysis of the epithelial cells. 12 Moreover, normal gastric mucosa is relatively impermeable to H+ and Na+. This mucosal barrier can be broken by a variety of agents such as bile. The backdiffusion of hydrogen ion and fluxes of N a+ is increased after contact of bile with gastric mucosa. 13 On the other hand Kim and lvy 14 have observed an increase in the gastric secretion after bile administration. Bile reduces acid secretion but increases volume of gastric juice. The reduction in acid secretion may be due to H+ back-diffusion. The relation between aspirin administration and bile regurgitation is not yet known. Duodenogastric reflux, after the introduction of acid into the duodenum had been noted previously. The degree of regurgitation was proportional to the amount of acid present in the duodenum. However, this does not hold in the case of aspirin because hypersecretion of acid has not yet been proved after aspmn administration. 7 Rhodes 15 in his recent review on the etiology of gastric ulcer stated that "reflux of bile into the stomach is common in gastric ulcer but unusual in normal subjects." He attributed the damaging effects of the bile on gastric mucosa to the disturbances of the mucosal barrier and increased secretion of acid. Increased secretion of acid was confirmed by the recent works of Bedi et al. 16 and N ahrwold. 17 They attributed this effect to the release of gastrin by bile salts. Davenports has shown that for lesion for-
Vol. 65, No.4
mation to occur, not only must the gastric mucosal barrier to H+ back-diffusion be broken, e.g., by aspirin, but an adequate concentration of acid must also be present. Menguy and Koger's showed that bile duct ligation in the rat markedly reduces acid secretion. One may suggest that this reduction in acid secretion, rather than the absence of bile regurgitation, be the preventive mechanism acting in this study. But the presence of ulceration in the stomach of bile duct-ligated and pylorus-ligated animals treated with bile (with a pH very close to the neutral) and aspirin exclude the above suggestion. From the above findings the sequence of events may be suggested to be as follows. Aspirin damages gastric mucosal barrier. Bile regurgitates and damages gastric mucosal barrier also. In addition, it releases gastrin and increases gastric secretion. These changes lead to gastric ulceration. Whatever these mechanisms may be, the results of these experiments show that the presence of bile in the stomach may play a part in the production of gastric mucosal lesions induced by aspirin in rats. REFERENCES 1. Wormsley KG: Aspects of duodeno·gastric reflux in man. Gut 13:243-250, 1972 2. du Plessis DJ: Pathogenesis of gastric ulceration. Lancet 1:974-978, 1965 3. Capper WM, Airth GR, Kilby JO : A test for pyloric regurgitation . Lancet 2:621-623, 1966 4. Rhodes J, Barnardo DE, Phillips SF, et a!: Increased reflux of bile into the stomach in patients with gastric ulcer. Gastroenterology 57:241- 252, 1969 5. DenBesten L, Hamza KN: Effect of bile salts on ionic permeability of canine gastric mucosa dur· ing experimental shock. Gastroenterology 62:417- 424, 1972 6. Armitage P: Statistical methods in medical re· search. New York, John Wiley & Sons hie, 1971, p 101- 107 7. Brodie DA, Chase BJ : Role of gastric acid in aspirin·induced gastric irritation in the rat. Gas· troenterology 35:604- 610, 1967 8. Davenport HW: Salicylate damage to the gastric mucosal barrier. N Eng! J Med 276:1307- 1312, 1967 9. Hingson DJ, Ito S: Effect of aspirin and related compounds on the find structure of mouse gastric mucosa. Gastroenterology 61:156-177, 1971
October 1973
BILE AND ASPIRIN ULCERATION
10. Menguy R: Gastric mucosal injury by aspirin. Gastroenterology 51:430-432, 1966 11. Smith GM: An experimental study of the relation of bile to ulceration of the mucous membrane of the stomach. J Med Res 30: 174- 183, 1914 12. Grant R, Grossman MI, Wang KJ, et al: The cytolytic action of some gastrointestinal secretions and enzymes on the epithelial cells of the gastric and duodenal mucosa. J Cell Physiol 37:137-161, 1951 13. Davenport HW: Destruction of the gastric mucosal barrier by detergents and urea. Gastroenterology 54:175- 181, 1968 14. Kim MS, Ivy AC: The gastric secretagogic value
15. 16.
17. 18.
633
of various digestive sec retions. Am J Physiol 115:386-394, 1936 Rhodes J: Etiology of gastric ulcer. Gastroenterology 63:171-182, 1972 Bedi BS, Debas HT, Gillespie G, et a l: Effects of bile salts on antral gastrin release. Gastroenterology 60:256-262, 1971 Nahrwold DL: Bile as a gastric secretory stimulant. Surgery 71:157-160, 1972 Menguy R, Koger E: Mechanism of inhibition of gastric secretion in the rat following bile duct ligation . Proc Soc Exp Bioi Med 101:666-668, 1959
65: 630- 633, 1973 Copyright© 1973 by The Williams & Wilkins Co. GASTROENTEHOLOGY
Printed in U.S.A.
PREVENTION OF ASPIRIN-INDUCED GASTRIC ULCERATION BY BILE DUCT OR PYLORUS LIGATION IN THE RAT BIJAN DJAHANGUIRI, M .D., FOROUGH
s. ABTAHI,
M . D. , AND MASOUD HEMMATI, M .D .
Department of Experimental Medicine and Pharmacology, School of M edicine , Uni versity of Tehran , Tehran , Iran
The oral administration of aspirin, 200 mg per kg, produced gastric ulceration in 100% of rats. Aspirin-induced ulcerations are prevented by bile duct or pylorus ligation. In bile duct- or pylorus-ligated rats the concomitant administration of bile + aspirin produced ulcerations in a number of animals similar to that of aspirin treatment alone. The mechanisms by which aspirin and bile damage the gastric mucosa are discussed. It has been assumed that impaired mucosal resistance caused by the reflux of bile into the stomach is an important etiological factor in gastric ulcers. 1 Slight ref1ux of bile into the stomach is a normal finding. du Plessis 2 reported the presence of an excessive amount of bile acid conjugates in the fasting gastric aspirates of patients with gastric ulcer. Capper et al. 3 have injected barium into the duodenum and have studied duodenal reflux radiologically. Nineteen out of 29 patients with gastric ulcer had duodenal reflux compared with none of the 15 control subjects. Rhodes and associates 4 demonstrated that patients with ulceration of the proximal lesser curvature had significantly higher concentrations of bile acids in the stomach after eating. Recently DenBesten and Hamza 5 demonstrated the presence of bile reflux in hemorrhagic shock-induced gastric ulceration in the dog. Aspirin is known to produce gastric mucosal damage both in man and animals. The observations of du Plessis 2 and Rhodes and associates 4 prompted us to study the possible part played by bile in aspirininduced gastric mucosal ulceration in aniReceived February 6, 1973. Accepted May 4, 1973. Address requests for reprints to: Dr. Bijan Djahanguiri, Department of Experimental Medicine and Pharmacology , University of Tehran School of Medicine, Tehran, Iran .
mals. To delineate the part played by bile, we have studied the ulcerogenic action of aspirin in intact, bile duct-ligated, and pylorus-ligated rats. The effects of separate and concomitant administration of bile and aspirin on unoperated, sham-operated, bile duct-ligated, and pylorus-ligated rats are also studied.
Materials and Methods Sprague-Dawley rats of both sexes weighing 140 to 165 g were used . They were fasted 24 hr before experiment but had free access to water. Bile duct and py lorus ligation. Animals were anesthetized with ether . The abdomen was opened and the common bile duct was exposed to its root at the liver. The bile duct was tied low enough to prevent bile drainage from any lobe of the liver, but high enough so that pancreatic juice flow was not impaired. At autopsy animals were inspected for bile duct dilation which was considered as evidence of complete bile duct ligation . Only data from rats with this condition were used. For pylorus ligation the pyloric end of the stomach was tied off. This was checked at autopsy by observing the dilation of the stomach . Sham-operated animals underwent similar surgical procedures except that the bile duct and pylorus were not ligated. A spirin administration. Aspirin was suspended in 1% methylcellulose suspension and administered orally at the dose of200 mg per kg, 30 min after animals recovered from anesthesia. Bile administration. Bile was collected from the gallbladders of 2 healthy male dogs of 14 and 19 kg, anesthetized with Na pentobarbital.
630
October 1973
631
BILE AND ASPIRIN UL CERATION
It was diluted volume for volume with 0.15 M NaCI. After dilution, the bile salt concentration was 70 mEq per liter . The pH of diluted bile was 6.9. It was administered orally at the dose of 0.5 ml per 100 g of body weight, 5 min before aspirin treatment. Animals were divided into 12 groups of 10 rats each. Ten animals received aspirin and 10 other animals received bile alone without operation at all. Twenty animals were sham-operated a nd treated as the above groups . Forty animals were subjected to bile duct ligation. Ten rats from this group received aspirin and 10 other rats rece ived bile alone. Ten other rats received aspirin + bile and the remaining animals received 1 ml per rat of 0.85% NaCl solution . Forty other animals received the sa me treatment as the bile duct-ligated groups, but instead of bile duct the pylorus was ligated. Four hours after aspirin administration the animals were killed by a blow on the head. The abdomen was opened and the stomach was removed . It was opened along the lesser curvature and examined for the presence of ulceration by an observer who was not aware what treatment the animals received. The blood was gently wiped off from the surface of the stomach. Necrohemorrhagic spots larger than 2 mm in di ameter were considered as evidence of erosion formation . The frequency of these spots, found in t he glandular part of the stomach, ran ged from 2 to 6. Microscopic examination of erosion-containing stomachs, chosen at random , confirmed the presence of ulcerations in the mucosal layer, rarely reaching the muscularis mucosa, and always accompanied by edema, hemorrhage, and infiltration of inflammatory cells. The macroscopic and microscopic findings in positive cases were the same. Student's t-test was performed for the statistical analysis of the data. 6
Results The results are summarized in table 1. The table shows that the oral administration of aspirin, at the dose of 200 mg per kg and after 4 hr, produced gastric mucosal ulceration in 100% of rats. This confirmed the results obtained by Brodie and Chase. 7 The table also shows that aspirin-induced ulcerations are prevented significantly (P < 0.001) by bile duct or pylorus ligation . The concomitant administration of aspirin + bile, in bile duct- or pylorus-ligated rats, resulted in ulceration in a number of rats similar to aspirin administration alone.
TABLE
1. Effects of bile duct and pylorus ligation on
aspirin-induced gastric lesions in rats
Operation Groups performed• 1 2 3 4
5 6 7
so so BDL BDL BDL
10 11
BDL PL PL PL
12
PL
8 9
Drugs and dosages
Aspirin 200 mg/kg Bile 0.5 ml/100 g Aspirin 200 mg/kg Bile 0.5 ml/ 100 g Aspirin 200 m g/kg Bile 0.5 ml/ 100 g Aspirin 200 mg/kg + bile 0.5 ml/100 g 0.85% NaC11 ml/rat Aspirin 200 m g/kg Bile 0.5 ml/100 g Aspirin 200 mg/kg + bile 0.5 ml/100 g 0.85% NaC11 ml/rat
No. of rats
Percent· age of rats with ulceration
10 10 10 10 10 10 10
100 0 100 0 20" 0
10 10 10 10
0 30" 10
10
10
soc
7(]'
• SO, sham operation; BDL, bile duct ligation; PL, pylorus ligation . • Significantly diffe rent (P < 0.001) when compared with groups 1 an d 3. c No significant difference was observed when compared with groups 1 and 3.
Bile administration failed to produce gastric mucosal lesions in unoperated, shamoperated, bile duct-ligated, or pylorusligated rats . None of the bile duct-ligated animals showed ulceration, and only 1 out of 10 rats subjected to pylorus ligation showed gastric ulceration.
Discussion Several mechanisms have been proposed to explain the ulcerogenic action of aspirin. According to Davenport 8 aspirin damages the gastric mucosal barrier which allows back-diffusion of H +. When the mucosa is damaged by salicylates, histamine is released within it and capillary permeability is increased which is followed by bleeding. Hingson and lto 9 have studied the fine structure of mouse gastric mucosa after aspirin treatment. They have observed that pathological changes were first noted within the cell without being preceded by detectable damage to the cell membrance glycocalyx or junctional complex. Menguy 10 reported that parenteral ad-
632
DJAHANGUIRI ET AL.
ministration of aspirin to rats, or the oral administration of aspirin to dogs with antral pouches or Heidenhain pouches, reduced gastric secretion of mucus and increased the rate of cell loss from the gastric mucosal surface, loss which was not accompanied by an increased rate of cell turnover. What the bile does in the stomach is not well understood. Its ulcerogenic action is demonstrated in dogs and rats.'' The failure of bile to produce gastric mucosal lesion, in this experiment, may be due to the dose of bile used, or to its neutral pH, or both. However, it has been known that bile causes cytolysis of the epithelial cells. 12 Moreover, normal gastric mucosa is relatively impermeable to H+ and Na+. This mucosal barrier can be broken by a variety of agents such as bile. The backdiffusion of hydrogen ion and fluxes of N a+ is increased after contact of bile with gastric mucosa. 13 On the other hand Kim and lvy 14 have observed an increase in the gastric secretion after bile administration. Bile reduces acid secretion but increases volume of gastric juice. The reduction in acid secretion may be due to H+ back-diffusion. The relation between aspirin administration and bile regurgitation is not yet known. Duodenogastric reflux, after the introduction of acid into the duodenum had been noted previously. The degree of regurgitation was proportional to the amount of acid present in the duodenum. However, this does not hold in the case of aspirin because hypersecretion of acid has not yet been proved after aspmn administration. 7 Rhodes 15 in his recent review on the etiology of gastric ulcer stated that "reflux of bile into the stomach is common in gastric ulcer but unusual in normal subjects." He attributed the damaging effects of the bile on gastric mucosa to the disturbances of the mucosal barrier and increased secretion of acid. Increased secretion of acid was confirmed by the recent works of Bedi et al. 16 and N ahrwold. 17 They attributed this effect to the release of gastrin by bile salts. Davenports has shown that for lesion for-
Vol. 65, No.4
mation to occur, not only must the gastric mucosal barrier to H+ back-diffusion be broken, e.g., by aspirin, but an adequate concentration of acid must also be present. Menguy and Koger's showed that bile duct ligation in the rat markedly reduces acid secretion. One may suggest that this reduction in acid secretion, rather than the absence of bile regurgitation, be the preventive mechanism acting in this study. But the presence of ulceration in the stomach of bile duct-ligated and pylorus-ligated animals treated with bile (with a pH very close to the neutral) and aspirin exclude the above suggestion. From the above findings the sequence of events may be suggested to be as follows. Aspirin damages gastric mucosal barrier. Bile regurgitates and damages gastric mucosal barrier also. In addition, it releases gastrin and increases gastric secretion. These changes lead to gastric ulceration. Whatever these mechanisms may be, the results of these experiments show that the presence of bile in the stomach may play a part in the production of gastric mucosal lesions induced by aspirin in rats. REFERENCES 1. Wormsley KG: Aspects of duodeno·gastric reflux in man. Gut 13:243-250, 1972 2. du Plessis DJ: Pathogenesis of gastric ulceration. Lancet 1:974-978, 1965 3. Capper WM, Airth GR, Kilby JO : A test for pyloric regurgitation . Lancet 2:621-623, 1966 4. Rhodes J, Barnardo DE, Phillips SF, et a!: Increased reflux of bile into the stomach in patients with gastric ulcer. Gastroenterology 57:241- 252, 1969 5. DenBesten L, Hamza KN: Effect of bile salts on ionic permeability of canine gastric mucosa dur· ing experimental shock. Gastroenterology 62:417- 424, 1972 6. Armitage P: Statistical methods in medical re· search. New York, John Wiley & Sons hie, 1971, p 101- 107 7. Brodie DA, Chase BJ : Role of gastric acid in aspirin·induced gastric irritation in the rat. Gas· troenterology 35:604- 610, 1967 8. Davenport HW: Salicylate damage to the gastric mucosal barrier. N Eng! J Med 276:1307- 1312, 1967 9. Hingson DJ, Ito S: Effect of aspirin and related compounds on the find structure of mouse gastric mucosa. Gastroenterology 61:156-177, 1971
October 1973
BILE AND ASPIRIN ULCERATION
10. Menguy R: Gastric mucosal injury by aspirin. Gastroenterology 51:430-432, 1966 11. Smith GM: An experimental study of the relation of bile to ulceration of the mucous membrane of the stomach. J Med Res 30: 174- 183, 1914 12. Grant R, Grossman MI, Wang KJ, et al: The cytolytic action of some gastrointestinal secretions and enzymes on the epithelial cells of the gastric and duodenal mucosa. J Cell Physiol 37:137-161, 1951 13. Davenport HW: Destruction of the gastric mucosal barrier by detergents and urea. Gastroenterology 54:175- 181, 1968 14. Kim MS, Ivy AC: The gastric secretagogic value
15. 16.
17. 18.
633
of various digestive sec retions. Am J Physiol 115:386-394, 1936 Rhodes J: Etiology of gastric ulcer. Gastroenterology 63:171-182, 1972 Bedi BS, Debas HT, Gillespie G, et a l: Effects of bile salts on antral gastrin release. Gastroenterology 60:256-262, 1971 Nahrwold DL: Bile as a gastric secretory stimulant. Surgery 71:157-160, 1972 Menguy R, Koger E: Mechanism of inhibition of gastric secretion in the rat following bile duct ligation . Proc Soc Exp Bioi Med 101:666-668, 1959