EFFECT OF SECRETIN AND CHOLECYSTOKININ ON GASTRIC EMPTYING AND GASTRIC SECRETION IN MAN

Transcription

1 GA8TRONTROLOGY Copyright 197 by The Williams & Wilkins Co. Vol. 58, No.6 Fdnted in U.S.A. FFCT OF SCRTIN AND CHOLCYSTOKININ ON GASTRIC MPTYING AND GASTRIC SCRTION IN MAN W. Y. CHY, M.D., S. HITANANT, M.D., J. HNDRICKS, AND S. H. LORBR, M.D. Department of Gastroenterology, Division of Medicine, Temple University Health Sciences Center, Philadelphia, Pennsylvania The effects of secretin and cholecystokinin on gastric emptying and gastric secretion of acid were studied in man. The intravenous administration of secretin in a dose of 1 U per kg of body weight caused a significant decrease in gastric emptying measured 15 min after the intragastric instillation of 5 ml of normal saline solution in 1 subjects. The mean percentage of gastric emptying following the administration of secretin was 4.7% as compared with a control value of 85.2%. A decrease in gastric emptying of similar magnitude was observed in 9 subjects following the intravenous administration of cholecystokinin in a dose of.5 Ivy dog unit per kg. Gastric secretion of acid was stimulated by a continuous intravenous infusion of pentagastrin or histamine acid phosphate and both gastric and duodenal contents were collected simultaneously. The intravenous administration of secretin in a dose of 1 U per kg resulted in marked inhibition of acid secretion stimulated by either pentagastrin in a dose of.12 Ilg per kg per hr or histamine acid phosphate in a dose of.2 mg per kg per hr in 1 subjects. Secretin appeared to have a greater inhibitory effect on acid secretion stimulated by pentagastrin than on histamine-stimulated secretion. illhibition of acid secretion similar in magnitude to that produced by secretin was observed following the administration of cholecystokinin in a dose of 1 U per kg. Gastric secretion of acid stimulated by pentagastrin in a dose of 6 Ilg per kg per hr or histamine acid phosphate in a dose of.4 mg per kg per hr, however, was not influenced by the same dose of secretin in a dose similar to that which inhibited smaller doses of these stimuli. ill addition to its ability to stimulate external pancreatic secretion and bile flow, secretin has been shown to inhibit gastric secretion of acid in dogs H and motor ac- Received August 6, Accepted December 24, Address requests for reprints to: Dr. W. Y. Chey, Department of Gastroenterology, Temple University Health Sciences Center, Philadelphia, Pennsylvania This work was supported in part by Grant FR- 349 from the National Institutes of Health, United States Public Health Service. The authors thank Professor. Jorpes and Dr. V. Mutt, Karolinska Institute, Sweden, for supplying the preparations of secretin and cholecystokinin, and tivity of the stomach in both man 6 and dogs. 7 Cholecystokinin, which produces contraction of the gallbladder 8 and stimulates secretion of pancreatic enzymes,9 was shown recently to inhibit gastric secretion of acid in dogs 5. 1 and motor activity of the stomach in man 6, II as well as in dogs. 12 Chemical analyses have revealed that secretin is composed of 27 amino acid residues and 11 different amino acids. 13 Al- 82 Dr. T. Robitscher, Ayerest Laboratories, New York, for supplying the pentagastrin (A Y -668) used in this study. They are also grateful to Mrs. Shirley Braverman, of the Department of Biometrics, for statistical analysis of the data.

2 June 197 FFCT OF SCRTIN AND CHOLCYSTOKININ 821 though cholecystokinin and pancreozymin were considered to be separate hormones,8, 9 further study suggests that they are chemically identical 14 and are composed of 33 amino acid residues and 16 different amino acids. In The present investigation was undertaken to study the effects of secretin and cholecystokinin on gastric emptying and secretion of acid in man. Materials and Methods Subjects. Subjects studied included 16 males and 5 females whose ages ranged from 28 to 7 years (average, 42). Two had a history of chronic pancreatitis without evidence of malabsorption and 2 had duodenal ulcer disease. These 4 subjects were asymptomatic at the time of study. The remaining 16 had no evidence of gastrointestinal disease. Patients were fasted for a minimum of 12 hr prior to study. Gastric emptying. Two Rhefuss tubes, tied together with their tips 1 cm apart, were introduced into the stomach so that the tip of the distal tube rested in its most dependent portion. Tube positions were checked fluoroscopically. The stomach was lavaged with 25 ml of.9% NaCI saline solution (saline) introduced through the proximal tube and aspirated through the distal tube. Mter evacuating the stomach completely, 5 ml of saline containing 3 mg of phenol red were introduced rapidly by gravity through the proximal tube. At the end of 15 min the gastric contents were aspirated manually through the distal tube. This was followed by another infusion of 25 ml of saline and the residual gastric contents were aspirated. In order to ascertain the completeness of aspiration, another 25 ml of saline were infused in 6 subjects and the gastric contents were aspirated immediately. No measurable residual volume was obtained on the second lavage. One hour following the initial infusion, 1 ml of saline or secretin in a dose of 1 U per kg or cholecystokinin,.5 Ivy dog unit per kg, were administered intravenously in a period of 1 to 2 min and the experiment was repeated, The emptying rate of the stomach was calculated as follows. The volume of the test meal recovered from the stomach was calculated by the method described by Hunt and Knox l6 : Volume of gastric contents X concentration of phenol red in gastric contents concentration of phenol red in test meal Thus, the volume of the meal remaining in the stomach was determined and the percentage of emptying at 15 min following administration of the test meal was determined by subtracting the volume recovered from the original volume. Both secretin and cholecystokinin employed in the present investigation were supplied by Jorpes and Mutt, Karolinska Institute, Sweden, during 1967 and It has been claimed that 1 mg of secretin prepared by Jorpes and Mutt has 4 clinical units of biological activity and 1 mg of cholecystokinin, approximately 3 Ivy dog units. 15 Secretin or cholecystokinin was dissolved in saline in a concentration of 1 clinical units or 1 Ivy dog units per ml, respectively. Gastric secretion. To study the effect of secretin and cholecystokinin on gastric secretion, a Dreiling gastroduodenal tube was introduced orally, employing fluoroscopic observation, so that the tip of the proximal tube was located in the gastric antrum and the tip of the distal tube in the area of the ligament of Treitz. Mter aspirating the residual gastric contents completely, a steady state of gastric secretion was established employing a constant intravenous infusion of histamine acid phosphate in a dose of either.2 or.4 mg per kg per hr or pentagastrin in a dose of either.12 or 6 J,lg per kg per hr, The hourly dose of histamine or pentagastrin was mixed in 6 ml of saline and administered intravenously at a rate of 1 ml per min. Gastric contents were collected at 5-min intervals and the duodenal contents at 1-min intervals. After the secretion of gastric juice became steady for a minimum of 3 min, 1 ml of normal saline solution or a hormonal preparation were administered within 1 min via the intravenous route and the collections of both gastric and duodenal contents were continued for a minimum of 4 min or until the gastric output level returned to that of the control period. Gastric contents were analyzed for volume, ph, and titratable acid concentration. The latter was titrated to ph 7.4 with.2 N NaOH solution. Determinations made on the duodenal contents included ph and concentration of bicarbonate. Studies were discarded if duodenal contents regurgitated into the stomach as evidenced by a sudden increase in volume, contamination by bile, or an increase in the ph value, or if gastric juice contaminated duodenal contents as evidenced by a sudden decrease in ph or the development of turbidity of the duodenal contents. Regurgitation of the duodenal contents occurred in seven experiments performed in 4

3 822 CHY T AL. Vol. 58, No.6 subjects and contamination of duodenal contents by gastric juice was observed in two experiments. In order to determine the completeness of collection of gastric contents, a no. 1 French Levin tube was tied 1 cm proximal to the most proximal hole of the gastric portion of the gastroduodenal tube. One hundred milliliters of normal saline solution containing 3 mg of phenol red were infused continuously through the Levin tube at a rate of 1 ml per min and both gastric and duodenal contents were collected. Gastric secretion was stimulated by either pentagastrin or histamine. During the I-hr period of study, no detectable amount of dye appeared in serial samples of the duodenal contents in the 4 subjects studied. Student's t-test for paired values was employed to determine the significance of difference between the gastric emptying rate before and after the administration of saline solution or a hormonal preparation. In the studies employed to investigate the effect of each hormone on gastric secretion, the difference in acid output was calculated for each 5-min period during control experiments and for the corresponding period in experiments employing secretin or cholecystokinin. Differences were analyzed by analysis of variance. 17 Results ffect of secretin and cholecystokinin on gastric emptying. In duplicate control experiments performed on 8 subjects the intravenous administration of 1 ml of physiological saline solution resulted in similar percentages of gastric emptying at 15 min following the instillation of 5 ml of normal saline solution (fig. 1). The mean gastric emptying was 84.9% in the first experiment and 83.8% for the second. The intravenous administration of secretin in a dose of 1 U per kg resulted in a marked decrease in the rate of gastric emptying in all 1 subjects studied. Mean gastric emptying of 85.2% observed in the initial experiment was reduced to 4.7% by the administration of secretin. The difference between these two values was significant statistically at P <.1. Similar decreases in the magnitude of emptying were observed in 9 subjects following the administration of cholecystokinin in a dose of.5 U per kg. Mean gastric emptying of 8.1 % in the initial experiment was reduced to 44.2% following the administration of cholecystokinin. The difference between these two figures was significant statistically (P <.1). Among these subjects studied vide supra, 3 had control, secretin, and cholecystokinin experiments; 3 others had both control and cholecystokinin experiments. The interval between tests ranged from 2 to 8 days. In six experiments, duodenal contents were aspirated continuously in order to prevent regurgitation into the stomach and a comparable inhibition of gastric emptying was observed. Although we did not at- z!!2... «z >= "- CONTROL NO. OF SUBJCTS 8 CONTROl XPRIMNT POST-SCRTIN XPRIMNT POST-CHOlCYSTOKININ XPRIMNT MAN VALUS FIG. 1. ffects of secretin in a dose of 1 U per kg and cholecystokinin in a dose of.5 U per kg on gastric emptying.

4 June 197 FFCT OF SCRTIN AND CHOLCYSTOKININ 823 tempt to prevent regurgitation of duodenal contents in other experiments, no --: c gross contamination of gastric contents by '" duodenal juice was observed.... ffect of secretin and cholecystokinin on ;; Co gastric secretion of acid stimulated by pentagastrin or histamine. Gastric secretion was stimulated by the continuous "'u «intravenous administration of pentagastrin in a dose of.12 J.Lg per kg per hr and a steady state of acid secretion was established in approximately 2 to 3 min. Mter establishing a steady state of acid secretion for a minimum of 3 min, 1 ml of normal saline solution or a hormonal preparation in a dose of 1 U pe 7 kg w r e administered intravenously wlthm 1 mm. The administration of secretin resulted in a marked decrease in both volume and acid output. Data obtained from all 9 subjects are summarized in figure 2. Mean inhibition of acid output was most profound during the 1-min period following administration of secretin and significant inhibition lasted for as long as 3 min. During the period of administration of secretin, ph and concentration of bicarbonate of duodenal contents did not decrease but increased and the acid concentration of the gastric contents did not change, suggesting a lack of contamination by duodenal juice. Following the administration of secretin, the mean ph of the duodenal contents rose to 8.15 from 7.47 and the mean concentration of bicarbonate rose to 88.7 mq per liter from --:.: on "- '....! ;; Cl ;; "" v «2 IV PNTAGASTRIN 1 12 "g / Kg / Hr) 1 Secretin llu / Kg I - or Saline ---- p< Time In Minutes FIG. 2. ffect of intravenous administration of secretin or saline on mean gastric acid secretion in 9 subjects stimulated by pentagastrin in a dose of.12 /lg per kg per hr. "- ' 2 IV Histamine Acid Phosphote (.2mg/ Kg / Hri 15 Secretin (1 u/ Kg) or Saline Time In Minutes p < FIG. 3. ffe,;t of intravenous administration of secretin or saline on mean gastric acid secretion in 1 subjects stimulated by histamine acid phosphate in a dose of.2 mg per kg per hr mq per liter. Mean acidity was not influenced by secretin, measuring 96.3 mq per liter before and 94.8 mq e r liter after the administration of secretm. Similar studies were performed on gastric secretion stimulated by histamine acid phosphate in a dose of.2 mg per kg per hr (fig. 3). Decreases in both o l u m e and acid output produced by secretm were significant. In the 1 subjects studied, the mean duration of significant inhibition of acid secretion was 2 min. Of the subjects studied to observe the effects of secretin on acid secretion stimulated by either histamine or pentagastrin, 5 had comparable acid secretory responses to both stimuli. The means of inhibition produced by secretin on acid secretion stimulated by these two stimuli were statistically significant. Moreover, secretin caused more profound inhibition of acid secretion produced by histamine (fig. 4). The difference between the degrees of acid inhibition was statistically significant (P <.5). The interval between each experiment ranged from 3 to 8 days. In two groups of 5 subjects each, the effect of secretin on acid secretion stimulated by higher doses of pentagastrin or histamine acid phosphate was investigated. The dose of pentagastrin employed was 75 6 J.Lg per kg per hr and of histamine,.4 mg per kg per hr. No significant i n h i b i t i n of acid secretion was produced by secretm administered in a dose of 1 U per kg (fig. 5). Similar studies were performed to in-

5 . 824 CHY T AL. Vol. 58, No.6 vestigate the effect of cholecystokinin on c gastric secretion. Acid secretion was stimulated by the continuous intravenous in-? on fusion of pentagastrin in a dose of.12 J.lg per kg per hr. One unit per kilogram of cholecystokinin produced marked inhibi- tion of acid secretion for 3 min in 6 sub- jects (fig. 6). The mean ph of duodenal contents, following the administration of cholecystokinin, increased to 7.6 from 7.45 in the control period. A similar inhibitory effect of cholecystokinin was observed on gastric secretion of acid stimulated by the continuous intravenous administration of histamine acid phosphate in a dose of.2 mg per kg per hr. In 5 subjects, the mean inhibition of acid secretion lasted 15 min (fig. 7). Discussion The present investigation indicates that both secretin and cholecystokinin have similar inhibitory effects on gastric emptying and on gastric secretion of acid stimulated by pentagastrin or histamine in man. The rapid intravenous administration of secretin in a dose of 1 clinical unit per kg or cholecystokinin in a dose of.5 Ivy dog unit per kg caused inhibition of gastric motor function. That both hormones inhibit spontaneous motor activity of the stomach in man was demonstrated pre- c '" "- C" w 3 c. 3 - 'v -< 3 2 Secretin iuikg Tm.. in minutes Histamine acid phosphate. Penlopeptide P<.OO5 FIG. 4. ffect of intravenous administration of secretin on mean gastric secretion of acid stimulated by pentagastrin in a dose of.12 Ilg per kg per hr and histamine acid phosphate in a dose of.2 mg per kg per hr in the same 5 subjects. -< I Secreti n T r (Iu/Kg) i M e o n S. I \...r l ;: T L I I-- i I I!, T -..::::.1 r I (5 1ubjecls) 1 (5,ub;ects) t - R - H --- IV PNTAGASTRIN (6vg/ Kg / Hr).-. IV Histamine Ac id Phosphote (.4mg / Kg / Hr) T O r o Tim. In Minutes FIG. 5. ffects of intravenous administration of secretin on mean maximal acid secretion in 5 subjects each stimulated by pentagastrin and histamine acid phosphate. viously.6 Recently, we observed that both pure natural secretin, prepared by Jorpes and Mutt, and synthetic secretin, prepared by Ondetti, inhibited distentioninduced motor activity of the gastric antrum and Heidenhain pouch in dogs. 7 Furthermore, we observed recently that the intravenous administration of carboxyl terminal octapeptide of cholecystokinin prepared by Ondetti resulted in similar inhibition of motor activity of the canine stomach (unpublished data). In the present study the inhibitory effect of these two hormones on motor function of the stomach in man was demonstrated again by the delay they produced in gastric emptying. The inhibitory action of both secretin and cholecystokinin on the secretion of acid from the intact stomach or from a fundic pouch in response to gastrin, histamine, or a meat meal has been observed in dogs by several groups of investigators. I - 5,IO Of interest is the observation that the intravenous administration of natural cholecystokinin produced stimulation of basal gastric secretion, although the secretory response was slight in comparison with the marked effect evoked by histamine or gastrin preparations. I B - 2o Similar studies on the effects of these hormones on human gastric secretion have produced inconsistent results. The latter may relate to the technical difficulties encountered in obtaining complete collections of gastric contents, although the observations made by Kamionkowski et al. suggest that

6 June 197 FFCT OF SCRTIN AND CHOLCYSTOKININ 825 secretin extracts inhibit acid secretion stimulated by meat broth. 21 In the present investigation efforts were made to prevent both the loss of acid gastric juice to the duodenum and the regurgitation of duodenal contents into the stomach by collecting gastric and duodenal contents simultaneously. Gastric secretion of acid stimulated by a submaximal dose of pentagastrin or histamine was inhibited significantly by either secretin or cholecystokinin in a dose of 1 U per kg. In 5 subjects, with a similar acid secretory response to pentagastrin and histamine, secretin had a more profound inhibitory effect on the acid secretion stimulated by pentagastrin. Similar observations were made in dogs by Wormsley and Grossman. 4 They found that inhibition of gastrin-stimulated acid secretion by secretin was approximately twice that observed for histamine. Vagne and her associates observed similar biological actions of synthetic secretin administered to dogs. 22 In the present study, a similar dose of secretin, however, failed to inhibit maximal acid secretion stimulated by either histamine or pentagastrin. No attempt was made in this study to observe the effect of larger doses of secretin on acid secretion. It is possible that a higher dose of the hormone would inhibit maximal secretion of acid as was observed in dogs. 4 In addition, we were unable to study the effect of cholecystokinin in a dose of 1 U per kg on maximal acid secre- --:- IV PNTAGASTRIN (.12lJg/Kg/Hr.) 'e" OIl a w "1..--.! Q..., 1 CCK,(1u/Kg)-- u or «Saline --_. c 3 'e OIl IT W.! 2 :; o IV HISTAMIN ACID PHOSPHAT (.2mg/Kg/Hr; P<.Ol or Saline O l L Time In Minutes FIG. 7. ffect of intravenous administration of cholecystokinin (CCK) or saline on mean gastric secretion of acid in 5 subjects stimulated by histamine acid phosphate in a dose of.2 mg per kg per hr. tion. The present investigation has demonstrated, however, that both hormones can inhibit acid secretion stimulated by submaximal doses of histamine or pentagastrin in man. Recently, Stening et al. 23 reported that cholecystokinin administered intravenously to dogs in a dose of 4 U per kg per hr or in a single rapid injection in a dose of 4 U per kg resulted in 9% inhibition of maximal gastric secretion stimulated by gastrin. In contrast, the effect of cholecystokinin on acid secretion stimulated by histamine was found to depend upon the dose of histamine ad.ministeredo Acid secretion stimulated by low doses of histamine was inhibited and secretion initiated by intermediate doses of histamine was augmented. The response to maximal doses of histamine was not altered by cholecystokinin. Biological actions similar to those produced by secretin and cholecystokinin have been observed in dogs 4, 24 and man 25, 26 following the intraduodenal introduction of acid, fats, and hypertonic solutions. Johnston and Duthie observed.. p<.oi also that duodenal acidification in man inhibited gastric secretion of acid stimu lated by either histamine or gastrin Time In Minutes FIG. 6. ffect of intravenous administration of cholecystokinin or saline on mean gastric secretion of acid in 6 subjects stimulated by pentagastrin in a dose of.12 Ilg per kg per hr. Thus, both secretin and cholecystokinin have inhibitory effects on motor and secretory functions of the stomach in man as well as in dogs. In addition, both hormones help to maintain alkalinity of the

7 826 CHY T AL. Vol. 58, No. 6 duodenal contents by increasing flow of both pancreatic juice and hepatic bile and by inducing evacuation of concentrated bile from the gallbladder, an action initiated exclusively by cholecystokinin. All of the effects of these two hormones observed in this study could be important in the regulation of normal physiological activity as well as in the control of excessive duodenal acidification. Whether the amounts of secretin and cholecystokinin normally released from the upper intestinal mucosa are sufficient to produce inhibition of gastric acid secretion during the physiological events of digestion is yet to be determined. Moreover, the relationship between secretin and cholecystokinin as well as the possible presence of one or more chalones other than these two hormones in the intestinal mucosa are problems which remain to be clarified. RFRNCS 1. Greenlee, H. B.,. H. Longhi, J. D. Guerrero, T. S. Nelsen, A. L. IBedri, and L. R. Dragstedt Inhibitory effect of pancreatic secretin on gastric secretion. Amer. J. Physiol. 19: Jordan, P. H., Jr., and N. D. Petersen ffects of secretin upon gastric secretion. Ann. Surg. 156: McIlrath, D. C., and G. A. Hallenbeck Comparison of gastric inhibitory properties of two secretin preparations. Amer. J. Physiol. 26: Wormsley, K. G., and M. 1. Grossman inhibition of gastric acid secretion by secretin and endogenous acid in the duodenum. Gastroenterology 47: Gillespie, 1.., and M. 1. Grossman inhibitory effect of secretin and cholecystokinin on Heidenhain pouch responses to gastrin extract and histamine. Gut 5: Dinoso, V., Jr., W. Y. Chey, J. Hendricks, and S. H. Lorber Intestinal mucosal hormones and motor function of the stomach in man. J. Appl. Physiol. 26: Chey, W. Y., S. Kosay, J. Hendricks, and S. H. Lorber ffect of secretin on the motor activity of the stomach and Heidenhain pouch in dogs. Amer. J. Physiol. 217: Ivy, A. C., and. Oldberg A hormone mechanism for gall bladder contraction and evacuation. Amer. J. Physiol. 86: Harper, A. A., and H. S. Raper Pancreozymin, a stimulant of the secretion of pancreatic enzymes in extracts of the small intestine. J. Physiol. (London) 12: Bodi, B. S., J. P. Govaerts, J. P. Master, and 1.. Gillespie Inhibition of gastric acid secretion by intravenous cholecystokinin extract. Scand. J. Gastroent. 2: Johnson, L. P., J. C. Brown, and D. F. Magee ffect of secretin and cholecystokininpancreozymin extracts on gastric motility in man. Gut 7: Johnson, L. P., and D. F. Magee Cholecystokinin-pancreozymin extracts and gastric motor inhibition. Surg. Gynec. Obstet. 121: Jorpes, J.., V. Mutt, S. Magnusson, and B. B. Steele Amino acid composition and N-terminal amino acid sequence of porcine secretin. Biochem. Biophys. Res. Commun. 9: Jorpes, J.., and V. Mutt. The gastrointestinal hormones, secretin and cholecystokinin-pancreozymin. Ann. Intern. Med. 55: Jorpes, J The isolation and chemistry of secretin and cholecystokinin. Gastroenterology 55: Hunt, J. N., and M. T. Knox The regulation of gastric emptying of meals containing citric acid and salts of citric acid. J. Physiol. (London) 163: Scheffe, H The analysis of variance. J. Wiley and Sons, Inc., New York. 18. Preshaw, R. M., and M. 1. Grossman Stimulation of pancreatic secretion by extracts of the pyloric gland area of the stomach. Gastroenterology 48: Preshaw, R. M., K. Adashek, A. R. Cooke, and M. 1. Grossman Failure of urecholine to potentiate the pancreatic response to exogenous stimuli. Proc. Soc. xp. Biol. Med. 119: Magee, D. F., and N. Nakamura Action of pancreozymin preparations on gastric secretion. Nature (London) 212: Kamionkowski, M., S. Grossman, and B. FleshIer The inhibitory effect of secretin on brothstimulated gastric secretion in human subjects. Gut 5: Vagne, M., G. F. Stening, F. P. Brooks, and M. 1. Grossman Synthetic secretin: comparison with natural secretin for potency and spectrum of physiological actions. Gastroenterology 55: Stening, G. F., L. R. Johnson, and M. 1. Grossman ffect of cholecytokinin and caerulein on gastrin and histamine-evoked gastric secretion. Gastroenterology 57: 44-5.

8 June 197 FFCT OF SCRTIN AND CHOLCYSTOKININ Wang, C. G., and M. I. Grossman Physiological determination of the release of secretin and pancreozymin from intestine of dogs with transplanted pancreas. Amer. J. Physiol. 164: Shay, H. J., J. Gershon-Cohen, and S. S. Fels The role of upper small intestine in the control of gastric secretion: the effect of neutral fat, fatty acid and soaps: the phase of gastric secretion influenced and the relative importance of the psychic and chemical phases. Ann. Intern. Med. i3: Shay, H., J. Gershon-Cohen, and S. S. Fels A self-regulatory duodenal mechanism for gastric acid control and an explanation for the pathologic gastric physiology in uncomplicated duodenal ulcer. Amer. J. Dig. Dis. 9: Johnston, D., and H. L. Duthie ffect of acid in the duodenum on histamine-stimulated gastric secretion in man. Gut 5: Johnston, D., and H. L. Duthie Inhibition of gastric secretion in human stomach. Lancet 2: