Effects of Fundic Distention on Pentagastrin-Stimulated Gastric Acid Secretion in Man

73:447-452, 1977 Copyright © 1977 by the American Gastroenterological Association

Vol. 73, No.3

GASTROENTEROLOGY

Printed in U.SA .

EFFECTS OF FUNDIC DISTENTION ON PENTAGASTRINSTIMULATED GASTRIC ACID SECRETION IN MAN ULRICH GROTZINGER, M.D., STIG BERGEGARDH, M.D., AND LARS 0LBE, M.D. University of Goteborg, Department of Surgery II, Sahlgren's Hospital , Goteborg, Sweden

The acid secretory effect of combined stimulation with balloon distention of the fundus and body of the stomach and intravenous infusion of pentagastrin has been studied in patients with duodenal ulcer (DU) and in healthy subjects. In 8 nonoperated DU subjects and in 5 DU patients subjected to proximal gastric vagotomy, low grade fundic distention moderately enhanced the acid output evoked by a threshold dose of pentagastrin. Fundic distention with a balloon volume eliciting a maximal acid response to distention either left unchanged or suppressed the maximal acid secretory rate produced by pentagastrin in 7 nonoperated and 6 vagotomized DU patients and in 5 healthy subjects. The heterogeneous secretory effects of maximal stimulus combination suggest that fundic distention has a complex action on acid secretion eliciting a hitherto unknown inhibitory effect as well as a cholinergic activation of the parietal cell area. This complex action may explain the failure of fundic distention to augment markedly the action of pentagastrin in the present study. Cholinergic activation of the oxyntic gland area and gastrin action are two main stimuli in the physiological regulation of gastric acid secretion. The concept of neurohormonal secretory control as put forward by Uvnas3 involves a pronounced synergistic action between these two stimulants. In man, the significance of neurohormonal interaction is controversial,
Subjects Studied Patients with Duodenal Ulcer (DU) Experiments with fundic distention and pentagastrin infusion were designed to study the interaction at low and high intensity of combined stimulation before and after vagotomy. Consequently, four groups of male patients were studied. The diagnosis of chronic duodenal ulcer diseases was made on the history as well as by endoscopy and/or barium meal examination. No patient presented with any signs or symptoms suggesting gastric outlet obstruction. Proximal gastric vagotomy (PGV) without a drainage procedure was performed electively 10 and no complication occurred. Group A. This consisted of 8 nonoperated patients with a mean age of 35 years (range 23 to 59). Stimulation with pentagastrin and fundic distention was just above threshold for each of the two stimulants. Group B. In 7 nonoperated patients with a mean age of 44 years (range 27 to 56), the stimulation with pentagastrin and fundic distention was maximal for both stimuli. Group C. Five patients with a mean age of 49 years (range 31 to 59) were studied after PGV using just suprathreshold stimulation for both pentagastrin infusion and fundic distention. Group D. Six patients with a mean age of 45 years (range 27 to 55) had been subjected to PGV. Stimulation was maximal with each of the two stimulants.

Healthy Subjects Group E. Four men and 1 woman with a mean age of 23 years (range 22 to 24) and without any history of gastrointestinal illness were studied using maximal 447

448

GROTZINGER ET AL.

stimulation with pentagastrin and fundic distention. Care was taken to discuss the purely scientific purpose of the experiments with each volunteer and informed consent was obtained. The investigation has been ai?p.roved b;y the Ethical Committee of the Faculty of Med1cme, Umversity of Goteborg. Methods

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determination of acid output have been published elsewhere. 9 Experiments were performed on separate days not more than 3 weeks apart and not earlier than 1 month after operation. Any anticholinergic medication was discontinued at least 2 days before tests. After fasting overnight, the subjects were seated in a semirecumbent position and a double lumen nasogastric tube was passed, its tip being located in the antrum as verified by fluoroscopy. Residual gastric contents were aspirated and discarded. Throughout the experiments, the stomach was perfused with an aqueous solution of phenol red, the marker being delivered through a small caliber tube at a constant rate of 225 ml per 15 min. Gastric contents were continuously aspirated with an electrically driven pump giving intermittent subatmospheric pressure once per second and having the aspiration efficiency of about 3000 ml per 15 min. The aspirate was divided into 15-min samples and the volume and pH were recorded. From each sample a 100-ml aliquot was titrated potentiometrically against 0.1 mole per liter sodium hydroxide to pH 7.0. In each sample, the phenol red concentration was assessed spectrophotometrically and the percentage marker recovery was calculated. This permitted an estimation of the amount of acid secreted and all values given below are thus corrected for losses through the pylorus. Statistical evalutation. Student's t-test for paired data, the Wilcoxon matched-pairs signed-ranks test and the MannWhitney U-testlt were used when assessing the effect of stimulus combination. Assuming that the effect of low sub maximal stimulation with fundic distention is simply additive to the effect of low submaximal stimulation with pentagastrin, the null hypothesis to be tested is

Fundic distention . Details of the method for graded distention of the oxyntic gland area in man have been published previously. 9 A thin-walled rubber balloon was attached to a nasogastric tube and placed in the gastric fundus. The nasagastric tube was taped to the nose. The position of the air-filled balloon was easily identified and frequently checked by fluoroscopy. The balloon was never observed to migrate from the fundus and body of the stomach. Basal secretion was collected for 1 hr and thereafter the balloon was inflated with air to vo~umes of 150, 300, and 600 ml, each volume being maintamed for 1 hr. The gastric acid responses to graded fundic distention in healthy subjects and in DU patients before and after PGV have been presented elsewhere.9 • 10 In previous experiments we found that distention volumes exceeding 600 ml caused pain or nausea and dampened the secretory rate. In the present series, no subject experienced abdominal discomfort or nausea during distention. The smallest balloon volume resulting in a rise of acid output over basal levels as well as the balloon volume causing the largest obtainable acid response were determined in each subject with the exception of group D. The peak acid output evoked by fundic distention (PAOctist) denotes the mean of the two highest consecutive 15-min values observed during graded fundic distention. AOctist = AOpg + ctist -AAOpg (1) Pentagastrin infusion. After collection of basal secretion for 1 hr, graded doses of gastrin pentapeptide (Peptavlon, ICI) AOctist is the acid output during fundic distention alone with a were administered by constant intravenous infusion. In order balloon volume representing low submaximal stimulation. to determine the doses resulting in threshold and maximum AOpg + ctist is the acid output during infusion of a low submaxiacid responses, 0.5, 1.6, 9.0, 30, 90, and 300 JLg of pentagastrin mal dose of pentagastrin and concomitant fundic distention per hr was given in this order, each dose being infused for 45 with the balloon volume producing AOctist· AAOpg is the inmin. These determinations were carried out in all subjects. crease over basal caused by a low submaximal pentagastrin The peak acid output evoked by pentagastrin (PAOpg) is de- dose on the assumption that pentagastrin responses are addi12 fined as the mean ofthe two highest consecutive 15-min values t~ve to basal acid output. The following criterion of potentiation has been adopted. The response to combination of the observed during intravenous infusion of pentagastrin. Pentagastrin infusion and fundic distention. On another stimuli, each producing maximal stimulation exceeds the 13 ' day, basal secretion was collected for 1 hr. Pentagastrin was maximal response to either stimulus alone. then infused at a constant rate for 3.5 hr. Ninety minutes after Results the start of the pentagastrin infusion, when a stable level of Group A. (Combination of threshold stimulations in 8 secretion had been achieved, the fundic balloon was inflated for 1 hr after which the air was withdrawn. Acid secretion was nonoperated DU patients; table 1, fig. 1.) Fundic distenthen determined for another hour. In experiments with tion with 150 ml evoked an acid response amounting to threshold stimulation, the lowest pentagastrin dose and the 39 ± 5% (mean ± SE) of the maximun response to smallest balloon volume were used which had caused a slight pentagastrin while PAOctist reached 63 ± 6% of PAO increase in acid output over basal levels in the separate tests. The acid output elicited by the combination of a thre;h~ For maximal stimulation, the doses and volumes chosen were those which in the individual case had resulted in the highest old pentagastrin dose (0.5 or 1.6 1-Lg per hr) and fundic acid responses attainable with either stimulant. In the pa- distention with 150 ml was slightly larger than the tients of group D, the fundus was distended with the largest respon~e to 150-ml. distention alone. When calculating balloon volume easily tolerated by the subject (600 ml in 5 acco~dmg to equatwn (1), the acid increase evoked by the JUst suprathreshold pentagastrin dose subtracted patients, 450 ml in 1 case). Insulin tests. In patients subjected to PGV, postoperative from the acid output observed during combined stimulainsulin tests were performed on a separate day. The mean tion was not significantly different from the acid reinterval after surgery was 1.5 months in group C and 6 months sponse to 150-ml fundic distention. in group D. Basal secretion was collected for at least 90 min. Group B. (Combined maximal stimulation in 7 nonAfter intervenous injection of insulin (0.2 IU per kg), acid DU patients; table 1, fig. 2.) The peak secreoperated secretion was determined for 2 hr. All subjects displayed clear symptoms of hypoglycemia. Qualitative interpretation of the tory fraction of PAOpg obtained with fundic distention tests using multiple criteria and calculation of the peak postin- was 52 ± 7%. During maximal pentagastrin stimulation sulin increase over mean basal acid output (AP ACOins) were the fundus was distended with the balloon volume which had been found to produce P AOctist in the individmade as previously described. 10 Determination of acid secretion . Details of the methods for ual case. The addition of fundic distention did not sig-

September 1977 TABLE 1.

Secretory data from experiments with combined intravenous infusion of pentagastrin and fundic distention and from control studies with either stimulant alone. a Combination of pentagastrin and fundic distention Experimental group Basal

A. 8 nonoperated DU< patients; B. C.

D. E.

449

FUNDIC DISTENTION AND PENTAGASTRIN INFUSION IN MAN

threshold stimulation in distention experiments 7 nonoperated DU patients; maximal stimulation 5 DU patients after PGV;" threshold stimulation in distention experiments 6 DU patients after PGV; maximal stimulation 5 healthy subjects; maximal stimulation

Pentagastrin

Pentagastrin and distention

Fundic distention Basal

Distention

Pentagastrin distention, PAO""

•

3.17 ± 0.57

4.45 ± 0.66

5.81 ± 0.81

2.45 ± 0.57

4.89 ± 0.70

12.43 ± 0.92

1.62 ± 0.53

11.85 ± 1.05

10.80 ± 1.24

1.29 ± 0.49

6.48 ± 1.08

12.69 ± 1.01

0.36 ± 0.29

1.16 ± 0.34

2.82 ± 0.96

0.22 ± 0.12

0.57 ± 0.34

7.06 ± 0.70

0.64 ± 0.25

7.59 ± 1.55

6.47 ± 1.56

ND "

ND

8.07 ± 1.64

1.46 ± 0.51

9.39 ± 1.21

9.41 ± 1.63

1.30 ± 0.36

4.51 ± 0.73

10.55 ± 1.05

a The values for acid output are given in millimoles per 15 min and represent means (±SE) of the last two 15-min values in the respective steps of the experiments. b PAO""' pea k acid output evoked by pentagastrin. c DU, duodenal ulcer. d PGV, proximal gastric vagotomy. • ND, not determined. Fundic disttansion 150 ml

Acid output mm olt15 min

F undiC diSi tfiS IOfl

=

Fundic distt>nsion

~

~

8

Acid output mmoiJ15min

150-m/ fundic

"

B

12

distension alone-

6

10

A"d oulpu r mmoll.iSm•n

A

2

2

12 15 - min pt>riods

12

:: 1 ~

16

bL_:_ ~

8

11

16

clLY '

8

15 -m~t~

11 16 p r nods

16

15- min pt>riods

FIG. 1. Effect of low grade fundic distention on the acid output evoked by intravenous infusion of a threshold dose of pentagastrin in 8 nonoperated duodenal ulcer (DU) patients (group A). Column on right side ofgraph, mean of the last two 15-min values during fundic distention alone. In this and the following figures, the vertical bars indicate the standard errors of the means.

nificantly alter the mean secretory rate brought about by maximal pentagastrin stimulation (fig. 2A). However, the effect of combined maximal stimulation appeared to be heterogeneous. In 5 subjects (fig. 2B) the secretory level obtained with a maximal pentagastrin dose remained essentially unchanged during fundic distention, but in 2 patients distention markedly suppressed the pentagastrin-induced acid output by 36 and 47%, respectively (fig. 2C). In these two subjects, the acid response to 600-ml distention alone amounted to 6.26 mmoles per 15 min or 50% of PAOpg· Group C. (Combined threshold stimulation after vagotomy.) In 5 DU patients subjected to PGV, all criteria of the postoperative insulin test were negative and .!lPAOins amounted to 0.02 ± 0.01 mmole per 15 min, indicating complete vagotomy. PAOctist was 33 ± 12% of the postoperative PAOpg· Fundic distention with 150 ml did not stimulate acid secretion. A balloon volume of300 ml elicited only a small acid response (0.57 ± 0.34

FIG. 2. Combined maximal stimulation with fundic distention and intravenous pentagastrin. A , acid secretory response in 7 nonoperated duodenal ulcer (DU) patients (group B) . In 5 of these subjects the maximal acid response to pentagastrin remained unchanged during fundic distention (B) , whereas marked inhibition was observed in 2 of the 7 patients (C) .

mmole per 15 min or 7 ± 3% of the postoperative PAOpg) but enhanced the secretory rate produced by a threshold (1.6 or 9 f.Lg per hr) pentagastrin dose (table 1, fig. 3). However, the acid increase over basal induced by pentagastrin subtracted from the acid output during combined stimulation was not significantly different (P > 0.1) from the acid response to 300-ml distention alone when calculated according to equation (1). Group D. (Combination of maximal stimulations after vagotomy.) Six patients with DU were examined after PGV. The results of insulin tests suggested that vagotomy was complete, .!lPAOins amounting to 0.08 ± 0.04 mmole per 15 min. During maximal background stimulation with pentagastrin, the fundic area was distended with the largest balloon volume that was easily tolerated by the patient. Fundic distention did not significantly change the mean secretory rate evoked by a maximal pentagastrin dose (table 1, fig. 4), but again the individual findings were heterogeneous. In 2 patients, fundic distention markedly dampened the penta-

450

GROTZINGER ET AL .

gastrin-induced secretory rate (reductions 38 and 41 %), whereas no change was observed in the remaining 4 subjects. Group E. (Combined maximal stimulation in 5 healthy subjects; table 1, fig. 5.) PAOdist reached 42 ± 4% ofPAOpg· In the experiments with combined maximal stimulation, fundic distention with the balloon volume eliciting PAOdist in the control studies did not significantly change the mean maximum acid secretory Fundic distension 300 ml ~

300- ml fundi c distension alonE>

12

16

15- min periods

FIG. 3. Effect of low grade fundic distention on the acid output elicited by a low dose of intravenous pentagastrin in 5 vagotomized duodenal ulcer (DU) patients (group C). Column on right side of diagram, mean of the last two 15-min values observed during fundic distention alone.

Acid output mmo/115min

Fundic distension ~ ~

15- min periods

FIG. 4. Combined maximal stimulation with fundic distention and intravenous pentagastrin in 6 duodenal ulcer (DU) patients after proximal gastric vagotomy (group D).

Acid output mmoyl5min

Fundic distension ~~~'%1

15-min periods

FrG. 5. Combined maximal stimulation with fundic distention and intravenous infusion of pentagastrin in 5 healthy subjects (group E).

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level evoked by pentagastrin. However, in 1 male subject a suppression of the maximal secretory rate by 48% was observed during fundic distention. Discussion In man, fundic distention activates an atropine-sensitive, probably cholinergic mechanism for stimulation of the oxyntic glands. 10 In accordance with mechanisms established in the dog, I 4- w the acid-stimulatory action of fundic distention in man appears to be conveyed by two neural pathways: vagovagal and intramural reflexes, the latter remaining operative after complete vagotomy.10 In dog experiments, the acid response to fundic distention has been shown to be partly dependent on intact innervation of the pyloric antrum17 and an oxynto-pyloric distention reflex for release of gastrin has been established 18 in addition to a similar antral mechanism.19 In man, the existence of gastrin-releasing distention reflexes is doubtful inasmuch as distention of the whole stomach in healthy subjects20 and antr;1l distention in DU patients21 have not increased plasma gastrin levels. Furthermore, fundic distention failed to produce significant plasma gastrin increments in patients with DU. 22 The acid response to distention of denervated canine fundic pouches is markedly augmented by exogenous gastrin or histamine in doses having low secretory effects when given alone. 14· 23 In analogy, vagally released gastrin was found to stimulate acid secretion from the canine Heidenhain pouch if the collection method involved slight distention of this pouch,24 whereas no secretory effect was observed when distention was avoided. 25 Thus, there is no doubt that gastrin and distention-induced cholinergic activation of the oxyntic gland area act synergistically in the dog, but the effect of interaction in the intact stomach2B is not quite clear. It has also been shown in antrectomized Pavlov pouch dogs that cholinergic activation of the oxyntic glands by sham feeding is potentiated by threshold doses of gastrin,27· 28 and that a further increase of the gastrin dose in the submaximal range has only an additive secretory effect. 29 In the present experiments, threshold stimulus combination of pentagastrin and fundic distention in DU patients resulted in an additive secretory effect. Mter complete PGV, fundic distention may be looked upon as a means to increase endogenous cholinergic activity from a presumably minimal basal drive. 10 Thus, the experimental design aiming at an initiation of cholinergic activity during pentagastrin infusion failed to provide evidence for potentiation between these two stimulants in man. The combination of maximal stimulation with pentagastrin and fundic distention had heterogeneous effects on acid output both in DU patients and in healthy subjects. In the majority of subjects, fundic distention with a balloon volume known to elicit the highest individual acid response obtainable with distention did not change the secretory rate produced by a maximal dose of intravenous pentagastrin. Surprisingly, unequivocal inhibition occurred in 5 of18 persons (2 DU patients with an intact stomach, 2 DU patients

September 1977

FUNDIC DISTENTION AND PENTAGASTRIN INFUSION IN MAN

after PGV, and 1 healthy subject). It may be pointed out that no subject experienced abdominal discomfort or nausea during distention, so that this inhibition cannot be explained by nonspecific suppression associated with very large balloon volumes. 9 Our observations are at variance with a claimed potentiation of maximal pentagastrin-stimulated acid secretion by gastric distension. 30 In that study, distention of the stomach was achieved by a glucose test meal and the acid output was calculated indirectly. Under experimental conditions involving an increased cholinergic drive on the innervated human oxyntic gland area achieved by fundic distention, sham feeding, 5 or cholinomimetic drugs, 31 or when after PGV the cholinergic drive is increased by fundic distention or cholinomimetics, 8 the evidence has failed to support the concept that cholinergic activation of the parietal cells potentiates the action of humoral stimulants in man with the exception of one study. 30 However, this concept has received support also in another experimental situation: administration of carbacholine potentiated the postvagotomy maximal acid response to histamine in previously antrectomized DU patients and restored it to the prevagotomy level. 7 The unexpected finding in some subjects of the present series that fundic distention caused an unequivocal inhibition of the pentagastrin-induced maximal secretory rate appears to favor the view that fundic distention has a more complex action on acid secretion than was expected. It may produce cholinergic stimulation of the oxyntic glands and simulatneously elicit a hitherto unknown inhibitory effect. The hypothesis of such a distention-induced inhibitory mechanisms is supported by the observations that balloon distention of the pyloric antrum invariably suppressed basaP2 and pentagastrinstimulated33 acid secretion in healthy subjects. The postulated inhibitory mechanism seems to be independent of vagal innervation of the fundic region since this phenomenon was also observed in 2 patients after complete PGV. The effect of distention on pentagastrinstimulated acid output in man may then reflect the interaction between gastrin, cholinergic activation of the oxyntic gland area as well as a distention-induced inhibitory mechanism, leaving the pure interaction between the two stimuli open to question. Under this provision, the actual balance of stimulation and inhibition would determine the net secretory effect. Hence, the present observations could be reconciled with the occurrence of potentiation between gastrin action and cholinergic activation of the oxyntic glands as also supported by dog data 14 • 23 · 27· 28 and by cholinomimetic drug stimulation in patients subjected to antrectomy and subsequent vagotomy. 7 REFERENCES 1. Bergegardh S, Olbe L: Gastric acid response to distension of the stomach in man (abstr). Acta Physiol Scand 82:6A, 1971 2. Bergegardh S, Olbe L: Gastric acid response to distension of the antrum and the corpus-fundus region in man (abstr). In Gastrointestinal Hormones and Other Subjects. Edited by E Hess Thaysen. Copenhagen, Munksgaard, 1971, p 29-31

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3. Uvnas B: The part played by the pyloric region in the cephalic phase of acid secretion . Acta Physiol Scand (suppl13)4:1-86, 1942 4. Elder JB, Gillespie G, Gillespie IE, eta!: The effect of subthreshold doses of pentagastrin on the acid response to insulin in duodenal ulcer subjects before and after truncal vagotomy. Clin Sci 43:201-207, 1972 5. Knutson U, Olbe L: The effect of exogenous gastrin on the acid sham feeding response in antrum-bulb-resected duodenal ulcer patients. Scand J Gastroentenol 9:231-238 , 1974 6. Makhlouf GM: Dose-response curves to gastric secretory stimulants in man. In International Encyclopedia of Pharmacology and Therapeutics, Section 39 A, Pharmacology of Gastrointestinal Motility and Secretion, vol 1. Edited by P Holton. Oxford, England, Pergamon Press, 1973, p 173-194 7. Broome A: Mechanism of the vagotomy-induced suppression of the maximal acid response to histamine in duodenal ulcer patients. Scand J Gastroenterol 2:275-282, 1967 8. Roland M, Berstad A, Liavag 1: Acid and pepsin secretion in duodenal ulcer patients in response to graded doses of pentagastrin or pentagastrin and carbacholine before and after proximal gastric vagotomy. Sca nd J Gastroenterol 9:511-518, 1974 9. Grotzinger U, Bergegardh S , Olbe L: The effect of fundic distension on gastric acid secretion in man. Gut 18:105-110, 1977 10. Grotzinger U, Bergeardh S, Olbe L: The effect of atropine and proximal gastric vagotomy on the acid response to fundic distension in man. Gut (in press) 11. Siegel S: Nonparametric Statistics for the Behavioral Sciences. International Student Edition. Tokyo, McGraw-Hill Kogakusha 12. Bergegardh S, Broma n G, Knutson U, et a!: Gastric acid responses to graded i.v. doses of pentagastrin and histalog in peptic ulcer patients before and after antrum-bulb resection. Scand J Gastroenterol 11:337-346, 1976 13. Gillespie IE, Grossman MI: Potentiation between Urecholine and gastrin extract and between Urecholine a nd histamine in the stimulations of H eidenhain pouches. Gut 5:71-76, 1964 14. Grossman MI: Stimulation of secretion of acid by distention of denervated fundic pouches in dogs. Gastroenterology 41:385-390, 1961 15. Grossman MI: Secretion of acid and pepsin in response to distention of vagally innervated fundic gland area in dogs. Gastroenterology 42:718-721 , 1962 16. Harper AA , Kidd C, Scratcherd T: Vago-vagal reflex effects on gastric and panceratic secretion and gastrointestinal motility. J Physiol (Lond) 148:412-436, 1959 17 . Preshaw RM: Influence of the antrum on the acid response to distension of the body of the stomach in dogs. Can J Physiol Pharmacol 48:661-669 , 1970 18. Debas HT, Walsh JH , Grossman Ml: Evidence for oxyntopyloric reflex for release of antral gastrin. Gastroenterology 68:687-690, 1975 19. Debas HT, Konturek SJ, Walsh JH, et al: Proof of a pylorooxyntic reflex for stimulation of acid secretion. Gastroenterology 66:526-532' 1974 20. Schrumpf E, Stadaas J: Effect of gastric distension on motility and plasma gastrin concentration before and after secretin administration. Scand J Gastroenterol 9:119-122, 1974 21. Bergegardh S, Nilsson G, Olbe L: The effect of antral distention on acid secretion and plasma gastrin in duodenal ulcer patients. Scand J Gastroenterol 11:475-479 , 1976 22. Grotzinger U, Rehfeld JF, Olbe L: Is there an oxnto-pyloric reflex for release of gastrin in man? Gastroenterology (in press), 1977 23. Magee DF, Hu CY: Heidenhain pouch distension as a stimulus for acid and pepsin secretion. Ann Surg 182:121-123, 1975 24 . Pe Thein M, Schofield B: Release of gastrin from the pyloric antrum following vagal stimulation by sham feeding in dogs. J Physiol (Lond) 148:291-305, 1959

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29. Olbe L, Ridley PT, Uvnas B: Effects of gastrin and histamine on vagally induced acid and pepsin secretion in antrectomized dogs. Acta Physiol Scand 72:492-497, 1968 30. Cooke AR: Potentiation of acid output in man by a distention stimulus, Gastroenterology 58:633-637 , 1970 31. Roland M: Gastric secretory response to graded doses of pentagastrin alone or in combination with carbacholine in unoperated duodenal ulcer patients. Scand J Gastroenterol 10:603-608, 1975 32. Bergegardh S, Olbe L : Gastric acid response to antrum distension in man. Scand J Gastroenterol 10:171-176, 1975 33 . Olbe L, Bergegardh S, Grotzinger U: Stimulation and inhibition of gastric acid secretion in man by gastric distension (abstr). Gastroenterology 72:820, 1977