Grossman, 1975). Chemical ingredients of food, particularly the peptides and amino

J. Physiol. (1979), 295, pp. 229-239 229 With 4 text-ftgure8 Printed in Great Britain ROLE OF GASTRIC ANTRUM IN GASTRIC AND INTESTINAL PHASES OF GASTRIC SECRETION IN DOGS BY A. FOKINA, S. J. KONTUREK, N. KWIECIEN AND T. RADECKI From the Institute of Phy8iology Medical Academy, Krakow, Poland (Received 25 August 1978) SUMMARY 1. The gastric and intestinal phases of gastric secretions were selectively evoked before and after the removal of the antral mucosa in four dogs provided with a special cannula that allowed complete separation of the stomach and duodenum without interrupting neural connexions between them. 2. The gastric phase induced by 5 % liver extract meal administered into the stomach at various distention pressures (ranging from 0 to 15cm H20) resulted in an increase in acid output to about 56 % of the histamine maximum and in a marked rise in serum gastrin. 3. Following resection of the antral mucosa, the gastric acid response to meal of liver extract was reduced by about 50 % and serum gastrin response was completely eliminated. Exogenous gastrin (G-17) given during the gastric phase induced by such a meal in dogs with antral mucosectomy failed to restore acid output to pre-resection level. 4. Intestinal perfusion of meal of liver extract in graded amounts stimulated gastric acid secretion to about 30% of histamine maximum acid output and raised significantly serum gastrin level. 5. Antral mucosectomy abolished almost completely both gastric acid and serum gastrin response to intestinal meal of liver extract. 6. Exogenous gastrin given during the intestinal meal of liver extract failed to restore acid output to the pre-resection level, suggesting that this procedure greatly reduced the secretary capacity of the oxyntic glands. 7. We conclude that the antral gland area plays an important role in the gastric phase and that it is a prerequisite for the intestinal phase of gastric secretion. INTRODUCTION Food reaching the stomach induces gastric acid secretion by virtue of its physicochemical properties, that is, by activating enteroceptors which are susceptible to mechanical and chemical stimuli. Mechanical stimulation by gastric distention brings about acid secretion by means of several mechanisms such as direct cholinergic (Grossman, 1967) and non-cholinergic (Davidson & Schofield, 1977) activation of the oxyntic glands and neural release of antral gastrin (Grossman, 1967; Debas, Walsh & Grossman, 1975). Chemical ingredients of food, particularly the peptides and amino 0022-3751/79/5470-0702 801.50 1979 The Physiological Society

230 A. FOKINA AND OTHERS acids resulting from peptic digestion of proteins, stimulate acid secretion by direct excitation of the oxyntic glands (Debas & Grossman, 1975; Cieszkowski, Konturek, Obtulowicz & Tasler, 1975) and by releasing gastrin (Debas et al. 1975; Konturek, Tasler, Cieszkowski, Dobrzanska & Wunsch, 1977). Thus, an important component of both mechanical and chemical stimulation of gastric secretion appears to be gastrin released by a meal present both in the stomach and the intestine. This study was undertaken to evaluate the role played by gastrin and the antral mucosa in gastric and intestinal phases induced by distention or chemicals administered either into the stomach or into the duodenum in dogs before and after the removal of the antral mucosa. METHODS Animal preparation Four dogs weighing from 28 to 30 kg were prepared with a double-walled mucosal septum at the pylorus and a gastroduodenal cannula fitted with hollow obturator allowing for intermittent access either to the stomach or the duodenum during tests and free flow of food from the stomach to duodenum between tests (Konturek, Kaess, Kwiecien, Radecki & Teckentrup, 1976). After completing a series of experiments with gastric or intestinal test meals and with bombesin, the animals were reoperated under thiopentone anesthesia. The abdomen was reopened and the distal portion of the stomach was exposed. The vessels supplying this portion were clamped and the longitudinal incision was made midway between gastric curvatures. Then the antral mucosa was completely separated from the muscle layer and excised. The distal fundic mucosa and duodenal mucosa immediately below the pyloric ring were separately closed by suturing so that the body of the stomach was connected to the duodenum only by means of the gastroduodenal cannula. The muscle layers were tightly sutured together and the vessels released from clamps. The resected antral mucosa was examined histologically to assess the completeness of antral mucosectomy. In all dogs the resected mucosa included a zone of the oxyntic gland area on its proximal side and duodenal mucosa on its distal side. After surgery the animals were fed not as usual one meal per day as before the operation but small amounts of liquid food given 4-5 times daily. Four weeks after antral mucosectomy, a series of experiments were performed with gastric or intestinal meals with and without administration of exogenous gastrin or bombesin. Experimental design Secretory studies started about 2-3 weeks after surgery. Food, but not water, was withheld for 18 hr before each test. The interval between tests was at least 48 hr. The stomach was rinsed by irrigation through the cannula and then the hollow obturator was inserted. After a basal period of 30 min during which gastric juice was collected by gravity drainage through the hollow obturator, the test meal was introduced either into the stomach (gastric phase) or into the duodenum (intestinal phase). The test meal consisted of 5 % aqueous solution of liver extract (liver concentrate powder, Reheis Chemical Co., Chicago) or 0-15 M-NaCl solution. The ph of the test meals was adjusted to ph 7 0 by adding sufficiently diluted NaOH or HCl to each meal and the osmolarity was brought to about 350 m-osmole/l. by adding mannitol. Osmolarity was measured by freezing depression with a Fiske osmometer. In studies with the gastric phase, gastric acid output was measured by a modified intragastric titration technique described previously (Konturek et al. 1976; Konturek, Rayford & Thompson, 1977). A barostat device of 500 ml. volume was used to maintain constant intragastric pressure. The point at which the cannula of the gastric fistula disappeared in the abdomen was taken as the zero reference point for pressure measurement. Distending pressure was expressed as the difference in height between this point and the fluid level in the barostat. The adequacy of the barostat in maintaining the pressure was checked by measuring the actual pressure in the gastric lumen using the sensing device connected via a perfused tube to a transducer and a Sanborn recorder. The level of the barostat was adjusted to the zero position and intragastric titration was continued for six successive 15 min periods to reach a plateau of acid output. The barostat was

GASTRIC ANTRUM AND GASTRIC SECRETION then successively raised to 5, 10 and 15 cm, intragastric titration being made for 60 min at each pressure level. The response was taken as the sum of acid outputs in the last two 15 min periods at each pressure level. The intestinal phase was evoked by intraduodenal infusion of a test meal (5 % liver extract or 0-15 M-NaCl solution) adjusted to ph 7*0 and an osmolarity of 350 m-osmole/l. The infusion rate was increased twofold every 60 min so that amounts could be delivered that varied from 60 to 480 ml./hr in 1 day's test. Gastric juice was collected by simple gravity drainage, and the acid output was determined in each sample by the method described previously. The response was taken as the sum of acid outputs in the last two 15 min periods at each infusion rate. In a separate series of experiments gastric secretion was stimulated by bombesin (kindly supplied by Professor Erspamer, Rome, Italy). The peptide was infused intravenously into fasted dogs in graded doses ranging from 62 to 1000 ng/kg. hr. The dose level was doubled every 60 min and the acid response was taken as the sum of acid outputs in the last two 15 min periods in each dose level. In addition, the peptide was given for 1 hr period in a dose of 250 ng/kg. hr during gastric or intestinal phase stimulation by a meal of liver extract when gastric acid secretion reached a well sustained plateau. In dogs with antral mucosa removed, the test with gastric and duodenal meals as well as with bombesin were repeated. In addition, a series of experiments with gastric and intestinal liver extract meals were performed while dogs were reciving i.v. infusion of a constant dose of pure natural gastrin I (G-17) (gift from Professor R. A. Gregory). In tests with the gastric meal, gastrin was used in a dose of 150 p-mole/kg. hr and in tests on the intestinal phase in a dose of 50 p-mole/kg. hr. These particular doses were selected to reproduce the rise in serum gastrin level observed before antral mucosectomy during the gastric and intestinal phases. To minimize differences in the stomach size from dog to dog, gastric acid responses to the gastric or intestinal meals and to bombesin infusion before and after the removal of the antral mucosa were expressed as a percentage of the maximal response to histamine. The measurements of the histamine maximum were performed before and after antral mucosectomy in each dog. For this purpose, histamine was infused intravenously in a dose of 320 /csg/kg. hr for a 90 min period and the acid output during the last 60 min period was taken as histamine maximum acid output. Radioimmunoa88ay In all tests, blood samples were drawn for serum gastrin determinations (Yalow & Berson, 1970) under basal conditions and following gastric or intestinal meals and bombesin infusion. Antiserum. to gastrin was obtained by immunizing rabbits with synthetic human gastrin I (G-2-17) (I.C.I., England) covalently coupled to bovine serum albumin according to McGuigan (1968) and used in a final dilution of 1:100,000. This antiserum binds all known molecular forms of gastrin (G.14, G-17 and G-34) with equimolar potency. Monoiodinated synthetic human gastrin I (G-17) was used as tracer and G-17 as standard. The separation of antibody-bound from free hormone was carried out by dextra-coated charcoal and the labelled free and bound hormone was counted in an automatic gamma scintillation counter (Wallach, LKB, Sweden). All determinations were made in duplicate. The immunoassay system was sufficiently sensitive to detect serum gastrin, 5 pg/ml. Intra-assay variation was 9% and interassay variation was 16 %. Statistical procedure The difference between the acid outputs and serum gastrin levels in gastric or intestinal phases and following bombesin administration before and after the removal of antral mucosa was determined by a t test for paired values (Siegel, 1956). A P value of less than 0 05 was considered statistically significant. RESULTS Administration into the intact stomach of 5 % meal of liver extract adjusted to ph 7 0 produced an increase in acid output which achieved a peak at 5 cm H20 of gastric distention pressure and reached about 56 % of the histamine-induced maximal 231

232 A. FOKINA AND OTHERS acid output. The mean (± s.x. of mean) value of histamine maximum acid output in dogs with intact antral mucosa was 18*6 + 2-4 m-equiv/30 min. With further rise of intragastric pressure, the acid response to liver extract remained fairly constant. The serum gastrin level increased significantly from a mean basal level of 80 + 6 to about 123 + 21 pg/ml. at 5 cm H20 distention pressure. With further rises of intragastric pressure (10 and 15 cm H20), the serum gastrin level showed a tendency to decline. 180 r 5 % liver extract in stomach Antral mucosa intact E -C14 140 Antral mucosa removed + G -1 7 100 L a -I Antral mucosa removed 60 II X 10 - Antral mucosa.e 8 intact o - t XAntral mucosa + 6 remod + G-17 2 O f Antral mucosa a, 4 removed E 2-0 5 10 15 Pressurecm H210 Fig. 1. Gastric acid and serum gastrin responses to 5% meal of liver extract administered into the stomach at different distention pressures in dogs with intact and removed antral mucosa and with intravenous infusion of a constant dose of gastrin (G-17). En this and subsequent Figures each point is mean of six tests on three dogs (mean ± s.e. of mean). When the stomach was distended at higher pressure (about 15 cm H20), both acid secretion and serum gastrin were depressed and animals showed signs of restlessness and retching. These data are omitted from the presentation (Fig. 1). In control tests, introduction into the stomach of saline at various distention pressures ranging from 0 to 15 cm H20 resulted in a pressure related rise in acid output reaching a peak at 1Ocm H20 distention pressure and amounting to about 40% of the histamine maximum acid output. The serum gastrin level was not significantly changed by gastric distention with saline (Fig. 2). Intestinal perfusion of 5 % liver extract, at gradually increasing rates ranging from 62 to 500 ml./hr, caused a stepwise increase in acid secretion above the basal level reaching a peak at a rate of 250 ml./hr and amounting to about 30% of histamine

GASTRIC ANTRUM AND GASTRIC SECRETION 233 100 Saline in stomach.c 80 - t Antral mucosa intact I V ~ Antral mucosa removed 60 _ I I I 8.E 6 E II Antral mucosa intact I 4 _ < Antral mucosa 4 removed _2- I _ B 0 5 10 15 Pressure cm H20 Fig. 2. Gastric acid and serum gastrin responses to gastric distention with saline at various distention pressures in dogs before and after the removal of antral mucosa. 5 % liver extract in duodenum 100 I Antral mucosa 10 _removed + G-1 7.C 80 _nt I ucaitact 60 I- _ ; Antral mucosa remoe 10 _ Antral mucosa intact E Cr g Antral mucosa EP removed + G-17 _ 2 - ; ; ~ Antral mucosa removed i B 62 125 250 500 ml./hr Fig. 3. Gastric acid and serum gastrin responses to 5% meal ofliver extract administered into the intestines in graded amounts in dogs with intact and removed antral mucosa and with i.v. infusion of a constant dose of gastrin (G-17).

234 A. FOKINA AND OTHERS maximum acid output. Serum gastrin levels rose significantly from the basal value of about 68 + 4 to a peak of 80 + 10 pg/ml. at a perfusion rate of 125 ml./hr (Fig. 3). In control tests with intestinal perfusion of saline at increasing rates (62-500 ml./hr), peak gastric secretion increased at a perfusion rate of 250 ml./hr to about 22 % of histamine maximum acid output but no change in serum gastrin levels was observed. These data are omitted for clarity of presentation. 180- Antral mucosa c 140 17100 - E 6 -~~~ 140 ~~~intact Antral mucosa 7n 60-8- Antral mucosa intact I 4 - E 2r Antral mucosa removed 62 125 250 500 1000 Bombesin (ng/kg.hr) Fig. 4. Gastric acid and serum gastrin responses to bombesin given intravenously in graded doses before and after the removal of antral mucosa. Bombesin infused intravenously in graded doses (62-1000 ng/kg. hr) into fasted dogs produced a marked rise in acid output and serum gastrin levels. The mean peak acid output was achieved at a dose of 250 pg/ml. and it amounted to about 36 % of histamine acid output. Significant elevations in serum gastrin levels above basal values were noted during bombesin infusion but they were not dose-dependent (Fig. 4). Bombesin given intravenously during the gastric or intestinal phase induced by liver extract resulted in a small but significant rise in acid secretion and caused a marked augmentation of serum gastrin level (Table 1). Following the removal of antral mucosa, there was a significant reduction in the histamine maximum acid output. The mean ( ± s.e. of mean) value of this post-antral mucosectomy histamine level was 14*1 + 1.5 m-equiv/30 min. The acid response to gastric 5 % lever extract meal was also suppressed at all levels of distention pressure and the highest acid output, reached at 10 cm H20 distention pressure, amounted to about 42 % of the histamine maximum acid output. Mean basal serum gastrin was significantly lower (61 + 3 pg/ml.) than in dogs with intact antrum and was completely unaffected by the gastric meal of liver extract at any level of distention pressure. Exogenous gastrin (G-17) infused intravenously in a dose (150 p-mole/kg. hr) which raised serum gastrin to a level similar to that observed during the gastric

GASTRIC ANTRUM AND GASTRIC SECRETION meal of liver extract in dogs with an intact stomach, resulted in a significant rise of gastric meal-induced acid output which, however, did not reach a preoperative level (Fig. 1). The removal of antral mucosa caused a marked reduction in the acid response to gastric distention with saline. The peak acid output was attained at 10 cm H20 distention pressure and reached only about 23 % of the histamine acid output. As in tests on dogs with intact stomach, saline distention in animals with removed antral mucosa did not result in any significant change in serum gastrin levels (Fig. 2). TABLE 1. Effect of bombesin on gastric acid and serum gastrin responses to gastric and intestinal LE meal in dogs before and after antral mucosectomy Antral mucosa intact After antral mucosectomy Acid output Serum gastrin Acid output Serum gastrin Type of test (m-equiv/30 min) (pg/ml.) (m-equiv/30 min) (pg/ml.) Gastric liver extract meal 10-5 + 1.3 210 + 32 6.3 + 0 9 65 + 5 Gastric liver extract 12.5 + 1.2* 320 ± 40* 4.7 + 0 7 68± 10 meal + bombesin Intestinal liver extract 8*4 ± 1*3 82 12 1.2 + 0.3 62 ± 8 meal Intestinal liver extract 10*3 ± 2.8* 230 42* 3.6 + 0.9* 66 ± 10 meal + bombesin * Significant increase above control with gastric or intestinal meal of liver extract alone. Antral mucosectomy caused almost complete removal of gastric acid response to intestinal perfusion of the test meal (Fig. 3). Basal serum gastrin levels were lowered to about 58 + 3 pg/ml. and there were no significant differences from basal values at any rate of intraduodenal instillation of the meal. Exogenous gastrin (G-17) infused intravenously in a dose (50 p-mole/kg. hr) which raised serum gastrin to the levels similar to those observed during duodenal instillation of liver extract meal in dogs with an intact stomach caused a small but significant increase in acid output reaching only about 20 % of the histamine maximum acid output. Intestinal perfusion with saline, at increasing rates, in dogs with removed antral mucosa, did not cause any change in both gastric acid and serum gastrin levels and these data are omitted for the presentation. In the postantral mucosectomy study, an I.v. infusion of bombesin into fasted dogs, in gradually increasing doses, evoked a significant rise in acid output, reaching a peak of about 12 % of histamine acid output. Serum gastrin levels during bombesin infusion showed a tendency to increase, which was statistically significant only at higher dose levels (500 and 1000 ng/kg. hr) of this peptide. Bombesin given during the gastric or intestinal phase resulted in a significant increase in acid response to gastric or intestinal meal without affecting significantly serum gastrin levels (Table 1, Fig. 4). DISCUSSION This study shows that the antral gland area plays an important role in both the gastric and intestinal phases of gastric secretion and that following the removal of 235

236 A. FOKINA AND OTHERS the antral mucosa, there is a relatively greater reduction in the intestinal phase than in the gastric phase stimulation of gastric acid secretion. Our results show that simple saline distention of the fully innervated stomach with the antral gland area intact resulted in a pressure-relased stimulation of acid secretion amounting to about 40% of histamine maximum acid output. Thus, the distention of the whole stomach elicits only a moderate secretary response of the oxyntic glands, presumably mediated by oxynto-oxyntic and pyloro-oxyntic reflexes involving the vagi (Debas, Konturek P Grossman, 1974). The serum gastrin level was not affected by gastric distention, suggesting that antral gastrin is not essential to distention-induced stimulation of gastric secretion. This cannot be interpreted, however, to mean that this hormone is not involved at all in the acid response to the distention stimulus. This is well demonstrated by a marked reduction in distentioninduced acid secretion in our animals after resection of the antral mucosa. It is reasonable to accept, therefore, that a background of gastrin release even if not detectable by measuring the serum hormone level, might be required for the maximal effectiveness of the distention stimulus as suggested previously by Grossman, Robertson & Ivy (1948). The gastric acid response to liver extract kept in the stomach at various distention pressures was significantly greater than to saline distention and accompanied by a marked increase in serum gastrin concentration. Following removal of the antral mucosa, the gastric acid response to the gastric test meal was reduced by about 50 % at all distention pressures and the serum gastrin response was completely eliminated. This marked reduction in gastric response to a meal could be attributed not only to the removal of antral gastrin, but probably also to the reduction of oxyntic gland secretary capacity and to the elimination of pyloro-oxyntic reflex as antral mucosectomy may remove or damage the receptors involved in this reflex.- It is noteworthy that a stomach with the antral mucosa removed still responds to a liver extract meal about twice as much as to simple distention with saline. This suggests that a meal of liver extract, consisting mainly of peptides and amino acids, stimulates acid secretion not only by gastrin release and neural reflexes but also by other mechanisms perhaps involving direct chemical excitation of the oxyntic glands. This direct chemical stimulation has been described previously, but its physiological significance has not been proved unequivocally (Cieszkowski et al. 1975; Debas & Grossman, 1975). Our study shows that exogenous G-17 given to dogs with the antral mucosa resected in a dose which raised the serum gastrin to a level similar to that observed after a gastric meal of liver extract in the same animals with the stomach intact, did not restore acid response to such a meal to the antral mucosectomy. This suggests that the observed decrease in gastric secretary response evoked by antral mucosectomy could be attributed, at least in part, to a general decrease in gastric secretary capacity. This is supported by the finding that antral mucosectomy results in about 25 % fall in histamine acid output. Previous attempts to determine the role of the gastric antrum in the intestinal phase stimulation of gastric secretion have given conflicting results. Studies of Gregory & Ivy (1941) and of Woodward, Lyon, Landor & Dragstedt (1954) suggested that the antrum is of little important in the intestinal stimulation of gastric secretion. On the other hand, the vital role of the antrum in intestinal phase stimulation has

GASTRIC ANTRUM AND GASTRIC SECRETION 237 been verified by numerous investigators (Konturek, 1977). Jordan & de la Rosa (1964) suggested that an intestinal meal might cause the release of antral hormone either by a neural reflex or by the action of the intestinal hormones on the antral G cells. The possibility of the release of antral hormone by a stimulant in the intestine has been further explored by Grossman and his associates (Debas, Slaff & Grossman, 1975; Thompson, Debas, Walsh & Grossman, 1976), who found in dogs with innervated antral pouches a significant rise in the serum gastrin level during intestinal perfusion with a meal of liver extract and observed a disappearance of this response after antrectomy. Present study shows that dogs with intact stomachs responded to intestinal perfusion of a liver meal with a significant increase in both acid secretion and serum gastrin level. The removal of the antral mucosa almost completely eliminated the intestinal phase induced stimulation of gastric secretion and gastrin release, indicating that the presence of the antral gland area is a prerequisite for the intestinal stimulatory mechanism of gastric secretion. As in the gastric phase, stimulation by exogenous gastrin (G-17), given during an intestinal meal of liver extract in dogs with the antral mucosa resected, significantly increased gastric acid response but did not restore it to the preresection level. This again suggests that besides elimination of gastrin release, the decrease in the intestinal phase stimulation following antral mucosectomy may be attributed to a general decrease in secretary capacity or to the activation of an as yet unknown mechanism. Thompson, Debas, Walsh & Grossman (1976) have recently shown that an increase in serum gastrin after instillation of a liver extract meal into the intestines of dogs with innervated antral pouches cannot be suppressed by antral acidification. Since the only form of gastrin release known to be resistant to antral acidification is that induced by the peptide bombesin (Erspamer & Melchiorri, 1975), it was important to study the gastric response to this substance before and after antral mucosectomy. Our study showed that this peptide, in dogs with the stomach intact, caused an abundant release of gastrin under basal conditions and a marked augmentation of serum gastrin response to a gastric or intestinal meal. Bombesin was, however, a relatively poor stimulant of gastric secretion. The peak output achieved with bombesin was only about 36 % of histamine maximum acid output, suggesting that this peptide perhaps also releases gastric inhibitors such as cholecystokinin (Erspamer, Improta & Melchiorri, 1974), and gastric inhibitory polypeptide (Becker, Borger, Schafmayer & Werner, 1978), which were previously reported to inhibit gastrininduced gastric secretion in the dog (Johnson & Grossman, 1970; Pederson & Brown, 1972). Following antral mucosectomy, bombesin resulted in a small (12 % of histamine acid output) but significant increase in gastric acid secretion which was accompanied by a barely detectable rise in the serum gastrin level both under basal conditions and after gastric or intestinal meal. The mechanism of gastric acid stimulation by bombesin in dogs after antral mucosectomy is not apparent from this study but it might be attributed to the release of small amounts of gastrin from extragastric sources or of other hormones (e.g. cholecystokinin) stimulating gastric secretion when the major source of endogenous gastrin is eliminated.

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GASTRIC ANTRUM AND GASTRIC SECRETION 239 from an antral pouch by liver extracts bathing oxyntic cells and intestinal mucosa. Physiologist, Wash. 19, 390. WALSH, J. H. (1975). Biological activity and disappearance rates of big, little and minigastrins in dog and man. In Gastrointestinal Hormones, ed. THOMPSON, J. C., pp. 75-83. Austin and London: University of Texas Press. WOODWARD, E. R., LYON, E. S., LANDOR, L. & DRAGSTEDT, L. R. (1954). The physiology of the gastric antrum. Gastroenterology 27, 766-785. YALOW, R. S. & BERSON, S. A. (1970). Radioimmunoassay of gastrin. Gastroenterology 58, 1-4.