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Secretin and Cholecystokin/Pancreozymin in Combination in the Inhibition of Gastric Acid Secretion

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Secretin and Cholecystokin/Pancreozymin in Combination in the Inhibition of Gastric Acid Secretion Gut: first published as 10.1136/gut.12.12.968 on 1 December 1971. Downloaded from Gut, 1971, 12, 968-972 Secretin and cholecystokin/pancreozymin in combination in the inhibition of gastric acid secretion B. S. BEDI, H. T. DEBAS, A. E. 0. WASUNNA, B. F. BUXTON, AND I. E. GILLESPIE From the University Department ofSurgery, Western Infirmary, Glasgow SUMMARY Both secretin, and the single substance which possesses both cholecystokinin and pancreozymin activity, have been shown to inhibit gastric acid secretory responses. Since potentiation may occur between pairs of stimulants of gastric secretion, the effects of combining secretin and cholecystokiniu/pancreozymin have been studied in Heidenhain pouches stimulated by contin- uous intravenous pentagastrin. Evidence suggesting potentiation between these two inhibitor agents is presented. Inhibition of gastric acid secretion is caused when Materials and Methods the mucosa of the upper small intestine is bathed either by fat (Feng, Hou, and Lim, 1929), acid The observations were made on three dogs with (Sokolov, 1904) or hyperosmolar solutions (Konturek Heidenhain type fundic pouches, the gastrointestinal and Grossman, 1965). The studies of Andersson tract otherwise being intact. The dogs' weights were (1960) suggest that the inhibition caused by acid in between 15 and 20 kg and all operative procedures the duodenum is mediated by a humoral agent. had been completed more than three months before There is therefore interest in the possible inhibitor the present experiments. http://gut.bmj.com/ properties on gastric acid secretion of extracts Acid secretion from the Heidenhain pouch was prepared from duodenal mucosa (Jorpes, 1968). stimulated by a continuous constant-rate intravenous Under certain experimental conditions in dogs, infusion of pentagastrin at a dose which gave the relatively pure secretin (Gillespie and Grossman, maximal acid response from the Heidenhain pouch. 1964a; Wormsley and Grossman, 1964) and During each experiment the secretion from the relatively pure cholecystokinin/pancreozymin Heidenhain pouch was collected continuously, and and (Gillespie Grossman, 1964, Bedi, Govaerts, every 15 minutes the volume was measured in milli- on October 1, 2021 by guest. Protected copyright. Master, and Gillespie, 1967) have been demonstrated litres and the acid concentration estimated by to inhibit Heidenhain pouch acid responses to titration against 0 01N sodium hydroxide with stimulation by gastrin and it has been suggested phenol red indicator, end-point 6.8 to 8.4. Acid that these agents may in fact be the principal outputs were derived from multiplication of the mediators of the inhibition. volume and concentration values. A plateau of acid There is evidence of potentiation at the level of the secretion from the Heidenhain pouch to the intra- acid-producing cells between pairs of stimulants, eg, venous infusion of pentagastrin was considered to gastrin extract and stable choline ester (Gillespie have been achieved when four consecutive 15- and Grossman, 1964b), and gastrin and histamine minute acid outputs varied less than 15 %. (Passaro, Gillespie, and Grossman, 1964). Bedi, The relatively pure secretin and cholecystokinin/ Debas, Gillespie, and Gillespie (1971) have also pancreozymin preparations were purchased from shown potentiation between bile salts and acetylcho- Professor Jorpes of the Karolinska Institute, line in the release of gastrin from the pyloric antrum. Stockholm. The substance with both cholecystokinin It is possible that potentiation may also exist between and pancreozymin activities will hereafter be referred various inhibitors of gastric acid secretion. The to simply as cholecystokinin. present experiments were therefore designed to At the start of each experiment two continuous explore the possibility that both secretin and intravenous infusions were established, one to infuse cholecystokinin/pancreozymin acting together may the pentagastrin in 09 % saline solution, and the result in facilitated or potentiated inhibition. other with 0 9% saline for the subsequent infusion of Received for publication 17 September 1971. the inhibitor agents. Once a plateau acid response to 968 Gut: first published as 10.1136/gut.12.12.968 on 1 December 1971. Downloaded from Secretin and cholecystokinin/pancreozymin in combination in the inhibition ofgastric acid secretion 969 pentagastrin had been established, the secretin or minutes, after which there was a return to control cholecystokinin, or both combined, were given levels. through the second continuous constant rate intra- venous infusion set over a one-hour period. EFFECT OF CHOLECYSTOKININ ALONE ON THE Differences between test and control mean values ACID RESPONSE OF THE HEIDENHAIN POUCH TO for each 15-minute period were tested for statistical PENTAGASTRIN significance by Student's t-test for paired values. The results of two experiments in each of the three dogs are shown in Figure 2. Seventy-five clinical units Results of cholecystokinin infusion over one hour caused a significant reduction of the acid response of the EFFECT OF SECRETIN ALONE ON THE ACID Heidenhain pouch to pentagastrin for 90 minutes. RESPONSE OF THE POUCH TO PENTAGASTRIN Figure 1 shows the effect of75 clinical units ofsecretin infusion on the acid response of the Heidenhain HEIDENHAIN POUCH DOGS pouch to the maximal dose of pentagastrin. The inhibition of acid secretion occurred rapidly after the PENTAGASTRIN 40-80Mg/hr W/ start of the secretin infusion, being present within C IOLECYSTOKININ 15 minutes, and statistically significant for 105 75 units/hrI ACID OUTPUT as % of CONTROL HEIDENHAIN POUCH DOGS 100% = 3.44 mEq/ hr PENTAGASTRIN 40-80Aag/hr 110,1 SECRETIN 75 units/hr ACID OUTPUT as % of CONTROL 100 % = 3-88 mEq/hr http://gut.bmj.com/ on October 1, 2021 by guest. Protected copyright. 0 2 4 6 8 10 12 15 MINUTE INTERVALS 6 Expts Fig. 2 The effects ofan infusion ofcholecystokinin on xx Heidenhain pouch secretion stimulated by intravenous _1_3 Dogs Control infusion ofpentagastrin. .-------.Continuous line shows the means and shaded areas the I I 1 1 1 1 1 1 1 1 i standard errors of these means for each 15-minute acid 0 output. The crosses denote statistically significant 2 4 6 8 10 12 difference from control levels; two crosses indicate 15 MINUTE INTERVALS p < 0.01 and one cross P < 0.05. Fig. 1 The effects ofan infusion ofsecretin on In order to determine whether the two agents given Heidenhain pouch secretion stimulated by intravenous simultaneously might potentiate each other in the infusion ofpentagastrin. acid secretion it was to infuse Continuous line shows the means and shaded areas the inhibition of necessary standard errors ofthese means for each 15-minute acid smaller doses than those used in these foregoing output. The crosses denote statistically significant experiments. It was decided to establish the doses of differencefrom control levels; two crosses indicate secretin and of cholecystokinin which, given p<0-01. separately, would bejust subthreshold for inhibition Gut: first published as 10.1136/gut.12.12.968 on 1 December 1971. Downloaded from 970 B. S. Bedi, H. T. Debas, A. E. 0. Wasunna, B. F. Buxton, and L E. Gillespie of the acid response to maximal stimulation by give significant inhibition. Therefore 9.5 clinical units pentagastrin, and then observe the effects of simul- of secretin was regarded as a subthreshold dose for taneous infusion of these subthreshold doses of both inhibition. agents. In this way we could apply a criterion for potentiation analogous to that employed for EFFECT OF VARYING DOSES OF CHOLECYSTO- potentiation between two stimulants of secretion, KININ INFUSION ON ACID RESPONSE OF HEIDEN- namely, the response to the combined agents HAIN POUCH TO PENTAGASTRIN exceeding that to twice the dose of either agent The dose-response pattern to cholecystokinin given alone, proposed by Gillespie and Grossman infusion is shown in Figure 4. With this material (1964b), based on the work of Gaddum (1959). HEIDENHAIN POUCH DOGS EFFECT OF VARYING DOSES OF SECRETIN INFUSION ON ACID RESPONSE OF HEIDENHAIN ,PENTAGASTRIN 40- 4g/hr// POUCH TO PENTAGASTRIN In Figure 3 are shown the results of the inhibitor dose-response studies using secretin alone. With CHOLECYSTOKININIfSON i'' progressive reduction in the dose of secretin there was parallel fall in both degree and duration of ACID OUTPUT inhibition of acid output. With 19 units of secretin as % of CONTROL inhibition of the pentagastrin response was still present, but 9.5 clinical units of secretin failed to HEIDENHAIN POUCH DOGS PENTAGASTRIN 40-80Ahr ¶ ISECRETIN r INFUION http://gut.bmj.com/ ACID OUTPUT as % of CONTROL 0 2 4 6 8 10 12 15 MINUTE INTERVALS on October 1, 2021 by guest. Protected copyright. Fig. 4 The eftects of infusion of 75 units (light interrupted line) and 37-5 units (heavy continuous line) ofcholecystokinin on Heidenhain pouch acid response to intravenous infusion ofpentagastrin. Six experiments in three dogsfor each dose studied. __,___ also -there was a reduction in both the degree and duration of inhibition of acid response of the 1 1 1 1 1 1 12 Heidenhain pouch to pentagastrin when smaller -j 2 6 8 1 12 doses were infused. In this instance the subthreshold 1S MINUTE INTERVALS inhibitory dose of cholecystokinin was 19 clinical units. Fig. 3 The effects ofinfusion of 75 units (heavy interrupted line), 37.5 units (light interrupted line), and EFFECT OF SIMULTANEOUS INFUSIONS OF 19 units (heavy continuous line) ofsecretin on Heidenhain ON pouch
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