Effect of Antrectomy and Subsequent Vagotomy on the Serum Gastrin Response to Food in Dogs ROBERT A.D. BOOTH, F.R.C.S., DAVID D REEDER, M.D., JAMES

The effect of food on serum gastrin and gastric acid secretion has been studied in dogs with denervated pouches before and after antrectomy and subsequent vagotomy. A Billroth I anastomosis was used in one group of dogs and a Billroth II in the other. Serum gastrin was measured by radioimmunoassav. In both groups of dogs antrectomy significantly depressed mean basal levels of serum gastrin and abolished the rise in serum gastrin in response to a meat meal. Meal-induced pouch acid secretion was considerably lowered by antrectomy after either Billroth I or Billroth II anastomosis. Vagotomy after antrectomy increased basal levels of gastrin, but did not restore the serum gastrin response to a meat meal in either group of dogs. It is suggested that biologically active forms of gastrin are released from the antrum in response to a meal. Biologically inactive basal levels of gastrin apparently originate from extra-antral sources. The post-vagotomy increase in basal (static) gastrin suggests vagal control of the metabolism of static, extra-antral gastrin. YU ANTITIIES of extra-antral gastrin within the gastrointestinal tract of man and animals have

PI')BCLAB:LH1.

been demonstrated by radioimmunoassay36'152125 and by immunohistochemical techniquies.8'2 The effect of food, the ordinary physiological stimuluis, uipon stores of extra-antral gastrin is not completely uinderstood. In man after gastrectomy,"° antrectomy," or antrectomy and vagotomy,"'0'8 feeding continuies to elicit an increase in the serum concentration of gastrin apparently as a consequence of the release of extra-antral gastrin. We have demonstrated"4 only minute rises in seruim gastrin after feeding in dogs after gastrectomy. This suiggests an important difference in the availability of extra-antral gastrin of the dog compared with man. The effects of antrectomy alone on the serum gastrin response to food in dogs are uinknown. The present experiments were indertaken to study Stubmitted for puiblication Jtuly 1, 1974. Suipported by a grant from the National Instittutes of Health (AM 15241) and b) a grant from the John A. Hartford Fouindation, Inc. Reprint requiests: James C. Thompson, M.D., Department of Suirgery, The University of Texas Medical Branch, Galveston, Texas 77550.

C. THOMPSON, M.D.

From the Department of Surgery, The University of Texas Medical Branch, Galveston, Texas

fturther the release of extra-antral gastrin stimulated by food in dogs. Materials and Methods Twelve healthy aduilt mongrel dogs, 15-25 kg, with denervated fuindic Heidenhain pouches (HP) were studied. Sertum gastrin concentrations and HP acid secretion were measuired in response to a standard meat meal before and 3 weeks after antrectomy. Each dog tunderwent an 18 hour fast after which a catheter was placed in a hindleg vein for sampling. Duiplicate basal blood samples were drawn for serum gastrin determination and two basal 15-minute HP collections were made. The dogs were then fed a 200 gm meat meal. Blood samples were drawn at frequent intervals and HP collections were made every 15 minutes during the subsequient 3 houirs.

The dogs were then stubjected to antrectomy under sodiuim pentothal anesthesia. The antrum was defined in each dog at laparotomy. A distal gastrotomy was performed and the acid-secreting area of the stomach was outlined with pH paper 15 minuites after the subcuitaneouis injection of 50 mg of Histalog. The entire antrum was excised, along with a 1 cm margin of acid-secreting mucosa. The distal line of resection was the pylorus. Dogs were randomly divided into two groups; in one group, gastrointestinal continuity was restored by means of a Billroth I gastroduiodenal anastomosis, and in the second group a Billroth II gastrojejinostomy was performed. Three weeks after antrectomy, food stuidies were repeated. Three to five days after the food studies, four of the dogs with a Billroth I anastomosis and five of the Billroth II dogs were again anesthetized and uinderwent bilateral truncal

191

Ann. Stirg. Febrtiary 1975 BOOTH, REEDER AND THOMPSON 192 vagotomy. Three weeks later, food studies were again minuite integrated gastrin response was 3.94 ± 1.42 ngrepeated. min/ml before antrectomy and 1.39 ± 0.74 ng-min/ml after antrectomy To secuire more information on the effect of antrectomy (p < 0.05). and vagotomy on basal gastrin, four additional blood HP acid secretion before antrectomy rose to a peak of samples were taken from each dog preoperatively, after an- 0.51 ± 0.19 mEq/15 minuites after feeding (Fig. 2). After antrectomy HP acid secretion was significantly diminished trectomy and after vagotomy. Acid ouitpuit, expressed as milliequivalents (mEq)/15 (p < 0.05). Duiring the third hour after feeding, acid ouitput minuites, was calculated by measuring the amount of acid in increased, but the response remained significantly lower a 1 ml aliquiot of HP secretion which was titrated with 0.1 N than prior to antrectomy. NaOH, uising phenol red as indicator. After vagotomy basal serum gastrin was 83 ± 15 pg/ml Seruim gastrin was measured by radioimmunoassay.9 The with Billroth I anastomosis and 79 ± 8 pg/ml with Billroth antigastrin antibody used was developed in rabbits to syn- II anastomosis (Fig. 3). There was no significant alteration thetic huiman gastrin I (amino acid residues 2-17) con- in serum gastrin in response to food in either group. HP acid jtigated to bovine seruim albuimin. All samples were assayed responses to food in both Billroth I and Billroth II dogs were in duiplicate; reproduicibility was within ± 10%. The average not significantly altered by the addition of vagotomy. In the additional stuidy on the effect of antrectomy and of the dtuplicates was uised. Gastrin concentrations are expressed in picograms (pg)/ml. Integrated gastrin responses vagotomy on basal gastrin, the average of four basal gastrin to food were calcuilated from the product of the mean serum valuies in the Billroth I grouip was 71 ± 3 pg/ml before angastrin level duiring each time period after feeding mtil- trectomy and 59 ± 2 pg/ml after antrectomy (p < 0.05). In tiplied times the nuimber of minutes in the study minus the the Billroth II dogs, the pre-antrectomy gastrin values were produict of mean basal gastrin level and the number in 74 ± 4 pg/ml. After antrectomy, the average levels were 56 minuites.20 Integrated gastrin was expressed as ng-min/ml ± 2 pg/ml (p < 0.05). After vagotomy, serum gastrin levels for the time period. Results were expressed as arithmetic were 89 ± 7 pg/ml in Billroth I dogs and 85 ± 4 pg/ml in means and standard errors of the mean. Student's "t" test Billroth II; both levels were higher (p < 0.01 for both was uised to determine significance of differences between grouips) than after antrectomy alone. means. Differences with p values less than 0.05 were conDiscussion sidered significant. These resuilts demonstrate that antrectomy diminished Results basal concentrations of gastrin, abolished the post-prandial Seruim gastrin levels and HP secretory responses to food rise in sertum gastrin and considerably diminished gastric before and after antrectomy with Billroth I anastomosis are acid secretion in response to a meat meal. When vagotomy shown in Fig. 1. Basal serum gastrin was 69 ± 4 pg/ml was added to antrectomy, basal gastrin was significantly inbefore antrectomy and 62 ± 3 pg/ml after antrectomy (p > creased, buit the previous abolition of the gastrin response to 0.05). Before antrectomy, serum gastrin rose significantly a meal and the diminished HP acid response to food were after food to a peak of 146 ± 10 pg/ml (p < 0.05) at 15 tunchanged. Althouigh antrectomy significantly depressed basal levels mintutes and remained elevated. After antrectomy, there was no significant increase in serum gastrin values after of seruim gastrin it did not abolish them, suggesting that sites of extra-antral gastrin were present and were actively food. Pouich acid secretion before antrectomy rose at 105 produicing gastrin. Since antrectomy abolished the postminuites to a peak of 0.54 ± 0.15 mEq/15 minutes in prandial rise of gastrin (kinetic gastrin) but decreased only response to food. After antrectomy, the HP response was slightly the basal levels (static gastrin), it may be that the diminished; the differences were significant (p < 0.05) at all antrtum is chiefly responsible for kinetic gastrin (that is, gastrin released in response to food) and the small bowel for except the first collection period. Restults of serum gastrin and HP acid measurements static (or basal) gastrin. Yalow and Wu27 found that big big before and after antrectomy with Billroth II anastomosis are gastrin was a major component of unstimuilated (static) gasshown in Fig. 2. Before antrectomy, the basal concentration trin, and Yalow26 fouind that big big gastrin was not released of sertum gastrin was 79 ± 9 pg/ml; the value was by feeding. It may be that in dogs at least, the antrum consignificantly lower after antrectomy (55 ± 2 pg/ml, p < tribuites the major component of kinetic, biologically active 0.05). Prior to antrectomy, serum gastrin after food rose to a gastrin (presuimably 17-amino acid and 34-amino acid gaspeak of 120 ± 11 pg/ml and remained elevated. After an- trin) and the small intestine may be chiefly responsible for trectomy, feeding produced no significant alteration of basal, non-biologically active levels (presumably chiefly big basal levels of seruim gastrin. If basal values are different, big gastrin27. The rise in basal gastrin after vagotomy the post-prandial gastrin levels are best compared by an suiggests that the vaguis influiences mechanisms for the evaluiation of the integrated gastrin response.20 The 180- release or catabolism of extra-antral gastrin. -

N'o,1 181 * No, 2

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BOOTH, REEDER AND THOMPSON

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Ann. Stirg. *

Febrtiary 1975

After ontrectomy and vogotomy

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Fig. 3. Basal and postprandial seruim gastrin and Heidenhain pouch acid valtues after antrectomy and vagotomy in five dogs with antrectomy and gastrojejiunostomy (B II) and fotur dogs after antrectomy and gastrodtuodenostomy (B I). Acid valuies in vagotomized dogs with antrectomy and Billroth I anastomosis are shown by the open bars and acid valuies in vagotomized dogs with antrectomy and Billroth II anastomosis are shown by the striped bars.

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The half-life of gastrin, both exogenous" and kinetic endogenous,11,23 is known to be short. Catabolic mechanisms which probably contribuite to the short half-life have been identified in the fuindtis of the stomach,7 the small bowel2 and the kidney;5 basal concentrations of gastrin are apparently not affected by transit of these organs22 as reflected by the prolonged half-life of big big gastrin (90 min,

gastrin was recorded after vagotomy and pyloroplasty.' The role of the vaguis in controlling the release of gastrin in man may be importantly related to these species differences. Studies in man have suggested that truncal vagotomy causes significant post-prandial gastrin release from extra-gastric sites.'" The present studies show clearly that this is not true in dogs since vagotomy Yalow26). following antrectomy did not influence the postprandial Extra-antral gastrin is known to exist within the gastric levels of seruim gastrin. In other studies in dogs with denerfundtis,25 small bowel4" 1225 and pancreas.8"12 In man, high vated antral pouiches,'9 vagal stimulation by sham feeding concentrations of gastrin have been found in the proximal or insuilin-induced hypoglycemia did not appear to release small bowel, especially within the proximal duodenuim.'5

Gastrin can be released from the proximal duodenuim and jejtunuim in dogs by locally applied agents,3 but the mechanisms of release are not well uinderstood. If they are uinder the same stimuilatory and inhibitory controls that are known to influence the release of antral gastrin, it is difficult to uinderstand why food, the most potent physiologic releasing agent for antral gastrin, failed to elicit increased levels of seruim gastrin after antrectomy. Abolition of the post-prandial rise in serum gastrin by antrectomy indicates that the proximal intestine does not make a major contribuition to post-prandial increases in seruim gastrin in dogs althotugh it seems clearly to occur in man."4,10,18 This stuggests a most important species difference in response to feeding. Recent studies in dogs24 have shown that the post-prandial rise in serum gastrin is lowered by truincal vagotomy. This contrasts strongly with the findings in man in whom a marked post-prandial rise

in seruim

detectable amouints of extra-antral gastrin. Antrectomy greatly diminished the HP acid ouitpuit after food in the Billroth I dogs and nearly abolished it in the Billroth II grouip. The difference presumably is due to duiodenal inhibitory mechanisms (secretin and others) which are operative in dogs after gastroduodenostomy and are presuimably lost in dogs with gastrojejunostomy. In man, it has been suggested'7 that the serum gastrin response to food is lost in antrectomized patients with a Billroth II anastomosis buit that the response persists in Billroth I patients. Another study,'0 however, has reported significant increases in gastrin levels in post-antrectomy patients with a gastrojejuinostomy. There was no difference in the present stuidy in the seruim gastrin levels (basal and post-prandial) in the Billroth I and Billroth II groups. Vagotomy after antrectomy caused no change in the previouis greatly reduiced HP acid ouitpuit after food. This finding is different from that of Middleton and coworkers'

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Vol. 181 * No. 2

increased the HP acid outpuit in gastrectomized dogs. The reason for the difference is unex-

who fouind that

vagotomy

plained. References 1. Becker, H. D., Reeder, D. D. and Thompson, J. C.: Effect of Trtncal Vagotomy with Pyloroplasty or With Antrectomy on Food Stimuilated Gastrin Values in Patients with Dtuodenal Ulcer. Suirgery, 74:580, 1973. 2. Becker, H. D., Reeder, D. D. and Thompson, J. C.: Extraction of Circuilating Endogenouis Gastrin by the Small Bowel. Gastroenterology, 65:903, 1973. 3. Becker, H. D., Reeder, D. D. and Thompson, J. C.: Direct Measurement of Gastrin Release from Duiodenuim and Jejuintim in Dogs. Am. J. Physiol., 227:418, 1974. 4. Berson, S. A. and Yalow, R. S.: Natuire of Immtnoreactive Gastrin Extracted from Tissuies of Gastrointestinal Tract. Gastroenterology, 60:215, 1971. 5. Booth, R. A. D., Reeder, D. D., Hjelmquiist, U. B., et al.: Renal Inactivation of Endogenouis Gastrin in Dogs. Arch. Surg., 106:851, 1973. 6. Charters, A. C., Reeder, D. D. and Thompson, J. C.: Measurement of Gastrin in the Gastrointestinal Mutcosa by Radioimmtnoassay. Suirg. Foruim, 20:310, 1969. 7. Evans, J. C. W., Reeder, D. D., Becker, H. D. and Thompson, J. C.: Extraction of Circuilating Endogenotus Gastrin by the Gastric Funduls. Gtut, 15:112, 1974. 8. Greider, M. H. and McGuigan, J. E.: Cellular Localization of Gastrin in the Htuman Pancreas. Diabetes, 20:389, 1971. 9. Jackson, B. M., Reeder, D. D. and Thompson, J. C.: Dynamic Characteristics of Gastrin Release. Am. J. Sturg., 123:137, 1972. 10. Korman, M. G., Soveny, C. and Hansky, J.: Extragastric Gastrin. Gut, 13:346, 1972. 11. Lanciauilt, G., Bonoma, G., Karreman, G. and Brooks, F. P.: Kinetics of Gastrin Release and Degradation in Response to Electrical Vagal Stimuilation in the Dog. Proc. Soc. Exp. Biol. Med., 142:740, 1973. 12. Lomsky, R., Langr, F. and Vortel, V.: Immunohistochemical Demonstration of Gastrin in Mammalian Islets of Langerhans. Natture, 223:618, 1969. 13. Middleton, M., Kelly, K. A., Nyhtus, L. M. and Harkins, H. N.: Selective Vagal Effects on the Intestinal Phase of Gastric Secretion. Gtut, 6:296, 1965.

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14. Miller, J. H., Jackson, B. M. and Thompsord, J. C.: Effect of Total Gastrectomv and Partial Evisceration on Circuilating Gastrin Concentration. Sturg. Foruim, 21:295, 1970. 15. Nilsson, G., Yalow, R. S. and Berson, S. A.: Distribuition of Gastrin in the Gastrointestinal Tract of Huiman, Dog, Cat and Hog. In Nobel Symposiuim 16. Frontiers in Gastrointestinal Hormone Research. S. Andersson, ed. Stockholm, Almqvist & Wiksell, 95, 1973. 16. Reeder, D. D., Jackson, B. M., Brandt, E. N., Jr. and Thompson, J. C.: Rate and Pattern of Disappearance of Exogenouis Gastrin in Dogs. Am. J. Physiol, 222:1571, 1972. 17. Stern, D. H. and Walsh, J. H.: Release of Gastrin in Postoperative Duiodenal Ulcer Patients. Gastroenterology, 62:817, 1972. 18. Stern, D. H. and Walsh, J. H.: Gastrin Release in Postoperative Ulcer Patients: Evidence for Release of Duiodenal Gastrin. Gastroenterology, 64:363, 1973. 19. Tepperman, B. L., Walsh, J. H., Preshaw, R. M.: Effect of Antral Denervation on Gastrin Release by Sham Feeding and Insuilin Hypoglycemia in Dogs. Gastroenterology, 63:973, 1972. 20. Thompson, J. C., Reeder, D. D., Bunchman, H. H., et al.: Effect of Secretin on Circuilating Gastrin. Ann. Suirg., 176:384, 1972. 21. Thompson, J. C., Reeder, D. D., Davidson, W. D., et al.: Sttudies on the Metabolism of Gastrin. In Nobel Symposiuim 16. Frontiers in Gastrointestinal Hormone Research. S. Andersson, ed. Stockholm, Almqvist & Wiksell, 111, 1973. 22. Thompson, J. C., Becker, H. D., Evans, J. C. W., et al.: Stuidies on the Catabolism of Gastrin. In Endocrinology of the Gut. W. Y. Chey and F. P. Brooks, eds. Thorofare, N. J., Charles B. Slack, Inc., 295, 1974. 23. Villar, H. V., Reeder, D. D., Brandt, E. N., Jr., et al.: Disappearance Half-time of Autogenouis Antral Gastrin in Circulation. Physiologist, 17:349, 1974. 24. Walsh, J. H., Csendes, A. and Grossman, M. I.: Effect of Truncal Vagotomy on Gastrin Release and Heidenhain Pouch Secretion in Response to Feeding in Dogs. Gastroenterology, 63:593, 1972. 25. Watson, L. C., Reeder, D. D., LaGrone, L. and Thompson, J. C.: Gastrin Concentrations in Upper Gastrointestinal Muicosa in Dogs. Surgery, 76:419, 1974. 26. Yalow, R. S.: Gastrins: Small, Big and Big-big. In Endocrinology of the Guit. W. Y. Chey and F. P. Brooks, eds. Thorofare, N. J., Charles B. Slack, Inc., 261, 1974. 27. Yalow, R. S. and Wit, N.: Additional Stuidies on the Natuire of Big Big Gastrin. Gastroenterology, 65:19, 1973