Gastric Acid Response to Pentagastrin and Histamine After Extragastric Vagotomy in Dogs

Vol. 59, No. 3 Printed in U.S.A.

GASTROENTEROLOGY

Copyright © 1970 by The Williams & Wilkins Co.

GASTRIC ACID RESPONSE TO PENTAGASTRIN AND HISTAMINE AFTER EXTRAGASTRIC VAGOTOMY IN DOGS G. FRANK STENING, F.R.A.C.S., AND MORTON I. GROSSMAN, M.D., PH .D. Veterans Administration Center and the Departments of Medicine and Physiology, University of California School of M edicine, Los Angeles, California

In dogs extragastric vagotomy (cutting the hepatic and celiac branches) caused an increase in submaximal and maximal responses to pentagastrin from vagally denervated stomach (main stomach with selective gastric vagotomy or Heidenhain pouch). This effect of extragastric vagotomy was seen only with pentagastrin stimulation, not with histamine, and only in vagally denervated stomach, not in the main stomach with intact vagal innervation. We postulate that this effect may be the result of withdrawal of an inhibitor, of unknown source and nature, that is released by spontaneous activity of vagal efferent fibers. Transformation of vagally innervated Pavlov pouches into vagally denervated Heidenhain pouches greatly reduced the maximal response to gastrin, but the maximal response to histamine was not changed. 1 Truncal vagotomy increased the maximal response to gastrin from Heidenhain pouches but did not alter the maximal response to histamine. 2 After truncal vagotoml -5 or after extragastric vagotomy6-~ (division of the celiac and hepatic vagal branches), Heidenhain pouches secreted more acid in response to meals. The present study shows that the increased maximal response to gastrin of Heidenhain pouches that has been seen after truncal vagotoml can be reproduced by extragastric vagotomy.

Methods Stage I Six mongrel dogs (weighing 18.5 to 24.2 kg) were prepared with vagally denervated Heidenhain pouches, gastric fistulas, and pyloroplasties of the Heinecke-Mickulicz type. A Gregory cannula 10 drained the pouch and a Thomas cannula 11 the main stomach. Studies were started 3 weeks after surgery. After an 18-hr fast , during which the dogs had free access to water, secretions were collected from the Heidenhain pouch and gastric fistula as 15-min samples. Volume was recorded and acid concentration determined by titration with 0.2 N NaOH to pH 7 on an automatic titrator (Radiometer, Copenhagen, Denmark). Studies were separated by at least 48 hr. During tests the dogs stood on tables and were supported by cloth slings. Throughout each test a peristaltic pump (Harvard, Millis, Mass .) delivered 154 mM NaCl at 60 ml per hr through polyethylene tubing (PE50) inserted into a leg vein. Basal secretion was collected from the pouch and main stomach for two 15-min periods, then pentagastrin (4, 8, 16, and 32 J.Lg per kg-hr) or histamine dihydrochloride (0.04, 0 .08, 0.16, and 0.32 mg per kg-hr) was added to the NaCl infusion and maintained for 10 periods of 15 min. Only one dose of a test agent was given each test day. Each dose was given twice. In other tests, insulin (0.25 U per kg) was given

Received December 31, 1969. Accepted March 18, 1970. Address requests for reprints to: Dr. Morton I. Grossman, Veterans Administration Center, Building 115, Room 115, Los Angeles, California 90073. This work was supported by Veterans Administration research funds and by Grant AM8354 from the United States Public Health Service. Dr. Stening's present adress is: Department of Surgery, University of Sydney, Sydney, Australia. The authors are grateful to John Washington for expert technical assistance. 364

POSTVAGOTOMY GASTRIC ACID RESPONSE

September 1970

365

as a single rapid injection through a three-way stopcock inserted in the infusion tubing.

Stage II

®

DORSAL

VAGAL

®vENTRAL VAGAL

BRANCHES

BRANCHES

FIG. 1. Schematic diagram of vagal branches, dor-

sal (A) and ventral (B) . The dorsal trunk divides into gastric and celiac branches. The ventral trunk divides into gastric and hepatic branches. All of the trunks and branches may be multiple; when multiple nerves were encountered, all were cut. Selective extragastric vagotomy (A-A and A1-A1) cuts the hepatic branch of the ventral vagus and the celiac branch of the dorsal vagus, leaving the gastric branches intact. Selective gastric vagotomy (B-B and B 1- Bd cuts the gastric branches of the dorsal and ventral vagal trunks but spares the hepatic and celiac branches. In practice, all of the gastric branches along the lesser curvature were cut, not just the main gastric branches as shown for convenience in the diagram . Truncal vagotomy (C-C and c~-CJ), performed in the thorax, cuts the dorsal and ventral vagal trunks, thus cutting both gastric and extragastric branches. The vagotomies performed were as follows . Group I stage I, extragastric vagotomy (A-A and A1-A J) ; stage II, t runcal vagotomy (C-C and C1-CI ). Group II stage I, gastric vagotomy (B- B and B1 - B1); stage II, truncal vagotomy (C-C and C1-CJ ).

At the conclusion of the above tests the dogs were randomly divided into two groups of 3. Group I. Dogs in this group (weighing 19.5 to 24.2 kg) had selective extragastric vagotomies (fig. 1) performed through a midline abdominal incision. The hepatic branches were located as they originated from the ventral vagal trunk just below the esophageal hiatus and were divided as they passed through the lesser omentum toward the porta hepatis. The celiac branches arising from the dorsal vagal trunk were divided as they passed to the celiac plexus in association with the left gastric artery. Care was taken to preserve the nerves originating from both the ventral and dorsal vagal trunks that descend a long the lesser curvature and to the gastric antrum. Group II. This group of dogs (weighing 18.5 to 21.5 kg) had selective gastric vagotomies (fig. 1) performed through a midline abdominal incision. The main vagal trunks were identified at the most distal esophagus a nd all gastric vagi, ventral and dorsal , transected. The celiac and hepatic branches were carefully avoided and preserved. Starting 3 weeks after surgery both groups of dogs were retested with pentagastrin (4, 8, 16, and 32 11g per kg-hr) and the dose of histamine dihydrochloride which produced maximal acid secretion before vagotomy (0.32 mg per kg-hr for group I, 0.16 mg per kg-hr for group II) . All dogs received insulin (0.25 U per kg) .

Stage III After completion of stage II tests both groups of dogs had transthoracic complete truncal vagotomies. The nerves were cut about 5 em above the diaphragm. Starting 3 weeks after surgery the tests performed in stage 2 were repeated. Statistical analysis was performed using the t-test for unpaired values."

Results

Group I. Maximal acid output from the Heidenhain pouch and gastric fistula was produced by 0.32 mg per kg-hr of histamine dihydrochloride and 32 J.Lg per kghr of pentagastrin. In the Heidenhain pouch histamine produced a maximal re-

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STENING AND GROSSMAN

sponse 1. 7 times that to pentagastrin, but in the gastric fistula there was no significant difference in maximal response to the two stimulants (table 1). After extragastric vagotomy there was a significant increase in response of the Heidenhain pouch to all doses of pentagastrin (fig. 2). The responses of the Heidenhain pouch to histamine (0.32 mg per kg-hr) and of the gastric fistula to histamine, pentagastrin, and insulin were not altered, table 1). Truncal vagotomy did not significantly alter the response to pentagastrin of the Heidenhain pouch but reduced the response of the gastric fistula (fig. 2). The TABLE

Vol. 59, No. 3

response to histamine was unaltered in the H eidenhain pouch but was reduced from the gastric fistula (table 1). The response of the gastric fistula to insulin was abolished (table 1). Group II. Maximal acid output from the Heidenhain pouch and gastric fistula was produced by 0.16 mg per kg-hr of histamine dihydrochloride and 16 11g per kghr of pentagastrin. Histamine produced a higher maximal response than pentagastrin from the Heidenhain pouch but the responses from the gastric fistula did not differ significantly (table 2). Selective gastric vagotomy caused no significant alteration in response of the

1. Acid outputs before and after selective extragastric vagotomy (EG V) and then

truncal vagotomy (TV) in Group I Acid outputs 'fest agent

After EGV

Change"

Afte r TV

Chang e~

mEq / 15 min

,.,,,

mEq/15 min

n·

1.98 9. 20

1.91 8.98

-3.5 -2 . 4

1.86 7.56

- 5.2 - 17 .9*

1.14 8.73

1.61 8 .97

+41.1 * +2 . 7

1.44 7.60

+26.1* -12.9

7 .30

6.84

- 7.4

0.11

- 98.5*

Control

Histamine (0.32 mg/kg-hr) HP' GF" .. . . .. . . . . .. ... Pentagastrin' HP . . . . . . . . . . .' . GF Insulin (0.25 U/kg) GF .. •

•

•

•

•

•

•

•

mEq/15 min

0

•

•

0

•••

•••

,,

" Change: percentage increase ( +) or decrease (-) from control. *, P < 0.05. ' The response to pentagastrin is the highest obtained with any dose. ' HP, Heidenhain pouch. d GF, gastric fistula. GROUP I

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EXTR AGASTRIC VAG0 TOMY 2

3

GASTRIC FISTULA

HEIDENHAIN POUCH

• 32 16 8 PENTAGASTRIN )'Q/kg-hr

4

16

32

PENTAGASTRIN )'Q/kg-hr

FIG. 2. Acid outputs to pentagastrin following selective extragastric vagotomy (EG\1) and then truncal vagotomy (TV) in group I. +. statistically significant (p < 0.05) difference from control. Each point represents mean of two tests in each of 3 dogs.

POSTVAGOTOMY GASTRIC ACID RESPONSE

September 1970 TABLE

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2. Acid outputs before and after selective gastric vagotomy (GV) and then truncal vagotomy (TV) in Group II Acid outputs

Test agent

Histamine (0.16 mg/kg-hr) HP' GF" ......... .. . b Pentagastrin . . . . . . . . . .. HP GF .. Insulin (0.25 U/kg) GF . . . . . . . . . . . . . . ..

Co ntrol

After GV

C h nn~c'

After TV

mEq/15 min

mEq/15 min

'.,

mEq/15 min

1.96 10.54

1. 78 9.07

-9.2 -14 .0*

1. 76 8.27

- JO. il - 21. 6*

0 .88 9.89

0.89 5 . 46

+1.7 - 44 .8*

1.19 8 .85

+ 35.5* - 10 .5

6.46

0 . 22

- 96.4*

0.31

-95.il*

Change"

" Change: percentage increase ( +) or decrease (-) from control. *, P < 0.05. ' The response to pentagastrin is the highest obtained with any dose. ' HP, Heidenhain pouch. d GF, gastric fistula. GROUP U

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10

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32

PENTAGASTRIN )'o / kg · h<

2 GASTRIC FISTULA

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PENTAGASTRIN )'o / ku·h<

FIG. 3. Acid outputs following selective gastric vagotomy (GV) and then truncal vagotomy (TV) in group II. +, statistically significant (p < 0.05) difference from control. Each point represents mean of two tests in each of 3 dogs.

Heidenhain pouch to either agent. The response of the gastric fistula decreased, 14% to histamine and 459-i) to pentagastrin (table 2). The response of the gastric fistula to insulin was abolished (table 2). Truncal vagotomy did not alter the response of the Heidenhain pouch to histamine but increased the response to all doses of pentagastrin (fig. 3). The maximal response of the gastric fistula to pentagastrin was increased by 62% (fig. 3), whereas the response to histamine decreased by 22% (table 2). The effects of the various types of va-

gotomy on the maximal response to pentagastrin from the gastric fistula (GF) and Heidenhain pouch (HP) are summarized in table 3 according to groups and stages and in table 4 according to presence or absence of gastric and extragastric vagal innervation. These tabulations may be summarized as follows. Extragastric vagotomy increased the maximal response to pentagastrin in vagally denervated stomach (G F after gastric vagotomy or HP) but had no effect on response of vagally innervated stomach (GF before gastric vagotomy). The effect of extragastric vagotomy on the HP

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S TEN ING AND GROSSMA N TABLE

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3. Effect of various types of vagotomy on maximal response to pentagastrin from gastric fistulas (GF) and Heidenhain p ouches (HP) Effect of procedure on maxi mal response to Pentagastrin

State of vagal innervation

Group

I

I

II

II

Procedure

Sta ~e

Extragastric vagotomy

I

Truncal vagotomy

II

Gastric vagotomy

I

Truncal vagotomy

II

TABLE

Before or after procedure

Extragastric

GF

HP

Before After

+

+ +

-

No chan ge

Increase

Before After

-

+

No further cha n ge

-

-

No chan ge

-

Before After

+ +

+

-

Decrease

No change

-

Before After

+

-

-

Increase

Increase

-

-

-

-

HP

GF

4. Effect of extragastric vagotomy or gastric vagotomy on maximal response to p entagastrin from gastric fistulas (GF) or Heidenhain pouches (HP)" Example

Procedure

Status o f inn ervation

T est object

Effect on maximal response to pentagastrin

Group

Ext ragastric vagotomy

Vagal innervation of GF

+

GF GF

+

HP HP

-

Gastric vagotomy

Sta~e

No change Increase Increase Increase

I II I II

I II I II

Decrease No change No change No change

II I II I

I II I II

Extragastric vagal innervation

+

GF GF

+

HP HP

-

-

a

After selective gastnc vagotomy, truncal vagotomy was eqUivalent to extragastnc vagotomy (group II, stage II) ; after selective extra gastric vagotomy, truncal vagotomy was equivalent to gastric vagotomy (group I, stage II) .

was independent of the presence or absence of vagal innervation to the GF. Gastric vagotomy decreased the maximal response to pentagastrin of the gastric fistula if the extragastric vagi were intact but had no effect if the extragastric vagi had been cut. Gastric vagotomy had no effect on the maximal response to pentagastrin of the HP regardless of presence or absence of extragastric vagal innervation.

Discussion That truncal vagotomy increases 24hr acid output from vagally denervated Heidenhain pouches in dogs has been known for many years.6 - 9 Earlier workers thought the increased secretion resulted from prolonged release of endogenous gastrin due to gastric stasis and reduced antral acidification, but Dragstedt and colleagues1 3 showed that truncal vagotomy

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POSTVAGOTOMY GASTRIC ACID RESPONSE

in antrectomized dogs similarly increased secretion from Heidenhain pouches. They suggested that this might be the result of reduced duodenal inhibition secondary to lowered gastric secretion. Further studies"· 7 in dogs with total gastrectomy, denervated pouches, and preservation of the extragastric vagi showed that truncal vagotomy, which in effect was extra gastric vagotomy, increased pouch secretion in response to a test meal 7 or as measured by 24-hr collections." These workers concluded that a reduction in duodenal acidification, as postulated by Dragstedt et al. , could not be responsible for the phenomenon and speculated that extragastric vagotomy might produce intestinal stasis with prolonged intestinal gastrin release, but they offered no evidence to support this hypothesis. Landor, 8 using antrectomized dogs, and Shiina and Griffith, u using nonantrectomized dogs, confirmed the observation that extragastric vagotomy increased the 24-hr secretion from Heidenhain pouches. Conversion of a vagally innervated fundic pouch into a vagally denervated pouch by separating the pouch from the main stomach greatly reduced the submaximal and maximal response to exogenous gastrin 1 • 14 without altering the maximal response to histamine. 1 Emas and Grossman~ found that truncal vagotomy increased the response of the Heidenhain pouch to exogenous gastrin without changing the response to histamine. If one assumes that extragastric vagotomy increases the responsiveness of Heidenhain pouches to endogenous antral and intestinal gastrin just as it does to exogenous gastrin, then a single explanation can be provided for the findings of all workers. The results of the present study together with previous work 6 - u indicate that the increased responsiveness to exogenous and endogenous gastrin is produced by cutting the extragastric vagi and that the outcome is not affected by whether the gastric vagi are also cut. It is not known how the extragastric vagi influence gastric secretion. An inhibi-

369

tor under vagal control has been postulated. ~ Since the phenomenon occurs without specific vagal stimulation it would be necessary further to postulate that spontaneous or tonic vagal activity releases the hypothetical inhibitor. The identified inhibitors of intestinal origin, secretin and cholecystokinin, fit the requirements for the hypothetical inhibitor in that they selectively inhibit gastrin and not histamine, 15 but they are not known to be under vagal control. That high rates of pancreatic secretion cannot be produced by vagal stimulation can be regarded as evidence that vagal stimulation does not release large amounts of secretin. Secretin is a noncompetitive inhibitor of gastrin stimulated acid secretion, 11 ; so it could depress the maximal response to gastrin, but cholecystokinin, a competitive inhibitor, 17 could not. However, secretin, unlike the hypothetical inhibitor, counteracts gastrin stimulated secretion in both vagally innervated and vagally denervated stomach. 1" Why the increased response to gastrin occurs only in vagally denervated stomach is not known. No inhibitor that is effective only in the vagally denervated stomach is known. Under some circumstances vagally innervated stomach is more readily inhibited by acid in the intestine than vagally denervated stomach. 1!1, "' The presence or absence of vagal innervation to the main stomach did not alter the effect of extragastric vagotomy in increasing the response of the Heidenhain pouch to pentagastrin. The main stomach that had been selectively vagotomized showed the same pattern of responses as the Heidenhain pouch. In both instances the maximal response to histamine exceeded the maximal response to pentagastrin and in both instances cutting the extragastric vagi increased the maximal response to pentagastrin without changing the response to histamine. In cats the maximal responses to gastrin and histamine are equal in vagally denervated pouches/ 1 so the phenomenon of increased response to gastrin after extragastric vagotomy might not occur in this

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STENING AND GROSSMAN

species. Acid secretion induced by gastrin was inhibited less by secretin in cats than 22 in dogs. Selective gastric vagotomy is now widely used in the surgical treatment of duodenal ulcer. There have been several reports claiming a higher incidence of negative insulin tests with selective than with truncal vagotomy. 23- 26 Griffith 23 believes that this is attributable to better anatomical accuracy with the selective technique. However, it may be that leaving the extragastric vagi intact preserves a vagally controlled inhibitor in man as we postulate for dog. Pentagastrin- and histamine-stimulated acid secretion were equally depressed after truncal vagotomy in man 27 and histamine-induced secretion was equally strongly depressed by selective as by truncal vagotomy. 28 If studies should show that pentagastrin-stimulated acid secretion is reduced more than histaminestimulated secretion after selective vagotomy in man, a response pattern like that seen in the Heidenhain pouch, this would be strong evidence that the phenomenon observed in this study in dogs also occurs in man. REFERENCES 1. Andersson S, Grossman MI: Effect of vagal de-

nervation of pouches on gastric secretion in dogs with intact or resected antrums. Gastroenterology 48:449-457, 1965 2. Emas S, Grossman MI: Response of Heidenhain pouch to histamine, gastrin and feeding before and after truncal vagotomy in dogs. Scand J Gastroent 4:497-503, 1969 3. Storer EH, Schmitz, EJ, Sauvage LR, et al: Gastric secretion in Heidenhain pouches following section of the vagus nerves to the main stomach. Proc Soc Exp Bioi Med 80:325-332, 1952 4. Evans SO , Zubiran JM , McCarthy JD, et a!: Stimulating effect of vagotomy on gastric secretion in Heidenhain pouch dogs. Amer J Physiol 174:219-228, 1953 5. Schmitz EJ, Kanar EA, Storer EH, eta!: Effect of vagotomy of the main stomach on Heidenhain pouch secretion . Surg Forum 3:17, 1952 6. Kelly KA, Nyhus LM, Harkins HN: The vagal nerve and the intestinal phase of gastric secretion. Gastroenterology 46:163-171, 1964 7. Middleton MD, Kelly KA, Nyhus LD, et a!: Selective vagal effects on the intestinal phase of gastric secretion. Gut 6:296-303, 1965

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8. Landor JH: The effect of extragastric vagotomy on Heidenhain pouch secretion in dogs . Amer J Dig Dis, 9:256- 269, 1964 9. Shiina E, Griffith CA: Selective and total vagotomy without drainage. Ann Surg 169:326333, 1969 10. Gregory RA: Gastric secretory responses after portal venous ligation . J Physiol (London) 144:123-127, 1958 11. Thomas JE: An improved cannula for pancreatic and gastric fistulas. Proc Soc Exp Bioi Med 46:260-261, 1941 12. Snedecor GW, Cochran WG: Statistical Methods. Ames, Iowa, Iowa State Press, 1968 13. Dragstedt LR, Johnson AN, Singer ER, et al: The effect of vagotomy on the intestinal phase of gastric secretion. Surg Forum 11:336, 1960 14. Andersson S, Olbe 1: Gastric acid secretory responses to gastrin and histamine in dogs before before and after vagal denervation of the gastric pouch. Acta Physiol Scand 60:51-62, 1964 15. Johnson LR, Grossman Ml: Effects of fat , secretin and cholecystokinin on histamine stimulated gastric secretion. Amer J Physiol 216:1176-1180, 1969 16. Johnson LR, Grossman MI: Characteristics of the inhibition of gastric secretion by secretin. Amer J Physiol 217:1401-1404, 1969 17. Johnson LR, Grossman MI: Analysis of inhibition of acid secretion by cholecystokinin in dogs. Amer J Physiol 218:550- 554, 1970 18. Wormsley KG, Grossman MI: Inhibition of gastric acid secretion by secretin and by endogenous acid in the duodenum. Gastroenterology 47:7281 , 1964 19. Code CF, Watkinson G: Importance of vagal innervation in the regulatory effect of acid in the duodenum on gastric secretion of acid . J Physiol (London) 130:233-252, 1955 20. Sircus W: Studies on the mechanisms in the duodenum inhibiting gastric secretion. Quart J Exp Physiol 43:114-129, 1958 21. Emas S, Grossman MI: Acid responses to graded doses of histamine and gastrin in Heidenhain pouch cats . Gastroenterology 55:72-84, 1968 22. Stening GF , Johnson LR, Grossman MI: Effect of secretin on acid and pepsin secretion in cat and dog. Gastroenterology 56:468-479, 1969 23. Griffith CA: Completeness of gastric vagotomy by the selective technique . Amer J Dig Dis 12:333-351, 1967 24. Kennedy T, Connell AM: Selective or truncal vagotomy? Lancet 1:899-901, 1969 25. Sawyers JL, Scott HW, Edwards WH, et a!: Comparative studies of the clinical effects of truncal and selective gastric vagotomy. Amer J Surg 115:168-185, 1968 26. Marckmann A, Baden H, Amdrup E: Selective

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POSTVAGOTOMY GASTRIC ACID RESPONSE

anterior and total posterior vagotomy compared with bilateral selective vagotomy in treatment of duodenal ulcer in 116 patients. Scand J Gastroent 3:439-449, 1968 27. Payne RA, Cox AG, Spencer J, et a!: Effect of vagotomy on gastric acid secretion stimulated

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by pentagastri n and histamine. Brit Med ,J 4:456-461, 1967 28. Bank S, Marks IN, Louw ,J!-I: Histamine and insulin stimulated gastr ic acid secretion after selective and truncal vagotomy. Gut S::lG-~8. 1967