World J. Surg. 3, 615-622, 1979
WofldJournal
of Sdrgery
Effect of Vagotomy on Gastrointestinal Hormones H.D. Becker, M.D., H.W. B6rger, M.D., and A. Schafmayer, M.D. Departmentof Surgery,Universityof G6ttingen,WestGermany Different types of vagotomy have been widely used in the treatment of peptic ulcer disease. A close relationship between the vagus nerve and the release or action of gastrointestinal hormones is necessary for the optimal activation of the gastrointestinal tract. The serum concentrations of the antral hormone gastrin are elevated after all types of vagotomy. The postvagotomy hypergastrinemia is due to the change in pH in the antral lumen or the gastric motility changes, both of which may lead to a proliferation of G cells. The reduction in pancreatic secretion after vagotomy is not due to changes in intestinal hormone release, but may be caused by the interruption of a postulated enteropancreatic reflex. Postprandial GIP release and serum insulin levels are not affected by vagotomy, but basal GIP levels are increased after vagotomy. Postprandial pancreatic polypeptide release is nearly abolished by vagotomy, but seems to normalize in the later postoperative course. These findings may be important for the interpretation of pathophysiologic changes after vagotomy.
been widely used in the surgical treatment of peptic ulcer disease, so that the effect of vagotomy on GI hormones is of major importance for the understanding of pathophysiologic changes induced by vagotomy. Gastrin
The relationship between the vagus nerve and the antral hormone gastrin includes gastrin release by vagal stimulation, vagal control of gastrin release by local stimuli, and behavior of serum gastrin and antral mucosa gastrin content after vagotomy. Uvn/is [2] in 1942 found strong evidence that stimulation of the antral vagus nerve resulted in release of gastrin from the antrum. These findings were confirmed by several other groups [3, 4]. Measurement of serum gastrin concentrations by RIA during electrical vagal stimulation [5-8], sham feeding [9, 10], or insulin hypoglycemia [11, 12] showed an increase in gastrin levels in man and laboratory animals. Gastrin release induced by insulin hypoglycemia also occurs after vagotomy, indicating that a noncholinergic mechanism is involved [12]. It has been known for some time that in dogs with denervated Heidenhain pouches (HP), transection of the vagal fibers to the innervated main stomach results in an increase of basal [13, 14] and foodstimulated [14-16] HP acid secretion. Since acid secretion stimulated by exogenous gastrin also is increased, it was postulated that vagotomy abolished a vagally controlled inhibitor ("vagogastrone"). Furthermore, vagotomy of the extragastric vagal fi-
A continuous interplay between the vagus nerve, which is responsible for the parasympathetic innervation of most of the intra-abdominal organs, and the gastrointestinal hormones is necessary for optimal activation of the gastrointestinal (GI) tract after food intake. After the development of sensitive, specific radioimmunoassays (RIA) for direct measurements of GI hormone concentrations, new aspects of these interrelationships were demonstrated. The vagus nerve controls the release of several GI hormones. Furthermore, the GI hormone, gastrin, has been found in the vagus nerve [1], and may function as a neurotransmitter. Vagotomy has
Reprint requests: Dr. H.D. Becker, Department of Surgery, University of G6ttingen, D-3400 G6ttingen, West Germany.
0364-2313/79/0003-0615 $01.60 9 1979 Soci6t6 Internationale de Chirurgie 615
616
World J. Surg. Vol. 3, No. 5, 1979
mv
o- - - - .4
SGV
,,= - - = ,
Control i SPV
SPV
9 ....... 9
SGV
Control
*
TV I ~
300 12,5
25,0
T
250
Gastrin pg/ml
20O 150
~,~
....
/e ,+> ...... ..e.'"
"~- --..4 "*'"'I
. ... . ... .o~176 . . .. . ... e ,.. .
,.~
10,0
20,0
Jnteg. Gastrin n g . m i n 7,5 ml
15.0
5,0
10+0
2.5
5.0
]nteg Gastrin ng.min rn[
.
100
0-90
91-180
0-180
Minutes
6 6,'o1's"3'o
6'o 9'0 Go 16o 40 Minutes
Fig. 1. Serum gastrin response to food in 6 dogs after different types o f vagotomy [43].
bers alone stimulated HP acid secretion [15, 17]. Several studies in the last years have demonstrated that truncal vagotomy (TV), selective gastric vagotomy (SGV), and selective proximal vagotomy (SPV) result in an increase of basal serum gastrin concentrations in man and animals [18-24]; food-stimulated gastrin output in most studies is slightly elevated. TV causes either a diminution [12] or an abolition [25] of gastrin release by insulin hypoglycemia, whereas after SPV, sham feeding-induced gastrin release in duodenal ulcer (DU) patients is potentiated. Patients with complete vagotomy have been reported to have a higher gastrin level than those with incomplete vagotomy [26], which suggests that in this instance, the loss of acid inhibition in the antrum outweighed the loss of gastrin release by the vagus [27]; these results could not be confirmed by Jaffe and colleagues [28]. Medical vagotomy by atropinization does not alter [29-31] or decreases slightly [32] basal serum gastrin levels in normal man, DU patients, and dogs, but depresses the hypergastrinemia in achlorhydric patients [31]. Food-stimulated gastrin levels are enhanced by atropine in man [30, 32, 33]. Vagally induced gastrin release by sham feeding is totally blocked by atropine [29], whereas gastrin release during electrical vagal stimulation is not altered [34]. Insulin-stimulated serum gastrin levels have been reported to be either slightly [35] or strongly [36, 37] enhanced by atropine, which indicates that a major part of the hypoglycemic release of gastrin is independent of a cholinergic mechanism. After TV, atropine depresses the gastrin response to a meal strongly in dogs [38], whereas in man the postprandial gastrin output is enhanced [39].
Fig. 2. Integrated postprandial gastrin output after different types of vagotomy [43]. There is still some controversy about whether the extent of vagotomy influences postoperative gastrin levels. Hansky and colleagues [40] reported the highest postprandial gastrin increase after TV, whereas SGV and SPV did not differ significantly. Fisher and colleagues [41] compared DU patients who received either SPV or SGV plus pyloroplasty (P). Both types of vagotomy showed an identical increase in postoperative basal serum gastrin levels; however, the gastrin response to food was augmented only by SPV. These findings were not confirmed by Jaffe and colleagues [28]. Brandsborg and colleagues [42] reported an insignificant increase of integrated postprandial gastrin output after SPV with or without a drainage procedure, but a large increase after selective gastric vagotomy plus drainage. In order to compare the different types of vagotomy with regard to their postprandial gastrin release, we [43] have performed these operations in dogs successively to avoid individual variations (Fig. 1). Basal serum gastrin levels were significantly elevated after SPV, but were further increased after SGV and TV. The postprandial gastrin output (Fig. 2) was increased by all types of vagotomy; however, the highest gastrin levels, especially 2-3 hours after food intake, were observed after TV, which indicates disturbed gastric emptying. Adding a pyloroplasty to SPV, where the gastric antrum remains innervated, does not alter postvagotomy hypergastrinemia [25, 42]. In SGV, Jaffe and colleagues [28] found lower postprandial gastrin levels in DU patients with a pyloroplasty, compared to patients without a drainage procedure. However, all studies show that the addition of a drainage procedure does not decrease serum gastrin levels to preoperative values, which indicates that either postvagotomy stasis is only a minor factor in postvagotomy hypergastrinemia, or that the drainage
H.D. Becker et al.: Effect of Vagotomy on GI Hormones
Table 1. Influence of vagus nerve on pancreatic secretion [55]. I.
II.
III.
IV.
Cephalic phase of pancreatic secretion [79-81] Weak stimulation of volume during sham feeding Weak stimulation of bicarbonate during sham feeding Distinct stimulation of protein during sham feeding Gastric phase of pancreatic secretion [82-85] Gastric acid release of secretin Gastrin = a partial agonist for enzyme secretion Gastropancreatic reflex Intestinal phase of pancreatic secretion [49, 50, 86] Possible cholinergic control of hormone released by intestinal stimuli Possible interruption of an enteropancreatic reflex Direct vagal effects on the pancreas [55, 87] Interaction of acetylcholine, secretin, and CCK on amylase secretion from isolated acinar cells Postganglionic cholinergic fibers stimulate acinarcell secretion of amylase
procedures do not normalize disturbed gastric emptying. An important factor responsible for the postvagotomy hypergastrinemia is the reduction of acid secretion. However, in studies in DU patients using constant pH values during food stimulation by intragastric titration pre- and postvagotomy, postprandial gastrin levels were significantly higher 3-6 months after SPV compared to preoperative values. An explanation for the increased gastrin liberation at constant pH after vagal denervation is suggested by the increase in gastrin concentrations in the antral mucosa [44], and the increase in G-cell numbers [45]. Eight weeks after TV and P in rats, the known increase in basal and postprandial serum gastrin levels was accompanied by a 3-fold increase in gastrin content of antral mucosa and a 2-fold increase in G cells per area; the activity of the single G cell seemed to be unaltered. These findings were confirmed by other groups [46, 47]. The increase ofgastrin content and G cells in the antral mucosa is most likely due to the chronic hypochlorhydria after vagotomy, since similar changes are observed in patients with pernicious anemia.
Secretin and Cholecystokinin (CCK) The polypeptide hormones secretin and CCK are localized in mucosa of the upper small intestine, and represent the major humoral factors that regulate pancreatic secretion. The stimulus for pancreatic water and H C Q - secretion is secretin released by gastric acid, whereas CCK is the major stimulus for enzyme secretion in response to protein and fat
617
digestion products in the intestine. Since RIA methods for direct measurement of serum concentrations of both hormones are not yet well developed, most of our knowledge is based upon pancreatic secretory studies. Only Ward and Bloom [48] have measured by RIA the release of secretin stimulated by intraduodenal instillation of hydrochloric acid in normal subjects, DU patients, patients with TV plus P, SGV plus P and SPV. A highly significant response occurred in all groups. There was no significant difference between the groups, either in the magnitude or timing of the response, which indicates that secretin release is not dependent upon intact innervation of the small intestine in man. Proven or postulated actions of the vagus nerves on pancreatic responses to a meal are summarized in Table 1. TV or anticholinergics depress the pancreatic response to different intestinal stimuli while having little or no effect on the response to exogenous secretin or CCK [49-52]. After SPV, an increased sensitivity of the bicarbonate-producing cells to low doses of secretin, and a decreased bicarbonate secretory capacity of the pancreas have been reported [53]. Others have observed a fall in basal pancreatic secretion, while in stimulated secretion, volume, bicarbonate output, and enzyme output were unchanged [54]. In dogs, Debas and colleagues [51] observed that after extragastric vagotomy, the protein secretory response to intestinal perfusion with oleate (CCK release) was decreased, and that subsequent TV caused a further loss of response. Pancreatic secretion stimulated by the exogenous octapeptide of CCK was unchanged by either type of vagotomy. These studies do not allow us to determine whether the reduction of pancreatic secretion after vagotomy is due to removal of a physiologic background of vagal activity which allows an optimal release of secretin or CCK from the intestinal mucosa, or whether the pancreatic response to intestinal stimuli is mediated by an enteropancreatic reflex with both afferent and efferent limbs in the vagus nerve [55]. This problem can be solved only by using the autotransplanted pancreas preparation described by Wang and Grossman [56]. Solomon and Grossman [55] were able to show that truncal vagotomy did not alter the response of the transplanted pancreas to intestinal stimuli such as tryptophan, oleate, or hydrochloric acid. These findings indicate that the reduction in pancreatic secretion after vagotomy is not due to changes in intestinal hormone release, but is more likely due to interruption of an enteropancreatic reflex. However, a definite answer must await the development of reliable RIA's for both hormones.
618
World J. Surg. Vol. 3, No. 5, 1979
Insulin
Pancreatic Polypeptide (PP)
There is strong evidence that the vagus nerve plays a role in the release of insulin. In studies using the isolated, perfused rat pancreas, acetylcholine induced a prompt release of insulin [57], and direct vagal stimulation resulted in a release of insulin [58, 59]. Several studies [60-63] have demonstrated that after SPV or SGV plus P, basal serum insulin levels and the postprandial insulin output were not changed. After TV, the insulin response to an oral glucose tolerance test or a test meal was either diminished [60, 62] or unchanged [61, 63, 64].
Pancreatic polypeptide is a 36-amino acid polypeptide that has been localized to secretory granules in the islets, acinar tissue, and duct epithelium of the pancreas. At present, it seems likely that PP acts on the exocrine pancreatic tissue as a local regulator of secretion in a way that may be conceived as an anti-CCK and secretin-enhancing action. The effect of parasympathetic stimulation on PP secretion was extensively studied by Schwartz and colleagues [70]. Plasma PP concentration increased in response to insulin-induced hypoglycemia in both normal subjects and DU patients. The PP response to hypoglycemia was diminished by atropine in normal subjects and abolished by vagotomy in DU patients. Electrical vagal stimulation induced an increase of PP levels in the portal vein, which was inhibited by atropine. Acetylcholine stimulated the secretion of PP from isolated perfused pancreas. After a meal, PP concentrations in plasma increased rapidly. Vagotomy markedly reduces the PP response to a meal [71, 72]; therefore, it has been suggested that postprandial PP release may be an important test for the completeness of vagotomy. Atropine also decreases postprandial PP output [73]. These findings indicate that vagal cholinergic stimulation is a major regulator of PP secretion.
Pancreatic Glucagon
Like insulin, pancreatic glucagon is released by vagal stimulation from the pancreas [58]. In studies of the pancreatic glucagon release during insulin hypoglycemia in patients with either SGV or TV, Russell and colleagues [61] found no change in basal glucagon levels, but significantly lower glucagon concentrations after insulin injection in TV patients, compared to SGV patients. Gastric Inhibitory Polypeptide (GIP)
In 1969 Brown and colleagues [65] isolated a polypeptide from intestinal mucosa that inhibited gastric acid secretion stimulated by pentagastrin, insulin, and histamine, and stimulated insulin release in the presence of glucose. GIP is released after food intake, but its inhibitory effect on gastric acid secretion may be pharmacologic. TV in man [63] and dogs [66] results in an increase of basal serum GIP levels. Our studies showed that postprandial serum GIP concentrations in DU patients are not altered either by truncal vagotomy or selective proximal vagotomy. The increase of GIP levels after vagotomy, which has been described by Thomford and colleagues [67], was due to the fact that DU patients show a higher GIP output than controls. However, atropine seems to strongly inhibit postprandial GIP release [68].
Somatostatin
Somatostatin, the growth hormone-release-inhibiting hormone, is found in large quantities in the upper GI tract. Almost nothing is known about the relationship between the vagus nerve and somatostatin. Uvn/is-Wallensten and colleagues [74] observed that electrical vagal stimulation caused an increase of somatostatin release into the antral lumen of cats, when the antrum was perfused with HC1 and gastrin output was reduced. During alkalinization of the antral lumen, vagal stimulation failed to release somatostatin, whereas gastrin levels in gastric juice were high.
Other Hormones Enteroglucagon
A number ofpeptides can be extracted from the mucosa of the GI tract that are glucagon-like in their behavior towards antisera raised against pancreatic glucagon. Lefebvre and colleagues [69] observed no glucagon release from the stomach during electrical vagal stimulation. Russell and colleagues [61] found no difference in plasma enteroglucagon levels when comparing patients with TV and SGV plus P.
Nothing is known about the relationship between VIP, motilin, chymodenin, bulbogastrone, enterooxyntin, and the vagus nerve. Enterogastrone, which may include several other hormones such as secretin and GIP, is released after intraduodenal instillation of HC1 and fat. Several authors [75, 76] reported a diminution of the inhibitory effect of intraduodenal acid on gastric secretion after TV or SPV, whereas others [77] could not confirm these
H.D. Becker et al.: Effect of Vagotomy on GI Hormones
findings. The inhibitory effect of intraduodenal fat was not altered by TV [78]. R6surn~ Divers types de vagotomie ont 6t6 utilis6s dans le traitement de la maladie ulc6reuse. Pour l'activit6 optimale du tube digestif, il doit exister une relation 6troite entre le neff vague et la lib6ration ou l'effet des hormones gastro-intestinales. La gastrin6mie est 6levee apr~s tous les types de vagotomie. Ceci r6sulte de modifications du pH antral ou de la motilit6 gastrique, ces deux facteurs pouvant stimuler la prolif6ration des cellules G. La r6duction de la s6cr6tion pancr6atique apr6s vagotomie n'est pas due ~t des modifications des lib6rations hormonales, mais r6sulte peut-~tre d'une interruption d'un hypoth6tique reflux ent6ro-pancr6atique. Apr6s vagotomie, la lib6ration postprandiale de GIP et l'insulin6mie ne sont pas modifi6es, mais le taux basal de GIP est accru. La lib6ration postprandiale de polypeptide pancr6atique est presque abolie par la vagotomie, mais elle se normalise tardivement apr6s l'op6ration. Ces observations peuvent 6tre importantes pour l'interpr6tation des cons6quences physiologiques et pathologiques de la vagotomie. References 1. Uvn~is-Wallensten, K., Rehfeld, J.F., Larsson, I., Uvniis, B.: Heptadecapeptide gastrin in vagal nerve. Proc. Natl. Acad. Sci. U.S.A. 74:5707, 1977 2. Uvn~is, B.: The part played by the pyloric region in the cephalic phase of gastric secretion. Acta Physiol. Scand. 4[Suppl. 13]:1, 1942 3. Pe Thein, M., Schofield, B.: Release of gastrin from the pyloric antrum following vagal stimulation by sham feeding in dogs. J. Physiol. (Lond.)184:295, 1959 4. Olbe, L.: Vagal release of gastrin. In Gastrin, Grossman, M.I., editor. London, Butterworth, 1964 5. Becker, H.D., Reeder, D.D., Thompson, J.C.: Direct measurement of vagal release of gastrin. Surgery 75:101, 1974 6. Lanciault, G., Bonoma, C., Brooks, F.P.: Vagal stimulation, gastrin release and acid secretion in anesthetized dogs. Am. J. Physiol. 225:546, 1973 7. Uvniis, B., Uvniis-Wallensten, K., Nilsson, G.: Release of gastrin on vagal stimulation in the cat. Acta Physiol. Scand. 94:167, 1975 8. Klempa, I., Becker, H.D.: Vagus--Gastrin--Magensekretion. Stuttgart, Thieme, 1977 9. Knutson, U.L., Olbe, L., Ganguli, P.C.: Gastric acid and plasma gastrin responses to sham feeding in duodenal ulcer patients before and after resection of the antrum and duodenal bulb. Scand. J. Gastroenterol. 9:351, 1974 10. Mayer, G., Arnold, R., Feurle, G., Fuchs, K., Ketterer, H., Track, N.S., Creutzfeldt, W.: Influence of feeding and sham feeding upon gastrin and gastric acid secretion in control subjects and duodenal ulcer patients. Scand. J. Gastroenterol. 9:703, 1974 11. Stadil, F., Rehfeld, J.F.: Hypoglycemic release ofgastrin in man. Scand J. Gastroenterol. 7:509, 1972 12. Stadil, F.: Gastrin and insulin hypoglycemia. Scand. J. Gastroenterol. 9[Suppl. 23]: 1, 1974
619
13. Evans, S.O., Zubiran, J.N., McCarthy, J.D., Radius, H., Woodward, E.R., Dragstedt, L.R.: Stimulating effect of vagotomy on gastric secretion in Heidenhain pouch dogs. Am. J. Physiol. 174:219, 1953 14. Oberhelman, H.A., Johnson, A.N., Dragstedt, L.R.: Relationship of antral and fundic denervation of gastric secretion. Am. J. Physiol. 201:171, 1961 15. Landor, J.H.: The effect of extragastric vagotomy on Heidenhain-pouch secretion in dogs. Am. J. Dig. Dis. 9:256, 1964 16. Emits, S., Grossman, M.I.: Response of Heidenhain pouch to histamine, gastrin and feeding before and after truncal vagotomy in dogs. Scand. J. Gastroenterol. 4:497, 1969 17. Stening, G.F., Grossman, M.I.: Gastric acid response to pentagastrin and histamine after extragastric vagotomy in dogs. Gastroenterology 59:364, 1970 18. McGuigan, J.E., Trudeau, W.L.: Serum gastrin levels before and after vagotomy and pyloroplasty or vagotomy and antrectomy. N. Engl. J. Med. 286:184, 1972 19. Walsh, J.H., Csendes, A., Grossman, M.I.: Effect oftruncal vagotomy on gastrin release and Heidenhain pouch acid secretion in response to feeding in dogs. Gastroenterology 63:593, 1972 20. Jaffe, B.M., Clendinnen, B.G., Clarke, R.J., Alexander-Williams, J.: Gastrin response to selective and parietal cell vagotomies. Surg. Forum 23:324, 1972 21. Becker, H.D., Reeder, D.D., Thompson, J.C.: Effect of truncal vagotomy with pyloroplasty or with antrectomy on food-stimulated gastrin values in patients with duodenal ulcer. Surgery 74:580, 1973 22. Becker, H.D., Reeder, D.D., Thompson, J.C.: Vagal control of gastrin release. In Gastrointestinal Hormones, Thompson, J.C., editor. Austin, University of Texas Press, 1975, p. 437 23. Stern, D.H., Walsh, J.H.: Gastrin release in postoperative ulcer patients: evidence for release of duodenal gastrin. Gastroenterology 64:363, 1973 24. Stadil, F.: Gastrin response to food in duodenal ulcer patients before and after highly selective vagotomy. Br. J. Surg. 61:884, 1975 25. Hansky, J., Soveny, C., Korman, M.G.: Role of the vagus in insulin-mediated gastrin release. Gastroenterology 63:387, 1972 26. Walsh, J.H., Grossman, M.I.: Circulating gastrin in peptic ulcer disease. Mt. Sinai J. Med. 40:374, 1973 27. Thompson, J.C.: The effect of vagotomy on circulating gastrin. In Vagotomy: Latest Advances, Holle, F., Andersson, S., editors. New York, Springer-Verlag, 1974, p. 59 28. Jaffe, B.M., Clendinnen, B.G., Clarke, R.J., Alexander-Williams, J.: Effect of selective and proximal gastric vagotomy on serum gastrin. Gastroenterology 66:944, 1974 29. Nilsson, G., Simon, J., Yalow, R.S., Berson, S.A.: Plasma gastrin and gastric acid responses to sham feeding and feeding in dogs. Gastroenterology 63:51, 1972 30. Walsh, J.H., Yalow, R.S., Berson, S.A.: The effect of atropine on plasma gastrin response to feeding. Gastroenterology 60:16, 1971 31. Schrumpf, E., Myren, J.: Effect of atropine on plasma concentration of gastrin in fasting subjects. Scand. J. Gastroenterol. 9:123, 1974 32. Becker, H.D., Reeder, D.D., Thompson, J.C.: The effect of atropine on basal and food stimulated gastrin levels in man. Gastroenterology 64:694, 1973 33. Korman, M.G., Soveny, C., Hansky, J.: Serum gastrin in duodenal ulcer. Part I. Basal levels and effect of food and atropine. Gut 12:899, 1971 34. Uvniis-Wallensten, K., Anderson, H.: Effect of atropine and methiamide on vagally induced gastric acid secretion and gastrin release in anesthetized cats. Acta Physiol. Scand. 99:496, 1977 35. Stadil, F., Malmstr0m, J., Rehfeld, J.F., Miyata, M.: Effect of atropine on hypoglycemic release of gastrin in man. Acta Physiol. Scand. 92:391, 1974
620 36. Schrumpf, E., Vatn, M.H., Semb, L.S.: Effect of atropine on insulin-stimulated gastrin release and gastric secretion of acid pepsin and intrinsic factor. Scand. J. Gastroenterol. 9:665, 1974 37. Farooq, O., Walsh, J.H.: Atropine enhances serum gastrin response to insulin in man. Gastroenterology 68:662, 1975 38. Debas, H.T., Walsh, J.H., Grossman, M.I.: After vagotomy atropine suppresses gastrin release by food. Gastroenterology 70:1082, 1976 39. Hansky, J., King, R.W.F.: Effect of atropine on food-stimulated gastrin release after truncal vagotomy in man. Gastroenterology 73:205, 1977 40. Hansky, J., Korman, M.G., Coupland, G.A.E., Cumberland, V.H.: Gastrin studies after parietal cell vagotomy. Digestion 8:1, 1973 41. Fischer, J.E., Kragelund, E., Nielson, A., Wesdorp, R.I.C.: Basal and meat extract plasma gastrin before and after parietal cell vagotomy and selective gastric vagotomy with drainage in patients with duodenal ulcer. Ann. Surg. 183:167, 1976 42. Brandsborg, O., Brandsborg, M., Lcvgreen, N.A., Mikkelsen, K., Moiler, B., Rokkjaer, M., Amdrup, E.: Influence of parietal cell vagotomy and selective gastric vagotomy on gastric emptying rate and serum gastrin concentration. Gastroenterology 72:212, 1977 43. Becker, H.D., Reeder, D.D., Thompson, J.C.: Effect of vagotomy on postprandial gastrin levels and Heidenhain-pouch secretion in the dog. Dtsch. Med. Wochenschr. 99:1023, 1974 44. Becker, H.D., Reeder, D.D., Thompson, J.C.: Influence of vagotomy on tissue gastrin levels in stomach and pancreas in rats. Surgery 74:778, 1973 45. Becker, H.D., Arnold, R., B6rger, H.W., Creutzfeldt, C., Schafmayer, A., Creutzfeldt, W.: Influence of truncal vagotomy on serum and antral gastrin and G cells. Gastroenterology 72:811, 1977 46. Hughes, W.S., Hernandez, A.J.: Antral gastrin concentration in patients with vagotomy and pyloroplasty. Gastroenterology 71:720, 1976 47. Malmstrcm, J., Stadil, F., Christensen, K.C.: Effect oftruncal vagotomy on gastroduodenal content of gastrin. Br. J. Surg. 64:34, 1977 48. Ward, A.S., Bloom, S.R.: Effect of vagotomy on secretin release in man. Gut 16:951, 1975 49. Konturek, S.J., Becker, H.D., Thompson, J.C.: Effect of vagotomy on hormones stimulating pancreatic secretion. Arch. Surg. 108:704, 1974 50. Moreland, H.J., Johnson, L.R.: Effect of vagotomy on pancreatic secretion stimulated by endogenous and exogenous secretin. Gastroenterology 60:425, 1971 51. Debas, H.T., Konturek, S.J., Grossman, M.I.: Effect ofextragastric and truncal vagotomy on pancreatic secretion in the dog. Am. J. Physiol. 228:1172, 1975 52. MacGregor, I.L., Parent, J., Meyer, J.H.: Gastric emptying of liquid meals and pancreatic and biliary secretion after subtotal gastrectomy or truncal vagotomy and pyloroplasty in man. Gastroenterology 72:195, 1977 53. Berstad, A., Roland, M., Peterson, H., Liavag, I.: Altered pancreatic function after proximal gastric vagotomy in man. Gastroenterology 71:958, 1976 54. Lindskov, J., Amtorp, O., Larsen, H.R.: The effect of highly selective vagotomy on exocrine pancreatic function in man. Gastroenterology 70:545, 1976 55. Solomon, T., Grossman, M.I.: Vagal control of pancreatic exocrine secretion. In Nerves and the Gut, Brook, F.P. editor. Thorofare, N.J., Charles B. Slack, 1977 56. Wang, C.C., Grossman, M.I.: Physiological determination of release of secretin and pancreozymin from intestine of dogs with transplanted pancreas. Am. J. Physiol. 164:527, 1961 57. Loubati6res-Mariam, M.M., Chapal, J., Alric, R., Loubati6res, A.: Studies of the cholinergic receptors involved in the secretion of insulin using isolated perfused rat pancreas.
World J. Surg. Vol. 3, No. 5, 1979
Diabetologia 9:439, 1973 58. Bloom, S.R., Edwards, A.V., Vaugham, N.I.A.: The role of the autonomic innervation in the control of glucagon release during hypoglycemia in the calf. J. Physiol. (Lond.)236:611, 1974 59. Daniel, P.M., Henderson, J.R.: The effect of vagal stimulation on plasma insulin and glucose levels in the baboon. J. Physiol. (Lond.) 192:317, 1967 60. Aagard, P., Deckert, T., Fenger, H.J.: Serum insulin after intravenous administration of glucose before and after total vagotomy. Scand. J. Gastroenterol. 8:699, 1973 61. Russell, R.G.G., Thompson, J.P.S., Bloom, S.R.: The effect of truncal and selective vagotomy on the release of pancreatic glucagon, insulin, and enteroglucagon. Br. J. Surg. 61:821, 1974 62. Humphrey, C.S., Dykes, J.R., Johnston, D.: Effects oftruncal, selective, and highly selective vagotomy on glucose tolerance and insulin secretion in patients with duodenal ulcer. Br. Med. J. 2:114, 1975 63. Becker, H.D., Arnold, R., B6rger, H.W., Ebert, R., Schafmayer, A., Creutzfeldt, W.: Effect of selective proximal vagotomy (SPV) on serum concentrations of GIP, insulin and gastrin in duodenal ulcer patients. Gastroenterology 74:1007, 1978 64. Grossman, M.I. and others: Candidate hormones of the gut. I. Introduction. Gastroenterology 67:730, 1974 65. Brown, J.C., Peterson, R.A., Jorpes, E., Mutt, V.: Preparation of highly active enterogastrone. Can. J. Physiol. Pharmacol. 47:113, 1969 66. Becker, H.D., Schafmayer, A., B6rger, H.W.: Effect ofextragastric and truncal vagotomy on gastric secretion, serum gastrin, serum insulin, and serum GIP levels. Abstract, International Congress of Gastroenterology, Budapest, 1976 67. Thomford, N.R., Sirnick, K.R., Croche, H.S.E., Mazzaferri, E.L., Cataland, S.: Gastric inhibitory polypeptide. Response to oral glucose after vagotomy and pyloroplasty. Arch. Surg. 109:177, 1974 68. Baumert, J.E., Cataland, S., Tetirick, C.E., Pace, W.G., Mazzaferri, E.L.: Effect of atropine on meal-stimulated gastrin and gastric inhibitory polypeptide (GIP) release. J. Clin. Endocrinol. Metab. 46:473, 1978 69. Lefebvre, P.J., Luycks, A.S., Brassine, A.H.: Vagal stimulation and its role in eliciting gastrin but not glucagon release from the isolated perfused dog stomach. Gut 19:185, 1978 70. Schwartz, T.W., Holst, J.J., Fahrenkrug, J., Lindkaer-Jensen, S., Nielsen, O.V., Rehfeld, J.F., Schaffalitzky de MuckadeU, O.B., Stadil, F.: Vagal, cholinergic regulation of pancreatic polypeptide secretion. J. Clin. Invest. 61:781, 1978 71. Schwartz, T.W., Rehfeld, J.F., Stadil, F., Larsson, L.I., Chance, R.E., Noon, N.: Pancreatic polypeptide response to food in duodenal ulcer patients before and after vagotomy. Lancet 1 : 1102, 1976 72. Adrian, T.E., Bloom, S.R., Besterman, H.S., Barnes, A.J., Cooke, T.J.C., Russell, R.C.G., Faker, R.G.: Mechanism of pancreatic polypeptide release in man. Lancet 1:161, 1977 73. Taylor, I.L., Impicciatore, M., Walsh, J.H.: Effect of atropine and vagotomy on the pancreatic polypeptide response to a meal. Gastroenterology 72:1139, 1977 74. Uvn~is-Wallensten, K., Efendic, F., Luft, R.: Vagal release of somatostatin into the antral lumen of cats. Acta Physiol. Scand. 99:126, 1977 75. Ward, A.S.: The effect of vagotomy on the inhibition of gastric secretion by intraduodenal acid. Br. J. Surg. 61:698, 1974 76. Linares, C.A., Falesca, C.A., Sartorio, G.C., Soto, R.J.: Effect of intraduodenal acid on the pre- and postvagotomy basal gastric secretion and gastrin. Surgery 81:392, 1977 77. Kaminsky, D.L., Ruwart, M.J.: The effect of vagotomy on the canine enterogastrone mechanism. Surgery 81:80, 1977 78. Christiansen, J.: Fat-induced inhibition of gastric acid secretion in duodenal ulcer patients before and after truncal vagotomy. Ann. Surg. 186:573, 1977
H.D. Becker et al.: Effect of Vagotomy on GI Hormones
79. Preshaw, R.M., Cooke, A.P., Grossman, M.I.: Sham feeding and pancreatic secretion in the dog. Gastroenterology 50:171, 1966 80. Sarles, H., Dani, R., Prezelin, G.: Cephalic phase of pancreatic secretion in the dog. Gastroenterology 50:171, 1966 81. Novis, B.H., Bank, S., Marks, I.N.: The cephalic phase of pancreatic secretion in man. Scand. J. Gastroenterol. 6:417, 1971 82. Blair, E.L., Brown, J.C., Harper, A.A.: A gastric phase of pancreatic secretion. J. Physiol. (Lond.)184:812, 1966 83. Preshaw, R.M., Cooke, A.R., Grossman, M.I.: Stimulation of pancreatic secretion by a humoral agent from the pyloric gland area of the stomach. Gastroenterology 49:617, 1965
Invited Commentary Haile T. Debas, M.D. Faculty of Medicine, University of British Columbia, Vancouver, B.C., Canada
The gastrointestinal (GI) tract contains more endocrine cells than all the other organs in the body put together. These cells release peptides that influence GI function not only as hormones, in the classic sense of the word, but also as local humoral agents (paracrine) and as neural transmitters (neurocrine). In the past, we have considered vagal control of GI secretion (exocrine and endocrine) as being cholinergic. Recently, however, noncholinergic mechanisms have been described, and increasing numbers of peptides have been found in vagal nerve endings in the gut. Among these are VIP, substance P, and somatostatin--peptides also found in the brain itself, thus constituting a "mind-gut axis." Hitherto, we have considered vagotomy as disruption of the cholinergic control of the gut. We have yet to learn what vagotomy does in terms of disrupting this peptidergic system. In their timely review of the effect of vagotomy on GI hormones, Becker and colleagues stress that all forms of vagotomy lead to basal hypergastrinemia and to an exaggerated gastrin response to a meal. They attribute this phenomenon to raised intragastric pH as a result of the vagotomy. I believe the mechanism of postvagotomy hypergastrinemia is more complex, although, undoubtedly, pH changes are important. At least 2 more components of the mechanism can be defined. First, the vagus itself contains fibers inhibitory to gastrin release, as was shown by selective cooling of these fibers by Cairns et al. [1]. Farooq and Walsh [2], in a classic experiment, showed that atropine enhances serum gastrin response to insulin in man when any effects of pH were abolished. Indeed, I believe the vagus should be regarded more as an inhibitory nerve of gastrin release than as a
621
84. White, T.T., Lundh, G., Magee, D.F.: Evidence for the existence of a gastropancreatic reflex. Am. J. Physiol. 198:725, 1960 85. Magee, D.F., Fragola, L.F., White, T.T.: Gastric acid and the gastropancreatic distention reflex. Gastroenterology 44:811, 1963 86. Andrews, C.J.H., Andrews, W.H.H.: Receptors, activated by acid, in the duodenal wall of rabbits. Q. J. Exp. Physiol. 56:221, 1971 87. Solomon, T.E., Solomon, N., Shanbour, L.L., Jacobson, E.D.: Direct effects of cholinergic stimulation on pancreatic secretion. Gastroenterology 64:804, 1973
stimulatory one. Second, we have evidence that the fundus has an inhibitory control of gastrin release through a neurohormonal mechanism that appears to require intact vagal pathways. Following proximal gastric vagotomy, Yamagishi et al. [3] showed that food-stimulated gastrin release was exaggerated within 1 week of the operation, even though pH was held constant by intragastric titration. More recently, Soon-Shiong et al. [4] have shown that excision of the parietal cell mucosa leads to an exaggerated gastrin release after a meal and to an enhanced Heidenhain pouch acid response to gastrin and histamine. What we do not know is to what degree, if at all, the peptides found at the vagal nerve endings subserve the mechanism of these changes. Becker and his colleagues have shown that, following vagotomy, antral tissue gastrin and the number of G cells in the antrum increase [5, 6]. These changes could be due to chronic pH changes as they have suggested, but additional mechanisms have not been excluded. Among these additional explanations could be decreased release of an inhibitor of gastrin release and changes in the paracrine and neurocrine control of the antrum secondary to vagotomy. Before the advent of radioimmunoassay, we, as surgeons, believed that vagotomy reduced acid secretion by decreasing antral gastrin release. We now know differently. The observations that v.agotomy, in fact, leads to hypergastrinemia stresses the fact that the main mechanisms for postvagotomy reduction of acid secretion are withdrawal of direct vagal action on the parietal cell and cholinergic sensitization of the cell to the action of gastrin. We now think that this acid reduction is the main reason why ulcers heal after vagotomy. Could the hypergastrinemia that follows vagotomy be important in the healing of ulcers? This intriguing hypothesis has found some support in the interesting findings of Takeuchi and Johnson [7], who showed that pentagastrin protects against stress ulceration in rats. I think it is too early to be sure of the effect of vagotomy on the release of secretin and cholecys-
WofldJournal
of Sdrgery
Effect of Vagotomy on Gastrointestinal Hormones H.D. Becker, M.D., H.W. B6rger, M.D., and A. Schafmayer, M.D. Departmentof Surgery,Universityof G6ttingen,WestGermany Different types of vagotomy have been widely used in the treatment of peptic ulcer disease. A close relationship between the vagus nerve and the release or action of gastrointestinal hormones is necessary for the optimal activation of the gastrointestinal tract. The serum concentrations of the antral hormone gastrin are elevated after all types of vagotomy. The postvagotomy hypergastrinemia is due to the change in pH in the antral lumen or the gastric motility changes, both of which may lead to a proliferation of G cells. The reduction in pancreatic secretion after vagotomy is not due to changes in intestinal hormone release, but may be caused by the interruption of a postulated enteropancreatic reflex. Postprandial GIP release and serum insulin levels are not affected by vagotomy, but basal GIP levels are increased after vagotomy. Postprandial pancreatic polypeptide release is nearly abolished by vagotomy, but seems to normalize in the later postoperative course. These findings may be important for the interpretation of pathophysiologic changes after vagotomy.
been widely used in the surgical treatment of peptic ulcer disease, so that the effect of vagotomy on GI hormones is of major importance for the understanding of pathophysiologic changes induced by vagotomy. Gastrin
The relationship between the vagus nerve and the antral hormone gastrin includes gastrin release by vagal stimulation, vagal control of gastrin release by local stimuli, and behavior of serum gastrin and antral mucosa gastrin content after vagotomy. Uvn/is [2] in 1942 found strong evidence that stimulation of the antral vagus nerve resulted in release of gastrin from the antrum. These findings were confirmed by several other groups [3, 4]. Measurement of serum gastrin concentrations by RIA during electrical vagal stimulation [5-8], sham feeding [9, 10], or insulin hypoglycemia [11, 12] showed an increase in gastrin levels in man and laboratory animals. Gastrin release induced by insulin hypoglycemia also occurs after vagotomy, indicating that a noncholinergic mechanism is involved [12]. It has been known for some time that in dogs with denervated Heidenhain pouches (HP), transection of the vagal fibers to the innervated main stomach results in an increase of basal [13, 14] and foodstimulated [14-16] HP acid secretion. Since acid secretion stimulated by exogenous gastrin also is increased, it was postulated that vagotomy abolished a vagally controlled inhibitor ("vagogastrone"). Furthermore, vagotomy of the extragastric vagal fi-
A continuous interplay between the vagus nerve, which is responsible for the parasympathetic innervation of most of the intra-abdominal organs, and the gastrointestinal hormones is necessary for optimal activation of the gastrointestinal (GI) tract after food intake. After the development of sensitive, specific radioimmunoassays (RIA) for direct measurements of GI hormone concentrations, new aspects of these interrelationships were demonstrated. The vagus nerve controls the release of several GI hormones. Furthermore, the GI hormone, gastrin, has been found in the vagus nerve [1], and may function as a neurotransmitter. Vagotomy has
Reprint requests: Dr. H.D. Becker, Department of Surgery, University of G6ttingen, D-3400 G6ttingen, West Germany.
0364-2313/79/0003-0615 $01.60 9 1979 Soci6t6 Internationale de Chirurgie 615
616
World J. Surg. Vol. 3, No. 5, 1979
mv
o- - - - .4
SGV
,,= - - = ,
Control i SPV
SPV
9 ....... 9
SGV
Control
*
TV I ~
300 12,5
25,0
T
250
Gastrin pg/ml
20O 150
~,~
....
/e ,+> ...... ..e.'"
"~- --..4 "*'"'I
. ... . ... .o~176 . . .. . ... e ,.. .
,.~
10,0
20,0
Jnteg. Gastrin n g . m i n 7,5 ml
15.0
5,0
10+0
2.5
5.0
]nteg Gastrin ng.min rn[
.
100
0-90
91-180
0-180
Minutes
6 6,'o1's"3'o
6'o 9'0 Go 16o 40 Minutes
Fig. 1. Serum gastrin response to food in 6 dogs after different types o f vagotomy [43].
bers alone stimulated HP acid secretion [15, 17]. Several studies in the last years have demonstrated that truncal vagotomy (TV), selective gastric vagotomy (SGV), and selective proximal vagotomy (SPV) result in an increase of basal serum gastrin concentrations in man and animals [18-24]; food-stimulated gastrin output in most studies is slightly elevated. TV causes either a diminution [12] or an abolition [25] of gastrin release by insulin hypoglycemia, whereas after SPV, sham feeding-induced gastrin release in duodenal ulcer (DU) patients is potentiated. Patients with complete vagotomy have been reported to have a higher gastrin level than those with incomplete vagotomy [26], which suggests that in this instance, the loss of acid inhibition in the antrum outweighed the loss of gastrin release by the vagus [27]; these results could not be confirmed by Jaffe and colleagues [28]. Medical vagotomy by atropinization does not alter [29-31] or decreases slightly [32] basal serum gastrin levels in normal man, DU patients, and dogs, but depresses the hypergastrinemia in achlorhydric patients [31]. Food-stimulated gastrin levels are enhanced by atropine in man [30, 32, 33]. Vagally induced gastrin release by sham feeding is totally blocked by atropine [29], whereas gastrin release during electrical vagal stimulation is not altered [34]. Insulin-stimulated serum gastrin levels have been reported to be either slightly [35] or strongly [36, 37] enhanced by atropine, which indicates that a major part of the hypoglycemic release of gastrin is independent of a cholinergic mechanism. After TV, atropine depresses the gastrin response to a meal strongly in dogs [38], whereas in man the postprandial gastrin output is enhanced [39].
Fig. 2. Integrated postprandial gastrin output after different types of vagotomy [43]. There is still some controversy about whether the extent of vagotomy influences postoperative gastrin levels. Hansky and colleagues [40] reported the highest postprandial gastrin increase after TV, whereas SGV and SPV did not differ significantly. Fisher and colleagues [41] compared DU patients who received either SPV or SGV plus pyloroplasty (P). Both types of vagotomy showed an identical increase in postoperative basal serum gastrin levels; however, the gastrin response to food was augmented only by SPV. These findings were not confirmed by Jaffe and colleagues [28]. Brandsborg and colleagues [42] reported an insignificant increase of integrated postprandial gastrin output after SPV with or without a drainage procedure, but a large increase after selective gastric vagotomy plus drainage. In order to compare the different types of vagotomy with regard to their postprandial gastrin release, we [43] have performed these operations in dogs successively to avoid individual variations (Fig. 1). Basal serum gastrin levels were significantly elevated after SPV, but were further increased after SGV and TV. The postprandial gastrin output (Fig. 2) was increased by all types of vagotomy; however, the highest gastrin levels, especially 2-3 hours after food intake, were observed after TV, which indicates disturbed gastric emptying. Adding a pyloroplasty to SPV, where the gastric antrum remains innervated, does not alter postvagotomy hypergastrinemia [25, 42]. In SGV, Jaffe and colleagues [28] found lower postprandial gastrin levels in DU patients with a pyloroplasty, compared to patients without a drainage procedure. However, all studies show that the addition of a drainage procedure does not decrease serum gastrin levels to preoperative values, which indicates that either postvagotomy stasis is only a minor factor in postvagotomy hypergastrinemia, or that the drainage
H.D. Becker et al.: Effect of Vagotomy on GI Hormones
Table 1. Influence of vagus nerve on pancreatic secretion [55]. I.
II.
III.
IV.
Cephalic phase of pancreatic secretion [79-81] Weak stimulation of volume during sham feeding Weak stimulation of bicarbonate during sham feeding Distinct stimulation of protein during sham feeding Gastric phase of pancreatic secretion [82-85] Gastric acid release of secretin Gastrin = a partial agonist for enzyme secretion Gastropancreatic reflex Intestinal phase of pancreatic secretion [49, 50, 86] Possible cholinergic control of hormone released by intestinal stimuli Possible interruption of an enteropancreatic reflex Direct vagal effects on the pancreas [55, 87] Interaction of acetylcholine, secretin, and CCK on amylase secretion from isolated acinar cells Postganglionic cholinergic fibers stimulate acinarcell secretion of amylase
procedures do not normalize disturbed gastric emptying. An important factor responsible for the postvagotomy hypergastrinemia is the reduction of acid secretion. However, in studies in DU patients using constant pH values during food stimulation by intragastric titration pre- and postvagotomy, postprandial gastrin levels were significantly higher 3-6 months after SPV compared to preoperative values. An explanation for the increased gastrin liberation at constant pH after vagal denervation is suggested by the increase in gastrin concentrations in the antral mucosa [44], and the increase in G-cell numbers [45]. Eight weeks after TV and P in rats, the known increase in basal and postprandial serum gastrin levels was accompanied by a 3-fold increase in gastrin content of antral mucosa and a 2-fold increase in G cells per area; the activity of the single G cell seemed to be unaltered. These findings were confirmed by other groups [46, 47]. The increase ofgastrin content and G cells in the antral mucosa is most likely due to the chronic hypochlorhydria after vagotomy, since similar changes are observed in patients with pernicious anemia.
Secretin and Cholecystokinin (CCK) The polypeptide hormones secretin and CCK are localized in mucosa of the upper small intestine, and represent the major humoral factors that regulate pancreatic secretion. The stimulus for pancreatic water and H C Q - secretion is secretin released by gastric acid, whereas CCK is the major stimulus for enzyme secretion in response to protein and fat
617
digestion products in the intestine. Since RIA methods for direct measurement of serum concentrations of both hormones are not yet well developed, most of our knowledge is based upon pancreatic secretory studies. Only Ward and Bloom [48] have measured by RIA the release of secretin stimulated by intraduodenal instillation of hydrochloric acid in normal subjects, DU patients, patients with TV plus P, SGV plus P and SPV. A highly significant response occurred in all groups. There was no significant difference between the groups, either in the magnitude or timing of the response, which indicates that secretin release is not dependent upon intact innervation of the small intestine in man. Proven or postulated actions of the vagus nerves on pancreatic responses to a meal are summarized in Table 1. TV or anticholinergics depress the pancreatic response to different intestinal stimuli while having little or no effect on the response to exogenous secretin or CCK [49-52]. After SPV, an increased sensitivity of the bicarbonate-producing cells to low doses of secretin, and a decreased bicarbonate secretory capacity of the pancreas have been reported [53]. Others have observed a fall in basal pancreatic secretion, while in stimulated secretion, volume, bicarbonate output, and enzyme output were unchanged [54]. In dogs, Debas and colleagues [51] observed that after extragastric vagotomy, the protein secretory response to intestinal perfusion with oleate (CCK release) was decreased, and that subsequent TV caused a further loss of response. Pancreatic secretion stimulated by the exogenous octapeptide of CCK was unchanged by either type of vagotomy. These studies do not allow us to determine whether the reduction of pancreatic secretion after vagotomy is due to removal of a physiologic background of vagal activity which allows an optimal release of secretin or CCK from the intestinal mucosa, or whether the pancreatic response to intestinal stimuli is mediated by an enteropancreatic reflex with both afferent and efferent limbs in the vagus nerve [55]. This problem can be solved only by using the autotransplanted pancreas preparation described by Wang and Grossman [56]. Solomon and Grossman [55] were able to show that truncal vagotomy did not alter the response of the transplanted pancreas to intestinal stimuli such as tryptophan, oleate, or hydrochloric acid. These findings indicate that the reduction in pancreatic secretion after vagotomy is not due to changes in intestinal hormone release, but is more likely due to interruption of an enteropancreatic reflex. However, a definite answer must await the development of reliable RIA's for both hormones.
618
World J. Surg. Vol. 3, No. 5, 1979
Insulin
Pancreatic Polypeptide (PP)
There is strong evidence that the vagus nerve plays a role in the release of insulin. In studies using the isolated, perfused rat pancreas, acetylcholine induced a prompt release of insulin [57], and direct vagal stimulation resulted in a release of insulin [58, 59]. Several studies [60-63] have demonstrated that after SPV or SGV plus P, basal serum insulin levels and the postprandial insulin output were not changed. After TV, the insulin response to an oral glucose tolerance test or a test meal was either diminished [60, 62] or unchanged [61, 63, 64].
Pancreatic polypeptide is a 36-amino acid polypeptide that has been localized to secretory granules in the islets, acinar tissue, and duct epithelium of the pancreas. At present, it seems likely that PP acts on the exocrine pancreatic tissue as a local regulator of secretion in a way that may be conceived as an anti-CCK and secretin-enhancing action. The effect of parasympathetic stimulation on PP secretion was extensively studied by Schwartz and colleagues [70]. Plasma PP concentration increased in response to insulin-induced hypoglycemia in both normal subjects and DU patients. The PP response to hypoglycemia was diminished by atropine in normal subjects and abolished by vagotomy in DU patients. Electrical vagal stimulation induced an increase of PP levels in the portal vein, which was inhibited by atropine. Acetylcholine stimulated the secretion of PP from isolated perfused pancreas. After a meal, PP concentrations in plasma increased rapidly. Vagotomy markedly reduces the PP response to a meal [71, 72]; therefore, it has been suggested that postprandial PP release may be an important test for the completeness of vagotomy. Atropine also decreases postprandial PP output [73]. These findings indicate that vagal cholinergic stimulation is a major regulator of PP secretion.
Pancreatic Glucagon
Like insulin, pancreatic glucagon is released by vagal stimulation from the pancreas [58]. In studies of the pancreatic glucagon release during insulin hypoglycemia in patients with either SGV or TV, Russell and colleagues [61] found no change in basal glucagon levels, but significantly lower glucagon concentrations after insulin injection in TV patients, compared to SGV patients. Gastric Inhibitory Polypeptide (GIP)
In 1969 Brown and colleagues [65] isolated a polypeptide from intestinal mucosa that inhibited gastric acid secretion stimulated by pentagastrin, insulin, and histamine, and stimulated insulin release in the presence of glucose. GIP is released after food intake, but its inhibitory effect on gastric acid secretion may be pharmacologic. TV in man [63] and dogs [66] results in an increase of basal serum GIP levels. Our studies showed that postprandial serum GIP concentrations in DU patients are not altered either by truncal vagotomy or selective proximal vagotomy. The increase of GIP levels after vagotomy, which has been described by Thomford and colleagues [67], was due to the fact that DU patients show a higher GIP output than controls. However, atropine seems to strongly inhibit postprandial GIP release [68].
Somatostatin
Somatostatin, the growth hormone-release-inhibiting hormone, is found in large quantities in the upper GI tract. Almost nothing is known about the relationship between the vagus nerve and somatostatin. Uvn/is-Wallensten and colleagues [74] observed that electrical vagal stimulation caused an increase of somatostatin release into the antral lumen of cats, when the antrum was perfused with HC1 and gastrin output was reduced. During alkalinization of the antral lumen, vagal stimulation failed to release somatostatin, whereas gastrin levels in gastric juice were high.
Other Hormones Enteroglucagon
A number ofpeptides can be extracted from the mucosa of the GI tract that are glucagon-like in their behavior towards antisera raised against pancreatic glucagon. Lefebvre and colleagues [69] observed no glucagon release from the stomach during electrical vagal stimulation. Russell and colleagues [61] found no difference in plasma enteroglucagon levels when comparing patients with TV and SGV plus P.
Nothing is known about the relationship between VIP, motilin, chymodenin, bulbogastrone, enterooxyntin, and the vagus nerve. Enterogastrone, which may include several other hormones such as secretin and GIP, is released after intraduodenal instillation of HC1 and fat. Several authors [75, 76] reported a diminution of the inhibitory effect of intraduodenal acid on gastric secretion after TV or SPV, whereas others [77] could not confirm these
H.D. Becker et al.: Effect of Vagotomy on GI Hormones
findings. The inhibitory effect of intraduodenal fat was not altered by TV [78]. R6surn~ Divers types de vagotomie ont 6t6 utilis6s dans le traitement de la maladie ulc6reuse. Pour l'activit6 optimale du tube digestif, il doit exister une relation 6troite entre le neff vague et la lib6ration ou l'effet des hormones gastro-intestinales. La gastrin6mie est 6levee apr~s tous les types de vagotomie. Ceci r6sulte de modifications du pH antral ou de la motilit6 gastrique, ces deux facteurs pouvant stimuler la prolif6ration des cellules G. La r6duction de la s6cr6tion pancr6atique apr6s vagotomie n'est pas due ~t des modifications des lib6rations hormonales, mais r6sulte peut-~tre d'une interruption d'un hypoth6tique reflux ent6ro-pancr6atique. Apr6s vagotomie, la lib6ration postprandiale de GIP et l'insulin6mie ne sont pas modifi6es, mais le taux basal de GIP est accru. La lib6ration postprandiale de polypeptide pancr6atique est presque abolie par la vagotomie, mais elle se normalise tardivement apr6s l'op6ration. Ces observations peuvent 6tre importantes pour l'interpr6tation des cons6quences physiologiques et pathologiques de la vagotomie. References 1. Uvn~is-Wallensten, K., Rehfeld, J.F., Larsson, I., Uvniis, B.: Heptadecapeptide gastrin in vagal nerve. Proc. Natl. Acad. Sci. U.S.A. 74:5707, 1977 2. Uvn~is, B.: The part played by the pyloric region in the cephalic phase of gastric secretion. Acta Physiol. Scand. 4[Suppl. 13]:1, 1942 3. Pe Thein, M., Schofield, B.: Release of gastrin from the pyloric antrum following vagal stimulation by sham feeding in dogs. J. Physiol. (Lond.)184:295, 1959 4. Olbe, L.: Vagal release of gastrin. In Gastrin, Grossman, M.I., editor. London, Butterworth, 1964 5. Becker, H.D., Reeder, D.D., Thompson, J.C.: Direct measurement of vagal release of gastrin. Surgery 75:101, 1974 6. Lanciault, G., Bonoma, C., Brooks, F.P.: Vagal stimulation, gastrin release and acid secretion in anesthetized dogs. Am. J. Physiol. 225:546, 1973 7. Uvniis, B., Uvniis-Wallensten, K., Nilsson, G.: Release of gastrin on vagal stimulation in the cat. Acta Physiol. Scand. 94:167, 1975 8. Klempa, I., Becker, H.D.: Vagus--Gastrin--Magensekretion. Stuttgart, Thieme, 1977 9. Knutson, U.L., Olbe, L., Ganguli, P.C.: Gastric acid and plasma gastrin responses to sham feeding in duodenal ulcer patients before and after resection of the antrum and duodenal bulb. Scand. J. Gastroenterol. 9:351, 1974 10. Mayer, G., Arnold, R., Feurle, G., Fuchs, K., Ketterer, H., Track, N.S., Creutzfeldt, W.: Influence of feeding and sham feeding upon gastrin and gastric acid secretion in control subjects and duodenal ulcer patients. Scand. J. Gastroenterol. 9:703, 1974 11. Stadil, F., Rehfeld, J.F.: Hypoglycemic release ofgastrin in man. Scand J. Gastroenterol. 7:509, 1972 12. Stadil, F.: Gastrin and insulin hypoglycemia. Scand. J. Gastroenterol. 9[Suppl. 23]: 1, 1974
619
13. Evans, S.O., Zubiran, J.N., McCarthy, J.D., Radius, H., Woodward, E.R., Dragstedt, L.R.: Stimulating effect of vagotomy on gastric secretion in Heidenhain pouch dogs. Am. J. Physiol. 174:219, 1953 14. Oberhelman, H.A., Johnson, A.N., Dragstedt, L.R.: Relationship of antral and fundic denervation of gastric secretion. Am. J. Physiol. 201:171, 1961 15. Landor, J.H.: The effect of extragastric vagotomy on Heidenhain-pouch secretion in dogs. Am. J. Dig. Dis. 9:256, 1964 16. Emits, S., Grossman, M.I.: Response of Heidenhain pouch to histamine, gastrin and feeding before and after truncal vagotomy in dogs. Scand. J. Gastroenterol. 4:497, 1969 17. Stening, G.F., Grossman, M.I.: Gastric acid response to pentagastrin and histamine after extragastric vagotomy in dogs. Gastroenterology 59:364, 1970 18. McGuigan, J.E., Trudeau, W.L.: Serum gastrin levels before and after vagotomy and pyloroplasty or vagotomy and antrectomy. N. Engl. J. Med. 286:184, 1972 19. Walsh, J.H., Csendes, A., Grossman, M.I.: Effect oftruncal vagotomy on gastrin release and Heidenhain pouch acid secretion in response to feeding in dogs. Gastroenterology 63:593, 1972 20. Jaffe, B.M., Clendinnen, B.G., Clarke, R.J., Alexander-Williams, J.: Gastrin response to selective and parietal cell vagotomies. Surg. Forum 23:324, 1972 21. Becker, H.D., Reeder, D.D., Thompson, J.C.: Effect of truncal vagotomy with pyloroplasty or with antrectomy on food-stimulated gastrin values in patients with duodenal ulcer. Surgery 74:580, 1973 22. Becker, H.D., Reeder, D.D., Thompson, J.C.: Vagal control of gastrin release. In Gastrointestinal Hormones, Thompson, J.C., editor. Austin, University of Texas Press, 1975, p. 437 23. Stern, D.H., Walsh, J.H.: Gastrin release in postoperative ulcer patients: evidence for release of duodenal gastrin. Gastroenterology 64:363, 1973 24. Stadil, F.: Gastrin response to food in duodenal ulcer patients before and after highly selective vagotomy. Br. J. Surg. 61:884, 1975 25. Hansky, J., Soveny, C., Korman, M.G.: Role of the vagus in insulin-mediated gastrin release. Gastroenterology 63:387, 1972 26. Walsh, J.H., Grossman, M.I.: Circulating gastrin in peptic ulcer disease. Mt. Sinai J. Med. 40:374, 1973 27. Thompson, J.C.: The effect of vagotomy on circulating gastrin. In Vagotomy: Latest Advances, Holle, F., Andersson, S., editors. New York, Springer-Verlag, 1974, p. 59 28. Jaffe, B.M., Clendinnen, B.G., Clarke, R.J., Alexander-Williams, J.: Effect of selective and proximal gastric vagotomy on serum gastrin. Gastroenterology 66:944, 1974 29. Nilsson, G., Simon, J., Yalow, R.S., Berson, S.A.: Plasma gastrin and gastric acid responses to sham feeding and feeding in dogs. Gastroenterology 63:51, 1972 30. Walsh, J.H., Yalow, R.S., Berson, S.A.: The effect of atropine on plasma gastrin response to feeding. Gastroenterology 60:16, 1971 31. Schrumpf, E., Myren, J.: Effect of atropine on plasma concentration of gastrin in fasting subjects. Scand. J. Gastroenterol. 9:123, 1974 32. Becker, H.D., Reeder, D.D., Thompson, J.C.: The effect of atropine on basal and food stimulated gastrin levels in man. Gastroenterology 64:694, 1973 33. Korman, M.G., Soveny, C., Hansky, J.: Serum gastrin in duodenal ulcer. Part I. Basal levels and effect of food and atropine. Gut 12:899, 1971 34. Uvniis-Wallensten, K., Anderson, H.: Effect of atropine and methiamide on vagally induced gastric acid secretion and gastrin release in anesthetized cats. Acta Physiol. Scand. 99:496, 1977 35. Stadil, F., Malmstr0m, J., Rehfeld, J.F., Miyata, M.: Effect of atropine on hypoglycemic release of gastrin in man. Acta Physiol. Scand. 92:391, 1974
620 36. Schrumpf, E., Vatn, M.H., Semb, L.S.: Effect of atropine on insulin-stimulated gastrin release and gastric secretion of acid pepsin and intrinsic factor. Scand. J. Gastroenterol. 9:665, 1974 37. Farooq, O., Walsh, J.H.: Atropine enhances serum gastrin response to insulin in man. Gastroenterology 68:662, 1975 38. Debas, H.T., Walsh, J.H., Grossman, M.I.: After vagotomy atropine suppresses gastrin release by food. Gastroenterology 70:1082, 1976 39. Hansky, J., King, R.W.F.: Effect of atropine on food-stimulated gastrin release after truncal vagotomy in man. Gastroenterology 73:205, 1977 40. Hansky, J., Korman, M.G., Coupland, G.A.E., Cumberland, V.H.: Gastrin studies after parietal cell vagotomy. Digestion 8:1, 1973 41. Fischer, J.E., Kragelund, E., Nielson, A., Wesdorp, R.I.C.: Basal and meat extract plasma gastrin before and after parietal cell vagotomy and selective gastric vagotomy with drainage in patients with duodenal ulcer. Ann. Surg. 183:167, 1976 42. Brandsborg, O., Brandsborg, M., Lcvgreen, N.A., Mikkelsen, K., Moiler, B., Rokkjaer, M., Amdrup, E.: Influence of parietal cell vagotomy and selective gastric vagotomy on gastric emptying rate and serum gastrin concentration. Gastroenterology 72:212, 1977 43. Becker, H.D., Reeder, D.D., Thompson, J.C.: Effect of vagotomy on postprandial gastrin levels and Heidenhain-pouch secretion in the dog. Dtsch. Med. Wochenschr. 99:1023, 1974 44. Becker, H.D., Reeder, D.D., Thompson, J.C.: Influence of vagotomy on tissue gastrin levels in stomach and pancreas in rats. Surgery 74:778, 1973 45. Becker, H.D., Arnold, R., B6rger, H.W., Creutzfeldt, C., Schafmayer, A., Creutzfeldt, W.: Influence of truncal vagotomy on serum and antral gastrin and G cells. Gastroenterology 72:811, 1977 46. Hughes, W.S., Hernandez, A.J.: Antral gastrin concentration in patients with vagotomy and pyloroplasty. Gastroenterology 71:720, 1976 47. Malmstrcm, J., Stadil, F., Christensen, K.C.: Effect oftruncal vagotomy on gastroduodenal content of gastrin. Br. J. Surg. 64:34, 1977 48. Ward, A.S., Bloom, S.R.: Effect of vagotomy on secretin release in man. Gut 16:951, 1975 49. Konturek, S.J., Becker, H.D., Thompson, J.C.: Effect of vagotomy on hormones stimulating pancreatic secretion. Arch. Surg. 108:704, 1974 50. Moreland, H.J., Johnson, L.R.: Effect of vagotomy on pancreatic secretion stimulated by endogenous and exogenous secretin. Gastroenterology 60:425, 1971 51. Debas, H.T., Konturek, S.J., Grossman, M.I.: Effect ofextragastric and truncal vagotomy on pancreatic secretion in the dog. Am. J. Physiol. 228:1172, 1975 52. MacGregor, I.L., Parent, J., Meyer, J.H.: Gastric emptying of liquid meals and pancreatic and biliary secretion after subtotal gastrectomy or truncal vagotomy and pyloroplasty in man. Gastroenterology 72:195, 1977 53. Berstad, A., Roland, M., Peterson, H., Liavag, I.: Altered pancreatic function after proximal gastric vagotomy in man. Gastroenterology 71:958, 1976 54. Lindskov, J., Amtorp, O., Larsen, H.R.: The effect of highly selective vagotomy on exocrine pancreatic function in man. Gastroenterology 70:545, 1976 55. Solomon, T., Grossman, M.I.: Vagal control of pancreatic exocrine secretion. In Nerves and the Gut, Brook, F.P. editor. Thorofare, N.J., Charles B. Slack, 1977 56. Wang, C.C., Grossman, M.I.: Physiological determination of release of secretin and pancreozymin from intestine of dogs with transplanted pancreas. Am. J. Physiol. 164:527, 1961 57. Loubati6res-Mariam, M.M., Chapal, J., Alric, R., Loubati6res, A.: Studies of the cholinergic receptors involved in the secretion of insulin using isolated perfused rat pancreas.
World J. Surg. Vol. 3, No. 5, 1979
Diabetologia 9:439, 1973 58. Bloom, S.R., Edwards, A.V., Vaugham, N.I.A.: The role of the autonomic innervation in the control of glucagon release during hypoglycemia in the calf. J. Physiol. (Lond.)236:611, 1974 59. Daniel, P.M., Henderson, J.R.: The effect of vagal stimulation on plasma insulin and glucose levels in the baboon. J. Physiol. (Lond.) 192:317, 1967 60. Aagard, P., Deckert, T., Fenger, H.J.: Serum insulin after intravenous administration of glucose before and after total vagotomy. Scand. J. Gastroenterol. 8:699, 1973 61. Russell, R.G.G., Thompson, J.P.S., Bloom, S.R.: The effect of truncal and selective vagotomy on the release of pancreatic glucagon, insulin, and enteroglucagon. Br. J. Surg. 61:821, 1974 62. Humphrey, C.S., Dykes, J.R., Johnston, D.: Effects oftruncal, selective, and highly selective vagotomy on glucose tolerance and insulin secretion in patients with duodenal ulcer. Br. Med. J. 2:114, 1975 63. Becker, H.D., Arnold, R., B6rger, H.W., Ebert, R., Schafmayer, A., Creutzfeldt, W.: Effect of selective proximal vagotomy (SPV) on serum concentrations of GIP, insulin and gastrin in duodenal ulcer patients. Gastroenterology 74:1007, 1978 64. Grossman, M.I. and others: Candidate hormones of the gut. I. Introduction. Gastroenterology 67:730, 1974 65. Brown, J.C., Peterson, R.A., Jorpes, E., Mutt, V.: Preparation of highly active enterogastrone. Can. J. Physiol. Pharmacol. 47:113, 1969 66. Becker, H.D., Schafmayer, A., B6rger, H.W.: Effect ofextragastric and truncal vagotomy on gastric secretion, serum gastrin, serum insulin, and serum GIP levels. Abstract, International Congress of Gastroenterology, Budapest, 1976 67. Thomford, N.R., Sirnick, K.R., Croche, H.S.E., Mazzaferri, E.L., Cataland, S.: Gastric inhibitory polypeptide. Response to oral glucose after vagotomy and pyloroplasty. Arch. Surg. 109:177, 1974 68. Baumert, J.E., Cataland, S., Tetirick, C.E., Pace, W.G., Mazzaferri, E.L.: Effect of atropine on meal-stimulated gastrin and gastric inhibitory polypeptide (GIP) release. J. Clin. Endocrinol. Metab. 46:473, 1978 69. Lefebvre, P.J., Luycks, A.S., Brassine, A.H.: Vagal stimulation and its role in eliciting gastrin but not glucagon release from the isolated perfused dog stomach. Gut 19:185, 1978 70. Schwartz, T.W., Holst, J.J., Fahrenkrug, J., Lindkaer-Jensen, S., Nielsen, O.V., Rehfeld, J.F., Schaffalitzky de MuckadeU, O.B., Stadil, F.: Vagal, cholinergic regulation of pancreatic polypeptide secretion. J. Clin. Invest. 61:781, 1978 71. Schwartz, T.W., Rehfeld, J.F., Stadil, F., Larsson, L.I., Chance, R.E., Noon, N.: Pancreatic polypeptide response to food in duodenal ulcer patients before and after vagotomy. Lancet 1 : 1102, 1976 72. Adrian, T.E., Bloom, S.R., Besterman, H.S., Barnes, A.J., Cooke, T.J.C., Russell, R.C.G., Faker, R.G.: Mechanism of pancreatic polypeptide release in man. Lancet 1:161, 1977 73. Taylor, I.L., Impicciatore, M., Walsh, J.H.: Effect of atropine and vagotomy on the pancreatic polypeptide response to a meal. Gastroenterology 72:1139, 1977 74. Uvn~is-Wallensten, K., Efendic, F., Luft, R.: Vagal release of somatostatin into the antral lumen of cats. Acta Physiol. Scand. 99:126, 1977 75. Ward, A.S.: The effect of vagotomy on the inhibition of gastric secretion by intraduodenal acid. Br. J. Surg. 61:698, 1974 76. Linares, C.A., Falesca, C.A., Sartorio, G.C., Soto, R.J.: Effect of intraduodenal acid on the pre- and postvagotomy basal gastric secretion and gastrin. Surgery 81:392, 1977 77. Kaminsky, D.L., Ruwart, M.J.: The effect of vagotomy on the canine enterogastrone mechanism. Surgery 81:80, 1977 78. Christiansen, J.: Fat-induced inhibition of gastric acid secretion in duodenal ulcer patients before and after truncal vagotomy. Ann. Surg. 186:573, 1977
H.D. Becker et al.: Effect of Vagotomy on GI Hormones
79. Preshaw, R.M., Cooke, A.P., Grossman, M.I.: Sham feeding and pancreatic secretion in the dog. Gastroenterology 50:171, 1966 80. Sarles, H., Dani, R., Prezelin, G.: Cephalic phase of pancreatic secretion in the dog. Gastroenterology 50:171, 1966 81. Novis, B.H., Bank, S., Marks, I.N.: The cephalic phase of pancreatic secretion in man. Scand. J. Gastroenterol. 6:417, 1971 82. Blair, E.L., Brown, J.C., Harper, A.A.: A gastric phase of pancreatic secretion. J. Physiol. (Lond.)184:812, 1966 83. Preshaw, R.M., Cooke, A.R., Grossman, M.I.: Stimulation of pancreatic secretion by a humoral agent from the pyloric gland area of the stomach. Gastroenterology 49:617, 1965
Invited Commentary Haile T. Debas, M.D. Faculty of Medicine, University of British Columbia, Vancouver, B.C., Canada
The gastrointestinal (GI) tract contains more endocrine cells than all the other organs in the body put together. These cells release peptides that influence GI function not only as hormones, in the classic sense of the word, but also as local humoral agents (paracrine) and as neural transmitters (neurocrine). In the past, we have considered vagal control of GI secretion (exocrine and endocrine) as being cholinergic. Recently, however, noncholinergic mechanisms have been described, and increasing numbers of peptides have been found in vagal nerve endings in the gut. Among these are VIP, substance P, and somatostatin--peptides also found in the brain itself, thus constituting a "mind-gut axis." Hitherto, we have considered vagotomy as disruption of the cholinergic control of the gut. We have yet to learn what vagotomy does in terms of disrupting this peptidergic system. In their timely review of the effect of vagotomy on GI hormones, Becker and colleagues stress that all forms of vagotomy lead to basal hypergastrinemia and to an exaggerated gastrin response to a meal. They attribute this phenomenon to raised intragastric pH as a result of the vagotomy. I believe the mechanism of postvagotomy hypergastrinemia is more complex, although, undoubtedly, pH changes are important. At least 2 more components of the mechanism can be defined. First, the vagus itself contains fibers inhibitory to gastrin release, as was shown by selective cooling of these fibers by Cairns et al. [1]. Farooq and Walsh [2], in a classic experiment, showed that atropine enhances serum gastrin response to insulin in man when any effects of pH were abolished. Indeed, I believe the vagus should be regarded more as an inhibitory nerve of gastrin release than as a
621
84. White, T.T., Lundh, G., Magee, D.F.: Evidence for the existence of a gastropancreatic reflex. Am. J. Physiol. 198:725, 1960 85. Magee, D.F., Fragola, L.F., White, T.T.: Gastric acid and the gastropancreatic distention reflex. Gastroenterology 44:811, 1963 86. Andrews, C.J.H., Andrews, W.H.H.: Receptors, activated by acid, in the duodenal wall of rabbits. Q. J. Exp. Physiol. 56:221, 1971 87. Solomon, T.E., Solomon, N., Shanbour, L.L., Jacobson, E.D.: Direct effects of cholinergic stimulation on pancreatic secretion. Gastroenterology 64:804, 1973
stimulatory one. Second, we have evidence that the fundus has an inhibitory control of gastrin release through a neurohormonal mechanism that appears to require intact vagal pathways. Following proximal gastric vagotomy, Yamagishi et al. [3] showed that food-stimulated gastrin release was exaggerated within 1 week of the operation, even though pH was held constant by intragastric titration. More recently, Soon-Shiong et al. [4] have shown that excision of the parietal cell mucosa leads to an exaggerated gastrin release after a meal and to an enhanced Heidenhain pouch acid response to gastrin and histamine. What we do not know is to what degree, if at all, the peptides found at the vagal nerve endings subserve the mechanism of these changes. Becker and his colleagues have shown that, following vagotomy, antral tissue gastrin and the number of G cells in the antrum increase [5, 6]. These changes could be due to chronic pH changes as they have suggested, but additional mechanisms have not been excluded. Among these additional explanations could be decreased release of an inhibitor of gastrin release and changes in the paracrine and neurocrine control of the antrum secondary to vagotomy. Before the advent of radioimmunoassay, we, as surgeons, believed that vagotomy reduced acid secretion by decreasing antral gastrin release. We now know differently. The observations that v.agotomy, in fact, leads to hypergastrinemia stresses the fact that the main mechanisms for postvagotomy reduction of acid secretion are withdrawal of direct vagal action on the parietal cell and cholinergic sensitization of the cell to the action of gastrin. We now think that this acid reduction is the main reason why ulcers heal after vagotomy. Could the hypergastrinemia that follows vagotomy be important in the healing of ulcers? This intriguing hypothesis has found some support in the interesting findings of Takeuchi and Johnson [7], who showed that pentagastrin protects against stress ulceration in rats. I think it is too early to be sure of the effect of vagotomy on the release of secretin and cholecys-
