Effects of truncal vagotomy and antrectomy on bombesin-stimulated pancreatic secretion,release of gastrin,and pancreatic polypeptide in the anesthetized dog

The short-term effects of truncal vagotomy and antrectomy on bombesin-stimulated pancreatic secretion and release of gastrin and pancreatic polypeptide (PP) were studied in 18 anesthetized dogs. Together with an intravenous infusion of secretin (250 ng/kg/hr) bombesin (500 ng/kg/hr) was given before and after truncal vagotomy, antrectomy, and sham operation (N=6 dogs per group). Peak incremental pancreatic protein output in procedures (tachyphylaxis). Neither truncal vagotomy nor antrectomy significantly altered the pancreatic protein response to bombesin when compared with sham operation. Bombesin produced a mean 1-hr increase over basal of 196 pM for gastrin, which was abolished by antrectomy but not appreciably affected by truncal vagotomy and sham operation. The mean 1-hr increment (207 pM) for PP in response to bombesin was not changed by truncal vagotomy, antrectomy, and sham operation. This study shows in the anesthetized dog that exogenous bombesin stimulates release of PP as well as gastrin; that the release of gastrin by bombesin is not vagally dependent; that neither truncal vagotomy nor antrectomy alter the release of PP by bombesin; and that the action of bombesin on pancreatic protein secretion does not depend on release of gastrin or on intact vagal nerves.Parts of this paper have been presented at the 12th European Pancreatic Club Meeting, Copenhagen, Denmark, October 11–13, 1979, and at the 3rd International Symposium on Gastrointestinal Hormones, Cambridge, England, September 15–18, 1980.     

Cerebroventricular bombesin inhibits gastric acid secretion in dogs

Bolus injections of bombesin into a lateral cerebral ventricle of conscious beagle dogs inhibited pentagastrin-stimulated gastric acid secretion from both the innervated stomach (gastric fistula) and the vagally denervated Heidenhain pouch in a dose dependent manner. Bombesin (300 ng/kg), injected into the lateral ventricle, inhibited acid secretion from the gastric fistula and Heidenhain pouch by 66% +/- 5% and 93% +/- 4%, respectively. Central administration of bombesin also suppressed acid secretion in response to a meal by 52% +/- 15%; postprandial gastrin response was not affected. By contrast, intravenous infusion of bombesin stimulated both gastrin release and acid secretion without affecting the acid response to a submaximal dose of pentagastrin. The opposing effects of central and peripheral bombesin on acid secretion indicate that the gastric response to intracerebrally administered bombesin is mediated by the central nervous system. Furthermore, the inhibitory action of bombesin injected into the lateral cerebral ventricle is independent of the vagus and is not mediated by the inhibition of gastrin release. These observations demonstrate that bombesin-like peptides may act centrally to alter gastric secretion.     

Effect of loxiglumide on basal and gastrin- and bombesin-stimulated gastric acid and serum gastrin levels.

The effect of the specific cholecystokinin-receptor antagonist loxiglumide on basal and bombesin-, and gastrin 17-I-stimulated gastric acid secretion and serum gastrin levels was studied in 12 healthy subjects. Loxiglumide (10 mg.kg-1.h-1) significantly augmented basal gastric acid output from 1.8 +/- 0.3 to 3.9 +/- 0.6 mmol H+/h (P less than 0.005) but did not significantly influence integrated basal serum gastrin concentrations (2 +/- 21 vs. 32 +/- 21 pmol L-1.h-1). Both gastric acid secretion and integrated serum gastrin concentrations stimulated by bombesin infusion (92.6 pmol.kg-1.h-1) were significantly augmented by loxiglumide [from 4.0 +/- 0.3 to 10.0 +/- 1.3 mmol H+/h (P less than 0.005) and from 1251 +/- 93 to 2558 +/- 206 pmol.L-1.h-1 (P less than 0.005), respectively]. Gastric acid output and serum gastrin concentrations during infusion of 5 pmol.kg-1.h-1 of synthetic human gastrin 17-I (9.6 +/- 2.9 mmol H+/h and 1045 +/- 177 pmol.L-1.h-1) and during infusion of 15 pmol.kg-1.h-1 of gastrin 17-I (14.5 +/- 3.1 mmol H+/h and 2412 +/- 312 pmol.L-1.h-1) were not significantly influenced by loxiglumide (10.3 +/- 2.3 mmol H+/h and 1291 +/- 257 pmol.L-1.h-1 for the 5-pmol.kg-1.h-1 gastrin 17-I infusion dose with loxiglumide and 13.6 +/- 3.4 mmol H+/h and 2611 +/- 305 pmol.L-1.h-1 for the 15-pmol.kg-1.h-1 gastrin 17-I infusion dose with loxiglumide). These data indicate that endogenous cholecystokinin inhibits gastric acid secretion under basal conditions and gastrin release and gastric acid secretion during infusion of bombesin in humans and suggest that the augmented effect of loxiglumide on bombesin-stimulated gastric acid secretion may be explained largely by enhanced gastrin release.     

Influence of verapamil on gastric acid secretion and gastrin release in dogs

Gastric secretion is supposed to be calcium-dependent. The effect of verapamil (0.3 mg/kg/h i.v.), a calcium channel-blocking agent, on stimulated gastric acid secretion and gastrin release was investigated in 8 mongrel dogs. Stimulation was either performed by bombesin (1.0 microgram/kg/h i.v.) or by insulin (0.3 U/kg i.v.). Verapamil significantly inhibited both the bombesin- and the insulin-stimulated gastric acid secretion. Mean total gastric acid output over a 120-min period was 9.5 +/- (SEM) 2.2 mmol after bombesin stimulation and 6.3 +/- 2.0 mmol after bombesin and verapamil (p less than 0.01). The respective values were 15.3 +/- 2.0 mmol for insulin stimulation and 7.0 +/- 1.6 mmol for insulin and verapamil (p less than 0.01). There was no significant influence of verapamil on plasma gastrin concentrations. Thus, the impairment of acid secretion by verapamil is not due to an inhibition of gastrin release in intact dogs.     

Serum gastrin in duodenal ulcer: Part III Influence of vagotomy and pylorectomy

Following truncal vagotomy and anterior pylorectomy for duodenal ulcer, fasting serum gastrin levels were higher at 84 +/- 7.9 pg per ml than in unoperated patients with duodenal ulcer (16 +/- 1.5 pg per ml). In response to a standard protein meal, the peak serum gastrin achieved in the vagotomized group was 259 +/- 37.8 pg per ml at 75 minutes after ingestion, a much higher response than that obtained with a standard meal plus prior atropinization in the unoperated duodenal ulcer patients.These results suggest that truncal vagotomy allows release of gastrin which was previously inhibited with the vagi intact and the temporal characteristics of the response indicate that some of this gastrin is derived from an extragastric source. The results also exemplify the dependence of gastrin estimations as measured by this immunoassay on the acidity of the contents bathing the gastric antrum.     

Regulatory mechanism of bombesin on gastrin release

Bombesin has been demonstrated to stimulate gastrin release by an atropine-resistant mechanism. In the present study, the effects of truncal vagotomy and chemical sympathectomy on the gastrin release by exogenous and endogenous bombesin using rat antral mucosa in tissue culture were studied. Exogenous bombesin 10^-8 mol/l significantly stimulated gastrin release. The stimulation of gastrin release by bombesin was abolished by truncal vagotomy, but not altered by chemical sympathectomy. Bombesin antiserum inhibited gastrin release by blocking the effect of endogenous bombesin. The inhibition of gastrin release by bombesin antiserum was abolished by truncal vagotomy, but not altered by chemical sympathectomy. In addition, the concentrations of bombesin-like immunoreactivity in antral mucosa were not altered by truncal vagotomy. These results suggest that the mechanism of gastrin release by bombesin is influenced by non-cholinergic local nerves under vagal control.     

Effect of two types of beta-adrenergic blockade on gastric acid secretion during pentagastrin stimulation in non-vagotomized and in vagotomized gastric fistula dogs.

The effect of beta-adrenoceptor blockade by propranolol and practolol on submaximally pentagastrin-stimulated gastric acid secretion was studied in conscious non-vagotomized and in vagotomized gastric fistula dogs. Propranolol (0.5 mg/kg) intravenously augmented gastric acid output in vagotomized dogs, more after truncal and selective vagotomy than after parietal cell vagotomy. Vagally innervated dogs also showed an increase, but to a lesser degree and not statistically significant. The increase restored the acid output to preoperative levels in the vagotomized dogs. Practolol (1.0 mg/kg) intravenously resulted in a slight and insignificant increase in acid output in dogs with truncal vagotomy and had only a negligible effect in vagally innervated dogs and after selective and parietal cell vagotomy. It is concluded that propranolol augments pentagastrin-stimulated acid output in vagotomized dogs, and this augmentation was most pronounced in the totally vagotomized stomach. Practolol had minor influence on gastric acid secretion. This effect of the two beta-blocking agents indicates that beta 2-blockade is most important for the secretory augmentation. The restoration of postvagotomy acid secretion to preoperative levels suggests that adrenergic influence is important for the decrease in pentagastrin-stimulated acid secretion after vagotomy.     

Mechanism of gastric acid response to pylorus ligation: effects of nephrectomy

In the rat nephrectomy raises the serum gastrin concentration but makes the parietal cells refractory to gastrin. Pylorus ligation stimulates the gastric acid output by a long vago-vagal reflex in innervated animals and by an intramural reflex in chronically vagotomized animals. Nephrectomy reduced the acid response to pylorus ligation in vagally intact rats but enhanced it in vagotomized rats. The acid response to pylorus ligation in all the experimental groups was inhibited by a muscarinic blocker, atropine, and by an H2-antagonist, metiamide. The serum gastrin concentration was raised by nephrectomy and by vagal denervation. Histamine mobilization from gastric endocrine cells is reflected in the activity of gastric histidine decarboxylase. The enzyme activity in pylorus-ligated innervated rats was raised by pentagastrin, atropine, and metiamide. In nephrectomized rats the basal enzyme activity was high, and it was raised further, slightly but significantly, by pentagastrin. The basal enzyme activity in pylorus-ligated rats was also quite high after vagotomy, and it was raised further by pentagastrin. After vagotomy + nephrectomy the basal enzyme activity was very high; it was not raised further by pentagastrin. It appears that both vago-vagal and intramural reflexes involve a cholinergic and a histaminergic pathway, that gastrin is not important for the neurally mediated acid response elicited by pylorus ligation, and that the postulated histaminergic pathway does not involve histamine derived from the gastric endocrine-like cells.     

The cephalogastric phase of the pancreatic response to food in the dog

We studied post-meal pancreatic secretion and gastrin release in conscious dogs with duodenal Thomas cannulas. Normal dogs were tested in physiological conditions and with an i.v. infusion of atropine 20 micrograms/kg/h or secretin 0.5 CU/kg/h. The responses were also studied after antral and truncal vagotomy. In the early phase (0-20 min) of the response, before gastric emptying started, antral vagotomy reduced fluid and protein outputs, and truncal vagotomy reduced them still more. Atropine reduced only the protein response. Gastrin release reached a peak after 20-25 min. After antral and truncal vagotomy, gastrin release was reduced within 10 min after the meal. Late-phase (greater than 20 min) pancreatic secretion depended on the presence of chyme in the duodenum. The effects of atropine and antral vagotomy in the cephalogastric phase could be explained by antropancreatic reflexes stimulating fluid secretion (atropine-resistant pathway) and protein output (atropine-sensitive pathway).     

In vivo action of bombesin on exocrine pancreatic secretion in the rat: independent of cholecystokinin and cholinergic mediation

This study evaluates the effect of bombesin on pancreatic enzyme secretion in the rat and determines whether the stimulatory action of bombesin is mediated through the release of cholecystokinin (CCK) or via a cholinergic pathway. We performed in vivo experiments on conscious rats prepared with cannulae inserted in the pancreatic duct, in the external jugular vein, and in the duodenum. Intravenous infusion of bombesin stimulated pancreatic protein output in a dose-dependent fashion. Bombesin infused at 5 micrograms/kg/h stimulated pancreatic protein secretion from a basal of 12 +/- 5 to 42 +/- 10 mg/h. Infusion of proglumide (400 mg/kg/h) did not affect the stimulatory effect of bombesin on pancreatic protein secretion (38 +/- 5 mg/h). In contrast, infusion of proglumide abolished the pancreatic protein output elicited by intravenous infusion of CCK8 (500 ng/kg/h). This suggests that bombesin does not act through CCK to mediate exocrine pancreatic secretion. In separate studies we intravenously infused rats with atropine (100 micrograms/kg/h) prior to infusion with bombesin. Administration of atropine slightly decreased secretory volume but did not affect the action of bombesin. Combined administration of atropine and proglumide also did not affect pancreatic protein output stimulated by bombesin. Since infusion of neither proglumide nor atropine inhibited the stimulatory action of bombesin, the action of bombesin in the rat is probably direct and not through the release of CCK or via a cholinergic pathway.     

Neural pathways for the release of gastrin,cholecystokinin, and pancreatic polypeptide after a meal in dogs

We have measured gastrin, cholecystokinin (CCK), and pancreatic polypeptide (PP) release after a meal in normal dogs under basal conditions and during atropine infusion, and after various neural sections. Denervation of the gastric antrum (antral vagotomy) abolished the early part of the gastrin response to food. Truncal vagotomy, celiac ganglionectomy, and atropine reduced the early release of CCK, which occurred before the start of gastric emptying, suggesting that a neural, cholinergic mechanism may release CCK immediately after a meal. PP release was abolished by truncal vagotomy, and also by antral vagotomy. As no direct pathways are known between the antrum and the pancreas, this suggests either that antral afferents are essential for this response or that vagally mediated hormone release from the antrum mediates PP release.     

Release of vasoactive intestinal peptide by distention of the proximal stomach in dogs.

The effect of transient proximal gastric distention was studied in six conscious dogs previously submitted to antrectomy and Billroth I anastomosis (and in which the intragastric pH was not altered), and in five anaesthetised dogs prepared with an innervated acute fundic pouch in which the pouch lumen was acidified with 0.15 M hydrochloric acid. Levels of vasoactive intestinal peptide (VIP) in portal and peripheral plasma were measured by radioimmunoassay. In conscious antrectomised dogs, distention of the proximal stomach to volumes of 250 and 500 ml evoked a significant rise of portal VIP concentration, with a maximal variation of 32.7 +/- 4.4 to 67.7 +/- 14.8 pg ml-1, which was hardly reflected in systemic blood. In the anaesthetised dogs, transient distention of the acute fundic pouch with 0.15 M hydrochloric acid under a pressure of 40 cm of water elicited a significant rise of portal VIP from 36.2 +/- 8.9 to 59.8 +/- 12.4 pg ml-1 (P < 0.05) without any significant variation of the peptide concentration in peripheral plasma. These results indicate that vasoactive intestinal peptide is released under transient proximal gastric distention in dogs, and that this response is not solely dependent upon the acid secretory effect of distention in this species.     

Inhibition of bombesin-stimulated gastric acid secretion by secretin, glucagon and caerulein in patients with duodenal ulcer.

The inhibitory effects of intravenous infusions of secretin, glucagon and caerulein on the gastric acid response to bombesin were studied in 8 duodenal ulcer patients. Bombesin was found to be a very potent stimulator of gastric acid secretion in patients with duodenal ulcer. There were no significant differences in acid outputs per 15-min period between bombesin infused in a dose of 0.9 microgram/kg/h and pentagastrin infusion administered in a maximal dose, at a rate of 6.0 microgram/kg/h. Secretin (1 U/kg/h), glucagon (30 microgram/kg/h) and caerulein (0.1 microgram/kg/h) produced significant decreases in gastric acid secretion evoked by bombesin given in a dose of 0.9 microgram/kg/h. Percentages of inhibition were 48.6, 45.2 and 35.5, respectively. It is supposed that secretin and glucagon given in pharmacological doses are capable of interfering with the action of gastrin released from antrum by means of bombesin on the parietal cell by noncompetitive kinetics. Caerulein administered in a pharmacological dosis, however, can inhibit the effect of gastrin released by bombesin on the parietal cells by a competitive kinetic.     

Cholecystokinin release by gastric distension--an atropine-sensitive mechanism

The effect of gastric distension on plasma cholecystokinin (CCK), pancreatic polypeptide (PP) and gastrin concentrations was investigated in healthy volunteers. Fundic and antral distension was achieved by balloons attached to a gastric tube and inflated with 300 and 600 ml and 100 and 200 ml of air for fundic and antral distension, respectively. Gastric juice was continuously aspirated. Fundic distension was additionally studied during a concomitant intravenous infusion of atropine (5 micrograms/kg/h) or a bolus injection of propranolol (2 mg). Fundic distension with 300 ml caused a significant increase in PP release (+17% above basal). Distension with 600 ml significantly stimulated CCK (+81%), gastrin (+31%) and PP output (+74%) over 30 min. Atropine completely blocked PP release and almost abolished CCK release, whereas gastrin output was enhanced. Propranolol did not prevent CCK release induced by fundic distension, whereas gastrin and PP responses were diminished. Antral distension did not cause any significant changes in hormone response. In conclusion, we demonstrated a gastric phase of CCK release which is atropine sensitive, but not influenced by propranolol.     

Mechanisms for regulation of gastrin and somatostatin release from isolated rat stomach during gastric distention

AIM: To investigate the intragastric mechanisms forregulation of gastric neuroendocrine functions during gastricdistention in isolated vascularly perfused rat stomach.METHODS: Isolated vascularly perfused rat stomach wasprepared, then the gastric lumen was distended with either5,10 or 15 ml pH7 isotonic saline during a period of 20 min.During the distention, the axonal blocker tetrodotoxin (TTX),the cholinergic antagonist atropine, or the putativesomatostatin-antagonist cyclo [7-aminoheptanoyl-Phe-D-Trp-Lys-Thr(Bzl)] were applied by vascular perfusion. Thereleases of gastrin and somatostatin were then examinedby radioimmunoassay.RESULTS: The graded gastricdistention caused a significantvolume-dependent decrease in gastrin secretion [-183±75 (5ml), -385±86 (10 ml) and -440±85 (15 ml) pg/20 min] and asignificant increase of somatostatin secretion [260±102 (5 ml),608±148 (10 ml) and 943±316 (15 ml) pg/20 min]. In responseto 10 ml distention, the infusion of either axonal blocker TTX(10-6 M) or cholinergic blocker atropine (10-7 M) had a similaraffect. They both attenuated the decrease of gastrin releaseby approximately 50 %, and attenuated the increase ofsomatostatin release by approximately 40 %. The infusion ofsomatostatin-antagonist cyclo [7-aminoheptanoyl-Phe-D-Trp-Lys-Thr (Bzl)] (10-6M) attenuated the decrease of gastrin releaseby about 60 %. Furthermore, combined infusion of thesomatostatin-antagonist and atropine completely abolisheddistention-induced inhibition of gastrin release.CONCLUSION: The present data suggest that distention ofisolated rat stomach stimulates somatostatin release viacholinergic and non-cholinergic TTX-insensitive pathways. Bothsomatostatin and intrinsic cholinergic pathways are responsiblefor distention-induced inhibition of gastrin release.     

Responses of serum gastrin and gastric acid output before and after bilioenteric by-pass in the dog and man.

Responses of serum gastrin and gastric acid output levels were studied in four dogs before and after a bilioenteric by-pass. Serum gastrin levels during bombesin infusion were measured in eight patients submitted to Roux-en-Y hepatocholangiojejunostomy. No change was observed in acid secretion from the main stomach or from the Heidenhain pouch in dogs following biliojejunostomy. The peak acid output, however, occurred significantly earlier after diversion of bile from the duodenum. Serum gastrin levels decreased significantly in dogs after bilioenteric by-pass and in the operated patients compared with normal subjects. The possible role played by bile in the release of duodenal gastrin is hypothesized.     

Divergent effects of bombesin and bethanechol on stimulated gastric secretion in duodenal ulcer and in normal men

To further investigate differences in the responses of normals and patients with duodenal ulcer with respect to gastrin release and acid and pepsin secretion, we infused bombesin (1 microgram/kg X h) or bethanechol (40 micrograms/kg X h) during the middle hour of a 3-h infusion of pentagastrin and compared the results with a pentagastrin infusion without added drug. Pentagastrin dosage (0.1 microgram/kg X h) was set to give about half-maximal response, to detect either inhibition or further stimulation of gastric secretion, whereas the dose of bombesin was chosen to give maximal gastrin but less than maximal acid secretion. Serum gastrin and somatostatin were also measured. In all subjects tested, bethanechol produced no effects on acid, gastrin, or somatostatin release but increased pepsin output. By contrast, bombesin inhibited pentagastrin-stimulated acid output in all 6 normal men by an average of 55%, whereas it inhibited acid output in only 2 of the 9 men with duodenal ulcer. Serum gastrin increases after bombesin in duodenal ulcer were three to four times greater than in normals. Although bombesin stimulates acid only by releasing gastrin, we postulate that bombesin may also simultaneously limit acid and pepsin secretion and speculate that this effect could be mediated by bombesin-induced somatostatin release. The cause for differences between duodenal ulcer and normal remain speculative.     

Effect of acute suppression of acid secretion by omeprazole on postprandial gastrin release in conscious dogs

The effect of acute suppression of acid secretion induced by administration of a single dose of omeprazole (2 mg/kg body wt) on postprandial gastrin release was studied in 10 conscious dogs. In omeprazole-treated dogs, a sustained gastrin release was observed during a 10-h period after feeding, although greater than 95% of the meal had left the stomach after 4 h. This sustained gastrin release could be inhibited by acidification of the gastric lumen, by somatostatin, and by atropine. Insulin and bombesin induced considerable gastrin release in omeprazole-treated dogs, but plasma gastrin concentrations returned almost to basal values after 3 h. Omeprazole administered alone had no significant effect on basal gastrin levels. These data indicate that, in dogs, when acid secretion is suppressed by omeprazole a meal induces a sustained gastrin release lasting for up to 10 h. This gastrin release is probably related to the fact that food has been in contact with the gastric lumen, as neither vagal nor bombesin stimulation induced such a sustained activity of the G cells.     

Inhibition of gastrin release induced by fundic distension. Evidence of a defective inhibition in duodenal ulcer patients.

The serum gastrin response to an infusion of gastrin-releasing peptide (GRP), with or without simultaneous fundic distension, was studied in healthy volunteers and in patients with duodenal ulcer disease before and after a complete proximal gastric vagotomy (PGV). We also studied the effect of fundic distension alone on gastrin release and intraluminal gastric pressure in healthy volunteers and in patients after PGV. We observed an increased intraluminal pressure in patients after PGV compared with healthy subjects. During fundic distension with 600 ml of air no significant increase in gastrin values was observed in healthy subjects or in duodenal ulcer patients. In healthy subjects fundic distension significantly inhibited the gastrin response to the higher dose of GRP. This inhibitory effect exerted by fundic distension was counteracted by cholinergic blockade. In contrast, fundic distension did not alter the gastrin response to GRP in duodenal ulcer patients, suggesting a defective inhibitory mechanism in duodenal ulcer patients. After PGV, GRP infusion resulted in an enhanced gastrin response, and fundic distension seemed to facilitate the gastrin-stimulatory effect of GRP. This supports the concept of a vagally dependent inhibitory oxyntopyloric mechanism and that fundic distension can elicit both inhibitory and stimulatory secretory mechanisms.     

Serum gastrin in duodenal ulcer: Part IV Effect of selective gastric vagotomy

Serum gastrin has been measured in 30 patients following selective gastric vagotomy. Basal serum gastrin was 52+/-5.7 pg/ml which was significantly lower than the corresponding level in 50 patients following truncal vagotomy (84+/-7.9 pg/ml). After a standard protein meal serum gastrin rose to 136+/-8.3 pg/ml at 60 minutes after the meal. The peak rise above basal levels was significantly lower than that achieved in patients who had undergone truncal vagotomy.These results complement our previous hypothesis that section of extragastric vagal fibres permits the release of additional gastrin above that expected with the diminution of acid secretion, and hence the decrease in inhibition of gastrin release from the antrum.