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.     

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).     

After vagotomy atropine suppresses gastrin release by food.

Changes in serum gastrin in response to feeding a meal of beef liver (15 g kg(-1)) were studied in 5 gastric fistula dogs with and without administration of atropine sulfate (0.2 mg kg(-1) intravenously). The studies were repeated after a truncal vagotomy that abolished acid secretion in response to 2-deoxyglucose. Before vagotomy atropine had little effect on the gastrin response to a meal. After vagotomy the gastrin response to feeding was greatly enhanced, but now atropine depressed the gastrin response at all times after the meal. It is concluded that vagotomy enhances the serum gastrin response to feeding and that atropine counteracts this enhancement.     

Pancreatic polypeptide response to a meal before and after cutting the extrinsic nerves of the upper gastrointestinal tract and the pancreas in the dog

The role of the sympathetic and parasympathetic innervation in the release of pancreatic polypeptide (PP) basally and in response to a meal was studied after stepwise extrinsic denervation of the pancreas and the upper gastrointestinal tract in conscious dogs with gastric fistulae. One set of seven dogs was fed a meat meal (35 g/kg body weight) before and after truncal vagotomy and after truncal vagotomy plus celiac and superior mesenteric ganglionectomy, ie, extrinsic denervation of the pancreas and the upper gastrointestinal tract. In another set of six dogs, only ganglionectomy was performed. Experiments were repeated in the presence of atropine (50 g/kg body weight, given as an intravenous bolus 60 min prior to the meal). Truncal vagotomy significantly (P<0.05) reduced the postprandial 120-min integrated plasma PP response (IPPPR) by 84% as compared to the prevagotomy response. Before truncal vagotomy, atropine significantly reduced the IPPPR by 57%. After truncal vagotomy, atropine completely abolished the residual PP response. Additional celiac and superior mesenteric ganglionectomy did not alter the IPPPR already reduced by truncal vagotomy. With the vagus nerves intact, ganglionectomy alone had no effect on the IPPPR whether or not atropine was given. These findings indicate that (1) the splanchnic nerves do not play a significant role in postprandial PP release and (2) that the vagus nerves are important mediators of the response to a meal. The effect of atropine on postprandial PP release after truncal vagotomy may be due to interruption of short enteropancreatic reflexes, suppression of the intrinsic cholinergic activity of the pancreas, or inhibition of hormonally induced PP release.     

The type of anastomosis after selective gastric vagotomy and precise antrectomy is of no importance for basal and postprandial serum gastrin concentration

Twenty-six patients were treated for duodenal or recurrent ulcer with selective gastric vagotomy plus precise antrectomy--that is, complete removal of the entire antrum. Sixteen had a gastroduodenal anastomosis and 10 a gastrojejunal anastomosis. Fasting and protein meal-stimulated serum gastrin concentration was measured in 10 patients before antrectomy and in all after the operation. Fasting serum gastrin concentration was reduced and food-stimulated gastrin response abolished irrespective of the type of the anastomosis. It is concluded that a postprandial gastrin rise means retained antral tissue in the gastric remnant and that neither protein nor mechanical stimulation of the passage of food through the duodenum stimulates the duodenal G-cells to gastrin release.     

The Type of Anastomosis after Selective Gastric Vagotomy and Precise Antrectomy Is of No Importance for Basal and Postprandial Serum Gastrin Concentration

Twenty-six patients were treated for duodenal or recurrent ulcer with selective gastric vagotomy plus precise antrectomy—that is, complete removal of the entire antrum. Sixteen had a gastroduodenal anastomosis and 10 a gastrojejunal anastomosis. Fasting and protein meal-stimulated serum gastrin concentration was measured in 10 patients before antrectomy and in all after the operation. Fasting serum gastrin concentration was reduced and food-stimulated gastrin response abolished irrespective of the type of the anastomosis. It is concluded that a postprandial gastrin rise means retained antral tissue in the gastric remnant and that neither protein nor mechanical stimulation of the passage of food through the duodenum stimulates the duodenal G-cells to gastrin release.     

Autonomic regulation of postprandial plasma somatostatin, gastrin, and insulin.

To evaluate the neural regulation of postprandial somatostatin release we studied the effect of blockade of (a) alpha-adrenergic and beta-adrenergic and (b) cholinergic receptors on the plasma somatostatin, gastrin and insulin responses to a standard meal in two groups of five fasting healthy male volunteers. Thymoxamine (0.1 mg/kg iv over two minutes then 10 mg/hour for two hours) and propranolol (0.15 mg/kg iv over two minutes, then 0.75 mg/kg/hour for two hours) were started just before eating while atropine (0.04 mg/kg/im) was given at 15 minutes on completion of the meal. There was a prompt and sustained rise in plasma somatostatin after a control meal in all experiments. This rise was arrested by atropine but not altered by either thymoxamine or propranolol. The plasma gastrin response to a meal was moderately enhanced by thymoxamine and markedly enhanced by atropine. Postprandial insulin release was not affected by alpha- or beta-adrenergic blockade but was abolished by atropine. The effect of atropine on the postprandial plasma somatostatin rise might have been mediated through reduction in gastric acidity or delay in gastric emptying. Hence we gave five fasting male volunteers and intraduodenal infusion of fat emulsion (25 calories in 30 minutes) on two occasions both alone and after atropine. Plasma somatostatin rose during the fat infusion alone and this rise was abolished by atropine. These data suggest that (a) cholinergic but not adrenergic mechanisms are important modulators of plasma somatostatin release after orally ingested and intraduodenally infused nutrients (b) atropine abolishes plasma somatostatin release independently of its effects on gastric acidity and motility and (c) are consistent with the hypothesis that atropine potentiates postprandial gastrin release through reduction of somatostatin mediated inhibition.     

Control factors in the release of gastrin by direct electrical stimulation of the vagus

The release of gastrin by direct electrical stimulation of the vagus was studied together with the relative effects on the response of antral and duodenal acidification. As expected, gastrin levels increased to three times the normal simulated response following antral neutralization. In contrast, duodenal acidification failed to influence the vagal release of gastrin when the antrum was neutralized although it had a minor effect when the antrum was acidified. Thus the antral pH dominates over duodenal pH as a factor in controlling gastrin release. Surprisingly, atropine in doses which blocked acid release and produced marked cardiac effects failed to inhibit the release of gastrin from the antrum on vagal stimulation. This suggests that, using this model, vagal release of gastrin, if cholinergic, is highly resistant to atropine.     

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.     

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.     

Pancreatic polypeptide and gastrin release during sham feeding in man

During modified sham feeding (MSF) the role of endogenous gastric acid secretion and the influences of the autonomic nervous system on the release of pancreatic polypeptide (PP) and gastrin have been studied in 12 healthy subjects (aged 24-38 years). Sham feeding was performed without pretreatment (control) and after pretreatment with 400 mg cimetidine, 80 mg propranolol (both given orally) or 1 mg atropine administered subcutaneously 60 min prior to sham feeding. MSF induced a significant increase (about 100%) in PP release. Its early peak was reduced by pretreatment with propranolol whereas cimetidine had no effect. Atropine completely abolished the PP response. Gastrin release was stimulated by MSF only after prior administration of cimetidine and, to a lesser extent, after atropine pretreatment. It is concluded that: (1) the PP release after stimulation is under strong cholinergic control but is also mediated--particularly in the early phase--by adrenergic mechanisms; (2) endogenously released acid during vagal stimulation plays a minor role in the modulation of PP secretion, but (3) masks gastrin response to MSF.     

Role of antrum and duodenum in the control of postprandial gastric acid secretion and plasma gastrin concentration in dogs.

Three dogs were provided with Pavlov pouches. In two subsequent operations the antrum and the duodenal bulb were removed and the gastrointestinal continuity was restored by gastroduodenostomy. Gastric acid and gastrin secretion were stimulated by a test meal. The feeding experiments were repeated after each operation. The gastrin response to a test meal was markedly reduced but not eliminated by antral resection. Additional removal of the duodenal bulb significantly lowered the basal plasma gastrin concentration and abolished the gastrin response to feeding. The acid response to test meals was significantly increased by antrectomy. Extirpation of the duodenal bulb reduced the postprandial acid output to or below preantrectomy levels. The findings indicate that the antrobulbar region exerts a complex influence on gastric acid secretion which may result in stimulation or inhibition of the HCl glands. Removal of the pyloric antrum and the duodenal bulb does not effectively reduce postprandial acid secretion.     

Is antral gastrin important in the resistance of duodenal ulcers to H2 receptor antagonists or in recurrent ulceration after highly selective vagotomy?

Basal serum gastrin, integrated gastrin response to a meal, and integrated gastrin response to insulin induced hypoglycaemia were measured in 60 patients with duodenal ulcer before and after elective highly selective vagotomy to determine whether antral gastrin has a role in resistance to H2 receptor antagonist treatment which the patients had received before surgery or in the development of recurrent ulceration after vagotomy. The basal gastrin, integrated gastrin response to a meal, and the integrated gastrin response to insulin were similar in patients whose ulcers healed after H2 receptor agonist treatment or were refractory to at least three months of this treatment. The same parameters measured before or after highly selective vagotomy were similar in patients who eventually developed recurrent ulceration compared with those who did not. As expected the basal and meal stimulated (but not insulin stimulated) serum gastrin values increased after highly selective vagotomy. Ulcer patients with particularly high gastrin values (whether basal or stimulated) were not more resistant to H2 receptor antagonist treatment or prone to develop ulcer recurrence after highly selective vagotomy. This study suggests that antral gastrin is not important in 'resistance' of duodenal ulceration either to H2 receptor antagonist treatment or to highly selective vagotomy.     

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.     

Gastric motility and emptying in normal and post-vagotomy subjects.

The effects of proximal gastric vagotomy (PGV) and vagotomy with pyloroplasty (V and P) on gastric motility were studied using a solid meal labelled with a radiopharmaceutical agent. In having on-line computer facilities it was possible not only to record the rate of emptying but also to analyse the relative roles of the fundus and the antrum within the overall framework of gastric emptying. In normal subjects the fundus filled and then emptied in an almost linear pattern. The antrum, however, did not completely fill until well after the meal was eaten and thereafter appeared to maintain a constant volume during the study. The redistribution of contents between fundus and antrum was reflected in the total stomach emptying curve as a delay, or lag phase before gastric emptying commenced. After both types of vagotomy fundic filling was delayed, representing a slower eating time, which was presumably due to early satiety. Antral filling and volume was disturbed only after V and P, which was also reflected by a loss of the lag phase seen on the total stomach curve. PGV retained antral function but there was significant delay in the redistribution of contents between fundus and antrum, though this did not have clinical significance. The rate of emptying was unaffected by either operation. It was concluded PGV did maintain antral function and a more normal pattern of emptying compared with V and P. After V and P the changes in antral function were considerable and these changes are probably associated with some of the complications resulting from this operation.     

How radioimmunoassay has added to our knowledge about gastrin

Radioimmunoassay of gastrin has confirmed most of the earlier notions about factors controlling release of gastrin deduced from studies using secretion of acid to monitor gastrin release. These confirmations include vagal cholinergic release of gastrin, release of gastrin by distention of the gastric antrum, inhibition of gastrin release by acid bathing the antral mucosa, and release of gastrin from duodenal mucosa by food. New and unexpected information about gastrin that has come from radioimmunoassay includes: (1) disproof of the hypothesis that all gastrin release is cholinergic; atropine blocks vagal gastrin release but not release by food in the stomach; (2) vagal release of gastrin is substantial, not just a trace as had been supposed from acid studies; (3) the possibility that release of gastrin by hypoglycemia may be in part nonvagal; (4) the possibility that intestinal mucose releases stimulants of acid secretion in addition to those that are immunoreactive with antibodies to antral gastrin; and (5) Berson's discovery that the main forms of gastrin in blood plasma are larger molecules than the heptadecapeptide, little gastrin, that is the main form in antral mucose; big gastrins contain little gastrin in covalent linkage and trypsin splits off little gastrin from big gastrins.     

Morphology of the gastric mucosa, gastric secretion and serum gastrin concentration following a test meal

In 32 subjects, the HCl secretion, the histological state of the antral and fundic mucosa and the gastrin response to a liquid meal extract were studied. Atrophy of the antrum was associated with normal gastrin concentration in the fasting state and after the test meal, in the presence of normal fundic mucosa and HCl secretion. In achlorhydria and atrophic gastritis, fasting gastrinemia was significantly elevated in subjects with a normal antrum, and only moderately increased in subjects with an atrophic antrum. The gastrin response to feeding was correlated to the fasting gastrin concentration in achlorhydric subjects with normal antral mucosa, in contrast to a uniformly reduced output in achlorhydric subjects with atrophic lesions of the antral mucosa.     

Effects of ethanol on meal-stimulated secretion of pancreatic polypeptide and cholecystokinin: Comparison of healthy volunteers,heavy drinkers,and patients with chronic pancreatitis

Tiscornia and Dreiling (Physiopathogenic Hypothesis of Alcoholic Pancreatitis: Supranormal Ecbolic Stimulation of the Pancreon Units Secondary to the Loss of the Negative Component of Pancreas Innervation. Pancreas 1987;2:604–612.) proposed that hypertonicity of intrapancreatic cholinergic neurons provoked by chronic alcoholism may contribute to the pathogenesis of chronic pancreatitis (CP). In the present study, the validity of this hypothesis was investigated in humans by studying the effects of atropine, cisapride, and ethanol on the meal-stimulated secretion of pancreatic polypeptide (PP) and cholecystokinin (CCK) in healthy volunteers, heavy drinkers, and CP patients. In healthy volunteers, the early phase PP response (0–40 min) to a test meal was completely blocked by atropine, whereas it was augmented by cisapride, an enhancer of acetylcholine release from cholinergic nerves. The early phase PP response to a test meal was inhibited by ethanol in healthy volunteers, whereas, in heavy drinkers, the response was augmented and the inhibition by ethanol was abrogated. In CP patients, ethanol tended to enhance the early phase PP response. Ethanol did not affect the early phase CCK response to a test meal in any group, but it significantly enhanced the late phase CCK response (40–120 min) in CP patients. These results suggest that: (i) oral ethanol may inhibit the post-prandial activation of the cholinergic neural pathway to the pancreas in healthy subjects, (ii) in heavy drinkers, postprandial cholinergic tone may be augmented and become resistant to the inhibition by ethanol, and (iii) the ethanol-induced increase in the postprandial CCK response in CP patients may play some role in the pathophysiology of this disease.     

Relation between cholecystokinin and antral innervation in the control of gastric emptying in the rat.

BACKGROUND: Antral motility and the hormone cholecystokinin (CCK) are major determinants of the rate of gastric emptying. The relation between CCK and antral neurons in regulating gastric emptying is uncertain. Benzalkonium chloride (BAC) causes selective lesions in gut myenteric neurons after serosal application. AIM: To develop a model of antral denervation using BAC to enable the study of the relation between CCK and antral neurons in regulating gastric emptying. METHODS: BAC, vehicle or the afferent neurotoxin capsaicin were applied to the serosal surface of the rat antrum or corpus; neurochemical markers of intrinsic and afferent neurons were detected by using immunohistochemistry and radioimmunoassay. Gastric retention of solids was determined after fasting, and emptying of liquids was measured in rats with gastric fistulae. RESULTS: In BAC treated rats radioimmunoassay of tissue extracts revealed a dose related specific loss of gastrin releasing peptide, substance P, and vasoactive intestinal polypeptide immunoreactivities from the treated region, and immunohistochemistry revealed loss of the neuronal marker PGP 9.5 and the afferent neuropeptide calcitonin gene related peptide (CGRP). Adjacent untreated regions were unaffected by BAC, with the exception that CGRP was depleted in both corpus and antrum after antral treatment. After antral BAC treatment fasted rats retained solids for over 48 hours. Moreover, in antrally denervated rats with gastric fistulae, the emptying of saline, acid and peptone was delayed substantially. The CCK dependent inhibition of gastric emptying of peptone was preserved after antral treatment with BAC. CONCLUSIONS: Serosal BAC causes lesions in the innervation of the treated region of the stomach. The innervation of the antrum is essential for normal emptying of both liquids and solids, but the inhibition of gastric emptying produced by CCK is not dependent on antral neurons.     

Gastric and extragastric gastrin release in normal subjects in duodenal ulcer patients, and in patients with partial gastrectomy (Billroth I).

In 10 normal subjects, in 32 patients with duodenal ulcer (DU), and in 11 patients with partial gastrectomy (Billroth I), serum gastrin rose significantly after an oral and intraduodenal test meal. The highest increases were observed in DU patients after the oral as well as after the intraduodenal test meal. After the intraduodenal test meal in 4 normal subjects and in 17 DU patients an increase of gastric acid secretion and serum gastrin was measured. In basal state, after an intraduodenal or an oral test meal, DU patients with normal gastric acid secretory capacity had higher serum gastrin concentrations than DU patients with gastric hypersecretion. There was a good correlation between peak serum gastrin levels after the oral and after the intraduodenal test meal. From these data it is concluded: (1) Intraduodenal application of a test meal results in release of gastrin from extragastric sites. (2) Extragastric gastrin is biologically active. (3) DU patients are able to release more antral and more extragastric gastrin in response to a test meal. Further studies, however, are necessary to show the significance of these findings in the pathogenesis of peptic ulcer disease.