Central versus peripheral effects of bombesin on the release of gastrointestinal hormones in dogs.

This study compared the effects of bombesin given intracerebroventricularly and intravenously on circulating levels of gastrin, pancreatic polypeptide (PP), and cholecystokinin (CCK-33). Bilateral cannulas were implanted permanently into the lateral cerebral ventricles of five dogs. An intravenous (IV) bolus injection of bombesin (0.25 microgram/kg) significantly elevated circulating levels of gastrin, PP, and CCK-33. Vagotomy inhibited the release of PP that was induced by IV bombesin, but vagotomy did not affect gastrin and CCK-33 responses. Intracerebroventricular injection of bombesin (5.0 micrograms) significantly elevated circulating gastrin levels but did not affect circulating levels of CCK-33 and PP. Vagotomy did not alter gastrin release induced by intracerebroventricular injection of bombesin.

Cytoprotective effect of pentagastrin and epidermal growth factor on stress ulcer formation. Possible role of somatostatin.

This study was designed to test the effects of pentagastrin and epidermal growth factor (EGF) on stress-induced ulceration and on the antral content of gastrin and somatostatin (SLI) in rats. Four groups of 14 to 15 rats had been prepared for 7 days by one of the following methods: saline injection (control); injection of pentagastrin (250 micrograms/kg, 3 times/day); injection of EGF (10 micrograms/kg, 3 times/day); or injection of EGF plus pentagastrin. At the end of the treatment period, half of each group of rats were sacrificed (nonstress group). There were no ulcers in the nonstress control groups of rats. Stress was applied by water immersion in the remaining half of the rats. The injections of pentagastrin and/or EGF resulted in substantial increase in antral content of SLI. After 20 hours of stress, the ulcer index was 40.5 +/- 3.3 in the controls, compared to 6.4 +/- 1.2 and 16.2 +/- 2.3 in rats that received pentagastrin or EGF, respectively. Injections of both pentagastrin and EGF resulted in an ulcer index of 26.2 +/- 2.0, which was significantly lower than that in controls, but higher than that in rats treated with either peptide alone. The stress resulted in significant decrease in antral SLI in all groups of rats, whereas SLI content in rats treated with pentagastrin and/or EGF remained significantly higher than that of controls. Antral content of gastrin did not differ significantly in the four groups tested. The ulcer index was inversely correlated with antral SLI content. We confirm and extend previous observations that pentagastrin and EGF prevent stress ulcer formation, and suggest that endogenous SLI may account, at least in part, for their antiulcer activity.

Effect of acetylsalicylic acid on the constituents of the gastric mucosal barrier.

The effect of luminal application of acetylsalicylic acid (ASA) on the liberation of gastric mucosal barrier constituents at pH 5.0 and 2.0 was investigated. The Lucite chamber stomach-flap preparation was used in 18 dogs whose basal H+ secretion was inhibited by cimetidine. An ASA dose of 10 mmol at pH 5.0 caused a moderate increase in content of proteins, glycoproteins, and glycolipids in the instillates. This was accompanied by an increase in transmucosal potential difference (PD) without concomitant changes in the appearance of the gastric mucosa. However, the content of mannose used as an indicator of plasma leakage remained unchanged. A 20 mmol ASA dose at pH 5.0 produced further enrichment of the instillates in mucus constituents, and an increase in mannose content was observed, but PD still remained elevated. In contrast, the same dose of ASA at pH 2.0 severely depleted the gastric mucosal barrier of its mucus constituents and caused a marked increase in leakage of plasma elements. These changes were accompanied by a substantial drop of PD and gastric mucosal damage. These data indicate that the topical application of ASA causes the liberation of mucus constituents, which results in weakening of the gastric mucosal barrier and thus facilitates the pepsin and acid penetration of gastric mucosa. The extent of mucosal damage caused by aspirin strongly depends on the pH of luminal exposure.

Effect of 16,16-dimethyl prostaglandin E2 and ethanol on the constituents of gastric mucus.

The effect of ethanol, 16,16-dimethyl prostaglandin E2 (DMPGE2), and ethanol after DMPGE2 pretreatment on the solubilization of protein, glycoprotein, and glycolipid constituents of gastric mucus was investigated. The Lucite chamber stomach-flap preparation was used in dogs whose basal H+ secretion was inhibited by intravenous cimetidine. Graded concentrations (5-80%) of ethanol produced a dose-dependent decrease in potential difference (PD) which was accompanied by an increase in the content of proteins, glycoproteins, and glycolipids of the instillates. This effect was most pronounced at 40% ethanol. Exposure of gastric mucosa to DMPGE2 at 0.01 microgram/ml had no effect on the transmucosal PD, and the content of investigated components in the instillates increased only slightly over the saline control levels. DMPGE2 at 0.1 microgram/ml, although it did not induce an evident fall of PD, evoked a moderate increase in glycoprotein and glycolipid liberation. Higher doses (above 1.0 microgram/ml) of DMPGE2 were associated with the fall of PD and the increased solubilization of proteins, glycoproteins, and glycolipids. Pretreatment of the mucosa with DMPGE2 in a dose of 1.0 microgram/ml diminished the liberation of the investigated components from the gastric mucosa by 5 and 10% ethanol, but did not prevent the changes evoked by higher concentrations (20-80%) of ethanol. These data indicate that DMPGE2 applied topically protects in part the gastric mucosa against the ethanol-induced solubilization of mucus constituents.

Release of cholecystokinin in conscious dogs: correlation with simultaneous measurements of gallbladder pressure and pancreatic protein secretion.

We have used an antibody that cross-reacts with cholecystokinin-33/39 to measure cholecystokinin release into plasma; this release was correlated with simultaneous measurements of gallbladder pressure and pancreatic protein secretion in response to intestinal administration of fat. Nine conscious dogs were prepared with chronic gastric, pancreatic, and gallbladder fistulas. Plasma cholecystokinin, gallbladder pressure, and pancreatic protein output were measured simultaneously before, and at intervals during, a 2-h intraduodenal infusion of sodium oleate. This infusion resulted in significant (p less than 0.05) elevations of plasma cholecystokinin (from 64 +/- 7 to 181 +/- 27 pg/ml), in gallbladder pressure (from 13 +/- 1 to 27 +/- 3 cmH2O), and in pancreatic protein output (from 65 +/- 7 to 148 +/- 21 mg/15 min); all measurements are from the basal state to 120 min after the onset of duodenal perfusion. Plasma concentrations of cholecystokinin were significantly correlated with gallbladder pressure (r = 0.91, p less than 0.05) and pancreatic protein output (r = 0.84, p less than 0.05). These data provide evidence that release of endogenous cholecystokinin, as measured by radioimmunoassay, can be correlated with the classic biologic actions ascribed to cholecystokinin.

Effect of enkephalin and naloxone on gastric acid and serum gastrin and pancreatic polypeptide concentrations in humans.

The effects of a synthetic enkephalin analogue with prolonged opioid activity, D-ala-2-enkephalin (ala-enk) and naloxone given alone or in combination, on vagally, pentagastrin- and histamine-induced gastric secretion and plasma hormonal responses to vagal stimulation have been studied in healthy subjects. D-ala-2-enkephalin reduced basal gastric acid and pepsin secretion, and caused a dose-dependent inhibition of gastric secretory responses to modified sham-feeding and pentagastrin but not to histamine. It increased serum gastrin concentration and suppressed plasma pancreatic polypeptide response to modified sham-feeding. Naloxone alone at lower dose levels did not affect gastric secretion and plasma hormonal concentrations but at higher doses it reduced both basal and modified sham-feeding-induced secretion. When combined with ala-enk it reversed in part gastric secretory and plasma hormonal changes induced by this peptide during modified sham-feeding and pentagastrin stimulation. These results indicate that (1) stable enkaphalin analogue inhibits basal and vagally or pentagastrin-induced gastric secretion, and affects plasma hormonal response to vagal stimulation, at least in part, via activation of opioid receptors and (2) endogenous opioid substances may be involved in the stimulation of gastric secretion in man.

Organ removal and disappearance half-time of synthetic human pancreatic polypeptide.

Human pancreatic polypeptide (HPP) was infused into 6 anesthetized dogs at a constant dose of 1.0 micrograms/kg/h over 60 min. Blood samples for RIA of pancreatic polypeptide were taken repeatedly from a carotid artery, jugular vein, femoral vein, renal vein and mesenteric vein. The calculated tissue removal of HPP in a single passage through these four vascular beds ranged from 24 to 40% and did not differ significantly among them. Mean disappearance half-time on stopping the infusion was 4.5 +/- 0,8 min. The results indicate that HPP is removed at all of the capillary beds tested.

Gastric alkaline response to mucosa-damaging agents: effect of 16,16-dimethyl prostaglandin E2.

We investigated the effects of luminal application of graded concentrations of conventional mucosal barrier breakers such as ethanol, aspirin (ASA), and sodium taurocholate (TCh), as well as 16,16-dimethyl prostaglandin E2 (DMPGE2) on gastric alkaline output (GAO) and transmucosal potential difference (PD). The Lucite chamber stomach-flap preparation was used in 50 dogs whose basal H+ secretion was inhibited by intravenous cimetidine. Graded concentrations of ethanol, and TCh at pH 5.0, and acidified solutions of ASA (at pH 5.0--2.0) were found to produce a dose-dependent increase in GAO accompanied by a stepwise decline in PD. Increasing concentrations of DMPGE2 above 1.0 microgram/ml caused a dose-related increase in GAO and a reduction in PD. The combination of DMPGE2 with ethanol aggravated the PD changes, whereas GAO induced by these agents was decreased. Alterations in GAO and PD evoked by the ASA solutions varying in pH were not significantly affected by the addition of 1.0 microgram/ml DMPGE2 to the bathing fluid. These results indicate that stimulation of gastric alkalinization with concomitant fall in PD is a common feature for various mucosa-irritant substances, and pretreatment with DMPGE2 does not prevent these effects.

Gastric secretory and plasma hormonal responses to sham-feeding of varying duration in patients with duodenal ulcer.

Gastric acid and serum gastrin, pancreatic polypeptide, and insulin responses to cephalic vagal stimulation were studied in eight patients with duodenal ulcer using modified sham-feeding for periods varying from four to 30 minutes. In addition, the maximal acid response to sham-feeding was compared with that induced by pentagastrin in 10 healthy subjects and 14 patients with duodenal ulcer. It was found that the gastric acid response to modified sham-feeding reached the maximal value after 15 minutes of sham-feeding and amounted to about 68% of the pentagastrin maximum. The serum pancreatic polypeptide response was also increased after modified sham-feeding and depended on the duration of this procedure, whereas gastrin and insulin responses were not significantly affected by modified sham-feeding. When the peak acid output induced by modified sham-feeding was normalised as percentage of the peak response to pentagastrin, it was similar in healthy subjects and in patients with duodenal ulcer; this indicates that the increased peak acid response to modified sham-feeding observed in patients with duodenal ulcer corresponded with their greater parietal cell mass rather than with increased vagal tone.

Pancreatic polypeptide and vagal stimulation of gastric and pancreatic secretion in dogs.

In four dogs provided with pancreatic, gastric, and esophageal fistulae, the effects of bovine pancreatic polypeptide (BPP) infused at a physiological dose level (240 pmol per kg/hr) on gastric and pancreatic responses to sham-feeding were studied. The maximal gastric and pancreatic secretion was produced by pentagastrin and secretin, and OP-CCK infusion, respectively, with or without additions of BBP. Exogenous BPP did not change gastric acid and pepsin outputs stimulated by pentagastrin or sham-feeding, but significantly inhibited basal and maximally stimulated pancreatic protein secretion. The peak pancreatic protein, but not bicarbonate response to sham-feeding was reduced by about 31% by BPP. This reduction by BPP amounted to about 57% when the pancreas was stimulated maximally by OP-CCK. It is concluded the PP released by cephalic-vagal excitation does not affect gastric secretion, but inhibits pancreatic protein secretion, and thus might contribute to the lower pancreatic response to sham-feeding as compared with that produced by exogenous stimulants such as secretin and OP-CCK.

Effect of pancreatic polypeptide and its C-terminal hexapeptide on meal and secretin induced pancreatic secretion in dogs.

1. Gastric acid and pancreatic bicarbonate and protein secretion as well as immunoreactive serum gastrin and pancreatic polypeptide concentrations in response to a meal and secretin have been measured before and after infusion of bovine pancreatic polypeptide or its C-terminal hexapeptide. 2. Liver extract meal kept in the stomach at pH 5.5 (by intragastric titration) produced a marked increase in gastric acid and pancreatic protein secretion accompanied by a rise in serum gastrin and pancreatic polypeptide levels. Exogenous bovine pancreatic polypeptide caused little change in gastric secretion and serum gastrin but resulted in a profound suppression of pancreatic secretion. 3. Ordinary feeding a liver meal produced a marked increase in pancreatic bicarbonate and protein secretion that was dose-dependently inhibited by bovine pancreatic polypeptide or its C-terminal hexapeptide, the degree of inhibition being closely correlated with the increments in plasma pancreatic polypeptide. 4. Bovine pancreatic polypeptide and its C-terminal hexapeptide also inhibited secretin and caerulein-induced pancreatic secretion in a dose-dependent manner. 5. This study shows that bovine pancreatic polypeptide inhibits pancreatic secretion at least in part by acting directly on the exocrine pancreas and that its biological activity resides in its C-terminal hexapeptide fragment.

Effects of pirenzepine and atropine on gastric secretory and plasma hormonal responses to sham-feeding in patients with duodenal ulcer.

The effects of atropine and pirenzepine on sham-feeding stimulated gastric secretion and serum gastrin and pancreatic polypeptide levels have been studied in 12 patients with duodenal ulcer. Both atropine and pirenzepine caused a dose-dependent decrease in acid and pepsin secretion induced by sham-feeding. Serum gastrin response to sham-feeding was negative and it was enhanced by atropine but suppressed by pirenzepine. Plasma pancreatic polypeptide level, which was markedly increased by sham-feeding, was abolished both by atropine and pirenzepine. This study shows that pirenzepine is a more selective inhibitor of gastric secretory and serum hormonal responses to sham-feeding than atropine and that it may be a useful tool for studying the cholinergic innervation of the oxyntic glands and the G-cells in man.

Effect of orally administered 15(R)-15-methyl prostaglandin E2 and/or an anticholinergic drug on meal-induced gastric acid secretion and serum gastrin level in patients with duodenal ulcers.

The purpose of the present series of tests was to measure and compare the effects of ingestion of gelatin capsules containing 15(R)-15-methyl PGE2 (PG) and/or an anticholinergic drug (methscopolamine bromide, Pamine) on meal-induced gastric acid secretion and serum gastrin level. Eleven duodenal ulcer patients were stimulated by a 5% peptone meal. Acid secretion was determined by the intragastric titration technique, and serum gastrin was measured by radioimmunoassay. The tests were randomized and double-blind. PG alone given 30 min before a test meal at a dose of 50 micrograms or 100 micrograms produced no side effects and inhibited meal-stimulated acid secretion by about 43% and 55%, respectively. Gastric acid inhibition after a single dose of PG was most pronounced in the first hour of a test meal and was accompanied by almost complete suppression of the meal-induced serum gastrin level. Pamine alone in a dose of 2.5 mg reduced gastric acid response to a meal by about 29% but caused a further rise of postprandial serum gastrin level over control values. The combination of PG, 50 micrograms, and Pamine, 2.5 mg, did not result in significantly greater acid inhibition (about 48%) than when either compound was given alone. When the higher dose of PG (100 micrograms) was given together with Pamine (2.5 mg), the degree of inhibition produced by PG alone was not changed. It is concluded that PG given orally in capsules is a potent inhibitor of gastric acid and serum gastrin response to a meal and that this effect may be of potential value in the treatment of peptic ulcer disease.

Effect of selective proximal vagotomy and truncal vagotomy on gastric acid and serum gastrin responses to a meal in duodenal ulcer patients.

To assess the effectiveness of selective proximal vagotomy (SPV) in reducing the acid response to food, we have compared pre- and postoperative gastric acid and serum gastrin responses to a meal in 11 duodenal ulcer patients with intractable pain treated by SPV, with those of seven ulcer patients with gastric outlet obstruction treated by truncal vagotomy and drainage (TV + D). Acid secretion was measured by an intragastric titration method which measures acid response to food within the stomach (5% amino acid meal) adjusted to various pH levels (5.5, 2.5, and 1.5). Studies were performed before and two to six weeks after operation. The preoperative intragastric acid output (IGAO) was about 50% of maximal acid response to Histalog. The mean preoperative IGAO at pH 5.5 For 11 SPV patients was 17.4 +/- 3.1 mEq/hour; this was decreased by 72% to 4.3 +/- 1.1 mEq/hour after operation. The mean IGAO at pH 5.5 in nine patients treated by TV + D was 21.6 +/- 3.4 mEq/hour; this was decreased by 67% to 7.3 +/- 2.1 mEq/hour. Gastrin levels were significantly higher in postop than in preop SPV PATIENTS EVEN THOUGH PH values were constant. Gastrin levels were higher in postop TV + D patients than in postop SPV patients. This study demonstrates that acid reduction achieved by SPV is reliable and at least comparable with that achieved by turncal vagotomy. Postoperative elevation of gastrin in the SPV patients suggests that the vagus may release a humoral inhibitor of gastrin release from the gastric fundus; there may also be a further direct vagal inhibitor of antral gastrin release.

Influence of vagus on mechanisms for stimulation and inhibition of gastrin release.

In studies in dogs the gastrin response to food, to bombesin (1 micrgoram/kg-hr), and to somatostatin (2.5 and 5.0 microgram/kh-hr) plus food before and after truncal vagotomy was determined. Vagotomy caused an increase in basal levels of gastrin and in the release of gastrin after bombesin and food. Vagotomy augmented somatostatin suppression of food-stimulated gastrin release in a dose-dependent manner. We suggest that vagotomy causes a loss of both stimulatory and inhibitory vagal effects on gastrin release. Loss of vagal inhibition results in increased gastrin release to bombesin and food. Loss of vagal stimulation results in intensification of somatostatin-induced inhibition of postprandial gastrin release.

Concentrations of gastrin and secretin in the alimentary tract of the cat.

The distribution of gastrin and secretin in the alimentary tract of the cat was determined from the esophagogastric junction to the ileocecum. The total content and concentration of each of these hormones in mucosal extracts taken from the gastric fundus, gastric antrum, proximal and distal duodenum, proximal and distal jejunum, and ileum were measured with specific radioimmunoassays. The gastric antrum contained the highest concentration of gastrin, but appreciable amounts also were found in the duodenum. The highest concentrations of secretin were found in the duodenum, but impressive quantities were measured in the jejunum. The role of extra-antral gastrin and of those stores of secretin beyond the proximal duodenum (where the pH probably never falls to levels associated with release of secretin) currently are unknown.

Effect of somatostatin on meal-induced gastric secretion in duodenal ulcer patients.

The effect of somatostatin, a growth hormone releasing-inhibiting hormone (GH-RIH) on basal and meal-, pentagastrin-, or histamine-stimulated gastric acid and pepsin secretion was studied in six duodenal ulcer patients. Intravenous GH-RIH infused in graded doses ranging from 0.62 to 5.0 microgram/kg/hr produced a dose-related inhibition of pentagastrin-induced acid secretion reaching about 15% of control level at the dose of 5.0 microgram/kg/hr. Acid inhibition was paralleled by a decrease in the pepsin output and accompanied by a dose-dependent reduction in serum growth hormone and insulin levels measured by radioimmunoassay. GH-RIH used in a single dose of 2.5 microgram/kg/hr produced about 85% inhibition of acid secretion induced by a meal (measured by intragastric titration) accompanied by a significant decrease in serum gastrin and insulin levels. The effect of GH-RIH on histamine-stimulated secretion was very modest and observed only after stopping the GH-RIH infusion. Thus GH-RIH suppressed acid and pepsin secretion induced by pentagastrin and a meal, and this effect was accompanied by a suppression of serum growth hormone and gastrin levels which may contribute to the inhibition of gastric secretion observed.

Acid and endocrine responses to meals varying in pH in normal and duodenal ulcer subjects.

Recent studies suggest that duodenal ulcers may develop because of increased drive to secrete acid and decreased effectiveness of feedback mechanisms that inhibit acid output. This study was designed to compare gastric acid, gastrin, gastric inhibitory peptide (GIP) and secretin responses to meals (varying in pH) in 12 normal subjects and nine duodenal ulcer patients. Acid secretion was measured by an intragastric titration method which allows actual measurement of acid response to food within the stomach (ten per cent amino acid meal (AAM) adjusted to various pH levels, 7-1.5). Blood samples were collected at each pH level for radioimmunoassay of gastrin, secretin and GIP. Gastric acid and gastrin responses to AAM were found to be significantly greater in duodenal ulcer patients than in normal subjects. In duodenal ulcer patients, acid response to AAM at pH 7 or 5.5 reached 82% of Histalog maximum. Decreasing the pH of the meal resulted in a stepwise reduction in both acid secretion and gastrin in normal subjects and duodenal ulcer patients. At pH 1.5, acid inhibition was complete, but gastrin inhibition was partial. Secretin increased significantly at pH 1.5; there was no difference in secretin release between the groups. Plasma GIP was highest at pH 7 in all individuals. Use of a marker substance showed 80% recovery of AAM at pH 7-4; below pH 4, recovery rose to about 90%. We conclude that gastric acid and gastrin release are pH-dependent in normal and duodenal ulcer subjects. Inhibition of gastric secretion by acidified meals is associated with a pH-dependent suppession of gastrin and GIP levels and elevation of plasma secretin. This study confirms increased acid and gastrin responses in duodenal ulcer patients but shows no evidence of defective feedback inhibition of gastric secretion and gastrin release.