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.

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.

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 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.

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.

Effect of alcohol on the release of secretin and pancreatic secretion.

The effect of alcohol on the release of secretin was studied in man by radioimmunoassay, and in dogs and cats by radioimmunoassay and bioassay (secretion of water and bicarbonate by the pancreas). In man plasma secretin levels increased significantly from a basal of 121 +/- 14 to 164 +/- 24 pg/ml at 60 minutes after oral ingestion of alcohol. Intraduodenal administration of alcohol in man, dogs, and cats did not release secretin or affect pancreatic water and bicarbonate secretion in dogs and cats, but a moderate increase in pancreatic protein output was observed in these two species. Plasma gastrin levels rose significantly from a basal of 52 +/- 4 to 64 +/- 3 pg/ml after ingestion of alcohol in man and from 33 +/- 5 to 51 +/- 8 pg/ml after administration of alcohol into the stomach of dogs. Administration of alcohol into the duodenum in man, dogs, and cats did not release gastrin. We conclude that alcohol probably does not release secretin directly. The mechanism of release of secretin in man is unknown; it clearly involves the stomach and may be mediated via the release of gastric acid.