Effect of somatostatin on pancreatic protein secretion induced by cholecystokinin.

Using an in vivo rabbit pancreas preparation, studies were conducted to determine the effect of somatostatin on pancreatic protein secretion induced by the octapeptide of cholecystokinin (OP-CCK) when directly infused intraarterially into the pancreatic parenchyma. Compared to control experiments in which no drugs were given, intraarterial infusion of OP-CCK (30 ng/ml) continuously for 1 hr at a rate of 0.33 ml/min significantly increased (P < 0.005) protein concentration and total protein output in the pancreatic juice without a corresponding change in volume. When given in combination with somatostatin (5 μg/ml) OP-CCK-induced pancreatic protein secretion was markedly inhibited (P < 0.05) without any effect on pancreatic volume output. The observation that volume flow remained unchanged during OP-CCK infusion alone and in combination with somatostatin suggests that the inhibitory effect of somatostatin is mediated through direct inhibition of protein synthesis or release at the level of the pancreatic acinar cell.     

Effect of duodenal osmolality on gastrin and secretin release and on gastric and pancreatic secretion

We have measured the osmolality of duodenal contents in 9 dogs after a hypertonic meal, given either by mouth or directly into the stomach or perfused into the duodenum. A test meal of 2,475 mosm/kg, given by mouth, raised the intraduodenal osmolality to 700–1,500 mosm/kg over a 1-hour period. Hypertonic glucose solutions (2,000 and 3,400 mosm/kg), given into the stomach, were found to be diluted to about 700 and 1,100 mosm/kg, respectively, at the level of the mid-duodenum 30 minutes later. Hypertonic saline solutions (1,800 and 2,700 mosm/kg), perfused into the duodenum, created a stable intraluminal osmolality of 800 and 1,200 mosm/kg, respectively, (about 45% that of the perfusate) after 30 minutes. In 6 Heidenhain pouch dogs, gastric secretion and gastrin release stimulated by food were significantly diminished by administration of hypertonic sodium chloride solution (1,800 mosm/kg) into the duodenum. This hyperosmolality caused greater suppression of acid secretion (52%) than of gastrin release (28%). Stimulation of pancreatic water and bicarbonate secretion and of release of radioimmunoassayable secretin by intraduodenal HCl (pH 1.3) were significantly suppressed when the osmolality of the HCl solution was raised to 2,700 mosm/kg. Pancreatic protein secretion remained unchanged with hypertonic solutions. We have confirmed that stimulation of intraduodenal osmoreceptors inhibits gastric acid secretion in dogs, and we suggest that this is due, at least in part, to a suppression of gastrin release. We further suggest that duodenal osmolar inhibition of pancreatic secretion involves suppression of secretin but does not appear to involve cholecystokinin.

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Résumé Nous avons mesuré l'osmolalité du contenu duodénal chez 9 chiens après un repas hypertonique administré soit per os, soit directement dans l'estomac, soit par perfusion dans le duodénum. Un repas à 2,475 mosm/kg, administré per os, élève l'osmolalité duodénale à 700–1,500 mosm/kg pendant une heure. Des solutions de glucose hypertonique à 2,000 et 3,400 mosm/kg, introduites directement dans l'estomac, sont, 30 minutes plus tard, diluées à 700 et 1,100 mosm/kg au niveau de la partie moyenne du duodénum. Des solutions salines hypertoniques à 1,800 et 2,700 mosm/kg, en perfusion intraduodénale, donnent, après 30 minutes, une osmolalité duodénale de 800 et 1,200 mosm/kg (±45% de la solution perfusée).Chez 6 chiens à poche de Heidenhain, la sécrétion gastrique et la libération de gastrine provoquées par un repas sont réduites de façon significative par la perfusion intraduodénale de chlorure de sodium en solution hypertonique (1,800 mosm/ kg). Cette hyperosmolalité réduit plus la sécrétion d'acide (52%) que la libération de gastrine (28%). La perfusion dans le duodénum d'une solution d'HCl (pH 1.3), dont l'osmolalité est portée à 2,700 mosm/kg, diminue la stimulation des sécrétions d'eau et de bicarbonate pancéatiques et la libération de sécrétine mesurable par radio-immunoessai. La sécrétion pancréatique de protéines n'est pas modifiée par les solutions hypertoniques. Nous avons done confirmé l'inhibition de la sécrétion gastrique d'acide chez le chien par stimulation des osmorécepteurs duodénaux; nous pensons que cette inhibition est due, en partie en tous cas, à la suppression de la libération de gastrine. Nous estimons de plus que l'inhibition de la sécrétion pancréatique par l'hyperosmolalité duodénale résulte d'une suppression de la libération de sécrétine, mais est sans effet sur la libération de cholécystokinine.

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Supported by grants from the National Institutes of Health (AM 15241) and the John A. Hartford Foundation, Inc.

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An abstracted preliminary report of a portion of this work has appeared (Physiologist 20:93, 1977).

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Recipient of a grant from the Deutsche Forschungsgemeinschaft (Te 79/1).     

豚鼠体内生长抑素和血管活性肠肽在胆囊结石形成中的作用

目的 探讨体内生长抑素和血管活性肠肽在胆囊结石形成中的作用。方法 采用放射免疫分析法（ＲＩＡ）和受体放射配基结合分析法（ＲＢＡ）分别测定豚鼠体内门静脉血产乐、胆囊壁组织、胆汁中的ＳＳ、ＶＩＰ和胆囊壁上ＶＩＰ受体（ＶＩＰ－Ｒ）。与对照组比较观察在诱发豚鼠胆囊结石实验的第２、６、８周后胆空腹体积（ＦＶ）、胆囊空腹胆汁量（ＦＢ）、胆汁成分及上述胃肠肽的变化。结果 实验２周后ＦＶ增大,５６周和８周后ＦＢ亦     

Effect of colectomy on cholecystokinin and gastrin release.

Studies were conducted to determine the effect of resection of the colon on the release of cholecystokinin (CCK) and gastrin. A standard food stimulation test was performed in five dogs. Peripheral blood samples were collected for future measurement of CCK and gastrin by specific radioimmunoassay. Each dog underwent subtotal colectomy with side-to-end ileoproctostomy. The food stimulation test was repeated at approximately weekly intervals for eight weeks after colectomy. Basal plasma CCK levels of 139 +/- 21 pg/ml before colectomy did not change after colectomy. Total amount CCK released after food was increased significantly at both four (5.94 +/- 0.78 ng min/ml) and eight (13.00 +/- 2.72 ng min/ml) weeks after colectomy in comparison with that observed prior to colectomy (2.94 +/- 0.54 ng min/ml). Basal serum gastrin levels of 28 +/- 9 pg/ml did not change significantly after colectomy. Total amount of gastrin released after food was increased significantly at both two (8651 +/- 2294 pg min/ml) and three (6940 +/- 1426 pg min/ml) weeks after operation, but at none of the later weeks. The precolectomy output, used for comparison, was 5608 +/- 1346 pg min/ml. It was concluded that resection of the colon leads to an increase in release of CCK and gastrin after food stimulation. This finding provides further evidence that the colon contains a factor that inhibits the release of CCK and gastrin, and that the colon functions as an endocrine organ.     

Serum gastrin and secretin levels after the Exalto-Mann-Williamson procedure.

The Exalto-Mann-Williamson procedure produces peptic ulceration in nearly 100% of experimental animals but the mechanism is unknown. To investigate the possible hormonal role of the gastric acid hypersecretion seen after this procedure, we investigated preoperative and postoperative serum gastrin and secretin concentrations. There was no significant change in serum gastrin; however, serum secretin concentrations increased to 2 1/2 times the preoperatve value, most likely secondary to the enhanced secretion of gastric acid. These data do not suppport the theory that alterations in circulating secretin or gastrin levels are responsible for the gastric acid hypersecretion following the Exalto-Mann-Williamson operation.     

Gastric somatostatin release: evidence for direct mediation by calcitonin gene-related peptide and vasoactive intestinal peptide

It has previously been demonstrated that somatostatin (SRIF) directly inhibits parietal cell secretion. However, the significance of SRIF as a paracrine agent and mechanisms of local gastric SRIF release are not clear. Vasoactive intestinal peptide (VIP) and calcitonin gene-related peptide (CGRP) are neuropeptides which have been localized in the gastric fundus and have been demonstrated to inhibit gastric acid secretion in vivo. The present study examines the hypothesis that CGRP and VIP act via the release of gastric fundic SRIF. The study utilized rabbit isolated gastric glands prepared by collagenase digestion. Glands were incubated alone, or with 10(-10)-10(-6) M CGRP or 10(-10)-10(-6) M VIP for 30 min. Supernatant SRIF was measured using a specific radioimmunoassay. Unstimulated SRIF release was 101 +/- 16 fmole/ml. CGRP (10(-7) and 10(-6) M) and VIP (10(-7) and 10(-6) M) resulted in significant SRIF release. The maximum release of SRIF by CGRP (506 +/- 113 fmole/ml) was significantly greater than that by VIP (293 +/- 33 fmole/ml) (P less than 0.05). However, both these concentrations of SRIF are comparable to the ID50 concentration (4.5 X 10(-10) M) for SRIF inhibition of acid secretion by isolated parietal cells as assessed by [14C]aminopyrine accumulation. These results are consistent with the hypothesis that CGRP and VIP inhibition of acid secretion may be mediated, at least in part, by the local release of SRIF from the gastric fundus. These data further support the significance of paracrine interactions in the modulation of cellular secretory function.     

Pulmonary clearance of vasoactive intestinal peptide.

Vasoactive intestinal peptide causes bronchodilatation when given intravenously but is less effective in both animals and man when given by inhalation. This difference may be due to poor transit of the peptide across the bronchial epithelium. To test this hypothesis pulmonary clearance of radiolabelled vasoactive intestinal peptide was measured in Sprague Dawley rats and compared with that of pertechnetate (TcO4-) and diethylene triamine pentaacetate (DTPA). Despite a molecular weight (MW) of 3450, iodinated vasoactive intestinal peptide was cleared rapidly from the lungs, with a mean half time (t1/2) of 19 minutes after an initial slower phase. This compares with a t1/2 of 10 minutes with TcO4- (MW 163) and a t1/2 of 158 minutes with DTPA (MW 492). The possibility that vasoactive intestinal peptide mediates a non-specific increase in permeability was discounted by the fact that the combination of vasoactive intestinal peptide and DTPA did not alter DTPA clearance significantly. Chromatography and radioimmunoassay of blood taken after intratracheal administration of vasoactive intestinal peptide demonstrated a metabolite but no unchanged peptide. An intravenous injection of the peptide disappeared on first pass through the lung. It is concluded that inhaled vasoactive intestinal peptide lacks efficacy as a bronchodilator not because of slow diffusion to airway smooth muscle but because it is metabolised at an early stage of its passage through the respiratory epithelium.     

Changes in circulating levels of cholecystokinin,gastrin, and pancreatic polypeptide after small bowel resection in dogs

The postresectional meal-stimulated concentrations of gastrin were significantly increased 6 weeks after intestinal resection, and returned to preoperative levels within 10 weeks. Preoperatively, the onset of release of cholecystokinin occurred 120 minutes after food intake, 3 weeks after surgery it occurred at 90 minutes after food intake, and at 10 and 15 weeks after operation at 15 and 5 minutes after food intake, respectively. Postprandial release of pancreatic polypeptide was not affected by massive small bowel resection. We suggest that postresectional hypergastrinemia results from loss of a distal inhibitor and that the abnormally high basal concentrations of gastrin may augment the basal pancreatic polypeptide. We further suggest that the increased cholecystokinin concentrations, and the alterations of the temporal pattern of the release, are secondary to accelerated gastric emptying and intestinal transit. The mechanism responsible for postresectional hypergastrinemia is short-lived but the mechanism for postresectional increases in cholecystokinin release is not.     

Effect of infused vasoactive intestinal peptide on airway function in normal subjects.

Vasoactive intestinal peptide, one of the putative neurotransmitters of non-adrenergic inhibitory nerves in human airways, is a potent relaxant of human airways in vitro. Previous in vivo studies of infused vasoactive intestinal peptide in asthmatic subjects have shown only a small bronchodilator effect, which may have been secondary to the cardiovascular effects of the peptide. The effect on airway function of infused vasoactive intestinal peptide was studied in normal subjects, who readily develop bronchodilation in response to a beta agonist. Separate experiments were designed to assess whether there is any synergy between this peptide and the beta agonist isoprenaline. Incremental doses of 1, 3, and 6 pmol/kg/min of vasoactive intestinal peptide were infused for 15 minutes. At 6 pmol/kg/min it caused a mean fall in systolic blood pressure from 108 to 88 mm Hg and a rise in heart rate from 71 to 95 beats/min. There was no significant change in specific airways conductance (sGaw) at any dose of vasoactive intestinal peptide. No significant changes were found with placebo. Isoprenaline (400 microgram) given by inhalation at the end of the infusion produced a mean increase in sGaw of 50%. Infused peptide caused no significant change in the cumulative dose-response curve for inhaled isoprenaline. The lack of effect of vasoactive intestinal peptide on airway responses in vivo may be due to rapid enzymatic breakdown of the peptide or to the fact that dosage has to be limited by the cardiovascular effects.     

Effect of alcohol on the release of cholecystokinin and pancreatic enzyme secretion

Ethanol is often implicated in the pathogenesis of acute pancreatitis, but the pathophysiologic processes of alcohol-induced acute pancreatitis remains poorly understood. We found that ingestion of alcohol by healthy volunteers did not stimulate release of cholecystokinin, which is the chief hormonal stimulant of pancreatic enzyme secretion, nor did it significantly alter fasting levels of pancreatic polypeptide, a hormonal inhibitor of pancreatic enzyme secretion. In conscious dogs prepared with chronic pancreatic fistulas, direct intraduodenal instillation of ethanol significantly reduced pancreatic protein output, and this reduction corresponded to a decline in plasma concentrations of cholecystokinin that was similar in the percentage of diminution and in duration. These data suggest that, in patients who do not have chronic pancreatitis, alcohol does not induce acute pancreatitis, either by stimulating cholecystokinin release or by stimulating enzyme secretion directly.     

Role of gastrin in vagally-stimulated pancreatic secretion.

In an attempt to clarify the contribution of antral gastrin to the vaginal stimulation of pancreatic secretion, we have measured the effect of total excision of the antral mucosa on pancreatic secretion induced by electrical vagal stimulation in eight anesthetized dogs. Stimulation was done before excision of the mucosa, and after excision, with and without a gastrin background. Mucosal excision reduced pancreatic volume response to 25% and pancreatic protein response to 32% of the respective responses obtained before excision; gastrin release in response to vagal stimulation was completely abolished. With a gastrin background (0.5 microgram/kg-hr of synthetic human gastrin-17-I), which resulted in serum gastrin concentrations higher than those obtained by vagal stimulation before excision of antral mucosa, the pancreatic volume and protein response showed only partial restoration. These studies provide evidence that vagal pancreatic secretion is only partially gastrin-dependent, and that other antral factors, probably vagally modulated intramural cholinergic pathways, are involved.     

胃肠道神经肽对胆道Oddi括约肌活动和心血管功能影响的实验研究

为了揭示胆道流体力学和心血管功能相互关系，以及从静脉输注胆囊收缩素八肽（Ｃｈｏｌｅｃｙｓ－ｔｏｋｉｎｉｎ，ＣＣＤ－ＯＰ）、血管活性性肠肽（Ｖａｓｏａｃｔｉｖｅｉｎｔｅｓｔｉｎａｌｐｅｐｔｉｄｅ，ＶＩＰ）和Ｐ物质（ＳｕｂｓｔａｎｃｅＰ，ＳＰ）等胃肠道神经肽对它们相互关系的影响，作者观察了９１只豚鼠在静脉输注ＣＣＤ－ＯＰ、ＶＩＰ、ＳＰ及ＣＣＫ－ＯＰ和ＶＩＰ同时输注时左心室活动，Ｏｄｄｉ约肌活动和胆总管