R. Nustede

Cephalic stimulation of gastrointestinal secretory and motor responses in humans

The present study was designed (a) to investigate the cephalic phase of gastropancreatic secretion, antroduodenal motility, and regulatory peptide release in six healthy young men and (b) to assess its regulation by the cholinergic system and endogenous cholecystokinin. Sham feeding performed for 15 minutes induced a concurrent stimulation of gastropancreatic secretion, antroduodenal motility, and pancreatic polypeptide release that lasted for 30 minutes. Reappearance of interdigestive phases III was retarded in the post-sham-fed state. Atropine abolished secretory, motor, and pancreatic polypeptide responses to sham feeding and enhanced gastrin release. The cholecystokinin receptor antagonist loxiglumide did not attenuate pancreatic enzyme response but diminished antral motor response by 72% (P less than 0.05) and release of pancreatic polypeptide by 91% (P less than 0.05); it enhanced gastrin release and abolished retardation of reappearance of phase III with sham feeding. It is concluded that (a) there is a distinct cephalic phase of gastropancreatic secretion, antroduodenal motility, and pancreatic polypeptide release in humans that is primarily under cholinergic control and that (b) endogenous cholecystokinin is involved in antral motor, gastrin, and pancreatic polypeptide responses to sham feeding.

IS DELAYED GASTRIC EMPTYING FOLLOWING PANCREATICODUODENECTOMY RELATED TO PYLORUS PRESERVATION

Abstract  Background: Delayed gastric emptying (DGE) is the most frequent postoperative complication after pylorus-preserving pancreaticoduodenectomy (PPPD). This prospective, non-randomized study was undertaken to determine whether the incidence of DGE may be reduced by modifying the original reconstructive anatomy with a retrocolic duodenojejunostomy towards an antecolic duodenojejunostomy. Patients and methods: The study was comprised of 51 patients who underwent PPPD between August 1994 and November 1997. The operation was carried out as originally described but was modified by performing the duodenojejunostomy antecolically. Clinical data were recorded prospectively, with special regard to DGE. Results: After PPPD, the nasogastric tube could be removed at a median of 2 days (range 1–22 days) postoperatively; in two patients, the nasogastric tube was reinserted because of vomiting and nausea. A liquid diet was started at a median of 5 days (3–11 days); the patients were able to tolerate a full, regular diet at a median of 10 days (7–28 days). The overall incidence of DGE was 12% (n=6). No postoperative complications other than DGE were exhibited by 36 patients (71%). In this group, DGE was only seen in one patient (3%). In the second group, where postoperative complications other than DGE occurred (n=15), five patients (30%) exhibited DGE (P=0.002). Conclusions: DGE after PPPD seems to be of minor clinical importance following uncomplicated surgery. When taking the results into consideration, it can be said that, despite the lack of a control group, antecolic duodenojejunostomy might be the key to a low incidence of DGE after PPPD. In our experience, DGE is linked to the occurrence of other postoperative complications rather than to pylorus preservation.

Cholecystokinin is a negative regulator of gastric acid secretion and postprandial release of gastrin in humans

BACKGROUND/AIMS The role of cholecystokinin (CCK) in the regulation of gastric acid secretion is still controversial. This study examined the effect of the CCK-A receptor antagonist loxiglumide (lox) on gastrin- or CCK-induced gastric acid secretion and meal-stimulated plasma gastrin levels in a placebo-controlled study. METHODS Acid output was studied in eight subjects who received intravenously gastrin-17 (15, 30, and 60 pmol.kg-1.h-1); gastrin-17 plus lox; cholecystokinin octapeptide (CCK-8) (15, 30, and 60 pmol.kg-1.h-1); CCK-8 plus lox; or gastrin plus CCK-8. Sham feeding-induced acid output and meal-stimulated gastrin secretion were studied during lox infusion. RESULTS Gastrin-17 dose-dependently stimulated acid output to near-maximal levels. CCK-8 (15 pmol.kg-1.h-1) increased acid secretion 2.5-fold over basal; higher infusion rates had less or no effect. When combined with lox, CCK-8 produced a near-maximal acid response (6-fold over basal). CCK-8 together with gastrin-17 inhibited gastrin-induced acid output by 67%. Meal-stimulated plasma gastrin concentrations were elevated 3.2-fold, whereas sham feeding-induced acid secretion was not modified by lox. CONCLUSIONS Blockade of CCK-A receptors converts CCK-8 into a potent acid secretagogue and augments postprandial gastrin secretion. A CCK-mediated stimulation of paracrine somatostatin secretion from antral and fundic D cells represents a candidate mechanism for the inhibition of the parietal and gastrin cell in humans.

Vagal Influence on Cholecystokinin and Neurotensin Release in Conscious Dogs

Cholecystokinin (CCK) release in seven conscious dogs was investigated by means of modified sham feeding. After sham feeding mean CCK concentrations rose from a basal value of 1.0 +/- 0.2 pmol/l to a peak value of 2.4 +/- 0.3 pmol/l (p less than 0.005). The release in response to sham feeding amounted to half of that seen after normal feeding. Atropine significantly altered CCK output after sham feeding (basal, 1.0 +/- 0.2 pmol/l; peak 1.3 +/- 0.3 pmol/l). Sham feeding did not affect neurotensin release. It is concluded that an important cephalic phase of CCK release exists which seems to be dependent on a cholinergic mechanism.

Plasma concentrations of neurotensin and CCK in patients with chronic pancreatitis with and without enzyme substitution.

The peptide hormones neurotensin (NT) and cholecystokinin (CCK) are commonly attributed with a physiological role in the stimulation of exocrine pancreatic secretion. However, on the other hand, little is known about the effect of diminished exocrine pancreatic function and of the resulting maldigestion on postprandial plasma levels of these two gastrointestinal pep-tides. We investigated, therefore, the effect of enzyme substitution therapy on the magnitude and time course of plasma concentrations of both hormones in patients suffering from severe chronic pancreatitis. Pancreatic insufficiency led to elevated NT-concentrations, in response to a standard meal, which could be reduced by enzyme replacement therapy. Prior to enzyme therapy, the mean integrated postprandial release of NT amounted to 2800 ± 250 pg/ml after 60 min in patients with severe chronic pancreatitis. This amount was significantly reduced to 1250 ±150 pg/h after 60 min after enzyme therapy, compared to 810 ± 90 pg/ml after 60 min in healthy volunteers after the standard meal. The integrated postprandial CCK level in patients investigated was significantly lower (35 2 4.8 pmol/L after 60 min) without any substitution therapy, compared to the integrated peptide amount in healthy volunteers (145 ± 13.5 pmo/L after 60 min). Enzyme therapy in patients suffering from chronic pancreatitis led to an increased postprandial CCK-level (80 ± 9.6 pmol/L after 60 min). Elevated CCK-plasma concentrations have not been demonstrated in these patients with pancreatic insufficiency. We therefore suggest that CCK might not play a major role in feedback regulation in patients with chronic pancreatitis. However, in light of elevated NT plasma concentrations in patients with chronic pancreatitis, NT-mediated influence on the pancreas deserves further study.

Cholecystokinin receptor antagonist loxiglumide modulates plasma levels of gastro‐entero‐pancreatic hormones in man Feedback control of cholecystokinin and gastrin secretion

Abstract. The effect of the potent specific cholecystokinin (CCK) receptor antagonist loxiglumide on meal‐stimulated plasma concentrations of CCK, gastrin, pancreatic polypeptide (PP), neurotensin, glucosedependent insulinotropic polypeptide (GIP), insulin and C peptide was investigated in a placebo‐controlled study in 10 healthy male volunteers. Intravenous infusion of loxiglumide (10 mg kg‐1 h‐1) significantly augmented integrated incremental IR‐CCK levels 7·3‐fold after stimulation by a standard breakfast (504·54 vs 3·665±365 pmol‐1 135 min‐1, P<0·001), as measured by a specific CCK radioimmunoassay. Basal IR‐CCK concentrations were not affected by administration of loxiglumide. Oral treatment with bile acids (2 g ursodeoxycholic acid plus 2 g chenodeoxycholic acid) together with the meal abolished this augmentation, whereas high‐dose substitution with pancreatic enzymes (4·2 g pancreatin) reduced elevated IR‐CCK levels by only 38%. CCK‐like bioactivity, determined by a bioassay using rat pancreatic acini, was not detectable in all samples that contained loxiglumide at plasma concentrations of 100–250 μg ml‐1. Plasma gastrin concentrations in response to the breakfast were elevated 3·2‐fold during loxiglumide infusion and not influenced by substitution with bile acids or pancreatic enzymes. Meal‐stimulated integrated incremental plasma PP concentrations were significantly suppressed (55–65% inhibition, P<0·01) by loxiglumide. Infusion of the CCK receptor antagonist only slightly increased postprandial peak plasma glucose, insulin and C‐peptide levels, whereas GIP and neurotensin levels were not significantly influenced. These findings suggest: (i) CCK secretion is under feedback control by intraduodenal bile acids and to a lesser extent by pancreatic enzymes; (ii) simultaneous extraction of CCK and loxiglumide results in circulating plasma CCK‐like bioactivity of zero; (iii) gastrin secretion is feedback controlled via an indirect mechanism probably involving CCK‐induced somatostatin secretion; (iv) release of PP is under inhibitory control of CCK; (v) CCK does not play a major role as insulinotropic hormone in the entero‐insular axis in humans.

Role of Ornithine Decarboxylase and Polyamines in Camostate (Foy-305)-Induced Pancreatic Growth in Rats

This study was designed to investigate changes of ornithine decarboxylase and polyamines during pancreatic adaptation in response to feeding of the synthetic protease inhibitor camostate. alpha-Difluoromethylornithine, an irreversible and specific inhibitor of ornithine decarboxylase, was applied simultaneously to elucidate the essential role of polyamines in pancreatic growth. Cholecystokinin (CCK) plasma levels in camostate-fed rats increased from basal values of 3-4 pmol/l to a maximal level of 27.4 pmol/l after 2h; they then decreased up to 12 h but remained elevated above controls throughout the 30-day experiments. In the camostate group pancreatic ornithine decarboxylase activity was elevated after 2 h, reaching a maximum after 6 h (1,858.5 pmol 14CO2/h/mg DNA, about 200-fold above controls) followed by a significant increase in putrescine after 4 h and spermidine after 24 h while spermine remained unchanged. The trophic parameters increased in the following time sequence: thymidine kinase (12 h), DNA polymerase (12 h), protein (24 h), pancreatic weight (24 h) and DNA (5 days). alpha-Difluoromethylornithine significantly delayed and reduced the camostate-induced increase in ornithine decarboxylase activity and polyamine concentrations as well as the trophic parameters. Application of the CCK receptor antagonist L-364,718 resulted in complete inhibition of the increases in ornithine decarboxylase, polyamines and all trophic parameters. These data indicate an important role for ornithine decarboxylase and polyamines in camostate-induced pancreatic growth and hormonal mediated pancreatic adaptation in rats.

Impact of Gastrin-Releasing Peptide on Intestinal Microcirculation after Ischemia-Reperfusion in Rats

We investigated the effect of gastrin-releasing peptide (GRP) and its antagonist RC-3095 on intestinal microcirculation after ischemia-reperfusion. Intestinal ischemia was induced in female Wistar rats by occlusion of the superior mesenteric artery for 40 min. Ten minutes prior to reperfusion, infusion of GRP or RC-3095 was started. A jejunal segment was exteriorized and the microhemodynamics of the mucosa and submucosa were examined by intravital microscopy and compared both with normal and ischemic controls (without application of the regulatory peptide). Ischemia-reperfusion significantly decreased functional capillary density from 891.2 ± 14.1 to 398.3 ± 11.4 cm–1. Capillary red blood cell velocity was reduced from 0.46 ± 0.01 to 0.37 ± 0.01 mm/s (p < 0.05). Furthermore, both sticking and rolling of leukocytes were enhanced. 3.4 ± 1.1% of the villi were not perfused at all. GRP infusion reversed the microcirculatory ischemia-reperfusion injury by increasing functional capillary density to 669.8 ± 8.3 cm–1 and red blood cell velocity to 0.62 ± 0.01 mm/s (p < 0.05). In addition, application of GRP resulted in a complete absence of stasis (0%) in the villi. Leukocyte-endothelium adherence remained unchanged when compared to the ischemic controls. In contrast, application of RC-3095 caused an aggravation of microcirculatory disturbances demonstrated by a markedly increased number of non-perfused villi (42.5 ± 4.2%; p < 0.05 vs. ischemic controls) and a significantly reduced functional capillary density (346.2 ± 8.4 cm–1, p < 0.05 vs. ischemic controls). In addition, RC-3095 led to an increased permanent leukocyte adherence in postcapillary venules whereas rolling was significantly reduced when compared to normal controls. We conclude that GRP in pharmacological doses has a protective effect on intestinal microcirculation during reperfusion. Furthermore, these data suggest that endogenous GRP may play a decisive role in the maintenance of microvascular integrity during reperfusion.

Pancreatic trophism following colectomy in rats : the potential role of gastrointestinal hormones

It has been shown that the large bowel contains substances with a potential to inhibit exocrine pancreatic function. Following large bowel removal in rats, there is an increase of pancreatic weight, digestive enzyme concentration, and secretion capacity in vitro. To evaluate the role of various GI hormones in the exocrine pancreatic adaptation following colectomy, we measured plasma cholecystokinin (CCK), neurotensin, glucagon, and insulin after meal stimulation. The test meal was applied via a transabdominal gastric tube in eight colectomized Wistar rats after a median of 18 days following surgery. Ten rats with a gastric tube without previous bowel surgery served as controls. After large bowel removal, there was impaired glucose tolerance and attenuated plasma insulin secretion. Baseline plasma glucagon levels were increased after colon removal, whereas the total postprandial glucagon release was decreased. Baseline and postprandial neurotensin values were comparable in both the experimental and control animals. Baseline and postprandial CCK plasma levels were intensely increased in the colectomized rats. It is assumed that the baseline and postprandial CCK pattern in rats after subtotal colectomy is responsible for exocrine pancreatic adaptation.

Induction of the fed pattern of human exocrine pancreatic secretion by nutrients: role of cholecystokinin and neurotensin.

SummaryThe aim of the present study was to assess the role of cholecystokinin and neurotensin in converting the cyclical interdigestive pattern of pancreatic secretion into the non-cyclical fed pattern. Six healthy male volunteers were studied on 4 separate days. During each experiment a mixed liquid meal or solutions of individual nutrients were perfused intraduodenally for 180 min at 2 ml/min. The mixed meal contained 4.3 g glucose, 2.0 g fractionated soya oil, and 1.7 g casein hydrolysate per 100 ml, which delivered a caloric load of 0.9 kcal/min into the duodenum. The isocaloric and isotonic solutions of individual nutrients contained 44.5 g glucose, 17.8 g fractionated soya oil, or 44.5 g hydrolysed serum bovine albumin per liter and delivered 0.36 kcal/min into the duodenum. Duodenal aspirates and blood samples were collected at regular intervals for determination of pancreatic enzyme outputs and plasma levels of cholecystokinin and neurotensin, respectively. The mixed meal converted the cyclical interdigestive secretory pattern into the noncyclical fed pattern whereas none of the three individual nutrients abolished the interdigestive pattern. Not only the mixed meal but also lipid and protein perfusion consistently stimulated cholecystokinin release. Integrated incremental cholecystokinin release amounted to 32.3±9.9 pg/ml × 180 min with the mixed meal, 23.2±6.5 with lipid perfusion (P< 0.05 versus mixed meal) and 13.4±3.8 with protein perfusion (P<0.05 versus mixed meal). The carbohydrate solution did not significantly release cholecystokinin. None of the duodenal perfusates raised neurotensin plasma levels. We conclude that (a) intraduodenal delivery of a mixed meal at 0.9 kcal/min converts the interdigestive pattern of pancreatic secretion, (b) cholecystokinin but not neurotensin is involved in converting this pattern in response to low-caloric meals, and (c) a threshold amount of CCK release must be exceeded to convert the secretory pattern.