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Background & Aims We recently showed that intracisternal injection of apolipoprotein A-IV (apo A-IV), a protein produced by the small intestine in response to fat, inhibits gastric acid secretion. The aim of this study was to investigate the mechanism of acid inhibition by central apo A-IV. Methods Gastric acid secretion was determined in pylorus-ligated conscious rats. The effect of intracisternal injection of apo A-IV on gastric acid secretion stimulated by pentagastrin, bethanechol, or intracisternal thyrotropin-releasing hormone (central vagal stimulant) was examined. The effects of vagotomy, indomethacin, and adrenergic blockers on the acid inhibition of apo A-IV were examined to investigate the role of the vagal system, prostaglandin pathways, and adrenergic system. Results Intracisternal apo A-IV significantly inhibited pentagastrin-, bethanechol-, and thyrotropin-releasing hormone-stimulated gastric acid secretion in a similar fashion. Inhibition of pentagastrin-stimulated acid secretion by apo A-IV still occurred even in vagotomized rats. Yohimbine but not indomethacin or propranolol eliminated apo A-IV-induced inhibition of acid. Conclusions Intracisternal apo A-IV inhibits gastric acid secretion through α2-adrenergic receptors. The vagal pathway and the prostaglandin system are not involved in apo A-IV-induced acid inhibition.

Background/Aims: Fat feeding increases not only serum but also cerebrospinal fluid concentration of apolipoprotein (apo) A-IV, a protein produced mainly by the small intestine in the rat. We hypothesized that apo A-IV may have a central effect on gastric secretion. Methods: Gastric juice was collected by the pylorus ligation method. Rats underwent pylorus ligation and received intracistemal injection of apo A-IV under brief isoflurane anesthesia. Two hours after the injection, gastric juice was collected and gastric acid output determined. Results: Intracistemal injection of 0.5 μg apo A-IV had no effect on gastric secretion. However, gastric acid secretion was significantly inhibited by intracistemal injection of 1 ug apo A-IV. Furthermore, intracistemal administration of higher doses of apo A-IV (2.0 and 4.0 μg) resulted in greater inhibition of gastric acid secretion in a dose-dependent manner. On the contrary, 4 μg of apo A-I intracisternally injected failed to inhibit gastric acid secretion. Intraperitoneal administration of 15 μg of apo A-IV did not alter gastric secretion. Conclusions: These results suggest that apo A-IV may act in the brain to inhibit gastric acid secretion. Apo A-IV might be a central enterogastrone, which is a gastric inhibitor produced by the small intestine in response to fat feeding.

Background/Aims Pancreatic polypeptide (PP), a hormone released from the pancreas, inhibits pancreatic secretion in vivo but not in vitro, suggesting that the inhibitory action of PP on pancreatic secretion is indirect. Circulating PP in physiological concentrations binds to specific receptors in the dorsal vagal complex in the brainstem. Therefore, the hypothesis of this study was that PP acts centrally and inhibits pancreatic secretion by modulating vagal tone. Methods The effects of microinjection of PP into the dorsal motor nucleus on 2-deoxy-d-glucose-stimulated and cholecystokinin octapeptide (CCK-8)-stimulated pancreatic secretion were examined in urethane-anesthetized rats. Results Microinjection of PP to the dorsal motor nucleus but not brainstem sites outside it inhibited 2-deoxy-d-glucose-stimulated pancreatic flow and protein output. CCK-8-stimulated pancreatic protein output was inhibited by PP in the dorsal motor nucleus in dose-dependent and site-specific manners. The inhibitory effect of PP on CCK-8-stimulated protein output was eliminated by vagotomy. Conclusions The results suggest that PP acts in the dorsal motor nucleus to modulate vagal tone on the pancreas, thereby inhibiting pancreatic secretion. This study shows for the first time that the dorsal motor nucleus is involved in central feedback inhibition of the exocrine pancreas.

Background: Neuropeptide Y (NPY), a centrally located neurotransmitter, is known to increase appetite in fasted and satiated animals. In addition to evaluating NPY's effect on eating behavior, this study was intended to determine whether intracerebroventricular (ICV) NPY would have an effect on canine gastric and pancreatic secretion. Methods: Four dogs were prepared with cerebroventricular guides and gastric and pancreatic fistulas. ICV and intravenous NPY was administered during intragastric titration of a glucose and peptone meal. During this study, gastric and pancreatic secretion was measured, as well as insulin levels and pancreatic polypeptide (PP). An additional set of four dogs were prepared with esophageal fistulas and cerebroventricular guides, and the effect of ICV NPY on sham feeding was studied. Results: ICV NPY significantly increased sham feeding, meal-stimulated gastric and pancreatic secretion, basal gastric acid, pancreatic bicarbonate, insulin levels, and PP. Vagotomy blocked the effect of ICV NPY on gastric acid secretion in a urethane-anesthetized rat model with acute gastric fistula. Conclusions: ICV NPY increased sham feeding, gastric and pancreatic secretion, insulin levels, and PP in the dogs. NPY's effect on gastric secretion was blocked by vagotomy in a rat model. NPY should be considered a candidate mediator of cephalic phase secretion.

This study was performed to determine the effects of exogenous prostaglandin and a prostaglandin synthetase inhibitor on experimental pancreatitis in mice. An ethoinine-supplemented choline-deficient diet was used to induce pancreatitis in 4–6-wk-old Swiss Webster mice. Mice were injected subcutaneously with 16,16-dimethyl prostaglandin E2 (0.1, 1.0, 10 μg kg-1 · day-1), indomethacin (0.05, 0.5, 5 mg · kg-1 · day-1), or saline for 7 days. The ethionine-supplemented choline-deficient diet was introduced 24 h after the first injection, and animals ate the test diet for 48 h. A 55% mortality was observed in control animals (n = 100) treated with carrier alone. Treatment with 10 μg · kg-1 · day-1 of 16,16-dimethyl prostaglandin E2 significantly decreased (p

Obesity can be reversed in ob/ob mice by parabiosis to lean littermates, by islet transplantation, and by injection of pancreatic polypeptide. These observations suggest that obese mice have functioning satiety centers but lack a circulating satiety factor of pancreatic origin which could be pancreatic polypeptide. This hypothesis has been difficult to test because antisera currently available do not cross-react with rodent pancreatic polypeptide. We have raised an antiserum against the biologically active carboxyl-terminal hexapeptide that measures mouse pancreatic polypeptide specifically. This antiserum has been used to compare circulating and tissue concentrations of pancreatic polypeptide in obese and lean mice. Although pancreatic contents were significantly (p

There are apparent similarities in the mechanisms of the intestinal phase of exocrine and pancreatic polypeptide (PP) secretion by the pancreas. To characterize this relationship, we measured incremental responses of protein, bicarbonate, and PP to graded doses of intravenous secretin, caerulein, CCK8, CCK33, bethanechol, and intraduodenally perfused HCl, sodium oleate, and L-phenylalanine in dogs with gastric and pancreatic fistulas and compared them with average postprandial values. Secretin did not release PP at any dose studied, whereas intraduodenal HCl increased PP levels slightly at a load maximal for pancreatic secretion. Caerulein produced dose-related increases in PP secretion (maximal, 106% of meal response) but CCK8 and CCK33 had much less effect at doses equivalent for protein secretion. Bethanechol was a weak stimulant for PP only at the largest tolerable dose. L-Phenylalanine and sodium oleate markedly increased protein secretion, but only oleate clearly stimulated PP. Our results suggest a greater quantitative importance of the intestinal phase for exocrine than endocrine (PP) pancreatic secretion.

In dogs with gastric fistulas, intravenous infusion of graded doses of bombesin gave graded increases in plasma concentrations of pancreatic polypeptide and of gastrin. The maximally effective dose, 500 ng kg−1 h−1, gave a mean peak increase over basal of 240 pM for pancreatic polypeptide and 93 pM for gastrin. Atropine sulfate (0.1 mg kg−1 iv) inhibited the pancreatic polypeptide response to bombesin by 60 ± 13% (P

Achalasia is characterized by an intrinsic denervation of the esophagus. It is not known whether this process extends to other parts of the gastrointestinal tract. By means of the modified sham feeding test, we studied the innervation of the stomach and the pancreas in 13 patients with achalasia. We compared the results with those from a group of 15 healthy controls and a group of 10 vagotomized patients. We saw two patterns of response in the achalasia group: 6 patients secreted acid and released pancreatic polypeptide, as did the controls. The other 7 patients neither secreted acid nor released pancreatic polypeptide after modified sham feeding, as did the vagotomized patients. We conclude that some patients with achalasia have denervation of the stomach and pancreas, as assessed by the modified sham feeding test. These differences are unrelated to age, sex, and duration and severity of the disease or treatment. Interestingly, all patients who responded normally developed reflux esophagitis after dilatation. Besides being an interesting pathophysiologic observation, the response to modified sham feeding can help identify those patients at greater risk of developing reflux esophagitis after esophageal dilatation.

The influence of gastric emptying of nutrients on plasma cholecystokinin and pancreatobiliary functions is poorly understood. We therefore temporally related the emptying of fat, protein, and glucose of a mixed meal to release of the gut hormones cholecystokinin, pancreatic polypeptide, and peptide YY and outputs of trypsin, lipase, bilirubin, and bile salts. Five healthy volunteers with a multilumen duodenal tube ingested a mixed meal with phase-specific markers for the aqueous phase, liquid fat, solid fat, and solid protein phases. Duodenal passage was determined by intraduodenal infusion of a second set of phase-specific nonabsorbable markers. Plasma cholecystokinin levels and pancreatobiliary secretions rose to a maximum at 30-60 min and then gradually declined (p less than 0.01) despite continued entry of protein and fat into the duodenum throughout the whole 4-h experimental period. High levels of both pancreatic polypeptide and peptide YY were observed in the last 2 h of the experiment. Release of factors capable of inhibiting cholecystokinin release and subsequently pancreatobiliary secretion may be responsible for the observed time-course.

In dogs with gastric and pancreatic fistulas, porcine pancreatic polypeptide (PP) was infused intravenously in doses of 50, 100, 200, 400, and 800 pmol kg-1 hr-1 in the basal state and in doses of 100, 200, and 400 pmol kg-1 hr-1 during stimulation with submaximal doses of secretin (125 ng kg-1 hr-1) plus caerulein (50 ng kg-1 hr-1). Plasma concentrations of PP were measured by radioimmunoassay, and pancreatic bicarbonate and protein outputs were monitored. The half-time for disappearance of PP was 5.5 +/- 1.0 min, the metabolic clearance rate was 25.6 +/- 1.0 ml kg-1, and the volume of distribution was 209 +/- 42 ml kg-1. Basal pancreatic flow and protein output were significantly inhibited by the lowest dose of PP tested, 50 pmol kg-1 hr-1. The lowest dose of PP significantly inhibiting stimulated pancreatic secretion was 100 pmol kg-1 hr-1 for bicarbonate output and 200 pmol kg-1 hr-1 for protein output. The mean +/- SE peak increment in PP concentration in response to a meal of meat, 210 +/- 39 pM, was greater than the mean peak increment with the 400 pmol kg-1 hr-1 dose of exogenous PP, 175 +/- 19 PM. We conclude that exogenous doses of PP that produce smaller increments in PP concentration than those seen after feeding inhibit pancreatic bicarbonate and protein secretion stimulated by secretin and caerulein. This suggests that the amount of PP released by a meal is sufficient to inhibit pancreatic secretion.

Peptide YY is an ileocolonic peptide that inhibits meal-stimulated pancreatic secretion when infused in a dose of 400 pmol/kg X h. In this study pancreatic secretion was monitored in response to increasing doses of secretin or cholecystokinin-octapeptide (62.5, 125, 250, and 500 ng/kg X h) during the simultaneous infusion of either saline or peptide YY (400 pmol/kg X h). Peptide YY significantly (p less than 0.05) inhibited the secretory response to the three lowest doses of each pancreatic secretogogue, reducing the bicarbonate response to the 62.5-ng/kg X h dose of secretin by 86% +/- 6% and the protein response to the same dose of cholecystokinin by 57% +/- 16%. In the second limb of the study, the half-life of peptide YY (11.7 +/- 21 min) and the metabolic clearance rate (13.8 +/- 1.6 ml/kg X min) were found to be similar to those of other gastrointestinal hormones. We conclude that inhibition of meal-stimulated pancreatic secretion by peptide YY can be explained by its ability to decrease the responsiveness of the pancreas to endogenous secretogogues.

Peptide YY (PYY), neuropeptide Y, and pancreatic polypeptide (PP) are the third family of structurally related peptides to be extracted from the brain-gut axis. In the present study we have validated a sensitive and specific assay for PYY and used it to measure the distribution of PYY in the canine gastrointestinal tract. In addition we have compared the PYY and PP responses to both an intragastric meal and to insulin hypoglycemia. The highest concentration of PYY was present in the canine ileum (1610 +/- 123 ng/g) and colon (1607 +/- 194 ng/g). Significant (p less than 0.05) increases in both circulating PP and PYY concentrations were observed in response to the meal (mean delta PP = 180 +/- 43 pg/ml; mean delta PYY = 205 +/- 61 pg/ml). In contrast, only serum PP concentrations (mean delta PP = 294 +/- 36 pg/ml) increased significantly (p less than 0.01) in response to insulin hypoglycemia, demonstrating differences in the sensitivity of the PP and PYY cells to vagal stimulation. The present demonstration of PYY release in response to a physiological stimulus fulfills one of the prerequisites for hormonal status.

Little is known about how gastric and pancreatobiliary responses differ after intake of elemental diets from responses to polymeric food. We therefore compared pancreatic and biliary secretions after gastric instillation of albumin (7 g%, with dextrose 21 g%) with an elemental diet in 6 healthy volunteers. The elemental diet contained amino acids (7 g%, with dextrose 21 g%) in the same molar composition as the albumin. Furthermore, we studied the effect of a pure intragastric dextrose solution (21 g%) on pancreatobiliary secretions, as glucose constitutes a major component of elemental diet formulas. The various pancreatobiliary responses were tested against a maximal i.v. cholecystokinin stimulus. The dextrose, amino acid, and albumin meals emptied at similar rates, and gastric emptying was completed within 3 h. Similar pancreatobiliary responses were observed after the albumin and amino acid meals, but response to both the amino acid and albumin meals was smaller than to the intravenous cholecystokinin stimulus. The glucose meal caused a marked and sustained stimulation of pancreatobiliary outputs, which did not differ significantly from the other test meals. However, lower cholecystokinin levels were observed after the glucose meal compared with distinct cholecystokinin release after the albumin and amino acid meals. We conclude first that there are no major differences in secretory responses between elemental (amino acid) and polymeric (protein) meals and second, that intragastric pure glucose meals strongly stimulate pancreatobiliary secretions. The marked pancreatic and biliary responses to intragastric dextrose cannot be fully explained on the basis of cholecystokinin release, suggesting that this response is probably mediated by neural mechanisms.

Peptide YY is a candidate enterogastrone localized to endocrine cells of the ileocolonic mucosa. The purpose of the present study was to determine if blood levels of peptide YY observed after perfusion of the intestine with fatty acids are capable of slowing gastric emptying. Gastric emptying of a 300-ml saline meal was monitored during intravenous infusion of normal saline or graded doses of peptide YY. Gastric emptying was significantly inhibited by infusion of peptide YY in doses of 200 and 400 pmol/kg X h. During the saline control study, 229 +/- 12 ml of the 300-ml saline meal emptied by 10 min. This figure was reduced (p less than 0.01) to 110 +/- 28 ml by the infusion of peptide YY at a dose of 200 pmol/kg X h. This dose of peptide YY produced plasma concentrations (delta PYY = 239 +/- 50 pM) that were lower than those seen in response to intestinal perfusion of oleic acid (delta PYY = 395 +/- 55 pM) in the same animals. We conclude that perfusion of the intestine with oleic acid releases peptide YY in amounts sufficient to slow gastric emptying.

The hypothesis that pancreatic polypeptide promotes postcontractile gallbladder filling was tested in the prairie dog model. Fifteen animals underwent laparotomy with catheter placement into the gallbladder, distal common bile duct (vent), and femoral vein. The gallbladder was perfused with [14C]polyethylene glycol labeled lactated Ringer's solution at 0.03 ml/min and vent effluent was collected at 2.5-min intervals. All animals received a 20-min intravenous infusion of cholecystokinin-octapeptide, 2.5 ng/kg X min, immediately followed by 60-min infusions of either lactated Ringer's solution or bovine pancreatic polypeptide (PP), 10 or 50 ng/kg X min. Gallbladder emptying and intragallbladder pressure were similar for all three groups after cholecystokinin-octapeptide. When lactated Ringer's was administered after cholecystokinin-octapeptide, gallbladder filling increased by 15.6% with a minimal change in gallbladder pressure. In contrast, infusion of PP10 resulted in a significant (p less than 0.02) increase in gallbladder filling, 64.1% +/- 17.1%, and a significant (p less than 0.05) decrease in intragallbladder pressure, as compared to controls. Similar findings were noted with PP50. These data indicate that exogenous PP significantly increases gallbladder filling after cholecystokinin-induced gallbladder contraction. This enhanced filling results from gallbladder relaxation as manifested by decreased intraluminal pressure. These findings coupled with the observation that serum PP levels remain elevated for up to 6 h after a meal suggest that PP may play a role in the regulation of postprandial gallbladder filling.