Pancreatic secretory response to intrajejunal tryptophan: studies in dogs with an autotransplanted entire jejunoileum.

In two sets of dogs with gastric, duodenal, and jejunal fistulas, we studied the effect of atropine (14 nmol/ kg/h) on the pancreatic secretory response to intrajejunal tryptophan (0.12-10.0 mmol/h; given against a secretin background) before (n = 7) and after extrinsic denervation of the jejunoileum (orthotopical autotransplantation; n = 6). Plasma levels of cholecystokinin were determined by radioimmunoassay. The incremental bicarbonate response to tryptophan was not significantly different between the two sets of dogs. Atropine had no effect on the incremental bicarbonate response to tryptophan. In both sets of dogs, intrajejunal tryptophan caused a dose-dependent increase in pancreatic protein output, which was reduced by atropine. The tryptophan-stimulated levels of plasma cholecystokinin were not significantly altered by denervation and or atropine. We conclude that in dogs (1) intrajejunal tryptophan stimulates pancreatic bicarbonate and protein secretion via release of hormones, (2) extrinsic denervation of the jejunoileum does not significantly alter the incremental bicarbonate and protein responses to intrajejunal tryptophan, (3) the cholinergic intrinsic nerves of the jejunoileum and the hormone cholecystokinin are probably involved in control of the pancreatic protein response to tryptophan, and (4) the release of cholecystokinin by intrajejunal tryptophan does not depend on the extrinsic and intrinsic cholinergic nerves of the jejunoileum.

Comparison of the effects of the M1-receptor antagonist telenzepine and the CCK-receptor antagonist loxiglumide on the pancreatic secretory response to intraduodenal tryptophan in dogs.

In six conscious dogs with chronic gastric and pancreatic fistulas we compared the action of different doses (20.25 to 81.0 nmol/kg/h) of the muscarinic M1-receptor antagonist telenzepine, the cholecystokinin (CCK) antagonist loxiglumide (2.5 to 10.0 mg/kg/h) and several combinations of both drugs on the pancreatic secretory response to intraduodenal perfusion of graded loads of tryptophan (0.37-10.0 mmol/h) given against a background of secretin (20.5 pmol/kg/h i.v.). Except for 20.25 nmol/kg/h telenzepine, all tested doses of telenzepine and/or loxiglumide decreased the 180-min integrated bicarbonate response to tryptophan by 55 to 119%. Except of 20.25 nmol/kg/h telenzepine and/or 2.5 mg/kg/h loxiglumide, all tested doses of telezepine and/or loxiglumide inhibited the tryptophan stimulated integrated pancreatic protein responses by 54 to 88%. While telenzepine mainly inhibited the bicarbonate and protein response to the lower loads of tryptophan (0.37-1.1 mmol/h), loxiglumide decreased the response to all loads of tryptophan. The inhibition evoked by the combinations of telenzepine and loxiglumide was not significantly greater than that by single infusion of either drug. The CCK plasma levels basally and in response to tryptophan were not significantly altered by telenzepine and/or loxiglumide. These findings indicate that (1) both enteropancreatic cholinergic reflexes and the hormone CCK are mediators of the protein response to intraduodenal trytophan (2) enteropancreatic cholinergic reflexes are probably the dominant mediators of the response to low amounts of tryptophan, whereas CCK is the major mediator of the response to high loads of tryptophan, (3) the two mediators seem to act independently of each other, and (4) the release of CCK by intestinal trytophan is not influenced by telenzepine or loxiglumide.

Inhibition of canine exocrine pancreatic secretion by peptide YY is mediated by PYY-preferring Y2 receptors.

It is still unclear, which receptor subtype, Y1 and/or Y2, mediates the inhibitory action of PYY on exocrine pancreatic secretion. The present study was undertaken to characterize functionally the Y receptor subtype that mediates the inhibition of exocrine pancreatic secretion by peptide YY (PYY). In eight conscious dogs with chronic gastric and pancreatic fistulas, we compared the action of intravenous infusion of 200 and 400 pmol/kg/h of the Y receptor agonists PYY 1-36, PYY 3-36, PYY 13-36, Pro34PYY 1-36, and NPY 1-36 on the pancreatic secretory response to secretin (20.5 pmol/kg/h) and cerulein (29.6 pmol/kg/h). PYY 13-36, Pro34PYY 1-36, and NPY 1-36 were also studied by giving a fivefold dose (1,000 and 2,000 pmol/kg/h). PYY 1-36 and the Y2 receptor agonist PYY 3-36 significantly inhibited pancreatic secretory responses to secretin and cerulein, whereas inhibition by NPY 1-36 and the Y2 receptor agonist PYY 13-36 was attainable only at doses of 1,000 and 2,000 pmol/kg/h. The Y1 receptor agonist Pro34PYY 1-36 was without effect on pancreatic secretion. We conclude that in dogs the inhibition of exocrine pancreatic secretion by PYY is mediated via Y2 receptors of a PYY-preferring subtype.

Central and peripheral neural control of pancreatic exocrine secretion.

Efferent vagal impulses act on the exocrine pancreas via pancreatic ganglia, where the impulses are modulated and modified, and terminate via postganglionic fibers at the acinar cells. Acinar muscarinic receptors of the subtype M1 play an important role for the mediation of the stimulatory vagal influences on pancreatic exocrine secretion. In dogs, a potentiative interaction exists between the two most important mediators of the pancreatic exocrine response to intraduodenal stimuli, efferent vagal impulses and CCK. In contrast to humans and rats, in which all action of CCK on pancreatic enzyme output is vagally mediated, CCK acts in dogs in part as a classical humoral factor independent of the cholinergic system. Although several peptides found in pancreatic nerve cell bodies or fibers can stimulate or inhibit pancreatic exocrine secretion, their physiological importance in the neural control of the exocrine pancreas needs to be further evaluated.

[Neurohormonal control of exocrine pancreas secretions by intra-ileal and intracolonic nutrients]. / Neurohormonale Kontrolle der exokrinen Pankreassekretion durch intraileale und intrakolonische Nährstoffe.

While the duodenum controls pancreatic exocrine secretion mainly via stimulatory mechanisms, intraileal and intracolonic nutrients have mainly inhibitory effects on the postprandial and interdigestive pancreatic secretion, which are described in particular. The inconsistent findings in dogs in contrast to other species (cat, rat, human) referring to the effects of intraileal nutrients are discussed. Possible mechanisms for the neurohormonal mediation of the effects of intraileal and intracolonic nutrients on the pancreatic secretion as well as the possible physiological importance of these effects are discussed.

[Effects of peptide YY on functions of the gastrointestinal tract]. / Die Wirkungen von Peptid YY auf Funktionen des Gastrointestinaltraktes.

The present report gives a review about the localization, release and gastrointestinal actions of peptide YY in different animal species and in humans. Possible mechanisms of action, the physiological and pathophysiological significance of peptide YY and the role of peptide YY 3-36 are discussed. Finally, unanswered questions are specified.

Effects of M1 and CCK antagonists on latency of pancreatic amylase response to intestinal stimulants.

In six conscious dogs with gastric and duodenal cannulas, secretin (164 pmol. kg(-1). h(-1) iv) was given to provide a flow of pancreatic juice of approximately 1 drop/s. Amylase activity was measured in each drop before and after rapid intravenous injection of caerulein (7.4 pmol/kg) or intraduodenal injection of L-tryptophan (1 mmol), sodium oleate (3 mmol), and HCl (3 mmol). All experiments were repeated in the presence of the M1 receptor antagonist telenzepine (81 nmol. kg(-1). h(-) iv) and the cholecystokinin (CCK) receptor antagonist L-364718 (0.1 mg/kg iv). Latency of amylase response (time between injection of stimulant and sustained increase in amylase activity greater than mean + 3 SD of prestimulatory activity) to tryptophan (17 +/- 7 s; n = 6) and oleate (16 +/- 5 s) was significantly (P < 0.05) shorter than to caerulein (28 +/- 4 s) and HCl (120 +/- 47 s). Telenzepine significantly increased the latency of amylase response to tryptophan and oleate by >10-fold but not the latency to caerulein or HCl. L-364718 abolished the amylase response to all stimulants. These findings indicate that the early amylase response to intraduodenal tryptophan and oleate is mediated by a neural enteropancreatic reflex ending on M1 receptors rather than by hormone release. However, the activation of (possibly vagal) CCK receptors is essential to run the reflex. The early amylase response to intraduodenal HCl is probably mediated by the release of CCK into the blood circulation.

Pancreatic exocrine studies in intact animals: historic and current methods.

This report presents a review of the historic and current methods for performing pancreatic exocrine studies in intact animals. Special emphasis is given to the various surgical procedures--pancreatic fistulas, duodenal pouches, and duodenal fistulas--and practice of collecting pancreatic secretion in dogs. Procedures in other animal species--rat, cat, pig, rabbit, cattle, sheep, and horse--also are specified. The advantages and disadvantages, as well as the indications and limitations of the distinct methods, are discussed.

A review: acute and chronic effects of ethanol and alcoholic beverages on the pancreatic exocrine secretion in vivo and in vitro.

Whereas oral or intraduodenal ethanol causes a moderate stimulation of pancreatic bicarbonate and enzyme output, intravenous ethanol inhibits basal and hormonally stimulated pancreatic exocrine secretion in humans, dogs, cats, pigs, rabbits, and rats. This inhibition could be mediated by inhibitory cholinergic mechanisms or be the result of a direct cellular effect of ethanol. In vitro investigations have specified several signaling molecules that may be involved in the action of ethanol on stimulus-secretion coupling in the exocrine pancreas, including cyclic adenosine monophosphate, intracellular calcium, and cholecystokinin and somatostatin receptors. In difference to pure ethanol solutions and distilled spirits, beer strongly stimulates pancreatic enzyme output, probably by nonalcoholic fermentation products. During chronic alcoholism, the ethanol-induced inhibition is replaced by an enhanced enzyme output that causes intraductal protein precipitation. In vitro investigations suggest that this increase is reversible after alcohol withdrawal. The occurrence of protein precipitates is considered to be a crucial step in the development of chronic alcoholic pancreatitis in humans. Other ethanol-induced secretory alterations that may contribute to the development of alcoholic pancreatitis are a decreased secretion of trypsin inhibitor, an increased cholinergic tone, and changes in the concentration of lithostathine.

[Neurohormonal control of gallbladder motility by intra-ileal and intracolonic nutrients--a review]. / Neurohormonale Kontrolle der Gallenblasenmotilität durch intraileale und intrakolonische Nährstoffe--Ubersichtsreferat.

The duodenum controls gallbladder motility mainly via stimulatory mechanisms, whereas intraileal and intracolonic nutrients have mainly inhibitory effects on postprandial as well as interdigestive gallbladder motility, which are described in particular. Possible mechanisms for the neurohormonal mediation of the effects of intraileal and intracolonic nutrients on gallbladder motility as well as the possible physiological importance of these effects are discussed.

[Effect of 8-week administration of enalapril plus additional 2-week administration of furosemide on heart rate and exocrine pancreas secretion in dogs]. / Wirkung einer 8-wöchigen Dauergabe von Enalapril plus anschliessender zusätzlicher 2-wöchiger Furosemidgabe auf die Herzfrequenz und die exokrine Pankreassekretion des Hundes.

Alteration of pancreatic secretion could be a pathogenetic factor for generation of an acute pancreatitis after administration of angiotensin-converting-enzyme (ACE) inhibitors. Therefore in 6 conscious dogs (weight 10-12 kg) with chronic gastric and duodenal fistulas according to Thomas, we studied single-blind, placebo-controlled and randomized the effect of a long-term (74 d) daily oral administration of 5 mg of the ACE inhibitor enalapril and of additionally daily oral administration of the diuretic furosemide from the 60th day on the secretin- (20.5 pmol/kg/h) and caerulein- (7.4, 14.8, 29.6, 59, and 118 pmol/kg/h) stimulated pancreatic bicarbonate and protein secretion at day 1, 29, 57, 60, and 74 after beginning of enalapril administration. Heart rate was measured daily and during the experiments. Neither enalapril nor enalapril plus furosemide significantly altered heart rate. The hormonally stimulated pancreatic bicarbonate secretion was significantly (p < 0.05) increased at day 57, 60, and 74 by 353%, 397%, and 79%. The hormonally stimulated pancreatic protein secretion was also distinctly increased, although not reaching statistical significance. The present study shows, that a long-term administration of therapeutic doses of enalapril +/-furosemide is capable to enhance the pancreatic bicarbonate secretion. Whether this altered pancreatic secretion can be taken for a primary origin of the observed cases of acute pancreatitis after therapeutic administration of enalapril is uncertain but not refutable.

Pancreatic secretory response to intraileal amino acids: studies in dogs with an in situ neurally isolated ileum.

BACKGROUND: Intraileal carbohydrates and lipids affect the pancreatic exocrine secretion, but the effect of intraileal amino acids and the role of the extrinsic nerves of the ileum as mediators of the pancreatic bicarbonate and enzyme output are unknown. METHODS: Four dogs underwent total extrinsic denervation of the entire ileum. Thomas-like cannulas were placed into the stomach, duodenum (to collect pure pancreatic juice), and at the jejuno-ileal junction. Eight neurally intact control dogs received only the three fistulas. After recovery, in both sets of dogs, dose-response studies of the pancreatic secretory response to intraileal infusion with graded loads of tryptophan (0.12-10.0 mmol/h) were performed, given against an intravenous (iv) background of secretin (20.5 pmol/kg/h) and cerulein (29.6 pmol/kg/h). On separate days, control experiments with intraileal infusion of 0.15 M NaCl were performed. RESULTS: In both sets of dogs, iv secretin plus cerulein significantly (p < 0.05) increased pancreatic bicarbonate and protein output above basal. Intraileal tryptophan caused a dose-dependent decrease in the pancreatic bicarbonate and protein response to secretin plus cerulein. In the dogs with denervated ileum, this inhibition was significantly stronger than in the intact animals. In both sets of dogs, the 225-min integrated bicarbonate (IBR) and protein response (IPR) to all loads of tryptophan were significantly lower than in control experiments. Both IBR and IPR were significantly lower in the denervated as compared with the intact animals. CONCLUSIONS: 1) Extrinsic denervation of the entire ileum is a valuable preparation to study the role of nerves in the control of pancreatic exocrine secretion; 2) both in the intact and denervated animals the amino acid tryptophan induces an "ileal brake" of the hormonally stimulated pancreatic bicarbonate and protein output; 3) the extrinsic nerves of the ileum are probably not the dominant mediators of the inhibitory action of intraileal tryptophan but rather counteract this effect.

Comparison of the effects of two cholecystokinin-receptor antagonists, loxiglumide and L-364,718, on the pancreatic secretory response to intraduodenal tryptophan in dogs.

BACKGROUND: The aim of the study was to compare the effects of the cholecystokinin (CCK)-receptor antagonists loxiglumide and L-364, 718 on the endogenously stimulated pancreatic exocrine secretion. METHODS: In six conscious dogs with chronic gastric and pancreatic fistulas we compared the action of different doses of loxiglumide (2.5 to 10.0 mg/kg/h) and L-364, 718 (0.025 to 0.1 mg/kg/h) on the pancreatic secretory response to intraduodenal perfusion of graded loads of tryptophan (0.37-10.0 mmol/ h), given against a background of secretin (20.5 pmol/kg/h intravenously). RESULTS: Both loxiglumide and L-364, 718 inhibited the secretin-stimulated pancreatic bicarbonate output by up to 47% and 48%, respectively. The pancreatic protein output during secretin was significantly inhibited by all doses of L-364,718 (by 65% to 82%) but not by loxiglumide. All doses of loxiglumide and L-364, 718 abolished the 180-min integrated bicarbonate response to tryptophan. The two higher doses of loxiglumide (5.0-10.0 mg/kg/h) and L-364,718 (0.05-0.1 mg/kg/h) significantly decreased the 180-min integrated response to tryptophan by 59% and 79% (loxiglumide) and by 72% and 97% (L-364, 718). The plasma CCK-like immunoreactivity basally and in response to tryptophan was not significantly altered by loxiglumide or L-364, 718. CONCLUSIONS: These findings indicate that in dogs 1) the pancreatic bicarbonate response to secretin is augmented by the hormone CCK; 2) L-364, 718 but not loxiglumide decreases pancreatic protein output during secretin; 3) endogenous released CCK is involved in the pancreatic bicarbonate response and is a major mediator of pancreatic protein response to intraduodenal tryptophan; and 4) the release of CCK by intraduodenal tryptophan is not influenced by loxiglumide and L-364, 718.

Effects of telenzepine and L-364,718 on canine pancreatic secretion before and after vagotomy.

In six conscious dogs we compared the action of the M1-receptor antagonist telenzepine (20.25-81.0 nmol.kg-1.h-1), the cholecystokinin (CCK) antagonist L-364,718 (0.025-0.1 mg.kg-1.h-1), and combinations of both on the pancreatic secretory response to intraduodenal tryptophan, given against a secretin background before and after truncal vagotomy. Before vagotomy, the higher doses of telenzepine and of L-364,718 significantly (P < 0.05) decreased the protein response to tryptophan by up to 97%. After vagotomy, all doses of L-364,718 abolished the protein response, whereas telenzepine had no further effect. Before and after vagotomy, all combinations abolished the protein response. The plasma CCK-like immunoreactivity basally, during secretin, and in response to tryptophan was not altered by vagotomy, telenzepine, and/or L-364,718. These findings indicate that in dogs 1) potentiation exists between M1 receptors and CCK for stimulation of the pancreatic enzyme response to intraduodenal tryptophan, 2) the cholinergic fibers of the enteropancreatic reflex activated by tryptophan run within the vagus nerves and end at least in part on M1 receptors, 3) CCK acts in part independently of the vagal nerves, and 4) the CCK release by intestinal tryptophan is not influenced by vagotomy, telenzepine, and/or L-364,718.

Pancreatic bicarbonate response to intraduodenal tryptophan in dogs: role of muscarinic M1-receptors and cholecystokinin.

CONCLUSIONS: In dogs, 1. Activation of cholecystokinin-receptors is needed for an adequate pancreatic bicarbonate response to secretin; 2. Cholinergic nerve fibers ending on M1-receptors are probably of little or no importance for the bicarbonate response to secretin in the given dose; 3. The bicarbonate response to tryptophan, given with a secretin background, is controlled by cholinergic M1-fibers and by cholecystokinin; 4. M1-fibers mainly mediate the bicarbonate response to low loads of tryptophan, whereas cholecystokinin controls the response to low and high loads of tryptophan; and 5. Both mediators interact in a synergistic manner. METHODS: In six conscious dogs with chronic gastric and duodenal fistulas, we compared the action of the M1-receptor antagonist telenzepine (20.25-81.0 nmol/kg/h), the cholecystokinin-receptor antagonist L-364,718 (0.025-0.1 mg/kg/h), and combinations of both on the pancreatic bicarbonate response to graded loads of intraduodenal tryptophan (0.37-10.0 mmol/h), given against a background of secretin (20.5 pmol/kg/h). RESULTS: Secretin significantly (p < 0.05) stimulated the pancreatic bicarbonate output above basal levels. All doses of L-374,718, but not telenzepine, significantly decreased the bicarbonate response to secretin by up to 64%. Additional administration of telenzepine together with L-364,718 had no further inhibitory effect on the secretin-stimulated bicarbonate output as compared to L-364,718 given alone. All loads of tryptophan significantly increased the bicarbonate output over that seen with secretin alone (= incremental bicarbonate response to tryptophan). Telenzepine significantly decreased the incremental bicarbonate response to the two lower loads (0.37-1.1 mmol/h) of tryptophan (by 82-124%); L-364,718 decreased the incremental bicarbonate response to all loads of tryptophan (by 50-118%). The incremental bicarbonate output, as well as the 180-min integrated bicarbonate response to all loads of tryptophan, were abolished by all combinations of both antagonists.

Gastroenteropancreatic effects of xenin in the dog.

Xenin is a 25 amino acid peptide detected in the gastric mucosa of various mammals. It has since been found in low concentrations in other tissues. Xenin plasma concentrations increase after meals. The present study reports some gastroenteropancreatic effects of this peptide in the dog. Intravenous infusion of 64 pmol/kg min synthetic xenin significantly inhibited pentagastrin-stimulated gastric acid secretion and stimulated exocrine pancreatic secretion of volume and protein. Further, intravenous infusion of xenin in a dose of 1.0 pmol/kg min stimulated jejunal motility in the anaesthetized dog. An intravenous infusion of 32 pmol/kg min xenin raised plasma concentrations of pancreatic polypeptide, vasoactive intestinal polypeptide, insulin and glucagon. The present experiments therefore indicate manifold bioactive properties of intravenously infused xenin in the dog, with jejunal motility the most sensitive target. Conclusions as to the physiological role of xenin cannot be drawn from the present experiments. The release of other hormonal peptides indicates a complex action of xenin.