Elke Niebergall-Roth

Secretion from acinar cells of the exocrine pancreas: Role of enteropancreatic reflexes and cholecystokinin

Although the molecular machinery and mechanism of cell secretion in acinar cells of the exocrine pancreas is well documented and clear, only recently has the pharmacophysiology of pancreatic exocrine secretion come to light. Therefore, we focus in this article on the current understanding of the pharmacophysiology of pancreatic exocrine secretion. The pancreatic secretory response to ingestion of a meal is mediated via a complex interplay of neural, humoral and paracrine mediators. A major role in the control of the intestinal phase of pancreatic secretion is attributed to vago‐vagal enteropancreatic reflexes. In the scheme of this control mechanism, afferents originating in the duodenal mucosa, and efferents mediating central input on the pancreatic ganglia, activate intrapancreatic postganglionic neurons. Experiments utilizing specific receptor antagonists demonstrate the involvement of both muscarinic M1 and M3 receptors expressed in pancreatic acinar cells. Cholecystokinin (CCK), originally implicated in the humoral secretion of pancreatic enzymes, through a direct action on acinar CCK receptors, is also essential to the enteropancreatic reflex mechanism. CCK stimulation of the exocrine pancreatic secretion through excitation of sensory afferents of the enteropancreatic reflexes, is a paracrine mode of CCK action, and is probably the only one in humans and the predominant one in rats. In dogs, however, CCK acts on the pancreas via both the humoral and a paracrine route. More recent experiments suggest further possible sites of CCK action. Additionally, at the brain stem, vago‐vagal enteropancreatic reflexes may be modulated by input from higher brain centres, particularly the hypothalamic‐cholinergic system in the tonic stimulation of preganglionic neurons of the dorsal motor nucleus of the vagus projecting into the pancreas.

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.

Enteropancreatic reflexes mediating the pancreatic enzyme response to nutrients

The observation that in dogs electrical stimulation of the vagus nerve elicited a strong secretory activity of the pancreas, prompted I. P. Pavlov in 1888 to conclude that the pancreatic secretory response to nutrients is mediated by enteropancreatic reflexes involving the vagus nerves. It took, however, more than 90 years until by studying the latency of pancreatic amylase response to exogenous and endogenous stimuli for the first time experimental evidence was provided for the actual existence of cholinergic vago-vagal enteropancreatic reflexes. Follow-up studies, based on stepwise extrinsic denervation of the pancreas, ruled out possible splanchnic pathways for enteropancreatic reflexes. In more recent years, experiments utilizing specific antagonists demonstrated a physiological role for both cholinergic M1 and cholecystokinin (CCK) receptors within the enteropancreatic reflex. At least a significant portion of the cholinergic fibres of the enteropancreatic reflex end on muscarinic receptors of the subtype M1. CCK, the most important hormone stimulating pancreatic enzyme secretion, appears to act at least in part on CCK receptors located on vagal afferent nerves, which in turn elicit a vago-vagal reflex, implying that CCK exerts its effect on the pancreas at least in part through vago-vagal reflexes. Furthermore, pharmacological blockade of CCK receptors totally abolished the early pancreatic amylase response to intestinal nutrients, suggesting that the activation of (probably vagal) CCK receptors is essential to run the enteropancreatic reflex.

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

SummaryBackground: 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.

Control of Pancreatic Exocrine Secretion via Muscarinic Receptors: Which Subtype(s) Are Involved?

The present report gives an overview of the experimental, pharmacological and molecular investigations that have been undertaken during the past two decades to characterize and identify the muscarinic receptor subtype(s) involved in the cholinergic control of pancreatic exocrine secretion in humans and different animal species. The results published in the literature clearly indicate that both M1 and M3 receptors contribute to the regulation of pancreatic enzyme secretion, although contradictory conclusions have been drawn from secretory studies using specific M1 and M3 receptor antagonists in vivo and in vitro. Binding studies using specific M1 and M3 receptor antagonists have supported the existence of both M1 and M3 receptors on pancreatic acinar cells, which was confirmed by the demonstration of specific mRNA for both receptor subtypes in rat pancreatic acinar cells. In addition, experimental evidence exists that nonacinar (possibly presynaptic) M1 receptors also contribute to the control of pancreatic enzyme secretion. The role of the different muscarinic receptor subtypes in the control of pancreatic fluid and bicarbonate output, however, still needs to be clarified. Future research should cover the evaluation of the relative contribution of the different receptor subtypes to the regulation of pancreatic exocrine function, the localization of the receptors involved as well as possible species differences.

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

SummaryConclusionsIn dogs1.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; and5.Both mediators interact in a synergistic manner.MethodsIn six conscious dogs with chronic gastric and duodenal fistulas, we compared the action of the M1-receptor antagonisttelenzepine (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).ResultsSecretin 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 secretinstimulated 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.

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.

Vagally stimulated gastric acid and pancreatic enzyme secretion-different roles of nitric oxide (NO)

In 6 conscious dogs with chronic gastric and duodenal fistulas we compared the effect of the cholinerigic MI-receptor antagonist telenzepine (81 nmol/kg/h iv.) and the nitric oxide synthase inhibitor N°-nitro-L-arginine (L-NNA; 2.5 mg/kg + 0.5 mg/kg/h iv.) on the pancreatic protein response to graded loads of intraduodenal tryptophan (0.37-10.0 mmol/h), given against a background of secretin (20.5 pmol/kg/h iv.). The incremental protein output (i.e. observed protein output minus the response to secretin alone) was calculated. Results: Telenezpine and L-NNA significantly (p<0.05) decreased the pancreatic protein output during secretin infusion by 84 % and 68 %, respectively. Tryptophan dose-dependently increased the protein output over that seen with secretin alone. Both telenzepine and L-NNA significantly decreased the incremental protein responses to the lower loads (0.37-3.3 mmol/h) of tryptophan by 77 to 87 % and by 70 to 84 %, respectively. Neither telenzepine nor L-NNA had a significant effect on the incremental protein response to the highest load (10.0 mmolJh) of tryptophan. Conclusions: In dogs, 1) Ml-receptors and endogenous nitric oxide are stimulatory mediators of the basal pancreatic protein output and the protein response to lower loads of intraduodenal tryptophan; 2) the similar inhibitory pattern of the antagonists of these mediators indicate that both Ml-receptors and nitric oxide take part in the same pathway to stimulate pancreatic enzyme output; 3) the pancreatic enzyme response to high loads of tryptophan is mainly controlled by other (probably humoral) mediators.