Stephan Teyssen

Novel generation of hormone receptor specificity by amino terminal processing of peptide YY

The physiological significance of multiple Y receptors has not been determined since until recently only one form of endogenous agonists was known, namely PYY1-36 and NPY1-36. Recently, a new molecular form of PYY was characterized as des(Tyr-Pro)PYY (PYY3-36 or PYY-II). Its ability to interact at various Y receptors was not characterized. Analytical chromatography of fresh canine colon extracts shows two peaks of immunoreactivity eluting in the positions of PYY-II and PYY1-36 (PYY). PYY-II was about 40% of the total PYY immunoreactivity indicating that it is one of the major forms of PYY expressing its biological activity. It is shown that PYY-II will not displace label from the Y1 receptors found on a human neuroblastoma cell line. It is further shown that PYY-II is as potent as PYY for the inhibition of pancreatic secretion, which must occur through Y2 receptors. The enzymatic removal of Tyr-Pro from PYY to form PYY-II must therefore regulate the relative expression of a non-selective agonist (PYY) to a highly selective Y2 agonist (PYY-II). Amino terminal processing of PYY represents a novel type of regulation of peptide hormone specificity. It has important biological implications for PYY and potential relevance for other peptide hormone receptor systems.

Maleic acid and succinic acid in fermented alcoholic beverages are the stimulants of gastric acid secretion

Alcoholic beverages produced by fermentation (e.g., beer and wine) are powerful stimulants of gastric acid output and gastrin release in humans. The aim of this study was to separate and specify the gastric acid stimulatory ingredients in alcoholic beverages produced by fermentation. Yeast-fermented glucose was used as a simple model of fermented alcoholic beverages; it was stepwise separated by different methods of liquid chromatography, and each separated solution was tested in human volunteers for its stimulatory action on gastric acid output and gastrin release. Five substances were detected by high-performance liquid chromatography and were analyzed by mass spectrometry and 1H-13C nuclear magnetic resonance spectroscopy. At the end of the separation process of the five identified substances, only the two dicarboxylic acids, maleic acid and succinic acid, had a significant (P < 0.05) stimulatory action on gastric acid output (76% and 70% of fermented glucose, respectively), but not on gastrin release. When given together, they increased gastric acid output by 100% of fermented glucose and by 95% of maximal acid output. We therefore conclude that maleic acid and succinic acid are the powerful stimulants of gastric acid output in fermented glucose and alcoholic beverages produced by fermentation, and that gastrin is not their mediator of action.

Action of beer and its ingredients on gastric acid secretion and release of gastrin in humans

The intragastric action of beer and its known ingredients before and after fermentation on gastric acid secretion and release of gastrin was studied in healthy humans. None of 11 tested ingredients of fermented beer (2 x 500 mL, pH 5.5, given either alone or in combination) or hop extract had any significant effect. Finished beer (6 weeks old) and new beer were potent stimuli of acid output, causing 93% and 76% of the incremental maximal acid output in response to pentagastrin (6 micrograms/kg SC), respectively. Before the addition of yeast, preproducts of beer were considerably less potent. Thus, first and finished wort caused only a minor acid response which was 48% and 46% of maximal acid output. Foreign fermentation in first and finished wort is presumably the reason for the stimulatory action because glucose solutions in concentrations (11.5% wt/vol) seen in wort did not stimulate acid secretion. However, glucose solutions to which yeast was added, resulting in fermentation, were as potent stimuli of acid secretion as beer. Lyophilization of beer at pH 11.0 and dialysis (cutoff mol wt, 1000) removed the stimulatory substances. The plasma gastrin responses paralleled the gastric acid response to the different stimulants. It was concluded that (a) the addition of yeast to finished wort and the following alcoholic fermentation are the essential steps for the stimulatory action of beer on gastric acid secretion and release of gastrin; (b) carbohydrate metabolites with a molecular weight of less than 1000 are the acid-stimulatory agents in fermented beer; and (c) gastrin is the mediator of the stimulation of acid secretion because all substances that had a potent acid-stimulatory action also were potent stimuli of gastrin release.

Alcohol-related diseases of the oesophagus and stomach.

This chapter deals with the most clinically relevant alcohol-related diseases of the oesophagus and stomach. Despite the early findings of W. Beaumont 170 years ago that excessive drinking is associated with gastric bleeding, systematic studies on the action of alcohol and alcoholic beverages on the function of the stomach have only been performed in the last 15 years. The aim of this review is to summarize the data on the effect of acute and chronic alcohol consumption/abuse on the oesophagus and stomach.

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.

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.

Comparison of two dose-response techniques to study the pancreatic secretory response to intraduodenal tryptophan in the absence and presence of the M1-receptor antagonist telenzepine

To answer the questions if the type of continuous dose-response technique influences the pancreatic secretory response to intraduodenal tryptophan and if the M1-receptor antagonist telenzepine influences the intestinal absorption of tryptophan, we determined, in 12 conscious dogs with chronic gastric and duodenal fistulas, pancreatic bicarbonate and protein secretion and tryptophan plasma concentrations following intraduodenal tryptophan perfusion using two dose-response techniques. With an ascending continuous dose-response technique (aDRT), tryptophan was perfused in loads ranging from 0.12 to 10.0 mmol h−1 starting with the lowest load and tripling it every 45 min. With the descending continuous dose-response technique (dDRT), the order of tryptophan loads was reversed, with the highest load being given first. All studies were done on a fixed background of intravenous secretin (20.5 pmol kg−1 h−1) and repeated in the presence of the anticholinergic M1-receptor antagonist telenzepine (243 nmol kg−1 h−1). The bicarbonate and protein response as well as the tryptophan plasma concentrations to the same loads of tryptophan did not differ significantly between the two techniques. Using both techniques, telenzepine significantly (p < 0.05) inhibited the overall pancreatic protein response by 65% (dDRT) to 81% (aDRT). The overall bicarbonate response was only numerically, and not statistically significantly, inhibited by telenzepine. Tryptophan plasma concentrations after duodenal perfusion with tryptophan were neither influenced by the order of tryptophan loads nor altered by telenzepine. These findings indicate that in the intact animal (a) either the aDRT or the dDRT may be used to study the pancreatic secretory response to enteral infusion of amino acids, (b) at least part of the pancreatic secretory response to tryptophan is mediated through cholinergic M1 receptors, and (c) the duodenal absorption of tryptophan is not affected by telenzepine and therefore most likely not mediated by neuronal M1 receptors.

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.

Alkohol und Magen

Alkohol und die verschiedenen alkoholischen Getranke haben unterschiedliche Wirkungen auf die Funktion (i. e. Magensauresekretion) des Magens beim gesunden Menschen. Alkohol bewirkt reversible und moglicherweise auch irreversible Organschaden des Magens. Akuter Alkoholmisbrauch kann eine akute (hamorrhagische) Gastritis zur Folge haben. Folgende Pathomechanismen sind hieran beteiligt: die Zerstorung der Mukosabarriere, Freisetzung von Entzundungsmediatoren sowie die Aktivierung von neutrophilen Granulozyten mit Bildung und Freisetzung von reaktiv oxygenen Metaboliten und Proteasen. Der Stellenwert des. akuten und chronischen Alkoholkonsums hinsichtlich der Inzidenz des Ulcus ventriculi et duodeni, der chronischen atrophischen Gastritis und des Magenkarzinoms wird diskutiert.

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.