J. Tasler

Adrenergic Pathway in the Inhibition of Pancreatic Secretion by Peptide YY in Dogs

Peptide YY (PYY) is released by perfusion of an ileocolonic segment with oleate and inhibits exocrine pancreatic secretion. This study was designed to determine the role of the adrenergic pathway in the PYY-induced inhibition of pancreatic secretion. After intravenous administration of PYY, there was a dose-dependent inhibition of pancreatic HCO3 and protein responses to secretin, cholecystokinin, and feeding in conscious dogs and a reduction in pancreatic blood flow in anesthetized animals. These inhibitory effects of PYY on pancreatic secretion and blood flow were abolished in the presence of combined phentolamine and propranolol. Ileal perfusion with oleate caused a rise in plasma PYY levels similar to that observed after intravenous infusion of exogenous PYY. Combined alpha- and beta-adrenergic blockade also antagonized the effects of ileal perfusion with oleate on hormonal and postprandial pancreatic secretion. We conclude that exogenous PYY or endogenous PYY released by ileal oleate inhibits pancreatic secretory responses to exogenous secretin, cholecystokinin, or a meal and causes pancreatic vasoconstriction. Both these effects are mediated, at least in part, by the adrenergic pathway.

Effect of pancreatic polypeptide and its C‐terminal hexapeptide on meal and secretin induced pancreatic secretion in dogs.

1. Gastric acid and pancreatic bicarbonate and protein secretion as well as immunoreactive serum gastrin and pancreatic polypeptide concentrations in response to a meal and secretin have been measured before and after infusion of bovine pancreatic polypeptide or its C‐terminal hexapeptide. 2. Liver extract meal kept in the stomach at pH 5.5 (by intragastric titration) produced a marked increase in gastric acid and pancreatic protein secretion accompanied by a rise in serum gastrin and pancreatic polypeptide levels. Exogenous bovine pancreatic polypeptide caused little change in gastric secretion and serum gastrin but resulted in a profound suppression of pancreatic secretion. 3. Ordinary feeding a liver meal produced a marked increase in pancreatic bicarbonate and protein secretion that was dose‐dependently inhibited by bovine pancreatic polypeptide or its C‐terminal hexapeptide, the degree of inhibition being closely correlated with the increments in plasma pancreatic polypeptide. 4. Bovine pancreatic polypeptide and its C‐terminal hexapeptide also inhibited secretin and caerulein‐induced pancreatic secretion in a dose‐dependent manner. 5. This study shows that bovine pancreatic polypeptide inhibits pancreatic secretion at least in part by acting directly on the exocrine pancreas and that its biological activity resides in its C‐terminal hexapeptide fragment.

Effect of Cholecystokinin Receptor Antagonist on Pancreatic Responses to Exogenous Gastrin and Cholecystokinin and to Meal Stimuli

Exocrine pancreatic response to food is believed to result from the interaction of neural and hormonal factors, but their contribution in the net postprandial secretion is unknown. Recent description of a highly specific and potent cholecystokinin (CCK)-receptor antagonist permitted the evaluation of the physiologic role of CCK in postprandial pancreatic secretion. In dogs with chronic pancreatic fistula, CCK antagonism caused little alteration in sham feeding- or urecholine-induced pancreatic protein secretion, but reduced by approximately 60% the pancreatic protein response to a gastrointestinal meal and virtually abolished the pancreatic responses to duodenal perfusion with amino acids or oleate and to exogenous CCK, but not to secretin or neurotensin. The pancreatic protein responses, particularly to lower doses of gastrin, were also reduced by CCK-receptor antagonist, but no changes in the responses to secretin or neurotensin were detected. Cholecystokinin antagonism also significantly reduced the pancreatic polypeptide responses to CCK, gastrin, and the gastrointestinal meal, possibly due to removal of the CCK-mediated release of pancreatic polypeptide. We conclude that CCK plays a crucial role in the mediation of the gastrointestinal phase, but not the cephalic phase, of pancreatic secretion.

Comparison of Somatostatin and Its Highly Potent Hexa- and Octapeptide Analogs on Exocrine and Endocrine Pancreatic Secretion

Abstract The effects on pancreatic responses of highly potent cyclic hexapeptide (cyclo (N-Me-Ala-Phe-D-Trp-Lys-Thr-Phe)) (Veber analog) and octapeptide analogs of somatostatin such as D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-ol (SMS 201–995), D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2 (RC-121), and D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2 (RC-160) have been compared with somatostatin tetradecapeptide (SS-14) and atropine. The parameters evaluated were pancreatic responses to secretin and meat feeding in conscious dogs with chronic pancreatic fistula and amylase release from the dispersed pancreatic acini. The analogs were administered intravenously or intraduodenally. The cyclic hexapeptide and octapeptide analogs, given iv in graded doses against a constant background stimulation with secretin, produced similar and dose-dependent inhibition of pancreatic HCO− 3 and protein secretion. Analogs RC-121, RC-160, and the Veber analog were about two to four times more active than SS-14 in suppressing HCO− 3 secretion and equipotent in reducing protein secretion, but SMS 201–995 was only about half as potent as somatostatin in inhibiting HCO− 3. RC-160 was effective in inhibiting secretin-induced protein secretion at lower doses than other analogs. In tests with feeding, SMS 201–995, the Veber analog, RC-121, and RC-160 were more potent inhibitors of exocrine pancreatic secretion of HCO− 3 and protein and exhibited more prolonged inhibitory effects than SS-14. The Veber analog, RC-121, and RC-160 were also more effective after intraduodenal administration. Atropine also caused significant inhibition of both HCO− 3 and protein responses to secretin and meal feeding. All four analogs decreased the postprandial insulin and pancreatic polypeptide release to a similar degree as SS-14. Neither SS-14 nor the analogs tested significantly affected basal or caerulein-, gastrin-, secretin-, or bethanechol-stimulated amylase release from the dispersed canine pancreatic acini. Atropine reduced amylase release induced by bethanechol, but not that stimulated by caerulein, gastrin, or secretin. This indicated that the analogs, as somatostatin, are ineffective as secretory inhibitors in vitro. We conclude that cyclic hexapeptide and octapeptide analogs are more potent and longer acting inhibitors of pancreatic secretion than somatostatin-14 in vivo.

Role of endogenous prostaglandins in duodenal alkaline response to luminal hydrochloric acid or arachidonic acid in conscious dogs.

Duodenal secretion of HCO-3 and luminal release of PGE2 were measured in conscious dogs. The results show that the HCO-3 secretion is closely correlated with the luminal release of PGE2 and that both the HCO-3 and the PGE2 outputs increase dose-dependently after topical application of hydrochloric acid or arachidonic acid. Indomethacin reduced basal HCO-3 and PGE2 release and prevented their increase in response to hydrochloric acid or arachidonic acid. We conclude that mucosal PGE2 plays an important role in the alkaline secretion from the duodenum.

Role of cholecystokinin in the inhibition of gastric acid secretion in dogs.

1. This study was designed to determine the involvement of cholecystokinin (CCK) in the gastric secretory responses to exogenous and endogenous secretagogues in conscious dogs with chronic gastric fistulae (GF), pancreatic fistulae (PF) and Heidenhain pouches (HP). 2. A meal of meat or intragastric application of peptone (300 mosM) increased secretion of HCl from the HP and pancreatic secretion of protein and plasma levels of gastrin, CCK and somatostatin. 3. The CCK receptor antagonist L‐364,718 caused a further increase in the postprandial HCl secretion from the HP and in the plasma levels of gastrin and CCK but pancreatic output of protein and plasma concentration of somatostatin were significantly reduced. 4. Addition to intragastric peptone of 10% oleate or its acidification to pH 3.0 profoundly inhibited the HP secretion and gastrin release but significantly increased pancreatic secretion of protein and plasma levels of CCK and somatostatin. Administration of L‐364,718 reversed the fall in the HP secretion and plasma gastrin while significantly attenuating pancreatic protein secretion and plasma somatostatin levels. 5. Intragastric administration of hyperosmolar (1200 mosM) peptone also inhibited HCl secretion from the HP but this was not affected by L‐364,718. 6. Exogenous CCK and bombesin (but not gastrin) caused a small increase in HCl secretion from the HP and marked stimulation of pancreatic protein secretion accompanied by a significant rise in plasma levels of gastrin, CCK and somatostatin. Administration of L‐364,718 resulted in a further increase in the HCl response of HP to bombesin and in plasma levels of gastrin and CCK but caused a reduction in plasma levels of somatostatin. 7. We conclude that CCK released by a meal of meat, intragastric peptone, oleate or acidified peptone and intravenous bombesin exerts tonic inhibitory influences on gastric acid secretion and that this effect is mediated, at least in part, by somatostatin.

Enkephalin inhibits the release and action of secretin on pancreatic secretion in the dog.

1. Pancreatic bicarbonate and protein secretion as well as immuno‐reactive plasma secretin concentration in response to a meal, duodenal acidification and exogenous secretin or octapeptide of cholecystokinin (OP‐CCK) have been measured following administration of methionine‐enkephalin in chronic pancreatic fistula dogs. 2. Methionine‐enkephalin inhibited pancreatic responses to both exogenous hormones (secretin and OP‐CCK) and to endogenous hormones released from the gut by food or duodenal acidification. 3. Naloxone, a potent opiate receptor antagonist, partly prevents this methionine‐enkephalin‐induced inhibition of pancreatic secretion suggesting that this effect might be mediated by opiate receptors. 4. The inhibitory effect of methionine‐enkephalin on pancreatic response to endogenous stimulants was more pronounced than that to exogenous hormones and was accompanied by a significant reduction in plasma immuno‐reactive secretin concentration. 5. This study indicates that methionine‐enkephalin inhibits pancreatic secretion, at least in part, by suppressing the release of the intestinal hormones stimulating the exocrine pancreas.

Chemical stimulatory mechanism in gastric secretion.

1. The serum gastrin level, gastric mucosal blood flow and acid secretion from the canine Heidenhain pouch have been measured in response to the introduction of bovine serum albumin, pepsin‐digested albumin, an amino acid mixture, liver extract and mannitol used as control. 2. Distention of the Heidenhain pouch with mannitol or albumnin at pH 5‐0 produced a similar pressure‐related increase of acid secretion reaching a peak of only 10 percent of the maximal response to histamine. Pepsin‐digested albumin was capable of producing larger acid outputs than undigested albumin.The highest acid output, attaining about 80 percent of the maximal response to histamine, was obtained with liver extract both before and after exhaustive dialysis to remove all the amino acids and short peptide fragments. An amino acid mixture containing all essential amino acids was also found to stimulate acid secretion but a lesser degree than liver extract. 3. This concluded that it is not the intact protein but the products of its digestion, the polypeptides and free amino acids, which are potent chemical stimulants of acid secretion from the oxyntic gland area. Since the serum gastrin level was not changed during acid secretion induced by peptic digests bathing the oxyntic gland area, the mechanism of chemical stimulation appears to be gastrin‐independent. 4. The response to chemical stimulation by peptic digests can be greatly potentiated by combining this with distention of the oxyntic gland area. Topical application of xylocaine or atropine causes a marked decrease of Heidenhain pouch response to peptic digests, suggesting a possible neural reflex component in the mechanism of chemical stimulation of the oxyntic gland area. 5. When the pH of the liver extract in the Heidenhain pouch was gradually decreased in sequential order from 5–0 to 1–0, this resulted in a pH‐related decrease in acid secretion and in the mucosal blood flow falling to the basal level at pH 1–0. Exogenous secretion given in graded doses from 0–5 to 8–0 u./kg. hr caused a small but dose‐related inhibition of acid response to liver extract accompanied by a decrease of mucosal blood flow but without any significant change in the serum gastrin level. 6. The results indicate that the chemical stimulation of the oxyntic gland area by peptic digests is capable of inducing acid secretion by a local, gastrin‐independent, partially neural reflex mechanism; sensitive to pH, pressure and secretin.

Effects of anorexigenic peptide on gastric and pancreatic secretion.

1. Gastric and pancreatic secretion as well as serum gastrin an insulin levels have been measured after sham‐feeding, real feeding or exogenous hormonal stimulation in conscious dogs receiving (pyro) Glu‐His‐Gly, an appetite depressing peptide (AP). 2. Sham‐feeding produced a marked increase in gastric acid and pepsin outputs accompanied by an elevation of serum gastrin and insulin concentrations. AP infusion before and after sham‐feeding reduced the peak gastric secretion and suppressed gastrin and insulin responses to sham‐feeding. 3. Liver extract meal administered into the stomach resulted in an increase in gastric acid and serum gastrin and insulin levels. AP inhibited acid response to liver extract without affecting serum hormonal levels. Pentagastrin stimulation produced similar acid secretion to that obtained with liver extract and AP infusion also inhibited this secretion. 4. Secretin infusion or feeding a meat meal produced a similar rate of pancreatic bicarbonate secretion in dogs with chronic pancreatic fistula. AP infusion inhibited the bicarbonate response to feeding or secretin without affecting serum gastrin or insulin levels. 5. This study demonstrates that pyro‐Glo‐His‐Gly suppresses serum hormonal and gastric secretory response to cephalic stimulation and reduces gastrin and pancreatic secretory responses to ordinary feeding or exogenous hormonal stimuli.

Mechanisms of the Inhibitory Action of Prostaglandins on Meal-Induced Gastric Secretion

In dogs with gastric fistula and Heidenhain pouch (HP), 15(S)-15-methyl prostaglandin E2 methyl ester (PG-S) infused intravenously in graded doses (0.5--2.0 microgram/kg/h) inhibited dose-dependently, meal-induced acid secretion both from the vagally innervated main stomach and from the HP. This inhibition was associated with a marked reduction in mucosal blood flow but without significant change in the ratio of aminopyrine concentration in the gastric juice and blood plasma, indicating that the reduction in gastric microcirculation was probably secondary to the inhibition of gastric secretion. In dogs with special cannulae that allowed complete separation of the stomach and the intestine, PG-S caused stronger inhibition of gastric acid and serum gastrin responses to gastric and intestinal meals after application directly to the gastric mucosa, than following duodenal administration. PG-S applied topically to the HP mucosa also suppressed direct chemical stimulation of the HP by L-histidine meal. We conclude that PG-S exerts its inhibitory action on gastric secretion both by local contact with the mucosa via suppression on gastrin release from the antral G-cells and by direct inhibition of the secretory activity of the oxyntic glands.