J. Bilski

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.

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.

Gastrointestinal secretory, motor and circulatory effects of corticotropin releasing factor (CRF)

This study was designed to determine the effects of CRF on the gastrointestinal functions such as secretion, motility and circulation in dogs. CRF was found to inhibit dose-dependently gastric acid response to pentagastrin but not to histamine. CRF stimulated pancreatic bicarbonate and protein secretion under basal conditions and in response to secretin or cholecystokinin (CCK). This stimulation was accompanied by an increase in plasma levels of pancreatic polypeptide (PP), but not of secretin or gastrin. CRF caused a partial inhibition of the migrating motor complexes in fasted dogs and increased spike activity of the small bowel. These motor effects of CRF probably resulted from the action of the released PP on the intestinal smooth muscle. CRF is also a potent and selective stimulant of the mesenteric blood flow. This effect may be secondary to the stimulation of intestinal motility and metabolism.

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.

Role of cholecystokinin in the intestinal fat- and acid-induced inhibition of gastric secretion

This study was designed to determine the role of cholecystokinin (CCK) in the inhibition of gastric HCl secretion by duodenal peptone, fat and acid in dogs with chronic gastric and pancreatic fistulas. Intraduodenal instillation of 5% peptone stimulated both gastric HCl secretion and pancreatic protein secretion and caused significant increments in plasma gastrin and CCK levels. L-364,718, a selective antagonist of CCK-A receptors, caused further increase in gastric HCl and plasma gastrin responses to duodenal peptone but reduced the pancreatic protein outputs in these tests by about 75%. L-365,260, an antagonist of type B receptors, reduced gastric acid by about 25% but failed to influence pancreatic response to duodenal peptone. Addition of 10% oleate or acidification of peptone to pH 3.0 profoundly inhibited acid secretion while significantly increasing the pancreatic protein secretion and plasma CCK levels. Administration of L-364,718 reversed the fall in gastric HCl secretion and significantly attenuated pancreatic protein secretion in tests with both peptone plus oleate and peptone plus acid. Exogenous CCK infused i.v. in a dose (25 pmol/kg per h) that raised plasma CCK to the level similar to that achieved by peptone meal plus fat resulted in similar inhibition of gastric acid response to that attained with fat and this effect was completely abolished by the pretreatment with L-364,718. We conclude that CCK released by intestinal peptone meal, containing fat or acid, exerts a tonic inhibitory influence on gastric acid secretion and gastrin release through the CCK-A receptors.

Effects of peptide YY on dog and rat pancreatic secretion in vivo and in vitro

SummaryThe action of peptide YY (PYY) on exocrine pancreatic secretion in dogs and rats was compared in in vivo and in vitro studies. PYY infused i.v. in the physiological dose range (125–1000 pmol/kgxadh) reduced in a dose-dependent manner the pancreatic protein response to caerulein and suppressed basal and meat feeding or duodenal oleate-induced pancreatic secretion in conscious dogs. Both meat feeding and duodenal oleate caused significant elevation of plasma PYY levels and these showed several-fold increase during infusion of exogenous PYY (500 pmol/kgxadh) inducing significant inhibition of the postprandial or oleate-stimulated pancreatic secretion. PYY in a dose range of 2.5–40 nmol/kg.xadh also inhibited the response to caerulein in conscious rats but failed to prevent the increment in the postprandial protein secretion in this species. PYY added in various concentrations (10−11–10−6 M) to the incubation medium of the isolated dog and rat pancreatic acini failed to affect basal or caerulein- and urecholine-stimulated amylase release. This study shows that PYY is an effective inhibitor of the pancreatic secretion in vivo but not in vitro suggesting that the inhibition is mediated by an indirect mechanism.

Effects of Leukotrienes on Gastric Acid and Alkaline Secretions

This study was designed to determine the influence of leukotriene C4 on gastric acid and alkaline secretion. Leukotriene C4 was found to be a potent inhibitor of gastric acid secretion induced in vagally innervated and denervated portions of the stomach of conscious dogs by a variety of stimulants such as histamine, pentagastrin, and meat feeding. Leukotriene C4 was also an effective inhibitor of acid formation in the isolated gastric glands stimulated by histamine or dibutyryl cyclic adenosine monophosphate without or with addition of indomethacin, indicating that this compound acts directly on the parietal cells without mediation of endogenous prostaglandins. Leukotriene C4 was also an effective stimulant of gastric alkaline secretion. However, this effect was probably mediated by an increase in the generation of endogenous prostaglandin, as it was accompanied by an increase in the luminal release of prostaglandin E2 and indomethacin prevented both the stimulation of alkaline secretion and luminal prostaglandin E2 release by leukotriene C4.

Role of secretin and CCK in the stimulation of pancreatic secretion in conscious dogs. Effects of atropine and somatostatin

SummaryThe role of gut hormones, such as secretin and CCK, in the stimulation of pancreatic secretion by duodenal HCl or oleate and by meat feeding has been studied in conscious dogs before and after pretreatment with atropine and somatostatin. Plasma hormones were measured by specific and sensitive radioimmunoassays. Duodenal perfusion with HCl and oleate stimulated dose-dependently pancreatic HCO3 and protein secretion and raised plasma levels of secretin and CCK, respectively. Atropine reduced significantly both HCO3 and protein secretion but did not affect plasma secretin and CCK levels in these studies. Both exocrine pancreatic secretion and plasma secretin and CCK levels were suppressed by somatostatin. Meat feeding caused a marked pancreatic HCO3 and protein secretion accompanied by a significant increase in plasma secretin and CCK which seem to play an important role in the postprandial pancreatic stimulation. Both atropine and somatostatin reduced the pancreatic secretion induced by exogenous hormones but only somatostatin, but not atropine, significantly decreased plasma secretin and CCK responses to intestinal stimulants. We conclude that both atropine and somatostatin reduce the pancreatic responses to duodenal HCl or oleate or to meat feeding but only somatostatin is capable of suppressing the release of secretin and CCK.

The importance of gastric secretion in the feedback control of interdigestive and postprandial pancreatic secretion in rats

Previous studies demonstrated that pancreatic enzyme secretion in rats is stimulated by the diversion of pancreatic juice from the duodenum or by the inhibition of pancreatic proteinases in the intestinal lumen but little attention has been paid to the role of gastric secretion in this stimulation. This study, carried out on conscious rats with large gastric (GF) and pancreatic fistulas, confirms that diversion of pancreatic juice in rats with the GF closed results in the progressive stimulation of pancreatic secretion reaching the maximum similar to that induced by exogenous CCK. When the GF was kept open, the diversion resulted in only small increment in pancreatic secretion and this was accompanied by progressive increase in gastric acid outputs. Similar amounts of HCl (25-400 mumol/h) instilled intraduodenally (i.d.) in rats with the GF open fully reproduced the increase in pancreatic secretion observed after the diversion of pancreatic juice and this effect was completely abolished by the pretreatment with L-364,718, a specific CCK receptor antagonist. Pretreatment with omeprazole to suppress completely gastric acid secretion in the diverted state resulted in a decline in pancreatic secretion similar to that observed after opening the GF. Camostate given in graded doses (6-200 mg/kg) either i.d. or s.c. in rats with pancreatic juice returned to the duodenum caused a dose-dependent increase in pancreatic secretion, but after opening the GF or after omeprazole this increase was reduced by about 50% while after L-364,718 it was abolished. This study provides evidence that gastric secretion plays an important role in the pancreatic response to diversion of pancreatic juice or inhibition of luminal proteinases (but not to feeding) and the elimination of gastric acid reduces this response.