Pancreatic Secretory Response Research Articles

Role of Gastric Juice in Feedback Regulation of Rat Pancreatic Secretion by Luminal Proteases

The role of gastric juice in the intestine on the pancreatic secretory response to intraduodenal infusion of trypsin inhibitors or to diversion of bile and pancreatic juice from the intestine was studied in conscious rats with pylorus ligation and gastric juice drainage. In absence of gastric juice in the intestine, diversion of bile and pancreatic juice from the intestine stimulated pancreatic secretion, but the incremental protein and fluid secretory responses to diversion of bile and pancreatic juice were increased approximately 2.9-fold and 2.5-fold, respectively, by intraduodenal infusion of HCl (60 microEq/h). Intraduodenal infusion of HCl (240 microEq/h) had no effect on the pancreatic secretory response to infusion of lima bean trypsin inhibitor (20 mg). These results support the hypothesis that the inhibitory effect of atropine on the pancreatic secretory response to diversion of pancreatic juice or bile and pancreatic juice is secondary to inhibition of gastric acid secretion. The lack of effect of HCl on the pancreatic response to trypsin inhibitor contradicts the hypothesis that acid in the intestine is important or necessary for the feedback response to loss of intraluminal protease activity. It is proposed that acid in the intestine augments the pancreatic response to diversion of pancreatic juice or bile and pancreatic juice by reducing intraluminal pH and thereby inactivating residual pancreatic proteases.

Duodenal Alkalinization Releases Secretin and Vasoactive Intestinal Polypeptide and Stimulates Exocrine Pancreatic Secretion in the Anesthetized Rat

The effect of various intraduodenal alkaline solutions (0.1 M NaHCO3, 0.1 M Na2CO3 and 0.025 M NaOH) on exocrine pancreatic secretion and the release of two peptides, secretin and vasoactive intestinal polypeptide, was studied in anesthetized rats. The flow rate of the pancreatic juice was stimulated up to a maximum of 179, 158 and 180% and the protein output up to 181, 131 and 162% (compared with basal) after duodenal perfusion of, respectively, 0.1 M NaHCO3, 0.1 M Na2CO3 and 0.025 M NaOH. Maximum increases in portal plasma secretin concentrations of 143, 146 and 190% and maximum increases in VIP of 116, 155 and 147% after, respectively, intraduodenal 0.1 M NaHCO3, 0.1 M Na2CO3, and 0.025 M NaOH were found. In conclusion duodenal alkalinization in the rat produces a pancreatic exocrine secretory response that may be partially ascribed to the effect of secretin and VIP.

Caerulein-induced acute pancreatitis in the rat. Pancreatic secretory response to cholecystokinin

The response of pancreatic exocrine secretion to cholecystokinin (CCK), has been studied in experimental acute pancreatitis induced in rats by supramaximal doses of caerulein. Several doses of caerulein were used (4, 20 and 40 micrograms/Kg) and each one was administered by four subcutaneous injections over 3 h at hourly intervals. Pancreatic juice was collected 9 h after the first injection. The caerulein-treated animals showed a statistically significant increase in serum amylase levels. Secretory activity of ductular cells remained unchanged in all the caerulein-treated animals, but total protein and amylase secretion decreased significantly at all the caerulein doses used, both in resting conditions and under stimulation with CCK (1.25 micrograms/Kg/h). Despite this the acinar cells of rats treated with the lowest dose of caerulein retained a certain degree of secretory function since amylase activity in pancreatic juice was greater than in other groups of rats treated with higher doses of caerulein. Moreover, the percentage of increase observed in total protein and amylase in response to CCK respect to basal secretion is similar to that of the untreated animals. At higher doses (20 and 40 micrograms/Kg) the secretory capacity in response to CCK was inhibited. Therefore CCK administration in slight acute pancreatitis could be used as a therapy since it favours the secretion of pancreatic enzymes at percentual levels similar to those of the controls.

Effects of an antral mucosectomy, L-364,718 and atropine on cephalic phase of gastric and pancreatic secretion in dogs

The purpose of this study was to determine the role of gastrin and cholecystokinin in the cephalic phase of gastrin release and gastric and pancreatic secretion in conscious dogs. Sham feeding in intact dogs increased gastric acid output to about 65% of histamine maximum and pancreatic protein to 23% of caerulein maximum. Significant increases in plasma gastrin and pancreatic polypeptide but not cholecystokinin occurred. Similar effects were obtained using insulin hypoglycemia or 2-deoxy-D-glucose glucocytopemia. Atropine eliminated gastric acid response to sham feeding, insulin, or 2-deoxy-D-glucose, significantly reduced the pancreatic protein response by about 60%, and abolished plasma pancreatic polypeptide but not plasma gastrin. Blocking of cholecystokinin receptors by L-364,715 did not affect gastric or pancreatic secretory responses to sham feeding, insulin, or 2-deoxy-D-glucose and failed to influence the accompanying increments in plasma gastrin and pancreatic polypeptide. In antral-mucosectomized dogs, sham feeding-induced acid output reached only 17% of histamine maximum but the increase in pancreatic protein output was similar to that in intact dogs. In these animals, background stimulation with G17I (62 pmol/kg per h) potentiated the gastric acid response to sham feeding but had little effect on pancreatic protein output. This study provides evidence that unlike gastric acid, the pancreatic protein response to physiological or pharmacological cephalic stimulation does not depend on vagally released gastrin but probably on direct vagal stimulation of the pancreas.

Effect of Fatty Acid on Secretin Release and Cholinergic Dependence of Pancreatic Secretion in Rats

We investigated the effects of oleic acid in the duodenum on pancreatic exocrine secretion and plasma secretin, and determined the role of cholinergic dependence on pancreatic secretion and secretin release in response to oleic acid in anesthetized rats. Oleic acid emulsion (pH 6.5) in three different doses of 0.06, 0.25, and 1 mmol/h was infused intraduodenally for 1 h with or without intravenous administration of atropine in a dose of 100 micrograms/kg/h. Intraduodenal administration of oleic acid resulted in significant increases in pancreatic juice volume and bicarbonate output, in a dose-related manner (p less than 0.001). Plasma secretin concentration caused dose-dependent elevation (p less than 0.001) by oleic acid, which correlated very well with bicarbonate output in response to oleic acid (p less than 0.001). Atropine inhibited pancreatic secretion including juice volume and bicarbonate output stimulated by oleic acid in each dose, statistically significantly (p less than 0.05-0.01), but did not affect plasma secretin concentration. Thus, we conclude that oleic acid in the duodenum stimulates pancreatic secretion and endogenous secretin release in rats, and that secretin release is not influenced by the cholinergic tone, although pancreatic secretory response is inhibited significantly.

Plasma secretin, CCK, and pancreatic secretion in response to dietary fat in the rat.

The role of fat in regulation of pancreatic secretion was studied in conscious rats by measuring pancreatic secretion and plasma cholecystokinin (CCK) and secretin responses to intraluminal infusion of fat, protein, or trypsin inhibitor via the duodenum. In rats with pancreatic juice continuously returned to the intestine, intraduodenal infusion of 20% emulsified fat (Liposyn), 10% casein, and 0.4% ovomucoid trypsin inhibitor (OMTI) stimulated equivalent increases of approximately threefold in pancreatic protein output. Proglumide reduced fat-stimulated pancreatic protein secretion by greater than 90% but did not inhibit the response to OMTI. Fat significantly increased plasma CCK from basal levels of 0.5 pM to 2-3 pM, but it was a weaker stimulant of CCK secretion than casein (peak CCK levels greater than 10 pM) or OMTI (peak CCK levels 5-6 pM). Fat significantly stimulated secretin release (21.7 pM) compared with casein (6.8 pM), OMTI (4.4 pM), and NaCl (3.5 pM). The inhibition of fat-stimulated pancreatic secretion by proglumide indicates that the small amounts of CCK released by fat are necessary for a normal pancreatic response, suggesting that this response may be the result of potentiation between secretin and small amounts of CCK.

Meal-induced peptide tyrosine tyrosine inhibition of pancreatic secretion in the rat.

In the present studies we examined the distribution, release, and biological actions of peptide tyrosine tyrosine (PYY) in the rat. The concentration and distribution of PYY was highest in the ileum and colon as determined by both radioimmunoassay of rat tissue extracts and immunocytochemistry. An ultrastructural comparison of rat and dog colonic PYY cells revealed a bipolar distribution of peptide-containing secretory granules in both species. Serum PYY and pancreatic exocrine secretory responses were monitored after presentation of a meal to meal-trained rats (n = 12). A significant increase in PYY concentrations was not observed until 120 min after meal presentation, a delayed response similar to that previously observed in the dog. PYY responses were also observed in rats after perfusion of the intestine at the level of the duodenum and ileum with an 80 mOsm micellar solution of sodium oleate. Duodenal instillations of the fatty acids resulted in a maximum PYY response after 120 min, whereas rats subject to ileal perfusion of fat exhibited maximum PYY release within the first hour. In other experiments, infusion of exogenous PYY at 100 pmol.kg-1.h-1, which reproduced plasma PYY levels observed after a meal and perfusion of the gut with fat, significantly inhibited CCK-stimulated bile pancreatic volume (P less than 0.02), protein (P less than 0.01), and amylase (P less than 0.01) output. These studies demonstrate a bipolar distribution of PYY-containing secretory granules in cells of the jejunal, ileal, and colonic mucosa, and show that PYY is released in response to a meal in amounts sufficient to inhibit cholecystokinin-stimulated pancreatic secretion. Evidence is presented that PYY may mediate the delayed inhibition of pancreatic secretion that is observed in the rat after ingestion of a meal.

Intraluminal calcium binding does not mediate fatty acid-induced pancreatic bicarbonate secretion

Since the chain length dependency of fatty acid-induced pancreatic exocrine secretion parallels that of fatty acid-induced inhibition of gastric emptying, similar mechanisms of action may be involved. An earlier study suggested that binding of calcium might mediate fatty acid-induced inhibition of gastric emptying. This study investigated possible mediation of fatty acid-induced pancreatic secretion by calcium binding. Pancreatic secretory response to intraduodenal administration of dodecanoate and various calcium chelators (sodium EDTA, calcium-saturated EDTA, sodium dodecyl sulfate, sodium dioctyl sulfosuccinate, and sodium taurocholate) was studied in three dogs equipped with chronic pancreatic fistulae. Calcium affinity of the various test solutions was quantitated by titrating aliquots of perfusate against a standard CaCl2 solution. Sodium EDTA was found to be the most potent calcium binder (pKc 8.3); sodium dodecanoate, sodium dodecyl sulfate, and sodium dioctyl sulfosuccinate were moderate calcium binders (pKc 7.3, 7.2, 6.9, respectively), whereas sodium taurocholate and calcium-saturated EDTA were poor calcium binders. Sodium dodecanoate evoked brisk bicarbonate output (0.6-1.6 mEq/15 min). Minimal secretory responses were observed in response to all other agents tested. These findings suggest that calcium binding is not involved in mediation of fatty acid-induced pancreatic bicarbonate secretion.

Caerulein stimulates pancreatic secretory response in conscious newborn rats.

The aim of our study was to measure age-dependent, caerulein-stimulated pancreatic enzyme secretion of conscious CFY suckling rats without pancreatic duct cannulation. Pancreatic secretory response was expressed as the decrease in specific enzyme (trypsin, amylase) activity compared to saline-injected control. The study was performed in three phases. In 10-d-old conscious newborn rats, single 1 and 3 micrograms/kg sc doses of caerulein induced significant decreases in specific trypsin (42 and 47%) and amylase (34 and 33%) activity 15 min after the caerulein injection; the same doses injected at 0 and 30 min evoked a similar decrease 90 min after the first injection. The 0.5 microgram/kg dose was ineffective. In 10-d-old anesthetized rats, the 90-min-decrease in total pancreatic trypsin activity, induced by graded doses (1,3,10, and 30 micrograms/kg) of caerulein, was compared to the 90-min output of trypsin in their bile-pancreatic juice. Each of the applied doses induced significant change in the total trypsin activity both in the pancreas (-33-57%) and juice (+21 +/- 49%) and its decrease in the gland corresponded quantitatively well (r = 0.52; p less than 0.01) to the increase in the simultaneous 90-min trypsin output. The age- and dose-dependent pancreatic response of 3-, 5-, 10-, and 20-d-old conscious rats was investigated under the effect of 1,3,10, and 30 micrograms/kg sc doses of caerulein injected at 0 and 30 min. In 3-d-old rats, the 10 and 30 micrograms/kg and in 20-d-old rats, the 1 and 3 micrograms/kg doses were effective, whereas in 5- and 10-d-old rats each caerulein dose applied evoked a significant decrease in pancreatic-specific trypsin activity. The pancreas of newborn rats is in vivo less sensitive to caerulein between postnatal d 3 and 10 than in already weaned rats.

Pancreatic secretory response to intravenous caerulein and intraduodenal tryptophan studies: Before and after stepwise removal of the extrinsic nerves of the pancreas in dogs

In two sets of 6 dogs with gastric and pancreatic fistulas, we studied the effect of atropine (14 nmol/ kg h i.v.) on the pancreatic secretory response to intravenous caerulein and to intraduodenal perfusion with tryptophan (both given with a secretin background) before and after stepwise removal of the extrinsic nerves of the pancreas, i.e., celiac and superior mesenteric ganglionectomy alone or truncal vagotomy alone and truncal vagotomy plus celiac and superior mesenteric ganglionectomy. Atropine significantly (p < 0.05) depressed the protein output in the basal state and in response to secretin at each stage of innervation. The incremental protein response to caerulein was not altered by the various denervation operations nor by atropine. Truncal vagotomy alone significantly decreased the incremental protein response to low (0.12, 0.37, and 1.1 mmol/h) but not high loads of tryptophan. Ganglionectomy in combination with vagotomy did not further depress the incremental protein response to low loads of tryptophan. Atropine significantly reduced the incremental protein response to low loads of tryptophan only in intact innervated animals. Ganglionectomy alone did not alter the incremental protein response to any load of tryptophan. Ganglionectomy, truncal vagotomy, and atropine did not alter basal or tryptophan-stimulated levels of plasma cholecystokininlike immunoreactivity. We conclude that (a) neither the extrinsic nor the intrinsic cholinergic pancreatic nerves modulate the protein response to caerulein; (b) the sympathetic pancreatic nerves do not mediate the response to tryptophan; (c) the protein response to intraduodenal tryptophan is at least in part mediated by long, cholinergic, enteropancreatic reflexes with both afferent and efferent fibers running within the vagus nerves; and (d) release of cholecystokinin by intestinal tryptophan is not under cholinergic or splanchnic control.

Pancreatic Secretory Response to Intravenous Caerulein and Intraduodenal Tryptophan Studies: Before and After Stepwise Removal of the Extrinsic Nerves of the Pancreas in Dogs

In two sets of 6 dogs with gastric and pancreatic fistulas, we studied the effect of atropine (14 nmol/kg.h i.v.) on the pancreatic secretory response to intravenous caerulein and to intraduodenal perfusion with tryptophan (both given with a secretin background) before and after stepwise removal of the extrinsic nerves of the pancreas, i.e., celiac and superior mesenteric ganglionectomy alone or truncal vagotomy alone and truncal vagotomy plus celiac and superior mesenteric ganglionectomy. Atropine significantly (p less than 0.05) depressed the protein output in the basal state and in response to secretin at each stage of innervation. The incremental protein response to caerulein was not altered by the various denervation operations nor by atropine. Truncal vagotomy alone significantly decreased the incremental protein response to low (0.12, 0.37, and 1.1 mmol/h) but not high loads of tryptophan. Ganglionectomy in combination with vagotomy did not further depress the incremental protein response to low loads of tryptophan. Atropine significantly reduced the incremental protein response to low loads of tryptophan only in intact innervated animals. Ganglionectomy alone did not alter the incremental protein response to any load of tryptophan. Ganglionectomy, truncal vagotomy, and atropine did not alter basal or tryptophan-stimulated levels of plasma cholecystokininlike immunoreactivity. We conclude that (a) neither the extrinsic nor the intrinsic cholinergic pancreatic nerves modulate the protein response to caerulein; (b) the sympathetic pancreatic nerves do not mediate the response to tryptophan; (c) the protein response to intraduodenal tryptophan is at least in part mediated by long, cholinergic, enteropancreatic reflexes with both afferent and efferent fibers running within the vagus nerves; and (d) release of cholecystokinin by intestinal tryptophan is not under cholinergic or splanchnic control.

Inhibition of Polyamine Synthesis by α-Difluoromethylornithine and its Effects on Pancreatic Secretion and Growth in the Rat

The role played by the polyamines in mediating the pancreatic growth and secretory responses to hormonal stimulation is uncertain. The effect of an inhibitor of ornithine decarboxylase (ODC), alpha-difluoromethylornithine (DFMO), on rat pancreatic protein secretion and synthesis and on growth in response to hormonal stimulation was therefore studied. Anesthetized rats were given an intravenous injection of DFMO (50, 100, or 150 mg/kg), followed by a 7-h continuous infusion (15, 25, or 35 mg/kg/h, respectively). After a basal 1-h period an intravenous infusion of 2.5 micrograms/kg/h of the cholecystokinin-like peptide Thr28Nle31CCK25-33 (CCK-LP) was added and continued for 6 h. The control rats received CCK-LP only. The ODC activity in the pancreas was markedly reduced by DFMO, but DFMO did not affect pancreatic juice volume or protein output. In another series conscious rats were given a continuous intravenous infusion of 2.5 micrograms/kg/h of CCK-LP for 8, 24, and 48 h or 5.0 micrograms/kg/h of secretin for 8 and 48 h, with or without DFMO (100 mg/kg as an injection initially and thereafter 25 mg/kg/h). The ODC activity and putrescine concentration in the pancreas were significantly reduced by DFMO at 8 and 24 h but not at 48 h. DFMO also significantly reduced the activities of RNA polymerase, DNA polymerase, and thymidine kinase at 24 h, but not at 48 h. The present study thus indicates that polyamines play a role in the initiation of the growth response to hormonal stimulation but does not support a similar dependence for early pancreatic protein synthetic and secretory responses.

Interaction of neurotensin with caerulein or secretin on digestive tract growth in rats

Because neurotensin may potentiate exocrine pancreatic secretory responses to cholecystokinin and secretin, we examined interactions of neurotensin with caerulein or secretin on growth of pancreas, stomach, small intestine, and colon. Rats were injected with saline, neurotensin (100 μg/kg), caerulein (0.67 μg/kg), secretin (100 μg/kg), or neurotensin plus caerulein or secretin every 8 h for 5 days. Pancreas, stomach, small intestine, and colon were weighed and assayed for DNA, protein, and digestive enzymes. Although neurotensin increased pancreatic weight ( P < 0.01), DNA ( P < 0.01), and protein content ( P < 0.05) by 20–30%, it had less than additive effects on responses to caerulein and secretin. Neurotensin had no effects on pancreatic enzymes or on responses to caerulein or secretin. Neurotensin alone had no effects on growth of the oxyntic gland area or antrum but inhibited increases in antral weight, DNA, and protein caused by secretin. Neurotensin increased small intestine weight (9%, P < 0.05) and protein content (23%, P < 0.01). Secretin also increased weight (22%), DNA (29%), and protein content (48%) of the small intestine (all P < 0.01), but neurotensin and secretin together had less than additive effects. Our results suggest that neurotensin inhibits rather than potentiates certain growth effects of caerulein or secretin on the pancreas and other organs.

Cephalic phase response of pancreatic exocrine secretion in conscious dogs.

The effects of three taste solutions on the cephalic phase of pancreatic secretion were studied in conscious dogs. Male beagle dogs weighing 9-11 kg were prepared with gastric and duodenal fistulas. Gustatory receptors were stimulated for 5 min with 100 ml of 0.5% agar solutions containing 0.05, 0.12, and 0.3 M of either sodium chloride, sucrose, or monosodium glutamate (MSG). Pancreatic juice was collected every 5 min before and after stimulation, and volume flow and protein output were measured. Pancreatic secretory responses were found to vary with the type of taste stimulus. Sucrose was a better stimulus than MSG for both protein output and volume flow. Taste stimulation with sodium chloride produced a lower pancreatic response than those with sucrose or MSG.

Pancreatic secretory response to ordinary meals: Studies with pure pancreatic juice

We have studied the pancreatic secretory response to a normal meal in 5 subjects with an external drainage of the main pancreatic duct carried out after biliary tract surgery. Pancreatic juice was collected at 60-min intervals from 10 am to 7 pm, starting 2 h before and ending 7 h after lunch, and was analyzed for volume, bicarbonate content, and protein content. Large doses of pancreatic extract were given between and during meals. Both bicarbonate and protein output increased rapidly after the beginning of the meal and the increase persisted, with minor fluctuations, for the entire 7-h study period between lunch and dinner. The peak postprandial bicarbonate and protein outputs were higher (on average by 20% and 26%, respectively) than bicarbonate and protein outputs induced by exogenous infusion of submaximal doses of secretin and cerulein. The profile and magnitude of the bicarbonate secretory pattern elicited by food were not substantially different from those of protein secretion. In an additional patient who had undergone a duodenocephalopancreatectomy plus two-thirds distal gastrectomy before the study, the pancreatic response to meals showed an initial phase characterized by an increase in pancreatic secretion during the first postprandial hour followed by a tendency to decrease in the subsequent 2 h, and a later phase (from the fourth postprandial hour to the end of the study) characterized by a more marked and more persistent increase in pancreatic secretion than occurred in the initial 3 h. These data indicate that (a) the pancreatic secretory response to ordinary meals is much more prolonged than is generally believed. The late phase of the response is not dependent on gastric emptying of food into the duodenum, but is probably related to the arrival of chyme in the distal ileum. (b) The pancreatic secretory response to a normal meal is quantitatively slightly higher than that produced by exogenous pancreatic stimulation with submaximal doses of secretin and cerulein. (c) The pattern of postprandial bicarbonate secretion is similar to that for protein.

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 α- and β-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.

Nervous control of gastric and pancreatic secretory response to 2-deoxy-D-glucose in the dog.

The relative contribution of the vagus and splanchnic nerves as mediators of the action of 2-deoxy-D-glucose (2-DG) on the stomach and the pancreas is largely unknown. In conscious dogs with gastric and pancreatic fistulas, the effect of 2-DG (100 mg kg-1, given as an intravenous bolus) on gastric acid and pancreatic exocrine secretion was tested before and after bilateral truncal vagotomy and after truncal vagotomy plus celiac and superior mesenteric ganglionectomy (i.e. extrinsic denervation of the stomach and the pancreas). In another set of dogs, only ganglionectomy was performed and the same experiments were done as in the first set of dogs. With the extrinsic nerves intact, 2-DG caused a rapid (within 15 min) and prolonged increase in gastric acid output as well as in pancreatic flow rate, bicarbonate and protein output. Truncal vagotomy abolished the gastric acid and pancreatic secretory response to 2-DG; additional ganglionectomy had no further effect. Ganglionectomy alone did not significantly alter 2-DG-stimulated gastric acid output, pancreatic flow rate and bicarbonate output; protein output, however, was significantly diminished by 57%. These results indicate that (a) intravenous 2-DG is a potent stimulant of gastric acid and pancreatic bicarbonate and protein output; (b) the vagus nerves are the major mediators of the gastric and pancreatic secretory response to 2-DG; (c) the sympathetic nerve fibers running through the celiac and superior mesenteric ganglia are probably not involved in the mediation of the 2-DG-induced gastric acid and pancreatic bicarbonate secretion. The diminished protein response to 2-DG after ganglionectomy is probably due to cut vagal fibers running through these ganglia.

Effect of 15(R), 15-methyl prostaglandin E2 and indomethacin on pancreatic secretion in man

In addition to gastric mucosal cytoprotective and antisecretory effects, prostaglandin E2 has a beneficial effect on experimental pancreatitis in some animal models, while prostaglandin synthesis inhibitors such as indomethacin and salicylates may induce pancreatitis at maximal doses. However, their effect on human pancreas is unclear. For this reason we considered it necessary to delineate their actions on human pancreatic secretion. Six healthy volunteers were studied on six separate days. On day 1, against a background of 1 pmol/kg/hr secretin, increasing doses of CCK were infused intravenously. On day 2, increasing doses of an amino acid mixture were infused intraduodenally and both studies were repeated on two occasions, following 100 micrograms 15(R), 15-methyl prostaglandin E2 per os on one and following indomethacin 50 mg orally 12 and 1 hr prior to the study on the other. Both indomethacin and PGE2 had no significant effect on pancreatic secretion in response to graded doses of CCK. 15(R),15-Methyl prostaglandin E2 and indomethacin caused a reduction of amylase output in response to the higher doses of intraduodenal amino acids. The prostaglandin E2 derivative also elicited a significant increase in basal bicarbonate output. the acute effects of 15(R),15-methyl prostaglandin E2 and indomethacin on human pancreatic secretion do not seem to offer an explanation for the mechanisms of protection against experimental acute pancreatitis or an association with pancreatitis, respectively.

Short-term cholinergic desensitization of rat pancreatic secretory response

Dispersed pancreatic acini were first exposed to carbamylcholine (10(-7)-10(-4) M) for 60 min, washed, and reexposed to this same agonist (10(-8)-10(-3) M) for 15 min. During this second incubation, the functional secretory capacity of these acini was evaluated by measuring amylase release. Acini preexposed to concentrations of carbamylcholine of 10(-6) M or greater showed shifts to the right in the subsequent carbamylcholine dose-response curves of amylase release. A 3-h recovery period (without carbamylcholine) did not restore the altered carbamylcholine dose-response curve. Ca2+ concentrations of 10(-7) M or 2.5 X 10(-3) M instead of 0.5 X 10(-3) M during the 60-min preincubation did not affect the desensitization process. With use of N-[3H]methylscopolamine to evaluate muscarinic receptors, the only changes observed after desensitization were a significant decrease in the high-affinity and an equivalent increase in that of the low-affinity receptors. After cholinergic exposure amylase release stimulated by caerulein was only slightly modified, whereas amylase release in response to a phorbol ester 12-O-tetradecanoylphorbol-13-acetate and to the ionophore A23187 was not altered. These data indicate that short-term desensitization with a cholinergic agent is relatively specific to muscarinic agonists, causes changes in the muscarinic receptor high- and low-affinity concentration but does not alter intracellular steps after calcium mobilization or protein kinase C activation known to be involved in the secretion process.

Effects of antral distension on pancreatic exocrine secretion in dogs: evidence for a short reflex.

In chloralose anesthetized dogs and decerebrated dogs whose pyloric sphincter was submucosally ligated, the pancreatic exocrine secretory response to antral distension was studied. Distensions of the antral pouch with Tyrode's solution and 0.1 N HCl caused graded rises in pancreatic flow and protein and bicarbonate outputs. The serum gastrin concentration gradually rose after the distention with Tyrode's solution, while no rise in serum gastrin was elicited by acid distension. After cervical vagotomy, a reduced pancreatic response persisted but no rise in the serum gastrin was seen. After splanchnicectomy following vagotomy, the pancreatic response became greater than before splanchnicectomy. This pancreatic response was observed even after caeliac and superior mesenteric ganglionectomies, but was completely abolished by an external tight ligature around the pyloric sphincter, or by administration of hexamethonium or atropine sulfate. The results suggest the existence of an antropancreatic short reflex in addition to a long route vago-vagal reflex.