Pancreatic Secretory Response Research Articles

Pancreatic secretory response to intestinal stimulants: a review.

In humans and many laboratory animals, protein digestion products such as peptides and amino acids and fat digestion products such as fatty acids and monoglycerides are potent intestinal stimulants of pancreatic enzyme secretion. The pancreatic enzyme response to these intestinal stimulants is related to the perfused load (amount per unit time) rather than to concentration. Both neural and hormonal pathways mediate the enzyme response to these intestinal stimulants. Enteropancreatic, cholinergic, vago-vagal reflexes are probably the most important mediators of the enzyme response to low loads of amino acids and fatty acids; hormones, such as cholecystokinin, seem to be the major mediators of the response to high loads of amino acids and fatty acids. Under physiological conditions it is probably the interplay of neural and hormonal mechanisms which regulates the pancreatic response to these stimulants. Gastric acid is the major regulator of postprandial pancreatic bicarbonate secretion. Secretion released by HCl is probably the most important physiological hormonal mediator of postprandial pancreatic bicarbonate secretion; its effect being potentiated by extrinsic (vagal) and intrinsic (intrapancreatic) cholinergic nerves and release of other hormones, such as cholecystokinin.

Dose-response effects of atropine on pancreatic secretory response to intestinal tryptophan in dogs.

In dogs with gastric and pancreatic fistulas, we studied the effect of intravenous infusion of atropine in doses of 0.9, 1.8, 7, and 29 nmol X kg-1 X h-1 on the pancreatic secretory response to graded loads of intraduodenal infusions of tryptophan, given with a secretin background. Infusions of 1.8, 7, and 29, but not 0.9 nmol X kg-1 X h-1 of atropine sulfate significantly (P less than 0.05) decreased the incremental protein response to all loads of tryptophan. The cumulative incremental protein output was reduced by 44, 37, and 52%, respectively. Infusions of 1.8, 7, and 29 nmol X kg-1 X h-1 of atropine significantly decreased by approximately 50% the incremental bicarbonate response to low (0.12 and 0.37 mmol/h) but not high loads (1.1, 3.3, and 10 mmol/h) of tryptophan. The inhibitory potency of the effective doses of atropine did not differ significantly. Only the highest dose of atropine significantly increased heart rate by 76%. These findings indicate that 1) in the intact animal, the minimal dose of atropine required for inhibition of pancreatic bicarbonate and protein response to intraduodenal tryptophan seems to be 1.8 nmol X kg-1 X h-1, a dose that causes probably few systemic effects, since it does not increase heart rate; and 2) the inhibitory action of atropine on the pancreatic response to tryptophan appears to be an "all-or-none" effect.

Stimulatory effect of hypercalcemia on pancreatic secretion is prevented by pretreatment with cholecystokinin and cholinergic agonists.

Recently, we demonstrated that hypercalcemia causes marked stimulation of feline exocrine pancreatic secretion, and that this effect is absent when a large dose of cholecystokinin (CCK) is infused prior to induction of hypercalcemia. To investigate this effect in more detail, anesthetized cats were given calcium i.v. after preadministration of CCK or urecholine (a cholinergic agonist) at specific doses, or of saline as a control. We found that the hypercalcemia-induced stimulation of pancreatic protein secretion was abolished after preadministration of CCK at large doses. After the prestimulus dose was decreased or the calcium dose was increased, however, the pancreatic secretory response to hypercalcemia was preserved. In contrast, the response to a submaximal dose of CCK was unchanged after prestimulation with a large dose of CCK. Similar results were obtained when urecholine instead of CCK was used as prestimulus. These findings indicate that loss of pancreatic responsiveness to hypercalcemia following prestimulation with CCK is dependent on doses of both prestimulus and calcium used, and that it is not specific for prestimulation with CCK but also inducible by cholinergic agonists. They further suggest that this phenomenon is not due to exhaustion of pancreatic secretory capacity, but may reflect decreased sensitivity to the hypercalcemic stimulus instead.

Contraindication for osmotic mini-pump in the abdominal cavity to study muscarinic cholinergic control of pancreatic enzyme secretion and muscarinic receptors

Alzet mini-pumps were used to study modulation of rat pancreatic muscarinic receptors and the acinic secretory response to long-term N-methylscopolamine (NMS) treatment. Infused intraperitoneally (i.p.), NMS, 25 mg.kg-1.day-1 for 14 days, resulted in a shift to the left in the amylase dose-response curve to carbamylcholine (Cch) and an increase in receptor concentration compared to saline-infused group. Compared to previously published control data [4,5] the saline-infused group exhibited desensitization with increased EC50 for secretion. An alternative mode of saline treatment, subcutaneous (s.c.) infusion showed normal pancreatic secretory response. Desensitization by i.p. saline infusion was prevented by NMS infusion. In conclusion, a foreign body such as a mini-pump in the abdominal cavity can cause desensitization of the pancreatic secretory function under neural cholinergic control.

Release of cholecystokinin and exocrine pancreatic secretion in response to an elemental diet in human subjects.

We investigated in human volunteers the effects of an elemental diet (ED) containing amino acids on release of endogenous cholecystokinin (CCK) using a highly sensitive and specific radioimmunoassay of CCK and exocrine pancreatic secretion using a dye dilution technique with polyethylene glycol 4000 as a nonabsorbable marker. Intrajejunal administration of ED at three different infusion rates (12.5, 25, and 50 ml/30 min) resulted in a significant increase in plasma CCK concentration in a dose-related manner. Plasma concentrations of gastrin or secretin, however, did not change. Pancreatic secretion of protein, amylase, and bicarbonate also increased significantly. The change in pancreatic secretion of protein, amylase, and bicarbonate output paralleled that of the circulating CCK level but not that of plasma secretin. Thus, the dose of amino acid contained in ED recommended for clinical use can significantly stimulate the release of CCK from the upper small intestine, raising the plasma concentration of CCK. This level can evoke a significant increase in exocrine pancreatic secretion.

A reduced pancreatic protein secretion in response to cholecystokinin (CCK) in the obese Zucker rat correlates with a reduced receptor capacity for CCK.

Pancreatic membrane receptors for cholecystokinin (CCK) in obese and nonobese Zucker rats were compared with the use of a biologically active [125I]iodo-CCK-8 radioprobe. Membrane homogenates from obese rats bound half the amount of radioligand in 2 h as did membranes from lean rats (specifically bound, 7.0% vs. 14.0%; P less than 0.001). The reduced binding in membranes from obese rats did not result from kinetic effects or radioligand degradation; similar rates of association and dissociation of [125I]iodo-CCK-8 were obtained in membrane preparations from both, and no differences were found in the extent of radioligand degradation in the two membrane preparations. These differences also did not reflect an effect of cell size, as pancreatic acinar cells from obese and nonobese rats had about the same perimeters (24.6 and 26.3 micron, respectively) and areas (30.1 and 34.2 micron 2, respectively). Scatchard-type plots of competitive displacement data for CCK-binding sites on pancreatic membranes from both genotypes were curvilinear and were analyzed by a two-site binding model. The Kd values for both the high (0.56 vs. 0.45 nM) and low (9.0 vs. 14 nM) affinity sites on membranes from nonobese and obese rats, respectively, were the same (P greater than 0.1), whereas the capacities for CCK in the high (365 vs. 165 fmol/mg protein) and low (1020 vs. 360 fmol/mg protein) affinity regions were significantly different (P less than 0.025). This difference in CCK receptor capacity was reflected by a reduced pancreatic protein secretory response in the obese rat. After injections of 40, 80, 160, and 320 ng CCK/kg BW, total pancreatic protein secretion in nonobese rats increased 5, 12, 19, and 21 times above basal levels, whereas the same doses caused 2-, 6-, 12-, and 13-fold increases in obese rats. Whereas the reduced secretion in the obese rat may reflect a difference in the intracellular machinery leading to protein secretion between the two genotypes, these data are more consistent with a direct mechanism, whereby reduced numbers of pancreatic receptors for CCK are responsible for reduced protein secretion.

Effect of atropine on rat pancreatic secretory response to trypsin inhibitors and protein.

The effect of atropine on the exocrine pancreatic secretory response to intestinally infused trypsin inhibitor and protein in conscious rats was investigated. Bile and pancreatic juice were collected and continuously returned to the intestine throughout all experiments. Ovomucoid trypsin inhibitor (OMTI) was infused at 1, 3, 6, 12, and 30 mg/h id, simultaneously with intravenously infused atropine (100 micrograms X kg-1 X h-1) or 0.15 M NaCl. Casein was infused at 300 mg/h id with or without intravenous atropine. Atropine inhibited basal pancreatic protein and fluid secretion 65.7 and 24.7%, respectively. Atropine had no effect on incremental (above basal) pancreatic protein and fluid output during infusion of maximally effective doses of OMTI (12 and 30 mg/h) and increased the incremental responses to submaximal doses of OMTI and to casein. The results are consistent with the hypothesis that cholecystokinin mediates negative feedback regulation by luminal proteases and that cholinergic mechanisms are not directly involved in this regulatory mechanism.

Dose-response effects of atropine on pancreatic secretory response to intravenous cerulein in dogs.

In conscious dogs with gastric and pancreatic fistulas, we studied the effect of i.v. atropine in doses ranging from 1.8 to 29 nmol/kg/h on the pancreatic secretory response to i.v. cerulein in doses ranging from 3.7 to 118 pmol/kg/h. Cerulein was given with an i.v. background infusion of secretin (20.5 pmol/kg/h), started 1 h before the lowest dose of cerulein was given. Secretin alone did not stimulate pancreatic protein output above basal. Doses of 7 and 29 nmol/kg/h of atropine significantly (p less than 0.05) decreased the protein output during secretin. A dose of 29 nmol/kg/h, but not lower doses, of atropine significantly inhibited the bicarbonate response to secretin. A dose of 3.7 pmol/kg/h and all higher doses of cerulein significantly stimulated bicarbonate and protein output above the value observed during secretin alone. None of the three doses of atropine given had any significant effect on the incremental bicarbonate and protein responses to cerulein. Secretin and cerulein did not alter basal heart rate; only the highest dose (29 nmol/kg/h) of atropine significantly increased heart rate. These findings are compatible with the hypothesis that cholinergic nerves do not alter the effect of exogenous cerulein, a CCK analogue, on pancreatic bicarbonate and protein secretion in dogs.

Physiological role and localization of cholecystokinin release in dogs.

In dogs with pancreatic fistulas, meat feeding and intestinal perfusion with a sodium oleate or amino acid mixture increased pancreatic protein secretion to approximately 110, 100, and 50%, respectively, of the response to cholecystokinin (CCK) at a dose of 85 pmol X kg-1 X h-1. Plasma CCK response increased in these studies to approximately 100, 180, and 40%, respectively, of the value obtained with exogenous CCK, suggesting that, in addition to CCK, other neurohormonal factors contribute to pancreatic enzyme secretion in response to endogenous stimulants. Feeding and duodenal oleate or amino acids also stimulate the release of pancreatic polypeptide (PP), which may be involved in the control of pancreatic secretion in response to endogenous stimulants, including CCK. Perfusion of the intact intestine with graded amounts of oleate (0.5-16 mmol/h) produced dose-dependent increments in plasma CCK and pancreatic protein similar to those obtained with intravenous infusion of graded doses of CCK (0.85-255 pmol X kg-1 X h-1). Oleate perfusion of isolated Thiry loops (30 cm long) made of duodenojejunal (D-J) and ileal (I) segments also stimulated protein secretion but elevated plasma CCK only after perfusion of the D-J but not of the I loop. We conclude that 1) the endogenous CCK released by various luminal stimulants drives the pancreatic protein secretion; 2) the release of CCK is confined to the foregut; and 3) PP concomitantly released by various intestinal stimulants may contribute to the control of pancreatic secretion induced by endogenous CCK.

Action of atropine on the pancreatic secretory response to secretin before and after cutting the extrinsic nerves of the pancreas in dogs

In two sets of dogs with gastric and pancreatic fistulas, we studied the effect of atropine on the pancreatic secretory response to intravenous secretin before and after cutting the extrinsic nerves of the pancreas, i.e., celiac and superior mesenteric ganglionectomy alone or truncal vagotomy plus celiac and superior mesenteric ganglionectomy. Neither truncal vagotomy alone nor ganglionectomy alone, nor the two together, altered the incremental bicarbonate response to secretin. Irrespective of the degree of integrity of the extrinsic vagal and splanchnic innervation of the pancreas, intravenous atropine (14 nmol/kg · h) significantly (p < 0.05) depressed the incremental bicarbonate responses to the two lowest (5.2 and 10.3 pmol/kg · h) doses of secretin by 85% and 61%, respectively, but had no significant effect on responses to high doses. We conclude that the pancreatic bicarbonate response to secretin, and the action of atropine on that response, are independent of an intact extrinsic innervation of the gland. The observation of the persistent inhibitory action of atropine after extrinsic denervation of the pancreas is compatible with the hypothesis that endogenous cholinergic activity augments the pancreatic bicarbonate response to secretin.

What is the maximal effective dose of caerulein in stimulating pancreatic secretion in man?

The pancreatic exocrine secretory response to increasing doses of exogenous caerulein with and without a background infusion of secretin was studied in 5 healthy volunteers. Caerulein over a full range of doses (2.3-37 pmol/kg/h) produced increasing enzyme secretion up to 18.5 pmol/kg/h, whereas 37 pmol/kg/h was clearly supramaximal and caused submaximal enzyme release. We conclude that maximal pancreatic enzyme secretion is achieved with lower caerulein doses than generally used in pancreatic function tests.

Effect of Diversion of Bile-Pancreatic Juice to the Ileum on Pancreatic Secretion and Adaptation in the Rat

Cannulas were implanted to collect bile and pancreatic juice, and the collected secretions were pumped back into the intestine at the level of the duodenum or the proximal ileum. The effect of 6 days of such treatment on pancreatic secretion and on pancreatic growth was determined. The effect on pancreatic secretion was studied by measuring the pancreatic secretory response to a stimulus, provided by acute diversion of bile-pancreatic juice from the proximal intestine. Trophic effects were studied in a separate group of rats by measuring pancreatic weight, protein content, and chymotrypsin activity after an overnight fast. Stimulated pancreatic secretion was 2.1 times greater for protein output and 3.4 times greater for fluid output in rats with chronic diversion of bile-pancreatic juice to the ileum. Pancreatic weight, protein content, and chymotrypsin activity were increased 2.6, 2.9, and 4.8 times, respectively, by chronic diversion of bile-pancreatic juice to the ileum. These results indicate that pancreatic hypertrophy and hyperplasia reported in rats with bile-pancreatic duct transposition to the ileum are the result of loss of feed-back inhibition from bile-pancreatic juice in the proximal intestine.

Dose-response effects of atropine on pancreatic response to secretin before and after truncal vagotomy.

In dogs with gastric and pancreatic fistulas, we studied the effect of intravenous atropine in doses ranging from 0.9 to 58 nmol X kg-1 X h-1 on the pancreatic secretory response to secretin before and after truncal vagotomy. Truncal vagotomy did not alter the incremental bicarbonate response to secretin. Before and after truncal vagotomy, 7 nmol X kg-1 X h-1 and all higher doses of atropine sulfate significantly decreased the bicarbonate response to low doses (5.2 and 10.3 pmol X kg-1 X h-1) of secretin but had no significant effect on responses to high doses (20.5 and 41 pmol X kg-1 X h-1). The inhibitory potency of the effective doses of atropine did not differ significantly. Secretin did not stimulate pancreatic protein output above basal. Truncal vagotomy reduced protein output basally and during secretin by about 50%. Before and after truncal vagotomy, 7 nmol X kg-1 X h-1 and all higher doses of atropine significantly decreased protein output basally and during secretin. Secretin and truncal vagotomy did not alter basal heart rate. Only the three highest doses (14, 29, and 58 nmol X kg-1 X h-1) of atropine significantly increased heart rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Can Plasma Human Pancreatic Polypeptide Be Used To Detect Diseases of the Exocrine Pancreas?

Plasma concentrations of human pancreatic polypeptide (HPP) parallel exocrine pancreatic secretion in response to stimulation with cholecystokinin. We determined prospectively the relationships among fasting HPP level, integrated HPP response to infusion of cholecystokinin, and output of trypsin and also the sensitivity, specificity, and predictive values of the fasting HPP level in the diagnosis of exocrine pancreatic disease. Our study group consisted of 19 patients with acute pancreatitis, 17 with chronic pancreatitis, and 25 with ductal adenocarcinoma of the pancreas and 27 control subjects. In the control patients and those with chronic pancreatitis, significant correlations were detected between HPP level and output of trypsin (P less than 0.001) in response to infusion of cholecystokinin and between fasting HPP and integrated HPP levels (P less than 0.004); no correlation was detected between HPP level and steatorrhea. The sensitivity, specificity, and negative and positive predictive values of the fasting HPP level for detection of either chronic pancreatitis or pancreatic cancer were similar and approximated 0.88, 0.67, 0.88, and 0.66, respectively. The HPP concentration had no value in detecting acute pancreatitis. Because the fasting HPP level has a high degree of negative predictability and is simpler to measure than the integrated HPP level or the output of trypsin, it may be a useful test in patients suspected of having either chronic pancreatitis or pancreatic cancer. A fasting HPP level of 125 pg/ml or greater could be used to exclude chronic pancreatitis or pancreatic cancer, but the finding of a value of less than 125 pg/ml necessitates use of other diagnostic tests for reliable determination of the presence of these diseases.

The relationship of insulin production to glucose metabolism in severe sepsis.

Basal glucose metabolism was evaluated in eight stable, infected patients by measuring hepatic glucose production rates in relation to stress endocrine profile and by comparing these data to five injured, noninfected patients. All patients exhibited normal total-body oxygen consumptions and cardiac indices. Fasting basal insulin values were similar in both groups (6 microU/cc) despite a significantly higher plasma glucose level in septic patients (106 +/- 14 mg/dL) compared to nonseptic patients (88 +/- 10 mg/dL). Septic patients exhibited splanchnic glucose production and calculated glucose clearance rates, 53% and 34% higher, than injured nonseptic patients, respectively. In addition, septic patients exhibited a decreased pancreatic insulin secretory response to an intravenous glucose tolerance test as evidenced by a significantly depressed peak insulin value (17 microU/cc) relative to injured patients (77 microU/cc). These findings indicate that insulin suppression is evident in sepsis even in the absence of shock and suggest that sepsis-related basal hyperglycemia does not appear to be associated with peripheral insulin resistance.

Effects of verapamil on exocrine pancreatic secretion in man.

Calcium ions are thought to mediate hormonal and cholinergic stimulation of exocrine pancreatic secretion. In order to further eludicate the role of calcium ions in stimulus-secretion coupling of the pancreas, the effect of the calcium antagonist verapamil, which inhibits transmembrane calcium influx, was studied on pancreatic secretion in 35 healthy male volunteers. Every subject had two stimulation periods of 2 hr each with a 3-hr period between the two. Pancreatic secretion was stimulated by cholecystokinin in 12 subjects, by secretin in 14 subjects, and by sham feeding in 6 subjects. Three subjects were studied without any secretory stimulus. Verapamil as an intravenous bolus of 150 micrograms/kg followed by an intravenous infusion of 150 micrograms/kg/hr or saline were given during the two 2-hr stimulation periods in a randomized order. The pancreatic secretory responses to stimulation by cholecystokinin, secretin, or sham feeding, as well as the basal pancreatic secretion without a secretory stimulus were left unaffected by verapamil when compared to the saline control. The results, therefore, call into question the hypothesis that transmembrane calcium influx is a major mediator of pancreatic secretion in response to hormonal or cholinergic stimulation in man.

Effect of aging on pancreatic secretion in rats

We have characterized the effects of aging on the pancreatic exocrine secretory response to the normal stimulatory hormones, secretin, and cholecystokinin. Young (6 month old) and aged (26 months old) male Sprague-Dawley rats were prepared with pancreatic fistulas and challenged with different doses of secretin (0.03, 0.06, and 0.12 nmol/kg) and cholecystokinin-8 (0.3, 0.6, and 1.2 nmol/kg) intravenously. The pancreatic secretion was measured for volume and bicarbonate and protein outputs. Our results show that in aged rats, the basal pancreatic secretion volume and protein and bicarbonate outputs were significantly reduced, and the pancreatic secretion volume and protein and bicarbonate responses to graded doses of secretin or cholecystokinin-8 were significantly reduced. This study demonstrates that pancreatic exocrine function in rats diminishes with age.

Inhibition of Pancreatic Secretory and Trophic Response to Caerulein by the H&lt;sub&gt;2&lt;/sub&gt;-Receptor Antagonist Ranitidine in the Rat

The effect of ranitidine (20 mg . kg-1) and cimetidine (50 mg . kg-1) on pancreatic secretory and trophic responses to caerulein (1 microgram . kg-1) was studied in the rat. Ranitidine or cimetidine were administered alone or combined with caerulein twice a day for 7 days. Saline-treated rats were used as controls. At the end of treatment animals were anesthetized and pancreatic juice was collected for 1 h after intravenous secretin plus CCK-PZ (8 U . kg-1). Afterwards rats were sacrificed and growth and composition of pancreatic tissue were determined. Compared with control (saline) values, volume of pancreatic juice and output of trypsin and amylase were increased by treatment with caerulein. Ranitidine, when given combined with caerulein, completely abolished the secretory response induced by the peptide, whereas it was totally ineffective when given alone. Cimetidine (alone or combined with caerulein) was always ineffective. Caerulein increased pancreatic weight, total pancreatic trypsin, amylase and RNA content. Here again ranitidine, combined with caerulein, abolished almost completely the trophic effect of caerulein on the pancreas, but when given alone it did not influence pancreatic growth and composition. Also in this case, cimetidine was completely inactive. These results suggest that ranitidine affects exocrine pancreas with an action independent of the H2-receptor blockade.

Pancreatic carcinogenesis-enhancement by cholecystokinin in the hamster-nitrosamine model.

The role of the pancreaticotrophic hormone cholecystokinin (CCK) in modifying the pancreatic response to carcinogen has been examined in the hamster-nitrosamine pancreatic cancer model. Exogenous CCK, 30 IDU kg-1, stimulated a maximal pancreatic secretory response when given intravenously and caused hypertrophy and hyperplasia of the pancreas when given subcutaneously over a period of 6 weeks (pancreatic wet weight, mg per 100 g body weight, controls 295.6 +/- 61; CCK treated 466.4 +/- 77, P less than 0.001). When the same dose of CCK was given to animals receiving N-nitrosobis (2-oxopropyl)amine (BOP; 5 mg kg-1 weekly) there was a reduction in latency period and increase in induction rate of tumour development (CCK + BOP vs. BOP alone, 12 animals with tumours vs. 2 at 15 weeks; P less than 0.02). These effects are consistent with CCK acting as a co-carcinogen or promoter of pancreatic carcinogenesis in this model.

Exocrine pancreatic secretion in response to a new CCK-analog, CCK33 and caerulein in dogs

We studied the relative molar potencies of a newly synthetized cholecystokinin nonapeptide [Thr 28,Nle 31]CCK[25–33], natural porcine CCK33 and synthetic caerulein in conscious dogs with chronic gastric and pancreatic fistulas. Peptides were dissolved in albumin-containing solutions to prevent loss from solution. The three peptides were found to be equipotent on a molar basis in stimulating exocrine pancreatic secretion. As [Thr 28,Nle 31]CCK9 is a peptide less susceptible to oxidation than other forms of CCK, it is an interesting analog with many uses for medical and biological research.