Inhibition Of Pancreatic Secretion Research Articles

High-dose intravenous glucocorticoid induces hyperamylasemia: a case series

BackgroundGlucocorticoids have many side effects, and high-dose intravenous application may cause rare adverse reactions such as hyperamylasemia. The aim of this study is to explore the clinical characteristics, treatment, and prognosis of hyperamylasemia induced by high-dose intravenous glucocorticoids.Case presentationFour Asian female patients, aged between 26 and 71 years, were diagnosed with hyperamylasemia after intravenous administration of high-dose glucocorticoid. Amylase levels were elevated to varying degrees in all patients, but the peaks were below three times the upper limit of normal, and imaging showed no significant pancreatic abnormalities. Two patients developed abdominal pain, which was resolved by inhibition of pancreatic secretion, while the other patients were asymptomatic. Two patients were discharged after a significant decrease in amylase levels, while the other two were discharged after improvement of the primary disease.ConclusionHigh-dose intravenous glucocorticoid can cause hyperamylasemia, which should be given enough attention by clinicians. Etiological differentiation of hyperamylasemia should be emphasized in clinical practice, especially when the diagnosis of acute pancreatitis is not clear.

Management of pancreatico-pleural fistula: 5 years of experience

Background: Pancreatico-pleural fistula is a rare entity with an incidence of 0.4% seen both in patients with acute and chronic pancreatitis or may follow traumatic and surgical disruption of the pancreatic duct. It presents as massive pleural fluid accumulation and has a high tendency to recur following treatment. Conservative management like inhibition of pancreatic secretion with octreotide and pancreatic duct stenting may help fistula closure in about 31 to 45% of cases. Surgical correction has high mortality up to 10% and but has increased fistula closure rate of 80-90%. Here we present our experience with pancreatico-pleural fistula. Methods: Data of patients admitted with pancreatico-pleural fistula from 2010-2015 in our department were retrospectively analysed. Ten patients were included in this analysis. The average age of presentation was 28.3 years. Results : There were 8 male and 2 female patients. Alcoholic pancreatitis - most common cause with chronic pancreatitis (80% n = 8), idiopathic pancreatitis (20% n=2). Mean hospital stay was 18 days; intercostal drainage and inj. octreotide were done in all patients; ERCP (n=5; In 4 patients successful PD stenting was done and in 1 patient could not be done; four patients required pigtail drainage for peripancreatic collection. Recurrence (20% n = 2); Surgery in 3; Mortality – nil. Conclusions: Pancreatico-pleural presents with significant morbidity but can be managed effectively with medical therapy and ERCP stenting in most of the patients. Surgery may be required for failed conservative therapy or for recurrences.

Hemodiafiltration Combined with Resin-Mediated Absorption as a Therapy for Hyperlipidemic Acute Pancreatitis

The aim of this study is to investigate whether hemodiafiltration combined with resin-mediated absorption is a better therapy for hyperlipidemic acute pancreatitis. Patients (n = 67) with acute pancreatitis treated in ICU from January 2009 to December 2012 were included in this study. Seven of these 67 cases were diagnosed hyperlipidemic acute pancreatitis (HLAP). All the 7 HLAP patients went through fast, gastrointestinal decompression, anti-shock treatment, inhibition of pancreatic secretion, antiseptic treatments, and hemoperfusion (HP) combined with continuous veno venous hemodiafiltration (CVVHDF). After one round of treatment by resin adsorption, there was a significant decrease in serum triglycerides (TG) (29.78 %) and total cholesterol (TC) (24.02 %) levels (p < 0.01). TG and TC levels dropped by 49.02 and 37.66 %, respectively, after 1-day treatment of HP + CVVHDF; by 62.81 and 47.37 % on day 2 post-treatment; and by 69.57 and 49.47 % on day 3 post-treatment. All the 7 patients survived. The average time spent in the ICU was 7 ± 3.8 days, and the average duration of hospitalization was 19 ± 15.1 days. Our results show that hemoperfusion combined with hemodiafiltration is an efficient treatment as this approach can reduce plasma lipid levels effectively and reduce the risk of acute pancreatitis due to hyperlipidemia.

Neurohumoral control of exocrine pancreatic secretion

Reports over the past year provide significant advances in our knowledge of the neurohumoral control of exocrine pancreatic secretion, especially related to human physiology. Major findings include those demonstrating that human pancreatic acinar cells do not respond to cholecystokinin stimulation and that a major circulating form of cholecystokinin is CCK-58. These findings establish that in humans, cholecystokinin causes pancreatic secretion via a neural circuit after interacting with neural sensory receptors in the mucosa of the intestine and that CCK-58 is the likely form of cholecystokinin that stimulates the neural pathways. Other findings demonstrate significant differences in the pancreatic secretory response in humans as a function of the type of nutrient delivered to the gut, especially the fact the elemental diets and medium-chain triglycerides cause much less stimulation of pancreatic secretion than do complex diets. Finally, convincing evidence demonstrating that pancreatic proteases cause inhibition of pancreatic secretion in humans has been presented. In addition to new insights into the neurohumoral control of pancreatic secretion, these findings provide information relevant to both the pathogenesis of pancreatic disorders and their treatment.

Endogenous nitric oxide mediates pancreatic exocrine secretion stimulated by secretin and cholecystokinin in rats.

Nitric oxide (NO) is one of the important biologic mediators in regulation of gastrointestinal (GI) functions, but the influence of NO on the release of secretin and cholecystokinin (CCK) and exocrine pancreatic secretion has not been adequately investigated in the rat. The aim of this study was to determine the role of NO on endogenous and exogenous secretin- or CCK-stimulated pancreatic exocrine secretion both in anesthetized and conscious rats. Experiments were carried out in four different groups of rats with duodenal pancreatobiliary cannulas and jugular vein catheters. Group 1: During duodenal infusion of 0.05N HCl or 15% casein (pH 7.0), N-nitro-L-arginine (NNA), an inhibitor of NO-synthase in graded doses (2.5, 5, 10 mg/kg/h), was infused intravenously. Group 2: One hour after starting intravenous secretin at 5 pmol/kg/h or intravenous CCK-8 at 0.06 microg/kg/h, NNA in graded doses was administered intravenously. Group 3: In conscious rats, NNA (5 mg/kg/h) was given intravenously for 1 hour after a meal. Group 4: L-Arginine at 100 mg/kg/h was infused intravenously during the period of NNA (5 mg/kg/h) infusion in groups 1, 2, and 3. Pancreatic juice was collected at 30-minute intervals to measure volume, as well as output of bicarbonate and protein. At the end of the experiment, plasma secretin, vasoactive intestinal polypeptide (VIP) and CCK levels were determined by radioimmunoassay (RIA). NNA dose dependently inhibited the pancreatic secretion of fluid and bicarbonate stimulated by duodenal acidification, exogenous secretin, and a meal. NNA dose dependently inhibited the pancreatic secretion of protein stimulated by duodenal infusion of casein, exogenous CCK, and a meal. L-Arginine significantly reversed the NNA-induced inhibition of pancreatic secretion in all experiments. NNA did not alter significantly the plasma levels of secretin, VIP, and CCK. Our results indicated that endogenous NO plays a significant role in the regulation of pancreatic exocrine secretion stimulated by secretin and CCK. However, NO does not influence the release of secretin, VIP, or CCK in the rat.

PYY regulates pancreatic exocrine secretion through multiple receptors in the awake rat.

Peptide YY (PYY) is one of several regulatory peptides reported to modulate pancreatic secretion. PYY circulates in two forms, PYY1-36 and PYY3-36, and binds to multiple receptor subtypes. We sought to determine if PYY1-36 or PYY3-36 regulates neurally mediated pancreatic secretion through the Y1, Y2, and/or Y5 receptor subtypes. Experiments were conducted in awake, surgically recovered rats. In order to determine the effects of the PYYs on basal pancreatic secretion, either PYY1-36, [Pro34] PYY1-36 (a Y1/Y5 agonist), or PYY3-36 (a Y2/Y5 agonist) were infused for 40 min at doses of 0, 12.5, 25, or 50 pmol/kg/hr while measuring pancreatic juice volume and protein. PYY1-36 increased pancreatic protein secretion at 25 and 50 pmol/kg/hr (P < 0.05) in a dose-dependent manner (P < 0.001, R2 = 0.990). The Y2/Y5 receptor agonist PYY3-36 significantly inhibited pancreatic juice volume and protein at 12.5 and 25 pmol/kg/hr, but stimulated protein secretion at higher doses (P < 0.001, R2 = 0.995). The Y1/Y5 agonist, [Pro34] PYY1-36, had no significant effect on basal pancreatic exocrine secretion. Therefore, PYY1-36, PYY3-36 and [Pro34] PYY1-36 produced different, dose-dependent changes on basal pancreatic exocrine secretion. Inhibition of pancreatic secretion by circulating PYY1-36 and PYY3-36 are primarily mediated by the Y2 receptor. Since [Pro34] PYY1-36 did not change pancreatic secretion, it can be concluded that circulating PYY1-36 or PYY3-36 does not modulate pancreatic secretion through the Y1 or Y5 receptors. Since the stimulatory effects of PYY1-36 on pancreatic secretion could not be explained by the actions of PYY3-36 or [Pro34] PYY1-36 on Y1 or Y2 receptors, and since PYY1-36 fails to bind to Y3 or Y4 receptors, we also conclude that PYY1-36 may stimulate pancreatic secretion in a dose-dependent mechanism through a PYY receptor subtype different from Y1, Y2, Y3, Y4 or Y5.

Chronic pancreatitis: complications and management.

Chronic pancreatitis is characterized by progressive and irreversible loss of pancreatic exocrine and endocrine function. In the majority of cases, particularly in Western populations, the disease is associated with alcohol abuse. The major complications of chronic pancreatitis include abdominal pain, malabsorption, and diabetes. Of these, pain is the most difficult to treat and is therefore the most frustrating symptom for both the patient and the physician. While analgesics form the cornerstone of pain therapy, a number of other treatment modalities (inhibition of pancreatic secretion, antioxidants, and surgery) have also been described. Unfortunately, the efficacy of these modalities is difficult to assess, principally because of the lack of properly controlled clinical trials. Replacement of pancreatic enzymes (particularly lipase) in the gut is the mainstay of treatment for malabsorption; the recent discovery of a bacterial lipase (with high lipolytic activity and resistance to degradation in gastric and duodenal juice) represents an important advance that may significantly increase the efficacy of enzyme replacement therapy by replacing the easily degradable porcine lipase found in existing enzyme preparations. Diabetes secondary to chronic pancreatitis is difficult to control and its course is often complicated by hypoglycaemic attacks. Therefore, it is essential that caution is exercised when treating this condition with insulin. This paper reviews recent research and prevailing concepts regarding the three major complications of chronic pancreatitis noted above. A comprehensive discussion of current opinion on clinical issues relating to the other known complications of chronic pancreatitis such as pseudocysts, venous thromboses, biliary and duodenal obstruction, biliary cirrhosis, and pancreatic cancer is also presented.

Inhibition of pancreatic exocrine secretion via vagal afferent nerve after short-term pancreatic duct occlusion in conscious rats

The basal pancreatic exocrine secretion was maintained at a constant level in conscious rats, and transient pancreatic duct occlusion (PDL) such as 0.5-h, did not affect pancreatic secretion, although long-term PDL produced pancreatic damage. In the present study, we examined how long PDL continued, pancreatic secretion was affected, and whether the changes in secretions were reversible. Methods: Male Wistar rats (300-330g) were prepared with cannulae draining bile-pancreatic juice (BPJ) separately and with a duodenal cannula. Rats were placed in restraint cages and experiments were conducted 4 days after the operation without anesthesia. BPJ were collected every 30-min, and previously collected bile and 7 mg/ml of porcine trypsin were mixed and infused (1 ml/h) into the duodenum instead of BPJ to avoid feedback hypersecretory response and to maintain the basal secretion level (Miyasaka et al. Gastroenterology 1993). After 2-h basal collection, pancreatic cannula was stuffed with patty and the pancreatic secretion was interrupted for 0.5, 1, 2, 3, 4-h. Then, the patty was removed after the respective time periods, and the collection of pancreatic juice was started again for following 2-4-h. In some animals, bilateral vagotomy or capsaicin treatment was conducted. The changes in fluid, bicarbonate and protein secretion were measured, the plasma CCK levels, and the pancreatic histology were examined. Results: The pancreatic secretion was constant and the plasma CCK levels did not increase throughout the experimental period. Pancreatic secretion following the 0.5-2h PDL was comparable for the basal secretion. 3 and 4-h PDL significantly inhibited secretion after the removal of PDL, and the inhibition remained for 2-3-h, then recovered to the basal level. No pathological finding by HE staining after 3,4-h of PDL was observed. Both vagotomy and capsaicin treatment abolished the inhibition produced by 3,4-h PDL. Conclusion: It is speculated that auto-regulation via vagal nerve system may work to inhibition of pancreatic secretion when the pancreatic duct was occluded.

Intensive care management of acute pancreatitis

Acute pancreatitis is characterized by an intense inflammatory process which leads to early widespread organ dysfunction and late local complications. Currently, for the 80% of patients who suffer a moderate attack, management is largely supportive. The remaining 20% who develop severe pancreatitis have an increased risk of major complications which may require intensive care management. In these patients both general supportive and some specific therapeutic measures may be necessary. General measures include restoration and maintenance of plasma volume, respiratory, renal and nutritional support, analgesia and antibiotics. Specific measures, such as inhibition of pancreatic secretion or pancreatic enzyme activation, have not been successful in clinical trials. However, most of these studies have included small numbers of patients with moderate pancreatitis. Further evaluation of this approach is required with larger numbers and sicker patients. When bacterial infection of pancreatic necrosis becomes evident, surgical intervention should be considered. This includes percutaneous drainage, endoscopic removal of impacted gallstones and aggressive surgery for necrosis.

Effect of vagotomy on the feedback inhibition of pancreatic secretion

Chronic experiments on fistulized dogs showed that the pancreatic secretion stimulated by intraduodenal administration of acidified hydrolysine was depressed after bilateral supradiaphragmatic truncal vagotomy, and that the inhibitory influence of exogenous pancreatic enzymes on pancreatic secretion disappeared on postoperative days 10–16. Subsequently, the feedback inhibition of pancreatic secretion was slowly restored, but even 45 days after vagotomy it was still weaker than in intact dogs. It is concluded that the feedback inhibition of pancreatic secretion is centrally controlled from the duodenum via the vagus nerves.

Inhibition of pancreatic secretion under long-term octreotide treatment in humans.

The somatostatin analogue octreotide (SMS 201-995) is a potent inhibitor of human exocrine pancreatic secretion. In the present study we analyzed the effect of octreotide (3 x 100 micrograms, daily) given over a time period of 7 days on hormone-stimulated exocrine pancreatic secretion in 6 healthy volunteers using a secretin-ceruletide test. The secretin-ceruletide test was carried out before, following the first injection of octreotide (day 1) and after a 7-day treatment with 3 x 100 micrograms octreotide daily. Duodenal fluid was collected over 30 min without stimulation, over 60 min following a bolus injection of 1 U/kg body weight secretin, and over 60 min during a continuous infusion of secretin and ceruletide. Following the first injection of octreotide and following 7 days of octreotide treatment secretin/ceruletide-stimulated amylase secretion was significantly reduced. Trypsin and chymotrypsin secretion was significantly reduced after the first injection of octreotide when pancreatic secretion was stimulated by secretin and ceruletide simultaneously. However, secretin and ceruletide-induced trypsin and chymotrypsin secretion was not inhibited after 7 days of octreotide treatment. Baseline, secretin and secretin/ceruletide-stimulated bicarbonate output were not influenced by octreotide either following the first injection of octreotide or the 7 days' treatment. Octreotide is a potent inhibitor of secretin/ceruletide-stimulated pancreatic amylase, trypsin and chymotrypsin secretion. However, following a 7-day treatment with octreotide this inhibition is only persistent for pancreatic amylase secretion.

Peptide-YY, a New Partner in the Negative Feedback Control of Pancreatic Secretion*

Peptide YY (PYY), a newly discovered ileocolonic peptide, is released by nutrients in the proximal and distal intestine and inhibits pancreatic secretion. However, it is not clear whether PYY can be released in the absence of nutrients in the intestine or whether a physiological role exists for endogenous PYY in negative feedback regulation of pancreatic secretion by pancreatic proteases. In the present study we measured plasma PYY concentrations and determined the effects of anti-PYY serum during stimulation of pancreatic secretion by pancreatic juice diversion (PJD). The effect of SMS 201-995 (SMS; an analog of somatostatin), another inhibitor of pancreatic secretion, on regulation of PYY release induced by PJD was also investigated. Male Wistar rats equipped with pancreatic, biliary, duodenal, and jugular venous cannulas were studied 4-6 days postoperatively. After 90 min of basal collection, pancreatic juice was diverted for 4 h with or without infusion of SMS (2 micrograms/kg.h), given either iv or intraduodenally (ID). Plasma PYY concentrations were significantly increased from a basal level of 177 +/- 15 pg/ml to a peak level of 328 +/- 43 pg/ml 2 h after PJD. These increases in PYY concentration paralleled those in pancreatic protein and fluid outputs. Both iv and ID infusion of SMS during the first 2 h of PJD markedly decreased the plasma PYY concentration to 134 +/- 27 pg/ml and 156 +/- 19 pg/ml, respectively; the total incremental PYY release during 4 h of PJD was inhibited by 100% and 84% by iv and ID SMS, respectively. One milliliter of anti-PYY serum given iv significantly augmented the increment in protein and fluid output during PJD. These results suggest that endogenous PYY released by PJD may play a physiological role in negative feedback regulation of pancreatic secretion in rats.

Somatostatin Analog, SMS 201-995, Inhibits Pancreatic Exocrine Secretion and Release of Secretin and Cholecystokinin in Rats

We studied the effect of a synthetic octapeptide somatostatin analog, SMS 201-995 (sandostatin), on pancreatic exocrine secretion and on plasma secretin and cholecystokinin (CCK) levels in vivo in anesthetized rats. The exocrine pancreas was stimulated by either intravenous infusion of both secretin (0.06 CU/kg/h) and cholecystokinin octapeptide (CCK-8) (0.03 micrograms/kg/h) or intraduodenal infusion of oleic acid (pH 6.5) in a dose of 0.25 mmol/h. Intravenous administration of SMS 201-995 in three different doses of 100, 200, and 400 ng/kg/h resulted in dose-related inhibition of pancreatic secretion in terms of volume, bicarbonate, and amylase stimulated by exogenous secretin and CCK. Intraduodenal oleic acid stimulated pancreatic secretion, including volume, bicarbonate, and amylase, and this was accompanied by a significant elevation in the plasma concentrations of secretin and CCK. Intravenous administration of SMS 201-995 in the three different doses described above caused dose-dependent suppression of the increase in pancreatic exocrine secretion as well as the plasma concentration of secretin and CCK induced by intraduodenal infusion of oleic acid. It is concluded that SMS 201-995 inhibits pancreatic exocrine secretion and the release of endogenous hormones, such as secretin and CCK, in rats.

Characterization of saturable binding sites for circulating pancreatic polypeptide in rat brain

Pancreatic polypeptide (PP) inhibits pancreatic exocrine secretion by indirect mechanisms that may be centrally mediated. The central site of action of PP that results in inhibition of pancreatic secretion has not been identified. Using autoradiography to identify 125I-PP binding to frozen sections of rat brain, we have identified saturable, high-affinity PP receptors in high concentrations in the interpenduncular nucleus, area postrema (AP), nucleus tractus solitarius, and dorsal motor nucleus of the vagus. The PP receptor differs from neuropeptide Y and peptide YY receptors in its binding specificity and location. Because PP is not produced in the brain, and the blood-brain barrier (BBB) excludes circulating peptides from most areas in the brain, we employed an in vivo radioreceptor assay to determine whether circulating PP binds to areas such as the AP that has both an incomplete BBB and a high concentration of PP receptors. 125I-PP and 131I-bovine serum albumin were infused simultaneously into rats through a peripheral vein with or without excess unlabeled PP. After 10 min, rats were killed and the brains were removed and cut into eight regions based on the autoradiographic localization of PP receptors. There was a significant (P less than 0.02) increase in saturable radiolabeled PP accumulation in the region that included the AP, demonstrating that circulating PP can bind to this area of the brain in vivo. PP is released into the circulation after a meal via mechanisms that exhibit vagal and cholinergic dependence. We speculate that PP completes a feedback loop by binding to receptors in the AP and interacting with the adjacent vagal nuclei to inhibit vagal activity.

Meal‐induced peptide tyrosine tyrosine inhibitor of pancreatic secretion

Meal‐induced peptide tyrosine tyrosine inhibitor of pancreatic secretion

Inhibitory effect of high caloric load of carbohydrates or lipids on human pancreatic secretions: a jejunal brake

Effects of jejunal infusion of a saline solution, a protein meal, and a mixed protein and carbohydrate meal on biliopancreatic secretions were compared in six healthy volunteers. Protein infusion stimulated biliopancreatic secretions whereas carbohydrate infusion inhibited these secretions compared with saline infusion. The roles of lipid, carbohydrate, and caloric load on the inhibition of pancreatic secretions by jejunal infusion of nutrients was investigated in six other healthy volunteers. Carbohydrate, lipid, and the mixed meal inhibited pancreatic secretions whereas the carbohydrate solution was the only one that inhibited biliary secretion. These studies indicate that the mechanism of jejunal brake seems mainly related to the jejunal caloric load. In malabsorption or in the short bowel syndrome, a high caloric load or unabsorbed nutrients in the jejunum further inhibits pancreatic secretion, contributing to the loss of nutrients from the intestinal tract.

Regulation of Pancreatic Enzyme Secretion in Conscious Rats by Intraluminal Somatostatin: Mechanism of Action*

These studies were undertaken to characterize 1) the immunoreactive somatostatin (SS) forms found in the gastrointestinal lumen and 2) to assess the possible role of luminal SS on pancreatic exocrine function. Results indicate that different forms of SS are secreted into the rat gastric and duodenal lumen in proportions corresponding to their gastric and duodenal contents. Inhibition of diversion-stimulated pancreatic exocrine secretion by intraduodenal infusion of SS (SS-ID) is dose dependent with a maximal effective dose of 24 micrograms/kg-1h-1 for volume and 48 micrograms/kg-1h-1 for protein output. Infusion of supramaximal doses result in a loss of the inhibitory effect of SS-ID on both volume and protein outputs. Comparison between inhibition of pancreatic secretion by iv SS (SS-IV) and SS-ID indicates that SS-ID is about 20 times less potent than SS-IV in its inhibition of stimulated pancreatic exocrine secretion. Intraileal (SS-IL) infusion of SS at 48 micrograms/kg-1h-1 did not inhibit stimulated pancreatic secretion but was rather stimulatory possibly through the inhibition of putative ileal inhibitors. Likewise, passive immunization against circulating SS did not affect the inhibitory effects of SS-ID on pancreatic secretion. These data indicate that SS is secreted into the rat gastrointestinal lumen and that its infusion into the duodenal lumen inhibits stimulated pancreatic secretion in a dose-dependent fashion. The observation that SS-IL did not inhibit pancreatic secretion and that passive immunization against circulating SS did not affect the inhibitory effect of SS-ID suggest that the action of SS-ID on stimulated exocrine pancreatic secretion is probably indirect and may involve a duodenal signal, possibly an inhibition of endogenous release of cholecystokinin and/or secretin.

Inhibitory regulation of rat exocrine pancreas by peptide YY and pancreatic polypeptide

Peptide YY (PYY) and pancreatic polypeptide (PP) have been shown to inhibit exocrine pancreatic secretion in vivo in a variety of species. This study evaluates the type of stimulation inhibited by PYY and PP by examining, in urethan-anesthetized rats, the inhibition of pancreatic secretion when stimulated to a comparable extent by cholecystokinin (CCK), 2-deoxy-D-glucose (2DG), bethanecol, and electrical vagal nerve stimulation. PYY at maximal infusion rates inhibited stimulation by CCK by 83%, bethanecol by 55%, and electrical nerve stimulation by 40%. The inhibition of CCK stimulation was half maximal at 250 pmol.kg-1.h-1. By contrast, PYY totally inhibited 2DG-stimulated secretion with half-maximal inhibition at 10 pmol. kg-1.h-1. PP acted similarly to PYY in inhibiting CCK and 2DG-stimulated pancreatic protein secretion but was fivefold weaker in each case. These findings indicate that PYY and PP have multiple actions but preferentially inhibit neurally mediated pancreatic secretion at a preacinar cell locus, possibly at a central site of action.

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

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 HCO3- 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 HCO3- secretion and equipotent in reducing protein secretion, but SMS 201-995 was only about half as potent as somatostatin in inhibiting HCO3-. 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 HCO3- 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 HCO3- 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.

Immunoneutralization of circulating pancreatic polypeptide and pancreatic secretion.

To determine the role of endogenous pancreatic polypeptide (PP) as a physiological inhibitor of pancreatic secretion, normal rabbit serum (control) or rabbit PP-antiserum was administered intravenously to dogs with chronic esophageal, gastric, and pancreatic fistulas. In all dogs tested, sham-feeding and ordinary feed with a meat meal resulted in a marked rise in the plasma level of immunoreactive PP that coincided with an increase in the exocrine pancreatic secretion of HCO3- and protein. After intravenous administration of PP antiserum, endogenous plasma PP was almost completely bound by infused antibodies to PP, whereas no such binding was detected after infusion of normal rabbit serum. In contrast, plasma gastrin remained unchanged both under basal and stimulated conditions. Immunoneutralization of PP, released endogenously, failed significantly to affect gastric acid and pancreatic protein responses to sham-feeding and the pancreatic HCO3- and protein responses to feeding a meat meal in chronic pancreatic fistula dogs. However, the PP antiserum abolished, in part, the inhibitory effect of exogenous PP on pancreatic secretion stimulated by exogenous hormones. We conclude that endogenous PP is not a physiological inhibitor of exocrine pancreatic secretion, as has been suggested previously.