Infusion Of Secretin Research Articles

Potential methodologic problems with in vivo immunoneutralization of pancreatic polypeptide.

Dogs with chronic pancreatic fistulae were given 0.5 ml of nonimmune rabbit serum or antibody S5, an antibody raised against the C-terminal pancreatic polypeptide (PP) hexapeptide. A 3-h infusion of secretin (125 ng/kg/h) and CCK8 (50 ng/kg/h) was started 30 min after injecting serum. Exogenous BPP (400 pmol/kg/h) was administered during the middle secretin/CCK hour. In a second protocol, 30 min after injecting nonimmune serum or PP-anti-serum, the animals were fed 15 g/kg cooked ground beef. Pretreatment with S5 enhanced secretin/CCK-induced bicarbonate outputs; protein outputs did not differ. Exogenous BPP inhibited pancreatic secretion, even in S5-treated animals. Meal-induced pancreatic secretion was not altered by S5 pretreatment. Significant increments in PP were measured by radioimmunoassay during administration of secretin/CCK and during BPP infusion. Anti-PP pretreatment abolished the former and significantly decreased, but did not abolish, the latter. The meal evoked significant postprandial increments in PP which were essentially abolished following S5 pretreatment. A physiological role for PP cannot be proved or refuted because antiserum pretreatment failed to block the effects of exogenous hormone. The latter must be established before excluding a peptide's physiological role based on negative in vivo immunoneutralization data.

Localization and resection of gastrinomas in Zollinger-Ellison syndrome.

From 1971-1986, 24 patients were diagnosed as having Zollinger-Ellison syndrome (ZES) and 22 patients had laparotomy. Of this group, gross tumor was identified in 15 of 22 patients. Ten of 15 patients had resection of their gastrinomas with the specific aim of curing the disease. This group had responded favorably to either cimetidine or ranitidine before operation. Preoperative transhepatic portal venous sampling (PVS) with gastrin determinations was performed in six patients; three patients had this procedure twice. The tumor was correctly localized by PVS in five of six patients. In four of six patients, the tumor was easily found at surgery. In two of six patients (33%) PVS was vital to intraoperative decisions. Criteria for biochemical cure are normal periodic fasting gastrin and secretin infusion tests. Of the 10 patients who had resection for potential cure, two patients failed within 48 hours of surgery on the basis of an elevated fasting serum gastrin level in one patient and a positive secretin infusion test in the other patient. Eight patients were considered cured with follow-up from 6 months through 15 years. Of the eight cured patients, the tumors were located as follows: four were extraintestinal and extrapancreatic, four were in the duodenal wall, one patient had a tumor located in the uncinate process of the pancreas, and one tumor was located in a lymph node along the lesser curve of the stomach. Two patients had mobilization of the pancreas and duodenum for a "blind" pancreatoduodenectomy based on preoperative PVS (2 procedures each patient). In one patient a 3-mm gastrinoma was enucleated from the posterior uncinate process. The second patient had pancreatoduodenectomy with findings of two duodenal wall gastrinomas. Both patients remained cured of ZES beyond 2 years. It is concluded that PVS does indeed locate some tumors before operation, even those not easily found at surgery. ZES can be cured by an aggressive approach combining preoperative tumor localization and tumor resection. Of the eight patients biochemically and perhaps biologically cured, follow-up was greater than four years in five patients, greater than two years in two patients, and beyond six months in one patient.

Mechanical factors regulating gastric emptying examined by the effects of exogenous cholecystokinin and secretin on canine gastroduodenal motility.

The aim of this study was to elucidate the variables of gastroduodenal motility determining gastric emptying. For this purpose the effects of exogenous cholecystokinin, secretin, and gastric inhibitory polypeptide on motility and gastric emptying were studied during a meal. Motility was measured with extraluminal strain gage force transducers and induction coils in unanaesthetized dogs. The pyloric diameter and the duodenal lumen were evaluated from radiographs. Gastric emptying of an acaloric cellulose meal was determined radiographically. When compared with control infusion of saline, cholecystokinin (1.7 Ivy units X kg-1 X h-1) and secretin (1.7 clinical units X kg-1 X h-1) delayed gastric emptying and diminished the force of the antral contractions, the force and frequency of the duodenal contractions, and opening of the pylorus. The contractile patterns of the duodenum were changed from propulsive to segmenting activity. Cholecystokinin additionally diminished the duodenal lumen. In contrast, gastric inhibitory polypeptide (1.5 microgram X kg-1 X h-1) did not influence gastroduodenal motility and gastric emptying. It is concluded that the motility parameters that were significantly altered by cholecystokinin and secretin are involved in the control of gastric emptying, while other parameters that remained unchanged play a minor role in the regulating process.

Effect of chronic bombesin on pancreatic size, composition and secretory function in the rat.

Bombesin administered subcutaneously to rats, three times daily for four days, induces pancreatic growth at a dose of 10 micrograms/kg. Growth was characterised by an increased pancreatic weight and content in protein and RNA, accompanied by cellular hypertrophy. Chronic bombesin also enhanced the pancreatic content in chymotrypsin and to a lesser degree its contents in amylase and lipase. The volume of the secretion and the output of enzymes in response to CCK under an infusion of secretin, however, remained unchanged although the functional capacity of individual cells to secret amylase and lipase was reduced. It is concluded that chronic bombesin exerts a trophic action on the rat pancreas but decreases the sensitivity of each cell to hormonal stimulation.

The significance of plasma CCK and secretin in the oleate-stimulated pancreatico-biliary secretion in man

In eight normal persons the plasma levels of secretin and cholecystokinin (CCK) measured after intraduodenal oleate were reproduced by intravenous (i.v.) infusion of synthetic secretin (3.4 pmol.kg-1.h-1) and CCK-8 (17.5 pmol.kg-1.h-1), either alone or in combination. Using an indicator dilution technique, the combined infusions of the two hormones were found to account for all the pancreatico-biliary secretion of amylase, bicarbonate, bile salts and volume elicited in response to intraduodenal oleate, pH 6. Furthermore, the bicarbonate secretion and the flow rate elicited by secretin were augmented by CCK, whereas no augmentation was found with regard to the CCK-stimulated enzyme and bile salts output.

Cholecystokinetic and Pancreozymic Effect of O-Sulfated Gastrin Compared With Nonsulfated Gastrin and Cholecystokinin

To assess whether sulfated gastrin contributes to the cholecystokinetic and pancreozymic activity of plasma in humans, 8 healthy subjects on separate days received a mixed meal, graded i.v. infusions of synthetic human tyrosine-O-sulfated gastrin 17 (10.9, 32.7, and 98.1 pmol/kg X h), which was compared with nonsulfated gastrin 17 (12.2, 36.6, and 109.8 pmol/kg X h) and O-sulfated cholecystokinin-octapeptide (5.5, 16.5, and 49.5 pmol/kg X h). Gallbladder volumes were measured by ultrasonography, and the concentrations of gastrin and cholecystokinin in the circulation were determined by specific radioimmunoassays. Neither of the gastrins induced changes in gallbladder volume at serum concentrations occurring postprandially, whereas cholecystokinin-octapeptide produced a significant reduction in gallbladder volume even at a plasma cholecystokinin concentration lower than observed postprandially. Another 8 subjects received the same infusions in combination with a background infusion of synthetic secretin (0.3 CU/kg X h). Gastric and duodenal juice was continuously aspirated using a double-marker perfusion technique. Neither of the gastrins caused an increase in the output of amylase, lipase, trypsin, chymotrypsin, or bilirubin, but both induced a modest increase in the output of bicarbonate and duodenal juice, the former only significantly during infusion of sulfated gastrin 17. The output of all parameters was significantly elevated during all doses of cholecystokinin-octapeptide. The results indicate that neither of the gastrins stimulates gallbladder contraction and pancreatic enzyme secretion in humans under physiologic conditions. However, gastrin may, like cholecystokinin, potentiate the effect of secretin on pancreatic secretion of juice and bicarbonate.

EFFECTS OF SUBSTANCE P ON PANCREATIC EXOCRINE SECRETION STIMULATED BY SECRETIN, DOPAMINE AND CHOLECYSTOKININ IN DOGS

The effect of substance P (SP) on pancreatic exocrine responses to exogenous cholecystokinin, secretin, and dopamine, were studied in the isolated and blood-perfused pancreas of dogs. Intra-arterial injection of SP had a significant biphasic effect on pancreatic secretion: an initial transient inhibition, followed by an increase in the secretion stimulated by the infusion of cholecystokinin. However, SP caused only an inhibition of secretion stimulated by the infusion of secretin and dopamine. SP increased protein concentration but not bicarbonate concentration in juice stimulated by cholecystokinin, but SP did not affect significantly either protein or bicarbonate concentrations in juice stimulated by secretin and dopamine. These results suggest that SP has greater effects on the pancreatic secretion stimulated by cholecystokinin than that stimulated by secretin and dopamine.

Bile acid secretion in cystic fibrosis: evidence for a defect unrelated to fat malabsorption.

In order to define basic biliary defects not related to steatorrhoea in cystic fibrosis, we studied 12 control and 18 cystic fibrosis subjects, with a wide range of pancreatic function. Duodenal aspirates were collected over three consecutive 20 minute periods, during continuous intravenous infusion of cholecystokinin and secretin using a marker perfusion technique, and analysed for pancreatic enzyme output (colipase, lipase, trypsin), bile acid output and concentration, and biliary lipids. Cystic fibrosis patients, at all levels of pancreatic function, had significantly reduced total bile acid output (mumol/kg/h) with delayed appearance of the bile acid peak, compared with control subjects. Actual duodenal bile acid concentrations were significantly higher in cystic fibrosis subjects than in controls, however, probably because of the markedly reduced water output shown in these patients. The lithogenic index was not raised in cystic fibrosis patients at any level of pancreatic function. The reduced bile acid output and the delayed peak appearance probably reflect a defect in gall bladder responsiveness which is independent of pancreatic function and steatorrhoea. Whether this defect is related to gall bladder filling or a defective peptide hormone response awaits further study.

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.

Effects of neurohormonal agents on jejunal contraction spread and transit in the fed dog

The jejunal contraction patterns of dogs in response to intravenous infusion of neurotensin, somatostatin, secretin, and met-enkephalin were analyzed. The peptides were given after administration of a noncaloric viscous cellulose meal. A computer was used to determine the length of spread of contraction waves, their contraction force, the contraction frequency, and the motility index. Transit rates of luminal content were assessed videofluoroscopically. During saline infusion the cellulose meal was propelled aborally at a transit rate of 3.1 ± 1.1 cm/s; the corresponding length of spread of contraction waves was 10.3 ± 1.5 cm. All peptides decreased both the transit rate (0.45–1.81 cm/s) and the contraction spread (3.7–6.2 cm). Neurotensin increased the contraction force, but had no effect on contraction frequency and motility index. The other peptides reduced the motility index and the frequency and force of contractions. It was shown that the peptides influenced intestinal contraction patterns and the transit rate of luminal content. The length of spread of contraction waves was found to be most important in the regulation of transit.

Modulatory effect of glucose, amino acids, and secretin on CCK-8-induced somatostatin and pancreatic polypeptide release in dogs.

Protein- and fat-rich test meals elicit a strong stimulatory effect on postprandial somatostatin (SLI) and pancreatic polypeptide (PP) release, whereas carbohydrate-rich meals rather attenuate the response of both hormones. Since there is evidence that intestinal hormones might contribute to the postprandial SLI and PP response, it was the aim of the present study to determine in dogs the effect of low-dose cholecystokinin octapeptide (CCK-8) on basal hormone levels and also during a background infusion of amino acids or glucose. In a group of six conscious dogs, sulfated CCK-8 was infused intravenously (i.v.) via a hindleg vein at stepwise increasing infusion rates of 10, 30, and 50 pmol X kg-1 X h. The infusion of CCK was applied during a background infusion of saline (2 ml/min), glucose (0.2 g/min), or an amino acid mixture (8.5%, 2 ml/min). CCK-8 had no effect on plasma insulin and glucagon levels under all experimental conditions. Plasma SLI levels were significantly stimulated by all doses of CCK. This stimulatory effect was similar during background infusions of either saline, glucose, or amino acids, respectively. Pancreatic polypeptide (PP) levels rose 200-300 pg/ml during CCK plus saline. This was slightly attenuated by glucose. During CCK plus amino acids, the PP response was augmented to 600-800 pg/ml. Since secretin is also released after the ingestion of a meal and intraduodenal acidification is a potent stimulus not only of secretin but also of gastric and pancreatic SLI release, the effect of secretin was examined additionally.(ABSTRACT TRUNCATED AT 250 WORDS)

Action of dopamine on the exocrine pancreatic secretion of the intact dog.

The effects of dopamine and domperidone, a dopamine antagonist, have been studied on the exocrine secretion of the dog pancreas. The purpose of this study was to see if dopamine acted on enzyme secretion and if its action was merely 'pharmacological' or had a physiological role. Conscious Beagle dogs, fitted with Thomas cannulae were studied following infusions of dopamine 125-1000 micrograms kg-1 h-1. During dopamine infusion, a secretory peak lasting 10 min was observed. This was followed by a stable plateau which was approximately 1/3 of the peak. The pattern of water, bicarbonate and protein secretion was similar. The maximum effect was obtained with 500 micrograms kg-1 h-1 dopamine. The stimulatory action of dopamine was blocked by domperidone, without any detected effect on the central nervous system, but not by propranolol or phenoxybenzamine. Domperidone 10 micrograms kg-1 almost completely suppressed the secretory response to the maximally effective dose of dopamine. This inhibition was not competitive. Atropine decreased the secretory response to dopamine. The protein response was not observed when dopamine was infused against a background infusion of secretin. This suggests that the effect of dopamine on protein secretion could be due to a wash-out phenomenon. The maximally effective dose of domperidone, 10 micrograms kg-1, did not modify the pancreatic response to a solid meal. Thus, in the non-anaesthetized dog, the effect of dopamine on water and bicarbonate secretion has been confirmed. It is concluded that dopamine had no detectable action on protein secretion and that the physiological role of dopamine with respect to pancreatic secretion is still questionable.

Effects of endogenous and exogenous secretin on plasma pancreatic polypeptide concentrations in dogs.

The effects of exogenous and endogenous secretin with or without intravenous glucose infusion upon islet hormone secretion were studied in four conscious mongrel dogs fitted with a duodenal fistula. Intravenous infusion of secretin for 1 h at doses of 0.5 and 4 U/kg raised plasma secretin concentrations to physiological and pharmacological levels respectively, without affecting plasma insulin and pancreatic polypeptide concentrations. In contrast, bolus injections of secretin at high concentrations produced significant increases of plasma insulin at 0.5 U/kg and 4 U/kg and of pancreatic polypeptide at 4 U/kg. Plasma glucagon did not change during intravenous infusion of low dose secretin (0.5 U X kg-1 X h-1), but decreased during infusion of 4 U X kg-1 X h-1 or bolus injection of secretin (0.5 U/kg). Intravenous infusion of glucose together with secretin (0.5 U/kg and 4 U/kg) did not affect plasma insulin, glucagon, or pancreatic polypeptide levels significantly compared with the changes caused by glucose infusion alone. Intraduodenal instillation of HCl, which produced plasma secretin concentrations similar to those evoked by intravenous infusion of secretin (4 U X kg-1 X h-1), led to a rise in plasma pancreatic polypeptide. It is concluded that the stimulatory effects of secretin on insulin and pancreatic polypeptide and the inhibitory effect on glucagon are pharmacological, and that increase of plasma pancreatic polypeptide after intraduodenal infusion of HCl is not mediated by endogenous secretin.

Decrease in plasma amino acid level after secretin and pancreozymin as an indicator of exocrine pancreatic function

Total plasma amino acids were determined by the ninhydrin method in 37 controls and 30 patients with chronic pancreatitis and normal (n = 7) pancreatic enzyme output or mildly (n = 6), moderately (n = 8), and severely (n = 9) reduced pancreatic enzyme output. Intravenous injection of synthetic secretin did not change plasma amino acid levels. During a combined intravenous infusion of secretin (1 CU/kg · h) and pancreozymin (1 Ivy dog unit/kg · h), amino acid concentrations decreased maximally by 31% ± 19% (mean ± SD) in controls, but only by 6.3% ± 4.7% in patients with exocrine pancreatic insufficiency (p < 0.001 vs. controls). At a cutoff limit of ≤ 12% for the decrease in total amino acids, mild exocrine insufficiency (20%–40% of mean normal chymotrypsin output) was identified with a sensitivity of 67%, whereas moderately to severely impaired function was detected in every case (overall sensitivity 91%). Pancreatic function, as assessed by duodenal intubation and the tubeless amino acid test, was significantly correlated (e.g., rS = 0.73 for chymotrypsin output, p ≪ 0.001). In 15 controls and 13 patients with mildly (n = 5) to severely impaired pancreatic function, individual amino acids were estimated. Plasma serine kinetics completely distinguished both groups. Kinetics of serine, valine, isoleucine, and histidine correlated even better with pancreatic function than those of total amino acids.

Lack of effect of amiloride, furosemide, bumetanide and triamterene on pancreatic NaHCO3 secretion in pigs

This study examines the effects of the Na entry blockers amiloride, furosemide, bumetanide and triamterene on pancreatic NaHCO3 secretion. The purpose of the study was to elucidate whether Na flux through a Na-H-antiport, a Na,K,Cl-symport or a Na-K(H)-antiport respectively, may be rate limiting for pancreatic NaHCO3 secretion. The effect of each drug on secretion was tested in four groups of six anaesthetized pigs (20-25 kg body wt) during supramaximal, intravenous secretin infusion (3.0 CU kg-1 body wt. h-1), following laparotomy and cannulation of the pancreatic duct. Secretion was measured over a wide range of arterial pH values, both before and after drug administration in each animal. Pancreatic NaHCO3 secretion averaged 268 (219-308) mumol min-1 at physiological arterial pH 7.40 in the control period. Neither amiloride (90 mg kg-1 body wt), furosemide (10 mg kg-1 body wt), bumetanide (0.6 mg kg-1 body wt) nor triamterene (25 mg kg-1 body wt) affected the rate of secretin-dependent NaHCO3 secretion or the relation between NaHCO3 secretion and arterial pH. It is concluded that Na flux through neither a Na-H-antiport, a Na,K,Cl-symport nor a Na-K(H)-antiport appears to be rate limiting for pancreatic secretion of NaHCO3.

Pancreatic tissue oxygenation during secretory stimulation

Pancreatic acinar tissue O2 tension (PO2) was measured in anesthetized rats using recessed-tip microelectrodes (tip diam 1-2 micron). Pancreatic blood flow was measured using radioactive microspheres. Volume rate of pancreatic secretion, as well as protein concentration, was also measured. Average resting PO2 was 24.8 +/- 1.6 mmHg, with relatively little variation evident within a given pancreas. Bolus intravenous infusion of cholecystokinin octapeptide (CCK-OP, 4 micrograms X kg body wt-1) induced a reduction in tissue PO2 and profoundly increased protein output, while not directly affecting pancreatic blood flow. By contrast, secretin infusion (1.0 CU X kg body wt-1 iv bolus) affected neither tissue PO2 nor blood flow, although secretory rate increased by nearly sevenfold. This difference in PO2 response to the two compounds is interpreted in light of the fact that CCK-OP primarily stimulates acinar cell function, while secretin preferentially activates secretory epithelium. Pancreatic PO2 was found to be linearly related to resting blood flow at flows above 44 ml X min-1 X 100 g-1. No regional differences in blood flow were found in the head, body, and tail of the pancreas.

Control of O2 supply to the pancreas during a vasopressin-induced vasoconstriction.

In the anesthetized dog, the metabolic level of the pancreas was elevated by a secretin infusion (1.2 U/kg/hr iv), displaying a metabolic control of tissue oxygenation and blood flow. Question was raised how this system would response to a decrease in O2 supply, as induced by increasing doses of vasopressin (2-131 mU/kg, iv). These vasopressin administrations progressively diminished blood flow (down to 20%), as well as secretory rate (down to 7%) and O2 consumption (down to 33%). The O2 extraction was increased up to 227%. Capillary density, mitochondrial O2 consumption, capillary PO2 and cellular PO2 were calculated by simulating these data with the model of the metabolic control of tissue oxygenation. The changes mentioned above could be simulated adequately. These simulations revealed that a. in the pancreas vasopressin primarily increases arteriolar resistance; the inhibition of metabolism is secondary to the vasopressin-induced vasoconstriction. b. The pancreas responds with a small compensatory capillary recruitment (up to 29%), which in itself would increase tissue oxygenation. c. The main consequence of the lowering of blood flow is a dramatic decrease of mean capillary PO2 (down to 38%), as well as a lowering in mean cellular PO2 (down to 41%). This lowering of O2 supply to the tissue will slow down the metabolic rate, as evidenced by the decrease of the volume of the excretion.

Abnormal pancreatic electrolyte secretion in cystic fibrosis. Reliability as a diagnostic marker.

We performed pancreatic function tests on sixty-five cystic fibrosis (CF), and eleven control children. The technique used continuous IV infusion of cholecystokinin and secretin, with duodenal juice collection over a 90 min period, and was made quantitative by continuous duodenal infusion and distal collection of an unabsorbable marker (bromosulphthalein). Some CF patients had near normal pancreatic enzyme outputs, some had impaired but measurable levels, but most (79%) had almost absent trypsin secretion. CF children with better pancreatic function, were younger and more likely to be male. All controls showed a large increase in bicarbonate concentration and secretion rate per kilogram body weight during the test, but most children with CF (96.5%) did not. Because two of our CF patients had water and bicarbonate secretion within the control range, this finding does not exclude the diagnosis of CF. Sodium, potassium and chloride ion secretion in CF patients was lower than controls but overlap occurred. We found a linear correlation between acinar and tubular secretion in CF patients which indicates that there is probably not a primary genetic defect in pancreatic bicarbonate secretion in CF.

Effect of acetylcholine and secretin on medullary collecting duct function in the rat.

Microcatheterization was used to study the effect of renal arterial infusion of acetylcholine or secretin on medullary collecting duct function in anaesthetized rats. Acetylcholine infusion was associated with natriuresis and increased sodium delivery to, and decreased reabsorption in, the collecting duct. No changes from control function were found with secretin. Renal blood flow was increased with acetylcholine (+82%, p less than 0.001), but unchanged with secretin (+15%, nonsignificant). We conclude that acetylcholine natriuresis is due to inhibition of tubular reabsorption of sodium in the medullary collecting duct, as well as in upstream nephron segments. While the latter may be hemodynamically mediated, the former indicates a direct transport effect of the hormone in the terminal nephron segment.

Rapid adaptation of pancreatic enzyme secretion in the conscious rat. II. Effects of fasting and dietary modulation.

The influence of fasting and dietary modulation on basal and stimulated pancreatic enzyme secretion was studied in conscious rats with cannulated pancreatic ducts. Two days' fasting decreased pancreatic secretion by about 30%. After stimulation of the secretion rate by acute derivation of pancreatic juice or by intravenous infusion of cerulein (0.2 micrograms/kg/h) no rapid change of enzyme composition was found. In further experiments, two groups of rats were fed with carbohydrate-rich and carbohydrate-poor diets, respectively. After pancreatic duct cannulation and a postsurgical recovery period, the diets were interchanged. An adaptation of pancreatic enzyme secretion to the new diet was observed in pancreatic juice. Stimulation of the secretion rate during the adaptation process by acute derivation of the juice or by intravenous infusion of either cerulein, secretin, carbachol or cerulein plus secretin did not further modify the composition of pancreatic proteins. 'Nonparallel' secretion of enzymes was never found when sufficient time for recovery from pancreatic duct surgery was allowed.