Chronic Pancreatic Fistulas Research Articles

НОВЫЕ ВОЗМОЖНОСТИ В ЛЕЧЕНИИ ХРОНИЧЕСКИХ ПАНКРЕАТИЧЕСКИХ СВИЩЕЙ

Abstract. Introduction. External post-necrotic pancreatic fistulas can persist for months, worsening the quality of the patient’s life. Conservative and minimally invasive treatment methods are priorities for this pathology, with the primary focus on diagnosing and correcting intraductal hypertension. Aim. To present clinical observations on the minimally invasive elimination of external pancreatic fistulas resulting from necrotizing pancreatitis. Materials and Methods. We analyzed cases of 6 patients over 3 years with necrotic forms of acute pancreatitis that developed complications, such as persistent external pancreatic fistulas. After having verified the fistula and corrected intraductal hypertension, we performed sclerotherapy on these external fistulas. This article also describes the first one of these clinical cases. Results and Discussions. In all six cases, we observed the rapid closure of chronic post-necrotic pancreatic fistulas and maintenance of the achieved effect over more than a year of follow-up. Conclusions. Experience of Russian and foreign surgery colleagues shows the priority of using minimally invasive techniques in treating most complications of necrotizing pancreatitis, particularly external pancreatic fistulas. Extensive surgical interventions in such patients generally carry high risks. We were the first to apply sclerotherapy using aethoxysklerol for this complication; the successful experience suggests its further application, alone or in combination with other minimally invasive techniques.

Management of Refractory Pancreatic Fistula: A Review of Literature

Background Chronic non-healing or refractory pancreatic fistulae are rare complications of pancreatic surgery (pancreaticoduodenectomy, distal pancreatectomy) or pancreatitis. Materials and Methods We conducted a thorough literature search of electronic databases such as PubMed, Google Scholar, BioMed Central, and Cochrane Library using the keywords and medical subject headings (MeSH) terms “chronic pancreatic fistula”, “post-operative fistula”, “fistula management” and “refractory pancreatic fistula”. The purpose of this review is to evaluate the management options for refractory pancreatic fistula (PF). Results Literature reveals that refractory pancreatic fistulae have been managed by techniques like endoscopic ultrasound (EUS)-guided techniques like transmural puncture by clamping, puncture of the fistula tract, transmural placement of pigtail stent, and EUSguided pancreaticogastrostomy. Other techniques are postoperative endoscopic pancreatic stent placement in Grade C pancreatic fistula, intestinal decompression catheter insertion into the jejunum, embedding fistulojejunostomy, and fistulojejunostomy. Conclusion In conclusion, embedding fistulojejunostomy, EUS-guided transmural puncture by clamping, and EUS-guided transmural placement of pigtail stent are effective techniques for the management of refractory pancreatic fistulae. Yet further studies in a larger population are recommended.

Salvage anastomosis for postoperative chronic pancreatic fistula.

Salvage anastomosis for postoperative chronic pancreatic fistula is challenging, and its safety and surgical outcomes remain unclear. Four patients with postoperative chronic pancreatic fistulas who underwent surgical interventions in our institute were retrospectively reviewed. A re-pancreatojejunostomy was performed in two patients with a disruption of the pancreatojejunostomy and a dilated main pancreatic duct of the remnant pancreas. A fistulojejunostomy was performed in the remaining two patients with a duct disruption after necrosectomy for necrotic severe acute pancreatitis and non-dilated main pancreatic duct. The median duration from the onset of the pancreatic fistula to the surgical intervention was 4.5months (range 4-6months). The median operation time was 151min (range 38-257min) and the median blood loss was 200mL (range 5-350mL). According to the Clavien-Dindo classification, one patient had grade 0, two patients had grade I, and one patient had grade II (wound infections). The median length of hospital stay was 22days (range 21-28days). There were no recurrences of pancreatic fistulas. Salvage anastomosis according to the simple radiologic classification for postoperative chronic pancreatic fistulas is a safe and effective procedure.

Surgical treatment of pancreatic pseudocysts.

Abstract Twenty-five patients with pancreatic pseudocysts were treated surgically. The operative mortality was 4 per cent. Morbidity after external drainage was higher (86 per cent) than after internal drainage (36 per cent), mainly due to the presence of chronic postoperative pancreatic fistulas. A standard procedure based on our own results and published data for management of pancreatic pseudocysts is proposed.

The effect of acute ethanol administration on the exocrine pancreatic secretion of the pig.

The acute effect of intravenous and intragastric alcohol on exocrine pancreatic secretion was studied in pigs with chronic pancreatic and gastric fistulas. A new H-type pancreatic cannula was designed for the study. With intravenous alcohol and the gastric fistula open, increased gastric acid secretion occurred but pancreatic enzyme output was inhibited. When acid was allowed to inter the duodenum by closing the gastric fistula, intravenous alcohol produced a secretin-like effect of increased pancreatic volume and bicarbonate secretion. Intragastric alcohol caused an increase in volume, bicarbonate and enzyme output. This was probably due initially to direct gastroduodenal stimulation as the same response occurred following intragastric mannitol of similar volume, pH and osmolality. The subsequently sustained increase in volume and bicarbonate was possibly a secondary secretin-like response following absorption of alcohol. It is concluded that the pig pancreas responds to alcohol as has been described in other animals. The use of a single model has allowed clarification of various phases of response invoking the effects of secretin, gastric and glucagon.

A modification of a chronic pancreatic fistula in the dog.

A modification of a chronic pancreatic fistula in the dog.

Long-term bile diversion enhances basal and duodenal oleate-stimulated pancreatic exocrine secretion in dogs.

There have been no previous reports whether long-term bile diversion enhances pancreatic exocrine secretion. The aim of this study was to elucidate the effect of long-term bile diversion on pancreatic exocrine secretion. Four mongrel dogs were prepared for chronic gastric and pancreatic fistulas and received intraduodenal sodium oleate infusion (controls). These dogs, then underwent diversion of bile from the intestines by ligating the common bile duct and interposing a segment of jejunum between the gallbladder and the urinary bladder (total biliary diversion [TBD]). After three weeks, the dogs received an identical sodium oleate infusion. TBD augmented basal pancreatic exocrine secretion compared with controls (4.4-fold increase in basal flow volume; 9.0-fold increase in bicarbonate output; and 3.3-fold increase in protein output). Likewise, TBD augmented oleate-stimulated exocrine secretion (2.0-fold increase in cumulative flow volume; 2.6-fold increase in bicarbonate output; and 1.4-fold increase in protein output). TBD also augmented basal and oleate-stimulated plasma cholecystokinin levels. Administration of a Cholecystokinin-A receptor antagonist (loxiglumide) after TBD reduced the flow volume and bicarbonate output to the control levels, and the protein output to less than a half of the control level. Long-term bile diversion enhances basal and oleate-stimulated pancreatic exocrine secretion, at least partly via increased cholecystokinin secretion.

Insulin inhibits secretin-induced pancreatic bicarbonate output via cholinergic mechanisms.

Exogenous insulin inhibits secretin-stimulated pancreatic bicarbonate output via a dose-dependent mechanism; this effect is prevented by pancreatic denervation. To investigate possible cholinergic mediation, we examined the effect of bethanechol on secretin-stimulated pancreatic secretion during euglycemic, hyperinsulinemic clamp. In four dogs with chronic pancreatic fistulas, euglycemic, hyperinsulinemic clamp (1.25 mU/kg/min) was begun after a 30-minute basal period; computer-assisted glucose administration maintained euglycemia. Control studies were performed with volume-matched and rate-matched vehicle infusion. After 1 hour, secretin infusion was begun at a dosage of 16 ng/kg/h; the dose was doubled every 30 minutes. The studies were then repeated during background bethanechol infusion (90 microg/kg/h) begun 30 minutes after clamp initiation. Pancreatic juice was analyzed for bicarbonate and protein; serum samples were analyzed for glucose and insulin. Exocrine outputs and serum glucose and insulin levels did not differ in the basal period. Insulin levels were significantly elevated during the euglycemic, hyperinsulinemic clamp (62 microU/mL versus 12 microU/mL; p < 0.01); glucose levels did not differ. As before, secretin-induced bicarbonate output was inhibited by euglycemic, hyperinsulinemic clamp. The inhibitory effect of insulin was reversed by bethanechol. Despite the euglycemic, hyperinsulinemic clamp, secretin-induced bicarbonate output was potentiated by bethanechol at higher secretin doses (p < 0.05). These data confirm that cholinergic mechanisms mediate insulin's inhibition of secretin-induced pancreatic bicarbonate output.

Complicated pancreatic disease management--radiologist/interventionist batting cleanup?

Abstract The long term results of various interventional procedures used in the treatment of patients with chronic pancreatic fistulas or severe pancreatic pain syndrome, after failure of both surgery and endoscopic catheterization, are described. Five patients were divided into two groups. Group 1 contained three patients with recurrent severe abdominal pain with superimposed episodes of acute pancreatitis. Two patients had undergone prior Whipple procedures but remained symptomatic. The third had a 6-yr history of alcoholic pancreatitis. All three had failed selective pancreatic endoscopy because of a proximal pancreatic duct stricture. The pancreatic duct was dilated to between 7 and 10 mm by CT or ultrasound imaging. Group 2 patients had pancreaticocutaneous fistulas that developed after surgical and percutaneous pseudocyst drainage. Both patients’ fistulas had been unresponsive to therapy with somatostatin analogues, and had been controlled by means of percutaneous drains. Patients were treated under either general anesthesia (two patients, patient preference) or conscious sedation. Each received preprocedure antibiotics and had normal coagulation profiles. Oral contrast was given to opacify the colon the night before the procedure. Ultrasound or fluoroscopic guidance was used to puncture the pancreatic duct, either directly or through the stomach (after placement of T fasteners). The procedures were then individualized to fit the particular pathology and anatomical situation. At least one procedure required endoscopic assistance (rendezvous procedure) for guidewire stabilization to deliver an angioplasty catheter across a pancreatic duct stricture. The criteria for successful treatment included partial or complete relief of abdominal pain, with normalization of pancreatic duct caliber in group 1 and cure of the pancreatic fistulas in group 2 without recurrent episodes of pancreatitis. All three patients in group 1 had prompt relief of abdominal pain after placement of percutaneous pancreatic duct drains. All had return to normal caliber of the pancreatic duct by imaging. One patient had a recurrent episode of abdominal pain after drain removal, but this was found to be due to a ureteral stricture. The details of the procedures for treating the fistulas have been previously reported (1) . Cope and colleagues’ report assesses long term efficacy of these interventions. Both patients with fistulas were cured out to 5-yr follow-up after removal of their drains. None of these percutaneous procedures showed early complications such as leakage of pancreatic juice, sepsis, hemorrhage, or acute pancreatitis, as determined symptomatically by hematological screening and abdominal imaging. The authors conclude that percutaneous pancreatic duct drainage and stent placement is safe in selected cases. It is particularly useful when endoscopic stent placement is unsuccessful and surgery too risky. They also suggest several other situations in which this technique may be beneficial.

Complicated pancreatic disease management—radiologist/interventionist batting cleanup?

The long term results of various interventional procedures used in the treatment of patients with chronic pancreatic fistulas or severe pancreatic pain syndrome, after failure of both surgery and endoscopic catheterization, are described. Five patients were divided into two groups. Group 1 contained three patients with recurrent severe abdominal pain with superimposed episodes of acute pancreatitis. Two patients had undergone prior Whipple procedures but remained symptomatic. The third had a 6-yr history of alcoholic pancreatitis. All three had failed selective pancreatic endoscopy because of a proximal pancreatic duct stricture. The pancreatic duct was dilated to between 7 and 10 mm by CT or ultrasound imaging. Group 2 patients had pancreaticocutaneous fistulas that developed after surgical and percutaneous pseudocyst drainage. Both patients’ fistulas had been unresponsive to therapy with somatostatin analogues, and had been controlled by means of percutaneous drains. Patients were treated under either general anesthesia (two patients, patient preference) or conscious sedation. Each received preprocedure antibiotics and had normal coagulation profiles. Oral contrast was given to opacify the colon the night before the procedure. Ultrasound or fluoroscopic guidance was used to puncture the pancreatic duct, either directly or through the stomach (after placement of T fasteners). The procedures were then individualized to fit the particular pathology and anatomical situation. At least one procedure required endoscopic assistance (rendezvous procedure) for guidewire stabilization to deliver an angioplasty catheter across a pancreatic duct stricture. The criteria for successful treatment included partial or complete relief of abdominal pain, with normalization of pancreatic duct caliber in group 1 and cure of the pancreatic fistulas in group 2 without recurrent episodes of pancreatitis. All three patients in group 1 had prompt relief of abdominal pain after placement of percutaneous pancreatic duct drains. All had return to normal caliber of the pancreatic duct by imaging. One patient had a recurrent episode of abdominal pain after drain removal, but this was found to be due to a ureteral stricture. The details of the procedures for treating the fistulas have been previously reported (1). Cope and colleagues’ report assesses long term efficacy of these interventions. Both patients with fistulas were cured out to 5-yr follow-up after removal of their drains. None of these percutaneous procedures showed early complications such as leakage of pancreatic juice, sepsis, hemorrhage, or acute pancreatitis, as determined symptomatically by hematological screening and abdominal imaging. The authors conclude that percutaneous pancreatic duct drainage and stent placement is safe in selected cases. It is particularly useful when endoscopic stent placement is unsuccessful and surgery too risky. They also suggest several other situations in which this technique may be beneficial.

Captopril inhibits secretin-induced pancreatic bicarbonate output

Background. Renin-angiotensin systems function at both the organ and systemic levels. Previous studies suggest that angiotensin II (Ang II) stimulates pancreatic secretion in vitro. In contrast, in vivo studies suggest that Ang II inhibits pancreatic secretion. To further assess Ang II's influence on pancreatic secretion, we examined the effect of captopril on secretin-stimulated pancreatic output. Methods. After a 30-min basal period, four conscious dogs with chronic gastric and Herrera pancreatic fistulas received an intravenous bolus of captopril (0.1 mg/kg) followed by a continuous infusion (25 μg/kg/ min). Control studies were performed with volume-and rate-matched saline infusion. After 1 h, secretin infusion was begun at 16 ng/kg/h, doubling the dose every 30 min. Pancreatic juice was analyzed for bicarbonate and protein. A paired t test was used to assess statistical significance. Results. When compared to controls, pancreatic bicarbonate outputs were lower during captopril administration; the difference between captopril and control was statistically significant at the highest secretin dose. Protein outputs also appeared lower during captopril administration, although these differences were not statistically significant. Conclusion. These data suggest that Ang II may augment secretin-induced pancreatic secretion. Further, the data seemingly refute the inhibitory role attributed to Ang II in earlier studies.

Percutaneous Management of Chronic Pancreatic Duct Strictures and External Fistulas with Long-term Results

THE treatment of chronic pancreatitis with severe intermittent abdominal pain or chronic low-output pancreaticocutaneous fistulas remains a major challenge. The 20%–40% of patients who do not respond to intensive medical therapy, including abstinence from alcohol, are traditionally treated by surgical resection or drainage of the diseased pancreas; surgery leads to partial or complete pain relief in 60%– 90% of cases of ductal obstruction, but with a mortality rate of 2%–5% and a serious complication rate of 20%–40% (1–3). Evolving endoscopic pancreatic duct drainage and stent placement procedures (4–7) for treating pancreatic duct (PD) strictures, sealing PD disruptions, and draining PD pseudocysts can offer an alternative to surgery with low major morbidity and mortality. There remains a small group of patients for whom endoscopic and surgical treatment of PD obstruction or fistulas is not possible or advisable; it has been shown in a few case reports that the management of these patients by percutaneous PD drainage with or without stent placement can be effective (8–10). We describe a variety of interventional techniques that we have used to successfully treat five patients with chronic fistula or severe pancreatic pain syndrome, after both surgery and endoscopic catheterization had failed. A follow-up of 5–10 years was possible in most cases.

Hyperglycemia alone does not inhibit secretin-induced pancreatic bicarbonate secretion.

Administration of exogenous insulin (INS) inhibits secretin-stimulated pancreatic bicarbonate (HCO3) output via a dose-dependent, neurally mediated mechanism. To determine whether this effect was due to systemic hyperinsulinemia or to reduced endogenous insulin production, we examined the effect of hyperglycemia on secretin-stimulated pancreatic secretion. Chronic pancreatic fistulae were created in six dogs. After 30 minutes of equilibration, a computer-assisted hyperglycemic clamp protocol was used to maintain glucose (GLU) levels 100 or 150 mg/dL above basal in clamp animals; control animals received volume- and rate-matched infusions of 0.9% saline. One hour after beginning the clamp period, intravenous secretin dose-response (16-125 ng/kg/h) was begun, doubling the dose every half hour. Unstimulated (0-30 minutes) HCO3, GLU, and INS levels did not differ between groups. INS and GLU levels in clamp animals were significantly elevated during clamp (30-90 minutes) and stimulated (90-210 minutes) periods. For the same periods, HCO3 secretion was not significantly changed despite profound hyperinsulinemia. We conclude that systemic hyperinsulinemia alone does not inhibit secretin-stimulated HCO3 output. Since exogenous INS exerts feedback regulation on the pancreas, we propose that suppression of endogenous INS secretion mediates the previously reported inhibitory response.

The role of CGRP and afferent nerves in the modulation of pancreatic enzyme secretion in the rat.

Stimulation of pancreatic sensory nerves by capsaicin produced secretory effects probably caused, at least in part, by the release of CGRP. In the pancreas calcitonin gene-related peptide (CGRP) has been localized in the sensory nerves, but its physiological role is unknown. This study was undertaken to compare the changes of pancreatic enzyme secretion produced by CGRP and by stimulation or destruction of sensory nerves. To stimulate sensory nerves, low doses of capsaicin (0.25-0.5 mg/kg) were given intraduodenally to the conscious rats with chronic pancreatic fistula. To inactivate sensory nerves high doses of capsaicin (100 mg/kg) were given subcutaneously 10 d before tests. For the in vitro experiments pancreatic slices and isolated pancreatic acini were prepared from intact and capsaicin-denervated rats. In conscious rats, CGRP given subcutaneously (5-10 micrograms/kg) and low doses of capsaicin given intraduodenally reduced basal pancreatic secretion. In isolated pancreatic acini, CGRP (10(-10)-10(-6) M), but not capsaicin, increased basal or secretagog-stimulated amylase release. In pancreatic slices (containing nerve fibers) capsaicin (10(-10)-10(-6) M) increased enzyme secretion, and this secretion was abolished by previous inactivation of sensory nerves by this neurotoxin. Capsaicin deactivation did not affect the secretory response of pancreatic acini to CGRP, cerulein, or urecholine. Sensory denervation by capsaicin did not change basal protein secretion, but reduced that produced by feeding or diversion of pancreatic juice to the exterior during first 2 h of the tests.

Inhibition of canine exocrine pancreatic secretion by peptide YY is mediated by PYY-preferring Y2 receptors.

It is still unclear, which receptor subtype, Y1 and/or Y2, mediates the inhibitory action of PYY on exocrine pancreatic secretion. The present study was undertaken to characterize functionally the Y receptor subtype that mediates the inhibition of exocrine pancreatic secretion by peptide YY (PYY). In eight conscious dogs with chronic gastric and pancreatic fistulas, we compared the action of intravenous infusion of 200 and 400 pmol/kg/h of the Y receptor agonists PYY 1-36, PYY 3-36, PYY 13-36, Pro34PYY 1-36, and NPY 1-36 on the pancreatic secretory response to secretin (20.5 pmol/kg/h) and cerulein (29.6 pmol/kg/h). PYY 13-36, Pro34PYY 1-36, and NPY 1-36 were also studied by giving a fivefold dose (1,000 and 2,000 pmol/kg/h). PYY 1-36 and the Y2 receptor agonist PYY 3-36 significantly inhibited pancreatic secretory responses to secretin and cerulein, whereas inhibition by NPY 1-36 and the Y2 receptor agonist PYY 13-36 was attainable only at doses of 1,000 and 2,000 pmol/kg/h. The Y1 receptor agonist Pro34PYY 1-36 was without effect on pancreatic secretion. We conclude that in dogs the inhibition of exocrine pancreatic secretion by PYY is mediated via Y2 receptors of a PYY-preferring subtype.

Exogenous insulin does not influence CCK- and meal-stimulated pancreatic secretion.

Although previous reports suggest interactions between the endocrine and the exocrine pancreas, insulin's effect on pancreatic exocrine function remains unclear. Chronic pancreatic fistulae were created in five dogs; these animals were studied using the euglycemic, hyperinsulinemic clamp technique. After a 30-min unstimulated period, both groups received a 60-min, 1.5 mU/kg/min insulin (clamp) or vehicle (control) infusion. Cholecystokinin (CCK) or meal stimulation was then begun. Intravenous CCK was initiated at 12.5 ng/kg/h; the CCK dose was doubled every 30 min until 100 ng/kg/h was achieved. The intraduodenal liquid test meal (1.5 kcal/ml; 15% protein, 32% fat, 53% carbohydrate) was administered at 100 ml/h. Unstimulated (0- to 30-min) serum glucose and insulin levels and pancreatic bicarbonate and protein outputs did not differ between groups. Clamp (30- to 90-min) and stimulated (90- to 210-min) insulins were significantly elevated in clamp groups (p < 0.001); glucose and bicarbonate were unchanged. Exocrine outputs during clamp periods were unaffected by insulin. Neither CCK- nor meal-stimulated pancreatic secretion (90-210 min) was influenced by insulin administration. These data suggest that hyperinsulinemia does not alter pancreatic acinar cell secretion in the intact animal.

Insulin inhibits secretin-stimulated pancreatic bicarbonate output by a dose-dependent neurally mediated mechanism

Although previous reports suggest interactions between endocrine and exocrine pancreas, insulin's effect on pancreatic exocrine function remains unclear. Chronic pancreatic fistulas were created in six dogs with innervated INN and five dogs with denervated (DEN) pancreata; these animals were studied using the euglycemic, hyperinsulinemic clamp technique. After a 30-min unstimulated period, both groups received a 60-min 1.5 mU.kg-1.min-1 insulin (clamp) or vehicle (control) infusion. Intravenous secretin was then initiated at 16 ng.kg-1.h-1; the secretin dose was doubled every 30 min until 125 ng.kg-1.h-1 was achieved. These studies were then repeated in INN animals during infusion of a 10 micrograms.kg-1.h-1 atropine background. Finally, INN animals underwent a similar unstimulated period followed by a 1.25 mU.kg-1.min-1 insulin (clamp) or vehicle (control) infusion. after 60 min, a 64 ng.kg-1.h-1 secretin infusion was initiated. Insulin infusion was then increased by 0.25 mU.kg-1.min-1 at 30-min intervals until 2.0 mU.kg-1.min-1 was reached. Unstimulated (0-30 min) serum glucose and insulin levels and pancreatic bicarbonate and protein outputs did not differ between groups. Clamp (30-90 min) and stimulated (90-210 min) insulin were each significantly elevate in clamp groups (81.9 +/- 2.4 vs. 7.0 +/- 0.3 microU/ml, P < 0.001); glucose and bicarbonate were unchanged. Protein outputs during clamp (64 +/- 9 vs. 24 +/- 6 mg/10 min; P < 0.05) and secretin-stimulated (52 +/- 9 vs. 29 +/- 3 mg/10 min; P < 0.05) periods were diminished by atropine but were unaffected by insulin. Secretin-stimulated (90-210 min) bicarbonate output was diminished by insulin (0.03 +/- 0.01 vs. 0.31 +/- 0.05 meq/10 min; P < 0.003) in INN but not DEN animals; this effect was partially reversed by atropine. Dose-response studies demonstrated a threshold for insulin's inhibitory actions between 1.5 and 1.75 mU.kg-1.min-1. These data provide further evidence for exocrine-endocrine regulatory interactions and suggest that insulin may influence secretin's stimulation of ductal cell secretion by a mechanism that is at least partially cholinergic in character.

The involvement of endogenous nitric oxide in vagal-cholinergic stimulation of exocrine and endocrine pancreas in dogs.

Previous studies showed that nitric oxide (NO), synthesized from L-arginine (L-arg) by NO synthase (NOS) in vascular epithelium and nerve terminals, affects exocrine pancreatic secretion, but its role in control of endocrine pancreas has not been studied. In this study, the role of NO in the control of pancreatic secretion in response to vagal-cholinergic stimulation and duodenal infusion of nutrients was determined in conscious dogs with chronic pancreatic fistulas. Sham feeding (SF), urecholine iv infusion, and duodenal perfusion with nutrients were used to stimulate the pancreatic protein secretion, and insulin and glucagon release in tests without and with iv infusion of NG-nitro-L-arginine (L-NNA), an inhibitor of NO synthase, L-arg, a substrate of NOS, or their combination was used. SF, urecholine, and duodenal nutrient resulted in the stimulation of pancreatic protein secretion reaching, respectively, 50, 20, and 42% of cerulein maximum. Infusion of L-arg almost doubled the basal protein secretion and tended to increase the secretory response to SF and duodenal nutrient. After infusion of L-NNA, the pancreatic secretory responses to SF, urecholine, and duodenal nutrient were inhibited by about 70, 30, and 75%, respectively. When L-arg was combined with L-NNA, the reduction in pancreatic secretion by L-NNA was significantly attenuated. SF resulted in a significant rise in plasma insulin and glucagon, and this response was completely abolished by L-NNA infusion. Urecholine and duodenal nutrient also resulted in a marked increment in plasma insulin and glucagon, the insulin (but not glucagon) increment being abolished by the pretreatment with L-NNA and reversed by the addition of L-arg.(ABSTRACT TRUNCATED AT 250 WORDS)

Somatostatin Inhibits Cholecystokinin-Induced Pancreatic Protein Secretion via Cholinergic Pathways

Although somatostatin is a potent inhibitor of pancreatic exocrine secretion in vivo, its mechanism of action remains unclear. The influence of extrapancreatic nerves and intrapancreatic cholinergic activity on somatostatin-induced inhibition of pancreatic exocrine secretion was studied in conscious dogs. Chronic pancreatic fistulae were created in six mongrel dogs, and a second group of six dogs also underwent complete pancreatic denervation. The pancreatic responses to graded doses of cholecystokinin (12.5-200 ng/kg/h) and bethanechol (57-916 micrograms/kg/h), both alone and during background infusion of somatostatin-14 (800 pm/kg/h), were determined in all dogs. The cholecystokinin dose-response with a somatostatin-14 background was then repeated with the addition of atropine (10 micrograms/kg/h). In both groups of animals, cholecystokinin elicited a dose-dependent increase in pancreatic protein secretion that was inhibited significantly by somatostatin-14. Regardless of the status of extrapancreatic nerves, atropine further inhibited cholecystokinin-induced protein secretion beyond that evoked by somatostatin-14. In both innervated and denervated animals, cholinergic stimulation with bethanechol elicited a dose-dependent increase in pancreatic protein secretion that was unaffected by somatostatin-14. We conclude that extrapancreatic nerves do not mediate the inhibitory effects of somatostatin-14. Somatostatin-14 appears to inhibit cholecystokinin-induced pancreatic secretion by an intrapancreatic cholinergic mechanism.

Preduodenal mechanisms compensate completely for absent pancreatic enzymes to stimulate gallbladder after meals.

We studied gallbladder emptying with gamma scintigraphy in nine dogs prepared with chronic pancreatic fistulas, so that pancreatic enzymes could be either completely excluded from the duodenum or supplied in normal amounts. During duodenal perfusion of the fasted dogs with fat emulsions, gallbladder emptying was significantly less rapid when the emulsion contained inactive vs active enzymes, confirming the potency of lipolytic products in the intestine as stimuli of gallbladder emptying. However, after feeding either a 115-g or a 460-g meal, each 18% fat, the gallbladders emptied identically whether or not pancreatic enzymes were excluded from the duodenum. We concluded that while products of pancreatic lipolysis in the small intestine are potent stimuli of gallbladder contraction, preduodenal mechanisms can compensate completely for the absence of pancreatic hydrolysis in stimulating gallbladder emptying after a meal.