Structure-activity studies including a Psi(CH(2)-NH) scan of peptide YY (PYY) active site, PYY(22-36), for interaction with rat intestinal PYY receptors: development of analogues with potent in vivo activity in the intestine.

Peptide YY (PYY) is a gut hormone that inhibits secretion and promotes absorption and growth in the intestinal epithelium. We have performed structure-activity studies with the active site, N-alpha-Ac-PYY(22-36)-NH(2), for interaction with intestinal PYY receptors. Investigation of aromatic substitutions at position 27 resulted in analogues that exhibited potent in vitro antisecretory potencies with N-alpha-Ac-[Trp(27)]PYY(22-36)-NH(2) exhibiting even greater potency than intact PYY. In vivo studies in dogs revealed that this analogue also promoted intestinal absorption of water and electrolytes during continuous intravenous and intraluminal infusion. Investigations carried out to identify features that would enhance stability revealed that incorporation of Trp(30) increased affinity for PYY receptors. A "CH(2)-NH" scan revealed that incorporation of reduced bonds at position 28-29 or 35-36 imparted greater receptor affinity. In general, disubstituted analogues designed based on the results of single substitutions exhibited good receptor affinity with N-alpha-Ac-[Trp(27),CH(2)-NH(35-36)]PYY(22-36)-NH(2) having the greatest affinity (IC(50) = 0.28 nM). Conservative multiple substitutions with Nle-->Leu and Nva-->Val also imparted good affinity. An analogue designed to encompass most of the favored substitutions, N-alpha-Ac-[Nle(24,28),Trp(30),Nva(31), CH(2)-NH(35-36)]PYY(22-36)-NH(2), exhibited a proabsorptive effect in dogs comparable to, but longer lasting than, that of intact hormone. Selected analogues also exhibited good antisecretory potencies in rats with N-alpha-Ac-[Trp(30)]PYY(22-36)-NH(2) being even more potent than PYY. However, the potencies did not correlate well with the PYY receptor affinity or the proabsorptive potencies in dogs. These differences could be due to species effects and/or the involvement of multiple receptors and neuronal elements in controlling the in vivo activity of PYY compounds. PYY(22-36) analogues exhibited good affinity for neuronal Y2 receptors but poor affinity for Y1 receptors. Also, crucial analogues in this series hardly bound to Y4 and Y5 receptors. In summary, we have developed PYY(22-36) analogues which, via interacting with intestinal PYY receptors, promoted potent and long-lasting proabsorptive and antisecretory effects in in vivo models. These compounds or analogues based on them may have useful clinical application in treating malabsorptive disorders observed under a variety of conditions.

Perioperative blood transfusions and decreased long-term survival in esophageal cancer.

We evaluated retrospectively the effect of perioperative blood transfusions on survival in esophageal cancer. The records of all patients who underwent esophageal resection (n = 316) at UCLA Medical Center from 1970 to 1993 were reviewed. Statistical analysis included univariate (log-rank chi 2) and multivariate (Cox proportional hazards) analyses with other known risk factors. High-volume blood transfusions (> 8 units) but not low-volume blood transfusions (1 to 8 units) were associated with a significant decrease in long-term survival (median survival: no transfusion, 22 months; low-volume blood transfusion, 14.5 months, versus high-volume blood transfusions, 6.5 months; p < 0.01). Multivariate analysis revealed that the shorter survival with high-volume blood transfusions was a result of an increased number of postoperative complications. High-volume blood transfusions were not associated with increases in tumor recurrence or infectious complications. The association between shorter survival and high-volume blood transfusions in esophageal cancer may, therefore, be because of the circumstances necessitating transfusion rather than any immunosuppressive effects of the transfused blood. These findings suggest that the transfusion of blood does not by itself decrease the chance of cure after esophageal resection.

Small intestinal sarcoidosis with massive hemorrhage: report of a case.

Sarcoidosis of the small intestine is a rarely described complication of systemic sarcoidosis. Although bleeding from sarcoidosis of the esophagus, stomach, and colon has been reported, massive bleeding from this condition in the small intestine has not been previously described. We present here the first case of hemorrhage from a jejunal sarcoid lesion that was unsuspected and undiagnosed until laparotomy with resection was performed. As with most pathologic conditions of the small intestine, preoperative diagnosis is difficult. Furthermore, the refractory nature of bleeding from this lesion made resection necessary in this patient, suggesting the need for similar therapy in other affected patients.

Proximal jejunal and biliary effects on the enteroinsular axis.

The objective of this study was to investigate the roles of the proximal jejunum and endogenous bile within the proximal jejunum on the enteroinsular axis. Twelve Sprague-Dawley rats underwent proximal jejunal bypass, 11 rats underwent Roux-en-Y cholangiojejunostomies, and 12 rats underwent sham operations. After 3 months, oral glucose tolerance tests were performed in unanesthetized animals and venous blood was collected for plasma glucose and insulin measurements. The surgical procedures did not significantly affect the basal glucose and insulin levels compared with sham-operated animals. The insulin response in rats with excluded proximal jejunal segments was inhibited. The decreased insulinogenic index seen in these animals indicates a possible diabetogenic effect of this procedure. An oral glucose challenge resulted in significant hyperinsulinemia, with an increased insulinogenic index in animals that had undergone Roux-en-Y cholangiojejunostomies. These findings suggest that bile is a potential mediator in the proximal jejunal involvement in the enteroinsular axis.

Adenocarcinoma of the ileostomy: the latent risk of cancer after colectomy for ulcerative colitis and familial polyposis.

A case of a primary adenocarcinoma of an ileostomy is reported along with 15 other cases collected from the literature. These rare tumors are seen on the average 24 years after colectomy with ileostomy and in all cases are associated with a past history of ulcerative colitis or familial polyposis. Most of the reported cases of these tumors have appeared in the literature within the past 5 years, suggesting that there is a rising incidence of this disease corresponding to completion of a biologic latency period that began when the Brooke ileostomy was introduced for ulcerative colitis in 1951. In our case a mucinous adenocarcinoma occurred at the ileostomy site 34 years after colectomy. Adjacent to the tumor was mucosa showing colonic metaplasia and focal dysplasia. Subsequent biopsy specimens of the revised stoma showed inflammatory lesions morphologically suggestive of inflammatory (pseudo) polyps. The clinical and morphologic features in this case suggest that there is transition from ileal mucosa to colonic mucosa to colonic dysplasia to adenocarcinoma. Annual evaluation of the ileostomy for colonic metaplasia, inflammatory lesions consistent with ulcerative colitis and dysplasia, is recommended. In the presence of dysplasia, stomal revision is advised. Wide local excision is advised for adenocarcinoma.

Interleukin-10 prevents death in lethal necrotizing pancreatitis in mice.

BACKGROUND: Cytokines derived from macrophages may play an integral role in the evolution of acute pancreatitis. Interleukin-10 (IL-10), a potent antiinflammatory cytokine, prevents the activation of macrophages and their release of inflammatory cytokines. The aim of this study was to determine whether treatment with IL-10 decreased the severity of experimental acute pancreatitis. METHODS: Thirty female Swiss Webster mice were divided into three groups. Acute pancreatitis was induced by using a choline-deficient, 0.5% ethionine supplemented (CDE) diet. Group A (controls) received CDE diet alone. Group B was pretreated with 10,000 units of intraperitoneal IL-10 at the onset of feeding and every 8 hours thereafter. Group C received IL-10 33 hours after beginning the CDE diet and every 8 hours thereafter. One half of the animals in each group was killed at 54 hours; the remaining living animals were killed at 80 hours. Serum amylase levels (units per liter) were determined at 54 and 80 hours. Pancreata were harvested and fixed in formalin. Histologic characteristics were graded on a scale from 0 to 4 (normal to most abnormal) in a blinded fashion by two investigators. RESULTS: Serum amylase level and histologic score (edema, inflammation, hemorrhage, and necrosis) were significantly reduced when IL-10 was administered either prophylactically or therapeutically (p < 0.01). At 54 hours all animals were alive. Mortality was reduced at 80 hours in both groups treated with IL-10 compared with those fed the CDE diet alone (p < 0.001). CONCLUSIONS: These results suggested that macrophages play an integral role in determining the severity of acute pancreatitis in this animal model. The finding that IL-10 decreased inflammation and prevented death, even when given after acute pancreatitis was established, suggests that it may have potential for clinical use.

Addition of glucagon to total parenteral nutrition (TPN) prevents hepatic steatosis in rats.

Hepatic steatosis is one of the two principal hepatic complications of total parenteral nutrition (TPN), the other being cholestasis. While the cause is uncertain, an excess of carbohydrate calories in rats leads to an elevated portal insulin/glucagon (I/G) molar ratio, periportal fatty infiltration, and increased total hepatic lipid content. Insulin causes fatty acid biosynthesis, whereas glucagon causes hepatic release and inhibition of fatty acid synthesis. Thus we attempted to add glucagon to lower the I/G to see if this would affect the degree of hepatic fatty infiltration by encouraging hepatic fat mobilization. Adult rats (n = 21) received internal jugular catheters; Group 1 (n = 7) was given saline solution (3 ml/h) and chow ad libitum; Group 2 (n = 7), 25% dextrose-base (D25W) TPN solution; Group 3 (n = 7), D25W TPN + 33 micrograms/100 gm/day glucagon. At 7 days portal and peripheral venous blood samples were drawn for insulin and glucagon radioimmunoassay and blood glucose determination; livers were removed for histologic study and lipid determination. Blood glucose did not differ in any group. Hepatic lipid and peripheral and portal venous I/G were increased and periportal fatty infiltration was extensive in Group 2, whereas hepatic lipid and I/G were decreased and periportal fatty infiltration was absent in glucagon-infused rats (Group 3). An abnormally high I/G ratio in portal blood elicited by high-glucose TPN may be responsible, at least in part, for hepatic steatosis. By increasing hepatic lipid export, addition of glucagon to TPN may play a major role in decreasing hepatic steatosis.

Interleukin-10 reduces the systemic inflammatory response in a murine model of intestinal ischemia/reperfusion.

BACKGROUND: Intestinal ischemia/reperfusion (I/R) is known to increase systemic cytokine levels, as well as to activate neutrophils in distant organs. This study was designed to investigate the effect of interleukin-10 (IL-10) on cytokine release, pulmonary neutrophil accumulation, and histologic changes in a murine model of I/R. METHODS: Forty female Swiss-Webster mice were divided into four groups. Group 1 underwent 45 minutes of superior mesenteric artery occlusion followed by 3-hour reperfusion (I/R). Group 2 underwent laparotomy alone (Sham). Group 3 underwent I/R, but was treated with IL-10, 10,000 units IP every 2 hours, starting 1 hour before reperfusion (Pretreatment). Group 4 was treated with an equal dose of IL-10, starting 1 hour after reperfusion (Posttreatment). All animals were killed at 3 hours, standard assays were performed for serum cytokine levels, and lung myeloperoxidase activity and intestinal histology were scored. RESULTS: Serum cytokines (TNF-alpha and IL-6), lung myeloperoxidase levels, and histologic score were significantly reduced when IL-10 was administered either before or after reperfusion. CONCLUSIONS: IL-10 reduced the severity of local and systemic inflammation in a murine model of intestinal I/R when given before or after reperfusion injury. These observations suggest that IL-10 may exert its effect by blocking cytokine production and distant organ neutrophil accumulation.

Peptide YY immunoneutralization inhibits meal-induced absorption in vivo.

BACKGROUND: Plasma peptide YY (PYY) levels rise after a meal and have recently been shown to increase small bowel-absorption. The purpose of this study was to determine whether immunoneutralization of PYY would block postprandial absorption in vivo. METHODS: Exteriorized, neurovascularly intact jejunal and ileal segments (25 cm) were created in six mongrel dogs. After a 2-week recovery luminal perfusion with an isotonic buffer, containing [14C]-polyethylene glycol as a volume marker, was used to analyze water and sodium flux after an oral meal. Each meal was accompanied by either intravenous anti-PYY (0.5 mg.kg-1.h-1) or nonspecific immunoglobulin IG (control). PYY antibody binding was determined by radioimmunoassay. RESULTS: Displacement studies showed complete PYY neutralization. In control experiments feeding increased absorption of sodium and water in both segments. PYY immunoneutralization had no effect on jejunal absorption but significantly diminished ileal absorption (p < 0.05). CONCLUSIONS: These results suggest that PYY acts selectively in the ileum to increase postprandial fluid and electrolyte absorption after a meal. Agents directed at PYY-stimulated absorption may prove to be of therapeutic benefit in patients with malabsorptive conditions.

Pancreatic denervation does not influence glucose-induced insulin response.

BACKGROUND: Pancreatic transplantation results in denervation and loss of splanchnic venous drainage and inflicts numerous metabolic abnormalities. However, it is unclear whether denervation or loss of splanchnic venous drainage is responsible for the observed metabolic abnormalities. METHODS: To discern denervation's role in these abnormalities, four mongrel dogs underwent extrinsic pancreatic denervation with preservation of splanchnic venous drainage. These animals, as well as four innervated control subjects, underwent standardized enteral and intravenous glucose tolerance testing. In addition, hyperglycemic clamps that maintained stable serum glucose elevations at either 2.8 or 8.3 mmol/L above basal were also performed. RESULTS: Prestimulated glucose (90.4 +/- 2.7 vs 92.6 +/- 4.9 mg/dl) and insulin levels (6.8 +/- 1.7 vs 8.5 +/- 1.4 muU/ml) did not differ between innervated and denervated groups. Integrated incremental enteral glucose (5320 +/- 1900 vs 7790 +/- 2000 mg/dl) and insulin (2565 +/- 350 vs 2836 +/- 598 muU/ml) levels did not differ between groups. Integrated incremental intravenous glucose (3680 +/- 400 vs 3950 +/- 1000 mg/dl) and insulin (741 +/- 70 vs 1053 +/- 326 muU/ml) levels also did not differ. During glucose clamp studies, time-weighted 60 to 120-minute insulin levels (2.8 mmol/L, 30 +/- 5.0 vs 24 +/- 4.8 muU/ml; 8.3 mmol/L, 57 +/- 5.9 vs 50 +/- 9.8 muU/ml) did not differ between groups. In addition, glucose disposal, cyclic insulin release, and insulin sensitivity indexes were unchanged by denervation. CONCLUSIONS: Extrinsic pancreatic neural elements are not necessary for cyclic insulin release in response to enteral or parenteral glucose challenge or physiologic and pharmacologic hyperglycemia. These findings suggest that the previously described posttransplantation glucose and insulin abnormalities are not attributable to denervation.

Up-regulation of Na+,K+ adenosine triphosphatase after massive intestinal resection.

BACKGROUND: The mechanisms of intestinal adaptation after resection are not completely defined. The purpose of this study was to examine the changes after resection in the enterocyte basolateral Na+,K+ adenosine triphosphatase (ATPase) known to play a critical role in epithelial transport and homeostasis. METHODS: Lewis rats underwent 70% small bowel resection or transection. At 6 hours, 24 hours, 1 week, and 2 weeks, jejunum and ileum were harvested for analysis of Na+,K+ ATPase activity, kinetic analysis, and alpha 1-ATPase messenger RNA and protein levels. RESULTS: Na+,K+ ATPase activity increased (p < 0.05) in both the jejunum and ileum by 2 weeks after resection. This rise in activity correlated with an increase in the maximal activity of ATPase, from 20.8 to 101.01 mumol inorganic phosphate.mg-1.hr-1. ATPase messenger RNA levels increased sixfold in the jejunum and tenfold in the ileum by 2 weeks after resection (p < 0.05). Protein levels rose at 6 hours and remained elevated in both tissues. CONCLUSIONS: After intestinal resection, enterocyte Na+,K+ ATPase activity rises as a result of an increase in the number of transporters per cell. This occurs through both transcriptional and translational mechanisms. It appears that intestinal adaptation after resection involves not only an increase in absorptive surface area but also functional adaptation by the individual enterocyte.

Y2 receptors decrease human pancreatic cancer growth and intracellular cyclic adenosine monophosphate levels.

BACKGROUND: Peptide YY (PYY), a 36 amino acid enteric hormone, is known to decrease pancreatic exocrine and endocrine function. Previous studies with BIM-43004-1, a modified PYY(22-36) Y2 receptor agonist, have revealed diminished mitochondrial activity in pretreated pancreatic cancer cells in vitro. We investigated the effects of both PYY and BIM-43004-1 on pancreatic cancer growth in vivo. METHODS: The 100,000 to 150,000 human pancreatic cancer cells, Mia PaCa-2, were orthotopically transplanted into 48 male athymic mice. After 1 week animals were treated with either PYY or BIM-43004-1 at 200 pmol/kg/hr via miniosmotic pumps for 2, 3, or 4 weeks. Paired controls received saline solution. At death tumor size and mass were measured. Receptor binding studies and intracellular cyclic adenosine monophosphate (cAMP) levels were measured in vitro. RESULTS: All mice had significant human cancer growth within the pancreas by histologic sections at 2, 3, and 4 weeks. Tumor mass was decreased by 60.5% in BIM-43004-1 treated mice and 27.1% in PYY treated mice. Receptor binding studies revealed binding of [125I]-BIM-43004-1 and displacement of ligand on competitive addition of nonradioactive BIM-43004-1. K dissociation constant of 4.5 nmol and 27,000 receptors per cell were quantitated by receptor binding studies. In BIM-43004-1 treated pancreatic cells a 52.5% decrease in intracellular cAMP levels was noted, whereas a 15.3% decrease was seen in PYY treated cells. CONCLUSIONS: BIM-43004-1, a novel Y2 synthetic agonist, specifically binds to human pancreatic cancer cells, decreases intracellular cAMP levels, and suppresses tumor growth in vivo. Adjuvant hormonal treatment with this Y2 receptor analog may be beneficial in the treatment of patients with pancreatic adenocarcinoma.

The pull-through procedure: technical factors in influencing outcome, with emphasis on pouchitis.

BACKGROUND: The purpose of the study was to review those features that we believed to be critical to the successful performance of the ileal pouch-anal anastomosis, or pull-through, procedure, and specifically the complication of pouchitis. METHODS: The charts of 205 patients who successfully underwent ileal pouch-anal anastomosis procedure were reviewed. No follow-up was available in five patients; therefore, the basis of this report and its analysis was based on 200 consecutive procedures in which at least two of the three surgeons participated. Particular emphasis was placed on continence, particularly nighttime continence. The incidence of pouchitis, either a single episode or intermittent episodes, was surveyed. Particular attention was paid to the level of rectal mucosectomy and anastomosis at the top of the columns of Morgagni, thus retaining the transitional zone. RESULTS: Only 5% of patients were incontinent in the absence of pouchitis. Twenty-five patients (13%) wore a pad at night, but only nine (5%) wore a pad during the day. Of those patients with pouchitis, 6% (12) have had a single episode and 12% (23) were intermittently on medication. Therapy of pouchitis was usually carried out with ciprofloxacin 500 mg by mouth everyday or twice a day. CONCLUSIONS: Ileal pouch-anal anastomosis is an excellent procedure, provided technical details are adhered to. Satisfactory outcome with respect to nighttime continence can be achieved with rectal mucosectomy with minimal manipulation and retaining the transitional epithelium, performing the pouch anastomosis at the top of the columns of Morgagni. The incidence of pouchitis is disappointing but need not be inhibiting of either patients or carrying out this life-saving procedure in patients with ulcerative colitis and familial polyposis.

Gossypiboma of the abdomen.

Intra-abdominal cysts may rise from a variety of organs. However, foreign-body reaction and cyst formation should be considered in the differential diagnosis. In this report, we describe the finding of a preoperatively undetected gossypiboma. A gossypiboma is a mass within the body that is composed of a cotton matrix; in this case, an unmarked laparotomy sponge. The evaluation, findings, and prevention of gossypiboma are discussed.

Intraluminal ileal recovery of pancreatic polypeptide.

Pancreatic polypeptide (PP) is a normal constituent of pancreatic islet cells. Enterocytes containing PP have been identified but incompletely characterized. We previously demonstrated independent intravascular and intraluminal release of two related peptides, peptide YY and neuropeptide Y. In this study, using ileal segments in conscious dogs, we evaluated the intravascular and ileal intraluminal presence of PP to test meals. Fasted plasma and recoverable ileal PP concentrations averaged 139 +/- 2 and 65 +/- 4 pg/mL, respectively. A mixed protein meal resulted in a sustained rise of circulating PP levels associated with a brief evaluation of ileal luminal PP levels. Fat meals were followed by elevations in plasma PP levels without luminal changes. Glucose ingestion altered neither plasma nor luminal PP levels. Our data support the existence of ileal PP-containing cells that respond independently of circulatory PP-releasing cells to different ingested stimuli.

What is the best method of surgical training?: A report of America's leading senior surgeons.

OBJECTIVES: To characterize the career choices and developments made by leading senior surgeons in this country and to examine hypothetically whether application of a short tracking program would have hindered their career decisions. DESIGN: A survey pertaining to each surgeon's career, decisions, and opinions concerning surgical training. SETTING AND PARTICIPANTS: Senior surgeons of regional and national surgical societies. MAIN OUTCOME MEASURE: Survey responses. RESULTS: A total of 352 surveys (41.4%) were received. Respondents answered that the most common reasons for choosing a specialty were role models or mentors (56%), research (51%), and available patient population (23%). The 2 most common stages in a career at which the respondents became interested in a specialty, or an area of expertise, were at the junior residency level (when the specialty was chosen) and at the assistant professor level (when a more specific topic within the specialty was chosen). The most common stage at which the group believed they acquired their expertise was also at the assistant professor level. Seventy-one percent of respondents believed broad training was superior to a short tracking system, although none had participated in shortened surgical training. CONCLUSIONS: Most leading senior surgeons in this country still believe that broad surgical training is superior and should be maintained. Because career specialties in this surveyed group were generally chosen in early residency, a hypothetical application of the short tracking system would have still allowed for these important decisions to be made. Also, it seems likely that specialty and career development would not have been hindered because "expertization" mostly occurred after training was completed. Regardless of training method, a role model or mentor seems most important in career choices and developments.

The role of neoadjuvant therapy in surgically resectable esophageal cancer.

OBJECTIVE: To determine the effect of neoadjuvant therapy (NT) (preoperative chemotherapy, radiation therapy, or both) in surgically resectable esophageal cancer. DESIGN: A retrospective review over a 20-year period. SETTING: A tertiary academic medical center. PARTICIPANTS: All patients undergoing surgical resection for esophageal cancer (N = 316) over this time period. MAIN OUTCOME MEASURES: Perioperative morbidity and mortality, local and distant recurrences, and overall survival. RESULTS: Patients undergoing NT (n = 106) had prognostic factors similar to those treated with surgery alone (n = 210). No increase was noted in surgical morbidity with NT (anastomotic leaks, reoperation rates, complications, or extended hospital stays). Overall survival was not improved by NT (median survival, 14 months) except in the subset of patients (11/83) who responded completely (100% histological necrosis) to preoperative chemotherapy (median survival, 79.2 months; P < .02). Complete response to radiation therapy alone was not associated with improved survival. Partial necrosis of the primary tumor was seen in 13 (15%) of 83 patients but conferred no survival advantage. Complete response to preoperative chemotherapy was associated with squamous cell pathological features and excellent performance status as measured by preanesthesia evaluation. CONCLUSIONS: The addition of NT did not increase perioperative morbidity or mortality. Only the subset of patients who had a complete response to preoperative chemotherapy showed a survival advantage. Excellent performance status and squamous cell pathological features were associated with an increased chance of complete pathological response following preoperative chemotherapy.

Radioimmunoassay to determine postprandial changes in plasma neuropeptide Y levels in awake dogs.

A specific, precise and sensitive double-antibody radioimmunoassay for Neuropeptide Y (NPY) has been developed. There was no appreciable cross-reactivity with the structurally related peptides, peptide YY (PYY) and pancreatic polypeptide (PP). The minimum detectable plasma NPY level was 3 nM. Application of radioimmunoassay to canine models revealed that portal and systemic NPY levels increased significantly following a standard meal.

Primary small cell carcinoma of the esophagus.

A primary small cell carcinoma of the esophagus in a 61-year-old woman was treated by transhiatal esophagectomy. The clinical data were correlated with data obtained from a review of the 129 cases reported in the world literature, thereby providing a clinical profile and suggested management strategy for this rare type of esophageal malignancy. Presenting symptoms of esophageal small cell carcinoma include dysphagia (75.3%), weight loss (38.4%), and chest pain (23.3%). Treatment regimens have included surgical intervention in 58%, radiotherapy in 10%, chemotherapy in 6%, or some combination of these in 26%. Overall survival is only 20.7 weeks after diagnosis. The fact that three fourths of affected patients had metastatic disease at the time of diagnosis leads us to recommend surgical intervention plus systemic chemotherapy in these patients.

The effect of pancreatic denervation and atropine on the cholecystokinin-induced pancreatic exocrine response.

To study the influence of extrapancreatic neural and cholinergic activity on the pancreatic response to cholecystokinin (CCK), six dogs underwent creation of Herrera pancreatic fistulas, placement of Thomas gastric cannulas, and distal pancreatectomies (innervated; INN). Six additional dogs were prepared similarly, with the addition of total extrinsic pancreatic denervation (denervated; DEN). The pancreatic protein and bicarbonate response to graded 12.5 to 200 ng/kg/h CCK doses was determined for INN and DEN animals both alone and with 10 micrograms/kg/h atropine infusion. The influence of extra-pancreatic neural and cholinergic activity on secretin's potentiation of the CCK-induced pancreatic response was then determined by repeating the studies with a 125 ng/kg/h secretin infusion. The latter results were compared to those predicted by summating the responses seen during separate 12.5-200 ng/kg/h CCK dose-response and 125 ng/kg/h secretin studies. Unstimulated protein output was diminished by atropine in INN animals (78 +/- 21 vs. 39 +/- 9 mg/15 min; p < 0.05) but not in DEN animals. Unstimulated bicarbonate outputs, integrated bicarbonate and protein outputs, and bicarbonate and protein dose-response curves were unaffected by denervation or atropine. Potentiation of CCK-induced bicarbonate output by secretin was also unaffected by atropine and denervation. We conclude that cholinergic elements are involved in unstimulated, but not CCK-induced, enzyme secretion. Further, potentiation of CCK-induced bicarbonate output by secretin does not depend on extrinsic neural or cholinergic elements.