Biomedical subjects

D W McFadden

Publications and source records attributed to D W McFadden.

At least 19 recordsLinked to original sources

PubMed1995

A novel synthetic analog of peptide YY, BIM-43004, given intraluminally, is proabsorptive.

Peptide YY (PYY), a proabsorptive hormone, is released into the circulation and lumen of the small intestine after a meal. We have recently found that intraluminal PYY is proabsorptive in the ileum. The purpose of this study was to examine the effects of intraluminal administration of a new substituted PYY (22-36) analog on intestinal absorption of electrolytes and water. Twelve conditioned 20-kg dogs had 25-cm jejunal, 25-cm ileal, or 20-cm colonic Thiry-Vella fistulas (TVF) surgically constructed under general anesthesia (jejunal and ileal TVF, N = 6, and colonic TVF, N = 6). After a 2-week recovery period, the animals received the intraluminal PYY analog, BIM-43004, in the ileum (200 pmole/kg) or colon (300 pmole/kg) for 60 min after a 90-min steady-state basal period was confirmed. The TVF were perfused with an isotonic buffer solution containing [14C]polyethylene glycol as a volume marker. Ion and water transport were measured every 15 min. Net water absorptions were significant in the ileum and colon but not in the jejunum upon intraluminal administration of the PYY analog, BIM-43004. Colonic water absorptions were increased more than twofold above basal absorption rates and ileal absorptions were increased more than 1.5-fold upon addition of intraluminal BIM-43004. Sodium and chloride ion absorption in the colon and ileum paralleled water fluxes. We are describing for the first time a synthetic peptide analog of PYY that produces significant water and electrolyte absorption in the ileum and colon when administered luminally. This synthetic analog may have therapeutic potential in patients with malabsorptive disorders.

Animals↗

PubMed1995

Na+/H+ exchange mediates postprandial ileal water and electrolyte transport.

Feeding stimulates fluid and electrolyte absorption in the small intestine. Previous studies have suggested that Na+/glucose cotransport is important in initiating this response in the jejunum. The purpose of this study was to determine whether Na+/H+ exchange plays a role in meal-induced absorption. Exteriorized, neurovascularly intact jejunal and ileal loops (25 cm) were constructed in dogs. Following a two-week period of postoperative recovery, the loops of awake dogs were perfused with standard buffer alone or with increasing concentrations of amiloride, a Na+/H+ exchange inhibitor. Water, sodium, and chloride fluxes were calculated following a meal using [14C]PEG as a volume marker. The meal significantly increased absorption in both the jejunum (P < 0.001) and ileum (P < 0.01) in those animals perfused with buffer alone. More significantly, amiloride suppressed the increased absorption seen following a meal in the ileum (P < 0.001) but not the jejunum. The response in the ileum was dose dependent. These findings suggest that a major mediator of postprandial sodium and water absorption in the ileum is the Na+/H+ exchanger.

Amiloride↗

PubMed1995

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.

Animals↗

PubMed1995

Adrenergic pathways do not mediate peptide YY-induced inhibition of pancreatic exocrine secretion.

The influence of extrapancreatic nerves and intrapancreatic adrenergic activity on the inhibition of pancreatic exocrine secretion by peptide YY (PYY) was studied in conscious dogs. Chronic pancreatic fistulae were created in five mongrel dogs while a second group of five dogs also underwent complete pancreatic denervation. After recovery, a continuous infusion of secretin (62 ng/kg/h) and cholecystokinin (CCK; 50 ng/kg/h) was administered over 2 h. An infusion of PYY (400 pmol/kg/h) was then given randomly, during either the first or second experimental hour. The experiments were then replicated after establishing adrenergic blockade with continuous background infusions of either phentolamine (0.2 mg/kg/h), propranolol (0.5 mg/kg bolus) or a combination of phentolamine and propranolol. The secretin/cholecystokinin-induced bicarbonate and protein outputs were significantly inhibited by PYY in both the innervated and denervated animals. Adrenergic blockade failed to eliminate the inhibitory effects of PYY. We conclude that extrapancreatic neural pathways, including adrenergic mechanisms, do not mediate the inhibitory effects of PYY. The results suggest that PYY inhibits secretin/cholecystokinin-induced pancreatic response by an indirect nonadrenergic mechanism.

Adrenergic Antagonists↗

PubMed1995

Laparoscopic surgery for inflammatory bowel disease.

In the setting of inflammatory bowel disease (IBD), laparoscopic approaches have been avoided because of the often fragile intestinal tissue, thickened mesentery, malnutrition, immunosuppression, and the presence of dense adhesions. In this article, we report 10 successfully managed laparoscopic cases in IBD patients (five with ulcerative colitis, five with Crohn's Disease). Patients with ulcerative colitis underwent total abdominal colectomies, mucosal proctectomies, J-pouch construction, and diverting ileostomies. Procedures in patients with Crohn's disease included ileocecectomy (3), sigmoid colectomy with takedown of a transverse colonic fistula (1), and stricturoplasty (1). One of the 10 cases was converted to an open technique for technical reasons. Six of the 10 patients were on high dose corticosteroids for disease control. Hospital stay ranged from 6-13 days, with a median of 7 days. The morbidity rate was 20 per cent, and included one case of mild postoperative pancreatitis in a Crohn's disease patient and one delayed peri-ileostomy fistula in an ulcerative colitis patient. There was no mortality. Based on these results, we conclude that laparoscopic intestinal surgery is both feasible and safe in selected patients with inflammatory bowel disease. Use of laparoscopic techniques in these patients may reduce hospital stay, lessen adhesion formation, and improve cosmetic results in this generally young group of patients.

Adolescent↗

PubMed1995

Early regional expression and secretion of peptide YY and enteroglucagon after massive resection of small bowel.

BACKGROUND: Previous studies suggest that peptide YY (PYY) and enteroglucagon have an important role in intestinal adaptation after massive small bowel resection. This study was done to define the mechanisms, timing, and anatomic distribution of the PYY and enteroglucagon response. STUDY DESIGN: Lewis rats underwent resection of 70 percent of the small bowel (leaving equal segments of jejunum and ileum), transection, or laparotomy alone. Jejunum, ileum, and colon were compared in resected, transected, and control bowel six hours, 24 hours, one week, and two weeks postoperatively. RESULTS: Analysis of DNA, RNA, and protein per cm of bowel demonstrated hyperplastic changes. Radioimmunoassay revealed plasma PYY and enteroglucagon to be significantly elevated 24 hours after resection and they remained so through week two. In contrast, tissue PYY and enteroglucagon content decreased significantly in all tissues (p < 0.05) after resection. Reverse transcriptase polymerase chain reaction and Southern blot analysis demonstrated an immediate and sustained increase in PYY messenger RNA (mRNA) in both the ileum (fourfold) and in the colon (2.5-fold) at six hours (p < 0.05). A gradual increase in PYY mRNA was also demonstrated in the jejunum with significance at two weeks (p < 0.05). Proglucagon mRNA was significantly higher in the jejunum, compared with the ileum and colon, at 24 hours, one week, and two weeks postresection. CONCLUSIONS: Alterations in PYY and enteroglucagon synthesis occur early in the ileum and colon after massive small bowel resection. The residual jejunum, however, is primarily responsible for the adaptive hyperenteroglucagonemia. These findings suggest that although PYY and enteroglucagon are colocalized to the same cell type, there is a gene-specific response for these two peptides after resection.

Adaptation, Physiological↗

PubMed1994

Inhibition of pancreatic exocrine secretion by galanin.

The influence of extrapancreatic nerves on the inhibition of meal- and secretogogue-induced pancreatic secretion by galanin was studied in conscious dogs. Chronic pancreatic fistulae were created in five mongrel dogs and a second group of five dogs also underwent complete pancreatic denervation. After recovery, galanin dose response (150-1,200 pmol/kg/h) revealed that 600 pmol/kg/h was the lowest dose of galanin to significantly inhibit pancreatic exocrine secretion. Pancreatic responses to a mixed meal, cholecystokinin (CCK) dose response (12.5-200 ng/kg/h), and secretin dose response (16-500 ng/kg/h) were determined. The experiments were then replicated with a continuous background infusion of galanin (600 pmol/kg/h). Galanin inhibited meal-, CCK-, and secretin-induced bicarbonate outputs in both the innervated and denervated pancreas. Galanin also inhibited meal- and CCK-induced protein responses in both groups. We conclude that extrapancreatic nerves do not mediate the inhibitory effects of galanin.

Animals↗

PubMed1992

Neuropeptide Y secretion from a malignant extraadrenal retroperitoneal paraganglioma.

A patient with a malignant extraadrenal retroperitoneal paraganglioma had elevated levels of immunoreactive neuropeptide Y (NPY) in the peripheral blood (5988 pg/ml; normal, 123 +/- 30 pg/ml [mean +/- standard error of the mean]). A 6-month course of chemotherapy allowed surgical removal of the previously unresectable primary tumor. Postoperatively, the plasma NPY level initially fell to 1089 pg/ml; continued chemotherapy caused an additional decrease to 440 pg/ml. Four months after surgery, the plasma NPY level increased to 940 mg/ml, coincident with hepatic metastases. This case is the first report of a NPY-secreting clinically nonfunctional malignant extraadrenal paraganglioma. Determination of circulating NPY levels may be useful in the diagnosis and follow-up of patients with neuroendocrine tumors.

Female↗

PubMed1992

Embryonal sarcoma of the liver in an adult treated with preoperative chemotherapy, radiation therapy, and hepatic lobectomy.

A rare case of embryonal sarcoma of the liver in a 28-year-old man is reported. The patient was treated preoperatively with a combination of chemotherapy and radiation therapy. Complete surgical resection, 4.5 months after diagnosis, consisted of a left hepatic lobectomy. No viable tumor was found in the operative specimen. The patient was disease-free 20 months postoperatively.

Adult↗

PubMed1992

Effects of intraluminal peptide YY on pancreatic function.

Peptide YY (PYY) is released postprandially into both the circulation and the distal intestinal lumen. While circulating PYY inhibits pancreatic secretion and insulin release, the effects of intraluminal PYY on pancreatic function are unknown. The aim of the present study was to evaluate the effect of exogenous, intraileal luminal PYY on pancreatic exocrine function and fasting glucose levels. Chronic pancreatic and ileal fistulae (50 cm from the ileocecal valve) were created in nine mongrel dogs. The animals were given intravenous infusions of secretin (125 ng/kg/h) and cholecystokinin octapeptide (CCK-8, 50 ng/kg/h) for four hours. At the beginning of the second hour, either normal saline or PYY, at low [physiologic (2 ng/min)] or high [supraphysiologic (50 ng/min)] levels, was infused antegrade into the ileal fistula for two hours. Pancreatic juice was collected for PYY and glucose levels. Ileal luminal PYY infusions had no effect on pancreatic bicarbonate or protein output. Fasting serum PYY and glucose concentrations were unaffected by either dose of intraluminal PYY. We conclude that ileal luminal PYY does not influence pancreatic exocrine function or fasting glucose levels.

Animals↗

PubMed1992

Roux-en-Y jejunal bypass abolishes postprandial neuropeptide Y release.

Numerous physiologic aberrations occur after Roux-en-Y bypass procedures. Neuropeptide Y (NPY), a 36 amino acid polypeptide, has been shown to have many effects on gastrointestinal physiology, including alterations in blood flow, motility, and secretion and absorption. Recent work demonstrating a postprandial increase in circulating NPY prompted this investigation into its potential roles after Roux-en-Y bypass. Three groups of rats underwent Roux-en-Y cholangiojejunostomy, jejunojejunostomy, or proximal jejunal transection with reanastomosis. After a 3-month recovery, the animals were tested with both mixed and fat meals. Control animals had rapid increases in circulating NPY after the mixed meal. This response was not seen in either of the Roux-en-Y groups (P less than 0.05). No animals had circulating changes in NPY after the fat meal. Additionally, small intestinal NPY receptor analysis revealed high NPY affinity to the epithelial cells of the proximal small intestine. Our results demonstrate a dependence of postprandial NPY release on proximal small intestinal continuity that is abolished by Roux-en-Y bypass of a jejunal segment. The absence of postprandial elevation in plasma NPY after proximal jejunal bypass and the abundance of NPY receptors in the proximal small intestine merits further investigation into the physiologic roles of NPY in the foregut.

Anastomosis, Roux-en-Y↗

PubMed1992

Extrinsic neural contribution to ileal peptide YY (PYY) release.

Peptide YY (PYY) release into the ileal lumen is stimulated by cholecystokinin (CCK) and glucose ingestion. Previous data have implicated vagal activity in the mediation of PYY release into both the systemic circulation and the ileal lumen. The present study was designed to evaluate extrinsic neural involvement in CCK and glucose-stimulated circulating and ileal intraluminal PYY release. Distal ileal Thiry-Vella loops (TVL) of 25 cm were created in seven mongrel dogs. On separate days fasted dogs were given continuous infusions of CCK at 500 ng/kg/hr during the first hour of the study or an oral glucose (1.5 g/kg) tolerance test (OGTT) was performed. Peripheral blood samples and ileal effusates were collected before tests and following either CCK or glucose stimulation for 120 min at 20-min intervals. Ileal PYY recoveries were measured by the instillation and collection of 20 cc of normal saline from the TVL for each 20-min period. The dogs were again tested after surgical denervation of the TVL. OGTT resulted in a significant rise of PYY recovery from the TVL (P less than 0.05), while not affecting circulating PYY. Intravenous CCK resulted in significant increases in both plasma and ileal PYY concentrations (P less than 0.05). Denervation of the TVL decreased PYY recovery from the TVL after both CCK and OGTT, whereas this procedure did not affect circulating PYY levels or basal luminal levels. These data demonstrate the inhibition of CCK- and glucose-stimulated ileal PYY recovery from denervated ileal loops. The extrinsic neural pathways are involved in the mediation of glucose- and CCK-stimulated mechanisms for ileal PYY release.

Animals↗

PubMed1992

Postprandial peptide YY release is mediated by cholecystokinin.

Peptide YY (PYY), a 36 amino acid peptide, is a member of the structurally and functionally related pancreatic polypeptide (PP) family of gastrointestinal and neurally active peptides. Peptide YY is released postprandially from the distal small intestine and colon and has been shown to inhibit many physiologic actions of cholecystokinin (CCK), an integral foregut hormonal stimulant of pancreatic and gastric secretion. The specific signals for the release of PYY have not been ascertained, although foregut signals, both neural and hormonal, are likely. In this study, we evaluated the possible role for CCK in postprandial PYY release in eight conscious dogs. Conscious dogs were given a fat meal or a one hour intravenous infusion of CCK-8. On separate days, the dogs were pretreated with the specific CCK receptor antagonist L-364,718. Peripheral blood samples were collected for radioimmunoassay for PYY, PP and neuropeptide Y. The fat meal and exogenous CCK stimulated PYY and PP release, effects that were abolished by pretreatment with the CCK receptor antagonist. The results provide support for a physiologic role of CCK in the mediation of postprandial PYY and PP release. Furthermore, an inhibitory feedback loop is suggested between the hindgut (PYY) and the foregut (CCK).

Animals↗

PubMed1991

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.

Animals↗

PubMed1991

A simple method for biliary-enteric anastomosis and chronic bile diversion in the rat.

A simple method of biliary-enteric anastomosis, without the use of surgical microscopy, is described. There were no signs of cholestasis after 3 mo of follow-up. A modified procedure using a silicone elastomer catheter as a stent for the biliary-enteric anastomosis resulted in biliary obstruction within 3 wk after surgery. Our experimental bile duct implantation technique is a simple and useful experimental method for the investigation of chronic biliary diversion and biliary physiology. Additionally, it can be performed safely and easily in a rodent model without sophisticated microscopic techniques.

Anastomosis, Surgical↗

PubMed1991

Effects of glucose on circulating and ileal intraluminal peptide YY and pancreatic polypeptide release.

Peptide YY (PYY) and pancreatic polypeptide (PP) are related hormones released systemically after a meal. The effects of glucose stimulation and vagal involvement on circulating and ileal luminal PYY and PP concentrations were evaluated in awake dogs. An oral glucose tolerance test (OGTT), intravenous glucose tolerance test (IVGT), 2-deoxyglucose bolus (2-DG), or atropine pretreatment prior to OGTT were administered to awake dogs with 25-cm ileal Thiry-Vella fistulas. Circulating and ileal intraluminal PYY and PP levels were measured by radioimmunoassay. No changes were noted in circulating PYY, and circulating PP increased (p less than 0.05) only after administration of 2-DG. Ileal luminal PP recovery was minimal (less than 60 pg/mL) and was unchanged after all tests. Ileal luminal PYY recovery increased significantly after both OGTT and IVGT. Pretreatment with atropine abolished the luminal PYY response to OGTT, and 2-DG did not affect luminal PYY recovery. Blood glucose and insulin levels were similar in all groups. Peripheral cholinergic control of luminal PYY release is suggested by our findings, whereas a central mediation of circulatory PP release is supported by 2-DG stimulation.

Animals↗

PubMed1991

The effect of SMS 201-995 on meal and CCK-stimulated peptide YY release.

Somatostatin is known to inhibit the postprandial release of most gastrointestinal hormones. The aim of the present study was to evaluate the effect of an analog of somatostatin, SMS 201-995 (120 ng/kg/hr), on both meal-induced and cholecystokinin octapeptide (CCK-8, 500 ng/kg/hr)-induced peptide YY (PYY) release. Six mongrel dogs with distal ileal Thiry-Vella loops were used in this study. PYY was measured in both plasma and ileal luminal effluent. SMS 201-995 did not affect interdigestive plasma or ileal luminal PYY concentrations. CCK-8 and a fat meal both stimulated PYY release into the circulation. SMS 201-995 completely inhibited the CCK-8 and fat-stimulated circulatory release of PYY. Both CCK-8 and a mixed meal increased ileal luminal PYY recovery. SMS 201-995 inhibited CCK-8-induced, but not meal-induced, ileal luminal PYY recovery. These findings support previous studies that describe independent circulatory and ileal luminal PYY release. We conclude that both somatostatin and CCK may have a regulatory role in postprandial circulatory release of PYY.

Animals↗

PubMed1991

Vagal cooling blocks circulating neuropeptide Y (NPY), peptide YY (PYY), and pancreatic polypeptide (PP) release.

Neuropeptide Y (NPY), peptide YY (PYY), and pancreatic polypeptide (PP) are regulatory peptides that constitute a new family of gastrointestinal and neural peptides. The influence of vagal integrity on NPY, PYY, and PP basal and postprandial release was evaluated using a new technique of reversible cryogenic cervical vagal blockade in an awake canine model. Cooling coils were placed around bilateral cervical vagal trunks in five dogs along with omocervical arterial catheters. Vagal transmission was monitored by pulse and arterial pressure monitoring. Cryogenic blockade of vagal nerves was performed by circulating a mixture of 0 degrees C ethanol and water through the cooling coils. NPY, PYY, and PP were measured using standard radioimmunoassays. Vagal cooling decreased basal NPY and PYY levels (P less than 0.05) but not PP. After a standard meal, vagal cooling blocked the postprandial rise seen in circulating NPY and PP (P less than 0.05). These data demonstrate a technique of reversible vagal blockade to evaluate the role of cervical vagal integrity in gastrointestinal endocrinology. Cryogenic vagal blockade inhibits the postprandial rise of circulating PP into the circulation. Vagal pathways appear to contribute to fasting activity of PYY and NPY releasing cells. Inhibited meal-stimulated release of NPY supports a role for vagal modulation of postprandial NPY release into the circulation.

Animals↗