Neural control of the release and action of secretin.

The release and physiological actions of secretin on pancreatic exocrine secretion and gastric secretion of acid and motility are regulated by neuro-hormonal control. The release of secretin by duodenal acidification is mediated by a secretin releasing peptide (SRP). The release and action of SRP are neurally mediated depending on vagal afferent pathway. SRP activity in acid perfusate of the duodenum was substantially decreased when rats were treated with tetradotoxin (TTX), perivagal application of capsaicin, a beta-adrenergic blocker, Met-enkephalin (MEK) or vagotomy. The release of secretin by SRP was abolished in rats treated with TTX, mucosal or perivagal application of capsaicin, MEK or vagotomy. Both release of secretin and pancreatic exocrine secretion (PES) elicited by duodenal acidification were also inhibited dose-dependently by Met-enkepahlin, 5-HT(2) antagonist, ketanserin and 5-HT(3) antagonist, ondansetron. Stimulation of PES and inhibition of gastric acid secretion and motility by secretin in a physiological dose are also dependent on the vagal afferent pathway as these effects of secretin are abolished by perivagal capsaicin treatment or vagotomy. In conscious rats, vagotomy, vagal ligation, or perivagal colchicine but not capsaicin treatment reduced the number of secretin binding sites in the forestomach suggesting another mode of neural regulation that affects gastric motility. Except in the rat, stimulation of PES by secretin in a physiological dose is profoundly inhibited by atropine indicating the importance of a cholinergic input. In isolated and perfused rat pancreas, electrical field stimulation potentiated secretin-stimulated PES that was suppressed by atropine and anti-GRP serum, suggesting the roles of intrapancreatic cholinergic and GRP-containing neurons. In rats, secretin-stimulated PES was inhibited by a NO synthase inhibitor suggesting mediation by NO. However, the neuropeptides and neurotransmitters involved in regulation of the release and action of secretin and their sites of action remain to be elucidated.

Double blind, placebo controlled trial of the remission inducing and steroid sparing properties of an ICAM-1 antisense oligodeoxynucleotide, alicaforsen (ISIS 2302), in active steroid dependent Crohn's disease.

BACKGROUND AND AIMS: To evaluate the safety and efficacy of the intercellular adhesion molecule 1 (ICAM-1) antisense phosphorothioate oligonucleotide alicaforsen (ISIS 2302) in Crohn's disease. METHODS: Active (Crohn's disease activity index (CDAI) 200-350), steroid dependent (prednisone 10-40 mg) Crohn's patients were randomised into three treatment groups: placebo versus ISIS 2302 (2 mg/kg intravenously three times a week) for two or four weeks. Patients were treated in months 1 and 3, with steroid withdrawal attempted by week 10. The primary end point (steroid free remission) was a CDAI <150 off steroids at the end of week 14. RESULTS: A total of 299 patients were enrolled, with a mean baseline CDAI of 276 and steroid dose of 23 mg/day. Rates of steroid free remission were equivalent for the two and four week ISIS 2302 groups (20.2% and 21.2%) and the placebo group (18.8%). At week 14, steroid withdrawal was successful in more ISIS 2302 patients compared with placebo treated patients (78% v 64%; p=0.032). Steroid free remission was highly correlated with exposure (p=0.0064). Other clinical responses were correlated with exposure, with significant results versus placebo being observed in the highest area under the curve subgroup. CDAI scores decreased by 136 (112) at week 14 versus 52 (107) for placebo (p=0.027) and inflammatory bowel disease score questionnaire improved by 43 (31) versus 15 (36) for placebo (p=0.027). CONCLUSIONS: Although the primary outcomes failed to demonstrate efficacy, pharmacodynamic modelling suggests that alicaforsen (ISIS 2302) may be an effective therapy for steroid dependent Crohn's disease.

A randomized controlled clinical trial of the serotonin type 3 receptor antagonist alosetron in women with diarrhea-predominant irritable bowel syndrome.

BACKGROUND: Irritable bowel syndrome (IBS) is a common gastrointestinal disorder seen in primary care practice. The symptoms of IBS, including abdominal pain, discomfort, and abnormal bowel function, may be modulated by activity of the serotonin type 3 receptor (5-HT(3)). The efficacy and tolerability of the 5-HT(3) receptor antagonist alosetron hydrochloride in nonconstipated female patients with IBS were evaluated in a double-blind, randomized, placebo-controlled trial. METHODS: Patients received either 1 mg of alosetron hydrochloride (n = 309) or placebo (n = 317) twice daily for 12 weeks, followed by a 4-week posttreatment period. Adequate relief of IBS pain and discomfort was the primary end point. Secondary end points included improvements in urgency, stool frequency, stool consistency, incomplete evacuation, and bloating. RESULTS: Seventy-one percent of patients were classified as having diarrhea-predominant IBS. Forty-three percent of alosetron-treated patients with diarrhea-predominant IBS reported adequate relief for all 3 months compared with 26% of placebo-treated patients (P<.001; percentage point difference = 17; 95% confidence interval, 8.0-25.4). Improvement with alosetron compared with placebo was observed by the end of the fourth week of treatment and persisted throughout the remainder of treatment. Alosetron significantly decreased urgency and stool frequency and caused firmer stools within 1 week of starting treatment. Effects were sustained throughout treatment and symptoms returned following treatment cessation. No significant improvement in the percentage of days with sense of incomplete evacuation or bloating was observed compared with placebo during the first month of treatment. Constipation was the most commonly reported adverse event. CONCLUSION: Alosetron hydrochloride, 1 mg twice daily for 12 weeks, is effective in relieving pain and some bowel-related symptoms in diarrhea-predominant female patients with IBS.

Infliximab for refractory ulcerative colitis.

Eight patients with active ulcerative colitis (UC), refractory to usual combination medical therapy, were treated with a single i.v. dose of chimeric monoclonal antibody to recombinant human tumor necrosis factor alpha; many of these patients were scheduled for surgical colectomy because of their active disease. All patients responded extremely well to a single 5 mg/kg infusion of infliximab, with marked improvement after the infusion clinically, colonoscopically, and histologically on colonic biopsy. There were no significant complications or side effects; mean duration of remission has not been determined because none of the patients have relapsed. Infliximab appears to be a potent agent for inducing remission in refractory patients with ulcerative colitis.

Pancreatic phospholipase A2 from the small intestine is a secretin-releasing factor in rats.

A secretin-releasing activity exists in the upper small intestine and pancreatic juice in the rat and the dog. Group I pancreatic phospholipase A2 (PLA2) in canine pancreatic juice and porcine pancreatic PLA2 stimulate the release of secretin from both STC-1 cells and a secretin-producing cell (S cell)-enriched preparation isolated from rat duodenal mucosa. We investigated the distribution and release of pancreatic PLA2-like immunoreactivity in the gastrointestinal tract and the role of PLA2 on the release of secretin and pancreatic exocrine secretion in response to duodenal acidification in anesthetized rats. PLA2-like immunoreactivity was detected in the mucosa throughout the gastrointestinal tract. High concentrations of PLA2 were found in both the small intestine and the pancreas. Duodenal acidification significantly increased the release of PLA2 from the upper small intestine (385% over basal secretion). Intravenous infusion of an anti-PLA2 serum (anti-PLA2) dose-dependently inhibited the release of secretin and pancreatic exocrine secretion in response to duodenal acid perfusion. Preincubation of the concentrate of intestinal acid perfusate (10-fold) from donor rats with the anti-PLA2 significantly suppressed its stimulation of secretin release and pancreatic exocrine secretion in recipient rats. We conclude that pancreatic PLA2 also functions as a secretin-releasing factor in the small intestine that mediates acid-stimulated release of secretin in rats.

Colonic motility abnormality in patients with irritable bowel syndrome exhibiting abdominal pain and diarrhea.

OBJECTIVES: Although colon dysmotility is recognized as a pathophysiological factor in irritable bowel syndrome (IBS), it has not been characterized. We have investigated motility patterns in IBS patients with abdominal pain and frequent defecation or diarrhea and in healthy volunteers. METHODS: A recording catheter that had six polyvinyl tubes with infusion ports was placed in the transverse, descending, and sigmoid colon under fluoroscopy. After 2-h basal recordings, motility responses to cholecystokinin octapeptide (CCK-8) and a meal were studied for 3 h. The motility index (MI) and number of high amplitude propagating contractions (HAPCs) in 10 IBS patients were compared with those of 10 controls. HAPCs were correlated with abdominal pain, and colon transit time using radio-opaque markers was determined. Using human colon muscle strips, the effect of CCK-8 on muscle contractions was also studied. RESULTS: The MI and mean number and peak amplitude of HAPCs in IBS patients were significantly greater than in controls. These abnormalities paralleled markedly shortened colonic transit time. Abdominal pain coincided with >90% of HAPCs. Dose-dependent muscle contraction by CCK-8 was profoundly suppressed both by loxiglumide and atropine. CONCLUSIONS: The dysmotility in this subset of IBS patients was characterized by significantly increased occurrences of powerful HAPCs that paralleled rapid colon transit and were accompanied by abdominal pain. Thus, it is suggested that this powerful contraction is one of the causes of abdominal pain. The action of CCK-8 seems to be mediated via the colon enteric nervous system.

Infliximab for patients with refractory ulcerative colitis.

Conventional treatment options for patients with severe corticosteroid-refractory ulcerative colitis (UC) include intravenous cyclosporine, which is frequently limited by toxicity, or colectomy. The efficacy of infliximab was investigated in the treatment of 16 patients with severely active UC refractory to conventional therapy; 7 of these patients were considered for colectomy pending medical failure. All patients received a single infusion of infliximab, 5 mg/kg; 6 of 16 patients (38%) received a second infusion approximately 5 months later. Efficacy was assessed by clinical response (defined as the lack of symptoms) as well as endoscopic and histologic outcomes. Clinical, endoscopic, and histologic improvement was observed in 14 of 16 patients (88%) after treatment with infliximab. Surgery was avoided in six of seven surgical candidates (86%). Clinical remission was maintained in 14 of 16 patients (88%) for > or = 4 months, and 4 of 16 patients (25%) for 7-10 months. Most of the treated patients were completely withdrawn from corticosteroid therapy. Treatment with infliximab induced endoscopic remission at 30 days and a significant improvement from baseline in mean histologic score (p < 0.001). In conclusion, infliximab improved clinical, endoscopic, and histologic outcomes in patients with severely active UC refractory to conventional therapy, allowing corticosteroid sparing and reducing the need for colectomy.

MEK inhibits secretin release and pancreatic secretion: roles of secretin-releasing peptide and somatostatin.

We investigated the mechanism of action of methionine enkephalin (MEK) on HCl-stimulated secretin release and pancreatic exocrine secretion. Anesthetized rats with pancreatobiliary cannulas and isolated upper small intestinal loops were perfused intraduodenally with 0.01 N HCl while bile and pancreatic juice were diverted. The effect of intravenous MEK on acid-stimulated secretin release and pancreatic exocrine secretion was then studied with or without coinfusion of naloxone, an anti-somatostatin (SS) serum, or normal rabbit serum. Duodenal acid perfusate, which contains secretin-releasing peptide (SRP) activity, was collected from donor rats with or without pretreatment with MEK, MEK + naloxone, or MEK + anti-SS serum, concentrated by ultrafiltration, and neutralized. The concentrated acid perfusate (CAP), which contains SRP bioactivity, was infused intraduodenally into recipient rats. MEK increased plasma SS concentration and inhibited secretin release and pancreatic fluid and bicarbonate secretion dose-dependently. The inhibition was partially reversed by naloxone and anti-SS serum but not by normal rabbit serum. In recipient rats, CAP increased plasma secretin level and pancreatic secretion. CAP SRP bioactivity decreased when it was collected from MEK-treated donor rats; this was partially reversed by coinfusion with naloxone or anti-SS serum. These results suggest that in the rat, MEK inhibition of acid-stimulated pancreatic secretion and secretin release involves suppression of SRP activity release. Thus the MEK inhibitory effect appears to be mediated in part by endogenous SS.

Tolerability and safety of alosetron during long-term administration in female and male irritable bowel syndrome patients.

OBJECTIVES: Alosetron (Lotronex) is a new therapeutic agent for irritable bowel syndrome (IBS) in women with diarrhea-predominant IBS. This multicenter randomized, double-blind, placebo-controlled study assessed the safety and tolerability of alosetron during long-term (< or = 12 months) treatment. METHODS: A total of 859 subjects (637 female and 222 male) with IBS were enrolled from 130 sites in the United States and were randomized 3:1 to receive 1 mg alosetron or placebo b.i.d. for 48 wk; of the subjects, 649 (76%) were randomized to the alosetron group and 212 (24%) to the placebo group. Of the original group, 850 subjects received at least one dose of alosetron (n = 640) or placebo (n = 210). RESULTS: In all, 59% of the subjects completed the study. Safety data were similar in treatment groups and within age, sex, racial origin, and hormone use. Adverse events were reported by 83% (530/640) and 76% (159/210) of subjects in the alosetron and placebo groups, respectively, (p < 0.05) and were similar with the exception of constipation; 32% of subjects receiving alosetron reported constipation, compared to 5% in the placebo group (p < 0.001). Most reports (72%) of constipation were of mild or moderate severity, and 66% of subjects with constipation had single episode of 8 days median duration. Constipation occurred a median of 13 days after initiating treatment and resolved spontaneously, with laxative, or after a brief interruption of therapy. Of the subjects, 4% (11/210) in the alosetron and 5% (28/ 640) in the placebo group experienced serious adverse events. Two deaths occurred in subjects with pre-existing cardiovascular risk factors; neither death was attributed to the study drug. CONCLUSIONS: Alosetron 1 mg b.i.d. for 12 months was well tolerated. Constipation is the most frequent adverse event, with a higher incidence of transient constipation in alosetron-treated patients, typically occurring in the first month of treatment.

Roles of 5-HT receptors in the release and action of secretin on pancreatic secretion in rats.

5-Hydroxytryptamine (serotonin, 5-HT) is a hormone and neurotransmitter regulating gastrointestinal functions. 5-HT receptors are widely distributed in gastrointestinal mucosa and the enteric nervous system. Duodenal acidification stimulates not only the release of both 5-HT and secretin but also pancreatic exocrine secretion. We investigated the effect of 5-HT receptor antagonists on the release of secretin and pancreatic secretion of water and bicarbonate induced by duodenal acidification in anesthetized rats. Both the 5-HT(2) receptor antagonist ketanserin and the 5-HT(3) receptor antagonist ondansetron at 1-100 microg/kg dose-dependently inhibited acid-induced increases in plasma secretin concentration and pancreatic exocrine secretion. Neither the 5-HT(1) receptor antagonists pindolol and 5-HTP-DP nor the 5-HT(4) receptor antagonist SDZ-205,557 affected acid-evoked release of secretin or pancreatic secretion. None of the 5-HT receptor antagonists affected basal pancreatic secretion or plasma secretin concentration. Ketanserin or ondansetron at 10 microg/kg or a combination of both suppressed the pancreatic secretion in response to intravenous secretin at 2.5 and 5 pmol x kg(-1) x h(-1) by 55-75%, but not at 10 pmol x kg(-1) x h(-1). Atropine (50 microg/kg) significantly attenuated the inhibitory effect of ketanserin on pancreatic secretion but not on the release of secretin. These observations suggest that 5-HT(2) and 5-HT(3) receptors mediate duodenal acidification-induced release of secretin and pancreatic secretion of fluid and bicarbonate. Also, regulation of pancreatic exocrine secretion through 5-HT(2) receptors may involve a cholinergic pathway in the rat.

Photopatch testing in seven cases of photosensitive drug eruptions.

OBJECTIVE: The most important goal in the management of photosensitive drug eruptions, as in other types of drug eruptions is identification of the causative drugs to prevent reexposure to them. CASE SUMMARIES: Seven patients whose lesions were mainly distributed on sun-exposed areas underwent laboratory tests, phototests, and photopatch tests with suspected drugs. Phototests were done with ultraviolet A (UVA), UVB, and visible light. Drugs used in the photopatch tests were usually prepared as 10% concentrations in petroleum base, which did not produce reactions in 10 control subjects, followed by irradiation of suberythema doses of UVA. Systemic provocation by oral administration of small doses of causative drugs with irradiation of suberythema doses of UVA was performed to confirm the results of skin tests in four patients. Two patients were not rechallenged with the causative drugs. None of the patients had systemic lupus erythematosus, porphyria, or pellagra. All showed positive reactions to photopatch testing. Systemic provocation confirmed the results of photopatch tests in four patients. The two patients who were not rechallenged had no recurrence of lesions. One patient ingested only one drug at the time of eruptions, and provocation or avoidance was not attempted. A photoallergic mechanism was considered in five cases. CONCLUSIONS: Although there is no information about the appropriate concentrations or vehicles for suspected drugs, photopatch testing could be reliable for identification of causes of photosensitive drug eruptions. Besides piroxicam (a well-known photosensitizer) and carbamazepine, isoniazid and triflusal were identified as the causes of the reactions.

Neural hormonal regulation of exocrine pancreatic secretion.

Exocrine pancreatic secretion is regulated by hormone-hormonal and neural-hormonal interactions involving several regulatory peptides and neurotransmitter from the gut, the pancreas and the vagus nerve. The roles of the gastrointestinal peptides including secretin, CCK, neurotensin, motilin, PYY and pancreatic islet hormones including insulin, pancreatic polypeptide and somatostatin have been established. Interactions among secretin, CCK and neurotensin produce synergistic stimulatory effect. Motilin modulates the cyclic pattern of pancreatic secretion while local insulin provides a permissive role for the action of secretin and CCK at physiological concentration. Somatostatin, PYY and pancreatic polypeptide are inhibitory regulators, acting either on the release of secretin and CCK or on the action of the two stimulatory hormones. The vagal afferent-efferent pathway mediates the actions of many of these regulatory peptides, particularly of secretin and CCK. Acetylcholine and nitric oxide are the neurotransmitters known to mediate the actions of secretin and CCK. Serotonin (5-HT) released from enterochromaffin cells in the intestinal mucosa and nerve terminals of the enteric nervous system and intrapancreatic nerves may be involved in both stimulatory and inhibitory mechanism through its various receptor subtypes. 5-HT also mediates the action of secretin and CCK. The regulatory roles of neuropeptides, PACP and GRP, are now established, whereas those of others are being uncovered. Pancreatic juice provides both positive and negative feedback regulation of pancreatic secretion through mediation of both secretin- and CCK-releasing peptides. Three CCK-releasing peptides have been purified: monitor peptide from pancreatic juice, diazepam-binding inhibitor from porcine intestine, and luminal CCK-releasing factor from rat intestinal secretion. All have been shown to stimulate CCK release and pancreatic enzyme secretion. Pancreatic phospholipase A2 from pancreatic juice and intestinal secretion appears to function as a secretin-releasing peptide. However, the detailed map of neurohormonal regulatory pathways of exocrine pancreatic secretion is yet to be constructed.

Neurohormonal control of exocrine pancreas.

The exocrine pancreas is regulated by various hormonal factors derived from the gut through hormone-hormonal and neurohormonal interactions. Physiologic stimuli entering the upper small intestine elicit the release of intestinal hormones and activate sensory reflex mechanisms from the intestinal mucosa to stimulate or inhibit exocrine pancreatic secretion. In addition, the endocrine pancreas, intrapancreatic nerves, and some extrapancreatic neural pathways, with or without mediation by the vagus nerve, are known to participate in regulation of exocrine pancreatic secretion. It has been established that two key intestinal hormones, secretin and cholecystokinin (CCK), in physiologic doses, act through the vagal afferent pathway and interact with each other as well as with other gut hormones. The releases of these two hormones are mediated through the corresponding releasing peptides. In the past few years, the roles of secretin- and CCK-releasing peptides have become more clearly defined. The participation of several neurotransmitters and regulatory peptides in the regulation of exocrine pancreatic secretion has also been established. In addition, neurotransmitters and neuropeptides released from the central nervous system may participate in the regulation of pancreatic secretion. It is conceivable that a few neurotransmitters and neuropeptides are involved in each neural regulatory pathway. However, their roles and sites of action in each pathway remain to be determined.

Release of distal gut peptide YY (PYY) by fat in proximal gut depends on CCK.

We tested the hypothesis that the release of PYY by fat confined to the proximal small intestine is dependent on CCK. Using a multi-fistulated model, plasma PYY levels were compared in 6 dogs after 60 mM oleate was perfused into the proximal one-half of the small intestine following i.v. administration of saline or devazepide, a CCK-A antagonist. Plasma PYY increased with fat (P < 0. 05), but plasma PYY level was lower following devazepide at 60 min and 90 min (P < 0.05). We conclude that CCK serves as a foregut signal linking fat in the proximal gut with the release of distal gut PYY.

Giant fundic polyp complicating attenuated familial adenomatous polyposis.

This case details the development of a rapidly growing polypoid mass in the proximal stomach in a patient with known attenuated familial adenomatous polyposis. Surgical resection was required and histology showed hyperplasia with extensive areas of dysplastic adenomatous change. This case illustrates that patients with the attenuated form of familial adenomatous polyposis are at risk for multiple neoplasia distinct from those patients with the classic form of familial adenomatous polyposis.

Cellular mechanism of sodium oleate-stimulated secretion of cholecystokinin and secretin.

Long-chain fatty acids are potent stimulants of secretin and CCK release. The cellular mechanisms of fatty acid-stimulated secretion of these two hormones are not clear. We studied the stimulatory effect and mechanism of sodium oleate (SO) on secretin- and CCK-producing cells. SO stimulated the release of secretin or CCK from isolated rat mucosal cell preparations enriched in either secretin- or CCK-producing cells, respectively. SO also time- and dose-dependently stimulated secretin and CCK release from STC-1 cells. In STC-1 cells, SO-stimulated secretin and CCK release was potentiated by IBMX and inhibited by a protein kinase A-selective inhibitor and a cAMP-specific antagonist. SO-stimulated releases of the two hormones were also inhibited by downregulation or inhibitors of protein kinase C, a calmodulin antagonist and an inhibitor of calmodulin-dependent protein kinase II. Chelating of extracellular Ca(2+) or addition of an L-type calcium channel blocker diminished SO-stimulated hormone releases. SO caused an increase in intracellular Ca(2+) concentration that was partially reversed by diltiazem but had no effect on production of cAMP, cGMP, or inositol-1,4,5-triphosphate. These results indicate that SO acts on secretin- and CCK-producing cells. Its stimulatory effect is potentiated by endogenous protein kinase A and mediated by activation of Ca(2+) influx through the L-type channels and of protein kinase C and Ca(2+)/calmodulin-dependent protein kinase II.

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

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

Role of GRPergic neurons in secretin-evoked exocrine secretion in isolated rat pancreas.

Effects of intrapancreatic gastrin-releasing peptide (GRP)-containing neurons on secretin-induced pancreatic secretion were investigated in the totally isolated perfused rat pancreas. Electrical field stimulation (EFS) increased secretin (12 pM)-induced pancreatic secretions of fluid and amylase. EFS induced a twofold increase in GRP concentration in portal effluent, which was completely inhibited by tetrodotoxin but not modified by atropine. An anti-GRP antiserum inhibited the EFS-enhanced secretin-induced secretions of fluid and amylase by 12 and 43%, respectively, whereas a simultaneous infusion of the antiserum and atropine completely abolished them. Exogenous GRP dose-dependently increased the secretin-induced pancreatic secretion with an additive effect on fluid secretion and a potentiating effect on amylase secretion, which was not affected by atropine. In conclusion, excitation by EFS of GRPergic neurons in the isolated rat pancreas results in the release of GRP, which exerts an additive effect on fluid secretion and a potentiating effect on amylase secretion stimulated by secretin. The release and action of GRP in the rat pancreas are independent of cholinergic tone.

Canine vagus nerve stores cholecystokinin-58 and -8 but releases only cholecystokinin-8 upon electrical vagal stimulation.

Cholecystokinin-58 has been shown to be the major form of cholecystokinin (CCK) released to the circulation upon lumenal stimulation of the small intestine in humans and dogs. In anesthetized dogs, electrical vagal stimulation evokes pancreatic exocrine secretion that is in part mediated through the release of CCK. We studied the molecular form of CCK stored in canine vagus nerves and that released into circulation upon electrical vagal stimulation. Gel filtration and radioimmunoassay of the water and acid extracts of canine vagus nerves indicated CCK-8 (35%) and CCK-58 (65%) as the major molecular forms in the vagus nerve. Both forms of CCK isolated from the vagal extracts were equally bioactive as the standard CCK-8 and CCK-58, respectively, in stimulation of amylase release from isolated rat pancreatic acini. Analysis of plasma collected after electrical vagal stimulation indicated that CCK-8 is the only form released into the circulation. The release of CCK-8 upon electrical vagal stimulation was not affected by application of lidocaine to the upper small intestinal mucosa, suggesting that it was released from vagal nerve terminals.

Inhibition of gastric acid secretion in rat stomach by PACAP is mediated by secretin, somatostatin, and PGE(2).

Pituitary adenylate cyclase-activating polypeptide (PACAP), existing in two variants, PACAP-27 and PACAP-38, is found in the enteric nervous system and regulates function of the digestive system. However, the regulatory mechanism of PACAP on gastric acid secretion has not been well elucidated. We investigated the inhibitory action of PACAP-27 on acid secretion and its mechanism in isolated vascularly perfused rat stomach. PACAP-27 in four graded doses (5, 10, 20, and 50 microg/h) was vascularly infused to determine its effect on basal and pentagastrin (50 ng/h)-stimulated acid secretion. To study the inhibitory mechanism of PACAP-27 on acid secretion, a rabbit antisecretin serum, antisomatostatin serum, or indomethacin was administered. Concentrations of secretin, somatostatin, PGE(2), and histamine in portal venous effluent were measured by RIA. PACAP-27 dose-dependently inhibited both basal and pentagastrin-stimulated acid secretion. PACAP-27 at 10 microg/h significantly increased concentrations of secretin, somatostatin, and PGE(2) in basal or pentagastrin-stimulated state. The inhibitory effect of PACAP-27 on pentagastrin-stimulated acid secretion was reversed 33% by an antisecretin serum, 80.0% by an antisomatostatin serum, and 46.1% by indomethacin. The antisecretin serum partially reduced PACAP-27-induced local release of somatostatin and PGE(2). PACAP-27 at 10 microg/h elevated histamine level in portal venous effluent, which was further increased by antisomatostatin serum. However, antisomatostatin serum did not significantly increase acid secretion. It is concluded that PACAP-27 inhibits both basal and pentagastrin-stimulated gastric acid secretion. The effect of PACAP-27 is mediated by local release of secretin, somatostatin, and PGE(2) in isolated perfused rat stomach. The increase in somatostatin and PGE(2) levels in portal venous effluent is, in part, attributable to local action of the endogenous secretin.