Exendin(9-39)amide is an antagonist of glucagon-like peptide-1(7-36)amide in humans.

The gastrointestinal hormone, glucagon-like peptide-1(7-36)amide (GLP-1) is released after a meal. The potency of synthetic GLP-1 in stimulating insulin secretion and in inhibiting glucagon secretion indicates the putative physiological function of GLP-1. In vitro, the nonmammalian peptide, exendin(9-39)amide [ex(9-39)NH2], is a specific and competitive antagonist of GLP-1. This in vivo study examined the efficacy of ex(9-39)NH2 as an antagonist of exogenous GLP-1 and the physiological role of endogenous GLP-1. Six healthy volunteers underwent 10 experiments in random order. In each experiment, a 30-min period of euglycemia was followed by an intravenous infusion of glucose for 150 min that established a stable hyperglycemia of 8 mmol/liter. There was a concomitant intravenous infusion of one of the following: (1) saline, (2) GLP-1 (for 60 min at 0.3 pmol . kg-1 . min-1 that established physiological postprandial plasma levels, and for another 60 min at 0.9 pmol . kg-1 . min-1 to induce supraphysiological plasma levels), (3-5) ex(9-39)NH2 at 30, 60, or 300 pmol . kg-1 . min-1 + GLP-1, (6-8) ex(9-39)NH2 at 30, 60, or 300 pmol . kg-1 . min-1 + saline, (9 and 10) GIP (glucose-dependent insulinotropic peptide; for 60 min at 0.8 pmol . kg-1 . min-1, with saline or ex(9-39)NH2 at 300 pmol . kg-1 . min-1). Each volunteer received each of these concomitant infusions on separate days. ex(9-39)NH2 dose-dependently reduced the insulinotropic action of GLP-1 with the inhibitory effect declining with increasing doses of GLP-1. ex(9-39)NH2 at 300 pmol . kg-1 . min-1 blocked the insulinotropic effect of physiological doses of GLP-1 and completely antagonized the glucagonostatic effect at both doses of GLP-1. Given alone, this load of ex(9-39)NH2 increased plasma glucagon levels during euglycemia and hyperglycemia. It had no effect on plasma levels of insulin during euglycemia but decreased plasma insulin during hyperglycemia. ex(9-39)NH2 did not alter GIP-stimulated insulin secretion. These data indicate that in humans, ex(9-39)NH2 is a potent GLP-1 antagonist without any agonistic properties. The pancreatic A cell is under a tonic inhibitory control of GLP-1. At hyperglycemia, the B cell is under a tonic stimulatory control of GLP-1.

Gastric emptying and release of incretin hormones after glucose ingestion in humans.

This study investigated in eight healthy male volunteers (a) the gastric emptying pattern of 50 and 100 grams of glucose; (b) its relation to the phase of interdigestive motility (phase I or II) existing when glucose was ingested; and (c) the interplay between gastric emptying or duodenal perfusion of glucose (1.1 and 2.2 kcal/min; identical total glucose loads as orally given) and release of glucose-dependent insulinotropic peptide (GIP), glucagon-like peptide-1(7-36)amide (GLP-1), C-peptide, insulin, and plasma glucose. The phase of interdigestive motility existing at the time of glucose ingestion did not affect gastric emptying or any metabolic parameter. Gastric emptying of glucose displayed a power exponential pattern with a short initial lag period. Duodenal delivery of glucose was not constant but exponentially declined over time. Increasing the glucose load reduced the rate of gastric emptying by 27.5% (P < 0.05) but increased the fractional duodenal delivery of glucose. Both glucose loads induced a fed motor pattern which was terminated by an antral phase III when approximately 95% of the meal had emptied. Plasma GLP-1 rose from basal levels of approximately 1 pmol/liter of peaks of 3.2 +/- 0.6 pmol/liter with 50 grams of glucose and of 7.2 +/- 1.6 pmol/liter with 100 grams of glucose. These peaks occurred 20 min after glucose intake irrespective of the load. A duodenal delivery of glucose exceeding 1.4 kcal/min was required to maintain GLP-1 release in contrast to ongoing GIP release with negligibly low emptying of glucose. Oral administration of glucose yielded higher GLP-1 and insulin releases but an equal GIP release compared with the isocaloric duodenal perfusion. We conclude that (a) gastric emptying of glucose displays a power exponential pattern with duodenal delivery exponentially declining over time and (b) a threshold rate of gastric emptying of glucose must be exceeded to release GLP-1, whereas GIP release is not controlled by gastric emptying.

Glucagon-like peptide 1 improves the ability of the beta-cell to sense and respond to glucose in subjects with impaired glucose tolerance.

Impaired glucose tolerance (IGT) and NIDDM are both associated with an impaired ability of the beta-cell to sense and respond to small changes in plasma glucose concentrations. The aim of this study was to establish if glucagon-like peptide 1 (GLP-1), a natural enteric peptide and potent insulin secretagogue, improves this defect. Two weight-matched groups, one with eight subjects having IGT (2-h glucose, 10.1 +/- 0.3 mmol/l) and another with seven subjects with diet-treated NIDDM (2-h glucose, 14.5 +/- 0.9 mmol/l), were studied on two occasions during a 12-h oscillatory glucose infusion, a sensitive test of the ability of the beta-cell to sense and respond to glucose. Glucose was infused with a mean rate of 4 mg x kg(-1) x min(-1), amplitude 33% above and below the mean rate, and periodicity of 144 min, with infusion of saline or GLP-1 at 0.4 pmol x kg(-1) x min(-1) for 12 h. Mean glucose levels were significantly lower in both groups during the GLP-1 infusion compared with during saline infusion: 9.2 +/- 0.4 vs. 6.4 +/- 0.1 mmol/l in the IGT subjects (P < 0.0004) and 14.6 +/- 1.0 vs. 9.3 +/- 0.7 mmol/l in NIDDM subjects (P < 0.0002). Despite this significant reduction in plasma glucose concentration, insulin secretion rates (ISRs) increased significantly in IGT subjects (513.3 +/- 77.6 vs. 583.1 +/- 100.7 pmol/min; P < 0.03), with a trend toward increasing in NIDDM subjects (561.7 +/- 122.16 vs. 642.8 +/- 128 pmol/min; P = 0.1). These results were compatible with enhanced insulin secretion in the presence of GLP-1. Spectral power was used as a measure of the ability of the beta-cell to secrete insulin in response to small changes in the plasma glucose concentration during the oscillatory infusion. Spectral power for ISR increased from 2.1 +/- 0.9 during saline infusion to 7.4 +/- 1.3 during GLP-1 infusion in IGT subjects (P < 0.004), but was unchanged in NIDDM subjects (1.0 +/- 0.4 to 1.5 +/- 0.6; P = 0.3). We concluded that low dosage GLP-1 improves the ability of the beta-cell to secrete insulin in both IGT and NIDDM subjects, but that the ability to sense and respond to subtle changes in plasma glucose is improved in IGT subjects, with only a variable response in NIDDM subjects. Beta-cell dysfunction was improved by GLP-1 infusion, suggesting that early GLP-1 therapy may preserve beta-cell function in subjects with IGT or mild NIDDM.

Mechanisms of the antidiabetic action of subcutaneous glucagon-like peptide-1(7-36)amide in non-insulin dependent diabetes mellitus.

Twelve patients with non-insulin dependent diabetes mellitus (NIDDM) under secondary failure to sulfonylureas were studied to evaluate the effects of subcutaneous glucagon-like peptide-1(7-36)amide (GLP-1) on (a) the gastric emptying pattern of a solid meal (250 kcal) and (b) the glycemic and endocrine responses to this solid meal and an oral glucose tolerance test (OGTT, 300 kcal). 0.5 nmol/kg of GLP-1 or placebo were subcutaneously injected 20 min after meal ingestion. GLP-1 modified the pattern of gastric emptying by prolonging the time to reach maximal emptying velocity (lag period) which was followed by an acceleration in the post-lag period. The maximal emptying velocity and the emptying half-time remained unaltered. With both meals, GLP-1 diminished the postprandial glucose peak, and reduced the glycemic response during the first two postprandial hours by 54.5% (solid meal) and 32.7% (OGTT) (P < 0.05). GLP-1 markedly stimulated insulin secretion with an effect lasting for 105 min (solid meal) or 150 min (OGTT). The postprandial increase of plasma glucagon was abolished by GLP-1. GLP-1 diminished the postprandial release of pancreatic polypeptide. The initial and transient delay of gastric emptying, the enhancement of postprandial insulin release, and the inhibition of postprandial glucagon release were independent determinants (P < 0.002) of the postprandial glucose response after subcutaneous GLP-1. An inhibition of efferent vagal activity may contribute to the inhibitory effect of GLP-1 on gastric emptying.

The efficacy of a 40-mg extended-release formulation of cisapride in the treatment of patients with gastro-oesophageal reflux.

BACKGROUND: This study was conducted to assess the efficacy of a novel 40-mg extended-release formulation of cisapride in reducing gastro-oesophageal reflux. METHODS: According to a double-blind, randomized, placebo-controlled design, 19 patients with pathological gastro-oesophageal reflux were treated with extended (40 mg o.d.) or immediate (10 mg q.d.s.) release formulations for two periods of 4 days each (pH-monitoring on day four). Patients received identical treatments in both periods to allow limits of agreement defining equivalent potency of both formulations to be derived from intra-individual variability of treatment effects. RESULTS: The extended-release formulation decreased total and upright reflux times by 5.5 +/- 1.3% and 8.1 +/- 2.1% (P < 0.001), respectively. It did not change the percentage supine reflux time but diminished the mean duration of reflux episodes by 1.0 +/- 0.4 min (P=0.005). The total number of reflux episodes remained unaltered with both formulations. Immediately-released cisapride decreased total, upright, and supine acid exposures by 5.8 +/- 1.3%, 6.8 +/- 1.6% (P < 0.002) and 3.6 +/- 1.8%, respectively, and mean duration of episodes by 0.9 +/- 0.2 min (P

A double-blind, randomized, multicentre, crossover study to prove equivalence of pancreatin minimicrospheres versus microspheres in exocrine pancreatic insufficiency.

BACKGROUND: Modern pancreatin preparations consist of enteric-coated microspheres to protect the enzymes from gastric acid. There are, however, no clinical trials comparing different sizes of pancreatin microspheres with regard to fat excretion and fat intake. AIM: To prove both equivalent efficacy and safety of conventional pancreatin microspheres and smaller pancreatin minimicrospheres in patients with exocrine insufficiency due to chronic pancreatitis. METHODS: In this prospective, randomized, double-blind, multicentre, crossover trial, patients with a stool fat excretion of > 7.5 g/day during a placebo period were randomly assigned either to the minimicrosphere/microsphere treatment sequence or vice versa. The primary end-point was the coefficient of fat absorption, which was calculated from fat excretion and fat intake during the course of a standardized diet. Stool weight, clinical symptoms and the safety of the preparations were also evaluated. RESULTS: Thirty-seven patients entered the study, of whom 23 fulfilled the criteria for the crossover period. In the per protocol analysis (n=18), the 90% confidence intervals for the coefficient of fat absorption of both crossover periods lay entirely within the equivalence range (P=0.02). The intention-to-treat analysis revealed similar results, but the equivalence range was slightly missed (P=0.07). Similar results were obtained for the secondary parameters and the reported adverse events. CONCLUSIONS: Pancreatin minimicrospheres have been shown to be equally effective as microspheres in improving the coefficient of fat absorption in patients with exocrine insufficiency due to chronic pancreatitis.

Duodenal secretion and fecal excretion of pancreatic elastase-1 in healthy humans and patients with chronic pancreatitis.

Fecal elastase-1 is a candidate for a sensitive noninvasive test detecting chronic pancreatitis. This prospective study enrolled 10 healthy male controls and 23 patients referred for tube testing of pancreatic function. It was designed (a) to correlate duodenal outputs and fecal concentrations of elastase-1 with duodenal outputs of amylase, lipase, trypsin, and chymotrypsin in the fed state (duodenal perfusion of a mixed liquid meal at 2.5 kcal/min for 150 min), (b) to compare the diagnostic accuracy of fecal elastase-1 and fecal chymotrypsin, and (c) to characterize the cyclical pattern of postprandial pancreatic secretion in healthy subjects and patients with chronic pancreatitis. Based on their enzyme responses to duodenal meal perfusion and imaging procedures, 12 patients were classified as having normal pancreatic function and 11 patients as having chronic pancreatitis. Duodenal enzyme outputs of elastase-1 were markedly lowered in chronic pancreatitis (p < 0.0001) and correlated well with the outputs of the other four enzymes (r > 0.71, p < 0.00001). Fecal concentrations of elastase-1 were also clearly reduced in chronic pancreatitis (p < 0.0001). Fecal chymotrypsin was less strongly associated with duodenal enzyme outputs (r = 0.33 to r = 0.587), whereas fecal elastase-1 correlated more precisely with the duodenal outputs of all five enzymes (r = 0.637 to r = 0.830, p < 0.00001). Sensitivity and specificity in the detection of chronic pancreatitis amounted to 0.64 and 0.95 for fecal elastase-1 and 0.27 and 0.95 for fecal chymotrypsin, respectively. In the postprandial state, peaks of enzyme secretion occurred at a frequency of about 1 peak/150 min. The amplitude but not the frequency of secretory peaks was markedly reduced in chronic pancreatitis (p < 0.01). We conclude that fecal elastase-1 clearly exceeds the sensitivity of fecal chymotrypsin in the diagnosis of chronic pancreatitis but does not reliably detect all cases with mild to moderate disease. The pattern of postprandial pancreatic secretion is cyclical, even with minimal secretory outputs in chronic pancreatitis.

[Conservative treatment of florid peptic esophageal stenosis. Complete elimination by dilatation and omeprazole in H2-blocker refractory cases]. / Konservative Behandlung der floriden peptischen Osophagusstenose. Komplette Beseitigung durch Bougierung und Omeprazol bei H2-Blocker-refraktären Fällen.

23 patients with severe reflux oesophagitis complicated by peptic erosive strictures requiring dilatation and resistant to H2-blocker therapy were treated with the proton pump inhibitor omeprazole (initial dosing: 40 mg daily) and dilated. Combination of dilatations (median 2, range 1 to 12 courses) and omeprazole therapy facilitated complete resolution of strictures and disappearance of peptic lesions after four and eight weeks in 30% and 70%, respectively. In all remaining cases healing could be achieved by perpetuation of omeprazole therapy though three patients (13%) required omeprazole doses higher than 40 mg daily for healing and maintenance. Follow-up investigations available in 17 patients during continuation of omeprazole therapy revealed no recurrence of strictures. It is concluded that more pronounced and particularly longer lasting inhibition of acid secretion is effective even in these most severe cases of reflux oesophagitis.

[Electrochemical measuring system for the registration of transmucosal gastrointestinal potential differences]. / Elektrochemisches Messsystem für die Registrierung transmucosaler gastrointestinaler Potentialdifferenzen.

An electrochemical measuring system for the recording of transmucosal gastrointestinal potential differences based on silver electrodes with double-junctions and continuous-flow saline bridges is described. Under bioelectrochemical control, a probe can passed from the esophagus via the stomach into the duodenum can be accurately assigned to each of these three segments of the intestine. Measurements are demonstrated and applications discussed.

[Diagnosis and treatment of esophageal motility disorders]. / Diagnostik und Behandlung von Motilitätsstörungen der Speiseröhre.

Apart from gastroesophageal reflux disease, achalasia, non-cardiac chest pain and functional dysphagia are the most important manifestations of disturbed esophageal motility. Achalasia is characterized by esophageal aperistalsis and impaired deglutitive relaxation of the lower esophageal sphincter. The morphological correlate is a degeneration of nitrergic neurons in the myenteric plexus. Diagnosis is based on barium esophagram or esophageal manometry with the latter setting the gold standard. Endoscopic exclusion of a tumor at the gastroesophageal junction is mandatory. Appropriate therapeutic interventions are pneumatic dilatation or (laparoscopic myotomy) of lower esophageal sphincter. In patients unfit for these procedures endoscopic injection of botulinum toxin into the lower esophageal sphincter is appropriate. Non-cardiac chest pain may be of esophageal origin. Gastroesophageal reflux, spastic motility disorders and visceral hypersensitivity are arguable underlying mechanisms. The most important diagnostic procedure is 24 h esophageal pH metry correlating symptoms and reflux episodes. Proton pump inhibitors and tricyclic antidepressants serving as visceral analgesics are appropriate therapeutic approaches. Functional dysphagia defines the sensation of impaired passage without mechanical obstruction or a neuromuscular disease with known pathology, e.g. scleroderma. Impaired transit is proven by esophageal scintigraphy or radiogram both using solid boluses. Manometry assesses the underlying mechanisms.

GLP-1 regulates gastroduodenal motility involving cholinergic pathways.

The gut-born incretin hormone glucagon-like peptide-1 (GLP-1) delays gastric emptying. To elucidate the mechanisms by which GLP-1 affects gastroduodenal motility and glycaemia, we studied the effects of exendin(9-39), a potent GLP-1 receptor antagonist, on gastroduodenal motility and pancreatic hormones. In this randomized, double-blind, placebo-controlled, four-arm, cross-over trial, 10 healthy volunteers were studied during the interdigestive period followed by duodenal perfusion of a mixed liquid meal (250 kcal). On four separate days, exendin(9-39), atropine, exendin(9-39) + atropine or saline were infused intravenously. Antro-pyloro-duodenal and fundic motility were assessed. The compliance of the proximal stomach was determined by isobaric distensions. During fasting, exendin(9-39) did not influence proximal gastric volume, pyloric tone, and duodenal contractility. Exendin(9-39) significantly increased antral waves only in the absence of atropine. During duodenal meal perfusion, exendin(9-39) significantly reduced proximal gastric volume accommodation, abbreviated postprandial antral inhibition, reduced the postprandial increase in pyloric tone, and reduced gastric compliance. Atropine abolished the effects of exendin(9-39) on gastric volume accommodation but did not affect its effects on postprandial antroduodenal motility and on gastric compliance. Exendin(9-39) increased fasting and postprandial glycaemia and plasma glucagon but not insulin concentrations. Atropine did not affect GLP-1 secretion. Cholinergic mechanisms mediate the effects of GLP-1 on postprandial gastric accommodation but not on antro-pyloro-duodenal motility. GLP-1 reduces fasting and postprandial glycaemia, in part by reducing glucagon secretion.

Endogenous glucagon-like peptide 1 controls endocrine pancreatic secretion and antro-pyloro-duodenal motility in humans.

BACKGROUND: Exogenous use of the intestinal hormone glucagon-like peptide 1 (GLP-1) lowers glycaemia by stimulation of insulin, inhibition of glucagon, and delay of gastric emptying. AIMS: To assess the effects of endogenous GLP-1 on endocrine pancreatic secretion and antro-pyloro-duodenal motility by utilising the GLP-1 receptor antagonist exendin(9-39)amide (ex(9-39)NH2). METHODS: Nine healthy volunteers underwent four experiments each. In two experiments with and without intravenous infusion of ex(9-39)NH2 300 pmol/kg/min, a fasting period was followed by intraduodenal glucose perfusion at 1 and 2.5 kcal/min, with the higher dose stimulating GLP-1 release. Antro-pyloro-duodenal motility was measured by perfusion manometry. To calculate the incretin effect (that is, the proportion of plasma insulin stimulated by intestinal hormones) the glycaemia observed during the luminal glucose experiments was mimicked using intravenous glucose in two further experiments. RESULTS: Ex(9-39)NH2 significantly increased glycaemia during fasting and duodenal glucose. It diminished plasma insulin during duodenal glucose and significantly reduced the incretin effect by approximately 50%. Ex(9-39)NH2 raised plasma glucagon during fasting and abolished the decrease in glucagon at the high duodenal glucose load. Ex(9-39)NH2 markedly stimulated antroduodenal contractility. At low duodenal glucose it reduced the stimulation of tonic and phasic pyloric motility. At the high duodenal glucose load it abolished pyloric stimulation. CONCLUSIONS: Endogenous GLP-1 stimulates postprandial insulin release. The pancreatic alpha cell is under the tonic inhibitory control of GLP-1 thereby suppressing postprandial glucagon. GLP-1 tonically inhibits antroduodenal motility and mediates the postprandial inhibition of antral and stimulation of pyloric motility. We therefore suggest GLP-1 as a true incretin hormone and enterogastrone in humans.

Nutritional implications of cephalic phase gastrointestinal responses.

Palatable cephalic stimuli induce a simultaneous activation of gastrointestinal motility, gastric acid and pancreatic enzyme secretion, as well as, release of the gastrointestinal hormones gastrin and pancreatic polypeptide. Cholinergic neural input is the dominant mediator of these responses with cholecystokinin and gastrin acting as additional stimulatory modulators. Central cholinergic circuits, neuropeptide Y, and thyrotropin releasing hormone are candidate central stimulators of the cephalic phase. There are good arguments for glucagon-like peptide-1 and peptide YY to be physiological inhibitors of cephalic-phase responses with these peptides being released in the intestinal phase of digestion and putatively contributing to termination of the cephalically stimulated pattern. Cephalic-phase responses are used clinically as diagnostic tests to assess completeness of selective proximal vagotomy and to explore autonomic neuropathy. Pancreatic polypeptide secretion with sham feeding is an appropriate test of abdominal vagal function. Cephalically stimulated motor and secretory activity contribute greater than 50% of overall postprandial responses. Pharmacological inhibition of cephalic-vagal stimulation, resulting in reduced food intake, may be a novel approach to obesity management. Glucagon-like peptide-1 is a particular candidate because it inhibits the cephalic phase of digestion, diminishes food intake, and reduces the glycemic excursion after a meal by retarding gastric emptying, stimulating insulin and lowering glucagon release.

Ulcerative colitis and Crohn's disease: factor XIII, inflammation and haemostasis.

An important role has been ascribed to plasma factor XIII (FXIII) in inflammation and wound healing. FXIII is necessary for fibrin stabilization and interacts with connective tissue and adhesive proteins and cells. In a prospective study, FXIII activity and parameters of coagulation, fibrinolysis and inflammation, were determined in patients with ulcerative colitis (UC; 13 active, 22 moderate) and Crohn's disease (CD; 36 active, 45 moderate). FXIII levels were lower in active than in moderate UC and CD, and were < 70% of normal values in 7/13 patients with active UC, and in 7/36 patients with active CD, although the median values did not fall below the normal range. FXIII was somewhat higher in active UC patients responding to therapy. The FXIII levels were widely scattered, and low values appear to be due to greatly enhanced turnover. A correlation between FXIII and the systemic levels of markers of activation of haemostasis and inflammation was lacking, but there was a correlation with the extent of bowel involvement. FXIII levels were lower in the patients with involvement beyond the sigmoid colon in CU (p = 0.0045), and both small and large bowel segments in CD (p = 0.0223) patients. This points to local consumption and/or loss of FXIII within the inflamed tissue, and provides an argument for FXIII substitution in the treatment of acute episodes of inflammatory bowel diseases.

Cisapride stimulates human esophageal motility.

The potency of cisapride to stimulate esophageal motility is still a matter of conjecture. This double-blind placebo-controlled study assessed the effect of repeated oral doses of cisapride at 10 and 20 mg on interdigestive esophageal motility in 10 healthy male volunteers. In each experiment, esophageal motility was recorded continuously for 60 min with a sleeve sensor straddling the lower esophageal sphincter and four series of 10 wet swallows being performed. Analysis of motor events was computer assisted. Plasma cisapride levels amounted to 72.3 +/- 6.1 ng/ml with 10 mg cisapride and 142.5 +/- 11.9 ng/ml with 20 mg cisapride (p < 0.001 vs. 10 mg). Lower esophageal sphincter pressure increased from 20.6 +/- 2.3 mm Hg (placebo) to 28.9 +/- 2.3 mm Hg with 10 mg cisapride (p < 0.0001 vs. placebo) and to 26.8 +/- 1.8 mm Hg with 20 mg cisapride (p < 0.001 vs. placebo). Cisapride increased amplitude, duration, and area but not contractility and peristaltic velocity of esophageal contraction waves. Cisapride caused a maximum rise in amplitude of 22.4%, in area of 19.4%, and in duration of 9.6%. Its effects were greatest in the proximal and middle smooth muscle segments and more pronounced with 10 than with 20 mg. We conclude that cisapride clearly increases lower esophageal sphincter pressure and, to a lesser extent, raises amplitude and prolongs duration of esophageal contraction waves. Effects on contraction waves seem to correlate with the density of cholinergic innervation. Increasing the dose above 10 mg in the steady state does not further enhance the effect in healthy subjects.

Gastrointestinal motor and secretory responses to cholinergic stimulation in humans. Differential modulation by muscarinic and cholecystokinin receptor blockade.

The present study investigated how a cholinergic agonist modifies interdigestive motility and secretion of the upper gastrointestinal tract and how muscarinic and cholecystokinin receptor blockade interfere with this direct cholinergic stimulation. In eight healthy volunteers, gastrointestinal motor and secretory responses to bethanechol (12.5, 25, and 50 micrograms kg-1 h-1) with and without a background of atropine (5 micrograms kg-1 h-1) or loxiglumide (10 mg kg-1 h-1) were studied. Stepdoses of bethanechol caused a parallel stimulation of antroduodenal motility and gastropancreatic secretion (P < 0.01) without inducing a fed pattern. However, duration of phase I was shortened (P < 0.05). Only high doses of bethanechol enhanced gastrin (P < 0.05), cholecystokinin (P < 0.05), and pancreatic polypeptide (P < 0.01) release. Atropine completely antagonized motor and secretory responses to cholinergic stimulation. Loxiglumide left cholinergically stimulated motility and pancreatic enzyme secretion unaltered. With co-infusion of bethanechol and loxiglumide, PP release dropped by 63% (P < 0.01); gastric acid output, gastrin and CCK release increased by 56%, 16%, and 25%, respectively (P < 0.05). We conclude that stimulation by a cholinergic agonist preserves the interdigestive pattern. Low dose muscarinic receptor blockade abolishes cholinergic stimulation over the full dose range. Inhibition of somatostatin release would explain stimulation of gastrin release and gastric acid secretion with co-infusion of bethanechol and loxiglumide. Endogenous CCK appears to interact with direct cholinergic stimulation at the pancreatic PP cell and the gastric D-cell but not at pancreatic acinar and antroduodenal smooth muscle cells.

Cephalic stimulation of gastrointestinal secretory and motor responses in humans.

The present study was designed (a) to investigate the cephalic phase of gastropancreatic secretion, antroduodenal motility, and regulatory peptide release in six healthy young men and (b) to assess its regulation by the cholinergic system and endogenous cholecystokinin. Sham feeding performed for 15 minutes induced a concurrent stimulation of gastropancreatic secretion, antroduodenal motility, and pancreatic polypeptide release that lasted for 30 minutes. Reappearance of interdigestive phases III was retarded in the post-sham-fed state. Atropine abolished secretory, motor, and pancreatic polypeptide responses to sham feeding and enhanced gastrin release. The cholecystokinin receptor antagonist loxiglumide did not attenuate pancreatic enzyme response but diminished antral motor response by 72% (P less than 0.05) and release of pancreatic polypeptide by 91% (P less than 0.05); it enhanced gastrin release and abolished retardation of reappearance of phase III with sham feeding. It is concluded that (a) there is a distinct cephalic phase of gastropancreatic secretion, antroduodenal motility, and pancreatic polypeptide release in humans that is primarily under cholinergic control and that (b) endogenous cholecystokinin is involved in antral motor, gastrin, and pancreatic polypeptide responses to sham feeding.