GR 38032F (Ondansetron), a selective 5HT3 receptor antagonist,slows colonic transit in healthy man

The newly recognized class of 5-hydroxytryptamine receptors (5HT₃) may be involved in the induction of nausea, since their pharmacological antagonists are effective against emesis induced by chemotherapy. 5HT₃ receptors are present on enteric neurons, and 5HT₃ blockers may produce mild constipation; we thus hypothesized that 5HT₃ receptors would modulate colonic motility. To determine if GR 38032F, a selective 5HT₃ antagonist known to have antiemetic effects, influences colonic transit in health, a randomized, double-blind, placebo-controlled crossover study was performed. Using a radiopaque marker technique, colonic transit was quantified in 39 healthy volunteers (19 men, 20 nonpregnant women) 18–70 years of age. On a standard 25-g fiber diet, 16 mg of GR 38032F was given orally thrice daily. Gastrointestinal peptides (peptide YY, human pancreatic polypeptide, neurotensin, motilin, gastrin-cholecystokinin, substance P) were also measured in plasma fasting and postprandially. Mean total colonic transit time on placebo was 27.8 hr, while on GR 38032F it was 39.1 hr (P<0.0005). Transit times through the left colon (P<0.0005) and rectosigmoid (P<0.05) were prolonged by the drug, but right colonic transit was not significantly altered. Transit times did not correlate with age or gender, but subjects with shorter transit times were significantly more affected than were those with longer transit times. The peak release of peptide YY was minimally decreased following GR 38032F (P<0.01), but the peak and integrated postprandial responses of human pancreatic polypeptide, neurotensin, motilin, gastrin-cholecystokinin, and substance P were not significantly altered by the drug. We conclude that 5HT₃ receptors may be involved in the regulation of colonic transit in healthy man.Supported in part by a grant from Glaxo Group Research, Ltd., and the Mayo Digestive Disease Center (grant DK34988, National Institutes of Health, Bethesda, Maryland).Presented, in part, at the American Motility Socicty in October 1988, and published as an abstract inGastroenterology 95:891, 1988.     

Terbutaline,A β2-Adrenoreceptor agonist,inhibits gastric acid secretion and stimulates release of peptide YY and gastric inhibitory polypeptide in dogs

Terbutaline, a ₂-adrenoreceptor agonist, inhibits pentagastrin-stimulated gastric acid secretion. The purpose of this study was to examine the effect of intravenous administration of terbutaline on plasma levels of peptide YY(PYY) and gastric inhibitory polypeptide (GIP), both of which are known to inhibit gastric acid secretion. Seven dogs with gastric and duodenal fistulas were given pentagastrin (1 g/kg/hr) intravenously for 150 min in combination with terbutaline (10 or 20 g/kg/hr) or saline during the 60- to 120-min period of pentagastrin infusion. Pentagastrin-stimulated gastric acid secretion was significantly (P <0.05) inhibited by intravenous administration of terbutaline. Terbutaline significantly increased plasma PYY levels, 24% in response to terbutaline at 10 g/kg/hr, and 59% at 20 g/kg/hr. Plasma GIP levels were also increased significantly, 24% with terbutaline at 10 g/kg/hr, and 39% at 20 g/kg/hr. Our data suggest that terbutaline-induced inhibition of pentagastrin-stimulated gastric acid secretion is mediated, at least in part, by the release of PYY and GIP. The adrenergic nervous system may influence gastric acid secretion through the release of PYY and GIP.Supported by grants from the National Institutes of Health (5 R37 DK 15241-17, PO1 DK 35608, and RO1 DK 37406), and the John Sealy Memorial Endowment Fund (2723).     

Small doses of melatonin increase intestinal motility in rats

Since melatonin receptors are present in the intestines, the possibility that this hormone may affect intestinal motility has been studied in the rat. Sprague-Dawley male rats were given a carmine cochineal powder meal and were injected intraperitoneally with 1, 10, 100, or 1000 g/kg melatonin. Sixty minutes after treatment, intestinal transit was found to be faster in animals treated with small doses of melatonin (1 or 10 g/kg) than in saline-injected controls. This effect, however, appear to be clearly reversed with 100 or 1000 g/kg melatonin. In fact, these doses of the hormone reduced intestinal transit in rats. The nonselective melatonin receptor antagonist, luzindole (administered intraperitoneally in a dose of 0.25 mg/kg, 15 min prior to melatonin injection) totally prevented the accelerating effect of melatonin (10 g/kg) on intestinal transit. Luzindole per se failed to affect gut motility. Injection of the reversible acetylcholinesterase inhibitor and cholinergic agent, neostigmine, accelerated intestinal transit but failed to influence melatonin effect on this parameter. In contrast, intraperitoneal injection of the muscarinic receptor antagonist atropine delayed intestinal transit per se but did not reduce the stimulating effect of melatonin on this parameter. Intestinal myoelectrical recording revealed that intestinal myoelectrical activity was increased by intraperitoneal injection of melatonin (10 g/kg). Administration of luzindole totally prevented melatonin-induced increase of intestinal myoelectrical activity. These results indicate that melatonin may affect intestinal motility in rats when administered in small doses. This effect might be mediated by melatonin receptors in the intestines, although the involvement of central receptors for the hormone is also possible.     

Gut hormones and gastrointestinal motility in children with cystic fibrosis

Intestinal dysmotility may be an important factor contributing to various gastrointestinal complications associated with cystic fibrosis. Motilin, enteroglucagon, neurotensin, and peptide YY may each play a role as endocrine hormones influencing gastrointestinal motor activity. Fasting children with cystic fibrosis (N=8) and controls (N=18) received a liquid nutrient test meal (fat 4 g/100 ml, protein 4 g/100 ml, carbohydrate 20 g/100 ml, 125 kcal/100 ml; 200 ml/m²) containing lactulose (5 g/100 ml), and the plasma concentrations of these peptides were studied. Mouth-to-cecum transit time was simultaneously studied using the breath H₂ technique. Fasting levels of peptide YY and the postprandial response of all four peptides were significantly increased in those with cystic fibrosis. In repeat studies on those with cystic fibrosis after a period of altered pancreatic enzyme supplementation, no significant changes in peptide concentrations were observed. A rise in breath H₂ permitting estimation of mouth-to-cecum transit time was noted in 17 control subjects (70–220 min, median 140). In contrast, a rise occurred in only two with cystic fibrosis after low-dose enzyme (70 and 180 min), and four after high-dose enzyme replacement (120–230 min, median 155). Altered gut hormone secretion may play a role in the pathophysiology of intestinal dysmotility in patients with cystic fibrosis.     

Effects of Very Long Chain Versus Long Chain Triglycerides on Gastrointestinal Motility and Hormone Release in Humans

Fish oil (a very long chain triglycerides, VLCT) has received much attention because of its favorable metabolic properties; however, its effect on gastrointestinal function has not been studied. We investigated the effects of intraduodenally administered VLCT on gut-hormone release [cholecystokinin (CCK), neurotensin, peptide YY (PYY)], gallbladder emptying, antroduodenal motility, and small bowel transit time (SBTT) in comparison to intraduodenal administration of saline and long chain triglycerides (LCT, corn oil) in nine healthy volunteers. Gallbladder contraction duration was significantly shorter after VLCT than after LCT (138 ± 16 min vs 233 ± 38 min, P < 0.05). Both fats induced a fed motility pattern, while SBTT was not significantly altered. CCK secretion was significantly reduced after VLCT compared to LCT (36 ± 12 pM × 120 min vs 78 ± 15 pM × 120 min, P < 0.05), whereas PYY and neurotensin release were not significantly different. In conclusion, effects of triglycerides on CCK and gallbladder motility appear to be chain-length dependent, in contrast to the effects on distal gut-hormone release and intestinal motility and transit, which appear to be chain-length independent.     

Central and peripheral serotonergic influences on viscerovisceral inhibitory reflex during duodenal distension in sheep

The effects of duodenal distension on forestomach and abomasal motility were investigated in conscious sheep chronically fitted with intraparietal electrodes, a duodenal cannula, and an intracerebroventricular cannula. Duodenal distensions with a balloon inflated with 40 ml (DD40) of water reduced the frequency of forestomach and abomasal contractions by 45 and 32%, respectively, while distension with 80 ml (DD80) induced a total inhibition. Methysergide, a mixed 5HT₁-5HT₂ antagonist administered intravenously (200 g/kg) or intracerebroventricularly (20 g/kg) suppressed the DD40-induced inhibition and reduced that induced by DD80. Sprioxatrine, a selective 5HT_1A antagonist, intravenously (100 g/kg) or intracerebroventricularly (10 g/kg), suppressed the DD40 and DD80-induced inhibition, which was also attenuated by the 5HT₂ antagonist ritanserin given intravenously (200 g/kg) or intracerebroventricularly (20 g/kg). Granisetron, a 5HT₃ antagonist, injected intravenously (150 g/kg), abolished the effects of DD40 and DD80 while it had no antagonistic action on DD40 and DD80 when given intracerebroventricularly (15 g/kg). It is concluded that in sheep, duodenal distension inhibits forestomach and abomasal motility through 5HT_1A and 5HT₂ receptors at the level of the central nervous system and 5HT₃ receptors located peripherally.This work was presented in part at the First United European Gastroenterology Week, September 25–30, 1992, Athens, Greece.     

Mediation of anaphylaxis-induced jejunal circular smooth muscle contraction in rats

Altered intestinal motility and diarrhea are features of food protein-induced intestinal anaphylaxis in the conscious rat. These experiments were performed to determine the mediator(s) responsible for jejunal circular smooth muscle contraction during this response. Hooded-Lister rats were sensitized by intraperitoneal injection of 10-g egg albumin, and controls were sham-sensitized with saline. Fourteen days later the contractility of the circular muscle in jejunal segments (mucosa intact) was examined in standard tissue baths in response to antigen (Ag) or other agents. While control and sensitized tissues contracted in similar fashion in response to stretch, bethanechol, histamine, or 5-hydroxytryptamine (5HT), Ag contracted only the segments of sensitized animals. The contractile response was: (1) specific to the sensitizing Ag, as bovine serum albumin did not induced contraction and (2) could be passively transferred with serum containing specific immunoglobulin E antibody (IgE-Ab). Concanavalin A, which degranulates both mucosal and connective tissue-type mast cells, and compound 48/80, which degranulates only connective tissue-type mast cells produced contractile responses. Ag-induced contraction was significantly inhibited by the mucosal and connective tissue-type mast cell stabilizer doxantrazole, but not the connective tissue mast cell stabilizer disodium cromoglycate. Diphenhydramine and cimetidine together significantly inhibited histamine-induced contraction, but failed to effect the Ag-induced contraction in sensitized tissues. While the contractile response to 5HT was reduced in the presence of methysergide (5HT₁-receptor antagonist), cinanserin (5HT₂-receptor antagonist), and ICS 205-930 (5HT₃-receptor antagonist), only cinanserin significantly inhibited the contractile response to Ag. Indomethacin significantly inhibited Ag-induced contraction. Ag-induced contraction was resistant to atropine and tetrodotoxin. Thus, food protein-induced alterations in intestinal motility in sensitized rats are due in part to an IgE-mediated mast cell degranulation, 5HT release, prostaglandin synthesis, and contraction of the circular smooth muscle.     

Neurotensin prevents intestinal mucosal hypoplasia in rats fed an elemental diet

Liquid elemental diets are associated with mucosal hypoplasia of both the small intestine and colon. Neurotensin, a tridecapeptide widely distributed in the gut, is trophic for the small intestine of rats fed a normal chow diet. The purpose of this study was to determine whether neurotensin could reverse the hypoplasia of intestinal mucosa that is associated with feeding a liquid elemental diet. Forty male Sprague-Dawley rats were randomized into five groups. Four groups were fed (for seven days) a glutamine-free liquid elemental diet. Subcutaneuos injection of saline (control) or neurotensin (33, 100, or 300 g/kg) were given to the groups of rats every 8 hr for seven days. Group five (Chow) received rat chowad libitum for seven days. Rats were killed on day 8, and the proximal jejunum, distal ileum, and proximal colon removed. Mucosal weight, DNA, RNA, and protein contents were determined. Neurotensin (300 g/kg) increased the cellularity of the small intestinal mucosa and reversed mucosal hypoplasia due to an elemental diet; a more pronounced effect was noted in the jejunum compared to the ileum. Neurotensin (33 and 100 g/kg) increased mucosal DNA content in the jejunum but was not effective in reversing the hypoplasia. Neurotensin had no effect on growth of colonic mucosa. These results suggest that neurotensin may be an important trophic hormone for the small intestine. Administration of neurotensin may alleviate hypoplasia of the small bowel mucosa and maintain functional integrity of the gut during prolonged feeding of an elemental diet.Supported by grants from the National Institutes of Health (5R37DK 15241-17, P01 DK 35608), the American Cancer Society (PDT-220), and the National Cancer Institute (CA 17701).A preliminary report has appeared inSurgical Forum (1).Dr. Evers is a recipient of an American Surgical Association Foundation Fellowship Award.     

Ileoanal pouch function and release of peptide YY

PURPOSE: This study evaluates peptide tyrosine-tyrosine (PYY), intestinal transit, fecal retention time, and anal sphincter manometry in colectomized patients with ileal pouch-anal anastomosis. METHODS: Plasma and pouch PYY, mouth-to-pouch transit time, fecal retention time, and anal canal pressures were studied in 27 patients with ileoanal pouches a mean of 50 (range, 3–84) months after loop ileostomy closure. RESULTS: Basal and peak postprandial plasma PYY were significantly reduced in patients with pouches compared with controls (P<0.0001). Pouch PYY was decreased compared with control ileal PYY (P=0.0003). No significant correlation was noted between intestinal transit and total integrated PYY response in patients with pouches (r=0.36;P=0.06). Fecal retention time was related to postprandial total integrated response of plasma PYY (r=0.43;P=0.02), mouth-to-pouch transit (r=0.87;P<0.0001), and resting (r=0.44;P=0.02) and squeeze (r=0.62;P=0.0006) anal sphincter pressures. CONCLUSIONS: Colectomized ileoanal patients with pouches showed decreased plasma and pouch PYY compared with controls. Intestinal transit was not significantly related to PYY release. However, prolonged pouch fecal retention was associated with greater PYY release, mouth-to-pouch transit, and anal sphincter pressures.Supported in part by the State of Nebraska Cancer and Smoking Related Diseases Program (LB595).Read at the meeting of The American Society of Colon and Rectal Surgeons, Montreal, Quebec, Canada, May 7 to 12, 1995. This article received the Research Forum Award.     

Influence ofin situ neural isolation of jejunoileum on postprandial pancreatobiliary secretion and gastric emptying

Our aims were to examine the influence of neural isolation of the jejunoileum on opstprandial pancreatobiliary secretion. In four dogs, duodenal perfusion and aspiration catheters were implanted, and serosal electrodes were placed along the proximal small bowel. Control studies of gastric emptying output of bile acids and amylase, and plasma concentrations of peptide YY and neurotensin were performed on three occasions following ingestion of a 340-kcal mixed-nutrient liquid meal. The dogs then underwent our model ofin situ jejunoileal neural isolation, and the meal studies were repeated. Neural isolation, when compared to control, did not affect either postprandial conversion of intestinal myoelectric activity to the fed pattern, gastric emptying (T1/2,X±se of the liquid meal (74±6 vs 79±7 min;P>0.05), or cumulative amylase output (373±59 vs 305±66 kU;P>0.05). Neural isolation decreased cumulative postprandial bile acid output from 6.6±0.9 mM to 3.4±1.1 mM (P<0.05) and increased postprandial plasma concentrations of peptide YY and neurotensin. Our findings suggest that the jejunoileal denervation that accompanies thein situ neural isolation of the jejunoileum is not associated with changes in postprandial motility patterns, gastric emptying, or pancreatic amylase secretion. Loss of this innervation, however, may decrease postprandial output of bile acids and lead to a compensatory increase in the postprandial release of neurotensin and peptide YY.This work was supported by NIH grants DK34988, AM07198, DK39337, and by the U.S. Surgical Corporation.Part of this work was presented and published in abstract form at the Surgical Forum of the American College of Surgeons, November 1989.     

Co-localisation and secretion of glucagon-like peptide 1 and peptide YY from primary cultured human L cells

Aims/hypothesis

Targeting the secretion of gut peptides such as glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) is a strategy under development for the treatment of diabetes and obesity, aiming to mimic the beneficial alterations in intestinal physiology that follow gastric bypass surgery. In vitro systems are now well established for studying the mouse enteroendocrine system, but whether these accurately model the human gut remains unclear. The aim of this study was to establish and characterise human primary intestinal cultures as a model for assessing GLP-1 and PYY secretion in vitro.

Methods

Fresh surgical biopsies of human colon were digested with collagenase to generate primary cultures from which GLP-1 and PYY secretion were assayed in response to test stimuli. GLP-1 and PYY co-localisation were assessed by flow cytometry and immunofluorescence microscopy.

Results

GLP-1 and PYY were found localised in the same cells and the same secretory vesicles in human colonic tissue samples. GLP-1 release was increased to 2.6-fold the control value by forskolin?+?isobutylmethylxanthine (10 μmol/l each), 2.8-fold by phorbol myristate acetate (1 μmol/l) and 1.4-fold by linoleic acid (100 μmol/l). PYY release was increased to 2.0-, 1.8- and 1.3-fold by the same stimuli, respectively. Agonists of G-protein-coupled receptor (GPR)40/120 and G-protein-coupled bile acid receptor 1 (GPBAR1) each increased GLP-1 release to 1.5-fold, but a GPR119 agonist did not significantly stimulate secretion.

Conclusions/interpretation

Primary human colonic cultures provide an in vitro model for interrogating the human enteroendocrine system, and co-secrete GLP-1 and PYY. We found no evidence of PYY-specific cells not producing GLP-1. GLP-1 secretion was enhanced by small molecule agonists of GPR40/120 and GPBAR1.     

Involvement of primary afferent nerves after abdominal irradiation: consequences on ileal contractile activity and inflammatory mediator release in the rat

In this study we analyzed the role of substance P (SP) from afferent nerves in ileum contractibility and in the release of inflammatory mediators (neurotensin, Il-1, and TNF-) in ileal mucosa and muscularis layers after a 10-Gy -irradiation of the abdomen. Six hours after irradiation, SP concentrations were lower than in control rats, and 3 days after irradiation SP-induced contractile activity was higher. Irradiation significantly increased the levels of neurotensin, Il-1, and TNF- in both layers. Pretreatment with capsaicin depleted afferent nerve endings of SP and reduced SP levels by about 50%. Capsaicin treatment reduced SP concentrations further, beyond the levels due to irradiation, thereby suggesting that all sources of SP are affected by irradiation. Capsaicin treatment prevented the irradiation from affecting SP-induced contractile response or increasing neurotensin levels. This finding suggests that SP released by afferent nerve endings controls these functions. Proinflammatory cytokine release was not reduced by capsaicin treatment.     

Gastrointestinal transit through esophagus,stomach, small and large intestine in patients with progressive systemic sclerosis

Liquid esophageal transit and gastric emptying, mouth-to-cecum transit, and whole gut transit of a solid-liquid meal were measured in 14 patients with PSS, 16 control subjects (esophageal transit), and 20 control subjects (gastrointestinal transit), respectively, by using scintigraphic techniques, the hydrogen breath test, and stool markers. In patients with PSS, the glucose hydrogen breath test for detection of small intestinal overgrowth was performed and various gastrointestinal symptoms were determined. Esophageal transit and gastric emptying were significantly prolonged in PSS patients with 11 of 14 PSS patients (79%) disclosing delayed esophageal transit and eight of 14 PSS patients (57%) disclosing delayed gastric emptying. All PSS patients with prolonged gastric emptying also had delayed esophageal transit and there was a significant positive correlation between esophageal transit and gastric emptying (r=0.696,P<0.01). No significant differences between PSS patients and controls were detected concerning mouth-to-cecum transit and whole gut transit, but abnormally delayed mouth-to-cecum transit was found in four of 10 PSS patients (40%) and abnormally prolonged whole gut transit was detected in three of 13 PSS patients (23%). Small bacterial overgrowth was diagnosed in three of 14 PSS patients (21%). Delayed esophageal transit and gastric emptying were associated with dysphagia, retrosternal pain, and epigastric fullness, while prolonged whole gut transit was associated with constipation. It is concluded that delayed gastric emptying is frequently associated with esophageal transit disorders in PSS patients and may be one important factor for the development of gastroesophageal reflux disease in these patients.     

Gluten-Free Diet Normalizes Mouth-to-Cecum Transit of a Caloric Meal in Adult Patients with Celiac Disease

The mechanisms responsible for boweldisturbances in celiac disease are still relativelyunknown. Recent reports suggested that small bowel motorabnormalities may be involved in this pathologicalcondition; however, there are no studies addressing smallbowel transit in celiac disease before and after agluten-free diet. We studied the mouth-to-cecum transittime of a caloric liquid meal in a homogeneous group of celiac patients presenting with clinical andbiochemical evidence of malabsorption and complaining ofdiarrhea. Sixteen patients were recruited andinvestigated by means of hydrogen breath test through ingestion of 20 g lactulose together with anenteral gluten-free diet formula. A urinary D-xylosetest was also done in each patient. Both breath testsand D-xylose tests were carried out basally and after a period of gluten-free diet. Twenty healthyvolunteers were recruited as a control group andunderwent the same breath testing. At the time of thediagnosis, mouth-to-cecum transit time was significantly prolonged in celiacs with respect to controls(243 ± 10 vs 117 ± 6 min, P = 0.0001). TheD-xylose test was also abnormal (average urinaryconcentration 2.8 ± 0.25 g, normal values>4.5). No correlation was found in patients between mouth-to-cecum transit timeand urinary D-xylose output (r = 0.22). After thegluten-free diet period, mouth-tocecum transit time inceliacs was significantly reduced compared to prediet transit (134 ± 8 vs 243 ± 10 min,P = 0.0001) and did not show statistical difference whencompared to that found in controls (P = 0.1). TheD-xylose test reverted to normal in all but twosubjects, who were found to be noncompliant with the diet.Mouth-to-cecum transit time is significantly prolongedin patients affected by untreated celiac disease whencompared to healthy controls. This alteration might notbe correlated to intestinal malabsorption, and theprolonged orocecal transit could be due to impairedsmall bowel function (deranged motility?). Sinceintestinal transit returned to normal values after an adequate gluten-free period, a link with severeactive mucosal lesions is suggestive.     

Determination of transferrin-like immunoreactivity in the mucosal homogenate of the duodenum,jejunum, and ileum of normal and iron deficient rats

Summary 1. In intestinal mucosal tissue a transferrin-like immunoreactivity (TLIR) was determined after loading with ⁵⁹Fe-(FeCl₃) in vivo. The scraped-off mucosal tissue was homogenized and centrifuged at 100 000×g. The supernatant was fractionated chromatographically. The TLIR was determined by the Mancini-test.2. Extrapolated to infinite dilutions of the homogenate the following contents of the TLIR were calculated per cm of the intestinal segment: 28, 20, and 13, g/cm in the duodenum, jejunum, and ileum of iron-deficient animals and 15, 14, and 12 µg/cm in the corresponding intestinal segments of normal rats, respectively.3. The content of TLIR was compared with the iron uptake of the mucosal tissue from the intestinal lumen during absorption. An iron turnover number of 1.6±0.2 iron atoms per min during the absorption in duodenal and jejunal segments and of 0.5±0.1 in ileal segments of either iron-deficient and normal animals was calculated for the mucosal transferrin represented by the TLIR.Supported by a grant of the Wissenschafts-Ministerium Nordrhein-Westfalen     

Stimulatory actions of insulin-like growth factor-I and transforming growth factor-alpha on intestinal neurotensin and peptide YY.

Proliferation of the gastrointestinal mucosa is stimulated by the growth factors, insulin-like growth factor-I (IGF-I) and transforming growth factor-alpha (TGF-alpha), or the closely related epidermal growth factor (EGF), as well as the gastrointestinal hormones, gastrin, neurotensin (NT), and peptide YY (PYY). The stimulatory actions of these growth factors or gastrointestinal hormones on the gastrointestinal mucosa may be direct or mediated in part by gastrointestinal peptides or the growth factors, respectively. The purpose of these studies therefore was to examine the effects of IGF-I and TGF-alpha on stomach gastrin and intestinal NT and PYY gene expression [i.e. messenger RNA (mRNA), peptide levels] and secretion. Mice were given recombinant human IGF-I (3, 6 mg/kg BW/day x 14 days). Transgenic mice with the rat TGF-alpha gene linked to a metallothionein promoter were used as a model of chronic TGF-alpha excess. IGF-I and TGF-alpha did not affect gastrin gene expression. Steady-state intestinal NT and PYY mRNA and peptide levels were elevated in a dose-related manner by IGF. TGF-alpha also increased intestinal expression of NT and PYY peptide, but not mRNA levels. Basal serum levels of PYY were elevated by IGF-I and TGF-alpha. IGF-I and TGF-alpha did not increase intestinal chromogranin A (CGA) gene expression, a marker of endocrine cells, or the density of PYY-containing cells in the colon, indicating that the elevations in intestinal gut peptide gene expression by IGF-I and TGF-alpha are not due simply to an increased number of enteroendocrine cells. IV infusion of EGF also stimulated release of PYY in the dog. Together, these findings indicate that IGF-I and TGF-alpha may cause secretion of gut hormones and exert a major upregulatory influence on the regulation of intestinal peptide hormone homeostasis.     

Peptide YY release after colectomy in slow transit constipation

BACKGROUND: The gut hormone peptide YY is abundant in the colonic mucosa. Circulating PYY inhibits gastrointestinal motility and decreases food intake. The aim was to determine whether colectomy decreases PYY release in patients with slow transit constipation. METHODS: Plasma PYY concentrations were measured in 10 patients with slow transit constipation before and 3-24 months after total abdominal colectomy with ileorectal anastomosis, and in 8 healthy controls. A liquid meal was infused intraduodenally to stimulate PYY release. RESULTS: Postprandial PYY significantly (P < 0.05) increased from a basal value of 15.6 +/- 1.8 pM to a peak of 71.2 +/- 11.6 pM after colectomy. Basal and postprandial plasma PYY concentrations were not significantly different from the results before surgery. Fasting, but not postprandial, plasma peptide YY after colectomy was significantly higher than that in healthy volunteers, 10.9 +/- 0.9 pM. CONCLUSION: Despite removal of a major source of PYY-secreting cells, colectomy with ileorectal anastomosis does not induce major impairment of PYY release in slow transit constipation.     

Peptide YY kinetics and effects on blood pressure and circulating pancreatic and gastrointestinal hormones and metabolites in man

Peptide YY (PYY) is a 36 amino acid peptide produced by mucosal endocrine cells of the ileum and colon which inhibits acid secretion and intestinal transit in man. To assess its effects on metabolites and digestive hormones PYY was infused into 18 fasting normal subjects at three dose levels (0.06, 0.19, and 0.57 pmol kg-1 min-1), each for a period of 1 h. During the infusions mean plasma PYY levels increased by 8, 25, and 73 pmol/liter, respectively. The mean disappearance half-time on stopping the infusions was 9.2 +/- 0.4 (SEM) min. The mean MCR was 7.3 +/- 0.7 ml kg-1 min-1 and the apparent volume of distribution was calculated to be 94 +/- 9 ml kg-1. During the highest dose infusion there was a significant increase in both systolic and diastolic blood pressure, of 8.6 +/- 3.7 mmHg (P less than 0.05) and 10.9 +/- 3.0 mmHg (P less than 0.01), respectively. PYY caused a significant 50% reduction in plasma pancreatic polypeptide concentrations (P less than 0.05) and a 55% reduction in circulating motilin levels (P less than 0.05). PYY had no significant effect on circulating concentrations of insulin, glucagon, gastrin, gastric inhibitory peptide, neurotensin, enteroglucagon, or vasoactive intestinal peptide. PYY also had no significant effect on circulating concentrations of glucose, lactate, glycerol, or nonesterified fatty acids. This recently discovered human intestinal hormonal peptide thus has significant effects both on gastrointestinal hormones (motilin and pancreatic polypeptide) and blood pressure in man, but appears not to influence glucose or lipid metabolism.     

Peptide YY release after colectomy in slow transit constipation

Background: The gut hormone peptide YY is abundant in the colonic mucosa. Circulating PYY inhibits gastrointestinal motility and decreases food intake. The aim was to determine whether colectomy decreases PYY release in patients with slow transit constipation. Methods: Plasma PYY concentrations were measured in 10 patients with slow transit constipation before and 3–24 months after total abdominal colectomy with ileorectal anastomosis, and in 8 healthy controls. A liquid meal was infused intraduodenally to stimulate PYY release. Results: Postprandial PYY significantly (P?Conclusion. Despite removal of a major source of PYY‐secreting cells, colectomy with ileorectal anastomosis does not induce major impairment of PYY release in slow transit constipation.     

Effects of thromboxane A2 agonist STA2 on rapidly adapting pulmonary stretch receptors in vagotomized rabbits

We investigated the responses of rapidly adapting pulmonary stretch receptors (RARs) and tracheal pressure (P_T) to right atrial injections of the thromboxane A₂ (TXA₂) stable analogue STA₂ (0.3, 1.0, and 3.0 g/kg) before and after administration of atropine sulfate (1 mg/kg), isoprenaline (200 g/kg), indomethacin (1 mg/kg), or S-145 (0.5 mg/kg) in artificially ventilated, bilaterally vagotomized rabbits. The RARs increased their activity after STA₂ administration, and the increase was dose-dependent. However, intraatrial injections of STA₂ at all the doses examined had no significant effect on P_T. The excitatory responses of RAR activity to STA₂ (0.3–3.0 g/kg) were not significantly altered by administration of atropine sulfate (anticholinergic agent), isoprenaline (bronchodilator), or indomethacin (cyclooxygenase inhibitor). However, S-145 treatment (TXA₂ antagonist) blocked the STA₂-induced RAR stimulation. To determine whether or not administration of STA₂ causes release of acetylcholine (ACh), we also examined the effects of vagal efferent stimulation (10–15 V, 10 Hz, 1 ms), STA₂ administration (3.0 g/kg), and their combination on P_T in rabbits associated with both artificial ventilation and bilateral vagotomy. The vagally mediated bronchoconstriction that led to an increase in P_T was not enhanced by simultaneous administration of STA₂ at 3.0 g/kg in all of the tested animals. These results suggest that the stimulation of RARs by STA₂ is not mediated by the release of ACh from the nerve endings but is probably due to a local inflammatory bronchoconstriction that does not significantly alter the value of P_T.Offprint requests to: S. Matsumoto