Effects of psychological stress on small intestinal motility and expression of cholecystokinin and vasoactive intestinal polypeptide in plasma and small intestine in mice

AIM: To investigate the effects of psychological stress on small intestinal motility and expression of cholecystokinin (CCK) and vasoactive intestinal polypeptide (VIP) in plasma and small intestine, and to explore the relationship between small intestinal motor disorders and gastrointestinal hormones under psychological stress. METHODS: Thirty-six mice were randomly divided into psychological stress group and control group. A mouse model with psychological stress was established by housing the mice with a hungry cat in separate layers of a two-layer cage. A semi-solid colored marker (carbon-ink) was used for monitoring small intestinal transit. CCK and VIP levels in plasma and small intestine in mice were measured by radioimmunoassay (RIA). RESULTS: Small intestinal transit was inhibited (52.18±19.15% vs70.19±17.79%, P<0.01) in mice after psychological stress, compared to the controls. Small intestinal CCK levels in psychological stress mice were significantly lower than those in the control group (0.75±0.53 μg/g vs1.98±1.17 μg/g, P<0.01), whereas plasma CCK concentrations were not different between the groups. VIP levels in small intestine were significantly higher in psychological stress mice than those in the control group (8.45±1.09 μg/g vs7.03±2.36 μg/g, P<0.01), while there was no significant difference in plasma VIP levels between the two groups. CONCLUSION: Psychological stress inhibits the small intestinal transit, probably by down-regulating CCK and up-regulating VIP expression in small intestine.     

Effect of substance P on Rat gastrointestinal transit

The in vivo effect of substance P and related peptide analogs on gastrointestinal transit in unanesthetized rats was studied. Fasted male rats were given intragastrically 0.5 ml of a powdered charcoal (BaSo4.H2O) meal and were concomitantly injected intraperitoneally with 8 micrograms/kg of substance P or a related peptide. In control rats, the percentage of small intestine traversed by the meal 15 min after feeding was 44.9 +/- 1.4 (N = 12). Substance P, [pGlu6]SP, [pGlu6, gPhe8, mGly9]SP and [pGlu5, N-MePhe8, N-MeGly9]SP significantly accelerated intestinal transit: 59.5 +/- 3.1% (N = 7); 66.0 +/- 3.8% (N = 14), 66.8 +/- 2.4% (N = 25), and 58.4 +/- 4.4% (N = 4), respectively. Concomitant injection of [pGlu6]SP and BOC-Phe-Phe-Gly-NHOH, an inhibitor of enzyme degradation at a dose of 800 micrograms/kg lowered by 10-fold the dose of [pGlu6]SP needed to induce the same degree of intestinal transit acceleration. These results indicate that in rats, substance P and related peptides accelerate gastrointestinal transit.     

Octreotide Inhibition of Flushing and Colonic Motor Dysfunction in Carcinoid Syndrome

Objectives: Previous studies showed increased plasma motilin and substance P concentrations and accelerated motor function in the small bowel and colon in patients with carcinoid diarrhea. Octreotide is beneficial in patients with carcinoid syndrome. Our hypothesis was that octreotide inhibits accelerated motility and gut neuropeptides in carcinoid syndrome. Methods : In 12 patients with metastatic carcinoid syndrome, we investigated the effect of octreotide 50 μg s.c. t.i.d (n = 6) or placebo (n = 6) on postprandial symptoms, GI transit, colonic motility, and circulating levels of selected circulating peptides and amines. Results : Octreotide reduced postprandial flushing ( p = 0.03) but not pain. Octreotide significantly retarded overall colonic transit and proximal colonic emptying ( p < 0.05); it tended to prolong small bowel transit time ( p = 0.13) and to reduce postprandial colonic tone ( p = 0.08) compared with placebo. Octreotide also reduced circulating levels of peptide YY, neurotensin, vasoactive intestinal polypeptide, and substance P but had no effect on plasma motilin, neuropeptide Y, calcitonin gene-related peptide, or histamine after meal ingestion. Conclusion : Octreotide ameliorates gut motor dysfunctions that characterize carcinoid diarrhea; the potential role of specific antagonism of serotonin, substance P, and vasoactive intestinal polypeptide alone or in combination with agents that inhibit their release in carcinoid diarrhea deserves further study.     

Plasma cholecystokinin, plasma peptide YY and gallbladder motility in patients with slow transit constipation: effect of intestinal stimulation

BACKGROUND/AIM: Because cholecystokinin and peptide YY are gut hormones with potent effects on gastrointestinal motility, we determined whether abnormalities of cholecystokinin and peptide YY exist in slow transit constipation. METHODS: Plasma concentrations of these hormones before, during and after intraduodenal infusion of a liquid meal in 21 patients with slow transit constipation were compared with the results in 8 healthy controls. RESULTS: Fasting levels of plasma cholecystokinin (3.1+/-0.2 vs. 2.4+/-0.2 pM; p = 0.02) were higher in patients. Basal plasma peptide YY (11.4+/-1.4 vs. 8.9+/-0.7 pM; p = 0.1) tended to be higher in patients. After the meal (60-90 min), incremental cholecystokinin (p<0.05), but not peptide YY, was significantly higher in patients. During intraduodenal infusion of the meal (0-60 min), incremental plasma cholecystokinin (251+/-20 pM.min) and peptide YY (1,146+/-186 pM. min) in patients were almost similar to control values (262+/-22 and 901+/-166 pM. min). Gallbladder volumes before, during and after the meal were not different between the 2 groups. Gastric emptying of a solid meal was delayed in the majority of patients (12 of 18). Abnormalities of plasma cholecystokinin were observed only in patients with delayed gastric emptying. CONCLUSION: Plasma levels of cholecystokinin are elevated in the fasting state and decrease more slowly after stimulation, but maximum release in response to intestinal nutrients is not altered in patients with slow transit constipation. The abnormality seems to be confined to a subgroup of patients with delayed gastric emptying.     

The impact of chronic hepatitis B viral infection on gastrointestinal motility

OBJECTIVES: Disturbed gastrointestinal (GI) motility probably exists in alcoholic cirrhotic patients; however, the influence of chronic hepatitis B virus (HBV) infection on GI motility remains unknown. The purpose of this prospective study was to determine the impact of chronic HBV infection on human GI transit, and to explore the possible patient factors modulating GI motility. METHODS: We used a non-invasive hydrogen breath test measuring the oro-caecal transit time (OCTT) to assess the GI motility in 45 asymptomatic HBV carriers, 26 patients with chronic hepatitis B, 23 patients with HBV-related liver cirrhosis, and 45 age- and sex-matched healthy volunteers. Their clinical symptoms and various blood parameters, such as platelet count, prothrombin time, etc. were recorded. Plasma substance P, nitrate/nitrite and endothelin-1 levels were also measured. RESULTS: The OCTTs in controls, HBV carriers, chronic hepatitis B and liver cirrhosis patients were (mean +/- SEM) 78.4 +/- 5.8, 80.9 +/- 4.2, 93.9 +/- 8.8 and 106.5 +/- 12.4 min, respectively. The OCTT was delayed in patients with HBV-related liver cirrhosis compared to that of controls (P=0.039). Among the cirrhotic patients, presentation with ascites delayed OCTT (145.7 +/- 27.2 versus 91.3 +/- 11.9 min, P=0.039). Neither Child- Pugh grade, portal hypertension, various blood parameters, plasma substance P, nitrate/nitrite or endothelin-1 levels had any influence on OCTT. CONCLUSIONS: HBV infection alone does not alter GI motility, whereas the patients with liver cirrhosis may have delayed GI motility. Ascites is most likely a factor responsible for the delayed GI transit among chronic HBV-infected subjects.     

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.     

Gastric emptying and orocecal transit time in pregnancy

Purpose. To evaluate the effects of pregnancy on gastrointestinal function, we determined gastric emptying time, orocecal transit time, and fasting gastrointestinal hormone levels (cholecystokinin, gastrin, pancreatic polypeptide, neurotensin) in 11 women with mild dyspeptic symptoms during the first and third trimesters of their pregnancies, and again 4–6 months after delivery. Methods. After the women ingested a disaccharide solution, orocecal transit time was determined by monitoring breath hydrogen concentrations at 10-min intervals, and values were compared with the postpartum value. Ultrasound examinations of gastric emptying were performed during the same intervals. Results. The half-emptying time and the final gastric emptying time did not differ in the first and third trimesters and postpartum, but gastrointestinal transit time was significantly longer in the third trimester of pregnancy than postpartum ([100.0 min (range, 50.5–240.0 min] vs 70.0 min [range, 40.5–240.0 min; P < 0.05]), respectively. Mean plasma pancreatic polypeptide values were lower in the third trimester of pregnancy than postpartum, and a negative correlation was observed between pancreatic polypeptide levels and transit time in the third trimester (r = −0.65; P = 0.0261). The plasma levels of other gastrointestinal hormones did not differ in the various periods studied. Conclusions. Our study shows that, despite evident dyspeptic symptoms, there were no significant alterations in gastric emptying or orocecal transit time during the first trimester of pregnancy. Conversely, in the third trimester, orocecal transit time was significantly longer. Received: October 6, 2000 / Accepted: February 23, 2001     

Gastrointestinal growth factors and pancreatic islet hormones during postoperative IGF-I supplementation in man

Insulin-like growth factor-I (IGF-I) has been demonstrated to exert a nitrogen sparing effect, both experimentally and in patients after abdominal surgery. IGF-I is a major mediator for the anabolic effects of growth hormone (GH). Whether elevated circulating IGF-I levels are the sole mediator of the anabolic effects following GH has not been clarified. IGF-I influences glucose metabolism, both through its own specific receptor and by activating the insulin receptor, and has also been proposed to influence pancreatic islet secretion directly. In the present study, the postoperative effects of IGF-I on plasma levels of other gastrointestinal and pancreatic islet hormones and growth factors were measured in patients after abdominal surgery. Fifteen patients who were candidates for large bowel resection were randomly divided into two groups: IGF-I-treated (n=8) and placebo-treated (n=7). The IGF-I group received daily two s.c. injections of human recombinant IGF-I (80 microg/kg body weight) for five days, beginning on the morning of the first postoperative day. The other group received placebo injections. Fasting plasma levels of gastrointestinal growth factors (epidermal growth factor, transforming growth factor-alpha, IGF-II), gastrointestinal hormones (gastrin, enteroglucagon, peptide YY), and islet hormones (insulin, islet amyloid polypeptide (IAPP) and pancreatic glucagon) were determined by RIA preoperatively and after five days of treatment. No significant effects of IGF-I on other growth factors or gastrointestinal hormones were seen. A marked increase in plasma insulin postoperatively compared with the preoperative levels (42+/-3 vs 61+/-5 pM, P<0.05) was seen in the placebo group, whereas the postoperative levels in the IGF-I-treated patients remained unchanged (44+/-3 vs 45+/-4 pM). A similar pattern was observed for IAPP and cortisol concentrations. No differences in glucagon concentrations were seen. In conclusion, these results suggest that IGF-I does not influence production of other gastrointestinal hormones thought to be involved in alimentary growth or pancreatic glucagon. In contrast, IGF-I caused a marked reduction of insulin and IAPP secretion. The inhibition of beta-cell secretion could be direct or, alternatively, could involve an improvement in postoperative insulin resistance, perhaps by reducing serum cortisol.     

Tegaserod accelerates orocecal transit in patients with constipation-predominant irritable bowel syndrome

BACKGROUND & AIMS: This study evaluated the effects of a partial 5-hydroxytryptamine (5-HT)(4) agonist, tegaserod, on gastric small bowel and colonic transit in constipation-predominant irritable bowel syndrome (IBS). METHODS: After a 1 week run-in period, 24 patients with constipation-predominant IBS were randomized to 1 week of tegaserod, 2 mg twice daily, or placebo treatment. Scintigraphic gastric emptying, small bowel transit, and colonic transit were determined before administration of study drug and after 1 week on the medication. Colonic transit was also measured using radiopaque markers and a single radiograph on day 5. RESULTS: Gastric emptying was unaltered by tegaserod. Proximal colonic filling at 6 hours, a measure of orocecal transit, was accelerated by tegaserod (70.4% +/- 1.3% [mean +/- SEM] vs. placebo, 46.4 +/- 1.9; P = 0.015). Proximal colonic emptying half-time and geometric center at 48 hours were also accelerated by tegaserod compared with baseline, but not compared with placebo. Mean colonic transit time was similar in both groups at baseline and after drug administration (tegaserod, 59.5 +/- 2.1 hours; placebo, 62.1 +/- 2.1 hours). CONCLUSIONS: Tegaserod accelerates orocecal transit, tends to accelerate colonic transit, and deserves further study in patients with constipation-predominant IBS.     

Involvement of Cholecystokinin Receptor in the Inhibition of Gastrointestinal Motility by Estradiol in Ovariectomized Rats

Background: The effects of estradiol benzoate (EB) on gastric emptying, gastrointestinal transit and plasma levels of cholecystokinin (CCK) were studied in ovariectomized rats. Methods: Gastrointestinal motility was assessed in rats 15 min after intragastric instillation of a test meal containing charcoal and Na 2 51 CrO 4. Gastric emptying was determined by measuring the amount of radiolabeled chromium contained in the small intestine as a percentage of the initial amount received. Gastrointestinal transit was evaluated by calculating the geometric center of distribution of the radiolabeled marker. Blood samples were collected for E 2 and CCK radioimmunoassay. Results: After treatment of EB (4-25 &#119 g/kg), gastric emptying and gastrointestinal transit were inhibited, whereas plasma concentrations of E 2 and CCK were increased in a dose-dependent manner. The selective CCK A receptor antagonists, devazepide and lorglumide, effectively attenuated the EB-induced inhibition of gastric emptying and gastrointestinal transit. L-365,260, a selective CCK B receptor antagonist, did not alter the EB-induced inhibition of gastric emptying and gastrointestinal transit. Conclusions: The results suggest that EB inhibits gastric emptying and gastrointestinal transit in ovariectomized rats via a mechanism involving CCK stimulation and CCK A receptor activation.     

Effects of galanin on insulin responses to hormonal, neuropeptidal, and pharmacological stimuli in conscious dogs

Galanin, a recently characterized neuropeptide, lowers basal plasma canine insulin levels and inhibits plasma canine insulin responses to parenteral administration or oral ingestion of nutrients. This study determined the effect of galanin on the recognized insulin secretagogue effects of selected hormonal, neuropeptidal, and pharmacological agents in five conscious dogs. Bolus injections of cholecystokinin, the glucose-dependent insulinotropic polypeptide, and glucagon during saline infusions resulted in prompt elevation of plasma insulin levels (peak values, respectively: 57.8 +/- 14.6 microU/ml, 39.0 +/- 9.8 microU/ml, 60.8 +/- 14.4 microU/ml) but insulin responses after administration of these hormones during galanin infusions were statistically significantly blunted (peak values, respectively: 10.8 +/- 3.5 microU/ml, 3.0 +/- 2.8 microU/ml, 8.8 +/- 2.8 microU/ml). Bolus injection of the gastrin-releasing polypeptide, a neuropeptide, during saline infusions resulted in a peak plasma insulin level of 28.2 +/- 8.6 microU/ml but, during galanin infusions, the maximum level attained was significantly lower at 3.4 +/- 2.0 microU/ml. Similarly, tolbutamide administration during saline infusions elevated plasma insulin levels to a peak value of 28.6 +/- 6.2 microU/ml but during galanin infusions, the peak value seen after tolbutamide administration was 4.8 +/- 1.6 microU/ml. Hence, in the conscious dog, galanin effectively inhibits insulin secretion induced by hormones (cholecystokinin, glucose-dependent insulinotropic polypeptide, glucagon), a neuropeptide (gastrin-releasing polypeptide), and a pharmacological agent (tolbutamide). The results from the present and previous studies demonstrate that galanin has a broad spectrum of inhibitory activity on the beta-cell and suggest that it acts on a fundamental step in the insulin secretory process.     

Characterization of CS-045, a new oral antidiabetic agent, II. Effects on glycemic control and pancreatic islet structure at a late stage of the diabetic syndrome in C57BL/KsJ-db/db mice

Antidiabetic effects of CS-045 were evaluated in 5-month-old C57BL/KsJ-db/db mice (db/db). CS-045 administered for 3 weeks to diabetic db/db mice as a 0.2% food admixture improved hyperglycemia (855 +/- 25 v 298 +/- 62 mg/dL, P less than .01) and glucose intolerance, and lowered plasma triglyceride (299.6 +/- 28.7 v 76.3 +/- 20.7 mg/dL, P less than .01) and free fatty acid (FFA) levels (1.16 +/- 0.14 v 0.57 +/- 0.07 mEq/L, P less than .01). Food intake was not changed, while a small but significant increase in body weight was observed in CS-045-treated mice. Plasma insulin levels gradually increased after 5 days of CS-045 treatment, and a nonsignificant increase was observed in plasma insulin levels after 3 weeks (1.85 +/- 0.50 v 4.54 +/- 1.47 mg/mL). In contrast, the plasma glucagon levels decreased after 3 weeks of CS-045 treatment. Histological examination by aldehyde-fucshin staining demonstrated that pancreatic beta cells in CS-045-treated db/db mice were heavily regranulated, whereas most of the beta cells were extensively degranulated in nontreated db/db mice. The heavily regranulated state of beta cells was also compatible with an increase in pancreatic insulin content in CS-045-treated db/db mice. Electron microscopic analysis showed a well-developed endoplasmic reticulum and the accumulation of much amorphous structural material in the intracisternal space of beta cells from CS-045-treated db/db mice, which were suggestive of an increase in insulin synthesis. Moreover, CS-045 treatment decreased exocrine-containing islets, which was associated with the islets' degeneration process. Immunohistochemical staining of islets showed that CS-045 treatment normalized the distribution pattern of endocrine cells in the islets of db/db mice, reflected by a predominantly peripheral location of alpha and delta cells.(ABSTRACT TRUNCATED AT 250 WORDS)     

Activation of the parasympathetic nervous system is necessary for normal meal-induced insulin secretion in rhesus macaques

Meal-induced insulin secretion is thought to be regulated primarily by absorbed nutrients and incretin hormones released from the gastrointestinal tract. In addition, the parasympathetic nervous system (PNS) is known to mediate preabsorptive, or cephalic phase, insulin secretion. Despite evidence that the PNS remains activated during the absorptive phase of the meal, its role in mediating postprandial insulin secretion has not been established. To study the role of the PNS in absorptive phase insulin release, we measured plasma concentrations of glucose as well as islet hormones and incretins in six healthy rhesus monkeys before and for 60 min after meals while they were infused with saline (control), atropine (muscarinic blockade), or trimethaphan (nicotinic blockade). During the infusion of saline, plasma levels of glucose, pancreatic polypeptide (PP), insulin, glucose-dependent insulinotropic polypeptide, and glucagon-like peptide-1 increased promptly after meal ingestion and remained elevated throughout the 60 min of the study. The PP response was nearly abolished in animals treated with trimethaphan, indicating functional blockade of PNS input to the islet, and in contrast to the control study, there were minimal changes in plasma concentrations of glucose, incretin hormones, and insulin. Because trimethaphan inhibited glycemic and incretin stimuli in addition to blocking PNS input to the islet, it was not possible to discern the relative roles of these factors in the stimulation of insulin secretion. Atropine also significantly decreased PNS transmission to the islet, as reflected by PP levels similar to those observed with trimethaphan. Unlike the trimethaphan study, plasma glucose levels rose normally during atropine treatment and were similar to those in the control study over the course of the experiments (114 +/- 22 and 132 +/- 23 mmol/L.60 min, respectively). In addition, the rise in plasma glucagon-like peptide-1 following the meal was not suppressed by atropine, and the glucose-dependent insulinotropic polypeptide responses were only modestly decreased. Despite the significant increases in circulating glucose and incretins, plasma insulin levels were greatly attenuated by atropine, so that the 60 min responses were more comparable to those during trimethaphan treatment than to those in the control study (atropine, 3,576 +/- 1,284; trimethaphan, 4,128 +/- 2,616; control, 15,834 +/- 5,586 pmol/L.60 min; P: < 0.05). Thus, muscarinic blockade markedly suppressed the meal-induced insulin response despite normal postprandial glycemia and significant elevations of incretins. These results indicate that activation of the PNS during the absorptive phase of meals contributes significantly to the postprandial insulin secretory response.     

Comparative effects of ricinoleic acid and senna on orocecal and oroanal transit time in healthy subjects. Application of the salacylazosulfapyridine method]

The appearance in plasma of sulphapyridine after oral administration of salicylazosulphapyridine (Salazopyrin) was shown to be useful for measuring the orocecal transit time in normal subjects. The purpose of this study was to use this method in diarrhea with accelerated intestinal transit time. A two-step study was performed in 12 healthy volunteers: a) under resting conditions; b) 2 weeks later with ricinoleic acid 40 ml (n = 6) or senna 19 mg (X-Prep = 1.2 g; n = 6) administration. In each step, Salazopyrin (2 g) and 20 radiopaque markers were ingested with a 200 kcal meal (Polydiet TCM = 200 ml). The following parameters were determined: a) plasmatic level of sulphapyridine (spectrophotometry) at 30 min intervals during 12 h; b) 2-day stool frequency and weight; c) oro-anal transit time (passage of the first marker and half of the markers in stools). In one subject, no sulphapyridine level was detected after administration of ricinoleic acid. With senna, 2 day stool frequency and weight increased by 80 and 131 percent respectively: orocecal transit time decreased from 6.1 +/- 1.3 to 4.8 +/- 1.2 h (m +/- SD; P less than 0.01) and oro-anal transit time (first marker) decreased from 31.8 +/- 9.6 to 20.7 +/- 8.9 (P less than 0.05). With ricinoleic acid, 2 day stool frequency and weight increased by 212 and 350 percent respectively; orocecal transit time decreased from 5.8 +/- 1.8 to 2.2 +/- 0.7 (P less than 0.01) and oroanal transit time (first marker) decreased from 25.3 +/- 7.1 to 8.0 +/- 6.8 h (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Blockade of GRP receptors inhibits gastric emptying and gallbladder contraction but accelerates small intestinal transit

BACKGROUND & AIMS: This study was designed to characterize [D-F(5)Phe(6)D-Ala(11)]Bn(6-13)OMe (BIM26226) as a gastrin-releasing peptide (GRP)-preferring bombesin receptor antagonist and to determine whether GRP physiologically regulates gastrointestinal motility. Intravenous BIM26226 (5-500 microg. kg(-1). h(-1)) inhibits GRP-induced gallbladder contraction and plasma cholecystokinin (CCK) release in a dose-dependent fashion. METHODS: Gastric emptying and small bowel transit of a solid meal were quantified using scintigraphy. Meal-stimulated gallbladder contraction was measured by sonography in a 2-period crossover design. RESULTS: Intravenous BIM26226 potently inhibited gastric lag time (114 +/- 7 vs. 41 +/- 6 minutes [control]) and gastric emptying rate (0.11 +/- 0.02%/min vs. 0.26 +/- 0.04%/min [control]), whereas concomitant infusion of BIM26226 accelerated small bowel transit time (153 +/- 41 vs. 262 +/- 20 minutes [control]). A continuous liquid meal perfusion into the duodenum induced complete gallbladder contraction (t(50%), 35 +/- 4 minutes), which BIM26226 inhibited significantly (t(50%), 64 +/- 8 minutes). BIM26226 did not alter plasma CCK response, indicating that circulating CCK did not mediate these effects. CONCLUSIONS: These data show that BIM26226 is a potent antagonist of exogenous and endogenous GRP and suggest that GRP is a major physiologic regulator of gastric emptying, small bowel transit, and gallbladder contraction.     

Involvement of cholecystokinin receptor in the inhibition of gastrointestinal motility by estradiol in ovariectomized rats

BACKGROUND: The effects of estradiol benzoate (EB) on gastric emptying, gastrointestinal transit and plasma levels of cholecystokinin (CCK) were studied in ovariectomized rats. METHODS: Gastrointestinal motility was assessed in rats 15 min after intragastric instillation of a test meal containing charcoal and Na2 51CrO4. Gastric emptying was determined by measuring the amount of radiolabeled chromium contained in the small intestine as a percentage of the initial amount received. Gastrointestinal transit was evaluated by calculating the geometric center of distribution of the radiolabeled marker. Blood samples were collected for E2 and CCK radioimmunoassay. RESULTS: After treatment of EB (4-25 microg/kg), gastric emptying and gastrointestinal transit were inhibited, whereas plasma concentrations of E2 and CCK were increased in a dose-dependent manner. The selective CCK(A) receptor antagonists, devazepide and lorglumide, effectively attenuated the EB-induced inhibition of gastric emptying and gastrointestinal transit. L-365,260, a selective CCK(B) receptor antagonist, did not alter the EB-induced inhibition of gastric emptying and gastrointestinal transit. CONCLUSIONS: The results suggest that EB inhibits gastric emptying and gastrointestinal transit in ovariectomized rats via a mechanism involving CCK stimulation and CCK(A) receptor activation.     

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.     

Morphine tissue levels and reduction of gastrointestinal transit in rats. Correlation supports primary action site in the gut

Overnight-fasted male rats given a single dose of tritium-labeled morphine either intraperitoneally or intravenously were fed a charcoal test meal by stomach tube. The drug remaining in tissues was assayed by liquid scintillation counting of thin-layer chromatograms from homogenates, and gastrointestinal transit was tested by measuring the portion of the small intestine traversed by charcoal in 5 min. Morphine, 0.15 mg/kg, given intraperitoneally either 10 min or 30 min before testing substantially reduced gastrointestinal transit (to 23% and 55% of drug-free controls, respectively), and produced maximum drug levels 5 min after administration in small intestine longitudinal muscle with attached myenteric plexus (500 +/- 42 ng/g, mean +/- SE, n = 4). Intact small intestine, plasma, and brain, respectively, contained decreasing drug concentrations that, in the latter, never exceeded 2%-3% of that in longitudinal muscle. Rats receiving 0.15 mg/kg morphine intravenously presented only minor and short-lived inhibition of gastrointestinal transit that was significantly below (approximately 35%) that of drug-free controls at 10 min, but not 30 min, after drug administration. Morphine levels in the brain and plasma of these rats were up to five times higher, and in the intact small intestine longitudinal muscle were up to 20 times lower than in intraperitoneally treated rats. Morphine concentration in the tissues assayed was plotted against the effect on gastrointestinal transit at the same interval for individual rats regardless of dose, administration route, and observation time: data analysis, in small intestine longitudinal muscle, but not in the brain or plasma, indicated a highly significant correlation and fitting of computer-generated curves described by a currently accepted equation according to the receptor occupation theory of drug response. In view of these findings, and of the complete prevention by the "peripherally selective" narcotic antagonist N-methyl naloxone of gastrointestinal transit inhibition after an intravenous analgesic dose of morphine (1 mg/kg), the investigated animal model is consistent with the primary role of a gut-located action site in opiate-induced constipation.     

结肠水疗联合针刺治疗慢传输型便秘与胃肠激素关系的研究

背景：近年便秘患者数量呈逐年上升趋势,其中以慢传输型便秘（STC）居多。研究提示STC的发病机制中有胃肠激素参与。目的：观察结肠水疗联合针刺治疗对STC患者的临床疗效,以及胃肠激素水平变化在其中的作用。方法：36例STC患者接受结肠水疗联合针刺治疗,30例健康体检者作为正常对照组。以放射免疫法测定STC组治疗前后空腹血浆生长抑素（SS）、胃动素（MTL）、P物质（SP）和血管活性肠肽（VIP）水平,比色法测定空腹血清一氧化氮合酶（NOS）水平。结果：STC组治疗后临床症状改善总有效率为88．9％。患者治疗前血浆SS、VIP和血清NOS水平显著高于正常对照组,血浆MTL、SP水平显著低于正常对照组（P〈0．05）;经结肠水疗联合针刺治疗后,上述胃肠激素水平均较治疗前显著改善（P〈0．05）：结论：结肠水疗联合针刺治疗能改善STC患者的临床症状,调节胃肠激素水平。血SS、MTL、SP、VIP、NOS水平改变可能参与了该疗法对STC患者临床症状的改善作用。     

Acylation stimulating protein (ASP) acute effects on postprandial lipemia and food intake in rodents

BACKGROUND: In vitro studies have shown that acylation stimulating protein (ASP) stimulates triglyceride (TG) synthesis and storage in adipocytes. We have previously demonstrated that intraperitoneal (i.p.) injection of ASP in C57BL/6J mice accelerated TG clearance following an orally-administered fat load as well as reducing postprandial glucose levels. RESULTS: In the present study, we first examined the effect of i.p. and intracerebroventricular (i.c.v.) injection of ASP on food intake in Sprague-Dawley rats. Intraperitoneal injection resulted in a short-term increase in food intake (maximum increase 29.3% within the first hour, P<0.025) decreasing thereafter as compared to vehicle alone. i.c.v. Administration of a comparable dose of ASP resulted in a similar but delayed increase in food intake with a maximum at 2-4 h, suggesting that the actions of ASP are peripherally mediated. However, there was no significant difference in 24 h food intake with either i.p. or i.c.v. injection. We also examined the effects of ASP on TG clearance in two obese mouse strains with different metabolic profiles: ob/ob (C57BL/6J-Lep(ob)) and db/db (C57BLKS/J-Lepr(db)). In a crossover design, the response to an oral fat load was determined with and without i.p. injection of exogenous ASP. In ob/ob mice, there was a 44% greater clearance of postprandial TG (area under the curve (AUC)=245+/-49 control vs 138+/-43 mg/dl h with ASP; P<0.05 by RM ANOVA). The db/db mice showed a greater response, with a 62% decrease in postprandial TG (AUC=4080+/-1489 control vs 1540+/-719 mg/dl h with ASP; P=0.004 by RM ANOVA). In addition there were decreases in postprandial glucose and non-esterified fatty acid (NEFA) levels in response to ASP. CONCLUSION: These results are the first to report that ASP can increase food intake in rats and also enhance postprandial TG clearance in obese animals. These data therefore support previous in vitro evidence pointing to ASP as a regulator of lipid metabolism.