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PubMed1983

Purification and characterization of canine intestinal motilin.

A 22 amino acid peptide with motilin-like immunoreactivity was purified from acetic acid extracts of small intestinal mucosa from mongrel dogs. Sequential chromatography on carboxymethyl-cellulose, Sephadex G-50, CM cellulose, Biogel P6, and two steps of high-performance liquid chromatography were used for purification. Microsequence analysis of the purified product permitted unambiguous identification of residues 2-22 as -VPIFTHSELQKIREKERNKGQ. The sequence of porcine intestinal motilin is FVPIFTYGELQRMQEKERNKGQ. The amino terminal residue of the canine peptide could not be assigned with certainty since Phe, Lys, and Ser all were identified by analysis of PTH derivatives on the first sequencing cycle. Definite amino acid differences between canine and porcine motilin thus were identified in positions 7, 8, 12, 13 and 14. These differences did not alter immunoreactivity of canine motilin with antibodies specific for the carboxyl-terminal portion of porcine motilin, but probably explain markedly diminished immunoreactivity with antibodies to the amino or mid-portion of porcine motilin. Synthetic Phe1 canine motilin was prepared by a solid phase method. The synthetic peptide had the same pattern of immunoreactivity as natural canine motilin and was biologically active with a potency similar to synthetic porcine motilin for induction of premature activity fronts of the interdigestive motor complex in the small intestine of fasting dogs.

Amino Acid Sequence↗
PubMed1984

GRP neurones in the rat small intestine issue long anal projections.

Gastrin releasing peptide (GRP) immunoreactive nerve fibres are numerous in the gut wall. Nerve cell bodies containing GRP are regularly found in the myenteric ganglia. The projections of GRP neurones in the rat small intestine were studied after myectomy or transection of the gut wall. Operated rats were left for 8-10 days or 5 weeks. Specimens were studied by immunocytochemistry, immunochemistry and in vitro for motor activity. GRP fibres were absent and GRP was markedly reduced in the gut wall underlying the area of myectomy and 10 mm anally to the myectomy or site of transection. Further anally, GRP and the GRP fibres gradually returned and were back to normal 25-30 mm from the lesion. Myenteric GRP neurones in the rat small intestine thus project anally over a distance of approximately 20-25 mm. A series of experiments was performed in order to test the idea that GRP is directly involved in intestinal motor functions. The results did not support this view. Strips of longitudinal smooth muscle with adherent myenteric ganglia were taken orally and anally to the myectomy and the motor activity of the specimens was compared. Electrical stimulation evoked a contractile response in the oral segment that was 6 times greater than that of the anal segment. However, GRP (10(-9)-10(-5) M) did not evoke contraction and the electrically induced contractile response was unaffected by GRP but could be blocked by atropine. The reduced contractile response in the 'denervated' anal segment is thus probably not due to a shortage of GRP fibres.

Animals↗
PubMed1987

Effect of atropine and somatostatin on bombesin-stimulated plasma gastrin, cholecystokinin and pancreatic polypeptide in man.

Infusion of the neuropeptide bombesin stimulates the secretion of several gastrointestinal hormones by an unknown mechanism. We have investigated the effects of atropine (15 ng/kg as bolus followed by 2.5 ng/kg X 30 min) and somatostatin (125 micrograms as i.v. bolus followed by 62.5 micrograms/30 min) on the stimulation of 3 hormones (gastrin, cholecystokinin and pancreatic polypeptide) by 60 pmol/kg X 20 min bombesin in 6 healthy volunteers. Plasma samples for measurement of hormones by sensitive and specific radioimmunoassays were obtained at -5, 0, 2.5, 5, 7.5, 10, 15, 20, 25 and 30 min. Bombesin induced significant increases in plasma gastrin (12 +/- 2 to 34 +/- 3 pM; P less than 0.0005), cholecystokinin (1.2 +/- 0.2 to 8.9 +/- 0.7 pM; P less than 0.0001) and pancreatic polypeptide (22 +/- 4 to 72 +/- 19 pM; P less than 0.05). There were great differences between the effects of atropine and somatostatin on the hormonal responses to bombesin. Atropine slightly increased the response of gastrin by 19% and that of cholecystokinin by 15%, but strongly inhibited the bombesin-stimulated pancreatic polypeptide secretion by 97%. On the other hand, somatostatin inhibited the bombesin-induced secretion of gastrin by 48%, cholecystokinin by 82% and pancreatic polypeptide by 107%. These results point to considerable qualitative and quantitative differences in the stimulatory mechanisms of bombesin on the hormones studied.

Adolescent↗
PubMedDate not supplied

Gene expressions of cholecystokinin (CCK) and CCK receptors, and its satiety effect in young and old male rats.

Cholecystokinin (CCK), one of the first discovered gastrointestinal hormones, which stimulates pancreatic enzyme secretion and induces gallbladder contraction, is one of the most abundant neurotransmitter peptides in the brain and is implicated in satiety via CCK-A receptors. We compared the suppressive effect of central administration of CCK on food intake in young and old rats. The suppressive effect on food intake was enhanced in old rats. To examine the mechanism of this enhanced suppression, we measured the mRNA levels of CCK, CCK-A and CCK-B receptors in the cerebral cortex and the hypothalamus of young and old male rats. The mRNA level of CCK-A receptors in the hypothalamus decreased with age, whereas the mRNA levels of CCK-B receptors in the hypothalamus and cerebral cortex did not. The mRNA level of CCK in the cerebral cortex decreased significantly in old rats, although the decrease in the hypothalamus was not significant. Therefore, the enhanced sensitivity to CCK of old rats could not be explained by changes in gene expressions of CCK and CCK receptors. Moreover, the effects of aging on the gene expressions of CCK-A and CCK-B receptors were different.

Journal Article↗
PubMed1989

Cholecystokinin in the entero-insular axis.

Cholecystokinin (CCK) is a well-characterized gastrointestinal hormone which is released into the general circulation after meals. Targets for CCK include not only the gallbladder and the exocrine pancreas but also the endocrine pancreas. In this paper, we review the role of CCK from the perspective of the entero-insular axis, where CCK seems to function as one component of incretin and can raise insulin release synergistically with other incretin components. CCK also increases the sensitivity of B cells to subsequent glucose stimulation. At present, the role of CCK as incretin in disease states is uncertain. The pathophysiological role of CCK is likely to be revealed using CCK-specific radioimmunoassay and bioassay techniques and CCK receptor antagonists.

Animals↗
PubMed1981

Neurohormonal control of gastrointestinal motor activity in conscious dogs.

Interdigestive migrating contractions (IMC) were analyzed for their occurrence interval, duration, migrating velocity, and frequently in long term records obtained by means of chronically implanted force transducers in the main stomach and the extrinsically denervated fundic pouches or in the intact jejunum and the extrinsically denervated Thirty loop in 10 conscious dogs. Plasma immunoreactive motilin (IRM) was measured simultaneously. It was found that concomitant occurrence of IMC in the main stomach and pouch was closely associated with increase in plasma IRM concentration. On the other hand, in the extrinsically denervated jejunal loop, IMC-like contractions occurred independently of and more frequently than those in the intact jejunum and did not correlate with an increase in IRM concentration. It is concluded that gastric motor activity is under humoral control but in the jejunum, autoregulation by the intrinsic nerve plexus is more predominant than humoral factor(s).

Animals↗
PubMed1985

Peptides and feeding.

This report reviews the hypothesis that peptides play a role in appetite modulation, stressing that the available evidence is predominantly pharmacological and thus caution needs to be taken in assigning physiological significance at this time. Two peptide systems have been postulated--a peripheral satiety system, typified by the gastrointestinal hormone cholecystokinin and a central feeding system driven by the opioid peptides and neuropeptide Y. This review also discusses the putative role of peptides in the anorexia of aging, drinking elicited by feeding and as mediators of the autonomic effects seen in association with ventromedial hypothalamic lesions.

Aging↗
PubMedDate not supplied

Modulation of motilin-induced somatostatin release in dogs by naloxone.

Somatostatin release in dogs is modulated by exogenous and endogenous opioids. Since postprandial somatostatin secretion is in part due to the stimulatory effect of postprandially activated gastrointestinal hormones as well as endogenous opioids, it was of interest to determine the interaction between motilin, a known stimulus of somatostatin release, and endogenous opioids with regard to activation of D-cell function. In a group of eight conscious dogs the infusion of synthetic porcine motilin at doses of 0.05, 0.25 and 0.5 micrograms/kg X hr elicited a significant increase of peripheral vein plasma somatostatin-like immunoreactivity (SLI), confirming previously reported data. The additional infusion of the opiate receptor antagonist naloxone attenuated this SLI response, suggesting that endogenous opioids participate in motilin-induced SLI release. Since previous studies have shown that the interaction between endogenous opioids and postprandial somatostatin secretion is modified by elevated plasma glucose levels, the experiments were repeated during an IV glucose (0.2 g/min) background infusion increasing circulating glucose levels by 20-30 mg/dl. During IV glucose, the SLI response to motilin was almost abolished. In this group the addition of naloxone restored the SLI response, indicating that the inhibitory effect of elevated glucose on D-cell function is, at least in part, mediated by endogenous opioids. These data suggest that motilin has to be considered as one regulatory factor which participates in the previously observed interaction between glucose and endogenous opioids during postprandial SLI release.

Animals↗
PubMed1985

Biosynthesis of peptides in the skin of Xenopus laevis: isolation of novel peptides predicted from the sequence of cloned cDNAs.

From skin of Xenopus laevis, a few peptides have been isolated which are identical or homologous to gastrointestinal hormones and/or neurotransmitters of mammalian origin. We have studied the biosynthesis of these peptides using recombinant DNA techniques. From cDNA librariers constructed from skin mRNA, clones with inserts coding for the precursors of caerulein, thyrotropin releasing hormone and a new peptide termed PGLa have been isolated and sequenced. In the case of caerulein, a small family of precursors containing one, three or four copies of the end product have been detected. The caerulein sequences are separated by homologous sequences which potentially could give rise to additional constituents of skin secretion. Three such peptides have been detected which are presumably liberated from caerulein precursors by cleavage at single arginine residues.

Amino Acid Sequence↗
PubMedDate not supplied

Influence of bombesin, CCK, secretin and CRF on corticosterone concentration in the rat.

The ingestion of food increases adrenoglucocorticoid secretion in humans and rats and influences the circadian periodicity of ACTH and corticosterone in rats fed on restricted schedules. The purpose of this study was to determine the influence of the brain-gut polypeptides CCK33 (10 U/kg), bombesin (10 micrograms/kg) and secretin (10 U/kg) on corticosterone concentrations in fed rats. The responses were compared to that of CRF (1 micrograms/kg). All experiments were begun at 10 a.m., 3 hours after the lights came on. The rats were given single, IP injections of peptide or vehicle (1 ml/kg) then sacrificed 0, 5, 10, 15, 30 or 60 minutes later. Corticosterone was measured fluorometrically. The control injection (vehicle) alone caused a mild stress response with corticosterone levels peaking between 10 and 15 minutes after the injection then returning to baseline. Both CCK33 and bombesin significantly increased corticosterone to approximately 2.5-fold above the control level in a fashion similar to that of CRF. In all three instances corticosterone levels peaked at 30 minutes post-injection. Secretin had no effect on corticosterone secretion. None of the peptides tested stimulated in vitro corticosterone output from isolated adrenal cells. These findings indicate that both CCK and bombesin cause pituitary-adrenal activation which may be related to the response of this system to food ingestion.

Animals↗
PubMedDate not supplied

The role of cholecystokinin (CCK8) on glucose production and elimination, and on plasma insulin and glucose in rats.

The effects of the gastrointestinal hormone and neurotransmitter cholecystokinin (CCK8) are complex, since it exhibits both an insulinotropic and a glucagonotropic effect. We investigated CCK8 in vivo with respect to glucose fluxes (production and elimination) at both low (6 mM) and high plasma glucose levels (9 mM) using the primed constant D-[3-3H]glucose infusion technique. In the presence of high glucose levels there was a dose-dependent increase in glucose elimination by CCK8. No effect of CCK8 on glucose production at a high glucose infusion rate (500 mg/kg per h) was observed in contrast to a low glucose infusion rate (100 mg/kg per h); plasma glucagon levels were elevated. All effects on glucose production and elimination were specific, since they were abolished by the CCK receptor antagonist L-364,718. In summary, glucose elimination was slightly increased by CCK8 at low glucose levels but increased to a greater extent at high glucose levels; glucose production was increased by CCK8 only at low glucose levels. Thus, CCK is a regulator of glucose homeostasis.

Animals↗
PubMedDate not supplied

Neuropeptide Y, peptide YY, and pancreatic polypeptide modulate duodenal and colonic motility at a thoracic spinal site in rats.

Neuropeptide Y, PYY, and PP (200 pmol) alter intraluminal pressure in the duodenum and colon of rats following their administration into the thoracic (T8-T10) region of the spinal cord. Neuropeptide Y decreases the tone of the duodenum and the colon following intrathecal (T8-T10) administration prior to an increase in tone to baseline or greater. There is no effect on intraluminal pressure of either the duodenum or the colon following intrathecal administration of NPY or PP into the lumbar (L4-L5) region of the spinal cord. Following intrathecal (T8-T10) administration of PYY and PP, increases in intraduodenal pressures are observed (+2.1 and +3.0 mmHg from saline baseline). Phasic contractions of the duodenum are increased following intrathecal administration of PYY into the thoracic spinal cord of rats. Neuropeptide Y, PYY, and PP increase intracolonic pressure +2.2, +3.3, and +3.7 mmHg from saline baseline, respectively. Phasic contractions of the colon are increased following PP intrathecal thoracic administration. Responsiveness of the duodenum or colon to the different ligands of the PP-fold peptide family in the absence of alpha-adrenergic blockade did not vary. The increases in intraluminal pressure of the duodenum and colon following intrathecal administration of the PP-fold peptides are attenuated by both alpha-1 adrenergic (prazosin) and alpha-2 adrenergic (yohimbine) blockade. There is a difference in responsiveness of the colon between the ligands of the PP-fold family in the presence of the alpha-2 adrenergic blockade. The findings of this study indicate that duodenal and colonic motility are modulated by the PP-fold peptides at thoracic spinal sites via alteration of sympathetic outflow.

Animals↗
PubMedDate not supplied

The peripheral modulation of duodenal and colonic motility in rats by the pancreatic polypeptide-fold family: neuropeptide Y, peptide YY, and pancreatic polypeptide.

Neuropeptide Y (NPY), peptide YY (PYY), and pancreatic polypeptide (PP) altered intraluminal pressure in the duodenum and colon of fasted anesthetized rats following intravenous bolus administration. There were rapid increases in intraluminal pressure of the duodenum and colon of anesthetized rats following peripheral injections of NPY, PYY and PP. Administration (IV) of NPY, PYY, and PP increased intraduodenal pressure +1.8, +3.2, and +3.7 mmHg compared to saline baseline. Prazosin, an alpha-2 adrenergic antagonist, did not alter the response of the duodenum of urethane-anesthesized rats to any of the PP-fold peptides following peripheral administration. Yohimbine, an alpha 2-adrenergic antagonist, attenuated the excitatory response of rat duodenum following NPY (IV) but did not alter the duodenal response to PP (IV). Intravenous NPY, PYY, and PP increased intracolonic pressure +2.0, +3.3, and +6.2 mmHg compared to saline baseline. In the presence of prazosin, an alpha 1-adrenergic antagonist, the intraluminal pressure of the colon increased +2.6, +2.4, and +8.1 mmHg compared to saline baseline by NPY, PYY, and PP (IV), respectively. In the presence of alpha 2-adrenergic blockade by yohimbine, NPY, PYY, and PP (IV) increased intraluminal pressure of the colon +4.2, +2.9, and +2.5 mmHg compared to saline baseline. The response of the duodenum to the excitatory effect of PYY (IV) was enhanced in the presence of yohimbine. Duodenal and colonic tone were modulated by the PP-fold peptides following peripheral administration. The alpha-adrenergic nervous system played only a minor role in the modulation of GI motility by the PP-fold peptides at peripheral sites.

Animals↗
PubMed1979

Projections of intestinal neurons showing immunoreactivity for vasoactive intestinal polypeptide are consistent with these neurons being the enteric inhibitory neurons.

Experiments were performed to determine if the distribution of vasoactive intestinal peptide(VIP)-like immunoreactivity in nerve cell bodies and axons of the myenteric plexus and circular muscle of the small intestine is consistent with VIP being the transmitter of enteric inhibitory neurons. Immunoreactivity for VIP was found in nerve cell bodies of the myenteric plexus and in axons within the myenteric plexus and circular muscle. When the axons in the myenteric plexus were interrupted, there was accumulation of material showing reactivity for VIP on the oral side, indicating that the neurons project in an anal direction. The VIP-like immunoreactivity in axons which supply the circular muscle disappeared after a myectomy in which the overlying myenteric plexus was removed, but remained intact when extrinsic nerves were served. The projections of VIP neurons from the myenteric plexus to the circular muscle correspond to the expected projections of enteric inhibitory neurons determined by functional studies.

Animals↗
PubMed2005

Anisomycin induces COX-2 mRNA expression through p38(MAPK) and CREB independent of small GTPases in intestinal epithelial cells.

Cyclooxygenase (COX)-2 expression in intestinal epithelial cells is associated with colorectal carcinogenesis. COX-2 expression is induced by numerous growth factors and gastrointestinal hormones through multiple protein kinase cascades. Here, the role of mitogen activated protein kinases (MAPKs) and small GTPases in COX-2 expression was investigated. Anisomycin and sorbitol induced COX-2 expression in non-transformed, intestinal epithelial IEC-18 cells. Both anisomycin and sorbitol activated p38(MAPK) followed by phosphorylation of CREB. SB202190 and PD169316 but neither PD98059 nor U0126 blocked COX-2 expression and CREB phosphorylation by anisomycin or sorbitol. Clostridium difficile toxin B inhibition of small GTPases did not affect anisomycin-induced COX-2 mRNA expression or phosphorylation of p38MAPK and CREB but did inhibit sorbitol-dependent COX-2 expression and phosphorylation of p38MAPK and CREB. Angiotensin (Ang) II-dependent induction of COX-2 mRNA and induced phosphorylation of p38MAPK and CREB were inhibited by toxin B. Reduction of CREB protein in cells transfected with CREB siRNAs inhibited anisomycin-induced COX-2 expression. These results indicate that activation of p38MAPK signaling is sufficient for COX-2 expression in IEC-18 cells. Ang II and sorbitol require small GTPase activity for COX-2 expression via p38MAPK while anisomycin-induced COX-2 expression by p38MAPK does not require small GTPases. This places small GTPase activity down-stream of the AT1 receptor and hyperosmotic stress and up-stream of p38MAPK and CREB.

Animals↗
PubMed2004

Exocrine pancreatic secretion of phospholipid, menaquinone-4, and caveolin-1 in vivo.

The exocrine pancreas releases secretory products essential for nutrient assimilation. In addition to digestive enzymes, the release of lipoprotein-like particles containing the membrane trafficking protein caveolin-1 from isolated pancreatic explants has been reported. The present study examined: (1) if gastrointestinal hormones induce the apical secretion of phospholipid in vivo and (2) a potential association of caveolin-1 and the lipid-soluble vitamin K analog menaquinone-4 (MK-4) with these structures. Analysis of isolated acinar cells, purified zymogen granules, and pancreatic juice collected in vivo indicated the presence a caveolin-1 immunoreactive protein that was acutely released in response hormone stimulation. Chloroform-extracted fractions of pancreatic juice also contained high concentrations of MK-4 that was secreted in parallel to protein and phospholipid. The presence of caveolin-1 and MK-4 in the phospholipid fraction of pancreatic juice places these molecules in the secretory pathway of exocrine cells and suggests a physiological role in digestive enzyme synthesis and/or processing.

Animals↗
PubMed2006

Evaluation of the antidiabetic activity of DPP IV resistant N-terminally modified versus mid-chain acylated analogues of glucose-dependent insulinotropic polypeptide.

Glucose dependent insulinotropic polypeptide (GIP) is a gastrointestinal hormone with therapeutic potential for type 2 diabetes due to its insulin-releasing and antihyperglycaemic actions. However, development of GIP-based therapies is limited by N-terminal degradation by DPP IV resulting in a very short circulating half-life. Numerous GIP analogues have now been generated exhibiting DPP IV resistance and extended bioactivity profiles. In this study, we report a direct comparison of the long-term antidiabetic actions of three such GIP molecules, N-AcGIP, GIP(Lys(37)PAL) and N-AcGIP(Lys(37)PAL) in obese diabetic (ob/ob) mice. An extended duration of action of each GIP analogue was demonstrated prior to examining the effects of once daily injections (25nmolkg(-1) body weight) over a 14-day period. Administration of either N-AcGIP, GIP(Lys(37)PAL) or N-AcGIP(Lys(37)PAL) significantly decreased non-fasting plasma glucose and improved glucose tolerance compared to saline treated controls. All three analogues significantly enhanced glucose and nutrient-induced insulin release, and improved insulin sensitivity. The metabolic and insulin secretory responses to native GIP were also enhanced in 14-day analogue treated mice, revealing no evidence of GIP-receptor desensitization. These effects were accompanied by significantly enhanced pancreatic insulin following N-AcGIP(Lys(37)PAL) and increased islet number and islet size in all three groups. Body weight, food intake and circulating glucagon were unchanged. These data demonstrate the therapeutic potential of once daily injection of enzyme resistant GIP analogues and indicate that N-AcGIP is equally as effective as related palmitate derivatised analogues of GIP.

Animals↗
PubMed2005

The inhibitory effects of peripheral administration of peptide YY(3-36) and glucagon-like peptide-1 on food intake are attenuated by ablation of the vagal-brainstem-hypothalamic pathway.

The vagus nerve forms a neuro-anatomical link between the gastrointestinal tract and the brain. A number of gastrointestinal hormones, including cholecystokinin and ghrelin, require an intact vagal-brainstem-hypothalamic pathway to affect CNS feeding circuits. We have shown that the effects of peripheral administration of both peptide YY(3-36) (PYY(3-36)) and glucagon-like peptide-1 (GLP-1) on food intake and activation of hypothalamic arcuate feeding neurones are abolished following either bilateral sub-diaphragmatic total truncal vagotomy or brainstem-hypothalamic pathway transectioning in rodents. These findings suggest that the vagal-brainstem-hypothalamic pathway may also play a role in the effects of circulating PYY(3-36) and GLP-1 on food intake.

Animals↗