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Biomedical subjects

S R Bloom

Publications and source records attributed to S R Bloom.

At least 19 recordsLinked to original sources
PubMed1992

The purification and sequence analysis of an avian neuromedin U.

In this study we have purified an avian homologue of neuromedin U from the chicken. Each step of the purification process was followed by a specific radioimmunoassay developed using porcine neuromedin U. Microsequence analysis characterised the peptide to be 25 amino acid residues long with the following sequence: Y-K-V-D-E-D-L-Q-G-A-G-G-I-Q-S-R-G-Y-F-F-F-R-P-R-N. Chicken neuromedin U has marked sequence similarity with the porcine peptide at its bioactive C-terminal region. Our findings demonstrate that the amino acid sequence of neuromedin U is markedly conserved in species which have diverged millions of years ago in evolutionary terms.

Amino Acid Sequence↗
PubMed1992

The physiology of calcitonin gene-related peptide in the islet compared with that of islet amyloid polypeptide (amylin).

Following the discovery of a second gene containing a CGRP-like sequence, we demonstrated that "beta-CGRP" was indeed translated as a 37-amino acid peptide in vivo and was the predominant form of CGRP produced by the enteric nervous system. The presence of CGRP in the islet has been reported by several groups. We now show that beta-CGRP is again the major form. Another 37-amino acid peptide was recently isolated from islet amyloid deposits and found to have approximately 50% amino acid sequence homology with CGRP. Islet amyloid polypeptide, or amylin, is co-localized with insulin to the beta-cell secretory granule and is synthesized and released in parallel with insulin in response to a range of physiological and pharmacological stimuli. IAPP was subsequently shown, like CGRP, to inhibit the release of insulin pharmacologically. Interestingly, it was also shown to decrease the uptake of glucose by striated muscle, though it was considerably less potent than CGRP. This led to the suggestion that IAPP might be a circulating hormone regulating peripheral insulin sensitivity. Infusion of IAPP in human volunteers to produce plasma concentrations more than 100-fold higher than those seen physiologically, however, failed to alter peripheral glucose disposal. We conclude that beta-CGRP and IAPP are likely to play a role in local paracrine control of the islet.

Amyloid↗
PubMed1992

Neuropeptide content of purified rat brain cholinergic synaptosome subpopulations.

Cholinergic synaptosomes from rat cerebral cortex were isolated by a magnetic immunoaffinity technique, i.e. immunomagnetophoresis. This subpopulation was extracted and subjected to radioimmunoassay for 4 neuropeptides:neuropeptide Y (NPY); vasoactive intestinal peptide (VIP); substance P (SP); and somatostatin (SRIF). Three of the 4 neuropeptides were enriched in the sorted fraction compared with the mother fraction with respect to the cytosolic marker lactate dehydrogenase (LDH). The most enriched neuropeptide was NPY followed by SP and VIP. Somatostatin was not enriched in the cholinergic synaptosome subpopulation. The presence of NPY has not previously been reported in cortical cholinergic neurones.

Animals↗
PubMed1992

Investigation of the interaction of VIP binding sites with VIP and PACAP in human brain.

We have compared the binding of [125I]vasoactive intestinal polypeptide (VIP) to human brain membranes with that of [125I]PACAP27. [125I]VIP was displaced by PACAP27, VIP and two synthetic peptides, peptide-1 (N-terminal PACAP27/C-terminal VIP) and peptide-2 (N-terminal VIP/C-terminal PACAP27), but the IC50 of PACAP27 and peptide-1 were 10-20 times lower than those of VIP and peptide-2. [125I]PACAP27 was readily displaced by PACAP27 and peptide-1, with an IC50 of less than 1 nM, but poorly by VIP and peptide-2. Chemical cross-linking revealed that both labels were bound to polypeptides of Mr 66,000 and Mr 50,000. The results indicate that in human brain membranes both binding sites have a higher affinity to the N-terminal sequence of PACAP27, and VIP binding sites prefer PACAP27 to VIP itself.

Adenylyl Cyclases↗
PubMed1992

Glucose transporter expression and glucose utilization in skeletal muscle and brown adipose tissue during starvation and re-feeding.

Starvation (48 h) decreased the concentration of mRNA of the insulin-responsive glucose transporter isoform (GLUT 4) in interscapular brown adipose tissue (IBAT) (56%) and tibialis anterior (10%). Despite dramatic [7-fold (tibialis anterior) and 40-fold (IBAT)] increases in glucose utilization after 2 and 4 h of chow re-feeding, no significant changes in GLUT 4 mRNA concentration were observed in these tissues over this re-feeding period. The results exclude changes in GLUT 4 mRNA concentration in mediating the responses of glucose transport in these tissues to acute re-feeding after prolonged starvation.

Adipose Tissue, Brown↗
PubMed1992

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.

Adolescent↗
PubMed1992

Nutrient-independent increases in proglucagon and ornithine decarboxylase messenger RNAs after jejunoileal resection.

To assess potential mediators of adaptive bowel growth, ileal proglucagon messenger RNA (mRNA) ornithine decarboxylase (ODC) mRNA, plasma enteroglucagons, and plasma glucagonlike peptide I (GLP-I) were analyzed in rats soon after jejunoileal resection or control transection. Analyses were performed before and after refeeding to establish whether responses are nutrient dependent. The elevation of ileal proglucagon and ODC mRNAs within 12 hours after resection and before refeeding shows a nutrient-independent component of the adaptive response. The onset of adaptive growth of the ileum required luminal nutrient but occurred very rapidly, within 4 hours of refeeding. The onset of adaptive growth was accompanied by transient elevation of ileal ODC mRNAs. Ileal proglucagon mRNA and plasma GLP-I levels were also elevated, and these increases were sustained up to 8 days after resection. These early and sustained increases in proglucagon mRNA and plasma GLP-I indicate that in addition to the enteroglucagons, other intestinal proglucagon-derived peptides must be considered as potential mediators of adaptive growth after jejunoileal resection.

Adaptation, Physiological↗
PubMed1992

The presence of neuropeptides in GABAergic and cholinergic rat cerebrocortical synaptosome sub-populations.

GABAergic and cholinergic synaptosomes from rat cerebral cortex were isolated by a magnetic immunoaffinity technique, i.e. immunomagnetophoresis. These subpopulations were extracted and subjected to radioimmunoassay for four neuropeptides: Neuropeptide Y (NPY); vasoactive intestinal peptide (VIP); substance P (SP); and somatostatin (SRIF). In each of the sub-populations three of the four peptides were enriched in the sorted fraction compared with the mother fraction with respect to the cytosolic marker lactate dehydrogenase (LDH). In the GABAergic sub-population the order was SP > SRIF > NPY > or = VIP whilst in the cholinergic sub-population they were enriched in the order VIP > or = NPY > SP > SRIF. The presence of NPY has not previously been reported in cortical cholinergic neurons.

Animals↗
PubMed1992

The effects of various peptides on human isolated gut muscle.

The effects of eleven peptides of gastrointestinal origin have been studied on the contraction, relaxation and spontaneous activity of circular and longitudinal muscle strips from different regions of the human gastrointestinal tract. The effects varied with the peptides and sometimes with the region and muscle layer. There was either contraction, no effect, or relaxation and/or inhibition of an acetylcholine-induced contraction. Responses to some peptides are consistent with the possibility that they may contribute directly to the control of motility: galanin, neurotensin and substance P might be involved in contraction, and vasoactive intestinal peptide, peptide histidine isoleucine and peptide histidine methionine might be inhibitory transmitters.

Acetylcholine↗
PubMed1992

Gut regulatory peptides and intestinal permeability in acute infantile gastroenteritis.

The plasma concentrations of seven gut regulatory peptides were measured in 11 infants suffering from acute gastroenteritis. Samples were taken at the time of the acute illness, upon reintroduction of feeding, and three months after recovery. These results were compared with controls. In the infants with diarrhoea, a massive increase in the fasting plasma mean (SEM) concentrations of enteroglucagon was found at the time of illness (1292 (312) v 79 (27) pmol/l), with concentrations of pancreatic glucagon, peptide tyrosine tyrosine, and motilin also being increased (17.8 (3.1) v 6.3 (1.1) pmol/l, 114.6 (15.2) v 37.0 (11.0) pmol/l, 217.6 (44.1) v 98.5 (18.3 pmol/l) respectively). The preprandial concentrations of motilin were found to be still increased at recovery (183.9 (35.4) pmol/l), but the concentrations of the other three peptides had returned to normal values. No differences in plasma concentrations of vasoactive intestinal polypeptide, neurotensin, or pancreatic polypeptide were found. An increased intestinal permeability was demonstrated at the time of diarrhoea by the urinary ratio of lactulose to mannitol, suggesting simultaneous gut damage. The effects of regulatory peptides may be relevant to the pathophysiology of gastroenteritis in infants.

Acute Disease↗
PubMed1992

Localisation of endothelin like immunoreactivity in adult and developing human gut.

The distribution of immunoreactivity for the potent vasoconstrictor endothelin-1 was studied in adult and developing human gut using antisera to endothelin-1 (1-21) and the C terminus of big endothelin-1. The coexistence of these peptides with other neuropeptides was investigated using comparative immunocytochemistry. Endothelin-1 like immunoreactivity was detected in extracts of adult (range 20-60 fmol/g wet weight) and fetal (33 fmol/g) gastrointestinal tract and was shown by chromatography to be the predominant isoform of endothelin present in both. It was localised by immunocytochemistry to ganglion cells in the submucous and myenteric plexuses and to scattered nerves, whereas big endothelin-1 like immunoreactivity was found in the submucous plexus only. Colocalisation studies showed immunoreactivity for both endothelin-1 and vasoactive intestinal peptide in the same ganglion cells of the submucous plexus. Although endothelin-1 immunoreactivity was not detected by immunocytochemistry in the fetal human gut until the 32nd week of gestation, big endothelin-1 was found as early as 11 weeks in the developing neural structures and epithelial cells. The latter were shown to be endocrine cells by their immunoreactivity for chromogranin. Our results indicate that endothelin is a neuropeptide found in adult human gut which shows transient expression in endocrine cells during development.

Adult↗
PubMed1992

Effects of bolus doses of fat on small intestinal structure and on release of gastrin, cholecystokinin, peptide tyrosine-tyrosine, and enteroglucagon.

To investigate the enterotrophic effects of bolus doses of long chain triglycerides, two groups of eight female Wistar rats were fed identical diets with 48.2% total calories as the essential fatty acid rich oil Efamol. To one group the oil was given in twice daily bolus doses by gavage, while for the other group the oil was mixed with the remainder of the feed and thus consumed over 24 hours. The animals were killed after 20 to 22 days. Bolus dosing significantly increased parameters of mucosal mass along the length of the small intestine in association with an increase in two hour accumulation of vincristine arrested metaphases in small intestinal crypts. In a second experiment, four replicate studies were carried out, each involving two groups of 12 rats respectively fed as described above. After 21 days one animal from each group was killed every two hours, providing regular plasma samples over 24 hours for measurement of gastrin, cholecystokinin, peptide tyrosine-tyrosine and enteroglucagon. Bolus dosing markedly enhanced release of peptide tyrosine-tyrosine and enteroglucagon, but not of gastrin or cholecystokinin. Thus, the enhanced enterotrophic effects of bolus doses of long chain triglycerides could be mediated by release of a distally located gut peptide, perhaps enteroglucagon.

Animals↗
PubMed1992

Difficulties in localization and treatment of insulinomas in type 1 multiple endocrine adenomatosis (MEA).

A 15 year old girl with a family history of type 1 multiple endocrine adenomatosis presented with reversible neurological disturbances, hypoglycaemia and hyperinsulinaemia. Initial radiology was normal, but portal venous sampling suggested an insulinoma in the tail of the pancreas which was removed with conservation of the spleen. Hypoglycaemia persisted despite high doses of diazoxide and intravenous dextrose. A second laparotomy revealed a pancreatic endocrine tumour and sub-total pancreatectomy was performed. Histology revealed islet cell microadenomatosis. Hypoglycaemia persisted despite treatment with somatostatin analogues and 40% intravenous dextrose was required to maintain normoglycaemia. A possible lesion near the splenic hilum on computed tomographic scan was reported as a splenunculus although further peripheral, hepatic and portal venous sampling suggested hepatic or systemic lesions. A positron emission scan and selective visceral angiography suggested a lesion in the left upper quadrant. Acute lactic acidosis, rhabdomyolysis and renal failure supervened. Post mortem revealed the putative 'splenunculus' to be a residual insulinoma, whilst the splenic vein was thrombosed, accounting in part for discrepant venous sampling data. Hyperinsulinaemia in type 1 multiple endocrine adenomatosis may require more aggressive surgical and hormonal intervention than when dealing with solitary insulinomas. Insulinomas may mimic developmental abnormalities on computed tomographic scanning.

Adolescent↗
PubMed1992

Effects of peptide YY on the human cardiovascular system: reversal of responses to vasoactive intestinal peptide.

Peptide YY (PYY) reverses the increased intestinal secretion stimulated by vasoactive intestinal peptide (VIP) in humans. VIP also dilates blood vessels, so we investigated the effect of PYY on the cardiovascular system. Six volunteers received PYY, 0.4 and 1.2 pmol.kg-1 x min-1 i.v. for 2 h, reproducing plasma levels seen postprandially and during a diarrheal illness, respectively. Cardiac function was assessed by echocardiography. PYY infused at 0.4 pmol.kg-1 x min-1 had no effect on cardiovascular parameters. PYY infused at 1.2 pmol.kg-1 x min-1 caused a fall in both stroke volume from 128 +/- 8 to 110 +/- 8 ml/beat (mean +/- 95 confidence interval, P < 0.01) and cardiac output from 7.2 +/- 0.4 to 6.1 +/- 0.4 l/min (P < 0.01). Effects of infusion of PYY into the brachial artery at doses of 0-16 pmol/min were assessed using venous occlusion plethysmography in six subjects. PYY infusion caused a dose-dependent fall in forearm blood flow. Six subjects received VIP, 5 pmol.kg-1 x min-1 i.v., causing a rise in heart rate from 55 +/- 3 to 70 +/- 3 beats/min and increased cardiac output from 7.3 +/- 1.1 to 13.1 +/- 1.1 l/min. The addition of PYY, 0.4 pmol.kg-1 x min-1 i.v., did not affect the heart rate significantly but decreased the cardiac output to 10.4 +/- 1.1 l/min (P < 0.01). Infusions of PYY into the brachial artery at 5 pmol/min decreased local vasodilation induced by VIP infused at 2 pmol/min at the same site by 40% (P < 0.01), even though this dose of PYY had no significant effect on local blood flow when given alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

The presence, characterisation and synthesis of neuromedin B in the human pituitary gland.

Neuromedin B is a 10-amino-acid mammalian peptide of the bombesin family. We have used a specific radioimmunoassay and Northern blot hybridisation to investigate the possible synthesis of neuromedin-B-like immunoreactivity in the human pituitary gland. The concentration of immunoreactive neuromedin B in whole human pituitary was 15.2 +/- 4.2 pmol/g wet weight in males and 12.8 +/- 2.7 pmol/g wet weight in females (mean +/- SEM, n = 10). In pituitary tumour extracts, neuromedin B immunoreactivity was 9.1 +/- 1.7 pmol/g wet weight (mean +/- SEM, n = 14) in inactive tumours, 18.4 +/- 6.9 pmol/g wet weight (mean +/- SEM, n = 4) in somatotrophs and 10.4 +/- 2.7 pmol/g wet weight (mean +/- SEM, n = 2) in prolactinomas, with no apparent significant difference between the groups. Gel permeation chromatography of pituitary extracts revealed two immunoreactive peaks, the major one of which corresponded in position to that of neuromedin B-32 and a later minor peak to the position of the neuromedin B-10 standard. On fast protein liquid chromatography, neuromedin-B-like immunoreactivity again eluted in two peaks, a minor peak corresponding to the synthetic neuromedin B standard, and a major more hydrophobic peak which was the big neuromedin B form. Northern blot analysis of poly(A)+RNA from human pituitaries revealed the presence of a hybridising band of between 750 and 850 base pairs. These results suggest that neuromedin B is synthesised in the human pituitary gland where it may be of importance in the regulation of pituitary function. Furthermore, the adenomatous condition is not associated with abnormal levels of this peptide.

Aged↗
PubMed1992

Plasma and tissue hormones in the dog after administration of the prostaglandin analogue, misoprostol.

Dogs were given a prostaglandin analogue, misoprostol, at a dose that significantly increases gastrointestinal epithelial cell proliferation. Both basal and postprandial concentrations of gastrin were significantly higher in the misoprostol-treated dogs and more than doubled after the meal in both the controls and in the test group. Plasma enteroglucagon, cholecystokinin, insulin and glucose-dependent insulinotrophic peptide all increased postprandially, with no effect of misoprostol. Tissue concentrations of bombesin, gastrin and somatostatin were unaffected by misoprostol, but the fundic glucagon-like immunoreactivity was significantly increased. Thus high doses of misoprostol have only minor effects on gastrointestinal regulatory peptides, suggesting that the trophic effect of prostaglandins on the intestinal tract may be direct.

Animals↗
PubMed1992

Investigation and characterization of binding sites for islet amyloid polypeptide in rat membranes.

Islet amyloid polypeptide (IAPP) is a 37-amino acid peptide shown to be cosecreted with insulin from the pancreatic beta-cells. We have investigated the existence and characteristics of IAPP binding sites in the rat. Specific binding sites for [125I]IAPP were found to be highest in the lung followed by the stomach fundus, spleen, brain stem, hypothalamus, and the liver, respectively. The interaction of [125I]IAPP with its binding site was rapid and temperature dependent, displaying optimum binding at 4 C. This may be explained by the rapid degradation of the label observed at 22 C and 37 C, as determined by fast protein liquid chromatography analysis, and also degradation of the receptor at 37 C. Binding of [125I]IAPP was rapidly dissociated by the addition of 200 nM unlabeled peptide. The presence of nonmetabolizable GTP-gamma-S (0.5 microM) reduced binding, thus suggesting the coupling of the binding site to a G protein. Rat IAPP displaced [125I]IAPP displaying an IC50 of 5.75 x 10(-9) M (mean, n = 4). Displacement was also seen with human IAPP (IC50 = 5.53 x 10(-8) M), human alpha-calcitonin gene-related peptide (CGRP) (IC50 = 3.8 x 10(-8) M), rat alpha-CGRP (IC50 = 9.0 x 10(-7) M), and rat beta-CGRP (IC50 = 5.53 x 10(-8) M); suggesting an IAPP-specific binding site. Scatchard plots for rat IAPP binding in the lung gave a dissociation constant of 10.4 +/- 2.63 nM (mean +/- SE, n = 4) and maximal binding of 3.1 +/- 0.97 pmol/mg (mean +/- SE, n = 4), displaying a single class of binding site. Chemical cross-linking analysis showed binding of IAPP to sites of Mr 67,000, 64,000, and 38,000. These findings suggest that specific IAPP binding sites exist which differ from the CGRP receptors in rat tissues. This indicates a possible novel autocrine/paracrine role for IAPP.

Adenosine Triphosphate↗