Aspects of neurohormonal peptides.
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Animals↗
Biomedical subjects
S R Bloom
Publications and source records attributed to S R Bloom.
Reduced cholecystokinin levels in the limbic lobe in schizophrenia. A marker for pathology underlying the defect state?
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Cholecystokinin↗
Effects of certain metabolites on pancreatic endocrine responses to stimulation of the vagus nerves in conscious calves.
The effects of exogenous glucose (0.05 mmol/kg . min) and vamin (0.02 mmol/kg . min) on the pancreatic endocrine responses to stimulation of the peripheral ends of the vagus nerves have been investigated in conscious 3-6-week-old calves with cut splanchnic nerves. Exogenous glucose potentiated both the basal release of insulin and that which occurred in response to vagal stimulation, while inhibiting both the basal release of glucagon and that during vagal stimulation. Vamin significantly inhibited basal release of insulin but not that which occurred during vagal stimulation although it significantly inhibited vagal release of glucagon. The inhibitory effect of exogenous glucose on the basal and vagally stimulated release of pancreatic glucagon were both significantly reduced in the presence of vamin. Neither glucose nor mixed amino acids were found to affect the release of pancreatic polypeptide either at rest or during nerve stimulation. It is concluded that the effects of vagal activity on the alpha- and beta-cells of the islets of Langerhans are normally modified by the existing concentration of both glucose and amino acids in these animals.
Amino Acids↗
The role of the sympathetic system in the control of insulin release in response to hyperglycaemia in conscious calves.
The effects of the adrenoceptor blocking agents, phentolamine and propranolol, on the release of pancreatic glucagon and insulin in response to exogenous glucose have been investigated in conscious 2--6-week-old calves. There were no significant differences between the changes in mean plasma glucagon or insulin concentration, which occurred in response to hyperglycaemia, in calves pre-treated with both propranolol and phentolamine, phentolamine alone and normal calves. However, the rise in mean plasma insulin concentration was effectively abolished by pre-treatment with propranolol alone and there was a small but significant fall in mean plasma glucagon concentration which was not observed in any of the other groups. The results are discussed in relation to previous studies of the role of the autonomic innervation to the endocrine pancreas in the control of insulin release during hyperglycaemia in conscious calves and weaned lambs.
Animals↗
Pancreatic neuroendocrine responses to butyrate in conscious sheep.
The role of the autonomic innervation in the control of pancreatic endocrine responses to I.V. infusions of butyrate (0.02 mmol kg-1 min-1 for 10 min) has been investigated in conscious 4-6 month old weaned lambs. Intravenous butyrate produced a small rise in mean arterial plasma pancreatic glucagon concentration which was unlikely to have had any physiological effect and produced no consistent or statistically significant changes in mean plasma pancreatic polypeptide concentration in any of the groups studied. In contrast, butyrate produced an abrupt and substantial rise in mean plasma insulin concentration, which rose to a peak incremental value of about 300 pmol l-1 in normal control lambs. This response was unaffected by pre-treatment with either phentolamine or propranolol alone, but was significantly reduced by simultaneous administration of these drugs, as it was either by pre-treatment with atropine or prior section of the splanchnic nerves. The rise in mean plasma insulin concentration was inhibited most effectively by combined treatment with propranolol, phentolamine and atropine, which was significantly more effective than administration of atropine to lambs with cut splanchnic nerves (P less than 0.01). It is concluded that both divisions of the autonomic nervous system are likely to be involved in mediating the release of insulin from the pancreas, in response to butyrate, in this species under these experimental conditions and also in the resting state.
Animals↗
Influence of somatostatin and bombesin on plasma enteroglucagon and cell proliferation after intestinal resection in the rat.
The possible relationship between enteroglucagon and cellular proliferation in a rat model of intestinal adaptation after suppression and stimulation of enteroglucagon by somatostatin and bombesin has been investigated. Forty eight rats were divided into three groups of 16 animals, each group being further sub-divided into eight animals having intestinal resection and eight having intestinal transection. Group 1 was given somatostatin to suppress enteroglucagon, group 2 was given bombesin to stimulate enteroglucagon and group 3 (control group) had neither peptide. All animals were killed 12 days after operation. Circulating enteroglucagon and crypt cell production rate (CCPR) in the terminal ileum were measured. After administration of somatostatin (group 1) both CCPR and plasma enteroglucagon were lower after resection than controls (group 3) (p less than 0.001). Transected rats receiving somatostatin showed a reduction in both plasma enteroglucagon and CCPR, but only the fall in enteroglucagon was statistically significant (p less than 0.001). Transected rats receiving bombesin (group 2) had raised plasma enteroglucagon and CCPR compared with the control group (group 3) (P less than 0.005) but there was no significant further rise in these already raised parameters in resected animals. This study indicates that cell proliferation in the rat small bowel after surgery can be influenced by regulatory peptides. The changes in enteroglucagon corresponded closely with changes in CCPR, and this peptide remains a favoured candidate for the humorally mediated trophic influence on the small bowel.
Adaptation, Physiological↗
Positive correlation between symptoms and circulating motilin, pancreatic polypeptide and gastrin concentrations in functional bowel disorders.
Motilin, pancreatic polypeptide and gastrin blood concentrations in response to drinking water have been studied in 40 patients with functional bowel disease and compared with results in two groups of healthy control subjects. Patients with slow transit constipation and idiopathic megacolon showed impaired motilin release. Pancreatic polypeptide release was reduced in patients with slow transit constipation, but increased in those with functional diarrhoea. Gastrin release was impaired in all groups complaining of chronic constipation. Circulating motilin, pancreatic polypeptide and gastrin concentrations appear to bear some relationship to intestinal transit time in patients with functional bowel disorders.
Adult↗
Is raised plasma peptide YY after intestinal resection in the rat responsible for the trophic response?
The relationship between the adaptive response and plasma PYY concentrations after small bowel resection has been investigated. Seventy five per cent proximal small bowel resection resulted in a rise in plasma PYY at six days from 28 +/- 3.1 to 85 +/- 12.3 pmol/l (p less than 0.001) and this difference was maintained to 48 days. Plasma PYY correlates both with crypt cell production rate (CCPR) in the ileum and with plasma enteroglucagon levels. In a second study, PYY or saline was infused over a 12 day period. There were no significant changes in intestinal wet weight or CCPR in any part of the bowel studied. This indicates that it is unlikely that PYY exerts a major trophic effect on the gastrointestinal tract.
Animals↗
Treatment of patients with pancreatic endocrine tumours using a new long-acting somatostatin analogue symptomatic and peptide responses.
Seven patients with gut and pancreatic endocrine tumours have been treated with a long acting somatostatin analogue (SMS 201-995), given as a twice daily subcutaneous injection. This produced dramatic improvement in their endocrine related symptoms, in association with a fall in circulating tumour peptides. One of these patients has now been treated for seven months with this analogue which has controlled his previously life threatening diarrhoea caused by a malignant VIP secreting tumour. He gives his own injections twice daily, and has returned to a full and active life. This is a promising agent both for acute treatment of peptide hypersecretion, and for the long term management of some patients who are unresponsive to other available therapy.
Adult↗
Hyperenteroglucagonaemia and small intestinal mucosal growth after colonic perfusion of glucose in rats.
Beside intraluminal factors, humoral agents play an important role in intestinal adaptation. Enteroglucagon, the mucosal concentration of which is maximal in the terminal ileum and colon, is the strongest candidate for the role of small intestinal mucosal growth factor. The present experiment was designed to study the role of colonic enteroglucagon in stimulating mucosal growth in rats with a normal small intestine. After eight days of glucose large bowel perfusion, enteroglucagon plasma concentrations were 120.7 +/- SEM 9.2 pmol/l, versus 60.1 +/- 6.8 in mannitol perfused control rats (p less than 0.001). Gastrin, cholecystokinin, neurotensin, pancreatic glucagon, and insulin plasma concentrations were unchanged. Crypt cell proliferation, measured by the vincristine metaphase arrest technique, increased significantly in the small intestine of glucose perfused animals (p less than 0.005-0.001) in comparison with the controls. This resulted in a greater mucosal mass in both proximal and distal small bowel: mucosal wet weight, DNA, protein and alpha D-glucosidase per unit length intestine were all significantly higher (p less than 0.05-0.001) than in mannitol perfused rats. Our data, therefore, support the hypothesis that enteroglucagon is an enterotrophic factor and stress the possible role of the colon in the regulation of small bowel trophicity.
Animals↗
Somatostatin in the human heart and comparison with guinea pig and rat heart.
Somatostatin has been shown to have negative inotropic and chronotopic effects and to restore sinus rhythm in some cases of cardiac arrhythmia. Using acid extracts, regions of human heart were examined by radioimmunoassay to determine their somatostatin content. Mean (SD) concentrations of 4.1 (0.8) pmol/g and 2.9 (0.8) pmol/g were found in atrioventricular node and right atria respectively and were significantly higher than in other heart regions. Using fresh heart tissue from guinea pigs, somatostatin was localised to cardiac nerves by immunocytochemistry. Nerves containing somatostatin were most abundant in the atria, where the concentrations measured by radioimmunoassay were 7.6 (1.0) and 2.6 (0.4) pmol/g for right and left atria respectively. Somatostatin contained in cardiac nerves may have a physiological role in the cardiac conduction system.
Animals↗
Distribution of galanin immunoreactivity in the respiratory tract of pig, guinea pig, rat, and dog.
Galanin, a newly discovered peptide isolated from porcine intestine, is known to cause contraction in rat smooth muscle preparations and to induce hyperglycaemia in dogs. By the use of radioimmunoassay and immunohistochemical techniques the concentration and distribution of galanin immunoreactivity were determined in several areas of the respiratory tract of five dogs, five guinea pigs, five rats, and two pigs. Antibodies were raised in rabbits to whole unconjugated natural porcine galanin. The highest galanin concentrations were found in the bronchus and the trachea of the dog, guinea pig, rat (2 pmol/g in each case), and pig (less than 1 pmol/g). The lowest galanin concentrations were found in the lung parenchyma. Gel chromatographic analysis in the pig showed one molecular form of galanin coeluting with the porcine galanin standard. By means of the indirect immunofluorescence technique on sections of tissues fixed in benzoquinone solution, galanin was found to be confined to nerve fibres in different regions of the respiratory tract. In the nasal mucosa of the pig nerve fibres containing galanin were distributed around seromucous glands and blood vessels and beneath the epithelium. In the trachea, bronchus, and major intrapulmonary airways of the pig, dog, and guinea pig galanin immunoreactive fibres were detected predominantly in smooth muscle, as well as around seromucous glands and in the adventitia of blood vessels. Rarely, galanin immunoreactive nerve fibres were found in the lung parenchyma. A few galanin immunoreactive ganglion cells also containing vasoactive intestinal polypeptide were found in the adventitia of the tracheobronchial wall of the pig and dog. The distribution of galanin suggests that it may have some influence on airway, vascular, and secretory functions in the mammalian respiratory tract.
Animals↗
Gastrointestinal peptides and the adaptation to extrauterine nutrition.
The adaptation to extrauterine nutrition involves complex physiological changes at birth which may be regulated by genetic endowment; enteral nutrients, secretions, and bacteria; and endogenous hormones and exogenous hormones in breast milk. The hypothesis is explored that enteral feeding after birth may trigger key adaptations in the gut and in metabolism partly through the mediation of gastrointestinal hormone secretion. Gut peptides are found in the early human fetal gut and by the second trimester some are found in high concentrations in the fetal circulation and amniotic fluid. Major plasma hormonal surges occur during the neonatal period in term and preterm infants: notably in enteroglucagon, gastrin, motilin, neurotensin, gastrointestinal peptide, and pancreatic polypeptide. These events do not occur in neonates deprived of enteral feeding. A progressive development of dynamic gut hormonal responses to feeding is observed. The pattern of gut endocrine changes after birth is influenced by the type and route of feeding. Potential pathophysiological effects of depriving high risk neonates of enteral feeding are considered. It is speculated that infants committed to prolonged total parenteral nutrition from birth may benefit from the biological effects of intraluminal nutrients used in subnutritional quantities.
Adaptation, Physiological↗
The hormonal regulation of food intake, digestion, and absorption.
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Absorption↗
Lymph, pancreatic and gastrointestinal hormones in response to feeding in the conscious pig.
Concentrations of several gastrointestinal hormonal peptides were measured in lymph from the cisterna chyli and in arterial plasma; in healthy, conscious pigs during ingestion of a meal. Lymph concentrations of the pancreatic hormones insulin, glucagon and pancreatic polypeptide were small compared with plasma concentrations, although postprandial increments were significant. In contrast lymph concentrations of gastrin, cholecystokinin, motilin and gastric inhibitory peptide (GIP) from the foregut showed a more marked postprandial rise than the pancreatic hormones. Indeed the total integrated responses of these peptides in lymph reached about 50% of those seen in arterial plasma. It would appear unlikely that the lymphatics constitute an important transport mechanisms for these regulatory peptides. However, lymph concentrations of hormones may reflect levels in interstitial fluid better than plasma and may be of value in assessing putative physiological actions within a target tissue.
Animals↗
Studies on the hormonal regulation of fuel metabolism in the human newborn infant undergoing anaesthesia and surgery.
Little is known of the endocrine and metabolic milieu in preterm and term neonates exposed to surgical stress. In order to define the effects of anaesthesia and surgery on the hormonal regulation of intermediary metabolism, the levels of plasma insulin, glucagon, adrenaline and noradrenaline were measured in addition to blood glucose, lactate, pyruvate, alanine, acetoacetate, hydroxybutyrate, glycerol and plasma-free fatty acids in 38 neonates (23 term, 15 preterm) undergoing surgery. Blood samples were drawn pre-operatively, at the end of surgery, and at 6, 12 and 24 h post-operatively. Plasma levels of adrenaline and noradrenaline increased significantly in response to surgery. In term neonates, plasma insulin concentrations were unaltered at the end of surgery, but were significantly increased throughout the post-operative period; plasma glucagon levels were unchanged at the end of surgery but had significantly decreased by 24 h after surgery. Insulin levels in preterm neonates remained unchanged during surgery as well as in the post-operative period. All neonates developed a significant peri-operative hyperglycaemia which persisted up to 12 h after surgery. Blood lactate and pyruvate increased during surgery, accompanied by significant increases in plasma free fatty acids, total ketone bodies and glycerol concentrations by the end of surgery. Blood glucose concentrations were significantly correlated with plasma adrenaline levels at the end of surgery and with plasma glucagon at 6 h post-operatively. The insulin/glucose ratio was significantly decreased at the end of surgery in term and preterm neonates. Further analysis showed that total parenteral nutrition given just before surgery and thiopentone anaesthesia given during surgery significantly augmented the peri-operative hyperglycaemic response of term neonates. Thus, stress-related hormonal changes in preterm and term neonates may precipitate a catabolic state characterized by glycogenolysis, gluconeogenesis, lipolysis and mobilization of gluconeogenic substrates in the post-operative period. Prevention of these metabolic derangements by anaesthetic or hormonal manipulation may possibly help to improve the clinical outcome of neonates undergoing surgery.
Anesthesia, General↗
Effect of food on porcine gut regulatory peptides in arterial and portal venous blood.
The concentrations of gut regulatory peptides were monitored simultaneously in the portal and arterial circulations of 8 healthy conscious swine in the fasted state and after a standard mixed meal. The sampling was achieved via chronic cannulations of these two vessels. Portal/arterial differences of insulin and glucagon were similar to those previously described, indicating the importance of hepatic extraction of these two hormones. Portal/arterial differences for the gastrointestinal regulatory peptides were relatively small, however, and the liver is unlikely to be of major importance in the metabolism of these peptides.
Animals↗
Somatostatin-14 modulates postprandial glucose levels and release of gastrointestinal and pancreatic hormones.
Ingestion of a 4,500-kcal mixed meal by healthy volunteers resulted in a significant rise of plasma somatostatin-14-like immunoreactivity (9 +/- 1 pmol l-1. Whether this peptide has a role as a humoral agent or not is still controversial and, until recently, most studies investigating its effects by exogenous administration have produced vastly supraphysiological circulating plasma levels. In order to reproduce the rise obtained following the large meal, synthetic somatostatin-14 was infused at a dose of 0.8 pmol kg-1 min-1 before and during a 530-kcal test breakfast. This resulted in a rise of 8 + 2 pmol l-1 in the peripheral circulation. This infusion produced a significant reduction in the postprandial release of insulin, gastric inhibitory polypeptide, pancreatic polypeptide and in the preprandial motilin levels. In contrast, blood glucose levels following the breakfast were elevated when compared to the control saline infusion. This suggests that somatostatin possesses true endocrine functions and is capable of profoundly altering the postprandial glucose and hormone response.
Adult↗