Biomedical subjects

M A Ghatei

Publications and source records attributed to M A Ghatei.

At least 307 records · Page 17Linked to original sources

PubMed1985

Infusion of a novel peptide, calcitonin gene-related peptide (CGRP) in man. Pharmacokinetics and effects on gastric acid secretion and on gastrointestinal hormones.

Calcitonin gene-related peptide (CGRP) is a recently discovered widespread regulatory peptide which is encoded in the same gene as calcitonin. We assessed the effect of systemic infusion of synthetic rat CGRP at low dose (range 0.32-2.56 pmol/kg per min) on submaximal pentagastrin-stimulated gastric secretion and on gastrointestinal hormones. To assess its pharmacokinetic parameters in man the MCR and plasma half-life were estimated by the continuous infusion method. Gastric acid output and pepsin secretion were significantly reduced by CGRP (-29% of basal, P less than 0.01 and -40% of basal, P less than 0.005, respectively). There was a significant fall in basal levels of gastrin (-39%, P less than 0.001); gastric inhibitory peptide (-44.7%, P less than 0.001); enteroglucagon (-25%, P less than 0.001) and neurotensin (-33%, P less than 0.05). There was no significant change in plasma levels of insulin, motilin, pancreatic polypeptide or glucose. Suppression of gastric secretion and the fall in gastrointestinal hormones was prolonged and basal levels were not re-established after stopping the CGRP infusion. The disappearance curve of immunoreactive CGRP from the plasma was bi-exponential. The plasma half-life of immunoreactive CGRP was calculated as 6.9 +/- 0.9 min for the fast decay and 26.4 +/- 4.7 min for the slow decay. The calculated MCR was 11.3 +/- 1.2 ml/kg per min. Except for flushing of the face no untoward effects were observed. The results of this study suggest the possibility that CGRP could play a role in the regulation of gastric secretion and gastrointestinal hormone release.

Adult↗

PubMed1985

Distribution and chromatographic characterisation of CGRP-like immunoreactivity in the brain and gut of the rat.

Radioimmunoassay, chromatography and immunocytochemistry were used to study the occurrence of calcitonin gene-related peptide in the brain and gastrointestinal tract of the rat. In the brain, the highest concentrations of the peptide were found in the medulla oblongata (58.3 +/- 6.8 pmol/g) where immunocytochemistry showed the presence of immunoreactive cell bodies. Significant concentrations were also found in the pancreas and throughout the gastrointestinal tract, the highest levels occurring in the pyloric sphincter (48.0 +/- 6.0 pmol/g). CGRP-like immunoreactivity in the gastrointestinal tract was restricted to nerve fibers. Chromatographic analysis of the CGRP-like immunoreactivity occurring in these tissues showed that at least 70% was indistinguishable from the synthetic peptide. However, there was also evidence of a number of smaller cross-reacting molecular species.

Animals↗

PubMed1985

Presence of neuromedin B-like immunoreactivity in the brain and gut of rat and guinea-pig.

A recently developed specific radioimmunoassay for neuromedin B, originally isolated from porcine spinal cord, was used to investigate its distribution in rat and guinea-pig brain and gut. In both species, neuromedin B-like immunoreactivity was present in several regions of brain, and high concentrations occurred in the pituitary. The immunoreactivity was widely distributed throughout the entire length of gastrointestinal tract and pancreas, and relatively high concentrations were found in the oesophagus and rectum. Immunocytochemistry localised neuromedin B-like immunoreactivity to nerve fibers in the rat brain and gut. Immunoreactive fibres were visualized in the medial thalamus and were found very frequently in the circular muscle of the gut. Gel permeation chromatography of pituitary and intestinal extracts from both species revealed presence of two peaks of neuromedin B-like immunoreactivity, the later of which co-eluted with the synthetic porcine neuromedin B standard. Reverse phase high pressure liquid chromatography showed that material corresponding to the later peak was eluted in the exact position of synthetic porcine neuromedin B, whereas the larger molecular size material from the earlier peak was more hydrophobic in nature.

Amino Acid Sequence↗

PubMed1985

Calcitonin gene-related peptide in cardiovascular tissues of the rat.

The distribution of calcitonin gene-related peptide immunoreactivity in the cardiovascular system of the rat was investigated by radioimmunoassay and immunocytochemistry. The nature of the immunoreactivity was studied by gel permeation and high performance liquid chromatography. Immunocytochemistry demonstrated the existence of calcitonin gene-related peptide-containing nerve fibres throughout the cardiovascular system. These were present in all regions of the heart, particularly in association with the coronary arteries, within the papillary muscles and within the sinoatrial and atrioventricular nodes. Calcitonin gene-related peptide-containing fibres were found mainly in the adventitia of the arteries and veins. Calcitonin gene-related peptide concentrations were high in major arteries and veins but comparatively low in the heart, aortic arch and thoracic aorta. Chromatography showed that approximately 70% of the total immunoreactivity was identical to synthetic calcitonin gene-related peptide. Calcitonin gene-related peptide concentrations in the blood vessels of rats treated neonatally with capsaicin were not found to be significantly different from those in control animals although capsaicin caused significant reductions of calcitonin gene-related peptide levels in certain other tissues. The results of this study suggest that calcitonin gene-related peptide-containing fibres are likely to be of importance in the innervation of vascular tissues and raise the possibility that these fibres are different in character from calcitonin gene-related peptide-containing fibres found in other tissues.

Animals↗

PubMed1985

Distribution and localization of neuromedin B-like immunoreactivity in pig, cat and rat spinal cord.

The distribution and localization of neuromedin B, a novel bombesin-like decapeptide isolated from porcine spinal cord, was investigated by newly established radioimmunoassay and immunocytochemistry in the pig, cat and rat spinal cord. Neuromedin B-like immunoreactivity was found to be concentrated particularly in the dorsal part of lumbosacral segments in all species studied and the highest concentration of immunoreactivity was 25.7 +/- 3.4 pmol/g wet wt in the dorsal part of sacral region of pig spinal cord. The nature of the immunoreactivity was studied by gel permeation and high pressure liquid chromatography. Chromatography of spinal cord extracts from three species revealed two major peaks of neuromedin B-like immunoreactivity and the prevalent molecular from co-eluted with synthetic porcine neuromedin B. Immunocytochemistry localized neuromedin B immunoreactivity to fibres and terminals throughout the entire length of the spinal cord of pig, cat and rat. Fibres were most abundant in laminae I and II of the dorsal horn, the area around the central canal (lamina X) and intermediolateral cell columns of thoracic and sacral segments. In lumbosacral segments neuromedin B-immunoreactive fibres were slightly more numerous, in both dorsal and ventral spinal cord, than in cervical and thoracic regions.

Animals↗

PubMed1985

Calcitonin gene-related polypeptide as a mediator of the neurogenic ocular injury response.

Calcitonin gene-related polypeptide (CGRP) has been localised immunochemically within the rat and guinea pig anterior uvea to nerve fibres of trigeminal origin. As with substance P (1-3) the level of CGRP in the iris-ciliary body is depleted after thermal damage to the Gasserian ganglion and elevated in chronically sympathectically denervated eyes. Unlike substance P, a potent pupillary constrictor (4,5), CGRP has no notable miotic action, but does, however, cause an elevation of the intraocular pressure (IOP) accompanied by disruption of the blood-aqueous barrier. It is proposed that the diverse actions of these two sensory neuropeptides conjointly mediate the antidromic ocular injury response.

Afferent Pathways↗

PubMed1985

Gastrin-releasing peptide-like immunoreactivity in medullary thyroid carcinoma.

Gastrin-releasing peptide, the mammalian counterpart of amphibian bombesin, has been found to be present in high concentration by radioimmunoassay in eight histologically confirmed medullary thyroid carcinomas and to be undetectable in postmortem normal thyroid tissue. Chromatographic analysis of the tumor extracts by gel permeation revealed two major peaks of gastrin-releasing peptide-like immunoreactivity (GRP-LI). However, reverse-phase high-pressure liquid chromatography demonstrated three immunoreactive peaks of GRP-LI. None of these immunoreactive peaks was coeluted with synthetic porcine GRP or amphibian bombesin, but one of the peaks exactly emerged in the position of neuromedin C (C-terminal decapeptide of GRP). Sections from nine primary or secondary tumours were immunostained for GRP using a peroxidase/anti-peroxidase technic. All the medullary thyroid carcinomas were shown to contain GRP-LI, specifically localized to the tumor cells. This immunoreactivity is elevated in plasma from some patients with this malignancy, raising the possibility that it may be used as an additional tumor marker.

Carcinoma↗

PubMed1985

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↗

PubMed1985

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↗

PubMed1985

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↗

PubMed1985

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↗

PubMed1985

Plasma enteroglucagon and neurotensin levels in gnotobiotic calves infected with enteropathogenic and non-enteropathogenic viruses.

Five gnotobiotic calves were each infected with five viruses. Each calf was inoculated with coronavirus at seven days old, followed by astrovirus, Newbury agent, parainfluenzavirus type 3 and rotavirus at intervals of two weeks. Three of the viruses were enteropathogenic (bovine coronavirus, bovine calici-like virus and bovine rotavirus) and two were not (bovine astrovirus and parainfluenzavirus type 3). Plasma levels of the peptide hormones enteroglucagon and neurotensin and faecal output were measured daily and xylose absorption was studied before and after each infection. A close correlation was found between a rise in plasma enteroglucagon and neurotensin and infection with enteropathogenic viruses. The three enteropathogenic viruses caused increased daily faecal output, and elevated plasma levels of enteroglucagon and neurotensin, while the non-enteropathogens did not. The calici-like virus and rotavirus but not the coronavirus caused xylose malabsorption.

Animals↗

PubMed1984

Bombesin-like immunoreactivity in the pancreas of man and other mammalian species.

Bombesin-like immunoreactivity has been measured in pancreatic tissues of man (12.4 +/- 1.2 pmol/g), pig (15.8 +/- 3.2), calf (4.3 +/- 0.9), rat (8.5 +/- 1.2) and guinea-pig (2.8 +/- 0.6) by a specific radioimmunoassay. Gel filtration of the pancreatic extracts revealed 2 major immunoreactive peaks: the earlier peak was eluted in the position of porcine gastrin-releasing peptide, and the later peak was eluted just after the amphibian bombesin standard. Immunocytochemistry demonstrated the presence of bombesin-like immunoreactivity in nerves in the rat pancreas, particularly in the exocrine pancreas, and occasionally in the peri-insular spaces. Isolated rat pancreatic islets were found to contain small quantities of bombesin-like immunoreactivity (0.037 +/- 0.003 fmol/islet) suggesting that mammalian bombesin-like peptides may be involved in the regulation of endocrine as well as exocrine pancreatic secretion.

Animals↗

PubMed1984

Regional distribution of bombesin and seven other regulatory peptides in the human brain.

In order to compare within the same brains the quantitative distributions of a range of neuropeptides, bombesin, N- and C-terminal glucagon, cholecystokinin, neurotensin, somatostatin, substance P and vasoactive intestinal polypeptide immunoreactivities were determined by radioimmunoassay in 24 regions of 5 normal adult human brains. Each peptide showed a different distribution pattern. Of the peptides not previously mapped in detail in the human brain, bombesin-like immunoreactivity was present in all regions with the highest concentrations in particular areas of the hypothalamus, septal nuclei, nucleus accumbens, globus pallidus, amygdala, periaqueductal grey and substantia nigra. C- and N-terminal glucagon immunoreactivities were detected only in the ventromedial hypothalamus. The concentrations of the remaining 5 peptide immunoreactivities, and their molecular forms, were in good general agreement with those reported individually by others in both human brains and those of experimental animals. The quantitative mapping of the regulatory peptides in the human brain provides an essential base for further comparative study in diseased postmortem brains.

Adult↗

PubMed1984

Plasma enteroglucagon and CCK levels and cell proliferation in defunctioned small bowel in the rat.

Luminal nutrients exert a powerful trophic effect on small bowel mucosa. Recent evidence suggests that a circulating factor, possibly enteroglucagon, is also growth-promoting. In order to study the isolated effect of nonluminal influences on bowel mucosa, Thiry-Vella fistulae (TVF) were constructed in rats. Circulating enteric hormone concentrations were manipulated by resecting different lengths of remaining gut. Thirty-two male Wistar rats had either 25%, 50%, 75%, or 90% proximal small bowel resection. In each animal the first 25% of resected bowel was exteriorized as a Thiry-Vella fistula. Seven control rats underwent jejunal transection. Twelve days postoperatively the fasted animals were killed, and circulating and tissue concentrations of enteroglucagon and CCK were estimated by radioimmunoassay. Crypt-cell production rate was used as an index of cellular proliferation in the Thiry-Vella fistulae. Proximal small bowel defunctioned in the Thirty-Vella fistulae had a significantly lower crypt-cell production rate and enteroglucagon and CCK content than the equivalent segment in transected rats. Further small bowel resection produced a subsequent increase in circulating enteroglucagon and CCK concentrations, an increase in the Thiry-Vella fistula content of these hormones, and a doubling of the crypt-cell production rate in the Thiry-Vella fistulae. These results show that circulating enteroglucagon and CCK concentrations match closely with enterocyte production even when luminal influences are excluded. It is suggested that circulating factors may play a major role in postresectional ileal hyperplasia. This hyperplasia apparently affects endocrine cells as well as enterocytes.

Animals↗

PubMed1984

Neuroendocrine responses to stimulation of the splanchnic nerves in bursts in the conscious adrenalectomized calf.

Effects of stimulation of the peripheral ends of the splanchnic nerves below behavioural threshold at either 4 or 2 Hz continuously for 10 min, and at 40 or 20 Hz for 1 s at 10 s intervals for 10 min, have been compared in conscious calves. Cardiovascular responses were apparently unaffected by the pattern of the stimulus, whereas pancreatic neuroendocrine responses were significantly enhanced by stimulation in bursts, as was the rise in mean arterial plasma glucose concentration. Release of bombesin-like immunoreactivity was substantially potentiated by intermittent stimulation at relatively high frequencies and the significance of this discovery is discussed in relation to the effects that this peptide is known to evoke in this species.

Adrenalectomy↗

PubMed1984

Effects of certain metabolites on pancreatic endocrine responses to gastrin-releasing peptide in conscious calves.

The effects of intravenous infusions of synthetic gastrin-releasing peptide (GRP; 5 pmol/kg X min) have been investigated in 3- to 6-week-old conscious calves receiving continuous intravenous infusions of either glucose or amino acids or both at a dose of 0.03 mmol/kg X min and the results compared with the effects of the same dose of the peptide in control calves. Pre-treatment with amino acids alone caused a statistically significant fall in mean plasma glucose concentration, which was associated with a significant rise in mean pancreatic glucagon concentration. Additional infusion of glucose prevented this rise in plasma glucose concentration and resulted in a delayed, but very substantial rise in mean plasma insulin concentration. Pre-treatment with amino acids alone substantially and significantly increased the rise in mean plasma insulin that occurred in response to GRP. The rise in mean plasma glucagon concentration in response to GRP that occurred in the control group, the group pre-treated with amino acids alone and the group given both glucose and amino acids, was virtually eliminated in the group pre-treated with glucose alone. The normal rise in plasma pancreatic polypeptide concentration in response to GRP was invariably abolished in the presence of amino acids. No significant change in either mean neurotensin-like or gastric-inhibitory-peptide-like immunoreactivity was observed in response to GRP in any of these groups. The results are discussed in relation to possible physiological functions that GRP may subserve.

Amino Acids↗

PubMed1984

The ileal brake--inhibition of jejunal motility after ileal fat perfusion in man.

The possibility that malabsorbed fat passing through the human ileum exerts an inhibitory feedback control on jejunal motility has been investigated in 24 normal subjects by perfusing the ileum with a fat containing solution designed to produce ileal luminal fat concentrations similar to those in steatorrhoea (30-40 mg/ml). Mean transit times through a 30 cm saline perfused jejunal segment were measured by a dye dilution technique. Thirty minutes after ileal fat perfusion, mean transit times rose markedly to 18.9 +/- 2.5 minutes from a control value of 7.5 +/- 0.9 minutes (n = 5; p less than 0.05). This was associated with an increase in volume of the perfused segment which rose to 175.1 +/- 22.9 ml (control 97.6 +/- 10.3 ml, n = 5; p less than 0.05). Transit times and segmental volumes had returned towards basal values 90 minutes after completing the fat perfusion. Further studies showed that ileal fat perfusion produced a pronounced inhibition of jejunal pressure wave activity, percentage duration of activity falling from a control level of 40.3 +/- 5.0% to 14.9 +/- 2.8% in the hour after ileal perfusion (p less than 0.01). Ileal fat perfusion was associated with marked rises in plasma enteroglucagon and neurotensin, the peak values (218 +/- 37 and 68 +/- 13.1 pmol/l) being comparable with those observed postprandially in coeliac disease. These observations show the existence in man of an inhibitory intestinal control mechanism, whereby ileal fat perfusion inhibits jejunal motility and delays caudal transit of jejunal contents.

Adult↗