Biomedical subjects

M A Ghatei

Publications and source records attributed to M A Ghatei.

At least 109 records · Page 6Linked to original sources

PubMed1997

Peptide analogue studies of the hypothalamic neuropeptide Y receptor mediating pituitary adrenocorticotrophic hormone release.

Hypothalamic neuropeptide Y (NPY) is thought to be important in the regulation of feeding and also in the release of Adrenocorticotrophic hormone (ACTH). Intracerebroventricular administration of NPY to male rats significantly increased plasma ACTH 10 min after injection and stimulated 2-h food intake. A series of analogues of NPY that have a greatly reduced affinity for the Y1 [human pancreatic polypeptide (human PP), NPY(3-36)], the Y2 ([Pro34]NPY, human PP), the Y3 (peptide YY), and the Y6 (human PP) receptor, all markedly stimulated ACTH release. Rat PP, which binds with high affinity to the Y4 receptor, was unable to stimulate ACTH release. A novel analogue fragment [Pro34]NPY(13-36) was synthesized as a ligand with low Y1 and Y2 receptor affinity. Interestingly, neither [Pro34]NPY(13-36) nor the selective Y5 receptor agonist [D-Trp32]NPY stimulated food intake, whereas both significantly increased plasma ACTH. Thus the hypothalamic NPY receptor mediating increases in plasma ACTH has a fragment activation profile unlike the Y1-Y4 or Y6 receptors and appears distinct from the NPY receptor controlling food intake.

Adrenocorticotropic Hormone↗

PubMed1997

Leptin interacts with glucagon-like peptide-1 neurons to reduce food intake and body weight in rodents.

The adipose tissue hormone, leptin, and the neuropeptide glucagon-like peptide-1 (7-36) amide (GLP-1) both reduce food intake and body weight in rodents. Using dual in situ hybridization, long isoform leptin receptor (OB-Rb) was localized to GLP-1 neurons originating in the nucleus of the solitary tract. ICV injection of the specific GLP-1 receptor antagonist, exendin(9-39), at the onset of dark phase, did not affect feeding in saline pre-treated controls, but blocked the reduction in food intake and body weight of leptin pre-treated rats. These findings suggest that GLP-1 neurons are a potential target for leptin in its control of feeding.

Animals↗

PubMed1997

Possible evidence for endogenous production of a novel galanin-like peptide.

Galanin mRNA and peptide are not detectable in normal islets. We studied the effect of galanin antagonists on insulin secretion in the rat beta cell line, RIN5AH, and in perifused rat islets. In RIN cell membranes galanin and its antagonists showed high affinity for 125I-galanin binding sites [Kd: (galanin) 0.03+/-0.01; Ki for galanin antagonists: (C7) 0.12+/- 0.02, (M35) 0.21+/-0.04, and (M40) 0.22+/-0.03 nM, mean+/- SEM, n = 4]. Galanin (1 microM) inhibited glucose-induced insulin release in islets (control 21.2+/-1.5 vs. galanin 4.5+/-0.2 fmol/islet per min, P < 0.001, n = 6) and RIN5AH cells (control 0.26+/-0.01 vs. galanin 0.15+/-0.02 pmol/10(6) cells per h, P < 0.001, n = 9). In RIN5AH cells, all antagonists blocked the inhibitory effects of galanin and stimulated insulin release in the absence of galanin. C7 and M40 (1 microM) alone significantly stimulated glucose-induced insulin secretion. Purified porcine galanin antibody (GAb) enhanced glucose-induced insulin release from islets (control 100+/- 16.3% vs. GAb 806.1+/-10.4%, P < 0.001, n = 6), and RIN5AH cells (control 100+/-9.6% vs. GAb 149+/-6.8%, P < 0. 01, n = 6). Western blotting of dexamethasone-treated islet extracts using GAb showed a specific band of similar molecular weight to porcine galanin not detected using a rat specific galanin antibody. One possible explanation for these results is the presence of an endogenous galanin-like peptide.

Amino Acid Sequence↗

PubMed1997

Fermentable dietary fibre, intestinal microflora and plasma hormones in the rat.

1. Conventional and germ-free rats were fed a fibre-free elemental diet with or without the addition of fermentable dietary fibres. We have previously reported that fibre was associated with greatly increased epithelial cell proliferation, but only in the conventional group, implying that it is the breakdown of fibre by the colonic microflora that is the main determinant of mucosal proliferation in the hind gut. The relationship of these changes to various plasma hormones implicated in intestinal growth control are described in this paper. 2. The most dramatic finding was that plasma levels of enteroglucagon and peptide YY were greatly increased in the germ-free groups. The response of these rats to fibre differed in that fibre decreased levels of enteroglucagon and peptide YY in the germ-free animals, but increased them in the conventional rats. Gastrin and insulin levels were significantly lowered in the fibre-supplemented groups, but were not affected by the microflora. 3. These results corroborate our previous findings that the effects of fibre and its fermentation are dynamically complex, and demonstrate that, like proliferation, direct effects and indirect fermentation-derived effects on plasma hormones also coexist.

Analysis of Variance↗

PubMed1997

Plasma immunoreactive leptin concentration in end-stage renal disease.

1. Leptin is thought to be an inhibitor of appetite. As the kidney helps clear several polypeptide hormones, plasma leptin may accumulate in end-stage renal disease. 2. Plasma immunoreactive leptin was measured in four groups of subjects: haemodialysis, continuous ambulatory peritoneal dialysis and renal transplant patients and a group of healthy controls. Leptin was also measured before and after a single dialysis session. 3. There was a strong correlation between plasma immunoreactive leptin and body mass index in all groups except female haemodialysis patients. Leptin was higher in females than in males in all groups when controlled for body mass index. Mean plasma leptin [mean (SD)] was significantly higher in all renal groups [haemodialysis, 15.1 (3.6) ng/ml; continuous ambulatory peritoneal dialysis, 25.4 (4.3) ng/ml; transplants, 11.6 (2.6) ng/ml] compared with controls [5.3 (2.3) ng/ml]. There was a significant difference in the regression equations relating leptin and body mass index (dialysis > transplants > controls), even when controlled for gender. Leptin correlated modestly with serum creatinine in non-dialysis subjects. Plasma leptin immunoreactivity was slightly reduced by haemodialysis, but post-dialysis leptin was still significantly higher than that found in controls. 4. Chromatographic characterization of the high level of leptin immunoreactivity found in haemodialysis subjects showed a single elution peak corresponding to that of the highly purified human leptin standard. 5. In conclusion, leptin is higher than expected for body mass index in end-stage renal disease. Hyperleptinaemia could contribute to the anorexia and poor nutritional status commonly seen in renal failure.

Adult↗

PubMed1997

Glucagon-like peptide-1 (GLP-1): a trial of treatment in non-insulin-dependent diabetes mellitus.

Glucagon-like peptide-1 (7-36) amide (GLP-1) is released from the gut into the circulation after meals and is the most potent physiological insulinotropic hormone in man. In contrast to presently available therapeutic agents for non-insulin-dependent diabetes mellitus (NIDDM), GLP-1 has the advantages of both suppressing glucagon secretion and delaying gastric emptying. We report the first chronic study of subcutaneous (s/c) GLP-1 treatment in NIDDM. Five patients with poorly controlled NIDDM were entered into a six-week, double-blind crossover trial. Each received three weeks treatment with s/c GLP-1 40 nmol or saline, given three times a day immediately before meals. A standardized test meal was given at the beginning and end of each treatment period. GLP-1 reduced plasma glucose area under the curve (AUC) following the standard test meal by 25% (AUC, 0-180 mins, GLP-1 start of treatment 482.2 +/- 38.2 vs. saline start of treatment 635.7 +/- 45.4 mmol min L-1, F = 16.4, P < 0.02). The beneficial effect of GLP-1 on plasma glucose concentration was fully maintained for the three-week treatment period. Plasma glucagon levels were significantly lower for 60 min postprandially after GLP-1 treatment. In this group of patients there was no significant increase in postprandial insulin levels with GLP-1. We have demonstrated a significant improvement in postprandial glycaemic control with s/c GLP-1 treatment that was fully maintained over a three-week treatment period. GLP-1 improves glycaemic control even in the absence of an insulinotropic effect and is a potential treatment for NIDDM.

Blood Glucose↗

PubMed1997

Pancreatic endocrine responses to the peptides VIP and PACAP in the conscious calf.

Pancreatic endocrine responses to vasoactive intestinal peptide (VIP), pituitary adenylate cyclase-activating peptide (PACAP) and acetylcholine have been investigated in conscious calves, while continuously monitoring aortic blood pressure and heart rate, in order to assess the effects of these neuropeptides under normal physiological conditions. VIP was found to modulate the release of pancreatic polypeptide (PP) in response to acetylcholine at a dose which had no significant effect on the release of either pancreatic glucagon or insulin. PACAP stimulated the release of insulin and the effect was potentiated during infusions of exogenous glucose. PACAP, when infused together with acetylcholine, also stimulated the release of pancreatic glucagon in the absence of exogenous glucose but not in its presence. Release of PP was stimulated during infusions of PACAP, whether or not exogenous glucose was given, and this effect was found to be additive with that of acetylcholine.

Acetylcholine↗

PubMed1997

Airway endothelin levels in asthma: influence of endobronchial allergen challenge and maintenance corticosteroid therapy.

Endothelins (ETs) are 21 amino acid peptides which, in addition to their other properties, are potent bronchoconstrictors. Whilst there is evidence of the involvement of ET in the pathophysiology of chronic asthma, its contribution to the acute allergic response is undefined. To examine this, we have undertaken segmental bronchoprovocation with allergen and saline at separate sites in six atopic asthmatics receiving treatment with bronchodilators only and six atopic asthmatics additionally receiving treatment with inhaled corticosteroids. Each challenged segment was lavaged 10 min after bronchoprovocation and concentrations of immunoreactive ET were measured in bronchoalveolar lavage fluid. In the non-steroid-treated subjects, there were significantly lower ET levels at the allergen-challenged sites compared to the saline-challenged sites (p<0.05). In the steroid-treated subjects, on the other hand, there was no significant difference between the two sites. Levels of ET at the saline-challenged sites were significantly lower in the steroid-treated subjects compared to the non-steroid-treated subjects (p<0.04). These findings do not support the hypothesis that allergen exposure in asthma results in immediate release of endothelin. However, release at later time-points and a role for endothelin in late-phase bronchoconstriction are not excluded.

Adrenal Cortex Hormones↗

PubMed1997

Melanin-concentrating hormone acutely stimulates feeding, but chronic administration has no effect on body weight.

Melanin-concentrating hormone (MCH) has recently been proposed as both a central stimulator and an inhibitor of food intake. To clarify its role, we investigated the effects of MCH and the prepro-MCH-derived peptide neuropeptide E-I injected intracerebroventricularly (icv) in rats. MCH (0.15-15 micrograms) was injected icv at the beginning of the light phase. Food intake at 2 h showed a dose-dependent increase from 325 +/- 7% of the control value (1.5-microgram dose; P < 0.05) to 462 +/- 30% of the control value (15-microgram dose; P < 0.005). When 10 ng, 100 ng, and 5 micrograms MCH were injected icv at the beginning of the dark phase, only 5 micrograms stimulated feeding (166 +/- 16% of the control value; P < 0.05). At no dose did MCH inhibit feeding. Twice daily icv injections of MCH (5 micrograms) caused an average 197 +/- 9% increase in 2-h food intake for the first 5 days. Injections from days 6-8 did not stimulate feeding. Food intake and body weight at 24 h remained unchanged. Intracerebroventricular neuropeptide E-I had no effect on food intake alone and did not alter MCH-induced feeding. These studies show a dose-dependent stimulation of feeding by acute central administration of MCH. Tolerance is seen with chronic administration. These findings support a role for MCH in the immediate regulation of food intake, but not in body weight control.

Animals↗

PubMed1997

Neuropeptide Y induced feeding in the rat is mediated by a novel receptor.

There are now six recognized neuropeptide Y (NPY) receptor subtypes (Y1-Y4 and two recently cloned distinct receptors labeled Y5), of which Y1 and one of the Y5's have been suggested could mediate the effect of NPY on feeding. The fragments NPY(2-36) and NPY(3-36), which bind Y1 only poorly, were injected intracerebroventricularly (icv) and found to have similar dose-response relationships to NPY in the stimulation of feeding. However NPY (13-36), which stimulates both Y2 and Y5, caused no increase in food intake, even at high doses. Maximal stimulation with the classical Y1 agonist [Pro34]-NPY produced only 50% of the maximum effect of NPY itself despite fully inhibiting adenylyl cyclase activity in vitro in a Y1 system. The novel fragment [Pro34]-NPY(3-36) is as effective at stimulating food intake as the classical Y1 analogue [Pro34]-NPY but bound to the Y1 receptor with only 1/20th of the affinity of NPY and failed to inhibit adenylyl cyclase through this receptor. [Pro34]-NPY(3-36) is therefore a relatively appetite-selective ligand. Coadministration of high dose NPY(13-36) and [Pro34]NPY did not enhance feeding compared with [Pro34]-NPY alone. In addition, the NPY Y1 receptor antagonist BIBP-3226, which does not bind Y2, Y4, or Y5 receptors, significantly reduced NPY induced feeding. These results indicate that the feeding effect of icv NPY involves a novel receptor and that it is functionally distinct from the recognized receptor subtypes.

Adenylyl Cyclases↗

PubMed1997

Expression of adrenomedullin (ADM) and its binding sites in the rat uterus: increased number of binding sites and ADM messenger ribonucleic acid in 20-day pregnant rats compared with nonpregnant rats.

RIA of nonpregnant rat uterus extracts showed 0.68 +/- 0.08 pmol/g adrenomedullin (ADM) and 3.23 +/- 0.08 pmol/g calcitonin gene-related peptide (CGRP). In the pregnant (20 days gestation) uterus, the ADM content was 0.90 +/- 0.17 pmol/g, and CGRP could not be detected. ADM messenger RNA was detected at high levels in the uterus, with a 1.8-fold increase in expression in pregnancy. Pharmacologically distinct binding sites for ADM (Bmax = 21 +/- 2 fmol/mg protein, dissociation constant = 80 +/- 6 pM), and CGRP (Bmax = 101 +/- 18 fmol/mg protein, dissociation constant = 140 +/- 20 pM) were identified in nonpregnant uterus. Competition for 125I[Tyr0]alphaCGRP binding was shown by both ADM and CGRP (8-37), whereas CGRP and CGRP (8-37) did not compete for 125I-ADM-binding sites. The density of the ADM-binding sites was 10 times greater in pregnant uterus (Bmax = 211 +/- 39 fmol/mg protein, P < 0.01) than nonpregnant uterus. CGRP receptor messenger RNA was identified in both nonpregnant and pregnant uteri. In isolated nonpregnant rat uteri, CGRP and ADM attenuated the contractile response to galanin by 77 +/- 10% and 57 +/- 10%, respectively. The responses to both CGRP and ADM were abolished by CGRP (8-37). These results demonstrate, for the first time, the presence of ADM and specific binding sites for both ADM and CGRP in the rat uterus.

Adrenomedullin↗

PubMed1997

Circulating adrenomedullin does not regulate systemic blood pressure but increases plasma prolactin after intravenous infusion in humans: a pharmacokinetic study.

Adrenomedullin has been proposed to be a circulating hormone regulating systemic and pulmonary blood pressure. A potential therapeutic role in the management of pulmonary hypertension has been suggested based on animal studies, but the pharmacokinetics and pharmacodynamics in human subjects have not been studied. We have infused adrenomedullin into volunteers at 3.2 pmol/kg.min, which more than quadrupled (52 pmol/L) normal circulating concentrations. At this dose no change in heart rate or blood pressure was noted. When infused at 13.4 pmol/kg.min to achieve a concentration over 40 times normal circulating levels (448 pmol/L), there was a significant fall in diastolic blood pressure from 69 +/- 2 to 53 +/- 2 mm Hg and a significant increase in pulse rate from 57 +/- 3 to 95 +/- 4 beats/min. Circulating PRL concentrations rose from 197 +/- 46 to 372 +/- 64 IU/L (mean +/- SEM; P < 0.01). No effect was seen on ACTH, TSH, FSH, LH, or cortisol. When the infusion was discontinued, baseline pulse and blood pressure were reestablished after 20 min. Adrenomedullin has a MCR of 27.4 +/- 3.6 mL/kg.min, with a circulating half life of 22 +/- 1.6 min and an apparent volume of distribution of 880 +/- 150 mL/kg. Column chromatography of plasma taken during infusion and decay of adrenomedullin showed no evidence of the production of additional molecular forms. These results are consistent with a peptide that is markedly tissue bound. Plasma adrenomedullin concentrations were increased in patients with renal impairment (14.1 +/- 0.9 pmol/L) compared to those in healthy volunteers (8.1 +/- 0.7 pmol/L), with a good correlation (r = 0.86) between circulating adrenomedullin and plasma creatinine. The circulating concentration of adrenomedullin necessary to affect blood pressure greatly exceeds that observed in healthy volunteers and in patients with a range of pathological conditions. Thus, adrenomedullin may be a paracrine regulator of vascular smooth muscle in humans.

Adrenomedullin↗

PubMed1997

Regulation of anterior pituitary galanin and vasoactive intestinal peptide by oestrogen and prolactin status.

The neuropeptides vasoactive intestinal peptide (VIP) and galanin are synthesized in the anterior pituitary, galanin in the lactotroph and VIP probably in another cell type, and both stimulate prolactin secretion. Oestrogen regulates anterior pituitary VIP and galanin, galanin expression reflecting physiological variation in oestrogen status, whilst VIP is induced by pharmacological concentrations of oestrogen. Implanting anterior pituitaries under the renal capsule to induce hyperprolactinaemia we studied the regulation of anterior pituitary VIP and galanin synthesis and storage by prolactin and its interaction with oestrogen status. Five groups of animals were studied: control, hypophysectomized implanted, implanted, hyperoestrogenized (oestradiol-17 beta; 250 micrograms/day) and hyperoestrogenized implanted. Spontaneously cycling animals were followed through two cycles prior to implanting and were maintained for at least 1 week and then killed once they were in dioestrus. Circulating prolactin levels were significantly elevated in implanted animals but not in hypophysectomized implanted animals compared with controls. There was a more marked increase in prolactin levels in hyperoestrogenized animals and hyperoestrogenized implanted animals, with no significant difference between these two groups. Native anterior pituitary galanin and VIP content was suppressed in implanted animals, and markedly increased in hyperoestrogenized animals. Pituitary implantation only marginally reduced the effect of hyperoestrogenization on galanin content but abolished the effect of hyperoestrogenization on VIP content. Implant peptide content was suppressed to less than 10% of native anterior pituitary content. Galanin was not detected in implants from hypophysectomized-implanted animals but implant VIP content was unaffected by hypophysectomy. VIP content was increased in implants from hyperoestrogenized implanted animals but implant galanin content was unaffected by hyperoestrogenization. Peptide mRNA levels changed in parallel with peptide content except that the implant galanin mRNA levels were increased by hyperoestrogenization. Thus it appears that prolactin negatively regulates anterior pituitary galanin and VIP gene expression and content, probably due to a direct effect on the anterior pituitary and by altered secretion of hypothalamic factors. Oestrogen is a potent stimulus to expression of both peptide genes. Its positive effect on anterior pituitary peptide gene expression and content is greatly diminished by the effect of implant-induced hyperprolactinaemia, suggesting that circulating prolactin levels may be controlled by a negative feedback effect of prolactin on galanin and VIP. A similar effect of hyperoestrogenization is observed in the implants, except that galanin content remains at a low level, suggesting that the combination of hyperoestrogenization and the absence of dopamine may lead to uncontrolled release of high levels of galanin.

Animals↗

PubMed1996

Specific adrenomedullin binding sites and hypotension in the rat systemic vascular bed.

The potent vasodilator peptide, adrenomedullin, has been shown to be present in plasma, suggesting a physiological role in cardiovascular control. Here we investigated the hypotensive action of adrenomedullin in vivo, using the anaesthetised rat as the bioassay model, and adrenomedullin binding sites using ligand binding assays on rat blood vessel membranes. Rat alpha CGRP and both human and rat adrenomedullins induced dose-dependent, powerful and long-lasting hypotensive effects. At peptide doses used in this study (0.02-2 nmol/kg), the efficacy of both human and rat adrenomedullins was lower than that of rat alpha CGRP. The CGRP1-receptor antagonist, human CGRP(8-37) (200 nmol/kg) was able to completely inhibit the hypotensive effect of rat alpha CGRP (0.2 nmol/kg) but not that of rat adrenomedullin (2 nmol/kg), implying that the adrenomedullin action is independent of CGRP1-receptors. Ligand binding assays confirmed the presence of both CGRP and adrenomedullin binding sites in rat blood vessels. The 125I-rat adrenomedullin binding site has a Kd = 0.32 +/- 0.12 nM (n = 4) for rat adrenomedullin but has a Ki > 10(-6) M for rat alpha CGRP. Chemical cross-linking and SDS-PAGE analysis revealed theadrenomedullin binding protein to have a M(r) of 83000 with a minor band of M(r) = 99000. The results suggest that the hypotensive effect of adrenomedullin may be mediated via specific adrenomedullin binding sites, in vivo.

Adrenomedullin↗

PubMed1996

A role for glucagon-like peptide-1 in the central regulation of feeding.

The sequence of glucagon-like peptide-1 (7-36) amide (GLP-1) is completely conserved in all mammalian species studied, implying that it plays a critical physiological role. We have shown that GLP-1 and its specific receptors are present in the hypothalamus. No physiological role for central GLP-1 has been established. We report here that intracerebroventricular (ICV) GLP-1 powerfully inhibits feeding in fasted rats. ICV injection of the specific GLP-1-receptor antagonist, exendin (9-39), blocked the inhibitory effect of GLP-1 on food intake. Exendin (9-39) alone had no influence on fast-induced feeding but more than doubled food intake in satiated rats, and augmented the feeding response to the appetite stimulant, neuropeptide Y. Induction of c-fos is a marker of neuronal activation. Following ICV GLP-1 injection, c-fos appeared exclusively in the paraventricular nucleus of the hypothalamus and central nucleus of the amygdala, and this was inhibited by prior administration of exendin (9-39). Both of these regions of the brain are of primary importance in the regulation of feeding. These findings suggest that central GLP-1 is a new physiological mediator of satiety.

Animals↗

PubMed1996

Cardiovascular and hormonal responses to a meal in hypertrophic cardiomyopathy: a comparison of patients with and without postprandial exacerbation of symptoms.

Some patients with hypertrophic cardiomyopathy experience postprandial exacerbation of symptoms. The aim of this study was to determine whether the hemodynamic and/or hormonal responses to a meal differ between patients with and without postprandial symptoms. Ten hypertrophic cardiomyopathy patients with postprandial symptoms, 10 patients without postprandial symptoms, and 10 normal subjects ate a 740 Kcal meal, following which heart rate, blood pressure, and echocardiographic and gastrointestinal hormone changes were compared among the three groups. Heart rate increased (p < 0.001) and diastolic blood pressure fell (p < 0.001) to a similar degree in the three groups. Left ventricular outflow tract velocity increased (p < 0.01) and some patients had substantial increases in outflow tract pressure gradient; however, this was independent of the presence or absence of postprandial symptoms. The atrial contribution to filling increased in normal subjects and in both groups of hypertrophic cardiomyopathy patients. There was no significant difference in the gastrointestinal hormone changes in the three groups. In summary, there is no evidence for a distinctive hemodynamic or hormonal response to food in hypertrophic cardiomyopathy patients with postprandial symptoms. These symptoms more likely reflect differences in underlying cardiac disease characteristics and severity.

Adult↗

PubMed1996

Increased ileal proglucagon expression after jejunectomy is not suppressed by inhibition of bowel growth.

After jejunectomy, a rapid and sustained increase in the abundance of proglucagon mRNA occurs in residual ileum and is accompanied by increases in plasma intestinal proglucagon-derived peptides. This response may be a component of adaptive growth, or proglucagon-derived peptides may regulate adaptive growth. To distinguish these possibilities, rats were treated with difluoromethylornithine, blocking ornithine decarboxylase activity and thereby adaptive bowel growth. Three groups fed ad libitum were compared: (1) resect: rats with 80% proximal small bowel resection; (2) resect + difluoromethylornithine: resected rats given difluoromethylornithine in drinking water; and (3) transect: transected controls. Six days after surgery, the resect + difluoromethylornithine group demonstrated inhibition of adaptive bowel growth. Abundance of ileal proglucagon mRNA in resect and resect + difluoromethylornithine groups was double that in the transect group (P < 0.02), whereas ornithine decarboxylase mRNA levels did not differ. Plasma enteroglucagon and glucagon-like peptide-I levels were greater in resect than transect groups (P < 0.002) and did not differ between resect and resect + difluoromethylornithine groups. The rise in ileal proglucagon mRNA after proximal small bowel resection is not inhibited by difluoromethylornithine despite blocking bowel growth and, therefore, is not merely a component of adaptive growth. Proglucagon-derived peptides are possible modulators of adaptive bowel but cannot stimulate growth when ornithine decarboxylase activity is inhibited.

Adaptation, Physiological↗

PubMed1996

Characterisation and molecular identification of adrenomedullin binding sites in the rat spinal cord: a comparison with calcitonin gene-related peptide receptors.

Calcitonin gene-related peptide (CGRP) and its receptors are found in mammalian spinal cord. We show, for the first time, binding sites for the novel related peptide adrenomedullin in rat spinal cord microsomes. 125I-Adrenomedullin binding showed high affinity (KD = 0.45 +/- 0.06 nM) and sites were abundant (Bmax = 723 +/- 71 fmol/mg of protein). CGRP, amylin, and calcitonin did not compete at these sites (Ki > 10 microM). High-affinity CGRP binding sites (KD = 0.18 +/- 0.01 nM) were much less numerous (Bmax = 17.7 +/- 2.4 fmol/mg of protein) and showed competition by unlabeled adrenomedullin (Ki = 34.6 +/- 2.4 nM). Chemical cross-linking revealed a major band for 125I-adrenomedullin of M(r) = 84,400 +/- 1,200 and a minor band of M(r) = 122,000 +/- 8,700. 125I-CGRP cross-linking showed bands of lower molecular weight (M(r) = 74,500 +/- 5,000 and 61,000 +/- 2,200). Enzymic deglycosylation of the adrenomedullin binding site showed a considerable carbohydrate content. Neither adrenomedullin nor CGRP was able to increase cyclic AMP in spinal cord. Adrenomedullin mRNA was present in spinal cord, at one-third of its level in lung, and adrenomedullin immunoreactivity was present, at a low concentration (40 fmol/g of tissue). Thus, the presence of abundant binding sites and adrenomedullin mRNA and immunoreactivity anticipate an as yet undefined function for this peptide in spinal cord.

Adenylyl Cyclases↗