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M J Ellis

Publications and source records attributed to M J Ellis.

At least 37 records · Page 2Linked to original sources
PubMed1997

Staphylococcus aureus alpha-toxin: characterization of protein/lipid interactions, 2D crystallization on lipid monolayers, and 3D structure.

Staphylococcus aureus alpha-toxin was characterized with respect to surface activity and its interaction with lipid monolayers. The protein alone had a detergent-like behavior at the air/water interface. Its affinity was higher for negatively charged than for neutral phospholipids. The interaction was pH dependent, showing a maximum increase at pH 7.0. Only a small part of the protein oligomer appeared to be inserted into the monolayers. Crystalline sheets of alpha-toxin were formed using negatively charged phospholipids. Electron microscopy of such areas, at different tilt angles, allowed reconstruction of a three-dimensional model following image processing. The sheets analyzed consisted of two protein layers arranged on a tetragonal lattice. Under the conditions used to grow the crystals the toxin formed 90-A-wide cylinders with a height of 70 A. One of the imposed fourfold axes running perpendicular to the plane of the crystalline layer is positioned at a protein-deficient region which forms a 25-A-wide pore through the oligomer.

Air↗
PubMed1997

Atrial natriuretic peptide and C-type natriuretic peptide do not acutely inhibit the release of adrenocorticotropin from equine pituitary cells in vitro.

It has been suggested that atrial natriuretic peptide (ANP) is the long-sought inhibitor of corticotropin (ACTH) secretion, but the evidence is conflicting. We have examined the effect of ANP and C-type natriuretic peptide (CNP) on the secretion of ACTH by perifused equine pituitary cells in an in vitro milieu intended to mimic the in vivo milieu in the horse. Corticotropin-releasing hormone (20 pM) and cortisol (0 or 100 nM) were perifused continuously and 7 pulses of arginine vasopressin (AVP; 10 nM) applied for 5 min at 30-min intervals. ANP (1 nM) or CNP (1 nM) were perifused continuously for 75 min, beginning before the 3rd AVP pulse. Neither ANP nor CNP, with or without cortisol, significantly altered the ACTH secretory response to the AVP pulses. We conclude that these natriuretic peptides are unlikely to act at the pituitary as rapid inhibitors of ACTH secretion in the horse.

Adrenocorticotropic Hormone↗
PubMed1996

The effect of beta-endorphin on basal and insulin-hypoglycaemia stimulated levels of hypothalamic-pituitary-adrenal axis hormones in normal human subjects.

OBJECTIVE: It has been demonstrated that beta-endorphin reduces CRH production and hypoglycaemia-induced ACTH secretion in the rat. We aimed to determine whether supraphysiological levels of beta-endorphin inhibit the ACTH and CRH response to insulin-induced hypoglycaemia in human subjects. DESIGN: Plasma glucose, prolactin, cortisol, ACTH, CRH and AVP were measured at intervals over a 3-hour period. Intravenous beta-endorphin 5 mg/50 ml or an equal volume of normal saline was infused between 30 and 90 minutes, with soluble insulin 0.15 units/kg administered i.v. at 60 minutes in a cross-over design. SUBJECTS: Six healthy male volunteers aged 20-35 years. MEASUREMENTS: Prolactin was measured by a fluoroimmunometric assay, ACTH, CRH and AVP by radioimmunoassay, and cortisol was measured by enzyme-linked immunosorbent assay. Haemodynamic measurements were recorded prior to each blood sample. Results are expressed as mean +/- standard error of the mean. RESULTS: beta-Endorphin resulted in a significant decrease in baseline cortisol (P < 0.05) but not ACTH. Plasma glucose (P < 0.001) and CRH (P < 0.05) and PRL (P < 0.05) increased significantly during beta-endorphin compared to normal saline. After insulin administration, glucose reached a similar nadir during beta-endorphin and normal saline (2.1 +/- 0.1 and 1.9 +/- 0.15 mmol/l, respectively) but the fall in plasma glucose was delayed during beta-endorphin (P < 0.01 by ANOVA). This resulted in a significantly altered time-course for the ACTH and cortisol responses (P < 0.05 for each), but no difference overall in the magnitude of the response. In contrast, neither the timing nor the magnitude of the CRH and AVP responses were affected. Prolactin also reached a similar peak value after the administration of insulin, while the haemodynamic responses to hypoglycaemia were not significantly altered during beta-endorphin. CONCLUSIONS: While beta-endorphin has been shown to be inhibitory to basal ACTH and cortisol secretion in humans, we note a significant increase in plasma CRH in response to beta-endorphin, which may be arising from a peripheral source. Intravenous beta-endorphin increases plasma glucose and delays the onset of hypoglycaemia following insulin but does not result in significant inhibition of the ACTH and cortisol response. This may reflect the poor penetration of beta-endorphin into the central nervous system, although a hypothalamic effect of beta-endorphin is implied by the increased PRL. The significantly delayed time course in ACTH and cortisol secretion noted during beta-endorphin is not explained by a later response of either CRH or AVP. Although peripheral levels of these hormones may be a relatively insensitive measure of hypothalamic function, an additional factor may influence ACTH release during hypoglycaemia.

Adrenocorticotropic Hormone↗
PubMed1996

Plasma cortisol, PRL, ACTH, AVP and corticotrophin releasing hormone responses to direct current cardioversion and electroconvulsive therapy.

OBJECTIVE: We aimed to evaluate and contrast the hypothalamo-pituitary-adrenal (HPA) response to direct current (DC) cardioversion and electroconvulsive therapy (ECT). SUBJECTS: Six male subjects (mean age 61.2 years, range 46-74) with chronic atrial fibrillation were selected for cardioversion. Six subjects with depression (one male, five female; mean age 43.2 years, range 31-59) were selected for ECT. Those taking glucocorticoid drugs, opiates or beta-adrenoceptor antagonists were excluded. MEASUREMENTS: Patients attended for serial blood sampling on the day of cardioversion or ECT, and for an equivalent time period on a control day at least one week before. Intravenous propofol was given to each subject for anaesthesia on the day of cardioversion or ECT. On both study and control days, blood samples were taken at -30, -15, 0 (just prior to cardioversion or ECT), +5, +10, +15, +30, +60, +90 and +120 minutes for assay of cortisol, PRL, ACTH, AVP and CRH. RESULTS: For cardioversion: plasma cortisol increased from 252.5 +/- 39.8 to a maximum of 721.3 +/- 50 nmol/l at 30 minutes (P < 0.0001 compared with control day). ACTH increased from 12.8 +/- 2.8 to a maximum of 64 +/- 14 pmol/l at 5 minutes (P < 0.0001 compared with control day). AVP increased from 6.6 +/- 3.3 to a maximum of 42.9 +/- 16 pmol/l at 5 minutes post-cardioversion (P < 0.005 compared with control day). PRL increased from 141 +/- 28 mlU/l to a maximum of 873 +/- 219 mlU/l at 10 minutes (P < 0.001 compared with control day). There was no significant difference in CRH responses between cardioversion and control days. There was no significant correlation between total electrical energy delivered and maximum ACTH and AVP responses (R = 0.54 and -0.13, respectively). For ECT: on the day of ECT plasma cortisol increased from 419.5 +/- 25.9 to a maximum of 614.7 +/- 26.9 nmol/l (P < 0.002 compared with control day). ACTH increased from 22.7 +/- 6.2 to a maximum of 77.8 +/- 19.1 pmol/l (P < 0.0003 compared with control day). PRL increased from 771 +/- 317 to a maximum of 3152 +/- 703 mlU/l (P < 0.001 compared with control day, and significantly greater than the peak response to cardioversion, P < 0.03). AVP increased from 13.0 +/- 10.8 to a maximum of 35.1 +/- 5.6 pmol/l (P < 0.02 compared with control day). There was no significant difference in CRH responses between ECT and control days. Peak cortisol and ACTH responses did not differ significantly between ECT and cardioversion. Baseline cortisol levels, however, were significantly higher in the depressed group compared with the cardioversion group, P < 0.02, but not ACTH or AVP. CONCLUSION: Significant hypothalamic-pituitary-adrenal activation and PRL release occur in response to both cardioversion and ECT. AVP may have an important role in mediating the acute ACTH response to electrical stimulation.

Adrenocorticotropic Hormone↗
PubMed1996

Affinity for the insulin-like growth factor-II (IGF-II) receptor inhibits autocrine IGF-II activity in MCF-7 breast cancer cells.

We have investigated the autocrine regulation of insulin-like growth factor-II (IGF-II) signaling by the insulin-like growth factor-I receptor (IGF-IR) and the insulin-like growth factor-II/mannose 6-phosphate receptor (IGF-IIR) in MCF-7 breast cancer cells, employing retroviruses encoding both IGF-I, IGF-II, and IGF-I and II mutants with reductions in affinity for either the IGF-IR or the IGF-IIR. These studies revealed reciprocal roles for IGF-IR and IGF-IIR affinity in the regulation of autocrine IGF-II activity. IGF-IR affinity was required for serum-free proliferation but also for efficient IGF-II secretion. In contrast, cellular proliferation, receptor tyrosine kinase-dependent signaling, and extracellular IGF-II protein accumulation were all reduced in the presence of IGF-IIR affinity. Inhibition of IGF-II signaling appeared to be the sole consequence of IGF-IIR affinity, as no cellular responses attributable to selective IGF-IIR binding by a reduced IGF-IR affinity IGF-II mutant could be detected. By operating as an IGF-II antagonist, the IGF-IIR has tumor suppressor-like properties, a suggestion consistent with reports of loss of heterozygosity at the IGF-IIR locus in a variety of human malignancies.

Amino Acid Sequence↗
PubMed1995

The effects of alcoholism on the hypothalamic-pituitary-adrenal axis: interaction with endogenous opioid peptides.

BACKGROUND: Abnormal baseline hypothalamic-pituitary-adrenal axis function and dexamethasone suppressibility seen in withdrawing alcoholics returns to normal on abstinence, but some studies report blunting of the ACTH response to CRH persisting during the early abstinence phase. Reduced central levels of endogenous opioid peptides have been postulated to have an aetiological role in alcohol addiction. AIMS: To evaluate hypothalamic-pituitary-adrenal axis function in a group of recently abstinent alcoholics using basal hormone data, naloxone (an opioid receptor antagonist), and ovine CRH. SUBJECTS: Nine alcoholics (age 41.4 +/- 3.1 years) studied more than one week after the acute withdrawal period but within 6 weeks of cessation of drinking, and nine age and sex matched non-alcoholic controls. PROTOCOL: Cortisol, ACTH, CRH and AVP levels were measured every 20 minutes for 2 hours between 0900 and 1100h Twenty mg naloxone i.v. was administered at 1100h (0 minutes) and further samples for the above hormones were taken at 15, 30, 45, 60, 90 and 120 minutes. On a separate occasion, again at 1100h, oCRH 1 microgram/kg (n = 7 alcoholics, n = 6 controls) was administered, with samples for cortisol, ACTH and AVP taken at the same times. STATISTICS: Results were examined by analysis of variance for repeated measures (ANOVA), while incremental hormone response and area under the secretory curve (AUC) in alcoholics versus controls were compared by the two-tailed Student's t-test. Linear regression analysis was carried out to examine the relation between basal cortisol and hormone responses to naloxone and oCRH. RESULTS: Basal hormone levels did not differ between the groups. The alcoholics had a blunted ACTH incremental response to naloxone (11.4 +/- 3.0 vs 21.1 +/- 2.5 pmol/l, P < 0.05) but the cortisol response was not significantly different (205 +/- 51 vs 305 +/- 42 nmol/l, P = 0.15). The alcoholics also had a blunted ACTH incremental response to oCRH (28.7 +/- 4.2 vs 41.2 +/- 3.7 pmol/l, P = 0.052) and by ANOVA a significant main effect of group (alcoholic vs control) was seen (P < 0.02) for the ACTH response to oCRH. There was no difference between the groups in the cortisol incremental response to oCRH. In the control subjects, a negative correlation was found between basal cortisol and the cortisol increment (r = -0.82, P < 0.05) and ACTH increment (r = -0.81, P = 0.052) following oCRH, while in contrast, basal cortisol correlated positively with cortisol increment (r = 0.72, P < 0.05) following naloxone. There was also a trend for basal cortisol to correlate positively with ACTH increment following naloxone in the controls (r = 0.63, P < 0.07). In the alcoholics, the normal negative effect of basal cortisol on the cortisol increment after oCRH was reversed, with a positive correlation between basal cortisol and cortisol increment (r = 0.75, P = 0.05). CONCLUSIONS: Recently abstinent alcoholics with normal basal HPA axis hormone levels have a blunted ACTH response to naloxone and oCRH. While reduced levels of central endogenous opioid peptides may be a factor in the blunted ACTH response to naloxone in the alcoholics, it is proposed that the alcoholics have reduced pituitary responsiveness to CRH. This may be via a direct pituitary effect of the chronic ethanol exposure or by a reduction in hypothalamic-hypophyseal vasopressin levels.

Adrenocorticotropic Hormone↗
PubMed1995

The acute effects of oral ethanol on the hypothalamic-pituitary-adrenal axis in normal human subjects.

OBJECTIVE: To evaluate the acute effects of oral ethanol on the hypothalamic-pituitary-adrenal axis in normal human subjects and, in particular, to examine the effect of background alcohol intake and gastrointestinal side-effects on this response. DESIGN: Plasma ethanol, cortisol, ACTH, corticotrophin-releasing hormone (CRH) and AVP were measured half-hourly for 4 hours following 1.1 ml/kg of 95% ethanol or placebo in a cross-over study. At least one week elapsed between each procedure. SUBJECTS: Twelve healthy non-alcoholic volunteers with a wide range of background alcohol intakes. MEASUREMENTS: Peptide hormones were measured by radioimmunoassay, cortisol by ELISA and blood ethanol by headspace gas chromatography. Results are expressed as mean +/- SEM. RESULTS: Blood ethanol levels peaked at one hour post ethanol ingestion. Three subjects developed significant gastrointestinal (GI) side-effects, with two vomiting and one experiencing moderate to severe nausea. There was no difference between peak blood ethanol levels in the groups with and without GI side-effects (34.5 +/- 2.4 mmol/l vs 34.3 +/- 1.7 mmol/l respectively). ACTH and cortisol rose in those subjects who experienced GI side-effects (P < 0.0001 for each). The remaining subjects had a tendency for ACTH and cortisol to be higher on the placebo day. The group with GI side-effects following ethanol administration had a significant rise in AVP (P < 0.02) that was synchronous with ACTH and cortisol. No consistent alcohol related changes were seen in peripheral CRH levels, although there was a significant increase over time on both active and placebo days (P < 0.0001). In the group with no GI side-effects, AVP did not significantly fall in the first half hour following ethanol, while a significant fall did occur following placebo (P < 0.05). Plasma renin activity was, however, increased by ethanol (P < 0.05). The background alcohol intake of the group with GI side-effects was significantly lower than the group without (18 +/- 7 vs 235 +/- 51 g/week, P < 0.05), but no hormonal response was seen in two subjects with a relatively low alcohol intake (< 100 g/week) who did not experience GI side-effects. CONCLUSION: Intoxicating levels of ethanol per se do not result in activation of the hypothalamic-pituitary-adrenal axis in humans. However, gastrointestinal side-effects induced by the ethanol do result in such activation, which appears to be mediated by AVP as the dominant ACTH secretagogue. One of the factors which influences the blood ethanol level at which GI side-effects occur appears to be background alcohol intake.

Adrenocorticotropic Hormone↗
PubMed1995

A comparison of the naloxone test with ovine CRH and insulin hypoglycaemia in the evaluation of the hypothalamic-pituitary-adrenal axis in normal man.

OBJECTIVE: It has been suggested that naloxone might be useful in clinical testing of the hypothalamic-pituitary-adrenal (HPA) axis. We have therefore evaluated this non-selective opioid receptor antagonist, as a test of HPA axis function, and compared the results to ovine corticotrophin-releasing hormone (oCRH) and the insulin tolerance test (ITT). DESIGN: Following i.v. administration at time zero of naloxone 20 mg (n = 12) on day 1, and either oCRH 1 microgram/kg (n = 6) or soluble insulin 0.15U/kg (n = 6) on day 2, venous blood was sampled at times 120, 0, 15, 30, 45, 60, 90 and 120 minutes for cortisol, ACTH and AVP. Peripheral CRH was also measured following naloxone and insulin hypoglycaemia. SUBJECTS: Twelve normal males (age 20-57 years) with no history of hypothalamic-pituitary-adrenal axis disease. MEASUREMENTS: Peptide hormones in plasma samples were measured by radioimmunoassay and cortisol by ELISA. Results are expressed as mean +/- SEM. RESULTS: Following naloxone, there was a highly significant overall rise in ACTH (P < 0.0005) and cortisol(P < 0.0001), but 1 out of the 12 subjects failed to respond. This subject had a normal ACTH and cortisol response to oCRH, indicating normal pituitary-adrenal function. Peripheral levels of CRH also increased significantly following naloxone (P < 0.002), while AVP did not alter significantly (P = 0.38). Maximal levels of CRH were seen following the ACTH peak however, at a time when ACTH was returning to baseline. All six subjects who received oCRH had an increase in ACTH and cortisol, and the ACTH response to oCRH was greater that that to naloxone (P < 0.05). One subject who developed nausea and hypotension following oCRH had a large rise in AVP and very high levels of ACTH and cortisol. Following insulin each subject had symptomatic hypoglycaemia and significant rises in cortisol (P < 0.0001), ACTH (P < 0.0001), AVP (P < 0.0005) and CRH (P < 0.01) were seen. Both cortisol and ACTH responses to ITT were significantly greater than those to naloxone (P < 0.05 for each). CONCLUSION: The HPA axis response to naloxone is smaller in magnitude overall compared to oCRH or insulin hypoglycaemia and is variable in normal subjects. This variability probably reflects changes in central opioid tone rather than alterations in pituitary responsiveness to CRH. It is unlikely that the naloxone test will replace currently used clinical tests of HPA axis function, particularly in the setting of a possible ACTH deficiency, because some subjects wit ha normal HPA axis appear not to respond to naloxone. As the mechanism involved in the ACTH response to naloxone has not yet been defined with certainty, the naloxone test should not be regarded simply as a test of endogenous CRH release.

Adrenocorticotropic Hormone↗
PubMed1995

Elevated basal adrenocorticotropin and evidence for increased central opioid tone in highly trained male athletes.

Basal cortisol and ACTH levels have previously been shown to be elevated in highly trained athletes, whereas the ACTH response to ovine CRH has been reported to be diminished compared to that in nonathletic controls. Naloxone, a nonselective opioid receptor antagonist, is known to stimulate ACTH and cortisol secretion. The mechanism of this response is thought to be via increased hypothalamic CRH secretion. The aim of this study was to examine basal and naloxone-stimulated levels of hypothalamic-pituitary-adrenal axis hormones in male athletes. Ten highly trained male athletes and 10 nonathletic controls took part in the study. Peripheral venous blood was sampled for cortisol, ACTH, CRH, and arginine vasopressin (AVP) for 2 h before the administration of 20 mg naloxone, i.v., and 15, 30, 45, 60, 90, and 120 min after naloxone treatment. Body mass index was significantly lower in the athletes (P < 0.001). Basal (prenaloxone) ACTH levels were higher in the athletes (P < 0.05), whereas levels of cortisol, CRH, and AVP were similar in both groups. After naloxone treatment, there was a significantly greater rise in ACTH in the athletes (P < 0.02). There was also a trend for the cortisol response to be greater, which was not statistically significant (P < 0.07). Although in both groups, peripheral CRH rose after naloxone treatment (P < 0.005), a rise of similar magnitude occurred over the 2-h period before naloxone (P < 0.0001). Plasma AVP did not change significantly after naloxone treatment. Neither the plasma cortisol level at baseline nor the body mass index correlated significantly with the ACTH or cortisol response to naloxone. The presence of an enhanced ACTH response to naloxone is evidence that central opioid tone may be increased in highly trained athletes. However, there is no associated suppression of the hypothalamic-pituitary-adrenal axis, and basal ACTH levels are raised, without any detectable change in peripheral plasma CRH or AVP. An additional factor (other than CRH) that stimulates ACTH secretion may be released after naloxone administration.

Adrenocorticotropic Hormone↗
PubMed1995

Activating transcription factor-1 is a specific antagonist of the cyclic adenosine 3'.5'-monophosphate (cAMP) response element-binding protein-1-mediated response to cAMP.

We have investigated the molecular basis of the variability of the somatostatin cAMP response element (CRE) function in different cell lines. All cells tested contain detectable levels of the CRE-binding protein CREB-1, which mediates transactivation in response to the cAMP-dependent protein kinase (protein kinase-A), in forms that can bind to a somatostatin CRE. Although both responsive and nonresponsive cells contain CREB-1 in heterodimers with activating transcription factor-1 (ATF-1), only cells that allow a cAMP response have a significant proportion of CREB-1 in a homodimeric form. Transfection experiments demonstrate that ATF-1 is capable of antagonizing CREB-1-dependent activation, suggesting that the ability of CREB-1 to mediate a cAMP response is down-regulated by heterodimer formation with ATF-1.

Activating Transcription Factor 1↗
PubMed1995

A novel cyclic AMP response element-binding protein-1 (CREB-1) splice product may down-regulate CREB-1 activity.

In this report we identify novel spliced forms of cyclic AMP (cAMP) response element-binding protein-1 (CREB-1) mRNA. These forms contained an additional 17 nucleotide insert, which we refer to as the beta exon, located between exons 4 and 7 of the delta, and 5 and 7 of the alpha forms of CREB-1 transcript (nomenclature of Ruppert et al. 1992; EMBO Journal 11, 1503-1512). The inclusion of the beta exon led to the generation of mRNAs in which the frame of CREB-1 sequences 3' to the exon was shifted such that the encoded proteins terminate after the transactivation domain, but before the target serine for cAMP-dependent protein kinase. The beta exon-containing CREB-1 mRNAs were more abundant in tissues that respond poorly to cAMP, suggesting that the generation of beta CREB-1 mRNAs may contribute to the down-regulation of CREB-1 activity and cAMP responsiveness.

Amino Acid Sequence↗
PubMed1994

NF-kappa B-independent activation of beta-interferon expression in mouse F9 embryonal carcinoma cells.

We have examined the behaviour of the beta-interferon promoter in mouse F9 embryonal carcinoma cells. In undifferentiated cells, the beta-interferon promoter is not responsive to dsRNA or to Sendai virus. In cells stimulated to differentiate into parietal endoderm by treatment with retinoic acid, the beta-interferon promoter responds to both inducers, but only Sendai virus can activate the transcription factor NF-kappa B previously thought to be essential for beta-interferon induction. Differentiated F9 cells therefore present an unprecedented situation in which induction of the beta-interferon gene does not require NF-kappa B. In addition to these differences, induction by dsRNA, but not by Sendai virus, is significantly enhanced by a pretreatment with interferon (priming). These observations suggest that paramyxo-viruses can participate in beta-interferon induction in a manner that is distinct from a simple generator of dsRNA. Analysis of the promoter requirements for induction in differentiated F9 cells suggests that induction is brought about by a novel mechanism using the currently identified regulatory domains.

Animals↗
PubMed1994

Insulin-like growth factor mediated stromal-epithelial interactions in human breast cancer.

The prominent 'desmoplastic' or stromal reaction seen in many invasive breast carcinomas lead to early speculation that stromal cells play a role in breast cancer pathogenesis. Experimental evidence now supports this hypothesis and interactions between stromal cells and epithelial cells appear to be important for both normal mammary development and neoplasia. The identification of genes that are selectively expressed in the stroma of malignant breast lesions has recently provided new insights into the molecular basis of stromal-epithelial interactions. Stromally expressed genes include growth factors, proteases and extracellular matrix proteins, all biological activities with potential roles in malignant progression. Investigations discussed here concern the nature of the paracrine signals provided by malignant epithelial cells that activate changes in stromal gene expression, the effect that the stromally derived factors have on the behavior of malignant epithelial cells and the identification of novel factors and receptors in either stroma or epithelia that contribute to their mutual interactions. These questions will be addressed in the context of this laboratory's studies on insulin-like growth factors, as these molecules show marked differences in stromal expression between benign and malignant breast tissue and thus provide a useful paradigm for investigations into the paracrine environment of an evolving breast tumor.

Breast Neoplasms↗
PubMed1994

Plasma corticotrophin releasing hormone, vasopressin, ACTH and cortisol responses to acute myocardial infarction.

OBJECTIVES: We assessed the magnitude and duration of the response of hypothalamic-pituitary-adrenal hormones to the stress of myocardial infarction, in the presence and absence of angiotensin converting enzyme inhibitors. In particular, we wished to analyse the interrelationships between peripheral plasma levels of corticotrophin releasing hormone (CRH), vasopressin (AVP) and adrenocorticotrophin (ACTH), and also between ACTH and cortisol, during a prolonged medical stress. DESIGN: All hormones were measured within 6 hours of the onset of an acute myocardial infarction. Patients were randomly allocated to three different study groups according to a double blind procedure. PATIENTS: Group 1 (10 patients) received placebo treatment, Group 2 (13 patients) received a maintenance dose of captopril 25 mg three times daily, Group 3 (11 patients) received enalapril 5 mg three times daily. MEASUREMENTS: Peptide hormones were measured by radioimmunoassay, and cortisol by ELISA. Reference ranges for all hormones were obtained from 40 or more volunteers from the electoral roll. RESULTS: At the start of the study, mean +/- SEM plasma AVP (27.9 +/- 4.6 pmol/l) was significantly (P < 0.001) raised above the mean for the reference range (1.82 +/- 0.09 pmol/l), and 12 patients had values > 50 pmol/l. Mean plasma cortisol (960 +/- 89.6 nmol/l) was also raised above the reference range mean (554 +/- 28 nmol/l, P < 0.001), as was mean plasma CRH (4.97 +/- 0.5 pmol/l, reference mean 1.52 +/- 0.09 pmol/l, P < 0.001). By contrast, mean ACTH (3.88 +/- 0.66 pmol/l) was significantly less than the reference mean (10.7 +/- 0.7 pmol/l, P < 0.001). During the 72-hour observation period there was a highly significant fall (P < 0.001) in plasma CRH, AVP and cortisol. By contrast, plasma ACTH rose, and the change with time of ACTH was significantly different from the fall in plasma CRH, AVP or cortisol (P < 0.001 for each comparison). No significant differences in plasma CRH, AVP, ACTH or cortisol responses to placebo, captopril or enalapril were observed. CONCLUSIONS: Within 6 hours of a myocardial infarction, mean plasma CRH, AVP and cortisol values were very significantly raised above mean control values, while ACTH was very significantly reduced. During the 3 days following an acute myocardial infarction, plasma CRH, AVP and cortisol fell substantially, and this pattern was not influenced by angiotensin converting enzyme inhibitors. By contrast, plasma ACTH showed a significant increase with time. This suggests that the usual relationships between CRH, AVP and ACTH, and between ACTH and cortisol are disturbed in patients admitted to hospital with myocardial infarction. Maximum levels of AVP observed in 12 patients exceeded 50 pmol/l, which may be sufficiently high to interfere with tissue perfusion. It is postulated that V1 AVP receptor antagonists may have a therapeutic application in limiting infarct size.

Adrenocorticotropic Hormone↗
PubMed1994

The effects of corticotrophin-releasing hormone, arginine vasopressin and their antagonists on ACTH release from perifused horse anterior pituitary cells.

Antagonists are useful for probing hormone action and receptor characteristics. In this study we have investigated the inhibitory effects of analogues of arginine vasopressin (AVP) and corticotrophin-releasing hormone (CRH) on stimulated release of immunoreactive ACTH from perifused equine anterior pituitary cells in vitro. Our aims were to gain some insight into the characteristics of the CRH and AVP receptors of the horse pituitary and to establish whether the response induced by AVP and CRH together could be blocked by combining antagonists. Experimental design included 5-min pulses of AVP (12.5 nmol/l), CRH (0.3 nmol/l) or CRH plus AVP given every 40 min alternately with pulses of secretagogue(s) plus appropriate antagonist(s). The effect of combined antagonists on the response to lower secretagogue concentrations (CRH, 0.03 nmol/l plus AVP, 2.5 nmol/l) was also tested. Response in the presence of an antagonist was compared with the mean response to secretagogue in the immediately preceding and following pulse and was expressed as per cent expected ACTH. The ACTH response to AVP was inhibited over the dose range 0.4-50 mumol/l by Phaa-D-Tyr(Et)2Lys6Arg3VP (P < 0.002; ANOVA) and by d(CH2)5[Tyr(Me)2]AVP (P < 0.001). Suppression of the expected ACTH response to AVP by these two antagonists was most effectively achieved by antagonist concentrations of 10 mumol/l (to 28 +/- 2.1%) and 25 mumol/l (to 22 +/- 5.1%) respectively. Inhibition was not improved by preinfusion compared with a bolus pulse. Aaa-D-Try(Et)2Val4Abu6Arg8.9VP and the non-peptide antagonist OPC-21268 had no inhibitory effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗
PubMed1994

Horse plasma corticotrophin-releasing hormone (CRH): characterisation and lack of a late gestational rise or a plasma CRH-binding protein.

Immunoreactive corticotrophin-releasing hormone (irCRH) was present in methanolic extracts of equine peripheral blood and showed no elevation in maternal peripheral serum in late gestation (0.54 +/- 0.25 pmol/l; mean +/- S.D.) compared with control horses (0.41 +/- 0.15 pmol/l). The irCRH of methanolic extracts of pituitary venous plasma had a similar elution position following reverse-phase HPLC to synthetic human CRH(1-41) and to irCRH released from horse stalk-median eminence tissue incubated in vitro. Gel chromatographic studies showed no evidence for a plasma CRH-binding protein (CRHBP) analogous to that found in human plasma in either peripheral blood from normal or pregnant horses or in pituitary venous plasma sampled from a cannulated horse. CRH-binding activity was detectable in peripheral plasma from one horse, however the molecular size of this was indicative of a gamma-globulin rather than the 37 kDa CRHBP. These studies suggest that, unlike in the human, CRH does not rise to high values in late gestation nor circulate in a bound form in equine plasma.

Animals↗
PubMed1993

Metyrapone induced increase in plasma corticotropin is not associated with changes in peripheral venous arginine vasopressin or corticotropin releasing factor.

The responses of the "stress hormones" cortisol, 11-deoxycortisol, ACTH, vasopressin (AVP), and corticotropin releasing factor (CRF) were studied in 6 normal males in response to acute cortisol deficiency induced by the 11-beta-hydroxylase inhibitor, metyrapone. A 750 mg dose was administered orally at 08:00 h on day 1 and at 4 hourly intervals over a 24-h period. A 20 mg tablet of hydrocortisone or placebo was then given at 08:00 h on day 2, according to a randomized cross-over design. Each subject was restudied after an interval of at least one month. Blood samples were taken for all hormones at 08:00 h on day 1 and at 04:00 h on day 2. Thereafter ACTH and AVP were sampled at 10-min intervals, CRF at 20-min intervals, and cortisol and 11-deoxycortisol at hourly intervals until 12:00 h on day 2. Cortisol (mean +/- SE) fell from 628 +/- 218 nmol/l at 08:00 h (day 1) to a minimum of 230 +/- 78 nmol/l at 05:00 h on day 2. Plasma 11-deoxycortisol rose from 14.0 +/- 0.8 nmol/l to a maximum of 622 +/- 36 nmol/l and plasma ACTH rose from 8.71 +/- 1.64 pmol/l to a maximum of 166.2 +/- 57.5 pmol/l. Diurnal rhythmicity of plasma ACTH was maintained. There was no detectable change in plasma levels of AVP or CRF from baseline (AVP 2.5 +/- 0.8 pmol/l, CRF 3.4 +/- 0.5 pmol/l).(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗