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R Corder

Publications and source records attributed to R Corder.

At least 55 records · Page 3Linked to original sources
PubMed1993

The effects of chronic glucocorticoid excess, adrenalectomy and stress on neuropeptide Y in individual rat hypothalamic nuclei.

Several lines of evidence indicate a role for neuropeptide Y (NPY) in the modulation of the corticotroph axis. In two separate studies reported here, the concentrations of NPY and noradrenaline (NA), as well as corticotropin-releasing factor (CRF) and arginine vasopressin (AVP), were measured in extracts of individual rat hypothalamic nuclei after various manipulations producing either a state of chronic glucocorticoid excess or depletion, and also following repeated restraint stress. Alterations induced in the activity of hypothalamic neurones were inferred from the respective changes in these concentrations. 12 days after bilateral adrenalectomy (ADX), NPY levels were decreased by 24% in the arcuate nucleus (ARC) and 23% in the paraventricular nucleus (PVN, p < 0.05 vs controls). Forced immobilization of the animals for 4 h each day for 9 consecutive days (repeated stress) also decreased NPY content of the ARC by 25% (p < 0.01 vs controls), an effect blocked by the administration of glucocorticoids. NA levels in both hypothalamic nuclei were unaffected by repeated stress or ADX. Administration of glucocorticoids in the first of these studies induced decreases in NA levels by 15% and 25% in the ARC and PVN respectively (p < 0.05 vs controls). However, in subsequent experiments no significant effect of glucocorticoids on NA was observed. Our results demonstrate that the activity of the hypothalamic NPY-ergic neurones is modulated by glucocorticoids and by chronic stress. They also suggest that brainstem catecholaminergic and hypothalamic NPY-ergic neurones are differentially affected by altered glucocorticoid concentrations or by chronic stress, possibly in a stimulus-specific way.

Adrenalectomy↗
PubMed1993

Calcium ionophores inhibit the release of endothelin-1 from endothelial cells.

We have determined the effect on endothelin-1 (ET-1) release of stimulating cultured endothelial cells for 24 h with Ca2+ ionophores. The results obtained using cultured bovine aortic endothelial cells (BAECs) were compared with those using the human endothelial cell line (EA.hy 926). ET-1 was measured using a radioimmunoassay specific for the C-terminal ET[16-21] sequence. Ionomycin (1 microM) lessened ET-1 accumulation over 24 h in the conditioned medium from BAECs (-37%) and EA.hy 926 (-25%). A23187 was a more potent inhibitor of ET-1 release. With BAECs, ET-1 release was inhibited by 28% and 77% at 0.1 microM and 1 microM A23187, respectively. The corresponding decreases for EA.hy 926 were 20% and 98%. A23187 at 0.2 microM lowered ET-1 concentrations in the medium after 24 h by 44% and 24% for BAECs and EA.hy 926, respectively. Neither NG-monomethyl-L-arginine (0.2 mM) nor indomethacin (10 microM), either alone or in combination, affected the inhibition by A23187. Thus, this inhibitory effect is not dependent on the stimulation of nitric oxide or prostacyclin synthesis. Additional factors in endothelial cells, activated by elevated Ca2+ levels, may be important in exerting an inhibitory influence on ET-1 formation.

Animals↗
PubMed1993

Evidence for vesicles that transport endothelin-1 in bovine aortic endothelial cells.

To facilitate studies of the intracellular processing of endothelin-1 (ET-1) in endothelial cells we developed an enrichment procedure for the isolation of transport or secretory vesicles containing ET-1. Cultured bovine aortic endothelial cells (BAECs) were disrupted using a tight-fitting Dounce homogenizer, and subcellular fractions were isolated by sucrose-density-gradient ultracentrifugation. ET-1 immunoreactivity (ET-IR) in the fractions was measured with a specific ET[16-21] radio-immunoassay (RIA). The major peak of ET-IR was consistently localized at the 1.0/1.2 M sucrose interface (10.96 fmol/10(6) cells) in each preparation of subcellular fractions. The mean level of ET-IR at this interface, expressed as a percentage of the total, was 47.9 +/- 3.5% (n = 6). This finding provides strong evidence for the existence of a vesicle that transports ET-1 within BAECs, which may be an important site for endogenous ET-1 processing. A number of studies have reported that the final processing step in ET-1 biosynthesis by the hypothetical endothelin-converting enzyme (ECE) is inhibited by phosphoramidon (PHOS). Therefore, levels of PHOS-sensitive ECE activity in each fraction were assessed in parallel with ET-IR levels. The ECE activity associated with the peak of ET-IR (2.67 pmol ET-1/h/10(6) cells) was insensitive to 100 microM PHOS. However, the peak of ECE-like activity (10.4 pmol ET-1/h/10(6) cells) localized in the 0.8 M sucrose band was inhibited by 79% in the presence of 100 microM PHOS.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Effects of phosphoramidon in endothelial cell cultures on the endogenous synthesis of endothelin-1 and on conversion of exogenous big endothelin-1 to endothelin-1.

Several studies have shown that phosphoramidon (PHOS) reduces the release of endothelin-1 (ET-1) from cultured endothelial cells. Moreover, the main endothelin-converting enzyme (ECE) activity in these cells is a membrane-bound metallopeptidase that is also inhibited by PHOS. We have investigated further the role of the PHOS-sensitive ECE in the conversion of big ET-1 to ET-1. ET-1 was measured using a radioimmunoassay specific for the C-terminal ET[16-21] sequence. The effect of PHOS on the production of ET-1 from endogenous precursors was determined using cultured bovine aortic endothelial cells (BAECs) and the human endothelial cell line (EA.hy 926). The concentrations of ET-1 accumulating in the medium over 24 h from BAECs were lowered by PHOS (-27% 10 microM, -76% 100 microM). In contrast, with EA.hy 926 cells, the same concentrations of PHOS increased by five- to sixfold the amount of ET-1 present in the medium after 24-h incubation. In other experiments, incubation of big ET-1 (1 microM) with intact BAECs or EA.hy 926 cells resulted in the generation of ET-1, and with both cell types this was inhibited by PHOS (IC50: BAECs = 6.4 microM; EA.hy 926 = 0.26 microM). These results are consistent with both cell types having a PHOS-sensitive ECE that is readily accessible to exogenous big ET-1 and is therefore probably located on the plasma membrane. Furthermore, another intracellular ECE may play a part in the endogenous intracellular formation of ET-1 in EA.hy 926 cells.

Amino Acid Sequence↗
PubMed1993

Vasoconstriction in the rat kidney induced by endothelin-1 is blocked by PD 145065.

We have previously shown that the receptors mediating the renal and systemic vasoconstrictor effects of endothelin-1 (ET-1) are of two distinct endothelin receptor subtypes. Here, we evaluate the effect of PD 145065, a nonselective endothelin receptor antagonist, on the renal vasoconstrictor effects of ET-1 in the rat kidney. ET-1 induced concentration-dependent increases in perfusion pressure in the isolated perfused kidney of the rat. The ETA receptor-selective antagonists BQ-123 (10 microM) and FR 139317 (10 microM) lowered the ET-1-induced rise in perfusion pressure by 57% and 61%, respectively, at 3 x 10(-10) M ET-1. By comparison, the ET-1-induced vasoconstriction was fully antagonized (96% inhibition) by PD 145065 (10 microM). In the anesthetized rat, ET-1 produced a dose-dependent increase in mean arterial pressure, which was attenuated by PD 145065. The initial depressor response to ET-1 was completely blocked by PD 145065, as were the reduction in renal blood flow and increase in renal vascular resistance induced by ET-1. These results suggest that both the ETA and a non-ETA receptor subtype play an important role in mediating the vasoconstrictor effects of ET-1 in the rat kidney.

Amino Acid Sequence↗
PubMed1993

Comparative studies with the endothelin receptor antagonists BQ-123 and PD 142893 indicate at least three endothelin receptors.

Endothelin-1 (ET-1), endothelin-3 (ET-3), sarafotoxin 6b (SX6b), and sarafotoxin 6C (SX6c) were used as agonists, and BQ-123 (ETA-selective) and PD 142893 (ET receptor-nonselective) were used as antagonists to characterize the receptors mediating the effects of the ET/SX peptides on a variety of isolated smooth-muscle preparations. Contractions of the rat thoracic aorta, rat isolated perfused mesentery, and guinea pig ileum and potentiation of twitch of the rat vas deferens were mediated by ETA receptors in that they showed the order of potency ET-1 = SX6b > ET-3 >> SX6C. These effects were antagonized by BQ-123 or PD 142893. Contractions of the rabbit pulmonary artery and rat stomach strip, inhibition of twitches in the guinea pig ileum, and vasodilatations of the rat isolated perfused mesentery showed the order of potency ET-1 = SX6b = ET-3 = SX6c and were unaffected by BQ-123, suggesting involvement of ETB receptors. However, in these tissues, PD 142893 antagonized only dilatations of the rat mesentery to ET-1 but not any of the other effects of ET-1. Thus, we suggest that there are three types of endothelin receptors: ETA and two subtypes of ETB.

Amino Acid Sequence↗
PubMed1993

Heterogeneous receptors mediate endothelin-1-induced changes in blood pressure, hematocrit, and platelet aggregation.

Using selective endothelin (ET) receptor antagonists, we investigated which ET receptor subtypes mediate the changes in blood pressure and hematocrit produced by intraarterial injection of ET-1 in the anesthetized rabbit. In addition, the receptor through which ET-1 stimulates the release of prostacyclin (PGI2) and, hence, inhibits ex vivo platelet aggregation, was identified. FR 139317 (ETA antagonist, 0.6 mg kg-1 min-1 preceded by a loading dose of 3 mg kg-1 i.v.) and PD 145065 (nonselective ETA/ETB antagonist, 0.6 mg kg-1 min-1 preceded by a loading dose of 3 mg kg-1 i.v.) attenuated the ET-1 (1 nmol kg-1 i.a.)-induced rise in mean arterial pressure (MAP) by 89% and 75%, respectively. In contrast to FR 139317, PD 145065 also abolished the initial, transient depressor response brought about by ET-1. ET-1 caused a significant increase in hematocrit 15 min after its injection. PD 145065 caused a significantly greater inhibition of this hemoconcentration than FR 139317. ET-1 inhibited ex vivo platelet aggregation by 96%, measured 5 min after injection of the peptide. PD 145065, but not FR 139317, abolished the antiaggregatory effects of ET-1. Thus, the ET-1-induced vasoconstriction in the anesthetized rabbit is predominantly mediated via the ETA receptor, whereas the depressor and antiaggregatory actions of ET-1 are caused by activation of the ETB receptor. Moreover, activation of both receptor subtypes by ET-1 accounts for the increase in hematocrit produced by ET-1 in vivo.

Animals↗
PubMed1993

Incomplete inhibition of the pressor effects of endothelin-1 and related peptides in the anaesthetized rat with BQ-123 provides evidence for more than one vasoconstrictor receptor.

1. The effects of the ETA receptor antagonist, BQ-123 on blood pressure changes induced by various members of the endothelin (ET)/sarafotoxin (SX) peptide superfamily were investigated in the anaesthetized rat. 2. ET-1 (1 nmol kg-1, i.v. bolus) induced a sustained increase in mean arterial pressure (MAP, maximum increase 44 +/- 3 mmHg). Intravenous injection of BQ-123 at 0.2, 1.0 or 5.0 mg kg-1 5 min before ET-1 inhibited the pressor response by 18, 50 and 61%, respectively. The ET-1 pressor response was inhibited by 75% when the peptide was given 60 min after the start of a 120 min i.v. infusion of BQ-123 (0.2 mg kg-1 min-1). 3. In addition to ET-1, BQ-123 (1 mg kg-1, i.v. bolus) attenuated the pressor responses to big ET-1 (1 nmol kg-1, i.v., bolus, maximum increase in MAP: 68 +/- 7 mmHg), ET-3 (3 nmol kg-1, i.v., bolus, maximum response: 30 +/- 3 mmHg), SX6b (1 nmol kg-1, i.v., bolus, maximum response: 41 +/- 5 mmHg) and SX6c (1 nmol kg-1, i.v., bolus, maximum response: 24 +/- 4 mmHg) by 65, 60, 88 and 50%, respectively. 4. With the exception of big ET-1, all the peptides used in this study induced an initial transient depressor response (-32 +/- 3 mmHg, n = 18). Although BQ-123 (1 mg kg-1, i.v., bolus) did not affect the absolute magnitude of the fall in MAP, the ETA receptor antagonist significantly prolonged the depressor responses induced by ET-3 and SX6b. 5. Thus, BQ-123 attenuates the pressor, but not the depressor effects of ET-1, big ET-1, ET-3, SX6b and SX6c. Complete inhibition of the pressor responses could not be achieved, suggesting that a component of the pressor response is not mediated via the ETA receptor.

Amino Acid Sequence↗
PubMed1993

Use of the endothelin antagonists BQ-123 and PD 142893 to reveal three endothelin receptors mediating smooth muscle contraction and the release of EDRF.

1. We have compared the receptors mediating the contractions of rings of rat thoracic aorta or rabbit pulmonary artery and rat stomach strips in response to the endothelin/sarafotoxin (ET/SX) family of peptides and to those mediating endothelium-dependent vasodilations within the isolated perfused mesentery of the rat. To discriminate ETA receptors from ETB receptors we have used the criteria that ET-1 is more active than SX6c on ETA receptors, and that the ET/SX peptides are equiactive on ETB receptors. We have also assessed the effects of the ETA receptor-selective antagonist BQ-123, and the non-selective ET receptor antagonist PD 142893 on the responses of each preparation to the ET/SX peptides. 2. ET-1-induced constrictions of the rat thoracic aorta (EC50 3 x 10(-10) M), a prototypic ETA receptor-mediated response, or isolated perfused mesentery of the rat were antagonized by BQ-123 (10(-5) M) or PD 142893 (10(-5) M). SX6c did not constrict either the rat isolated perfused mesentery or the rat thoracic aorta. Thus, ETA receptors mediate these constrictions. 3. ET-1 and SX6c were approximately equipotent in constricting rabbit pulmonary artery rings (EC50S 3-6 x 10(-10) M). Neither BQ-123 (10(-5) M) nor PD 142893 antagonized the contractions induced by ET-1. These effects suggest mediation by ETB receptors but PD 142893 (10(-5) M) did give a 3 fold antagonism of constrictions induced by SX6c. 4. SX6c was more potent than ET-1 in contracting the rat stomach strip (threshold concentrations 10(-10) and 3 x 10(-10) M). Contractions to ET-1 or SX6c were unaffected by BQ-123 (10-5 M), again indicative of ETB receptor-mediated events. PD 142893 (10-5 M) was ineffective against ET-1 but produced a 3 fold antagonism of SX6c.5. In the rat isolated perfused mesentery ET-1 or SX6c (0.3-300pmol) were equipotent in producing dose-related vasodilatations that were unaffected by BQ-123 (10-6 M), indicative of an ETB receptor mediated response. In contrast to the other ETB-mediated responses, PD 142893 (10-6 M) strongly antagonized these vasodilatations.6. Thus, ETA receptors mediate constrictions of the rat thoracic aorta and rat isolated perfused mesentery whereas ETB receptors mediate constrictions of the rabbit pulmonary artery and rat stomach strip and endothelium-dependent dilatations within the mesentery. However, within the group of ETB receptor-mediated responses, endothelium-dependent vasodilatations are sensitive to PD 142893, whereas contractions of the isolated smooth muscle preparations are not. Thus, the receptor present on the endothelium responsible for the release of nitric oxide in response to the ET/SX peptides is most probably different from that present on smooth muscle that mediates BQ-123-insensitive contractions.

Amino Acid Sequence↗
PubMed1993

A tissue culture model of the hypophysiotrophic CRF producing neuronal system.

To investigate functional and chemical properties of anatomically characterized corticotropin-releasing factor-41 (CRF-41) producing neurons in vitro, hypothalamic slices of 6-day-old rats were maintained in culture for up to 6 weeks using a modified roller culture technique. This technique yields thick (100 microns) slices that contained an average of 300-400 CRF-41-immunostained neurons. The majority of CRF-41-positive cells were of small size (12-15 microns in diameter), and contained CRF-41-labeled dense core vesicles of 100 nm diameter as detected by electron microscopic postembedding immunocytochemistry. These cells represented the only CRF-41-positive cell population in the culture. Light microscope double immunolabelling of colchicine-treated cultures kept in a serum-containing media (SCM) indicated that about 60% of these CRF-41-positive neurons contains detectable levels of vasopressin-associated neurophysin (VP-NP). Culturing slices in serum-free, chemically defined media (SFM) resulted in an increased VP-NP immunostaining: parvicellular neurons labeled for both CRF-41 and VP-NP could be detected without colchicine treatment, and practically all CRF-41-positive neurons expressed VP-NP immunoreactivity. At the electron microscopic level there was a significant increase in VP-NP labeling density in the dense core vesicle compartment of CRF-41-positive varicosities. Adding dexamethasone (10 nM) to the SFM restored the staining pattern originally observed in SCM. Hence, the increased VP-NP and CRF-41 immunostaining after culturing CRF-41 neurons in SFM is most likely due to the absence of inhibitory glucocorticoids. The capacity of cultured paraventricular cells to release CRF-41 was assessed using an immunoassay. Unstimulated (basal) secretion of CRF-41 was not altered by five successive samplings at 2-hour intervals and stimulation of the same culture with 56 mmol K+ significantly increased (2-3 times) the CRF-41 content in the medium. The presence of dexamethasone (10 nM) in SFM induced a 6-fold reduction of K(+)-stimulated CRF-41 release and a 5 times reduction in tissue content in relation to cultures maintained in SFM without dexamethasone. In summary, we have demonstrated that cultured CRF-41 cells display morphological and biochemical features, as well as responsiveness to glucocorticoids, that is reminiscent to the situation in vivo. Thus, the model is well suited for studies of hypophysiotrophic CRF-41 cell functions.

Animals↗
PubMed1992

Age-related changes in cortico-releasing factor, somatostatin, neuropeptide Y, methionine enkephalin and beta-endorphin in specific rat brain areas.

We investigated the age-related changes in the tissular protein, cortico-releasing factor (CRF), somatostatin (SOM), neuropeptide Y(NPY), methionine enkephalin (M-ENK) and beta-endorphin (beta-END) levels in frontal cortex, hippocampus, striatum and hypothalamus of young (4-month-old), mature (18-month-old) and senescent (26-month-old) Wistar male rats, bred in a specific pathogen free environment. Between the age of 4 and 18 months, the tissular protein levels increased in all 4 structures studied. The CRF and SOM levels increased in the hippocampus, while the NPY levels decreased. During this time, the NPY content increased in the striatum, whereas the SOM and M-Enk striatal levels decreased. Concomitantly, the NPY and beta-End levels decreased in the hypothalamus. Interestingly, no significant variations were found to occur in the frontal cortex whatever the neuropeptide studied. Between the age of 18 and 26 months, no significant changes in the tissular protein levels were detected, except in the hippocampus. The changes in the neuropeptide concentrations observed during this period depended on the neuropeptide and the brain structure studied. The CRF and beta-End levels decreased in the frontal cortex and the hypothalamus, respectively. The NPY peptidergic systems seem to be preferentially affected by aging processes since 3 out of the 4 structures studied--the frontal cortex, the striatum and the hypothalamus--showed a decrease in their tissular NPY content. During the same period, none of the 5 neuropeptides studied were affected in the hippocampus.

Aging↗
PubMed1992

Central and peripheral effects of repeated stress and high NaCl diet on neuropeptide Y.

This study was performed to investigate the influence of repeated psychological stress alone or combined with high NaCl intake on the function of the sympathetic nervous system. In addition, NPY levels have been measured in brain regions of potential importance in the central regulation of stress responses (ventrolateral and dorsomedial medulla, paraventricular and arcuate nucleus of the hypothalamus, and frontal cortex). Normotensive Wistar rats received a standard diet alone or supplemented with NaCl. To accentuate differences in sodium balance, rats on the high NaCl diet (HNa) were uninephrectomized. Half the animals on each diet were subjected to chronic stress using daily sessions (1 h) of immobilization stress. After 12 days, plasma levels of neuropeptide Y (NPY), norepinephrine (NE), and epinephrine (E) were measured basally and in response to acute footshock stress. HNa intake or chronic stress alone did not significantly alter either basal or stimulated plasma levels of NPY. However, combining the treatments produced a significant interaction, increasing the NPY response to footshock by 31% compared to HNa alone (p = 0.039) and by 98% compared to stress alone (p less than 0.001). Chronic stress increased basal levels of NE and enhanced the response to subsequent acute stress: combining the treatments did not yield further increases. Plasma levels of E were not significantly affected by the treatments. In the brain, stress alone had no effect on the NPY levels in the structures studied. HNa intake induced a significant increase in NPY levels of the arcuate nucleus, and produced a significant interaction with stress in the dorsomedial medulla. In a supplementary experiment, to evaluate the role of the autonomic nervous system in plasma NPY responses, treatment with the ganglion blocker hexamethonium was shown to significantly attenuate stress-induced changes in NPY, NE, and E.

Animals↗
PubMed1991

Responses of the rat pituitary-adrenal axis to hypotensive infusions of corticotropin-releasing factor, vasoactive intestinal peptide and other depressor agents.

We have assessed in male rats the response of the hypothalamo-pituitary-adrenal axis to hypotension induced by 30 min i.v. infusions of corticotropin-releasing factor (CRF; 0.1, 0.2 and 0.5 nmol/kg/min), calcitonin gene-related peptide (CGRP; 0.25 nmol/kg/min), vasoactive intestinal peptide (VIP; 0.25 nmol/kg/min) and nitroprusside (NP; 150 micrograms/kg/min). Infusions of CRF produced dose-dependent decreases in mean arterial blood pressure of 10, 35 and 43 mmHg at 30 min, and the other treatment had depressor effects comparable with the higher CRF doses (between -35 and -44 mmHg). Plasma ACTH levels were increased from 383% to 595% by CGRP, NP and the three different CRF infusions (P less than 0.001 vs. controls), whereas they were raised more than 10-fold by VIP administration (P less than 0.001 vs. other treatments), a level 60% higher than the maximum achieved with CRF. Corticosterone levels were increased by 112% to 146% following infusion of the three different CRF doses, CGRP and NP (P less than 0.001 vs. controls), and by 240% after VIP (P less than 0.001 vs. other treatments). Plasma aldosterone values were increased by 112% to 140% after infusion of NP and the two higher CRF doses (P less than 0.01 vs. controls), and by 223% following VIP (P less than 0.05 vs. CRF 0.2 and NP). CGRP infusion, although resulting in similar haemodynamic changes, did not alter circulating aldosterone. The levels measured after CGRP were identical to those observed after the infusion of atrial natriuretic peptide (ANP; 1 nmol/kg/min), a known inhibitor of aldosterone secretion. These results demonstrate that the combination of hypotension and direct pituitary stimulation by CRF does not increase circulating ACTH levels above those obtained with hypotension alone (NP and CGRP), whereas VIP, which has only minimal direct effects on corticotroph function, markedly enhanced the ACTH response, suggesting that it may modulate ACTH release by an indirect mechanism. Evaluation of aldosterone levels after the different infusions indicates that CGRP prevented the rise normally associated with acute hypotension, thus confirming recent observations in other species that stimulated aldosterone secretion can be inhibited by CGRP.

Adrenocorticotropic Hormone↗
PubMed1991

Effects of dexamethasone on growth hormone (GH)-releasing hormone, arginine- and dopaminergic stimulated GH secretion, and total plasma insulin-like growth factor-I concentrations in normal male volunteers.

In man, glucocorticoid treatment and endogenous corticosteroid excess generally suppress stimulated GH release. However, such effects are not entirely consistent and depend on both the duration of pituitary exposure to steroids and the secretagogue employed. To further evaluate the effects of glucocorticoids in man, we have studied the response to four different GH stimulation tests before and after treatment with dexamethasone (DEX; 2 mg twice daily during 84 h). Twelve healthy male volunteers were divided into two groups of six subjects (groups A and B). Group A underwent stimulation tests with arginine (500 mg/kg, i.v.) and GH-releasing hormone (GHRH, 100 micrograms, i.v.) before and after DEX treatment. Group B were subjected to stimulation tests with two dopaminergic agents, a novel nonergot D2-dopamine agonist CV205-502 (CV; 10 micrograms, i.v.) and dopamine (4 micrograms/kg.min, i.v.), before and after DEX. Within each group, the effect of DEX on the different secretagogues was studied 4 weeks apart. GHRH-stimulated GH release was significantly blunted by DEX treatment [median peak GH value, 34.2 micrograms/L; 25-75th percentiles, 22.1-56.2), control, vs. 19.8 (9.7-34.5), DEX; P less than 0.05; integrated GH secretion expressed as the area under the curve (AUC) was 48% lower after DEX; P less than 0.01]. In the same group, DEX treatment significantly enhanced the response to arginine [10.6 (8.0-22.8), control, vs 26.1 (15.1-38.6), DEX; P less than 0.01; with an increase in AUC of 72%; P less than 0.01]. In group B, under control conditions before glucocorticoid administration, the GH response to CV was significantly greater than that to dopamine in terms of both peak response [25.1 (8.6-30.9), CV, vs. 11.8 (5.5-16.4), dopamine; P less than 0.05] and AUC [2406 +/- 654 (CV) vs. 658 +/- 125 (dopamine); P less than 0.01], suggesting that CV may be a useful adjunct in the diagnosis of GH deficiency. After DEX administration, responses to both dopaminergic agents were suppressed [CV, 6.7 (4.0-21.2); P less than 0.01 vs. control response; and dopamine, 5.3 (4.8-7.9); P less than 0.05 vs. control response]. When compared with the effects of dexamethasone on the GH response to arginine, the results with dopaminergic agents highlight important differences in the mechanisms of action of these indirectly acting GH secretagogues. Moreover, this may be of physiological importance, because in contrast to the inhibitory effect of glucocorticoid on GHRH-stimulated GH release, DEX treatment significantly increased basal plasma GH levels [1.4 (0.5-5.1) vs. control 0.3 (0.1-0.6) microgram/L; P less than 0.001].(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1991

Dexamethasone treatment in man induces changes in 24-hour growth hormone (GH) secretion profile without altering total GH released.

Glucocorticoids inhibit growth in man and laboratory animals and reduce the GH response to the majority of exogenously administered stimuli. Recently, however, glucocorticoids have been shown to have varying effects on GH secretion depending on the time of administration and, furthermore, to be potent secretagogues in their own right. To investigate this further, we have carried out sampling over two 24-h periods in six normal male volunteers both before and directly after treatment with dexamethasone (DEX; 2 mg twice daily) for 96 h. After DEX administration, all volunteers showed an increase in mean GH secretion during the first 9 h of sampling (0900-1800 h) compared with pre-DEX control profiles (5.1 +/- 1.2 vs. 1.7 +/- 0.5 micrograms/L; P less than 0.001). DEX treatment also had the effect of delaying and attenuating the nocturnal peak; mean GH secretion between 0000-0200 h was significantly greater before DEX (13.6 +/- 2.7 micrograms/L) than after DEX (3.6 +/- 0.7 micrograms/L; P less than 0.001), whereas that between 0300-0800 h was greater after DEX (5.5 +/- 0.8 vs. 0.7 +/- 0.2 micrograms/L; P less than 0.001). Individual nocturnal peaks ranged from 7.0-56.8 micrograms/L, occurring between 0030-0200 h before DEX, and 2.6-21.2 micrograms/L, occurring between 0300-0400 h after DEX. Overall mean GH secretion was not significantly altered by DEX treatment (3.8 +/- 0.6 vs. 4.2 +/- 0.5 micrograms/L; P = NS). Total insulin-like growth factor-I (IGF-I) levels, measured after acid-ethanol extraction, were significantly increased by DEX treatment, with mean IGF-I over the 24-h sampling period rising from 292.2 +/- 31.8 to 425.9 +/- 37 micrograms/L (P less than 0.005). All individuals showed an increase in mean 24-h IGF-I of between 10-75%. In a second study, 12 male volunteers were treated with DEX in an identical manner, and blood was taken at 0800 h daily. Total IGF-I levels rose steadily from 307.9 +/- 13.3 micrograms/L, reached a plateau at 72 h and remained elevated at 96 h (424.9 +/- 16.5 micrograms/L; P less than 0.001). These results suggest that glucocorticoids alter the normal pattern of GH secretion with an increase in daytime levels, but a delaying and attenuating effect on the nocturnal pulse. Previous studies have suggested that IGF-I concentrations are decreased by steroid treatment, but these have been based on bioassay systems. Total IGF-I, measured by RIA, would appear to be consistently elevated; the apparent decrease seen in bioassay systems may be due to glucocorticoid-induced changes in binding protein concentrations.

Adult↗
PubMed1991

Effects of glucocorticoid treatment and acute passive immunization with growth hormone-releasing hormone and somatostatin antibodies on endogenous and stimulated growth hormone secretion in the male rat.

Despite causing marked inhibition of somatic growth, glucocorticoids enhance both the response to GH-releasing hormone (GHRH) and the amplitude of naturally occurring GH secretory pulses in the male rat. The relative contribution of the two major hypothalamic regulatory factors for GH (somatostatin and GHRH) to these observed effects remains speculative. In the present studies, we have investigated endogenous and stimulated GH release in rats pretreated with glucocorticoid or vehicle, and the effects of passive immunoneutralization of somatostatin or GHRH. In an initial study, four groups of eight rats were treated with either saline or various doses of a depot preparation of betamethasone: low dose, 0.85 mg; medium dose, 1.7 mg; high dose, 3.4 mg. All doses significantly suppressed body weight gain, total adrenal weight and concentrations of both plasma corticosterone and pituitary ACTH. Seven days after betamethasone treatment, GH responses to an i.v. injection of 1 microgram human GHRH(1-29) were evaluated during pentobarbitone anaesthesia. Compared with saline-treated controls (peak GH concentration of 506.0 +/- 68.5 micrograms/l), peak GH levels were enhanced by the low dose (704.4 +/- 47.8 micrograms/l, P less than 0.05), unaltered by the medium dose (543 +/- 65.8 micrograms/l) and suppressed by the high dose (312.7 +/- 55.2 micrograms/l, P less than 0.05) of betamethasone. Similarly, the area under the secretory curves was increased by 46% following the low dose (P less than 0.01), unaltered by the medium dose and reduced by 33% after the high dose of betamethasone. In a second study, rats were pretreated for 7 days before blood sampling with either the medium dose of betamethasone or saline. On day 5, 48 h before blood sampling, an indwelling venous catheter was fitted enabling sampling of conscious rats. On the day of study, blood samples were taken at 30-min intervals over an initial 2-h period (10.00-12.00 h). Following the sample at 12.00 h, rats were given the reconstituted and dialysed immunoglobulin fraction from either control sheep serum (NSIgG), sheep anti-rat GHRH serum (GHRHab) or sheep anti-somatostatin serum (SRIHab), and samples were taken for a further 90 min (12.30-14.00 h). Directly after the sample at 14.00 h, GH stimulation was effected in all rats using 1 microgram human GHRH(1-29) with samples taken at 5, 10, 20 and 40 min following stimulation.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1990

Involvement of neuropeptide Y in neuroendocrine stress responses. Central and peripheral studies.

Neuropeptide Y (NPY) is closely associated to stress-reactive structures in the central and peripheral nervous system. In the periphery, the peptide is colocalized with catecholamines in postganglionic sympathetic fibres and the adrenal medulla. In the brain, the paraventricular nucleus of the hypothalamus receives a dense innervation of NPYergic neurons, some of which also contain monoamines. With the use of a specific immunoradiometric assay, we have demonstrated that NPY is released into the peripheral circulation during psychological stress together with catecholamines. The postganglionic origin of the peptide was demonstrated by the activity of the nicotinic antagonist hexamethonium to attenuate the response. Adrenalectomy or insulin-induced hypoglycemia did not alter basal or stimulated NPY plasma levels, showing that the adrenal is not a major source of circulating NPY in the rat. Although NPY and noradrenaline are frequently released in parallel in various experimental conditions, a clear dissociation can be found in several cases, such as cold stress or the response to phentolamine, where no change can be seen in plasma NPY despite a large activation of noradrenergic terminals. Furthermore, the neuropeptide may play a role in stress-induced pathological states such as hypertension, since its release is greater in animals previously submitted to chronic stress and high-sodium diet. On the other hand, its role in the central nervous system control mechanisms of the stress response is far from being clear, but to understand the interaction of NPY we need a better knowledge of the role of noradrenergic neurons in the central control of the adrenocortical axis or sympathetic nervous system activity.

Adrenal Glands↗