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      Effects of Dexamethasone and Alprazolam, a Benzodiazepine, on the Stimulatory Effect of Hexarelin, a Synthetic GHRP, on ACTH, Cortisol and GH Secretion in Humans

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          Abstract

          Hexarelin (HEX) is a synthetic GHRP which acts on specific receptors at both the pituitary and the hypothalamic level to stimulate GH release both in animals and in humans. Like other GHRPs, HEX possesses also acute ACTH and cortisol-releasing activity similar to that of hCRH. The mechanisms underlying the stimulatory effect of GHRPs on hypothalamo-pituitary-adrenal (HPA) axis are still unclear, although a CNS-mediated action has been demonstrated. In 6 normal healthy young women (26–34 years) we studied the effects on ACTH and cortisol secretion of HEX (2.0 µg/kg i.v. at 0 min) alone and preceded by dexamethasone (DEXA, 1 mg p.o. at 23.00 h on the previous night) or alprazolam (ALP, 0.02 mg/kg p.o. at –90 min), a benzodiazepine which binds to GABA receptors and possesses CRH-mediated inhibitory activity on HPA axis. ACTH and cortisol secretion after saline administration as well as the GH response to HEX alone and preceded by DEXA or ALP were also studied. HEX administration elicited an increase in ACTH (peak vs. baseline, mean ± SEM: 28.0 ± 6.7 vs. 11.7 ± 2.2 pg/ml, p < 0.05) and cortisol secretion (162.6 ± 15.0 vs. 137.7 ± 12.6 µg/l, p < 0.05). DEXA pretreatment strongly inhibited basal ACTH (3.2 ± 0.7 pg/ml, p < 0.01) and cortisol levels (11.3 ± 2.5 µg/l, p < 0.001) and abolished the ACTH and cortisol responses to HEX (3.6 ± 0.9 pg/ml, p < 0.01 and 10.7 ± 2.0 µg/l, p < 0.001), respectively. On the other hand, ALP pretreatment did not significantly modify basal ACTH (7.9 ± 2.0 pg/ml) and cortisol levels (127.6 ± 14.5 µg/l) but abolished the HEX-induced ACTH and cortisol secretions (8.6 ± 2.4 pg/ml, p < 0.05 and 111.0 ± 6.0 µg/l, p < 0.05), respectively. ACTH and cortisol levels after HEX when preceded by ALP overlapped with those recorded during saline. HEX induced a clear GH response (peak at 15 min vs. baseline: 65.5 ± 20.5 vs. 2.2 ± 0.7 µg/l, p < 0.03) which was blunted by ALP (peak at 15 min: 21.5 ± 5.5 µg/l, p < 0.05) while it was not modified by DEXA pretreatment (78.7 ± 7.6 µg/l). In conclusion, our present data demonstrate that the ACTH- and cortisol-releasing effect of HEX is abolished by either dexamethasone or alprazolam, a benzodiazepine, which is even able to blunt the GH-releasing activity of the hexapeptide. These findings suggest that, in physiological conditions, the stimulatory effect of GHRPs on HPA axis is sensitive to the negative glucocorticoid feedback and could be mediated by GABAergic mechanisms; the latter seem also involved in the GH-releasing activity of GHRPs.

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          Most cited references 3

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          Blocked growth hormone-releasing peptide (GHRP-6)-induced GH secretion and absence of the synergic action of GHRP-6 plus GH-releasing hormone in patients with hypothalamopituitary disconnection: evidence that GHRP- 6 main action is exerted at the hypothalamic level

           V. Popović (1995)
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            Identification of a new G-protein-linked receptor for growth hormone secretagogues

             S S Pong (1996)
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              Does alprazolam, in contrast to diazepam, activate alpha 2-adrenoceptors involved in the regulation of rat growth hormone secretion?

              The conventional benzodiazepine diazepam and the novel triazolobenzodiazepine alprazolam were compared with respect to effects on growth hormone (GH) release in reserpine pretreated rats. The reserpine pretreatment was undertaken to eliminate brain monoaminergic influence on GH secretion, hence obtaining a low GH baseline from which a drug induced increase could be easily detected. Previous studies have indicated that activation of brain alpha 2-adrenoceptors is an indispensable prerequisite for GH release induced by other agents such as serotonin and opiate receptor agonists. In line with these findings, diazepam was found to induce GH release in reserpine pretreated rats only when the alpha 2-receptor agonist clonidine was simultaneously administered. In contrast, alprazolam caused a dose-dependent increase in plasma GH when given alone to reserpine pretreated rats. This effect of alprazolam was effectively antagonized by either of the two selective alpha 2-receptor antagonists yohimbine or idazoxane. The data indicate that alprazolam, but not diazepam, activates brain alpha 2-adrenoceptors involved in rat GH regulation. The possibility that an alpha 2-agonistic profile of alprazolam may contribute to the suggested effectiveness of the drug in the treatment of panic disorder is discussed.
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                Author and article information

                Journal
                NEN
                Neuroendocrinology
                10.1159/issn.0028-3835
                Neuroendocrinology
                S. Karger AG
                0028-3835
                1423-0194
                1998
                April 1998
                22 May 1998
                : 67
                : 4
                : 310-316
                Affiliations
                a Division of Endocrinology, Department of Internal Medicine, University of Turin, Italy; b Europeptides, Argenteuil, France
                Article
                54328 Neuroendocrinology 1998;67:310–316
                10.1159/000054328
                9641612
                © 1998 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 3, References: 46, Pages: 7
                Categories
                Growth Hormone, Growth Hormone Releasing Peptides

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