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      Role of Nitric Oxide and Carbon Monoxide in Modulating the ACTH Response to Immune and Nonimmune Signals

      Neuroimmunomodulation

      S. Karger AG

      Cytokines, Stress, Nitric oxide, Carbon monoxide, ACTH, Hypothalamus, Corticotropin-releasing factor

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          Abstract

          The role played by nitric oxide (NO) and carbon monoxide (CO) was explored in the adult male rat by determining whether antagonizing the activity of the enzymes responsible for the formation of these gases altered the response of the hypothalamic-pituitary-adrenal (HPA) axis to immune (cytokines) or nonimmune (mild electroshocks) signals. The arginine derivative N<sub>ω</sub>nitro- L-arginine-methylester ( L-NAME), which inhibits all three NO synthase (NOS) isoforms [inducible (i), endothelial (e) and neuronal (n)] significantly augments the ACTH response to blood-borne cytokines, but decreases it in rats exposed to shocks or other physico-emotional stresses. The effect of L-NAME in both models is mimicked by L-nitroarginine ( L-NNA) and L-nitromethylarginine ( L-NMMA), which block constitutive (e and n) forms of NOS, but not by aminoguanidine (which blocks iNOS) or 7-nitroindazole (which specifically blocks nNOS). Despite the ability of L-NAME to markedly augment the stimulatory effect of vasopressin on ACTH secretion, removal of this peptide does not interfere with the interaction between L-NAME and systemically administered interleukin-1β (IL-1β). In contrast, blockade of prostaglandin formation prevents both the stimulatory effect of IL-1β on ACTH release, and its potentiation by L-NAME. In contrast to the investigation of the importance of endogenous NO, studies focused on the role of CO remain scarce. Our preliminary results suggest that while blockade of the formation of this gas decreases the ACTH response to various stimuli, it also significantly interferes with the effect of L-NAME in rats systemically administered cytokines, and further decreases the ACTH response to shocks in animals also injected with arginine analogs. These results indicate the possible presence of functional interactions between NO and CO in regulating the activity of the HPA axis. Our present working hypothesis is that in the presence of elevated circulating cytokine levels, endogenous NO acts presynaptically to inhibit the release of ACTH secretagogues from nerve terminals in the infundibulum. As the acute ACTH response to these immune proteins is believed to primarily depend on events taking place within the median eminence, blockade of NO formation results in exaggerated ACTH release. During exposure to shocks and other nonimmune stresses, on the other hand, increased ACTH secretion is primarily due to activation of hypothalamic neurons. In this case, because of the stimulatory influence of endogenous NO on hypothalamic perikarya that manufacture corticotropin-releasing factor (CRF) and/or of the afferents to these neurons, blockade of NOS activity blunts CRF production, and consequently ACTH release. What remains undetermined is the net effect of the opposite influences of NO during long-term exposure to immune or nonimmune stress. Finally, it is possible that the conflicting results reported by investigators who study the role of NO and CO in isolated cell preparations may reflect, at least in part, these opposite effects of NO on different elements of the HPA axis.

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          Most cited references 16

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          Distinct mechanisms underlie activation of hypothalamic neurosecretory neurons and their medullary catecholaminergic afferents in categorically different stress paradigms.

          Intermittent electrical footshock induces c-fos expression in parvocellular neurosecretory neurons expressing corticotropin-releasing factor and in other visceromotor cell types of the paraventricular hypothalamic nucleus (PVH). Since catecholaminergic neurons of the nucleus of the solitary tract and ventrolateral medulla make up the dominant loci of footshock-responsive cells that project to the PVH, these were evaluated as candidate afferent mediators of hypothalamic neuroendocrine responses. Rats bearing discrete unilateral transections of this projection system were exposed to a single 30-min footshock session and sacrificed 2 hr later. Despite depletion of the aminergic innervation on the ipsilateral side, shock-induced up-regulation of Fos protein and corticotropin-releasing factor mRNA were comparable in strength and distribution in the PVH on both sides of the brain. This lesion did, however, result in a substantial reduction of Fos expression in medullary aminergic neurons on the ipsilateral side. These results contrast diametrically with those obtained in a systemic cytokine (interleukin 1) challenge paradigm, where similar cuts ablated the Fos response in the ipsilateral PVH but left intact the induction seen in the ipsilateral medulla. We conclude that (i) footshock-induced activation of medullary aminergic neurons is a secondary consequence of stress, mediated via a descending projection transected by our ablation, (ii) stress-induced activation of medullary aminergic neurons is not necessarily predictive of an involvement of these cell groups in driving hypothalamic visceromotor responses to a given stressor, and (iii) despite striking similarities in the complement of hypothalamic effector neurons and their afferents that may be activated by stresses of different types, distinct mechanisms may underlie adaptive hypothalamic responses in each.
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            • Record: found
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            Nitric oxide: A radical neurotransmitter in the central nervous system

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              • Abstract: not found
              • Article: not found

              Carbon Monoxide: An Emerging Regulator of cGMP in the Brain.

               M Maines (1993)
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                Author and article information

                Journal
                NIM
                Neuroimmunomodulation
                10.1159/issn.1021-7401
                Neuroimmunomodulation
                S. Karger AG
                978-3-8055-6766-4
                978-3-318-00353-6
                1021-7401
                1423-0216
                1998
                August 1998
                04 September 1998
                : 5
                : 3-4
                : 203-213
                Affiliations
                The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, La Jolla, Calif., USA
                Article
                26338 Neuroimmunomodulation 1998;5:203–213
                10.1159/000026338
                9730687
                © 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: 12, References: 65, Pages: 11
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