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      Nitric Oxide Stimulates Growth Hormone Secretion in vitro through a Calcium- and Cyclic Guanosine Monophosphate-Independent Mechanism

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          Abstract

          In the last years, nitric oxide (NO) has emerged as an important intra- and intercellular transmitter involved in the control of the hypothalamic-pituitary axis, and NO synthase (NOS) has been identified in pituitary cells. To determine the role of NO in the control of GH secretion acting directly at the pituitary level, we have studied GH release by hemipituitaries incubated in the presence of different concentrations (10<sup>–7</sup>–10<sup>–3</sup> M) of sodium nitroprusside (SNP), a potent NO donor. We found that SNP (10<sup>–4</sup>–10<sup>–3</sup> M) stimulated GH release. This effect was mediated by the release of NO since it was abolished in the presence of hemoglobin, a scavenger of NO, but preserved in the presence of rhodanese + sodium thiosulfate (inactivators of cyanides generated from SNP). To analyze the participation of cyclic guanosine monophosphate (cGMP), the second messenger for a wide range of NO actions, in SNP-stimulated GH secretion, hemipituitaries were incubated in the presence of 8-bromo-cGMP (8-Br-cGMP; 10<sup>–7</sup>–10<sup>–3</sup> M). In addition, hemipituitaries were stimulated with SNP plus oxadiazoloquinoxaline (OQD) or LY 83,583 (inhibitors of guanylyl cyclases). We found that 8-Br-cGMP was ineffective in eliciting GH release, and that the stimulatory effect of SNP was maintained in presence of OQD and LY 83,583. Finally, to analyze calcium dependence, the SNP effect was studied in hemipituitaries incubated in free medium calcium, in the presence of nifedipine and verapamil (blockers of calcium channels) and after depletion of intracellular Ca<sup>2+</sup> stores with caffeine. We found that the SNP-induced GH secretion is also detected after incubation of hemipituitaries in free calcium medium, in the presence of nifedipine and verapamil, and after caffeine preincubation. We conclude that NO stimulates GH secretion in vitro through a specific calcium-cGMP-independent mechanism.

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          Most cited references 7

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          Vascular endothelial cells synthesize nitric oxide from L-arginine.

          Nitric oxide (NO) released by vascular endothelial cells accounts for the relaxation of strips of vascular tissue and for the inhibition of platelet aggregation and platelet adhesion attributed to endothelium-derived relaxing factor. We now demonstrate that NO can be synthesized from L-arginine by porcine aortic endothelial cells in culture. Nitric oxide was detected by bioassay, chemiluminescence or by mass spectrometry. Release of NO from the endothelial cells induced by bradykinin and the calcium ionophore A23187 was reversibly enhanced by infusions of L-arginine and L-citrulline, but not D-arginine or other close structural analogues. Mass spectrometry studies using 15N-labelled L-arginine indicated that this enhancement was due to the formation of NO from the terminal guanidino nitrogen atom(s) of L-arginine. The strict substrate specificity of this reaction suggests that L-arginine is the precursor for NO synthesis in vascular endothelial cells.
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            Localization of nitric oxide synthase indicating a neural role for nitric oxide.

            Nitric oxide (NO), apparently identical to endothelium-derived relaxing factor in blood vessels, is also formed by cytotoxic macrophages, in adrenal gland and in brain tissue, where it mediates the stimulation by glutamate of cyclic GMP formation in the cerebellum. Stimulation of intestinal or anococcygeal nerves liberates NO, and the resultant muscle relaxation is blocked by arginine derivatives that inhibit NO synthesis. It is, however, unclear whether in brain or intestine, NO released following nerve stimulation is formed in neurons, glia, fibroblasts, muscle or blood cells, all of which occur in proximity to neurons and so could account for effects of nerve stimulation on cGMP and muscle tone. We have now localized NO synthase protein immunohistochemically in the rat using antisera to the purified enzyme. We demonstrate NO synthase in the brain to be exclusively associated with discrete neuronal populations. NO synthase is also concentrated in the neural innervation of the posterior pituitary, in autonomic nerve fibres in the retina, in cell bodies and nerve fibres in the myenteric plexus of the intestine, in adrenal medulla, and in vascular endothelial cells. These prominent neural localizations provide the first conclusive evidence for a strong association of NO with neurons.
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              Cloned and expressed nitric oxide synthase structurally resembles cytochrome P-450 reductase.

              Nitric oxide is a messenger molecule, mediating the effect of endothelium-derived relaxing factor in blood vessels and the cytotoxic actions of macrophages, and playing a part in neuronal communication in the brain. Cloning of a complementary DNA for brain nitric oxide synthase reveals recognition sites for NADPH, FAD, flavin mononucleotide and calmodulin as well as phosphorylation sites, indicating that the synthase is regulated by many different factors. The only known mammalian enzyme with close homology is cytochrome P-450 reductase.
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                Author and article information

                Journal
                HRE
                Horm Res Paediatr
                10.1159/issn.1663-2818
                Hormone Research in Paediatrics
                S. Karger AG
                1663-2818
                1663-2826
                1999
                May 1999
                02 November 1999
                : 51
                : 5
                : 242-247
                Affiliations
                Department of Physiology, Faculty of Medicine, Córdoba University, Córdoba, Spain
                Article
                23378 Horm Res 1999;51:242–247
                10.1159/000023378
                10559669
                © 1999 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: 6, References: 28, Pages: 6
                Categories
                Original Paper

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