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      Nitric Oxide Releases Calcitonin-Gene-Related Peptide from Rat Dura mater Encephali Promoting Increases in Meningeal Blood Flow

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          Abstract

          Nitric oxide (NO) and calcitonin-gene-related peptide (CGRP) are implicated in the pathophysiology of vascular headaches. We studied the interaction of these two vasodilatory mediators in an animal model and suggest that NO may increase meningeal blood flow not only by its direct vasodilatory action but also by stimulating CGRP release. First, CGRP release from the rat cranial dura mater was measured in vitro using an enzyme immunoassay. Hemisected skulls with adhering dura mater were filled with synthetic interstitial fluid and stimulated with the NO donor diethylamine-NONOate (10<sup>–5</sup>–10<sup>–3</sup> M) or with NO gas (1,000 ppm), which caused concentration-dependent increases in CGRP release up to 166.8%. Second, meningeal blood flow was recorded in vivo in the exposed dura mater using laser Doppler flowmetry. Topical application of the NO donors NONOate, S-nitroso-N-acetylpenicillamine and N-ethyl-2-(1-ethyl-2-hydroxy-2-nitrosohydrazino)-ethenamine (10<sup>–5</sup>–10<sup>–3</sup> M) caused concentration-dependent increases in blood flow. These increases were significantly reduced by local preliminary application of the CGRP receptor antagonist CGRP<sub>8–37</sub> (10<sup>–4</sup> M). We conclude that NO stimulates the release of CGRP from dural afferents. The blood-flow-increasing effect of NO seems to be partly mediated by CGRP. The interaction of NO and CGRP may be relevant for the development of vascular headaches.

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          Most cited references 13

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          Release of substance P, calcitonin gene-related peptide and prostaglandin E2 from rat dura mater encephali following electrical and chemical stimulation in vitro.

          Neurogenic inflammation of the dura, expressed in plasma extravasation and vasodilatation, putatively contributes to different types of headache. A novel in vitro preparation of the fluid-filled skull cavities was developed to measure mediator release from dura mater encephali upon antidromic electrical stimulation of the trigeminal ganglion and after application of a mixture of inflammatory mediators (serotonin, histamine and bradykinin, 10(-5) M each, pH 6.1) to the arachnoid side of rat dura. The release of calcitonin gene-related peptide, substance P and prostaglandin E2 from dura mater was measured in 5-min samples of superfusates using enzyme immunoassays. Orthodromic chemical and antidromic electrical stimulation of dural afferents caused significant release of calcitonin gene-related peptide (2.8- and 4.5-fold of baseline). The neuropeptide was found to be increased during the 5-min stimulation period and returned to baseline (20.9 +/- 12 pg/ml) in the sampling period after stimulation. In contrast, release of substance P remained at baseline levels (19.3 +/- 11 pg/ml) throughout the experiment. Prostaglandin E2 release was elevated during chemical and significantly also after antidromic electrical stimulation (6- and 4.2-fold of baseline, which was 305 +/- 250 pg/ml). Prostaglandin E2 release outlasted the stimulation period for at least another 5 min. The data support the hypothesis of neurogenic inflammation being involved in headaches and provide new evidence for prostaglandin E2 possibly facilitating meningeal nociceptor excitation and, hence, pain.
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            Nitric oxide is a key molecule in migraine and other vascular headaches.

            Nitric oxide (NO) may play a key role in migraine and other vascular headaches since glyceryl trinitrate (a donor of NO) and histamine (which probably activates endothelial NO formation) both cause a pulsating dose-dependent headache with several migrainous characteristics. At relatively high doses of glyceryl trinitrate, migraine sufferers develop stronger and more migraine-like headaches and more pronounced cerebral arterial dilatation than controls. After the infusion of glyceryl trinitrate, non-migraineurs remain headache-free while migraineurs develop a migraine-like attack. In this review, Jes Olesen, Lars Thomsen and Helle Iversen suggest that migraine may be caused by increased amounts and/or affinity of an enzyme in the NO-triggered cascade of reactions. NO may also be involved in the pathogenesis of other vascular headaches.
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              Arterial supersensitivity to nitric oxide (nitroglycerin) in migraine sufferers.

              The sensitivity to nitroglycerin-induced dilatation of large intracranial arteries was studied in 17 patients with migraine without aura, 17 age and sex-matched healthy subjects and 9 patients with episodic tension-type headache. Nitroglycerin in the doses of 0.015, 0.03, 0.25 microgram/kg/min was successively infused for 15 min per dose. Blood velocity (Vmean) in the middle cerebral artery (MCA) was recorded with transcranial Doppler before and at the end of every infusion period, and 30 and 60 min after end of the last infusion. In all three groups Vmean decreased with increasing doses (p < 0.001). The response was more pronounced in migraine patients at the two higher doses (p < 0.05). Since nitroglycerin acts as an exogenous source of nitric oxide (NO), these data support that NO supersensitivity may be an important molecular mechanism of migraine pain.
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                Author and article information

                Journal
                JVR
                J Vasc Res
                10.1159/issn.1018-1172
                Journal of Vascular Research
                S. Karger AG
                1018-1172
                1423-0135
                2002
                December 2002
                17 January 2003
                : 39
                : 6
                : 489-496
                Affiliations
                aDepartment of Physiology and Experimental Pathophysiology, University of Erlangen-Nürnberg, Erlangen, Germany, and bDepartment of Physiology, Faculty of Medicine, University of Szeged, Szeged, Hungary
                Article
                67206 J Vasc Res 2002;39:489–496
                10.1159/000067206
                12566974
                © 2002 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: 4, Tables: 2, References: 59, Pages: 8
                Categories
                Research Paper

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