Meningeal blood flow is controlled by H2S-NO crosstalk activating a HNO-TRPA1-CGRP signalling pathway

M. Dux, Christine Will, Birgit Vogler, Milos R. Filipovic, Karl Messlinger

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Background and Purpose Meningeal blood flow is controlled by CGRP released from trigeminal afferents and NO mainly produced in arterial endothelium. The vasodilator effect of NO may be due to the NO-derived compound, nitroxyl (HNO), generated through reaction with endogenous H2S. We investigated the involvement of HNO in CGRP release and meningeal blood flow. Experimental Approach Blood flow in exposed dura mater of rats was recorded by laser Doppler flowmetry. CGRP release from the dura mater in the hemisected rat head was quantified using an elisa. NO and H2S were localized histochemically with specific sensors. Key Results Topical administration of the NO donor diethylamine-NONOate increased meningeal blood flow by 30%. Pretreatment with oxamic acid, an inhibitor of H2S synthesis, reduced this effect. Administration of Na2S increased blood flow by 20%, an effect abolished by the CGRP receptor antagonist CGRP8-37 or the TRPA1 channel antagonist HC030031 and reduced when endogenous NO synthesis was blocked. Na2S dose-dependently increased CGRP release two- to threefold. Co-administration of diethylamine-NONOate facilitated CGRP release, while inhibition of endogenous NO or H2S synthesis lowered basal CGRP release. NO and H2S were mainly localized in arterial vessels, HNO additionally in nerve fibre bundles. HNO staining was lost after treatment with L-NMMA and oxamic acid. Conclusions and Implications NO and H2S cooperatively increased meningeal blood flow by forming HNO, which activated TRPA1 cation channels in trigeminal fibres, inducing CGRP release. This HNO-TRPA1-CGRP signalling pathway may be relevant to the pathophysiology of headaches.

Original languageEnglish
Pages (from-to)431-445
Number of pages15
JournalBritish Journal of Pharmacology
Volume173
Issue number3
DOIs
Publication statusPublished - Feb 1 2016

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Oxamic Acid
Dura Mater
Calcitonin Gene-Related Peptide Receptors
omega-N-Methylarginine
Topical Administration
Laser-Doppler Flowmetry
Vasodilator Agents
Nerve Fibers
Endothelium
Headache
Cations
Head
Staining and Labeling
nitroxyl
sodium sulfide
1,1-diethyl-2-hydroxy-2-nitrosohydrazine
Therapeutics

ASJC Scopus subject areas

  • Pharmacology

Cite this

Meningeal blood flow is controlled by H2S-NO crosstalk activating a HNO-TRPA1-CGRP signalling pathway. / Dux, M.; Will, Christine; Vogler, Birgit; Filipovic, Milos R.; Messlinger, Karl.

In: British Journal of Pharmacology, Vol. 173, No. 3, 01.02.2016, p. 431-445.

Research output: Contribution to journalArticle

Dux, M. ; Will, Christine ; Vogler, Birgit ; Filipovic, Milos R. ; Messlinger, Karl. / Meningeal blood flow is controlled by H2S-NO crosstalk activating a HNO-TRPA1-CGRP signalling pathway. In: British Journal of Pharmacology. 2016 ; Vol. 173, No. 3. pp. 431-445.
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abstract = "Background and Purpose Meningeal blood flow is controlled by CGRP released from trigeminal afferents and NO mainly produced in arterial endothelium. The vasodilator effect of NO may be due to the NO-derived compound, nitroxyl (HNO), generated through reaction with endogenous H2S. We investigated the involvement of HNO in CGRP release and meningeal blood flow. Experimental Approach Blood flow in exposed dura mater of rats was recorded by laser Doppler flowmetry. CGRP release from the dura mater in the hemisected rat head was quantified using an elisa. NO and H2S were localized histochemically with specific sensors. Key Results Topical administration of the NO donor diethylamine-NONOate increased meningeal blood flow by 30{\%}. Pretreatment with oxamic acid, an inhibitor of H2S synthesis, reduced this effect. Administration of Na2S increased blood flow by 20{\%}, an effect abolished by the CGRP receptor antagonist CGRP8-37 or the TRPA1 channel antagonist HC030031 and reduced when endogenous NO synthesis was blocked. Na2S dose-dependently increased CGRP release two- to threefold. Co-administration of diethylamine-NONOate facilitated CGRP release, while inhibition of endogenous NO or H2S synthesis lowered basal CGRP release. NO and H2S were mainly localized in arterial vessels, HNO additionally in nerve fibre bundles. HNO staining was lost after treatment with L-NMMA and oxamic acid. Conclusions and Implications NO and H2S cooperatively increased meningeal blood flow by forming HNO, which activated TRPA1 cation channels in trigeminal fibres, inducing CGRP release. This HNO-TRPA1-CGRP signalling pathway may be relevant to the pathophysiology of headaches.",
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AB - Background and Purpose Meningeal blood flow is controlled by CGRP released from trigeminal afferents and NO mainly produced in arterial endothelium. The vasodilator effect of NO may be due to the NO-derived compound, nitroxyl (HNO), generated through reaction with endogenous H2S. We investigated the involvement of HNO in CGRP release and meningeal blood flow. Experimental Approach Blood flow in exposed dura mater of rats was recorded by laser Doppler flowmetry. CGRP release from the dura mater in the hemisected rat head was quantified using an elisa. NO and H2S were localized histochemically with specific sensors. Key Results Topical administration of the NO donor diethylamine-NONOate increased meningeal blood flow by 30%. Pretreatment with oxamic acid, an inhibitor of H2S synthesis, reduced this effect. Administration of Na2S increased blood flow by 20%, an effect abolished by the CGRP receptor antagonist CGRP8-37 or the TRPA1 channel antagonist HC030031 and reduced when endogenous NO synthesis was blocked. Na2S dose-dependently increased CGRP release two- to threefold. Co-administration of diethylamine-NONOate facilitated CGRP release, while inhibition of endogenous NO or H2S synthesis lowered basal CGRP release. NO and H2S were mainly localized in arterial vessels, HNO additionally in nerve fibre bundles. HNO staining was lost after treatment with L-NMMA and oxamic acid. Conclusions and Implications NO and H2S cooperatively increased meningeal blood flow by forming HNO, which activated TRPA1 cation channels in trigeminal fibres, inducing CGRP release. This HNO-TRPA1-CGRP signalling pathway may be relevant to the pathophysiology of headaches.

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