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

• Published in: British journal of pharmacology Vol. 173; no. 3; pp. 431 - 445
• Main Authors: Dux, Mária, Will, Christine, Vogler, Birgit, Filipovic, Milos R, Messlinger, Karl
• Format: Journal Article
• Language: English
• Published: London Blackwell Publishing Ltd 01-02-2016; John Wiley and Sons Inc
• Subjects: Blood flow; Calcitonin gene-related peptide; Doppler effect; Dura mater; Endothelium; Enzyme-linked immunosorbent assay; Headache; Hydrogen sulfide; Research Paper; Research Papers; Rodents; Signal transduction; Sodium sulfide
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/bph.13164

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.