British Journal of Pharmacology 2016-02-01

Meningeal blood flow is controlled by H2 S-NO crosstalk activating a HNO-TRPA1-CGRP signalling pathway.

Mária Dux, Christine Will, Birgit Vogler, Milos R Filipovic, Karl Messlinger

Index: Br. J. Pharmacol. 173 , 431-45, (2016)

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Abstract

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 H2 S. We investigated the involvement of HNO in CGRP release and meningeal blood flow.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 H2 S were localized histochemically with specific sensors.Topical administration of the NO donor diethylamine-NONOate increased meningeal blood flow by 30%. Pretreatment with oxamic acid, an inhibitor of H2 S synthesis, reduced this effect. Administration of Na2 S 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. Na2 S dose-dependently increased CGRP release two- to threefold. Co-administration of diethylamine-NONOate facilitated CGRP release, while inhibition of endogenous NO or H2 S synthesis lowered basal CGRP release. NO and H2 S were mainly localized in arterial vessels, HNO additionally in nerve fibre bundles. HNO staining was lost after treatment with L-NMMA and oxamic acid.NO and H2 S 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.© 2015 The British Pharmacological Society.