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The vasodilator effect of NO<\/jats:roman><\/jats:styled-content> may be due to the NO<\/jats:roman><\/jats:styled-content>\u2013derived compound, nitroxyl (HNO<\/jats:styled-content>), generated through reaction with endogenous H2<\/jats:sub>S<\/jats:roman><\/jats:styled-content>. We investigated the involvement of HNO<\/jats:styled-content> in CGRP<\/jats:styled-content> release and meningeal blood flow.<\/jats:p><\/jats:sec>Experimental Approach<\/jats:title>Blood flow in exposed dura mater of rats was recorded by laser D<\/jats:styled-content>oppler flowmetry. CGRP<\/jats:styled-content> release from the dura mater in the hemisected rat head was quantified using an elisa<\/jats:sc>. NO<\/jats:roman><\/jats:styled-content> and H2<\/jats:sub>S<\/jats:roman><\/jats:styled-content> were localized histochemically with specific sensors.<\/jats:p><\/jats:sec>Key Results<\/jats:title>Topical administration of the NO<\/jats:roman><\/jats:styled-content> donor diethylamine\u2010NONO<\/jats:roman><\/jats:styled-content>ate increased meningeal blood flow by 30%. Pretreatment with oxamic acid, an inhibitor of H2<\/jats:sub>S<\/jats:roman><\/jats:styled-content> synthesis, reduced this effect. Administration of Na2<\/jats:sub>S<\/jats:roman><\/jats:styled-content> increased blood flow by 20%, an effect abolished by the CGRP<\/jats:styled-content> receptor antagonist CGRP<\/jats:styled-content>8\u201037<\/jats:sub> or the TRPA<\/jats:styled-content>1 channel antagonist HC<\/jats:styled-content>030031 and reduced when endogenous NO<\/jats:roman><\/jats:styled-content> synthesis was blocked. Na2<\/jats:sub>S<\/jats:roman><\/jats:styled-content> dose\u2010dependently increased CGRP<\/jats:styled-content> release two\u2010 to threefold. Co\u2010administration of diethylamine\u2010NONO<\/jats:roman><\/jats:styled-content>ate facilitated CGRP<\/jats:styled-content> release, while inhibition of endogenous NO<\/jats:roman><\/jats:styled-content> or H2<\/jats:sub>S<\/jats:roman><\/jats:styled-content> synthesis lowered basal CGRP<\/jats:styled-content> release. NO<\/jats:roman><\/jats:styled-content> and H2<\/jats:sub>S<\/jats:roman><\/jats:styled-content> were mainly localized in arterial vessels, HNO<\/jats:styled-content> additionally in nerve fibre bundles. HNO<\/jats:styled-content> staining was lost after treatment with L<\/jats:styled-content>\u2010NMMA<\/jats:styled-content> and oxamic acid.<\/jats:p><\/jats:sec>Conclusions and Implications<\/jats:title>NO<\/jats:roman><\/jats:styled-content> and H2<\/jats:sub>S<\/jats:roman><\/jats:styled-content> cooperatively increased meningeal blood flow by forming HNO<\/jats:styled-content>, which activated TRPA<\/jats:styled-content>1 cation channels in trigeminal fibres, inducing CGRP<\/jats:styled-content> release. This HNO<\/jats:styled-content>\u2010TRPA<\/jats:styled-content>1\u2010CGRP<\/jats:styled-content> signalling pathway may be relevant to the pathophysiology of headaches.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.13164","type":"journal-article","created":{"date-parts":[[2015,4,17]],"date-time":"2015-04-17T10:17:01Z","timestamp":1429265821000},"page":"431-445","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":54,"title":["Meningeal blood flow is controlled by H2<\/sub>S\u2010NO<\/scp> crosstalk activating a HNO<\/scp>\u2010TRPA<\/scp>1\u2010CGRP<\/scp> signalling pathway"],"prefix":"10.1111","volume":"173","author":[{"given":"M\u00e1ria","family":"Dux","sequence":"first","affiliation":[{"name":"Department of Physiology University of Szeged Szeged Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Will","sequence":"additional","affiliation":[{"name":"Institute of Physiology and 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