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Meningeal blood flow is controlled by H 2 S‐NO crosstalk activating a HNO ‐ TRPA 1‐ CGRP signalling pathway
Author(s) -
Dux Mária,
Will Christine,
Vogler Birgit,
Filipovic Milos R,
Messlinger Karl
Publication year - 2016
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13164
Subject(s) - calcitonin gene related peptide , chemistry , endogeny , vasodilation , blood vessel , antagonist , blood flow , medicine , endocrinology , receptor , biochemistry , neuropeptide
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 H 2 S . 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 D oppler flowmetry. CGRP release from the dura mater in the hemisected rat head was quantified using an elisa . NO and H 2 S were localized histochemically with specific sensors. Key Results Topical administration of the NO donor diethylamine‐ NONO ate increased meningeal blood flow by 30%. Pretreatment with oxamic acid, an inhibitor of H 2 S synthesis, reduced this effect. Administration of Na 2 S increased blood flow by 20%, an effect abolished by the CGRP receptor antagonist CGRP 8‐37 or the TRPA 1 channel antagonist HC 030031 and reduced when endogenous NO synthesis was blocked. Na 2 S dose‐dependently increased CGRP release two‐ to threefold. Co‐administration of diethylamine‐ NONO ate facilitated CGRP release, while inhibition of endogenous NO or H 2 S synthesis lowered basal CGRP release. NO and H 2 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. Conclusions and Implications NO and H 2 S cooperatively increased meningeal blood flow by forming HNO , which activated TRPA 1 cation channels in trigeminal fibres, inducing CGRP release. This HNO ‐ TRPA 1‐ CGRP signalling pathway may be relevant to the pathophysiology of headaches.