Meningeal blood flow is controlled by H 2 S‐NO crosstalk activating a HNO ‐ TRPA 1‐ 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: 01-02-2016
• 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
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.