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Cardiovascular Research Advance Access [Accepted Manuscript] published online on January 17, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn012
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

A reactive oxygen species-mediated component in neurogenic vasodilatation

Anna Starra, Rabea Graepela, Julie Keebleb, Sabine Schmidhubera, Natalie Clarka, Andrew Grantc, Ajay M Shaha and Susan D. Brain, PhDa,*

a Cardiovascular Division, King's College London, Franklin-Wilkins Building, Waterloo Campus, London SE1 9NH, U.K.
b Pharmaceutical Sciences Division, King's College London, School of Medicine, Bessemer Road, London SE5 9PJ, UK
c Wolfson Centre for Age-Related Diseases, King's College London, Wolfson House, Guys Campus, London, SE1 1UL.

* Correspondence. Tel: +44-207-848-4453Fax: +44-207-848-3743 E-mail address: sue.brain{at}kcl.ac.uk

Aim: Activation of the transient receptor potential vanilloid receptor 1 (TRPV1) leads to release of potent microvascular vasodilator neuropeptides. This study was designed to investigate in vivo mechanisms involved in TRPV1-mediated peripheral vasodilatation.

Methods: Wildtype and TRPV1 knockout (KO) mice were investigated in a model of peripheral vasodilatation. Blood flow was measured by laser Doppler flowmetry under anaesthesia and following local application of the TRPV1 agonist capsaicin.

Results: A sustained (60 min) increase in blood flow was observed in wildtype but not TRPV1 knockout mouse ears. This response was resistant to blockers of classic vasodilators but inhibited in pharmacogenetic experiments that targeted blockade of the substance P and calcitonin gene-related peptide (CGRP) pathways. The TRPV1-mediated vasodilatation was also attenuated by treatment with superoxide dismutase and the hydrogen peroxide scavenger catalase, but not by deactivated enzymes, supporting a novel role for reactive oxygen species (ROS) generation. Furthermore, neurogenic vasodilatation was observed neither in the presence of the selective NADPH inhibitor apocynin, nor in gp91phox KO mice, under conditions where prostaglandin E1-induced vasodilatation occurred. Finally, a role of neuropeptides in initiating a ROS-dependent component was verified as superoxide dismutase, catalase, and apocynin inhibited substance P and CGRP vasodilatation.

Conclusions: These studies provide in vivo evidence that ROS are involved in mediating TRPV1- and neuropeptide-dependent neurogenic vasodilatation. An essential role of NADPH-dependent ROS is revealed that may be of fundamental importance to the neurogenic vasodilator component involved in circulatory homeostasis and the pathophysiology of certain cardiovascular diseases.

Time for primary review: 17


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