A reactive oxygen species-mediated component in neurogenic vasodilatation.
OBJECTIVE
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.


RESULTS
Wildtype (WT) 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. A sustained (60 min) increase in blood flow was observed in WT but not TRPV1 KO mouse ears. This response was resistant to blockers of classic vasodilators but inhibited in pharmacogenetic experiments that targeted blockade of the substance P (SP) 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 gp91 phox 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 SP 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 oxidase-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.
Starr
Anna
A
Cardiovascular Division, King's College London, Franklin-Wilkins Building, Waterloo Campus, London SE1 9NH, UK.
Graepel
Rabea
R
Keeble
Julie
J
Schmidhuber
Sabine
S
Clark
Natalie
N
Grant
Andrew
A
Shah
Ajay M
AM
Brain
Susan D
SD
D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology; D001783:Blood Flow Velocity; D001808:Blood Vessels / Q000294:innervation*; D015740:Calcitonin Gene-Related Peptide / Q000235:genetics / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology; D002374:Catalase / Q000378:metabolism; D004423:Ear / Q000098:blood supply*; D007213:Indomethacin / Q000494:pharmacology; D017078:Laser-Doppler Flowmetry; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009475:Neurons, Afferent / Q000201:enzymology / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D018040:Receptors, Neurokinin-1 / Q000235:genetics / Q000378:metabolism; D012039:Regional Blood Flow; D013482:Superoxide Dismutase / Q000494:pharmacology; D050916:TRPV Cation Channels / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D019789:Tetraethylammonium / Q000494:pharmacology; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
D000098:Acetophenones; D000975:Antioxidants; D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; D018040:Receptors, Neurokinin-1; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D014665:Vasodilator Agents; D019789:Tetraethylammonium; C056165:acetovanillone; D002374:Catalase; D013482:Superoxide Dismutase; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin