Abstract
Background and PurposeTransient receptor potential ankyrin‐1 (TRPA1) activation is known to mediate neurogenic vasodilatation. We investigated the mechanisms involved in TRPA1‐mediated peripheral vasodilatation in vivo using the TRPA1 agonist cinnamaldehyde.Experimental ApproachChanges in vascular ear blood flow were measured in anaesthetized mice using laser Doppler flowmetry.Key ResultsTopical application of cinnamaldehyde to the mouse ear caused a significant increase in blood flow in the skin of anaesthetized wild‐type (WT) mice but not in TRPA1 knockout (KO) mice. Cinnamaldehyde‐induced vasodilatation was inhibited by the pharmacological blockade of the potent microvascular vasodilator neuropeptide CGRP and neuronal NOS‐derived NO pathways. Cinnamaldehyde‐mediated vasodilatation was significantly reduced by treatment with reactive oxygen nitrogen species (RONS) scavenger such as catalase and the SOD mimetic TEMPOL, supporting a role of RONS in the downstream vasodilator TRPA1‐mediated response. Co‐treatment with a non‐selective NOS inhibitor L‐NAME and antioxidant apocynin further inhibited the TRPA1‐mediated vasodilatation. Cinnamaldehyde treatment induced the generation of peroxynitrite that was blocked by the peroxynitrite scavenger FeTPPS and shown to be dependent on TRPA1, as reflected by an increase in protein tyrosine nitration in the skin of WT, but not in TRPA1 KO mice.Conclusion and ImplicationsThis study provides in vivo evidence that TRPA1‐induced vasodilatation mediated by cinnamaldehyde requires neuronal NOS‐derived NO, in addition to the traditional neuropeptide component. A novel role of peroxynitrite is revealed, which is generated downstream of TRPA1 activation by cinnamaldehyde. This mechanistic pathway underlying TRPA1‐mediated vasodilatation may be important in understanding the role of TRPA1 in pathophysiological situations.
Highlights
Primary sensory neurons are widely distributed in the central and peripheral nervous system, and have a physiological role in maintaining vascular homeostasis (Russell et al, 2014), their exact pathophysiological relevance is unclear
This study shows that transient receptor potential ankyrin-1 (TRPA1) stimulation by cinnamaldehyde can mediate neurogenic vasodilatation in the peripheral vasculature mediated to a large extent by the sensory neuropeptide CGRP
We show for the first time that independent of transient receptor potentials vanilloid-1 (TRPV1), reactive oxygen nitrogen species (RONS) are involved in cinnamaldehyde-mediated vasodilatation, possibly generated through a reaction between NO and superoxide downstream of TRPA1 activation
Summary
Primary sensory neurons are widely distributed in the central and peripheral nervous system, and have a physiological role in maintaining vascular homeostasis (Russell et al, 2014), their exact pathophysiological relevance is unclear. The discovery of transient receptor potential ankyrin-1 (TRPA1), which is located in 60–75% of transient receptor potentials vanilloid-1 (TRPV1) expressing C- and Aδ-sensory fibres (Story et al, 2003; Kobayashi et al, 2005) has dramatically increased our understanding of the mechanism underlying activation of the sensory neurons and release of neuropeptides (Bautista et al, 2005). TRPA1 is expressed on rat sensory nerves (Bautista et al, 2005) and human skin (Atoyan et al, 2009) It is activated by various exogenous agonists, including pungent extracts such as allyl isothiocyanate (AITC) from mustard oil, cinnamaldehyde from cinnamon and allicin from garlic, which all modify cysteine and lysine residues on the N-terminus of the TRPA1 channel (Bandell et al, 2004; Bautista et al, 2005; Hinman et al, 2006). We investigated the mechanisms involved in TRPA1-mediated peripheral vasodilatation in vivo using the TRPA1 agonist cinnamaldehyde.
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