TRPA1 channel activation with cinnamaldehyde induces cutaneous vasodilation through NOS, but not COX and KCa channel, mechanisms in human

Transient receptor potential (TRP) channels exist in various cells and tissues including nerves and vascular endothelium. TRP channels are implicated in the regulation of several sensory organs associated with pain, pressure, and temperature. While there exists a number of TRP channels, transient receptor potential vanilloid 1 (TRPV1) and 4 (TRPV4) channels in human skin have been shown to modulate cutaneous vasodilation (Fujii et al., 2019; Wong et. al., 2012). Transient receptor potential ankyrin 1 (TRPA1) subtype, which belongs to the TRP channel, is thought to be activated by cold and possibly warm/hot temperatures (Wang and Siemens, 2015). Recently, we showed that TRPA1 channel activation with cinnamaldehyde induced cutaneous vasodilation in humans (Fujii et al., 2020). However, the mechanisms underlying this response remains to be determined. A previous study using mouse ear showed that nitric oxide (NO) synthase (NOS), which is a meditator of endothelium‐dependent vasodilation, can modulate the TRPA1 channel induced cutaneous vasodilation (Aubdool et al., 2016). However, it is unclear if this relationship exists in humans. Moreover, whether cyclooxygenase (COX) and Ca2+ activated K+ (KCa) channels, which are also established modulators of endothelium‐dependent vasodilation, contribute to TRPA1 channel induced cutaneous vasodilation remains to be directly assessed in humans. Based on the above, we evaluated the hypothesis that NOS, COX, and KCa channels mediate the TRPA1 channel induced cutaneous vasodilation in humans. To assess our hypothesis, cutaneous vascular conductance (CVC) was assessed in 9 healthy young adults (29 ± 6 years, 4 women) at four dorsal forearm skin sites treated by intradermal microdialysis with either: 1) vehicle control (98 % propylene glycol + 0.015% lactated Ringer solution + 1.985 % dimethyl sulfoxide), 2)10 mM N(G)‐Nitro‐L‐arginine methylester, a non‐selective NOS inhibitor, 3)10 mM ketorolac, a non‐selective COX inhibitor, or 4) 50 mM tetraethylammonium, a non‐selective KCa channel blocker. Cinnamaldehyde, a TRPA1 channel activator, was administered to each skin site in a dose‐dependent manner (2.9, 8.8, 26 and 80% of cinnamaldehyde concentrations, each lasting at least 30min). Administration of ≥8.8 % cinnamaldehyde increased CVC from baseline at the vehicle control site (e.g., 27.4± 2.7 % increase in CVC, P<0.05). NOS inhibition attenuated the cinnamaldehyde induced‐cutaneous vasodilation at 2.9, 8.8, 26 and 80% concentrations relative to the vehicle control site (all P<0.05). COX inhibition and KCa channel blockade did not attenuate the cinnamaldehyde induced‐cutaneous vasodilation relative to the vehicle control site at all concentrations (all P>0.05). We conclude that in human skin in vivo, NOS plays a role in modulating the regulation of cutaneous vasodilation in response to TRPA1 channel activation with negligible contributions of COX and KCa channels.

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